sign in sign up
<<
Home , Bile acid malabsorption

1004 Gut, 1991, 32, 1004-1006 Idiopathic

a review of clinical presentation, diagnosis, Gut: first published as 10.1136/gut.32.9.1004 on 1 September 1991. Downloaded from and response to treatment

A J K Williams, M V Merrick, M A Eastwood

Abstract ment of faecal bile acid excretion, but is much Between 1982 and 1989, the seven day reten- simpler to perform.I' 12 We have reviewed a total tion of 75SeHCAT was measured in 181 of 500 patients with diarrhoea investigated with patients with chronic diarrhoea that remained the 75SeHCAT test since 1982 in order to deter- unexplained after full investigation. Altogether mine its impact on the management ofindividual 121 of the 181 had a seven day 75SeHCAT patients when used as a routine clinical investiga- retention ¢15% and thus had no evidence of tion rather than a research one. abnormal bile acid turnover. Twenty one had a This study considers 181 of the 500 investi- seven day 75SeHCAT retention : 10% but gated because ofidiopathic diarrhoea - the group <15%. Their clinical features were typical of in whom no cause had been found after extensive the , and none ofeight investigation. treated with cholestyramine showed sympto- SeHCAT is the conjugate of a synthe- matic improvement. Sixteen patients had a tic cholic acid analogue.'3 It is absorbed and seven day retention ¢"5% and <10%, six of excreted at the same rate as cholic acid'4 but is whom had improved symptoms after treatment resistant to deconjugation and dehydroxylation.6 with bile acid chelating agents. The remaining Because there is effectively no passive diffusion 23 patients had a 75SeHCAT retention of <5% of this compound, it is a pure tracer for active at seven days and responded to bile acid transport. chelators. This group had a characteristic 75SeHCAT has been shown to be a simple and illness with intermittent watery diarrhoea, but reliable method of assessing bile acid no constitutional upset. It was not possible to absorption." 12 15 The aim of the present study distinguish the patients with bile acid mal- was to determine the clinical characteristics of absorption exclusively on the basis of the patients with idiopathic bile acid malabsorption

clinical symptoms and investigations, other and to identify their response to treatment. http://gut.bmj.com/ than "SeHCAT retention. We conclude that the measurement of 75SeHCAT retention is useful, appropriate, and necessary in patients Patients and methods with unexplained chronic diarrhoea. All patients referred for measurement of 75SeHCAT retention were entered prospectively into a departmental data base which recorded the

Although bile acids are absorbed both actively a priori diagnosis and relevant diagnostic infor- on October 1, 2021 by guest. Protected copyright. and passively, symptomatic bile acid malabsorp- mation. This was scanned in mid-1989, and 181 tion results from failure of the active transport of patients were identified who had been referred bile acids in the terminal one metre of the . during this period because of unexplained Three types ofbile acid malabsorption are recog- diarrhoea. Patients with inflammatory bowel nised as follows:24 disease who had undergone previous radio- Type 1, following ileal resection, disease, or therapy to the abdomen, any form of bowel bypass of the terminal ileum; resection, or other abdominal surgery were Type 2, primary idiopathic malabsorption; excluded. Stool culture, rigid sigmoidoscopy, Type 3, associated with ,5 I barium enema, barium follow through, jejunal peptic ulcer surgery, chronic , biopsy, and vitamin B-12 absorption studies ,7 and diabetes mellitus. were performed in all patients, and were normal. The aetiology of types 2 and 3 is unclear. Only Those patients who were investigated as the dihydroxy bile acids (chenodeoxycholic acid inpatients underwent three day stool collection and deoxycholic acid) are cathartic to the human for weight and inspection. The notes of all colonic mucosa. They inhibit colonic sodium patients with a retention of less than 15% were Departments of Nuclear Medicine and reabsorption and thus reduce water transport retrieved between January and May 1989 and the , when the concentration in the aqueous faecal final diagnosis, management, and any follow up Western General phase is greater than 1 5 mmol/1.1 determined. Hospital, Edinburgh Diarrhoea caused by primary idiopathic bile 75SeHCAT absorption was assessed as pre- A J K Williams M V Merrick acid malabsorption is considered very rare.9 One viously described, by administering one capsule M A Eastwood centre with a special interest in the disease saw containing 40 kBq (1 [iCi) 7'SeHCAT after an Correspondence to: only 12 cases in 10 years."' However, detection overnight fast. The 100% value for whole body Dr M A Eastwood, Department of by direct measurement of faecal bile acids is a retention was obtained at 30 minutes and the Gastroenterology, Western difficult and unpleasant procedure in patients measurement was repeated at seven days using a General Hospital, Crewe Road, Edinburgh EH4 2XU. experiencing multiple bowel actions. The shadow shield whole body counter. During the Accepted for publication 75SeHCAT test has previously been shown to initial evaluation of 75SeHCAT a lower limit of 19 November 1990 correlate very closely with the direct measure- 15% retention at seven days was established on Idiopathic bile acid malabsorption - a review ofclinicalpresentation, diagnosis, and response to treatment 1005

TABLE I Characteristics of23 patients with severe bile acid TABLE III Characteristics of21 patients with mild bile acid malabsorption (<5% retention of"SeHCAT) malabsorption (¢'10%, <15% retention of5SeHCAT) Sex (M/F) 10/13 Sex (M/F) 18/13 Age (yrs), mean (range) 45 (17-77) Age (yrs), mean (range) 30 (13-72) Gut: first published as 10.1136/gut.32.9.1004 on 1 September 1991. Downloaded from Duration of symptoms (yrs), mean (range) 3-3 (0-08-5) Duration of symptoms (yrs), mean (range) 7 (1-25)j Stool frequency (motions/24 hrs), mean (range) 8 (4-12)* Stool frequency (motions/24 hrs), mean (range) 4 (2-10) Stool weight (g), mean (range) 450 (400-800)* Stool weight (g), mean (range) 160 (8-200)* Nocturnal diarrhoea (%) 11/23 (48) Dose of cholestyramine (g), mean (range) 12 (8-24) *Data from 8 patients. *Data from 8 patients nocturnal diarrhoea. The patients who responded to bile acid chelators could not be the basis of comparison with normal controls.'4 distinguished from those who did not respond. Sixty patients had a "SeHCAT retention of Twenty one patients had a 75SeHCAT reten- <15% at seven days and were therefore con- tion of ¢ 10% but <15% at seven days (Table sidered abnormal by our published criteria. III). All complained of intermittent watery These patients were subdivided into three diarrhoea but none had a nocturnal component, groups - those with a retention <5%, those with and in five the diarrhoea was confined to the a retention 2 5% but <10%, and those with morning. Eight patients complained of urgency, a retention -10% but <15%. The clinical lower abdominal pain relieved by defaecation, characteristics of each group were identified by and . None of the eight patients who reference to the clinical notes and the response to received cholestyramine were improved. bile acid chelators when administered.

Discussion Results The cut off value of 15% was based on a Table I lists the characteristics of patients with a comparison between normal controls and seven day retention of <5%. All these patients patients with known disease.'2 It is well known complained of intermittent watery diarrhoea, that such studies, although necessary in the with a nocturnal component in 11 of the 23. initial stages ofevaluating a new test, are likely to The diarrhoeal illness was of variable require modification on the basis of further duration with no associated constitutional upset. clinical experience. It is clear from the present In all cases it began abruptly and was not study that the lower limit of normal should be associated with any other discernible illness. In revised downwards - in any patient with a seven two it started while the patient was abroad. day 75SeHCAT retention of 10% or more, bile Twenty one patients were treated with chole- acid malabsorption is not the cause of the styramine, which resulted in a reduction in stool diarrhoea. frequency and improvement in stool consist- The sustained response to specific treatment http://gut.bmj.com/ ency. Cholestyramine was administered in in all patients with a retention of <5% confirms divided doses in powder form (4 g sachets) that these patients did indeed have bile acid during the day. A therapeutic response was induced diarrhoea. The aetiology of this condi- defined as a reduction in stool frequency to -2 tion remains obscure. None of the patients had bowel actions/day with a concomitant increase in any systemic upset; all responded to treatment stool consistency occurring within 48 hours of

within 48 hours, and the response was sustained. on October 1, 2021 by guest. Protected copyright. beginning treatment. The mean dose of choles- This pattern is similar to that previously des- tyramine was 12 g. Four patients required doses cribed. '° Although initially characterised as greater than 12 g/day to control their symptoms. causing continuous watery diarrhoea, two pre- One patient was intolerant of cholestyramine but viously reported cases had intermittent responded to aluminium hydroxide. The diarrhoea with large volume stools which never- remaining patient responded to aluminium theless responded overnight to cholestyramine.'o hydroxide as the initial treatment. The nocturnal component seen in half of our Sixteen patients had a seven day 75SeHCAT patients has not previously been described and is retention of ¢e5% but <10% and 13 received a useful diagnostic indicator when present. treatment with bile acid chelators (Table II). However, it was present in only 11 of the 23 Three responded to a dose of 12 glday of patients with a retention of <5% and none of the cholestyramine, three to aluminium hydroxide, patients with a retention of -5% and <10%. while the remaining seven did not respond Thus, the absence of this feature does not to these agents. None of these patients had exclude bile acid malabsorption. The most puzzling group is the 16 who TABLE II Characteristics of13 patients with moderate bile retained -5% and <10% 75SeHCAT at seven acid malabsorption (¢5%, <1O% retention 75SeHCAT) days, six of whom responded to treatment with treated with bile acid chelators bile acid chelators. There were no features that enabled the patients who did respond to be Responders Non-responders distinguished from those who did not. The 21 No of patients 6 7 a of and < 15% had Sex (M/F) 4/2 5/2 patients with retention 10% Age (yrs), mean (range) 49 (25-64) 40 (28-52) features typical of the irritable bowel syndrome Duration of symptoms (yrs), and none improved with bile acid chelators. mean (range) 2 35 (0-3-5) 4 3 (0-12-14) Stool frequency (motions/ These findings are compatible with the role that 24 hrs), mean (range) 4 (3-5) 4 (2-6) has been proposed for bile acid in the patho- Stool weight (g), mean (range) 280 (80-480)* 290 (200-400)* genesis of at least some patients with irritable *Data from 3 patients bowel syndrome.'6 1006 Williams, Memick, Eastwood

The pathogenesis of idiopathic bile acid present data would be 25%. The false positive malabsorption remains unknown. Two mecha- rate remains unknown and it is therefore impos- nisms have been proposed'7 - an increased sible to determine the accuracy or specificity of production of bile acids overwhelming the the therapeutic trial. In view of the simplicity, Gut: first published as 10.1136/gut.32.9.1004 on 1 September 1991. Downloaded from normal ileal transport system or a selective accuracy, and reliability ofthe 75SeHCAT test we abnormality in the active transport of bile acids believe that this should be regarded as a routine in the ileum. A priori, the latter is the more investigation in patients with idiopathic probable mechanism as overproduction of bile diarrhoea for which no explanation has been acids should be relatively easily measurable, but found after full investigation. The condition is this has not been shown. The fact that all of the substantially more common than is generally patients reported were adults and the condition appreciated, but is readily treatable. has not been described in children is more suggestive of an acquired than an inherited 1 Mekhjian HS, Phillips SF, Hofmann AF. Colonic secretion of condition. The severity of symptoms in any water and electrolytes induced by bile acids: perfusion individual may well be related to the composition studies in man. J Clin Invest 1971; 50: 1569-77. 2 Merrick MV. Bile acid malabsorption (clinical presentations of the bile. Thus, if there is a continuous and diagnosis). Dig Dis 1988; 6: 159-69. spectrum ofbile acid absorption efficiency rather 3 Hofmann AF. The syndrome of ileal disease and the broken enterohepatic circulation: cholerheic . Gastro- than an 'all or nothing' process, differences in the enterology 1967; 52: 752-7. ratio of dihydroxy to trihydroxy bile acids and 4 Fromm H, Malavolti M. Bile acid induced diarrhoea. Clin Gastroenterol 1986; 15: 567-82. variations in faecal pH are likely to alter the 5 Fromm H, Farivar S, McJunkin B. 'Type 3' Bile acid severity of symptoms, especially in patients with malabsorption and diarrhoea - evidence for a new clinical entity. Gastroenterology 1977; 72: 1060. intermediate levels of malabsorption. 6 Suhr 0, Danielsson A, Nyhlin H, Trudesson H. Bile acid It has been suggested that the 75SeHCAT test malabsorption demonstrated by SeHCAT in chronic diarrhoea, with special reference to the impact of is of no value in the routine investigation of cholecystectomy. ScandJ7 Gastroenterol 1988; 23: 1187-94. patients with diarrhoea. 8 There are large 7 Merrick MV, Eastwood MA, Ford MJ. Is bile acid malabsorp- tion underdiagnosed? An evaluation of accuracy ofdiagnosis amounts of documented data contradicting this by measurement of SeHCAT retention. BMJ 1985; 290: viewpoint.7"1' The 75SeHCAT test must, 665-8. 8 McJunkin B, Fromm H, Sarva RP, Amin P. Factors in the however, be interpreted in the context of the mechanism of diarrhoea in bile acid malabsorption: faecal patient's clinical condition, with particular refer- pH - a key determinant. Gastroenterology 1981; 80: 1454-64. 9 Thaysen EH, Pedersen L. Idiopathic bile acid catharsis. Gut ence to stool volumes and the results of other 1976; 17: 965-70. gastrointestinal investigations. 10 Thaysen EH. Idiopathic bile acid diarrhoea reconsidered. Scand]7 Gastroenterol 1985; 20: 452-6. Cholestyramine does cause in 11 Delhez H, Van der Berg JWO, Van Blankerstein M, normal individuals, as reported in the hypo- Meerwaldt JH. New method for the determination of bile acid turnover using 7Se-homocholic acid taurine. EurJ Nucl lipidaemic drug trials.202' In the American lipid Med 1982; 7: 269-71. research clinics program,20 39% of 2000 patients 12 Nyhlin H, Merrick MV, Eastwood MA, Brydon WG. Evalua- treated with a mean daily dose of 16 g of tion ofileal function using 23-selena-25-homotaurocholate, a y-labelled conjugated bile acid. GastroenteroloV 1983; 84: http://gut.bmj.com/ cholestyramine were constipated at one year 63-8. 13 Boyd GS, Merrick MV, Monks R, Thomas IL. Se-75-labelled compared with 10% of controls, although at bile acid analogues, new radiopharmaceuticals for seven years only 8% remained constipated. investigating the enterohepatic circulation. .7 Nucl Med 1981; 22: 720-5. However, the facts that all patients with severe 14 Monks R, Boyd GS. Biologic stability of tauro-23-[75 Se] bile acid malabsorption responded to chole- Selena-25-homocholic acid. J Nucl Med 1988; 29: 1411-8. 15 Scheulen C, Kruis W, Bull U, Stellaard F, Lang P, styramine and no patient with mild bile acid Paumgartner G. Comparison of 'SeHCAT retention half life malabsorption improved, and that the improve- anf fecal content of individual bile acids in patients with chronic diarrheal disorders. 1986; 35: 102-8. on October 1, 2021 by guest. Protected copyright. ment was sustained, suggest a primary role of 16 Eastwood M, Merrick MV. Bile acids in irritable bowel bile acids in the pathogenesis of their diarrhoea. syndrome. In: Northfield T, Jasrawi R, eds. Bile acids in health and disease. Dordrecht: Kulwer Academic, 1989: 267- A therapeutic trial of cholestyramine has been 73. suggested as an alternative to measuring 17 Fine KD, Kreis G, Fordtran JS. In: Sleisenger MH, Fordtran JS, eds. . London: WB Saunders, 75SeHCAT retention as an assessment ofbile acid 1989:310. malabsorption causing diarrhoea. 8 In the 18 Orholm M, Pedersen JO, Arnfred T, Rodbro P, Thaysen EH. Evaluation of the applicability of the SeHCAT test in the present study, however, four of the 23 patients investigation of patients with diarrhoea. Scand . with diarrhoea and a 75SeHCAT retention of Gastroenterol 1988; 23: 113-7. 19 Sciarretta G, Vicini G, Fagloli G, Verri A, Ginevra A, Malaguti <5% required more than 12 g/day of chole- P. Use of 23-selena-25-homocholyltaurine to detect bile acid styramine to control their symptoms and would malabsorption in patients with ileal dysfunction or diarrhoea. Gastroenterology 1986; 91: 1-9. therefore have been considered as negative 20 Lipid research clinics program. The Lipid research clinics with the cholestyramine test. The false negative coronary primary prevention trial results 1. JAMA 1984; 251: 351-64. rate of a therapeutic trial of cholestyramine has 21 Knodel C, Talbert RL. Adverse effects of hypolipidaemic not previously been determined, but from the drugs. Medical Toxicology 1987; 2: 10-32.