Hereditary hemochromatosis is characterized by iron accumulation in several tissues, i.e., in the parenchymal cells of the liver, heart, pancreas, and other endocrine organs. This toxic accumulation occurs as a result of increased intestinal uptake of dietary iron.

Hereditary hemochromatosis is a common disorder in France, Britain, Ireland, and Northern Europe. In the majority of cases, it is caused by a homozygous c.845G > A mutation in the HFE gene, located on chromosome 6p21.3, resulting in the C282Y change in the protein. The mutation is considered to have appeared about 1,500 years ago. The prevalence of C282Y homozygosity in Caucasians is about 1:250. However, the penetrance is low and depends on additional risk factors, e.g., male gender, alcohol use, and unknown factors. The age at disease onset is 40–50 years. Another mutation (H63D) in HFE may, when present as combined heterozygosity together with C282Y, cause steatosis or chronic hepatitis but with a less severe iron accumulation in the liver than in C282Y homozygosity. HFE protein is expressed in the crypt cells of duodenum and regulates iron transport by decreasing the iron uptake by transferrin.

The clinical picture of HFE-related hemochromatosis ranges from biochemical abnormalities in iron metabolism to severe disease with organ damage, including hepatosplenomegaly, liver cirrhosis, diabetes mellitus, hyperpigmentation, cardiomyopathy, and hypogonadism. Initial diagnostic findings are elevated serum iron levels with increased transferrin saturation and increased serum ferritin levels. Increased liver iron content verifies the diagnoses, assessed either with liver biopsy, specific iron content imaging, or magnetic resonance imaging. Diabetes mellitus is a risk factor for severe iron accumulation in HFE C287Y homozygotes.

In homozygotes for C287Y or in compound heterozygotes C287Y/H63D with increased serum ferritin level, treatment should be initiated with repeated blood withdrawings to achieve a serum ferritin level of 30–100 ug/L.


Serum Ferritin Level Iron Accumulation Transferrin Saturation Hereditary Hemochromatosis Idiopathic Pulmonary Hemosiderosis 
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  1. Bartnikas TB (2012) Known and potential roles of transferrin in iron biology. Biometals 25:677–686PubMedCentralPubMedCrossRefGoogle Scholar
  2. Cheng R, Barton JC, Morrison ED, Phatak PD, Krawitt EL et al (2009) Differences in hepatic phenotype between hemochromatosis patients with HFE C282Y homozygosity and other HFE genotypes. J Clin Gastroenterol 43:569–573PubMedCentralPubMedCrossRefGoogle Scholar
  3. Collardeau-Frachon S, Heissat S, Bouvier R, Fabre M, Baruteau J et al (2012) French retrospective multicentric study of neonatal hemochromatosis: importance of autopsy and autoimmune maternal manifestations. Pediatr Dev Pathol 15:450–470PubMedCrossRefGoogle Scholar
  4. Dogu O, Krebs C, Kaleagasi H, Demirtas Z, Oksuz N et al (2013) Rapid disease progression in adult-onset mitochondrial membrane protein-associated neurodegeneration. Clin Genet 84:350–355. doi: 10.1111/cge.12079 PubMedCrossRefGoogle Scholar
  5. Fellman V (2002) The GRACILE syndrome, a neonatal lethal metabolic disorder with iron overload. Blood Cells Mol Dis 29:444–450PubMedCrossRefGoogle Scholar
  6. Fellman V, Rapola J, Pihko H, Varilo T, Raivio KO (1998) Iron-overload disease in infants involving fetal growth retardation, lactic acidosis, liver haemosiderosis, and aminoaciduria. Lancet 351:490–493PubMedCrossRefGoogle Scholar
  7. Fellman V, Visapaa I, Vujic M, Wennerholm UB, Peltonen L (2002) Antenatal diagnosis of hereditary fetal growth retardation with aminoaciduria, cholestasis, iron overload, and lactic acidosis in the newborn infant. Acta Obstet Gynecol Scand 81:398–402PubMedCrossRefGoogle Scholar
  8. Fellman V, Lemmela S, Sajantila A, Pihko H, Jarvela I (2008) Screening of BCS1L mutations in severe neonatal disorders suspicious for mitochondrial cause. J Hum Genet 53:554–558PubMedCrossRefGoogle Scholar
  9. Gil-Borlado MC, Gonzalez-Hoyuela M, Blazquez A, Garcia-Silva MT, Gabaldon T et al (2009) Pathogenic mutations in the 5′ untranslated region of BCS1L mRNA in mitochondrial complex III deficiency. Mitochondrion 9:299–305PubMedCrossRefGoogle Scholar
  10. Hanson PI, Whiteheart SW (2005) AAA +proteins: have engine, will work. Nat Rev Mol Cell Biol 6:519–529PubMedCrossRefGoogle Scholar
  11. Hinson JT, Fantin VR, Schonberger J, Breivik N, Siem G et al (2007) Missense mutations in the BCS1L gene as a cause of the Bjornstad syndrome. N Engl J Med 356:809–819PubMedCrossRefGoogle Scholar
  12. Knisely AS, Gelbart T, Beutler E (2004) Molecular characterization of a third case of human atransferrinemia. Blood 104:2607PubMedCrossRefGoogle Scholar
  13. Kotarsky H, Karikoski R, Mörgelin M, Marjavaara S, Bergman P et al (2010) Characterization of complex III deficiency and liver dysfunction in GRACILE syndrome caused by a BCS1L mutation. Mitochondrion 10:497–509PubMedCrossRefGoogle Scholar
  14. Pietrangelo A (2004) The ferroportin disease. Blood Cells Mol Dis 32:131–138PubMedCrossRefGoogle Scholar
  15. Pietrangelo A (2010) Hereditary hemochromatosis: pathogenesis, diagnosis, and treatment. Gastroenterology 139:393–408PubMedCrossRefGoogle Scholar
  16. Poggi V, Lo Vecchio A, Menna F, Menna G (2011) Idiopathic pulmonary hemosiderosis: a rare cause of iron-deficiency anemia in childhood. J Pediatr Hematol Oncol 33:e160–e162PubMedCrossRefGoogle Scholar
  17. Rapola J, Heikkila P, Fellman V (2002) Pathology of lethal fetal growth retardation syndrome with aminoaciduria, iron overload, and lactic acidosis (GRACILE). Pediatr Pathol Mol Med 21:183–193PubMedCrossRefGoogle Scholar
  18. Roberts EA et al (2006) Disorders of copper, zinc and iron metabolism. In: Blau N (ed) Physician’s guide to the treatment and follow-up of metabolic diseases. Springer, Heidelberg, pp 353–363CrossRefGoogle Scholar
  19. Schneider SA, Bhatia KP (2013) Excess iron harms the brain: the syndromes of neurodegeneration with brain iron accumulation (NBIA). J Neural Transm 120:695–703PubMedCrossRefGoogle Scholar
  20. Sethi GR, Singhal KK, Puri AS, Mantan M (2011) Benefit of gluten-free diet in idiopathic pulmonary hemosiderosis in association with celiac disease. Pediatr Pulmonol 46:302–305PubMedCrossRefGoogle Scholar
  21. Tuppen HA, Fehmi J, Czermin B, Goffrini P, Meloni F et al (2010) Long-term survival of neonatal mitochondrial complex III deficiency associated with a novel BCS1L gene mutation. Mol Genet Metab 100:345–348PubMedCrossRefGoogle Scholar
  22. Visapaa I, Fellman V, Vesa J, Dasvarma A, Hutton JL et al (2002) GRACILE syndrome, a lethal metabolic disorder with iron overload, is caused by a point mutation in BCS1L. Am J Hum Genet 71:863–876PubMedCentralPubMedCrossRefGoogle Scholar
  23. Wood MJ, Powell LW, Dixon JL, Ramm GA (2012) Clinical cofactors and hepatic fibrosis in hereditary hemochromatosis: the role of diabetes mellitus. Hepatology 56:904–911PubMedCrossRefGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Department of PediatricsLund UniversityLundSweden

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