Digestive Diseases News
Winter 2007

NIDDK Explores Causes, Treatment, and Research Challenges for Acute Liver Failure

Researchers from several continents convened in Bethesda, MD, in December to share knowledge about the causes, management, and prevention of acute liver failure (ALF) and to make recommendations for future basic and clinical research.

ALF affects an estimated 2,000 people in the United States annually and is due to a variety of causes that result in the same clinical condition characterized predominantly by severe liver test abnormalities and often accompanied by multiorgan failure. The causes of ALF vary from country to country even though the clinical manifestations remain the same, according to William M. Lee, M.D., a professor at the University of Texas Southwestern Medical School in Dallas.

For example, acetaminophen overdosing accounts for about half of all adult ALF cases in the United States but is a virtually unknown cause in India. Because of these disparate causes, “multicenter studies and possible international studies are the best way to go about addressing this disease,” Lee said at a 2-day meeting sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

Research Progress

ALF research was limited by the disease’s rarity until about 1998, when the Acute Liver Failure Study Group (ALFSG), funded by the NIDDK and headquartered at the University of Texas Southwestern Medical Center, began collecting detailed prospective information and biosamples on more than 1,100 patients from more than 20 U.S. medical centers. ALF is now studied by separate adult and pediatric study groups comprising 23 medical centers for recruiting adults and 18 for recruiting children.

The University of Texas Southwestern Medical Center continues to serve as the Data Coordinating Center for the adult ALF study group and the University of Pittsburgh for the pediatric study group. Both the adult and pediatric study groups have three major goals:

• to collect detailed data
• to perform ancillary studies
• to perform therapy trials

The ALFSG is nearing completion of a clinical trial begun in 1999 to test the effectiveness of n-acetyl cystiene (NAC) for treating ALF cases not due to acetaminophen overdose. Final results from the trial are expected at the end of 2007.

NAC treatment is highly effective for acetaminophen overdose, but doctors must administer the treatment “urgently” because it is most effective when taken as soon after the overdose as possible, according to Timothy Davern, M.D., assistant professor in the Department of Medicine at the University of California at San Francisco (UCSF).

Davern pointed out that while medical treatment for ALF is currently limited, “liver transplant represents a lifesaving therapy for patients with severe, medically unresponsive ALF.” The 1-year survival rate for these patients following a liver transplant is better than 90 percent at UCSF, according to Davern.

Liver transplantation is responsible for improving the outcome of ALF from nearly 100 percent mortality to the current overall mortality rate of 40 percent, according to Lorenzo Rossaro, M.D., professor of medicine in the Department of Internal Medicine and Transplant at the University of California at Davis Medical Center.

Complicating Factors

Pursuing a liver transplant for a person with ALF is a complex process because

• prognostic scores for demise due to ALF are imperfect

• the availability of a liver donor organ is unpredictable

• a liver transplant in people who would have survived without a transplant subjects them to the morbidity associated with lifelong immunosuppression

• spontaneous survival is possible even with advanced ALF

Future Research

Research on ALF treatment, according to meeting attendees, is or should be headed toward

• determining which perturbations in homeostatic mechanisms drive the clinical syndrome of ALF

• discovering and developing novel, mechanistically designed agents aimed at limiting hepatocyte injury and death and promoting hepatic repair and regeneration

• prospective studies of long-term outcomes that explore the persistence or recurrence of liver disease, general health status, neurological sequelae, and quality of life of people who recover from ALF

• long-term outcomes of the live donors of liver transplants for ALF

• identifying specific interventions to avoid liver transplantation in defined subgroups

• developing accurate markers to predict liver recovery to avoid unnecessary transplantation

• developing clinically effective liver support and assist devices

The NIDDK also funds the Drug-induced Liver Injury Network, a five-center network that collaborates on research related to the magnitude, diversity, and mechanisms of drug-induced liver injury.

For more information about NIDDK research on liver diseases, visit www.niddk.nih.gov/research/resources/resource.asp?program=liver#2.

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NIH Publication No. 07–4552
March 2007