Association between hereditary hemochromatosis and hepatocellular carcinoma: a comprehensive review

Abstract

Hepatocellular carcinoma (HCC) is a significant global health problem with high morbidity and mortality. Its incidence is increasing exponentially worldwide with a close overlap between annual incidence and death rates. Even though significant advances have been made in HCC treatment, fewer than 20% of patients with HCC are suitable for potentially curative treatment. Hereditary hemochromatosis (HH) is an important genetic risk factor for HCC. HH is an autosomal recessive disorder of iron metabolism, characterised by elevated iron deposition in most organs including the liver, leading to progressive organ dysfunction. HCC is a complication of HH, nearly always occurring in patients with cirrhosis and contributes to increased mortality rates. Identifying the susceptibility of development of HCC in HH patients has gained much traction. This review summarises the current knowledge with regard to the association of HH and HCC in order to encourage further research. In this review, we focus particularly on HFE gene-related HH. Herein, we highlight and discuss emerging clinical research which addresses the prevalence of HCC in HH patients and the coincidence of HH with other risk factors for HCC development. We also focus on the therapeutic tools in the management of HCC associated with HH.

Keywords

Hepatocellular carcinoma / hereditary hemochromatosis / HFE gene / C282Y mutation / H63D mutation / liver cirrhosis

References

[1] Venook AP,Furuse J.The incidence and epidemiology of hepatocellular carcinoma: a global and regional perspective..Oncologist2010;15:5-13

[2] Siegel RL,Jemal A.Cancer statistics, 2017..CA Cancer J Clin2017;67:7-30

[3] Galun D,Bogdanovic A,Zuvela M.Targeted therapy and personalized medicine in hepatocellular carcinoma: drug resistance, mechanisms, and treatment strategies..J Hepatocell Carcinoma2017;4:93-103 PMCID:PMC5513853

[4] Llovet JM,Sia D.Molecular therapies and precision medicine for hepatocellular carcinoma..Nat Rev Clin Oncol2018;15:599-616

[5] Ikeda M,Ueno M,Ishii H.Chemotherapy for hepatocellular carcinoma: current status and future perspectives..Jpn J Clin Oncol2018;48:103-14

[6] Abou-Alfa GK,O’Reilly EM.Current management of advanced hepatocellular carcinoma..Gastrointest Cancer Res2008;2:64-70 PMCID:PMC2630820

[7] Llovet JM,Bruix J.Hepatocellular carcinoma..Lancet2003;362:1907-17

[8] McGlynn KA,London WT.Global epidemiology of hepatocellular carcinoma: an emphasis on demographic and regional variability..Clin Liver Dis2015;19:223-38 PMCID:PMC4712629

[9] Bacon BR,Kowdley KV,Tavill AS.Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases..Hepatology2011;54:328-43 PMCID:PMC3149125

[10] Liver EAFTSOT.EASL clinical practice guidelines for HFE hemochromatosis..J Hepatol2010;53:3-22

[11] Crawford DHG.Hereditary hemochromatosis types 1, 2, and 3..Clin Liver Dis (Hoboken)2014;3:96-7 PMCID:PMC6448708

[12] Merryweather-Clarke AT,Jouanolle AM,Robson KJ.Geography of HFE C282Y and H63D mutations..Genet Test2000;4:183-98

[13] Olynyk JK,Aquilia S,Summerville L.A population-based study of the clinical expression of the hemochromatosis gene..N Engl J Med1999;341:718-24

[14] Phatak PD,Kowdley KV.Hereditary hemochromatosis: time for targeted screening..Ann Intern Med2008;149:270-2

[15] Beutler E.Iron storage disease: facts, fiction and progress..Blood Cells Mol Dis2007;39:140-7 PMCID:PMC2030637

[16] Gan EK,Olynyk JK.Natural history and management of HFE-hemochromatosis..Semin Liver Dis2011;31:293-301

[17] Golfeyz S,Weisberg IS.Hemochromatosis: pathophysiology, evaluation, and management of hepatic iron overload with a focus on MRI..Expert Rev Gastroenterol Hepatol2018;12:767-78

[18] Niederau C,Sonnenberg A,Trampisch HJ.Survival and causes of death in cirrhotic and in noncirrhotic patients with primary hemochromatosis..N Engl J Med1985;313:1256-62

[19] Feder JN,Thomas W,Ruddy DA.A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis..Nat Genet1996;13:399-408

[20] de Campos WN,Cançado ELR,Simões AL.Comprehensive analysis of..World J Hepatol2019;11:186-98

[21] Barton JC.HLA-A and -B alleles and haplotypes in hemochromatosis probands with HFE C282Y homozygosity in central Alabama..BMC Med Genet2002;3:9

[22] Adams PC.Haemochromatosis..Lancet2007;370:1855-60

[23] Allen KJ,Constantine CC,Delatycki MB.Iron-overload-related disease in HFE hereditary hemochromatosis..N Engl J Med2008;358:221-30

[24] Trifa AP,Militaru MS,Crişan TO.HFE gene C282Y, H63D and S65C mutations frequency in the Transylvania region, Romania..J Gastrointestin Liver Dis2012;21:177-80

[25] Feder JN,Irrinki A,Lebrón JA.The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding..Proc Natl Acad Sci U S A1998;95:1472-7 PMCID:PMC19050

[26] Giannetti AM.HFE and transferrin directly compete for transferrin receptor in solution and at the cell surface..J Biol Chem2004;279:25866-75

[27] Schmidt PJ,Giannetti AM,Andrews NC.The transferrin receptor modulates Hfe-dependent regulation of hepcidin expression..Cell Metab2008;7:205-14 PMCID:PMC2292811

[28] Vujić Spasić M,Herrmann T,Martinache S.Hfe acts in hepatocytes to prevent hemochromatosis..Cell Metab2008;7:173-8

[29] Zhao N,Enns CA.Iron regulation by hepcidin..J Clin Invest2013;123:2337-43 PMCID:PMC3668831

[30] Zhang AS.Molecular mechanisms of normal iron homeostasis..Hematology Am Soc Hematol Educ Program2009;207-14 PMCID:PMC5831338

[31] Ganz T.Hepcidin and iron homeostasis..Biochim Biophys Acta2012;1823:1434-43 PMCID:PMC4048856

[32] Deugnier Y.Iron and liver cancer..Alcohol2003;30:145-50

[33] Beutler E,West C,Adams M.Mutation analysis in hereditary hemochromatosis..Blood Cells Mol Dis1996;22:187-94

[34] Mura C,Férec C.HFE mutations analysis in 711 hemochromatosis probands: evidence for S65C implication in mild form of hemochromatosis..Blood1999;93:2502-5

[35] Bacon BR,Brunt EM,Wolff RK.HFE genotype in patients with hemochromatosis and other liver diseases..Ann Intern Med1999;130:953-62

[36] Gurrin LC,Dalton GW,Constantine CC.HFE C282Y/H63D compound heterozygotes are at low risk of hemochromatosis-related morbidity..Hepatology2009;50:94-101 PMCID:PMC3763940

[37] Walsh A,Ramm GA,Lincoln DJ.The clinical relevance of compound heterozygosity for the C282Y and H63D substitutions in hemochromatosis..Clin Gastroenterol Hepatol2006;4:1403-10

[38] Cardoso CS.HFE, the MHC and hemochromatosis: paradigm for an extended function for MHC class I..Tissue Antigens2003;61:263-75

[39] Torres FR,D’Almeida Couto AA,Cavasini CE.Frequency of the HFE C282Y and H63D polymorphisms in Brazilian malaria patients and blood donors from the Amazon region..Genet Mol Res2008;7:60-4

[40] Fargion S,Piperno A,Fracanzani AL.Survival and prognostic factors in 212 Italian patients with genetic hemochromatosis..Hepatology1992;15:655-9

[41] Kew MD.Pathogenesis of hepatocellular carcinoma in hereditary hemochromatosis: occurrence in noncirrhotic patients..Hepatology1990;11:1086-7

[42] Elmberg M,Ekbom A,Olsson S.Cancer risk in patients with hereditary hemochromatosis and in their first-degree relatives..Gastroenterology2003;125:1733-41

[43] Fracanzani AL,Fraquelli M,Mattioli M.Increased cancer risk in a cohort of 230 patients with hereditary hemochromatosis in comparison to matched control patients with non-iron-related chronic liver disease..Hepatology2001;33:647-51

[44] Haddow JE,McClain M.Hereditary haemochromatosis and hepatocellular carcinoma in males: a strategy for estimating the potential for primary prevention..J Med Screen2003;10:11-3

[45] Hsing AW,Olsen JH,Wacholder S.Cancer risk following primary hemochromatosis: a population-based cohort study in Denmark..Int J Cancer1995;60:160-2

[46] Strohmeyer G,Stremmel W.Survival and causes of death in hemochromatosis. Observations in 163 patients..Ann N Y Acad Sci1988;526:245-57

[47] Yang Q,Khoury MJ,Parrish RG.Hemochromatosis-associated mortality in the United States from 1979 to 1992: an analysis of Multiple-Cause Mortality Data..Ann Intern Med1998;129:946-53

[48] Cauza E,Ulrich-Pur H,Gschwantler M.Mutations of the HFE gene in patients with hepatocellular carcinoma..Am J Gastroenterol2003;98:442-7

[49] Ezzikouri S,El Kihal L,Benazzouz M.Prevalence of common HFE and SERPINA1 mutations in patients with hepatocellular carcinoma in a Moroccan population..Arch Med Res2008;39:236-41

[50] Fargion S,Fracanzani AL,Sampietro M.Mutations in the HFE gene and their interaction with exogenous risk factors in hepatocellular carcinoma..Blood Cells Mol Dis2001;27:505-11

[51] Hellerbrand C,Hartmann A,Lock G.HFE C282Y heterozygosity in hepatocellular carcinoma: evidence for an increased prevalence..Clin Gastroenterol Hepatol2003;1:279-84

[52] Lauret E,González S,López-Vázquez A.HFE gene mutations in alcoholic and virus-related cirrhotic patients with hepatocellular carcinoma..Am J Gastroenterol2002;97:1016-21

[53] Nahon P,Rufat P,Thabut G.Liver iron, HFE gene mutations, and hepatocellular carcinoma occurrence in patients with cirrhosis..Gastroenterology2008;134:102-10

[54] Pirisi M,Uzzau A,Avellini C.Carriage of HFE mutations and outcome of surgical resection for hepatocellular carcinoma in cirrhotic patients..Cancer2000;89:297-302

[55] Ropero P,López-Alonso G,González Fernández FA.The H63D mutation in the HFE gene is related to the risk of hepatocellular carcinoma..Rev Esp Enferm Dig2007;99:376-81(in Spanish)

[56] Shi WJ,Zhou B.Association of mutations of HFE gene and hepatocellular carcinoma following chronic hepatitis B..Zhonghua Gan Zang Bing Za Zhi2005;13:682-4(in Chinese)

[57] Willis G,Lonsdale R,Watson MA.Incidence of liver disease in people with HFE mutations..Gut2000;46:401-4 PMCID:PMC1727850

[58] Willis G,Lonsdale R.Haemochromatosis gene mutation in hepatocellular cancer..Lancet1997;350:565-6

[59] Sánchez-Luna SA.Clinical burden of liver disease from hemochromatosis at an academic medical center..Hepatol Commun2017;1:453-9 PMCID:PMC5721419

[60] Ellervik C,Tybjaerg-Hansen A.Hemochromatosis genotypes and risk of 31 disease endpoints: meta-analyses including 66,000 cases and 226,000 controls..Hepatology2007;46:1071-80

[61] Ye Q,Yin WL,Han T.Association between the HFE C282Y, H63D polymorphisms and the risks of non-alcoholic fatty liver disease, liver cirrhosis and hepatocellular carcinoma: an updated systematic review and meta-analysis of 5,758 cases and 14,741 controls..PLoS One2016;11:e0163423 PMCID:PMC5033482

[62] Asberg A,Thorstensen K,Kannelønning K.Screening for hemochromatosis: high prevalence and low morbidity in an unselected population of 65,238 persons..Scand J Gastroenterol2001;36:1108-15

[63] Gharib AF,Pasha HF,Elsawy WH.Polymorphisms of hemochromatosis, and alpha-1 antitrypsin genes in Egyptian HCV patients with and without hepatocellular carcinoma..Gene2011;489:98-102

[64] Harrison SA.Relation of hemochromatosis with hepatocellular carcinoma: epidemiology, natural history, pathophysiology, screening, treatment, and prevention..Med Clin North Am2005;89:391-409

[65] Tarao K,Ikeda T,Komatsu H.Real impact of liver cirrhosis on the development of hepatocellular carcinoma in various liver diseases-meta-analytic assessment..Cancer Med2019;8:1054-65 PMCID:PMC6434205

[66] Villanueva A,Hoshida Y.Inherited hepatocellular carcinoma..Best Pract Res Clin Gastroenterol2010;24:725-34

[67] Bradbear RA,Siskind V,Webb S.Cohort study of internal malignancy in genetic hemochromatosis and other chronic nonalcoholic liver diseases..J Natl Cancer Inst1985;75:81-4

[68] Blanc JF,Bernard PH,Winnock M.Increased incidence of HFE C282Y mutations in patients with iron overload and hepatocellular carcinoma developed in non-cirrhotic liver..J Hepatol2000;32:805-11

[69] Hiatt T,Kam I.Hepatocellular carcinoma in a noncirrhotic patient with hereditary hemochromatosis..Am J Med Sci2007;334:228-30

[70] Asare GA,Kew MC,Kahler-Venter CP.Hepatocellular carcinoma caused by iron overload: a possible mechanism of direct hepatocarcinogenicity..Toxicology2006;219:41-52

[71] Willis G,Fellows IW,Wimperis JZ.Hepatocellular carcinoma and the penetrance of HFE C282Y mutations: a cross sectional study..BMC Gastroenterol2005;5:17 PMCID:PMC1175847

[72] Fracanzani AL,Stazi MA,Amoroso P.Association between heterozygosity for HFE gene mutations and hepatitis viruses in hepatocellular carcinoma..Blood Cells Mol Dis2005;35:27-32

[73] Nowak A,Krayenbuehl PA.Higher age at diagnosis of hemochromatosis is the strongest predictor of the occurrence of hepatocellular carcinoma in the Swiss hemochromatosis cohort: a prospective longitudinal observational study..Medicine (Baltimore)2018;97:e12886 PMCID:PMC6211894

[74] Boige V,de Roux N,Ducot B.Lack of association between HFE gene mutations and hepatocellular carcinoma in patients with cirrhosis..Gut2003;52:1178-81 PMCID:PMC1773773

[75] Jin F,Shen XZ.Association between C282Y and H63D mutations of the HFE gene with hepatocellular carcinoma in European populations: a meta-analysis..J Exp Clin Cancer Res2010;29:18 PMCID:PMC2845109

[76] Campo S,Villari D,Cucinotta D.Analysis of haemochromatosis gene mutations in a population from the Mediterranean Basin..Liver2001;21:233-6

[77] Constantine CC,McLaren CE,Anderson GJ.SNP selection for genes of iron metabolism in a study of genetic modifiers of hemochromatosis..BMC Med Genet2008;9:18 PMCID:PMC2289803

[78] Racchi O,Rapezzi D,Nobile MT.Mutations of the HFE gene and the risk of hepatocellular carcinoma..Blood Cells Mol Dis1999;25:350-3

[79] Kew MC.Hepatic iron overload and hepatocellular carcinoma..Liver Cancer2014;3:31-40 PMCID:PMC3995380

[80] Shen Y,Zhao B,Wang S.Iron metabolism gene expression and prognostic features of hepatocellular carcinoma..J Cell Biochem2018;119:9178-204

[81] Pantopoulos K.Inherited disorders of iron overload..Front Nutr2018;5:103 PMCID:PMC6215844

[82] Worthen CA.The role of hepatic transferrin receptor 2 in the regulation of iron homeostasis in the body..Front Pharmacol2014;5:34 PMCID:PMC3944196

[83] Andrews NC.Disorders of iron metabolism..N Engl J Med1999;341:1986-95

[84] Nemeth E,Powelson J,Donovan A.Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization..Science2004;306:2090-3

[85] West AP,Sellers VM,Enns CA.Comparison of the interactions of transferrin receptor and transferrin receptor 2 with transferrin and the hereditary hemochromatosis protein HFE..J Biol Chem2000;275:38135-8

[86] Lesbordes-Brion JC,Bennoun M,Ramey G.Targeted disruption of the hepcidin 1 gene results in severe hemochromatosis..Blood2006;108:1402-5

[87] Wu XG,Wu Q,Liu W.HFE interacts with the BMP type I receptor ALK3 to regulate hepcidin expression..Blood2014;124:1335-43 PMCID:PMC4624447

[88] Gao J,Kramer M,Zhang AS.Interaction of the hereditary hemochromatosis protein HFE with transferrin receptor 2 is required for transferrin-induced hepcidin expression..Cell Metab2009;9:217-27 PMCID:PMC2673483

[89] Zacharski LR,Woloshin S.Association of age, sex, and race with body iron stores in adults: analysis of NHANES III data..Am Heart J2000;140:98-104

[90] Asare GA,Kew MC,Mossanda KS.Iron-free neoplastic nodules and hepatocellular carcinoma without cirrhosis in Wistar rats fed a diet high in iron..J Pathol2006;208:82-90

[91] Ioannou GN.Iron, HFE mutations, and hepatocellular carcinoma: is hepatic iron a carcinogen?.Clin Gastroenterol Hepatol2003;1:246-8

[92] Ramm GA,Powell LW,Fletcher LM.Hepatic stellate cell activation in genetic haemochromatosis. Lobular distribution, effect of increasing hepatic iron and response to phlebotomy..J Hepatol1997;26:584-92

[93] Yu Y,Richardson DR.Tuning cell cycle regulation with an iron key..Cell Cycle2007;6:1982-94

[94] Toyokuni S.Role of iron in carcinogenesis: cancer as a ferrotoxic disease..Cancer Sci2009;100:9-16

[95] Fargion S,Fracanzani AL.Role of iron in hepatocellular carcinoma..Clin Liver Dis (Hoboken)2014;3:108-10 PMCID:PMC6448713

[96] Moukhadder HM,Cappellini MD.Hepatocellular carcinoma as an emerging morbidity in the thalassemia syndromes: a comprehensive review..Cancer2017;123:751-8

[97] Marshall A,Kutter C,Alexander G.Global gene expression profiling reveals SPINK1 as a potential hepatocellular carcinoma marker..PLoS One2013;8:e59459 PMCID:PMC3601070

[98] Miyanishi K,Sakamoto H.The role of iron in hepatic inflammation and hepatocellular carcinoma..Free Radic Biol Med2019;133:200-5

[99] Muto Y,Ichihara K,Shimizu H.Disruption of FBXL5-mediated cellular iron homeostasis promotes liver carcinogenesis..J Exp Med2019;216:950-65 PMCID:PMC6446870

[100] Hussain SP,Harris CC.p53 tumor suppressor gene: at the crossroads of molecular carcinogenesis, molecular epidemiology, and human risk assessment..Ann N Y Acad Sci2000;919:79-85

[101] Ichiba M,Mukoyama T,Yasui S.Expression of 8-hydroxy-2’-deoxyguanosine in chronic liver disease and hepatocellular carcinoma..Liver Int2003;23:338-45

[102] Valerio LG.Characterization of hepatic iron overload following dietary administration of dicyclopentadienyl iron (Ferrocene) to mice: cellular, biochemical, and molecular aspects..Exp Mol Pathol2000;68:1-12

[103] Kowdley KV.Iron, hemochromatosis, and hepatocellular carcinoma..Gastroenterology2004;127:S79-86

[104] Olynyk JK,Britton RS,Bacon BR.Duration of hepatic iron exposure increases the risk of significant fibrosis in hereditary hemochromatosis: a new role for magnetic resonance imaging..Am J Gastroenterol2005;100:837-41

[105] Cabantchik ZI,Zanninelli G.LPI-labile plasma iron in iron overload..Best Pract Res Clin Haematol2005;18:277-87

[106] Asare GA,Naidoo V.Synergistic interaction between excess hepatic iron and alcohol ingestion in hepatic mutagenesis..Toxicology2008;254:11-8

[107] Nahon P,Pessayre D,Charnaux N.Do genetic variations in antioxidant enzymes influence the course of hereditary hemochromatosis?.Antioxid Redox Signal2011;15:31-8

[108] Houglum K,Chojkier M.TGF-beta and collagen-alpha 1 (I) gene expression are increased in hepatic acinar zone 1 of rats with iron overload..Am J Physiol1994;267:G908-13

[109] Wallace DF.Co-factors in liver disease: the role of HFE-related hereditary hemochromatosis and iron..Biochim Biophys Acta2009;1790:663-70

[110] Hann HW,Hann CL.Effect of iron and desferoxamine on cell growth and in vitro ferritin synthesis in human hepatoma cell lines..Hepatology1990;11:566-9

[111] Shen Y,Su Y,Zhang B.Downregulation contributes to aggressive hepatocellular carcinoma via mechanism mediated by cyclin4-dependent kinase-1/STAT3 pathway..Diagnostics (Basel)2019;9: PMCID:PMC6628061

[112] Djeha A.Effect of transferrin, lactoferrin and chelated iron on human T-lymphocytes..Br J Haematol1992;80:235-41

[113] Green R,Schreiber R.Iron inhibits the nonspecific tumoricidal activity of macrophages. A possible contributory mechanism for neoplasia in hemochromatosis..Ann N Y Acad Sci1988;526:301-9

[114] Cozma A,Vulturar R,Orăşan OH.DNA methylation and micro-RNAs: the most recent and relevant biomarkers in the early diagnosis of hepatocellular carcinoma..Medicina (Kaunas)2019;55: PMCID:PMC6780418

[115] Lehmann U,Brakensiek K,Becker T.Epigenetic defects of hepatocellular carcinoma are already found in non-neoplastic liver cells from patients with hereditary haemochromatosis..Hum Mol Genet2007;16:1335-42

[116] Adams P,Brissot P,Cabantchik I.Therapeutic recommendations in HFE hemochromatosis for p.Cys282Tyr (C282Y/C282Y) homozygous genotype..Hepatol Int2018;12:83-6 PMCID:PMC5904234

[117] Loréal O,Robin F,Guggenbuhl P.Iron as a therapeutic target in HFE-related hemochromatosis: usual and novel aspects..Pharmaceuticals (Basel)2018;11: PMCID:PMC6315470

[118] Phatak P,Wurster M,Bonkovsky HL.A phase 1/2, dose-escalation trial of deferasirox for the treatment of iron overload in HFE-related hereditary hemochromatosis..Hepatology2010;52:1671-779 PMCID:PMC3034044

[119] Tauchenová L,Kubánek M,Melenovský V.Successful treatment of iron-overload cardiomyopathy in hereditary hemochromatosis with deferoxamine and deferiprone..Can J Cardiol2016;32:1574.e1-e3

[120] Whitnall M,Ponka P.A class of iron chelators with a wide spectrum of potent antitumor activity that overcomes resistance to chemotherapeutics..Proc Natl Acad Sci U S A2006;103:14901-6 PMCID:PMC1595448

[121] Richardson DR,Ponka P.The potential of iron chelators of the pyridoxal isonicotinoyl hydrazone class as effective antiproliferative agents..Blood1995;86:4295-306

[122] Wadler S,Clairmont C,Fehn K.Phase I and pharmacokinetic study of the ribonucleotide reductase inhibitor, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, administered by 96-hour intravenous continuous infusion..J Clin Oncol2004;22:1553-63

[123] Fung E,Hsu J,Ganz T.High-throughput screening of small molecules identifies hepcidin antagonists..Mol Pharmacol2013;83:681-90 PMCID:PMC3583499

[124] MacPhail AP,Bloom PD,Rouault TA.Measurements of iron status and survival in African iron overload..S Afr Med J1999;89:966-72

[125] Mandishona E,Gordeuk VR,Paterson AC.Dietary iron overload as a risk factor for hepatocellular carcinoma in Black Africans..Hepatology1998;27:1563-6

[126] Turlin B,Moirand R,Loréal O.Increased liver iron stores in patients with hepatocellular carcinoma developed on a noncirrhotic liver..Hepatology1995;22:446-50

[127] Blonski W,Forde KA.Non-viral causes of hepatocellular carcinoma..World J Gastroenterol2010;16:3603-15 PMCID:PMC2915420