Mayo Researchers Help Discover Genetic Cause for Primary Biliary Cirrhosis

Researchers have discovered a novel molecular path that predisposes patients to develop primary biliary cirrhosis, a disease that mainly affects women and slowly destroys their livers. Primary biliary cirrhosis has no known cause.

The finding, significant because it is a first step toward developing a targeted treatment and a cure, will be published in the June 11, 2009, issue of the New England Journal of Medicine.

"Now that we better understand the molecular basis of primary biliary cirrhosis, we can look for ways to specifically fix those elements," says Konstantinos Lazaridis, M.D., a Mayo Clinic hepatologist and a senior researcher in the study.

Currently, treatments for primary biliary cirrhosis can slow progression of the disease, which affects 1 in 2,500 Americans, 90 percent of them women. However, about half of patients do not respond to medical therapy. For some patients, a liver transplant cures the condition. But not all patients qualify for a transplant, and some transplant recipients experience a recurrence within five to 10 years.

The study was conducted at the University of Toronto using blood samples of patients collected at several medical centers in Canada and at Mayo Clinic's campus in Rochester, Minn., through its Primary Biliary Cirrhosis Genetic Epidemiology Research Resource. This resource comprises the biospecimens of hundreds of primary biliary cirrhosis patients and individuals who do not have the disease (controls) --matched for age, sex, race and state of residence. Mayo Clinic and the University of Toronto are among the largest treatment centers in North America for primary biliary cirrhosis.

The University of Texas MD Anderson Cancer Center in Houston provided historical controls and conducted the statistical analysis of the study.

The genetic link to primary biliary cirrhosis has been well-established by previous studies. "Indeed, mothers, sisters and daughters in the same family have a significantly higher tendency to develop the disease compared with the general population," says Dr. Lazaridis.

To learn more about the cause of the illness, researchers designed a three-phase study to identify genetic markers associated with the disease. In phase one, researchers conducted a genome-wide association analysis, comparing the genotypes of 536 patients with primary biliary cirrhosis to those of 1,536 people who did not have the disease. Researchers looked at more than 300,000 single-nucleotide polymorphisms (SNPs), the most common genetic variations, among the approximately 11 million known to be present in the human genome.

"There were significant differences between the patients with primary biliary cirrhosis and the control group," says Dr. Lazaridis. As a result, researchers narrowed their focus to 16 SNPs significantly linked to primary biliary cirrhosis.

In phases two and three, researchers conducted "replication" and "fine-mapping" studies to confirm the initial results and to further detail the genetic variations most closely linked to primary biliary cirrhosis.

Researchers discovered that variants of two genes, interleukin 12A (IL12A) and interleukin 12RB2 (IL12RB2), were strongly associated with primary biliary cirrhosis. These two genes constitute a pathway of the immune system. Potential therapeutic manipulation of this pathway provides new possibilities for more effective treatments of these patients, says Dr. Lazaridis.

Researchers also confirmed that the human leukocyte antigen (HLA) region of the genome is linked to primary biliary cirrhosis, an association which had been identified in previous research.

"Although both the HLA region and the IL12 pathway are equally involved with susceptibility to primary biliary cirrhosis, HLA is very complicated to dissect genetically, with multiple pathways," says Dr. Lazaridis. "It will be difficult to modulate with the intention to treat, while IL12 is a single pathway and thus more amenable to treatment."

The reliability of the newly discovered association is very strong; statistically, there's about a one in 10 trillion chance that the pathway isn't linked to primary biliary cirrhosis, Dr. Lazaridis noted.

"That strong association is remarkable, given that the researchers started by looking at 300,000 genetic markers across approximately three billion base pairs that comprise our entire genetic material," he says. "Needle in a haystack doesn't begin to convey the challenge of this search."

Dr. Lazaridis describes this finding as the "end of the beginning" in learning more about the predisposing genetic factors to primary biliary cirrhosis. The newly discovered IL12 pathway does not account for all instances of primary biliary cirrhosis. There is more work to be done on additional genetic links, and exactly how IL12A and IL12RB2 contribute to primary biliary cirrhosis remains unknown. But researchers now have, for the first time, the knowledge to begin to develop targeted treatments and better predict outcomes for some patients with primary biliary cirrhosis.
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CDC Expands Testing Recommendations For Chronic Hepatitis B Virus Infection

The U.S. Centers for Disease Control and Prevention (CDC) today (September 18, 2008) published new recommendations for health care providers that are designed to increase routine testing in the United States for chronic hepatitis B, a major cause of liver disease and liver cancer. CDC recommends testing all individuals born in Asia and Africa, as well as testing additional at-risk populations, including men who have sex with men (MSM) and injection-drug users (IDUs). The recommendations, published today in CDC′s Morbidity and Mortality Weekly Report (MMWR) Recommendations & Reports, also for the first time give health professionals guidance for effective management of chronically infected hepatitis B patients.

“Chronic hepatitis B affects the lives of more than one million Americans, many of whom do not even know they are infected. These new recommendations are critical to identifying people who are living with the disease without the benefits of medical attention,” said John W. Ward, M.D., director of CDC′s Division of Viral Hepatitis. “Testing is the first step to identify infected persons so that they can receive lifesaving care and treatment, which can break the cycle of transmission, slow disease progression, and prevent deaths from liver cancer.”

In the United States, chronic hepatitis B is the underlying cause of an estimated 2,000 – 4,000 deaths each year from cirrhosis and liver cancer. The CDC recommendations are key to increasing the early diagnosis of chronic hepatitis B virus (HBV) infection, since many of the estimated 800,000 – 1.4 million Americans with chronic HBV infection have no symptoms and are unaware of their disease.

Highlights of the recommendations

The new testing recommendations build upon and reinforce past recommendations to test all pregnant women, infants born to infected mothers, household contacts and sex partners of infected individuals, and people with HIV.

Along with continued testing of those groups, routine testing is now recommended for additional populations, including:

* Individuals born in Asia, Africa, and other geographic regions with 2 percent or higher prevalence of chronic HBV infections: Previous CDC recommendations called for testing of people born in areas with 8 percent prevalence or higher. Expanded testing is essential since the rate of liver cancer deaths and chronic HBV in the United States remains high among foreign-born U.S. populations from these areas. For example, nearly one in 12 Asian Americans and Pacific Islanders living in the United States is HBV-infected, and one-third or more are unaware.
* Men who have sex with men and injection drug users: Routine testing is needed for these persons since both have a higher prevalence of chronic HBV infection than the overall U.S. population. Up to 3 percent of MSM and up to 6 percent of IDUs are estimated to be chronically infected with HBV, compared to three tenths of one percent of the general population.
* Persons with abnormal liver function tests (not explained by other conditions) and persons who require immunosuppressive therapy (e.g., chemotherapy for malignant diseases).

The new CDC report also gives recommendations for referral of HBV-infected persons to specialists for ongoing monitoring and medical care. Such guidelines are needed now to assist providers, since most of the effective medications for chronic HBV treatment have become available only in the last five years. In addition, the recommendations advise healthcare providers to provide culturally-sensitive ongoing patient education, begin lifelong monitoring for progression of liver disease, and ensure protection of household members and other close contacts of infected persons.

Testing recommendations are a critical component of CDC’s strategy to eliminate HBV transmission. CDC continues to work with the medical community to promote comprehensive prevention and treatment efforts for HBV, which include vaccination for all infants and at-risk adults; catch-up vaccination of previously unvaccinated children; routine screening for all pregnant women; treatment of newborns of infected or untested mothers; and testing household contacts and sex partners of HBV-infected persons.

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