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

Introduction: Iron overload and its complications are recognized to be morbid and fatal in patients with congenital hemolytic anemias. Much of what is assumed regarding the long-term complications of iron overload in these patients is extrapolated from other patient populations, primarily those with hereditary hemochromatosis. 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.

Methods: 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 (1983-2023). Patients were identified via electronic database query, and eligibility was confirmed and data collection performed via manual chart review. Multivariable logistic modeling was used to assess the associations between depth of iron overload (as measured by lifetime peak ferritin measurement) or duration of iron overload (as measured by years of ferritin >500 ng/mL and >1000/mL) and complications of iron overload, including diabetes mellitus, heart disease, malignancy, and bone density disorders (osteopenia and osteoporosis), as well as death.

Results:

Patients and Iron Overload Exposure: 184 patients with congenital hemolytic anemias developing iron overload were included. Median (range) age was 32 (2-75) years at iron overload diagnosis and 105 patients (57%) were female. The cohort included 94 patients with sickle cell disease (51%), 30 patients with beta-thalassemia major (16%), and 60 patients with another hemolytic anemia (including thalassemia intermedia, hemoglobin H disease, and others). The cohort included a total of 2,139 patient-years of iron overload exposure (mean 11.6 years per patient).

Association of Degree and Duration of Iron Overload with Development of Complications: During the observation period, 47 patients (26%) developed diabetes mellitus, 39 patients (21%) developed cardiac disease, 50 patients (27%) developed a bone density disorder, and 16 patients (8.7%) developed malignancy. More years experienced of ferritin >500 ng/mL and >1000 ng/mL were associated with development of diabetes mellitus with adjusted odds ratios (OR) (95% confidence interval [CI]) of 2.65 (1.12-6.08) per 10-year increment, P=0.025 and 3.76 (1.38-9.33) per 10-year increment, P=0.010, respectively (FIGURE 1). Similarly, more years experienced of ferritin >1000 ng/mL were associated with development of cardiac disease (adjusted OR [95% CI] 3.88 [1.51-9.96] per 10-year increment, P=0.005 [FIGURE 2]). Peak lifetime ferritin of >10000 ng/mL was associated with over 7-fold odds of development of both diabetes and cardiac disease (P=0.013 and P=0.011, respectively; FIGURES 1 & 2). No associations were observed between duration or degree of iron overload and development of malignancy or bone density disease.

Association of Degree and Duration of Iron Overload with Death: During the observation period, 33 patients (18%) died. Peak lifetime ferritin of >10000 ng/mL was associated with over 9-fold odds of death (adjusted OR [95% CI], 9.06 [1.85-44.39], P=0.007). More years experienced of ferritin >1000 ng/mL were associated with death (adjusted OR [95% CI], 2.66 [0.99-7.17] per 10-year increment, P=0.053).

Conclusions: In models controlling for sex, years of iron overload exposure, and underlying congenital hemolytic anemia, both the degree (as measured by peak lifetime ferritin) and duration (as measured by years of ferritin above 500 or 1000 ng/mL) of iron overload were associated with markedly increased odds of diabetes mellitus and cardiac disease, but not bone density disease or malignancy, in iron overloaded patients with congenital hemolytic anemias. While greater severity of iron overload was in general required for development of heart disease, prolonged exposure to relatively modest iron overload (serum ferritin >500 ng/mL) was associated with 3-fold increased odds of diabetes. Our findings emphasize the need for aggressive iron chelation therapy in these patients, highlight potential differences in risk of complications between these patients and those with hereditary hemochromatosis, and provide novel and valuable prognostic data for clinicians as they counsel patients.