Laboratory methodologies for indicators of iron status: strengths, limitations, and analytical challenges

Abstract

Biochemical assessment of iron status relies on serum-based indicators, such as serum ferritin (SF), transferrin saturation, and soluble transferrin receptor (sTfR), as well as erythrocyte protoporphyrin (EP). These indicators present challenges for clinical practice and national nutrition surveys, and often iron status interpretation is based on the combination of several indicators. The diagnosis of iron deficiency (ID) through SF concentration, the most commonly used indicator, is complicated by concomitant inflammation. sTfR concentration is an indicator of functional ID that is not an acute-phase reactant, but challenges in its interpretation arise due to the lack of assay standardization, common reference ranges, and common cutpoints. It is unclear which indicators are best suited to assess excess iron status. The value of hepcidin, non-transferrin bound iron, and reticulocyte indices is being explored in research settings. Serum-based indicators are generally measured on fully-automated clinical analyzers available in most hospitals. Although international reference materials have been available for years, the standardization of immunoassays is complicated by the heterogeneity of antibodies used and the absence of physico-chemical reference methods to establish “true” concentrations. From 1988 to 2006, the assessment of iron status in the National Health and Nutrition Examination Survey (NHANES) was based on the multi-indicator ferritin model. However, the model did not indicate the severity of ID and produced categorical estimates. More recently, iron status assessment in NHANES has used the total body iron stores (TBI) model, in which the log ratio of sTfR to SF is assessed. Together, sTfR and SF concentrations cover the full range of iron status. The TBI model better predicts the absence of bone marrow iron than SF concentratio alone and TBI can be analyzed as a continuous variable. Additional consideration of methodologies, interpretation of indicators, and analytical standardization is important for further improvements in iron status assessment.