Lecture 3: GI Diarrhea & Malabsorption

Intraluminal digestion

proteins, carbohydrates & fats are broken down in Gut Lumen before absorption

Terminal digestion

hydrolysis of carbohydrates & peptides by disaccharidases & peptidases in brush border of the small intestinal mucosa

Transepithelial transport

nutrients, fluid, & electrolytes are transported across & processed within the small intestinal epithelium

Lymphatic transport

of absorbed lipids

Malabsorption defect in chronic pancreatitis

Intraluminal digestion

Malabsorption defect in cystic fibrosis

Intraluminal digestion

Malabsorption defect in disaccharide deficiencies

Terminal digestion

Malabsorption defect in Whipple Disease

Lymphatic Transport

Malabsorption defect in Abetalipoproteinemia

Transepithelial transport

Celiac Disease (Sprue)

Gluten-sensitive Enteropathy; Nontropical Sprue

common in Europeans, less in East Asians, Africans

MHC II alleles HLA-DQ2 or DQ8 confer susceptibility

Negative genetic testing virtually excludes Celiac Disease

Chronic disease with nutrient Malabsorption caused by immune-mediated injury to small intestinal mucosa due to exposure to wheat Gliadin, an alcohol soluble, degradation resistant protein in Gluten

Celiac Disease Pathogenesis

Gluten is digested by the intestinal luminal & brush border enzymes to α-Gliadin peptide (resistant to further degradation)

α-Gliadin → epithelial cells to secrete IL-15 → recruits & activates T-cells (CD8+ Intraepithelial lymphocytes/IEL) + epithelial expression MIC-A, which is an antigenic target for T-cells → epithelial damage that enhances passage of additional α-Gliadin into lamina propria where it is Deamidated by Tissue Transglutaminase

Deamidated Gliadin is then presented by APC MHC II (DQ2 or DQ8) to CD4 Lymphs, which become activated & secrete Cytokines that do further tissue injury & induce B-cell Autoantibody production

Enterocyte injury results in villous atrophy → decreased absorptive surface

Celiac Disease

Celiac Disease Morphology

Second (Descending) part of duodenum & proximal jejunum demonstrate Dx changes best

↑ intraepithelial T-lymphocytes (CD8+/CTLs) are first sign with plasma cells, eosinophils, & mast cells in upper lamina propria

Atrophy or total loss of villi (blunted villi/flat mucosa like the colon)

↑ Crypt mitotic activity

Bx changes alone are not specific for celiac disease

Celiac Disease Clinical Features

Malabsorptive diarrhea, weight loss, fatigue

Onset at age 6-14 months with introduction of gluten → failure to thrive; weight loss, wasting, abdominal distension; chronic diarrhea

Older children often atypical

Deficiencies in Iron (refractory to oral therapy), Vit D (Osteopenia), calcium, vitamin B12, folic acid, zinc

Dermatitis Herpetiformis - vesicular skin rash with deposits of IgA

IgA anti-TG antibodies

IgA antiendomysial antibodies

Environmental Enteric Dysfunction (Tropical sprue)

poor sanitation

No accepted diagnostic criteria; No single infectious agent identified

reported to have variable immune cell infiltrates & variable villous atrophy

Oral antibiotics or nutritional supplementation do not reverse or prevent

irreversible failures of development (height, weight, cognition)

Autoimmune Enteropathy

severe persistent diarrhea & autoimmune disease that occurs most often in young children

IPEX (immune dysregulation, polyendocrinopathy, enteropathy) affects the FOXP3 gene on the X-Chromosome involved in Th4 regulatory cell function

↑ IELs & polys in small bowel but not to the extent seen in celiac disease

What drug causes intestinal morphologic features indistinguishable from celiac disease?

Olmesartan enteropathy/sprue

Olmesartan is an Angiotensin Receptor Blocker (ARB) for treatment of hypertension

Median onset: 3 years of medication (early reported case 6 months)

Clinically & histologically identical to celiac disease, EXCEPT:

has negative celiac serology (no Ab) & no response to gluten-free diet

is Reversible on upon discontinuation

Cystic Fibrosis

mutation of CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) which transports Cl- ions across epithelial membranes

dehydration of luminal secretions

Thick, viscous duct contents can form obstructing intraductal concretions, creating duct dilations (cysts) & insufficiency of pancreatic enzyme secretions into the duodenal lumen

Process begins in utero

Chronic low-grade pancreatitis (autodigestion) persists→ Exocrine Pancreatic insufficiency

Pancreatic Insufficiency impairs intraluminal digestion resulting in Malabsorption

Lactase Deficiency

Lactose → Glucose & Galactose by the brush-border enzyme Lactase to enable absorption by the villus enterocytes

Without Lactase, Lactose cannot be absorbed & remains in the gut lumen → exerts an osmotic force to draw water → diarrhea

Congenital (explosive diarrhea; often fatal prior to availability of soy-based infant formula)

Acquired (↓ Lactase gene expression with age or temporarily after enteric viral or bacterial infections)

Abdominal fullness, diarrhea, flatulence (fermentation of Lactose by colonic bacteria produce Hydrogen gas)

Diarrheal stool > 50 mOsm than plasma

Decreased lactase activity

Abetalipoproteinemia

Duodenal Enterocytes with a clear cytoplasm (due to lipid accumulation)

Abetalipoproteinemia

Acanthocytosis of RBCs

Abetalipoproteinemia

Autosomal Recessive

Presents in infancy as failure to thrive, Diarrhea, Steatorrhea

Caused by inability to transfer lipids to Apolipoprotein B to make Lipoproteins

Defect in Microsomal TG transfer protein (MTP) → lipids stay inside enterocytes

Plasma is devoid of all Lipoprotein particles containing Apolipoprotein B

Blind loop/Small Bowel Bacterial Overgrowth (SBBO) syndrome

chronic watery diarrhea and/or steatorrhea, & with anemia due to B12 deficiency

Weight loss & abdominal pain

Bacterial overgrowth in the small bowel in areas of stagnation or slowing of peristaltic stream stricture, stenosis, fistulas, diverticula, complication of abdominal surgery that create blind loops (Gastrojejunostomy; “bowel-shortening” surgery for obesity,), impaired intestinal motility (Diabetic Autonomic Neuropathy), Systemic Sclerosis, loss of gastric acidity, radiation to the abdomen, Crohn disease, hypogammaglobulinemia

Chronic diarrhea & malabsorption occur due to bacterial overgrowth & recurrent GI infections

Cholera

Vibrio Cholera, a comma-shaped Gram-Negative bacterium

Spread via human Fecal contamination of drinking water

Causes a Secretory watery diarrhea via Cholera toxin by stimulation of cAMP which opens CFTR to secrete Cl- into the intestinal lumen

Most cases asymptomatic or mild diarrhea

Severe symptomatic disease:

rice water stools with flecks of mucus

Diarrhea leads to dehydration → relative polycythemia, anuria, electrolyte loss with muscle cramping; hypotension; hypovolemic shock, & w/o therapy, often death

Fluid replacement

Antibiotics for severely ill

Prophylactic Vaccine available

Campylobacter jejuni

comma-shaped, flagellated, gram-negative

traveler's diarrhea & food poisoning

Infections are most often associated with ingestion of improperly cooked chicken, but outbreaks can also be caused by unpasteurized milk or contaminated water

Morphology: colonic neutrophilic cryptitis or crypt abscesses

Watery diarrhea, either acute or following an influenza-like prodrome

dysentery (bloody diarrhea)

Infection can result in Reactive Arthritis, primarily in HLA-B27 +

Erythema Nodosum & Guillain-Barré syndrome via molecular mimicry to nervous system gangliosides

Shigellosis

gram-negative facultative anaerobe

Bloody diarrhea (Dysentery)

Humans are only reservoir; highly transmissible by the fecal-oral route or via contaminated water, food

Resistant to gastric acid → invade M cells over Peyer Patches first → escape into lamina propria & cause inflammation & invade epithelial cells from below causing aphthous ulcers

Shigella Dysenteriae serotype 1 also releases Shiga toxin (Stx/Verotoxin) → inhibits eukaryotic protein synthesis → cell damage/death including systemic endothelial cell injury → HUS (Hemolytic-Uremic syndrome)

Self-limited disease characterized by 7-10 days of Diarrhea, fever, & abdominal pain

Watery diarrhea → dysenteric phase; constitutional symptoms can persist for as long as 1 month

Antibiotics shorten clinical course & duration of bacterial shedding in stools

Reactive Arthritis that preferentially affects HLA-B27–positive men 20-40 years old

Toxic megacolon & intestinal obstruction are rare

Salmonella

gram-negative bacilli

Salmonella typhi (cause of Typhoid Fever) & nontyphoid Salmonella Enteritidis

Infection is most common in young children & older adults, with peak incidence in the summer & fall

Salmonella is transmitted via contaminated food, particularly raw or undercooked meat, poultry, eggs, & milk

Vaccines are available for both humans & farm animals

Loose stools to cholera-like profuse diarrhea to dysentery

Fever often resolves within 2 days, but diarrhea can persist for a week, & organisms can be shed in the stool for several weeks

Antibiotic therapy is not recommended as it can prolong the carrier state or cause relapse & does not shorten the duration of diarrhea

Antibiotics are indicated for Salmonella typhi

Reactive arthritis, meningitis, & even death, particularly in patients with malignancies, immunosuppression, alcoholism, cardiovascular dysfunction, sickle cell disease, or hemolytic anemia

Typhoid Fever (Enteric Fever)

Salmonella typhi & S. paratyphi
Humans are only reservoir

person to person or via food or contaminated water

Chronic carrier states are associated with Gallstone colonization as biofilms

S. typhi disseminates via lymphatic & blood vessels causing systemic reactive hyperplasia of lymphoid tissues

S. typhi is resistant to gastric acid & initially invade via small intestinal M cells

Terminal Ileum Mucosal Lymphoid Hyperplasia: Enlargement of mucosal Peyer’s patches (plateau-like, well delineated elevations)

Oval mucosal ulcerations oriented along the long axis of the ileum, overlying hyperplastic Peyer’s patches are a risk of perforation

Mesenteric lymphadenopathy

Splenomegaly: soft; homogenous due to diffuse infiltrates of macrophages

Typhoid nodules: macrophage aggregates surround necrosis in liver, bone marrow, lymph nodes

Symptoms/Stages of Typhoid Fever

Abd. pain, anorexia, nausea, vomiting, bloody diarrhea

Sepsis; bacteremia: fever, chills, flu-like

Blood cultures usually positive

Relative Bradycardia; Neutropenia

Abdominal pain from hepatosplenomegaly

Rose spots: Maculopapular erythema anterior trunk

S. typhi may be cultured from biopsy

Ulceration Peyer’s patches, GI bleeding/risk of perforation & shock

Systemic complications include inflammation of CNS, heart, lungs

Gallstone biofilm colonization → resistant to Antibiotics → chronic carrier state

Antibiotics halt progression

Yersinia Enterocolitica + Pseudotuberculosis

Ingestion of pork, raw milk, contaminated water & tend to cluster in the winter

Preferentially involves the Ileocecum

Peyer’s patch lymphoid hyperplasia/ apthous ulcers

Abdominal pain, N & V, & abdominal tenderness, Fever & diarrhea

Pharyngitis, arthralgia, & erythema nodosum

Peyer patch invasion with Mesenteric Adenitis can mimic acute Appendicitis (Pseudoappendicitis)

In teenagers & young adults can also cause Appendicitis (Granulomatous)

Enteritis & colitis predominate in younger children

Reactive arthritis with urethritis & conjunctivitis (Reiter Syndrome), myocarditis, erythema nodosum, & kidney disease

Antibiotics for severe cases

Escherichia Coli

gram-negative bacilli

fecal-oral route (contaminated food or water), except for EHEC which has a natural reservoir in cows

Enterotoxigenic E. coli (ETEC)

Principal cause of traveler's diarrhea

Noninvasive but secrete heat-labile (LT) & heat-stable (ST) toxins → watery diarrhea

minimal histologic changes (Non-inflammatory)

Dehydration & shock

Enteropathogenic E. coli (EPEC)

endemic diarrhea + diarrheal outbreaks, particularly in children less than 2 years of age

bacteria attach tightly to small enterocyte apical membranes & cause local loss of microvilli & cause watery diarrhea

Enterohemorrhagic E. coli (EHEC)/Shiga-toxin producing (STEC)

E. coli O157:H7 or non-O157:H7 serotypes

Inadequately cooked ground beef (natural reservoir in cows) or contaminated milk & vegetables

Bloody diarrhea & Shiga-like toxins → systemic endothelial injury → Hemolytic-Uremic Syndrome

Antibiotics are not recommended (bacterial killing releases the Shiga-like toxins & ↑ risk of HUS, especially in children)

Enteroinvasive E. coli (EIEC)

Bacteriologically like Shigella, but do NOT produce toxins

Usually watery diarrhea

Common among young children in third world

Enteroaggregative E. coli (EAEC)

“stacked brick” morphology when bound to epithelial cells

Causes non-bloody diarrhea in children & adults worldwide, including traveler's diarrhea

Pseudomembranous Colitis

caused by Clostridioides difficile

Diarrhea due to disruption of normal colonic microbiota by antibiotics that allows overgrowth of toxigenic strains of C. difficile

spore-forming, Gram-positive anaerobic bacillus, exotoxins → mucosal injury & inflammation (toxin A & toxin B)

diarrhea in hospitalized patients

Risk factors for toxigenic C. difficile-associated colitis include antibiotic Rx, advanced age, hospitalization & immunosuppression

fever, leukocytosis, abdominal pain, cramps, watery diarrhea & dehydration

Toxic megacolon, marked dilatation of the colon, resulting from marked injury to the colonic wall

C Diff Lab Testing

PCR assays for genes encoding toxins

Culture not useful

Enzyme immunoassay detects both Toxin A & Toxin B separately (both A & B must be assayed)

Fecal leukocytes & occult blood may be present

Patients with formed stools should not be tested for C. difficile!

Colonized patients may be test positive for toxigenic C. Diff. & have no symptoms!

Dx requires both detection of toxigenic C. difficile + clinical symptoms or characteristic pseudomembranous colitis by biopsy histopathology

C diff

“Volcanic eruption” or “Mushroom clouds” (mucopurulent exudate extends from abscessed crypts into the lumen)

C diff

“Volcanic eruption” or “Mushroom clouds” (mucopurulent exudate extends from abscessed crypts into the lumen)

C diff

Surface epithelium denuded; lamina propria infiltrated by neutrophils

Pseudomembranes = plaque-like adhesion of purulent/necrotic debris to mucosa

C diff

Pseudomembrane

C diff

Pseudomembrane

C diff

C diff

Crypt abscess with mucosal explosive or volcano lesions

Whipple Disease

Caused by infection & proliferation gram-positive Actinobacterium, Tropheryma whipplei

Bacteria-laden macrophages accumulate within the small intestinal lamina propria & mesenteric lymph nodes, causing Lymphatic Obstruction

Malabsorptive diarrhea due to impaired lymph drainage

Malabsorptive diarrhea, weight loss, & arthralgia

Extraintestinal symptoms may precede malabsorption: arthritis, fever, lymphadenopathy, & neurologic, cardiac, or pulmonary disease

Bacteria-laden macrophages can accumulate

Endoscopic small bowel

Periodic acid-Schiff (PAS) + AFB - Macrophages in lamina propria

Antibiotics long term (1-2 years)

Whipple Disease

effacement of lamina propria by a sheet of distended macrophages

Whipple Disease

effacement of lamina propria by a sheet of distended macrophages

Intestinal Tuberculosis (Mycobacterium Tuberculosis)

immigrants, immunosuppressed

GI tract may be involved without active pulmonary disease

Ileo-cecal region of intestine is most commonly affected

mucosal destruction causes malabsorption; strictures & fistulae

Biopsy also may contain granulomas

Mycobacterium via AFB stain, PCR or culture of biopsy tissue

mycobacteria are also positive with acid-fast stain

Norovirus

Humans are only reservoir

Transmission: contaminated food or water or via person-to-person fecal-oral transmission, & includes airborne droplets & fomites

vomiting; cramping abdominal pain; watery diarrhea; headache, chills, myalgias

Small bowel ↑ intraepithelial & lamina propria lymphocytes & crypt hypertrophy

Can cause chronic diarrhea in the immunocompromised

Many people are “Non-secretors” & are resistant to infection because they lack the carbohydrate groups that serve as ligands for viral infection

Rotavirus

Rotavirus infects & destroys small bowel mature enterocytes with loss of absorptive function

Usually asymptomatic in adults, but may cause diarrhea

Rotavirus vaccine

Adenovirus

pediatric diarrhea

also affects immunocompromised patients

diarrhea, vomiting, & abdominal pain

Fever may also be present

Strongyloides

entire life cycle inside patient (Autoinfection)

infection persists for life & in immunosuppression can lead to overwhelming infection

Entamoeba histolytica (Amebiasis)

Fecal-oral spread

abd pain, bloody diarrhea, weight loss

Cecum, ascending colon most involved

flask-shaped mucosal ulcers which can coalesce

Ameba resemble macrophages; ingest RBCs

Liver abscess with dysentery

Rx: Metronidazole

Giardia intestinalis (lamblia)

Water-borne by fecal contamination; not killed by chlorine

Flagellated protozoan in two forms

Cyst form enables fecal-oral infection

Trophozoites: Multiply in duodenal lumen; flagella; binucleate; adheres to brush border of villous enterocytes but do not invade

Parasite proteins damage brush border

enzymes decreased, including lactase

microvillous damage; apoptosis may lead to blunted villous processes

Clinical forms: subclinical, acute diarrhea, chronic diarrhea, constipation

Malabsorptive diarrhea (steatorrhea; weight loss)

Severe in malnourished individuals or in IgA deficiency or agammaglobulinemia (plasma cells absent in lamina propria)

Acquired lactase deficiency

Recurrence/relapse common (continuously modifies major surface antigen)

Treatment: Metronidazole

Giardia

Giardia

Giardia

Giardia

Cryptosporidium

Massive, persistent watery diarrhea

Acute self-limited disease in immunologically normal hosts

may cause traveler’s diarrhea

oocysts resistant to chlorine

Species include C parvum & C. hominis

Ingested oocysts activated by by gastric acid; attach to enterocyte brush border forms vacuole

Pathogenesis of diarrhea: sodium malabsorption; chloride secretion; tight junction permeability

infectious enterocolitis GI Panel

Multiplex PCR stool testing that can be done in an hour