As described below, we demonstrate that hepatic Hif1a, while upregulated, has minimal impact on Epo excess and polycythemia, while hepatic Hif2a not only drives Epo excess and polycythemia but also contributes to aberrant hepatic gene expression, increased dietary iron absorption, and systemic Mn excess in Slc30a10-deficient mice. Here, EPAS1 is linked to polycythemia.