Microscopic Colitis – In 2010 A Better Defined and Common Cause of Chronic Diarrhea

1. Microscopic Colitis – In 2010 A Better Defined and Common Cause of Chronic Diarrhea R.G. Strickland, MD, MACP Emeritus Professor, GI Division

2. Case • 63F Evaluation of chronic diarrhea • 6 months ago developed profuse watery, non-bloody diarrhea • Insidious onset • Better with fasting, but still present • 10 – 12+ BMs per day. Occasional Fecal Incontinence. • Awakens at night to have BMs

3. Case • Diarrhea is episodic, lasts for 2-3 weeks, tapers off, recurs within 2 weeks • No travel, well water, raw meats, antibiotics or other new meds, pets, sick contacts prior to onset • No exacerbating or remitting factors • Loperamide has helped some, no response from probiotic. • Mild-mod cramping, better after BM • Has lost 10 pounds since the onset

4. Case • 3 months prior to current evaluation • Colonoscopy: “Normal” • Random biopsies not performed

5. Past Medical History • Diabetes Mellitus – type 2 • Hypertension • Hyperlipidemia • GERD • Hypothyroidism • No prior abdominal surgeries

6. Home Medications • Pioglitazone 45 mg daily • Insulin glargine [rDNA origin] 40 units daily • Atorvastatin 40 mg daily • Metoprolol 25 mg twice a day • Esomeprazole 40 mg twice a day • All begun ≥ 6 mo before onset of diarrhea

7. Family & Social History • No family history of GI illness or cancer • Smoked 1ppd for 30 years – Quit 2 months ago • 2 glasses of wine per week; no alcohol in 4 months • Presently retired. Worked as attorney and has no identifiable risk factors for HIV

8. Physical Exam and Labs • PE: Normal • Labs: albumin 3.4 g/dL, creatinine 1.5 mg/dL, K 3.0, bicarb 20, TSH normal. Sed Rate 30, CRP 1.8 HbA1c 8.1 • Anti-tTG, EMA, HIV, negative • Stool cx, O and Ps, Giardia, Cryptosporidium, C. difficle toxin negative • Fecal calprotectin – elevated • Abdo CT, SBFT normal • EGD and colonoscopy grossly normal. Distal duodenal and random biopsies from R & L colon obtained

9. Pathology • Colon: • Marked surface epithelial lymphocytosis with surface injury, increased lymphocytes/plasma cells in lamina propria. Findings consistent with microscopic (lymphocytic) colitis. No crypt architectural alterations. • Small bowel: • No diagnostic alteration

10. Treatment Partial response to Mesalamine 2.4 g/day and Cholestyramine 4 g/day. Budesonide (Entocort) 9 mg/day - Diarrhea resolved in 3w Budesonide 6mg/day for 3 mo – sustained remission Recurrence within 2 mo after discontinuing Budesonide

11. Chronic Diarrhea - Definition • Change in bowel habit for greater than 1 mo • Defecation frequency greater than 3 per day • Stool consistency decreased / fluidity increased • Stool weight greater than 200g per day

12. Chronic Diarrhea in the Western World • Chronic Diarrhea affects ≈5% of individuals in Western populations (7-14% in the elderly) • A common cause for consultation with general practitioner, internist or gastroenterologist • Once regarded as a rare cause, microscopic colitis now accounts for 10-15% of instances of chronic diarrhea, higher in elderly Thomas et al GUT (2003) 52: suppl 5:1. Talley NJ et al Gastroenterology (1992) 102:895

13. Non-IBD, Noninfectious Colitis

14. Microscopic ColitisHistorical Background • Term first used in 1980 (Read et al Gastroenterology 78: 264) – A pathophysiologic study of 27 patients with longstanding chronic diarrhea. Significance of colonic mucosal pathology present in 30% uncertain. In retrospect probably lymphocytic colitis. • Collagenous Colitis (CC) – Lindström et al (1976) Pathol Eur 11: 87. Freeman et al (1976) Ann R Coll Phys Surg Can 9: 45. • Lymphocytic Colitis (LC) – Lazenby et al (1989) Hum. Pathol 20: 18

15. Microscopic Colitis – Recent Publications • Population-Based Studies Spain - Am. J. Gastroenterol (1999) 94: 418 Iceland - Dig Dis Sci (2002) 47: 1122 Sweden - GUT (2004) 53: 346 USA - GUT (2007) 56: 504 Canada - Clin Gastroenterol Hepatol (2008) 6: 35 France - DDW (2010) • Systematic Reviews – Freeman HJ Gastroenterology (2005), 129:338 – Nylin et al Aliment Pharmacol Ther (2006) 23: 1525 - Tysk C et al World J Gastroenterol (2008) 14:7280 • Cochrane Reviews – Interventions for treating Collagenous (Controlled trials) Colitis, Lymphocytic Colitis (2007) Issue 4 – Chande et al, Am J Gastroenterol (2009) 104: 235 • Association with – Green, PHR et al Clin Gastroenterol Hepatol Celiac Disease (2009) 7:1210

16. Microscopic Colitis Histologic Diagnosis in Endoscopically Normal Colon *Tagkalidis PP et al (2007) J Clin Path 60:382

17. Microscopic Colitis – Histopathology Normal Colonic Mucosa Lymphocytic Colitis Collagenous Colitis Distal biopsies often normal (30-70%). Pathology can be patchy.

18. Microscopic Colitis Age and Sex Specific Annual IncidenceÖrebro, Sweden Incidence ≈ 10 per 100,000. LC=CC Approximates frequency of IBD in Western Populations Olesen et al Gut 2004 53: 346

19. Changing Incidence of Microscopic Colitis Over Time – Olmsted County, Minn. Increased Incidence? Increased Awareness and Detection? Pardi et al Gut (2007) 56: 504

20. Microscopic Colitis - Diagnosis • Consider in patients with ‘idiopathic’ chronic non-bloody diarrhea, especially the elderly. • Differential includes • Infectious Colitis (Most resolve in 1-2 mo) • IBD – UC/Crohns • Dietary intolerances – lactose, fructose, sorbital • Celiac Disease (CD) – Coexistent MC in 5-10%. CD appears to be more prevalent in Western populations (1 in 100-200) now* • Laxative abuse – Less frequent than previously • SI BO – “New kid on the block” • Other causes of non-IBD, non-infectious colitis • Hormone – secreting syndromes (VIP, serotonin, etc) • Diarrhea – predominant IBS, particularly post-infectious. • Diagnosis established by colonoscopy with biopsies of endoscopically normal mucosa. Must include proximal biopsies Catassi, C et al (2010) Ann. Med (online)

21. Microscopic ColitisPrognosis and clinical course – Similar in CC and LC • Chronic continuous or intermittent relapsing course • Symptoms affect quality of life, but the disease process is largely benign • Long term follow-up (years) – Resolution without maintenance therapy in two thirds • Evolution to IBD reported but rare - Crohns or CUC • Conversion of LC to CC or CC to LC reported but rare • Colonic mucosal tears (31), perforation (20) during colonoscopy reported in CC. • No increased risk of colon cancer Bonner, G et al (2000) Inflammatory Bowel Disease 6: 21 Aqel, B et al (2003) dig. Dis. Sci 48: 2323 Nickbom, A et al (2006) Scand. J. Gastroent 41: 726 Kao, KT et al (2009) World J. Gastroenterol 15:3122

22. Microscopic Colitis – Etiology/Pathogenesis Not Established but Factors Implicated: • Familial occurrence and HLA associations suggest genetic susceptibility – HLA-DR3, DQ2; Familial overlap of LC and CC. • Increasing prevalence over past 20 years corresponds with “pharmacomania” and implicates medications in pathogenesis. • Association with Celiac disease, Autoimmune disorders suggest immune-based intestinal injury • Infectious Agent(s) – May initiate MC. Example -Brainerd Diarrhea. Preceding Yersinia, Campylobacter, C. Difficile implicated in some studies. • Bile-acid malabsorption present in 20-40%, with or without physiologic antecedent – Cholecystectomy, ileal resection.

23. Microscopic Colitis – Pathophysiologic Importance of Fecal Stream Janerot et al Gastroenterology (1995) 109: 449 • 9 Females with medically unresponsive collagenous colitis • Fecal Diversion resulted in clinical remission, reduced subepithelial collagen band width, IE Lymphocytes • Restoration of bowel continuity lead to relapse – clinical and histologic

24. Celiac Disease (CD) and Microscopic Colitis (MC) • MC in 44 of 1009 (4.3%) CD patients – A 45-fold increased relative risk compared to general population • CD was first diagnosis in 64%; CD and MC identified at same time in 25%; MC the first diagnosis in 11% • Majority (75%) of those with MC had LC; CC in 25% • GFD was ineffective in reversing MC in majority (>90%) • MC responded to medications in two thirds (Bismuth Subsalicylate, Mesalamine, Budesonide, Prednisone, Azathioprine, Cyclosporin). Maintenance therapy required in 50% • Practice guideline – In MC rule out CD. In CD not responding to GFD rule out MC. Green PHR et al Clin. Gastroenterol. Hepatol (2009) 7:1210

25. Drugs and MC: Keypoints • Many drugs implicated, few with strong evidence. Lansoprazole (Prevacid), NSAIDs, Carbamezapine, Ranitidine, Ticlopidine, Sertraline (Zoloft), acarbose, Statins • Review all drugs – Prescribed and OTC • Stop all new drugs, known potential triggers • If drug is causative, symptoms should resolve within 30 days Beaugerie L and Pardi D Alimentary Pharmacol. Ther (2005) 40:344 Fernandez-Benares F et al Am J Gastroenterol (2007) 102:324

26. Lansoprazole – Induced Microscopic Colitis (MC) • Formulary change from Omeprazole to Lanzoprazole at one VA hospital in 1997 • 850 patients exposed to this change. A number developed persistent diarrhea. • 6 patients evaluated in detail. All 6 had normal colonoscopies but MC on colonic biopies (LC, 5; CC,1) • Discontinuation of Lanzoprazole led to clinical and histologic remission in all 6 patients • Post marketing surveillance of patients with GERD taking Lanzoprazole long-term indicate diarrhea is commonest side effect (2-5%) Thompson RD et al Gastroenterology (2002) 97: 2908

27. Brainerd Diarrhea • Outbreak of acute onset watery non-bloody diarrhea affecting 121 residents of Brainerd, Minn in 1983 • Transmission traced to raw milk ingestion. Secondary spread absent - ? Infection or toxin • Prolonged course (median duration 15 months) Urgency/incontinence prominent, eventual resolution in all. Colonic pathology similar to lymphocytic colitis but milder inflammation. • Seven similar outbreaks since 1983, 6 in USA • Infectious etiology suspected. No agent yet identified. Poor response to antibiotics, anti-inflammatory drugs. Osterholm, MT et al (1986) JAMA 256: 484 Bryant, DA et al (1996) AM J Surg Pathol 20: 1102

28. Microscopic ColitisUncontrolled Treatment Trials • Antidiarrheals • Bismuth Subsalicylate • Cholestyramine • Mesalamine, Sulfasalazine • Systemic Steroids, Budesonide • AZA/6-MP/Methotrexate Response Rates 40-90% in both L.C. and C.C. Chande, N et al The Cochrane Library (2007) Issue 4.

29. Budesonide (Entocort EC) • Synthetic corticosteroid – FDA approved, Oct 2001 • High topical (ileocolonic) activity, high (80-90%) first pass metabolism in liver, limited systemic bioavailability • Biotransformed by CYP3A4 to inactive metabolites; urinary & fecal excretion. Note – grapefruit juice a CYP3A4 inhibitor, raising systemic budesonide level. • Less suppression of endogenous cortisol concentrations / impairment of HP axis function than prednisone • Fewer symptoms/signs of hypercorticism • Initial trials were in Crohn’s disease. Response in active ileo-colonic disease with Budesonide 9mg per day. Efficacy greater than Mesalamine, less than Prednisolone. Cost greater for Budesonide ($1200 per Mo). Maintenance of CD remission with Budesonide 6mg per day not lasting.

30. Budesonide for Induction of Remission in Microscopic Colitis • 4 DB, PC, RTs in CC (3), LC (1) • 9 mg/d x 6-8 weeks • N=94 (CC); N=42 (LC) • Clinical remission 81% (B) vs 17% (P). CC and LC equally responsive • Pooled odds ratio for response =12, NNT = 2 • Histologic remission (inflammation, collagen band) reported in all 4 trials • Relapse observed after B cessation - 61%, most within 3 mos. Retreatment 3-9mg/day successful in 65% Baert, I et al (2002) Gastroenterology 122: 20 Bonderup, OK et al (2003) Gut 52: 248 Miehlke, S et al (2002) Gastroenterology 123: 978 Miehlke, S et al (2009) Gastroenterology 136: 2092

31. Collagenous ColitisMaintenance of Clinical Remission with Budesonide 6mg/day P<0.002 P<0.002 P<0.001 Sustained Histologic Remission in 93% on Budesonide Miehlke, S et al Gastroenterology (2008) 135:1510

32. Collagenous ColitisMaintenance of Remission with Budesonide • 34 patients in remission following 6w Budesonide 9mg/day randomized to Budesonide 6mg/day (n=17) or Placebo (n=17) maintenance • Relapse at 24w was 23% with Budesonide and 88% with placebo (p<0.001) • At 48w (No active treatment for additional 24W in both groups) 76% in Budesonide arm & 88% in placebo arm had relapsed (p=ns) Bonderup, OK et al Gut (2009) 58:68

33. Randomized Trials of other Medications in Microscopic Colitis • Bismuth Subsalicylate in CC – n=9, 3 tabs TiD for 8 weeks – Clinical and histologic response in 4 of 4 (BS) vs 0 of 5 (P). Presented as abstract, no full publication. • Prednisolone in CC – n=11, Clinical response in 5 of 8 (Pred) Vs 0 of 3 (P). Histology not studied. • Mesalamine vs. Mesalamine-cholestyramine for 6 mo (CC 23; LC 41). Clinical response in CC (73-100%) and LC (85-86%). Histologic response in CC (90%) and LC (90%); 13% relapse. No placebo arm. 84% clinical responses within 2w. Fine K et al Gastroenterology (1999) 116: A880 Munck LK et al Scan J Gastroenterol (2003) 38:606 Calabrese C et al J. Gastroenterol Hepatol (2007) 22:809

34. Refractory Microscopic Colitis • Present in <10% of patients with MC • No randomized trials • Uncontrolled observations indicate efficacy for Prednisolone, Immuno-suppressives (Azathioprine, 6-MP, Methotrexate) • Surgery rarely indicated but reports of success with diversion, colectomy in single case studies. Pardi, D. et al (2001) Gastroenterology 120:1483 Riddell, J. et al (2007) J Gastroenterol. Hepatol22:1589

35. Question How would you manage our patient with Lymphocytic Colitis who has relapsed following cessation of maintenance Budesonide 6 mg per day? • Begin prednisolone 40 mg and Azathioprine 2mg per kg. Plan prednisolone taper with response. • Reinduction of remission with Budesonide 9mg per day followed by slower taper over 3-4 mos. • Reinduction with Budesonide 6mg per day. Dosage reduction to lowest level providing sustained remission. Monitor for steroid side effects. • Refer to surgery for colectomy

36. Answer Reinduction with Budesonide 6mg/day. Dosage reduction to lowest level providing sustained remission. Monitor for steroid side effects.

37. Microscopic Colitis – An Approach to Treatment • Medication (Prescribed and OTC) Review • Rule out Celiac Disease – Serology, Biopsy • Medical therapy – “Step-up” approach since spontaneous resolution possible over time and steroids, once started, likely to be long-term. • Antidiarrheal – Loperamide 2mg up to 8x per day • Bismuth Subsalicylate – 3 x 262mg tid for 8 weeks. Longer use – concern for neurotoxicity.

38. Microscopic Colitis – An Approach to Treatment cont… • Mesalamine 2.4g per day with Cholestyramine 4g per day for 3 Mos, Continue Mesalamine if response • Budesonide 3 x 3mg per day for 8 weeks. If response reduce dose to lowest that sustains remission (Maybe 3 mg every other day) • Prednisolone/Azathroprine or 6-MP/Methotrexate for refractory disease. • Surgery – Diversion or colectomy rarely indicated. Chande, N (2008) Can. J Gastroenterol 22:686

39. Microscopic Colitis One disease…or two…or more? Lymphocytic Colitis (LC) Collagenous Colitis (CC) • Shared epidemiology, Risk factors, Pathology (including immunopathology), Identical clinical features, natural history, response to therapy – suggest a spectrum of one disorder • Transition of LC to CC, Histologic over-lap in same patient – rare – supports two discrete disorders • With increased recognition of MC atypical forms are being described particularly Paucicellular LC – implying an even broader pathologic spectrum in MC

40. Paucicellular Lymphocytic Colitis (PLC) Less Severe Form of LC? • Retrospective review of MC cases in Terrassa, Spain 2004-2006 (CC17; LC19; PLC 26) • PLC – IEL counts <20 but >7; Mild LP inflammatory cell infiltrate. Less epithelial cell injury • PLC clinically similar to LC and CC and similar course and treatment response Fernandez-Banares F. et al Am J Gastroenterol (2009) 104:1189

41. How Far Does the MC Spectrum Extend?What about D-IBS? • Substantial overlap of symptoms of MC with D-IBS • Reports of an intestinal mucosal inflammatory component in D-IBS • Post infectious onset in 25% D-IBS • SIBO identified in 25% D-IBS, Responsive to antibiotics H. Lin, 2010

42. Microscopic Colitis - Summary • Microscopic Colitis (MC), first described 30 years ago by pathologists includes CC and LC. MC is an increasingly common cause of chronic diarrhea particularly in elderly females. MC should be a leading consideration by PCPs when consulted for chronic diarrhea. • Pathogenesis not firmly established but is likely to involve colonic mucosal inflammatory and immunologic responses to intestinal luminal components such as drugs, bile salts, infection, dietary components, intestinal microflora. • Associated Celiac Disease (CD) must be considered in all patients with MC. MC is one cause of non-responsive CD • Diagnosis established by colonoscopy with random biopsies of (usually normal appearing) R & L colon

43. Microscopic Colitis - Summary • Disease course is relapsing/remitting, benign, and ultimately (often years) leads to resolution in many. • The only established (by RCT) therapy is Budesonide. Other treatment approaches (Antidiarrheals, Bismuth subsalicylate, cholestyramine, mesalamine) & particularly medication review/cessation may suffice and should be first line approaches before using Budesonide. • Outcomes include (rarely) development of frank IBD, Mucosal tears/perforations in CC. MC is not a risk factor for colon cancer