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New NIDDK Branch Focuses on Liver Disease

A new Liver Disease Research Branch at the National Institute of Diabetes and Digestive and Kidney Diseases will focus research efforts on the critical areas of hepatitis B and C, clinical liver disease, liver and biliary diseases and liver transplantation.

Heading the new branch is Dr. Jay H. Hoofnagle, former director of NIDDK's Division of Digestive Diseases and Nutrition (DDN), and one of the world's leading authorities in the field of liver disease.

Dr. Jay H. Hoofnagle heads NIDDK's new Liver Disease Research Branch.

"This is not just a shuffling of the deck chairs," says Hoofnagle, noting that the new branch is the result of "strong interest" from Congress and the lay community in raising the status of liver disease within the institute. The new branch will function within the DDN division, but with its own branch chief, staff and an exclusive focus on the liver and liver disease. "This will give liver research its own home at the NIH," Hoofnagle says. Dr. Stephen James, former deputy director of DDN, is now the division's acting director.

Thirty years ago, 75 percent of chronic liver disease was believed due to alcohol and 99 percent was considered untreatable. "We now know that alcohol actually represents a minority of cases — about 20 percent — and there are many forms of the disease that are now treatable or preventable," says Hoofnagle, whose own research at NIH with interferon during the 1980s resulted in the first cures of hepatitis C-infected individuals. "We still see the original patients from those studies, and they haven't had any evidence of residual liver disease or the virus," he notes.

While the incidence of alcoholic liver disease is declining, hepatitis C-related liver disease is up, due to increased use of injection drugs and multiple sexual partners. "The lifestyle that came in the 1960s was bad on the liver," says Hoofnagle.

With more than 3 million Americans infected with the virus, one-third of whom will develop cirrhosis, many eventually requiring liver transplantation, hepatitis C will be a primary focus of the new branch, which will fund extramural efforts at research centers across the country. Optimal treatment with new, long-acting pegylated interferon (PEG interferon alfa) and the antiviral drug ribavirin has resulted in eradication of the virus in 50 percent of patients, according to Hoofnagle. "Hepatitis C is the big issue," he says. "There's marvelous research going on — better understanding of the virus, new insights in how it harms the liver, and recently, better antivirals, protease inhibitors, helicase inhibitors and cytokines, like interferon. There's a light at the end of this tunnel."

Hepatitis B is also coming under control, he says. There are currently three licensed treatments — interferon, lamivudine (Epivir) and adefovir (Hepsera). "There's also a handful of drugs pending and combination therapy being tested," says Hoofnagle. "I think hepatitis B will be a fully treatable disease in the next 5 to 10 years."

NASH, or nonalcoholic steatohepatitis, a newly identified liver disease common among obese individuals and people with diabetes, is high on the new branch's targeted list. Studies to find the cause, natural history and treatment of NASH are under way. "Five years ago, we didn't have a single grant for NASH," Hoofnagle says. NASH seems to be caused by obesity and insulin resistance. Treatments, he says, will likely include weight loss, physical activity, anti-oxidants and anti-diabetes drugs.

Autoimmune liver diseases, like autoimmune hepatitis, primary biliary cirrhosis and sclerosing cholangitis "are tough," according to Hoofnagle. "We don't know what causes them and treatments improve but do not cure them." Autoimmune hepatitis is treated with steroids, while primary biliary cirrhosis, which affects one in 2,000 women and eventually leads to liver transplantation, can be slowed down by a drug called ursodiol (Actigall). "We have to get at the cause of this disease, prevent and actually cure it," says Hoofnagle.

One in 5,000 children born each year has biliary atresia — lacking bile ducts — and most of these children will eventually need a liver transplant. The supply of donor livers for these children — as well as for adults with cirrhosis or liver cancer and for others approaching liver failure — will be a big issue for the new branch.

The branch will be directly responsible for liver research funding by NIDDK but will also have the charge to collaborate with and promote liver research in other institutes involved in such work. Efforts in other institutes include the study of liver cancer at NCI, viral hepatitis at NIAID and NIDA, biliary atresia at NICHD, alcoholic hepatitis at NIAAA and imaging of the liver with NIBIB.

Liver transplantation is extremely successful; long-term survival is possible and some patients are able to stop all their immunosuppressive medications. However, there are not enough livers available for all the people who need them. "Several thousand people die on the transplant list a year," says Hoofnagle. "We need to find more donors and other sources of livers."

The solution to these pressing clinical issues is most likely to come from basic liver research, including studies of how the liver is formed, how stem cells differentiate into adult liver cells, how the liver functions, how to overcome liver transplantation rejection and how to engineer artificial livers or how to prepare animal livers that can be used in humans (xenotransplantation), says Hoofnagle.

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