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.

Keywords: infection; inflammation; iron status; preschool children; serum ferritin; soluble transferrin receptor; total-body iron stores; women of reproductive age.

FIGURE 1

Prevalence of inflammation in PSC and WRA: the BRINDA project. Countries are ordered from lowest to highest inflammation on the basis of elevated CRP in PSC. AGP, α1-acid glycoprotein; BRINDA, Biomarkers Reflecting Inflammation and Nutrition Determinants of Anemia; CRP, C-reactive protein; PNG, Papua New Guinea; PSC, preschool children; WRA, nonpregnant women of reproductive age. Figured created from data presented in Merrill et al. (28) with permission.

FIGURE 2

Pooled estimated (95% CI) ID in preschool children according to ferritin and sTfR concentrations and TBI by CRP decile: the BRINDA project. The analysis was restricted to countries that measured both CRP and α1-acid glycoprotein; cutoffs to define estimated ID were as follows: ferritin concentration <12 μg/L, sTfR concentration >8.3, and TBI <0. The bold vertical line indicates the commonly used cutoff for CRP. BRINDA, Biomarkers Reflecting Inflammation and Nutrition Determinants of Anemia; CRP, C-reactive protein; ID, iron deficiency; sTfR, soluble transferrin receptor; TBI, total body iron. Adapted from Namaste et al. (30) with permission.

FIGURE 3

Estimated (95% CI) ID according to low ferritin concentrations by CRP decile in NHANES preschool children and nonpregnant women of reproductive age. The bold vertical line indicates the commonly used cutoff for CRP. The small sample size in preschool children led to missing values at CRP deciles 3, 8, and 10. CRP, C-reactive protein; ID, iron deficiency.