REVIEW – things he went over in the review cases or that were in review quiz are indicated in the document

with a ⭐
Cases:
- DKA → Sxs, clinical presentation, labs, DI, treatment
- Primary adrenal insufficiency/Addison’s disease → Sxs, clinical presentation, labs, DI, tx, diet, follow up
- T1DM → Sxs, clinical presentation, labs, treatment
- SIADH → Labs, etiology, tx
- Hyperprolactinemia → Sxs, clinical presentation, DI/labs, tx
- Hypothyroid → Sxs, clinical presentation, DI/labs, tx
- Pituitary adenoma → Sxs, clinical presentation, DI/labs, tx
- T2DM → Sxs, clinical presentation, labs, tx, follow ups
- Graves + Graves ophthalmopathy → Sxs, clinical presentation, labs, DI, tx
- Parathyroidism → Sxs, clinical presentation, labs, DI (kidney stones), tx → meds + surgery

EXAM OVERVIEW:
45 questions – 1-2 extra credit
3 true/false
2 (including EC) are short answer – the rest are multiple choice
DKA – 7 questions
DM – 9 questions
Adrenal – 8 questions
Thyroid – 8 questions
Pituitary – 8 questions
MEN – 4 questions
 PITUITARY & HYPOTHALAMUS – 8 questions

Neuroendocrine overview:
● Hypothalamic pituitary axis:
● Neuroendocrine System: link between nervous & endocrine
● Neurosecretory cells: neural cells that can secrete hormones
● Direct connection (neuroectoderm) - posterior pituitary (vasopressin/ADH, oxytocin)
● Vascular connection - anterior pituitary
○ Neurons end at median eminence where hormones enter portal vessels
● Normal hypothalamic-pituitary function (feedback loops)
○ Functions to maintain control of heat, water, and energy balance within the body, also known as homeostasis (Negative feedback loops)
○ Accomplishes this through a series of feedback loops
● Hormonal Functions: Hypothalamus “FLAT PGS” → anterior pituitary
○ Corticotropin-releasing hormone (CRH): stimulates release of adrenocorticotropic hormone (ACTH) from anterior pituitary
■ Release of ACTH stimulates secretion of corticosteroids from adrenal cortex, primarily glucocorticoids and mineralocorticoids
● Primary glucocorticoid is cortisol – many functions “stress hormone”
⭐
⭐
○ Thyrotropin-releasing hormone (TRH): stimulates release of thyroid-stimulating hormone (TSH) from anterior pituitary
■ Release of TSH stimulates the thyroid gland to begin synthesis and secretion of thyroid hormones → T3 & T4
○ Growth hormone releasing hormone (GHRH): stimulates release of growth-hormone (GH) from anterior pituitary
■ Release of GH stimulates protein synthesis and growth in bone, muscle, and other tissues
○ Growth hormone-inhibiting hormone (GHIH/Somatostatin): inhibits release of growth hormone (GH) from anterior pituitary
○ Prolactin-inhibiting hormone (PIH/Dopamine): inhibits release of prolactin hormone (PH) from anterior pituitary
○ Prolactin-releasing hormone (PRH): stimulates release of prolactin hormone (PH) from anterior pituitary
■ Release of prolactin stimulates milk production in the mammary glands
○ Gonadotropin-releasing hormone (GnRH): stimulates release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from anterior
pituitary
■ Release of LH stimulates testosterone synthesis in testes, and will stimulate ovulation / formation of corpus luteum / estrogen
synthesis / and progesterone synthesis in ovaries
■ Release of FSH stimulates sperm maturation in testes and follicular development and estrogen synthesis in ovaries
● Also see synthesis of inhibin in the Sertoli cells of the testes and the granulosa cells of the ovaries to act as negative
feedback loop to decrease production of FSH
○ Release of melanocyte stimulating hormone (MSH) stimulates melanin production (neither anterior or posterior → inbetween them??)
● Posterior pituitary
○ Oxytocin: released from the posterior pituitary
■ Stimulates smooth muscle contraction in uterus and mammary glands in females
■ Stimulates smooth muscle contraction in the ductus deferens and prostate gland in males
○ Antidiuretic hormone (ADH/Vasopressin)
■ Released from the posterior pituitary
■ Stimulates water reabsorption in the distal renal tubules, smooth muscle contraction in arterioles and capillaries
Hypothalamic tumors:
Clinical Presentation
Hypo- Abnormal growth of
thalamic hypothalamic neurons (benign,
Hamartoma asymptomatic)
Precocious Precocious Puberty:
- Girls < 8 y/o, and boys <
Puberty 9 y/o
- Normal ranges = 8-12 y/o
for girls and 9-13 y/o for
boys
Effect of hypothalamic disease on
pituitary function: hypothalamic
hypergonadism
2 Types:
1. Central - gonadotropin-
dependent:
- Early maturation of the entire
hypothalamic-pituitary-gonadal
(HPG) axis, with the full spectrum
of physical and hormonal
changes of puberty
2. Precocious pseudopuberty
(much less common):
- Conditions in which increased
production of sex steroids is
gonadotropin-independent
- These are tumors of the adrenal
gland, ovary, or testis, other causes
Treatment
Removal vs GnRH analogues (LH
agonists)
- Give GnRH analogue if they’re
younger
- Remove if they’re older
To evaluate use Hx, PE, GnRH stimulation,
MRI (looking for tumor):
GRnH stimulation → Measuring LH and
FSH levels 30-60 minutes after stimulation
with GnRH
- Need a baseline LH, FSH,
Estradiol/Testosterone
→ No increase in LH and FSH levels after
infusion of GnRH suggests precocious
pseudopuberty
- Sex steroids are being produced
independently
Tx: Based on cause → continuous GnRH
agonist (leuprolide)
Other
What is the potential problem here?
- Mass effects
- Some secrete GnRH - precocious puberty
Incidence rate = 0.19/100,000/year
Bimodal peak rates when looking at age distribution:
- Childhood (age 0-19) and adults (age 45-84)
Pituitary adenomas w/ suprasellar extension:
- Craniopharyngiomas
- Suprasellar dysgerminomas (children)
- Hamartomas - MC
Central Etiology → Premature activation of the GnRH
pulse generator = hamartoma/astrocytoma/other CNS
lesion/trauma/idiopathic
Hormonal changes similar to normal puberty
↑ pulsatile LH release, ↑ gonadotropin response to GnRH,
↑gonadal steroid secretion, normal sequence of pubertal
events
NORMAL Pubertal Sequence of Events:
Adrenarche - activation of adrenal cortex for production of
adrenal androgens, occurs before the onset of puberty
Gonadarche - activation of gonads by pituitary hormones
FSH and LH
Pubarche - appearance of pubic hair
Thelarche - appearance of breast tissue
Menarche - age of onset of first menstrual period
Spermarche - age at first ejaculation (nocturnal sperm
emissions and appearance of sperm in the urine)
Disorders of the anterior pituitary:
Clinical Presentation Treatment Other

Hypo- Diagnosis → History and PE Diminished production of 1 or more anterior pituitary

pituitarism hormones
Loss of hypothalamic stimulation or direct loss of pituitary function - Rare: internationally about 4.2/100,000/year
- Decreased lab values of pertinent hormones Etiology:
Stimulate pituitary to produce hormone - Genetic, neoplasms, radiation, vascular,
infiltrative disorders, etc.
Tx: replace hormone physiologically – avoid over-replacement - Neoplasms (pituitary microadenomas) are
- Ex. For pituitary failure to secrete TSH – give levothyroxine most common cause of acquired
- Monitor dosing → clinical changes +/- based on labs hypopituitarism

Panhypo- Several or all hormones are not in line:

pituitarism

Pituitary
Tumors hormone produced ⭐
Functioning/Hormone releasing → Sx related to Tx = Usually
surgical removal,
trans-sphenoidal
-
-
-
Microadenoma: < 10 mm diameter
Macroadenoma: >10 mm diameter
Macroadenoma with extrasellar extension
Non-Functioning or silent → Mass effects – size & approach (pushing down)
location specific
- HA, vision changes ⭐
Growth hormone pathologies:
Clinical Presentation Treatment Other

GH Pituitary Dwarfism = Adult Children: GH injections daily Children: 1:4,000 to 1:10,000

Deficiency height of less than 147cm
(4’10”)
Normal body proportions,
unlike dwarfism caused by
achondroplasia (genetic)
Adults: GH injections daily(?)
GH treatment can increase lean body
mass, decrease fat mass, and improve
the sense of well-being in adults with
documented GH deficiency
- Complete deficiency: slow linear growth rates
- Incomplete/acquired: decreased lipolysis (likely
have more adipose tissue)
GH causes release of IGF-I (insulin-like growth factor)
→ Low IGF-I is consistent with GH deficiency
If we want to test the level of GH, we test IGF-I

Insulin-induced hypoglycemia activates CNS pathways,

leading to stimulation of both GH and ACTH secretion

IGF-I mediates the effects of GH on almost all cells, also

has similar effects to insulin

GH excess Symptoms due to local mass effects of the tumor depend on size of tumor
- Bitemporal hemianopsia due to pressure on the optic chiasm
- HA
- Damage to normal pituitary tissue can cause deficiencies of ACTH, LH, FSH, TSH (one or more)

Symptoms due to excess of GH/IGF-I

- Soft tissue swelling and enlargement of extremities
- Increase in ring and/or shoe size
- Hyperhidrosis (increased sweating)
- Coarsening of facial features (shortening)
- Prognathism (protruding jaw)
- Macroglossia (large tongue)
- Arthritis
- Increased incidence of obstructive sleep apnea
- Increased incidence of glucose intolerance or DM, HTN, cardiovascular disease
- 2 – 3x increased mortality rate
GH Excess: Sxs as above
Acromegaly
Acromegaly = adults
Gigantism = children (very
rare)
Incidence: 3 / million
M=F
Age @ diagnosis: 40
Etiology = Usually GH
secreting pituitary tumor
Tx → Transsphenoidal surgery –
first-line therapy
- Fast response, most likely only
option when mass effects are
present
Medications:
- Dopamine agonists
(bromocriptine, cabergoline)
- Somatostatin analogues:
first-line pharmaceutical
therapy octreotide, lanreotide
Testing: GH varies in levels during the day
- IGF-1 does not vary as much as GH, if elevated
in someone with acromegaly, likely GH related
***IGF-1 decreases with age and kidney disease or
poorly controlled diabetes and increases with pregnancy
Oral glucose suppression/tolerance test
- Normal: Glucose high, GH suppressed
- Not all acromegalic pts suppress GH (ectopic
tumors)
MRI – No pituitary tumor seen? → Check for ectopic
tumors of chest, abdomen, or pelvis (neuroendocrine
tumor)

Prolactinomas:
Clinical Presentation Treatment Other

Hypo- Rarely sole deficiency → tends to occur with combined deficiencies

prolactinemia Clinical manifestation → No postpartum lactation

Hyper- **Suppresses GnRH Diagnosis: ⭐

1. Prolactin level
Etiology:
- Pituitary disease including adenoma
prolactinemia
Pre-menopausal women: - > 20 ng/mL in men and postmenopausal - Hypothalamic disease
infertility, oligomenorrhea/ women - Medications (antipsychotics MC, ex:

⭐
amenorrhea, galactorrhea - > 30 ng/mL in premenopausal women
2. MRI or CT
risperidone & haloperidol)

Men: hypogonadism, low
testosterone – diminished
libido, impotence, infertility,
rarely galactorrhea
Medication causes:
Treatment: - Dopamine-receptor antagonists
1. Stop meds that cause it (metoclopramide)
2. Slow growing tumors – based on symptoms - Dopamine-depleting agents (reserpine)

Visual field defects, HA

⭐
3. Bromocriptine is medication of choice (bro
milk)
Disorders of sex hormones:
Clinical Presentation Treatment Other

Hypo- Women = breast atrophy, Men → Testosterone Caused by Low FSH & LH (usually caused by low
gonadotropic vaginal dryness, low libido Clomiphene (SERM) (selective estrogen GnRH)
Hypo- receptor messenger) – inhibits negative
Men = decreased libido feedback and promotes Secondary causes → weight loss, anorexia, stress,
gonadism and sexual function gonadotropin-independent testosterone heavy exercise, severe illness
secretion by the testes (NIH) → less side
effects than testosterone

Women → Oral contraceptive pills (replace

hormones)

FSH and LH- Tumors typically do not Diagnosis: Clinically = Difficult → CT or MRI, Male:
Producing cause characteristic hormone levels usually normal FSH: stimulate sperm production
Tumors hormone excess LH: androgen production

Clinically like non

functioning tumor – mass
radiation⭐
Management → trans-sphenoidal surgery,
Female:
FSH: induce enzymes for estrogen biosynthesis
effects → Visual field
changes, headaches ⭐ LH: androgens
- Menstruation - FSH: follicular recruitment; LH:
ovulation

M > F , older age

● Posterior pituitary → 2 hormones synthesized in neurons in hypothalamus

○ Vasopressin / ADH: water-retaining hormone
○ Oxytocin: milk secretion
■ Present in same amount in male & female
■ Prolactin makes the milk, but oxytocin secretes it
■ Oxytocin also role in childbirth – uterine contraction to limit uterine bleeding
■ Similar in structure to vasopressin
● Serum Osmolality → Remember hypothalamus/pituitary act as osmostat
○ Normal serum osmolality: 275-290 mosmol/kg
○ Normal serum sodium: 135-145 mEq/L
● Hyponatremia can be classified into subcategories: Acute or Chronic
○ Acute hyponatremia: present for a period <48 hours
○ Chronic hyponatremia: present for >48 hours or unknown time of presentation
 ○ Subdivided into mild, moderate, or severe
■ Mild: Sodium concentration 130-134 mEq/L
■ Moderate: Sodium concentration 120-129 mEq/L
■ Severe: Sodium concentration <120 mEq/L
○ Dangerous → acute > chronic (chronic has time to compensate), as water will move intracellularly
■ Leads to edema due to expansion of ICF, may start with malaise and nausea, can advance to coma and respiratory
arrest → Example: cerebral edema
● Hypernatremia: Serum sodium concentration >145 mEq/L → Most commonly due to water loss (dehydration)
○ Do not confuse with hypovolemia which is salt & water loss
○ Dangerous → acute > chronic (chronic has time to compensate), as water will move extracellularly → Edema due to
excess water in ECF → Example: brain shrinkage – water moving to subdural spaces
■ Neurological dysfunction: lethargy, weakness, irritability, seizures, or coma can develop
● Vasopressin (ADH) → Osmostat in the hypothalamus sends neuronal signal to posterior pituitary to release vasopressin
○ Hormone stimulates thirst & causes water retention
■ Acts on antidiuretic receptors in the kidneys to retain water (antagonist = alcohol)
■ Responds to dehydration, low BP (volume and pressure of vessels)

Disorders of the posterior pituitary:

Clinical Presentation Treatment Other

Diabetes
Insipidus (increased drinking)⭐
Polyuria (increased urination) & Polydipsia
Central: Hypotonic polyuria after head trauma
or cranial surgery – thirst usually maintained
- ADH low/normal, hypernatremia, good
response to desmopressin
Dx:
1. Low osmolality of urine & high osmolality
of blood
2. Serum vasopressin (low, normal,
elevated?)
3. Fasting BG (blood glucose) → rule out
DM (glucosuria is osmotic diuretic)
“Insipidus” – tasteless
Large volume of hypotonic,
tasteless urine
3 Main Causes:
1. Central (hypothalamus)
→ Inability to synthesize or

Nephrogenic: ⭐ Inherited or drug-related (no

negative feedback)
4. Electrolytes → check Na+, also
hypokalemia can diminish kidney’s ability
to concentrate the urine
excrete vasopressin
2. Nephrogenic → Kidney
does not respond to
- ADH high/normal, hypernatremia, little or no 5. BUN, Creatinine: check kidney function vasopressin
response to desmopressin 6. Water deprivation test, desmopressin test 3. Primary polydipsia →
7. MRI Disorder of thirst
Primary Polydipsia: Excessive fluid intake stimulation
- ADH low, usually Na normal, good response Tx → Depends on the cause
to desmopressin 1. Central: desmopressin *Gestational: destruction due to
2. Nephrogenic: HCTZ, in absence of ADH vasopressinase
Gestational: Elevated vasopressinase (breaks may cause proximal salt and water
down ADH) retention – secondary to mild hypovolemia
- ADH very low, hypernatremia
Syndrome of Excessive levels of vasopressin (ADH) → Most Result: ⭐ ⭐
Etiology → CNS issue, tumor,
Inappropriate
Antidiuretic patients⭐
common cause of hyponatremia in hospitalized - Hyponatremia
- hypo-osmolality
- high urine osmolality
drugs, malignancy

Hormone CP: - high urine sodium

(SIDAH) - May be none - low BUN
- severe/quick → cerebral edema: - normal creatinine
headache, lethargy, seizures
Tx → Treat underlying condition
1. Water restriction (< 800 mL/day)
2. IV hypertonic saline (for acute severe
hyponatremia)
3. Vasopressin receptor antagonists:
tolvaptan

IV Hypertonic Sodium correction should not exceed a rate of 8 mEq/L over 24 hours, with generalized recommendations of about 4-6 mEq/L over 24 hours
Saline:
Danger zone Too rapid of correction can result in ODS (Osmotic Demyelination Syndrome)
1. Leads to neurological dysfunction over 2-6 days → the symptoms are delayed for 2-6d
2. Often irreversible or only partially reversible
3. Most severe cases “locked in” syndrome → Pt is awake but unable to move anything but eyes

MEN TYPE I:
Definition
Rare heritable disorder characterized by a
predisposition to tumors of the parathyroid
glands, anterior pituitary, and pancreatic islet
cells – “PPP”
Clinically defined as:
1. Presence of 2 or more primary MEN1
tumor types
2. Family members who have a clinical
diagnosis of MEN1
3. Occurrence of a MEN1-associated tumor
Epidemiology/Etiology
Epidemiology:
Prevalence rate = 0.25%
Those with clinical manifestations of MEN1:
- Primary hyperparathyroidism: prevalence
is 1-18%
- Pancreatic islet tumors: prevalence is
16-38%
- Pituitary tumors: prevalence is < 3%
Penetrance is about 50% by age 20 → rare to
see any clinical manifestations before age 5
yo (Majority of patients have clinical
manifestations by 40-50 years old)
Etiology:
Genetic mutation of tumor suppressor gene
on 11q13 (MC)
Sometimes there are sporadic mutations
that are not inherited forms
MULTIPLE ENDOCRINE NEOPLASIA – 4 questions
Genetics
MEN1 gene mutation on chromosome 11q13, affects
function of “menin” protein, which is responsible for
tumor suppression → Over 1000 mutations have
been detected
Autosomal dominant (50% chance of being passed
on)
Not all cases of MEN1 are due to a mutation of 11q13
→ Other mutations include p27, p15, p18, p21
(cyclin-dependent kinase inhibitor genes): CDKN1B,
CDKN2B, CDKN2C, and CDKN1A
Most often see parathyroid tumors, with > 90%
penetrance by age 40-50 yo
Clinical presentation
Clinical manifestations → Asymptomatic
Symptoms related to organ involvement:
Parathyroid gland (MC) → hyperparathyroidism
(bones, stones, groans, moans, fatigue
overtones)
Pituitary gland → acromegaly, prolactinomas,
Cushing disease, mass effects
Pancreas / GI → Zollinger-Ellison syndrome (ZES),
insulinomas, glucagonomas
Thymus → carcinoid tumors
Cutaneous → angiofibromas, collagenomas,
lipomas
Patho
Inherited MEN1 gene causes 1st hit to tumor
suppression → 2nd hit, often via gross deletion, leads
to loss of tumor suppression → This leads to
unchecked proliferation
Workup
Workup → labs for patients identified as having
MEN1
1. Rule out Gastrinomas
Fasting gastrin 10x > than normal upper limit of 100
pg/mL, in presence of hypochlorhydria or pH < 2
- If gastrin levels below 1000 pg/mL, gastrin
stimulation test*
2. Rule out Insulinomas
Supervised 72-hour fast; increased plasma insulin
with hypoglycemia occurs → Also see elevated
C-peptide and proinsulin levels
- Start screening by age 5 yo
3. Rule out Glucagonomas
Elevated serum glucagon and hyperglycemia is
present
- Start screening before age 10 yo
Workup → imaging studies
- X-ray: if assessing for hyperparathyroidism
may see resorption of bone
- CT w/wo contrast: chest, abdomen, pelvis
- MRI w/wo contrast chest, abdomen, liver &
of head wo contrast
- Endoscopic ultrasound (EUS)
 Diagnosis Treatment Prognosis

Clinical diagnosis can be made if:
1. ≥ 2 primary MEN1 tumor types are
present (parathyroid, anterior pituitary,
and pancreatic/GI)
2. 1 MEN1-associated tumor is present with
a FHx of clinical diagnosis of MEN1
**Genetic testing can confirm diagnosis if
MEN1 mutation present
Will likely refer to several specialists
(endocrinology, GI, neurosurgery, general
surgery, oncology, dermatology)
Parathyroid tumors → surgery, calcimimetic
agents (cinacalcet) inhibit PTH production
Pituitary adenomas → surgery, medical
management (ex: bromocriptine for prolactinoma,
octreotide for acromegaly)
Pancreatic islet cell / GI → ZES: surgery usually
not curative, medical management usually
accomplished with PPI (omeprazole)
- Insulinoma: surgery, medical management
accomplished with antihypoglycemics
(diazoxide)
Significantly lower 20-year overall survival rate
compared to age / gender / geographically matched
population → 50% probability of death by age 50 yo
- MC cause of death was due to metastatic
islet cell tumors
Malignant pancreatic tumors and thymic carcinoid
tumors are associated with increased risk of death
Associated with higher levels of anxiety, depression,
fatigue, decreased social functioning, increased
financial burden, and worse health-related quality of
life

Other

Labs continued…
Vasoactive intestinal polypeptidomas (VIPomas)
- Elevated serum VIP
- Watery diarrhea with hypokalemia and achlorhydria, stool volume of > 0.5-1 L per day during fasting
- Start screening by age 10 yo
Pancreatic polypeptidomas (PPomas)
- Elevated PP levels
- Elevated chromogranin A levels
- Start screening by age 10 yo
Carcinoid tumors
Pituitary tumors
- Elevated GH, IGF-1, and prolactin levels
- Start screening by age 5 yo
Hyperparathyroidism
- Elevated serum calcium, PTH (may be inappropriately normal)
- Start screening by age 8 yo
Genetic testing → Testing for MEN1 mutation recommended for the following:
- 2 or more MEN1-associated endocrine tumors
- First-degree relative (parents, siblings, children) of known MEN1 mutation carrier
- (genetic screening should be done before age 5 yo)
MEN TYPE II:
Definition Epidemiology/Etiology

Inherited disorder characterized by the
development of medullary thyroid
cancer (MTC), parathyroid tumors,
and pheochromocytoma (Medscape)
- Classic MEN2A
Separated into 2 syndromes
MEN2 frequency = 1 case per 30,000-50,000 people → 50% of those with MEN2A, RET gene mutations, develop
disease by age 50 yo
Genetic inheritance, autosomal dominant
Classical MEN2A is MC variant → Heritable predisposition to medullary thyroid cancer, pheochromocytoma,
and primary parathyroid hyperplasia

Further classified into several Mutation of RET proto-oncogene and the RET protein it produces, causes increased function and leads to increased
subtypes growth and differentiation signals in tissues that express the RET protein (C-cells of thyroid, adrenal medulla,
neurons)

Clinical presentation Workup

Varies on subtype: Genetic testing for RET mutations:

Medullary thyroid cancer (MTC) → Solitary Appropriate evaluations for pheochromocytoma,

thyroid nodule or non-tender anterior cervical
lymphadenopathy; Elevated calcitonin levels;
Diarrhea, flushing, Cushing's syndrome
Pheochromocytoma (commonly bilateral) in
MEN2 vs. unilateral in sporadic cases) →
Paroxysmal anxiety, HA, diaphoresis,
palpitations, tachycardia – HTN
hyperparathyroidism, and MTC
Imaging studies include CT or MRI of the adrenals if
suspecting pheochromocytoma, may need to evaluate
for metastasis if calcitonin levels are elevated
- OctreoScan or PET scan can be useful for
examining for mets of MTC

Primary parathyroid hyperplasia → High or

inappropriately normal PTH with hypercalcemia;
Stones, bones, groans, moans, fatigue
overtones

Other findings that may be associated, based

on subtype:

(2A) Cutaneous lichen amyloidosis (CLA) → Pruritic, scaly, papular, pigmented lesion
located in the interscapular region or on the extensor surfaces of the extremities

(2A) Hirschsprung disease → Absence of autonomic ganglion cells in distal colon; Chronic
obstruction and megacolon with difficulty with defecation

(2B) Marfanoid habitus → High-arched palate; Pectus excavatum (sunken in chest);

Bilateral pes cavus (high arch); scoliosis
 Treatment Prognosis

Referral to endocrinology & possibly oncology should be done Early treatment can prevent death
Surgery is the mainstay of treatment
- Thyroidectomy at minimum, not curative very often when MTC already present as mets to MTC is present in all subtypes
cervical nodes is common
- Adrenalectomy for pheochromocytoma, often bilateral disease
- Parathyroidectomy for symptomatic disease, may observe if asymptomatic
Symptom control
- Will need to supplement TH with levothyroxine
- Will need long-term glucocorticoid & mineralocorticoids if bilateral adrenalectomy
is performed (cortisone and fludrocortisone)
Long-term monitoring
- Likely reevaluate every 6 months and eventually annually if asymptomatic
- Evaluation should include physical exam
- CEA level
- Calcitonin level
- Calcium level
- 24-hour urine catecholamine, metanephrine, and vanillylmandelic acid levels

Cutaneous Lichen Amyloidosis (CLA)

 THYROID & PARATHYROID – 8 questions
● Thyroid gland overview:
○ Highly vascular and ductless
○ Cellular composition
■ Follicle = functional unit of thyroid gland → outside layer of epithelial cells surrounding cavity filled with colloid
● Colloid = 30% of thyroid mass
■ Follicular (epithelial) cells → help thyroid hormone synthesis – these cells line the capillaries that supply the follicles
■ Parafollicular (C) cells → help produce calcitonin for calcium metabolism
● Thyroid hormones → T3 (more POTENT) & T4 (more PREVALENT)
○ Controlled by hypothalamus and pituitary gland
○ Increases O2 consumption
○ Increases thermogenesis
○ Increases expression of LDL receptor → leading to hyperlipidemia
Thyroid – Hypothyroidism:
Clinical Presentation Treatment Other

Hypo- Sxs: ⭐ Very nonspecific and

usually insidious → Fatigue,
thyroidism
lethargy, weakness,
arthralgias, Weight gain with
poor appetite, Depression, Hair
loss (thinning of eyebrows),
Bradycardia, Constipation, Cold
intolerance, Hoarseness
PE: Coarse, dry skin, Thinning of
scalp hair and lateral eyebrows,
Brittle nails, non-pitting edema of
and reflexes ⭐
LEs(myxedema), slow speech
Lab Studies → TSH elevated and Free T4 low ⭐
****Isolated elevated TSH (with normal T4) may be due
to recovery from illness, renal failure, adrenal
insufficiency
Antithyroid Ab → antithyroglobulin and
antithyroperoxidase ab (more sensitive)
1. 10% of histologic AI thyroiditis have no circulating
antithyroid ab
2. Hoshimoto’s Thyroiditis – autoimmune
Other labs → Anemia, hyponatremia, hypoglycemia,
Elevated CPK, prolactin, TG, total and LDL cholesterol
DI → ECG – sinus bradycardia and low voltage in limb
leads & CXR – look for pericardial effusion
Insufficient production of thyroid hormone
Primary etiologies:
● *Hashimoto’s thyroiditis
● Surgical resection (head/neck CA, thyroidectomy)
● Radioablation
● Infiltrative destruction
● Impaired thyroid hormone synthesis
○ Iodine deficiency (rarely dietary in US)
○ Drugs
Secondary/tertiary etiologies:
● Insufficient TRH (sarcoid infiltration of hypothalamus,
masses that impinge on pituitary stalk)
● Insufficient TSH (pituitary surgery)

Complications:
● Myxedema coma → Hypothermia, Bradycardia,
weight ⭐
Tx = levothyroxine → Dose relates to lean body

***Fe, Ca++ can interfere with Tx

Hypotension, Altered mental status, Multisystem
organ failure
● Iatrogenic thyrotoxicosis → Treatment too
aggressive?
Excess replacement
1. bone mineral loss, esp. in postmenopausal women Prognosis → Can return to normal with lifetime
2. increased risk of atrial fibrillation in older individuals levothyroxine replacement
3. in patients with underlying coronary artery disease,
the positive chronotropic and inotropic effects of
thyroxine may exacerbate myocardial ischemia
Thyroid – Hyperthyroidism:
Clinical Presentation Treatment Other

Hyper- PE: Orange peel skin (peau d’orange),

Pretibial myxedema; Thyroid: diffusely
Labs → TSH low + Free T4 high + T3 high ⭐ F > M; 30-60 yo; Genetic predisposition
thyroidism/
Graves Ophthalmopathy ⭐
enlarged, rubbery, smooth, bruit or thrill, Grave’s:
● Multinodular goiter
⭐
Etiology → Thyroid-stimulating autoantibodies
that bind to activate TSH receptor, thyroid

⭐
disease
Sxs: ⭐ Fatigue, insomnia, anxiety,
irritability, etc; Weight loss despite
● Negative Antithyroid Ab

⭐
● Positive Thyroid stimulating immunoglobulin →
this is specific to Grave’s disease
hormone secretion increased, ↑gland growth

Possible triggers → Exposure to cigarette smoke,

increased appetite; Heat intolerance,
palpitations, tremor; Hyperdefecation;
Hypercapnia, dyspnea
Exam:
- Resting tachycardia
- Systolic HTN
- Prominent apical impulse
- Proximal muscle weakness
- Brisk DTRs
- CXR may show cardiomegaly
-
⭐
ECG: resting sinus tach, Afib
Tx: 1st line is beta-blocker + thioamides
-
⭐
Beta-blocker for Tx of palpitations, tremor,
anxiety, HR
- Anti-thyroid drugs → Thioamides:
Methimazole or propylthiouracil inhibit
synthesis
- Radioactive iodine – will cause
HYPOthyroidism
- Surgery → last resort
Glucocorticoids can inhibit peripheral conversion of
T4 to T3 → short term benefit can be seen
Increased dietary iodine, Stress (sudden severe
life-changing events), Infections, Drugs
(iodine-containing like amiodarone or iodine
contrasts from CT)
Prognosis → Most will progress (worsen) without
treatment
- Monitor Methimazole or propylthiouracil Tx
with thyroid function tests q 3-12 weeks to
avoid hypothyroidism
Radioactive Tx: progressive ablation → Tx thyroid
storm more aggressively

Graves
ophthalmo
Eyelid retraction, periorbital edema,

proptosis/exophthalmos ⭐
conjunctival swelling (chemosis), at night; surgery⭐
Tx: protect corneas with drops, glasses, tape shut Inflammation & swelling of extraocular muscles and
orbital fat
pathy
Ocular irritation, foreign body sensation

Severe: exposure keratitis & corneal

ulceration, diplopia

Thyroid Fever 104 to 106ºF is common;
storm/ Tachycardia, heart failure
thyrotoxic Diarrhea, nausea, vomiting, and
crisis hepatic failure with jaundice
Agitation, delirium, psychosis,
stupor, or coma are common
- Admit to ICU/IV fluids/Oxygen Rare but life-threatening complication
- High doses IV propranolol
- Thioamides (methimazole or Can be triggered by illness, surgery, Rad Rx,
propylthiouracil) non-compliance, iatrogenic
- Ice packs/cooling blankets/Tylenol for
hyperthermia
- IV corticosteroids: ↓ peripheral conversion
of T4 to T3

Other Toxic Adenoma → Thyroid tumor that secretes thyroid hormone independent of TSH stimulation
causes: - Usually benign

Toxic Multinodular Goiter → Multiple nodules that secrete thyroid hormone

Thyroid – Subacute Thyroiditis:

Clinical Presentation Treatment Other

Subacute Painful enlargement of the thyroid
Thyroiditis gland, often with dysphasia, pain
may radiate to the ear; mild fever
and fatigue
Transient thyrotoxicosis followed by
transient or persistent
hypothyroidism – back to normal
Labs → T4 & ESR elevated
Tx:
1. Symptomatic in thyrotoxic phase
2. Thyroid replacement in the hypothyroid phase
**If thyrotoxic crisis, treat with beta blockers,
glucocorticoids, bile acid sequestrants (cholestyramine to
reduce hepatic recycling of thyroid hormone), excess
iodine solution blocks release of T4 & T3 within hours
Leakage of thyroid hormone from inflamed
gland
Stored hormone usually exhausted in 2-8
weeks and thyrotoxicosis resolves
Men and women of all ages
Etiology → Viral/URI; Postpartum
Can be painful or silent

Thyroid – Thyroid nodules:

Overview Physical examination of the thyroid nodule should seek to define its size, consistency, surface texture, mobility, and tenderness

Epidemiology → About 4-6.5%, overall, related to some form of cancer

Greater risk of cancer in certain populations → Children; Adults under 30 or over 60-years old; Family history; History of head / neck irradiation

Low TSH → Order a thyroid scan – “Cold” nodules are more likely to be cancerous

High TSH → Check antithyroid antibody titers – Use US to distinguish between hyperplasia and distinct nodules

Normal or Indeterminate TSH → FNA biopsy

FNA Bx Benign: (~70%) → No therapy needed unless a cosmetic issue or if enlargement leads to compressive symptoms

FNA Bx is Malignant: (~5%)

- Papillary, follicular, or medullary thyroid carcinoma: Go to surgery
- Anaplastic thyroid carcinoma or thyroid lymphoma: Chemo and radiation

FNA Non-diagnostic: (~15%) → Go to ultrasound-guided FNA biopsy

FNA Indeterminate: (10%) → Surgery vs. thyroid scan

Papillary Most common type of all thyroid cancers 70-80%

Thyroid - Females about 3 times more likely than males
- More common between ages 30-60-years old
Cancer - Typically more aggressive in older patients
- Does not usually spread beyond the neck
Follicular 10-15%
Cell Thyroid - Females 3 times more likely than males
- More common in adults age 40-60-years old
Cancer - Can be more aggressive in older patients
- More likely to metastasize to bone/lung tissue

Medullary 3-5% and more likely family history

Thyroid - Females and males equally
- Most common in 40-50-years old
Cancer - Typically metastasis has already occurred by time it is identified
- Usually associated with increased calcitonin

Anaplastic <2%
Thyroid - Very rare, but the worst prognosis
- About 70% of cases occur in women
Cancer - Average age at diagnosis about 65-years old
- Very aggressive, metastasis is likely present and diffuse (median survival is 3-7 months after diagnosis)
 Parathyroid function:
Calcitonin PTH

- Primarily produced in thyroid - Secreted by parathyroid

- Antagonistic to PTH - Stimulates reabsorption of calcium from bone
- Decreases serum calcium levels - Stimulates reabsorption of calcium in the kidneys as well as in
- Stimulates deposition in the bones and secretion from the GI tract
the kidneys - Antagonist to calcitonin
- Increases serum calcium levels

Disorders of the parathyroid gland:

Clinical Presentation Treatment Other

Hypo-
parathyroidism
Symptoms (hypocalcemia) Laboratory Studies:
- Serum Ca low ⭐ Chvostek’s sign → Abnormal reaction to the
stimulation of the facial nerve
Muscle cramps; Abdominal pain ⭐
Acute → Tingling lips, fingers, toes; -
-
-
Serum phosphate high
PTH low
Serum Mg low (may be the
***When the facial nerve is tapped at the angle of the
jaw (masseter muscle), the facial muscles on the
same side of the face will contract momentarily
Chronic → Brittle nails; Cataracts; cause) because of hypocalcemia with resultant
Tetany Low magnesium can cause reduced PTH hyperexcitability of nerves
secretion or induce PTH resistance.
Signs: - What is serum albumin? Trousseau’s sign → BP cuff is placed around the
- Chvostek’s sign - Why do we care: arm and inflated to a pressure greater than the
- Trousseau’s sign hypoalbuminemia systolic blood pressure and held in place for 3
⭐
Others – muscle stiffness and spasms causes drop in total
Ca++
Calcium binds to albumin, thus corrected
minutes (occlude brachial artery)
****In the absence of blood flow, hypocalcemia and
subsequent neuromuscular irritability will induce
calcium level is needed for patients with spasm of the muscles of the hand and forearm (wrist
hypoalbuminemia, may have low levels at and MCP joints flex, the DIP and PIP joints extend,
testing, but normal levels once corrected and the fingers adduct)
(this is ionized calcium) - Also known as main d'accoucheur ("hand of
the obstetrician") because it supposedly
Corrected calcium (mg/dL) = measured resembles the position of an obstetrician's
total calcium (mg/dL) + 0.8 (4 – serum Alb hand in delivering a baby
g/dL)
Etiology → related to neck/thyroid surgery or
Management: autoimmune mediated
1. Correct low Mg
2. Calcium supplementation → Epidemiology → rare, no exact data available
Which is always accompanied by
Vitamin D Pseudohypoparathyroidism → increased PTH, low
- Need vitamin D for Ca++, high phos
calcium to be absorbed
in the gut.
Hyper- Sxs → Most are asx and discovered on Labs: Epidemiology
parathyroidism routine screening

Symptomatic patients have “bones,

-

-
normal ⭐
Serum Ca – usually high, may be

Serum phosphate – low or low

-
-
> in postmenopausal women
May be genetic link

stones, abdominal groans, psychic

moans with fatigue overtones.”
⭐ -
normal
Serum PTH – high or high-normal
Etiology → hypersecretion of PTH
Parathyroid adenoma (80-90%)

“Bones” → Excess PTH induces

chronic bone resorption, producing:
Management → Surgical ⭐
Medical – continue to monitor if
Parathyroid hyperplasia (~2%)
Parathyroid carcinoma (rare, ~1%)
Lithium use, Hx radioactive iodine Tx, Rad Rx to
- Diffuse demineralization asymptomatic neck, familial
- Bone cysts
- Pathologic fractures Complications of Surgery → recurrent Drugs - Thiazide diuretics are a med that are
- **Bone pain and arthralgias laryngeal nerve injury or inadvertent notorious for increased calcium levels
“Abdominal Groans” removal of all 4 glands, resulting in
- Constipation permanent hypoparathyroidism
- N/V
- Abdominal pain Prognosis is excellent with surgery
- Pancreatitis (rarely)
“Stones” → Hypercalcemia
overwhelms ability of renal tubules to
reabsorb Ca, resulting in hypercalciuria
producing
-
-
**Kidney stones
Nephrocalcinosis
⭐
- Renal failure
- Polyuria and polydipsia d/t
“Psychic Moans / Fatigue Overtones”
- Poor concentration
- Depression
- Psychosis (rare)
- Fatigue, lethargy, weakness
 ADRENAL DISORDERS – 8 questions
● Adrenal gland overview:
○ Bilateral endocrine glands resting on the superior pole of the kidneys
○ Composed of two main regions:
■ Adrenal Cortex – produces steroid hormones (corticosteroids) [“GFR-ACE” mnemonic]
● Glomerulosa (G) – produces mineralocorticoids (primarily aldosterone (A))
● Fasciculata (F) – produces glucocorticoids (primarily cortisol (C))
● Reticularis (R) – produces adrenal androgens (primarily estrogen/dehydroepiandrosterone (DHEA))
■ Adrenal Medulla – produces catecholamines (think “fight or flight”)
● Epinephrine
● Norepinephrine
● Dopamine
○ Disorders of the Adrenal Glands:
■ Hypoaldosteronism
■ Cushing’s Syndrome (Cushing’s Disease is a pituitary disorder)
■ Adrenal Insufficiency (chronic + acute)
■ Pheochromocytoma
○ Aldosterone:
■ Plays an important role of sodium, chloride, potassium, and indirectly, water homeostasis
■ Thus called mineralocorticoid hormone (class of corticosteroid)
■ Synthesized by zona glomerulosa
■ Stimulates renal tubular Na+ reabsorption and renal K+/H+ secretion – keep Na, dump K
■ Secretion primarily stimulated by hyperkalemia and angiotensin II
● Angiotensin II is stimulated by hypovolemia/hypotension
Disorders of the Adrenal Cortex:
Clinical Presentation
Hyper- Refractory hypertension → this
aldosteronism should raise a red flag to search
for secondary causes
How many meds should we
prescribe before we are clued in
that the HTN is refractory? → 5
or more according to the AHA
HA, muscular weakness, fatigue,
muscle cramps – if present with
refractory HTN
HTN with adrenal incidentaloma
If some of the above mentioned
symptoms are present with low
K+ levels (9-37% have this
finding) and possibly metabolic
alkalosis, suspicion should
increase
Treatment
Dx:
BMP – assess for hypokalemia, hypernatremia (less
common), metabolic acidosis
Plasma renin activity – low in primary, high in secondary
hyperaldosteronism → Plasma aldosterone level
- Plasma aldosterone: plasma renin activity >20
suggestive of primary hyperaldosteronism
After confirming primary hyperaldosterone biochemically,
CT of adrenal glands to find etiology (adenoma vs
hyperplasia?)
→ Often this happens in the reverse order; CT
incidentaloma found out and biological assays are used to
find if it is secreting hormones
Tx:
Adrenalectomy → not preferred in bilateral adrenal
hyperplasia (then we end up with renal insufficiency) may
be helpful for a unilateral secreting tumor
Spironolactone (Aldactone) – mineralocorticoid
antagonist diuretic (ex: K+ sparing diuretic/aldosterone
agonist)
Hypertension management
This is important beyond controlling HTN
Over time, aldosterone is known to stimulate left
ventricular hypertrophy, which can lead to diastolic heart
failure
For secondary hyperaldosteronism, we treat the underlying
condition
Other
F>M
Hyperaldosteronism → Excessive secretion of
aldosterone by adrenals
- Rare cause of secondary HTN
Primary hyperaldosteronism (Conn’s
Syndrome): Secondary to adrenal hyperplasia
(50-60%), adrenal adenoma (40-50%), adrenal
carcinoma (very rare) (Renin-independent)
- Elevated aldosterone, low renin due to
negative feedback
- Uninhibited aldosterone secretion
Secondary hyperaldosteronism: Secondary to
renovascular HTN (renal artery stenosis),
diuretic use, severe heart failure
- Elevated aldosterone and elevated
renin
- Body attempting to increase perfusion to
kidneys
Secondary Hyperaldosteronism and
Pharmacotherapy
- The secretion of renin is in part based on the
juxtaglomerular cells assessment of volume
status
- If the kidneys have decreased perfusion due
to severe CHF or bilateral renal artery
stenosis, renin is released and aldosterone
is secreted
- In these cases, the juxtaglomerular cells are
“faked” into thinking there is a state of
hypovolemia
- This can worsen cardiac hypertrophy and
fluid retention due to the effects of
aldosterone
- This highlights the need for ACEi and
aldosterone antagonists in evidence-based
treatment of CHF
Hyper- AKA: Cushing's Syndrome or Dx: Cortisol → Steroid hormone produced by the
cortisolism Cushing’s Disorder Labs → Hyperglycemia, Glucosuria, Hyperlipidemia, zona fasciculata of the adrenal cortex
Leukocytosis, Elevated serum/urine free cortisol Released in response to a stressor (through HPA
Symptoms of Cushing’s axis) or low blood glucose concentration
Syndrome: Step 1: Is hypercortisolism actually present?
Three approaches generally:
⭐
Generalized: Extensive and complex functions include:
- Weight gain 1. 11pm salivary cortisol – Enhance hepatic
- Slow healing 2. 24-hour urine free cortisol glycogenolysis/gluconeogenesis and
3. Overnight 1 mg Dex Suppression
⭐
- Glucose intolerance counteracting insulin in the peripheral tissues (all
- Moon face Healthy individuals have low cortisol levels at night of which results in increased blood glucose
- Buffalo hump levels)
Skin Step 2: – Suppressing the immune system and
Serum ACTH
⭐
- Thinning defense response associated with stress, illness,
- Striae - If normal/elevated → ACTH secreting tumor and infection
- Acanthosis nigricans (Cushing’s disease, paraneoplastic secretion of – Stimulating gastric acid secretion (thus the
Vascular → High BP ACTH) need for stress ulcer prophylaxis!!)
Bones → Increased risk of - If suppressed → Adrenal cushing (cortisol – Reduce bone formation and collagen
fractures secreting adrenal tumor, iatrogenic Cushing synthesis (thus the use of bisphosphonates in
syndrome) chronic glucocorticoid users!)
MRI of the pituitary→ Is there a tumor? – Aiding in the metabolism of fat, protein, and
- 10% of the population have incidental, benign carbs
tumors of the pituitary – Producing procoagulant factors and impairing
CT scan of the adrenal glands →Is there a tumor? fibrinolysis
- Consider CT of the chest if looking for an ectopic – Promoting sodium absorption in the small
source such as small cell lung cancer intestine
– Increasing vascular tone
Tx → Transsphenoidal pituitary adenoma resection (for
Cushing’s disease) Cushing’s Syndrome: a symptom complex that
- Adrenal tumor resection (if adenoma present) reflects excessive tissue exposure to
- Bilateral adrenalectomy (if bilateral adrenal glucocorticoids (MC 20-50 y/o; 10-15 million
hyperplasia is the cause or for symptom people being affected each year)
management for inoperable Cushing’s disease
patients) Cushing’s Disease: when Cushing’s Syndrome
- Resection of ectopic ACTH producing tumors is secondary to hypersecretion of ACTH
- Radiation therapy → risk of hypopituitarism secondary to a pituitary tumor (F>M; 5:1)
Medical Therapy: - Rarely due to ectopic ACTH production
- Ketoconazole / metyrapone inhibit steroid secondary to non pituitary ACTH
synthesis secreting tumors (sometimes seen in
- Mifepristone blocks steroid effects - for patients lung cancers or adrenal tumors)
with glucose intolerance
- Mitotane is cytotoxic to adrenal cortical cells
Disorders of the Adrenal Cortex – Adrenal Insufficiency:
Clinical Presentation
Adrenal AKA: Addison’s Disease
Insufficiency
Primary adrenal insufficiency →
disease of the adrenal glands
Presentation vague! ⭐
May present with history of malaise,
fatigue, anorexia, weight loss, joint
pain, back pain, or darkening of the
skin (creases of hands, extensor
surfaces, recent scars, buccal and
vaginal mucosa, and nipples)
May crave salt and may develop
unusual food preferences such as
drinking the brine from pickles (from
low aldosterone)
PE:
- Orthostatic hypotension
- Dry mucous membranes
- Hyperpigmentation
Treatment
Labs → Hyponatremia, Hyperkalemia, Hypoglycemia, Eosinophilia, Elevated ACTH, Low cortisol
Step 1: Is hypocortisolism present?
1. AM plasma/salivary cortisol (when cortisol should be high) is not a sensitive test, a low value would be consistent with
adrenal insufficiency
2. 24 hour urine cortisol can also be used but is less reliable because it can be low/normal with only partial adrenal
insufficiency, a low value would be expected in adrenal insufficiency
3. ACTH stimulation test (gold standard) - a large dose of ACTH is injected IM or IV, 60 minutes later cortisol levels are
drawn, low values indicate adrenal insufficiency
If “yes” to Step 1 → Step 2: What is the cause?
Serum ACTH
- High ACTH indicates the problem is the adrenal glands and the diagnosis could be primary adrenal insufficiency
- Low ACTH indicates that there is a pituitary or hypothalamic disease (secondary or tertiary disease)
In the case of suspected primary adrenal insufficiency, plasma aldosterone and renin levels can also be obtained.. What
results would we expect?
1. Low aldosterone (primary destruction of adrenals)
2. Elevated renin (compensatory for decreased aldosterone)
Abdominal X-rays: adrenal calcification in half the patients with TB Addison’s disease
CT is more sensitive detector of adrenal calcification and adrenal enlargement
- Bilateral adrenal involvement may be seen with TB, fungal infections, CMV, malignant and nonmalignant
infiltrative diseases, and adrenal hemorrhage
Tx:
Acute Management:
- Steroids, typically hydrocortisone (has glucocorticoid and mineralocorticoid activity)
- IV dextrose (correct hypoglycemia)
- IV 0.9% NS (volume) → D5/0.9% NS would be a good choice for IVF
● Search for cause
Chronic Management:
- Lifetime treatment with oral glucocorticoid: hydrocortisone (split dosing), Prednisone (once daily) → Adjust
dose based on symptoms
- Don’t limit salt intake
- Mineralocorticoid: Fludrocortisone (Florinef) → Titrate dose until plasma renin normalizes
- DHEA
Other
Adrenal Crisis
- Acute primary adrenal insufficiency presents with orthostatic hypotension, agitation, confusion, circulatory
shock, abdominal pain, nausea, vomiting, and possibly fever
- Acute generally caused by hemorrhage, metastases, or acute infection
- Can also occur in already diagnosed Addison’s patient who can’t take their medications or in one who is severely
stressed (severe infection/surgery) without increasing steroid dosing
- This can be fatal
Secondary Secondary adrenal sufficiency → Dx: See Step 2 above; low ACTH indicates that there For both primary and secondary:
Adrenal disruption of the HPA axis is a pituitary or hypothalamic disease (secondary or Good outlook with treatment (normal life
tertiary problem) expectancy)
Insufficiency
Abdominal X-rays, CT is more sensitive → Same as 100% lethal without treatment!!
above

Tx →Same as above

Management of adrenal insufficiency secondary to

long-term glucocorticoid use:
- Recovery thought to take one month for every
month of suppression with 9-12 months needed
to recovery from glucocorticoid therapy lasting
>1 year
- Slow steroid taper using either hydrocortisone
or prednisone until ACTH normalizes
Disorders of the Adrenal Medulla:
Catecholamines Increased BP (due to peripheral vasoconstriction), myocardial contractility, cardiac Epinephrine (Adrenaline) and Norepinephrine
conduction velocity are both synthesized by and stored in the adrenal
medulla
Stimulation of B1 receptors increases renin secretion, bronchodilation, vasodilation in
skeletal muscle, etc. Dopamine is the precursor of norepinephrine
and is found in the adrenal medulla

All 3 act as a neurotransmitters and hormones

Norepi and dopamine are also stored in

peripheral sympathetic nerves

Have widespread effects and “ramp up”

sympathetic nervous system effects, which
mediates the “flight or flight” response

Biologic half life of circulating catecholamines is

only between 10 and 100 seconds, thus leading
to highly fluctuating serum concentrations

Noticeable effects:
Pupils dilate
Muscles tense
Heart pumps faster
Palpitations
Sweating

Hidden effects:
Blood pressure rises
Liver releases glucose to provide energy for muscles
Digestion slows or ceases
 Clinical Presentation

Pheochromocytoma Symptoms are secondary to excessive circulating catecholamines and can be sustained or paroxysmal, these paroxysms can be
fatal
1. Refractory HTN (secondary HTN) → on multiple meds without response or with adequate response
2. Forceful heartbeat, pallor, tremor, headache, and diaphoresis
3. The spell may start with a “rush” in the chest followed by sense of shortness of breath, followed by a pounding heartbeat, this might
progress to a throbbing headache
4. Peripheral vasoconstriction results in cold hands, feet, and facial pallor
5. Increased body heat and sweating are common symptoms that can occur, sometimes at the end of a spell

SSx
Hypersensitive retinopathy
Orthostatic HTN
Angina
Nausea
Constipation
Hyperglycemia
Raynaud’s phenomenon
Livedo reticularis
Mass effects from the tumor

“Spells”

May be spontaneous or precipitated by postural change ⭐ ⭐

, anxiety , meds (such as anesthetic agents), exercise, or maneuvers
that increase intraabdominal pressure (change in position, lifting, defecation, exercise, colonoscopy, pregnancy, trauma)
Although highly variable, spells tend to be stereotypical for each patient

May occur multiple times a day or as infrequently as once a month

Typical duration of pheochromocytoma spell is 15-20 minutes, but may be shorter or last several hours

Most patients with spells do not have a pheochromocytoma

“The 5 P’s”
Pressure: sudden increase in BP – especially paroxysmal
Pain: HA, chest, and abdomen
Perspiration
Palpitation
Pallor
 Epidemiology Diagnosis

Pheochromocytoma Part of MEN2a and MEN2b
syndromes, which are autosomal
dominant disorders, thus if you
patient has one of the associated
components of these syndromes,
suspicion for pheochromocytoma
can increase
MEN2a – adrenal
pheochromocytoma, medullary
carcinoma of the thyroid,
hyperparathyroidism, cutaneous
lichen amyloidosis
MEN2b – adrenal
pheochromocytoma, medullary
carcinoma of the thyroid, mucosal
neuromas, marfanoid body habitus
Even if adrenal mass is noted and symptoms support diagnosis, diagnosis is by increased
plasma ⭐
concentration of fractionated catecholamines and fractionated metanephrines in urine or
→ Metanephrines are “breakdown” products of epi/norepi
24 hour urine fractionated metanephrines and catecholamines → Most reliable method given
short half life and tendency of paroxysms (98% sensitivity, 98% specificity) Pretty darn accurate
Plasma fractionated metanephrines have longer half-life than catecholamines → This is why only
they are drawn when using plasma testing
- Useful to exclude pheochromocytoma, but poor specificity (96-100% sensitivity, 85-89%
specific)
Also expect hyperglycemia, normal thyroid panel, and possible leukocytosis
Tricyclic antidepressants interfere most frequently with 24 hour urine results → For effective
detection of catecholamine secreting tumors, treatment with tricyclic antidepressants should be
tapered and discontinued at least 2 weeks before any hormonal assessments
- Catecholamine secretion may be appropriately increased in situations of physical stress or
illness (stroke, MI, CHF, OSA)
Imaging → Only to be used after biochemical testing has returned a positive result
- CT or MRI imaging of the adrenal glands and abdomen

Treatment While waiting for surgery Follow up

Pheochromocytoma Tumor excision: surgical survival
rates are 98-100%
Most catecholamine-secreting
tumors are benign and can be totally
excised
Tumor excision usually cures
hypertension
Pre-operative HTN management -
prevent hypertensive crisis due to
release of catecholamines
Post-op urinary catecholamines
chemotherapy for metastatic
pheochromocytoma
Combined alpha/beta adrenergic blockade is
used to control HTN and to prevent intraoperative
hypertensive crisis; Get the alpha blockade
started first!
- Alpha blockade: phenoxybenzamine or
prazosin, terazosin, doxazosin
- Beta blockade: propranolol or
metoprolol
- Carvedilol (Coreg) is a non-selective
B-blocker and an alpha-1 blocker
If only beta-adrenergic blockade is performed,
unopposed a-adrenergic stimulation in response
may make HTN more severe
24 hour urinary excretion of fractionated
catecholamines and metanephrines or plasma
fractionated metanephrines should be checked
annually for life
Assess for metastatic disease, tumor recurrence
in adrenal bed, or delayed appearance of multiple
primary tumors
Follow up CT or MRI not needed unless the
metanephrine or catecholamine levels become
elevated (or original tumor not assoc with
catecholamine or metanephrine excess)
 DIABETES MELLITUS – 9 questions

● Important definitions:
○ Glucose – the primary source for energy into the cell (not the only one, FFAs, etc.)
○ Glycogen – polysaccharide of “stored glucose”
○ Glucagon – hormone from the pancreas that promotes glycogen → glucose in the liver
○ Incretins – augment insulin secretion in the pancreas
● Insulin:
○ Action: insulin exerts its effects by first binding to a specific insulin receptor that is present on many cells throughout the body:
■ Brain: decrease hepatic glucose production, decrease lipoprotein production, increases hunger
■ Liver: increases glycogen synthesis, decreases glucose synthesis
■ Adipose tissue: increases glucose metabolism and lipogenesis, decreases lipolysis
■ Peripheral muscle: increases glucose metabolism, glycogen synthesis
○ Several genetic syndromes of severe insulin resistance have been identified are associated with point mutations of the insulin receptor genes
○ These patients have marked hyperinsulinemia and sometimes other abnormalities such as acanthosis nigricans and hyperandrogenism.

Type 1 Diabetes (T1DM)

Intro/Etiology Pathogenesis

- One of the most common chronic diseases in childhood Incidence of T1DM varies based upon:
- Caused by insulin deficiency following destruction of the 1. Geographical variation
insulin producing pancreatic beta cells. 2. Age and gender – the age of presentation of T1DM has a bimodal
- Most commonly presents in childhood distribution.
- 25% of T1DM presents in adulthood - One peak at 4-6 y/o
- 2nd peak at early puberty (10-14 y/o)
- 45% of children present before 10 y/o

Lifetime Risks Pathogenesis

The lifetime risk of developing T1DM is significantly increased in close Type 1DM results from autoimmune destruction of the insulin producing
relatives of a patient with T1DM.
- No family history = 0.4%
- Offspring of an affected mother = 1 to 4%
- Offspring of an affected father = 3 to 8%
- Offspring of both parents affected = 30%
- Non-twin sibling of affected patient = 3 to 6%
- Dizygotic twin = 8%
- Monozygotic twin: 30% within 10 years of dx of 1st twin
beta cells in the islets of Langerhans.
- Occurs in genetically susceptible subjects and is triggered by one or
more environmental agents
- Usually progresses over many months or years
- Genetic markers for T1DM are present from birth
- Immune markers are detectable after the onset of the autoimmune
process
- Metabolic markers can be detected with sensitive tests once enough
beta cell damage has occurred
 Pathogenesis – MHC Complex/Autoantigens
MHC Genes (Major histocompatibility complex):
- MHC genes are the major susceptibility genes for T1DM.
- They are in the HLA region on chromosome 6p.
- MHC binds to the antigens involved in the pathogenesis of
T1DM.
- This binding allows it to be presented to antigen receptors on
T cells which are the main effector cells of the destructive
autoimmune process → don't need to know gene right now
Autoantigens:
Insulin: early appearance of anti insulin antibodies suggests that
insulin is an important autoantigen.
Glutamic acid decarboxylase: antibodies to GAD are found in
approximately 70% of patients with T1DM.
Insulinoma associated protein 2: autoantibodies to IA2 usually
appear later than autoantibodies to insulin and GAD.
Pathogenesis – Diet
Cow’s milk: some components of albumin in cow’s milk may trigger
an autoimmune response and increased risk for T1DM,
Cereals: in infants at high risk for T1DM, the timing of initial exposure
to cereals may affect the risk of developing islet cell antibodies.
Vitamin D supplements: vitamin D has a protective role to decrease
the risk to develop T1DM.
Omega 3 fatty acids: studies support a protective role of omega 3
fatty acids in the inflammatory response associated with autoimmune
islet cell destruction.
Pathogenesis – Environmental
Perinatal factors: pregnancy-related and perinatal factors are associated
with a small increase in risk of T1DM including preeclampsia, neonatal
respiratory disease, jaundice, especially that due to ABO blood group
incompatibility.
Role of viruses: viruses can cause diabetes in animal models either by
directly infecting and destroying beta cells or by triggering an autoimmune
attack against these cells → ex: Coxsackie B virus and enteroviral infections
Childhood immunization: there has been concern that childhood
vaccination may be associated with later development of chronic diseases,
including T1DM, however immunization of genetically predisposed infants
(siblings with T1DM) with viral and bacterial antigens doesn’t appear to be
associated with an increased risk of developing T1DM. At this time it appears
we are still safe to vaccinate these children.
Clinical Presentation
New onset of chronic polydipsia, polyuria and weight loss
- Diabetic Ketoacidosis
- Silent (asymptomatic) incidental discovery.
- Hyperglycemia without acidosis is the most common
presentation
Patients may present with the following “classic” symptoms…
1. Polyuria: occurs when serum glucose rises above 180 mg/dl,
increased urinary glucose excretion ⭐
exceeding the renal threshold for glucose which leads to
→ may present as nocturia, bedwetting, or daytime incontinence in a
previously continent child, in children who are not toilet trained, parents may
note an increased frequency of wet diapers and/or diapers that are unusually
heavy
from hyperglycemia and hypovolemia ⭐
2. Polydipsia: increased thirst due to increased serum osmolality
3. Weight loss: a result of hypovolemia and increased catabolism, as
⭐
insulin deficiency in diabetic children impairs glucose utilization in
skeletal muscle
 Clinical Presentation – DKA
The second most common presentation of T1DM.
The reported frequency of DKA as the initial presentation for
childhood is approximately 30%
Symptoms of DKA include:
- Polyuria
- Polydipsia
- weight loss but more severe
- “fruity” smelling breath and neurologic findings
including drowsiness and lethargy
Diagnosis
Signs of Abnormal Glucose Metabolism:
- Fasting plasma glucose >126 on more than one occasion
- Random venous plasma glucose >200 in patients with classic
symptoms of hyperglycemia
- Plasma glucose >200 mg/dl measured 2 hrs. after a glucose
load of 1.75 g/kg in an oral glucose tolerance test.
- A1C >6.5 percent
Hemoglobin A1C: measures the percent of hemoglobin A bound
to glucose via non enzymatic glycation and indicates the average
blood glucose level for 10-12 weeks.
- A1C >6.5 percent is now an accepted criterion for
diagnosis of DM in adults
→ The diagnostic utility of A1C for children is less well established
than for adults.
Clinical Presentation – Silent
Some children will be diagnosed with T1DM before the onset of clinical
symptoms
This presentation is least common and typically occurs in children who have
another close family member with T1DM.
Pediatric Management
Balancing the goal of strict glycemic control which reduces the risk of
long-term sequelae of chronic hyperglycemia against the goal of avoiding
severe hypoglycemia.
Setting realistic goals for each child and their family.
Training the patient and family to provide appropriate daily diabetes care:
- Monitoring BG
- Administering appropriate insulin
- Monitoring diet
What to do in a diabetic emergency outside of the hospital?
→ Give glucose
- If the patient is in a diabetic coma from hyperglycemia, you may just
wake them up; conversely, if the patient is in DKA or HHS, probably
not going to make that BG go much higher or make their condition
worse.
Maintaining normal growth, development and emotional maturation with
increasing independence and self care of diabetes as a child grows older
- Trying to make their life as normal as possible
 Initial Management
1. Basic understanding → the diabetes team teaches the patient and family
the cause and treatment, how to maintain a daily schedule and record of
blood glucose, insulin administration and carbohydrate content of meals and
snacks
2. Blood glucose testing
3. Insulin administration → teaching the family about different types of
prescribed insulin, how to measure and inject insulin and rotate injection sites. measured serum glucose of <70 mg/dL
4. Hypoglycemia → families are taught to recognize the signs and symptoms
of hypoglycemia
5. Blood or urine ketones → families are taught to check urine for ketones
or measure blood beta hydroxybutyrate concentration at times of illness
and/or if 2 consecutive blood glucose readings are greater than 250 mg/dl
Hypoglycemia – Clinical Presentation
Infants and Children:
Neurogenic (autonomic) symptoms: caused by response of the
sympathetic nervous system; BG less than or equal to 55 to 60 mg/dL.
- Sweating, tremor, palpitations, tachycardia, and hunger
Neuroglycopenic symptoms: caused by insufficient supply of glucose to the
brain, BG less than or equal to 50 mg/dL
- lethargy, confusion, irritability, loss of consciousness, and seizure.
Adults:
Neurogenic symptoms → Tremor, palpitations, sweating, hunger, and
anxiety/arousal (catecholamine-mediated, adrenergic) and paresthesias
(acetylcholine-mediated, cholinergic)
Neuroglycopenic symptoms → Dizziness, weakness, drowsiness, delirium,
confusion, seizure, and coma
Although profound, prolonged hypoglycemia can cause brain death in the
unobserved patient with diabetes, the vast majority of episodes are reversed
after the glucose level is raised. The rare fatal episodes are generally thought
to be the result of ventricular arrhythmia.
Hypoglycemia
The insufficiently low concentration of available glucose in the serum
- Infants and Children: <50 mg/dL
- Adults: usually <70 mg/dL
Severe Hypoglycemia: an event requiring an outside individual to administer
carbohydrates, glucagon, or other resuscitation
Documented Symptomatic Hypoglycemia: symptoms of hypoglycemia with a
Asymptomatic Hypoglycemia: a measured serum glucose of <70 mg/dL with no
symptoms of hypoglycemia
Probable Symptomatic Hypoglycemia: event with typical symptoms of
hypoglycemia and no measured serum glucose
Pseudohypoglycemia: event in which a diabetic reports symptoms of hypoglycemia
with a measured serum glucose >70 mg/dL
Hypoglycemia – Management
Management depends on the AGE, cognitive ability and emotional maturity
Infants → highest risk of severe hypoglycemia because infants are unable to communicate their
symptoms (poor feeding, lethargy, jitteriness and hypotonia). Severe hypoglycemia can
present with seizures or coma which may cause permanent neurologic sequelae.
Toddlers → avoiding hypoglycemia can be challenging because of erratic food intake and
activity levels of toddlers.
Preschool and early school aged children → shared care with the child is appropriate at this
age only under direct parental supervision.
School aged children (8 to 11 years old) → the child can learn to administer the routine insulin
injection but still needs significant assistance and supervision.
- Psych impact – depression, anxiety, difficulty with social interactions → due to
perception that they are different from their peers.
Adolescents → increasing independence:
- Driving – test blood glucose levels before driving → understand the risks of driving
while hypoglycemic and carry carbohydrate snacks
- Alcohol intake – associated with severe hypoglycemia
- Smoking – risk factor for long term diabetic complications
- Sexual activity – adolescent girls should be given preconception counseling that
includes the risks of diabetes complications to themselves and potentially the fetus →
encourage use of contraception
 Management Goals
Target A1C of <7.5 percent
Target blood glucose level 90 to 130 mg/dl before meals and 90 to 150
mg/dl at bedtime and overnight
Fingerstick: blood glucose should me tested at least four times a day (in the
fasting state aka before meals and at bedtime)
Continuous glucose monitoring: subcutaneous glucose sensors that
continuously measure interstitial fluid glucose are available and approved for
use in children → CGM can be incorporated into insulin pump therapy.
Insulin & Insulin Delivery
Insulin: insulin therapy is the mainstay of treatment for T1DM.
- GOAL: replace the deficient hormone and to attain normoglycemia
Insulin preparations:
Rapid acting (lispro, aspart, glulisine) and/or short acting insulins (regular insulin)
- Typically administered as a pre meal bolus
- 5 to 15 minutes before the meal for the rapid acting insulins
- 20 to 30 minutes before meals for the short acting type
- Based on carbohydrate content of food and blood glucose level
Intermediate acting (NPH) → provides some coverage for meals.
Long-acting insulin preparations ( insulin glargine, insulin detemir)
- given once or twice a day → (“Basal-bolus” method, also incorporate a
“sliding scale”)
Needle and syringe: the advantage is NPH and short or rapid acting can be mixed in
a single injection.
Pens: pens are supplied pre-filled with insulin, the ease of use and portability of pens
are appealing to many patients.
Insulin pump: insulin pump therapy should be considered for patients with one or
more of the following characteristics:
1. Recurrent severe hypoglycemia
2. Wide fluctuations in blood glucose levels
3. Suboptimal diabetes control
4. Microvascular complications
 Type 2 Diabetes (T2DM)
Intro/Epidemiology
Diabetes is one of the major causes of early illness and death
worldwide
Affects ~8% of the United States population
Worldwide the prevalence of type 2 diabetes is estimated at 6.4% in
adults, varying from 3.8 to 10.2% by region
Type 2 diabetes accounts for >90% of patients with diabetes
Genetics:
The prevalence of type 2 diabetes varies among ethnic groups living
in the same environment → Type 2 DM is 2 to 6 times more prevalent
in African Americans, Native Americans, Pima Indians and Hispanic
Americans in the USA than in whites
39% of patients with type 2 DM have at least one parent with the
disease
Pathogenesis – Diet, Obesity, & Inflammation
Diet, Obesity, & Inflammation → The prevalence of impaired
glucose tolerance and type 2 DM has increased dramatically in the
USA in the past 2 decades. The most striking features in these groups can inhibit insulin-stimulated glucose uptake in patients with type 2 DM
are increased weight gain and decreased physical activity
Obesity causes peripheral resistance to insulin mediated glucose
uptake and decreases the sensitivity of the beta cells to glucose
Inflammation has a role as a common mediator linking obesity to
both the pathogenesis of diabetes and atherosclerosis (hardening of
the arteries)
- The incidence of type 2 DM has been correlated with
increased levels of markers of inflammation including
C-reactive protein, interleukin 6, plasminogen activator 1
inhibitor, tumor necrosis factor alpha and white cell count
Pathogenesis – Impaired Insulin Secretion
Impaired insulin secretion and insulin resistance:
Insulin secretion: insulin secretion by beta cells requires glucose transport into the
cell which is mediated by the glucose transporter 2
- High fat diet negatively affects GLUT-2 causing glucose intolerance.
Insulin resistance: the best predictor of T2DM.
- Insulin resistance becomes more severe with increasing age and weight.
Impaired insulin processing:
- Insulin production in normal subjects involves cleavage of insulin from
proinsulin
- 10 to 15% of secreted insulin is proinsulin → In type 2 diabetes mellitus
proinsulin is increased to 40%
Islet Amyloid Polypeptide:
- Amylin is stored in insulin secretory granules in the pancreatic beta cells
- Co-secreted with insulin resulting in serum concentrations one-tenth of
insulin
- High concentrations of amylin decreases glucose uptake and inhibit
endogenous insulin secretion suggesting that amylin may be directly
involved in the pathogenesis of type 2 DM. (not used commonly)
Pathogenesis – Free Fatty Acids/Factor Released From Adipose Tissue
Free Fatty acids → plasma FFA concentrations are high in obese patients, high
concentration of FFA is a risk factor for type 2 DM as they inhibit insulin secretion and
Factors released from Adipose Tissue:
Leptin: produced by adipocytes in proportion to adipocyte mass, signals
hypothalamus about the quantity of stored fat → leptin deficiency and leptin
resistance are associated with obesity and insulin resistance
Adiponectin: an adipocyte derived cytokine reduces levels of FFAs and has been
associated with improved lipid profiles, better glycemic control and reduced
inflammation in diabetic patients → Deficiency of adiponectin plays a role in the
development of insulin resistance and subsequent type 2 DM.
Tumor necrosis factor-alpha: studies in genetically obese animals suggest that
increased release of TNFa from adipose tissue play a major role in the impairment in
insulin action. → This suggestion is based on the following observations:
administration of anti-TNFa antibody led to marked improvement in glucose
 Pathogenesis – Drug Induced Screening

A large number of drugs can impair glucose tolerance Who? Adults with hypertension or hyperlipidemia as well as for those 40-70
y/o with BMI >25.
They act by decreasing insulin secretion, increasing hepatic glucose
production or causing resistance to the action of insulin: Screening tests:
- Glucocorticoids
- Oral contraception
- Beta blockers
- A1C >6.5 ⭐
- Fasting plasma glucose >126 mg/dl

- Two-hour plasma glucose >200 mg/dl

- Thiazide diuretics - Random plasma glucose >200 mg/dl
- Antipsychotics (A1C usually not approved through insurance without hyperlipidemia)
- Nicotinic acid Clinical Presentation:
- Statins - Polyuria
- Polydipsia
- Recurrent infection ⭐
Management – Initial/Newly Diagnosed Management – A1c >7.5-8 → FIRST line tx

Patients with newly diagnosed diabetes should participate in a For patients with A1C at or above target level >7.5 to 8 percent,
comprehensive diabetes self management education program, which pharmacologic therapy should be initiated.
includes instruction on nutrition and eating pattern, physical activity.

Weight reduction through diet, exercises and behavioral modifications

First-Line Therapy → Metformin:
can all be used to improve glycemic control.
Beware of side effects with T2DM medications:
- Biguanides: lactic acidosis
- Sulfonylureas: hypoglycemia
- GLP-1 Agonists: hypoglycemia (only if combined with
sulfonylureas)
- DPP-4 Inhibitors: pancreatitis (some correlation, no data
regarding causation)
- SGLT-2 Inhibitors: increased risk of DKA and UTIs
⭐
- Begin with 500 mg po daily and if tolerated add a second 500 mg.
- Max dose 2500 mg/day.
- Metformin is the preferred initial therapy because of glycemic
efficacy, absence of weight gain and hypoglycemia
- Beware of GI complaints (MC) and lactic acidosis (rare but
potentially deadly) in those with renal impairment
**Do not need to know doses**
 Management – A1c >7.5-8 → SECOND line tx Other Medications

Second-Line GLP-1 Agonists → In normal physiology, GLP-1 stimulates insulin secretion,

For patients with CVD or high CVD risk who cannot take metformin, it’s recommended
to prescribe:
- GLP-1 (glucagon like peptide-1) agonist
- SGLT2 (sodium-glucose co transporter 2) inhibitor
For patients with heart failure or CKD (GFR 30-60)
- SGLT2 inhibitor
**These drugs also reduce the incidence of new-onset macroalbuminuria or worsening
nephropathy suggesting renal protective effect.
Patients with A1C 8.5 to 9.5 percent (or more) or fasting BG >250, it’s recommended to
ADD insulin or a GLP-1 receptor agonist for initial therapy.
- A1C >9.5 with ketonuria – ADD insulin (to address ketonuria)
For patients with A1C <8.5 and C/I to metformin → sulfonylureas, SGLT2 inhibitors,
DPP-4 inhibitors
If weight loss is a priority → GLP-1 receptor agonists or SGLT 2(→ water weight loss)
If cost is a concern → short acting sulfonylurea such as glipizide
If avoidance of hypoglycemia is a priority SGLT 2 inhibitors, DPP-4 inhibitors are
associated with low hypoglycemic risk
also slows gastric emptying, and lower hepatic glucose output via glucagon
secretion suppression
- Always a second-line option when not contraindicated
- A hypoglycemic risk
- Examples: Liraglutide (Victoza), Semaglutide (Ozempic), Exenatide
(Byetta), Dulaglutide (Trulicity)
DPP-4 Inhibitors → DPP-4 is expressed on most cells and results in breakdown of
GLP-1 among other things (DPP-4i therefor reduce breakdown of GLP-1)
- May be considered monotherapy for those with metformin C/I (CKD)
- can also be an add-on for those already on metformin
- Examples: Sitagliptin (Januvia), Saxagliptin (Onglyza), Linagliptin
(Tradjenta)
SGLT-2 Inhibitors → Increases urinary glucose excretion (not a hypoglycemic
but…UTIs?)
- Examples: Canagliflozin (Invokana), Dapaglifozin (Farxiga)
Sulfonylureas → Increases insulin secretion by sensitizing the beta cells of
pancreas → this is A hypoglycemic risk
- Examples: Glipizide→ usually uses this one, Glimepiride

Follow-up Prognosis/Complications

Examinations: T2DM is a lifelong condition

1. Visit and Physical Exam 2-4x/year → you can get an A1c every 3 months Some patients may achieve a “remission” through weight loss, diet, and exercise that
- Height/weight reduces the insulin resistance and improves overall function of insulin → These
- Blood Pressure patients are rare, but those that achieve “remission” often do not require further
- Visual foot inspection: nail problems, callous formation, trauma, etc. that may
cause problems → you should do this yearly treatment with medical intervention, either for a period of time or throughout their

⭐ ⭐⭐
- Neuropathy can lead to these issues lifetime; however, they are still type-2 diabetics and require regular monitoring and
2. ANNUAL Dilated eye exam – by ophthalmology follow-up.
3. ANNUAL Dental examination – by dental
4. ANNUAL Comprehensive foot exam – by PCM Complications: ****KNOW THIS
- Inspection, pedal pulses, protective sensation - Diabetic retinopathy.
Labs: - Diabetic nephropathy – ACE-inhibitors (microalbuminuria)
-
-
-
A1C → q3-4mos
Urine creatinine-albumin ratio – annually→ Micro-/macroalbuminuria
Serum creatinine – annually → More often if CKD complicates
⭐ -
-
Peripheral vascular disease
Coronary artery disease → ASA 81
- Lipids – initial, as indicated - Anti-hyperlipidemic (statin)
Vaccinations: - Diabetic neuropathy - Gabapentin
- Pneumococcus:
⭐
⭐⭐
→ PPSV23: one dose at age 19-64 y/o Every T2DM should be on: ***KNOW THIS
→ PCV13: one dose ≥65 y/o – needs 1 year between these 1. Glucose control

⭐
- Influenza → annual 2. ACE inhibitors
- Hepatitis B: 3. Aspirin → due to high risk of vascular disease
→ 19-59 y/o: administer
→ 60 and over: administer based on risk
to vascular risks ⭐
4. Statin (or other med for lipids) → usually a comorbidity for T2DM + due
 DKA/HHS – 7 questions

Overview & A TRUE Medical emergency that occurs in the setting of absolute or relative insulin deficiency
Epidemiology Accounts for 14% of all hospital admissions in diabetic patients
- Overall, age-adjusted annual hospitalization rates for DKA = 6.3%
MC in young adults <65 years old & F>M
Characteristically occurs in type 1 DM, but can also occur in type 2 DM or in new-onset diabetes
Very rapid onset, usually over 24 hours

Normal Glucose/Insulin Metabolic Pathway vs Effects of Absolute or relative insulin deficiency

Pathogenesis
1. Two hormonal abnormalities largely responsible for DKA
a. Insulin deficiency and/or resistance
b. Glucagon excess – not essential in order for DKA to occur
2. Increased secretion of catecholamines, cortisol, and growth hormone also contributes to increase in glucose & keto acid production
a. These products oppose the actions of insulin → This is what usually tips the patient over into DKA
3. These hormonal alterations induce hyperglycemia due to:
a. Impaired glucose utilization in peripheral tissues
b. Increased hepatic and renal gluconeogenesis
c. Increased glycogenolysis

Insulin deficiency & resistance → enhanced lipolysis from peripheral fat stores → free fatty acids and glycerol are released
→ Fatty acids are taken up by hepatocytes → activated by coenzyme A (CoA) to form acyl-CoA (i.e., fatty acid-CoA)
→ Due to low insulin and increased glucagon activity (no opposition to glucagon in the form of insulin) in liver cells → acyl-CoA entry into mitochondria is
accelerated
→ Within mitochondria, beta-oxidation splits acyl-CoA → acetyl-CoA, which can have one of three fates:
1. Enter Krebs cycle to form CO2 & H20 (thus creating ATP)
2. Be indirectly exported into the cytoplasm where the acetyl-CoA is used to synthesize fatty acids
3. Enter ketogenic metabolic path to form acetoacetic acid

When there is a high amount of fatty acid being delivered to mitochondria, entry into Krebs cycle is bottlenecked (rate-limiting step) → thus, acetyl-CoA is instead
converted into acetoacetic acid
- This true ketoacid is the first “ketone body” which forms in DKA
- Acetoacetic acid may then be reduced to beta-hydroxybutyric acid, also an organic acid, or non enzymatically decarboxylated to acetone, which is
not an acid
- Ketones provide an alternate water-soluble energy source when glucose availability is reduced

The production of beta-hydroxybutyric and acetoacetic acids result in Anion Gap Metabolic Acidosis → Anion Gap= Serum Sodium – (Serum Chloride +
Bicarbonate)
- The sodium used is measured sodium, not corrected sodium
Severity of metabolic acidosis & degree of anion gap depend on several factors:
1. Rate & duration of keto acid production
2. Rate of metabolism of the ketoacids
3. Rate of urinary excretion of ketoacids
4. Volume of distribution of ketoacid anions
5. Rate of renal net acid excretion
So, we have a state with a ton of glucose in the serum, a ton of ketones as well, and disturbances in blood chemistry….including hypokalemia…but why?
1. Glucose is reabsorbed in the proximal convoluted tubule but is overwhelmed by the high amount of glucose spilling into the urine
2. Water is going to follow the solutes, glucose in this case, which creates a state of diuresis
Well, we have mechanisms to combat this:
1. ADH
2. Aldosterone → What do we remember about aldosterone? It trades Na+ for K+ -- keep the sodium, dump the potassium; this is how it helps us to
reabsorb more water in the nephron during a state of hypovolemia, which all DKA patients are in
But we aren’t always seeing hypokalemia in DKA…why?
- Due to the deficiency in insulin, K+ is shifted extracellularly which unintentionally compensates for the hypokalemia

Precipitating factors
1. Acute illness → Infection (30-40%), CVA, MI, Acute pancreatitis⭐
⭐
2. Inadequate insulin treatment or noncompliance
3. New-onset type 1 diabetes (20-25%)
4. Decreased water intake/severe dehydration
5. Drugs → Clozapine or olanzapine, Cocaine, Lithium, SGLT2 inhibitors, Terbutaline

Clinical presentation
1. Earliest symptoms of hyperglycemia include polyuria, polydipsia, and weight loss

⭐
2. Neurologic symptoms – obtundation may occur in DKA patients who have lesser degree of hyperosmolality with severe acidosis
3. Abdominal pain, N/V
a. More common in children but can be seen in adults
b. Severity of pain correlated with severity of metabolic acidosis
4. Symptoms of precipitating factor

Physical Exam

⭐
1. Signs of volume depletion

⭐
a. Decreased skin turgor

⭐
b. Dry axillae and oral mucosa

⭐
c. Low JVP, Tachycardia

⭐
d. Hypotension (if severe)

⭐
2. Neurologic findings → obtundation, stupor, coma

⭐
3. Fruity odor – due to exhaled acetone
4. Kussmaul respirations – deep & quick respirations; compensatory hyperventilation
a. To blow out CO2 when we have too much acid (compensation)
Diagnosis

⭐
1. Basic metabolic panel (BMP)
a. Elevated serum glucose, typically 350-500 mg/dL
b. High anion gap (often >20 mEq/L)
c. Low arterial pH (<7) in severe ketoacidosis when hyperventilation is compromised → Anion gap metabolic acidosis

⭐
d. Elevated potassium (hyperkalemia) – potassium shifts from intracellular (IC) to extracellular (EC) spaces in acidosis (one reason for the ECG)

e. Decreased sodium (hyponatremia) – water shifts from extravascular to intravascular spaces due to vomiting, polyuria, and hyperglycemia ⭐
⭐
f. Elevated phosphate (hyperphosphatemia) – phosphate shifts to EC spaces in acidosis
g. Elevated BUN and creatinine – due to reduction in GFR induced by dehydration
2. Complete blood count (CBC) with differential

⭐
a. Elevated WBCs (leukocytosis), even in the absence of infection → WBC >25,000 µL or >10% bands increases suspicion for insidious infection

⭐
3. Urinalysis and urine ketones by dipstick → Serum ketones if urine ketones are present
a. Elevated serum ketones and beta-hydroxybutyrate - KNOW THIS**
4. Plasma osmolality (Posm) → Occasionally, elevated plasma osmolality
5. Arterial blood gas (ABG) if serum bicarbonate substantially reduced or hypoxia is suspected
6. Electrocardiogram (ECG/EKG)

⭐
7. Other tests may be ordered on case-by-case basis, including: urine, sputum, and/or blood cultures; serum lipase & amylase; CXR; and hemoglobin A1C
a. Elevated serum amylase and lipase, even in the absence of pancreatitis
b. If acute pancreatitis is suspected, lipase is the more specific lab; also, imaging should be performed if pancreatitis is suspected

⭐
Diagnostic Criteria → DKA is characterized by the triad of:
1. Hyperglycemia (>250 mg/dL) → Typically between 350-500 mg/dL, and usually <800 mg/dL
2. Anion gap metabolic acidosis (>10 mEq/L) – often the major finding → Typically >20 mEq/L
3. Ketonemia – Demonstrated by elevated beta-hydroxybutyrate

Euglycemic DKA → Management differs from hyperglycemic DKA**

- DKA in the presence of normal or near normal serum glucose levels
- This has been described in:
- Patients with poor oral intake
- Patients who had treatment with insulin prior to arrival
- Pregnant women
- Patients who take sodium-glucose co-transporter 2 (SGLT2) inhibitors
 ⭐
Management Overview:
1. Correction of fluid and electrolyte abnormalities → most important
a. Hyperosmolality
b. Hypovolemia
c. Metabolic acidosis

⭐
d. Potassium depletion
2. Administration of insulin
3. Frequent monitoring
4. Identification and correction of underlying precipitating event

⭐
Fluid is the first step in the treatment of DKA
- Expands intracellular volume and stabilizes cardiovascular status
- Also increases insulin responsiveness by lowering the plasma osmolality, reducing vasoconstriction and improving perfusion, and reducing stress
hormone levels

⭐
Initial fluid replacement rates – depends on clinical stat of patient
- Hypovolemic shock: infuse 0.9% NaCl (NS) (or LR) as quickly as possible → Something like 2L bolus
- Hypovolemic without shock (and without heart failure): NS infused at rate of 15-20 mL/kg lean body weight for first 2 hours, with maximum of <50
mL/kg in the first 4 hours
After 2nd or 3rd hour, optimal fluid replacement depends on the state of hydration, serum electrolyte levels, and urine output
The most appropriate IV fluid composition is determined by corrected serum concentration
- Corrected [Na+] = Measured[Na+] + [1.6(Serum Glucose-100)/100]
- If corrected [Na+] <135 mEq/L: NS should be continued at rate of ~200-500 mL/hr
- If corrected [Na+] is normal or elevated: IV fluid is generally switched to ½ NS
- Concurrent potassium replacement may be another indication for using ½ NS
Switch to D5W if glucose drops to 200 mg/dL to prevent hypoglycemia (don't want to bottom out)

Fluid replacement can initially reduce serum glucose by 35-70 mg/dL per hour due to
1. ECF expansion and dilution
2. Increased urinary losses

⭐
3. Amelioration of high “stress hormone” levels
Potassium replacement is initiated immediately if serum [K+] is < 5.3 mEq/L
- Almost all DKA patients have substantial K+ deficit, however serum K+ is usually normal or elevated due to K+ movement out of cells
- If initial serum [K+] is < 3.3 mEq/L: administer IV KCl at 20-40 mEq/hr

⭐
- If initial serum [K+] is between 3.3-5.3 mEq/L: add IV KCl 20-30 mEq to each liter of IV replacement fluid and continue this until serum [K+] has
increased to the 4-5 mEq/L range

⭐
- If initial serum [K+] is > 5.3 mEq/L: potassium replacement should be delayed until its concentration has fallen below this level (because once we
give insulin…)
 ⭐
Altered potassium distribution is rapidly reversed with administration of insulin
1. Can result in dramatic fall in serum[K+] despite replacement
2. However, further potassium replacement must be done cautiously if renal function remains depressed and/or urine output does not increase to a level

3.
>50 mL/hour
Careful monitoring of serum[K+] is essential in management of DKA ⭐
⭐
Insulin replacement

⭐
- Low dose IV insulin should be initiated in all patients with moderate-severe DKA who have a serum potassium > or equal to 3.3 mEq/L
- The only indication for delaying insulin therapy is if serum [K+] < 3.3 mEq/L
- Insulin would worsen the hypokalemia by driving K+ into the cells, potentially causing complications such as cardiac arrhythmias, cardiac
arrest, and respiratory muscle weakness
- These patients should receive aggressive fluid and K+ replacement prior to treatment with insulin
- IV regular insulin and rapid-acting insulin analogs are equally effective in treatment of DKA but regular insulin is preferred

Effects of insulin therapy include:

1. Lowering of serum glucose by decreasing hepatic glucose production (the major effect) and enhancing peripheral glucose utilization
2. Diminishing ketone production by reducing both lipolysis and glucagon secretion
3. Augmentation of ketone utilization – it tells the liver to SHUT OFF KETOGENESIS (essentially)

Moderate-Severe DKA
- IV bolus of regular insulin (0.1 units/kg body weight) followed within five minutes by a continuous infusion of regular insulin of 0.1 units/kg/hour
- Or, bolus can be omitted if higher dose of continuous IV regular insulin (0.14 units/kg/hour) is initiated
- These doses of IV regular insulin typically decrease the serum glucose by ~50-70 mg/dL per hour
- Higher insulin typically does not produce a more prominent hypoglycemic effect
Mild DKA can be safely treated with subcutaneous rapid-acting insulin analogs
- Initial dose is 0.3 units/kg, followed by hourly injections of 0.1 units/kg until resolution of hyperglycemia and ketoacidosis

Bicarbonate therapy for correction of metabolic acidosis is controversial and generally not recommended, except with the following
1. Patients with arterial pH < or equal to 6.9
a. Give 100 mEq sodium bicarbonate in 400 mL sterile water administered over 2 hours
b. If serum potassium < 5.3 mEq/L, add 20 mEq of KCl
2. Patients with potentially life-threatening hyperkalemia (> 6.4 mEq/L)
Venous pH and bicarbonate concentration should be monitored q 2 hours
Bicarbonate doses can be repeated until pH rises above 7.0

Phosphate depletion is common in DKA → However, routine replacement of phosphate is not recommended, unless serum phosphate is < 1 mg/dL, especially
if cardiac dysfunction, hemolytic anemia, and/or respiratory depression develop
- Potassium phosphate or sodium phosphate 20-30 mEq can be added to 1 L of IV fluid
Patients with mild DKA can be treated in the ED, while moderate-severe DKA requires admission to ICU or step down unit
- Gastric intubation is recommended in the comatose patient to prevent vomiting and aspiration (as result of gastric atony)
- Central venous line in patient with severe cardiovascular collapse or pre-existing cardiac or renal failure to evaluate the degree of hypovolemia and ot
monitor subsequent fluid administration
Blood glucose should be checked hourly; electrolytes and pH at least q 2-4 hours during initial treatment

The hyperglycemic crisis is considered resolved WHEN:

1. The ketoacidosis has resolved, as evidenced by normalization of serum anion gap (< 12 mEq/L) and blood beta-hydroxybutyrate levels
2. The patient is able to eat
Note: in the absence of severe renal disease, almost all patients develop a non-anion gap metabolic acidosis during the resolution phase of DKA
- This will slowly resolve as kidneys excrete ammonium chloride and regenerate bicarb

IV insulin infusion should be tapered and a multiple-dose, subcutaneous insulin schedule be started when blood glucose is < 200 mg/dL, the patient is able to
eat, and at least two of the following are met:
1. Serum anion gap < 12 mEq/L
2. Serum bicarbonate > or equal to 15 mEq/L
3. Venous pH > 7.30
Discontinue IV insulin when two consecutive blood glucose < 200 mg/dL and insulin drip requirement is < 1 unit/hour
- In patients who were previously being treated with insulin, their home regimen of insulin may be restarted
- In insulin-naive patients, a multidose insulin regimen should be started at a dose of 0.5-0.8 units/kg/day, including bolus and basal insulin, until an
optimal dose is established

Follow up
1. Outpatient follow-up with endocrinologist and PCP ⭐
2. Dietitian follow-up
3. Diabetes education
4. Home glucose monitoring
5. Hypoglycemia management

Prognosis
- In-hospital case-facility rates are ~0.4%
- Younger patients who gain proper treatment have excellent prognosis, especially those with no associated intercurrent illnesses
- Prognosis worsens with increased age, and in the presence of coma or hypotension
DDx = Hyperosmolar Hyperglycemic State (HHS)
- Most commonly develops in patients >65 years old with T2DM
- Accounts for <1% of all primary diabetic hospital admissions
- Mortality rate = 10-20%
- Serum glucose frequently >1,000 mg/dL but without ketoacidosis
1. In HHS, residual insulin secretion is sufficient to minimize ketoacidosis
2. Glucagon does not increase as much in HHS, also minimizing ketoacidosis
3. Serum bicarbonate is normal or only mildly reduced in HHS
Effective Plasma osmolality (Posm) is always elevated (typically >320 mosmol/kg; reference range approximately 275-295 mosmol/kg)
- Effective "Posm"=[2∗Na(mEq/L)]+[Glucose(mg/dL)/18]

Precipitating factors
1. Inadequate insulin treatment or noncompliance (21-41%)
2. Acute illness → Infection (32-60%; typically PNA, UTI, or sepsis), CVA, MI, acute pancreatitis, acute PE, intestinal obstruction, peritoneal dialysis,
mesenteric thrombosis, renal failure, heat stroke, hypothermia, subdural hematoma, severe burns
3. Endocrine pathology → Acromegaly, thyrotoxicosis, Cushing’s syndrome
4. Drugs/Therapy → B-blockers, CCBs, chlorpromazine, chlorthalidone, cimetidine, clozapine, diazoxide, ethacrynic acid, immunosuppressive agents,
L-asparaginase, loxapine, olanzapine, phenytoin, propranolol, steroids, thiazide diuretics, total parenteral nutrition (TPN)
5. Previously undiagnosed diabetes

Clinical presentation
- Mental obtundation & coma (25-50%) more frequent
- Focal neurologic signs (hemiparesis & hemianopsia) and/or seizures may be seen
- Abdominal pain is unusual (unlike DKA)
- Triad: dehydration/increase osmolarity, hyperglycemia, potassium deficit

Dx Criteria
1. Serum glucose frequently >1000 mg/dL
2. Posm typically >320 mosmol/kg, sometimes as high as 380 mosmol/kg
3. Neurologic abnormalities
4. Most patients with HHS have pH >7.30, serum bicarbonate >20 mEq/L, serum glucose >600 mg/dL, and test negative for ketones in serum & urine
(though mild ketonemia can be seen)

Significant overlap between DKA & HHS reported in >1/3rd of patients

Treatment
Essentially the same as DKA, with some modifications:
1. IV saline solution is switched to D5W when serum glucose = 250-300 mg/dL
a. Try to avoid glucose dipping below 250-300 mg/dL to prevent cerebral edema
2. IV insulin infusion can be tapered & multiple-dose, subQ insulin schedule started when serum glucose falls below 250-300 mg/dL
Crisis is resolved when:
1. Patient is mentally alert
2. Effective plasma osmolality has fallen <315 mosmol/kg
3. Patient is able to eat