Anemia in Patients With Resistance to Thyroid Hormone α: A Role for Thyroid Hormone Receptor a in Human Erythropoiesis

Context: Patients with resistance to thyroid hormone (TH) alpha (RTH alpha) are characterized by growth retardation, macrocephaly, constipation, and abnormal thyroid function tests. In addition, almost all RTH alpha patients have mild anemia, the pathogenesis of which is unknown. Animal studies suggest an important role for TH and TH receptor (TR)alpha in erythropoiesis. Objective: To investigate whether a defect in TR alpha affects the maturation of red blood cells in RTH alpha patients. Design, Setting, and Patients: Cultures of primary human erythroid progenitor cells (HEPs), from peripheral blood of RTH alpha patients (n = 11) harboring different inactivating mutations in TR alpha (P398R, F397fs406X, C392X, R384H, A382fs388X, A263V, A263S), were compared with healthy controls (n = 11). During differentiation, erythroid cells become smaller, accumulate hemoglobin, and express different cell surface markers. We assessed cell number and cell size, and used cell staining and fluorescence-activated cell sorter analysis to monitor maturation at different time points. Results: After similar to 14 days of ex vivo expansion, both control and patient-derived progenitors differentiated spontaneously. However, RTH alpha-derived cells differentiated more slowly. During spontaneous differentiation, RTH alpha-derived HEPs were larger, more positive for c-Kit (a proliferation marker), and less positive for glycophorin A (a differentiation marker). The degree of abnormal spontaneous maturation of RTH alpha-derived progenitors did not correlate with severity of underlying TR alpha defect. Both control and RTH alpha-derived progenitors responded similarly when differentiation was induced. T3 exposure accelerated differentiation of both control-and RTH alpha patient-derived HEPs. Conclusions: Inactivating mutations in human TR alpha affect the balance between proliferation and differentiation of progenitor cells during erythropoiesis, which may contribute to the mild anemia seen in most RTH alpha patients.