A case of refractory diarrhea

Case continued: Features of microscopic colitis

In our patient, colonic biopsy reveals a mildly expanded lamina propria, intraepithelial lymphocytes, and a patchy but prominent thickening of the subepithelial collagen table. This set of features is consistent with collagenous colitis, a variant of microscopic colitis. Histologic signs on biopsy specimens are fairly specific for the disease.⁵

Chronic, intermittent, secretory diarrhea without bleeding is the hallmark of microscopic colitis. Associated symptoms may include abdominal pain, weight loss, and fatigue. If biopsies are not taken at the time of the initial evaluation, and the colonic pathology is overlooked, patients with collagenous colitis may be diagnosed with irritable bowel syndrome with diarrhea.⁶ The sedimentation rate is often elevated, and the antinuclear antibody test can be positive.⁷ Steatorrhea or protein-losing enteropathy can occur, and fecal leukocytes are present in more than 50% of patients.⁸

This patient fits well the demographics of the typical collagenous colitis patient: ie, a middle-aged woman in her 6th decade in otherwise good general health. The female-to-male ratio is 15:1 overall, although the relative frequency of collagenous colitis in women is greater than that of lymphocytic colitis.⁹ In a population-based study, the incidence of collagenous colitis was 5.1 per 100,000 per year, with a prevalence of 36 per 100,000; the incidence of lymphocytic colitis was 9.8 per 100,000 per year, with a prevalence of 64 per 100,000.¹⁰

Symptoms are typically vague and range from an annoyance to more than 20 non-bloody stools per day. The course of the disease also varies. Case series have reported a spontaneous remission rate of 15% to 20%,¹¹ though flare-ups are common. Microscopic colitis is largely a benign disease. It does not increase a person’s risk of colon cancer.

CAUSES OF COLLAGENOUS COLITIS

2. What causes of collagenous colitis have been identified?

• Alcohol abuse
• Previous gastrointestinal surgery
• Drug-induced injury to colon

Neither alcohol use nor previous gastrointestinal surgery has been associated with the development of collagenous colitis.

Collagenous colitis has, however, been linked to several causes. Abnormal collagen metabolism has been demonstrated in patients as a result of increased expression of procollagen I and metalloproteinase inhibitor TIMP-1.¹² Bacterial toxins and a bile-acid malabsorption defect in the terminal ileum and subsequent exposure of the colon to high concentrations of bile acids have also been linked to the development of collagenous colitis.

Many drugs have been linked to the development of collagenous colitis. Damage to the large intestine related to the use of non-steroidal anti-inflammatory drugs has been attributed to the blockage of prostaglandin synthesis.¹³ Simvastatin (Zocor), lansoprazole (Prilosec), and ticlopidine (Ticlid) have been linked to collagenous colitis; ticlopidine, flutamide (Eulexin), gold salts, lansoprazole, and sertraline (Zoloft) have been linked to the development of lymphocytic colitis.¹⁴ In one small series, patients developed colitis after switching from omeprazole (Prevacid) to lansoprazole. All patients had their symptoms and biopsy findings resolve within 1 week of stopping the drug.¹⁵

WHICH DRUG IS BEST?

3. Which drug is best for microscopic colitis, based on the current evidence?

• Bismuth (eg, Kaopectate, Pepto-Bismol)
• Sulfasalazine (Sulfazine)
• Budesonide (Entocort)
• Prednisolone

Studies have evaluated bismuth subsalicylate, Boswellia serrata extract, probiotics, prednisolone, budesonide, and other drugs for treating collagenous colitis.¹⁶

Bismuth trials have been small. In an open-label study of bismuth,¹⁷ symptoms improved in 11 of 12 patients.

Prednisolone recipients had a trend towards clinical response with treatment vs placebo, but it was not statistically significant, and there was incomplete remission of disease.¹⁸

Boswellia serrataextract¹⁹ and probiotics²⁰ showed no clinical improvement.

Cholestyramine has been shown to be helpful when used in conjunction with an anti-inflammatory agent,²¹ and it may be helpful when used alone.

Aminosalicylate compounds have not been tested in prospective randomized trials, even though they are the cornerstone of treatment for ulcerative colitis. Retrospective trials have been equivocal.²²

Budesonide currently has the best evidence of efficacy in collagenous colitis,^23,24 and some evidence suggests it is also effective for other variants of microscopic colitis.

A total of 94 patients were enrolled in three placebo-controlled trials of budesonide at 9 mg daily or on a tapering schedule for 6 to 8 weeks. The pooled odds ratio for clinical response to treatment with budesonide was 12.32 (95% confidence interval 5.53–27.46), with a number needed to treat of 1.58. Significant histologic improvement with treatment was noted in all three trials.²³

Quality of life has also been studied in patients with microscopic colitis who take budesonide. Symptoms, emotional functioning, and physical functioning are improved. Budesonide also improved stool consistency and significantly reduced the mean stool frequency compared with placebo.²⁴

Compared with cortisol, budesonide has a 200 times greater affinity for the glucocorticoid receptor, and a 1,000 times greater topical anti-inflammatory potency. It is also well absorbed in the gastrointestinal tract but is substantially modified into very weak metabolites as a result of first-pass metabolism in the liver.²⁵ This localized effect further supports the use of budesonide in patients with any form of microscopic colitis.

Although studies have shown budesonide to be effective, not every patient with a histologic diagnosis of microscopic colitis needs it. It is reasonable to try antidiarrheal agents, bismuth, or both as a first step because they are inexpensive and have few side effects. If budesonide is used, it should be given for 6 to 8 weeks, then stopped, and the patient should then be monitored for symptom recurrence. If a flare does occur, budesonide can be restarted and continued as maintenance therapy.