Management of patients with hereditary hemochromatosis
- Stanley L Schrier, MD
Stanley L Schrier, MD
- Editor-in-Chief — Hematology
- Section Editor — Myeloproliferative Disorders; Red Cell Disorders
- Professor of Medicine
- Stanford University School of Medicine
- Bruce R Bacon, MD
Bruce R Bacon, MD
- Professor of Internal Medicine
- Saint Louis University School of Medicine
Hereditary hemochromatosis (HH, genetic hemochromatosis) is an inherited disorder in which mutations in the HFE gene or, less commonly, hemojuvelin, hepcidin, ferroportin, or ceruloplasmin genes (table 1), result in increased intestinal iron absorption, iron overload, and, in advanced disease, tissue damage. The treatment of HH will be discussed here. The genetics, pathophysiology, clinical manifestations, diagnosis, and issues related to screening for HH are discussed separately. (See "Genetics of hereditary hemochromatosis" and "Clinical manifestations and diagnosis of hereditary hemochromatosis" and "Approach to the patient with suspected iron overload" and "Screening for hereditary hemochromatosis".)
RATIONALE FOR TREATMENT
Symptomatic patients — Although there have been no randomized, controlled studies of phlebotomy versus observation in patients with HH, the following observations provide strong support for the early treatment of symptomatic HH using this modality.
Effect on survival — The major causes of death in symptomatic HH are decompensated cirrhosis, hepatocellular carcinoma (HCC), diabetes mellitus, and cardiomyopathy [1-3], with HCC being responsible for approximately 45 percent of all deaths in patients with HH . A number of observational studies have indicated that these complications can be minimized, or even avoided, when adequate treatment (ie, phlebotomy) is initiated when this disorder is promptly diagnosed and treated. As an example, with few exceptions, those with HH and HCC do so in the presence of cirrhosis, consistent with observations that treatment of HH prior to the development of cirrhosis has a major impact on overall survival in this disorder. (See 'Prognosis' below.)
●An early study, reported in 1976, in 85 patients with HH treated with phlebotomy as compared with a historical group of 26 untreated patients, indicated significantly longer five-year (66 versus 18 percent) and 10-year (32 versus 6 percent) overall survivals for the treated group . Of interest, 10 of the 85 treated patients, all of whom had cirrhosis at the time of diagnosis, died of HCC 3 to 15 years later, despite having received treatment with phlebotomy.
●In an observational study of 163 patients with HH, survival was similar to that of a normal population in the 51 patients in whom treatment (eg, phlebotomy) was initiated before the development of cirrhosis or diabetes [1,2]. Further, overall survival was markedly reduced in those patients who could not be depleted of iron during the first 18 months of phlebotomy therapy, as compared with those who could be depleted during this time interval.
- 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.
- Niederau C, Fischer R, Pürschel A, et al. Long-term survival in patients with hereditary hemochromatosis. Gastroenterology 1996; 110:1107.
- Fargion S, Fracanzani AL, Piperno A, et al. Prognostic factors for hepatocellular carcinoma in genetic hemochromatosis. Hepatology 1994; 20:1426.
- Kew MC. Hepatic iron overload and hepatocellular carcinoma. Liver Cancer 2014; 3:31.
- Bomford A, Williams R. Long term results of venesection therapy in idiopathic haemochromatosis. Q J Med 1976; 45:611.
- Milman N, Pedersen P, á Steig T, et al. Clinically overt hereditary hemochromatosis in Denmark 1948-1985: epidemiology, factors of significance for long-term survival, and causes of death in 179 patients. Ann Hematol 2001; 80:737.
- Fracanzani AL, Fargion S, Romano R, et al. Portal hypertension and iron depletion in patients with genetic hemochromatosis. Hepatology 1995; 22:1127.
- Powell LW, Dixon JL, Ramm GA, et al. Screening for hemochromatosis in asymptomatic subjects with or without a family history. Arch Intern Med 2006; 166:294.
- Rivers J, Garrahy P, Robinson W, Murphy A. Reversible cardiac dysfunction in hemochromatosis. Am Heart J 1987; 113:216.
- Easley RM Jr, Schreiner BF Jr, Yu PN. Reversible cardiomyopathy associated with hemochromatosis. N Engl J Med 1972; 287:866.
- 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.
- Kelly TM, Edwards CQ, Meikle AW, Kushner JP. Hypogonadism in hemochromatosis: reversal with iron depletion. Ann Intern Med 1984; 101:629.
- Siemons LJ, Mahler CH. Hypogonadotropic hypogonadism in hemochromatosis: recovery of reproductive function after iron depletion. J Clin Endocrinol Metab 1987; 65:585.
- Cundy T, Butler J, Bomford A, Williams R. Reversibility of hypogonadotrophic hypogonadism associated with genetic haemochromatosis. Clin Endocrinol (Oxf) 1993; 38:617.
- Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 31-1994. A 25-year-old man with the recent onset of diabetes mellitus and congestive heart failure. N Engl J Med 1994; 331:460.
- Williams R, Smith PM, Spicer EJ, et al. Venesection therapy in idiopathic haemochromatosis. An analysis of 40 treated and 18 untreated patients. Q J Med 1969; 38:1.
- Dymock IW, Cassar J, Pyke DA, et al. Observations on the pathogenesis, complications and treatment of diabetes in 115 cases of haemochromatosis. Am J Med 1972; 52:203.
- Brandhagen DJ, Alvarez W, Therneau TM, et al. Iron overload in cirrhosis-HFE genotypes and outcome after liver transplantation. Hepatology 2000; 31:456.
- 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.
- Yu L, Ioannou GN. Survival of liver transplant recipients with hemochromatosis in the United States. Gastroenterology 2007; 133:489.
- Bulaj ZJ, Ajioka RS, Phillips JD, et al. Disease-related conditions in relatives of patients with hemochromatosis. N Engl J Med 2000; 343:1529.
- Beutler E, Felitti VJ, Koziol JA, et al. Penetrance of 845G--> A (C282Y) HFE hereditary haemochromatosis mutation in the USA. Lancet 2002; 359:211.
- Andersen RV, Tybjaerg-Hansen A, Appleyard M, et al. Hemochromatosis mutations in the general population: iron overload progression rate. Blood 2004; 103:2914.
- Olynyk JK, Hagan SE, Cullen DJ, et al. Evolution of untreated hereditary hemochromatosis in the Busselton population: a 17-year study. Mayo Clin Proc 2004; 79:309.
- Allen KJ, Bertalli NA, Osborne NJ, et al. HFE Cys282Tyr homozygotes with serum ferritin concentrations below 1000 microg/L are at low risk of hemochromatosis. Hepatology 2010; 52:925.
- Adams PC, Barton JC. How I treat hemochromatosis. Blood 2010; 116:317.
- van Bokhoven MA, van Deursen TB, Swinkels DW. Diagnosis and management of hereditary hemochromatosis. Br Med J 2011; 342:218.
- Bacon BR, Adams PC, Kowdley KV, et al. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology 2011; 54:328.
- Barton JC, McDonnell SM, Adams PC, et al. Management of hemochromatosis. Hemochromatosis Management Working Group. Ann Intern Med 1998; 129:932.
- Bardou-Jacquet E, Ben Ali Z, Beaumont-Epinette MP, et al. Non-HFE hemochromatosis: pathophysiological and diagnostic aspects. Clin Res Hepatol Gastroenterol 2014; 38:143.
- Pietrangelo A. Non-HFE hemochromatosis. Hepatology 2004; 39:21.
- Tan L, Khan MK, Hawk JC 3rd. Use of blood therapeutically drawn from hemochromatosis patients. Council on Scientific Affairs, American Medical Association. Transfusion 1999; 39:1018.
- Olynyk JK, Luxon BA, Britton RS, Bacon BR. Hepatic iron concentration in hereditary hemochromatosis does not saturate or accurately predict phlebotomy requirements. Am J Gastroenterol 1998; 93:346.
- Bolan CD, Conry-Cantilena C, Mason G, et al. MCV as a guide to phlebotomy therapy for hemochromatosis. Transfusion 2001; 41:819.
- Bacon BR, Powell LW, Adams PC, et al. Molecular medicine and hemochromatosis: at the crossroads. Gastroenterology 1999; 116:193.
- Tavill AS, American Association for the Study of Liver Diseases, American College of Gastroenterology, American Gastroenterological Association. Diagnosis and management of hemochromatosis. Hepatology 2001; 33:1321.
- European Association For The Study Of The Liver. EASL clinical practice guidelines for HFE hemochromatosis. J Hepatol 2010; 53:3.
- Bacon BR, Sadiq SA. Hereditary hemochromatosis: presentation and diagnosis in the 1990s. Am J Gastroenterol 1997; 92:784.
- Lynch SR, Skikne BS, Cook JD. Food iron absorption in idiopathic hemochromatosis. Blood 1989; 74:2187.
- Rombout-Sestrienkova E, Nieman FH, Essers BA, et al. Erythrocytapheresis versus phlebotomy in the initial treatment of HFE hemochromatosis patients: results from a randomized trial. Transfusion 2012; 52:470.
- 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.
- Muncunill J, Vaquer P, Galmés 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.
- 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.
- Rombout-Sestrienkova E, van Noord PA, van Deursen CT, et al. Therapeutic erythrocytapheresis versus phlebotomy in the initial treatment of hereditary hemochromatosis - A pilot study. Transfus Apher Sci 2007; 36:261.
- Grabmer C, Schmid D, Mayer G, et al. Iron depletion with a novel apheresis system in patients wth hemochromatosis. Transfusion 2015; 55:996.
- Nielsen P, Fischer R, Buggisch P, Janka-Schaub G. Effective treatment of hereditary haemochromatosis with desferrioxamine in selected cases. Br J Haematol 2003; 123:952.
- 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.
- Finkenstedt A, Wolf E, Höfner E, et al. Hepatic but not brain iron is rapidly chelated by deferasirox in aceruloplasminemia due to a novel gene mutation. J Hepatol 2010; 53:1101.
- Miyajima H, Takahashi Y, Kamata T, et al. Use of desferrioxamine in the treatment of aceruloplasminemia. Ann Neurol 1997; 41:404.
- 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.
- Hutchinson C, Geissler CA, Powell JJ, Bomford A. Proton pump inhibitors suppress absorption of dietary non-haem iron in hereditary haemochromatosis. Gut 2007; 56:1291.
- Celada A, Rudolf H, Donath A. Effect of experimental chronic alcohol ingestion and folic acid deficiency on iron absorption. Blood 1979; 54:906.
- Fletcher LM, Dixon JL, Purdie DM, et al. Excess alcohol greatly increases the prevalence of cirrhosis in hereditary hemochromatosis. Gastroenterology 2002; 122:281.
- McLaran CJ, Bett JH, Nye JA, Halliday JW. Congestive cardiomyopathy and haemochromatosis--rapid progression possibly accelerated by excessive ingestion of ascorbic acid. Aust N Z J Med 1982; 12:187.
- Herbert V. Hemochromatosis and vitamin C. Ann Intern Med 1999; 131:475.
- Elmberg M, Hultcrantz R, Ebrahim F, et al. Increased mortality risk in patients with phenotypic hereditary hemochromatosis but not in their first-degree relatives. Gastroenterology 2009; 137:1301.
- 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.
- Crooks CJ, West J, Solaymani-Dodaran M, Card TR. The epidemiology of haemochromatosis: a population-based study. Aliment Pharmacol Ther 2009; 29:183.
- RATIONALE FOR TREATMENT
- Symptomatic patients
- - Effect on survival
- - Effect on disease complications
- Asymptomatic patients
- - Family screening
- - Population screening
- MANAGEMENT OF HH
- Patients without iron overload
- Patients with iron overload
- - Schedule
- - Endpoints
- - Maintenance
- Iron chelation
- Dietary limitations
- - Dietary iron intake
- - Agents for reducing iron absorption
- - Avoidance of excessive ethanol
- - Avoidance of ascorbic acid (vitamin C) supplements
- - Avoidance of uncooked seafood
- Screening for hepatocellular carcinoma
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS