Is an elevated serum transferrin saturation associated with the development of diabetes?

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Original Research

Is an elevated serum transferrin saturation associated with the development of diabetes?

J Fam Pract. 2002 November;51(11):933-936

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References

1. Feder JN, Penny DM, Irrinki A, et al. The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding. Proc Natl Acad Sci 1998;95:1472-7.

2. Looker AC, Johnson CL. Prevalence of elevated serum transferrin saturation in adults in the United States. Ann Intern Med 1998;129:940-5.

3. Baer DM, Simons JL, Staples RL, Rumore GJ, Morton CJ. Hemochromatosis screening in asymptomatic ambulatory men 30 years of age and older. Am J Med 1995;98:464-8.

4. McDonnell SM, Hover A, Gloe D, Ou C, Cogswell ME, 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;107:30-7.

5. Edwards CQ, Griffen LM, Goldgar D, Drummond C, Skolnick MH, Kushner JP. Prevalence of hemochromatosis among 11,065 presumably healthy blood donors. N Engl J Med 1988;318:1355-62.

6. Leggett BA, Halliday JW, Brown NN, Bryant S, Powell LW. Prevalence of haemochromatosis amongst asymptomatic Australians. Br J Haematol 1990;74:525-30.

7. Witte DL, Crosby WH, Edwards CQ, Fairbanks VF, Mitros FA. Practice guideline development task force of the College of American Pathologists. Hereditary hemochromatosis. Clin Chim Acta 1996;245:139-200.

8. Mainous AG III, Gill JM, Pearson WS. Should we screen for hemochromatosis? An examination of downstream effects on morbidity and mortality. Arch Intern Med 2002;162:1769-1774.

9. Cogswell ME, McDonnell SM, Khoury MJ, Franks AL, Burke W, Brittenham G. Iron overload, public health, and genetics: evaluating the evidence for hemochromatosis screening. Ann Intern Med 1998;129:971-9.

10. Niederau C, Fischer R, Sonnenburg A, Stremmel W, Trampisch HJ, Strohmeyer G. Survival and causes of death in cirrhotic and noncirrhotic patients with primary hemochromatosis. N Engl J Med 1985;313:1256-62.

11. Adams PC, Speechley M, Kertesz AE. Long term survival analysis in hereditary hemochromatosis. Gastroenterology 1991;101:368-72.

12. Flynn D, Fairney A, Jackson D, Clayton B. Hormonal changes in thalassemia major. Arch Dis Child 1976;51:828-36.

13. Yang Q, McDonnell SM, Khoury MJ, Cono J, Parrish RG. Hemochromatosis associated mortality in the United States from 1979 to 1992: an analysis of multiple-cause mortality data. Ann Intern Med 1998;129:946-53.

14. Buysschaert M, Paris I, Selvais P, Hermans MP. Clinical aspects of diabetes secondary to idiopathic haemochromatosis in French speaking Belgium. Diabetes Metab 1997;23:308-13.

15. Powell LW, Jazwinska E, Halliday JW. Primary iron overload. In: Brock JH, Halliday JW, Pippard MJ, et al, eds. Iron Metabolism in Health and Disease. London: Saunders; 1994;228-70.

16. George DK, Evans RM, Crofton RW, Gunn IR. Testing for haemochromatosis in the diabetic clinic. Ann Clin Biochem 1995;32:521-6.

17. O’Brien T, Barrett B, Murray DM, Dinneen S, O’Sullivan DJ. Usefulness of biochemical screening of diabetic patients for hemochromatosis. Diabetes Care 1990;13:532-4.

18. Yaouanq JM. Diabetes and haemochromatosis: current concepts, management and prevention. Diabetes Metab 1995;21:319-29.

19. Bothwell TH, MacPhail AP. Hereditary hemochromatosis: etiologic, pathologic, and clinical aspects. Semin Hematol 1998;35:55-71.

20. Ober KP. Polyendocrine syndromes. In: Leahy JL, Clark NG, Cefalu WT, eds. Medical Management of Diabetes Mellitus. New York: Marcel Dekker; 2000;699-717.

21. Stremmel W, Niederau C, Berger M, Kley HK, Kruskemper HL, Strohmeyer G. Abnormalities in estrogen, androgen, and insulin metabolism in idiopathic hemochromatosis. Ann N Y Acad Sci 1988;526:209-23.

22. Hramiak IM, Finegood DT, Adams PC. Factors affecting glucose tolerance in hereditary hemochromatosis. Clin Invest Med 1997;20:110-8.

23. Edwards CQ, Kushner JP. Screening for hemochromatosis. N Engl J Med 1993;328:1616-20.

24. Shah, BV, Barnwell BG, Hunt PN, LaVange LM. SUDAAN User’s Manual. Release 5.50. Research Triangle Park, NC: Research Triangle Institute; 1991.

25. McDonnell SM, Phatak PD, Felitti V, Hover A, McLaren GD. Screening for hemochromatosis in primary care settings. Ann Intern Med 1998;129:962-70.

26. Balan V, Baldus W, Fairbanks V, Michels V, Burritt M, Klee G. Screening for hemochromatosis: a cost effectiveness study based on 12,258 patients. Gastroenterology 1994;107:453-9.

27. Karlsson M, Ikkala E, Reunanen A, Takkunen H, Vuori E, Makinen J. Prevalence of hemochromatosis in Finland. Acta Med Scand 1988;224:385-90.

The findings of this study have implications for whether screening for hemochromatosis is worthwhile, assuming that prevention of diabetes is a goal. Hemochromatosis has many characteristics that make it attractive for screening: the disorder is common, it posseses a long asymptomatic phase, a simple screening test is available, and treatment is effective. To be a reasonable candidate for screening, the condition also needs to cause substantial morbidity or mortality, and treatment in the asymptomatic phase should be more effective than treatment initiated after the onset of symptoms.²⁵ The findings of this study suggested that screening for and treatment of hemochromatosis are not worthwhile as a way to prevent diabetes. However, the relation between hemochromatosis, treatment, and the development of cirrhosis or hepatocellular carcinoma may warrant screening for hemochromatosis. There is preliminary evidence from an observational study that diagnosing patients with hemochromatosis in the precirrhotic stage and treating them with phlebotomy results in a normal life expectancy, whereas those diagnosed with hemochromatosis and cirrhosis have a shortened life expectancy and a high risk of liver cancer, even when iron depletion has been achieved.¹⁰

Our study had several limitations. First, the estimate from the NHANES I was based on an elevated serum transferrin saturation level. This is an appropriate first step in a diagnosis of hemochromatosis. Some investigators have recommended that elevated serum transferrin levels should be confirmed with a second fasting level or an elevated ferritin level.^26,27 Further, we did not have access to liver biopsy data, which is considered the gold standard for diagnosing hemochromatosis. Thus, a single elevated transferrin saturation level may have resulted in overestimates of the prevalence of hemochromatosis in the study population. Second, the estimate also might have been affected by the use of the lower levels of serum transferrin saturation (> 45%, > 50%, or > 55%). Although using a more stringent level, eg, greater than 60%, might have strengthened the conclusions, so few people with this level developed diabetes that we could not accurately make a population estimate.

In summary, diabetes does not seem to be a likely complication of hemochromatosis as indicated by the presence of an elevated serum transferrin saturation. Consequently, cost-effectiveness models of screening for hereditary hemochromatosis may need to be reevaluated.