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Table of Contents
Anatomy 7
Cardiovascular System 7
Ear, Nose & Throat (ENT) 11
Endocrine, Diabetes & Metabolism 13
Female Reproductive System & Breast 13
Gastrointestinal & Nutrition 15
Male Reproductive System 20
Miscellaneous (Multisystem) 21
Nervous System 21
Ophthalmology 35
Pregnancy, Childbirth & Puerperium 36
Pulmonary & Critical Care 37
Renal, Urinary Systems & Electrolytes 38
Rheumatology/Orthopedics & Sports 39
Biochemistry 46
Biochemistry (General Principles) 46
Genetics (General Principles) 60
Hematology & Oncology 60
Infectious Diseases 64
Nervous System 64
Poisoning & Environmental Exposure 66
Biostatistics 69
Biostatistics & Epidemiology 69
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Embryology 81
Dermatology 82
Nervous System 86
Genetics 91
Biochemistry (General Principles) 91
Biostatistics & Epidemiology 91
Dermatology 92
Genetics (General Principles) 94
Nervous System 103
Histology 106
Dermatology 106
Nervous System 109
Immunology 112
Allergy & Immunology 112
Dermatology 121
Ophthalmology 127
Pathology (General Principles) 127
Pharmacology (General Principles) 128
Microbiology 131
Dermatology 131
Microbiology (General Principles) 159
Nervous System 163
Ophthalmology 166
Pathology 173
Dermatology 187
Nervous System 230
Ophthalmology 245
Pathophysiology 276
Dermatology 290
Nervous System 313
Ophthalmology 318
Pharmacology 341
Dermatology 354
Nervous System 379
Ophthalmology 386
Pharmacology (General Principles) 387
Physiology 407
Nervous System 428
Ophthalmology 430
Psychiatric/Behavioral & Substance Abuse 444
Psychiatric/Behavioral & Substance Abuse 444
Social Sciences (Ethics/Legal/Professional) 462
Social Sciences (Ethics/Legal/Professional) 462
Anatomy
Cardiovascular System
AORTIC AND PERIPHERAL ARTERY DISEASES
Aortic dissection
The intimal tear in Stanford type A aortic dissection (involving the ascending aorta) usually originates in the
sinotubular junction whereas the intimal flap in Stanford type B aortic dissection usually starts near the origin of the
left subclavian artery. Dissections can propagate distally to the thoracoabdominal aorta. [12151]
Blunt thoracic trauma

Traumatic aortic rupture is most often caused by the rapid deceleration that occurs in motor vehicle collisions. The
most common site of injury is the aortic isthmus, which is tethered by the ligamentum arteriosum and is relatively
fixed and immobile compared to the adjacent descending aorta. [2130]
Retinal artery occlusion

Retinal artery occlusion is a cause of acute, painless, monocular vision loss. It is usually caused by thromboembolic
complications of atherosclerosis traveling from the internal carotid artery and through the ophthalmic artery. [11832]
Subclavian steal syndrome

Subclavian steal syndrome occurs due to severe stenosis of the proximal subclavian artery, which leads to reversal in
blood flow from the contralateral vertebral artery to the ipsilateral vertebral artery. Patients may have symptoms
related to arm ischemia in the affected extremity (eg, exercise-induced fatigue, pain, paresthesias) or vertebrobasilar
insufficiency (eg, dizziness, vertigo). [12046]
Superior vena cava syndrome

The brachiocephalic vein drains the ipsilateral jugular and subclavian veins. The bilateral brachiocephalic veins
combine to form the superior vena cava (SVC). Brachiocephalic vein obstruction causes symptoms similar to those
seen in SVC syndrome, but only on one side of the body. [1943]
Varicocele
Pressure in the left renal vein may become elevated due to compression where the vein crosses the aorta beneath
the superior mesenteric artery. This "nutcracker effect" can cause hematuria and flank pain. Pressure can also be
elevated in the left gonadal vein, leading to formation of a varicocele. [1805]
CARDIAC ARRHYTHMIAS
Atrial fibrillation
Atrial fibrillation is associated with increased risk of systemic thromboembolism. The left atrial appendage is the
most common site of thrombus formation in atrial fibrillation. [11842]
Implantable cardioverter defibrillator

Left ventricular leads in biventricular pacemakers course through the coronary sinus, which resides in the
atrioventricular groove on the posterior aspect of the heart. [7646]
CONGENITAL HEART DISEASE
Patent ductus arteriosus

The ductus arteriosus is derived from the sixth embryonic aortic arch. A patent ductus arteriosus (PDA) causes left-
to-right shunting of blood that can be heard as a continuous murmur over the left infraclavicular
region. Indomethacin (a PGE2 synthesis inhibitor) can be used to close a PDA in premature infants, but surgical
ligation is often necessary in older patients. [1751]
CORONARY HEART DISEASE
CABG
The great saphenous vein is a superficial vein of the leg that originates on the medial side of the foot, courses anterior
to the medial malleolus, and then travels up the medial aspect of the leg and thigh. It drains into the femoral vein
within the region of the femoral triangle, a few centimeters inferolateral to the pubic tubercle. [1967]
Cardiac catheterization
To access the left side of the heart, cardiac venous catheters must cross the interatrial septum at the site of the
foramen ovale. Entry into the left atrium allows for direct measurement of left atrial pressure and for access to
arrhythmogenic foci on the left atrial myocardium or pulmonary veins. [15197]
The optimal site for obtaining vascular access in the lower extremity during cardiac catheterization is the common
femoral artery below the inguinal ligament. Cannulation above the inguinal ligament can significantly increase the
risk of retroperitoneal hemorrhage. [11764]
Myocardial infarction
Leads I and aVL correspond to the lateral limb leads on ECG. Therefore, ST elevation or Q waves in these leads are
indicative of infarction involving the lateral aspect of the left ventricle, which is supplied by the left circumflex artery.
[10467]
Papillary muscle rupture is a life-threatening complication that typically occurs 3-5 days after myocardial infarction
and presents with acute mitral regurgitation and pulmonary edema. The posteromedial papillary muscle is supplied
solely by the posterior descending artery, making it susceptible to ischemic rupture. [12144]
Low-grade atrioventricular block (ie, first-degree, Mobitz type I second-degree) involves conduction disruption within
the AV node. The occurrence of low-grade AV block in the setting of myocardial infarction suggests obstruction of
the right coronary artery because it supplies blood to the AV node in approximately 90% of patients. [19173]
MISCELLANEOUS
Penetrating thoracic trauma

The left ventricle forms the apex of the heart and can reach as far as the fifth intercostal space at the left
midclavicular line (MCL). All other chambers of the heart lie medial to the left MCL. The lungs overlap much of the
anterior surface of the heart. [654]
The right ventricle composes most of the heart's anterior surface. A deep, penetrating injury at the left sternal
border in the fourth intercostal space would puncture the right ventricle. [1699]
MYOPERICARDIAL DISEASES
Pericardial effusion
Acute viral pericarditis is commonly complicated by pericardial effusion. Classic features of pericardial effusion
include tachycardia and ECG findings of low voltage QRS and electrical alternans. Chest x-ray classically reveals an
enlarged cardiac silhouette with clear lungs. [20258]
NORMAL STRUCTURE AND FUNCTION OF THE CARDIOVASCULAR SYSTEM
Av node
The atrioventricular node is located on the endocardial surface of the right atrium, near the insertion of the septal
leaflet of the tricuspid valve and the orifice of the coronary sinus. [11956]
Cardiovascular anatomy
The inferior epigastric artery branches off the external iliac artery immediately proximal to the inguinal ligament. It
provides blood supply to the lower anterior abdominal wall as it runs superiorly and medially up the abdomen. [11831]
The inferior vena cava is formed by the union of the right and left common iliac veins at the level of L4-L5. The renal
arteries and veins lie at the level of L1. The inferior vena cava returns venous blood to the heart from the lower
extremities, portal system, and abdominal and pelvic viscera. [1884]
The left atrium forms the majority of the posterior surface of the heart and resides adjacent to the
esophagus. Enlargement of the left atrium can compress the esophagus and cause dysphagia. [8332]
The descending thoracic aorta lies posterior to the esophagus and the left atrium. This position permits clear
visualization of the descending aorta by transesophageal echocardiography, allowing for the detection of
abnormalities such as dissection or aneurysm. [8333]
Central venous catheter
The femoral triangle (lateral to medial) consists of the femoral nerve, femoral artery, femoral vein, and deep inguinal
nodes/lymphatic vessels. Cannulation of the femoral vein should occur approximately 1 cm below the inguinal
ligament and just medial to the femoral artery pulsation. [11763]
The common cardinal veins of the developing embryo drain directly into the sinus venosus. These cardinal veins
ultimately give rise to the superior vena cava and other constituents of the systemic venous circulation. [2023]
Community acquired pneumonia

On posteroanterior chest x-ray, the right middle lobe is seen adjacent to the right border of the heart, which is
primarily formed by the right atrium. Consolidation in the right middle lobe can obscure the x-ray silhouette of the
right heart border. [1883]
Coronary blood flow

The inferior wall of the left ventricle forms most of the inferior (diaphragmatic) surface of the heart and is supplied by
the posterior descending artery. In 85%-90% of individuals, the posterior descending artery derives from the right
coronary artery (right dominant coronary circulation). [1871]
Coronary dominance is determined by the coronary artery supplying the posterior descending artery. The posterior
descending artery originates from the right coronary artery in approximately 70%-80% of patients (right dominant),
both the right coronary and left circumflex artery in 10%-20% (codominant), and the left circumflex artery in 5%-10%
(left dominant). The dominant coronary artery supplies blood to the atrioventricular (AV) node via the AV nodal
artery. [11837]
Pulmonary blood flow

Pulmonary artery occlusion pressure is measured at the distal tip of the pulmonary artery catheter after an inflated
balloon occludes blood flow through a pulmonary artery branch. It closely corresponds to left atrial and left
ventricular end-diastolic pressure. [11780]
Pulmonary embolism
The inferior vena cava (IVC) courses through the abdomen and inferior thorax in a location anterior to the right half of
the vertebral bodies. The renal veins join the IVC at the level of L1/L2, and the common iliac veins merge to become
the IVC at the level of L5. IVC filters are placed in patients with deep venous thrombosis who have contraindications
to anticoagulation therapy. [1538]
Sinoatrial node
The sinoatrial node consists of specialized pacemaker cells located at the junction of the right atrium and superior
vena cava. It is the site of earliest electrical activation in patients with sinus rhythm. [11730]
VALVULAR HEART DISEASES
Left atrial enlargement

Cardiovascular dysphagia can result from external compression of the esophagus by a dilated and posteriorly
displaced left atrium in patients with rheumatic heart disease and mitral stenosis/regurgitation. [1623]
Tricuspid regurgitation
Infective endocarditis in intravenous drug users commonly affects the tricuspid valve, often leading to septic
pulmonary emboli. Patients can have an early- or holo-systolic murmur of tricuspid regurgitation, which is best
auscultated in the 4th or 5th intercostal space at the left lower sternal border. [8294]
Ear, Nose & Throat (ENT)
DISORDERS OF THE EAR, NOSE, AND THROAT
Airway emergency
Cricothyrotomy is indicated when an emergency airway is required and orotracheal or nasotracheal intubation is
either unsuccessful or contraindicated. The cricothyrotomy incision passes through the superficial cervical fascia,
pretracheal fascia, and the cricothyroid membrane. [8631]
Cleft lip and cleft palate

Patients with cleft palate are at increased risk of chronic or recurrent acute otitis media, partly because of
dysfunction of the muscles (eg, levator veli palatini) that contract against the soft palate to open the eustachian tube.
[21438]
Epistaxis
Epistaxis is commonly caused by irritation of the highly vascular mucosa at the anterior nasal septum. The anterior
nasal septum contains the Kiesselbach plexus. The anterior ethmoidal, sphenopalatine, and superior labial arteries
anastomose in this region. [11783]
Foreign body aspiration

The internal laryngeal nerve mediates the afferent limb of the cough reflex above the vocal cords. Foreign bodies (eg,
fish bones) can become lodged in the piriform recess and may cause damage to the nerve, impairing the cough reflex.
[8703]
Head and neck cancers

Referred otalgia is common in head and neck pathology because many cranial nerves innervate the ear (eg, CN V, VII,
IX, X). In particular, tumors in the hypopharynx, larynx, or base of tongue cause referred otalgia due to sensory
contributions from the glossopharyngeal and vagus nerves. [19130]
The eustachian tube connects the middle ear to the nasopharynx. Cancer located in the nasopharynx can lead to
obstruction of the eustachian tube, causing a middle ear effusion. [18627]
Hearing loss
Prolonged exposure to loud noises causes hearing loss due to damage to the stereociliated hair cells of the organ of
Corti. [1633]
Laryngotracheobronchitis
Croup is a viral infection in which edema and narrowing of the proximal trachea (ie, subglottis) result in a barky cough
and inspiratory stridor. [19972]
Lymphatic drainage
Head and neck squamous cell carcinomas typically spread first to the anterior cervical (ie, jugular) lymph nodes via
the lymphatics. Distant spread occurs after regional lymph node involvement. [18645]
Orbital fracture
Blunt trauma to the globe can cause orbital blowout fractures. These fractures most commonly involve the medial or
inferior orbital walls due to the thin bone bordering the ethmoid and maxillary sinuses. [1698]
Otitis externa
The vagus nerve provides cutaneous sensation to the posterior external auditory canal via its small auricular
branch. Sensation to the rest of the canal is from the mandibular division of the trigeminal nerve. [1814]
Temporomandibular disorders
Temporomandibular joint disorder is associated with dysfunction of the temporomandibular joint and
hypersensitivity of the mandibular nerve (CN V3). This can result in pathologic contraction of the muscles of
mastication, including the masseter and pterygoids. [18584]
Temporomandibular joint disorder is associated with derangement of the temporomandibular joint and
hypersensitivity of the mandibular nerve (CN V3). [18597]
The lateral pterygoid muscles are the only muscles of mastication that aid in depressing the mandible (ie, opening the
jaw). Spasm of the lateral pterygoids prevents spontaneous reduction of an anterior dislocation of the
temporomandibular joint. [18598]
Thyroid cancer
The recurrent laryngeal nerve travels in close proximity to the inferior thyroid artery and can be injured during
thyroid surgery, resulting in vocal cord paralysis (eg, hoarseness). [1686]
Endocrine, Diabetes & Metabolism
ENDOCRINE TUMORS
Thyroid cancer
The external branch of the superior laryngeal nerve is at risk of injury during thyroidectomy due to its proximity to the
superior thyroid artery and vein. This nerve innervates the cricothyroid muscle. [1747]
HYPOTHALAMUS AND PITUITARY DISORDERS
Diabetes insipidus
Injury to the hypothalamus or posterior pituitary (eg, head trauma, transsphenoidal neurosurgery, suprasellar
masses) can result in central diabetes insipidus (DI). Damage to the posterior pituitary gland typically causes
transient DI, whereas damage to the hypothalamic nuclei often causes permanent DI. [206]
Female Reproductive System & Breast
BREAST DISORDERS
Breast cancer
Invasive breast carcinoma typically presents as an irregularly shaped, adherent breast mass, most commonly in the
upper outer quadrant. Malignant infiltration of suspensory ligaments of the breast can cause skin retractions. [1056]
CONGENITAL AND DEVELOPMENTAL ANOMALIES
Amenorrhea
Adolescent girls with primary amenorrhea, normal secondary sexual characteristics, and progressively worsening
abdominopelvic pain may have an imperforate hymen. Examination typically shows a smooth vaginal bulge
(hematocolpos) and a palpable mass anterior to the rectum. [8390]
GENITAL TRACT TUMORS AND TUMOR-LIKE LESIONS
Adenomyosis
Adenomyosis typically presents with regular (ie, cyclic), heavy, painful menses. Gross pathology reveals a uniformly
enlarged, globular uterus with the abnormal presence of endometrial glands and stroma in the myometrium. [20237]
Uterine fibroids
Subserosal uterine leiomyomas (fibroids) can cause irregular uterine enlargement and bulk-related symptoms (eg,
pelvic pressure). Posterior leiomyomas can cause constipation due to pressure on the colon. [11885]
MISCELLANEOUS
Constipation
Pelvic organ prolapse, the herniation of pelvic organs (eg, rectum) into the vagina, occurs due to damage to the
levator ani muscle complex. Patients with prolapse of the posterior vaginal wall (ie, rectocele) classically have chronic
constipation and a vaginal bulge. [18919]
Ovarian Torsion
Ovarian torsion typically involves twisting of the infundibulopelvic ligament, often due to the weight of a large
adnexal mass. The resulting occlusion of the blood supply to the ovary results in severe, acute pelvic pain and ovarian
ischemia. [11901]
Pelvic organ prolapse

Pudendal nerve injury during vaginal delivery leads to gradual denervation and weakness of the pelvic floor
muscles. In combination with age-related tissue atrophy, this injury contributes to pelvic organ prolapse (eg,
cystocele). [18918]
Ureter injury
The ureter can be injured during pelvic surgery due to its proximity to major pelvic ligaments and vessels such as the
uterine artery within the cardinal ligament. Unintentional suturing of the ureter can present postoperatively with
unilateral back pain (ie, hydronephrosis) due to ureteral obstruction. [11781]
NORMAL STRUCTURE AND FUNCTION OF THE FEMALE REPRODUCTIVE SYSTEM AND BREAST
Anesthesia
A pudendal nerve block provides anesthesia to most of the perineum and external genitalia. It is performed by
transvaginal injection of a local anesthetic medial to the ischial spine and through the sacrospinous ligament. [1739]
Lymphatic drainage
Squamous cell carcinoma of the vulva can metastasize via lymphatic drainage. The vulva first drains to the
inguinofemoral nodes of the groin, which should be the target for sentinel lymph node biopsy because they are the
most likely lymph nodes to have tumor involvement. [20169]
Ovarian cancer
The suspensory ligament of the ovary (ie, infundibulopelvic ligament) contains the ovarian artery, ovarian vein,
lymphatics, and nerves. The ovarian artery is the major blood supply to the ovary. Therefore, the suspensory
ligament of the ovary must be ligated during an oophorectomy to prevent heavy bleeding. [1632]
Ovarian vein thrombosis

Ovarian vein thrombosis (infected ovarian vein thrombus) is a rare complication associated with the postpartum
period and is typically right sided. Because ovarian venous drainage is asymmetric, a thrombus in the right ovarian
vein can extend into the inferior vena cava. In contrast, a left ovarian vein thrombosis would extend first to the left
renal vein. [11920]
Perineal lacerations
The perineal body, which is relatively inelastic, can be damaged in an obstetric perineal laceration. The structures
that form and attach to the perineal body are the bulbospongiosus, superficial transverse perineal, and external anal
sphincter muscles. [11823]
Postpartum hemorrhage
The internal iliac artery (hypogastric artery) supplies blood to the pelvis, including the uterus via the uterine
artery. Therefore, bilateral ligation of the internal iliac artery is a potential surgical management option for
postpartum hemorrhage due to uterine atony. [11908]
Gastrointestinal & Nutrition
BILIARY TRACT DISORDERS
Cholecystitis
Gallstone ileus results from passage of a large gallstone through a cholecystenteric fistula into the small bowel, where
it ultimately causes obstruction at the ileum. Patients typically present with symptoms/signs of small bowel
obstruction, and an abdominal x-ray may reveal gas within the gallbladder and biliary tree. [1525]
GASTROESOPHAGEAL DISORDERS
Gastroesophageal reflux disease

The esophagus is located between the trachea and the vertebral bodies in the superior thorax. It is typically
collapsed with no visible lumen on CT images of the chest. [1706]
Hiatal hernia
Hiatal hernias occur when contents of the abdominal cavity herniate through the diaphragm at the esophageal hiatus
into the thoracic cavity. Sliding hiatal hernias occur due to laxity of the phrenoesophageal membrane, leading to
herniation of the gastroesophageal junction and proximal stomach, whereas paraesophageal hernias occur due to
defects in the membrane, resulting in the gastric fundus herniation. [14880]
Peptic ulcer disease

The gastroduodenal artery lies along the posterior wall of the duodenal bulb and is likely to be eroded by posterior
duodenal ulcers. Ulceration into the gastroduodenal artery can be a source of life-threatening hemorrhage. [291]
Most gastric ulcers arise along the lesser curvature of the stomach, usually at the transitional zone between the
gastric corpus (body) and antrum. The left and right gastric arteries run along the lesser curvature and are likely to be
penetrated by ulcers, causing gastric bleeding. [292]
HEPATIC DISORDERS
Cirrhosis
In cirrhosis, portal hypertension arises from increased resistance to portal flow at the hepatic sinusoids. This causes
increased pressure in the portosystemic collateral veins within the lower end of the esophagus, anterior abdomen,
and lower rectum. Dilation of these collateral vessels is responsible for the esophageal varices, caput medusae, and
anorectal varices commonly seen in patients with cirrhosis. [8547]
Ischemic hepatitis
Organ susceptibility to infarction after occlusion of a feeding artery is ranked from greatest to least as follows: central
nervous system, myocardium, kidney, spleen, and liver. The presence of a dual and/or collateral blood supply (as
seen in the liver, which is supplied by the hepatic artery and portal vein) enables an organ to tolerate arterial
occlusion better than those with end-arterial circulations. [1875]
Penetrating abdominal trauma

Occlusion of the portal triad can be used to distinguish the source of right upper quadrant bleeding. If the bleeding
subsides following occlusion, the source is likely to be the hepatic artery or portal vein. If hepatic bleeding persists
after occlusion, the inferior vena cava or hepatic veins are likely to be injured. [10583]
Portal hypertension
The portal vein can be identified on cross-sectional scans lying medial to (or just within) the right lobe of the liver and
anterior to the inferior vena cava. The pressure in the portal system is elevated in liver cirrhosis. [1537]
INTESTINAL AND COLORECTAL DISORDERS
Appendicitis
The teniae coli are 3 separate smooth muscle ribbons that travel longitudinally on the outside of the colon and
converge at the root of the vermiform appendix. If the appendix cannot be identified by palpation during an
appendectomy, it can be located by following the teniae coli to their origin at the cecal base. [11782]
Appendicitis causes dull visceral pain at the umbilicus due to afferent pain fibers entering at the T10 level in the spinal
cord. Progressive inflammation in the appendix irritates the parietal peritoneum and abdominal wall to cause more
severe somatic pain shifting from the umbilicus to McBurney's point (two-thirds of the distance from the umbilicus to
the anterior superior iliac spine). [11775]
Bowel obstruction
Superior mesenteric artery syndrome occurs when the transverse portion of the duodenum is entrapped between
the SMA and aorta, causing symptoms of partial intestinal obstruction. This syndrome occurs when the
aortomesenteric angle critically decreases, secondary to diminished mesenteric fat, pronounced lordosis, or surgical
correction of scoliosis. [303]
Constipation
The pelvic splanchnic nerves (S2-S4) provide parasympathetic innervation to the bowel and bladder, and their
impairment in cauda equina syndrome can cause constipation and difficulty urinating. Other signs of cauda equina
syndrome include radicular low back pain and leg weakness (sciatic nerve) as well as saddle anesthesia (pudendal,
ilioinguinal nerves). [17005]
Dyssynergic defecation occurs when the puborectalis muscle or the internal or external anal sphincter fails to relax
during defecation, leading to chronic constipation. Dyssynergic defecation is usually considered a functional disorder
and occurs more commonly in the elderly but may also occur with certain neurologic disorders (eg, Parkinson disease,
multiple sclerosis) or trauma. [17004]
H pylori
Gastric acid is neutralized by bicarbonate from the submucosal glands of the duodenum (Brunner glands) and from
pancreatic duct secretions. Chronic overproduction of gastric acid can lead to hyperplasia of the submucosal glands.
[129]
Hemorrhoids
External hemorrhoids, which originate below the dentate line, are covered by modified squamous epithelium and
have cutaneous (somatic) nervous innervation from the inferior rectal nerve, a branch of the pudendal nerve. [11771]
Perforated viscus
Pneumoperitoneum is air or gas in the peritoneal cavity; it can be seen as free air under the diaphragm in an upright
chest x-ray. The most common cause is a perforated duodenal ulcer, but perforation can occur anywhere along the
gastrointestinal (or female reproductive) tract. Subsequent peritonitis can lead to diffuse abdominal pain with
rebound and guarding, sometimes with referred shoulder pain due to diaphragmatic irritation. [14837]
MISCELLANEOUS
Groin hernias
Femoral hernias can present with groin discomfort and a tender bulge on the upper thigh inferior to the inguinal
ligament, lateral to the pubic tubercle and lacunar ligament. The structure that lies immediately lateral to the hernia
within the femoral sheath is the femoral vein. Incarceration and strangulation are common complications of femoral
hernias. [417]
Direct inguinal hernias occur most commonly in older men due to weakness of the transversalis fascia. They protrude
medial to the inferior epigastric vessels into the Hesselbach triangle and pass only through the superficial inguinal
ring with no direct route to the scrotum. [8669]
The inferior epigastric vessels are useful as a landmark during laparoscopic hernia repair to classify the type of
inguinal hernia. Indirect inguinal hernias protrude through the deep inguinal ring into the inguinal canal lateral to the
inferior epigastric vessels. In contrast, direct inguinal hernias protrude through Hesselbach's triangle medial to the
inferior epigastric vessels. [418]
Hemorrhoids
Hemorrhoids result from abnormal distension of a portion of the anal arteriovenous plexus. The vascular
components of internal hemorrhoids drain into the superior rectal vein, which subsequently drains into the inferior
mesenteric vein. Band ligation of hemorrhoids cuts off their blood supply, causing them to degenerate. [11840]
Spleen rupture
Any abdominal process (eg, ruptured spleen, peritonitis, hemoperitoneum) irritating the phrenic nerve sensory fibers
around the diaphragm can cause referred pain to the C3-C5 shoulder region (Kehr sign). [11753]
NORMAL STRUCTURE AND FUNCTION OF THE GI TRACT
Anterior abdominal wall

Horizontal transection of the rectus abdominis muscle must be performed with great caution as the inferior epigastric
arteries enter this muscle at the level of the arcuate line. The inferior epigastric arteries below the arcuate line are
susceptible to injury (eg, hematoma) due to lack of a supporting posterior rectus sheath. [11850]
Bowel obstruction
Abdominal structures are susceptible to mass effect when supportive elements (eg, mesenteric fat) are
depleted. Loss of mesenteric fat (eg, anorexia nervosa) allows the superior mesenteric artery to compress the
transverse segment of the duodenum, resulting in small bowel obstruction (ie, superior mesenteric artery syndrome).
[107787]
Cardiovascular anatomy
The superior mesenteric artery and inferior mesenteric artery are the 2 main vessels supplying the small and large
intestines. They are connected by a pair of anastomoses: the marginal artery of Drummond, which is the principal
anastomosis, and the inconsistently present arc of Riolan (mesenteric meandering artery). [11839]
The celiac trunk is the first main branch of the abdominal aorta; it provides oxygenated blood to the spleen, stomach,
liver, abdominal esophagus, and parts of the duodenum and pancreas. The proper hepatic artery branches off the
common hepatic artery from the celiac trunk and provides arterial blood supply to the liver. [11760]
Gastrointestinal blood supply

The splenic artery originates from the celiac artery and gives off several branches to the stomach and pancreas
(pancreatic, short gastric, and left gastroepiploic arteries) before finally reaching the spleen. Due to poor
anastomoses, the gastric tissue supplied by the short gastric arteries is vulnerable to ischemic injury following splenic
artery blockage. [8574]
Forceful retching can lead to superficial mucosal lacerations (eg, Mallory-Weiss tears) of the distal esophagus, an area
that receives most of its arterial blood supply from branches of the left gastric artery. The proximal esophagus
receives arterial blood from the inferior thyroid artery, whereas the midesophagus is supplied by branches of the
thoracic aorta. [20079]
Gastrointestinal hemorrhage
The hindgut encompasses the distal one-third of the transverse colon, the descending colon, the sigmoid colon, and
the rectum. These structures receive their main arterial blood supply from the inferior mesenteric artery. [1744]
Lymphatic drainage
Lymphatic drainage of the rectum proximal to the anal dentate line occurs via the inferior mesenteric and internal
iliac lymph nodes. Areas distal to the dentate line drain primarily into the inguinal nodes. [11817]
Obesity
The lesser omentum is a double layer of peritoneum that extends from the liver to the lesser curvature of the
stomach and the beginning of the duodenum. It is divided into the hepatogastric and hepatoduodenal ligaments.
[8587]
Vagotomy
Branches of the vagus nerve (ie, anterior and posterior vagal trunks) pass through the esophageal hiatus. Damage to
these branches, which can occur during esophageal hiatal hernia repair (eg, fundoplication), may result in delayed
gastric emptying and gastric hypochlorhydria. [20080]
PANCREATIC DISORDERS
Chronic pancreatitis
Chronic pancreatitis often presents with epigastric pain and pancreatic exocrine insufficiency resulting in fat
malabsorption/steatorrhea. On abdominal CT scan, the pancreas can be identified by its head in close association
with the second part of the duodenum; its body overlying the aorta, left kidney, and renal vessels; and its tail lying
within the splenorenal ligament. [1738]
The short gastric veins drain blood from the gastric fundus into the splenic vein. Pancreatic inflammation (eg,
pancreatitis, pancreatic cancer) can cause a blood clot within the splenic vein, which can increase pressure in the
short gastric veins and lead to gastric varices only in the fundus. [11795]
Retroperitoneal hematoma
Retroperitoneal hematoma is a common complication of abdominal and pelvic trauma. The pancreas is a
retroperitoneal organ, and pancreatic injury is frequently a source of retroperitoneal bleeding. [838]
TUMORS OF THE GI TRACT
Gastrointestinal blood supply

The third part of the duodenum courses horizontally across the abdominal aorta and inferior vena cava at the level of
the third lumbar vertebra. The superior mesenteric vessels lie anterior to the duodenum at this location. [1832]
Lymphatic drainage
Most of the cutaneous lymph from the umbilicus down, including the anus below the dentate line, drains to the
superficial inguinal lymph nodes. Exceptions are the glans penis and posterior calf, which drain to the deep inguinal
nodes. [1631]
Male Reproductive System
DISORDERS OF THE MALE REPRODUCTIVE SYSTEM
Benign prostatic hyperplasia

The prostate is located between the pubic symphysis and the anal canal and is visible on inferior sections of the pelvis
on CT scan. Benign prostatic hyperplasia is a common, age-related condition that causes urinary symptoms (eg,
hesitancy, straining, incomplete voiding). It can be medically treated with α-adrenergic blockers and 5-α reductase
inhibitors. [1737]
Cryptorchidism
The superficial and deep inguinal rings are physiologic openings in the external abdominal oblique aponeurosis and
the transversalis fascia, respectively. Surgical repair of an undescended testicle lodged in the inguinal canal involves
moving the testis through the superficial inguinal ring and fixing it in the scrotum (ie, orchiopexy). [11762]
Hydrocele
A communicating hydrocele results when serous fluid accumulates within the tunica vaginalis in the setting of a
patent processus vaginalis. It presents as a painless swelling that transilluminates on examination. [1827]
Male sexual dysfunction

The prostatic plexus (inferior hypogastric nerves plus pelvic and sacral splanchnic nerves) lies within the fascia of the
prostate and innervates the corpus cavernosa of the penis, which facilitates penile erection. As a result,
prostatectomy or injury to the prostatic plexus can cause erectile dysfunction. [11800]
Prostate cancer
The skeletal system is a common site of metastasis due to hematogenous seeding. Cancers of the pelvis, including
the prostate, spread to the lumbosacral spine via the vertebral venous plexus, which in turn communicates with a
number of venous networks, including the prostatic venous plexus. [11747]
Testicular torsion
Testicular torsion is due to twisting of the testis around the spermatic cord (containing the gonadal artery), which can
eventually lead to ischemia. The gonadal arteries arise from the abdominal aorta. The right gonadal vein drains
directly into the inferior vena cava while the left gonadal vein drains into the left renal vein. [11658]
Testicular torsion is characterized by spermatic cord twisting due to an anatomic defect that allows increased
testicular mobility. The presentation includes severe scrotal pain and swelling due to venous compression and
hemorrhagic infarction of the testis. [15800]
Urethral injury
Injury to the posterior urethra is associated with pelvic fractures, and the anterior urethra is most commonly
damaged in straddle injuries. Inability to void with a full bladder sensation, a high-riding boggy prostate, and blood at
the urethral meatus are suggestive of urethral injury, particularly in the presence of a pelvic fracture. If urethral
injury is suspected, placement of a Foley catheter is contraindicated. [839]
NORMAL STRUCTURE AND FUNCTION OF THE MALE REPRODUCTIVE SYSTEM
Lymphatic drainage
Lymph from the testes drains through lymph channels directly back to the para-aortic lymph nodes. In contrast,
lymph from the scrotum drains to the superficial inguinal lymph nodes. [2021]
Due to its intra-abdominal origin, lymphatic drainage of the testis is to the para-aortic lymph nodes. In contrast,
lymph drainage from the scrotum goes into the superficial inguinal lymph nodes. [8326]
Miscellaneous (Multisystem)
MISCELLANEOUS
Lymphatic drainage
In the lower extremities, the superficial lymphatic system is divided into medial and lateral tracks. The medial track
runs up to the superficial inguinal lymph nodes, bypassing the popliteal nodes. Consequently, lesions on the medial
foot cause inguinal lymphadenopathy, whereas lateral lesions are more likely to cause lymphadenopathy in both the
popliteal and inguinal areas. [11830]
Rib fracture
The left kidney lies immediately deep to the tip of the 12th rib. [1700]
Nervous System
CNS INFECTIONS
Brain abscess
A single brain abscess is usually caused by direct spread of a contiguous infection. Temporal lobe abscess is usually a
result of otitis media that has spread to the mastoid air cells, while frontal lobe abscess is usually due to ethmoid or
frontal sinusitis. Multiple brain abscesses typically indicate hematogenous dissemination of a distant infection (eg,
endocarditis, empyema). [14898]
Spinal anatomy
The optimal location for needle insertion during a lumbar puncture is the L3/L4 or L4/L5 space as this is well below
the spinal cord termination site (L1 in adults). The L4 vertebral body lies on a line drawn between the highest points
of the iliac crests. [12084]
CEREBROVASCULAR DISEASE
Abducens palsy
An expanding aneurysm in the cavernous portion of the internal carotid artery (ICA) is most likely to initially cause
headache and diplopia (ipsilateral lateral rectus weakness) due to compressing or stretching of the abducens nerve
(CN VI) as it runs next to the ICA in the cavernous sinus. Other commonly affected nerves include the oculomotor
nerve (CN III), trochlear nerve (CN IV), and the V1 and V2 branches of the trigeminal nerve (CN V). [15646]
Anoxic brain injury

The upper midbrain contains neural structures (eg, optic nerve, pretectal nuclei, Edinger-Westphal nuclei, oculomotor
nerve) that mediate the direct and consensual pupillary light reflex. [12119]
Aphasia
A lesion in Wernicke's area can cause receptive aphasia, which is characterized by well-articulated, nonsensical
speech paired with a lack of language comprehension (Wernicke-Word salad). Wernicke's area is located in the
auditory association cortex within the posterior portion of the superior temporal gyrus in the dominant temporal
lobe. The middle cerebral artery supplies Broca's area (superior division) and Wernicke's area (inferior division). [1846]
Broca (motor, nonfluent) aphasia results from damage to the inferior frontal gyrus of the dominant
hemisphere. Patients are often frustrated as they understand language but cannot properly formulate the motor
commands to write or form words (eg, slow, fragmented speech). Aphasia may be associated with right upper limb
and face weakness due to extension of the lesion into the primary motor cortex. [1955]
Brain herniation
Expanding space-occupying lesions can increase intracranial pressure, causing transtentorial herniation of the
uncus. Uncal herniation often compresses the ipsilateral oculomotor nerve (CN III) as it exits the midbrain, resulting
in CN III palsy with a fixed dilated pupil (due to preganglionic parasympathetic nerve fiber damage). [11804]
Carotid artery stenosis

Transient ischemic attacks resulting in left leg weakness and vision loss in the right eye are likely due to emboli
originating from the right internal carotid artery. The brachiocephalic artery branches from the aortic arch, then
divides into the right subclavian and right common carotid arteries. The left common carotid and left subclavian
arteries branch directly from the aortic arch. [19802]
Cavernous sinus thrombosis
Infection of the medial face, sinuses (ethmoidal or sphenoidal), or teeth may spread through the valveless facial
venous system into the cavernous sinus, resulting in cavernous sinus thrombosis. Patients typically present with
headache, fever, proptosis, and ipsilateral deficits in cranial nerves III, IV, VI, and V (ophthalmic and maxillary
branches). [12029]
Epidural hematoma
The middle meningeal artery is a branch of the maxillary artery, which enters the skull at the foramen spinosum and
courses intracranially deep to the pterion (where the frontal, parietal, temporal, and sphenoid bones meet). Skull
fractures at this site may cause laceration of this vessel, leading to an epidural hematoma. [1813]
Hemorrhagic stroke
Spontaneous deep intracerebral hemorrhage is typically caused by hypertensive vasculopathy involving the small,
penetrating branches of the major cerebral arteries. The most frequently affected locations include the basal ganglia
(putamen), cerebellar nuclei, thalamus, and pons. The putamen is supplied by the lenticulostriate arteries, which are
deep, small vessel branches off the middle cerebral arteries. [12007]
The locus ceruleus is a paired brainstem nucleus located in the posterior rostral pons near the lateral floor of the
fourth ventricle and functions as the principal site for norepinephrine synthesis in the brain. It projects to virtually all
parts of the central nervous system and helps control mood, arousal (reticular activating system), sleep-wake states,
cognition, and autonomic function. [12226]
Intraventricular hemorrhage
Neonatal intraventricular hemorrhage usually originates from the fragile germinal matrix in infants born before 32
weeks gestation and/or with birth weight <1,500 g (3 lb 5 oz). It is a common complication of prematurity that can
lead to long-term neurodevelopmental impairment. [8564]
Ischemic stroke
A stroke in the pons can lead to contralateral weakness of the arm and leg with ipsilateral facial weakness. Facial
weakness occurs in a lower motor neuron pattern (ipsilateral, affects upper face) because the damage occurs at the
level of the facial nerve (CN VII) origination. [105500]
A lateral medullary infarct (Wallenberg syndrome) leads to vertigo (vestibular nucleus), loss of pain/temperature
sensation on the ipsilateral face (trigeminal nucleus) and contralateral body (spinothalamic tract), bulbar weakness
(lower cranial nerves), and ipsilateral Horner syndrome (descending sympathetic nervous system fibers). [105533]
The anterior cerebral artery (ACA) supplies the medial aspects of the frontal and parietal lobes, which contain the
upper motor neurons responsible for contralateral lower extremity motor control. Thromboembolic occlusion of the
ACA characteristically results in contralateral lower extremity weakness with hyperreflexia. [15765]
Upper motor neuron lesions (ie, internal capsule stroke) cause contralateral weakness with clasp-knife spastic rigidity,
hyperreflexia, and a positive Babinski sign. These lesions damage the pyramidal motor system (eg, corticospinal
tracts), which runs from the precentral gyrus (primary motor cortex) through the internal capsule to the brainstem
and spinal cord. [1687]
A stroke in the lateral brainstem can lead to ipsilateral Horner syndrome because sympathetic neurons travel next to
the spinothalamic tract in the lateral medulla. [105558]
The anterior cerebral artery supplies the medial aspects of the frontal and parietal lobes. Occlusion can lead to
sensory and motor deficits of the contralateral leg. Occlusion of the anterior cerebral artery distal to the anterior
communicating artery can lead to more severe symptoms because there is no collateral blood flow from the Circle of
Willis. [21589]
Because the parietal association cortex integrates multisensory information, damage can lead to difficulties in
comprehension and problem-solving in the absence of motor or sensory deficits. Specific injury to the angular gyrus
classically results in Gerstmann syndrome (agraphia, acalculia, finger agnosia, and left-right disorientation). [12023]
A stroke involving the middle cerebral artery often leads to contralateral hemiparesis and/or hemisensory loss. If it is
in the nondominant (typically right) hemisphere, hemineglect and an unawareness of the condition are often present;
aphasia is absent. [105495]
The most common findings with posterior cerebral artery stroke are contralateral homonymous hemianopia with
macular sparing due to damage to the occipital cortex and contralateral hemisensory loss due to damage to the
thalamus. [2127]
A stroke impacting the thalamus can lead to sensory loss affecting all tactile modalities (eg, touch, pain/temperature,
vibration/proprioception) in the contralateral face, arm, and leg. [2076]
Lacunar infarctions are the result of small-vessel occlusion (due to lipohyalinosis and microatheroma formation) in
the penetrating vessels supplying the deep brain structures. Uncontrolled hypertension and diabetes mellitus are
major risk factors for this condition. [2077]
The anterior cerebral arteries supply the medial portions of the 2 hemispheres (frontal and parietal lobes). Occlusion
can cause contralateral motor and sensory deficits of the lower extremities, behavioral changes, and urinary
incontinence. [1696]
Occlusion of the middle cerebral artery (MCA) typically results in contralateral hemiparesis and hemisensory loss of
the face and upper limb with relative preservation of lower limb function. If the occluded MCA is in the dominant
(usually left) hemisphere, aphasia may also occur. [21]
Cervical spine trauma can lead to dissection of the vertebral artery, resulting in infarction of the lateral medulla and
causing vertigo/nystagmus, ataxia, loss of pain/temperature sensation in the ipsilateral face and contralateral body,
bulbar weakness, and ipsilateral Horner syndrome. [12155]
Crossed signs (ie, cranial nerve dysfunction with contralateral limb weakness) raise suspicion for brainstem
stroke. Midbrain infarction due to occlusion of the posterior cerebral artery results in Weber syndrome characterized
by ipsilateral oculomotor nerve (CN III) dysfunction accompanied by contralateral hemiparesis. [105530]
Ischemic injury to the bilateral ventral pons can lead to locked-in syndrome, a condition in which patients are unable
to move or speak (due to interruption of the corticospinal and corticobulbar tracts) but retain consciousness,
sensation, eye opening, and vertical eye movements. [19833]
Posterior inferior cerebellar artery occlusion causes lateral medullary (Wallenberg) syndrome. This disorder is
characterized by vertigo/nystagmus, ipsilateral cerebellar signs, loss of pain/temperature sensation in the ipsilateral
face and contralateral body, bulbar weakness, and ipsilateral Horner syndrome. [19612]
Crossed signs (ie, ipsilateral cranial nerve dysfunction with contralateral limb weakness) are typical of a brainstem
stroke. A stroke in the medial medulla often results in contralateral limb weakness with ipsilateral tongue weakness,
which causes tongue deviation to the weak side. [105531]
Transient global amnesia

Transient global amnesia is a self-limited syndrome characterized by the sudden onset of prominent anterograde
amnesia accompanied by repetitive questioning. Symptoms correlate with transient dysfunction of the hippocampus,
the brain area responsible for the formation of new memories. [19618]
Visual pathway
Visual loss in only one eye indicates that the lesion is anterior to the optic chiasm. Images projected onto the retina
are inverted and reversed. [19633]
An aneurysm of the internal carotid artery can laterally impinge on the optic chiasm. This can cause ipsilateral nasal
hemianopia by damaging uncrossed optic nerve fibers from the temporal portion of the retina. [8636]
Lesions of the occipital cortex (eg, posterior cerebral artery occlusion) can produce contralateral homonymous
hemianopia with macular sparing. [8592]
Wilson disease
Wilson's disease can cause cystic degeneration of the putamen as well as damage to other basal ganglia
structures. The putamen is located medial to the insula and lateral to the globus pallidus on coronal sections. [1689]
DEMYELINATING DISEASES
Visual pathway
The optic nerve carries the afferent limb of the pupillary light reflex pathway, which activates the efferent limb
bilaterally and causes both direct and consensual pupillary constriction. Unilateral optic nerve lesions (eg,
demyelination due to optic neuritis) can result in impaired pupillary constriction bilaterally when light enters the eye
ipsilateral to the lesion. When light enters the contralateral eye, pupillary constriction occurs normally in both eyes.
[1735]
DISORDERS OF PERIPHERAL NERVES AND MUSCLES
Appendicitis
The iliohypogastric nerve provides sensation to the suprapubic and gluteal regions and motor function to the
anterolateral abdominal wall muscles. Abdominal surgery (eg, appendectomy) can damage the nerve and cause
decreased sensation and/or burning pain at the suprapubic region. [11769]
Axillary nerve injury
Injury to the axillary nerve most commonly occurs in the setting of shoulder trauma (eg, anterior dislocation, humeral
fracture) and presents with sensory loss over the lateral shoulder and weakness on shoulder abduction (due to
denervation of the deltoid muscle). [11681]
Bell's palsy
Because of the diverse functions of the facial nerve (CN VII), patients with Bell palsy may experience decreased tear
production, hyperacusis, and/or loss of taste sensation over the anterior two-thirds of the tongue, in addition to
unilateral facial weakness. [8329]
Breast cancer
Multiple nerves are at risk for injury during axillary lymph node dissection. Intercostobrachial nerve injury results in
sensory dysfunction (eg, burning, numbness) to the skin of the axilla and medial upper arm. Injury to the long
thoracic (serratus anterior), thoracodorsal (latissimus dorsi), medial pectoral (pectoralis minor and major), or lateral
pectoral (pectoralis major) nerves result in motor deficits to corresponding muscles. [19291]
Cranial nerve palsy

Lesions involving the oculomotor nerve (CN III) cause ptosis, a downward and laterally deviated eye, impaired
pupillary constriction and accommodation, and diagonal diplopia. The most dreaded cause of CN III palsy is an
enlarging intracranial aneurysm. [8701]
The oculomotor nerve (CN III) is most susceptible to injury from ipsilateral posterior communicating artery
aneurysms. Aneurysmal compression of CN III produces mydriasis (due to superficial parasympathetic fiber damage)
with diplopia, ptosis, and down and out deviation of the ipsilateral eye (due to somatic efferent fiber injury). [2126]
Lesions of the glossopharyngeal nerve result in loss of the gag reflex (afferent limb); loss of sensation in the upper
pharynx, posterior tongue, tonsils, and middle ear cavity; and loss of taste sensation on the posterior third of the
tongue. [1815]
The oculomotor nerve (CN III), ophthalmic nerve (CN V1) branches, trochlear nerve (CN IV), and abducens nerve (CN
VI) enter the orbit via the superior orbital fissure. [1703]
The spinal accessory nerve is vulnerable to injury in the posterior triangle of the neck. Injury results in weakness of
the trapezius muscle, which presents with drooping of the shoulder, impaired abduction of the arm above 100
degrees, and lateral displacement of the scapula. [11772]
Lesions of the jugular foramen can result in jugular foramen (Vernet) syndrome, which is characterized by the
dysfunction of cranial nerves IX, X, and XI. Symptoms include dysphagia, hoarseness, loss of gag reflex on the
ipsilateral side, and deviation of the uvula toward the normal side. [8522]
The trochlear nerve innervates the superior oblique muscle, which causes the eye to intort (internally rotate) and
depress while adducted. Trochlear nerve palsy is typically traumatic or idiopathic and presents with vertical diplopia
that worsens when the affected eye looks down and toward the nose (eg, walking downstairs, up-close
reading). Patients may compensate by tucking the chin and tilting the head away from the affected eye. [1933]
Facial nerve
The facial nerve (CN VII) exits the stylomastoid foramen and courses through the substance of the parotid gland,
where it divides into its 5 terminal branches that innervate the muscles of facial expression. Malignant tumors of the
parotid gland often compress and disrupt the facial nerve and its branches, causing ipsilateral facial droop. [12025]
The stapedius muscle is innervated by the stapedius nerve (a branch of the facial nerve). Paralysis of the stapedius
muscle results in hyperacusis (eg, increased sensitivity to sound). [1452]
Falls
Superior gluteal nerve injury results in weakness and paralysis of the gluteus medius, gluteus minimus, and tensor
fasciae latae muscles. This causes the pelvis to tilt downward toward the contralateral side (positive Trendelenburg
sign). Patients will also lean toward the ipsilateral side when walking to help stabilize the pelvis (gluteus medius gait).
[1639]
Herpes zoster
Herpes zoster ophthalmicus is caused by viral reactivation within the trigeminal nucleus. It affects the ophthalmic
branch of the trigeminal nerve (CN V1) and can lead to blindness due to acute keratitis because V1 conveys sensory
information from the cornea. [18606]
Lung cancer
Sensation to the parietal pleura, chest wall, and skin of the chest is supplied by the intercostal nerves that derive from
the ventral nerve rami. A nerve block can be used to control pain from these areas when opioids are ineffective,
contraindicated, or have intolerable adverse effects. [19613]
Median nerve injury

The median nerve is most commonly injured within the carpal tunnel, leading to pain and numbness in the first 3
digits and lateral half of the fourth, as well as weakness of thumb flexion and opposition. More proximal injury (in
the forearm) additionally causes decreased sensation over the thenar eminence and weakness of flexion in the wrist
and second and third digits. [15727]
The carpal tunnel is formed by the carpal bones and the transverse carpal ligament (flexor retinaculum). Carpal
tunnel syndrome results from compression of the median nerve as it passes through the carpal tunnel with 9 flexor
tendons. Longitudinal incision of the transverse carpal ligament can decrease pressure within the carpal tunnel,
improving patients' symptoms. [11683]
In the forearm, the median nerve courses between the humeral and ulnar heads of the pronator teres muscle and
between the flexor digitorum superficialis and flexor digitorum profundus muscles. Compression prior to the takeoff
of the palmar branch (eg, between the heads of the pronator teres) results in sensory loss over the lateral palm and
palmar aspects of the first 3½ digits. [1749]
Meralgia paraesthetica
Meralgia paresthetica is caused by compression of the lateral femoral cutaneous nerve, typically due to tight
clothing. It presents with pain, paresthesia, and numbness in the lateral thigh without motor weakness. Risk factors
include obesity, pregnancy, and diabetes mellitus. [19784]
Orbital fracture
Fractures to the orbital floor commonly result from direct frontal trauma to the orbit. The infraorbital nerve runs
along the orbital floor in a groove in the maxilla before exiting the skull just inferior to the orbit. Damage can result in
paresthesia of the upper cheek, upper lip, and upper gingiva. In addition, the inferior rectus muscle can also become
entrapped, limiting vertical gaze. [11742]
Peroneal neuropathy
The common fibular nerve is susceptible to injury at the lateral neck of the fibula due to compression (ie, prolonged
lying on the affected side) or fracture. Patients typically have weakness in foot dorsiflexion, foot eversion, and toe
extension along with sensory loss over the lateral leg and dorsal foot. [1149]
Trauma/sustained pressure to the neck of the fibula can injure the common fibular nerve, causing weakness on foot
dorsiflexion and eversion along with impaired sensation over the lateral shin, dorsal foot, and between the first and
second toes. [1748]
Radial neuropathy
Radial nerve injury can occur with repetitive pressure/trauma at the axilla (eg, improperly fitted crutches). Findings
include weakness of the forearm, hand, and fingers extensors (eg, wrist drop, absent triceps reflex) and sensory loss
over the posterior arm and forearm, dorsolateral hand, and dorsal thumb. More distal lesions spare the triceps
brachii. [1685]
Injury to the radial nerve at the supinator muscle may occur due to repetitive pronation/supination of the forearm,
direct trauma, or subluxation of the radius. Patients typically have weakness during finger and thumb extension (ie,
finger-drop) without wrist drop or sensory deficits. [1694]
Radiculopathy
The C5-C6 spinal nerves mediate the biceps and brachioradialis reflexes. [11779]
Sciatica is a nonspecific term for low back pain that radiates down the leg due to compression of the lumbosacral
nerve roots (eg, from vertebral disc herniation). The S1 nerve root is commonly involved, resulting in pain/sensory
loss down the posterior thigh and calf to the lateral aspect of the foot. Patients may also have weakness on thigh
extension, knee flexion, and foot plantarflexion with an absent Achilles reflex. [1692]
Spinal nerves in the lumbosacral spine exit through the neural foramina that is below the corresponding vertebral
body level (eg, L5 nerve root exits between L5 and S1 vertebral bodies) and can be compressed at the neural
foramina due to osteophyte formation. In addition to back pain, L5 radiculopathy often presents with sensory loss
over the lateral thigh, calf, and dorsal foot and weakness of great toe extension and foot dorsiflexion, inversion, and
eversion. [11834]
Sciatic neuropathy
Sciatic neuropathy is a common complication of hip fracture and/or arthroplasty because of the proximity of the
sciatic nerve to the hip joint. Injury to the sciatic nerve in the pelvis causes neurological deficits across the sciatic
nerve (knee flexion), common peroneal nerve (dorsiflexion, numbness of the calf and dorsal foot), and tibial nerve
(plantar flexion, ankle reflex). [15705]
Temporomandibular disorders
Temporomandibular disorder is associated with dysfunction of the temporomandibular joint and hypersensitivity of
the mandibular nerve (CN V3). This can result in pathologic contraction of the pterygoid muscles (eg, jaw
pain/dysfunction) and the tensor tympani in the middle ear (eg, ear pain, muffled hearing). [11663]
Ulnar nerve neuropathy

Ulnar nerve injury most commonly occurs at the elbow (eg, compression due to resting arm on a hard surface while
using a computer) and usually presents with discomfort and sensory loss/paresthesia in the fifth digit, medial half of
the fourth digit, and the hypothenar eminence. In severe cases, patients can also have weakness on wrist flexion and
adduction (ie, ulnar deviation) along with finger weakness/clumsiness. [1743]
Upper motor neuron lesion

The jaw jerk reflex is a pathologic cranial nerve reflex present in patients with bilateral upper motor neuron lesions,
such as amyotrophic lateral sclerosis. Both the afferent and efferent pathways are mediated by the mandibular
division of the trigeminal nerve (CN V3). [18599]
Vestibular schwannoma
Vestibular schwannomas arise from the vestibulocochlear nerve (CN VIII) and are usually located at the
cerebellopontine angle. These tumors can cause a range of symptoms by damaging the vestibulocochlear nerve
(unsteadiness and ipsilateral sensorineural hearing loss with tinnitus), trigeminal nerve (ipsilateral facial paresthesia
and diminished corneal reflex), and facial nerve (ipsilateral facial paresis). Bilateral acoustic neuromas are associated
with neurofibromatosis type 2. [1306]
Acoustic neuromas are Schwann cell-derived tumors that typically arise from the vestibular portion of the
vestibulocochlear nerve and are commonly located at the cerebellopontine angle (between the cerebellum and
lateral pons). Patients usually present with unilateral sensorineural hearing loss and tinnitus. [11609]
MISCELLANEOUS
Fecal incontinence
Pudendal nerve injury can occur due to excessive stress on the pelvic floor during labor and delivery (eg, prolonged
second stage). Nerve injury leads to denervation and weakness of the perineal musculature (eg, external anal
sphincter), which can present as new-onset fecal incontinence. [11952]
Hydrocephalus
CSF flow occurs as follows: lateral ventricles → interventricular foramina of Monro → third ventricle → cerebral
aqueduct of Sylvius → fourth ventricle → lateral foramina of Luschka or midline foramen of Magendie →
subarachnoid space. [1635]
Lung cancer
A tumor of the lung apex (Pancoast tumor) can compress both the brachial plexus and the stellate ganglion of the
sympathetic chain, leading to lower motor neuron arm weakness and ipsilateral Horner syndrome. [566]
Visual pathway
Damage to the left temporal hemiretina will disrupt the transmission of visual information along the ipsilateral optic
nerve, lateral optic chiasm, optic tract, lateral geniculate body, optic radiations, and primary visual cortex. [11685]
NEURODEGENERATIVE DISORDERS AND DEMENTIAS
Huntington disease
The head of the caudate lies in the inferolateral wall of the frontal horn of the lateral ventricle. It is separated from
the globus pallidus and putamen by the internal capsule. Atrophy of the caudate nuclei with enlargement of the
lateral ventricles is characteristic of Huntington disease and can be observed on neuroimaging. [1690]
Thiamine deficiency
Wernicke encephalopathy is a complication of thiamine deficiency and is characterized by oculomotor dysfunction,
encephalopathy, and ataxia. Chronic deficiency results in Korsakoff syndrome (eg, anterograde and retrograde
amnesia, confabulation, apathy). Thiamine is involved in glucose metabolism, and areas of the brain with high
metabolic demands are particularly susceptible; the mammillary bodies are most commonly affected. [2129]
NORMAL STRUCTURE AND FUNCTION OF THE NERVOUS SYSTEM
Anesthesia
A femoral nerve block below the inguinal ligament (ie, in the inguinal crease) will anesthetize the skin and muscles of
the anterior thigh, femur, and knee. This type of block can be used in patients requiring tendon repair after a knee
injury (eg, quadriceps rupture). [11777]
Av malformation
Cerebral arteriovenous malformations (AVMs) are vascular malformations histologically characterized by a tangle of
abnormal vessels, including large veins with thickened walls and irregular arteries. AVMs may present with
intracranial hemorrhage, headache, and/or seizures. Radiologic findings include abnormal vasculature with a "bag of
worms" appearance and multiple dark flow voids. [19808]
Bladder cancer
The obturator nerve is the only major nerve that exits the pelvis through the obturator foramen. Nerve injury
typically results from compression (eg, due to pelvic trauma, surgery, or tumor) and presents with weakness on thigh
adduction and sensory loss over the distal medial thigh. [1802]
Brachial plexus
An interscalene nerve block is used to provide anesthesia for the shoulder and upper arm by anesthetizing the upper
brachial plexus (C5-C7) as it passes between the anterior and middle scalene muscles. Anesthetic also transverses
along the interscalene sheath, frequently resulting in transient ipsilateral diaphragmatic paralysis due to involvement
of the phrenic nerve roots (C3-C5). [11744]
The inferior trunk of the brachial plexus carries nerve fibers from the C8 and T1 spinal levels that are responsible for
innervating all the intrinsic muscles of the hand (via the median and ulnar nerves). Sudden upward stretching on the
arm at the shoulder can damage the inferior trunk, resulting in hand clumsiness and total claw hand deformity. [1829]
The radial nerve provides sensory innervation to the skin of the posterior arm, forearm, and dorsal lateral hand and
provides motor innervation to all the extensor muscles of the upper limb below the shoulder. Damage to the
proximal radial nerve (eg, at the axilla or midshaft humerus) may result in wrist drop. [1930]
The musculocutaneous nerve innervates the coracobrachialis (flexes and adducts the arm) and the major elbow
flexors (eg, biceps brachii, brachialis) and then continues distally to provide sensory innervation to the lateral
forearm. It is derived from the upper trunk of the brachial plexus (C5-C7) and can be injured by trauma or strenuous
upper extremity exercise. [1636]
Brain death
The gag reflex is mediated by afferents predominantly from the glossopharyngeal nerve (CN IX) and efferents from
the vagus nerve (CN X). An absent gag reflex may indicate dysfunction of the medulla oblongata, where the involved
cranial nerve nuclei reside. [19667]
Brain tumors
The nuclei of the vestibulocochlear nerve (CN VIII) are located in the pons. The vestibular portion of CN VIII conveys
information about head position and movement and helps to stabilize the gaze during head movement; damage can
lead to nystagmus. [19973]
The hypothalamus is a key region responsible for homeostasis. The ventromedial nucleus mediates satiety; lesions of
this area of the hypothalamus can result in hyperphagia and obesity. [2020]
The cerebellar hemispheres are responsible for motor planning and coordination of the ipsilateral extremities via
their connections with the lateral descending motor systems. Consequently, cerebellar hemisphere lesions typically
result in ipsilateral dysdiadochokinesia, limb dysmetria, and/or intention tremor. [11995]
Cavernous sinus thrombosis

The abducens nerve (CN VI) innervates the lateral rectus muscle, which originates at the annular tendon and inserts
on the temporal (ie, lateral) surface of the globe. It functions to abduct the eye. [20016]
Cerebral palsy
Spasticity can be caused by the loss of descending inhibitory signals from upper motor neurons, leading to a
hyperactive stretch reflex that results in increased muscle tone. Disruption of the afferent (sensory) arm of the
stretch reflex through a selective dorsal rhizotomy can improve spasticity without causing paralysis. [19893]
Constipation
Sacral spinal cord injury can lead to lower motor neuron injury of the S2-S4 nerve rootlets; these contribute
parasympathetic innervation to the distal colon to stimulate peristalsis and voluntary motor innervation to the
external anal sphincter. Lesions in this area can lead to distal colon stool retention, fecal incontinence, and a weak
external anal sphincter. [20056]
Dental injury
The inferior alveolar nerve travels within the mandibular canal to provide sensation to the lower teeth and can be
injured during dental procedures. It gives off the mental nerve, which exits through the mental foramen to provide
sensation to the chin and lower lip. [20060]
Diaphragmatic paralysis
The right phrenic nerve courses along the pericardium overlying the right side of the heart and is at risk for injury
during procedures in or near the right atrium (eg, radiofrequency ablation). Right phrenic nerve injury is typically
recognized by elevation of the right hemidiaphragm. [15158]
Generalized anxiety disorder

Serotonin-releasing neurons in the central nervous system (CNS) are located in the raphe nuclei. These neurons
disseminate widely to synapse on numerous structures in the CNS. Antidepressants such as selective serotonin
reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and tricyclic antidepressants inhibit serotonin
reuptake at these synapses. [1834]
Groin hernias
Postherniorrhaphy neuropathy refers to groin pain following hernia repair due to injury involving the cutaneous
nerves of the lower abdomen/groin. Neuropathy of the ilioinguinal nerve presents with pain and allodynia in the
anterior scrotum (labia majora in women), base of the penis (mons pubis), and medial thigh. [19979]
Hemiballismus
The subthalamic nucleus plays an important role in the modulation of basal ganglia output. Damage to this structure
(eg, due to lacunar stroke) may result in contralateral hemiballism, characterized by wild, involuntary, large-
amplitude, flinging movements of the proximal limbs (eg, arm and/or leg) on one side of the body. [635]
Herpes zoster
Herpes zoster reactivation typically occurs in a single or multiple-adjacent dorsal spinal ganglia, leading to a vesicular
rash in a dermatomal distribution. The L3 and L4 dermatomes supply the anteromedial thigh and medial leg. [19688]
Ischemic stroke
A lesion of the somatosensory cortex, located just posterior to the central sulcus, leads to contralateral sensory
deficits and cortical sensory signs. [105534]
Cortical blindness occurs due to damage to the primary visual cortex, located in the occipital lobes, which are
supplied by the posterior cerebral arteries. [105581]
Nausea and vomiting

The vomiting reflex is initiated by the chemoreceptor trigger zone (ie, area postrema) and nucleus tractus solitarius
within the dorsal medulla at the caudal end of the fourth ventricle. The area postrema does not have a well-
developed blood brain barrier, allowing it to be activated directly by emetogenic substances (eg, drugs, toxins) or
indirectly by ascending afferents from the bowel wall (eg, chemotherapy-induced release of serotonin). [1741]
Peripheral neuropathy
The Romberg test is a test of proprioception in which patients are observed for unsteadiness as they stand with their
feet close together, arms to the sides, and eyes closed. Failure to maintain this posture indicates sensory ataxia,
which may be caused by defects in the posterior column or peripheral nerves (eg, tabes dorsalis, vitamin B12
deficiency). [12035]
The dorsal columns are located in the posterior spinal cord and convey vibration, proprioception, and light touch
sensation. Sensation from the lower limbs is carried in the gracile fasciculus, which is located in the medial aspect;
sensation from the upper limbs is carried in the cuneate fasciculus, which is located in the lateral aspect. [19954]
Tremor
Cerebellar tremors are classically low frequency (<5 Hz) and high amplitude and increase as an action approaches a
target. They are often accompanied by other cerebellar signs, including ataxia, dysmetria, and impaired rapidly
alternating movements. [19544]
Trigeminal nerve
The third (mandibular) branch of the trigeminal nerve exits the skull through the foramen ovale and innervates the
muscles of mastication, including the masseter, the medial and lateral pterygoids, and the temporalis muscles. [2024]
General sensation from the anterior 2/3 of the tongue is carried by the mandibular division of the trigeminal
nerve. Gustatory innervation of the anterior 2/3 of the tongue is provided by the chorda tympani branch of the facial
nerve. [1453]
Infarcts involving the anterior portion of the medial pons can produce dysarthria and contralateral hemiparesis/lower
facial palsy due to disruption of the ipsilateral corticospinal and corticobulbar tracts. The trigeminal nerve arises at
the level of the middle cerebellar peduncle at the lateral aspect of the mid-pons. [2125]
The maxillary division of the trigeminal nerve (CN V2) provides sensory innervation to the cheek. It passes through
the foramen rotundum, then the pterygopalatine fossa, and then exits the maxilla through the infraorbital
foramen. Nerve blocks to provide anesthesia to the cheek are frequently performed at the infraorbital foramen.
[20004]
Urinary incontinence
Urge incontinence can be treated with neuromodulation directed toward the S2-S4 nerve roots, which improves
pelvic floor muscle strength and contraction of the external urethral sphincter; it may also impact the bladder stretch-
contraction reflex. [20008]
SEIZURES AND EPILEPSY
Seizures
The primary somatosensory cortex (postcentral gyrus) is responsible for processing all somatic sensory input from the
contralateral side of the body. A focal onset seizure originating in this region of the cerebral cortex often results in
contralateral sensory disturbance (eg, numbness, paresthesia). [12008]
SPINAL CORD DISORDERS
Cauda equina syndrome

Compressive lesions (eg, disk herniation, tumors) affecting the L1-L5 vertebral levels can impinge upon the conus
medullaris and/or T12-S4 nerve roots, causing radicular low back pain, changes in bowel/bladder function,
saddle/perianal anesthesia (eg, loss of anocutaneous reflex), and lower extremity weakness. Perianal sensation is
carried by the S2-S4 nerve roots. [1693]
Radiculopathy
Cervical radiculopathy typically results in neck and/or arm pain associated with neurologic deficits that follow a
dermatomal/myotomal pattern. Osteophytes that form due to degenerative changes in the vertebral joints can
progressively narrow the neural foramina leading to nerve root compression. [19319]
Spinal cord injury

Brown-Séquard syndrome results from hemisection of the spinal cord. It is characterized by ipsilateral paralysis due
to corticospinal tract injury; ipsilateral loss of vibratory, proprioceptive, and light touch sensation (dorsal columns);
and contralateral loss of pain, temperature, and crude touch sensation (spinothalamic tract) below the level of the
injury. [12030]
Ischemia of the anterior two-thirds of the spinal cord can occur with disruption of the anterior spinal artery blood
supply. The resulting anterior cord syndrome causes bilateral distal loss of pain, temperature, and crude touch
sensation (from injury to the spinothalamic tracts) and paralysis (from injury to the lateral corticospinal tracts). [18680]
Vitamin b12 deficiency

Neurologic damage associated with vitamin B12 deficiency classically includes subacute combined degeneration of
the dorsal columns (loss of position and vibration sensation, positive Romberg sign) and lateral corticospinal tracts
(muscle weakness, spastic paresis). [12031]
TRAUMATIC BRAIN INJURIES
Brain herniation
Subfalcine herniation occurs when the cingulate gyrus is displaced under the falx cerebri. Subfalcine herniation may
compress the ipsilateral anterior cerebral artery, resulting in ischemia and contralateral leg weakness. [20495]
Skull fractures
In addition to much of the hearing apparatus (eg, ossicles, cochlea, vestibulocochlear nerve), the temporal bone also
contains the facial nerve, which can be injured in temporal bone fractures. [15903]
Traumatic brain injury

Olfactory signals are relayed via the olfactory nerve (CN I) through the cribriform plate to the olfactory bulb, which
then projects to the primary olfactory cortex in the medial temporal lobe. Head trauma can tear olfactory nerve (CNI)
rootlets as they cross the cribriform plate, causing anosmia. Anosmia is often interpreted by patients as loss of taste.
[12227]
TUMORS OF THE NERVOUS SYSTEM
Brain tumors
Meningiomas are common adult intracranial tumors that typically arise in regions of dural reflection (eg, falx cerebri,
tentorium cerebelli). Parasagittal lesions compressing the medial portion of the primary somatosensory cortex in the
parietal lobe can result in contralateral lower limb sensory loss along with contralateral hemineglect if there is also
damage to the parietal association cortex (nondominant hemisphere). [1150]
Germinomas are the most common pineal gland tumor and present with obstructive hydrocephalus and dorsal
midbrain (Parinaud) syndrome. Germinomas in the suprasellar region cause endocrinopathies due to
pituitary/hypothalamic dysfunction. [1261]
Ophthalmology
DISORDERS OF THE EYE AND ASSOCIATED STRUCTURES
Autonomic nervous system

Anisocoria (asymmetric pupils) is caused by a lesion in the ocular parasympathetic (constriction) or sympathetic
(dilation) pathways. In this patient, anisocoria increases in bright light, indicating that the larger right pupil is unable
to constrict due to a defect in the right parasympathetic pathway. [106294]
Cranial nerve palsy

The oculomotor nerve (CN III) provides innervation to many of the extraocular muscles (superior rectus, medial
rectus, inferior rectus, inferior oblique), parasympathetic innervation to the pupil, and somatic innervation of the
levator palpebrae superioris. Dysfunction of CN III leads to a characteristic triad of a "down and out" pupil, an
efferent pupillary defect, and ptosis. [8557]
Horner syndrome
Pupillary asymmetry (ie, anisocoria) is caused by a lesion in the ocular parasympathetic (pupillary constriction) or
sympathetic (pupillary dilation) pathways. In this patient, the pupillary asymmetry increases in a dim room, indicating
that the smaller right pupil is unable to dilate due to a lesion in the right oculosympathetic pathway. [16172]
Internuclear ophthalmoplegia
Internuclear ophthalmoplegia is a disorder of impaired horizontal gaze caused by a lesion in the medial longitudinal
fasciculus (MLF). The affected eye (ipsilateral to the lesion) is unable to adduct while the contralateral eye is able to
abduct (often with associated nystagmus). Convergence and the pupillary light reflex are preserved because these
pathways bypass the MLF. [12083]
Visual pathway
Injury to Meyer's loop in the temporal lobe results in contralateral superior quadrantanopia. [8594]
Pregnancy, Childbirth & Puerperium
DISORDERS OF PREGNANCY, CHILDBIRTH, AND PUERPERIUM
Placental accreta
Placenta percreta is placental invasion through the myometrium and uterine serosa and into extrauterine
structures. An anterior placenta percreta is most likely to invade structures anterior to the uterus such as the
bladder. [19901]
Preeclampsia
Pregnant women with severe preeclampsia can develop HELLP (Hemolysis, Elevated Liver enzymes, Low Platelet
count) syndrome. Nausea/vomiting and right upper quadrant pain occur due to liver ischemia and/or hemorrhage
(eg, subcapsular hematoma). These patients are also at risk for seizure, renal insufficiency, and disseminated
intravascular coagulation due to widespread endothelial dysfunction. [19436]
Scalp hematomas
Subgaleal hemorrhage is a potentially fatal neonatal bleed that occurs during delivery when emissary veins between
the dural sinuses and scalp are sheared. The accumulation of blood between the periosteum and galea aponeurosis
presents with a diffuse, progressive, fluctuant scalp and neck swelling; massive blood loss can lead to shock and death
if not promptly recognized. [15704]
Pulmonary & Critical Care
CRITICAL CARE MEDICINE
Pneumothorax
The lung apices extend above the level of the clavicle and first rib through the superior thoracic
aperture. Penetrating injury in this area may lead to pneumothorax, tension pneumothorax, or hemothorax. [1695]
Thoracentesis
A chest tube for drainage of pleural effusion is placed through the skin and subcutaneous fat into the 4th or 5th
intercostal space in the anterior axillary or midaxillary line. The tube traverses through the serratus anterior muscle,
intercostal muscles, and parietal pleura. [11741]
Thoracentesis should be performed below the 6th rib in the midclavicular line, the 8th rib along the midaxillary line,
or the 10th rib along the paravertebral line in order to minimize the risk of lung injury. Insertion of a needle lower
than 9th rib increases the risk of penetrating abdominal structures. The needle should also be inserted along the
upper border of the rib to prevent injury to the intercostal vessels. [844]
MISCELLANEOUS
Pleural effusion
The thoracic duct carries lymph from most of the body and drains into the junction between the left subclavian and
jugular veins. Although most commonly injured in thoracic procedures, it can also be injured in neck procedures
where it travels through the neck. Injury may result in a chylothorax. [18656]
NORMAL PULMONARY STRUCTURE AND FUNCTION
Aspiration pneumonia
Due to gravity, supine patients typically aspirate into the posterior segments of the upper lobes and superior
segments of the lower lobes. Patients who are upright tend to aspirate into the basilar segments of the lower
lobes. Aspirated material is more likely to travel down the right main bronchus. [1745]
Lung anatomy
Pulmonary consolidation is caused by the accumulation of material (eg, fluid, cellular debris) in the alveoli, which can
be visualized on radiographs as an area of opacification with indistinct borders. A sharply defined horizontal or
oblique line indicates that the consolidation abuts one of the lung fissures. Consolidation that is sharply defined
inferiorly by the horizontal fissure is consistent with right upper lobe pneumonia. [16285]
OBSTRUCTIVE LUNG DISEASE
Obstructive sleep apnea

Neuromuscular weakness of the oropharynx is involved in the pathophysiology of obstructive sleep apnea. Electrical
stimulation of the hypoglossal nerve increases the diameter of the oropharyngeal airway and decreases the
frequency of apneic events. [11845]
PULMONARY INFECTIONS

Irritation of the parietal pleura will cause sharp pain, which is worse on inspiration. Pain arising from the mediastinal
or diaphragmatic pleura will be carried by the phrenic nerve and referred to the C3-C5 distribution. [1535]
Renal, Urinary Systems & Electrolytes
Congenital anomalies of kidney and urinary tract

In horseshoe kidney, the kidneys are usually fused at the lower poles. The location of the isthmus (ie, fused portion)
of the horseshoe kidney between the aorta and the inferior mesenteric artery (IMA) results in limitation of the proper
ascent of the horseshoe kidney by the IMA. [2]
MISCELLANEOUS
Bladder trauma
The dome of the bladder rises into the peritoneal cavity when distended with urine. Blunt lower abdominal trauma
can abruptly increase intravesicular pressure and rupture the bladder dome, spilling urine into the intraperitoneal
cavity. [17307]
NORMAL STRUCTURE AND FUNCTION OF THE KIDNEYS AND URINARY SYSTEM
Hematuria
The bladder trigone is formed by 2 slit-like ureteric orifices and the internal urethral opening. Blood within the
ureteric orifice suggests upper urinary tract bleeding originating in the kidney (eg, renal papillary necrosis) or ureter.
[20178]
Ureter injury
The ureters pass posterior to the ovarian (gonadal) vessels within the retroperitoneum and cross anterior to the
common/external iliac arteries to reach the true pelvis. Within the true pelvis, the ureters lie anterior to the internal
iliac artery and posterior to the uterine artery. [1804]
The proximal ureter receives its blood supply from the renal artery whereas the distal ureter is supplied by the
superior vesical artery. Circulation to the middle portions of the ureter is variable and anastomotic. [1680]
Urinary retention
The bladder is extraperitoneal. In placement of a suprapubic cystostomy, the trocar and cannula will pierce the layers
of the abdominal wall but will not enter the peritoneum. [11708]
URINARY INCONTINENCE
Stress incontinence, involuntary leakage of urine with increased intraabdominal pressure, can occur due to urethral
sphincter dysfunction (eg, decreased sphincter tone). Risk factors include multiple prior vaginal deliveries, which can
injure the external urethral sphincter or pudendal nerve. [10962]
Stress urinary incontinence is involuntary urine leakage with increased intraabdominal pressure (eg, coughing,
sneezing). Pelvic floor muscle (Kegel) exercises target and strengthen the levator ani muscle complex, improving
support around the urethra and bladder and symptoms of stress urinary incontinence. [11820]
Rheumatology/Orthopedics & Sports
ARTHRITIS AND SPONDYLOARTHROPATHIES
Bursitis
Olecranon bursitis presents with localized swelling at the olecranon process. Pain and erythema are typically minimal
or absent unless significant inflammation is present. A bursa is not an intraarticular structure; therefore, range of
motion of the associated joint is typically preserved and pain-free. [20092]
BONE/JOINT INJURIES AND INFECTIONS
Ankle trauma
Lateral ankle sprain is due to inversion of a plantar-flexed foot and most commonly involves the anterior talofibular
ligament. Stronger forces can cause joint instability by injuring additional ligaments. [11799]
Bursitis
A bursa is a fluid-filled synovial sac that serves to alleviate pressure from bony prominences and reduce friction
between muscles and tendons. Acute trauma or chronic repetitive pressure can cause injury, leading to localized pain
and tenderness. Prepatellar bursitis causes anterior knee pain and is usually due to repetitive or prolonged kneeling.
[1491]
Clavicle fracture
The clavicle is commonly fractured in children after a fall on an outstretched arm. In a distal clavicle fracture, the
deltoid muscle and the weight of the arm cause inferolateral displacement of the distal fragment, whereas the
sternocleidomastoid and trapezius muscles cause superomedial displacement of the proximal fragment. [1702]
Hand injury
The lunate bone is the more medial (ulnar) of the 2 proximal carpal bones that articulate with the radius. A fall onto
an outstretched hand can cause dislocation of the lunate bone with resulting compression of the median nerve (eg,
wrist pain, numbness in the first 3½ digits). [1682]
Hip fracture
The greater trochanter of the femur serves as the site of insertion for the gluteus medius muscle, which is responsible
for hip abduction and stabilization of the pelvis during ambulation. Fractures of the greater trochanter (eg, fragility
fracture from a fall) can disrupt the integrity of the gluteus medius tendon and result in lateral hip pain with gait
instability and weakness of hip abduction. [15660]
Posterior hip dislocation (ie, femoral head displaced posteriorly from the acetabulum) can occur in motor vehicle
collisions in which the knee strikes the dashboard or from falls in elderly patients. On examination, the leg appears
shortened and internally rotated, with the hip held in flexion and adduction. The sciatic nerve is vulnerable to injury
in posterior hip dislocation. [18583]
Knee trauma
The posterior cruciate ligament prevents posterior displacement of the tibia relative to the femur when the knee is
flexed. It attaches to the posterior part of the intercondylar area of the tibia and the anterior part of the lateral
surface of the medial epicondyle of the femur. [1969]
The posterior cruciate ligament prevents posterior displacement of the tibia relative to the femur. It originates from
the anterolateral surface of the medial femoral condyle and inserts into the posterior intercondylar area of the
tibia. Its integrity can be tested in the clinical setting by using the posterior drawer test. [1968]
Patella fractures are most commonly due to a direct impact to the anterior aspect of the knee. Signs include an
acutely swollen knee, focal patella tenderness, inability to extend the knee against gravity, and a palpable gap in the
extensor mechanism. [11659]
The anterior cruciate ligament (ACL) can be damaged by sudden changes in direction or awkward landings (eg,
excessive internal rotation or valgus stress) during sports activity. ACL tears are typically associated with rapid-onset
hemarthrosis. Physical examination shows anterior laxity of the tibia relative to the femur (eg, Lachman test, anterior
drawer test). [1697]
Lateral epicondylitis
Lateral epicondylitis (ie, tennis elbow) is characterized by overuse of wrist extensor muscles (eg, extensor carpi
radialis, extensor digitorum), leading to angiofibroblastic tendinosis at their attachment on the lateral epicondyle.
[11684]
Lower extremity long bone fracture
The medial circumflex femoral artery and its branches provide the majority of the blood supply to the femoral head
and neck. Injury to these vessels due to a displaced femoral neck fracture can cause osteonecrosis of the femoral
head. [1956]
Medial collateral ligament injury

The medial collateral ligament resists force that pushes the knee medially. Increased laxity of the knee with the
valgus stress test indicates injury to the medial collateral ligament. [11801]
Peroneal neuropathy
The common peroneal nerve is vulnerable to injury where it courses around the neck of the fibula. Fibular neck
fractures can injure this nerve, causing weakness of dorsiflexion (deep peroneal nerve) and eversion (superficial
peroneal nerve) of the foot as well as loss of sensation over the dorsum of the foot. [1803]
Radial head subluxation

Radial head subluxation (ie, nursemaid's elbow) is the displacement of the annular ligament into the radiohumeral
joint, classically resulting from sudden axial traction (eg, pulling) on the arm of a child age <5. Although most patients
do not have any obvious swelling or deformity, they avoid moving the arm due to pain and hold it with the elbow
flexed and forearm pronated. [8579]
Radial neuropathy
Supracondylar humeral fractures commonly occur after hyperextension of the elbow as a result of a fall onto an
outstretched arm. The radial nerve runs along the anterolateral aspect of the elbow and is the structure most likely
to be injured with anterolateral displacement of the proximal fracture fragment. The brachial artery runs with the
median nerve on the anteromedial aspect of the elbow and will usually be spared in these patients (eg, intact radial
pulse). [11855]
Scaphoid fracture
Fracture of the scaphoid bone may result from a fall on an outstretched hand and should be suspected if examination
shows tenderness in the anatomic snuff box. Scaphoid fracture can disrupt retrograde blood supply to the proximal
scaphoid, increasing risk of avascular necrosis. [8670]
Shoulder dislocation
Flattening of the deltoid muscle with acromial prominence after a shoulder injury suggests an anterior humerus
dislocation. This injury most commonly results from a blow to an externally rotated and abducted arm. There is
often associated axillary nerve injury, resulting in deltoid paralysis and loss of sensation over the lateral shoulder.
[1924]
Ulnar nerve neuropathy

The ulnar nerve can be injured at the medial epicondyle of the humerus ("funny bone") or in Guyon's canal near the
hook of the hamate and pisiform bone in the wrist. Patients often have sensory loss over the medial 1½ digits and
hypothenar eminence, and weakness on wrist flexion/adduction, finger abduction/adduction, and flexion of the
fourth/fifth digits. The hypothenar eminence may flatten due to muscle atrophy. [1634]
Upper extremity long bone fracture

The deep brachial (profunda brachii) artery and radial nerve run together along the posterior aspect of the
humerus. Midshaft fractures of the humerus risk injury to these structures. [1704]
The proximal humerus and glenohumeral joint receive their blood supply via the anterior and posterior circumflex
humeral arteries, which are branches of the axillary artery that form an anastomosis at the neck of the
humerus. Humeral neck fractures can disrupt this blood flow, leading to avascular necrosis of the humeral head.
[20010]
Wrist injury
Volar dislocation of the lunate from its normal position within the floor of the carpal tunnel can cause median nerve
compression and/or injury. Median nerve injury at the level of the carpal tunnel may result in weakness of thumb
abduction, flexion, and opposition. [16595]
Osgood schlatter disease

The quadriceps muscle group is connected to the patella, which is attached to the tibial tubercle by the patellar
ligament. Repetitive quadriceps contraction (eg, jumping) in adolescents can result in Osgood-Schlatter disease,
which is characterized by focal anterior knee pain and swelling due to chronic avulsion of the tibial tubercle. [11819]
Thoracic outlet syndrome

Thoracic outlet syndrome (TOS) is most often caused by compression of the brachial plexus as it passes through the
scalene triangle, the space bordered by the anterior and middle scalene muscles and the first rib. Symptoms typically
include upper extremity numbness, tingling, and weakness that worsen with repetitive overhead arm
movements. The presence of an anomalous cervical rib is a risk factor for TOS. [11778]
MISCELLANEOUS
Osgood schlatter disease

Repetitive traction at the tibial tubercle due to quadriceps contraction can lead to avulsion and fragmentation of the
tibial tubercle in skeletally immature children, causing Osgood-Schlatter disease. [19958]
NORMAL STRUCTURE AND FUNCTION OF THE MUSCULOSKELETAL SYSTEM
Abdominal wall muscles

The Valsalva maneuver increases vagal tone and can be used to abolish paroxysmal supraventricular tachycardia. The
rectus abdominis is the most important muscle in achieving the increased intraabdominal and intrathoracic pressure
of the Valsalva maneuver. [1730]
Brachial plexus
Dissection of the axillary lymph nodes can injure the long thoracic nerve. This results in weakness of the serratus
anterior muscle with winging of the scapula and impaired abduction of the shoulder past the horizontal position. [1812]
The latissimus dorsi is a large thoracolumbar muscle that originates from the iliac crest and lumbar fascia to the
spinous processes of T7-12 and lower ribs, and inserts at the bicipital groove of the humerus. It is innervated by the
thoracodorsal nerve. Primary functions include extension, adduction, and medial (internal) rotation of the humerus.
[11679]
Bursitis
Greater trochanteric pain syndrome is an overuse tendinopathy of the gluteus medius and gluteus minimus at their
insertion on the greater trochanter of the femur. Examination shows tenderness over the greater trochanter; pain is
reproduced by resisted hip abduction and internal rotation (when the hip is flexed). [20099]
Compartment syndrome
Acute compartment syndrome (ACS) is caused by increased pressure within fascial compartments of the limbs,
leading to impaired perfusion. ACS can cause severe pain, myonecrosis, and nerve injury. The anterior compartment
of the leg, which contains the deep peroneal (fibular) nerve, is the most common site of ACS. [11635]
Femoral neuropathy
Femoral nerve mononeuropathy can occur due to trauma; compression from a retroperitoneal hematoma or abscess,
or injury during surgery or childbirth. Findings include quadriceps weakness, decreased patellar reflex, and sensory
loss over the anterior and medial thigh and medial leg. [8671]
Hip muscle
Muscles used when sitting up from the supine position include the external abdominal obliques, the rectus
abdominis, and the hip flexors. The iliopsoas muscle is the most important of the hip flexors and includes the psoas
major, psoas minor, and iliacus. The rectus femoris, sartorius, tensor fascia lata, and the medial compartment of the
thigh also contribute to hip flexion. [7621]
Jersey finger
The flexor digitorum profundus tendon inserts onto the base of the distal phalanx and flexes the distal
interphalangeal (DIP) joint. It is susceptible to rupture when an actively flexed DIP joint is forcefully hyperextended.
[19719]
Median nerve injury

The brachial artery runs alongside the median and ulnar nerves in the medial bicipital groove of the upper
arm. Proximal to the elbow, the median and ulnar nerves diverge, and the brachial artery continues with the median
nerve through the cubital fossa. Injury to the median nerve at the cubital fossa frequently injures the brachial artery.
[18765]
Injections given in the superomedial quadrant of the buttock have a high risk of injuring the superior gluteal nerve,
resulting in gluteus medius weakness and Trendelenburg gait. The superolateral quadrant of the buttock is a
relatively safe site for intragluteal injections, although the anterolateral gluteal region is preferred. [1640]
Psoas abscess
The psoas muscle originates from the anterior surface of the transverse processes and lateral surface of the vertebral
bodies and functions primarily as a hip flexor. Psoas abscess may form due to direct spread of infection from an
adjacent structure (eg, vertebral bodies, appendix, hip joint) or from hematogenous seeding from a distant site. [1885]
Psoas abscess presents with fever, back or flank pain, an inguinal mass, and difficulty walking. Inflammation of the
psoas muscle leads to pain with extension at the hip (ie, psoas sign). Psoas abscess can develop due to
hematogenous or lymphatic seeding from a distant site, particularly in patients with diabetes mellitus, intravenous
drug use, and immunosuppression (eg, HIV infection). [8710]
Quadriceps muscle and tendon injuries

The rectus femoris, iliopsoas, and sartorius are the major hip flexors. Of these, only the rectus femoris and sartorius
also affect knee movement. The sartorius flexes the knee while the rectus femoris extends the knee. [19828]
Rotator cuff
The most commonly injured structure in rotator cuff syndrome is the tendon of the supraspinatus muscle. Because
the supraspinatus is an abductor of the humerus, injury to its tendon causes pain on abduction of the arm. [1733]
The rotator cuff muscles attach to the proximal humerus and move the arm at the shoulder. Infraspinatus and teres
minor are primarily responsible for external rotation. When one is torn, the other hypertrophies to compensate,
resulting in preserved strength in external rotation. [20101]
The supraspinatus muscle assists in abduction of the arm and stabilization of the glenohumeral joint. The
supraspinatus tendon is vulnerable to injury due to impingement between the acromion and the head of the
humerus. Supraspinatus tendinopathy is the most common cause of rotator cuff syndrome. [1732]
The rotator cuff muscles (supraspinatus, infraspinatus, teres minor, and subscapularis) all insert onto the humeral
head, allowing them to stabilize the shoulder joint and move the arm at the shoulder. An infraspinatus injury would
result in shoulder pain and weak, painful external rotation of the arm against resistance. [11776]
Sciatic neuropathy
The piriformis passes through the greater sciatic foramen and is involved with external hip rotation. Muscle injury or
hypertrophy can compress the sciatic nerve in the foramen, causing piriformis syndrome. [11727]
Tibial nerve injury

The tibial nerve may be injured at the level of the popliteal fossa due to deep penetrating trauma or knee
surgery. Patients typically have weakness on foot plantarflexion, foot inversion, and toe flexion, with sensory loss
over the sole. [1638]
SPINAL DISORDERS AND BACK PAIN
Radiculopathy
Motor and sensory deficits across multiple peripheral upper extremity nerves (eg, radial and median) indicate a lesion
in the brachial plexus proximal to the formation of the terminal branches. In the absence of a history of trauma or
malignancy, the most likely cause is nerve root compression due to cervical spondylosis (cervical radiculopathy).
[15553]
Spinal stenosis
Spinal stenosis occurs most commonly in the lumbar region and presents with posture-dependent lower extremity
pain, numbness/paresthesia, and weakness. The most common cause is degenerative arthritis of the spine, which
results in narrowing of the spinal canal due to intervertebral disc herniation, ligamentum flavum hypertrophy, and
osteophyte formation affecting the facet joints. [12073]
Spondylolysis
Fracture of the posterior vertebral arch often occurs at the pars interarticularis (ie, spondylolysis). Bilateral
disruption of the pars interarticularis can lead to anterior displacement of the vertebral body (ie, spondylolisthesis).
[20013]
Biochemistry
Biochemistry (General Principles)
AMINO ACIDS, PROTEINS, AND ENZYMES
Ehlers danlos syndrome

Ehlers-Danlos syndrome (EDS) is a heritable connective tissue disease associated with abnormal collagen
formation. EDS usually manifests clinically as overflexible (hypermobile) joints, overelastic (hyperelastic) skin, and
fragile tissue susceptible to bruising, wounding, and hemarthrosis. [1244]
Ehlers-Danlos syndrome is a group of rare hereditary disorders characterized by defective collagen synthesis. It can
be caused by procollagen peptidase deficiency, which results in impaired cleavage of terminal propeptides in the
extracellular space. Patients often have joint laxity, hyperextensible skin, and tissue fragility due to the formation of
soluble collagen that does not properly crosslink. [1245]
Enzyme kinetics
Competitive inhibitors compete with substrate for active binding sites on enzymes. Additional substrate is required
to achieve the same rate of reaction, increasing the measured value of the Michaelis constant (Km). Competitive
inhibitors do not affect enzyme function; therefore, maximal velocity (Vmax) is unchanged in their presence. [12066]
Homocysteine
Elevated levels of plasma homocysteine are an independent risk factor for thrombotic events. Homocysteine can be
metabolized to methionine via remethylation or to cystathionine via transsulfuration. Hyperhomocysteinemia is
most commonly due to genetic mutations in critical enzymes or deficiencies of vitamin B12, vitamin B6, and folate.
[788]
Homocystinuria is most commonly caused by a defect in cystathionine synthase, resulting in an inability to form
cysteine from homocysteine. Cysteine becomes essential in affected patients, and homocysteine buildup leads to
elevated methionine. Homocysteine is prothrombotic, resulting in premature thromboembolic events (eg,
atherosclerosis, acute coronary syndrome) in these patients. [1332]
Lysosomal storage disorder

Inclusion cell disease is a lysosomal storage disorder in which a defect in protein targeting prevents the
phosphorylation of mannose residues required to tag acid hydrolases for transport to lysosomes. Without these
lysosomal proteins, cellular debris cannot be degraded and therefore accumulates within lysosomes, forming
inclusion bodies characteristic of the disease. [11930]
Niacin deficiency
Hartnup disease is caused by impaired transport of neutral amino acids in the small intestine and proximal tubule of
the kidney. Symptoms include pellagra-like skin eruptions and cerebellar ataxia, which occur as a result of niacin
deficiency. The diagnosis can be confirmed through detection of excessive amounts of neutral amino acids in the
urine. [1334]
Organic acidemias
Propionyl-CoA is derived from the metabolism of valine, isoleucine, methionine, threonine, and odd-chain fatty
acids. Congenital deficiency of propionyl-CoA carboxylase, the enzyme responsible for the conversion of propionyl-
CoA to methylmalonyl-CoA, leads to the development of propionic acidemia. The condition presents with lethargy,
poor feeding, vomiting, and hypotonia 1-2 weeks after birth. [1340]
Phenylketonuria
Deficiency of the enzyme phenylalanine hydroxylase or its cofactor tetrahydrobiopterin causes accumulation of
phenylalanine in body fluids and the central nervous system. Homozygous infants are normal at birth but gradually
develop severe intellectual disability and seizures if left untreated. Hypopigmentation of the skin, hair, eyes, and
catecholaminergic brain nuclei is also frequently seen. [1483]
Dihydrobiopterin reductase deficiency results in impaired tetrahydrobiopterin (BH4) levels. BH4 is an important
cofactor for both phenylalanine hydroxylase and tyrosine hydroxylase. Although phenylalanine levels can be
corrected with dietary restriction, downstream deficiencies of dopamine, norepinephrine, epinephrine, and serotonin
lead to progressive neurologic deterioration. [1501]
Phenylketonuria (PKU) results from an inability to convert phenylalanine to tyrosine by the phenylalanine hydroxylase
system, making tyrosine an essential amino acid in these patients. Classic clinical features of untreated PKU include
intellectual disability, seizures, light pigmentation, and a "musty" odor. [1484]
Principles of cell biology

Cellular compartmentalization allows multiple biochemical processes to occur simultaneously at maximum
efficiency. Beta-oxidation of fatty acids, the TCA cycle, and the carboxylation of pyruvate (gluconeogenesis) all occur
within the mitochondria. The enzymes responsible for glycolysis, fatty acid synthesis, and the pentose phosphate
pathway reside in the cytosol. [1119]
Protein structure
Glycine is the most abundant amino acid in collagen. The triple helical conformation of collagen molecules occurs
due to the repetitive amino acid sequence within each alpha chain, in which glycine (Gly) occupies every third amino
acid position (Gly-X-Y). [1248]
Protein synthesis
Orotic aciduria is a rare autosomal recessive disorder of de novo pyrimidine synthesis that occurs due to a defect in
uridine 5'-monophosphate (UMP) synthase. Children typically present with physical and mental retardation,
megaloblastic anemia, and large amounts of urinary orotic acid. Uridine supplementation can improve symptoms as
uridine is converted to UMP via nucleoside kinases. [2066]
Pyridoxine
Transamination reactions typically occur between an amino acid and an α-keto acid. The amino group from the
amino acid is transferred to the α-keto acid, and the α-keto acid in turn becomes an amino acid. Pyridoxal phosphate
(active vitamin B6) serves as a cofactor in amino acid transamination and decarboxylation reactions. [1482]
Second messengers
After a ligand binds to a G protein-coupled receptor that activates phospholipase C, membrane phospholipids are
broken down into diacylglycerol (DAG) and inositol triphosphate (IP3). Protein kinase C is subsequently activated by
DAG and calcium; the latter is released from the endoplasmic reticulum under the influence of IP3. [995]
Tca cycle
Alanine is the major amino acid responsible for transferring nitrogen to the liver for disposal. During the catabolism
of proteins, amino groups are transferred to α-ketoglutarate to form glutamate. Glutamate is then processed in the
liver to form urea, the primary disposal form of nitrogen in humans. Free ammonia is also excreted into the urine by
the kidney for regulation of acid-base status. [1369]
Urea cycle
Arginase is a urea cycle enzyme that produces urea and ornithine from arginine. Arginase deficiency results in
progressive spastic diplegia, growth delay, and abnormal movements. Treatment includes an arginine-free, low-
protein diet. [1480]
Patients with urea cycle disorders typically have discrete episodes of vomiting, tachypnea, and confusion/coma
secondary to hyperammonemia (a metabolic emergency). Ornithine transcarbamylase deficiency is the most
common disorder of the urea cycle and is characterized by hyperammonemia and elevated urinary orotic acid. [1370]
Ornithine transport into mitochondria is necessary for proper function of the urea cycle, which is the major disposal
pathway for waste nitrogen generated by catabolism of amino acids. Urea cycle defects typically cause neurological
damage due to the accumulation of ammonia. Protein restriction improves this condition by reducing the amount of
amino acid turnover. [1372]
Vitamin C deficiency
The hydroxylation of proline and lysine residues in collagen helps it attain its maximum tensile strength. This process
occurs in the rough endoplasmic reticulum and requires vitamin C as a cofactor. Impaired collagen synthesis resulting
from vitamin C deficiency (scurvy) can lead to fragile vessels, predisposing to gingival bleeding, ecchymosis, and
petechia. [1247]
BIOENERGETICS AND CARBOHYDRATE METABOLISM
Fructose metabolism
Unlike hereditary fructose intolerance (aldolase B deficiency) and classic galactosemia (galactose-1-phosphate uridyl
transferase deficiency), essential fructosuria (fructokinase deficiency) is a benign disorder. Although affected patients
are asymptomatic, their urine will test positive for a reducing sugar due to the presence of unmetabolized fructose.
[1067]
Aldolase B deficiency causes hereditary fructose intolerance. This disease manifests after introduction of fructose
into the diet with vomiting and hypoglycemia about 20-30 minutes after fructose ingestion. These infants can
present with failure to thrive, jaundice, and hepatomegaly. [1069]
Essential fructosuria is a benign disorder of fructose metabolism caused by fructokinase deficiency. In patients with
essential fructosuria, some of the dietary fructose load is converted by hexokinase to fructose-6-phosphate, which
can then enter glycolysis; this pathway is not significant in normal individuals. [1070]
Aldolase B deficiency, or hereditary fructose intolerance, leads to accumulation of the toxic metabolite fructose-1-
phosphate. Patients have hypoglycemia and vomiting when fructose or sucrose is consumed. Treatment involves
strict removal of both carbohydrates from the diet. [1073]
G6PD deficiency
The pentose phosphate pathway consists of an oxidative (irreversible) branch and a nonoxidative (reversible) branch,
and each can function independently based on cellular requirements. Transketolase, an enzyme of the nonoxidative
branch, is responsible in part for the interconversion of ribose-5-phosphate (nucleotide precursor) and fructose-6-
phosphate (glycolytic intermediate). [1035]
Glucose-6-phosphate dehydrogenase (G6PD) is the rate-limiting enzyme of the pentose phosphate pathway. G6PD
deficiency is a common X-linked recessive disorder resulting in episodes of hemolytic anemia during times of
increased oxidative stress (eg, use of antimalarials/sulfonamide, infections). [1036]
Galactosemia
Lenticular accumulation of galactitol in the lenses of patients with galactosemia can cause osmotic damage and
development of cataracts. Cataracts may be the only manifestation of galactokinase deficiency. [1074]
Classic galactosemia results from deficiency of galactose-1-phosphate uridyl transferase. Clinical features include
vomiting, lethargy, jaundice, and Escherichia coli sepsis. Cessation of breastfeeding and switching to soy milk-based
formula is recommended. [1071]
Gluconeogenesis
Ethanol inhibits gluconeogenesis and can cause hypoglycemia once hepatic glycogen stores are depleted. [1866]
After 12-18 hours of fasting, gluconeogenesis becomes the principal source of blood glucose. Gluconeogenesis uses
many glycolytic enzymes, but hexokinase, phosphofructokinase, and pyruvate kinase need to be bypassed as they are
unidirectional. The initial steps of gluconeogenesis involve the conversion of pyruvate to oxaloacetate and
oxaloacetate to phosphoenolpyruvate by pyruvate carboxylase and phosphoenolpyruvate carboxykinase,
respectively. [997]
Acetyl-CoA stimulates gluconeogenesis by increasing the activity of pyruvate carboxylase when acetyl-CoA is
abundant. This regulatory step allows pyruvate to be shunted toward acetyl-CoA production when acetyl-CoA levels
are low, preventing the cell from becoming depleted of energy. [1034]
Glycogen storage disease
Myophosphorylase deficiency (McArdle disease, or glycogen storage disease type V) causes failure of muscle
glycogenolysis, resulting in decreased exercise tolerance, muscle pain, cramping, and myoglobinuria shortly after
initiating physical activity. [1032]
Glycogen debrancher deficiency (Cori disease) causes accumulation of glycogen with abnormally short outer chains
(limit dextrins) due to the inability to degrade branch points. Patients have hypoglycemia, ketoacidosis,
hepatomegaly, muscle weakness, and hypotonia. [1030]
Acid maltase (alpha-glucosidase) deficiency presents in early infancy with cardiomegaly, macroglossia, and profound
muscular hypotonia. Abnormal glycogen accumulation within lysosomal vesicles is seen on muscle biopsy. [1023]
Glycolysis
Under anaerobic conditions, NADH transfers electrons to pyruvate to form lactate and regenerate NAD+. NAD+ is
required to convert glyceraldehyde-3-phosphate to 1-3-bisphosphoglycerate in glycolysis. [1019]
Hyperphosphatemia
Glucose-6-phosphate dehydrogenase is the rate-limiting enzyme in the pentose phosphate pathway, the major
source of cellular NADPH. This molecule is necessary for reducing glutathione (protects red blood cells from oxidative
damage) and for the biosynthesis of cholesterol, fatty acids, and steroids. [1066]
Metabolic acidosis
Impaired intestinal blood flow (eg, acute mesenteric ischemia) creates an anaerobic environment that leads to an
elevated NADH/NAD+ ratio. This decreases activity of pyruvate dehydrogenase (converts pyruvate → acetyl-CoA)
while stimulating lactate dehydrogenase (converts pyruvate → lactate), shunting the metabolic fate of pyruvate
toward lactate production. Patients with significant tissue ischemia are therefore at risk of lactic acidosis. [996]
Niacin deficiency
Niacin is a precursor for nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate
(NADP), two important cofactors for many dehydrogenase and reductase enzymes. Niacin deficiency results in
pellagra (ie, diarrhea, dementia, and dermatitis). [12276]
Physical exercise
Synchronization of glycogen degradation with skeletal muscle contraction occurs due to release of sarcoplasmic
calcium following neuromuscular stimulation. Increased intracellular calcium causes activation of phosphorylase
kinase, stimulating glycogen phosphorylase to increase glycogenolysis. [1028]
Tca cycle
GTP is synthesized by succinyl-CoA synthetase during the conversion of succinyl-CoA to succinate in the citric acid
cycle. During gluconeogenesis, phosphoenolpyruvate carboxykinase uses GTP to synthesize phosphoenolpyruvate
from oxaloacetate. [1022]
Riboflavin is a precursor of the coenzymes FMN and FAD. FAD participates in the tricarboxylic acid cycle and electron
transport chain by acting as an electron acceptor for succinate dehydrogenase (complex II), which converts succinate
into fumarate. [1807]
Pyruvate dehydrogenase complex deficiency is an inherited inborn error of metabolism causing lactic acidosis and
neurologic defects. Patients are unable to convert pyruvate to acetyl-CoA, resulting in a shunting of pyruvate to lactic
acid. In these patients, metabolism of exclusively ketogenic amino acids (eg, lysine, leucine) can provide energy in the
form of acetyl-CoA without increasing lactate production. [998]
Thiamine deficiency
Decreased erythrocyte transketolase activity is seen with deficiency of thiamine (vitamin B1), which is a cofactor for
several enzymes (eg, pyruvate dehydrogenase) involved in glucose metabolism. Severe deficiency can lead to heart
failure (wet beriberi), which in infants may manifest as respiratory distress and feeding intolerance with cardiomegaly
and hepatomegaly. [107111]
CELL AND MOLECULAR BIOLOGY
Cell adhesion molecules

Adhesion of cells to the extracellular matrix involves integrin-mediated binding to fibronectin, collagen, and
laminin. Differential expression of integrin subtypes affects adhesion properties of individual cells, and has been
found to correlate with malignant behavior in a number of tumors. [1872]
Cell mediated immunity

Apoptosis can occur through either the intrinsic (mitochondria-mediated) pathway or the extrinsic (receptor-
initiated) pathway. Both pathways converge in the activation of caspases. Caspases are proteolytic enzymes that
cleave cellular proteins. [1756]
Cellular transports
Transport of glucose into the cells of most tissues occurs by means of facilitated diffusion. Glucose moves from areas
of high concentration to areas of low concentration with the help of transmembrane glucose transporter proteins
(GLUT). These carrier proteins are stereoselective and have preference for D-glucose. [1355]
Carrier-mediated transport includes facilitated diffusion and active transport. Movement of substrate across the cell
membrane by these mechanisms depends on the presence of carrier proteins that can become saturated at high
substrate concentrations. [1378]
Colorectal polyps and cancer

Regulation of the Ras-MAPK signal transduction pathway requires a balance between active (GTP-bound) and inactive
(GDP-bound) Ras proteins. RAS gene mutations, which result in constitutively activated Ras proteins, are implicated
in the development of malignant tumors. [790]
Gluconeogenesis
In a fasting state, glucagon and epinephrine bind to transmembrane receptors and prevent hypoglycemia by
increasing hepatic glycogenolysis and gluconeogenesis. Prolonged fasting increases the secretion of cortisol, a steroid
hormone that binds to an intracellular receptor and acts to increase transcription of enzymes involved in
gluconeogenesis, lipolysis, and proteolysis. [989]
Hormone receptor
DNA-binding proteins include transcription factors (Myc, CREB), steroid receptors (cortisol, aldosterone,
progesterone), thyroid hormone receptor, fat-soluble vitamin receptors (vitamin D, retinoic acid), and DNA
transcription and replication proteins. [2031]
Hypercalcemia
Calcium-sensing receptors are G protein–coupled receptors that regulate the secretion of parathyroid hormone in
response to changes in circulating calcium levels. Familial hypocalciuric hypercalcemia is a benign autosomal
dominant disorder caused by defective calcium-sensing receptors in the parathyroid gland and kidneys. [992]

Posttranslational modification of proteins is important for targeting proteins to the correct location. This step is
defective in I-cell disease, which is characterized by a lack of mannose residue phosphorylation, resulting in
inappropriate trafficking of acid hydrolases to the extracellular space instead of to lysosomes. [21501]
Mitochondrial disorders
Mitochondrial DNA (mtDNA) is the most common non-nuclear DNA found in eukaryotic cells. It resembles
prokaryotic DNA and is maternally derived. Mutations involving mtDNA (or nuclear DNA that codes for mitochondrial
proteins) can cause a variety of mitochondrial disorders, including Leigh syndrome and MELAS. [1473]
Protein structure
Integral membrane proteins contain transmembrane domains composed of alpha helices with hydrophobic amino
acid residues (eg, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, methionine, proline, glycine). These
transmembrane domains help anchor the protein to the phospholipid bilayer of the cell membrane. [1383]
Protein synthesis
The rough endoplasmic reticulum (RER) is covered with ribosomes and is involved in the transfer of proteins to the
cell membrane and extracellular space. The RER is well developed in protein-secreting cells. The smooth ER lacks
surface ribosomes and functions in lipid synthesis, carbohydrate metabolism, and detoxification of harmful
substances. [757]
Resting membrane potential and action potential

When a specific ion channel opens, the respective ions will flow across the membrane in a direction that brings the
resting membrane potential closer to that ion's equilibrium potential. [1381]
The resting membrane potential is the difference in the electrical charges across the cell membrane under steady-
state conditions. The ions that are most permeable to the cell membrane make the largest contribution to the
resting membrane potential. In general, a high potassium efflux and some sodium influx are responsible for the value
of the resting potential, which is typically about -70 mV. [1382]
Signal transduction
The phosphoinositol second messenger system begins with ligand-receptor binding and Gq-protein activation leading
to activation of phospholipase C (PLC). PLC then hydrolyzes phosphatidyl inositol bisphosphate and forms
diacylglycerol and inositol triphosphate (IP3). Finally, IP3 activates protein kinase C via an increase in intracellular
Ca2+. [1122]
Transcription
Zinc-finger motifs are composed of chains of amino acids bound together around a zinc atom via linkages with
cysteine and histidine residues. They recognize specific DNA sequences and are used by many transcription factors to
bind DNA and alter activity of target genes. Intracellular receptors that bind steroids, thyroid hormone, and fat-
soluble vitamins act directly as transcription factors and contain zinc-finger binding domains. [11950]
Ubiquitin proteasome pathway

Ubiquitin is a protein that undergoes ATP-dependent attachment to other proteins, labeling them for
degradation. These modified proteins enter the proteasome and are degraded into small peptides. Impairment of
the ubiquitin-proteasome system can contribute to the development of neurodegenerative disorders, including
Parkinson’ s and Alzheimer’ s diseases. [8385]
LIPID METABOLISM
Beta oxidation
Impaired beta-oxidation of fatty acids causes hypoglycemia after prolonged fasting and insufficient levels of ketone
bodies. Acyl-CoA dehydrogenase catalyzes the first step in the beta-oxidation pathway and is the most commonly
deficient enzyme. [1888]
Carnitine deficiency impairs fatty acid transport from the cytoplasm into mitochondria, preventing β-oxidation of
fatty acids into acetyl CoA. This leads to cardiac and skeletal myocyte injury (lack of ATP from citric acid cycle) and
impaired ketone body production by the liver during fasting periods. [1886]
Cytosolic acetyl-CoA carboxylase converts acetyl-CoA to malonyl-CoA during the rate-limiting step of de novo fatty
acid synthesis. Malonyl-CoA also inhibits the action of mitochondrial carnitine acyltransferase, thereby inhibiting
beta-oxidation of newly formed fatty acids. [11918]
MISCELLANEOUS
Chronic myeloid leukemia

Reverse transcription polymerase chain reaction (RT-PCR) is used to detect and quantify levels of mRNA in a
sample. It uses reverse transcription to create a complementary DNA template that is then amplified using the
standard PCR procedure. RT-PCR can be used to diagnose chronic myelogenous leukemia by identifying an mRNA
transcript containing both BCR and ABL exons in affected cells. [12278]
Folic acid deficiency

Reduced forms of folate serve as methyl group donors in the synthesis of methionine. Folate deficiency leads to
impaired methionine synthesis with accumulation of homocysteine, a precursor to methionine. Methylmalonic acid
metabolism is unaffected by folate deficiency. [107590]

Hurler syndrome is a mucopolysaccharidosis caused by a deficiency of alpha-L-iduronidase, which hydrolyzes
dermatan and heparan sulfate. Accumulation of these substances results in the characteristic features of intellectual
disability, coarse facial features, corneal clouding, and hepatosplenomegaly. Early death due to cardiac complications
(eg, myocardial infarction) is expected. [21503]
HYPERTENSION
Calcium channel blocker

Contraction initiation in cardiac and smooth muscle cells is dependent on extracellular calcium influx through L-type
calcium channels, which can be prevented by calcium channel blockers (eg, verapamil). Skeletal muscle is resistant to
calcium channel blockers, as calcium release by the sarcoplasmic reticulum is triggered by a mechanical interaction
between L-type and RyR calcium channels. [144]
Dilated cardiomyopathy
Thiamine deficiency causes beriberi and Wernicke-Korsakoff syndrome. Dry beriberi is characterized by symmetrical
peripheral neuropathy; wet beriberi includes the addition of high-output congestive heart failure. [1047]
Alkaptonuria
Alkaptonuria is an autosomal recessive disorder in which the lack of homogentisic acid dioxygenase blocks the
metabolism of tyrosine, leading to an accumulation of homogentisic acid. Clinical features include a black urine color
when exposed to air, a blue-black pigmentation on the face, and ochronotic arthropathy. [1502]
Homocystinuria
Homocystinuria is most commonly caused by cystathionine synthase deficiency. Affected individuals have marfanoid
habitus, ectopia lentis, and developmental delay. Significant morbidity and mortality are due primarily to
thromboembolism. Many patients with homocystinuria respond dramatically to pyridoxine (vitamin B6)
supplementation. [1504]
Maple syrup urine disease

Maple syrup urine disease classically presents within the first few days of life with irritability, dystonia, poor feeding,
and sweet-smelling urine. Dietary restriction of branched-chain amino acids (eg, leucine, isoleucine, valine) is the
mainstay of treatment. [1335]
Maple syrup urine disease (MSUD) is caused by a deficiency of branched-chain alpha-keto acid dehydrogenase, an
enzyme that requires several coenzymes (thiamine; lipoate; coenzymes A, FAD, NAD) to metabolize branched-chain
amino acids (BCAAs). Some patients with milder forms of MSUD improve with high-dose thiamine treatment. [1336]
Niemann pick
:In Niemann-Pick disease, sphingomyelinase deficiency causes accumulation of the lipid sphingomyelin. Clinical
features include hepatosplenomegaly, neurologic regression, and a cherry-red macular spot in infancy. [1991]
Niemann-Pick disease is an autosomal recessive disorder that has a much higher incidence in the Ashkenazi Jewish
population than in the general population. It is characterized by sphingomyelinase deficiency and sphingomyelin
(phospholipid) accumulation, which cause neurologic regression, hepatosplenomegaly, and retinal opacification (ie,
cherry-red macula). [1990]
Turner syndrome
Growth hormone binds to cell surface receptors, leading to intracellular activation of the JAK-STAT
pathway. Cytokines (eg, interferon) and hematopoietic growth factors (eg, erythropoietin, G-CSF) also use this
pathway. [1720]
DIABETES MELLITUS
Diabetes mellitus
Stress hyperglycemia is transiently elevated blood glucose levels in the context of severe illness (eg, sepsis, burns,
major hemorrhage) in patients without preexisting diabetes mellitus. Cortisol and catecholamines released in
response to severe metabolic stress act on the liver to increase glycogenolysis and gluconeogenesis. [19219]
Glucose transport protein (GLUT)-4 is an insulin-sensitive glucose transporter expressed in skeletal muscle cells and
adipocytes that translocates to the plasma membrane in response to increasing insulin levels. In contrast, GLUT-1, 2,
3, and 5 are always present on the plasma membrane and constitutively transport glucose in an insulin-independent
manner. [847]
Insulin is an anabolic hormone that acts via receptor tyrosine kinase signaling to increase the synthesis of glycogen,
proteins, fatty acids, and nucleic acids. Tyrosine kinase/phosphatidylinositol-3-kinase stimulation promotes glycogen
synthesis by activating protein phosphatase, an enzyme that dephosphorylates (activates) glycogen synthase. [1121]
In the polyol pathway, aldose reductase converts glucose into sorbitol, which is slowly metabolized into fructose by
sorbitol dehydrogenase. Chronic hyperglycemia overwhelms this pathway, causing intracellular sorbitol
accumulation and increased osmotic/oxidative stress. This accelerates cataract development in patients with
diabetes, and contributes to the pathogenesis of diabetic retinopathy, neuropathy, and nephropathy. [934]
Insulin release by pancreatic beta cells is stimulated by increased glucose metabolism and ATP
production. Glucokinase functions as a glucose sensor in pancreatic beta cells by controlling the rate of glucose entry
into the glycolytic pathway. Mutations in the glucokinase gene lead to a state in which higher glucose levels are
required to stimulate insulin secretion and are a cause of maturity-onset diabetes of the young. [1010]
In hyperglycemic states, aldose reductase converts glucose to sorbitol at a rate faster than sorbitol can be
metabolized. Sorbitol accumulates in certain cells such as lens cells, causing an influx of water and resulting in
osmotic cellular injury. Depletion of NADPH by aldose reductase also increases oxidative stress, which accelerates
development of cataracts and diabetic microvascular complications (eg, neuropathy, retinopathy). [846]
Fructose 2 6 biphosphate
Fructose 2,6-bisphosphate (F2,6BP) activates phosphofructokinase-1 (increasing glycolysis) and inhibits fructose 1,6-
bisphosphatase (decreasing gluconeogenesis). F2,6BP concentration is regulated by a bifunctional enzyme complex:
phosphofructokinase-2 increases F2,6BP levels in response to insulin, and fructose 2,6-bisphosphatase decreases
F2,6BP levels in response to glucagon. [1031]
Hypoglycemia
Phosphofructokinase-1 (PFK1) catalyzes the rate-limiting step in glycolysis, and the most potent stimulator of PFK1 is
fructose 2,6-bisphosphate. Insulin increases production of fructose 2,6-bisphosphate by phosphofructokinase-2
(PFK2), thereby stimulating glycolysis. [6692]
Second messengers
Protein kinase A is responsible for the intracellular effects of the G protein-mediated adenylate cyclase second
messenger system. Hormone receptors that use this system include the TSH, glucagon, and PTH receptors. [994]
ENDOCRINE TUMORS
Pheochromocytoma
Cortisol increases the conversion of norepinephrine to epinephrine in the adrenal medulla by increasing the
expression of phenylethanolamine-N-methyltransferase. [602]
Body fluid distribution

Volume contraction and expansion can be divided into isosmotic, hyposmotic, and hyperosmotic
states. Hyperosmotic volume contraction is caused by a loss of free water (with retention of electrolytes). It can
occur in patients with diabetes insipidus or as a result of decreased fluid intake/excessive sweating. [1379]
NORMAL STRUCTURE AND FUNCTION OF ENDOCRINE GLANDS
Gluconeogenesis
When glycogen stores are depleted during fasting, ketone bodies are produced in the liver and can be used as an
energy source in the mitochondria of peripheral tissues. The brain preferentially uses glucose, but will utilize ketones
for most of its energy needs during prolonged starvation. Erythrocytes lack mitochondria and are unable to use
ketones. [1887]
Steroid hormones
The initial step in the synthesis of steroid hormones is the conversion of cholesterol to pregnenolone in the
mitochondria. The remainder of steroidogenesis occurs in the smooth endoplasmic reticulum. Steroid-producing
cells contain a well-developed smooth endoplasmic reticulum. [2016]
OBESITY AND DYSLIPIDEMIA
Dyslipidemia
Familial dysbetalipoproteinemia (type III hyperlipoproteinemia) is an autosomal recessive disorder characterized by
elevated cholesterol and triglyceride levels. It is caused by defects in ApoE3 and ApoE4, leading to decreased
clearance of chylomicrons and VLDL remnants. Patients can develop eruptive and palmar xanthomas and premature
atherosclerosis. [2064]
Triglyceride metabolism
Hormone-sensitive lipase is found in adipose tissue, where it functions to drive the breakdown of stored triglycerides
into free fatty acids and glycerol. During times of starvation, this enzyme provides substrates for hepatic
gluconeogenesis and ketone body formation. [11917]
Glycerol produced by the degradation of triglycerides in adipose tissue can be used by glycerol kinase in the liver and
kidney to synthesize glucose during gluconeogenesis. [1889]
DISORDERS OF NUTRITION

Folate deficiency inhibits the synthesis of nucleic acids, particularly the formation of thymidine. This leads to
defective DNA synthesis and increased apoptosis affecting hemopoietic cells (megaloblastic anemia). Thymidine
supplementation bypasses the enzyme thymidylate synthase and can reduce erythroid cell apoptosis. [1847]
Niacin deficiency
Niacin (vitamin B3) can be synthesized endogenously from tryptophan and is an essential component of NAD and
NADP. A deficiency of this vitamin results in pellagra, which is characterized by dermatitis, diarrhea, and dementia.
[1064]
Obesity
Metabolism of 1 g of protein or carbohydrate produces 4 Calories of energy; metabolism of 1 g of fat produces 9
Calories. [755]
Leptin is a protein hormone produced by adipocytes in proportion to the quantity of fat stored. Leptin acts on the
arcuate nucleus of the hypothalamus to inhibit production of neuropeptide Y (decreasing appetite) and stimulate
production of alpha-MSH (increasing satiety). Mutations in the leptin gene or receptor result in hyperphagia and
profound obesity. [8425]
Tca cycle
Biotin acts as a CO2 carrier on the surface of carboxylase enzymes and is an essential cofactor for numerous
reactions, including the conversion of pyruvate to oxaloacetate and fatty acid metabolism. Excess ingestion of avidin,
found in egg whites, has been associated with biotin deficiency. This condition presents with mental status changes,
myalgias, anorexia, macular dermatitis, and lactic acidosis. [1063]
Vitamin C is a cofactor for the hydroxylation of proline and lysine during collagen synthesis, which is essential for
maximum tensile strength. Deficiency (scurvy) is characterized by periodontal disease, impaired wound healing,
vascular wall fragility (eg, perifollicular, subperiosteal hemorrhage), follicular hyperkeratosis, and corkscrew hairs.
[1061]

Vitamin B12 is obtained through the diet solely from animal sources, which places strict vegans at risk for dietary
deficiency. This deficiency takes years to develop due to the large hepatic vitamin B12 reserve, and presents with
megaloblastic anemia and potentially irreversible neurologic deficits (eg, paresthesia, weakness, ataxic gait). [1838]
Vitamin B12 deficiency often presents with megaloblastic anemia (impaired DNA synthesis) and neurologic deficits
(impaired myelin synthesis). Characteristic neurologic findings include subacute combined degeneration of the dorsal
columns and lateral corticospinal tract. Elevations in methylmalonic acid and homocysteine levels occur due to
decreased metabolism of these molecules. [64]
HEPATIC DISORDERS
Gallstone disease
Fibrate medications (eg, fenofibrate, gemfibrozil) inhibit cholesterol 7α-hydroxylase, which catalyzes the rate-limiting
step in the synthesis of bile acids. The reduced bile acid production results in decreased cholesterol solubility in bile
and favors the formation of cholesterol gallstones. [67]
Brown pigment gallstones are composed of calcium salts of unconjugated bilirubin and arise secondary to bacterial or
helminthic infection of the biliary tract. Beta-glucuronidase released by injured hepatocytes and bacteria hydrolyzes
bilirubin glucuronides to unconjugated bilirubin. The liver fluke Clonorchis sinensis has a high prevalence in East
Asian countries and is a common cause of pigment stones. [70]
Hepatic Encephalopathy
Hyperammonemia in advanced liver failure occurs as a direct result of the cirrhotic liver's inability to metabolize
nitrogenous waste products. Ammonia crosses the blood-brain barrier and causes excess glutamine to accumulate
within astrocytes. This decreases the amount of glutamine available for conversion to glutamate in the neurons,
resulting in disruption of excitatory neurotransmission. [8578]
Lactose intolerance
Secondary lactase deficiency can occur after inflammatory (eg, celiac disease) or infectious (eg, giardiasis) processes
damage the microvilli of the small intestines. Clinical presentation includes abdominal distension and cramping,
flatulence, and diarrhea. [1072]
Lynch syndrome
Lynch syndrome is an autosomal dominant disease caused by abnormal nucleotide mismatch repair. The mismatch
repair system involves several genes, including MSH2 and MLH1, which code for components of the human MutS and
MutL homologs. Mutations in these 2 genes account for around 90% of cases of Lynch syndrome. [2028]
Glycolysis
Dietary fructose is phosphorylated in the liver to F1P and is rapidly metabolized because it bypasses PFK-1, the major
rate-limiting enzyme of glycolysis. Other sugars (eg, glucose, galactose, mannose) enter glycolysis prior to PFK-1 and
as a result are metabolized more slowly. [1068]
Neonatal jaundice
Pathophysiology of benign neonatal hyperbilirubinemia involves increased bilirubin production and decreased
bilirubin conjugation as well as increased enterohepatic circulation. Indirect hyperbilirubinemia and jaundice typically
peak in the first few days of life and usually resolve without intervention. [21081]
Genetics (General Principles)
CLINICAL GENETICS
Genetic testing
Southern blotting is a technique used to identify DNA mutations. It involves restriction endonuclease digestion of
sample DNA, gel electrophoresis, and gene identification with a labeled DNA probe. [2034]
DNA STRUCTURE, REPLICATION, AND REPAIR
Transcription
Primase is a DNA-dependent RNA polymerase that incorporates short RNA primers into replicating DNA. [2017]
MISCELLANEOUS
Dna structure & function

Southwestern blotting is used to detect DNA-binding proteins such as transcription factors, nucleases, and histones.
[2044]
Hematology & Oncology
HEMOSTASIS AND THROMBOSIS
Vitamin k deficiency
Vitamin K is a cofactor for gamma-glutamyl carboxylase, an enzyme that activates coagulation factors II, VII, IX, and X
via posttranslational gamma carboxylation. Intestinal diseases associated with malabsorption (eg, inflammatory
bowel disease) are a risk factor for vitamin K deficiency, which typically presents with mucosal bleeding, bruising, and
prolonged PT and PTT (if severe). [106673]
MISCELLANEOUS
Genetic testing
Polymerase chain reaction is used to amplify small fragments of DNA (eg, genes, exons, noncoding regions) by
repeated replication. It requires primers that are complementary to the regions of DNA flanking the segment of
interest. Thermostable DNA polymerase, deoxynucleotide triphosphates, and a source DNA template strand are also
necessary. [2043]
NORMAL HEMATOLOGIC STRUCTURE AND FUNCTION
Fetal hemoglobin
Hemoglobin F (Hb F) is the predominant hemoglobin type in the second and third trimesters of pregnancy and during
the first few months after birth. Hb F consists of 2 alpha and 2 gamma protein subunits (α2γ2) and has a high affinity
for oxygen, which facilitates oxygen transport across the placenta to the fetus. Hb A (α2β2) is the major hemoglobin
in adults. [868]
Glycolysis
2,3-BPG decreases hemoglobin's affinity for oxygen. Therefore, in the presence of lower blood oxygen
concentrations, higher 2,3-BPG levels within erythrocytes enable increased oxygen delivery in the peripheral
tissues. 2,3-BPG is produced from 1,3-BPG by the enzyme bisphosphoglycerate mutase. This reaction bypasses an
ATP-generating step of glycolysis, causing no net gain in ATP. [1029]
Heme metabolism
Acute intermittent porphyria attacks are due to the accumulation of aminolevulinate (ALA) and porphobilinogen
(PBG), resulting from inherited PBG deaminase deficiency combined with ALA synthase induction (typically due to
certain medications, alcohol use, or a low-calorie diet). Management with glucose or hemin inhibits ALA synthase
activity. [1338]
Maturing erythrocytes lose their ability to synthesize heme when they lose their mitochondria, which are necessary
for the first and final 3 steps of heme synthesis. [1455]
Heme oxygenase converts heme to biliverdin, a pigment that causes the greenish color to develop in bruises several
days after an injury. [1456]
Hemoglobin properties
P50 refers to the partial pressure of oxygen at which hemoglobin is 50% saturated. Hemoglobins with high oxygen
affinity have a decreased P50 that is represented by a leftward shift of the oxygen dissociation curve. The reduced
ability to release oxygen within the peripheral tissues leads to renal hypoxia, increased erythropoietin synthesis, and
compensatory erythrocytosis. [1384]
The individual subunits of the hemoglobin molecule are structurally analogous to myoglobin. If separated, the
monomeric subunits will demonstrate a hyperbolic oxygen-dissociation curve similar to that of myoglobin. [1413]
A left shift of the hemoglobin oxygen dissociation curve indicates increased hemoglobin O2 affinity and can be caused
by increased pH, decreased 2,3-bisphosphoglycerate, and decreased temperature. Leftward shifts of the curve inhibit
the release of O2 within peripheral tissues. [1385]
2,3-bisphosphoglycerate (2,3-BPG) normally forms ionic bonds with the beta subunits of deoxygenated hemoglobin
A, facilitating oxygen release in the peripheral tissues. Mutations that result in loss of the 2,3-BPG binding pocket's
positive charge cause hemoglobin A to resemble fetal hemoglobin, which binds oxygen with a higher affinity due to
its inability to interact with 2,3-BPG. [1387]
PLATELET DISORDERS
Von willebrand disease

Following endothelial damage, von Willebrand factor (vWF) binds glycoprotein Ib receptors on platelets to mediate
platelet adherence. The ristocetin cofactor assay measures platelet agglutination via binding of glycoprotein Ib
receptors to vWF; it will be abnormal in vWF deficiency but will correct with the addition of normal (vWF-containing)
plasma. [346]
PRINCIPLES OF ONCOLOGY
Glycolysis
Rapidly dividing cells such as stem cells and cancer cells generate energy through anaerobic glycolysis (Warburg
effect). This pathway converts the majority of glucose to lactate despite the presence of adequate oxygen to run
oxidative phosphorylation. Therefore, cancer cells generally produce far more lactate than a normal terminally
differentiated cell. [22845]
RED BLOOD CELL DISORDERS
Carbon monoxide poisoning

Carbon monoxide binds heme iron in hemoglobin with an affinity much greater than oxygen, generating
carboxyhemoglobin. Remaining binding sites on carboxyhemoglobin have an increased affinity for oxygen that
causes the oxygen dissociation curve to shift to the left, impeding oxygen delivery to tissues. [1240]
Cyanide poisoning
Cyanide is a potent mitochondrial toxin that binds to the ferric ion in the heme center of cytochrome c oxidase. This
blocks the electron transport chain and uncouples oxidative phosphorylation. Hydroxocobalamin, an antidote for
cyanide poisoning, rapidly binds to cyanide and forms the nontoxic metabolite cyanocobalamin, which is excreted in
the urine. [1415]
G6PD deficiency
Glucose 6-phosphate dehydrogenase deficiency causes hemolytic anemia and jaundice secondary to increased
oxidative stress due to the lack of NADPH. Glutathione reductase deficiency has a similar clinical consequence as its
absence results in an inability to utilize NADPH to reduce glutathione. [1037]
Hemoglobin c disease
Hemoglobin C is caused by a missense mutation that results in a glutamate residue being substituted by lysine in the
beta globin chain. This results in an overall decrease in negative charge for the hemoglobin molecule. The speed of
hemoglobin movement during gel electrophoresis is hemoglobin A > hemoglobin S > hemoglobin C. [1470]
Methemoglobinemia
Methemoglobinemia causes dusky discoloration of the skin (similar to cyanosis), and because methemoglobin is
unable to carry oxygen, a state of functional anemia is induced. However, the blood partial pressure of oxygen will be
unchanged as it is a measure of oxygen dissolved in plasma and is unrelated to hemoglobin function. [1416]
Porphyria cutanea tarda

Enzyme deficiencies of the early steps in porphyrin synthesis cause neuropsychiatric manifestations without
photosensitivity, whereas late step derangements lead to photosensitivity. Photosensitivity manifests as vesicle and
blister formation on sun-exposed areas as well as edema, pruritus, pain, and erythema. [1337]
Pyridoxine
Vitamin B6 (pyridoxine) is a required cofactor for the enzyme 5-aminolevulinate synthase, which catalyzes the first,
rate-limiting step in porphyrin synthesis. Defects in this enzyme cause X-linked sideroblastic anemia. [107448]
Sickle cell
Homozygous sickle cell disease is marked by a point mutation in both beta globulin genes. This leads to the
generation of a new predominant hemoglobin called hemoglobin S (HbS), which polymerizes when
deoxygenated. Because hemoglobin F (HbF) prevents HbS polymerization, hydroxyurea is often administered to
increase HbF levels and reduce complications of the disease. [21415]
Hemoglobin S (HbS) contains valine in place of glutamic acid at the sixth amino acid position of the beta globin
chain. This promotes hydrophobic interaction among Hb molecules and results in HbS polymerization and
erythrocyte sickling. [1242]
Exertional dyspnea, pneumonia resulting in life-threatening acute chest syndrome, and recurrent abdominal and
bone pain are clinical features of sickle cell anemia. Sickle cell anemia results from a point mutation that causes
valine to substitute for glutamic acid in the sixth position of the b-globin chain of hemoglobin. [1905]
Hemoglobin S (HbS) aggregates in the deoxygenated state. HbS polymers form fibrous strands that reduce red blood
cell membrane flexibility and promote sickling. Sickling occurs under conditions associated with anoxia including low
pH and high levels of 2,3-bisphosphoglycerate. These inflexible erythrocytes predispose to microvascular occlusion
and microinfarcts. [1241]
Sideroblastic anemia
Isoniazid inhibits pyridoxine phosphokinase, leading to impaired activation of pyridoxine (vitamin B6). Pyridoxine is a
cofactor for δ-aminolevulinic acid synthase, the enzyme that catalyzes the rate-limiting step of heme
synthesis. Inhibition of this step can result in sideroblastic anemia. [11816]
Thalassemia
HbF contains γ-globin instead of β-globin. Patients with homozygotic β-thalassemia (β-thalassemia major) are
asymptomatic at birth due to the presence of γ-globins and HbF. Switching to HbA production and the cessation
of γ-globin synthesis precipitates the symptoms of β-thalassemia. [1243]
WHITE BLOOD CELL DISORDERS
Laboratory techniques
Fluorescence in situ hybridization (FISH) can identify specific chromosomal translocations, duplications, or deletions
using a single-stranded, complementary DNA segment that is tagged with a radiotracer. FISH is rapid, highly sensitive
and specific, and can be used on tissues with low mitotic rates. However, the targeted chromosomal abnormality
must be somewhat large in order to be identified. [15301]
Infectious Diseases
BACTERIAL INFECTIONS
Escherichia coli
During bacterial DNA replication, DNA polymerase I functions to remove RNA primers (via 5' to 3' exonuclease
activity) and replace them with DNA (via 5' to 3' polymerase activity). DNA polymerase I is the only bacterial DNA
polymerase that possesses 5' to 3' exonuclease activity. [1471]
MISCELLANEOUS
Vitamin C is a required cofactor for the hydroxylation of proline and lysine residues during collagen
synthesis. Vitamin C deficiency (scurvy), primarily seen in patients with malnutrition (eg, alcohol use disorder), leads
to capillary bleeding (eg, epistaxis), poor wound healing, follicular hyperkeratosis, and periodontal disease. [311]
Nervous System
Lesch Nyhan Syndrome

Lesch-Nyhan syndrome is an X-linked recessive disorder caused by a defect in hypoxanthine-guanine
phosphoribosyltransferase (HGPRT). This results in failure of the purine salvage pathway, leading to increased
degradation of hypoxanthine and guanine to uric acid. De novo purine synthesis must increase to replace the lost
bases, necessitating an increase in phosphoribosyl pyrophosphate (PRPP) amidotransferase activity. [2067]
Metabolic acidosis
Methylmalonic acidemia is an organic acidemia due to complete or partial deficiency of methylmalonyl-CoA
mutase. Complete deficiency classically presents with lethargy, vomiting, and tachypnea in a newborn. Laboratory
testing shows hyperammonemia, ketotic hypoglycemia, and metabolic acidosis. The diagnosis is confirmed by
elevated urine methylmalonic acid and propionic acid. [1341]
Phenylketonuria
Tetrahydrobiopterin (BH4) is a cofactor used by hydroxylase enzymes in the synthesis of tyrosine, dopamine, and
serotonin. Phenylketonuria can result from BH4 deficiency due to dihydropteridine reductase deficiency. Intellectual
disability is the hallmark of this condition and results in neurotransmitter (eg, serotonin) deficiency and
hyperphenylalanemia. Treatment involves a low phenylalanine diet and BH4 supplementation. [1500]
Spinal muscular atrophy

Small nuclear ribonucleoproteins (snRNPs) are important components of the spliceosome, a molecule which removes
introns from pre-mRNA during processing within the nucleus. Spinal muscular atrophy is a disorder caused by
mutations in the SMN1 gene, resulting in impaired assembly of snRNPs in lower motor neurons. Infants often have
flaccid paralysis due to degeneration of anterior horn cells in the spinal cord. [2036]
Tay sachs
Tay-Sachs disease is an autosomal recessive disorder caused by β-hexosaminidase A deficiency, which results in GM2
ganglioside accumulation in neuronal lysosomes. Key clinical features include progressive neurodegeneration (eg,
developmental regression), an exaggerated startle reflex, and a cherry-red macular spot. [8524]
Organophosphate poisoning
Organophosphates are cholinesterase inhibitors that are widely used as pesticides in agriculture. They inhibit the
breakdown of acetylcholine, leading to a state of cholinergic excess. Symptoms of organophosphate poisoning
include salivation, lacrimation, diaphoresis, bradycardia, and bronchospasm. [1998]
HEADACHE
Vitamin A
Signs of chronic vitamin A toxicity include benign intracranial hypertension (eg, headache, vomiting, papilledema), dry
skin, and hepatomegaly. Risk factors include excessive dietary intake (eg, egg, liver, kidney) or retinoid-containing
medications. [1048]
Thiamine deficiency
Chronic thiamine (vitamin B1) deficiency impairs glucose use, particularly in mammillary bodies, as seen in Wernicke
encephalopathy. This occurs due to decreased activity of the enzymes that use thiamine as a cofactor (eg,
transketolase). Low erythrocyte transketolase activity that increases after the addition of thiamine pyrophosphate is
diagnostic. [598]
Peroxisomal disorders
The buildup of very long chain and branched-chain (eg, phytanic) fatty acids due to impaired oxidation is the hallmark
of peroxisomal disorders (eg, Zellweger syndrome, adrenoleukodystrophy). Accumulation of these fatty acids in the
brain results in permanent neurologic dysfunction. [1120]
Poisoning & Environmental Exposure
ENVIRONMENTAL EXPOSURE
Lead poisoning
Young children who reside in homes built before 1978 are at significant risk for lead toxicity. Lead directly inhibits
ferrochelatase and δ-aminolevulinic acid (ALA) dehydratase, resulting in anemia, ALA accumulation, and elevated zinc
protoporphyrin levels. Neurotoxicity is also a significant long-term complication. [1454]
TOXICOLOGY
Mushroom poisoning
Amatoxins are found in a variety of poisonous mushrooms (eg, Amanita phalloides, known as death cap) and are
potent inhibitors of RNA polymerase II (halting mRNA synthesis). [8482]
Niacin toxicity
Niacin (vitamin B3) is the precursor for NAD and NADP. Niacin toxicity leads to increased prostaglandin production,
which causes cutaneous vasodilation, flushing, and pruritus that may be avoided by pretreating with nonsteroidal
anti-inflammatory drugs. [107167]
Respiratory physiology
The binding of O2 to hemoglobin increases the affinity for binding of subsequent O2 molecules (cooperative
binding). In the lungs, the binding of O2 to hemoglobin drives the release of H+ and CO2 from hemoglobin (Haldane
effect). In the peripheral tissues, high concentrations of CO2 and H+ facilitate O2 unloading from hemoglobin (Bohr
effect). [1386]
Alpha1 antitrypsin deficiency

The rubber-like properties of elastin are due to high content of nonpolar (hydrophobic) amino acids and extensive
cross-linking between elastin monomers facilitated by lysyl oxidase. Patients with alpha-1 antitrypsin deficiency can
develop early-onset, lower lobe–predominant emphysema due to excessive alveolar elastin degradation. [1249]
BONE METABOLISM
Vitamin D deficiency
Lack of vitamin D effect (eg, vitamin D deficiency, vitamin D receptor mutation) causes hypocalcemia due to
inadequate calcium absorption. The compensatory rise in parathyroid hormone (PTH) causes increased bone
resorption, renal calcium reabsorption, and renal phosphorus wasting. PTH also induces 1-alpha-hydroxylase activity,
leading to elevated 1,25-dihydroxyvitamin D levels. [22188]
FLUID, ELECTROLYTES, AND ACID-BASE
Metabolic acidosis
Acidosis stimulates renal ammoniagenesis, a process by which renal tubular epithelial cells metabolize glutamine to
glutamate, generating ammonium that is excreted in the urine and bicarbonate that is absorbed into the blood. This
process is responsible for the vast majority of renal acid excretion in chronic acidotic states. [11939]
Alkaptonuria
Alkaptonuria is an autosomal-recessive disorder caused by a deficiency of homogentisic acid dioxygenase, an enzyme
involved in tyrosine metabolism. Excess homogentisic acid causes diffuse blue-black deposits in connective
tissues. Adults have sclerae and ear cartilage hyperpigmentation along with osteoarthropathy of the spine and large
joints. [1503]
Gout
Gout occurs with increased frequency in patients with activating mutations involving phosphoribosyl pyrophosphate
synthetase due to increased production and degradation of purines. [2090]
Nonsteroidal anti-inflammatory drugs (NSAIDs) are first-line therapy for treating acute gouty arthritis. They inhibit
cyclooxygenase and exert a broad anti-inflammatory effect that includes inhibition of neutrophils. When NSAIDs are
contraindicated (eg, peptic ulcer disease, renal impairment), colchicine is useful in the acute management of gout as
it inhibits neutrophil chemotaxis and phagocytosis by preventing microtubule formation. [2091]
AUTOIMMUNE DISORDERS AND VASCULITIDES
Splice site mutation

Small nuclear RNA (snRNA) is synthesized by RNA polymerase II in the nucleus and complexes with specific proteins to
form small nuclear ribonucleoproteins (snRNPs). snRNPs are an essential component of spliceosomes, which remove
introns from pre-mRNA to form mature mRNA. Patients with systemic lupus erythematosus can have autoantibodies
directed against snRNPs (eg, anti-Smith antibody). [361]
Marfan syndrome
Marfan syndrome is due to a defect in fibrillin-1, an extracellular glycoprotein that acts as a scaffold for elastin. It is
abundant in the zonular fibers of the lens, periosteum, and aortic media. Aortic root dilation with dissection and
rupture is a common cause of death. [1250]
METABOLIC BONE DISORDERS
Osteoporosis
The receptor activator of nuclear factor kappa B (RANK)/RANK ligand (RANK-L) interaction is essential for the
formation and differentiation of osteoclasts. Osteoprotegerin blocks binding of RANK-L to RANK and reduces
formation of mature osteoclasts. Low estrogen states cause osteoporosis by decreasing osteoprotegerin production,
increasing RANK-L production, and increasing RANK expression in osteoclast precursors. [640]
Biostatistics
Biostatistics & Epidemiology
EPIDEMIOLOGY AND POPULATION HEALTH
Bias
Misclassification bias is an incorrect categorization of subjects regarding their exposure, outcome status, or both. In
case-control studies, recall bias usually leads to misclassification of the exposure status. [19732]
Epidemics and pandemics

The attack rate is the ratio of the number of people who contract an illness divided by the number of people who are
at risk of contracting that illness. [10443]
Morbidity and mortality rates

Case-fatality rate is calculated by dividing the number of fatal cases of a disease or condition by the total number of
people with that disease or condition. [1208]
Number Needed To Treat

The number needed to treat (NNT) is the number of patients who need to receive a treatment to prevent 1 additional
negative event. NNT is the inverse of the absolute risk reduction. The lower the NNT, the more effective the
treatment because fewer patients need be treated to prevent 1 additional negative event. [19511]
The number needed to treat (NNT) is the number of patients who need to be treated with a specific treatment to
avoid an additional negative event. NNT is the inverse of the absolute risk reduction. [19496]
Number needed to harm

The number needed to harm (NNH) is the number of people who must be exposed to a treatment to cause harm to 1
person who otherwise would not have been harmed. To calculate NNH, the absolute risk increase (ARI) between the
treatment and control groups must be known:
NNH = 1 / ARI [19741]
Odds ratio
The odds ratio (OR) is a measure of association calculated as: OR = (odds of exposure in cases) / (odds of exposure in
controls). For a contingency table in the standard format:
OR = (ad) / (bc) [19810]
The odds ratio (OR) is a measure of association calculated as: OR = (odds of exposure in cases) / (odds of exposure in
controls). For a correctly formatted contingency table:
OR = (ad) / (bc) [19806]
Prevalence and incidence

Unlike period prevalence, point prevalence considers only the number of disease cases that are active at a specific
point in time. [14853]
The cumulative incidence of a disease is the number of new cases of a disease over a specific period divided by the
total population at risk at the beginning of the study (ie, the proportion of at-risk individuals who contract the disease
over the specified period). [1270]
Prevention levels
Health promotion, according to the World Health Organization, is "the process of enabling people to increase control
over their health and its determinants, and thereby improve their health." [11105]
Principles and methods of epidemiology

There are three types of population pyramids: expansive (ie, young and growing population; high birth and mortality
rates), stationary (ie, stable population; declining birth rates and low mortality rates), and constrictive (ie, shrinking
population; significantly low birth and mortality rates). [20250]
Receiver Operating Characteristic

The accuracy of screening or diagnostic tests is quantified by the area under the ROC curve (AUC). The more accurate
the test is (ie, higher sensitivity and specificity), the closer the AUC value is to 1.0. Tests with higher AUCs are more
accurate than tests with lower AUCs. [19723]
Risk
The relative risk (RR) is the measure of association between the exposure to a risk factor or treatment and an
outcome or disease and is commonly used in cohort and experimental studies. The interpretation of the RR depends
on which groups are identified as exposed and unexposed. [19665]
Risk, rate, prevalence and incidence

Prevalence equals the incidence rate multiplied by the average disease duration. Changing disease prevalence in a
steady-state population with a constant incidence rate means that there is an additional factor affecting the duration
of the condition. A factor that prolongs disease duration (eg, improved quality of care) will increase disease
prevalence, as affected patients survive longer. [1187]
Prevalence is the actual number of existing cases (old and new) of disease, either at a particular point in time (point
prevalence), or during a period of time (period prevalence). Estimates of disease prevalence in a population are
affected by population dynamics. [19517]
Incident cases represent new cases diagnosed in a given period of time. Prevalent cases are the total number of
cases (both old and new) at a particular point in time. Any treatment that prolongs survival but does not cure the
disease will increase prevalence due to an increase in the number of afflicted (but still living) individuals over time.
[1171]
Incidence corresponds to the number of new cases of a disease in a certain population at risk over a given time
period. Prevalence is the total number of cases in the population over a given period. [10579]
Absolute risk reduction (ARR) describes the difference in risk between control and treatment groups. It is calculated
as follows:
ARR = (Riskcontrol − Risktreatment). [19410]
Sensitivity and specificity

The specificity of a test is its ability to correctly identify individuals without the disease. Specificity can be calculated
as follows:
specificity = true negatives / (true negatives + false positives). [19848]
The specificity of a test is its ability to correctly identify individuals without the disease. Specificity can be calculated
as follows:
Specificity = True negatives / (True negatives + False positives) [19431]
Sensitivity, specificity, NPV, PPV

False negatives (FN) refer to individuals who test negative for a disease but who truly have the disease. The number
of FN can be calculated using the number of individuals who truly have the disease and the sensitivity of the test, or
by using the formula:
FN = (1 − Sensitivity) × (Number of patients who truly have the disease). [19798]
Positive predictive value is the probability that an individual has a disease given a positive test. It is calculated as
follows:
true positives / (true positives + false positives). [19451]
Negative predictive value (NPV) is the probability that an individual does not have a disease given a negative test
result. It is equal to the number of individuals who do not have the disease and who have a negative test result (ie,
true negatives [TN]) divided by the total number of individuals with a negative test result (TN + false negatives [FN]):
NPV = TN / (TN + FN) [19445]
Predictive values change depending on the prevalence of disease in a study population. As disease prevalence
increases, the positive predictive value increases, and the negative predictive value decreases. [19468]
Statistical vs. clinical significance
The relative risk (RR) is a measure of association: RR < 1.0 indicates a lower risk of disease in the exposed group
relative to the nonexposed group; RR = 1.0 indicates no association between exposure and disease; and RR > 1.0
indicates a greater risk of disease in the exposed group relative to the nonexposed group. A confidence interval (CI)
that includes the null value for an RR (ie, RR = 1) is not statistically significant, and a CI that excludes the null value (ie,
RR = 1) is statistically significant. [19447]
Relative risk is the ratio of the probability of an event (eg, disease outcome) occurring in the exposed group (eg,
treatment group) versus the probability of the event occurring in the unexposed group (eg, control group). [19441]
MEASURES AND DISTRIBUTION OF DATA
Accuracy and precision

A precise tool is one that consistently provides very similar or the same value when measuring a fixed quantity. An
accurate tool is one that provides a measurement identical or similar to the actual value (as reflected in a gold
standard measurement). [1765]
Central tendency (mean, median, mode, outliers)

An outlier is defined as an extreme and unusual observed value in a dataset. It can affect measures of central
tendency (mean, median, mode) as well as measures of dispersion (standard deviation, variance). Modes tend to be
resistant to outliers. [1183]
The average (or mean) of a dataset of values is the sum of the values divided by the total number of values. [1209]
The median is the value that is located in the precise center of an ordered dataset. It separates the right half of the
data from the left half. [1281]
Measures of association
Relative risk reduction (RRR) measures how much a treatment reduces the risk of an unfavorable outcome. Two
methods to calculate it are:
RRR = (Riskcontrol – Risktreatment)/Riskcontrol
RRR = 1-relative risk[19309]
A cohort study is used to compare incidence of disease between exposed and nonexposed individuals. A common
measure of association in cohort studies is the relative risk. [19308]
Normal distribution
In a normal (bell-shaped) distribution curve, 68% of observations lie within 1 standard deviation (SD) of the mean,
95% of observations lie within 2 SDs of the mean, and 99.7% of observations lie within 3 SDs of the mean. [1172]
In a normal (bell-shaped) distribution, 68% of all values are within 1 standard deviation (SD) of the mean; 95% are
within 2 SD of the mean; and 99.7% are within 3 SD of the mean. [19022]
In a normal (bell-shaped) distribution: 68% of all values are within 1 standard deviation from the mean; 95% of all
values are within 2 standard deviations from the mean; 99.7% of all values are within 3 standard deviations from the
mean. [1201]
In general, in a positively skewed distribution, the mean is the most shifted in the positive direction (to the right),
followed by the median and then the mode. In such a situation, the median often reflects a central tendency better
than the mean does. [1282]
PROBABILITY AND PRINCIPLES OF TESTING
Hypothesis testing
Reducing the significance level alpha (α) in a study allows researchers to report any significant findings with greater
confidence. [19262]
The odds ratio (OR) is a measure of association used in case-control studies. It quantifies the relationship between an
exposure and a disease; its null value (ie, null hypothesis value) is always 1 (ie, OR = 1). [19619]
Normal distribution
In a normal (bell-shaped) distribution, 68% of all values are within 1 standard deviation (SD) of the mean; 95% are
within 2 SDs of the mean; and 99.7% are within 3 SDs of the mean. [19314]
P-value and confidence interval

The p-value is the probability of obtaining a result (ie, sample estimate) at least as large as the one observed when
the population value claimed in the null hypothesis is assumed to be true. A p-value <0.05 typically indicates that
results are statistically significant. [19621]
The power of a test is the probability of making the correct decision of rejecting a false H0 (ie, determining there is a
correlation when one truly exists). The p-value is the probability of obtaining the observed result (or results more
extreme) when H0 is assumed to be true; it is informally interpreted as the probability that the observed results are
due to chance. [19800]
Probability theory
If events are independent, the probability that all events will turn out the same is the product of the separate
probabilities for each event. The probability of at least 1 event turning out differently is given as 1 - P(all events being
the same). [1284]
The multiplication law of probability states that the probability of 2 or more independent events occurring together
can be calculated by multiplying the individual probabilities of each event. The multiplication law of probability can
be extended to complementary events (1 − probability of event) in the same manner. [12854]
Quantitative diagnostic tests

The cutoff value of a quantitative diagnostic test determines whether a given result is interpreted as positive or
negative. Lowering the cutoff point typically causes more patients with the disease to test positive, decreasing the
number of false negatives and increasing test sensitivity. Consequently, more patients without the disease will also
test positive, resulting in an increased number of false positives and decreased specificity. [1191]
Sensitivity and specificity

When undergoing diagnostic testing, patients with the disease can test positive (true positive, TP) or negative (false
negative, FN). The sensitivity of a test determines the proportion of patients that are correctly classified:
TP = (Sensitivity) x (Number of patients with the disease)
FN = (1-Sensitivity) x (Number of patients without the disease) [1229]
Specificity is the number of true negatives divided by the total number of subjects confirmed as not having the
disease. [1230]
The degree of overlap between the healthy and the diseased population curves limits the maximum combined
sensitivity and specificity of a quantitative diagnostic test. The degree to which sensitivity or specificity is affected
depends on the chosen cutoff value. [1285]
The sensitivity of a test refers to its ability to correctly identify those with the disease. A highly sensitive test should
always be considered over a highly specific test when screening for life-threatening diseases, where identification of
every person with the disease is important. [1300]
Sensitivity, specificity, NPV, PPV

Various parameters are used to evaluate the accuracy and usefulness of diagnostic tests. Positive and negative
predictive values are influenced by disease prevalence in the target population; sensitivity, specificity, and likelihood
ratios are not prevalence-dependent. [1271]
Sensitivity = true positives / (true positives + false negatives). Screening tests should have high sensitivity. [1177]
Positive and negative predictive values depend on disease prevalence in the tested population. The sensitivity and
specificity of a diagnostic test are not affected by disease prevalence. [1169]
The specificity of a test is its ability to correctly identify individuals without the disease. Specificity should be high in
confirmatory tests to decrease false positives. [1178]
Positive predictive value represents the probability of truly having a disease given a positive test result. It increases
with increasing disease prevalence and decreases with decreasing disease prevalence. [1232]
The positive predictive value (PPV) of a test answers the question: If the test result is positive, what is the probability
that a patient has the disease? PPV = true positives / (true positives + false positives). [1192]
Negative predictive value (NPV) represents the probability of not having a disease given a negative test result. NPV is
inversely proportional to the prevalence of a disease. When a patient has characteristics similar to the overall
population (eg, age, sex, risk factor status), the disease prevalence is a valid estimate of the pretest probability of
disease. [1233]
Negative predictive value (NPV) is the probability of not having a disease when the test result is negative. The NPV
will vary with the pretest probability of a disease. A patient with a high probability of having a disease will have a low
NPV with a negative test, but a patient with a low probability of having a disease will have a high NPV with a negative
test. [1190]
Statistical tests
The paired t-test compares the mean of 2 related groups. The test requires that a quantitative dependent variable
(ie, outcome) be evaluated in 2 related (ie, matched, paired) groups. [19239]
The two-sample t test is a statistical method commonly employed to compare the means of 2 groups of subjects.
[1283]
Validity And Reliability

A precise/reliable test is reproducible in that it gives similar results on repeat measurements. Reliability is maximal
when random error is minimal. [1278]
STUDY DESIGN AND INTERPRETATION
Bias
Lead-time bias occurs when a new test diagnoses a condition earlier than conventional studies, causing an apparent
increase in survival time despite no improvement in overall mortality. Long-term mortality rates, not survival times,
should be considered for measuring the effect of early screening and treatment. [1170]
The Hawthorne effect (observer effect) is the tendency of study subjects to change their behavior as a result of their
awareness that they are being studied. [1302]
Observer bias occurs when the investigator's evaluation is affected by preconceived expectations or prior knowledge,
typically leading to overestimation of the disease association or treatment effects. This type of bias can be reduced
by conducting a blinded study in which observers are unaware of study details and patient characteristics that could
unduly influence them. [1275]
Matching is used in case-control studies in order to control confounding. Matching variables should always be the
potential confounders of the study (eg, age, race). Cases and controls are then selected based on the matching
variables so that both groups have a similar distribution in accordance with the variables. [1189]
Recall bias results from study participants' inaccurate recall of past exposure and occurs most often in retrospective
studies such as case-control studies. People who have experienced an adverse event are more likely to recall risk
factors than those who have not experienced an adverse event. [1273]
The main purpose of blinding is to prevent patient or researcher expectancy from interfering with an outcome. [1301]
Case control studies

In a case-control study, potential participants are initially identified as cases or controls according to their disease
status. The frequency of past exposure to ≥1 risk factors of interest is then compared between cases and controls to
estimate the association between the risk factors and the outcomes. [19691]
Clinical trials
Phase IV (postmarketing) trials are conducted with drugs that have already been approved for use in order to study
long-term effectiveness and better characterize uncommon or delayed adverse effects. They are typically designed
to identify small treatment effects (ie, a high power study with large numbers of participants) in diverse patient
populations, and the results may be used to refine the use of drugs in clinical practice. [19398]
A phase I trial assesses the pharmacokinetics, pharmacodynamics, and safety profile (eg, adverse events, toxicity) of a
new treatment in humans. It is usually conducted on a small number of healthy subjects. [19388]
Phase II studies are small- to medium-sized trials conducted with participants having the condition of interest to
assess treatment efficacy, toxicity, adverse effects, and optimal dosing strategies; they are sometimes called pilot
studies. [19391]
Confounding, effect modification, bias, errors

Effect modification is present when the effect of the main exposure on the outcome is modified by the presence of
another variable. Effect modification is not a bias. [1279]
In prospective studies, disproportionate loss to follow-up between the exposed and unexposed groups creates the
potential for attrition bias, which is a form of selection bias. As a result, investigators generally try to achieve high
patient follow-up rates in prospective studies. [1188]
Confounding occurs when the exposure-disease relationship is muddled by the effect of an extraneous factor
associated with both exposure and disease. Confounding bias can result in the false association of an exposure with a
disease. [1173]
Correlation coefficient
The correlation coefficient (r) ranges from −1 to +1 and describes the strength and polarity of a linear association.
[1210]
The correlation coefficient (r) indicates whether there is a negative (r <0) or positive (r >0) linear relationship between
2 variables. The closer r is to −1 or +1, the stronger the linear relationship. A statistically significant (ie, p-value <
significance level) linear relationship between 2 variables does not imply that the relationship is causal. [19632]
Meta analysis
A meta-analysis groups results of several trials to increase statistical power and provide an overall pooled effect
estimate. [10672]
Number Needed To Treat

The number needed to harm (NNH) represents the number of people who must be treated before 1 additional
adverse event occurs. In order to calculate NNH, the absolute risk increase between the treatment and control
groups must be known: NNH = 1 / Absolute risk increase [1231]
The number needed to treat (NNT) is the number of patients that need to be treated with a medication to avoid an
additional negative outcome. NNT is calculated by dividing 1 by the absolute risk reduction (the difference between
the control and experimental group event rates). Lower NNT values represent more beneficial treatments. [1174]
Odds ratio
The odds ratio (OR) is a measure of the strength of an association between an exposure and an outcome. Specifically,
it represents the odds that an outcome occurred in the presence of a particular exposure compared with the odds
that the outcome occurred in the absence of that exposure. In a standard contingency table, OR = ad/bc. [1205]
A case-control study is used to compare the exposure status of people with the disease (ie, cases) to the exposure
status of people without the disease (ie, controls). The main measure of association is the odds ratio. [1277]
P-value and confidence interval

In a normal (bell-shaped) distribution, 68% of all values are within 1 standard deviation (SD) from the mean; 95% are
within 2 SD from the mean; and 99.7% are within 3 SD from the mean. [19105]
A result is considered statistically significant if the 95% confidence interval does not cross the null value, which
corresponds to a p-value <0.05. [1274]
Genome-wide association studies aim to identify associations between thousands of genetic variants and a
disease. Because of the increased risk of false-positive results when multiple tests are performed simultaneously, a
smaller genome-wide p-value is typically used. [18995]
The standard deviation reflects the spread of individual values in a normal distribution (ie, it measures the variability
of the observations within a single sample). The standard error of the mean reflects the variability of means (ie,
variance between the means of different samples) and helps estimate the true mean of the underlying population.
[1299]
Power and sample size

The power of a study indicates the probability of seeing a difference when there is one. The formula is Power = 1 – β,
where β is the type II error rate. [1204]
An inappropriately small sample will fail to identify important clinically significant differences as statistically
significant because of a lack of sufficient statistical power. [19734]
Power (1 − β) is the probability of rejecting a null hypothesis when it is truly false. It is typically set at 80% and
depends on sample size and difference between outcomes. [1272]
A study's power increases as its sample size increases. Therefore, the larger the sample, the greater the ability of a
study to detect a difference when one truly exists. [1303]
Randomized control trials

Randomization refers to the process of using random methods to assign subjects to experimental groups. Its purpose
is to make experimental groups as similar as possible (except for the treatment assignment) to ensure that any
difference observed between the groups is due exclusively to the treatment and not to other underlying factors.
[19315]
Intention-to-treat analysis includes each subject in their initial randomization group even if subjects stop the
intervention or shift to a different intervention. This approach tends to provide a conservative but more valid
estimate of the intervention effect in real-world scenarios (ie, clinical settings). [19406]
Risk
Risk is the probability of developing a disease over a certain period of time. To calculate this probability, divide the
number of affected subjects by the total number of subjects in the corresponding exposure group. [1185]
The relative risk (RR) represents the risk of an outcome in the exposed divided by the risk of that outcome in the
unexposed. Applying the correct formula for RR calculations depends on the proper formatting of a 2×2
(contingency) table. [1207]
The concept of accumulation effect can be applied to disease pathogenesis and exposure to risk
modifiers. Cumulative exposure to a risk factor or risk reducer must sometimes occur for prolonged periods before a
clinically significant effect is detected. [1280]
Absolute risk reduction = event rate in the control group − event rate in the treatment group. [1175]
The attributable risk percent (ARP) in the exposed represents the excess risk in the exposed population that can be
attributed to the risk factor. It can be easily derived from the relative risk (RR) using the formula:
ARPexposed = 100 × [(RR – 1)/RR] [1186]
Relative risk reduction = (absolute riskcontrol − absolute risktreatment) / absolute riskcontrol [1176]
Statistical tests
Correlation analysis is a statistical technique used to describe the strength and direction of a linear relationship
between 2 quantitative variables. [19199]
A regression analysis is a statistical technique used to describe the effect that 1 or more independent variables (eg,
exposures, risk factors), which may be quantitative or qualitative, can have on 1 quantitative dependent variable (ie,
outcome). [19197]
The analysis of variance test compares the means of ≥3 groups. The test requires a categorical independent variable
(ie, exposure) that is used to divide the study pool into ≥3 groups and a quantitative dependent variable (ie, outcome)
for which an average (eg, mean) can be calculated. [19195]
A t-test is used to compare the difference between the means of 2 groups. Analysis of variance (ANOVA) compares
the difference between the means of 2 or more groups. Results from a t-test and ANOVA test will be equivalent
when comparing the difference between the means of 2 groups. [8519]
A 2 × 2 table is normally used to record the presence or absence of exposure and disease in research. Rows and
columns represent the different levels for each categorical (ie, exposure and disease) variable. The chi-square test for
independence is used to evaluate the association between 2 categorical variables. [1184]
Study designs
In a cross-sectional study, exposure and outcome are measured simultaneously at a particular point in time
("snapshot study"). In other study designs, a certain time period separates the exposure from the outcome. [1276]
In a crossover study, subjects are randomly allocated to a sequence of 2 or more treatments given consecutively. A
washout (no treatment) period is often added between treatment intervals to limit the confounding effects of prior
treatment. [8422]
The unit of analysis in ecological studies is populations rather than individuals. [10570]
A randomized control trial is an experiment in which participants are randomly allocated to ≥2 groups to assess the
effect of specific interventions (eg, treatments). [14861]
A case series is a descriptive observational study design in which a group of patients with a similar diagnosis or
treatment is described at a point in time or followed over a certain period. This study design has no comparison
group; therefore, it cannot establish associations between risk factors (eg, treatments) and outcomes (eg, diseases).
[19247]
A case-control study is an observational study design; it begins with individuals who have the outcome ("cases") and
compares them with individuals who do not have the outcome ("controls") according to history of exposure to ≥1 risk
factors. [19742]
A case-control study is an observational study design; it begins with individuals who have the outcome (cases) and
compares them with individuals who do not have the outcome (controls) according to history of exposure to ≥1 risk
factors. [14857]
Prospective cohort studies are organized by selecting a group of individuals (i.e., cohort), determining their exposure
status, and then following them over time for development of the disease of interest. [1203]
In a cohort study, subjects should be initially selected from the population of interest (eg, T2DM) based on their
exposure status to a risk factor (eg, presence or absence of morbid obesity). Subjects are then monitored during the
study period for development of the outcome of interest (eg, diabetic nephropathy). [14859]
A case-control study is an observational study design; it begins with selecting individuals who have the outcome
("cases") and individuals who do not have the outcome ("controls") and then retrospectively comparing their history
of exposure to risk factors. [14862]
Selection of control subjects in case-control studies is intended to provide an accurate estimation of exposure
frequency among the nondiseased general population. Cases and controls should be selected based on disease
status, not exposure status. [1202]
DIABETES MELLITUS
Diabetes mellitus
Smoking cessation is by far the most effective preventive intervention in almost all patients, and this is especially true
in those with diabetes. [1013]
Prevalence and incidence

According to 2019 estimates, the most common cancers (excluding basal and squamous cell skin cancer) in women by
order of incidence are breast, lung, and colorectal cancer. In terms of mortality, lung cancer claims the most lives,
followed by breast and colorectal cancer. [1206]
Embryology
Atrial septal defect

The foramen ovale is patent in approximately 25% of normal adults. Although the foramen ovale usually remains
functionally closed, transient increases of right atrial pressure above left atrial pressure can produce a right-to-left
shunt, leading to paradoxical embolism of venous clots into the arterial circulation. [202]
Tetralogy of fallot
Tetralogy of Fallot results from anterior and cephalad deviation of the infundibular septum during embryologic
development, resulting in a malaligned ventricular septal defect (VSD) with an overriding aorta. As a result, the
patient has right ventricular outflow obstruction (resulting in a systolic murmur) and squats to increase the peripheral
systemic vascular resistance (afterload) and decrease right-to-left shunting across the VSD. [1705]
Transposition of the great vessels

An echocardiogram showing an aorta lying anterior to the pulmonary artery is diagnostic of transposition of the great
arteries (TGA). This life-threatening cyanotic condition results from failure of the fetal aorticopulmonary septum to
spiral normally during septation of the truncus arteriosus. [35]
Embryologic derivatives
The common carotid artery and the proximal portion of the internal carotid artery are derived from the third aortic
arch. The third aortic arch is associated with the third pharyngeal arch, which gives rise to the glossopharyngeal
nerve (CN IX), parts of the hyoid bone, and the stylopharyngeus muscle. [1750]
Fetal circulation
Immediately after birth, decreased pulmonary vascular resistance (due to oxygenation and ventilation of the lungs)
and increased systemic vascular resistance (due to removal of the placenta from circulation) reverse the flow across
the ductus arteriosus to left-to-right. Because the right ventricle no longer contributes to systemic blood flow, the
left ventricle becomes responsible for the total cardiac output. [19523]
The most highly oxygenated blood in the fetus is carried by the umbilical vein, which empties directly into the inferior
vena cava via the ductus venosus. [1833]
Dermatology
SKIN TUMORS AND TUMOR-LIKE LESIONS
Melanoma
The most common metastatic tumors to the brain are lung cancer, renal cancer, and melanoma. Melanoma is a
malignancy of melanocytes, which are embryologically derived from neural crest cells. [1960]

Cleft lip results when the maxillary prominence fails to fuse with the intermaxillary segment during the fifth-sixth
week of embryonic development. Cleft palate occurs when the palatine shelves fail to fuse with one another or with
the primary palate. Cleft lip and palate can occur together or in isolation. [1740]
Craniofacial anomalies
Pierre Robin is characterized as a sequence because the primary defect (hypoplasia of the mandibular prominence)
leads to a cascade of further malformations (ie, micrognathia, posteriorly displaced tongue, U-shaped cleft palate).
[19204]
Thyroglossal duct cyst

Thyroglossal duct cysts form from epithelial remnants of the thyroglossal duct along the path of thyroid
descent. They present as midline masses that rise with swallowing or tongue protrusion. [15028]
Digeorge syndrome
DiGeorge syndrome results from maldevelopment of the third (inferior parathyroid and thymus) and fourth (superior
parathyroid) pharyngeal/branchial pouches. Subsequent parathyroid and thymic hypoplasia results in hypocalcemia
and T cell deficiency. [543]
Ectopic thyroid
The thyroid gland is formed from evagination of the pharyngeal epithelium and descends to the lower neck. Due to
failure of migration, the thyroid can reside anywhere along the thyroglossal duct's usual path, including the tongue
(lingual thyroid). [763]
ENDOCRINE TUMORS
Pheochromocytoma
Neural crests are embryological structures composed of parallel strips of cells arising from the ectoderm at the
margin of the neural tube. Structures derived from neural crest cells include Schwann cells, odontoblasts,
melanocytes, enterochromaffin cells, spinal membranes, adrenal medulla/ganglia, laryngeal cartilage, and tracheal
cartilage. [771]
Amenorrhea
Patients with müllerian agenesis (ie, Mayer-Rokitansky-Küster-Hauser syndrome) have variable uterine development
and no upper vagina (eg, shortened vagina). These patients are 46,XX females with normal ovaries and secondary
sexual characteristics. [1809]
Mullerian anomaly
In females, the paramesonephric (Müllerian) ducts fuse to form the fallopian tubes, uterus, cervix, and upper
vagina. Disruptions in this process can lead to various Müllerian duct anomalies (eg, bicornuate uterus, uterine
didelphys). Renal anomalies are a common comorbidity. [1831]
Down syndrome
Down syndrome (trisomy 21) is associated with decreased maternal serum alpha-fetoprotein and increased nuchal
translucency. Duodenal atresia, the most commonly associated gastrointestinal complication, occurs due to failure of
duodenal recanalization in early gestation. [1824]
Hirschsprung's disease
Hirschsprung disease is a congenital disorder caused by failure of normal craniocaudal migration of neural crest cells
during embryogenesis. The affected colon segment (eg, rectosigmoid) lacks ganglionic innervation and is unable to
relax, resulting in obstruction with failure to pass meconium and bilious emesis. Forceful expulsion of gas and stool
on rectal examination is typical. [19675]
Hirschsprung disease is caused by abnormal migration of neural crest cells (ganglion cell precursors) during
embryogenesis. Because neural crest cells migrate caudally down the bowel from the foregut, the rectum is always
affected. [330]
Intestinal malrotation
Intestinal malrotation occurs when the midgut undergoes incomplete physiologic rotation in utero. A life-threatening
complication of malrotation is midgut volvulus, in which the small intestines twist around the superior mesenteric
artery due to the abnormally mobile mesenteric base. Patients have bilious emesis, and an upper gastrointestinal
series typically shows proximal small intestinal loops on the right side of the abdomen. [22149]
Intestinal malrotation occurs when the midgut undergoes incomplete counterclockwise rotation during embryologic
development. It often presents in the neonatal period with bilious emesis due to extrinsic duodenal compression by
Ladd bands or due to midgut volvulus with intestinal ischemia. [318]
Meckel diverticulum
Meckel diverticulum results from incomplete obliteration of the vitelline duct and usually presents with painless
lower gastrointestinal bleeding. 99mTc-pertechnetate localizes to heterotopic gastric mucosa that is often contained
within a Meckel diverticulum, and uptake in the periumbilical area or right lower quadrant is diagnostic. [329]
Meckel diverticulum, which classically causes painless hematochezia but can present with acute abdominal pain if
inflamed (ie, diverticulitis), is an anatomic connection between the ileum and umbilicus resulting from incomplete
obliteration of the vitelline duct. This congenital anomaly is a true diverticulum, consisting of all 3 layers of the
intestinal wall (mucosa, submucosa, and muscularis). [328]
The vitelline (omphalomesenteric) duct normally obliterates during early embryologic development. Incomplete
obliteration can result in a spectrum of anomalies, including vitelline duct cyst (ie, cyst connected by fibrous bands to
the ileum and umbilicus) and Meckel diverticulum. [322]
Tracheoesophageal fistula
Tracheoesophageal fistula with esophageal atresia results from failure of the primitive foregut to appropriately divide
into separate trachea and esophageal structures. Infants present shortly after birth with excessive secretions and
choking/cyanosis during feeds. [11962]
Umbilical hernia
Umbilical hernias are caused by a defect in the linea alba and present as protrusions at the umbilicus that are soft,
reducible, and benign. They can occur in isolation or in association with other conditions (eg, Down syndrome). [11803]
Diaphragmatic hernia
Congenital diaphragmatic hernia is caused by failure of the pleuroperitoneal folds to close. Immediately after birth,
newborns have respiratory distress, unilateral decreased breath sounds, and a scaphoid abdomen, with imaging
revealing thoracic bowel loops and mediastinal shift. [16900]
Intestinal atresia
Intestinal atresia involving bowel distal to the duodenum occurs due to vascular occlusion in utero. Superior
mesenteric artery occlusion results in ischemia of the jejunum and ileum, resulting in a blind-ending proximal jejunum
and a distal ileum that spirals around the ileocolic vessel that perfuses it (apple peel atresia). [319]
The spleen is a large, wedge-shaped lymphatic organ in the left posterosuperior aspect of the abdominal cavity. In
contrast to the endodermal origin of most other abdominal organs, the spleen is derived from the mesoderm in the
dorsal mesentery. Other mesoderm-derived tissues include muscle, bone, and kidney. [12198]
Spleen rupture
The spleen is of mesodermal origin (dorsal mesentery), but its blood supply (splenic artery) is derived from the major
foregut vessel, the celiac trunk. [2022]
Acute pancreatitis
Annular pancreas, or pancreatic tissue encircling the descending duodenum, is caused by failure of the ventral
pancreatic bud to properly migrate and fuse with the dorsal bud during the seventh and eighth week of fetal
development. Annular pancreas is usually asymptomatic but may present with duodenal obstruction or pancreatitis.
[438]
Hydrocele
Communicating hydroceles and indirect inguinal hernias are caused by an incomplete obliteration of the processus
vaginalis. The resultant connection between the scrotum and abdominal cavity can allow for fluid leakage
(hydrocele) or the passage of abdominal contents (indirect inguinal hernia). [419]
Hypospadia and epispadia
In males, incomplete fusion of the urethral (urogenital) folds results in hypospadias, an abnormal opening of the
urethra proximal to the glans penis along the ventral shaft of the penis. [1870]
Sexual differentiation
The SRY gene on the Y chromosome codes for the testes-determining factor, which differentiates the primitive
gonads into testes. Sertoli cells produce anti-Müllerian hormone, which causes regression of the Müllerian ducts and
suppresses female internal reproductive organ development. Leydig cells produce testosterone, differentiating
Wolffian ducts into internal male reproductive organs. Dihydrotestosterone is required for differentiation of the
external male genitalia. [1449]
MISCELLANEOUS
Nephron induction
Reciprocal induction is a type of signaling that occurs between two tissues that requires both be present to induce
normal development. Reciprocal induction occurs in development of the kidney (ie, between metanephric blastema
and ureteric bud) and the eye (ie, between optic vesicle and surface ectoderm). [107719]
Nervous System
Holoprosencephaly
A developmental field defect describes multiple malformations that occur secondary to an embryonic disturbance in
an adjoining group of cells. Holoprosencephaly is a developmental field defect characterized by a spectrum of fetal
anomalies due to incomplete division of the forebrain (prosencephalon). [252]
Holoprosencephaly is due to failure of the primitive forebrain (prosencephalon) to divide into the right and left
hemispheres, resulting in a spectrum of brain and midface abnormalities (eg, facial clefts, cyclopia). Trisomy 13 is the
most commonly associated etiology. [19964]
Neural tube defects

Neural tube defects most often occur when the neural folds fail to fuse in the region of the anterior or posterior
neuropores. Persistent communication between the spinal canal and the amniotic cavity allows leakage of alpha-
fetoprotein (AFP) and acetylcholinesterase (AChE) into the amnionic fluid, leading to elevated levels of AFP and AChE
that can be detected on amniocentesis. [502]
Failure of neural tube closure results in neural tube defects (eg, anencephaly, meningomyelocele). Folate deficiency
is the greatest risk factor, and medications that impair folate metabolism (eg, valproate) are associated with an
increased risk. [496]
Methotrexate and other folic acid antagonists adversely affect rapidly dividing cells (eg, epithelial cells, stem cells,
neural tube cells) by limiting the production of precursors essential to DNA synthesis and repair. If used in the first
trimester of pregnancy, these drugs can cause major congenital abnormalities (eg, cardiovascular abnormalities,
neural tube defects). [15637]
Neurofibromatosis
Neurofibromatosis type I (von Recklinghausen disease) is an autosomal dominant disorder caused by mutations in the
NF1 tumor suppressor gene. Patients characteristically develop numerous cutaneous neurofibromas comprised
mostly of Schwann cells, which are embryologically derived from the neural crest. [1534]
Pharyngeal arches
The development of derivatives of the first (eg, trigeminal nerve, mandible, maxilla, zygoma, incus, malleus) and
second (eg, facial nerve, stapes, styloid process, lesser horn of hyoid) pharyngeal arches can be disrupted in genetic
disorders (eg, Treacher-Collins syndrome), resulting in hypoplasia of the mandibular and zygomatic bones. [1691]
MISCELLANEOUS
Pituitary adenoma
All adult cells and tissues can be traced back to the 3 primary germ layers: ectoderm, mesoderm, and endoderm. The
ectoderm gives rise to the surface ectoderm, neural tube, and neural crest. [8702]
Neural tube defects

Defects in primary neurulation result in open neural tube defects, such as a myelomeningocele, in which the spinal
cord and meninges protrude through a vertebral arch defect. Findings typically include an elevated maternal alpha
fetoprotein and a complex cystic mass overlying the lower spine. [21405]
Neural tube defects

Open neural tube defects are a result of defects in primary neurulation (development and closure of the neural
tube). Defective anterior (rostral) neuropore closure (eg, anencephaly) results in failure of the skull and meninges to
form, allowing exposure of the developing brain to the destructive effects of amniotic fluid. [21404]
Closed spinal dysraphism (spina bifida occulta or closed neural tube defect) often presents with cutaneous
lumbosacral findings (eg, deep pit, hemangioma, tuft of hair) in the newborn period. Pathogenesis involves failure of
vertebral arch fusion, and imaging may suggest an underlying tethered cord (eg, low-lying conus medullaris,
thickened filum terminale). [21406]
Clubfoot
A deformation anomaly is caused by extrinsic forces on a developing fetus. Talipes equinovarus (ie, clubfoot), in
which the foot is rigidly flexed downward and inward, is a deformation anomaly involving an underdeveloped talus
bone. [20319]
Multiple gestation
Dizygotic twins occur due to fertilization of 2 oocytes by 2 different sperm, can be different sexes, and almost always
have 2 chorions and 2 amnions (eg, dichorionic/diamniotic). In contrast, monozygotic twins arise from the
fertilization of a single oocyte, are the same sex, and can be dichorionic/diamniotic (days 0-4),
monochorionic/diamniotic (days 4-8), monochorionic/monoamniotic (days 8-12), or monochorionic/monoamniotic
conjoined twins (> 13 days). [8406]
Polyhydramnios
Polyhydramnios (excessive accumulation of amniotic fluid) presents with increased abdominal circumference out of
proportion to gestational age. The etiology is decreased fetal swallowing or increased fetal urination. Fetal
anomalies associated with impaired swallowing include gastrointestinal obstruction (eg, duodenal, esophageal, or
intestinal atresia) and anencephaly. [337]
NORMAL PREGNANCY, CHILDBIRTH, AND PUERPERIUM
Normal pregnancy
β-hCG is produced by the syncytiotrophoblast after implantation, which generally occurs 6-7 days after fertilization at
the earliest. β-hCG typically is detectable in the maternal serum 8 days after fertilization, whereas it is detectable in
the urine 14 days after fertilization. [1772]
β-hCG secretion begins with blastocyst implantation and syncytiotrophoblast invasion. Syncytiotrophoblast cells arise
from the outer layer of the blastocyst (trophectoderm) and produce β-hCG, which maintains corpus luteum
progesterone production and supports the developing early pregnancy. [106637]
Diaphragmatic hernia
Congenital diaphragmatic hernia (herniation of abdominal contents into the thorax) causes pulmonary hypoplasia
from compression of the lungs. Neonates present with respiratory distress shortly after birth. X-ray findings include
thoracic bowel loops; the distal end of a feeding tube may also be seen within the thorax. [19780]
Neonatal respiratory distress syndrome

Both maternal and fetal cortisol help to accelerate fetal lung maturation by stimulating surfactant
production. Betamethasone or dexamethasone is administered to pregnant women at risk of premature delivery to
prevent neonatal respiratory distress syndrome. [550]
Fetal lung maturity correlates with increased quantity and improved quality of surfactant production. Amniotic fluid
markers of maturity during late gestation include increased phosphatidylcholine (lecithin) and phosphatidylglycerol
and low sphingomyelin. [800]
Congenital anomalies of kidney and urinary tract

The mature upper urinary tract is derived from the metanephros, which comprises the metanephric blastema and
metanephric diverticulum (ureteric bud). The metanephric blastema gives rise to the glomeruli, Bowman space,
proximal tubules, loop of Henle, and distal convoluted tubules. The ureteric bud becomes the collecting system of
the kidney (eg, collecting tubules and ducts, major and minor calyces, renal pelvis, ureters). [1736]
The urachus is a remnant of the allantois that connects the bladder with the yolk sac during fetal
development. Failure of the urachus to obliterate at birth results in a patent urachus, which can facilitate discharge
of urine from the umbilicus. [652]
Potter sequence
Potter sequence results from a urinary tract anomaly (eg, bilateral renal agenesis) that causes decreased fetal urine
output and severe oligohydramnios. The lack of amniotic fluid causes increased fetal compression (eg, flat facies,
limb deformity) and pulmonary hypoplasia (eg, neonatal hypoxia), which is the most common cause of death in
affected neonates. [1752]
A sequence is a predictable series of anatomically related anomalies that develop as a consequence of a known
primary anomaly (ie, cause-and-effect relationship). Oligohydramnios leads to fetal compression and the predictable
cascade of findings in Potter sequence (eg, pulmonary hypoplasia, facial and limb anomalies). [107624]
CYSTIC KIDNEY DISEASES
Polycystic kidney disease

Amniotic fluid is largely composed of fetal urine, and oligohydramnios (low fluid) is often associated with kidney
dysfunction in the fetus (eg, diffuse cysts seen in autosomal recessive polycystic kidney disease). Extrinsic fetal
compression from a low amniotic fluid level leads to Potter sequence with characteristic findings of flattened facies,
limb deformities, and pulmonary hypoplasia. [1915]
NEPHROLITHIASIS AND URINARY TRACT OBSTRUCTION
Urinary tract obstruction

Inadequate canalization of the ureter at the ureteropelvic junction (the connection site between the kidney and the
ureter) is the most common cause of severe, unilateral fetal hydronephrosis. [837]
Myasthenia gravis
Myasthenia gravis is associated with abnormalities of the thymus (eg, thymoma, thymic hyperplasia). The thymus
and inferior parathyroid glands arise from the third pharyngeal pouch. [756]
Genetics
Biochemistry (General Principles)
MISCELLANEOUS
Genetic testing
Northern blots detect target mRNA in a sample and can be used to assess the degree of gene transcription. [2042]
Biostatistics & Epidemiology
EPIDEMIOLOGY AND POPULATION HEALTH
Genetic inheritance
The Hardy-Weinberg equation can be used to estimate carrier frequency, disease frequency, and frequency of
different genotypes if at least 1 of these values is known. [11835]
Down syndrome
Down syndrome is most commonly caused by maternal meiotic nondisjunction, a process by which the fetus receives
3 full copies of chromosome 21. Dysmorphic features (eg, flat facial profile, protruding tongue, small ears, upslanting
palpebral fissures) and cardiac defects (eg, endocardial cushion defects) are characteristic. [882]
Turner syndrome
Aortic coarctation in a child/young adult presents with lower-extremity claudication (eg, pain and cramping with
exercise), blood pressure discrepancy between the upper and lower extremities, and delayed or diminished femoral
pulses. Turner syndrome (45,XO) is associated with coarctation of the aorta in up to 10% of cases. [30]
Turner syndrome is associated with congenital anomalies of the aorta, and the most common defect is a bicuspid
aortic valve. A nonstenotic bicuspid aortic valve can manifest as an early systolic, high-frequency click over the right
second interspace. Bicuspid aortic valves are at risk for stenosis, insufficiency, and infection. [8292]
Autosomal dominant mutations in the TTN gene, which encodes for the sarcomere protein titin, are the most
common cause of familial dilated cardiomyopathy. [13600]
Hypertrophic cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is an autosomal dominant genetic disorder caused by mutation in one of several
genes encoding the myocardial contractile proteins of the cardiac sarcomere. Mutations that affect cardiac myosin
binding protein C or cardiac beta-myosin heavy chain are responsible for the majority of identifiable mutations in
patients with HCM. [22793]
Dermatology
DISORDERS OF EPIDERMAL APPENDAGES
Hair loss
Androgenetic alopecia is the most common cause of hair loss in both males and females. The pattern and severity of
the baldness depend on both hormonal (circulating androgens) and genetic factors and vary between males and
females. The condition is polygenic with variable expressivity. [1725]

Most cases (approximately two-thirds) of cleft lip with cleft palate have multifactorial inheritance related to complex
interactions of polygenetic and environmental factors. [21127]
THYROID DISORDERS
Hypothyroidism
Congenital hypothyroidism is usually asymptomatic at birth. After maternal T4 wanes, infants develop constipation,
lethargy, hypotonia, macroglossia, an umbilical hernia, and a large anterior fontanelle. [1407]
Gestational trophoblastic disease

A complete hydatidiform mole usually results when an empty ovum is fertilized by a haploid sperm. Subsequent
duplication of the paternal genetic complement (23X) results in the characteristic 46,XX genotype. [1830]
Mosaicism
Mosaicism is defined as the presence of multiple, genetically different cell lines within the body. It can result from
several processes, including chromosomal nondisjunction or a mutation during the first stages of embryonic
development. Somatic mosaicism results in a mixture of normal and mutated somatic cells, often leading to a milder
form of the disease. [12225]
Turner syndrome
Streak ovaries, amenorrhea, and infertility are the gynecologic complications of Turner syndrome (TS). In addition,
patients with TS usually have short stature, webbed neck, shield chest, and low posterior hairline. Bicuspid aortic
valve is the most common cardiac comorbidity. [256]
Patients with Turner syndrome may have karyotype 45,X (complete monosomy), 45,X/46,XX (mosaicism), or 46,XX
(with partial deletion of one X chromosome). Complete monosomy X usually results from meiotic nondisjunction
during gametogenesis. [1810]
Turner syndrome (45,X) manifests in the neonate with lymphedema and cystic hygromas. Short stature, primary
amenorrhea, and aortic anomalies are the other important clinical features. [339]
Common manifestations of Turner syndrome include primary amenorrhea, short stature, a high arched palate, and
widely spaced nipples. Primary amenorrhea occurs in these patients due to in utero degeneration of the ovarian
follicles (gonadal dysgenesis). [7489]
In vitro fertilization using a donated ovum is the most promising means of achieving pregnancy in a woman with
Turner syndrome. Pregnancy can occasionally occur spontaneously in some patients with Turner syndrome, but the
risk of spontaneous abortion, Down syndrome and Turner syndrome are all increased in such cases. [12298]
Pancreatic cancer
Oncogenesis in pancreatic ductal adenocarcinoma is almost always due to an early activating mutation in the KRAS
oncogene, which produces a constitutively active protein that allows for uncontrolled proliferation of tumor cells.
[22178]
Genetics (General Principles)
CLINICAL GENETICS
Achondroplasia
Achondroplasia is an autosomal dominant (AD) disorder that results in a gain-of-function mutation in the FGFR3
gene. Most individuals affected by AD disorders are heterozygous and have a 50% chance of transmitting the
mutation to their offspring. [701]
Albinism
Locus heterogeneity describes when a similar phenotype is produced by mutations in different genetic loci (eg,
oculocutaneous albinism). [21307]
Aneuploidy
Common findings in Down syndrome include cognitive impairment, facial dysmorphism, and cardiac defects; 95% of
cases are caused by the presence of an extra chromosome 21 (trisomy) resulting from nondisjunction. Unbalanced
Robertsonian translocations or mosaicism are less common causes. [1610]
Cell cycle
Nondisjunction is the failure of chromosome pairs to separate properly during cell division. This could be due to a
failure of homologous chromosomes to separate in meiosis I or a failure of sister chromatids to separate during
meiosis II or mitosis. [8328]
Genetic inheritance
Autosomal recessive disorders affect 25% of offspring of asymptomatic heterozygous carrier parents. Classical
galactosemia is the most common and severe galactosemic disorder and presents within days of birth with jaundice,
vomiting, and hepatomegaly. [1728]
In X-linked recessive inheritance 1) affected males will always produce unaffected sons and carrier daughters, and 2)
carrier females have a 50% chance of producing affected sons and carrier daughters. G6PD deficiency follows this
inheritance pattern and causes acute hemolytic anemia in response to oxidant drugs. [1727]
Given phenotypically normal parents, the probability that a female sibling of a male affected by an X-linked recessive
disease will give birth to an affected child is 1/8. [1788]
The probability that an autosomal recessive disease will be transmitted to a child can be calculated based on the
maternal and paternal pedigrees. An unaffected individual (with unaffected parents) who has a sibling affected by an
autosomal recessive condition has a 2/3 chance of being a carrier for that condition. [1790]
The human leukocyte antigen (HLA) genes encode major histocompatibility complex (MHC) molecules that are key to
activation of the immune system in response to foreign (non-self) antigens. All the HLA genes are clustered together,
meaning that there is a low rate of crossover and that offspring essentially inherit 2 HLA haplotypes, one from each
parent. Therefore, the probability that a sibling would be an identical HLA match is 1/4. [14781]
Sickle cell anemia is an autosomal recessive disease that results in recurrent episodes of anemia, jaundice, and painful
swelling of the hands and feet. Offspring of carrier parents have a 25% chance of being affected and a 50% chance of
being heterozygous carriers, resulting in a 75% chance of inheriting at least one mutant allele. [11960]
Huntington disease
An increased number of trinucleotide repeats on the HTT gene is associated with Huntington disease. The larger the
number of repeats, the earlier the onset of the disease. Trinucleotide expansion occurs more frequently during
paternal transmission, causing a genetic phenomenon called anticipation. [633]
Linkage disequilibrium
Two allele loci are said to be in linkage disequilibrium when a pair of alleles are inherited together in the same
gamete (haplotype) more often or less often than would be expected given random pairing. This most often occurs
when the genes are in close physical proximity on the same chromosome. [8283]
Mitochondrial diseases are characterized by exclusively-maternal inheritance. The variable severity of these diseases
is explained by the random distribution of normal and mutated mitochondria between daughter cells during mitosis;
as a result, some cells may have completely healthy mitochondria, while other cells contain mitochondria affected by
genetic mutation (heteroplasmy). MELAS is a mitochondrial syndrome. [596]
Mitochondrial dysfunction frequently presents with myopathy, nervous system dysfunction, lactic acidosis, and
ragged red fibers on muscle biopsy. Mitochondrial myopathies due to mtDNA mutations are inherited solely in a
maternal fashion (ie, maternal inheritance). Therefore, transmission occurs only through affected females and never
through males. [11914]
Multifactorial inheritance
Many frequently encountered diseases (eg, hypertension, spinal bifida) display multifactorial inheritance, which
involves the complex interaction of numerous genetic and environmental factors to determine phenotypic
expression. Although the exact inheritance risk cannot be determined, the closer a relative is to the affected person,
the more likely the relative is to develop the trait. [11904]
Mutations
Duchenne muscular dystrophy presents with progressive proximal muscle weakness in young boys due to increased
muscle fiber degeneration. It is caused by frameshift mutations (most common) or nonsense mutations in the
dystrophin gene that lead to the formation of a truncated, defective protein. Nonsense mutations introduce
premature stop codons (eg, UAA, UAG, UGA) in the coding sequence of mRNA. [1487]
Deletion or addition of a number of bases that is not divisible by 3 in the coding region of a gene will cause a
frameshift mutation. Frameshift mutations alter the reading frame of the genetic code, resulting in the formation of
nonfunctional proteins. [1412]
Phenylketonuria
Intellectual disability, gait or posture abnormality, eczema, and a musty body odor in a toddler are signs of
phenylketonuria (PKU). Most infants with PKU are born to 2 heterozygous carrier parents. The probability that
heterozygous carrier parents will transmit an autosomal recessive disease such as PKU to a child is 1/4. [1789]
Pleiotropy
Pleiotropy describes instances where multiple phenotypic manifestations result from a single genetic mutation. Most
syndromic genetic illnesses exhibit pleiotropy. [1970]
DNA STRUCTURE, REPLICATION, AND REPAIR
Aging
Critical shortening in telomere length can signal for programmed cell death. Telomerase is a reverse transcriptase
(RNA-dependent DNA polymerase) that lengthens telomeres by adding TTAGGG repeats to the 3' end of
chromosomes. Stem cells have long telomeres due to high telomerase activity, allowing them to proliferate
indefinitely in a controlled manner. [1438]
Telomeres help maintain chromosomal integrity and are preserved in rapidly dividing cell lines (eg, epithelial cells,
lymphocytes, hematopoietic stem cells) by telomerase. Disorders involving telomerase function (eg, dyskeratosis
congenita) result in premature death of cells with high turnover, characteristically causing mucocutaneous changes
(eg, oral leukoplakia, dystrophic nails), bone marrow failure, and pulmonary fibrosis. [15340]
Brain tumors
Cancer cells alter expression of genes controlling survival and replication by histone modification, transcription factor
expression, and CpG methylation. Methylation of the CpG region adjacent to the MGMT gene, which produces an
enzyme that repairs DNA, makes tumor cells much more susceptible to alkylating chemotherapy. [21310]
Dna replication
DNA synthesis can occur only in the 5'→3' direction. Okazaki fragments are short stretches of newly synthesized DNA
that are separated by RNA primers. They are formed by the discontinuous synthesis of DNA on the lagging strand
during replication. [1418]
Bloom syndrome is a rare autosomal recessive condition caused by mutations in the BLM gene encoding helicase, an
enzyme that unwinds the double helix during DNA replication. Patients typically present with growth retardation,
facial anomalies, photosensitive skin rash, and immunodeficiency due to chromosomal instability and breakage. [1436]
All 3 prokaryotic DNA polymerases can remove mismatched nucleotides via their 3' to 5' exonuclease
("proofreading") activity. Only DNA polymerase I has 5' to 3' exonuclease activity, which is used to remove the RNA
primer synthesized by RNA primase. [1435]
DNA replication occurs in the 5'→3' direction on both strands. In contrast to the continuous synthesis of the leading
strand, lagging strand synthesis occurs discontinuously and is composed of short stretches of RNA primer plus newly
synthesized DNA segments (Okazaki fragments). As a result, lagging strand synthesis requires the repetitive action of
DNA primase and DNA ligase. [1419]
Multiple origins of replication make eukaryotic DNA replication quick and effective despite the large size and
complexity of the genome compared to that of prokaryotic organisms. [1437]
In prokaryotes, DNA polymerase I has 5' to 3' exonuclease activity in addition to 5' to 3' polymerase and 3' to 5'
exonuclease activities. This 5' to 3' exonuclease activity functions to remove the RNA primer created by RNA primase
and repair damaged DNA sequences. [1434]
Dna structure & function

Base excision repair is used to correct single-base DNA defects induced spontaneously or by exogenous chemicals. In
this process, glycosylases remove the defective base, and the corresponding empty sugar-phosphate site is cleaved
and removed by the action of endonuclease and lyase. DNA polymerase then replaces the missing nucleotide, and
ligase seals the final remaining nick. [1475]
X-inactivation occurs in genetically normal females and results in conversion of the inactivated X chromosome into
compact heterochromatin (Barr body). Heterochromatin is condensed chromatin composed of heavily methylated
DNA in tight association with deacetylated histones. It has a low level of transcriptional activity. In contrast,
euchromatin is loosely arranged and exhibits a high level of transcriptional activity. [1486]
Nucleosomes are composed of DNA wrapped around a core of 8 histone proteins (2 molecules each of H2A, H2B, H3,
and H4). H1 histone is located outside of this histone core and helps package nucleosomes into more compact
structures by binding and linking the DNA between adjacent nucleosomes. [1472]
Mutations
A frameshift mutation occurs with the deletion/addition of a number of bases not divisible by 3 in the coding region
of a gene. Frameshift mutations alter the reading frame of the genetic code, dramatically changing the protein
structure and often resulting in the formation of a premature stop codon. [2027]
Ovarian cancer
Telomerase is an RNA-dependent DNA polymerase that synthesizes telomeric DNA sequences that can replace the
lost chromosomal ends of the telomeres. Cancer cells typically contain increased telomerase activity to allow for
continued proliferation. [11912]
Radiation injury
Exposure to ionizing radiation, including therapeutic and palliative radiation therapy, induces DNA damage through
DNA double-strand fractures and the formation of oxygen free radicals. [1474]
Sunburn
Pyrimidine dimers are formed in DNA as a result of ultraviolet light exposure. They are recognized by a specific
endonuclease complex that initiates the process of repair by nicking the damaged strand on both sides of the
pyrimidine dimer. The damaged segment is then excised, and replacement DNA is synthesized by DNA polymerase.
[1477]
Xeroderma pigmentosum
Xeroderma pigmentosum develops due to a defect in nucleotide excision repair. This disease is characterized by
increased sensitivity to ultraviolet radiation and a high incidence of cutaneous malignancy. [883]
Xeroderma pigmentosum is an autosomal recessive disorder characterized by defective nucleotide excision repair
often caused by a deficiency in UV-specific endonuclease. Affected children usually have severe photosensitivity,
hyperpigmentation in sun-exposed areas, and a greatly increased risk for skin cancer. [1476]
GENE EXPRESSION AND REGULATION
Gene expression
Alternative splicing is a process where the exons of a gene are reconnected in multiple ways during post-
transcriptional processing. This creates different mRNA sequences and subsequently, different protein isoforms. It is
a normal phenomenon in eukaryotes that greatly increases the biodiversity of proteins encoded by the genome. [8276]
Myotonic Dystrophy
Anticipation describes an inherited condition that presents earlier and with more severe disease in successive
generations. In myotonic dystrophy, increasing length of the pathogenic trinucleotide repeat expansion accounts for
severe hypotonia in a neonate (congenital) and mild symptoms (eg, myotonia, facial weakness) in a parent (classic
[adult]). [22214]
Transcription
Homeobox genes encode DNA-binding transcription factors that play an important role in the segmental organization
of the embryo along the cranio-caudal axis. [2015]
Genomic imprinting refers to the phenomenon in which an offspring's genes are expressed in a parent-specific
manner. Genomic imprinting is caused by DNA methylation, an epigenetic process in which genes can be silenced by
attaching methyl groups to cytosine residues in the DNA molecule. [7791]
Alternative splicing is a process by which a single gene can code for various unique proteins by selectively including or
excluding different DNA coding regions (exons) into mature mRNA. [11913]
The TATA and CAAT boxes are promoters of transcription in eukaryotic cells and are located approximately 25 and 75
bases upstream from the transcription start site, respectively. They promote initiation of transcription by serving as
binding sites for transcription factors and RNA polymerase II. [12263]
Enhancers and silencers may be located upstream, downstream, or within a transcribed gene; these gene sequences
function to increase and decrease the rate of transcription, respectively. In contrast, promoter regions are typically
located 25 or 75 bases upstream from their associated genes and function to initiate transcription. [2025]
MISCELLANEOUS
Down syndrome
Trisomy 21 (which is diagnostic for Down syndrome) is detectable by cytogenetic karyotype analysis. Patients are at
increased risk of developing hematologic malignancies, including acute lymphoblastic leukemia and acute
megakaryoblastic leukemia. [1599]
PROTEIN SYNTHESIS
Genetic testing
Western blotting is used to identify proteins, Northern blotting identifies specific RNA sequences, and Southern
blotting identifies specific DNA sequences in an unknown sample. [2041]
RNA STRUCTURE, SYNTHESIS, AND PROCESSING
Genetic code
Translation of the mRNA template proceeds in the 5' to 3' direction. Because complementary sequences align in
antiparallel fashion, during translation tRNA anticodons will be oriented in the opposite 3' to 5' direction. Stop
codons (UAA, UAG, and UGA) halt protein synthesis by binding a release factor; they do not add amino acids to the
polypeptide chain. [1420]
Poly a tail
The poly-A tail is not transcribed from DNA; instead, it is added as a post-transcriptional modification downstream of
the consensus sequence (AAUAAA) located near the 3' end of the mRNA molecule. This tail protects mRNA from
degradation within the cytoplasm after it exits the nucleus. [2033]
Protein synthesis
The nucleolus is the site of ribosomal RNA (rRNA) transcription and ribosomal subunit assembly. RNA polymerase I
functions exclusively within the nucleolus to transcribe the 45S pre-rRNA gene, which codes for most of the rRNA
components (18S, 5.8S, and 28S rRNAs). [2039]
Rna structure & function

The 3' CCA tail of tRNA serves as the amino acid binding site. Aminoacyl tRNA synthetase is the enzyme responsible
for "loading" the appropriate amino acid to the 3' terminal hydroxyl group of the CCA tail. [1428]
The sequence of amino acids in a growing polypeptide chain is dictated by the interaction of the mRNA codon with
the tRNA anticodon. tRNA that is mischarged with the incorrect amino acid (and not corrected by aminoacyl-tRNA
synthetase proofreading) will incorporate the wrong amino acid into the growing polypeptide chain. [2032]
The nucleolus is a dense intranuclear body visible by light and electron microscopy that functions as the primary site
of ribosome synthesis and assembly. All ribosomal RNA except 5S rRNA is transcribed in the nucleolus. [1417]
The genetic code is considered "degenerate" because more than 1 codon can code for a particular amino acid. Some
of this degeneracy is explained by the wobble hypothesis, which states that the first 2 nucleotide positions on the
mRNA codon require traditional (Watson-Crick) base pairing, whereas the third "wobble" nucleotide position may
undergo less stringent (nontraditional) base pairing. [1424]
When mRNA is first transcribed from DNA, it is in an unprocessed form called pre-mRNA or heterogeneous nuclear
mRNA (hnRNA). Several processing steps are required before finalized mRNA molecules can leave the nucleus,
including 5'-capping, poly A tail addition, and intron splicing. Cytoplasmic P bodies play an important role in mRNA
translation regulation and mRNA degradation. [2035]
Splice site mutation

Splicing is performed by spliceosomes, which remove introns containing GU at the 5' splice site and AG at the 3' splice
site. Splice site mutations may result in inappropriate removal of exons and retention of introns, leading to the
formation of dysfunctional proteins. [2038]
Transcription
The TATA box is a promoter region that binds transcription factors and RNA polymerase II during the initiation of
transcription. It is located approximately 25 bases upstream from the beginning of the coding region. [2030]
Translation
Transfer RNA (tRNA) is a small, noncoding form of RNA that contains chemically modified bases (eg, dihydrouridine,
ribothymidine, pseudouridine). tRNA has a CCA sequence at its 3'-end that is used as a recognition sequence by
proteins. The 3' terminal hydroxyl group of the CCA tail serves as the amino acid binding site. [2037]
Releasing factors recognize stop codons (eg, UAA, UAG, and UGA) and terminate protein synthesis. They facilitate
release of the polypeptide chain from the ribosome and dissolution of the ribosome-mRNA complex. [2029]
Short non-coding RNA sequences (eg, microRNA and small interfering RNA) induce posttranscriptional gene silencing
by base-pairing with complementary sequences within target mRNA molecules. [11595]
MISCELLANEOUS
Tuberous sclerosis
Tuberous sclerosis complex is a neurocutaneous disorder in which enhanced mTOR signaling due to defective tuberin-
hamartin complex results in uncontrolled cellular proliferation and tumor formation (eg, subependymal nodules).
[15237]
Bone marrow transplantation

Patients who require stem cell transplantation due to a congenital genomic disease typically receive matched
unrelated donor cells because they will have matched human leukocyte antigen alleles but will not have the genomic
mutation that caused the condition. [20769]
Sickle cell
Sickle cell anemia is an autosomal recessive hemoglobinopathy. In order for a child to have sickle cell disease, both
parents must be carriers. Hemoglobin electrophoresis can be used to determine the carrier status of a prospective
parent who has no history of sickle cell anemia. [2040]
Sickle cell disease is the result of a missense mutation that causes valine to replace glutamic acid at position 6 in the
hemoglobin beta-globin chain. RNA contains the pyrimidine base uracil, whereas DNA contains the base thymidine.
[12019]
Thalassemia
The Kozak consensus sequence occurs on eukaryotic mRNA and helps initiate protein translation by identifying the
proper methionine start codon (AUG). [2086]
β thalassemia results in hypochromic, microcytic anemia due to decreased β globin chain synthesis. Unpaired α
chains precipitate within red cells and cause membrane damage, leading to ineffective erythropoiesis and hemolysis.
[2087]
Infectious Diseases
VIRAL INFECTIONS
Viral genetics
Viruses with segmented genomes (eg, orthomyxoviruses, rotaviruses) are capable of genetic shifts through
reassortment. Reassortment (genetic shift) involves exchange of entire genomic segments, a far more dramatic
process than the point mutations responsible for genetic drift. [1469]
Cystic fibrosis
CFTR gene mutations are the most common cause of congenital bilateral absence of the vas deferens
(CBAVD). Patients with CBAVD have azoospermia and infertility but normal levels of FSH, LH, and
testosterone. Elevated sweat chloride levels are diagnostic of cystic fibrosis. [807]
Klinefelter syndrome
47,XXY is the most common genotype causing Klinefelter syndrome. Patients present with tall stature; small, firm
testes; azoospermia; and gynecomastia. Mild intellectual disability is seen in some patients, and the severity
generally increases with each additional X chromosome. [343]
MISCELLANEOUS
Digeorge syndrome
Chromosome 22q11.2 microdeletion results in DiGeorge syndrome (cardiac anomalies, hypoplastic or absent thymus,
and hypocalcemia) and velocardiofacial syndrome (cleft palate, cardiac anomalies, dysmorphic facies). Fluorescence
in situ hybridization is the "gold standard" for detecting a microdeletion. [34]
Myotonic Dystrophy
Myotonic dystrophy is an autosomal dominant condition caused by a trinucleotide repeat expansion; successive
generations typically have an increased number of repeats, resulting in earlier and more severe disease (ie,
anticipation). In children, cognitive/behavioral issues may be the initial findings before development of muscle
weakness and myotonia. [7583]
Trisomy 13
Patau syndrome (trisomy 13) usually occurs secondary to meiotic nondisjunction in mothers of advanced maternal
age. Key physical findings reflect defective prechordal mesoderm fusion resulting in midline defects (eg,
holoprosencephaly, microphthalmia, cleft lip/palate, omphalocele) as well as polydactyly and cutis aplasia. [1822]
Trisomy 18
Trisomy 18, or Edwards syndrome, is most commonly the result of meiotic nondisjunction due to advanced maternal
age. Key findings include fetal growth retardation, hypertonia (clenched hands with overlapping fingers), rocker
bottom feet, and cardiac/gastrointestinal/renal defects. [1823]
Nervous System
Down syndrome
Patients with trisomy 21 (Down syndrome) have 3 copies of the amyloid precursor protein gene located on
chromosome 21. This increases amyloid-beta accumulation in the brain, placing these patients at high risk for
developing early-onset Alzheimer disease. [590]
Fragile x syndrome
Fragile X syndrome, an X-linked disorder, is the most common cause of inherited intellectual disability. The
pathogenesis involves an unstable expansion of trinucleotide repeats (CGG) in the fragile X mental retardation 1
(FMR1) gene. Key physical findings include dysmorphic facial features (eg, large jaw, protruding ears, long face) and
macroorchidism. [344]
Fragile X syndrome is caused by an increased number of CGG trinucleotide repeats on the fragile X mental retardation
1 (FMR1) gene on the long arm of the X chromosome. This leads to hypermethylation and inactivation of FMR1. [1421]
Fragile X syndrome is an X-linked disorder that presents with a long, narrow face, a prominent chin and forehead, and
large testes. Patients often have developmental delay and neuropsychiatric findings that overlap with anxiety
disorders, autism, and attention deficit-hyperactivity disorder. [1808]
Neurofibromatosis
Neurofibromatosis type 1 is a single-gene autosomal-dominant disorder. It occurs due to mutation of the NF1 gene
located on chromosome 17. Café-au-lait spots, multiple neurofibromas, and Lisch nodules are the most common
symptoms. [1307]
Alzheimer disease
Early-onset familial Alzheimer disease is associated with three gene mutations: APP (chromosome 21), presenilin 1
and presenilin 2. Late-onset familial Alzheimer disease is associated with apolipoprotein E4 genotype. [591]
Huntington disease
Hypo-acetylated histones bind tightly to DNA and prevent transcription of genes in their associated
regions. Alteration of gene expression in Huntington disease occurs in part due to deacetylation of histones. This
prevents the transcription of certain genes that code for neurotrophic factors, contributing to neuronal cell death.
[840]
"Red ragged" muscle fibers are seen in mitochondrial diseases. Muscle fibers have this appearance because
abnormal mitochondria accumulate under the sarcolemma. Mitochondrial diseases show maternal inheritance. [357]
Down syndrome
Unbalanced Robertsonian translocations account for a minority of Down syndrome cases. Karyotyping shows 46
chromosomes with a translocation between 2 acrocentric nonhomologous chromosomes [eg, 46, XX, t(14;21)]. [1825]
Down syndrome is the most common chromosomal anomaly. It is associated with low levels of maternal serum
alpha-fetoprotein (AFP) and estriol, while β-hCG and inhibin A levels are increased. Elevated AFP levels are seen in
multiple gestation, open neural tube defects, and abdominal wall defects. [312]
Primary oocytes are completely developed in female embryos by the fifth month of gestation, at which point they are
arrested in prophase of meiosis I. Normal menstrual cycle hormones stimulate the primary oocyte to resume
differentiation. Prior to fertilization, secondary oocytes are arrested in metaphase of meiosis II. [1688]
Cystic fibrosis
ΔF508 is the most common mutation in the cystic fibrosis transmembrane regulator (CFTR) protein in patients with
cystic fibrosis. This mutation leads to protein misfolding and failure of glycosylation, followed by proteasome-
mediated degradation and significantly decreased number of transmembrane CFTR proteins. [805]
Cystic fibrosis (CF) is most commonly due to a 3-base pair deletion in the CF transmembrane conductance regulator
(CFTR) gene at amino acid position 508 (ΔF508). This mutation impairs post-translational processing of CFTR,
resulting in shunting of CFTR toward the proteasome, with complete absence of the protein on the cell
surface. Elevated sweat chloride concentrations are found in most patients with CF. [802]
NEOPLASMS OF THE KIDNEYS AND URINARY TRACT
Renal cell carcinoma

Sporadic and hereditary (associated with von Hippel-Lindau disease) renal cell carcinomas are associated with
mutations involving the VHL gene on chromosome 3p. The VHL gene is a tumor suppressor that inhibits hypoxia-
inducible factors; mutations lead to constitutive activation of these proteins, resulting in the activation of multiple
angiogenic and tumorigenic growth factors (eg, VEG-F, PDG-F). [904]
The presence of lactic acidosis and ragged skeletal muscle fibers histologically suggests a mitochondrial
myopathy. Variable clinical expressions in affected family members can occur due to heteroplasmy, which is the
coexistence of distinct versions of mitochondrial genomes in an individual cell. [1935]
Histology
Irreversible myocardial ischemic injury initiates a series of predictable morphologic changes over the hours to weeks
after the initial injury. From 1 and 3 days after the initial injury, neutrophils infiltrate the border zone of the injured
tissue (where myocytes are relatively normal) in response to proinflammatory cytokines (eg, IL-6, IL-8), eventually
migrating to the central portion of the infarct. [15868]
Type I collagen is the primary collagen in mature scars (eg, remote myocardial infarction). It is the most prevalent
type of collagen and provides strength and support throughout the human body, particularly in bones, tendons,
ligaments, and skin. [8711]
Dermatology
INFLAMMATORY DERMATOSES AND BULLOUS DISEASES
Contact dermatitis
Allergic contact dermatitis (eg, nickel allergy) is a type IV hypersensitivity reaction characterized by epidermal
intercellular edema (ie, spongiosis) and an inflammatory infiltrate (eg, lymphocytes, eosinophils). Clinical findings can
include vesicles, erythema, and pruritus for acute lesions and lichenification for chronic lesions. [21262]
NORMAL STRUCTURE AND FUNCTION OF SKIN
Histiocytosis
Langerhans cells are dendritic cells found in the skin that act as professional antigen presenting cells. These cells are
derived from the myeloid cell line and they possess characteristic racquet-shaped intracytoplasmic granules known as
Birbeck granules. [588]
Wound healing
Keratinocytes are responsible for wound reepithelization. They migrate into the wound from its edges and are
repopulated by replication within the stratum basale. Keratinocytes continue to migrate and proliferate until they
contact other similar cells, a regulatory mechanism known as contact inhibition. [20884]
SKIN AND SOFT TISSUE INFECTIONS
Warts
Cutaneous warts (ie, verruca vulgaris) are caused by human papillomavirus and typically present as rough, skin-
colored papules. If necessary, biopsy can confirm the diagnosis and shows epidermal hyperplasia, thickened stratum
corneum, papilloma formation, and cytoplasmic vacuolization. [15363]
ENDOCRINE TUMORS
Pheochromocytoma
Chromaffin cells are modified neuroendocrine cells derived from the neural crest. Chromaffin cells in the adrenal
medulla are stimulated by acetylcholine released by sympathetic preganglionic neurons and secrete catecholamines
directly into the bloodstream to amplify sympathetic nervous system activity. [8424]
BREAST DISORDERS
Breast cancer
Paget disease of the breast is a malignant breast condition characterized by a unilateral, painful/pruritic, eczematous
rash on the nipple/areolar skin. Diagnosis is with biopsy showing the infiltration of the nipple/areolar epidermis by
Paget cells (intraepithelial adenocarcinoma cells). [21642]
Intraductal papilloma
Intraductal papilloma is characterized by epithelial and myoepithelial cells lining fibrovascular cores in a cyst wall or
duct. It is the most common cause of bloody nipple discharge and typically presents without breast masses or skin
changes. [11890]
Adenomyosis
Adenomyosis is the abnormal presence of endometrial glands and stroma within the uterine myometrium. Affected
patients are typically multiparous women with dysmenorrhea, heavy menses, and a uniformly enlarged uterus. [1957]
Normal pregnancy
Gap junctions facilitate communication and coordination between cells and play an important role in labor
contractions. Gap junctions are composed of connexin proteins, which are upregulated in the uterus in response to
rising estrogen levels. [11888]
HEPATIC DISORDERS
Nonalcoholic fatty liver disease

Stellate (Ito) cells are the primary cells involved in hepatic fibrosis. In response to hepatic injury, the stellate cells are
activated and transform into myofibroblasts capable of proliferating, promoting chemotaxis, and producing large
quantities of collagen. Collagen stains blue with Masson trichrome stain. [15024]
Celiac disease
Celiac disease (gluten-sensitive enteropathy) classically presents between age 6-24 months with abdominal pain,
diarrhea, vomiting, and weight loss. Duodenal biopsy reveals crypt hyperplasia, villous atrophy, and intraepithelial
lymphocyte infiltration. Treatment with a gluten-free diet resolves symptoms and normalizes serology and histology.
[324]

Pernicious anemia is an autoimmune disorder caused by the cell-mediated destruction of parietal cells in the
superficial upper glandular layer of the gastric body and fundus. Parietal cells are responsible for the secretion of
hydrochloric acid and intrinsic factor, a glycoprotein involved in the absorption of B12. Deficiency leads to
megaloblastic anemia and neurologic dysfunction. [124]
Infectious Diseases
HIV AND SEXUALLY TRANSMITTED INFECTIONS
Human papilloma virus

Human papilloma virus (HPV) is a small DNA virus with a tropism for stratified squamous epithelium, which
protectively lines anatomical areas that undergo frequent friction and abrasion, including the true vocal cords, cervix,
and anus. Infants can acquire respiratory papillomatosis via passage through an HPV-infected birth canal. [483]
Nervous System
Parkinson disease
The blood-brain barrier is formed by tight junctions between nonfenestrated capillary endothelial cells that prevent
the paracellular passage of fluid and solutes. This barrier only permits the passage of substances from the blood to
the brain via transcellular movement across the endothelial plasma membrane, which is limited by diffusion or
carrier-mediated transport. [1536]
Neuronal physiology
Kinesin is a microtubule-associated motor protein that functions in the anterograde transport of materials and
organelles within cells. Reactivation of latent herpes simplex virus requires anterograde transport of viral particles
from neuronal cell bodies in the sensory ganglia to the skin and oral mucosa. [1922]
Kinesin is a microtubule-associated, ATP-powered motor protein that facilitates the anterograde transport of
neurotransmitter-containing secretory vesicles down axons to synaptic terminals. [1936]
Ectopic pregnancy
Ectopic pregnancy should be suspected in patients with a pregnancy of unknown location (ie, no visible intrauterine
gestation) and abnormally rising β-hCG levels. Despite their extrauterine location, ectopic pregnancies promote
endometrial decidualization, which appears as dilated, coiled endometrial glands and vascularized, edematous
stroma. [334]
Respiratory mucosa
Type II pneumocytes have 2 important functions: regeneration of the alveolar lining following injury and surfactant
production. [478]
Bronchi have a ciliated pseudostratified columnar epithelium with mucin-secreting goblet cells and submucosal
mucoserous glands. The airway epithelium gradually changes to ciliated simple cuboidal by the level of the terminal
bronchioles. Bronchioles lack glands and cartilage, and the number of goblet cells decreases distally, ending before
the terminal bronchioles. Ciliated epithelium persists up to the respiratory bronchioles. [480]
COPD
Thickened bronchial walls, lymphocytic infiltration, mucous gland enlargement, and patchy squamous metaplasia of
the bronchial mucosa are features of chronic bronchitis. Tobacco smoking is the leading cause of chronic bronchitis.
[524]
GLOMERULAR DISEASES
Anti GBM disease

Anti-glomerular basement membrane (GBM) antibodies react with collagen type IV, causing rapidly progressive
glomerulonephritis with glomerular crescent formation on light microscopy. Immunofluorescence demonstrating
linear deposits of IgG and C3 along the GBM is characteristic. [9]
Poststreptococcal Glomerulonephritis
Poststreptococcal glomerulonephritis is most common in children and presents with nephritic syndrome (eg, renal
failure, hypertension, hematuria with red blood cell casts) 2-4 weeks after an infection with group A beta-hemolytic
Streptococcus. Immunofluorescence microscopy shows granular deposits of IgG, IgM, and C3 in the mesangium and
basement membranes. [8]
Poststreptococcal glomerulonephritis is an immune complex–mediated disease that occurs 2-4 weeks after group A
beta-hemolytic Streptococcus infection. Immune complexes composed of IgG, IgM, and C3 are deposited along the
glomerular basement membrane and are visible on electron microscopy as large, dome-shaped, subepithelial,
electron-dense deposits. [27]
Bone remodeling
Osteocytes have long intracanalicular processes that extend through the ossified bone matrix. These cytoplasmic
processes send signals to and exchange nutrients and waste products with the osteocytes within neighboring
lamellae via gap junctions. Osteocytes can sense mechanical stresses and send signals to modulate the activity of
surface osteoblasts, thereby helping to regulate bony remodeling. [1159]
Muscle structure & physiology

A single sarcomere is defined as the distance between two Z lines. Thin (actin) filaments in the I band are bound to
structural proteins at the Z line, whereas thick (myosin) filaments in the A band are bound to structural proteins at
the M line. [1734]
Immunology
Allergy & Immunology
ANAPHYLAXIS AND ALLERGIC REACTIONS
ACE inhibitors
Angioedema is a rare and serious adverse effect of ACE inhibitor therapy. ACE inhibition increases bradykinin levels,
which increase vascular permeability and lead to angioedema. Symptoms include tongue, lips, or eyelid swelling and,
less frequently, laryngeal edema and difficulty breathing. ACE inhibitors should be discontinued in affected patients.
[949]
Anaphylaxis
Wheal-and-flare lesions usually result from allergic (type I hypersensitivity) reactions. On initial exposure, an allergen
(eg, insect venom) promotes antibody class switching to IgE. Subsequent exposure promotes cross-linking of IgE on
basophils and mast cells, resulting in degranulation and release of multiple vasoactive mediators, including histamine.
[556]
Anaphylaxis is the result of widespread mast cell and basophil degranulation and the release of preformed
inflammatory mediators, including histamine and tryptase. Tryptase is relatively specific to mast cells and can be
used as a marker for mast cell activation. [2068]
The high-affinity IgE receptor (FcεRI) is found on the surface of mast cells and basophils and normally binds the Fc
portion of circulating IgE antibodies. Cross-linking of multiple membrane-bound IgE antibodies by a multivalent
antigen results in aggregation of the FcεRI receptors, causing degranulation and the release of preformed mediators
(eg, histamine, tryptase) that initiate an allergic response. [2069]
Angioedema
Hereditary angioedema is characterized by recurrent episodes of cutaneous and/or mucosal swelling due to C1
inhibitor deficiency. C4 levels are low due to uninhibited cleavage of C4 by excess activated C1. [20747]
Rhinitis
Glucocorticoids inhibit transcription of proinflammatory mediators and promote apoptosis of eosinophils, T cells, and
monocytes. [15544]
Serum sickness
Serum sickness is an immune complex–mediated type III hypersensitivity reaction that typically forms 5-14 days after
exposure to foreign proteins in an antitoxin, antivenom, monoclonal antibody, or vaccine. Patients typically develop
fever, urticarial rash, and arthralgia that resolve spontaneously over days as the immune complexes are cleared by
the mononuclear phagocyte system. [20701]
Syncope
Vasovagal syncope is a known complication of vaccine administration, particularly in adolescents. It typically involves
a prodrome and can be differentiated from anaphylaxis based on skin findings (pallor vs urticaria), absence of
respiratory symptoms (eg, upper airway edema, bronchospasm), and presence of bradycardia (vs tachycardia). [20697]
AUTOIMMUNE DISEASES
Atopic dermatitis
Atopic dermatitis presents with dry, erythematous patches or papules that are caused in part by a Th2-skewed
immune response. Th2 cytokines (eg, IL-4, IL-13) stimulate IgE production, suppress epidermal barrier component
expression, and impair host immune responses against secondary microbial infections. [21258]

FOXP3 is a transcriptional regulator protein that is required for the development of regulatory T cells; it triggers
production of cytokines (eg, IL-10, transforming growth factor-beta) and ligands (eg, cytotoxic T-lymphocyte antigen-
4) that suppress immune activation. FOXP3 mutations result in immune dysregulation marked by excessive
immunoglobulin production and the development of autoimmunity. [15331]
Corticosteroids
The acute effects of corticosteroids on the white blood cell count include an increased neutrophil count and
decreased lymphocyte, monocyte, basophil, and eosinophil counts. The increase in the neutrophil count results from
"demargination" of neutrophils previously attached to the vessel wall. [549]
SLE
Systemic lupus erythematosus is an autoimmune disorder that occurs most commonly in women. Hematologic
abnormalities are common; autoantibodies against blood cell antigens (ie, type II hypersensitivity) can cause
pancytopenia (ie, anemia, thrombocytopenia, leukopenia). In contrast, lupus nephritis is caused by immune complex
deposition (ie, type III hypersensitivity) in the glomeruli. [875]
IMMUNE DEFICIENCIES
Chronic granulomatous disease

Chronic granulomatous disease (CGD) is due to defective NADPH oxidase and is diagnosed by dihydrorhodamine
testing, which measures neutrophil respiratory burst. When NADPH oxidase is stimulated, dihydrorhodamine is
normally oxidized and fluoresces green (increased fluorescence intensity); it remains colorless (ie, no oxidation) in
patients with CGD. [22331]
Chronic granulomatous disease should be suspected in a child with recurrent infections by catalase-positive
organisms (eg, Staphylococcus aureus, Aspergillus) who has normal immunoglobulins and no
leukopenia. Pathogenesis involves the defective intracellular killing of phagocytized organisms within neutrophils due
to an impaired respiratory burst. [20297]
Complement deficiency
Initial control of encapsulated bacteria is largely reliant on the formation of membrane attack complexes (MACs) due
to activation of the alternative complement cascade. Patients with deficiency in the proteins that generate MACs
(C5-9) are at high risk for recurrent encapsulated bacterial infection; evaluation will show reduced activity of the
classical (CH50) and alternative (AH50) complement cascades. [22579]
Deficiency of the complement factors that form the membrane attack complex (C5-C9) results in recurrent infections
of the lung and meninges by encapsulated bacteria (eg, Streptococcus pneumoniae, Neisseria meningitidis). [739]
Hyper ige syndrome

Hyper-IgE syndrome is characterized by elevated IgE levels and is caused by impaired neutrophil activation and
migration due to a defect in T-helper cell type 17 cells. Typical findings include noninflammatory (ie, cold) abscesses,
recurrent sinopulmonary infections, and chronic atopic dermatitis. [21342]
Hyper-igm syndrome
Hyper-IgM syndrome is usually caused by a defect in CD40 ligand, which prevents B cells from undergoing class-
switch recombination. Clinical features include recurrent sinopulmonary, gastrointestinal (eg, Giardia), and
opportunistic infections. Laboratory findings include elevated IgM and low or absent IgG, IgA, and IgE. [541]
Hyper-IgM syndrome presents with recurrent sinopulmonary and gastrointestinal infections due to the absence of
CD40 ligand on CD4+ T cells. Lack of interaction between CD40L and CD40 on B cells prevents the development of
secondary germinal centers and impairs B-cell activation and immunoglobulin class switching. [21499]
Hypersensitivity reactions
The Candida antigen skin test assesses the activity of cell-mediated immunity because it requires an intact CD4 cell
response. Failure to respond to candida antigen testing is typical in patients with severe combined
immunodeficiency. [2079]
Primary immunodeficiency disorder

Inherited defects involving the interferon-γ signaling pathway result in disseminated mycobacterial disease in infancy
or early childhood. Patients require lifelong treatment with antimycobacterial agents. [8384]
Chronic granulomatous disease is a primary immunodeficiency due to impaired NADPH oxidase, an enzyme that
generates reactive oxygen species in phagolysosomes. Diminished intracellular killing within neutrophils leads to
susceptibility to recurrent infection with catalase-producing bacteria (eg, Staphylococcus aureus, Nocardia) and fungi
(eg, Aspergillus). [557]
Severe combined immunodeficiency is caused by a genetic defect in T cell development, leading to loss of both
cellular and humoral immunity. Patients present in infancy with recurrent bacterial, viral, fungal, and opportunistic
infections as well as failure to thrive and chronic diarrhea. [2078]
Leukocyte adhesion deficiency is due to the absence of CD18 antigens, which are necessary for the formation of
integrins. Failure of leukocyte adhesion and migration results in recurrent skin and mucosal infections without
purulence, delayed umbilical cord separation, and peripheral leukocytosis. [538]
Severe combined immunodeficiency disease
Adenosine deaminase (ADA) inhibition/absence is highly lymphocytotoxic. Medications that block ADA are used to
treat lymphocyte-derived cancers. Inherited gene mutations in ADA lead to the autosomal recessive disease of
severe combined immunodeficiency. [15293]
Wiskott-aldrich syndrome
Wiskott-Aldrich syndrome is characterized by the triad of eczema, thrombocytopenia, and combined B and T cell
deficiency. Patients can have thrombocytopenia at birth, with eczema and repeated infections due to encapsulated
and/or opportunistic organisms usually developing later around 6 to 12 months of age. [537]
X-linked agammaglobulinemia
X-linked agammaglobulinemia is characterized by low or absent circulating mature B cells (ie, CD19+, CD20+, CD21+
cells) and pan-hypogammaglobulinemia. Affected patients have increased susceptibility to pyogenic bacteria,
enteroviruses, and Giardia lamblia due to the absence of opsonizing and neutralizing antibodies. [1763]
X-linked agammaglobulinemia, an immunodeficiency characterized by low circulating B lymphocytes and

immunoglobulins, should be suspected in an infant with severe, life-threatening enteroviral infection. [19629]
MISCELLANEOUS

Abatacept, a disease-modifying antirheumatic drug, is a fusion of CTLA4 with the Fc portion of IgG. CTLA4 binds to
CD80/86 on antigen-presenting cells, which prevents CD80/86 from binding to CD28 on T cells. This reduces T cell
costimulation and leads to anergy, which reduces inflammation. [18613]
NK cells recognize and kill cells with decreased MHC class I antigen cell surface expression, such as virus-infected cells
and tumor cells. They are large lymphocytes that contain perforins and granzymes in cytoplasmic granules. NK cells
kill target cells by inducing apoptosis. [745]
Immature T-lymphocytes express both the CD4 and CD8 cell surface antigens in addition to a complete TCR or a pro-
TCR. These lymphocytes exist in the thymic cortex where they undergo positive selection and in the thymic medulla
where they undergo negative selection. [559]
The Fas receptor acts to initiate the extrinsic pathway of apoptosis. Mutations involving the Fas receptor or Fas
ligand can prevent apoptosis of autoreactive lymphocytes, thereby increasing the risk of autoimmune disorders such
as systemic lupus erythematosus. [298]
Traumatic injury to the eye, a site that displays immune privilege, can lead to the release of previously sequestered
antigens that T cells recognize as foreign. This can lead to sight-threatening inflammation in both the injured and
uninjured eye. [18609]
Tuberculin skin testing triggers a type IV delayed-hypersensitivity reaction in patients with previous infection due to
the presence of primed, antigen-specific CD4 T lymphocytes. These lymphocytes recognize tuberculin proteins
displayed on antigen-presenting cells (APCs) and become activated following a costimulatory interaction between
CD28 on the T cell and CD80/86 on the APC. [18764]
Cytokines
Interferons α and β are produced by most human cells in response to viral infections. The production of α and β
interferons helps suppress viral replication by halting protein synthesis and promoting apoptosis of infected cells,
limiting the ability of viruses to spread through the tissues. [1468]
Drug structure and properties

The suffix of a biological agent indicates whether a medication is a monoclonal antibody (mab), a receptor molecule
(cept), or a kinase inhibitor (nib). Monoclonal antibodies also include in their names the type of target (eg, bacterial
or immune system) and their origin (eg, human or mouse). [8523]
Poison ivy dermatitis is a form of allergic contact dermatitis, which is a type IV hypersensitivity reaction mediated
primarily by T lymphocytes. It manifests as intensely pruritic erythematous papules, vesicles, or bullae that often
form linear patterns. [1133]
Immunoglobulins
The live attenuated oral (Sabin) poliovirus vaccine produces a stronger mucosal secretory IgA immune response than
does the inactivated poliovirus (Salk) vaccine. This increase in mucosal IgA offers immune protection at the site of
viral entry by inhibiting attachment to intestinal epithelial cells. [1467]
IgG, IgA, and IgD have a hinge region between the Fab fragment and the Fc fragment of the immunoglobulin. The
hinge region increases flexibility of the Fab arms, which makes the antibody more likely to bind to more than one site
on the antigen. This increases the avidity of the immunoglobulin but makes it more susceptible to destruction by
bacterial proteases. [540]
Immunoglobulin contains a Fab fragment that binds to antigen and an Fc fragment that activates complement and/or
interacts with immune cells. The Fc fragment of IgG activates the classical complement cascade (constant heavy
chain region 2) and serves as a ligand for the Fc receptor on phagocytes (constant heavy chain region 3). [539]
Immunology principles
A radioimmunoassay uses specific antibodies and a fixed quantity of radiolabeled antigen to determine the amount of
antigen present in an unknown sample. This is done by measuring the amount of radiolabeled antigen displaced from
the antibodies in the system. [12299]
CD8+ cells recognize foreign antigens presented with MHC class I proteins. Each MHC class I molecule consists of a
heavy chain and a β2-microglobulin. [746]
Inflammation
Inflammation is characterized by the passage of circulating inflammatory leukocytes into the inflamed tissue. The
steps involved include margination, rolling, activation, tight adhesion and crawling, and transmigration. [8480]
Leukotriene B4 stimulates neutrophil migration to sites of inflammation. Other important chemotactic agents include
5-HETE (leukotriene precursor), complement component C5a, and IL-8. [1800]
Major histocompatibility class
Transporter associated with antigen processing (TAP) proteins are necessary for loading of cytoplasmic (eg, viral)
proteins onto major histocompatibility complex (MHC) class I molecules. The MHC class I–peptide complex can then
activate CD8+ cytotoxic T cells through interaction with the T cell receptor and CD8 coreceptor. [17446]
MHC class II is expressed on the surface of antigen presenting cells (APC) and presents extracellular antigens to T cells
after extracellular protein is degraded within acidified lysosomes. Failure to acidify lysosomes would lead to deficient
expression of MHC class II-antigen complexes with subsequent impaired interaction between APCs and T cells. [542]
Major histocompatibility complex (MHC) class II molecules are encoded by the HLA-DP, HLA-DQ, and HLA-DR genes
and present extracellular antigens processed in acidified lysosomes by antigen-presenting cells (eg, B cells,
macrophages). Absence of MHC class II expression impairs activation of B and T cells, resulting in a form of severe
combined immunodeficiency. [17447]
Morbiliform drug eruption

Morbilliform drug eruption is a type IV hypersensitivity reaction caused by drugs (eg, anticonvulsants, antibiotics) or
their metabolites that typically occurs 5-21 days following drug initiation. Lesions consist of erythematous macules
and papules, distributed symmetrically on the trunk and extremities, sometimes accompanied by low-grade
fever. Mucosal involvement is absent. [106668]
PRINCIPLES OF IMMUNOLOGY
Abo incompatibility
With maternal blood types A or B, hemolytic disease of the fetus and newborn very rarely occurs because maternal
antibodies (anti-A or anti-B) are of the IgM type and cannot cross the placenta. In contrast, mothers with blood type
O also produce IgG antibodies (anti-A and anti-B), which can cross the placenta and cause fetal hemolysis. [8261]
Aging
Immunosenescense is the normal age-related decline that impairs most aspects of immune function, including the
production of naive B and T cells. This results in a diminished antibody-based immune response to novel antigens
(eg, infections, vaccinations). The immune response to previously experienced pathogens is typically intact due to
normal or increased levels of memory B and T cells and preserved antibody quality. [17448]
Biologic agents
Rituximab is a monoclonal antibody directed against CD20, a cell surface receptor on developing and mature B
cells. Binding of rituximab to CD20 results in B-cell cytotoxicity and phagocytosis, which reduces the B-cell
population. This reduces inflammatory symptoms in a wide range of rheumatologic diseases. [20781]

Eosinophils play a role in host defense during multicellular parasitic infection. When stimulated by antibodies bound
to a parasitic organism, they destroy the parasite via antibody-dependent cell-mediated cytotoxicity with enzymes
from their cytoplasmic granules. Another function of eosinophils is regulation of type I hypersensitivity reactions. [750]
IL-12 stimulates the differentiation of naive Th0 cells into Th1 cells. Patients with IL-12 receptor deficiency are
susceptible to severe mycobacterial infections due to the inability to mount a strong cell-mediated granulomatous
immune response; therefore, they require treatment with IFN-γ. [762]
CD40-ligand (CD40L) is expressed primarily on activated T cells. It binds to CD40 on antigen-presenting cells,
including B cells, leading to their full activation (costimulation). Therefore, CD40L plays a vital role in both the cell-
mediated and humoral immune response. [21091]
The process of negative selection in T cell maturation is essential for eliminating T cells that bind to self MHC or self
antigens with overly high affinity. This process occurs in the thymic medulla. If these cells were permitted to survive,
they would likely induce immune and inflammatory reactions against self antigens leading to autoimmune disease.
[558]
Humoral immunity
The primary immune response to a new antigen initially results in plasma cells that produce only IgM. Isotype
switching occurs later in germinal centers and gives B cells the ability to produce antibodies of differing isotypes (eg,
IgG, IgA). [1614]
The late phase of dermatologic type I hypersensitivity reactions manifests as an indurated skin lesion hours after
exposure to the allergen due to local tissue damage caused by major basic protein released from eosinophils. In
contrast, type IV hypersensitivity reactions develop over days because of the time needed to produce a cell-mediated
immune response. [17600]
Type IV (delayed) hypersensitivity reactions (eg, Candida extract skin test, contact dermatitis) are characterized by
erythema and induration that develops 24-48 hours after repeat exposure to an antigen. T lymphocytes mediate the
inflammation in these reactions through cytokine release, CD8+ cytotoxicity, and macrophage recruitment. [544]
Immunizations
Pneumococcal conjugate vaccines are strongly immunogenic in infancy due to both B and T cell recruitment. They
provide higher, longer-lasting antibody titers relative to pneumococcal polysaccharide vaccines. The pneumococcal
polysaccharide vaccine is poorly immunogenic in infants due to their relatively immature humoral antibody response.
[11872]
The Haemophilus influenzae serotype b vaccine consists of a capsular polysaccharide conjugated to a carrier protein
(tetanus toxoid [TT] protein or outer membrane protein [OMP] of Neisseria meningitidis). Protein conjugation causes
a T cell-mediated immune response leading to long-term immunity through production of memory B-lymphocytes.
[965]
Plasma contains polyclonal antibodies, a pool of antibodies that bind different epitopes on an antigen. In contrast,
monoclonal antibodies bind a single epitope on an antigen. Polyclonal antibodies are often better at neutralizing
complex antigens because they contain antibodies that bind several different epitopes. [20818]
Immunotherapy medications often utilize fragments of a monoclonal immunoglobulin rather than the full
immunoglobulin; because fragments are smaller, they typically have better tissue penetration and
pharmacokinetics. Fab fragments contain a variable domain and the first constant region from a heavy and light
chain; because they do not contain an Fc receptor, Fab fragments cannot trigger cell killing via complement or
phagocytosis. [20817]
Immunotherapy
The binding of programmed cell death protein 1 (PD-1) to one of its ligands (programmed death-ligand 1 [PD-L1])
downregulates the immune response by inhibiting cytotoxic T cells. Many types of cancers evade immunodetection
by increasing expression of PD-L1 on their surface. Monoclonal antibodies against PD-1 upregulate the T-cell
response and promote tumor cell apoptosis. [12048]
Inflammation
Interleukin-8 is a chemokine produced by macrophages that induces chemotaxis and phagocytosis in
neutrophils. Other significant chemotactic agents include leukotriene B4, 5-HETE (the leukotriene precursor), and
complement component C5a. [8539]
Innate immunity
Pattern recognition receptors (PRRs) are part of the innate immune response; they recognize damaged host proteins
or conserved microbial molecules and trigger inflammation. Toll-like receptors, a type of PRR on macrophages and
dendritic cells, recognize lipopolysaccharide and promote the release of inflammatory cytokines (eg, IL-1/6/12, TNF-
alpha) via NF-kB signaling. [21420]
Latex Allergy
IL-4 is produced by the TH2 subset of T helper cells. It facilitates proliferation of B cells and TH2 lymphocytes and
stimulates antibody isotype switching to IgE which mediates type I hypersensitivity (allergic) reactions. [759]
Phagocytosis
Opsonization occurs when host proteins such as immunoglobulins or complement bind to foreign cells such as
bacteria and coat the surface, enhancing phagocytosis. The most important opsonins (coating proteins) are
immunoglobulin G and complement C3b. [11677]
SLE
The binding of autoantibodies to host antigens can trigger the classical complement cascade, leading to low C4 and
C3 levels. Because autoantibodies do not activate the alternative complement cascade, factor B levels remain
normal. This pattern is frequently seen in rheumatologic diseases such as systemic lupus erythematosus. [7609]
Sepsis
Tumor necrosis factor-alpha is released from activated macrophages and is one of the most important mediators of
the systemic inflammatory response in sepsis. Other cytokines responsible for inducing the systemic inflammatory
response include IL-1 and IL-6. [1799]
Serum sickness
Serum sickness is an immune complex–mediated type III hypersensitivity reaction that occurs 1-2 weeks after
exposure to nonhuman protein in antitoxins (eg, antivenom), monoclonal antibodies (eg, rituximab), or vaccines (eg,
rabies antigens). Deposition of immune complexes in tissue leads to complement activation and subsequent self-
limited fever, arthralgia, and urticarial rash. [20698]
Thermal burn
The earliest morphologic change that occurs after a superficial thermal burn is erythema due to the release of
preformed mediators (eg, histamine) from mast cells. Deeper (eg, partial-thickness) burn wounds form blisters due
to fluid extravasation through gaps between damaged venule endothelial cells. [17853]
Transplant rejection
Hyperacute rejection is caused by preformed antibodies in the recipient that recognize and attack donor antigens (ie,
type II hypersensitivity). These are often anti-ABO blood group or anti-HLA antibodies. Vascular injury and capillary
thrombotic occlusion lead to rapid ischemic necrosis of the renal graft, often evidenced by gross cyanosis and
mottling immediately following graft perfusion. [569]
Tuberculosis
Interferon-gamma (IFN-γ) release assays test for latent tuberculosis infection by measuring the amount of IFN-γ
released by T lymphocytes when exposed to antigens unique to Mycobacterium tuberculosis. [11525]
The caseating granulomas of tuberculosis are almost always surrounded by large epithelioid macrophages with pale
pink granular cytoplasm. CD14 is a surface marker specific to the monocyte-macrophage cell lineage. [1598]
TRANSPLANT MEDICINE
Calcineurin inhibitors
Calcineurin is an essential protein in the activation of interleukin-2, which promotes the growth and differentiation of
T cells. Immunosuppressants such as cyclosporine and tacrolimus work by inhibiting calcineurin activation. [1155]
Graft versus host disease

Graft-versus-host disease can occur following transplantation of organs rich in lymphocytes (eg, liver). T lymphocytes
found in the donor organ become sensitized against the MHC antigens of the recipient and subsequently attack the
host's tissues. The skin, liver, and gastrointestinal tract are most frequently affected. [1613]
Lung transplantation
Chronic lung transplant rejection is due primarily to progressive scarring of the small airways, leading to bronchiolitis
obliterans. Manifestations occur months or years after transplantation and include obstructive lung disease (eg,
reduced FEV1) with dyspnea and dry cough. [534]
Organ rejection can be hyperacute, acute, or chronic. Acute rejection most often occurs within weeks or up to 6
months after transplant and is predominantly cell-mediated, involving sensitization of host T lymphocytes against
donor MHC antigens. There is typically graft dysfunction with histology showing a dense, mononuclear (ie,
lymphocytic) infiltrate. [546]
Chronic renal allograft rejection manifests months to years after a transplant and presents with worsening
hypertension and a gradual decline in renal function. It involves a chronic cell-mediated and antibody-mediated
response against donor antigens and leads to obliterative vascular wall thickening, tubular atrophy, and interstitial
fibrosis. The process is usually irreversible and eventually leads to graft failure. [744]
Sirolimus binds to the immunophilin FK binding protein (FKBP) in the cytoplasm, forming a complex that binds and
inhibits mTOR (mammalian target of rapamycin). Inhibition of mTOR signaling blocks IL-2 signal transduction and
prevents cell cycle progression and lymphocyte proliferation. [11786]
Heart transplantation
Acute cardiac transplant rejection usually occurs weeks to months following transplantation and is primarily a cell-
mediated process. In acute cellular rejection, endomyocardial biopsy shows an interstitial lymphocytic infiltrate with
myocyte damage. [568]
Dermatology
Atopic dermatitis
Atopic dermatitis increases the risk for allergic rhinitis, asthma, and food allergies, likely because of an immune
response that favors IgE production. In addition, skin barrier dysfunction facilitates food allergen penetration and
sensitization, increasing the risk for food allergies. [21462]
Contact dermatitis
Allergic contact dermatitis is a type IV (delayed-type) hypersensitivity reaction. Initially, Langerhans cells present
haptens to naive T cells, leading to clonal expansion. On reexposure, sensitized CD8+ T cells are recruited to skin and
destroy tissue. Release of interferon gamma by T cells further amplifies the immune response. [20556]
Allergic contact dermatitis is a delayed-type hypersensitivity reaction. Initially, Langerhans cells travel to regional
lymph nodes and present haptens to naive T cells, leading to clonal expansion. On reexposure to the hapten,
sensitized T cells cause tissue destruction that manifests as pruritic erythema, vesicles, and/or bullae 2-3 days after
exposure. [20586]
Wound healing
Elevated blood glucose induces the release of reactive oxygen species and proinflammatory cytokines from
neutrophils while inhibiting the production of anti-inflammatory cytokines (eg, IL-10) and growth factors needed for
fibroblast proliferation and reepithelialization in a healing wound. As a result, patients with uncontrolled diabetes
frequently have nonhealing wounds with evidence of ongoing inflammation. [17855]
Melanoma
Melanoma lesions often have multiple color variations. The different colors represent different activities within the
tumor. Whitish/gray areas occur when cytotoxic T cells recognize tumor antigens and destroy malignant cells, leading
to melanocyte regression. Red areas arise due to vessel ectasia and local inflammation, whereas brown or black
areas are generally due to advancing malignant melanocytes. [16862]
Programmed-death receptor 1 (PD-1) is a checkpoint inhibitor that downregulates the cytotoxic T-cell
response. Neoplastic cells often exploit this receptor via the overexpression of PD-1 ligand. PD-1 receptor inhibitors
(eg, Pembrolizumab) restore the T-cell response, allowing cytotoxic T cells to invade the tumor and induce apoptosis
of neoplastic cells. [16895]
Skin and soft tissue infections

Granulomatous inflammation is a form of chronic inflammation characterized by aggregates of activated
macrophages that assume an epithelioid appearance. Persistent granulomatous inflammation with subsequent
fibrosis can cause organ dysfunction, which is seen in a number of granulomatous diseases. [8334]
Rhinitis
Sensitization to aeroallergens occurs when inhaled antigens induce T-helper (Th) cells to differentiate into Th2
cells. Th2 cells then promote B-cell maturation and isotype class switching to IgE. [20705]
Inflammatory bowel disease

Of the cytokines released in the setting of tissue injury, IL-10 plays important anti-inflammatory and
immunomodulatory roles, especially in the pathogenesis of inflammatory bowel disease. IL-10 attenuates the
immune response through the inhibition of TH1 cytokines, reduction of major histocompatibility complex class II
expression, and suppression of activated macrophages and dendritic cells. [1597]
MISCELLANEOUS
Monoclonal antibody
Cancer immunotherapy often includes the administration of monoclonal antibodies against a target overexpressed on
the cancer cell surface. The Fc portion of the bound antibody is identified by natural killer cells via CD16, leading to
antibody-dependent cellular cytotoxicity via the release of granzymes and perforin. [15279]

Autologous hematopoietic stem cell transplantation reinfuses host cells from the patient's peripheral blood or
banked cord blood to reconstitute the bone marrow. Because the reinfused cells are genetically identical to the
host's, there is no risk of graft rejection or graft versus host disease. Although there is also no risk of transferring a
new bloodborne pathogen, chronic or latent infections (eg, Epstein-Barr virus, cytomegalovirus, varicella-zoster virus)
may worsen due to the transient immunosuppression induced by myeloablative chemotherapy. [20771]
Immunotherapy
Because tumors with defective DNA mismatch repair generate high levels of neoantigens, they are particularly
dependent on adaptations (eg, overexpression of immune checkpoints) to avoid cytotoxic T-cell
destruction. Treatment with immune checkpoint inhibitors restore antitumor cytotoxic T-cell activity and often
dramatically reduce tumor burden. [22785]
Acute hemolytic transfusion reaction is an antibody-mediated (type II) hypersensitivity reaction caused by pre-
existing anti-ABO antibodies that bind antigens on transfused donor erythrocytes. Subsequent complement
activation results in erythrocyte lysis, vasodilation, and symptoms of shock. Common findings include fever,
hypotension, chest and back pain, and hemoglobinuria. [747]
Rhesus alloimmunization
Hemolytic disease of the newborn most commonly occurs from maternal sensitization to Rh antigens during a prior
pregnancy with an Rh(D)+ fetus. In subsequent Rh(D)+ pregnancies, maternal anti-Rh(D) IgG antibodies cross the
placenta and cause a severe autoimmune hemolytic anemia in the fetus and life-threatening hydrops fetalis. [545]
Anti-Rh immunoglobulin consists of anti-D IgG antibodies that bind to Rh-positive fetal erythrocytes, promoting
clearance by maternal reticuloendothelial macrophages and preventing maternal Rh sensitization. It is routinely
administered to Rh-negative women during gestation and immediately postpartum. [1683]
TRANSFUSION MEDICINE
Blood transfusion
Delayed hemolytic transfusion reactions are usually mild, hemolytic reactions that occur >24 hours after blood
transfusion. They are a type of anamnestic response (delayed immunologic response) that occurs in patients
previously exposed to a minor RBC antigen (eg, previous blood transfusion, pregnancy). [17780]
Multiple myeloma
Multiple myeloma is associated with the clonal proliferation of plasma cells in the bone marrow. This prevents
normal B-cell lymphogenesis and increases the risk of bacterial infection due to decreased production of normal
immunoglobulins. [15466]
Nonhodgkin lymphoma
Chimeric antigen receptor (CAR) T-cell therapy involves extracting T cells from a patient with malignancy, inserting a
CAR gene against a protein overexpressed by the malignancy, and then reinfusing the modified T cells back into the
patient. CAR T-cell therapy against CD19 is used to treat B-cell malignancy because CD19 is expressed only by B cells.
[15048]
X-linked agammaglobulinemia
X-linked (Bruton) agammaglobulinemia is caused by a defect in B cell maturation, resulting in absent mature B cells
and severely low immunoglobulin levels. T cell numbers and function remain intact. Due to the absence of B cells,
primary lymphoid follicles and germinal centers do not form within lymph nodes. [1134]
Infectious Diseases
Meningococci
Paroxysmal nocturnal hemoglobinuria leads to the formation of membrane attack complexes on
erythrocytes. Treatment with monoclonal antibody against C5, the first component of the membrane attack
complex, can improve symptoms. However, it also increases risk for encapsulated bacterial infection. Therefore,
patients require vaccination and antibiotic prophylaxis against Neisseria meningitidis and Streptococcus pneumoniae.
[18594]
Tetanus
Clostridium tetani produces the neurotoxin tetanospasmin, which blocks inhibitory neurotransmission in the spinal
cord and leads to tonic muscular contraction. Tetanus is prevented by immunization with an inactivated toxoid that
triggers the production of antitoxin antibodies (active immunity). [760]
Toxic shock syndrome

Toxic shock syndrome is typically associated with the prolonged use of tampons or wound packing, which allows
Staphylococcus aureus to replicate locally and release pyrogenic toxic superantigens (eg, toxic shock syndrome toxin-
1) into the blood. Superantigens bind to the MHC-II complex of antigen-presenting cells without processing and
nonspecifically activate T cells. This leads to a dramatic release of inflammatory cytokines, which causes the
manifestations of the disease (eg, hypotension; high fever; organ failure; diffuse, erythematous rash). [15509]
Superantigens (eg, toxic shock syndrome toxin) interact with major histocompatibility complex molecules on antigen-
presenting cells and the variable region of the T lymphocyte receptor to cause nonspecific, widespread activation of T
cells. This results in the release of interleukin (IL)-2 from the T cells and IL-1 and tumor necrosis factor from
macrophages. This immune cascade is responsible for the manifestations of toxic shock syndrome. [676]
Tuberculosis
Approximately 25% of patients with active TB have false-negative tuberculin skin testing (TST) (anergy) due to an
impaired cell-mediated immune response. These individuals are at greater risk for severe, disseminated disease and
death. False-negative TST can also be seen with immunocompromise, improper injection technique, and recent
infection. [19440]
FUNGAL INFECTIONS
Febrile neutropenia
Neutrophils are the most important immune cell in the defense against invasive Candida infection; therefore, patients
with neutropenia (eg, following cytotoxic chemotherapy) are at high risk for invasive disease (eg, candidemia,
meningitis). In contrast, T lymphocytes are more important for prevention of superficial, mucocutaneous infection
(eg, thrush). [112]
Hepatitis b
The presence of anti-HBc and anti-HBs antibodies in the serum without detectable viral antigens indicates recovery
from acute hepatitis B infection. In contrast, patients vaccinated against hepatitis B will have anti-HBs antibodies
without detectable levels of anti-HBc. Chronic hepatitis B is indicated by persistent levels of HBsAg and HBV DNA in
the serum. [380]
MISCELLANEOUS
Immunizations
Initial vaccination generates an early IgM response by short-lived plasma cells followed by a delayed-onset, longer-
lasting IgG response due to T-cell dependent class switching (IgM peaks before IgG). Due to formation of memory B
cells, secondary responses (eg, booster vaccination, pathogen exposure) are characterized by a rapid and sustained
IgG response with a short-term, more muted IgM response. [15152]
Torch infections
Organism-specific IgM is diagnostic of congenital infection in a symptomatic neonate (eg, growth restriction,
microcephaly, hepatosplenomegaly, blueberry muffin rash). Because maternal IgG titers are expected with a past
infection and neonatal IgG at birth is maternally derived, elevated newborn IgG is also expected. [20628]
VIRAL INFECTIONS
Hepatitis b
Immunization against hepatitis B virus uses recombinant HBsAg to generate anti-HBs antibodies. These antibodies
prevent infection by binding to the envelope of circulating virus and inhibiting viral entry. [15177]
Immunizations
mRNA vaccines deliver mRNA molecules encoding foreign protein into the cytoplasm of host cells (particularly
antigen presenting cells that avidly engulf the associated carrier compound). The mRNA is then translated by
ribosomes and displayed on the cell surface, leading to a robust adaptive immune response. [105489]
Inactivated (killed or component) viral vaccines primarily generate a humoral immune response against extracellular
viral antigens, preventing viral entry into the cell. In contrast, live attenuated viral vaccines can generate a strong
cell-mediated immune response that can kill virally-infected cells, in addition to providing humoral immunity. [1466]
Infectious mononucleosis
Reactive (atypical) lymphocytes are activated, pathogen-specific cytotoxic T cells or natural killer cells that form in
response to certain intracellular infections. In contrast to normal lymphocytes, reactive lymphocytes are large,
scalloped, and have abundant cytoplasm. Reactive lymphocytosis is a diagnostic feature of infectious mononucleosis.
[15490]
MISCELLANEOUS
Inflammation
Serum sickness is an immune complex–mediated, type III hypersensitivity reaction that occurs when immune
complexes deposit in skin and joints and activate the classical complement cascade. This generates the highly
inflammatory anaphylatoxins C3a and C5a, leading to skin rash, joint arthralgia/arthritis, and high fever. [7656]
Ophthalmology
NORMAL STRUCTURE AND FUNCTION OF THE EYE AND ASSOCIATED STRUCTURES
Traumatic injury to the eye, an area of the body that has inherent immune privilege, can lead to the release of
previously sequestered antigens that T cells recognize as foreign. This can lead to subsequent inflammation and
blindness in both the injured and uninjured eye. [15838]
Pathology (General Principles)
CELLULAR PATHOLOGY
Immotile cilia syndrome

Kartagener syndrome is a form of primary ciliary dyskinesia characterized by the triad of situs inversus, chronic
sinusitis, and bronchiectasis. It occurs due to mutations that impair the structure or function of cilia. Cystic fibrosis
also causes chronic respiratory infections, but it is not associated with situs inversus. [1611]
NEOPLASIA
General principles of cancer

Tumor cells must develop adaptations to avoid destruction by the innate and adaptive immune response. A common
adaptation is to overexpress programmed cell death 1 ligand 1 (PD-L1), which converts effector T cells to exhausted T
cells. Other adaptations include down-regulating class I major histocompatibility complexes, blocking T-cell
costimulation, and increasing immunoinhibitory cytokine secretion. [22656]
Pharmacology (General Principles)
MISCELLANEOUS
Cytokines
Interleukin-2 (IL-2) is endogenously produced by CD4 cells, CD8 cells, and natural killer (NK) cells and has strong
proinflammatory and some anti-inflammatory effects. High-dose IL-2 therapy can be used for advanced renal cell
carcinoma and metastatic melanoma; this can lead to long-lasting remission due to increased cytotoxic activity of NK
cells against the tumor. [8530]
Anaphylaxis
Type I hypersensitivity reactions are mediated by the interaction of allergen with preexisting IgE bound to basophils
and mast cells. This facilitates cross-linking of the surface IgE molecules that signals the cell to degranulate releasing
chemical mediators (eg, histamine, heparin). These agents are responsible for the immediate signs and symptoms of
allergy, from a local wheal and flare to life-threatening anaphylaxis. [1131]
Selective iga deficiency

Selective IgA deficiency is the most common primary immune deficiency and can present with recurrent
sinopulmonary and gastrointestinal infections as well as autoimmune disease. Patients with severe IgA deficiency can
have anaphylaxis during transfusion of blood products that contain small amounts of IgA. [1130]
INTERSTITIAL LUNG DISEASE
Sarcoidosis
Sarcoidosis is characterized by noncaseating granulomas due to dysregulated cell-mediated immunity. Activated
antigen-presenting cells produce IL-12, which stimulates the differentiation of Th1-type CD4+ cells. Th1 cells produce
IL-2 and interferon-γ, which stimulate Th1 cell proliferation and macrophage activation, respectively. [797]
Asthma
An excess of Th2 cell activity relative to Th1 cell activity may underlie the pathogenesis of asthma. In the asthma
sensitization phase, inhaled antigens stimulate Th2 cells to secrete IL-4 and IL-13, which together promote B-
lymphocyte class switching for IgE synthesis, leading to mast cell priming. Th2 cells also secrete IL-5, which activates
eosinophils. [526]
Tuberculosis
T helper subtype 1 cells release interferon-gamma, leading to the activation of macrophages, a process critical for
control of Mycobacterium tuberculosis infection. Activated macrophages form mature phagolysosomes that destroy
phagocytosed mycobacteria and can differentiate into epithelioid and Langhans giant cells to wall off extracellular
mycobacteria within caseating granulomas. [301]
Mycobacteria tuberculosis primarily replicates within the phagosome, leading to display of mycobacterial antigens on
major histocompatibility complex class II molecules. This results in the activation of CD4 cells and subsequent control
of the infection with macrophages. [1218]
Mycobacterium tuberculosis triggers CD4 T lymphocytes to release interferon-gamma, which leads to macrophage
activation (improves intracellular killing ability) and differentiation into epithelioid histiocytes. These cells, along with
horseshoe-shaped, multinucleated Langhans giant cells (fused, activated macrophages) are a key component of
granuloma formation. [1220]
GLOMERULAR DISEASES
IgA vasculitis
Henoch-Schönlein purpura is an IgA-mediated, leukocytoclastic vasculitis that presents with palpable purpura,
arthralgia/arthritis, abdominal pain, and/or hematuria. Renal involvement is due to mesangial deposition of IgA
immune complexes with subsequent mesangial cell proliferation, neutrophilic infiltration, and glomerular damage.
[758]
Poststreptococcal glomerulonephritis is the most common cause of nephritic syndrome (eg, hematuria, edema,
hypertension) in children, typically occuring 2-4 weeks after a streptococcal infection (eg, impetigo, cellulitis,
pharyngitis). It is caused by a type III (immune-complex–mediated) hypersensitivity reaction resulting from
nephritogenic strains of group A beta-hemolytic Streptococcus. [567]
Ankylosing spondylitis
The pathogenesis of ankylosing spondylitis likely originates with defects in the intestinal mucosal barrier and
exposure to the gut microbiome that lead to an enhanced IL-17–mediated inflammatory response. IL-17 stimulates
production of additional inflammatory factors, primarily tumor necrosis factor-alpha and prostaglandins, which have
synergistic proinflammatory effects and induce bony erosions and abnormal bone regrowth in the skeleton. [19493]
The seronegative spondyloarthropathies include ankylosing spondylitis, reactive arthritis, psoriatic arthritis, and
arthritis associated with inflammatory bowel disease. Individuals expressing HLA B27 (a specific HLA class I molecule)
are at increased risk for the seronegative spondyloarthropathies. [752]
Rheumatoid arthritis
Rheumatoid arthritis results from an immune response directed against autoantigens in the joints. Infiltrating CD4+ T
cells secrete cytokines that promote inflammatory synovitis. They also stimulate B cells to produce rheumatoid
factor (IgM antibody specific for Fc component of IgG) and anti-citrullinated protein antibodies that contribute to
chronic inflammation and joint destruction. [754]

Adalimumab is a recombinant human IgG that binds tumor necrosis factor-alpha (TNF-alpha). Antidrug antibodies
can develop against adalimumab (or other immunoglobulin-based anti-TNF agents) that can block its interaction with
TNF-alpha, preventing the drug from functioning and leading to more rapid drug clearance. [14805]
Microbiology
IMMUNE DEFICIENCIES
Splenectomy
The spleen acts as both a blood filter capable of removing circulating pathogens and as a major site of opsonizing
antibody synthesis. Asplenic patients are prone to infections caused by encapsulated organisms such as
Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis. [732]
Dermatology
Staphylococcal scalded skin syndrome

Staphylococcal scalded skin syndrome occurs in infants and children due to the production of exfoliative exotoxins by
Staphylococcus aureus. The toxins cleave desmoglein in desmosomes, leading to widespread epidermal blistering
and shedding, especially with gentle pressure (ie, Nikolsky sign). Mucous membranes are spared. [680]
Bartonella
Bartonella henselae causes cat-scratch disease, bacillary angiomatosis, and culture-negative endocarditis. Cat-scratch
disease is characterized by low fever, lymphadenopathy, and a self-limited course. [1898]
Cutaneous larva migrans

Hookworm infections are transmitted via direct contact between human skin and contaminated soil/sand (eg,
walking barefoot). Dermal penetration is often characterized by an intensely pruritic papule that may form
serpiginous tracks due to the subcutaneous migration of hookworm larvae. [15431]
Febrile neutropenia
Ecthyma gangrenosum is a cutaneous necrotic disease with a strong association with Pseudomonas aeruginosa
bacteremia. It occurs from perivascular invasion and release of tissue-destructive exotoxins, causing vascular
destruction and insufficient blood flow to patches of skin that become edematous and subsequently
necrose. Pseudomonas infections are common in patients who are neutropenic, are hospitalized, have burns, or have
indwelling catheters. [973]
Herpes zoster
A unilateral vesicular rash localized on a single dermatome in an older patient is most likely herpes
zoster. Postherpetic neuralgia is the most common neurologic complication of varicella zoster virus infection. [1553]
Leishmaniasis
Leishmania species are obligate intracellular protozoa that mature in macrophages and can be identified on biopsy by
the presence of rod-shaped kinetoplasts. They are transmitted to humans by infected sand flies and cause the clinical
syndrome of cutaneous leishmaniasis, characterized by a chronic, pinkish papule that evolves into a nodule or plaque.
[15448]
Leprosy
The severity of leprosy, a systemic illness caused by Mycobacterium leprae, depends on the strength of the cell-
mediated immune (CMI) response, with tuberculoid leprosy representing the milder form (intact Th1 CMI response)
and lepromatous leprosy, the more severe form (weak CMI response). [1313]
Lice infestation
Pediculus humanus capitis (ie, head lice) infestation is common in school children and adults who come into close
contact with infested individuals. Transmission is usually by direct contact. The eggs (nits) are attached to the hair
shaft and can be identified on inspection. First-line treatment includes topical pediculicides (eg, permethrin,
ivermectin). [17230]
Scabies
Scabies is a highly contagious disease that presents with an intensely pruritic rash (usually worse at night) involving
the flexor surfaces of the wrist, lateral surfaces and webs of the fingers, elbow extensor surfaces, and axillary
folds. Patients usually have excoriations with small, crusted, red papules scattered around the affected
areas. Diagnosis is confirmed by skin scrapings from excoriated lesions that show mites, ova, and feces under light
microscopy. [10168]
Scabies is a human mite infection associated with a pruritic papular rash with excoriations and burrows. Patients with
impaired cell-mediated immunity (eg, HIV) often develop a very high mite burden. Treatment with topical
permethrin and/or ivermectin is generally curative. [13911]

The most common cause of nonpurulent cellulitis is beta-hemolytic streptococci, particularly group A
streptococcus. The most common cause of purulent cellulitis is Staphylococcus aureus. [15339]
Tinea
Pityriasis versicolor (tinea versicolor) is a superficial skin infection caused by Malassezia species. It causes
erythematous, hyper- or hypopigmented macules and patches. Malassezia forms spores and hyphae, producing the
characteristic "spaghetti and meatballs" appearance on KOH preparation light microscopy. [104]
Tinea corporis presents with round or ovoid lesions with a raised, scaly border and central clearing. Trichophyton
rubrum is the most common cause and infects keratinized matter in the stratum corneum of the superficial epidermis
but does not invade the dermis or subcutaneous tissues. [15579]
Warts
Cutaneous warts are caused by human papillomavirus (HPV) and typically present as skin-colored papules with a dry,
whitish surface. HPV is usually transmitted by direct contact. [15364]
Otitis externa
Pseudomonas aeruginosa is a nonlactose-fermenting, oxidase-positive, motile, Gram-negative rod. It is the most
common cause of malignant otitis externa (MOE), a serious infection of the ear seen in elderly diabetic
patients. MOE presents with exquisite ear pain and drainage, and granulation tissue is often seen within the ear
canal. [8342]
Otitis media
Acute otitis media usually occurs after a viral upper respiratory infection causes obstruction of the eustachian
tube. This obstruction leads to the accumulation of secretions, which encourages bacterial growth. The most
common bacterial causes are respiratory colonizers, including Streptococcus pneumoniae, Haemophilus influenzae,
and Moraxella catarrhalis. [18141]
Nontypeable strains of Haemophilus influenzae are part of the normal upper respiratory tract flora and are a
common cause of acute otitis media, sinusitis, and bronchitis. Because nontypeable strains do not form a
polysaccharide capsule, immunity is not conferred by vaccination with the H influenzae type b vaccine. [1102]
Upper respiratory tract infections

For a purified RNA molecule to induce viral protein synthesis in a host cell, it must be able to act directly as mRNA
using the host's intracellular machinery for translation. Therefore, in general, purified single-stranded positive-sense
RNA can be infectious; single-stranded negative sense or double-stranded RNA is not. [1373]
GENITOURINARY TRACT INFECTIONS
Bacterial vaginosis
Bacterial vaginosis is associated with a grayish-white, malodorous vaginal discharge due to an overgrowth of
Gardnerella vaginalis, a facultative anaerobic, gram-variable rod. Clue cells (squamous epithelial cells covered with
bacterial organisms) are seen on wet mount microscopy or cytology. [1929]
Bacterial vaginosis is caused by a disruption of the vaginal bacterial flora and is characterized by a thin, gray-white,
malodorous vaginal discharge. Clue cells (squamous epithelial cells with adherent bacteria) are seen on wet mount
microscopy. [11765]
Cervicitis
Neisseria gonorrhoeae and Chlamydia trachomatis can cause acute cervicitis (eg, purulent cervical discharge, friable
cervix). Untreated, cervicitis can progress to pelvic inflammatory disease and long-term complications such as tubal
factor infertility and ectopic pregnancy. [1008]
HSV infection
Primary genital herpes (herpes simplex virus type 1 or 2 infection) presents as multiple, grouped vesicles on the
genitals that progress to ulcers. Primary infections can cause systemic symptoms (eg, fever, malaise) and painful
inguinal lymphadenopathy. Because HSV can invade and lie latent in the sacral dorsal root ganglia, patients are at
risk for viral reactivation and recurrent genital lesions. [1549]
Mucocutaneous candidiasis
Antibiotic use alters the balance of normal vaginal flora (eg, decreases the number of gram-positive lactobacilli) and
facilitates Candida overgrowth. Patients can develop vulvovaginal candidiasis, which presents with
vulvar/vaginal/perianal pruritis; erythema; and a thick, white vaginal discharge. [110]
Pelvic inflammatory disease

A ruptured ectopic pregnancy can cause abdominal pain, vaginal bleeding, and hemodynamic instability. A common
risk factor is tubal scarring from a prior upper genital tract infection (ie, pelvic inflammatory disease) due to Neisseria
gonorrhoeae or Chlamydia trachomatis. [1932]
Urinary tract infection

The most common cause of urinary tract infection is Escherichia coli, a nitrate reductase–producing
bacterium. Dipstick analysis should be significant for leukocyte esterase, nitrites, and a mildly acidic pH. [1096]
Vulvovaginitis
Vulvovaginal candidiasis typically presents with thick, white, clumpy vaginal discharge; vulvovaginal erythema and
pruritus; and pseudohyphae on wet mount microscopy. Treatment is with an antifungal medication (eg, fluconazole).
[15546]
Trichomonas vaginalis is a sexually transmitted motile protozoan which can be seen on wet mount microscopy of
vaginal discharge. It presents with yellow-green, frothy vaginal discharge and vulvovaginal erythema. [11802]
Achalasia
Chagas disease is caused by a chronic infection by Trypanosoma cruzi and causes secondary achalasia due to
destruction of the submucosal (Meissner) and myenteric (Auerbach) plexus. Other manifestations can include
nonischemic cardiomyopathy and megacolon. [278]
Esophagitis
Infectious esophagitis is common in patients with HIV. The most common cause is Candida albicans, although
cytomegalovirus and herpes simplex virus are also frequently implicated. Diagnosis is based on endoscopic and
microscopic findings. [283]
Schistosomiasis
Schistosomiasis, a parasitic blood fluke infection, is common in rural portions of sub-Saharan Africa. Initial infection is
often asymptomatic, but some patients develop chronic hepatosplenic (eg, portal hypertension,
hepatosplenomegaly, esophageal varices) or urinary (eg, bladder cancer) complications years or decades later. The
presence of eosinophilia is an important diagnostic clue. [18523]
HEPATIC DISORDERS
Hepatitis a
Transmission of the hepatitis A virus occurs through the fecal-oral route and is common in areas with overcrowding
and poor sanitation. Outbreaks frequently result from contaminated water or food, and raw or steamed shellfish is a
common culprit in the United States. [372]
Hepatitis b
The main modes of transmission of hepatitis B virus include sexual (among both heterosexual partners and men who
have sex with men) and percutaneous (eg, intravenous drug use, needlestick accidents, blood transfusions). The risk
of sexual transmission of hepatitis C virus is low. [386]
Hepatitis c
Chronic hepatitis C virus infection is treated with direct-acting antiviral (DAAs) medications such as ledipasvir and
sofosbuvir. These medications target specific HCV enzymes (eg, protease, NS5A, RNA polymerase), which inhibits
viral replication and assembly. Treatment with DAAs results in cure in >97% of patients. [15144]
The hepatitis C virus is genetically unstable because it lacks proofreading 3' → 5' exonuclease activity in its RNA
polymerase. Its envelope glycoprotein sequences also contain a hypervariable region prone to frequent genetic
mutation. [388]
Hepatitis d
The hepatitis B surface antigen of hepatitis B virus must coat the hepatitis D antigen of hepatitis D virus before it can
infect hepatocytes and multiply. [47]
Liver abscess
Staphylococcus aureus can cause hepatic abscesses via hematogenous seeding of the liver. Enteric bacteria (eg,
Escherichia coli, Klebsiella, and enterococci) can cause hepatic abscesses by ascending the biliary tract (ie, ascending
cholangitis), portal vein pyemia, or direct invasion from an adjacent area (eg, cholecystitis). [62]
Appendicitis
Intraabdominal infections are polymicrobial, with B. fragilis and E. coli being the most prominent organisms isolated.
[7573]
Clostridioides difficile infection

Clostridioides (formerly Clostridium) difficile infection is associated with yellow-white, patchy pseudomembranes on
the bowel mucosa. These pseudomembranes consist of a neutrophil-predominant inflammatory infiltrate, fibrin,
bacteria, and necrotic epithelium. Patients may develop a nonobstructive colonic dilation known as toxic megacolon,
which can lead to colonic perforation. [6510]
Clostridioides difficile commonly presents with watery diarrhea and abdominal pain; hospitalization and antibiotic
use increase the risk of contracting the disease. A nucleic acid amplification test is the most sensitive method for
diagnosis of C difficile infection in patients with clinical symptoms. [15049]
Pathogenic Clostridioides difficile can proliferate due to loss of commensal gut flora following the use of broad-
spectrum antibiotics (eg, clindamycin). C difficile toxins A and B stimulate an inflammatory reaction and disrupt the
actin cytoskeletal structure, resulting in pseudomembranous colitis characterized by crampy abdominal pain, watery
diarrhea, and leukocytosis. [1397]
Alteration of the normal intestinal microbial flora (eg, antibiotic therapy, gastric acid suppression) can allow
overgrowth of pathogenic strains of Clostridioides difficile, which produce enterotoxin (toxin A) and cytotoxin (toxin
B). Clinical disease can range from transient diarrhea to severe pseudomembranous colitis. [1398]
Cryptosporidiosis
Cryptosporidium may lead to severe and protracted diarrhea in immunocompromised patients (eg, advanced
HIV). Diagnosis is usually made by visualizing acid-fast staining oocysts in the stool. The presence of basophilic
organisms lining the brush border on intestinal histopathology is also diagnostic. [7642]
Strongyloides
Strongyloides stercoralis infection occurs when filariform (infective) larvae in contaminated soil penetrate human
skin, travel to the lungs through the bloodstream/lymphatics, and ascend the tracheobronchial tree to be
swallowed. They then enter the small intestine, mature, and reside in the mucosa. Rhabditiform (noninfective)
larvae are excreted into the stool and can be detected on stool microscopy, which is diagnostic. [8873]
MISCELLANEOUS
Botulism
Infant botulism can result from consumption of honey, which frequently contains C botulinum spores that can
germinate and produce botulinum toxin. Symptoms of infant botulism include constipation, mild weakness, lethargy,
poor feeding, and, in severe cases, flaccid paralysis. The diagnosis can be confirmed by identification of C botulinum
spores or toxins in the stool. [1400]

Mycoplasma pneumoniae binds an oligosaccharide on the respiratory epithelium that is also present on erythrocytes,
leading to the generation of cross-reacting IgM antibodies (cold agglutinins). Patients with M pneumoniae infections
often develop mild, transient hemolytic anemia that resolves as IgM antibody titers decline (6-8 weeks after infection
begins). [957]
Sickle cell
Patients with sickle cell disease become functionally asplenic within the first few years of life due to repeated
microinfarction of splenic vascular beds. This dramatically increases the risk for fulminant infections with
encapsulated bacterial organisms, particularly Streptococcus pneumoniae. Patients with sickle cell disease are also at
increased risk for other bacterial infections, most notably salmonella osteomyelitis. [896]
In patients with sickle cell anemia and other chronic hemolytic disorders, the most common viral cause of an aplastic
crisis is infection of erythroid progenitor cells with parvovirus B19, a nonenveloped single-stranded DNA virus. [1496]
Infectious Diseases
ANTIMICROBIAL DRUGS
Acyclovir
The most effective treatment for herpes simplex virus encephalitis is intravenous acyclovir; whose mechanism of
action is complete inhibition of the viral DNA polymerase (synthesizes viral DNA). [11729]
Antimicrobial resistance
A change in the structure of penicillin-binding proteins that prevents cephalosporin binding is one mechanism of
bacterial resistance to cephalosporins. [2111]
Cephalosporins
Penicillins and cephalosporins function by irreversibly binding to penicillin-binding proteins such as transpeptidases.
[2110]
Shigella
Conjugation is a form of horizontal gene transfer that involves the formation of a pilus and the direct passing of
genetic material from one bacterium to another. It is a common source of antibiotic resistance and environmental
adaptation. The other forms of bacterial horizontal gene transfer are transduction (viral vector) and transformation
(uptake of free DNA). [105599]
Actinomycosis
Actinomyces is an anaerobic, gram-positive bacillus with acute-angle branching. It can colonize intrauterine devices
(IUDs) and may cause pelvic inflammatory disease (eg, fever, abdominal pain, mucopurulent cervical
discharge). Treatment is with IUD removal and penicillin. [15204]
Actinomyces species are gram-positive, branching, filamentous bacteria that may cause cervicofacial infections when
introduced to the submucosa during mechanical trauma (eg, tooth extraction). Manifestations include a slowly
enlarging, nonpainful, chronic mandibular mass that evolves into multiple abscesses and sinus tracts draining yellow-
orange sulfur granules. [1678]
Acute diarrhea
Shigella species require a low infectious dose to cause gastrointestinal disease. The mechanism primarily involves
their ability to survive in the acidic (low pH) gastric environment. [1136]
Enterohemorrhagic Escherichia coli (EHEC) is primarily contracted after eating undercooked ground beef. EHEC
produces Shiga toxin, which causes hemorrhagic colitis and can lead to hemolytic-uremic syndrome (HUS). HUS is
characterized by acute renal failure, thrombocytopenia, and microangiopathic hemolytic anemia; children age <10
are at greatest risk. [1097]
Nontyphoidal Salmonella causes gastroenteritis that classically causes self-limited fever, vomiting, and
diarrhea. Invasive disease can occur, including spread to the long bones (osteomyelitis), and risk is greatest in those
with sickle cell disease, impaired immunity, or extremes of age. [15205]
Acute-onset bloody diarrhea is most commonly due to Escherichia coli O157:H7, Shigella, or Campylobacter
infection. Shigella infection also classically causes high fever and left-sided abdominal tenderness (due to
rectosigmoid involvement) and often occurs in outbreaks (eg, day care center). [105601]
Campylobacter gastroenteritis, which is typically acquired from contaminated poultry or domesticated animals (eg,
dogs), causes an inflammatory diarrhea characterized by fecal leukocytes and red blood cells. Manifestations include
fever, abdominal pain, and diarrhea that may be grossly bloody. [1422]
Campylobacter jejuni is an oxidase-positive, gram-negative, curved rod that is a leading cause of gastroenteritis. The
pathogen is a zoonotic organism most commonly contracted by consuming contaminated, undercooked poultry. The
infection is marked by fever, abdominal pain, and diarrhea that may be bloody. [6731]
Animal and human bite injuries

Pasteurella multocida is a cause of soft-tissue infection that develops within 24 hours following a dog or cat
bite. Management includes wound care and antibiotics targeted against this organism. [11547]
Anthrax
Bacillus anthracis is a large, sporulating, gram-positive rod that is encased in an antiphagocytic polypeptide capsule
composed of D-glutamic acid. Inhalation of B anthracis spores can cause pulmonary anthrax, which is usually
characterized by nonspecific symptoms followed by hemorrhagic mediastinitis, shock, and death. [972]
Aminoglycosides work by interfering with the 30S ribosomal subunit and causing the cell to misread messenger RNA,
thereby halting protein synthesis. An important mechanism of resistance is the methylation of the aminoglycoside-
binding portion of the ribosome, which inhibits the ability of aminoglycoside to interfere with protein translation.
[11709]
Echinocandins (eg, caspofungin, micafungin) are antifungal medications that inhibit synthesis of the polysaccharide
glucan, an essential component of the fungal cell wall. [277]
The main groups of antifungal drugs are polyenes, azoles, echinocandins, and pyrimidines. Polyene antifungals (eg,
amphotericin B, nystatin) act by binding ergosterol in the fungal cell membrane. [271]
The aminoglycoside streptomycin inhibits protein synthesis by inactivating the 30S (small) ribosomal subunit.
Decreased activity of bacterial catalase-peroxidase is a mechanism of mycobacterial resistance to isoniazid. Structural
alteration of enzymes involved in RNA synthesis (DNA dependent RNA polymerase) is the mechanism through which
organisms become resistant to rifampin. [1310]
Bartonella
Bacillary angiomatosis is primarily seen in patients with advanced AIDS. It is caused by the gram-negative bacterium
Bartonella henselae, which is typically transmitted by a cat scratch. Patients usually develop highly vascular,
violaceous, cutaneous lesions over weeks or months. Histology of the lesions reveals large endothelial cells forming
small vascular channels with a surrounding inflammatory infiltrate. [15067]
Catscratch disease is caused by Bartonella henselae, a gram-negative coccobacillus transmitted by a cat scratch or
bite. Patients commonly present with tender lymphadenopathy proximal to the inoculation site (eg, axillary,
epitrochlear lymph nodes). Lymph node histopathology often shows necrotizing granulomas and stellate-shaped
microabscesses. [20207]
Catheter related bloodstream infection

The most important steps for prevention of central venous catheter infections are as follows:
- Proper hand hygiene
- Full barrier protection during insertion
- Chlorhexidine disinfection
- Avoidance of the femoral insertion site
- Removal of the catheter when it is no longer needed [8282]
Chancroid
Chancroid, due to Haemophilus ducreyi, presents as deep, painful (you "do cry" with H ducreyi) ulcers with ragged
borders that are associated with a grey exudate and inguinal lymphadenopathy. Diagnosis is established by Gram
stain and culture of the organism from a scraping of the ulcer base. [11927]
Cholera
Vibrio cholerae and enterotoxigenic Escherichia coli cause a purely toxin-mediated watery diarrhea. The toxins
secreted by these organisms modify electrolyte handling by enterocytes but do not cause cell death; therefore, no
erythrocytes or leukocytes are typically noted on stool microscopy. [976]
Vibrio cholerae must survive the acidic environment of the stomach to reach the small intestine and cause
disease. Because the organism is easily destroyed by acid, a high burden of organisms must be ingested to cause
infection. However, conditions that decrease gastric acidity (eg, antacid use) lower the minimum infectious dose of V
cholerae by multiple orders of magnitude. [977]
Clostridial myonecrosis
Clostridium septicum is a spore-forming, exotoxin-producing, gram-positive organism that is the most common cause
of spontaneous gas gangrene (eg, rapid-onset pain, hemorrhagic bullae, tissue crepitus). Underlying colonic
malignancy is the greatest risk factor for infection. [15027]
Clostridium perfringens causes late-onset food poisoning and clostridial myonecrosis (gas gangrene). The food
poisoning is toxin-mediated, late-onset, and causes transient watery diarrhea. [1394]
Clostridium difficile requires additional contact precautions, including handwashing with soap and water, a gown for
any patient contact, and nonsterile gloves that should be changed after contact with contaminated
secretions. Alcohol-based hand sanitizers do not kill the bacterial spores. [11459]

The virulence of Streptococcus pneumoniae is predominantly due to its polysaccharide capsule, which impedes
phagocytosis and complement binding. [6643]
Mycoplasma pneumoniae is a leading cause of atypical pneumonia. Because this pathogen lacks a cell wall, it does
not show up on Gram stain and cannot be treated with beta-lactam antibiotics. Protein synthesis inhibitors (eg,
macrolides, tetracycline) are the treatment of choice. [6781]
Cystic fibrosis
In patients with cystic fibrosis, pathogenic bacteria colonize the respiratory tract early in the disease course. The
leading pathogen in adults is Pseudomonas aeruginosa, which forms a thick biofilm to prevent its full elimination
from the body. [14916]
Patients with cystic fibrosis are at risk for pulmonary exacerbations due to Staphylococcus aureus, Pseudomonas
aeruginosa, nontypeable Haemophilus influenzae, and Burkholderia cepacia complex. [19381]
Diphtheria
Lysogenic bacteriophages are responsible for converting nonpathogenic Corynebacterium into toxigenic
Corynebacterium. Toxigenic strains elaborate the diphtheria exotoxin, which causes pseudomembranous pharyngitis
and potentially life-threatening systemic effects (eg, myocarditis, neuritis). [1389]
Diphtheria toxin is an AB exotoxin that ribosylates and inactivates elongation factor-2. This action inhibits protein
synthesis and ultimately leads to cell death. [1094]
Toxigenic strains of Corynebacterium diphtheriae produce diphtheria toxin, which irreversibly inhibits host protein
synthesis due to ADP-ribosylation of elongation factor-2. Local effects include pseudomembranous pharyngitis;
systemic effects include potentially life-threatening myocarditis and neuritis. Immunization with diphtheria toxoid
generates protective circulating IgG against the exotoxin B subunit. [1092]
Diphtheria exotoxin inhibits host cell protein synthesis by catalyzing the ADP-ribosylation of host cell elongation
factor-2. [1093]
The primary treatment for diphtheria is diphtheria antitoxin (passive immunization), which inactivates circulating
toxin. Antibiotics should also be administered to reduce continued production of toxin. [1388]
Diphtheria toxin and pseudomonal exotoxin A act by ribosylating and inactivating elongation factor-2, inhibiting host
cell protein synthesis and causing cell death. [1390]
Ehrlichiosis & anaplasmosis
Ehrlichia chaffeensis is harbored in white-tailed deer and transmitted to humans by tick bite. It replicates in vacuoles
within monocytes and forms mulberry-shaped, intraleukocytic inclusions (morulae). Manifestations usually include
nonspecific symptoms (eg, fever, chills, myalgia), maculopapular rash, and significant laboratory abnormalities,
particularly lymphopenia. [15543]
Endocarditis
Staphylococcus aureus causes acute bacterial endocarditis with rapid onset of symptoms, including shaking chills
(rigors), high fever, dyspnea on exertion, and malaise. In intravenous drug users, it can cause right-sided endocarditis
with septic embolization into the lungs. [729]
Streptococcus gallolyticus (formerly S bovis) endocarditis and bacteremia are associated with gastrointestinal lesions
(colon cancer) in ~25% of cases. When S gallolyticus is cultured in the blood, workup for colonic malignancy with
colonoscopy is essential. [1001]
Viridans streptococci produce dextrans that aid them in colonizing host surfaces, such as dental enamel and heart
valves. These organisms cause subacute bacterial endocarditis, classically in patients with preexisting cardiac valvular
defects after dental manipulation. [1002]
Enterococcus is a component of the normal colonic and urogenital flora and is capable of growing in hypertonic saline
and bile. It is gamma-hemolytic, catalase-negative, and pyrrolidonyl arylamidase-positive. Genitourinary
instrumentation or catheterization has been associated with enterococcal endocarditis. [733]
Epiglottitis
Epiglottitis causes rapidly progressive respiratory distress and a swollen epiglottis ("thumbprint sign") on lateral neck
x-ray. The most common pathogen is Haemophilus influenzae (ie, type b, nontypeable strains), a gram-negative
coccobacillus that often causes concomitant bacteremia. [20014]
Febrile neutropenia
Chemotherapy-associated neutropenic fever is most often caused by endogenous commensal bacteria that have
translocated across damaged mucosal sites. [15566]
Patients with neutropenic fever (ie, temperature >38.3 C [>101 F] and absolute neutrophil count <500/mm3) are at
risk for overwhelming bacterial infections. The majority of severe infections that cause rapid clinical deterioration
(eg, 4 hours) are caused by gram-negative organisms that produce endotoxins. [106465]
Foodborne illness
Staphylococcal food poisoning is mediated by the ingestion of a preformed, heat-stable enterotoxin that induces
rapid-onset (<6 hours) nausea and vomiting. Most cases arise due to improper food handling and storage. Common
culprit foods include eggs, dairy products, and mayonnaise-based salads. [644]
Staphylococcal foodborne illness is due to the consumption of a preformed enterotoxin in contaminated food. Most
cases can be prevented by washing hands thoroughly prior to food preparation (prevents contamination) and
ensuring proper refrigerated storage (prevents bacterial proliferation/enterotoxin production). [15210]
Group b streptococcal infection
Streptococcus agalactiae (group B Streptococcus), one of the most common causes of early neonatal sepsis, is
typically identified by the presence of a narrow zone of beta-hemolysis when plated on blood agar. It is also
identified by the production of CAMP factor, which enhances beta-hemolysis by particular strains of Staphylococcus
aureus. [15578]
Haemophilus influenzae
Haemophilus influenzae is a "blood-loving" organism that requires X (hematin) and V (NAD+) factors for growth. This
can be accomplished by growing H influenzae in the presence of Staphylococcus aureus and demonstrating the
"satellite phenomenon," whereby H influenzae grow only near the β-hemolytic S aureus colonies that produce the
needed X and V factors. [963]
Legionella
Intracellular bacterial organisms such as Legionella pneumophila are primarily countered by the cell-mediated
immune response. Intracellular pathogens that replicate within phagosomes (eg, Legionella, Mycobacterium
tuberculosis) trigger activation and differentiation of T-helper subtype 1 cells with subsequent macrophage activation
via interferon-gamma. [14923]
Leptospirosis
Leptospirosis is a zoonotic infection caused by the motile spirochete Leptospira. Transmission primarily occurs when
humans come into contact with water contaminated with animal urine during outdoor recreational or occupational
activities. Patients classically have a mild, self-limited, flulike illness but may develop more serious complications
such as renal or hepatic failure. [15407]
Listeria
Listeria monocytogenes is a facultative, intracellular, gram-positive rod that produces a very narrow zone of beta
hemolysis on blood agar, shows tumbling motility at room temperature, and can grow at refrigerated
temperatures. Intracellular pathogens such as Listeria are largely eliminated by the cell-mediated immune response
(eg, T-cells, macrophages, cytokines). Patients with impaired cell-mediated immunity are at risk for invasive Listeria
infections. [1391]
Listeria monocytogenes is a gram-positive rod associated with outbreaks of gastroenteritis via ingestion of
contaminated foods (eg, unpasteurized milk, deli meats). It can cause sepsis in susceptible patients, including
neonates, older adults, pregnant women, and immunocompromised individuals. [19196]
Listeria monocytogenes is a facultative intracellular, gram-positive rod that most often causes febrile
gastroenteritis. Pathogenesis is mediated largely by listeriolysin O, an enzyme that creates pores in phagosomes,
which allows the bacteria to escape lysosomal destruction. Pregnant women in the third trimester are at greatest
risk; infection increases the risk of fetal demise, early labor, and neonatal infection. [14895]
Meningitis
The Haemophilus influenzae type b (Hib) vaccine induces anticapsular antibodies that facilitate complement-
mediated phagocytosis of the bacterium. The vaccination series has drastically reduced the incidence of invasive
disease caused by Hib, such as meningitis, bacteremia, pneumonia, and epiglottitis. [1103]
Listeria is a relatively common foodborne illness associated with outbreaks after the consumption of contaminated
food, particularly processed meats and dairy products. Healthy patients may develop gastroenteritis; patients with
impaired cell-mediated immunity are at risk for invasive infection (eg, sepsis, meningoencephalitis); and listeriosis in
pregnancy is associated with adverse fetal outcomes (eg, fetal death, premature birth). [11650]
Group B Streptococcus is a common cause of neonatal meningitis. Its major virulence factor is a polysaccharide
capsule with abundant sialic acid, which dramatically reduces the effectiveness of host defense mechanisms due to
molecular mimicry. [14883]
Ampicillin is the treatment of choice for Listeria, which is not sensitive to cephalosporins. Listeria most commonly
causes disease in those with deficient cell-mediated immunity, such as young infants or immunocompromised
patients. [1393]
Rifampin is the most frequently used agent for chemoprophylaxis of meningococcal disease. Persons with exposure
to the respiratory secretions of a patient with meningococcal disease require chemoprophylaxis. Vaccination is an
important public health strategy but is not useful for post-exposure prophylaxis. [1004]
Meningococci
The Thayer-Martin medium is used to isolate pathogenic Neisseria species such as N meningitidis and N
gonorrhoeae. It is a chocolate sheep blood agar that contains vancomycin to inhibit the growth of gram-positive
organisms; colistin and trimethoprim to inhibit gram-negative bacteria (other than pathogenic Neisseria); and
nystatin to inhibit yeasts. [1024]
Necrotizing soft tissue infections

Necrotizing fasciitis is a severe infection of the subcutaneous tissue and deep fascia and is a surgical emergency. The
infection is often polymicrobial, but monomicrobial cases due to Streptococcus pyogenes (group A Streptococcus) can
also occur. S pyogenes is a PYR-positive, beta-hemolytic, gram-positive coccus that grows in chains. [8857]
Nontuberculous mycobacterial diseases

Mycobacterium avium complex (MAC) infections are common in patients with advanced AIDS. The bacterium often
spreads through the bloodstream and reticuloendothelial system and causes nonspecific symptoms (eg, fever,
fatigue, weight loss, diarrhea), lymphadenopathy, and hepatosplenomegaly. Diagnosis is often made on blood
culture or bone marrow aspirate (intracellular acid-fast bacteria that are not Mycobacterium tuberculosis). [1312]
Parapneumonic effusion & Empyema

Empyema is an accumulation of pus within the pleural space that can result from multiple sources of bacterial
contamination. It usually represents advanced progression of a complicated parapneumonic effusion resulting from
bacterial translocation from the alveoli. [18779]
Pertussis
Bacillus anthracis edema factor is an adenylate cyclase that increases intracellular cyclic AMP, leading to neutrophil
and macrophage dysfunction and tissue edema. This mechanism of action is similar to that of adenylate cyclase
toxin, produced by Bordetella pertussis. [1101]
Bordetella pertussis, a gram-negative coccobacillus, most commonly infects unvaccinated/undervaccinated infants

and children. The bacterium is largely noninvasive and secretes several exotoxins that damage ciliated respiratory
epithelium. Symptoms include a mild cough and rhinorrhea followed by severe, paroxysmal cough that may be
associated with an inspiratory whoop and vomiting. [7650]
Pharyngitis
Group A streptococcus (GAS) should be suspected in those with acute-onset sore throat, exudative
tonsillopharyngitis, and no evidence of viral symptoms (eg, coryza, cough, conjunctivitis). In-office throat swab with
rapid antigen detection testing (immunoassay for GAS antigens) can provide on-site microbiologic confirmation,
allowing for early initiation of treatment. [15418]
The major virulence factor of Streptococcus pyogenes is M protein, an alpha-helical coiled-coil protein that shares
structural homology with tropomyosin and myosin. It extends from the cell wall and prevents phagocytosis, inhibits
complement binding, and mediates bacterial adherence. Antibodies against M protein form shortly after acute
infection and may cross-react with epitopes on myosin, leading to rheumatic carditis. [723]
Plague
Yersinia pestis, the cause of bubonic plague, is transmitted primarily by rodent fleas. Manifestations include rapid-
onset systemic symptoms (eg, high fever, chills, weakness, headache) and painful, purulent regional
lymphadenitis. First-line treatment is with aminoglycosides, which block bacterial protein synthesis by binding to the
30S ribosomal subunit. [107139]
Bubonic plague causes a febrile illness with regional inflammatory lymphadenopathy (buboes). The underlying
pathogen is Yersinia pestis, a small gram-negative bacillus/coccobacillus that exhibits bipolar staining (resembling a
closed safety pin). The major environmental reservoir is rodents; transmission usually occurs via rodent fleabite.
[15400]
Glomerulonephritis is associated with prior streptococcal pharyngeal or skin infection; acute rheumatic fever is
associated with prior streptococcal pharyngitis but not skin infection. Streptococci are catalase-negative,
staphylococci are catalase-positive. Streptococcus pyogenes (Group A Streptococcus) is β-hemolytic, bacitracin-
susceptible, and pyrrolidonyl arylamidase-positive. Streptococcus pneumoniae is bile-soluble and optochin-
susceptible. [722]
Rheumatic fever
Acute rheumatic fever is a complication of untreated group A streptococcal pharyngitis. Rheumatic heart disease is
the most common cause of acquired valvular heart disease and cardiovascular death in developing countries. The
incidence of acute rheumatic fever and rheumatic heart disease has been reduced in industrialized nations with
prompt treatment of streptococcal pharyngitis with penicillin. [726]
Rocky mountain spotted fever

Rocky mountain spotted fever is a tick-borne illness due to Rickettsia rickettsii, a weakly gram-negative, obligate
intracellular organism that has an affinity for vascular endothelial cells. Patients usually have nonspecific symptoms
(eg, fever, malaise, myalgia) followed by a macular-petechial rash that begins on the ankles and wrists and spreads to
the center of the body as well as to the palms and soles. Urgent treatment with doxycycline, an inhibitor of bacterial
protein synthesis, is required. [15075]
Salmonella
Typhoid fever is caused by Salmonella Typhi or Paratyphi and presents with escalating fever, followed by abdominal
pain, formation of rose spots on the chest/abdomen, and hemorrhagic enteritis with possible bowel
perforation. Humans are the only reservoir; transmission is fecal-oral and primarily occurs due to ingestion of food or
water contaminated with feces. [1138]
Typhoidal strains of Salmonella contain a capsular antigen (Vi) and other virulence factors that inhibit neutrophil
phagocytosis, neutrophil recruitment, and macrophage-mediated destruction. Therefore, typhoidal Salmonella
undergoes extensive replication in macrophages and is able to spread through the lymphatic and reticuloendothelial
system, leading to widespread systemic disease (typhoid fever). [1137]
Scarlet fever
Scarlet fever is characterized by fever, pharyngitis, sandpaper-like rash, circumoral pallor, and a strawberry tongue. It
is caused by strains of Group A streptococcus that produce pyrogenic exotoxins. Scarlet fever can predispose to
acute rheumatic fever and glomerulonephritis. [8565]
Sepsis
Pathogenesis of Escherichia coli sepsis involves the release of lipopolysaccharide (ie, endotoxin) from bacterial
cells. Lipid A is the major virulence factor of lipopolysaccharides that induces macrophages to release cytokines (eg,
IL-1, tumor necrosis factor-alpha), leading to the manifestations of septic shock (eg, end-organ dysfunction). [1141]
Septic arthritis
Septic arthritis in a young, sexually active adult should raise suspicion for disseminated Neisseria gonorrhoeae
infection. Patients may also have the triad of polyarthritis, a vesiculopustular skin rash, and tenosynovitis. N
gonorrhoeae is a gram-negative diplococci that is usually identified by microscopy, culture, or nucleic acid
amplification. [1007]

Staphylococcus aureus is the most common cause of skin and soft-tissue abscess (eg, furuncle). Treatment of the
abscess with incision and drainage and antibiotics can eliminate the local infection but does not eliminate
colonization of the anterior nares and skin. Therefore, recurrent infections are common. [727]
"Hot tub folliculitis" is a superficial and self-limited Pseudomonas aeruginosa infection of the hair follicles that tends
to occur in minor outbreaks following exposure to a pool or spa in which the chemicals have not been maintained at
appropriate concentrations. Pseudomonas are gram-negative, oxidase-positive, nonlactose-fermenting, motile rods
that produce green pigment. [974]
Poststreptococcal glomerulonephritis is a potential complication of group A streptococcal infection (eg, impetigo,

pharyngitis). Symptoms include proteinuria (often associated with periorbital or generalized edema) and
hematuria. Acute rheumatic fever is a postinfectious sequelae of streptococcal pharyngitis only, not impetigo. [725]
Pseudomonas aeruginosa is a major pathogen in burn patients. Only a few specific penicillins (eg, ticarcillin,
piperacillin) and cephalosporins (eg, ceftazidime, cefepime) have activity against it. Certain aminoglycosides,
fluoroquinolones (eg, ciprofloxacin, levofloxacin), and carbapenems (eg, imipenem, meropenem) are also effective.
[8858]
Staphylococci
Staphylococcus epidermidis is a common cause of foreign body infections due to its ability to produce adherent
biofilms. [8533]
Streptococcus pneumoniae
Streptococcus pneumoniae is virulent primarily due to a polysaccharide capsule. A conjugant vaccine provides long-
lasting immunity against serotypes in the vaccine but provides no significant immunity against nonvaccinated
serotypes. Therefore, infection can still occur due to serotypes not covered by the vaccine. [14934]
Tetanus
Neonatal tetanus can be prevented by hygienic delivery and umbilical cord care and universal immunization of
women who are pregnant or may become pregnant. Immunized mothers provide passive immunity via
transplacental IgG, protecting infants until they receive active immunization (vaccination) around age 2 months. [968]
Tuberculosis
Mycobacterium tuberculosis infection is controlled by coordination between macrophages and T
lymphocytes. Conditions that impair immune function increase the risk of active tuberculosis; this includes chronic
kidney disease, diabetes mellitus, HIV, substance abuse, malnutrition, and advanced age. [19422]
Active tuberculosis is never treated with drug monotherapy due to the fast emergence of mycobacterial antibiotic
resistance from rapid, selective gene mutations. Isoniazid monotherapy may be used for patients who have a
positive PPD and a negative chest x-ray (ie, no evidence of clinical disease). [1225]
Mycobacterial resistance to isoniazid (INH) can be accomplished through non-expression of the catalase-peroxidase
enzyme or through genetic modification of the INH binding site on the mycolic acid synthesis enzyme. [1223]
Tularemia
Francisella tularensis is a highly virulent, gram-negative coccobacillus transmitted to humans during contact with an
infected wild animal (eg, hare, rabbit, squirrel) or due to a bite with a tick or mosquito that recently fed on an
infected animal. The most common manifestation is ulceroglandular disease, which is characterized by rapid-onset
fever, a single papuloulcerative lesion with central eschar at the site of inoculation, and painful regional
lymphadenopathy. [106795]
Urethritis
Neisseria gonorrhoeae has high antigenic variability of surface molecules (eg, porins, Opa proteins,
lipooligosaccharide), which prevents the formation of protective immunity and leads to susceptibility to repeat
infection. [1026]

The duration of catheterization (especially >48 hr) is the most important risk factor for catheter-associated urinary
tract infection. Prevention strategies include avoiding inappropriate catheterization (eg, placing catheter solely due
to incontinence) and promptly removing the catheter when it is no longer needed. [22577]
Pseudomonas aeruginosa is an oxidase-positive, non-lactose-fermenting, Gram-negative organism. It is a common

cause of urinary tract infections in patients with indwelling bladder catheters. [1146]
Escherichia coli is the most common cause of urinary tract infection (UTI) in both healthy adults and elderly
patients. E coli is part of the normal gastrointestinal flora, and special adhesive proteins (pili) allow some strains to
colonize and ascend the urinary tract, causing UTI, pyelonephritis, and bacteremia/sepsis. UTIs are the most common
cause of E coli bacteremia. [1142]
Nitrites on dipstick are highly specific for urinary tract infections. False negative results can occur when the
incubation time of nitrate reductase–producing bacteria in the bladder is insufficient (eg, frequent urination) to allow
for accumulation of bacterial metabolites. [106575]
Escherichia coli are lactose-fermenting, indole-positive, gram-negative rods that grow on MacConkey agar and are
the most common pathogen causing urinary tract infection. [11766]
Vibrio vulnificus
Vibrio vulnificus is a curved, gram-negative, free-living bacterium that grows in marine environments. Transmission
primarily occurs due to the consumption of raw seafood (eg, oysters) or wound contamination. Manifestations are
often mild, but individuals with liver disease or iron overload are at very high risk of severe, fulminant infection (eg,
sepsis, necrotizing fascitis). [15255]
FUNGAL INFECTIONS
Aspergillosis
Immunosuppressed patients are at risk for Aspergillus fumigatus infection. This fungus produces thin, septate hyphae
with acute, V-shaped branching, causing invasive aspergillosis, aspergillomas, and allergic bronchopulmonary
aspergillosis. [105]
Patients with profound and prolonged neutropenia are at especially high risk for fungal infections. The most common
fungal causes are Aspergillus and Candida species. Invasive pulmonary aspergillosis presents with some combination
of fever, chest pain, cough, dyspnea, and hemoptysis. [11637]
Febrile neutropenia
Microscopic examination of Candida albicans, a common invasive infection in patients with neutropenia, reveals
budding yeasts and pseudohyphae. It can be differentiated from other Candida species by a positive germ tube test.
[109]
Oral thrush is caused by Candida albicans infection and usually presents as white, plaque-like oropharyngeal lesions
that are easily scraped off with a tongue depressor. Affected patients typically have disruption to local microbial flora
(eg, antibiotic use) or impairment in cell-mediated immunity (eg, corticosteroids, HIV). Young, otherwise healthy
patients with thrush should be tested for HIV. [111]
Mucormycosis
Mucormycosis is an opportunistic infection caused by Rhizopus, Mucor, and Absidia species. The classic clinical
picture is paranasal sinus involvement in a diabetic or immunosuppressed patient. The fungi form broad nonseptate
hyphae that branch at right angles. [106]
Normal flora
Expectorated sputum cultures are often contaminated by normal oral flora. The growth of Candida albicans, a
normal commensal of the gastrointestinal tract and skin, almost always indicates oral contamination rather than true
pulmonary infection. [119]
Sporotrichosis
Sporotrichosis typically presents as papulonodular lesions distributed along the lymphatics and is histologically
characterized by granulomatous and neutrophilic inflammation. It is caused by the dimorphic fungus Sporothrix
schenckii, which is often inoculated into the skin during outdoor activities such as gardening. [20205]
Anal cancer
Human papillomavirus (HPV) types 16 and 18 are strongly associated with anal and cervical squamous cell
carcinoma. HIV infection increases the prevalence of HPV infection and the risk of anal carcinoma; this risk is further
augmented in men who have sex with men. [1723]
Epididymitis
Urinalysis in patients with Chlamydia trachomatis infection classically shows sterile pyuria (positive urine white blood
cells, no bacteria on Gram stain, no growth on culture) because the C trachomatis bacterium is an obligate
intracellular parasite with minimal peptidoglycan in its cell wall. The diagnostic test of choice is nucleic acid
amplification testing. [20315]
Gonococcal infection
Neisseria gonorrhoeae is spread sexually by genitourinary secretions and can be prevented by the consistent use of
condoms. Genitourinary infections are often asymptomatic, which increases the risk of spread through the
bloodstream, leading to disseminated gonococcal infection. Patients with disseminated disease typically present with
the triad of polyarthralgia, tenosynovitis, and dermatitis or purulent arthritis. [15518]
IgA protease is produced by Neisseria meningitidis, N gonorrhoeae, Streptococcus pneumoniae, and Haemophilus
influenzae. This enzyme cleaves secretory IgA at its hinge region, rendering it ineffective. Secretory IgA exists on
mucosal surfaces and in secretions and acts to bind and inhibit the action of pili as well as other cell surface antigens
that normally mediate mucosal adherence and subsequent penetration. [560]
Gonococci use their pili to mediate adherence to the mucosal epithelium. Through antigenic variation, each
gonococcus can modify the pilus protein expressed, thereby avoiding host defenses (to some degree) and making
vaccination directed against the pilus protein difficult. [1025]
HIV
Initial HIV infection is often associated with mononucleosis-like symptoms (eg, fever, lymphadenopathy, sore throat)
2-4 weeks after transmission. Important diagnostic clues are oropharyngeal ulcers and a diffuse maculopapular
rash. As the humoral antibody response is not fully activated early in infection, laboratory results typically show HIV
in the serum (positive viral load and p24 antigen) but negative HIV serology. [15069]
HIV pol gene mutations are responsible for acquired resistance to reverse transcriptase inhibitors, protease
inhibitors, and integrase strand transfer inhibitors. Mutations of the env gene enable escape from host-neutralizing
antibodies. [1722]
Most cases of AIDS worldwide are caused by HIV-1. However, AIDS can also be caused by infection with HIV-2, which
is endemic to West Africa. HIV-2 infection is associated with lower viral loads, less risk of transmission, and a slower
progression to AIDS. The diagnosis is often suspected when HIV tests are incongruent (positive screening serology
but indeterminate Western blot and negative plasma HIV-1 RNA). Confirmation can be made using HIV-1/HIV-2
immunodifferentiation assay. [15125]
Patients with advanced HIV and low CD4 counts are at risk for opportunistic infections and require antimicrobial
prophylaxis. Pneumocystis jiroveci pneumonia prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX) is
indicated when CD4 count is <200/mm3. [15066]
The chemokine receptor CCR5 is a coreceptor that enables the HIV virus to enter cells. Blockade of CCR5 by
chemokine receptor antagonists prevents viral entry into host cells. [953]
Tenofovir is a nucleotide reverse transcriptase inhibitor that is a common component of HIV therapy. This drug is
generally well tolerated but may occasionally cause damage to the proximal tubule of the kidney, leading to acute
kidney injury and/or proximal tubule impairment (eg, phosphoruria, glucosuria, proteinuria, water retention). Biopsy
typically reveals a normal glomerulus and renal interstitium but damage to the proximal tubule. [15113]
In the HIV replication cycle, polyprotein precursors are encoded by the structural genes gag, pol, and env. Only the
env gene polyprotein product (gp160) is glycosylated. This polyprotein is subsequently cleaved in the Golgi apparatus
to form the envelope glycoproteins gp120 and gp41. [1672]
Antiretroviral therapy during pregnancy reduces the risk of perinatal transmission of HIV to 1%-2% and is
recommended for all pregnant women with HIV. [1463]
HSV infection
Herpes simplex virus is a common, sexually transmitted infection marked by the formation of painful genital
ulcers. Tzanck smear can reveal the characteristic cytopathic effects of the virus, including multinucleated giant cells,
ground-glass intranuclear inclusions, acantholytic cells, keratinocyte ballooning, and nuclear molding. [15565]
Primary herpes simplex virus type 1 (HSV-1) infection in children causes gingivostomatitis (vesicular lesions on the lips
and hard palate). HSV-1 and other herpesviruses are double-stranded, enveloped DNA viruses. [1409]
A new-onset genital vesicular rash with a positive Tzanck smear in a previously asymptomatic patient is suggestive of
primary genital herpes simplex virus (HSV) infection due to HSV-2. Recurrences of genital herpes can be reduced
through daily treatment with oral valacyclovir, acyclovir, or famciclovir. Condom use can help prevent a primary
genital HSV infection but does not prevent reactivation of latent infection. [1550]
The finding of multiple painful genital ulcers and constitutional symptoms in a sexually active patient is highly
suggestive of primary genital infection with herpes simplex virus. The diagnosis can be established by PCR testing,
direct fluorescence antibody testing, or Tzanck smear. [11604]
Patients infected with herpes simplex virus develop a lifelong latent infection of the sensory ganglion. Periodic viral
replication can lead to symptoms that flare and resolve over time. [6547]
Herpetic gingivostomatitis is a severe vesicular or ulcerative disease following primary infection with herpes simplex
virus type 1. The diagnosis is supported by the presence of multinucleated giant cells in a Tzanck smear. Involvement
of the gingiva, tongue, palate, and pharynx along with systemic symptoms (eg, fever, malaise) is common. In
contrast, herpes reactivation in the trigeminal ganglia generally results in mild perioral vesicles. [1499]
Hepatitis b
If HBeAg persists for several months and host anti-HBeAg remain at low or undetectable levels, suspect chronic
hepatitis B infection with high infectivity. [379]
Hepatitis B virus has a partially double-stranded DNA genome and contains a viral DNA polymerase with reverse
transcriptase activity. Reverse transcriptase serves a crucial step in viral replication; it converts transcribed positive
sense single-stranded RNA into the partially double-stranded DNA genome of viral progeny. [15169]
Lymphogranuloma venerum
Chlamydia trachomatis serotypes L1 through L3 cause lymphogranuloma venereum, a sexually transmitted disease
characterized initially by painless ulcers with later progression to painful inguinal lymphadenopathy ("buboes") and
ulceration. Chlamydial inclusion bodies are seen in host cell cytoplasm. [1154]
Syphilis
The clinical presentation of tertiary syphilis includes cardiovascular involvement and gummas. Gummas are
necrotizing granulomas occurring on the skin, mucosa, subcutaneous tissue, and bones and within other
organs. Neurosyphilis can occur at any stage of infection. [651]
Penicillins, structurally similar to D-alanine-D-alanine, inhibit transpeptidase by binding covalently to its active
site. The result is failed synthesis of the bacterial peptidoglycan cell wall. [1952]
Patients with early syphilis (eg, chancre) often have false-negative initial serologic testing. Direct visualization of the
organism (Treponema pallidum) by dark-field microscopy or fluorescent antibody testing is the gold standard for
diagnosis but is not widely available. [1315]
Syphilis is caused by the spirochete Treponema pallidum. Confirmation of the diagnosis requires 2 forms of serologic
testing to prevent false-positive results. Nontreponemal tests (eg, rapid plasma reagin, VDRL) evaluate for
anticardiolipin antibodies (nonspecific); treponemal tests evaluate for antibodies targeted against T pallidum. [1316]
Warts
Condylomata acuminata (anogenital warts) present as pink- or skin-colored plaques, papules, and verrucous lesions
on the genitalia, perineum, or perianal skin; they are caused by human papillomavirus, primarily types 6 and
11. These lesions are associated with increased risk for HIV infection, and HIV testing is recommended. [15203]
INFECTION CONTROL

Nosocomial bloodstream infections are usually associated with intravascular catheters, which allow skin commensals
such as Staphylococcus aureus and coagulase-negative staphylococci to enter the bloodstream. [728]
Cns lymphoma
Primary central nervous system lymphoma is typically composed of B-lymphocytes. [2083]
Infection control
Hand hygiene is the single most important measure to reduce the risk of transmission of hospital-acquired infections.
[11514]
Toxoplasmosis
In patients with HIV, the presence of multiple ring-enhancing lesions with mass effect is most often indicative of
toxoplasmosis, followed by primary central nervous system lymphoma. [2082]
MISCELLANEOUS

The presence of a central vascular catheter and receipt of parenteral nutrition are risk factors for
candidemia. Candida display a morphology of branching pseudohyphae with blastoconidia. [11633]
Syphilis
Congenital syphilis should be suspected in a neonate with rhinorrhea and a desquamating, maculopapular rash
involving the palms/soles, particularly in those with limited prenatal care. Nonspecific findings of congenital infection
include fever, hepatosplenomegaly, and lymphadenopathy. [22142]
Congenital syphilis is acquired via transplacental transmission of the spirochete Treponema pallidum and may present
with pain and limited extremity movement due to long bone involvement (eg, metaphyseal erosions, periosteal
inflammation). Nonspecific manifestations include hepatosplenomegaly and lymphadenopathy. [22143]
PARASITIC AND HELMINTHIC INFECTIONS
Amebiasis
Entamoeba histolytica is an amoeba that causes colitis characterized by trophozoites and flask-shaped ulcers on
biopsy. It can occasionally (~1%) invade the colonic wall and disseminate through the blood to the liver, brain, or
lungs. A single amebic liver abscess is the most common extraintestinal manifestation. [15230]
Angiostrongylus infection
Eosinophilic meningitis is most often due to helminth infection (eg, Angiostrongylus). Peripheral eosinophilia is
largely mediated by the release of IL-5 in response to helminths, allergens, drugs, or rheumatic disease. [107248]
Babesiosis
Babesiosis and Lyme disease are transmitted by the Ixodes tick and occur in similar geographic regions. Coinfection is
common. [11540]
Babesiosis should be considered in patients with febrile illness who reside in geographic areas with Ixodes ticks. The
diagnosis can be established with identification of intraerythrocytic organisms on peripheral blood smear. [11524]
Chagas disease
Chagas disease is a protozoal illness that is endemic to Latin America. Patients in rural areas are at greatest risk when
their houses harbor the vector (Triatome bug) in adobe walls or thatched roofs. Acute infections are often
asymptomatic, but patients can develop Chagas cardiomyopathy (eg, heart failure, ventricular arrhythmias,
ventricular aneurysms) several decades later. [15436]
Cryptosporidiosis
Cryptosporidium is a fecal-orally transmitted protozoan that causes severe and protracted watery diarrhea in patients
with impaired immunity (eg, AIDS, immunosuppression). The presence of acid-fast staining oocytes in a stool
specimen is diagnostic. [105676]
Giardia
Giardia lamblia is the most common enteric parasite in the United States and Canada and is a common cause of
diarrhea in campers/hikers. Iodine-stained stool smear classically shows pear-shaped, flagellated trophozoites or
ellipsoidal cysts with smooth, well-defined walls and 2+ nuclei. Metronidazole is the treatment of choice. [1574]
Intestinal helminth parasites

Hookworms are transmitted when human skin comes into contact with soil contaminated with human feces. The
larvae penetrate the skin, travel to the lungs, are coughed up, and then subsequently swallowed. Adult hookworms
live in the small intestine and feed on human blood. Therefore, chronic iron deficiency anemia (microcytic anemia) is
the greatest complication. [15243]
Ascaris lumbricoides is transmitted via contaminated food or water. Eggs hatch into larvae in the small intestine,
penetrate the intestinal wall, and migrate across the lung into the alveoli. Larvae are subsequently coughed up and
swallowed into the gastrointestinal tract, where they mature to adult worms. Most patients are asymptomatic, but
some develop early pulmonary manifestations (Loeffler syndrome) or later gastrointestinal symptoms. [15549]
Lice infestation
Phthirus pubis is the human pubic louse. It is transmitted sexually via skin-to-skin contact and causes intense
pruritus. Louse and nits can often be visualized on examination, which is diagnostic. Treatment with topical
permethrin is generally curative. [15076]
Malaria
Malaria is generally asymptomatic for 1-4 weeks after transmission. Manifestations arise once the pathogen lyses
erythrocytes, which releases inflammatory cytokines. Initial manifestations typically include periods of high fever and
nonspecific, flu-like symptoms. [107521]
Malaria is diagnosed when intraerythrocytic diamond ring–shaped parasites are seen on peripheral blood smear. This
disease should be suspected in travelers to endemic regions who develop a febrile illness. [15457]
Blood microscopy findings that show red blood cells filled with multiple small rings suggest Plasmodium infection
(malaria). Erythrocytic forms of this parasite are treated with antimalarials such as chloroquine (in nonresistant
areas), atovaquone-proguanil, or artemisinins. Primaquine is required to kill Plasmodium vivax and Plasmodium
ovale liver hypnozoites. [1908]
Plasmodium falciparum can achieve much higher levels of parasitemia than other species of malaria due to its ability
to infect erythrocytes of all ages. In contrast, Plasmodium ovale and Plasmodium vivax primarily infect reticulocytes,
and Plasmodium malariae primarily infects old erythrocytes. [107525]
Meningitis
Naegleria fowleri is a free-living, motile protozoan that lives in warm water. Exposure can result in primary amebic
encephalitis, which is characterized by acute fever, headache, confusion, and neck stiffness. The diagnosis is
confirmed when motile trophozoites are seen on cerebrospinal fluid wet mount. Nearly all patients die. [15077]
Neurocysticercosis
Neurocysticercosis is a common cause of adult-onset seizures in patients from rural developing regions. Suspicion
should be raised when brain imaging in these individuals shows cystic or calcified lesions. [11670]
Neurocysticercosis is a helminth infection that occurs after the ingestion of Taenia solium eggs. It often presents with
adult-onset seizure in patients from an endemic area. Imaging reveals ≥1 cystic brain lesions. The presence of a
scolex, the anterior portion of the worm with hooks and suckers, is diagnostic. [22124]
Neurocysticercosis is common in developing regions and usually presents years after infection with new-onset
seizure. Physical examination, laboratory evaluation, and cerebrospinal fluid analysis are generally normal. However,
brain imaging typically shows ≥1 cysts in various stages of viability. [22125]
Schistosomiasis
Humans acquire schistosomiasis via contact with freshwater sources that contain snails infected with Schistosoma
larvae. S japonicum and S mansoni cause intestinal and hepatic schistosomiasis, and S haematobium causes urinary
schistosomiasis. [8541]
Strongyloides
Strongyloides stercoralis is transmitted in tropical/subtropical climates when human skin comes into direct contact
with filariform larvae. The larvae penetrate the skin, enter the bloodstream, pass through the lungs, and are
swallowed into the digestive system. Common manifestations include linear skin rash and irritative
digestive/respiratory symptoms. [20848]
Toxoplasmosis
Pregnant women should avoid consumption of undercooked meat to prevent infection with Toxoplasma gondii, an
intracellular, crescent-shaped parasite that can cross the placenta to the fetus. Typical features of congenital
toxoplasmosis include chorioretinitis, hydrocephalus, and diffuse intracranial calcifications. [15588]
VIRAL INFECTIONS
Acute diarrhea
Rotavirus is a common cause of self-limited childhood diarrhea in unvaccinated individuals. It infects villous
enterocytes in the duodenum and proximal jejunum and results in villous blunting, proliferation of secretory crypt
cells, and a loss of brush border enzymes; this results in watery diarrhea without fecal leukocytes. [15215]
Norovirus is the most common cause of viral gastroenteritis. Outbreaks in crowded settings (eg, schools, cruise ships,
nursing homes) are common, and symptoms include vomiting and watery diarrhea. [1498]
Antiretroviral therapy
The HIV genome contains 3 major structural genes that are translated as polyproteins and subsequently cleaved by
host protease (env gene products) or viral protease (gag-pol gene products) into the individual proteins that compose
the HIV virus. Protease inhibitors block viral protease from cleaving gag-pol polyproteins, which results in the
formation of immature virions that are noninfectious. [7229]
Arbovirus
Arboviruses, small RNA viruses transmitted by biting arthropods, are the most common cause of encephalitis
outbreaks in the United States. Because no vaccines are currently available, prevention primarily involves eliminating
the vector arthropods (eg, infected mosquitos). [15491]
Bronchiolitis
Viral bronchiolitis is most commonly caused by respiratory syncytial virus and presents with low-grade fever, cough,
and respiratory distress (eg, tachypnea, retractions) in children age <2 years. Examination typically shows diffuse
wheezes and/or crackles. [1668]
Chicken pox
Primary varicella zoster virus infection presents with a prodromal illness (eg, fever, malaise) followed by pruritic,
vesicular lesions that appear in successive crops in different stages. [15375]
Chikungunya fever
Chikungunya is an alphavirus transmitted by mosquitoes in tropical and subtropical areas. Initial manifestations
include fever, diffuse rash, and severe polyarthralgia. Although fever and rash quickly resolve, many patients have
chronic arthralgia, polyarthritis (eg, wrist, fingers, ankles), or tenosynovitis. [14903]
Cytomegalovirus
Cytomegalovirus (CMV) is typically associated with subclinical infection in the immunocompetent, with the occasional
individual developing a mononucleosis-like syndrome that is heterophile antibody (Monospot) negative. In the
immunocompromised, primary or reactivated CMV infection can result in severe retinitis, pneumonia, esophagitis,
colitis, or hepatitis. [1592]
Cytomegalovirus (CMV) is a common cause of colitis in patients with advanced AIDS. It is the second most common
CMV reactivation disease in this population (CMV retinitis is the most common). Patients with CMV colitis often have
abdominal pain, fever, diarrhea, and weight loss. Colonoscopy usually shows erythema, erosions, and ulcerations;
colonic biopsy typically reveals large cells with prominent basophilic intranuclear inclusions. [7228]
The Monospot test is positive in most cases of Epstein-Barr virus-associated mononucleosis. In immunocompetent
patients with a heterophile antibody-negative mononucleosis-like syndrome, the most likely diagnosis is
cytomegalovirus infection. [1593]
Dengue fever
There are 4 different serotypes of dengue virus. Repeat infection occurs when a person is exposed to a serotype not
previously encountered. Secondary infections are often far more severe than primary infections and may be
associated with a life-threatening shock syndrome. [11395]
Aedes mosquitoes transmit the viruses that cause dengue, chikungunya, Zika, and yellow fever; simultaneous
outbreaks and coinfections are common. Dengue usually presents as an acute febrile illness with headache,
retroorbital pain, arthralgia, and myalgia; hemorrhagic signs (eg, thrombocytopenia, petechiae, mucosal bleeding)
often occur within days. [11377]
Hand, foot, mouth disease

Hand, foot, and mouth disease (oral ulcerations and rash on the palms/soles) is a common manifestation of
Enterovirus infection. Although Enterovirus infections are typically self-limited, rare but serious complications include
myocarditis and aseptic meningitis. [15419]
Most oropharyngeal carcinomas (eg, tonsil, base of tongue) are caused by human papilloma virus (HPV)
infection. HPV-16 and HPV-18 are particularly likely to cause malignant transformation. [15228]
Hepatitis a
Hepatitis A virus infection is most commonly silent or subclinical ("anicteric") in young children but can also present
as an acute, self-limited illness characterized by jaundice, malaise, fatigue, anorexia, nausea, vomiting, right upper-
quadrant pain, or an aversion to smoking. [373]
Hepatitis b
The most common outcome in HBV-infected adults (> 95%) is acute hepatitis with mild or subclinical symptoms that
eventually completely resolve. [390]
Infants born to HBeAg-positive mothers have a high risk of acquiring perinatal hepatitis B virus (HBV)
infection. Infected neonates have high levels of HBV replication and are at high risk for chronic infection, but are
usually asymptomatic or have only mildly elevated liver function tests. [46]
Vertical transmission of hepatitis B from pregnant females to the unborn child can occur in women with active
hepatitis B infection. The presence of HBeAg (a marker of viral replication and increased infectivity) in the mother
greatly increases the risk of vertical transmission of the virus. Because of this concern, the newborns of all mothers
with active hepatitis B are passively immunized at birth with hepatitis B immune globulin (HBIG), followed by active
immunization with recombinant HBV vaccine. [378]
Individuals who are successfully immunized against hepatitis B virus develop protective anti-HBs
antibody. Individuals who recover from hepatitis B infection, however, have anti-HBs as well as anti-HBc
antibodies. The presence of circulating HBsAg indicates active infection. [377]
Hepatitis c
:The most common outcome of hepatitis C infection without antiviral treatment is lifelong persistent infection (ie,
chronic hepatitis C). Of those with chronic hepatitis C, approximately 20% develop cirrhosis, and only a minority
experiences complications (eg, ascites, variceal bleeding, hepatocellular carcinoma). [21018]
Hepatitis d
Hepatitis D virus (HDV) is a replication-defective RNA virus that is capable of causing infection only in the setting of
coinfection with hepatitis B virus (HBV). HBV provides hepatitis B surface antigen for the HDV envelope. [45]
Hepatitis e
Hepatitis E virus is an unenveloped, single-stranded RNA virus spread through the fecal-oral route. The most
concerning feature of hepatitis E infection is the high mortality rate observed in infected pregnant women. [48]
Human herpesvirus 6
Human herpesvirus 6 infection (roseola) classically presents with fever for 3-5 days followed by a truncal rash. It is
also the most common cause of febrile seizures. [11822]
Typical clinical and laboratory features of Epstein-Barr virus (EBV) mononucleosis include fever, pharyngitis,
lymphadenopathy, splenomegaly, and atypical lymphocytosis. EBV is generally transmitted from an asymptomatic
virus shedder to a susceptible individual through saliva transfer (eg, kissing). [1595]
Epstein-Barr virus (EBV) commonly infects B cells, stimulating them to proliferate continuously ("transformation" or
"immortalization"). EBV is an oncogenic virus that promotes polyclonal B cell proliferation and heterophile antibody
production. The heterophile antibody test is sensitive and highly specific for EBV infection. [1594]
Measles
Measles presents with fever, cough, rhinorrhea, and conjunctivitis followed by a maculopapular rash that starts on
the face and spreads downwards. Koplik spots are pathognomonic for measles and characterized by tiny white or
blue-gray lesions on the buccal mucosa. [1670]
Vitamin A can be beneficial in the treatment of measles infection by reducing comorbidities (eg, ocular complications,
diarrhea, pneumonia), recovery time, and length of hospital stay. [1045]
Molluscum contagiosum
Molluscum contagiosum is caused by a poxvirus and presents with small, firm, rounded, papules that often have a
central umbilication. Adults who are immunocompromised (eg, HIV) or sexually active are at increased risk. Biopsy
shows intracytoplasmic eosinophilic inclusion bodies of poxvirus in keratinocytes. [15362]
Nasopharyngeal carcinoma
Nasopharyngeal cancer is endemic in southern China due to genetic and dietary factors that promote nasopharyngeal
epithelial pre-malignant lesions. In almost all cases, malignant transformation occurs due to infection of
premalignant cells with Epstein-Barr virus and the subsequent expression of oncogenic viral proteins. [1572]
Parvovirus
Infection with parvovirus B19 (a nonenveloped single-stranded DNA virus) can cause arthralgia with or without rash
in adults. An infected fetus may develop hydrops fetalis (severe anemia, heart failure, pleural effusions, pericardial
effusions, and ascites). [1374]
Progressive multifocal leukoencephalopathy

Patients with advanced AIDS can have reactivation of JC virus, which causes progressive multifocal
leukoencephalopathy. This condition usually presents with slowly progressive confusion, ataxia, and motor
deficits. Brain MRI reveals multifocal areas of white matter demyelination with no mass effect or enhancement.
[15068]
Q fever
Q fever is a zoonotic infection that occurs in farm workers exposed to waste from cattle and sheep. Its causative
agent is Coxiella burnetii. A patient with exposure to waste from farm animals who develops a nonspecific illness
(myalgias, fatigue, fever [>10 days], retroorbital headache) with a normal leukocyte count, thrombocytopenia, and
increased liver enzymes should be evaluated for acute Q fever infection. [11859]
Rabies
In the United States, bats are the main source of rabies (only transmitted by mammals). Agitation and spasms
progressing to coma within weeks of exposure is strongly suggestive of rabies encephalitis. Prophylactic vaccination
is recommended for individuals at high risk for exposure to rabid animals or their tissues. The approved rabies
vaccines consist of various rhabdovirus strains grown in tissue cell culture and then inactivated. [1465]
Upper respiratory tract infections

Adenovirus is a self-limiting, year-round infection that causes the acute onset of fever, cough, congestion, pharyngitis,
and conjunctivitis. This pharyngoconjunctival disease can occur in outbreaks among those living in close quarters (eg,
camp dormitories, military barracks). [1497]
Zika virus
Zika virus is a single-stranded RNA virus that infects fetal neural progenitor cells, causing severe congenital
malformations (eg, microcephaly, arthrogryposis), cerebral cortical thinning, and possible fetal demise. [15034]
Prostatitis
Acute bacterial prostatitis is usually caused by reflux of urine and organisms from the bladder and urethra. The risk is
greater in patients with anatomic abnormalities (eg, strictures) or bladder catheterization. Escherichia coli is the
most common cause of acute bacterial prostatitis and other urinary tract infections because of adhesins on its
fimbriae that promote adherence to urothelial or mucosal cells. [15538]
Microbiology (General Principles)
BACTERIOLOGY
Acute diarrhea
Shiga toxin–producing Escherichia coli O157:H7 elaborates Shiga toxin, which inactivates 60S ribosomal subunits in
colonic mucosal cells, leading to the inhibition of protein synthesis and apoptosis; clinical manifestations include
bloody diarrhea. Hematogenous spread of Shiga toxin to renal endothelial cells can also lead to hemolytic uremic
syndrome. [1100]
Shigella is a non–lactose fermenting organism that does not produce hydrogen sulfide on triple sugar iron
agar. Mucosal invasion is the primary pathogenic mechanism for Shigella infection, which presents with
bloody/mucoid diarrhea. [1135]
Traveler's diarrhea is most frequently due to enterotoxigenic Escherichia coli, which produces plasmid-encoded, heat-
labile (LT) and heat-stable (ST) enterotoxins. LT resembles cholera toxin and activates adenylate cyclase, leading to
increased intracellular cyclic AMP; ST activates guanylate cyclase, leading to increased intracellular cyclic GMP. Both
can contribute to watery diarrhea due to loss of water and electrolytes. [1099]
Shiga toxin is produced by enterohemorrhagic Escherichia coli and Shigella dysenteriae. It inhibits the 60S ribosomal
subunit in human cells, blocking protein synthesis and causing cell death. [1098]
Bacterial gene transfer

Streptococcus pneumoniae is able to undergo transformation, which allows the bacterium to take up exogenous DNA
fragments and express the encoded proteins. Through this method, strains of S pneumoniae that do not form a
capsule can acquire the genes that code for the capsule and therefore gain virulence. [736]
Endocarditis
Viridans streptococci are normal inhabitants of the oral cavity and are a cause of transient bacteremia after dental
procedures in healthy and diseased individuals. In patients with pre-existing valvular lesions, viridans streptococci
can adhere to fibrin-platelet aggregates and establish infection that leads to endocarditis. [1003]
Staphylococcus epidermidis, a gram-positive coccus that grows in clusters, is a skin commensal that is a common
cause of infection in patients with prosthetic devices such as artificial joints or heart valves. Unlike S aureus, S
epidermidis is coagulase-negative. Unlike S saprophyticus (another coagulase-negative staphylococci species), S
epidermidis is susceptible to novobiocin. [679]
Infection control
Spore-forming bacteria can survive boiling temperatures. Bacillus and Clostridium species are common pathogenic
spore-forming bacteria. [1779]
Lac operon
The lac operon is regulated by two distinct mechanisms: negatively by binding of the repressor protein to the
operator locus and positively by cAMP-CAP binding upstream from the promoter region. Constitutive expression of
the structural genes of the lac operon occurs with mutations that impair the binding of the repressor protein (Lac I) to
its regulatory sequence in the operator region. [1479]
Neonatal sepsis
Escherichia coli, a gram-negative rod, is a common cause of neonatal meningitis. The major virulence factor for E coli
strains that cause neonatal meningitis is the K1 capsular antigen, which allows bacteria to survive in the bloodstream
and invade the meninges. [1140]

Protein A is a virulence factor found in the peptidoglycan cell wall of Staphylococcus aureus that binds to the Fc
portion of IgG, leading to impaired complement activation, opsonization, and phagocytosis. [677]
Urethritis
Neisseria can be isolated by culture on selective media such as the Thayer-Martin VCN (vancomycin/colistin/nystatin)
medium, which inhibits growth of contaminants such as gram-positive organisms, gram-negative organisms other
than Neisseria, and fungi. [1912]

Enterococcus is an important cause of urinary tract infections. These organisms are gram-positive cocci in pairs and
chains and, when grown on blood agar, they do not cause hemolysis (gamma-hemolytic). [11812]
S saprophyticus is responsible for almost half of all UTIs in sexually active young women. Staphylococcus
saprophyticus belongs to coagulase negative staphylococci and is unique among these because it is resistant to
novobiocin. [678]
Escherichia coli is the most common cause of urinary tract infections. The primary virulence factor of uropathogenic
E coli are P fimbriae (pili) which allow the bacteria to adhere to uroepithelial cells and infect the bladder, ureters, and
kidneys. [1139]
MISCELLANEOUS
Giardia
Giardia lamblia causes injury to the duodenal and jejunal mucosa by adhering to the intestinal brush border and
releasing molecules that induce a mucosal inflammatory response. Secretory IgA, which impairs adherence, is the
major component of adaptive immunity against G lamblia infection. Conditions causing IgA deficiency predispose
patients to chronic giardiasis. [1596]
Malaria
Plasmodium vivax is the most common cause of malaria in non-African countries. It is transmitted by the female
Anopheles mosquito and is associated with a latent liver phase that must be treated (with primaquine) independently
of the erythrocytic phase to fully eliminate the organism. [15325]
MYCOLOGY
Histoplasmosis
Tumor necrosis factor–alpha inhibitors are associated with impairments to the cell-mediated immune response and
increase the risk of infection with intracellular bacteria and granulomatous fungi (eg, Histoplasma
capsulatum). Histoplasma replicates within the intracellular space of macrophages and can spread from the lungs to
the lymph nodes and the reticuloendothelial system (liver, spleen, bone marrow). [15057]
Mucormycosis
Facial pain, headache, and a black necrotic eschar in the nasal cavity of a patient with diabetic ketoacidosis are highly
suggestive of mucormycosis. Histologic examination of the affected tissue is necessary to confirm the diagnosis. The
fungi show broad nonseptate hyphae with right-angle branching. Treatment consists of surgical debridement and
antifungal therapy. [107]
PARASITOLOGY
Malaria
Mefloquine chemoprophylaxis for malaria must be continued for 4 weeks after return from an endemic region to
ensure the elimination of hepatic schizonts (which develop in the liver over 8-30 days). [15453]
VIROLOGY
Epstein barr virus

The initial attachment of the virion envelope or capsid surface proteins to the complementary host cell surface
receptors is essential to viral tropism for specific tissues and invasion of cells. Many viruses bind to normal host cell
plasma membrane receptors to enter host cells. Known host cell receptor and virion/virion protein binding
specificities include: CD4 with HIV gp120, CD21 with Epstein-Barr virus gp350, and erythrocyte P antigen with
parvovirus B19. [1375]
Hepatitis b
The hepatitis B virus (HBV) replicates via the following sequence: double-stranded DNA → +RNA template → partially
double-stranded DNA progeny. Although it is a DNA virus, HBV uses reverse transcription to generate new viral DNA
from a positive-sense RNA template. [374]
Replication of the hepatitis B genome occurs within a newly synthesized capsid through the action of reverse
transcriptase on an RNA template. The mature capsid contains partially double-stranded circular DNA and reverse
transcriptase. [376]
Hepatitis c
Genetic variations created during hepatitis C virus (HCV) replication result in marked variety in the antigenic structure
of HCV envelope proteins. The production of host antibodies lags behind that of new mutant HCV strains, preventing
infected individuals from mounting an effective immune response. [44]
Influenza
The tissue tropism of viruses is primarily mediated by viral surface glycoproteins that bind to specific host cell
receptors. Mutations to viral surface glycoproteins can alter tissue tropism and cause noninfective viruses to become
infectious. [1411]
Alcohol-based disinfectants kill enveloped viruses (eg, influenza) by dissolving their outer lipid
envelope. Nonenveloped viruses are less susceptible to some alcohol-based disinfectants because they have no lipid
envelope to target. [1377]
Parvovirus
Erythema infectiosum (fifth disease) is caused by parvovirus B19 and presents with a nonspecific prodrome (eg,
malaise, fever, congestion) followed by a classic "slapped-cheek" facial rash and a lacy, reticular body
rash. Parvovirus is highly tropic for erythroid precursor cells and replicates predominantly in the bone marrow. [1495]
Viral genetics
Influenza epidemics and pandemics are typically caused by reassortment of the RNA segments coding for
hemagglutinin or neuraminidase proteins (major antigenic shifts). This process can occur between human and animal
strains of influenza A virus in avian or swine hosts. [12708]
Phenotypic mixing refers to coinfection of a host cell by 2 viral strains, resulting in progeny virions that contain
nucleocapsid proteins from one strain and the unchanged parental genome of the other strain. Because there is no
change in the underlying viral genomes (no genetic exchange), the next generation of virions revert to their original,
unmixed phenotypes. [1462]
Recombination refers to gene exchange that occurs through the crossing over of 2 double-stranded DNA
molecules. Reassortment describes the mixing of genome segments in segmented viruses that infect the same host
cell. [1461]
Nervous System
CNS INFECTIONS
Cryptococcal infections
Cryptococcus neoformans is a round/oval yeast with a thick polysaccharide capsule. It is a common cause of
meningoencephalitis (eg, headache, vomiting, confusion, seizure) in patients with untreated AIDS. The yeast can
frequently be visualized in the cerebrospinal fluid by India ink or silver stain. [15580]
HSV infection
Herpes simplex virus type 1 encephalitis is a potentially fatal complication from primary infection or reactivation of
latent disease. Nervous system invasion leads to necrosis of the temporal lobe, which can result in aphasia and
personality changes in addition to classic features of encephalitis (eg, headache, fever, altered mental status, seizure).
[907]
Meningitis
Fever; meningeal signs (eg, headache, neck stiffness); and cerebrospinal fluid that shows lymphocytic pleocytosis, a
modestly elevated protein level (<150 mg/dL), and normal glucose are suggestive of aseptic meningitis. Enteroviruses
are the most common cause of aseptic meningitis. [1966]
Pili are the primary virulence factor that allow Neisseria meningitidis to initially attach to and colonize the
nasopharyngeal epithelial surface. Pili undergo significant antigenic variation, which makes them a difficult
vaccination target. [1005]
Cryptococcus neoformans is a yeast with a thick polysaccharide capsule that is found primarily in soil contaminated
by bird droppings. Inhalation of the pathogen into the lungs leads to asymptomatic primary infection usually
followed by life-long latent infection. However, immunocompromised (eg, advanced AIDS) patients are at high risk
for reactivation with spread to the CNS. [113]
Antibodies against the polysaccharide capsule of Neisseria meningitidis provide immunity against this
pathogen. Quadrivalent meningococcal vaccines contain capsular polysaccharides from major serotypes (A, C, Y, and
W) of N meningitidis. Serotype B vaccinations use recombinant proteins. [1853]
Cryptococcus neoformans causes meningoencephalitis in patients with untreated AIDS. Diagnosis can be made by
detecting the polysaccharide capsule in cerebrospinal fluid using the latex agglutination test. India ink staining of
cerebrospinal fluid is also used for diagnosis and can demonstrate round or oval budding yeast. [118]
The classic triad of fever, stiff neck, and altered mentation should raise suspicion for acute bacterial
meningitis. Evaluation requires prompt blood cultures, empiric antibiotics, and lumbar puncture with cerebrospinal
fluid analysis. [11862]
Patients with suspected cryptococcal meningitis can be diagnosed using India ink staining of the cerebrospinal
fluid. Treatment with amphotericin B and flucytosine is required at first, followed by long-term fluconazole
maintenance therapy. [116]
Listeriosis is most commonly transmitted through food ingestions and can cause meningitis in immunocompromised
adults. Listeria is a gram-positive rod with tumbling motility. It grows well in cold temperatures and can therefore
contaminate refrigerated food. [1392]
Neisseria meningitidis can cause sepsis and circulatory collapse in previously healthy young
individuals. Lipooligosaccharide, a virulence factor in the pathogens outer membrane, is the major underlying cause
of disease severity. [738]
Primary amebic encephalitis occurs when the free-living, motile protozoan Naegleria fowleri penetrates the olfactory
mucosa and migrates in a retrograde fashion through the olfactory nerve to the brain. This rare, deadly infection
primarily occurs after exposure to warm, fresh water during recreational activities. [19963]
Neisseria meningitidis is transmitted primarily by aerosolized droplets and subsequently colonizes the
nasopharyngeal epithelium. Penetration of the epithelium can lead to bloodstream infection. Spread to the
meninges occurs via transcellular penetration of the cerebral capillary endothelium or entry at the choroid plexus.
[737]
Bacterial meningitis causes an increase in cerebrospinal fluid (CSF) neutrophil count and protein concentration as well
as a decrease in CSF glucose. Streptococcus pneumoniae is a leading cause of community-acquired pneumonia, otitis
media, and meningitis in adults. S pneumoniae appears on Gram stain as lancet-shaped, Gram-positive cocci in pairs.
[735]
Rabies
Rabies virus has a bullet-shaped envelope with knob-like glycoproteins that bind to nicotinic acetylcholine
receptors. Once transmission occurs (usually due to a bite wound from an infected animal), the virus replicates
locally in muscle tissue for several days or weeks before spreading in a retrograde fashion through the peripheral
nerve axons to the central nervous system. [8324]
Toxoplasmosis
Toxoplasma gondii is an intracellular parasite that is typically transmitted to humans after accidental ingestion of
contaminated cat feces (eg, cat handling, litter box). Most initial cases are asymptomatic. However, the organism
establishes a latent infection that can reactivate in the setting of severe immunocompromise, particularly advanced
AIDS. Patients usually develop encephalitis with multiple ring-enhancing lesions. [14905]
Congenital toxoplasmosis is an infection acquired in utero that can present with hydrocephalus, intracranial
calcifications, and chorioretinitis due to prolonged CNS inflammation. [1038]
The finding of multiple ring-enhancing lesions in an HIV patient is most likely due to toxoplasmosis. [1573]
West Nile virus infection

West Nile virus is a single-strand flavivirus transmitted by mosquitoes, most commonly in the summer. Most
infections are asymptomatic or may present with a flu-like illness (West Nile fever), often with a maculopapular or
morbilliform rash. Neuroinvasive disease manifests as meningitis, encephalitis, or asymmetric flaccid paralysis;
patients may have parkinsonian features. [1906]
West Nile virus is harbored in birds and transmitted to humans by mosquitos. Most patients are asymptomatic, but
the virus can cause an influenza-like illness or neuroinvasive disease with meningitis, encephalitis, and flaccid
paralysis. [15587]
Botulism
Botulinum toxin blocks the presynaptic exocytosis of ACh vesicles, causing impaired muscarinic and nicotinic
neurotransmission; it characteristically presents as a symmetric, descending paralysis that first manifests with cranial
nerve abnormalities, often following consumption of home-canned foods. [1997]
Clostridium botulinum is a spore-forming, gram-positive, anaerobic bacillus that synthesizes botulinum toxin, which
prevents the presynaptic release of acetylcholine from the nerve terminal at the neuromuscular junction. Botulinum
toxin can be used to treat focal dystonia and other disorders of abnormal muscle contraction. [1401]
Botulinum neurotoxin produced by Clostridium botulinum prevents the release of acetylcholine from presynaptic
nerve terminals. The toxin impairs peripheral muscarinic and nicotinic neurotransmission, causing both autonomic
symptoms (eg, fixed pupillary dilation, dry mouth) and skeletal muscle weakness (eg, diplopia, dysphagia, respiratory
depression). Its effects at the neuromuscular junction can be seen on electromyography as a decrease in muscle
response following stimulation of a motor nerve. [1399]
Guillain Barre syndrome

Guillain-Barré syndrome represents a group of immune-mediated polyneuropathies that are thought to be caused by
molecular mimicry, leading to demyelination of the peripheral nerves. Up to one-third of GBS cases are preceded by
a Campylobacter jejuni infection, which is a common cause of acute diarrheal illness. [1601]
Herpes zoster
Primary varicella-zoster virus infection (chickenpox) occurs most commonly in childhood. Subsequently, the virus
migrates to the sensory ganglia, where it lies dormant for decades. Over time, waning cell-mediated immunity allows
reactivation of the virus, which spreads down a single nerve to cause a painful, erythematous, vesicular rash in a
dermatomal distribution. [1552]
Tetanus
Tetanus is caused by infection with toxigenic strains of the anaerobic bacterium Clostridium tetani. Transmission
typically occurs when spores are inoculated into the skin via a puncture wound. The bacteria germinate, replicate
locally, and elaborate tetanospasmin (tetanus toxoid). The toxin spreads in a retrograde fashion through the lower
motor neurons to the spinal cord, where it blocks inhibitory interneurons and causes spasmodic muscle contraction
(eg, trismus, risus sardonicus). [1402]
Ophthalmology
Cytomegalovirus
The most common eye-related complication of congenital cytomegalovirus infection is chorioretinitis. [11551]
Endophthalmitis
Candida endophthalmitis typically occurs due to hematogenous dissemination to the choroid layer in the setting of
fungemia. Most cases arise in hospitalized patients with indwelling central catheters. Patients usually have unilateral
eye floaters and progressive vision loss. [106633]
Herpes zoster
Herpes zoster ophthalmicus is caused by reactivation of varicella-zoster virus in the ophthalmic division of the
trigeminal nerve (CN V1). It is characterized by a painful, dermatomal rash and ocular involvement (eg, acute
keratitis, corneal ulceration). It most commonly occurs in elderly and immunosuppressed patients. [107365]
Abortion
Symptoms of septic abortion typically include fever, abdominal pain, uterine tenderness, and/or malodorous
discharge after pregnancy termination. Common pathogens include Enterobacteriaceae, group A Streptococcus, and
Staphylococcus aureus. Treatment involves urgent surgical evacuation and broad-spectrum antibiotics. [11961]
Rubella
The classic triad of findings for congenital rubella syndrome includes cataracts, sensorineural hearing loss, and patent
ductus arteriosus. Prevention consists of maternal preconception immunization with the live attenuated rubella
vaccine. [1464]
Maternal rubella infection classically causes a maculopapular rash with cephalocaudal progression, joint pain, and
postauricular lymphadenopathy. Transplacental transmission to the fetus leads to congenital rubella syndrome,
which is characterized by sensorineural deafness, cataracts, patent ductus arteriosus, and growth restriction (eg,
microcephaly). [1575]
COPD
Most chronic obstructive pulmonary disease exacerbations are triggered by viral or bacterial upper respiratory
infections, with rhinovirus, influenza virus, Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus
pneumoniae being among the most common causes. [13402]
Actinomycosis
Pulmonary actinomycosis develops most commonly following aspiration and can be confused with lung abscess,
malignancy, or tuberculosis. Microscopic findings include filamentous, branching, gram-positive bacteria and sulfur
granules. [10993]
Aspergillosis
Aspergillus fumigatus causes a wide spectrum of disease. It can be an opportunistic infection in immunosuppressed
and neutropenic patients (invasive pulmonary aspergillosis). Aspergillosis can be colonizing (aspergilloma) when it
forms a fungus ball within a preexisting lung cavity. It can also cause a lung hypersensitivity reaction in allergic
bronchopulmonary aspergillosis in individuals with asthma. [108]
Allergic bronchopulmonary aspergillosis (ABPA) due to Aspergillus fumigatus may complicate asthma. ABPA can
result in transient recurrent pulmonary infiltrates and eventual proximal bronchiectasis. [665]
Blastomycosis
Dimorphic fungi grow as molds at 25-30ºC and as yeast at body temperature (35-37ºC). Medically important
dimorphic fungi include Sporothrix, Coccidioides, Histoplasma, Blastomyces and Paracoccidioides species. [103]
Blastomyces dermatitidis is a dimorphic fungus seen in tissue as round or oval yeasts with thick walls and broad-
based budding. It is endemic in the southeastern United States (states east of the Mississippi River). The lungs are
the primary site of involvement, and the skin and bone are the major sites of dissemination. [120]
Blastomyces dermatitides can cause pulmonary disease in the immunocompetent host. Dissemination (most
commonly to skin and bones) occurs in immunocompromised individuals. [121]
Coccidioidomycosis
Coccidioides immitis is a dimorphic fungus endemic to the southwestern United States. It exists in the environment
as a mold (with hyphae) that forms spores. These spores are inhaled and turn into spherules in the lungs. [269]
Coccidioides immitis infection can be asymptomatic or it can cause pulmonary disease ranging from a flulike illness to
chronic pneumonia. It causes disseminated disease in immunocompromised patients. Spherules containing
endospores are found in tissue samples. [268]

Streptococcus pneumoniae vaccination reduces the risk of invasive disease and is recommended for young patients
and the elderly. The pneumococcal polysaccharide vaccine is an unconjugated vaccine that induces a T-cell–
independent humoral immune response. In contrast, the pneumococcal conjugate vaccine contains polysaccharide
material attached to a protein antigen, which creates a robust T-cell–mediated humoral immune response. [734]
All organisms in the Mycoplasma genus, including Ureaplasma urealyticum, lack peptidoglycan cell walls and are
therefore resistant to agents that target the cell wall such as penicillins, cephalosporins, carbapenems, and
vancomycin. Mycoplasma infections can be treated with antiribosomal agents (eg, tetracyclines, macrolides). [1677]
The most common cause of community-acquired pneumonia in both HIV-infected and HIV-uninfected individuals is
Streptococcus pneumoniae. Risk of invasive pneumococcal disease is significantly increased in patients with HIV
regardless of CD4 count. [1767]
Infection with Mycoplasma pneumoniae can result in the formation of cold agglutinins, which are IgM antibodies
(primarily) that bind red blood cells and cause clumping/agglutinations at low body temperatures. Other illnesses
resulting in cold agglutinin formation include infectious mononucleosis and certain hematologic malignancies. [958]
Legionella pneumophila commonly contaminates natural bodies of water, municipal water supplies, and water-based
cooling systems. The organism is inhaled in aerosolized water and establishes infection via the pulmonary
route. Diagnosis is generally made by urine antigen testing, silver stain, or culture on buffered charcoal yeast extract
agar supplemented with L-cysteine and iron. [961]
Klebsiella is an encapsulated, lactose-fermenting, gram-negative bacillus that appears mucoid in culture. It causes
pneumonia in individuals with impaired host defenses, especially patients with alcohol use disorder. Klebsiella
pneumonia is characterized by tissue necrosis and early abscess formation with production of thick, mucoid, blood-
tinged sputum (currant jelly sputum). [9989]
Influenza infection alters the respiratory epithelium and can increase the risk of secondary bacterial pneumonia. The
leading pathogens are Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae. The elderly
are affected most commonly, but S aureus can cause secondary pneumonia in young, previously healthy patients.
[1666]
Staphylococcus aureus strains that express Panton-Valentine leukocidin (PVL), a protease that kills leukocytes and
causes necrosis, are most likely to cause skin or soft-tissue abscess and invasive disease (eg, necrotizing
pneumonia). PVL expression is most common in community-acquired, methicillin-resistant strains. [14926]
Mycoplasma pneumoniae is the causative agent of "walking pneumonia," an infection typically characterized by a
nagging nonproductive cough, low-grade fever, and malaise. Often, the chest x-ray suggests a severe pneumonia
even though the patient appears relatively well. Mycoplasma species require cholesterol supplementation to grow
on artificial media. [1679]
Streptococcus pneumoniae are gram-positive, α-hemolytic, optochin-sensitive, bile-soluble diplococci. Viridans group
streptococci are also α-hemolytic, but they are optochin-resistant and bile insoluble. Streptococcus pyogenes (Group
A Streptococcus) appear as gram-positive cocci in chains with bacitracin susceptibility. [731]
Legionella pneumophila is a facultative intracellular gram-negative bacillus that can cause a systemic
infection. Symptoms frequently include high fever, cough, confusion, and diarrhea. The most common laboratory
abnormality seen with Legionella pneumonia is hyponatremia, and sputum Gram stain often shows many neutrophils
but few or no organisms. [8257]
Legionella pneumophila infection is typically marked by high fever and fatigue followed by significant gastrointestinal,
pulmonary, and constitutional symptoms. The organism is not well visualized on Gram stain and does not grow on
traditional culture media; L pneumophila infection is primarily diagnosed by polymerase chain reaction or urine
antigen testing. [960]
The primary virulence factor of Streptococcus pneumoniae is a polysaccharide capsule that inhibits opsonization and
phagocytosis. The polysaccharide capsule of the most virulent strains is targeted by the pneumococcal vaccine,
which confers immunity against those subtypes. [730]
Cryptococcal infections
Cryptococcus neoformans is the only pathogenic fungus that has a polysaccharide capsule. The capsule appears red
on mucicarmine stain and as a clear unstained zone with India ink. [117]
Meningoencephalitis is the most common symptomatic presentation of Cryptococcus neoformans infection and
typically occurs in immunocompromised patients. Microscopically, C neoformans appears as budding yeasts with
thick polysaccharide capsules, which can be demonstrated using mucicarmine or India ink staining. [114]
Cytomegalovirus
In a transplant patient, pneumonia with intranuclear and cytoplasmic inclusion bodies histologically points to
opportunistic infection with cytomegalovirus, an enveloped virus that contains a double-stranded DNA genome. [1576]
Epiglottitis
Epiglottitis causes rapidly progressive airway obstruction and classically presents with fever, dysphagia, drooling,
stridor, and tripod positioning. Individuals with incomplete immunization against Haemophilus influenzae type b are
at greatest risk. [967]
Polyribosylribitol phosphate is a capsule component and major virulence factor for Haemophilus influenzae type b
(Hib). Hib is the most common cause of epiglottitis, which presents with fever, stridor, and dyspnea. [962]
Group b streptococcal infection

Group B Streptococcus is a major cause of neonatal sepsis. Its virulence factor is the polysaccharide capsule, which
contains sialic acid residues that prevent phagocytosis via molecular mimicry. [999]
Haemophilus influenzae
Most chronic obstructive pulmonary disease exacerbations are caused by infection with an upper respiratory
pathogen. The leading bacterial cause is Haemophilus influenza and the leading viral cause is rhinovirus. [14925]
Histoplasmosis
Histoplasma capsulatum is endemic to the Ohio and Mississippi River valleys and is found primarily in soil
contaminated with bird or bat droppings. It exists in tissues as an ovoid/round yeast predominantly within the
intracellular space of macrophages. Immunocompetent patients are often asymptomatic but can infrequently
develop subacute pneumonia with hilar and mediastinal lymphadenopathy. [266]
Histoplasma capsulatum is a dimorphic fungus that exists as a small, ovoid yeast at tissue temperatures. It replicates
within macrophages and spreads through the lymphatic and reticuloendothelial system. Immunocompetent patients
usually have an asymptomatic pulmonary infection, but those who are immunocompromised (eg, advanced AIDS) can
develop disseminated disease to the liver, spleen, and bone marrow. [267]
Influenza
Major adaptive immune mechanisms that prevent reinfection with the influenza virus include anti-hemagglutinin
antibodies. [1649]
Laryngotracheobronchitis
Brassy, barking cough; dyspnea; and recent history of upper respiratory infection in a child are suggestive of viral
laryngotracheitis (croup). The most common cause of croup is parainfluenza virus. [1667]
Lung abscess
Lung abscess usually occurs in individuals with episodes of impaired consciousness (eg, alcohol/substance use
disorder, dementia) or decreased ability to swallow (eg, esophageal strictures). They are generally caused by
aspiration of anaerobic and aerobic bacteria from the oral cavity into the lower respiratory tract. [532]
Nocardiosis
Nocardia is a filamentous, branching, gram-positive bacteria that is partially acid-fast. It most commonly causes
pneumonia and brain abscesses in immunocompromised patients. [11638]
Pertussis
Pertussis should be considered in any adult who has not had updated vaccination boosters. The clinical presentation
is a paroxysmal cough lasting >2 weeks that is associated with post-tussive emesis or inspiratory whoop after a severe
coughing episode. [11630]
Pneumocystis pneumonia
Pneumocystis pneumonia is common in patients with advanced HIV and usually presents with slowly worsening
cough and dyspnea, hypoxia, and bilateral interstitial infiltrates. Diagnosis requires visualizing the organism in
respiratory secretions using special stains (eg, methenamine silver stain). First-line treatment is trimethoprim-
sulfamethoxazole. [14840]
Septic arthritis
Haemophilus influenzae is a gram-negative coccobacillus that requires both X factor (hematin) and V factor (NAD+) to
grow. H influenzae type b has an antiphagocytic polysaccharide capsule, which allows it to spread hematogenously
and cause invasive disease such as septic arthritis and meningitis. [964]
Tuberculosis
Primary tuberculosis infection is marked by initial unchecked Mycobacterium tuberculosis replication within the
alveolar space and alveolar macrophages. After a few weeks, CD4 lymphocytes are stimulated to release interferon-
gamma, which activates macrophages and allows them to destroy the mycobacteria. [1217]
The acid-fast stain identifies organisms that have mycolic acid present in their cell walls, including Mycobacterium
and some Nocardia species. Acid-fast staining is carried out by applying an aniline dye (eg, carbolfuchsin) to a smear
and then decolorizing with acid alcohol to reveal whether the organisms present are "acid fast." [1215]
Mycobacterium tuberculosis grows in long, serpentine cords due to the presence of cord factor, a surface glycolipid,
on the cell wall. Cord factor is a primary virulence factor of M tuberculosis; it protects the bacteria from digestion by
macrophages and also leads to the formation of caseating granulomas. [1216]
Clostridial myonecrosis
Lecithinase (alpha toxin) is the main toxin produced by Clostridium perfringens. It degrades lecithin, a component of
cellular phospholipid membranes, which leads to membrane destruction, cell death, and widespread necrosis and
hemolysis. [1395]
Osteomyelitis
Hematogenous osteomyelitis is predominantly a disease of children that most frequently affects the long
bones. Staphylococcus aureus is implicated in most cases secondary to a bacteremic event. Streptococcus pyogenes
(group A streptococcus) is the second most common cause of hematogenous osteomyelitis. [646]
Vertebral osteomyelitis should be suspected in patients with new or worsening back pain, fever, and recent
endocarditis or bacteremia (especially Staphylococcus aureus). It should also be suspected if there are new
neurologic findings and fever with or without back pain. MRI of the spine is preferred for diagnosis. [11868]
MISCELLANEOUS
Sporotrichosis
Sporothrix schenckii is a dimorphic fungus that exists as yeasts at body temperature. It is found in decaying plant
matter and soil and is usually transmitted via cutaneous or subcutaneous inoculation while a person is farming,
gardening, or landscaping. The major manifestation is a slowly progressive nonpurulent, nonpainful, nodular
lymphangitis that progresses proximally along the lymphatic chain. [270]
Pathology
Anaphylaxis
Anaphylaxis (type 1 hypersensitivity) can quickly lead to respiratory compromise (eg, bronchospasm, oropharyngeal
edema) and distributive shock. The most common autopsy findings include upper airway edema, hyperinflation of
the lungs from airway obstruction, and cerebral edema from hypoxia. [20720]
Angioedema
C1 inhibitor (C1INH) deficiency causes increased cleavage of C2 and C4 and results in inappropriate activation of the
complement cascade. C1INH also blocks kallikrein-induced conversion of kininogen to bradykinin, a potent
vasodilator associated with angioedema. [11667]
AUTOIMMUNE DISEASES
Granulomatosis with polyangiitis

Necrotizing vasculitis of the upper and lower respiratory tract (causing nasal ulcerations, sinusitis, hemoptysis) and
rapidly progressive glomerulonephritis—producing a variable degree of renal failure—is characteristic of
granulomatosis with polyangiitis (Wegener). This disease is associated with C-ANCAs, which may target neutrophil
proteinase 3. [459]
IgA vasculitis
Henoch-Schönlein purpura, or IgA vasculitis, classically presents with palpable purpura, with or without abdominal
pain, arthralgias, and renal involvement. Histopathologic examination of the skin lesions reveals damaged small
vessels with fibrinoid necrosis, perivascular neutrophilic inflammation, and nuclear debris (ie, leukocytoclastic
vasculitis). Immunofluorescence reveals deposition of IgA and C3. [458]
Odontogenic infections
Sjögren syndrome is characterized by autoimmune inflammation of exocrine glands (eg, salivary, lacrimal,
vaginal). Patients typically have severe dry mouth (xerostomia) due to reduced saliva production, which can lead to
an increased rate of dental caries and other oral infections (eg, thrush) because of the loss of protective factors in
saliva. Biopsy of the salivary glands shows a lymphocytic infiltrate, often with germinal centers. [15557]
MISCELLANEOUS
Lymphadenopathy
Germinal centers are the sites where activated B cells proliferate and undergo affinity maturation during generation
of a humoral immune response. The formation of multiple germinal centers is typically marked by lymphadenopathy,
pain, and inflammation in the affected lymph node due to cellular recruitment and the release of inflammatory
cytokines. [15251]
Aortic aneurysm
Myxomatous changes, with pooling of mucopolysaccharides in the media layer of large arteries, are found in cystic
medial degeneration, which predisposes affected patients to the development of aortic aneurysms. Medial
degeneration in younger individuals is frequently due to Marfan syndrome. [462]
Thoracic aortic aneurysms are usually asymptomatic until they grow large enough to compress surrounding
structures or cause rupture. The most common symptomatic presentation is chest or back pain, but compression of
nearby structures can cause dysphagia, hoarseness, cough, or dyspnea. [15839]
Abdominal aortic aneurysm is associated with risk factors (eg, age >60, smoking, hypertension, male sex, family
history) that lead to chronic transmural inflammation and extracellular matrix degradation within the wall of the
aorta. This leads to weakening and progressive expansion of the aortic wall, resulting in aneurysm formation,
typically below the renal arteries. [463]
Ruptured abdominal aortic aneurysm is a surgical emergency that usually presents with the acute onset of severe
abdominal and back pain in patients with appropriate risk factors (eg, advanced age, smoking,
atherosclerosis). Accompanying syncope, hypotension, and shock may occur quickly (intraperitoneal rupture) or may
be delayed (retroperitoneal rupture). [15840]
Aortic coarctation
Adults with coarctation of the aorta often have chronic hypertension and are at increased risk of developing life-
threatening aneurysms of the aorta (eg, dissection, rupture) and cerebral vessels (ie, intracranial hemorrhage). [31]
Aortic dissection
Marfan syndrome involves a deleterious mutation in fibrillin that mainly affects the structural integrity of the
cardiovascular and musculoskeletal systems. Aortic root disease predisposes to aortic dissection, which can present
with sudden-onset chest or back pain, acute aortic regurgitation, and heart failure. Common histologic findings in
aortic disease include fragmentation and loss of the elastic lamellae with fibrosis and cystic medial degeneration.
[15886]
Aortic dissection classically presents with severe retrosternal pain that radiates to the back. This condition develops
when overwhelming hemodynamic stress leads to tearing of the aortic intima with blood subsequently dissecting
through the aortic media. The resulting intramural hematoma can extend both proximally and distally and can
compress major arterial branches and impair blood flow. [464]
Cystic medial degeneration (necrosis) is the classic histologic finding in aortic dissection, as it weakens the aortic wall
and allows a small intimal tear to readily propagate. Collagen, elastin, and smooth muscle are replaced by a
basophilic mucoid extracellular matrix with elastic tissue fragmentation and cystic collections of mucopolysaccharide.
[15891]
Acute aortic dissection typically presents with sudden-onset, severe chest pain that is sharp or tearing in
nature. Upper extremity blood pressure asymmetry can result from extension of the dissection plane into the
subclavian artery, and additional complications (eg, stroke, myocardial ischemia) can result from extension into other
vessels. Extension into the pericardium can cause acute tamponade with reduced cardiac output and shock. [15885]
Hypertension is the single most important risk factor for the development of intimal tears leading to aortic
dissection. Hypertension, smoking, diabetes mellitus, and hypercholesterolemia are all major risk factors for
atherosclerosis, which predisposes more to aortic aneurysm formation than aortic dissection. [473]
Atrial myxoma
Myxomas are the most common primary cardiac neoplasm and approximately 80% originate in the left
atrium. Patients may present with symptomatic mitral valve obstruction that may worsen with certain body
positions, constitutional findings (eg, fever, weight loss), or systemic embolization (eg, stroke, mesenteric ischemia,
acute limb ischemia). [14997]
Chronic venous insufficiency

Varicose veins are dilated, tortuous veins most commonly found in the superficial veins of the leg. They are caused
by chronically increased intraluminal pressure and/or loss of tensile strength in the vessel wall, leading to
incompetence of the venous valves. Common complications include edema, stasis dermatitis, skin ulcerations, poor
wound healing, and infections. [474]
Stasis dermatitis is characterized by chronic erythema, fibrosis, and reddish-brown discoloration due to deposition of
hemosiderin (from breakdown of extravasated red cells). Symptoms are typically bilateral, and usually worse at or
above the ankles. Complications include poor wound healing, weeping, and ulceration. [14984]

Granulomatosis with polyangiitis is an ANCA-associated systemic vasculitis that typically presents with upper (eg,
purulent nasal discharge) and lower (eg, cavitary lung lesion) respiratory manifestations and renal insufficiency due to
glomerulonephritis. Biopsy typically reveals a necrotizing arteritis with granulomatous inflammation (eg, epithelioid
histiocytes, multinucleated giant cells) and lack of immunoglobulin/complement deposition. [6445]
Kawasaki disease
Kawasaki disease is a vasculitis of medium-sized arteries that presents with persistent fever for >5 days, bilateral
conjunctivitis, cervical lymphadenopathy, and mucocutaneous involvement. Coronary artery aneurysms are a serious
complication of Kawasaki disease. [1852]
Peripheral vascular disease

Thromboangiitis obliterans (Buerger disease) is a segmental, inflammatory vasculitis that affects the small- and
medium-sized arteries and veins of the distal extremities with inflammatory, intraluminal thrombi and sparing of the
vessel wall. It is usually seen in young, heavy smokers, and can present with digital ischemia and ulceration,
extremity claudication, Raynaud phenomenon, and superficial thrombophlebitis. [451]
Intermittent claudication describes muscle pain that is reproducibly caused by exercise and relieved by rest; it occurs
due to atherosclerotic stenoses (lipid-filled intimal plaques) in the large arteries that prevent sufficient blood flow to
exercising muscle. The lower extremities are most commonly affected; however, proximal lesions (ie, aortoiliac
occlusion) can cause gluteal claudication and/or impotence. [448]
Polyarteritis nodosa
Polyarteritis nodosa is characterized by segmental, transmural, necrotizing inflammation of medium-sized muscular
arteries. Manifestations arise due to tissue ischemia from arterial lumen narrowing/thrombosis or bleeding from
microaneurysms. The vessels of the kidneys, skin, peripheral nerves, and gastrointestinal tract are affected most
commonly; the lung is typically spared. [460]
Renal artery stenosis

Renal artery stenosis is most often due to atherosclerosis. It can cause severe, refractory hypertension due to
activation of the renin-angiotensin-aldosterone system. Over time, renal atrophy may occur due to chronic oxygen
and nutrient deprivation. Histologic examination may show crowded glomeruli, tubulointerstitial atrophy and
fibrosis, and focal inflammatory infiltrates. [453]
In unilateral renal artery stenosis, the narrowed renal artery causes hypoperfusion of the affected kidney with
subsequent ischemic damage (eg, tubular atrophy, interstitial ischemia, glomerular crowding). In contrast, the
contralateral kidney is exposed to high blood pressure and typically shows changes of hypertensive nephrosclerosis
(eg, arteriolar wall thickening due to hyaline or hyperplastic arteriolosclerosis). [7568]
Renal infarction
Renal infarction presents with flank pain, hematuria, elevated lactate dehydrogenase, and a wedge-shaped kidney
lesion on CT scan. The most common cause of renal infarction is systemic thromboembolism, often due to thrombus
formation during atrial fibrillation. The brain and kidneys are more likely than other organs to suffer embolic
infarctions because they are perfused at a higher rate. [809]
Takayasu arteritis
Takayasu arteritis is a chronic, large-artery vasculitis that primarily involves the aorta and its branches. It presents
with constitutional (eg, fever, weight loss) and arterio-occlusive (eg, claudication, blood pressure discrepancies, pulse
deficits) findings in patients age <40. Histopathology shows granulomatous inflammation of the vascular media. [452]
Thrombophlebitis
A paraneoplastic syndrome of hypercoagulability may be seen in some patients with cancer, especially
adenocarcinomas of the pancreas, colon, or lung. Superficial venous thromboses may therefore appear in one site
and then resolve, only to recur in another site. This is known as Trousseau syndrome (migratory superficial
thrombophlebitis), an indication of visceral cancer. [475]
CARDIAC ARRHYTHMIAS
Electrical injury
Although lightning injuries are rare, they are associated with a 25% fatality rate. Two-thirds of lightning-related
deaths occur within the first hour after injury, with fatal arrhythmias and respiratory failure as the most common
causes. Patients with minor cutaneous involvement may still have major internal injury after lightning strikes and
high-voltage electrical contact. [8458]
Heart block
Third-degree (complete) atrioventricular block involves dysfunction of the atrioventricular node, resulting in total lack
of communication between the atria and ventricles. On ECG, there is dissociation of P waves and QRS complexes,
with P waves marching out at the intrinsic rate of the sinoatrial node and QRS complexes at the intrinsic rate of the
His bundle or ventricles (escape rhythm). [15555]
Long QT syndrome
Jervell and Lange-Nielsen syndrome is an autosomal recessive disorder characterized by profound bilateral
sensorineural hearing loss and congenital long QT syndrome, which predisposes to ventricular arrhythmias and
sudden cardiac death. This condition occurs secondary to mutations in genes that encode voltage-gated potassium
channels. [91]
Unprovoked syncope in a previously asymptomatic young person may result from a congenital QT prolongation
syndrome. The two most important congenital syndromes with QT prolongation, Romano-Ward syndrome and
Jervell and Lange-Nielsen syndrome, are thought to result from mutations in a K+ channel protein that contributes to
the delayed rectifier current (IK) of the cardiac action potential. [84]
Congenital long QT syndrome is most often caused by genetic mutations in a K+ channel protein that contributes to
the outward-rectifying potassium current. A decrease in the outward K+ current leads to prolongation of action
potential duration and QT interval. This prolongation predisposes to the development of life-threatening ventricular
arrhythmias (eg, torsades de pointes) that can cause palpitations, syncope, seizures, or sudden cardiac death. [86]
Lyme disease
Early disseminated Lyme disease can have cardiac involvement (Lyme carditis) that most commonly manifests with
varying degrees of atrioventricular (AV) conduction block. Patients may be asymptomatic, but those with complete
AV conduction block are likely to have dyspnea, lightheadedness, or syncope. [15559]
Aortic coarctation
Aortic coarctation classically leads to lower extremity claudication and increased blood pressure in the arms, as
compared to the legs. Over time, unrepaired defects may lead to a compensatory collateral circulation that supplies
blood to the descending aorta and creates a continuous murmur heard over the back. [19605]

Atrial septal defects cause right-sided volume overload resulting in right atrial and ventricular enlargement. Excessive
right-sided blood flow causes a characteristic systolic ejection murmur (ie, pulmonic flow murmur) and wide and fixed
splitting of S2. [19556]
Atrioventricular canal defect

A complete atrioventricular (AV) canal defect is comprised of an atrial septal defect, a ventricular septal defect, and a
common AV valve. It is the most common congenital cardiac anomaly associated with Down syndrome. [188]

Lower extremity differential clubbing and cyanosis without pulse discrepancy is caused by a large patent ductus
arteriosus complicated by Eisenmenger syndrome (reversal of shunt flow from left-to-right to right-to-left). In
contrast, intracardiac right-to-left shunting in patients with large septal defects and Tetralogy of Fallot results in
whole-body cyanosis. [32]
Ventricular septal defect

Ventricular septal defect (VSD) typically presents in the neonatal period after pulmonary vascular resistance has
declined. The clinical presentation depends on the size of the defect, which ranges from an asymptomatic
holosystolic murmur (small VSD) to heart failure (large VSD). [203]
Aging
Lipofuscin is a yellow-brown pigment composed of lysosomal breakdown products of lipid polymers and protein-
complex phospholipids. It is considered a wear-and-tear product and marker of aging because it accumulates over
time, and residual bodies containing lipofuscin are prevalent in low-turnover cells (eg, heart, liver, central nervous
system) of the elderly. [300]
Atherosclerosis
Atherosclerosis is a pathophysiologic process involving endothelial cell dysfunction, and it develops most rapidly in
areas with bends and branch points that encourage turbulent blood flow. The lower abdominal aorta and coronary
arteries are the vascular beds most susceptible to atherosclerosis; they tend to develop atherosclerosis earliest in life
and have the highest overall atherosclerotic burden. [11636]
During the development of atherosclerotic plaque (atheroma), activated macrophages, platelets, and endothelial
cells release growth factors (eg, platelet-derived growth factor) that stimulate recruitment of smooth muscle cells
from the arterial wall media and their subsequent proliferation in the intima. [446]
The likelihood of plaque rupture is related to plaque stability rather than plaque size or the degree of luminal
narrowing. Plaque stability largely depends on the mechanical strength of the fibrous cap. Inflammatory
macrophages in the intima may reduce plaque stability by secreting metalloproteinases, which degrade extracellular
matrix proteins (eg, collagen). [447]
Stable angina pectoris results from myocardial oxygen demand-supply mismatch and manifests as chest pressure,
tightness, or pain that is reliably produced by exertion and relieved by rest. It most commonly occurs due to a fixed
atherosclerotic plaque obstructing >70% of the coronary artery lumen that limits blood flow during exertion. [36]
Atherosclerosis is initiated by repetitive endothelial cell injury, which leads to a chronic inflammatory state in the
underlying intima of large elastic arteries as well as in large- and medium-sized muscular arteries. [442]
Gradually developing myocardial ischemia encourages the formation and maturation of collateral vessels and is most
likely to occur in the setting of a slow-growing, stable atherosclerotic plaque. An unstable atherosclerotic plaque (eg,
that with active inflammation, a lipid-rich core, and/or a thin fibrous cap) is more likely to rupture, resulting in the
abrupt onset of ischemia/infarction that precludes the development of viable collateral vessels. [39]
Fatty streaks are the earliest lesions of atherosclerosis and can be seen as early as the second decade of life. They
appear as a collection of lipid-laden macrophages (foam cells) in the intima that can eventually progress to
atherosclerotic plaques. [444]
Coronary artery disease

Medial smooth muscle cells are responsible for synthesizing the extracellular matrix proteins (eg, collagen,
proteoglycans) that form the fibrous cap of a mature atheroma. Progressive atheroma enlargement increases the
likelihood of plaque rupture with resulting luminal thrombosis. [443]
Ventricular fibrillation is the most common mechanism of sudden cardiac death due to acute myocardial infarction. It
results from arrhythmogenic foci triggered by electrical instability in the ischemic myocardium. [192]
Mitochondrial vacuolization is typically a sign of irreversible cell injury, signifying that the involved mitochondria are
permanently unable to generate ATP. [176]
Myocardial infarction that causes ischemia of the papillary muscle or nearby left ventricular wall can result in acute
mitral regurgitation with development of a new systolic murmur. Timely restoration of blood flow can improve
papillary muscle dysfunction and lead to resolution of the regurgitation. [14978]
Right ventricular infarction (right-sided heart failure) can lead to shock via impaired forward blood flow to the left
heart, which lowers left-sided preload (decreased pulmonary capillary wedge pressure) and decreases cardiac
output. The reduced right ventricular output also raises right atrial and central venous pressure. [7666]
Severe systemic hypotension (eg, shock) is most likely to cause ischemia first in areas of high metabolic demand (eg,
hippocampus) or watershed zones, which are areas that are supplied by the distal branches of two different major
arteries. Commonly affected areas in the colon include the splenic flexure and rectosigmoid junction. [7667]
Hibernating myocardium refers to the presence of left ventricular systolic dysfunction due to reduced coronary blood
flow at rest that is partially or completely reversible by coronary revascularization. [43]
After myocardial infarction, transforming growth factor-beta (TGF-β) reduces inflammation and promotes tissue
remodeling due to fibroblast proliferation and collagen deposition, resulting in fibrosis in the area damaged by
ischemia. Abnormal myocardium at the scar border can predispose patients to sudden death as a result of
arrhythmia. [15188]
Ion pump failure due to ATP deficiency during cardiac ischemia causes intracellular accumulation of Na+ and
Ca2+. The increased intracellular solute concentration draws free water into the cell, causing the cellular and
mitochondrial swelling that is observed histologically. [1882]
After the onset of severe ischemia leading to myocardial infarction (MI), early signs of coagulative necrosis do not
become apparent on light microscopy until 4 hours after the onset of MI. [40]
ST-elevation myocardial infarction involves transmural (full-thickness) infarction of the myocardial wall, and usually
results from acute atherosclerotic plaque rupture with the development of overlying thrombus that fully occludes the
coronary artery lumen. It classically presents with sudden-onset substernal chest pain that is not relieved by rest or
short-acting nitrates. ECG demonstrates ST elevation in the affected leads with subsequent development of Q waves.
[37]
HEART FAILURE AND SHOCK
Acute heart failure

The chest x-ray in acute decompensated heart failure typically shows prominent pulmonary vessels; patchy, bilateral
airspace opacification; and blunting of the costophrenic angles due to pleural effusions. [8610]
Acute cardiogenic pulmonary edema results from increased pulmonary venous pressure. The alveolar capillaries
become engorged with blood and there is a transudation of fluid plasma across the alveolar-capillary membrane,
appearing as pink, acellular material within the alveoli. [7616]
Chronic heart failure

Alveolar hemosiderin-laden macrophages indicate alveolar hemorrhage. They most commonly result from chronic
elevation of pulmonary capillary hydrostatic pressure in the setting of left-sided heart failure. [185]
Pulmonary embolism
A large, acute pulmonary embolism causes a rapid increase in right ventricular (RV) pressure that leads to RV cavity
enlargement and RV dysfunction. Thickening of the RV wall is not seen in acute pulmonary embolism, as there is no
time for compensatory hypertrophy to occur in response to the increased pressure load. [15554]
HYPERTENSION
Hypercalcemia
Thiazide diuretics cause hypercalcemia by increasing the distal tubular reabsorption of Ca2+. The increased
circulating calcium levels result in suppression of parathyroid hormone, which distinguishes this effect from
hyperparathyroidism. [980]
Primary hypertension
Concentric left ventricular (LV) hypertrophy involves uniform thickening of the LV walls with reduction in LV cavity
size and most commonly results from prolonged systemic hypertension. It can progress to hypertensive heart disease
with impaired diastolic filling and heart failure with preserved ejection fraction. Histopathology demonstrates
transverse thickening of cardiomyocytes with prominent hyperchromatic nuclei and interstitial fibrosis. [15542]
Hypertensive emergency is severely elevated blood pressure (typically >180/120 mm Hg) with evidence of end-organ
damage. In the kidneys, this can manifest as malignant nephrosclerosis, characterized by fibrinoid necrosis and
hyperplastic arteriolosclerosis ("onion-skin" appearance). A microangiopathic hemolytic anemia can occur due to
erythrocyte fragmentation and platelet consumption at the narrowed arteriolar lumen. [449]
Concentric hypertrophy is characterized by uniform thickening of the ventricular wall and narrowing of the
ventricular cavity due to increased afterload (eg, chronic hypertension, aortic stenosis). Eccentric hypertrophy is
characterized by reduced ventricular wall thickness with an associated increase in chamber size due to volume
overload. [181]
MISCELLANEOUS
Atrial myxoma
Myxomas are the most common primary cardiac neoplasm and usually arise within the left atrium. The tumors
typically cause position-dependent obstruction of the mitral valve, leading to a mid-diastolic murmur and symptoms
of decreased cardiac output (eg, dyspnea, syncope). Constitutional symptoms (eg, fever, weight loss) may also be
present. Histologically, the tumors demonstrate scattered cells within a mucopolysaccharide stroma and blood
vessels with hemorrhage. [8296]
Costochondritis
Costosternal syndrome (costochondritis) usually occurs after repetitive activity and is characterized by pain that is
reproducible with palpation and worsened with movement or changes in position. [11640]
Lymphedema
Chronic lymphedema is most commonly caused by an acquired disruption of lymphatic drainage (eg, due to
malignancy or lymphadenectomy), and typically presents with swelling and thickened skin in one or more
extremities. Treatment is usually conservative and involves compression bandages and physiotherapy; diuretics are
ineffective and contraindicated. [14980]
Acute pericarditis
Pericarditis is the most common cardiovascular manifestation associated with systemic lupus erythematosus. It
presents with sharp pleuritic chest pain that is relieved by sitting up and leaning forward. [1040]
Fibrinous pericarditis is the most common type of pericarditis and is characterized by pericardial inflammation with a
serous, fibrin-containing exudate in the pericardial space. Pleuritic chest pain and a triphasic friction rub are
frequently seen. Common causes include viral infection, myocardial infarction, uremia, and rheumatologic disease
(eg, systemic lupus erythematosus, rheumatoid arthritis). [14999]
In contrast to angina, the chest pain of pericarditis is sharp and pleuritic and may be exacerbated by swallowing or
coughing. Peri-infarction pericarditis (PIP) occurs between 2 and 4 days following a transmural myocardial infarction
(MI). PIP is an inflammatory reaction to cardiac muscle necrosis that occurs in the adjacent pericardium. [89]
Viral infection is the most common cause of acute pericarditis. It causes a fibrinous or serofibrinous pericarditis that
is often characterized by pleuritic chest pain, a friction rub on cardiac auscultation, diffuse ST elevation on ECG, and
mild to moderate-sized pericardial effusion. [15000]
Amyloidosis
Restrictive cardiomyopathy can be caused by infiltrative diseases (eg, amyloidosis, sarcoidosis, hemochromatosis)
and often results in diastolic heart failure due to ventricular hypertrophy with impaired ventricular filling. Cardiac
amyloidosis is characterized histologically by areas of myocardium infiltrated by an amorphous and acellular pink
material (amyloid). [94]
Amyloid cardiomyopathy, caused by the accumulation of misfolded amyloid fibrils, appears as pink, amorphous
extracellular material on light microscopy. The ventricular walls become stiff and uniformly thickened, leading to
impaired diastolic relaxation, a dilated left atrial cavity, and progressive left- and right-sided heart failure. Left
ventricular cavity size is typically normal or decreased. [15214]
Atrial myxoma
Myxomas are the most common primary cardiac neoplasm, and approximately 80% originate in the left
atrium. Patients may have systemic embolization (eg, stroke) or symptomatic mitral valve obstruction that may be
worse with certain body positions. Histopathologic examination reveals amorphous extracellular matrix with
scattered stellate or globular myxoma cells within abundant mucopolysaccharide ground substance. [14998]
Cardiac tamponade
Blunt chest trauma can lead to several life-threatening cardiopulmonary injuries. Progressive hypotension with
tachycardia, jugular venous distension, and bilateral vesicular breath sounds suggests acute cardiac tamponade. [1439]
Chagas disease
Chagas disease is endemic to Central and South America and can lead to chronic Chagas cardiomyopathy, a dilated
cardiomyopathy. Unlike the diffuse ventricular wall thinning that occurs in most dilated cardiomyopathies, chronic
Chagas cardiomyopathy is characterized by localized apical wall thinning with large apical aneurysm development.
[15213]
Constrictive pericarditis
In constrictive pericarditis, normal pericardium is replaced by dense, rigid pericardial tissue that restricts ventricular
filling, leading to low cardiac output and progressive right-sided heart failure. Physical examination findings in such
patients include elevated jugular venous pressure (JVP), pericardial knock, pulsus paradoxus, and a paradoxical rise in
JVP with inspiration (Kussmaul sign). [98]
Dilated cardiomyopathy results from primary myocardial dysfunction leading to eccentric remodeling of the left
ventricle. Patients can develop left ventricular mural thrombus and are at risk for sudden cardiac death due to
ventricular arrhythmia. Familial dilated cardiomyopathy is typically inherited in an autosomal dominant pattern, and
most commonly results from truncating mutations of the TTN gene that codes for the sarcomere protein titin. [14993]
Peripartum cardiomyopathy is a relatively uncommon cause of dilated cardiomyopathy that may be related to
impaired function of angiogenic growth factors. Dilated cardiomyopathy involves compensatory eccentric
hypertrophy, which increases ventricular compliance and also allows for temporary maintenance of cardiac
output. Over time, overwhelming wall stress leads to left ventricular failure with reduced ejection fraction and
symptomatic heart failure. [14992]
Dilation of the left ventricular cavity commonly occurs in response to systolic dysfunction (eg, ischemic heart disease,
dilated cardiomyopathy) or certain types of valvular disease (ie, aortic regurgitation, mitral regurgitation). Chronic
volume overload causes progressive eccentric hypertrophy that eventually leads to reduced ventricular contractility
and decompensated heart failure. [92]
Hemochromatosis
Hereditary hemochromatosis is characterized by excessive intestinal iron absorption with deposition of iron in
parenchymal tissues. Cardiac manifestations include diastolic dysfunction (initial), dilated cardiomyopathy (later),
and conduction system disease (eg, sinus node dysfunction). [394]
In patients with hypertrophic cardiomyopathy, left ventricular outflow tract (LVOT) obstruction results from a
hypertrophied interventricular septum and abnormal systolic anterior motion of the anterior leaflet of the mitral
valve. The degree of LVOT obstruction is dynamic and varies with changes in left ventricular blood volume. [76]
Hypertrophic cardiomyopathy (HCM) is an autosomal dominant inherited condition resulting from mutations
affecting genes that encode for myocardial contractile proteins of the sarcomere; myosin-binding protein C and beta-
myosin heavy chain are the most commonly affected proteins. HCM is characterized by asymmetric septal
hypertrophy and increased risk of sudden cardiac death. [83]
Hypertrophic cardiomyopathy is caused by genetic mutations affecting structural proteins of cardiac sarcomeres (eg,
beta-myosin heavy chain, myosin-binding protein C) and is one of the most common causes of sudden cardiac death
in young adults. Histologically, it is characterized by cardiomyocyte hypertrophy with haphazard cellular arrangement
and interstitial fibrosis. [95]
Hypertrophic cardiomyopathy is a common cause of sudden cardiac death (SCD) in young adults. Histologic features
include cardiomyocyte hypertrophy and myofiber disarray with increased interstitial fibrosis. The structural disarray
creates a substrate for ventricular arrhythmia (eg, ventricular tachycardia, ventricular fibrillation) that can lead to
SCD. [82]
Myocarditis
Acute myocarditis is most commonly caused by a viral infection (eg, coxsackievirus, adenovirus, influenza). It often
resolves without noticeable symptoms, but patients can develop serious complications, including decompensated
heart failure due to dilated cardiomyopathy or sudden cardiac death due to ventricular arrhythmia. Histopathology
typically demonstrates myocyte necrosis with inflammatory mononuclear infiltrate. [14789]
Malignancy is a common cause of pericardial effusion, which is often subacute due to slower accumulation of
pericardial fluid with compensatory pericardial stretching. Pericardiocentesis can acquire fluid for cytologic analysis
(eg, atypical cells) to help confirm the etiology. [20259]
Rheumatic fever
Interstitial myocardial granulomas (Aschoff bodies) are found in carditis due to acute rheumatic fever, which develops
after an untreated group A streptococcal pharyngeal infection. Aschoff bodies contain plump macrophages with
abundant cytoplasm and central, slender ribbons of chromatin (Anitschkow, or caterpillar, cells). [240]
Stress cardiomyopathy
Stress-induced (takotsubo) cardiomyopathy is characterized by hypokinesis of the mid and apical segments and
hyperkinesis of the basal segments of the left ventricle, resulting in systolic dysfunction. The condition is likely caused
by a surge of catecholamines in the setting of physical or emotional stress. It usually affects postmenopausal women
and resolves on its own within several weeks. [14989]
Coronary blood flow

In 90% of individuals, occlusion of the right coronary artery can result in transmural ischemia of the inferior wall of
the left ventricle, producing ST elevation in leads II, III, and aVF as well as possible sinus node dysfunction. Occlusion
of the proximal LAD would be expected to result in anteroseptal transmural ischemia, with ST elevations in leads V1–
V4. Occlusion of the LCX would produce transmural ischemia of the lateral wall of the left ventricle, with ST
elevations mainly in V5 and V6, and possibly also in I and aVL. [179]
Aortic regurgitation
Eccentric ventricular hypertrophy results in a dilated cavity with relatively thin ventricular walls due to the addition of
myocardial contractile fibers in series in response to chronic volume overload. Chronic aortic regurgitation can result
from aortic root dilation and is a common cause of eccentric hypertrophy. [15195]
Aortic stenosis
Calcific degeneration of the trileaflet aortic valve is the most common cause of aortic stenosis (AS) in developed
nations. AS is characterized by progressive aortic valve leaflet thickening and calcification, leading to restricted leaflet
excursion and mobility. AS murmur is usually a harsh ejection-type systolic murmur heard best at the base of the
heart in the "aortic area" (second right intercostal space) with radiation to the carotid arteries. [242]
Aortic stenosis most commonly results from age-related calcific aortic valve disease (CAVD). The early pathogenesis
of CAVD closely mimics that of arterial atherosclerosis. In the later stages, fibroblasts differentiate into osteoblast-
like cells and deposit bone matrix, leading to progressive valvular calcification and stenosis. [14964]
The murmur of valvular aortic stenosis is typically an ejection or midsystolic murmur of crescendo-decrescendo
configuration with maximum intensity over the right second interspace and radiation to neck and carotid
arteries. The most common cause of aortic stenosis in elderly patients (age >70) is degenerative calcification of the
aortic valve leaflets. [939]
Concentric left ventricular hypertrophy involves thickening of the ventricular walls and reduction in the ventricular
cavity size. It occurs via the addition of myocardial contractile fibers in parallel in response to chronic pressure
overload. Aortic stenosis and prolonged systemic hypertension are common causes of concentric left ventricular
hypertrophy. [15196]
Carcinoid tumors
Carcinoid syndrome typically presents with episodic flushing, secretory diarrhea, and wheezing. It can lead to
pathognomonic plaque-like deposits of fibrous tissue on the right-sided endocardium, causing tricuspid regurgitation
and right-sided heart failure. Elevated 24-hour urinary 5-hydroxyindoleacetic acid can confirm the diagnosis. [74]
Endocarditis
Microemboli from the valvular vegetations of bacterial endocarditis are the most common cause of subungual
splinter hemorrhages. The presence of these lesions necessitates careful cardiac auscultation to detect a possible
new-onset regurgitant murmur. [228]
Janeway lesions are nontender, macular, and erythematous lesions typically located on the palms and soles of
patients with acute infective endocarditis and are the result of septic embolization from valvular vegetations. [72]
Chronic valvular inflammation and scarring associated with rheumatic heart disease predispose to an increased risk of
infective endocarditis, which is characterized by valvular vegetations with destruction of the underlying cardiac
tissue. [2074]
Vegetations are caused by bacterial colonization and growth on a sterile fibrin-platelet nidus that forms on the
damaged/disrupted endothelial surface of the valvular apparatus. [2075]
Mitral valve prolapse with regurgitation is the most common predisposing condition for native valve infective
endocarditis (IE) in developed nations. Rheumatic heart disease remains a frequent cause of IE in developing nations.
[230]
Nonbacterial thrombotic endocarditis is characterized by valvular deposition of sterile platelet-rich thrombi. It likely
results from valvular damage due to inflammatory cytokines in the setting of an underlying hypercoagulable state,
and it is most commonly seen with advanced malignancy (especially mucinous adenocarcinoma) or systemic lupus
erythematosus. [231]
Marfan syndrome
Marfan syndrome is a connective tissue disorder in which defective fibrillin-1 decreases tissue integrity and increases
expression of transforming growth factor-beta. Cardiac effects include myxomatous degeneration and prolapse of
the mitral valve with associated regurgitation, which manifests as a midsystolic click and mid-to-late systolic murmur.
[14987]
Mitral stenosis
Rheumatic mitral stenosis is characterized by diffuse fibrous thickening and distortion of the mitral valve leaflets
along with commissural fusion at the leaflet edges. Patients often present with a diastolic murmur, dyspnea, and
fatigue and are at increased risk of atrial fibrillation and thromboembolism (eg, stroke). [232]
Left atrial enlargement can sometimes cause left recurrent laryngeal nerve impingement. Neurapraxia resulting in
left vocal cord paresis and hoarseness may result. [236]
Mitral valve prolapse

Mitral valve prolapse is most often caused by defects in connective tissue proteins that predispose to myxomatous
degeneration of the mitral leaflets and chordae tendineae. Cardiac auscultation typically reveals a midsystolic click
followed by a mitral regurgitation murmur; the click and murmur occur later in systole or disappear completely with
maneuvers (eg, squatting) that increase left ventricular end-diastolic volume. [947]
Pulmonary stenosis
Pulmonic valve stenosis causes a crescendo-decrescendo systolic murmur (best heard at the left upper sternal
border) and delays closure of the pulmonic valve, resulting in widened splitting of S2. Inspiration increases blood
flow to the right side of the heart, causing increased intensity of the murmur and even later closure of the pulmonic
valve. [15198]
Rheumatic fever
Sydenham chorea presents with involuntary, rapid, irregular jerking movements involving the face, arms, and legs. It
occurs months after group A streptococcal infection and is one of the major clinical manifestations of acute
rheumatic fever. Patients with this condition carry a high risk of chronic valvular disease. [241]
SLE
Cardiovascular manifestations of lupus include accelerated atherosclerosis, small-vessel necrotizing vasculitis,
pericarditis, and Libman-Sacks endocarditis (small, sterile vegetations on both sides of the valve). Renal involvement
classically manifests as diffuse proliferative glomerulonephritis, which is characterized by diffuse thickening of the
glomerular capillary walls with "wire-loop" structures on light microscopy. [73]
Dermatology
Acne vulgaris
Risk factors for acne include increased androgen levels; obstruction of pilosebaceous glands by oil-based hair
products; and mechanical irritation of skin follicles. Sports participation frequently triggers acne due to the use of
tight-fitting clothing and protective gear. [15373]
Acne vulgaris is an inflammatory disorder of pilosebaceous follicles. Contributing factors include hyperkeratinization
and obstruction of follicles; sebaceous gland enlargement with increased secretion of sebum; colonization and
proliferation in the gland by Propionibacterium (Cutibacterium) acnes; and follicular and perifollicular inflammation.
[15374]
Hidradenitis suppurativa
Hidradenitis suppurativa results from the occlusion of folliculopilosebaceous units. Subsequent follicular rupture and
inflammation form painful nodules and abscesses, which may progress to sinus tracts, scars, and comedones with
chronic, recurrent disease. [20587]
Ichthyoses
Ichthyosis vulgaris is caused by filaggrin gene mutations that result in defective keratinocyte desquamation. It is
characterized by dry, scaly skin; manifestations are diffuse but are typically worse on the trunk and the extensor
surfaces of the extremities. [15441]
Neurofibromatosis
Neurofibromas are benign nerve sheath tumors composed of cells normally found in peripheral nerves, including
neoplastic Schwann cells, as well as non-neoplastic fibroblasts, perineural cells, and mast cells. Cutaneous
neurofibromas often arise from small nerves in the dermis. [22599]
Radiation injury
Late-stage radiation dermatitis occurs months to years after radiation exposure and is characterized grossly by
pigment changes, telangiectasias, and chronic ulceration. Typical histologic changes include vascular abnormalities,
fibroblast proliferation, and homogenization of dermal collagen (ie, fibrosis) due to the increased expression of
transforming growth factor-beta. [18927]
Vitiligo
Vitiligo is a common condition characterized by the loss of epidermal melanocytes. It occurs more commonly in
patients with autoimmune disorders (eg, autoimmune thyroiditis, type I diabetes) and results in well-defined, variably
sized patches of hypopigmentation. [1110]
Atopic dermatitis
Atopic dermatitis is characterized by epidermal barrier dysfunction due to loss-of-function mutations in filaggrin, a
key epidermal component. Increased transepidermal water loss, skin permeability, and inflammation result in
erythematous dry skin and pruritus, with chronic disease presenting as lichenification from repeated scratching. [15411]
Atopic dermatitis (eczema) is a common, chronic inflammatory disorder caused by impairment of the skin's barrier
function. Eczema presents with pruritus and erythematous papules and plaques and is associated with other atopic
diseases, such as allergic rhinitis and asthma. [876]
Bullous pemphigoid
Bullous pemphigoid is an autoimmune blistering disease that typically occurs in patients >60. It presents with tense
bullae with rare mucosal involvement. Autoantibodies against hemidesmosomes create subepidermal
cleavage. Immunofluorescence shows linear deposition of IgG and/or C3 along the basement membrane. [15026]
Bullous pemphigoid is caused by autoantibodies against hemidesmosomes along the basement membrane of the
dermal-epidermal junction. This causes the entire epidermis to separate from the dermis and form tense,
subepidermal blisters. [1105]
Contact dermatitis
Acute allergic contact dermatitis (ACD), caused by a type IV (delayed) hypersensitivity reaction to an antigen on the
skin surface, typically presents with pruritic, erythematous, papulovesicular, weeping lesions. Microscopically, acute
ACD is characterized by spongiosis (ie, accumulation of fluid between keratinocytes in the epidermis). [1115]
Dermatitis herpetiformis
Dermatitis herpetiformis is characterized by erythematous pruritic papules, vesicles, and bullae that appear
symmetrically on extensor surfaces. It is strongly associated with celiac disease, a disorder characterized
histologically by small intestinal intraepithelial lymphocytosis, crypt hyperplasia, and villous atrophy. [1111]
Epidermolysis bullosa
Epidermolysis bullosa is a group of inherited disorders characterized by epithelial fragility (eg, bullae, erosions, ulcers)
triggered by minor trauma. It is caused by mutations affecting proteins in the intraepidermal and dermoepidermal
adhesion complexes; keratin mutations are responsible for the most common form (EB simplex). [16852]
Erythema multiforme
Erythema multiforme is a target-shaped, inflammatory skin lesion that typically arises in the setting of infection,
particularly with herpes simplex virus or Mycoplasma pneumoniae. It is caused by the deposition of infectious
antigens in keratinocytes, leading to a strong cell-mediated (eg, cytotoxic T-cell) immune response. [15695]
Erythema multiforme is a cell-mediated inflammatory disorder of the skin characterized by erythematous papules
that evolve into target lesions. It is most commonly associated with herpes simplex virus. [11662]
Lichen planus
Lichen planus presents with pruritic, purple/pink, polygonal papules and plaques that can affect the flexural surfaces
of the wrists and ankles, along with the nails, oral mucous membranes, and genitalia. Histologic findings include
hyperkeratosis (thickening of stratum corneum), lymphocytic infiltrates at the dermoepidermal junction,
hypergranulosis (prominent granular layer), sawtooth rete ridges, and scattered eosinophilic colloid bodies. [16395]
Lichen planus is an immune-mediated condition that presents with pruritic, pink papules and plaques, often with lacy,
scaly, white markings (Wickham striae). The lesions typically occur on the flexural surfaces of the wrists and ankles
but can also involve the nails, oral mucous membranes, and genitalia. [15439]
Pemphigus vulgaris
Pemphigus vulgaris is an autoimmune bullous disease characterized by autoantibodies directed against desmosomal
proteins (eg, desmogleins). It presents with painful, flaccid bullae and erosions affecting the skin and mucosal
membranes. The bullae spread laterally with pressure, and new blisters may form with gentle rubbing. [2065]
Psoriasis
Psoriasis is a common inflammatory skin disorder characterized by hyperkeratosis (overgrowth of the stratum
corneum) and epidermal hyperplasia. Plaque psoriasis is the most common form and presents with chronic, well-
demarcated, erythematous plaques with a thick, silver scale. [17062]
Psoriasis is histologically characterized by diffuse epidermal hyperplasia with elongated and clubbed rete ridges
(corresponding to the typical erythematous plaques), confluent parakeratosis (producing the characteristic silvery
scales seen on examination), and dilated capillaries in the dermal papillae (pinpoint bleeding). [15408]
Psoriasis is characterized by hyperkeratosis and confluent parakeratosis of the stratum corneum, and epidermal
hyperplasia (acanthosis) with elongated rete ridges. Neutrophilic foci in the stratum corneum and epidermis may
coalesce to form microabscesses (Munro microabscesses). [1117]
Common complications of psoriasis include psoriatic arthritis, nail changes, and uveitis. [1116]

Bullous impetigo is a superficial infection by Staphylococcus aureus that is most common in young children. It is
characterized by a blistering skin rash with tan- to honey-colored crusts. The blistering in bullous impetigo is caused
by exfoliative toxin A, which targets desmoglein 1 in epidermal cellular junctions and causes a loss of cell adhesion.
[15361]
Urticaria
A number of medications, including opioids, radiocontrast agents, and some antibiotics (eg, vancomycin), can trigger
IgE-independent mast cell degranulation. Common symptoms include diffuse itching and pain, bronchospasm, and
localized swelling (urticaria). [11852]
Urticaria is a transient hypersensitivity disorder characterized by pruritic erythematous plaques that arise suddenly
and resolve over hours. They are most often caused by IgE-mediated degranulation of mast cells, leading to
increased permeability of the microvasculature with edema of the superficial dermis. [1114]
Wound healing
During the remodeling phase of wound healing, matrix metalloproteinases facilitate the degradation of collagen and
other proteins in the extracellular matrix, causing the replacement of type III, disorganized collagen with type I, well-
organized, and cross-linked collagen. This leads to both increased tensile strength and flattening of the scar. [1874]
Wound healing
Angiogenesis is the process by which new blood vessels are formed. It primarily occurs during the proliferation phase
of wound healing and is stimulated by growth factors such as fibroblast growth factor and vascular endothelial
growth factor. [20885]
Hand, foot, mouth disease

Hand-foot-and-mouth disease is a common childhood illness characterized by painful, vesicular mouth lesions; ulcers
on the extremities; and low-grade fever. It is caused by the ingestion and subsequent dissemination of an enterovirus
(eg, Coxsackievirus). [15550]
Herpes zoster
Herpes zoster (shingles) develops due to reactivation of varicella zoster virus in the dorsal root ganglia (sensory
neurons). It presents with a painful vesicular rash in a dermatomal distribution. Intranuclear inclusions in
keratinocytes and multinucleated giant cells are seen on light microscopy. [1042]
Leprosy
The lepromin skin test will be positive in patients with tuberculoid leprosy as they exhibit a strong CD4+ TH1 cell-
mediated immune response to Mycobacterium leprae. Patients with lepromatous leprosy will test negative due to
their weak TH1 cell-mediated immune response. [1314]
Acanthosis nigricans
Acanthosis nigricans presents with thickening and hyperpigmentation of skin in the flexural areas. The lesions have a
classic "velvety" texture. Acanthosis nigricans is commonly associated with insulin-resistant states (eg, diabetes
mellitus, acromegaly, obesity) and gastrointestinal malignancies. [936]
Actinic keratoses
Actinic keratoses (AKs) are small (usually <1 cm), erythematous epidermal lesions with adherent scale that are the
result of chronic sun exposure. Histologic findings include keratinocyte atypia, hyperkeratosis, and parakeratosis. A
small percentage of AKs progress to invasive squamous cell carcinoma; therefore, frequent monitoring is necessary.
[1993]
Actinic keratosis (AK) develops on chronically sun-exposed areas of the skin in predisposed individuals. The lesions
consist of erythematous papules with a central scale and a rough "sandpaper-like" texture. AKs are considered
premalignant lesions and have the potential to progress to squamous cell carcinoma. [935]
Actinic keratoses often appear as scaly, erythematous lesions in sun-exposed areas. Histologic examination typically
shows proliferation of atypical keratinocytes (eg, hyperchromatic, pleomorphic nuclei) that does not involve the full
thickness of the epidermis. [15423]
Cherry angioma
Cherry hemangiomas are small, red, cutaneous papules common in aging adults. They do not regress spontaneously
and typically increase in number with age. Light microscopy of these lesions shows proliferation of capillaries and
post-capillary venules in the papillary dermis. [826]
Dyslipidemia
Xanthomas are suggestive of hyperlipidemia, especially when present in conjunction with a family history of early
cardiac death. [1108]
Glomus tumor
A benign glomus tumor (glomangioma) can produce a very tender, small (a few millimeters in diameter), red-blue
lesion under the nail bed. This type of tumor originates from the modified smooth muscle cells that control the
thermoregulatory functions of dermal glomus bodies. [467]
Hemangioma
Infantile hemangiomas are benign vascular tumors composed of proliferating endothelial cells that most frequently
affect the head or neck region. Natural history of these lesions involves rapid growth of a red, cutaneous plaque
followed by spontaneous regression. [20374]
Infantile hemangioma is a common, benign vascular tumor that presents soon after birth as a bright red, raised,
sharply demarcated plaque. The natural course of hemangiomas is proliferation in infancy followed by regression in
early childhood. [466]
Hereditary hemorrhagic telangiectasia
Osler-Weber-Rendu syndrome (hereditary hemorrhagic telangiectasia) is an autosomal dominant condition marked
by the presence of telangiectasias in the skin as well as the mucous membranes of the lips, oronasopharynx,
respiratory tract, gastrointestinal tract, and urinary tract. Rupture of these telangiectasias may cause epistaxis,
gastrointestinal bleeding, or hematuria. [469]
Kaposi sarcoma
Kaposi sarcoma often presents as multiple red, purple, or brown lesions on the lower extremities in patients with HIV
infection. It is a vascular tumor caused by human herpesvirus type 8 infection of endothelial cells. [22603]
Kaposi sarcoma is a vascular tumor strongly associated with human herpesvirus type 8. It typically presents as red,
purple, or brown papules and plaques on the extremities of patients who are HIV positive. [1761]
Keloid
Transforming growth factor-β (TGF-β) is critical for fibroblast migration, proliferation, and connective tissue
synthesis. Increased TGF-β activity is responsible for the hypertrophic/keloid scarring and fibrosis of the lung, liver,
and kidney that occur with chronic inflammation. [11738]
Lung cancer
Melanoma is a highly aggressive malignancy that often metastasizes early in the disease course. Patients may be
asymptomatic for years prior to onset of metastatic manifestations. Diagnosis is generally made when a
histopathologic sample shows cellular atypia with cells containing brown pigment (melanin granules);
immunostaining for melanocytic markers (eg, S-100, HMB-45) is generally positive. [15460]
Lymphedema
Angiosarcomas classically occur after the treatment of breast cancer from either radiation exposure or chronic
lymphedema with firm, violaceous nodules on the ipsilateral extremity. [1937]
Melanocytic nevus
Compound nevi are benign proliferations of melanocytes that involve both the dermis and the epidermis. The lesions
appear as slightly raised papules with uniform pigmentation and symmetric sharp borders. [11502]
Melanoma
Melanoma is often diagnosed when immunostaining of biopsy samples reveals multiple melanocyte markers (eg, S-
100, HMB-45, MART-1). [16865]
BRAF is a protein kinase involved in activation of signaling pathways for melanocyte proliferation; the BRAF V600E
mutation is seen in 40%-60% of patients with melanoma. [7707]
Melanoma often has an early horizontal growth phase with low metastatic potential followed by a nodular, vertical
growth phase with a significantly increased risk of metastasis. Depth of invasion (Breslow thickness) is the most
important prognostic indicator in malignant melanoma. [1113]
Nonmelanoma skin cancer
Basal cell carcinoma (BCC) commonly presents as a pearly, skin-colored papule/nodule on the face. Biopsy classically
shows nests of basaloid keratinocytes with peripheral palisading and clefting artifact. Unresected BCCs rarely
metastasize but may undergo continued local growth, causing progressive surrounding tissue destruction. [14184]
Cutaneous squamous cell carcinoma (SCC) classically presents as a rough or scaly (keratinized) nodule. Diagnosis is
made with biopsy, which typically reveals nests of dysplastic keratinocytes with eosinophilic cytoplasm (due to
keratin filaments). Dermal involvement signifies invasive SCC. [22608]
Natural killer cells and the cell mediated immune response play a major role in cancer cell detection and
destruction. Therefore, patients who are immunocompromised from medication or infection are at much higher risk
for cancer. [15425]
Basal cell carcinomas arise from keratinocytes in the basal layer of the epidermis or hair follicle. They most
commonly occur on the face and often appear as pearly or translucent, pink or skin-colored papules with central
telangiectatic vessels. [22600]
Primary biliary cholangitis

A yellowish eyelid papule or plaque containing lipid-laden macrophages is most likely xanthelasma. Xanthelasma may
occur in association with primary or secondary hyperlipidemia. Cholestatic conditions such as primary biliary
cholangitis are a potential cause of hypercholesterolemia leading to xanthelasma. [1867]
Primary hemostasis
Ecchymoses frequently indicate a deep hemorrhage (hematoma) due to bony fracture, ligamentous rupture, or
muscular injury. They do not blanch under pressure as the red blood cells are not contained within the
vasculature. Ecchymoses often pass through an evolution of color change (blue or red to brown, green, and yellow),
which can be used to estimate the age of the injury. [1878]
Seborrheic keratosis
Seborrheic keratoses are pigmented macules or plaques with a greasy surface and well-demarcated borders. Rapid
onset of numerous lesions is an indicator of internal malignancy (Leser-Trélat sign), especially gastric
adenocarcinoma. [7649]
Seborrheic keratosis is a common epidermal tumor that presents as a tan or brown, round lesion with a well-
demarcated border and "stuck-on" appearance. Microscopic examination shows small cells resembling basal cells,
with pigmentation, hyperkeratosis, and keratin-containing cysts. Rapid onset of numerous lesions is often associated
with internal malignancy (Leser-Trélat sign). [1112]

Field cancerization can occur when a large area of cells is exposed to carcinogens that induce mutations, leading to a
higher risk of forming cancers. [18650]
Head and neck squamous cell carcinoma is likely in a patient with cervical adenopathy and a base of tongue mass,
especially with a history of tobacco use. Classic histologic findings include intercellular bridges and keratin pearls.
[18647]
Leukoplakia
Oral leukoplakia is a potentially premalignant lesion; the risk for progression to invasive carcinoma is related to the
degree of dysplasia. [22476]
Recurrent respiratory papillomatosis

Vertical direct transmission of human papillomavirus subtypes 6 and 11 can cause recurrent respiratory
papillomatosis, which results in wart-like growths most commonly on the true vocal cords. [19035]
Rhinitis
Allergic rhinitis often causes nasal congestion, sneezing, rhinorrhea, and conjunctivitis due to an IgE-mediated
hypersensitivity response. Patients can often distinguish patterns that suggest reactions to specific allergens. [20706]
ADRENAL DISORDERS
Adrenal insufficiency
Primary adrenal insufficiency (PAI) is characterized by weight loss, abdominal pain, fatigue, and
hyperpigmentation. Physiologic stress in patients with PAI can trigger acute adrenal crisis (eg, fever, shock, mental
status changes). Autoimmune adrenalitis is the most common cause of PAI and leads to bilateral adrenal atrophy.
[17246]
Primary adrenal insufficiency usually involves autoimmune destruction of the bilateral adrenal cortex. Reduced
aldosterone production leads to renal salt wasting with hypovolemia, hypotension, and hyperkalemia. The
hypovolemia and reduced cortisol-induced inhibition of antidiuretic hormone lead to water retention and
hyponatremia. Reduced cortisol also causes decreased circulating epinephrine with a compensatory increase in
norepinephrine. [17244]
Congenital adrenal hyperplasia

Deficiency of 21-hydroxylase causes adrenal cortical hyperplasia due to excess stimulation of the adrenal cortex by
ACTH. The classic, non–salt-wasting form presents in boys age 2-4 with early virilization, accelerated linear growth,
and elevated levels of 17-hydroxyprogesterone and androgens. [2080]
Treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency involves low doses of exogenous
corticosteroids to suppress excess ACTH secretion, which reduces production of androgens by the adrenal cortex.
[2081]
Pituitary tumors
[221]
DIABETES MELLITUS
Diabetes mellitus
Pancreatic islet amyloid deposition is characteristic of type 2 diabetes mellitus. A strong linkage with HLA class II gene
makeup, pancreatic islet infiltration with leukocytes (insulitis), and antibodies against islet antigens are frequently
seen in type 1 diabetes. [848]
Hemoglobin A1c is produced by nonenzymatic glycosylation of the hemoglobin molecule. A hemoglobin A1c assay
provides an estimate of chronic glycemic control over the life span of circulating erythrocytes (~3 months). However,
rapid erythrocyte turnover (eg, hemolytic anemia) can give a misleadingly low hemoglobin A1c in relation to glycemic
status. [1996]
Autoimmune insulitis with progressive beta cell loss is the most common cause of type 1 diabetes mellitus. Insulin
resistance accompanied by relative insulin deficiency is the main cause of type 2 diabetes mellitus. [1012]
Patients with noncoronary atherosclerotic disease, diabetes mellitus, or chronic kidney disease are at the same risk of
cardiovascular events (eg, myocardial infarction, stroke) as patients with known coronary heart disease. Coronary
heart disease is the most common cause of death in patients with diabetes mellitus. [1011]
Diabetic foot
Neuropathic foot ulcers can occur in diabetic patients when loss of pain sensation and proprioception delays
recognition of injury due to trauma, friction, or sustained pressure (on plantar surface of foot bones). The risk is
greatest in patients with longstanding diabetes who have poor glycemic control. [15675]
Hypoglycemia
Hypoglycemia is characterized by tremor, diaphoresis, and confusion in association with a low blood glucose level and
resolution of symptoms when the blood glucose level is corrected. Hypoglycemia with elevated insulin and low C-
peptide levels suggests exogenous insulin injection, whereas elevated C-peptide suggests an insulin secretagogue or
insulin-secreting tumor. [8531]
ENDOCRINE TUMORS
Cushing syndrome
Cushing syndrome caused by a pituitary adenoma or ectopic (paraneoplastic) ACTH secretion is associated with
elevated ACTH levels. High-dose dexamethasone suppresses ACTH and cortisol secretion when Cushing syndrome is
caused by a pituitary adenoma (Cushing disease) but not when it is caused by ectopic ACTH secretion (eg, small cell
lung cancer). [927]
Paraneoplastic hypercortisolism, most commonly caused by small cell lung cancer, is due to ectopic ACTH
secretion. Clinical features include hypertension, hyperglycemia, edema, and hyperpigmentation. Unlike
nonparaneoplastic Cushing syndrome, central obesity is uncommon. [1921]
Multiple endocrine neoplasia

Multiple endocrine neoplasia type 2B is characterized by medullary thyroid cancer, pheochromocytoma, marfanoid
habitus, and oral and intestinal mucosal neuromas. [1844]
Multiple endocrine neoplasia type 1 consists of hyperparathyroidism (eg, hypercalcemia, constipation, kidney
stones), pituitary tumors, and pancreatic endocrine tumors (eg, gastrinoma). The genetic defect involves mutations
of the MEN1 gene. [986]
Neuroendocrine tumors
Glucagonoma presents with hyperglycemia (often as newly diagnosed diabetes mellitus) and necrolytic migratory
erythema (blistering erythematous plaques with central clearing) affecting the groin, face, and extremities. The
diagnosis is made by detecting elevated glucagon levels. [585]
Pituitary adenoma
Prolactinomas are the most common pituitary adenoma and can cause galactorrhea, menstrual irregularities, and
infertility in premenopausal women. Large pituitary adenomas can cause headaches from mass effect and
bitemporal hemianopsia from compression of the optic chiasm. [1262]
Thyroid cancer
Follicular neoplasms typically present as slowly enlarging, painless thyroid nodules. Differentiation between a
follicular adenoma and follicular thyroid carcinoma is not possible using only fine-needle aspiration results. Histologic
evidence of invasion of the tumor capsule and/or surrounding blood vessels is needed to diagnose follicular thyroid
carcinoma. [17236]
Papillary thyroid carcinoma is the most common type of thyroid cancer. Characteristic microscopic features include
large cells with nuclei containing finely dispersed chromatin, giving them an empty or ground-glass appearance (ie,
Orphan Annie eye), as well as intranuclear inclusions and nuclear grooves. [1658]
Medullary thyroid cancer is a neuroendocrine tumor that arises from parafollicular calcitonin-secreting C cells. It is
characterized by nests or sheets of polygonal or spindle-shaped cells with extracellular amyloid deposits derived from
calcitonin. [1659]
Acromegaly
Acromegaly can affect the joints in both the axial and the appendicular skeleton. Excessive growth hormone and
insulin-like growth factor-1 cause hyperplasia of articular chondrocytes and synovial hypertrophy, leading to later
degeneration of articular cartilage and periarticular bone. [20526]
Acromegaly is caused by excessive production of growth hormone, usually due to a pituitary somatotroph
adenoma. Musculoskeletal manifestations include bony hypertrophy (eg, frontal bossing; enlarged jaw, hands, and
feet) and osteoarthritis. Left ventricular hypertrophy is often common in acromegaly and may progress to heart
failure. [7651]
Hypopituitarism
High estrogen levels during pregnancy cause enlargement of the pituitary gland without a proportional increase in
blood supply. Peripartum hypotension can cause ischemic necrosis of the pituitary leading to panhypopituitarism
(Sheehan syndrome). Patients commonly develop failure of lactation due to deficiency of prolactin. [220]
Pituitary apoplexy
Acute pituitary hemorrhage (pituitary apoplexy) is characterized by severe headache, bitemporal hemianopsia
(compression of the optic chiasm), and ophthalmoplegia (compression of the oculomotor nerve [CN III]). It usually
occurs in a preexisting pituitary adenoma. Pituitary apoplexy is a medical emergency that requires urgent treatment
with glucocorticoids to prevent acute adrenal crisis and circulatory collapse. [225]
Atherosclerosis
Familial hypercholesterolemia, one of the most common autosomal dominant disorders, is the result of heterozygous
or homozygous LDL receptor gene mutations, which cause hepatocyte under-expression of functional LDL
receptors. This condition can lead to accelerated atherosclerosis and early-onset coronary artery disease. [190]
Dyslipidemia
Familial chylomicronemia syndrome frequently presents in childhood with recurrent episodes of acute
pancreatitis. Patients with this disorder are not usually at increased risk for premature coronary artery
disease. Eruptive skin xanthomas may be present in hypertriglyceridemia, but tendon xanthomas and xanthelasmas
are primarily seen with hypercholesterolemia. [782]
Xanthelasmas, a type of xanthoma, are yellowish macules/papules found on the medial eyelids. They are dermal
accumulations of macrophages containing cholesterol and triglycerides, and are generally associated with a primary
or secondary hyperlipidemia or dyslipidemia. An LDL receptor abnormality is the most common cause. [191]
REPRODUCTIVE ENDOCRINOLOGY
Androgenic steroids
Androgenic steroid abuse may lead to erythrocytosis, testicular atrophy, acne, and virilization in women (eg,
clitoromegaly, hirsutism). [1901]
Anorexia nervosa
Functional hypothalamic amenorrhea is a common cause of secondary amenorrhea and occurs due to decreased
amplitude and frequency of pulsatile gonadotropin-releasing hormone release from the hypothalamus, which in turn
leads to low FSH, LH, and estrogen levels. Causes include anorexia nervosa (eg, distorted body image, restricted diet,
lanugo), excessive strenuous exercise, and chronic illness. [1839]
Kallmann syndrome
In Kallmann syndrome, there is an absence of GnRH secretory neurons in the hypothalamus due to defective
migration from the olfactory placode. These patients have central hypogonadism and anosmia, and often present
with delayed puberty. [579]
THYROID DISORDERS
Hypothyroidism
Postpartum thyroiditis occurs within 12 months of pregnancy and is characterized by autoimmune destruction of
thyroid follicles. It begins with a hyperthyroid phase due to release of preformed thyroid hormone, followed by a
transient hypothyroid phase due to depletion of thyroid hormone. Histologic inspection demonstrates lymphocytic
infiltration, sometimes with formation of germinal centers. [20306]
Chronic lymphocytic (Hashimoto) thyroiditis is a common cause of primary hypothyroidism. Histopathology findings
include intense lymphoplasmacytic infiltrate, often with germinal centers. Residual follicles may be surrounded by
Hürthle cells (large cells with granular, eosinophilic cytoplasm). [769]
Thyroiditis
Subacute granulomatous (de Quervain) thyroiditis is characterized by painful thyroid enlargement and usually follows
a viral illness. Biopsy shows a mixed inflammatory infiltrate with macrophages and multinucleated giant cells. [768]
BREAST DISORDERS
Fibroadenoma breast
Fibroadenomas are the most common benign tumor of the breast. They are characterized histologically by a myxoid
stroma that encircles and sometimes compresses epithelium-lined glandular and cystic spaces. [1109]
Pituitary adenoma
Prolactinomas are the most common hormonally active pituitary adenomas. The excess prolactin produced by these
tumors can cause galactorrhea and amenorrhea in premenopausal women. With a large mass, visual changes and
headaches may occur due to compression of the optic chiasm. [1917]
Cervical cancer
Human papillomavirus (HPV) infection, especially types 16 and 18, is the strongest risk factor for the development of
high-grade cervical dysplasia (cervical intraepithelial neoplasia) and cervical cancer. Immunosuppression (eg, HIV) is
another risk factor because it allows for persistent HPV infection, increasing the oncogenic potential of the virus. [1992]
Ectopic pregnancy
Ectopic pregnancy occurs when the embryo implants in an extrauterine location, most commonly the fallopian
tube. Risk factors for ectopic pregnancy include tubal scarring (eg, prior pelvic surgery, pelvic inflammatory disease),
tobacco use, and in vitro fertilization. [19970]
Endometriosis
Endometriosis is the presence of endometrial glands and stroma in an extrauterine location. Ectopic implants within
the intraperitoneal cavity degenerate during menses and can cause abdominopelvic inflammation and the formation
of tissue adhesions. Therefore, patients with endometriosis may have dysmenorrhea, dyspareunia, and infertility.
[333]
Histologic features of endometriosis include endometrial glands (lined by columnar epithelium), endometrial stroma,
and hemosiderin. Endometriosis commonly involves the ovary, which is covered by a simple cuboidal surface
epithelium. [2056]

Human papillomavirus (HPV) oncogenicity relies on the inhibitory effects of viral proteins E6 and E7 on cell cycle
regulatory proteins p53 and Rb. This allows cells infected with HPV to undergo unchecked cellular proliferation and
evasion of apoptosis, promoting genomic instability and malignant transformation. [11929]
Human papillomavirus infection of basal cervical epithelial cells can cause dysplasia known as cervical intraepithelial
neoplasia (CIN). CIN is classified as low-grade (if involving the lower one third of the epithelium) or high-grade (if
extending above the lower one third). Basement membrane invasion signifies invasive cancer. [11858]
Ovarian cancer
Epithelial ovarian cancer is the most common ovarian malignancy. Histologic findings include anaplasia of epithelial
cells with invasion into the stroma and multiple papillary formations with cellular atypia. Epithelial ovarian tumors
are associated with elevated cancer antigen 125, which can be used as a serum marker for this condition. [1837]
Teratomas are the most common subtype of ovarian germ cell neoplasms and occur most frequently in women age
10-30. Mature teratomas are benign and show mature tissues derived from multiple germ layers, frequently
including skin, hair, and teeth. [11652]
Mature cystic teratomas (ie, dermoid cysts) are derived from all 3 germ cell layers; therefore, the typical gross
appearance is a multicystic mass containing yellow sebaceous fluid, solid components (eg, teeth, cartilage), and
hair. Although often asymptomatic, affected patients are at increased risk of ovarian torsion. [20083]
A Krukenberg tumor is a gastric tumor that has metastasized to the ovary and can present with unintentional weight
loss, epigastric pain, and adnexal masses. Histologically, the metastatic tumor cells have large amounts of mucin with
displaced nuclei, resulting in a signet ring appearance. [127]
Granulosa cell tumors are ovarian sex-cord stromal tumors that often secrete estrogen (eg, postmenopausal
bleeding, endometrial hyperplasia). Gross pathology typically shows a large, unilateral, solid and cystic mass, which
may appear yellow. Call-Exner bodies (ie, neoplastic granulosa cells forming follicle-like structures around central
eosinophilic material) are often seen on microscopy. [1158]
Sertoli-Leydig cell tumors of the ovary arise from the sex cord stroma and secrete testosterone. Therefore, patients
typically have signs and symptoms of hyperandrogenism, including rapid-onset virilization (eg, hirsutism,
clitoromegaly, voice deepening) and amenorrhea. [1928]
Uterine fibroids
Uterine leiomyomas (ie, fibroids) are common, benign tumors arising from the uterine myometrium that occur due to
monoclonal proliferation of myocytes and fibroblasts. [19641]
Uterine sarcoma is a rare but aggressive malignant tumor of the uterine myometrium and/or endometrial stromal
tissue. Patients typically have clinical features similar to those with uterine leiomyomas (eg, abnormal uterine
bleeding, immobile pelvic mass), but uterine sarcoma can be distinguished by microscopy, which typically shows
characteristic malignant features such as nuclear atypia, abundant mitoses, and tumor necrosis. [18233]

Human papillomavirus (HPV) infection causes cutaneous and genital warts as well as benign and malignant
intraepithelial neoplasia. Koilocytosis is a hallmark sign of HPV infection. Koilocytes are pyknotic, superficial or
immature squamous cells with a dense, irregularly staining cytoplasm and perinuclear halo-like clearing. [1015]

Women are at high risk for urinary tract infections due to a shorter urethra that is close to the anus and vaginal
introitus, which allows enteric pathogens to colonize the vagina and ascend to the bladder. Acute simple cystitis is
generally marked by dysuria, urinary frequency/urgency, suprapubic tenderness, and pyuria/bacteriuria on urinalysis.
[15869]
Both upper (eg, pyelonephritis) and lower (eg, cystitis) urinary tract infections (UTIs) can show microscopic
hematuria, pyuria, and bacteriuria on urinalysis with microscopy. However, the presence of white blood cell (WBC)
casts can confirm the diagnosis of pyelonephritis in patients with UTI symptoms because WBC casts form only in the
renal tubules. [888]
MISCELLANEOUS
Endometriosis
Endometriosis causes chronic pelvic pain due to ectopic implantation of endometrial glands and stroma in the
abdominopelvic cavity. Bladder implants may also result in dysuria while rectovaginal implants may cause dyschezia,
rectovaginal nodularity, and pelvic fibrosis (eg, immobile uterus). [20285]
Cholangitis
Acute cholangitis is a life-threatening infection characterized by fever, right upper quadrant pain, and jaundice
(Charcot triad); hypotension and altered mental status (Reynold pentad) occur in severe cases. Acute cholangitis
typically develops in the setting of biliary obstruction; common etiologies include gallstones, malignancy, and
strictures. [16175]
Cholecystitis
Acute calculous cholecystitis is an acute inflammation of the gallbladder initiated by gallstone obstruction of the
cystic duct. Subsequent steps in pathogenesis include mucosal disruption by lysolecithins, bile salt irritation of the
luminal epithelium, prostaglandin release with transmural inflammation, gallbladder hypomotility, increased
intraluminal pressure causing ischemia, and bacterial invasion. [79]
Acute acalculous cholecystitis is an acute inflammation of the gallbladder in the absence of gallstones. It typically
occurs in critically ill patients (eg, those with sepsis, severe burns, trauma, immunosuppression) due to gallbladder
stasis and ischemia. Clinical findings may be subtle and include fever, right upper quadrant pain, and leukocytosis. [81]
Cholestasis
Cholestatic liver disease can cause malabsorption and nutritional deficiencies of fat-soluble vitamins. [364]
Gallstone disease
Black pigment stones arise from conditions that increase the amount of unconjugated bilirubin in bile, which
promotes calcium bilirubinate precipitation. This may occur in the setting of chronic hemolysis (eg, sickle cell anemia,
β-thalassemia, hereditary spherocytosis) and increased enterohepatic cycling of bilirubin (eg, ileal disease). [69]
Most gallstones occur due to the supersaturation of cholesterol, which precipitates out of bile with mucin and
calcium salts to form white or yellow cholesterol stones. Factors that promote the formation of cholesterol stones
include increased cholesterol synthesis, gallbladder hypomotility, increased calcium or mucin concentration, and
decreased bile acid synthesis or recirculation. [16116]
Neonatal jaundice
Excess unconjugated bilirubin in the neonatal period, often caused by increased hemolysis, can cross the blood-brain
barrier and deposit in the basal ganglia and brainstem nuclei. If inadequately treated, this can lead to chronic,
irreversible neurologic dysfunction, including abnormal movements (eg, chorea, dystonia) and impaired vision and
hearing. [21083]
Porcelain gallbladder
Porcelain gallbladder is a potential manifestation of chronic cholecystitis and is often found in association with
multiple gallstones. It is due to dystrophic intramural deposition of calcium salts in the setting of chronic
inflammation. Porcelain gallbladder is associated with an increased risk of adenocarcinoma of the gallbladder. [87]
Primary Sclerosing Cholangitis

Primary sclerosing cholangitis is characterized by inflammation, fibrosis, and stricture of intrahepatic and extrahepatic
bile ducts. Histologic findings include fibrous obliteration of bile ducts and concentric periductal connective tissue
deposition (eg, onion skin–like pattern). Manifestations reflect cholestasis and include jaundice, pruritus, fatigue, and
a cholestatic injury pattern (ie, elevated alkaline phosphatase, direct hyperbilirubinemia). [49]

Primary biliary cholangitis is a chronic liver disease characterized by autoimmune destruction of the intrahepatic bile
ducts and cholestasis (elevated alkaline phosphatase). The condition is most common in middle-aged women, with
severe pruritus (especially at night) often one of the first reported symptoms. [401]
Primary biliary cholangitis is an autoimmune disorder that most commonly affects middle-aged women and is
characterized by fatigue, pruritus, jaundice, cholestasis (eg, elevated alkaline phosphatase, elevated gamma-glutamyl
transferase, direct hyperbilirubinemia), and antimitochondrial antibodies. Histologic findings include dense
lymphocytic portal tract inflammation with granulomatous destruction of interlobular bile ducts. [403]
Abetalipoproteinemia
Abetalipoproteinemia is an inherited inability to synthesize apolipoprotein B, an important component of
chylomicrons and very low-density lipoprotein. Lipids absorbed by the small intestine cannot be transported into the
circulation and instead accumulate in the intestinal epithelium, resulting in enterocytes with clear or foamy
cytoplasm. [327]
Cystic fibrosis
The most common gastrointestinal disorder in patients with cystic fibrosis is pancreatic insufficiency. Mutations in
the cystic fibrosis transmembrane conductance regulator gene lead to thick, viscous secretions in the lumens of the
pancreas, resulting in obstruction, inflammation, and subsequent fibrosis. Clinical manifestations include
steatorrhea, failure to thrive, and deficiency of fat-soluble vitamins. [358]
Absence of the submucosal (Meissner) and myenteric (Auerbach) plexuses in Hirschsprung disease causes the
affected rectosigmoid region to become narrowed. The submucosa of the narrowed area is the most superficial layer
where the absence of ganglion cells can be confirmed during biopsy procedures. [331]
Intussusception
Meckel diverticulum is the most common pathologic lead point for intussusception, a condition in which a portion of
the intestine telescopes into itself. Meckel diverticula frequently contain ectopic gastric mucosa, which can aid in
diagnosis. [19295]
Necrotizing enterocolitis
Necrotizing enterocolitis is one of the most common gastrointestinal emergencies affecting newborns. It is
characterized by bacterial invasion and ischemic necrosis of the bowel wall, and is associated with prematurity and
initiation of enteral feeding. Abdominal x-ray showing pneumatosis intestinalis (ie, air in the bowel wall) confirms the
diagnosis. [9920]

Atrophic gastritis can result in profound hypochlorhydria, inadequate intrinsic factor production, vitamin B12
deficiency, and elevated methylmalonic acid levels. Once vitamin B12 replacement therapy is initiated, the
reticulocyte count increases dramatically and peaks around 1 week; hemoglobin levels and erythrocyte counts rise
more gradually and take up to 8 weeks to normalize. [1848]
Vitamin e
Vitamin E is a fat-soluble vitamin, and deficiency can occur in individuals with fat malabsorption due to recurrent
pancreatitis. Vitamin E deficiency is associated with increased susceptibility of the neuronal and erythrocyte
membranes to oxidative stress. Clinical manifestations include decreased proprioception, ataxia, peripheral
neuropathy (eg, hyporeflexia), and hemolytic anemia. [1806]
Vitamin K is necessary for carboxylation of coagulation factors II, VII, IX, and X. Newborns who do not receive
prophylactic supplementation are at risk for life-threatening bleeding (eg, intracranial hemorrhage). Patients with
cystic fibrosis are also at increased risk for vitamin K deficiency due to malabsorption of fat-soluble vitamins. [710]
Barretts esophagus
Barrett esophagus is a metaplastic condition in which the normal squamous epithelium of the distal esophagus is
replaced by intestinal-type columnar epithelium. It occurs most often in longstanding acid reflux and is associated
with an increased risk of adenocarcinoma. [282]
Cytomegalovirus
Cytomegalovirus esophagitis can occur in transplant patients and usually presents with odynophagia or dysphagia
that can be accompanied by fever or burning chest pain. Endoscopy typically shows linear and shallow ulcerations in
the lower esophagus, and histology usually shows enlarged cells with intranuclear inclusions. [11548]
Diffuse esophageal spasm

Diffuse esophageal spasm is characterized by periodic, simultaneous, and non-peristaltic contractions of the
esophagus due to impaired inhibitory innervation within the esophageal myenteric plexus. Patients typically present
with liquid/solid dysphagia and chest pain due to inefficient propulsion of food into the stomach. [280]
Esophagitis
Herpes simplex virus esophagitis is most common in those with impaired cell-mediated immunity. Endoscopy
typically reveals small vesicles and "punched-out" ulcers. Findings on biopsy usually include multinucleated giant
cells and eosinophilic intranuclear inclusions (Cowdry type A inclusion bodies). Acyclovir is the treatment of choice.
[14891]
Eosinophilic esophagitis is a Th2 cell−mediated disorder leading to eosinophilic infiltration of the esophageal
mucosa. It occurs most commonly in males with a history of atopic conditions and typically presents with solid food
dysphagia, reflux, and occasionally food impaction. Classic endoscopic findings include stacked, circular, ringlike
indentations; linear furrowing; and scattered, small, whitish papules (ie, eosinophilic microabscesses). [14892]

Pregnant women often develop gastroesophageal reflux disease (GERD) due to elevated levels of estrogen and
progesterone, which relax the smooth muscle of the lower esophageal sphincter (LES). Later in pregnancy, GERD can
also develop when the gravid uterus presses on the stomach and leads to an altered LES angle or increased gastric
pressure. [14873]
Gastroesophageal reflux disease is caused primarily by gastroesophageal junction incompetence and can be
associated with extraesophageal symptoms (eg, nocturnal cough) in the absence of heartburn ("silent GERD"). Acidic
gastric contents irritate the esophageal mucosa, leading to characteristic histologic findings that include basal zone
hyperplasia, elongation of the lamina propria papillae, and scattered eosinophils. [286]
Hirschsprung disease is characterized by absent submucosal and myenteric ganglion cells in the distal colon. Contrast
enema classically shows a narrowed aganglionic segment (most commonly rectosigmoid) with an abrupt transition
zone to the dilated, histologically normal proximal colon. [19682]
Hypertrophic pyloric stenosis
Infantile hypertrophic pyloric stenosis is characterized by smooth muscle overgrowth of the pylorus. Gastric outlet
obstruction leads to the classic presentation of nonbilious, projectile emesis and dehydration in an infant age 3-6
weeks. [128]
Mallory-weiss syndrome
Mallory-Weiss tears account for about 10% of cases of upper GI hemorrhage. They occur due to increased
intraluminal gastric pressure due to retching, vomiting, or other abdominal straining. [281]

Helicobacter pylori produces the enzyme urease, which splits urea into CO2 and ammonia and neutralizes the local
acidic gastric pH. Active infection can be confirmed through rapid urease testing, in which gastric mucosa is
evaluated in the presence of urea and a pH indicator. Evidence of alkalization (due to ammonia formation) is
confirmatory. [1604]
Helicobacter pylori is a common cause of peptic ulcers. Duodenal ulcers are associated with heavy colonization in the
gastric antrum, whereas colonization in the gastric corpus is associated with gastric ulcers. [7710]
Acute Helicobacter pylori infection initially causes nonatrophic antral gastritis and an increased risk for duodenal
ulcers. Chronic infection results in patchy, multifocal, atrophic gastritis with loss of parietal cells and G cells in the
gastric body; this is associated with decreased acid secretion and an increased risk of gastric ulcers, gastric
adenocarcinoma, and MALT lymphoma. [1918]
Helicobacter pylori antral gastritis is associated with the formation of duodenal ulcers due to increased gastric acid
production. This increase in acidity is caused by unchecked gastrin production due to the destruction of
somatostatin-secreting cells in the gastric antrum. [1603]
Duodenal ulcers are not associated with an increased risk of carcinoma in the same location. In contrast, ulcers
located in the esophagus, stomach (gastric), and colon may be malignant, and biopsy is required. [130]
Peptic ulcers are most commonly caused by Helicobacter pylori infection or nonsteroidal anti-inflammatory drug
(NSAID) use. NSAIDs inhibit cyclo-oxygenase-1, leading to increased gastric acid formation, decreased mucosal
bicarbonate production, and decreased mucosal blood flow, which promote mucosal injury and ulcer formation.
[15018]
Polymyositis and dermatomyositis

Dermatomyositis is characterized by proximal muscle weakness resembling polymyositis, with additional
inflammatory features affecting the skin (eg, heliotrope rash, Gottron papules). In both conditions, involvement of
striated muscle in the oropharynx and heart can lead to dysphagia, pulmonary aspiration, and myocarditis. [15603]
Portal vein thrombosis

Portal vein thrombosis causes portal hypertension, splenomegaly, and varicosities at portocaval anastomoses. It does
not cause histologic changes to the hepatic parenchyma. Ascites is uncommon as the obstruction is presinusoidal;
ascites typically only develops in conditions that cause sinusoidal hypertension. [1701]
Stress gastric ulcer
Stress-related mucosal disease is usually caused by local ischemia in the setting of severe physiologic stress (eg,
shock, extensive burns, sepsis, severe trauma). Ulcers arising in the setting of severe trauma/burns are called Curling
ulcers. Ulcers arising from intracranial injury are caused by direct vagal stimulation and are called Cushing ulcers. [125]
Systemic sclerosis
Systemic sclerosis may result in esophageal dysmotility and incompetence of the lower esophageal sphincter due to
atrophy and fibrous replacement of the esophageal muscularis. This can cause gastroesophageal reflux with an
increased risk of Barrett esophagus and stricture formation. [284]
Zollinger ellison syndrome

Patients with Zollinger-Ellison syndrome develop peptic ulcer disease and parietal cell hyperplasia with gastric fold
enlargement due to gastrin hypersecretion. [304]
Zollinger-Ellison syndrome is caused by gastrin-secreting tumors (gastrinomas) involving the small intestine or
pancreas. Patients typically have peptic ulcers (often beyond the duodenal bulb), abdominal pain/acid reflux, and
diarrhea. The condition is frequently associated with multiple endocrine neoplasia type 1. [586]
Zollinger-Ellison syndrome is caused by gastrinomas located in the small intestine/pancreas and presents with peptic
ulcers (especially distal duodenal ulcers), heartburn, and diarrhea. Patients typically have elevated gastrin levels that
rise in response to exogenous secretin administration. In contrast, secretin inhibits release of gastrin from normal
gastric G cells. [305]
HEPATIC DISORDERS
Abnormal lfts
A moderately elevated alkaline phosphatase of unclear etiology should be followed up with γ-glutamyl
transpeptidase. [99]
Acute heart failure

Congestive hepatopathy is a common complication of right-sided heart failure. Patchy hemorrhage and necrosis
predominantly affect the centrilobular regions (zone 3) where hepatic congestion is most prominent. The
centrilobular necrosis, combined with relatively normal-appearing periportal regions (zone 1), creates an overall
heterogenous appearance sometimes referred to as "nutmeg liver." [15535]
Acute liver failure

The P450 microsomal oxidase system plays an important role in detoxification. In carbon tetrachloride poisoning,
however, it produces free radicals that start a vicious cycle of hepatic injury. [314]
Alcoholic liver disease
The pathogenesis of alcohol-induced hepatic steatosis involves excess NADH production (via ethanol metabolism),
which inhibits free fatty acid oxidation and promotes lipogenesis. Steatosis is microscopically characterized by clear
cytoplasmic vacuoles within hepatocytes. [370]

Alpha-1 antitrypsin (AAT) is a serine protease inhibitor that regulates the activity of elastase in the lung. Inherited
deficiency of AAT leads to alveolar destruction and panacinar emphysema; in addition, accumulation of improperly
folded AAT proteins in hepatocytes can lead to liver dysfunction and cirrhosis in some patients. [400]
Autoimmune hepatitis
Autoimmune hepatitis results from an immune response against hepatic antigens, leading to a lymphoplasmacytic
infiltrate in the portal and periportal regions of the liver. Manifestations include fatigue, weight loss, nausea, and/or
signs of acute hepatitis (eg, jaundice, abdominal discomfort). Characteristic laboratory abnormalities include a
hepatocellular pattern of liver injury, anti–smooth muscle autoantibodies, and hypergammaglobulinemia. [18693]
Cirrhosis
Portal hypertension, as seen in alcoholic liver disease, produces splenomegaly by causing congestion of blood within
the spleen, which produces expansion of the red pulp. [7214]
In patients with cirrhosis, gynecomastia often occurs due to hyperestrinism, which can also promote the formation of
spider angiomata. [100]
Cirrhosis is characterized by diffuse hepatic fibrosis with replacement of the normal lobular architecture by fibrous-
lined parenchymal nodules. Chronic viral hepatitis (eg, hepatitis B and C), alcohol, hemochromatosis, and
nonalcoholic fatty liver disease are the most common causes of cirrhosis in the United States. [368]
Increased aspartate aminotransferase and alanine aminotransferase are indicators of hepatocellular damage, and
increased alkaline phosphatase and gamma-glutamyl transpeptidase indicate biliary injury. Serum albumin levels,
bilirubin levels, and prothrombin time are reflective of liver function and are of greatest prognostic significance in
patients with cirrhosis. [1423]
Esophageal varices
Acute management of variceal hemorrhage requires rapid lowering of portal pressure. Somatostatin and octreotide
(a long-acting somatostatin analog) inhibit the release of hormones that induce splanchnic vasodilation, indirectly
causing splanchnic vasoconstriction and reduced portal blood flow. [7215]
Focal nodular hyperplasia

Focal nodular hyperplasia is a benign liver lesion marked by a central stellate scar with radiating fibrous septa that
microscopically contain abnormally large, thick-walled arteries. It usually arises in asymptomatic young women, and
most cases are found incidentally. [16070]
Gallstone disease
Black gallstones form due to supersaturation of the bile with bilirubin, which precipitates with calcium to form
calcium bilirubinate stones. This typically occurs in the setting of chronic hemolysis (eg, sickle cell disease) or altered
enterohepatic circulation of bilirubin (eg, Crohn disease, ileal resection). [16117]
The gallbladder functions to actively absorb water from bile. Gallbladder hypomotility causes the bile to become
concentrated, promoting precipitation and accumulation of particulate material. This forms a viscous biliary sludge
that can cause transient bile duct obstruction (biliary colic) and promote cholesterol gallstone formation. [71]
Hemangioma
Cavernous hemangioma is the most common benign liver tumor. Microscopically, these tumors consist of cavernous,
blood-filled vascular spaces of variable size lined by a single epithelial layer. The biopsy of a suspected hemangioma
is not advisable, as the procedure has been known to cause fatal hemorrhage and is of low diagnostic yield. [54]
Hepatitis a
Acute hepatitis A is a self-limited infection that typically presents acutely with prodromal symptoms (eg, fever,
malaise, anorexia, nausea/vomiting, right upper quadrant pain) followed by signs of cholestasis (eg, jaundice,
pruritus, dark-colored urine, clay-colored stool). [366]
Acute hepatitis due to most hepatotropic viruses causes hepatocyte injury (eg, ballooning degeneration) and cell
death with mononuclear cell infiltration. [1863]
Hepatitis A presents with fever, jaundice, hepatomegaly, leukocytosis, and aminotransferase levels >1,000 U/L. It
triggers a robust CD8+ lymphocytic response to clear infected hepatocytes. The resulting hepatocellular damage is
self-limited, with complete resolution within 2-3 months. [19701]
Hepatitis b
Hepatitis B infection causes the hepatocellular cytoplasm to fill with hepatitis B surface antigen. These inclusions are
highly specific for hepatitis B infection and have a finely granular, pale eosinophilic, ground-glass appearance. [367]
Hepatitis c
Acute hepatitis C is characterized by panlobular lymphocytic inflammation with hepatocyte injury (eg, ballooning
degeneration) and cell death (eg, Councilman bodies). Chronic hepatitis C leads predominantly to portal lymphocytic
infiltration, including lymphoid follicle formation, and fibrosis. Histologic findings of cirrhosis include extensive
fibrosis and the formation of bridging septa that surround regenerative nodules. [21019]
Intravenous drug use is a risk factor for acute viral hepatitis, which is marked by panlobular inflammation, hepatocyte
injury, and cell death. To control the infection, cytotoxic T-cell–mediated signals cause hepatocyte apoptosis, which
is characterized microscopically by Councilman bodies (ie, round, intensely eosinophilic bodies). [1927]
Hepatocellular cancer
Aflatoxin B1 is a carcinogen produced by Aspergillus that contaminates food (eg, corn) in hot, humid environments
(eg, Southeast Asia). Chronic aflatoxin B1 ingestion is associated with inactivating p53 mutations that increases the
risk for hepatocellular carcinoma. [57]
Hereditary hyperbilirubinemias
Gilbert syndrome is a benign disorder that presents with recurrent scleral icterus and jaundice, typically triggered by
stress (eg, fasting, illness). Pathogenesis involves decreased activity of UDP glucuronosyltransferase (impaired
bilirubin conjugation), and an isolated mild unconjugated hyperbilirubinemia is typical. [362]
Neonatal jaundice
Benign neonatal hyperbilirubinemia presents with jaundice and elevated indirect bilirubin levels that peak at age 2-5
days. Pathophysiology includes impaired bilirubin clearance by the liver due to decreased hepatic UDP
glucuronosyltransferase, an enzyme responsible for bilirubin conjugation. [21085]
Reye syndrome
Reye syndrome is characterized by liver failure and encephalopathy following salicylate (aspirin) administration in
children with a febrile illness. Aspirin-induced mitochondrial dysfunction causes impaired fatty acid metabolism and
microvesicular steatosis of the liver. [881]
Acute diarrhea
Shigella initially invades the intestinal epithelial barrier by passing through microfold (M) cells overlying ileal Peyer
patches. Once at the basolateral mucosal surface, Shigella can more efficiently enter enterocytes and then spread
laterally into other epithelial cells, causing cell death and ulceration with bloody/mucoid diarrhea. [1143]
Anal fissure
Anal fissures are longitudinal tears in the mucosa. They are usually due to passage of hard stool in patients with
chronic constipation. Most fissures occur at the posterior midline, likely due to decreased blood flow in this
area. Fissures in other areas may be due to less common causes. [255]
Appendicitis
Obstruction of the appendiceal lumen (eg, fecalith, lymphoid hyperplasia) is frequently the inciting event in
pathogenesis of acute appendicitis, which typically presents with periumbilical pain that shifts to the right lower
quadrant. Gross pathologic examination often shows an edematous, erythematous appendix with purulent exudate.
[426]
Bowel obstruction
Gallstone ileus is a mechanical bowel obstruction caused when a large gallstone erodes into the intestinal
lumen. Pneumobilia (air in the biliary tract) is a common finding. [88]
Celiac disease
Celiac disease is caused by an immune-mediated reaction to gluten and classically leads to chronic gastrointestinal
symptoms. Diagnosis is confirmed by elevated tissue transglutaminase IgA antibody levels and duodenal biopsy
showing villus flattening, intraepithelial lymphocyte infiltration, and crypt hyperplasia. [326]
Celiac disease, an immune-mediated disorder triggered by gluten, causes small intestinal intraepithelial
lymphocytosis, villous atrophy, and crypt hyperplasia. Monoclonal T-cell expansion can occur in the small-bowel
mucosa of patients, leading to enteropathy-associated T-cell lymphoma. [20390]
Celiac disease is an autoimmune disorder triggered by dietary gluten that develops almost exclusively in patients with
HLA-DQ2 or -DQ8 serotypes. It often causes diarrhea and malabsorption (eg, iron deficiency anemia). The earliest
histologic finding is duodenal intraepithelial lymphocytosis; crypt hyperplasia and villous blunting develop later. [20400]

Antibiotics disrupt the normal intestinal flora and can allow for overgrowth of Clostridioides difficile, an anaerobic,
gram-positive, spore-forming bacillus. C difficile produces 2 toxins that penetrate colonic epithelial cells leading to
watery diarrhea, abdominal cramping, and colitis. The presence of a pseudomembrane (exudate on colonic mucosa
consisting of fibrin and inflammatory cells) is highly suggestive of C difficile infection. [1396]
Colonic ischemia
The splenic flexure and rectosigmoid junction lie between regions of perfusion of major arteries. These "watershed"
areas are susceptible to ischemic damage during hypotensive states, especially in patients with underlying arterial
insufficiency. [413]

Adenomatous and sessile serrated polyps are neoplastic polyps that have malignant potential. Increasing polyp size is
the most important risk factor for cancer; villous histology and high-grade dysplasia are additional risk factors. [427]
Adenomatous polyps are either tubular, villous, or tubulovillous, depending on their histologic appearance. Villous
adenomas tend to be larger, sessile, and more severely dysplastic than tubular adenomas. Villous adenomas can
cause a secretory diarrhea from increased mucin production; patients may develop hypoproteinemia and
hypokalemia. [430]
Diverticular disease
Colonic diverticula form at weak points in the colon wall, typically in areas where the vasa recta penetrate through
the smooth muscle. As diverticula enlarge, the vasa recta are exposed and become vulnerable to chronic injury,
which can lead to intraluminal hemorrhage and painless hematochezia. [14901]
Diverticulitis is characterized by inflammation of colonic diverticula. Patients have abdominal pain, nausea, vomiting,
and changes in bowel habits. Low-grade fever and leukocytosis are common, and physical examination may
demonstrate a tender mass in the left lower quadrant. [14907]
Colonic diverticulosis refers to multiple sac-like outpouchings within the sigmoid colon. Complications include
diverticular bleeding and diverticulitis. Risk factors for diverticulosis include a diet high in red meat and fat and low in
fiber, as well as obesity and physical inactivity. [14900]
Colonic diverticula often involve the sigmoid colon and develop due to exaggerated contractions of colonic smooth
muscle segments. This results in increased intraluminal pressure, causing outpouching of the mucosa and submucosa
through the muscularis (false diverticula). Individuals (typically age >60) may be asymptomatic or have hematochezia
or diverticulitis. [415]
Food protein-induced allergic proctocolitis

Food protein–induced allergic proctocolitis is a non–IgE-mediated reaction that causes inflammation and eosinophilic
infiltration of the distal colon. Classic presentation is in early infancy with painless, blood-streaked stools that resolve
with dietary avoidance of the offending food protein (eg, cow's milk). [20693]

Crohn disease is an inflammatory bowel disease characterized by patchy inflammation that can occur throughout the
entire gastrointestinal tract. Gross pathology demonstrates skip lesions, cobblestoning of the mucosa, bowel wall
thickening, and creeping fat. [407]
Crohn disease typically presents with prolonged diarrhea and abdominal pain. Constitutional symptoms (eg, low-
grade fever, fatigue), malabsorption, and weight loss are also common. Transmural inflammation of the bowel wall
may result in the formation of fistulas (eg, enteroenteric, enterocutaneous), abscesses, and fibrotic strictures. [404]
Granulomas are characterized by a large number of epithelioid macrophages that may fuse together to form
multinucleated cells (Langhans giant cells) surrounded by a band of lymphocytes. Granuloma formation involves
chronic Th1 and macrophage activation in response to a difficult-to-eradicate antigen. [406]
Crohn disease is characterized by patchy, transmural inflammation of the gastrointestinal tract. It can affect any part
of the tract from the mouth to the anus. Complications include strictures (due to bowel wall edema, fibrosis, and
thickening of the muscularis mucosae), fistulas (due to penetration of ulcers through the intestinal wall), and
abscesses. [409]
Noncaseating granulomas are a hallmark of Crohn disease and can help distinguish it from ulcerative colitis, which
does not form granulomas. Histopathology in Crohn disease also demonstrates transmural inflammation, distortion
of the normal architecture, and Paneth cell metaplasia. [405]
Crohn disease typically presents with the insidious onset of abdominal pain, diarrhea, and constitutional symptoms
(eg, weight loss, fever). Patients are prone to developing fistulas/abscesses as the lesions affect the entire thickness
of the bowel wall. Perianal disease (eg, skin tags, fissures) is also common. [1783]
Intussusception
Intussusception, which presents with colicky abdominal pain, is characterized by telescoping of one intestinal
segment into an adjacent one, most commonly at the ileocecal junction. Pathophysiology usually involves
hypertrophy of intestinal lymphoid follicles (Peyer patches), which can act as lead points of the invaginated bowel.
[416]
Mesenteric ischemia
Chronic mesenteric ischemia is characterized by atherosclerosis of the mesenteric arteries, resulting in diminished
blood flow to the intestine after meals. This causes postprandial epigastric pain (intestinal angina) with associated
food aversion/weight loss. Its pathogenesis is similar to angina pectoris. [414]
Short Bowel Syndrome

Short bowel syndrome typically occurs in patients with massive small bowel resection and/or Crohn disease due to
loss of intestinal absorptive surface area and a decrease in intestinal transit time. Patients usually present with
postprandial voluminous diarrhea and weight loss due to malabsorption. Loss of functional distal ileum may result in
vitamin B12 deficiency. [12062]
Toxic megacolon
Toxic megacolon is a well-recognized complication of ulcerative colitis. Patients typically present with abdominal
pain/distension, bloody diarrhea, fever, and signs of shock. Plain abdominal x-ray is the preferred diagnostic imaging
study. Barium contrast studies and colonoscopy are contraindicated due to the risk of perforation. [410]
Whipple disease
Whipple disease is caused by a chronic infection with Tropheryma whipplei, a gram-positive bacterium that can affect
multiple organ systems. It typically presents in middle-aged men with malabsorption and arthralgia. Intestinal biopsy
characteristically shows foamy macrophages in the lamina propria filled with bacilli that are positive for periodic acid–
Schiff stain. [132]
Whipple disease, caused by the gram-positive actinomycete Tropheryma whipplei, is a rare systemic illness that often
involves the small intestine, joints, and CNS. Classic intestinal histologic findings include foamy macrophages in the
lamina propria filled with bacilli positive for periodic acid–Schiff stain. Treatment is with antibiotics. [131]
MISCELLANEOUS
Hemochromatosis
Hereditary hemochromatosis is most commonly caused by a missense mutation in the HFE gene, resulting in
excessive intestinal iron absorption and organ damage (eg, cirrhosis, diabetes mellitus, cardiomyopathy, arthropathy)
due to iron accumulation within parenchymal tissues. [393]
Kaposi sarcoma
Kaposi sarcoma, a vascular neoplasm that often presents in HIV-positive individuals, may involve the gastrointestinal
tract, causing bloody diarrhea, weight loss, and abdominal pain. Endoscopy characteristically reveals red-violet
maculopapular lesions, raised hemorrhagic nodules, or polypoid masses. Histopathology often shows spindle-shaped
endothelial cells, slit-like vascular spaces, and extravasated red blood cells. [8290]
Acute pancreatitis
Eighty percent of acute pancreatitis cases are caused by gallstones and chronic alcoholism. Less common causes
account for the other 20%. Inherited or acquired hypertriglyceridemia can cause acute pancreatitis if the serum level
of triglycerides exceeds 1000 mg/dL. [440]
In acute pancreatitis, release of lipase and other digestive enzymes causes fat necrosis with precipitation of insoluble
calcium salts (ie, saponification), imparting a chalky white gross appearance. Microscopically, necrotic fat cells with
calcium deposits are seen. In severe cases, fat necrosis can involve the mesentery, omentum, and other parts of the
abdominal cavity. [439]
Pancreatic pseudocyst is a common complication of acute pancreatitis. It is a collection of fluid rich in enzymes and
inflammatory debris. Its walls consist of granulation tissue and fibrosis. Unlike true cysts, pseudocysts are not lined
by epithelium. [435]
After gallstones, chronic alcohol use is the second most common cause of acute pancreatitis. Macrocytosis and an
AST:ALT ratio >2 are indirect indicators of chronic alcohol consumption. Alcohol-related macrocytosis can occur
independently of folate deficiency. [434]
Diarrhea, weight loss, and epigastric calcifications in a patient with chronic alcohol use suggest chronic pancreatitis
with resulting pancreatic exocrine insufficiency and malabsorption. [1547]
Pancreatic cancer
Pancreatic ductal adenocarcinoma is the most common pancreatic malignancy and typically presents with epigastric
pain, weight loss, jaundice (more common if in the pancreatic head), or back pain (more common if in the pancreatic
body/tail). It appears radiographically as an ill-defined hypoattenuating lesion within the pancreatic parenchyma. It
is characterized microscopically by haphazardly arranged pleomorphic glandular cells surrounded by dense stromal
fibrosis (eg, desmoplasia). [21994]
Carcinoid tumors
Well-differentiated neuroendocrine tumors (ie, carcinoid tumors) arise from neuroendocrine cells and are composed
of uniform tumor cells with round nuclei, salt and pepper chromatin, and eosinophilic cytoplasm. Although most are
found incidentally (ie, asymptomatic), some may obstruct the lumen, causing acute appendicitis. [424]
Cholangiocarcinoma
Cholangiocarcinoma is a malignancy of the bile duct epithelium that eventually obstructs biliary drainage, resulting in
cholestasis (elevated alkaline phosphatase, hyperbilirubinemia) with jaundice, weight loss, pain in the right upper
quadrant, and hepatomegaly. Imaging often demonstrates dilated bile ducts in the absence of an obstructive
gallstone, and biopsy reveals an adenocarcinoma with columnar cells, mucin production, and a significant
desmoplastic reaction. [16107]

Prognosis of colorectal adenocarcinoma is directly related to the stage of the tumor (not to the grade!). [423]
Colon adenocarcinoma is the most common gastrointestinal malignancy. Right-sided lesions are more likely to bleed
and cause iron deficiency anemia; left-sided lesions tend to present with obstructing symptoms (eg, altered bowel
habits, constipation, abdominal distension, nausea and vomiting). [257]
Tumor stage (degree of invasion/spread) is the most important prognostic determinant for colorectal cancer. Tumors
confined to the basement membrane and lamina propria are early stage and have the best prognosis. Outcomes
generally deteriorate as the stage advances: spread of tumor into the muscularis propria → regional lymph nodes →
distant sites. [15011]
Most hepatic neoplasms are due to metastatic disease from a distant site. Colorectal cancer is the most common
cause of hepatic metastases due to direct blood flow from the colon (and superior rectum) to the liver via the portal
venous circulation. [15012]
Adenomatous polyps contain dysplastic mucosa and are premalignant. Regular screening with timely excision of
polyps is effective for prevention of colon adenocarcinoma. Studies have linked increased activity of cyclooxygenase-
2 to some forms of colon adenocarcinoma and suggest that regular aspirin use decreases adenomatous polyp
formation. [431]
Inflammatory bowel disease, especially ulcerative pancolitis, is associated with a significant risk for colorectal
carcinoma. Compared with sporadic colorectal cancer, colitis-associated colorectal cancer is more likely to occur at a
younger age, is typically more aggressive with a higher histopathologic grade, often evolves from flat (nonpolypoid)
lesions, and is frequently multifocal. Patients should be monitored regularly via colonoscopy with random biopsies.
[411]
Carcinoembryonic antigen (CEA) levels are increased in colon cancer but are also elevated in a number of other
conditions (eg, pancreatic cancer, COPD, cirrhosis). CEA cannot be used to diagnose colon cancer, but it is helpful for
detecting residual disease and recurrence. [253]
Familial adenomatous polyposis (FAP) is an autosomal dominant disorder caused by germline mutation to the tumor
suppressor gene adenomatous polyposis coli. Patients with FAP develop hundreds or thousands of colonic polyps;
lifetime risk of colon cancer is close to 100%. [15020]
Right-sided colon cancers usually grow as exophytic masses and present with occult bleeding and symptoms of iron
deficiency anemia. Left-sided colon cancers tend to infiltrate the intestinal wall and encircle the lumen, causing
constipation and symptoms of intestinal obstruction. Rectosigmoid involvement often causes hematochezia. [432]
Esophageal cancer
The histopathologic features of esophageal squamous cell carcinoma include solid nests of neoplastic squamous cells
with abundant eosinophilic cytoplasm and distinct borders. Areas of keratinization and the presence of intercellular
bridges are also characteristic. Patients typically present with progressive solid and eventually liquid dysphagia and
weight loss. [287]
Esophageal adenocarcinoma usually occurs in the distal esophagus due to underlying Barrett esophagus. Long-
standing gastroesophageal reflux disease is the most important risk factor. Obesity, smoking, use of medications that
lower esophageal sphincter pressure, and consumption of foods containing nitroso compounds also increase the risk.
[14879]
Major risk factors for esophageal squamous cell carcinoma include smoking, excessive alcohol consumption, and
intake of foods containing N-nitroso compounds. [122]
Esophageal squamous cell carcinoma presents mostly in the proximal two-thirds of the esophagus and frequently
metastasizes to the mediastinal lymph nodes. Histology characteristically shows sheets of atypical squamous cells
with keratin pearls and intercellular bridges. [14878]
Gastric cancer
There are 2 morphological variants of gastric adenocarcinoma. The intestinal type forms a solid mass that projects
into the stomach lumen and is composed of gland-forming cuboidal or columnar cells. In contrast, diffuse-type
adenocarcinoma infiltrates the stomach wall (linitis plastica) and displays signet ring cells on light microscopy. [307]
Intestinal-type gastric adenocarcinoma is visualized endoscopically as an ulcerated mass with irregular folded or
heaped-up edges. Histologically, it resembles colon adenocarcinoma and is characterized by glandular structures
containing intestinal-like columnar (or cuboidal) cells. Risk factors include Helicobacter pylori infection, a high-salt
diet, n-nitroso–containing compounds, and autoimmune atrophic gastritis. [14915]
Alpha-fetoprotein is a serum tumor marker that is often moderately elevated in patients with chronic viral
hepatitis. However, it can be strikingly elevated in those with hepatocellular carcinoma, and a sudden rise can be a
sign that a patient with chronic liver disease is harboring hepatocellular carcinoma. [56]
Hepatic angiosarcoma is an aggressive vascular malignancy associated with exposure to carcinogens (eg, vinyl
chloride). The tumor cells express CD31 (ie, platelet endothelial cell adhesion molecule [PECAM1]), an endothelial
cell marker important for leukocyte transmigration. [471]
Metastatic liver disease

Malignant hepatic lesions most often represent metastasis from another primary site (eg, breast, lung, colon);
primary liver neoplasms (eg, hepatocellular carcinoma) are much less common. [59]
Pancreatic cancer
Smoking is the most important environmental risk factor for pancreatic cancer. Other risk factors include advanced
age, chronic pancreatitis, and genetic predisposition (eg, Peutz-Jeghers syndrome). [436]
Anticoagulants
Warfarin inhibits proteins C and S (natural anticoagulants present in blood), which can lead to skin necrosis,
particularly in patients with protein C or S deficiency. This complication is usually seen in the first few days of
warfarin therapy. [1088]
Antiphospholipid syndrome
Many patients with systemic lupus erythematosus have antiphospholipid antibodies, which can cause paradoxical PTT
prolongation and false-positive RPR/VDRL results; antiphospholipid antibody syndrome is characterized by arterial or
venous thrombosis and increased obstetric morbidity (eg, recurrent pregnancy loss). [742]
Coagulopathy
Abnormal bleeding in patients with uremia is due to a qualitative platelet disorder that causes prolonged bleeding
time with normal platelet count, prothrombin time, and activated partial thromboplastin time. [1293]
DIC
Disseminated intravascular coagulation commonly occurs in the setting of sepsis and is characterized by widespread
activation of the coagulation cascade with formation of microthrombi. Laboratory results reveal prolonged PT/PTT,
thrombocytopenia, and low fibrinogen (ie, a consumptive coagulopathy), and patients usually have signs of bleeding
(eg, oozing from venipuncture sites). [1298]
Disseminated intravascular coagulation (DIC) can occur with abruptio placentae due to release of tissue factor, a
procoagulant that activates the coagulation cascade, from the damaged decidua into the maternal circulation. DIC
classically presents with thrombocytopenia and bleeding from mucosal surfaces (eg, gums) and intravenous line sites.
[1296]
Acute disseminated intravascular coagulation is a consumptive coagulopathy linked to severe trauma. Widespread
formation of microvascular thrombi leads to consumption of platelets, coagulation factors, and
fibrinogen. Subsequent activation of anticoagulant proteins leads to low protein C/S; fibrinolysis elevates D-
dimer. Most patients have bleeding complications (eg, oozing from venipuncture/catheter sites) and end organ
damage to the lungs or kidneys. [16441]
Disseminated intravascular coagulation is a common complication of gram-negative bacterial sepsis due to activation
of the coagulation cascade by bacterial endotoxins, which leads to the formation of microthrombi. Peripheral smear
shows fragmented erythrocytes (schistocytes) and thrombocytopenia. Laboratory tests show decreased fibrinogen
levels and prolonged PT and PTT. [1295]
Inherited thrombophilia
Heterozygote carriers of a mutation in factor V Leiden, which is modified to resist activated protein C, have a
hypercoagulable state that predisposes to deep vein thromboses (the source of most pulmonary emboli). [1879]
Inherited causes of hypercoagulability should be considered in patients younger than age 50 who present with
thrombosis and no obvious explanation for an acquired prothrombotic state. The factor V Leiden mutation, which
causes factor Va resistance to inactivation by activated protein C, may account for approximately 20% of cases of
atypical venous thrombosis. [465]
Pulmonary embolism
Saddle pulmonary embolism straddles the bifurcation of the main pulmonary artery. Venous thromboembolism (ie,
pulmonary embolism or deep vein thrombosis) arises due to the Virchow triad of endothelial injury, venous stasis,
and a hypercoagulable state. Malignancy causes a hypercoagulable state and is a strong risk factor for venous
thromboembolism. [1880]
Renal vein thrombosis

Nephrotic syndrome is a hypercoagulable state. Sudden-onset abdominal or flank pain, hematuria, and left-sided
varicoceles suggest renal vein thrombosis, a well-known complication of nephrotic syndrome. Loss of anticoagulant
factors, especially antithrombin III, is responsible for the thrombotic and thromboembolic complications of nephrotic
syndrome. [26]
Deficiency of vitamin C, a water-soluble vitamin, results in impaired collagen production. Manifestations include
cutaneous findings of coiled hair and perifollicular keratosis, in addition to hemorrhagic complications such as gingival
bleeding and easy bruising. PT, PTT, and platelet count are normal. [7589]
MISCELLANEOUS
Mediastinal masses
The most common masses in the anterior mediastinum are the 4 Ts: thymoma, teratoma (and other germ cell
tumors), "terrible" lymphoma, and thyroid neoplasm. An anterior mediastinal mass with elevated serum levels of
alpha fetoprotein and β-hCG is classic for a nonseminomatous germ cell tumor. [20877]
Thrombocytosis
Reactive thrombocytosis is the most common cause of elevated platelet count in all age groups. It is generally caused
by high levels of inflammatory cytokines (eg, IL-6), which prompt the liver to release thrombopoietin. Reactive
thrombocytosis is seen in chronic infection, rheumatologic disease, and burns; it can also occur with hemolysis and
iron deficiency anemia. [15292]
PLASMA CELL DISORDERS
Multiple myeloma
Multiple myeloma is a plasma cell malignancy that replicates in the bone marrow and causes osteolytic bone lesions,
bone destruction, hypercalcemia, and pathologic fractures. Histopathology will show replacement of the normal
bone marrow with plasma cells and plasmablasts. [15467]
PLATELET DISORDERS
Heparin induced thrombocytopenia

Heparin-induced thrombocytopenia and thrombosis results from the production of IgG antibodies against complexes
of heparin and platelet factor 4. The Fc component of these antibodies binds to platelets, resulting in widespread
platelet activation and a prothrombotic state. [15120]
ITP
Autoimmune platelet destruction is a common cause of thrombocytopenia and should be suspected in patients with
ecchymoses, petechiae, mucosal bleeding, and no other obvious causes of thrombocytopenia (eg, medications, bone
marrow failure). [1954]
Thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura classically presents with the pentad of severe thrombocytopenia,
microangiopathic hemolytic anemia (eg, schistocytes on peripheral smear), renal insufficiency, neurologic symptoms,
and fever. However, all these signs and symptoms are rarely present. Diagnosis is often made by identifying severe
deficiency of ADAMTS-13, a protease that cleaves large von Willebrand factor multimers off the endothelium. [15483]
Thrombotic thrombocytopenic purpura frequently results from impaired function of the von Willebrand factor
(vWF)–cleaving protease ADAMTS-13, which causes the accumulation of uncleaved vWF multimers that are
significantly more prothrombotic. Patients develop diffuse microvascular thrombosis, which leads to
thrombocytopenia and microangiopathic hemolytic anemia. [11625]

von Willebrand disease is the most common inherited bleeding disorder. It has an autosomal dominant pattern of
inheritance and variable penetrance. Absence of von Willebrand factor leads to impaired platelet function
(prolonged bleeding time) and coagulation pathway abnormalities due to decreased factor VIII activity (prolonged
partial thromboplastin time). [1923]
Lung cancer
Between 1950 and 2000, rising rates of tobacco use resulted in an increase in female lung cancer incidence and
mortality. Lung cancer is currently the most common cause of cancer death in both women and men in the United
States. [1286]
Anemia
Vitamin B12 and folic acid deficiencies cause similar hematological pictures. However, neurological dysfunction is
only seen in patients with vitamin B12 deficiency. If megaloblastic anemia due to vitamin B12 deficiency is mistakenly
treated with folate alone, the neurologic dysfunction can worsen. [789]
The underlying biochemical feature of megaloblastosis is a defect in DNA synthesis. In patients with chronic alcohol
use, megaloblastic macrocytic anemia can result from a nutritional deficiency of vitamin B12 or of folate, which
impairs synthesis of purine and pyrimidine bases. [1580]
Aplastic anemia
Aplastic anemia is a form of bone marrow failure due to destruction of multipotent hematopoietic stem cells. It is
marked by pancytopenia and profound hypocellularity of the bone marrow with an abundance of fat cells and
stroma. Impaired reticulocytosis and an absence of splenomegaly are important features. [1785]
Aplastic anemia is a form of bone marrow failure in which patients have decreased production of all cell lines
(platelets, erythrocytes, and leukocytes). It is primarily caused by the autoimmune destruction of multipotent
hematologic stem cells due to an alteration in their surface antigens, leading to a cytotoxic T-cell response and
release of interferon-gamma from T-helper cells (triggers apoptotic cell death). [20460]
Aplastic anemia is a form of bone marrow failure caused by direct toxic injury or cytotoxic T-cell destruction of
multipotent hematologic stem cells, which leads to pancytopenia. Bone marrow examination will show profound
hypocellularity, an abundance of fat cells, and small clusters of morphologically normal hematologic cells. [1787]
Aplastic anemia (AA) is a form of bone marrow failure associated with pancytopenia and bone marrow
aplasia/hypoplasia. Although erythropoietin levels are high, reticulocytes remain low because the production of new
erythrocytes is impaired by a paucity of bone marrow stem cells. However, the blood cells produced by the
remaining stem cells are normal in morphology and red cell indexes (eg, mean corpuscular volume) are usually
normal. [1861]
G6PD deficiency
Glucose-6-phosphate dehydrogenase deficiency is an X-linked recessive disorder that causes acute hemolysis after
exposure to oxidizing medications, foods, or acute infection. Nearly all affected persons are male, but heterozygous
females can become symptomatic due to skewed lyonization. [894]
Glucose-6-phosphate dehydrogenase deficiency is an X-linked recessive disorder that limits the availability of
antioxidants in erythrocytes. Affected patients are susceptible to acute hemolysis following exposure to oxidative
insults, particularly acute infection, oxidizing foods, and medications (eg, fluoroquinolones). [1426]
Hemochromatosis
HFE protein mutations are the most common cause of primary hemochromatosis. Inactivation of the HFE protein
results in decreased hepcidin synthesis by hepatocytes and increased DMT1 expression by enterocytes, leading to
iron overload. Patients with hemochromatosis are at an increased risk for liver cirrhosis and hepatocellular
carcinoma. [395]
Hemolytic anemia
Iron overload (hemosiderosis) is a common and serious complication of chronic hemolytic anemia and frequent blood
transfusions. Accumulation of yellow-brown hemosiderin pigment is the cardinal histologic finding. Chelation
therapy is indicated to reduce parenchymal iron deposition. [294]
Pyruvate kinase deficiency causes hemolytic anemia due to failure of glycolysis and resultant failure to generate
sufficient ATP to maintain erythrocyte structure. In this case, splenic hyperplasia results from increased work of the
splenic parenchyma, which must remove these deformed erythrocytes from the circulation. [1020]
Schistocytes (helmet cells) are fragmented erythrocytes. They occur secondary to mechanical trauma from
microangiopathic hemolytic anemias or prosthetic cardiac valves (macroangiopathic). Intravascular hemolytic
anemias are characterized by decreased serum haptoglobin levels as well as increased LDH and bilirubin. [829]
The presence of erythroid precursors in organs such as the liver and spleen is indicative of extramedullary
hematopoiesis, a condition characterized by erythropoietin-stimulated, hyperplastic marrow cell invasion of
extramedullary organs. Extramedullary hematopoiesis is most frequently caused by severe chronic hemolytic
anemias, such as β-thalassemia. [1859]
Anemia with an elevated reticulocyte count (ie, reticulocytosis) indicates that the bone marrow is responding
appropriately to the anemia by generating new erythrocytes. Reticulocytosis is commonly seen in patients with
hemolysis or acute bleeding. Many other causes of anemia are associated with low reticulocyte count, including
bone marrow suppression (eg, parvovirus), iron deficiency anemia, vitamin B12/folate deficiency, and anemia of
chronic disease. [19138]
Red blood cell fragments, burr cells and helmet cells are associated with either microangiopathic hemolytic anemia or
mechanical red cell destruction. In patients with prostatic valves, red blood cells are exposed to excessive shear and
turbulence in the circulation causing damage from mechanical trauma. [1297]
Hemolytic uremic syndrome

Schistocytes suggest microangiopathic hemolytic anemia (eg, hemolytic-uremic syndrome [HUS], thrombotic
thrombocytopenic purpura [TTP], disseminated intravascular coagulation [DIC]) or mechanical damage [eg, prosthetic
valve]). In childhood, HUS is often preceded by bloody diarrhea. Coagulation studies (prothrombin time and partial
thromboplastin time) are normal in HUS-TTP but abnormal in DIC. [1294]
Hemophilias
Hemophilia is an X-linked recessive coagulopathy that presents with intramuscular hemorrhage, hemarthroses, and
delayed bleeding after procedures. Laboratory results show partial thromboplastin time prolongation; other tests of
hemostatic function are generally normal. [1953]
Bleeding after a tooth extraction and history of hemarthrosis are suggestive of hemophilia. Decreased levels of factor
VIII or IX lead to failure to convert prothrombin into thrombin and deficient thrombus formation. The addition of
thrombin to the blood of a patient with hemophilia results in clotting. [941]
Hereditary spherocytosis
Hereditary spherocytosis results from red cell cytoskeleton abnormalities, most commonly spectrin and
ankyrin. Hemolytic anemia, jaundice, and splenomegaly are classic manifestations. Spherocytes are seen on
peripheral blood smear. [889]
Hereditary spherocytosis results from red blood cell cytoskeleton abnormalities, most commonly in the proteins
spectrin and ankyrin. The diagnosis can be confirmed with a positive osmotic fragility test. Hemolytic anemia,
jaundice, and splenomegaly are classic manifestations. Complications include pigmented gallstones and aplastic
crises. [891]
Iron deficiency anemia

Reticulocytes (immature red blood cells) appear as blue-gray (ie, polychromatophilic) red blood cells on Wright-
Giemsa staining due to the presence of ribosomal RNA. In patients with iron deficiency anemia, iron
supplementation results in increased bone marrow erythropoiesis and accelerated release of reticulocytes into the
bloodstream. [1796]
Hypochromic, microcytic anemia is most commonly due to iron deficiency. Blood loss, especially occult loss from the
gastrointestinal tract, must be ruled out in a patient with iron deficiency anemia. [1793]
Anemia in women of childbearing age is typically caused by iron deficiency secondary to menstrual blood loss. Iron
deficiency is associated with decreased serum ferritin, increased total iron-binding capacity (transferrin), and
microcytic, hypochromic red blood cells. [1794]
Iron poisoning
Chelation therapy with deferoxamine should be implemented in patients receiving chronic red blood cell
transfusions. Deferoxamine prevents iron-induced cardiotoxicity and congestive heart failure from developing in this
patient population. [6535]
Lead poisoning
Coarse basophilic stippling (dark blue-purple granules throughout red blood cells) and hypochromic, microcytic
anemia are common peripheral blood smear findings in lead poisoning. High-risk groups include young children
ingesting paint chips and industrial workers inhaling particulate lead. [1865]
Paroxysmal nocturnal hemoglobinuria

Paroxysmal nocturnal hemoglobinuria is due to a gene defect that leads to uncontrolled complement-mediated
hemolysis. The classic triad includes hemolytic anemia (hemoglobinuria), pancytopenia, and thrombosis at atypical
sites. Chronic hemolysis can cause iron deposition in the kidney (hemosiderosis). [11869]
Polycythemia
Polycythemia vera is a myeloproliferative disorder characterized by uncontrolled erythrocyte production. Virtually all
patients with polycythemia vera have a mutation in JAK2, a non-receptor (cytoplasmic) tyrosine kinase associated
with the erythropoietin receptor. [8591]
Renal cortical cells sense hypoxia and respond by synthesizing and releasing erythropoietin. Erythropoietin
stimulates the production of erythrocytes in the bone marrow. [1941]
Polycythemia vera (PV) is a clonal myeloproliferative disease characterize by an increased RBC mass, increased
plasma volume, and low erythropoietin levels. PV can be differentiated from secondary polycythemia by the
presence of leukocytosis, thrombocytosis, and/or splenomegaly. The majority of patients with PV have a JAK2
mutation rendering hematopoietic stem cells more sensitive to growth factors. [8559]
Pure red cell aplasia
Pure red cell aplasia is a rare form of marrow failure characterized by severe hypoplasia of marrow erythroid
elements in the setting of normal granulopoiesis and thrombopoiesis. Pure red cell aplasia is associated with
thymoma, lymphocytic leukemias, and parvovirus B19 infection. [1786]
Sickle cell
Parvovirus B19 infection can cause transient aplastic crisis, particularly in those with underlying hemoglobin disorders
such as sickle cell anemia. Patients develop symptomatic anemia (eg, exertional dyspnea, fatigue, low hematocrit)
due to inhibition of erythropoiesis by the virus. Bone marrow examination will show giant pronormoblasts with
glassy, intranuclear viral inclusions. [15562]
Patients with sickle cell trait are typically asymptomatic and have relative protection from malaria caused by
Plasmodium falciparum. These patients usually have normal hemoglobin, reticulocyte, and red blood cell index
values. Life expectancy is the same as that of the general population. [895]
Sickle cell disease is characterized by repeated splenic infarctions that ultimately result in splenic atrophy and fibrosis,
a process that is typically complete by late childhood/adolescence. After autosplenectomy, patients are predisposed
to infections with encapsulated bacterial organisms. [2084]
An MCV >110 µm3 is highly suggestive of megaloblastic anemia, such as that caused by folic acid or vitamin B12
deficiency. Patients with chronic hemolytic anemia have increased folic acid requirements due to increased
erythrocyte turnover and are predisposed to developing macrocytosis. [2085]
In patients with sickle cell disease, repetitive splenic infarctions caused by microvessel occlusion result in a small, firm
splenic remnant (ie, autosplenectomy). [1842]
Acute lymphoblastic leukemia

Acute lymphoblastic leukemia typically presents with signs/symptoms of bone marrow failure (eg, bleeding due to
thrombocytopenia). Immunophenotyping by flow cytometry establishes the specific subtype; B-lymphoblastic
leukemia shows expression of terminal deoxynucleotidyl transferase (TdT) (marker expressed in lymphoblasts) and B-
cell markers (eg, CD10, CD19). [1571]
T-lymphoblastic leukemia often presents in adolescents with a mediastinal mass that can cause respiratory symptoms
or superior vena cava syndrome. The diagnosis is confirmed via flow cytometry by identifying a population of T
lymphoblasts (ie, TdT and CD3 positive). [1798]
T-lymphoblastic leukemia (T-ALL) is characterized by circulating lymphoblasts that express terminal deoxynucleotidyl
transferase (TdT) and CD3. T-ALL often presents in adolescents/young adults with a mediastinal mass. [15278]
Acute myeloid leukemia

The finding of Auer rods (linear purple-red inclusions within immature myeloid precursors) is helpful in making the
diagnosis of acute myeloid leukemia. Auer rods are not found in acute lymphoblastic leukemia. In chronic myeloid
leukemia, there are more mature cells and fewer blasts. [1570]
Acute promyelocytic leukemia is the M3 variant of acute myelogenous leukemia. It affects adult patients and may
present with disseminated intravascular coagulation. The cytogenetic abnormality t(15;17) leads to formation of the
promyelocytic leukemia-retinoic acid receptor alpha (PML/RARα) fusion gene, which is unable to signal for proper
cellular differentiation, unlike the normal retinoic acid receptor. [1404]
Auer rods are deformed azurophilic granules found in the cytoplasm of myeloblasts that stain positively for
myeloperoxidase. Auer rods are found in abundance in AML M3 (acute promyelocytic leukemia). [1406]
Acute promyelocytic leukemia

The cytogenetic defect t(15;17) is associated with acute promyelocytic leukemia (APML). A translocation involving
the retinoic acid receptor alpha (RARA) gene from chromosome 17 and the promyelocytic leukemia (PML) gene on
chromosome 15 leads to the formation of PML/RARA, a fusion gene whose product inhibits differentiation of
myeloblasts and triggers the development of APML. [1403]
Acute promyelocytic leukemia (APL) can present with persistent infection and coagulopathy, causing hemorrhagic
signs and symptoms. Bone marrow examination classically reveals abnormal promyelocytes with intracytoplasmic
Auer rods. APL is associated with a t(15;17) chromosomal translocation that fuses the retinoic acid receptor-alpha
and promyelocytic leukemia genes. [1963]
The presence of rod-shaped intracytoplasmic inclusions (known as Auer rods) is characteristic of many forms of acute
myeloid leukemia (AML). The M3 variant of AML, acute promyelocytic leukemia, is associated with the cytogenetic
abnormality t(15;17) and typically shows abnormal promyelocytes with abundant cytoplasmic granules, multiple Auer
rods, and bilobed nuclei. [1405]
Burkitt lymphoma
Burkitt lymphoma is usually associated with translocations of the MYC gene on chromosome 8 to the immunoglobulin
heavy chain region of chromosome 14 [t(8;14)], resulting in MYC overexpression. It presents with a rapidly growing
mass (eg, jaw) and is histologically characterized by a "starry sky" appearance, with numerous mitotic figures and
apoptotic bodies. [1629]
Burkitt lymphoma, an aggressive B-cell malignancy, can be associated with Epstein-Barr virus infection. It typically
presents as a rapidly growing mass (eg, abdomen). Histopathology shows sheets of uniform, medium-sized lymphoid
cells with numerous mitotic figures (ie, high proliferation rate) and apoptotic bodies. [1630]
Burkitt lymphoma is characterized by aggressive rapid growth and a "starry sky" microscopic
appearance. Translocation between the c-Myc oncogene on the long arm of chromosome 8 with the Ig heavy chain
region on chromosome 14 leads to overexpression of Myc, a nuclear phosphoprotein that functions as a transcription
activator. [1755]
Chronic lymphocytic leukemia

Chronic lymphocytic leukemia is a lymphoproliferative disorder marked by the progressive accumulation of mature B
cells. Most patients are asymptomatic for years but eventually develop anemia, thrombocytopenia, and/or
neutropenia. The diagnosis is generally made when complete blood count reveals dramatic leukocytosis, and flow
cytometry subsequently shows a clonal population of leukocytes with B-cell markers such as CD19, CD20, and CD23.
[15545]
Chronic myeloid leukemia
Chronic myelogenous leukemia (CML) and leukemoid reaction can have presentations similar to leukocytosis;
however, leukocyte (neutrophil) alkaline phosphatase level is normal or elevated in a leukemoid reaction but
decreased in CML. The definitive diagnosis of CML requires demonstration of the Philadelphia chromosome t(9;22)
or BCR-ABL fusion gene or mRNA. [1569]
Some patients with non-small cell lung carcinoma (NSCLC) harbor a chromosomal rearrangement that creates a
fusion gene between EML4 (echinoderm microtubule-associated protein-like 4) and ALK (anaplastic lymphoma
kinase). This results in a constitutive active tyrosine kinase that causes malignancy. [8281]

Folic acid deficiency anemia commonly occurs in alcoholism. It is a megaloblastic anemia that can develop within
weeks. Peripheral blood smear shows macrocytosis, ovalocytosis, and neutrophils with hypersegmented nuclei. [873]
Gauchers Disease
Gaucher disease is a lysosomal storage disorder caused by beta-glucocerebrosidase deficiency that presents with
bone pain, hepatosplenomegaly, and cytopenias. Glucocerebroside accumulation leads to distended macrophages
with a "wrinkled tissue paper" appearance (Gaucher cells) that can be found in affected tissues (eg, bone marrow).
[11864]
HIV
Patients with HIV have much higher rates of lymphoma than the general population. Many cases are due to
underlying Epstein-Barr virus infection, which acts synergistically with HIV to promote uncontrolled B lymphocyte
proliferation. [1724]
Hairy cell leukemia

Hairy cell leukemia is an indolent B-cell neoplasm predominantly found in middle-aged men and characterized by
bone marrow failure and infiltration into the reticuloendothelial system, causing massive splenomegaly. Other
typical features include a "dry tap" (unsuccessful bone marrow aspiration) and the presence of lymphocytes with
cytoplasmic projections. [11750]
Both hepatitis B (HBV) and hepatitis C virus infections increase the risk of hepatocellular carcinoma due to chronic
hepatic inflammation and cell turnover. HBV is also carcinogenic due to the production of oncogenic proteins and the
insertion of the HBV genome into host chromosomes. [58]
Hodgkins lymphoma
Reed-Sternberg cells are large binucleated cells with an "owl's eyes" appearance that appear on a background of
lymphocytic infiltrates. Reed-Sternberg cells must be present histopathologically in order to make the diagnosis of
Hodgkin lymphoma. [1864]
The presence of Reed-Sternberg (RS) cells on lymph node biopsy is a diagnostic feature of classic Hodgkin
lymphoma. RS cells have abundant cytoplasm, a multilobed nucleus or multiple nuclei, and inclusion-like nucleoli.
[1626]
Epstein-Barr virus causes infectious mononucleosis in teenagers and young adults. It is also associated with a number
of malignant conditions, including Burkitt lymphoma and nasopharyngeal carcinoma. [1757]
The primary immune response to Epstein-Barr virus is mediated by CD8+ T lymphocytes, which are activated through
the presentation of viral antigens on infected CD21+ B lymphocytes. These reactive (atypical) CD8+ T lymphocytes
can be observed in the peripheral blood smears of patients with infectious mononucleosis. [7643]
Leukocytosis
Leukemoid reaction is a significant leukocytosis (may exceed 50,000/mm3) that occurs in response to an underlying
condition, commonly severe infection. Blood smear often shows neutrophilia with reactive features (eg, Döhle
bodies), as well as increased neutrophil precursors (eg, bands, metamyelocytes, myelocytes). The leukocyte alkaline
phosphatase score is normal or increased. [11456]
Infection triggers increased circulating neutrophils by stimulating the release of neutrophils, bands, and late
granulocyte precursors from the bone marrow. This is mediated by increased cytokines (eg, TNF-alpha) and
complement activation. Demarginalization of neutrophils from endothelial attachment also contributes to
leukocytosis. [15512]
Multiple myeloma
Amyloid light-chain amyloidosis is associated with multiple myeloma and other monoclonal plasma cell dyscrasias
due to the deposition of insoluble immunoglobulin light-chain fibrils in major organs (eg, kidneys, heart, neurologic
system). A bone marrow sample with >10% plasma cells is strongly suggestive of multiple myeloma. [872]
Multiple myeloma is associated with elevated circulating paraproteins (monoclonal immunoglobulins), which causes
erythrocytes to stack like coins (rouleaux formation). Patients classically have normocytic anemia, hypercalcemia,
bone pain, and renal insufficiency. [6530]
The finding of a high peak in the gamma-globulin region on serum protein electrophoresis (SPEP) usually represents
an M protein consisting of an overproduced monoclonal immunoglobulin. Multiple myeloma causes an M protein
peak on SPEP as well as anemia (weakness), lytic bone lesions (back pain, pathologic fractures), and renal
insufficiency (related to amyloid deposition and hypercalcemia). [1964]
Myelodysplastic syndrome
Myelodysplastic syndrome is a clonal hematologic neoplasm marked by ≥1 cytopenias and cellular dysplasia (eg, oval
macrocytic erythrocytes, hyposegmented granulocytes). Bone marrow evaluation usually reveals a hypercellular
marrow, a mild or moderate increase in myeloblasts (<20% of total cells), and dysplastic erythrocytes/granulocytes.
[20673]
Myelofibrosis
The chronic myeloproliferative disorders (polycythemia vera, essential thrombocytosis, and primary myelofibrosis)
often have a mutation in Janus kinase 2 (JAK2), a cytoplasmic tyrosine kinase. This results in constitutive tyrosine
kinase activity, and consequently, in the cytokine-independent activation of signal transducers and activators of
transcription (STAT) proteins (JAK-STAT signaling pathway). [8540]
Primary myelofibrosis is a myeloproliferative disorder associated with the clonal expansion of megakaryocytes. Bone
marrow fibrosis accounts for most of the major manifestations, including hepatosplenomegaly, cytopenias, and blood
smear evidence of dacrocytes. Bone marrow aspiration is usually dry, but bone marrow biopsy will show marked
fibrosis with occasional clusters of atypical megakaryocytes. [14816]
Neutropenia
Cyclic neutropenia occurs as a result of a mutation in the gene encoding neutrophil elastase. This leads to
accelerated apoptosis of neutrophil precursors with characteristic bone marrow findings of nuclear
fragmentation and membrane blebbing. Cyclic neutropenia is characterized by episodic (every 3 weeks), severe
neutropenia that causes recurrent fever and mucositis. [106780]
Nonhodgkin lymphoma
Follicular lymphoma is the most common indolent non-Hodgkin lymphoma in adults. It is of B-cell origin and presents
with painless waxing and waning (ie, fluctuating) lymphadenopathy. The cytogenetic change t(14;18) is characteristic
and results in overexpression of the BCL2 oncogene. [1086]
Follicular lymphoma is a common, indolent non-Hodgkin lymphoma. It is characterized by a translocation involving

BCL2 on chromosome 18, which becomes positioned near the immunoglobulin heavy-chain gene on chromosome 14,
resulting in overexpression of BCL2 (an antiapoptotic protein). [1911]
BCL2 protein inhibits apoptosis by blocking the release of proapoptotic factors (eg, cytochrome c protein) from the
mitochondria. BCL2 is overexpressed in follicular lymphoma secondary to the t(14;18) translocation involving BCL2
and immunoglobulin heavy-chain genes. [1758]
Follicular lymphoma is histologically characterized by neoplastic follicles that obscure the normal lymph node
architecture. Most cases have the t(14;18) translocation, which causes overexpression of the antiapoptotic BCL2
protein. [1627]
Benign lymph node enlargement in response to antigenic stimulation is associated with a polyclonal proliferation of
lymphocytes. A monoclonal lymphocytic proliferation is strong evidence of malignancy. [1754]
Infectious Diseases
Acute parotitis
Acute bacterial parotitis occurs more commonly in elderly postoperative patients who are intubated or
dehydrated. Staphylococcus aureus is the most common bacterial etiology. Diagnosis can be confirmed by imaging
and an elevated serum amylase level (with a normal serum lipase level and no evidence of pancreatitis). [11596]
Meningococcal meningitis is a rapidly progressive infection that can spread systemically (ie, meningococcemia) and
lead to septic shock, multiorgan failure, and disseminated intravascular coagulation. Meningococcemia is also
associated with bilateral hemorrhagic infarction of the adrenal glands, which can result in acute adrenal insufficiency
(Waterhouse-Friderichsen syndrome) with worsening shock and rapid clinical deterioration. [931]

Acute phase reactants (APRs) are proteins whose serum concentrations change by ≥25% during periods of
inflammation. Procalcitonin is a unique APR that can rise or fall depending on the etiology of the infection; elevated
levels correlate with a bacterial source, whereas low levels indicate a viral source. [14921]
Lyme disease
Lyme disease should be suspected in any individual from an endemic area who develops erythema migrans, a slowly
expanding annular lesion with central clearing (bull's-eye rash). Most cases are not pruritic or painful, but patients
sometimes have systemic symptoms (eg, fever, myalgia, headache). [1676]
Bacterial vaginosis
Bacterial vaginosis causes a thin, gray or clear, malodorous discharge from overgrowth of anaerobes (eg, Gardnerella
vaginalis) and a loss of lactobacilli in the vaginal flora. Diagnosis is confirmed by the presence of clue cells and a
positive amine whiff test with potassium hydroxide. Treatment is with clindamycin or metronidazole. [1958]
Universal vaccination of children against HBV would likely cause a steep decline in the worldwide incidence of
hepatocellular carcinoma. [60]
Syphilis
Tertiary syphilis can result in thoracic aortic aneurysm. If the aneurysm compresses adjacent structures and dilates
the aortic valve ring, a murmur and mediastinal widening might be present. The pathogenesis begins with vasa
vasorum endarteritis and obliteration, resulting in inflammation, ischemia, and weakening of the aortic
adventitia. Fluorescent treponemal antibody absorption testing is specific for syphilis. [472]
Histopathologic examination of syphilitic lesions classically demonstrates a proliferative endarteritis with a
surrounding plasma cell infiltrate. Most of the manifestations of syphilis are due to localized tissue ischemia resulting
from endarteritis. [14855]
MISCELLANEOUS
Cns lymphoma
Primary CNS lymphomas occur in immunosuppressed patients, such as those suffering from AIDS. These tumors arise
from B cells and are universally associated with EBV. They are high-grade tumors with a poor prognosis. [1260]
Schistosomiasis
Schistosomiasis is a parasitic blood fluke infection that is associated with bathing in freshwater contaminated with
cercariae from infected snails. Patients often are asymptomatic for months or years but may eventually develop
eosinophilic granulomatous inflammation in the liver, spleen, gastrointestinal tract, or genitourinary system. One
common manifestation of genitourinary schistosomiasis is painless terminal hematuria; eggs can often be identified
in the urine or on biopsy. [15438]
Bronchiectasis
Primary ciliary dyskinesia results from an autosomal recessive mutation in the proteins responsible for normal
flagellar and ciliary structure and function (eg, dynein, assembly proteins). Clinical manifestations include situs
inversus, chronic sinusitis, bronchiectasis, and infertility. [664]
Cryptorchidism
In undescended testes, the seminiferous tubules atrophy if uncorrected due to higher body temperatures, resulting in
decreased fertility and increased risk for malignancy. Orchiopexy (surgical placement of the testes in the scrotal sac)
can minimize damage and decrease risk for testicular cancer. [580]
Epididymitis
Epididymitis presents with acute testicular pain, tenderness, and pyuria. It is caused by retrograde passage of
organisms from the urethra into the ejaculatory duct and vas deferens. The microbiology is largely influenced by
patient age: epididymitis in young men is usually due to sexually acquired infections (eg, Chlamydia trachomatis,
Neisseria gonorrhoeae), whereas in older men (age >35) it is usually due to gram-negative colonic flora. [15560]
Hemochromatosis
Hereditary hemochromatosis can cause secondary hypogonadism due to deposition of iron in the pituitary gland,
resulting in decreased gonadotropin secretion. Patients who develop secondary hypogonadism are also at risk for
deficiencies in other pituitary hormones (eg, central hypothyroidism). [19591]
Pathologic gynecomastia should be suspected in patients who also have signs of hypogonadism (eg, small/firm testes,
absent pubic hair). Klinefelter syndrome (47,XXY) is the most common cause of primary hypogonadism, and patients
have low testosterone, elevated gonadotropin (FSH, LH), and relatively increased estradiol levels. [1055]

Psychogenic causes of erectile dysfunction include performance anxiety, depression, sexual trauma, relationship
problems, and stress. Important clues include sudden-onset and normal nocturnal erections. [8351]
Prostate cancer
Prostate cancer is graded by Gleason grade, which is a measure of glandular architecture disruption and risk of extra-
organ spread; poorly differentiated prostate cancer (eg, no glandular structure) is assigned a high Gleason grade,
whereas well-differentiated prostate cancer (eg, well-formed glandular structure) is assigned a low Gleason
grade. Staging is a marker of the extent of spread from the primary cancer site; regional lymph node involvement or
distant metastases indicate a higher stage of disease. [16005]
Prostate cancer is common in older men and metastasizes primarily to bone due to bone-specific tumor adhesion
molecules and receptor ligands on the cellular surface. Prostate cancer causes osteoblastic lesions that result in new
bone growth. Biopsy would show disordered trabeculae and signs of prostate cancer such as irregular glands with
enlarged nuclei and prominent nucleoli. [16002]
Most prostate cancer arises in the peripheral zone of the gland, which abuts the rectum. Therefore, prostate biopsies
are primarily obtained via the transrectal approach; multiple random core samples of the prostate are typically
taken. Because only a small part of the peripheral zone encases the distal urethra, patients with prostate cancer do
not typically present with urinary symptoms. [16003]
Prostate adenocarcinoma is generally diagnosed with transrectal prostate biopsy, which often reveals atypical cells
with enlarged nuclei and prominent nucleoli forming crowded, infiltrative glands. [16001]
Testicular cancer
Human chorionic gonadotropin (hCG) has a structure similar to TSH. Patients with testicular germ cell tumors or
gestational trophoblastic disease may develop very high serum hCG concentrations, which can stimulate TSH
receptors and cause paraneoplastic hyperthyroidism. [624]
Most cases of testicular cancer are either seminomatous or nonseminomatous germ cell tumors. Nonseminomatous
germ cell tumors are composed of partially differentiated germ cells, which often retain the ability to secrete human
chorionic growth hormone and alpha-fetoprotein (serum tumor markers). Serum lactate dehydrogenase, a marker of
tissue injury and cell turnover, is also frequently increased. [15828]
A painless, solid scrotal mass should be considered testicular cancer until proven otherwise. Examination generally
reveals a solid, firm, or fixed nodule in the tunica albuginea that is ovoid in shape and painless to
palpation. Testicular tumors do not transilluminate. [15804]
MISCELLANEOUS
Atrophy
Pathologic atrophy can be caused by decreased physical workload, loss of innervation, decreased blood supply,
inadequate nutrition, absent endocrine stimulation, aging, or mechanical pressure. [295]
Tuberous sclerosis
Tuberous sclerosis complex is an autosomal dominant disorder characterized by benign hamartomas of the brain (ie,
cortical glioneuronal hamartomas and subependymal nodules) and skin. Seizures and ash-leaf spots are common
presenting signs. [7605]
Renal angiomyolipoma is a benign tumor composed of blood vessels, smooth muscle, and fat. Bilateral renal
angiomyolipomas are associated with tuberous sclerosis, an autosomal dominant condition. [6]
Von hippel lindau disease

Von Hippel-Lindau (VHL) disease is an autosomal dominant condition caused by a mutation in a tumor suppressor
gene, which is associated with the development of pheochromocytomas, retinal and cerebellar hemangioblastomas,
and renal cell carcinomas. Because of the potential for serious complications from these tumors, patients with VHL
should receive annual surveillance, including plasma metanephrines, abdominal imaging, ophthalmologic
examination, and MRI of the brain and spine. [19187]
Nervous System
CNS INFECTIONS
HIV
HIV-associated dementia should be suspected in patients with AIDS who have progressive cognitive decline. The
characteristic histopathologic finding is microglial nodules (groups of activated microglia/macrophages around small
areas of necrosis) and multinucleated giant cells. [11568]
HIV-associated dementia has become rare since the advent of antiretroviral treatment but may still develop in
patients with inadequately treated, late-stage HIV infection. In the CNS, HIV preferentially infects and replicates in
macrophages. [19486]
HSV infection
Viral infections of the central nervous system are usually characterized by an elevated white blood cell count with a
lymphocytic predominance, normal glucose, and elevated (or normal) protein. Patients with herpes encephalitis also
usually have elevated erythrocytes in the cerebrospinal fluid due to hemorrhagic inflammation of the temporal lobes.
[908]
Prion disease
Prion diseases are rapidly progressive neurodegenerative disorders caused by the accumulation of an abnormally
folded protein within the brain. Prion proteins are normally found in an alpha helix form; a conformation change into
a beta-sheet form confers resistance to proteases and can trigger similar conformational changes in other normally
folded proteins. Characteristic microscopic findings include spongiform degeneration of the gray matter with
vacuolization of neurons, gliosis, and cyst formation. [912]
Creutzfeldt-Jakob disease is a prion disease characterized by rapidly progressive dementia, myoclonus, and death
within a year of symptom onset. It is caused by the accumulation of an abnormally folded (ie, beta pleated sheet)
protein that is resistant to proteases and can trigger similar conformational changes in other normally folded
proteins. [911]
Syphilis
Tabes dorsalis, a late form of neurosyphilis, causes progressive degeneration of the dorsal columns and dorsal roots
of the spinal cord. Manifestations include loss of proprioception and vibratory sensation, severe lancinating pains,
and sensory ataxia (eg, wide-based gait, positive Romberg sign). Many patients also have Argyll Robertson pupils. [906]
Tuberculosis
Tuberculous (TB) meningitis is characterized by formation of a thick, gelatinous exudate in the base of the brain;
cerebral vasculitis; and hydrocephalus. It frequently presents with subacute, slowly progressive nausea, vomiting,
fever, cranial nerve deficits, and strokes. [19420]
Brain herniation
Uncal herniation is a possible complication of an expanding ipsilateral mass lesion (eg, hemorrhage, tumor). The first
sign of uncal herniation is a fixed, dilated pupil on the side of the lesion. Contralateral or ipsilateral hemiparesis and
contralateral homonymous hemianopsia with macular sparing may also occur. [495]
Epidural hematoma
Epidural hematoma is an accumulation of blood between the bone and dura mater. It typically occurs due to a tear
of the middle meningeal artery associated with fracture of the pterion region of the skull (often involving the
temporal bone). Patients characteristically have transient loss of consciousness followed by a lucid interval before
increasing intracranial pressure leads to neurologic deterioration. [505]
Giant cell arteritis
Polymyalgia rheumatica occurs in more than half of patients with temporal arteritis. It is characterized by neck, torso,
shoulder, and pelvic girdle pain and morning stiffness. Fatigue, fever and weight loss may also occur. Monocular
vision loss is a common complication of temporal arteritis. [913]
Hemangioma
Cavernous hemangiomas are vascular malformations that occur most commonly within the brain parenchyma; they
carry an increased risk of intracerebral hemorrhage and seizure. [11627]
Hemorrhagic stroke
Cerebral amyloid angiopathy is the most common cause of spontaneous lobar hemorrhage, particularly in the
elderly. The most common sites of hemorrhage include the occipital and parietal lobes. [499]
Deep intraparenchymal hemorrhage is most commonly caused by hypertensive vasculopathy of the small penetrating
branches of the cerebral arteries (Charcot-Bouchard aneurysm rupture). This is in contrast to rupture of saccular
aneurysms, which typically cause subarachnoid hemorrhage. [498]
Acute lesions to the cerebellar vermis typically cause truncal and gait ataxia due to impaired modulation of the
medial-descending motor systems. Involvement of the lower vermis and the flocculonodular lobe also causes
vertigo/nystagmus due to dysregulation of the vestibular nuclear complex. [11632]
Hydrocephalus
Communicating hydrocephalus is a common complication of subarachnoid hemorrhage that presents with
deteriorating mental status. It typically results from blood-induced impairment of absorption of cerebrospinal fluid
by the arachnoid granulations. [18543]
Ischemic stroke
Wallerian degeneration refers to the process of axonal degeneration and breakdown of the myelin sheath that occurs
distal to a site of injury. Axonal regeneration does not occur in the central nervous system due to the persistence of
myelin debris, secretion of neuronal inhibitory factors, and development of dense glial scarring. [11576]
Inadequate blood supply to the brain (eg, arterial thrombosis or embolism) leads to ischemic stroke. The first
microscopic changes are typically seen 12-24 hours after irreversible ischemic injury and include intense eosinophilic
staining of the neuronal cytoplasm (red neurons) and nuclear fragmentation. [19]
CNS injury is associated with astrocyte hypertrophy and proliferation (gliosis). This process leads to the formation of
a glial scar, which compensates for the volume loss that occurs after neuronal death. [493]
Global cerebral ischemia is typically precipitated by systemic hypotension (eg, cardiac arrest). The cells most
susceptible to ischemia are the CA1 pyramidal neurons of the hippocampus. Other areas of the brain that are
damaged early in the course of global cerebral ischemia include the cerebellar Purkinje cells and the pyramidal
neurons of the neocortex. [18]
Several months to years after ischemic brain infarction, the necrotic area appears as a cystic cavity surrounded by a
wall composed of dense fibers formed by astrocytic processes (glial scar). [501]
The primary mechanism underlying cytotoxic (early) edema following cerebral ischemia is the accumulation of
intracellular Na+ and water due to the failure of ATP-dependent ion transporters in hypoxic cells. Cerebral edema
causes progressive neurologic decline by raising intracranial pressure, which can directly damage neural tissue or
result in mechanical damage due to brain herniation. [15649]
Lacunar infarcts are small, ischemic infarcts (usually <15 mm) involving the deep brain structures (eg, basal ganglia,
pons) and subcortical white matter (eg, internal capsule, corona radiata). They most often occur due to
hypertension, which causes hardening/thickening of the vessel wall (hypertensive arteriolar sclerosis), predisposing
patients with this condition to thrombotic vessel occlusion. [22]
Microglia are the predominant cell in the necrotic area 3-7 days after the onset of ischemia and phagocytize the
fragments of neurons, myelin, and necrotic debris. [20]
Neurons that sustain irreversible ischemic injury begin to develop characteristic histopathologic changes 12-24 hours
after the inciting event. These changes include shrinkage of the cell body, pyknosis of the nucleus, loss of Nissl
bodies, and cytoplasmic eosinophilia (red neurons). [492]
Sustained cerebral hypoperfusion (eg, hypotension, shock) may cause global cerebral ischemia and watershed
infarction. These watershed zones are located at the borders between areas perfused by the anterior, middle, and
posterior cerebral arteries and typically appear as symmetric, bilateral wedge-shaped strips of necrosis over the
cerebral convexity, parallel and adjacent to the interhemispheric fissure. [23]
Necrosis
Liquefactive necrosis is characterized by complete digestion and removal of necrotic tissue with formation of a cystic
cavity. Irreversible ischemic CNS injury is typically followed by liquefactive necrosis due to the release of lysosomal
enzymes from inflammatory cells and damaged neurons. [871]
Subarachnoid hemorrhage
The most common complication of aneurysmal subarachnoid hemorrhage is vasospasm, which typically occurs 3-12
days after the initial insult and can cause delayed cerebral ischemia (eg, sudden change in mental status, new focal
neurological deficits). The CT scan usually remains unchanged, unlike with rebleeding. [500]
Sudden-onset, severe headache with signs of meningeal irritation (eg, neck pain, stiffness) should raise suspicion for
subarachnoid hemorrhage (SAH). SAH usually results from rupture of a saccular (berry) aneurysm, and it is
recognized on CT scan by blood pooling in the cerebral sulci and basal cisterns. [15866]
Intracranial berry aneurysms of the circle of Willis are often seen in patients with ADPKD; when ruptured, they cause
subarachnoid hemorrhage that presents with sudden onset of "thunderclap headache". [4]
Subarachnoid hemorrhage presents with a generalized, excruciating headache. It is classically described by patients
as "the worst headache of my life." Subarachnoid hemorrhage usually occurs due to rupture of saccular (berry)
aneurysms or arteriovenous malformations. Berry aneurysms of the circle of Willis are associated with autosomal
dominant polycystic kidney disease. [497]
Vascular dementia
Vascular dementia often presents with prominent executive dysfunction. MRI typically reveals signs of multiple small
infarcts, microbleeds, and areas of hyperintensity in the white matter that represent demyelination or axon loss.
[21189]
Ataxia telangiectasia
Ataxia-telangiectasia is an autosomal-recessive disorder resulting from a defect in DNA-repair genes. The DNA of
these patients is hypersensitive to ionizing radiation. Manifestations include cerebellar ataxia, oculocutaneous
telangiectasias, repeated sinopulmonary infections, and an increased incidence of malignancy. [673]
Av malformation
Arteriovenous malformations occur when an artery directly anastomoses with veins without an interposed capillary
bed. They may result in spontaneous intracerebral hemorrhage or seizures, or they may be discovered incidentally
when brain imaging is obtained for another reason. [15745]
Cerebral palsy
Cerebral palsy is a nonprogressive neurologic injury that most commonly presents with delayed gross motor
milestones, spasticity, and hyperreflexia. Premature infants are particularly susceptible due to periventricular
leukomalacia (white matter necrosis). [21408]
Charcot marie tooth disease

Charcot-Marie-Tooth is a group of hereditary peripheral neuropathies characterized by mutations in genes coding for
peripheral nerve axonal or myelin proteins. Manifestations typically include progressive, symmetric distal muscle
atrophy and weakness most prominent in the feet and calf musculature, with sensory loss, areflexia, pes cavus (ie,
high arches), and hammer toes. [15594]
Chiari malformation
Chiari malformations are congenital disorders that result from underdevelopment of the posterior fossa, causing
parts of the cerebellum and medulla to herniate through the foramen magnum. Chiari type I is relatively benign and
presents during adulthood with occipital headache and cerebellar dysfunction. Chiari type II is a more severe form
that affects neonates and is often associated with lumbar myelomeningocele and hydrocephalus. [504]
Dandy walker syndrome

Dandy-Walker malformation is a developmental anomaly characterized by hypoplasia/absence of the cerebellar
vermis and cystic dilation of the fourth ventricle with posterior fossa enlargement. Patients often present during
infancy with developmental delay and progressive skull enlargement. Other features may include cerebellar
dysfunction and non-communicating hydrocephalus. [11843]
Friedreich ataxia
Friedreich ataxia is characterized by cerebellar ataxia (spinocerebellar tract degeneration) and loss of
position/vibration sensation (dorsal column/dorsal root ganglia degeneration), kyphoscoliosis, and hypertrophic
cardiomyopathy. Foot abnormalities and diabetes mellitus are also common. [672]
Friedreich ataxia is an autosomal recessive condition that presents during childhood/adolescence with progressive
gait ataxia (due to degeneration of the spinocerebellar tracts) and impaired joint and vibration sense (due to
degeneration of the posterior columns and dorsal root ganglia). Other features include hypertrophic cardiomyopathy
(most common cause of death), skeletal abnormalities (eg, kyphoscoliosis, pes cavus), and diabetes mellitus. [636]
Neurofibromatosis
Bilateral acoustic neuromas are associated with neurofibromatosis type 2, an autosomal dominant condition caused
by mutation of the NF-2 gene on chromosome 22. [1305]
Von hippel lindau disease

A cerebellar hemangioblastoma in association with congenital cysts of the kidneys, liver, and/or pancreas is highly
suggestive of von Hippel–Lindau disease, a rare autosomal dominant condition. [468]
Wilson disease
Wilson disease is an autosomal recessive condition characterized by excessive copper deposition into tissues (eg,
liver, basal ganglia, cornea). It typically presents in young adults with liver disease, neuropsychiatric symptoms (eg,
gait disturbance, dysarthria, depression, personality changes), and Kayser-Fleischer rings on slit lamp examination.
[397]
Central pontine myelinolysis

Rapid correction of chronic hyponatremia may lead to osmotic demyelination syndrome (also known as central
pontine myelinolysis). It typically manifests 2-6 days after the osmotic insult with spastic quadriplegia, pseudobulbar
palsy, and locked-in syndrome. [915]
Multiple sclerosis
Multiple sclerosis is an immune-mediated disorder of the central nervous system characterized by focal
demyelination (plaques). Histologically, plaques contain foci of perivenular inflammatory infiltrates made up
primarily of autoreactive T lymphocytes and macrophages. Patchy demyelination occurs followed by astrocyte
hyperplasia (glial scarring). [919]
Multiple sclerosis is an autoimmune disorder of the central nervous system characterized by recurrent episodes of
demyelination, leading to reduced saltatory conduction. Internuclear ophthalmoplegia and optic neuritis are
common manifestations. [917]
Multiple sclerosis is characterized by episodic, progressive neurologic deficits involving multiple anatomic regions
within the central nervous system. Demyelinating plaques are commonly seen as hyperintense lesions on T2-
weighted MRI of the brain and spinal cord. Common manifestations include optic neuritis, internuclear
ophthalmoplegia, sensory deficits, and fatigue, which may worsen with heat exposure. [916]
The pathogenesis of multiple sclerosis involves an autoimmune response (T cell and antibody-mediated) targeting
oligodendrocytes and myelin in the central nervous system, leading to slowed nerve conduction with neurologic
deficits. [11631]
Multiple sclerosis (MS) is an autoimmune demyelinating disease that results from oligodendrocyte depletion. Within
the lesions, inflammatory infiltrates of lymphocytes and macrophages are seen surrounding oligodendrocytes and
myelin sheaths. Oligoclonal bands are highly sensitive but nonspecific in patients with MS. [918]
Cranial nerve palsy

Diabetic mononeuropathy often involves cranial nerve III. It is caused by predominantly central ischemia, which
affects the somatic nerve fibers but spares peripheral parasympathetic fibers. Symptoms include ptosis, a "down and
out" gaze, and normal light and accommodation reflexes. [1060]
Diabetic neuropathy
Diabetes mellitus is the most common cause of peripheral polyneuropathy in adults. Common findings include
numbness and paresthesias in a stocking-glove distribution and decreased proprioception due to degeneration of
large-fiber sensory axons. [15667]
Eaton lambert myasthenic syndrome

Lambert-Eaton myasthenic syndrome is characterized by antibodies against presynaptic voltage-gated calcium
channels. Patients develop progressive proximal muscle weakness with reduced/absent reflexes that predominantly
involves the lower extremities. The syndrome is often associated with malignancy, particularly small cell lung cancer.
[1267]
Facial nerve
Hyperacusis (increased sensitivity to sound) is an indication of damage to the facial nerve (CN VII) close to its origin
from the brainstem. [12252]
Guillain Barre syndrome

Guillain-Barré syndrome is an acute, demyelinating polyneuropathy thought to be caused by molecular
mimicry. Antibodies formed against infectious agents cross-react with myelin and Schwann cells, leading to immune-
mediated demyelination. Light microscopy shows segmental demyelination and an endoneurial inflammatory
infiltrate composed of lymphocytes and macrophages. [66]
Guillain-Barré syndrome is an acute demyelinating polyneuropathy. It is thought to be due to molecular mimicry and
is commonly preceded by an upper respiratory viral illness or gastroenteritis. Segmental demyelination of the
peripheral nerves and an endoneural inflammatory infiltrate are seen on light microscopy. [1058]
Lung cancer
The phrenic nerve arises from the C3-C5 segments of the spinal cord and innervates the ipsilateral
hemidiaphragm. Intrathoracic spread of lung cancer may affect the phrenic nerve, causing hiccups and diaphragmatic
paralysis with dyspnea. Brachial plexus involvement can cause pain in the distribution of the C8, T1, and T2 nerve
roots. Involvement of the recurrent laryngeal nerve may cause hoarseness. [647]
Median nerve injury

Carpal tunnel syndrome is a peripheral neuropathy characterized by pain/paresthesias in a median nerve distribution
(palmar surface of the first 3 digits and radial half of the 4th digit), weakness on thumb abduction/opposition, thenar
atrophy, and a positive Tinel and/or Phalen test. It is caused by median nerve compression at the transverse carpal
ligament. [1264]
Myasthenia gravis
Myasthenia gravis is an autoimmune disorder caused by an autoantibody-mediated attack on the acetylcholine
receptors of the postsynaptic neuromuscular junction, leading to a reduced number of acetylcholine receptors. It is
characterized by fatigable weakness of the skeletal muscles; respiratory failure can occur due to diaphragmatic
weakness. [6554]
Myasthenia gravis is caused by circulating antibodies directed against acetylcholine receptors of the neuromuscular
junction. Autoantibody binding leads to receptor degradation, producing fluctuating weakness that worsens
throughout the day and most commonly affects the extraocular muscles (eg, ptosis, diplopia). Most patients have
thymic abnormalities (eg, thymoma). [749]
Myotonic Dystrophy
Myotonic dystrophy is characterized by muscle weakness and myotonia (impaired muscle relaxation) with muscle
atrophy, particularly of the type I (slow-twitch) muscle fibers. Pathophysiology involves a trinucleotide repeat
expansion causing mutant RNA that disrupts muscle contraction and relaxation. [1268]
Diabetic peripheral neuropathy is characterized by numbness and paresthesia in a stocking-and-glove distribution. It
results from nonenzymatic glycosylation of proteins, leading to hyalinization of endoneurial arteries and ischemic
nerve damage. In addition, accumulation toxic substances within neurons results in deranged metabolism and
increased oxidative stress. [1059]
Vestibular schwannoma
Schwannomas present histologically with a biphasic pattern of cellularity (Antoni A and B areas) and S-100 positivity
(indicating neural crest origin). Schwannomas can arise from the peripheral nerves, nerve roots, and cranial nerves
(except CN II and CN I). Acoustic neuromas are the most common type of intracranial schwannoma and are located
at the cerebellopontine angle at CN VIII. [1304]
HEADACHE
Cluster headache
Cluster headaches cause severe, episodic, unilateral periorbital and temporal pain associated with ipsilateral
autonomic symptoms (eg, lacrimation, nasal congestion, miosis, conjunctival injection). The headaches typically last
15-180 minutes and tend to occur in clusters (often at the same time each day). Males are affected more commonly
than females. [1962]
Cluster headaches often present with rapid-onset, severe, unilateral pain accompanied by ipsilateral autonomic
symptoms (eg, ptosis, miosis, nasal congestion, conjunctival injection). [19569]
Migraine
Migraines are an episodic neurological disorder that results in severe, unilateral, throbbing headaches often
associated with photophobia, phonophobia, and nausea/vomiting. Migraines typically last 4-72 hours, and up to 25%
of patients also develop an aura (focal, reversible neurologic symptoms that precede or accompany the headache).
[15683]
Tension headache
Tension headaches are the most common form of headache. They are characterized by an achy or pressure-like pain
that is often bilateral and associated with pericranial muscle tenderness. Tension headaches are not associated with
other neurologic symptoms and do not typically limit a patient's ability to perform daily functions. [7492]
HYDROCEPHALUS
Hydrocephalus
Hydrocephalus ex vacuo can occur due to neurodegenerative disease (eg, HIV infection) when significant neuronal
loss leads to a compensatory increase in the volume of cerebrospinal fluid. [14]
Symmetrical enlargement of the ventriculi is characteristic of communicating hydrocephalus. Communicating

hydrocephalus usually occurs secondary to dysfunction or obliteration of subarachnoid villi. This dysfunction is
usually a sequelae of meningeal infection (including tuberculosis meningitis) or subarachnoid/intraventricular
hemorrhage. [15]
Normal pressure hydrocephalus

Normal pressure hydrocephalus presents with progressive gait difficulties, cognitive disturbances, and urinary
incontinence. It is a form of communicating hydrocephalus characterized by ventriculomegaly without persistent
elevations in intercranial pressure. Brain imaging reveals ventricular enlargement out of proportion to sulci
enlargement. [16]
Normal pressure hydrocephalus occurs due to decreased cerebrospinal fluid absorption, resulting in ventriculomegaly
with normal intracranial pressure. This causes stretching of the descending cortical fibers (corona radiata) from the
frontal lobe and contributes to the classic triad of symptoms (ie, dementia, gait abnormalities, urinary
incontinence). Loss of cortical inhibition of the sacral micturition center leads to urge incontinence. [17]
MISCELLANEOUS
Brain death
Persistent vegetative state (PVS), a chronic state of wakefulness without awareness, is a common post-coma
outcome following severe brain injury. Patients with PVS have sufficient brainstem function to maintain vital
processes such as spontaneous respiration, but require continuous medical care due to absence of purposeful
movement and communication. [21833]
Delirium
Delirium involves the acute onset of fluctuating disturbances in attention (eg, altered consciousness) and cognition
(eg, disorientation, hallucinations). When no clear medical illness is apparent, medication-induced delirium should be
suspected. Psychoactive drugs (eg, anticholinergics, antihistamines, benzodiazepines, sedative-hypnotics, opioids)
are common causes, and over-the-counter agents and unauthorized prescriptions should not be overlooked. [15702]
Dystonia
Dystonia is a syndrome of prolonged, repetitive muscle contractions. This condition may be the result of impaired
function of the basal ganglia. Cervical dystonia (spasmodic torticollis), blepharospasm, and writer's cramp are the
most common types of focal dystonia. [634]
Tremor
Essential tremor most often presents as a tremor of the hands that is suppressed at rest, exacerbated by
outstretched arms, and more pronounced during goal-directed movements. It is often hereditary (autosomal
dominant) and can be associated with a head tremor, but it is not associated with other neurologic symptoms. [19543]
Trigeminal neuralgia
Trigeminal neuralgia is caused by compression of the trigeminal nerve (CN V) root as it enters the pons, usually by an
abnormal vessel loop. This leads to atrophy and demyelination of the nerve and causes short paroxysms of
neuropathic pain. [21909]
Vertigo
Vertigo is a sensation of excessive motion compared to physical reality. It is most commonly due to dysfunction
within the vestibular system. [8859]
Alzheimer disease
Alzheimer dementia typically presents insidiously with memory loss (especially of recent events), executive
dysfunction, and visuospatial impairment. Classic histopathologic findings include amyloid plaques (central amyloid
beta core surrounded by dystrophic neurites) and neurofibrillary tangles (aggregates of hyperphosphorylated tau
protein). [7490]
Amyloid is an abnormally folded (insoluble) extracellular protein that has apple-green birefringence when stained
with Congo red and viewed under polarized light. Alzheimer disease is associated with beta-amyloid deposits in the
brain parenchyma (neuritic plaques) and walls of cerebral vessels (amyloid angiopathy). [592]
The hippocampus is the area of the brain demonstrating the greatest degree of atrophy in Alzheimer's
disease. Hippocampal atrophy on MRI is highly suggestive of the diagnosis. [794]
Alzheimer disease is characterized by decreased levels of acetylcholine in the nucleus basalis of Meynert and the
hippocampus, caused by diminished activity of choline acetyltransferase. [593]
Amyotrophic lateral sclerosis

Patients with amyotrophic lateral sclerosis often develop respiratory failure due to inspiratory muscle weakness
(causing decreased vital capacity), expiratory muscle weakness (causing a weak cough), and bulbar dysfunction
(causing dysphagia and chronic aspiration). [19214]
Upper motor neuron damage leads to spastic paralysis, hyperreflexia, and an upgoing plantar reflex (Babinski sign)
due to loss of descending inhibition over lower motor neurons in the anterior horn. Conversely, lower motor neuron
lesions cause flaccid paralysis, hypotonia, hyporeflexia, muscle atrophy, and fasciculations. [674]
Amyotrophic lateral sclerosis causes both upper and lower motor neuron degenerative lesions. Loss of upper motor
neurons leads to atrophy of the precentral motor gyrus and degeneration of the corticospinal tracts. Loss of lower
motor neurons leads to thinning of the anterior roots of the spinal cord and atrophy of cranial nerve motor nuclei.
[675]
Amyotrophic lateral sclerosis causes degeneration of both upper and lower motor neurons and can result in bulbar
and skeletal muscle weakness. Denervation atrophy can affect the diaphragm and contribute to respiratory failure.
[19218]
Cerebellar degeneration
Paraneoplastic syndromes can occur due to the production of hormone-like substances from tumor cells. They can
also result from immune reactions against tumor cells that cross-react with normal cells, causing dysfunction and/or
damage to healthy organs and tissues. Neurologic paraneoplastic syndromes (eg, paraneoplastic cerebellar
degeneration) are an autoimmune phenomenon. [595]
Frontotemporal dementia
Frontotemporal dementia is associated with pronounced atrophy of the prefrontal cortex with later degeneration of
the anterior temporal cortex. It manifests initially with changes in personality, social behavior, and language that
progress over time to a more global dementia with obvious neurocognitive deficits. [594]
Frontotemporal dementia presents with early personality change, executive dysfunction, compulsivity, and
hyperorality. It is associated with neurofibrillary tangles due to abnormal tau proteins (also seen in Alzheimer
dementia) and pathologically ubiquitinated TDP-43 (also seen in amyotrophic lateral sclerosis). [20918]
Huntington disease
Huntington disease is an autosomal dominant neurodegenerative disorder that manifests with chorea (eg,
involuntary, jerky, fidgety movements) and behavioral abnormalities (eg, aggressiveness, depression). Characteristic
neuroimaging findings include atrophy of the caudate nuclei which results in enlargement of the frontal horns of the
lateral ventricles. [632]
Huntington disease is an autosomal dominant neurodegenerative disease that leads to the accumulation of
abnormal, toxic huntingtin protein in neural cells. Inhibitory GABAergic neurons in the caudate nuclei are most
susceptible, and their loss is responsible for the characteristic manifestations of Huntington disease (eg, chorea,
behavioral abnormalities). [902]
Measles
Subacute sclerosing panencephalitis is a rare complication of measles infection that occurs several years after
apparent recovery from initial infection. Oligoclonal bands of measles virus antibodies are found in the cerebrospinal
fluid of these patients. [910]
Parkinson disease
Nigrostriatal degeneration in Parkinson disease impairs thalamic stimulation of the motor cortex, resulting in
bradykinesia, rigidity, and resting tremor. Patients with medically intractable symptoms may benefit from surgery to
decrease output of the globus pallidus interna or subthalamic nucleus, promoting thalamocortical disinhibition with
improvement in Parkinson symptoms. [11462]
Bradykinesia, resting tremor, and rigidity are features of Parkinson disease, which is caused by dopaminergic
neurodegeneration. Traumatic brain injuries can accelerate neurodegeneration, leading to a higher incidence and
earlier onset of Parkinson disease. [106622]
Thiamine deficiency
Oculomotor dysfunction, ataxia, and confusion form the triad of Wernicke syndrome. Most of these symptoms
usually resolve after thiamine administration. Korsakoff syndrome is a chronic and irreversible complication of
Wernicke encephalopathy, the hallmarks of which are permanent memory loss and confabulation. [63]
Thiamine is a cofactor for several enzymes involved in glucose metabolism. A complication of thiamine deficiency is
Wernicke encephalopathy (encephalopathy, ataxia, oculomotor dysfunction), which can be precipitated by a high
glucose load causing rapid depletion of limited thiamine stores. [597]
Vascular dementia
Small artery cerebral arteriolosclerosis can lead to ischemia that predominantly affects the subcortical areas. This can
lead to vascular dementia associated with focal motor deficits, abnormal gait, urinary symptoms, and psychiatric
symptoms. [15446]
Neuronal physiology
The changes in the body of a neuron after the axon has been severed are called axonal reaction. This process reflects
an increased protein synthesis that facilitates axon repair. Enlarged, rounded cells with peripherally located nuclei
and dispersed finely granular Nissl substance are seen. [494]
Seizures
Seizures are classified as either focal onset if they originate from a localized region of one cerebral hemisphere or
generalized if they involve both hemispheres at onset. Focal seizures can be subclassified as retained awareness
(patients remain interactive) or impaired awareness (patients appear awake but do not interact
appropriately). Manifestations of focal seizure depend on the brain region in which the seizure activity occurs. [12175]
Temporal lobe epilepsy is most commonly due to hippocampal sclerosis. Histopathology of hippocampal sclerosis
demonstrates atrophy of the hippocampal neurons with marked reactive gliosis (astrocyte proliferation in response
to injury). [15170]
Syringomyelia
The combination of fixed segmental loss of upper extremity pain and temperature sensations, upper extremity lower
motor neuron signs, and/or lower extremity upper motor neuron signs in the setting of scoliosis suggests
syringomyelia. [1904]
Syringomyelia is characterized by the formation of a cavity (syrinx) in the cervical region of the spinal cord. The syrinx
damages the ventral white commissure, leading to bilateral loss of pain and temperature sensation that is limited to
the affected levels (typically the arms and hands); distal sensation is preserved. Destruction of the motor neurons in
the ventral horns (due to extension of the syrinx) results in flaccid paralysis and atrophy of the intrinsic muscles of the
hand. [503]

Vitamin B12 (cobalamin) deficiency can cause subacute combined degeneration due to impaired myelination in the
ascending dorsal columns and spinocerebellar tracts (diminished position/vibration sense, ataxia), as well as the
descending lateral corticospinal tracts (eg, muscle weakness, spastic paresis). [65]
Child abuse
Abusive head trauma can be caused by vigorous shaking of an infant and results in subdural hemorrhage (due to
tearing of bridging veins) and retinal hemorrhages. Additional red flags are injuries inconsistent with history or
developmental age. [347]
Subdural hematoma
Subdural hematoma occurs due to the rupture of cortical bridging veins. In young patients, it results from a fall or
motor vehicle accident, and manifests with gradual onset of headache and confusion. In elderly patients it may occur
after a minor trauma and present with a variety of neurologic symptoms. You should know how to recognize this on
CT scan. [506]

Brain herniation causes abnormal posturing due to disruption of descending motor tracts (eg, rubrospinal,
vestibulospinal). Damage above the level of the red nucleus (eg, cerebral hemispheres, internal capsule) typically
results in decorticate (flexor) posturing. Damage at or below the red nucleus (eg, midbrain to pons) typically results
in decerebrate (extensor) posturing. [11574]
Diffuse axonal injury (DAI) is a type of traumatic brain injury that results from disruption of the white matter
tracts. Microscopically, DAI is visible as widespread axonal swelling, most pronounced at the gray-white matter
junction, with accumulation of transport proteins (eg, amyloid precursor, alpha-synuclein) at the site of injury. [15678]
TUMORS OF THE NERVOUS SYSTEM
Brain tumors
A cystic tumor in the cerebellum of a child is most likely a pilocytic astrocytoma. Biopsy will show a well-
differentiated neoplasm comprised of spindle cells with hair-like glial processes that are associated with
microcysts. These cells are mixed with Rosenthal fibers and granular eosinophilic bodies. [1153]
Tumors at the cerebellopontine angle can cause unilateral progressive hearing loss due to compression of the
vestibulocochlear nerve (CN VIII). These tumors are most likely vestibular schwannomas or meningiomas; histologic
analysis is often required to differentiate between them. [22063]
Meningiomas are slow-growing, well-circumscribed, benign intracranial tumors typically found at the cerebral
convexities in adults. Characteristic histopathologic features include syncytial nests and a whorled pattern of cellular
growth, which may calcify into round, laminar structures called psammoma bodies. [1151]
Meningiomas arise from the meningothelial cells of the arachnoid. Therefore, when they form in the spinal cord,
they are located within the meninges in the intradural extramedullary space. [22121]
Synaptophysin is a protein found in the presynaptic vesicles of neurons, neuroendocrine and neuroectodermal
cells. CNS tumors of neuronal origin frequently stain positively for synaptophysin on immunohistology. Neoplasms of
glial origin (astrocytomas, ependymomas, and oligodendrogliomas) stain for GFAP. [880]
Glioblastoma multiforme is the most common primary brain tumor in adults. Histopathology showing increased
vascularity and pseudopalisading tumor cells around areas of necrosis is diagnostic. [614]
Glioblastoma is an aggressive primary brain neoplasm that generally presents with slowly worsening headache,
seizure, and/or focal neurologic issues. Most cases are associated with oncogenic mutations that increase epidermal
growth factor receptor expression on the tumor cells, leading to increased transduction of growth signals that
promote cellular survival and proliferation. [15659]
Glioblastoma is the most common primary cerebral neoplasm of adults that is typically located within the cerebral
hemispheres and may cross the midline ("butterfly glioma"). These tumors are highly malignant and grossly contain
areas of necrosis and hemorrhage. [613]
Medulloblastoma is the second most common brain neoplasm of childhood. It is located in the cerebellum, often at
the vermis, and consists of sheets of small, blue cells. Like other "PNET" tumors, medulloblastomas are poorly
differentiated and have a bad prognosis. [1259]
Pilocytic astrocytomas are the most common brain tumors in children. They frequently arise in the cerebellum and
can be differentiated from medulloblastomas by the presence of both cystic and solid components on imaging. [615]
Ependymomas originate from the ependymal cells that line the ventricular system and the central canal of the spinal
cord. Ventricular ependymomas can block the flow of cerebrospinal fluid through the interventricular foramina,
causing signs of increased intracranial pressure (eg, headache, papilledema) due to obstructive (noncommunicating)
hydrocephalus. [15638]
Hemangioma
Cavernous hemangiomas are vascular malformations composed of abnormally dilated capillaries separated by thin
connective tissue septa. The lack of structural support gives them a tendency to bleed, and those that occur in the
brain can present with neurologic deficits and seizures. [12283]
Neuroblastoma
Opsoclonus-myoclonus is a paraneoplastic syndrome associated with neuroblastoma, the most common extracranial
solid neoplasm in children. The tumor typically arises from the neural crest cells of the adrenal medulla and presents
with an abdominal mass and elevated catecholamine breakdown products. [1263]
Pituitary adenoma
Large pituitary adenomas can cause bitemporal hemianopia due to compression of the optic chiasm. [7670]
Prolactinomas, the most common hormonally active pituitary tumors, can cause severe
hyperprolactinemia. Moderate hyperprolactinemia can also occur in nonprolactinoma tumors because prolactin
secretion is under negative regulation by dopamine from the hypothalamus. [7671]
Pituitary tumors
Craniopharyngiomas are suprasellar tumors found in children and composed of calcified cysts containing cholesterol
crystals. They arise from remnants of Rathke's pouch, an embryonic precursor of the anterior pituitary. [1152]
Spinal cord compression

Neoplastic spinal cord compression most commonly results from local extension of vertebral metastases into the
epidural space. Presenting symptoms typically include severe back pain (often worse at night), motor weakness,
and/or sensory deficits. Urinary and fecal retention or incontinence are common late-stage findings. [15591]
Ophthalmology
Diabetic retinopathy
Chronic hyperglycemia in patients with diabetes can lead to increased permeability and arteriolar obstruction in
retinal vessels. The resulting ischemia stimulates production of vascular endothelial growth factor and other
angiogenic factors, leading to neovascularization (proliferative diabetic retinopathy). Complications include retinal
hemorrhage, retinal detachment, and vision loss. [15668]
Hypertensive retinopathy
Severe hypertension in retinal precapillary arterioles causes endothelial disruption, leakage of plasma into the
arteriolar wall, and fibrinous necrosis. The necrotic vessels can then bleed into the nerve fiber layer, which can be
seen on examination as dot- or flame-shaped hemorrhages. [11675]

The pathogenesis of retinopathy of prematurity involves an initial downregulation of proangiogenic factors (eg, VEGF)
due to hyperoxia following delivery. Subsequently, increased metabolic demand causes relative retinal hypoxia,
which stimulates a pathological increase in VEGF leading to aberrant vessel formation. Neonatal oxygen
supplementation increases the risk in premature infants. [799]
Retinoblastoma
Familial retinoblastoma occurs as a result of mutations of each of the two Rb genes ("two hits"). These patients have
an increased risk of secondary tumors, especially osteosarcomas, later in life. [863]
Wilson disease
The Kayser-Fleischer ring is an ophthalmologic finding most strongly associated with Wilson's disease. It is seen most
frequently in patients with neuropsychiatric complications. Basal ganglia atrophy is typically present in these
patients. [398]
CELLULAR PATHOLOGY
Apoptosis
Cytochrome c is a mitochondrial enzyme that activates caspases and indirectly brings about cell death through
intrinsic pathway apoptosis. [297]
Cancer anorexia cachexia syndrome
The ubiquitin-proteasome pathway mediates targeted protein degradation, which allows for rapid disposal of
unneeded intracellular proteins. In cancer-related cachexia, high levels of pro-inflammatory cytokines lead to
increased ubiquitination of sarcomeric muscle proteins, which in turn leads to extensive skeletal muscle loss. [14772]
Compartment syndrome
As an antioxidant, superoxide dismutase neutralizes reactive oxygen species, preventing cell injury. In a pathologic
state such as post-ischemic reperfusion, oxidative stress is high and reactive oxygen species production exceeds the
neutralizing capability of antioxidants, leading to increased cell damage and death. [11916]
Necrosis
Irreversible ischemic injury to brain tissue causes tissue digestion by hydrolytic enzymes (liquefactive necrosis). The
infarcted CNS tissue is eventually replaced with a cystic astroglial scar. In other organs, lethal ischemic injury results
in coagulative necrosis. [177]
Lethal tissue ischemia causes coagulative necrosis in most tissues (eg, kidney, myocardium); cellular architecture is
maintained but nuclei are absent. The exception is ischemic cell death in the CNS, which causes liquefactive necrosis.
[178]
Radiation injury
Ionizing radiation causes cellular and DNA damage primarily through generation of reactive oxygen species, which can
trigger progressive inflammation and tissue damage. In the gastrointestinal tract, the acute effects of radiation
exposure typically occur several weeks after radiotherapy is initiated and manifest as abdominal pain and diarrhea
due to mucosal denudation, inflammation, and edema. [18929]
INFLAMMATION AND REPAIR
Acute phase response

Chronic inflammation is associated with increased circulating pro-inflammatory cytokines (eg, IL-1, IL-6, tumor
necrosis factor-alpha), which stimulates the liver to release acute-phase reactants (eg, C-reactive protein,
fibrinogen). The presence of acute-phase reactants increases the erythrocyte sedimentation rate, a nonspecific
marker for inflammation. [1801]
Ubiquitin proteasome pathway

An essential step in the activation of the cellular immune response to a virus is the breakdown of intracellular viral
proteins by the ubiquitin proteasome pathway. This pathway is initiated by ubiquitin ligases, which recognize specific
protein substrates and attach a ubiquitin tag. The target proteins are then degraded by a proteasome into peptide
fragments, which are coupled with major histocompatibility complex class I proteins and presented on the cell
surface for surveillance by cytotoxic CD8+ lymphocytes. [11674]
Wound healing
Wounds typically heal according to an organized sequence of 4 phases: hemostasis (fibrin clot formation),
inflammation (cellular infiltration), proliferation (reepithelization, fibroplasia, and angiogenesis), and maturation
(collagen remodeling). [20879]
NEOPLASIA
Bone tumor
Osteosarcoma is the most common primary bone malignancy in children and young adults. It occurs most frequently
at the metaphyses of long bones and presents with local pain and swelling. Most cases are associated with sporadic
or inherited mutations in RB1 (hereditary retinoblastoma) and TP53 (Li-Fraumeni syndrome). [15645]
Breast cancer
Estrogen- or progesterone-receptor positivity in breast cancer indicates expected sensitivity to tamoxifen and
aromatase inhibitor treatment. HER2 overexpression in breast cancer suggests a more aggressive tumor that typically
responds to therapy with the anti-HER2 monoclonal antibody trastuzumab. [1762]
Undifferentiated (anaplastic) tumors bear no resemblance to the tissue of origin. They are composed of pleomorphic
cells with large, hyperchromatic nuclei that grow in a disorganized fashion. Anaplastic tumors may also contain
numerous, abnormal mitoses and giant tumor cells. [1759]
Hereditary breast cancer is most commonly associated with mutations in BRCA1 and BRCA2. These tumor suppressor
genes are involved in DNA repair, and their mutations increase the risk of developing breast and ovarian cancer. [1083]
Cytokeratin is a commonly used immunohistochemical marker of epithelial cell carcinomas. [2092]
The HER2 oncogene encodes for a transmembrane glycoprotein with intrinsic tyrosine kinase activity and is a
member of the family of epidermal growth factor receptors. Overexpression of this protein is associated with a
worse prognosis and increased risk of disease recurrence. [2093]
Cancer anorexia cachexia syndrome

Tumor necrosis factor-α is thought to mediate paraneoplastic cachexia in humans by suppressing appetite and
increasing basal metabolic rate. [1039]
Cell cycle
Dihydrofolate reductase and DNA polymerase are enzymes involved in DNA synthesis, which occurs during the S
phase of the cell cycle. The Rb protein, in its active (dephosphorylated) form, regulates cell cycle progression by
preventing the transition from the G1 phase to the S phase. Phosphorylation of the Rb protein inactivates it, allowing
cells to progress through the G1/S checkpoint and proliferate. [1718]
Cervical cancer
Dysplasia, characterized by the disruption of organized epithelial cell differentiation with atypical cells, does not
always progress to malignancy. Mild to moderate dysplastic changes may reverse when the causal factor is
withdrawn. [1753]

Most tumors possess multiple cytogenetic abnormalities. Activation of proto-oncogenes results in stimulation of
cellular proliferation. Inactivation of anti-oncogenes eliminates oversight of the cell cycle. [1760]
The size of adenomatous polyps determines their malignant potential. Adenomas <1 cm are unlikely to undergo
malignant transformation, whereas those >4 cm are very likely to progress to adenocarcinoma. KRAS protooncogene
mutation facilitates the growth of adenomas by causing uncontrolled cell proliferation. [421]
The adenoma to carcinoma sequence is a series of gene mutations that leads to the development of colon
adenocarcinoma. TP53 tumor suppressor gene mutation is part of the final step in the sequence and leads to
malignant transformation of preexisting large adenomatous polyps. [420]
Activating mutations of the KRAS gene lead to constitutive activation of the epidermal growth factor receptor (EGFR)
pathway, promoting increased cell proliferation and growth. Tumors harboring these mutations are resistant to
treatment with anti-EGFR drugs (eg, cetuximab, panitumumab). [12049]
Mutation of the APC tumor suppressor gene is the first step in the classic adenoma-to-carcinoma sequence; it is
found in most cases of sporadic colon cancer and in all patients with familial adenomatous polyposis. The
microsatellite instability pathway is characterized by mutations in DNA mismatch repair genes and is implicated in the
development of hereditary nonpolyposis colorectal cancer (Lynch syndrome). [428]
Familial adenomatous polyposis

Familial adenomatous polyposis is an autosomal-dominant hereditary disorder that results in the formation of
innumerable colonic polyps and a nearly 100% risk of colorectal cancer. It arises due to germline mutation in the
adenomatous polyposis coli tumor suppressor gene. [15021]

Metaplasia is the substitution of one differentiated cell type for another due to the presence of an adverse
environmental stimulus. It is often seen in the bronchi of chronic cigarette smokers (substitution of ciliated columnar
epithelium with stratified squamous cells) and the distal esophagus of patients with chronic gastroesophageal reflux
(substitution of stratified squamous epithelium with intestinal columnar cells). Metaplasia can lead to subsequent
dysplasia and malignant transformation. [285]
General principles of cancer

Malignant cells undergo several changes to metastasize from the site of origin. They detach from other cells by
down-regulating cadherins and detach from the basement membrane by altering integrin expression. They secrete
collagenases to create a path through the extracellular matrix and then enter the bloodstream and/or lymphatic
system to disseminate. [22635]
Hemangioma
The key growth factors that promote angiogenesis in neoplastic and granulation tissue are vascular endothelial
growth factor (VEGF) and fibroblast growth factor. Proinflammatory cytokines (eg, interleukin-1, interferon-γ) can
indirectly promote angiogenesis through increased VEGF expression. The laminin in basement membranes may pose
a physical barrier to the sprouting of new blood vessels. [1873]
Immunohistochemistry
The proteins that compose intermediate filaments (IFs) vary based on tissue type. Cytokeratins are a type of IF
protein found in epithelial cells. Positive staining for cytokeratin in tumor cells suggests that a tumor has epithelial
origin (eg, carcinoma). [1160]
Inflammation
Nuclear factor-kappa B (NF-κB) is a transcription factor with a critical role in the immune response to infection. NF-κB
is normally present in the cytoplasm in a latent, inactive state bound to its inhibitor protein, IκB. Extracellular
substances such as lipopolysaccharide can initiate a signal cascade that results in the destruction of IκB and
translocation of free NF-κB to the nucleus. [11955]
Li-fraumeni syndrome
Li-Fraumeni syndrome is caused by an autosomal dominant mutation in the tumor suppressor gene TP53. Leukemia,
sarcomas, and tumors of the breast, brain, and adrenal cortex are most common. [345]
Lynch syndrome
Hereditary nonpolyposis colon cancer (HNPCC), or Lynch syndrome, leads to occurrence of colonic adenocarcinomas
at a young age (age <50) along with a predisposition for extraintestinal malignancies. Mutations of DNA mismatch
repair genes are responsible for HNPCC. [429]
Matrix metalloprotease
Metalloproteinases are zinc-containing enzymes that degrade the extracellular matrix. They participate in normal
tissue remodeling and in tumor invasion through the basement membrane and connective tissue. [1084]
Nonmelanoma skin cancer

Tumor grade describes how much a tumor's cells resemble normal, mature cells of their type and estimates the cells'
likely aggressiveness. Tumor stage is a marker of a tumor's degree of spread; regional lymph node involvement or
distant metastases indicate a higher stage of disease. [22637]
Oncogenes and tumor suppressor genes

p53 is a tumor suppressor gene that controls cell division and apoptosis. It is inactivated in many tumors. [313]
Inactivation of retinoblastoma protein activity by human papillomavirus can lead to the formation of head and neck
squamous cell carcinoma. [18628]
Prostate cancer
Imaging of bone metastases assists in cancer diagnosis. Bone metastases are characterized as osteolytic or
osteoblastic. Bony pain in an older man with osteoblastic lesions on imaging is highly suspicious for prostate cancer.
[11754]
Retinoblastoma
Retinoblastoma is associated with inactivating mutations of the RB1 tumor suppressor gene, which normally restricts
cells from passing the G1/S checkpoint until the cell is ready to divide. Impaired function of the Rb protein allows
unrestricted progression through the G1/S checkpoint, leading to uncontrolled cell division. [1717]
Thyroid cancer
Medullary thyroid cancer is a neuroendocrine tumor that arises from calcitonin-secreting C (parafollicular) cells. It is
often seen in the context of multiple endocrine neoplasia type 2 (A and B), although the majority of cases are
sporadic. Both sporadic and familial medullary thyroid cancers are associated with mutations in the RET proto-
oncogene. [1660]
Lead poisoning
Lead poisoning can cause neurologic, gastrointestinal, renal, and hematologic complications. Although symptoms can
be vague, lead poisoning should be suspected if these symptoms arise while residing in a home built before
1978. Diagnosis is made by measuring the patient's blood lead level. [11949]
Radiation injury
Ionizing radiation induces DNA damage (eg, double-strand breakage, free radical generation) that predominantly
affects highly proliferative cells (eg, skin stem cells, hematogenous progenitors, intestinal crypt cells). These rapidly
dividing cells are the first to be lost following significant radiation exposure, resulting in hair loss, pancytopenia,
diarrhea, and nausea/vomiting. [19080]
Gestational diabetes
Neonates born to mothers with poorly controlled diabetes during pregnancy are exposed to high maternal glucose
levels in utero, resulting in beta cell hyperplasia followed by excessive fetal insulin production. Fetal
hyperinsulinemia causes neonatal hypoglycemia, polycythemia, and macrosomia. [1440]
Placental accreta
Placenta accreta spectrum occurs due to placental invasion into the myometrium through defects in the decidua
basalis. This creates a morbidly adherent placenta that does not detach after fetal delivery, leading to postpartum
hemorrhage. Manual placental extraction typically yields small placental fragments and increases bleeding. [11891]
Preeclampsia
Patients with preeclampsia are at risk for fetal growth restriction and oligohydramnios due to abnormal placental
spiral artery development, which leads to increased placental vascular resistance, decreased uteroplacental
perfusion, and decreased umbilical vein oxygen delivery. [19392]
Preeclampsia is new-onset hypertension after 20 weeks gestation with signs of end-organ damage (eg,
headache). Renal effects of preeclampsia include oliguria with increased specific gravity, proteinuria, and serum
creatinine levels. [1914]
Syphilis
Patients with an atypical delivery (eg, preterm) require placental evaluation. Umbilical cord inflammation with
abscess-like foci of necrosis suggests congenital syphilis (ie, spirochete infection with Treponema pallidum). [22144]
Torticollis
Congenital torticollis is typically noted by 2 to 4 weeks of age, after which the child prefers to hold the head tilted to
one side. It is most commonly the result of malposition of the head in utero or birth trauma. Most cases resolve with
conservative therapy and stretching exercises. [8325]
Cystic fibrosis
Meconium ileus is a distal small bowel obstruction due to abnormally dehydrated meconium in a patient with cystic
fibrosis (CF). Persistent, treatment-resistant infectious pneumonias, bronchiectasis, and cor pulmonale account for
most deaths due to CF. [803]
Recurrent sinopulmonary infections and exocrine gland fibrotic atrophy in a young patient are suggestive of cystic
fibrosis (CF). CF can lead to pancreatic insufficiency, fat malabsorption, and a deficiency of vitamins A, D, E and
K. Vitamin A maintains orderly differentiation of specialized epithelia, including the mucus-secreting columnar
epithelia of the ocular conjunctiva, respiratory and urinary tracts, and pancreatic and other exocrine
ducts. Avitaminosis A can cause squamous metaplasia of such epithelia to a keratinizing epithelium. [806]
ARDS
Pancreatitis is a major risk factor for acute respiratory distress syndrome as it results in the release of large amounts
of inflammatory cytokines and pancreatic enzymes, which leads to activation of neutrophils in the alveolar
tissues. During the initial phase, interstitial and intraalveolar edema, inflammation, and fibrin deposition cause the
alveoli to become lined with waxy hyaline membranes. [485]
Acute respiratory distress syndrome is characterized by hypoxia and bilateral pulmonary infiltrates and is associated
with pneumonia, sepsis, trauma, and pancreatitis. The associated pulmonary edema is noncardiogenic in nature, so
the pulmonary capillary wedge pressure will be within the normal range (6-12 mm Hg). [486]
Acute respiratory distress syndrome is caused by injury of the pulmonary epithelium and/or endothelium, and occurs
most often due to sepsis or pneumonia. Cytokines recruit neutrophils to the lung tissue, which cause capillary
damage and leakage of protein-rich fluid into the alveoli. Later, cellular proliferation and collagen deposition occurs,
and in some patients, this leads to irreversible pulmonary fibrosis. [1579]
Aspiration pneumonia
Patients with dementia or hemiparesis may have dysphagia, which is a risk factor for aspiration
pneumonia. Dependent lung consolidation is commonly seen in aspiration pneumonia. [2102]
Metabolic acidosis
Lactic acidosis in septic shock results from tissue hypoxia, which impairs oxidative phosphorylation and causes
shunting of pyruvate to lactate following glycolysis. Hepatic hypoperfusion also contributes to the buildup of lactic
acid as the liver is the primary site of lactate clearance. [2101]

Lamellar bodies of type II pneumocytes store and release surfactant, which decreases alveolar surface tension and
facilitates lung expansion. A low lamellar body count reflects surfactant deficiency and lung immaturity, as in
neonatal respiratory distress syndrome, which results in alveolar collapse and diffuse atelectasis. [479]
Pleural effusion
A pleural effusion is a collection of fluid between the visceral pleura that lines the lungs and the parietal pleura that
lines the thoracic cavity. The fluid acts to insulate vibrations and sounds that originate in the airways of the lung;
therefore, tactile fremitus and breath sounds are decreased over a pleural effusion. Dullness to percussion is also
present. [15429]
Pneumothorax
Primary spontaneous pneumothorax occurs in patients without preexisting pulmonary disease when a large change in
the alveolar or intrapleural pressure results in a break in the visceral (eg, ruptured superficial bleb) pleura and air
trapping between the pleural spaces. [490]
Asbestos
Patients with a long history of asbestos exposure are at risk for developing asbestosis, pleural disease, and
malignancies such as bronchogenic carcinoma and mesothelioma. Bronchogenic carcinoma is the most common
malignancy in this population, although mesothelioma is more specific for asbestos exposure. [553]
Malignant mesothelioma is a rare neoplasm typically arising from the pleura. It is strongly associated with asbestos
exposure and presents with progressive dyspnea, cough, and chest pain. Unilateral pleural thickening or plaque
formation is seen on imaging; pleural effusions are also common and may be hemorrhagic. Microscopic examination
reveals tumor cells with numerous long, slender microvilli and abundant tonofilaments. [649]
Asbestos-related pleural disease is characterized by pleural plaques (focal pleural thickening, typically with
calcifications). Common occupational exposures include shipbuilding, insulation manufacturing and application, and
drywall application. Most affected patients remain asymptomatic for 20-30 years following initial exposure. [669]
Hypersensitivity pneumonitis
Hypersensitivity pneumonitis results from an exaggerated immunologic response to an inhaled antigen (eg, mold,
animal protein), and presents with cough and dyspnea of variable acuity. Bronchoalveolar lavage typically shows high
relative lymphocyte count (eg, >20%), which helps support the diagnosis. [19244]
Hypersensitivity pneumonitis involves an exaggerated immunologic response to an inhaled antigen and can have an
acute or chronic presentation. Chronic disease presents with gradually progressive cough, dyspnea, fatigue, and
weight loss, and lung biopsy reveals lymphocytic infiltrate, poorly formed noncaseating granulomas, and septal
fibrosis. [15485]
Interstitial lung disease

Idiopathic pulmonary fibrosis is an interstitial lung disease characterized by chronic progressive dyspnea,
nonproductive cough, inspiratory crackles, and subpleural (peripheral) lung honeycombing. In IPF, repetitive
microinjury to the alveolar epithelium (eg, smoking, acid reflux) is focally repaired by fibroblast proliferation/collagen
deposition instead of normal restoration via type 2 pneumocyte differentiation. [666]
Pulmonary fibrosis presents with gradual-onset progressive dyspnea, nonproductive cough, fatigue, eventual weight
loss, and bilateral reticulonodular opacities on chest x-ray. Pulmonary function tests reveal a restrictive
pattern. Patients with rheumatoid arthritis can develop interstitial lung diseases, both from the pulmonary
manifestations of the disease itself and from certain therapies (eg, methotrexate, cyclophosphamide, sulfasalazine).
[653]
Histologic findings of idiopathic pulmonary fibrosis are most prominent in the lung periphery and include a
heterogeneous mixture of chronic inflammation and patchy interstitial fibrosis, focal fibroblast proliferation, and
formation of fibrotic cystic spaces in a honeycomb pattern. [7648]
Sarcoidosis
Sarcoidosis often presents in young women with the insidious onset of respiratory symptoms (eg, cough, dyspnea,
chest pain) accompanied by fatigue, fever, and weight loss. The characteristic histopathologic feature is noncaseating
granulomas, which consist of aggregates of epithelioid macrophages, frequently with multinucleated giant cells. [795]
Sarcoidosis is a CD4+ T-cell mediated disease, in which large numbers of CD4+ lymphocytes release interferon-gamma
and tumor necrosis factor-alpha to drive macrophage activation and granuloma formation. Bronchoalveolar lavage
fluid in pulmonary sarcoidosis demonstrates a lymphocytic predominance with a high CD4+/CD8+ ratio. [796]
Hypercalcemia in sarcoidosis is caused by parathyroid hormone-independent formation of 1,25-dihydroxyvitamin D

by activated macrophages. This leads to increased intestinal absorption of calcium. [984]
Sarcoidosis is a systemic inflammatory disorder characterized by noncaseating granulomas in a variety of

tissues. Most patients develop liver involvement, which typically manifests as asymptomatic hepatomegaly with mild
liver function test abnormalities. Liver biopsy frequently demonstrates scattered noncaseating granulomas. [798]
Sarcoidosis is an inflammatory disorder characterized histologically by noncaseating granulomas consisting of

aggregates of epithelioid macrophages and multinucleated giant cells. Common manifestations include hilar
adenopathy, pulmonary infiltrates, skin rash, ophthalmic findings, and constitutional symptoms. [1147]
Sarcoidosis commonly presents with hilar adenopathy, pulmonary infiltrates, and skin findings (eg, erythema
nodosum). Biopsy shows noncaseating granulomas composed of epithelioid cells (activated macrophages) and giant
multinucleated cells. Oral glucocorticoids are the initial treatment of choice. [877]
Silicosis
Silicosis is characterized by dyspnea and productive cough occurring years after inhalational exposure to crystalline
silica. Histologically, it is characterized by birefringent silicate particles within dense, whorled collagenous nodules
surrounded by dust-laden macrophages. Radiography typically demonstrates numerous small, rounded nodules
predominant in the upper lobes; calcification of the rim of hilar nodes (eggshell calcification) may also be seen. [668]
LUNG CANCER
Barretts esophagus
Squamous bronchial metaplasia is a reversible, adaptive response to chronic irritation, such as smoking. The normal
columnar epithelium is replaced by squamous epithelium, which is more resistant to irritation but has reduced
mucociliary clearance. Metaplasia also occurs with Barrett esophagus, in which esophageal squamous epithelium is
replaced by intestinal columnar epithelium with goblet cells in response to chronic acid exposure. [1041]
Lung cancer
Adenocarcinoma, the most common pulmonary malignancy, is characterized histopathologically by invasive glandular
cells with abundant cytoplasm and eccentrically placed nuclei; mucin production is common. Imaging typically
demonstrates a discrete mass or pneumonia-like consolidation at the periphery of the lung. [564]
Adenocarcinoma is the most common primary lung cancer in the general population, women, and
nonsmokers. Epidermal growth factor receptor (EGFR) mutations and ALK gene rearrangements are seen more
commonly in nonsmokers and thought to contribute to disease formation in this subgroup. Adenocarcinoma is
typically located peripherally and may be associated with clubbing or hypertrophic osteoarthropathy. [554]
Small cell lung cancer is strongly associated with smoking and is usually centrally located. Histopathology shows
small round/oval cells with scant cytoplasm, hyperchromatic (blue) nuclei, and granular chromatin; abundant mitoses
are also usually seen. Immunohistochemical stains are frequently positive for neuroendocrine markers (eg,
chromogranin, synaptophysin, neural cell adhesion molecule [CD56]). [555]
Small cell carcinoma of the lung is the most aggressive type of lung cancer and is commonly associated with
paraneoplastic syndromes (eg, SIADH, Cushing syndrome). It is thought to have a neuroendocrine origin; tumor cells
express neuroendocrine markers (eg, neural cell adhesion molecule, chromogranin, synaptophysin) and contain
neurosecretory granules in the cytoplasm. [650]
Lung nodule
Hamartomas are common, slow-growing, benign lung neoplasms microscopically characterized by nodules of
disorganized, mature connective tissue (eg, cartilage, fat) and entrapped respiratory epithelium. They are often
detected incidentally by imaging, appearing as well-circumscribed, peripheral, solitary lung lesions. [552]
SIADH
Small cell lung cancer is a neuroendocrine malignancy associated with several paraneoplastic syndromes. It is the
most common cause of syndrome of inappropriate antidiuretic hormone (SIADH) due to ectopic secretion of
antidiuretic hormone. SIADH is characterized by hyponatremia, decreased serum osmolality, and urine osmolality
>100 mOsm/kg H2O. [12293]
MISCELLANEOUS
Atelectasis
An obstructive lesion in a mainstem bronchus can prevent ventilation of an entire lung, leading to large-volume
atelectasis and complete lung collapse. Characteristic findings on chest x-ray include unilateral opacification and
deviation of the mediastinum toward the opacified lung. [2116]
Fat embolism
Fat embolism syndrome most commonly results from the release of fat globules from bone marrow following a long-
bone or pelvic fracture. The fat globules form inflammatory aggregates that cause microvessel obstruction and
systemic inflammation leading to the triad of respiratory distress, neurologic dysfunction, and petechial rash. [197]
Fat embolism syndrome should be strongly suspected in a patient with severe long-bone and/or pelvic fractures who
develops acute-onset neurologic abnormalities, hypoxemia, and a petechial rash. Occlusion of the pulmonary
microvessels by fat globules is an early histologic finding of this syndrome. [1876]
SIDS
Maternal tobacco use during pregnancy and secondhand smoke exposure are associated with an increased risk for
sudden infant death syndrome (SIDS). Pathophysiology of the association between smoke exposure and SIDS may
relate to impaired arousal and cardiovascular response to stimuli (eg, airflow obstruction). [310]

Alpha-1 antitrypsin is the major serum inhibitor of neutrophil elastase. Alpha-1 antitrypsin deficiency typically causes
early-onset panacinar emphysema, predominantly affecting the lower lung lobes. [491]
Alveolar fluid contains neutral proteases (eg, elastases) that are derived from alveolar macrophages and infiltrating
neutrophils. These proteases can cause destruction of terminal lung parenchyma (eg, emphysema) when secreted in
excess or if left unchecked by deficient antiprotease activity. [484]
Asthma
Intermittent respiratory symptoms in a patient with a normal chest x-ray, sputum eosinophils, and reduced FEV1
suggest asthma. Common asthma triggers include exercise, cold air, respiratory infection, and exposure to inhaled
allergens (eg, dust mites, cockroaches, pet dander, mold, pollen). [1925]
COPD
Emphysema (ie, alveolar destruction and enlargement) develops from a combination of inflammation and leukocyte
infiltration, increased protease activity, and oxidative stress, usually in response to cigarette smoke exposure. In
severe disease, large air spaces known as subpleural blebs can form in the lung apices. [15212]
Hyperplasia of the submucosal bronchial glands is the major contributor to bronchial wall thickening in chronic
bronchitis. The Reid index is the ratio of the thickness of the submucosal bronchial glands to the thickness of the
bronchial wall between the epithelial basement membrane and the bronchial cartilage. Higher values correlate with
increased duration and severity of chronic bronchitis. [525]
Cystic fibrosis
Massive, life-threatening hemoptysis is typically due to hemorrhage from the high-pressure bronchial
circulation. Bronchiectasis is a common etiology because chronic airway inflammation causes hypertrophied
bronchial arteries that are prone to rupture with coughing. [19380]
Cystic fibrosis is an autosomal recessive disorder in which a defective chloride channel causes impaired clearance of
thick, viscous airway secretions. Patients typically develop a chronic cough, recurrent pulmonary infections, and
bronchiectasis (dilated bronchial tree). [19382]
Lung transplantation
Chronic rejection is a major problem in lung transplant recipients; it affects small airways, causing bronchiolitis
obliterans. It is characterized by lymphocytic inflammation, fibrosis, and, ultimately, destruction of the bronchioles.
[535]

Infants with secondhand smoke exposure are at increased risk for pneumonia because cigarette smoke affects
alveolar macrophage function and impairs mucociliary clearance. [19657]
Lobar pneumonia is marked by the cytokine-mediated accumulation of neutrophils and proteinaceous material in the
alveoli. Over several days, the proteinaceous material becomes fibrinous, neutrophils are replaced by macrophages,
and macrophages digest the fibrinous exudate, thereby restoring normal lung histology. [531]
Histoplasmosis
Histoplasma capsulatum replicates within macrophages and often spreads from the lungs through the pulmonary
lymphatics to the reticuloendothelial system (eg, spleen, liver). Most healthy individuals quickly contain the infection
within granulomas and do not become ill; a minority develop self-limited pneumonia. Over time, the granulomas at
the initial sites of infection calcify and may be seen incidentally on radiographic imaging. [15061]
Lung abscess
Lung abscess is most often due to aspiration of anaerobic oral bacteria such as Peptostreptococcus, Prevotella,
Bacteroides, and Fusobacterium species. Risk factors for lung abscess include conditions that increase aspiration risk,
such as alcoholism, drug abuse, seizure disorders, previous stroke, and dementia. [533]
Lung cancer
The most common cause of digital clubbing in adults is pulmonary malignancy (especially lung
adenocarcinoma). More generally, clubbing is a sign of chronic cardiopulmonary disease associated with activation of
hypoxic-inflammatory signaling (eg, chronic chest infections, right-to-left shunting). [820]

Parapneumonic effusions are exudative by Light criteria and are classified into uncomplicated and
complicated. Uncomplicated parapneumonic effusions result from movement of sterile exudate into the pleural
space, whereas complicated parapneumonic effusions involve inflammatory disruption of the visceral pleural
membrane with bacterial translocation into the pleural space. [14927]
Tuberculosis
Primary tuberculosis causes the formation of Ghon foci in the lower lungs. Secondary (reactivation) tuberculosis
occurs in patients with prior tuberculosis infection that never cleared completely. Reactivation tuberculosis occurs
most often in immunosuppressed patients and is characterized by apical cavitary lesions and hemoptysis. [1219]
The Ghon complex describes the two initial sites (lower lobe of lung, ipsilateral hilar lymph node) of primary
tuberculosis infection. Over time, these sites become calcified and fibrosed and can be visualized on gross pathology
and radiographic imaging (Ranke complex). [1221]
Control of Mycobacterium tuberculosis infection is mediated primarily by activated macrophages, which surround
extracellular mycobacteria and wall them off within granulomas. The release of digestive enzymes by these cells not
only helps control the infection, but also leads to damage of the surrounding tissue and the formation of cavitary lung
lesions. [1222]
PULMONARY VASCULAR DISEASE
Acute heart failure

Acute pulmonary edema is a common consequence of acute myocardial infarction affecting the left
ventricle. Elevated hydrostatic pressure in the pulmonary venous system leads to engorged alveolar capillaries with
transudation of fluid into the alveoli, appearing as acellular pink material on microscopy. Hemosiderin-laden
macrophages are indicative of chronic lung congestion and are not present acutely. [1881]
Kaposi sarcoma
Kaposi sarcoma (KS), a vascular tumor associated with human herpesvirus 8, often arises in immunosuppressed
patients (eg, HIV infection). KS typically involves the skin but can also affect the viscera, including the gastrointestinal
tract (eg, abdominal pain) and pulmonary system (eg, cough, hemoptysis). Biopsy shows spindle-shaped endothelial
cells forming slit-like vascular spaces, extravasated red blood cells, and inflammation. [107526]
Pulmonary embolism
Ventilation-perfusion (V/Q) scans use radiotracers to compare the ventilation and blood perfusion of each area of the
lung. V/Q mismatch with perfusion defects are often indicative of a pulmonary embolism, which are most commonly
caused by deep vein thrombosis in the lower extremities that embolizes to the pulmonary vasculature. [476]
Massive pulmonary embolism can lead to sudden cardiac death (SCD) due to a sudden loss of cardiac output. Less
commonly, SCD may result from cardiac arrhythmia triggered by right ventricular strain and ischemia. [15070]
The risk of venous thromboembolism (ie, pulmonary embolism or deep vein thrombosis) in hospitalized patients can
be greatly reduced with the administration of prophylactic anticoagulation, usually with low-molecular-weight
heparin. [529]
Pulmonary infarcts are typically hemorrhagic (red) and wedge-shaped in the periphery of the lung. Intravenous drug
users are at increased risk of tricuspid valve endocarditis, which can cause multiple septic pulmonary infarcts due to
embolization of tricuspid valve vegetation fragments. [975]
Systemic sclerosis
Pulmonary arterial hypertension, a vascular complication of systemic sclerosis, involves fibroproliferative remodeling
of the vessel wall, leading to increased pulmonary vascular resistance and right-sided heart failure. [825]
ACUTE KIDNEY INJURY
Acute kidney injury

Ischemic acute tubular necrosis primarily involves the corticomedullary junction (ie, proximal convoluted tubule) and
the outer medulla (ie, thick ascending loop) due to a mismatch in oxygen supply and demand. [7242]
Acute tubular necrosis can be caused by ischemia or nephrotoxins. Potential nephrotoxins include aminoglycosides,
amphotericin B, radiographic contrast dye, heavy metals, and myoglobin. [7243]
Acute tubular necrosis is characterized by focal tubular epithelial necrosis with denuding of the basement
membrane. Most patients experience tubular re-epithelization and regain normal renal function. [1053]
Surgeries complicated by significant blood loss or those requiring the use of cardiopulmonary bypass or clamping of
the aorta can cause sustained renal hypoperfusion and result in acute tubular necrosis (ATN). ATN presents with
oliguria, increased serum creatinine, and blood urea nitrogen/creatinine ratio <20:1. Urinalysis is characterized by
muddy brown granular casts composed of sloughed renal tubular epithelial cells. [15225]
Acute tubular necrosis can be caused by renal ischemia and is characterized by oliguria, increased serum creatinine,
and muddy brown casts. Ischemic injury predominantly affects the renal medulla, which has a relatively low blood
supply. The proximal tubules and the thick ascending limb of the loop of Henle are the most commonly involved
portions of the nephron. [885]
Contrast-induced nephropathy is characterized by an acute rise in creatinine and blood urea nitrogen after radiologic
contrast administration, followed by a gradual return to baseline. It is characterized histologically by diffuse necrosis
of the proximal tubular cells (acute tubular necrosis). Urinalysis usually demonstrates muddy brown casts. [18667]
Acute tubular necrosis is characterized by tubular injury due to renal ischemia or direct cytotoxicity. The course of
the disease takes place in 3 stages: initiation (initial insult), maintenance (oliguric renal failure), and recovery. During
the recovery stage, glomerular filtration rate improves prior to restoration of renal tubular resorptive capacity, so
transient polyuria and electrolyte wasting (eg, hypokalemia) can occur. [886]
Ethylene glycol ingestion causes acute tubular necrosis with vacuolar degeneration and ballooning of the proximal
tubular cells. Typical clinical findings include altered mentation, renal failure, high anion gap metabolic acidosis,
increased osmolar gap, and calcium oxalate crystals in the urine. [887]
Aminoglycoside
Aminoglycosides are filtered across the glomerulus and concentrate in the renal tubules, leading to proximal tubular
injury and acute tubular necrosis. This is visualized histologically as focal tubular epithelial necrosis, often with
extensive granular casts that obstruct the tubular lumen and lead to rupture of the basement membrane. [15227]
Atheroembolism
Invasive vascular procedures can be complicated by atheroembolic disease, which may involve the kidneys,
gastrointestinal tract, CNS, and the skin. Light microscopy shows a partially or completely obstructed arterial lumen
with needle-shaped cholesterol clefts within the atheromatous embolus. [810]
Interstitial nephritis
Acute interstitial nephritis is a common cause of renal dysfunction; up to 75% of cases are due to medications
including nonsteroidal anti-inflammatory drugs, antibiotics, diuretics, and proton pump inhibitors. Presenting
features include fever, rash, and eosinophilia. Urinalysis often demonstrates pyuria and white blood cell casts with
elevated urine eosinophils. [15172]
Fever, maculopapular rash, and acute renal failure occurring 1-3 weeks after beginning a new medication (eg,
antibiotics, proton pump inhibitors) is highly suggestive of acute interstitial nephritis. Peripheral eosinophilia, sterile
pyuria, eosinophiluria, and white blood cell casts may also be seen. Histology reveals leukocyte infiltration and
edema of the renal interstitium. [835]
Multiple myeloma
Multiple myeloma should be suspected in elderly patients with any combination of hypercalcemia, normocytic
anemia, bone pain, elevated gamma gap, or renal failure. Renal failure is commonly caused by light chain cast
nephropathy; large, waxy, eosinophilic casts composed of Bence Jones proteins are seen in the tubular lumen. [1054]
NSAIDs
Patients with intravascular volume depletion (eg, congestive heart failure, diarrhea, excessive diuresis) and chronic
kidney disease depend on renal prostaglandin production to dilate the afferent glomerular arteriole and maintain the
glomerular filtration rate. Nonsteroidal anti-inflammatory drugs inhibit prostaglandin synthesis, which can cause
prerenal azotemia in at-risk patients. [15229]
Prerenal azotemia
Blood volume loss can cause prerenal or intrinsic acute renal failure (ARF). Prerenal ARF is associated with normal
nephron function (eg, low urine sodium level, low fractionated sodium excretion, high urine osmolarity, and a high
BUN/creatinine ratio), whereas intrinsic ARF features diminished renal reabsorptive capacity (eg, lower urine
osmolarity, higher urinary sodium, normal serum BUN/creatinine ratio). [7624]
Hypovolemia results in a reduced renal plasma flow (RPF) and glomerular filtration rate (GFR). This leads to
compensatory efferent arteriolar vasoconstriction, which raises the filtration fraction and maintains GFR at near-
normal levels. As RPF continues to decline, increasing glomerular oncotic pressure will eventually overwhelm the
compensatory increase in hydrostatic pressure, leading to a precipitous drop in GFR and renal failure. [1016]
Rhabdomyolysis
Rhabdomyolysis is characterized by the release of intracellular muscle contents (eg, myoglobin, electrolytes) due to
myocyte injury; it is common with crush injuries, seizures, or drug use (eg, statins). Heme pigment (released from
myoglobin after degradation in the kidney) is toxic to tubular cells and can cause acute tubular necrosis. Positive
blood on urine dipstick in the absence of red blood cells on microscopic urinalysis suggests myoglobinuria. [15218]
Rhabdomyolysis usually presents with myalgia, proximal muscle weakness, and dark urine (myoglobinuria) in the
setting of trauma, sepsis, or overexertion. Kidney injury occurs due to heme pigment-mediated tubular injury,
leading to acute tubular necrosis. Urine microscopy typically reveals granular, muddy brown casts. [15217]
Systemic sclerosis
Scleroderma renal crisis (SRC) is a life-threatening complication of systemic sclerosis characterized by acute renal
failure and severe hypertension. SRC is caused by immune-mediated injury to small renal vessels that leads to
reduced renal perfusion due to vascular narrowing and obliteration. [19446]
CHRONIC KIDNEY DISEASE
Chronic kidney disease

Chronic kidney disease usually causes hyperphosphatemia (binds serum Ca2+) and low 1,25-dihydroxyvitamin D
(decreases intestinal Ca2+ absorption and Ca2+ release from bone). The resulting hypocalcemia stimulates release of
parathyroid hormone, causing secondary hyperparathyroidism. [979]
Osteitis fibrosa cystica is a form of renal osteodystrophy characterized by abnormally high bone turnover caused by
chronic parathyroid hormone stimulation of osteoclasts to a greater degree than that of osteoblasts. Bone biopsy
would show an increased number of both osteoclasts and osteoblasts. [1663]
Chronic kidney disease causes disordered mineralization and bone metabolism that usually presents with
hyperphosphatemia, secondary hyperparathyroidism, and decreased calcitriol levels. Patients can be asymptomatic
or develop weakness, bone pain, and fractures. [11977]
Hypertensive nephropathy
Homogeneous deposition of eosinophilic hyaline material in the intima and media of small arteries and arterioles
characterizes hyaline arteriolosclerosis. This is typically produced by untreated or poorly controlled hypertension
and/or diabetes. [455]
NSAIDs
Analgesic nephropathy is a form of chronic kidney disease caused by prolonged, heavy intake of nonsteroidal anti-
inflammatory drugs and/or acetaminophen. Pathologic characteristics include chronic interstitial nephritis and
papillary necrosis. [1049]
Hyperplastic arteriosclerosis ("onion-skinning") and fibrinoid necrosis of the renal arterioles are typical morphologic
findings in hypertensive (malignant) nephrosclerosis. End-organ damage can be prevented by treatment of high
blood pressure with antihypertensives. [7571]
Chronic hypertension can result in hypertensive nephrosclerosis, which is characterized by compensatory medial
hypertrophy and fibrointimal proliferation; endothelial damage from elevated systemic pressure also leads to hyaline
arteriolosclerosis. The narrowed arteriolar lumens cause a progressive decrease in renal blood flow, resulting in
glomerular ischemia and fibrosis (glomerulosclerosis). [7570]
Cystinuria
Cystinuria results from defective cystine reabsorption by proximal renal tubular epithelial cells. It most often
presents with recurrent stone formation at a young age. Urinalysis shows pathognomonic hexagonal cystine crystals,
and the sodium cyanide-nitroprusside test can be used to detect excess cystine in the urine. [814]
Diabetes insipidus
Vasopressin-2 receptor mutations are a cause of congenital nephrogenic diabetes insipidus, a condition in which renal
resistance to antidiuretic hormone results in excessive urinary water losses. Expected findings include high baseline
serum osmolality (typically with hypernatremia), persistently dilute urine after water deprivation (low urine
osmolality), and lack of response to desmopressin. [18560]

Fibromuscular dysplasia is characterized by abnormal tissue growth within arterial walls, resulting in stenotic and
tortuous arteries that can cause tissue ischemia and are prone to aneurysm formation. Pathology typically
demonstrates alternating fibromuscular webs and aneurysmal dilation with absent internal elastic lamina (string-of-
beads appearance). Renovascular hypertension occurs due to renal artery stenosis and activation of the renin-
angiotensin-aldosterone system. [15247]
Marked unilateral kidney atrophy is suggestive of renal artery stenosis. It occurs in elderly individuals due to
atherosclerotic narrowing of the renal artery and is often seen in association with other atherosclerotic risk factors or
diseases (eg, chronic mesenteric ischemia, coronary artery disease, peripheral vascular disease). Hypertension and
abdominal and flank bruits are often present. [832]
Vesicoureteral reflux
Vesicoureteral reflux is characterized by retrograde urine flow from the bladder into the ureter. Affected patients are
at increased risk of chronic pyelonephritis and subsequent renal scarring (eg. dilated calyces with overlying cortical
atrophy). [833]
CYSTIC KIDNEY DISEASES
Polycystic kidney disease

Autosomal dominant (adult) polycystic kidney disease is caused by mutations in the polycystin genes (PKD1, PKD2),
which result in cystic enlargement of the kidneys and progressive renal dysfunction. Clinical features include
hypertension, abdominal/flank pain, and gross hematuria; extrarenal manifestations include liver cysts and
intracranial aneurysms. [3]
Autosomal dominant polycystic kidney disease typically manifests in patients age 40-50 with enlarged kidneys, flank
pain, and hypertension. In newborns, the kidneys are of normal size, and the cysts are too small to be detected on
abdominal ultrasonography. As the cysts enlarge, they compress the renal parenchyma and cause symptoms. [1052]
Diabetic ketoacidosis
Metabolic acidosis is characterized by a decrease in serum pH and serum bicarbonate. PaCO2 will also decrease due
to respiratory compensation for the primary metabolic acidosis. [2072]
The treatment of choice for diabetic ketoacidosis is intravenous normal saline and insulin. These therapies increase
serum bicarbonate and sodium levels, lower serum glucose and potassium levels, and decrease overall serum
osmolarity. [2073]
Metabolic alkalosis
Severe vomiting characteristically causes hypokalemic, hypochloremic metabolic alkalosis. The metabolic alkalosis is
initiated by loss of gastric H+ from the body, worsened by hypovolemia-induced activation of the renin-angiotensin-
aldosterone system, and perpetuated by profound gastric and renal losses of Cl− that lead to hypochloremia and
impaired renal HCO3− excretion. Hypokalemia primarily results from aldosterone-mediated renal K+ losses. [18871]
GLOMERULAR DISEASES
Amyloidosis
:Beta2-microglobulin is renally cleared and poorly dialyzed. It accumulates as amyloid in dialysis patients, increasing
in prevalence with dialysis duration, and has a predilection for osteoarticular surfaces. Shoulder pain and carpal
tunnel syndrome are common. Bone cysts and pathologic fractures may also occur. [7625]
AA amyloidosis results from excessive serum amyloid A produced in rheumatoid arthritis and other chronic
inflammatory conditions. Renal disease, the most common manifestation, presents as nephrotic syndrome. Light
microscopy shows amorphous pink deposits with apple-green birefringence on Congo red stain under polarized light.
[7628]
Renal amyloidosis typically presents with proteinuria and nephrotic syndrome. The diagnosis is confirmed by kidney
biopsy showing apple-green birefringence with Congo red stain under polarized light. Serum protein electrophoresis
demonstrating a monoclonal protein helps establish the diagnosis of immunoglobulin light chain (AL) amyloidosis.
[7611]
Anti GBM disease

Goodpasture syndrome is caused by autoantibodies against the alpha 3 chain of type IV collagen in glomerular and
alveolar basement membranes (anti-GBM antibodies). Patients typically present with rapidly progressive
glomerulonephritis (nephritic syndrome) and alveolar hemorrhage (shortness of breath, hemoptysis). [7]
Diabetic kidney disease

Moderately increased albuminuria (urine albumin 30-300 mg/day) is the earliest manifestation of diabetic
nephropathy. Screening for diabetic nephropathy is best achieved using an albumin-specific urine assay (regular
dipstick urinalysis has low sensitivity). [1913]
Nodular glomerulosclerosis is characterized by increased mesangial matrix deposition, forming Kimmelstiel-Wilson
nodules. It is most commonly caused by diabetic nephropathy and indicates irreversible glomerular damage with a
rapid decline in kidney function. [884]
Endocarditis
The most likely cause of fever and fatigue with new-onset cardiac murmur is infective endocarditis (IE). Diffuse,
proliferative glomerulonephritis secondary to circulating immune complex deposition may complicate IE and can
result in acute renal insufficiency. [229]
Glomerular disorders
Minimal change disease is the most common cause of nephrotic syndrome in children. Systemic T-cell dysfunction
leads to the production of glomerular permeability factor, which causes podocyte foot process fusion and decreases
the anionic properties of the glomerular basement membrane. The loss of negative charge leads to selective
albuminuria. [383]
Crescent formation on light microscopy is diagnostic for rapidly progressive glomerulonephritis. Crescents consist of
glomerular parietal cells, lymphocytes, and macrophages along with abundant fibrin deposition. Crescents eventually
become fibrotic, disrupting glomerular function and causing irreversible renal injury. [24]
Minimal change disease is caused by immune dysregulation and overproduction of a glomerular permeability factor,
which damages podocytes and decreases the anionic properties of the glomerular basement membrane. This results
in selective loss of albumin in the urine, in contrast to the nonselective proteinuria seen in other forms of nephrotic
syndrome. [385]
Minimal change disease is the most common childhood nephrotic syndrome. Increased glomerular capillary
permeability causes massive protein (eg, albumin) loss in the urine. Hypoalbuminemia reduces plasma oncotic
pressure, which causes a fluid shift into the interstitial space, resulting in edema. Low oncotic pressure also triggers
increased lipoprotein production in the liver (ie, hyperlipidemia). [28]
Minimal change disease is the most common cause of nephrotic syndrome in children. Classic manifestations include
proteinuria, hypoalbuminemia, and edema that are usually reversible with corticosteroids. The principal lesion is a
diffuse foot process effacement that can be seen on electron microscopy. Light and immunofluorescence microscopy
are normal. [384]
Immune glomerular injury results from immune complexes (ICs) or neutrophil activation. IC formation in the kidney
typically produces renal-limited disease (except anti–glomerular basement membrane disease). Preformed
circulating IC deposition is usually associated with small vessel vasculitis and hypocomplementemia. [16598]
IgA nephropathy (Berger disease) frequently presents as recurrent, self-limited, painless hematuria; episodes often
occur concurrently with an upper respiratory tract infection. Kidney biopsy will show mesangial IgA deposits on
immunofluorescence. In contrast, poststreptococcal glomerulonephritis is seen 1-3 weeks after streptococcal
pharyngitis and is usually not recurrent. [10]
Minimal change disease is the most common cause of nephrotic syndrome in children. It is often idiopathic but may
be triggered by drugs, immunizations, or malignancy. Light microscopy shows normal glomeruli, with no
immunoglobulin or complement deposits on immunofluorescent staining. However, electron microscopy shows
diffuse podocyte foot process effacement and fusion. [15355]
Penicillamine is a copper-chelating agent used as first-line treatment in Wilson disease. Adverse effects include
nephrotic syndrome (ie, proteinuria) due to membranous nephropathy. [19550]
Membranous nephropathy is a common cause of nephrotic syndrome in adults and can occur in association with solid
malignancy, viral hepatitis, and systemic lupus erythematosus. Immune-complex deposition in the subepithelial
portion of the glomerular capillary wall causes diffuse thickening of the glomerular basement membrane (without
increased cellularity); these glomeruli have a "spike and dome" appearance when stained with a silver stain. [382]

Pauci-immune rapidly progressive glomerulonephritis frequently occurs as a manifestation of antineutrophil
cytoplasmic antibodies (ANCA)-associated vasculitides (eg, granulomatosis with polyangiitis, microscopic
polyangiitis). It is characterized by glomerular crescent formation without immunoglobulin or complement deposits.
[13]

Hemolytic uremic syndrome is a common cause of acute renal failure in children. It is characterized by the triad of
microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Most cases develop following a
diarrheal illness caused by Shiga toxin-producing organisms (eg, Escherichia coli O157:H7, Shigella dysenteriae). [1849]
IgA nephropathy
IgA nephropathy is characterized as recurrent hematuria that occurs spontaneously or within a few days of upper
respiratory or pharyngeal infection (synpharyngitic hematuria). Unlike other causes of immune complex–mediated
nephritic syndromes (eg, poststreptococcal glomerulonephritis), IgA nephropathy is associated with normal serum
complement levels. [15353]
IgA vasculitis
Henoch-Schönlein purpura is an IgA-mediated leukocytoclastic vasculitis that commonly causes lower extremity
palpable purpura, abdominal pain (± gastrointestinal bleeding), renal disease (eg, hematuria), and joint pain. [1850]
Membranous nephropathy
Membranous nephropathy is a common cause of nephrotic syndrome in adults. Electron microscopy of the
glomerular capillary demonstrates irregular, subepithelial, electron-dense immune deposits on the glomerular
basement membrane with moderate effacement of the podocyte foot processes; immunofluorescence microscopy
demonstrates a diffuse granular pattern of IgG along the capillary loops. [15346]
Primary (idiopathic) membranous nephropathy is associated with IgG4 antibodies to the phospholipase A2 receptor,
which might play a role in development of the disease. Antibody titers are useful for diagnosis and correlate with
disease activity. [2131]
Poststreptococcal glomerulonephritis is the most common cause of nephritic syndrome in children. Light microscopy
demonstrates enlarged, hypercellular glomeruli. Laboratory findings in poststreptococcal glomerulonephritis include
elevated antistreptococcal antibodies (eg, antistreptolysin O, anti–DNase B) and decreased C3 and total complement
levels. C4 levels are usually normal. [12]
Poststreptococcal glomerulonephritis presents most commonly in children with hematuria, hypertension, and
periorbital edema. Red blood cell casts and mild proteinuria may be present on urinalysis, and serum creatinine may
be elevated. [1]
Poststreptococcal glomerulonephritis presents with edema, hypertension, and hematuria after a streptococcal
infection. Most children recover completely, but adult patients have a relatively poor prognosis and higher risk of
chronic hypertension and renal insufficiency. [25]
Poststreptococcal glomerulonephritis is an immune complex–deposition disease that occurs 2-4 weeks after exposure
to group A beta-hemolytic Streptococcus species (eg, pharyngitis, skin infection). Light microscopy shows enlarged,
hypercellular glomeruli. Immunofluorescence demonstrates "lumpy-bumpy" granular deposits of IgG and C3 on the
glomerular basement membrane, and subepithelial, electron-dense deposits are seen on electron microscopy. [11]
SLE
Systemic lupus erythematosus is an autoimmune disease characterized by the formation of antinuclear antibodies
(eg, anti-DNA antibodies). Lupus nephritis occurs primarily due to the formation of immune complexes containing
DNA and anti-DNA in the circulation. These are deposited in the glomerulus where they result in complement
activation, recruitment of inflammatory cells, and renal injury (type III hypersensitivity). [15619]

Primary thrombotic microangiopathy (TMA) syndromes share common clinical and pathologic features and result in
platelet activation and diffuse microthrombosis in arterioles and capillaries. They present with hemolytic anemia,
schistocytes, thrombocytopenia, and organ injury (eg, brain, kidneys). [11608]
MISCELLANEOUS
Renal infarction
Renal infarctions are most commonly caused by cardioembolic disease; atrial fibrillation is the greatest risk
factor. Clinical features include flank pain, nausea, vomiting, low-grade fever, and hypertension (due to renin release
from hypoxic tissue). Gross pathology demonstrates sharply demarcated, yellow-white, wedge-shaped areas with
surrounding hyperemia. [15288]
Renal papillary necrosis

Renal papillary necrosis classically presents with gross hematuria, acute flank pain, and passage of tissue fragments in
urine. It is most commonly seen in patients with sickle cell disease or trait, diabetes mellitus, analgesic nephropathy,
or severe obstructive pyelonephritis. [834]
Bladder cancer
Urothelial (transitional cell) bladder cancer typically affects the elderly and presents with gross hematuria. A history
of smoking or occupational exposure to rubber, plastics, aromatic amine–containing dyes, textiles, or leather
increases the risk. [7623]
Urothelial (transitional cell) carcinoma is the most common type of bladder cancer. Tumor stage is the most
important factor for determining prognosis and is based on the depth of invasion into the bladder wall and the
degree of regional (eg, lymph nodes) and metastatic spread. Tumor invasion into the muscularis propria layer of the
bladder wall carries an unfavorable prognosis. [336]
Major risk factors for urothelial cancer of the bladder include age >60, cigarette smoking, and occupational exposure
to rubber, plastics, or aromatic amine-containing dyes. Cyclophosphamide therapy also increases the risk. [15186]
Renal cell carcinoma

Renal cell carcinoma tends to invade the renal vein; inferior vena cava obstruction can occur by intraluminal
extension of the tumor. Obstruction of the inferior vena cava produces symmetric bilateral lower extremity edema,
often associated with prominent development of venous collaterals in the abdominal wall. [7226]
Renal cell carcinoma causes a variety of paraneoplastic syndromes including erythrocytosis (due to excessive
erythropoietin production) and hypercalcemia (due to parathyroid hormone–related peptide). [7227]
Renal cell carcinoma may present with a combination of hematuria, abdominal mass, or flank pain; however, this
triad occurs together in <10% of cases. Pathology demonstrates rounded, polygonal cells with clear cytoplasm. Risk
factors include smoking, toxin exposure, and certain hereditary disorders (eg, von Hippel-Lindau syndrome). [15176]
The most common renal malignancy is clear cell carcinoma, which arises from renal proximal tubular cells. Rounded
or polygonal cells with abundant clear cytoplasm are seen on light microscopy. The cells contain large amounts of
glycogen and lipids that dissolve during routine tissue preparation, leaving clear spaces within the cytoplasm. [1862]
Clear cell carcinoma is the most common subtype of renal cell carcinoma and is composed of large, rounded, or
polygonal cells with clear cytoplasm. These tumors are often detected incidentally at an advanced stage; the lung is
the most common site for metastasis, followed by osteolytic bone and liver. [818]
Clear cell carcinoma is the most common type of renal cell carcinoma and originates from the epithelial cells of the
proximal renal tubules. Gross pathology typically demonstrates a sphere-like mass composed of golden-yellow cells
(due to high lipid content) with areas of necrosis and hemorrhage. [905]
Classic signs and symptoms of renal cell carcinoma (RCC) include hematuria, an abdominal mass, flank pain, and
weight loss. Hypercalcemia and erythrocytosis are common paraneoplastic syndromes associated with RCC. [11806]

Benign prostatic hyperplasia (BPH) is associated with stromal and glandular growth in the periurethral and
transitional zone of the prostate. The hyperplastic cells are supported by the formation of new blood vessels, which
may be friable. Therefore, BPH is often associated with microscopic or gross hematuria. [14797]
Benign prostatic hyperplasia leads to progressive bladder outlet obstruction. Over time, increased urinary pressures
can cause hydronephrosis and renal parenchymal atrophy with scarring. This can progress to chronic kidney disease.
[811]
Benign prostatic hyperplasia can increase resistance to urine flow in the urethra and lead to incomplete bladder
emptying during micturition. The residual urine can act as a growth medium for pathogenic bacteria and increase the
risk for urinary tract infection. [14798]
Hyperparathyroidism
Most kidney stones are made of calcium salts and are idiopathic, but conditions that increase renal calcium excretion
can increase the risk of stones. Hyperparathyroidism is a common cause of recurrent kidney stones and is typically
associated with mild hypercalcemia and hypophosphatemia. [15270]
Prostate cancer
Fibrosis and strictures are late effects of radiation therapy. Radiotherapy for prostate cancer may lead to urethral
fibrosis and result in obstructive uropathy. [7631]
Renal calculi
Urine supersaturation is the main mechanism underlying all types of renal stones. Low fluid intake increases the
concentration of stone-forming agents, thereby promoting stone formation. All patients with nephrolithiasis should
be advised to maintain adequate fluid intake. [816]
Formation of uric acid kidney stones is promoted by low urine pH, which favors formation of insoluble uric acid over
soluble urate ion. Gastrointestinal bicarbonate loss due to chronic diarrhea leads to chronic metabolic acidosis and
production of acidic urine, promoting formation of uric acid stones. [12081]
Renal calculi occur due to an imbalance of the factors that facilitate or inhibit stone formation. Increased urinary
concentrations of calcium, oxalate, and uric acid promote salt crystallization, whereas increased urinary citrate
concentration and high fluid intake prevent calculi formation. [817]
Urine sediment in acute ureterolithiasis typically shows free red blood cells (hematuria) and crystals consistent with
the type of stone. Ultrasound can reveal ureteral and calyceal dilation (hydronephrosis), but small stones themselves
may not be visible. [15271]
Staghorn calculi are large renal stones that take on the shape of the renal calyces. They are composed primarily of
struvite (magnesium ammonium phosphate) and are associated with recurrent upper urinary tract infections by
urease-producing organisms (eg, Proteus, Klebsiella). Hydrolysis of urea yields ammonia, which alkalinizes the urine
and facilitates precipitation of struvite crystals. [6739]
Struvite stones are typically seen in patients with recurrent upper urinary infection by urease-producing organisms
(eg, Proteus, Klebsiella). Hydrolysis of urea yields ammonia, which alkalinizes the urine and facilitates precipitation of
magnesium ammonium phosphate. Urinalysis shows hematuria and elevated urine pH. [15259]

Acute urinary retention is characterized by anuria and bladder distension and can result in hydronephrosis and acute
kidney injury. A palpable, distended bladder is present on examination, and abdominal and flank pain may be
present. The most common cause of urinary retention is bladder outlet obstruction (urethral compression) due to
benign prostatic hyperplasia. [15200]
The ureters run in close proximity to the pelvic lymph nodes and the uterine artery in the female pelvis, which
predisposes them to injury during pelvic surgery. [1916]
Ankylosing spondylitis is an inflammatory spondyloarthropathy characterized by simultaneous erosion of bone and
new bone formation. Bone erosions occur primarily in vertebral bodies; however, new bone formation typically
occurs at the junction of the periosteal margin and adjacent cartilage, leading to bridging syndesmophytes and
ankylosis. This causes spinal rigidity, postural alterations, and increased risk of fracture. [19491]
Ankylosing spondylitis presents with chronic back pain with reduced spinal mobility. X-rays of the spine and pelvis
can aid in diagnosis by identifying specific findings such as sacroiliitis (eg, joint erosions with subchondral sclerosis
and eventual ankylosis) and bridging syndesmophytes (heterotopic ossification affecting vertebral body margins).
[19492]
Hemochromatosis
Hereditary hemochromatosis is an autosomal recessive disease characterized by excessive gastrointestinal absorption
of iron, which is then stored as hemosiderin in various tissues. Secondary arthritis is common and typically involves
the second and third metacarpophalangeal joints. Other manifestations include liver disease, skin
hyperpigmentation, diabetes mellitus, pituitary hormone deficiencies (eg, central hypogonadism), and
cardiomyopathy. [15663]
Lung cancer
Hypertrophic osteoarthropathy is characterized by abnormal growth of new bone and presents with digital clubbing,
painful arthropathy, periostosis of long bones, and joint effusions. It commonly occurs in the setting of pulmonary
malignancy, primarily adenocarcinoma, other lung disorders (eg, cystic fibrosis, bronchiectasis), and cyanotic heart
disease. [19443]
Osteoarthritis
Osteoarthritis is characterized by progressive fissuring and erosion of articular cartilage. Risk factors include
advancing age, obesity, joint trauma, and repetitive stress. Patients may have mild effusion and crepitus on physical
examination, but signs of synovitis (eg, redness, warmth) are less prominent than in the classic inflammatory arthritic
disorders. [7556]
Osteoarthritis of the hands is characterized by osteophyte formation leading to hard bony enlargement of the distal
interphalangeal joints (Heberden nodes) and proximal interphalangeal joints (Bouchard nodes). Brief morning
stiffness may be present. [1771]
Parvovirus
Parvovirus B19 causes erythema infectiosum (fifth disease) in children and arthritis in adults. Parvovirus arthritis can
mimic rheumatoid arthritis but is usually self-resolving. [1896]
Pseudogout
Synovial fluid analysis showing rhomboid-shaped calcium pyrophosphate dihydrate crystals is diagnostic of
pseudogout. These crystals are positively birefringent under compensated polarized light. The knee joint is involved
in >50% of cases. [1451]
Joint destruction in rheumatoid arthritis is characterized by synovial hyperplasia, an inflammatory infiltrate, and
synovial angiogenesis. The joint space often becomes replaced by pannus, an invasive mass composed of fibroblast-
like synovial cells, granulation tissue, and inflammatory cells that can erode into the articular cartilage and underlying
bone. [15627]
Rheumatoid arthritis is characterized by synovial hyperplasia with inflammatory infiltrates. The accelerated
metabolic rate of the inflamed synovium causes local hypoxia, which leads to synovial angiogenesis. As the disease
progresses, the joint space is replaced by a rheumatoid pannus (an invasive mass of fibroblast-like synovial cells,
granulation tissue, and inflammatory cells) which can destroy the articular cartilage and underlying subchondral
bone. [15629]
Rheumatoid arthritis causes progressive joint destruction involving the hands, wrists, elbows, and knees. Cervical
spine involvement can lead to spinal instability and cord compression. [11821]
Eaton lambert myasthenic syndrome

Lambert-Eaton myasthenic syndrome (LEMS) is a neuromuscular disorder characterized by autoantibodies against
presynaptic voltage-gated calcium channels. It causes progressive proximal muscle weakness and decreased deep
tendon reflexes that improve with exercise (postexercise facilitation); cranial nerve involvement and autonomic
symptoms may also occur. LEMS is strongly associated with small cell lung cancer. [1900]
Eosinophilic granulomatosis with polyangiitis
Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) is a small to medium vessel vasculitis characterized by
late-onset asthma, rhinosinusitis, and eosinophilia. Mononeuritis multiplex due to involvement of the epineural
vessels of peripheral nerves is common. [667]

Giant cell arteritis is characterized by granulomatous inflammation of the media with intimal thickening and
predominantly involves branches of the carotid artery, especially the temporal artery. It is strongly associated with
polymyalgia rheumatica; both conditions respond promptly to glucocorticoid therapy. [450]
Giant cell arteritis (GCA) is characterized by granulomatous inflammation of the media with fragmentation of the
internal elastic lamina most often affecting the medium and small branches of the carotid artery. Ischemic optic
neuropathy with irreversible blindness is a potential complication of GCA; therefore, patients with suspected GCA
require immediate glucocorticoid therapy. [461]
Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) have very high sensitivity for giant cell (temporal)
arteritis. Patients with suspected giant cell arteritis who have an elevated ESR or CRP level should be referred for
temporal artery biopsy to confirm the diagnosis. [914]
Leukocytoclastic vasculitis
Cutaneous small vessel vasculitis is associated with medication (eg, penicillins, cephalosporins) use and typically
presents with palpable purpura in the lower extremities. Characteristic histopathologic findings include marked
perivascular inflammation of small blood vessels with fibrinoid necrosis and a predominance of neutrophils and
fragmented neutrophilic nuclei (leukocytoclastic vasculitis). [12255]
Polyarteritis nodosa
Polyarteritis nodosa is a systemic vasculitis of medium-sized muscular arteries marked by segmental, transmural,
arterial wall inflammation with fibrinoid necrosis. This narrows the arterial lumen and increases risk of thrombosis
and tissue ischemia/infarction. Damage to the internal and external elastic laminae also increases the risk of
microaneurysm. Tissue damage primarily occurs in the kidneys, gastrointestinal tract, neurologic system, and skin;
the lungs are usually spared. [18996]
Polyarteritis nodosa (PAN) is a systemic vasculitis characterized by constitutional manifestations and ischemic
symptoms in the kidneys, skin, gastrointestinal tract, and neurologic system. Biopsy will show segmental, transmural
arterial inflammation with fibrinoid necrosis and damage to the internal and external elastic lamina. PAN is often
associated with underlying viral hepatitis B and C. [457]

Dermatomyositis is characterized by proximal muscle weakness (similar to polymyositis) and dermal manifestations
(eg, heliotrope rash, Gottron papules). Laboratory testing shows elevated muscle enzymes (eg, creatine kinase) and
autoantibodies (eg, antinuclear, anti-Jo-1). Initial treatment includes systemic glucocorticoids and evaluation for
potential underlying malignancy. [940]
Rheumatic fever
The primary cause of morbidity in acute rheumatic fever is heart failure from severe pancarditis. Mitral stenosis
develops years or decades after the original illness. Joint involvement is usually transient. [239]
SLE
Systemic lupus erythematosus is characterized by loss of immune self-tolerance with production of autoantibodies
against nuclear antigens. Binding of autoantibodies to self antigens leads to deposition of immune complexes in
tissues and consumption of complement. [11798]
Sjogren syndrome
Sjögren syndrome is an autoimmune disorder characterized by lymphocytic inflammation in exocrine glands (eg,
lacrimal, salivary). It presents with dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia). Chronic B-cell
proliferation increases the risk for non-Hodgkin lymphoma. [15597]
Sjögren syndrome is an autoimmune disorder characterized by inflammation of exocrine glands. Biopsy of the labial
salivary glands shows periductal lymphocytic infiltrates (focal lymphocytic sialadenitis), often with germinal centers;
the glandular tissue is typically atrophic and fibrotic. [15596]
Systemic sclerosis
CREST syndrome (limited scleroderma) manifests with calcinosis, Raynaud's phenomenon, esophageal dysmotility,
sclerodactyly and telangiectasias. Anti-centromere antibodies are found in about 40% of patients with CREST
syndrome. Anti-DNA topoisomerase I (Scl-70) antibodies are highly specific for systemic sclerosis. [340]
BONE TUMORS AND TUMOR-LIKE LESIONS
Bone tumor
Osteosarcoma is the most common primary malignant bone tumor in children and young adults and typically arises
near the metaphyses of long bones (eg, femur, tibia), causing progressive pain and soft tissue swelling. X-ray typically
reveals a lytic and sclerotic bone lesion, and histopathology shows malignant tumor cells that produce neoplastic
osteoid and mineralized bone. [15636]
Ewing sarcoma is a malignant bone tumor that typically arises in the long bones or pelvis in children and often
metastasizes to the lungs. Imaging classically reveals a poorly defined, lytic lesion with an "onion skin" periosteal
reaction. Histopathology shows sheets of uniform, small, round, blue tumor cells. [15635]
Ganglion cyst
A ganglion cyst is a connective tissue outpouching arising from tendon sheaths and joint structures. It is typically
round, firm, well-circumscribed, and transilluminates on penlight examination. Most resolve spontaneously. [19775]
Lipoma
Lipomas are common, benign tumors that arise from the subcutaneous fat and present as soft, mobile masses that
are stable or enlarge slowly over time. The diagnosis is usually made clinically, but histopathology shows well-
differentiated, mature adipocytes with a fibrous capsule. [15665]
Hip fracture
McCune-Albright syndrome is characterized by the triad of fibrous dysplasia of the bone, endocrine abnormalities,
and café-au-lait spots. The condition results from an activating mutation in the G protein/CAMP/adenylate cyclase
signaling pathway. [11653]
Osteomyelitis
Mycobacterium tuberculosis spondylitis (Pott disease) is usually the result of hematogenous seeding of vertebrae
from primary pulmonary infection. Manifestations typically arise months or years later (due to reactivation) and
include chronic, progressive back pain, fever, and radiographic evidence of vertebral bone destruction and fluid
collection. [15666]
Hematogenous osteomyelitis occurs most commonly in children. It usually affects the metaphysis of long bones due
to the presence of slow-flowing sinusoids that are conducive to bacterial seeding. Fever and refusal to bear weight
are common manifestations in young children who are unable to localize the pain. [721]
Osteonecrosis
Osteonecrosis (avascular necrosis) occurs due to disruption of the macrovasculature or microvasculature of
bone. The femoral head is the most common location. Sickle cell disease can cause osteonecrosis due to the
thrombotic occlusion of arteries. Other major risk factors include embolic disorders, high-dose systemic
corticosteroids, excessive alcohol use, vasculitis (eg, systemic lupus erythematosus), and femoral neck fracture. [316]
Septic arthritis
A high synovial fluid leukocyte count (>100,000/mm3) and absent crystals on microscopic examination strongly
suggest bacterial joint infection. Septic arthritis requires antibiotic treatment to prevent joint destruction,
osteomyelitis, and sepsis. [1835]
Acute monoarthritis is characterized by pain, erythema, swelling, and reduced range of motion in a joint. It may
represent serious pathology such as septic arthritis, especially if accompanied by fever. Urgent synovial fluid analysis
should be performed to evaluate for infection. [11818]
Duchenne dystrophy
Duchenne muscle dystrophy manifests with proximal muscle weakness and atrophy. True hypertrophy of the distal
muscle is noted early in the disease as distal muscles compensate for weak proximal ones. Muscle fibers of the distal
extremities are later replaced by fat and connective tissue (pseudohypertrophy). [1266]
Duchenne muscular dystrophy is an X-linked recessive myopathy that manifests with proximal muscle weakness and
enlargement of the calf muscles in boys age 2-5. It most often results from frameshift deletions affecting the
dystrophin gene. Dystrophin provides a stabilizing interaction between the sarcolemma and the intracellular
contraction apparatus, and disruption of the protein results in membrane damage and myonecrosis. [1265]
Osteogenesis imperfecta
Osteogenesis imperfecta results from defective synthesis of type 1 collagen by osteoblasts. Clinical findings include a
history of fractures after only minimal trauma, blue sclerae, and small, malformed teeth. In most patients,
osteogenesis imperfecta is transmitted by autosomal dominant inheritance. [702]
Osteoporosis
Initially in osteoporosis, bone loss predominantly affects trabecular bone, leading to trabecular thinning and
perforation with loss of interconnecting bridges. Over time, cortical bone, which composes most of the appendicular
skeleton, also becomes involved. [629]
Pagets disease of bone

Paget disease of bone is characterized by disordered bone formation. Involvement of long bones can lead to bone
pain, bowing, fracture, or arthritis of adjacent joints. Serum alkaline phosphatase is elevated due to increased
production of new bone, but calcium and phosphorus levels remain normal. [15677]
Paget disease of bone is characterized by excessive and disordered bone formation. It commonly affects the skull,
long bones, and vertebral column. The increased formation of new bone is associated with an elevated serum
alkaline phosphatase level. Radiographs shows lytic or mixed lytic-sclerotic lesions, thickening of cortical and
trabecular bone, and bony deformities. [15696]
Vitamin D deficiency decreases intestinal absorption of calcium. Parathyroid hormone secretion increases to
maintain plasma calcium, which causes renal phosphate wasting and impaired bone mineralization. In children, this
causes rickets characterized by excessive unmineralized osteoid matrix at the epiphyseal cartilage. [630]
MISCELLANEOUS
Dupuytren's contracture
Dupuytren contracture is caused by progressive fibrosis of the superficial palmar fascia due to excessive fibroblast
proliferation. Pathognomonic fibrotic nodules and cords form along the flexor tendons, limiting extension of the
affected digits. [19911]
Myositis ossificans
Myositis ossificans is characterized by the formation of lamellar bone in extraskeletal tissues (ie, heterotopic
ossification), often triggered by trauma. It typically presents as a painful, firm, mobile mass within a muscle (eg,
quadriceps). Histologic examination shows benign metaplastic bone and proliferating fibroblasts without mitotic
atypia. [19823]
SPINAL DISORDERS AND BACK PAIN
Prostate cancer
Clinical features that suggest a malignant cause of back pain include persistent pain at night, no relief with rest, onset
at age >50, and systemic symptoms. Common malignancies with a propensity for bony metastasis include prostate,
breast, kidney, thyroid, and lung. [341]
Pathophysiology
Anaphylaxis
In anaphylaxis, allergen exposure triggers widespread IgE-mediated release of inflammatory chemical mediators (eg,
histamine, prostaglandin, leukotrienes). These chemical mediators cause peripheral vasodilation and increase
vascular permeability, leading to hypotension. [20767]
Anaphylaxis is an IgE-mediated response to an allergen that results in the release of histamine by mast cells and
basophils. Histamine causes widespread physiologic effects, including vasodilation and increased vascular
permeability (eg, hypotension), increased catecholamine secretion (eg, tachycardia), and bronchoconstriction (eg,
wheezing). [20715]
Immunizations
Vaccine reactogenicity is a local (eg, warmth, swelling, edema) and systemic (eg, fatigue, fever, headache)
inflammatory reaction to the vaccine due to the innate immune response. It is primarily caused by pattern
recognition receptors present on the surface of macrophages and mast cells, which identify the antigen and release
inflammatory cytokines (eg, IL-1, IL-6). [20696]
AUTOIMMUNE DISEASES
Malabsorption
Crohn disease with ileal resection or extensive ileal involvement can cause bile acid malabsorption, which may lead to
impaired absorption of fat-soluble vitamins (A, D, E, K). Vitamin K deficiency can result in impaired coagulation with
easy bruising, large hematoma formation in deep tissues and joints (eg, hemarthrosis) after minor trauma, and
prolonged bleeding after surgery. [12047]
SLE
Antinuclear antibodies are found in almost all patients with systemic lupus erythematosus but are also found in many
other autoimmune disorders and have low specificity. Anti–double-stranded DNA antibodies and anti-Smith
antibodies have lower sensitivity but higher specificity. [761]
Serum sickness
Serum sickness is a type III hypersensitivity reaction to nonhuman proteins characterized by vasculitis resulting from
tissue deposition of circulating immune complexes. Clinical findings include fever, pruritic skin rash, arthralgias, and
low serum C3 and C4 complement levels. [741]
IMMUNE DEFICIENCIES
Chediak higashi syndrome

Chédiak-Higashi syndrome is an autosomal recessive disorder affecting lysosomal trafficking that results in
immunodeficiency, albinism, neurologic abnormalities (eg, nystagmus). Giant granules are seen within neutrophils.
[1132]
Primary immunodeficiency disorder

Chronic granulomatous disease (CGD) results from defective NADPH oxidase. Normally, this enzyme participates in
the respiratory burst pathway to produce reactive oxygen species critical in intracellular pathogen killing. Patients
with CGD develop recurrent bacterial and fungal infections predominantly caused by 5 catalase-positive organisms:
Staphylococcus aureus, Burkholderia cepacia, Serratia marcescens, Nocardia, and Aspergillus. [1441]
Chronic granulomatous disease is due to NADPH oxidase deficiency, which leads to an inability of neutrophils to
generate a respiratory burst and produce the reactive oxygen species necessary to kill organisms in their
phagolysosomes. Absence of fluorescence on dihydrorhodamine flow cytometry testing can confirm the diagnosis.
[571]
DiGeorge syndrome causes an extreme deficiency in the number of mature T lymphocytes, leading to poor
development of the lymph node paracortex. In contrast, agammaglobulinemia causes an absence of B cells,
preventing primary lymphoid follicles and germinal centers from forming in the lymph node cortex. [8532]
Severe combined immunodeficiency disease

Severe combined immune deficiency is characterized by combined T and B cell dysfunction. It is a life-threatening
condition that presents in infancy with severe bacterial and viral infections; mucocutaneous candidiasis; persistent
diarrhea; and failure to thrive. Laboratory findings include absent T cells and hypogammaglobulinemia. The thymic
shadow is not usually present due to severe T cell deficiency. [1995]
The second most common cause of severe combined immunodeficiency is autosomal recessive deficiency of
adenosine deaminase, an enzyme necessary for the elimination of excess adenosine within cells. Toxic levels of
adenosine accumulate within lymphocytes in this condition, leading to lymphocyte cell death and resultant cellular
and humoral immunodeficiency. Patients with this condition can be treated with hematopoietic cell transplantation
or gene therapy. [561]
Aortic aneurysm
Abdominal aortic aneurysm is focal dilation of the abdominal aorta >50% above normal (or >3 cm in diameter). It is
generally asymptomatic until aneurysm rupture, which is frequently fatal. Risk factors include age >65, smoking, and
male sex. [15354]
Chronic venous insufficiency
Chronically elevated venous pressure in the lower extremities can lead to incompetent venous valves and venous
dilation (varicose veins). Venous congestion and tissue ischemia can result in venous stasis dermatitis. [878]

Reperfusion injury is thought to occur secondary to oxygen free radical generation, mitochondrial damage, and
inflammation. [293]
CARDIAC ARRHYTHMIAS
Atrial fibrillation
Age, independent of comorbidities, is one of the strongest risk factors for atrial fibrillation as age-related change to
the atrial myocardium is one of the primary contributors to atrial remodeling. Left atrial dilation is the other primary
contributor to atrial remodeling; therefore, comorbidities that cause left atrial dilation (eg, hypertension, heart
failure, mitral valve disease) are also strongly associated with atrial fibrillation. [21472]
Atrial remodeling is the major pathogenic contributor to atrial fibrillation. Age and comorbidities that cause atrial
dilation (eg, hypertension, heart failure, mitral valve disease) cause atrial structural changes that predispose to atrial
fibrillation development. In addition, age and previous atrial fibrillation cause atrial conduction system changes that
further propagate atrial fibrillation. [21478]
Carotid sinus hypersensitivity

Carotid sinus hypersensitivity is most commonly seen in elderly men and involves an exaggerated vasovagal response
to tactile stimulation of carotid sinus baroreceptors (eg, adjusting a shirt collar or necktie). The resulting increase in
parasympathetic output leads to a prolonged sinus pause that contributes to the excessive drop in blood pressure,
leading to transient loss of cerebral perfusion that manifests as presyncope (eg, lightheadedness) or syncope. [19561]
Carotid sinus hypersensitivity is a common cause of syncope associated with tactile stimulation of the carotid sinus
(eg, shaving). The syncope results from an exaggerated vagal response stimulated by the carotid baroreceptors,
which leads to slowed heart rate and marked peripheral vasodilation with a resulting transient loss of cerebral
perfusion. [19560]
Sick Sinus Syndrome

Sick sinus syndrome results from degeneration (usually age-related) of the sinoatrial node, leading to impaired
conduction and reduced cardiac output with symptoms of dyspnea, fatigue, lightheadedness, presyncope, and
syncope. ECG typically demonstrates bradycardia with sinus pauses (delayed P waves), sinus arrest (dropped P
waves), and junctional escape beats. [15574]
Supraventricular tachycardia
Atrioventricular nodal reentrant tachycardia is the most common type of paroxysmal supraventricular tachycardia,
resulting from abnormal conduction through 2 distinct atrioventricular nodal pathways. ECG typically demonstrates a
narrow QRS complex tachycardia with a regular rhythm and buried (not visible) P waves. [19577]
Supraventricular tachycardia is characterized by an elevated heart rate with a regular rhythm and narrow QRS
complexes due to an abnormal electrical impulse originating above the ventricles. Sustained tachycardia shortens
ventricular diastole, leading to decreased stroke volume and cardiac output and subsequent hypotension. [19574]
Wolff parkinson white syndrome

Wolff-Parkinson-White syndrome is characterized by symptomatic paroxysmal supraventricular tachycardia (eg,
atrioventricular reentrant tachycardia) due to the presence of an accessory conduction pathway. During normal sinus
rhythm, the presence of this accessory pathway causes ventricular preexcitation, which can be identified on ECG by
the triad of a shortened PR interval, early upslope of the QRS complex (delta wave), and a widened QRS interval. [90]
Wolff-Parkinson-White (WPW) pattern is characterized by a shortened PR interval, widening of the QRS complex, and
slurred initial upstroke of the QRS complex (delta wave). It is caused by an accessory pathway that bypasses the
atrioventricular node, causing preexcitation of the ventricles. Patients with WPW pattern can develop symptomatic
arrhythmia (eg, atrioventricular reentrant tachycardia) due to reentry of electrical impulses through the accessory
conduction pathway. [11797]

Atrial septal defects cause wide, fixed splitting of the second heart sound due to right-sided volume overload from
left-to-right shunting. Uncorrected defects can lead to irreversible medial hypertrophy of the pulmonary arteries
with pulmonary hypertension and reversal to right-to-left shunting (ie, Eisenmenger syndrome). [201]
Bicuspid aortic valve

Aortic stenosis is the most common complication of bicuspid aortic valves. Patients with bicuspid aortic valves
develop clinically significant aortic stenosis on average around age 50. In comparison, senile calcific stenosis of
normal aortic valves generally becomes symptomatic age >65. [33]
Congenital cardiac defects

Increased blood oxygen saturation between 2 right-sided vessels or chambers indicates the presence of a left-to-right
shunt. If the abnormal oxygen increase occurs between the right atrium and the right ventricle, a ventricular septal
defect (VSD) is likely present. Small VSDs produce a holosystolic murmur that is loudest over the lower left sternal
border. [187]
Embolic stroke
Paradoxical embolism occurs when a thrombus from the venous system crosses into the arterial circulation via an
abnormal connection between the right and left cardiac chambers (eg, patent foramen ovale, atrial septal defect, or
ventricular septal defect). Atrial left-to-right shunts cause wide and fixed splitting of S2 and can facilitate paradoxical
embolism due to periods of transient shunt reversal (eg, during straining or coughing). [189]
Marfan syndrome
Cardiovascular lesions are the most life-threatening complications associated with Marfan syndrome. Early-onset
cystic medial degeneration of the aorta predisposes to aortic dissection, the most common cause of death in these
patients. [194]

Closure of a patent ductus arteriosus results in decreased pulmonary venous return to the left atrium (decreased left
ventricular preload) and increased diastolic blood pressure in the aorta (increased left ventricular
afterload). Together, these changes acutely lower left ventricular stroke volume and cardiac output. [19534]
After birth, pulmonary vascular resistance progressively decreases and systemic vascular resistance progressively
increases, resulting in decreased pulmonary pressure and increased systemic pressure. As the relative pressures in
the pulmonary artery and aorta change, the patent ductus arteriosus (PDA) murmur evolves from systolic only to
continuous before the PDA closes and the murmur disappears. [19535]
A patent ductus arteriosus (PDA) causes a continuous murmur best heard at the left infraclavicular or posterior
interscapular region. A small PDA is often asymptomatic and detected incidentally during routine cardiac
auscultation. It most commonly occurs in patients born prematurely and those with cyanotic congenital heart
disease. [2109]
Persistent pulmonary hypertension

Differential cyanosis (ie, postductal < preductal oxygen saturation) in a neonate suggests right-to-left shunting across
a patent ductus arteriosus, such as in persistent pulmonary hypertension of the newborn (PPHN). Patients with PPHN
typically have an underlying pulmonary disorder with respiratory distress and strong femoral pulses. [19636]
Tetralogy of fallot
In patients with Tetralogy of Fallot, the degree of right ventricular outflow tract obstruction is the major determinant
of the degree of right-to-left intracardiac shunting and resulting cyanosis. [204]
The major defects in tetralogy of Fallot are right ventricular outflow tract (RVOT) obstruction and a ventricular septal
defect (VSD). In many patients, activities (eg, feeding, crying) can precipitate cyanotic episodes (tet episodes) by
causing a dynamic increase in RVOT obstruction. During these episodes right ventricular pressure is increased and
pulmonary arterial and left atrial pressures are decreased as blood is shunted away from the pulmonary circulation
(ie, right-to-left shunting through the VSD). [19540]
Severe tetralogy of Fallot is a ductal-dependent lesion that requires blood flow through the ductus arteriosus (from
the aorta to the pulmonary artery) for adequate oxygenation. Prostaglandin E1 prevents closure of the ductus
arteriosus and should be immediately administered to all cyanotic neonates with suspected ductal-dependent
lesions. [19541]
Tetralogy of Fallot involves right ventricular outflow tract (RVOT) obstruction and a ventricular septal defect
(VSD). Cyanotic ("tet") episodes are commonly precipitated by a dynamic increase in RVOT obstruction that increases
right-to-left shunting through the VSD. These episodes involve decreased blood flow through the RVOT, causing
disappearance of the associated systolic murmur, and reduced oxygen saturation of the left ventricular blood being
pumped into the systemic circulation. [19539]
Polycythemia is commonly due to increased erythropoietin stimulated by conditions causing chronic hypoxemia, such
as cyanotic congenital heart disease (eg, tetralogy of Fallot). Hypoxemia in these cases is caused by right-to-left
shunting (ie, underperfusion of the pulmonary arteries). [19537]
Transposition of the great vessels

Cyanotic congenital heart disease, characterized by right-to-left shunting, should be considered in neonates with
severe cyanosis that does not improve with oxygen administration. In transposition of the great arteries,
deoxygenated blood from the right ventricle is delivered to the systemic circulation while oxygenated blood cycles
through the pulmonary circulation. [20910]
Transposition of the great arteries is characterized by parallel circulations of deoxygenated and oxygenated
blood. Initial management includes maintaining a left-to-right mixing lesion (eg, patent ductus arteriosus, patent
foramen ovale) to provide systemic circulation with partially oxygenated blood. [20911]

A ventricular septal defect (VSD) commonly causes a harsh, holosystolic murmur at the left lower sternal border; the
murmur increases in intensity during maneuvers that increase left ventricular afterload (eg, handgrip maneuver). A
small VSD is usually asymptomatic and produces a relatively loud murmur due to a high interventricular pressure
gradient. [2117]
Atheroembolism
Atheroembolic disease typically occurs after an invasive vascular procedure due to mechanical dislodgement of
atherosclerotic plaque, resulting in the showering of cholesterol-rich microemboli into the circulation. Needle-
shaped cholesterol clefts in affected vessels are diagnostic. Commonly involved organs include the kidneys (eg, acute
kidney injury), skin (eg, blue toe syndrome, livedo reticularis), gastrointestinal tract (eg, bleeding, infarction), and CNS
(eg, stroke, amaurosis fugax). [15250]

Stable angina results from fixed coronary artery stenosis that limits blood flow to downstream myocardium,
preventing the myocardial oxygen supply from increasing during exertion. Dobutamine mimics the effects of exercise
and increases myocardial oxygen demand; it can be used during stress testing to provoke areas of ischemic
myocardium, which can be recognized on imaging by a localized and transient decrease in contractility (ie, wall
motion defect). [15180]
Left ventricular (LV) free-wall rupture is an uncommon but devastating mechanical complication of transmural
myocardial infarction that occurs up to 2 weeks following the event (frequently within 5 days). Rupture leads to
cardiac tamponade that causes hypotension and shock with rapid progression to cardiac arrest. Autopsy typically
reveals a slitlike tear at the site of infarction in the LV wall. [193]
Loss of cardiomyocyte contractility occurs within 60 seconds after the onset of total ischemia. When ischemia lasts
less than 30 minutes, restoration of blood flow leads to reversible contractile dysfunction (myocardial stunning), with
contractility gradually returning to normal over the next several hours to days. However, after about 30 minutes of
total ischemia, ischemic injury becomes irreversible. [42]
Cocaine intoxication causes increased sympathetic activity, which may be recognized by agitation, dilated pupils,
tachycardia, and hypertension. Cocaine-induced chest pain typically results from myocardial oxygen supply-demand
mismatch (ie, myocardial ischemia) in the setting of coronary artery vasoconstriction. Sublingual nitroglycerin and
benzodiazepines help improve the myocardial ischemia and relieve the chest pain. [15875]
The dominant right coronary artery perfuses both the inferior wall of the left ventricle and the majority of the right
ventricle. Proximal occlusion can cause right ventricular myocardial infarction, which presents with hypotension
(reduced cardiac output) and distended jugular veins (elevated central venous pressures). The lungs will be clear on
auscultation and x-ray (lack of pulmonary edema) unless concomitant left-sided heart failure is also present. [11833]
The right ventricle (RV) is relatively protected from myocardial infarction (MI), and contractile function of the RV
usually returns to normal following MI. Factors contributing to this protection include relatively small muscle mass
with high capacity to increase oxygen extraction, perfusion throughout the cardiac cycle, and heightened ischemic
preconditioning. [20476]
Left ventricular free wall rupture is a mechanical complication that can occur within 5 days or up to 2 weeks following
transmural (ST-elevation) myocardial infarction. Patients usually develop acute cardiac tamponade with hypotension
and obstructive shock that rapidly leads to cardiac arrest. [195]
Vasospastic angina
Vasospastic angina involves hyperreactivity of coronary artery smooth muscle. Patients are usually young (age <50)
and without significant risk factors for coronary artery disease; they experience recurrent episodes of chest
discomfort that typically occur during rest or sleep and resolve within 15 minutes. [15001]
Acute heart failure

Asymptomatic left ventricular systolic dysfunction is a common stage in the progression of heart
failure. Neurohormonal mechanisms, including the sympathetic nervous system and renin-angiotensin-aldosterone
system, help maintain the asymptomatic period by increasing volume retention and peripheral resistance to maintain
organ perfusion. Although these mechanisms are beneficial in the short term, they are ultimately deleterious,
increasing hemodynamic stress and cardiac remodeling that eventually lead to decompensated heart failure. [15528]
Patients with decompensated heart failure have elevated left ventricular end-diastolic pressure and decreased
cardiac output that is most often primarily due to left ventricular dysfunction. Right atrial pressure (ie, central venous
pressure) is also elevated in advanced heart failure due to volume overload; right-sided heart failure (most often
occurring secondary to left-sided failure) can also contribute to elevated right atrial pressure. [15650]
Anaphylaxis
Anaphylaxis can cause distributive shock due to widespread release of inflammatory mediators (eg, histamine) that
leads to massive peripheral vasodilation. Arteriolar vasodilation decreases systemic vascular resistance to cause
hypotension, and venular vasodilation decreases central venous pressure and pulmonary capillary wedge
pressure. Cardiac output is often increased in early distributive shock due to reduced SVR and a baroreceptor reflex–
mediated increase in heart rate. [19284]
Ascites
Right-sided heart failure promotes the formation of ascites due to increased central venous pressure, which is
transmitted to the hepatic sinusoids, leading to increased capillary hydrostatic pressure. Capillary permeability is
unaffected. Although chronic passive congestion may eventually result in hepatic synthetic dysfunction
(hypoalbuminemia) with low oncotic pressures, the oncotic pressure will remain normal for several weeks at least.
[18160]

Left-sided heart failure leads to chronically elevated pulmonary venous and capillary pressures, with resulting
pulmonary edema and extravasation of red blood cells into the alveolar parenchyma. The iron from red blood cells is
taken up by alveolar macrophages and stored as hemosiderin, appearing as brown pigment on microscopy. [15534]
Decreased cardiac output in heart failure triggers neuroendocrine compensatory mechanisms to maintain organ
perfusion; however, the compensatory mechanisms are maladaptive over the long term. Increased sympathetic
output and activation of the renin-angiotensin-aldosterone system stimulate vasoconstriction and volume retention,
compounding the hemodynamic stress on an already failing heart and creating a vicious cycle of decompensation.
[843]
An S3 is a low-frequency sound that occurs just after S2 and is typically associated with ventricular volume
overload. It is commonly heard in patients with mitral or aortic regurgitation or heart failure with reduced ejection
fraction (eg, dilated cardiomyopathy). [2108]
The ventricular myocardium secretes brain natriuretic peptide (BNP) in response to the ventricular stretch and strain
that typically occurs with volume overload. BNP, along with atrial natriuretic peptide secreted by the atrial
myocardium, stimulates vasodilation and salt and water excretion to help relieve volume overload. [15651]
The reduced cardiac output in heart failure leads to decreased renal perfusion and consequent stimulation of the
renin-angiotensin-aldosterone system in a maladaptive effort to maintain effective blood volume. Inactive
angiotensin I is converted into active angiotensin II by endothelial-bound angiotensin-converting enzyme in the lungs.
[1532]
Cor pulmonale
Peripheral edema results from the accumulation of fluid in the interstitial spaces. Factors that promote edema
include elevated capillary hydrostatic pressure, decreased plasma oncotic pressure, and impaired lymphatic
drainage. In chronic heart failure, increased lymphatic drainage initially offsets factors favoring edema, temporarily
delaying edema development. [1578]
Diastolic dysfunction
Diastolic dysfunction is a common cause of heart failure with preserved ejection fraction. It typically results from
concentric left ventricular hypertrophy in response to prolonged systemic hypertension (ie, increased afterload). [186]
An S4 is a low-frequency, late diastolic sound that immediately precedes S1. It is caused by blood striking a stiffened
ventricular wall during atrial contraction; concentric left ventricular hypertrophy due to chronic hypertension (or less
commonly due to aortic stenosis) is a common cause of an S4. [246]
Hyperthyroidism
Hyperthyroidism causes characteristic cardiovascular changes. Increased metabolic demand in the tissues and a
direct vasodilatory effect of thyroid hormone lead to reduced systemic vascular resistance (and decreased diastolic
blood pressure). A direct sympathetic-like effect of thyroid hormone on the myocardium leads to increased heart
rate, contractility, and cardiac output. Increased stroke volume increases pulse pressure and systolic blood pressure.
[19514]
Sepsis
Septic shock causes widespread arteriolar vasodilation, which leads to a decrease in systemic vascular resistance and
a compensatory increase in cardiac output. Central venous pressure and pulmonary capillary wedge pressure are
also decreased due to pooling of blood in the dilated veins. Increased flow rates through the peripheral capillaries
lead to incomplete oxygen extraction by the tissues and high mixed venous oxygen saturation. [13979]
Septic shock can present with either hyper- or hypothermia. The initial disturbance is peripheral vasodilation leading
to decreased systemic vascular resistance, decreased central venous pressure, and decreased pulmonary capillary
wedge pressure. A compensatory increase in sympathetic drive causes an increase in cardiac output; the resulting
high flow rates lead to incomplete oxygen extraction in the tissues, resulting in high mixed venous oxygen saturation.
[15241]
HYPERTENSION
Acute kidney injury

In patients with long-standing hypertension, a chronic autoregulatory shift in the blood pressure–flow relationship
occurs, affording less perfusion (flow) at any given pressure. Therefore, excessively rapid correction of blood
pressure toward normal may induce relative ischemia. [21356]
Concentric left ventricular hypertrophy (LVH) is a common complication of chronic hypertension, characterized by
uniformly thickened ventricular walls and enlarged cardiomyocytes and nuclei. The vasoconstrictors angiotensin II
and endothelin likely have a prominent role in the development of concentric LVH independent of their effects on
blood pressure. Angiotensin II receptor blockers are more effective than other antihypertensive agents in reducing
LVH. [20966]
Plasma renin activity (PRA) is a measure of the amount of angiotensin I generated per unit of time. It provides a
useful assessment of the renin-angiotensin-aldosterone axis. Factors that increase PRA include low sodium intake
and antihypertensive medications such as diuretics (eg, hydrochlorothiazide), ACE inhibitors, and angiotensin II
receptor blockers (eg, valsartan). [11849]
Acute pericarditis
Purulent pericarditis is usually caused by hematogenous dissemination from distant infection or direct extension from
an adjacent infection or chest wall trauma. Although a variety of organisms cause purulent pericarditis,
Staphylococcus aureus is the most common pathogen, particularly in the setting of a portal from the skin to the
bloodstream (eg, catheter) or pericardium (eg, recent chest surgery, penetrating injury). [20253]
Acute-onset, sharp, and pleuritic chest pain that decreases with leaning forward is characteristic of acute
pericarditis. Fibrinous/serofibrinous pericarditis is the most common form of pericarditis and a pericardial friction
rub is the most specific physical finding. Viral pericarditis is often preceded by an upper respiratory infection. [97]
Athletes heart
Athlete's heart refers to physiologic cardiac adaptations that improve cardiac function in response to high-level
endurance training. There is predominant left ventricular (LV) eccentric hypertrophy with a small component of
concentric hypertrophy, leading to an overall increase in LV mass, enlarged LV cavity size, slightly increased LV wall
thickness, and decreased resting heart rate. [15269]
Cardiac tamponade
Cardiac tamponade typically presents with hypotension with pulsus paradoxus, elevated jugular venous pressure, and
muffled heart sounds (Beck's triad). Pulsus paradoxus refers to an abnormal exaggerated decrease in systolic blood
pressure >10 mm Hg on inspiration, and is a common finding in patients with pericardial effusion with cardiac
tamponade. [96]
Cardiac tamponade involves restriction of diastolic filling of the right-sided heart chambers, with engorgement and
decreased inspiratory collapse of the inferior vena cava seen on echocardiography. Pulsus paradoxus (>10 mm Hg
drop in systolic blood pressure during inspiration) is commonly present with tamponade. [20257]
Cardiac tamponade involves increased pericardial pressure that restricts diastolic filling of the right-sided heart
chambers, leading to obstructive shock with increased central venous pressure and decreased stroke volume and
cardiac output. As tamponade progresses, diastolic pressures in all 4 cardiac chambers increase and equalize with
pericardial pressure (and with one another), stagnating blood flow within the heart. [20262]
Constrictive pericarditis
The symptomatic presentation of constrictive pericarditis mimics that of right-sided heart failure, with patients
experiencing slowly progressive dyspnea, lower extremity edema, ascites, and weight gain. Calcification and
thickening of the pericardium are typical features of constrictive pericarditis on CT scan. [2071]
Dilated cardiomyopathy results from direct damage to cardiomyocytes leading to myocardial contractile dysfunction
(systolic dysfunction), volume overload, and ventricular dilation. Viral myocarditis is a common cause of dilated
cardiomyopathy and should be suspected in young patients who develop heart failure following a symptomatic viral
prodrome. [75]
Endocarditis
Patients who inject drugs are at high risk for infective endocarditis (IE) due to the concurrent injection of abrasive
particulate material and microorganisms. Most cases arise on the tricuspid valve. Patients with tricuspid valve IE
often present with right-sided heart failure or septic pulmonary emboli. Echocardiography generally reveals valvular
vegetations and incomplete valve closure (regurgitation). [7218]
Heart sounds
An S4 is a low frequency, extra heart sound that occurs at the end of diastole (just before S1). It is caused by blood
striking a stiff ventricular wall during atrial contraction; it can be a normal finding in elderly patients (eg, age >70), but
typically indicates pathologic ventricular wall stiffening in younger patients (most commonly due to concentric left
ventricular hypertrophy in response to chronic hypertension). [2107]
Hemodynamic monitoring
On the jugular venous pulsation waveform, the A wave is generated by atrial contraction at the end of right
ventricular diastole just before tricuspid valve closure. [2070]
Patients with hypertrophic cardiomyopathy (HCM) may be asymptomatic. Echocardiographic findings consistent with
HCM include an overall increase in left ventricular (LV) mass, reduced LV cavity size with impaired diastolic function,
LV hypertrophy predominantly affecting the septum, and normal or increased LV ejection fraction. [15310]
The degree of left ventricular (LV) outflow tract obstruction in hypertrophic cardiomyopathy is minimized by
relatively high LV blood volume. High LV end-diastolic blood volume (ie, preload) is encouraged by adequate
hydration and low heart rate. High LV end-systolic volume is encouraged by relatively low stroke volume, which is
facilitated by high LV afterload and low LV contractility. [22693]
Hypertrophic cardiomyopathy (HCM) is characterized by asymmetric ventricular septal hypertrophy and dynamic left
ventricular outflow tract (LVOT) obstruction. Decreases in LV blood volume, via maneuvers or conditions that
decrease preload (eg, abrupt standing, Valsalva strain phase) or afterload, worsen LVOT obstruction and increase the
intensity of the HCM murmur. [85]
Pulsus paradoxus
Pulsus paradoxus is defined by a decrease in systolic blood pressure of >10 mm Hg with inspiration. It is most
commonly seen in patients with cardiac tamponade but can also occur in severe asthma, chronic obstructive
pulmonary disease, and constrictive pericarditis. [2099]
Asthma and chronic obstructive pulmonary disease (COPD) exacerbation are the most frequent causes of pulsus
paradoxus in the absence of significant pericardial disease. Beta-adrenergic agonists control acute asthma and COPD
exacerbations by causing bronchial smooth muscle relaxation via increased intracellular cAMP. [2100]
Restrictive cardiomyopathy
Diastolic heart failure (DHF) is caused by decreased ventricular compliance and is characterized by normal left
ventricular (LV) ejection fraction, normal LV end-diastolic volume, and elevated LV filling pressures. Hypertension,
obesity, and infiltrative disorders (eg, transthyretin-related amyloidosis, sarcoidosis) are important causes of DHF. [93]
Vancomycin
Rapid infusion of vancomycin can lead to the direct activation of mast cells, which results in a massive release of
histamine. This causes "red man" syndrome, a nonallergic reaction marked by flushing, erythema, and pruritis within
seconds or minutes of vancomycin infusion. Because this reaction is not IgE-mediated, vancomycin can be safely
resumed at a slower rate once symptoms have resolved. [7219]
Cardiac physiology
During pregnancy, increased metabolic demands lead to multiple physiologic cardiovascular changes, including
decreased systemic vascular resistance and increased blood volume. These changes cause increased preload and
decreased afterload, resulting in increased stroke volume and cardiac output. Heart rate also gradually increases
during pregnancy and is the major contributor to increased cardiac output in late pregnancy. [19518]
Coronary blood flow

Increases in resting blood flow to ischemic myocardium are primarily mediated by locally-acting substances (eg,
adenosine, nitric oxide) that trigger coronary arteriolar vasodilation. Pharmacologic arteriolar vasodilators (eg,
adenosine, dipyridamole) mimic the vasodilation that occurs with exercise and may cause redistribution of blood flow
from ischemic to nonischemic areas of myocardium (ie, coronary steal). [952]
The coronary sinus communicates freely with the right atrium and will become dilated secondary to any factor that
causes increased right atrial pressure. The most common cause is pulmonary hypertension, leading to elevated right
heart pressures. [2124]
Prostacyclins
Prostacyclin (prostaglandin I2) is synthesized from prostaglandin H2 by prostacyclin synthase in vascular endothelial
cells. Once secreted, it inhibits platelet aggregation and causes vasodilation to oppose the functions of thromboxane
A2 and help maintain vascular homeostasis. [751]

A ventricular septal defect, classically characterized by a harsh, holosystolic murmur at the left lower sternal border,
causes left-to-right shunting of oxygenated blood from the left ventricle to the right ventricle. Therefore, right
ventricular oxygen saturation is increased compared to normal. [19531]
Aging
Dystrophic calcification occurs in damaged or necrotic tissue in the setting of normal calcium levels; metastatic
calcification occurs in normal tissue in the setting of hypercalcemia. [296]
Transcatheter aortic valve implantation (TAVI) allows for minimally invasive management of severe aortic stenosis in
elderly patients who are unable to tolerate open surgical valve replacement. Paravalvular aortic regurgitation is a
common complication of TAVI, resulting from improper sealing of the prosthetic valve to the native aortic valve
annulus. [16596]
Aortic regurgitation causes a decrescendo diastolic murmur with maximal intensity occurring just after closure of the
aortic valve, when the pressure gradient between the aorta and left ventricle is the highest. The pressure tracing for
aortic regurgitation is characterized by loss of the aortic dicrotic notch, steep diastolic decline in aortic pressure, and
high-peaking systolic pressures. [227]
Aortic regurgitation (AR) causes a high-pitched, blowing, diastolic murmur with a decrescendo intensity pattern. The
murmur of AR due to aortic root dilation is best heard at the right upper sternal border, whereas the murmur of AR
due to valvular pathology is best heard at the left third intercostal space. [2105]
In chronic aortic regurgitation, persistent left ventricular volume overload triggers eccentric hypertrophy, which
causes a compensatory increase in stroke volume to maintain cardiac output. This compensatory mechanism allows
for a relatively long asymptomatic period in most patients; however, left ventricular dysfunction eventually occurs,
leading to heart failure. [237]
Chronic aortic regurgitation (AR) causes a reduction in diastolic blood pressure and a compensatory increase in left
ventricular stroke volume. These changes create a high-amplitude, rapid rise-rapid fall pulsation (ie, widened pulse
pressure) and the other characteristic findings of AR (eg, head bobbing, "pistol-shot" femoral pulses). [238]
Aortic stenosis
The murmur of aortic stenosis (AS) is a systolic ejection-type, crescendo-decrescendo murmur that starts after the
first heart sound and typically ends before the A2 component of the second heart sound. The intensity of the
murmur is proportional to the magnitude of the left ventricle to aorta pressure gradient during systole. [243]
In patients with chronic aortic stenosis and concentric left ventricular hypertrophy, atrial contraction contributes
significantly to left ventricular filling. Loss of atrial contraction due to atrial fibrillation can reduce left ventricular
preload and cardiac output sufficiently to cause systemic hypotension. Decreased forward filling of the left ventricle
can also result in backup of blood in the left atrium and pulmonary veins, leading to acute pulmonary edema. [244]
A bicuspid aortic valve is a common cause of aortic stenosis in the United States. The classic auscultatory finding in
aortic stenosis is a harsh, crescendo-decrescendo systolic ejection murmur best heard at the right upper sternal
border with radiation to the carotids. [2106]
Angina often occurs in aortic stenosis even in the absence of obstructive coronary artery disease. It results from
increased myocardial oxygen demand due to an increase in left ventricular mass (ie, concentric hypertrophy) and
ventricular wall stress. [14966]
Mitral regurgitation
Regurgitant flow into the left atrium in acute mitral regurgitation leads to increased left atrial pressure and increased
left ventricular end-diastolic volume (preload). The low-resistance regurgitant pathway also decreases left ventricular
afterload with a resulting increase in ejection fraction but overall decrease in forward stroke volume. Increased left
atrial pressure and decreased cardiac output result in pulmonary edema and severe hypotension, respectively. [11851]
Left ventricular systole corresponds to the time of passive filling of the left atrium (atrial diastole). Mitral valve
regurgitation leads to markedly elevated left atrial pressure during this period, creating the characteristic early and
large V wave on left atrial pressure tracing. [945]
In patients with mitral regurgitation, left ventricular afterload is determined by the balance of resistance between
forward flow (aortic pressure) and regurgitant flow (left atrial pressure). A reduction in systemic vascular resistance
increases the ratio of forward to regurgitant blood flow and improves cardiac output. [943]
Decompensated heart failure is a common cause of secondary (functional) mitral valve regurgitation. Increased left
ventricular end-diastolic volume causes dilation of the mitral valve annulus and restricted movement of the chordae
tendineae with subsequent regurgitation. Treatment with diuretics and vasodilators can improve heart failure-
induced MR. [200]
Mitral regurgitation causes a blowing holosystolic murmur best heard at the cardiac apex and with radiation to the
axilla. Rheumatic heart disease is a common cause of both mitral regurgitation and mitral stenosis and is most
commonly seen in patients who grew up in Latin America, Africa, or Asia. [2096]
Patients with severe mitral regurgitation develop left-sided volume overload with an S3 gallop due to the large
volume of regurgitant flow reentering the ventricle during mid-diastole. The absence of an S3 gallop excludes severe
chronic MR. [944]
Mitral stenosis
Isolated mitral stenosis causes elevated upstream pressures in the left atrium and pulmonary veins and arteries. Left
ventricular end diastolic pressure (LVEDP) is normal or decreased due to obstruction of blood flow through the
stenotic valve. An elevated LVEDP suggests additional downstream pathology (eg, aortic valve disease, left
ventricular failure). [234]
The best and most reliable auscultatory indicator of the degree of mitral stenosis is the A2-OS interval. A shorter
interval indicates more severe stenosis. Other auscultatory findings can include a diastolic rumbling murmur with
presystolic accentuation due to left-atrial contraction. [233]
Cardiac auscultation in patients with mitral stenosis reveals a loud first heart sound, an early diastolic opening snap
after the second heart sound, and a low-pitched diastolic rumble best heard at the cardiac apex. The opening snap is
caused by the sudden opening of the mitral valve leaflets when the left ventricular pressure falls below the left atrial
pressure at the beginning of diastole. [235]
Severe tricuspid valve regurgitation (TR) can lead to right-sided heart failure, evidenced by jugular venous distension,
hepatomegaly, lower extremity edema, and the absence of pulmonary edema. Permanent pacemaker placement can
cause TR because the right ventricular lead passes through the tricuspid valve orifice and can disrupt valve closure.
[15729]
Dermatology
Acne vulgaris
Acne is characterized by the obstruction of pilosebaceous follicles (ie, comedones) due to hyperkeratinization and
excessive sebum accumulation. Androgens stimulate production of sebum, which serves as a nutrient source for
Cutibacterium acnes. Within the follicles, C acnes proliferation triggers an inflammatory response, resulting in
formation of red papules and pustules. [15379]
MISCELLANEOUS
Albinism
Oculocutaneous albinism is an autosomal recessive disorder of melanin biosynthesis typically due to defective
tyrosinase activity. Patients have reduced or absent melanin pigment in the skin, hair, and eye, as well as abnormal
development of the fovea and optic nerve fibers, leading to reduced visual acuity and nystagmus. [21305]
Diaper dermatitis
Irritant contact diaper dermatitis is the most common diaper rash and is characterized by skin barrier breakdown as a
result of exposure to fecal bacteria that causes increased local skin pH. Treatment is with a barrier ointment that
prevents skin contact with urine and stool. [21107]
Aging
:Photoaging is a product of excess exposure to ultraviolet A wavelengths and is characterized by epidermal atrophy
with flattening of rete ridges. In addition, there is decreased collagen fibril production and increased degradation of
collagen and elastin in the dermis. [1860]
Wound healing
Fibroblast and vascular proliferation (ie, granulation tissue) induced by vascular endothelial growth factor (VEGF) is
essential to normal wound healing. However, if this tissue proliferation becomes excessive (eg, in wounds left to heal
by secondary intention), the resulting hypergranulation tissue can impair wound reepithelization and remodeling.
[17854]
Accessory nipple
Accessory nipples are the most common congenital breast anomaly resulting from failed regression of the mammary
ridge in utero. They are usually asymptomatic but can become tender along with breast tissue during times of
hormonal fluctuation. [8904]
Keloid
Keloids result from excessive collagen formation during the remodeling phase of wound healing, which occurs due to
overexpression of transformation growth factor beta and excessive fibroblast proliferation. They typically present as
raised, painful, and pruritic lesions that grow beyond the original wound borders. [874]
Cholesteatoma
Cholesteatomas are collections of squamous cell debris that form a mass behind the tympanic
membrane. Cholesteatomas can be congenital or may occur as an acquired primary lesion or following infection,
trauma, or surgery of the middle ear. They can cause hearing loss due to erosion into auditory ossicles. [11628]
Cystic fibrosis
Chronic rhinosinusitis with nasal polyposis in children should prompt evaluation for cystic fibrosis, especially when
signs of pancreatic insufficiency (eg, loose stools, failure to thrive, weight loss) are present. [19576]
Meniere disease
Ménière disease is characterized by tinnitus, vertigo, and sensorineural hearing loss. Its pathogenesis is related to an
increased volume and pressure of endolymph in the vestibular apparatus. [308]
Otitis media
Acute otitis media presents with an erythematous, bulging tympanic membrane and can be complicated by
inflammation or infection of nearby structures. Spread of infection to the facial nerve (CN VII), which travels through
the middle ear, can result in facial neuritis with unilateral facial paralysis. [20119]
A brain abscess appears as a ring-enhancing lesion on imaging and typically causes headache with or without fever
and neurologic symptoms (eg, seizure). Pathogenesis often involves direct spread from head and neck space
infections, such as acute otitis media. [20020]
ADRENAL DISORDERS
Patients with adrenal insufficiency are not able to increase glucocorticoid production in response to acute stress (eg,
illness, surgery). Adrenal crisis is characterized by severe hypotension, abdominal pain, vomiting, weakness, and
fever. In addition to aggressive fluid resuscitation, treatment requires immediate glucocorticoid supplementation.
[932]
Administration of metyrapone will cause a decrease in cortisol synthesis via inhibition of 11-β-hydroxylase. In
patients with an intact hypothalamic-pituitary-adrenal axis, this will cause a reactive increase in ACTH, 11-
deoxycortisol, and urinary 17-hydroxycorticosteroid levels. [608]
:Patients with type 1 diabetes mellitus are at increased risk for other autoimmune endocrinopathies, including
primary adrenal insufficiency (Addison disease). Electrolyte abnormalities in primary adrenal insufficiency include
hyponatremia, hyperkalemia, hyperchloremia, and nonanion gap metabolic acidosis. [924]
Cushing syndrome
ACTH is the major trophic hormone of the zona fasciculata and reticularis, whereas the zona glomerulosa is primarily
regulated by angiotensin II. Excess production of ACTH causes increased cortisol synthesis within the zona fasciculata
(Cushing's manifestations) and increased androgen production within the zona reticularis (irregular menstruation,
hirsutism in women). [1163]
Long-term use of supraphysiologic doses of glucocorticoids causes suppression of the hypothalamic-pituitary-adrenal

axis, which in turn leads to bilateral adrenocortical atrophy involving the zona fasciculata and reticularis. Sudden
cessation of the exogenous corticosteroids can precipitate adrenal crisis. [928]
Hyperaldosteronism
Hypersecreting adrenocortical tumors can have functionality resembling the outer (aldosterone/Conn syndrome),
middle (cortisol/Cushing syndrome), or inner (androgens/hirsutism and virilization) layers of the adrenal cortex. [454]
Primary hyperaldosteronism is caused by excessive aldosterone secretion, typically as a result of bilateral nodular
hyperplasia of the zona glomerulosa or an aldosterone-producing adrenal adenoma. Clinical findings include
hypertension, low plasma renin activity, hypokalemia, and metabolic alkalosis. [547]
Primary hyperaldosteronism increases distal Na+ reabsorption (secondary hypertension), leading to increased urinary
excretion of H+ and K+ (metabolic alkalosis and hypokalemia). Overt volume overload is not seen due to aldosterone
escape, and serum Na+ concentration is typically normal due to preserved antidiuretic hormone function. [929]
Congenital adrenal hyperplasia

Deficiency of 17 alpha-hydroxylase is a rare form of congenital adrenal hyperplasia characterized by impaired
synthesis of androgens, estrogens, and cortisol with excess production of mineralocorticoids. Genetic males with this
deficiency may have phenotypically female external genitalia and present with hypertension and hypokalemia around
the expected time of puberty. [610]
The most common form of congenital adrenal hyperplasia is 21-hydroxylase deficiency. Genetically female infants
typically have ambiguous genitalia (virilization) at birth, whereas males have phenotypically normal genitalia, with
salt-wasting or precocious puberty appearing later. Elevated 17-hydroxyprogesterone is diagnostic. [793]
Nonclassic congenital adrenal hyperplasia is due to mild deficiency of 21-hydroxylase, an enzyme that converts
progesterone to 11-deoxycorticosterone and 17-hydroxyprogesterone to 11-deoxycortisol. In adolescent girls, it
presents with signs of hyperandrogenism (eg, hirsutism, acne, menstrual irregularities) as well as increased 17-
hydroxyprogesterone and testosterone levels. [19975]
11β-hydroxylase deficiency typically results in excessive adrenal androgen and mineralocorticoid (11-
deoxycorticosterone) production. Genetically female infants are born with ambiguous genitalia, and affected
individuals develop hypertension and hypokalemia early in life. [611]
Classic 21-hydroxylase deficiency causes decreased cortisol and aldosterone production with increased adrenal
androgen production. In boys, this deficiency presents 1-2 weeks after birth with vomiting, hypotension,
hyponatremia, and hyperkalemia due to salt wasting; genitalia are normal. In girls, it presents at birth with
ambiguous genitalia. [930]
Hypothyroidism
Thyroid dysgenesis (ie, hypoplasia, aplasia, ectopy) is the most common cause of primary congenital
hypothyroidism. In this condition, TSH is elevated and thyroxine (T4) is low. [20168]
DIABETES MELLITUS
Cystic fibrosis
Cystic fibrosis (CF) causes the accumulation of thick, viscous secretions in ducts throughout the body. CF-related
diabetes occurs after the progressive destruction of pancreatic islet cells leads to decreased insulin production. [19345]
Pancreatic disease in cystic fibrosis is characterized by nonselective destruction of alpha and beta cells. Because
alpha cells make up the minority of islet mass, glucagon deficiency and fasting hypoglycemia occur early in the
diabetic disease course. [106771]
Diabetes mellitus
Type 1 diabetes mellitus typically presents subacutely with polyuria and polydipsia accompanied by fatigue and
weight loss. The diagnosis can be confirmed with a fasting blood glucose or hemoglobin A1c measurement. [921]
Most patients with diabetic ketoacidosis have normal to increased serum potassium levels despite a total body
potassium deficit. Replacement of potassium is a crucial step in the management of patients with diabetic
ketoacidosis. [985]
Maternal hyperglycemia causes increased transplacental transfer of glucose to the infant, resulting in fetal
hyperglycemia and subsequent pancreatic beta cell hyperplasia. The pancreatic beta cell hyperplasia causes
hyperinsulinemia, leading to fetal macrosomia and neonatal hypoglycemia. [922]
Hypoglycemia
Glucagon increases serum glucose by increasing hepatic glycogenolysis and gluconeogenesis. Glucagon also
stimulates insulin secretion from the pancreas. Unlike epinephrine, glucagon has an insignificant effect on glucose
homeostasis in the skeletal muscle, adipose tissue, and renal cortex. [849]
Neonatal hypoglycemia is common in infants of diabetic mothers. The pathophysiology involves maternal
hyperglycemia, which in turn causes fetal hyperglycemia and compensatory hyperfunctioning of the pancreas (ie,
hyperinsulinemia). After birth, persistently elevated insulin levels lead to transient hypoglycemia. [19748]
Metabolic acidosis
Normally, metabolic acidosis is partially compensated for by respiratory alkalosis. When the steady-state PaCO2
persists above the range given by the Winter formula (PaCO2 = [1.5 * HCO3−] + 8 ± 2), the patient has a
superimposed respiratory acidosis (respiratory failure). [1979]
Diabetic autonomic neuropathy is common in type 1 diabetics and can cause overflow incontinence due to inability to
sense a full bladder and incomplete emptying. Postvoid residual (PVR) testing with ultrasound or catheterization can
confirm inadequate bladder emptying. [11040]
ENDOCRINE TUMORS
Cushing syndrome
In Cushing syndrome due to an ACTH-secreting pituitary adenoma (Cushing disease), ACTH is high and cortisol
production can be suppressed by high-dose, but not low-dose, dexamethasone. In patients with ectopic ACTH
production (eg, from malignant tumors), cortisol and ACTH production are not suppressed by low- or high-dose
dexamethasone. [612]
Cushing syndrome can be categorized as ACTH-dependent or ACTH-independent. Excess ACTH secretion in ACTH-
dependent Cushing syndrome leads to hyperpigmentation. In addition to increased cortisol production, ACTH
stimulates production of adrenal androgens (eg, testosterone, dehydroepiandrosterone sulfate) leading to hirsutism
and menstrual irregularities. [15063]
Gastrointestinal hormones
Reduced gallbladder contractility, due to decreased cholecystokinin secretion, is responsible for biliary stones in
patients with somatostatinoma. [601]
Hyperparathyroidism
Hypercalcemia inhibits nerve depolarization, leading to impaired smooth muscle contraction and reduced colonic
motility. Symptoms include constipation, crampy abdominal pain, and nausea. [20449]
Hyperprolactinemia
In patients with prolactinoma, high levels of circulating prolactin suppress GnRH secretion from the hypothalamus,
leading to reduced secretion of LH and subsequent hypogonadism, anovulation, and amenorrhea. The resulting
estrogen deficiency can cause osteoporosis with an increased risk for fragility fractures, and lead to vaginal dryness
and atrophy. [218]
Hyperprolactinemia suppresses secretion of GnRH, which leads to reduced estrogen in women. Low estrogen levels
are a risk factor for accelerated bone loss. [223]
Multiple endocrine neoplasia

Multiple endocrine neoplasia type 2 is caused by germline activating mutations in the RET proto-oncogene and
frequently results in both medullary thyroid cancer and pheochromocytoma. In patients with undiagnosed
pheochromocytoma, induction of anesthesia (eg, preparation for thyroidectomy) can precipitate a catecholamine
surge, leading to hypertensive crisis, flash pulmonary edema, and atrial fibrillation. [15105]
Multiple endocrine neoplasia type 1 syndrome is characterized by tumors of the pituitary, parathyroid gland, and
pancreas (the "3 Ps"). [1845]
Multiple endocrine neoplasia type 2B is characterized by medullary thyroid cancer, pheochromocytomas, mucosal
neuromas, and marfanoid habitus. Hyperparathyroidism is not a feature of this syndrome. [988]
Pheochromocytoma
Pheochromocytoma is a tumor arising from the chromaffin cells of the adrenal medulla characterized by excess
production of catecholamines. Clinical features include episodic hypertension, diaphoresis, and
palpitations. Microscopic examination of the tumor cells shows electron-dense, membrane-bound secretory
granules, and immunohistochemistry is positive for synaptophysin, chromogranin, and neuron-specific enolase. [926]
Pituitary adenoma
Pituitary tumors can present with headaches, bitemporal hemianopsia, and hypopituitarism; the most common
hormonally active (functional) adenomas are prolactin-secreting adenomas (prolactinomas). Prolactinomas can cause
galactorrhea and amenorrhea in women. In men, they often present with hypogonadism. [210]
Large prolactin-secreting pituitary tumors can compress the optic chiasm, causing bitemporal hemianopsia. In
addition, elevated prolactin levels suppress release of GnRH, leading to decreased LH secretion and subsequently
impaired testosterone production in men. [213]
SIADH
The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is characterized by low plasma sodium and
osmolality, inappropriately concentrated urine, and clinically normal volume status (euvolemic hyponatremia). An
important cause of SIADH is a paraneoplastic effect secondary to small cell carcinoma of the lung. [226]
Acromegaly
Gigantism is caused by excess growth hormone (GH) during childhood and is characterized by accelerated linear
growth, prognathism, and bony enlargement of the hands and feet. GH excess after closure of the epiphysial growth
plates causes acromegaly. GH has direct effects on target tissues and indirect effects mediated by insulin-like growth
factor-1 secretion from the liver. [224]
Hyperprolactinemia
The release of prolactin is under inhibitory control by dopamine secretion from the hypothalamus. Disruption of
dopaminergic pathways or blockade of dopamine D2 receptors can cause hyperprolactinemia. [214]
Hypopituitarism
Suppression of the hypothalamus-pituitary-adrenal axis by glucocorticoid therapy is the most common cause of
adrenal insufficiency. In these patients, adrenal crisis can be precipitated by stressful situations (eg, infections,
surgery) if the glucocorticoid dose is not increased appropriately. [609]
SIADH
Hyponatremia following cerebral injury (eg, subarachnoid hemorrhage) is commonly due to the syndrome of
inappropriate antidiuretic hormone secretion. Injury to the hypothalamus leads to increased secretion of antidiuretic
hormone, which in turn leads to water retention, low serum osmolality, and increased urinary sodium excretion.
[18546]
MISCELLANEOUS
Gynecomastia
Physiologic gynecomastia is a benign condition caused by a transient proestrogenic hormonal imbalance during
midpuberty; it presents in adolescent boys with unilateral or bilateral tender breast enlargement. Patients should be
reassured that the condition typically self-resolves within a year. [14817]
Hyperparathyroidism
Parathyroid hormone directly stimulates osteoblasts, leading to increased bone formation. Expression of RANK-L on
osteoblasts induces increased bone resorption via a paracrine effect on nearby osteoclasts. Hyperparathyroidism
causes increased RANK-L expression and decreased expression of osteoprotegerin, leading to net bone loss. [19947]
Metabolic syndrome
Visceral obesity as measured by waist circumference or waist-to-hip ratio is an important predictor of insulin
resistance. [1327]
Amenorrhea
Functional hypothalamic amenorrhea results from loss of pulsatile gonadotropin-releasing hormone release from the
hypothalamus and is caused by weight loss, strenuous exercise, systemic illness, or abnormal eating habits. Loss of
cyclic gonadotropin release leads to a decrease in LH and FSH secretion from the pituitary, which in turn causes low
circulating estrogen levels. [925]
Gynecomastia
5-alpha reductase inhibitors (eg, finasteride, dutasteride) are used in the treatment of benign prostatic
hyperplasia. They block the conversion of testosterone to dihydrotestosterone; the excess testosterone is then
available for conversion to estrogens (eg, estradiol) by aromatase, which can lead to gynecomastia. [14818]
Adolescent gynecomastia is often physiologic due to an imbalance of estrogens and testosterone in early
puberty. Features suggestive of pathologic gynecomastia include onset before or after midpuberty (eg, no secondary
sexual characteristics), findings consistent with systemic illness (eg, goiter), as well as size >4 cm, rapid progression,
and location eccentric to the nipple areolar complex. [21761]
Klinefelter syndrome (47,XXY) causes infertility characterized by primary hypogonadism (elevated FSH and LH, low
testosterone) and azoospermia. Other findings include long lower extremities; small, firm testes; and gynecomastia.
[582]
Polycystic ovary disease

Male-pattern hair growth in a woman is called hirsutism; the most common cause is polycystic ovary
syndrome. Combination oral contraceptive pills can treat hirsutism by suppressing pituitary LH secretion and
subsequently decreasing ovarian androgen production. [656]
Precocious puberty
Idiopathic precocious puberty is characterized by early-onset, pulsatile GnRH secretion, resulting in increased
estrogen production. Estrogens promote bone growth but also growth plate (physis) closure, so without treatment,
patients typically have an early growth spurt but a shorter-than-expected adult height. [698]
THYROID DISORDERS
Hyperthyroidism
Pretibial myxedema and Graves ophthalmopathy are specific features of Graves disease. They are caused by an
autoimmune response directed against the TSH receptor that results in the accumulation of glycosaminoglycans
within the affected tissues. [623]
Exogenous hyperthyroidism is characterized by elevated free thyroxine (T4), suppressed TSH, and low/undetectable
thyroglobulin. It can occur with surreptitious levothyroxine misuse, animal-sourced thyroid supplements, and
erroneous dosing of thyroid replacement therapy. Over time, the lack of TSH stimulation causes the thyroid follicles
to become atrophic. [15016]
Hypothyroidism
Thyrotoxicosis, whether due to endogenous hyperthyroidism or over-replacement with thyroid hormone in patients
with hypothyroidism, causes a hyperadrenergic state that can lead to atrial fibrillation, high-output heart failure, and
worsening of angina pectoris. [14985]
Hypothyroid myopathy presents with myalgias, proximal muscle weakness, elevated creatine kinase levels, and
delayed relaxation of deep tendon reflexes. The diagnosis can be confirmed with an elevated TSH level. Other
common causes of myopathy with elevated creatine kinase levels include inflammatory myopathies, muscular
dystrophies, and HMG-CoA reductase inhibitors. [765]
The thyroid releases thyroid hormone (triiodothyronine [T3] and thyroxine [T4]) in response to TSH from the
pituitary, which is regulated by thyrotropin-releasing hormone (TRH) from the hypothalamus. Thyroid hormone
suppresses the secretion of TSH and TRH via negative feedback, and small changes in thyroid hormone levels cause
large changes in TSH. Serum TSH is the most sensitive test for primary hypothyroidism. [764]
Central hypothyroidism is characterized by low serum TSH and thyroxine (T4) levels and is due to hypothalamic-
pituitary dysfunction. Sheehan syndrome is ischemic necrosis of the pituitary gland and is typically caused by
systemic hypotension during delivery. In addition to central hypothyroidism, patients may also develop deficiencies
of other pituitary hormones (eg, ACTH, prolactin, gonadotropins). [14995]
Thyroiditis
thyroid follicles. It typically begins with a hyperthyroid phase due to the release of preformed thyroid hormone,
followed by a hypothyroid phase due to depletion of thyroid hormone and an eventual return to a euthyroid
state. Histologic inspection demonstrates lymphocytic infiltration with the formation of germinal centers, which is
similar to chronic lymphocytic (Hashimoto) thyroiditis. [20366]
thyroid follicles. It typically has a hyperthyroid phase due to release of preformed thyroid hormone, followed by a
hypothyroid phase due to depletion of thyroid hormone stores and eventual return to a euthyroid state. Thyroid
metabolic activity during the hyperthyroid phase is suppressed, and glandular blood flow and radioiodine uptake are
low. [20204]
BREAST DISORDERS
Breast cancer
Peau d'orange is an erythematous, itchy breast rash with skin texture changes that resemble an orange peel. It is the
key dermatologic presentation of inflammatory breast cancer and is caused by cancerous cells spreading to the
dermal lymphatic spaces and obstructing lymphatic drainage. [1877]
Cervical cancer
Human papillomavirus (HPV) infections, particularly types 16 and 18, are the primary cause of cervical dysplasia and
cancer. The risk is higher in patients with increased HPV exposure (eg, multiple sexual partners, lack of barrier
contraception use) or impaired immunity (eg, HIV) due to persistent HPV infection. [869]
Ectopic pregnancy
Ectopic pregnancy occurs when a fertilized embryo implants in an extrauterine location (eg, the fallopian
tube). Patients can have pelvic cramping, vaginal bleeding, and a palpable adnexal mass. [19969]
Endometrial cancer
Endometrial hyperplasia and cancer often present with postmenopausal bleeding. A common risk factor for
endometrial cancer is obesity due to the peripheral aromatization of androgens to estrogens in adipose tissue, which
leads to chronic unopposed estrogen exposure and uncontrolled endometrial tissue proliferation. [18654]
Ovarian Torsion
Ovarian torsion typically occurs in reproductive-aged women due to rotation of the ovary around the
infundibulopelvic (suspensory) and uteroovarian ligaments. Patients typically have sudden-onset unilateral pelvic
pain and a tender adnexal mass. [19886]
Ovarian cancer
The risk of epithelial ovarian cancer increases with the lifetime number of ovulatory cycles. Combined oral
contraceptive pills, multiparity, and breastfeeding are protective factors because they suppress ovulation and
decrease the lifetime number of ovulatory cycles. [578]
Struma ovarii is an ovarian germ cell tumor composed of >50% mature thyroid tissue that can secrete thyroid
hormone. Therefore, struma ovarii can be a rare cause of thyrotoxicosis (eg, weight loss, irregular menses, low TSH
level). [20084]
Uterine fibroids
Leuprolide is a GnRH agonist used to treat symptomatic uterine fibroids (eg, heavy menses, anemia). When
administered in a continuous fashion, leuprolide inhibits the release of endogenous hypothalamic GnRH and
downregulates pituitary GnRH receptors, thereby decreasing GnRH, FSH, and estrogen levels (ie, hypogonadotropic
hypogonadism). [19189]
Pelvic inflammatory disease

Tubal factor infertility, which occurs due to tubal scarring and obstruction, is a complication of pelvic inflammatory
disease. The risk for permanent tubal scarring increases with inadequate antibiotic treatment due to persisting or
prolonged infection of the upper genital tract. [1027]
Pelvic organ prolapse

Stress urinary incontinence (intermittent, involuntary leakage of urine) is caused by weakened pelvic floor muscle
support that often occurs due to chronically increased intraabdominal pressure (eg, obesity, chronic cough, prior
pregnancies). [18930]

Retrograde urine flow through the ureterovesical junction, either due to anatomic abnormalities (eg, short
intravesical ureter) or functional disruption (eg, neurogenic bladder, chronic inflammation), contributes to the
development of acute pyelonephritis. [831]
MENSTRUAL DISORDERS AND CONTRACEPTION

Polycystic ovary syndrome (PCOS) may present with menstrual irregularities, signs of hyperandrogenism (eg, acne,
hirsutism), and obesity. Patients with PCOS typically have bilateral, enlarged, cystic ovaries. [21791]
Biliary atresia
Biliary atresia, or obstruction of extrahepatic bile ducts, presents with jaundice, dark urine, and acholic stools in the
first 2 months of life due to conjugated hyperbilirubinemia. Biopsy reveals intrahepatic bile duct proliferation, portal
tract edema, and fibrosis. [317]
Cholecystitis
Acute cholecystitis is most often caused by gallstones obstructing the cystic duct. The diagnosis can be made by
identifying signs of gallbladder inflammation (eg, wall thickening, pericholecystic fluid) on ultrasonography. When
ultrasound is inconclusive, nuclear medicine hepatobiliary scanning (ie, cholescintigraphy) can be used to assess cystic
duct patency and make the diagnosis. [80]
Primary biliary cholangitis is a chronic autoimmune liver disease characterized by lymphocytic infiltrates and
destruction of small and midsized intrahepatic bile ducts. Similar findings are seen in hepatic graft versus host
disease, highlighting the immunologic etiology of both disorders. [402]
Dubin-Johnson syndrome is a benign disorder characterized by defective hepatic excretion of bilirubin glucuronides
across the canalicular membrane, resulting in direct hyperbilirubinemia and jaundice. Grossly, the liver appears black
due to impaired excretion of epinephrine metabolites, which histologically appear as dense pigments within
lysosomes. [101]
Vitamin A
Vitamin A deficiency causes night blindness and hyperkeratosis. Deficiency of this lipid-soluble vitamin can develop in
patients with fat malabsorption due to chronic biliary obstruction, exocrine pancreatic insufficiency, or small-bowel
resection. [1581]

A vegan diet is characterized by abstinence from all animal-sourced products. Individuals who consume a vegan diet
are often deficient in vitamin B12, calcium, and vitamin D. Those with increased dietary iron requirements (eg,
menstruating women, children) may also develop iron deficiency. Supplementation is routinely recommended. [21497]
Pernicious anemia is an autoimmune disease characterized by CD4+ cell–mediated destruction of parietal

cells. Because these cells normally produce hydrochloric acid, patients with pernicious anemia have elevated gastric
pH, which upregulates gastrin secretion. Decreased parietal cell secretion of intrinsic factor also results in vitamin
B12 deficiency (eg, megaloblastic anemia). [12068]
Vitamin e
Fat-soluble vitamins (A, D, E, K) require micelle formation for absorption, and risk factors for deficiency include
disorders affecting bile production (eg, primary biliary cholangitis). Vitamin E deficiency is characterized by hemolytic
anemia and neurologic deficits (eg, ataxia, loss of vibratory sensation, hyporeflexia). [106480]
Achalasia
Achalasia is caused by reduced numbers of inhibitory ganglion cells in the esophageal wall. Esophageal manometry in
achalasia shows decreased amplitude of peristalsis in the mid esophagus, with increased tone and incomplete
relaxation at the lower esophageal sphincter. [828]
Bariatric surgery
The pyloric sphincter prevents incompletely digested hyperosmolar food particles from entering the intestines too
rapidly; when the sphincter is bypassed or surgically removed, dumping syndrome may occur. Symptoms are related
to excessive intestinal fluid (eg, abdominal cramps, diarrhea, nausea), vasomotor hyperactivity (eg, diaphoresis,
palpitations, flushing), and intravascular volume depletion (eg, hypotension, tachycardia). [20189]
Gastrectomy
Intrinsic factor is a glycoprotein that is normally secreted by parietal cells in the stomach that is necessary for the
majority of vitamin B12 absorption in the ileum. Patients who have undergone a total gastrectomy require lifelong
vitamin B12 supplementation due to inability to produce intrinsic factor. [1605]

New-onset odynophagia in the setting of chronic gastroesophageal reflux disease should raise suspicion for erosive
esophagitis with esophageal ulcers. Diagnosis is made by upper endoscopy. [11591]
Gastroparesis
Diabetic gastroparesis results from the destruction of enteric neurons due to chronic hyperglycemia, leading to
impaired relaxation and disordered and ineffective peristalsis. This causes delayed gastric emptying, which presents
as postprandial fullness, regurgitation of undigested food, nausea, and vomiting. [15652]
Mallory-weiss syndrome
A Mallory-Weiss tear is a tear in the gastric mucosa near the gastroesophageal junction. It typically results from
repetitive forceful vomiting, which can also cause metabolic alkalosis. [1662]
Mastocytosis
Systemic mastocytosis is characterized by the abnormal proliferation of mast cells and increased histamine
release. Histamine causes hypersecretion of gastric acid by parietal cells in the stomach as well as a variety of other
symptoms (eg, hypotension, flushing, pruritus). [306]
Zenker diverticulum
Diminished relaxation of cricopharyngeal muscles during swallowing results in increased intraluminal pressure in the
oropharynx. This may eventually cause the mucosa to herniate through a zone of muscle weakness in the posterior
hypopharynx, forming a Zenker (false) diverticulum, which presents in elderly patients with oropharyngeal dysphagia,
halitosis, regurgitation, and recurrent aspiration. [279]
HEPATIC DISORDERS
Acute liver failure

Inhaled anesthetics, such as halothane, can be associated with a highly lethal fulminant hepatitis that cannot be
distinguished histologically from acute viral hepatitis. Patients have significantly elevated aminotransferase levels
due to massive hepatocellular injury and a prolonged prothrombin time due to failure of hepatic synthetic function.
[369]
Alcoholic liver disease
Alcoholic hepatitis presents with fever, right upper quadrant pain, and jaundice. Typical laboratory findings include
elevated aminotransferases with an AST/ALT ratio >2:1. Histopathology is characterized by marked intrahepatic
neutrophil infiltration, hepatocellular ballooning, Mallory-Denk bodies, and steatosis. [15220]
Gallstone disease
Elevated cholesterol concentrations increase the likelihood of cholesterol precipitation and gallstone formation. High
levels of bile salts and phosphatidylcholine increase cholesterol solubility and decrease the risk of gallstones. [78]
Patients with Crohn disease affecting the terminal ileum (most common site of involvement) are prone to developing
gallstones. Decreased bile acid reabsorption by the inflamed terminal ileum promotes cholesterol supersaturation of
the bile, resulting in gallstone formation. [412]
The absence of normal enteral stimulation in patients receiving total parenteral nutrition leads to decreased
cholecystokinin release, biliary stasis, and increased risk of gallstones. Resection of the ileum can also increase the
risk of gallstones due to disruption of normal enterohepatic circulation of bile acids. [77]
Hepatic Encephalopathy
Hepatic encephalopathy is caused by increased levels of ammonia and other neurotoxins in the circulation that lead
to increased inhibitory neurotransmission and impaired excitatory neurotransmitter release. Hepatic
encephalopathy is frequently precipitated by a stressor (eg, gastrointestinal bleeding, infection) that increases blood
ammonia levels. [102]
Hepatitis b
Hepatitis B virus does not have a cytotoxic effect itself; however, the presence of viral HBsAg and HBcAg on the cell
surface stimulate the host's cytotoxic CD8+ T lymphocytes to destroy infected hepatocytes. [375]
Acute hepatitis B infection can cause a serum sickness-like syndrome with joint pain, lymphadenopathy, and a pruritic
urticarial rash. Other features may include right upper quadrant pain, hepatomegaly, and elevated hepatic
transaminase levels. [365]
Gilbert syndrome is characterized by indirect hyperbilirubinemia due to decreased bilirubin conjugation. Patients
have recurrent, self-resolving episodes of scleral icterus and jaundice triggered by stress. [21115]
Reye syndrome
:Reye syndrome is characterized by acute liver failure (eg, hepatomegaly, elevated aminotransferases, coagulopathy)
and rapidly progressive encephalopathy related to hyperammonemia. It usually develops in susceptible children
during a viral infection after administration of salicylates (eg, aspirin), which cause damage to the mitochondria and
impair fatty acid beta-oxidation within hepatocytes. [21128]
Wilson disease
Wilson disease is caused by defective copper transport within hepatocytes, which leads to impaired biliary excretion
of copper. Hepatic copper accumulation eventually results in the release of free copper into the bloodstream and
copper deposition into extrahepatic tissues (eg, basal ganglia, cornea). [396]
Celiac disease
Celiac disease is an immune-mediated disorder triggered by dietary gluten that causes small-bowel
malabsorption. Because the proximal small bowel is primarily affected, iron deficiency leading to microcytic anemia
is common. Histopathology is characterized by intraepithelial lymphocytosis, loss of intestinal villi, and mucosal
atrophy. [20428]
Diabetic neuropathy
Prolonged hyperglycemia in diabetes mellitus can injure the parasympathetic and sympathetic nervous system,
resulting in diabetic autonomic neuropathy. This can lead to disordered small-bowel and colonic motility and
increased intestinal secretions, resulting in secretory-like diarrhea (eg, fasting bowel movements). [19407]
Groin hernias
Small bowel obstruction (SBO) occurs when a mechanical or functional obstruction disrupts the normal flow of
intestinal intraluminal contents. A herniated bowel loop (eg, inguinal hernia) can cause SBO if it becomes trapped (ie,
incarcerated) outside the peritoneal cavity. [19981]

Crohn disease is associated with oxalate kidney stones. Impaired bile acid absorption in the terminal ileum leads to
loss of bile acids in feces with subsequent fat malabsorption. Intestinal lipids then bind calcium ions, and the
resulting soap complex is excreted. Free oxalate (normally bound by calcium to form an unabsorbable complex) is
absorbed and forms urinary calculi (enteric oxaluria). [408]
Lactose intolerance
The small bowel mucosa of patients with primary lactase deficiency is normal on histologic examination. [134]
Lactose intolerance presents with flatulence, crampy abdominal pain, and watery diarrhea after dairy product
consumption. It can be acquired by inflammatory/infectious conditions that injure the mucosal brush border of the
small intestine where lactase is expressed. Studies can show increased breath hydrogen content, reduced stool pH,
and elevated stool osmolality. [133]
Malabsorption
Malabsorption is a syndrome of impaired intestinal digestion and absorption. Fats are typically the most severely
affected macronutrient in generalized malabsorption, and testing the stool for fat (eg, with Sudan III stain) is the most
sensitive strategy for screening for malabsorptive disorders. [323]
Small intestinal bacterial overgrowth
Small intestinal bacterial overgrowth is characterized by bacterial proliferation in the small bowel, leading to mucosal
inflammation with subsequent fermentation of carbohydrates and fat malabsorption; it manifests with diarrhea,
abdominal distension, and flatulence. Patients with impaired intestinal peristalsis (eg, systemic sclerosis) are at
increased risk. Treatment includes oral antibiotics. [19356]
MISCELLANEOUS
Hemochromatosis
Hereditary hemochromatosis is characterized by increased intestinal iron absorption with deposition of excess iron in
parenchymal tissues. Men typically develop manifestations in their 30s and 40s. However, premenopausal women
have ongoing blood and iron losses due to menstruation, which partially offsets the excess iron absorption and delays
the onset of symptoms. [391]

Chronic pancreatitis may cause vitamin B12 deficiency due to decreased production of pancreatic proteolytic
enzymes (eg, exocrine insufficiency), which are needed to release vitamin B12 from R protein. Other manifestations
of chronic pancreatitis include chronic epigastric pain, weight loss, and steatorrhea. [17682]
Acute pancreatitis
Pancreatic zymogens are normally converted into their active form by trypsin in the duodenal lumen. Premature
cleavage of trypsinogen to trypsin within the pancreas leads to uncontrolled activation of these zymogens, causing
pancreatic autodigestion and acute pancreatitis. [441]
Multiple inhibitory mechanisms exist to prevent premature activation of trypsinogen before it reaches the duodenal
lumen, including cleavage inactivation of trypsin by trypsin itself and production of trypsin inhibitors (eg,
SPINK1). Gene mutations that render trypsin insensitive to cleavage inactivation cause hereditary pancreatitis. [433]
Chronic pancreatitis is an inflammatory disorder leading to pancreatic fibrosis and atrophy, resulting in endocrine (ie,
insulin) and exocrine (eg, lipase, elastase, amylase, trypsin, chymotrypsin) insufficiencies. Patients typically have
postprandial steatorrhea (ie, bulky diarrhea that is difficult to flush) and epigastric pain with meals. Low fecal
elastase, positive Sudan staining, and elevated hemoglobin A1c support the diagnosis. [14939]
Cystic fibrosis
Pancreatic insufficiency is common in cystic fibrosis because thick, viscous secretions in the pancreas block digestive
enzymes, leading to malabsorption (eg, steatorrhea, failure to thrive). The presence of low fecal elastase is an
accurate and noninvasive method for diagnosing pancreatic insufficiency. [19355]
Malabsorption
Polysaccharides must be degraded to monosaccharides by pancreatic and brush border amylases before they can be
absorbed. Monosaccharides can be absorbed directly. D-xylose is a monosaccharide whose absorption is not
affected by exocrine pancreatic insufficiency, and can be used to differentiate between pancreatic versus mucosal
causes of malabsorption. [1907]
Anal cancer
Anal squamous cell carcinoma is strongly associated with human papillomavirus and typically presents with rectal
bleeding, pruritus, and/or pain; examination demonstrates an ulcerated or nodular, exophytic anal lesion. Histology
reveals large, eosinophilic, hyperchromatic squamous cells arranged in islands with nuclear atypia and prominent
keratinization. [19112]
Carcinoid tumors
Carcinoid tumors confined to the intestine do not cause carcinoid syndrome as their secretory products are
metabolized by the liver before entering the systemic circulation. In contrast, intestinal carcinoids that metastasize
to the liver and extraintestinal (eg, bronchial) carcinoids release vasoactive substances that avoid first-pass
metabolism, resulting in carcinoid syndrome (eg, flushing, diarrhea, bronchospasm). [425]
Anticoagulants
Direct factor Xa inhibitors (eg, apixaban, rivaroxaban) increase the prothrombin and activated partial thromboplastin
times but do not affect the thrombin time. Unfractionated heparin and direct thrombin inhibitors (eg, dabigatran)
prolong the thrombin time. [2133]
Atrial fibrillation
Patients started on warfarin develop a transient hypercoagulable state due to the short half-life of protein C. This
hypercoagulability is further exaggerated by preexisting protein C deficiency and can result in thrombotic occlusion of
the microvasculature with skin necrosis. [1292]
Av malformation
Patients with severe aortic stenosis are at high risk for mucocutaneous and colonic bleeding due to acquired von
Willebrand deficiency. The von Willebrand factor multimers become unfolded by the high shear stress, leading to
increased destruction by the ADAMTS13 metalloproteinase. [20730]
Cirrhosis
Vitamin K-dependent coagulation factors (II, VII, IX, and X) are synthesized in the liver. Factor VII has the shortest
half-life of the coagulation factors. Failure of the prothrombin time to correct with vitamin K supplementation
indicates factor VII deficiency, which is often due to underlying liver disease. [1291]
Coagulopathy
A normal bleeding time indicates adequate platelet hemostatic function. A normal activated partial thromboplastin
time (aPTT) indicates an intact intrinsic coagulation system. Prolonged prothrombin time in the setting of normal
aPTT indicates a defect in the extrinsic coagulation system at a step that is not shared with the intrinsic system. [1903]
DIC
Disseminated intravascular coagulation is marked by widespread activation of the coagulation cascade, leading to
excessive thrombin production and formation of microthrombi. Subsequent conversion of plasminogen to plasmin
results in increased fibrinolysis to clear the thrombi. Laboratory studies show a consumption of clotting factors
(prolonged PT/PTT) and platelets (thrombocytopenia) and signs of excessive fibrinolysis (eg, elevated D-dimer). [16442]
Patients with cystic fibrosis are at risk for fat-soluble vitamin (ie, A, D, E, K) deficiency due to fat malabsorption from
pancreatic insufficiency. Vitamin K is an important cofactor in the activation of coagulation factors II, VII, IX, and
X. Vitamin K deficiency leads to easy bruising, mucosal bleeding, and prolonged PT. [20361]
MISCELLANEOUS

Vitamin B12 is an essential cofactor in the recycling of 5-methyl-tetrahydrofolate to tetrahydrofolate, which is
required for amino acid, purine, and thymidine synthesis. Deficiency primarily affects hematopoiesis and is marked
by impaired nuclear maturation, leading to macrocytic red blood cells and hypersegmented neutrophils; increased
apoptosis often also leads to anemia and mild thrombocytopenia/leukopenia. [16287]
NORMAL HEMATOLOGIC STRUCTURE AND FUNCTION
Aging
Patients of advanced age have increased bone marrow fat and reduced bone marrow mass, leading to impaired bone
marrow reserve. This results in an inability to rapidly generate new blood cells in response to acute stress (eg, blood
loss, hypoxia). [19289]
PLATELET DISORDERS
Heparin induced thrombocytopenia

Heparin-induced thrombocytopenia type 2 results from the formation of IgG antibodies to complexes of heparin and
endogenous platelet factor 4. The major manifestation is thrombocytopenia, which typically occurs 5-10 days after
heparin initiation due to the destruction of antibody-coated platelets by splenic macrophages. Widespread
intravascular platelet activation also results in a high risk of arterial and venous thrombosis. [14791]
Platelet dysfunction
Chronic kidney disease increases the risk for platelet dysfunction, which is thought to be due to inappropriately
upregulated nitric oxide, causing decreased platelet adhesion, activation, and aggregation. Coagulation studies and
platelet count are typically normal. [106238]

Thrombotic thrombocytopenic purpura is a thrombotic microangiopathy resulting in microangiopathic hemolytic
anemia and thrombocytopenia, findings that are essential for making the diagnosis. It is triggered by severe
deficiency in ADAMTS13 levels. [11624]

Von Willebrand disease is the most common inherited bleeding disorder and is usually transmitted in an autosomal
dominant fashion. Symptomatic patients typically present with easy bruising and mucosal bleeding. Laboratory
evaluation will show normal platelets, normal PT, and either normal or prolonged PTT due to low levels of factor VIII.
[16705]
Patients with von Willebrand disease often present with a lifelong history of mucosal bleeding, including gingival
bleeding, epistaxis, and/or menorrhagia. These patients have normal platelet levels but typically have a prolonged
bleeding time due to impaired platelet functioning. [2097]
von Willebrand factor (vWF) functions as a promoter of platelet adhesion at sites of vascular injury by binding platelet
glycoproteins to subendothelial collagen on injured blood vessel walls. It also acts as a protective carrier protein for
circulating factor VIII. [2098]

Head and neck squamous cell carcinomas typically spread first to the anterior cervical lymph nodes via the
lymphatics. The involvement of anterior cervical lymph nodes affects the staging of the disease. [18649]
Tumor lysis syndrome

Tumor lysis syndrome occurs when tumors with a high cell turnover are treated with chemotherapy. The lysis of
tumor cells causes intracellular ions, such as potassium and phosphorous, and uric acid (metabolite of tumor nucleic
acid) to be released into serum. Uric acid is soluble at physiologic pH, but it can precipitate in the normally acidic
environment of distal tubules and collecting ducts. The prevention of tumor lysis syndrome includes urine
alkalinization and hydration, as high urine flow and high pH along the nephron prevents crystallization and
precipitation of uric acid. [1050]
Acute intermittent porphyria

Acute intermittent porphyria is an autosomal dominant condition caused by porphobilinogen deaminase
deficiency. Most patients remain asymptomatic, but a minority present with acute attacks characterized by
abdominal pain and vomiting, peripheral neuropathy, neuropsychological symptoms, and reddish-brown
urine. Treatment consists of intravenous glucose or heme preparations, which downregulate ALA synthase activity.
[1339]
Anemia of inflammation
Anemia of chronic disease is caused by chronic elevations in inflammatory cytokines, which lead to reduced iron
absorption and increased iron retention in the reticuloendothelial system. This impairs iron availability and causes a
normocytic or slightly microcytic anemia with low serum iron and low total iron-binding capacity. [19136]
Anemia of chronic disease is caused by elevated inflammatory cytokine levels (eg, hepcidin), which increase
sequestration of iron within the reticuloendothelial system and reduce circulating iron levels. Many patients have
improvement in anemia with treatment of the underlying condition that caused the inflammation. [19123]
Anemia of chronic disease (ACD) occurs in patients with rheumatologic diseases, chronic infection, malignancy,
congestive heart failure, and morbid obesity due to chronic elevation of inflammatory cytokines. The primary
mediator is hepcidin, a peptide released from the liver that inhibits iron channels on enterocytes and
reticuloendothelial macrophages. This reduces iron availability for erythropoiesis, which leads to normocytic (or
slightly microcytic) anemia with a poor reticulocyte response. [19125]
Anemia of chronic disease is a consequence of chronically elevated inflammatory cytokines, most importantly
hepcidin. This peptide inactivates iron channels on enterocytes and reticuloendothelial macrophages, leading to
reduced iron absorption and reduced iron release from the reticuloendothelial system. The net result is normocytic
or slightly microcytic anemia with low reticulocyte response, low serum iron level, and normal or low total iron-
binding capacity. [19124]

Folate is essential for nucleic acid metabolism, and deficiency causes ineffective hematopoiesis with a low
reticulocyte count. Characteristic megaloblastic changes include hypersegmented neutrophils and macrocytic red
blood cells. Macrocytic erythrocytes are prone to hemolysis, which can increase serum bilirubin and lactate
dehydrogenase. [107400]
G6PD deficiency
Glucose-6-phosphate dehydrogenase deficiency is marked by periods of acute hemolysis after oxidative stress (eg,
dapsone exposure). It presents with anemia and hemolysis. Peripheral smear shows denatured hemoglobin
inclusions called Heinz bodies. [19137]
Hemolytic anemia
In patients with hemolytic anemia, peripheral blood smear usually reveals evidence of reticulocytosis, spherocytes,
and nucleated red blood cells. [19140]
Hemolytic uremic syndrome (HUS) manifests with acute kidney injury, microangiopathic hemolytic anemia, and
thrombocytopenia. Characteristic laboratory abnormalities include decreased hemoglobin and platelet count and
increased bleeding time, lactate dehydrogenase, bilirubin, blood urea nitrogen, and creatinine. [1851]
Hereditary spherocytosis
In spherocytosis, mean corpuscular hemoglobin concentration (MCHC) is increased due to mild dehydration of the
red blood cell. Markers of hemolysis are often evident and include elevated lactate dehydrogenase, reticulocytosis,
and decreased haptoglobin. [890]

Patients with severe iron deficiency anemia (IDA) typically have evidence of hypochromic, microcytic erythrocytes on
peripheral blood smear with poikilocytosis. Laboratory studies will reveal low red blood cell count, low hepcidin, and
high transferrin. Although erythropoietin is markedly elevated in IDA, there is not enough iron to efficiently generate
erythrocytes; therefore, reticulocyte count is low. [19135]
Infants who do not receive adequate iron supplementation are at risk for developing iron deficiency, which
progresses in stages as total body iron is depleted. The earliest stage involves loss of iron in storage (decreased
serum ferritin), followed by iron-limited erythropoiesis with decreased serum iron and transferrin saturation. Frank
iron deficiency anemia, involving the classic findings of low hemoglobin, microcytic/hypochromic erythrocytes, and a
low reticulocyte count, is a late finding. [106040]
Lead poisoning
Lead poisoning in adults typically occurs through occupational exposure. Symptoms include colicky abdominal pain,
constipation, lead lines on the gum, peripheral neuropathy, and anemia. Laboratory testing shows microcytic anemia
with normal iron studies, and peripheral blood smear may reveal basophilic stippling. [1156]
Paroxysmal nocturnal hemoglobinuria

The triad of hemolytic anemia, hypercoagulability, and pancytopenia suggests paroxysmal nocturnal hemoglobinuria
(PNH). PNH results from an acquired mutation in the PIGA gene that causes absence of the
glycosylphosphatidylinositol anchor and associated deficiency of CD55 and CD59 complement inhibitor proteins. [897]
Sickle cell
Howell-Jolly bodies on peripheral smear reflect splenic dysfunction, which occurs in sickle cell disease due to
recurrent infarction of the splenic vasculature. Functional asplenia increases the risk of invasive infection with
encapsulated organisms. [12375]
Dactylitis (painful swelling of the hands and feet) is a common presentation of sickle cell disease (SCD) in young
children. It is one of many vasoocclusive manifestations of SCD. Sickling episodes result in hemolysis, which leads to
increased indirect bilirubin and lactate dehydrogenase and decreased levels of haptoglobin. [1855]
Splenectomy
Target cells form when erythrocytes have reduced cell volume (eg, thalassemia, iron deficiency) or excessive
membrane (eg, obstructive liver disease, postsplenectomy). Patients who undergo splenectomy usually develop
target cells because the spleen is the primary organ that prunes excessive red cell membrane. [14983]
Thalassemia
Beta-thalassemia is caused by mutations that result in defective transcription, processing, and translation of beta-
globin mRNA. This leads to deficiency of the beta-globin chains required for normal hemoglobin synthesis. [1940]

Allogeneic hematopoietic stem cell grafts normally include donor CD3+ T cells that can initiate graft versus host
disease (GVHD), a widespread inflammatory response that can damage multiple organs. Depletion of donor CD3+ T
cells prior to transplant decreases the risk of GVHD but also decreases the beneficial graft versus tumor effect,
increasing the likelihood of cancer relapse. [16141]
Lymphadenopathy
Lymph node enlargement is most commonly due to infection-triggered cellular proliferation but can be caused by
clonal expansion of malignant cells. Enlargement of the supraclavicular lymph nodes, which drain the chest and
abdomen, is unlikely to be caused by common childhood infections and is concerning for malignancy. [19442]
Multiple myeloma
Multiple myeloma is a plasma cell malignancy associated with purely radiolucent (osteolytic) bone lesions due to the
stimulation of osteoclasts and the inhibition of osteoblasts. Myeloma cells stimulate osteoclast development by
secreting RANK-ligand and destroying osteoprotegerin, which increases RANK activity and results in osteoclast
differentiation. [15134]
Multiple myeloma should be suspected in elderly patients who have any combination of osteolytic lesions,
hypercalcemia, anemia, or acute kidney injury. Renal disease is most commonly caused by light chain cast
nephropathy, in which free light chains form obstructive casts in the renal tubules. Monoclonal paraproteins are not
detected by urine dipstick (which detects only albumin), but both spot and 24-hour protein concentrations will be
elevated. [15133]
Myelofibrosis
Primary myelofibrosis is a chronic myeloproliferative disorder associated with bone marrow fibrosis. Extramedullary
hematopoiesis leads to marked expansion of the splenic red pulp with hematopoietic progenitor cells, resulting in
massive splenomegaly. Patients also usually have hepatomegaly, cytopenias, and peripheral smear abnormalities (eg,
dacrocytes, nucleated red cells, immature granulocytes). [15248]
Infectious Diseases
Febrile neutropenia
Cytotoxic chemotherapy nonselectively kills rapidly dividing cells, including tumor, hair follicle, bone marrow, and
gastrointestinal epithelial cells. Severe infections are common due to neutropenia from myelosuppression and
commensal bacterial invasion via gastrointestinal epithelial damage from mucositis. [106397]
Patients who undergo cytotoxic chemotherapy are at high risk for bacterial infections due to
neutropenia. Neutropenic fever often manifests with fever, chills, and hypotension but purulence is rare due to a
lack of neutrophils. [106389]
Rheumatic fever
Acute rheumatic fever is an autoimmune reaction following an untreated group A streptococcal pharyngitis. Anti-
group A Streptococcus antibodies (eg, anti-M protein, anti-N-acetyl-beta-D-glucosamine) cross-react and attack
cardiac and central nervous system antigens. [724]
FUNGAL INFECTIONS
Pneumocystis pneumonia
Pneumocystis pneumonia is an atypical fungal infection seen primarily in those with impaired cell-mediated immunity
(eg, advanced AIDS). Manifestations often include slowly worsening pulmonary symptoms, hypoxia, and bilateral
interstitial infiltrates on chest x-ray. The cystic organism can be visualized using silver stain of respiratory secretions.
[14870]
Echinococcosis
Echinococcus granulosus is the most common cause of hydatid cysts. Spilling of cyst contents can cause anaphylactic
shock. Surgical manipulation should be performed with caution. [61]
Infertility
Androgen receptor dysfunction in patients with partial androgen insensitivity syndrome leads to decreased facial,
axillary, and pubic hair; oligospermia; gynecomastia; and undervirilization of external genitalia (eg,
microphallus). Loss of feedback inhibition of gonadotropin-releasing hormone results in elevated LH and
testosterone levels. [19030]
Testicular torsion
Testicular torsion presents with acute, severe, progressive unilateral scrotal pain. Classic examination findings
include scrotal edema and discoloration, a high-riding testicle, and an absent cremasteric reflex (ie, absence of
testicular elevation when stroking the ipsilateral thigh). [20231]
MISCELLANEOUS
Aging
Physiologic age-related changes in the cardiopulmonary system can lead to reduced ability to cope with critical
illness. These changes include reduced maximal heart rate and cardiac output due to decreased responsiveness to
adrenergic stimuli, reduced retention of arterial blood volume due to decreased arterial compliance, and reduced
respiratory strength and gas exchange efficiency. [19259]
Kawasaki disease
Kawasaki disease is a vasculitis characterized by fever for ≥5 days and ≥4 of the following findings: nonexudative
conjunctivitis, extremity changes, cervical lymphadenopathy, mucositis, and polymorphous rash. [20774]
Nervous System
ANESTHESIA
Anesthesia
In patients with malignant hyperthermia, exposure to certain anesthetic agents (eg, succinylcholine, inhalational
gasses) causes unregulated passage of calcium from the sarcoplasmic reticulum into the intracellular space. This
results in sustained muscle contraction that leads to hypercarbia, hyperthermia, and acidosis. [18755]
CNS INFECTIONS
Meningitis
Pneumococcal meningitis is associated with massive cerebrospinal fluid inflammatory cytokine release in response to
bacterial cell wall components. Treatment with dexamethasone prior to antibiotic therapy has been shown to reduce
inflammation and decrease the risk of adverse outcomes (eg, seizures, focal neurologic deficits) and death. Other
forms of bacterial meningitis do not seem to benefit from glucocorticoid treatment. [14899]
Cocaine
Cocaine blocks the presynaptic reuptake of catecholamine neurotransmitters, including norepinephrine and
dopamine. With cocaine toxicity, excessive postsynaptic stimulation by catecholamines can lead to arterial
vasospasm and increased sympathetic drive, resulting in increased risk of stroke and myocardial infarction. [19402]
Ischemic stroke
Glutamate is released from injured neurons, causing pathologic hyperactivation of NMDA receptors and leading to
depolarization, calcium overload, and death of neighboring cells. This cascade of excitotoxicity contributes to
neurodegeneration and propagation of neuron death after focal injury. [21212]
Upper motor neuron signs include abnormal plantar flexion (Babinski sign), spastic paralysis, increased muscle tone,
clasp-knife rigidity, hyperreflexia, pronator drift, and pyramidal weakness (weakness more pronounced in lower
extremity flexors and upper extremity extensors). Lower motor neuron signs include flaccid paralysis, weakness with
hypotonia and muscle atrophy, fasciculations, and suppressed or absent reflexes. [1920]
Ataxia telangiectasia
Ataxia-telangiectasia is an autosomal recessive disorder resulting from defective DNA break repair. Classic findings
include cerebellar ataxia, telangiectasias, and recurrent sinopulmonary infections. [587]
Myotonic Dystrophy
Myotonic dystrophy type 1 is due to a cytosine-thymine-guanine trinucleotide repeat expansion in the dystrophia
myotonica protein kinase (DMPK) gene, resulting in untranslatable mutant mRNAs. The mutant mRNAs form hairpin
structures and accumulate in the nucleus, sequestering certain RNA-binding proteins and leading to aberrant
splicing. Nondividing cells of the brain, skeletal muscles, and myocardium are particularly affected. [22189]
Central pontine myelinolysis

Osmotic demyelination syndrome results from overly rapid correction of chronic hyponatremia. Clinical features
include quadriplegia, pseudobulbar palsy, and reduced level of consciousness. MRI demonstrates focal
demyelination of the pons. [15600]
Bell's palsy
Because the upper face receives bilateral input from the motor cortices, central nervous system lesions typically
cause unilateral lower facial weakness that spares the forehead. In contrast, peripheral lesions (eg, Bell palsy) cause
weakness of the entire side of the face. Bell palsy may also result in decreased tear production, hyperacusis, and
reduced taste sensation. [21725]
Critical illness polyneuromyopathy
Critical illness can lead to weakness due to both myopathy (eg, atrophy of muscles) and polyneuropathy (eg, axonal
degeneration, decreased nerve excitability). This can lead to both extremity weakness and difficulty breathing due to
chest wall weakness. [19487]
Myasthenia gravis
Progressively weakening diaphragmatic contractions during maximal voluntary ventilation with intact phrenic nerve
stimulation indicate neuromuscular junction pathology (eg, myasthenia gravis) and/or abnormally rapid
diaphragmatic muscle fatigue (eg, restrictive lung or chest wall disease). [1657]
Myasthenia gravis is an autoimmune disease that causes a decrease in the number of functional acetylcholine
receptors within the neuromuscular junction. This reduces the number of postsynaptic cation channels that can open
in response to acetylcholine, which reduces the amplitude of motor end plate potential and prevents muscle fiber
depolarization. [2061]
The treatment of myasthenia gravis involves the use of a cholinesterase inhibitor, immunosuppressants, and possible
thymectomy. Cholinesterase inhibitors may cause adverse effects related to muscarinic overstimulation, which can
be ameliorated by the use of an antimuscarinic agent such as glycopyrrolate, hyoscyamine, or propantheline. [2062]
Neuronal physiology
A neuroma forms when regenerating axons are unable to find their distal target and create a haphazard mass of
axons and supporting cells. Upregulation of voltage-gated sodium channels, which generate and propagate action
potentials, is likely responsible for the increased pain of these lesions. [19887]
Ulnar neuropathy is characterized by numbness of the fourth and fifth digits, pain, and weakness. It is most
commonly caused by compressive injury, leading to tissue ischemia and demyelination (Schwann cell injury). A nerve
conduction study can help differentiate demyelinating versus axonal neuropathies; demyelination causes slowed or
blocked nerve conduction velocity whereas axonal injury leads to a reduction in signal strength. [15612]
Seafood poisoning
Pufferfish poisoning is caused by tetrodotoxin, a neurotoxin produced by microorganisms associated with the
fish. Tetrodotoxin binds to voltage-gated sodium channels in nerve and cardiac tissue, preventing sodium influx and
depolarization. [8352]
Tetanus
Tetanus is a clinical diagnosis that should be suspected in patients who have characteristic symptoms (eg, lockjaw,
muscle pain/spasms, difficulty swallowing), particularly if they are unlikely to be adequately vaccinated or have an
antecedent cutaneous injury. [969]
Tetanospasmin is a neuro-exotoxin released by Clostridium tetani. The toxin blocks the release of glycine and
gamma-aminobutyric acid (GABA) from the spinal inhibitory interneurons that regulate the lower motor
neurons. These disinhibited motor neurons cause increased activation of muscles, leading to spasms and
hyperreflexia. [966]
HEADACHE
Migraine
Migraines are episodic, unilateral, throbbing headaches associated with nausea, vomiting, and sensitivity to light. The
pathogenesis of migraines involves a genetic predisposition to increased cerebral excitability (eg, cortical spreading
depression), which leads to abnormal neuronal activation of trigeminal afferents and the release of calcitonin gene-
related peptide, a vasoactive neuropeptide involved in the transmission of pain signals. [18974]
HYDROCEPHALUS
Hydrocephalus
Congenital hydrocephalus often presents with macrocephaly and poor feeding. Imaging studies showing enlarged
ventricles are diagnostic. Untreated hydrocephalus leads to developmental delays, poor growth, and muscle
spasticity (due to stretching of the periventricular pyramidal tracts). [1854]
MISCELLANEOUS
Anoxic brain injury

Neuronal damage after hypoxic-ischemic injury is often related to the formation of reactive oxygen species, which
mediate widespread cellular damage. Therapeutic hypothermia decreases the formation of reactive oxygen species
by decreasing cellular metabolism and slowing reperfusion. [19639]
Alzheimer disease
Neuropathologic features of Alzheimer disease include neurodegeneration, amyloid plaques (ie, extracellular
accumulations of beta amyloid), and neurofibrillary tangles. Neurofibrillary tangles are formed when tau, a protein
associated with neuronal microtubules, becomes hyperphosphorylated and disassociates from the microtubules to
form paired helical filaments. [19476]
The frontal lobes are involved in personality, language, motor functions, and executive functions (eg,
abstraction). Frontal lobe function may be diagnosed by testing abstraction ability (eg, asking about the similarities
between two related objects) on the mental status examination. [15648]
Parkinson disease
The majority of substantia nigra dopaminergic neurons (>60%) are lost prior to the onset of motor symptoms in
idiopathic Parkinson disease. During this prodromal period, dopamine depletion is offset by several compensatory
mechanisms, including the upregulation of postsynaptic dopamine receptors. [106625]
Neuromuscular junction
Acetylcholine release from presynaptic terminal vesicles at the neuromuscular junction depends upon the influx of
extracellular calcium into the presynaptic terminal. Calcium influx into the nerve terminal occurs following neuronal
depolarization and opening of voltage-gated calcium channels. [1934]
Febrile seizure
Febrile seizure is usually a benign neurologic disorder that occurs most commonly in children age 6 months to 5 years
who have high fever due to a viral illness. The pathophysiology involves hyperthermia-induced neuronal dysfunction
triggering a short (<5 min) generalized seizure; treatment is generally supportive with antipyretics for fever reduction.
[866]
Reye syndrome
Reye syndrome should be suspected in a young child with acute liver failure and encephalopathy after receiving
aspirin for a virus-induced fever. Aspirin in this setting is a mitochondrial toxin that leads to hepatic steatosis,
hyperammonemia, and diffuse astrocyte swelling (ie, cerebral edema). [21132]
Seizures
Recurrent focal impaired awareness seizures that are preceded by a distinctive aura (eg, uneasy epigastric sensation,
olfactory hallucinations) are characteristic of mesial temporal lobe epilepsy. The most common etiology is
hippocampal sclerosis (mesial temporal sclerosis), which is associated with childhood febrile seizures. [15728]
Focal-onset seizures most commonly occur due to a focal structural abnormality (eg, stroke, neoplasm) that causes a
region of hyperexcitable neuronal activity in one cerebral hemisphere. These seizures begin with localized
symptomatology (eg, muscle twitching, paresthesia) and are classified according to level of consciousness (eg, aware,
impaired awareness). They can progress to bilateral tonic-clonic seizures if the excitatory neuronal activity spreads to
involve both cerebral hemispheres. [15947]
SLEEP DISORDERS
Insomnia
Age-related sleep changes may be reported as insomnia and must be differentiated from primary sleep disorders and
other disorders. Normal changes include decreased total sleep time, increased nighttime awakenings, sleepiness
earlier in the evening with earlier morning awakening, and increased daytime napping. [15644]
Narcolepsy
Hypocretin-1 (orexin-A) and hypocretin-2 (orexin-B) are neuropeptides produced in the lateral hypothalamus that
promote wakefulness and inhibit REM sleep–related phenomena. Most patients who have narcolepsy with cataplexy
have undetectable levels of hypocretin-1 in their cerebrospinal fluid. [8878]
Narcolepsy is a chronic sleep disorder characterized by excessive daytime sleepiness, cataplexy, and REM sleep-
related phenomena (ie, hypnagogic/hypnopompic hallucinations, sleep paralysis). [1458]
Parasomnias
REM sleep is characterized by dreaming and voluntary muscle paralysis, and occurs more often during the final third
of the night. Nightmares occur during REM sleep and can be differentiated from sleep terrors, a non-REM
parasomnia characterized by incomplete arousals and lack of recall of dream content. [15523]
Sleepwalking, a common non-REM parasomnia of childhood, occurs during slow-wave sleep (stage N3), which is
characterized by delta waves on EEG. Sleepwalking typically occurs during the first half of the night, when slow-wave
sleep is most prominent. [15762]
Long-standing rheumatoid arthritis can affect the cervical spine, causing vertebral malalignment (subluxation) that
can affect the atlantoaxial joint. Extension of the neck during endotracheal intubation can worsen the subluxation,
leading to acute compression of the spinal cord and/or vertebral arteries. [11793]
Vitamin e
Neurologic symptoms of vitamin E deficiency closely mimic those of Friedreich ataxia and include ataxia
(spinocerebellar tract degeneration), loss of position and vibration sense (dorsal columns degeneration), and
weakness and hyporeflexia (peripheral nerve degeneration). [671]
Ophthalmology
Cataract
Cataracts are characterized by progressive opacification of the lens with chronic loss of visual acuity. Aging and
environmental exposures (eg, UV light) contribute to cataract formation by inducing nuclear sclerosis, photooxidative
damage to lens crystallins, and osmotic injury. [18951]
Idiopathic Intracranial Hypertension

Idiopathic intracranial hypertension (pseudotumor cerebri) presents in young obese women with daily headache
(which worsens during the Valsalva maneuver), bilaterally symmetric papilledema, and transient visual
disturbances. Increased intracranial pressure compresses the optic nerves, resulting in impaired axoplasmic flow and
optic disc edema. [12257]
Macular degeneration
A scotoma is a visual field defect that occurs due to a pathologic process that involves parts of the retina or the optic
nerve resulting in a discrete area of altered vision surrounded by zones of normal vision. Lesions of the macula cause
central scotomas. [1356]
Refractive errors
Myopia (nearsightedness) is a refractive error in which the focal point of an image falls anterior to the retina due to
an increased anterior-posterior diameter of the eyes. Patients have difficulty seeing objects at a distance and have
normal near vision. [18896]
Retinal artery occlusion

Central retinal artery occlusion presents with sudden, painless, and permanent monocular blindness. Funduscopic
examination reveals a pale retina and a "cherry-red" macula. [360]
Retinitis pigmentosa
Retinitis pigmentosa is a genetic condition resulting in progressive dystrophy of retinal pigmented epithelium and
photoreceptors. Patients typically present with progressive night blindness and loss of peripheral vision due to early
loss of rods, which are highly metabolically active. Funduscopic examination may show dark pigments deposited in a
bone-spicule pattern in addition to retinal vessel attenuation and optic disc pallor. [19126]
NEOPLASIA
Posttransplantation lymphoproliferative disorder

Posttransplantation lymphoproliferative disorder occurs in patients who have undergone solid-organ or stem cell
transplantation and are taking high-dose immunosuppressive medications. Most cases are caused by the reactivation
of Epstein-Barr virus, which generates viral proteins that stimulate B-cell proliferation and survival. Patients usually
have mononucleosis-like symptoms. [20932]
Heat related illness

Nonexertional heat stroke (NHS) is a life-threatening disorder characterized by hyperthermia (typically >40 C [104 F])
associated with CNS dysfunction (eg, encephalopathy, syncope). Anticholinergic medications promote heat stroke by
impairing diaphoresis. Other medications associated with NHS include sympathomimetics, dopamine antagonists,
diuretics, and beta blockers. [19088]
Exercise-associated collapse typically occurs after intense exercise in well-conditioned athletes. It is characterized by
loss of postural tone or syncope immediately following the cessation of exercise and occurs due to impaired venous
return to the heart. [19084]
Elderly patients are at increased risk of developing heat-related illness due to several features of normal aging that
impair normal thermoregulatory mechanisms, including tonic contraction of the peripheral vasculature, reduced
sweat gland density, and reduced effective epidermal area available for heat transfer. [19108]
TOXICOLOGY
Mercury toxicity
Mercury impairs the breakdown of catecholamines, and toxicity can lead to excessive stimulation of the sympathetic
nervous system (eg, tachycardia, hypertension, diaphoresis). A desquamating hypersensitivity rash can also occur,
and deposition in the CNS can result in personality changes, insomnia, and tremor. [107146]
Salicylate poisoning
Salicylate intoxication should be suspected in patients with the triad of fever, tinnitus, and tachypnea. Salicylates
both stimulate central respiratory drive to cause primary respiratory alkalosis and disrupt cellular metabolism to
cause primary anion gap metabolic acidosis. Therefore, toxicity classically presents with a mixed acid-base
disturbance and a blood pH sometimes within the normal range. [1544]
Abruptio placentae
Abruptio placentae, detachment of the placenta from the uterus prior to fetal delivery, presents with painful vaginal
bleeding; a tender, firm uterus; and fetal heart rate abnormalities. Risk factors include abdominal trauma, maternal
hypertension, and tobacco or cocaine use. [19885]
Amniotic fluid embolism

Amniotic fluid embolus syndrome is a rare but catastrophic obstetric emergency that leads to respiratory failure and
obstructive shock with an elevated central venous pressure and a decreased pulmonary capillary wedge pressure and
cardiac index. It also commonly involves a consumptive coagulopathy with widespread hemorrhage. [106231]
Aromatase deficiency
Aromatase is responsible for converting androgens into estrogens. Deficiency of this enzyme causes accumulation of
androgens during pregnancy, resulting in ambiguous external genitalia in newborn females and maternal gestational
virilization. [955]
Ectopic pregnancy
Ectopic pregnancy may present with unilateral lower abdominal pain, adnexal tenderness, and vaginal
bleeding. Patients with a ruptured ectopic pregnancy have severe intraabdominal bleeding, which causes diffuse
abdominal pain with rebound/guarding and hemodynamic instability. [20380]
Gallstone disease
Estrogen-induced cholesterol hypersecretion and progesterone-induced gallbladder hypomotility are responsible for
the increased incidence of cholelithiasis in women who are pregnant or using oral contraceptives. [68]
Gestational trophoblastic disease

A partial mole will have a triploid karyotype (eg, 69,XXX or XXY) and contain fetal tissue with some edematous villi
with focal trophoblastic proliferation, and normal-appearing villi. Patients present with vaginal bleeding, and prior
miscarriage is a risk factor. [792]
Choriocarcinoma is a malignant form of gestational trophoblastic disease composed of anaplastic cytotrophoblasts

and syncytiotrophoblasts without villi. It often presents as dyspnea/hemoptysis due to pulmonary metastasis from
hematogenous spread. [335]
A complete hydatidiform mole is composed of multiple cystic edematous hydropic villi resulting from trophoblast
proliferation. Serial measurements of β-hCG should be performed following evacuation of a hydatidiform
mole. Persistently elevated or rising levels may signify the development of an invasive mole or choriocarcinoma. [791]
Postpartum hemorrhage
Tranexamic acid (TXA) is an antifibrinolytic medication that stabilizes blood clots in hemorrhaging patients. It inhibits
plasmin formation, thereby preventing fibrin degradation and clot dissolution. TXA used for the treatment of
postpartum hemorrhage improves maternal morbidity and mortality. [16525]
Preeclampsia
Preeclampsia causes widespread endothelial dysfunction, resulting in dysregulated vascular tone, increased vascular
permeability, and decreased end-organ perfusion. Therefore, a common presentation is headache with visual
changes (eg, scotomata) due to dysregulated cerebral blood flow and retinal artery vasospasm. [19437]
Abruptio placentae is caused by rupture of maternal vessels at the uteroplacental interface that leads to premature
separation of the placenta from the myometrium. Patients typically have painful vaginal bleeding and a tender, firm
uterus. Preeclampsia increases the risk of abruptio placentae. [19438]
HELLP (Hemolysis, Elevated Liver enzymes, Low Platelet count) syndrome is a thrombotic microangiopathic disorder
that causes microangiopathic hemolytic anemia (eg, increased indirect bilirubin levels), thrombocytopenia, and
hepatocellular injury (eg, increased alanine aminotransferase). Patients may have hypertension and right upper
quadrant pain with nausea/vomiting. [19435]
Preeclampsia is new-onset hypertension (systolic ≥140 mm Hg or diastolic ≥90 mm Hg) with proteinuria and/or signs
of end-organ damage (eg, renal insufficiency). Preeclampsia is associated with widespread maternal endothelial
dysfunction, which occurs due to increased antiangiogenic factor release and decreased proangiogenic factor activity
(eg, vascular endothelial growth factor). [16021]
Preeclampsia is new-onset hypertension at ≥20 weeks gestation plus proteinuria and/or signs of end-organ
damage. Preeclampsia is caused by widespread maternal endothelial cell damage due to release of antiangiogenic
factors from an ischemic placenta. The result is widespread capillary leakage (proteinuria, edema) and vasospasm
(hypertension, end-organ hypoperfusion [eg, renal failure]). [19389]
Stress urinary incontinence, the leakage of urine with increased intraabdominal pressure (eg, coughing), is common in
pregnancy due to decreased external urethral sphincter tone and increased pelvic floor muscle laxity. [11926]
Neonates are at risk for vitamin K deficiency primarily due to poor transplacental transfer and low content in breast
milk. Because vitamin K is necessary for clotting factor activity, neonates who do not receive vitamin K prophylaxis at
birth are predisposed to bleeding complications such as intracranial hemorrhage. [1062]
Back pain
During pregnancy, increased relaxin levels promote sacroiliac joint laxity and widening of the pubic symphysis to help
facilitate vaginal delivery. [19581]
Normal pregnancy
β-hCG is a hormone secreted by the placental syncytiotrophoblast after uterine invasion that signals the ovary to
maintain the corpus luteum, which produces progesterone in early pregnancy. [20128]
Physiologic murmur
Normal pregnancy is associated with an increase in blood volume and cardiac output that frequently causes a
pulmonic flow murmur and S3. [20313]
Prenatal Care
The maternal serum quadruple screen assesses for risk of congenital defects and fetal aneuploidy and includes
measurement of alpha-fetoprotein levels, which are dependent on gestational age. An abnormal alpha-fetoprotein
level is most commonly due to a dating error (eg, inaccurate gestational age). [342]
Respiratory alkalosis
The normal physiology of pregnancy involves chronic hyperventilation caused by elevated progesterone levels
stimulating an increase in central respiratory drive. This creates an expected respiratory alkalosis with metabolic
compensation (increased renal bicarbonate excretion) that helps facilitate the transport of acidic wastes from, and
the transport of oxygen to, the developing fetus. [19065]
Cystic fibrosis
Patients with cystic fibrosis (CF) produce eccrine sweat with higher-than-normal concentrations of sodium and
chloride. Exposure to high temperature or exercise can lead to hyponatremia and hypochloremia due to excessive
sodium chloride loss through sweat; therefore, salt supplementation is recommended. [1939]
Patients with cystic fibrosis have thick, viscous mucus that accumulates in the airways and promotes colonization of
bacteria, particularly Pseudomonas. This gram-negative rod can produce biofilms, which act as a protective matrix
that allows bacterial macrocolonies to develop, causing persistent infection. [19341]
In cystic fibrosis, impairment of the cystic fibrosis transmembrane conductance regulator (CFTR) protein reduces
chloride secretion and increases sodium absorption by the respiratory epithelia, resulting in dehydrated
mucus. When saline is applied to the nasal mucosa, the increased sodium absorption in patients with CF causes a
more negative nasal transepithelial potential difference, which can be used to diagnose cystic fibrosis. [804]
ARDS
Severe hypoxemia that does not correct with 100% supplemental oxygen is consistent with a right-to-left
shunt. Intrapulmonary shunt effect occurs when an alveolar filling process (eg, diffuse pulmonary edema) causes
poor alveolar ventilation despite continued perfusion; this improves with positive end-expiratory pressure. [105670]
Acute respiratory distress syndrome involves acute neutrophilic lung inflammation with widespread alveolar damage
due to proteases and reactive oxygen species, leading to failure of the vascular barrier and exudative pulmonary
edema. [19626]
Survivors of acute respiratory distress syndrome commonly have reduced lung function that persists for months or
years and is sometimes permanent. The majority of patients have reduced diffusion capacity that eventually
normalizes after several years, whereas a small percentage develop extensive fibrosis with a marked and permanent
reduction in diffusion capacity. [19625]
High altitude illness
High-altitude pulmonary edema presents with dyspnea and cough within several days of arrival at high altitude. It is
driven by reduced ambient oxygen, which leads to hypoxic pulmonary vasoconstriction and pulmonary arterial
hypertension. Individuals with unevenly distributed pulmonary vasoconstriction can develop areas of high capillary
perfusion pressure that disrupts the alveolar-capillary membrane, leading to patchy, bilateral pulmonary edema.
[18938]
Mechanical ventilation
Positive end-expiratory pressure helps treat acute respiratory distress syndrome by opening collapsed alveoli to
reduce intrapulmonary shunting and increase functional residual capacity (FRC). The increased FRC decreases
ventilation-perfusion mismatching and increases the oxygen reserves in the lungs. [19919]
Prone positioning may be used to improve arterial oxygenation in patients with severe acute respiratory distress
syndrome. The improvement likely results from reduced compression of the posterior lung segments, where the
majority of alveoli are located. This leads to more evenly distributed ventilation throughout the lungs with reduced
intrapulmonary shunting and improved ventilation-perfusion matching. [19624]

Neonatal respiratory distress syndrome is characterized by inadequate surfactant production, resulting in increased
alveolar surface tension and decreased alveolar compliance. Diffuse alveolar collapse (atelectasis) is seen on chest x-
ray as ground-glass opacities with air bronchograms. [19617]
Respiratory distress syndrome classically presents in premature infants with increased work of breathing and hypoxia
at birth due to surfactant deficiency. Poor alveolar compliance leads to widespread atelectasis and decreased
functional residual capacity. Airway resistance is often increased due to lung inflammation and edema. [19614]
Pleural effusion
Transudative effusions are typically caused by alterations in hydrostatic or oncotic pressure (eg, heart failure,
cirrhosis, nephrotic syndrome), whereas exudative effusions typically result from inflammation and consequent
increased vascular membrane permeability (eg, infection, malignancy, rheumatologic disease). Exudative effusions
are characterized by a high ratio of pleural fluid to serum total protein (>0.5) or lactate dehydrogenase (>0.6), or high
absolute levels of lactate dehydrogenase. [15420]
Fluid in the pleural space acts to insulate sound vibrations that originate in the airways; therefore, pleural effusion
causes decreased tactile fremitus and decreased intensity of breath sounds. The high density of pleural fluid
compared to normal lung tissue also causes dullness to percussion. [7614]
Transudative pleural effusions result from increased intracapillary pressure (eg, heart failure) and exudative effusions
develop from inflammatory disruption of the vascular membrane. Transudative pleural effusions have low
fluid/serum ratios of total protein and lactate dehydrogenase and low absolute levels of lactate dehydrogenase
compared to exudative effusions. [15430]
Pneumothorax
Tension pneumothorax involves progressively increasing intrapleural pressure that leads to contralateral mediastinal
shifting (eg, tracheal deviation) and vena cava collapse. Hypotension, tachycardia, and obstructive shock develop due
to decreased venous return to the heart. [19335]
Traumatic pneumothorax can involve puncture of either the chest wall (eg, penetrating chest trauma) or the lung (eg,
by fractured ribs), allowing air to enter the pleural space. Patients usually experience chest pain and difficulty
breathing. Crepitus, caused by air in the subcutaneous tissues of the chest wall, is often present on physical
examination. [16899]
Pneumothorax is recognized on chest x-ray by a continuous line without lung markings peripheral to it. Decreased
tactile fremitus, decreased breath sound intensity, and hyperresonance to percussion are expected on physical
examination. [19332]
Spontaneous pneumothorax is common in cystic fibrosis and involves alveolar rupture, leading to loss of intrapleural
negative pressure. Patients have sudden-onset shortness of breath, unilaterally decreased breath sounds, and,
sometimes, subcutaneous crepitus. Hypotension and tachycardia suggest the development of tension
pathophysiology. [19334]
Radiation injury
Radiation-induced lung injury typically occurs following thoracic irradiation (eg, breast cancer), which damages
pneumocytes and vascular endothelial cells and initiates an inflammatory response (eg, IL-1, TNFα, TGF-β). This
immune response can have both acute (eg, exudative alveolitis, hyaline membrane formation) and delayed (eg, dense
fibrosis) effects that typically manifest with cough and dyspnea. [18928]
Respiratory alkalosis
An acute ventilation/perfusion mismatch (eg, due to pulmonary embolism or pneumonia) causes hypoxemia and
triggers hyperventilation. Because the removal of CO2 is directly dependent on ventilation but the absorption of O2
is capped by the high baseline saturation of hemoglobin, the hyperventilation response typically leads to respiratory
alkalosis (low arterial partial pressure of carbon dioxide) with persistent hypoxemia. [528]
Sepsis
Sepsis is a host inflammatory response to infection that can lead to multiple organ dysfunction due to defective
mitochondrial oxidative respiration, resulting in a widespread dissociation between oxygen delivery and
extraction. This manifests as elevated central venous oxygen saturation. [21505]
Septic shock is a dysfunctional host response to an infectious pathogen resulting from massive upregulation of
vasodilators. A vasopressin deficit contributes to unbalanced vasodilation and refractory hypotension. [19339]
Asbestos
Mesothelioma is a neoplasm arising from mesothelial cells and is strongly associated with asbestos exposure. In early
mesothelioma, multiple nodules form on the parietal pleura and gradually encase the lung
parenchyma. Immunohistochemistry is important for diagnosis; nearly all mesotheliomas stain positive for
cytokeratins and many also stain positive for calretinin. [15370]
Asbestosis is a pneumoconiosis that occurs with inhalation of asbestos fibers, most commonly in patients with
occupational exposure (eg, insulation installation, shipbuilding, pipe work). Histopathology demonstrates diffuse
interstitial fibrosis and ferruginous asbestos bodies (translucent fibers coated with a golden iron-containing
material). Pleural disease (eg, plaques, benign effusions) is common. [15335]

The work of breathing is minimized in patients with increased elastic resistance (eg, pulmonary fibrosis) when their
respiratory rate is high and tidal volume is low (fast, shallow breaths). In contrast, patients with diseases that
increase airflow resistance (eg, asthma, chronic obstructive pulmonary disease) breathe at a lower respiratory rate
and higher tidal volume (slow, deep breaths) to minimize the work of breathing. [8260]
Pulmonary alveolar proteinosis

Pulmonary alveolar proteinosis is a rare condition characterized by progressive respiratory dysfunction due to the
accumulation of surfactant (periodic acid–Schiff positive material forming lamellar bodies) within the alveolar
spaces. The condition occurs most often due to the impaired clearance of surfactant by alveolar macrophages (eg,
decreased granulocyte-monocyte colony-stimulating factor signaling). [20303]
Pulmonary function test

Pulmonary function testing involves having the patient inhale completely and then forcefully exhale as much air as
possible as quickly as possible. Restrictive lung disease causes reduced total volume of air expelled (ie, reduced
forced vital capacity [FVC]), reduced volume of air expelled in 1 second (ie, reduced forced expiratory volume in 1
second [FEV1]), and a normal or sometimes increased FEV1/FVC ratio. [19926]
Sarcoidosis
Sarcoidosis is characterized by noncaseating granulomas. Multinucleated giant cells, formed by macrophage fusion,
are frequently seen. Sarcoidosis commonly involves the lungs with interstitial or nodular infiltrates; extrapulmonary
manifestations can affect lymph nodes, eyes (eg, uveitis), skin, internal organs, and salivary glands. [15181]
Silicosis
In silicosis, internalized silica particles impair macrophage function by disrupting phagocytosis and promoting
apoptosis. This increases the risk of mycobacteria infection (particularly M tuberculosis). [670]
LUNG CANCER
Lung cancer
Tumors located in the lung apex (superior sulcus) are called Pancoast tumors. Invasion of surrounding structures can
lead to ipsilateral Horner syndrome, rib destruction, atrophy of hand muscles, and pain in the distribution of C8, T1,
and T2 nerve roots. [648]
Superior vena cava syndrome
Extrinsic compression of the superior vena cava by a mediastinal mass (eg, malignancy) can cause superior vena cava
syndrome, with impaired venous return from the upper body. Signs and symptoms include facial swelling, distended
collateral veins, headache, and dyspnea. [565]
MISCELLANEOUS
Aging
Age-related changes to the respiratory system include decreased chest wall compliance and decreased alveolar
elastic recoil with resulting alveolar enlargement and air trapping. These changes limit the potential increase in tidal
volume and also increase the alveolar-arterial O2 gradient (ie, decrease the efficiency of alveolar-capillary gas
exchange), reducing the ability to compensate for hypoxemia. [19287]
Av malformation
Hereditary hemorrhagic telangiectasia presents with mucocutaneous telangiectasias, epistaxis, and visceral
arteriovenous malformations (AVMs) (eg, liver, lung, brain). Lung involvement includes pulmonary AVMs (eg, digital
clubbing, platypnea) and pulmonary hypertension (eg, a loud P2) due to high-output heart failure from underlying
systemic AVMs. [19809]
Myasthenia gravis
Myasthenia gravis is characterized by autoantibodies against postsynaptic nicotinic acetylcholine receptors at the
neuromuscular junction, which result in receptor degradation. Patients typically have extraocular, bulbar, and facial
weakness that worsens with activity. In severe cases, the respiratory muscles may be affected, leading to
hypoventilation and respiratory failure. [15611]
Obesity
Obesity, particularly morbid, central obesity, can cause a pattern of extrinsic restrictive pulmonary function
tests. The most common indicator of obesity-related disease is a reduction in expiratory reserve volume and
functional residual capacity, but forced expiratory volume in 1 second, forced vital capacity, and total lung capacity
are also typically decreased. [11900]
Pleural effusion
Pulmonary infection (eg, community-acquired pneumonia, tuberculosis) causes pleural effusion primarily via an
inflammatory increase in vascular and pleural membrane permeability. Such effusions are exudative by Light criteria,
typically with relatively high pleural fluid protein and lactate dehydrogenase concentrations. Tuberculosis pleural
effusions typically demonstrate a lymphocyte-predominant leukocyte pattern. [20176]
Patients with cirrhosis complicated by abdominal ascites may develop a hepatic hydrothorax, which is a transudative,
usually right-sided pleural effusion that results from passage of intraabdominal fluid into the chest cavity through
small fenestrations in the diaphragm. [20174]
Pneumothorax
The lungs exert collapsing force, and the resting chest wall exerts expanding force. These opposing forces are in
equilibrium at the functional residual capacity and generate sustained intrapleural negative pressure that allows the
lung and chest wall to move together as a combined respiratory unit. Loss of intrapleural negative pressure (eg,
pneumothorax) disrupts the combined system, causing the chest wall to spring outward to its equilibrium position,
enlarging the hemithorax. Similarly, the lung collapses to its equilibrium position where inspiratory compliance is
decreased. [19916]
Respiratory mucosa
Acute respiratory distress syndrome is a severe inflammatory reaction that occurs in the lungs and results in
hypoxemia and noncardiogenic pulmonary edema. Pulmonary injury leads to an inflammatory response resulting in
breakdown of the capillary-alveolar barrier (created by type I pneumocytes and endothelial cells), increased capillary
permeability, intraalveolar fluid accumulation, and hyaline membrane formation. [14949]
Diffusion of oxygen across the alveolar-capillary membrane is normally very rapid. Decreased diffusion rate (eg,
interstitial lung disease) can lead to diffusion-limited oxygen transfer, especially when the perfusion rate increases
(eg, exertion). [15106]

The major serum inhibitor of extracellular elastase is alpha-1 antitrypsin (AAT); patients with AAT deficiency typically
develop early-onset panacinar emphysema due to unchecked elastase activity. Exposure to tobacco smoke
dramatically accelerates the development of emphysema in patients with AAT deficiency and should be avoided. [489]
Emphysema most commonly results from chronic smoking but can also occur in genetically predisposed individuals
with alpha-1 antitrypsin deficiency. Patients with emphysema have a decreased forced expiratory volume in 1
second/forced vital capacity ratio, increased total lung capacity, and decreased diffusing capacity. [1919]
Patients with severe emphysema typically have chronic CO2 retention leading to chronic respiratory acidosis with
metabolic compensation (high PaCO2, compensatory high bicarbonate, slightly acidic pH), often accompanied by
hypoxemia (PaO2 <75 mm Hg on room air). [15206]
Alpha-1 antitrypsin (AAT) is a serum protein that, through the inhibition of neutrophil elastase, reduces tissue
damage caused by inflammation. Histologically, AAT deficiency can demonstrate reddish-pink globules on periodic
acid–Schiff stain; these globules represent unsecreted, polymerized AAT in the periportal hepatocytes. [399]
Asthma
Occupational asthma is characterized by airway inflammation, bronchial hyperreactivity, and a variable airflow
obstruction triggered by workplace exposure. Exposure can be immunologic (atopic), due to exposure to a workplace
aeroallergen causing a Th2-mediated IgE formation, or nonimmunologic, due to exposure to workplace irritants that
lead to denudation of the bronchial mucosa. [15155]
Bronchodilators induce bronchial smooth muscle relaxation to relieve airway spasm and bronchoconstriction in
patients with asthma. Bronchodilation is most commonly accomplished with beta-2 receptor agonists (eg, albuterol),
which function by increasing cyclic AMP levels in bronchial smooth muscle. [15156]
Paroxysmal breathlessness and wheezing in a young patient that are unrelated to ingestion of aspirin, pulmonary
infection, inhalation of irritants, and/or exercise should raise a strong suspicion for atopic (extrinsic) asthma. Classic
sputum findings include eosinophils and Charcot-Leyden crystals. Eosinophils are recruited and activated by IL-5
secreted by TH2 type T cells. [527]
Bronchial challenge testing is a highly sensitive but nonspecific measure that can help exclude a diagnosis of
asthma. A provocative stimulus (typically aerosolized methacholine) is administered at increasing concentrations to
induce bronchoconstriction. Patients with asthma are hyperresponsive to this stimulus and experience a decline in
FEV1 at lower doses than nonasthmatics. [663]
COPD
The pathogenesis of centriacinar emphysema associated with chronic, heavy smoking predominantly involves the
release of proteases, especially elastase, from infiltrating neutrophils and alveolar macrophages. [488]
Chronic obstructive pulmonary disease involves components of chronic bronchitis and emphysema. Bronchial airway
obstruction from chronic bronchitis and decreased alveolar elasticity from emphysema result in air-trapping and lung
hyperinflation. The functional residual capacity is increased, as are residual volume and total lung capacity. [522]
Neutrophils, macrophages, and CD8+ T lymphocytes are the primary mediators of disease in chronic obstructive
pulmonary disease. They secrete enzymes and proteases that cause and perpetuate both the alveolar destruction of
emphysema and the mucus hypersecretion found in chronic bronchitis. [12082]
Chronic obstructive pulmonary disease is a combination of emphysema and chronic bronchitis and commonly
presents with progressive dyspnea and recurrent upper respiratory infections. Bronchial obstruction and alveolar
destruction cause air trapping that manifests on pulmonary function testing as decreased forced expiratory volume in
1 second (FEV1), forced vital capacity (FVC), and FEV1/FVC ratio. Residual volume and total lung capacity are
increased. [521]
Chronic obstructive pulmonary disease causes air trapping and hyperinflation; consequently, these patients breathe
at higher baseline lung volumes (higher functional residual capacity). The volume of air in the lungs that is not
respired (residual volume) increases substantially, as does the fraction of air in the lungs that is not involved in
respiration (residual volume/total lung capacity ratio). [15233]
Smoking is the strongest risk factor for chronic obstructive pulmonary disease (COPD) and is responsible for
accelerated decline in forced expiratory volume in 1 second (FEV1) in patients with COPD. Smoking cessation will
slow the accelerated decline in FEV1, but FEV1 will not return to the level it would have been had the patient never
smoked. [7558]
Supplemental oxygen administration in patients with chronic obstructive pulmonary disease can lead to increased
CO2 retention (oxygen-induced hypercapnia), resulting in confusion and depressed consciousness. The major cause is
reversal of hypoxic pulmonary vasoconstriction, which increases physiologic dead space as blood is shunted away
from well-ventilated alveoli. [12141]
The flow-volume loop for chronic obstructive pulmonary disease is characterized by increased residual volume and
total lung capacity, as well as a "scooped-out" expiratory pattern due to reduced expiratory flow rates. Both airway
narrowing due to chronic bronchitis and decreased elasticity due to emphysematous destruction of interalveolar
walls are responsible for the hyperinflation and airflow limitation. [487]
Cystic fibrosis
Pulmonary function testing in cystic fibrosis reveals an obstructive pattern, characterized by a decreased FEV1/FVC
ratio and an increased total lung capacity and residual volume. [19379]
Eosinophilic pneumonia
Eosinophils have bilobed nuclei and numerous eosinophilic granules in the cytoplasm and are important in allergic
disease and defense against parasitic infection. The eosinophilic granules predominantly contain major basic protein,
which acts as a potent antihelminthic toxin. Major basic protein also damages epithelial and endothelial cells and is a
major cause of chronic lung damage in asthma. [523]

Obstructive sleep apnea presents in obese individuals with excessive daytime sleepiness and signs of nocturnal upper
airway obstruction (eg, snoring, gasping). The condition is associated with systemic hypertension. Prolonged,
untreated obstructive sleep apnea can also cause pulmonary hypertension and right heart failure. [1985]
Obstructive sleep apnea, the most common sleep-related breathing disorder, is characterized by recurrent
obstruction of the upper airways. Relaxation of the oropharyngeal and/or soft palate musculature during sleep
results in a functional collapse of the airway, producing periods of reduced (hypopnea) or absent (apnea) airflow
despite continued breathing efforts. [8262]
Obstructive sleep apnea is due to relaxation of oropharyngeal muscle tone with occlusion of the upper
airway. Symptoms include daytime sleepiness, headaches, and depression. Complications include systemic and
pulmonary hypertension, right heart failure, and an increased risk for cardiac events. [1460]
Polycythemia
In response to tissue hypoxia, specialized interstitial cells in the renal medulla and cortex release erythropoietin to
stimulate the bone marrow to increase red blood cell production and improve the oxygen-carrying capacity of the
blood. This response, known as secondary polycythemia, is an expected finding in diseases or conditions that cause
significant chronic hypoxemia (eg, chronic obstructive pulmonary disease). [1942]
Rhinitis
Type I hypersensitivity reactions are an allergic response triggered by the binding of previously recognized antigen to
IgE antibodies on mast cells. In the early phase of the response, histamine, already stored in preformed granules in
mast cells, is the first chemical mediator released. Once released, histamine stimulates smooth muscle contraction
(bronchoconstriction), increases vascular permeability (edema), and increases mucus secretion. [661]

Alveolar consolidation occurs when the alveoli become filled with fluid (eg, inflammatory exudate in bacterial
pneumonia). The increased compactness of the alveolar fluid (compared to air) causes sound to travel faster and
more efficiently, resulting in bronchophony, increased tactile fremitus (vibration), and increased intensity of breath
sounds over the affected area. Dullness to percussion is also present. [14922]
The green discoloration of pus or sputum seen during common bacterial infections is due to the presence of
myeloperoxidase, a blue-green heme-based enzyme that is released from neutrophil azurophilic granules and forms
hypochlorous acid (bleach). [1910]
Epiglottitis
Laryngeal airway obstruction can occur with epiglottitis. It leads to inspiratory stridor due to the dynamic collapse of
the larynx during inspiration. [20235]
Lung abscess
Abscess formation is largely driven by neutrophil recruitment and activation leading to the release of cytotoxic
granules that kill bacteria but also cause liquefying necrosis of surrounding tissue. [302]
Hypoxic pulmonary vasoconstriction (HPV) limits perfusion to nonventilated alveoli, shunting blood toward better-
ventilated ones, preserving ventilation-perfusion matching to maintain oxygenation. HPV can be impaired by
inflammatory vasodilation (eg, pneumonia or sepsis), and restoration of HPV optimizes oxygenation despite minimal
improvement in ventilation of consolidated alveoli. [21124]
Acute heart failure

Left-sided heart failure is common following myocardial infarction affecting the left ventricle. The resulting
accumulation of edema in the pulmonary interstitium makes the lungs heavy and stiff, restricting inspiratory
expansion and decreasing lung compliance. [1585]
Av malformation
Pulmonary arteriovenous malformations cause hypoxemia through right-to-left shunting that is refractory to
supplemental oxygenation. The shunt can be visualized during pulmonary angiography, which demonstrates direct
communication between the inflow artery and outflow vein. [19820]
Pulmonary Arterial Hypertension
Pulmonary arterial hypertension results from endothelial dysfunction that leads to an increase in vasoconstrictive,
proproliferative mediators (eg, endothelin, thromboxane A2) and a decrease in vasodilative, antiproliferative
mediators (eg, nitric oxide, prostacyclin). The relative imbalance in these mediators leads to vasoconstriction and
intimal-wall thickening with a consequent increase in pulmonary vascular resistance. [14959]
Pulmonary hypertension should be suspected in young and otherwise healthy patients with fatigue, progressive
dyspnea, atypical chest pain, or unexplained syncope. Long-standing pulmonary hypertension leads to hypertrophy
and/or dilation of the right ventricle (cor pulmonale). [196]
Hereditary pulmonary arterial hypertension develops in 2 steps. An abnormal BMPR2 gene predisposes affected
individuals to excessive endothelial and smooth muscle cell proliferation. An insult (eg, infection, drugs) is thought to
then activate the disease process, resulting in vascular remodeling, increased pulmonary vascular resistance, and
progressive pulmonary hypertension. [530]
Left-sided heart failure can cause secondary pulmonary hypertension via elevated left-sided diastolic filling pressures
transmitting backward to the pulmonary veins, resulting in pulmonary venous congestion. Over time, pulmonary
arterial remodeling (medial hypertrophy and intimal thickening with fibrosis) can occur, but not to the extent that
occurs in (primary) pulmonary arterial hypertension. [198]
Pulmonary hypertension can be recognized on physical examination by a loud pulmonic component of S2 and an
accentuated, palpable impulse at the left sternal border (left parasternal lift due to right ventricular heave). [15199]
Advanced hypoxic lung disease (eg, chronic obstructive pulmonary disease, interstitial lung disease, obesity
hypoventilation syndrome) is a common cause of pulmonary hypertension (ie, increased right ventricular
afterload). The increase in pulmonary arterial pressure mainly results from chronic and diffuse hypoxic
vasoconstriction, with a lesser degree of vascular remodeling than in (primary) pulmonary arterial hypertension.
[14958]
Pulmonary embolism
Ventilation/perfusion scanning can be useful for diagnosing pulmonary embolism. A large perfusion defect without
ventilation defect is the characteristic positive test result. [12184]
The lungs are supplied by dual circulation from both the pulmonary and bronchial arteries. This collateral circulation
can help protect against lung infarction due to pulmonary artery occlusion (ie, pulmonary embolism), as the bronchial
circulation can continue to provide blood to the lung parenchyma. [11774]
SLEEP DISORDERS

Obstructive sleep apnea is due to upper airway muscle relaxation leading to repetitive pharyngeal collapse. The
degree of collapse is highest when muscle tone is globally inhibited during rapid eye movement sleep. Collapse is
also greatest in the supine position due to the effect of gravity on the upper airway structures. [21965]
ACUTE KIDNEY INJURY
Acute kidney injury

Loss of epithelial cell polarity is an early change that occurs in renal tubular cells in response to ischemia (ie, acute
tubular necrosis). Depletion of ATP causes rapid cytoskeletal disruption; this leads to a loss of cell-cell adhesion and
causes redistribution of integrins and Na-K-ATPases from the basolateral membrane to the apical membrane. [106935]
Prerenal azotemia
Hypovolemia triggers a variety of compensatory mechanisms to improve tissue perfusion. These include activation of
the renin-angiotensin-aldosterone system (resulting in increased aldosterone and endothelin release), increased
vasopressin release, and increased sympathetic tone. [15209]
Compensatory mechanisms for hypovolemia include activation of the renin-angiotensin-aldosterone system and
increased antidiuretic hormone release. This results in increased renal sodium, chloride, water, and urea
reabsorption with increased potassium excretion. [15208]
Decompensated heart failure involves a vicious cycle of hemodynamic alterations and maladaptive neurohormonal
changes resulting from decreased renal perfusion. Cardiorenal syndrome is a complication of this cycle, in which back
pressure from the failing heart increases renal venous pressure to the point that the glomerular filtration rate drops
substantially. [15221]
Hypovolemia (eg, excessive diuresis) can cause acute kidney injury due to reduced renal blood flow (prerenal
azotemia). Urine sodium and fractional excretion of sodium levels are low, and the BUN/creatinine ratio is
elevated. In severe cases, acute tubular necrosis can occur and cause an intrinsic renal injury pattern (ie, high urine
sodium, normal BUN/creatinine ratio) with muddy brown casts on urinalysis. [15207]
BONE METABOLISM
Hypercalcemia
Serum calcium >13 mg/dL is suggestive of an underlying malignancy. Secretion of parathyroid hormone-related
protein (PTHrP), which closely resembles parathyroid hormone at the bioactive amino-terminal region, is a frequent
cause of malignancy-related hypercalcemia and is commonly seen with squamous cell carcinomas (eg, lung, neck).
[978]
Multiple myeloma is associated with increased bone resorption due to the production of tumor-related
cytokines. This results in elevated serum calcium levels, which reduce parathyroid hormone (PTH) production. Low
PTH decreases renal calcium reabsorption (hypercalciuria), and, in combination with renal insufficiency, reduces 1,25-
dihydroxyvitamin D synthesis. [12101]
Hyperparathyroidism
Increased bone resorption in primary hyperparathyroidism leads to osteoporosis primarily involving the cortical bone
of the appendicular skeleton. The cortical thinning appears radiologically as subperiosteal erosions. More advanced
disease can present as osteitis fibrosa cystica (ie, granular decalcification of the skull, osteolytic cysts, and brown
tumors). [631]
Hypoparathyroidism
Hypocalcemia can cause muscle cramps, perioral paresthesias, hypotension, and neuromuscular
hyperexcitability. Injury to the parathyroid glands during thyroid surgery is a common cause of hypoparathyroidism
and acute hypocalcemia. [1656]
Malabsorption caused by celiac disease can lead to vitamin D deficiency. Patients have decreased serum phosphorus,
increased serum parathyroid hormone (secondary hyperparathyroidism), and low (or normal) serum calcium. [981]

In chronic kidney disease, reduced excretion of phosphate can cause hyperphosphatemia. This induces hypocalcemia
directly by binding free calcium and depositing in tissues, and indirectly by triggering fibroblast growth factor 23
secretion (decreases calcitriol production and intestinal calcium absorption). The resulting hypocalcemia can
manifest as neuromuscular excitability (eg, carpal spasm). [15289]
Cystinuria
Cystinuria is an autosomal recessive disorder caused by defective transportation of cystine, ornithine, arginine, and
lysine across the intestinal and renal tubular epithelium. Recurrent nephrolithiasis is the only clinical
manifestation. Urinalysis shows pathognomonic hexagonal cystine crystals. [815]
Fanconis syndrome
Defects in either the proximal or distal convoluted tubule (eg, bicarbonate loss, acid retention) can result in a normal
anion gap metabolic acidosis. However, the proximal tubule is responsible for reabsorption of glucose, amino acids,
and phosphate in addition to bicarbonate; therefore, generalized proximal tubular dysfunction (Fanconi syndrome)
can also cause failure to thrive, glucosuria, and rickets. [7626]

Renal artery stenosis causing significant renal hypoperfusion will result in a decreased glomerular filtration rate and
activation of the renin-angiotensin-aldosterone system. This leads to increased renin release by modified smooth
muscle (juxtaglomerular) cells in the walls of afferent glomerular arterioles. Chronic renal hypoperfusion can cause
hyperplasia of the juxtaglomerular apparatus. [7569]
DIABETES INSIPIDUS
Diabetes insipidus
Nephrogenic diabetes insipidus is characterized by polyuria, dilute urine (low urine specific gravity), hypernatremia,
and high antidiuretic hormone. Treatment includes thiazide diuretics and replacement of water losses. [18553]
Primary polydipsia
Primary (psychogenic) polydipsia is characterized by excessive intake of free water, leading to hyponatremia and
production of large volumes of dilute urine. Water restriction normalizes serum sodium levels and increases urine
osmolality. [212]
SIADH
Ectopic production of antidiuretic hormone (ADH) from malignancy can lead to the syndrome of inappropriate ADH
secretion, a condition of impaired urinary water excretion. This condition manifests with low serum osmolality,
hyponatremia, high urine osmolality, and high urine sodium. [18548]
Metabolic alkalosis
Severe vomiting leads to metabolic alkalosis through multiple mechanisms, including loss of H+ from the
gastrointestinal tract, volume and Cl− depletion that induces renal retention of HCO3−, and hypokalemia-induced
intracellular shifting of H+. [18873]
Total body chloride depletion is often important in the pathophysiology of metabolic alkalosis. Measurement of urine
chloride can be helpful in determining the underlying etiology. [956]
Opioids
Acute opioid overdose is characterized by altered level of consciousness, pinpoint pupils, and central respiratory
depression. Patients are expected to have acute respiratory acidosis (low pH, high PaCO2) due to
hypoventilation. Serum bicarbonate is typically near normal as there is not time for metabolic compensation in the
acute setting. [15276]
Renal tubular acidosis

Type 4 renal tubular acidosis (RTA) results from a reduced aldosterone effect on the kidneys and is characterized by
hyperkalemia (reduced potassium excretion) and nonanion gap metabolic acidosis (reduced hydrogen excretion in
the form of ammonium). Sodium reabsorption is decreased, leading to decreased total body sodium, but the serum
sodium concentration is often unchanged due to the appropriate function of antidiuretic hormone. [106038]
GLOMERULAR DISEASES

In diabetic nephropathy, early adaptive changes in the kidney cause a transient increase in glomerular filtration
(hyperfiltration). As diabetic nephropathy progresses, glomerular filtration falls, with a concurrent increase in urine
albumin loss. [15239]
Glomerular disorders
Frothy or foamy urine may be caused by proteinuria. Heavy proteinuria, as in nephrotic syndrome, can cause
regional or generalized interstitial edema because the decrease in serum albumin and total protein concentrations
lowers the plasma oncotic pressure and increases net plasma filtration in capillary beds. [1577]
MISCELLANEOUS

Urinary tract infections (UTIs) are common in hospitalized patients with indwelling urinary catheters. The risk for UTI
can be reduced by avoiding unnecessary catheterization, using sterile technique when inserting the catheter, and
removing the catheter as soon as possible. [11516]
Renal calculi
Hypercalciuria is the most common risk factor for calcium (calcium oxalate and calcium phosphate) kidney stones in
adults; contributing factors may include increased gastrointestinal absorption, increased mobilization of calcium from
bone, or decreased renal tubular calcium reabsorption. However, most patients remain normocalcemic due to
regulation of plasma calcium levels by vitamin D and parathyroid hormone. [813]

Urinary tract obstruction causes reflux of urine into the renal tubules and increased tubular hydrostatic pressure. The
intraglomerular capillary hydrostatic pressure is unchanged, resulting in a decreased hydrostatic pressure gradient
across the glomerular capillary wall and a reduction in glomerular filtration. Oncotic pressure is maintained by large
plasma proteins which are not filtered across the glomerular capillary basement membrane; it is unaffected by a
urinary tract obstruction. [15193]
Aging
Normal aging results in multiple physiologic and structural alterations that lead to a slow decline in renal
function. These include reductions in renal mass and functional glomeruli (ie, reduced glomerular filtration rate and
creatinine clearance), decreased renal blood flow, and limited hormonal responsiveness (eg, renin, parathyroid
hormone). [19292]
Patients with multiple sclerosis most commonly develop urge incontinence due to loss of central nervous system
inhibition of detrusor contraction in the bladder. As the disease progresses, the bladder can become atonic and
dilated, leading to overflow incontinence. [11038]
Patients with multiple sclerosis often develop a spastic bladder a few weeks after developing an acute lesion of the
spinal cord. These patients present clinically with increased urinary frequency and urge incontinence. Urodynamic
studies show the presence of bladder hypertonia. [11464]
Ankylosing spondylitis is characterized by stiffness and fusion of axial joints (ankylosis) and inflammation at the site of
insertion of tendons into bone (enthesitis). Involvement of the thoracic spine and costovertebral and costosternal
junctions can limit chest wall expansion, leading to hypoventilation. [753]
Enthesitis (inflammation at the bony insertions of tendons, ligaments, and joint capsules) is a prominent
manifestation of spondyloarthritis (eg, ankylosing spondylitis). Common clinical syndromes include Achilles
tendinitis, plantar fasciitis, and dactylitis. Achilles tendinitis affects the site of insertion of the Achilles tendon on the
calcaneus and presents with severe pain at the posterior aspect of the foot. [19494]
Gout
Gout results from the deposition of monosodium urate crystals in the joints and soft tissues. Under polarized light,
urate crystals appear needle-shaped and negatively birefringent. Conditions that increase uric acid production or
decrease uric acid clearance can increase the risk of gout. [1450]
Reactive arthritis
The classic triad of reactive arthritis is nongonococcal urethritis, conjunctivitis, and arthritis. It is an HLA-B27-
associated arthropathy that occurs within several weeks following a genitourinary or enteric infection. It belongs to
the group of seronegative spondyloarthropathies (including ankylosing spondylitis) and can cause sacroiliitis in about
20% of cases. [743]
Reactive arthritis is a spondyloarthropathy associated with HLA-B27 that can occur following infection with
Chlamydia, Campylobacter, Salmonella, Shigella, or Yersinia. It presents with sterile arthritis due to deposition of
immune complexes. [1600]
Rheumatoid arthritis is characterized by symmetric polyarthritis (involving the metacarpophalangeal and proximal
interphalangeal joints) with prolonged morning stiffness and associated fatigue. Antibodies to citrullinated
peptides/proteins have a high specificity for the condition. [8802]
The pathogenesis of rheumatoid arthritis involves early activation of CD4+ T cells (especially Th1 and Th17 subsets)
with release of cytokines such as tumor necrosis factor-alpha and IL-1 that cause destruction of cartilage and
bone. Monoclonal antibodies that inhibit tumor necrosis factor-alpha or IL-1 receptors can slow progression of the
disease. [14677]

Cell-mediated immunity is the primary mechanism underlying giant cell arteritis. The production of cytokines, in
particular interleukin-6, is an important driver of this process and closely correlates with the severity of symptoms.
[11770]
IgA vasculitis
Henoch-Schönlein purpura is an IgA-mediated small vessel vasculitis that manifests with palpable purpura on the
lower extremities, abdominal pain, arthralgia/arthritis, and renal disease (hematuria ± proteinuria). Renal
involvement is due to IgA deposition in the mesangium. [20508]
Myasthenia gravis
Myasthenia gravis results from an autoimmune type II (antibody-mediated) hypersensitivity reaction against skeletal
myocyte surface acetylcholine receptors. Goodpasture syndrome similarly involves autoantibodies against basement
membrane collagen in the renal glomeruli and lung alveoli. [740]

Dermatomyositis is characterized by proximal muscle weakness resembling polymyositis, with additional
inflammatory features involving the skin (heliotrope rash, Gottron papules). Both dermatomyositis and polymyositis
may occur alone or as a paraneoplastic syndrome associated with an underlying adenocarcinoma (eg, ovary, lung,
pancreas). [11805]
Polymyositis causes symmetric proximal muscle weakness. Muscle biopsy reveals inflammation, necrosis, and
regeneration of muscle fibers. Over-expression of major histocompatibility complex class I proteins on the
sarcolemma leads to infiltration with CD8+ T lymphocytes and myocyte damage. [748]
Polymyositis and dermatomyositis are characterized by symmetric proximal muscle weakness and are associated with
antinuclear and anti–tRNA synthetase (anti-Jo-1) autoantibodies. Biopsy in polymyositis shows patchy endomysial
inflammatory infiltrate (ie, direct invasion of individual muscle fibers), whereas dermatomyositis causes perifascicular
inflammation (ie, localized around blood vessels and the septa between muscle fascicles). [11646]
Systemic sclerosis
The pathogenesis of systemic sclerosis (scleroderma) involves vascular endothelial cells (increased expression of
endothelin 1 and adhesion molecules), T lymphocytes (production of cytokines that activate fibroblasts), and dermal
fibroblasts (increased production of collagen and ground substance). [15563]
Systemic sclerosis (SS) is an autoimmune disease characterized by the widespread fibrosis of multiple organ
systems. Histology demonstrates expansion of the dermal layer with diffuse collagen deposition and atrophy of the
intradermal adipose tissue and dermal appendages. Pulmonary complications are common (eg, interstitial lung
disease, pulmonary hypertension). [15564]
BONE TUMORS AND TUMOR-LIKE LESIONS
Ganglion cyst
Ganglion cysts are benign, fluid-filled masses that occur due to mucoid degeneration of periarticular tissue. They
present as painless, smooth, rubbery, round structures that overlie joints (eg, wrist) or tendons and transilluminate
with a penlight. Most resolve spontaneously without intervention. [18661]
Osteoporosis
The nuclear factor kappa B (RANK)/RANK-ligand (RANK-L) interaction is essential for the formation and differentiation
of osteoclasts. Osteoprotegerin (OPG) blocks binding of RANK-L to RANK and reduces formation of mature
osteoclasts, leading to decreased bone resorption. Denosumab is a monoclonal antibody used in the treatment of
postmenopausal osteoporosis that works in a manner similar to OPG. [14930]
Achondroplasia
Unlike the process of intramembranous ossification that forms flat bones, endochondral ossification proceeds along a
cartilage template and is responsible for the formation of long bones. Achondroplasia is characterized by an
exaggerated inhibition of chondrocyte proliferation in the growth plates of long bones and manifests with proximal
limb shortening, midface hypoplasia, and macrocephaly. [700]
Osteoporosis
Patients with osteoporosis have low bone mass, resulting in increased susceptibility to fragility fractures (ie, those
occurring with minimal or no trauma). In primary osteoporosis (not caused by a medical disorder), serum calcium,
phosphorus, and parathyroid hormone levels are typically normal. [982]
Bone pain and elevated alkaline phosphatase level in an elderly patient can occur with osteoblast metastases and
Paget disease of bone (PDB). Biopsy showing a mosaic pattern of lamellar bone is diagnostic for PDB. The initial
phase in PDB is characterized by an increase in osteoclastic activity. [987]
MISCELLANEOUS
Fibromyalgia
Fibromyalgia occurs most commonly in women age 20-55 and presents with diffuse musculoskeletal pain, fatigue,
and neuropsychiatric disturbances. It is characterized by abnormal central processing of painful stimuli. Although
initially painful, aerobic exercise helps to improve pain and functioning in these patients. [867]
Pharmacology
Anaphylaxis
Anaphylactic shock is characterized by vasodilatation, increased vascular permeability, and
bronchoconstriction. Epinephrine counteracts these physiological mechanisms and is the drug of choice for the
treatment of anaphylaxis. [1366]
Anaphylaxis is a type 1 (immediate) hypersensitivity reaction involving IgE-mediated mast cell and basophil
degranulation. Epinephrine is the primary treatment for anaphylaxis because it decreases further mast cell release of
inflammatory mediators and counteracts existing systemic inflammatory effects (eg, shock, bronchoconstriction).
[21470]
Angioedema
Angioedema can be hereditary (autosomal dominant) or acquired (associated with angiotensin-converting enzyme
[ACE] inhibitor treatment). In hereditary angioedema, low C1 esterase inhibitor activity leads to increases in
bradykinin activity. ACE inhibitors should not be used in these patients. [1612]
Antihistamines
First-generation antihistamines can cause significant side effects due to blockade of cholinergic, alpha-adrenergic,
and serotonergic pathways. They should be avoided in older patients with cognitive or functional impairments. [174]
Drug allergy
Red man syndrome (RMS) is the most common adverse reaction to vancomycin. It occurs due to rapid vancomycin
infusion, which leads to the direct activation of mast cells and the subsequent release of vasoactive
mediators. Patients develop flushing, pruritus, and an erythematous rash on the upper torso, face, and neck within
minutes of initiation. Because RMS is not a true allergic reaction (not IgE mediated), vancomycin can be restarted at
a slower rate of infusion once symptoms resolve. [19115]
Opioids
Opioids (eg, morphine) can generate a pseudoallergic response by directly activating mast cells to stimulate
degranulation, releasing histamine and other vasoactive mediators. This nonimmunologic reaction can cause itching,
urticarial rash, wheezing, hypotension, and tachycardia that closely mimic true IgE-mediated type 1
hypersensitivity. However, true IgE-mediated allergic reaction is rare with opioids. [14793]
AUTOIMMUNE DISEASES
Atopic dermatitis
Topical corticosteroids are the first-line therapy for atopic dermatitis. Their mechanism of action includes decreasing
tissue production of proinflammatory prostaglandins and leukotrienes through the inhibition of phospholipase A2;
they also inhibit transcription of many other proinflammatory mediators. [21294]
Azathioprine
Azathioprine is an immunosuppression drug that inhibits purine nucleotide synthesis and incorporates false purine
nucleotides into DNA and RNA. These effects reduce the proliferation and activity of both B and T lymphocytes. [18704]
Corticosteroids
Budesonide, like other glucocorticoids, reduces inflammation by binding to a cytosolic receptor, translocating into the
nucleus, and inhibiting proinflammatory transcription factors such as nuclear factor-kappa-B (NF-κB). It is especially
useful in reducing transmural bowel inflammation in patients with Crohn disease because it has high topical potency
and limited systemic adverse effects due to high first-pass metabolism. [18802]
Glucocorticoids have a variety of effects that can be useful in reducing inflammation and limiting end-organ damage
in inflammatory diseases (eg, sarcoidosis). These include decreased proinflammatory cytokine (IL-1, interferon-
gamma) production, increased anti-inflammatory cytokine (eg, IL-10) production, and impaired migration of
leukocytes (eg, neutrophils) to sites of inflammation. [18803]
TRANSPLANT MEDICINE
Mycophenolate is an immunosuppression drug that inhibits inosine 5'-monophosphate dehydrogenase in the de novo
purine synthesis pathway. It provides relatively specific suppression of lymphocyte proliferation, largely because
activated lymphocytes lack an established purine salvage pathway that is present in other hematopoietic cell lines.
[18706]
Aortic dissection
The primary goal of medical therapy for acute aortic dissection is to reduce aortic wall shear stress by minimizing the
change in aortic blood pressure per time (dP/dt). Esmolol, a selective beta-1 receptor blocker, decreases left
ventricular contraction velocity and heart rate to reduce dP/dt. [18709]
Dyslipidemia
Fibrates lower triglyceride levels by activating peroxisome proliferator-activated receptor alpha, which leads to
decreased hepatic VLDL production and increased lipoprotein lipase activity. Fish oil supplements containing high
concentrations of omega-3 fatty acids lower triglycerides by decreasing production of VLDL and apolipoprotein B.
[11844]

Symptomatic management of peripheral artery disease (PAD) includes a graded exercise program and
cilostazol. Cilostazol is a phosphodiesterase inhibitor that inhibits platelet aggregation and acts as a direct arterial
vasodilator. Patients with PAD should also receive an antiplatelet agent (aspirin or clopidogrel) for secondary
prevention of coronary heart disease and stroke. [1080]
Phosphodiesterase inhibitors
Atrial natriuretic peptide, brain natriuretic peptide, and nitric oxide activate guanylyl cyclase and increase conversion
of guanosine 5′-triphosphate to cyclic guanosine 3′,5′-monophosphate (cGMP). Phosphodiesterase inhibitors (eg,
sildenafil) decrease the degradation of cGMP. Elevated intracellular cGMP levels lead to relaxation of vascular
smooth muscle and vasodilation. [1118]
Sympathomimetic agents
Blanching of a vein into which norepinephrine is being infused together with induration and pallor of the tissues
surrounding the IV site are signs of norepinephrine extravasation and resulting vasoconstriction. Tissue necrosis is
best prevented by local injection of an α receptor blocking drug, such as phentolamine. [1164]
CARDIAC ARRHYTHMIAS
Amiodarone
Amiodarone is 40% iodine by weight. It can cause hypothyroidism due to decreased production of thyroid
hormone. Amiodarone can also cause hyperthyroidism due to increased thyroid hormone synthesis or destructive
thyroiditis with release of preformed thyroid hormone. [625]
Antiarrhythmic drugs
Amiodarone (and other class III and class IA antiarrhythmic agents) causes lengthening of the cardiac action potential,
which manifests as QT interval prolongation on ECG. QT prolongation caused by amiodarone, in contrast to other
drugs, is associated with a very low risk of torsades de pointes. [899]
The class IA antiarrhythmics (quinidine, procainamide, and disopyramide) are sodium channel-blocking agents that
depress phase 0 depolarization. They also prolong repolarization due to moderate potassium channel- blocking
activity, increasing action potential duration in cardiac myocytes. [1509]
Class III antiarrhythmic drugs (eg, amiodarone, sotalol, dofetilide) predominantly block potassium channels and
inhibit the outward potassium currents during phase 3 of the cardiac action potential, thereby prolonging
repolarization and total action potential duration. [901]
Adenosine causes hyperpolarization of the nodal pacemaker to briefly block conduction through the atrioventricular
node, and it is effective in the initial treatment of paroxysmal supraventricular tachycardia. Common adverse effects
include flushing, chest burning (due to bronchospasm), hypotension, and high-grade atrioventricular block. [898]
Class 1C antiarrhythmic agents (flecainide) block the fast sodium channels responsible for ventricular depolarization
(phase 0), prolonging QRS duration with little effect on the QT interval. Class 1A and class III agents cause the most
QT prolongation. [1508]
Amiodarone primarily functions as a class III antiarrhythmic, inhibiting the delayed rectifier potassium current to slow
ventricular repolarization and prolong the QT interval. It also inhibits fast sodium channels (class I effect) to slow
ventricular depolarization and prolong QRS complex duration. Beta blockade (class II effect) and inhibition of slow L-
type calcium channels (class IV effect) slow conduction in the sinus node and atrioventricular node causing decreased
sinus rate and a prolonged PR interval. [18889]
Beta blockers decrease AV nodal conduction, leading to an increased AV nodal refractory period. This correlates to
PR interval prolongation on an ECG. [2006]
For class I antiarrhythmics, sodium-channel-binding strength is IC > IA > IB. Use dependence describes the
phenomenon in which higher heart rates lead to increased sodium channel blockade due to cumulative blocking
effects over multiple cardiac cycles. Class IC antiarrhythmics demonstrate the most use dependence due to their
slow dissociation from the receptor, and class IB drugs have the least use dependence as they rapidly dissociate. [159]
Lidocaine is a class IB antiarrhythmic drug that tends to bind to inactivated sodium channels and rapidly
dissociates. As a result, it is effective in suppressing ventricular tachyarrhythmias induced by rapidly depolarizing and
ischemic myocardium. [900]
Sotalol has both beta adrenergic-blocking and class III antiarrhythmic (K+ channel-blocking) properties and is
occasionally used in treatment of atrial fibrillation. Major side effects of sotalol include bradycardia, proarrhythmia,
and most commonly torsades de pointes due to QT interval prolongation. [1506]
Class 1C antiarrhythmics such as flecainide are potent sodium channel blockers that have increased effect at faster
heart rates (use-dependence). This makes them more effective at treating tachyarrhythmias, but can also cause
prolonged QRS duration (a proarrhythmic effect) at higher heart rates. [8869]
Class III antiarrhythmic drugs (amiodarone, sotalol, dofetilide) predominantly block potassium channels and inhibit
the outward potassium currents during phase 3 of the cardiac action potential, thereby prolonging repolarization and
total action potential duration. [1507]
Bradycardia
Conduction impairment is common with acute inferior wall myocardial infarction. Sinus bradycardia often occurs due
to nodal ischemia and an increase in vagal tone triggered by infarction of myocardial tissue; the enhanced vagal tone
can be counteracted by the anticholinergic effects of atropine. [14780]
Digoxin
Digoxin can be used to improve ventricular rate control in patients with atrial fibrillation, as it decreases
atrioventricular node conduction by increasing parasympathetic (vagal) tone. Digoxin also has a positive inotropic
effect that can be useful in patients with left ventricular systolic dysfunction. [155]
Digoxin toxicity typically presents with cardiac arrhythmias and nonspecific gastrointestinal (nausea, vomiting),
neurological (confusion, weakness), and visual symptoms. Elevated potassium is another sign of digoxin toxicity and
is caused by inhibition of Na-K-ATPase pumps. [147]
Heart block
Common adverse effects of nondihydropyridine calcium channel blockers (eg, diltiazem, verapamil) include
constipation, bradycardia, atrioventricular block (negative chronotropic effect), and worsening of heart failure in
patients with left ventricular systolic dysfunction (negative inotropic effect). [153]
Long QT syndrome
Methadone slows the delayed rectifier potassium current responsible for ventricular repolarization, and high doses
are associated with QT interval prolongation. QT interval prolongation predisposes to the development of torsade de
pointes, a serious ventricular arrhythmia that can cause syncope and sudden cardiac death. [18630]
Congenital long QT syndrome is commonly caused by a mutation that slows the delayed rectifier potassium current
that repolarizes the cardiomyocyte action potential. Certain medications (eg, macrolide antibiotics, antipsychotics,
antiemetics) also slow the potassium repolarization current and prolong the QT interval. Excessive QT prolongation
can trigger serious cardiac arrhythmia (ie, torsades de pointes), resulting in syncope or sudden cardiac death. [15693]
SLE
Procainamide and hydralazine have the highest risk of causing drug-induced lupus erythematosus (DILE), which is
characterized by the development of lupus-like symptoms in addition to positive ANA and anti-histone
antibodies. Unlike with SLE, anti-dsDNA antibodies are rarely seen. [1505]
Syncope
Clonidine, an antihypertensive agent, stimulates central alpha-2 adrenergic receptors, causing a decrease in
presynaptic release of norepinephrine and a decrease in sympathetic outflow. This prevents the normal baroceptor-
mediated increase in peripheral vascular resistance and heart rate during standing and can cause orthostatic syncope.
[21419]
Torsades de pointes
Torsades de pointes (TdP) refers to polymorphic ventricular tachycardia that occurs in the setting of a congenital or
acquired prolonged QT interval. TdP is most commonly precipitated by medications that prolong the QT interval such
as certain antiarrhythmics (sotalol, quinidine), antipsychotics (haloperidol), and antibiotics (macrolides,
fluoroquinolones). [7640]
Dofetilide and ibutilide are class III antiarrhythmics that treat atrial fibrillation by blocking the rapid component of the
delayed-rectifier potassium current to slow repolarization and increase the effective refractory period. As a result,
the QT interval is prolonged, creating an increased risk of polymorphic ventricular tachycardia (torsade de pointes).
[14744]
CARDIOVASCULAR DRUGS
Atrial fibrillation
Digoxin slows atrioventricular node conduction by increasing parasympathetic tone. This mechanism is effective at
controlling ventricular rate in atrial fibrillation at rest, but it poorly controls ventricular rate during exercise, when
parasympathetic output is low relative to high levels of sympathetic tone. [21458]
Beta blockers
When exposed to a prolonged environmental stimulus, cells can adjust their sensitivity to the stimulus by
upregulating or downregulating surface membrane receptors. Prolonged beta blockade leads to upregulation of
beta-adrenergic receptors and increased sensitivity to circulating catecholamines, causing an enhanced beta-
adrenergic response on abrupt beta blocker cessation (ie, beta blocker withdrawal syndrome). [15306]
β1 adrenergic receptors are found in cardiac tissue and on renal juxtaglomerular cells, but not in vascular smooth
muscle. Selective blockade of the β1 receptor (eg, with atenolol) leads to decreased cAMP levels in cardiac and renal
tissue without significantly affecting cAMP levels in vascular smooth muscle. [8289]
Dyslipidemia
Niacin is used in the treatment of hyperlipidemia. It increases HDL levels and decreases LDL levels and
triglycerides. Niacin causes cutaneous flushing, which is mediated by prostaglandins and can be diminished by
pretreatment with aspirin. [160]
Nitrates
Nitrates (via conversion to nitric oxide) activate guanylate cyclase and increase intracellular levels of cyclic guanosine
monophosphate (cGMP). Increased levels of cGMP lead to myosin light-chain dephosphorylation, resulting in
vascular smooth muscle relaxation. [136]
The main adverse effects seen with nitrate therapy include headaches and cutaneous flushing along with
lightheadedness and hypotension due to systemic vasodilation. [140]
Using nitrates together with phosphodiesterase (PDE) inhibitors used for erectile dysfunction and pulmonary
hypertension causes a profound systemic hypotension because they both increase intracellular cGMP which causes
vascular smooth muscle relaxation. Their use together is absolutely contraindicated. [143]
Orthostatic hypotension
Orthostatic hypotension is a frequent cause of lightheadedness and syncope and is defined as a decrease in systolic
(>20 mm Hg) or diastolic (>10 mm Hg) blood pressure on standing from the supine position. Medications (α1-
adrenergic antagonists, diuretics), volume depletion, and autonomic dysfunction are common causes of orthostatic
hypotension. [1342]
Norepinephrine stimulates cardiac β1 adrenoreceptors, which increases cAMP concentration within cardiac myocytes
and leads to increased contractility, conduction, and heart rate. Peripheral vasoconstriction occurs via stimulation of
α1 adrenoreceptors in vascular smooth muscle cells and activation of an IP3 signaling pathway. [1367]
Isoproterenol is a β-1 and β-2 adrenergic receptor agonist that causes increased myocardial contractility and
decreased systemic vascular resistance. [1836]
Dobutamine is a β-adrenergic agonist with predominant activity on β1 receptors and weak activity on β2 and α1
receptors. Stimulation of β1 receptors leads to an increased production of cAMP and increased cytosolic Ca2+
concentration. This facilitates the interaction between actin and myosin, resulting in increased myocardial
contractility. [11925]
α-adrenergic agonists increase systolic and diastolic blood pressure by stimulating α1-adrenoreceptors in the vascular
walls, causing vasoconstriction. The elevated systemic blood pressure then causes a reflexive increase in vagal tone,
resulting in decreased heart rate and slowed atrioventricular node conduction. [1343]
Epinephrine increases systolic blood pressure (α1 + β1) and heart rate (β1), and either increases or decreases
diastolic blood pressure depending on the dose (either α1 or β2 predominates). Pretreatment with propranolol
eliminates the β effects of epinephrine (vasodilatation and tachycardia), leaving only the α effect (vasoconstriction).
[1364]
Syncope
Fludrocortisone improves hypovolemia and orthostatic hypotension in primary adrenal insufficiency by decreasing
urine sodium excretion (thereby increasing circulating blood volume) and increasing the sensitivity of the vasculature
to endogenous vasoconstrictors (eg, norepinephrine). [21524]

Patency of the ductus arteriosus is maintained in utero due to placental production of prostaglandin E2 (PGE2) and
low oxygen levels in the fetal circulation. Persistence after birth (ie, patent ductus arteriosus) is associated with
elevated postnatal PGE2 and typically presents with a continuous murmur, widened pulse pressure, and bounding
pulses in a preterm infant. [315]
Angina
Pharmacologic nitrates (eg, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate) are metabolized to nitric oxide
and S-nitrothiols in vascular smooth muscle cells, leading to an increase in cyclic guanosine monophosphate (cGMP)
that stimulates vasodilation. Large veins are predominantly affected, leading to increased venous capacitance and
reduced venous return (preload), which decreases left ventricular wall stress and myocardial oxygen demand to
relieve anginal symptoms. [137]
Clopidogrel irreversibly blocks the P2Y12 component of ADP receptors on the platelet surface and prevents platelet
aggregation. Clopidogrel is as effective as aspirin in the prevention of cardiovascular events in patients with coronary
heart disease. [1828]
Drug induced liver injury

Common side effects of HMG-CoA reductase inhibitors (statins) include muscle and liver toxicity. Hepatic
transaminases should be checked prior to initiating therapy and repeated if symptoms of hepatic injury occur. [780]
Drug induced myopathy

Statins inhibit the intracellular rate-limiting step of cholesterol biosynthesis via competitive inhibition of HMG-CoA
reductase. This leads to enhanced hepatic LDL receptor recycling and increased LDL clearance from the
circulation. Statin-induced myopathy (eg, myalgia, elevated creatine kinase) is the most common complication of
statin use. [712]
Dyslipidemia
Although low HDL concentration is associated with increased cardiovascular risk, the use of medications to raise HDL
levels does not improve cardiovascular outcomes. HMG-CoA reductase inhibitors (statins) lower total cholesterol and
LDL levels. Statins are the most effective lipid-lowering drugs for primary and secondary prevention of cardiovascular
events, regardless of baseline lipid levels. [781]
Treatment with statins causes hepatocytes to increase their LDL receptor density, leading to increased uptake of
circulating LDL. [711]
Beta blockers are used in acute myocardial infarction to reduce morbidity and mortality by decreasing cardiac output
and myocardial oxygen demand. Non-cardioselective beta blockers (eg, propranolol, nadolol) can trigger
bronchospasm in patients with underlying asthma or chronic obstructive pulmonary disease. Cardioselective beta
blockers (eg, metoprolol) predominantly affect beta-1 receptors and are preferred in such patients. [1196]
In the fibrinolytic pathway, tissue plasminogen activator (tPA) converts plasminogen to plasmin, which then breaks
down fibrin clot. The administration of a tPA analogue (eg, alteplase, tenecteplase, streptokinase) triggers fibrinolysis
and can restore myocardial perfusion in patients with ST-elevation myocardial infarction who cannot undergo timely
percutaneous coronary intervention. [1082]
Fibrinolytic therapy for acute ST segment elevation myocardial infarction is a reasonable reperfusion technique for
patients with no contraindications to thrombolysis. Fibrinolytic agents such as alteplase bind to fibrin in the
thrombus (clot) and activate plasmin, which leads to thrombolysis. The most common adverse effect of thrombolysis
is hemorrhage (eg, gastrointestinal, intracerebral). [823]
Nitrates
Sublingual nitroglycerin is used for rapid symptom relief in patients with stable angina. The primary anti-ischemic
effect of nitrates is mediated by venodilation with a decrease in left ventricular end-diastolic volume and wall stress,
resulting in decreased myocardial oxygen demand and relief of angina symptoms. [138]
Vasospastic angina
Vasospastic angina is the result of intermittent coronary vasospasm caused by endothelial dysfunction and autonomic
imbalance. Although acetylcholine normally stimulates vasodilation, it triggers coronary vasospasm in affected
patients due to a deficiency of vasodilatory endothelial nitric oxide. [38]
Aging
Digoxin is a cardiac glycoside that is predominantly cleared by the kidneys. Elderly patients typically exhibit age-
related renal insufficiency, even in the presence of normal creatinine levels. The dose of digoxin must be reduced in
these patients to prevent toxicity. [1780]
Aldosterone antagonists
All diuretics except for the potassium-sparing class cause potassium loss by increasing sodium delivery to the late
distal tubule and cortical collecting duct, where aldosterone-induced sodium reabsorption occurs at the expense of
potassium. Potassium-sparing diuretics (eg, spironolactone, amiloride) act on the late distal tubule and cortical
collecting duct to antagonize the effects of aldosterone. [2005]
Mineralocorticoid receptor antagonists (eg, spironolactone, eplerenone) improve survival in patients with congestive
heart failure and reduced left ventricular ejection fraction. They should not be used in patients with hyperkalemia or
renal failure. [686]
Cardiogenic shock
Dobutamine is a beta adrenergic agonist with predominant activity on beta-1 receptors. It causes an increase in heart
rate and cardiac contractility, leading to an increase in myocardial oxygen consumption. [1344]

Drugs that have been shown to improve long-term survival in patients with heart failure with reduced ejection
fraction include beta blockers, ACE inhibitors, angiotensin II receptor blockers, angiotensin receptor-neprilysin
inhibitors, and aldosterone antagonists. [1944]
Neurohormones (eg, norepinephrine, angiotensin II, and aldosterone) play a large role in the deleterious cardiac
remodeling that occurs in heart failure with reduced ejection fraction. ACE inhibitors, angiotensin-receptor blockers,
mineralocorticoid receptor antagonists, beta blockers, and angiotensin receptor-neprilysin inhibitors reduce mortality
in these patients by reducing neurohormonal-mediated cardiac remodeling. [1565]
Milrinone is a phosphodiesterase-3 inhibitor that reduces the degradation of cyclic adenosine monophosphate to
provide 2 beneficial effects for treating systolic heart failure. Calcium influx into cardiomyocytes is increased, which
increases cardiac contractility. In addition, calcium-myosin light chain kinase interaction is reduced, which causes
vasodilation and reduces cardiac preload and afterload. [149]
Digoxin
Digoxin toxicity presents with nonspecific gastrointestinal (eg, anorexia, nausea, vomiting) and neurologic (eg,
fatigue, confusion, weakness) symptoms. Changes in color vision are a more specific, but rarer, finding. Life-
threatening ventricular arrhythmias are the most serious complication. [156]
Digoxin directly inhibits the Na-K-ATPase pump in myocardial cells, leading to a decrease in sodium efflux and an
increase in intracellular sodium levels. This reduces the forward activity of the sodium-calcium exchanger, causing
increased intracellular calcium concentration and improved myocyte contractility. [148]
Loop diuretics
Thiazide diuretics, especially metolazone, potentiate the diuretic effect of loop diuretics (eg, furosemide) by blocking
the reabsorption of the increased distal tubular sodium delivery caused by loop diuretics. [18639]
Sepsis
Norepinephrine potently stimulates alpha-1 receptors to cause peripheral vasoconstriction, increasing systemic
vascular resistance and blood pressure. This triggers a baroreceptor–mediated reflexive decrease in heart rate that
completely offsets or overrides the direct beta-1–mediated increase in heart rate caused by norepinephrine, resulting
in overall unchanged or slightly decreased heart rate. [19337]
Phenylephrine is a selective alpha-1 agonist with no effect on alpha-2 or beta receptors. It causes peripheral
vasoconstriction that increases systemic vascular resistance and blood pressure. It has no direct effect on the heart
but stimulates a reflex–mediated decrease in heart rate and myocardial contractility. [6811]
HYPERTENSION
ACE inhibitors
In the kidney, angiotensin II preferentially constricts the efferent arteriole, thereby maintaining the glomerular
filtration rate (GFR) within normal range. ACE-inhibitors promote efferent arteriolar dilation, causing GFR reduction.
[1841]
Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) reduce the risk of chronic
kidney disease in patients with hypertension and diabetes. ACE inhibitors raise levels of bradykinin and can cause a
nonproductive cough, an effect not seen with ARBs. [1166]
Angiotensin receptor blockers

Angiotensin II receptor blockers (ARBs) work by blocking angiotensin II type 1 receptors, inhibiting the effects of
angiotensin II. This results in arterial vasodilation and decreased aldosterone secretion. The resulting fall in blood
pressure increases renin, angiotensin I, and angiotensin II levels. ARBs do not affect the activity of angiotensin-
converting enzyme, and therefore they do not affect bradykinin degradation and do not cause cough. [691]
Beta blocker poisoning
Patients who have overdosed on beta blockers should be treated with glucagon, which increases heart rate and
contractility independent of adrenergic receptors. Glucagon activates G-protein-coupled receptors on cardiac
myocytes, causing activation of adenylate cyclase and raising intracellular cAMP. The result is calcium release from
intracellular stores and increased sinoatrial node firing. [1444]
Calcium channel blocker

Calcium channel blockers inhibit the L-type calcium channel on vascular smooth muscle and cardiac
cells. Dihydropyridines (eg, nifedipine, amlodipine) primarily affect peripheral arteries and cause
vasodilation. Nondihydropyridines (eg, verapamil, diltiazem) affect the myocardium and can cause bradycardia and
slowed atrioventricular conduction. [145]
Amlodipine is a dihydropyridine calcium channel blocker commonly used as monotherapy or in combination with
other agents for treatment of hypertension. Major side effects include headache, flushing, dizziness, and peripheral
edema. [154]
Hyperkalemia
ACE inhibitors block the conversion of angiotensin I to angiotensin II, thereby reducing vasoconstriction and
aldosterone secretion. Decreased aldosterone leads to potassium retention, which can cause hyperkalemia,
especially in patients with renal insufficiency and those taking other medications that raise potassium levels (eg,
angiotensin II receptor blockers, mineralocorticoid receptor blockers). [697]
Hypokalemia
Potassium-sparing diuretics are often added to loop or thiazide diuretics to prevent hypokalemia. Amiloride and
triamterene directly inhibit the epithelial sodium channel, preventing sodium from entering the principal cell, which
reduces the electrochemical gradient (ie, negative luminal charge) that helps drive potassium secretion. [18860]
Malignant hypertension
Fenoldopam is a selective peripheral dopamine-1 receptor agonist. It causes vasodilation of systemic and renal
arterioles to lower blood pressure while also increasing renal perfusion, urine output, and natriuresis, making it
useful in the treatment of hypertensive emergency in patients with renal insufficiency. [689]
Labetalol is a nonselective vasodilatory beta blocker that blocks beta-1, beta-2, and alpha-1 adrenergic
receptors. Alpha-1 receptor blockade outweighs beta-2 receptor blockade to cause peripheral vasodilation with
decreased venous return and lower systemic vascular resistance. The relatively balanced vasodilation reduces blood
pressure without changing stroke volume. Beta-1 receptor blockade overrides the expected baroreflex-mediated
increase in heart rate, resulting in overall decreased heart rate. [19601]
Nitrates
Nitrates are primarily venodilators and increase peripheral venous capacitance, thereby reducing cardiac preload and
left ventricular end-diastolic volume and pressure. Nitrates also have a modest effect on arteriolar dilation and cause
a decrease in systemic vascular resistance and cardiac afterload. [11836]
Beta blockers inhibit release of renin from renal juxtaglomerular cells through antagonism of beta-1 receptors on
these cells. Inhibition of renin release prevents activation of the renin-angiotensin-aldosterone pathway, which
results in decreased vasoconstriction and decreased renal sodium and water retention. [1948]
Direct arteriolar vasodilators lower blood pressure but trigger reflex sympathetic activation and stimulate the renin-
angiotensin-aldosterone axis. This results in tachycardia and edema. To counteract such compensatory effects, these
agents are often given in combination with sympatholytics and diuretics. [1252]
MISCELLANEOUS
ACE inhibitors
Following myocardial infarction, collagen deposition and fibrosis within the infarct region and eccentric hypertrophy
of surviving myocytes can lead to progressive left ventricular (LV) dilation and worsening contractile
dysfunction. Because much of this remodeling is driven by neurohormonal signaling via angiotensin II, ACE inhibitors
(eg, lisinopril) reduce deleterious cardiac remodeling following myocardial infarction, minimizing LV dilation and
helping preserve contractile function. [18840]
Chronic cough
Cough is a very well recognized side effect of ACE inhibitor therapy. Cough secondary to ACE inhibitor therapy is
characterized as dry, nonproductive, and persistent. The mechanism behind ACE inhibitor induced cough is
accumulation of bradykinin, substance P, or prostaglandins. Because angiotensin receptor blockers (ARBs) do not
affect ACE activity, they theoretically should not cause cough. [948]
Nitrates
Patients taking daily maintenance nitrates need to have a nitrate-free period every day to avoid tolerance to the
drug. [142]
Low-dose dopamine infusion stimulates D1 receptors in the renal and mesenteric vasculature, resulting in
vasodilation and increased blood flow to these sites. Increasing doses of dopamine stimulate β1 and α1 receptors,
resulting in increased cardiac output and elevated systemic vascular resistance. At the high end of the dose range,
the increase in afterload can result in decreased cardiac output. [1365]
Anthracycline cardiotoxicity
Anthracycline chemotherapeutic agents (eg, doxorubicin, daunorubicin) cause cardiotoxicity mainly through the
formation of anthracycline–topoisomerase II DNA cleavage complexes that affect healthy cardiomyocytes. The
cardiotoxicity is dependent on the cumulative dose of anthracycline received, and it manifests as dilated
cardiomyopathy. [1014]
Trastuzumab is a monoclonal antibody that blocks human epidermal growth factor receptor-2 (HER2) to disrupt
malignant cell signaling and encourage apoptosis. Because HER2 helps preserve cardiomyocyte function,
trastuzumab can cause cardiotoxicity that manifests as a decrease in myocardial contractility without cardiomyocyte
destruction or myocardial fibrosis. [14844]
Left ventricular outflow tract obstruction in hypertrophic cardiomyopathy worsens with decreased left ventricular
blood volume. Therefore, medications that decrease preload (eg, nitrates), afterload (eg, hydralazine), or both (eg,
dihydropyridine calcium channel blockers, ACE inhibitors) should be avoided. [141]
Hypertrophic cardiomyopathy commonly involves dynamic left ventricular (LV) outflow tract obstruction that
worsens with decreased LV blood volume and improves with increased LV blood volume. Nondihydropyridine
calcium channel blockers (eg, verapamil) decrease heart rate (ie, negative chronotropy) and LV contractility (ie,
negative inotropy) to increase LV blood volume, reduce LV outflow tract obstruction, and improve symptoms. [22787]
Many patients with hypertrophic cardiomyopathy have exercise intolerance due to left ventricular (LV) outflow tract
obstruction. This outflow obstruction is worsened by decreased LV blood volume. Beta blockers decrease heart rate
and LV contractility to increase LV blood volume, reduce LV outflow tract obstruction, and improve symptoms. [15515]
Dose response curves

Phenoxybenzamine is an irreversible α1 and α2 adrenergic antagonist that effectively reduces the arterial
vasoconstriction induced by norepinephrine. Because phenoxybenzamine is an irreversible antagonist, even very
high concentrations of norepinephrine, such as those seen in pheochromocytoma, cannot overcome its effects. [1947]
A permissive hormone has no effect on a physiologic process by itself but allows another hormone to exert its
maximal effect on that process. Cortisol exerts a permissive effect on catecholamines to potentiate vasoconstriction
and bronchodilation; it also has a permissive effect on glucagon to increase glucose release from the liver. [551]
Endocarditis
Initial empiric treatment of coagulase-negative staphylococcal infection should include vancomycin due to
widespread methicillin resistance, especially in nosocomial infections. If susceptibility results indicate a methicillin-
susceptible isolate, vancomycin can be switched to nafcillin or oxacillin. [645]
Dermatology
Androgenic steroids
Androgens stimulate follicular epidermal hyperproliferation and excessive sebum production, thereby promoting
acne development. Androgenic steroid supplementation is a known cause of acne, especially in competitive athletes.
[7585]
Hair loss
Androgenetic alopecia causes hair loss primarily at the anterior scalp and vertex. It shows polygenic inheritance, with
dihydrotestosterone (DHT) being the primary pathogenic factor. Five-alpha reductase inhibitors decrease the
conversion of testosterone to DHT and are effective for treating the condition. [1726]
Atopic dermatitis
Local adverse effects of chronic topical corticosteroid therapy include cutaneous atrophy, telangiectasias, and
corticosteroid-induced acne. Effects are more pronounced with high-potency corticosteroids and in areas of thin skin
(eg, flexural areas). [1214]
Psoriasis
First-line treatment options for localized psoriasis include high-potency topical corticosteroids and vitamin D
analogs. Vitamin D analogs inhibit T-cell and keratinocyte proliferation and stimulate keratinocyte
differentiation. Corticosteroids also have anti-inflammatory and antiproliferative properties; their mechanism of
action is complementary to the vitamin D analogs. [8569]
MISCELLANEOUS
Calcineurin inhibitors
Atopic dermatitis is an inflammatory condition that can be treated with calcineurin inhibitors (eg, pimecrolimus,
tacrolimus) as second-line therapy after topical corticosteroids. Calcineurin inhibitors work by inhibiting T-cell
signaling needed to transcribe the proinflammatory cytokine IL-2, thereby decreasing inflammation. [18707]
Imiquimod
Imiquimod is a widely used topical immunomodulatory agent that stimulates a potent cellular and cytokine-based
immune response to aberrant cells (eg, human papillomavirus-infected cells in anogenital warts) by activating toll-like
receptors and upregulating NF-κB. Other antiproliferative effects of imiquimod include inhibition of angiogenesis and
induction of apoptosis. [14488]
Tinea
Terbinafine is used for treatment of dermatophytosis. It inhibits synthesis of fungal membrane ergosterol by
suppressing the enzyme squalene epoxidase. [836]
Nystatin is a polyene antifungal and the drug of choice for oropharyngeal candidiasis in patients without advanced
immunodeficiency. It acts by binding to ergosterol in the fungal cell membrane, causing the formation of pores and
leakage of fungal cell contents. Nystatin is not absorbed from the gastrointestinal tract and is administered as an oral
"swish and swallow" agent. [1195]
Rhinitis
Topical preparations of α-adrenergic agonists cause vasoconstriction of the nasal mucosa vessels and are used as
decongestants. Overuse of these drugs causes negative feedback, resulting in decreased norepinephrine synthesis
and release from nerve endings, which diminishes their effect (ie, tachyphylaxis). [1345]
DIABETES MELLITUS
Antidiabetic drugs
Sodium-glucose cotransporter-2 inhibitors (eg, canagliflozin, dapagliflozin) decrease renal reabsorption of glucose,
leading to urinary glucose loss and decreased blood glucose levels. However, the resultant glycosuria can lead to
genitourinary tract infections and genital mycotic infections. [18956]
Diabetes mellitus
Long-acting insulin analogues (eg, glargine) have an extended duration of action without a noticeable peak in activity
and are typically given once daily to mimic basal insulin secretion. Rapid-acting insulins (eg, aspart, lispro) are quickly
absorbed from the injection site and are given at mealtimes to replicate postprandial insulin secretion. [850]
Sodium-glucose cotransporter-2 inhibitors (eg, canagliflozin, dapagliflozin) lower glucose levels by decreasing renal
reabsorption of glucose and have cardioprotective and renoprotective effects. Checking serum creatinine is
recommended prior to initiation because the antihyperglycemic effect of these medications becomes less
pronounced as renal function declines. [604]
Metformin lowers blood glucose by reducing hepatic gluconeogenesis and increasing insulin-dependent peripheral
glucose uptake. Lactic acidosis is a rare complication of metformin therapy; the risk is increased in patients with
underlying renal insufficiency. [607]
Metformin reduces hepatic gluconeogenesis and release of glucose into circulation; increases peripheral glucose
uptake and utilization; and reduces circulating lipid levels. Circulating insulin levels are unchanged or slightly
decreased; therefore, metformin carries low risk of hypoglycemia. In addition, metformin reduces caloric intake due
to decreased appetite and decreased absorption of glucose, leading to modest weight loss. [18952]
Glucagon-like peptide-1 (GLP-1), degraded by dipeptidyl peptidase-4 (DPP-4), helps regulate blood glucose by slowing
gastric emptying, suppressing glucagon secretion, and increasing glucose-dependent insulin release. DPP-4 inhibitors
(eg, sitagliptin) increase the effects of GLP-1 and improve glycemic control. Because the effect on insulin is glucose
dependent, there is minimal risk of hypoglycemia. [16324]
Sodium-glucose cotransporter 2 inhibitors decrease renal reabsorption of glucose and sodium, leading to increased
urinary glucose excretion and decreased blood glucose levels. In addition, natriuresis and osmotic diuresis lead to a
small decrease in extracellular fluid volume, total body sodium content, and blood pressure. [18958]
Sulfonylureas inhibit the ATP-sensitive potassium channel on the pancreatic beta cell membrane, inducing
depolarization Ca2+ influx, and insulin release independent of blood glucose concentrations. Sulfonylureas can
induce hypoglycemia because they stimulate insulin secretion even when blood glucose levels are normal. [606]
Sulfonylureas inhibit the ATP-sensitive potassium channel on the pancreatic beta cell membrane, inducing
depolarization and L-type calcium channel opening. The increased Ca2+ influx stimulates beta cell insulin release
independent of blood glucose concentrations. Sulfonylureas stimulate insulin secretion, even when blood glucose
levels are normal, which can lead to hypoglycemia. [15881]
Alpha-2 adrenergic receptors inhibit insulin secretion, and beta-2 adrenergic receptors stimulate insulin
secretion. The alpha-2-mediated inhibitory effect is generally predominant, causing sympathetic stimulation to lead
to overall inhibition of insulin secretion. [1324]
Sodium-glucose cotransporter-2 inhibitors (eg, canagliflozin, dapagliflozin) decrease renal reabsorption of glucose
and sodium. The resultant osmotic diuresis and natriuresis lead to reduced blood pressure, decreased mortality in
heart failure, and slowed progression of diabetic nephropathy. [15770]
Intravenous regular insulin has a rapid onset and short half-life, allowing the rapid adjustments needed in diabetic
ketoacidosis management. In contrast, regular insulin given subcutaneously starts working within 30 minutes, peaks
in 2-4 hours, and lasts 5-8 hours, making it usable as a premeal insulin that treats postprandial hyperglycemia. [600]
Glucagon-like peptide-1 (GLP-1) agonists slow gastric emptying, suppress glucagon secretion, and increase glucose-
dependent insulin release. These agents cause significant weight loss by suppressing the appetite and increasing
satiety. [14136]
Physiologic insulin secretion can be approximated by separate administrations of long-acting and rapid-acting insulin
analogues. Long-acting preparations (eg, glargine) replicate basal insulin secretion, whereas premeal, rapid-acting
insulin (eg, lispro) replicates meal-related insulin surges. [15876]
Sulfonylureas (eg, glyburide, glimepiride) increase insulin secretion by pancreatic beta cells independent of blood
glucose concentration. These medications have a high incidence of hypoglycemia, especially in the elderly
population. [11565]
Proinsulin is cleaved into insulin and C-peptide; therefore, C-peptide is a marker of endogenous insulin
secretion. Diabetic medications that increase endogenous insulin secretion (eg, sulfonylureas) elevate the C-peptide
level. [1655]

In patients with diabetes mellitus, excess glucose in the proximal tubule causes increased concurrent reabsorption of
sodium by sodium-glucose cotransporter-2 (SGLT2). This leads to decreased sodium delivery to the macula densa and
increased renin secretion, which increases glomerular filtration pressure and promotes glomerular
hyperfiltration. SGLT2 inhibitors increase sodium delivery to the macula densa, decreasing renin production and
reducing hyperfiltration. [18959]
Gastroparesis
Erythromycin stimulates upper gastrointestinal motility by acting as an agonist on motilin receptors in the muscularis
externa. Therefore, it can be used to treat gastroparesis (ie, delayed gastric emptying), a condition that frequently
occurs in patients with long standing diabetes mellitus. [6705]
Hypoglycemia
Nonselective beta blockers exacerbate hypoglycemia and mask hypoglycemic symptoms mediated by
norepinephrine/epinephrine. [1492]
Severe hypoglycemia causing impaired conciousness can be treated by a caregiver or bystander with injectable or
intranasal glucagon. Glucagon rapidly corrects hypoglycemia by increasing hepatic glycogenolysis, resulting in
the release of glucose from preexisting hepatic glycogen stores. [1984]
Physician patient communication

Insulin can cause weight gain due to physiologic (eg, increased peripheral glucose uptake, reduced renal loss of
glucose) and behavioral (eg, increased snacking in response to hypoglycemia, less rigorous attention to diet)
factors. Counseling should elicit the patient's perspective on appetite, changes in dietary patterns, and hypoglycemic
symptoms. [18965]
ENDOCRINE TUMORS
Hypothyroidism
Coadministration of levothyroxine with various foods (eg, soy products) and certain medications (eg, iron, calcium,
antacids) can lead to poor intestinal absorption of levothyroxine and symptoms of hypothyroidism while on therapy.
[19756]
Pituitary adenoma
Galactorrhea is abnormal secretion of breast milk not associated with pregnancy or breastfeeding. It is most
commonly due to excess prolactin, as seen in prolactin-secreting pituitary adenomas. Prolactin is under negative
regulation by hypothalamic dopaminergic neurons, and dopamine agonists can be used to treat hyperprolactinemia.
[15303]
Acromegaly
Acromegaly is usually treated with resection of the somatotroph pituitary adenoma, but additional medical therapy is
needed for patients with residual tumor. Octreotide is a long-acting somatostatin analogue that inhibits growth
hormone secretion and, subsequently, insulin-like growth factor-1 release. It also reduces residual adenoma size in
many patients. [20588]
Hyperprolactinemia
Prolactin is under negative regulation by dopaminergic neurons via the pituitary stalk. Dopamine agonists (eg,
cabergoline) are used in patients with prolactin-secreting pituitary adenomas (prolactinomas) to suppress prolactin
production and reduce tumor size. Benefits are typically seen within the first few weeks of therapy. [21663]
MISCELLANEOUS
Corticosteroids
Glucocorticoids are predominantly catabolic, causing muscle weakness, skin thinning, impaired wound healing,
osteoporosis, and immunosuppression. However, they also cause increased hepatic synthesis of gluconeogenic and
glycogenic proteins to increase glucose availability. This, along with peripheral antagonism of insulin, contributes to
the development of hyperglycemia. [548]
High levels of cortisol, as seen in patients with Cushing syndrome, frequently cause hypertension due to the increased
production of angiotensinogen, adrenergic hypersensitivity, and activation of renal mineralocorticoid receptors,
which induces sodium reabsorption. The combined effect leads to expanded blood volume and increased systemic
vascular resistance. [18801]
Lipodystrophy
Highly-active antiretroviral therapy (HAART) for HIV is commonly associated with body fat
redistribution. Subcutaneous lipoatrophy involving the face and extremities is associated with nucleoside reverse
transcriptase inhibitors (especially stavudine and zidovudine) and protease inhibitors. Central fat accumulation in the
trunk and viscera can occur with any HAART regimen. [1673]
Osteoporosis
Chronic or recurrent glucocorticoid (eg, prednisone) use can lead to loss of bone density. Glucocorticoids inhibit
replication and differentiation of osteoblast precursor cells, increase osteoclast activity, and promote intestinal and
renal calcium wasting. [19949]
Parathyroid hormone (PTH) is released in a combination continuous/tonic and pulsatile pattern. Continuous high
levels of PTH lead to excessive release of calcium from bones and increase the risk of osteoporosis; however, pulsatile
secretion has an anabolic effect on bone metabolism, stimulating osteoblast proliferation and inducing increased
formation of new bone. [19948]
Acute pancreatitis
In patients with severe hypertriglyceridemia, pancreatic lipases can cause toxic levels of free fatty acids to be released
within the pancreatic tissue, leading to acute pancreatitis. Fibrates (eg, fenofibrate) are the most effective agents for
the treatment of hypertriglyceridemia. [166]
Dyslipidemia
Binding of proprotein convertase subtilisin kexin 9 (PCSK9) to low-density lipoprotein receptor (LDL-R) on the
hepatocyte cell surface increases degradation of LDL-R, leading to decreased uptake of circulating LDL. PCSK9
inhibitors (eg, evolocumab, alirocumab) decrease LDL-R degradation, resulting in greater uptake of LDL in the liver
and lower circulating LDL levels. [20921]
Ezetimibe reduces intestinal absorption of cholesterol. As a result, the amount of dietary cholesterol reaching the
liver decreases. To compensate, the liver increases LDL receptor expression, which draws cholesterol out of the
circulation. [11634]
Bile acid-binding resins inhibit the enterohepatic circulation of bile acids. This leads to diversion of hepatic
cholesterol to synthesis of new bile acids, increased uptake of cholesterol from the circulation, and reduced blood
LDL levels. However, bile acid-binding resins increase hepatic production of triglycerides and can cause
hypertriglyceridemia. [163]
Obesity
Norepinephrine-releasing agents (eg, phentermine) are sympathomimetic weight-loss drugs indicated for short-term
treatment of obesity. They stimulate the release and inhibit the reuptake of norepinephrine. Subjective effects
include an increased sensation of satiety, leading to reduced caloric intake. Weight regain after cessation is common
with these drugs. [18595]
Aromatase inhibitors
Estrogen is the main hormone responsible for the growth and development of estrogen receptor (ER)-positive breast
tumors. Aromatase inhibitors (eg, anastrozole, letrozole, exemestane) decrease the synthesis of estrogen from
androgens, suppressing estrogen levels and slowing progression of ER-positive tumors. [584]

5-alpha-reductase inhibitors (eg, finasteride) reduce conversion of testosterone to dihydrotestosterone. In men with
benign prostatic hyperplasia, these agents reduce prostate volume and alleviate obstruction of urinary
flow. However, they are associated with androgen-deficiency effects, including decreased libido, erectile dysfunction,
and decreased ejaculate volume. [658]
Breast cancer
Selective estrogen receptor modulators (eg, tamoxifen, raloxifene) are competitive inhibitors of estrogen binding to
estrogen receptors. They can have agonist or antagonist effects depending on the specific tissue. Tamoxifen has an
estrogenic effect on the uterus and can cause endometrial hyperplasia and cancer. [581]
Gynecomastia
Gynecomastia is the development of glandular breast tissue in males and is commonly seen in men receiving
androgen deprivation therapy for prostate cancer. Tamoxifen inhibits the effect of estrogen on breast tissue and can
reduce the risk of gynecomastia in these patients. [11657]

Testosterone replacement therapy is indicated for men with symptomatic hypogonadism. It is associated with an
increase in serum prostate-specific antigen and may raise the risk of prostate cancer. In addition, testosterone
therapy can cause erythrocytosis (leading to thromboembolism), and hematocrit should be regularly monitored.
[19000]
Osteoporosis
Raloxifene is a selective estrogen receptor modulator (SERM) that has estrogen agonist activity on bone and
decreases bone resorption. Medicines with estrogen agonist activity, including SERMs, oral contraceptives, and
hormone replacement therapy, can increase the risk for venous thromboembolism. [14920]
Long-term use of GnRH agonists (eg, leuprolide) suppresses pituitary LH release and leads to the reduced production
of testosterone. The lower levels of circulating testosterone produce a clinical effect similar to that of surgical
orchiectomy and can lead to accelerated bone loss and increased risk for osteoporosis. [14952]
Prostate cancer
Leuprolide is a GnRH agonist used to treat prostate cancer. It initially stimulates pituitary LH secretion, which leads to
a rise in androgen levels. However, the GnRH receptor is subsequently down-regulated, which dramatically drops LH
release and leads to a long-term decrease in androgen production. [209]
THYROID DISORDERS
Hyperthyroidism
Hyperthyroidism causes a hyperadrenergic state characterized by hypertension, palpitations/tachycardia, sweating,
heat intolerance, tremor, and hyperreflexia. Beta blockers can relieve these symptoms. Exophthalmos in Graves
disease is due to an immune-mediated increase in orbital soft tissue mass and does not improve with beta blockers.
[1945]
Beta blockers provide rapid relief of the adrenergic-mediated symptoms of thyrotoxicosis and can be given while
awaiting diagnostic evaluation and definitive management. [6797]
Thioamides (eg, methimazole, propylthiouracil) decrease the formation of thyroid hormones via inhibition of thyroid
peroxidase, the enzyme responsible for both iodine organification and coupling of iodotyrosines. Propylthiouracil
also decreases the peripheral conversion of T4 to T3. [626]
Postoperative hypoparathyroidism with resultant hypocalcemia is a common complication of thyroidectomy due to

inadvertent injury or removal of the parathyroid glands. Postoperative supplementation with oral calcium and
vitamin D can be used to treat and prevent postoperative hypocalcemia. [11664]
Graves ophthalmopathy is caused by stimulation of orbital fibroblasts by thyrotropin receptor antibodies and
cytokines released by activated T-cells. Excess deposition of extracellular glycosaminoglycans and inflammatory
infiltration lead to expansion of extraocular muscles and retro-orbital tissues. Glucocorticoids improve Graves
ophthalmopathy by decreasing the severity of inflammation and reducing the excess extraocular volume. [622]
Hyperthyroidism causes upregulation of beta-adrenergic receptor expression, leading to increased catecholamine

effect. Beta blockers are used to blunt the adrenergic manifestations of hyperthyroidism. In addition, lipid-soluble
beta blockers reduce conversion of T4 to T3 by inhibiting 5'-monodeiodinase in peripheral tissues. [1213]
Thionamide antithyroid drugs (eg, propylthiouracil [PTU], methimazole) are used to decrease thyroid hormone
production. Methimazole is preferred for most patients due to the hepatotoxicity of PTU. However, methimazole
has potential teratogenic effects, so PTU is preferred in the first trimester of pregnancy. [14953]
Drug-induced neutropenia is the major side effect of the first-line medications used to treat Graves disease. Initial
manifestations usually include fever and oropharyngeal ulcers. [637]
Menopause
An increase in estrogen activity, as seen in pregnancy or postmenopausal estrogen replacement therapy, increases
the level of thyroxine-binding globulin. This leads to an increase in total thyroid hormone levels, but feedback control
maintains normal levels of free (biologically active) thyroid hormone. [772]
Radiation injury
Potassium iodide competitively inhibits thyroid uptake of radioactive iodine isotopes and is often administered
following nuclear accidents to protect the thyroid and prevent development of radiation-induced thyroid carcinoma.
[767]
Endometriosis
Continuously administered GnRH receptor agonists (eg, leuprolide) initially stimulate pituitary FSH and ovarian
estrogen secretion. However, prolonged use eventually inhibits endogenous GnRH release and downregulates
pituitary GnRH receptors, causing decreased GnRH, FSH, and estrogen levels. The resulting hypogonadotropic,
hypogonadal state induces amenorrhea, thereby improving dysmenorrhea associated with endometriosis. [18747]
Contraception
Combined hormonal contraceptives are effective at preventing pregnancy by decreasing the release of
gonadotropins, which suppresses folliculogenesis and inhibits ovulation. [879]
Estrogen-containing contraceptive pills (eg, combined estrogen/progestin oral contraceptive pills) are contraindicated
in patients with migraine with aura due to the increased risk for ischemic stroke. [577]
MISCELLANEOUS
Aromatase inhibitors
Polycystic ovary syndrome can present with irregular menses, enlarged ovaries, and anovulatory infertility. Letrozole,
an aromatase inhibitor, acts on the ovary and peripheral adipose tissue to inhibit androgen-to-estrogen conversion by
the enzyme aromatase; the subsequent decrease in estrogen production causes the pituitary to release more FSH
and LH, thereby stimulating ovulation. [18714]
Dyslipidemia
Gemfibrozil (and other fibrates) can reduce cholesterol solubility and promote gallstone formation by reducing bile
acid synthesis. Caution should be used when prescribing fibrate therapy to patients with underlying gallbladder
disease. [164]
Cystic fibrosis
In a young Caucasian patient, the combination of recurrent respiratory infections with Pseudomonas aeruginosa,
diarrhea, and failure to thrive suggests a diagnosis of cystic fibrosis. Cystic fibrosis causes steatorrhea and failure to
thrive due to malabsorption secondary to pancreatic insufficiency, which can be corrected by pancreatic enzyme
supplementation. [808]

Iron absorption occurs predominantly in the duodenum and proximal jejunum. Bypass of this segment of small bowel
by gastrojejunostomy results in iron deficiency anemia that can be corrected with pharmacologic iron
supplementation. Malabsorption of thiamine, folate, vitamin B12, fat-soluble vitamins (especially vitamin D), and
calcium is also common following gastric bypass procedures. [7584]
Obesity
Ghrelin is produced in the stomach in response to fasting; levels surge leading up to meals and fall after
eating. Ghrelin stimulates appetite and promotes weight gain. Patients who have undergone gastrectomy have
reduced ghrelin levels, leading to weight loss. [18615]
Achalasia
Achalasia is caused by loss of inhibitory ganglion cells in the distal esophageal wall and is characterized by the
absence of esophageal peristalsis and incomplete relaxation of a hypertonic lower esophageal sphincter. Botulinum
toxin prevents acetylcholine release into the neuromuscular synapse, resulting in inhibition of cholinergic neurons
and lower esophageal sphincter relaxation. [14890]
Esophagitis
Pill esophagitis, which can be caused by tetracyclines (eg, doxycycline), results from prolonged contact of caustic
medication with the esophageal mucosa. It most often occurs in locations where the esophagus is in close proximity
to other anatomic structures, such as where the proximal esophagus comes in contact with the aortic arch and the
carina. [15383]

Management of gastroesophageal reflux disease includes lifestyle and dietary modifications (eg, weight loss, tobacco
avoidance) and medications such as proton pump inhibitors (PPIs) (eg, pantoprazole, omeprazole) or histamine 2
receptor antagonists (eg, famotidine). PPIs irreversibly inhibit the H+/K+ ATPase on parietal cells, which decreases
gastric acid secretion. [14872]
Magnesium salts and aluminum hydroxide are basic mineral salts used to neutralize gastric acid and relieve
gastroesophageal reflux symptoms. Side effects include diarrhea and constipation, respectively. Therefore, these
medications are often combined to offset the adverse effects of the individual medications. [14877]

Proton pump inhibitors (eg, omeprazole, lansoprazole) block the final common pathway of gastric acid secretion from
parietal cells, which is stimulated by acetylcholine, histamine, and gastrin. [1766]
Elevated gastric pH stimulates secretion of gastrin, a polypeptide hormone that increases gastric acid
production. Proton pump inhibitors block gastric acid production by parietal cells; the resultant increase in pH leads
to hypergastrinemia, which can cause rebound hypersecretion of gastric acid when the drug is withdrawn. [14894]
Most duodenal peptic ulcers are caused by Helicobacter pylori infection. The most effective method to prevent
disease recurrence is to eradicate the infection with antibiotics (eg, tetracycline, metronidazole), typically in
combination with proton pump inhibitors (eg, omeprazole) and, often, bismuth subsalicylate (quadruple therapy).
[1778]
Proton pump inhibitors
Proton pump inhibitors (PPI) prevent the hydrogen-potassium-ATPase pump found in parietal cells from releasing
hydrochloric acid into the stomach lumen. Chronic PPI use protects exogenously administered lipase and enhances
fat absorption in patients dependent on pancreatic enzyme replacement therapy. [19343]
HEPATIC DISORDERS
Acetaminophen poisoning
Acetaminophen and ethanol are metabolized by same cytochrome P450 enzyme. Through competitive inhibition,
acute (not chronic) ingestion of ethanol can lead to decreased conversion of acetaminophen to N-acetyl-p-
benzoquinone imine (a toxic metabolite), potentially reducing acetaminophen-induced hepatotoxicity. However,
cytochrome P450 2E1 activity is upregulated by chronic ethanol use. As a result chronic alcohol consumption
increases NAPQI concentrations and the risk of hepatotoxicity during an acetaminophen overdose. [21465]
Ascites
Ascites in cirrhosis develops from hemodynamic changes related to portal hypertension. Splanchnic vasodilation
decreases the systemic vascular resistance, which causes activation of the renin-angiotensin-aldosterone system and
promotes vasoconstriction and sodium and water retention. Spironolactone, an aldosterone antagonist, is used to
induce natriuresis and resolve ascites without blocking the critical vasoconstrictive effects of angiotensin. [18549]
Cirrhosis
Treatments for hepatic encephalopathy include lactulose (increases conversion of ammonia to ammonium) and
rifaximin (decreases intraluminal ammonia production). [11661]
Dyslipidemia
Simvastatin decreases hepatic cholesterol production, while cholestyramine increases hepatic cholesterol and bile
acid synthesis. Combination therapy results in a synergistic reduction in plasma LDL level. [165]
Gallstone disease
Medical therapy to dissolve cholesterol gallstones is an option in patients refusing cholecystectomy or with high
surgical risk. Hydrophilic bile acids (eg, ursodeoxycholic acid) improve cholesterol solubility by reducing the amount
of cholesterol secreted into the bile and increasing biliary bile acid concentration. [11739]
Wilson disease
Penicillamine, a first-line treatment for Wilson disease, is a copper chelating agent that increases the urinary
excretion of copper. [19554]
Acute diarrhea
Oral rehydration solutions contain equimolar amounts of dextrose (glucose) and sodium, which are absorbed through
intestinal cotransport to maintain intravascular volume status. They also contain potassium to compensate for
gastrointestinal losses, and citrate to buffer metabolic acidosis. [105665]
Antidiarrheal agents
Loperamide is an opioid agonist that exerts its antidiarrheal effects by binding to mu opiate receptors in the colonic
myenteric plexus, which inhibits acetylcholine release, decreases intestinal smooth muscle activity, and slows
peristalsis. It undergoes high first-pass metabolism and does not cross the blood-brain barrier, thus avoiding systemic
opiate-related adverse events (eg, sedation, respiratory depression). [18541]
Constipation
Bisacodyl is a commonly used stimulant laxative that stimulates the enteric neurons within the colonic myenteric
plexus, thereby increasing peristaltic activity and enhancing colonic motility. [18542]
Polyethylene glycol is an osmotic laxative. Diarrhea associated with lactase deficiency is also osmotic and occurs due
to accumulation of nonabsorbable lactose in the intestinal lumen. Magnesium hydroxide (and other magnesium-
containing compounds, such as magnesium citrate) is another osmotic laxative that is often used, although its efficacy
is questionable and there is not enough evidence to support its widespread use. [865]
Constipation is a common adverse effect of non–dihydropyridine calcium channel blockers (eg, diltiazem,
verapamil). Other medications that cause constipation include opiates, 5-HT3 antagonists, iron tablets, aluminum-
containing antacids, and medications with anticholinergic properties. [17003]

Crohn disease is an inflammatory bowel disorder that causes patchy inflammation throughout the gastrointestinal
tract. Characteristic histopathologic findings include noncaseating granulomas, transmural inflammation, and Paneth
cell metaplasia. Tumor necrosis factor-alpha (TNF-α), a cytokine produced by macrophages, plays a central role in the
pathogenesis of CD; anti–TNF-α agents (eg, infliximab, adalimumab) are often used as first-line therapy. [14947]
Irritable bowel syndrome

Diphenoxylate is an opioid antidiarrheal drug that binds mu opiate receptors in the gut to slow motility. Overuse can
lead to euphoria and physical dependence. To discourage abuse, diphenoxylate is combined with atropine, which
induces adverse effects if taken in high doses. [1290]
Opioids
Constipation is the most common side effect of opiate therapy and occurs due to the binding of µ-opioid receptors in
the gastrointestinal tract, which decreases intestinal motility and inhibits ion and fluid secretion. Methylnaltrexone, a
peripherally acting µ-opioid receptor antagonist that does not cross the blood-brain barrier, can alleviate opioid-
induced constipation without inducing opiate-related withdrawal symptoms. [18586]
MISCELLANEOUS
Antiemetics
5-HT3 receptor antagonists are useful for the treatment of visceral nausea due to gastrointestinal insults, such as
gastroenteritis, chemotherapy, and general anesthesia. Antihistamines and anticholinergics are recommended for
vestibular nausea. Dopamine antagonists are useful for nausea associated with migraine. [10999]
Nausea and vomiting

Ondansetron inhibits serotonin (5-HT3) receptors and is used primarily to treat nausea and vomiting following
chemotherapy. 5-HT3 receptors are located peripherally in the presynaptic nerve terminals of the vagus nerve in the
gastrointestinal tract. These receptors are also present centrally in the chemoreceptor trigger zone and the solitary
nucleus and tract. [1817]
Dyslipidemia
Triglyceride-induced pancreatitis is initiated by impaired blood flow in pancreatic capillaries due to excessive
concentrations of chylomicrons and VLDL particles. Insulin upregulates lipoprotein lipase (an enzyme that hydrolyzes
triglycerides in chylomicrons and VLDL) in adipose tissue capillaries; the liberated fatty acids are taken up by adipose
cells, lowering serum triglyceride levels. [20602]
Carcinoid tumors
Carcinoid syndrome may accompany extraintestinal metastases of gastrointestinal carcinoid tumors. Octreotide is a
synthetic somatostatin analog used to control the symptoms of carcinoid syndrome. [309]
Anticoagulants
Direct oral anticoagulants (DOACs) such as rivaroxaban are often preferred over vitamin K antagonists (VKAs) such as
warfarin in the treatment of conditions that require anticoagulation due to less variability in therapeutic drug effect;
in contrast to VKAs, the efficacy of DOACs is unaffected by dietary changes and most medications. Therefore,
patients given DOACs do not require laboratory monitoring. [18686]
Both vitamin K and fresh frozen plasma are used for reversing warfarin-induced anticoagulation. Fresh frozen plasma
rapidly reverses warfarin's effects whereas vitamin K requires time for clotting factor re-synthesis. [709]
Rifampin, phenobarbital, and phenytoin are potent enhancers of the cytochrome P-450 pathway; concurrent use of
warfarin with these medications results in decreased efficacy of warfarin. In contrast, cimetidine, amiodarone, and
trimethoprim-sulfamethoxazole inhibit warfarin metabolism, increasing the risk of bleeding. [1090]
Patients on warfarin who take antibiotics that target gram-negative microorganisms (eg, metronidazole, macrolides,
fluroquinolones) can develop supratherapeutic INR due to disruption of vitamin K–producing intestinal flora. [18689]
Andexanet alfa is a factor Xa decoy that has no proteolytic effect. It is administered to patients on factor Xa inhibitors
(eg, rivaroxaban, apixaban) who have life-threatening bleeding in order to reverse the anticoagulation effect. [15390]
Heparin is an indirect anticoagulant that alters the shape of antithrombin (AT) III, thereby converting it from a slow to
rapid inactivator of clotting factors. Because AT primarily neutralizes factor Xa and thrombin, patients on heparin
have decreased factor Xa activity and prolonged thrombin time/partial thromboplastin time. In contrast, direct oral
anticoagulants specifically target a single enzyme in the coagulation cascade, such as thrombin (eg, dabigatran) or
factor Xa (eg, rivaroxaban). [18727]
Enoxaparin is a low-molecular-weight heparin (LMWH) that functions like heparin in that it binds and activates
antithrombin III (AT III). Activated AT III binds to factor Xa and stops factor Xa from converting prothrombin to
thrombin. Due to its fewer number of molecules, LMWH acts primarily on factor Xa, not thrombin. [1784]
Heparin-induced thrombocytopenia (HIT) is treated with direct thrombin inhibitors (DTIs) such as argatroban. Both
high molecular weight heparin and LMWH should be avoided in these patients. [1078]
Protamine sulfate binds to heparin, causing chemical inactivation. Vitamin K and fresh frozen plasma can be used to
reverse warfarin effects. [1087]
Both unfractionated heparin and LMWH can bind to antithrombin to increase its activity against Factor Xa. Only
unfractionated heparin is able to bind to both antithrombin and thrombin to allow antithrombin to inactivate
thrombin. [2132]
Warfarin is an oral anticoagulant that inhibits the carboxylation of vitamin K-dependent coagulation factors II, VII, IX,
and X. It is used in atrial fibrillation, deep venous thrombosis, and pulmonary thromboembolism. Prothrombin time
(PT)/International Normalized Ratio (INR) should be monitored regularly during treatment with warfarin. Activated
partial thromboplastin time (aPTT) is used for monitoring unfractionated heparin. [1200]
Warfarin blocks epoxide reductase, which lowers the reduced form of vitamin K in the liver; this prevents gamma
carboxylation of vitamin K–dependent clotting factors (II, VII, IX, and X). Because warfarin only blocks the generation
of new clotting factors, therapeutic effect is delayed 3-5 days until preexisting clotting factors are consumed. [18688]
Heparin is commonly used for the prevention of deep venous thrombosis in nonambulatory patients or those
undergoing elective surgery, especially hip and knee surgery. Heparin increases the effect of the naturally occurring
anticoagulant antithrombin III. [1077]
Venous thromboembolism
Heparins are ideal anticoagulants for most patients with thromboembolic disease in pregnancy as they do not cross
the placenta and therefore the risk of fetal bleeding or teratogenicity is low. Low molecular weight heparin (eg,
enoxaparin) is the preferred therapy, with patients transitioned to unfractionated heparin at term. [1194]
Rivaroxaban is an oral anticoagulant that directly inhibits factor Xa. It is used in venous thromboembolism and atrial
fibrillation. [11731]
MISCELLANEOUS
NSAIDs
Aspirin is a nonsteroidal anti-inflammatory drug that primarily and irreversibly inhibits cyclooxygenase-1 (COX-1)
when given in low doses. Because irreversible COX-1 inhibition decreases platelet thromboxane A2 production for
the duration of their lifespan (ie, 3-7 days), preoperative aspirin discontinuation is recommended at least 5 days prior
to surgery to avoid excessive bleeding. [714]
PLASMA CELL DISORDERS
Multiple myeloma
Multiple myeloma is often treated with medications that block proteasome activity (eg, bortezomib) or increase
ubiquitination of specific transcription factors (eg, lenalidomide). Lenalidomide increases E3 ubiquitin ligase binding
to transcription factors overexpressed in myeloma, which results in increased transcription factor destruction by the
proteosome and subsequent cancer cell death. [20631]
PLATELET DISORDERS
Glanzmann thrombasthenia
Abciximab is a blocker of glycoprotein (GP) IIb/IIIa receptor, which normally promotes platelet binding to
fibrinogen. GP IIb/IIIa is either deficient or defective in patients with Glanzmann thrombasthenia. [1079]

The von Willebrand factor (vWF) enhances clotting through both augmentation of platelet binding and stabilization of
factor VIII. Patients with von Willebrand disease are deficient in functional vWF and present with increased
bruisability and prolonged mucosal bleeding. Desmopressin can alleviate bleeding through endothelial release of
vWF. [219]
Patients with symptomatic von Willebrand disease can be treated with desmopressin (DDAVP), a synthetic
antidiuretic hormone analogue that has no vasoconstrictive effects. DDAVP transiently increases von Willebrand
factor and factor VIII release from endothelial cell storage through indirect mechanisms; it can be used
prophylactically prior to procedures or to treat minor bleeding. [942]
Cell cycle
Cyclin-dependent kinases (CDKs) 4/6 regulate the movement of cells from G1→S phase. Cancers often have
mutations that enhance the activity or downstream effects of CDK 4/6, which contribute to unregulated cellular
growth. Inhibitors to CDK 4/6 can be used to treat certain forms of cancer. However, they can inhibit cellular
replication in other rapidly dividing cells such as the hematologic cells in the bone marrow (eg, neutropenia, anemia,
or thrombocytopenia). [15299]
Chemotherapy
The vinca alkaloids are cell cycle-specific agents that prevent proper separation of chromosomes into daughter cells
during the M phase of the cell cycle. The main dose-limiting side effect of vincristine is neurotoxicity, which
commonly manifests as peripheral neuropathy. [1893]
Methotrexate and 5-FU both effectively inhibit thymidylate formation, but the chemotherapeutic effect of
methotrexate is overcome by N5-formyl-tetrahydrofolate (folinic acid, leucovorin) supplementation. [1892]
Tumors can acquire resistance to multiple chemotherapeutic agents by increasing expression of P-glycoprotein, a
transmembrane ATP-dependent efflux pump that has broad specificity. [1819]
Neurotoxicity is the dose-limiting adverse effect of vincristine therapy. Vincristine inhibits axonal microtubule
formation, resulting in impaired axonal transport and peripheral neuropathy (eg, numbness, tingling). [1894]
Etoposide is a chemotherapeutic agent that inhibits the sealing activity of topoisomerase II. Treatment with
etoposide causes chromosomal breaks to accumulate in dividing cells, ultimately causing cell death. [2018]
Chemotherapy induced nausea and vomiting

Vomiting is a reflex regulated mainly by 5 receptors, including M1 muscarinic, D2 dopaminergic, H1 histaminic, 5-HT3
serotonergic, and neurokinin 1 (NK1) receptors. 5-HT3 and NK1 receptor antagonists are particularly useful for
chemotherapy-induced vomiting. [11728]
Chemotherapy-induced nausea and vomiting is mediated by peripheral and central mechanisms. It can be treated
with serotonin receptor antagonists (eg, ondansetron) to prevent serotonin stimulation of afferent vagal fibers in the
bowel wall (peripheral cause) and neurokinin-1 receptor antagonists (eg, aprepitant) to prevent the effects of
substance P in the brainstem (central cause). [15706]
Immunotherapy
Cancer cells avoid immune recognition by overexpressing programmed death-ligand 1 (PD-L1), which binds to the
programmed cell death-1 (PD-1) receptor on cytotoxic T cells and inhibits their response (T-cell
exhaustion). Monoclonal antibodies that block PD-L1 and PD-1 are effective against cancers that express high levels
of neoantigens on their surface because these tumors are particularly susceptible to immune recognition by cytotoxic
T cells. [14956]

Bleomycin is an antineoplastic agent that binds to iron and oxygen molecules to create free radicals that cause DNA
strand breaks. The most clinically important adverse effect of bleomycin is lung toxicity, usually manifesting as
pulmonary fibrosis. Patients develop dyspnea and nonproductive cough, and pulmonary function testing shows a
restrictive pattern with reduced diffusion capacity for carbon monoxide (DLCO). [14848]
Methotrexate
Methotrexate is a folic acid antagonist used to treat ectopic pregnancy. It competitively inhibits the enzyme
dihydrofolate (DHF) reductase, which catalyzes the synthesis of tetrahydrofolate. DHF reductase inhibition causes
the intermediate DHF to accumulate intracellularly. [1857]
Trastuzumab
Human epidermal growth factor receptor 2 (HER2) is a tyrosine kinase receptor that is overexpressed in 20% of breast
cancer patients. In such patients, HER2 blockade with the monoclonal antibody trastuzumab downregulates cellular
proliferation and promotes apoptosis. [11585]

Tumor lysis syndrome primarily develops during chemotherapy for cancers with rapid cell turnover, substantial tumor
burden, or high sensitivity to chemotherapy. It is characterized by hyperphosphatemia, hypocalcemia, hyperkalemia,
and hyperuricemia. Prevention involves intravenous fluids to flush the kidneys and the use of hypouricemic agents
(eg, rasburicase, allopurinol, febuxostat). [8542]
Wound healing
Bevacizumab is a monoclonal antibody that inhibits the binding of vascular endothelial growth factor (VEGF) to its
receptor. This inhibits angiogenesis and limits blood supply to tumors (ie, cancer-starving therapy). However, it also
impairs wound healing and can lead to wound dehiscence. [19198]
Aplastic anemia
Aplastic anemia (AA) is bone marrow failure due to multipotent hematopoietic stem cell destruction. Cases are often
triggered by medications, radiation, toxins, or viruses. Medication-induced AA can be due to dose-dependent bone
marrow damage (eg, chemotherapy, immunosuppressive drugs) or idiosyncratic reactions (eg, antiseizure medicines,
sulfonamides, nifedipine) that may occur at any point during or after therapy. [359]
Chemotherapy
6-mercaptopurine (6-MP) is an immunosuppression drug that is inactivated by 2 enzymes, xanthine oxidase and
thiopurine methyltransferase. Reduced function of either enzyme causes increased levels of the active metabolites
of 6-MP, leading to increased immunosuppression and risk of toxicity. [1890]
Hemolytic anemia
Penicillins and cephalosporins are common triggers for drug-induced hemolytic anemia because they can bind to the
erythrocyte surface and act as haptens for IgG attachment. Subsequent clearance of IgG-coated erythrocytes by
splenic macrophages leads to hemolytic anemia. Withdrawal of the offending drug usually leads to complete
resolution of symptoms. [19160]
Hemophilias
Hemophilia A is an X-linked disorder associated with a deficiency of factor VIII. Emicizumab—a bispecific, monoclonal
antibody—mimics the activity of factor VIII by binding to both factor IXa and factor X, bringing them into close
proximity to allow for factor X activation. [15489]
Sickle cell
Hydroxyurea increases fetal hemoglobin production, which reduces erythrocyte sickling in patients with sickle cell
disease. It also inhibits ribonucleoside reductase, which decreases deoxynucleoside triphosphates available for DNA
synthesis; this leads to macrocytosis and, with high doses, pancytopenia. [19689]
Hydroxyurea is used in patients with sickle cell disease to increase expression of gamma globin chains, which leads to
increased circulating fetal hemoglobin (Hb F) concentration. This reduces vasoocclusive crises and symptomatic
anemia episodes. [892]
Bcl 2
Chronic lymphocytic leukemia is associated with overexpression of BCL-2, an anti-apoptotic protein, on the
mitochondrial membrane. Treatment with a BCL inhibitor causes cancer cell death by promoting cytochrome c
release from the mitochondria, which subsequently activates caspases. [15821]
Multiple myeloma
Multiple myeloma, a plasma cell malignancy associated with significant production of secretory proteins (eg,
monoclonal immunoglobulins), is frequently treated with proteasome inhibitors (eg, bortezomib). These drugs block
the degradation of ubiquitinated proteins by the proteosome, which leads to accumulation of abnormally folded
proteins that trigger cellular apoptosis. [11584]
Nonhodgkin lymphoma
Rituximab is a monoclonal antibody directed against the CD20 antigen. Its introduction has improved the prognosis
of some lymphomas. [1628]
Infectious Diseases
ANTIMICROBIAL DRUGS
Acyclovir
Intravenous acyclovir can cause crystalline nephropathy if adequate hydration is not also provided. [1642]
Monophosphorylation of acyclovir by a viral thymidine kinase is the first (and rate-limiting) step in conversion of
acyclovir to its active triphosphate form. Acyclovir and related drugs (eg, famciclovir, valaciclovir) are more effective
against herpes simplex virus and varicella zoster virus than cytomegalovirus and Epstein-Barr virus. [1645]
Antiviral drugs currently recommended for the treatment of primary genital herpes include the nucleoside analogs
(eg, acyclovir). These are incorporated into newly replicating viral DNA and ultimately terminate viral DNA chain
synthesis. [1551]
Adverse drug reaction

Hypokalemia and hypomagnesemia are common electrolyte disturbances in patients undergoing treatment with
amphotericin B and reflect an increase in distal tubular membrane permeability. [275]
Amebiasis
Symptomatic Entamoeba histolytica infection must be treated with a tissue agent followed by an intraluminal
agent. Tissue agents (eg, metronidazole) kill trophozoites responsible for symptomatic disease, and intraluminal
agents (eg, paromomycin) eradicate intestinal cyst carriage. [105693]
Aminoglycoside
Aminoglycoside (eg, gentamicin) resistance is most commonly due to antibiotic-modifying enzymes. These enzymes
add chemical groups to the antibiotic, which diminishes its ability to bind to the 16S ribosomal RNA within the 30s
ribosomal subunit. [1000]
Aminoglycosides inhibit genetic code reading and protein synthesis by binding to the prokaryotic 30S ribosomal
subunit. [1488]
Antifungals
Azoles inhibit the synthesis of ergosterol by the fungal cytochrome P450 enzymes. They also suppress the human
P450 system, resulting in many drug-drug interactions. [276]
Cephalosporins
The bacterial cell wall protects the organism from osmotic stress. Antibiotics that target the cell wall result in
bacterial lysis in hypotonic solutions. Fosfomycin, vancomycin, penicillins, and cephalosporins all disrupt bacterial cell
wall synthesis. [959]
Folate antimetabolites
Trimethoprim, methotrexate, and pyrimethamine inhibit dihydrofolate reductase. Trimethoprim restricts bacterial
growth through this process, and works particularly well in conjunction with sulfonamide, which inhibits an earlier
step in the bacterial folic acid pathway. [1104]
Foscarnet
Foscarnet is an analog of pyrophosphate that can chelate calcium and promote nephrotoxic renal magnesium
wasting. These toxicities can result in hypocalcemia and hypomagnesemia, which can cause seizures. [1643]
Hyperkalemia
Hyperkalemia is a common adverse effect of trimethoprim-sulfamethoxazole due to the trimethoprim-induced
blockade of the sodium channels in the collecting duct, which prevents sodium-potassium exchange and reduces
renal excretion of potassium (similar to the action of amiloride). This effect is often magnified in the elderly
population, those with renal failure, or those given other potassium-sparing diuretics, ACE inhibitors, or angiotensin
receptor blockers. [18682]
Penicillin
Beta-lactamase inhibitors (eg, clavulanic acid, sulbactam, tazobactam) prevent beta-lactamase from inactivating
penicillin class drugs, which extends the spectrum of their activity. [1091]
Clavulanic acid, sulbactam and tazobactam are beta-lactamase inhibitors. Concurrent administration of clavulanate
with amoxicillin expands amoxicillin's spectrum of activity to include strains of β-lactamase synthesizing bacteria that
are resistant to amoxicillin alone. [1959]
Pharmacodynamics
Antibiotics exhibiting concentration-dependent killing can be administered using relatively high doses given at lower
frequency. This allows for effective microbial killing while preventing adverse effects that may occur with prolonged
systemic exposure. [18624]
Quinolones
Fluoroquinolones can form insoluble chelate complexes with polyvalent cations (eg, calcium, iron, aluminum,
magnesium) in the gastrointestinal tract, leading to impaired absorption. This effect can be seen with over-the-
counter antacids containing calcium, magnesium, and/or aluminum salts and in patients taking calcium salts (eg,
calcium carbonate, calcium citrate) for treatment of osteoporosis. [18550]
Tinea
Tinea pedis is a superficial infection of the epidermis caused by dermatophytes (eg, Trichophyton rubrum). It most
often presents as a pruritic, erythematous rash between the toes that frequently extends along the sole. Microscopy
of skin scrapings shows branching hyphae. Treatment options include a variety of topical antifungals (eg,
clotrimazole), but not nystatin. [16855]
Tuberculosis
Isoniazid can be directly hepatotoxic, causing acute, mild hepatic dysfunction in 10%-20% of patients and frank
hepatitis (fever, anorexia, and nausea, sometimes progressing to hepatic failure) in a small percentage of patients.
[1774]

Acute simple cystitis often occurs in young, otherwise healthy women, particularly following sexual
intercourse. Common manifestations include dysuria, urinary frequency/urgency, and urinalysis evidence of
pyuria/bacteriuria. Empiric treatment with nitrofurantoin or trimethoprim-sulfamethoxazole is typically curative.
[18521]
Vancomycin binds to the terminal D-alanine–D-alanine in bacterial pentapeptide peptidoglycan subunits, which
prevents transpeptidase from binding to the pentapeptide, thereby inhibiting cell wall cross-linking. Resistance stems
primarily from substitution of the terminal D-alanine with D-lactate, which prevents vancomycin binding. [643]
Extended-spectrum beta-lactamases can be produced by gram-negative bacteria, rendering cephalosporins and other
beta-lactam antibiotics inactive. These genes can be transmitted between organisms through plasmid conjugation.
[11626]
Methicillin-resistant Staphylococcus aureus is resistant to all β-lactam antibiotics, including beta-lactamase-resistant

antibiotics, as it has an altered penicillin-binding protein that does not bind β-lactams effectively. [642]
Methicillin-resistant Staphylococcus aureus (MRSA) is resistant to most beta-lactam medications (eg, oxacillin,
methicillin, cephalosporins) due to the acquisition of a mobile genetic element that contains the mecA gene. This
gene encodes for a specialized penicillin-binding protein that has low affinity for beta-lactam antibiotics. Treatment
of MRSA therefore requires a non–beta-lactam medication such as trimethoprim-sulfamethoxazole, clindamycin,
doxycycline, or vancomycin. [15347]
Diabetic foot
Piperacillin-tazobactam is a combination of extended-spectrum penicillin with β-lactamase inhibitor. It is effective
against most gram-negative enteric rods (including Pseudomonas aeruginosa) and against Bacteroides fragilis. [1198]
Pertussis
Pertussis is a clinical diagnosis (eg, prolonged, forceful cough; household contact with prolonged cough; lack of
immunization; lymphocytosis) and should be treated empirically. The treatment of choice is a macrolide antibiotic
(eg, azithromycin), which binds to the bacterial ribosomal subunit and inhibits protein synthesis. [107368]
Syphilis
The Jarisch-Herxheimer reaction is an acute inflammatory reaction that occurs within hours of treatment for
spirochetal infections (eg, syphilis). The rapid lysis of spirochetes releases inflammatory bacterial lipoproteins into
the circulation and causes acute fever, rigors, and myalgias. [7581]
Tuberculosis
Ethambutol can cause optic neuropathy that results in color blindness, central scotoma, and decreased visual
acuity. This adverse side effect may be reversed with discontinuation of the drug. [1228]
Isoniazid is an antimycobacterial agent that specifically inhibits the synthesis of mycolic acids, which are essential
components of the mycobacterial peptidoglycan cell wall. Without mycolic acids, the mycobacteria lose their acid-
fastness and become unable to synthesize new cell walls or multiply. [1309]
The rifamycins block the action of the bacterial DNA-dependent RNA polymerase, thereby inhibiting
transcription. Resistance is acquired by modification of the rifampin binding site on the bacterial DNA-dependent
RNA polymerase. Common side effects include hepatotoxicity, blood dyscrasias, and harmless red-orange
discoloration of body fluids. [1226]
FUNGAL INFECTIONS
Azole antifungal medications (eg, fluconazole) block the fungal enzyme lanosterol 14-alpha-demethylase, a
cytochrome p-450–dependent enzyme that converts lanosterol to ergosterol. Mutations to the gene for 14-alpha-
demethylase can lead to azole resistance. [106713]
Aspergillosis
Amphotericin B binds the ergosterol of fungal cell membranes to exert its antifungal effects. However, it also binds
cholesterol to some degree, causing toxicity to human tissues. The most important adverse effects of amphotericin B
are nephrotoxicity, hypokalemia, and hypomagnesemia. [273]
Mucormycosis
Amphotericin B is a polyene antifungal drug notorious for its renal toxicity. Severe hypokalemia and
hypomagnesemia are commonly seen during therapy and often require daily supplementation. [274]
Antiretroviral therapy
Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are antiretroviral drugs that do not require activation via
intracellular phosphorylation. The more common NNRTIs include nevirapine and efavirenz. [1674]
Protease inhibitors are HIV antiretroviral medications that inhibit cleavage of the polypeptide precursor into mature
viral proteins. Their side effects as a class include hyperglycemia, lipodystrophy, and drug-drug interactions due to
inhibition of cytochrome P450. [819]
Integration of double-stranded HIV DNA into the host cell's chromosomes is necessary to induce viral gene expression
and prevent degradation of the viral genome. Raltegravir is an integrase inhibitor that disrupts HIV genome
integration, preventing synthesis of viral mRNA. [8371]
Abacavir hypersensitivity reaction occurs in 2%–8% of patients and is strongly associated with the HLA-B*57:01 allele.
[11590]
Zidovudine (ZDT) is a nucleoside reverse transcriptase inhibitor used to prevent maternal to fetal transmission of HIV
during labor (when the mother is not virally suppressed). It is a thymidine analogue that does not have the normal 3′-
hydroxyl group found on thymidine. Because new nucleotides are added to growing DNA chains only at the 3′-
hydroxyl group, the addition of ZDT into DNA results in chain termination. [2019]
Fusion inhibitors (eg, enfuvirtide) bind the HIV transmembrane glycoprotein gp41 and prevent it from approximating
the viral and host cellular membranes, which prevents HIV penetration into new host cells. [1675]
HIV
R5 strains (macrophage-tropic) of HIV attach to the host CD4 receptor and CCR5 chemokine coreceptor; CCR5
inhibitors such as maraviroc can be used in the treatment of R5 virus. X4 strains (T lymphotropic) of HIV bind to the
CD4 receptor and CXCR4 chemokine receptor; X4 virus cannot be treated with CCR5 inhibitors. [15107]
Syphilis
Syphilis is caused by the corkscrew-shaped organism Treponema pallidum. Secondary syphilis develops in untreated
patients weeks or months after the initial infection, and presents with a diffuse, macular rash and generalized
lymphadenopathy. First-line treatment is penicillin, which blocks the last step in bacterial cell wall synthesis
(transpeptidation). [18620]
Urethritis
Infectious urethritis in men is typically caused by Neisseria gonorrhoeae, Chlamydia trachomatis, or Mycoplasma
genitalium. Diagnosis is generally made by nucleic acid amplification testing, but microscopy with Gram stain can be
used to quickly diagnose gonococcal infection. Patients with gonorrhea and positive or uncertain Chlamydia status
require ceftriaxone and doxycycline; ceftriaxone alone can be used in those who do not have Chlamydia coinfection.
[1949]
Urethritis in young men is usually due to sexually transmitted infection. Treatment for gonococcal urethritis with
uncertain or positive Chlamydia coinfection status is ceftriaxone plus doxycycline. Treatment for gonococcal
urethritis with negative Chlamydia is ceftriaxone alone. Patients with no gonorrhea who have Chlamydia are treated
with azithromycin or doxycycline monotherapy. [1895]
INFECTION CONTROL
Infection control
Alcohols function by disorganizing the lipid structure in membranes, causing them to be leaky, and by denaturing
cellular proteins. They are bactericidal, tuberculocidal, fungicidal, and virucidal, but do not destroy bacterial spores.
[8593]
MISCELLANEOUS

Clostridioides difficile infection can be treated with oral fidaxomicin or oral vancomycin. Fidaxomicin is a macrolide
antibiotic that inhibits RNA polymerase. It is bactericidal against C difficile. [10401]
Intestinal helminth parasites

Enterobius vermicularis infection (enterobiasis) occurs most frequently in children and presents with perianal
pruritus. Diagnosis is made by identifying eggs in the perianal region (cellulose tape test). Treatment options include
albendazole, mebendazole, and pyrantel pamoate. [8538]
Malaria
Chloroquine is the treatment of choice for uncomplicated malaria in a chloroquine-sensitive geographic region. It
eliminates susceptible erythrocytic forms of all Plasmodium species. Primaquine is added for Plasmodium vivax and
Plasmodium ovale infections to eradicate the intrahepatic stages (hypnozoites) of these malarial species, which are
responsible for relapses. [1965]
Schistosomiasis
Schistosomiasis is a blood fluke infection that occurs when humans bathe or swim in freshwater that contains
contaminated snails. Adult worms mature in the liver, lodge in the mesenteric venules or vesicular venous plexus,
and secrete eggs into feces or urine. Eggs can trigger granulomatous inflammation, leading to symptoms in the
gastrointestinal, urinary, or periportal tract. Diagnosis is typically made when round or oval eggs with a terminal or
lateral spine are identified in urine, feces, or biopsy. [18489]
VIRAL INFECTIONS
Cytomegalovirus
Of all the antiviral agents that bind and inhibit DNA polymerase in herpesvirus and reverse transcriptase in HIV, the
pyrophosphate analog foscarnet is one of few that do not require intracellular activation by viral or cellular kinases.
[1644]
First-line therapy for CMV colitis and retinitis is ganciclovir. This medication inhibits viral synthesis by blocking CMV
DNA polymerase. However, ganciclovir also blocks host DNA polymerase to a lesser degree, which can lead to
hematologic side effects such as neutropenia, anemia, and thrombocytopenia. [1647]
Influenza
Oseltamivir is a neuraminidase inhibitor useful in the treatment and prevention of both influenza A and B virus
infections. This medication impairs the release of newly formed virions from infected host cells and impairs viral
penetration of mucous secretions that overlie the respiratory epithelium. [1648]

Finasteride acts on epithelium and alpha-1 blockers act on smooth muscles of prostate and bladder base. [19029]
5-alpha reductase inhibitors (eg, finasteride, dutasteride) block the conversion of testosterone to
dihydrotestosterone in the prostate. These drugs reduce prostate volume in patients with benign prostatic
hyperplasia and relieve the fixed component of bladder outlet obstruction. [8930]
Gynecomastia
Spironolactone is an aldosterone antagonist commonly used to treat heart failure. It has significant antiandrogenic
effects and can cause gynecomastia, decreased libido, and impotence. Eplerenone is a more selective aldosterone
antagonist with fewer adverse effects. [687]

Management of male hypogonadism includes testosterone therapy, which can improve libido and erectile function,
increase bone density, and facilitate muscle development. [19013]
Priapism
The penile flaccid state is maintained by tonic alpha-adrenergic (norepinephrine) sympathetic activity, causing high
vascular and trabecular smooth muscle tone, preventing corporal engorgement with blood. Priapism can be treated
with penile injections of an alpha-adrenergic agonist (eg, phenylephrine), which induce smooth muscle contraction,
leading to detumescence. [19697]
Trazodone is a highly sedating antidepressant commonly used to treat insomnia. Priapism is a rare but serious
adverse effect. [707]
Prostate cancer
Patients with advanced or castration-resistant prostate cancer are often treated with an 17-alpha-hydroxylase
inhibitors (eg, abiraterone), which block the generation of androgens in the adrenal glands, testes, and tumor
cells. This reduces systemic androgen levels, which limit prostate cancer growth. [19031]
Flutamide is a nonsteroid anti-androgen that acts as a competitive inhibitor of testosterone receptors. It is used in
combination with long-acting gonadotropin-releasing hormone agonists for the treatment of prostate cancer. [657]
Because prostate cancer is an androgen-dependent tumor, patients with advanced disease are generally treated with
surgical or medical orchiectomy. Medical orchiectomy uses GnRH analogues to reduce LH production, which
subsequently reduces androgen production in the testes. Because there is an initial surge in androgens at the start of
therapy (due to stimulation of the GnRH receptor), patients prescribed GnRH therapy are usually treated with a few
weeks of androgen-receptor inhibitors (eg, bicalutamide). [16004]
Alpha-1 blockers such as doxazosin, prazosin, and terazosin are useful for the treatment of both benign prostatic
hyperplasia and hypertension. To minimize adverse effects and drug interactions, it is desirable to prescribe a
medication that can address multiple issues at once. [150]
MISCELLANEOUS
Route of administration & bioavailability

Bioavailability refers to the fraction of administered drug that reaches the systemic circulation. For a drug
administered by any route other than intravenous (IV), bioavailability is usually less than 100%. Bioavailability can be
determined by graphing plasma drug concentrations over time for a given dose administered by both the IV route
and the other route being studied. Oral (PO) bioavailability is calculated by dividing the area under the PO curve by
the area under the IV curve. [1709]
Nervous System
ANESTHESIA
Anesthesia
The arteriovenous concentration gradient reflects the overall tissue solubility of an anesthetic. Anesthetics with high
tissue solubility are characterized by large arteriovenous concentration gradients and slower onsets of action. [660]
Epinephrine is often added to lidocaine to produce vasoconstriction, which prolongs lidocaine's duration of action,
decreases bleeding during the procedure, and reduces systemic lidocaine absorption. [18655]
Local anesthetics diffuse through the neuronal cell membrane to block the influx of sodium into the cell. This
prevents depolarization and inhibits action potential propagation. [15712]
Succinylcholine, a depolarizing neuromuscular blocking agent, is rapidly hydrolyzed by plasma

pseudocholinesterase. Patients with pseudocholinesterase deficiency have prolonged neuromuscular paralysis after
drug administration. [18735]
Almost all volatile anesthetics increase cerebral blood flow. It is an undesirable effect as it results in increased
ICP. Other important effects of inhalation anesthetics are myocardial depression, hypotension, respiratory
depression and decreased renal function. [854]
Propofol and other highly lipophilic drugs readily diffuse across membranes, quickly accumulating in tissues receiving
high blood flow; this accounts for their rapid onset of action. These compounds are subsequently redistributed to
organs receiving less blood flow, which explains their short duration of action. [856]

The onset of action of a gas anesthetic depends on its solubility in the blood (blood/gas partition coefficient). Drugs
with high blood/gas partition coefficients are more soluble in the blood, demonstrate slower equilibration with the
brain, and have longer onset times. [659]
Efficacy and potency
The minimal alveolar concentration (MAC) is a measure of potency of an inhaled anesthetic. It is the concentration of
the anesthetic in the alveoli that renders 50% of patients unresponsive to painful stimuli (ED50). Potency is inversely
proportional to the MAC: the lower the MAC, the more potent the anesthetic. [851]
Malignant hyperthemia
Malignant hyperthermia presents with widespread muscle rigidity after administration of inhalation anesthetics
and/or succinylcholine to genetically susceptible individuals. It is treated with dantrolene, which blocks ryanodine
receptors to prevent the release of calcium from the sarcoplasmic reticulum into the cytoplasm of skeletal muscle
fibers. [855]
Neuromuscular blocker
Succinylcholine can cause significant potassium release and life-threatening arrhythmias in patients at high risk for
hyperkalemia, including those with burns, myopathies, crush injuries, and denervating injuries or disease. [8481]
Opioids
Opiate analgesics reduce pain by binding to mu receptors and inhibiting synaptic activity in the central nervous
system. Activation of presynaptic mu receptors on the primary afferent neuron leads to closure of voltage-gated
calcium channels and reduced excitatory neurotransmitter release. Binding to mu receptors on the postsynaptic
membrane causes opening of potassium channels and membrane hyperpolarization. [776]
CNS INFECTIONS
Organophosphates inhibit cholinesterase in both muscarinic and nicotinic cholinergic synapses, leading to decreased
acetylcholine degradation and overstimulation of the corresponding receptors. Atropine reverses muscarinic effects
but does not prevent the development of nicotinic effects such as muscle paralysis. Pralidoxime is a cholinesterase-
reactivating agent that allows for degradation of excess acetylcholine and treats both the muscarinic and nicotinic
effects of organophosphates. [1323]
Subarachnoid hemorrhage
Delayed cerebral ischemia due to cerebral vasospasm usually presents 3-12 days after the initial subarachnoid
hemorrhage (SAH) with an acute change in mental status and/or new focal neurological deficits. Nimodipine, a
selective calcium channel blocker, improves outcomes in patients with cerebral vasospasm by inducing cerebral
vasodilation and decreasing calcium-dependent excitotoxicity. [146]
Transient ischemic attack

Transient ischemic attacks (TIAs) are transient episodes of focal neurologic impairment that occur due to local brain
ischemia; tissue infarction does not occur, and brain imaging is normal. Patients with TIA are at increased risk of
future stroke; secondary prevention includes antiplatelet agents (eg, aspirin, clopidogrel), statins, and lifestyle
modifications (eg, tobacco cessation, exercise) to reduce future risk. [15766]
Spasticity
Cerebral palsy results in spasticity (eg, hypertonia, hyperreflexia) due to a loss of descending inhibitory
control. Medications used to enhance the activity of GABA, the primary inhibitory neurotransmitter of the CNS, can
improve spasticity. [18496]
Capsaicin
Topical capsaicin causes defunctionalization of afferent pain fibers and depletion of substance P. Initial application
results in a burning and stinging sensation, but chronic exposure leads to reduced pain transmission. [11680]
Diabetic neuropathy
Pain due to diabetic neuropathy may be difficult to control and require multiple medications. To reduce the risk of
adverse effects and improve pain control, medications should work through different mechanisms. One such
combination may include a tricyclic antidepressant (eg, nortriptyline) and an anticonvulsant (eg, gabapentin). [19484]
Myasthenia gravis
Myasthenia gravis (MG) is caused by autoantibodies against postsynaptic nicotinic acetylcholine receptors, leading to
fewer functional receptors and fatigable muscle weakness. Nondepolarizing neuromuscular blocking agents (eg,
vecuronium) are competitive antagonists of nicotinic receptors; due to the depletion of receptors, patients with MG
are extremely sensitive to these agents. [14850]
Exacerbation of myasthenia gravis in a patient treated with long-acting acetylcholinesterase inhibitors (eg,
pyridostigmine) occurs due to myasthenic or cholinergic crisis. The edrophonium (Tensilon) test helps to differentiate
these 2 conditions. Clinical improvement after edrophonium administration indicates that the patient is
undertreated (myasthenic crisis). [1320]
Neuroleptic malignant syndrome

Neuroleptic malignant syndrome is a life-threatening reaction to antipsychotic medications characterized by diffuse
muscle rigidity, hyperthermia, autonomic instability, and altered sensorium. The antipsychotic should be stopped
and supportive care provided; dantrolene, a ryanodine receptor blocker that inhibits calcium release from the
sarcoplasmic reticulum, is an effective antidote. [11676]
Patients with long-standing, poorly controlled diabetes mellitus are at high risk for developing distal symmetric
polyneuropathy (diabetic neuropathy). Symptoms generally include progressive numbness, tingling, and
burning/stabbing pain in the feet and/or toes that progresses proximally. Painful neuropathy is treated with
serotonin-norepinephrine reuptake inhibitors, gabapentinoids, or tricyclic antidepressants. [18491]
Serotonin-norepinephrine reuptake inhibitors are often used for neuropathic pain. They increase norepinephrine in
the central synapses, which modulates the descending pain pathway, leading to decreased central perception of pain.
[19482]
Tuberculosis
Isoniazid is structurally similar to pyridoxine (vitamin B6) and competes for binding sites on pyridoxine-dependent
enzymes. This leads to decreased synthesis of certain neurotransmitters, which may result in peripheral
neuropathy. Management involves pyridoxine supplementation. [1308]
HEADACHE
Antiemetics
Dopamine receptor blockers (eg, metoclopramide, prochlorperazine) act as antiemetics and pain relievers for severe
migraine headache associated with nausea and vomiting. However, dopamine blockade can also result in excess
cholinergic activity (eg, acute dystonic reactions); diphenhydramine can be co-administered with dopamine receptor
blockers to prevent these reactions due to its anticholinergic activity. [18978]
Migraine
Migraine is an episodic disorder characterized by severe, often unilateral headache, commonly associated with
nausea and sensitivity to light and sound. Treatment is divided into abortive therapy (eg, mild analgesics, triptans,
antiemetics, ergotamines) for acute symptoms and preventive therapy (eg, beta blockers, tricyclic antidepressants,
anticonvulsants [topiramate, valproate]) to reduce the frequency of headaches. [15684]
The pathogenesis of migraines is complex and multifactorial but includes neurogenic inflammation, vasodilation, and
sensitization of trigeminal afferents in the meninges. Triptans are serotonin 5-hydroxytryptamine 1B/1D agonists
that stimulate the trigeminovascular serotonin receptors, resulting in inhibition of vasoactive peptide release,
intracranial vasoconstriction, and decreased pain. They are used as abortive therapy for acute migraine. [8476]
Trigeminal neuralgia
Trigeminal neuralgia presents with brief episodes of sudden and severe "electric shock-like" or "stabbing" pain in the
distribution of CN V (particularly V2 and V3). Carbamazepine is the drug of choice. [354]
The first-line treatment for trigeminal neuralgia is carbamazepine, a medication that inhibits neuronal high-frequency
firing by blocking sodium channels. Carbamazepine can cause bone marrow suppression; therefore, complete blood
cell counts should be monitored periodically. [1199]
MISCELLANEOUS
Beta blockers
Beta blockers are used in the treatment of essential tremor. Propranolol, a nonselective beta blocker, is the most
commonly used therapy and prevents the interaction of epinephrine and norepinephrine with beta-1 and beta-2
receptors to relieve tremor symptoms. However, inhibition of pulmonary beta-2 receptors in patients with
underlying reactive airway disease can cause bronchoconstriction, leading to cough, wheeze, and dyspnea. [2000]
Parkinson disease
Dopamine agonists have a chemical structure similar to that of the neurotransmitter dopamine and directly stimulate
dopamine receptors. They can be used instead of, or in addition to, levodopa therapy to treat the motor symptoms
of Parkinson disease (eg, bradykinesia, rigidity, tremor). [703]
Restless legs syndrome

Restless legs syndrome is characterized by an uncomfortable sensation in the legs accompanied by an urge to move
them; symptoms worsen with inactivity and at night and are temporarily relieved with movement. Alpha-2-delta
calcium channel ligands (eg, gabapentin, pregabalin) and dopamine agonists (eg, pramipexole) can be used to treat
persistent symptoms. [10362]
Tremor
Essential tremor is the most common movement disorder. Patients experience a slowly progressive, symmetric
postural and/or kinetic tremor that most commonly affects the upper extremities. Essential tremor is often inherited
in an autosomal dominant fashion (referred to as familial tremor). First-line treatment is the nonspecific β-adrenergic
antagonist propranolol. [1946]
Alzheimer disease
Alzheimer disease (AD) is a progressive dementia featuring diffuse cortical atrophy involving loss of cholinergic
neurons. Memory, cognitive, and functional impairments of AD are partially mediated by insufficient cholinergic
output. Cholinesterase inhibitors (eg, donepezil) enhance cholinergic neurotransmission to compensate for this
defect. [1442]
Dementia
Cholinesterase inhibitors (eg, donepezil, galantamine) may provide modest symptomatic improvement of cognitive
symptoms and temporarily improve functioning in patients with Alzheimer disease. However, these medications do
not alter the inevitable disease progression. [18497]
Impulse control disorders

Dopamine agonist medications used to treat Parkinson disease have been associated with the abrupt onset of
impulse control disorders, including pathological gambling, compulsive buying, and compulsive sexual behavior. The
behavior is thought to be mediated by stimulation of central dopamine receptors. [18540]
Parkinson disease
Adding carbidopa can reduce most of the peripheral adverse effects of levodopa. However, the central effects of
dopamine (eg, anxiety, agitation, behavioral changes) from levodopa can worsen with the addition of carbidopa
because more dopamine becomes available in the brain. [262]
Parkinson disease is typically treated with levodopa (immediate precursor of dopamine), which crosses the blood-
brain barrier. Levodopa is administered with DOPA decarboxylase inhibitors (eg, carbidopa) and sometimes catechol
O-methyltransferase inhibitors (eg, entacapone) to reduce the peripheral metabolism of levodopa, resulting in
increased levodopa bioavailability within the brain. [265]
Syncope
Syncope results from a transient loss of cerebral perfusion, and numerous medications can cause or contribute to
syncope. Acetylcholinesterase inhibitors (eg, donepezil, rivastigmine) may cause syncope due to enhanced
parasympathetic tone that leads to bradycardia and atrioventricular block with reduced cardiac output. [18498]
Autonomic nervous system

The autonomic nervous system utilizes three types of signal pathways: cAMP, IP3, and ion channels. Nicotinic
receptors are ligand-gated ion channels that open after binding acetylcholine. This results in an immediate influx of
Na+ and Ca2+ into the cell and an outflux of K+ from the cell. [1360]
The sympathetic nervous system typically regulates visceral function via 2-neuron signal transmission involving
cholinergic preganglionic neurons and adrenergic postganglionic neurons. Eccrine sweat glands and the adrenal
medullae are exceptions to this rule as they are both innervated by cholinergic neurons. The parasympathetic system
uses both preganglionic and postganglionic cholinergic neurons. [1359]
Although beta-2 receptors are predominant in the lungs and vasculature, they are also found on all cell membranes,
including those of the uterus. Stimulation of uterine receptors results in smooth muscle relaxation (tocolysis), while
stimulation of sodium-potassium ATPase pumps can result in hypokalemia. [1368]
Antiepileptics
Phenytoin metabolism depends on the function of hepatic P450 oxidases and is dose-dependent. Drugs that induce
hepatic microsomal enzymes (phenobarbital, carbamazepine, and rifampin) enhance phenytoin metabolism and
decrease its serum concentration. [351]
Lamotrigine can be used to treat partial and generalized seizures and works by blocking voltage-gated sodium
channels. Stevens-Johnson syndrome and toxic epidermal necrolysis are rare, life-threatening adverse effects
characterized by flu-like symptoms followed by widespread mucocutaneous epidermal necrosis. [356]
Phenytoin and other antiepileptic medications are inducers of cytochrome P-450 (CYP) enzymes, including CYP24,
which converts 25-hydroxyvitamin D to 24,25-dihydroxyvitamin D (inactive form). As a result, there is less 25-
hydroxyvitamin D available for conversion to 1,25-dihydroxyvitamin D (active form), leading to deficiency. [14044]
Gingival hyperplasia is a common side effect of phenytoin and is sometimes reversible when phenytoin is
withdrawn. Phenytoin causes increased expression of platelet-derived growth factor (PDGF). When gingival
macrophages are exposed to increased amounts of PDGF, they stimulate proliferation of gingival cells and alveolar
bone. Phenytoin toxicity mainly affects the cerebellum and vestibular system, causing ataxia and nystagmus. [1197]
Benzodiazepines
First-generation H1-histamine receptor antagonists, including diphenhydramine and chlorpheniramine, can cause
significant sedation, especially when used with other medications that cause CNS depression (such as
benzodiazepines). [352]
DRESS syndrome
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome typically occurs 2-8 weeks after exposure
to high-risk drugs such as anticonvulsants (eg, phenytoin, carbamazepine), allopurinol, sulfonamides (eg,
sulfasalazine), and antibiotics (eg, minocycline, vancomycin). Patients typically develop fever, generalized
lymphadenopathy, facial edema, diffuse skin rash, eosinophilia, and internal organ dysfunction. [508]
Seizures
Absence seizures are a type of generalized epilepsy characterized by brief staring spells with momentary loss of
awareness followed by an abrupt return to full consciousness. A classic 3-Hz spike-wave is seen on
electroencephalogram; the treatment is ethosuximide. [250]
Intravenous benzodiazepines (eg, lorazepam) are the initial drug of choice for status epilepticus. They work by
enhancing the effect of gamma-aminobutyric acid (GABA) at the GABA-A receptor, leading to increased chloride influx
and suppression of action potential firing. [11665]
Older children with absence seizures may also develop generalized onset tonic-clonic or myoclonic
seizures. Although ethosuximide is effective against isolated absence seizures, it is not effective for tonic-clonic
seizures. Valproic acid is a broad-spectrum antiepileptic that treats both types of seizures. [249]
Status epilepticus is a single seizure lasting >5 minutes or the occurrence of multiple discrete seizures with
incomplete recovery of consciousness between episodes. The initial treatment includes intravenous lorazepam and
phenytoin given concurrently. Phenytoin is a long-acting anticonvulsant that inhibits neuronal high-frequency firing
by reducing the ability of sodium channels to recover from inactivation. [353]
Broad-spectrum anticonvulsants (eg, levetiracetam, valproic acid) treat both focal and generalized onset seizures,
whereas narrow-spectrum anticonvulsants (eg, carbamazepine, phenytoin) are primarily used only for focal onset
seizures. Because the seizures in juvenile myoclonic epilepsy are usually generalized onset (ie, affect both cerebral
hemispheres at onset), treatment is with a broad-spectrum agent such as valproic acid. [355]
Ethosuximide, the first-line treatment for absence seizures, prevents neuronal burst firing by blocking thalamic T-type
Ca2+ channels. Phenytoin, carbamazepine, and valproic acid inhibit neuronal high-frequency firing by reducing the
ability of Na+ channels to recover from inactivation. [509]
SLEEP DISORDERS
Insomnia
Benzodiazepines, antihistamines, and sedating antidepressants should be avoided in the treatment of insomnia in
elderly patients due to their adverse effects. Ramelteon, a melatonin agonist, has a lower side-effect burden than
other sedative-hypnotic agents and is effective in reducing time to sleep onset in the elderly. [348]
Nonbenzodiazepine medications (eg, zolpidem, zaleplon, eszopiclone) stimulate specific subtypes of GABAA
receptors. As a result, nonbenzodiazepines are primarily hypnotics and do not produce the anxiolytic, muscle
relaxant, or anticonvulsant effects associated with benzodiazepines. [349]
Narcolepsy
Treatment for narcolepsy includes psychostimulants (eg, modafinil) for daytime sleepiness. [8259]
Ophthalmology
Corticosteroids
Cataracts are related primarily to chronic photooxidative injury. Most patients with cataracts first develop symptoms
at age >60 but exposure to systemic or ophthalmic glucocorticoids can cause cataracts at an early age. Other causes
of premature cataract formation include diabetes mellitus, ocular trauma, and external radiation exposure. [18804]
Cytomegalovirus
Cytomegalovirus retinitis is the most common cause of ocular disease in patients with untreated AIDS who have CD4
counts <50/mm3. Diagnosis is made by funduscopy, which typically reveals yellow-white, fluffy retinal lesions near
the retinal vessels with associated hemorrhage. Treatment with ganciclovir is required to prevent blindness. [1646]
Glaucoma
Acute angle-closure glaucoma occurs when the space between the cornea and iris is narrowed, limiting the flow of
aqueous humor out of the anterior chamber and raising pressure in the eye. Medications that cause pupillary dilation
(eg, alpha-adrenergic agonists, anticholinergics) can trigger acute angle-closure glaucoma. [13554]
Atropine is indicated for the treatment of bradycardia as it decreases vagal influence on the SA and AV nodes. A
common side effect is increased intraocular pressure. It may precipitate acute closed-angle glaucoma in susceptible
individuals. [1322]
Glaucoma is a form of optic neuropathy characterized by increased intraocular pressure associated with increased
production or decreased outflow of aqueous humor. Topical prostaglandins (eg, latanoprost) increase outflow of
aqueous via the uveoscleral pathway and are the preferred treatment for open-angle glaucoma. [11841]
Open-angle glaucoma is characterized by progressive loss of peripheral vision from elevated intraocular
pressure. Timolol and other nonselective beta blockers work by diminishing the secretion of aqueous humor by the
ciliary epithelium. Acetazolamide, a carbonic anhydrase inhibitor, also decreases aqueous humor secretion by the
ciliary epithelium. Prostaglandin F2α (eg, latanoprost, travoprost) and cholinomimetics (eg, pilocarpine, carbachol)
decrease intraocular pressure by increasing the outflow of aqueous humor. [1363]
Macular degeneration
Wet age-related macular degeneration is characterized by retinal neovascularization due to increased vascular
endothelial growth factor (VEGF) levels. Patients typically have acute vision loss and metamorphopsia with
funduscopy showing a grayish-green subretinal membrane and/or subretinal hemorrhage. Treatment includes
smoking cessation and VEGF inhibitor therapy (eg, ranibizumab, bevacizumab). [7721]
Phosphodiesterase inhibitors
Phosphodiesterase 5 inhibitors (eg, sildenafil, tadalafil) can cause a transient bluish discoloration to vision. Less
common ocular effects include sudden monocular vision loss due to nonarteritic anterior ischemic optic neuropathy;
findings include an afferent pupillary defect, decreased visual acuity, and optic disc edema. [18588]
Antihistamines
In addition to blocking histamine receptors, first-generation antihistamines (eg, chlorpheniramine, diphenhydramine)
have antimuscarinic, anti-alpha adrenergic, and anti-serotonergic properties. Anticholinergic effects on the ocular
ciliary muscles impair accommodation and cause blurring of vision for close objects. [173]
Pharmacology (General Principles)
DRUG METABOLISM AND TOXICITY
Excessive acetaminophen use causes toxicity through its metabolite N-acetyl-p-benzoquinone imine, which disrupts
hepatocyte mitochondrial function and induces oxidative injury throughout the liver. The resulting hepatocellular
liver injury markedly elevates aminotransferase, with levels sometimes exceeding 1,000 U/L. [21437]
Anticholinergics
Physostigmine is a cholinesterase inhibitor with a tertiary ammonium structure that can reverse both the central and
peripheral nervous system symptoms of anticholinergic toxicity. Neostigmine, edrophonium, and pyridostigmine
have a quaternary ammonium structure that limits central nervous system penetration. [1564]
Anticoagulants
St John's wort induces cytochrome P450 hepatic microsomal enzymes. As a result, a wide variety of drugs that are
metabolized by these enzymes, such as warfarin, will have lower plasma concentrations and decreased efficacy. [1777]
Antiplatelet therapy
Gastrointestinal (GI) mucosal injury and bleeding are the most common side effects of aspirin. These are due
primarily to cyclooxygenase-1 inhibition, which results in impaired prostaglandin-dependent GI mucosal defense and
decreased platelet aggregation. [713]
Biologic agents
Monoclonal antibodies (mAbs) are not eliminated by hepatic or renal clearance. Therefore, no dose adjustment is
necessary with impaired hepatic/renal function or use of cytochrome P450 inducers or inhibitors. [15941]
Chemotherapy
Hemorrhagic cystitis during therapy with cyclophosphamide or ifosfamide is caused by the urinary excretion of the
toxic metabolite acrolein. It can be prevented by aggressive hydration, bladder irrigation, and administration of
mesna, a sulfhydryl compound that binds acrolein in the urine. [1816]
Drug induced myopathy

Statins, primarily simvastatin, lovastatin, and atorvastatin, are metabolized by CYP3A4. Drugs that inhibit this enzyme
(eg, macrolide antibiotics, ketoconazole, non–dihydropyridine calcium channel blockers, amiodarone) can cause
increased statin drug levels and lead to statin myopathy. [161]
The primary side effects of statins include myopathy and hepatitis. Fibrates such as gemfibrozil can impair hepatic
clearance of statins, increasing the risk of severe myopathy. [778]
Drug metabolism and clearance

In first-order kinetics, a constant fraction (or proportion) of drug is metabolized per unit of time, so the amount
metabolized changes based on the serum concentration. In zero-order kinetics, a constant amount of drug is
metabolized per unit of time, independent of serum levels. [1716]
Methotrexate
Folinic acid (leucovorin) can reverse the toxicity of methotrexate in non-cancerous cells in the gastrointestinal
mucosa and bone marrow if administered at the appropriate time. Leucovorin serves as a reduced form of folic acid
that does not require the action of dihydrofolate reductase. [1818]
Motion sickness
Antimuscarinic agents and antihistamines with antimuscarinic action are most effective for motion sickness
prevention. [175]
Nitrates
Isosorbide dinitrate has a low bioavailability due to extensive first-pass hepatic metabolism prior to release in
systemic circulation. Sublingual nitroglycerin is absorbed directly from oral mucosa into the venous circulation and
has a higher bioavailability. [139]
Opioids
Chronic opioid use leads to the development of tolerance to analgesic effects and most side effects, with the
exception of constipation and miosis. To prevent bowel complications, it is recommended that patients be treated
prophylactically with adequate fluid intake and daily laxatives. [1257]
Morphine generates 2 major metabolites that are metabolically active and renally cleared. These metabolites can
accumulate in the bloodstream of patients with renal dysfunction and lead to opioid toxicity, evidenced by miosis,
respiratory depression, and CNS depression. [18563]
Osteoporosis
Medication-induced esophagitis is a common adverse effect of bisphosphonates. Bisphosphonates are also
associated with increased risk of osteonecrosis of the jaw and atypical femoral fractures. [14919]
Pharmacogenomics
Cytochrome P450 enzymes found in the liver are responsible for the majority of drug metabolism. Polymorphisms
occurring in the genes coding for these enzymes result in various phenotypes that differ in their rates of metabolism;
individual differences in phenotype alter treatment efficacy and drug toxicity. [1711]
Isoniazid is metabolized by acetylation. The speed with which a patient is able to acetylate drugs depends on
whether they are genetically "fast" or "slow" acetylators. The presence of fast and slow acetylators within the same
population results in a bimodal distribution of the speed of isoniazid metabolism. Slow acetylators are at increased
risk of adverse side effects. [1712]
Serotonin syndrome
Serotonin syndrome is characterized by a triad of autonomic instability, altered mental status, and neuromuscular
irritability. It may develop when a monoamine oxidase inhibitor (MAOI) antidepressant or a non-antidepressant with
MAOI activity (eg, linezolid) is combined with a serotonergic medication such as a selective serotonin reuptake
inhibitor, serotonin-norepinephrine reuptake inhibitor, or tricyclic antidepressant. [8327]
DRUG RECEPTORS AND PHARMACODYNAMICS
Dose response curves

Efficacy is a measure of the maximum pharmacodynamic effect achievable with a drug. Potency refers to the dose of
drug that is required to produce a given effect. Drugs that bind their receptors with a higher affinity or are better
able to gain access to their target tissues will have greater potency (lower ED50). [1707]
The changes in the log dose-response curve expected for the effect of a reversible competitive antagonist added to a
full agonist are:
1) a parallel shift to the right in the log-dose response curve, illustrating an increase in the ED50, and
2) no change in the maximum effect (Emax).
* Competitive=change ED50=shift right; noncompetitive=change Emax=shift down. [1708]

Certain lysosomal storage diseases, including Gaucher disease, can be treated with enzyme-replacement therapy (eg,
recombinant glucocerebrosidase). Because enzymes are large proteins that cannot be orally absorbed, the
replacement enzyme must be administered intravenously. Entry into the cell occurs by endocytosis after the
replacement enzyme binds to mannose 6-phosphate receptors on the cell surface. [18421]
Rhinitis
First-generation antihistamines are nonspecific and interact with multiple receptors, including the muscarinic
receptor. This leads to anticholinergic effects (eg, fever, flushing, mydriasis, urinary retention, tachycardia, altered
mental status). [1869]
Toxoplasmosis
Congenital toxoplasmosis is treated with sulfadiazine plus pyrimethamine. These medications work synergistically to
inhibit formation of tetrahydrofolate, a necessary cofactor for purine nucleotide synthesis. [20604]
MISCELLANEOUS
Adverse drug reaction

Most adverse drug reactions are predictable and due to known pharmacologic properties of the drug. Unpredictable
reactions are less common and are typically driven by patient-specific genetics (eg, enzyme deficiency, immunologic
idiosyncrasy). [11740]
Drug interaction
Calcineurin inhibitor nephrotoxicity with resultant impairment of renal function is the most significant adverse effect
of cyclosporine. Cytochrome P450 3A (CYP3A) is responsible for cyclosporine metabolism in the small intestine and
liver. Grapefruit juice inhibits this enzyme and increases the nephrotoxicity of cyclosporine by raising circulating drug
levels (pharmacokinetic interaction). [11761]

Antibody-drug conjugates improve drug efficacy and minimize toxicity by allowing conventional chemotherapeutic
agents (eg, cisplatin) to selectively target and kill cancer cells while sparing healthy cells (ie, targeted delivery). [18722]
Opioids
Chronic opioid therapy leads to the development of acquired pharmacodynamic tolerance via downregulation and
decreased responsiveness of opioid receptor systems. [18644]
Polypharmacy
The Beers criteria identify drugs that should be used with caution in geriatric patients. Common drugs to avoid
include anticholinergics (eg, first-generation antihistamines), centrally acting alpha-2 agonists, tricyclic
antidepressants, benzodiazepines (and other sedating medications), antipsychotics, many antiarrhythmics (eg,
digoxin), and skeletal muscle relaxants. [11567]
Rhinitis
Activation of adrenergic receptors results in arrestin binding and receptor internalization. This effect is responsible
for the tolerance effect seen with alpha-adrenergic (eg, decongestants, vasopressors) and beta-adrenergic (eg,
bronchodilators) agonists. [17511]
Volume of distribution
P-glycoprotein is an efflux pump found on brain capillary endothelial cells (part of the blood-brain barrier) that
inhibits a wide range of substrates from entering the brain. Inhibition of p-glycoprotein can improve drug delivery to
the CNS. [18419]
PHARMACOKINETICS
Aging
Neonates have a higher proportion of body water compared to adults. This can result in lower plasma concentrations
of water-soluble drugs if they are administered at the same weight-based dosage as given to adult patients. [18648]
Anesthesia
Following intravenous administration, a highly lipophilic drug will be rapidly distributed to organs with high blood
flow (eg, brain, liver, kidneys, lungs). The drug is then redistributed to tissues with relatively lower blood flow (eg,
skeletal muscle, fat, bone). This accounts for the short duration of action of many commonly used anesthetics, such
as propofol. [852]
Drug interaction
Tetracyclines interact with polyvalent cations (eg, iron, calcium, aluminum, magnesium) to form nonabsorbable
chelate complexes in the gastrointestinal tract. This can lead to significantly decreased drug absorption and
therapeutic effect. Fluoroquinolones and thyroxine are also susceptible to chelation. [18565]

Heart failure leads to reduced liver and kidney perfusion, resulting in reduced drug clearance. Metformin is excreted
unchanged by the kidney; therefore, patients with significant renal insufficiency due to heart failure or other causes
(eg, chronic kidney disease) are at increased risk of toxicity (eg, lactic acidosis). [18457]

Characteristics of a drug such as high molecular weight, high plasma protein binding, high charge, and hydrophilicity
tend to trap the drug in the plasma compartment resulting in a low Vd (3-5 L). [1710]
While the kidney is the primary site of elimination of most drugs, the liver is the main site of biotransformation of
these agents in preparation for elimination. Drugs that are more lipophilic (high Vd, good penetration into CNS) are
preferentially processed by the liver into more polar compounds for easier elimination in the bile and urine. Liver
disease (e.g., cirrhosis) or the concomitant use of other drugs may limit or enhance the clearance of drugs
metabolized in the liver. [1715]
Route of administration & bioavailability

Bioavailability is the fraction of an administered drug that reaches the systemic circulation unchanged. Drugs
administered orally enter the portal circulation and are subject to first-pass metabolism. Rectal administration is
capable of partially bypassing first-pass metabolism as a proportion of rectal blood flow enters the systemic
circulation directly. Drugs that undergo extensive first-pass metabolism have increased bioavailability when
administered rectally. [1713]
Sustained-release drug preparations have reduced and delayed peak levels compared to immediate-release
preparations due to slower absorption in the gastrointestinal tract. Dampening of peak levels and prolonged
absorption of the drug help maintain effective drug levels while minimizing toxicity. [18022]
Serum drug levels and half-life

The half-life (t1/2) of a drug is the time required to lower its concentration by 50%. The volume of distribution (VD)
refers to how well the drug distributes into tissues compared to plasma; the higher the VD, the greater the drug
distribution into the tissues. The drug concentration (mg/L) is equal to drug dose (mg) divided by VD (L). [11678]
Clearance (CL) determines the dose rate required to maintain a given steady-state plasma concentration (Css):
Maintenance dose = CSS × CL × dosing interval [8291]
Drug dosing regimens with more frequent dosing have lower peak and average drug levels, which can help reduce
drug toxicity. [17636]
During continuous infusion of a drug metabolized by first-order kinetics, the steady state concentration is reached in
4 to 5 half-lives. [2112]
Half-life (t1/2) is a measure of how quickly a drug with first-order kinetics is eliminated from the body. A drug is
almost completely eliminated after 5 half-life intervals. The half-life can be calculated from the drug's volume of
distribution (Vd) and clearance rate (CL) using the following equation:
t1/2 = (0.7 × Vd) / CL [1714]
Volume of distribution
Many drugs are dosed based on total body weight to improve safety and efficacy. In obese individuals, use of lean
body weight or an adjusted body weight may be necessary when dosing hydrophilic drugs (eg, aminoglycosides) that
do not distribute into adipose tissue. [17635]
Androgenic steroids
Patients with severe burn injury commonly develop a hypermetabolic response that results in an increased basal
metabolic rate and, often, lean muscle wasting. Administration of oxandrolone, a synthetic testosterone analogue,
enhances muscle protein synthesis and decreases protein catabolism, reducing lean muscle loss. [19261]
TOXICOLOGY
Acetaminophen overdose overwhelms normal metabolic pathways in the liver and depletes intrahepatic glutathione
stores, leading to excessive production of N-acetyl-p-benzoquinone imine (NAPQI), a toxic metabolite. Management
includes administration of N-acetylcysteine, which increases intrahepatic glutathione stores and facilitates NAPQI
detoxification. [18748]
Agonism and antagonism

Methanol and ethylene glycol have relatively little direct toxicity (similar to ethanol) but are metabolized into highly
toxic compounds by alcohol and aldehyde dehydrogenase. Treatment involves administration of fomepizole, a
competitive inhibitor of alcohol dehydrogenase (increases Km without reducing Vmax). [18021]
Anticholinergics
Anticholinergic toxicity is characterized by fever; confusion; cutaneous flushing; dry oral mucosa; and dilated, poorly
reactive pupils. Tricyclic antidepressants, particularly amitriptyline, have strong anticholinergic effects. [1868]
Anticholinergic agents (eg, atropine, scopolamine) competitively inhibit acetylcholine at the muscarinic acetylcholine
receptor. The effects can be memorized with the mnemonic, "Blind as a bat, mad as a hatter, red as a beet, hot as a
hare, dry as a bone, full as a flask, and fast as a fiddle," and can be reversed by cholinesterase inhibitors
(physostigmine). [1321]
Anticoagulants
Most available rodenticides contain brodifacoum, a long-acting 4-hydroxycoumarin derivative. A patient who has
ingested a quantity of rodenticide sufficient to cause coagulopathy and abnormal bleeding (similar to warfarin
toxicity) requires immediate treatment with fresh frozen plasma in addition to vitamin K. [1448]
Arsenic poisoning
Acute arsenic poisoning impairs cellular respiration and presents with abdominal pain, vomiting, diarrhea,
hypotension, and a garlic odor on the breath. Insecticides and contaminated water are common sources of
arsenic. Dimercaprol is the chelating agent of choice. [841]
Benzodiazepines
Flumazenil is a benzodiazepine receptor antagonist. It can reverse the sedative effects of benzodiazepines related to
overdose and procedural sedation. [15606]
Beta blocker poisoning

Beta blockers act as competitive antagonists for endogenous catecholamines; therefore, toxicity presents with
hypotension, bradycardia, bronchospasm, and hypoglycemia. The hypotension and hypoglycemia contribute to
altered mental status. [19182]
Cyanide poisoning
Cyanide toxicity is an important adverse effect of nitroprusside. Blockage of mitochondrial electron transport leads
to impaired oxygen utilization, causing lactic acidosis, neurologic dysfunction, and cardiovascular collapse. [1254]
Methemoglobinemia
Acquired methemoglobinemia can be precipitated by benzocaine and result in the conversion of Fe2+ to Fe3+, which
results in functional anemia and a left shift of the oxygen dissociation curve. Patients have cyanosis that does not
improve with supplemental oxygen. [18830]
Opioids
Naloxone is a short-acting opioid antagonist used for the treatment of opioid overdose (eg, respiratory depression,
decreased level of consciousness, miosis, decreased bowel sounds). Naloxone frequently requires redosing to
prevent recurrent overdose symptoms due to its short half-life (<1 hr). [16052]
The classic triad of opioid intoxication is decreased respiratory rate, pupillary constriction (ie, miosis), and depressed
mental status. Hypothermia, hypotension, and decreased tidal volume are also common findings. [12504]
Organophosphates inhibit acetylcholinesterase, leading to symptoms of muscarinic (mnemonic: DUMBELS) and
nicotinic (neuromuscular dysfunction) cholinergic hyperstimulation. Management includes atropine, a competitive
inhibitor of acetylcholine at the muscarinic receptor (reverses muscarinic symptoms), followed by pralidoxime, a
cholinesterase-reactivating agent that treats both nicotinic and muscarinic symptoms. [18623]
Organophosphates are acetylcholinesterase inhibitors that are commonly used as agricultural pesticides. Toxicity is
characterized by signs of cholinergic excess (eg, miosis, bronchospasm, muscle fasciculations/weakness, diarrhea,
vomiting, lacrimation). First-line therapy is atropine, a competitive inhibitor of acetylcholine at the muscarinic
receptor. [18622]
Salicylate toxicity typically presents with mixed primary respiratory alkalosis and anion gap metabolic
acidosis. Sodium bicarbonate facilitates conversion to the lipophobic, ionized form of salicylate (Sal−), which traps
much of the compound in the bloodstream and increases its urinary excretion. [18626]
Selective serotonin reuptake inhibitors
Serotonin syndrome is characterized by altered mental status, autonomic hyperactivity, and neuromuscular
excitation (eg, hyperreflexia, clonus). Causes include high doses and/or combinations of serotonergic drugs (eg, SSRI
and MAOI). Tryptophan is a precursor for serotonin. [2088]
Cyproheptadine is an antihistamine with antiserotonergic properties that can be used as an antidote in severe cases
of serotonin syndrome that do not respond to supportive measures. [2089]
Theophyline
Seizures are the major cause of morbidity and mortality from theophylline intoxication. Tachyarrhythmias are the
other major concern. [172]
Toxic alcohols
Ethylene glycol and methanol are toxic alcohols that cause anion gap metabolic acidosis and an elevated osmolar
gap. Toxicity occurs after metabolization by alcohol dehydrogenase; fomepizole is a competitive inhibitor of alcohol
dehydrogenase and is used for the treatment of acute poisoning. [15235]
Tricyclic antidepressants
Symptoms of tricyclic antidepressant overdose include seizures, anticholinergic toxicity, hypotension, and cardiac
toxicity (eg, QRS widening, ventricular arrhythmias). [20603]
ACE inhibitors
ACE inhibitors and angiotensin II receptor blockers are teratogens. Both decrease angiotensin II activity, leading to
abnormal fetal renal development, oligohydramnios, and potential neonatal Potter sequence (ie, pulmonary
hypoplasia, limb deformity). [12262]
Abortion
Progesterone is necessary for implantation and maintenance of pregnancy. Mifepristone is a progesterone
antagonist that is used with misoprostol (a prostaglandin-E1 agonist) to terminate a first-trimester pregnancy. [583]
Acne vulgaris
Isotretinoin is used to treat severe acne with significant scarring. Pregnancy is an absolute contraindication due to
the risk of teratogenicity. Sexually active women should be advised to use 2 forms of contraception and take monthly
pregnancy tests. [1568]
Ectopic pregnancy
Ectopic pregnancy occurs due to pregnancy implantation in an extrauterine location (eg, fallopian tube). Medical
treatment is with methotrexate, which inhibits DNA synthesis and cell reproduction, primarily in actively proliferating
cells such as fetal cells and trophoblasts. [20372]
Opioids
Neonatal abstinence syndrome due to maternal opioid use causes neurologic, gastrointestinal, and autonomic
symptoms; irritability, tremors, diarrhea, and sneezing are classic findings. Patients with symptoms refractory to
nonpharmacologic therapy warrant opioid replacement (eg, morphine). [1255]
Teratogens
Valproate is a teratogenic medication that decreases maternal folate levels and increases the risk of fetal neural tube
defects (eg, meningocele, myelomeningocele). [507]
Lithium is commonly used to treat bipolar disorder. Its use during pregnancy is associated with Ebstein's anomaly,
which is characterized by apical displacement of the tricuspid valve leaflets, decreased right ventricular volume, and
atrialization of the right ventricle. [1490]
Neuromuscular blocker
Succinylcholine is a fast-acting, depolarizing neuromuscular blocking agent used for rapid-sequence intubation that
causes equal reduction of all 4 twitches during train-of-four stimulation (phase I blockade). Prolonged administration
of succinylcholine or use in patients with abnormal plasma cholinesterase activity causes transition to a phase II
(nondepolarizing) block, seen as a progressive reduction in each of the 4 twitches. [1212]
Succinylcholine is a depolarizing neuromuscular blocking agent used to induce skeletal muscle relaxation; it typically
has a very short duration of action due to metabolism by plasma pseudocholinesterase. Pseudocholinesterase
deficiency is an autosomal recessive disorder that results in the inability to metabolize succinylcholine, leading to
prolonged neuromuscular paralysis after drug administration. [18666]

Histologic findings of idiopathic pulmonary fibrosis include patchy dense collagen fibrosis in the interstitium, focal
fibroblastic proliferation, honeycombing, and mild lymphoplasmacytic infiltrates with hyperplasia of type 2
pneumocytes. Therapies are directed at slowing the progression of fibrosis by inhibiting transforming growth factor-
beta and other fibrogenic growth factors (eg, PDGF, fibroblastic growth factor, and VEGF). [15126]
MISCELLANEOUS
Anesthesia
Ketamine can be used for anesthesia induction. The side effects of increased catecholamine release (eg,
bronchodilation) are often exploited in patients with bronchospasm. [18732]
Etomidate, a GABA agonist, is often used for anesthesia induction to provide sedation and amnesia. It is
hemodynamically neutral, but it can result in transient adrenocortical suppression because it inhibits cortisol
synthesis. [18733]
Chronic cough
Dextromethorphan (DXM) is a popular over-the-counter antitussive agent that acts on sigma receptors to suppress
the medullary cough center. DXM also has an off-target action on serotonin transports and receptors in the
CNS. Overdose or accidental interaction with other serotonergic medications (eg, selective serotonin reuptake
inhibitors, antidepressants) can precipitate serotonin syndrome. [18669]
Smoking Cessation
Varenicline is a partial agonist of nicotinic acetylcholine receptors. It can help patients stop using tobacco by reducing
withdrawal symptoms and attenuating the rewarding effects of nicotine. [8754]
Asthma
Asthma is characterized by reversible airway obstruction, and lung function tests may be normal between
exacerbations. Bronchoprovocation can be used to aid diagnosis in patients with normal spirometry; methacholine is
administered and followed by serial spirometry. Patients with asthma demonstrate hyperresponsivity to the
stimulus, leading to FEV1 reductions at lower doses than in those without asthma. [1523]
Asthma is characterized by chronic airway inflammation, which leads to airway remodeling, airway
hyperresponsiveness, and bronchoconstriction. Corticosteroids reduce airway inflammation and are used for both
chronic asthma management (inhaled administration) and acute exacerbations (systemic administration). [169]
Cromolyn and nedocromil are mast cell-stabilizing agents that inhibit mast cell degranulation independent of the
triggering stimulus. They are less effective than inhaled glucocorticoids and are considered second-line treatments
for allergic rhinitis and bronchial asthma. [171]
Improper administration of inhaled glucocorticoids for the treatment of asthma can lead to adverse effects, including
oropharyngeal candidiasis and dysphonia. Using a spacer during administration and rinsing the mouth after each use
can help prevent these adverse effects. [168]
IgE-binding monoclonal antibodies (eg, omalizumab) are effective in treating asthma that remains uncontrolled
despite optimal therapy with bronchodilators and inhaled corticosteroids. IgE-binding monoclonal antibodies reduce
airway inflammation by blocking the binding of IgE to the IgE receptors on mast cells and preventing the release of
proinflammatory substances, including histamine and leukotrienes. [2128]
COPD
Ipratropium, an anticholinergic agent and derivative of atropine, treats obstructive lung disease by blocking
acetylcholine at muscarinic receptors, which prevents bronchoconstriction and reduces mucus secretion from
tracheobronchial submucosal glands. [170]
Corticosteroids
Corticosteroids (eg, fluticasone, budesonide) have multiple beneficial effects in the treatment of asthma. In addition
to their anti-inflammatory effect, corticosteroids upregulate beta-2 receptors on bronchial smooth muscle to increase
cellular responsiveness to adrenergic stimuli and potentiate the bronchodilatory response to inhaled beta-2 agonists
(eg, albuterol). [18805]
Leukotriene receptor antagonists

The cysteinyl-containing leukotrienes (ie, leukotriene C4, D4, and E4) are inflammatory mediators that stimulate
bronchoconstriction, bronchial mucus secretion, and bronchial edema to contribute to the pathogenesis of
asthma. Leukotriene receptor antagonists (eg, montelukast, zafirlukast) treat asthma by binding to leukotriene
receptors on bronchial smooth muscle cells and blocking these effects. [18809]
Theophyline
Theophylline is an adenosine receptor antagonist and indirect adrenergic agent with a narrow therapeutic index. It is
predominantly metabolized by the hepatic cytochrome oxidases. Inhibition of these enzymes by concurrent illness
(eg, infection with fever) or ingestion of certain drugs or substances (eg, ciprofloxacin) can raise serum theophylline
concentrations and cause toxicity (eg, seizures, cardiac arrhythmias). [11752]
Lung abscess
Patients with alcohol use disorder are at increased risk for lung abscess due to the aspiration of oral flora during
periods of unconsciousness. Most cases involve a mixture of upper respiratory aerobes and oral cavity anaerobes
(eg, Bacteroides, Prevotella, Fusobacterium, Peptostreptococcus). Manifestations include subacute fever, cough, and
foul-smelling sputum. [1446]

Empyema involves bacterial invasion of the intrapleural space with progressive inflammation, pus accumulation, and
organized fibrosis. Drainage with a chest tube is often difficult due to loculations and high fluid viscosity, but it can be
aided by the intrapleural administration of a fibrinolytic agent (eg, tissue plasminogen activator) in combination with
a nucleic acid cleaving enzyme (ie, deoxyribonuclease). [20108]

Pulmonary arterial hypertension (PAH) typically affects young women and can be familial. It is characterized by
luminal narrowing of the pulmonary arteries and arterioles, with medial hypertrophy, intimal fibrosis, and the
eventual development of plexiform lesions. Bosentan is a competitive antagonist of endothelin receptors used for
the treatment of PAH. [903]
Pulmonary hypertension can occur due to a primary change in the pulmonary arteries (ie, pulmonary arterial
hypertension) or it can be secondary to a separate disease process such as left-sided heart failure (ruled out by
normal pulmonary capillary wedge pressure). Endothelin receptor antagonists (eg, bosentan, ambrisentan) lower
pulmonary arterial pressure and improve dyspnea in patients with pulmonary arterial hypertension. [14847]

Chronic kidney disease can cause hyperphosphatemia due to decreased renal excretion of phosphorus. Dietary
phosphorus restriction is recommended, but oral phosphate binders are often needed. Sevelamer is a nonabsorbable
anion-exchange resin that binds intestinal phosphate to reduce absorption. [15312]
Erythropoietin
Patients with chronic kidney disease often develop normocytic anemia due to erythropoietin (EPO)
deficiency. Treatment with recombinant EPO can dramatically improve tissue oxygen delivery and reduce
mortality. However, prolonged or high-dose treatment can have serious side effects, most notably increased risk of
hypertension and thromboembolism. [18950]

In renal artery stenosis, increased production of angiotensin II causes increased systemic blood pressure (to increase
renal perfusion) and preferential constriction of the glomerular efferent arteriole (to increase glomerular
filtration). Patients with bilateral renal artery stenosis are dependent on this response to maintain renal function;
initiation of ACE inhibitors or angiotensin II receptor blockers can precipitate acute renal failure. However, urinalysis
is typically unremarkable (ie, no hematuria, proteinuria, or casts). [695]
Renal artery stenosis (eg, severe hypertension, abdominal bruits) causes decreased renal artery perfusion, which
activates the renin-angiotensin-aldosterone system. Increased secretion of renin leads to increased production of
angiotensin I and angiotensin II, which causes increased peripheral resistance and elevated systemic blood
pressure. Increased aldosterone secretion causes increased renal Na+ reabsorption and K+ and H+ excretion,
resulting in relative hypokalemia and metabolic alkalosis. [15246]
DIABETES INSIPIDUS
SIADH
The syndrome of inappropriate antidiuretic hormone (SIADH) presents with hypotonic hyponatremia (ie, low serum
osmolality and serum sodium), concentrated urine (ie, high urine osmolality), and euvolemia. Carbamazepine can
cause SIADH by increasing antidiuretic hormone (ADH) secretion and renal sensitivity to ADH. [18547]
Acetazolamide
Carbonic anhydrase inhibitors (eg, acetazolamide) block the reabsorption of sodium bicarbonate in the proximal
tubule to cause metabolic acidosis. These drugs can be used to help offset the metabolic alkalosis caused by loop
diuretics. [18937]
Carbonic anhydrase inhibitors (eg, acetazolamide) reduce intraocular pressure in patients with glaucoma by reducing
production of aqueous humor. Carbonic anhydrase is also found in the renal proximal tubule, where it catalyzes
reactions necessary for bicarbonate (HCO3) reabsorption. Acetazolamide therefore induces a mild diuresis with
increased urine pH and resulting mild metabolic acidosis. [682]
Aldosterone antagonists
Aldosterone acts on the principal and intercalated cells of the renal collecting tubules to increase resorption of
sodium and water and increase excretion of potassium and hydrogen ions. Aldosterone receptor antagonists (eg,
spironolactone, eplerenone) inhibit these effects. [1533]
Beta 2 agonists
Potassium is primarily stored intracellularly (~98% of total body stores) through the action of the Na-K-ATPase
pump. Beta-adrenergic activity increases the activity of the Na-K-ATPase pump; therefore, both endogenous
catecholamines and therapeutic beta-2 agonists (eg, albuterol, dobutamine) can cause transient hypokalemia due to
increased transport of potassium intracellularly. [18807]
Hyperkalemia
Patiromer is a nonabsorbable cation exchange resin used to treat hyperkalemia. It binds colonic potassium in
exchange for calcium, trapping potassium within the resin where it is then excreted in the feces. Adverse effects
include diarrhea, hypokalemia, hypercalcemia, and hypomagnesemia. [18841]
Common side-effects of ACE-inhibitors include decreased glomerular filtration rate (GFR), hyperkalemia, and
cough. Angioedema is a rare, but life-threatening, side-effect. [1148]
Hypokalemia
Thiazide diuretics decrease intravascular fluid volume, which stimulates aldosterone secretion and leads to increased
excretion of potassium and hydrogen ions in the urine. This results in hypokalemia and metabolic alkalosis. [1425]
Idiopathic Intracranial Hypertension
Carbonic anhydrase inhibitors (eg, acetazolamide) are weak diuretics that block reabsorption of sodium bicarbonate
(NaHCO3) in the proximal tubule. The main effect is increased HCO3- excretion, leading to increased urine pH, mild
metabolic acidosis (with compensatory respiratory alkalosis), mild hypokalemia, and mild hypocalcemia. [18940]
Lithium
Lithium-induced diabetes insipidus is the result of lithium's antagonizing effect on the action of vasopressin on
principal cells within the collecting duct system. [2113]
Loop diuretics
Loop diuretics act by inhibiting the Na-K-2Cl cotransporter in the thick ascending limb of the loop of Henle, increasing
Na+, Cl−, and H2O excretion. They are the most potent diuretics and are used as first-line therapy for rapid relief of
symptoms in patients with acute decompensated heart failure. [681]
Ototoxicity secondary to loop diuretics usually occurs with higher dosages, pre-existing chronic renal disease, rapid
intravenous administration, or when used in combination with other ototoxic agents (aminoglycosides, salicylates,
and cisplatin). Hearing impairment is usually reversible but may be permanent in some cases. [685]
Mannitol
Mannitol increases plasma osmolality, leading to the flow of water down its concentration gradient from the
intracellular space to the plasma, helping to reduce intracranial pressure. The resulting plasma expansion also
reduces serum sodium levels and increases glomerular filtration/tubular flow. Mannitol is freely filtered and not
reabsorbed by the renal tubules, resulting in a hyperosmolar glomerular filtrate. [18941]
Mannitol is an osmotic diuretic that works by increasing plasma or tubular fluid osmolality. Increased plasma and
fluid osmolality causes extraction of water from the interstitial space into the vascular space or tubular lumen, with
subsequent diuresis. In the brain, water redistribution from the tissues into the plasma helps reduce edema and
intracranial pressure in the setting of cerebral edema. One of the more severe toxicities of aggressive osmotic
diuretics is pulmonary edema. [688]
Metabolic alkalosis
Overuse or abuse of loop diuretics (eg, furosemide) characteristically causes hypokalemic, hypochloremic metabolic
alkalosis. Urine electrolyte findings depend on how recently the diuretic was last ingested; increased urine Na+, Cl−,
and K+ are expected with recent ingestion. [18872]
SIADH
Vaptans (eg, tolvaptan) are vasopressin V2 receptor antagonists (ie, aquaretics) used to treat hyponatremia. Vaptans
block the effects of antidiuretic hormone (vasopressin), increasing renal free water excretion without directly
affecting excretion of sodium or potassium. Diuresis of free water with vaptans results in increased plasma
osmolality, increased serum sodium, increased urine output, and lowered urine osmolality. [18948]
Acute salicylate toxicity causes a primary respiratory alkalosis and a primary metabolic acidosis with an anion gap due
to increased lactate production. Symptoms include tinnitus, tachypnea, hyperthermia, vomiting, and altered mental
status. [18924]
GLOMERULAR DISEASES

The risk of progression of diabetic nephropathy in patients with proteinuria can be reduced by appropriate glycemic
and blood pressure control. ACE inhibitors and angiotensin II receptor blockers are the preferred antihypertensive
agents due to their antiproteinuric effects, which are independent from their effects on systemic blood pressure. [151]
MISCELLANEOUS
ACE inhibitors
ACE inhibitors reduce angiotensin II levels and cause efferent arteriole dilation, thereby decreasing the glomerular
filtration pressure and filtration rate. This can precipitate acute renal failure in patients with reduced intrarenal
perfusion pressure at baseline (eg, renal artery stenosis, congestive heart failure, hypovolemia). [696]
Patients with bilateral renal artery stenosis have reduced renal perfusion (due to atherosclerotic blockage) and are
dependent upon angiotensin II-induced efferent vasoconstriction to maintain glomerular filtration rate. ACE
inhibitors block angiotensin II-mediated vasoconstriction, which can reduce systemic blood pressure and lower renal
perfusion. In addition, ACE inhibitors cause dilation of the efferent arteriole, leading to a reduction in glomerular
filtration rate and renal filtration fraction. [694]
Beta blockers
Beta-adrenergic blocking drugs inhibit renin release by blocking beta-1 receptor-mediated regulation of the renin-
angiotensin-aldosterone system. This reduces plasma renin activity, with a resulting reduction in angiotensin I,
angiotensin II, and aldosterone levels. [692]
Erythropoietin
Erythropoiesis-stimulating agents (ESAs) can substantially improve anemia symptoms, avoiding the need for blood
transfusions in chronic kidney disease and dialysis patients. However, ESAs are associated with increased risk for
hypertension and thromboembolic events. [11945]
Thiazides
Thiazide and loop diuretics cause significant volume depletion, activating the renin-angiotensin-aldosterone system,
which can lead to hypokalemia and metabolic alkalosis. Thiazide diuretics are more likely to cause hyponatremia and
hypercalcemia; loop diuretics cause hypocalcemia. [8884]
Thiazide diuretics work by blocking Na+-Cl- symporters in the distal convoluted tubules, causing enhanced Na, Cl, and
water excretion. Since only a small amount of filtered Na+ reaches the distal tubules, thiazides are not as efficacious
as loop diuretics. Unlike loop diuretics, thiazides can cause hypercalcemia. [683]
Urgency incontinence, or overactive bladder, is caused by uninhibited bladder contractions (detrusor instability) that
results in a sudden urge to void followed by an involuntary loss of urine. Treatment with beta-3 adrenergic receptor
activation (eg, mirabegron) relaxes the detrusor muscle, promotes urine storage, and decreases incontinent episodes.
[18866]
Urinary retention
Cholinomimetics are indicated in non-obstructive urinary retention, paralytic ileus, and glaucoma. Their side effects
include nausea, vomiting, abdominal cramps, diarrhea, dyspnea and increased secretions (sweating, lacrimation and
salivation). [1362]
Postoperative urinary retention, with incomplete bladder emptying, is a common complication thought to involve
decreased micturition reflex activity, decreased contractility of the bladder detrusor, and/or increased vesical
sphincter tone. This condition may be treated with a muscarinic agonist (bethanechol) or an α1 blocking drug. [1211]
Hyperaldosteronism
Aldosterone excess will cause hypertension, hypokalemia, metabolic alkalosis and depressed renin. Alternatively,
hypoaldosteronism is the cause of type IV renal tubular acidosis. Aldosterone antagonists such as spironolactone or
eplerenone can be used as medical therapy for Conn's syndrome. [152]
Thiazides
Thiazide diuretics effectively increase renal calcium reabsorption. In patients with recurrent calcium nephrolithiasis,
thiazide diuretics can help prevent stone formation by decreasing urine Ca2+ excretion. [2003]
Renin angiotensin aldosterone system

Angiotensin-converting enzyme (ACE) inhibitors block the effect of ACE, decreasing angiotensin II and aldosterone
levels. By decreasing angiotensin II levels, ACE inhibitors directly interrupt negative feedback loops, thereby
increasing renin and angiotensin I levels. ACE is also responsible for the breakdown of bradykinin; ACE inhibitors
therefore increase bradykinin levels. [690]
Urge incontinence, or overactive bladder syndrome, is caused by uninhibited bladder contractions (detrusor
instability). It results in a sense of urgency accompanied by an involuntary loss of urine. If behavioral therapy alone is
unsuccessful, pharmacologic therapy with an antimuscarinic drug (targeting M3 receptors) can help improve
symptoms. [8249]
Biologic agents
Tumor necrosis factor-alpha (TNF-α) inhibitors impair cell-mediated immunity. All patients beginning treatment with
TNF-α inhibitors should be evaluated for latent tuberculosis. [720]
Cox 2 inhibitor
Selective cyclooxygenase 2 (COX 2) inhibitors relieve pain with lower risk of bleeding and gastric ulceration than
nonselective nonsteroidal anti-inflammatory drugs. [716]
Gout
Nonsteroidal anti-inflammatory drugs are the first-line treatment for acute gouty arthritis. They inhibit
cyclooxygenase and therefore decrease prostaglandin synthesis and exert a broad anti-inflammatory effect that
includes inhibition of neutrophils. [860]
Colchicine inhibits tubulin polymerization into microtubules and can be used for acute treatment and prophylaxis of
gout. Important side effects of colchicine include nausea, abdominal pain, and diarrhea. [859]
Gout occurs in the setting of hyperuricemia and causes an inflammatory arthritis characterized by negative
birefringent, needle-shaped crystals visible on joint fluid microscopy. Most diuretics (eg, hydrochlorothiazide,
furosemide) can cause hyperuricemia and trigger gout flares by causing relative volume depletion, which decreases
the fractional excretion of uric acid. [167]
Colchicine is used for treatment of acute gouty arthritis in patients who cannot take nonsteroidal anti-inflammatory
drugs. It inhibits leukocyte migration and phagocytosis by blocking tubulin polymerization. Significant side effects of
colchicine include nausea and diarrhea. [858]
Colchicine is a second-line agent for treating acute gouty arthritis. It inhibits tubulin polymerization and microtubule
formation in leukocytes, reducing neutrophil chemotaxis and emigration to sites inflamed by tissue deposition of
monosodium urate crystals. Gastrointestinal mucosal function is also impaired by microtubule disruption, leading to
diarrhea and, less commonly, nausea, vomiting, and abdominal pain. [1168]
Patients undergoing solid organ transplantation are at increased risk of gout due to medications that impair renal
clearance of uric acid. Cyclosporine is particularly associated with gout in the post-transplantation period due to
decreased uric acid excretion. [14967]
Chronic uric acid-lowering therapy is recommended for patients with gout who have frequent gouty attacks, uric acid
kidney stones, tophi, or chronic joint destruction from gout. Xanthine oxidase inhibitors are the preferred treatment.
[861]
Lyme disease
Early Lyme disease causes flu-like symptoms and erythema chronicum migrans. The second stage of Lyme disease
may involve atrioventricular block and facial palsy. Late Lyme disease can cause chronic asymmetric large joint
arthritis and encephalopathy. Lyme disease is easily treated with doxycycline or penicillin-type antibiotics (eg,
ceftriaxone). [1897]
NSAIDs
Cyclooxygenase-2 (COX-2) is an inducible enzyme upregulated during inflammation by interleukin-1 and TNF-
α. Selective COX-2 inhibitors (eg, celecoxib) decrease inflammation by inhibiting COX-2 production of pro-
inflammatory arachidonic acid metabolites. Because they do not affect COX-1, they have minimal gastroduodenal
toxicity. [7792]
The foundation of management for rheumatoid arthritis is disease-modifying antirheumatic drugs, which alleviate
pain and inflammation and reduce long-term joint destruction. However, the response to treatment may take several
weeks. Nonsteroidal anti-inflammatory drugs and glucocorticoids can provide rapid symptom relief in the interim.
[719]
Methotrexate is the preferred disease-modifying treatment for patients with moderate to severe rheumatoid
arthritis. Significant adverse effects include stomatitis, bone marrow suppression, and liver function abnormalities.
[718]
Azathioprine
Azathioprine is an immunosuppression drug that is metabolized into active metabolites by HGPRT and,
conversely, inactivated by xanthine oxidase. Coadministration with a xanthine oxidase inhibitor (eg, allopurinol,
febuxostat) shunts azathioprine metabolism toward the production of active metabolites, resulting in increased
immunosuppression and risk of cellular toxicity. [11749]
Azathioprine is an immunosuppressant that functions via inhibition of purine synthesis by its pharmacologically active
6-thioguanine metabolites. In addition to the desired effect of reduced lymphocyte proliferation, the proliferation of
other hematologic cell lines (eg, neutrophils, erythrocytes, platelets) is reduced, leading to a common adverse effect
of pancytopenia. [18703]

Ocular manifestations in giant cell arteritis (temporal arteritis) can lead to rapid, severe, and irreversible vision
loss. Involvement of the ciliary arteries in GCA leads to anterior ischemic optic neuropathy, which presents with a
painless, rapidly progressive decrease in visual acuity. Treatment includes systemic glucocorticoids (eg, prednisone,
methylprednisolone). [18475]
SLE
Drug-induced lupus erythematosus (DILE) is characterized by abrupt onset of lupus symptoms (eg, fever, arthralgias,
pleuritis) with positive anti-histone antibodies. It has been linked to drugs metabolized by N-acetylation in the liver
(eg, procainamide, hydralazine, isoniazid). Genetically predisposed individuals who are slow acetylators are at
greater risk for developing DILE. [1253]
Corticosteroids
Osteoporosis is a common cause of fragility fractures, which occur in the absence of significant trauma. Chronic or
recurrent use of glucocorticoids (eg, prednisone) promotes osteoporosis and increases the risk of fractures. [1773]
Osteoporosis
Selective estrogen receptor modulators exhibit estrogen antagonist and agonist properties in a tissue-specific
manner. Raloxifene has estrogen agonist activity on bone, which decreases bone resorption and improves bone
density. Raloxifene has an estrogen antagonist effect on breast tissue and can decrease the risk of breast cancer; it
also acts as an estrogen antagonist in the uterus, and does not increase the risk of endometrial cancer. [1795]
Long-term acid suppression with proton pump inhibitors may be associated with an increased risk of osteoporotic
fractures, possibly due to decreased calcium absorption. Other medications associated with an increased risk of
osteoporosis include glucocorticoids, aromatase inhibitors, and anticonvulsants that induce cytochrome P450. [10930]
Bisphosphonates have a chemical structure similar to that of pyrophosphate and attach to hydroxyapatite binding
sites on bony surfaces to inhibit bone resorption by osteoclasts. [11564]
Thiazides
Thiazide diuretics increase calcium absorption in the distal convoluted tubules within the nephron. Thiazides are
associated with increased bone mineral density and are recommended for treatment of hypertension in patients at
risk for osteoporosis. Loop diuretics increase urinary calcium loss. [993]
Physiology
Av fistula
An arteriovenous fistula allows blood to shunt from the arterial circulation to the venous circulation, bypassing the
high resistance of the systemic arterioles. This leads to reduced systemic vascular resistance (ie, reduced afterload),
increased venous return (ie, increased preload), and increased stroke volume. Left ventricular contractility is
unchanged. [1518]
Carotid sinus hypersensitivity

The carotid sinus is a dilation of the internal carotid artery located just above the bifurcation of the common carotid
artery. The carotid sinus reflex has an afferent limb that arises from the baroreceptors in the carotid sinus and travels
to the vagal nucleus and medullary centers via the glossopharyngeal nerve (CN IX); the efferent limb carries
parasympathetic impulses via the vagus nerve (CN X). [1609]
CARDIAC ARRHYTHMIAS
Antiarrhythmic drugs
Class IV antiarrhythmics (eg, verapamil, diltiazem) are commonly used to prevent recurrent nodal arrhythmias (eg,
paroxysmal supraventricular tachycardia). They work by blocking calcium channels in slow-response cardiac tissues,
slowing phase 4 (spontaneous depolarization) and phase 0 (upstroke). This reduces impulse conduction velocity in
the sinoatrial and atrioventricular nodes. [1973]
Atrial fibrillation
Atrial fibrillation occurs due to irregular, chaotic electrical activity within the atria and presents with absent P waves,
irregularly irregular R-R intervals, and narrow QRS complexes. The atrioventricular node refractory period regulates
the number of atrial impulses that reach the ventricles and determines the ventricular contraction rate in conditions
where the atria undergo rapid depolarization. [1977]
Atrial fibrillation is recognized by an irregularly irregular rhythm with variable R-R intervals and absence of P waves on
ECG. The development of AF most commonly involves ectopic electrical foci in the pulmonary veins that trigger
fibrillatory conduction in abnormal (remodeled) atrial tissue. [14743]
:The slow inward calcium current within the atrioventricular node decreases the transmission rate of rapid impulses
generated by the atrial myocardium (eg, atrial fibrillation/flutter), acting as a conduction rate buffer between the
atria and the ventricles. [21457]
Atrial fibrillation is the most common cause of an irregularly irregular rhythm. It often presents with palpitations and
is confirmed by ECG showing an absence of organized P waves and irregularly irregular R-R intervals. [2055]
Atrial flutter
Atrial flutter demonstrates rapid and regular atrial activity in a saw-toothed pattern (flutter or F waves) on
ECG. Typical atrial flutter is caused by a large reentrant circuit that traverses the cavotricuspid isthmus of the right
atrium, which is the target site for radiofrequency ablation. [14745]
Heart block
The sinoatrial node is the main pacemaker of the cardiac conduction system, typically initiating electrical impulses at
a rate of 60-100/min. Other parts of the conduction system (eg, atrioventricular node, His bundle) have their own
intrinsic pacemakers, and they initiate impulses at a slower rate when impulses from the sinoatrial node are blocked.
[1976]
Premature ventricular contractions

A premature ventricular contraction is recognized on ECG by a wide QRS complex, opposite-facing T wave, and brief
ensuing sinus pause. Left ventricular filling is less than normal at the time of the PVC. The ensuing sinus pause allows
for greater-than-normal filling during the post-PVC beat. [21037]
Supraventricular tachycardia
Carotid sinus massage leads to an increase in parasympathetic tone causing temporary inhibition of sinoatrial node
activity, slowing of conduction through the atrioventricular (AV) node, and prolongation of the AV node refractory
period. It is a useful vagal maneuver for termination of paroxysmal supraventricular tachycardia. [1515]
Syncope
Vasovagal syncope typically involves a trigger (eg, prolonged standing), a prodrome (eg, warmth, light-headedness),
and rapid recovery (eg, within 1-2 min). It results from a transient, autonomic nervous system–mediated
cardioinhibitory and vasodepressor response. [21156]
CARDIOVASCULAR DRUGS
Phenylephrine increases blood pressure via an alpha-1 receptor-mediated increase in inositol triphosphate in vascular
smooth muscle cells. The abrupt increase in blood pressure triggers a reflexive increase in parasympathetic activity
while decreasing sympathetic outflow. This leads to decreased cyclic AMP activity in the heart (mediated by beta-1
adrenergic and muscarinic-2 receptors), which decreases heart rate and myocardial contractility. The reduction in
heart rate is driven in part by decreased inward calcium current in sinoatrial cells. [18618]

Atrial septal defects result in increased right-sided blood flow due to left-to-right shunting and characteristic findings
of a systolic ejection murmur (ie, pulmonic flow murmur) and widely split, fixed S2. [19558]

Patent ductus arteriosus results in increased left ventricular preload (due to increased pulmonary venous return to
the left atrium) and decreased systemic vascular resistance (due to the continuous left-to-right shunt). This
combination of higher preload and lower afterload leads to an early increase in left ventricular cardiac output. [19525]
In patients with patent ductus arteriosus, left-to-right shunting of oxygenated blood from the aorta into the
pulmonary artery results in a higher-than-expected oxygen concentration in the pulmonary artery. Oxygen saturation
in the left and right heart chambers is unchanged. [19526]
Tetralogy of fallot
In patients with Tetralogy of Fallot, squatting during a Tet spell increases systemic vascular resistance and decreases
right-to-left shunting, thereby increasing pulmonary blood flow and improving oxygenation status. [205]

Perfusion pressure decreases distal to a significant coronary artery stenosis, resulting in an initial decrease in blood
flow. Coronary autoregulation stimulates arteriolar vasodilation, which reduces downstream vascular resistance and
helps return blood flow to near-normal levels to prevent myocardial ischemia. [19674]
Acute heart failure

Stroke volume is the absolute volume of blood ejected from the left ventricle with each contraction and is calculated
by subtracting left ventricular end-systolic volume from left ventricular end-diastolic volume (LVEDV). Ejection
fraction is the relative volume of blood ejected from the left ventricle with each contraction; it is calculated by
dividing stroke volume by LVEDV. Cardiac output, the volume of blood ejected into the aorta per unit time, is
estimated by multiplying stroke volume by heart rate. [15526]
Cardiogenic shock
Myocardial infarction may cause acute left ventricular (LV) failure and cardiogenic shock. Decreased cardiac
contractility leads to reduced cardiac output and hypotension. In response, systemic vascular resistance is increased
(via peripheral vasoconstriction) to maintain blood pressure. The LV systolic failure increases LV end-diastolic
pressure, which is transmitted backward to increase pulmonary capillary wedge pressure and pulmonary arterial
pressure. [19280]
Myocardial infarction may be complicated by acute left ventricular failure (LV) and cardiogenic shock. In cardiogenic
shock, increased LV end-diastolic pressure is transmitted backward to cause increased pulmonary capillary wedge
pressure (evidenced by pulmonary edema) and increased central venous pressure. There is markedly decreased
cardiac output, which causes hypotension and decreased coronary perfusion pressure. [19281]

The reduced cardiac output in heart failure triggers compensatory activation of the sympathetic nervous system and
renin-angiotensin-aldosterone pathway, resulting in vasoconstriction (increased afterload), fluid retention (increased
preload), and deleterious cardiac remodeling. These mechanisms perpetuate a downward spiral of cardiac
deterioration, leading to symptomatic decompensated heart failure. [8546]
Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are secreted by atrial and ventricular
cardiomyocytes in response to myocardial stretching induced by hypervolemia. These natriuretic peptides inhibit the
renin-angiotensin-aldosterone system and stimulate peripheral vasodilation and increased urinary excretion of
sodium and water. Neprilysin inhibitors (eg, sacubitril) prevent the degradation of ANP and BNP, enhancing their
beneficial effects in heart failure. [1978]
Neprilysin is responsible for the breakdown of the natriuretic peptides and angiotensin II; therefore, inhibition of
neprilysin increases the activity of these peptides. For treatment of heart failure, neprilysin inhibition is combined
with angiotensin II receptor blockade to optimize the positive effects of the natriuretic peptides (eg, vasodilation,
diuresis) while blocking the negative effects of angiotensin II (eg, vasoconstriction, fluid retention). [11745]
Diastolic dysfunction
Prolonged systemic hypertension leads to concentric left ventricular (LV) hypertrophy via the addition of myocardial
contractile fibers in parallel. The thickening of the LV walls reduces LV compliance, leading to impaired diastolic filling
and heart failure with preserved ejection fraction. In response to reduced cardiac output, the kidneys activate the
renin-angiotensin-aldosterone system, stimulating sodium retention and vasoconstriction that worsens volume
overload and can lead to decompensated heart failure. [15391]
Sodium nitroprusside is a short-acting agent that causes balanced vasodilation of the veins and arteries to decrease
both left ventricular (LV) preload and afterload. The balanced vasodilation allows for maintenance of stroke volume
and cardiac output at a lower LV pressure (lower cardiac work). [1652]
Hypovolemia
Low blood pressure results in decreased arterial distension and reduced firing of aortic and carotid
baroreceptors. This leads to an increase in sympathetic outflow and decrease in parasympathetic outflow,
stimulating vasoconstriction and increased heart rate and contractility in order to help maintain blood
pressure. Hypovolemia reduces atrial stretch, causing decreased atrial natriuretic peptide secretion. [18535]
Intravenous fluids increase the intravascular and left ventricular end-diastolic volumes. The increase in preload
stretches the myocardium and increases the end-diastolic sarcomere length, leading to an increase in stroke volume
and cardiac output by the Frank-Starling mechanism. [1512]
Hypovolemic shock
Hypovolemic shock results from markedly decreased blood volume, which reduces central venous pressure and
cardiac output and leads to increased systemic vascular resistance (peripheral vasoconstriction). Shock causes
reduced organ and tissue perfusion, which leads to lactic acidosis (metabolic acidosis) and a compensatory increase in
ventilation (ie, compensatory respiratory alkalosis). [19331]
Mitral regurgitation
A third heart sound (S3) occurs due to sudden limitation of ventricular movement during passive ventricular filling in
diastole. An S3 in patients age >40 suggests abnormal ventricular cavity enlargement such as occurs in chronic severe
mitral regurgitation, chronic aortic regurgitation, or dilated cardiomyopathy. [7238]
Pleural effusion
Heart failure can cause transudative pleural effusion due to an increase in pulmonary capillary hydrostatic
pressure. Light criteria are useful to differentiate transudative and exudative pleural effusions; transudative effusions
are characterized by low protein and lactate dehydrogenase content compared to serum values. [7239]
HYPERTENSION
The isolated systolic hypertension commonly seen in elderly patients results from age-related stiffening (ie,
replacement of elastin with collagen) and reduced compliance of the aorta and other large arteries. [456]
Aortic compliance progressively decreases with age, especially in those age >65. This leads to an increase in pulse
pressure, a slight decrease in diastolic pressure, and the characteristic isolated systolic hypertension commonly seen
in the elderly population. [20985]
Hypertrophic cardiomyopathy typically involves asymmetric left ventricular hypertrophy (LVH) that is most prominent
in the interventricular septum and commonly causes left ventricular (LV) outflow tract obstruction. The LVH also
impairs diastolic LV filling, with an S4 commonly heard as blood strikes the thick, stiffened LV wall. [22698]
Hypertrophic cardiomyopathy (HCM) typically involves interventricular septal hypertrophy that obstructs left
ventricular (LV) outflow and creates a systolic murmur that decreases in intensity with maneuvers that increase LV
blood volume (eg, handgrip, passive leg elevation). HCM is characterized by increased LV muscle mass with a small LV
cavity, preserved ejection fraction, and impaired relaxation leading to diastolic dysfunction. [15516]
Pulsus paradoxus refers to an exaggerated drop (>10 mm Hg) in systolic blood pressure during inspiration. It is most
commonly seen in patients with cardiac tamponade but can also occur in severe asthma, chronic obstructive
pulmonary disease, or constrictive pericarditis. [1782]
Aging
Cardiomyocyte hypertrophy (ie, concentric left ventricular hypertrophy) occurs with age to allow for maintenance of
left ventricular contractility and ejection fraction despite cardiomyocyte dropout and increased left ventricular
afterload (due to reduced aortic compliance). [20986]
Normal morphological changes in the aging heart include a decrease in left ventricular chamber apex-to-base
dimension, development of a sigmoid-shaped ventricular septum, myocardial atrophy with increased collagen
deposition, and accumulation of cytoplasmic lipofuscin pigment within cardiomyocytes. [180]

Paradoxical embolization, or passage of a thromboembolism from the venous circulation to the arterial circulation,
most commonly occurs through a patent foramen ovale (PFO). A PFO is a one-way tissue valve in the atrial septum
that opens only when right atrial pressure exceeds left atrial pressure; venous return to the right atrium increases
during the release (ie, relaxation) phase of a Valsalva maneuver and encourages opening of a PFO. [19935]
Av fistula
High-output heart failure results from markedly decreased systemic vascular resistance (eg, large arteriovenous
fistula) that leads to increased venous return and increased cardiac output. Despite a sustained increase in cardiac
output, the left ventricle is unable to keep up with the increased venous return, and decompensated heart failure
develops. [1625]
Cardiac catheterization
Right-sided pressures in the heart are lower than left-sided pressures due to lower resistance in the pulmonary
vasculature. Right ventricular diastolic pressure is similar to right atrial/central venous pressure (1-6 mm Hg),
whereas pulmonary artery diastolic pressure is slightly higher (6-12 mm Hg) due to resistance to flow in the
pulmonary circulation. [1653]
Cardiac physiology
The Fick principle can be applied to calculate cardiac output using the rate of oxygen consumption and the
arteriovenous oxygen content difference:
Cardiac output = rate of O2 consumption / arteriovenous O2 content difference [1529]
The cardiac action potential conduction speed is slowest in the atrioventricular node and fastest in the Purkinje
system. Conduction speed of the atrial muscle is faster than that of the ventricular muscle. [1513]
In cardiac pacemaker cells, phase 0 depolarization is mediated by an inward flux of calcium. This differs from phase 0
of cardiomyocytes and Purkinje cells, which results from an inward sodium current. [1531]
The phase 4 slow depolarization in cardiac pacemaker cells occurs due to the closure of repolarizing K+ channels, the
slow influx of Na+ through funny channels, and the opening of T-type Ca2+ channels. Acetylcholine and adenosine
reduce the rate of spontaneous depolarization in cardiac pacemaker cells by prolonging phase 4. [1975]
A rightward shift of the bottom right corner (point 1) of the left ventricular (LV) pressure volume loop indicates
increased end-diastolic volume or preload, which occurs with infusion of normal saline. The increased preload causes
increased LV stretching and leads to increased stroke volume and a slight increase in afterload (Frank-Starling law).
[1511]
An increase in cardiac contractility shifts the top left corner (point 3) of the left ventricular pressure-volume loop up
and to the left and increases stroke volume due to an increase in the fraction of LV preload that is ejected during
systole (ie, increased ejection fraction). [1510]
Coronary blood flow

During ventricular systole, the coronary vessels supplying the left ventricle are compressed by the surrounding
muscle. As a result, the majority of left ventricular blood flow occurs during diastole. The systolic reduction in
coronary blood flow is greatest in the subendocardial region, making this portion of the left ventricle most prone to
ischemia and infarction. [183]
Myocardial oxygen extraction exceeds that of any other tissue or organ; therefore, the cardiac venous blood in the
coronary sinus is the most deoxygenated blood in the body. Due to the high degree of oxygen extraction, increases in
myocardial oxygen demand can only be met by an increase in coronary blood flow. [2009]
The high systolic intraventricular pressure and wall stress of the left ventricle prevent myocardial perfusion during
systole; therefore, the majority of left ventricular myocardial perfusion occurs during diastole. Shorter duration of
diastole is the major limiting factor for coronary blood supply to the left ventricular myocardium during periods of
tachycardia (eg, exercise). [951]
Coronary autoregulation allows coronary blood flow to be primarily driven by myocardial oxygen demand over a wide
range of perfusion pressures (60-140 mm Hg). It is mostly accomplished by alterations in vascular resistance via
release of adenosine and nitric oxide in response to myocardial hypoxia. [1516]
Heart sounds
An S4 sound is best heard near the cardiac apex at the point of maximal impulse with the patient in the left lateral
decubitus position. It results from the atrial contraction, which forces blood into an LV that has reached its limit of
compliance. Chronic hypertension causes left ventricular hypertrophy, which itself may promote the generation of an
S4 sound. [7618]
An S3 is a low-frequency sound occurring during early diastole, just after S2. Left ventricular gallops (S3 and S4) are
best heard with the bell of the stethoscope over the cardiac apex while the patient is in the left lateral decubitus
position at end expiration. [1557]
Hypovolemia
Hypovolemia due to loss of sodium and/or water causes increased concentration of red blood cells (ie, hematocrit)
and albumin as both of these blood components are trapped within the intravascular space. Hypovolemia also
triggers increased absorption of uric acid in the proximal renal tubule, resulting in an increased serum uric acid level.
[18536]
Calcium efflux from cardiac cells prior to relaxation is primarily mediated via an Na+/Ca2+ exchange pump and
sarcoplasmic reticulum Ca2+-ATPase pump. [1931]
Myocardial infarction causes a sharp decrease in cardiac output due to loss of function of a zone of myocardium. On
a cardiac function curve, myocardial infarction would decrease both the slope and the maximal height of the line.
[1624]
Natriuretic peptides
Atrial natriuretic peptide and brain natriuretic peptide are released from the atria and ventricles, respectively, in
response to myocardial wall stretch due to intravascular volume expansion. These endogenous hormones promote
increased glomerular filtration rate, natriuresis, and diuresis. [157]
Nitric oxide
Nitric oxide is synthesized from arginine by nitric oxide synthase. As a precursor of nitric oxide, arginine
supplementation may play an adjunct role in the treatment of conditions that improve with vasodilation, such as
stable angina. [8563]
Physical exercise
With endurance training, the physiologic changes of athlete's heart allow for increased maximum cardiac output via
an increase in stroke volume. The left ventricle undergoes eccentric hypertrophy to increase left ventricular cavity
size and improve diastolic filling capacity. The resulting increase in end-diastolic volume capacity allows for increased
stroke volume and cardiac output. Because end-diastolic volume and stroke volume are both proportionally
increased, left ventricular ejection fraction is mostly unchanged. [19570]
Intensive endurance training causes cavity enlargement of both the left ventricle and right ventricle to facilitate an
increase in stroke volume and cardiac output. The high stroke volume may cause a pulmonic valve flow murmur.
[19568]
Diastolic blood pressure (DBP) is largely determined by systemic vascular resistance (SVR), and pulse pressure is
largely determined by stroke volume. During aerobic exercise, reduced SVR leads to slightly decreased or unchanged
DBP, and increased stroke volume leads to increased pulse pressure and systolic blood pressure. [19895]
Exercising muscles can receive up to 85% of the total cardiac output during periods of strenuous activity. Although
sympathetic discharge during exercise causes increased cardiac output and splanchnic vasoconstriction, there is only
a modest increase in mean blood pressure as vasodilation within active skeletal muscles significantly decreases the
total systemic vascular resistance. [1622]
The cardiorespiratory response to exercise includes increased heart rate, cardiac output, and respiratory rate in order
to balance the increased total tissue oxygen consumption and carbon dioxide production. These coordinated
adaptations result in relatively constant arterial blood gas values whereas venous oxygen is decreased and venous
carbon dioxide is increased. [1589]
With moderate to heavy exercise, the changes to the left ventricular pressure-volume loop include increased preload
and increased contractility that both contribute to increased stroke volume. Although reduced systemic vascular
resistance decreases afterload, the increase in systolic pressure caused by increased preload and contractility
override the decrease, resulting in overall increased afterload. [19567]
Pulmonary blood flow

The circulatory system is a continuous circuit, and therefore the volume output of the left ventricle must closely
match the output of the right ventricle. This balance is necessary to maintain continuous blood flow through the
body and exists both at rest and during exercise. [1528]

The cardiac myocyte action potential consists of rapid depolarization (phase 0), initial rapid repolarization (phase 1),
plateau (phase 2), late rapid repolarization (phase 3), and resting potential (phase 4). The action potential is
associated with increased membrane permeability to Na+ and Ca++ and decreased permeability to K+. [1974]

Ventricular septal defect causes left-to-right shunting with increased right ventricular pressure and, if large, left-sided
volume overload with increased left ventricular and left atrial pressures. A holosystolic murmur is characteristic, and
failure to thrive and signs of heart failure (eg, poor feeding, diaphoresis) can occur. [19533]
Aortic regurgitation causes an increase in total stroke volume with abrupt distension and rapid falloff of peripheral
arterial pulses, resulting in a wide pulse pressure. This leads to bounding peripheral pulses and head bobbing with
each heartbeat. [1661]
Aortic regurgitation causes a rapid fall in aortic pressure during diastole with an increase in left ventricular end-
diastolic volume and a compensatory increase in stroke volume. These hemodynamic changes create characteristic
pressure changes, including reduced aortic diastolic pressure, increased aortic systolic pressure, and increased left
ventricular diastolic and systolic pressures. [14976]
Cardiac physiology
Ventricular pressure and volume curves allow one to identify the phases of the cardiac cycle and to determine the
exact time of opening and closure of the cardiac valves. The aortic valve opens when left ventricular pressure
exceeds the central aortic pressure at the end of isovolumetric contraction. [1530]
Endocarditis
During the normal cardiac cycle, central aortic pressure is higher than right ventricular pressure during systole and
diastole. Consequently, an intracardiac fistula between the aortic root and right ventricle will most likely
demonstrate a left-to-right cardiac shunt as blood continuously flows from the aortic root (high pressure) to the right
ventricle (low pressure). [12187]
Mitral stenosis
Mitral stenosis is characterized by an opening snap followed by a rumbling diastolic murmur that is best heard over
the cardiac apex. On the left ventricular pressure-volume loop, the opening snap occurs during mitral valve opening
at the end of isovolumetric relaxation, and it is followed by a diastolic rumble during diastolic filling. [1517]
Under normal circumstances, pulmonary capillary wedge pressure (PCWP) closely reflects left atrial (LA) and left
ventricular end-diastolic pressure (LVEDP). Mitral stenosis leads to an increase in the LA pressure that is reflected as
elevated PCWP during pulmonary artery catheterization. Left ventricular filling may be normal, resulting in an
increased pressure gradient between the LA and LV during diastole. [1591]
:Mitral stenosis usually occurs due to underlying rheumatic heart disease and initially presents with exertional
dyspnea. Orthopnea, paroxysmal nocturnal dyspnea, productive cough, and hemoptysis can develop as the disease
becomes more advanced. At rest, left ventricular diastolic pressure, afterload, and contractility remain normal until
the mitral stenosis is severe. [16532]
A holosystolic murmur that increases in intensity on inspiration most likely represents tricuspid regurgitation. The
other holosystolic murmurs (which are secondary to mitral regurgitation or a ventricular septal defect) do not
typically increase in intensity during inspiration. [1983]
Hearing loss
In conductive hearing loss, bone conduction will be greater than air conduction (abnormal Rinne test), and the Weber
test will lateralize to the affected ear. In sensorineural hearing loss, air conduction will be greater than bone
conduction (normal Rinne test), and the Weber test will lateralize to the unaffected ear. [8589]
ADRENAL DISORDERS
Reduced aldosterone production in primary adrenal insufficiency leads to renal sodium wasting with consequent
hypovolemia, orthostasis, and potassium retention (hyperkalemia). Low cortisol stimulates increased antidiuretic
hormone secretion, which leads to water retention and hyponatremia. [17247]
Cryptorchidism
Inhibin B is produced by the Sertoli cells and is the physiological inhibitor of FSH secretion. LH concentration is
controlled primarily by testosterone feedback. [217]
DIABETES MELLITUS
Diabetes mellitus
Cleavage of proinsulin in pancreatic beta-cell secretory granules yields insulin and C-peptide, which are stored in the
granules until they are secreted in equimolar amounts. [1768]
Incretin functions by stimulating insulin release following oral consumption of glucose. Incretin-stimulated insulin
release is independent of the increase in insulin secretion brought on by elevations in the blood glucose level. [6803]
Insulin has both renal and hepatic clearance. In patients with advanced chronic kidney disease and diabetes mellitus,
decreased renal clearance of insulin can lead to symptomatic hypoglycemia if exogenous insulin doses are not
adjusted based on the change in renal function. [15308]
Glucose uptake in skeletal muscle occurs primarily via glucose transporter (GLUT) 4. Muscle contraction and insulin
induce translocation of GLUT4 to the cell surface, increasing glucose uptake during exercise and the fed state,
respectively. Over time, regular exercise causes increased expression of GLUT4, leading to increased skeletal muscle
glucose uptake at any given insulin level and therefore lower blood glucose levels. [19237]
Normal blood glucose levels are maintained by the opposing effects of insulin and glucagon. Glucagon stimulates
hepatic glycogenolysis and gluconeogenesis, whereas insulin increases peripheral glucose uptake and inhibits lipolysis
and ketoacid formation. Insulin also suppresses glucagon release. [1540]
Hypoglycemia
Oxidative metabolism of glucose in pancreatic beta cells generates ATP. ATP-induced closure of the ATP-sensitive
potassium channels leads to membrane depolarization and subsequent insulin release. [1009]
Uptake of glucose by skeletal muscle is mediated by the glucose transporter type 4, which is translocated to the cell
membrane in response to insulin and muscle contraction. Hypoglycemia can be precipitated by exercise in patients
with insulin-treated diabetes due to the persistent effects of exogenous insulin. [1325]
Patients with type 1 diabetes mellitus are at increased risk of hypoglycemia because exogenous insulin will continue
to be absorbed from the injection site despite falling glucose levels. Those with long-standing diabetes may also have
decreased glucagon secretion and therefore have an even greater risk of rapid hypoglycemia. [19224]
Hypothyroidism
Prolactin production is regulated primarily by inhibitory effects of hypothalamic dopaminergic pathways. However,
prolactin secretion is stimulated by thyrotropin-releasing hormone (TRH). In patients with primary hypothyroidism,
the increased production of TRH by the hypothalamus can lead to hyperprolactinemia. [12512]
MISCELLANEOUS
Gynecomastia
The adrenal cortex produces estrogen precursors (eg, androstenedione, dehydroepiandrosterone [DHEA], DHEA
sulfate), which are subsequently aromatized to estrogens in peripheral tissues. In men with hypogonadism (low
testosterone), the resulting elevation in the estrogen/testosterone ratio can produce gynecomastia. [19002]
Oxidative phosphorylation
Brown adipose tissue is found in newborns and in hibernating mammals. Brown adipose cells contain several
intracytoplasmic fat droplets and many more mitochondria than white adipose cells. They function to produce heat
by uncoupling oxidative phosphorylation with the protein thermogenin. [821]
Testicular cancer
Secretion of hCG by testicular germ cell tumors impairs testosterone production in Leydig cells while increasing
aromatase activity and conversion of androgens to estrogens. The resulting increase in the estrogen/androgen ratio
can cause gynecomastia. [19004]
Rickets is characterized by defective mineralization at sites of rapid bone growth. It can be due to deficiency of
calcium or phosphorus. Calcium deficiency conditions are mainly due to vitamin D abnormalities or low dietary
calcium intake. Phosphorus deficiency is usually due to impaired renal reabsorption. [22438]
Vitamin d toxicity
Excessive vitamin D intake can lead to hypercalcemia and cause mental status changes, muscle weakness,
constipation, and polyuria/polydipsia. Activated macrophages in sarcoidosis and other granulomatous diseases
express 1-α-hydroxylase, leading to excess production of 1,25-dihydroxyvitamin D and hypercalcemia. [1065]
NORMAL STRUCTURE AND FUNCTION OF ENDOCRINE GLANDS
Aging
Normal aging in men is associated with a slow decline in gonadal testosterone production, a compensatory rise in LH,
and rising serum levels of sex hormone–binding globulin. Common, nonspecific symptoms include decreased
ejaculate volume, increased erectile latency and sexual refractory time, and moderately impaired erectile function.
[18999]
Hypothyroidism
Congenital hypothyroidism, most commonly caused by abnormal thyroid gland development or location (ie, ectopy),
is identified by elevated TSH and decreased thyroxine (T4) levels. Clinical manifestations of hypothyroidism are not
present at birth due to the transplacental transfer of small amounts of maternal T4. [19753]
Physical exercise
Intense exercise creates a high demand for ATP, and the primary method of ATP production varies with the duration
of exercise. The phosphocreatine shuttle is the primary source of ATP at the beginning of exercise, followed
sequentially by anaerobic glycolysis and then oxidative phosphorylation. [19566]
Obesity
Ghrelin stimulates appetite and promotes weight gain. Leptin and insulin act in the CNS to decrease appetite. Caloric
restriction leads to increased ghrelin levels along with decreased insulin and leptin levels, causing an increase in
appetite that can make it difficult to maintain weight loss. [15201]
Infertility
Pulsatile administration of gonadotropin-releasing hormone (GnRH) stimulates FSH and LH release and is useful for
the treatment of infertility. Nonpulsatile (constant) infusion of GnRH, or a long-acting analog, suppresses FSH and LH
release and subsequently suppresses gonadal function. [208]
Androgen abuse suppresses GnRH, LH, and FSH secretion, leading to reduced endogenous testosterone secretion,
impaired spermatogenesis, and testicular atrophy. In addition, excess testosterone is converted by aromatase to
estradiol, which can lead to gynecomastia. [19007]
LH stimulates the release of testosterone from the Leydig cells of the testes; FSH stimulates the release of inhibin B
from the Sertoli cells in the seminiferous tubules. Testosterone and inhibin B induce negative feedback on LH and
FSH production, respectively. [216]

Following unilateral orchiectomy, the drop in testosterone stimulates pituitary LH secretion, which stimulates
increased testosterone production in the remaining testis and maintains libido, erectile function, and secondary sex
characteristics. However, the loss of sperm-producing tissue usually causes a drop in sperm counts. [13776]
Menopause
Menopause occurs on average at age 51 and is diagnosable retrospectively after 12 months of amenorrhea. An
elevated serum FSH level confirms the diagnosis. [215]
Sexual differentiation
5α-reductase converts testosterone to dihydrotestosterone, which mediates development of the external genitalia in
the male fetus. Male neonates with 5α-reductase deficiency are born with ambiguous genitalia that typically
masculinize at puberty. [954]
THYROID DISORDERS
Euthyroid sick syndrome

Euthyroid sick syndrome (ESS) is a common pattern of thyroid function markers seen in severely ill patients. It is
characterized by decreased conversion of T4 to T3 in peripheral tissues. Initial findings include a low T3 level, but
later, T4 and thyroid-stimulating hormone levels may also decrease. ESS may represent a mild central hypothyroid
state, which functions to minimize catabolism in severe illness. [19745]
Hyperthyroidism
Hyperthyroidism causes increased bone turnover with net bone loss, potentially leading to osteoporosis. The bone
loss is driven by triiodothyronine, which stimulates osteoclast differentiation, increased bone resorption, and release
of calcium. [19946]
In exogenous thyrotoxicosis, radioactive iodine uptake and serum thyroglobulin level are low, indicating suppression
of endogenous thyroid metabolic activity. Serum T3 levels are often elevated. [20148]
Exogenous thyrotoxicosis can be caused by suppressive levothyroxine therapy for thyroid cancer. When exogenous
thyrotoxicosis is due to levothyroxine or mixed T3/T4 supplements, thyroxine (T4) levels are elevated;
triiodothyronine (T3) is produced primarily by the peripheral deiodination of T4, so T3 levels also are elevated even if
the patient is taking T4 only. [20146]
Graves disease is an autoimmune disorder triggered by thyrotropin receptor antibodies (TRAb) that bind and activate
the TSH receptor. Serum TRAb immunoassays have a high sensitivity and specificity for Graves disease. [14951]
The most common cause of secondary hyperthyroidism is a TSH-secreting pituitary adenoma. In addition to
hyperthyroid symptoms, TSH causes generalized hypertrophy of the thyroid gland (diffuse goiter). Laboratory
evaluation shows elevated levels of thyroid hormone (triiodothyronine and thyroxine) and TSH. [20265]
Thyroid hormone resistance is characterized by decreased sensitivity of peripheral tissues to thyroid hormones due to
a defect in the thyroid hormone receptor. Levels of thyroxine, triiodothyronine, and TSH are increased. Patients
classically have goiter and frequently develop attention deficit hyperactivity disorder. [19750]
Hypothyroidism
Thyroxine-binding globulin deficiency is a benign disorder characterized by low total thyroxine (T4) and normal free
T4 and TSH levels. Patients are euthyroid and do not require treatment. [19746]
Congenital goiter in the setting of hypothyroidism (ie, ↑ TSH, ↓ thyroxine) can be caused by transplacental passage
of maternal antithyroid medications (eg, propylthiouracil), which inhibit thyroid peroxidase and are used to treat
maternal hyperthyroidism. [19754]
Thyroid peroxidase (TPO) catalyzes the oxidation of iodide to iodine, the iodination of thyroglobulin tyrosine residues,
and the iodotyrosine coupling reaction that forms T3 and T4. Antibodies against TPO are present in >90% of patients
with chronic lymphocytic (Hashimoto) thyroiditis. [770]
TSH from the anterior pituitary stimulates the thyroid to produce thyroxine (T4) and a small amount of
triiodothyronine (T3). T4 is converted in peripheral tissues to T3 (active form) and reverse T3 (inactive form). TSH
secretion is under negative feedback by thyroid hormone on the hypothalamus and pituitary. [1615]
Primary hypothyroidism is characterized by decreased T4 levels and increased TSH. T3 is primarily produced by
conversion from T4 in peripheral tissues; serum levels widely fluctuate due to its short half life, and can often be
within the normal range in patients with hypothyroidism. [983]
TSH resistance due to a mutation in the TSH receptor gene presents with congenital hypothyroidism, which is
characterized by increased TSH and low thyroxine. The thyroid gland is normal in size and location. [19747]
Hypothyroidism causes decreased expression of LDL receptors in the liver, leading to decreased clearance of LDL and
increased blood LDL levels. It also causes hypertriglyceridemia due to decreased expression of lipoprotein lipase. The
adverse effects of hypothyroidism on lipid levels can increase the risk of coronary atherosclerosis. [14988]
Thyroiditis
Subacute (granulomatous, de Quervain) thyroiditis presents with fever; a painful, tender goiter; and an elevated
erythrocyte sedimentation rate. Patients initially develop hyperthyroidism due to the destruction of thyroid follicles
and release of preformed thyroid hormone. TSH is suppressed due to feedback inhibition on the pituitary; as a result,
thyroid metabolic activity and organification of iodine are decreased, and radioactive iodine uptake is low. [20375]

Polycystic ovary syndrome can present with irregular menses, hyperandrogenism (eg, acne, hirsutism), and
anovulatory infertility. Patients are at increased risk for endometrial hyperplasia and carcinoma due to increased
estrogen production and chronic anovulation. [258]
Menstrual cycles
Intermittent anovulatory cycles are common in the first few years after menarche due to an immature hypothalamic-
pituitary-ovarian axis producing low and irregular GnRH pulses. As a result, adolescent girls may have menstrual cycle
variability with intermenstrual spotting and heavier menstrual bleeding. [1899]
Apoptosis
Progesterone is secreted during the luteal phase of the menstrual cycle and transforms the endometrium from
proliferative to secretory. Progesterone withdrawal causes endometrial cells in the stratum functionalis to undergo
apoptosis, resulting in menstrual bleeding. [299]
Infertility
Anovulatory infertility can be treated with ovulation induction therapy, which may include a course of gonadotropins
to stimulate the ovarian follicles. Once the follicles mature, patients are administered an injection of hCG, which
mimics the LH surge and acts as the ovulation trigger. [207]
LH stimulates the theca interna cells of the ovarian follicle to produce androgens. Aromatase within the follicle's
granulosa cells subsequently converts these androgens to estradiol under FSH stimulation. The theca externa cells
serve as a connective tissue support structure for the follicle. [1560]
Menstrual cycles
The secretory phase of the menstrual cycle occurs between ovulation and menses, from days 15-28 of the normal
menstrual cycle. Progesterone released by the corpus luteum causes the uterine glands to coil and secrete glycogen-
rich mucus in preparation for embryo implantation. The endometrial stroma becomes edematous and completely
traversed by tortuous spiral arteries that extend from the deeper layers to the uterine lumen. [1986]
Cholecystitis
The release of cholecystokinin (CCK) from the duodenum and jejunum after fat-and protein-rich meals stimulates
gallbladder contraction. In patients with gallstones/biliary sludge, this can lead to temporary occlusion of gallbladder
outflow, causing postprandial upper abdominal pain that waxes and wanes with CCK levels ("biliary colic"). [1319]
Breastfeeding
The breast milk content of vitamins D and K is typically insufficient for the nutritional needs of the newborn. Vitamin
K is given parenterally to all newborns at birth to prevent hemorrhagic disease of the newborn. Exclusively breastfed
infants require vitamin D supplementation due to lack of sunlight exposure and to prevent rickets. [1926]
Dietary restrictions
Individuals on a vegan diet are at increased risk for deficiencies in calcium and vitamin D, which may increase the risk
for osteoporosis and bone fractures. Cobalamin (vitamin B12) deficiency can also occur. [19789]
HEPATIC DISORDERS
Aging
Normal age-related changes in the liver include decreased size, decreased perfusion, slower regenerative capability,
and the development of yellowish-brown lipofuscin inclusions within hepatocytes. [21011]
Ascites
Ascites in cirrhosis develops from hemodynamic changes related to portal hypertension. Splanchnic vasodilation
decreases the splanchnic vascular resistance and lowers the effective arterial blood volume, which causes activation
of the renin-angiotensin-aldosterone system and promotes sodium and water retention. Additionally, low oncotic
pressure (ie, hypoalbuminemia due to impaired hepatic function) reduces fluid resorption from the interstitium.
[17905]
Cirrhosis
Portal hypertension in cirrhosis leads to vasodilation and decreased systemic perfusion pressure, which causes
antidiuretic hormone release and activation of the renin-angiotensin-aldosterone system, promoting sodium and
water retention. However, due to resistance to splanchnic flow, low oncotic pressure, and hyperdynamic circulation,
the fluid is third-spaced into the extravascular compartments (eg, ascites). Therefore, despite increased total body
volume, patients with cirrhosis remain intravascularly volume depleted. [17969]
Acute diarrhea
Children with watery diarrhea should be treated with oral rehydration solutions containing hypotonic, equimolar
concentrations of sodium and glucose to help prevent dehydration and electrolyte abnormalities. [15244]
Constipation
Constipation is common during pregnancy and results from the inhibitory effect of progesterone on colonic smooth
muscle contractions and the fasting migrating myoelectric complex. Other common pregnancy-related changes of
the gastrointestinal system include decreased lower esophageal sphincter pressure (leading to gastroesophageal
reflux) and gallbladder stasis (leading to gallstone formation). [17006]
Small intestinal bacterial overgrowth

Small intestinal bacterial overgrowth is caused by bacterial proliferation in the small intestine. In normal individuals,
intestinal peristalsis clears bacteria and reduces the reflux of colonic organisms into the small bowel; however,
patients with impaired gut motility have an increased risk for bacterial overgrowth. [105712]
MISCELLANEOUS
Proton pump inhibitors

Parietal cells release hydrogen ions into the gastric lumen by means of the H/K ATPase, which requires hydrolysis of
ATP and is therefore an active transport mechanism. Omeprazole and other proton pump inhibitors suppress the
activity of the gastric parietal cell H/K ATPase leading to an increase in the pH of the gastric lumen. [1358]
Aging
Elderly patients have decreased saliva production due to acinar atrophy and fatty infiltration of the salivary
glands. Other age-related changes include oral mucosal atrophy; weakening of the muscles of mastication, tongue
muscles, and pharyngeal constrictors; and a decreased sense of taste and smell. As a result, elderly patients are at
increased risk of dysphagia, malnutrition, and pneumonia. [20988]
A number of changes occur in the liver with aging that can affect drug metabolism. Typical changes include
decreased liver mass and blood flow, decreased cytochrome P-450 expression and concentration, and reduced
hepatic regeneration after injury. However, hepatic aminotransferase levels are unchanged. [21033]
Dysphagia
The most important airway-protective movements during swallowing are the anterior/superior displacement of the
larynx, the tilting of the epiglottis to block the airway, and vocal fold adduction. A chin-tuck maneuver can be helpful
in some patients with aspiration by simulating the airway-protective movement of the larynx. [21353]
Gastric physiology
The cephalic and gastric phases stimulate gastric acid secretion, while intestinal influences tend to reduce gastric acid
secretion. [126]
Gastrointestinal hormones
Secretin is produced by S cells in the duodenal mucosa in response to stimulation by intraluminal acidity. Secretin
stimulates the release of bicarbonate-rich secretions from the exocrine pancreas, which is the major source of acid-
neutralizing bicarbonate entering the duodenum. [1546]
Pancreas physiology
Duodenal S-cells secrete secretin in response to increasing H+ concentrations. Secretin increases pancreatic
bicarbonate secretion. The chloride content of pancreatic secretions decreases in proportion to bicarbonate
concentration increases. [1971]
Malabsorption
The duodenal brush border enzyme enteropeptidase activates trypsin from its inactive precursor,
trypsinogen. Trypsin degrades complex polypeptides to dipeptides, tripeptides, and amino acids while activating
other pancreatic enzymes. Enteropeptidase deficiency impairs both protein and fat absorption, leading to diarrhea,
failure to thrive, and hypoproteinemia. [1251]
Vipoma
VIPomas are pancreatic islet cell tumors that hypersecrete vasoactive intestinal peptide (VIP), which increases
intestinal chloride loss into the stool and causes excess losses of the accompanying water, sodium, and
potassium. VIP also inhibits gastric acid secretion. Somatostatin inhibits the secretion of VIP and is used to treat the
symptoms of VIPoma. [1938]
Atrial fibrillation
Direct factor Xa inhibitors (eg, apixaban) are anticoagulants that block the active site of factor Xa, which leads to
reduced conversion of prothrombin to thrombin. This class of medications is administered orally and requires no
drug level monitoring. [14741]

Patients with hematologic malignancies that have high tumor cell burdens or rapid turnover rates are at high risk for
electrolyte abnormalities following the initiation of cytotoxic chemotherapy due to the massive lysis of tumor
cells. Patients generally develop hyperphosphatemia, hyperkalemia, hyperuricemia, and elevated lactate
dehydrogenase. [18769]
Carbon monoxide poisoning

Carbon monoxide (CO) binds to hemoglobin with much higher affinity than oxygen, thereby preventing oxygen
binding to hemoglobin. It also reduces oxygen unloading from hemoglobin in the tissues. CO poisoning increases
carboxyhemoglobin concentrations but does not affect the partial pressure of oxygen and does not precipitate
methemoglobinemia. [1545]
Chronic kidney disease is commonly associated with normocytic anemia due to reduced production of erythropoietin
by the kidneys. Erythropoietin signal transduction is primarily mediated by the Janus kinase 2/signal transducers and
activators of transcription (JAK2/STAT) pathway, which promotes erythrocyte precursor survival. [15323]
Erythropoietin
Erythropoietin (EPO) is produced by peritubular fibroblast cells in the renal cortex in response to decreased renal
oxygen delivery. EPO acts on erythrocyte precursors in the bone marrow to increase red blood cell
production. Patients with chronic kidney disease often have damage to renal EPO-producing cells, which results in
normocytic anemia. [15307]

Hepcidin is synthesized by the liver that acts as the central regulator of iron homeostasis. High iron levels and
inflammatory conditions increase the synthesis of hepcidin; hypoxia and increased erythropoiesis act to lower
hepcidin levels. Low hepcidin levels increase intestinal iron absorption and stimulate iron release by macrophages.
[787]
Polycythemia
Erythrocytosis is defined as a hematocrit level > 52% in men and > 48% in women. Measurement of red blood cell
mass is necessary to distinguish absolute from relative erythrocytosis. A normal red blood cell mass indicates plasma
volume contraction as the cause of polycythemia. [1586]
Blood transfusion
Citrate anticoagulants in high-volume blood transfusion can chelate plasma calcium, leading to hypocalcemia which
causes peripheral neuromuscular excitability (eg, paresthesia, muscle spasms). This is most common with very rapid
transfusion rates, but it can also be seen at lower rates in patients with hepatic insufficiency because citrate is
metabolized by the liver. [1654]
The most important determinant of intravenous infusion rate is the radius (diameter) of the intravenous
catheter. For patients requiring a rapid blood transfusion, the shortest possible catheter with the widest possible
diameter (eg, a large-bore peripheral intravenous catheter) should be selected. [21787]
Androgenic steroids
Adverse effects associated with the use of excessive doses of anabolic steroids include acne, gynecomastia,
azoospermia, decreased testicular size, and increased aggression. When measured, serum testosterone is typically
normal or elevated. However, endogenous testosterone production and spermatogenesis are decreased. [7606]
Contraception
Following vasectomy, viable sperm remain in the portion of the vas deferens distal to the transection. Patients can
still have viable sperm in the ejaculate for up to 3 months and at least 20 ejaculations after the procedure. [8468]
Infertility
Sertoli cells produce inhibin in response to FSH from the anterior pituitary. Inhibin suppresses FSH production in the
pituitary. Sertoli cells also facilitate spermatogenesis within the seminiferous tubules. Impaired Sertoli cell function
would lead to decreased production of inhibin, increased FSH levels, and impaired fertility. [1902]

Following bilateral orchiectomy, extragonadal androgen sources are inadequate to replace the loss of testosterone,
causing a hypogonadal state. Loss of testosterone leads to changes in body composition, including decreased lean
body weight, increased subcutaneous fat, and decreased bone density. Loss of testosterone also leads to a significant
decrease in prostate volume. [19020]
Psychogenic erectile dysfunction often begins abruptly following severe medical (eg, myocardial infarction) or
emotional stressors. The symptoms are often situational, with normal erections at night or during masturbation but
impaired with a partner. Libido is often normal. [19012]
MISCELLANEOUS

People traveling to elevations >2500 m (8000 ft) can develop high-altitude illness, characterized by hypobaric hypoxia
with the potential to develop life-threatening cerebral and/or pulmonary edema. Key adaptive responses to
hypoxemia include hyperventilation to increase blood oxygenation and increased synthesis of 2,3-
bisphosphoglycerate in erythrocytes (facilitating oxygen offloading into peripheral tissues). [12024]
Opioids
Beta-endorphin is one endogenous opioid peptide that is derived from proopiomelanocortin (POMC). POMC is a
polypeptide precursor that goes through enzymatic cleavage and modification to produce not only beta-endorphins,
but also ACTH and MSH. The fact that beta-endorphin and ACTH are derived from the same precursor suggests that
there may be a close physiological relationship between the stress axis and the opioid system. [775]

The pulmonary vascular bed is unique in that tissue hypoxia results in a vasoconstrictive response. Such hypoxic
vasoconstriction occurs in the small muscular pulmonary arteries to divert blood flow away from underventilated
lung regions and toward well-ventilated lung areas to minimize ventilation-perfusion mismatch, leading to more
efficient overall gas exchange. [1587]
Nervous System
Multiple sclerosis
The speed of conduction down an axon depends on 2 constants: the length constant and the time constant (ie,
velocity = length/time). Myelination increases the length constant and decreases the time constant, both of which
improve axonal conduction speed. Demyelination thus impairs stimulus transmission. [1318]
MISCELLANEOUS

A drug that binds to and activates GABA-A receptors (or enhances their activity) will increase the conductance of
chloride ions, leading to increased passive transport of chloride into the cell interior. This causes the membrane
potential to become hyperpolarized (more negative than the resting membrane potential) by approaching or
reaching the equilibrium potential for chloride. [11755]
Circadian rhythm
The suprachiasmatic nucleus regulates circadian rhythms by processing light information from the retina and
modulating body temperature and the production of hormones (eg, cortisol, melatonin). Dyssynchrony between the
local environment (eg, daylight hours, sleep schedules) and internal circadian rhythms can cause insomnia and
daytime sleepiness (ie, jet lag). Melatonin supplementation is recommended for the treatment of insomnia
associated with jet lag. [8573]
Neuronal physiology
Excessive activation of the glutamate NMDA receptor causes excitotoxic neuronal death through uncontrolled
calcium influx. At the hyperpolarized resting membrane potential, the NMDA receptor is blocked by a magnesium
plug, which is released by non–NMDA-mediated depolarization. [19670]
Glutamate is the main excitatory neurotransmitter of the CNS, inducing postsynaptic neuron depolarization and
calcium entry through the NMDA receptor. Calcium entry programs the neuron to depolarize more robustly to
repeated stimulation; this long-term potentiation forms a molecular basis for memory, learning, and addiction. [19722]
The pontine and medullary respiratory centers coordinate normal respiratory drive. Immaturity of these central
respiratory centers causes apnea of prematurity, which is common in extremely preterm newborns. [20275]

The action potential results from changes in the membrane permeability to K+ and Na+ ions. Depolarization results
from massive influx of Na+ through voltage-gated Na+ channels. Repolarization occurs due to closure of voltage-
gated Na+ channels and opening of voltage-gated K+ channels. K+ ion permeance is highest during the repolarization
phase of the action potential. [1380]
Changes in membrane potential occur in response to changes in neuronal membrane permeability to various cellular
ions. The more permeable the membrane becomes for a cellular ion, the more that ion's equilibrium potential
contributes to the total membrane potential. [2007]
Synapse
Voltage-gated sodium channels are important for the generation and propagation of action potentials. When the
action potential reaches the axon terminal, voltage-gated calcium channels open and allow the influx of calcium,
which is essential for the fusion and release of neurotransmitter vesicles into the synaptic cleft. [11682]
Spinal cord injury

The diaphragm is the principal muscle of inspiration and is innervated by the phrenic nerve, which originates from the
C3-5 nerve rootlets. Although expiration is largely achieved through passive recoil, active expiration is aided by the
internal intercostals (innervated by thoracic nerve rootlets) and abdominal muscles (innervated by thoracic and
lumbar nerve roots). [19274]

Carbon dioxide is a potent vasodilator of cerebral vasculature. Tachypnea causes hypocapnia and cerebral
vasoconstriction, thereby decreasing cerebral blood volume and intracranial pressure. [1493]
Ophthalmology
Aging
Presbyopia and skin wrinkles are age-related changes. Presbyopia occurs due to denaturation of structural proteins
within the lens, leading to loss of lens elasticity which can result in improved vision in patients with mild
myopia. Decreased synthesis and increased breakdown of collagen and elastin contribute to the development of skin
wrinkles. [862]
Accidental hypothermia
The hypothalamus controls thermoregulation by promoting alterations in the autonomic nervous system and the
adrenal and thyroid axes. Physiologic adaptations in response to hypothermia include increased sympathetic activity
and thyroid hormone release, shivering, and peripheral vasoconstriction. These actions normalize body temperature
by reducing heat loss and increasing metabolic rate (promoting thermogenesis). [19079]
TOXICOLOGY
Mushroom poisoning
Activation of muscarinic receptors by acetylcholine or cholinergic agonists results in peripheral vasodilation due to
synthesis of nitric oxide in endothelial cells, which leads to vascular smooth muscle relaxation (eg,
hypotension). Muscarinic receptor activation in other sites causes smooth muscle contraction. [1361]
Human placental lactogen creates a fetal glucose-sparing effect by increasing maternal insulin resistance during the
second and third trimesters, leading to a rise in serum glucose that helps provide adequate nutrition to the growing
fetus. Gestational diabetes occurs when the compensatory rise in maternal insulin secretion is inadequate to prevent
serum glucose levels from reaching excessively high levels. [8330]
Supine hypotension
Patients at >20 weeks gestation experience compression of the inferior vena cava by the gravid uterus while in the
supine or right lateral decubitus position. Without substantial collateral blood flow, the consequent reduction in
venous return and cardiac output can cause severe hypotension (supine hypotension syndrome). [8293]
Cardiac physiology
During pregnancy, systemic vascular resistance decreases and plasma blood volume increases. Venous capacitance
and a decrease in pulmonary vascular resistance allow for accommodation of increased blood volume without
affecting central venous pressure (CVP). Despite a normal CVP, peripheral edema is common in pregnancy due to
decreased capillary oncotic pressure that encourages leakage of fluid into dependent peripheral tissues (eg, lower
extremities). [20003]
Pregnant patients have marked increases in blood plasma volume (by 30%-50%) and red blood cell mass (by 20%-
30%), which helps improve fetal nutrient delivery while also protecting against excessive blood loss during
delivery. Because the expansion of blood plasma volume is greater than the increase in red blood cell mass, pregnant
women typically have mildly decreased hemoglobin concentrations (ie, dilutional anemia). [19521]
Normal pregnancy
Physiologic renal adaptations during pregnancy include increased glomerular filtration rate, greater basement
membrane permeability, and decreased tubular resorption of filtered protein. As a result, trace urinary protein
excretion (ie, <300 mg/24 hr) is a normal finding in pregnancy. [19178]
In pregnancy, progesterone is secreted by the corpus luteum and later by the placenta. Although prolactin secretion
increases as pregnancy progresses, high progesterone levels inhibit lactation by preventing binding of prolactin to
receptors on alveolar cells in the breast. [1987]
Pregnancy is a prothrombotic state due to increased procoagulant factors (eg, fibrinogen), decreased anticoagulant
factors (eg, protein S), and reduced fibrinolysis. These physiologic changes protect against maternal hemorrhage with
delivery but increase the risk of peripartum venous thromboembolism. [19588]
Gestational thrombocytopenia is common in the third trimester and is typically mild, asymptomatic, and not
associated with other laboratory abnormalities. It occurs due to hemodilution (ie, maternal plasma volume
expansion) and increased sequestration/consumption of platelets in the placenta. [19586]
Cystic fibrosis
Cystic fibrosis is an autosomal recessive disease caused by mutations in the CF transmembrane conductance
regulator (CFTR) gene. The CFTR protein is a transmembrane ATP-gated chloride channel. Defects in CFTR result in
thick, plugging mucous and elevated sodium and chloride levels in sweat. [1514]
Acute respiratory failure

There are 5 major causes of hypoxemia (low arterial partial pressure of oxygen [PaO2]): alveolar hypoventilation, low
partial pressure of inspired oxygen, ventilation-perfusion mismatch, diffusion impairment, and right-to-left
shunting. The A-a gradient is normal with alveolar hypoventilation and low partial pressure of inspired oxygen, which
helps distinguish these causes from other causes of hypoxemia. [1582]

The total oxygen content of blood (CaO2) is affected primarily by 2 variables: hemoglobin concentration and its
percentage of oxygen saturation (SaO2), which is directly affected by the arterial oxygen tension (PaO2). Anemia is
characterized by decreased hemoglobin concentration in the setting of normal SaO2 and PaO2. [1527]
Respiratory acidosis
Respiratory acidosis presents with low pH and high PaCO2. HCO3− initially remains near normal but becomes
elevated over several days as renal compensation develops. [1357]
Acute benzodiazepine (eg, alprazolam, lorazepam) overdose causes central respiratory depression with
hypoventilation. The hypoventilation leads to CO2 retention and acute respiratory acidosis. It also decreases the
PAO2, leading directly to hypoxemia (PaO2 <75 mm Hg). The efficiency of gas transfer between the lungs and the
circulation is intact; therefore, a normal alveolar-arterial O2 gradient (eg, <15 mm Hg) is expected. [19075]
Sepsis
The initial management of septic shock requires rapid fluid resuscitation to replace intravascular volume and restore
adequate end-organ perfusion. This is best accomplished with intravenous boluses of isotonic crystalloid in the form
of 0.9% (normal) saline or lactated Ringer solution because these solutions remain in the extracellular space. [15240]

Reduction in the slope of the curve depicting lung volume versus distending pressure indicates decreased lung
compliance (the hallmark of pulmonary fibrosis). [1650]
Interstitial lung disease is associated with decreased lung volumes and increased lung elastic recoil caused by fibrotic
interstitial tissue. The increased elastic recoil results in increased radial traction (outward pulling) on the airways,
leading to increased expiratory flow rates when corrected for the low lung volume. [1543]
MISCELLANEOUS
Obesity hypoventilation syndrome

Obesity hypoventilation syndrome commonly presents with chronic fatigue, dyspnea, and difficulty
concentrating. Patients will have BMI >30 kg/m2 and arterial blood gas while awake showing evidence of
hypoventilation, including hypercapnia (PaCO2 >45 mm Hg) and usually hypoxemia (PaO2 <75 mm Hg). The expected
alveolar to arterial oxygen gradient is normal (4-15 mm Hg) with hypoventilation. [1526]
Pleural effusion
Malignant pleural effusions are usually exudative by Light criteria and can occur via several mechanisms, including an
inflammation-induced increase in vascular permeability (leading to increased inflow) and blockage of pleural fluid
reabsorption by parietal pleura lymphatics (leading to decreased outflow). [20175]
Pleural effusion results from an increased rate of fluid inflow from the nearby vasculature or a decreased rate of fluid
outflow through the parietal pleural lymphatics. Decompensated heart failure causes pleural effusion primarily due
to increased fluid inflow from increased pulmonary capillary hydrostatic pressure; lymphatic outflow increases but is
unable to keep up with the increased inflow. [20173]
Pleural fluid normally enters the pleural space via filtration from the systemic circulation, primarily from the
intercostal microvessels of the parietal pleura, and exits the pleural space via stomata in the parietal pleura that drain
into the parietal pleura lymphatics. [20177]
Aging
Normal aging is characterized by decreased respiratory system compliance (increased lung compliance outweighed by
higher chest wall stiffness) and increased dead space (loss of alveolar surface area). For this reason, elderly persons
are less equipped to tolerate illnesses that impair respiratory compliance and/or gas exchange (eg, pneumonia,
pulmonary edema). [21036]
Normal aging is characterized by a gradual increase in ventilation-perfusion mismatch (due to basilar microatelectasis
causing shunt effect) and increased dead space (loss of alveolar surface area). This manifests as a wider alveolar-
arterial oxygen gradient (ie, decline in PaO2) without hypoventilation (normal PaCO2). [21034]
Aging is associated with steady decreases in chest wall compliance but increases in lung compliance due to a loss of
elastic recoil. This results in a marked increase in residual volume, a decrease in forced vital capacity, and relatively
unchanged total lung capacity. [12100]
An array of physiologic responses takes place to maintain adequate O2 delivery to the tissues in the hypoxic
environment at high altitude. These include hypoxic pulmonary vasoconstriction (increased pulmonary vascular
resistance), increased sympathetic activity to increase cardiac output, and aldosterone suppression to reduce plasma
volume. [19062]
At high altitude, the low partial pressure of inspired oxygen (PiO2) leads to hypoxemia that triggers hyperventilation
with increased exhalation of CO2 and resulting respiratory alkalosis. The kidneys compensate by increasing
bicarbonate (HCO3−) excretion to decrease serum HCO3− and help normalize pH. Hypoxemia persists, but
physiologic adjustments take place to improve O2 use. [1980]
Physical exercise
Physiologic changes in the respiratory system that occur with exercise include increased minute ventilation (via both
an increase in respiratory rate and tidal volume), reduced physiologic dead space, increased ventilation-perfusion
ratio, and increased extraction of oxygen by skeletal muscle (resulting in decreased mixed venous oxygen content).
[19571]
Pulmonary gas exchange

Gas exchange between the alveoli and pulmonary capillary blood depends on both perfusion and diffusion. The
exchange of O2 and CO2 in a normal individual at rest is perfusion-limited, so alveolar and capillary partial pressures
are equal. Situations in which O2 exchange becomes diffusion-limited (eg, emphysema, pulmonary fibrosis) cause a
large gradient between alveolar and capillary PO2; PCO2 is less affected due to the greater diffusing capacity of CO2.
[1522]
Respiratory mucosa
The pneumoconioses are diseases resulting from the inhalation of fine dust particles that reach the respiratory
bronchioles and alveoli. Particles that lodge in this region are normally cleared by alveolar macrophages. High
particulate burden can cause the excessive release of cytokines from macrophages, resulting in progressive
pulmonary fibrosis. [536]
Most inhaled particles that lodge in the bronchial tree are removed via proximal transport by ciliated epithelial cells
(mucociliary clearance). Mucus-secreting cells are present to the level of the larger bronchioles, after which club cells
become the prominent secretory cell type. [1548]
Minute ventilation is equal to the product of tidal volume and respiratory rate and includes dead space
ventilation. Alveolar ventilation is equal to the product of respiratory rate and the difference between tidal volume
and dead space volume. [1563]
The lungs generate a collapsing force and the chest wall generates an expanding force; the point at which these
opposing forces are equivalent is the resting equilibrium of the respiratory system, where alveolar pressure is equal
to atmospheric pressure (ie, 0 cm H2O) and lung volume is the functional residual capacity. The opposing forces
create negative intrapleural pressure throughout the respiratory cycle; intrapleural pressure at resting equilibrium (ie,
end-tidal expiration) is approximately -5 cm H2O. [1519]
Both perfusion and ventilation are highest in the base of the lung and lowest in the apex; however, the variability in
perfusion is greater than that in ventilation. This causes the ventilation/perfusion ratio to follow the opposite
gradient: it is lowest in the base and highest in the apex. [1541]
The pO2 in the left atrium and ventricle is lower than that in the pulmonary capillaries due to mixing of oxygenated
blood from the pulmonary veins with deoxygenated blood from the bronchial circulation and thebesian veins. [1542]
Panic attacks are typically accompanied by hyperventilation, leading to hypocapnia. Cerebral blood flow is directly
related to the arterial partial pressure of CO2; therefore, hypocapnia can lead to reduced cerebral blood flow and
symptoms of cerebral hypoperfusion (eg, blurred vision, dizziness, lightheadedness). [1494]
During physical exercise, there is increased skeletal muscle CO2 production that increases the CO2 content of venous
blood. Arterial O2 and CO2 content remains constant via increases in alveolar ventilation and gas exchange
efficiency. Venous O2 content remains constant or is decreased due to increased O2 extraction by the tissues that
matches or exceeds the rate of oxygen delivery (ie, O2 consumption during exercise is limited by cardiac output).
[1590]
The airway resistance at each level of the lower respiratory tract is inversely related to the total cross-sectional area
of all the airways at that level. Airway resistance is high in the trachea and reaches a peak in the medium-sized
bronchi, where total cross-sectional area is at a minimum. Airway resistance then progressively decreases as total
cross-sectional area increases through the smaller bronchioles, terminal bronchioles, and alveoli. [481]
The majority of CO2 produced in the tissues is transported to the lungs as bicarbonate ion (HCO3−). Within red blood
cells (RBCs), the enzyme carbonic anhydrase forms HCO3− from CO2 and water. The excess HCO3− is then
transferred out of RBCs into the plasma via exchange with chloride ions (Cl−). This exchange is known as "chloride
shift" and is the principal cause of high RBC chloride content in venous blood. [1414]
COPD
In chronic obstructive pulmonary disease, air-trapping leads to an increase in residual volume (RV) and total lung
capacity (TLC), as well as an increase in the RV/TLC ratio. Airway obstruction causes a decrease in forced vital
capacity (FVC), forced expiratory volume in 1 second (FEV1), and the FEV1/FVC ratio. [7601]
Chronic obstructive pulmonary disease causes air trapping and hyperinflation; consequently, these patients breathe
at higher baseline lung volumes (higher functional residual capacity). The absolute volume of air in the lungs that is
not respired (residual volume) increases substantially, as does the fraction of air in the lungs that is not involved in
respiration (residual volume/total lung capacity ratio). [1521]
Arterial partial pressure of carbon dioxide (PaCO2) is the major stimulator of respiration in healthy individuals; even a
slight increase in PaCO2 stimulates central chemoreceptors and triggers increased ventilation. In patients with
chronic obstructive pulmonary disease, the response to PaCO2 is blunted and hypoxemia can contribute to
respiratory drive. Peripheral chemoreceptors are primarily responsible for sensing arterial partial pressure of oxygen
(PaO2) and can be suppressed with oxygen administration. [1583]
Pulmonary embolism
Pulmonary embolism causes dead space ventilation, which leads to hypoxemia due to the consequent
ventilation/perfusion mismatch. [7660]
Patients being weaned from mechanical ventilation typically breathe at low tidal volumes, with a compensatory
increase in respiratory rate to maintain minute ventilation. Because at low tidal volumes a higher proportion of each
breath is composed of dead space, this type of breathing leads to an increase in wasted ventilation (inefficient
breathing). [7661]
Pulmonary embolism is common in hospitalized and postoperative patients, and classically presents with sudden-
onset shortness of breath and pleuritic chest pain. It causes hypoxemia due to ventilation/perfusion mismatch;
arterial PCO2 is usually normal or decreased. [1584]
The combination of calf swelling, history of prolonged immobility, and sudden-onset dyspnea is strongly suggestive of
acute pulmonary embolism (PE). PE typically presents with hypoxemia due to ventilation/perfusion mismatch and
acute respiratory alkalosis (hypocapnia) due to hyperventilation. [1981]
BONE METABOLISM
Hypercalcemia
Parathyroid hormone (PTH) causes increased bone resorption, increased serum calcium levels, and increased renal
phosphate excretion. Chronically high levels of PTH increase the risk of osteoporosis. However, intermittent
administration of recombinant PTH analogs (eg, teriparatide) induces a greater increase in osteoblast activity in
proportion to osteoclast activity and a net increase in bone formation. [641]
Hypocalcemia
Postoperative hypocalcemia is common after thyroid surgery, due to inadvertent removal or damage to the
parathyroid glands. The acute drop in parathyroid hormone level results in decreased calcium and phosphate
resorption from bone and decreased calcium reabsorption by the kidneys. [11660]

Vascular calcifications occur more commonly in patients with chronic kidney disease due to electrolyte abnormalities
(eg, hyperphosphatemia, hypercalcemia) and chronic inflammation (secondary to atherosclerosis and/or
uremia). These changes promote calcification and suppress calcification inhibitors, which can result in extensive
vascular calcifications. [15280]
Chronic kidney disease can cause hyperphosphatemia due to impaired renal excretion of phosphorus. Elevated blood
phosphate triggers the release of fibroblast growth factor 23, which lowers calcitriol production and intestinal
calcium absorption. The resulting hypocalcemia, along with hyperphosphatemia, leads to secondary
hyperparathyroidism. [15291]
When the glomerular filtration rate (GFR) is normal, relatively large decreases in GFR result in only small increases in
serum creatinine. Conversely, when the GFR is significantly decreased, small decrements in GFR produce relatively
large changes in serum creatinine. A good rule of thumb is that every time GFR halves, serum creatinine doubles.
[8881]
Creatinine, a waste product generated by the breakdown of creatine in the muscles, is used to estimate the
glomerular filtration rate (GFR). Creatinine formation is dependent on muscle mass and meat intake; therefore,
patients with low muscle mass (eg, elderly patient, those with amputations) or low intake (eg, low-protein vegetarian
diet) can have significantly lower GFRs for any given creatinine level. [16300]

Unilateral renal artery stenosis causes hypoperfusion and activation of the renin-angiotensin-aldosterone
system. Angiotensin II causes arteriolar vasoconstriction and increases aldosterone and antidiuretic hormone
synthesis. The resultant hypertension helps reduce the decline in glomerular filtration rate in the affected kidney, but
causes a pressure natriuresis with increased sodium excretion in the unaffected kidney. [15273]
DIABETES INSIPIDUS
Diabetes insipidus
The ascending limb of the loop of Henle is impermeable to water regardless of serum vasopressin
levels. Reabsorption of electrolytes by the Na+/K+/2Cl- cotransporter occurs in the thick ascending limb and
contributes to formation of the corticomedullary concentration gradient. [1043]
Patients with diabetes insipidus (DI) are unable to concentrate their urine in response to dehydration. Following
desmopressin administration during the water deprivation test, urine osmolality increases to normal levels in central
DI but does not change in complete nephrogenic DI. [211]
Vasopressin and desmopressin cause a V2 receptor-mediated increase in water and urea permeability at the inner
medullary collecting duct. The resulting rise in urea reabsorption (decreased urea clearance) enhances the medullary
osmotic gradient, allowing the production of maximally concentrated urine. [2012]
Urinalysis
Antidiuretic hormone acts on the medullary segment of the collecting duct to increase urea and water reabsorption,
allowing for the production of maximally concentrated urine. [1161]
Diabetic ketoacidosis (DKA) is characterized by polydipsia, polyuria, and a fruity odor to the breath and/or urine. DKA
is associated with elevated anion gap metabolic acidosis that is usually accompanied by compensatory respiratory
alkalosis. This combination yields a low pH, low serum bicarbonate, and low PaCO2. [2014]
The kidneys compensate for metabolic acidosis by completely reabsorbing filtered bicarbonate (HCO3-) and excreting
excess H+ in the urine. Most of the excreted H+ is buffered by phosphate (H2PO4-) and ammonium (NH4+), which
allows for large amounts of acid to be excreted without precipitously dropping the pH. [2008]

At high altitude, the low partial pressure of inspired oxygen (PiO2) leads to hypoxemia with consequent
hyperventilation and respiratory alkalosis. The hypoxemia and alkalemia can cause symptoms of altitude sickness
(eg, headache, fatigue, lightheadedness). The kidneys respond by creating a compensatory metabolic acidosis and by
increasing erythropoietin secretion. [6792]
Hyperphosphatemia
Patients with chronic kidney disease (CKD) can develop hyperphosphatemia due to decreased filtration of
phosphate. Fibroblast growth factor 23 (FGF23) is secreted in response to hyperphosphatemia and lowers plasma
phosphate by reducing intestinal absorption and renal reabsorption of phosphate. FGF23 levels are useful as an early
marker of abnormal phosphate metabolism in patients with CKD. [19634]
Hypokalemia
Hypokalemia can result from the intracellular shift of potassium, which can occur due to beta-adrenergic
hyperactivity (eg, beta-2 agonists, endogenous epinephrine release), increased insulin levels, elevated extracellular
pH, or increased cell production (eg, acute leukemia). [16978]
Hypophosphatemia
Refeeding syndrome occurs after the reintroduction of carbohydrates in patients with chronic malnourishment,
which stimulates insulin secretion and drives phosphorus intracellularly in an effort to maintain cellular energy
metabolism (eg, ATP production); this redistribution of phosphorus can result in severe hypophosphatemia. [18867]
Hypovolemia
Regardless of the patient's hydration status, the majority of water reabsorption in the nephron occurs in the proximal
tubule passively with the reabsorption of solutes. [1524]
Loop diuretics
Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin synthesis. Patients with intravascular volume
depletion (eg, cirrhosis) are dependent on the vasodilatory effects of prostaglandins to maintain adequate renal
plasma flow and glomerular filtration. NSAID use in this population reduces glomerular filtration rates and blunts the
effects of loop diuretics, leading to sodium and water retention. [684]
Metabolic acidosis
Severe diarrhea causes substantial loss of bicarbonate (HCO3−) in the stool and is a common cause of nonanion gap
metabolic acidosis. Low blood pH (<7.35) and low serum HCO3− (<24 mEq/L) are expected with compensatory low
arterial partial pressure of carbon dioxide (PaCO2) (compensatory respiratory alkalosis). [18879]
Advanced chronic kidney disease typically involves the accumulation of unmeasured acidic compounds in the blood;
therefore, anion gap metabolic acidosis with respiratory compensation is expected. [15290]
Primary metabolic acidosis is characterized by a pH <7.35 (ie, acidemia), low serum HCO3−, and a compensatory low
PaCO2. An anion gap (Na+ − [HCO3− + Cl−]) above normal (ie, 10-14 mEq/L) indicates a high anion gap metabolic
acidosis. [107616]
The infusion of excessive normal saline (sodium chloride) is a common cause of nonanion gap metabolic acidosis. The
excess intravascular chloride (Cl−) causes intracellular shifting of bicarbonate (HCO3−), reducing serum HCO3− and
decreasing blood pH. [18933]
Nonanion gap metabolic acidosis (NAGMA) results from the loss of bicarbonate (HCO3−) (usually from the kidneys or
gastrointestinal tract), leading to a relative increase in H+. Common causes include renal tubular acidosis and severe
diarrhea. NAGMA is also referred to as hyperchloremic acidosis because the decrease in serum HCO3− is
compensated for by an increase in serum chloride to maintain electronegative balance. [18878]
Salicylate poisoning causes mixed primary respiratory alkalosis and primary anion gap metabolic acidosis. Mixed acid-
base disturbances can be recognized by inappropriate secondary compensation for one of the primary disturbances,
indicating that an additional primary disturbance must be present. [7557]
MISCELLANEOUS
Hyperparathyroidism
Primary hyperparathyroidism is characterized by oversecretion of parathyroid hormone despite normal (or elevated)
serum calcium levels. Parathyroid hormone raises serum calcium and lowers serum phosphorus by increasing bone
resorption (freeing calcium and phosphate), increasing renal reabsorption of calcium, and decreasing proximal
tubular reabsorption of phosphate. [18863]
Hyperaldosteronism
Elevated serum aldosterone levels can manifest with hypertension, hypokalemia, and muscle weakness. Increased
levels of both renin and aldosterone are indicative of secondary hyperaldosteronism, which can be caused by
renovascular disease and renin-secreting tumors. [2013]

Erythropoietin (EPO) is produced primarily by peritubular fibroblast cells in the renal cortex in response to decreased
renal oxygen delivery (eg, decreased blood hemoglobin content). EPO acts on erythrocyte precursor cells in the bone
marrow to stimulate red blood cell production. Patients with chronic kidney disease have inflammatory damage to
renal EPO-producing cells and often develop normocytic anemia due to insufficient EPO. [15324]
Creatinine clearance
Glomerular filtration rate (GFR) can be assessed using an ideal filtration marker that is freely filtered across the
glomerulus and is not metabolized, secreted, or reabsorbed by the kidney tubules. In common practice, GFR is
estimated using creatinine clearance. However, creatinine is actively secreted by the proximal tubules, so
uncorrected creatinine clearance overestimates the GFR by approximately 10%-20%. [18861]
Diabetes mellitus
Glucose is reabsorbed from the proximal tubule by sodium-glucose cotransporter-2 (SGLT-2). Normally, nearly all
filtered glucose is reabsorbed. SGLT-2 inhibitors lower the threshold at which filtered glucose can be fully
reabsorbed; this increases urinary glucose losses and lowers blood glucose levels. [6772]

Renal excretion of a drug is dependent on:
- Glomerular filtration (reduced with low renal blood flow, kidney disease and high drug protein binding)
- Renal tubular secretion (reduced by coadministration of drugs with overlapping substrate specificity)
- Tubular reabsorption (may be altered by changes in urine pH) [2011]
Enuresis
Primary nocturnal enuresis (ie, bed-wetting at age ≥5 without prior nighttime urinary continence) is caused primarily
by a brain maturational delay in the development of bladder control. [20243]
GFR
Increases in the capillary hydrostatic pressure or the Bowman's space oncotic pressure will increase GFR, while
increases in capillary oncotic pressure or Bowman's space hydrostatic pressure will decrease GFR. The filtration
fraction (FF) can be calculated by dividing the GFR by the renal plasma flow (RPF). Increases in GFR or decreases in
RPF will increase the FF. [1618]
Acute ureteral constriction or obstruction decreases the glomerular filtration rate and filtration fraction. [1651]
Selective vasoconstriction of the efferent arteriole (up to certain extent) increases hydrostatic pressure in the
glomerular capillaries, and therefore increases the glomerular filtration rate. As efferent arteriolar constriction
continues to increase, the glomerular filtration rate begins to decrease due to a flow-mediated rise in oncotic
pressure in the glomerular capillaries. The filtration fraction always increases with increasing efferent arteriole
constriction. [1017]
At normal plasma concentrations of glucose, the renal tubules reabsorb the entire filtered load of glucose because it
is below the maximum tubular reabsorption ability (transport maximum of glucose). At higher plasma
concentrations, glucose is excreted when the filtered amount exceeds the transport maximum. The serum
concentration at which glucosuria begins, called the threshold of glucose, is approximately 200 mg/dL. [2010]
Pregnancy results in significant plasma expansion and widespread vasodilation, leading to increased renal plasma
flow and glomerular filtration rates. Serum creatinine is reduced by approximately 0.4 mg/dL in this population;
therefore, a rise in serum creatinine, even to levels that are normal in nonpregnant patients, represents significant
renal dysfunction. [19177]
The glomerular filtration rate (GFR) can be estimated by the inulin or creatinine clearance, while the renal plasma
flow (RPF) is calculated using the para-aminohippuric acid clearance. The filtration fraction (FF = GFR / RPF) is the
fraction of the RPF that is filtered across the glomerular capillaries into Bowman's space. It is usually equal to 20% in
healthy individuals. [1555]
The net filtration pressure is a result of pressure gradients formed by Starling forces and is calculated by subtracting
the oncotic pressure gradient from the hydrostatic pressure gradient. Angiotensin II preferentially constricts the
efferent arteriole, resulting in an increased hydrostatic pressure gradient and an increased net filtration pressure.
[1354]
Lithium
Diffusion speed across a semipermeable membrane increases with higher molecular concentration gradients, larger
membrane surface areas, and increased solubility of the diffusing substance. Diffusion speed decreases with
increased membrane thickness, smaller pore size, higher molecular weights, and lower temperatures. [1988]
Nephron structure & physiology

The filtration fraction is the fraction of plasma flowing through the glomeruli that is filtered across the glomerular
capillaries into Bowman's space (FF = GFR/RPF). Renal plasma flow can be determined from renal blood flow by
multiplying the renal blood flow by (1 – Hematocrit). [1982]
Dehydration stimulates ADH secretion. ADH acts on the collecting ducts, increasing their permeability to
water. Thus, in the presence of ADH, the collecting ducts contain the most concentrated fluid in the nephron, while
the distal convoluted tubule contains the most dilute fluid. [1608]
Antidiuretic hormone (ADH) acts primarily on the collecting ducts, increasing their permeability to water. In the
absence of ADH, the tubular fluid is most concentrated at the junction between the descending and ascending limbs
of the loop of Henle and most dilute in the collecting ducts. [1607]
K+ is freely filtered by the glomeruli and is mostly reabsorbed in the proximal tubule and loop of Henle. As such, the
late distal and cortical collecting tubules are the primary sites for regulation of K+ excretion in the urine. K+ depletion
stimulates α-intercalated cells to reabsorb extra potassium; principal cells secrete K+ under conditions of increased
K+ load. [1554]
The concentrations of creatinine and urea increase as fluid runs along the proximal tubule, whereas the
concentrations of bicarbonate, glucose, and amino acids decrease. Sodium and potassium are reabsorbed with water
in the proximal tubule, resulting in no concentration change. [1617]
Dehydration (eg, hypotension, high plasma osmolarity) increases circulating levels of antidiuretic hormone, increasing
the water permeability of the collecting duct and allowing production of highly concentrated urine. In the
dehydrated state, tubular fluid osmolarity will be lowest at the beginning of the distal convoluted tubule (ie, terminus
of loop of Henle). [6707]
In chronic kidney disease, conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D is impaired. In addition,
failure of glomerular and tubular function results in phosphate retention and hypocalcemia. This leads to a
compensatory rise in parathyroid hormone (secondary hyperparathyroidism) that can present with weakness, muscle
and joint pain, defective bone mineralization, and increased fracture risk. [991]
Sunlight exposure catalyzes conversion of 7-dehydrocholesterol to cholecalciferol (vitamin D3) in the

skin. Subsequent 25-hydroxylation in the liver and 1-hydroxylation in the kidneys produce 1,25-dihydroxyvitamin D,
the active form. Inadequate exposure to sunlight can lead to vitamin D deficiency. [990]
Bone remodeling
Bone-specific alkaline phosphatase levels correlate with osteoblast activity. Other markers of osteoblast activity
include N-terminal propeptide of type 1 procollagen, which is released during post-translation cleavage of type 1
procollagen. [638]
Osteoporosis
Regular exercise leads to increased peak bone mass, a reduced rate of bone loss, and a decreased risk of
osteoporosis. [628]

Osteoclasts originate from hematopoietic progenitor cells. Macrophage colony-stimulating factor and receptor for
activated nuclear factor kappa-B ligand (RANK-L) play an important role in osteoclast differentiation. Paget's disease
of bone is characterized by increased numbers of abnormal osteoclasts, excessive bone turnover and disorganized
bone remodeling. [639]

The H band is the region of the sarcomere that contains only thick (myosin) filaments. The H band is the part of the A
band (which is on either side of the M line) where thick filaments have no overlapping thin (actin) filaments. [1664]
The muscle spindle system is a feedback system that monitors and maintains muscle length, while the Golgi tendon
system is a feedback system that monitors and maintains muscle force. GTOs are exquisitely sensitive to increases in
muscle tension but are relatively insensitive to passive stretch. [8266]
The contractile mechanism in skeletal muscle depends on proteins (myosin II, actin, tropomyosin, and troponin) as
well as calcium ions. [7592]
During skeletal muscle contraction, calcium is released from the sarcoplasmic reticulum and binds troponin C,
thereby allowing the binding of actin to myosin. [1558]
Postural skeletal muscles such as the soleus and paraspinal muscles contain predominantly Type I, slow twitch muscle
fibers that derive ATP primarily via oxidative (aerobic) metabolism. [1858]
Muscle contraction involves continuous actin-myosin cross-bridge cycling driven by release of sarcoplasmic calcium
stores. After death, loss of ATP prevents both myosin head detachment and clearance of cytoplasmic calcium,
leading to diffuse and persistent skeletal muscle stiffening (rigor mortis). [1665]
Transverse tubules (T-tubules) are invaginations of the sarcolemma that transmit depolarization signals to the
sarcoplasmic reticulum to trigger the release of calcium and induce muscle contraction. The uniform distribution of
T-tubules in striated muscle fibers ensures that each myofibril contracts at the same time, which is necessary for
efficient contraction. [824]
Physical exercise
Type I muscle fibers (slow-twitch or red fibers) primarily use oxidative phosphorylation and contain high quantities of
lipids, myoglobin, and mitochondria. They specialize in sustained, low force contraction, and their function is
amplified by endurance training. Type II muscle fibers (fast-twitch or white fibers) primarily use glycolysis and
specialize in rapid bursts of high force contraction. Their function is amplified by resistance training. [19565]
Psychiatric/Behavioral & Substance Abuse
Psychiatric/Behavioral & Substance Abuse
ANXIETY AND TRAUMA-RELATED DISORDERS
Adjustment disorders
Adjustment disorder involves emotional or behavioral symptoms occurring within 3 months of an identifiable
stressor. The diagnosis is indicated when the patient has significant distress and impairment but does not meet full
criteria for another mental disorder. [15348]
Evaluation of depressive symptoms occurring in response to psychosocial stressors must take into account the
severity, duration, and degree of functional impairment. Mild or brief sadness without significant interference in
psychosocial functioning is consistent with normal sadness. [11619]
Anxiety
When benzodiazepines are used in the treatment of anxiety, drug selection should consider the medication's
duration of action. Short- to intermediate-acting benzodiazepines (eg, lorazepam) are preferred in situations in which
prolonged side effects of sedation and cognitive impairment must be minimized. [1352]
The differential diagnosis of anxiety includes medical conditions and substance-induced etiologies (eg, intoxication,
withdrawal). Primary anxiety disorders are not diagnosed when anxiety is caused by the physiological effects of a
medical condition (eg, hyperthyroidism) or drug. [11866]
Benzodiazepines
Benzodiazepines bind GABA A receptors, resulting in an increased frequency of chloride channel opening in the
presence of GABA. Indications for prescribing include short-term treatment of anxiety disorders and alcohol
withdrawal syndrome. [1443]
Benzodiazepines act by binding to the benzodiazepine binding site, which allosterically modulates the binding of
GABA, resulting in an increased frequency of chloride ion channel opening. The influx of chloride ions into the
neurons causes neuronal hyperpolarization and inhibition of the action potential. [937]
Generalized anxiety disorder

Buspirone is a nonbenzodiazepine anxiolytic used to treat generalized anxiety disorder. It has a slow onset of action,
lacks muscle relaxant or anticonvulsant properties, and carries no risk of dependence. [247]
Generalized anxiety disorder involves excessive uncontrollable worry about multiple issues with a symptom duration
of ≥6 months. Associated symptoms include restlessness, muscle tension, fatigue, sleep disturbance, irritability, and
difficulty concentrating. [2048]
Serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors are first-line medications for
generalized anxiety disorder. Benzodiazepines should be limited to short-term use while antidepressants take effect
and avoided in patients with a history of substance abuse. [248]
Illness anxiety disorder

Illness anxiety disorder is characterized by excessive concern about having a serious, undiagnosed disease, despite
few or no symptoms and negative medical workup. [15732]
Obsessive compulsive disorder

Obsessive-compulsive disorder (OCD) is characterized by persistent, intrusive thoughts leading to repetitive, ritualistic
behaviors. Selective serotonin reuptake inhibitors are considered first-line treatment for OCD and exert their effects
by inhibiting serotonin reuptake. [2049]
Obsessive-compulsive disorder is characterized by persistent, unwanted thoughts (obsessions) and repetitive, time-
consuming rituals (compulsions) that the individual feels driven to perform to alleviate anxiety. [11825]
Panic disorder
Panic disorder consists of recurrent and unexpected panic attacks characterized by an abrupt surge of anxiety and
distressing cardiopulmonary/neurologic symptoms. Agoraphobia, a common comorbid disorder, results in anxiety
about and avoidance of situations where patients may feel trapped and helpless in the event of a panic attack (eg,
crowds, enclosed spaces, public transportation). [15701]
Panic disorder involves recurrent, unexpected panic attacks characterized by an abrupt surge of fear accompanied by
physical and cognitive symptoms. Individuals experience persistent worry about future attacks and typically restrict
their activities as a result. [11751]
Selective serotonin reuptake inhibitors are first-line pharmacotherapy for panic disorder. Benzodiazepines are
reserved for patients who require immediate relief but should be avoided in those with substance misuse. [11838]
Panic disorder is characterized by recurrent anxiety attacks associated with prominent somatic symptoms. Abrupt
onset of characteristic physical symptoms that resolve within minutes and a negative medical workup should raise
suspicion for panic disorder. [15700]
Post traumatic stress disorder

Post-traumatic stress disorder is characterized by intrusive thoughts, nightmares, flashbacks, avoidance of trauma
reminders, hypervigilance, and sleep disturbance lasting ≥1 month. [2123]
Acute stress disorder is characterized by intrusive experiences (flashbacks, nightmares), arousal (poor concentration,
restless sleep), dissociative symptoms, and avoidance of traumatic reminders, as well as mood disturbances in
response to a life-threatening trauma. Symptoms last between 3 days and 1 month. [15349]
First-line treatment for post-traumatic stress disorder includes trauma-focused cognitive-behavioral therapy and
antidepressant medication. Selective serotonin reuptake inhibitors have the best evidence for efficacy. [11846]
Separation anxiety disorder
Separation anxiety disorder consists of excessive and distressing anxiety (≥4 weeks in children, ≥6 months in adults)
due to separation from attachment figures. Children with this disorder often experience physical symptoms and
nightmares. [11789]
Social anxiety disorder

Social anxiety disorder involves excessive fear of scrutiny or embarrassment in social or performance situations,
resulting in significant distress and functional impairment. [11759]
Social anxiety disorder is characterized by anxiety and fear of scrutiny in social situations and can result in marked
social-occupational impairment. Preferred pharmacotherapy is medication that inhibits serotonin reuptake (eg, SSRIs
or SNRIs). [15481]
Somatic symptom disorder

Somatic symptom disorder is best managed with regularly scheduled medical visits that are not contingent on having
active symptoms. Unnecessary diagnostic testing and specialist referrals should be avoided. [10581]
Specific phobia
Specific phobia is a common anxiety disorder characterized by high levels of anxiety and panic attacks triggered by
exposure, or anticipation of exposure, to a feared stimulus. As a result, these patients try to avoid the phobic
stimulus whenever possible. [15601]
Exposure-based cognitive-behavioral therapy, in which patients are systematically confronted with their feared
objects or situations, is the most effective long-term treatment for specific phobia. [11603]
EATING DISORDERS
Anorexia nervosa
Anorexia nervosa is characterized by a distorted body image and fear of weight gain despite significantly low body
weight. Patients may restrict their food intake and/or binge and purge. The key in distinguishing anorexia nervosa
from bulimia nervosa is abnormally low body weight. [15501]
Body dysmorphic disorder

Body dysmorphic disorder involves fixation on a perceived defect in appearance and repetitive behaviors in response
to the fixation. It can present with absent insight/delusional beliefs and result in significant psychosocial dysfunction.
[1346]
Bulimia nervosa
Hypokalemia in an otherwise healthy young adult with a normal BMI and preoccupation with body size is concerning
for self-induced vomiting associated with bulimia nervosa. Common physical examination findings in bulimia nervosa
include tachycardia, hypotension, painless bilateral parotid gland swelling, calluses or scarring on the dorsum of the
hand, and erosion of dental enamel. [15500]
Bulimia nervosa is characterized by episodes of binge eating and compensatory weight-reduction behaviors. Signs of
self-induced vomiting include hypokalemia, metabolic alkalosis, parotid gland enlargement, dorsal hand calluses, and
dental erosion. [1843]
Treatment options for bulimia nervosa include nutritional rehabilitation, cognitive-behavioral therapy, and
pharmacotherapy with selective serotonin reuptake inhibitors. Fluoxetine is the drug of choice. [11807]
Bulimia nervosa (BN) is characterized by recurrent episodes of binge eating followed by compensatory behaviors to
prevent weight gain (eg, fasting, exercising, vomiting, using laxatives). In contrast to patients with anorexia nervosa,
BN patients are normal weight to overweight. [2050]
Dietary restrictions
Abrupt dietary and other behavioral changes are common in adolescents and are often due to benign
reasons. However, an eating disorder (eg, anorexia nervosa) should also be considered, especially in a patient with a
low or low-normal BMI. [21433]

Pica is the compulsive consumption of a nonfood substance. It is often associated with iron deficiency anemia, which
is common during pregnancy, and other forms of nutritional deficiency (eg, zinc). [8893]
MISCELLANEOUS
Bulimia nervosa
Binge eating disorder is the most common eating disorder. It is differentiated from bulimia nervosa by the absence of
compensatory behaviors (eg, self-induced vomiting, excessive exercise). [15499]
Conversion disorder
Conversion disorder is characterized by neurologic symptoms and examination findings that are incompatible with a
known neurological disease. Patients do not consciously produce the symptoms like in factitious disorder or
malingering, and the condition may cause significant distress/impairment. [1433]
Delirium
Delirium is a reversible, acute-onset confusional state characterized by a fluctuating level of consciousness with
deficits in attention, memory, and executive function. In contrast, dementia has a gradual onset, is irreversible, and
does not involve fluctuations in consciousness. [2122]
Delirium may manifest as acute changes in cognition and behavior. When nonpharmacological interventions are
ineffective, low-dose antipsychotics (eg, haloperidol) are the medications of choice to treat the behavioral (eg, severe
agitation) and psychotic manifestations of delirium. [11899]
Dissociative amnesia
Dissociative amnesia involves an isolated inability to recall important autobiographical information that is
inconsistent with ordinary forgetfulness. It typically occurs abruptly following an overwhelming, traumatic event.
[15522]
Factitious disorder
Malingering is a behavior characterized by intentional falsification or exaggeration of symptoms to obtain an obvious
external reward. The presentation is typically based on a subjective report of symptoms, and these patients
commonly refuse to undergo invasive medical procedures. [15733]
Frontotemporal dementia presents with early personality change, executive dysfunction, compulsivity, and
hyperorality. Neuropathologic findings include neurofibrillary tangles due to abnormal tau proteins (also seen in
Alzheimer dementia) and pathologically ubiquitinated TDP-43 (also seen in amyotrophic lateral sclerosis). [15443]
Gender dysphoria
Gender dysphoria is characterized by a strong and persistent desire to live and be treated as another gender, which
causes distress or impairment. It is often accompanied by a desire to change one's primary or secondary sexual
characteristics. [15486]
Mild cognitive impairment

Mild cognitive impairment is diagnosed when cognitive decline is present but activities of daily living (eg, bathing,
preparing meals, managing finances) are preserved. In contrast, dementia is diagnosed when cognitive decline
interferes with activities of daily living. [15442]

Neuroleptic malignant syndrome (NMS) is characterized by severe muscular rigidity, mental status changes,
autonomic dysregulation, and hyperthermia. Dopamine antagonism, the mechanism of action of most
antipsychotics, has been implicated as a primary cause of NMS. [20474]

Obstructive sleep apnea is characterized by sleep-related apnea/choking spells, loud snoring, disrupted sleep,
excessive daytime somnolence, and symptoms that may overlap with depression (eg, low mood, fatigue, impaired
concentration). [15641]
Opioids
Buprenorphine is a semisynthetic opioid with mixed/partial agonist-antagonist activity, resulting in a therapeutic
ceiling. Relative to full opioid agonists, this reduces the risk of dose-dependent adverse effects such as respiratory
depression. [13994]
Parasomnias
REM sleep behavior disorder (RBD) is a parasomnia characterized by dream-enactment behaviors due to a loss of
atonia during REM sleep. Most patients with idiopathic RBD eventually develop a disorder of alpha-synuclein
neurodegeneration, most commonly Parkinson disease. [15521]
REM sleep behavior disorder

REM sleep behavior disorder is a parasomnia characterized by dream-enactment behaviors due to a loss of atonia
during REM sleep. Patients can usually be awakened fairly easily, are alert and oriented, and can immediately recall
their dreams. [20920]
Serotonin syndrome
Coadministration of tramadol with serotonergic medications such as selective serotonin reuptake inhibitors increases
the risk of serotonin syndrome, which presents with the characteristic triad of mental status changes (agitation,
confusion), autonomic instability (hyperthermia, diaphoresis), and neuromuscular hyperactivity (tremor, myoclonus).
[15608]
Urinary retention
Tricyclic antidepressants have strong anticholinergic properties. Potential side effects include confusion,
constipation, and urinary retention. These medications should be used with caution in elderly patients. [575]
MOOD DISORDERS
Antidepressants
Bupropion is a first-line antidepressant that is not associated with sexual side effects or weight gain. However, it is
associated with an increased seizure risk at high doses and is contraindicated in patients with seizure disorders,
anorexia nervosa, and bulimia. [704]
Antidepressants (eg, selective serotonin reuptake inhibitors) take 4-6 weeks to achieve maximal clinical effect. [15607]
Sexual dysfunction is seen in up to 50% of patients treated with selective serotonin reuptake inhibitors. Bupropion, a
norepinephrine-dopamine reuptake inhibitor, is a first-line treatment for major depressive disorder and does not
cause sexual dysfunction. [706]
Bipolar disorder
Lithium and the anticonvulsants valproate, carbamazepine, and lamotrigine are mood-stabilizing agents used in
bipolar disorder. Valproate is commonly used in the treatment of generalized as well as myoclonic seizures. [1193]
Patients experiencing a major depressive episode should be carefully screened for past manic episodes to rule out
bipolar disorder. Antidepressant monotherapy should be avoided in patients with bipolar disorder due to the risk of
precipitating mania. [11607]
The anticonvulsant valproate has mood-stabilizing properties and is an effective maintenance treatment for bipolar
disorder. Other maintenance options for bipolar disorder include lithium, lamotrigine, and quetiapine. [1348]
Bipolar I disorder is diagnosed in patients with ≥1 episodes of mania. Manic episodes are characterized by
elevated/irritable mood, impulsivity, hyperactivity, decreased need for sleep, pressured speech, and grandiosity and
may occur with psychotic features. [11758]
Patients who experience major depressive and hypomanic episodes are diagnosed with bipolar II disorder. In
contrast to manic episodes, hypomanic episodes are less severe, do not involve psychosis, and cause a lesser degree
of functional impairment. [11587]
Manic episodes are characterized by euphoric/irritable mood, impulsivity, hyperactivity, decreased need for sleep,
pressured speech, racing thoughts, and grandiosity. They may occur with or without psychotic features. [15730]
Antidepressant monotherapy can induce mania in susceptible patients, especially those with unrecognized bipolar
disorder. [518]
The goal of bipolar maintenance treatment is to delay or prevent recurrent manic and depressive episodes. Lithium is
first-line treatment and has the added benefit of reducing the risk of suicide. [15389]
Depression
Monoamine oxidase inhibitors are particularly useful in patients with treatment-resistant major depressive disorder
with atypical features. Increased appetite and sleep, leaden paralysis, rejection sensitivity, and mood reactivity are
hallmarks of the atypical subtype. [573]
Patients with sufficient depressive symptoms are diagnosed with major depressive disorder even if there is a clear
psychosocial stressor that precipitated the depression. [11622]
Major depressive disorder can present with loss of interest or pleasure without depressed mood. Patients may seek
treatment in the primary care setting for somatic symptoms such as fatigue, sleep disturbance, and pain. [15462]
Most available antidepressants target the neurotransmission of serotonin or norepinephrine, or both. Inhibition of
serotonin reuptake by blocking the serotonin transporter is the primary mechanism of action of selective serotonin
reuptake inhibitors. [11854]
Postpartum depression is diagnosed using the same diagnostic criteria used for major depressive episodes that occur
outside the postpartum period. It should be differentiated from postpartum blues, which is a milder and self-limited
form of depression that peaks at 5 days and resolves within 2 weeks. [15492]
Suicide risk assessment includes consideration of both risk and protective factors. A history of a previous suicide
attempt is the strongest single risk factor for further attempts and completed suicide. [11618]
Major depressive disorder (MDD) with psychotic features is a severe subtype of unipolar major depression
characterized by symptoms meeting the criteria for MDD and the presence of delusions and/or hallucinations. [11617]
Depression-related cognitive impairment refers to cognitive impairment that occurs in the context of major
depressive disorder (MDD), which may be mistaken for mild cognitive impairment or dementia. [15447]
Electroconvulsive therapy is a first-line treatment for major depressive disorder with psychotic features. It is
appropriate for severely depressed patients who require rapid intervention (eg, suicidal). [15385]
Somatic symptoms of depression (weight loss, low energy, sleep disturbance) are less reliable indicators of major
depressive disorder in patients with advanced medical illness. Focusing on nonsomatic symptoms, such as loss of
interest, anhedonia, worthlessness, excessive guilt, and suicidality, can assist in diagnosing comorbid depression in
these patients. [15384]
Postpartum mood disturbances include postpartum blues, postpartum depression, and, rarely, postpartum
psychosis. The most common disturbance, postpartum blues, is a benign, self-limited condition that begins several
days postpartum and resolves within 14 days without intervention. [1430]
Dysthymia
The DSM-5 diagnosis of persistent depressive disorder (dysthymia) is characterized by chronic depressed mood and at
least 2 other depressive symptoms lasting for at least 2 years. [1347]
Dystonia
Acute dystonic reaction is characterized by sudden, involuntary contraction of a major muscle group. It is a type of
extrapyramidal symptom and a common adverse effect of antipsychotic medications, particularly high-potency, first-
generation antipsychotics such as haloperidol. [105280]
Hypothyroidism
Hypothyroidism and nephrogenic diabetes insipidus are the most common adverse effects of long-term lithium
therapy. Serum TSH and renal function (blood urea nitrogen and creatinine) should be monitored routinely. [520]
Lithium
Chronic lithium toxicity (eg, confusion, ataxia, neuromuscular excitability) can be precipitated by volume depletion
and drug interactions with thiazide diuretics, ACE inhibitors, and nonsteroidal anti-inflammatory drugs. [519]
Lithium toxicity can be caused by drug interactions with nonsteroidal anti-inflammatory drugs, thiazide diuretics, ACE
inhibitors, tetracyclines, and metronidazole. Signs of lithium toxicity include confusion, ataxia, and tremor. [15388]
Monoamine oxidase inhibitors

Monoamine oxidase (MAO) is a mitochondrial enzyme that breaks down monoamine neurotransmitters (eg,
dopamine, norepinephrine, serotonin). Tyramine-induced hypertensive crisis can occur in patients taking MAO
inhibitors who consume foods containing high amounts of tyramine (eg, aged cheeses, cured meats, draft beer). [572]
Selective serotonin reuptake inhibitors

Selective serotonin reuptake inhibitors (SSRIs) have improved tolerability and a better side-effect profile compared
with tricyclic antidepressants and monoamine oxidase inhibitors but are associated with sexual
dysfunction. Physicians should routinely inquire about sexual dysfunction because it is a relatively common side
effect of SSRIs that may lead to nonadherence. [576]
Serotonin syndrome
Coadministration of selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase (MAO) inhibitors can
produce excessive synaptic serotonin levels secondary to decreased reuptake and decreased degradation of
serotonin, potentially causing serotonin syndrome. To avoid this risk, a 2-week washout period after discontinuing an
MAO inhibitor and before initiating SSRI therapy is required to allow sufficient time for MAO regeneration. [773]
Suicide
Access to firearms greatly increases the risk of completed suicide. Evaluation of a patient's access to guns is a key
part of suicide risk assessment. Other interventions to reduce suicide risk include decreasing stress, increasing
psychosocial support, treating psychiatric illness and substance use, and managing pain. [9814]
Patients with suicidal thoughts should be assessed for intent and plan. Patients with active suicidal ideation and
intent who have made preparations to carry out a specific method of suicide are at highest risk. [15454]
Depressed adolescents may display irritable rather than depressed mood, declining academic performance, and
withdrawal from social activities. Initial evaluation of all children and adolescents with suspected depression should
include a careful suicide risk assessment. [15452]
Tricyclic antidepressants
Tricyclic antidepressant overdose can cause fatal cardiac arrhythmias and refractory hypotension due to inhibition of
fast sodium channels in cardiac myocytes. Sodium bicarbonate is used to treat associated cardiac toxicity and works
by increasing serum pH and extracellular sodium (alleviating fast sodium channel blockade). [574]
NEURODEVELOPMENTAL DISORDERS
Attention deficit hyperactivity disorder

Attention-deficit hyperactivity disorder (ADHD) often persists into adulthood. Adults with ADHD are less overtly
hyperactive but experience chronic problems with distractibility, disorganization, and impulsivity that cause
significant social and occupational impairment. [15283]
Attention-deficit hyperactivity disorder is characterized by a pattern of inattention and/or hyperactivity/impulsivity

that interferes with functioning in ≥2 settings. [11732]
Decreased appetite and insomnia are the most common adverse effects of psychostimulant medications used to treat
attention-deficit hyperactivity disorder. They are usually mild and can be managed without stopping the medication.
[11809]
Diagnosis of attention-deficit hyperactivity disorder requires evidence of inattentive and/or hyperactive/impulsive

symptoms for ≥6 months in ≥2 settings (eg, home, school, after-school program). Teacher evaluations can assist in
diagnosis. [15285]
Stimulant medications are a first-line treatment for attention-deficit hyperactivity disorder. They work by increasing
the availability of norepinephrine and dopamine in the prefrontal cortex. [11784]
Atomoxetine is a norepinephrine reuptake inhibitor that can be considered as an alternate to stimulants in the
treatment of patients with attention deficit hyperactivity disorder who have a personal or family history of substance
abuse. [15282]
Autism spectrum disorders

Patients with milder forms of autism spectrum disorder frequently have normal language and cognitive
development. Characteristic features include deficits in social communication and reciprocal social interactions,
restricted interests, and behavioral rigidity that become more apparent as social and academic demands increase.
[15286]
Autism spectrum disorder is characterized by impaired social communication/interactions and restricted, repetitive
interests or behaviors. It can occur with or without language and intellectual impairment. [11737]
Conduct disorder
Conduct disorder involves a persistent pattern of violating major societal norms or the rights of others. Behaviors
include aggression toward people and animals, deceitfulness or theft, destruction of property, and serious violation
of rules. [11828]
Impulse control disorders

Intermittent explosive disorder is characterized by recurrent episodes of explosive verbal or physical aggression. The
aggressive behaviors are impulsive and grossly out of proportion to the provocation. [15482]
Language disorder
At age 2, children should have a vocabulary of 50-200 words and be using 2-word phrases. Parents' concerns about
delayed milestones should be validated; they should be reassured that children often catch up but may need
help. Further evaluation and regular monitoring are required. [11810]
Learning disorders
Learning disorders are characterized by difficulties with key academic skills (reading, writing, or mathematics),
resulting in performance well below expectations for age. Providers should consider a possible learning disorder in
any school-aged child with behavioral, academic, or social difficulties at school. [11814]
Oppositional defiant disorder

Oppositional defiant disorder is a behavioral disorder of childhood characterized by argumentative and defiant
behavior toward authority figures. It does not involve the more severe violations of the basic rights of others seen in
conduct disorder. [11592]
Rett syndrome
Rett syndrome is characterized by loss of speech and motor skills, deceleration of head growth, and stereotypic
purposeless hand movements after a period of normal development. It affects mainly girls and is associated with
mutations in the MECP2 gene. [11796]
Rett syndrome is a genetic disorder characterized by normal development until age 6-18 months, when regression of
speech, loss of purposeful hand movements, development of stereotypical movements, and gait abnormalities
occur. Neuropathology shows arrested brain development rather than neurodegeneration. [20300]
Tourette syndrome
Tourette syndrome is a common childhood neuropsychiatric disorder characterized by both vocal and multiple motor
tics. These tics characteristically wax and wane, can be suppressed temporarily, and are preceded by a premonitory
urge. [11874]
Wilson disease
Wilson disease is associated with copper accumulation in the liver, brain, and cornea. It can present in childhood or
adolescence with abnormal liver function tests and/or neuropsychiatric symptoms. Psychiatric symptoms may
predate other manifestations and include personality changes, depression, mania, and/or psychosis. [15602]
NORMAL BEHAVIOR AND DEVELOPMENT
Behavioral responses
Classical conditioning involves a neutral stimulus being repeatedly paired with a non-neutral stimulus that elicits a
reflexive, unconditioned response. Over time, the formerly neutral stimulus is able to evoke a conditioned response
by itself in absence of the non-neutral stimulus. [1729]
Child and adolescent mental health

Adolescence often involves some degree of moodiness, intense self-consciousness, and transient emotional
outbursts. Assessment of severity, persistence, and degree of social and academic impairment can help differentiate
normal adolescent behavior from behavioral changes requiring further evaluation. [11586]
Defense mechanisms
Splitting is a defense mechanism that involves organizing experiences of the self or others into extremes to keep
positive and negative aspects separated. It is commonly seen in patients with borderline personality disorder. [1350]
In displacement, emotions are transferred from the person causing the negative emotions to a more neutral, less
threatening person or object. [1234]
Suppression is a mature defense mechanism involving a conscious choice not to dwell on a particular thought or
feeling. [1351]
Projection is an immature defense mechanism involving the misattribution of one's unacceptable feelings or thoughts
to another person who does not actually have them. [1429]
Transference is the unconscious shifting of emotions associated with a significant person from one's past to a person
in the present. [2053]
Countertransference consists of a provider's response (eg, attitudes, thoughts, feelings, behaviors) toward a patient
based on past personal relationships. Countertransference can be positive or negative, conscious or unconscious; if
unrecognized, it may have detrimental effects on patient care. [15242]
Passive aggression is the expression of angry feelings in a nonconfrontational manner. [2051]
Reaction formation is a defense mechanism that involves replacing unacceptable feelings and impulses with their
extreme opposites. [1459]
Developmental milestones
By age 3, a child is expected to play imaginatively in parallel with others, speak in simple sentences, copy a circle, use
utensils, and ride a tricycle. [1781]
Grief
Normal grief presents with symptoms similar to those of a major depressive episode. However, in normal grief,
pervasive anhedonia, worthlessness, and suicidality are not present. [11773]
Preschool children have not developed an understanding of the finality of death, which typically occurs around age
7. They may have magical thoughts that death is temporary or reversible and believe that other people's grief is their
fault. [15493]
Transient behavioral disturbances are common in children after the death of a loved one. Hallucinations of recently
deceased relatives are part of a normal grief reaction and may not be indicative of major psychiatric illness. [10465]
Mental status examination

Quick clinical tests to assess attention and concentration include counting down from 100 by intervals of 3 or 7,
reciting the months of the year in reverse order, and spelling "world" backwards. [8295]
Normal child development

Although children understand the concept of gender by age 4, it is normal for them to explore activities culturally
associated with the opposite gender. In contrast, gender dysphoria is diagnosed when there is marked distress
associated with a prolonged and intense feeling that one is a different gender from one's birth sex. [11875]
Short attention span and varying degrees of hyperactivity and impulsivity are commonly seen in children under age
4. Attention-deficit hyperactivity disorder should not be diagnosed until age 4-5. [15284]
Stranger anxiety, which presents as crying or screaming when unfamiliar people approach, is a normal and expected
part of childhood development. It typically begins around age 6 months and resolves by 2 years of age. [15488]
Treatment adherence
Adolescents have low treatment adherence rates due to issues with autonomy, rebellion against authority, increased
self-consciousness, and a lack of understanding of potential risks. Peer behavior has a strong influence on adherence
due to adolescents' desire to fit in with their social groups. [11785]
PERSONALITY DISORDERS
Personality disorders
Borderline personality disorder is characterized by a persistent pattern of unstable relationships, mood lability, and
impulsivity. Individuals with this disorder may exhibit suicidal ideation or behavior in the context of an interpersonal
crisis in which they feel rejected or abandoned. [11593]
Schizotypal personality disorder is characterized by a long-standing pattern of eccentric behavior, odd beliefs,
perceptual distortions, and social anxiety despite familiarity. [11606]
Antisocial personality disorder involves a pattern of violating the rights of others, engaging in unlawful behaviors (eg,
physical aggression, illegal occupations), and lacking remorse for transgressions. Individuals must be age ≥18 for
diagnosis and have a history of conduct disorder prior to age 15. [15357]
Individuals with paranoid personality disorder exhibit a lifelong pattern of pervasive suspicion and distrust. Unlike
patients with psychotic disorders, they do not have fixed delusions and other psychotic symptoms. [11594]
Schizoid personality disorder consists of a persistent pattern of social detachment, preference for solitary activities,
and constricted range of affect in social interactions. [15358]
Avoidant personality disorder is a maladaptive pattern of behavior characterized by social inhibition, feelings of
inadequacy, and fear of embarrassment and rejection. [1431]

Patients with orbitofrontal cortex injury often experience personality changes, disinhibition, and irritability secondary
to impairment of the behavioral and emotional modulatory systems. [7752]
PSYCHOTIC DISORDERS
Alzheimer disease
Psychotic symptoms (eg, delusions, hallucinations) are common in Alzheimer disease and increase with the severity
of illness. [15399]
Antipsychotics
Second-generation antipsychotics block 5-HT2A receptors and have lower binding affinity at dopamine D2 receptor
sites, which is associated with a lower risk of extrapyramidal side effects. [15397]
First-generation antipsychotics can be classified according to high or low potency and have characteristic side effect
profiles. Low-potency antipsychotics are more likely to cause sedation, anticholinergic side effects, and orthostatic
hypotension. High-potency antipsychotics are more likely to cause extrapyramidal symptoms (eg, dystonia, akathisia,
parkinsonism). [515]
Tardive dyskinesia consists of abnormal involuntary movements of the mouth, tongue, face, extremities, or trunk
associated with prolonged exposure to antipsychotics. Characteristic movements include lip smacking, facial
grimacing, tongue protrusions, and choreoathetoid movements of the head, limbs, and trunk. [511]
Patients treated with clozapine are required to have regular monitoring of the absolute neutrophil count due to the
risk of life-threatening agranulocytosis. [516]
As a class, second-generation antipsychotics are associated with metabolic adverse effects (eg, weight gain,
dyslipidemia, hyperglycemia, increased risk of diabetes). Within the class, olanzapine and clozapine carry the
greatest risk. [11848]
Antipsychotic medications work by blocking dopamine-2 receptors in the mesolimbic dopamine pathway. Dopamine-
2 receptor blockade in the tuberoinfundibular pathway can result in galactorrhea and amenorrhea. [513]
Drug-induced parkinsonism is an extrapyramidal side effect caused by medications that block D2 receptors (eg,
antipsychotics). Management strategies include decreasing or discontinuing the offending medication and treatment
with an anticholinergic medication. [261]
The secretion of prolactin is controlled by the inhibitory effect of hypothalamic dopamine. Risperidone and other
antipsychotics cause hyperprolactinemia by blocking D2 receptors on lactotrophs. Elevated prolactin leads to
amenorrhea (inhibition of gonadotropin-releasing hormone release), galactorrhea, and breast soreness. [222]
Akathisia is an extrapyramidal side effect of antipsychotic medication characterized by inner restlessness and an
inability to sit or stand in one position. Treatment involves a reduction in the antipsychotic dose, if possible, or the
addition of a beta blocker or benzodiazepine. [510]
Delirium
Because disruption of the sleep-wake cycle is both a risk factor and manifestation of delirium, facilitation of nocturnal
sleep (eg, minimizing noise & patient interventions, appropriate day/night lighting) is helpful for delirium prevention
and management. [15410]
Dystonia
Second-generation antipsychotics are associated with a lower risk of extrapyramidal side effects compared with first-
generation antipsychotics but may cause adverse metabolic effects. [15416]

Neuroleptic malignant syndrome (NMS) is an adverse reaction to antipsychotic medication characterized by severe
"lead-pipe" rigidity, hyperthermia, sympathetic hyperactivity, and mental status changes. NMS is characterized by
severe rigidity rather than the neuromuscular irritability (eg, hyperreflexia, myoclonus) seen in serotonin syndrome.
[512]
Psychosis
Huntington disease is an autosomal dominant, progressive neurodegenerative disorder characterized by chorea,
psychiatric symptoms, and dementia. Psychiatric symptoms may occur early in the disease course and include
irritability, anxiety, apathy, depression, and psychosis. [15328]
Brief psychotic disorder is characterized by ≥1 psychotic symptoms lasting >1 day and <1 month with full return to
previous levels of functioning. Onset is typically sudden and associated with a stressor. [15253]
In addition to positive psychotic symptoms (eg, delusions, hallucinations, disorganization), patients with
schizophrenia frequently exhibit negative symptoms such as flat affect (ie, lack of facial expression). Negative
symptoms typically persist between acute psychotic episodes and are more resistant to treatment. [15252]
Schizophreniform disorder is characterized by psychotic symptoms (delusions, hallucinations, disorganized speech

and behavior, negative symptoms) lasting ≥1 month and <6 months. [2063]
Antipsychotic medications are first-line pharmacotherapy for schizophrenia. Their primary mechanism of action is D2
receptor antagonism. [15254]
Delusional disorder is characterized by ≥1 delusions for ≥1 months in the absence of other psychotic
symptoms. Behavior is not obviously bizarre, and functioning is not significantly impaired apart from the direct
impact of the delusions. [2046]
Schizoaffective disorder
For diagnosis of schizoaffective disorder, psychosis must occur in the absence of major mood episodes, but mood
episodes must be present for a majority of this lifelong illness. In bipolar disorder and major depression with
psychotic features, psychotic symptoms occur exclusively during mood episodes. [2047]
Schizophrenia
The antipsychotic clozapine is the drug of choice for treatment-resistant schizophrenia. Treatment requires
monitoring of the absolute neutrophil count due to the risks of neutropenia and agranulocytosis. [11743]
Positive symptoms of schizophrenia (eg, delusions, hallucinations) are associated with increased activity of dopamine
in the mesolimbic pathway. Antipsychotics work by antagonizing dopamine receptors in this pathway. [15327]
Schizophrenia is diagnosed in patients with signs of disturbance for ≥6 months, including at least 1 month of ≥2 of the
following active symptoms (with at least 1 from the first 3): delusions, hallucinations, disorganized speech,
disorganized/catatonic behavior, and negative symptoms. [106670]
Favorable prognostic factors in schizophrenia include predominantly positive psychotic symptoms, acute onset
(shorter prodrome) with an identifiable precipitant, and older age at onset. [15326]
The diagnosis of schizophrenia requires ≥2 of the following 5 symptoms: delusions, hallucinations, disorganized
speech, grossly disorganized behavior, and negative symptoms. The total impairment duration must be ≥6 months.
[2045]
Substance-induced psychotic disorder

Stimulant intoxication can present with paranoid ideation and must be differentiated from primary psychiatric
disorders. Physical signs of stimulant intoxication include mydriasis, tachycardia, hypertension, and diaphoresis.
[11605]
SOMATOFORM DISORDERS
Depersonalization disorder
Depersonalization/derealization disorder is a dissociative disorder involving recurrent episodes of feeling detached
from one's body or surroundings and/or feelings of unreality. [11824]
Factitious disorder
Factitious disorder is characterized by the intentional falsification of symptoms or induction of illness. In factitious
disorder, the goal is to assume the patient role, and there is no obvious external reward. [11792]
SUBSTANCE USE DISORDERS
Alcohol use disorder

The opioid antagonist naltrexone is a first-line pharmacotherapy for moderate-to-severe alcohol use disorder, and
works by preventing the reinforcing effects of alcohol use. [11577]
In the transtheoretical stages of change model, the preparation stage represents the stage in which the individual has
committed to behavioral change and is considering change strategies but has not determined or instituted a specific
course of action. Individuals at this stage may be weighing options and seeking additional support. [11787]
Alcohol withdrawal
Alcohol withdrawal should be considered in hospitalized patients who develop tremulousness, agitation, and
elevated pulse and blood pressure within 48 hours following admission. Benzodiazepines act as a substitute for the
effects of alcohol on GABA receptors, preventing alcohol withdrawal from occuring. [350]
Chronic alcohol use downregulates inhibitory GABA receptors and upregulates excitatory NMDA glutamate
receptors. Therefore, sudden cessation of alcohol leads to decreased GABA activity and increased glutamate activity,
resulting in CNS overexcitation (eg, agitation, disorientation, tremulousness, autonomic hyperactivity). [15738]
Tremulousness is typically one of the earliest symptoms of alcohol withdrawal. Other common symptoms include
gastrointestinal distress, agitation, anxiety, and autonomic disturbance. Delirium tremens is the most severe
manifestation of alcohol withdrawal and typically begins 48-96 hours after the last drink. [870]
Benzodiazepines
Benzodiazepine withdrawal is characterized by anxiety, tremor, insomnia, and sympathetic hyperactivity (eg,
diaphoresis, palpitations). Severe benzodiazepine withdrawal may also be accompanied by psychosis, seizures, or
death. [13907]
Cannabis
Marijuana contains tetrahydrocannabinol, which stimulates cannabinoid receptors to produce a mild euphoria with
inappropriate laughter, increased appetite, slowed reaction time/motor speed, and cognitive
impairment. Tachycardia and conjunctival injection are the 2 most immediate physical symptoms of marijuana use.
[1289]
Cocaine
Cocaine is a stimulant that inhibits the presynaptic reuptake of norepinephrine, dopamine, and
serotonin. Intoxicated patients develop agitation, tachycardia, hypertension, and light-responsive mydriasis due to
increased sympathetic activity. Cocaine is also a potent vasoconstrictor that can cause myocardial ischemia and
atrophy of the nasal mucosa and septum. [2001]
Cocaine withdrawal is characterized by the development of acute depression accompanied by fatigue, hypersomnia,
hyperphagia, and vivid dreams. [11746]
Cocaine intoxication can produce psychotic symptoms (eg, paranoid delusions), euphoria, and agitation. Physical
signs indicating sympathetic stimulation (eg, tachycardia, diaphoresis, mydriasis) can assist in differentiating cocaine
intoxication from primary psychiatric disorders. [15615]
Fetal alcohol syndrome

Typical features of fetal alcohol syndrome include facial dysmorphism (short palpebral fissures, thin upper lip, smooth
philtrum), growth retardation, neurological abnormalities, and behavioral difficulties. [15609]
Inhalants
Inhalant intoxication is characterized by immediate onset of euphoria, lethargy, ataxia, and/or loss of consciousness
followed by rapid recovery within 45 minutes. Perioral and perinasal dermatitis (ie, "glue sniffer's rash") may be seen
in chronic users. [15613]
Neonatal abstinence syndrome

Neonatal abstinence syndrome is caused by infant withdrawal to opiates (eg, heroin) and usually presents in the first
few days of life. It is characterized by irritability, a high-pitched cry, poor sleeping, tremors, seizures, sweating,
sneezing, tachypnea, poor feeding, vomiting, and diarrhea. [106226]
Opioids
Most patients with acute pain (eg, trauma, post-operation) have significant improvement within 3-5 days and may be
prescribed a brief course of opioid medication for breakthrough pain with low risk of addiction. Physicians should
minimize opioid duration and dose, counsel patients on proper use, and maximize concurrent non-opioid therapies
(eg, NSAIDs). [20736]
Buprenorphine is a partial opioid receptor agonist that binds with high affinity but has low intrinsic activity. In
patients on long-term opioid therapy, buprenorphine can displace other opioids and precipitate withdrawal. [774]
Chronic opioid therapy can lead to tolerance (ie, increased amount of opioids to achieve the same pain relief),
physical dependence (ie, development of withdrawal symptoms after abrupt cessation), and opioid use disorder (ie,
uncontrolled use despite harmful effects). [106307]
Opioid withdrawal is marked by mydriasis, abdominal pain, diarrhea, piloerection, lacrimation, and yawning. It is
generally nonlife-threatening, unlike withdrawal from alcohol and benzodiazepines. [1353]
Methadone is a potent, long-acting opioid agonist used in the maintenance treatment of opioid use disorder. Its
prolonged effects suppress withdrawal symptoms and cravings . [1287]
Naloxone is a pure opioid receptor antagonist used to treat opioid intoxication or overdose. Although it binds to mu,
kappa, and delta opioid receptors, it has the greatest affinity for mu receptors (which mediate opioid-induced
bradycardia and respiratory depression), making it an ideal agent for treating opioid intoxication. [1256]
Methadone is a mu-opioid receptor agonist used for maintenance treatment for opioid use disorder; it is metabolized
by the cytochrome P-450 system, particularly by CYP3A4. Certain inhibitors of CYP3A4 (eg, azoles, fluvoxamine,
ciprofloxacin, clarithromycin, cimetidine) can increase plasma methadone concentration and lead to opioid toxicity
(eg, sedation, respiratory depression, miosis). [18668]
Phencyclidine
Phencyclidine (PCP) is a hallucinogen that causes dissociative symptoms, agitation, hallucinations, and violent
behavior. Ataxia, nystagmus, and memory loss are other distinguishing symptoms of PCP abuse. [1288]
Phencyclidine (PCP) is primarily an N-methyl-D-aspartate receptor antagonist, with lesser effects on the reuptake
inhibition of biogenic amines and other receptors. It can have dissociative and anesthetic effects but may also cause
psychosis and severe agitation, leading to violent trauma. Ataxia, horizontal and vertical nystagmus, and memory
loss can also be present. [1165]
Stimulants
Stimulant withdrawal is characterized by dysphoric mood, fatigue, hypersomnia, hyperphagia, and vivid dreams. In
contrast to many other withdrawal syndromes, stimulant withdrawal is not associated with significant findings on
physical examination. [15616]
Substance use disorders

Physicians have a responsibility to identify signs of potential drug-seeking behavior and prescription drug
misuse. This involves being alert to red flags (eg, lost or stolen medication, pain inconsistent with physical
examination) and attempting to clarify medication history by using prescription drug–monitoring programs or other
information sources. [11829]
Thiamine deficiency
Several enzymes involved in glucose metabolism (eg, pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase)
require thiamine as a cofactor. The administration of glucose to thiamine-deficient patients (eg, chronic alcohol use)
can precipitate Wernicke encephalopathy (eg, acute confusion, ophthalmoplegia, ataxia) due to rapid thiamine
consumption. [1021]
Social Sciences (Ethics/Legal/Professional)
Social Sciences (Ethics/Legal/Professional)
COMMUNICATION AND INTERPERSONAL SKILLS
Advance directive/surrogate decision maker

Patient participation in advance care planning (ACP), the process of identifying a patient's health care goals in case of
serious illness, is low, especially for ethnic minorities (eg, due to mistrust or suboptimal physician
communication). Physicians should engage patients in ACP by first explaining its primary purpose of patient
empowerment (eg, allowing the patient's voice to be heard). [21178]
Aggression
In agitated patients, especially those admitted for self-inflicted injuries or recent violence, the potential for further
violence should be addressed directly. Patients should be asked if they are having any thoughts or impulses to hurt
themselves or others. [21423]
Complementary and alternative medicine

When discussing complementary and alternative medical interventions, the physician should be honest, helpful, and
nonjudgmental, developing a trusting physician-patient relationship conducive to sharing evidence-based
information. Physicians should obtain more information on unfamiliar products and follow up with the patient or
direct the patient to reliable information sources. [21973]
Physicians should routinely ask their patients about the use of herbal preparations and nutritional supplements and
advise them on the quality, safety, and efficacy of these products. [11629]
Cultural considerations
Ethnic minorities are more likely to be undertreated for pain, potentially due to physician bias or suboptimal
communication. Cross-cultural care can promote optimal pain management by establishing the shared goal of
patient well-being. This can be facilitated by exploring the cultural values (eg, stoicism, deference) that influence
patient perceptions of pain and comfort. [21176]
Health literacy
Low health literacy is a common and underrecognized barrier to health care. It is important to assess patients'
understanding of provided information without shaming or causing embarrassment. [19253]
Immunizations
The first step in approaching parents who are vaccine-hesitant is to initiate an open dialogue that begins with the
shared goal of ensuring the child's health and safety. Discussion should also acknowledge parental concerns, correct
misinformation, and explain the evidence-based risks and benefits of immunization. [21742]
Informed consent
Patients and surrogate decision-makers often have misconceptions regarding medical conditions and the potential
risks and benefits of treatment. The initial step in counseling patients and surrogate decision-makers regarding
treatment refusal is to calmly probe their understanding of the disease process. This can be followed by counseling
and education tailored to the decision-maker's level of understanding and health literacy. [18695]
Interpreters
Hospitals are required to provide patients of limited English proficiency access to health care services in their
preferred language. Interpretation services should be provided by qualified interpreters (eg, telephone or qualified
bilingual staff) with demonstrated language fluency and training in interpreter skills and ethics. [13968]
Interviewing Technique
Patient-centered medical interviewing should focus on the patient's perspective of the illness. Interviews are best
initiated with an open-ended question that elicits the patient's major concerns in the patient's own words. [1432]
Intimate partner violence

Routine screening for intimate partner violence (IPV) includes the use of direct questioning (eg, "Have you ever been
hit by your partner?") to encourage disclosure. However, patients with suspected active IPV (eg, multiple bruises)
may be less forthcoming and require indirect questioning (eg, "How are things going at home?"). [107453]
Patients experiencing intimate partner violence should be approached in a supportive, nonjudgmental, open-ended
manner. A thorough safety assessment and development of a personalized emergency safety plan are essential.
[10659]
Medical futility
When approaching goals of care, the specific meaning of a patient or family's request that "everything be done"
should be explored and revisited regularly, including whenever there is a major change in clinical status. [21625]
Menopause
Patient-centered care involves being responsive to the patient's expressed concerns and providing necessary
information to assist the patient in making an informed health care decision. The emphasis should be on shared
decision-making, taking into account the patient's preferences and avoiding premature judgments. [19317]
Motivational interviewing
When counseling a patient who has multiple unhealthy behaviors, the best approach is to focus on 1 or 2 specific
behaviors the patient feels most ready to change. This improves the likelihood of change by focusing on realistic
goals the patient is more likely to pursue. [21246]
Motivational interviewing is a patient-centered approach to help change maladaptive behaviors; it matches strategies
to the patient's stage of readiness to make a change. This includes acknowledging the patient's resistance and
developing the patient's own motivation to change. [21168]
Motivational interviewing supports and develops patients' sense of self-efficacy in making behavioral
changes. Eliciting patients' strengths and focusing on past successes can help build patients' internal motivation and
confidence in their ability to make changes. [21167]
Principles of motivational interviewing can be used in the treatment of substance use disorders to guide responses to
patients who relapse. This technique helps build patients' sense of self-efficacy by emphasizing their past successes
in maintaining abstinence and by supporting patients' belief in their ability to make changes. [21165]
Obesity
Patients in a precontemplation stage of change do not acknowledge the negative consequences of current behaviors
and are not ready to implement specific lifestyle changes. Providers working with patients in the precontemplation
stage should avoid recommending specific actions but instead discuss patients' understanding of their condition and
its effect on their future health. A nonjudgmental discussion of lifestyle can often facilitate more productive
conversations in the future. [18636]
Opioids
When misuse of prescription opioids is suspected, physicians should first engage patients in a nonjudgmental,
collaborative discussion to understand the reasons for the misuse. [8943]
Patient autonomy
Patients have the right to refuse to receive medical information for individual or cultural reasons. In some cultures,
family members may make health care decisions to avoid perceived harm, disrespect, or mental distress caused by
direct disclosure to the patient. [2059]
When family members and patients have different opinions on treatment, the patient should be provided the
opportunity to talk confidentially with the physician. This respects the patient's autonomy and facilitates obtaining
valid informed consent. [21697]
Patient safety
Physicians must be able to identify patients with limited English proficiency and ensure that professional interpreters
are made available in high-risk clinical situations. [11531]
Physician patient communication

Low literacy can be a significant barrier to appropriate treatment and may be difficult to identify. For patients with
suspected low literacy, alternative methods of communication (eg, visual resources) should be used to improve
understanding. [11518]
Hearing loss can impair communication, resulting in adverse health outcomes. Strategies to improve communication
include minimizing background noise, facing the patient directly, and speaking clearly at a normal pace. [21708]
Physicians may become frustrated with a patient who is hopeless about treatment, often compelling the physician to
refer the patient to a specialist prematurely. Empathizing with the patient's frustration over past treatment failures
can help build the physician-patient relationship. [10452]
Initial encounters with angry patients are best managed by acknowledging their distress and responding to their
immediate concerns. [18762]
Physicians should not feel pressured to respond to questions that they find overly personal or intrusive. Exploring
why patients are asking is a helpful strategy that can assist the physician in gaining a deeper understanding of their
specific concerns. [105279]
Physicians should respond to disclosure of past sexual abuse with empathy and concern. Clearly acknowledging the
trauma and communicating a willingness to discuss it when the patient is ready will help strengthen the physician-
patient relationship. [2054]
Sexual history is an essential part of gathering a complete medical history. This topic may be uncomfortable for both
patient and physician, so it is important to normalize it as a routine part of a medical evaluation. [18874]
Patient-centered communication involves acknowledging the patient's perspective, showing respect, and being
nondefensive and nonjudgmental. Long delays are best handled with a straightforward apology and a focus on the
patient's concerns. [18760]
When speaking with a patient following a medical error, clinicians should directly discuss the error. The conversation
should allow opportunity for the patient to ask questions. A plan to rectify the error should be provided. Finally, the
provider should convey concern for the patient and remain engaged with the patient's care. [18798]
Empiric antibiotic therapy for patients with uncomplicated upper respiratory infections is
contraindicated. Responding to requests for inappropriate antibiotics involves a patient-centered approach that
validates the patient's concerns, educates the patient about the adverse effects of antibiotics and their lack of
efficacy in treating viral infections, and provides options to treat the patient symptomatically. [10458]
Overutilization refers to provision of services that are not expected to improve patient outcomes or meaningfully
change management. Patient–centered health care requires care to be delivered with respect to patients' concerns,
preferences, and priorities, but does not require unnecessary testing or treatment if patient input is otherwise
solicited and respected when appropriate. [18783]
Deaf and hard of hearing patients should be offered the services of an interpreter trained in medical translation and
American Sign Language, subject to patient preference and consent. Alternate modes of communication include
computer-assisted real-time transcription and assistive listening devices. [7487]
Failure of oral medications is common in long-standing type 2 diabetes mellitus due to progressive loss of pancreatic
beta cell function. Patients should be counseled that because of the natural history of the condition, the need for
supplemental insulin is common and does not represent a personal failure. [18964]
Physicians are frequently asked to evaluate whether a patient is entitled to disability benefits. When interacting with
demanding patients, it is best to explain that the physician has a responsibility to perform a thorough assessment
prior to making this determination. [1123]
Physicians must ensure the appropriate use of medical interpreters to promote adequate patient understanding and
participation in the decision-making process. This is particularly important when obtaining informed consent for
treatment. [10488]
Although physicians should be responsive to patient requests, they should not feel pressured to make a
recommendation before fully evaluating the patient. The best approach is to validate the patient's concerns and
gather more information. [18836]
Predischarge counseling should begin with exploring patients' level of understanding and health literacy. Patients
should have an opportunity to ask questions and express their concerns about factors at home that could lead to
readmission. If possible, education should be provided by a multidisciplinary care team, and the plan for home care
and follow-up should be clear. [18808]
Taking a sexual history is a key part of comprehensive care and requires an inclusive and nonjudgmental
approach. Physicians should avoid making assumptions about a patient's sexual history and use an open-ended
inquiry about all sexual partners. [10975]
Communicating the news of a suspected diagnosis of Down syndrome at the time of delivery requires an empathic
approach. A shift from "breaking bad news" to "sharing unexpected news" can help prepare the parents to receive
the information without imposing negative value judgments. [19842]
Initial encounters with new patients often set the tone for the physician-patient relationship. When in doubt about
how to address patients, the physician should ask them their preferred form of address. [10289]
When confronting an angry patient, the physician should use a nondefensive, empathic approach that acknowledges
the patient's anger and attempts to explore the patient's underlying concerns. [10449]
Gender-diverse patients require culturally competent medical care, which includes a tactful inquiry about preferred
identifiers (eg, name, pronouns) followed by accurate and consistent documentation in the electronic medical record.
[106757]
Before disclosing any significant information to patients, physicians should determine patient preferences for how to
receive information and which companions should be present during the discussions. Only when patients'
preferences are clear should significant information be disclosed. [21177]
Delivering serious news requires allowing the patient time to process the information and express
emotions. Empathic, supportive communication should include acknowledging the patient's distress and being open
to answering any questions. [1145]
Trust is central to the provider-patient therapeutic alliance and is associated with improved outcomes. Distrust by
minority patients may result from numerous factors (eg, historical legacy, experience of discrimination, low cultural
inclusivity). Providers can build trust through open-ended discussion and focused reassurance using culturally
relevant materials. [21171]
Trust is central to the physician-patient relationship, and distrust may arise from prior negative experiences (eg,
adverse events, bias). Physicians can build trust by identifying shared goals, seeking patient perspectives, and
prioritizing patient-centered care. [21215]
Counseling on pediatric obesity (body mass index ≥95th percentile) should focus on achieving a healthy weight and
improving functional status (eg, stronger, faster) without placing blame or using offensive terms (eg, obesity). In
addition, making specific and realistic goals is more likely to result in behavior change than trying to attain an "ideal
weight." [105567]
In situations in which a parent's presence may interfere with obtaining honest answers from an adolescent patient,
physicians should politely ask the parent to wait outside and interview the patient privately. All adolescent visits
should include an opportunity to interview the patient alone to discuss topics such as drugs, alcohol, tobacco, and
sexual activity. [1126]
Planned home birth

Desiring a planned home birth may reflect low satisfaction or negative experiences with a prior in-hospital
delivery. Therefore, providers should assess what, if any, aspects of the prior in-hospital delivery were concerning to
the patient. [21678]
Professional conduct
When a patient raises an unexpected concern during an office appointment and adequate time has not been allotted
to evaluate it, the physician should generally ask the patient to schedule an appointment at a later date to address
that concern. [107420]
Sexual assault
Physicians are often the first line of support for survivors of sexual assault. Disclosure of sexual assault should be met
with supportive, nonjudgmental, and patient-centered statements. Patients are encouraged to set the pacing of the
evaluation. [21466]
Smoking Cessation
Patients who are either unaware of or appear to be minimizing the harms of smoking can benefit from a
nonjudgmental, collaborative approach. This involves asking for the patient's perspective, knowledge, and concerns
about smoking; providing relevant information; and then eliciting the patient's understanding of the information.
[21978]
For patients who are not ready to quit smoking, it is helpful to explore their perspective about the pros and cons of
continuing to smoke. Acknowledging resistance in a nonjudgmental manner while exploring ambivalence can help
develop patients' internal motivation to change. [21977]
Suicide
Responding to bereaved individuals following a suicide requires a compassionate and open-ended
approach. Clinicians should acknowledge the bereaved individual's emotional distress and offer to answer any
questions pertaining to clinical course and treatment that may help to make sense of what happened. [22308]
Terminal illness
Denial is commonly experienced by patients diagnosed with terminal illness and can help them cope with
overwhelming thoughts and feelings. When denial is not interfering with receiving end-of life care or discussing goals
of care, it should not be confronted. [10468]
Treatment adherence
The psychological impact of serious illness frequently affects patients' self-image and personal health decisions,
including medication adherence. Encouraging patients to develop positive associations (eg, linking treatment with
improved health), rather than negative associations (eg, linking treatment with memories of disease), can improve
adherence to therapy. [21737]
Inconsistent dosing due to patient misconceptions regarding antidepressant use can result in loss of efficacy and the
potential for toxicity and withdrawal. Physicians must assess the patient's understanding and provide targeted
education to address misconceptions. [11536]
Physicians should use a nonjudgmental, patient-centered approach in discussing treatment

nonadherence. Acknowledging the difficulty of taking medication regularly can strengthen the therapeutic alliance,
potentially improving patient receptiveness to educational efforts. [1144]
The first step in maximizing long-term medication adherence is building a therapeutic environment characterized by
openness and mutual trust. Developing a trusted partnership that incorporates the patient's goals into the
management plan is a necessity, and can make specific interventions to maximize adherence more effective. [21735]
Identifying and managing nonadherence is critical to improving outcomes for many chronic conditions, including
hypertension. Creating an alliance by validating the patient's perspective and using an open-ended, nonjudgmental
question is the most effective way to initiate a discussion. [10398]
Nonadherence is common in patients with hypertension because the condition is generally asymptomatic, whereas
medication has cost, inconvenience, and symptomatic adverse effects. The most effective interventions to improve
adherence are those that can easily be integrated into the patient's schedule or linked to an established habit. [21736]
HEALTHCARE POLICY AND ECONOMICS
End of life care

Patients with advanced metastatic cancers or other terminal illnesses and a life expectancy of <6 months should be
evaluated for hospice care. [10290]
Health insurance
A health maintenance organization (HMO) is an insurance plan with low monthly premiums, low copayments and
deductibles, and low total cost for the patient. HMOs reduce utilization by confining patients to a limited panel of
providers, requiring referral from a primary care provider prior to specialist consultations, and denying payment for
services that do not meet established guidelines. [11668]
Capitation is an arrangement in which a payor pays a fixed, predetermined fee to provide all the services required by
a patient. Payors may negotiate a capitated contract with an insurance company that then pays the providers, or a
large medical group may negotiate directly with the payor. [8456]
Medicare is a federal socialized medical insurance program that covers individuals age 65 and older who have a work
history and younger individuals with disabilities. [11602]
Patient confidentiality
Under the Health Insurance Portability and Accountability Act, physicians may disclose patient information to friends
and family members in emergency situations or when the patient is otherwise incapacitated, depending on what is in
the best interest of the patient. Otherwise, patient information may be disclosed only when the patient gives explicit
permission or does not object when given a reasonable opportunity. [784]
Patient confidentiality is strongly protected because patients must feel free to disclose details of all aspects of their
lives so that physicians can provide optimal care. Exceptions to patient confidentiality include suspected child,
disabled person, or elder abuse; knife or gunshot wounds; diagnosis of a reportable communicable disease; and
patients at risk of physically harming themselves or others. [1129]
Patient confidentiality prohibits physicians from disclosing a patient's protected health information (eg, diagnosis,
treatment) to anyone not directly involved in the patient's medical care, including physician colleagues. Physicians
should not identify their patients when it is not medically necessary because doing so is a breach of patient privacy.
[7733]
Physicians must be cautious about discussing protected patient health information in public places, including public
settings within the hospital, even with other medical personnel. Conversations regarding patients should be deferred
to a later time when a more private setting can be arranged. [10509]
The Health Insurance Portability and Accountability Act protects health information by requiring verbal or written
authorization for release of information. Family members who contact the physician for information about their
relative should not be given any information about the patient without the patient's consent. [10510]
MEDICAL ETHICS AND JURISPRUDENCE
Advance directive/surrogate decision maker

A health care proxy is a person legally designated to make medical decisions if the patient loses decision-making
capacity. The health care proxy has more authority than all other surrogate decision makers and is expected to act in
accordance with the best estimate of what the patient would have chosen. [10534]
Advance directives detail patients' instructions for future medical care. A living will is a written document that
specifies a patient's wishes, whereas a health care proxy is designation of a surrogate who is authorized to make
health care decisions on the patient's behalf. Advance directives take precedence over the wishes of family
members. [10532]
The admission process must include discussion of whether the patient has advance directives, along with code status,
to ensure that medical personnel adhere to the patient's specific wishes should the patient become incapacitated.
[1235]
Conflict of interest
Providing informal treatment to friends and family is ethically problematic due to lack of objectivity that can
negatively impact clinical judgment. It should generally be limited to emergency situations in which no other
physician is available. [10450]
Decision making capacity

When a patient is unable to give consent for care and does not have a designated surrogate, decision-making capacity
falls to the next of kin, generally determined by the proximity of relationship. In an emergency, the physician can
treat an incapacitated patient without obtaining consent. [10542]
Patients who refuse medical interventions must be assessed for decision-making capacity. Patients with decision-
making capacity have the right to refuse treatment. [2058]
It is a physician's duty to advocate for the best interests of a child. When a child is at significant risk of harm, parental
authority to make medical decisions can be challenged. In cases where educational and collaborative efforts fail,
protective services should be contacted. [10533]
When a patient is unable to communicate his or her wishes regarding care and does not have an advance directive or
designated surrogate decision-maker, decision-making falls to the next of kin (eg, spouse). The next of kin is generally
determined by the proximity of relationship and is responsible for making decisions based on what they believe the
patient would want and the patient's best interest. [1124]
The capacity to refuse treatment requires the ability to express a choice, understand the relevant medical
information, appreciate the potential consequences of treatment options, and offer a rationale for the
decision. Patients with Alzheimer disease in the mildly affected range often retain decision-making capacity. [1179]
Direction for medical care can be obtained from an advance directive, either a living will or previously designated
health care proxy. In the absence of an advance directive, decision-making falls to a default surrogate who is
responsible for making decisions based on what the patient would have chosen (substituted judgment standard).
[21596]
Emancipated minor
Minors do not require parental consent for medical treatment of conditions that may be sensitive or stigmatizing
such as sexually transmitted infections, pregnancy, and substance abuse. [2057]
Informed consent
Patients have the right to withdraw consent for a procedure at any time. When patients change their minds and
refuse treatment, it is the physician's responsibility to engage them in a new discussion of informed consent or
informed refusal. [19055]
The essential components of informed consent include explanation of the patient's diagnosis and proposed
treatment, other treatment options, the risks and benefits of the proposed treatment, and the risks of refusing the
proposed treatment. [19044]
Directive counseling is ethically appropriate when only one treatment option is medically reasonable and has clearly
superior evidence-based support. Patients with complete placenta previa should be counseled that cesarean delivery
is medically necessary. [19387]
The process of informed consent involves discussing the indications, risks, and benefits of treatment. Assessing a
patient's understanding of the discussion and responding to specific concerns or confusion is essential to obtaining
valid consent. [14111]
Physicians should support patient autonomy in making reproductive health decisions. Physicians should counsel
patients regarding the risks, benefits, and alternatives to any procedure they are requesting. [1125]
Informed consent (IC) should be obtained by the attending physician performing the procedure, who can best explain
the procedure and answer any questions. If IC is delegated to another provider on the care team, the team member
must thoroughly understand the procedure and be able to answer the patient's questions. [10545]
Intimate partner violence

Intimate partner violence (IPV) increases during pregnancy and the postpartum period and can cause significant
maternal and pregnancy complications. Pregnant patients affected by IPV require immediate safety planning (eg,
information about a domestic violence program) and resources for long-term planning. [19664]
Patient autonomy
Autonomy, which supports a patient's right to know his or her diagnosis, is a fundamental ethical principle. However,
limiting disclosure of a diagnosis may be appropriate under certain circumstances (eg, patient preference, imminent
safety concerns). An understanding, open approach is necessary to uncover these circumstances. [106484]
Patients have the right to have information withheld from them regarding their medical condition. Physicians must
respect their wish not to know but should also explore the patient concerns to better understand their preferences
and maximize their involvement in subsequent medical decision-making. [1237]
Patient confidentiality
The ethical obligation to maintain patient confidentiality prohibits physicians from disclosing information about a
patient's diagnosis or treatment (ie, protected health information) to anyone not directly involved in, or necessary to,
the patient's medical care. [106486]
Physician misconduct
Physicians are ethically and legally obligated to report impaired colleagues in a timely manner. Reporting protects
patient safety and can assist the impaired physician in receiving appropriate evaluation and treatment. [10399]
It is ethically problematic for physicians to accept expensive gifts as they may influence or appear to influence
professional judgment. These gifts should be declined after expressing appreciation for the gesture. [7767]
Romantic and sexual relationships with current patients as well as former psychiatric patients are always
unethical. Relationships with former non-psychiatric patients may be acceptable provided the physician-patient
relationship is terminated well beforehand. [10464]
Medical decision-making often involves balancing conflicting ethical principles (ie, autonomy, beneficence,
nonmaleficence, justice). While recognizing patients' rights to make personal health care decisions (ie, autonomy),
the provider has the responsibility to use specialized training to incorporate the best interests of the patient into the
provision of care (ie, beneficence), which includes limiting nonindicated interventions. [1182]
MISCELLANEOUS
Abortion
Conscientious refusal of treatment occurs when a provider refuses to provide care due to moral conflict. Providers
who cannot, in good conscience, provide treatment that a patient requests, are obligated to refer the patient in a
timely fashion to another provider who can. This respects the patient's autonomy. [10463]
Child abuse
Physicians are obligated to report suspected child abuse or neglect to child protective services (CPS) for further
investigation. Reporting is mandatory, and reasonable suspicion is sufficient to make a report. [1107]
Elder Abuse & Neglect

Physicians should be alert for signs of elder mistreatment, including evidence of neglect, deterioration in medical
conditions and malnutrition, atypical injuries, and behavioral changes. It is mandatory to report suspected elder
mistreatment to Adult Protective Services. [8457]
PATIENT SAFETY
Antihistamines
Review of medications to determine if any are unnecessary or causing adverse effects is essential in providing high-
quality patient care. The cumulative anticholinergic burden of multiple medications is especially problematic in the
elderly. [11537]
Patient safety
Communication failures between physicians during patient handoffs are a major cause of medical errors and can be
reduced by use of a standardized handoff process including systematic sign-out notes. [11757]
Avoiding the use of unsafe abbreviations and trailing zeros in medication orders can help reduce the incidence of
medication errors. [11535]
Sleep deprivation in physicians often causes cognitive impairment, resulting in medical errors. Although mandated
resident work-hour limitations are in place, it is the responsibility of all physicians to self-regulate their workloads to
promote patient safety. [11532]
Root cause analysis is a quality improvement measure that identifies what, how, and why a preventable adverse
outcome occurred. The first step involves collecting data mainly through interviewing multiple individuals involved in
the steps leading to the outcome. [10508]
Physicians have an ethical responsibility to disclose errors caused by system failures to patients. Full disclosure
includes providing details of the error and why it happened and explaining steps to minimize consequences and
prevent future occurrences. [106288]
A preventable adverse event is defined as injury to a patient due to failure to follow evidence-based best practice
guidelines. [11847]
Polypharmacy
Falls are a common problem in elderly nursing home patients. Optimal management includes a careful medication
review with the goal of limiting the use of agents associated with increased fall risk. [11533]
Physicians are ethically obligated to question orders that raise concern about potential harm to patients. Issues
should initially be discussed directly with the physician who made the order and not involve ancillary staff. [970]
Veracity
Physicians should disclose medication errors and provide an apology in a timely fashion regardless of whether harm
has occurred. [10507]
SYSTEM BASED-PRACTICE AND QUALITY IMPROVEMENT
Patient safety
Risk of wrong-site surgery can be reduced by requiring "dual identifiers" (usually a nurse and physician) to
independently confirm that they have the correct patient, site, and procedure. Checks must be truly independent to
ensure patient safety. [11515]
A discharge checklist detailing medication changes and follow-up appointments can significantly facilitate a patient's
transition from the hospital and improve adherence to outpatient treatment. Individuals who experience a smooth
transition from the inpatient to the outpatient setting are at lower risk for early rehospitalization. [11550]
Health care providers working on a team should employ closed-loop communication, in which team members repeat
back the information received to ensure that the correct information has been conveyed. This highly effective form
of communication reduces the risk of medical errors in the health care setting. [11549]
Study designs
Obesity-related health disparities affect vulnerable populations (eg, lower socioeconomic status) and arise from
patient, health care, and community-related factors. Cross-sectional analysis can identify specific risk factors (eg,
insurance status, health behaviors) correlated to obesity in different settings, helping to generate hypotheses for
further research. [20527]

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UWorld Notes Step 1

Ear, Nose & Throat (ENT) 11

Endocrine, Diabetes & Metabolism 13

Female Reproductive System & Breast 13

Gastrointestinal & Nutrition 15

Male Reproductive System 20

Pregnancy, Childbirth & Puerperium 36

Pulmonary & Critical Care 37

Renal, Urinary Systems & Electrolytes 38

Rheumatology/Orthopedics & Sports 39

Biochemistry (General Principles) 46

Endocrine, Diabetes & Metabolism 54

Gastrointestinal & Nutrition 57

Genetics (General Principles) 60

Hematology & Oncology 60

Poisoning & Environmental Exposure 66

Pulmonary & Critical Care 66

Renal, Urinary Systems & Electrolytes 67

Rheumatology/Orthopedics & Sports 67

Biostatistics & Epidemiology 69

Endocrine, Diabetes & Metabolism 79

Ear, Nose & Throat (ENT) 82

Endocrine, Diabetes & Metabolism 82

Female Reproductive System & Breast 83

Gastrointestinal & Nutrition 83

Male Reproductive System 85

Pregnancy, Childbirth & Puerperium 88

Pulmonary & Critical Care 89

Renal, Urinary Systems & Electrolytes 89

Rheumatology/Orthopedics & Sports 90

Biochemistry (General Principles) 91

Biostatistics & Epidemiology 91

Ear, Nose & Throat (ENT) 92

Endocrine, Diabetes & Metabolism 92

Female Reproductive System & Breast 93

Gastrointestinal & Nutrition 93

Genetics (General Principles) 94

Hematology & Oncology 100

Infectious Diseases 101

Male Reproductive System 102

Miscellaneous (Multisystem) 102

Nervous System 103

Pregnancy, Childbirth & Puerperium 104

Pulmonary & Critical Care 104

Renal, Urinary Systems & Electrolytes 105

Cardiovascular System 106

Endocrine, Diabetes & Metabolism 107

Female Reproductive System & Breast 107

Gastrointestinal & Nutrition 108

Infectious Diseases 109

Nervous System 109

Pregnancy, Childbirth & Puerperium 109

Pulmonary & Critical Care 110

Renal, Urinary Systems & Electrolytes 110

Rheumatology/Orthopedics & Sports 111

Allergy & Immunology 112

Cardiovascular System 121

Ear, Nose & Throat (ENT) 122

Gastrointestinal & Nutrition 123

Hematology & Oncology 123

Infectious Diseases 125

Miscellaneous (Multisystem) 127