Page 68 - Read Online

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

Other risk factors that may synergise with cirrhosis include chronic viral hepatitis, alcohol abuse, diabetes,
age and gender [47,71] [Table 2]. Patients with HCC and diabetes mellitus were 82 times more likely to have
[47]
HH . The risk of HCC was higher in males who were C282Y homozygotes when compared to C282Y
homozygous females - reflecting in part the higher iron burden in men [44,49,71] . A study reported 1.3%-2.1%
[71]
penetrance of the C282Y homozygous genotype in HH patients with HCC for males and zero for females .
Another study found penetrance of the C282Y homozygous genotype in male HH patients with HCC was
[23]
5.56% . Studies have also found an unequivocal relationship between risk of HCC and C282Y mutation in
patients with chronic hepatitis B and male gender [56,72] . Another study identified increased age at diagnosis
as a strong predictor for the development of HCC in HH patients and the authors suggested that this is a
[73]
surrogate marker of duration of exposure to iron . This latter finding has not been substantiated in other
studies. Serum ferritin level of above 1000 mg/L at diagnosis confirming high iron overload was a risk
[73]
factor for HCC in the study by Nowak et al. . A serum ferritin concentration of over 1000 mg/L is also
associated with a high risk of cirrhosis, which is the likely explanation for that association. In contrast to
[73]
other studies, this study found no association between alcohol consumption and HCC development .
However, the level of alcohol consumption defined as “considerable” was greater than 10 g/day for women
and 20 g/day for men and this may below the oncogenic threshold.

Collectively, these data illustrate that the presence of cirrhosis is the primary risk factor for the development
of HCC in patients with HH. Other risk factors, as discussed above, seem to amplify the oncogenic
potential of cirrhosis. Importantly, some of these other risks can be reduced by lifestyle modifications and/
or therapy of other liver diseases, particularly chronic viral hepatitis.

HFE heterozygotes and the risk of HCC in patients with cirrhosis of other causes
This area is controversial and there are conflicting data on the role of heterozygosity for HFE mutations in the
[51]
development of HCC in patients with cirrhosis from other causes. For example, Hellerbrand et al. indicated
that HCC patients with cirrhosis were more likely to be C282Y heterozygotes compared to cirrhotic patients
without HCC or normal controls. Additionally, elevated levels of transferrin saturation, serum ferritin and
liver iron deposition were reported in HCC patients harbouring the heterozygous C282Y mutation compared
[51]
to those lacking this mutation, suggesting that altered hepatic iron metabolism played a pathogenic role .
The prevalence of the heterozygous C282Y and H63D mutation was also observed to be higher in 81 Italian
[52]
[50]
patients with cirrhosis and HCC than in 128 normal controls (8.6% vs. 1.6%) . Similarly, Lauret et al. found
a 20.9% prevalence of the C282Y heterozygous mutation in 43 Spanish HCC patients. In 301 cirrhotic French
patients prospectively followed up for six months, hepatic iron overload and the heterozygous C282Y mutation
were associated with an increase in the incidence of HCC in cirrhotic patients with alcohol-related problems
[53]
but not in patients with hepatitis C viral infection .
In contrast, a large prospective multicentre French study compared the prevalence of HFE mutations in 133
[74]
cirrhotic patients with HCC and 100 cirrhotic patients without HCC with a follow up of 2.5 years . This
[74]
study concluded that C282Y mutation is not linked to an increased risk of HCC in cirrhotic patients .
Similarly, in another study of 162 patients with HCC and cirrhosis, the frequency of the C282Y mutation
[48]
did not differ between the patients with cirrhosis or healthy controls .

Initially, it was proposed that the H63D mutation has no direct association with HH [19,33] . In line with
this, several studies reported no association between the prevalence of the H63D mutation and the risk
[75]
of developing HCC . Conversely, other studies have implicated occurrence of H63D mutation with an
increased risk of HCC in HH patients [55,61,63] . In a study of 196 HCC patients and 181 healthy controls,
[55]
the H63D mutation was associated with an increased risk of HCC . HCC developed in HH patients
exhibiting H63D mutations along with predisposing factors such as liver cirrhosis due to chronic hepatitis
[55]
C virus infection and/or ethanol abuse and chronic hepatitis B virus-infection . Another large study