Ursodeoxycholic Acid: From Dissolution of Gallstones to Lipid-Lowering Agent

Abstract

Administration of ursodeoxycholic acid (UDCA), a naturally occurring bile acid, effectively desaturates bile. Currently, this agent is indicated for dissolution of gallstones in selected patients. UDCA has also been evaluated for the treatment of hepatobiliary diseases, such as primary biliary cirrhosis.1Rubin RA Kowalski TE Khandelwal M Malet PF Ursodiol for hepatobiliary disorders.Ann Intern Med. 1994; 121: 207-218Crossref PubMed Scopus (72) Google Scholar In this issue of the Mayo Clinic Proceedings (pages 923 to 929), Balan and associates show how UDCA can have a beneficial effect on the hypercholesterolemia associated with primary biliary cirrhosis. The availability of such a noninvasive treatment modality, with a low frequency of potential side effects, improves the treatment armamentarium for both disorders. This report also demonstrates what useful information a carefully designed protocol can provide beyond testing of the major hypothesis of the study. These data are meaningful spin-offs of a clinical trial and exemplify the effective use of databases. The study was primarily designed to test the effect of UDCA on the hepatic structural and functional abnormalities of primary biliary cirrhosis. Hypercholesterolemia is a prominent feature of primary biliary cirrhosis. Any therapy for primary biliary cirrhosis lends itself to assessment for effectiveness in managing serum lipid levels. The major hypothesis tested by the study was whether UDCA has a beneficial effect in patients with primary biliary cirrhosis. The secondary hypothesis was whether UDCA has a beneficial effect on the hypercholesterolemia associated with primary biliary cirrhosis. Logically, one would assume that if it were beneficial for the hepatic disease, it would also be beneficial for the lipid abnormalities. Both hypotheses were indeed confirmed. The issue arises as to the mechanism of action for the lipid-lowering effect of UDCA. The authors describe a series of potential mechanisms for the beneficial effect of UDCA on the hyperlipidemia associated with primary biliary cirrhosis, including effects on hydroxymethylglutaryl-coenzyme A reductase, absorption of cholesterol, and the bile acid pool. The regression of the liver disease may have decreased the lipid levels; however, the possibility still exists that the UDCA has an effect on the metabolism of lipids and the reduction of lipid levels, unrelated to the hepatic disease. An intriguing possibility is that hyperlipidemia may have a toxic effect on the primary biliary cirrhosis. The hyperlipidemia present in primary biliary cirrhosis may aggravate the hepatic dysfunction. A similar mechanism has been postulated for the hyperlipidemia associated with renal disease.2Diamond JR Hyperlipidemia of nephrosis: pathophysiologic role in progressive glomerular disease.Am J Med. 1989; 87 (5–29N): 5-25NGoogle Scholar Thus, the beneficial effect of UDCA in primary biliary cirrhosis may be entirely related to its lipid-lowering action. Recently, Laurin and colleagues3Laurin JM Crippin JS Gossard A Gores GJ Ludwig J McGill DB et al.Ursodeoxycholic acid improves indices of liver injury in nonalcoholic steatohepatitis [abstract].Gastroenterology. 1994; 106: A926Google Scholar reported preliminary information on the beneficial effect of UDCA on nonalcoholic steatohepatitis. Those authors, however, observed no significant change in lipid levels, nor in the hepatic fibrosis or inflammation, with use of UDCA. The current report by Balan and coworkers provides sufficient evidence to prompt the study of the effect of UDCA on primary hypercholesterolemia. New effective and safe antilipid agents are needed to expand the treatment armamentarium for lipid disorders. UDCA should be tested in clinical trials to determine its efficacy in primary hypercholesterolemia, without associated liver disease. The current study and previous studies have indicated that UDCA is relatively free of side effects. If it proves to be effective in primary hypercholesterolemia, it would be an ideal therapeutic agent for this disorder. The issue remains its efficacy in decreasing serum lipid levels in nonhepatic hyperlipidemia. If UDCA is effective in primary hyperlipidemia, this use will be a promising new application for this medication. Additional studies are needed to determine the degree of effectiveness of UDCA in reducing lipid levels and the mechanism of action that produces this effect. In clinical trials with the drug, patients with primary hypercholesterolemia should not be subjected to a continued risk of cardiovascular disease when the efficacy of UDCA versus placebo is tested. UDCA could also be compared for efficacy and safety with other currently available agents, such as the hydroxymethylglutaryl-coenzyme A reductase inhibitors. Obviously, UDCA needs to be tested further.