Genotype–Phenotype Relationship in Hereditary Hemochromatosis


The majority of patients of northern European descent with hereditary hemochromatosis are homozygous for the C282Y mutation in the HFE gene product. A significant proportion of patients with this genotype have elevated iron indices; however, most will not develop symptoms or organ damage. Age, gender and alcohol are the key factors known to influence this wide variation in clinical penetrance. The authors describe the three stages of disease ranging from only genetic abnormality to overt disease and review the other factors that modify the genotype–phenotype relationship. Algorithms for use in clinical practice are included to aid clinicians in diagnosis, risk stratification and treatment.

Key Concepts:

  • Mutations in the HFE gene are relatively common.

  • The vast majority of patients with iron overload are homozygous for the C282Y mutation in the HFE gene product.

  • Biochemical penetrance, that is, elevated iron stores are present in 70–91% of males and 30–60% of females who are C282Y homozygotes.

  • End‐organ damage is less common and occurs in approximately one‐quarter of males and 1% of females.

  • End‐organ damage is extremely unlikely if serum ferritin is less than 1000 µg l−1.

  • The principal modifiers of disease are gender, age and alcohol. The wide variation in expression of clinical disease is largely unexplained.

  • Various genes have been shown to have variable modifying effects on disease penetrance.

  • Phlebotomy is a safe and effective treatment that depletes iron stores, prevents end‐organ damage and confers normal life expectancy. It is best initiated on discovery of elevated iron stores, that is, stage‐II or stage‐III disease.

Keywords: hereditary hemochromatosis; genotype; phenotype; HFE; C282Y; clinical penetrance; iron overload; ferritin; phlebotomy; cirrhosis

Figure 1.

Algorithm for risk stratification and referral for phlebotomy based on HFE genotype and ferritin.

Figure 2.

Algorithm for phlebotomy referral based on ferritin and HFE genotype.

Figure 3.

Algorithm for phlebotomy referral for patients with proven iron overload.



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Further Reading

Bacon BR , Adams PC , Kowdley KV , Powell LW and Tavill AS (2011) American Association for the Study of Liver Diseases. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology 54(1): 328–343.

European Association For The Study Of The, L. (2010) EASL clinical practice guidelines for HFE hemochromatosis. Journal of Hepatology 53(1): 3–22.

Olynyk JK , Trinder D , Ramm GA , Britton RS and Bacon BR (2008) Hereditary hemochromatosis in the post‐HFE era. Hepatology 48: 991–1001. 10.1002/hep.22507

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Ayres, Lachlan RO, Jayasekeran, Vanoo, and Olynyk, John K(Dec 2013) Genotype–Phenotype Relationship in Hereditary Hemochromatosis. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024259]