Malabsorption syndromes: Pathology review

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Case Study0:00–0:56

At the gastroenterology clinic, there is a 53 year- old man from the United Kingdom, named George, who came in complaining of periodic foul-smelling, bulky and frothy stools, as well as recurrent abdominal pain after meals and weight loss, despite not dieting.
On further history, he admits that he has been consuming alcohol with almost every meal for the last 10 years. An upright abdominal x-ray shows calcifications in the epigastric area.
Next to him is a 9 year- old girl from Iran, named Yasmin, whose parents are concerned about her short stature and inadequate weight gain despite following a balanced diet.
On examination, her height and weight are below the 3rd percentile for her age and sex. She also has an itchy rash consisting of small vesicles on both of her knees.

Pathology0:56–4:27

At first glance, you’d think George’s and Yasmin symptoms have nothing in common. But the fact is, they both have different forms of malabsorption syndromes.
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.
In general, unabsorbed nutrients are allowed to linger in the gastrointestinal lumen for longer than usual, disrupting the proper formation of stool, which results in diarrhea, bloating and flatulence.
And since these nutrients are lost in the stool, malabsorption will also lead to unintentional weight loss and various nutritional deficiencies.
For macronutrients, let’s start big, with fat malabsorption which causes steatorrhea, meaning fatty, greasy, floating, voluminous and terribly smelling stools.
And it’s important to know that screening for fat malabsorption is done with a fecal fat test, known as Sudan III stain.
A high yield fact to remember is that there will also be a decrease in the absorption of the fat-soluble vitamins; A, D, E, and K, and that might be the only clue you get for fat malabsorption!
So, in a question stem with symptoms like night blindness, eye dryness, corneal ulcerations or thickened skin, think of vitamin A deficiency.
In a child with rickets or an adult with osteomalacia there’s vitamin D deficiency. Neuromuscular disease, like ataxia, impaired proprioception and vibratory sensation, or hemolytic anemia might be a sign of vitamin E deficiency.
And finally, increased bleeding tendency should be a clue for vitamin K deficiency. Okay, next, if there’s protein or carbohydrate malabsorption, these nutrients will attract water into the lumen, resulting in a typically watery diarrhea.
But what sets them apart is that protein loss can also cause edema since there’s less oncotic pressure in the blood vessels and the fluid leaks out.
Now, shifting to micronutrients. Besides the fat soluble vitamins we discussed earlier, malabsorption of iron can lead to microcytic anemia, with a mean corpuscular volume or MCV less than 80 femtoliter.
Likewise, malabsorption of folate or B12 can lead to macrocytic anemia, with an MCV above 100 femtoliter. Alright, causes of malabsorption can be broadly divided into two major groups: digestive disorders where the food can’t be broken down in the intestinal lumen, and absorption defects, where intestinal tissue can’t take in the nutrients.
Okay, so, first, common digestive disorders include exocrine pancreatic insufficiency, cholestasis, and lactose intolerance.

EPI4:27–7:31

In exocrine pancreatic insufficiency, there’s a lack of pancreatic digestive enzymes, like amylase, lipase and elastase, which breaks down carbohydrates, lipids and proteins respectively.
Without digestive enzymes, symptoms of global malabsorption appear, like chronic or recurrent diarrhea with steatorrhea, unintentional weight loss, abdominal distention, and bloating.
Now exocrine pancreatic insufficiency typically results from chronic pancreatitis, which is inflammation of the pancreas leading to destruction of its exocrine portion.
For your exams, a person with chronic pancreatitis often complains of intense abdominal pain in the epigastric region, that sometimes radiates to the back and usually presents after meals.
In acute pancreatitis, pancreatic enzymes like lipase and amylase can leak out from the damaged tissue and enter the circulation.
However, in chronic pancreatitis there might not be enough healthy pancreatic tissue left to make these enzymes, so their serum levels remain low.
Now, remember that in adults, the greatest risk factor for chronic pancreatitis is alcohol abuse. That’s because alcohol makes pancreatic juices really viscous and thick, it forms a plug that can block the duct.
This causes the pancreatic juices to back up, and the digestive enzymes actually start eating away at the pancreas itself.
A high yield fact here is that calcium deposits often accumulate on these plugs, and these calcifications are often visible in imaging tests, like an abdominal x- ray or CT- scan, Now, if you see chronic pancreatitis in a child, remember that the number one cause is cystic fibrosis.
This is a genetic disorder that causes a mutation in Cl- channels, leading to thick and sticky pancreatic secretions, much like in alcohol abuse.
These children will also develop thick lung secretions, so there will be serious or recurrent pneumonias, as well as nasal polyps which are tissue growths in the nose, and digital clubbing where the fingernails begin to spoon around the fingertips, or infertility in males.
Diagnosis of cystic fibrosis is typically based on high levels of chloride in a sweat test. Okay, ultimately, regardless of the cause of chronic pancreatitis, the damage to the pancreatic tissue gradually leads to pancreatic insufficiency.
The diagnostic workup for exocrine pancreatic insufficiency is also frequently tested. This is based on low serum trypsinogen level, which is another pancreatic enzyme, or low bicarbonate in the duodenal fluid after stimulation with the hormone secretin.
Management includes administering a mixture of pancreatic enzymes. Nextup, digestion could be affected by cholestasis, which is another name for impaired bile flow.

Cholestasis7:31–11:15

Since bile builds up in the liver, on histology it looks like yellowish-green “bile lakes”. The blockage results in not enough bile reaching the intestine to emulsify fats and make them easier to absorb.
So, prolonged cholestasis can result in fat malabsorption, which translates to steatorrhea and fat-soluble vitamin deficiencies.
For your exams, it’s helpful to split the causes of cholestasis into two types; hepatocellular cholestasis, where hepatocytes don’t make enough bile, and obstructive cholestasis, where something’s physically blocking bile flow.
In both cases, conjugated bilirubin doesn't get secreted into gastrointestinal tract, where it would have turned into stercobilin, which normally gives the stool its darker color.
This results in clay colored stool. Instead, bilirubin builds up in the blood and deposits in the skin and sclera, causing them to turn yellow.
Furthermore, it will get excreted in the urine, turning it dark. Now, for hepatocellular cholestasis, a really important culprit is the hormone estrogen, which inhibits the export pump that usually move bile acid from the hepatocytes to the biliary tract.
So clues include pregnancy or oral contraceptive pills. Obstructive cholestasis could be caused from primary sclerosing cholangitis, where the immune system attacks the bile ducts, causing inflammation and scarring and blocking bile flow.
For your exams, it’s important that for unknown reasons, primary sclerosing cholangitis is strongly associated with inflammatory bowel disease, and especially ulcerative colitis.
Also, in a magnetic resonance cholangiopancreatography, or MRCP, which is a technique that uses a magnetic field to visualize the biliary ducts, these ducts appear beaded or have a “pruned tree” appearance with multiple strictures.
Next, carcinomas on the head of the pancreas may also obstruct bile flow, since the common bile duct passes through this region.
For your test, an individual with pancreatic cancer will typically complain of persistent epigastric abdominal pain and on labs, might have elevated serum lipase or CA 19.9 levels.
Imaging tests, like an abdominal ultrasound or CT- scan, will reveal the mass in the pancreas. Finally, obstructive cholestasis in newborns could be caused by a lot of different things.
If an ultrasound of the upper abdomen shows an absent gallbladder and no dilatation of the biliary tree, then it’s likely biliary atresia.
That’s when there’s a congenital malformation resulting in a blockage or absence of the extrahepatic biliary system. A hepatobiliary scintiscanning, or HIDA scan, can be also done, and will show that the tracer will fail to get excreted into the bowel.
In other cases, the ultrasound might show choledochal cysts. These are congenital abnormal dilatations of the bile duct, which provide a place for the bile to sludge and obstruct the normal flow.
Both biliary atresia and choledochal cysts are treated surgically. Another extremely common digestive disorder is lactose intolerance, which specifically affects the absorption of lactose, a type of carbohydrate found in dairy products.

Lactose Intolerance11:15–12:46

In lactose intolerance, there’s decreased activity of the enzyme lactase, which chops off lactose into glucose and galactose which can be absorbed by the intestines.
Instead, lactose gets fermented by normal intestinal microbes into a mix of gases like hydrogen, which contribute to symptoms of, uh, gas and bloating.
Short-chain fatty acids are also produced by bacteria, which attract water into the gut lumen, leading to diarrhea and abdominal pain after ingestion of milk or other dairy products.
Lactose intolerance might be congenital, which is rare, or acquired, which typically occur in people of Asians and Africans descent.
To diagnose lactose intolerance, a hydrogen breath test is used, where increased hydrogen content is found. In a stool test, lactose also decreases its pH and increases its osmolality.
Exams sometimes try to trick you by having the more specific “intestinal biopsy” as an answer choice. However, this is usually the wrong answer since it's far too invasive.
And besides, it would just show normal intestinal mucosa. Treatment of lactose intolerance consists of eliminating lactose from the diet.
Alright, let’s move on to absorption defects. Here we have diseases that cause damage to the small intestine mucosa, reducing the surface area available for absorption.

Absorption Defects12:46–13:38

These individuals will have symptoms of global malabsorption, just like with exocrine pancreatic insufficiency. One way to differentiate between the two is the D-xylose test.
D-xylose is a monosaccharide which can be directly absorbed from the intestinal mucosa without the need of pancreatic enzymes.
So, D-xylose is administered orally and if the mucosa is intact, it gets absorbed and serum and urine levels will be high.
On the flip side, if there’s an intestinal mucosa defect, less d-xylose is absorbed, so its serum and urine levels will be low.
Now, an important cause of absorption defects is celiac disease. This is an autoimmune condition where the gluten in food like wheat and grains triggers the body’s immune cells to attack the intestinal mucosa.

Celiac Disease13:38–16:39

Gluten is broken down into gliadin which then binds to secretory IgA on the mucosal membrane of the duodenal cells. This gliadin-IgA complex binds to a transferrin receptor, or TfR, and gets transcytosed across the cell and into the lamina propria.
Once there, an enzyme called tissue transglutaminase, or tTG, cuts off of an amide group. Deamidated gliadin is then eaten up by macrophages and served up on its MHC class II molecules.
A very high yield fact here is that MHC molecules of individuals with celiac disease are typically encoded by specific human leukocyte antigen genes, called HLA-DQ2 or HLA-DQ8.
At this point, CD4+ T- cells in the lamina propria recognize the gliadin and stimulate B cells to start pumping out IgA antibodies against the gliadin, the transglutaminase enzyme, and the proteins of the endomysium, a layer of connective tissue around muscle fibers.
These are known as endomysial antibodies, or EMAs. For your test, remember that diagnosis of celiac disease is most often based on finding these antibodies in the serum.
Okay, so these antibodies cause helper T cell to release cytokines that initiate inflammation, and directly damage and destroy epithelial cells in the villi of the small intestine.
So, an effective, yet more invasive way to diagnose celiac disease is an endoscopic biopsy of the duodenum, which is where the damage is typically most severe, probably because it’s the first part of the small intestine to come in contact with the most gluten.
What we’ll see is plenty of lymphocytes in the lamina propria, while the villi will appear flattened out, called villous atrophy, and the crypts will be longer; called crypt hyperplasia.
Finally, bare in mind that a child with celiac disease might sometimes have no gastrointestinal manifestations at all and present solely with failure to thrive, delayed puberty, and dermatitis herpetiformis -which despite its name, has nothing to do with the herpes virus.
It’s actually a bumpy skin rash made of small, intensely itchy vesicles that pops up symmetrically in the extensor surfaces, like the knees and elbows.
It arises from circulating IgA antibodies that mistakenly bind to the transglutaminase in the dermal papillae of the epidermis.
Treatment of celiac disease consists of eliminating gluten from the diet. Another cause of intestinal mucosa defect is tropical sprue.

Tropical Sprue16:39–17:19

It’s thought to be the result of bacterial overgrowth, most commonly from Klebsiella, E. coli, and Enterobacter species.
These bacteria release toxins as they ferment the food in the small intestine, which can lead to chronic inflammation and subsequent flattening of the small intestinal villi, which ultimately results in global malabsorption just like celiac disease.
So, the biggest clue is that tropical sprue mostly affects tropical regions of the world, like the Caribbean, India, and Southeast Asia.
It can be treated with antibiotics like the tetracyclines. Finally, a rare but commonly tested cause of intestinal mucosa defect is Whipple’s disease, which is caused by Tropheryma whipplei.

Whipple’s Disease17:19–18:34

Tropheryma whipplei is a gram positive bacillus that spreads through fecal- oral contamination. Typically, Whipple’s disease involves the small intestine, so just like tropical sprue, it’s another infectious cause of global malabsorption symptoms.
The key distinction here is that it also affects large joints, causing migratory arthralgias. Less commonly it can involve the central nervous system and cause dementia or psychiatric symptoms, or the heart, leading to endocarditis.
The exam will typically describe a middle- aged Caucasian male with global malabsorption, whose small intestine biopsy revealed multiple enlarged, foamy macrophages loaded with granules positive for periodic acid Schiff or PAS stain.
These are actually lysosomes containing partially digested bacteria. It's the glycoprotein in the cell wall of these bacteria colors magenta with this stain.
This disease can be treated with antibiotics like trimethoprim- sulfamethoxazole. Alright, to review, malabsorption syndromes can be caused by either inadequate digestion or absorption of nutrients.

Review18:34–19:10

Inadequate digestion disorders include exocrine pancreatic insufficiency, which causes global malabsorption, cholestasis, which specifically causes fat malabsorption and lactose intolerance, which only affects lactose absorption.
Inadequate absorption disorders include intestinal mucosal defects like celiac disease, tropical sprue and Whipple disease, and they all cause global malabsorption.
Okay, let’s not forget about George and Yasmin! George, the 53-year old man, had steatorrhea, weight loss and postprandial abdominal pain which suggest exocrine pancreatic insufficiency, The fact that he’s a chronic alcohol user also supports this diagnosis and the pancreatic calcification on x-ray confirms the presence of chronic alcoholic pancreatitis.

Summary19:10–20:09

He was given capsules of pancreatic enzymes, started on individual and group therapy and now he is doing much better! Yasmin, the young girl from Iran, was diagnosed with celiac disease, after detecting elevated serum IgA anti-tissue transglutaminase and anti-endomysial antibodies.
What’s impressive is that her only symptoms were failure to thrive and dermatitis herpetiformis! After eliminating gluten from her diet, her height and weight have improved dramatically and the rash has disappeared.