Adjusting soluble transferrin receptor concentrations for inflammation: Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project

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Abstract

Background: Iron deficiency is thought to be one of the most prevalent micronutrient deficiencies globally, but an accurate assessment in populations who are frequently exposed to infections is impeded by the inflammatory response, which causes iron-biomarker alterations.

Objectives: We assessed the relation between soluble transferrin receptor (sTfR) concentrations and inflammation and malaria in preschool children (PSC) (age range: 6–59 mo) and women of reproductive age (WRA) (age range: 15–49 y) and investigated adjustment algorithms to account for these effects.

Design: Cross-sectional data from the Biomarkers Reflecting the Inflammation and Nutritional Determinants of Anemia (BRINDA) project from 11,913 PSC in 11 surveys and from 11,173 WRA in 7 surveys were analyzed individually and combined with the use of a meta-analysis. The following 3 adjustment approaches were compared with estimated iron-deficient erythropoiesis (sTfR concentration >8.3 mg/L): 1) the exclusion of individuals with C-reactive protein (CRP) concentrations >5 mg/L or α-1-acid glycoprotein (AGP) concentrations >1 g/L, 2) the application of arithmetic correction factors, and 3) the use of regression approaches.

Results: The prevalence of elevated sTfR concentrations incrementally decreased as CRP and AGP deciles decreased for PSC and WRA, but the effect was more pronounced for AGP than for CRP. Depending on the approach used to adjust for inflammation, the estimated prevalence of iron-deficient erythropoiesis decreased by 4.4–14.6 and 0.3–9.5 percentage points in PSC and WRA, respectively, compared with unadjusted values. The correction-factor approach yielded a more modest reduction in the estimated prevalence of iron-deficient erythropoiesis than did the regression approach. Mostly, adjustment for malaria in addition to AGP did not significantly change the estimated prevalence of iron-deficient erythropoiesis.

Conclusions: sTfR may be useful to assess iron-deficient erythropoiesis, but inflammation influences its interpretation, and adjustment of sTfR for inflammation and malaria should be considered. More research is warranted to evaluate the proposed approaches in different settings, but this study contributes to the evidence on how and when to adjust sTfR for inflammation and malaria.

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Adjusting plasma ferritin concentrations to remove the effects of subclinical inflammation in the assessment of iron deficiency: a meta-analysis.

David Thurnham, Linda D McCabe, Sumanto Haldar … (2010)

The World Health Organization recommends serum ferritin concentrations as the best indicator of iron deficiency (ID). Unfortunately, ferritin increases with infections; hence, the prevalence of ID is underestimated. The objective was to estimate the increase in ferritin in 32 studies of apparently healthy persons by using 2 acute-phase proteins (APPs), C-reactive protein (CRP) and alpha(1)-acid glycoprotein (AGP), individually and in combination, and to calculate factors to remove the influence of inflammation from ferritin concentrations. We estimated the increase in ferritin associated with inflammation (ie, CRP gt 5 mg/L and/or AGP gt 1 g/L). The 32 studies comprised infants (5 studies), children (7 studies), men (4 studies), and women (16 studies) (n = 8796 subjects). In 2-group analyses (either CRP or AGP), we compared the ratios of log ferritin with or without inflammation in 30 studies. In addition, in 22 studies, the data allowed a comparison of ratios of log ferritin between 4 subgroups: reference (no elevated APP), incubation (elevated CRP only), early convalescence (both APP and CRP elevated), and late convalescence (elevated AGP only). In the 2-group analysis, inflammation increased ferritin by 49.6% (CRP) or 38.2% (AGP; both P lt 0.001). Elevated AGP was more common than CRP in young persons than in adults. In the 4-group analysis, ferritin was 30%, 90%, and 36% (all P lt 0.001) higher in the incubation, early convalescence, and late convalescence subgroups, respectively, with corresponding correction factors of 0.77, 0.53, and 0.75. Overall, inflammation increased ferritin by ap 30% and was associated with a 14% (CI: 7%, 21%) underestimation of ID. Measures of both APP and CRP are needed to estimate the full effect of inflammation and can be used to correct ferritin concentrations. Few differences were observed between age and sex subgroups.

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Combined measurement of ferritin, soluble transferrin receptor, retinol binding protein, and C-reactive protein by an inexpensive, sensitive, and simple sandwich enzyme-linked immunosorbent assay technique.

Juergen Erhardt, John Estes, Christine M Pfeiffer … (2004)

The measurement of vitamin A (VA) and iron status is very important in the assessment of nutritional deficiencies. The objective of this research was to develop a sandwich ELISA technique for the simultaneous measurement of ferritin, soluble transferrin receptor, retinol binding protein, and C-reactive protein (CRP) as indicators for VA and iron status. The inclusion of CRP as marker of infection allows for more accurate interpretation of VA and iron status. This is accomplished in a 30-microL serum or plasma sample using an ELISA with different capture and detection antibodies and different dilutions of the sample. Commercially available clinical serum controls were used for calibration purposes. The developed assays were compared to commercially available traditional tests. Regression coefficients comparing both assays were better than 0.84 (P < 0.001). Using a limited sample set, the sandwich ELISA assay produced very similar specificity and sensitivity compared to traditional methods when common cutoff values were applied. Intra- and interassay variability was between 5 and 14% for all tests. The cost of the materials for all 5 measurements decreases to less than $1/sample if a large number of samples is analyzed. Due to the low cost, high throughput, and comparability to traditional tests, this procedure has several advantages for assessing VA and iron status in population surveys.

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Inflammation and Nutritional Science for Programs/Policies and Interpretation of Research Evidence (INSPIRE)12345

Daniel J Raiten, Fayrouz Ashour, A Ross … (2015)

An increasing recognition has emerged of the complexities of the global health agenda—specifically, the collision of infections and noncommunicable diseases and the dual burden of over- and undernutrition. Of particular practical concern are both 1) the need for a better understanding of the bidirectional relations between nutritional status and the development and function of the immune and inflammatory response and 2) the specific impact of the inflammatory response on the selection, use, and interpretation of nutrient biomarkers. The goal of the Inflammation and Nutritional Science for Programs/Policies and Interpretation of Research Evidence (INSPIRE) is to provide guidance for those users represented by the global food and nutrition enterprise. These include researchers (bench and clinical), clinicians providing care/treatment, those developing and evaluating programs/interventions at scale, and those responsible for generating evidence-based policy. The INSPIRE process included convening 5 thematic working groups (WGs) charged with developing summary reports around the following issues: 1) basic overview of the interactions between nutrition, immune function, and the inflammatory response; 2) examination of the evidence regarding the impact of nutrition on immune function and inflammation; 3) evaluation of the impact of inflammation and clinical conditions (acute and chronic) on nutrition; 4) examination of existing and potential new approaches to account for the impact of inflammation on biomarker interpretation and use; and 5) the presentation of new approaches to the study of these relations. Each WG was tasked with synthesizing a summary of the evidence for each of these topics and delineating the remaining gaps in our knowledge. This review consists of a summary of the INSPIRE workshop and the WG deliberations.

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Author and article information

Journal

Journal ID (nlm-ta): Am J Clin Nutr

Journal ID (iso-abbrev): Am. J. Clin. Nutr

Journal ID (publisher-id): ajcn

Title: The American Journal of Clinical Nutrition

Publisher: American Society for Nutrition

ISSN (Print): 0002-9165

ISSN (Electronic): 1938-3207

Publication date (Print): July 2017

Publication date (Electronic): 14 June 2017

Publication date PMC-release: 14 June 2017

Volume: 106

Issue: Suppl 1

Pages: 372S-382S

Affiliations

[1 ]GroundWork, Fläsch, Switzerland;

[2 ]Strengthening Partnerships, Results, and Innovations in Nutrition Globally, Arlington, VA;

[3 ]Helen Keller International, Washington, DC;

[4 ]Emory University, Atlanta, GA;

[5 ]Nutrition Branch, CDC, Atlanta, GA;

[6 ]Department of Nutrition and Food Science, University of Maryland, College Park, MD;

[7 ]International Food Policy Research Institute, Washington, DC;

[8 ] Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD; and

[9 ]Independent Public Health Nutrition Consultant, Cambridge, United Kingdom

Author notes

Address correspondence to FR (e-mail: fabian@ 123456groundworkhealth.org ).

Report of the collaborative research group called Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA), which was formed in 2012 by the Centers for Disease Control and Prevention (CDC), the Global Alliance for Improved Nutrition (GAIN), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). For additional information on the BRINDA project, please see www.BRINDA-nutrition.org

Supported by the Bill & Melinda Gates Foundation, the CDC, the Global Alliance for Improved Nutrition, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. This is an open access article distributed under the CC-BY license ( http://creativecommons.org/licenses/by/3.0/).

The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the CDC, the NIH, or the US Agency for International Development.

Supplemental Tables 1–5 and Supplemental Figure 1 are available from the “Online Supporting Material” link in the online posting of the article and from the same link in the online table of contents at http://ajcn.nutrition.org.

Author information

Fabian Rohner http://orcid.org/0000-0003-0579-6952

Sorrel ML Namaste http://orcid.org/0000-0002-6857-8461

O Yaw Addo http://orcid.org/0000-0003-1269-759X

Parminder S Suchdev http://orcid.org/0000-0002-0350-3469

Anne M Williams http://orcid.org/0000-0001-6599-9116

Article

Publisher ID: 142232

DOI: 10.3945/ajcn.116.142232

PMC ID: 5490651

PubMed ID: 28615256

SO-VID: 0a82f764-6164-44e3-906b-54ebadbc7ff1

License:

This is an open access article distributed under the CC-BY license ( http://creativecommons.org/licenses/by/3.0/).

Adjusting soluble transferrin receptor concentrations for inflammation: Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project

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Most cited references 31

Adjusting plasma ferritin concentrations to remove the effects of subclinical inflammation in the assessment of iron deficiency: a meta-analysis.

Combined measurement of ferritin, soluble transferrin receptor, retinol binding protein, and C-reactive protein by an inexpensive, sensitive, and simple sandwich enzyme-linked immunosorbent assay technique.

Inflammation and Nutritional Science for Programs/Policies and Interpretation of Research Evidence (INSPIRE)12345

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