Need for reclassification of diabetes secondary to iron overload in the ADA and WHO classifications.

In the current classifications of diabetes by the American Diabetes Association (ADA) (2006) (1) and the World Health Organization (WHO) (1999) (2), hereditary hemochromatosis is listed under the heading “diseases of the exocrine pancreas”; however, this classification does not comply with the current evidence of diabetes secondary to iron overload. The common form of hereditary hemochromatosis is an autosomal recessive disease characterized by lifelong iron accumulation. Nonhereditary hemochromatosis may arise from chronic use of iron supplements, chronic liver disease, and chronic erythrocyte transfusion therapy for anemia in patients with ineffective erythropoiesis; e.g., patients with b-thalassemia major. Iron accumulates mainly in the endocrine pancreas, liver, and heart, leading to diabetes, liver cirrhosis, hepatocellular carcinoma, and heart failure (3). In the common form of hereditary hemochromatosis, onset is usually after 30 years of age in men and after menopause in women; in b-thalassemia, onset usually occurs in childhood. Iron restriction or iron chelation protects from diabetes and loss of b-cell function. In hemochromatosis with end-organ damage, histopathological deposition of hemosiderin in the exocrine pancreas may be seen in the acinar cells, but features of chronic pancreatitis (i.e., inflammation, destruction of lobular architecture, significant fibrosis) are lacking (4). In autopsies of patients with hemochromatosis and diabetes, impaired glucose tolerance, or impaired fasting glucose, pancreatic involvement seems to be a continuum from mild hemosiderosis involving acinar cells and stroma to severe hemosiderosis with b-cell iron deposition and degranulation. Functionally, diabetes secondary to hemochromatosis is characterized by both insulin deficiency and insulin resistance mimicking both type 1 and 2 diabetes, and is most likely caused by iron-dependent catalysis via the Fenton reaction of reactive oxygen species (ROS), which impair insulin signaling in skeletal muscle and liver and causeb-cell destruction due to insufficient b-cell antioxidant defense. Iron-catalyzed ROS2mediated damage is aggravated by islet inflammation by cytokine-dependent upregulation of cellular iron import by the divalent metal ion transporter-1 (DMT-1), and inducible b-cell2specific knockout of DMT-1 protects against inflammatory and high-fat diet2induced diabetes (5), suggesting that b-cell iron overload also contributes to the primary forms of diabetes. In clinical studies, hemochromatosis accounts for 1% of patients with diabetes (6). In epidemiologic studies, hemochromatosis is associated with increased risk of developing or dying from diabetes, is inversely correlated with serum insulin, and is proportionally correlated with blood glucose concentrations. Phlebotomy and iron chelation improve b-cell function and insulin sensitivity and reverse impaired glucose tolerance. We suggest that future classification includes a novel subgroup: diabetes secondary to iron overload associated with hereditary hemochromatosis, multiple erythrocyte transfusions, and other iron overload conditions. We believe that awareness of diabetes secondary to iron overload with its own subgroup classification will improve diagnosis and treatment of these patients in analogy to the maturity-onset diabetes of the young forms of diabetes.