Molecular therapeutics of liver disease.

Fundamental advances in biomedical research will revolutionize the prevention and treatment of liver disease during the early twenty-first century. Recent progress in gene-, cell-, and recombinant protein-based therapeutics will contribute to this revolution, although formidable obstacles currently prevent the clinical application of these novel therapies. Eventually, these obstacles will be overcome, and molecular therapeutics of liver disease will become a clinical reality. As a result, the new millennium will be a very interesting time to practice hepatology.

Clinical outcome and virological characteristics of hepatitis B-related acute liver failure in the United States.

The role of hepatitis B virus (HBV) genotypes in the outcome of acute HBV infection is unclear. In this study, we aimed to evaluate the clinical and virological features of patients with hepatitis B-related acute liver failure (HBV-ALF) in the US. Clinical and laboratory features of consecutive patients with HBV-ALF from the US ALF Study Group were analysed. Prevalence of HBV genotypes, precore stop (G1896A) and core promoter dual (T1762A, A1764T) variants among patients with HBV-ALF were compared with a cohort of 530 patients with chronic HBV infection. Thirty-four HBV-ALF patients were studied: mean age 41 years, 56% men, 25 had detectable HBV-DNA. HBV genotypes A, B, C and D were found in 36, 24, 8 and 32% patients, respectively. Precore stop and core promoter dual variants were detected in 32 and 44% of patients, respectively. Twenty-three (68%) patients survived: 14 after liver transplant, nine without transplant. Older age was the only independent factor associated with poor outcome. Compared with patients with chronic HBV infection, patients with ALF were more likely to be non-Asians (88% vs 44%, P = 0.005) and to have genotype D (32% vs 10%, P < 0.01). A higher prevalence of HBV genotype D persisted even after matching for race and HBeAg status (32% vs 16%, P = 0.007). We concluded that HBV genotype D was more frequently found in patients with HBV-ALF than those with chronic HBV infection in the US. Further studies are needed to determine if HBV genotypes play a role in the outcome of acute HBV infection.

Recurrent disease after liver transplantation.

Most liver diseases for which liver transplantation is performed recur after liver transplantation. The clinical impact of recurrence varies. For autoimmune liver diseases, such as primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis, clinically significant recurrence appears to be relatively rare. Whether these diseases recur in any meaningful way after liver transplantation is still controversial. For the chronic viral diseases, hepatitis B and C, the issue is not whether they recur--they clearly do--but whether the recurrence affects prognosis and how best to manage recurrent disease. For hepatitis B virus (HBV), reinfection can lead to accelerated liver injury, graft loss, and dramatically worse patient and graft survival rates, whereas the prognosis of recurrent hepatitis C virus (HCV), at least in the short-term, appears to be more benign. Major advances have been made in preventing liver allograft reinfection with HBV. Before these advances, chronic hepatitis B was considered a relative contraindication to liver transplantation because the allografts almost always became reinfected. With the current strategies for preventing HBV reinfection, however, the graft and patient survival rates after transplantation for chronic hepatitis B approach those for nonviral diseases. The development of resistance to antiviral therapy is likely to represent the major problem in the future and mandate the use of combination therapy. There is currently no effective therapy available for recurrent hepatitis C. Until such therapy is developed, recurrent hepatitis C remains the most challenging problem facing liver transplant physicians and surgeons.

Gene therapy for liver disease.

With major advances in biomedical science over the last 2 decades, the possibility of treating human disease at a genetic level has become a tantalizing possibility. As a result, a growing number of investigators are focusing on the development of techniques to deliver therapeutic genes into cells. The liver has been a model organ in the development of this gene transfer technology. This review focuses on the attributes and limitations of the current gene delivery systems that have been explored in the context of liver disease and highlights the obstacles that must be addressed before hepatic gene therapy becomes a clinical reality.

Severe liver injury after treatment with the leukotriene receptor antagonist zafirlukast.

BACKGROUND: In registration trials, zafirlukast, an asthma medication, caused asymptomatic elevated aminotransferase levels in up to 5% of participants. Until now, however, no cases of severe hepatitis attributed to zafirlukast have been reported. OBJECTIVE: To report the clinical characteristics of three patients with severe hepatitis due to zafirlukast. DESIGN: Case report. SETTING: One community hospital and two university hospitals. PATIENTS: Three middle-aged women taking zafirlukast, 20 mg twice per day. INTERVENTION: Discontinuation of zafirlukast therapy in three patients, steroid therapy in two patients, and orthotopic liver transplantation in one patient. MEASUREMENTS: Serum aminotransferase and bilirubin levels, standard blood tests for causes of hepatitis other than drug toxicity, and liver biopsy in two patients. RESULTS: Patient 1 recovered spontaneously, had a severe relapse after inadvertent rechallenge with the medication, and ultimately made a complete recovery. Patient 2 developed subfulminant hepatic failure and required liver transplantation. Patient 3 developed severe hepatitis that improved after treatment with corticosteroids. Liver tissue was available from two patients and showed histologic changes commonly associated with drug reactions. CONCLUSION: Patients receiving zafirlukast may develop severe liver injury and should be observed for signs and symptoms of hepatitis.

Troglitazone-induced fulminant hepatic failure. Acute Liver Failure Study Group.

The three reported cases demonstrate that troglitazone is an idiosyncratic hepatotoxin that can lead to irreversible liver injury. Thus, troglitazone should be prescribed with caution and should not be used as a first-line agent in the treatment of type II DM when potentially less toxic alternatives are available. It remains to be seen whether the hepatotoxicity associated with troglitazone is a drug-class effect or specific to troglitazone. Other thiazolidinediones currently in clinical trials may be able to provide the therapeutic benefits of troglitazone without significant hepatotoxicity. If troglitazone is used, frequent monitoring of serum aminotransferases and symptoms is mandatory. However, as illustrated by these and other cases reported to date, the onset of troglitazone-induced liver injury is insidious and temporally variable. Thus, the value of close monitoring and when, if ever, it is safe to stop such monitoring are currently unclear.