Population Heterogeneity in Iron Biomarkers by Age, Sex, Menopausal Status, and Race in Healthy U.S. Adults: A Cross-Sectional Analysis from the All of Us Research Program

Background/Objectives: Blood iron biomarkers are commonly interpreted using fixed clinical reference intervals, although iron metabolism varies by age, sex, menopausal status, and race. This study aimed to characterize the distribution of iron biomarkers across demographic subgroups and to examine their distribution relative to commonly used reference intervals. Methods: In this cross-sectional study, 7990 adults (≥18 years) from the All of Us Research Program were classified as premenopausal women, postmenopausal women, men < 53 years, or men > 56 years. Serum iron, ferritin, total iron-binding capacity, unsaturated iron-binding capacity, and transferrin saturation (TSAT) were summarized across groups and compared descriptively with commonly used reference intervals. Results: Iron biomarkers varied across demographic groups. Mean serum iron was 82.3 µg/dL overall, with lower levels in premenopausal women (79.5 ± 36.7 µg/dL) and higher levels in men < 53 years (86.8 ± 41.8 µg/dL). Mean TSAT was 25.6% and generally located toward the lower end of commonly used reference ranges. Ferritin showed substantial variability, with higher mean levels in younger men (258.0 ± 581.0 ng/mL) and lower levels in premenopausal women (102.1 ± 224.9 ng/mL). Premenopausal women had higher iron-binding capacity, whereas older men had lower values. Black participants had lower serum iron and TSAT but higher ferritin compared with White participants. A substantial proportion of participants had values outside commonly used reference intervals, particularly for serum iron and TSAT. Conclusions: Iron biomarker distributions differ across demographic subgroups and may not be fully reflected by commonly used reference intervals. These findings highlight the importance of context-specific interpretation and underscore the need for further studies to evaluate the applicability of current reference intervals across diverse populations.