Impact of Iron Overload on Incidence of Diabetes Mellitus, Cardiac Disease, and Death in Congenital Hemolytic Anemias

• Iron overload in adults with congenital hemolytic anemias is associated with incidence of diabetes mellitus, cardiac disease, and death.

• Peak ferritin and length of time with elevated ferritin are useful proxies for iron overload and correlate with clinical outcomes.

Iron overload and its complications are recognized to be morbid and fatal in patients with congenital hemolytic anemias. In patients with iron overload caused by congenital hemolytic anemias, there has been no study evaluating the dose-response relationship between serum markers of iron overload and long-term health complications. Filling this critical gap was the aim of the present study. We evaluated outcomes in a 5-hospital observational cohort study of adults with congenital hemolytic anemias diagnosed with iron overload over a 40-year period, and assessed associations between depth and duration of iron overload, and clinical complications including diabetes, heart disease, malignancy, bone density disorders, and death. 170 patients with congenital hemolytic anemias developing iron overload were included. More years experienced of ferritin over 500 ng/mL and over 1000 ng/mL were associated with the development of diabetes mellitus with adjusted odds ratios of 2.61 per 10-year increment, p=0.034 and 3.24 per 10-year increment, p=0.035, respectively. More years experienced of ferritin >1000 ng/mL were associated with development of heart disease (adjusted OR 5.30 per 10-year increment, p=0.002). Peak lifetime ferritin of >10000 ng/mL was associated with 6-fold odds of developing diabetes (p=0.04) and a 10-fold odds of developing heart disease (p=0.007). A peak ferritin >10,000 ng/mL was associated with an increase in mortality (adjusted OR 6.77, p=0.033). In conclusion, iron overload in patients with congenital hemolytic anemias is associated with diabetes mellitus, cardiac disease, and death. Prolonged exposure to relatively modest iron overload was associated with nearly 3-fold increased odds of diabetes.