title: Cyclosporine A-induced reduction of bile salt synthesis associated with increased plasma lipids in children after liver transplantation.
abstract: Hyperlipidemia is a common side effect of cyclosporine A (CsA) after solid organ transplantation. CsA also markedly reduces the synthesis rate of bile salts in rats and can inhibit biliary bile salt secretion. It is not known, however, whether CsA inhibits the synthesis of bile salts in humans, and whether the hyperlipidemic effects of CsA are related to bile salt metabolism. Our objective was to assess the effects of CsA on the synthesis rate of bile salts and on plasma triglycerides and cholesterol levels in pediatric liver transplant patients. Before and after discontinuation of CsA treatment after liver transplantation, synthesis rate and pool size of the primary bile salts cholate and chenodeoxycholate were determined using a stable isotope dilution technique and related to plasma lipids. In 6 children (age: 3-16 years) CsA treatment was discontinued at 2 years (median 2.3 years) after liver transplantation. Discontinuation of CsA increased synthesis rate of chenodeoxycholate (+38%, P <.001) and cholate (+21%, P <.05) and the pool size of chenodeoxycholate (+54%, P <.001). Discontinuation of CsA decreased plasma levels of cholesterol (-18%, P <.05) and triglycerides (-23%, P <.05). Bile salt synthesis rate appeared to be inversely correlated with plasma cholesterol (Spearman rank correlation coefficient [r(s)] = -0.82, P <.01) and plasma triglyceride levels (r(s) = -0.62, P <.05). In conclusion, CsA inhibits bile salt synthesis and increases plasma concentration of cholesterol and triglycerides in pediatric liver transplant patients. Suppression of bile salt synthesis by long-term CsA treatment may contribute to hyperlipidemia and thus to increased risk for cardiovascular disease.
authors.affiliation: Groningen University Institute for Drug Exploration, Center for Liver, Digestive and Metabolic Diseases, Pediatric Gastroenterology, Department of Pediatrics; University Hospital, Groningen, The Netherlands. c.hulzebos@bkk.azg.nl
authors.forename: Christian V
authors.initials: CV
authors.lastname: Hulzebos
authors.forename: Charles M A
authors.initials: CM
authors.lastname: Bijleveld
authors.forename: Frans
authors.initials: F
authors.lastname: Stellaard
authors.forename: Folkert
authors.initials: F
authors.lastname: Kuipers
authors.forename: Vaclav
authors.initials: V
authors.lastname: Fidler
authors.forename: Maarten J H
authors.initials: MJ
authors.lastname: Slooff
authors.forename: Paul M J G
authors.initials: PM
authors.lastname: Peeters
authors.forename: Pieter J J
authors.initials: PJ
authors.lastname: Sauer
authors.forename: Henkjan J
authors.initials: HJ
authors.lastname: Verkade
mesh_terms: D000293:Adolescent; D001647:Bile Acids and Salts / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D002648:Child; D002675:Child, Preschool; D016572:Cyclosporine / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008055:Lipids / Q000097:blood*; D016031:Liver Transplantation / Q000276:immunology*; D008297:Male; D013997:Time Factors
chemical_list: D001647:Bile Acids and Salts; D007166:Immunosuppressive Agents; D008055:Lipids; D016572:Cyclosporine