eISSN: 1896-9151
ISSN: 1734-1922
Archives of Medical Science
Current issue Archive Manuscripts accepted About the journal Special issues Editorial board Abstracting and indexing Subscription Contact Instructions for authors
SCImago Journal & Country Rank
vol. 14
State of the art paper

Management of cardiac hemochromatosis

Wilbert S. Aronow

Arch Med Sci 2018; 14, 3: 560–568
Online publish date: 2017/06/30
View full text
Get citation
JabRef, Mendeley
Papers, Reference Manager, RefWorks, Zotero
Iron-overload syndromes may be hereditary or acquired. Patients may be asymptomatic early in the disease. Once heart failure develops, there is rapid deterioration. Cardiac hemochromatosis is characterized by a dilated cardiomyopathy with dilated ventricles, reduced ejection fraction, and reduced fractional shortening. Deposition of iron may occur in the entire cardiac conduction system, especially the atrioventricular node. Cardiac hemochromatosis should be considered in any patient with unexplained heart failure. Screening for systemic iron overload with serum ferritin and transferin saturation should be performed. If these tests are consistent with iron overload, further noninvasive and histologic confirmation is indicated to confirm organ involvement with iron overload. Cardiac magnetic resonance imaging is superior to other diagnostic tests since it can quantitatively assess myocardial iron load. Therapeutic phlebotomy is the therapy of choice in nonanemic patients with cardiac hemochromatosis. Therapeutic phlebotomy should be started in men with serum ferritin levels of 300 µg/l or more and in women with serum ferritin levels of 200 µg/l or more. Therapeutic phlebotomy consists of removing 1 unit of blood (450 to 500 ml) weekly until the serum ferritin level is 10 to 20 µg/l and maintenance of the serum ferritin level at 50 µg/l or lower thereafter by periodic removal of blood. Phlebotomy is not a treatment option in patients with anemia (secondary iron-overload disorders) nor in patients with severe congestive heart failure. In these patients, the treatment of choice is iron chelation therapy.

hemochromatosis, cardiomyopathy, iron overload

Cheng CF, Lian WS. Prooxidant mechanisms in iron overload cardiomyopathy. Biomed Res Int 2013; 2013: 740573.
Lakhal-Littleton S, Wolna M, Carr CA, et al. Cardiac ferroportin regulates cellular iron homeostasis and is important for cardiac function. Proc Natl Acad Sci USA 2015; 112: 3164-9.
Skinner C, Kenmure AC. Haemochromatosis presenting as congestive cardiomyopathy and responding to venesection. Br Heart J 1973; 35: 466-8.
Cascales A, Sanchez-Vega B, Navarro N, et al. Clinical and genetic determinants of anthracycline-induced cardiac iron accumulation. Int J Cardiol 2012; 154: 282-6.
Furth PA, Futterweit W, Gorlin R. Refractory biventricular heart failure in secondary hemochromatosis. Am J Med Sci 1985; 290: 209-13.
Wasserman AJ, Richardson DW, Baird CL, et al. Cardiac hemochromatosis simulating constrictive pericarditis. Am J Med 1962; 32: 316-23.
Feely J, Counihan TB. Haemochromatosis presenting as angina and responding to venesection. Br Med J 1977; 2: 681-2.
Aronow WS, Meister L, Kent JR. Atrioventricular block in familial hemochromatosis treated by permanent synchronous pacemaker. Arch Intern Med 1969; 123: 433-5.
Wu VC, Huang JW, Wu MS, et al. The effect of iron stores on corrected QT dispersion in patients undergoing peritoneal dialysis. Am J Kidney Dis 2004; 44: 720-8.
Rose RA, Sellan M, Simpson JA, et al. Iron overload decreases CaV1.3-dependent L-type Ca2+ currents leading to bradycardia, altered electrical conduction, and atrial fibrillation. Circ Arrhythm Electrophysiol 2011; 118: 174-7.
Klintschar M, Stiller D. Sudden cardiac death in hereditary hemochromatosis: an underestimated cause of death? Int J Legal Med 2004; 118: 174-7.
Campbell S, George DK, Robb SD, et al. The prevalence of haemochromatosis gene mutations in the West of Scotland and their relation to ischaemic heart disease. Heart 2003; 89: 1023-6.
Candore G, Balistreri CR, Lio D, et al. Association between HFE mutations and acute myocardial infarction: a study in patients from Northern and Southern Italy. Blood Cells Mol Dis 2003; 31: 57-62.
Schmitt B, Golub RM, Green R. Screening primary care patients for hereditary hemochromatosis with transferrin saturation and serum ferritin level: systematic review for the American College of Physicians. Ann Intern Med 2005; 143: 522-36.
Qaseem A, Aronson M, Fitterman N, et al. Assessment subcommittee of the American College of Physicians Screening for hereditary hemochromatosis: a clinical practice guideline from the American College of Physicians. Ann Intern Med 2005; 143: 517-21.
Tran T, Eubanks SK, Schaffer KJ, et al. Secretion of ferritin by rat hepatoma cells and its regulation by inflammatory cytokines and iron. Blood 1997; 90: 4979-86.
Brownell A, Lowson S, Brozovic M. Serum ferritin concentration in sickle cell crisis. J Clin Pathol 1986; 39: 253-5.
Balkan C, Tuluce SY, Basol G, et al. Relation between NT-proBNP levels, iron overload, and early stage of myocardial dysfunction in beta-thalassemia major patients. Echocardiography 2012; 29: 318-25.
Hahalis G, Manolis AS, Apostolopoulos D, et al. Right ventricular cardiomyopathy in beta-thalassaemia major. Eur Heart J 2002; 23: 147-56.
Aessopos A, Farmakis D, Deftereos S, et al. Thalasse­mia heart disease: a comparative evaluation of thalassemia major and thalassemia intermedia. Chest 2005; 127: 1523-30.
Palka P, Macdonald G, Lange A, et al. The role of Doppler left ventricular filling indexes and Doppler tissue echocardiography in the assessment of cardiac involvement in hereditary hemochromatosis. J Am Soc Echocardiogr 2002; 15: 884-90.
Wood JC. Magnetic resonance imaging measurement of iron overload. Curr Opin Hematol 2007; 14: 183-90.
Mavrogeni SI, Gotsis ED, Markussis V, et al. T2 relaxation time study of iron overload in beta-thalassemia.
MAGMA 1998; 6: 7-12.
Anderson LJ, Holden S, Davis B, et al. Cardiovascular T2-star (T2*) magnetic resonance for the early diagnosis of myocardial iron overload. Eur Heart J 2001; 22: 2171-9.
Wood JC. History and current impact of cardiac magnetic resonance imaging on the management of iron overload. Circulation 2009; 120: 1937-9.
Pepe A, Positano V, Santarelli MF, et al. Multislice multiecho T2* cardiovascular magnetic resonance for detection of the heterogeneous distribution of myocardial iron overload. J Magn Reson Imaging 2006; 23: 662-8.
Kirk P, Roughton M, Porter JB, et al. Cardiac T2* magnetic resonance for prediction of cardiac complications in thalassemia major. Circulation 2009; 120: 1961-8.
Mavrogeni S, Gotsis E, Verganelakis D, et al. Effect of iron overload on exercise capacity in thalassemic patients with heart failure. Int J Cardiovasc Imaging 2009; 25: 777-83.
Cheong B, Huber S, Muthupillai R, et al. Evaluation of myocardial iron overload by T2* cardiovascular magnetic resonance imaging. Tex Heart Inst J 2005; 32: 448-9.
Kremastinos DT, Farmakis D. Iron overload cardiomyopathy in clinical practice. Circulation 2011; 124: 2253-63.
Gujjaosing DR, Tripodi DJ, Shizukuda Y. Iron overload cardiomyopathy: better understanding of an increasing disorder. J Am Coll Cardiol 2010; 56: 1001-12.
Mavrogeni S, Markousis-Mavrogenis G, Markussis V, Kolovou G. The emerging role of cardiovascular magnetic resonance imaging in the evaluation of metabolic cardiomyopathies. Horm Metab Res 2015; 47: 623-32.
Olson LJ, Edwards WD, Holmes DR Jr, et al. Endomyocardial biopsy in hemochromatosis: clinicopathologic correlaes in six cases. J Am Coll Cardiol 1989; 13: 116-20.
Cooper LT, Baughman KL, Feldman AM, et al. The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology endorsed by the Heart Failure Society of America and the Heart Failure Society of the European Society of Cardiology. Eur Heart J 2007; 28: 3076-93.
Rivers J, Garrahy P, Robinson W, et al. Reversible cardiac dysfunction in hemochromatosis. Am Heart J 1987; 113: 216-7.
Easley RM Jr, Screiner BF Jr, Yu PN. Reversible cardiomyopathy associated with hemochromatosis. N Engl J Med 1972; 287: 866-7.
Niederau C, Fischer R, Sonnenberg A, et al. Survival and causes of death in cirrhotic and in noncirrhotic patients with primary hemochromatosis. N Engl J Med 1985; 313: 1256-62.
Rahko PS, Salerni R, Uretsky BF. Successful reversal by chelation therapy of congestive cardiomyopathy due to iron overload. J Am Coll Cardiol 1986; 8: 436-40.
Barton JC, McDonnell SM, Adams PC, et al. Management of hemochromatosis. Ann Intern Med 1998; 129: 932-9.
Jomova K, Valko M. Importance of iron chelation in free radical-induced oxidative stress and human disease. Curr Pharm Des 2011; 17: 3460-73.
Crosby WH. Hemochromatosis. Treatment to alleviate injury. Arch Intern Med 1986; 146: 1910-1.
Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guidelines for the management of heart failure: executive summary. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Developed in collaboration with the American College of Chest Physicians, Heart Rhythm Society, and International Society for Heart and Lung Transplantation. Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation. J Am Coll Cardiol 2013; 62: 1495-539.
Adams PC, Barton JC. How I treat hemochromatosis. Blood 2010; 116: 317-25.
Pietrangelo A. Non-HFE hemachromatosis. Hepatology 2004; 39: 21-9.
Bacon BR, Adams PC, Kowdley KV, et al. American Association for the Study of liver diseases. Diagnosis and management of hemochromatosis: 2011 practice guidelines by the American Association for the Study of Liver Diseases. Hepatology 2011; 54: 328-43.
Adams PC, Kertesz AE, Valberg LS. Rate of iron reaccumulation following iron depletion in hereditary hemochromatosis. Implications for venesection therapy. J Clin Gastroenterol 1993; 16: 207-10.
Shizukuda Y, Bolan CD, Tripodi DJ, et al. Significance of left atrial contractile function in asumptomatic subjects with hereditary hemochromatosis. Am J Cardiol 2006; 98: 954-9.
Dabestani A, Child JS, Henze E, et al. Primary hemochromatosis: anatomic and physiologic characteristics of the cardiac ventricles and their response to phlebotomy. Am J Cardiol 1984; 54: 153-9.
Cecchetti G, Binda A, Piperno A, et al. Cardiac alterations in 36 consecutive patients with idiopathic haemochromatosis: polygraphic and echocardiographic evaluation. Eur Heart J 1991; 12: 224-30.
Fabio G, Minonzio F, Delbini P, et al. Reversal of cardiac complications by deferiprone and deferoxamine combination therapy in a patient affected by a severe type of juvenile hemochromatosis (JH). Blood 2007; 109: 362-4.
Kontoghiorghes GL, Eracleous E, Economides C, et al. Advances in iron overload therapies: prospects for effective use of deferiprone (L1), deferoxamine, the new experimental chelators ICL670, GT56-252, LINA11 and their combinations. Curr Med Chem 2005; 12: 2663-81.
Glickstein H, El RB, Link G, et al. Action of chelators in iron-loaded cardiac cells: accessibility to intracellular labile iron and functional consequences. Blood 2006; 108: 3195-203.
Kontoghiorghes GL, Kolnagou A, Peng CT, et al. Safety issues of iron chelation therapy in patients with normal range iron stores including thalassemia, neurodegenerative, renal and infectious diseases. Expert Opin Drug Saf 2010; 9: 201-6.
Olivieri NF, Brittenham GM. Iron-chelating therapy and the treatment of thalassemia. Blood 1997; 89: 739-61.
Mamtani M, Kulkarni H. Influence of iron chelators on myocardial iron and cardiac function in transfusion-dependent thalassemia: a systematic review and meta-analysis. Br J Haematol 2008; 141: 882-90.
Davis BA, O’Sullivan C, Jarritt PH, et al. Value of sequential monitoring of left ventricular ejection fraction in the management of thalassemia major. Blood 2004; 104: 263-9.
Anderson LJ, Westwood MA, Holden S, et al. Myocardial iron clearance during reversal of siderotic cardiomyopathy with intravenous desferrioxamine: a prospective study using T2* cardiovascular magnetic resonance. Br J Haematol 2004; 127: 348-55.
Pennell DJ, Carpenter JP, Roughton M, et al. On improvement in ejection fraction with iron chelation in thalassemia major and the risk of future heart failure. J Cardiovasc Magn Reson 2011; 13: 45.
Modell B, Khan M, Darlison M. Survival in beta-thalassemia major in the UK: data from the UK Thalassaemia Register. Lancet 2000; 355: 2051-2.
Pepe A, Rossi G, Capra M, et al. A T2* MRI prospective survey on heart and liver iron in thalassemia major patients treated with deferasirox versus deferiprone and desferrioxamine in monotherapy (abstract 4267). Blood 2010; 116: 1731.
Pepe A, Meloni A, Capra M, et al. Deferasirox, deferiprone and desferrioxamine treatment in thalassemia major patients: cardiac iron and function comparison determined by quantitative magnetic resonance imaging. Haematologica 2011; 96: 41-7.
Beris P. Introduction: management of thalassemia. Semin Hematol 1995; 32: 243.
Farmaki K, Tzoumari I, Pappa C, et al. Normalisation of total body iron load with very intensive combined chelation reverses cardiac and endocrine complications of thalassaemia major. Br J Haematol 2010; 148: 466-75.
Tanner MA, Galanello R, Dessi C, et al. Combined chelation therapy in thalassemia major for the treatment of severe myocardial siderosis with left ventricular dysfunction. J Cardiovasc Magn Reson 2008; 10: 12.
Chirnomas D, Smith AL, Braunstein J, et al. Deferasirox pharmacokinetics in patients with adequate versus inadequate response. Blood 2009; 114: 4009-13.
Cappellini MD, Cohen A, Piga A, et al. A phase 3 study of deferasirox (ICL670), a once-daily oral iron chelator, in patients with beta-thalassemia. Blood 2006; 107: 3455-62.
Pennell DJ, Porter JB, Cappellini MD, et al. Efficacy of deferasirox in reducing and preventing cardiac iron overload in beta-thalassemia. Blood 2010; 115: 2364-71.
Cappellini MD, Bejaoui M, Agaoglu L, et al. Iron chelation with deferasirox in adult and pediatric patients with thalassemia major: efficacy and safety during 5 years’ follow-up. Blood 2011; 118: 884-93.
Pennell DJ, Porter JB, Cappellini MD, et al. Deferasirox for up to 3 years leads to continued improvement of myocardial T2* in patients with beta-thalassemia major. Haematologica 2012; 97: 842-8.
Wood JC, Kang BP, Thompson A, et al. The effect of deferasirox on cardiac iron in thalassemia major: impact of total body iron stores. Blood 2010; 116: 537-43.
Borsari M, Gabbi C, Ghelfi F, et al. Silybin, a new iron-chelating agent. J Inorg Biochem 2001; 85: 123-9.
Barton JC. Drug evaluation: deferitrin (GT-56-252; NaHBED) for iron overload disorders. IDrugs 2007; 10: 270-81.
Harmatz P, Grady RW, Dragsten P, et al. Phase 1b clinical trial of starch-conjugated deferoxamine (40SD02): a novel long-acting iron chelator. Br J Haematol 2007; 138: 374-81.
El Sayed SM, Abou-Taleb A, Mahmoud HS, et al. Percutaneous excretion of iron and ferritin (through Al-hijamah) as a novel treatment for iron overload in beta-thalassemia major, hemochromatosis and sideroblastic anemia. Med Hypotheses 2014; 83: 238-46.
McLaran CJ, Bett JH, Nye JA, et al. Congestive cardiomyopathy and haemochromatosis-rapid progression possibly accelerated by excessive ingestion of ascorbic acid. Aust N Z J Med 1982; 12: 187-8.
Herbert V. Hemochromatosis and vitamin C. Ann Intern Med 1999; 131: 475-6.
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: 543-9.
Conrad ME, Barton JC. Anemia and iron kinetics in alcoholism. Semin Hematol 1980; 17: 149-63.
Celada A, Rudolph H, Donath A. Effect of experimental chronic alcohol ingestion and folic acid deficiency on iron absorption. Blood 1979; 54: 906-15.
Mariani R, Pelucchi S, Perseghin P, et al. Erythrocytapheresis plus erythropoietin: an alternative therapy for selected patients with hemochromatosis and severe organ damage. Haematologica 2005; 90: 717-8.
Kohan A, Niborski R, Daruich J, et al. Erythrocytapheresis with recombinant human erythropoietin in hereditary hemochromatosis therapy: a new alternative. Vox Sang 2000; 79: 40-5.
Muncunill J, Vaquer P, Galmes A, et al. In hereditary hemochromatosis, red cell apheresis removes excess iron twice as fast as manual whole blood phlebotomy. J Clin Apher 2002; 17: 88-92.
Rombout-Sestrienkova E, van Noord PA, van Deursen CT, et al. Therapeutic erythrocytapheresis versus phlebotomy in the initial treatment of heredtary hemochromatosis – a pilot study. Transfus Apher Sci 2007; 36: 261-7.
Rombout-Sestrienkova E, De Jonge N, Martinakova K, et al. End-stage cardiomyopathy because of hereditary hemochromatoss successfully treated with erythrocytapheresis in combination with left ventricular assist device support. Circ Heart Fail 2014; 7: 541-3.
Pennell DJ, Udelson JE, Arai AE, et al. Cardiovascular function and treatment in beta-thalassemia major: a consensus statement from the American Heart Association. Circulation 2013; 128: 281-308.
Caines AE, Kpodonu J, Massad MG, et al. Cardiac transplantation in patients with iron overload cardiomyopathy. J Heart Lung Transplant 2005; 24: 486-8.
Jermyn R, Soe E, D’Alessandro D, et al. Cardiac failure after liver transplantation requiring a biventricular assist device. Case Rep Transplant 2014; 2014: 946961.
Raichlin E, Daly RC, Rosen CB, et al. Combined heart and liver transplantation: a single-center experience. Transplantation 2009; 88: 219-25.
Kuppahally SS, Hunt SA, Valantine HA, et al. Recurrence of iron deposition in the cardiac allograft in a patient with non-HFE hemochromatosis. J Heart Lung Transplant 2006; 25: 144-7.
Garcia-Manero G. Myelodysplastic syndromes: 2012 update on diagnosis, risk-stratification, and management. Am J Hematol 2012; 87: 692-701.
Bernaudin F, Socie G, Kuentz M, et al.; SFGM-TC. Long-term results of related myeloablative stem-cell transplantation to cure sickle cell disease. Blood 2007; 110: 2749-56.
Elborai Y, Uwumugambi A, Lehmann L. Hematopoietic stem cell transplantation for thalassemia. Immunotherapy 2012; 4: 947-56.
Mugishima H, Ohga S, Ohara A, et al. Aplastic Anemia Committee of the Japanese Society of Pediatric Hematology. Hematopoietic stem cell transplantation for Diamond-Blackfan anemia: a report from the Aplastic Anemia Committee of the Japanese Society of Pediatric Hematology. Pediatr Transplant 2007; 11: 601-7.
Oudit GY, Sun H, Trivieri MG, et al. L-type Ca2+ channels provide a major pathway for iron entry into cardiomyocytes in iron-overload cardiomyopathy. Nat Med 2003; 9: 1187-94.
Murphy CJ, Oudit GY. Iron-overload cardiomyopathy: pathophysiology, diagnosis, and treatment. J Card Fail 2010; 16: 888-90.
Kumfu S, Chattipakorn S, Srichairatanakool S, et al. T-type calcium channel as a portal of iron uptake into cardiomyocytes of beta-thalassemic mice. Eur J Haematol 2011; 86: 156-66.
Crowe S, Bartfay WJ. Amlodipine decreases iron uptake and oxygen free radical production in the heart of chronically iron overloaded mice. Biol Res Nurs 2002; 3: 189-97.
Kumfu S, Chattipakorn S, Chinda K, et al. T-type calcium channel blockade improves survival and cardiovascular function in thalassemic mice. Eur J Haematol 2012; 88: 535-48.
Viatte L, Nicolas G, Lou DQ, et al. Chronic hepcidin induction causes hyposideremia and alters the pattern of cellular iron accumulation in hemochromatotic mice. Blood 2006; 107: 2952-8.
Brissot P, Bardou-Jacquet E, Jouanolic AM, et al. Iron disorders of genetic origin: a changing world. Trends Mol Med 2011; 17: 707-13.
Gardenghi S, Ramos P, Marongiu MF, et al. Hepcidin as a therapeutic tool to limit iron overload and improve anemia in beta-thalassemic mice. J Clin Invest 2010; 120: 4466-77.
Musallam KM, Cappellini MD, Wood JC, Taher AT. Iron overload in non-transfusion-dependent thalassemia: a clinical perspective. Blood Rev 2012; 26 (Suppl 1): S16-9.
Camaschella C. Treating iron overload. N Engl J Med 2013; 368: 2325-7.
Ramos E, Ruchala P, Goodnough JB, et al. Minihepcidins prevent iron overload in a hepcidin-deficient mouse model of severe hemochromatosis. Blood 2012; 12: 3829-36.
Gelderman MP, Baek JH, Yalananoglu A, et al. Reversal of hemochromatosis by apotransferrin in non-transfused and transfused Hbbth3/+ (heterozygous B1/B2 globin gene deletion) mice. Haematologica 2015; 100: 611-22.
Payen E, Lebouich P. Advances in stem cell transplantation and gene therapy in the beta-hemoglobinopathies. Hematol Am Soc Hematol Educ Program 2012; 2012: 276-83.
Townes TM. Gene replacement therapy for sickle cell disease and other blood disorders. Hematol Am Soc Hematol Educ Program 2008; 193-6.
Ezquer F, Nunez MT, Rojas A, et al. Hereditary hemochromatosis: an opportunity for gene therapy. Biol Res 2006; 39: 113-24.
Lucijanic M, Pejsa V, Mitrovic Z, et al. Hemochromatosis gene mutations may affect the survival of patients with myelodysplastic syndrome. Hematology 2015; May 4 ahead of print.
Quick links
© 2019 Termedia Sp. z o.o. All rights reserved.
Developed by Bentus.
PayU - płatności internetowe