IM board review A self-test Jennifer Monti, BA J. Harry Isaacson, MD Bret Lashner, MD* on a Cleveland Clinic Lerner College Department of General Internal Medicine, Department of Gastroenterology and clinical of Medicine of Case Western Reserve Cleveland Clinic; Associate Professor of Hepatology, Cleveland Clinic; Director, Center University Medicine, Cleveland Clinic Lerner College of for Inflammatory Bowel Disease; Director, case Medicine of Case Western Reserve University Gastroenterology and Hepatology Fellowship Program; Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University

A case of refractory

68-year-old white woman with irritable On physical examination, she does not A bowel syndrome has had worsening symp- appear to be in acute distress. Her pulse is 64 toms of right-sided abdominal pain, excessive and her blood pressure is 112/78 mm Hg. The bloating, and loose stools. Her bowel move- cardiopulmonary examination is normal. Her ments have increased from one a day to two abdomen is soft, symmetrical, nondistended, or three a day. She has not noted any mucus and nontender. Bowel sounds are normal. No or blood in the stool. She cannot identify any abdominal masses, palpable organomegaly, or alleviating or aggravating factors, and the pain abdominal bruits are noted. is not related to eating. Results of basic laboratory tests, including She consumes a normal diet, including meat thyroid-stimulating hormone (TSH), complete and dairy. Over-the-counter antidiarrheal medi- blood count, blood chemistries, renal function, cations do not relieve the symptoms. She has and liver function, are normal. Colonoscopy had no fevers, chills, or night sweats, and she has shows normal mucosa as far as the cecum. not lost weight over the past year. Her medical history includes breast cancer ■■DIFFERENTIAL DIAGnosis (in remission), alcohol abuse (in remission), and hypothyroidism, osteoporosis, and su- In addition to irritable bowel syndrome, praventricular tachycardia, all controlled with 1which of these can explain her symptoms? She has treatment as noted below. She has never un- □□ a history of dergone abdominal surgery. □□ Celiac disease irritable bowel A general review of systems is normal. □□ Microscopic colitis Her current include oxybutynin □□ Hyperthyroidism syndrome, (available as Ditropan, others), calcium poly- □□ Lactase deficiency but could it carbophil (FiberCon, others), risedronate (Actonel), levothyroxine (Synthroid, oth- Ulcerative colitis typically presents with be something ers), simethicone (Maalox Anti-Gas, others), blood and mucus in the stool and gross ab- more? atenolol (Tenormin), trazodone (Desyrel), a normalities on colonoscopy, none of which is calcium supplement, and aspirin. She began present in this patient. taking duloxetine (Cymbalta) 18 months ago, Hyperthyroidism can be ruled out by the and the dose was increased from 60 mg to 90 normal TSH level. mg 1 week before this visit. Lactase deficiency or lactose intoler- She has never smoked, and she has ab- ance is unlikely because it is present in only stained from alcohol for 10 years. She has no 15% of people of northern European descent family history of colon cancer, celiac disease, (compared with 80% of blacks and Hispan- or inflammatory bowel disease. She has not ics and up to 100% of Native Americans and traveled outside the country in the past several Asians).1 Furthermore, her pain is apparently years, and she notes no change in her source of not related to consuming dairy products. drinking water. The hydrogen breath test can aid in the di- agnosis of lactase deficiency. This test relies on the breakdown of malabsorbed lactose by co- *Dr. Lashner has disclosed that he has received consulting fees from Prometheus corporation for membership on advisory committees or review lonic flora. This is the most widely used test for panels. this deficiency, but its high false-negative rate

CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 75 • NUMBER 9 SEPTEMBER 2008 677 Downloaded from www.ccjm.org on September 25, 2021. For personal use only. All other uses require permission. IM board review

of 25% means that a negative result does not phocytes, and a patchy but prominent thick- exclude the diagnosis and should not be relied ening of the subepithelial collagen table. This on in working up a patient with chronic diar- set of features is consistent with collagenous rhea.2 Simply noting whether symptoms de- colitis, a variant of microscopic colitis. Histo- velop after ingesting 50 g of lactose is clinically logic signs on biopsy specimens are fairly spe- useful when lactase deficiency is suspected. cific for the disease.5 Based on the information so far, it is rea- Chronic, intermittent, secretory diarrhea sonable in this patient to evaluate for celiac without bleeding is the hallmark of microscopic disease and for microscopic colitis. colitis. Associated symptoms may include ab- Celiac disease, also called gluten-sensitive dominal pain, weight loss, and fatigue. If biop- enteropathy, has a varied presentation that sies are not taken at the time of the initial evalu- includes nonspecific symptoms such as those ation, and the colonic pathology is overlooked, in this patient. Classically, it causes diarrhea, patients with collagenous colitis may be diag- but patients may present with a single nutri- nosed with irritable bowel syndrome with diar- ent deficiency and no diarrhea. rhea.6 The sedimentation rate is often elevated, This patient lacks the elevated alkaline and the antinuclear antibody test can be posi- phosphatase or evidence of vitamin deficien- tive.7 Steatorrhea or protein-losing enteropathy cies characteristic of malabsorption in celiac can occur, and fecal leukocytes are present in 3 8 disease (ie, vitamins A, B12, D, K, and folate). more than 50% of patients. She also lacks evidence of malnutrition, such This patient fits well the demographics of as iron deficiency anemia, weight loss, or low the typical collagenous colitis patient: ie, a mid- serum albumin. Finally, she does not have the dle-aged woman in her 6th decade in otherwise dermatitis herpetiformis rash to suggest au- good general health. The female-to-male ratio toimmune gluten-sensitive enteropathy, nor is 15:1 overall, although the relative frequency does she have evidence of follicular hyper- of collagenous colitis in women is greater than plasia or petechiae due to vitamin malabsorp- that of lymphocytic colitis.9 In a population- tion.3 based study, the incidence of collagenous colitis Symptoms of Because no single serologic test is ideal for was 5.1 per 100,000 per year, with a prevalence microscopic diagnosing gluten-sensitive enteropathy, sev- of 36 per 100,000; the incidence of lymphocytic eral tests are typically used: immunoglobulin colitis was 9.8 per 100,000 per year, with a prev- colitis range A (IgA) antigliadin antibody, IgG antigliadin alence of 64 per 100,000.10 from an antibody, IgA antitransglutaminase antibody, Symptoms are typically vague and range ‘annoyance,’ to and IgA antiendomysial antibody. IgA an- from an annoyance to more than 20 non- titransglutaminase antibody is 92% to 98% bloody stools per day. The course of the dis- 20 stools a day sensitive and 91% to 100% specific for celiac ease also varies. Case series have reported a disease. IgG antigliadin antibody is 92% to spontaneous remission rate of 15% to 20%,11 97% sensitive and 99% specific. The positive though flare-ups are common. Microscopic predictive value of the IgA and IgG antiglia- colitis is largely a benign disease. It does not din antibody tests is less than 2% in the gen- increase a person’s risk of colon cancer. eral population, whereas the positive predic- tive value for antiendomysial antibody and ■■ CAUSES OF COLLAGENOUS COLITIS antitransglutaminase antibody are 15.7% and 21.8%, respectively.4 A positive serologic test What causes of collagenous colitis have for antiendomysial antibody is nearly 100% 2been identified? specific. □□ Alcohol abuse Our patient’s entire celiac antibody panel □□ Previous gastrointestinal surgery is negative, and thus celiac disease is unlikely. □□ Drug-induced injury to colon Case continued: Neither alcohol use nor previous gastrointes- Features of microscopic colitis tinal surgery has been associated with the de- In our patient, colonic biopsy reveals a mildly velopment of collagenous colitis. expanded lamina propria, intraepithelial lym- Collagenous colitis has, however, been

678 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 75 • NUMBER 9 SEPTEMBER 2008 Downloaded from www.ccjm.org on September 25, 2021. For personal use only. All other uses require permission. MONTI AND COLLEAGUES

linked to several causes. Abnormal collagen when used alone. metabolism has been demonstrated in pa- Aminosalicylate compounds have not been tients as a result of increased expression of tested in prospective randomized trials, even procollagen I and metalloproteinase inhibitor though they are the cornerstone of treatment TIMP-1.12 Bacterial toxins and a bile-acid ma- for ulcerative colitis. Retrospective trials have labsorption defect in the terminal ileum and been equivocal.22 subsequent exposure of the colon to high con- currently has the best evi- centrations of bile acids have also been linked dence of efficacy in collagenous colitis,23,24 and to the development of collagenous colitis. some evidence suggests it is also effective for Many drugs have been linked to the de- other variants of microscopic colitis. velopment of collagenous colitis. Damage to A total of 94 patients were enrolled in the large intestine related to the use of non- three placebo-controlled trials of budesonide steroidal anti-inflammatory drugs has been at 9 mg daily or on a tapering schedule for 6 attributed to the blockage of prostaglandin to 8 weeks. The pooled odds ratio for clini- synthesis.13 Simvastatin (Zocor), lansoprazole cal response to treatment with budesonide was (Prilosec), and ticlopidine (Ticlid) have been 12.32 (95% confidence interval 5.53–27.46), linked to collagenous colitis; ticlopidine, flu- with a number needed to treat of 1.58. Signifi- tamide (Eulexin), gold salts, lansoprazole, cant histologic improvement with treatment and sertraline (Zoloft) have been linked to was noted in all three trials.23 the development of lymphocytic colitis.14 In Quality of life has also been studied in one small series, patients developed colitis af- patients with microscopic colitis who take ter switching from omeprazole (Prevacid) to budesonide. Symptoms, emotional function- lansoprazole. All patients had their symptoms ing, and physical functioning are improved. and biopsy findings resolve within 1 week of Budesonide also improved stool consistency stopping the drug.15 and significantly reduced the mean stool fre- quency compared with placebo.24 ■■ Which drug is best? Compared with , budesonide has a 200 times greater affinity for the glucocorticoid Microscopic Which drug is best for microscopic colitis, receptor, and a 1,000 times greater topical anti- colitis affects 3based on the current evidence? inflammatory potency. It is also well absorbed 15 times as □□ Bismuth (eg, Kaopectate, Pepto-Bismol) in the but is substantially □ modified into very weak metabolites as a result many women □ (Sulfazine) 25 □□ Budesonide (Entocort) of first-pass metabolism in the liver. This lo- as men □□ calized effect further supports the use of budes- onide in patients with any form of microscopic Studies have evaluated bismuth subsalicylate, colitis. Boswellia serrata extract, probiotics, predniso- Although studies have shown budesonide lone, budesonide, and other drugs for treating to be effective, not every patient with a his- collagenous colitis.16 tologic diagnosis of microscopic colitis needs Bismuth trials have been small. In an it. It is reasonable to try antidiarrheal agents, open-label study of bismuth,17 symptoms im- bismuth, or both as a first step because they proved in 11 of 12 patients. are inexpensive and have few side effects. If Prednisolone recipients had a trend to- budesonide is used, it should be given for 6 to wards clinical response with treatment vs pla- 8 weeks, then stopped, and the patient should cebo, but it was not statistically significant, then be monitored for symptom recurrence. If and there was incomplete remission of dis- a flare does occur, budesonide can be restarted ease.18 and continued as maintenance therapy. Boswellia serrata extract19 and probiot- ics20 showed no clinical improvement. ■■ key considerations Cholestyramine has been shown to be helpful when used in conjunction with an an- Microscopic colitis is diagnosed histologically, ti-inflammatory agent,21 and it may be helpful while irritable bowel syndrome is a clinical

CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 75 • NUMBER 9 SEPTEMBER 2008 679 Downloaded from www.ccjm.org on September 25, 2021. For personal use only. All other uses require permission. IM board review

diagnosis. In population-based cohorts of his- first to manage symptoms. If symptoms persist, tologically confirmed microscopic colitis, 50% patients can be treated with budesonide (En- to 70% met symptom-based Rome criteria for tocort EC) 9 mg by mouth daily for 8 weeks to the diagnosis of irritable bowel syndrome. The induce remission, or 6 mg by mouth daily for 3 clinical symptom-based criteria for irritable months as maintenance therapy. bowel syndrome are not specific enough to rule out the diagnosis of microscopic colitis. ■■ OUR Patient’S Course Therefore, patients with suspected diarrhea- predominant irritable bowel syndrome should Our patient’s list includes dulox- undergo colonoscopy with biopsy to investi- etine, a serotonin-norepinephrine reuptake in- gate microscopic colitis if symptoms are not hibitor related to drugs that have been associat- well controlled by antidiarrheal therapy.26 The ed with the development of microscopic colitis. patient’s management may be very different We tapered the duloxetine, and her symptoms depending on whether colonoscopy is done. improved by 50%. Her symptoms were eventu- Management of microscopic colitis should ally controlled after an 8-week course of oral include stopping any drugs associated with it. budesonide 9 mg and ongoing intermittent use Simple antidiarrheal agents should be tried of (Imodium). ■

■■ References 15. Thomson RD, Lestine LS, Bensen SP, et al. Lansoprazole- associated microscopic colitis: a case series. Am J Gastro- 1. Swagerty DL Jr, Walling AD, Klein RM. Lactose intoler- enterol 2002; 97:2908–2913. ance. Am Fam Physician 2002; 65:1845–1856. 16. Chande N, McDonald JWD, MacDonald JK. Cochrane 2. Thomas PD, Forbes A, Green J, et al. Guidelines for the Inflammatory Bowel Disease and Functional Bowel Disor- investigation of chronic diarrhea, 2nd edition. Gut 2003; ders Group. Interventions for treating collagenous colitis. 52(suppl 5):1–5. Cochrane Database Syst Rev 2007 Jan 24;(1):CD006096. 3. Nelsen DA Jr. Gluten-sensitive enteropathy (celiac dis- 17. Fine K, Lee E. Efficacy of open-label bismuth subsalicylate ease): more common than you think. Am Fam Physician for the treatment of microscopic colitis. Gastroenterol- 2002; 66:2259–2266. ogy 1998; 114:29–36. 4. Bardella MT, Trovato C, Cesana BM, Pagliari C, Gebbia C, 18. Munck LK, Kjeldsen J, Philipsen E, Fscher Hansen B. In- Peracchi M. Serological markers for coeliac disease: is it complete remission with short-term prednisolone treat- time to change? Dig Liver Dis 2001; 33:426–431. ment in collagenous colitis: a randomized study. Scand J 5. Barta Z, Mekkel G, Csipo I, et al. Micropscopic colitis: a Gastroenterol 2003; 38:606–610. retrospective study of clinical presentation in 53 patients. 19. Madisch A, Miehlke S, Eichele E, et al. Boswellia serrata World J Gastroenterol 2005; 11:1351–1355. extract for the treatment of collagenous colitis: a ran- 6. Tremaine WJ. Diagnosing collagenous colitis: does it domized, double-blind, placebo-controlled, multicenter make a difference? Eur J Gastroenterol Hepatol 1999; trial. Int J Colorectal Dis 2007; 22:1445–1451. 11:477–479. 20. Wildt S, Munck LK, Vinter-Jensen L, et al. Probiotic treat- 7. Bohr J, Tysk C, Yang P, Danielsson D, Järnerot G. Autoan- ment of collagenous colitis: a randomized, double-blind, tibodies and immunoglobulins in collagenous colitis. Gut placebo-controlled trial with Lactobacillus acidophilus 1996; 39:77–81. and Bifidobacterium animalis subsp. lactis. Inflamm 8. Zins BJ, Tremaine WJ, Carpenter HA. Collagenous colitis: Bowel Dis 2006; 12:395–401. mucosal biopsies and association with fecal leukocytes. 21. Calabrese C, Fabbri A, Areni A, Zahlane D, Scialpi C, Di Mayo Clin Proc 1995; 70:430–433. Febo G. with or without cholestyramine in 9. Olsen M, Eriksson S, Bohr J, Järnerot G, Tysk C. Lympho- the treatment of microscopic colitis: randomized con- cytic colitis: a retrospective clinical study of 199 Swedish trolled trial. J Gastroenterol Hepatol 2007; 22:809–814. patients. Gut 2004; 53:536–541. 22. Wall GC, Schirmer LL, Page MJ. Pharmacotherapy for 10. Pardi DS. Microscopic colitis: an update. Inflamm Bowel microscopic colitis. Pharmacotherapy 2007; 27:425–433. Dis 2004; 10:860–870. 23. Feyen B, Wall GC, Finnerty EP, DeWitt JE, Reyes RS. Meta- 11. Fernandez-Banares F, Salas A, Esteve M, Espinos J, Forne analysis: budesonide treatment for collagenous colitis. M, Viver JM. Collagenous and lymphocytic colitis: evalu- Aliment Pharmacol Ther 2004; 20:745–749. ation of clinical and histological features, response to 24. Madisch A, Heymer P, Voss C, et al. Oral budesonide treatment, and long-term follow-up. Am J Gastroenterol therapy improves quality of life in patients with collag- 2003; 98:340–347. enous colitis. Int J Colorectal Dis 2005; 20:312–316. 12. Aignet T, Neureiter D, Müller S, Küspert G, Belke J, 25. Craig CR, editor. Modern Pharmacology With Clinical Ap- Kirchner T. Extracellular matrix composition and gene plication. 6th edition. Philadelphia: Lippincott Williams expression in collagenous colitis. Gastroenterology 1997; and Wilkins, 2003:481. 113:136–143. 26. Limsui D, Pardi DS, Camilleri M, et al. Symptomatic over- 13. Parfitt JR, Driman DK. Pathological effects of drugs on lap between irritable bowel syndrome and microscopic the gastrointestinal tract: a review. Hum Pathol 2007; colitis. Inflamm Bowel Dis 2007; 13:175–181. 38:527–536. 14. Fernández-Bañares F, Esteve M, Espinós JC, et al. Drug ADDRESS: J. Harry Isaacson, MD, General Internal Medicine, consumption and the risk of microscopic colitis. Am J A91, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH Gastroenterol 2007; 102:324–330. 44195; e-mail [email protected].

680 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 75 • NUMBER 9 SEPTEMBER 2008 Downloaded from www.ccjm.org on September 25, 2021. For personal use only. All other uses require permission.