Incidence
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, accounting for 75%–86% of cases, and is a major global health concern. Primary liver cancer is the sixth most common cancer worldwide and the third leading cause of cancer-related deaths both globally and in the United States as of 2020. Men are affected approximately two to three times more than women, with higher incidence and mortality observed across most countries. Notable racial and ethnic disparities exist, with American Indian, Hispanic, and Black populations disproportionately affected compared to non-Hispanic White individuals. In the United States, HCC incidence and mortality rose between 1970 and 2010 but began to decline in incidence in 2011 and plateau in mortality in 2013, with recent data showing a ∼3% annual decrease. This improvement is likely due to advances in prevention, early detection, treatment, and shifts in demographics and risk factors. However in the UK the incidence and mortality of this cancer has been raising in the last 3 decades, with figures similar to the US, 6.2 for women and 14.3 for men per 100000 people.

Risk Factors for HCC
The strongest risk factor for HCC is cirrhosis from any liver disease etiology, which is present in 80-90% of HCC cases. Patients with cirrhosis have an estimated annual risk of ∼2% for developing HCC. Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections remain predominant global risk factors, though their contribution is declining in regions implementing effective viral hepatitis elimination programs. For example, universal HBV vaccination programs in Asia have led to significant reductions in HCC incidence. In contrast, areas without robust elimination efforts, such as sub-Saharan Africa, continue to experience a high burden of HBV-related HCC. Here, vertical transmission contributes to earlier disease onset, with a median age of diagnosis of 46 years and projections indicating a potential doubling of HCC incidence by 2040. This age disparity persists in HBV-infected individuals who emigrate, as more than one-third of those from Africa develop HCC before age 40.
Antiviral therapies for HBV and HCV significantly reduce the risk of HCC, although patients with cirrhosis and advanced fibrosis remain at persistent risk. Consequently, while viral hepatitis-related HCC has plateaued in developed regions, including the United States, it remains a major challenge in areas lacking effective prevention and treatment programs.
Incidence studies within western population tend to show that sex, age, ethnicity and deprived areas are factors associated with higher incidence of HCC. People who live in more deprived areas are up to five times more likely to die of liver disease than those who live in wealthier area. Asian and Black ethnic groups both associate higher incidence. Men are between three and five times more likely to develop liver cancer than women, regardless of the aetiology of their underlying CLD (Chronic liver disease).
Cofactors
- Alcohol use as a cofactor with other etiologies increases HCC risk as much as 5-fold.
- Smoking is associated with a 20%–86% increased risk of HCC, which can return nearly to baseline after 30 years of smoking cessation.
- Obesity is associated with a 1.5–4.5 times higher risk of HCC and contributes to nearly 10% of HCC worldwide.
- Metabolic syndrome components, including diabetes, nearly double HCC risk in the absence of overweight/obesity

Given the enourmous global burden of HCV (170 million) and HBV (400million), these two chronic infections accounts for most HCC cases in the world.
- Worldwide,Chronic HBV- and HCV-associated liver disease are the risk factors in over 80% of HCC cases > Chronic HCV infection is the most common underlying liver disease among patients with HCC in North America, Europe and Japan whereas Chronic HBV infection is the major cause of HCC in Asia and Africa and approximately 20% of cases in the Western countries.
- MASLD-associated HCC is estimated to contribute around 10–14% of HCC cases in Western population, and this tendency is getting bigger as obeisty raises.
- MASLD has also become the leading cause of HCC in the absence of cirrhosis, with approximately one-fourth to one-third of NAFLD-related HCC occurring in the absence of cirrhosis; however HBV integrates into the host genomes and also induce mutagenesis , can potentially cause HCC even wihtout advanced fibrosis or cirrhosis, althouth the majority of the HBV HCC occur in cirrhotic patients.
Protective factors
HBV vaccination significantly reduces HCC risk, so this should be performed in all newborns as well as high-risk adults who failed to undergo vaccination at birth.
Antiviral treatment significantly decreases HCC risk in patients with and without cirrhosis from HBV or HCV infection and remains one of the most effective methods of primary prevention for HCC. In HCV the aim is to eradicate the infection, whereas in HBV the aim is to prevent viral replication and liver insult where aiming for HBeAg seroconversion. HBV with high age, male gender, serum HBV DNA >2000 IU/mL, high serum hepatitis B surface antigen level >1000 IU/mL and a family history of HCC are additional independent risk factors and should prompt consideraiton of treatment,.
Coffee has been shown to significantly reducing HCC risks in a meta-analysis of case-control and cohort studies, this is at least 1 cup a day ,but being dose-dependent. EASL guidelines recommends that coffee consumption should be encouraged in all patients with chronic liver disease.
Multiple medications have been suggested to have a protective effect, such aspirin (43%–60% reduction if >5 years ) and statin (0.54 RR). Metformin has been more conflicting in proving real benefit. The issue is that this studies are observational and in risk of bias and coufounder, and all medications can potentially come with side effects, therefore their use as primary prevention is not yet recommended in the guidelines.