Genetic Links to Rare Liver Disease Found

WEDNESDAY June 10, 2009 -- Scientists have found genetic variations that appear to increase the risk of developing primary biliary cirrhosis, a baffling disease that can destroy the liver.

Primary biliary cirrhosis is an autoimmune disorder that blocks the bile ducts in the liver. It is a condition that mostly affects women, striking about one in 2,500 Americans. The current treatment works in about half of patients. The other half will need a liver transplant at sometime in the course of the disease, according to researchers, but the condition has been known to return even after transplantation.

"We have known virtually nothing about what causes primary biliary cirrhosis," said lead researcher Dr. Katherine Siminovitch, a senior investigator at the Samuel Lunenfeld Research Institute of Mount Sinai Hospital in Toronto. "What we have found are some of the major genetic causes of the disease," she said.

"About half the patients will respond to that treatment, but half won't. Of the half that won't, some will be OK, but many won't and they will have to have a liver transplant," she explained. "So, we urgently need a new medical therapy."

Siminovitch thinks the findings indicate that drugs already being used to treat other autoimmune diseases might work for primary biliary cirrhosis. "This is terrific for us, because we can now begin to do early trials to see if it will change the outcome of this disease," she said.

It is also possible new, more-targeted drugs could be made to treat the disease, she said.

In addition, the findings may also make it possible to predict who is likely to develop the disease and possibly prevent it, Siminovitch said.

The report is published in the June 11 issue of the New England Journal of Medicine.

For the study, Siminovitch's team analyzed blood samples from patients with primary biliary cirrhosis as well as samples from people who did not have the condition.

In the first phase of the study, researchers did a genomewide analysis, comparing the genotypes of 536 patients with primary biliary cirrhosis with 1,536 people who did not have the disease. In the next phase, researchers conducted genetic mapping to confirm the initial results and to identify genetic variations closely associated with primary biliary cirrhosis.

Siminovitch's group found variants of two genes, interleukin 12A (IL12A) and interleukin 12RB2 (IL12RB2), that were strongly linked with the disease. In addition, they confirmed that the human leukocyte antigen (HLA) area of the genome is associated with primary biliary cirrhosis, a link that had been identified before.

Dr. Scott L. Friedman, chief of the division of liver diseases at Mount Sinai School of Medicine in New York City and president of the American Association for the Study of Liver Diseases, said the discoveries are an important step in understanding this disease, but the interaction between genes and environmental triggers is complicated.

"I don't think this is going to translate to a significant change in therapy in the near term," Friedman said. "But it opens the door to scientific investigation of other therapies."

Dr. Nathan M. Bass, medical director of the liver transplant service for adults at University of California, San Francisco, noted the study was the first of its kind in primary biliary cirrhosis "that appears to shed light on the mechanism of this uncommon, but puzzling, disease."

"Primary biliary cirrhosis is a distressing condition that mainly affects women, and which has eluded our understanding despite many years of research, although a disorder in immune regulation has been suspected for some time," Bass said.

"The findings of this study suggest that the key problem may rest within the interleukin-12 immunoregulatory-signaling pathway, offering a novel new insight into the pathogenesis of primary biliary cirrhosis, with the attendant opportunity to better understand the key mechanisms in the evolution and progression of this disease, and to ultimately develop new therapies based on this understanding," he said.

More information

For more information on primary biliary cirrhosis, visit the U.S. National Institute of Diabetes and Digestive and Kidney Diseases.

Posted: June 2009


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