Mulder

Microscopic colitisChris J. J. Mulder1, Ivar M. Harkema2, Jos W. R. Meijer3 1 Department of Gastroenterology, Vrije Universiteit Medisch Centrum / Free University Medical Centre, Amsterdam, the Netherlands 2 Department of Gastroenterology, Ziekenhuis Rijnstate / Rijnstate Hospital, Arnhem, the Netherlands 3 Department of Pathology, Ziekenhuis Rijnstate / Rijnstate Hospital, Arnhem, the Netherlands Mulder CJJ, Harkema IM, Meijer JWR. Microscopic colitis. Folia Gastroenterol Hepatol 2004; 2 (2): 81 - 86. Abstract. Microscopic colitis is viewed as an umbrella term applicable to both lymphocytic and collagenous
colitis. The first case was published in 1976, a new entity with chronic watery diarrhoea with lymphocytic colitis, with or without a subepithelial collagen deposition. Patients are usually middle-aged women. The pathogenesis is unknown. The response to steroids and the female predominance underscores an autoimmune disease. Up to 40 % non-steroidal anti-inflammatory drugs-induced and lansoprazole-induced microscopic colitides are well- known. Biopsies during sigmoideoscopy in unexplained diarrhoea must be standard. Treatment is empirical. The most important step is to ban all non-steroidal anti-inflammatory drugs and other microscopic colitis indu- cing agents. Immunosuppressive treatment must be considered. However, the disease has a benign course and Key words: microscopic colitis, lymphocytic colitis, collagenous colitis
Microscopic colitis (MC) is viewed as an umbrella with a female/male ratio from 3 - 20 : 1 (27,44). Most term applicable to both lymphocytic colitis (LC) and are in the fifth or sixth decade, age range of 10 - 90 collagenous colitis (CC) (28,29,38). The first case of years with a mean age of 50 - 60 years (6,36,44). The CC was published in 1976 by Lindström, who descri- incidence of CC is estimated between 0.2 - 2.3 / 105 bed a new entity in which chronic watery diarrhoea inhabitants (27). In LC there is a less pronounced pre- was associated with a thick, subepithelial collagen dominance of women 1.6 - 3 : 1 (36). The peak onset deposition in biopsy samples of endoscopically nor- for LC is similarly in the fifth or sixth decade, the same mal colonic mucosa (29). The term lymphocytic colitis age range as CC, with a mean of 50 - 65 years was proposed in 1989 considering the absence of the (36,44). Differences in incidence probably reflect the collagen band on histological evaluation (28). These lack of unification of these entities. Familial clustering entities are now generally recognized and MC has of CC has been recognized (25,42,44).
become a common condition of unknown cause especially affecting the large bowel (27). MC features PATHOGENESIS
are chronic watery diarrhoea without blood, abdomi- The pathogenesis of MC is unknown. There are nal pain, normal blood test results, no signs of malab- many features, which suggest that MC might be an sorption, normal microbiology, radiology and endo- autoimmune disease. The response to steroids and the scopic findings. Histopathology reveals a thickening of female predominance emphasise this hypothesis.
the subepithelial collagen layer beneath the basement Remission has been reported during pregnancy (6).
membrane throughout the colon with lymphocytic A luminal agent or an immunological reaction against infiltrates in the lamina propria. The pathogenesis and significance of these findings are still unknown. Table 1 Reported associations of microscopic colitis and other
Therapeutical options are mainly based on case autoimmune diseases
reports. However, in recent literature budesonide and Disease
Association in %
Reference
azathioprine seem promising. In some cases, the EPIDEMIOLOGY
Patients with CC are usually middle-aged women, an endogenous antigen produced by enterocytes might trigger the disease (6). Immunoglobulin IgM is Adverse drug effects are implicated to cause mic- increased in CC (40 %) (9). Positive antinuclear antibo- roscopic colitis. Best known are non-steroidal anti- dies were found in 30 % - 50 % (36,44). P-ANCA was inflammatory drugs (NSAIDs)-induced and lansopra- found positive in 10 - 14 % of patients (44). Up to 40 % zole-induced MC (16,27,49). NSAIDs-induced MC is of patients have one or more associated autoimmune characterized by histopathological features of CC and diseases (36). Coeliac disease in 6 - 40 % (36,39), thy- hypoproteinaemia. This might be caused by NSAIDs- roid diseases in up to 20 % (20,36), diabetes mellitus induced protein-losing enteropathy. The watery stool in 10 % and rheumatoid arthritis in 2.5 % of MC pati- can even obtain mucus and/or blood. Ulcerations and ents are reported. Other autoimmune diseases have perforations have been described (49). NSAIDs might been reported such as CREST syndrome, Sjögren’s be an aetiologic factor in CC. NSAIDs inhibit the synt- syndrome, psoriasis, Raynaud phenomenon, dermato- hesis of prostaglandins, especially of PGE2, and give myositis, polymyalgia rheumatica, Wegener’s granulo- rise to an increased production of collagen (16). Some matosis, Beh,cet’s disease and systemic lupus erythe- suggest that colitis caused by NSAIDs should be clas- matodes (36). Intraepithelial lymphocytes in patients sified as a different entity, because of differences in with CC are increased. These lymphocytes are predo- clinical features (49). Withdrawal of NSAIDs is usually minantly CD8+ T-lymphocytes with the α/β heterodi- followed by improvement of the clinical and histologi- mer, whereas the lymphocytes in the lamina propria cal abnormalities. These patients seem to be more are dominated by CD4+ T-lymphocytes. However, the prone to use aspirin or other NSAIDs (30 - 60 %) (36).
distribution of CD8+ T-lymphocytes in the epithelium However, withdrawal did not mean a disappearance of versus CD4+ T-lymphocytes in the lamina propria is the same as in normal intestinal mucosa.
Lansoprazole-induced MC shows histopathological abnormalities as seen in CC and LC. The mechanism Luminal agent
is unexplained. Toxic or immunological factors may The observation that diversion of the faecal stream be involved. Symptoms are watery stool and mild can normalize or reduce the histopathological chan- abdominal pain. These complaints can occur in up to ges in CC support the hypothesis of a luminal agent 5 % of lansoprazole-users (23). Discontinuing the as a possible aetiological factor (24). These presumed drug resolves the complaints and histology normali- agents in the faecal stream presumably cause epithe- zes (43). Similar observations about other PPI have lial leakage and vacuolisation of the enterocytes.
been reported as case-reports, but not confirmed by They become flattened or cuboidal without a cove- others (43,48). Other agents causing MC are ticlopidi- ring mucin layer. This weakens the epithelial barrier ne (LC) (5), cimetidine (22), ranitidine (LC and CC) (3), resulting in thickening of the subepithelial collagen cyclo 3 fort (LC) (4,44), carbamazepine (LC) (31), sim- layer, constructing a new barrier. The predominant vastatin (17), vinca alkaloid (LC) (19), tardyferon (LC) abnormalities of MC in the proximal colon support the luminal agent hypothesis. The luminal agent might be phagocytosed by macrophages and then presented Fibroblast dysfunction
to immunocompetent cells stimulating the immune A synthesis dysfunction in the fibroblast sheet has system and initiate a cascade of inflammatory reacti- been reported. Decreased levels of interstitial collage- ons involving fibroblast proliferation possibly respon- nase (Matrix Metalloproteinases MMP-1) and increa- sible for the excessive collagen deposits. Microbiolo- sed expression of TIMP-1, a tissue inhibitor of MMP- gic studies in MC give no clear explanation. Yersinia 1, have been found in patients with MC suggesting enterocolitica has been suggested as a factor in that reduced matrix degradation and not overactivati- developing MC (7). Resolution of CC after antibiotic on of matrix synthesis leads to subepithelial accumu- treatment for Helicobacter pylori supports the micro- lation of matrix proteins like collagen type III and espe- biological hypothesis (34). Nitric oxide and plasma cially type IV and tenascin. These findings indicate nitrate and nitrite levels are increased in CC patients.
that inadequate local fibrinolysis is a major cause of It is not clear whether nitric oxide is produced by the collagen accumulation in CC (33,45). Smoking has inflamed mucosa or is of bacterial origin (30,44). been suggested to protect against MC (36,44). CLINICAL FEATURES
junctions (15). The definitive diagnosis of MC relies on The onset of MC is in 60 % insidious, and in 40 % histologic diagnosis on biopsies taken from the colon, (sub)acute. The symptoms are watery diarrhoea (4 - 10 stools per day), nocturnal diarrhoea, faecal urgen- 1) A diffuse thickening of the collagen layer beneath cy, bloating, abdominal pain, and meteriorism. Some- times symptoms are intermittent. Weight loss is quite throughout the colon in CC but absent in LC with common. Dehydration is uncommon. When sticky lymphocytic infiltration in the lamina propria in CC faeces is found one should suspect coeliac disease.
and more pronounced in LC. The presence of more Vice versa persistent diarrhoea in treated coeliacs than 10 intraepithelial lymphocytes per 100 epithe- means strong suspicion of MC. The course of MC is lial cells seems specific and helpful for diagnosing relapsing and benign (36). Sometimes, patients beco- CC and/or LC (36). The thickness of the subepithe- me socially disabled caused by frequent diarrhoea.
lial layer in normal individuals varies from 0 - 3 Although the majority of patients are female, the µm (29). A thickness of 10 µm or more has been symptoms and progression is similar in men and accepted to establish the diagnosis CC. A collagen women. Laboratory findings can show a mild eleva- thickness exceeding 45 µm might be an epithelial ted erythrocyte sedimentation rate, a normocytaemic barrier (20,34). Stool weight correlates with severi- anaemia and occasionally abnormalities in serum ty of mucosal inflammation and not with collagen levels of IgG, C3 or C4 complement (8). Differences in thickness (44). The basement membrane consists HLA haplotype between CC and LC have been sug- of collagen type IV. The collagen layer in CC bene- gested. In LC there is an increase in HLA A1 and ath the basement membrane consists of collagen a decrease in HLA A3 haplotype whereas in CC there types I, III and IV, and VI. Collagen I and III are are no differences between patients and controls (6).
thought to be important in tissue repair (6,16).
However, data are limited. Microbiology remains However type VI collagen might be considered to negative. Steatorrhoea and increased excretion of fae- be a pathologic collagen deposition (16).
cal leukocytes are reported in more than 50 % of pati- 2) The inflammation in the lamina propria is domina- ents (44). P-ANCA and other autoimmunologic factors ted by lymphocytes and plasma cells. Eosinophils are found positive, implicating a link with auto-immu- and mast cells can be found but neutrophils are ne diseases. Colonoscopy is the preferred diagnostic very rarely observed (6). Cryptitis and crypt abces- tool given the possibility for proximal and distal biop- ses do not exclude the diagnosis of MC (26).
sies. Radiology is not helpful in recognizing MC.
3) The epithelial cells appear to be flattened and vacuolized. Intraepithelial lymphocyte infiltration is DIAGNOSIS AND HISTOPATHOLOGY
present but is more prominent in LC. A histopatho- Diagnosis is based on classical symptoms of chro- logic diagnosis can be made with endoscopy. Sub- nic watery diarrhoea without blood, abdominal pain, tle endoscopic changes in up to 30 % of cases, normal blood test results, no signs of small bowel such as mucosal oedema, erythema or mucosal malabsorption, and normal microbiology, radiology paleness have been described. Detachment of the and endoscopy. The pathophysiology of the watery surface epithelium can occur. Haemorrhagic diarrhoea has been investigated, with special interest mucosal laceration after insufflation in CC patients for the disturbed electrolyte and water transport in with a thick collagen layer has been recognized CC (15). The mechanisms for diarrhoea in MC inclu- (21). Taking biopsies of macroscopical normal de: I) malabsorption of fluid due to hampered trans- mucosa in cases of diarrhoea is mandatory (27).
port and to collagenous bands. II) secretory diarrho- Considering the patchy distribution of MC in the ea due to anion (chloride) secretion, and III) "leak flux- colon, sigmoideoscopy seems insufficient. Rectal induced diarrhoea" due to an impaired epithelial bar- biopsies might be insufficient in up to 75 % becau- rier secondary to lymphocyte infiltration and thicke- se the collagenous layer seems more prominent in ning of the collagenous band which is comparable the proximal colon. Others could not reproduce with data in Yersinia colitis (15), and to a passive back any diagnostic accuracy between sigmoideoscopy leak of ions and water into the intestine lumen. This is and colonoscopy (32,40,44). Subepithelial collagen probably related to decreased function of the tight deposits are reported in case reports in duodenum and ileum mucosa in CC-patients, so-called colla- matory bowel disease is not significant different from genous enterocolitis or as a primary entity (6). Col- prednisolone but it leads to significant fewer side lagenous gastritis in combination with CC has effects (45). It has effects on both the inflammatory been reported (16,47). Collagenous and lymphocy- mucosal changes as well as the thickness of the col- tic gastritis seems strongly associated with coeliac lagen band (12,33). It is recommended to treat these disease in up to 40 % of the patients (41). Consi- patients during a course with 9 mg budesonide dering the benign course of the disease without (2,10,33). Azathioprine and methotrexate should be any evidence of premalignant potential there considered in steroid-dependent and steroid-refrac- seems to be no need for routine follow-up colo- tory patients (35,46) or as steroid-sparing agent. Data concerning these therapeutics are limited. Azathiopri- ne seems successful in a dose of 2 mg/kg daily (46).
MANAGEMENT
The long term follow-up results are promising with Treatment of MC is still empirical. The first and most high response rates (13). In a minority of patients the important step is to ban all NSAIDs and other colitis diarrhoea remains severe despite treatment. In these inducing medications (44). Additional medication is patients, diverting ileostomy with or without colecto- mostly symptomatic such as bismuth subsalicylate, my is effective, interestingly showing normal ileosto- antidiarrhoeals (loperamide, dephenoxylate, atropine) mic volumes postsurgery (44). These data are similar and high fiber diet. Although bismuth is effective and for CC and LC. Abdo et al. (1) investigated several cli- well tolerated its use in Western Europe is limited nical and histological predictors of response in the because it is not regularly available (2). Step two: treatment of CC. They found that the age of onset 5-ASA agents might be helpful (45% response) determining. Older patients were most likely to be (13,27). Bonner et al. found a short term response in controlled with antidiarrhoeal agents or no medicati- 17/22 (81%) patients using an average 5-ASA dose of on. The younger patients needed more medication.
1500 mg during a-six week period (13). Step three: NSAIDs use at time of presentation was associated (topical) corticosteroids, immunosuppressives such as with greater need for 5-ASA and steroid therapy azathioprine, and octreotide and step four, as a last (1,27). Interestingly, cessation of NSAID in 60 % did resort, surgery. In our experience step four has never not affect the course. Also the degree of inflammati- been necessary. In some studies 40 % of the subjects on of the lamina propria can be used as a predictor.
had complete resolution of symptoms without therapy The more intense the inflammation, the more patients (36). The first group of medication is often well tolera- are likely to fail on symptomatic treatment (1). ted showing good beneficial effects (36). If the patient presents with severe watery diarrhoea, DISCUSSION
step two medication is introduced. If there is no res- MC forms a subclass of inflammatory bowel disea- ponse, corticosteroids are the next step. The respon- se. Some suggest a gradual transition from a LC-like se is 80 % - 100 % but relapses occur during tape- colitis to CC. Wilcox et al. (48) described a patient with ring. Steroids have many side effects. For most, the histological findings of CC and later LC in reaction to usually benign course of MC does not justify prolon- lansoprazole. The thickening of the subepithelial colla- ged use of steroids. Budesonide is a topical acting gen band in CC is believed to be secondary to chro- steroid with a high lipophilicity leading to both a high nic inflammation. Also the similarity in treatment sug- receptor-binding affinity and a high first-pass effect in gests a common pathologic pathway. The collagen the liver. Clinical efficiency of budesonide in inflam- band is the latest microscopic factor to resolve during treatment, stressing the more chronic component. The Table 2 Reported treatment options for microscopic colitis
diagnosis is often only assessed by biopsy. It is Drug
Dosage (mg)
Response (%) Reference
recommendable to obtain at least two specimens from transverse colon, descending colon, sigmoid colon, and rectum. This should lead to the diagnosis in the majority of the patients. Colonoscopy should be used in patients with high suspicion for CC or LC. This is because of the declining histopathological changes from the proximal to the distal colon. The aetiology of similar. First of all, NSAIDs and other colitis-inducing MC is unknown. Three major theories are suggested.
medication should be withdrawn. In mild diarrhoea, First, the lymphocytic infiltration is probably based on fibers and antidiarrhoeal agents can be successfully an adequate immunoresponse to a foreign luminal used. In some cases antibiotics such as erythromycin agent (toxin, microbiological or other substrates).
and metronidazole seemed effective. If this is not suf- Secondly, the CD4 and CD8 lymphocyte distribution ficient, 5-ASA can be added. For more severe mani- in this form of colitis show similarities with coeliac festations of diarrhoea (stool frequency > 5 times/day) disease. The latter suggesting a possible autoimmune topical steroids such as budesonide are the drug of aetiologic factor. Associations with other autoimmune choice. The symptoms resolve quickly and overall it is diseases such as thyroiditis, rheumatoid arthritis, ANA well tolerated. If the disease is relapsing or it is refrac- positive diseases, diabetes mellitus and coeliac dis- tory, long-term immunosuppressives should be consi- ease support this theory. Thirdly, the collagen band dered. The first results with azathioprine are promi- seems secondary to disorders in collagen matrix and sing. Usually the disease has a benign course and in fibrinolytic factors. The treatment in CC and LC is 15.Bürgel N, Bojarski C, Mankertz J, Zeitz M, Fromm M, Schulzke JD. Mechanisms of diarrhoea in collagenous colitis. Gastroen- 1.Abdo A, Raboud J, Freeman HJ, Zetler P, Tilley J, Chaun H, Whittaker JS, Amar J, Halparin L, Enns R. Clinical and histolo- 16.Castellano VM, Munoz MT, Colina F, Nevado M, Casis B, Solis- gical predictors of response to medical therapy in collagenous Herruzo JA. Collagenous gastrobulbitis and collagenous coli- colitis. Am J Gastroenterol 2002; 97: 1164 - 1168. tis. Case report and review of the literature. Scand J Gastroen- 2.Baert F, Schmit A, D’Haens G, Dedeurwaerdere F, Louis E, Cabooter M, De Vos M, Fontaine F, Naegels S, Schurmans P, 17.Chagnon JP, Cerf M. Simvastatin-induced protein-losing ente- Stals H, Geboes K, Rutgeerts P; Belgian IBD Research Group; ropathy. Am J Gastroenterol 1992; 87: 257. Codali Brussels. Budenoside in collagenous colitis: a double- 18.Chan JL, Tersmette AC, Offerhaus GJ, Gruber SB, Bayless TM, blind, placebo-controlled trail with histological follow up. Gast- Giardiello FM. Cancer risk in collagenous colitis. Inflamm 3.Beaugerie L, Luboinsky J, Brousse N, Cocnes J, Chatelet FP, 19.Chauveau E, Prignet JM, Carloz E, Duval JL, Gilles B. Lym- Gendre JP, Le Quintrec Y. Drug induced lymphocytic colitis.
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epiphenomenon of autoimmune disorders? Rom J Gastroente- Professor Chris J.J. Mulder, VU Medical Centre, Department of Gastroenterology, P. O. Box 7057, 1007 MB Amsterdam, 40.Shah DI, Fenoglio-Preiser C, Bleau BL, Giannella RA. Useful- ness of colonoscopy with biopsy in the evaluation of patients

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