Illustrations by Cyril Cabry THINK BEFORE YOU DRINK A collaborative center looks into the risk factors of alcoholic liver and pancreatic diseases.
by Lori OliwensteinEach year, between 15,000 and 20,000 people in the United States die of alcoholic liver disease, or ALD. As many as 20 percent of them die in Los Angeles.
"This is a city plagued with alcohol-related disease," says Hide Tsukamoto, Ph.D., professor of medicine and pathology. Most often, that disease is cirrhosis of the liver, a condition in which liver cells deteriorate and are replaced with scar tissue. At least half of all cases of cirrhosis result from alcoholism; the other half are generally the result of viral hepatitis. A smaller but still significant number of alcoholics will suffer from some sort of pancreatic injury.
Just how alcohol destroys liver and pancreatic cells is the focus of the USC-UCLA Research Center for Alcoholic Liver and Pancreatic Diseases, headquartered on the USC Health Sciences Campus. Tsukamoto is director of the center, which has a $7.9 million, 5-year grant from the National Institute for Alcoholism and Alcohol Abuse to study alcohol-induced liver or pancreatic injuries at the cellular level, and try to find ways to intervene before the worst of the damage is done.
"This is a truly multidisciplinary program," says Tsukamoto. "There's no central laboratory. We are all mostly established investigators with a long-standing interest in our respective complementary, and yet unique, areas. Bringing these people together was the essence of the center's creation."
The investigators include USC researchers such as Neil Kaplowitz, M.D., chief of the division of gastrointestinal and liver diseases and director of the Research Center for Liver Diseases, with which the Alcohol Center collaborates; Samuel French, M.D., chief of anatomic pathology at Harbor-UCLA Medical Center, and Stephen Pandol, M.D., professor of medicine at the Veterans Administration Greater Los Angeles Healthcare System and UCLA. Together with Tsukamoto, they are responsible for the four main research projects at the center:
Tsukamoto and colleagues are looking into the role iron plays in promoting liver inflammation and fibrosis. The focus is on a type of liver cell, called a Kupffer cell, which normally acts to defend the liver against invading organisms or cancerous cells. "We and others have shown that in people with alcoholic liver disease, these cells become activated to release inflammatory mediators that actually cause injury," Tsukamoto says, "and we've identified iron as the key signaling molecule in the activation of these cells. In fact, we've shown in animal models that you can prevent activation of Kupffer cells by removing iron from them."
French is investigating the way in which abnormal proteins accumulate in the liver, much as they do in the brains of Alzheimer's patients. These proteins get in the way of normal liver function and do not necessarily disappear even if the person stops drinking; instead, the condition continues to progress and is often fatal. French has also been looking at the role of dietary fats in ALD. He has shown that vegetable and fish oils, for instance, are central in the development of ALD while some animal fats seem to prevent it.
Pandol, an expert in pancreatic disease, is examining the mechanisms by which alcohol consumption makes the pancreas vulnerable to inflammation through routes that would not injure a normal pancreas.
Kaplowitz's focus is on the role of antioxidants in ALD. Evidence has showed that the alcoholic liver is more susceptible to damage from oxygen radicals, leading Kaplowitz to wonder whether the alcohol is somehow interfering with the function of antioxidants, such as the peptide glutathione. He found that an alcoholic liver suffers a huge drop in glutathione in its mitochondria-a cell's powerhouse, where oxygen radicals are produced as fuel is transformed into energy-and that this drop is what makes the liver vulnerable to toxic injury. "If that is indeed true, then we've uncovered a very fundamental aspect of the pathogenesis of alcoholic liver disease, and we can now work on a way to reverse this susceptibility," says Kaplowitz.
In addition to these four projects, the center also funds a Pilot Project Program. "This program is intended to stimulate research by funding junior investigators with no other funds," says Tsukamoto, "or by funding established investigators from other fields who want to extend their research to alcohol-induced organ injury." One such pilot project is being conducted by USC's Michael Lai, M.D., Ph.D., a Howard Hughes Medical Institute Investigator, who is working on the mechanism by which proteins produced by the hepatitis C virus sensitize liver cells to other toxins. "This will likely shed critical insight into the relationship between alcoholic liver injury and viral hepatitis," says Tsukamoto. Another pilot project by Anna Gukovskaya, Ph.D., a scientist at the West Los Angeles Veterans Medical Center, examines the role of fatty acid-alcohol metabolite in sensitizing the pancreas for injury.
"We've also been the force behind the establishment of a clinical research group," adds Tsukamoto. "The Southern California Alcohol Research Group (SCARG) brings together hepatologists, gastroenterologists, basic scientists and others from various institutions who are interested in translational research in the area of alcoholic liver and pancreatic diseases."
Tsukamoto is realistic about what his center is trying to accomplish. "I'm not in a position to advocate alcohol drinking," he notes, "but we have to admit that it's a socially accepted drug with some benefits-for instance, moderate drinking may be good for relaxation and cardiovascular disease."
That is why so much of the center's research is on the role that so-called secondary risk factors play in promoting ALD. Once understood, information about these factors can be used to help people reduce their risk of developing serious disease. "We can tell those who have secondary risk factors that they should be careful about the way they consume alcohol," says Tsukamoto. Those factors include increased dietary fat and dietary iron, gender (females are more at risk than males), the use of over-the-counter or illicit drugs in addition to alcohol (for instance, Tylenol and alcohol together can be dangerous) and viral infections.
"We know we're going to have an increasing number of patients dying of cirrhosis," says Tsukamoto. "Transplantation can't catch up and there's no medical treatment." That is why, he says, this center is so important-and why it is equally important that the center continues to grow and bring in additional grants and donations. "We need to develop a liver cirrhosis research program as an extension of the center; we certainly have expertise in this area. We wish to promote the multidisciplinary aspects of our consortium to enhance the center's potential to do some real translational research. And this sort of systematic, collaborative approach is the way to accomplish it."
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