CLINICAL REASONING – INTERNAL MEDICINE – GASTROENTEROLOGY
Clinical Reasoning: Gallbladder diseases
The gallbladder is a small, pouch-like organ that stores the bile produced by the liver.
After a fatty meal, the gallbladder contracts and releases bile to help break down fats in the diet.
Bile is made up mostly of water, bile salts, bilirubin and fats, as well as cholesterol.
Now, the most common gallbladder diseases have to do with an imbalance in bile fluid composition, which leads
to the formation of stones either in the gallbladder or somewhere along the biliary tree.
The biliary tree is made up of the left and right hepatic duct which come together and form the common hepatic
duct, as well the cystic duct, which unites with the common hepatic duct to form the common bile duct, also
known as choleducus duct.
Finally, the common bile duct joins with the main pancreatic canal to open in the second part of the duodenum.
Now, most gallbladder diseases are related to either the presence of stones in the gallbladder or in the common
bile duct, and whether those locations are infected as the result of an obstruction caused by the gallstones.
A gallstone in the gallbladder is called cholelithiasis, and a gallstone in the common bile duct is called
choledocolithiasis, and both are associated with mild inflammation. But, if the gallstones block the normal bile
flow this can cause severe inflammation in the biliary tree.
When there's a lot of inflammation, the gallbladder and common bile duct tissue becomes extremely susceptible
to infection. An infection of an obstructed gallbladder is called cholecystitis, and an infection of an obstructed
common bile duct is called cholangitis, or ascending cholangitis.
In cholelithiasis, gallstones often develop from an imbalance in bile composition.
For example, if there’s too much cholesterol, cholesterol gallstones form, and that happens mostly in female
individuals during the reproductive period, especially over the age of forty. Other risk factors include being
overweight and native American.
If, however, the bile has too much bilirubin, pigment gallstones form, and this happens with hemolysis, liver
cirrhosis, and sickle cell anemia.
In some cases mixed gallstones may appear, made up of variable amounts of both cholesterol and pigments. But
in practice, there’s no way to know the exact composition of the stone until the gallbladder is surgically
removed.
Typically, gallstones happily remain in the gallbladder for months to years without ever being noticed, because
they may not cause any symptoms. In fact, gallstones that are smaller than 5 millimeters, can pass through the
cystic duct and reach the small intestine and be eliminated.
So in individuals with gallstones, but without symptoms, the gallstones may be discovered incidentally during an
ultrasound - and that’s called cholelithiasis.
Now, if the individual is symptomatic, then we’re talking about gallstone disease rather than simply
cholelithiasis.
These individuals might have biliary colic, which is abdominal pain in the right upper quadrant or epigastric
region that can radiate to the shoulder or back, and typically lasts for less than an hour. Pain occurs because the
gallbladder contracts against a bunch of stones, and that can temporarily compress the cystic duct. This often
worsens after a high-fat meal.
Now, although it’s called biliary colic, the pain is usually constant, rather than colicky.
Associated symptoms include nausea, vomiting, and sweating.
The first and most accurate test for diagnosing cholelithiasis is an ultrasound of the right upper quadrant, which
shows a distended gallbladder with stones inside. On an ultrasound, the gallstones cast an acoustic shadow
below the gallbladder, and they also move freely when the individual turns from one side to the other, which
helps distinguish them from other conditions, such as carcinoma. In some cases, the gallstones are so small that
on the ultrasound they appear as a so called “sludge” which doesn’t cast an acoustic shadow.
Ok, now for most asymptomatic individuals, the usual plan is watchful waiting. However, for symptomatic
individuals or those at high risk for developing symptoms, treatment is necessary.
High risk individuals include those with hemolytic disorders like sickle cell disease, morbidly obese individuals
who undergo gastric bypass or individuals who have risk factors for developing gallbladder cancer, like gallstones
bigger than 3 centimeters, a calcified gallbladder wall, also called a porcelain gallbladder, and gallbladder
adenomas.
Initially gallstone disease is treated with spasmolytics such as butylscopolamine or in severe cases with opioids
such as buprenorphine to stop the gallbladder from contracting in order to ease the pain. After that, a
cholecystectomy - which is surgical removal of the gallbladder - can be done. Cholecystectomy is curative,
meaning that once it’s done, no further medication is needed.
However, some individuals are not eligible for surgery, like those who can’t tolerate anesthesia. In that situation,
a medication like ursodeoxycholic acid can be used.
Ursodeoxycholic acid decreases cholesterol absorption and that prevents new gallstones from forming, as well
as dissolve the existing ones.
Another option for those that don’t have a cholecystectomy is a technique called extracorporeal shock-wave
lithotripsy, or ESWL. ESWL is a machine that uses high-energy sound waves that produce shock waves to break
gallstones into smaller fragments which then can be dissolved in the bile.
ESWL is a non-invasive procedure that’s usually used to break down kidney stones, but it works in individuals
with a normal body mass index who have less than 3 gallstones between 4 to 30 millimeters.
There are some contraindications for ESWL like pregnancy, cholecystitis, choledocolithiasis, pancreatitis, and
coagulapathies.
In choledocolithiasis - try saying that three times fast - a stone gets stuck in the common bile duct. Most
frequently, this happens when a stone spontaneously passes through the cystic duct which is wider in some
individuals and gets stuck in the common bile duct. However, in rare situations, gallstones can also form directly
in the common bile duct. Those are typically made mainly of bilirubin and are called pigment gallstones.
The risk factors for choledocolithiasis are similar to the ones for cholelithiasis.
In choledocolithiasis, bile accumulates behind the obstruction, which blocks the flow of the entire biliary tree
and, in some cases, can back up into the liver resulting in jaundice.
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Other symptoms include abdominal pain in the right upper quadrant that lasts for more than one hour, nausea
and vomiting.
On clinical examination, Courvoisier’s sign may be present, meaning there’s a palpable gallbladder. This happens
as a result of the obstruction of the common bile duct which makes the gallbladder dilate.
Courvoisier’s sign is usually associated with malignant common bile duct obstruction, but it can also appear in
choledocolithiasis.
Blood tests will show leukocytosis, and because of cholestasis, meaning something- in this case, a stone- is
blocking the flow in the common bile duct to the duodenum, total bilirubin is high, and especially direct or
conjugated bilirubin, also alkaline phosphatase and gamma glutamyl transferase levels are high.
Some individuals have an associated reactive pancreatitis, which happens because the stones compress the
main pancreatic duct.
Pancreatitis can cause have pain in the upper abdomen which radiates in the shoulder and back, as well as
abdominal tenderness, and blood tests will show high amylase and lipase levels.
Other individuals have an associated hepatitis, because bile accumulates in the intra and extrahepatic ducts.
With hepatitis, alanine aminotransferase or ALT and aspartate aminotransferase or AST are also elevated.
To diagnose choledocolithiasis, a right upper quadrant ultrasound is done, and typically shows a dilated common
bile duct and intrahepatic bile ducts. The gallstones aren’t always visible, but they’re in the common bile duct,
and may also be in the gallbladder as well.
If the ultrasound is inconclusive, a magnetic resonance cholangiopancreatography or MRCP can be performed to
confirm the diagnosis. MRCP is a noninvasive technique that uses contrast or noncontrast MRI imaging, which is
very good at detecting fluids, such as bile, to visualize the biliary tract and pancreatic ducts and this can also
detect the gallstones in the common bile duct.
Treatment of choledocolithiasis starts with intravenous fluids to prevent dehydration and antibiotics while the
biliary tree is inflamed and more susceptible to an infection.
To remove the gallstones, a procedure called endoscopic retrograde cholangiopancreatography or ERCP is used.
With ERCP, a long, flexible tube is inserted through the mouth, down the esophagus, through the stomach and in
the duodenum. Once it gets there, a cannula is passed through the ampulla of Vater and a sphincterotomy, a
small cut, is made above it, where Oddi’s sphincter is located. Finally, a small balloon is inflated in the sphincter
to further dilate the common bile duct.
If the ERCP is successful, then gallstones are able to more easily pass into the duodenum. After that, a
cholecystectomy can be performed to eliminate the risk of another gallstone getting stuck in the common bile
duct.
In cholecystitis, bacteria like Escherichia coli, Klebsiella, or Streptococcus species, infect an obstructed
gallbladder. That’s because these bacteria are always lurking in the gastrointestinal tract and creep up the biliary
tree and into the gallbladder when there’s no bile washing them back out into the intestines.
There’s acute cholecystitis and chronic cholecystitis and they are both invariably related to gallstones, but
sometimes, acute cholecystitis may appear in individuals without gallstones - that’s called acalculous
cholecystitis- and it’s caused by bile stasis.
With chronic cholecystitis, gallstones block the cystic duct and then get dislodged and then again can block the
cystic duct and get dislodged. This cycle can happen over and over, and each time it causes inflammation that
may result in recurrent episodes of right upper quadrant pain.
The pain typically isn’t intense and it doesn’t last for more than an hour. This is why chronic cholecystitis isn’t
diagnosed until the gallbladder is surgically removed and chronic cell infiltration is seen on histopathology.
However, sometimes, probably because of the intermittent injury to the gallbladder, its walls can get calcified
and this is called a porcelain gallbladder which increases the risk for developing gallbladder carcinoma.
A porcelain gallbladder can be seen on an abdominal radiography as a well contoured balloon or on an
ultrasound where the gallbladder shows dense shadowing that can be mistaken for gallstones.
The treatment recommendation, once porcelain gallbladder is diagnosed, is cholecystectomy to minimize the
risk for gallbladder carcinoma.
With acute cholecystitis, the symptoms are usually severe and the individual has a fever, loss of appetite, and
pain in the right upper quadrant, which can radiate to the shoulder or back especially after a high-fat meal.
Typically, the pain is constant and severe and it usually starts as a biliary colic, but it can last up to 6 hours and is
associated with anorexia, nausea, and vomiting, as well as a mild fever and leukocytosis.
Most frequently, on clinical examination there is a Murphy’s sign - which is where an examiner firmly places
their hand in the right upper abdominal quadrant under the liver border and asks the individual to breathe in. If
the pain worsens, it’s called a positive Murphy sign, and it’s a classic sign of inflammation of the gallbladder and
it’s a classic sign of acute cholecystitis.
Sometimes, abdominal tenderness from peritoneal irritation may be present. However, a positive Murphy sign
alone cannot diagnose acute cholecystitis, so an ultrasound is usually done.
A right upper quadrant ultrasound may also result in a positive sonographic Murphy sign, which means
abdominal tenderness caused by the pressure of the probe on the gallbladder. It will also show a distended
gallbladder, thickening of the gallbladder wall and fluid around the gallbladder.
A HIDA scan or cholescintigraphy can also be performed to diagnose diseases of the gallbladder, liver, and bile
ducts. That’s where a radioactive tracer is injected into a peripheral vein. The tracer makes its way into the bile,
and from there it goes into the gallbladder, and then through the bile ducts and into the small intestine.
In acute cholecystitis, the biliary tree will fill without problems, but the gallbladder won’t fill up because there’s
an obstruction in the cystic duct.
Treatment of acute cholecystitis starts with analgesics such as non-steroidal anti-inflammatories like ketorolac,
to help with the severe pain. In addition, intravenous fluids to prevent dehydration and antibiotics are used to
treat the infection.
For mild and moderate cases, cephalosporins such as ceftriaxone or cefuroxime may be used.
For elderly, immunocompromised, or critically ill individuals, meropenem or piperacillin-tazobactam may be
used, or a combination of metronidazole plus ciprofloxacin or levofloxacin.
Like cholelithiasis, the gold standard of treatment in acute cholecystitis is cholecystectomy, which must be
performed as soon as possible.
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If the individual is not eligible for surgery, then a cholecystostomy can be done, which is where a percutaneous
catheter is placed in the gallbladder to allow it to drain out.

In cholangitis, gallstones get stuck in the common bile duct and that causes fluid to build up behind the
obstruction instead of flowing through. Once again, that invites a bacterial infection, this time in the common
bile duct.

Just like in choledocolithiasis, there’s cholestasis, and as a result the total bilirubin, alkaline phosphatase, and
gamma glutamyl transferase levels are elevated. Some individuals have a reactive hepatitis with high ALT and
AST levels or biliary pancreatitis with high amylase and lipase levels. However, a key difference is that with
cholangitis there’s severe inflammation in the biliary tree due to the bacterial infection and individuals can have
Charcot’s triad which includes: right upper quadrant pain, jaundice, and fever.

Specifically, unlike choledocolithiasis can have a really high fever, and be very ill-appearing or septic. In fact,
individuals can have Reynold’s pentad, which is hypotension and altered mental status along with Charcot’s triad
of pain, jaundice, and fever.

If cholangitis is suspected, the first step is to draw blood cultures to identify the bacteria culprit. Then, a right
upper quadrant ultrasound is performed, which shows dilated biliary ducts. Then, the individual undergoes
emergent ERCP, which can visualize the inflamed ducts, as well as remove the gallstones.

While the individual is getting ready for ERCP, intravenous fluids and broad spectrum antibiotics are
administered, to prevent dehydration and manage the bacterial infection.

After results from the blood culture come back, the antibiotic regimen is adjusted according to the specific
bacteria at fault.

Finally, cholecystectomy is also indicated in acute cholangitis, after the gallstone has been removed.

Summary

Now, as a quick recap, with cholelithiasis, individuals can be asymptomatic or present with biliary colic. On an
ultrasound the gallstones cast an acoustic shadow below the gallbladder. Treatment in this case is
cholecystectomy, ESWL in some cases and ursodeoxycholic acid for individuals unfit for surgery.

With choledocolithiasis, the individual presents jaundice, pain in the right upper quadrant, nausea and vomiting.
The blood work shows leukocytosis, high bilirubin levels, high alkaline phosphatase and gamma glutamyl
transferase levels, also high ALT and AST and high amylase and lipase if the liver and pancreas are affected. The
ultrasound shows dilated biliary ducts. Treatment is IV fluids, antibiotics and ERCP.

In cholecystitis the individual presents right upper quadrant pain, fever, a positive Murphy sign and leukocytosis.
The ultrasound shows thickening of the gallbladder wall, fluid around the gallbladder and also gallstones. If the
ultrasound is inconclusive, a HIDA scan is performed. Treatment of cholecystitis is IV fluids, antibiotics and
urgent cholecystectomy or cholecystostomy if the individual cannot undergo surgery.

Finally, with cholangitis, individuals present with Charcot’s triad: jaundice, fever and pain in the right upper
quadrant. Septic individuals more frequently present with Reynold’s pentad, which associates hypotension and
altered mental status to pain, jaundice and fever. Lab work is similar to choledocolithiasis and the ultrasound
reveals dilated biliary ducts. In this case, ERCP is emergent and while the individual is prepping for the procedure
iv fluids and antibiotics will be administered.

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Clinical Reasoning: Esophagitis
The esophagus is a 25-30 centimeter long muscular tube through which food and liquids pass from the pharynx
to the stomach. At the top and bottom of the esophagus there are the upper and lower esophageal sphincter,
respectively.
Esophagitis is inflammation of the esophagus, and it usually causes dysphagia or difficulty in swallowing,
odynophagia or painful swallowing, and retrosternal chest pain.
If the cause is unclear, the usual workup includes an upper endoscopy with a biopsy. And in case of retrosternal
chest pain, an electrocardiogram should always be done in order to rule out cardiac ischemia.
Now, the most common cause is gastroesophageal reflux disease or GERD, and in that situation it's called reflux
esophagitis.
In reflux esophagitis, the tone of the lower esophageal sphincter is lower than normal so it doesn’t have a tight
grip and allows gastric acid to easily pass into the esophagus. Over time, that leads to inflammatory lesions in
the esophagus.
In addition to the classic symptoms, reflux esophagitis can also cause heartburn and regurgitation.
In some cases, gastric acid can irritate the respiratory tract, cause symptoms like coughing, voice changes, and a
feeling of a lump in the throat.
An upper endoscopy usually shows signs of erosion and these lesions can be classified using the Savary-Miller
system or the Los Angeles system, both of which use a 4-point grading scale, where grade 1 or A is mild
esophagitis and grade 4 or D is severe esophagitis.
Treatment of reflux esophagitis starts with proton pump inhibitors or PPIs such as omeprazole for 8 weeks. If
symptoms disappear, then the dose of PPI is gradually decreased. If PPIs are needed for more than 6 months,
then it’s replaced by histamine 2 receptor agonists or H2RAs. Now, if the symptoms recur, then the lowest dose
of the medication that last controlled the symptoms is restarted.
For individuals with severe erosive esophagitis, a repeat upper endoscopy should be done after 8 weeks of
treatment to make sure that it’s healing and to rule out malignancy.
In medication induced esophagitis, the most common situation is that a medication directly injures the
esophagus, especially if it’s taken with a small amount of water.
Common medications are nonsteroidal anti-inflammatories or NSAIDs such as ibuprofen and aspirin which
disrupt the protective prostaglandine barrier, antibiotics like doxycycline which cause a local acid burn,
potassium chloride which can increase local osmolality leading to tissue damage, and bisphosphonates like
alendronate.
Symptom onset can vary from a few hours to a few weeks after taking the medication. In addition to the classic
symptoms, medication induced esophagitis can also rarely cause upper gastrointestinal bleeding and weight
loss.
In severe cases, an upper endoscopy is performed and typically shows ulcers that are mainly in the middle of the
esophagus. The lesions are sometimes coated with medication material, and in rare cases medication fragments
have to be removed during the procedure.
Treatment of medication induced esophagitis is mainly stopping the medication that caused esophagitis or in
some cases - switching to a liquid version of the medication.
Starting the individual on PPIs reduces gastric acid production and can also help reduce symptoms.
Treatment is continued until symptoms disappear and the culprit medication can be re-initiated if it’s absolutely
needed.
To prevent medication induced esophagitis, it’s often best to take medication with a full glass of water.
In caustic esophagitis, caustic agents which are strong acids like vinegar or strong bases like detergents are
ingested either accidentally - usually by children, or voluntarily by adults usually in a suicide attempt, and it leads
to esophageal lesions.
Generally speaking, strong bases are more injurious to the esophagus because they cause liquefaction necrosis
and thermal burns which can penetrate deeper into the tissue, while strong acids cause superficial coagulation
necrosis and formation of eschars that limit the depth of injury.
Individuals typically have retrosternal chest pain and odynophagia immediately after ingestion.
Oral burns can produce pain and drooling and there may be respiratory symptoms, like stridor, dyspnea and
voice changes.
Caustic injuries to the esophagus are emergencies. Thoracic Xrays and a CT scan are typically done right away to
look for complications like an esophageal perforation. In addition, an upper endoscopy should be done as soon
as possible.
The esophageal lesions are most often classified using Zargar’s 4 point grading system, where a 4 is a severe
injury, and a 1 is a mild injury. The higher the grade, the higher the risk for complications like esophageal
strictures.
There should never be an attempt to neutralize the pH in the esophagus, by giving more chemicals, because this
can cause further injury. In addition, emesis should never be induced because the gastric acid causes more
damage to the esophagus.
Treatment of caustic esophagitis includes general measures like airway protection- in severe cases, the
individual needs to be intubated, hemodynamic stabilization with intravenous fluids to prevent dehydration, and
broad spectrum antibiotics to prevent an infection. In addition, in severe injuries, a nasogastric feeding tube is
carefully inserted and the individual is placed on a liquid diet.
If the lesions are extensive or if there’s an esophageal perforation, then an esophagectomy-which is the surgical
removal of the esophagus and colonic or jejunal replacements may be needed.
In eosinophilic esophagitis, also known as allergic esophagitis, the esophagus gets inflamed as a reaction to
allergens, food or acid reflux. This happens mostly in males and in children, especially in individuals who also
have allergic diseases, like seasonal allergies, atopic dermatitis, and asthma.
Symptoms in children can be atypical, and may include failure to thrive, refusal to swallow, regurgitation, and
vomiting.
During an upper endoscopy, eosinophilic esophagitis has non-specific findings like mucosal fragility and
esophageal rings- which are thin mucosal bands that surround the esophagus. Typically, a biopsy will show an
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increased number of intraepithelial eosinophils and microabscesses with large clusters of eosinophils near the
surface.
Treatment of eosinophilic esophagitis begins with doing a prick skin test to identify potential foods that are
triggers, so that these foods can be avoided.
Treatment of CMV esophagitis is intravenous ganciclovir for 3 to 6 weeks.
Finally, for ganciclovir resistant strains of CMV, intravenous foscarnet can be used.
In HIV esophagitis, endoscopy shows large ulcerations.

Medical therapy with PPIs can be used to minimize the injury to the esophagus due to acid reflux and a low dose
of corticosteroids can be used to reduce inflammation. In fact, fluticasone propionate is sprayed into the mouth
and then swallowed and this is often preferable because it reaches the esophagus without getting absorbed into
the bloodstream and so it won’t cause side effects typically associated with corticosteroids, like hyperglycemia.
In infectious esophagitis, the most frequently involved microorganisms are Candida, Herpes simplex virus or
HSV, Cytomegalovirus or CMV, and human immunodeficiency virus or HIV.
Risk factors for infectious esophagitis include immunocompromised states such as acquired immunodeficiency
syndrome or AIDS as well as diabetes.
In addition to the classic symptoms, infectious esophagitis can also cause fevers.
In candida esophagitis, oral thrush is seen in the majority of cases.
In mild cases, the upper endoscopy shows small white raised plaques with surrounding erythema, and in severe
disease, there are confluent white plaques. When the plaques are dislodged, the underlying mucosa frequently
bleeds.
The diagnosis is confirmed by the presence of yeast and hyphal cells in the biopsy specimens.
HIV testing should be done if its suspected, and treatment should be based on viral loads and CD4 counts. With
respect to the esophagitis, treatment with oral corticosteroids or thalidomide can help the esophagus heal
faster.
Summary
Alright, as a quick recap. You can remember the causes of esophagitis using the mnemonic PIECE: pill
(medication), infectious, eosinophilic, caustic, and everything else meaning GERD.
The workup includes an upper endoscopy with mucosal biopsy.
With reflux esophagitis, treatment includes PPIs and in severe cases, a repeat upper endoscopy should be done
after 8 weeks of treatment to make sure that it’s healing and to rule out malignancy.
With medication induced esophagitis the ingestion of drugs such as NSAIDs, results in ulcers, erosions and
sometimes medication fragments seen on endoscopy. Treatment is stopping the culprit medication or replacing
it with a liquid formula and PPIs.
With caustic esophagitis, due to strong acids or strong bases, treatment includes airway protection,
hemodynamic stabilization, iv antibiotics, inserting an NG tube and a surgery may be needed for severe cases.

Mild candida esophagitis is treated with an antifungal like oral fluconazole for 7 to 14 days. With eosinophilic esophagitis, the upper endoscopy may show mucosal fragility and histopathological findings
show increased number of eosinophils. Treatment includes eliminating foods that cause allergies, as well as PPIs
Severe candida esophagitis is treated with intravenous therapy with caspofungin or amphotericin B. and oral fluticasone propionate.

In HSV esophagitis, there are usually lesions in the mouth as well. With Candida esophagitis, treatment is oral fluconazole or intravenous amphotericin B if the infection is severe.

Early on, the upper endoscopy typically shows lesions that look like small rounded vesicles, punched-out With HSV, treatment includes oral acyclovir or foscarnet if there is a resistant strain.
superficial ulcerations covered with dense exudates - that look a bit like tiny volcanos. In advanced stages, a
diffuse erosive esophagitis develops. With CMV, treatment with intravenous ganciclovir and foscarnet is initiated and finally with HIV, treatment with
oral corticosteroids or thalidomide can help.
Biopsy specimens from the edge of the ulcerations show giant cell formation and Cowdry type A inclusion bodies
within the nucleus.

Viral cultures can grow out HSV in a few days and can identify acyclovir resistant strains.

Treatment of HSV esophagitis is oral acyclovir for 14 to 21 days or oral valacyclovir for 7 days.

If the individual cannot swallow, intravenous acyclovir is used.

Finally for acyclovir resistant strains of HSV, intravenous foscarnet can be used.

In CMV esophagitis, the upper endoscopy shows large superficial ulcerations surrounded by normal appearing
mucosa. The biopsy specimen shows cytomegaly or enlarged cells with inclusion bodies in both the nucleus and
cytoplasm. This contrasts with HSV esophagitis, where inclusion bodies are exclusively in the nucleus.

Viral cultures can grow out CMV in a few days and can identify ganciclovir resistant strains.

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Clinical Reasoning: Esophageal disorders
The esophagus is a 25- 30 centimeter long tube through which food and liquids pass from the pharynx to the
stomach.
The esophageal wall is composed of 4 layers: inner mucosa which is made of stratified squamous epithelium
except at the lower esophageal sphincter where it joins the gastric epithelium to form the gastroesophageal
junction, submucosa, a muscular layer made of skeletal muscle in the upper third, smooth muscle in the lower
third and a combination of the two in the middle and finally an outer layer of connective tissue called adventitia.
At the top and bottom of the esophagus there are the upper and lower esophageal sphincter, respectively. Both
relax during swallowing to allow the passing of food or liquids propelled by peristaltic contractions.
Additionally, the lower esophageal sphincter also prevents acid reflux from leaving the stomach between meals.
Some esophageal disorders are functional meaning that they affect the muscles and nerves which control the
motility of the esophagus, whereas other esophageal disorders are mechanical meaning that there's something
within or just outside the esophagus that blocks the passageway.
With esophageal dysphagia, it’s important to know what type of food produces the symptoms: if dysphagia is
related to the ingestion of both liquids and solids, the most probable cause is a functional disorder.
On the other hand, dysphagia for solids only means that the lumen of the esophagus is really narrow, often less
than 13 millimeters due to a mechanical cause like a malignancy or esophageal stricture.
Dysphagia can also be intermittent or progressive.
Usually, intermittent dysphagia is related to both solids and liquids and appears in functional disorders, whereas
progressive dysphagia means that something is growing inside the esophagus and dysphagia gradually worsens.
Esophageal dysphagia also needs to be distinguished from oropharyngeal dysphagia.
With esophageal dysphagia, the individual can easily initiate a swallow, but after a few seconds will feel a lump
in the throat, whereas with oropharyngeal dysphagia the individual has difficulty in initiating a swallow most
commonly due to nerve and muscle damage in the upper sphincter of the esophagus or pharynx.
In some situations, there can be retrosternal chest pain, and in that situation it’s important to do an
electrocardiogram to rule out cardiac ischemia.
In order to diagnose the different types of esophageal disorders, three things come in handy: an upper
gastrointestinal tract radiography or a Barium swallow, an upper gastrointestinal endoscopy with biopsy, and
high resolution manometry or HRM.
A Barium swallow is a non-invasive, x-ray of the esophagus, stomach, and duodenum using orally ingested
barium as contrast.
Upper endoscopy is a minimally invasive procedure that helps visualize the esophagus, stomach and duodenum
through a flexible tube with a camera inserted in the mouth.
Upper endoscopy should generally be performed in individuals that present dysphagia in order to rule out
esophageal cancer.
Esophageal manometry is used to diagnose functional disorders. The way that it’s done is a sensitive pressure
catheter is inserted through the nose and sent down into the esophagus so it can measure the strength of
peristaltic contractions, as well as the pressure in both esophageal sphincters during swallows.
There are actually two types of esophageal manometry. In Classical manometry there are 4 to 8 pressure sensors
placed at different levels of the esophagus and a normal reading looks something like this.
In high resolution manometry there are more pressure sensors and the reading is color coded and looks like a
surface map, where red indicates the strongest contractions, and blue indicates the weakest contraction, so that
it looks something like this.
Now, let’s go over the functional disorders of the esophagus.
With achalasia, esophageal peristalsis is impaired and food isn’t effectively propelled through the esophageal
body.
In addition, the lower esophageal sphincter doesn’t completely relax during swallowing, so it doesn’t allow food
to pass through, leading to dilation of the esophagus.
Individuals typically have progressive dysphagia for both solids and liquids, regurgitation of undigested food,
chest pain, heartburn, and weight loss.
On a Barium swallow the esophagus looks dilated and has a narrow lower sphincter classically called a “bird’s
beak” appearance.
An upper endoscopy doesn’t diagnose achalasia, but it should be done in individuals with dysphagia and weight
loss to rule out an esophageal cancer.
High resolution manometry is the gold standard for diagnosing achalasia and it can show absent peristalsis in the
esophageal body and high pressure in the lower esophageal sphincter.
There isn’t a cure for achalasia, but there are options for relieving the symptoms and reducing the pressure of
the lower sphincter. The most effective option is a Heller laparoscopic myotomy.
That’s where a small cut is made in the lower sphincter to relieve the pressure and sometimes it’s accompanied
by Nissen’s fundoplication surgery to prevent acid reflux and this can work for more than 10 years.
Individuals above the age of 40 are considered high risk for a myotomy, so they’re usually treated with a
pneumatic dilation instead. That’s where a balloon is inserted through an endoscope in the lower sphincter and
filled with air for 40 to 50 seconds to stretch out the muscle layer of the lower sphincter. That typically works for
up to 10 years.
Individuals older than 65 years are poor candidates for these surgeries, so they are often treated with a
botulinum toxin that’s injected directly into the lower esophageal sphincter through an endoscope. That
typically works for up to a year.
Medical therapy is a generally ineffective treatment for achalasia, but it can be used in poor surgical candidates
if botulinum toxin injections didn’t work. Options include calcium channel blockers such as nifedipine and
sublingual nitrates which decrease pressure in the lower esophageal sphincter.
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With diffuse esophageal spasm, peristaltic contractions of the esophagus are intermittent and uncoordinated
which leads to ineffective contractions. In most cases, there’s also incomplete relaxation of the lower
esophageal sphincter, just like with achalasia.
Individuals often have retrosternal chest pain due to high-amplitude contractions and intermittent dysphagia for
both solids and liquids but rarely have food regurgitation.
On a barium swallow, the esophagus will have a “corkscrew” or “rosary bead” appearance.
Again, high resolution manometry is the gold standard in diagnosing diffuse esophageal spasm and it shows
uncoordinated high-amplitude peristaltic contractions.
Treatment is very similar to achalasia, but in this case, medical therapy with calcium channel blockers and
sublingual nitrates are first line treatment because they’re more effective.
Pneumatic dilation and botulinum injection therapy can be used in severe situations, but just like in achalasia,
they’re only short term measures.
With esophageal scleroderma, the smooth muscle in the esophagus begins to atrophy and as a result, the
peristaltic contraction in the mid and distal esophagus are absent. In addition, the lower esophageal sphincter
pressure is lower than normal, and that leads to gastroesophageal reflux disease.
Scleroderma or systemic sclerosis is an autoimmune disease in which there’s fibrosis of the skin and the
digestive system - particularly affecting the esophagus, the kidneys, heart, lungs, and muscles.
CREST syndrome is a limited form of the disease and it stands for: calcinosis which is calcium deposits in soft
tissues, Raynaud phenomenon, esophageal dysmotility, sclerodactyly which is skin tightening, and telangiectasia
or spider veins near the surface of the skin.
Most individuals with esophageal scleroderma have dysphagia, odynophagia, heartburn, and regurgitation.
The Barium swallow can appear normal, but an upper endoscopy with biopsy may show evidence of muscle
atrophy and fibrosis. High resolution manometry shows reduced esophageal peristalsis and low pressure in the
lower sphincter.
Since the smooth muscle of the esophagus is atrophied, treatment relies only on controlling gastroesophageal
reflux symptoms with proton pump inhibitors such as omeprazole.
Moving on to mechanical disorders of the esophagus. With Schatzki’s ring a thin symmetric mucosal band forms
- most often in the distal esophagus, and it can narrow the lumen and in most cases, a hiatal hernia is also
present. The exact cause is unknown, but a Schatzki’s ring can be associated with eosinophilic esophagitis and
hiatal hernia.
In most cases, the individual has no symptoms, but if the lumen of the esophagus is smaller than 13 millimeters,
individuals can have intermittent dysphagia for solids.
On a Barium swallow, Schatzki’s ring is seen as a small and regular ridge above the diaphragm that narrows the
lumen of the esophagus.
On an upper endoscopy, it appears as a thin circumferential membrane that projects into the lumen.
The main treatment for Schatzki’s ring is pneumatic dilation, but often the problem can recur over time,
requiring a repeat dilation. Long term medical therapy with proton pump inhibitors is often added to prevent
acid reflux.
With esophageal webs, a thin membrane made of squamous epithelium projects in the lumen of the esophagus,
but unlike Schatzki’s ring, an esophageal web is mostly found in the upper third of the esophagus and it doesn’t
occupy the entire circumference of the lumen.
Individuals often have intermittent dysphagia depending on how narrow the lumen of the esophagus becomes.
Plummer Vinson syndrome is known for causing esophageal webs, iron deficiency anemia, and glossitis - so
individuals with Plummer Vinson also have symptoms of fatigue and an inflamed tongue.
On a Barium swallow, esophageal webs appear just like Schatzki’s ring, only higher in the esophagus.
An upper endoscopy will show the esophageal webs as thin membranes in the lumen that don’t occupy the
entire circumference.
Treatment of esophageal webs is pneumatic dilation, with repeated dilations sometimes needed
With Zenker’s diverticulum, the mucosa and submucosa of the esophagus slide through an area of muscle
weakness right above the upper esophageal sphincter and form a pouch-like structure outside the lumen of the
esophagus.
It mostly occurs in elderly males that initially have intermittent oropharyngeal dysphagia, but then develop
halitosis or bad breath as solids accumulate in the pouch. They can also have pulmonary aspiration of foods as
well as regurgitation.
If the diverticulum is big enough, it can be seen and palpated on physical examination.
A Barium swallow localizes the diverticulum outside the lumen of the esophagus, and in this situation, an upper
endoscopy is not usually recommended due to the high risk of perforation.
Treatment in Zenker’s diverticulum is surgical removal of the diverticulum.
With benign esophageal stricture, there’s narrowing of the lumen of the esophagus mostly caused by reflux
esophagitis. But other causes include caustic ingestions, eosinophilic esophagitis, and radiation therapy.
Individuals have progressive dysphagia for solids, odynophagia, heartburn, and an unintended weight loss.
On a Barium swallow, the stricture causes the flow of barium to get obstructed so that it looks like a thin string
of contrast going through the esophagus.
On an upper endoscopy, the narrowing of the lumen as well as the esophageal stricture can usually be seen.
Treatment in benign esophageal strictures is pneumatic dilation, and repeated dilations are sometimes needed.
If pneumatic dilations don’t resolve the symptoms, then a stent may be placed at the site of the stricture.
With malignant strictures, there’s also narrowing of the lumen, but this time it’s caused by the tumor growing
inside the esophagus.
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Like in benign esophageal stricture, symptoms include progressive dysphagia for solids, odynophagia, heartburn, Whereas with malignant strictures, a biopsy is needed to stage the malignancy using the TNM grading and to
and an unintended weight loss. But in addition, there may be an upper gastrointestinal bleeding which can lead determine the appropriate treatment.
to iron deficiency anemia.

On the Barium swallow, the stricture again causes the flow of barium to get obstructed, but because tumors are
often irregular in shape the narrowing of the lumen will be irregular as well. It looks a bit like someone has
“eaten” parts of the esophagus.

On an upper endoscopy, a tumor mass can be seen within the esophagus and there are usually ulcers and
erosions as well. The biopsy will reveal malignancy and the type of esophageal cancer.

Although there are many types of esophageal malignancy, the most common ones are adenocarcinoma due to
Barrett’s esophagus, and squamous cell carcinoma.

In order to evaluate and classify the malignancy in the TNM system, which is tumor, node and metastasis,
further investigations are needed, like a CT and MRI scan.

Treatment is guided by the stage of the esophageal cancer which is classified into the Tumor-Nodes-Metastasis
or TNM system, which helps to categorize tumors based on their size and growth pattern.

Based on the TNM system, esophageal carcinoma has 5 stages, from 0 to 4, 0 meaning only the epithelial wall of
the esophagus is infiltrated and 4 meaning there are distant metastasis.

Usually, in the first 3 stages of esophageal carcinoma - 0, 1, and 2, the tumor can be surgically or endoscopically
resected. However, in the stage 3, the tumor is resectable only if it hasn’t invaded important structures, such as
the aorta, the trachea or the spine. If it has invaded those structures, then chemoradiation therapy is indicated.
Stage 4 is also unresectable, and only chemoradiation is usually used.

Now, as a quick recap, esophageal disorders can be functional - which usually causes intermittent dysphagia for
solids and liquids, or mechanical - which usually causes progressive dysphagia for solids.

With achalasia, individuals have progressive dysphagia for both solids and liquids, and a high resolution
manometry is the gold standard for diagnosis. Treatment primarily relies on Heller laparoscopic myotomy,
pneumatic dilation, and botulinum toxin injections.

With diffuse esophageal spasm, individuals present retrosternal chest pain, intermittent dysphagia for both
solids and liquids and again, high resolution manometry is the gold standard for diagnosis. Treatment in this case
mainly relies on calcium channel blockers and nitrates.

With esophageal scleroderma, there is no specific treatment for esophageal scleroderma, but proton pump
inhibitors can prevent acid reflux.

With Schatzki’s ring, a thin, symmetric mucosal band appears in the lower esophagus and treatment is
pneumatic dilation.

With esophageal webs, there are thin asymmetric membranes that appear in the upper esophagus and
treatment is also pneumatic dilation.

With Zenker’s diverticulum, individuals have dysphagia and halitosis, and treatment is surgical.

With benign esophageal strictures, treatment is pneumatic dilation.

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Clinical Reasoning: Gastroesophageal reflux disease
The esophagus is a 25-30 centimeter long tube that food and liquids pass through, from the pharynx to the
stomach.
The esophageal wall is made of 4 layers: the inner mucosa, which is made of stratified squamous epithelium,
except at the lower esophageal sphincter, where it joins the gastric epithelium to form the gastroesophageal
junction; the submucosa, a muscular layer; and an outer layer called adventitia.
At the top and bottom of the esophagus there are the upper and lower esophageal sphincters, respectively.
Both relax during swallowing to allow the passing of food or liquids, propelled by peristaltic contractions.
Additionally, the lower esophageal sphincter is closed between meals to prevent acid reflux and has a resting
pressure of 10 to 45 millimeters of mercury.
When the lower esophageal sphincter pressure is lower than normal, gastric acid reaches the esophagus and the
pH of the esophagus drops from 7 to 4, and this is called acid reflux.
Some degree of acid reflux is normal, and it happens mostly after a meal, but it doesn't cause esophageal
damage or associated symptoms.
Gastroesophageal reflux disease, or GERD, happens when the resting pressure of the lower esophageal sphincter
is below 10 millimeters of mercury, which allows the backflow of gastric acid in the esophagus, causing
esophageal lesions and symptoms that mostly happen at night.
GERD can be caused by a hiatal hernia, where the stomach and lower part of the esophagus slide above the
diaphragm and this usually happens in overweight, obese individuals. It can also occur during pregnancy due to
increased pressure in the abdomen from the growing fetus.
Other common causes are products that increase the production of gastric acid or decrease the tone of the
lower esophageal sphincter, like alcohol, spicy foods, caffeinated drinks including coffee, tea, and soda, citrus
fruits, tomatoes, and even peppermint!
With GERD, typical symptoms include heartburn and regurgitation. But, GERD can also cause atypical symptoms
such as retrosternal chest pain, dysphagia or difficulty swallowing, persistent coughing, voice changes, halitosis
or bad breath, dental erosions, ear or nose discomfort, or even nocturnal asthma that is unresponsive to asthma
therapy.
To help identify GERD as the cause of these atypical symptoms, a full workup can be done, which includes an
upper endoscopy with biopsy, esophageal manometry, and 24-hour pH-monitoring.
Now, in addition, some individuals with GERD can have signs and symptoms that may be worrisome for an
esophageal cancer. These include unintended weight loss, iron deficiency anemia, anorexia, odynophagia or
painful swallowing, and upper gastrointestinal bleeding. In these situations, to help identify GERD, upper
endoscopy and biopsy can be done.
Finally, in some individuals with risk factors for Barrett’s esophagus, which is a premalignant lesion, an upper
endoscopy and biopsy may be done. These risk factors include male sex, white race, age over 50 years, obesity,
tobacco use, having a hiatal hernia, and having a first degree relative with esophageal cancer.
An upper endoscopy with biopsy can detect various complications of GERD and it can rule out malignancy.
The most common complication is reflux esophagitis, and on upper endoscopy there are signs of erosion, even
small ulcers. These lesions can be classified using the Los Angeles system or the Savary-Miller system, both of
which use a 1 to 4 grading scale, where grade 1 is mild esophagitis and grade 4 is severe esophagitis.
A second complication is a peptic stricture, and on upper endoscopy there’s a narrowing of the lumen, most
often in the distal esophagus. These peptic strictures form when esophageal erosions and ulcers heal and form
fibrotic scars.
A third complication is Barrett’s esophagus, which is where metaplasia begins to develop. That’s where stratified
squamous epithelium of the distal esophagus is replaced by metaplastic columnar epithelium. That’s the same
cellular layer that’s found in the intestine and when it forms in the esophagus it becomes more likely to have
cancer develop there. That’s why Barrett’s esophagus is considered a premalignant lesion.
In Barrett’s esophagus the upper endoscopy show a change in the epithelium that’s at least 1 centimeter above
the gastroesophageal junction. A biopsy of that tissue confirms intestinal metaplasia, which is characterized by
goblet cells that secrete mucus.
Over time, the metaplastic cells of Barrett’s esophagus start to undergo genetic changes and they become
dysplastic. Meaning that the cells become bigger, pleomorphic, and being to proliferate quickly.
Based on the rate of proliferation, the tissue is categorized as low-grade dysplasia or high-grade dysplasia.
Biopsies typically show cytologic abnormalities like abnormally shaped cells with bigger nuclei that are
undergoing atypical mitosis.
With adenocarcinoma, the tissue has already mutated to the point where proliferation is happening without
regulation and the growing cell mass typically can break through normal tissue boundaries and invade
neighboring tissues.
In individuals with atypical symptoms, and a normal upper endoscopy, esophageal manometry may be done
next. This can help to identify functional esophageal disorders, such as achalasia and diffuse esophageal spasm,
and evaluate the peristaltic function of the esophagus before a surgical intervention for GERD.
Manometry uses a pressure sensitive catheter that is inserted through the nose in the esophagus so it can
measure the effectiveness of the peristaltic contractions, as well as the pressure in both upper and lower
esophageal sphincters and with GERD, the pressure in the lower esophageal sphincter is below 10 millimeters of
mercury, showing that the lower esophageal sphincter doesn’t close properly between meals and allows the
backflow of gastric acid.
Ambulatory 24-hour esophageal pH monitoring is used to confirm the diagnosis of GERD in individuals with
atypical symptoms or individuals that were unresponsive to medical therapy and still have symptoms. This is a
minimally invasive technique in which a flexible catheter with a pH sensor is inserted through the nose and
down into the distal esophagus. The outer part of the catheter is connected to a monitor on an individual’s belt.
After 24 hours, the data is analyzed and a Demeester score is calculated based on how many times the pH
dropped below 4, the number of reflux episodes, and how long the longest reflux episode lasted. A score above
14.7 is suggestive of GERD.
Treatment of GERD starts with lifestyle and dietary changes that include weight loss in overweight and obese
individuals. The goal is a Body Mass index between 18.5 to 25 kilograms per square meter.
In addition, it’s ideal have the head of the bed elevated at least 6 inches to prevent nocturnal GERD symptoms.
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Also, it’s best to not eat within two hours of going to sleep, and eliminating foods that increase gastric acid
production.
In individuals with less than two episodes of acid reflux per week and no complications on upper endoscopy -
step up therapy is used.
Typically, the first medication used is a low dose histamine 2 receptor antagonist or H2RA which decreases the
production of gastric acid. Sometimes an additional medication like a sodium alginate such as Sucralfate is used
to help mucosal healing.
If the symptoms haven’t improved after 2 to 4 weeks of treatment, then the dose of H2RA is increased for the
next 2 to 4 weeks. After that, if symptoms are still present, then the H2RA is discontinued and a proton pump
inhibitor or PPI such as Omeprazole is started at a low dose for another 2 to 4 weeks.
PPIs are generally more effective in decreasing gastric acid production, but are also generally more expensive
than H2RAs.
Once again, if symptoms are not controlled after 2 to 4 weeks of a PPI, then the dose of the PPI is increased
gradually.
If symptoms are controlled only with a high dose of PPIs, then a laparoscopic anti-reflux procedure, called a
Nissen’s fundoplication, may be done. That’s where the gastric fundus is wrapped around the distal esophagus
and stitched there, strengthening the lower esophageal sphincter.
However, if symptoms disappear after medical therapy, then the treatment is discontinued to see if the
symptoms reappear. If the symptoms do recur, then medical therapy is reinitiated with the medication and
dosage that last controlled the symptoms.
In individuals with more than two episodes of acid reflux per week or erosive esophagitis, step-down therapy is
used. In this situation, treatment begins with a standard dose of a PPI for 8 weeks.
If symptoms disappear, the dose of PPI is gradually decreased. If PPIs were taken for more than 6 months, then
the dose is decreased gradually and replaced by an H2RA.
If the symptoms do recur, then medical therapy is reinitiated with the medication and lowest dosage that last
controlled the symptoms.
For individuals diagnosed with erosive esophagitis that is severe, a repeat upper endoscopy should be done after
8 weeks of medical therapy to see if there’s evidence of healing and to rule out Barrett’s esophagus.
In individuals with Barrett’s esophagus, treatment begins with a standard dose of a PPI, and the dose is
increased until symptoms of GERD are controlled.
Barrett’s esophagus can develop into esophageal adenocarcinoma, so upper endoscopies with biopsies are
repeated depending on the results of the initial biopsy.
If the initial biopsy showed no dysplasia, then the upper endoscopy and biopsy is repeated after 3 to 5 years.
If the initial biopsy showed indefinite dysplasia, then the PPI dose is increased and the upper endoscopy and
biopsy is repeated after two months of medical therapy.
If the initial biopsy showed low grade dysplasia, localized high-grade dysplasia, or intramucosal carcinoma, then
the individual typically has an endoscopic resection of the esophageal mucosa and submucosa and then
radiofrequency ablation of the affected tissue.
Finally, in individuals with extensive high-grade dysplasia, an esophagectomy-which is the surgical removal of
the esophagus may be needed.
In individuals with esophageal adenocarcinoma, treatment depends on the stage of the adenocarcinoma and
this is assessed using computer tomography or magnetic resonance imaging that can identify the local extent of
the cancer and also the presence of metastasis.
These findings are then classified into the Tumor-Nodes-Metastasis or TNM system, which helps to categorize
tumors based on their size and growth pattern.
Based on the TNM system, adenocarcinoma has 5 stages, from 0 to 4, 0 meaning only the epithelial wall of the
esophagus is infiltrated and 4 meaning there are distant metastasis.
Usually, in the first 3 stages of adenocarcinoma - 0, 1, and 2, the tumor can be surgically or endoscopically
resected.
However, in the stage 3, the tumor is resectable only if it hasn’t invaded important structures, such as the aorta,
the trachea or the spine. If it has invaded those structures, then chemoradiation therapy is indicated.
Stage 4 is also unresectable, and only chemoradiation is usually used.
Summary
Alright, as a quick recap, in GERD, an upper endoscopy is indicated in individuals with atypical symptoms or
alarm symptoms. It can also be helpful in detecting complications of GERD, such as esophagitis, esophageal
stricture, Barrett’s esophagus, and adenocarcinoma.
Esophageal manometry is indicated in individuals with retrosternal chest pain and dysphagia to rule out
functional disorders and ambulatory 24-hour pH monitoring is indicated to confirm the diagnosis of GERD in
individuals with atypical symptoms and unresponsive to treatment with PPIs.
In individuals with less than two episodes per week, step up therapy is indicated and in individuals with more
than two episodes per week or erosive esophagitis, step down therapy is indicated.
In individuals with Barrett’s esophagus and adenocarcinoma, treatment is indicated depending on the grade of
dysplasia and the TNM stage of adenocarcinoma.
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Clinical Reasoning: Peptic ulcers and stomach cancer
Peptic ulcers are deep erosions in the lining of the stomach or duodenum that lead to inflammation in the
gastric or duodenal wall.
Sometimes, peptic ulcers develop acutely like after a toxic ingestion or ischemia, but more often the erosions
are chronic, developing slowly over time.
Chronic ulcers are mostly benign, but they can sometimes develop into a malignant ulcer, termed stomach
cancer, which is why an upper endoscopy with biopsy is essential to the diagnosis.
Chronic ulcers sometimes don't cause any symptoms. When they do, the most common symptom is dyspepsia.
Dyspepsia includes epigastric pain related to eating food, early satiety, postprandial belching, and nausea.
With gastric ulcers, epigastric pain worsens when eating a meal because of the hydrochloric acid that’s produced
in response to food.
With duodenal ulcers, epigastric pain is relieved while eating a meal, but it typically recurs 2 to 5 hours later or it
can appear at night. That’s because with duodenal ulcers, Helicobacter pylori is involved in most cases and it
increases the hydrochloric acid production by indirectly increasing gastrin production and when there’s no food
to act as a buffer, the pain worsens.
Sometimes peptic ulcers can erode deep into the gastric and duodenal wall resulting in complications.
If an ulcer erodes into a blood vessel, then it can cause hematemesis or melena.
If there’s an ulcer in the pyloric antrum or in the duodenum, then it can cause gastric outlet obstruction. That
can worsen the symptoms and even cause the individual to lose weight.
Peptic ulcers can also perforate into the peritoneal cavity causing peritonitis, and that causes severe abdominal
pain and fevers.
With stomach cancer, things get a little more complicated. Risk factors include chronic mucosal inflammation,
like in Helicobacter pylori infection, atrophic gastritis, and surgery on the stomach; as well as environmental
triggers like tobacco, and occupational exposures to coal, steel, or iron.
There are many types of stomach cancer, but the most frequent one is adenocarcinoma and this is found in 90%
of the cases.
However, a MALT lymphoma which stands for mucosal-associated lymphoid tissue lymphoma can develop when
there’s persistent antigenic stimulation of the gastric mucosa like in a Helicobacter pylori infection.
Symptoms of stomach cancer usually appear in advanced stages and includes unintended weight loss, diffuse
abdominal pain, hematemesis or melena and a sense of fullness in the upper abdomen after eating a small meal.
When a peptic ulcer is suspected, barium radiography, which uses barium as contrast, can sometimes be done.
On barium radiography, a peptic ulcer looks round or oval, and it’s surrounded by edematous mucosal folds
which radiate towards the ulcer.
In contrast, a malignant ulcer is more irregular and the mucosal folds don’t usually reach the margin of the ulcer.
Nowadays, barium radiography is not commonly done, because an upper endoscopy is better for diagnosing a
peptic ulcer and distinguishing it from stomach cancer. However, if the Barium radiography is done and shows a
peptic ulcer, then an upper endoscopy isn’t usually needed.
On the other hand, if the barium radiography is inconclusive or if it simply isn’t done at all, then an upper
endoscopy is done.
Normally, a peptic ulcer looks like a crater that has smooth margins and a flat base that may contain exudate.
In contrast a malignant ulcer looks like a crater that has thick and irregular margins with a mass resting within
the base.
In addition, the mucosa surrounding the malignant ulcer is often nodular and necrotic.
A biopsy of the erosion must be obtained to confirm whether it’s a peptic ulcer or a malignant ulcer.
Usually, duodenal ulcers rarely cause cancer and are biopsied only when the appearance suggests malignancy,
but gastric ulcers develop into stomach cancers more frequently, so they should always be biopsied.
Along with the biopsy, Helicobacter pylori testing should be done, because it’s a risk factor for peptic ulcers,
stomach cancer, and MALT lymphoma.
On biopsy, a newly formed acute peptic ulcer has regular margins and has inflammatory exudate with
neutrophils, and it’s considered active if it’s bleeding.
If it’s a chronic peptic ulcer then it typically has lymphocytes, and some signs of fibrinoid necrosis and new
granulation tissue at the base and margins.
In contrast, a malignant ulcer looks different depending on the type of cancer.
Gastric adenocarcinoma is split up into the intestinal subtype which has cells that look like intestinal cells or the
diffuse subtype which has cells that secrete mucus.
With MALT lymphoma, there are an abundance of B-cells which can be identified by cell surface markers, like
CD20.
If a gastric adenocarcinoma has been confirmed on the biopsy, then a CT scan of the thorax, abdomen, and
pelvis is done to stage the stomach cancer. The findings are then classified in the Tumor-Nodes-Metastasis or
TNM system.
Gastric adenocarcinoma has 5 stages, from 0 to 4, 0 meaning only the gastric mucosa is infiltrated and 4
meaning there are distant metastasis.
In the first two stages of cancer- 0 and 1, an endoscopic resection of the cancer can be done or else a subtotal or
total gastrectomy is indicated, meaning that a part of the stomach or the entire stomach is surgically removed.
In stage 2 and 3, chemotherapy is used before or after the surgery to shrink the tumor and lower the chances of
the cancer coming back and then a total gastrectomy is done. In this situation, the omentum and the nearby
lymph nodes are also removed. If the individual cannot undergo surgery, then chemoradiation may be used.
In stage 4 disease, palliative surgery like a gastric bypass or a subtotal gastrectomy, along with chemoradiation,
is used to relieve symptoms.
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If the biopsy and immunohistochemistry showed a MALT lymphoma, a CT scan of the neck, thorax, abdomen
and pelvis is done to stage the cancer, and H.pylori serology is done if it wasn’t already detected on the biopsy.
Then the MALT lymphoma is staged using the Lugano classification into 4 stages, where stage 1 means that the
cancer is confined in the gastrointestinal tract and stage 4 means that the cancer spread to distant organs or in
the lymph nodes of both sides of the diaphragm.
Treatment depends on whether H. pylori is present or not.
With stage 1 and 2 MALT lymphomas that are H.pylori positive, treatment is eradication of the H.pylori infection,
and this alone can induce regression of the cancer.
If H.pylori is not present or if the eradication of H.pylori with different treatment regimens repeatedly fails over
the course of a year, then radiation therapy, chemotherapy or immunotherapy can be tried.
With stage 3 and 4 MALT lymphomas, that are either H.pylori positive or H.pylori negative, the treatment
consists of chemotherapy or immunotherapy.
Now, let’s say that instead of stomach cancer, we’re dealing with peptic ulcers. The most common cause of
peptic ulcers is colonization with Helicobacter pylori. This is a gram negative bacteria that makes a home for
itself in the stomach by releasing proteases that injure the surrounding mucosa.
H. pylori also produces the enzyme urease which breaks down urea into carbon acid and ammonia. The
ammonia acts as a base and it raises the pH of the environment around the H.pylori just enough to let it survive.
All individuals with peptic ulcer disease, MALT lymphoma or a history of peptic ulcer disease or endoscopic
resection of a low grade gastric cancer, should be tested for H.pylori infection using endoscopy and biopsy.
With the biopsy, two tests can be done. The best test is histology which can directly show H.pylori using special
stains, like Giemsa.
The other test is the biopsy urease test which is where the biopsy specimen is placed in a medium that contains
urea and a pH reagent. The urease of H.pylori breaks down the urea, and that creates a color change in the
medium turning it from yellow to pink.
Now, in individuals with dyspepsia under the age of 60 that don’t have worrisome symptoms like unintended
weight loss and anorexia, there are non-invasive ways to test for H.pylori instead, like the urea breath test and
the stool antigen test.
During the urea breath test, a person swallows a tablet of urea labelled with an isotope, such as carbon-13 or
carbon- 14. If the isotope is detected in the carbon dioxide released in the breath, that means that the urea was
broken down by urease that’s made by H.pylori in the stomach.
The stool antigen test detects H. pylori antigens in the stool.
Now, the urea breath test and the stool antigen test can generate a false-negative result, if the individual is also
taking proton pump inhibitors or PPIs, bismuth, or antibiotics. To avoid this, whenever possible PPIs are replaced
with histamine-2 receptor antagonists (or H2 blockers), about 2 weeks before doing the test.
One final test for H.pylori is serum titers which specifically look for IgG antibodies in the blood against H. pylori.
Titers can’t differentiate a past infection from a current one, but on the positive side they do establish that there
was an infection at some point, and unlike other tests, titers aren’t influenced by the use of PPIs, bismuth, and
antibiotics.
So at the end of the day, individuals that test positive for H. pylori infection using any of these various tests,
should be treated.
The treatment is triple therapy with clarithromycin, amoxicillin, and a PPI like omeprazole for 14 days. If the
individual has a penicillin allergy, then amoxicillin is replaced with metronidazole.
If individuals have previously taken clarithromycin or other macrolides, then quadruple therapy can be done
with a PPI, bismuth, tetracycline, and nitroimidazole for 10 to 14 days.
After 4 weeks, the stool antigen is determined to check if the infection was successfully eradicated.
If the peptic ulcers caused by the bacteria cause complications like bleeding, then after triple or quadruple
therapy for eradication, the PPI should be continued for 8 to 12 weeks, with an upper endoscopy done at the
end of therapy to confirm that the ulcer is healing, and after that a stool antigen test is done to confirm that the
infection is gone.
Another common cause of chronic peptic ulcers are long term use of nonsteroidal anti-inflammatories (or
NSAIDs), such as ibuprofen and aspirin.
NSAIDs impair mucosal defenses by inhibiting the production of prostaglandins that normally increase the
production of gastric mucus and decrease the production of gastric acid and this way the mucosa can be
damaged and erosions appear.
On an upper endoscopy, peptic ulcers due to NSAIDS typically show a pattern of multiple small erosions in the
stomach or duodenum.
Treatment consists of stopping NSAIDs and initiating PPIs for at least 8 weeks. If the individual takes NSAIDs in
the future, which is quite common, a PPI should also be added in order to lower the risk of recurrence.
A special cause of peptic ulcer disease is Zollinger-Ellison syndrome.
In Zollinger-Ellison syndrome, there’s a gastrinoma which is a gastrin-secreting tumor that’s located in the
duodenum or pancreas. The high gastrin levels cause more hydrochloric acid production and this can damage
the mucosa and cause multiple ulcers to form, mostly in the first part of the duodenum and sometimes in the
jejunum.
Zollinger-Ellison syndrome is also specifically associated with Multiple Endocrine Neoplasia type 1 (or MEN1),
which is when there are tumors in the pituitary gland, parathyroid gland, and pancreas.
Finally, there are acute peptic ulcers, which are sometimes called stress ulcers.
Stress ulcers can develop after exposure to alcohol, chemotherapy, and NSAIDS. That’s right - NSAIDs can cause
both chronic peptic ulcers and stress ulcers - a double whammy. They can also form when there’s a substantial
reduction in mucosal blood flow like during a trauma or sepsis.
A specific type of stress ulcer - called a curling ulcer - classically occurs in individuals that have had a severe burn
injury. That’s because burns cause a sudden loss of fluid, which leads to hypovolemia and ischemia in the gastric
mucosa.
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Another specific type of stress ulcer - called a cushing ulcer - classically occurs in individuals that have elevated
intracranial pressure. That’s because there’s overstimulation of the vagus nerve which leads to excess
hydrochloric acid secretion, and that damages the stomach mucosa.

Regardless of the cause, stress ulcers typically cause similar symptoms as chronic peptic ulcers, but in this case,
symptoms develop shortly after the mucosa has been injured. These include abdominal pain, nausea, vomiting
and upper gastrointestinal bleeding.

An upper endoscopy typically shows multiple superficial erosions in the fundus or the body of the stomach, and
in rare cases in the duodenum or distal esophagus.

Stress ulcers prophylaxis should be given to all severely ill individuals - that includes those with sepsis,
individuals getting mechanical ventilation for more than 48 hours, individuals with a history of gastrointestinal
bleeding in the last year and those that have had a traumatic brain or spinal cord injury that lead to increased
intracranial pressure.

Prophylaxis can be done using a histamine 2 receptor antagonist like nizatidine or with a proton pump inhibitor
(PPI).

If an individual already has stress ulcers, then treatment starts with correcting the cause. For example, stopping
an offending medication or giving intravenous fluids to correct hypovolemia.

In addition, PPIs are also given to prevent further damage to the mucosa.

When it’s possible, an upper endoscopy is performed to assess the severity of the stress ulcers and to ensure
that they are healing.

Summary

Alright, as a quick recap. Chronic ulcers, can be evaluated with an upper endoscopy to differentiate a peptic
ulcer from a malignant ulcer.

Malignant ulcers need further investigations to identify the type of cancer.

With adenocarcinoma, there are 5 stages according to the TNM system and treatment in the first 3 stages is the
surgical removal of adenocarcinoma plus chemotherapy and palliative surgery and chemoradiation in stage 4.

With MALT lymphoma, there are 4 stages according to Lugano’s classification and treatment relies on treating
H.pylori infection if present in the first 2 stages and chemotherapy, radiation therapy or immunomodulatory
therapy in the last 2 stages.

With peptic ulcers, the two main causes are H. pylori and NSAIDs.

H.pylori related peptic ulcers are treated with triple therapy using Clarithromycin, Amoxicillin and PPIs for 14
days and after 4 weeks, the stool antigen test is used to see if treatment was successful.

NSAID related peptic ulcers are treated by stopping the NSAIDS and treating with 8 weeks of PPIs.

Acute peptic ulcers or stress ulcers usually develop in severely ill individuals, and should be prevented by using a
histamine 2 receptor antagonist or a PPI.

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Clinical Reasoning: Diarrhea
Diarrhea is defined as having more than 3 liquidy stools in 24 hours or having a stool weight of over 200 grams
per day, but nobody measures stool weight since that can get messy - especially if you're having diarrhea!
Diarrhea is also classified as acute if it lasts for less than 2 weeks, persistent if it lasts for 2 to 4 weeks, and
chronic if it lasts for more than a month.
Diarrhea can also be classified as either inflammatory or non-inflammatory.
Inflammatory diarrhea causes inflammation of the gastrointestinal epithelium and this usually happens with
invasive pathogens or as a result of a chronic inflammatory bowel disease, and usually there are systemic
symptoms like fever.
In contrast, non-inflammatory diarrhea can be either secretory or osmotic, and neither one usually causes
systemic symptoms like fever.
With secretory diarrhea, there’s increased water and electrolyte secretion and decreased absorption.
With osmotic diarrhea, some of the ingested nutrients aren’t fully absorbed, and they remain in the intestinal
lumen and pull in water through the process of osmosis!
Now, most cases of acute diarrhea are caused by pathogens, mostly viruses, but also bacteria, protozoa, and
parasites that mostly spread through fecal-oral transmission.
The minority of cases of acute diarrhea are due to non-infectious causes like stress, medications, or a toxic
ingestion.
Most people with acute diarrhea don’t need to come to the hospital, because symptoms aren’t severe and
resolve within 2 weeks. But in terms of figuring out the cause, it’s helpful to ask the right questions - like playing
Sherlock Holmes.
With infectious organisms, diarrhea is non-inflammatory and secretory, stools are watery and usually associated
with vomiting and this is mostly caused by viruses, such as norovirus and rotavirus.
Watery diarrhea can also be related to the ingestion of contaminated food - food poisoning - and in this case
timing offers a clue. If diarrhea occurs within six hours of the ingestion, then the culprit may be Staphylococcus
aureus or Bacillus cereus, if diarrhea occurs 8 to 16 hours after the ingestion, then the culprit may be Clostridium
perfringens, and if diarrhea occurs more than 16 hours after the ingestion, then the culprit may be
enterotoxigenic E. coli.
In contrast, when there’s inflammatory diarrhea, the stools are bloody and mucousy - called dysentery- and
other symptoms include severe abdominal pain and fever. This is mostly caused by invasive pathogens like
Salmonella, Shigella, Yersinia, Campylobacter, and enteroinvasive E. coli - and these are sometimes shortened to
SSYCE.
More specifically, exposure to contaminated foods - particularly animal products like meat, dairy, and eggs has
been associated with Salmonella infection, and drinking contaminated water can lead to a Giardia infection.
If there was any recent antibiotic use, Clostridium difficile may be the culprit because it can cause
pseudomembranous colitis.
On the physical examination, the most important thing is to assess the degree of dehydration, and based on the
volume lost through stools and/or vomiting, dehydration can be mild, moderate and severe.
Mild dehydration means that 5% of the total weight was lost and the individual may only be thirsty.
Moderate dehydration means that 6 to 9% of the total weight was lost and in this case the individual may have
dry mucous membranes, sunken eyes, decreased urine output, tachypnea, and tachycardia.
Finally, in severe dehydration, more than 10% of the body weight is lost and the individual might have very dry
mucous membranes, decreased skin turgor, cool limbs, anuria, significant tachypnea and tachycardia, and in
extreme cases hypotension and a loss of consciousness.
Laboratory tests are not usually done in individuals with acute diarrhea, but in severe cases where there are
signs of moderate or severe dehydration - electrolytes, creatinine and urea nitrogen should be taken in order to
rule out renal dysfunction.
In some cases, a CBC can also be helpful. For example, thrombocytopenia and anemia is suggestive for
hemolytic-uremic syndrome which is often caused by E. coli O157 which produces Shiga toxin. Another example,
is that there can be a very elevated white blood cell count in Clostridium difficile infections.
Finally, for individuals that are ill appearing, or in vulnerable populations like the elderly or with comorbid
conditions, or in fields that could cause a public health concern - like daycare workers, a more thorough workup
should be considered. That includes blood cultures, fecal leukocytes or fecal lactoferin which helps differentiate
inflammatory from non-inflammatory diarrhea, stool cultures for SSYCE, C.diff toxin assays, enterohemorrhagic
E.coli Shiga toxin, and Entamoeba histolytica testing which is done by sending three stool specimens that are
collected on consecutive days, because ova and parasite excretion can be intermittent. It’s also worth sending
off testing for common viruses like norovirus and rotavirus to make sure that it isn’t a severe viral
gastroenteritis.
Treatment of acute infectious diarrhea is mainly about fluid repletion and dietary adjustments.
Fluid repletion should be primarily done using oral rehydration solutions that are taken orally or with a
nasogastric tube, and in severe cases like individuals with severe hypovolemia should be given intravenous
fluids. One to two liters of isotonic crystalloids are given initially to restore tissue perfusion and this is continued
until the individual is euvolemic.
Typically the diet should be focused on liquids and simple foods like juices, soups, bread, and crackers. In
addition, dairy products like milk and cheese should be avoided for a few months, because acute infectious
diarrhea often causes secondary lactose malabsorption. Live culture yogurt is an exception because it contains
live active bacteria that help break down and digest the lactose in milk.
Empiric antibiotic treatment is given for individuals who are severely ill or have risk factors for complications or if
the onset of symptoms was travel-associated. Some common regimens are azithromycin 500mg once daily for
three days or fluoroquinolones such as ciprofloxacin 500 mg twice daily for 3 to 5 days.
If a specific pathogen is identified then it can be treated according to the antibiotic that it is most susceptible to.
But some bacteria, like enterohemorrhagic E. coli shouldn’t be treated with antibiotics because the use of
antibiotics increases the toxicity of E. coli’s Shiga toxin.
Antimotility medications like loperamide can also be used in individuals with diarrhea to help reduce the
frequency of stools. But they should be avoided in individuals with dysentary who aren’t on antibiotics, because
they can prolong or worsen the disease course.
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In persistent diarrhea, the causes differ a bit, and parasitic organisms like Giardia, Cryptosporidium, and
Entamoeba histolytica, are more common - especially in individuals who travel or who work in a daycare facility.
Giardia and Cryptosporidium cause non-inflammatory secretory diarrhea associated with abdominal pain,
whereas Entamoeba histolytica causes inflammatory diarrhea with bloody stools, severe abdominal pain, and
fever. In this situation, three ova and parasite samples are sent for testing, and stool antigen testing may also be
used to diagnose specific parasitic infections.
Finally, there’s chronic diarrhea, and the causes vary a bit based on the socio-economic status of the population.
In low-income countries, chronic diarrhea is mostly caused by infectious organisms such as Giardia, whereas in
high-income countries, chronic diarrhea is mostly caused by inflammatory bowel disease, and malabsorption
syndromes like celiac disease or lactose intolerance.
If infections with the organisms causing acute diarrhea persist and become chronic in spite of the treatment,
then the individual may be immunocompromised and HIV testing may be indicated.
A work up for chronic diarrhea typically includes a complete blood count, which is used to identify anemia, and
this is usually seen when there’s chronic disease or gastrointestinal bleeding. A complete blood count can also
identify an elevated white blood cell count like in inflammatory conditions.
Erythrocyte sedimentation rate, or ESR, and C-reactive protein, or CRP, are also done, and if they are elevated,
then again that’s a sign of inflammation.
Also, a total protein and albumin must be done- because chronic diarrhea can lead to malnutrition.
And finally, stool occult blood and antibody tests for HIV can be done.
If stools are watery, calculating the stool osmotic gap can help differentiate secretory diarrhea from osmotic
diarrhea.
The stool osmotic gap is determined by taking 290 milliosmoles per kilogram, which is the constant of the stool
osmolality, and subtracting the sum of stool sodium and stool potassium multiplied by 2.
For example, let’s say that our specimen contains 50 millimoles per litre of sodium and 20 millimoles per litre of
potassium. Here, the stool osmolar gap will be 290 milliosmoles per kilogram minus two times 50 plus 20. So 290
minus two times 70 or 290 minus 140, which is 150 milliosmoles per kilogram.
Now, if the stool osmotic gap is greater than 125 milliosmoles per kilogram, then it’s an osmotic diarrhea which
may be caused by malabsorption due to celiac disease, for example.
Celiac disease may cause steatorrhoea-which is the presence of fat in the stool, weight loss, abdominal pain, and
skin rashes.
Lactose intolerance causes watery diarrhea and abdominal pain.
If the stool osmotic gap is less than 50 milliosmoles per kilogram, then it’s a secretory diarrhea.
Chronic secretory diarrhea may be caused by a VIPoma which is a tumor that produces vasoactive intestinal
peptide that increases water and electrolyte secretion in the intestinal lumen.
The diagnosis here is made by measuring the serum level of VIP, which can exceed 75 picograms per milliliter if
there’s a VIPoma.
Another cause may be a carcinoid which is a neuroendocrine tumor that is usually located in the gastrointestinal
tract and secretes serotonin that leads to secretory diarrhea and flushing.
There’s also Zollinger Ellison syndrome, which is a neuroendocrine tumor that secretes gastrin and this can also
be a cause of chronic secretory diarrhea.
On the other hand, inflammatory bowel disease causes inflammatory diarrhea with bloody stools, fever, and
weight loss.
Another lab test - stool calprotectin - which is released by neutrophils in the gastrointestinal tract is a good
marker for inflammatory bowel disease.
With inflammatory diarrhea, both upper and lower endoscopy procedures are usually needed to assess the
extent of mucosal damage.
Each specific cause of chronic diarrhea has a specific treatment, but general measures that include fluid
repletion and dietary adjustments are indicated and also symptomatic treatment with loperamide can be tried
to lower the stool frequency.
Summary
Alright, as a quick recap. Acute diarrhea is mostly caused by infectious organisms, and in severe cases, laboratory
tests such as a CBC, electrolytes, urea nitrogen, creatinine, blood cultures and stool cultures are necessary.
Treatment of acute diarrhea relies on fluid repletion using oral rehydration solutions or intravenous fluids if
there’s severe hypovolemia. In some cases, empiric antibiotic therapy with azithromycin or ciprofloxacin can be
started.
With persistent diarrhea, the main cause is a parasitic infection.
And with chronic diarrhea, a full blood workup is done and this includes CBC, ESR, C reactive protein, total
protein and albumin, antibody test for HIV and stool occult blood.
With watery stools, the stool osmotic gap can be calculated.
In secretory diarrhea, the stool osmotic gap is lower than 50 millimoles per kilogram and this can happen with
VIPomas, Carcinoid tumors or Zollinger Ellison syndrome.
In osmotic diarrhea, the stool osmotic gap is greater than 125 millimoles per kilogram and this can happens with
malabsorption syndromes such as celiac disease and lactose intolerance.
With inflammatory diarrhea, stool calprotectin is a marker of inflammation and in most cases, an upper and
lower endoscopy are needed.
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Clinical Reasoning: Malabsorption
With malabsorption, nutrients are no longer effectively absorbed in the small intestine.
Nutrients can either be macronutrients, such as fats, proteins and carbs or micronutrients like vitamins and
minerals.
Malabsorption can either be global meaning that the absorption of all nutrients is affected or it can be partial
meaning that only specific nutrients cannot be absorbed.
Malabsorption presents differently based on which nutrients are being malabsorbed, the severity of the disease,
and the underlying cause.
Global malabsorption can present with chronic or recurrent diarrhea with pale, greasy, voluminous and terrible
smelling stools and unintentional weight loss.
In contrast, partial malabsorption causes symptoms specific to the nutrient involved.
With fat malabsorption, symptoms include steatorrhea - meaning fatty stools.
To confirm that it's really steatorrhea, a fecal fat test can be done to check for fat. If it’s negative and fat
malabsorption is still suspected, then a 72 hours stool collection should be done because that’s the gold
standard for diagnosing fat malabsorption.
To do that, an individual has to have a diet that includes 70 to 120 grams of dietary fat per day, which is the
equivalent of eating about 300 grams of cheese per day. Stool is collected for 72 hours, and if there’s more than
6 grams of fat per day, then it’s considered fat malabsorption.
Typically if there’s steatorrhea, the stool fat exceeds 20 grams per day.
If fat malabsorption is present, then the fat soluble vitamins - A, D, E, and K, might also not be getting absorbed.
Vitamin A deficiency causes symptoms like night blindness and thickened skin due to hyperkeratosis.
Vitamin D deficiency causes symptoms like paresthesias, and fractures due to osteomalacia.
Vitamin E deficiency can cause symptoms like muscle weakness.
And finally, vitamin K deficiency causes symptoms like easy bruising, excessive bleeding from wounds,
gastrointestinal bleeds, or hematuria.
With protein malabsorption, edema and muscle atrophy may be present and on the lab tests, there may be
hypoalbuminemia and a low total protein level in the blood.
With carbohydrate malabsorption, symptoms include watery diarrhea, flatulence, and bloating.
To identify carbohydrate malabsorption, the D-xylose test can be done. That’s where an individual fasts
overnight and then eats 25 grams of D-xylose, which is a monosaccharide that’s normally absorbed by the small
intestine. The serum D-xylose is checked after an hour and if it’s below 20 milligrams per deciliter that suggest
malabsorption.
In addition, urine is collected over the next five hours as fasting continues, and if urine excretion of D-xylose is
below 4.5 grams, then that also suggests malabsorption.
False-positive results can occur, especially in older individuals with a decreased glomerular filtration rate.
Now, malabsorption can also lead to anemia either because of reduced iron absorption in the small intestine
leading to iron deficiency anemia or reduced vitamin B12 or folate absorption in the small intestine leading to
megaloblastic anemia.
Usually, if the mean corpuscular volume or MCV is less than 80 femtoliters, then it’s microcytic and this usually
happens with iron deficiency anemia.
With iron deficiency anemia, serum iron and ferritin are decreased and total iron binding capacity or TIBC is
increased.
If the MCV is above 100 femtoliters, then a blood smear is necessary to see if the macrocytic anemia is
megaloblastic. If so, vitamin B12 or folate deficiency is the most likely the cause, and can be confirmed by
obtaining Vitamin B12 and folate levels.
Now, global malabsorption is caused by diseases that cause damage to the small intestine mucosa, reducing the
surface area available for absorption.
A common cause of this is celiac disease -sometimes called celiac sprue- which is an autoimmune condition
triggered by the gluten found in foods like wheat bread.
Individuals can develop symptoms of global malabsorption, like chronic or recurrent diarrhea - with steatorrhea,
unintentional weight loss, abdominal distention, and bloating.
In addition celiac disease can cause iron deficiency anemia; and vitamin B12 and folate deficiency.
Celiac disease is also associated with dermatitis herpetiformis -which is a chronic skin condition, along with short
stature, delayed puberty, and reduced fertility.
The diagnosis of celiac disease starts with checking for Immunoglobulin A anti-tissue transglutaminase antibody
or TTGA IgA.
If TTGA IgA is positive, then an upper endoscopy with biopsy is done to look for evidence of damage, villous
atrophy, and crypt hyperplasia in the duodenal mucosa.
If the TTGA IgA is negative, then total serum IgA levels are obtained. If they’re low, then TTGA IgG and
deamidated gliadin peptide or DGP are checked. If either one of those is positive, then an upper endoscopy with
biopsy is done.
Finally, many individuals who suspect having celiac disease can keep a food journal and can try to eliminate
gluten from their diet to see if that improves symptoms.
Now, some individuals and groups are managed slightly differently. For example, those with a first degree
relative with celiac disease, get an upper endoscopy with biopsy and have TTGA IgA levels checked. If both are
normal, then celiac disease is unlikely. If either are positive, then total serum IgA levels, TTGA IgG, and DGP are
obtained. In addition, Human leukocyte antigen testing or HLA testing is often performed when there seems to
be a genetic predisposition, because HLA DQ2 and HLA DQ8 are both known to be linked with celiac disease.
Another group that gets managed slightly differently are children suspected of having celiac disease. Typically
these children have classic symptoms of celiac disease, but may also have a failure to thrive or pubertal delay.
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In symptomatic children, a TTGA IgA is checked and if it’s positive, then an upper endoscopy with biopsy is
performed to see if histology is consistent with celiac disease. If there are signs of celiac disease, then the
individual is placed on a gluten-free diet to see if symptoms improve. If histology is not consistent with celiac
disease or if symptoms don’t improve after a gluten-free diet, then HLA testing is done. However, if the TTGA IgA
is negative but symptoms suggest celiac disease, then additional tests like total serum IgA levels, anti-
endomisium antibody or EMA, and DGP can be done, and if any of these suggest celiac disease, then an upper
endoscopy with biopsy is performed.
In addition children with other conditions like autoimmune thyroiditis, type 1 diabetes mellitus, and Down
syndrome are at high-risk for developing celiac disease. In these children a TTGA IgA level is checked. If it’s
normal, then the workup only continues if symptoms begin. If the TTGA Ig A is slightly elevated but less than 3
times the upper limit of normal, then the EMA is tested for. If the EMA is negative, then the workup only
continues if symptoms begin.
Now if the TTGA IgA level is above 3 times the upper limit of normal or if the EMA is positive, then an upper
endoscopy with biopsy is performed. If histology suggests celiac disease, then the individual is placed on a
gluten-free diet and if there is no clinical improvement, then HLA testing should be done to see if HLA DQ2 or
DQ8 are present. However, if there is clinical improvement, then celiac disease is confirmed.
The main treatment of celiac disease is eliminating the trigger - gluten - from the diet. Because gluten is included
in a variety of foods, it requires careful attention to ingredients when buying processed foods.
Typically, a gluten free diet improves symptoms within 2 weeks and after 6 weeks, the individual should have
repeat lab testing including a complete blood count, folate, vitamin B12 level, iron studies, and TTGA IgA. There
should also be a repeat upper endoscopy with biopsy, 6 months after being on a gluten free diet to make sure
that there are signs of healing.
Another cause of global malabsorption is tropical sprue and it mostly occurs in a tropical region that includes
Haiti, the Dominican Republic, Puerto Rico, and Cuba. The disease may be caused by a pathogen that hasn’t
been identified yet. The individual typically has global malabsorption symptoms, like chronic or recurrent
diarrhea - with steatorrhea, unintentional weight loss, abdominal distention, and bloating, as well as vitamin B12
and folate deficiency.
It’s a diagnosis of exclusion, that requires reuling out infectious and inflammatory causes of diarrhea. That
includes doing stool testing for ova and parasites to look for Entamoeba histolytica or Giardia lamblia.
Serologic testing starts with TTGA IgA to identify celiac disease.
If the workup is negative for other causes, then an upper endoscopy with biopsy is done to look for evidence of
damage, villous atrophy, and crypt hyperplasia in the duodenal mucosa - the same sort of findings as in celiac
disease. A key difference is that in tropical sprue the damage is typically less severe.
Tropical sprue is treated with 250 milligrams of tetracycline taken four times a day, along with 5 milligrams of
folate taken daily for three to six months. Unfortunately, even with this treatment, relapses sometimes occur.
Next up is exocrine pancreatic insufficiency. Here, there’s a lack of pancreatic digestive enzymes due to various
underlying diseases, and this also causes global malabsorption.
Mild exocrine pancreatic insufficiency can be asymptomatic, but moderate or severe exocrine pancreatic
insufficiency typically causes global malabsorption symptoms, as well as lipid-soluble vitamin deficiencies.
The workup for exocrine pancreatic insufficiency includes fecal-elastase-1 test -which is an enzyme produced by
the pancreas and can be detected in the stool.
If the fecal-elastase-1 level is lower than 200 micrograms per gram it’s considered abnormal.
Another test is taking the serum trypsinogen level- which is another enzyme produced by the pancreas and
activated in the small intestine- and if this is less than 20 nanograms per milliliter, then advanced exocrine
pancreatic insufficiency is present.
Pancreatic function can be further tested a number of different ways. One way is to stimulate pancreatic
secretion by giving an individual the hormone secretin which stimulates bicarbonate secretion in the pancreas,
and then seeing how much bicarbonate is in the duodenal fluid.
Duodenal fluid can be collected using an oroduodenal tube that goes through the mouth and in the duodenum
or endoscopically and under sedation.
If the bicarbonate in the duodenal fluid is less than 80 milliequivalents per liter, then exocrine pancreatic
insufficiency is confirmed and at that point an extensive workup is done to identify the cause. Some causes
include chronic pancreatitis, cystic fibrosis, and pancreatic duct obstruction.
In general, however, the treatment of exocrine pancreatic insufficiency is to give an individual capsules that
contain mixtures of pancreatic enzymes.
Finally, a rare cause of global malabsorption is Whipple’s disease, which is caused by Tropheryma whipplei.
Tropheryma whipplei is a gram positive bacillus that lives in the environment and spreads through fecal-oral
contamination.
Although, most individuals with the pathogen don’t develop any disease, some develop symptoms.
Typically, Whipple’s disease causes global malabsorption symptoms and migratory arthralgias of the large joints,
but it can also cause dementia, and endocarditis.
Whipple’s disease is rare, and more common conditions like inflammatory bowel disease, connective tissue
disease, and infectious diseases should be considered first.
But if Whipple’s disease is suspected and there are gastrointestinal symptoms, then an upper endoscopy with
biopsy should be done. The biopsy can test for T.whipplei using a periodic acid Schiff or PAS stain, PCR, or
immunohistochemistry to identify the bacilli within the macrophages. Alternatively, if an individual has joint or
neurological symptoms, then testing can be done on synovial fluid or cerebrospinal fluid.
Treatment for Whipple disease typically includes an initial phase with intravenous antibiotics that penetrate the
blood-brain barrier, such as penicillin or ceftriaxone, followed by a maintenance phase with trimethoprim-
sulfamethoxazole which lasts for about a year.
An alternative regimen of doxycycline plus hydroxychloroquine can be used, along with trimethoprim-
sulfamethoxazole if the individual presents neurological symptoms.
Now, some conditions only cause partial malabsorption. For example, lactose intolerance specifically affects
absorption of lactose - a type of carbohydrate.
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In lactose intolerance, there’s decreased activity of the enzyme lactase - so lactose cannot get absorbed into the With exocrine pancreatic insufficiency, fecal-elastase 1 is typically below 200 milligrams per gram, and treatment
intestines. consists of giving exogenous pancreatic enzymes.

Individuals develop diarrhea, abdominal pain, flatulence, and bloating after ingestion of milk or other dairy
products.
Milk and ice cream have the highest concentration of lactose, but the high fat content in ice cream decreases
gastric emptying and this allows some lactose intolerant individuals to eat ice cream without symptoms.
To diagnose lactose intolerance, a lactose breath hydrogen test is used. In that test, an individual ingests 50 g of
oral lactose and symptoms are initially assessed and a baseline is established on a scale, where 0 means no
symptoms and 5 means severe symptoms. During the test, symptoms are identified and scaled as they appear.
Whipple’s disease is caused by T.whipplei and it causes malabsorption symptoms, along with joint and
neurologic symptoms. Diagnosis is based on testing for T.whipplei from an upper endoscopy biopsy, and one
treatment regimen includes intravenous penicillin or ceftriaxone followed by prolonged therapy with TMP-SMX.
Partial malabsorption can be caused by lactose intolerance which can be diagnosed by having an individual
ingest 50 g of oral lactose, and then have symptoms or have a rise of hydrogen of 20 parts per million above the
baseline. Treatment consists of dietary lactose restriction or elimination.

In addition, breath hydrogen is checked at the beginning of the test by asking the individual to blow up balloon
like bags to establish the baseline hydrogen and then again at 30 minute intervals for three hours. Normally,
very little hydrogen is detected in the breath, but with lactose intolerance, hydrogen is produced when there’s
undigested lactose in the intestine.

If there’s an increase of symptoms of 2 over the baseline or if there’s a rise in hydrogen concentration of 20
parts per million over the baseline then a person is diagnosed with lactose intolerance.

Treatment of lactose intolerance consists of reducing or eliminating lactose from the diet, and making sure that
a person is getting adequate alternative sources of calcium and vitamin D.

Calcium-rich foods include oranges, walnuts, and almonds, and vitamin D-rich foods include mushrooms,
fortified foods like cereals, and fish.

In addition, replacement lactase enzyme can be given orally along with lactose-containing food.

Summary

Alright, as a quick recap. Fat malabsorption causes steatorrhea and the gold standard is a 72 hour stool
collection, which is positive if there’s more than 6 grams of fat per day.

Protein malabsorption causes edema and muscle atrophy and results in hypoalbuminemia and hypoproteinemia.

Carbohydrate malabsorption causes watery stools and can be identified with a a D-xylose serum levels are below
20 milligrams per deciliter.

There can also be iron, vitamin B12, or folate deficiency - all of which cause anemia.

Global malabsorption can be caused by celiac disease which typically causes an elevated TTGA IgA level, and on
an upper endoscopy there’s evidence of damage, villous atrophy, and crypt hyperplasia in the duodenal mucosa.
Sometimes additional testing like total serum IgA levels, TTGA IgG and DGP are done, along with HLA testing to
look for HLA DQ2 and HLA DQ8.

Treatment of celiac disease consists of eliminating gluten from the diet.

With tropical sprue, the presentation and biopsy results are similar to celiac disease, but a key difference is that
in tropical sprue the damage is typically less severe. The treatment is tetracycline and folate taken for three to
six months.

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Clinical Reasoning: Inflammatory bowel disease
Inflammatory bowel diseases are mainly broken down into two autoimmune conditions - ulcerative colitis and
Crohn's disease - both of which cause chronic inflammation in the gastrointestinal tract.
Ulcerative colitis mostly appears in individuals aged from 20 to 30 years old.
The chronic inflammation only involves the mucosal layer of the colon or the rectum and inflammation usually
starts in the rectum and goes retrograde through the colon.
Ulcerative colitis can involve only the rectum, in which case it's called ulcerative proctitis, can involve the rectum
and the sigmoid colon - called ulcerative proctosigmoiditis, or can involve the rectum, sigmoid colon and the
colon up to the splenic flexure - called distal ulcerative colitis. In some cases, it can also pass the splenic flexure,
but spare the cecum - called extensive colitis and finally it can involve the entire colon including the cecum -
called pancolitis.
The onset of the disease is gradual and symptoms are progressive over a few weeks. There may be systemic
symptoms, such as fatigue, fever, unintentional weight loss, as well as dyspnea and palpitations due to iron
deficiency anemia caused by blood loss.
Gastrointestinal symptoms include bloody diarrhea, colicky abdominal pain, and tenesmus.
Extraintestinal manifestations can sometimes occur, and they include arthritis, uveitis and episcleritis, and skin
lesions like pyoderma gangrenosum and erythema nodosum, as well as primary sclerosing cholangitis and
venous or arterial thromboembolism.
Acute complications of ulcerative colitis include severe gastrointestinal bleeding and fulminant colitis- which is
continuous bleeding and over 10 stools per day.
Another complication is toxic megacolon, which is where the nerves and muscles are damaged and the colon
becomes atonic and dilated. In severe cases, it can lead to perforation with peritonitis which causes fevers and
severe abdominal pain.
Finally, long-term complications of ulcerative colitis include an increased risk for colorectal cancer, as well as
strictures from repeated bouts of inflammation, that are usually located in the rectosigmoid colon, and can
sometimes lead to bowel obstruction.
Now, let’s switch gears and go over Crohn's disease which also causes chronic inflammation, but in this case it’s
transmural, meaning that it involves the full thickness of the gastrointestinal wall, and can happen anywhere in
the gastrointestinal tract, from mouth to perianal area.
Systemic symptoms of Crohn’s disease include fatigue, fever and unintentional weight loss.
Gastrointestinal symptoms include crampy abdominal pain, watery diarrhea, and sometimes malabsorption
symptoms like steatorrhea.
The transmural inflammation can allow fistulas to form, which are communications between two epithelial
organs. They can be enteroenteric meaning from one part of the intestines to another and can feel like a small
mass, or can be enterovesical where they go from the intestines to another organ like the bladder where they
can cause pneumaturia- which is the passing of gas in the urine. They can also be enterocutaneous fistulas which
is where the intestines connect to the skin surface.
Sometimes, a phlegmon can form, which is where there’s a localized area of inflammation in the intestinal wall
that can get infected and become an abscess.
Sometimes individuals get perirectal abscesses, fissures, and even cutaneous fistulas around the rectum.
There can be oral involvement, like aphthous ulcers or gingivitis, as well as esophageal symptoms like
odynophagia and dysphagia.
There can also be gallstones that lead to biliary colic.
Extraintestinal symptoms are similar to those of ulcerative colitis, those include arthritis, uveitis and episcleritis,
and skin lesions like pyoderma gangrenosum and erythema nodosum, as well as primary sclerosing cholangitis
and venous or arterial thromboembolism.
Now on top of all of those, Crohn's disease specifically can cause kidney stones as well.
For diagnosing inflammatory bowel disease -both ulcerative colitis and Crohn’s disease- labwork and
colonoscopy with biopsy are needed.
Typical lab work includes a CBC that shows anemia, and if there is anemia, then iron studies, vitamin B12, and
folate levels are checked to assess for deficiencies. Other common labs are an elevated ESR and CRP, a low
albumin, and typically there are electrolyte abnormalities from diarrhea and dehydration.
Typically electrolytes are sent if there’s chronic diarrhea, an AST and ALT to look for evidence of hepatitis, and
creatinine and urea nitrogen are sent to assess the kidneys.
Fecal calprotectin levels are typically elevated as well because it’s a protein released in large amounts by
neutrophils in the digestive tract during inflammation.
Now, it’s also important to exclude infectious causes. A routine workup includes stool cultures for Salmonella,
Shigella, Yersinia, Campylobacter, and E. coli, microscopy for ova and parasites, and antigen testing for Giardia
lamblia.
Pathogens associated with specific risk factors include Entamoeba histolytica which is associated with travel to
endemic countries, and Clostridium difficile which is associated with recent antibiotic use.
When ulcerative colitis is specifically suspected, testing for sexually transmitted diseases, such as Neisseria
gonorrhoeae, Chlamydia trachomatis, herpes simplex virus and Treponema pallidum may also be done,
especially in individuals with severe rectal symptoms, like tenesmus and fecal incontinence.
The next step is usually imaging, which isn’t needed for the diagnosis, but it can show some abnormal findings
for both ulcerative colitis and Crohn’s disease.
One specific imaging test is a double contrast enema. That’s where x-rays are taken of the colon and rectum
using barium and air as contrast.
In moderate and severe ulcerative colitis, there can be mucosal thickening and in severe cases, it can show collar
button ulcers which are deep mucosal ulcerations that also reach the submucosal layer. The circumferential
inflammation can destroy the haustras leading to a smooth section of colon which is called the “lead pipe” sign.
In severely ill individuals, a barium enema shouldn’t be done, because it can precipitate toxic megacolon.
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In Crohn’s disease, aphthous ulcers may be seen and these are shallow ulcerations of the mucosa and strictures
may also be seen and these allow a tiny stream of contrast material to pass through and that’s called a “string
sign”.
To evaluate small intestinal disease in Crohn’s disease, there are a few different imaging techniques that can be
done. One option is a wireless capsule endoscopy- this is when the individual ingests a tiny pill that contains an
even tinier video camera which can record images as it moves through the small intestine.
Another option is the upper gastrointestinal series with Small Bowel Follow-Through or SBFT- meaning that
radiologic images are taken while a barium solution is ingested. This can help identify narrowing of the lumen
with nodularity and ulcerations and a “string” sign if the narrowing is advanced, fistulas and a cobblestone
appearance may also be seen.
Ultimately the diagnosis of both ulcerative colitis and Crohn’s disease relies on a colonoscopy with biopsy.
In ulcerative colitis there’s typically circumferential inflammation or ulceration that’s continuous throughout an
entire section of the rectum or colon. In addition, the mucosa is often so damaged that it’s friable to the touch
and can spontaneously bleed. On histology, the damage is limited to the mucosa and submucosa.
In addition, there can be crypt abscesses due to the aggregation of lymphocytes and inflammatory process, that
eventually results in crypt atrophy. A bit like lymphocytes having a party in a crypt that gets a bit wild, and then
burns out over time.
In Crohn's disease, there’s usually lesions that look like linear patches of damaged tissue with normal GI mucosa
in between, and these are called skip lesions. These damaged areas get thicker, giving it a “cobblestone”
appearance. Usually, Crohn's disease doesn’t involve the rectum, so the mucosa there may be normal.
On histology, the damage is transmural - occurring in all of the layers of the GI wall, the mucosa, submucosa, the
muscularis propria, and serosa and there are inflammatory cells and non-caseous sarcoid granulomas may be
seen, as well as plasmacytosis and crypt abscesses.
Treatment of ulcerative colitis depends on disease severity, how much of the colon is involved, and the
frequency of disease relapse or flares.
Disease severity in ulcerative colitis is based on symptoms.
In mild ulcerative colitis, there are four or fewer stools per day with or without blood, with mild crampy
abdominal pain and occasional tenesmus.
In moderate ulcerative colitis, there are five bloody stools per day, abdominal pain, mild anemia, and sometimes
a low grade fever.
In severe ulcerative colitis, there are 6 or more bloody stools per day with severe abdominal pain, fever,
tachycardia, anemia, an elevated ESR, and weight loss.
The initial approach for mild and moderate ulcerative proctitis or proctosigmoiditis is treatment with the anti-
inflammatory drug - 5-aminosalicylic acid -5-ASA- also called mesalazine. This can be administered topically as a
suppository or enema, and it can induce disease remission most of the time. If applying it locally isn’t
comfortable, then 5-ASA can be given orally, although it’s generally not as effective as topical 5-ASA.
If the individual doesn’t respond to topical 5-ASA within 6 weeks, then 5-ASA should be given both orally and
topically or a steroid agent like beclomethasone can be added on. At that point, a clinical response or remission
usually occurs within 8 weeks.
Now, individuals with proctosigmoiditis and individuals with proctitis that have more than one relapse a year
should continue maintenance therapy with either topical or oral 5-ASA - whichever established remission for the
individual.
The initial approach for mild and moderate distal colitis, extensive colitis and pancolitis is a combination of oral
5-ASA plus either topical 5-ASA or topical steroids, like suppositories with hydrocortisone. If there’s no response
within 2 to 4 weeks, then budesonide multimatrix can be added to the treatment.
Budesonide multimatrix is an oral glucocorticoid that gets released within the colon at a controlled rate. If
individuals don’t respond to budesonide multimatrix, then oral prednisone is recommended.
Maintenance therapy is recommended in all individuals with distal and extensive ulcerative colitis as well as
pancolitis, and it’s done using oral 5-ASA along with intermittent topical 5-ASA or topical steroids.
Now with severe ulcerative colitis, the initial approach consists of oral glucocorticoids, high-dose oral 5-ASA,
along with either topical 5-ASA or topical steroids, such as hydrocortisone. If these individuals have evidence of
an infection, like a high fever or leukocytosis with neutrophilia, then intravenous antibiotics like ciprofloxacin or
metronidazole should also be given to empirically treat for an infection.
Individuals that don’t respond to initial therapy should receive intravenous fluids, if needed, as well as
intravenous steroids such as methylprednisolone. Individuals who do respond, should continue on maintenance
therapy with oral 5-ASA, topical 5-ASA, and oral glucocorticoids. For topical 5-ASA and oral glucocorticoids, the
doses are gradually lowered over a few months.
Finally, individuals who develop an acute complication like fulminant ulcerative colitis are treated with
intravenous fluids, along with broad spectrum antibiotics like ciprofloxacin and metronidazole and intravenous
glucocorticoids. If the individual doesn’t improve after 3 days, then intravenous cyclosporine or infliximab may
be tried, and if there’s no improvement within a week, then the individual may need to undergo a colectomy,
which is curative for ulcerative colitis.
Treatment of Crohn's disease depends on the severity and anatomic location of the disease.
Disease severity in Crohn's disease is based on the Crohn’s disease activity index or CDAI or the Harvey-
Bradshaw index or HBI which is a simplified version of the CDAI.
CDAI includes the stool pattern, general daily well being over 7 days, complications, presence of an abdominal
mass, anemia, and weight changes.
The CDAI score divides Crohn's disease into 4 major categories - asymptomatic or in remission, mild, moderate,
and severe disease. In addition, individuals can be either low risk or moderate-high risk for complications.
Low risk individuals are usually diagnosed above age 30, have no symptoms, have no prior intestinal resection,
and have no perianal involvement.
In contrast, moderate-high risk individuals are usually diagnosed below age 30, have extraintestinal symptoms,
prior intestinal resections, and perianal involvement.
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There are two approaches to the treatment of Crohn's disease. The first, is step-up therapy- where less potent
medications are initiated and are changed if they are ineffective. The second is step-down therapy- where more
potent medications are initiated and gradually decreased.

In individuals with mild Crohn's disease that are low-risk, step-up therapy is preferred and is initiated with oral
budesonide for 12 weeks if there’s ileal and colonic involvement. Oral prednisone or oral 5-ASA are alternatives,
if the individual doesn’t respond to budesonide. If there’s diffuse colitis or left colon involvement, oral
prednisone is initiated or if there’s only mild left colitis, then oral sulfasalazine- which is a modified sulfonamide
related to 5-ASA- can be used.

If remission was obtained with a glucocorticoid agent, the maintenance therapy is continued with the
glucocorticoid, and the dose is slowly lowered and eventually discontinued over a few weeks. If remission was
obtained with 5-ASA or sulfasalazine, then the same agents are used for maintenance therapy.

In individuals with moderate to severe Crohn's disease that are moderate-high risk, step-down therapy is
preferred and it’s initiated with a biologic agent like Infliximab along with an immunomodulator like
Azathioprine.

In individuals above 60 years old, Infliximab monotherapy can be used.

Finally, in individuals with severe disease, glucocorticoids such as oral prednisone or Budesonide may be used.

After remission, maintenance therapy with a biologic agent like Infliximab is used and it can be combined with
an immunomodulator like Azathioprine.

Summary

Alright, as a quick recap, ulcerative colitis involves only the rectum and the colon, and acute complications
include bleeding, fulminant colitis, and toxic megacolon, while chronic complications include strictures and
colorectal cancer.

Crohn’s disease can involve any part of the gastrointestinal tract and causes fistulas as well as renal stones.

The routine workup for inflammatory bowel diseases consists of a CBC, ESR, CRP, albumin, electrolytes, ALT, AST,
creatinine, urea nitrogen, fecal calprotectin, stool microscopy and stool cultures, along with testing for C.diff
toxin.

In ulcerative colitis, the colonoscopy shows continuous inflammation only in the mucosa and submucosa of the
rectum and colon.

In Crohn’s disease, the colonoscopy shows focal ulcerations that alternate with normal mucosa, giving a
cobblestone appearance.

Treatment of ulcerative colitis depends on the severity and extent of the disease and medication includes 5-ASA,
budesonide multimatrix and oral Prednisone. In severe cases, Infliximab and Cyclosporine may be used and if
there’s no improvement, colectomy is recommended.

Treatment for Crohn’s Disease depends on the severity and location of the lesions and includes Budesonide or
oral prednisone for low-risk individuals and Infliximab plus Azathioprine for moderate-high risk individuals.

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Clinical Reasoning: Gastroparesis
The gastrointestinal system depends on the coordination of the sympathetic and parasympathetic nervous
systems, pacemaker cells and neurons within the walls of the stomach and intestine, and the smooth muscle in
the gastrointestinal walls. If any part is disturbed, then it can lead to gastroparesis, which is delayed gastric
emptying in the absence of a mechanical obstruction.
Gastroparesis is usually idiopathic, but it's associated with a number of diseases like diabetes mellitus,
hypothyroidism, neurological conditions like Parkinson’s disease, viral infections, or even an autoimmune attack.
There are also iatrogenic causes like inadvertent vagal nerve damage during surgery, or can be due to
medications like opioids, alpha-2-adrenergic agonists like clonidine, tricyclic antidepressants like amitriptyline,
and anticholinergics like atropine.
Individuals with gastroparesis can have symptoms like nausea, vomiting, upper abdominal pain, early satiety,
bloating, and in severe cases, unintentional weight loss. On physical examination, there’s usually epigastric
distention or tenderness in the upper abdomen, but without guarding or rigidity.
When gastroparesis is suspected, individuals should undergo an upper endoscopy to make sure that there’s no
mechanical obstruction.
Because an upper endoscopy may not always reveal a mechanical obstruction, after the upper endoscopy, an
abdominal CT or magnetic resonance enterography can be done to confirm that there is no mechanical
obstruction.
Now, to establish the diagnosis of gastroparesis, a scintigraphic gastric emptying test should be done.
For this test, medications that affect the gastric motility should be stopped at least 48 hours before the test is
done. In addition, individuals with diabetes mellitus should have their glucose blood levels measured before the
test and if they are hyperglycemic, then this should be treated before the test is done as well.
For the test to be accurate, glucose levels should be lower than 275 milligrams per deciliter. Then the individual
usually ingests a low-fat egg-white meal and a tasteless radioactive material, usually Technetium, which shows
up on the scintigraphy. Imaging is performed immediately after the ingestion and then again at two, and four
hours after ingestion.
Delayed gastric emptying is defined as the retention of more than 60% of the gastric content at two hours and
more than 10% of the gastric contents at four hours. Based on the values at four hours, delayed gastric emptying
is considered mild if 10-15% of the gastric content is retained, moderate if 15-35% of the gastric content is
retained, or severe if more than 35% of the gastric content is retained.
Once the diagnosis of gastroparesis is established, it’s important to investigate the underlying cause.
Lab tests include hemoglobin to check for anemia, especially if malignancy is suspected, fasting plasma glucose,
serum total protein, albumin to assess for malnutrition, in individuals that have unintentional weight loss, TSH to
check for hypothyroidism, and an antinuclear antibody or ANA to search for an autoimmune disease.
In individuals with diabetes mellitus, HbA1C is also taken to assess glycemic control.
If the individual has a history of smoking, then ANNA-1 or anti-Hu antibodies are also obtained, because
gastroparesis may also appear as a paraneoplastic syndrome, particularly with lung cancer.
Next, it’s important to differentiate a myopathic process- a disorder of the skeletal muscles- such as
scleroderma, from a neuropathic process- a disorder of the nervous system- like diabetes. That can be done with
gastroduodenal manometry which is where a pressure-sensitive tube is endoscopically placed through the nose
and into the small intestine for 1 or 2 hours.
The tube senses pressure from muscle contractions. With a myopathic process, the muscle contractions are low-
amplitude, whereas with a neuropathic process, the muscle contractions are usually of normal amplitude.
Treatment of gastroparesis is generally based on dietary modifications and avoiding medications that delay
gastric emptying.
First of all, individuals with diabetes mellitus should try to maintain tight glycemic control, because acute
hyperglycemia can delay gastric emptying. These individuals should also avoid incretin based-therapies like
Pramlintide and glucagon like peptide-1 analogues because they can delay gastric emptying as well.
Dietary modifications that can help are eating smaller, more frequent meals, up to 5 times per day, that are low
in fat and contain soluble fiber, like black beans or broccoli. That’s because both fat and insoluble fibers such as
oats delay gastric emptying. Carbonated drinks, alcohol, and smoking should also be avoided for the same
reason.
Individuals with mild gastroparesis are told to focus on good hydration and are often given vitamin
supplementation. If the individual is unable to tolerate solids, then vitamins are added to liquid meals.
If dietary modifications aren’t enough to control the symptoms of gastroparesis, then medication therapy is
used.
Prokinetic medications, like metoclopramide is first-line therapy with gastroparesis, because it improves gastric
emptying by increasing antral contractions of the stomach and by decreasing gastric fundus relaxation after a
meal. If the individual doesn’t respond to metoclopramide, then another prokinetic medication, domperidone,
may be used.
Before and during treatment with domperidone, electrocardiograms must be done, because domperidone
increases the risk for cardiac arrhythmias.
If the individual doesn’t respond to prokinetic medications, then macrolide antibiotics, such as erythromycin can
be given because they induce high-amplitude gastric contractions that increase gastric emptying.
It’s important to keep in mind that Erythromycin can induce tachyphylaxis - meaning that the more it’s
administered, the less effective it will be.
Now, another condition that causes symptoms similar to gastroparesis is cyclic vomiting syndrome.
Cyclic vomiting syndrome is an idiopathic disorder where an individual has episodes of recurrent vomiting
alternating with periods of normal health.
The pattern of vomiting episodes is different for every individual, but in general vomiting begins early in the
morning and is accompanied by lethargy, abdominal pain, and anorexia.
In adults, the episodes of vomiting usually last up to 6 days, followed by a few months of normal health. In
children, vomiting episodes are more irregular and can happen every few weeks.
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Cyclic vomiting syndrome is associated with migraine headaches, as well as autonomic disorders like having an
elevated sympathetic tone, endocrine disorders that cause overstimulation of the hypothalamic-pituitary-
adrenal axis, various food allergies, and is linked to chronic cannabis use.

Cyclic vomiting syndrome is a diagnosis of exclusion, that requires excluding other causes of vomiting, like toxic
etiologies or bowel disorders.

Treatment includes supportive measures, like preventing dehydration with intravenous fluids, antiemetics like
dolasetron, and using sedatives like lorazepam.

Summary

Alright, as a quick recap, gastroparesis is a functional syndrome of delayed gastric emptying, that causes
symptoms like nausea, vomiting, abdominal pain, early satiety, and bloating.

An upper endoscopy, as well as an abdominal CT or an MRI are done to rule out a mechanical obstruction. A
scintigraphic gastric emptying test is done to confirm the diagnosis of gastroparesis and after 4 hours it’s
considered mild if 10-15% of the gastric content is in the stomach, moderate if 15-35% is left, and severe if more
than 35% is left.

To find the cause of gastroparesis, lab work includes: hemoglobin, fasting plasma glucose, serum protein,
albumin, TSH, ANA, HbA1c, ANNA-1 and anti-Hu.

A duodenal manometry may also be performed to differentiate a mipathic cause from a neuropathic cause of
gastroparesis.

Treatment includes dietary modifications, avoiding medication that decreases gastric emptying, hydrations and
nutrition and if the symptoms are not controlled with dietary modifications, medications such as
metoclopramide, domperidone, and erythromycin are used.

On the differential is cyclic vomiting syndrome which causes recurrent episodes of vomiting that alternate with
periods of normal health and is associated with migraine headaches and abdominal pain.

CVS is a diagnosis of exclusion and treatment includes supportive measures like intravenous fluids, antiemetics,
and sedatives.

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Clinical Reasoning: Colorectal cancer
Colorectal cancer or CRC is a malignancy that arises in the large intestines, which includes both the colon and
rectum. It is the most common cancer of the gastrointestinal tract, and a major cause of death and disease
around the world.
Most colorectal tumors develop due to sporadic mutations, but some are caused by inherited conditions like
familial adenomatous polyposis and Lynch syndrome.
Individuals at high-risk for CRC include those with inflammatory bowel disease, especially ulcerative colitis,
hereditary colorectal cancer syndromes, such as familial adenomatous polyposis, and those with a family history
of colorectal cancer or adenomatous polyps.
Individuals at medium-risk for CRC include the elderly, and those that smoke, drink alcohol, eat red meat, and
are obese.
Finally, well established protective factors include a high-fiber diet full of fruits and vegetables.
Sometimes, especially early on, colorectal cancer is asymptomatic and it's discovered by screening using either
stool based tests or direct visualization.
One stool based test is the guaiac-based fecal occult blood test or gFOBT which detects blood in the stool.
Another test is fecal immunochemical test or FIT. This time instead of guaiac, there’s an antibody that attaches
to any hemoglobin that’s present in the stool.
Finally there’s the FIT-DNA test-which combines FIT with a test that detects genes associated with colorectal
cancer in the stool, such as mutations in the adenomatous polyposis coli gene or APC gene.
One direct visualization test is a colonoscopy, which is when a camera is inserted retrograde into the colon and
rectum using a flexible tube and biopsies are taken.
Another one is a flexible sigmoidoscopy, which uses a flexible tube to visualize the rectum and sigmoid colon.
Finally, there’s CT colonography or a virtual colonoscopy- which is where CT scans are digitally assembled to
produce 3-dimensional views of the colon.
If a suspicious lesion is seen on a direct visualization test, it should be further investigated using colonoscopy and
biopsy.
A common example of a suspicious lesion is a colorectal polyp, which is a small bump or overgrowth of tissue
along the lining of the colon or rectum. The most common polyps are adenomatous polyps, also called colonic
adenomas.
Adenomatous polyps can be either pedunculated, meaning that they’re attached to the colon wall by a stalk and
therefore able to freely swing around, or sessile, which means that they’re firmly attached to the colon wall.
Sessile adenomatous polyps are more likely to become malignant, so they need to be closely observed.
If a polyp is found during a colonoscopy or during a flexible sigmoidoscopy, then a biopsy should also be done to
rule out or confirm cancer.
On histology, polyps can be tubular, where the growth has little holes within it on a cross section, or villous
where it looks like a little tree, or tubulovillous where it’s a mix between the two. Among these, villous polyps
are most likely to be malignant.
Now, if an adenomatous polyp can’t be entirely removed using the colonoscopy, then surgical resection may be
needed, especially if it’s a polyp that has a high-risk for malignancy, like a sessile polyp.
Another type of polyp is an inflammatory polyp, and these typically develop after a flare of ulcerative colitis or
Crohn's disease, and they usually don’t become malignant and don’t require excision.
A final group are hamartomatous polyps which are normally made up of a mixture of tissues and have a
distorted architecture.
Hamartomatous polyps are often associated with genetic syndromes like juvenile polyposis and Peutz-Jegher’s
syndrome.
How we screen for CRC depends on risk and which method is used. For medium-risk individuals, one option is to
do annual screening starting at age 50 with gFOBT or FIT. If FIT-DNA is used, screening can be done every one to
three years. CT colonography or flexible sigmoidoscopy should be done every 5 years, while colonoscopy- which
is the best screening test- should be done every 10 years.
With high-risk individuals, screening starts earlier than usual. if an individual has a family history of sporadic CRC,
then screening should start at age 40 with a colonoscopy and it should be repeated every 5 years. Alternatively,
a FIT test can be done annually.
Individuals with inflammatory bowel disease should get a colonoscopy every year.
Typically, screening stops between age 75 and 85, depending on the individual’s overall health.
Now, these guidelines are a bit different for hereditary colorectal syndromes. Lynch syndrome, which is also
called hereditary nonpolyposis colorectal cancer or HNPCC is the most common cause of inherited CRC. It should
be suspected in individuals that develop CRC before age 50, or develop other cancers typically seen in Lynch
syndrome like endometrial, ovarian, small bowel, stomach, and renal cancer.
Lynch syndrome is caused by a mutation in a DNA mismatch repair gene or the EPCAM gene. For a definitive
diagnosis, the mutations need to be confirmed using genetic testing.
Normally, screening for individuals with Lynch syndrome begins at age 20 or 25 every one or two years using
colonoscopy, and females with Lynch syndrome should also get a pelvic examination annually to look for signs of
endometrial or ovarian cancer.
Familial adenomatous polyposis or FAP is an autosomal dominant genetic disease caused by mutations in the
Adenomatous Polyposis coli gene or APC gene.
There is a classic form of FAP that is characterised by more than 100 colorectal polyps, and an attenuated form
of FAP that has less than 100 colorectal polyps.
FAP can also cause extracolonic symptoms, such as polyps in the stomach and duodenum, desmoid tumors-
which are connective tissue tumors- and these are usually localised in the abdomen and sometimes individuals
can present a nodular thyroid that in some cases may develop into thyroid cancer.
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There are also some variants of FAP, like Gardner syndrome which causes multiple colorectal polyps as well as
osteomas, which are bony growths that develop in the mandible, and soft tissue tumors like epidermoid cysts,
fibromas, and desmoid tumors.
Another one is Turcot syndrome- which consists of multiple colorectal polyps and brain tumors, like
medulloblastomas and gliomas. Turcot syndrome can also be associated with Lynch syndrome.
Now, the diagnosis of FAP should be suspected in any individual with more than 10 colorectal adenomas, a
history of colorectal adenomas with extracolonic manifestations, or with a family history of FAP. In these
situations, genetic testing is done to look for an APC gene mutation.
Screening for individuals with classic FAP begins around age 10 with an annual flexible sigmoidoscopy or
colonoscopy.
With classic FAP, the risk for eventually developing CRC is about 100%, and since every polyp cannot be removed
endoscopically, a colectomy is typically recommended.
For individuals with attenuated FAP, CRC typically develops later in life, so screening begins at age 25 and is done
every one to two years using colonoscopy.
Now, in addition to identifying CRC through screening, it may also get diagnosed in individuals that develop
symptoms like abdominal pain, unintentional weight loss, and a change in bowel habits, specifically diarrhea
alternating with constipation.
Left sided CRC is associated with pencil-shaped stools, and rectosigmoid cancer is associated with hematochezia
and tenesmus. CRC can also cause complications like peritonitis or intestinal obstruction.
On the physical examination, sometimes an abdominal or rectal mass can be felt.
A classic sign of metastasis is periumbilical adenitis, and in terms of organs, metastasis usually goes to the liver,
followed by the lungs and bones.
The workup for CRC includes a CBC- which can show anemia due to iron deficiency from blood loss, an ALT and
AST which may be elevated if there is liver metastasis, and a BUN and creatinine to assess renal function
because a large tumor can compress the ureters and cause renal impairment. The tumor marker
carcinoembryonic antigen or CEA is often elevated in CRC.
A barium enema can be useful as well. That’s where a liquid is injected into the rectum through a small tube, and
an X ray is taken to look for abnormalities in the large intestines. Classically, colorectal cancer will show an apple
core sign, which shows constriction of the lumen - most often in the descending colon.
A colonoscopy with biopsy is the gold standard for diagnosing CRC. Most commonly the mass is exophytic or
polypoid, meaning that the tumor grows into the lumen. But it can also be endophytic or ulcerative, meaning
that the tumor destroys healthy tissue and creates an erosion into the intestinal wall.
Finally, some tumors are considered diffuse and infiltrative, which is where they grow within the intestinal wall,
causing it to become thick and rigid.
All of these tumor types can be friable and necrotic, and can bleed easily.
On histology, most CRCs are adenocarcinomas, meaning that they arise from the cells lining the intestinal glands.
Once the diagnosis of a CRC is confirmed, the next step is to obtain a CT-scan of the chest, abdomen, and pelvis
to see if there is lymph node involvement or if there are any metastases.
Sometimes an MRI of the liver is specifically done to look for lesions.
CRC is staged according to the Tumor-Node-Metastasis or TNM system into five stages.
Stage 0 is carcinoma in situ, meaning that the tumor has not grown beyond the mucosa. Stage 1 is when the
tumor has grown beyond the mucosa, but has not spread to lymph nodes or distant organs and this usually
includes cancers that were part of a polyp. Stage 2 is when the tumor has invaded the whole colonic or rectal
wall, and may have reached nearby organs or tissues, but still hasn’t spread to lymph nodes or distant organs.
Stage 3 is when the tumor had spread to lymph nodes, but still hasn’t spread to distant organs. Finally, stage 4 is
metastatic, meaning that the tumor has spread to distant organs.
Treatment for colorectal carcinoma depends on the stage of the cancer.
For stage 0 and 1, surgical resection of the tumor is usually curative.
For stage 2, a partial colectomy may be needed, along with removing the nearby lymph nodes. Adjuvant
chemotherapy, meaning chemotherapy after surgery, is recommended when the cancer has a high risk of
recurrence. An example of this is when the CRC obstructs or causes a perforation in the colon or CRC that
develops near large blood vessels.
For CRC stage 3, a partial colectomy and surgical removal of the nearby lymph nodes is recommended, along
with adjuvant chemotherapy.
Chemotherapy typically includes the FOLFOX regimen, which consists of folinic acid or leucovorin, 5-fluorouracil,
and oxaliplatin or FOLFIRI regimen that consists of folinic acid, 5-fluorouracil, and irinotecan. One additional
regimen is called CAPOX, and it’s formed by capecitabine and oxaliplatin. In individuals that are severely ill and
cannot undergo surgery, radiation therapy with or without chemotherapy may be an option.
For CRC stage 4, neoadjuvant chemotherapy may be done to shrink the tumors before surgically resecting the
CRC along with any metastasis in the liver or in the lung.
If CRC blocks the colon, then a diverting colostomy- which is when the colon is cut above the location of the CRC
and is attached to an opening in the skin to allow waste to go out or even a colectomy- which is total removal of
the colon may be needed.
Now, if CRC has spread widely and surgical resection is no longer an option, then chemotherapy is the main
treatment.
Summary
Alright, as a quick recap, in colorectal cancer for medium-risk individuals, screening starts at age 50 and it can be
done using gFOBT or FIT annually, FIT-DNA every 1 to 3 years, flexible sigmoidoscopy or CT colonography every 5
years, or colonoscopy every 10 years.
For high-risk individuals, if there’s a family history of sporadic CRC, then screening should start at age 40 using
colonoscopy every 5 years.
If there’s inflammatory bowel disease, then a colonoscopy with biopsy is done every year.
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If Lynch syndrome is suspected, genetic testing for the MMR or EPCAM genes should be done, and screening
here begins at age 20 and is done every 1-2 years using colonoscopy.

If FAP is suspected, genetic testing for the APC gene should be done and screening begins at age 10 and is done
annually using colonoscopy.

In individuals with symptoms of CRC, the workup includes lab work and a barium enema which may show the
apple core sign.

The gold standard for diagnosis is a colonoscopy with biopsy, and typically the CRC is an adenocarcinoma.

After the diagnosis is confirmed, staging is done using a CT-scan. Based on the TNM system, CRC has five stages.

For CRC stage 0 and 1, a surgical resection of the tumor is usually curative.

For CRC stage 2, a partial colectomy may be needed, along with adjuvant chemotherapy.

For stage 3, surgical resection including the nearby lymph nodes and adjuvant chemotherapy is recommended.

For stage 4, a surgical resection may be done to remove the tumor and metastasis in the liver or lung, but if
surgery is not an option, then chemotherapy is the main treatment.

If complications appear, then a colectomy or a diverting colostomy may be needed.

Finally, chemotherapy regimens include FOLFOX, FOLFIRI or CAPOX.

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Clinical Reasoning: Diverticula
At the gastroenterology clinic, there is a 62- year- old man from Germany, named Karl, who came in for his
regular colonoscopy. He is totally asymptomatic, except for occasional vague abdominal discomfort after meals.
Next, a 65- year- old Native American named James came to the emergency department after two episodes of
painless bright red blood per rectum.
Finally, Zendaya, a 78- year- old African- American woman, was brought to the hospital from a nursing home by
paramedics, due to a severe pain in the left lower abdomen which started this morning. Her temperature was
measured at 101.8°F or 38.8°C at the nursing home.
On further history, they all had diets low in fiber and high in fat and red meat and suffered from chronic
constipation.
Zendaya's nursing home attendant reports that lately her constipation has been even worse than usual; in fact,
her last bowel movement was more than three days ago.
Karl, James and Zendaya all have diverticula in the colon.
Diverticula are small outpouchings that form along the walls of a hollow structure, most commonly, the large
intestine. According to their pathogenesis, they can be broadly grouped into traction and pulsion diverticula.
Traction diverticula occur due to the pulling forces of an adjacent inflammatory site, resulting in scarring and
outpouching of all layers of the intestinal wall. These are also known as true diverticula.
Next, there’s pulsion diverticula, which are a result of high pressures created during a strained bowel
movement. The pressure pushes on the mucosa and submucosa until they bubble out through weak spots along
the wall, like where a blood vessel penetrates the muscle layer of the intestine. These are also known as false or
pseudodiverticula since they don’t involve all layers of the intestinal wall.
For your exams, it’s important to know that, most of the time, diverticula in the large intestine, and particularly,
the left and sigmoid colon, are pulsion or false diverticula.
Having diverticula in the colon is called diverticulosis, and it’s more common in individuals older than 60 years
old, consuming a fiber low in fiber and high in fatty foods, like red meat.
Fiber helps stool move more easily through the colon, so diets low in fiber can lead to constipation which means
more force is required to move bulky, hard stool.
Most of the time, people won’t even know they have diverticulosis because they don’t have any symptoms
besides constipation and mild or vague abdominal discomfort after meals.
Diagnosis is typically made incidentally during a colonoscopy or CT scan that might be done for another reason
entirely.
Okay, so even though diverticulosis doesn’t cause major distress in the person, they can still cause serious
complications.
One complication is bleeding due to weakening and breaking of blood vessels near a diverticula.
It’s important to know that diverticulosis is the most common cause of acute lower gastrointestinal bleeding.
This will typically appear in your exam as an elderly patient with a history of chronic constipation and painless
hematochezia, which means bright red or maroon blood passing from the rectum.
Remember, bright red blood usually mean lower GI bleed, and painful hematochezia usually indicates hemroids.
Now, another complication of diverticulosis is acute diverticulitis, which is an infection of the diverticula.
Typically it starts when there’s increased pressure in the lumen of the intestines or food impaction in the
diverticulum that leads to micro-perforations in the diverticula. The bacteria in the lumen of the gut dive into
these microperforations, and cause infection within the intestinal wall.
Symptoms include left lower quadrant abdominal pain and low- grade fever, along with a change in bowel
habits, like alternating constipation and diarrhea.
Acute diverticulitis can also lead to the formation of an abscess within the inflamed diverticula.
The symptoms of a diverticular abscess are about the same as the symptoms of acute diverticulitis, the clue for
abscess is that the oral antibiotics are ineffective so the symptoms persist.
In some cases, inflammation leads to a partial obstruction of the colon, and that can cause abdominal distention,
nausea, vomiting. In other cases, if the diverticula becomes distended enough, it may rupture and cause
peritonitis, resulting in a tender, distended abdomen with guarding and rigidity.
Alternatively, it can create a fistula, which is a connection with an adjacent organ or structure.
Since it sits pretty close to the bladder, a fistula connecting the large intestine to the bladder may form, called a
colovesicular fistula, and this might result in dysuria, pneumaturia, or passage of gas in the urine, as well as
fecaluria, or stool in the urine.
Diagnosis of acute diverticulitis and its complications is usually made with a CT with contrast of the abdomen
and pelvis.
A key concept that is frequently tested is that colonoscopy is contraindicated in acute diverticulitis, because it
increases the risk for perforation and subsequent peritonitis.
Summary
Okay, to review! Diverticula are abnormal outpouchings from the colonic lumen and can be classified into
traction or true diverticula, which involve all layers of the intestinal wall and pulsion or false diverticula, which is
where only the mucosa and submucosa slide through the intestinal wall, are usually located in the left and
sigmoid colon- and these end up being more common.
The presence of diverticula is known as diverticulosis and risk factors include advanced age, chronic
constipation, and low-fiber, high-fat diet.
Diverticulosis is typically asymptomatic but can present with vague abdominal discomfort after meals.
Complications include diverticular bleeding, presenting as painless rectal bleeding and diverticulitis, presenting
as acute, left lower quadrant pain with fever.
Sometimes, acute diverticulitis can lead to abscess, fistula, partial colonic obstruction and perforation with
peritonitis.
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Now, back to the patients! All three of them have the risk factors for diverticulosis including old age,
constipation and low-fiber diet, high-fat diet.

Karl had vague abdominal discomfort after meals and diverticulosis was discovered incidentally during his
colonoscopy.

Meanwhile, James probably has diverticulosis with bleeding as a complication. This can be confirmed with a CT
scan or colonoscopy.

And Zendaya has the typical presentation of acute diverticulitis, with acute left lower abdominal pain and fever.
The fact that she hasn’t passed stool for more than 3 days might be a clue to partial colonic obstruction.

Diagnosis can be made with a CT, but a colonoscopy is contraindicated.

...And that’s the pathology in a nutshell.

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Clinical Reasoning: Pancreatitis
Pancreatitis is inflammation of the pancreas.
In acute pancreatitis, the pancreas' own digestive enzymes get suddenly get activated within the pancreas and
cause autodigestion which results in inflammation and hemorrhaging.
In chronic pancreatitis, there are indolent causes of inflammation that damage the pancreas, leading to
impairment of both endocrine and exocrine functions of the pancreas.
Now, first thing’s first. Acute pancreatitis is usually caused by gallstones and ethanol abuse, but there are other
causes as well, and the full list can be remembered using the mnemonic “I GET SMASHED”: where ‘I’ refers to
unknown, or Idiopathic, causes; ‘G’ is obstruction by Gallstones, ‘E’ is Ethanol abuse; ‘T’ is a pancreatic Trauma,
which is more likely if the trauma is the result of a puncture injury, like a knife wound rather than a punch; ‘S’ is
the use of Steroids; ‘M’ is infection with Mumps virus, ‘A’ is the result of Autoimmune diseases; the second ‘S’ is
the result of a Scorpion sting—which is probably the most exciting item on this list and one of the more rare
causes - so check your shoes!; ‘H’ is a cheat and stands for both Hypertriglyceridemia and for Hypercalcemia; ‘E’
is trauma from an Endoscopic retrograde cholangiopancreatography or ERCP which is a technique used to
diagnose and treat various biliary and pancreatic diseases; and finally ‘D’ stands for Drugs, like sulfa drugs,
reverse-transcriptase inhibitors, and protease inhibitors.
Individuals with acute pancreatitis usually have severe epigastric abdominal pain that radiates to the back, along
with nausea and vomiting over several hours.
In mild cases, there may be tenderness in the epigastrium, and in severe cases, there might be hypovolemic
shock which can cause tachypnea, hypoxemia, and hypotension or systemic inflammatory response syndrome or
SIRS, which can cause those same symptoms as well as fever.
So for SIRS - three of the hallmarks - tachypnea, hypotension, and fever - are identified in the vital signs.
Sometimes, there’s a Cullen sign which is an ecchymotic discoloration in the periumbilical region or a Grey
Turner sign where the ecchymotic discoloration is along the flank.
Both of these signs suggest retroperitoneal bleeding due to pancreatic necrosis.
Now, some clues also point to the etiology. With alcoholic pancreatitis, there may be hepatomegaly.
With hyperlipidemic pancreatitis there may be xanthomas - which are lipid deposits that can appear anywhere in
the body.
And with mumps pancreatitis, the parotid gland may be swollen.
In acute pancreatitis, the first set of lab work is aimed at confirming the diagnosis.
In pancreatitis, the serum lipase- which is the most sensitive test for acute pancreatitis- rises within 8 hours from
the onset of symptoms and returns to normal within 14 days- and serum amylase which rises within 12 hours
from the onset of symptoms and returns to normal within 5 days. Usually, both rise to at least 3 times the upper
limit of normal.
Next, to assess severity, a CBC may show leukocytosis or an elevated hematocrit due to dehydration or acute
hemorrhaging.
The CRP and LDH are usually elevated due to inflammation.
The BUN and creatinine are done to assess for signs of dehydration.
Ionized calcium levels can be low, because if there’s fat necrosis, this consumes the calcium.
The individual may also have hypoglycemia or hyperglycemia depending on levels of insulin and glucagon.
In addition, electrolytes, ALT and AST, bilirubin, and albumin should be obtained to rule out other causes of
abdominal pain like cholecystitis and finally triglyceride levels can be done to rule out or confirm
hypertriglyceridemia as a cause of acute pancreatitis.
In individuals with symptoms suggestive of SIRS, an ABG might show a pO2 below 60 mm Hg - which defines
hypoxemia.
Next, on an abdominal ultrasound the pancreas will be enlarged and hypoechoic.
And with gallstone pancreatitis, stones are usually present in the gallbladder.
If the diagnosis of acute pancreatitis is still unclear, then an abdominal CT with contrast can be done, and a
scoring system called the Balthazar score can be used.
This scoring system assesses the severity of acute pancreatitis based on the degree of necrosis, inflammation,
and fluid collection around the pancreas.
Abdominal and chest x-rays can also be done.
In severe cases, a sentinel loop may be seen on the abdominal x-ray due to ileus inflammation that’s caused by
adjacent pancreatic inflammation.
And on a chest x-ray, a pleural effusion may be present.
Next, the severity of acute pancreatitis is assessed. A frequently used scoring system is the Atlanta classification,
which has mild acute pancreatitis- where there’s no organ failure or complications, moderate acute pancreatitis-
where there’s transient organ failure that resolves within 48 hours plus or minus complications and severe
pancreatitis- in which organ failure persists for more than 48 hours.
There’s also the Ranson’s criteria which has a total of 11 parameters - 5 are assessed at admission and then 6 are
assessed 48 hours after admission.
At admission, the measured parameters are age over 55 years, high white blood cell count, hyperglycemia, high
LDH, and high AST, and at 48 hours, the criteria include low hematocrit, high BUN, low serum calcium, low
partial pressure of oxygen, elevated base deficit, and fluid sequestration.
The presence of 1 to 3 of these criteria represents mild pancreatitis, and the presence of more than 3 criteria
represents severe pancreatitis and a higher mortality risk.
Now, acute pancreatitis is usually mild, but with severe pancreatitis, there’s a systemic inflammatory response
triggered by cytokines and activated pancreatic enzymes that are released in the blood. This leads to significant
3rd spacing - where fluid shifts into the tissues - causing multiple organ failure, especially acute respiratory
failure and kidney failure.
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Treatment of mild pancreatitis, starts with fluid resuscitation which is done using isotonic crystalloid solutions,
like saline or lactated Ringer solution at a rate of 5 to 10 milliliters per kilogram per hour for the first 12 to 24
hours, and then adjusted based on hydration status.
Hydration is very important because if there’s persistent hypotension, it can lead to ischemia and necrosis of the
pancreas.
With severe pancreatitis, fluid resuscitation is done more aggressively at a rate of 20 milliliters per kilogram per
hour in the first 30 minutes followed by 3 milliliters per kilogram per hour for the next 12 hours.
If acute pancreatitis was caused by hypercalcemia, then lactated Ringer is contraindicated because it contains
calcium, so saline is used instead.
Pain control is done with IV opioids, such as Hydromorphone or Fentanyl.
In mild pancreatitis, oral nutrition can usually be started within 24 hours, but in severe pancreatitis, enteral
feeding is initiated- with a tube that extends from the nose to the jejunum.
Alternatively, parenteral nutrition can be done if the individual doesn’t tolerate enteral nutrition.
Early complications occur in the first few days and include ARDS and pleural effusions which can be caused by
the formation of a pancreaticopleural fistula, due to the inflamed pancreatic duct.
Other acute complications include ascites and saponification of fatty tissue around the pancreas. This happens
because pancreatic enzymes damage adipocytes which release their triglycerides, creating a “soap-like”
appearance on histology.
Additional complications that happen within a few weeks include formation of an acute peripancreatic fluid
collection which is a collection of fluid that’s not encapsulated that develops around the pancreas. Fortunately,
this is usually asymptomatic and doesn’t typically get infected.
There can also be an acute necrotic collection which is a collection of both fluid and necrotic tissue around the
pancreas which can get infected causing a fever.
Finally, there are late complications which develop over weeks to months later.
First, there’s a pancreatic pseudocyst- which is a collection of fluid just outside the pancreas with a well-defined
wall.
There may also be walled-off necrosis - a type of abscess - which is a collection of necrotic tissue with a well-
defined wall.
Both of these late complications can be asymptomatic, but if they get infected, then they can cause a fever.
If the individual develops ARDS, then intubation is typically needed.
If there are pleural effusions or ascites, it usually improves as the cause of acute pancreatitis is treated.
Usually, if there’s an acute peripancreatic fluid collection, it resolves on its own within 10 days. But if there’s an
acute necrotic collection or a walled-off necrosis, then empiric antibiotics like Meropenem or Ciprofloxacin are
used.
If the individual doesn’t improve within 4 weeks, then a necrosectomy is done, which is where the necrotic
pancreas is debrided endoscopically or surgically.
Finally, with an asymptomatic pseudocyst, watchful waiting is the way to go, but if the pseudocyst gets infected,
then it is drained endoscopically or surgically.
Finally, it’s always important to address the underlying cause of pancreatitis. If the individual has gallstone
pancreatitis and also cholangitis, then an ERCP is recommended to remove the stones and after the pancreatitis
resolves, a cholecystectomy is indicated. With alcoholic pancreatitis, the individual has to stop drinking alcohol.
Okay, now let’s move on to chronic pancreatitis, which can be due to a variety of causes like alcohol abuse,
genetic mutations, pancreatic duct obstruction due to tumors, a pseudocyst or gallstones, and autoimmune
conditions, like systemic lupus erythematosus.
Chronic pancreatitis may be asymptomatic for a long tifaceme, but at some point it can begin to cause
symptoms like epigastric abdominal pain that radiates to the back.
It can also cause symptoms of both pancreatic exocrine and endocrine insufficiency.
In pancreatic exocrine insufficiency the pancreas doesn’t produce enough enzymes to digest complex foods like
fatty foods. The result is fat malabsorption, which leads to steatorrhea and unintentional weight loss.
In pancreatic endocrine insufficiency, there’s insufficient insulin leading to glucose intolerance or in some cases
can lead to pancreatic diabetes.
Lab work for chronic pancreatitis includes serum lipase and amylase, CBC, electrolytes, AST, ALT, albumin,
bilirubin, and alkaline PANCREAphosphatase, or ALP - all of which are usually normal. In some cases, the bilirubin
and alkaline phosphatase can be elevated, suggesting that something is compressing the bile duct, like a tumor.
Next, immunoglobulin G4, rheumatoid factor, antinuclear antibodies or ANA, and anti-smooth muscle antibodies
may be obtained to assess for the presence of an autoimmune cause. After that, a 72 hour stool collection is
done because that’s the gold standard for diagnosing fat malabsorption.
A fecal-elastase-1 test is also done -this is a pancreatic enzyme and can be detected in the stool. If the level is
below 200 micrograms per gram it’s considered abnormal.
A transabdominal ultrasound and a CT scan can be done - and both will show calcifications in the pancreas, and
that’s the classic sign of chronic pancreatitis.
In addition, there may be ductal dilation, enlargement of the pancreas, and fluid collections around the
pancreas.
If calcifications are not seen, then MRCP may be used- which is a noninvasive technique that uses either contrast
or noncontrast MRI imaging to visualize the biliary tract and pancreatic ducts. Typically, this shows beading of
the main pancreatic duct and dilated side branches, which is diagnostic for chronic pancreatitis.
Treatment of chronic pancreatitis is mainly dietary modifications like not drinking alcohol, drinking at least 1.5
liters of water each day, and eating small low-fat meals.
In some cases, an individual may also be given pancreatic enzymes to help control the abdominal pain.
If pancreatic enzyme therapy fails to control the abdominal pain, then fentanyl patches can be used.
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Summary

Alright, as a quick recap. Acute pancreatitis is usually caused by gallstones and alcohol consumption and causes
epigastric abdominal pain, nausea, and vomiting.

Lab work includes amylase and lipase that will usually be elevated at least 3 times the upper limit of normal,
CBC, CRP, LDH, BUN, creatinine, ionized calcium, blood glucose levels, electrolytes, AST, ALT, bilirubin, albumin,
and triglyceride levels.

In severe cases, an ABG is done to look for hypoxia and SIRS. An abdominal ultrasound is done and a CT-scan is
done if the diagnosis is still unclear.

The severity of pancreatitis can be assessed using the Atlanta classification or Ranson’s criteria.

Treatment of acute pancreatitis relies on fluid resuscitation using saline or lactated Ringer, pain control using
hydromorphone or fentanyl, and nutrition.

Early complications include ARDS, pleural effusions, ascites and saponification, additional complications include
acute peripancreatic fluid collection and acute necrotic collection, and late complications include pseudocyst
and walled-off necrosis.

Chronic pancreatitis can cause abdominal pain and symptoms of exocrine or endocrine pancreatic insufficiency
like steatorrhea, unintentional weight loss, and glucose intolerance.

Lab work includes amylase, lipase, CBC, electrolytes, AST, ALT, bilirubin, albumin and alkaline phosphatase, and
immunoglobulin G4, rheumatoid factor, antinuclear antibodies or ANA and anti-smooth muscle antibodies to
rule out autoimmune causes.

Finally, a 72 hour stool collection and a fecal-elastase-1 test are done to confirm malabsorption and pancreatic
insufficiency.

Next, an abdominal ultrasound and a CT-scan are done to look for calcifications in the pancreas. Otherwise,
MRCP is done to look for beading of the main pancreatic duct and dilated side branches.

The main treatment includes drinking more water, not drinking alcohol, and eating small low-fat meals.

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Clinical Reasoning: GI bleeding
Gastrointestinal bleeding can be divided into upper and lower GI bleeding.
Upper GI bleeding arises above the ligament of Treitz- also called the suspensory ligament of the duodenum-
and it includes bleeding from the esophagus, stomach, or duodenum.
Common causes of upper GI bleeding include peptic ulcer disease, erosive esophagitis, esophageal varices, an
arteriovenous malformation or an AVM, Mallory-Weiss syndrome and cancers of the upper GI tract.
Lower GI bleeding arises below the ligament of Treitz and includes bleeding from the small intestines past the
ligament of Treitz, large intestines, rectum, and anus.
Common causes of lower GI bleeding include diverticulosis, hemorrhoids, colorectal cancer, AVMs, and intestinal
ischemia.
Now, both upper and lower GI bleedings can be either visible or occult- meaning that there's no visible evidence
of bleeding. This is usually detected by a fecal occult blood test or if there are signs of iron deficiency anemia.
Okay, first things first. A visible upper GI bleed causes hematemesis- which is vomiting of blood, and suggests
moderate to severe ongoing bleeding.
If the blood looks like coffee-grounds - it suggests that the blood has been oxidized by acid in the stomach so
that the iron in the blood has turned black. It’s a sign that bleeding was a small quantity or has stopped.
Melena refers to black and tarry stools, and that most often result from upper GI bleeding. In fact, it takes about
50 milliliters of blood in the stomach to turn the stools black.
A lower GI bleeding can cause hematochezia- which is fresh blood passing through the anus which may or may
not be mixed with stool.
In rare cases, if there’s a large upper GI bleed, that can cause hematochezia as well.
In an individual with a GI bleed, the first step is evaluating their hemodynamic stability.
In mild hypovolemia, less than 15% of the blood volume was lost, and it causes a resting tachycardia.
In moderate hypovolemia, 15% to 40% of the blood volume is lost, and it causes orthostatic hypotension- which
is a decrease of over 20 mm Hg in the systolic blood pressure.
In severe hypovolemia, over 40% of the blood volume is lost, and it causes hypotension.
Active GI bleeding requires a prompt workup, and lab work includes a CBC which usually shows a normal
hemoglobin level, because the individual is losing whole blood. Over the next 24 hours, there’s a physiologic
compensation of holding onto more water, and intravenous fluids are usually given - and that decreases the
hemoglobin level.
Electrolytes, BUN and creatinine are done to look for signs of dehydration or renal dysfunction.
ALT, AST, GGT, bilirubin and albumin are done to assess liver function.
Coagulation studies including fibrinogen, a PT, PTT, and INR are done to rule out bleeding disorders.
Importantly, cross-matching for blood transfusions are also done.
In some situations, a nasogastric lavage can be done as well. That’s where a tube is placed down from the nose
to the stomach to wash out the gastric contents. It’s usually done if an upper endoscopy will be done
afterwards.
Now, with hemodynamically stable individuals, when an upper GI bleeding is suspected, an upper endoscopy is
done within 24 hours and when lower GI bleeding is suspected, a colonoscopy is done within 24 hours to identify
the source of bleeding.
With hemodynamically unstable individuals with signs of hypovolemia, two large caliber peripheral intravenous
catheters - of at least 18 gauge or even larger-gauge are placed, and fluid resuscitation begins immediately with
500 milliliters of normal saline or lactated Ringer’s solution given over 30 minutes. Afterwards, the rate of fluid is
adjusted depending on their hemodynamic status.
Next, intravenous proton pump inhibitors or PPIs like esomeprazole are given, initially as a bolus of 80
milligrams, followed by 40 milligrams twice daily, because they promote hemostasis and lower the risk of
recurrent bleeding.
Blood transfusions may be done if the individual remains hemodynamically unstable.
Otherwise, in hemodynamically stable individuals, blood transfusions are done in older individuals with
comorbidities for a hemoglobin below 9 grams per deciliter and in young and healthy individuals with a
hemoglobin below 7 grams per deciliter.
Next, it’s important to do an upper endoscopy.
Now, in hemodynamically unstable individuals with a suspected upper GI bleeding, it’s important to have
surgical and interventional radiology teams nearby, because an upper endoscopy can precipitate complications
like perforation.
Alternatively, with a suspected lower GI bleeding, a nasogastric lavage or upper endoscopy is done to rule out
upper GI bleeding, and then a colonoscopy is done afterwards.
Treatment depends on the specific cause of bleeding.
Let’s start with causes of upper GI bleeding. First, there’s peptic ulcers which may be caused by Helicobacter
pylori infection and the use of NSAIDs.
Treatment is done during the upper endoscopy and includes thermocoagulation therapy using cautery probes.
Cautery probes use an electrical current to melt a tiny blood vessel and seal it shut to stop the bleeding. Another
option is placing hemostatic clips on the blood vessel to stop the bleeding. Both of these methods can be
combined with injecting epinephrine into the vicinity of the bleeding vessel which causes vasospasm and stops
the bleeding.
Next, we have esophageal varices- which are caused by portal hypertension which is usually a consequence of
cirrhosis.
Esophageal varices are diagnosed during an upper endoscopy and are dilated veins in the lower third of the
esophagus.
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Varices only appear in the lower third of the esophagus, because the superficial veins lining the mucosa drain
into the left gastric vein which in turn drains into the portal vein.
Treatment consists of intravenous octreotide which is a somatostatin analogue that decreases portal blood flow.
Antibiotic prophylaxis with IV ciprofloxacin is given for a week to lower the risk of a bacterial infection, and in
severely-ill individuals, IV ceftriaxone is given instead.
An upper endoscopy is done within 12 hours of presentation and variceal ligation is done. That’s where small
elastic bands are placed on the varices to stop them from bleeding. Another option is endoscopic sclerotherapy-
meaning that a sclerosant solution like sodium morrhuate is injected in the varices endoscopically.
If there’s massive bleeding or if endoscopic therapy fails to stop the bleeding, then balloon tamponade is done
using a Blakemore tube-which has two balloons- one balloon for the lower part of the esophagus and another
balloon for the stomach, as well as a third lumen, through which gastric aspiration is done.
An individual needs to be intubated before inserting the Blakemore tube, to prevent pulmonary aspiration of
gastric contents. The tube then is inserted through the nose and placed in the stomach before both esophageal
and gastric balloons are inflated. This applies direct pressure which can stop an ongoing bleed. It can only be
used for about 48 hours, because the pressure can further harm the esophagus and there’s often rebleeding
once the balloons are deflated and removed.
When endoscopic approaches fail, another procedure is a transjugular intrahepatic portosystemic shunt or TIPS,
which creates a path between the portal and systemic circulation in order to lower the portal pressure.To create
this path, a needle catheter is inserted in the jugular vein and then a stent is placed between the hepatic vein
and portal vein, linking the two circulations and bypassing the liver.
Mallory-Weiss syndrome happens due to forceful vomiting that leads to tears in the lower third of the
esophagus and proximal stomach. This is usually associated with alcohol abuse.
On an upper endoscopy, a Mallory-Weiss tear looks like one or sometimes a few longitudinal breaks in the
mucosa.
Treatment includes an antiemetic agent, like metoclopramide if there’s persistent vomiting. If there’s active
bleeding, then endoscopic therapy with thermocoagulation, hemostatic clips placement or endoscopic band
ligation is done.
A Dieulafoy lesion or exulceratio simplex Dieulafoy- is a more rare condition where there’s an unusually dilated
arteriole that erodes the overlying mucosa and starts bleeding. It most often occurs in the stomach.
Treatment is usually a combination of epinephrine injection with thermocoagulation or hemostatic clips
placement.
Another rare condition is Boerhaave syndrome, which is a rupture of the esophagus that’s caused by a sudden
increase in intraesophageal pressure like from straining or vomiting. The spontaneous perforation usually
involves the intrathoracic part of the esophagus. It leads to mediastinitis and mediastinal emphysema- which is
basically a pocket of air surrounding the heart.
Symptoms begin minutes to hours after a perforation. Typically there’s severe retrosternal chest pain and on the
physical examination, there’s crepitus on palpation of the chest wall due to subcutaneous emphysema. Later on,
the individual can develop odynophagia, dyspnea and signs of sepsis.
A contrast esophagogram is done to establish the diagnosis- this uses gastrografin as contrast- because it’s water
soluble and less irritating for the mediastinum. The extravasation of contrast material shows the location and
extent of the perforation.
If the perforation is small, then it’s managed by avoiding oral intake for 7 days, giving parenteral nutrition
support, and IV antibiotics like ticarcillin-clavulanate for 14 days, and drainage of any mediastinal fluid
collections.
In large perforations, the treatment includes surgery to repair the perforation.
In extreme cases, an esophagectomy-which is the surgical removal of the esophagus- may be needed.
Moving on to causes of lower GI bleeding. Diverticulosis is the presence of diverticula which sometimes can
bleed. A colonoscopy is performed within 24 hours of presentation.
Treatment is done during colonoscopy and includes thermocoagulation or injecting epinephrine in the vicinity of
the bleeding. If the bleeding can’t be stopped endoscopically, then angiography can be used to identify the
source of bleeding and vasoconstricting medication like vasopressin can be given. Alternatively, the bleeding
vessel can be embolized.
If neither colonoscopy nor angiography are able to identify and stop the bleeding, then surgery is required and a
segmental colectomy is done. That’s where part of the colon is removed.
Next, there’s colorectal cancer which is a serious cause of hematochezia, and it’s due to an ulcerated tumor.
Often, the tumor is friable and endoscopic therapy can lead to more bleeding or even a perforation. However, a
Hemospray can be applied during colonoscopy- this is a powder that basically forms a barrier over the vessel
wall to stop the bleeding.
Eventually, the colorectal cancer itself is treated with surgical resection of the tumor or chemotherapy.
Hemorrhoids are dilated submucosal veins in the anus.
Internal hemorrhoids are located above the pectinate line -which divides the upper two thirds and lower third of
the anal canal- and external hemorrhoids are located below the pectinate line.
Internal hemorrhoids usually bleed and don’t hurt, whereas external hemorrhoids hurt, but don’t bleed as much.
Hematochezia is associated with hemorrhoids and it’s when blood is on the external surface of the stool but not
actually mixed into the stool.
Both internal and external hemorrhoids can also cause irritation or pruritus in the anal area.
The diagnosis of hemorrhoids is typically done by inspection and the digital rectal exam.
Treatment consists of dietary and lifestyle modifications, such as drinking more water and having a diet rich in
fibers like from nuts and seeds because that helps to soften the stools.
Analgesic creams such as mixed hydrocortisone and lidocaine creams can relieve pain, along with
hydrocortisone suppositories and sitz-baths, which is a warm shallow bath that cleanses the perineum and
relieves irritation and pruritus.
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With internal hemorrhoids that persistently bleed, rubber band ligation can be done using an anoscope to view
the hemorrhoid and then tie it off at its base.
For external hemorrhoids, a hemorrhoidectomy can be done, which is the surgical removal of hemorrhoids.
Intestinal ischemia is caused by anything that reduces intestinal blood flow, like arterial or venous occlusion, or
vasospasm of blood vessel that supplies the small or large intestine.
When it affects the small intestine, it’s called mesenteric ischemia, and when it affects the large intestine it’s
called colonic ischemia- or ischemic colitis.
Colonic ischemia usually happens in the “watershed” regions of the colon, like the splenic flexure and the
rectosigmoid colon, where collateral blood flow is limited, so there’s a high-risk for ischemia.
Now, both mesenteric and colonic ischemia can be either acute or chronic.
Acute mesenteric ischemia causes severe abdominal pain- and it’s called a gut-attack, because the pain is like a
heart-attack.
In some cases, there’s hematochezia.
As ischemia progresses and the small bowel slowly dies, the intestinal wall loses integrity and that can lead to
peritonitis and sepsis.
Acute colonic ischemia is not usually as severe as acute mesenteric ischemia. Often there’s mild crampy left-
sided abdominal pain, hematochezia, and diarrhea.
With chronic mesenteric ischemia, the individual has recurrent abdominal pain after eating- because there’s not
enough blood to meet the demand of the intestine postprandially- and there’s unintentional weight loss.
With chronic colonic ischemia, the individual has recurrent abdominal pain that’s usually unrelated to meals,
bloody diarrhea, and unintentional weight loss.
Now, in severe cases of acute mesenteric and colonic ischemia, surgery is immediately done to resect the non
viable intestines.
If surgery is not needed urgently, then an abdominal CT angiography is done to confirm the diagnosis.
Treatment relies on pain control using opioids, such as morphine, systemic anticoagulation using heparin, and
broad spectrum antibiotics.
An arterial occlusion is treated with a surgical embolectomy-in which the blood clot is removed.
A venous thrombosis is treated using anticoagulant therapy, but if symptoms persist, then thrombolysis using
streptokinase may be done.
Treatment of chronic intestinal ischemia includes dietary and lifestyle modifications, like eating a plant-based
diet and whole grains, regular physical activity, and smoking and alcohol cessation.
If symptoms are severe, then revascularization therapies like surgical embolectomy for an arterial occlusion or
anticoagulant therapy for a venous occlusion are done to improve the blood flow.
AVMs are aberrant blood vessels of unknown cause found in the GI tract and are usually associated with end-
stage renal disease and sometimes with aortic stenosis- and this is called Heyde syndrome.
AVMs are most often found incidentally on an upper endoscopy or colonoscopy done for other reasons or
sometimes can be the source of an upper or lower GI bleeding.
Endoscopic treatment of AVMs is done using argon plasma coagulation- ionized argon gas is directed at the
lesion endoscopically and then high-frequency electric current is directed through the jet of gas causing
coagulation of the vessel. Other options include thermocoagulation and applying hemostatic clips.
Finally, when there’s occult GI bleeding, a workup is done to look for iron deficiency anemia. A CBC would show
a hemoglobin level below 13.5 grams per deciliter, a decreased serum iron and ferritin level, and an increased
total iron binding capacity or TIBC.
Usually both upper endoscopy and colonoscopy are done to identify `the source of bleeding, and if it isn’t
identified, then a wireless video capsule endoscopy is done. That’s where a pill with a video camera is ingested
takes pictures of the entire GI tract - specifically including the small intestines.
Common causes of occult GI bleeding include colorectal and other cancers, peptic ulcer disease, and
inflammatory bowel disease.
Summary
Alright, as a quick recap, an upper GI bleeding typically presents with hematemesis, while a lower GI bleeding
presents with hematochezia.
First step is to assess hemodynamic stability. Lab work includes CBC, electrolytes, BUN, creatinine, AST, ALT,
GGT, bilirubin, albumin, fibrinogen, PTT, bleeding time and thrombin time.
With hemodynamically stable individuals, if upper GI bleeding is suspected, an upper endoscopy is done.
If lower GI bleeding is suspected, then a colonoscopy is done.
With hemodynamically unstable individuals, IV fluids, IV PPIs, and a blood transfusion can be done at a
Hemoglobin level below 9 grams per deciliter in older and sicker individuals, and below 7 grams per deciliter in
young and healthy individuals.
When an upper GI bleeding is suspected, surgical and interventional radiology should be nearby.
When a lower GI bleeding is suspected, then a nasogastric lavage or an upper endoscopy may be done.
Treatment of peptic ulcers, Mallory-Weiss syndrome, and Dieulafoy lesion include endoscopic
thermocoagulation or hemostatic clips, as well as epinephrine injections.
With esophageal varices, IV octreotide is given and endoscopic variceal ligation or endoscopic sclerotherapy are
done.
Balloon tamponade is a temporary method used in severe cases.
When endoscopic therapy fails, TIPS is used.
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Boerhaave syndrome is diagnosed using a contrast esophagogram and treatment for a small perforation is
avoiding oral intake for 7 days, parenteral nutrition, IV antibiotics, and draining fluid collections. Whereas,
treatment for a large perforation is surgical.

Treatment of diverticular bleeding relies on epinephrine injection or thermocoagulation, whereas a bleeding

colorectal carcinoma may be treated with endoscopically applied Hemospray.

Treatment of hemorrhoids relies on dietary and lifestyle modifications.

Bleeding internal hemorrhoids are treated with rubber band ligation, while bleeding external hemorrhoids are
treated with hemorrhoidectomy.

With intestinal ischemia, a CT angiogram is done to confirm the diagnosis if symptoms aren’t severe. Otherwise,
surgery is needed to remove the unviable bowel.

Treatment of AVMs consists of plasma argon coagulation.

With occult GI bleeding, when there’s also iron deficiency anemia, an upper endoscopy, colonoscopy, and
ultimately a wireless capsule endoscopy can be done.

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Clinical Reasoning: Viral hepatitis
Viral hepatitis is liver inflammation caused by a viral infection and it can either be acute or chronic, and five
important causes are hepatitis A, B, C, D and E.
Acute viral hepatitis lasts for less than six months and the individual has nausea, vomiting, and right upper
quadrant pain. Sometimes if there's a high total bilirubin, it can lead to jaundice, pruritus, dark urine, and clay-
colored stools.
Chronic viral hepatitis lasts for more than six months and the individual can sometimes be asymptomatic. Other
times, chronic viral hepatitis can cause fever, fatigue, and loss of appetite, as well as extrahepatic symptoms like
arthralgias and skin rashes.
On the physical examination, with acute hepatitis, there’s typically hepatomegaly, but with chronic hepatitis, the
liver may feel normal on palpation, and if there’s cirrhosis, the lower margin of the liver can feel irregular.
A diagnostic workup for viral hepatitis includes a CBC, AST, ALT, total bilirubin and unconjugated bilirubin,
alkaline phosphatase, and PT, PTT, INR.
Thrombocytopenia, prolonged PT and prolonged PTT as well as an elevated INR can be present in both acute and
chronic hepatitis.
In acute hepatitis, levels of AST, ALT are over 100 international units per liter and sometimes the alkaline
phosphatase and total bilirubin are elevated as well. If the total bilirubin is above 2 milligrams per deciliter, then
an individual can appear jaundiced.
With chronic hepatitis, elevation of AST and ALT persists for more than six months but levels don’t usually rise
above 400 international units per liter. In addition, total bilirubin and alkaline phosphatase levels can also be
elevated.
During viral hepatitis, medications that are metabolized by the liver, like aspirin, or medications that can damage
the liver, like acetaminophen, should be used with caution, because they can further damage the liver.
Okay, now let’s start with hepatitis A which only causes acute hepatitis. It’s caused by contaminated food and
water and often affects travelers.
In hepatitis A, serum anti-hepatitis A virus IgM antibodies are elevated for about 6 weeks , and anti-hepatitis A
IgG antibodies begin to rise a couple weeks after IgM antibodies and usually persist for life.
So, if there are IgG antibodies and no IgM antibodies, that means that the person was vaccinated for hepatitis A
or had a prior infection and developed immunity.
Hepatitis A usually resolves within a few weeks, and the main treatment is giving fluids in case of dehydration.
Hepatitis A can be prevented by vaccinating children, as well as adults that are about to travel in countries with a
high rate of hepatitis A infection. Two doses of the vaccine are given 6 months apart.
Next up is Hepatitis E - which typically causes acute hepatitis, but can also cause chronic hepatitis in
immunocompromised individuals.
Like hepatitis A, it’s also caused by contaminated food and water, but it can also be transmitted from mother to
child during birth. Usually the symptoms are mild, but if it develops in pregnancy, it can be severe and lead to
acute liver failure.
In acute hepatitis E, anti-hepatitis E virus IgM are elevated for about 2 months and IgG antibodies begin to rise
around the same time as IgM antibodies, but they don’t persist for more than a few years. HEV RNA - which is a
marker of virus replication- is also checked in the stool or in the serum to confirm the infection and levels are
usually high.
With chronic hepatitis E, HEV RNA is detected in the serum or in the stool for more than six months.
Acute hepatitis E usually resolves within a few weeks, and the main treatment is giving fluids in case of
dehydration. However, in acute liver failure, a liver transplant may be needed.
In immunocompromised individuals with chronic hepatitis E, treatment involves lowering the doses of
immunosuppressants and giving ribavirin for 12 weeks.
Next is hepatitis B which can cause acute hepatitis and chronic hepatitis. It’s caused by contact with blood - like
sharing needles or syringes, and contact with body fluids - like unprotected sex and during passing from mother
to child during labor and delivery.
Testing for hepatitis B requires sending serology.
First, there’s HBsAg and Anti-Hbs, which is the antibody to Hepatitis B surface antigen. Usually, if one is positive,
the other’s negative, sort of like yin and yang. One exception is if an individual has never been exposed to the
hepatitis B virus or vaccine in their life - in which case they’re both negative.
Another exception is when a person has actually cleared the hepatitis B infection so the HBsAg is gone, but levels
of Anti-Hbs still haven’t risen high enough to be detected, so it appears to be negative, even though technically
there is Anti-Hbs floating around. That’s called the “window period”.
But most of the time, if HBsAg is positive and Anti-Hbs is negative, that means - there’s an acute or chronic
hepatitis B infection.
And if HBsAg is negative and Anti-Hbs is positive, that means that an individual has been immunized or has
recovered from a natural infection - either way, they’re protected from hepatitis B.
After looking at HBsAg and Anti-Hbs, the next step is to look at antibodies made against HBcAg, which is
hepatitis B core antigen.
There’s IgM-anti-HBc, which is IgM antibodies against hepatitis B core antigen, and there’s total anti-HBc, which
is total antibodies against hepatitis B core antigen, mostly made up of IgG antibodies. Neither of these rises with
the vaccine.
Now, in acute hepatitis, both the IgM-anti-HBc and the total anti-HBc become positive. But as weeks go by, the
IgM-anti-HBc becomes negative, while the total anti-HBc remains positive. That happens if the person clears the
hepatitis B infection, or if there’s chronic hepatitis - so it really tells you about the passage of time.
Finally there’s HBeAg, which is hepatitis B e antigen - try saying that 3 times quickly. If it’s positive then the virus
is actively replicating, and that means that the person is highly infectious. If it’s negative, it could be because the
virus isn’t actively replicating or because there’s no virus around at all.
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There’s also HBV DNA PCR, or Hepatitis B virus DNA PCR that can be sent, and it usually mirrors HBeAg but gives
even more information.
High HBV DNA levels mean that the virus is actively replicating and highly infectious low HBV DNA levels mean
that the virus is around but not actively replicating, and having no detectable HBV DNA means that there’s no
virus.
Now let’s put these Hepatitis B serological markers into a table and go through some scenarios. In someone
that’s susceptible to hepatitis B and hasn’t been immunized, HBsAg, Anti-Hbs, IgM-anti-HBc, total anti-HBc,
HBeAg, and HBV DNA are all negative.
In someone that is immunized, Anti-Hbs becomes positive, while HBsAg is negative, and the rest remain negative
as well.
Now in someone with acute hepatitis B infection, HBsAg is positive and Anti-Hbs is negative, and because it’s
acute - IgM-anti-HBc and total anti-HBc are positive. Typically the virus is actively replicating at this stage so
HBeAg and HBV DNA levels are elevated as well.
After a number of weeks later, IgM-anti-HBc becomes negative, while total anti-HBc remains positive for life.
Finally, if the infection gets brought under control to the point where the virus is no longer actively replicating,
then the HBeAg becomes negative and the HBV DNA levels fall, and anti-HBe antibodies appear.
Finally there’s chronic hepatitis B infection, which has a few phases. The immune-tolerant phase usually
develops in individuals that were infected during birth, and it can last a few decades. There’s minimal liver
inflammation, so the ALT and AST may be normal or slightly elevated.
During this phase, HBsAg is positive and Anti-Hbs is negative, and because it’s chronic - IgM-anti-HBc is negative,
while total anti-HBc remains positive.
Typically the virus is actively replicating at this stage so HBeAg and HBV DNA levels are elevated as well.
Then there’s the immune-active phase with positive HBeAg- which is when there’s more liver inflammation so
ALT and AST are elevated, and as a result the HBV DNA levels start to fall a bit, but in other ways the labs are the
same.
HBsAg is positive, Anti-Hbs is negative, IgM-anti-HBc is negative, and total anti-HBc remains positive.
And the virus is still actively replicating so HBeAg is positive.
Next there’s, immune-active phase with negative HBeAg- which is when the ALT and AST remain elevated, but
the HBV DNA levels fall even lower, and the HBeAg becomes negative - meaning that the individual is less
infectious.
In other ways the other labs are the same. HBsAg is positive, Anti-Hbs is negative, IgM-anti-HBc is negative, and
total anti-HBc remains positive.
Next there’s the inactive chronic HBV phase- which is when the ALT and AST normalize and HBV DNA levels fall
even lower, and the HBeAg remains negative.
And as before the other labs are the same. HBsAg is positive, Anti-Hbs is negative, IgM-anti-HBc is negative, and
total anti-HBc remains positive.
Finally, when someone successfully clears the infection, Anti-Hbs becomes positive, while HBsAg is negative,
total anti-HBc remains positive as well, and the IgM-anti-HBc, HBeAg, and HBV DNA are negative.
Now, an important complication of chronic hepatitis B is cirrhosis, which can lead to hepatocellular carcinoma.
In fact, high titers of HVA DNA and HBsAg correlate with a higher likelihood of developing cirrhosis. So every 6
months, an ultrasound is done and alpha fetoprotein levels can also be checked to monitor for possible tumors.
Treatment of acute hepatitis B is mainly supportive, like giving fluids and antiemetic medications like
metoclopramide.
Treatment of chronic hepatitis B largely depends on the HBV DNA and ALT levels and whether or not there’s
cirrhosis.
Individuals without cirrhosis that have HBV DNA levels above 20,000 international units or IU per milliliter and
ALT levels above 2 times the upper limit of normal, are started on treatment.
If the HBV DNA levels are above 20,000 IU per milliliter but ALT is below the 2 times upper limit cutoff, then ALT
levels are monitored every 3 to 6 months and if it ever reaches that cutoff, then treatment is started.
If HBV DNA levels are between 2,000 and 20,000 IU and levels of ALT are under 2 times the upper limit of
normal, then the labs are monitored every 1 to 3 months. If HBV-DNA remains between 2,000 and 20,000
international units per milliliter for 6 months, then treatment is started.
If the HBV DNA levels are below 2,000 IU and levels of ALT are under 2 times the upper limit of normal, then labs
are monitored every 3 to 6 months. If ALT levels rise above 2 times the upper limit of normal, then treatment is
started.
Treatment options include Pegylated interferon- or PegIFN- which is an antiviral agent that’s administered by
subcutaneous injection once a week for 48 weeks.
Other options include nucleoside or nucleotide analogues - like Entecavir or Tenofovir which are given orally
until HBeAg becomes negative and then for one more year after that.
If HBeAg was initially negative and HBV DNA levels rise above 2000 IU and ALT levels rise above 2 times the
upper limit of normal then the treatment is restarted, to prevent HBeAg from becoming positive. This time,
PegIFN is used for a year and the nucleoside or nucleotide analogues are used for several years.
Now treatment for chronic hepatitis B with cirrhosis. First, in individuals with compensated cirrhosis, where
there’s no jaundice or ascites- and HBV DNA is above 2,000 international units per milliliter, Entecavir or
Tenofovir is given indefinitely.
In individuals with compensated cirrhosis, and HBV DNA levels below 2,000 international units per milliliter,
Entecavir or Tenofovir is given only if ALT levels are elevated.
And in individuals with compensated cirrhosis, if HBV DNA levels are undetectable, then no treatment is started.
In individuals with decompensated cirrhosis, where there is jaundice or ascites, Entecavir is started, regardless of
ALT and HBV DNA levels.
In individuals with decompensated cirrhosis, and undetectable levels of HBV DNA, a liver transplant may be
done.
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Prevention of HBV infection is done by vaccination in infants and in adults that are not immune to HBV infection
and have a high-risk for developing it, such as healthcare personnel, injection drugs users, and
immunocompromised individuals. In newborns, three doses are given, the first shortly after birth, the next at
one month of age, and the last at 6 months. In adults, two doses are given, one month apart.
Okay, next is hepatitis D which can cause acute or chronic hepatitis. It’s caused by hepatitis D virus- or HDV-
which is a defective virus that needs HBV to cause an infection, because HBsAg makes up the outer envelope
within which the HDV genome resides.
So like Hepatitis B, Hepatitis D, it’s transmitted through blood and body fluids.
Now, acute hepatitis D, can be due to a coinfection- meaning that both B and D viruses infect the individual at
the same time or a superinfection- meaning that hepatitis D infection occurs after there’s a preexisting chronic
hepatitis B infection.
Oftentimes, an acute hepatitis D infection doesn’t get cleared, and it turns into a chronic hepatitis D infection.
Testing for hepatitis D requires confirmation of hepatitis B infection, as well as testing for HDV IgM, which is IgM
antibodies against hepatitis D, total HDV antibodies, which is total antibodies against hepatitis D, mostly made
up of IgG antibodies, serum HDV RNA, and HDAg which usually remains positive only briefly.
In acute hepatitis D coinfection or superinfection, HDV IgM is elevated, and total HDV antibodies may be
negative if the IgG levels haven’t climbed very high.
HDV RNA is usually positive, and HDAg may be positive or negative because it disappears so quickly.
Whereas with chronic HDV infection, HDV IgM is negative, total HDV antibodies are positive, HDV RNA is
positive, and HDAg is negative.
Treatment of hepatitis D is initiated in individuals that have elevated HDV RNA levels and elevated AST and ALT
levels.
Pegylated interferon alfa-2a or alfa-2b is given once a week for 12 months.
Prevention of hepatitis D is accomplished through hepatitis B vaccination.
Next is hepatitis C which is caused by hepatitis C virus and can cause acute or chronic hepatitis. It’s caused by
contact with blood - like sharing needles or syringes, and contact with body fluids - like unprotected sex and
during passing from mother to child during labor and delivery.
Hepatitis C can cause extrahepatic manifestations like cryoglobulinemia- which is where the blood viscosity is
high and causes headaches and confusion-, membranoproliferative glomerulonephritis and dermatologic
conditions, such as porphyria cutanea tarda which can cause erosions and blisters.
The first step in diagnosis is to look for anti-HCV IgG antibodies. If they’re positive, then the next step is to send
HCV RNA PCR. If HCV RNA is not detected, it likely means that it was a past infection that has now cleared. If HCV
RNA is detected, then the individual has a hepatitis C infection. If titers HCV RNA remains elevated for more than
6 months, then it’s considered a chronic hepatitis C infection, otherwise it’s considered an acute hepatitis C
infection.
Once the diagnosis is established, it’s helpful to calculate the APRI score - which is the AST to platelet ratio index.
It’s calculated by dividing the individual’s AST level by the normal value of AST, and then dividing by the platelet
count and multiplying by 100. This estimates the degree of liver fibrosis. If the score is below 0.5, there’s
minimal fibrosis, between 0.5 and 1.5 is in- between, and above 1.5 means that there is significant fibrosis.
In individuals with cirrhosis, there is a high-risk for developing hepatocellular carcinoma, so an ultrasound is
done every 6 months, and alpha fetoprotein levels can also be checked to monitor for possible tumors.
Treatment of hepatitis C in individuals without cirrhosis can be initiated using either Sofosbuvir coupled with
either velpatasvir or daclatasvir for 12 weeks or by using Glecaprevir and pibrentasvir for 8 weeks.
In individuals with hepatitis C with compensated cirrhosis, Sofosbuvir and velpatasvir can be used for 12 weeks
or Glecaprevir and Pibrentasvir can be given for 12 weeks or Sofosbuvir and daclatasvir can be given for 24
weeks.
In individuals with decompensated cirrhosis, sofosbuvir plus velpatasvir for 24 weeks or sofosbuvir plus
daclatasvir for 12 weeks can be used and some cases may require liver transplantation.
Summary
Alright, as a quick recap. Hepatitis A causes acute hepatitis, and anti-hepatitis A virus IgM antibodies rise, and
anti-hepatitis A IgG antibodies persist for life. Treatment is supportive.
Hepatitis E causes acute hepatitis, including fulminant hepatitis in pregnant women, but it can also cause chronic
hepatitis in immunocompromised individuals.
With acute hepatitis E, anti- hepatitis E virus IgM and HEV RNA are positive and treatment is supportive.
With chronic hepatitis E, HEV-RNA is detected in the stool or serum for more than 6 months and ribavirin can be
used.
Acute hepatitis B shows positive HBsAg, HBeAg and IgM anti-HBc antibodies, along with high levels of HBV DNA,
ALT and AST.
Chronic hepatitis B in the immune-tolerant phase, shows positive HBsAg, positive total anti-HBc, positive HBeAg,
and high levels of HBV DNA. In the immune-active phase, the HBeAg remains positive, but HBV DNA levels are
lower, while ALT and AST levels rise. Then there’s the immune-active phase with negative HBeAg, and the
inactive chronic HBV phase, where HBV DNA is low and AST, ALT levels are normal.
Treatment of acute hepatitis B is supportive, while chronic hepatitis B can be treated with Peg-IFN, Entecavir,
and Tenofovir.
Hepatitis D can cause acute or chronic hepatitis and needs HBV in order to cause an infection.
With a coinfection and superinfection, there’s positive HDV RNA and IgM anti-HDV antibodies.
With chronic hepatitis D, HDV RNA is positive and HDAg is negative. Treatment includes PEG-IFN for 12 months.
Hepatitis C can be acute or chronic and serology shows positive anti-HCV antibodies and elevated levels of HCV
RNA. In individuals without cirrhosis or with compensated cirrhosis, treatment includes Sofosbuvir coupled with
velpatasvir or daclatasvir or Glecaprevir plus pibrentasvir. In individuals with decompensated cirrhosis,
Sofosbuvir plus either velpatasvir and daclatasvir is used.
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Clinical Reasoning: Jaundice
Jaundice -also called icterus- is the yellowish pigmentation of the skin and sclera- and appears when total
bilirubin levels exceed 2 mg/dL in adults.
Total hyperbilirubinemia can be predominantly due to unconjugated- or indirect bilirubin or it can be due to
conjugated-or direct bilirubin and it largely depends on where bilirubin metabolism is disrupted.
So jaundice can be thought of as prehepatic, hepatocellular, or posthepatic.
A workup for jaundice includes total and conjugated bilirubin, AST, ALT, and alkaline phosphatase, which are
markers of liver injury.
In addition, albumin, PT, PTT, and INR which are markers of hepatocellular function are done.
If total bilirubin levels are elevated and conjugated bilirubin levels are normal and there's no other evidence of
liver injury or liver dysfunction, then that means that there’s a high amount of unconjugated bilirubin - and the
jaundice is most likely due to a prehepatic cause. At that point, additional labs can be sent, like a CBC, LDH,
haptoglobin, and a blood smear.
Common prehepatic causes of excess unconjugated bilirubin include hemolytic anemia and dyserythropoiesis-
which is macrophages inappropriately destroy too many red blood cells. These show anemia, an elevated LDH, a
decreased haptoglobin, and can show schistocytes on a blood smear.
Now, if the additional lab work comes back normal, then the cause of this jaundice may be hepatocellular.
One example of this is Gilbert syndrome, which is a genetic condition that causes a decrease in the enzyme
uridine glucuronyl transferase. As a result, hepatocytes are less effective at conjugating bilirubin. Individuals are
usually asymptomatic, but when there’s a trigger like fasting - adipocytes release a lot of unconjugated bilirubin
and that can overwhelm the hepatocytes.
Usually during an episode of jaundice, the unconjugated bilirubin doesn’t rise above 3 milligrams per deciliter
and it resolves within 24 hours after resuming a normal diet.
Usually, laboratory tests repeatedly show normal results between jaundice episodes over 18 months. In some
cases, the diagnosis can be confirmed with genetic testing.
There is no specific treatment required for Gilbert syndrome other than maintaining a normal caloric intake.
Now, if total bilirubin levels are elevated and conjugated bilirubin levels are normal and there is also evidence of
liver injury, such as high AST and ALT levels, then it could be due to medications such as rifampin and probenecid
and the treatment is to stop taking those medications.
Okay, now, if total bilirubin levels are high and conjugated bilirubin levels are high and there’s no other evidence
of liver injury or liver dysfunction, then the cause of jaundice may be hepatocellular.
One example of this is Dubin-Johnson syndrome which is a benign genetic condition that causes a decrease in
bilirubin transport out of the hepatocyte. As a result, conjugated bilirubin accumulates. Individuals present with
mild jaundice, that’s usually noted only during illnesses, pregnancy or after using certain medications, like oral
contraceptives- because they reduce bilirubin excretion and raise bilirubin levels. Serum total bilirubin levels are
usually between 2 and 5 milligrams per deciliter and almost half of this is made up of conjugated bilirubin.
In order to diagnose Dubin-Johnson syndrome, we have to check the urinary coproporphyrin excretion- which is
normal in quantity, but not in quality.
Coproporphyrin comes from heme synthesis and has 4 isomers that are numbered from I to IV.
Normally, coproporphyrin I is excreted in the bile, and coproporphyrin III is excreted in the urine. But, with
Dubin-Johnson syndrome, a lot of coproporphyrin I gets excreted in the urine.
Although it’s not usually done, if a liver biopsy is done, the tissue appears black from a pigment that’s similar to
melanin. No specific treatment is required.
Another example is Rotor syndrome which is another benign genetic condition that causes defects in proteins
that normally transport bilirubin from the blood into the liver for storage and excretion. The defective proteins
lead to an accumulation of conjugated bilirubin. Individuals usually have mild jaundice and the total bilirubin is
usually high, but usually below 5 milligrams per deciliter.
To differentiate Rotor syndrome from Dubin-Johnson syndrome, urinary coproporphyrin excretion is measured
and with Rotor syndrome, this is normal. Once again, no specific treatment is required.
Now, if both total and conjugated bilirubin levels are high and there is also evidence of liver injury, especially
high levels of AST, ALT and no evidence of liver dysfunction, then jaundice is still likely due to a hepatocellular
cause, with a variety of possibilities.
At this point, an additional workup is done, like hepatitis B serologies, anti-HCV antibody for hepatitis C, serum
iron, transferrin and ferritin for hemochromatosis, ceruloplasmin for Wilson disease, antinuclear anti-smooth
muscle and anti-liver-kidney microsomal antibodies for autoimmune hepatitis and antimitochondrial antibodies
for primary biliary cholangitis.
An abdominal ultrasound is also done to identify liver steatosis, if alcoholic hepatitis or non-alcoholic fatty liver
disease is present.
If conjugated bilirubin levels are high - which will also lead to high levels of total bilirubin- and there’s also
evidence of liver injury, especially high alkaline phosphatase levels and no evidence of liver dysfunction, then
jaundice is most likely posthepatic and this is usually caused by a biliary obstruction.
Associated symptoms include right upper quadrant pain, clay-colored stools- that’s because conjugated bilirubin
doesn’t get in the intestine and get turned into stercobilin -which normally colors the stool- and dark urine. This
happens because conjugated bilirubin builds up in the blood and is excreted in the urine.
Okay, now, biliary obstructions are usually caused by stones and this happens with choledocolithiasis and acute
cholangitis, which is an infection behind the blockage. An abdominal ultrasound is done and this shows dilated
bile ducts.
With choledocolithiasis, magnetic resonance cholangiopancreatography is done to confirm the diagnosis and
then ERCP is done to remove the stones.
With acute cholangitis, ERCP is done immediately to locate and remove the stones.
Another cause is cholangiocarcinoma- which is a tumor of the bile ducts - that can either be intrahepatic or
extrahepatic.
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Cholangiocarcinomas are usually asymptomatic, but they can cause right upper quadrant pain, pruritus, and Workup for jaundice includes serum total and conjugated bilirubin, AST, ALT, alkaline phosphatase, albumin, PT,
weight loss. PTT and INR.

An additional workup includes tumor markers like C19-9 and CEA which can be elevated. If there’s isolated unconjugated hyperbilirubinemia, then jaundice can be prehepatic, in which case additional
workup including CBC, LDH, haptoglobin and a blood smear is done to rule out hemolysis and dyserythropoiesis.
An abdominal ultrasound can show dilation of the biliary ducts, especially with an extrahepatic
cholangiocarcinoma. If labs come back normal, then jaundice may be hepatocellular and caused by Gilbert syndrome.

Next, an MRI or MRCP is performed to confirm the diagnosis and also assess the extent of the disease.
The main treatment is surgical resection of the tumor, but this is rarely curative, because cholangiocarcinomas
are often metastatic at diagnosis.
Treatment of an intrahepatic cholangiocarcinoma is a partial hepatectomy- where the part of the liver involving
the tumor is removed.
Treatment of an extrahepatic cholangiocarcinoma is more complicated because it requires removal of part of
the liver, the bile ducts, gallbladder and nearby lymph nodes.
When the tumor is really close to the pancreas, a Whipple procedure may also be necessary- this is when part of
the pancreas and small intestine is removed.
With unresectable tumors, chemotherapy and radiation therapy can be used.
Sometimes, the obstruction can be caused by primary sclerosing cholangitis- which is a progressive liver disease
where there’s inflammation, fibrosis, and strictures in both intra and extrahepatic biliary ducts. To confirm the
diagnosis, MRCP is done and the biliary ducts appear beaded or have a “pruned tree” appearance, due to the
presence of multiple strictures. The only curative treatment is a liver transplant.
If there’s isolated unconjugated hyperbilirubinemia and high levels of AST and ALT, then medications like
rifampin or probenecid can be the cause, in which case treatment is stopping the medication.
If total bilirubin and conjugated bilirubin levels are high, then jaundice can be hepatocellular and caused by
genetic syndromes, like Dubin-Johnson and Rotor syndrome.
If AST and ALT are high, then a large spectrum of liver conditions that lead to cirrhosis can be the cause and
additional workup includes hepatitis B serology, anti-HCV antibody for hepatitis C, serum iron, transferrin and
ferritin for hemochromatosis, ceruloplasmin for Wilson disease, antinuclear anti-smooth muscle and anti-liver-
kidney microsomal antibodies for autoimmune hepatitis and antimitochondrial antibodies or AMA for primary
biliary cholangitis and an ultrasound for alcoholic and non-alcoholic liver disease.
If alkaline phosphatase levels are high, then jaundice is posthepatic and caused by an obstruction of the biliary
tree.
Obstructions are caused by stones- like with choledocolithiasis and acute cholangitis, liver conditions like
primary sclerosing cholangitis and tumors like cholangiocarcinomas or pancreatic exocrine cancer.

Finally, the biliary tract can be compressed from the outside by a tumor - most often a pancreatic exocrine
cancer.

Symptoms of pancreatic cancer include epigastric abdominal pain and weight loss.

Additional tests include blood tests for serum lipase and CA 19.9 levels and both can be elevated.

Next, an abdominal ultrasound is done and this shows dilated bile ducts and sometimes the tumor can be seen
as a focal hypoechoic solid mass that has irregular margins.

An abdominal CT-scan can reveal an ill-defined mass within the pancreas.

If the diagnosis is unclear after imaging, then a percutaneous biopsy is done to confirm the diagnosis.

Depending on the extent of involvement and the location of the tumor, a Whipple procedure or a partial
pancreatectomy can be done. That’s where part of the pancreas is removed.

If the tumor has spread to nearby blood vessels or if metastasis is present, then chemotherapy and radiation
therapy are typically given.

Summary

Alright, as a quick recap, jaundice appears when total bilirubin levels are above 2 milligrams per decilitre in
adults.

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Clinical Reasoning: Cirrhosis
Cirrhosis is when chronic inflammation and liver damage causes the liver to become fibrotic and develop scar
tissue.
At a cellular level, the hepatocytes become impaired and this leads to hepatic dysfunction and portal
hypertension.
Cirrhosis is usually irreversible, so it's usually called “end-stage” or “late-stage” liver damage, and often requires
a liver transplant. However, in some cases, early treatment can slow down and even reverse the cirrhosis.
Compensated cirrhosis is when there are enough healthy cells to make up for the damaged ones, but minor
complications like hemorrhoids can still occur.
Decompensated cirrhosis is when healthy cells can no longer keep up with the workload, causing major
complications like hepatic encephalopathy, ascites, and esophageal and gastric variceal hemorrhage.
In compensated cirrhosis, although there aren’t any major complications, there may still be some symptoms
such as loss of appetite, fatigue, and muscle cramps. There may also be easy bruising and excessive bleeding
because there aren’t enough clotting factors produced by the liver.
Cirrhosis can also impair estrogen metabolism, causing amenorrhea and irregular menstrual bleeding in females,
and low libido and gynecomastia in males.
On physical exam, there may be hepatomegaly - where the liver can feel firm and nodular, but when there’s a lot
of scarring, the liver may be small so that it can’t be felt at all.
Another sign is spider angiomas- or spider nevi- which are swollen blood vessels just beneath the skin surface-
on the truck, face and upper limbs.
Palmar erythema- which is redness of the hands- can sometimes be seen.
There can also be hypertrophic osteoarthropathy- which is when there’s nail clubbing and periostitis- which is
inflammation around the small hand joints.
Sometimes, there are Dupuytren contracture, which is when one or more fingers are permanently flexed.
Portal hypertension can lead to splenomegaly, along with caput medusae- which are distended and engorged
paraumbilical veins on the surface of the abdomen.
Finally, there may be minor complications such as hemorrhoids identified on a digital exam.
In terms of diagnosing cirrhosis, lab work includes a CBC- which most commonly shows thrombocytopenia-
especially if there’s also splenomegaly, but can also show anemia and leukopenia.
Markers of liver injury are AST, ALT, alkaline phosphatase, and GGT and they’re usually elevated.
Total and conjugated bilirubin are usually normal in compensated cirrhosis.
Finally, markers of liver function like albumin can decrease as cirrhosis progresses, and PT, PTT, and INR- can
increase as cirrhosis progresses.
In addition, Fibrosure or Fibrotest is done using alpha-2-macroglobulin, haptoglobin, total gamma globulin,
apolipoprotein A1, GGT, and total bilirubin to generate a score that estimates liver fibrosis.
An abdominal ultrasound shows surface nodularity and increased echogenicity and sometimes there’s atrophy in
the right lobe and hypertrophy of the left and caudate lobe.
If there’s portal hypertension, then the diameter of the portal vein is over 13 millimeters.
There’s also ultrasound-based elastography- which measures tissue elasticity. Normal liver elasticity ranges from
2.6 to 6.2 kilopascals and when it’s above 7 kilopascals, that means that there’s significant fibrosis and when it’s
above 11 kilopascals, that means there’s cirrhosis.
A liver biopsy is the gold standard for diagnosing cirrhosis and also finding the cause, but it’s not always done,
especially when other findings strongly suggest cirrhosis. If it’s done, a liver biopsy will often show bridging
fibrosis and irregular nodules of regenerating hepatocytes.
Individuals with cirrhosis should avoid alcohol, medications that are hepatotoxic, such as acetaminophen and
also herbal and dietary supplements, that can damage the liver like germander. Individuals should also be
vaccinated for hepatitis A and B if they’re not already immune. Doses of certain medications, like tramadol
which is an opioid pain medications, may need to be adjusted to prevent further harm to the liver.
Individuals with cirrhosis should be monitored every 3 to 6 months using a CBC, markers of liver injury and
markers of liver dysfunction.
In addition, an ultrasound should be done and alpha fetoprotein levels can also be checked to monitor for
possible tumors, since cirrhotic individuals are at increased risk for developing hepatocellular carcinoma.
Okay, now, with decompensated cirrhosis, there are major complications which may be triggered by things like
acute infections, alcohol intoxication, constipation, or even bouts of dehydration. Treatment for these
complications starts with resolving the triggering event - like treating the infection or abstaining from alcohol.
One major complication of decompensated cirrhosis is jaundice - which can happen because the liver is unable
to conjugate bilirubin. Lab findings would show total bilirubin levels over 2 milligrams per deciliter.
Another complication is hepatic encephalopathy- and this happens because the liver is unable to effectively
remove toxins- like ammonia- from the blood. These toxins can build up and get into the brain causing
symptoms like insomnia or hypersomnia. As toxins accumulate, there can be mood changes, along with
confusion and even coma in some cases.
On physical exam, there may be asterixis- a flapping tremor of the hand that appears when the wrist is
extended- like a bird that’s flapping its wings.
Lab findings show high levels of ammonia, and it can be lowered using lactulose given orally or through an
enema. Lactulose is a non-absorbable sugar that decreases absorption of ammonia in the intestines and
prevents constipation.
If the individual doesn’t improve in 48 hours, then oral Rifaximin is given. That’s an antibiotic that kills ammonia-
producing bacteria in the intestines and also has anti-inflammatory proprietes.
Individuals with recurrent hepatic encephalopathy can be given ongoing treatment with lactulose.
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Now, although portal hypertension can seen in compensated cirrhosis - as things worsen, it can lead to major With SBP, there’s a single pathogen found and the common are Escherichia coli, Klebsiella pneumoniae, and
complications that are seen in decompensated cirrhosis. Streptococcus pneumoniae, whereas with secondary bacterial peritonitis, multiple pathogens are usually
involved. Empiric antibiotics for SBP are IV Cefotaxime.
Portal hypertension can cause peripheral edema as well as a build up of excess fluid in the peritoneal cavity -
resulting in ascites. Another major complication of portal hypertension is variceal hemorrhage- specifically bleeding from dilated
veins in the esophagus and stomach.
Ascites can cause abdominal distention, as well as shifting dullness on percussion and a positive fluid wave test.
Esophageal and stomach variceal veins are usually seen on an upper endoscopy which is usually done within 12
Additional lab work for ascites includes electrolytes in order to identify any imbalances, especially hyponatremia. hours of the bleeding. During that procedure variceal ligation or endoscopic sclerotherapy can be done to help
stop the bleeding. In addition, IV octreotide, which is a somatostatin analogue, is used to help decrease portal
An abdominal ultrasound can confirm the diagnosis- usually the fluid in ascites appears anechoic.
blood flow.
Next, a paracentesis is done to collect ascitic fluid. The ascitic fluid is typically crystal clear, and bloody ascitic
If there’s massive bleeding or if endoscopic therapy fails to stop the bleeding, then balloon tamponade is done
fluid suggests a tumor.
using a Blakemore tube. This applies direct pressure on the esophagus.
A cell count and differential is also done and with normal ascitic fluid there are below 250 neutrophils. In
If endoscopic approaches fail, a transjugular intrahepatic portosystemic shunt or TIPS procedure can be done-
addition, total protein levels are below 3 grams per deciliter, saying that the fluid is a transudate- while an
which creates a path between the portal and systemic circulation in order to lower the portal pressure.
exudate has more than 3 grams per deciliter of protein.
In moderately ill individuals, IV ciprofloxacin is given for a week to prevent an infection, and in severely-ill
Next, the ascitic fluid is tested for albumin to calculate the Serum-to-ascites albumin gradient- or SAAG. A SAAG
individuals, IV ceftriaxone is given instead.
above 1.1, means that portal hypertension is present.
Given the risk of bleeding, it’s important to spot varices early on, so in compensated cirrhosis - an upper
Because salt helps retain water, treatment of moderate ascites includes sodium restriction to 2 grams per day.
endoscopy is done every 2 to 3 years and in decompensated cirrhosis, it’s done every year.
In addition, a combination of diuretics like spironolactone- a potassium sparing diuretic- and furosemide- a loop
Individuals with varices should have endoscopic variceal ligation done, and those at high risk like individuals with
diuretic- is commonly used to get rid of excess fluid. Individuals without peripheral edema typically lose about
decompensated cirrhosis should get prophylactic beta-blockers- like propranolol- which reduce portal vein
0.5 kilograms daily, and individuals with peripheral edema lose about 1 kilogram daily. As the ascites resolves,
pressures.
the diuretics are tapered and then stopped.
Individuals with a history of ascites, or SBP, or variceal hemorrhage, are given trimethoprim-sulfamethoxazole as
If an individual develops hepatic encephalopathy or has severe hyponatremia- with sodium levels below 120
antibiotic prophylaxis.
milliequivalents per liter, then diuretic treatment is stopped and serial paracentesis is done to reduce the
ascites. Two more complications - hepatorenal syndrome and hepatopulmonary syndrome - describe failure of the liver
and kidneys and failure of the liver and lungs, respectively. They occur because portal hypertension causes
In severe hyponatremia, fluid intake is restricted to less than the urine volume.
arterial and capillary vasodilation which reduces systemic vascular resistance and can damage the kidneys and
Treatment of severe ascites is done using large volume paracentesis- where up to 5 liters of fluid is taken out of lungs.
the abdomen at one time without causing hypovolemia. When more than 5 liters of fluid is taken out, albumin is
Okay, now let’s switch gears and talk about hepatocellular carcinoma, which is a primary liver tumor that often
given afterwards.
occurs in cirrhosis.
A major complication of ascites is spontaneous bacterial peritonitis- or SBP- which is an infection of the ascitic
In some cases, there’s a paraneoplastic syndrome with symptoms like hypoglycemia- because the tumor
fluid. It can cause severe abdominal pain, fever, and an altered mental status.
consumes a lot of glucose, diarrhea- caused by vasoactive peptides that increase intestinal secretion, and
A paracentesis of the ascitic fluid is done- and the fluid looks turbid or cloudy, the cell count is over 250 hypercalcemia- due to secretion of parathyroid- like hormone.
neutrophils per millimeter square and total protein is above 1 gram per deciliter, and the SAAG is above 1.1.
Lab findings can include high levels of alpha fetoprotein and if there’s a paraneoplastic syndrome, there can be
In addition, the glucose is usually above 50 milligrams per deciliter- which distinguishes SBP from a secondary hypoglycemia and high levels of calcium. If there’s diarrhea, there may be hyponatremia or hypokalemia.
bacterial peritonitis, where glucose is below 50 milligrams per deciliter and the LDH is below 225 international
An ultrasound would show a hypoechoic mass in the liver and an abdominal CT-scan can help stage the tumor
units per liter.
using the Tumor-Node-Metastasis system.
Cultures and cgram stains are also sent.
Finally, a liver biopsy can be done and that typically shows broad trabeculae and pseudoglands.

Common sites of metastasis include the lungs, intra-abdominal lymph nodes and bone.

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Depending on the location and spread of the tumor, a partial hepatectomy or a liver transplant may be done.
If the tumor cannot be surgically removed, then ablation and embolization or chemoradiation can be done.
If lymph nodes were invaded or if there’s metastasis, then medications like sorafenib or lenvatinib can be used
to slow tumor growth and relieve the symptoms.
Now, let’s talk about the underlying causes of cirrhosis. First off, there’s chronic viral hepatitis which is usually
due to a hepatitis B or C infection that lasts for over 6 months. With chronic hepatitis B, HBsAg and anti-HBc
antibodies are positive, and with chronic hepatitis C, anti-HCV antibodies are positive and there are elevated
levels of HCV RNA.
Next, there’s alcoholic liver disease caused by drinking over 30 grams of alcohol per day- or more than 3 beers
daily, and nonalcoholic fatty liver disease or NAFLD -which is associated with metabolic syndrome- which
includes obesity, arterial hypertension, insulin resistance, and dyslipidemia. Both of these lead to steatosis-
which is the infiltration of liver cells with fat, and steatohepatitis- which is when there’s fatty infiltration along
with inflammation.
When NAFLD causes steatohepatitis, it’s called non-alcoholic steatohepatitis or NASH.
With alcoholic liver disease, lab findings can show anemia and an elevated MCV- suggesting vitamin B12 or
folate deficiency due to alcohol toxicity. The ESR can be elevated and AST to ALT ratio is above 2.
With NAFLD induced hepatic steatosis and NASH, other causes of hepatic steatosis need to be ruled out, like
alcoholic liver disease and viral hepatitis.
Next, an ultrasound is done and the liver typically appears hyperechoic with both alcoholic and non-alcoholic
liver disease.
On an abdominal CT-scan, the liver composition is compared to the spleen. A fatty liver has an attenuation that
is at least 10 Hounsfield units lower than the spleen.
On a liver biopsy, in steatosis, there’s fat accumulation, and in steatohepatitis there’s neutrophilic infiltration.
Treatment relies on alcohol abstinence and with NAFLD it requires management of metabolic syndrome.
Hemochromatosis is a hereditary disorder caused by a mutation in the HFE gene which lead to increased iron
absorption. The excess iron gets deposited in the liver, heart, pancreas and pituitary.
In advanced stages, individuals have a classic triad of cirrhosis, diabetes mellitus and skin pigmentation - the
latter two are lumped together in the term bronze diabetes.
Lab findings include a serum transferrin above 45%, and disease confirmation is done with genetic testing. T
reatment consists of reducing iron load with phlebotomies that remove up to 500 milliliters of blood weekly for
50 weeks, and after that every 2 to 4 months.
Autoimmune hepatitis is a condition where circulating antibodies attack liver cells.
Lab findings include an elevated total gamma globulin level, especially IgG, antinuclear antibodies or ANA, anti-
smooth muscle antibodies, anti-liver-kidney microsomal-1 antibodies, and antimitochondrial antibodies.
Autoimmune hepatitis is often associated with other autoimmune conditions, like autoimmune thyroiditis.
Initial treatment is typically done with oral glucocorticoids like prednisone and once there’s remission- meaning
that liver injury markers normalise and there are no symptoms- prednisone or azathioprine can be used for
maintenance therapy.
Primary sclerosing cholangitis is a progressive disease in which there’s inflammation, fibrosis, and strictures of
the medium and large ducts in the intra- and extra- hepatic parts of the biliary tree. Sometimes, there's an
elevated total gamma globulin level, especially IgM. Perinuclear antineutrophil cytoplasmic antibodies- or p-
ANCA- can also be high.
Next, an ultrasound is done and this shows bile duct wall thickening and focal bile duct dilations.
Diagnosis is confirmed by MRCP where the biliary ducts are beaded or have a “pruned tree” appearance,
meaning that there are multiple strictures.
If an ERCP is done, then a biopsy can be performed that shows onion skin fibrosis due to periductal fibrosis.
Treatment is done using ursodeoxycholic acid- which is a bile acid- that stimulates hepatobiliary secretion and
protects hepatocytes from being destroyed by bile acids. The only treatment for primary sclerosing cholangitis is
a liver transplant.
Primary biliary cholangitis sometimes called primary biliary cirrhosis, is an autoimmune condition in which the
epithelial cells lining the intrahepatic biliary ducts- are gradually destroyed. There can be distinctive skin changes
like hyperpigmentation as well as lesions like xanthomas and rashes that show dermatographism- which means
that it looks like someone has written or drawn on the skin.
Lab findings include elevated cholesterol levels, antimitochondrial antibodies which are the key findings, and
sometimes antinuclear antibodies are also present.
An ultrasound or MRCP are done to rule out an extrahepatic obstruction.
If a liver biopsy is done, it shows inflammation, abnormal connective tissue, or fibrosis in the portal and
periportal areas.
Treatment is done using ursodeoxycholic acid. The only curative treatment is a liver transplant.
Wilson disease is a genetic disorder that leads to excessive copper deposition in the liver, eyes, and brain.
Neurological symptoms include dysarthria, ataxia, dystonia, tremor, and parkinsonism. There can also be
psychiatric symptoms like depression and personality changes.
An ocular slit-lamp examination shows Kayser- Fleischer rings - which are dark rings around the iris.
Lab findings includes ceruloplasmin levels below 20 milligrams per deciliter - that’s the protein that transports
copper. In addition, a 24 hour urine copper test shows over 100 micrograms of copper in the urine.
Treatment includes avoiding foods with a high copper content like nuts, chocolate, and mushrooms. Treatment
includes cheltators that can bind to excess copper like D-Penicillamine and Trientine.
Alpha-1 antitrypsin deficiency is a genetic disorder that affects the lungs and the liver. In the lungs, there’s
excess protease activity that results in destruction of elastin, resulting in emphysema. In the liver, the abnormal
alpha-1 antitrypsin protein accumulates and causes inflammation.
Lab findings include alpha-1 antitrypsin levels below 11 micromol per liter.
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Next, isoelectric focusing can be done- this separates molecules based on their isoelectric point and can identify
different alpha-1 antitrypsin variants. PCR can be used to identify the different alpha-1-antitrypsin variants.

Pulmonary treatment is done with inhaled bronchodilators- such as Salmeterol, and prevention relies on
avoiding smoke exposure. There is no specific treatment for the liver disease.

Summary

Finally! As a quick recap, cirrhosis can be compensated- in which the individual is asymptomatic or presents
nonspecific symptoms. A work up includes a CBC- that can show thrombocytopenia, anemia, leukopenia,
markers of liver injury, like AST, ALT, alkaline phosphatase, GGT which are elevated, and total and conjugated
bilirubin which can be normal. Markers of liver function like albumin- can decrease as cirrhosis progresses -
while PT, PPT, and INR- can increase as cirrhosis progresses. An ultrasound is done next, along with FibroSure,
ultrasound-based elastography or a liver biopsy- which is the gold standard for diagnosing cirrhosis.

With decompensated cirrhosis, major complications are present. First, there’s jaundice where total bilirubin
levels are over 2 milligrams per deciliter.

With hepatic encephalopathy, there’s asterixis and high levels of ammonia. Treatment relies on eliminating
precipitating factors, lactulose, and rifaximin.

Another complication is severe portal hypertension which often leads to ascites- that’s usually treated with
sodium restriction and diuretic therapy, SBP- that’s treated with IV cefotaxime, and esophageal and gastric
variceal hemorrhage- that’s treated with endoscopic variceal ligation or endoscopic sclerotherapy or TIPS and
prevented with propranolol, hepatorenal syndrome and hepatopulmonary syndrome.

One complication of cirrhosis overall is hepatocellular carcinoma, which can be monitored with an ultrasound
every 3 to 6 months. A CT-scan is done to confirm the diagnosis and stage the condition using TNM system.
Treatment depends on the extent and location of the tumor.

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