In PV, opposing factors influence hepcidin expression in the liver. Expanded erythropoiesis and phlebotomies contribute to ID, which inhibits hepcidin. Congenital variants in the HFE gene (ie, C282Y known to be associated with hemochromatosis) may further worsen hepcidin deficiency. In contrast, inflammatory cytokines (via the GP130-coupled receptor pathway) stimulate hepcidin. The resulting variable degree of hepcidin suppression influences the phenotype severity, as suggested by manipulation of hepcidin in experimental models.