Figure 5. Supraphysiological concentrations of T3 signal eIF2a kinases, phosphorylating eIF2 alpha on Ser51 and leading to impeded formation of the 43S pre-initiation complex, decreased globin translation in red cell precursors, and microcytic anemia. (A) Under normal physiologic conditions (see text box for list of conditions), the ISR (Integrated Stress Response) is not activated. eIF2 is not phosphorylated. The eIF2 is active and acts to exchange GDP for GTP on the gamma subunit. The active eIF2 then initiates 43 pre-initiation complex formation and attachment to mRNA and scanning. Translation of abundant mRNAs is enhanced, globin is abundantly synthesized, and red cells (Rbc) of normal size and hemoglobin content are made. (B) Under stress conditions (see text box for list of conditions), the ISR pathway conveys signals from to four eIF2a kinases (PERK Protein Kinase RNA-Like ER kinase, PKR Protein Kinase R, GCN2 General Control Nonderepressible 2, HRI Heme Regulated Inhibitor). Under appropriate conditions, 1 or more of these kinases phosphorylates eIF2 on Serine 51 of the alpha subunit, leading to inhibition of the exchange activity, such that GDP remains bound and is not exchanged for GTP. The inactive eIF2 then fails to form the 43S pre-initiation complex, and there is decreased attachment to mRNA and decreased mRNA scanning. Translation of abundant mRNAs is impeded, globin synthesis is decreased, and red cells of decreased size and hemoglobin content are made. In our patient, supraphysiologic concentration of T3* induces cellular stress in various ways, likely via proteostasis changes and formation of stress granules in red cell precursors. The stress activates the integrated stress response (ISR), inducing kinase activity that can activate eIF2 kinases, in particular HRI*, and this leads to inactive eIF2 and decreased globin translation. The consequence is formation of small poorly hemoglobinized red cells (Rbc*), and thus microcytic anemia ensues [10].