Effects of long-term oral misoprostol administration on hepatic amino acid–nitrogen metabolism in patients with cirrhosis q Giampaolo Bianchi 1, * , Mara Brizi 2 , Rita Manini 2 , Andrea Fabbri 2 , Stefano Loffreda 1 , Marco Zoli 1 , Giulio Marchesini 2 1 Dipartimento di Medicina Interna, Cardioangiologia, Epatologia, Alma Mater Studiorum, Universita ` di Bologna, Policlinico S. Orsola-Malpighi, Bologna, Italy 2 Cattedra di Malattie del Metabolismo, Alma Mater Studiorum, Universita ` di Bologna, Policlinico S. Orsola, Bologna, Italy Background: The acute infusion of a Prostaglandin of E series 1 (PGE1) analogue results in nitrogen sparing in cirrhosis. Aims: To test the effects of long-term oral PGE1 on hepatic and whole-body nitrogen metabolism. Patients and methods: Ten patients with advanced cirrhosis were studied in paired experiments, before and 30–50 days after oral misoprostol therapy. a-Amino-nitrogen levels and urea-nitrogen synthesis rate were measured in the post-absorptive state and in response to continuous alanine infusion (2 mmol/kg per hour for 4.5 h). Data were used to compute the functional hepatic nitrogen clearance, i.e. the slope of the regression of a-amino-N levels to urea-N synthesis rate, and the apparent nitrogen exchange. Results: Misoprostol reduced urea-N synthesis rate (during fasting and in response to alanine), resulting in a positive nitrogen exchange. The functional hepatic nitrogen clearance slightly increased, and the regression line was rightwards shifted, indicating a reduced urea synthesis rate at any a-amino-N concentration. Amino acid- and ammonia-N did not accumulate in plasma. No systematic effects on insulin and glucagon were observed. Conclusions: Data are consistent with a nitrogen sparing mechanism of misoprostol, not mediated by hormone levels. These effects may be beneficial in clinical hepatology, and need to be tested in controlled trials. q 2002 European Association for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved. Keywords: Misoprostol; Liver cirrhosis; Prostaglandins of E series 1; Urea–nitrogen synthesis rate; Functional hepatic nitrogen clearance; Amino acids; Urea synthesis 1. Introduction There is growing interest in potential therapeutic uses of prostaglandins (PGs) in clinical hepatology. Hepatocytes have specific binding sites for PGs of the E series (PGE 1 and PGE 2 ) [1], which exert a cytoprotective effect on liver function, through a mechanism largely unknown [2]. PGE may have beneficial effects in acute liver injury [3], in acute rejection of liver transplants [4], while conflicting data were reported in primary non-function [5,6]. More recently, bene- ficial effects have also been reported on the clinical course of non-fulminant viral hepatitis [7–9], also improving virus clearance. In cirrhosis, data are available about a potential effect of PGE on metabolic activities, namely amino acid/protein metabolism. Short-term infusion of a PGE 1 analogue (alprostadil-a-ciclodestrin) reduced urea nitrogen synthesis rate (UNSR) [10], potentially improving whole-body protein conservation, a relevant topic for the increased cata- bolism [11] and malnutrition [12] observed in advanced cirrhosis. PGs act with insulin to stimulate tissue repair, namely in muscle, enhancing muscle synthesis [13] and lowering muscle proteolysis [14,15], whereas the effects on the liver are less clearly characterized. It was suggested Journal of Hepatology 37 (2002) 15–21 0168-8278/02/$20.00 q 2002 European Association for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved. PII: S0168-8278(02)00094-6 www.elsevier.com/locate/jhep Received 15 June 2001; received in revised form 28 February 2002; accepted 20 March 2002 q The authors of this study state that they have no relationship past or present with the pharmaceutical company involved with the drugs mentioned in the study, neither have they received funding from the compa- nies. * Corresponding author. Tel.: 1039-51-392-524; fax: 1039-51-340-877. E-mail address: bianmice@almadns.unibo.it (G. Bianchi).