Reports suggest Incidence of Microscopic Colitis approaches that of UC & CD

[David in Seattle]

I'm wondering how many here have had microscopic colitis ruled out? Note that by "older adults", the title refers to over 50.

Microscopic Colitis — A Common Cause of Diarrhoea in Older Adults

Age and Ageing. 2010;39(2):162-168. © 2010 Oxford University Press

Abstract

Diarrhoeal diseases are common in older populations and often markedly affect their quality of life. Although there are numerous potential causes, microscopic colitis (MC) is increasingly recognised as a major diagnostic entity in older individuals. MC is comprised of two distinct histological forms — collagenous colitis and lymphocytic colitis, both of which frequently occur in older populations. Recent studies suggest that between 10 and 30% of older patients investigated for chronic diarrhoea with an endoscopically normal appearing colon will have MC. It is unclear why MC is more common in older populations, but it is associated with both autoimmune disorders and several drugs that are commonly used by seniors. A definitive diagnosis can only be made with colonic biopsies. Since MC was first described in 1976 and only recently recognised as a common cause of diarrhoea, many practising physicians may not be aware of this entity. In this review, we outline the epidemiology, risk factors associated with MC, its pathophysiology, the approach to diagnosis and the management of these individuals.
Introduction

At any one point in time, ~9% of an older out-patient population will be experiencing diarrhoea.[1] While the prevalence of chronic diarrhoea in older patients is unknown, it is a significant cause of morbidity among them — especially in vulnerable populations like those residing in long-term care facilities. In older populations, chronic diarrhoea can arise from a variety of conditions like coeliac disease and inflammatory bowel disease (IBD).[2] Microscopic colitis (MC) has emerged as a new and common cause of chronic diarrhoea in the general population.

MC is an umbrella term for a group of inflammatory diseases of the colon where the colonic lining appears endoscopically normal, but histologic examination on biopsy reveals increased intraepithelial lymphocytes (IEL) in the colonic mucosa. MC is subgrouped into two different forms that are characterised by histological means - lymphocytic and collagenous colitis. While both subgroups have increased numbers of IELs, a thickened collagen band on the basement membrane of the colonic epithelium is seen in the latter subtype.

MC is frequently associated with systemic disorders (such as hypothyroidism) and the use of certain medications. Not surprisingly, the disorder is being increasingly recognised as a common cause of diarrhoea in middle-aged and older patients. For many of these patients, especially women, the looser and/or more frequent movements may lead to rectal urgency and faecal incontinence or may result in a exacerbation of a previously controlled but latent insufficient anal sphincter.[3]

Epidemiology

When first described over 30 years ago, MC was believed to be rare.[4, 5] However, studies have shown that it is a common cause of watery diarrhoea, particularly in older female patients.[6] MC is a disease that predominantly affects older patients, with incidence rates anywhere from 5 to 10 times higher in those over 65.

Some population-based studies have looked at the incidence of MC in European and North American populations.[7–12] The overall total population annual incidence of collagenous colitis has ranged from 1.1 to 5.2 cases per 100,000 (Table 1) while the annual incidence of lymphocytic colitis per 100,000 was reportedly 3.1–5.5 (Table 1). More recent studies suggest an even higher incidence for MC. This is likely because of an increased awareness of the entity with more colonic biopsies being performed. For example, American incidence rates of 7.1 and 12.6 per 100,000 person-years for collagenous and lymphocytic colitis, respectively, were recently reported with a point prevalence for MC of 103.0 (39.3 for collagenous and 63.7 for lymphocytic colitis per 100,000).[11] Reports suggest that the incidence of MC approaches that of ulcerative colitis and Crohn's disease.[7]

Risk Factors and Disease Associations

Increasing age,[7–9] female sex,[7–9] autoimmune diseases such as thyroid disease[13] and coeliac disease,[14, 15] past or current diagnosis of malignancy[12, 16] and solid organ transplant are identified as risk factors for MC.[17]

The incidence of MC increases substantially with advancing age.[7–9] The mean age of diagnosis of the condition is in the fifth and sixth decades. In one Canadian study, patients greater than 65 years of age were more than five times as likely to have developed MC.[12] The reasons for this are unknown. While a genetic or environmental component seems possible since familial cases have also been reported,[18–20] MC does appear to be an age-associated condition.

Female sex is also a major risk factor.[7–9, 11, 21, 22] This predisposition is more pronounced for the collagenous colitis subtype. Population-based studies report a female to male ratio of 4.4–7.9:1 for collagenous and 1.8–5.0:1 for lymphocytic colitis.[7–12] The reasons for the higher rate among women are also unknown but might be related to the higher likelihood of autoimmune diseases, hormonal alterations and/or an ascertainment bias as women may be more likely to seek help for intermittent watery diarrhoea.

Autoimmune diseases, particularly thyroid and/or coeliac disease, are associated with MC.[8, 11, 13–15, 21–24] Fifty-three percent of patients with collagenous and 43% of patients with lymphocytic colitis have at least one concomitant autoimmune disease. Thyroid disease is found in 8.6 to 21% of those with MC.[7, 13, 14] A recent epidemiological study of 164 patients with MC found that 18 (11.0%) had a prior diagnosis of hypothyroidism.[12] Several studies have documented an association between coeliac disease and MC. Later studies have supported that coeliac disease is found in 6–15% with lymphocytic[22, 24] and 3–23% in patients with collagenous colitis.[14, 22] In a recent study conducted by our group, 7% of patients with a new diagnosis of MC had a prior diagnosis of coeliac disease, which was nearly eight times higher than the expected rate for the general population.[12]

The association of MC with neoplasia is less well studied. Several case reports have linked collagenous colitis with solid tumours[25, 26] and lymphoproliferative disorders.[27] Nearly 12% of patients with MC were found to have either a past or current diagnosis of malignancy.[12] After adjusting for age and sex, the risk was only higher in women over the age of 65. Other studies examining the risk of developing a malignancy after the diagnosis of MC have been unable to document an association.[16, 28]

Only one study has looked at solid organ transplant recipients.[17] The authors reported a point prevalence of 8.8 cases of MC per 1,000 solid organ transplant patients and an annual incidence rate of 5.0 per 1,000 transplant person-years. This incidence rate is ~50-fold higher than the rate found in the general population.

MC has been associated with the use of several medications including NSAIDs, SSRIs, beta-blockers, statins, biphosphonates, ticlopidine, flutamide and PPIs.[23, 29–31] A recent study showed that those with collagenous colitis more commonly consumed NSAIDs and SSRIs, than controls, while those with lymphocytic colitis more commonly consumed SSRIs, beta-blockers, statins and biphosphonates.[30] Other agents including PPIs,[31] ticlopidine[30] and flutamide[29] have been linked in case studies. There have been a few reports of symptom improvement with cessation of NSAIDs.[32]

 

[David in Seattle]

Aetiology

Although MC is technically an IBD and shares a number of parallel etiological aspects with Crohn's disease and ulcerative colitis (the 'classical' IBDs), it is thought to be unrelated to the latter two disorders. The aetiology of MC is likely multi-factorial with a specific mucosal response to various noxious luminal agents occurring in predisposed hosts.
Genetics

Data suggesting a strong genetic contribution are lacking, but as noted familial clusters of MC have been described.[20] In addition, up to 12% of patients with MC have a family history of inflammatory bowel or coeliac disease.[24] Koskela et al. recently reported an association between HLA-DQ2 and MC and also found that MC patients more commonly had an uncommon polymorphism in the tumour necrosis factor alpha (TNFα) gene that results in increased TNFα production.[33]
Autoimmunity

There is some evidence of an autoimmune basis to the development of MC. There is a female preponderance and an association of MC with autoimmune-based disorders such as coeliac and thyroid disease. One study found that 40% of patients with Hashimotos' thyroiditis had histological findings compatible with lymphocytic colitis.[13] Although perinuclear antineutrophil cytoplasmic and antinuclear antibodies are increased in some patients with MC, to date specific autoantibodies for MC have not been defined.[34]
Exogenous Factors

An increased number of T cells in the epithelium raise the suspicion that MC is the result of a dysfunctional immunological response to a yet undetermined luminal toxin. This theory is supported by the observation that in some patients an elemental diet results in symptom resolution.[35] Further support stems from the observation that diverting the faecal stream with an ileostomy can result in normalisation of histopathological changes in collagenous colitis.[36] After closure, both symptoms and histopathology changes recurred.[36] Proposed luminal/environmental toxins include medications, GI infectious agents and bile salts.

Beaugerie and Pardi[37] have reported that multiple drugs have a high or intermediate probability of causality ( Table 2 ). The mechanism(s) underlying these associations is (are) unknown, but the strong relationship with the use of NSAIDs suggests that prostaglandins may play a role. With the remarkable ORs reported for a variety of medications and the occurrence of MC, which were detailed in the risk factors section, a possible role of these medications has to be considered and the therapeutic approach to MC should include medication withdrawal, if one of the risky medications is to be identified.

Some patients report a preceding gastrointestinal infection, and others with MC exhibit significant improvement with antibiotics.[29] Antibodies to Yesinia are more common in patients with collagenous colitis than in healthy controls,[38] and there are case reports linking MC to Clostridium difficile [39] and Campylobacter.[40]
Bile Acids

Bile acid malabsorption has been documented in 9–60% of patients with lymphocytic and 27–44% of patients with collagenous colitis.[41] Interestingly, bile acid-binding therapy can result in improvement in both those with and those without documented bile acid malabsorption.

Pathophysiology

The precise mechanism of diarrhoea in these patients is not well understood. Factors that may play a role include bile salt induced injury, active chloride excretion, decrease in net sodium absorption, creation of a diffusion barrier by collagen band and increased local inflammatory mediators such as nitric oxide and prostaglandins. It remains unclear which of these results in the symptoms reported by patients.

Two studies have looked at inflammatory cytokines in MC. Patients with MC seem to have a predominantly TH1 type cytokine profile with significant increases in interferon gamma, TNFα and interleukin 15 as well as an increased inducible nitric oxide synthase. Others have found increased levels of TGF-β in patients with collagenous colitis.[42]

Clinical Features

The clinical features of collagenous and lymphocytic colitis are similar. The two entities can only be differentiated on histopathological grounds. Both cause chronic (either recurrent or intermittent) watery, non-bloody diarrhoea. Although the clinical course is classically one of the chronic relapsing symptoms, a minority of patients present with an acute onset. Although the diarrhoea may be severe in some patients, complications such as dehydration are rare. Associated symptoms include nocturnal bowel motions, mild abdominal pain, fatigue, slight weight loss, arthralgias and faecal incontinence. Symptoms are often attributed to an irritable bowel syndrome.

The natural history of MC is variable. Many cases are self-limiting, with symptoms lasting a few weeks or months. Others may be symptomatic for years in a relapsing or continuous pattern. Although a small number of case reports have suggested that MC may lead to development of ulcerative colitis, a small case series of patients with MC showed that none developed ulcerative colitis or Crohn's disease after a follow-up of at least 6 years.[28] Similarly, MC does not appear to affect colorectal cancer risk.[16]

Diagnosis/Histopathology

The diagnosis of MC is dependent on (i) a convincing clinical history with other etiologies ruled out, (ii) normal or near normal endoscopic and/or radiographic findings and (iii) endoscopic biopsies with histopathologic findings consistent with MC ( Table 3 ).

The first step in the diagnostic process is a thorough history with particular attention paid to risk factors and the disease associated with MC. A complete history helps one to rule out other etiologies that may cause a similar clinical picture such as IBD, coeliac disease, diarrhoea-predominant irritable bowel syndrome or infectious colitis.

Laboratory and radiographic investigations can be employed to help rule out other entities on the differential diagnosis list, but they are typically unremarkable.

Endoscopy with biopsy is necessary to confirm the diagnosis. Colonoscopy generally reveals macroscopically normal mucosa. However, non-specific changes such as erythema, edema, abnormal vascular markings or even tears associated with perforation have been described.

Microscopic evaluation of the colonic mucosa reveals significant inflammatory changes as outlined in Table 3 . Both collagenous and lymphocytic colitis demonstrate lymphocytic infiltration of the lamina propria and epithelium. Collagenous is differentiated from lymphocytic colitis by the presence of marked thickening of the subepithelial collagen layer ( Table 3 ). Histological assessment by a pathologist familiar with MC is required.

Since the macroscopic appearance is generally normal and the microscopic lesions can be skipped, random colonic biopsies are recommended. There is currently no consensus whether flexible sigmoidoscopy or colonoscopy is the best initial approach.[43] Flexible sigmoidoscopy is an attractive option due to efficiency (takes less time), cost savings, easier bowel preparation and no requirement for sedation. However, some studies suggest that biopsies of the rectosigmoid colon alone may be insufficient to rule out a diagnosis[44, 45] as up to 40% of cases are missed. Offner et al . reported that the diagnostic yield was highest from biopsies of the transverse colon (83%) and right colon (70%) and lowest from the rectosigmoid (66%).[45] Other studies have reported lower false-negative rates with left-sided biopsies alone. Tanaka et al. reported that only 10% of patients with MC had isolated right-sided disease,[44] and a larger study by Fine et al. reported that all 80 patients evaluated for chronic diarrhoea who were diagnosed with MC had histological evidence of MC in the left colon, whereas biopsies taken from other regions of the colon could be false negative.[46]

The practical benefits of flexible sigmoidoscopy must be weighed against the potentially increased diagnostic yield of colonoscopy. The choice of which procedure to perform will depend on the clinical scenario, local expertise and resource constraints. If initial biopsies obtained on flexible sigmoidoscopy do not lead to a diagnosis and the suspicion of MC is high, we recommend a colonoscopy.

 

[David in Seattle]

Treatment

Treatment recommendations for MC are largely based on case reports and uncontrolled studies, and Table 4 gives a suggested algorithm. Specific agents evaluated include 5-aminosalicylic acid (5-ASA), prednisone, immunomodulators, bismuth, probiotics and Boswellia extract. Small randomised controlled trials have shown that agents such as budesonide offer promise as an effective form of symptomatic therapy for both collagenous and lymphocytic colitis.

As a first step in managing MC, an in depth medication history should be taken with potentially precipitating medications stopped where possible. Associated conditions such as coeliac disease should be appropriately managed. In patients with mild symptoms, dietary restrictions like avoiding caffeine and lactose might be helpful.
Anti-diarrhoeal Therapies

Non-specific anti-diarrhoeal therapies such as loperamide are commonly used in the management of MC. Retrospective studies have suggested benefit with doses ranging from 2 to 16 mg per day.[29, 47] Due to the safety of this agent and the possibility of spontaneous remission, we suggest loperamide for first-line therapy for MC. In our experience, however, those with moderate to severe diarrhoea or associated complaints of significant abdominal pain often fail to respond to anti-diarrhoeal therapy alone.
Aminosalicylates

Uncontrolled retrospective series have suggested symptomatic improvement in up to 50% of patients with MC treated with mesalamine (5-ASA).[24, 29, 48] A recent randomised trial of 64 MC patients compared mesalamine (800 mg tid) to mesalamine (800 mg tid) and cholestyramine (4 g/day).[49] Treatment resulted in resolution of diarrhoea in 84% overall after 2 weeks. If treatment was continued over 6 months, clinical and histological remission was achieved in 85% of those with lymphocytic and 91% of those with collagenous colitis. The number of relapsing patients after 6 months of treatment was low, and symptomatic relapses could be successfully retreated. Overall, the combination of mesalamine with cholestyramine was slightly superior.[48]
Budesonide

Budesonide is currently the most promising treatment for collagenous colitis. Three trials involving 94 patients have shown that budesonide therapy (9 mg daily for 6–8 weeks) compared to placebo resulted in statistically significant improvements in clinical symptoms[50–52] and quality of life.[53] A recent Cochrane database meta-analysis reported pooled odds ratio of 12.3 for clinical response with budesonide with a number needed to treat of two.[54] Although effective in the short-term, all trials showed a high rate (61–80%) of relapse within ~2 weeks of budesonide cessation. Age <60 was a significant risk factor for relapse. Although, there are no studies to support a tapering course of budesonide, many clinicians employ this in an effort to minimise the likelihood of relapse.

One randomised controlled trial of budesonide for the treatment of lymphocytic colitis has been conducted. When compared to the placebo arm, the patients randomised to budesonide (9 mg daily × 6 weeks) had a statistically significantly higher rate of remission (<3 bowel movements/day) at 3 and 6 weeks.[55]
Prednisolone

A double-blind, placebo-controlled randomised trial of oral prednisolone 50 mg daily for 2 weeks for collagenous colitis was inconclusive because of the low number of patients enrolled.[56] Studies examining the effect of prednisone in the treatment of lymphocytic colitis have not been performed.
Immunosuppressive Therapy

Immunosuppressive therapy with azathioprine or methotrexate has been utilised in patients either refractory to corticosteroid therapy or corticosteroid dependent, but there are no randomised controlled trials to guide therapy with these medications.[57, 58]
Other Therapies

Small clinical trials studying bismuth subsalicylate, Boswellia serrata extract, probiotics and empirical antibiotic treatment for collagenous and lymphocytic colitis look promising but cannot be suggested outside of such trials. Finally, case reports suggest that pentoxifylline, verapamil and subcutaneous octreotide might be treatment options, but their use cannot be recommended at this time. When medical therapy was unsuccessful and symptoms were very severe, surgical interventions such as a temporary or permanent loop ileostomy or even a proctocolectomy have been employed in smaller case series.
Recommended Approach to Treatment

Firstly, the diagnosis must be confirmed and other potential etiologies ruled out. Any complications related to chronic diarrhoea such as dehydration or electrolyte abnormalities must be identified and corrected. Potentially contributing medications such as PPIs or NSAIDs should be discontinued if possible. Depending on symptom severity, non-specific anti-diarrhoeal agents like loperamide, bile salt binding resins or bismuth should be tried. If this fails and the symptoms are sufficiently severe, the patient should be cared for or referred to someone with experience in dealing with this condition. Budesonide, 9 mg daily for at least 6 weeks, could then be used. Some clinical reports suggest a maintenance dose of budesonide 3–6 mg daily may be effective, but this approach has not been studied prospectively. If administration becomes long-term, patients have to be monitored for the development of the complications of chronic steroid therapy. If symptoms fail to improve, clinicians should consider alternative diagnoses. Prednisone, 5-ASA, immunosuppressive therapy or surgery could be cautiously considered for refractory cases.

Prognosis/Outcome

MC has a variable course, but overall, the long-term prognosis is good. Symptoms of diarrhoea and abdominal pain may precede the diagnosis by a number of months. These symptoms are generally mild. With most patients, symptoms resolve spontaneously or with symptomatic therapy. MC has not been associated with an increased risk of colorectal cancer — this information should be conveyed to the patients. There is only limited information about the long-term course and the prognosis of MC. One study followed 81 patients for an average of 37 months. Their initial symptoms were successfully treated with a number of different drugs. Approximately 30% of these patients relapsed with ~70% remaining symptom free.[59] Prospective observational and clinical trials are warranted to specifically address the issue of prognosis and the durability of the response to initial therapy.

Conclusion

MC is a common cause of diarrhoea in older patients. After ruling our other causes of diarrhoea, flexible sigmoidoscopy (or colonoscopy) with appropriate biopsies allows for the diagnosis of either lymphocytic or collagenous colitis by histological analysis. Based on symptom severity, a stepwise approach to the treatment is suggested.

 

[David in Seattle]

Table 1. Epidemiology of microscopic colitis

 

[David in Seattle]

Table 2. Drugs associated with microscopic colitis

 

[David in Seattle]

Table 3. Histopathological features of collagenous colitis and lymphocytic colitis

 

[David in Seattle]

Table 4. Suggested treatment algorithm