Hepcidin level predicts hemoglobin concentration in individuals undergoing repeated phlebotomy

Abstract

Dietary iron absorption is regulated by hepcidin, an iron regulatory protein produced by the liver. Hepcidin production is regulated by iron stores, erythropoiesis and inflammation, but its physiology when repeated blood loss occurs has not been characterized. Hepcidin was assayed in plasma samples obtained from 114 first-time/reactivated (no blood donations in preceding 2 years) female donors and 34 frequent (≥3 red blood cell donations in preceding 12 months) male donors as they were phlebotomized ≥4 times over 18-24 months. Hepcidin levels were compared to ferritin and hemoglobin levels using multivariable repeated measures regression models. Hepcidin, ferritin and hemoglobin levels declined with increasing frequency of donation in the first-time/reactivated females. Hepcidin and ferritin levels correlated well with each other (Spearman's correlation of 0.74), but on average hepcidin varied more between donations for a given donor relative to ferritin. In a multivariable repeated measures regression model the predicted inter-donation decline in hemoglobin varied as a function of hepcidin and ferritin; hemoglobin was 0.51 g/dL lower for subjects with low (>45.7 ng/mL) or decreasing hepcidin and low ferritin (>26 ng/mL), and was essentially zero for other subjects including those with high (>45.7 ng/mL) or increasing hepcidin and low ferritin (>26 ng/mL) levels (P<0.001). In conclusion, hepcidin levels change rapidly in response to dietary iron needed for erythropoiesis. The dynamic regulation of hepcidin in the presence of a low levels of ferritin suggests that plasma hepcidin concentration may provide clinically useful information about an individual's iron status (and hence capacity to tolerate repeated blood donations) beyond that of ferritin alone. Clinicaltrials.gov identifier: NCT00097006.

Figures

Figure 1.

Scatter plot of log10 hepcidin (ng/mL) by log10 ferritin (ng/mL) demonstrates the correlation between the two plasma assays and the clustering of baseline female values in the upper right quadrant of the graph: ( ) Female baseline visits ( ) Female other visits ( ) Male visits.

Figure 2.

Trend lines of laboratory values from individual first-time/reactivated female donors over multiple visits. These trend lines help to illustrate the decrease in laboratory values over repeated blood donations; however, they are not adjusted for important modifiers, such as time between visits. Adjusted values along with P-values indicating statistical significance are presented in Table 1. Donations are stratified by those who reported use of iron supplements (black lines) and those who reported not using iron supplements (red lines). The bold lines are aggregate trend lines from donors reporting iron supplement use (black lines) and those who reported not using iron supplements (red lines). (A) Change in venous hemoglobin (g/dL); (B) change in log10 ferritin (ng/mL); (C) change in log10 hepcidin (ng/mL).