chromosome 16? The answer is likely to involve a regulatory protein coded by the X chromosome which influences expression of the a-globin genes. The elucidation of this trans acting factor should provide an important insight into morphogenesis and the origins of associated mental retardation. With a little luck this accident of nature may lead to much bettei understanding of the mysterious sequence of event linking genotype with phenotype. 1. Neri G, Gurrieri F, Gal A, Lubs HA. XLMR genes: update 1990. Am J Med Genet 1991; 38: 186-89. 2. Weatherall DJ, Higgs DR, Bunch C, et al. Hemoglobin H disease and mental retardation—a new syndrome or a remarkable coincidence? N Engl J Med 1981; 305: 607-12. 3. Wilkie AOM, Buckle VJ, Harris PC, et al. Clinical features and molecular analysis of the &agr; thalassemia/mental retardation syndromes. I. Cases due to deletions involving chromosome band 16p13.3. Am J Hum Genet 1990; 46: 1112-26. 4. Wilkie AOM, Zeitlin HC, Lindenbaum RH, et al. Clinical features and molecular analysis of the &agr; thalassemia/mental retardation syndromes. II. Cases without detectable abnormality of the &agr; globin complex. Am J Hum Genet 1990; 46: 1127-40. 5. Gibbons RJ, Wilkie AOM, Weatherall DJ, Higgs DR. A newly defined X linked mental retardation syndrome associated with &agr; thalassaemia. J Med Genet 1991; 28: 729-33. 6. Harvey MP, Kearney A, Smith A, Trent RJ. Occurrence of the &agr; thalassaemia-mental retardation syndrome (non-deletional type) in an Australian male. J Med Genet 1990; 27: 577-81. 7. Cole TRP, May A, Hughes HE. &agr; thalassaemia/mental retardation syndrome (non-deletional type): report of a family supporting X linked inheritance. J Med Genet 1991; 28: 734-37. 8. Wilkie AOM, Gibbons RJ, Higgs DR, Pembrey ME. X linked &agr; thalassaemia/mental retardation: spectrum of clinical features in three related males. J Med Genet 1991; 28: 738-41. 9. Donnai D, Clayton-Smith J, Gibbons RJ, Higgs DR. The non-deletion &agr; thalassaemia/mental retardation syndrome: further support for X linkage. J Med Genet 1991; 28: 742-45.

Bile acids, diarrhoea, and SeHCAT Bile acids are reabsorbed by an active transport mechanism in the terminal ileum as part of an enterohepatic circulation. There is also some passive diffusion in the proximal small intestine and colon. Ileal malabsorption can lead to failure of colonic sodium reabsorption, a consequent reduction in water absorption, and thus colonic-type diarrhoea. This cholegenic diarrhoea, which is due to the presence in the colon of the two dihydroxy bile acids, chenodeoxycholic acid and deoxycholic acid, occurs when the dihydroxy bile acid concentration in the aqueous faecal phase is greater than 1-5 mmol/1.1 Three types of bile acid malabsorption are recognised. Type 1 follows ileal resection or disease (most commonly Crohn’s disease) or terminal ileal bypass. Type 2 is due to primary idiopathic malabsorption. In this type increased production of bile acids may overwhelm the normal ileal transport system or there may be a selective abnormality in the active ileal transport of bile acids. The latter possibility is more likely. This variety of malabsorption seems to be an acquired condition; variation in severity of symptoms may reflect the colonic pH and concentration of dihydroxy bile acids from day to day. Type 3 is

associated with cholecystectomy, previous peptic ulcer surgery, chronic pancreatitis, coeliac disease, and diabetes mellitus.All types are rare. 7sSe-Iabelled homocholic acid conjugated with taurine C5SeHCA T) can be used to measure bile acid pool loss. Tauroselcholic acid does not occur naturally but is an analogue of the naturally occurring bile acid conjugate, taurocholic acid. The physiological behaviour of this analogue is identical to that of taurocholic acid.The taurine conjugate is more resistant to deconjugation than the glycine conjugate, and SeHCAT is thought to be absorbed specifically by the active mechanism in the terminal ileum. After oral administration, it becomes mixed with the endogenous bile acid pool. Malabsorption can be assessed by regular faecal collections or, preferably, by assessing seven-day retention; the manufacturers (Amersham) suggest that the lower level of retention for normal individuals is 19%. The SeHCAT test correlates closely with the direct measurement of faecal bile acid excretion, and is much easier to do.3 It is more sensitive than the older 14C-glycocholate breath test4 for the detection of bile acid malabsorption and is not associated with any side-

effects. The SeHCAT test has been used to ascertain the incidence of type 2 primary idiopathic malabsorption of bile acids in patients with diarrhoea of obscure origin. This condition is thought to be very rare-eg, one centre with a special interest saw only 12 cases in ten years.s The Edinburgh group have now measured the seven-day retention opsSeHCA Tin 181 patients with chronic diarrhoea that was unexplained after full investigation between 1982 and 1989.623 patients had severe bile acid malabsorption, with a seven-day retention of 75SeHCAT of less than 5%. All these patients complained of intermittent watery diarrhoea and 11 of the 23 had diarrhoea during the night. The mean daily stool weight was 450 g (range 400-800 g) and mean daily stool frequency was 8 (range 4-12). The diarrhoea in these patients was of variable duration, had begun abruptly, and was not associated with constitutional upset; in 2 patients diarrhoea had started when they were abroad. There was an excellent response to treatment with cholestyramine in divided doses in nearly all the patients; mean dose was 12 g daily with a maximum of 24 g. 2 other patients responded to aluminium hydroxide. Researchers have previously noted that treatment with other drugs, especially antidiarrhoeals such as loperamide, is ineffective. Another 16 patients had moderate bile acid malabsorption, with a sevenday 7sSeHCAT retention of 5-10%. None of these patients had nocturnal diarrhoea. 25% of the treated patients responded to cholestyramine 12 g/day and 25% to aluminium hydroxide. The Edinburgh workers concluded that all the patients in the severe group and some in the moderate group had primary type 2 malabsorption. 21 patients had mild bile acid malabsorption, which was thought to have the


characteristics of the irritable bowel syndrome, with no response to cholestyramine. The investigators concluded that the lower level of normal retention at seven days should be revised downwards to 10%. Thus use of the 75 SEHCAT test can be justified in the investigation of idiopathic type 2 bile acid malabsorption in patients with obscure diarrhoea. Does it have other roles? In patients with terminal ileal disease or previous resection who get diarrhoea and do not have an obvious relapse of their underlying disease, a trial of cholestyramine or aluminium

hydroxide would seem a reasonable clinical approach. If there is still doubt about bile acid malabsorption, the 7sSeHCA T test should give the answer.4 The test may also have a role in type 3 disease. A study in post-cholecystectomy patients showed that 27-5% had unformed stools, 11-7% had liquid stools, and 35-9% had faecal urgency.Some of these patients may have cholegenic diarrhoea, possibly as a result of an increased bile acid recycling rate. A role for the 7sSeHCA T test and cholestyramine has also been shown in patients with diarrhoea following irradiation8 and peptic ulcer surgery.9 If a SeHCAT test shows severe bile acid malabsorption the clinician can confidently try medical treatment. McJunkin B, Fromm H, Sarva RP, Amin P. Factors in the mechanism of diarrhea in bile acid malabsorption: fecal pH—a key determinant. Gastroenterology 1981; 80: 1454-64. 2. Merrick MV, Eastwood MA, Anderson JR, Ross HM. Enterohepatic circulation in man of a gamma-emitting bile acid conjugate, 23-selena25-homotaurocholic acid (SeHCAT). JNucl Med 1982; 23: 126-30. 1.

Nyhlin H, Merrick MV, Eastwood MA, Bryden WG. Evaluation of ileal function using SeHCAT, a gamma labelled conjugated bile acid: an initial assessment. Gastroenterology 1983; 84: 63-68. 4. Hess Thaysen E, Orholm M, Arnfred T, Carl J, Rodbro P. Assessment of ileal function by abdominal counting of the retention of a gamma emitting bile acid analogue. Gut 1982; 23: 862-65. 5. Thaysen EH. Idiopathic bile acid diarrhoea reconsidered. Scand J Gastroenterol 1985; 20: 452-56. 6. Williams AJK, Merrick MV, Eastwood MA. Idiopathic bile acid malabsorption—a review of clinical presentation, diagnosis and response to treatment. Gut 1991; 32: 1004-06. 7. Parker D, Heaton KW. Diarrhoea after cholecystectomy: an underestimated problem? Gut 1991; 32: A1254. 8. Ludgate SM, Merrick MV. The pathogenesis of post-irradiation chronic diarrhoea: measurement of SeHCAT and B12 absorption for differential diagnosis determines treatment. Clin Radiol 1985; 36: 3.

275-78. 9. Merrick MV, Eastwood MA, Ford MJ. Is bile acid malabsorption underdiagnosed? An evaluation of accuracy of diagnosis by measurement of SeHCAT retention. Br Med J 1985; 290: 665-68.

Servicing perinatal research Ten years ago the National Perinatal Epidemiology Unit was created in Oxford, England, "to provide information which can promote effective use of resources in the perinatal health services". Funded from various sources (mainly the Department of Health), the unit has three functions: to gather data about current practice, to disseminate information, and to organise original research. Its interests, summarised in the latest annual report,’ have ranged

mortality rates to mothers’ with dissatisfaction maternity services. In disseminating information, the unit’s’ innovations include a computerised database of clinical trials and the landmark book Effective Care in Pregnancy and Childbirth (Oxford University Press), both of which review trials and distinguish treatments of proven effectiveness from those that are unproven or ineffective. Although the book and the database have been well received and show the way forward for other specialties, some obstetricians remain uneasy about the gap between the book’s conclusions and their own prejudices. How quickly these initiatives alter practice will depend on the relative robustness of clinical tradition and meta-analysis. The unit has collaborated with thousands of clinicians world wide. As the results of obstetric practice improve, increasingly large randomised trials are needed to show changes in outcome, and during, the past decade there has been a shift in emphasis from! single-centre to multicentre trials. To run these more, efficiently, in autumn 1990 the unit established a1 Perinatal Trials Service. The core team (funded by the Department of Health, with help from the charity, Birthright) consists of five people with complementary skills-eg, in epidemiology, statistics, and computing-who will draw on the skills of others in the unit, including those in its midwifery research’ programme. The team is now responsible for all the unit’s new projects and the service is available to clinicians who wish to set up research programmes. Will this resource be used? Hitherto obstetric research has been driven mainly by the need to save the lives of mothers and babies: reviews of the causes of maternal and perinatal deaths still guide improvements in obstetric practice. In Britain, where mortality is now below 1 in 10 000 and perinatal mortality is less than 1 %, the motivation for research may diminish. Cynics may argue that selection of treatments of proven effectiveness appeals to managers more than to clinicians, who risk having to discard favourite remedies. Nevertheless, pressure is building up from women, who are increasingly questioning the rationale behind obstetric interventions. Collaborative research may not appeal to those doctors who prefer to control their own projects. In hospitals, research tends to be carried out by middlegrade doctors to advance their careers; in universities, academics are partly motivated by the need to be seen obtaining grants. One of the achievements of the National Perinatal Epidemiology Unit has been to facilitate research in district hospitals by clinicians who are motivated by pure scientific enthusiasm; the new Perinatal Trials Service should enhance this from


process. 1. National Perinatal Epidemiology Unit. Report 1989-1990. National Perinatal Epidemiology Unit, Radcliffe Infirmary, Oxford OX2 6HE, 1991.

Bile acids, diarrhoea, and SeHCAT.

1563 chromosome 16? The answer is likely to involve a regulatory protein coded by the X chromosome which influences expression of the a-globin genes...
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