170 Gut 2000;46:170–175 Role of bile acids and bile acid binding agents in

patients with collagenous Gut: first published as 10.1136/gut.46.2.170 on 1 February 2000. Downloaded from

K-A Ung, R Gillberg, A Kilander, H Abrahamsson

Abstract aetiological agent.18 Despite the similarity in Background—In a retrospective study bile symptoms between bile acid acid malabsorption was observed in pa- and collagenous colitis, few attempts have been tients with collagenous colitis. made to study a possible relation between the Aims—To study the occurrence of bile two conditions. In a previous study, it was con- acid malabsorption and the eVect of bile cluded that there is no evidence of bile acid acid binders prospectively in patients with malabsorption in patients with collagenous chronic diarrhoea and collagenous colitis. colitis.19 However, according to the 75Se- Methods—Over 36 months all patients homocholic acid taurine (75SeHCAT) test referred because of chronic diarrhoea used, one of the eight patients in that study had completed a diagnostic programme, in- apparent , and another cluding gastroscopy with duodenal , patient had a borderline value. A few patients with , and the 75Se- have been reported to respond favourably to homocholic acid taurine (75SeHCAT) test the bile acid binding agent cholestyramine.320 for bile acid malabsorption. Treatment In one extensively investigated patient with with a bile acid binder (cholestyramine in collagenous colitis the symptoms and even the 24, colestipol in three) was given, irrespec- histological changes disappeared with cholesty- tive of the results of the 75SeHCAT test. ramine treatment.20 There was no direct or Results—Collagenous colitis was found in indirect evidence of bile acid malabsorption in 28 patients (six men, 22 women), 27 of this patient. whom had persistent symptoms and com- In a small retrospective study of 10 patients 75 pleted the programme. Four patients had with collagenous colitis we found the SeH- had a previous cholecystectomy or a distal CAT test to be abnormal in five patients, who gastric resection. The 75SeHCAT test was subsequently responded to treatment with 21 abnormal in 12/27 (44%) of the collagen- cholestyramine. These observations have ous colitis patients with 75SeHCAT values prompted this further study of the role of bile 0.5–9.7%, and normal in 15 patients (56%). acids in collagenous colitis. http://gut.bmj.com/ Bile acid binding treatment was followed The primary aim of the present study was to by a rapid, marked, or complete improve- investigate prospectively the occurrence of bile ment in 21/27 (78%) of the collagenous acid malabsorption in patients with collagen- colitis patients. Rapid improvement oc- ous colitis. Secondly, we wished to elucidate curred in 11/12 (92%) of the patients with the potential value of treatment with bile acid bile acid malabsorption compared with binding agents and to see whether the clinical

10/15 (67%) of the patients with normal eVect was linked to the presence of bile acid on September 29, 2021 by guest. Protected copyright. 75SeHCAT tests. malabsorption. Conclusion—Bile acid malabsorption is common in patients with collagenous Methods Over a period of 36 months all patients colitis and is probably an important (n=404) referred to our Unit pathophysiological factor. Because of a because of severe chronic diarrhoea without high response rate without serious side blood and with negative faecal culture for bac- eVects, bile acid binding treatment should teria, completed a diagnostic programme be considered for collagenous colitis, par- which included gastroscopy with duodenal ticularly patients with bile acid malab- biopsy, colonoscopy with biopsy, and the sorption. 75SeHCAT test for bile acid malabsorption.22 (Gut 2000;46:170–175) Some of the patients included had been Division of referred to our hospital because of persistent Gastroenterology, Keywords: bile acid malabsorption; collagenous colitis; Department of diarrhoea; cholestyramine; colestipol symptoms and a previous, incomplete diagnos- Internal Medicine, tic evaluation. In total 28 patients with Sahlgrenska University collagenous colitis were registered during the Hospital, S-413 45 Chronic diarrhoea is a disabling symptom and three year period. Twenty seven of the patients Göteborg, Sweden represents a considerable diagnostic challenge. had persistent severe diarrhoea. In one male K-A Ung Two possible diagnoses which should be patient the symptoms decreased spontaneously R Gillberg A Kilander considered for every patient with chronic after the colonoscopy; this patient declined the 1–3 75 H Abrahamsson watery diarrhoea are collagenous colitis and SeHCAT test and further treatment. bile acid malabsorption.4 The aetiopathogen- During colonoscopy, biopsy specimens were Correspondence to: esis of collagenous colitis is unknown. There is obtained from the left colon in all patients, Dr K-A Ung. an over representation of autoimmune disor- 3 5–17 Accepted for publication ders in this condition. Furthermore, a Abbreviation used in this paper: SeHCAT, Se 9 September 1999 luminal factor has been proposed as a possible labelled homocholic acid taurine. Bile acids in collagenous colitis 171

from the proximal colon in 22 patients, and six packets a day. If occurred, the from the distal in nine patients. Conven- patients were instructed to decrease the dose.

tional criteria for collagenous colitis were typi- The eVect on diarrhoea was evaluated two Gut: first published as 10.1136/gut.46.2.170 on 1 February 2000. Downloaded from cal microscopic inflammation including an months after the start of treatment. Rapid increased number of intraepithelial lym- improvement was defined as a positive re- phocytes, and a subepithelial collagen layer of sponse, with no more than two stools/day, at least 10 µm.1223Gastroscopy was performed within one week after reaching the optimal on all patients and a duodenal biopsy sample dose, and the patients reporting a persistent was taken for histological evaluation, including marked improvement or complete recovery in a test. In two of three patients the diarrhoeal symptoms at the two month with a history of coeliac disease, normalisation control. A few patients had a slow gradual of the duodenal mucosa with a gluten free diet improvement, taking more than two weeks for a had been shown before this study. clear cut eVect but remaining improved at the two month control point. These patients were 75 SeHCAT TEST not classified as rapid responders, although The procedure for measuring 75SeHCAT they preferred not to discontinue the bile acid retention followed the technique described by binder treatment. Thaysen et al.22 A capsule containing 0.3 MBq If bile acid binder treatment failed, we initi- 75SeHCAT was swallowed. Measurements were ated an optional strategy, based partly on performed with an uncollimated gamma cam- previous reports from small studies and partly era with the patients in a supine position and on the possible risks of long term treatment: the gamma camera positioned at a distance of instead of the bile acid binder, sulphasalazine 60 cm. The initial measurement (value for (Salazopyrin, Pharmacia) 1 g twice daily was 100%) was performed three hours after inges- prescribed for two months. If this therapy tion of the capsule. Retention was then failed, metronidazole 0.4 g was given three measured after four and seven days. A times daily for two weeks followed by 0.4 g retention value of less than 10% on day 7 was twice daily for six months. The final therapeu- considered abnormal.24 25 Medication that tic option of oral steroids was not necessary as could have a potential eVect on bile acid all patients had already responded to one of the absorption was stopped before the test. previous treatments.

TEST FOR BACTERIAL OVERGROWTH OF THE STATISTICAL ANALYSIS SMALL BOWEL The results for stool frequency are presented as The initial 20 patients were tested for bacterial medians, interquartile range, and 10th and overgrowth, either with the hydrogen breath 90th percentiles. A comparison between test after ingestion of 50 g glucose in 250 ml groups with and without bile acid malabsorp-

water (19 patients) or direct culture on duode- tion was performed using the Mann-Whitney http://gut.bmj.com/ nal aspirate (one patient). In one patient with a U test for unpaired data. positive breath test, bacterial overgrowth was confirmed by direct culture on a duodenal Results aspirate. The criteria for positive tests were an BILE ACID ABSORPTION increase in the hydrogen concentration of more Bile acid malabsorption, defined as a 75Se- than 14 ppm over the baseline values26 and a HCAT retention less than 10% on day 7, culture containing more than 105 colonic type occurred in 12 of 27 (44%) patients with colla- bacteria/ml,27 respectively. genous colitis. Figure 1 shows the results of the on September 29, 2021 by guest. Protected copyright. 75SeHCAT test in relation to age and sex. The STOOL FREQUENCY occurrence of bile acid malabsorption was not The stool frequency was recorded daily and the significantly related to age or sex. registration time corresponded to the seven 75 days when the SeHCAT test was performed. STOOL FREQUENCY Data were available for 24 patients. Figure 2A shows the mean number of stools per day for individual patients during the week TREATMENT of symptom registration. There was a signifi- All symptomatic patients (n=27) had a thera- cant negative correlation between the mean peutic challenge with an open label bile acid number of stools and the 75SeHCAT retention binder. Twenty four patients were prescribed on day 7 (p=0.02). Figure 2B shows that stool cholestyramine (Questran, Bristol-Myers frequency was significantly higher in patients Squibb) in dose packets of 4 g. In the case of with collagenous colitis and bile acid malab- three patients who reported considerable prob- sorption than in those without bile acid malab- lems with the smell and the taste of drugs, sorption. colestipol (Lestid, Upjohn) was given instead, in dose packets of 5 g. The patients were DURATION OF SYMPTOMS informed that there is no generally accepted Patients with bile acid malabsorption had a “drug of choice” for collagenous colitis al- significantly longer history of diarrhoea than though bile acid binders have been reported to patients without bile acid malabsorption (me- be eVective in some patients with this disorder. dian 8 years, range 0.5–30 years, n=12 versus The patients were instructed to start treatment median 2 years, range 0.5–15 years, n=15; with one packet two or three times daily. If the p<0.05). There was no significant relation eVect on diarrhoea was insuYcient, they were between the duration of symptoms and the age instructed to increase the dose, if possible up to of the patients. 172 Ung, Gillberg, Kilander, et al

45 acid malabsorption or between autoimmune Male disease and sex.

40 Female Gut: first published as 10.1136/gut.46.2.170 on 1 February 2000. Downloaded from EFFECT OF TREATMENT WITH BILE ACID BINDERS 35 Treatment with a bile acid binder was given to all symptomatic patients (cholestyramine to 24 30 patients, colestipol to three patients) with collagenous colitis. A rapid improvement with 25 a clear cut decrease in diarrhoea within one week was noted in 21 of the 27 patients (“rapid 20 responders” to bile acid binders). Six patients did not show this rapid response. Eleven of 12 15 patients with bile acid malabsorption (92%) showed a rapid response, while in patients with SeHCAT retention day 7 (%) SeHCAT 10 a normal 75SeHCAT test this response rate was 67%. Another two patients, including the non- 5 responding patient with bile acid malabsorp- tion, improved slowly over a period of one to 0 two months. All the non-responders were 20 30 4050 60 70 80 90 Age (years) women over 50 years old. However, there was no statistically significant relation between sex 75 Figure 1 SeHCAT retention on day 7 in 27 patients with collagenous colitis. or age and the outcome of treatment with bile 9 acid binders. A The daily dose of bile acid binder needed to 8 control diarrhoeal symptoms ranged from 0.5 7 to 6 (median: 2.5) packets daily (cholesty- ramine4gorcolestipol 5 g per packet). The 6 highest dose needed was cholestyramine 24 g 5 daily, in one particular patient. This dose could later be reduced to 16 g daily. All three patients 4 treated with colestipol, one with and two with- 3 out bile acid malabsorption, responded rapidly Number of stools/24 h 2 to treatment.

1 0 5 10 15 20 25 30 35 40 45 OUTCOME OF TREATMENT STRATEGY SeHCAT retention day 7 (%) Figure 3 illustrates the outcome of treatment of

the 27 symptomatic patients with collagenous http://gut.bmj.com/ 9 colitis. Twenty three of the symptomatic B p = 0.01 patients improved rapidly or slowly when 8 treated with a bile acid binder alone. Three of 7 the remaining four patients, with no improve- ment or only a slight improvement with a bile 6 acid binder, responded to either sulphasalazine 5 alone (two patients) or an inadvertent combi- nation of cholestyramine and sulphasalazine on September 29, 2021 by guest. Protected copyright. 4 (one patient). The remaining symptomatic 3 patient responded to metronidazole within two Number of stools/24 h weeks and remained asymptomatic during the 2 long term treatment period of six months with 1 metronidazole 0.8 g per day. SeHCAT < 10% SeHCAT > 10% As all patients with collagenous colitis had Figure 2 Relation between stool frequency and bile acid suYcient control of the diarrhoea before the malabsorption in patients with collagenous colitis. (A) The fourth optional treatment, steroids were not mean individual number of stools was negatively correlated to the 75SeHCAT retention on day 7 (p=0.02). (B) Box used in this study. plot of stool frequency in patients with and without bile acid malabsorption. COLLAGEN LAYER Ten of the patients with collagenous colitis had a collagen layer thicker than 20 µm. The ASSOCIATED DISEASES remaining patients had a collagen layer thick- Table 1 presents the occurrence of autoim- ness in the range 10–20 µm. There was no sta- mune diseases and previous abdominal sur- tistical diVerence in the 75SeHCAT test be- gery. Eleven patients (41%) had at least one tween the patients with a thick layer (median associated autoimmune disease. Four patients 75SeHCAT value 11%) and those with a layer had had one or two abdominal operations, 10–20 µm (median 75SeHCAT value 11%). including three patients with cholecystectomy, Eight of the nine patients who had ileal all showing bile acid malabsorption. Fourteen biopsies performed had normal histology. patients (52%) had no history of autoimmune Three of these had low 75SeHCAT values. One disease or a history of abdominal surgery. patient with coeliac disease had atrophy of the There was no statistical correlation between ileal and the duodenal mucosa but had a autoimmune disease and the occurrence of bile normal 75SeHCAT value of 13%. All of the Bile acids in collagenous colitis 173

Table 1 Number of patients with associated conditions, and the individual 75SeHCAT patient group was female dominated and there values in 27 patients with collagenous colitis was a high prevalence of autoimmune diseases, 3 5–17

comparable to previous reports. However, Gut: first published as 10.1136/gut.46.2.170 on 1 February 2000. Downloaded from Disease n 75SeHCAT retention (%) the occurrence of bile acid malabsorption in Diabetes mellitus 4 9.7; 21; 33; 33 our collagenous colitis patients showed no sta- Coeliac disease 3 5.0; 13; 31 Thyroid disease 2 0.8; 15 tistical association with sex, presence of Rheumatic disease 2 2.0;13 autoimmune disease, or age. The association Dermatitis herpetiformis 1 5.0 between bile acid malabsorption and cholecys- Pernicious anaemia 1 33 Abdominal surgery tectomy or gastric resection has been described Cholecystectomy 1 2.0 previously,22 28 although the present study Billroth I resection 1 31 shows that collagenous colitis might also Cholecystectomy and Billroth I resection 1 0.8 Cholecystectomy and sigmoid resection 1 5.0 contribute to diarrhoea in these patients. The simultaneous occurrence of bile acid Eleven patients (41%) had at least one autoimmune disease. malabsorption in patients with collagenous colitis may influence the clinical presentation Registered Bile acid Status Untreated Sulphasalazine Metronidazole of the patients. Despite similar histological patients binder findings, including the thickness of the collagen layer and similarities in other parameters Rapid between patients with and without bile acid improvement 21 2 1 malabsorption, patients with bile acid malab- 1–2 weeks sorption had more symptoms, manifested as significantly higher stool frequency. The patients with collagenous colitis and Symptomatic 28 27 4 1 concomitant bile acid malabsorption had a sig- nificantly longer history of diarrhoea than patients without bile acid malabsorption. The Slow reason for this is not obvious from the present improvement 1 2 1 data. > 1 month The aetiopathogenesis of bile acid malab- sorption and collagenous colitis is in many Figure 3 Resolution of diarrhoea in 28 patients with collagenous colitis. aspects still obscure. The high occurrence of autoimmune disorders in the present and pre- remaining patients had a normal duodenal vious reports suggests a genetic predisposition histopathology. Consequently, none had colla- to collagenous colitis.3 5–17 The occurrence of genous changes of the duodenal or the ileal small bowel bacteria or toxins of bacterial ori- mucosa. gin has also been suggested.14 20 However, we

found no obvious relation between small bowel http://gut.bmj.com/ TEST FOR BACTERIAL OVERGROWTH OF THE bacterial overgrowth and collagenous colitis. SMALL BOWEL Only one of 20 patients tested for bacterial Nineteen patients had a hydrogen breath test overgrowth in this study showed small bowel and one patient had a culture from duodenal bacterial overgrowth. This particular patient, aspirate to test for bacterial overgrowth. Nine apart from a previous cholecystectomy, had of these patients had bile acid malabsorption also had a previous Billroth I operation predis- and 11 patients had normal 75SeHCAT values. posing for bacterial overgrowth.29 She re- The bacterial culture on the duodenal aspirate sponded to continuous cholestyramine treat- on September 29, 2021 by guest. Protected copyright. was negative and the breath test showed ment. This patient had a few later relapses of increased hydrogen values compatible with diarrhoea during cholestyramine treatment. bacterial overgrowth in only one of the patients These relapses ceased when treatment for tested. In this particular patient, bacterial over- intestinal bacteria with norfloxacin was given growth was confirmed by a positive bacterial for periods of one to two weeks, during which culture on duodenal aspirate. This patient had she still had to maintain the ordinary dose of a history of cholecystectomy and Billroth I gas- cholestyramine to control the diarrhoea. In this tric resection due to . As 19 interesting case, the diarrhoea promoting of the first 20 patients tested were negative, and factors bacterial overgrowth and bile acid mal- the patient with bacterial overgrowth had a absorption were apparently independent of strong predisposing factor, the remaining seven each other. patients were not tested for bacterial over- Ileal biopsy specimens were available from growth. nine patients, three of whom had bile acid mal- absorption. However, ileal histology and duo- Discussion denal histology were normal except in one In this prospective study on the potential role patient, who had coeliac disease and atrophy of of bile acids in collagenous colitis we found the ileal and the duodenal mucosa but a using the 75SeHCAT method that bile acid normal 75SeHCAT value. As in previous series malabsorption occurred in a considerable pro- of patients with ,389 there portion (44%) of the patients. This is in was also an increased proportion of coeliac dis- accordance with a few earlier observations in ease in our study. None of the patients showed small studies, including our own initial report signs of collagenous or collagenous on the eVect of cholestyramine on patients with , conditions that have been previously collagenous colitis.32021 As in the previous described in a few case reports.30–33 In the series of patients with collagenous colitis, our present study, small bowel factors as shown by 174 Ung, Gillberg, Kilander, et al

tests of bacterial overgrowth and by the histol- context, it is of interest that in none of our ogy of duodenal and ileal mucosa, could not patients could the collagenous colitis related

explain the occurrence of collagenous colitis diarrhoea be linked to small bowel bacterial Gut: first published as 10.1136/gut.46.2.170 on 1 February 2000. Downloaded from and the associated bile acid malabsorption. overgrowth. The main pathophysiological mechanism for Hitherto, there has been no generally the occurrence of diarrhoea in collagenous accepted drug of choice for the treatment of colitis is suggested to be reduced permeability patients with collagenous colitis. In the present for electrolytes and water in the colonic study we had a treatment strategy with mucosa,11434while the active absorption of bile additional options based on the previously acids occurs in the terminal ileum.35 Other reported eVects of sulphasalazine, antibiotics, diarrhoeal disorders of colonic origin have not and steroids. The risk of long term treatment been shown to cause abnormal 75SeHCAT with metronidazole, particularly neuropathy, values.36 37 Diarrhoea per se might reduce the prompted us to choose sulphasalazine as the 75SeHCAT value but not to an abnormal second line drug and metronidazole as the level.25 38 39 This suggests that the low 75Se- third option, should bile acid binders fail. HCAT values found in the present study Remarkably, all 27 patients responded to one correspond to a reduced capacity to absorb bile of the first three choices and steroids, the acids in the ileum and are not due to a colonic fourth option, were not prescribed. Further malabsorption secondary to the diarrhoea studies are needed to evaluate the histological caused by collagenous colitis. improvement during the course of the various The present prospective study tested types of treatment. As steroids do not heal the whether the clinical response of patients with inflammatory changes in the colonic mucosa in collagenous colitis to treatment with an open patients with collagenous colitis,40 the strategy label bile acid binder is related to simultaneous of using a bile acid binder as the first line treat- bile acid malabsorption—that is, whether the ment with 5-acetylsalicylic acid/sulphasalazine result of the 75SeHCAT test could predict the and antibiotics as alternative drugs, seems outcome of treatment. All patients with bile attractive. Apart from the taste problem and for acid malabsorption, defined as a low value with some patients the smell, as well as the potential the 75SeHCAT test, responded to bile acid need for vitamin supplements, side eVects from binders. Eleven of 12 patients showed a rapid bile acid binders are rare. response. The twelfth patient showed a slower In patients with collagenous colitis without but positive response, which could be a drug bile acid malabsorption, bile acid binders may eVect or it could represent the natural course of also be the first option. However, apart from the disease similar to the spontaneously bile acid binders, bismuth subsalicylate has improved patient. recently been reported to have a good clinical There was no statistically significant diVer- eVect on patients with microscopic colitis.41 42

ence in the response rate in patients with and In one patient with microscopic colitis, a http://gut.bmj.com/ without bile acid malabsorption. This was due normal 75SeHCAT value, and disabling diar- to the relatively high response rate (67%) in rhoea, refractory to six diVerent drugs includ- non-bile acid malabsorption patients. The ing cholestyramine, the response to bismuth results suggest that in patients with collagenous subsalicylate was excellent.42 Further placebo colitis and bile acid malabsorption, treatment controlled studies should take various aetio- of the observed bile acid malabsorption was pathogenic factors into consideration and suYcient to obtain a clinical response and none evaluate the eVect of bile acid binders, of the drugs used for inflammatory bowel bismuth, and other drugs of potential interest. on September 29, 2021 by guest. Protected copyright. disease was needed. It seems less likely that the In conclusion, the present study shows that a rapid response, often within a few days, could considerable proportion of patients with colla- correspond to a normalisation of the colonic genous colitis have bile acid malabsorption and mucosa. However, no detailed information is as that in these patients bile acid binders seem to yet available regarding the regression of be the first line treatment. Moreover, in histological inflammation during bile acid collagenous colitis patients without bile acid binder treatment although this issue is now malabsorption, two thirds responded to a bile under investigation (Ung et al, to be pub- acid binder (cholestyramine or colestipol). The lished). results show that bile acids may be an The high response rate to the bile acid bind- important aetiopathogenic factor, although not ers, even in patients with a normal 75SeHCAT the only factor, in patients with collagenous test value, suggests that cholestyramine and colitis. colestipol may also have clinical eVects on col- lagenous colitis through mechanisms other This study was supported by the Swedish Medical Research than pure bile acid binding. This would be in Council (grant 8288) and by the Faculty of Medicine, Univer- agreement with a previous case report, where sity of Göteborg. This work was presented in part at the 1997 meeting of the American Gastroenterological Association and the patient with collagenous colitis responded published in abstract form (Gastroenterology 1997;112:A1108). to cholestyramine. However, direct tests of bile acid malabsorption were not performed in that 1 Lindström CG. “Collagenous colitis” with watery patient. The mechanisms of cholestyramine diarrhoea—a new entity? Pathol Eur 1976;11:87–9. were suggested to be binding of toxins and 2 Bogomoletz MV, Flejou JF. Newly recognised forms of 20 colitis: collagenous colitis, microscopic (lymphocytic) coli- other eVects on the intraluminal contents. tis and lymphoid follicular . Semin Diagn Pathol Alternatively, the colonic inflammation may be 1991;8:178–89. 3 Bohr J, Tysk C, Eriksson S, et al. Collagenous colitis: a ret- the result of an abnormal reaction to normal rospective study of clinical presentation and treatment in amounts of bile acids entering the colon. In this 163 patients. Gut 1996;39:846–51. Bile acids in collagenous colitis 175

4 Merrick MV, Eastwood MA, Ford MJ. Is bile acid 25 Fellous K, Jian R, Haniche M, et al. Mesure de lábsorption malabsorption underdiagnosed? An evaluation of accuracy ileale des sels biliaires par le test à l’homotaurocholate mar- of diagnosis by measurement of SeHCAT retention. BMJ qué au sélénium 75. Validation et signification clinique.

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