Inflammation and infection are known to affect measures of Iron deficiency (ID), and may lead to overestimation or underestimation of ID prevalence. Researchers investigated whether total body iron (TBI) values were subject to the same inaccuracies and found that TBI values underestimate the prevalence of ID in the presence of inflammation or infection and that adjustments must be made to record accurate values.
Iron deficiency (ID) is a common nutritional issue, often present in preschool children (PSC) and women of reproductive age (WRA). The World Health Organization (WHO) and Centers for Disease Control (CDC) recommend using measurements of ferritin and soluble transferrin receptor (sTfR) to measure the iron status of populations of interest. Both entities also suggest it may be useful to measure one or both acute phase proteins, C-reactive protein (CRP) and alpha-1-acid glycoprotein (AGP), to account for inflammation when interpreting ferritin concentration. Ferritin concentrations tend to increase when inflammation is present, which can lead to underestimation of the prevalence of ID at the population level, a significant concern in developing countries with high rates of inflammation or infection. Unlike ferritin, sTfR concentrations increase in ID and it is thought to be marginally influenced by the inflammatory response, despite findings that indicate sTfR values may be influenced by physiologic factors affecting erythropoietic activity, like malaria and low-grade chronic inflammation. This property may limit the use of sTfR as a marker of iron nutrition. Total body iron (TBI), developed by Cook and colleagues in 2003, is an estimate based on the ratio of sTfR to ferritin concentrations. It is a quantitative estimate, which expresses TBI based on an individual’s body weight and may allow for evaluation of the full range of iron status (deficiency to excess) within a population. Mei and colleagues hypothesized that the effects of inflammation may cancel each other out when calculating TBI, given that they are each affected in different directions by the inflammatory response. Their study, published in the American Journal of Clinical Nutrition, investigated whether inflammation-adjusted ferritin and sTfR concentrations affected TBI estimates, and subsequently, the prevalence of low TBI observed in PSC an WRA.
Researchers used data from the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project; obtained per country or region. Researchers included surveys which were conducted after 2004 and measured one or more markers of iron status (ferritin or sTfR) or vitamin A status (retinol-binding protein or retinol) and one or more markers of inflammation (AGP or CRP), as well as values for malaria in some countries.The target groups studied were PSC children (between 6-59 months) and WRA (between 15-49 years). A total of 8413 PSC and 4258 WRA observations were included in the analyses. Researchers calculated TBI from ferritin and sTfR concentrations. Mei and colleagues first calculated the prevalence of low TBI using unadjusted estimates of ferritin and sTfR values; they then calculated adjusted values to account for inflammation.
Results of the analyses demonstrate that prevalence of low TBI is underestimated if adjustments are not made for inflammation, especially in in children living in areas with a high prevalence of inflammation and infection. Ferritin concentrations that have been adjusted for inflammation reflect increased estimates of depleted iron stores and sTfR concentrations which have been adjusted for inflammation reflect decreased estimates of iron-deficient erythropoiesis. Therefore, the effects of inflammation on ferritin and sTfR do not cancel each other out when these values are used to calculate TBI. Adjustments made for malaria produced similar prevalence values of low TBI to those calculated using CRP or AGP; the authors concluded there is limited utility in adjusting TBI for malaria status.
Some limitations cited by the authors include: data was obtained from cross-sectional surveys, selection of data sets was based on convenience (those available from BRINDA study partners) and the lack of a gold-standard measure of iron status for comparison. They consider that the use of longitudinal data could provide more substantial information to separate nutritional ID from other physiologic influences and allow for examination of changes in TBI, CRP and AGP in response to an intervention. The use of CRP and AGP as markers for inflammation was also cited as a limitation, as values may not fully capture inflammation and produced biased results in making TBI adjustments. Other limitations of using TBI are the lack of a standard sTfR-assay method and a standard reference material. Mei and colleagues suggest that further studies are needed to investigate the validity of TBI as the best marker of ID as, during the development of TBI, inflammation was not accounted for.
Written By: Sara Alvarado BSc, MPH
Mei, Z., Namaste, S., Serdula, M., Suchdev, P., Rohner, F., Flores-Ayala, R., Addo, O., and Raiten, D. (2017). Adjusting total body iron for inflammation: Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project. DOI: 10.3945/ajcn.116.142307.