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RESEARCH UPDATE
Date: 5/20/99 2:01:57 PM Central Daylight Time
From: kkrivy@ (Kathryn Krivy)
Hi All:
The following is an update from Dr. Eric Gershwin on our survey. While the results of the study to not point to any one factor that causes PBC, they do help to point researchers in certain directions. As you can see, the PBCers and their families were essential to this study. We should all take pride and satisfaction in the fact that we have made an important contribution to the scientific knowledge on PBC.
In addition to the survey, the results of which have been incorporated into a major grant to the National Institutes of Health, Dr. Gershwin and his team are examining the saliva of people with PBC for specific properties. He tells me that this work has yielded some very exciting results and will send a copy of his report to us in the very near future.
There are other opportunities for us to become more involved in this important work. We need to find at least 10 PBCers (confirmed diagnosis only please), who have tested negative for Antimitochondrial Antibodies (AMA negative). Please contact me if you are interested.
We're looking for PBCers who were diagnosed with PBC PRIOR to the age of 25.
Please contact me.
Finally, we are still looking for PBCers whose siblings or parents have also been diagnosed with PBC. If you have not already responded to this request, please contact me.
ALL OF THIS WORK IS FOR US AND THE REST OF THE PEOPLE IN THE WORLD WHO HAVE PBC, FOR OUR CHILDREN AND THEIRS.
Dr. Gershwin's Report:
At the University of California at Davis, several hundred people helped in developing a very detailed profile of who gets primary biliary cirrhosis, what their family histories are like, and some descriptions of personal histories. The study took nearly one year and is still ongoing in order to extract every possible piece of data so that a much larger worldwide study can be done. In addition, a similar study under our direction is being done in parallel in Japan.
PBC is an enigmatic autoimmune disease characterized by the presence of antimitochondrial antibodies, destruction of small bile ducts and, ultimately, cirrhosis and liver failure. Clinical symptoms include fatigue, pruritus, and jaundice. The natural history of the disease is quite variable; cases can be asymptomatic for 10-12 years after being discovered. 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.
PBC is a disease of middle age, with most cases occurring between ages 40-60. Reported incidence and prevalence rates vary from one study to another. The range of incidence rates reported is 4-32 per million population and the prevalence rates reportedly range from 19-240 per million population. PBC is thought to be most prevalent in England and Scandinavia.
However, this belief may be due to the conduct of more rigorous epidemiologic studies from these countries as compared with other areas, rather than a true excess of cases. Curiously, no incidence or prevalence studies have been reported from the United States. Although the cause of PBC is unknown, some combination of environmental and genetic factors appears to be important.
As with other autoimmune disorders, predisposing genetic factors may be responsible for a susceptibility to the development of PBC. Minor associations between certain genes and PBC have been reported. This association, however, is only present in a small number of cases, suggesting that other factors are important is determining susceptibility.
The number of women with PBC far exceeds the number of men. Although gender ratios vary, most epidemiologic studies have reported 10-15 female patients for every male. The prevailing view is that this difference reflects the effects of sex hormones on the immune system. Some controversial evidence also suggests that the natural history of PBC differs in males and females, with early onset, asymptomatic, and less severe disease reportedly more common in men. Many autoimmune diseases have been associated with adverse reproductive outcomes including infertility, repeated pregnancy loss, endometriosis and premature ovarian failure. A large number of pregnancies in PBC patients have not been observed, probably due to the fact that the average age of diagnosis for many women is in their late 40s or early 50s.
Reduced fertility and amenorrhea have also been associated with PBC. It is also not known whether autoimmunity causes adverse reproductive outcomes or if reproductive failures are the first signs of autoimmune disorders.
Other autoimmune diseases have been associated with PBC. The most commonly associated autoimmune disorder is Sjogren's syndrome. Other associated diseases include: rheumatoid arthritis, scleroderma, thyroid disorders, cutaneous disorders, and pernicious anemia. Many studies have suggested that PBC may arise in individuals with a predisposition to autoimmune disorders.
Although the exact effect of smoking on the immune system is not well understood, it is postulated that the tissue damage caused by smoking leads to antibody production and a full fledged autoimmune response. Polyphenol rich glycoprotein (TGP), which is known to be present in cigarette smoke, has been found to stimulate a state of autoimmunity. No specific studies of the association of PBC with cigarette smoke have been conducted.
The results of laboratory studies suggest that diet may play a role in the development of autoimmune diseases such as PBC. Specifically, high fat diets may increase risk of autoimmune disease. The source of fat also appears to be important. In laboratory studies, mice fed a diet high in plant oils had a higher occurrence of autoimmune disorders than mice fed a diet high in fish oils.
In 1998, we conducted a mail survey of 241 PBC cases and 261 of their siblings. Questions regarding their medical history, smoking habits, diet and reproductive history were included in the questionnaire. Our primary goal was to detect significant differences between those with PBC and their siblings who did not have PBC. A total of 372 questionnaires were returned from the Internet Support Group; 201/241 patients with PBC and 171/261 siblings without PBC. The female to male ratio among cases in this sample was approximately 10:1. Among both cases and controls, the mean age was 52-53, and 97% of the sample described themselves as Caucasian. The most frequently occurring autoimmune diseases among PBC cases were Sjogren's syndrome (17.2%), Raynaud's syndrome (12.4%), and autoimmune thyroid disease (11.4%). These results are consistent with those of other studies. Approximately 6% of cases reported at least one family member with PBC, which is considerably higher than reported rates in other studies.
No significant variations in dietary fat intake were observed in cases in controls, probably due to the fact that cases and controls were siblings; the environment that they were raised was the same in most cases, thus decreasing the ability to detect potential differences in lifestyle factors such as diet which may affect PBC occurrence. With respect to smoking, a larger percentage of controls (26.5%) identified themselves as current smokers compared to 19.7% of cases. A larger proportion of the cases, however, reported that they were former smokers than did controls. One possible explanation for this is that a greater number of cases may have ceased to smoke after their diagnosis of PBC. Consistent with this explanation, is the fact that 21.4% of cases reported that they quit smoking due to health problems, compared to 14.5% of controls. The mean number of cigarettes smoked per day by current smokers was 15 in cases and about 26 in controls. Exposure to passive smoke among cases and controls was similar in workplace and other public settings. In the home, however, the mean number of hours per day that a case was exposed to smoke was 10, while among controls it was 7.6.
Approximately 70.1% of the cases indicated that they had not had a period in the past 12 months (post-menopausal), while 55.2% of the female controls were post-menopausal. Of the cases, 33.5% reported having had a hysterectomy and 24.1% had their ovaries removed; among controls, these numbers were 18.7% and 13.2%, respectively. Rates of oral contraceptive use were also slightly higher among cases (78.5%) than controls (71.0%).
Although the mean number of pregnancies and rates of tubal pregnancies were similar among cases and controls, the rate of stillbirths was higher among controls. In order to gain information about infertility problems, a question about the consequences of unprotected intercourse was included in the questionnaire. While 39% of cases and 37% of controls reported having had unprotected intercourse for 1 year or longer without getting pregnant, approximately two times as many cases (11.6%) as controls (5.7%) indicated that they had undergone clinical tests for reproductive problems.
Conclusions
At this time 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 difficult disease to study. In the future, we are proposing to perform the first large scale study conducted in the United States. We are proposing to conduct a survey of approximately 2000 PBC cases and 2000 controls (people who do not have PBC). We will ask them questions about their medical history, smoking habits, diet, and reproductive history.
Our goal is to compare differences between the PBC group and the group without PBC. Some of the questions we are hoping to answer include:
The identification of familial cases and also the identification of women who get PBC before the age of 25, is a major priority. Our hope is that genetic analysis of these patients will help us to understand the disease in everyone else.
