Populations at Risk

Hepatitis Viruses are Responsible for Over 80% of HCC Cases Worldwide^1,2,3

In general, cirrhosis of any etiology is the most important risk factor for hepatocellular carcinoma (HCC).⁴ Chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) and prolonged dietary exposure to aflatoxin are responsible for approximately 80% of all cases of HCC worldwide.⁵ Additional risk factors for HCC include primary hemochromatosis, alcoholic cirrhosis, and cirrhosis associated with genetic diseases of the liver.⁵ More recently, nonalcoholic fatty liver disease (NAFLD) and its more advanced stage, nonalcoholic steatohepatitis, have been shown to progress to cirrhosis and HCC.⁶

Cirrhosis

Malignant transformation of hepatocytes occurs through a pathway of increased liver cell turnover that is induced by chronic liver injury and regeneration in a setting of inflammation and oxidative DNA damage.⁷ Chronic viral hepatitis, alcohol, metabolic liver diseases, and NAFLD may act predominantly through this pathway of chronic liver injury, regeneration, and, eventually, cirrhosis.⁷ Accordingly, hepatic cirrhosis is the major clinical risk factor for HCC.⁷

Chronic Viral Hepatitis

Both hepatitis B virus (HBV) and hepatitis C virus (HCV) infections represent common etiologies for liver cancer.

Most cases of HCC occur after years of chronic hepatitis, which can create a cellular environment that fosters random genetic mutations. These cellular changes, in turn, can ultimately lead to the development of HCC.⁷ Worldwide, approximately 350 million persons have chronic HBV infection ⁸ and 170 million are infected with HCV.⁹ In the United States, it is estimated that
1 million to 1.25 million persons are infected with HBV and approximately
3.9 million are infected with HCV.⁴

Non-alcoholic Fatty Liver Disease

Although HCC can occur in the setting of non-alcoholic fatty liver disease (NAFLD), the specific risk factors for HCC have not yet been determined.⁶ However, multiple mechanisms of liver injury have been attributed to fat:

• Fatty acids have been reported to kill hepatocytes¹⁰
• Hepatocytes that are fat laden may have a dysfunctional mitochondrial respiratory chain, ultimately leading to cell death by a variety of processes¹⁰
• Liver fibrosis can be caused by steatosis¹⁰
• The inherent qualities of fat may directly cause liver injury or may result in the sensitization of liver cells to other agents¹⁰

More than 20% of the US population has NAFLD.¹¹ NAFLD seems to be associated with obesity and insulin-resistance states, such as diabetes, as well as with other features of metabolic syndrome, such as elevated serum triglycerides.⁶

Other

Aflatoxins are hepatocarcinogens produced by Aspergillus flavus that can contaminate food supplies (specifically grains and nuts) when they are stored in warm, moist environments—a situation that occurs frequently in southeast Asia and Africa. Aflatoxins can cause a mutation of the p53 gene and increase the risk of HCC development, especially in persons with HBV infection.¹²

Hereditary Hemochromatosis

Hereditary hemochromatosis is a genetic defect causing iron accumulation in the liver and other organs.¹² Iron itself may play a role in the development of HCC. The risk of developing HCC in persons with hereditary hemochromatosis is reported to be 20 to 200 times greater than that in healthy controls.¹²

Read more about:

• Liver Cancer: Incidence and Prevalence
• RAF Kinase Pathway in HCC
• Commitment of Bayer and Onyx
• Professional Resources

References

1. Anzola M. J Viral Hepat. 2004;11:383-393.
2. Wang XW et al. Toxicology. 2002;181-182:43-47.
3. Pons-Renedo F, Llovet JM. Med Gen Med. 2003;5:11.
4. Thomas MB, Abbruzzese JL. Opportunities for targeted therapies in hepatocellular carcinoma.J Clin Oncol. 2005;23:8093-8108.
5. Pang R, Tse E, Poon RTP. Molecular pathways in hepatocellular carcinoma. Cancer Lett . 2006;240:157-169.
6. Clark JM. The epidemiology of nonalcoholic fatty liver disease in adults. J Clin Gastroenterol. 2006;40(suppl 1):S5-S10.
7. Moradpour D, Blum HE. Pathogenesis of hepatocellular carcinoma. Eur J Gastroenterol Hepatol . 2005;17:477-483.
8. Lavanchy D. Hepatitis B Virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J Viral Hepat. 2004;11:92-107
9. Lavanchy D. Hepatitis C: public health strategies. J Hepatol. 1999;31:146-151.
10. Maher JJ. Mechanisms of liver injury due to fat. In: Liver Diseases: Mechanisms of Liver Injury in Emerging Therapeutics [AASLD postgraduate course]. 2006:89-96.
11. Cave M, Deaciuc I, Mendez C, et al. Nonalcoholic fatty liver disease: predisposing factors and the role of nutrition. J Nutr Biochem . 2007;18:184-195.
12. Lodato F, Mazzella G, Festi D, Azzaroli F, Colecchia A, Roda E. Hepatocellular carcinoma prevention: a worldwide emergence between the opulence of developed countries and the economic constraints of developing nations. World J Gastroenterol . 2006;12:7239-7249.