At Liver Center, a vital organ gets its due

The nation’s oldest liver research center sees a five-year renewal and expanding targets for therapies.

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.”

—Jennifer Kaylin

Spike in blood pressure may make weight lifters vulnerable to aortic aneurysm

In a research letter published in JAMA: The Journal of the American Medical Association in December, a team of Yale researchers reported that some weight lifters may be at risk of rupturing the aorta’s inner lining.

“We had seen a couple of patients in a row who had been weight lifting when this phenomenon occurred,” said John A. Elefteriades, M.D. ’76, HS ’81, FW ’83, chief of cardiothoracic surgery. Looking through his research projects, he found other cases. “I noticed that two or three of them were young people who otherwise wouldn’t have been expected to have an aortic dissection and were lifting weights at the time.”

They found that systolic pressure during heavy weight lifting can rise from a normal reading of 120 to highs of 280 and even 300. “If your aorta is weak due to your genetics and if it is mildly enlarged, weight lifting might be what puts you over the brink,” Elefteriades said.

The danger of a potentially fatal aortic dissection, which splits the artery in two, results from a confluence of events, starting with that genetic predisposition.

Elefteriades is working to pinpoint the genetic links in association with Celera Genomics, the company involved in the mapping of the human genome.

Those at risk include people with aneurysms, connective-tissue diseases and hypertension, as well as people with a family history of aneurysms or dissections and those above age 40.

—John Curtis

Et Cetera

Obesity bias a problem for doctors

Health professionals surveyed at an obesity conference in Quebec last year learned something surprising about themselves. The survey revealed a significant bias against overweight people among almost 400 physicians, researchers, pharmacologists and psychologists who treat and study obesity.

“The stigma of obesity is so strong that even those most knowledgeable about the condition infer that obese people have blameworthy behavioral characteristics that contribute to their problem, i.e., being lazy,” said Marlene B. Schwartz, Ph.D. ’96, a research scientist in the Department of Psychology and lead researcher of the study published in September in Obesity Research. “Furthermore, these biases extend to core characteristics of intelligence and personal worth.”

For the study 389 clinicians and researchers took the Implicit Association Test and filled out a questionnaire that assessed attitudes, personal experiences with obesity and demographic characteristics. The results were not all dispiriting, however. Those who work directly with obese patients showed less bias than those who do not.

—J.C.

Same chemical, different reaction

Drugs designed to improve memory consolidation in the elderly may also worsen working memory, according to a study by Yale researchers published in the journal Neuron in November.

The difference stems from the brain regions needed for different kinds of memory processing, according to Amy Arnsten, Ph.D., associate professor and director of graduate studies in neurobiology. The hippocampus handles long-term memory, while the prefrontal cortex is responsible for working memory. The two brain areas, Arnsten found, respond to chemicals differently.

Medications in development to improve long-term memory often try to enhance the activity of protein kinase A (PKA), an enzyme inside of cells. Arnsten and her colleagues found that when this protein was activated in the prefrontal cortex it worsened working memory.

—J.C.


			Originally published in Yale Medicine, Spring 2004. Copyright © 2004 Yale University School of Medicine. All rights reserved.