Results

BILE ACID ABSORPTION

Bile acid malabsorption, defined as a ⁷⁵SeHCAT retention less than 10% on day 7, occurred in 12 of 27 (44%) patients with collagenous colitis. Figure 1 shows the results of the⁷⁵SeHCAT test in relation to age and sex. The occurrence of bile acid malabsorption was not significantly related to age or sex.

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Figure 1

⁷⁵SeHCAT retention on day 7 in 27 patients with collagenous colitis.

STOOL FREQUENCY

Figure 2A shows the mean number of stools per day for individual patients during the week of symptom registration. There was a significant negative correlation between the mean number of stools and the ⁷⁵SeHCAT retention on day 7 (p=0.02). Figure 2B shows that stool frequency was significantly higher in patients with collagenous colitis and bile acid malabsorption than in those without bile acid malabsorption.

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Figure 2

Relation between stool frequency and bile acid malabsorption in patients with collagenous colitis. (A) The mean individual number of stools was negatively correlated to the⁷⁵SeHCAT retention on day 7 (p=0.02). (B) Box plot of stool frequency in patients with and without bile acid malabsorption.

DURATION OF SYMPTOMS

Patients with bile acid malabsorption had a significantly longer history of diarrhoea than patients without bile acid malabsorption (median 8 years, range 0.5–30 years, n=12 versus median 2 years, range 0.5–15 years, n=15; p<0.05). There was no significant relation between the duration of symptoms and the age of the patients.

ASSOCIATED DISEASES

Table 1 presents the occurrence of autoimmune diseases and previous abdominal surgery. Eleven patients (41%) had at least one associated autoimmune disease. Four patients had had one or two abdominal operations, including three patients with cholecystectomy, all showing bile acid malabsorption. Fourteen patients (52%) had no history of autoimmune disease or a history of abdominal surgery. There was no statistical correlation between autoimmune disease and the occurrence of bile acid malabsorption or between autoimmune disease and sex.

EFFECT OF TREATMENT WITH BILE ACID BINDERS

Treatment with a bile acid binder was given to all symptomatic patients (cholestyramine to 24 patients, colestipol to three patients) with collagenous colitis. A rapid improvement with a clear cut decrease in diarrhoea within one week was noted in 21 of the 27 patients (“rapid responders” to bile acid binders). Six patients did not show this rapid response. Eleven of 12 patients with bile acid malabsorption (92%) showed a rapid response, while in patients with a normal ⁷⁵SeHCAT test this response rate was 67%. Another two patients, including the non-responding patient with bile acid malabsorption, improved slowly over a period of one to two months. All the non-responders were women over 50 years old. However, there was no statistically significant relation between sex or age and the outcome of treatment with bile acid binders.

The daily dose of bile acid binder needed to control diarrhoeal symptoms ranged from 0.5 to 6 (median: 2.5) packets daily (cholestyramine 4 g or colestipol 5 g per packet). The highest dose needed was cholestyramine 24 g daily, in one particular patient. This dose could later be reduced to 16 g daily. All three patients treated with colestipol, one with and two without bile acid malabsorption, responded rapidly to treatment.

OUTCOME OF TREATMENT STRATEGY

Figure 3 illustrates the outcome of treatment of the 27 symptomatic patients with collagenous colitis. Twenty three of the symptomatic patients improved rapidly or slowly when treated with a bile acid binder alone. Three of the remaining four patients, with no improvement or only a slight improvement with a bile acid binder, responded to either sulphasalazine alone (two patients) or an inadvertent combination of cholestyramine and sulphasalazine (one patient). The remaining symptomatic patient responded to metronidazole within two weeks and remained asymptomatic during the long term treatment period of six months with metronidazole 0.8 g per day.

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Figure 3

Resolution of diarrhoea in 28 patients with collagenous colitis.

As all patients with collagenous colitis had sufficient control of the diarrhoea before the fourth optional treatment, steroids were not used in this study.

COLLAGEN LAYER

Ten of the patients with collagenous colitis had a collagen layer thicker than 20 μm. The remaining patients had a collagen layer thickness in the range 10–20 μm. There was no statistical difference in the ⁷⁵SeHCAT test between the patients with a thick layer (median ⁷⁵SeHCAT value 11%) and those with a layer 10–20 μm (median ⁷⁵SeHCAT value 11%).

Eight of the nine patients who had ileal biopsies performed had normal histology. Three of these had low ⁷⁵SeHCAT values. One patient with coeliac disease had atrophy of the ileal and the duodenal mucosa but had a normal ⁷⁵SeHCAT value of 13%. All of the remaining patients had a normal duodenal histopathology. Consequently, none had collagenous changes of the duodenal or the ileal mucosa.

TEST FOR BACTERIAL OVERGROWTH OF THE SMALL BOWEL

Nineteen patients had a hydrogen breath test and one patient had a culture from duodenal aspirate to test for bacterial overgrowth. Nine of these patients had bile acid malabsorption and 11 patients had normal ⁷⁵SeHCAT values. The bacterial culture on the duodenal aspirate was negative and the breath test showed increased hydrogen values compatible with bacterial overgrowth in only one of the patients tested. In this particular patient, bacterial overgrowth was confirmed by a positive bacterial culture on duodenal aspirate. This patient had a history of cholecystectomy and Billroth I gastric resection due to peptic ulcer disease. As 19 of the first 20 patients tested were negative, and the patient with bacterial overgrowth had a strong predisposing factor, the remaining seven patients were not tested for bacterial overgrowth.

Discussion

In this prospective study on the potential role of bile acids in collagenous colitis we found using the ⁷⁵SeHCAT method that bile acid malabsorption occurred in a considerable proportion (44%) of the patients. This is in accordance with a few earlier observations in small studies, including our own initial report on the effect of cholestyramine on patients with collagenous colitis.3 20 21 As in the previous series of patients with collagenous colitis, our patient group was female dominated and there was a high prevalence of autoimmune diseases, comparable to previous reports.3 5-17 However, the occurrence of bile acid malabsorption in our collagenous colitis patients showed no statistical association with sex, presence of autoimmune disease, or age. The association between bile acid malabsorption and cholecystectomy or gastric resection has been described previously,22 28 although the present study shows that collagenous colitis might also contribute to diarrhoea in these patients.

The simultaneous occurrence of bile acid malabsorption in patients with collagenous colitis may influence the clinical presentation of the patients. Despite similar histological findings, including the thickness of the collagen layer and similarities in other parameters between patients with and without bile acid malabsorption, patients with bile acid malabsorption had more symptoms, manifested as significantly higher stool frequency.

The patients with collagenous colitis and concomitant bile acid malabsorption had a significantly longer history of diarrhoea than patients without bile acid malabsorption. The reason for this is not obvious from the present data.

The aetiopathogenesis of bile acid malabsorption and collagenous colitis is in many aspects still obscure. The high occurrence of autoimmune disorders in the present and previous reports suggests a genetic predisposition to collagenous colitis.3 5-17 The occurrence of small bowel bacteria or toxins of bacterial origin has also been suggested.14 20 However, we found no obvious relation between small bowel bacterial overgrowth and collagenous colitis. Only one of 20 patients tested for bacterial overgrowth in this study showed small bowel bacterial overgrowth. This particular patient, apart from a previous cholecystectomy, had also had a previous Billroth I operation predisposing for bacterial overgrowth.29 She responded to continuous cholestyramine treatment. This patient had a few later relapses of diarrhoea during cholestyramine treatment. These relapses ceased when treatment for intestinal bacteria with norfloxacin was given for periods of one to two weeks, during which she still had to maintain the ordinary dose of cholestyramine to control the diarrhoea. In this interesting case, the diarrhoea promoting factors bacterial overgrowth and bile acid malabsorption were apparently independent of each other.

Ileal biopsy specimens were available from nine patients, three of whom had bile acid malabsorption. However, ileal histology and duodenal histology were normal except in one patient, who had coeliac disease and atrophy of the ileal and the duodenal mucosa but a normal⁷⁵SeHCAT value. As in previous series of patients with microscopic colitis,3 8 9 there was also an increased proportion of coeliac disease in our study. None of the patients showed signs of collagenous duodenitis or collagenous ileitis, conditions that have been previously described in a few case reports.30-33 In the present study, small bowel factors as shown by tests of bacterial overgrowth and by the histology of duodenal and ileal mucosa, could not explain the occurrence of collagenous colitis and the associated bile acid malabsorption.

The main pathophysiological mechanism for the occurrence of diarrhoea in collagenous colitis is suggested to be reduced permeability for electrolytes and water in the colonic mucosa,1 14 34while the active absorption of bile acids occurs in the terminal ileum.35 Other diarrhoeal disorders of colonic origin have not been shown to cause abnormal ⁷⁵SeHCAT values.36 37 Diarrhoea per se might reduce the⁷⁵SeHCAT value but not to an abnormal level.25 38 39 This suggests that the low⁷⁵SeHCAT values found in the present study correspond to a reduced capacity to absorb bile acids in the ileum and are not due to a colonic malabsorption secondary to the diarrhoea caused by collagenous colitis.

The present prospective study tested whether the clinical response of patients with collagenous colitis to treatment with an open label bile acid binder is related to simultaneous bile acid malabsorption—that is, whether the result of the ⁷⁵SeHCAT test could predict the outcome of treatment. All patients with bile acid malabsorption, defined as a low value with the ⁷⁵SeHCAT test, responded to bile acid binders. Eleven of 12 patients showed a rapid response. The twelfth patient showed a slower but positive response, which could be a drug effect or it could represent the natural course of the disease similar to the spontaneously improved patient.

There was no statistically significant difference in the response rate in patients with and without bile acid malabsorption. This was due to the relatively high response rate (67%) in non-bile acid malabsorption patients. The results suggest that in patients with collagenous colitis and bile acid malabsorption, treatment of the observed bile acid malabsorption was sufficient to obtain a clinical response and none of the drugs used for inflammatory bowel disease was needed. It seems less likely that the rapid response, often within a few days, could correspond to a normalisation of the colonic mucosa. However, no detailed information is as yet available regarding the regression of histological inflammation during bile acid binder treatment although this issue is now under investigation (Ung et al, to be published).

The high response rate to the bile acid binders, even in patients with a normal ⁷⁵SeHCAT test value, suggests that cholestyramine and colestipol may also have clinical effects on collagenous colitis through mechanisms other than pure bile acid binding. This would be in agreement with a previous case report, where the patient with collagenous colitis responded to cholestyramine. However, direct tests of bile acid malabsorption were not performed in that patient. The mechanisms of cholestyramine were suggested to be binding of toxins and other effects on the intraluminal contents.20Alternatively, the colonic inflammation may be the result of an abnormal reaction to normal amounts of bile acids entering the colon. In this context, it is of interest that in none of our patients could the collagenous colitis related diarrhoea be linked to small bowel bacterial overgrowth.

Hitherto, there has been no generally accepted drug of choice for the treatment of patients with collagenous colitis. In the present study we had a treatment strategy with additional options based on the previously reported effects of sulphasalazine, antibiotics, and steroids. The risk of long term treatment with metronidazole, particularly neuropathy, prompted us to choose sulphasalazine as the second line drug and metronidazole as the third option, should bile acid binders fail. Remarkably, all 27 patients responded to one of the first three choices and steroids, the fourth option, were not prescribed. Further studies are needed to evaluate the histological improvement during the course of the various types of treatment. As steroids do not heal the inflammatory changes in the colonic mucosa in patients with collagenous colitis,40 the strategy of using a bile acid binder as the first line treatment with 5-acetylsalicylic acid/sulphasalazine and antibiotics as alternative drugs, seems attractive. Apart from the taste problem and for some patients the smell, as well as the potential need for vitamin supplements, side effects from bile acid binders are rare.

In patients with collagenous colitis without bile acid malabsorption, bile acid binders may also be the first option. However, apart from bile acid binders, bismuth subsalicylate has recently been reported to have a good clinical effect on patients with microscopic colitis.41 42 In one patient with microscopic colitis, a normal ⁷⁵SeHCAT value, and disabling diarrhoea, refractory to six different drugs including cholestyramine, the response to bismuth subsalicylate was excellent.42 Further placebo controlled studies should take various aetiopathogenic factors into consideration and evaluate the effect of bile acid binders, bismuth, and other drugs of potential interest.

In conclusion, the present study shows that a considerable proportion of patients with collagenous colitis have bile acid malabsorption and that in these patients bile acid binders seem to be the first line treatment. Moreover, in collagenous colitis patients without bile acid malabsorption, two thirds responded to a bile acid binder (cholestyramine or colestipol). The results show that bile acids may be an important aetiopathogenic factor, although not the only factor, in patients with collagenous colitis.