Management of ascites.

The development of ascites indicates a pathological imbalance between the production and resorption of intraperitoneal fluid. The appearance and composition of ascites are variable, based on the underlying pathophysiology. Most commonly, ascites develops in the setting of decompensated cirrhosis, peritoneal infection, carcinomatosis, congestive heart failure or a combination (mixed ascites). The diagnosis can be difficult in some patients. Management options for ascites from decompensated liver disease focus on low-sodium diets and diuretics supplemented by large-volume paracentesis, transvenous intrahepatic portosystemic shunts and liver transplantation. The development of refractory ascites, hepatic hydrothorax, hyponatraemia or hepatorenal syndrome presents unique challenges to the provider and the patient. In some of these patients, therapy with liver transplantation will be the only viable therapeutic option. The diagnosis of infectious ascites, such as tuberculosis, and carcinomatous ascites remain diagnostic and therapeutic challenges for the clinician.

Methotrexate (MTX) plus ursodeoxycholic acid (UDCA) in the treatment of primary biliary cirrhosis.

This placebo-controlled, randomized, multicenter trial compared the effects of MTX plus UDCA to UDCA alone on the course of primary biliary cirrhosis (PBC). Two hundred and sixty five AMA positive patients without ascites, variceal bleeding, or encephalopathy; a serum bilirubin less than 3 mg/dL; serum albumin 3 g/dL or greater, who had taken UDCA 15 mg/kg daily for at least 6 months, were stratified by Ludwig's histological staging and then randomized to MTX 15 mg/m2 body surface area (maximum dose 20 mg) once a week while continuing on UDCA. The median time from randomization to closure of the study was 7.6 years (range: 4.6-8.8 years). Treatment failure was defined as death without liver transplantation; transplantation; variceal bleeding; development of ascites, encephalopathy, or varices; a doubling of serum bilirubin to 2.5 mg/dL or greater; a fall in serum albumin to 2.5 g/dL or less; histological progression by at least two stages or to cirrhosis. Patients were continued on treatment despite failure of treatment, unless transplantation ensued, drug toxicity necessitated withdrawal, or the patient developed a cancer. There were no significant differences in these parameters nor to the time of development of treatment failures observed for patients taking UDCA plus MTX, or UDCA plus placebo. The trial was conducted with a stopping rule, and was stopped early by the National Institutes of Health at the advice of our Data Safety Monitoring Board for reasons of futility. In conclusion, methotrexate when added to UDCA for a median period of 7.6 years had no effect on the course of PBC treated with UDCA alone.

Liver transplantation for alcoholic liver disease.

Patients with end-stage alcoholic liver disease should be considered for liver transplantation. A careful pretransplant evaluation must be undertaken to assess for both medical and psychiatric factors that will continue to require attention following transplantation. Although most programs require at least 6 months of ethanol abstinence before consideration of liver transplantation, there is little evidence that this conclusively predicts a reduction in recidivism. Most programs continue to exclude those with alcoholic hepatitis. Postoperatively, attention to psychiatric issues, recidivism, compliance, and assessment for tumors, especially squamous cell carcinomas, should be undertaken.

Prolonged follow-up of patients in the U.S. multicenter trial of ursodeoxycholic acid for primary biliary cirrhosis.

OBJECTIVE: Randomized, double-blind, placebo-controlled trials of ursodeoxycholic acid (UDCA) in patients with primary biliary cirrhosis (PBC) have not demonstrated improvement in survival during the placebo-controlled phases of these trials. Analyses purporting to demonstrate a survival advantage of UDCA are largely dependent on data obtained after the placebo phases were terminated, and placebo-treated patients were offered open-label UDCA. After completion of our 2-yr placebo-controlled trial of UDCA in which we observed no survival benefit for UDCA, we provided the patients with open-label UDCA to see if delay in providing UDCA for 2 yr had any effect on subsequent liver transplantation or death without liver transplantation. METHODS: In our previously reported 2-yr placebo-controlled trial, 151 patients with PBC were randomized to receive either UDCA (n = 77) or placebo (n = 74). The number of patients who progressed to liver transplantation or death without transplantation were similar in both the groups, 12 (16%) in the UDCA-treated and 11 (15%) in placebo-treated patients. All the patients were then offered open-label UDCA, with 61 original UDCA and 56 original placebo-treated patients now taking UDCA in an extended open-label phase of the trial. RESULTS: No significant differences were observed in the number of patients who underwent liver transplantation or died without liver transplantation in the open-label phase of the trial. Moreover, no difference in the time to these endpoints was seen over the period of observation of as long as 6 yr from the time of initial randomization. CONCLUSIONS: Results of open-label extensions of previous conducted placebo-controlled trials of UDCA in PBC leave uncertain whether UDCA impacts significantly on liver transplantation and death without liver transplantation in patients with PBC.