Viral trigger identified as cause of PBC

Researchers have suspected for years that primary biliary cirrhosis is an autoimmune disease whose idiopathic inflammation results from infection. But resolution of whether the culprit is viral or bacterial has so far been elusive.

Now, combined results from two open-label pilot studies point at a viral trigger. According to researchers, patients with primary biliary cirrhosis (PBC) who are treated with combination antiretroviral drugs experienced notable improvements in hepatic biochemistry shortly after therapy began, while rebound occurred after termination.

The results suggest that the identification of a retrovirus in PBC patients may be clinically relevant, said a lead study author, who spoke at the 2003 Canadian Digestive Disease Week. An associate professor of gastroenterology in the University of Alberta Department of Medicine in Edmonton, undertook the clinical trial after laboratory work indicated that PBC was viral in nature.

After identifying serologic and tissue evidence of a retrovirus in patients with PBC, he developed a model to determine whether patients truly harbored a transmissible agent. When normal biliary epithelial cells were mixed with lymph nodes from PBC patients, they behave subsequently like PBC cells, though the same did not occur when they were combined with other liver diseases.

In the first study, 11 patients with PBC were treated with lamivudine at 150mg/day for one year. Though subjects showed an initial reduction in liver function tests, the effect on disease progression was insignificant and there was little improvement in inflammation or in the number of bile ducts.

In the follow -up study, 11 patients received Combivir twice daily for one year; combivir comprises lamivudine 150mg and zidovudine 300mg. Seven patients from the lamivudine study has participated in the single-agnet study, and all subjects had been unresponsive to ursodeoxycholic acid.

Five combivir patients showed normalized alkaline phosphatase levels, and five h ad completely normal liver function tests. Three of the Combivir patients with normalized liver tests relapsed, while the others maintained normal hepatic biochemistry two years after discontinuation of therapy. After Combivir treatment, liver biopsies showed reductions in inflammation and a 30 percent increase in the number of bile ducts in the portal triad.

The studies showed that patients appear to be responsive to combination therapy but not single therapy. The numbers in both groups were small, so we’re cautious about interpreting the results. However, the fact that otherwise stable patients improved when they started on Combivir – that there was a temporal relationship – is suggestive of the drugs on the placebo-controlled trial are underway.

According to the commonly-held thought about the origins of PBC, bacteria stimulate an immune response to mitochondrial protein, leading to autoimmune disease.

Antimitochondrial antibodies, found in patients with PBC though rarely in the general population, recognized a protein in liver cells that is expressed aberrantly in PBC but not on normal epithelial cells. This argument, however, is flawed: if the protein expression is abnormal in the liver, then bacteria should be found in the liver – but this does not occur. In addition, several aspects of the disease are inconsistent with an infectious etiology, and population migration studies strongly imply environmental origins of the disease.

The pilot studies are suggestive of an effect but are by no means definitive, commented a consultant physicians at Queen Elizabeth Hospital in Birmingham, England. These drugs are potent, and their side effects must be balanced against benefits. One of the problems in PBC is to design studies that are clinically relevant. However, if antiviral drugs are effective, that supports the concept of a viral trigger.