Mild increases in serum hepcidin and interleukin‐6 concentrations impair iron incorporation in haemoglobin during an experimental human malaria infection

Abstract

Summary The correct selection of individuals who will benefit from iron supplements in malaria‐endemic regions requires improved insight in the effects of malaria on host iron homeostasis and innovative biomarkers. We assessed sequential changes in serum hepcidin and in traditional biochemical iron status indicators during an experimental Plasmodium falciparum malaria infection with five adult volunteers. The haemoglobin content of reticulocytes (Ret‐He) and of mature red blood cells (RBC‐He) represented iron incorporation into haemoglobin. Low‐density parasitaemia and its treatment induced a mild increase in interleukin (IL)‐6 and serum hepcidin concentrations. Despite this only mild increase, a marked hypoferraemia with a strong increase in serum ferritin concentrations developed, which was associated with a sharp fall in Ret‐He, while RBC‐He remained unchanged. The ratio of soluble transferrin receptor (sTfR) to log ferritin concentrations decreased to an average nadir of 63% of the baseline value. We concluded that even mild increases in serum hepcidin and IL‐6 concentrations result in a disturbed host iron homeostasis. Serum hepcidin, Ret‐He and Delta‐He (Ret‐He minus RBC‐He) are promising biomarkers to select those individuals who will benefit from iron supplements in malaria endemic regions, while the sTfR/log ferritin ratio should be used with caution to assess iron status during malaria.

Hepcidin Is Regulated during Blood-Stage Malaria and Plays a Protective Role in Malaria Infection

“…However, correlation analysis of our data reveals an inverse relationship between the levels of iron and hepcidin expression. This observation is consistent with a recent study of de Mast and colleagues (34). The results from these authors have indicated that an increase in serum hepcidin levels is associated with a decline in serum iron concentrations in human volunteers infected with P. falciparum.…”

“…Upregulation of hepcidin expression has been observed in livers of mice infected with pathogenic bacteria (8,9). Recent studies have indicated that urinary or serum hepcidin levels are increased in patients with malaria (18)(19)(20)34). However, little is known about the regulation of hepatic hepcidin expression during malaria infection.…”

Increased serum hepcidin and alterations in blood iron parameters associated with asymptomatic P. falciparum and P. vivax malaria

“…We recently showed in an experimental human malaria model that even a mild increase in serum hepcidin, to concentrations in the range of those observed in the current study, induces hypoferremia and a steep fall in the hemoglobin content of reticulocytes, which is suggestive of impaired iron incorporation in hemoglobin. 12 Moreover, the lower values of hemoglobin, mean corpuscular volume, serum iron concentration and transferrin saturation in children with asymptomatic parasitemia also support the presence of functional iron deficiency. Since asymptomatic P. falciparum and P. vivax parasitemia are chronic and relapsing conditions, a possible delocalization of iron with iron retention in monocytes/ macrophages may theoretically increase the risk of anemia and of infections with intracellular bacteria (e.g.…”

“…9,10 Previously, our group studied hepcidin expression in anemic Tanzanian children with febrile P. falciparum malaria with high parasite densities and in malaria-naïve Dutch volunteers who were experimentally infected with P. falciparum. 11,12 Hepcidin concentrations were increased in both groups and associated with profound disturbances in iron homeostasis, suggesting that iron supplements should be withheld during symptomatic P. falciparum malaria. To our knowledge, no data are yet available on the effects of asymptomatic P. falciparum or P. vivax parasitemia on hepcidin expression.…”

Reply

“…The difference between Ret-Hgb and RBC-Hgb, expressed as ⌬Hgb, provides information on the current iron availability and short-term iron incorporation for erythropoiesis owing to the long life span of mature erythrocytes compared to reticulocytes (3). As a consequence, in the presence of absolute iron deficiency, iron supplementation is expected to substantially raise the Ret-Hgb and ⌬Hgb within several days (4-6), while no effect, or only limited effect, is expected in the pure functional iron deficiency of the inflammatory state (patients with ACD).…”