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Jayachandran et al. Hepatoma Res 2020;6:8 I http://dx.doi.org/10.20517/2394-5079.2019.35 Page 7 of 14

involving 5758 cases and 14,741 controls demonstrated that H63D mutation was more likely to be involved
[61]
in susceptibility to HCC without cirrhosis in the African population . A positive association between
[61]
compound heterozygosity for C282Y/H63D and the risk of HCC was also observed . Conversely, no
[59]
cases of HCC were identified among the 44 compound heterozygotes examined in another study . In
[63]
an Egyptian cohort study, patients with the H63D mutation had a higher risk of developing HCC .
Additionally, the role of S65C in HCC remains to be elucidated. A number of other studies demonstrated
that individuals harbouring C282Y or H63D mutation did not develop HCC, suggesting there was no
association between HFE mutation and HCC [74,76-78] . Thus, whether there is a link between these HFE
mutations and the HCC risk remains somewhat uncertain with significant variation between different
populations groups, and different underlying diseases. More studies are needed to definitively assess the
influence of the HFE mutations on the development of HCC in HH patients.

Mechanisms of iron toxicity in HH leading to HCC
Iron is ubiquitously present in cells and a physiological optimal balance of iron is critical for the normal
functioning of cells [79,80] . Iron is essential for several important processes including the transfer of oxygen
throughout the body by haemoglobin, the mitochondrial electron transport chain and as a cofactor in
enzymatic reactions. However, excess iron can be very toxic to the cell due to its redox reactivity that
promotes oxidative stress [81,82] . Homeostasis of iron in the body is maintained by four major cell types:
duodenal enterocytes (dietary iron absorption), erythroid precursors (iron utilisation), reticuloendothelial
[83]
macrophages (iron storage and recycling) and hepatocytes (iron storage and endocrine regulation) .
Duodenal enterocytes absorb dietary iron and store it in the form of ferritin. Enterocytes release iron into
the circulation through the basolateral iron exporter, ferroportin. In the blood stream, iron binds to the
plasma iron transport protein transferrin [82,84] . The majority of iron in the body is found in the oxygen-
carrying haemoglobin of erythrocytes. Iron is also stored in the form of ferritin in hepatocytes and
reticuloendothelial macrophages. The macrophages phagocytose the senescent erythrocytes and the iron
[83]
from haemoglobin is loaded onto transferrin for iron recycling . Importantly, in humans, there are no
active mechanisms to eliminate excess iron from the body [15,42] .

Transferrin is highly saturated during iron overload and additional iron released into the circulation binds
to low-molecular-weight compounds and is termed non-transferrin bound iron (NTBI). Excess iron in
circulation enters into hepatocytes by binding the transmembrane TFR1 and TFR2 on hepatocytes [17,83] .
While both TFR1 and TFR2 are capable of iron uptake, TFR1 has a higher iron binding affinity than TFR2.
TFR2 is an iron sensor that regulates body iron uptake and is sensitive to changes in transferrin saturation
in the blood [82,85] . Hepatocytes have a significant role in iron homeostasis as they also produce the hormone
[86]
hepcidin, an important regulator of iron balance . Hepcidin binds ferroportin and stimulates the
internalisation and subsequent degradation of ferroportin, thus decreasing the absorption of iron from the
[84]
gut and release of iron into the circulation . HFE works in conjunction with multiple proteins including
[87]
TFR2 and Hemojuvelin to induce hepcidin expression . In HH patients harbouring the HFE mutations,
the hepcidin protein is not properly expressed, which leads to uncontrolled iron absorption, resulting
[17]
in iron overload . In addition, HFE mutation also leads to a loss of transferrin sensitivity, suggesting
[88]
that TFR2 and HFE complex may be involved in iron-sensing . The hepcidin-mediated increased iron
absorption from the gut leads to preferential iron loading of the hepatocytes. It has been hypothesised that
this in turn causes injury and subsequent malignant transformation of hepatocytes [79,89] . The mechanisms
responsible for a direct hepatocarcinogenic effect of iron have yet to be fully elucidated [79,89] .

Increase in iron absorption over time leads to iron accumulation in hepatocytes, leading to injury and
subsequent malignant transformation of hepatocytes [79,89] . The role of iron in hepatocarcinogenesis has
been suggested from epidemiologic studies, animal models and in vitro studies [90-93] . The carcinogenic effect
of iron has been related to its ability to form mutagenic hydroxyl radicals, enhance lipid peroxidation,
promote immune escape or facilitate chronic inflammation leading to cirrhosis.