dinoprost and Liver-Cirrhosis--Biliary

Ursodeoxycholic acid (UDCA) may slow progression in primary biliary cirrhosis (PBC), but its effect on survival is controversial. We have previously demonstrated that oxidant stress, with severely depressed plasma glutathione, is a feature of untreated PBC; this study examines the effect of UDCA on lipid peroxidation, antioxidant status and associated processes.. Markers of lipid peroxidation, antioxidant status, hepatic fibrogenesis, inflammation, cholestasis and synthetic function were measured at 0, 3, 6, 9 and 12 months in blood and urine from 35 PBC patients receiving UDCA.. Plasma glutathione, reflecting intrahepatic levels, climbed steadily on UDCA; although still subnormal, the median value at 12 months was 2.4-fold higher than the untreated level. Liver enzyme markers and C-reactive protein also improved, whilst PIIINP improved steadily, but the change did not attain statistical significance. Serum bilirubin remained unchanged and total antioxidant capacity, albumin and vitamin E decreased after 12 months' UDCA treatment. 8-Isoprostane increased and malondialdehyde was unchanged.. UDCA treatment partially corrected plasma glutathione status and some other biomarkers greatly improved, but lipid peroxidation was not reduced. UDCA may, therefore, require supplementation with glutathione precursors and/or antioxidant cocktails to reduce oxidant stress and thus delay disease progression to cirrhosis.

Topics: Adult; Aged; Antioxidants; Dinoprost; Disease Progression; Female; gamma-Glutamyltransferase; Glutathione; Humans; Lipid Peroxidation; Liver; Liver Cirrhosis, Biliary; Male; Middle Aged; Ursodeoxycholic Acid

Primary biliary cirrhosis (PBC) is a chronic cholestatic disorder characterised by an immunological, and often granulomatous, attack on bile ducts leading to fibrosis, cirrhosis, liver failure and death. Animal and human studies suggest that oxidant stress plays a key role in progression of other liver diseases, but no comprehensive investigation has been performed previously in PBC. A wide range of lipid peroxidation and antioxidant markers were measured in the blood and urine of 41 patients with histologically confirmed PBC. Lipid peroxidation markers were significantly elevated [plasma and urinary 8-isoprostane, P<0.001; plasma malondialdehyde (MDA), P=0.007] compared to age- and sex-matched controls. The most striking antioxidant depletion occurred with plasma total glutathione where levels were significantly reduced (30% of controls). Total serum antioxidant levels were decreased (P=0.013) and serum selenium and vitamin A were also lower (both P<0.001); vitamins C and E were normal. Most patients had early disease biochemically and were Child-Pugh grade A. Urinary 8-isoprostane correlated positively with Ludwig stage and markers of hepatic injury and cholestasis. This study clearly demonstrates that oxidant stress, as reflected in a comprehensive spectrum of lipid peroxidation and antioxidant markers, is a significant feature of early-stage PBC.

Topics: Antioxidants; Ascorbic Acid; Biomarkers; Cholestasis; Dinoprost; F2-Isoprostanes; Glutathione; Humans; Lipid Peroxidation; Liver; Liver Cirrhosis, Biliary; Malondialdehyde; Oxidants; Oxidative Stress; Selenium; Vitamin A; Vitamin E