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

One of the mechanisms by which iron accumulation in the liver may promote malignant transformation
[79]
of hepatocytes is directly by the mechanism of oxidative stress . It has been proposed that the formation
of free radicals by Fenton reaction causes oxidative stress, leading to the malignant transformation of
[94]
hepatocytes . Although the Fenton reaction has been implicated in carcinogenic effect of iron, there is
2+
relatively little direct or experimental data to support this claim. The excess ferrous iron (Fe ) accumulates
3+
in hepatocytes and undergoes a Fenton reaction by interacting with hydrogen peroxide to form Fe and
[95]
highly reactive oxygen free radicals (ROS) . Generation of ROS causes hepatocyte injury by inducing
peroxidation of membrane fatty acids followed by the production of toxic by-products that disrupt DNA
and protein synthesis [79,94,96] . In addition, ROS causes DNA damage and mutagenesis, which may lead to
neoplastic transformation over time [97-99] . Iron-generated ROS can induce mutations in p53, an important
tumour suppressor gene [100] . Iron-generated ROS also contributes to the production of a mutagenic and
cytotoxic oxidatively DNA-damaged product, 8-hydroxy-2’-deoxyguanosine (8-OHdG) [101,102] . 8-OHdG
causes G:C to T:A transversions, DNA unwinding and strand breaks [101,103,104] . A study has shown correlation
of 8-OHdG levels with iron levels in serum in HCC patients [101] . In liver tissue, the rate of DNA unwinding
[90]
and strand breaks have been associated with 8-OHdG levels . Another study has highlighted the link
[18]
between DNA unwinding and the risk of HCC in HH patients . An abnormal form of NTBI, called labile
plasma iron or reactive plasma iron, also contributes to oxidative stress and the subsequent liver damage
during HH [105] . Overall, several studies support the role of iron-induced ROS formation as the main
mechanism of development of HCC in HH [32,80,99,106,107] .

Iron accumulation can also lead to cirrhosis and the subsequent development of HCC, indirectly through
[79]
the induction of chronic inflammation . Excess hepatic iron promotes the activation of hepatic stellate
[92]
cells in HH . This can promote fibrogenesis. Iron has also been shown to induce transforming growth
factor-beta, which plays an important role in the development of liver fibrosis [108] . The combination of
elevated iron levels with environmental and acquired factors such as excessive alcohol consumption, viral
hepatitis and steatosis may act synergistically to precipitate the development of HCC [109] . Iron has a direct
effect on tumour growth by promoting cellular proliferation. In human HCC cell lines, iron enhances
proliferation and iron deprivation leads to cell cycle arrest and increased apoptosis [110] . It has been reported
that increased iron concentration in HCC cells was associated with enhanced migration, invasion, high
metastasis rate and recurrence [111] .

In addition, iron reduces immune surveillance for malignant transformation by impairing T-cell
proliferation and inhibiting tumoricidal activity of macrophages [79,103,104,112,113] . Epigenetic alterations due to
iron overload have also been implicated in hepatocarcinogenesis. Epigenetic defects such as increased DNA
methylation commonly occur in HCC [114] . Lehmann et al. [115] found 84% of the non-cancerous liver biopsies
derived from HH patients exhibited hypermethylation of genes that are often hypermethylated in HCC.
DNA hypermethylation was independent of age, cirrhosis or hepatitis infection. Several studies support the
role of iron in the development of HCC in HH.

Diagnosis and treatment of HCC in HH patients
Prior to the identification of HFE, the diagnosis of HH was based on parameters including clinical features,
[17]
increased ferritin levels, high serum transferrin saturation and characteristic findings on liver biopsy .
After the discovery of the HFE mutations, genetic screening became the preferred diagnostic test for HH.
HFE genetic testing together with measurements of serum transferrin saturation and ferritin levels have
gained traction as the diagnostic test of choice for HH [9-11] . A serum ferritin concentration of > 1000 µg/L in
[11]
patients with HH has been associated with an increased risk of cirrhosis and HCC . Magnetic resonance
imaging (MRI) has recently been applied as an imaging modality for the detection and quantification of
hepatic iron in those patients where there is diagnostic uncertainty. Additionally, MRI can be utilised to
[17]
evaluate HCC in HH patients .