ABSTRACT
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.
Subject(s)
Cholagogues and Choleretics/therapeutic use , Liver Cirrhosis, Biliary/drug therapy , Methotrexate/therapeutic use , Ursodeoxycholic Acid/therapeutic use , Adult , Aged , Bile/chemistry , Bile Acids and Salts/analysis , Cholagogues and Choleretics/adverse effects , Drug Therapy, Combination , Endoscopy , Female , Humans , Liver Cirrhosis, Biliary/blood , Liver Cirrhosis, Biliary/complications , Liver Cirrhosis, Biliary/metabolism , Male , Methotrexate/adverse effects , Middle Aged , Prevalence , Survival Analysis , Treatment Failure , Ursodeoxycholic Acid/adverse effects , Varicose Veins/epidemiology , Varicose Veins/etiology , Varicose Veins/pathologyABSTRACT
Hepatic iron deposition is common in patients with chronic hepatitis C (HCV) and may play a role in progression of liver disease. This pilot study examines the relationship between hepatic iron concentration (HIC) and histologic progression over time in patients with HCV. HIC was retrospectively measured in 14 patients with HCV who had 2 serial liver biopsies prior to the era of interferon therapy. The mean interval between biopsies was 56 +/- 46 months. Mean Knodell score worsened between first and second biopsies (10.0 +/- 2.8 versus 12.4 +/- 3.3; P = 0.007). There was increased portal inflammation (3.2 +/- 0.4 versus 3.6 +/- 0.5; P = 0.028) and fibrosis (1.8 +/- 1.3 versus 2.7 +/- 1.2; P = 0.002), but no significant change in piecemeal necrosis or lobular degeneration. There was no significant change in HIC between first and second biopsy (P = 0.66). However, HIC was noted to increase significantly among patients with cirrhosis on initial biopsy or those who progressed to cirrhosis (P = 0.009). In this pilot study, histologic progression in patients with precirrhotic HCV was not associated with an increase in HIC, whereas hepatic iron accumulation was observed in 3 patients once cirrhosis was present. The interaction between progression of hepatitis C and iron deposition warrants further study.
