Hepatitis C infection is a major health care problem worldHepatitis C is a common cause of chronic liver disease wide. A recent population-based study found that 1.8% of that may progress to cirrhosis. We conducted a multicenter the United States population is chronically infected with this double-blind placebo-controlled trial of ribavirin 600 mg given virus (Center for Disease Control, unpublished data, May orally twice daily for 36 weeks with follow-up off therapy for 1997). Following acute infection, more than 90% of individuan additional 16 weeks. Fifty-nine patients with compensated als develop chronic infection 1 that may be associated with a chronic hepatitis C were entered. Efficacy was measured at slowly progressive process of chronic hepatocyte injury and the end of therapy and after follow-up by normalization of fibrosis, leading to cirrhosis in as many as 50% of individualanine aminotransferase (ALT), improvement in liver histolals.2 Nearly 20% of the liver transplantations performed in ogy, reduction in hepatitis C virus (HCV) RNA level and improvement of symptoms. Among the ribavirin recipients, the United States and Canada in 1993 were performed for 12 of 29 (41.4%) had normal ALT values at 36 weeks com-liver failure resulting from chronic hepatitis C. Presently, pared with only 1 of 30 (3.3%) placebo recipients (P õ .001). in those patients judged appropriate candidates for therapy, No patient maintained a normal ALT when therapy was interferon alfa 2b is the most common treatment for the stopped. No significant decrease in level of HCV RNA was disease. Interferon, however, has limitations in its ability to observed during the study. Histological improvement among control chronic hepatitis C. Long-term normalization of sesubjects who normalized ALT (01.67 Knodell index) was rum aminotransferase values is achieved in 20% or less of significantly greater than that in other treated patients (/0.33 subjects treated with 3 million units subcutaneously for 6 Knodell index; P õ .05). Fatigue improved in 19.2% of ribavi-months.3-6 The therapy is associated with manageable but rin-treated subjects and in 8.3% of placebo recipients whereas significant toxicity and has not been approved for use in no worsening of fatigue was reported by ribavirin recipients many groups of patients infected with hepatitis C, including compared with 16.7% of controls. This difference in fatigue transplantation recipients, persons with hemophilia, and was significant at weeks 36 and 52 (P õ .05; .02, respectively). children. Adverse events were generally comparable between treatmentRecognizing the great need for more effective therapy of groups except for a reversible hemolytic anemia experienced chronic hepatitis C, additional agents are being evaluated. by ribavirin recipients. Chest pain was noted in four patients Ribavirin, synthesized in 1970, is a purine nucleoside anaon ribavirin. Ribavirin was well tolerated and improved ami-logue with demonstrated antiviral activity against DNA and notransferase values and reduced fa...

IntroductionSubjects with autosomal dominant polycystic kidney disease (ADPKD) who were taking tolvaptan experienced aminotransferase elevations more frequently than those on placebo in the TEMPO 3:4 (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and its Outcomes) clinical trial.MethodsAn independent, blinded, expert Hepatic Adjudication Committee re-examined data from TEMPO 3:4 and its open-label extension TEMPO 4:4, as well as from long-term (>14 months) non-ADPKD tolvaptan trials, using the 5-point Drug-Induced Liver Injury Network classification.ResultsIn TEMPO 3:4, 1445 subjects were randomized 2:1 (tolvaptan vs. placebo) and 1441 had post-baseline assessments of hepatic injury. Sixteen patients on tolvaptan and one on placebo had significant aminotransferase elevations judged to be at least probably related to study drug. No association with dose or systemic exposure was found. Two of 957 subjects taking tolvaptan (0.2 %) and zero of 484 taking placebo met the definition of a Hy’s Law case. One additional Hy’s Law case was identified in a TEMPO 4:4 subject who had received placebo in the lead study. The onset of a hepatocellular injury occurred between 3 and 18 months after starting tolvaptan, with gradual resolution over the subsequent 1–4 months. None of the events were associated with liver failure or chronic liver injury/dysfunction. No imbalance in hepatic events was observed between tolvaptan and placebo in lower-dose clinical trials of patients with hyponatremia, heart failure, or cirrhosis.ConclusionsAlthough hepatocellular injury following long-term tolvaptan treatment in ADPKD subjects was infrequent and reversible, the potential for serious irreversible injury exists. Regular monitoring of transaminase levels is warranted in this patient population.

The hepatotoxic potential of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in patients with underlying chronic liver disease remains controversial. We performed a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial that compared pravastatin (80 mg) to a placebo administered once daily to hypercholesterolemic subjects greater than 18 years of age with at least a 6-month history of compensated chronic liver disease and with a low-density lipoprotein cholesterol (LDL-C) level greater than or equal to 100 mg/dL and a triglyceride (TG) level lower than 400 mg/dL. The efficacy was determined by the percentage change in LDL-C [along with the total cholesterol (TC), high-density lipoprotein cholesterol, and TG] from the baseline to week 12. The safety was analyzed by the proportion of subjects who developed at least 1 alanine aminotransferase (ALT) value greater than or equal to 2 times the upper limit of normal for those with normal ALT at the baseline or a doubling of the baseline ALT for those with elevated ALT at the baseline during 36 weeks of treatment. A total of 630 subjects were screened, and 326 subjects were randomized; nonalcoholic fatty liver disease was present in 64%, and chronic hepatitis C was present in 23%. In the intent-to-treat population, pravastatin (80 mg/day) significantly lowered the mean LDL-C, TC, and TG values at week 12 and at other times (weeks 4, 8, 24, and 36) in comparison with the placebo. The incidence of subjects who met the primary prespecified ALT event definition was lower in the pravastatin group at all times over the 36 weeks of therapy in comparison with the placebo group, although the difference was not statistically significant. No differences were seen on the basis of the baseline ALT values or among the different liver disease groups. Conclusion: High-dose pravastatin (80 mg/day) administered to hypercholesterolemic subjects with chronic liver disease significantly lowered LDL-C, TC, and TGs in comparison with the placebo and was safe and well tolerated. The concern over an increased potential for statin-induced hepatotoxicity in patients with chronic liver disease appears to be lessened on the basis of these results.

Summary Background Most drugs have not been well studied in cirrhosis; recommendations on safe use are based largely on experience and/or expert opinion, with dosing recommendations often based on pharmacokinetic (PK) changes. Aim To provide a practical approach to prescribing medications for cirrhotic patients. Methods An indexed MEDLINE search was conducted using keywords cirrhosis, drug‐induced liver injury, pharmacodynamics (PDs), PKs, drug disposition and adverse drug reactions. Unpublished information from the Food and Drug Administration and industry was also reviewed. Results Most medications have not been adequately studied in cirrhosis, and specific prescribing information is often lacking. Lower doses are generally recommended based on PK changes, but data are limited in terms of correlating PD effects with the degree of liver impairment. Very few drugs have been documented to have their hepatotoxicity potential enhanced by cirrhosis; most of these involve antituberculosis or antiretroviral agents used for HIV or viral hepatitis. Paracetamol can be used safely when prescribed in relatively small doses (2–3 g or less/day) for short durations, and is recommended as first‐line treatment of pain. In contrast, NSAIDs should be used cautiously (or not at all) in advanced cirrhosis. Proton pump inhibitors have been linked to an increased risk of spontaneous bacterial peritonitis (SBP) in cirrhosis and should be used with care. Conclusions Most drugs can be used safely in cirrhosis, including those that are potentially hepatotoxic, but lower doses or reduced dosing frequency is often recommended, due to altered PKs. Drugs that can precipitate renal failure, gastrointestinal bleeding, SBP and encephalopathy should be identified and avoided.

The prevalence of apparent amiodarone-related hepatic injury in 104 patients followed prospectively is compared to that reported in the literature. Asymptomatic elevation of serum aminotransferase levels was detected in approximately one-fourth of the patients, a figure similar to the average of reported cases. The frequency of extrahepatic organ toxicity was increased in patients with elevated levels. Symptomatic "hepatitis" developed in 3% of this series and in less than 1% of cases in the literature. Evidence of hepatic phospholipidosis and the development of pseudoalcoholic liver injury is most likely due to the biochemical effects of the drug and to possible metabolic idiosyncrasy, respectively. Serial blood enzyme measurements, as recommended by the manufacturer, may offer some protection against the development of more serious liver injury. However, levels of amiodarone may persist in various tissues for weeks to months following withdrawal, and stopping the drug does not guarantee the prompt reversal of any organ toxicity. Accordingly, the risks posed and benefits offered by amiodarone should be carefully weighed prior to discontinuing the drug, as the risk of sudden cardiac death may outweigh the hazards of ongoing hepatic, pulmonary or other toxicity.