Digestive Diseases and Sciences

, Volume 57, Issue 11, pp 2988–2994

Diagnosis of Hereditary Hemochromatosis in the Era of Genetic Testing

  • Christiane Trieß
  • Guido von Figura
  • Manfred Stuhrmann
  • Barbara Butzeck
  • Pierre A. Krayenbuehl
  • Pavel Strnad
  • Hasan Kulaksiz
Original Article



Homozygous C282Y mutation in HFE gene is responsible for the majority of hereditary hemochromatosis cases. Since 1996 this mutation can be identified by a simple genetic test.


To determine the clinical presentations in patients with homozygous HFE C282Y mutation and the impact of genetic testing on the time needed for diagnosis.


A total of 414 patients diagnosed with C282Y homozygous hereditary hemochromatosis before and after the introduction of genetic testing were evaluated regarding symptoms and clinical findings at diagnosis as well as first hemochromatosis-related clinical features in their past medical history.


At the time of diagnosis, the predominant symptom was joint pain, in particular of the hands/wrists. Those patients presenting with hand/wrist arthralgia had significantly higher ferritin levels than patients without this joint involvement (p = 0.0005 for males and p < 0.0001 for females). After the introduction of the HFE genetic test an earlier diagnosis after first onset of hemochromatosis-associated clinical features was observed between 2006 and 2009 vs. 2000–2005 p = 0.01).


Arthralgia, in particular of the hands/wrists, is a hallmark of hereditary hemochromatosis and its presence is associated with higher ferritin levels. Despite the availability of a genetic test, it often takes more than 6 years from the first onset of clinical features to diagnose hereditary hemochromatosis. This underlines the importance of raising the awareness of hemochromatosis and its typical clinical presentations.


Hemochromatosis HFE Genetic test Arthralgia 

Supplementary material

10620_2012_2243_MOESM1_ESM.pdf (51 kb)
Correlation of ferritin levels with disease duration in symptomatic patients. Ferritin levels in blood at the time of diagnosis are plotted against the disease duration (n = 282). The disease duration was defined as the time between the diagnosis and the onset of clinical features such as elevated transaminase levels, elevated ferritin or unexplained arthralgia. Non-parametric Spearman’s rank correlation coefficient (rho) indicates a positive correlation between disease duration and patients’ ferritin levels (PDF 52 kb)
10620_2012_2243_MOESM2_ESM.pdf (41 kb)
Results of liver biopsy at the time of diagnosis. Depicted is the percentage of liver biopsy results that showed a mild fibrosis, severe fibrosis or cirrhosis with regard to the year of diagnosis (<2000; 2000–2005; >2005) (PDF 42 kb)


  1. 1.
    Merryweather-Clarke AT, Pointon JJ, Shearman JD, Robson KJ. Global prevalence of putative haemochromatosis mutations. J Med Genet. 1997;34:275–278.PubMedCrossRefGoogle Scholar
  2. 2.
    EASL clinical practice guidelines for HFE hemochromatosis. J Hepatol. 2010;53:3–22.Google Scholar
  3. 3.
    Allen KJ, Gurrin LC, Constantine CC, et al. Iron-overload-related disease in HFE hereditary hemochromatosis. N Engl J Med. 2008;358:221–230.PubMedCrossRefGoogle Scholar
  4. 4.
    Beutler E, Gelbart T, West C, et al. Mutation analysis in hereditary hemochromatosis. Blood Cells Mol Dis. 1996;22:187–194.PubMedCrossRefGoogle Scholar
  5. 5.
    Alexander J, Kowdley KV. HFE-associated hereditary hemochromatosis. Genet Med. 2009;11:307–313.PubMedCrossRefGoogle Scholar
  6. 6.
    Aellen P, Guerne PA, Zenagui D, Vischer TL. Arthropathy due to hemochromatosis: often inaugural manifestation of the disease. Schweiz Med Wochenschr. 1992;122:842–849.PubMedGoogle Scholar
  7. 7.
    Sinigaglia L, Fargion S, Fracanzani AL, et al. Bone and joint involvement in genetic hemochromatosis: role of cirrhosis and iron overload. J Rheumatol. 1997;24:1809–1813.PubMedGoogle Scholar
  8. 8.
    Valenti L, Fracanzani AL, Rossi V, et al. The hand arthropathy of hereditary hemochromatosis is strongly associated with iron overload. J Rheumatol. 2008;35:153–158.PubMedGoogle Scholar
  9. 9.
    Carroll GJ, Breidahl WH, Bulsara MK, Olynyk JK. Hereditary hemochromatosis is characterized by a clinically definable arthropathy that correlates with iron load. Arthritis Rheum. 2011;63:286–294.PubMedCrossRefGoogle Scholar
  10. 10.
    Rathmann W, Haastert B, Icks A, et al. High prevalence of undiagnosed diabetes mellitus in Southern Germany: target populations for efficient screening. The KORA survey 2000. Diabetologia. 2003;46:182–189.PubMedGoogle Scholar
  11. 11.
    Lecube A, Hernandez C, Pelegri D, Simo R. Factors accounting for high ferritin levels in obesity. Int J Obes (Lond). 2008;32:1665–1669.CrossRefGoogle Scholar
  12. 12.
    Beutler E, Felitti V, Ho NJ, Gelbart T. Relationship of body iron stores to levels of serum ferritin, serum iron, unsaturated iron binding capacity and transferrin saturation in patients with iron storage disease. Acta Haematol. 2002;107:145–149.PubMedCrossRefGoogle Scholar
  13. 13.
    Scotet V, Le Gac G, Merour MC, et al. Impact of HFE genetic testing on clinical presentation of hereditary hemochromatosis: new epidemiological data. BMC Med Genet. 2005;6:24.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Niederau C, Fischer R, Purschel A, Stremmel W, Haussinger D, Strohmeyer G. Long-term survival in patients with hereditary hemochromatosis. Gastroenterology. 1996;110:1107–1119.PubMedCrossRefGoogle Scholar
  15. 15.
    Cauza E, Hanusch-Enserer U, Etemad M, et al. HFE genotyping demonstrates a significant incidence of hemochromatosis in undifferentiated arthritis. Clin Exp Rheumatol. 2005;23:7–12.PubMedGoogle Scholar
  16. 16.
    Carlsson A. Hereditary hemochromatosis: a neglected diagnosis in orthopedics: a series of 7 patients with ankle arthritis, and a review of the literature. Acta Orthop. 2009;80:371–374.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Christiane Trieß
    • 1
  • Guido von Figura
    • 1
  • Manfred Stuhrmann
    • 2
  • Barbara Butzeck
    • 3
  • Pierre A. Krayenbuehl
    • 4
  • Pavel Strnad
    • 1
  • Hasan Kulaksiz
    • 1
    • 5
  1. 1.Department of Internal Medicine IUniversity Hospital UlmUlmGermany
  2. 2.Institute of Human GeneticsMedical School HannoverHannoverGermany
  3. 3.Hemochromatosis Association Germany (HVD)CologneGermany
  4. 4.Klinik und Poliklinik für Innere MedizinUniversitätsSpital ZürichZurichSwitzerland
  5. 5.Spital WaldshutWaldshut-TiengenGermany

Personalised recommendations