Clinical characteristics of HFE C282Y/H63D compound heterozygotes identified in a specialty practice: key differences from HFE C282Y homozygotes

References

• Barton JC, Edwards CQ, Acton RT. HFE gene: structure, function, mutations, and associated iron abnormalities. Gene. 2015 Dec 15;574(2):179–192.
   PubMed Web of Science ®Google Scholar
• Adams PC, Reboussin DM, Barton JC, et al. Hemochromatosis and iron-overload screening in a racially diverse population. N Engl J Med. 2005 Apr 28;352(17):1769–1778. doi: 10.1056/NEJMoa041534
   PubMed Web of Science ®Google Scholar
• Crownover BK, Covey CJ. Hereditary hemochromatosis. Am Fam Physician. 2013 Feb 1;87(3):183–190.
   PubMed Web of Science ®Google Scholar
• Yang Q, McDonnell SM, Khoury MJ, et al. Hemochromatosis-associated mortality in the United States from 1979 to 1992: an analysis of multiple-cause mortality data. Ann Intern Med. 1998 Dec 1;129(11):946–953. doi: 10.7326/0003-4819-129-11_Part_2-199812011-00005
   PubMed Web of Science ®Google Scholar
• Girelli D, Busti F, Brissot P, et al. Hemochromatosis classification: update and recommendations by the BIOIRON Society. Blood. 2022 May 19;139(20):3018–3029. doi: 10.1182/blood.2021011338
   PubMed Web of Science ®Google Scholar
• Feder JN, Gnirke A, Thomas W, et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet.1996 Aug;13(4):399–408.
   PubMed Web of Science ®Google Scholar
• Richardson KJ, McNamee AP, Simmonds MJ. Haemochromatosis: pathophysiology and the red blood cell1. Clin Hemorheol Microcirc. 2018;69(1–2):295–304. doi: 10.3233/CH-189128
   PubMed Web of Science ®Google Scholar
• McLaren GD, Gordeuk VR. Hereditary hemochromatosis: insights from the hemochromatosis and iron overload screening (HEIRS) study. Hematology Am Soc Hematol Educ Program. 2009;2009(1):195–206. doi: 10.1182/asheducation-2009.1.195
   Google Scholar
• Steinberg KK, Cogswell ME, Chang JC, et al. Prevalence of C282Y and H63D mutations in the hemochromatosis (HFE) gene in the United States. JAMA. 2001 May 2;285(17):2216–2222. doi: 10.1001/jama.285.17.2216
   PubMed Web of Science ®Google Scholar
• Phatak PD, Ryan DH, Cappuccio J, et al. Prevalence and penetrance of HFE mutations in 4865 unselected primary care patients. Blood Cells Mol Dis.2002 Jul;29(1):41–47.
   PubMed Web of Science ®Google Scholar
• Adams PC, Jeffrey G, Ryan J. Haemochromatosis. Lancet. 2023 May 27;401(10390):1811–1821.
   PubMed Web of Science ®Google Scholar
• Pilling LC, Tamosauskaite J, Jones G, et al. Common conditions associated with hereditary haemochromatosis genetic variants: cohort study in UK Biobank. BMJ. 2019 Jan 16;364:k5222.
   PubMedGoogle Scholar
• Hasan SMM, Farrell J, Borgaonkar M. C282Y/H63D compound heterozygosity is a low penetrance genotype for iron overload-related disease. J Can Assoc Gastroenterol. 2022 Oct;5(5):240–247. doi: 10.1093/jcag/gwac025
   PubMedGoogle Scholar
• Zaloumis SG, Allen KJ, Bertalli NA, et al. Natural history of HFE simple heterozygosity for C282Y and H63D: a prospective 12-year study. J Gastroenterol Hepatol.2015 Apr;30(4):719–725.
   PubMed Web of Science ®Google Scholar
• Gasser B, Courtois F, Hojjat-Assari S, et al. Hereditary hemochromatosis: presenting manifestations and diagnostic delay. Rev Med Interne.2014 Mar;35(3):160–165.
   PubMed Web of Science ®Google Scholar
• Barton JC, Chen WP, Emond MJ, et al. GNPAT p.D519G is independently associated with markedly increased iron stores in HFE p.C282Y homozygotes. Blood Cells Mol Dis. 2017 Mar;63:15–20. doi: 10.1016/j.bcmd.2016.11.009
   PubMed Web of Science ®Google Scholar
• Levstik A, Stuart A, Adams PC. GNPAT variant (D519G) is not associated with an elevated serum ferritin or iron removed by phlebotomy in patients referred for C282Y-linked hemochromatosis. Ann Hepatol. 2016 Nov;15(6):907–910. doi: 10.5604/16652681.1222109
   PubMed Web of Science ®Google Scholar
• Secondes ES, Wallace DF, Rishi G, et al. Increased frequency of GNPAT p.D519G in compound HFE p.C282Y/p.H63D heterozygotes with elevated serum ferritin levels. Blood Cells Mol Dis. 2020 Nov;85:102463. doi: 10.1016/j.bcmd.2020.102463
   PubMed Web of Science ®Google Scholar
• Gurrin LC, Bertalli NA, Dalton GW, et al. HFE C282Y/H63D compound heterozygotes are at low risk of hemochromatosis-related morbidity. Hepatology.2009 Jul;50(1):94–101.
   PubMed Web of Science ®Google Scholar
• 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 Dec;135(6):1945–1952.
   PubMed Web of Science ®Google Scholar
• Gordeuk VR, Reboussin DM, McLaren CE, et al. Serum ferritin concentrations and body iron stores in a multicenter, multiethnic primary-care population. Am J Hematol.2008 Aug;83(8):618–626.
   PubMed Web of Science ®Google Scholar
• Deugnier Y, Morcet J, Laine F, et al. Reduced phenotypic expression in genetic hemochromatosis with time: role of exposure to non-genetic modifiers. J Hepatol.2019 Jan;70(1):118–125.
   PubMed Web of Science ®Google Scholar
• Walsh A, Dixon JL, Ramm GA, et al. The clinical relevance of compound heterozygosity for the C282Y and H63D substitutions in hemochromatosis. Clin Gastroenterol Hepatol.2006 Nov;4(11):1403–1410.
   PubMed Web of Science ®Google Scholar
• Zoller H, Schaefer B, Vanclooster A, et al. Electronic address eee, European Association for the Study of the L. EASL clinical practice guidelines on haemochromatosis. J Hepatol.2022 Aug;77(2):479–502.
   PubMedGoogle Scholar
• Atkins JL, Pilling LC, Masoli JAH, et al. Association of hemochromatosis HFE p.C282Y homozygosity with hepatic malignancy. JAMA. 2020 Nov 24;324(20):2048–2057. doi: 10.1001/jama.2020.21566
   PubMed Web of Science ®Google Scholar
• Barton JC, McLaren CE, Chen WP, et al. Cirrhosis in hemochromatosis: Independent risk factors in 368 HFE p.C282Y homozygotes. Ann Hepatol. 2018 Aug 24;17(5):871–879. doi: 10.5604/01.3001.0012.3169
   PubMed Web of Science ®Google Scholar
• Danilowicz-Szymanowicz L, Swiatczak M, Sikorska K, et al. Pathogenesis, diagnosis, and clinical implications of hereditary hemochromatosis—the cardiological point of view. Diagn (Basel). 2021 Jul 16;11(7):1279. doi: 10.3390/diagnostics11071279
   PubMedGoogle Scholar
• Kremastinos DT, Farmakis D. Iron overload cardiomyopathy in clinical practice. Circulation. 2011 Nov 15;124(20):2253–2263.
   PubMed Web of Science ®Google Scholar
• Shizukuda Y, Tripodi DJ, Zalos G, et al. Incidence of cardiac arrhythmias in asymptomatic hereditary hemochromatosis subjects with C282Y homozygosity. Am J Cardiol. 2012 Mar 15;109(6):856–860. doi: 10.1016/j.amjcard.2011.11.011
   PubMed Web of Science ®Google Scholar
• Wyne KL, Nair L, Schneiderman CP, et al. Hypothyroidism prevalence in the United States: a retrospective study combining national health and nutrition examination survey and claims data, 2009-2019. J Endocr Soc. 2022 Nov 17;7(1):bvac172. doi: 10.1210/jendso/bvac172
   PubMed Web of Science ®Google Scholar
• Kane SF, Roberts C, Paulus R. Hereditary hemochromatosis: rapid evidence review. Am Fam Physician. 2021 Sep 1;104(3):263–270.
   PubMedGoogle Scholar