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Page 4 of 14 Jayachandran et al. Hepatoma Res 2020;6:8 I http://dx.doi.org/10.20517/2394-5079.2019.35

and population-based studies have confirmed that HFE mutations confer increased risk for HCC
development [48-57] . The exact incidence and prevalence of HCC varies considerably between different
studies, which is probably explained by the heterogeneity of the study cohorts. The characteristics of the
study cohort is critical in the interpretation of such studies given the variable phenotype of HH and also
because cirrhosis is such a critical risk factor for the development of HCC. Some studies report on cohorts
where a large proportion of patients had underlying cirrhosis. Other studies have clear referral bias due to
the authors’ interest in disorders of iron metabolism, are retrospective in nature or are from liver transplant
programs where one would expect cirrhosis and HCC to dominate the study cohort.

Population-based studies provide a more realistic assessment of the overall incidence and prevalence of
HCC in HH. In one such study, the US National Centre for Health Statistics reported a close association
between HH and HCC. In this study, patients who were diagnosed with HH and who died were 23-fold
[47]
more likely to have HCC in comparison with individuals without a diagnosis of HH . A further study
conducted in Sweden reported the risk of HCC in HH individuals to be approximately 20-fold higher
[42]
than in the general population . At 10 years of follow up, the absolute risk of HCC among HH men was
[42]
[58]
6%, which was higher than the risk in women (1.5%) . Willis et al. found that HCC patients had a
[59]
7% prevalence of the C282Y homozygous mutation. In a similar study, Sánchez-Luna et al. found that,
among 118 C282Y homozygotes, eight homozygotes developed HCC, representing 1.8% of patients with
HCC.
Meta-analyses have recently been conducted to clarify the effect of HFE polymorphisms on the
[60]
susceptibility to HCC. Ellervik et al. conducted a meta-analysis to examine associations between
C282Y and H63D mutations with HCC. An odds ratio of 11 for HCC occurrence was reported for C282Y
homozygotes (YY vs. CC). A further study conducted on 43 published articles (5758 cases and 14,741
controls) demonstrated that the HFE C282Y homozygous mutation was significantly associated with
[61]
increased risk of HCC compared to the overall population . Another meta-analysis including nine studies
based on European populations (1102 HCC cases and 3766 controls) showed an association between the Y
allele of C282Y and HCC risk overall as well as in alcohol-related cirrhosis patients but not in viral-related
[51]
cirrhosis patients . There are also contrary reports showing no association with the risk of developing
HCC [23,33,55,62,63] , possibly reflecting the low penetrance of the C282Y mutation in the populations studied.

Cirrhosis and other risk factors for HCC development in HH
[64]
HCC accounts for 25%-45% of disease-related premature deaths in HH . In HH, the primary risk factor
for the development of HCC is the presence of cirrhosis. Studies that have assessed the association of risk
factors for development of HCC in HH are listed in Tables 1 and 2. Some studies have indicated that the
risk of HCC in cirrhotic HH patients is higher than in patients with cirrhosis from other causes. In a meta-
analysis assessment of eight studies which included follow up of cirrhotic patients, the annual incidence
[65]
of HCC was 1.20% per year . One other study showed that, once cirrhosis has been established in HH
[66]
patients, the annual incidence of HCC is approximately 4% . Earlier studies have revealed that risk of
HCC developing in cirrhotic HH patients was 200-fold higher than non-cirrhotic control groups [18,67] . These
studies may have suffered referral bias and lacked HFE genetic testing with the diagnosis of HH based
on clinical features and biochemical tests [18,67] . Recent studies utilised a combination of HFE genotyping,
clinical examination and abnormal iron indices including transferrin saturation, serum ferritin, and iron
deposition in liver biopsies to confirm diagnosis of HH [42,44] . These studies have revealed that risk of HCC
developing in cirrhotic HH patients was 20-fold higher than non-cirrhotic control groups [42,44,48] . It is
worth noting that HCC has occasionally been found to occur in HH patients with no cirrhosis [64,68,69] . In
these patients, hepatic iron accumulation has been suggested to be directly involved in HCC development
independently of cirrhosis [64,69,70] . An increased risk of HCC with cirrhosis among individuals heterozygous
for HFE gene mutations has also been reported and is discussed below [42,51] .