These results indicate that BCHE may be involved in the pathogenesis of HCV-related fibrosis among injection drug users. (HEPATOLOGY 2012) Hepatitis C virus (HCV) affects approximately 170 million people worldwide.1, 2 Nearly 85% of these persons develop chronic infection; the natural history of chronic infection in many cases RG7204 datasheet leads to complications that are the leading reasons for liver transplantation in the United States. Complications usually begin with hepatic fibrosis, lead to cirrhosis, and can ultimately result in hepatocellular carcinoma.3 Progression

to hepatic fibrosis in chronic HCV infection has been previously associated with common downstream mechanisms such as transforming growth factor beta (TGF-β)4, 5 and platelet-derived growth factor (PDGF) signaling pathways6; however, the earliest molecular mechanisms underlying HCV-induced hepatic fibrosis are largely unknown. Therefore, determining how HCV induces hepatic fibrosis is crucial for identifying targetable biological determinants of progressive HCV infection. Progressive hepatic fibrosis is orchestrated by several cellular constituents; however, it is not well understood

how hepatocytes, the sites of HCV replication, contribute to the ensuing fibrosis separately from abundant inflammation and stellate cells that ultimately produce collagen. To understand the direct link between HCV infection and fibrosis, CTLA-4 antibody inhibitor we hypothesized that hepatocyte transcriptomes could be separated from bulk liver tissue and studied. Human liver biopsies deliver only a limited amount of material, and cell separation has

not been attempted to enrich transcriptomes. In addition, the absence of a representative animal model of progressive liver disease has compelled researchers to use in situ methods in studies of HCV pathogenesis. In this context, laser capture ADAMTS5 microdissection (LCM) is an emerging technology that allows isolation of specific cell types while preserving key anatomic relationships of the tissue. The present study was structured into three phases: in the first (discovery) phase, gene expression arrays were used to explore potential markers of fibrosis progression from laser captured hepatocytes and portal tracts. In the second (validation) phase, differential expression of the lead gene, butyrylcholinesterase (BCHE), a critical enzyme in cocaine and heroin metabolism, was confirmed in an expanded cross-sectional cohort of HCV-infected intravenous drug users (IDUs) by measuring a surrogate of BCHE protein expression in archived serum samples. In the third (longitudinal) phase, BCHE expression over time was measured in liver disease progressors and nonprogressors. BCHE, therefore, is a potential pathogenic node that may link drugs of abuse with the development of liver disease in persons with chronic HCV.