Graves' Disease and Microcytic Anemia: A Forgotten Connection

BACKGROUND Microcytic anemia has long been associated with thyrotoxicosis, but this correlation has been largely forgotten, and few literature references to this phenomenon exist since the 1980s. No mechanism for this association has been proposed. CASE REPORT Here, we present the case of a 56-year-old man who developed clinically significant hyperthyroidism in the setting of Graves' disease and simultaneous microcytic anemia. He was treated with methimazole, and the hyperthyroidism symptoms and biochemical parameters remitted. Simultaneously, the red cell microcytosis and anemia remitted. Notably, iron deficiency as indicated by high serum ferritin was not present during the acute illness, and the ferritin level decreased with methimazole treatment. CONCLUSIONS The supraphysiological concentration of 3,5,3'-triiodo-L-thyronine (T3) gained entry to the cells, bound to hormone receptors (TR), activating a set of responsive genes, via thyroid response elements (TREs). In red cell precursors, which were notably not iron deficient, proteotoxic stress was induced, leading to activation of HRI kinase activity as part of the integrated stress response. The phosphorylation of eIF2 on the critical Ser51 led to depletion of the ternary complex (eIF2-GTP-Met-tRNA) by preventing eIF2 from exchanging GDP for GTP. Formation of the preinitiation complex was hampered, and translation of the abundant globin mRNA was attenuated. Decreased globin synthesis in turn was coupled to smaller red cell size, as occurs in thalassemia.