Hemocromatosis

1 Merryweather-Clarke AT, Worwood M, Parkinson L, et al. The eff ect of HFE mutations on serum ferritin and transferrin saturation in the Jersey population. Br J Haematol 1998; 101: 369–73.
2 Merryweather-Clarke AT, Pointon JJ, Shearman JD, Robson KJ. Global prevalence of putative haemochromatosis mutations. J Med Genet 1997; 34: 275–78.
3 Bacon BR, Powell LW, Adams PC, Kresina TF. Molecular medicine and hemochromatosis: at the crossroads. Gastroenterology 1999; 116: 193–207.
4 Whitlock EP, Garlitz BA, Harris EL, Beil TL, Smith PR. Screening for hereditary hemochromatosis: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med 2006; 145: 209.
5 Wood MJ, Powell LW, Ramm GA. Environmental and genetic modifiers of the progression to fibrosis and cirrhosis in hemochromatosis. Blood 2008; 111: 4456–62.
6 Kasper D, Fauci A, Hauser S, Longo D, Jameson L, Loscalzo J (eds). Harrison’s Principles of Internal Medicine, 19th edn. New York: McGraw Hill Education, 2015.
7 Olynyk JK, Trinder D, Ramm GA, Britton RS, Bacon BR. Hereditary hemochromatosis in the post-HFE era. Hepatology 2008; 48: 991–1001.
8 Beutler E, Felitti VJ, Koziol JA, Ho NJ, Gelbart T. Penetrance of 845G→A (C282Y) HFE hereditary haemochromatosis mutation in the USA. Lancet 2002; 359: 211–18.
9 Nemeth E, Ganz T. The role of hepcidin in iron metabolism. Acta Haematol 2009; 122: 78.
10 Drakesmith H, Schimanski LM, Ormerod E, et al. Resistance to hepcidin is conferred by hemochromatosis-associated mutations of ferroportin. Blood 2005; 106: 1092–97.
11 Schimanski LM, Drakesmith H, Merryweather-Clarke AT, et al. In vitro functional analysis of human ferroportin (FPN) and hemochromatosis-associated FPN mutations. Blood 2005; 105: 4096–102.
12 Kono S. Aceruloplasminemia. Curr Drug Targets 2012; 13: 1190–99.
13 Miyajima H. Aceruloplasminemia. Neuropathology 2015; 35: 83–90.
14 Bacon BR, Britton RS. The pathology of hepatic iron overload: a free radical-mediated Process? Hepatology 1990; 11: 127–37.
15 Loreal O, Deugnier Y, Moirand R, et al. Liver fibrosis in genetic hemochromatosis. Respective roles of iron and non-iron-related factors in 127 homozygous patients. J Hepatol 1992; 16: 122.
16 Fletcher LM, Dixon JL, Purdie DM, Powell LW, Crawford DHG. Excess alcohol greatly increases the prevalence of cirrhosis in hereditary hemochromatosis. Gastroenterology 2002; 122: 281.
17 European Association for the Study of the Liver. EASL clinical practice guidelines for HFE hemochromatosis. J Hepatol 2010; 53: 3–22.
18 Allen KJ, Gurrin LCP, Constantine CCP, et al. Iron-overload-related disease in HFE hereditary hemochromatosis. N Engl J Med 2008; 358: 221–30.
19 Deugnier Y, Mosser J. Modifying factors of the HFE hemochromatosis phenotype. Expert Rev Gastroenterol Hepatol 2008; 2: 531–40.
20 Jackson HA, Carter K, Darke C, et al. HFE mutations, iron deficiency and overload in 10,500 blood donors. Br J Haematol 2001; 114: 474–84.
21 Adams PC, Reboussin DM, Barton JC, et al. Hemochromatosis and iron-overload screening in a racially diverse population. N Engl J Med 2005; 352: 1769–78.
22 Jacolot S, Le Gac G, Scotet V, Quere I, Mura C, Ferec C. HAMP as a modifi er gene that increases the phenotypic expression of the HFE pC282Y homozygous genotype. Blood 2004; 103: 2835–40.
23 Le Gac G, Scotet V, Ka C, et al. The recently identified type 2A juvenile haemochromatosis gene (HJV), a second candidate modifier of the C282Y homozygous phenotype. Hum Mol Genet 2004; 13: 1913–18.
24 Van Vlierberghe H, Langlois M, Delanghe J, et al. Haptoglobin phenotype 2-2 overrepresentation in Cys282Tyr hemochromatotic patients. J Hepatol 2001; 35: 707–11.
25 Milet J, Dehais V, Bourgain C, Jouanolle AM. Common variants in the BMP2, BMP4, and HJV genes of the hepeidin regulation pathway modulate HFE hemochromatosis penetrance. Am J Hum Genet 2007; 81: 799.
26 Milet J, Le Gac G, Scotet V, et al. A common SNP near BMP2 is associated with severity of the iron burden in HFE p.C282Y homozygous patients: a follow-up study. Blood Cells Mol Dis 2010; 44: 34–37.
27 Benyamin B, McRae AF, Zhu G. Variants in TF and HFE explain ~40% of genetic variation in serum-transferrin levels. Am J Hum Genet 2009; 84: 60.
28 de Tayrac M, Roth M-P, Jouanolle A-M, et al. Genome-wide association study identifies TF as a significant modifier gene of iron metabolism in HFE hemochromatosis. J Hepatol 2015; 62: 664–72.
29 Benyamin B, Esko T, Ried JS, Radhakrishnan A. Novel loci affecting iron homeostasis and their eff ects in individuals at risk for hemochromatosis. Nat Commun 2014; 5: 4926.
30 Stickel F, Buch S, Zoller H, et al. Evaluation of genome-wide loci of iron metabolism in hereditary hemochromatosis identifi es PCSK7 as a host risk factor of liver cirrhosis. Hum Mol Genet 2014; 23: 3883.
31 Pelucchi S, Mariani R, Calza S, et al. CYBRD1 as a modifier gene that modulates iron phenotype in HFE p.C282Y homozygous patients. Haematologica 2012; 97: 1818–25.
32 McLaren CE, Emond MJ, Subramaniam VN, et al. Exome sequencing in HFE C282Y homozygous men with extreme phenotypes identifies a GNPAT variant associated with severe iron overload. Hepatology 2015; 62: 429–39.
33 Besson-Fournier C, Martinez M, Vinel JP, Aguilar-Martinez P, Coppin H, Roth MP. Further support for the association of GNPAT variant rs11558492 with severe iron overload in hemochromatosis. Hepatology 2015; published online Sept 29.
DOI:10.1002/hep.28259.
34 Ryan E, Russel J, Ryan J, Crowe J, Stewart S. GNPAT variant is not associated with severe iron overload in Irish C282Y homozygotes.  Hepatology 2015; published online Sept 29. DOI:10.1002/hep.28258.
35 Bardou-Jacquet E, de Tayrac M, Mosser J, Deugnier Y. GNPAT variant associated with severe iron overload in HFE hemochromatosis. Hepatology 2015; 62: 1917–18.
36 Barton JC, Barton JC, Acton RT. Longer survival associated with HLA-A*03, B*14 among 212 hemochromatosis probands with HFE C282Y homozygosity and HLA-A and -B typing and haplotyping. Eur J Haematol 2010; 85: 439–47.
37 Aguilar-Martinez P, Bismuth M, Blanc F, et al. The southern French registry of genetic hemochromatosis: a tool for determining clinical prevalence of the disorder and genotype penetrance. Haematologica 2010; 95: 551–56.
38 Shimizu I. Impact of oestrogens on the progression of liver disease. Liver Int 2003; 23: 63–69.
39 Cade JE, Moreton JA, O’Hara B, et al. Diet and genetic factors associated with iron status in middle-aged women. Am J Clin Nutr 2005; 82: 813–20.
40 Tsukamoto H, Horne W, Kamimura S, et al. Experimental liver cirrhosis induced by alcohol and iron. J Clin Invest 1995; 96: 620–30.
41 Scotet V, Merour M-C, Mercier A-Y, et al. Hereditary hemochromatosis: eff ect of excessive alcohol consumption on disease expression in patients homozygous for the C282Y mutation. Am J Epidemiol 2003; 158: 129–34.
42 Adams PC, Agnew S. Alcoholism in hereditary hemochromatosis revisited: prevalence and clinical consequences among homozygous siblings. Hepatology 1996; 23: 724–27.
43 Powell EE, Ali A, Clouston AD, et al. Steatosis is a cofactor in liver injury in hemochromatosis. Gastroenterology 2005; 129: 1937–43.
44 Diwakaran HH, Befeler AS, Britton RS, Brunt EM, Bacon BR. Accelerated hepatic fibrosis in patients with combined hereditary hemochromatosis and chronic hepatitis C infection. J Hepatol 2002; 36: 687–91.
45 Milward EA, Baines SK, Knuiman MW, et al. Noncitrus fruits as novel dietary environmental modifiers of iron stores in people with or without HFE gene mutations. Mayo Clin Proc 2008; 83: 543–49.
46 Gurrin LC, Bertalli NA, Dalton GW, et al. HFE C282Y/H63D compound heterozygotes are at low risk of hemochromatosis-related morbidity. Hepatology 2009; 50: 94–101.
47 Wallace DF, Dooley JS, Walker AP. A novel mutation of HFE explains the classical phenotype of genetic hemochromatosis in a C282Y heterozygote. Gastroenterology 1999; 116: 1409.
48 Piperno A, Arosio C, Fossati L, et al. Two novel nonsense mutations of HFE gene in fi ve unrelated Italian patients with hemochromatosis. Gastroenterology 2000; 119: 441–45.
49 O’Neil J, Powell LW. Clinical aspects of hemochromatosis. Semin Liver Dis 2005; 25: 381–91.
50 Fracanzani AL, Piperno A, Valenti L, et al. Hemochromatosis in Italy in the last 30 years: role of genetic and acquired factors. Hepatology 2010; 51: 501–10.
51 Yamashita C, Adams PC. Natural history of the C282Y homozygote for the hemochromatosis gene (HFE) with a normal serum ferritin level. Clin Gastroenterol Hepatol 2003; 1: 388.
52 Asberg A, Hveem K, Kruger O, Bjerve KS. Persons with screening-detected haemochromatosis: as healthy as the general population? Scandi J Gastroenterol 2002; 37: 719–24.
53 Andersen RV, Tybjaerg-Hansen A, Appleyard M, Birgens H, Nordestgaard BG. Hemochromatosis mutations in the general population: iron overload progression rate. Blood 2004; 103: 2914–19.
54 Olynyk JK, Hagan SE, Cullen DJ, Beilby J, Whittall DE. Evolution of untreated hereditary hemochromatosis in the Busselton population: a 17-year study. Mayo Clin Proc 2004; 79: 309–13.
55 Gurrin LC, Osborne NJ, Constantine CC, et al. The natural history of serum iron indices for HFE C282Y homozygosity associated with hereditary hemochromatosis. Gastroenterology 2008; 135: 1945–52.
56 Sahinbegovic E, Dallos T, Aigner E, et al. Musculoskeletal disease burden of hereditary hemochromatosis. Arthritis Rheum 2010; 62: 3792.
57 Guggenbuhl P, Brissot P, Loreal O. Haemochromatosis: the bone and the joint. Best Pract Res Clin Rheumatol 2011; 25: 649–64.
58 Richette P, Ottaviani S, Vicaut E, Bardin T. Musculoskeletal complications of hereditary hemochromatosis: a case-control study. J Rheumatol 2010; 37: 2145–50.
59 Sinigaglia L, Fargion S, Fracanzani AL, et al. Bone and joint involvement in genetic hemochromatosis: role of cirrhosis and iron overload. J Rheumatol 1997; 24: 1809.
60 Guggenbuhl P, Deugnier Y, Boisdet JF, et al. Bone mineral density in men with genetic hemochromatosis and HFE gene mutation. Osteoporos Int 2005; 16: 1809–14.
61 Valenti L, Varenna M, Fracanzani AL, Rossi V, Fargion S, Sinigaglia L. Association between iron overload and osteoporosis in patients with hereditary hemochromatosis. Osteoporos Int 2009; 20: 549–55.
62 Eyres KS, McCloskey EV, Fern ED, et al. Osteoporotic fractures: an unusual presentation of haemochromatosis. Bone 1992; 13: 431–33.
63 Duquenne M, Rohmer V, Legrand E, Chappard D. Spontaneous multiple vertebral fractures revealed primary haemochromatosis. Osteoporos Int 1996; 6: 338.
64 Deugnier Y, Jouanolle A-M, Chaperon J, et al. Gender-specific phenotypic expression and screening strategies in C282Y-linked haemochromatosis: a study of 9396 French people. Br J Haematol 2002; 118: 1170–78.
65 Acton RT, Barton JC, Passmore LV, et al. Relationships of serum ferritin, transferrin saturation, and HFE mutations and self-reported diabetes in the hemochromatosis and iron overload screening (HEIRS) study. Diabetes Care 2006; 29: 2084–89.
66 Asberg A, Hveem K, Thorstensen K, et al. Screening for hemochromatosis: high prevalence and low morbidity in an unselected population of 65,238 persons. Scandi J Gastroenterol 2001; 36: 1108–15.
67 Adams P, Brissot P, Powell LW. EASL International consensus conference on haemochromatosis. J Hepatol 2000; 33: 487–96.
68 Powell L, Powell LW, Dixon JL, Hewett DG. Role of early case detection by screening relatives of patients with HFE-associated hereditary haemochromatosis. Best Pract Res Clin Rheumatol 2005; 18: 221–34.
69 Rochette J, Le Gac G, Lassoued K, Ferec C, Robson KJH. Factors influencing disease phenotype and penetrance in HFE haemochromatosis. Hum Genet 2010; 128: 233–48.
70 Fletcher L, Halliday J, Powell L. Interrelationships of alcohol and iron in liver disease with particular reference to the iron-binding proteins, ferritin and transferrin. J Gastroenterol Hepatol 1999; 14: 202–14.
71 Whitfi eld JB, Zhu G, Heath AC, Powell LW, Martin NG. Eff ects of alcohol consumption on indices of iron stores and of iron stores on alcohol intake markers. Alcohol Clin Exp Res 2001; 25: 1037–45.
72 McLaren CE, McLachlan GJ, Halliday JW, et al. Distribution of transferrin saturation in an Australian population: relevance to the early diagnosis of hemochromatosis. Gastroenterology 1998; 114: 543.
73 Olynyk JKMD, Cullen DJMBBS, Aquilia SBA, Rossi EP, Summerville LB, Powell LWMDP. A population-based study of the clinical expression of the hemochromatosis gene. N Engl J Med 1999; 341: 718–24.
74 Powell LW, Dixon JL, Ramm GA, Purdie DM. Screening for hemochromatosis in asymptomatic subjects with or without a family history. Arch Intern Med 2006; 166: 294–301.
75 Gan EK, Powell LW, Olynyk JK. Natural history and management of HFE-hemochromatosis. Semin Liver Dis 2011; 31: 293–301.
76 Adams PC. Implications of genotyping of spouses to limit investigation of children in genetic hemochromatosis. Clin Genet 1998; 53: 176–78.
77 Delatycki MB, Powell LW, Allen KJ. Hereditary hemochromatosis genetic testing of at-risk children: what is the appropriate age? Genet Test 2004; 8: 98–103.
78 Bacon BR, Adams PC, Kowdley KV, Powell LW, Tavill AS. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology 2011; 54: 328–43.
79 Adams PC. Biological variability of transferrin saturation and unsaturated iron-binding capacity. Am J Med 2007; 120: 999.
80 Guyader D, Jacquelinet C, Moirand R, et al. Noninvasive prediction of fibrosis in C282Y homozygous hemochromatosis. Gastroenterology 1998; 115: 929.
81 Crawford DHG, Murphy TL, Ramm LE, et al. Serum hyaluronic acid with serum ferritin accurately predicts cirrhosis and reduces the need for liver biopsy in C282Y hemochromatosis. Hepatology 2009; 49: 418–25.
82 Legros L, Bardou-Jacquet E, Latournerie M, et al. Non-invasive assessment of liver fi brosis in C282Y homozygous HFE hemochromatosis. Liver Int 2015; 35: 1731–38.
83 Stuart KA, Stuart KA, Busfi eld F, Jazwinska EC, Gibson P. The C282Y mutation in the haemochromatosis gene (HFE) and hepatitis C virus infection are independent cofactors for porphyria cutanea tarda in Australian patients. J Hepatol 1998; 28: 404–09.
84 Ajioka RS, Phillips JD, Weiss RB, et al. Down-regulation of hepcidin in porphyria cutanea tarda. Blood 2008; 112: 4723–28.
85 George DK, Goldwurm S, MacDonald GA, et al. Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fi brosis. Gastroenterology 1998; 114: 311.
86 Bonkovsky HL, Jawaid Q, Tortorelli K, et al. Non-alcoholic steatohepatitis and iron: increased prevalence of mutations of the HFE gene in non-alcoholic steatohepatitis. J Hepatol 1999; 31: 421–29.
87 Franchini M, Targher G, Capra F, Montagnana M, Lippi G. The eff ect of iron depletion on chronic hepatitis C virus infection. Hepatol Int 2008; 2: 335–40.
88 Costa-Matos L, Batista P, Monteiro N, Henriques P, Girao F, Carvalho A. HFE mutations and iron overload in patients with alcoholic liver disease. Arq Gastroenterol 2013; 50: 35.
89 Deugnier Y, Turlin B, le Quilleuc D, et al. A reappraisal of hepatic siderosis in patients with end-stage cirrhosis: practical implications for the diagnosis of hemochromatosis. Am J Surg Pathol 1997; 21: 669–75.
90 Cotler SJ, Cotler SJ, Bronner MP, Press RD, Carlson TH. End-stage liver disease without hemochromatosis associated with elevated hepatic iron index. J Hepatol 1998; 29: 257–62.
91 Ludwig J, Hashimoto E, Porayko MK, Moyer TP, Baldus WP. Hemosiderosis in cirrhosis: a study of 447 native livers. Gastroenterology 1997; 112: 882.
92 Bridle KR, Cheung T-K, Murphy TL, et al. Hepcidin is down-regulated in alcoholic liver injury: Implications for the Pathogenesis of Alcoholic Liver Disease. Alcohol Clin Exp Res 2006; 30: 106–12.
93 Harrison-Findik DD, Schafer D, Klein E, et al. Alcohol metabolism-mediated oxidative stress down-regulates hepcidin transcription and leads to increased duodenal iron
transporter expression. J Biol Chem 2006; 281: 22974–82.
94 Harrison-Findik DD, Klein E, Crist C, Evans J, Timchenko N, Gollan J. Iron-mediated regulation of liver hepcidin expression in rats and mice is abolished by alcohol. Hepatology 2007; 46: 1979–85.
95 Osborne NJ, Gurrin LC, Allen KJ, et al. HFE C282Y homozygotes are at increased risk of breast and colorectal cancer. Hepatology 2010; 51: 1311–18.
96 Niederau C, Fischer R, Purschel A, Stremmel W. Long-term survival in patients with hereditary hemochromatosis. Gastroenterology 1996; 110: 1107–19.
97 Adams PC, Speechley M, Kertesz AE. Long-term survival analysis in hereditary hemochromatosis. Gastroenterology 1991; 101: 368.
98 Bismuth M, Peynaud-Debayle E. Prise en charge de l’hemochromatose liee au gene HFE (hemochromatose de type 1): Haute Autorite de Sante (HAS). 2005. http://www.has-sante.fr/ portail/jcms/c_432802/fr/prise-en-charge-de-l-hemochromatoseliee-au-gene-hfe-hemochromatose-de-type-1 (accessed Aug 31, 2015).
99 Raymakers RAP, Raymakers RAP, Swinkels DW, Jorna AT. Synopsis of the Dutch multidisciplinary guideline for the diagnosis and treatment of hereditary haemochromatosis. Neth J Med 2007; 65: 452–55.
100 Barton JC, McDonnell SM, Adams PC, et al. Management of hemochromatosis. hemochromatosis management working group. Ann Intern Med 1998; 129: 932.
101 Falize L, Guillygomarc’h A, Perrin M, et al. Reversibility of hepatic fibrosis in treated genetic hemochromatosis: a study of 36 cases. Hepatology 2006; 44: 472–77.
102 Desmet VJ, Roskams T. Cirrhosis reversal: a duel between dogma and myth. J Hepatol 2004; 40: 860–67.
103 Desmet VJ, Desmet VJ. Comments on cirrhosis reversal. Dig Liver Dis
2005; 37: 909–16.
104 Niederau C, Fischer R, Sonnenberg A, Stremmel W, Trampisch HJ, Strohmeyer G. Survival and causes of death in cirrhotic and in noncirrhotic patients with primary hemochromatosis. N Engl J Med 1985; 313: 1256–62.
105 Waalen J, Nordestgaard BG, Beutler E. The penetrance of hereditary hemochromatosis. Best Pract Res Clin Haematol 2005; 18: 203–20.
106 Bardou-Jacquet E, Morcet J, Manet G, et al. Decreased cardiovascular and extrahepatic cancer-related mortality in treated patients with mild HFE hemochromatosis. J Hepatol 2015; 62: 682–89.
107 Delatycki MB, Gurrin LC, Ong SY, et al. Reduced mortality due to phlebotomy in moderately iron-loaded HFE haemochromatosis? The need for clinical trials. J Hepatol 2015; 63: 282–83.
108 Ong SY, Dolling L, Dixon JL, et al. Should HFE p.C282Y homozygotes with moderately elevated serum ferritin be treated? A randomised controlled trial comparing iron reduction with sham treatment (Mi-iron). BMJ Open 2015; 5: e008938.
109 Phatak P, Brissot P, Wurster M, et al. A phase 1/2, dose-escalation trial of deferasirox for the treatment of iron overload in HFE-related hereditary hemochromatosis. Hepatology 2010; 52: 1671.
110 Stefashyna O, Stefashyna O, Stern M, Infanti L, Holbro A. Pattern of care of blood donors with early-uncomplicated hereditary haemochromatosis in a Swiss blood donation centre. Vox Sang 2014; 106: 111–17.
111 Brissot P, Troadec M-B, Bardou-Jacquet E, et al. Current approach to hemochromatosis. Blood Rev 2008; 22: 195–210.
112 Loreal O, Turlin B, Pigeon C, et al. Aceruloplasminemia: new clinical, pathophysiological and therapeutic insights. J Hepatol 2002; 36: 851–56.
113 Moretti D, van Doorn GM, Swinkels DW, Melse-Boonstra A. Relevance of dietary iron intake and bioavailability in the management of HFE hemochromatosis: a systematic review. Am J Clin Nutr 2013; 98: 468–79.
114 Kaltwasser JP, Werner E, Schalk K, Hansen C, Gottschalk R, Seidl C. Clinical trial on the eff ect of regular tea drinking on iron accumulation in genetic haemochromatosis. Gut 1998; 43: 699–704.
115 Nienhuis AW. Vitamin C and iron. N Engl J Med 1981; 304: 170–71.
116 Crawford DHG, Fletcher LM, Hubscher SG, et al. Patient and graft survival after liver transplantation for hereditary hemochromatosis: implications for pathogenesis. Hepatology 2004; 39: 1655–62.
117 Yu L, Ioannou GN. Survival of liver transplant recipients with hemochromatosis in the United States. Gastroenterology 2007; 133: 489–95.
118 Powell LW, Dixon JL, Ramm GA, Purdie DM. Screening for hemochromatosis in asymptomatic subjects with or without a family history. Arch Intern Med 2006; 166: 294.
119 Kowdley KV, Hassanein T, Kaur S, et al. Primary liver cancer and survival in patients undergoing liver transplantation for hemochromatosis. Liver Transplant Surg 1995; 1: 237–41.
120 Kowdley KV, Brandhagen DJ, Gish RG, et al. Survival after liver transplantation in patients with hepatic iron overload: the national hemochromatosis transplant registry. Gastroenterology 2005; 129: 494–503.
121 Dar FS, Faraj W, Zaman MB, et al. Outcome of liver transplantation in hereditary hemochromatosis. Transpl Int 2009; 22: 717.
122 Bardou-Jacquet E, Philip J, Lorho R, et al. Liver transplantation normalizes serum hepcidin level and cures iron metabolism alterations in HFE hemochromatosis. Hepatology 2014; 59: 839–47.
123 Gandon Y, Olivie D, Guyader D, et al. Non-invasive assessment of hepatic iron stores by MRI. Lancet 2004; 363: 357–62.
124 Guyader D, Gandon Y, Sapey T, Turlin B. Magnetic resonance iron-free nodules in genetic hemochromatosis. Am J Gastroenterol 1999; 94: 1083–86.