Data‐driven physiologic thresholds for iron deficiency associated with hematologic decline

Abstract

Iron-deficiency contributes to a 50% of anemia prevalence worldwide, but reference intervals for iron status tests are not optimized for anemia diagnosis. To address this limitation, we identified the serum ferritin (SF) thresholds associated with hematologic decline in iron-deficient patients, and the SF thresholds from which an SF increase was associated with hematologic improvement. Paired red blood cell and SF measurements were analysed from two adult cohorts at Massachusetts General Hospital (MGH), from 2008-2011 (N = 48 409), and 2016-2018 (N = 10 042). Inter-patient measurements in the first cohort were used to define optimal SF thresholds based on the physiologic relationship between SF and red cell measurements. Intra-patient measurements (1-26 weeks apart) in the second cohort were used to identify SF thresholds from which an SF increase was associated, with an increase in red cell measurements. The identified optimal SF thresholds varied with age, sex and red cell measure. Thresholds associated with a 5% decline in red cell index were typically in the range 10-25 ng/mL. Thresholds for younger women (18-45 year) were 5 ng/mL lower than for older women (60-95 years), and 10 ng/mL lower than for men.Thresholds from which a subsequent increase in SF was associated with a concomitant increase in red cell measure showed similar patterns: younger women had lower thresholds (15 ng/mL) than older women (25 ng/mL), or men (35 ng/mL). These results suggest that diagnostic accuracy may be improved by setting different SF thresholds for younger women, older women, and men. This study illustrates how clinical databases may provide physiologic evidence for improved diagnostic thresholds.

Clinical thresholds for diagnosing iron deficiency: comparison of functional assessment of serum ferritin to population based centiles

“…Through a novel approach based on the functional association between serum ferritin and erythrocyte parameters, studies have identified serum ferritin thresholds with clinical relevance to iron deficiency anaemia 18 , 19 . Our objective was to determine whether a functional approach based on clinically relevant iron deficient erythropoiesis could provide a more clinically useful alternative to direct and indirect approaches.…”

Iron Deficiency – Not Only a Premenopausal Topic After Bariatric Surgery?

“…Other authors however showed that haematological parameters indicating a state of iron deficiency changed at higher serum ferritin levels in postmenopausal women than they did in premenopausal women. Therefore, the authors propose using different cut-off values of ferritin in pre- and postmenopausal women [ 27 ].…”

Functional Reference Limits: Describing Physiological Relationships and Determination of Physiological Limits for Enhanced Interpretation of Laboratory Results

“…Markus, et al [21] examined laboratory results from 54,896 children and proposed functional reference limits of 26 μg/L for children between 4 months and 13 years and of 39 μg/L for children aged 13-18 years using quantile regression models. Foy, et al [22] reported a 5% reduction in erythrocyte indices at serum ferritin concentrations of 10-25 μg/L based on data from 58,451 hospitalized adult patients, whereas Sezgin, et al [20] found a hematological plateau (where the erythrocyte value difference between subsequent correlated ferritin values becomes < 1) at a serum ferritin concentration of 10 μg/L. Choy, et al [38] found that analytical bias in ferritin measurement procedures between the Abbott and Siemens platforms did not significantly influence the functional reference limits.…”

“…A smooth curve is a curve with a continuously turning tangent (i.e., nonlinear component) without singular points with the aim to reduce the influence of extreme values and outliers. Fractional polynomial regression can be used to model relationships and produce a smooth continuous curve fit across a data range [ 22 ]. It should be noted that the application of different regression models to fit a curve may produce different impressions of the trends between the biomarker pair [ 7 ].…”

“…Foy, et al . [ 22 ] reported a 5% reduction in erythrocyte indices at serum ferritin concentrations of 10-25 μg/L based on data from 58,451 hospitalized adult patients, whereas Sezgin, et al . [ 20 ] found a hematological plateau (where the erythrocyte value difference between subsequent correlated ferritin values becomes <1) at a serum ferritin concentration of 10 μg/L.…”