A. Definition

1. Production of loose bowel movements at increased frequency
2. >200-400gm of stool per day (normal ~100-150gm/day)
3. Stools are unformed and watery

B. Pathogenic Classification

1. Infectious Diarrhea (Gastroenteritis)
   1. Viral
   2. Bacterial
   3. Protozoal
2. Food Poisoning
3. Malabsorption
4. Obstruction (post-obstruction)
5. Autoimmune/Inflammatory: Inflammatory Bowel Diseases
6. Secretory Diarrhea (including paraneoplastic)
7. Pharmaceuticals (Iatrogenic)
8. Miscellaneous
9. Expanded Differential Diagnosis - see below

C. Infectious Diarrhea (Gastroenteritis) [2,3]

1. Viral
   1. Common: Noroviruses (small round structured viruses) [10], adenovirus, rotavirus
   2. Uncommon: Hepatitis A, poliovirus, calcivirus, astrovirus, coronavirus, HSV, CMV
2. Bacterial
   1. Common: E. coli, Salmonella ssp, Campylobacter jejuni, C difficle (see below)
   2. Uncommon: Y. enterocolitica, Shigella ssp., Aeromonas ssp., Vibrios cholerae
   3. Increasing: Hemorrhagic E. coli (strains O157:H7, O104:H21; see below) [7]
   4. Rare: Bacillus cereus, chlamydia, syphilis, gonorrhea, Pleslomonas shigelloides
   5. Chronic, particularly AIDS patients: Brachyspira aalborgi (a spirochete)
   6. Other: Listeria monocytogenes (contaminated milk) [4]
   7. Antibiotic Associated (common): C. difficile
   8. Diarrhea in hospitalized patients is most commonly caused by C. difficile
   9. Hemorrhagic colitis associated with antibiotic use (uncommon): Klebsiella oxytoca [5]
   10. Only hemorrhagic (not enteroinvasive, enterotoxigenic, enteropathogenic) E. coli is routinely tested
3. Protozoan
   1. Common: Giardia lamblia, Entamoeba histolytica [6]
   2. Uncommon: Cyclospora, Toxoplasma gondii, Strongyloides
   3. Immunosuppressed: Microsporidia, Cryptosporidia, Isospora
4. Treatment Overview [3]
   1. Rehydration as needed - children and elderly highly suceptible
   2. Treatment of symptoms - bismuth subsalicylate; loperamide if non-bloody
   3. Evaluate for likely cause and treat as needed
5. Overview of Treatment of Adults with Antimicrobial Agents
   1. Traveller's Diarrhea - quinolones are mainstay (resistance to bismuth increasing)
   2. Bloody Diarrhea - usually due to bacteria; quinolones are mainstay
   3. Shigella - ciprofloxacin 500mg po bid x 5d or azithromycin 500mg x1, 250mg/d x 4d
   4. Campylobacter normally sensitive to fluoroquinolones; resistance reported
   5. Salmonella nontyphi - no treatment in mild to moderate disease in healthy host
   6. Salmonella nontyphi - severe disease or unhealthy host or age >50: fluoroquinolone 5-7 days or ceftriaxone 100mg/kg IM or IV
   7. E. coli (except hemorrhagic) - fluoroquinolones 1-3 days; TMP/SMX for susceptible
   8. Hemorrhagic E. coli - avoid antimotility agents and antibiotics
   9. Toxigenic C. difficile - oral vancomycin increasingly first line; metronidazole alternative
   10. Giardia - metronidazole 250-750mg tid for 7-10 days
   11. Cryptosporidium - in AIDS: paramomycin + azithromycin or nitazoxanide
   12. Isospora and/or Cyclospora - TMP/SMX (160/800mg) 7-10 days
   13. Microsporidia - 3 weeks albendazole 400mg bid
   14. Ameba - metronidazole 750mg tid for 5-10 days with iodoquinol 650mg tid x 20 days OR paromomycin 500mg tid for 7 days
6. Children
   1. Lactobacillus is safe and effective for children with acute infectious diarrhea [12]
   2. Watery Diarrhea (children) - oral rehydration therapy, racecadotril (acetorphan, an enkephalinase inhibitor) [13] and/or Lactobacillus [12]

D. Hemorrhagic E. coli O157:H7 Infection [7,8]

1. Overview
   1. Increasingly common cause of acute diarrhea, nearly always (>98%) bloody
   2. 73,000 cases and 60 deaths per year in USA
   3. May be most common cause of infectious bloody diarrhea in USA today
   4. Typically associated with eating undercooked (raw) hamburger or other meats
   5. Transmission from undercooked hamburger, farm animals, contaminated liquids [11]
   6. Also found in contaminated apple cider [9], deer meat [14], other food-borne routes
   7. Hand-washing can substantially reduce risk of transmission
   8. Fever may be low or absent during initial infection
   9. Hemolytic-uremic syndrome develops in 10-30% of cases, usually in children
2. E. coli Strain O157:H7
   1. This strain of E. coli produces at least two Shiga-like toxins
   2. Strains which produce only Type 2 toxin are linked to hemolytic uremic syndrome (HUS)
   3. Strains which produce only Type 1 toxin are rarely associated with HUS
3. Symptoms
   1. Severe abdominal cramps with low fever and initially watery diarrhea
   2. Grossly bloody diarrhea develops in many cases
   3. Associated with develpment of hemolytic uremic syndrome
4. Hemorrhagic colitis
   1. About 45% of E. coli O157:H7 infections lead to hemorrhagic colitis
   2. Of all cases of sporadic hemorrhagic colitis, O157:H7 is found in ~30%
   3. Severe abdominal cramping, nausea and/or vomiting may occur; fever in ~20-30%
   4. Median duration of diarrhea is ~5 days (3-7 days; longer in children)
   5. Mean leukocyte count ~13.5K/µL, often with immature neutrophils (bands)
   6. Note that antibiotic associated hemorrhagic colitis usually due to Klebsiella oxytoca [5]
5. Hemolytic Uremic Syndrome (HUS)
   1. Microangiopathic hemolytic anemia, thrombocytopenia, and renal failure
   2. E. coli O157:H7 has been isolated from majority of patients with HUS
   3. In outbreaks of E. coli O157:H7, ~10% of persons develop HUS
   4. The majority of these patients had blood diarrhea and high fevers
   5. Children with E. coli O157:H7 who receive antibiotics have ~15X increased risk for developing HUS [15]
   6. A minority of patients develop full-blown thrombotic thrombocytopenic purpura (TTP)
   7. Most fatilities occur in age extremes and range ~10-30% in outbreaks
6. Pathology
   1. Severe pathology in ascending and transverse colon
   2. Histology shows comination of ischemic colitis and infectious injury
   3. Pseudomembrane formation (similar to C. difficile colitis) is occasionally seen
   4. The Shiga-like toxins bind through globotriaosyl ceramide and inhibit protein synthesis
7. Diagnosis
   1. Most laboratories now screen for this organism on all stool cultures
   2. Toxin and serological assays are available in some centers
   3. DNA polymerase chain reaction (toxin genes) is investigational
8. Treatment
   1. No specific treatment for organism has been identified
   2. Trimethoprim/Sulfamethoxazole may increase toxin release by bacteria
   3. Ciprofloxacin may decrease toxin production by organism
   4. Anti-motility agents should be avoided (in all infectious diarrhea)
   5. Supportive therapy is mainstay of treatment
   6. Therapeutic plasma exchange for patients who develop HUS/TTP is effective [16]
9. Prevention
   1. Food contamination is major mode of transmission
   2. Thorough cooking will kill the organism and destroy the toxins

E. Rotavirus [17]

1. Major cause of severe diarrhea, mainly in children
2. About 100 deaths per year in USA, and >800,000 deaths / year worldwide
3. Four major serotypes cause disease in humans
4. Genome consists of 11 segments of double-stranded RNA
5. Nitazoxanide (Alinia®) [18]
   1. Thiazolide anti-infective agent
   2. Approved for Cryptosporidium and Giardia
   3. Effective for Entamoeba, Blastocystis, Clostridium difficile
   4. Dose 7.5mg/kg oral bid x 3 days in children with severe rotavirus significantly reduced disease duration from 75 hours (placebo) to 31 hours [18]
6. New Rotavirus Vaccines [19,20]
   1. RIX4414 G1P(8) (Rotarix®): attenuated live human rotavirus vaccine - 2 oral doses [19,27]
   2. Pentavalent human-bovine WC3 reassortment vaccine - 3 oral doses [20]
   3. Both vaccines very effective reducing hospitalizations by 85-95%
   4. Both vaccines reduced severe diarrhea 80-98%
   5. Both vaccines had no increased risk of intussusception compared with placebo
   6. Older rhesus attenuated vacccine (Rotashield®) withdrawn from market due to increased risk of intussusception [21]
   7. RotaTeq vaccine is now FDA approved for infants 6-32 weeks of age

F. Food Poisoning

1. Bacterial: living organisms
   1. Salmonella - chicken, raw eggs, sprouts [22]
   2. Vibrio vulnificus - raw oysters, usually with liver disease or immunosuppression [23]
   3. Hemorrhagic E. coli (see above)
   4. Non-hemorrhagic E. coli - sprouts (diarrhea, urinary tract infection) [22]
2. Toxins
   1. Staphylococcus aureus
   2. Baccilus cereus [24]
   3. Note that these toxins are not part of routine testing

G. Malabsorption Syndromes

1. Lactose intolerance
2. Celiac Disease
3. Pancreatic Insufficiency
4. Zollinger-Ellison Syndrome
5. Whipple's Disease
6. Short bowel syndrome

H. Obstruction (Post-Obstruction)

1. Downstream hyperperistalsis
2. Bacterial Overgrowth in small intestine

I. Inflammatory Bowel Disease

1. Crohn's Disease
2. Ulcerative Colitis
3. Lymphocytic Colitis
4. Collagenous Colitis

J. Secretory Diarrhea

1. Carcinoid
   1. Diarrhea, flushing, right sided heart valve dysfunction
   2. Due to secretion of bioactive amines, usually serotonin (5-hydroxytryptamine)
2. Neuroendocrine Tumors
   1. Gastrinomas (Zollinger-Ellison Syndrome): 66% sporadic, 33% MEN-1 associated
   2. Vasoactive Intestinal Polypeptide producting tumors (VIPoma)
3. Medullary Thyroid Carcinoma (MTC) - spontaneous (less common) or syndromic
4. Villous adenoma of rectum
5. Vibrios cholerae (toxin induced)
   1. Direct toxin effects leading to activated adenylate cyclase
   2. Activation of intrinsic secretomotor (neural) reflex
   3. This neural reflex appears to involve serotonin and substance P
6. WDHHA Syndrome - watery diarrhea, hypokalemia, hypochlorhydria, acidosis
7. Laxative Abuse
8. Evaluation of Secretory Diarrhea with Osmotic Gap Calculation
   1. Osmotic Gap = Stool Osm - 2x{[Na+]+[K+]}Stool < 50 implies secretory diarrhea
   2. Osmotic Diarrhea usually with Osmotic Gap > 50-100 (unabsorbed Osm)
   3. Laxative abuse, some steatorrhea have osmotic gaps >100
   4. Overlap occurs such that using stool osmotic gap for diagnosis is sometimes difficult
   5. In general, if gap is >100 and steatorrhea is ruled out, then laxative abuse is likely

K. Pharmaceuticals

1. Magnesium containing agents (such as Milk of Magnesia®)
2. Chronic Laxative Abuse [13]
   1. Loss of colonic haustra; may lead to malabsorption
   2. Leads to sodium and/or potassium depletion, dehydration
   3. Hypochloremic metabolic alkalosis
   4. Hypocalcemia and/or hypomagnesemia may occur
   5. Melanosis coli - dark brown pigmentation of colon ocurs with anthraquinone laxatives [11]
   6. Anthraquinones, such as senna, have direct toxic effect on epithelial cells
   7. Cecum and rectum are most common sites of melanosis coli
3. Cancer Chemotherapy
4. Lactulose, Sorbitol, Dulcolax®
5. Stool Osm, Na+ and K+, should be obtained; low stool Osm implies Factitious Diarrhea

L. Other

1. Irritable Bowel Syndrome (diarrhea variant) []
2. Ischemic Colitis (mesenteric ischemia)
3. Hyperthyroidism
4. Hypocalcemia
5. Upper GI Bleeding with melena
6. Colon Carcinoma
7. Small Bowel Lymphoma

DIFFERENTIAL DIAGNOSIS [25]
[Figure] "Evaluation of Diarrhea"

A. Bloody Diarrhea

1. Bacterial [3]
   1. Salmonella ssp.
   2. Enteroinvasive E. coli
   3. Enterohemorrhagic E. coli: O157:H7, other shiga-toxin producing strains [7]
   4. Campylobacter jejuni
   5. Yersinia enterocolitica
   6. Shigella ssp. - shiga-toxin producing strains
2. Antibiotic Associated Hemorrhagic Colitis: Klebsiella oxytoca [5]
3. Protozoal: Ameba (amoeba)
4. Inflammatory Bowel Disease (Ulcerative Colitis > Crohn's Disease)
5. Ischemic Bowel Disease: Mesenteric and/or Colonic
6. Diverticulitis
7. Colon Cancer (especially right sided colon Ca)

B. Non-Bloody Diarrhea

1. Viral Diarrheas
   1. Adults - Norwalk and related agents, adenovirus
   2. Children - Rotavirus (most common), echovirus, adenovirus
2. Bacteria [3]
   1. Common: E. coli, Aeromonas
   2. Antibiotic Associated: Clostridium difficile
   3. Immunosuppressed: Mycobacteria, Isospora, Cryptosporidia
   4. Uncommon in USA: Vibrio cholerae (secretory), Campylobacter
   5. Cyanobacteria (blue-green algae)
3. Protozoal
   1. Giardia lamblia
   2. Amoeba
   3. Strongylloides
   4. Cyclospora (usually food-borne, raspberries, others) [26]
   5. Many others, unusual in USA
4. Crohn's Colitis, Ileitis
5. Medications (see above)
6. Irritable bowel syndrome, diarrhea variant
7. Secretory Diarrheas
   1. Infectious: Cholera
   2. Intestinal Polyposis
   3. Hormonal: Carcinoid, Zollinger-Ellison Syndrome

C. Acute versus Chronic

1. Self Limited - probably infectious, usually viral
2. New onset diarrhea versus chronic diarrhea
3. New onset diarrhea in hospitalized patients is usually due to C. difficile
4. Weight loss and Systemic Symptoms should prompt thorough evaluation
5. Malabsorption, when present, is usually due to chronic diarrhea

D. Chronic Diarrhea

1. Chronic / Relapsing Intestinal Infection
   1. Protozoal: Ameba, Giardia
   2. Clostridium difficile
   3. HIV Enteropathy, atypical mycobacterium Infection
   4. Uncommon: other parasites, Strongylloides, Whipple's Disease
2. Inflammatory Bowel Disease
   1. Common: Crohn's Disease, Ulcerative Colitis
   2. Uncommon: Collagenous Colitis, Lymphocytic (microscopic) Colitis
3. Malabsorption Syndromes
   1. Carbohydrate Malabsorption
   2. Pancreatic Insufficiency
4. Endocrinopathy
   1. Adrenal Insufficiency
   2. Abnormal Thyroid Function
   3. Diabetes
   4. Uncommon: Carcinoid Tumors, Mastocytosis, Villous Adenoma
5. Medications: Laxatives, Antibiotics, Magnesium Antacids, Sweeteners
6. Ischemic Bowel Disease
7. Irritable Bowel Syndrome
8. Gut Infiltration (uncommon): scleroderma, amyloidosis, lymphoma
9. Radiation Enteritis / Colitis
10. Colon Cancer
11. Surgical: Short Bowel Syndrome, Gastrectomy, Cholecystectomy

LABORATORY EVALUATION OF DIARRHEA
[Figure] "Evaluation of Diarrhea"

A. Stool Specimens

1. Heme-occult very important but rarely diagnostic
2. Fecal Leukocytes
   1. This is probably the best overall test for differential diagnosi
   2. Inflammatory (infections) versus Non-Infectious
3. Stool Ova and Parasites (3 separate specimens)
4. Stool pH
5. Culture for Enteric Pathogens
   1. Salmonella
   2. Shigella
   3. Yersinia
   4. Campylobacter
   5. E. coli O157:H7
6. Toxin assays
   1. E. coli O157:H7
   2. C. difficile toxin (A and B chains)
   3. Shiga-toxin producing E. coli
7. AIDS Patients: Brachyspira aalborgi (a spirochete) detection (metronidazole sensitive)

B. Other Chemical / Physical Tests

1. Fecal Fat Collection (24-72 hours)
   1. Malabsorption syndromes may be detected with increased fecal fat
   2. Serum fat-soluble vitamin levels may be significantly reduced
2. Test for Laxative Abuse
   1. Alkali solution added to stool sample
   2. Phenolphthalein found in most laxatives and turns red with alkali
   3. Stool osmotic gap may be increased >50 mOsm
   4. Stool magnesium should be <45mMol
3. Other Tests
   1. Hydrogen breath test for bacterial overgrowth
   2. D-Xylose Absorption Test
   3. Schilling's Test
4. Stool Osmololity and Electrolytes
   1. Osmotic versus secretory diarrhea (see above)
   2. Magnesium levels can help with laxative abuse also
   3. In general, stool osm > 100 without steatorrhea makes laxative abuse likely
5. 72 hour fasting as inpatient may provide clues
   1. Infectious and secretory diarrheas will remain continuous
   2. Malabsorptive, Laxative, BIle Acid diarrheas will decrease

C. Radiographic Evaluation

1. Abdominal plain films
2. Barium Enema
3. Upper GI with small bowel follow through
4. Colonic Ultrasound (investigational)

D. Endoscopy

1. Colonoscopy, usually with biopsy
2. Upper Endoscopy with small bowel biopsy (and anti-endomysial antibody)
3. Video assisted small-bowel evaluation may be of some use

Resources

Coefficient of Fat Absorption

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