Hepatocellular carcinoma in nonalcoholic fatty liver: Role of environmental and genetic factors

• Published in: World journal of gastroenterology : WJG Vol. 20; no. 36; pp. 12945 - 12955
• Main Author: Dongiovanni, Paola
• Format: Journal Article
• Language: English
• Published: United States Baishideng Publishing Group Inc 28.09.2014
• Subjects: Animals; Carcinoma, Hepatocellular - etiology; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - mortality; Carcinoma, Hepatocellular - pathology; CHRONIC HEPATITIS-C; Cirrhosis; disease; Disease Progression; fatty; Fibrogenesis; Gastroenterologi och hepatologi; Gastroenterology and Hepatology; Gene-Environment Interaction; Genetic Predisposition to Disease; GENOME-WIDE ASSOCIATION; GREATER-THAN-G; Hepatoc; Hepatocellular carcinoma; HEREDITARY HEMOCHROMATOSIS; Humans; INSULIN-RESISTANCE; IRON OVERLOAD; Liver; Liver - metabolism; Liver - pathology; Liver Neoplasms - etiology; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - mortality; Liver Neoplasms - pathology; METABOLIC SYNDROME; Non-alcoholic Fatty Liver Disease - complications; Non-alcoholic Fatty Liver Disease - genetics; Non-alcoholic Fatty Liver Disease - metabolism; Non-alcoholic Fatty Liver Disease - mortality; Non-alcoholic Fatty Liver Disease - pathology; Nonalcoholic; Nonalcoholic fatty liver disease; Phenotype; PNPLA3 RS738409; Prognosis; Risk Assessment; RISK-FACTORS; Steatosis; Topic Highlight; UNITED-STATES; Cirrhosis; Liver disease; Patatin-like phospholipase domain-containing 3; Genetics; Hepatocellular carcinoma; Nonalcoholic fatty liver disease; Single nucleotide polymorphism; Fibrogenesis; Steatosis
• ISSN: 1007-9327; 2219-2840; 2219-2840
• DOI: 10.3748/wjg.v20.i36.12945

Hepatocellular carcinoma(HCC) is the fourth cause of cancer related mortality, and its incidence is rapidly increasing. Viral hepatitis, alcohol abuse, and exposure to hepatotoxins are major risk factors, but nonalcoholic fatty liver disease(NAFLD) associated with obesity, insulin resistance, and type 2 diabetes, is an increasingly recognized trigger, especially in developed countries. Older age, severity of insulin resistance and diabetes, and iron overload have been reported to predispose to HCC in this context. Remarkably, HCCs have been reported in non-cirrhotic livers in a higher proportion of cases in NAFLD patients than in other etiologies. Inherited factors have also been implicated to explain the different individual susceptibility to develop HCC, and their role seems magnified in fatty liver, where only a minority of affected subjects progresses to cancer. In particular, the common I148 M variant of the PNPLA3 gene influencing hepatic lipid metabolism influences HCC risk independently of its effect on the progression of liver fibrosis. Recently, rare loss-of-function mutations in Apolipoprotein B resulting in very low density lipoproteins hepatic retention and in Telomerase reverse transcriptase influencing cellular senescence have also been linked to HCC in NAFLD. Indeed, hepatic stellate cells senescence has been suggested to bridge tissue aging with alterations of the intestinal microbiota in the pathogenesis of obesity-related HCC. A deeper understanding of the mechanisms mediating hepatic carcinogenesis during insulin resistance, and the identification of its genetic determinants will hopefully provide new diagnostic and therapeutic tools.