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Page 2 of 14 Jayachandran et al. Hepatoma Res 2020;6:8 I http://dx.doi.org/10.20517/2394-5079.2019.35

INTRODUCTION
Hepatocellular carcinoma (HCC) is considered to be the most frequent primary liver cancer accounting for
[1]
80%-90% of cases . HCC has become a leading cause of cancer-related death globally in the last decades,
[2]
accounting for approximately 800,000 deaths annually . The incidence of HCC continues to escalate by
[3]
3%-9% cases annually worldwide with a nearly equal proportion of deaths . Surgical resection, trans-
arterial chemoembolization radiofrequency ablation and liver transplantation remain the treatments of
[4]
choice for HCC patients and are beneficial for patients in the early stages of the disease . The prognosis for
[5]
HCC patients in the advanced stages is poor due to the limited efficacy of current therapy .
Implementing HCC surveillance among at-risk populations is imperative to identify HCC at early stages
amenable to curative treatments. HCC mostly develops in patients with underlying chronic hepatic
disease [6-8] . Several at-risk populations for HCC have been identified including patients with cirrhosis,
hepatitis B and hepatitis C viral infection, alcoholism, aflatoxin, non-alcoholic steatohepatitis, type 2
[7]
diabetes, obesity and Wilson’s Disease . Hemochromatosis is also an important risk factor for HCC.
Hereditary hemochromatosis (HH) is a common inherited iron metabolism disorder, characterised by
increased deposition of iron in the liver and other organs. If left untreated, hepatic iron overload in HH
patients can result in liver injury, which can progress to cirrhosis and subsequently HCC [9,10] . Further
clarification of the risk factors in individual HH patients for HCC development remains an area of unmet
clinical need. Herein, we review the current literature concerning the association between HH and HCC
with a focus on HFE gene-related HH. This review highlights and discusses clinical studies that address the
prevalence of HCC in HH and risk factors linked with the development of HCC in patients with HH.

HEREDITARY HEMOCHROMATOSIS
[11]
HH comprises a number of inherited diseases of iron metabolism . Although its geographic distribution
is worldwide, HH is one of the most common genetic disorders in individuals of Northern European
ancestry, particularly Nordic or Celtic ancestry. In this population, the frequency of homozygous HFE
mutation is approximately 1 in 200-250 individuals [9,12-14] . There is considerable phenotypic diversity in HH
and associated biochemical changes are more common than the clinical manifestations of iron overload-
[15]
related disease. Indeed, advanced clinical expression of HFE-related hemochromatosis is rare . This
autosomal recessive condition is characterised by excessive iron absorption by the small intestine. This leads
to progressive iron loading over many years of the affected individual’s adult life. As hepatocytes store most
of the excess iron, the liver is the organ mostly afflicted by iron overload [16,17] . Long-term effects of excessive
iron loading include liver fibrosis, cirrhosis, HCC, cardiomyopathy, diabetes mellitus, hypogonadism and
arthropathy [10,11] . Early studies suggested that liver disease was the most frequent cause of death in HH
[18]
individuals . However, more readily available genetic testing, greater public awareness and an improved
understanding of the natural history of the condition means that most affected subjects are now diagnosed
before significant target organ injury occurs.

[17]
HH is classified into 6 groups depending on the nature of the underlying genetic mutation . Mutations
in the high iron gene (HFE) (Hemochromatosis Type 1, i.e., C282Y homozygosity, C282Y/H63D
compound heterozygosity and other HFE-related genotypes, e.g., S65C) are responsible for the majority
[19]
of hemochromatosis cases . Rarer forms of non-HFE associated HH have been attributed to mutations
in hemojuvelin (HJV) (Hemochromatosis Type 2a), hepcidin (HAMP) (Hemochromatosis Type 2b),
transferrin receptor 2 (TFR2) (Hemochromatosis Type 3), ferroportin (SLC40A1) (Hemochromatosis
[17]
Type 4) and ferritin heavy chain 1 (FTH1) (Hemochromatosis Type 5) gene . These latter conditions are
[9]
thought to account for most of the non-HFE forms of HH .