Internal Medicine & Patient Care

Biography

Dr. Bronze has been Chair of the Department of Medicine since July 2000.  He also holds the Stewart G. Wolf Endowed Chair in Medicine and serves on a number of national committees, including several for the National Board of Medical Examiners (USMLE).  He is treasurer of the Association of Professors of Medicine and serves on its Board of Directors as well as Chairs the Board of Directors of Academic Physicians Insurance Company.  He is a Fellow in the American College of Physicians and the Infectious Diseases Society of America.  He has won a number of teaching awards and most recently the Founders Medal from the Southern Society for Clinical Investigation.

Abstract

Hepatitis C (HCV) is a global infection due to Hepacivirus, a member of the Flaviviridae family. Parenteral routes including blood transfusion, injection drug use and exposure to medical procedures usually transmit infection; however, the virus can be transmitted maternally and in some patients, no known risk factor is identifiable.    Over 170 million persons worldwide are infected and chronic infection leads to cirrhosis, hepatocellular carcinoma and an increased all-cause mortality.  The majority of infected patients maintain a chronic infection leading to several hepatic and non-hepatic complications.   Linked to progressive infection is the presence of significant fibrosis within the liver and several risk factors predict which patients are likely to develop complications such as cirrhosis, hepatocellular carcinoma (HCC), and increased all-cause mortality.  HCC is the fifth most common cancer in males, seventh in females and is a major cause of cancer related death.  Eighty-five percent of cases occur in the developing world and HCV is a leading predisposition.  The pathogenesis of HCV related HCC is complex and unlike hepatitis B virus, HCV does not integrate into the host genome.  However, HCV does dysregulate cellular proliferation and differentiation pathways, creates chronic inflammation and inhibits tumor suppressor gene activity.  Our laboratory has focused on two aspects of HCC carcinogenesis, namely cancer like stem cells and chronic inflammation.  Hepatoma cells expressing a HCV subgenomic replicon express several cancer like stem cell markers, especially DCLK-1, a microtubule kinase that is a putative marker for intestinal and pancreatic cancers.  Expression of DCLK-1 is linked to HCV replication and tumorigenesis in xenograft models, and DCLK-1 is identifiable in tissue and plasma derived from patients with HCV associated cirrhosis and HCC.  SiRNA knockdown of DCLK-1 inhibits tumor growth in animal models suggesting that DCKL-1 might be a therapeutic marker.  Additionally, total RNA analysis of FCA4 cells, which also express a HCV subgenomic replicon, reveals upregulation of DCLK-1 and a number of pro-inflammatory markers including S100A9 and SMARCA.  These cells generate tumors in xenograft models that express DCLK-1, AFP and S100A9 and siRNA knockdown of DCLK-1 abrogates tumorigenesis and S100A9 expression. Over the last several years, there has been significant progress in the treatment of HCV infection.  New, pan-genotypic direct antiviral agents (DAA) have vastly improved our treatment strategies not only achieving cure in a large percentage of patients, but also showing promise in reducing the complications of HCV infection.