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Jayachandran et al. Hepatoma Res 2020;6:8 I http://dx.doi.org/10.20517/2394-5079.2019.35 Page 3 of 14

Hemochromatosis type 1
HFE is located on chromosome 6p21.3, has seven exons and five introns and encodes for a 343-amino acid
[20]
protein that is similar to human leucocytes antigen class Ι molecules . The HFE gene is important for
[19]
normal iron metabolism. Feder et al. first identified that a mutation in this gene caused HH. The three
most common mutations at exons 2 (187C→G and 193A→T) and exon 4 (845G→A) of the HFE gene were
[19]
[21]
linked with HH . However, not all HH patients harbour these mutations, as outlined above .
C282Y (845G→A) homozygotes
About 80%-85% of individuals with HH are C282Y (845G→A) homozygotes. This founder mutation
leads to a single-base change, resulting in the substitution of tyrosine (Y) for cysteine (C) in the amino
[10]
acid sequence of the HFE protein at position 282 . HFE-related HH is an adult onset disorder and in
expressing patients is characterised by increased transferrin saturation and serum ferritin levels compared
[22]
to the healthy population . Moreover, C282Y homozygotes are at particular risk of cirrhosis if serum
[23]
ferritin levels are greater than 1000 μg/L . Males and C282Y homozygotes of family members affected by
[22]
HH exhibit a higher penetrance of homozygous C282Y gene . However, due to the variable phenotypic
[22]
expression of this mutation, only some of these patients develop cirrhosis or HCC . The frequency of
the C282Y allele is high in European populations and the reported frequency varies from 0%-3% in South
Europe to 4%-10% in North Europe [20,24] .

This HFE mutant protein has reduced cell surface expression and undergoes rapid degradation. The
mechanisms by which HFE protein regulates iron homeostasis at the cellular level are beginning to emerge.
Earlier studies proposed that the HFE protein binds the transferrin receptor 1 (TFR1) to form a stable
complex, which in turn decreases its binding affinity for transferrin. The HFE mutant protein does not
form this complex, which results in transferrin binding to the transferrin receptor, leading to increased
cellular uptake of iron and subsequently causing iron overload [25,26] . Recent studies have demonstrated
that the HFE protein is an upstream regulator of the hormone hepcidin in hepatocytes [27,28] . Hepcidin is
synthesised and secreted by hepatocytes and is a master regulator of iron homeostasis in the body. Hepcidin
[29]
negatively regulates dietary iron uptake by the intestine . Under physiological conditions, hepatic
hepcidin expression is regulated by proteins that are predominantly expressed in hepatocytes, including
HFE, transferrin receptor 2 (TFR2), HJV, bone morphogenetic protein 6 (BMP6), matriptase-2 and
transferrin [29,30] . HH patients harbouring the HFE mutations have low levels of hepcidin protein allowing a
[31]
slow accumulation of iron over the individual’s lifetime, resulting in iron overload . Iron overload induces
reactive oxygen species (ROS) formation, which causes DNA damage and somatic mutations that may play
[32]
a role in the subsequent development of HCC over time .

HFE compound heterozygotes
Two other mutations in the HFE gene, namely 187C→G (H63D) and 193A→T (S65C), have been
identified [33,34] . These additional mutations alone have not been implicated in iron overload. However, the
co-occurrence of these mutations together with a C282Y mutation forming a compound heterozygote
[35]
(C282Y/H63D or C282Y/S65C) has been implicated in iron overload . HFE compound heterozygotes
might have increased iron indices but iron overload-related disease is most uncommon [36,37] . Clinical
disease may develop in HFE compound heterozygotes in conjunction with comorbid factors such as
[37]
obesity, excess alcohol consumption or diabetes . The Netherlands and the Iberian Peninsula have a high
[38]
frequency of the H63D allele that varies from 7.9% to 17.5% in the general population . The frequency of
S65C allele is low, 0%-1% in European and Brazilian populations [12,34,39] . Approximately 5% of individuals
with a clinical diagnosis of HH are compound heterozygotes [40,41] .

THE ASSOCIATION BETWEEN HH AND HCC
HCC develops in HH individuals and contributes to the increased mortality [42-47] . Although the biological
and physiological functions of HFE gene within the liver are not fully understood, several case-control