At Liver Center, a vital organ gets its due

Poets and philosophers may rhapsodize about the human heart, but James L. Boyer, M.D., HS ’67, says it’s actually the liver that is the body’s most fascinating organ.

“The ancients thought of the liver as the seat of the soul,” says Boyer, director of the Liver Center at the School of Medicine and Ensign Professor of Medicine. “Babylonians would consult a sheep’s liver before going into battle, and even today, a Frenchman who is not feeling well is said to have mal au foie. European societies have much more respect for the liver than we do.”

But at the Liver Center, the oldest research facility in the country devoted exclusively to liver research, this essential and complex organ gets its due. Roughly 40 scientists, all with independent funding totaling about $15 million, study the liver.

The value of the 20-year-old center was confirmed in December, when the National Institutes of Health (NIH) renewed the center’s funding for a fourth consecutive five-year term starting in September 2004. “We received the highest score in the history of the center,” Boyer says of the NIH’s evaluation. The center will receive $3.75 million, with the university getting an additional 62 percent of that in indirect NIH support.

Hepatology has existed as a medical subspecialty for only 50 years, and as recently as 20 years ago there were still very few treatments for liver disorders. But Boyer says that is changing. He points out that hepatitis B and C and biliary cirrhosis can now be treated with medications. There is a vaccine for hepatitis A and B, and liver transplantation is now a viable option. In fact, Yale is expanding its transplant program with the recent arrival of David Cronin, M.D., a liver specialist, in the Department of Surgery.

But while some liver disorders are treatable, new challenges loom. The biggest, Boyer says, is fatty liver disease related to obesity. Gerald I. Shulman, M.D., Ph.D., is a researcher in the Liver Center who has been studying liver diseases associated with insulin resistance. “Our work suggests that one of the earliest findings in type 2 diabetes is the presence of insulin resistance,” Shulman says. “That starts to happen years before the development of diabetes.”

Shulman’s research has also found that insulin resistance occurs in the liver and the muscles, and that it is caused by a transport deficit triggered by the presence of fatty acids. “Fatty acids build up in the liver and lead to deficits in insulin signaling,” he says. Shulman is now looking into the correlation between age and the onset of type 2 diabetes, even in adults who are not sedentary or overweight. “I’d say every third or fourth patient I see has adult-onset diabetes, which can have devastating complications,” Shulman says. “We’re working hard to sort it out.” Many of these patients have fatty liver disease.

Other groundbreaking work being done by researchers at the Liver Center includes:

• Discovery of the gene responsible for isolated autosomal dominant polycystic liver disease and description of the clinical characteristics of this inherited disorder, by a group led by Stefan Somlo, M.D., FW ’91.

• Fundamental discoveries made by a team led by Roberto J. Groszmann, M.D., at the VA Connecticut Healthcare System in West Haven and William C. Sessa, Ph.D., which have paved the way for therapies that will control the complications from portal hypertension in cirrhosis, such as intestinal bleeding.

• Demonstration that bone marrow cells are capable of migrating and establishing themselves in other tissues, such as the liver, by Diane S. Krause, M.D., Ph.D. This pioneering work is central to the future of gene therapy for genetic liver disorders.

“When I started out, we were mainly diagnosticians. We couldn’t cure many liver diseases,” Boyer says. “The changes have been enormous. It’s an exciting time to be working in this field.”