Risk factors and mechanisms of hepatocarcinogenesis with special emphasis on alcohol and oxidative stress

Abstract

Hepatocellular cancer is the fifth most frequent cancer in men and the eighth in women worldwide. Established risk factors are chronic hepatitis B and C infection, chronic heavy alcohol consumption, obesity and type 2 diabetes, tobacco use, use of oral contraceptives, and aflatoxin-contaminated food. Almost 90% of all hepatocellular carcinomas develop in cirrhotic livers. In Western countries, attributable risks are highest for cirrhosis due to chronic alcohol abuse and viral hepatitis B and C infection. Among those with alcoholic cirrhosis, the annual incidence of hepatocellular cancer is 1-2%. An important mechanism implicated in alcohol-related hepatocarcinogenesis is oxidative stress from alcohol metabolism, inflammation, and increased iron storage. Ethanolinduced cytochrome P-450 2E1 produces various reactive oxygen species, leading to the formation of lipid peroxides such as 4-hydroxy-nonenal. Furthermore, alcohol impairs the antioxidant defense system, resulting in mitochondrial damage and apoptosis. Chronic alcohol exposure elicits hepatocyte hyperregeneration due to the activation of survival factors and interference with retinoid metabolism. Direct DNA damage results from acetaldehyde, which can bind to DNA, inhibit DNA repair systems, and lead to the formation of carcinogenic exocyclic DNA etheno adducts. Finally, chronic alcohol abuse interferes with methyl group transfer and may thereby alter gene expression.

Role of free radicals in liver diseases

“…Most HCC occur in cirrhotic livers, and the common mechanism for hepatocarcinogenesis is chronic inflammation associated with severe oxidative stress [34]. There is a large body of evidence indicating that ROS play a pathogenetic role in carcinogenesis [35].…”

“…Direct DNA damage results from acetaldehyde, which can bind to DNA, inhibit DNA repair systems, and lead to the formation of carcinogenic exocyclic DNA ethenoadducts. Long-term alcohol abuse also interferes with the methyl group transfer and may alter gene expression [40].…”

Tumor initiation and progression in hepatocellular carcinoma: risk factors, classification, and therapeutic targets

“…While neonatal tolerance and juvenile partial tolerance seems to play an important role in viral persistence in patients infected at birth or before age 5 year, the basis for poor responsiveness in adult-onset infection is not well understood and requires further study. Some HLA types seem protective against chronic HBV infection [25,26] .…”

Non-Hfe Iron Overload: Is Phlebotomy the Answer?

“…When this occurs concurrently with dysregulated regeneration, cirrhosis and HCC may ensue [32]. HSCs are activated, in part, by oxidative stress due to Fe loading and a direct link between Fe and fibrogenesis via HSC activation has been demonstrated [33].…”