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5 5 0 Collagenous and lymphocytic 0 colitis: A clinical and histopathological review

Johan Bohr MD PhD, Martin Olesen MD, Curt Tysk MD PhD, Gunnar Järnerot MD PhD

J Bohr, M Olesen, C Tysk, G Järnerot. Collagenous and lym- Colite collagénique et lymphocytaire : revue phocytic colitis: A clinical and histopathological review. Can J Gastroenterol 2000;14(11):943-947. Collagenous colitis and clinique et histopathologique lymphocytic colitis are newly described colitides that are only di- RÉSUMÉ : La colite collagénique et la colite lymphocytaire sont des coli- agnosable microscopically; therefore, both are known under the tes nouvellement décrites qui ne sont diagnostiquables qu’au microscope. umbrella term ‘microscopic colitis’. This is a short review of the Par conséquent, les deux se retrouvent sous le terme « colite microscopi- clinical findings, and epidemiological and basic observations of que ». Voici une brève synthèse des signes cliniques et des observations these relatively little described colitides belonging to the group of épidémiologiques et fondamentales associés à ces colites relativement peu inflammatory bowel diseases. décrites, appartenant au groupe des maladies inflammatoires de l’intestin. Key Words: Collagenous colitis; Inflammatory bowel disease; Lym- phocytic colitis; Microscopic colitis

he term ‘microscopic colitis’ (MC) generally refers to this disease below the age of 12 years have been reported. Ttwo forms of colonic inflammation: collagenous colitis However, CC was diagnosed in 25% of 163 patients before (CC) and lymphocytic colitis (LC). CC was first described the age of 45 years, so it must be considered in younger sub- by Lindström (1) in 1976, and in an abstract the same year, jects with chronic watery diarrhea (6). Freeman et al (2) reported two patients with a similar histo- CC was regarded as a very rare disease, but the first epide- pathological picture. The term ‘LC’ was suggested by Lazenby miological study showed an incidence of 1.8 in 105 people et al (3) in 1989. The predominant clinical symptom in both per year and a prevalence of 15.7 in 105 people (4). The an- diseases is chronic watery diarrhea. In both cases, the colonic nual incidence reached a maximum of 14.6 in 105 inhabi- mucosa appears normal endoscopically and radiologically. tants in women aged 70 to 79 years, which is similar to that Microscopic examination of colonic mucosal biopsies, how- of ulcerative colitis (Figure 1). In a recent epidemiological ever, reveals specific histopathological features. study, the incidence of CC was 1.1 in 105 people per year (5); new preliminary data (Olesen, unpublished data) show 100 100 COLLAGENOUS COLITIS an even higher incidence of around four in 105 people per

95 Epidemiology: Patients with CC are typically middle-aged year. 95 women. The female to male ratio varies in the literature Histopathology: CC is diagnosed based on the following 75 from six to one, to nine to one (4,5). Only four children with histopathological features in the colorectal mucosa. 75

This mini-review was prepared from a presentation made at the World Congress of Gastroenterology, Vienna, Austria, September 6 to 11, 1998 Department of Medicine, Division of Gastroenterology, Örebro Medical Centre Hospital, Örebro, Sweden 25 Correspondence: Dr Johan Bohr, Department of Medicine, Division of Gastroenterology, Örebro Medical Centre Hospital, S-701 85 Örebro, 25 Sweden. Telephone +46-19-153762, fax +46-19-6021774, e-mail [email protected] 5 5 Received for publication June 24, 1999. Accepted June 28, 1999

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Figure 2) Biopsy from colon showing typical findings of collagenous coli- tis – increased subepithelial collagen layer, inflammation of lamina pro- Figure 1) Age- and sex-specific incidence of collagenous colitis. pria and epithelial lesions with intraepithelial lymphocytes Reprinted with permission from reference 4

· A diffuse noncontinuous thickening of a subepithelial with CC, these patients often use nonsteroidal anti-inflam- collagen layer beneath the basement membrane matory drugs (NSAIDs). In one study, the use of NSAIDs throughout the colon. The thickness of the was significantly more common in CC patients than in a subepithelial layer must be 10 µm or more on a well control group, and discontinuation of NSAIDs was followed orientated section of the mucosa, compared with by improvement of the diarrhea in some patients (15). Most 0 to 3 µm in healthy individuals. patients with CC, however, do not use NSAIDs; therefore, it · The inflammation in the lamina propria is dominated can only be one of several possible etiological factors (6). by lymphocytes and plasma cells. Eosinophils and The thickened subepithelial collagen layer may cause di- mast cells can be found, but neutrophils are very arrhea in patients with CC by reducing the permeability for rarely seen. electrolytes and water. However, fasting reduced the stool weight and sodium output in patients with CC, which im- · Flattening and vacuolization of the epithelial cells and plies that an osmotic mechanism is important (Bohr, unpub- detachment of the surface epithelium are seen. lished data). The inflammatory cell infiltrate in the lamina Intraepithelial lymphocyte infiltration is present, propria may also have a pathophysiological role; a correla- though not as prominent as in LC (3,7) (Figure 2). tion between the degree of inflammation in the lamina pro- The disease is mainly located in the colon and the rectum. pria and the stool frequency has been noted (16). Deposit of subepithelial collagen has infrequently been re- Nitric oxide is increased in patients with MC (17,18) and ported in the duodenum and stomach, as well as in the termi- seems to be correlated with the histopathological findings in nal ileum in some patients with CC. Within the colon and patients with CC (19) rather than with clinical symptoms. rectum, the collagenous layer is most prominent in the Nitric oxide is known to be increased in other forms of in- proximal part of the colon and may be absent in the rectal flammatory bowel disease as well (20). It functions as an in- mucosa in 18% to 73% of biopsy specimens (5,8,9). flammatory mediator, but its role is unclear (21). Etiology and pathophysiology: The etiology of CC is un- known. Based on the finding of an increased number of CLINICAL FEATURES AND DIAGNOSIS T lymphocytes in the epithelium, several authors have pro- In a study of 163 CC patients, 40% of the patients described posed and supported the theory that CC may be caused by an the onset as sudden (6). Some patients could even recall the abnormal immunological reaction to a luminal agent in pre- exact date of onset, just as in an infectious gastroenteritis. disposed individuals (7,10,11). Diversion of the fecal stream Watery diarrhea is the primary symptom in CC and may be normalizes or reduces the characteristic histopathological accompanied by nocturnal diarrhea, crampy abdominal pain

100 changes in CC (12), which supports the theory that an ex- and distension. Initial weight loss is common and occasion- 100 ogenous agent can trigger the disease. The effect of various ally pronounced. Serious dehydration is rare, although daily 95 antibiotics and the sudden onset of the disease in a propor- stool volumes up to 5 L have been reported. Mucus or blood 95 tion of the patients (6) suggest that such an agent may be of in the stools is uncommon (6). 75 microbiological origin. This view is further supported by a re- In patients with CC, the relative risk of developing colo- 75 cent study in which Yersinia enterocolitica was detected in rectal cancer does not appear to be increased (22). The three of six patients before diagnosis of CC (13), and a sero- course in the majority of cases seems to be chronic relapsing 25 logical study that showed that Yersinia species were more and benign (23). In a follow-up study, 63% of patients had 25 common in CC patients than in healthy controls (14). lasting remission after 3.5 years (24). For a number of CC 5 Due to the frequent occurrence of arthritis in patients patients, however, remission is difficult to achieve, and such 5

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95 patients have often tried many different treatments in vain Surgery is an alternative for patients with severe, 95 (6). unresponsive CC (12), but the increasing success of medical 75 Patients with CC often have concomitant diseases. Up to treatment in these patients makes it important to consider 75 40% have one or more associated autoimmune diseases. The carefully whether all other options have been tried. most common are rheumatoid arthritis, thyroid disorders,

25 celiac disease, asthma/allergy and diabetes mellitus (6). Co- LYMPHOCYTIC COLITIS 25 existence of Crohn’s disease or ulcerative colitis with CC has The term ‘MC’ was introduced in 1980 by Read et al (40) as 5 occasionally been reported (6). a name for a mild form of colonic inflammation in patients 5 There is no single parameter in the blood tests that makes with chronic watery diarrhea but normal results on endo- 0 0 screening for patients with CC possible. The erythrocyte scopy and barium enema. In 1989, Lazenby et al (3) proposed sedimentation rate may be mildly elevated (6). Analyses of changing the name of MC to LC based on comparative mor- perinuclear antineutrophil cytoplasmic antibodies (25) or phological studies because the major distinguishing feature serum procollagen III propeptide are not of diagnostic value of MC was an increased number of intraepithelial lympho- (26). Stool examinations reveal no pathological organisms, cytes. MC has evolved as an umbrella term that includes though increased excretions of fecal leukocytes have been both CC and LC. There is less scientific and clinical knowl- reported in more than half of the CC patients (27). edge of LC than of CC. The results of a barium enema and endoscopy are usually Epidemiology: In the only published, population-based, epi- normal (28), although subtle endoscopic changes such as demiological study of LC, an annual incidence of 3.1 cases mucosal edema, granularity and erythema may be seen in up per 105 population was found (5). There was a peak inci- to 30% of cases (6). Pancolonoscopy must be preferred to sig- dence in older women. The mean age at onset of symptoms moidoscopy because a thickened collagenous layer may be was 64 years, and the female to male ratio was 2.7 to one. absent in 18% to 73% of rectal biopsy specimens, as men- Preliminary unpublished data gave similar epidemiological tioned above. results (Olesen, unpublished data). Therapy: Loperamide and cholestyramine drugs have been Etiology: The cause of LC is unknown. There have been re- reported to be of benefit in the majority of CC patients and ports on drug-induced disease, particularly in association are recommended as primary treatment (6,29,30). with Cyclo 3 Fort (Laboratoires Pierre Fabre Cardiovascu- Sulphasalazine is often the second choice if treatment laire, France) and ticlopidine, and occasionally with raniti- with loperamide or cholestyramine fails. It is of benefit in dine, , or tardyferon treatment about 60% of cases (6,29). Mesalazine and olsalazine have (41-53). The onset of LC after an infection with Campylo- been tried in small series and case reports with effect in 50% bacter jejuni has been reported (54). Of special interest in this and 40%, respectively (6). context is the condition known as ‘Brainerd diarrhea’, a term Metronidazole and were the most frequently that has been applied to outbreaks of chronic watery diar- prescribed antibiotic drugs for the treatment of CC, and ap- rhea characterized by acute onset and prolonged duration proximately 60% of patients responded temporarily to one of (55). Colonic biopsies in these patients show epithelial lym- these treatments (6). phocytosis similar to CC and LC but not the surface epithe- is the most effective therapy, and up to 80% lial changes. Furthermore, abnormalities of colonic histology of patients respond. The effect, however, is usually not sus- resembling LC have been reported in patients with un- tained after withdrawal, and the dose required to maintain treated celiac disease (56). From these observations, it may remission is often unacceptably high – more than 20 mg/day be hypothesized that LC arises in predisposed individuals as a (6,31). Budesonide has been tried in several patients with a specific mucosal reaction to different mucosal insults. similar response rate as for prednisolone (6,32,33,34), even Clinical features, diagnosis and histopathology: The clini- in patients who are refractory to prednisone (35). As for cal picture of LC is similar to that of CC, and the predomi- prednisolone, the effect of budesonide is often not sustained nant symptom is chronic watery diarrhea, but a recent report after withdrawal, but in some patients it can be tapered to found that symptoms associated with LC were milder and 3 mg/day (32-35). more likely to disappear than those associated with CC (57). A positive effect of bismuth subsalicylate and bismuth The colonic mucosa is macroscopically normal, and the di- subnitrate in the treatment of CC has been reported (36,37). agnosis can only be made histopathologically. The major

100 In two recent reports (38,39), one of which was placebo histopathological features are epithelial lesions, an increase 100 controlled (39), patients with CC and LC responded both in intraepithelial lymphocytes (more than 20 lymphocytes 95 clinically and histopathologically to bismuth subsalicylate, per 100 epithelial cells), and an infiltration of the lamina 95 and the effect was mostly sustained after the treatment was propria with lymphocytes and plasma cells (Figure 3). The 75 withdrawn. One study of the use of bismuth subnitrate in intraepithelial lymphocytes are predominantly CD8+ lym- 75 seven CC patients and one LC patient showed a good imme- phocytes expressing the alpha-beta T-cell receptor, whereas diate clinical effect, but the diarrhea relapsed shortly after the lymphocytes in the lamina propria are mostly of the + 25 withdrawal (34). CD4 haplotype (58). 25 There are case reports on therapy with azathioprine, Because the histopathological features of CC and LC are 5 methotrexate and octreotide, but the data are very limited. similar, with the exception of the subepithelial collagen 5

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95 collagenous. However, most cases of LC remained un- 95 changed. In addition, there seems to be differences in the sex 75 ratio and in the distribution of human leukocyte haplotypes 75 between CC and LC, so that they are considered to be two separate but similar diseases. The importance of genetics in

25 MC is unknown. Familial occurrence of CC has been re- 25 ported in two families (59), and in one MC register, there 5 were five families in which two sisters in each family had 5 some form of MC (Järnerot, unpublished data). 0 0 Similar to CC, LC has been reported in association with autoimmune diseases. The occurrence of collagenous gastri- tis and LC (60), and primary ileal villous atrophy and LC have occasionally been reported (61). Figure 3) Biopsy from colon showing typical findings of lymphocytic co- Prognosis and therapy: The prognosis of LC seems to be litis – epithelial lesions with intraepithelial lymphocytes and inflammation in the lamina propria good. There is no increased mortality and no increased risk of subsequent bowel malignancy reported. Mullhaupt et al (62) reported a benign course in 27 cases with resolution of diarrhea and normalization of histology in more than 80% of band found only in the former condition, it has been pro- patients within 38 months. Although no controlled data on posed that CC is a later stage of LC. Indeed, a few reports the treatment of LC exist, the guidelines mentioned above have described the conversion of colitis from lymphocytic to for CC can be followed.

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