Primary Biliary Cirrhosis Lab | Rheumatology, Allergy and Clinical Immunology | Department of Internal Medicine | UC Davis Health

• There is an epidemiologic study in which we are attempting to identify common factors found in patients and controls who have PBC. Other institutions that collaborate with us include:
• Albert Einstein Medical Center
• Jefferson Medical Center
• California Pacific Medical Center
• Cedars-Sinai Medical Center (UCLA)
• Columbia University
• Mayo Clinic
• Mount Sinai Medical Center
• New England Medical Center (Tufts University)
• Ochsner Clinic (New Orleans)
• Stanford University Medical Center
• University of California, San Francisco
• University of Medicine and Dentistry, New Jersey
• University of Michigan
• University of Minnesota
• University of Nebraska
• University of Vermont
• Virginia Commonwealth University
• University of Washington Medical Center
• Northwestern University
• Beth Israel Medical Center, New York
• There is a study in which we are attempting to find anyone with PBC that has a twin (Twin Study). We are interested in such twins whether they both have PBC or not. We have received help and have identified twins throughout the world, but need to identify further twins. If you know of anybody who is a patient with PBC and has a twin, please contact us at: megershwin@ucdavis.edu
• We are studying the possibility that primary biliary cirrhosis is caused by a chemical exposure.
• We are trying to interrupt effector mechanisms in PBC. In other words, whether we know anything at all about what causes PBC, we would like to stop it.
• We are trying to identify families in whom two sisters or a brother/sister both have PBC (Family Study). We have found large numbers of such families throughout the world but would really like to find other such families. If you or someone you know has a sister or brother and both have PBC, please contact us.

Q: How do you get the disease?
A: Mechanisms leading to PBC are still unknown.

Q: Is it an infectious disease?
A: PBC is not an infectious disease.

Q: Does it run in the family?
A: Although a number of genetic factors have been indicated, PBC is not a hereditary disease.

Management

Q: Can PBC be asymptomatic?
A: Most cases of PBC are found during periodic check-ups or medical examinations for other reasons. Only advanced stages present with symptoms such as ascites (water in the abdomen), pruritus, jaundice, or digestive bleeding.

Q: Do I need any specific diet?
A: No specific diet is requested, although the maintenance of a normal weight and a healthy lifestyle is highly recommended.

Q: Can I drink alcohol?
A: Not drinking alcohol (in all forms) is the only dietary measure needed.

Q: Can I take medications?
A: Unless PBC is at an advanced stage, there's no restriction about taking other medications. We suggest you ask your physician for individual suggestions.

Therapy

Q: Is there any therapy?
A: The major pharmacologic therapy for PBC consists of ursodeoxycholic acid (UDCA) or tauro-ursodeoxycholic acid (TUDCA). They are both taken orally everyday and they seem to slow the progression of PBC.

Q: Does PBC lead to liver transplantation?
A: The only treatment for late-stage disease is liver transplantation. Only a fraction of PBC patients require it.

Miscellaneous

Q: Is PBC and pregnancy compatible?
A: Yes, unless in advanced stages of disease. Also UDCA and TUDCA have not shown any harmful effect on the fetus, but always consult with your doctor before taking any medicine during pregnancy.

Q: Where's the referral center for PBC?
A: PBC referral centers are available all over the United States and in countries worldwide.

When Kathryn Krivy was diagnosed with Primary Biliary Cirrhosis (PBC) in 1993, it came as a complete surprise. Krivy had none of the usual symptoms - severe itching, jaundice, fatigue. She had gone to see her doctor in Chicago about the pain she felt in her side while running. When her lab work revealed elevated liver functions, Krivy's astute primary-care physician suspected PBC and sent her to a specialist.

Additional tests confirmed his suspicions and led to a devastating prognosis: Krivy would eventually need a liver transplant, or she would die from this rare, progressive disease for which there was no cure.

Determined to learn all she could about PBC and fight the disease, Krivy looked for a support group. Some Internet research led her to a Web site connecting patients with autoimmune liver disease, including PBC. The woman who developed the site also had PBC. Krivy discovered that 90 percent of people with PBC are women between the ages of 30 and 60. Over time, she and a handful of other "PBCers" organized their own group, which grew to some 1,500 members from around the world who share information and encouragement over the Internet.

In 1997, Krivy attended an American Liver Foundation symposium on women's liver disease, where she met M. Eric Gershwin, chief of rheumatology, allergy and clinical immunology at UC Davis. Gershwin's primary research area was PBC; in fact, he was the only one in the country testing for antimitochondrial antibodies, one of the tests that had confirmed Krivy's diagnosis. She and 250 other PBCers agreed to collaborate with Gershwin on a scientific survey - a launching pin for a National Institutes of Health grant to study PBC. "This doctor was the research guru in the field," Krivy recalls. "I felt that if anyone could find a cure for PBC, it was Eric."

That initial collaboration led to a $1.5 million NIH grant. Krivy and many of her PBC friends also took part in this important research, sending Gershwin saliva, urine and blood specimens - and even their old livers after transplant - for his experiments. Gershwin's team of 15 researchers has used the NIH funding to conduct multifaceted studies of PBC, including its epidemiology, genetic characteristics, pathology and zenobiotics, to learn what triggers PBC and how best to treat the disease.

Cooperation of people like Krivy is key to this research. "We're grateful that patients are willing to participate and help us with basic research that will lead to understanding this disease," says Gershwin. "We could not do what we do without them." Having patients actively involved and getting to know them also makes the research work more personal and very rewarding. "These people are not just names on a test tube to us," notes Gershwin. "Everything we know, they want to know, and we communicate with them frequently." Contributing to the research process helped Krivy feel that she was doing something positive and gave her hope. "Participating gave me some degree of control," she explains. "Patients with PBC really want to be involved - we don't want to be out there in the dark. Eric engaged us in his research and spoke to us in terms we could understand. He was incredible."

The Department of Internal Medicine has one of the largest PBC research centers in the world, and UC Davis has produced more literature on the disease than any other institution. Krivy appreciates this strong commitment to research, despite PBC's small occurrence rate compared to heart disease, cancer or AIDS. "This research makes a huge difference for me and a lot of other people, even though PBC is so obscure," she says. "We rely on people like Eric to advance our cause, and we look to him for hope that we are going to find a cure for this disease."

Using data collected from Krivy and her fellow PBCers, Gershwin's team has made headway toward discovering how PBC destroys the liver, which will lead to more effective treatment. Additional NIH funding supports ongoing collaborative research with patients and organizations all over the world, including the Mayo Clinic. "We still need to find out what causes PBC," notes Gershwin. "We've hit a complicated, high-risk level of research, which means putting more effort in with no guarantee of results. But we will keep trying, because without taking some risk, we won't find the answers."

Meanwhile, Krivy had her transplant in June 2000 and is currently PBC-free. She has returned to her job as a health-care executive and looks forward to running a marathon next year. She spends a great deal of time raising funds for more PBC research. Even patients who are fortunate enough to receive a new liver know that transplantation is not a cure for the disease, which can reoccur after the procedure.

"Continued research is critical to finding a cure," emphasizes Krivy. "Without research, the only hope for people with PBC is a slower progression of the disease or a transplant that may not happen. Research is paramount."

Over the past two decades, nearly one hundred people in our laboratory at UC Davis helped to develop a very detailed immunological and demographical profile of who gets primary biliary cirrhosis (PBC). PBC still remains an enigmatic autoimmune disease characterized by the presence of antimitochondrial antibodies (AMA), destruction of small bile ducts and, ultimately over a variable time, cirrhosis. For this reason, the term 'primary biliary cirrhosis' is in most cases unfortunate and does not properly reflects the real liver condition where cirrhosis is not present. Other names that do not imply the presence of cirrhosis have been coined, including 'chronic autoimmune cholangitis', but none of these is currently used for clinical purposes.

Like most autoimmune diseases, PBC is much more common in women than men, with reported female to male ratios ranging from 3:1 in Sweden to 22:1 in Estonia. Our current estimate is that 9 out of 10 patients are females.

PBC is considered a disease of middle age individuals, with most cases diagnoses between ages 40-60. PBC occurrence is pediatric age is limited to two known cases diagnosed before the age of 16.

PBC is thought to be more commonly found in specific areas of the world. In particular, disease frequency varies between 10 and 400 cases per million population. It has been suggested that PBC is more common in northern countries, including England, Sweden, and Northern American states.

Clinics

Textbooks report that clinical symptoms and signs at presentation include tiredness, itching, and jaundice. However, with newer screening techniques made available over the past 10 years and increasing disease awareness in physicians worldwide, signs of advanced disease such as jaundice are rarely encountered at diagnosis. As for the other symptoms, the causes of pruritus (itching) are still largely unknown despite a theory implying a role for opioid receptors. Fatigue is also a poorly defined symptom as well as a non specific one (meaning that there could be hundreds of other causes to explain tiredness) and recently alterations of the central nervous system have been indicated as potential causes.

It is difficult to predict the progression rate of PBC in single cases. Observations from large number of patients indicates the natural history of the disease is variable, with some cases manifesting no sign of progression of decades and other rapidly progressing towards liver cirrhosis. What we know, however, is that PBC onset and AMA appearance usually precede the diagnosis by several years or decades. Furthermore, most recent data indicate that patients with PBC who do not have symptoms at the time of diagnosis have a life expectancy very similar to same-age subjects who do not have PBC.

Why do some people get PBC?

This is the question we are currently trying to answer in our laboratory and data are mounting to support that PBC results from (i) permissive genes and (ii) environmental factors. First, however, we emphasize that our efforts are also aimed at developing a PBC model in animals. Being able to cause animal PBC would allow tremendous progress in the study of therapeutic interventions in the disease.

Genetics

We obtained exciting data from the study of twins. Twins are a very interesting populations, particularly when identical (since they share 100% of genes), since they can demonstrate the importance of genetics. We identified 8 pairs of identical twin sisters in which at least one had PBC and reported that PBC in both sisters was found in five out of the eight pairs. On the other hand, the concordance for PBC between non-twin siblings is significantly less common. Taken altogether, these observations clearly indicate that genes confer a major part of the susceptibility to PBC. Importantly, this does NOT mean that PBC is a strictly hereditary disease and the risk for children, siblings, or parents of affected subjects is relatively low. Another exciting development we observed over the past three years is related to the role of sex chromosomes in PBC, based on the female predominance of the disease. We obtained data demonstrating that white blood cells from women with PBC lack one of the two X chromosomes more commonly that healthy women. The loss of an X chromosome is a common finding, particularly at older ages. However, we hypothesize that an enhanced loss of an X chromosome could play a role in PBC onset.

Environment

As suggested by the identical twins in which only one has PBC, genes are not sufficient to induce PBC. Several factors found in the environment have been implicated in the onset of PBC. We have recently completed the largest questionnaire-based study performed on 1032 US patients with PBC and 1041 controls of similar age, sex, race, and geographical origin. This study investigated the importance of a large number of factors in confirming a higher risk of having PBC. Data indicated that having smoked in life, having common urinary tract infections, and having a first-degree relative with PBC are the most important risk factors for having the disease. On the other hand, we demonstrated that there are no significant differences in reproductive life between women with PBC and healthy women as to the possibility of having children or the age at menopause. From an experimental point of view, we suggested that a bacterium called Novosphingobium aromaticivorans that can be found in water and ground yet not able to induce infection in humans could play a role in the induction of PBC. We emphasize that PBC is NOT an infectious disease and antibiotic treatments are not recommended. Similarly, there is no proof of a viral cause for PBC. Finally, we are in the process of studying hundreds of chemical compounds that, due to striking similarities, could 'trick' the immune system and lead to AMA appearance. Whether this is due to structure similarity only or to a causality effect is still under investigation.

Conclusions

The cause of PBC remains a mystery. Due to the rarity of the disease and the multiple factors that are thought to be involved in its occurrence, PBC remains a challenge. Yet, over the past five years we developed a large amount of promising data that, in our opinion, include critical clues on what causes PBC. Our goal is to help find a cure for PBC.