Food for thought about Primary Billiary Cirrhosis

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.

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.

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.

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.