1 / 43

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

Microscopic Colitis – In 2010 A Better Defined and Common Cause of Chronic Diarrhea . R.G. Strickland, MD, MACP Emeritus Professor, GI Division. Case. 63F Evaluation of chronic diarrhea 6 months ago developed profuse watery, non-bloody diarrhea Insidious onset

adair
Download Presentation

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

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  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

More Related