Etiology
Hepatitis B, hepatitis C, alcoholic liver disease, and non-alcoholic liver steatohepatitis/non-alcoholic fatty liver disease are the etiological factors for the development of hepatocellular carcinoma.
Viral Hepatitis
Chronic hepatitis B virus and chronic hepatitis C virus is associated with more than 70% of cases of hepatocellular carcinoma.
Hepatitis B virus- Hepatitis B virus (HBV) is an enveloped virus, partially double-stranded virus, circular DNA genome, and belonging to the family Hepadnavirus. Hepatitis B affects more than 250 million individuals worldwide and is the most common cause of chronic hepatitis worldwide. Integration of the hepatitis B virus genome into the host genome is the primary pathogenesis for oncogenesis in HBV. Insertion of viral genome in telomerase reverse transcriptase (TERT) promoter sites of the human genome resulting in mutation accounting for 60% of HCC cases.4 Other genetic alterations include mutations in TP53 (affecting cell cycle), beta-1 catenin (CTNNBI), axis inhibitor-1 (AXINI), AT-rich interaction domain-containing protein 1A (ARID1A), and ARID2(chromatin proliferation). The Hepatitis B virus and the Hepatitis C virus infection accounts for 56 % and 20% of HCC cases diagnosed worldwide, respectively. HCC can occur in the absence of cirrhosis in patients infected with the hepatitis B virus infection. More than 80% of HBV-related HCC have underlying cirrhosis.6 A strong risk predictor for hepatocellular carcinoma in patients with HBV includes elevated serum HBV DNA levels (equal to or more than 10,000 copies/mL).7 This is independent of the hepatitis B e antigen (HBeAg) status of the patient.8 Also, the positivity of the hepatitis B e antigen is associated with an increased incidence of HCC. This may be an indicator of a prolonged replication phase. HBV genotype C is associated with an increased risk for HCC. Patients with low hepatitis B virus load but high levels of hepatitis B surface antigen (HBsAg) with levels of more than 1000 IU/mL are significantly associated with HCC.10 Viral coinfection with the hepatitis C virus and the hepatitis delta virus increases the risk for the development of HCC.11
Hepatitis C virus- Hepatitis C virus (HCV) is a partially double-stranded, plus-sense RNA virus with 11 major genotypes, and 15 different subtypes. HCV genotype 1b is frequently associated with HCC.1213 HCV does not integrate with the host genome. Cirrhosis is a significant step in viral carcinogenesis for HCC. Chronic inflammation in chronic hepatitis C virus infection with subsequent fibrosis, necrosis, and regeneration contributes to HCC development. Molecular markers noted in liver carcinogenesis include viral structural and non-structural proteins (NS3, NS4A, NS4B, NS5A, and NS5B). HCV-associated HCC mostly occurs in patients with cirrhosis or advanced stages of fibrosis.14 Fewer cases of HCV-related HCC have been documented in patients without cirrhosis.15 20% of HCC cases diagnosed worldwide are caused by HCV. Viral coinfection with the hepatitis B virus is associated with increased risk for HCC.16
Non-Alcoholic Liver Steatohepatitis (NASH ) and Non-Alcoholic Fatty Liver Disease (NAFLD)
Non-alcoholic fatty liver disease is excess fat in the hepatocytes in the absence of a history of alcohol. NAFLD mostly occurs in the setting of metabolic syndrome. Metabolic syndrome occurs in patients with insulin resistance, hypertension, hypertriglyceridemia, and abdominal obesity, which increases cardiovascular risk. NAFLD is now a leading cause of HCC worldwide, especially in western countries. 13% of patients noted to have HCC without background cirrhosis were noted to have NAFLD.18 The incidence of HCC is expected to increase by 122% in the United States due to the increase in obesity and diabetes between 2016 and 2030.19
Alcohol
30% of HCC is related to a history of excessive alcohol ingestion in the United States. Alcohol can, directly and indirectly, cause HCC. Alcohol can indirectly cause HCC through cirrhosis. Alcohol leads to increased reactive oxidative stress and inflammation.2021 Drinking more than 80 g/day of alcohol increases HCC risk by fivefold.
Aflatoxins
Aflatoxin B1 is a mycotoxin produced by Aspergillus flavus and Aspergillus parasiticus. This is mostly found in Sub-Saharan Africa and Southeast Asia, where the fungus contaminates grains. Carcinogenesis is mostly through the mutation of the tumor suppressor gene (p53). Aflatoxin B1 is associated with increased risk for HCC in patients with chronic hepatitis B virus.
Other risk factors include iron overload, Glycogen storage disease, Wilson disease, alpha one antitrypsin disease, hypercitrullinemia, Alagille syndrome, and acute intermittent porphyrias.
