Table 1.
Main HCC risk factors
| Risk factor | Description |
|---|---|
| Liver cirrhosis | This is the most important clinical risk factor for HCC. The transition from chronic liver disease to cirrhosis involves inflammation and activation of hepatic stellate cells with ensuing fibrogenesis and angiogenesis. As many hepatocytes are lost, the liver loses the ability to metabolize bilirubin (which can result in an increased serum bilirubin and transaminase level). Liver cirrhosis is characterized by diffuse nodular regeneration surrounded by dense fibrotic septa with subsequent parenchymal extinction and liver structure collapse.58,59 |
| HBV infection | The hepatitis B virus is a DNA virus belonging to the Hepadnaviridae family. Many evidences support that HBv DNA is frequently integrated into the chromosomal DNA of hepatocytes in most HBV-infected patients. The mechanisms of carcinogenesis in HBV infection have been extensively studied, and a major factor is chronic necroinflammation with subsequent fibrosis and hepatocyte proliferation. However, HCC may occur in HBsAg carriers without cirrhosis. Therefore, viral factors are likely involved in HBV-related hepatocarcinogenesis. For instance, the HBx protein promotes cell cycle progression, inactivates negative growth regulators, and binds to and inhibits the expression of p53 and other tumor suppressor genes and senescence-related factors.5,6,60–62 |
| HCV infection | HCV is an enveloped, single-stranded, positive-sense RNA virus. Up to 80% of HCV-infected individuals fail to eliminate the virus acutely and progress to chronic HCV infection. Continuous inflammation and hepatocyte regeneration in the setting of chronic hepatitis and subsequent progression to cirrhosis are thought to lead to chromosomal damage and possibly to initiate hepatic carcinogenesis. HCV also induces steatosis; oxidative stress causes steatohepatitis and these pathways lead to liver injury or HCC in chronic HCv infection.6,63,64 |
| Aflatoxin (AFB1) | This is a difuranocoumarin-derivative mycotoxin from Aspergillus flavus and Aspergillus parasiticus. it is produced under certain climatic factors and storage techniques favoring the fungus growth and contaminating foods such as maize, groundnuts, rice, and sorghum. IARC ranked AFB1 as the most potent experimental hepatocarcinogen, and it is causally related to the development of HCC in humans. Hepatitis B virus infection may directly or indirectly sensitize hepatocytes to the carcinogenic effects of AFB1, raising the possibility of a synergistic hepatocarcinogenic interaction between these two agents, although the precise mechanism is still not well understood.6,65 |
| Alcohol | Alcohol use has definitely been recognized as a cause of HCC. This may be well related to the development of HCC due to direct (genotoxic) and indirect factors (cirrhosis development). ADH metabolizes ethanol to acetaldehyde; this metabolite is not only extremely toxic but also carcinogenic. Alcohol-related liver cirrhosis is most likely the main risk factor for HCC in groups of people with low rates of hepatitis B or C viral infection, such as the US and Northern europe. Some reports mention that 25–80 g/d of alcohol use for 10 years or more for men, and 12–20 g/d for women, increases the risk of developing cirrhosis.1,66 |
| DM | This metabolic disorder may predispose the liver to relative insulin resistance due to inadequate insulin secretion or receptor insensitivity to endogenous insulin. Several evidences showed that insulin resistance and DM induce the progression of NAFLD, including its most severe form, NASH, which has been identified as a cause of cirrhosis and HCC.1,67 |
| NAFLD | NAFLD defines liver abnormalities ranging from simple steatosis (abnormal hepatic fat accumulation) or nonalcoholic fatty liver to NASH with or without cirrhosis development. importantly, it is also closely linked to obesity and metabolic syndromes. Although there is significant progress in understanding carcinogenesis, the exact mechanism of HCC development from NAFLD has not yet been fully elucidated. However, a recent report suggests that the antiapoptotic protein survivin is differently expressed in NASH-HCC-related tissues compared with HCV-HCC-related samples. Besides, another study identified that mTOR was differently expressed in NAFLD-related cirrhosis compared with other causes of cirrhosis.68,69 |
| HH | HH is an inherited (genetic) disorder causing the body to absorb too much iron from the diet. The main storage sites of iron are the hepatocytes, and this metal is essential for their normal functioning, although iron is ubiquitous in human cells. The hepatotoxic and hepatocarcinogenic potential of excessive iron (>5 g) is due to its ability to generate ROS intermediates and oxidative stress (by the Fenton reaction). This stress damages DNA, lipids, and proteins, resulting in necrosis and apoptosis of hepatocytes. Patients with HH have an estimated 240-fold increased relative risk of developing HCC.1,70 |
| Tobacco use | Tobacco smoking has been suggested as a significant HCC risk factor. Nicotine, the main component of cigarette smoke, upregulates CYP2E1 activity in the liver of rodents and humans. CYP2E1 induction is associated with ROS generation and lipid peroxidation, which may be some mechanisms whereby tobacco smoke contributes to HCC.71 |
| Obesity | Obesity has been associated with HCC because lipid accumulation within hepatocytes leads to a chronic low-grade inflammation involving the release of proinflammatory cytokines and inhibition of anti-inflammatory cytokines, leading to hyperinsulinemia. increased levels of iGF-1 have important proliferative and antiapoptotic effects. This factor also promotes angiogenesis via increased vascular endothelial growth factor production, which in turn leads to proliferation of cancer cells.72 |
| OCs | OCs are combinations of estrogens and progestogens. Synthetic estrogens such as ethinyl estradiol and mestranol produce malignant liver tumors in rodents, probably by acting as promoting agents. Additionally, progestogens (norethisterone and norethynodrel) cause benign liver neoplasia in animals. OCs may cause liver cancer by mitogenesis because increased proliferation rates may enhance the rate of spontaneous mutations due to DNA polymerase errors.1,54 |
Abbreviations: ADH, alcohol dehydrogenase; DM, diabetes mellitus; HBsAg, hepatitis B surface antigen; HBv, hepatitis B virus; HCC, hepatocellular carcinoma; HCv, hepatitis C virus; HH, hereditary hemochromatosis; IARC, International Agency for Research on Cancer; IGF-1, insulin growth factor-1; mTOR, mechanistic target of rapamycin; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; OCs, oral contraceptives; ROS, reactive oxygen species.