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Alqahtani et al. Hepatoma Res 2020;6:58 I http://dx.doi.org/10.20517/2394-5079.2020.49 Page 3 of 18

preponderance, and several single-nucleotide polymorphisms have been identified to be associated with
a higher genetic susceptibility for HCC [16,18-22] . Also, the lifestyle of HBV carriers can have a profound
influence on HCC risk. For instance, heavy alcohol use was found to accelerate the development of cirrhosis
[23]
in HBV patients, ultimately resulting in a 1.3- to 8.4-fold increase in HCC risk . Similarly, tobacco
smoking in HBV carriers was described to be directly correlated with the development of liver cancer. In
this respect, a meta-analysis from 2010 reported a synergistic effect in HCC risk for individuals who smoke
and have HBV infection. Compared to HBV-negative nonsmokers, the risk of HCC was 1.87 times greater
[24]
for HBV-negative smokers, 15.8 for HBV-positive nonsmokers, and 21.6 for HBV-positive smokers . More
[25]
recently, this finding was confirmed in a large Chinese population-based case-control study . There is an
increasing body of evidence indicating an important role of metabolic risk factors in the disease process
of CHB. For example, a high body mass index (BMI) has been shown to worsen the disease outcomes of
HBV carriers. In a large Korean population-based cohort study, a strong association was revealed between
[26]
high BMI and a higher risk for HCC among patients with CHB infection . Also, diabetes mellitus (DM)
was shown to have a synergistic impact on the HBV disease course, as amply illustrated by a large meta-
[27]
analysis, including almost 22,000 patients with CHB . In this analysis, HBV patients with type 2 DM were
found to have a significantly increased risk of HCC (pooled HR = 1.77, 95%CI: 1.28-2.47) and worse overall
[27]
mortality (pooled RR = 1.93, 95%CI: 1.64-2.27) compared to CHB patients without DM . That being said,
the relationship between nonalcoholic fatty liver disease (NAFLD) and hepatitis is complex and requires
further clarification. Interestingly, HBV infection seems to protect patients from the development of
steatosis, metabolic syndrome, and insulin resistance , whereas the presence of NAFLD-related steatosis
[28]
impacts on the replication of HBV. The results of a large case-control study revealed that treatment-naïve
CHB patients with NAFLD had significantly lower levels of serum HBV DNA compared to CHB without
[29]
steatosis . This, however, does not protect against liver damage, as the presence of steatosis was found
to be associated with a higher rate of liver fibrosis and subsequent progression to HCC in HBV-infected
patients, independent of antiviral therapy [30,31] .

Also, specific virus-related features have been shown to impact the HCC risk, including HBV DNA levels,
viral genotype, hepatitis B e-antigen/surface antigen (HBeAg/HBsAg) levels, mutations in the HBV
genome, and coinfections with other hepatitis viruses or human immunodeficiency virus (HIV) [19,20,32-34] .
With respect to viral factors, a high viral load has proved to be a strong predictor of the HCC risk,
independent of whether or not the patient has cirrhosis, or displays high levels of serum HBsAg
levels [18,20,32] . In relation to the HBV genotype, a large meta-analysis, which included more than 14,500
patients, demonstrated that genotype C was associated with a higher risk of HCC compared to the other
major genotypes . In the past, several large-scale studies have established baseline HBV DNA levels as
[35]
a prognostic indicator in CHB patients. However, given the fact that the new effective antiviral therapies
can induce a complete viral response in the majority of patients, the prognostic significance of serum HBV
[36]
DNA levels has substantially diminished . Finally, studies have also identified double mutations in the
basal core promoter of the HBV genome as an independent predictor for an increased risk of HCC .
[37]
Accumulating evidence indicates that an occult hepatitis B infection (OBI) may be a risk factor for HCC.
OBI refers to a condition in which HBV DNA persists in the liver tissue (and the serum in some cases)
in the absence of circulating HBsAg . A long list of studies has demonstrated the persistence of HBV
[38]
[39]
infection in a large proportion of HBsAg-negative HCC patients . While the exact relationship between
OBI and HCC remains to be elucidated , the available data suggest that OBI is not carcinogenic per se,
[40]
but that the minimal lesions produced by the presence of the occult virus might induce a worse liver
[39]
disease course in the presence of co-existing causative agents of liver injury (e.g., HCV and alcohol abuse) .
This hypothesis is supported by studies indicating a higher prevalence of OBI in HCV-infected patients
with HCC compared to HCV carriers who do not develop HCC [41-43] . Other studies, however, failed to
show a correlation between serum anti-HBV detectability and HCC risk in HCV-infected patients [44,45] .