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Molecular genetic diagnostics and screening of hereditary hemochromatosis


Authors: J. Zlocha 1;  L. Kovács 1;  S. Požgayová 1;  V. Kupčová 2;  S. Durínová 2
Authors‘ workplace: II. detská klinika Lekárskej fakulty UK a Detskej fakultnej nemocnice s poliklinikou, Bratislava, Slovenská republika, prednosta prof. MUDr. László Kovács, DrSc., MPH 1;  III. interná klinika Lekárskej fakulty UK a FNsP akademika Dérera, Bratislava, Slovenská republika, prednosta prof. MUDr. Viliam Bada, CSc. 2
Published in: Vnitř Lék 2006; 52(6): 602-608
Category: Original Contributions

Overview

Background:
Hereditary hemochromatosis is considered one of the most common hereditary diseases in population of Caucasian origin. In recent years, a candidate gene for HLA-linked hemochromatosis, HFE, has been cloned, and a single G-to-A mutation resulting in a cysteine-to-tyrosine substitution (C282Y) has been identified in up to 80 % of study patients with type 1 hereditary hemochromatosis. The purpose of the paper was to confirm the importance of genetic testing for HFE mutations in making the diagnosis of hemochromatosis and find out a suitable diagnostic algorithm for the indication of this form of diagnostics in patients suspected of hereditary hemochromatosis.

Patients and methods:
The examination of C282Y mutation was conducted in 500 subjects. The most frequent indications for DNA analysis were hepatopathy of unknown ethiology, liver cirrhosis, diabetes mellitus, bronze skin pigmentation in connection with high serum iron concentration, elevated transferrin saturation and elevated serum ferritin levels.

Results:
In our group of patients, 29 homozygotes and 75 heterozygotes for C282Y mutation were identified, 10 patients carried both C282Y and H63D mutations of HFE gene (compound heterozygotes), whereas in 386 subjects the mutation was not found. The genotype-phenotype correlation showed that 22 homozygotes had liver affection proved by imaging and/or histologic methods. Except the liver disorders, the most common symptoms of these patients were type 2 diabetes mellitus or glucose tolerance disorder (10 patients), arthritis or joint pain (9 patients) and cardiovascular disorders, such as cardiomyopathy (2 patients). Bronze skin pigmentation was present in 9 homozygotes. Transferin saturation values were significantly higher in homozygotes for C282Y mutation as compared to C282Y heterozygotes (p < 0.001), C282Y/H63D compound heterozygotes (p < 0.05) or wild type subjects (p < 0.001) respectively. Also serum ferritin levels were significantly higher in homozygotes for C282Y mutation as compared to C282Y heterozygotes (p < 0.001), C282Y/H63D compound heterozygotes (p < 0.001) and wild type subjects (p < 0.001) respectively.

Conclusions:
Our observations confirm that DNA analysis significantly contributes to differential diagnostics of this severe, but in early recognition curable disease. Early detection and phlebotomy treatment prior to the onset of cirrhosis can reduce morbidity and normalize life expectancy. It is readily identified through biochemical testing for iron overload using serum transferrin saturation and genetic testing for C282Y homozygosity. DNA analysis is recommended in patients whose transferrin saturation is 45 % or more on a repeated test. General population screening has been waived in preference to targeting high-risk groups such as first-degree relatives of affected individuals and those with secondary iron overload, especially patients with chronic liver disorders and chronic anemia. This screening strategy is likely to continue until uncertainties regarding the natural history of the disease, age-related penetrance, and management of asymptomatic individuals are clarified.

Key words:
hereditary hemochromatosis – diagnosis – DNA analysis – screening


Sources

1. Powwel LW, Jazwinska E, Halliay JW. Primary iron overload. In: Brock JH, Halliday JW, Pippard MJ et al (eds). Iron Metabolism in Health and Disease. Philadelphia: WB Saunders 1994: 227-270.

2. Feder JN, Gnirke A, Thomas W et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet 1996; 13: 399-408.

3. Kovács L, Kuba D, Phillips JA. Herditárna hemochromatóza a hereditárna trombofília - naše „európske dedičstvo“? Med Monitor 1998, 12-15.

4. Zlocha J, Pažgayová S, Zacharová B et al. Význam Analýzy DNA v diferenciálnej diagnostike hereditárnej hemochromatózy. Lek Obzor 2003; 2: 40-44.

5. Cimburova M, Putova I, Provaznikova H et al. Hereditary hemochromatosis: detection of C282Y and H63D mutations in HFE gene by means of guthrie cards in population of Czech Republic. Genet Epidemiol 2002; 23: 260-263.

6. Půtová I, Čimburová M, Jarošová K et al. Mutace v genu HFE u osob s revmatickým postižením. Čas Lék Čes 2005; 144: 391-398.

7. Siah CW, Trinder D, Olynyk JK. Iron overload. Clin Chim Acta 2005; 358: 24-36.

8. McCullen MA, Crawford DH, Hickman PE Screening for hemochromatosis. Clin Chim Acta 2002; 315: 169-186.

9. Powell LW, George DK, McDonnell SM et al. Diagnosis of hemochromatosis. Ann Intern Med 1998; 129: 925-931.

10. Barton JC, McDonnell SM, Adams PC et al (Hemochromatosis Management Working Group). Management of hemochromatosis. Ann Intern Med 1998; 129: 932-939.

11. Davis WD, Arrowsmith WR. The effect of repeated phlebotomies in hemochromatosis: report of three cases. J Lab Clin Med 1952; 39: 526-532.

12. Brandhagen DJ, Fairbanks VF, Baldus W Recognition and management of hereditary hemochromatosis. Am Fam Physician 2002; 65: 853-860.

13. Hanson EH, Imperatore G, Burke W. HFE gene and hereditary hemochromatosis: a HuGE review. Human Genome Epidemiology. Am J Epidemiol 2001; 154: 193-206.

14. Crawford DH, Jazwinska EC, Cullen LM et al. Expression of HLA-linked hemochromatosis in subjects homozygous or heterozygous for the C282Y mutation. Gastroenterology 1998; 114: 1003-1008.

15. Niederau C, Niederau CM, Lange S et al. Screening for hemochromatosis and iron deficiency in employees and primary care patients in Western Germany. Ann Intern Med 1998; 128: 337-345.

16. McCune CA, Al-Jader LN, May A et al. Hereditary hemochromatosis: only 1% of adult HFE C282Y homozygotes in South Wales have a clinical diagnosis of iron overload. Hum Genet 2002; 111: 538-543.

17. David V, Moirand R, Le Gall JY et al. Preliminary studies before systematic screening of hemochromatosis: prevalence and penetrance of C282Y homozygosity. Am J Hum Genet 1999; 65: A213.

18. Phatak PD, Sham RL, Raubertas RF et al. Prevalence of hereditary hemochromatosis in 16031 primary care patients. Ann Intern Med 1998; 129: 954-961. 

19. Witte DL, Crosby WH, Edwards CQ et al. Practice guideline development task force of the College of American Pathologists. Hereditary hemochromatosis. Clin Chim Acta 1996; 245: 139-200.

20. McDonnell SM, Phatak PD, Felitti V et al. Screening for hemochromatosis in primary care settings. Ann Intern Med 1998; 129: 962-970.

21. Murtagh LJ, Whiley M, Wilson S et al. Unsaturated iron binding capacity and transferrin saturation are equally reliable in detection of HFE hemochromatosis. Am J Gastroenterol 2002; 97: 2093-2099.

22. Worwood M. HFE mutations as risk factors in disease. Best Pract Res Clin Haematol 2002; 15: 295-314.

23. Rasmussen ML, Folsom AR, Catellier DJ et al. A prospective study of coronary heart disease and the hemochromatosis gene (HFE) C282Y mutation: the Atherosclerosis Risk in Communities (ARIC) study. Atherosclerosis 2001; 154: 739-746.

24. Tuomainen TP, Kontula K, Nyyssonen K et al. Increased risk of acute myocardial infarction in carriers of the hemochromatosis gene Cys282Tyr mutation: a prospective cohort study in men in eastern Finland. Circulation 1999; 100: 1274-1279.

25. Hetet G, Elbaz A, Gariepy J et al. Association studies between haemochromatosis gene mutations and the risk of cardiovascular diseases. Eur J Clin Invest 2001; 31: 382-388.

26. Dúbrava M, Kovács L, Zacharová B. Hereditárna hemochromatóza - fikcia alebo potrebná diferenciálna diagnostická alternatíva aj pre geriatrického pacienta? Geriatria 2000; 6: 7-12.

27. Gochee PA, Powell LW, Cullen DJ et al. A population-based study of the biochemical and clinical expression of the H63D hemochromatosis mutation. Gastroenterology 2002; 122: 646-651.

28. Galhenage SP, Vialla CH, Olynyk JK Screening for hemochromatosis: patients with liver disease, families and populations. Curr Gastroenterol Rep 2004; 6: 44-51.

29. Adams PC, Speechley M, Kertesz A Long Term Survival Analysis in Hereditary Hemochromatosis. Gastroenterology 1991; 101: 368-372.

30. Niederau C, Fischer R, Pürschel A et al. Long-term Survival in Patients with Hereditary Hemochromatosis. Gastroenterology 1996; 110: 1107-1119.

31. Niederau C, Fischer R, Sonnenberg A et al. Survival and causes of death in cirrhotic and in noncirrhotic patients with primary hemochromatosis. N Engl J Med 1985; 313: 1256-1262.

32. Powell LW. Hemochromatosis: precirrhotic therapy restores normal life expectancy. Hepatology 1986; 6: 1423-1425.

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Diabetology Endocrinology Internal medicine

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Issue 6

2006 Issue 6

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