William Lee, M.D.
Professor of Medicine
Division of Liver Disease

Acute liver failure (ALF) is a dramatic syndrome in which previously healthy individuals rapidly lose hepatic function due to a variety of causes, develop hepatic encephalopathy, and become critically ill within days. The mortality is high, up to 94%. Even in the era of liver transplantation, many patients die either due to complications of this devastating disease or because of lack of available donor organs in a timely fashion. Since ALF occurs relatively infrequently, no one center in the US has a large enough experience to conduct important studies of this condition.

1) UT Southwestern has developed a multi-center ALF study group at 23 sites around the United States, with the broad aims of 1) gathering data concerning ALF etiology, natural history, and outcome, and 2) studying the use of N-acetylcysteine (NAC) as therapy for ALF through this collaborative mechanism. The Acute Liver Failure Study Group is in its 2nd full year of operation, and there is now a pediatric acute liver failure group. One important aspect has been the description of the incidence of drug-induced acute liver failure, which accounted for 50% of all cases in this study. The clinical trial of NAC for patients with acute liver failure not related to acetaminophen is under way at 15 of the sites. Numerous sub-projects connected with the ALF group have been undertaken. Our group is looking at the role of Gc protein in the actin scavenging system, a repair mechanism which clears the serum of actin excess following severe cell injury. Levels of Gc have been correlated with the outcome of ALF and this mechanism may be important in the prevention of the multi-organ failure seen in these patients.

2) A spin-off to the ALF Study Group is the initiative on drug-induced hepatotoxicity. Since more than 50% of acute liver failure is due to medications, a prospective study is underway to identify instances of severe liver injury due to drugs, setting the threshold for inclusion in the study lower than that required for ALF. A pilot retrospective study has already been performed in which we developed new case report forms, and identified 308 cases at 6 centers over a 4 year period. There is a need for better surveillance of drug reactions in the U.S., and this is one effort to improve the surveillance system.

3) Hepatitis C affects 4 million people in the U.S. It is more common than HIV, AIDS or hepatitis B. It is the most common cause of end-stage liver disease (cirrhosis) and liver cancer in the U.S. Efforts to treat hepatitis C have been directed at use of interferons, naturally occurring anti-virals which decrease viral replication and enhance the immune response to the virus. The best therapies currently only result in viral clearance in approximately 50% of patients. UT Southwestern's Liver Center is one of ten sites around the U.S. engaged in testing whether use of long acting interferons as maintenance therapy can slow the progression of the disease. A database developed at UT Southwestern has recorded all patients seen since the early 1990's when the epidemic was recognized. Serum samples are available. In collaboration with Dr. Michael Gale, Microbiology, who is an established molecular virologist, we are seeking to unravel the secret of why certain patients respond to treatment and others do not, using a combination of epidemiologic studies on the archived patient material and sophisticated molecular techniques, to tease out differences between patient responses.