Hepatocellular carcinoma (HCC) is the most prevalent form of primary liver
cancer and the third leading cause of cancer death in the world. HCC has a poor
prognosis unless recognized at an early stage, underscoring the importance of
prevention. HCC most often develops in cirrhosis associated with chronic viral, toxic,
or genetic liver injury. Notably, HCC has a rising incidence in developed societies with
an increasing evidence for the role of nonalcoholic fatty liver disease (NAFLD), which
has become the most common liver condition mirroring the spread of obesity and type
II diabetes. A significant proportion of HCC associated with NAFLD may occur in the
absence of advanced fibrosis or cirrhosis, posing a major challenge to cost-efficient risk
stratification. Beyond the strong tumorigenic milieu of cirrhosis, molecular
mechanisms of hepatocarcinogenesis in NAFLD include adipose tissue expansion with
a pro-inflammatory adipokine profile, general and tissue-specific lipotoxicity, and the
cell growth promoting effects of elevated insulin levels. Altered gut microbiota and
microRNA deregulation may also contribute to HCC development in NAFLD. After
reviewing these topics, the chapter provides a brief overview of the clinical
characteristics, screening, and novel opportunities in the chemoprevention of NAFLDrelated
HCC.
Keywords: Adipose expansion, Cancer prevention, Cancer surveillance,
Cirrhosis, Cryptogenic cirrhosis, Diabetes, Dysbiosis, Hepatocarcinogenesis,
Hepatocellular carcinoma, Hyperinsulinemia, Insulin resistance, Lipotoxicity,
microRNA, Nonalcoholic fatty liver disease, Nonalcoholic steatohepatitis,
Noncirrhotic cancer, Obesity, Oncogenesis, Proinflammatory adipokines.