Is an elevated serum transferrin saturation associated with the development of diabetes?
- OBJECTIVES: Diabetes mellitus is a common comorbid condition of hemochromatosis and is often identified as a complication of untreated hemochromatosis. However, there are few primary data examining the development of diabetes secondary to hemochromatosis. Our objective was to determine the likelihood of developing diabetes in a nationally representative cohort of patients who have an elevated serum transferrin saturation rate but no current diagnosis of diabetes.
- STUDY DESIGN: This is a retrospective cohort study based on merging the National Health and Nutrition Examination Survey I (1971–1974; NHANES I) with the NHANES I Epidemiologic Followup Study (1992).
- POPULATION: Individuals aged 25 to 74 years at the time of the NHANES I without diabetes (n = 9274).
- OUTCOMES MEASURED: The outcome was development of diabetes according to patient report, proxy report, or death certificate by the time of the follow-up interview.
- RESULTS: The incidence of diagnosed diabetes in the cohort was 10.2%. Among individuals with serum transferrin saturation levels above 55%, 7.5% developed diagnosed diabetes compared with 10.2% with a serum transferrin saturation of no more than 45% (P = .38). The relation remained nonsignificant in models adjusted for risk factors of diabetes and in analyses that assumed 10% of patients had received treatment for hemochromatosis.
- CONCLUSIONS: In this nationally representative cohort of adults, elevated serum transferrin saturation was not significantly associated with the development of diabetes.
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.
