Physiologically based ferritin thresholds for defining iron deficiency in U.S. Children 5-14 years

Iron deficiency (ID) is the most predominant nutritional deficiency globally. The current CDC iron guideline for ID screening uses serum ferritin (Ft) ≤15 μg/L for all individuals 6 months and older and was based on bone-marrow assessment. We aimed to evaluate physiologically based Ft thresholds for defining ID in children aged 5-14 years.

Ferritin and hemoglobin (Hb) data were analyzed from 3765 apparently healthy (no inflammation, infection, or risk of iron overload) US children, since such data are an indicator of iron-deficient erythropoiesis, erythrocyte zinc protoporphyrin (eZnPP). Nonlinear ferritin concentration curves (Hb-Ft, eZnPP-Ft) and differential equations were applied to identify ferritin thresholds at ID onset with inflection minima and plateau for each iron analyte.

Mean age was 10.3 years. The ferritin curve inflection for ID occurred at 23.9 μg/L (95% confidence interval, 21.7-27.3) with Hb and 25.0 μg/L (23.8-27.1) with eZnPP. No inter-analyte (P = 0.67), age (P = 0.49 with Hb, P = 0.95 with eZnPP), or sex (P = 0.39) differences observed. ID prevalence was 9.0% (7.3-10.7), and ID anemia (IDA) 0.5% (0.3-0.8) using CDC thresholds, versus 30.0% (27.4-32.5) and IDA was 1.0% (0.6-1.3)% using physiologically based thresholds.

Physiologically based ferritin thresholds for ID onset were consistently higher than current CDC thresholds across iron analyte, age, and sex. IDA remained unchanged with physiologically based thresholds, suggesting that anemia is not an adequate proxy for ID screening, and clinicians should consider higher ferritin as a functional threshold for defining ID in children.