Diagnosis and management of microscopic colitis: current perspectives.

Chronic diarrhea

Microscopic colitis (MC) encompasses the two morphologically distinct entities of collagenous colitis (CC) and lymphocytic colitis (LC). MC was first described less than 30 years ago but is presently recognized as a relatively common cause of chronic diarrhea in the adult population. Remarkably, up to 10% of adults who have a colonoscopy for the investigation of chronic diarrhea, and have endoscopically normal appearing mucosa, may have MC. Patients with MC generally present with chronic diarrhea, which can be associated with cramping and bloating. Endoscopic and radiological examinations are usually normal. Histological assessment reveals inflammation consisting predominantly of lymphocytic infiltration, and a thickened subepithelial collagen band is diagnostic of CC. Both LC and CC can be associated with autoimmune diseases such as celiac disease, diabetes, arthritis and thyroiditis, yet the mechanisms involved in the pathogenesis remain unclear. Emerging studies suggest that a stepwise approach be taken in the medical management of MC. This approach includes antidiarrheal agents and stopping of any offending agents; budesonide or bismuth subsalicylate; and cholestyramine or 5-acetylsalicylic acid agents. In resistant cases, oral corticosteroids and other immune modulatory therapy have been used.

Microscopic colitis is a common cause of chronic diarrhea. Over the last years the incidence and the prevalence of microscopic colitis are rising and this rise is largely attributed to a rising awareness, and concomitantly an increasing number of diagnoses are made. Patients with microscopic colitis report watery, nonbloody diarrhea of chronic, intermittent, or chronic recurrent course. Following an unremarkable physical examination the diagnosis of microscopic colitis is made by colonoscopy, which shows essentially a normal colonic mucosa. Biopsies taken during the colonoscopy procedure will then finally establish the correct diagnosis. Histological workup can then confirm a diagnosis of microscopic colitis and can distinguish the two distinct histological forms, namely, collagenous colitis and lymphocytic colitis. Presently both forms are diagnosed and treated in the same way; thus the description of the two forms is not of clinical value, though this may change in future. Depending on the patients age and gender 10–30% of patients investigated for chronic diarrhea will be diagnosed with microscopic colitis if biopsies are taken. Microscopic colitis is most common in older patients, especially in female patients and is frequently associated with autoimmune disorders and the consumption of several drugs. This review summarizes the present knowledge of the epidemiology, the pathophysiology, and the diagnosis of microscopic colitis and discusses the former and the present treatment options.

The incidence of collagenous and lymphocytic colitis is not well known. We sought to assess the incidence of collagenous and lymphocytic colitis in a well-defined population during a 5-yr study period. From January 1, 1993, to December 31, 1997, all new patients diagnosed with collagenous or lymphocytic colitis living in the catchment area of the Hospital Mutua de Terrassa (Barcelona, Spain) were identified. Since 1993 all patients with chronic diarrhea were referred for a diagnostic colonoscopy. Multiple biopsy sampling of the entire colon was performed when appearance of the colonic mucosa was grossly normal. Twenty-three cases of collagenous colitis and 37 of lymphocytic colitis were diagnosed. The female:male ratios were 4.75:1 and 2.7:1 for collagenous and lymphocytic colitis, respectively. The mean age at onset of symptoms was 53.4+/-3.2 (range, 29-82) yr for collagenous colitis, and 64.3+/-2.7 (range, 28-87) yr for lymphocytic colitis (p = 0.012). The mean annual incidence per 100,000 inhabitants based on the year of onset of symptoms was 1.1 (95% confidence interval [CI], 0.4-1.7) for collagenous colitis, and 3.1 (95% CI, 2.0-4.2) for lymphocytic colitis. A peak incidence was observed in older women in both diseases. A rate of microscopic colitis of 9.5 per 100 normal-looking colonoscopies performed in patients with chronic watery diarrhea was observed. Normal rectal biopsies were found in 43 % and 8% of patients with collagenous and lymphocytic colitis, respectively. The incidence of lymphocytic colitis is three times higher than that of collagenous colitis. Microscopic colitis should be considered as a major possibility in the work-up of chronic diarrhea in older women.

In some adult patients with chronic intractable diarrhea, the diagnosis remains elusive even after detailed evaluations, and colonic or duodenal biopsy specimens may appear unremarkable on routine hematoxylin-eosin staining. To assess the concentration of mast cells in colonic or duodenal biopsy specimens by immunohistochemical analysis for mast cell tryptase from patients with chronic intractable diarrhea and to evaluate their response to drugs affecting mast cell function. Mast cells per high-power field were assessed in biopsy specimens from 47 patients with chronic intractable diarrhea, from 50 control subjects, and from 63 patients with other specific diseases that cause chronic diarrhea (inflammatory bowel disease, celiac disease, collagenous colitis, and lymphocytic colitis). Patients with chronic intractable diarrhea who had more than 20 mast cells per high-power field were administered drugs affecting mast cell mediator function and release. The mean +/- SD concentration of mast cells in the 50 control subjects was 13.3 +/- 3.5 cells per high-power field; hence, patients with more than 20 mast cells per high-power field were considered to have increased mast cells. Thirty-three (70%) of 47 patients with chronic intractable diarrhea had increased mast cells, and symptoms were controlled by drug therapy in 22 (67%) of the 33 patients. No patient had systemic or cutaneous mastocytosis. No increase in mast cells was seen in patients with other common causes of chronic diarrhea. In chronic intractable diarrhea, colonic or duodenal biopsy specimens may appear unremarkable on routine hematoxylin-eosin staining, but increased mast cells may be demonstrated by immunohistochemistry for mast cell tryptase, with the novel term mastocytic enterocolitis describing this condition. Similar increases in mast cells are not apparent in control populations or in patients with other specific diseases that cause chronic diarrhea. The cause of the increased mast cells remains to be elucidated.

In recent years, microscopic colitis has been increasingly diagnosed. This review was carried out to evaluate demographic factors for microscopic colitis and to perform a systematic assessment of available treatment options. Relevant publications up to December 2013 were identified following searches of PubMed and Google Scholar using the key words 'microscopic colitis', 'collagenous colitis' and 'lymphocytic colitis'. Two-hundred and forty-eight articles were identified. The term microscopic colitis includes lymphocytic colitis and collagenous colitis. Both have common clinical symptoms but are well defined histopathologically. The clinical course is usually benign, but serious complications, including death, may occur. A peak incidence from 60 to 70years of age with a female preponderance is observed. Although most cases are idiopathic, associations with autoimmune disorders, such as coeliac disease and hypothyroidism, as well as with exposure to nonsteroidal anti-inflammatory drugs and proton-pump inhibitors, have been observed. The incidence and prevalence of microscopic colitis is rising and good-quality epidemiological research is needed. Treatment is currently largely based on anecdotal evidence and on results from limited clinical trials of budesonide. Long-term follow-up of these patients is not well established. The review synthesizes work on the definition of microscopic colitis and the relationship between collagenous and lymphocytic colitis. It reviews the international epidemiology and work on aetiology. In addition, it critically considers the efficacy of a range of treatments.

Introduction: Microscopic colitis (MC) refers to 2 medical conditions that cause chronic diarrhea: collagenous colitis (CC) and lymphocytic colitis (LC). Previous studies have reported an increased prevalence of microscopic colitis in the celiac disease population. These studies were limited by small numbers, and further characterization of the patients who harbor both conditions is needed. The aims of this study were: 1) to determine the strength of the association between MC and celiac disease; and 2) to compare the demographic and clinical characteristics of patients with MC and celiac sprue to those of patients with MC alone. Methods: Miraca Life Sciences is a nationwide pathology laboratory that receives specimens submitted by approximately 1,500 gastroenterologists distributed throughout the United States. From the electronic database of Miraca Life Sciences we extracted all patients who had an upper gastrointestinal endoscopy (EGD) and colonoscopy with biopsy sampling from the duodenum and colon between January 2008 and December 2013. We extracted demographic, clinical, and histopathologic information and stratified patients based on the presence of MC. We then performed a search of patients with celiac sprue, defined as duodenal villous atrophy (Marsh type 3a, b, or c histology), in a population of patients with MC, compared to a control population of patients without MC. Results: There were 156,399 patients who had both duodenal and colon biopsies during the study period. Of these, 4,417 had MC (2,266 with CC and 2,151 with LC). The mean age of the MC population was 61.9 years, with a female:male ratio of 3.83:1. Celiac sprue was diagnosed in 1,113 patients, of whom 116 also had microscopic colitis. Compared to controls without MC, there was a greater association of celiac sprue in patients with CC (OR 4.08; 95% CI 3.36, 4.96), LC (OR 4.71; 95% CI 3.66, 6.05), and all MC (OR 4.08; 95% CI 3.36, 4.96). In patients with MC and celiac sprue versus MC alone, average age was 54.0 years vs. 61.9 years (p<0.0001) with a similar female:male predominance (ratio 4.04:1). Of the 116 subjects with MC and celiac sprue, microscopic colitis was diagnosed before celiac sprue in 32 (28%) cases, simultaneously in 58 (50%), and after celiac sprue in 26 (22%). Conclusion: In a large nationwide pathology database, we found a significantly increased association of microscopic colitis and celiac disease. Such association could reflect on a shared set of risk factors or a common pathophysiology of the 2 disease entities. Disclosure - Dr. Genta is an employee of Miraca Life Sciences. Drs. Yen and Sonnenberg declare no relevant conflicts of interest.

Collagenous and lymphocytic colitis: evaluation of clinical and histological features, response to treatment, and long-term follow-up

Ragged cuticles and erythematous hands and feet in a pediatric patient with chronic diarrhea

Background: Microscopic colitis (MC) is an increasingly recognized, frequent cause of chronic diarrhea. Its epidemiology was described in several Western countries, however epidemiologic data from Eastern Europe is lacking. We aimed to investigate MC cases in our single tertiary referral center cohort. Methods: All cases of microscopic colitis diagnosed at colonoscopy over a 17-year period (January 1997 – August 2014) were retrieved at the 1st Department of Pathology and retrospectively reviewed. The diagnostic criteria for lymphocytic colitis (LC) were ≥20 intraepithelial lymphocytes per 100 epithelial cells, and for collagenous colitis (CC) a collagenous layer of ≥10 µm. Several demographic and clinical parameters were analyzed. Results: 110 patients (91 patients with LC, and 19 patients with CC) were included in the study. 79 (71%) patients were female with a mean age of 52.0 years (SD ± 16.8) for LC and a mean age of 57.5 years (SD ± 17.0) for CC. Comparing the period 1997 – 2005 and 2006 – 2014, the incidence increased in both genders (30 females, 9 males vs. 49 females, 23 males). Chronic, watery diarrhea was the most common symptom (74%). The diagnosis of LC would have been missed in 11% of cases, if only left-sided biopsies had been taken, whereas all cases (100%) of CC were diagnosed with distal colonic biopsies alone. Osteodensitometry was performed in only 20% of cases, however it was pathological in 64% of the cases: osteoporosis was diagnosed in 46% and osteopenia in 18% of these cases. Among associated autoimmune diseases, celiac disease was the most common with 9%, followed by hypothyroidism (7.3%). 31.5% of patients were taking any of the previously associated drugs (proton pump inhibitors, ACE inhibitors, beta blockers, calcium antagonists, statins, acetylsalicylic acid or antidepressants). Conclusions: The incidence of MC is increasing in Hungary, but still below of that reported in Western countries. LC seems to be more common than CC, but this might be due to underdiagnosis. Our results should be further examined in multicenter studies. This study was supported by the Hungarian Scientific Research Fund (OTKA-K111743 grant).

Microscopic colitis includes lymphocytic colitis and collagenous colitis. The entity is considered as an important cause for unknown chronic diarrhea, but rarely reported in China before. This study aimed to determine the prevalence of microscopic colitis in patients with chronic diarrhea and normal colonoscopy findings in Southern China, and to reveal the clinical feature of microscopic colitis in these patients. Patients with chronic diarrhea and normal colonoscopic findings were enrolled from three hospitals in Southern China from January, 2009 to June, 2010. Multiple colorectal biopsies were obtained in these patients and histological examination was underwent with hematoxyin and eosin stain, Masson's trichrome stain and immunohistochemistry for tenascin to screen lymphocytic colitis and collagenous colitis. The clinical symptom and risk factor of microscopic colitis were assessed by comparing with controls. The diagnostic overlap between microscopic colitis and irritable bowel syndrome or functional diarrhea was also analyzed. Randomly mucosal biopsies were performed in 613 patients with chronic diarrhea and normal or near normal colonoscopic finding. Fifty-nine cases of lymphocytic colitis and 28 cases of collagenous colitis were found by histological examination. The rates of rheumatoid arthritis in lymphocytic colitis group (15.4 %) and collagenous colitis group (14.3 %) were significant higher than in control group (2.2 %). Rheumatoid arthritis was confirmed as the risk factor of microscopic colitis by logistic regression analysis. There was no difference on the symptoms among the controls, patients with lymphocytic colitis, and patients with collagenous colitis. There were 13.8 % (12/87) of patients with microscopic colitis fulfilled Rome III criteria of irritable bowel syndrome and 42.5 % (37/87) fulfilled the criteria of functional diarrhea. Microscopic colitis is not an uncommon disorder in Chinese population. Rheumatoid arthritis is the risk factor of microscopic colitis. Microscopic colitis has a symptomatic overlap with irritable bowel syndrome and functional diarrhea. It is reasonable to obtain multiple biopsies in patients with chronic diarrhea when the mucosa grossly normal at colonoscopy.

Collagenous and lymphocytic colitis

INTRODUCTION: Collagenous colitis (CC), a subtype of Microscopic Colitis, is known to cause chronic diarrhea in the elderly. Steroid medication, particularly budesonide, has been rigorously studied and shown to be effective, leading to remission. Few studies have revealed the role diet has on decreasing these symptoms. CASE DESCRIPTION/METHODS: 69 y/o male with past medical history of chronic intermittent diarrhea for the past thirteen years. He initially presented with recurrence of non-bloody watery diarrhea, alternating with constipation and fecal incontinence for 2 weeks. Previous colonoscopy performed thirteen years ago revealed normal mucosa with diverticulosis. Further workup revealed a negative tTG- IgA, polypharmacy, or an infectious etiology. Labs were unremarkable. He underwent repeat colonoscopy, which demonstrated a fractured and nodular appearance of the cecum and ascending colon with small tears. Biopsies showed a focal increase in intraepithelial lymphocytes with a positive trichrome stain consistent with the diagnosis of CC. He was started on a GFD trial and had complete remission of his symptoms for three years. DISCUSSION: Chronic diarrhea affects approximately 5% of the population and at times can be challenging for gastroenterologists. When working up chronic diarrhea, microscopic colitis and celiac disease often play a large role. In this case, the patient was diagnosed with CC, however symptoms resolved on a GFD alone despite having multiple negative TTG levels. We believe that the multiple negative TTG levels were indicative of negative celiac disease. However, there is evidence showing that gluten can induce microscopic colitis. However, in women dietary gluten intake may not be a risk factor for the development of microscopic colitis in the absence of celiac disease. Nevertheless, the effects of gluten may be different in male veterans. CC is usually treated with a steroid based regimen, budesonide, to obtain remission. There are limited studies that have evaluated the impact that a GFD has upon the symptoms and histological findings in CC. Use of these medications can be associated with hyperglycemia, hypertension and metabolic bone disease which may be detrimental to the patient's health and prognosis. In conclusion, in patients diagnosed with CC consider starting a trial of GFD. Further studies are needed to evaluate the response of how a GFD affects the spectrum of severity in symptoms and histologic findings in patients diagnosed with CC, specifically in male veterans.

Celiac disease: India on the global map

Objective To analyze the clinical characteristics and risk factors of lansoprazole-induced microscopic colitis(MC). Methods PubMed, Da-Yi medical search, CHKD and Wanfang databases were searched and articles related to MC induced by lansoprazole were collected. The patients'primary diseases, coexisting diseases, the dosage, the way of administration, combination drugs, latent period, clinical manifestations, colonoscopic findings, the treatment measures, and the outcomes were recorded and the clinical characteristics, the risk factors of MC induced by lansoprazole were analyzed. Results A total of 30 articles and 62 patients with MCinduced by lansoprazole were retrieved. All articles were case reports and no randomized controlled trials were found. Of all the 62 patients, 22 were male (35.5%) and 40 were female (64.5%) with age from 36 to 92 years and the average age was (69±12) years; 57 patients (91.9%) were ＞50 years; 43 patients were with collagenous colitis(CC)(69.4%), 18 patients (29%) were with lymphocytic colitis(LC), and one patient with LC changed into CC(1.6%). All patients were treated with oral lansoprazole. The latent period of MCinduced by lansoprazole were 5d-6 years and within 1-6 months in 31 patients(60.8%). The most common clinical manifestations were non-bloody watery diarrhea (3-10 times daily in 59 patients,＞10 times daily in 3 patients). Intestinal mucosal screening was performed for all the patients and mild abnormalities or edema were observed in 37 patients, mucosal defect and mucosal laceration in 11 patients, epithelial collagen layer thickening, inflammatory cells infiltration in lamina propria,increased lymphocytes in intraepithelial spaces in 18 patients. High-risk drugs for drug-induced MC were combined use in 20 patients and the combination drugs in 13 patients were non steroidal antiinflammatory drugs. Fifty-eight patients with mild or moderate drug-induced MC returned to normal after withdrawl of lansoprazole and treatment with omeprazole or rabeprazole sodium and 4 patients with severe drug-induced MC recovered after withdrawl of lansoprazole and treatment with glucocorticoids. Conclusions The clinical characteristics in patients with MC induced by lansoprazole are watery diarrhea, mild abnormality or edema of colon mucosa, and thickening in the epithelium of colonic mucosa in histopathology. Age, gender, and combined use of drugs may be related to occurrence of MC induced by lansoprazole. Key words: Lansoprazole; Proton pump inhibitor; Colitis