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EXMD 509B: INTESTINAL MALABSORPTION AND DIARRHEA: Winter 2015.

Gary E. Wild, MD

EXMD 509B: INTESTINAL MALABSORPTION AND DIARRHEA: Winter 2015. Gary E. Wild, MD

G.I. Secretion & Absorption: the Balance Sheet

8.9 L Total absorbed by intestine
8.9 L
Total absorbed
by intestine

Intestinal Morphology

Intestinal Villus and Microvilli

Intestinal Villus and Microvilli Stem cells Secretory cells

Stem

cells Secretory
cells
Secretory

cells

The Large Intestine

The Large Intestine
Malabsorption and Maldigestion
Malabsorption and Maldigestion
•  Maldigestion is a defect in the hydrolysis of nutrients. •  Malabsorption is a defect
•  Maldigestion is a defect in the hydrolysis of
nutrients.
•  Malabsorption is a defect in the mucosal
absorption of nutrients and can occur in
multiple phases:
ü  Luminal phase – contact with digestive enzymes.
ü  Mucosal phase – absorption in the required
constituent form.
ü  Delivery phase – uptake into the cytoplasm and
delivery to lymphatics or portal venous system
constituent form. ü  Delivery phase – uptake into the cytoplasm and delivery to lymphatics or portal
Carbohydrate Malabsorption
Carbohydrate Malabsorption
•  Starch, sucrose and lactose comprise 85% of ingested carbs. •  Carbohydrate malabsorption caused by
•  Starch, sucrose and lactose comprise 85% of
ingested carbs.
•  Carbohydrate malabsorption caused by (1)
absolute or functional decreased mucosal
surface area, or, (2) decreased disaccharidases
or transporters.
•  Non-absorbed carbs increase osmolality in the
lumen and water enters lumen to maintain
isosmotic state. Non absorbed carbs are
fermented by colonic bacteria.
in the lumen and water enters lumen to maintain isosmotic state. Non absorbed carbs are fermented
Carbohydrate Malabsorption
Carbohydrate Malabsorption
•  Lactase deficiency is most common cause of carb malabsorption. •  Congenital lactase is rare.
•  Lactase deficiency is most common cause of
carb malabsorption.
•  Congenital lactase is rare. Primary lactase
deficiency has delayed onset and is common in
North America, Africa and Asia.
•  Acquired lactase deficiency can occur after
mucosal resection, mucosal disease or in the
post infectious state following gastroenteritis.
can occur after mucosal resection, mucosal disease or in the post infectious state following gastroenteritis.
Symptoms and Diagnosis
Symptoms and Diagnosis
•  Symptoms: Gas, bloating and osmotic diarrhea. •  Diagnosis: ü  Dietary history. ü  Increased stool
•  Symptoms: Gas, bloating and osmotic diarrhea.
•  Diagnosis:
ü  Dietary history.
ü  Increased stool osmotic gap.
ü  Stool pH < 6
ü  Hydrogen BT showing an increase of 20 ppm above
baseline which is indicative of colonic fermentation
of unabsorbed carb. False +ve from bascterial
overgrowth and False –ves from recent treatment
with antibiotics or from non H producers
False +ve from bascterial overgrowth and False –ves from recent treatment with antibiotics or from non
Fat Malabsorption
Fat Malabsorption
•  Fat absorption requires competent pancreas, liver, small bowel and lymphatics. •  Triglycerides are the
•  Fat absorption requires competent pancreas, liver, small bowel
and lymphatics.
•  Triglycerides are the major form of dietary fat.
•  Pancreatic lipase is the major hydrolytic enzyme and breaks down
TG into fatty acids and beta monoglycerol. The pH optimal is 8. It
can be inactivated by overproduction of acid.
•  Hepatic derived conjugated bile salts combine with these
constituents to form micelles which enter enterocytes.
•  TG are re-esterified and synthesized into chylomicrons which are
exported into lymphatics.
enter enterocytes. •  TG are re-esterified and synthesized into chylomicrons which are exported into lymphatics.
Fat Malabsorption
Fat Malabsorption
•  Medium chain TG do not require micellar formation and pass directly into portal blood.
•  Medium chain TG do not require micellar formation and pass
directly into portal blood.
•  Clinical features: Steatorrhea, weight loss and complications
from fat soluble vitamin deficiencies A,D, E and K.
•  Diagnosis: > 14 g of fat in a 3 day stool collection on a 100 g/d
fat diet.
•  Need to determine cause of fat malabsorption
ü  Small bowel (D-xylose testing)
ü  Pancreatic (imaging, lab, endoscopic)
to determine cause of fat malabsorption ü  Small bowel (D-xylose testing) ü  Pancreatic (imaging, lab, endoscopic)
Protein Malabsorption
Protein Malabsorption
•  Dietary proteins are cleaved initially by gastric pepsin (active at pH 1-3; inactive at
•  Dietary proteins are cleaved initially by gastric
pepsin (active at pH 1-3; inactive at pH > 5).
•  Pancreatic trypsin is activated by duodenal
derived enterokinase. Trypsin further activates
a series of pancreatic proteases which cleave
proteins into peptides and AA’ s.
•  Brush border oligopeptidases cleave small
peptides and subsequent OPD and free AA’ s
are transported into the enterocyte.
border oligopeptidases cleave small peptides and subsequent OPD and free AA’ s are transported into the
Protein Losing Enteropathy
Protein Losing Enteropathy
•  Loss of protein from intestinal tract. •  Liver attempts to compensate. •  Three categories
•  Loss of protein from intestinal tract.
•  Liver attempts to compensate.
•  Three categories
ü  Diseases with increased mucosal permeability
without erosions.
ü  Diseases with mucosal erosions.
ü  Diseases with increased lymphatic pressure.
permeability without erosions. ü  Diseases with mucosal erosions. ü  Diseases with increased lymphatic pressure.
Clinical Features
Clinical Features
•  Diarrhea, edema, ascites, possible concomitant CHO and fat malabsorption. •  Low serum protein, albumin
•  Diarrhea, edema, ascites, possible concomitant
CHO and fat malabsorption.
•  Low serum protein, albumin and Ig’ s (except
IgE).
•  Lymphopenia in setting lymphangiectasia.
•  Diagnosed by measuring absorption of
“ marker ” alpha-1-antitrypsin.
Lymphopenia in setting lymphangiectasia. •  Diagnosed by measuring absorption of “ marker ” alpha-1-antitrypsin.
Causes of Protein Losing Enteropathy
Causes of Protein Losing Enteropathy
Causes of Protein Losing Enteropathy
Mechanisms of Malabsorption
Mechanisms of Malabsorption
Mechanisms of Malabsorption
Mechanisms of Malabsorption
Mechanisms of Malabsorption
Mechanisms of Malabsorption
Diarrhea
Diarrhea
•  Mechanisms ü  Decreased absorption (Villous function) ü  Increased secretion (Crypt function) ü  Both
•  Mechanisms
ü  Decreased absorption (Villous function)
ü  Increased secretion (Crypt function)
ü  Both
•  Mechanisms ü  Decreased absorption (Villous function) ü  Increased secretion (Crypt function) ü  Both
Inflammatory vs Non-Inflammatory
Inflammatory vs Non-Inflammatory
•  Inflammatory diarrhea (IBD, invasive pathogens, ischemia, radiation) ü  Abdominal pain ü  Fever ü 
•  Inflammatory diarrhea (IBD, invasive pathogens, ischemia,
radiation)
ü  Abdominal pain
ü  Fever
ü  Tenesmus (urgency to defecate)
ü  Small volume mucoid stool with variable amounts of blood
and leukocytes
•  Non-Inflammatory diarrhea (Toxin producing infections).
ü  Watery diarrhea
amounts of blood and leukocytes •  Non-Inflammatory diarrhea (Toxin producing infections). ü  Watery diarrhea
Stool Osmotic Gap
Stool Osmotic Gap
•  Osmotic diarrhea ü  290 – 2(Na + K) = > 100 •  Secretory diarrhea
•  Osmotic diarrhea
ü  290 – 2(Na + K) = > 100
•  Secretory diarrhea
ü  290 -2 (Na + K) = < 50
•  Osmotic diarrhea ü  290 – 2(Na + K) = > 100 •  Secretory diarrhea ü 
Osmotic vs Secretory Diarrhea
Osmotic vs Secretory Diarrhea
Osmotic vs Secretory Diarrhea
Osmotic vs Secretory Diarrhea
Osmotic vs Secretory Diarrhea
Osmotic vs Secretory Diarrhea

Small Intestinal Resection and Short Bowel Syndrome

Diarrhea and malabsorption can result from any process that shortens the intestine (eg. Surgery, underlying disease). •Determining factors:

üLength resected. üWhat region resection (eg. Proximal vs ileum)

o Concept of intestinal adaptation

üIntegrity of the remaining intestine üPresence of colon

vs ileum) o   Concept of intestinal adaptation ü   Integrity of the remaining intestine ü
Ileal Resection and Bile Salt Reabsorption
Ileal Resection and Bile Salt Reabsorption
•  < 100 cm Ileal Resection. ü  Liver compensates by up regulating production. ü  Increased
•  < 100 cm Ileal Resection.
ü  Liver compensates by up regulating production.
ü  Increased bile salts enter colon an elicit secretory
diarrhea.
ü  Treated with cholestyramine
•  > 100 cm Ileal Resection.
ü  Liver can no longer compensate
ü  Bile salt deficiency ensues leading to steatorrhea
ü  Treatment with MCT ’ s
Liver can no longer compensate ü  Bile salt deficiency ensues leading to steatorrhea ü  Treatment with
Consequences of Ileal Resection
Consequences of Ileal Resection
•  Diarrhea with either excess or deficiency of bile salts. •  B12 deficiency •  Small
•  Diarrhea with either excess or deficiency of bile
salts.
•  B12 deficiency
•  Small intestinal bacterial overgrowth from loss
of ileao-cecal valve.
•  Gallstones from disruption of cholesterol pool
•  Calcium oxalate renal stones
loss of ileao-cecal valve. •  Gallstones from disruption of cholesterol pool •  Calcium oxalate renal stones
Small Intestinal Diseases
Small Intestinal Diseases
•  Celiac disease •  Whipples disease •  Eosinophilic gastroenteritis. •  Intestinal lymphangiectasia
•  Celiac disease
•  Whipples disease
•  Eosinophilic gastroenteritis.
•  Intestinal lymphangiectasia
•  Amyloidosis
•  Whipples disease •  Eosinophilic gastroenteritis. •  Intestinal lymphangiectasia •  Amyloidosis
Celiac Disease
Celiac Disease

Immune response to dietary gliadins (wheat, barley, rye). •Prevalence highest amongst people of European descent. •Prevalence of 1:100 in North America, 1:56 in symptomatic patients, 1:22 in FDR of patients. •Occurs at all ages; 20% over 60. •95% HLA DQ2, 5%HLA DQ8 however 30 to 40% of general population are DQ2 or DQ8.

Occurs at all ages; 20% over 60. •   95% HLA DQ2, 5%HLA DQ8 however 30

Diagnosis

Presence of symptoms congruent with the disease. These range from classic malabsorption to more atypical extraintestinal signs and symptoms. Atypical form is now the most common form of disease presentation. •Supportive serological studies. •Characteristic small intestinal biopsy findings. There are proxy endoscopic markers. •Clinical response to gluten free diet (GFD).

intestinal biopsy findings. There are proxy endoscopic markers. •   Clinical response to gluten free diet
Clinical Features of Celiac Disease
Clinical Features of Celiac Disease
Clinical Features of Celiac Disease
Clinical Features
Clinical Features
Clinical Features
Diseases Associated with Celiac Disease
Diseases Associated with Celiac Disease
Diseases Associated with Celiac Disease
IgA Based Serologic Tests for Celiac
IgA Based Serologic Tests for Celiac
IgA Based Serologic Tests for Celiac
Histology of Celiac
Histology of Celiac
Histology of Celiac
Histology of Celiac
Normal small intestine Celiac Disease
Normal small intestine
Celiac Disease

Normal villi

Villous atrophy

Spectrum of Histologic Findings
Spectrum of Histologic Findings
Spectrum of Histologic Findings
Causes of Villus Atrophy
Causes of Villus Atrophy
Causes of Villus Atrophy
Dermatitis Herpetiformis
Dermatitis Herpetiformis
Dermatitis Herpetiformis
Dermatitis Herpetiformis

Evaluation for Celiac Disease

Patient presents with symptoms of celiac disease

Disease Patient presents with symptoms of celiac disease Perform serologic IgA tTG antibody testing Positive Small

Perform serologic IgA tTG antibody testing

Positive
Positive
disease Perform serologic IgA tTG antibody testing Positive Small bowel biopsy Negative High clinical suspicion? No

Small bowel biopsy

IgA tTG antibody testing Positive Small bowel biopsy Negative High clinical suspicion? No Yes Positive Dx

Negative

tTG antibody testing Positive Small bowel biopsy Negative High clinical suspicion? No Yes Positive Dx confirmed,

High clinical suspicion?

No Yes
No
Yes
Positive
Positive

Dx confirmed, Gluten-free diet

Negative
Negative

F/U and consider Other dx, consider Repeat bx

Small bowel biopsy

and consider Other dx, consider Repeat bx Small bowel biopsy Low probability of celiac disease; consider

Low probability of celiac disease; consider total IgA test to R/O IgA deficiency

Negative
Negative

Positive

total IgA test to R/O IgA deficiency Negative Positive Tx and monitor Improvement? Celiac ruled out,
Tx and monitor

Tx and monitor

Tx and monitor
Tx and monitor

Improvement?

IgA deficiency Negative Positive Tx and monitor Improvement? Celiac ruled out, Look for other cause Yes

Celiac ruled out, Look for other cause

Yes
Yes

No

No

Evaluate for possible secondary cause of symptoms

Dx confirmed
Dx confirmed
Dx confirmed

Dx confirmed

Treatment and Potential Complications

Life long gluten-free diet. •Potential complications:

üUlcerative jejunitis. üRefractory disease. üEnteropathy associated T cell lymphoma üNon-Hodgkins lymphoma. üAdenocarcinoma of intestine üEsophageal cancer

T cell lymphoma ü   Non-Hodgkin ’ s lymphoma. ü   Adenocarcinoma of intestine ü  

Whipple s Disease

Multisystem disease. üDiarrhea üWeight loss üArthritis üCNS findings. •Gram +ve Tropheryma whippelii. •PAS +ve macrophages on small bowel biopsy. +ve PCR reaction. •Treatment with long term antibiotics

•   PAS +ve macrophages on small bowel biopsy. +ve PCR reaction. •   Treatment with