Inflammation overrides erythropoietic signals in determining hepcidin concentration in untreated tuberculosis
Iron absorption is blocked in untreated tuberculosis and progressively restored during treatment
Anemia of inflammation is a hallmark of tuberculosis. Factors controlling iron metabolism during anemia of inflammation and its resolution are uncertain. Whether iron supplements should be given during anti-tuberculosis treatment to support Hb recovery is unclear. Before and during treatment of tuberculosis, we assessed iron kinetics, and changes in inflammation and iron metabolism indices. In a 26-wk prospective study, Tanzanian adults with tuberculosis (n=18) were studied before treatment and then every two weeks during treatment; oral and intravenous iron tracers were administered before treatment, after intensive phase (8/12 wk) and complete treatment (24 wk); no iron supplements were given. Before treatment, hepcidin and erythroferrone (ERFE) were greatly elevated, erythrocyte iron utilization was high (~80%) and iron absorption was negligible (<1%). During treatment, hepcidin and IL-6 decreased ~70% after only 2 wk (p<0.001); in contrast, ERFE did not significantly decrease until 8 wk (p<0.01). ERFE and IL-6 were the main opposing determinants of hepcidin (p<0.05) and greater ERFE was associated with reticulocytosis and hemoglobin (Hb) repletion (p<0.01). Dilution of baseline tracer concentration was 2.6-fold higher during intensive phase treatment (p<0.01) indicating enhanced erythropoiesis. After treatment completion, iron absorption increased ~20-fold (p<0.001); Hb increased ~25% (p<0.001). In tuberculosis-associated anemia of inflammation, our findings suggest elevated ERFE is unable to suppress hepcidin and iron absorption is negligible. During treatment, as inflammation resolves, ERFE may remain elevated, contributing to hepcidin suppression and Hb repletion. Iron is well-absorbed only after tuberculosis treatment and supplementation should be reserved for patients remaining anemic after treatment. (ClinicalTrials.gov Identifier:NCT02176772).