Collagenous And Lymphocytic Colitis

Earn CME/CE in your profession:

Continuing Education Activity

Microscopic colitis is a common cause of chronic watery diarrhea that becomes more common as we age. Two types of microscopic colitis are collagenous and lymphocytic colitis. Patients with microscopic colitis typically present with chronic, watery, non-bloody diarrhea. This process is often overlooked and can easily be confused for irritable bowel syndrome or other conditions including infection or inflammatory bowel disease. This activity reviews the evaluation and treatment of microscopic colitis and highlights the role of the interprofessional team in the management of patients with this condition.


  • Describe the presentation of microscopic colitis.
  • Summarize the most definitive test for the diagnosis of microscopic colitis
  • Outline the risk factors for developing microscopic colitis.
  • Explain the importance of collaboration and communication amongst interprofessional team members to enhance care coordination for patients with microscopic colitis.


Microscopic colitis is a common cause of chronic watery diarrhea that becomes more common as we age.[1] Two types of microscopic colitis are defined based on findings by biopsy. These include collagenous and lymphocytic colitis. Clinical features of both of these are very similar. Patients will typically present with chronic, watery, non-bloody diarrhea. 

Histologic changes define the two types of microscopic colitis. Often this presentation of symptoms will lead to evaluation for other types of inflammatory bowel disease including Crohn disease and ulcerative colitis. The incidence has been increasing throughout northern Europe and northern North America, which is more common in females.[2]


There have been two possible causes of microscopic colitis theorized, and a genetic component that predisposes to the condition, including medications and smoking tobacco. Medications that have links as causative or that lead to flares include NSAIDs.[3][4] While this currently has the strongest link, other drugs also demonstrate correlations as potential causes including PPIs, especially lansoprazole, statins, selective serotonin reuptake inhibitors, and pembrolizumab which is a humanized antibody used in cancer immunotherapy.[5][6][7]

Smoking may play a role in microscopic colitis, as it has been linked to multiple other inflammatory conditions as well. It has been linked to an increased risk of microscopic colitis and can lead to the development of microscopic colitis more than ten years earlier than in non-smokers.[8][9]

Celiac disease is another inflammatory bowel condition that primarily affects the upper GI system. This syndrome is associated with HLA-DR3-DQ2 haplotype, which also correlates with microscopic colitis, similarly to celiac disease; the inflammatory process is similar between the two syndromes.[10]


The incidence of collagenous colitis ranges from 2.0 to 10.8 per 100000, and lymphocytic colitis ranges from 2.3 to 16 per 100000. There are higher incidences in northern Europe and the northern parts of North America.[11][12] Most patients receive their diagnosis around the age of 65, but approximately 25 percent of patients get diagnosed before 45.[12] This disease can happen in children but is very rare.[13] There is a female preponderance in both collagenous and lymphocytic colitis. The female to male ratio of collagenous colitis is 3.0 and is 1.9 in lymphocytic colitis.[14]

Several other diseases with autoimmune background have correlations with microscopic colitis. Like other aspects, it appears that concomitant autoimmune diseases are more common in patients with collagenous colitis when compared to lymphocytic colitis.[15][16] There have also been rare cases of concurrent microscopic colitis and inflammatory bowel disease, usually ulcerative colitis.[17] There have even been case reports of concurrent lymphocytic and collagenous colitis.[18]


The pathogenesis of microscopic colitis, while unclear, is likely multifactorial involving the immune response to luminal factors. The genetic susceptibility is unclear, though there have been reports of familial cases, and probably there is a genetic risk associated.[19] TGF (transforming growth factor) beta-1 has been shown to have increased expression in collagenous colitis which could have associations with the accumulation of collagen in the tissues.[20] There could also be a change in epithelial barrier function leading to increased permeability of the mucosa for antigens and bacteria to cause inflammation.[21] Inflammatory changes in the lamina propria are associated with the severity of symptoms, primarily diarrhea, secondary to decrease absorption of sodium chloride and active chloride secretion.


In general, both collagenous colitis and lymphocytic colitis present with inflammation within the mucosa. Specifically, in the lamina propria, there is mononuclear cell predominance, with few neutrophils and eosinophils. There are, however, other histological differences that are worth noting between the two types of microscopic colitis.

Collagenous colitis – A collagen band greater than 10 micrometers in diameter in the subepithelial layer defines this type of microscopic colitis.[22]

Lymphocytic colitis – 20 or more intraepithelial lymphocytes per 100 epithelial cells, typically without crypt distortion, defines lymphocytic colitis[23]

Microscopic colitis not otherwise specified – This terminology is used to describe a subgroup of patients with typical symptoms such as diarrhea, increased cellular infiltrate, and either an abnormal collagenous layer or increased intraepithelial lymphocytes that do not match the above criteria.[24]

History and Physical

A typical patient with microscopic colitis will present with non-bloody, watery diarrhea that has been present for some time. As this condition definitively presents with chronic diarrhea, symptoms should be present with that definition which is three or more loose or watery stools daily lasting more than 4 weeks. Typically, the patient presenting with these symptoms will be middle-aged or older, and female, however, this can present anytime in life and both genders. Symptoms are normally between four to nine watery bowel movements daily, though there have been reports of severe disease with 15 or more bowel movements daily. Associated symptoms can be fecal urgency, incontinence, nocturnal episodes, and half of the patients will have abdominal discomfort or pain. As this is a form of inflammatory bowel disease, there are reports of other manifestations such as arthralgia, arthritis, and/or uveitis. Between the primary two types of microscopic colitis, collagenous colitis seems to be associated with more severe bowel inflammation and lymphocytic colitis appears to occur earlier in life.[25]


Hematological laboratory findings in microscopic colitis are nonspecific and typically will not guide you. Half of the patients will have an elevated erythrocyte sedimentation rate, mild anemia, and positive autoantibodies.[25] These antibodies include rheumatoid factor, antinuclear antibodies, antimitochondrial antibodies, and antithyroid antibodies.[26] While some levels of inflammatory markers, eosinophil protein X, it appears that myeloperoxidase and tryptase are elevated and/or detected in the stool of patients, but these findings have not yet received validation at this time.[27] Occasionally a patient will have a protein wasting form of diarrhea associated with hypoalbuminemia, and an albumin level should be a consideration.

Stool studies for evaluation should include Clostridium difficile toxin, stool cultures, Escherichia coli O157: H7 testing, microscopy for ova and parasites, and a Giardia stool antigen test. Additional testing to be considered can include celiac disease serology (tissue transglutaminase IgA antibody). In most cases, all stool studies described above will be negative, leading to further diagnostic evaluation.[28]

Endoscopic evaluation with mucosal biopsies is the next step of evaluation; this also will typically establish the diagnosis. The procedure of choice is a colonoscopy, with biopsies performed in the left and right colon. During endoscopy, the appearance of the colon tends to be normal, though there can be edema, erythema, friability, exudative lesions, or scarring. Microscopic colitis diagnosis is dependent upon biopsy and histopathological findings.[29]

Treatment / Management

The goal of management is to achieve remission, defined as less than three stools daily and no watery stools, and to improve quality of life. The first aspect of management is to stop any possible offending agents causing symptoms, which includes some medications, including nonsteroidal anti-inflammatory drugs, and to avoid and/or stop smoking.[30]

Initial management of symptoms includes antidiarrheal agents such as loperamide.[31] These medications alone may be enough to control symptoms, but other medicines may be necessary for control. When using these medications, it is essential to complete an infectious workup first, as they can worsen symptoms of C. difficile infection. If the patient continues to have three or more stools daily with at least one being watery, the addition of a glucocorticoid such as budesonide is a recommended therapy. With budesonide, 6 to 8 weeks of therapy is typically necessary for complete resolution.[32] After this duration of therapy, the drug must be tapered. A typical dose starts at 9mg daily. Prednisone is another glucocorticoid that is an option for therapy; however, current research indicates that budesonide is more effective.

If patient symptoms continue despite the above therapy, additional agents may be needed. Cholestyramine at a dose of 4g four times per day may help until diarrhea resolves. Cholestyramine is a bile acid binding resin utilized for diarrhea with concurrent bile acid malabsorption, which can occur. If diarrhea continues to persist after 2 weeks, bismuth subsalicylate can be given at a dose of 524mg (3 tabs) 3 times daily.[33]

Some patient will continue to have symptoms despite the above treatment. It is important to realize that approximately 10 to 20 percent o patients are non-responders.[34] Other therapies then need to be pursued. Anti-tumor necrosis factor and immunomodulators currently have limited evidence from case series and need further research. Surgery is a mode of therapy reserved for patients that are refractory and intolerant to symptoms.

Currently, maintenance therapy is not recommended secondary to side effects with budesonide. However, if this is necessary, the lowest dose possible should be utilized, and the dose should not exceed 6mg daily. Patients can be treated intermittently with budesonide to induce remission as well.

Differential Diagnosis

Celiac disease can have a similar symptom profile of chronic diarrhea. Celiac disease should be tested for by serologic testing. If necessary, this can also be tested for by small bowel biopsy, which shows flattening of villi.

Crohn disease is an inflammatory bowel disease that typically will cause diarrhea. This particular disease typically will present with patchy colitis and has various other characteristics such as perianal disease, like fistulas of fissures. On biopsy, granulomas are generally present along with transmural inflammation.

Irritable bowel syndrome (IBS) that is diarrhea-predominant is also a consideration. IBS is typically considered a diagnosis of exclusion. Typically, symptoms of IBS include not only diarrhea but crampy abdominal pain that is improved by defecation and frequent changes in the consistency and frequency of bowel movements.


Many patients with microscopic colitis will have a chronic, intermittent course of disease symptoms. Diarrhea can sometimes resolve without treatment or will often resolve with treatment within weeks. Relapses of symptomatology are frequent. It is currently unclear if one form is worse than the other. At present, there is no associated increased risk of colorectal cancer with microscopic colitis.


Currently, there are no known complications of disease progression itself outside of recurrent symptoms. The primary concern would be complications of therapy with budesonide as this is a steroid with multiple complications associated with long term use.[35]

Deterrence and Patient Education

Microscopic colitis is one of the many causes of chronic diarrhea. It is diagnosed based on biopsy results obtained during colonoscopy. Symptom control and remission generally occur with medication management, but some patients will not find relief. Surgery is an option but should be avoided unless symptoms are severe and intolerable. Patients will typically have three3 or more bowel movements daily most of which are watery, and most patients will have at least nine bowel movements daily. The goal of therapy is three or fewer bowel movements daily with no watery bowel movements. Some known provoking factors of this disease include tobacco use, particularly smoking cigarettes, and NSAID use. Patients should be encouraged to stop smoking and to decrease or stop the use of non-steroidal anti-inflammatory agents such as ibuprofen. There is not currently a known association with an increased risk of colon cancer. Expect symptoms to recur, though it is important to note any change in symptoms for further evaluation.

Enhancing Healthcare Team Outcomes

Chronic diarrhea has an extensive differential diagnosis that includes microscopic colitis. It is imperative for nursing staff to be aware of a patient complaining of chronic diarrhea what the consistency, color, and associated symptoms are to advocate for further evaluation. A gastroenterologist will also be involved in these cases for evaluation. If the patient workup as an outpatient, depending upon the workup already performed the GI specialist will be instrumental in completing the workup with colonoscopy and biopsies. Primary care physicians and nurse practitioners will be the point of care leaders to diagnose and begin the workup. Pharmacists will be helping with the recommendation for antidiarrheal agents when it is known that the cause is not infectious, and for further recommendations for glucocorticoids.[36][37](Level II) All these disciplines need to work together as an interprofessional team to bring about optimal diagnosis, care, and clinical outcomes. [Level V]

Article Details

Article Author

Kelby A. Hempel

Article Editor:

Anuj V. Sharma


9/12/2022 9:16:31 PM



Cotter TG,Pardi DS, Current Approach to the Evaluation and Management of Microscopic Colitis. Current gastroenterology reports. 2017 Feb;     [PubMed PMID: 28265892]


Pardi DS, Diagnosis and Management of Microscopic Colitis. The American journal of gastroenterology. 2017 Jan;     [PubMed PMID: 27897155]


Verhaegh BP,de Vries F,Masclee AA,Keshavarzian A,de Boer A,Souverein PC,Pierik MJ,Jonkers DM, High risk of drug-induced microscopic colitis with concomitant use of NSAIDs and proton pump inhibitors. Alimentary pharmacology     [PubMed PMID: 26956016]


Keszthelyi D,Penders J,Masclee AA,Pierik M, Is microscopic colitis a drug-induced disease? Journal of clinical gastroenterology. 2012 Nov-Dec;     [PubMed PMID: 23060216]


Bonderup OK,Fenger-Grøn M,Wigh T,Pedersen L,Nielsen GL, Drug exposure and risk of microscopic colitis: a nationwide Danish case-control study with 5751 cases. Inflammatory bowel diseases. 2014 Oct;     [PubMed PMID: 25153503]


Bonderup OK,Nielsen GL,Dall M,Pottegård A,Hallas J, Significant association between the use of different proton pump inhibitors and microscopic colitis: a nationwide Danish case-control study. Alimentary pharmacology     [PubMed PMID: 30039564]


Ahmed M,Francis G, Pembrolizumab-Induced Microscopic Colitis. The American journal of gastroenterology. 2018 Apr;     [PubMed PMID: 29610496]


Verhaegh BPM,Pierik MJ,Goudkade D,Cuijpers YSMT,Masclee AAM,Jonkers DMAE, Early Life Exposure, Lifestyle, and Comorbidity as Risk Factors for Microscopic Colitis: A Case-Control Study. Inflammatory bowel diseases. 2017 Jun;     [PubMed PMID: 28471835]


Wickbom A,Nyhlin N,Montgomery SM,Bohr J,Tysk C, Family history, comorbidity, smoking and other risk factors in microscopic colitis: a case-control study. European journal of gastroenterology     [PubMed PMID: 28350750]


Fine KD,Do K,Schulte K,Ogunji F,Guerra R,Osowski L,McCormack J, High prevalence of celiac sprue-like HLA-DQ genes and enteropathy in patients with the microscopic colitis syndrome. The American journal of gastroenterology. 2000 Aug;     [PubMed PMID: 10950045]


Williams JJ,Kaplan GG,Makhija S,Urbanski SJ,Dupre M,Panaccione R,Beck PL, Microscopic colitis-defining incidence rates and risk factors: a population-based study. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2008 Jan;     [PubMed PMID: 18166476]


Bonderup OK,Wigh T,Nielsen GL,Pedersen L,Fenger-Grøn M, The epidemiology of microscopic colitis: a 10-year pathology-based nationwide Danish cohort study. Scandinavian journal of gastroenterology. 2015 Apr;     [PubMed PMID: 25645623]


Józefczuk J,Wozniewicz BM, Clear cell colitis: a form of microscopic colitis in children. World journal of gastroenterology. 2008 Jan 14;     [PubMed PMID: 18186560]


Tong J,Zheng Q,Zhang C,Lo R,Shen J,Ran Z, Incidence, prevalence, and temporal trends of microscopic colitis: a systematic review and meta-analysis. The American journal of gastroenterology. 2015 Feb;     [PubMed PMID: 25623658]


Kao KT,Pedraza BA,McClune AC,Rios DA,Mao YQ,Zuch RH,Kanter MH,Wirio S,Conteas CN, Microscopic colitis: a large retrospective analysis from a health maintenance organization experience. World journal of gastroenterology. 2009 Jul 7;     [PubMed PMID: 19575491]


Koskela RM,Niemelä SE,Karttunen TJ,Lehtola JK, Clinical characteristics of collagenous and lymphocytic colitis. Scandinavian journal of gastroenterology. 2004 Sep;     [PubMed PMID: 15513381]


Wickbom A,Bohr J,Nyhlin N,Eriksson A,Lapidus A,Münch A,Ung KA,Vigren L,Öst Å,Tysk C, Microscopic colitis in patients with ulcerative colitis or Crohn's disease: a retrospective observational study and review of the literature. Scandinavian journal of gastroenterology. 2018 Apr;     [PubMed PMID: 29546806]


Christ AD,Meier R,Bauerfeind P,Wegmann W,Gyr K, [Simultaneous occurrence of lymphocytic gastritis and lymphocytic colitis with transition to collagenous colitis]. Schweizerische medizinische Wochenschrift. 1993 Jul 31;     [PubMed PMID: 8367708]


Abdo AA,Zetler PJ,Halparin LS, Familial microscopic colitis. Canadian journal of gastroenterology = Journal canadien de gastroenterologie. 2001 May;     [PubMed PMID: 11381303]


Ståhle-Bäckdahl M,Maim J,Veress B,Benoni C,Bruce K,Egesten A, Increased presence of eosinophilic granulocytes expressing transforming growth factor-beta1 in collagenous colitis. Scandinavian journal of gastroenterology. 2000 Jul;     [PubMed PMID: 10972179]


Andersen T,Andersen JR,Tvede M,Franzmann MB, Collagenous colitis: are bacterial cytotoxins responsible? The American journal of gastroenterology. 1993 Mar;     [PubMed PMID: 8438843]


Lee E,Schiller LR,Vendrell D,Santa Ana CA,Fordtran JS, Subepithelial collagen table thickness in colon specimens from patients with microscopic colitis and collagenous colitis. Gastroenterology. 1992 Dec;     [PubMed PMID: 1451972]


Veress B,Löfberg R,Bergman L, Microscopic colitis syndrome. Gut. 1995 Jun;     [PubMed PMID: 7615277]


Chang F,Deere H,Vu C, Atypical forms of microscopic colitis: morphological features and review of the literature. Advances in anatomic pathology. 2005 Jul;     [PubMed PMID: 16096382]


Bohr J,Tysk C,Eriksson S,Abrahamsson H,Järnerot G, Collagenous colitis: a retrospective study of clinical presentation and treatment in 163 patients. Gut. 1996 Dec;     [PubMed PMID: 9038667]


Roth B,Gustafsson RJ,Ohlsson B, Auto-antibodies and their association with clinical findings in women diagnosed with microscopic colitis. PloS one. 2013;     [PubMed PMID: 23776613]


Lettesjö H,Hansson T,Peterson C,Ung KA,Ringström G,Abrahamsson H,Simrén M, Detection of inflammatory markers in stools from patients with irritable bowel syndrome and collagenous colitis. Scandinavian journal of gastroenterology. 2006 Jan;     [PubMed PMID: 16373277]


Systematic review with meta-analysis: diagnostic overlap of microscopic colitis and functional bowel disorders., Guagnozzi D,Arias Á,Lucendo AJ,, Alimentary pharmacology & therapeutics, 2016 Feb 24     [PubMed PMID: 26913568]


Mellander MR,Ekbom A,Hultcrantz R,Löfberg R,Öst Å,Björk J, Microscopic colitis: a descriptive clinical cohort study of 795 patients with collagenous and lymphocytic colitis. Scandinavian journal of gastroenterology. 2016;     [PubMed PMID: 26679722]


Beaugerie L,Pardi DS, Patients with drug-induced microscopic colitis should not be included in controlled trials assessing the efficacy of anti-inflammatory drugs in microscopic colitis. Gastroenterology. 2009 Oct;     [PubMed PMID: 19717133]


Kingham JG, Microscopic colitis. Gut. 1991 Mar;     [PubMed PMID: 2013415]


Miehlke S,Aust D,Mihaly E,Armerding P,Böhm G,Bonderup O,Fernández-Bañares F,Kupcinskas J,Munck LK,Rehbehn KU,Nacak T,Greinwald R,Münch A, Efficacy and Safety of Budesonide, vs Mesalazine or Placebo, as Induction Therapy for Lymphocytic Colitis. Gastroenterology. 2018 Dec;     [PubMed PMID: 30195447]


Calabrese C,Fabbri A,Areni A,Zahlane D,Scialpi C,Di Febo G, Mesalazine with or without cholestyramine in the treatment of microscopic colitis: randomized controlled trial. Journal of gastroenterology and hepatology. 2007 Jun;     [PubMed PMID: 17565633]


Miehlke S,Heymer P,Bethke B,Bästlein E,Meier E,Bartram HP,Wilhelms G,Lehn N,Dorta G,DeLarive J,Tromm A,Bayerdörffer E,Stolte M, Budesonide treatment for collagenous colitis: a randomized, double-blind, placebo-controlled, multicenter trial. Gastroenterology. 2002 Oct;     [PubMed PMID: 12360457]


Levy A,Borren NZ,Maxner B,Tan W,Bellavance D,Staller K,Chung D,Khalili H,Ananthakrishnan AN, Cancer risk in microscopic colitis: a retrospective cohort study. BMC gastroenterology. 2019 Jan 5;     [PubMed PMID: 30611218]


Miehlke S,Verhaegh B,Tontini GE,Madisch A,Langner C,Münch A, Microscopic colitis: pathophysiology and clinical management. The lancet. Gastroenterology     [PubMed PMID: 30860066]


Nguyen GC,Smalley WE,Vege SS,Carrasco-Labra A,Clinical Guidelines Committee., American Gastroenterological Association Institute Guideline on the Medical Management of Microscopic Colitis. Gastroenterology. 2016 Jan     [PubMed PMID: 26584605]