Collagenous Colitis in a Patient With Chronic Diarrhea: An Underdiagnosed and Undertreated Condition
Key words: Abdominal pain, budesonide, collagenous colitis, corticosteroids, diarrhea, weight loss.
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Diarrhea is one of the most common and frequently reported gastrointestinal symptoms. Common causes of diarrhea include infection, irritable bowel syndrome, lactose intolerance, inflammatory bowel disease, celiac disease, colon cancer, pancreatic cancer, carcinoid syndrome, hyperthyroidism, and medication effects. Microscopic colitis, a type of inflammatory bowel disease that includes collagenous colitis and lymphocytic colitis, is increasingly recognized as a major cause of persistent diarrhea, especially in middle-aged and elderly persons. This condition is an idiopathic, clinicopathologic syndrome of chronic, watery, nonbloody diarrhea that is associated with normal laboratory studies, radiology findings, and colonoscopy findings, but with characteristic histopathologic changes. Weight loss, abdominal pain and cramping, and fatigue are common in persons with the condition.
It should be noted that there is some difference of opinion regarding how microscopic colitis is classified, with some researchers considering collagenous colitis and lymphocytic colitis as distinct entities, whereas others consider them different phases of the same condition.1 Collagenous colitis, the focus of this article, is characterized by a thickened subepithelial band of collagen in the colonic mucosa, in association with mononuclear inflammatory cells in the lamina propria, as shown in Figure 1. Collagen is not affected in persons with lymphocytic colitis; tissue samples show an increase of lymphocytes between the cells that line the colon.2 A list of the clinical features of collagenous colitis is provided in Table 1.3
Collagenous colitis has a high rate of spontaneous resolution and relapse, making it difficult to diagnose, and effective treatment options are limited. We present the case of an 82-year-old woman with a 10-year history of collagenous colitis, marked with numerous remissions and relapses. Information on the course, prognosis, diagnosis, and management of collagenous colitis is provided in the discussion.
Case Report
An 82-year-old woman presented to our clinic in 2006 with episodic, light-brown, nonbloody, watery diarrhea daily for 2 weeks. She had been having these episodes approximately 10 times per year for the past 10 years, with a gradual weight loss of approximately 10 to 15 lb. Her diarrhea was associated with flatus, nausea, abdominal pain, bloating, fatigue, and leg cramps. The patient reported that citrus fruit, milk, and nonsteroidal anti-inflammatory drugs (NSAIDs) aggravated her symptoms and that bland food (eg, potatoes, bread, rice) relieved them. She had not traveled outside of her local area, had not used an antibiotic, and had no knowledge of contact with any sick persons.
Her medical history was significant for Raynaud’s phenomenon, osteoarthritis, hypertension, atrial fibrillation, esophageal reflux, and stroke. Her current medications were hydrochlorothiazide, benazepril, atenolol, propoxyphene/acetaminophen (no longer available in the United States), potassium chloride, clopidogrel, nisoldipine, and esomeprazole. The physical examination revealed a thin woman with a body mass index of 19.5 kg/m2 and stable vital signs. Pertinent findings included a soft, nondistended abdomen with no mass or tenderness observed on palpation. Bowel sounds were normal on auscultation. The patient reported arthritic changes in her fingers for several years.
Laboratory testing performed earlier that year at a different institution yielded unremarkable results, including a normal complete blood cell count, comprehensive metabolic panel, thyroid-stimulating hormone level, vitamin B12 level, stool studies (including for Clostridium difficile toxins A and B), and serology test results. An abdominal and pelvic computed tomography scan from 2005 did not show any inflammatory changes around the patient’s cecum. A colonoscopy performed in 2001 (5 years after the onset of symptoms) had revealed completely normal–appearing mucosa up to the cecum; however, random biopsies of tissue obtained throughout the colon were consistent with collagenous colitis, but were either not recognized as collagenous colitis at the time or the patient was lost to follow-up. The patient had tried loperamide in the past without success. No other specific pharmacotherapy for collagenous colitis had been tried.
The patient had learned to live with her symptoms and was somewhat resigned to having them for the rest of her life; however, her chronic diarrhea was impairing her quality of life and limiting her social interactions. Therefore, she sought to get another opinion and established care with our institution after having had primary care with another physician in another health system for a number of years.
Upon making the diagnosis, we made the patient aware of dietary triggers, such as caffeine and dairy products, and started her on a 6-week course of budesonide sustained-release (SR), with 9 mg daily for 2 weeks, then 6 mg daily for 2 weeks, and then 3 mg daily for 2 weeks. Within 5 weeks, the patient was experiencing a dramatic reduction in stool frequency, having a bowel movement one to two times per day, and her stool was less watery, leading to improved quality of life. Five months after the treatment ended, her weight had stabilized without use of nutritional supplements and her diarrhea improved, but was occasionally aggravated by certain foods that contained high amounts of sodium, such as soy sauce. The patient’s esomeprazole for her esophageal reflux was stopped because it was determined to be a possible offending medication. She relapsed several months later, and budesonide SR was restarted.
Discussion
First described in 1976 by Lindstrom,4 collagenous colitis often remains undiagnosed for several years after the onset of symptoms and, even after it is diagnosed, it may remain untreated for several years, as occurred with the case patient. The exact etiology of microscopic colitis is unknown. Some theories include drug effects, bacteria, smoking, and concurrent autoimmune disorders, such as celiac disease (Table 2).5-9
Although collagenous colitis is generally less common and less severe than other types of inflammatory bowel disease, such as Crohn’s disease and ulcerative colitis, its incidence is increasing, and it affects older women more often than older men. In a 2007 population-based study conducted in Minnesota from 1985 to 2001, the incidence of microscopic colitis increased significantly from 1.1 per 100,000 early in the study to 19.6 per 100,000 by the end of the study (P<.001).10 This incidence reported at the conclusion of the study exceeded that of Crohn’s disease and ulcerative colitis. Also, the incidence rates increased statistically with age (P<.001), with researchers calculating a peak annual incidence of 37 per 100,000 at age 80 years and older. The prevalence of microscopic colitis was reported as 103 per 100,000. By subtype, the incidence of collagenous colitis was 3.1 per 100,000 and was associated with being a woman, as 87% of study participants were women (P<.001), and the median age at diagnosis was 70 years. The prevalence of collagenous colitis was 39.3 per 100,000.10 Similar results and trends, some of which have been statistically significant, have been observed in other studies from Europe. For example, a 2004 Swedish epidemiologic study showed an incidence peak for collagenous colitis of 26.9 per 100,000 in women aged 60 to 69 years, which was as high as the incidence of ulcerative colitis, and the annual incidence of collagenous colitis increased during the study.11 Also, researchers found that the diagnostic yield was higher in older patients, and microscopic colitis was diagnosed in nearly 20% of persons older than 70 years.
Course of Collagenous Colitis
The course of collagenous colitis is variable, with remissions and relapses commonly occurring. Baert and colleagues12 reported complete symptomatic remission in 34% of patients with collagenous colitis (n=24; 7 patients with treatment, 17 patients without treatment) after 6-month follow-up, and Goff and associates13 reported a 48% recovery rate with treatment after 3.5 years of follow-up. Fernández-Bañares and colleagues14 discovered a cessation of diarrhea in approximately 70% of patients with treatment after
37 months.
On long-term follow-up, there is a high risk of clinical relapse after achieving clinical remission, such as occurred in the case patient. In the study by Fernández-Bañares and colleagues,14 30% of patients with collagenous colitis whose diarrhea had ceased experienced a relapse after a mean follow-up of approximately 3 years. In small studies of budesonide, 63% of individuals with collagenous colitis relapsed within 1 month of stopping treatment,15 80% of patients relapsed within 8 weeks,16 and 88% of relapses occurred within 3 months,17 respectively. In the study by Miehlke and colleagues,17 relapse was particularly common in patients younger than 60 years of age (odds ratio [OR]=7.4; 95% confidence interval [CI], 1.01-54.6; P=.048).
Prognosis of Collagenous Colitis
The long-term outcome of collagenous colitis is benign. There have been a few reports of collagenous colitis developing into other types of inflammatory bowel disease, such as Crohn’s disease or ulcerative colitis, but these reports are questionable as it is unknown whether they represent true evolvement, misdiagnosis, or variations in the histopathology of microscopic colitis.18-20 The risk of developing cancer, including colorectal carcinoma, and the mortality rate in persons with collagenous colitis are the same as in the general population.18,21
Diagnosing Collagenous Colitis
Persons with microscopic colitis usually have no signs of inflammation on the surface of the colon; therefore, it is diagnosed during microscopic examination of tissue collected during a colonoscopy or flexible sigmoidoscopy. Multiple biopsies are often needed.
Why Is Collagenous Colitis Underdiagnosed? Collagenous colitis may remain undiagnosed for several years after the onset of symptoms, and the interval between the onset of symptoms and the diagnosis vary. This indolent course can be confused with other inflammatory bowel diseases, such as Crohn’s disease or ulcerative colitis. The delay in diagnosis may be related to the length of time it often takes to diagnose collagenous colitis, and its variable course in middle-aged and elderly individuals.
There are a number of reasons for the underdiagnosis of collagenous colitis. First, since it is relatively uncommon in the general population, there is a lack of physician recognition and knowledge of the condition. Second, colonoscopy is typically not performed in cases of nonbloody diarrhea. In the aforementioned Swedish study on microscopic colitis, for instance, nonbloody diarrhea was an indication for colonoscopy in 15% of patients.11 Further, diagnosis is often missed on biopsy, with approximately one-third of microscopic colitis cases from the Swedish study missed in the primary histologic evaluation. There has been some controversy among pathologists on how to diagnose collagenous colitis histologically. According to Rubio and colleagues,22 focusing solely on the collagen band can result in both overdiagnosis and underdiagnosis. In an epidemiologic study, collagenous colitis was diagnosed in only 5% of persons with nonbloody diarrhea who had colonoscopies.11 In a 2006 study by Jaskiewicz and colleagues,23 11 cases of microscopic colitis (5 collagenous colitis, 6 lymphocytic colitis) were initially reported, but 37 cases (11 collagenous colitis, 26 lymphocytic colitis) were ultimately identified on pathology review. This condition is also underreported by patients, further contributing to its underdiagnosis. There are a variety of reasons to explain why patients may underreport symptoms, including embarrassment over having chronic diarrhea (and often, fecal incontinence), thinking that this may be a normal part of aging, and thinking that the diarrhea is cured when they are simply in remission. In addition, the underdiagnosis of collagenous colitis occurs because of its chronic, intermittent course, marked with remissions and relapses, making it a challenge to recognize.
Physicians often fail to recognize microscopic colitis as a side effect of medication; for example, it may be due to the absence of an immediate temporal relationship between a drug and the associated disorder. In a 2005 report by Beaugerie and colleagues,24 a scoring system was proposed for drug-induced microscopic colitis that adapted the existing criteria of drug causality, and a review of the literature was conducted using this framework. The authors found evidence suggesting a high or intermediate probability of causality for 17 drugs, including acarbose, aspirin, carbamazepine, lansoprazole, NSAIDs, ranitidine, sertraline, paroxetine, and ticlopidine.24 In a more recent case-control study, Fernández-Bañares and associates7 found a significant association of drug consumption with the risk of microscopic colitis after at least 2 weeks of treatment. Collagenous colitis was associated with the use of NSAIDs and selective serotonin reuptake inhibitors (SSRIs; specifically sertraline), while lymphocytic colitis was associated with the use of SSRIs, beta-blockers, statins, and bisphosphonates.7 Clearly, specific tests of causality need to be investigated.
Improving the Diagnostic Certainty of Collagenous Colitis. Increasing the knowledge and awareness of the condition among general practitioners and internists can improve the diagnosis. To that end, it is important that physicians are aware that the incidence is increasing and, as previously stated, that there are many possible causes of collagenous colitis, including medications, as shown in Table 2.5-9 It is important that physicians ask patients about their diarrhea and its characteristics. In the setting of high clinical suspicion, multiple biopsies may be needed to confirm the diagnosis.18 Fecal markers, such as increased levels of eosinophil protein X, myeloperoxidase, and tryptase, could be used to identify high-risk patients.25
Management of Collagenous Colitis
Not only is collagenous colitis difficult to diagnose, but there is also a lack of knowledge and evidence-based information on treatment options and response rates, the latter of which is attributed to spontaneous remission. In a 2006 study, researchers reported a resolution of diarrhea in nearly 50% of patients, most of whom received anti-inflammatory treatment, and a persistence of diarrhea in approximately 30% of patients after a follow-up of 10 years.26
Before pharmacotherapy is initiated in patients with collagenous colitis, nonpharmacologic treatment should be tried. Physicians may advise their patients to change their diet; low-fat, low-fiber, easy-to-digest foods may help alleviate diarrhea, and spicy or high-fat foods, as well as caffeine and dairy, should be avoided. Patients should increase their fluid intake, especially water. In addition, medication changes, such as avoiding NSAIDs, may be recommended. There are a number of therapeutic options for managing collagenous colitis, as shown in Figure 2.8,27 Although numerous therapies have been advocated for the treatment of collagenous colitis, only a few small, randomized controlled trials have been conducted on this topic.
Induction of Response. The most extensively studied agent for the management of collagenous colitis is budesonide, which is a topically acting, rapidly absorbed corticosteroid that is released in the small intestine and ascending colon. It has high glucocorticoid receptor–binding affinity and increased retention time in the mucosa. It also has high first-pass metabolism through the liver, thereby reducing corticosteroid-related side effects. Further, the dose required for the induction and maintenance of remission is low, and patients often relapse later after discontinuing treatment with budesonide than with traditional corticosteroids. It is effective even in corticosteroid-refractory patients.15
Three randomized, double-blind, placebo-controlled trials on budesonide for the treatment of collagenous colitis15,16,28 were examined in a review by Chande and colleagues.29 The three studies had a combined total of 94 patients and were conducted for 6 to 8 weeks. Although there were differences in dosing and duration among the trials, all three studies used at least 9 mg daily for 4 weeks. The pooled OR for clinical response to therapy was 12.32 (95% CI, 5.53-27.46), with a number needed to treat of two patients. The average clinical response rate for all three trials was 81%, with a 50% reduction in stool weight or frequency or three or fewer bowel movements daily. The authors also reported statistically significant histologic improvement in all three trials.29 Histologic response rate was approximately 61% to 100%, with a reduction in the thickness of the collagen layer and/or inflammation in the lamina propria observed. Another study by Madisch and colleagues30 found that budesonide improves quality of life in persons with collagenous colitis. The validated Gastrointestinal Quality of Life Index showed improvement in symptoms and physical and emotional functioning, but not in social functioning. A summary of the outcomes of these studies on budesonide is provided in Table 3.15,16,28-30
Bismuth subsalicylate is another commonly used treatment for collagenous colitis. However, only one randomized controlled trial with nine patients (taking nine 262-mg bismuth subsalicylate tablets daily for 8 weeks) has shown some clinical improvement (P=.003) and histologic improvement (P=.003), but these improvements were not significant enough to make any conclusions.31 A small, uncontrolled trial with 13 patients (taking eight chewable 262-mg bismuth subsalicylate tablets daily for 8 weeks) found that bismuth subsalicylate treatment for 2 months was safe, well-tolerated, and efficacious in patients with microscopic colitis.32
Prednisolone, a corticosteroid, is another treatment option for collagenous colitis, but only one randomized controlled trial with 11 patients has shown some clinical improvement (P=.064); histologic improvement was not assessed.33 Other treatment options for collagenous colitis, such as antidiarrheal medications, are based on unblinded, observational, and retrospective studies and have variable response rates; for example, 83% for corticosteroids, 71% for loperamide, 59% for cholestyramine, and 36% for aminosalicylates.34
Maintenance of Response. Two randomized, double-blind, placebo-controlled, 6-month trials of budesonide (N=80; subjects achieved a clinical response/remission with open-label budesonide) were conducted35,36 and examined in the previously mentioned review by Chande and colleagues.29 Both trials administered budesonide 6 mg daily for 6 months. Of the patients who took budesonide, 83% maintained clinical response compared with 28% of patients who received placebo (P=.0002). The authors reported a pooled OR for the maintenance of clinical response of 7.17 (95% CI, 3.00-17.12), with a number needed to treat of two patients.29 The median time to relapse after stopping 6 weeks of open-label budesonide was 207 days in the budesonide group and 45 days in the placebo group (P<.02). Although not all patients underwent a follow-up colonoscopy or sigmoidoscopy at the end of 6 months, more patients maintained a histologic response in the budesonide group than in the placebo group. The pooled OR for the maintenance of histologic response was reported as 4.84 (95% CI, 1.84-12.70).29 Quality of life was not examined in this review. A summary of these findings is provided in Table 4.29,35,36
After the completion of 6 months of therapy, the 2009 study by Bonderup and associates35 continued to follow patients in each group for an additional 6 months. Researchers found that most patients relapsed while off treatment. The median time to relapse was not significantly different in the budesonide group versus the placebo group. This suggests that once budesonide is discontinued, its effect at maintaining a response is not sustained.
Treatment of Relapse. The same medications given for initial treatment can be helpful in treating patients who have relapsed. Reinitiation of budesonide (3-9 mg/day depending on the severity of symptoms) may be beneficial after relapse without serious adverse effects.17 Miehlke and colleagues17 reported that clinical relapse was common in those under age 60 years and that budesonide 9 mg daily was used for the treatment of relapse in 80% of patients and induced clinical response in all of them.
Collagenous Colitis and Celiac Sprue
Pardi and colleagues10 showed that 10% of patients with collagenous colitis who had specific testing were found to have celiac sprue (3.8% of the entire cohort). These figures are similar to what has been reported previously37,38 and suggest that testing should be considered in those who have malabsorption and do not respond to usual medications. There is a possible association between microscopic colitis and gluten sensitivity, even in the absence of overt celiac disease; thus, a gluten-free diet should be tried if the patient is unresponsive to medical treatment.8
Conclusion
Collagenous colitis is a common and treatable form of chronic, watery diarrhea, the incidence of which appears to be increasing over time. Collagenous colitis often affects older adults (especially older women), and is frequently episodic and often remains undiagnosed and untreated. Collagenous colitis can be associated with weight loss, abdominal pain, fatigue, arthritis, and NSAID use. Diagnosis is made from multiple biopsies of colonic mucosa. Treatment includes lifestyle modifications, stopping the offending medications, and treatment with budesonide. Oral budesonide 9 mg daily in a tapering schedule over 6 to 8 weeks for inducing and 6 mg daily over 6 months for maintaining is highly effective in yielding clinical and histologic responses in patients with collagenous colitis. The results for budesonide are consistent across the three randomized trials for induction of response15,16,28 and the two randomized trials for maintenance of response,35,36 and provide strong evidence to serve as a guide for therapy of collagenous colitis.29 Budesonide may also be effective in the treatment of relapses. It improves patients’ quality of life and is well tolerated. If severe symptoms persist despite pharmacotherapy and lifestyle modifications, surgery may be necessary to remove all or part of the colon, but this is rarely recommended.27 Adalimumab has recently been reported to be successful in treating collagenous colitis refractory to budesonide and methotrexate.39 Future trials are needed on the efficacy and potential long-term side effects of budesonide and adalimumab over the course of the disease.
Acknowledgments
The authors would like to thank Barbara Messinger-Rapport, MD, PhD, Center for Geriatric Medicine, Cleveland Clinic, Cleveland, OH, and David V. Espino, MD, Department of Family and Community Medicine, University of Texas Health Science Center, San Antonio, for the helpful discussions about this topic and the review of this manuscript. The authors would also like to thank John Goldblum, MD, Anatomic Pathology, Cleveland Clinic, Cleveland, OH, for providing the histologic slide of collagenous colitis.
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Disclosures:
The authors report no relevant financial relationships.
Address correspondence to:
Theodore T. Suh, MD, PhD, MHS
UT Medicine Westover Hills
Medical Plaza I, Ste 100
11212 Hwy 151
San Antonio, TX 78251
suht@uthscsa.edu