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Collagenous and Lymphocytic Colitis
Introduction
Microscopic colitis is a common cause of chronic watery diarrhea that becomes more common as we age.[1] Based on biopsy findings, 2 types of microscopic colitis are defined: collagenous and lymphocytic colitis. The clinical features of both are very similar. Patients typically present with chronic, watery, non-bloody diarrhea.
Histologic changes define the 2 types of microscopic colitis. This presentation of symptoms often leads 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 women.[2]
Etiology
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Etiology
There have been 2 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 nonsteroid anti-inflammatory drugs.[3][4] While this currently has the strongest link, other drugs also demonstrate correlations as potential causes, including proton pump inhibitors, especially lansoprazole, statins, selective serotonin reuptake inhibitors, and pembrolizumab—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, including an increased risk of microscopic colitis, and can lead to the development of microscopic colitis more than 10 years earlier than in non-smokers.[8][9] Celiac disease is another inflammatory bowel condition primarily affecting the upper gastrointestinal system. This syndrome is associated with the HLA-DR3-DQ2 haplotype, which also correlates with microscopic colitis, similar to celiac disease; the inflammatory process is similar between the 2 syndromes.[10]
Epidemiology
The incidence of collagenous colitis ranges from 2 to 10.8 per 100000, and lymphocytic colitis ranges from 2.3 to 16 per 100000. There are higher incidences in northern Europe and northern North America.[11][12] Most patients are diagnosed around age 65, but approximately 25% get diagnosed before 45.[12] This disease can happen in children but is very rare.[13] There is a preponderance in women for both collagenous and lymphocytic colitis. The woman-to-man ratio of collagenous colitis is 3 and is 1.9 in lymphocytic colitis.[14]
Several other diseases with autoimmune backgrounds 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]
Pathophysiology
While unclear, the pathogenesis of microscopic colitis is likely multifactorial, involving the immune response to luminal factors. The genetic susceptibility is unclear, though there have been reports of familial cases, and there is most likely 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 mucosa permeability 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 decreased absorption of sodium chloride and active chloride secretion.
Histopathology
In general, 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. However, other histological differences are worth noting between the 2 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: Twenty or more intraepithelial lymphocytes per 100 epithelial cells, typically without crypt distortion, define lymphocytic colitis.[23]
Microscopic colitis not otherwise specified: This terminology describes a subgroup of patients with typical symptoms such as diarrhea, increased cellular infiltrate, and 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 presents 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 3 or more loose or watery stools daily lasting more than 4 weeks. Typically, the patient presenting with these symptoms is middle-aged or older and female; however, this can present anytime in life and both genders.
Symptoms are normally between 4 to 9 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, and nocturnal episodes, and half of the patients 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 2 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]
Evaluation
Hematological laboratory findings in microscopic colitis are nonspecific and typically do not guide you. Half the patients have an elevated erythrocyte sedimentation rate, mild anemia, and positive autoantibodies.[25] These antibodies include rheumatoid factor, antinuclear, antimitochondrial, 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 been validated.[27] Occasionally a patient has 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 can include celiac disease serology (tissue transglutaminase immunoglobulin A antibody). Most stool studies above are negative, leading to further diagnostic evaluation.[28]
Endoscopic evaluation with mucosal biopsies is the next evaluation step as this also typically establishes 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 3 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. When using these medications, completing an infectious workup first is essential, as they can worsen symptoms of Clostridium difficile infection. If the patient continues to have 3 or more stools daily, with at least 1 being watery, adding a glucocorticoid such as budesonide is recommended. 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 9 mg daily. Prednisone is another glucocorticoid that is an option for therapy; however, current research indicates that budesonide is more effective.(B3)
Additional agents may be needed if patient symptoms continue despite the above therapy. Cholestyramine at 4 grams, 4 times daily may help until diarrhea resolves. Cholestyramine is a bile acid-binding resin used for diarrhea with concurrent bile acid malabsorption, which can occur. If diarrhea persists after 2 weeks, bismuth subsalicylate can be given at 524 mg (3 tabs) 3 times daily.[33](A1)
Some patients continue to have symptoms despite the above treatment. Approximately 10% to 20% of patients are non-responders.[34] Other therapies then need to be pursued. Anti-tumor necrosis factor and immunomodulators have limited evidence from case series and need further research. Surgery is a mode of therapy reserved for patients who are refractory and intolerant to symptoms. Currently, maintenance therapy is not recommended secondary to the side effects of budesonide. However, the lowest dose possible should be used if necessary, and the dose should not exceed 6 mg daily. Patients can be treated intermittently with budesonide to induce remission as well.(A1)
Differential Diagnosis
Celiac disease can have a similar symptom profile to 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 causes diarrhea. This particular disease typically presents with patchy colitis and various other characteristics, such as perianal disease, like fistulas or fissures. On biopsy, granulomas are generally present along with transmural inflammation. Irritable bowel syndrome (IBS), which 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.
Prognosis
Many patients with microscopic colitis have a chronic, intermittent course of disease symptoms. Diarrhea can sometimes resolve without treatment or often resolve with treatment within weeks. Relapses of symptomatology are frequent. Currently, it is unclear if 1 form is worse than the other. At present, there is no associated increased risk of colorectal cancer with microscopic colitis.
Complications
There are no known complications of disease progression 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 1 of the many causes of chronic diarrhea. This condition is diagnosed based on biopsy results obtained during colonoscopy. Symptom control and remission generally occur with medication management, but some patients do not find relief. Surgery is an option but should be avoided unless symptoms are severe and intolerable. Patients typically have 3 or more bowel movements daily, most of which are watery, and most patients have at least 9 bowel movements daily.
The goal of therapy is 3 or fewer bowel movements daily with no watery bowel movements. Some known provoking factors of this disease include tobacco use, particularly smoking cigarettes and nonsteroid anti-inflammatory drug 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. Clinicians must be aware of a patient complaining of chronic diarrhea and what the consistency, color, and associated symptoms are to advocate for further evaluation. A gastroenterologist is also involved in these cases for evaluation. If the patient workup is as an outpatient, depending upon the workup already performed, the gastroenterologist specialist is instrumental in completing the workup with colonoscopy and biopsies. Primary care clinicians are the point of care leaders to diagnose and begin the workup. Pharmacists are helping with the recommendation for antidiarrheal agents when it is known that the cause is not infectious and for further glucocorticoid recommendations.[36][37] All these disciplines must work together as an interprofessional team to achieve optimal diagnosis, care, and clinical outcomes.
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