1. Difficult Diarrheas Arnold Wald, M.D., AGA-F Professor of Medicine University of Wisconsin School of Medicine & Public Health, Madison, WI

2. Case 1: Use of stool analysis for chronic diarrhea A 56-year-old man with an long history of diabetes mellitus presents with a 9-month history of watery diarrhea. The diarrhea occurs nocturnally, and with fasting. The patient eats a diet high in fruits and vegetables, and endorses consumption of sugarless mints on a daily basis. He takes acarbose and glipizide to control his diabetes. A 24-hour stool collection for stool volume and laboratory testing reveals a volume of 1.1 liters, Na 85, K 38, fat 3.5 Gm and a stool osmotic gap of 44 mOsm/kg. Which of the following is most likely contributing to his diarrhea? A. Excessive sorbitol consumption B. Excessive fructose consumption C. Small bowel bacterial overgrowth D. Acarbose E. Longstanding diabetes mellitus

3. Stool Collection Equipment

4. Osmotic vs Secretory Diarrhea Osmotic Diarrhea Secretory Diarrhea Daily Stool Volume 1 Liter Effect of 48-hr Fast Diarrhea Stops Diarrhea Continues Fecal Fluid Analysis: Osmolality (mOsmol/kg) 290*** 290*** Na (mEq/liter) 30 80 K (mEq/liter) 30 40 Na + K 60 120 [Na + K] x2* 120 240 Solute gap** 170 40 * Multiplied by 2 to account for anions ** Calculated by subtracting [Na + K] x2 from osmolality ***Fresh stool/ or assumed

5. Case 2: Another case with stool analysis A 38-year-old woman is seen for evaluation of chronic diarrhea for the past 9 months. She reports having 1-3 watery stools daily. Her weight has been stable and she denies any extraintestinal symptoms. Her labs, including electrolytes and TSH, are normal. You recommend that she submit a fresh stool sample for analysis. This reveals a negative calprotectin, negative qualitative fecal fat assessment, stool osmolality 400 mosm/kg and stool Na 170 mmol/L. What is the proper interpretation of her stool studies? A.She has a secretory diarrhea B.She has an osmotic diarrhea C.She is using laxatives surreptitiously D.She contaminated her specimen with urine E.She is taking excess sodium orally

6. Case 3: A 43-year-old man with systemic sclerosis presents with complaints of diarrhea. Over the past 6 months, the patient has experienced progressive foul-smelling diarrhea. Stool analysis reveals a spot fecal fat which is qualitatively positive. His labs are notable for a hemoglobin12.6 g/dL, MCV 104, albumin 3.2 g/dL (nl> 3.4), INR 1.4 (nl 290). Which of the following would be most specific in confirming the etiology of this patient’s diarrhea? A.Small bowel follow-through exam B.Capsule endoscopy C.Upper endoscopy with small bowel biopsy D.Culture of distal duodenal aspirate E.Glucose hydrogen breath testing

7. Pathogenesis of Bacterial Overgrowth Small intestinal lesions or motor disorders Intestinal stasis Bacterial overgrowth Vitamin B12 malabsorption Steatorrhea

9. Diagnosis of Bacterial Overgrowth Clinical suspicion – anemia, steatorrhea, diarrhea, predisposing intestinal lesion Document malabsorption of fat or carbohydrate; low vitamin B12 R/O mucosal, pancreatic, ileal diseases Specific tests (culture, breath test)

10. Diagnostic Tests For Bacterial Overgrowth Small intestine culture Glucose H2 breath test Therapeutic trial -antibiotics

11. Glucose H2 Breath Test Since glucose should be completely absorbed, increase in H2 over baseline is abnormal Sensitivity of 62%; specificity of 83% Elevated basal hydrogen may also indicate SBBO

12. Absorption Tests in Bacterial Overgrowth Fecal Fat D-Xylose Vit B12 (% intake) (Gm/5 hr) (urine %) Controls 2.5 6.0 14.0 SBO (No Rx) 25.0 2.5 1.0 SBO (Rx) 6.0 5.2 13.0

13. Case 4: A 56-year old woman undergoes a laparoscopic cholecystectomy for acute cholecystitis. Four months later, she presents to the GI clinic with complaints of watery diarrhea. She traces her symptoms back to the time of her cholecystectomy. Which of the following therapies would you recommend to this patient? A. Ursodiol B. Low fat diet C. Pancreatic enzyme supplementation D. Cholestyramine E. Rifaximin

14. PREVALENCE OF BILE ACID MALABSORPTION IN CHRONIC DIARRHEA Type 1 (Ileal dysfunction) a) Resection (CD): >90% b) Crohn’s: 11-52% Type 2 IBS and diarrhea: 33% Type 3 Postvagotomy or postcholecystectomy Barkun AN, et al.2013

15. Case 5: An 85 y.o. woman who lives in a nursing home develops crampy diarrhea with fecal incontinence. Two weeks earlier, she was treated with amoxicillin for a UTI with susceptible E. coli. Stool was positive for C difficile toxin and she was treated with metronidozole 250 mg tid for 10 days and improved. Three weeks later, she developed a similar illness and was treated with vancomycin 125 mg qid for 2 weeks and responded. However, 3 weeks later, she is hospitalized with crampy diarrhea, WBC 15,000 and dehydration requiring fluid restoration. Stool again is positive for C difficile toxin. Management at this point should be: A.Treat with fidaxomycin 125 mg QID for 2 weeks. B.Re-treat with vancomycin 250 mg QID for 2 months. C.Arrange for stool bacteriotherapy from a screened donor. D.Administer IV immunoglobin.

16. Current Challenges of Clostridium difficile Infection 1. Rising rates 2. Refractory disease 3. Recurrent infection

17. Recurrent CDI: Risk Factors Age > 65 years Severe/fulminant disease Previous recurrent CDI Intercurrent antibiotic use Low serum IgM and IgA to Toxin A ? PPI or antacid use ? Inflammatory bowel disease ? Renal disease

18. CDI and IBD Significant increase in Crohn’s (2x) and ulcerative colitis (3x) Risk factors: immunosuppression : colitis

19. TREATMENT OF 2ND RECURRENCE OF CDI Vancomycin taper: Week 1: 125 mg QID Week 2: 125 mg BID Week 3: 125 mg QD Week 4: 125 mg EOD Weeks 5-6: 125 mg q 3 d Vancomycin pulse: 125 mg q 2d or 500 mg q 3d for 3 weeks

20. Fidaxomycin: 200 mg bid for 10 – 20 days Rifaximin: 550 mg bid for 20 days Vancomycin: 250 – 500 mg QID for 10 days followed by S. boulardii: 500 mg (2 caps) bid for 28 days Dupont CGH 2013

21. FECAL THERAPY FOR SECOND RECURRENCE OF CDI Colonoscopy Colonic enemas Nasogastric or nasoenteric tube Capsules

22. References Barkun AN et al. Bile acid malabsorption in chronic diarrhea: pathophysiology and treatment. Can J Gastroenterol 2013;27(11):653-9. Bohm M et al. Diagnosis and management of small intestinal bacterial overgrowth. Nutr Clin Pract 2013; 28 (3):289-99. Khanna S, Pardi DS. Clostridium difficile infection: management strategies for a difficult disease. Ther Adv Gastroenterol 2014, March 7(2): 72-86. Schiller LR. Definitions, pathophysiology and evaluation of chronic diarrhea. Best Pract Clin Gastroenterol 2012;26(5):551-62.