Metabolic and Genetic Liver Diseases: Hemochromatosis

  • Matthew J. StottsEmail author
  • Bruce R. Bacon


Hereditary hemochromatosis is considered the most common genetic disorder identified in Caucasians. Inherited in an autosomal recessive fashion, patients homozygous for C282Y and occasionally those who are compound heterozygotes (C282Y/H63D) are at risk for developing iron overload. Patients with progressive iron overload may develop nonspecific symptoms including fatigue, and can eventually develop arthropathy, hypogonadism, and complications of chronic liver disease, diabetes, and heart failure.

With early diagnosis and treatment, patients can expect to have a normal life span. This underscores the importance of identifying patients with the disease and initiating treatment as early as possible. To identify these patients, those with abnormal iron or liver function tests—as well as those with any signs or symptoms of hemochromatosis—should be evaluated with serum iron studies and, if abnormal (either an elevated ferritin or a transferrin saturation of ≥45 %), with HFE mutation analysis. When a first degree family member has the diagnosis, HFE mutation analysis and serum iron studies should be done simultaneously.

If a patient is diagnosed with hemochromatosis and has an elevated ferritin, therapeutic phlebotomy should be initiated. Those with advanced disease may require screening for hepatocellular carcinoma and may require management of complications of chronic liver disease.


Hemochromatosis HFE C282Y H63D Iron Iron overload Cirrhosis Phlebotomy 


  1. 1.
    Sarigianni M, Liakos A, Vlachaki E, Paschos P, Athanasiadou E, Montori VM, et al. Accuracy of magnetic resonance imaging in diagnosis of liver iron overload: a systemic review and meta-analysis. Clin Gastroenterol Hepatol. 2015;13(1):55–63.Google Scholar
  2. 2.
    Bacon BR. Measurement of hepatic iron concentration. Clin Gastroenterol Hepatol. 2014; 13(1):64–65.Google Scholar
  3. 3.
    Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy DA, Basava A, et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet. 1996;13(4):399–408.CrossRefPubMedGoogle Scholar
  4. 4.
    European Association for the Study of the Liver. EASL clinical practice guidelines for HFE hemochromatosis. J Hepatol. 2010;53(1):3–22.CrossRefGoogle Scholar
  5. 5.
    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(1):328–43.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Adams PC, Barton JC. Haemochromatosis. Lancet. 2007;370(9602):1855–60.CrossRefPubMedGoogle Scholar
  7. 7.
    Pietrangelo A. Hereditary hemochromatosis: a new look at an old disease. N Engl J Med. 2004;350(23):2383–97.CrossRefPubMedGoogle Scholar
  8. 8.
    Niederau C, Fischer R, Purschel A, Stremmel W, Haussinger D, Strohmeyer G. Long-term survival in patients with hereditary hemochromatosis. Gastroenterology. 1996;110(4):1107–19.CrossRefPubMedGoogle Scholar
  9. 9.
    Adams PC, Reboussin DM, Barton JC, McLaren CE, Eckfeldt JH, McLaren GD, et al. Hemochromatosis and iron-overload screening in a racially diverse population. N Engl J Med. 2005;352(17):1769–78.CrossRefPubMedGoogle Scholar
  10. 10.
    Phatak PD, Bonkovsky HL, Kowdley KV. Hereditary hemochromatosis: time for targeted screening. Ann Intern Med. 2008;149(4):270–2.CrossRefPubMedGoogle Scholar
  11. 11.
    Allen KJ, Gurrin LC, Constantine CC, Osborne NJ, Delatycki MB, Nicoll AJ, et al. Iron-overload-related disease in HFE hereditary hemochromatosis. N Engl J Med. 2008;358(3):221–30.CrossRefPubMedGoogle Scholar
  12. 12.
    Beutler E, Felitti VJ, Koziol JA, Ho NJ, Gelbart T. Penetrance of 845 G → A (C282Y) HFE hereditary hemochromatosis mutation in the USA. Lancet. 2002;359(9302):211–8.CrossRefPubMedGoogle Scholar
  13. 13.
    Adams P, Brissot P, Powell LW. EASL international consensus conference on haemochromatosis. J Hepatol. 2000;33(3):485–504.CrossRefPubMedGoogle Scholar
  14. 14.
    Fleming RE, Britton RS, Waheed A, Sly WS, Bacon BR. Pathogenesis of hereditary hemochromatosis. Clin Liver Dis. 2004;8(4):755–73.CrossRefPubMedGoogle Scholar
  15. 15.
    Nemeth E, Ganz T. The role of hepcidin in iron metabolism. Acta Haematol. 2009;122(2–3):78–86.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, et al. Hepcidin regulates cellular efflux by binding to ferroportin and inducing its internalization. Science. 2004;306(5704):2090–3.CrossRefPubMedGoogle Scholar
  17. 17.
    Fleming RE, Britton RS. Iron imports. VI. HFE and regulation of intestinal iron absorption. Am J Physiol Gastrointest Liver Physiol. 2006;290(4):G590–4.CrossRefPubMedGoogle Scholar
  18. 18.
    Waheed A, Parkkila S, Saarnio J, Fleming RE, Zhou XY, Tomatsu S, et al. Association of HFE protein with transferrin receptor in crypt enterocytes of human duodenum. Proc Natl Acad Sci U S A. 1999;96(4):1579–84.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Goswami T, Andrews NC. Hereditary hemochromatosis protein, HFE, interaction with transferrin receptor 2 suggests a molecular mechanism for mammalian iron sensing. J Biol Chem. 2006;281(39):28494–8.CrossRefPubMedGoogle Scholar
  20. 20.
    Ganz T. Iron homeostasis: fitting the puzzle pieces together. Cell Metab. 2008;7(4):288–90.CrossRefPubMedGoogle Scholar
  21. 21.
    Fleming RE, Bacon BR. Orchestration of iron homeostasis. N Engl J Med. 2005;352(17):1741–4.CrossRefPubMedGoogle Scholar
  22. 22.
    Bacon BR, Tavill AS, Brittenham GM, Park CH, Recknagel RO. Hepatic lipid peroxidation in vivo in rats with chronic iron overload. J Clin Invest. 1983;71(3):429–39.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Bacon BR, Britton RS. The pathology of hepatic iron overload: a free radical-mediated process? Hepatology. 1990;11(1):127–37.CrossRefPubMedGoogle Scholar
  24. 24.
    Philippe MA, Ruddell RG, Ramm GA. Role of iron in hepatic fibrosis: one piece in the puzzle. World J Gastroenterol. 2007;13(35):4746–54.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Edwards CQ, Cartwright GE, Skolnick MH, Amos DB. Homozygosity for hemochromatosis: clinical manifestations. Ann Intern Med. 1980;93(4):519–25.CrossRefPubMedGoogle Scholar
  26. 26.
    Milder MS, Cook JD, Stray S, Finch CA. Idiopathic hemochromatosis, an interim report. Medicine (Baltimore). 1980;59(1):34–49.CrossRefGoogle Scholar
  27. 27.
    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(20):1256–62.CrossRefPubMedGoogle Scholar
  28. 28.
    Adams PC, Kertesz AE, Valberg LS. Clinical presentation of hemochromatosis: a changing scene. Am J Med. 1991;90(4):445–9.CrossRefPubMedGoogle Scholar
  29. 29.
    Bacon BR, Sadiq SA. Hereditary hemochromatosis: presentation and diagnosis in the 1990s. Am J Gastroenterol. 1997;92(5):784–9.PubMedGoogle Scholar
  30. 30.
    Bassett ML, Halliday JW, Ferris RA, Powell LW. Diagnosis of hemochromatosis in young subjects: predictive accuracy of biochemical screening tests. Gastroenterology. 1984;87(3):628–33.PubMedGoogle Scholar
  31. 31.
    Morrison ED, Brandhagen DJ, Phatak PD, Barton JC, Krawitt EL, El-Seraq HB, et al. Serum ferritin level predicts advanced hepatic fibrosis among U.S. patients with phenotypic hemochromatosis. Ann Intern Med. 2003;138(8):627–33.CrossRefPubMedGoogle Scholar
  32. 32.
    Powell LW, Dixon JL, Ramm GA, Purdie DM, Lincoln DJ, Anderson GJ, et al. Screening for hemochromatosis in asymptomatic subjects with or without a family history. Arch Intern Med. 2006;166(3):294–301.CrossRefPubMedGoogle Scholar
  33. 33.
    Bacon BR, Olynyk JK, Brunt EM, Britton RS, Wolff RK. HFE genotype in patients with hemochromatosis and other liver diseases. Ann Intern Med. 1999;130(12):953–62.CrossRefPubMedGoogle Scholar
  34. 34.
    Fletcher LM, Dixon JL, Purdie DM, Powell LW, Crawford DH. Excess alcohol greatly increases the prevalence of cirrhosis in hereditary hemochromatosis. Gastroenterology. 2002;122(2):281–9.CrossRefPubMedGoogle Scholar
  35. 35.
    Brunt EM. Pathology of hepatic iron overload. Semin Liver Dis. 2005;25(4):392–401.CrossRefPubMedGoogle Scholar
  36. 36.
    Lynch SR, Cook JD. Interaction of vitamin C and iron. Ann N Y Acad Sci. 1980;355:32–44.CrossRefPubMedGoogle Scholar
  37. 37.
    Brittenham GM, Klein HG, Kushner JP, Ajioka RS. Preserving the national blood supply. Hematol Am Soc Hematol Educ Program. 2001;1:422–32.Google Scholar
  38. 38.
    Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology. 2005;42(5):1208–36.CrossRefPubMedGoogle Scholar
  39. 39.
    Ashrafian H. Hepcidin: the missing link between hemochromatosis and infections. Infect Immun. 2003;71(12):6693–700.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Poulos JE, Bacon BR. Liver transplantation for hereditary hemochromatosis. Dig Dis. 1996;14(5):316–22.CrossRefPubMedGoogle Scholar
  41. 41.
    Farrell FJ, Nguyen M, Woodley S, Imperial JC, Garcia-Kennedy R, Man K, et al. Outcome of liver transplantation in patients with hemochromatosis. Hepatology. 1994;20(2):404–10.CrossRefPubMedGoogle Scholar
  42. 42.
    Yu L, Ioannou GN. Survival of liver transplant recipients with hemochromatosis in the United States. Gastroenterology. 2007;133(2):489–95.CrossRefPubMedGoogle Scholar
  43. 43.
    Gochee PA, Powell LW, Cullen DJ, Du Sart D, Rossi E, Olynyk JK. A population-based study of the biochemical and clinical expression of the H63D hemochromatosis mutation. Gastroenterology. 2002;122(3):646–51.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2017

Authors and Affiliations

  1. 1.Banner HealthColoradoUSA
  2. 2.Division of Gastroenterology & HepatologySt. Louis UniversitySaint LouisUSA

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