Many patients with polycythemia vera (PV) present with iron deficiency and nearly all develop iron deficiency as the disease progresses. A recent review in Nature highlighted the complex relationship between dysregulated iron metabolism and PV, with insight into new treatments that may better manage iron levels and improve symptoms.

The failure of hepcidin, the primary regulatory of the iron cycle, to respond to the declining iron levels and rising erythroferrone levels resulting from hyperplasia in PV as well as impaired iron absorption and other factors “strongly suggests that disordered iron metabolism in an important component of the pathobiology of PV,” according to lead author Yelena Z. Ginzburg, MD, of the Icahn School of Medicine at Mount Sinai in New York, and her colleagues. The authors note that anemia and iron deficiency are often used interchangeably, but that awareness of iron deficiency without anemia is essential to optimal management of PV.

Iron deficiency. Source: Getty

Repeated phlebotomy, a mainstay therapy, increases iron deficiency. While low iron levels slow erythropoiesis, a desirable outcome, they can also contribute to cognitive impairment and significant fatigue, even in the absence of anemia. Iron supplementation can increase erythrocytosis and the need for more frequent phlebotomy. Comparison of iron metabolism in PV patients with and without JAK2 mutations by the authors found that those with mutations demonstrated iron-restricted erythropoiesis, systemic iron deficiency, and lower serum Epo concentrations compared to patients without mutations.

The authors highlighted two options for PV treatment that address iron deficiency. Cytoreductive therapy with ruxolitinib normalizes iron levels in PV patients, though whether the increase occurs as a result of reduced use of phlebotomy or an effect on iron metabolism remains unknown.  

Based on research in mice, exogenous hepcidin may reverse erythrocytosis, reduce splenomegaly and sequester iron in splenic macrophages, alleviating symptoms of iron deficiency and eliminating the need for phlebotomy in low-risk PV patients without increasing erythropoiesis.    

Further research on the dysregulation of iron metabolism in PV may lead to development of novel therapeutics.