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Abbas et al. Hepatoma Res 2018;4:43 I http://dx.doi.org/10.20517/2394-5079.2018.26 Page 3 of 8

also found to be significantly associated with HCV-related HCC . Diabetes not only increases the risk of
[30]
HCC in treatment-naïve chronic hepatitis C patients but also in patients with eradicated HCV [1,9,12,32] .
[31]
Meanwhile, one of three studies analyzing body mass index demonstrated a significant association with HCC
risk (BMI ≥ 30.0 vs. BMI < 23; RR 4.13, 95% CI: 1.38-12.40) and two of the three studies analyzing steatosis
demonstrated the significantly higher risk of HCC associated with steatosis . Indeed, HCV patients in the
[28]
US were found to progress more rapidly to HCC than their counterparts in China and the underlying fatty
liver disease was found to be a major contributor to this difference .
[15]

HEPATITIS B CORE ANTIBODY POSITIVITY
The risk of HCC increases in patients with hepatitis C who have occult hepatitis B infection or are hepatitis B
core antibody positive [14,33] . In one study, the presence of hepatitis B core antigen was one of the independent
predictors associated with the occurrence of HCC in HCV patients without advanced fibrosis . On the
[34]
other hand, HCV sero-status (positive vs. negative among patients with chronic hepatitis B may also increase
the risk of HCC, independent of HBV viral load, with a HR of 2.5 (95% CI: 1.7-3.6) .
[35]

AFLATOXIN
Significant contamination of food by aflatoxin is an additional risk factor for HCC in some parts of Asia [36,37] .
While studies have shown synergism between aflatoxin and HBV in causing HCC, much less is known about
whether aflatoxin and HCV synergize in a similar fashion. It is interesting to note that HCV prevalence itself
is much higher in areas where aflatoxin exposure is also high .
[38]

ADVANCED FIBROSIS AND CIRRHOSIS
HCC develops in hepatitis C patients mostly in the setting of advanced fibrosis and liver cirrhosis . For
[13]
patients without pre-existing cirrhosis, a higher Fibrosis-4 (FIB-4) index translates to a higher risk of HCC .
[39]
Untreated patients with cirrhosis have a significantly higher HCC incidence rate (45.3 per 1000 person-years)
compared to those treated with either IFN or DAAs [40,41] . Moreover, liver cirrhosis, high AST to platelet ratio
index (APRI) levels, and IL28B rs12979860 at baseline are all associated with HCC development in patients
without sustained virological response (SVR) after peg-IFN combination therapy . Even with SVR, the
[42]
absolute risk of HCC is high in patients with established cirrhosis [1,8,9,12,43-46] .

HCV GENOTYPE
HCV patients infected with HCV genotype 3 are at higher risk for end-stage liver disease, HCC, and liver-
related death compared to other genotypes [11,43] . This association is independent of patients' age, diabetes,
body mass index, or antiviral treatment . The risk of HCC remains high even after eradication of genotype 3
[43]
HCV [1,46-48] . This genotype may have a particular oncogenic mechanism, leading to HCC development even
in non-cirrhotic patients . Certain polymorphisms of the core, NS3, and NS5A proteins of HCV genotype
[49]
1b may be associated with the development of HCC .
[50]

SINGLE NUCLEOTIDE POLYMORPHISMS
Genetic variations, such as single nucleotide polymorphisms (SNPs), may alter disease risk and thus may be
used as predictive markers of disease outcome. A genome-wide association study found a strong association
between the SNP rs17047200, located within the intron of the tolloid-like 1 gene (TLL1) on chromosome 4,
and the development of HCC in patients who achieved an SVR after treatment for chronic HCV infection .
[9]
Additionally, the association of variants in patatin-like phospholipase domain containing 3 (PNPLA3) and the
unfolded protein response regulator GRP78, with the risk of developing HCC, has been described in Italian