Assessment of iron status in settings of inflammation: challenges and potential approaches

Abstract

The determination of iron status is challenging when concomitant infection and inflammation are present because of confounding effects of the acute-phase response on the interpretation of most iron indicators. This review summarizes the effects of inflammation on indicators of iron status and assesses the impact of a regression analysis to adjust for inflammation on estimates of iron deficiency (ID) in low– and high–infection-burden settings. We overviewed cross-sectional data from 16 surveys for preschool children (PSC) (n = 29,765) and from 10 surveys for nonpregnant women of reproductive age (WRA) (n = 25,731) from the Biomarkers Reflecting the Inflammation and Nutritional Determinants of Anemia (BRINDA) project. Effects of C-reactive protein (CRP) and α1-acid glycoprotein (AGP) concentrations on estimates of ID according to serum ferritin (SF) (used generically to include plasma ferritin), soluble transferrin receptor (sTfR), and total body iron (TBI) were summarized in relation to infection burden (in the United States compared with other countries) and population group (PSC compared with WRA). Effects of the concentrations of CRP and AGP on SF, sTfR, and TBI were generally linear, especially in PSC. Overall, regression correction changed the estimated prevalence of ID in PSC by a median of +25 percentage points (pps) when SF concentrations were used, by −15 pps when sTfR concentrations were used, and by +14 pps when TBI was used; the estimated prevalence of ID in WRA changed by a median of +8 pps when SF concentrations were used, by −10 pps when sTfR concentrations were used, and by +3 pps when TBI was used. In the United States, inflammation correction was done only for CRP concentrations because AGP concentrations were not measured; regression correction for CRP concentrations increased the estimated prevalence of ID when SF concentrations were used by 3 pps in PSC and by 7 pps in WRA. The correction of iron-status indicators for inflammation with the use of regression correction appears to substantially change estimates of ID prevalence in low– and high–infection-burden countries. More research is needed to determine the validity of inflammation-corrected estimates, their dependence on the etiology of inflammation, and their applicability to individual iron-status assessment in clinical settings.

Reply to ST McSorley et al.

“…We would like to emphasize one of the key findings from the BRINDA project: that the relationships between examined biomarkers of inflammation (CRP, AGP) and biomarkers of nutrition (ferritin, serum soluble transferrin receptor, total body iron, retinol binding protein) were generally linear, such that even low levels of inflammation, below previously established cutoffs, changed nutrient biomarker concentrations (6–9). Thus, as different inflammation biomarkers are explored, we suggest continued use of a regression correction approach that accounts for the full range and severity of inflammation.…”

“…Applying the proposed BRINDA inflammation adjustment approaches in clinical settings remains an important research need (9). We thank the authors for emphasizing this point.…”

Integrating themes, evidence gaps, and research needs identified by workshop on iron screening and supplementation in iron-replete pregnant women and young children

“…A key confounder of the current hematologic indicators of iron status is inflammation because many of these indicators are acutephase proteins, including SF (2,27,28,31,32) and perhaps to a lesser extent sTfR (32). Even hepcidin concentration, the promising emergent indicator, is an acute-phase protein and will, therefore, be confounded by inflammation.…”

“…The multinational project Biomarkers Reflecting Inflammation and Nutrition Determinants of Anemia (BRINDA) explores approaches to adjust indicators of iron status for inflammation by using linear regression models based on indicators of acute (C-reactive protein) and chronic (a1-acid glycoprotein) inflammation. These adjustments have been developed and applied to SF concentration and TBI to reassess the prevalence of ID and IDA (32). For US women of reproductive age, the adjustment of TBI from NHANES resulted in a small increase in ID prevalence of 7% points.…”

Effect of total body iron on metabolic dysfunction among U.S. females in the Nhanes 2003-2010, aged 12-49.

“…Regardless of study design, however, serum ferritin and transferrin saturation have consistently been used in these investigations to estimate iron stores. Despite its clinical utility, ferritin is adversely affected by inflammation, with levels of serum ferritin rising under inflammatory conditions (44). In addition, transferrin saturation (TSAT), which is the ratio of serum iron to total iron binding capacity (TIBC), demonstrates diurnal variation (45) and increases in the presence of health conditions such as inflammation, cirrhosis, hepatitis and microbial infection (46)(47)(48)(49).…”