Skip to main content
NCBI home page
Gut logoLink to Gut
. 2000 Oct;47(4):575–579. doi: 10.1136/gut.47.4.575

HFE gene mutation (C282Y) and phenotypic expression among a hospitalised population in a high prevalence area of haemochromatosis

S Distante 1, J Berg 1, K Lande 1, E Haug 1, H Bell 1
PMCID: PMC1728064  PMID: 10986220

Abstract

BACKGROUND—Previous studies have shown that up to 0.5% of the Caucasian population is homozygous for the HFE gene C282Y mutation. High prevalence values have been reported in Northern Europe. To what extent the presence of this mutation is associated with overt clinical haemochromatosis is unclear.
AIM—To determine the prevalence of the C282Y allele in a hospitalised population of an acute medical department, and study the phenotypic expression in the homozygotes.
METHODS—Blood samples were obtained from 2027 hospitalised patients; 1900 Caucasians and 127 non-Caucasians. Serum iron, transferrin, and ferritin were measured at admission. The presence of the HFE gene mutation was determined by polymerase chain reaction based analysis. Follow up fasting blood samples were obtained from patients homozygous for the mutation.
RESULTS—Fourteen of the 1900 Caucasian subjects (0.74%) were homozygous and 224 (11.8%) were heterozygous for the C282Y mutation, including 32 subjects (1.7%) who were compound heterozygous for the C282Y and H63D mutations. Ten of 14 (71%) homozygous patients displayed mild to moderate biochemical expression of haemochromatosis with a serum ferritin level <550 µg/l, two (14%) patients were "non expressing", and two of five in whom liver biopsies were carried out had cirrhosis, including one with advanced hepatocellular carcinoma.
CONCLUSIONS—The prevalence of C282Y homozygosity in a hospitalised population was 0.74%. However, the majority of homozygous patients displayed mild to moderate biochemical expression. C282Y mutation screening may detect individuals that do not develop haemochromatosis. Transferrin saturation and ferritin, which are used as first line screening in haemochromatosis, may be highly unreliable in the presence of an inflammatory process.


Keywords: haemochromatosis; HFE gene mutation; inherited disorders; screening; ferritin; transferrin saturation

Full Text

The Full Text of this article is available as a PDF (135.0 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adams P. C., Gregor J. C., Kertesz A. E., Valberg L. S. Screening blood donors for hereditary hemochromatosis: decision analysis model based on a 30-year database. Gastroenterology. 1995 Jul;109(1):177–188. doi: 10.1016/0016-5085(95)90283-x. [DOI] [PubMed] [Google Scholar]
  2. Bassett M. L., Halliday J. W., Powell L. W. Value of hepatic iron measurements in early hemochromatosis and determination of the critical iron level associated with fibrosis. Hepatology. 1986 Jan-Feb;6(1):24–29. doi: 10.1002/hep.1840060106. [DOI] [PubMed] [Google Scholar]
  3. Bell H., Thordal C., Raknerud N., Hansen T., Bosnes V., Halvorsen R., Heier H. E., Try K., Leivestad T., Thomassen Y. Prevalence of hemochromatosis among first-time and repeat blood donors in Norway. J Hepatol. 1997 Feb;26(2):272–279. doi: 10.1016/s0168-8278(97)80041-4. [DOI] [PubMed] [Google Scholar]
  4. Burt M. J., George P. M., Upton J. D., Collett J. A., Frampton C. M., Chapman T. M., Walmsley T. A., Chapman B. A. The significance of haemochromatosis gene mutations in the general population: implications for screening. Gut. 1998 Dec;43(6):830–836. doi: 10.1136/gut.43.6.830. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cardoso E. M., Stål P., Hagen K., Cabeda J. M., Esin S., de Sousa M., Hultcrantz R. HFE mutations in patients with hereditary haemochromatosis in Sweden. J Intern Med. 1998 Mar;243(3):203–208. doi: 10.1046/j.1365-2796.1998.00270.x. [DOI] [PubMed] [Google Scholar]
  6. Carella M., D'Ambrosio L., Totaro A., Grifa A., Valentino M. A., Piperno A., Girelli D., Roetto A., Franco B., Gasparini P. Mutation analysis of the HLA-H gene in Italian hemochromatosis patients. Am J Hum Genet. 1997 Apr;60(4):828–832. [PMC free article] [PubMed] [Google Scholar]
  7. Crawford D. H., Jazwinska E. C., Cullen L. M., Powell L. W. Expression of HLA-linked hemochromatosis in subjects homozygous or heterozygous for the C282Y mutation. Gastroenterology. 1998 May;114(5):1003–1008. doi: 10.1016/s0016-5085(98)70320-8. [DOI] [PubMed] [Google Scholar]
  8. Cullen L. M., Summerville L., Glassick T. V., Crawford D. H., Powell L. W., Jazwinska E. C. Neonatal screening for the hemochromatosis defect. Blood. 1997 Nov 15;90(10):4236–4237. [PubMed] [Google Scholar]
  9. Datz C., Lalloz M. R., Vogel W., Graziadei I., Hackl F., Vautier G., Layton D. M., Maier-Dobersberger T., Ferenci P., Penner E. Predominance of the HLA-H Cys282Tyr mutation in Austrian patients with genetic haemochromatosis. J Hepatol. 1997 Nov;27(5):773–779. doi: 10.1016/s0168-8278(97)80312-1. [DOI] [PubMed] [Google Scholar]
  10. Distante S., Berg J. P., Lande K., Haug E., Bell H. High prevalence of the hemochromatosis-associated Cys282Tyr HFE gene mutation in a healthy Norwegian population in the city of Oslo, and its phenotypic expression. Scand J Gastroenterol. 1999 May;34(5):529–534. doi: 10.1080/003655299750026290. [DOI] [PubMed] [Google Scholar]
  11. Edwards C. Q., Griffen L. M., Goldgar D., Drummond C., Skolnick M. H., Kushner J. P. Prevalence of hemochromatosis among 11,065 presumably healthy blood donors. N Engl J Med. 1988 May 26;318(21):1355–1362. doi: 10.1056/NEJM198805263182103. [DOI] [PubMed] [Google Scholar]
  12. Edwards C. Q., Griffen L. M., Kaplan J., Kushner J. P. Twenty-four hour variation of transferrin saturation in treated and untreated haemochromatosis homozygotes. J Intern Med. 1989 Nov;226(5):373–379. doi: 10.1111/j.1365-2796.1989.tb01411.x. [DOI] [PubMed] [Google Scholar]
  13. FINCH S. C., FINCH C. A. Idiopathic hemochromatosis, an iron storage disease. A. Iron metabolism in hemochromatosis. Medicine (Baltimore) 1955 Dec;34(4):381–430. doi: 10.1097/00005792-195512000-00001. [DOI] [PubMed] [Google Scholar]
  14. Feder J. N., Gnirke A., Thomas W., Tsuchihashi Z., Ruddy D. A., Basava A., Dormishian F., Domingo R., Jr, Ellis M. C., Fullan A. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet. 1996 Aug;13(4):399–408. doi: 10.1038/ng0896-399. [DOI] [PubMed] [Google Scholar]
  15. Feder J. N., Penny D. M., Irrinki A., Lee V. K., Lebrón J. A., Watson N., Tsuchihashi Z., Sigal E., Bjorkman P. J., Schatzman R. C. The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding. Proc Natl Acad Sci U S A. 1998 Feb 17;95(4):1472–1477. doi: 10.1073/pnas.95.4.1472. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Feder J. N., Tsuchihashi Z., Irrinki A., Lee V. K., Mapa F. A., Morikang E., Prass C. E., Starnes S. M., Wolff R. K., Parkkila S. The hemochromatosis founder mutation in HLA-H disrupts beta2-microglobulin interaction and cell surface expression. J Biol Chem. 1997 May 30;272(22):14025–14028. doi: 10.1074/jbc.272.22.14025. [DOI] [PubMed] [Google Scholar]
  17. Gordeuk V. R., Ballou S., Lozanski G., Brittenham G. M. Decreased concentrations of tumor necrosis factor-alpha in supernatants of monocytes from homozygotes for hereditary hemochromatosis. Blood. 1992 Apr 1;79(7):1855–1860. [PubMed] [Google Scholar]
  18. Hallberg L., Björn-Rasmussen E., Jungner I. Prevalence of hereditary haemochromatosis in two Swedish urban areas. J Intern Med. 1989 Apr;225(4):249–255. doi: 10.1111/j.1365-2796.1989.tb00074.x. [DOI] [PubMed] [Google Scholar]
  19. Jeffrey G. P., Chakrabarti S., Hegele R. A., Adams P. C. Polymorphism in intron 4 of HFE may cause overestimation of C282Y homozygote prevalence in haemochromatosis. Nat Genet. 1999 Aug;22(4):325–326. doi: 10.1038/11892. [DOI] [PubMed] [Google Scholar]
  20. Jouanolle A. M., Gandon G., Jézéquel P., Blayau M., Campion M. L., Yaouanq J., Mosser J., Fergelot P., Chauvel B., Bouric P. Haemochromatosis and HLA-H. Nat Genet. 1996 Nov;14(3):251–252. doi: 10.1038/ng1196-251. [DOI] [PubMed] [Google Scholar]
  21. Lebrón J. A., Bennett M. J., Vaughn D. E., Chirino A. J., Snow P. M., Mintier G. A., Feder J. N., Bjorkman P. J. Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor. Cell. 1998 Apr 3;93(1):111–123. doi: 10.1016/s0092-8674(00)81151-4. [DOI] [PubMed] [Google Scholar]
  22. McDonnell S. M., Hover A., Gloe D., Ou C. Y., Cogswell M. E., Grummer-Strawn L. Population-based screening for hemochromatosis using phenotypic and DNA testing among employees of health maintenance organizations in Springfield, Missouri. Am J Med. 1999 Jul;107(1):30–37. doi: 10.1016/s0002-9343(99)00163-1. [DOI] [PubMed] [Google Scholar]
  23. McLaren C. E., McLachlan G. J., Halliday J. W., Webb S. I., Leggett B. A., Jazwinska E. C., Crawford D. H., Gordeuk V. R., McLaren G. D., Powell L. W. Distribution of transferrin saturation in an Australian population: relevance to the early diagnosis of hemochromatosis. Gastroenterology. 1998 Mar;114(3):543–549. doi: 10.1016/s0016-5085(98)70538-4. [DOI] [PubMed] [Google Scholar]
  24. Merryweather-Clarke A. T., Pointon J. J., Shearman J. D., Robson K. J. Global prevalence of putative haemochromatosis mutations. J Med Genet. 1997 Apr;34(4):275–278. doi: 10.1136/jmg.34.4.275. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Merryweather-Clarke A. T., Simonsen H., Shearman J. D., Pointon J. J., Nørgaard-Pedersen B., Robson K. J. A retrospective anonymous pilot study in screening newborns for HFE mutations in Scandinavian populations. Hum Mutat. 1999;13(2):154–159. doi: 10.1002/(SICI)1098-1004(1999)13:2<154::AID-HUMU8>3.0.CO;2-E. [DOI] [PubMed] [Google Scholar]
  26. Niederau C., Fischer R., Pürschel A., Stremmel W., Häussinger D., Strohmeyer G. Long-term survival in patients with hereditary hemochromatosis. Gastroenterology. 1996 Apr;110(4):1107–1119. doi: 10.1053/gast.1996.v110.pm8613000. [DOI] [PubMed] [Google Scholar]
  27. Olsson K. S., Eriksson K., Ritter B., Heedman P. A. Screening for iron overload using transferrin saturation. Acta Med Scand. 1984;215(2):105–112. doi: 10.1111/j.0954-6820.1984.tb04979.x. [DOI] [PubMed] [Google Scholar]
  28. Phatak P. D., Guzman G., Woll J. E., Robeson A., Phelps C. E. Cost-effectiveness of screening for hereditary hemochromatosis. Arch Intern Med. 1994 Apr 11;154(7):769–776. [PubMed] [Google Scholar]
  29. Recalcati S., Pometta R., Levi S., Conte D., Cairo G. Response of monocyte iron regulatory protein activity to inflammation: abnormal behavior in genetic hemochromatosis. Blood. 1998 Apr 1;91(7):2565–2572. [PubMed] [Google Scholar]
  30. Rhodes D. A., Raha-Chowdhury R., Cox T. M., Trowsdale J. Homozygosity for the predominant Cys282Tyr mutation and absence of disease expression in hereditary haemochromatosis. J Med Genet. 1997 Sep;34(9):761–764. doi: 10.1136/jmg.34.9.761. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Willis G., Wimperis J. Z., Smith K. C., Fellows I. W., Jennings B. A. Haemochromatosis gene C282Y homozygotes in an elderly male population. Lancet. 1999 Jul 17;354(9174):221–222. doi: 10.1016/S0140-6736(99)02195-9. [DOI] [PubMed] [Google Scholar]

Articles from Gut are provided here courtesy of BMJ Publishing Group

RESOURCES