A Retrovirus Implicated in Primary Biliary Cirrhosis
What are PBC and PSC, and how
do they differ?
By David Rhodes
When my son was diagnosed with primary sclerosing cholangitis (PSC) and ulcerative colitis (UC) in the summer of 2003, I set about chronic cholestatic liver diseases. Both are reading everything I could find about this (and related) liver and presumed to have an autoimmune basis.
inflammatory bowel diseases. Of the thousands of research abstracts I have read over the last 6 months, I was particularly impressed by destruction of bile ducts leading to chronic several authored by Dr. Andrew Mason (currently located at the cholestasis and liver cirrhosis. This is often University of Alberta; formerly of Tulane University, New Orleans) on the possible involvement of a retrovirus in primary biliary cirrhosis portal hypertension and liver failure. Both (PBC). It seemed to me that Dr. Mason's studies represent a significant breakthrough in the understanding of the "trigger" mechanism of a cholestatic disease; advances that may eventually help in understanding the cause(s) of PSC. In this article I briefly diseases are currently treated in their early stages with ursodeoxycholic acid (UDCA).
PBC has long been thought to be an autoimmune disease (1).
PBC involves progressive destruction of the However, several lines of evidence indicate that an infectious agent small, interlobular bile ducts. It affects might be involved in triggering the disease in genetically susceptible individuals (1). PBC has been documented in unrelated care providers and in non-related family members, and in one study it was associated with a particular water supply (reviewed in 1). Several unusual typically exhibit antimitochondrial anti- geographical clusters of the disease have recently been documented (7). PBC frequently recurs after liver transplantation (1). A hallmark of PBC is the occurrence of antimitochondrial antibodies primarily directed against the pyruvate dehydrogenase complex. These being the pyruvate dehydrogenase complex.
antibodies begin to reappear on the biliary epithelial cells of thetransplanted allograft following transplantation (1). A variety of organisms have been considered as possible causes of PBC, including stricturing of the intrahepatic and extra- viruses, bacteria and fungi, but a retrovirus has recently taken center stage (1). Retroviruses are infectious particles built on RNA rather than DNA. The most infamous retrovirus is HIV, the virus that causes AIDS. Other diseases thought to be caused by retroviruses include breast cancer and Sjogren's syndrome.
imately 75% of patients with PSC also haveinflammatory bowel disease (IBD), mostly Mason and colleagues first showed that serum of PBC patients had reactivity to certain proteins characteristic of retroviruses (2). Mason and colleagues then obtained evidence that a transmissible factor can typically exhibit perinuclear antineutrophil promote the appearance of antimitochondrial antibodies in normal cytoplasmic antibodies and/or other auto- biliary epithelial cells. Biliary epithelial cells extracted from normal liver were co-cultivated with homogenized lymph nodes from PBCpatients. Normal biliary epithelial cells developed pyruvate dehydrogenase antibodies 5 to 7 days after incubation with homogenized lymph nodes from PBC patients (5). This effect could advances in understanding the causes of one be halted by either ultra-centrifugation or by gamma irradiation of the may assist in understanding the causes of supernatants prior to incubation, suggesting that the lymph nodes of patients with PBC harbor a transmissible, particulate agent with aradiation-sensitive nucleic acid genome (5). The agent appears to be capable of replicating and producing the characteristic antibodies of PBC in biliary epithelial cells (1).
cholangitis. Clin. Liver Dis. 3: 529-570.
Electron microscopy studies also revealed virus-like particles in the References
extracellular space of biliary epithelial cells of PBC patients (5). Eachparticle was approximately 110 to 120 nm in diameter and had an 1. Mason A, Nair S (2002) Primary biliary oval, eccentric nuclear dense core, compatible with viral particles (5).
cirrhosis: new thoughts on patho-physiology and treatment. Curr.
More recently, a betaretrovirus has been cloned and sequenced from the lymphoid tissue of PBC patients (4). The retrovirus has strikingnucleotide homology with mouse mammary tumor virus (MMTV) and with retrovirus sequences derived from human breast cancer samples (4). The human betaretrovirus nucleic acid sequences cloned from PBC patients contain five sequences encoding proteins characteristic of retroviruses, including the superantigen (Sag) protein (4). The Detection of retroviral antibodies in primary retroviral superantigen may be responsible, in part, for triggering an biliary cirrhosis and other idiopathic biliary inflammatory cascade leading to autoantibody production, and cholangiocyte destruction (6). Because MMTV viral replication isregulated by the female hormone progesterone (5), this may provide an explanation for the predominantly female incidence of PBC.
A, Carman W, Neuberger J (1998)Expression of pyruvate-dehydrogenase These findings add further impetus to ongoing trials of anti-retroviral complex PDC-E2 on biliary epithelial cells therapies in PBC (1). Mason and colleagues have initiated small pilot trials of treatment of PBC patients with lamivudine or Combivir (a biliary cirrhosis. Lancet 352: 1595-1596.
combination of lamivudine and zidovudine) (1). Significantimprovements in serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (Alk Phos) levels were observed in patients after 6 months of Combivir treatment (1). A human betaretrovirus proviral genome from reduction in serum liver biochemistry was seen in most patients taking patients with primary biliary cirrhosis.
Combivir, but not lamivudine alone (1). A reduction of serum antimitochondrial antibody levels in the majority of patients followingtreatment also raises the possibility that antiretroviral therapy has an effect on the pathogenesis of the disease (1).
A, Joplin R, O'Donnell B, Aitken J, CarmanW, Neuberger J, Mason A (2003) Does a Poupon and Poupon (6) have recently called attention to the need for a clinical trial to further test the effectiveness of anti-retroviral therapy biliary cirrhosis? Proc. Natl. Acad. Sci.
in PBC. They urge that patients enrolled in such a trial will need to have a high concentration of viral sequences in blood or peripheralblood cells, and should be in an early stage of the disease (6).
6. Poupon R, Poupon RE (2004) Retrovirusinfection as a trigger for primary biliary How are these studies relevant to PSC? In 1998, Mason and colleagues also detected retroviral antibodies in patients with primarysclerosing cholangitis (2). As far as I am aware, these findings have not been pursued as tenaciously as they have been in PBC. I eagerly await follow-up investigations of the possible involvement of a retrovirus (or other infectious agents) in the pathogenesis of PSC.
Geographic clusters of primary biliarycirrhosis. Clin. Dev. Immunol. 10: 127-131.
David Rhodes is a member of the U.S.-based "Primary Sclerosing Cholangitis Support Group": He maintains a website with links to a large number of www resources and research abstracts on PSC, UC andallied diseases: David is a Professor in the Department of Horticulture and Landscape Architecture at Purdue University, WestLafayette, IN, U.S.A.


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