Multiple Roles for Hepatitis B and C Viruses and the Host in the Development of Hepatocellular Carcinoma

Abstract

Chronic hepatitis B and C viral infections are major risk factors for hepatocellular carcinoma (HCC) in the United States and worldwide. Direct and indirect mechanisms of viral infection lead to the development of HCC. Chronic viral infection leads to inflammation and liver damage, culminating in cirrhosis, the penultimate step in the progression toward HCC. Host, viral, and environmental factors likely interact to promote oncogenesis. Clinical considerations include recommendations for screening for HCC in persons at risk, treatment with antivirals, and an emerging role for immunotherapy in HCC. We pose unanswered questions regarding HCC susceptibility and pathogenesis in the setting of chronic hepatitis B and C.

Figure:. Multiple factors are involved in hepatocarcinogenesis with chronic HBV and HCV infection.

The vast majority of hepatocellular carcinomas (HCCs) develop in the setting of cirrhosis, whereas a fraction of HCCs can develop without cirrhosis in association with HBV or AAV2 genomic viral integration events. Cirrhosis develops after many years of necroinflammatory responses to viral infections, and is accelerated by alcohol, viral co-infection, and fatty liver disease. Cirrhosis is associated with epigenetic changes that drive the development of HCC. The earliest somatic mutations linked to HCC include disruption of p53, activation of β-catenin, and/or promoter mutations that activate TERT. Progression is associated with increasing load of mutations in tumors. Additional factors associated with HCC include male sex, hereditary factors, viral factors, and environmental toxins such as aristolochic acids and aflatoxin.