1. DIARRHEA A pathophysiological Approach to Diagnosis and Treatment Prof. J. Zimmerman Gastroenterology Hadassah-Hebrew University Medical Center

2. Diarrhea = Increased loss of water from the GI tract

3. Diarrhea is a common complaint. In the USA, >3.5 million outpatient visits for diarrhea occur each year.

4. About 10 liters of fluid pass daily through the GI Tract Volume, ml/day

5. 10 L 6 L absorbed 2.5 L absorbed JEJUNUMILEUM COLON 4 L 1.5 L 1.4 L absorbed 0.1 L

6. Water Absorption in the GI Tract Water movement in the GI tract is passive and follows osmotic gradients. The efficiency of water absorption is highest in the colon. The normal colon can absorb as much as 4-5 L of water daily.

7. Motility of the Intestine and Colon Normal motor functions are essential for absorption. Regulated gastric and ileal emptying facilitate reabsorption of electrolytes and fluid. Normally, the transit time through the small bowel is about 3 hours.

8. DEFINITIONS OF DIARRHEA As a symptom: Abnormal frequency: > 3 bowel movements/day; Abnormal consistency: increased stool fluidity; As a sign: Stool weight >200 g/day;

9. “Diarrhea” must be distinguished from: Hyper defecation: Passage of stool of a normal consistency ≥3 times/day; AND FROM Incontinence

10. CLINICAL CLASSIFICATION OF DIARRHEA BY TIME COURSE (ACUTE vs. CHRONIC); BY VOLUME (LARGE vs. SMALL); BY PATHOPHYSIOLOGY (OSMOTIC vs. SECRETORY); BY STOOL CHARACTERISTICS (WATERY, FATTY or INFLAMMATORY); BY EPIDEMIOLOGY AND CLINICAL BACKGROUND (TRAVEL, ANTIBIOTICS, etc.) ;

11. ACUTE DIARRHEA (< 4 week duration): Most Likely Causes Infection; Food poisoning; Medications; Initial presentation of chronic diarrhea;

12. INFECTIONS THAT CAUSE DIARRHEA Bacteria Shigella, salmonella, campylobacter jejuni, C. difficile; E. coli, vibrio, aeromonas, yersinia Viruses Rotavirus, adenovirus, norovirus Parasites/protozoa Giardia, E. histolytica, cryptosporidium, microsporidia, cyclospora.

13. MEDICATIONS THAT CAUSE DIARRHEA (1) Acid reducing agents (PPI, H 2 blockers) Antacids Antiarrhythmic (quinidine) Antibiotics Anti-inflammatory (NSAIDs) Antihypertensives (  -blockers)

14. MEDICATIONS THAT CAUSE DIARRHEA (2) Antineoplastic agents Antiretroviral agents Colchicine Heavy metals Prostaglanding analogs (misoprostol)

15. Workup of Diarrhea: Obey Sutton’s Law Willie Sutton 1901-1980

16. Stool Examination in Diarrhea Microscopy (WBC, RBC, parasites); Cultures; C. difficile toxin (when appropriate); Giardia antigen (if appropriate); IN CHRONIC DIARRHEA: Occult blood; Fecal fat; Stool [Na + ] and [K + ]; pH (if < 6 indicates CHO malabsorption) ; Laxative screen;

17. Diagnostic Importance of Fecal WBC Abundant WBC No or few WBC Infections: dysenteryviral C. difficile, amebafood poisoning IBDmedications Ischemialaxative abuse Irradiationsteatorrhea

18. CHRONIC DIARRHEA WATERY FATTY INFLAMMATORY

19. CHRONIC WATERY DIARRHEA Osmotic Secretory

20. Water Transport in the GI Tract The intestinal epithelium cannot maintain an osmotic gradient. The luminal content from the duodenum to the rectum is iso- osmotic (about 290 mOsmol/kg).

21. OSMOTIC DIARRHEA Caused by the presence of unusual amount of poorly absorbable, osmotically active solute in the lumen

22. Causes of Osmotic Diarrhea Disaccharidase deficiency; Monosaccharide malabsorption (fructose-corn syrup in soft drinks); Ingestion of nonabsorbable materials CHO: sorbitol, lactulose, mannitol Minerals: MgSO 4, Na 2 SO 4, Na citrate, antacids Generalized malabsorption

23. SECRETORY DIARRHEA Intestinal ion secretion or inhibition of normal active ion absorption

25. Causes of Secretory Diarrhea Enterotoxins (cholera, E. coli); Secretagogues elaborated by tumors (VIP, calcitonin); Laxatives (ricinoleic acid, phenol- phthalein, oxyphenisatin, aloe, senna); Bile acids/ FFA (in the colon); Congenital defects;

26. Differentiation between Osmotic and Secretory Diarrhea Effect of fasting; Volume; Stool electrolytes and osmotic gap;

27. CHARACTERISTICS OF OSMOTIC AND SECRETORY DIARRHEA OSMOTIC SECRETORY Volume, L/day: 1 Fasting (48 hrs): stopscontinues

28. Calculation of Stool Osmotic Gap The osmolarity of fecal fluid as it exits the rectum is close to that of plasma, i.e. 290 mOsmol/Kg. The osmolarity of fecal fluid can be estimated from the ion concentrations: ([Na + ] + [K + ]) x 2 An osmotic gap is the difference between this value and 290. A gap of up to 50 is normal.

29. OSMOTIC AND SECRETORY DIARRHEA: FECAL FLUID ANALYSIS OSMOTICSECRETORY [Na + ], meq/L30100 [K + ], meq/L30 40 [Na + ]+[K + ]60140 2x([Na + ]+[K + ])120280 Solute gap170 10

30. 0 50 100 150 200 250 300 OsmoticSecretory X Anions K Na OSMOLALITY, mOsmol/Kg

31. Osmotic and Secretory Diarrhea In secretory diarrhea, calculated stool osmolarity is close to 290. The osmotic gap is <50. In osmotic diarrhea, the stool osmolarity, as estimated from the fecal ion concentrations, is lower by more than 50 from a value of 290.

32. ABNORMAL MOTILITY AND DIARRHEA BOTH A RAPID AND A SLOW TRANSIT TIME MAY CAUSE DIARRHEA. A RAPID TRANSIT TIME PREVENTS ADEQUATE TIME FOR ABSORPTION (INTESTINAL HURRY). THE MECHANISM INVOLVES DYSFUNCTION OF THE ENTERIC NERVOUS SYSTEM. EXAMPLES: DIABETES, POST- VAGOTOMY, AMYLOIDOSIS, IBS.

33. ABNORMAL MOTILITY AND DIARRHEA (2) SLOW TRANSIT TIME PROMOTES BACTERIAL OVERGROWTH AND MAY CAUSE MALABSORPTION AND DIARRHEA.

34. COMPLEX DIARRHEA Many of the clinically significant diarrheas are complex and have both osmotic and secretory components.

35. Chronic Diarrhea ( >4 weeks’ duration): Most Likely Causes Lactase deficiency; IBS; IBD; Infections, mainly parasitic; Medications and food supplements; Previous surgery; Endocrine: DM, hyperthyroidism, Addison’s disease;

36. Diarrhea Evaluation (1) Dietary history: Intake of lactose, sorbitol, fructose, caffeine; Medications: antacids, antibiotics, quinidine, colchicine, Fe, etc. Abdominal pain; Tenesmus, rectal bleeding, mucus; Intermittent diarrhea and constipation; Nocturnal diarrhea; Exposure to infectious agents (travel, sexual preferences);

37. Diarrhea Evaluation (2) Past surgical procedures (vagotomy, gastrectomy, cholecystectomy, others); Desire to reduce weight; Family history (cancer, IBD, celiac);

38. Clues to diagnosis- Additional Symptoms SxDx Fever infection, IBD, TB, Ly Weight loss malabsorption, cancer, thyrotoxicosis Flushing Carcinoid

39. Clues to diagnosis- Associated Diseases DISEASEDx Liver diseaseIBD, cancer Chr. Lung diseaseCF Peptic ulcer ZE syndrome Frequent infectionsIg deficiency

40. Clues to diagnosis- Physical Findings FindingSuggested Dx Arthritis IBD, infection, Whipple’s disease LymphadenopathyLy, AIDS, Whipple NeuropathyDM, amyloid Postural hypotensionDM, Addison

41. Diarrhea Evaluation Physical Examination SEVERITY CAUSE HYPOVOLEMIA? FEVER? ABDOMINAL FINDINGS?

42. Diarrhea Evaluation Physical Examination SEVERITY CAUSE Clubbing; Abdominal mass or tenderness; Perianal disease; Rectal examination

43. Chronic Diarrhea Exclude medications and surgery BloodFeaturesPain No blood; p.r.Suggest relieved features of malabsorptionwith BM malabsorption Colonoscopy small bowel Bx ?IBS?CHO malabsor + Bx etc. Screenlactose BT

44. REFERENCE Sleisenger and Fordtran’s Gastrointestinal and liver disease. Chapter on diarrhea contains many useful tables of DD’s of diarrhea in different clinical settings.