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Jayachandran et al. Hepatoma Res 2020;6:8 I http://dx.doi.org/10.20517/2394-5079.2019.35 Page 9 of 14

Excess iron should be removed by venesection (phlebotomy) therapy and this should eliminate the risk of
progression to cirrhosis and the development of HCC in non-cirrhotic individuals. Early diagnosis and iron
[9]
depletion therapy has the potential of improving the survival rate of patients . HH is readily treated by
venesection therapy, which is very efficient in removing excess iron and involves two successive treatment
phases [116] . In the initial induction phase, the excess iron present at the time of diagnosis is removed by
1-2 weekly venesections (7.5 mL/kg body weight per venesection). After the removal of excess iron,
maintenance therapy, the second treatment phase, prevents recurrent iron overload. Maintenance therapy
involves removal of 2-4 units/year [117] .

Although venesection is the treatment of choice in hemochromatosis, other iron depletion therapies have
also been tested in HH patients [118,119] . Another iron depletion therapy involves the application of iron
chelation therapy to facilitate iron mobilisation and excretion. The iron chelating drugs desferioxamine,
deferiprone and deferasirox have been tested in HH patients [118,119] . A phase I/II clinical trial for
deferasirox has shown it to reduce iron burden in HH patients homozygous for the C282Y mutation [118] .
Desferioxamine is administered either by intravenous or subcutaneous route, while deferiprone and
deferasirox are oral iron chelators. These iron chelators have several side effects including skin rashes,
gastrointestinal disturbances and occasionally abnormal liver function tests and should only be considered
in patients in whom venesection is not a possibility [118] . Of interest, iron chelators with antitumor properties
and favourable toxicity profiles have emerged [120] . Several iron chelators with effective antitumor activities
have been identified [Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone), DpT (di-2-
pyridylketone thiosemicarbazone) and PKIH (di-2-pyridylketone isonicotinoyl hydrazone) analogues] but
these are not routinely used in clinical practice [120-122] . Both venesection and iron chelation therapies do
not target the biological mechanisms involved in iron metabolism. HH is characterised by low hepcidin
synthesis and clinical trials evaluating the role of therapeutic hepcidin by subcutaneous administration
are currently underway. Patients with cirrhosis should undergo six monthly surveillance by ultrasound
(with or without alpha-fetoprotein measurement) to detect HCC at an early stage when curative therapy
is more likely to be successful. Of interest, liver transplantation remains an option for some patients with
HCC within appropriate criteria and this procedure will also normalise hepcidin synthesis and prevent iron
overload (provided the donor does not have HH) [117,123] .

DISCUSSION
Early diagnosis and treatment of HH by preventing the development of cirrhosis may reduce the incidence
of HCC in the future. The American Association for the Study of Liver Diseases guidelines recommend
[9]
regular surveillance for HCC in cirrhotic patients only . It has been recommended that screening for HCC
be continued throughout life of the HH patients as HCC may develop years after the depletion of iron has
been achieved. Whilst controversial, some recommend iron depletion therapy in patients with even minor
increases in iron stores, when non-alcoholic fatty liver disease, hepatitis B or C coexist, in an attempt to
[72]
reduce the risk of progressive fibrosis and subsequent HCC . It is also recommended that family screening
for HH mutations and iron overload in all first-degree relatives of HH patients be performed. As HFE
gene mutation often synergises with other risk factors of HCC, HH patients with known HCC risk factors
should be regularly counselled to avoid environmental or toxic injury to the liver.

Besides HH, there are many other causes of iron overloading that result in excessive iron accumulation in
the liver and other organs. It has been reported that patients with high total body iron have a higher risk of
developing HCC in the absence of HH [124-126] . As iron overload is not a benign condition, it is recommended
that HCC surveillance be undertaken in patients with excess body iron, particularly in patients with
cirrhosis [127] .

Further studies to identify genetic or environmental factors that could act in concert with HFE mutations
to increase the risk of developing HCC are warranted. Investigations are underway to determine the role