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Bile acid malabsorption, whether caused by an inborn absence of the ileal transport system or by resection of the terminal ileum, causes diarrhoea because of the secretory effect of malabsorbed dihydroxy bile acids in the colon. There is now increasing evidence that bile acid malabsorption is also present and plays a causal role in many patients with intermittent or chronic diarrhoea who have no ileal pathology. Many of these patients have been labelled with the diagnosis of irritable bowel syndrome.1 In this issue, Fracchiaet al (see page 812) provide new information on this syndrome by defining biliary bile acid and lipid composition in 13 well characterised patients with idiopathic bile acid malabsorption.
Bile acids are secreted by the liver entirely in conjugated form. The conjugated bile acid anion is impermeable to cell membranes and too large to pass the paracellular junctions of the biliary and intestinal tract. The highly efficient conservation of bile acids, which is responsible for the accumulation of a recycling bile acid pool, results from both carrier mediated and passive absorption. Carrier mediated absorption is mediated mainly by an apical transporter located in the ileal enterocyte. This transporter, which has been cloned and characterised by Dawson and colleagues,2 is now termed the “apical bile salt transporter” (abst) because it is also present in the renal tubular epithelial cell and in the cholangiocyte. Passive absorption of unconjugated bile acids that are formed by bacterial enzymes present in the distal small intestine and colon also contributes to the efficient conservation of bile acids. The combination of active and passive absorption of bile acids in the small intestine means that in health, probably less than 5% of bile acids that are secreted into the small intestine enter the colon.
The efficiency of bile acid absorption, the chemical complexity of the spectrum of conjugated and unconjugated bile acids that are absorbed, and the intrinsic variability of first pass hepatic extraction mean that detection of mild degrees of bile acid malabsorption by examining the spillover of bile acids into the systemic circulation is unlikely to be successful. What seems preferable is to measure what is not absorbed using a labelled bile acid that is absorbed solely by the ileal abst and is resistant to bacterial deconjugation. Ideally the label should have a short physical or biological half life and be easily measured.
All of these desirable attributes were achieved in a fruitful collaboration between George Boyd, Professor of Biochemistry at Edinburgh University, now deceased, and his radiochemical colleagues at Amersham who synthesised a derivative of cholic acid in which a75Se atom was inserted between the β (C23) and γ (C22) carbon atoms of the side chain. The resulting seleno-(homo)-cholic acid was conjugated with taurine to give seleno-homo-cholyltaurine, abbreviated SeHCAT.3 SeHCAT is handled by the liver and the intestine quite similarly to taurocholate (also called cholyltaurine), but is more resistant to bacterial deconjugation (and dehydroxylation).
How should this bile acid surrogate be used to detect ileal bile acid malabsorption? The most commonly used technique is to measure total body radioactivity before and seven days after administering SeHCAT.4 This approach is simple, but can be influenced by colonic transit time.5 6 Nonetheless, using ileal resection patients as the gold standard, Fellous and colleagues in a recent meticulous study7 showed that the seven day SeHCAT retention test gave a sensitivity of 79% and a specificity of 90%. Earlier, in an attempt to correct for variability in colonic transit, Ferraris et al administered SeHCAT together with a non-absorbable marker and determined the ratio in faeces.6They showed that this approach was preferable because it was uninfluenced by colonic residence time.
A still more sensitive way of detecting bile acid malabsorption using SeHCAT is to measure the radioactivity located in the gall bladder area each day for several days. By plotting the natural logarithm of radioactivity against time, one can obtain the fractional turnover rate of the SeHCAT pool as the metabolism of most bile acids can be described by first order kinetics. Such an approach is based on the unproved assumption that most bile acids are stored in the gall bladder during the fasting state in the morning and that radioactivity in the gall bladder can be distinguished from that in the small and large intestine.
Fracchia and colleagues report measurements of biliary bile acid and biliary lipid composition in 13 patients with idiopathic bile acid malabsorption, and thus extend considerably our knowledge of this syndrome. The diagnosis of idiopathic bile acid malabsorption was based on the finding of an increased fractional turnover rate of SeHCAT and the lack of small intestinal pathology based on careful radiological and endoscopic studies including enteroclysis to exclude mucosal atrophy in the ileum. Fracchia et al found that biliary lipid composition, including biliary cholesterol saturation, and biliary bile acid composition did not differ significantly from those of control subjects who were studied similarly. Neither of these findings are so astonishing, but rational predictions should never substitute for experimental data. The enterohepatic circulation of bile acids should not be greatly perturbed in patients with idiopathic bile acid malabsorption, based on studies of patients with small ileal resections. Bile acid secretion is likely to decline modestly during the day; during overnight fasting, the increased hepatic synthesis should restore the bile acid pool to normal or near normal in size. Because the daily flux of bile acids through the hepatocyte is only modestly reduced, little change in biliary lipid secretion, the determinant of cholesterol saturation of bile, should occur. Patients with impaired transport function of abst can be expected to lose trihydroxy conjugated bile acids preferentially. However, the hepatocyte always synthesises trihydroxy bile acids preferentially, so that no great change in biliary bile acid composition should occur. Nonetheless, two of the patients did not have deoxycholic acid in bile. As deoxycholic acid is present in the biliary bile acids of most healthy adults, this finding suggests that the increased load of bile acids in the colon suppressed the growth of 7-dehydroxylating bacteria. A similar finding has been noted in some patients with bile acid malabsorption because of ileal resection.
Why should the busy gastroenterologist care about the presence of bile acid malabsorption in his patients with diarrhoea? Because treatment with a bile acid sequestrant may provide symptomatic benefit. In some patients the effective dose is quite small and dose titration is desirable. Some patients may prefer to ingest a sequestrant only when they are in a social situation where toilet facilities are remote. Some patients may prefer the inconvenience caused by increased faecal frequency and liquid stools to the unpalatableness of the resins. But all such patients should be relieved to know that their physician understands what is wrong and has a solution. New sequestrants are being developed that are considerably more potent than cholestyramine or colestipol. These will probably be available in capsule form and thus less distasteful than the currently available suspensions of resin granules. Relief of diarrhoea caused by bile acid malabsorption when a bile acid sequestrant was administered was described nearly 30 years ago, but the use of sequestrants for this purpose remains “off label” and has yet to be included in the colourful advertisements sponsored by the pharmaceutical industry.
As Hardison mentioned in an editorial over a decade ago, the availability of SeHCAT has helped to “illuminate a shadowy syndrome”.8 It is less shadowy after this careful study of Fracchia et al. Progress in understanding why bile acid malabsorption is present in these patients will probably require sequencing of the abst gene in individual patients. Site directed mutagenesis studies in such transporters have shown that a change in a single base pair may cause a profound change in transport function. Multiple types of defects in gene product expression and targeting have been shown for the glucose–galactose transporter of the small intestine, and the same can be anticipated for abst.Probably, the powerful techniques of molecular biology will soon shed new insights into the defects present in patients with idiopathic bile acid malabsorption who were once thought to have little more than irritable bowels.
The author’s work is supported by a grant from the National Institutes of Health (DK 21506) and a grant-in-aid from the Falk Foundation e.V., Freiburg, Germany
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