Etiology of Hepatocellular Carcinoma: Special Focus on Fatty Liver Disease

Abstract

Hepatocellular Carcinoma (HCC) is a highly aggressive cancer with mortality running parallel to its incidence and has limited therapeutic options. Chronic liver inflammation and injury contribute significantly to the development and progression of HCC. Several factors such as gender, age, ethnicity, and demographic regions increase the HCC incidence rates and the major risk factors are chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV), carcinogens (food contaminants, tobacco smoking, and environmental toxins), and inherited diseases. In recent years evidence highlights the association of metabolic syndrome (diabetes and obesity), excessive alcohol consumption (alcoholic fatty liver disease), and high-calorie intake (nonalcoholic fatty liver disease) to be the prime causes for HCC in countries with a westernized sedentary lifestyle. HCC predominantly occurs in the setting of chronic liver disease and cirrhosis (80%), however, 20% of the cases have been known in patients with non-cirrhotic liver. It is widely believed that there exist possible interactions between different etiological agents leading to the involvement of diverse mechanisms in the pathogenesis of HCC. Understanding the molecular mechanisms of HCC development and progression is imperative in developing effective targeted therapies to combat this deadly disease. Noteworthy, a detailed understanding of the risk factors is also critical to improve the screening, early detection, prevention, and management of HCC. Thus, this review recapitulates the etiology of HCC focusing especially on the nonalcoholic fatty liver disease (NAFLD)- and alcoholic fatty liver disease (AFLD)-associated HCC.

Keywords: alcoholic fatty liver disease; etiology; hepatitis viruses; hepatocellular carcinoma; metabolic syndrome; non-alcoholic fatty liver disease.

Figure 1

The etiology of hepatocellular carcinoma. A variety of risk factors have been associated with the development of HCC, including hepatitis viruses, carcinogens, heredity diseases, metabolic syndrome, and fatty liver disease. The mechanisms by which these etiological factors may induce hepatocarcinogenesis mainly include p53 inactivation, inflammation, oxidative stress, and telomere shortening leading to genomic instability and activation of multiple oncogenic signaling pathways.

Figure 2

Molecular mechanisms involved in nonalcoholic- and alcoholic-associated HCC. High-calorie diet and excessive alcohol consumption is the major risk factor for the development of NAFLD and AFLD respectively. Despite the divergent pathogenic origin, the pathological spectra of liver injury in promoting HCC development in NAFLD and AFLD share common molecular pathways.