Cirrhosis is a hard word to spell. Even tougher is suffering this severe liver disease. It comes in many forms or causes - notably alcoholic cirrhosis and primary biliary cirrhosis.
In popular concept, people who drink to excess are asking for a diagnosis of cirrhosis. But only 10 percent to 15 percent of hooked tipplers develop cirrhosis.
"There is no overlap whatsoever between primary biliary cirrhosis [PBC] and alcoholic cirrhosis - none," observed gastroenterologist Andrew Mason at the University of Alberta in Canada. "Cirrhosis," he explained, "is just a scarring of the liver. That can be caused by hepatitis B or C, genetic disorders and other toxins such as ethanol. So this has nothing to do with how alcohol affects the final pathway of the PBC damage to bile ducts in the liver. Cirrhosis occurs as the result of bile duct destruction," Mason added, "which is an immune-based disease, rather than alcohol-based toxic destruction of the liver. It was previously thought that bile duct destruction was autoimmune in nature, but we have devised an alternative hypothesis whereby retroviruses actually provoke autoantibody production in the biliary disease."
Mason is senior author of an article in the current Proceedings of the National Academy of Sciences (PNAS), released online June 17-27, 2003. Its title: "Does a betaretrovirus infection trigger primary biliary cirrhosis?"
"The salient finding of our paper in PNAS," Mason continued, "is linking the virus with the phenotype of the disease. The most interesting thing is that there's been literature for 30 years on this retrovirus infecting humans with breast cancer. So people have found the retroviral-B-type particles expressed in the breast milk of patients with breast cancer. Immunochemistry studies have shown those virus proteins in breast tissue, and more than one group has cloned out this sequence from breast cancer samples."
Retrovirus Should Tick The Bounce
"Now breast cancer," Mason pointed out, "has a lifetime risk of 8 percent in women. Just the thought that this malignancy is preventable should be of immense interest to the biotech world, because having a second disease where you find the virus should tick the bounce - tip the balance. Obviously," he went on, "I think this will kindle an interest by the biotech industry to have diagnostics just for primary biliary cirrhosis and liver disease. But there should also be diagnostics for breast cancer, especially in people at risk of it in family history. They want to know if they have the virus or not - if it's associated with breast cancer.
"The absolute number of patients who have this PBC is rare. It's one of 60,000 in industrialized countries, but in the target group - which is middle-aged women - the prevalence is as high as one in 500. And then considering the number of patients who require liver transplants, it's 10 percent of all liver transplantation. So it's a rare disease that's had visible mortality without organ graft replacements.
"The course of primary biliary cirrhosis is insidious," Mason stated. "You can have the disorder for many, many years before it becomes clinically apparent, but in North America it constitutes about 10 percent of all liver transplant patients.
"Prior to the introduction in 2000 of a newly tested drug called Urso [from Axcan Scandipharm Inc.], a bile acid specific for PBC therapy, the majority of patients ended up having liver transplants.
"PBC is an immune-mediated destruction of bile ducts internal to the liver mass. So if you have an immune response to the virus or an autoimmune response to both, we've shown that patients unresponsive to standard therapy can normalize their liver tests when given antiretroviral agents. And we believe that these will have a role to play in this PBC disease.
"We've been using lamivudine as a single agent, which has minimal effects," Mason recounted. "But when we used Combivir (which contains lamivudine and zidovudine formulated by GlaxoSmithKline plc), 40 percent of the patients normalized their liver tests, which pleased us. We also saw on biopsies reversal of bile duct destruction, and improvement in inflammation as well.
"The obvious final things that the biotech industry should be interested in," Mason suggested, "is whether these diagnostic tests for the virus blood products determine if the virus that we pass on to these patients is in blood-transfusion serum, etc. We do detect these viral particles in the blood of between 5 [percent] and 20 percent of patients. An important point for biotech."
Transfusion, Transplantation, Diagnostics, Vaccines
"The other significant thing," Mason went on, "is vaccine - especially in people at risk of primary biliary cirrhosis disease. We know that it runs in families, so relatives will certainly want to be vaccinated. And the same would hold for breast cancer. The other major element, I suppose, would be antiretrovirals. Most of the nonselective reverse transcriptase inhibitors should work on this virus. Now the protease inhibitors are HIV-specific, and the non-nucleotide reverse transcriptase inhibitors made for HIV are also HIV-specific. But there are these generic reverse transcriptase inhibitors, like lamivudine and a few others, that will have activity against this virus.
"So I think that drugs, vaccines and diagnostics should be interesting. They should be preventive if they clear the virus. One of the problems with these drugs against hepatitis B and HIV, and possibly primary biliary cirrhosis as well, is that we don't have enough evidence. Patients often have to be on them for a long period of time. In other words, you don't just treat the infection and it goes away. For prevention, there's not a one-shot remedy. Like HIV treatment, it has to be on it for some time.
"I think a vaccine would definitely be a huge market if this virus is associated with breast cancer. For liver disease we would vaccinate families in the same way we do for hepatitis B. All people should be vaccinated against that anyway, as it's a preventable disease.
"We've got the U.S. patent, issued Oct. 22, 2002, titled Identification of a novel retrovirus associated with primary biliary cirrhosis and autoimmune disorders.'
"My co-authors and I," Mason concluded, "are its inventors."