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Bile Acids in Hepatobiliary Disease. Basic Research/Clinical Applications. Edited by Paumgartner G, Stiehl A, Gerok W. (Pp 328; illustrated; £95.00/£156.00.) Dordrecht: Kluwer Academic Press, 1997. ISBN 0792387252.
The father of Dr Herbert Falk ran a dispensing chemist in Freiburg im Breisgau. This South German town was flattened by Allied bombing, but rebuilt largely on the original plan. It is now a thriving university and tourist city.
During the post-war reconstruction and thereafter, Dr Falk developed a very successful manufacturing pharmaceutical business, and generously devoted much of the profits to sponsorship of scores of first-rate international medical educational meetings.
Notable organisational successes include the 1979 Basel meeting on viral hepatitis. Three thousand delegates attended what was the largest meeting ever held on liver disease. Another particularly successful initiative was the series of biennial Bile Acid meetings, the 14th of which was held in Freiburg in October 1996 and forms the basis of this book. The high quality of these gatherings ensures that all the important players in bile acid laboratory research and clinical investigation were present. To attend is to find out what is really going on in the field, rather than wait two to three years for full publication of results.
The book reproduces the text of invited lectures reviewing the scene, and short papers describing recent work. There is also an important poster session held at each meeting, though abstracts are not included here.
The sections are entitled “Bile acid biosynthesis and metabolism; Hepatic bile acid transport; Intestinal bile acid transport; Biological effects of bile acids; and Bile acids in therapy” (at 30 pages the shortest contribution, but the most interesting for the clinician). The book itself is likely to be on the shelves of most of its intended purchasers already, since they either will have attended the meeting and bought it at subsidised rates, or have ordered it to keep abreast of events.
The first presentation reviewed the different bile acid composition of bile in mammals at various stages of development and in different species, relating this to the function of the intestine and its bacteria which are crucial to the intact enterohepatic circulation. A further contribution considered whether the prokinetic agent cisapride could overcome the lithogenic effect of octreotide, which is currently the most potent inducer of human gallstones known. The conclusions are preliminary and there is some promise, but for the present the only sure way of preventing gallstones in these patients (and in those who are losing weight after bariatric surgery) is additional treatment with bile acids such as ursodeoxycholic acid (UDCA) 750 mg daily.
Much of the work presented is of importance to the biochemist rather than the jobbing gastroenterologist, though mechanisms of gallstone formation and of cholestatic and other liver disease, and the actions of bile acids in treatment will be of interest.
Bile acids may increase cell membrane permeability, but the effect is much less notable with UDCA than with other types. By contrast UDCA has a very noticeable effect on hepatocyte cytosol calcium metabolism, which usefully enhances excretory function. UDCA may also have clinically important anti-oxidant effects, neutralising free oxygen radicals.
Other known therapeutic effects of UDCA include dilution of other more toxic bile acids in the intrahepatic circulation, stimulation of bile flow, modification of abnormal immune responses, and stabilisation of cell membranes.
Though the secondary bile acid deoxycholic acid continues to be regarded as the bad guy in gallstone disease, its role is not yet clearly defined or fully accepted. Short term deoxycholic acid feeding of patients leads to an increase in deoxycholic acid in the biliary bile acids from a quarter to two thirds. Simultaneously serum total cholesterol is reduced by 10%, but there is no alternation in biliary cholesterol saturation. However, bile nucleation time is prolonged four times, so this agent may actually have some protective effect against gallstones rather than being irredeemably lithogenic.
UDCA is now regarded as first-line therapy for primary biliary cirrhosis, where it improves life expectancy and controls the evidence of disease activity. It may slow progress of liver damage and actually reverse it in the occasional patients. Whether adjuvant treatment is justified remains a matter of debate. Many of the alternatives are moderately poisonous and drugs such as penicillamine have long been abandoned. Combination of UDCA with low dose prednisolone (10 mg daily) plus azathioprine (50 mg daily) has been proposed as superior to UDCA alone. However, this regimen may pay an unacceptable price in osteoporosis and immune suppression. Long term life table “body count” analysis over some years would be required before it could be recommended. Addition of budenoside to UDCA is also being investigated. This steroid is largely metabolised on first pass through the liver after absorption from the intestine so may confer hepatic benefit without systemic side effects. By contrast, it is known that the addition of colchicine or methotrexate to UDCA therapy is not more effective than UDCA alone.
UDCA may also improve outcome for patients with primary sclerosing cholangitis, but it does not affect major duct stenosis, and transplantation is the only long term solution for those patients with severe problems.
Another candidate disease for UDCA therapy is cholestasis of pregnancy. UDCA 1 g daily from 33 weeks improved symptoms and abnormal laboratory results. The outcome of pregnancy was also better with fewer patients coming to premature delivery.
All bile acid fans will want to own this book, and most of them will already do so. NHS gastroenterologists would certainly benefit from dipping into the library copy or one scrounged on loan from an erudite colleague
The Fifteenth International Bile Acid Meeting will be held at Titisee in October 1998 and will doubtless produce another volume in the unfolding story.
Watch this space!