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American Journal of Clinical Nutrition, Vol. 87, No. 6, 1892-1898, June 2008
© 2008 American Society for Nutrition

ORIGINAL RESEARCH COMMUNICATION

Comparison of plasma ferritin concentration with the ratio of plasma transferrin receptor to ferritin in estimating body iron stores: results of 4 intervention trials1,2

Zhenyu Yang, Kathryn G Dewey, Bo Lönnerdal, Olle Hernell, Camila Chaparro, Seth Adu-Afarwuah, Erin D McLean, Roberta J Cohen, Magnus Domellöf, Lindsay H Allen and Kenneth H Brown

1 From the Program in International and Community Nutrition, Department of Nutrition, University of California, Davis, Davis, CA (ZY, KGD, BL, CC, SA-A, EDM, RJC, LHA, and KHB); the Department of Clinical Sciences, Pediatrics, Umeå University, Umeå, Sweden (OH and MD); and the US Department of Agriculture, Agricultural Research Service Western Human Nutrition Research Center, Davis, CA (LHA)

2 Reprints not available. Address correspondence to KH Brown, Program in International and Community Nutrition, University of California, Davis, Davis, CA 95616. E-mail: khbrown{at}ucdavis.edu.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Efforts to develop global programs for the control of iron deficiency require simple, low-cost, and accurate indicators of iron status.

Objective: We aimed to compare estimates of body iron (BI) stores, as calculated from either plasma ferritin concentration alone (BI-ferritin) or the ratio of plasma transferrin receptor (TfR) to ferritin (BI-TfR/ferritin).

Design: Data were analyzed from 4 previously completed, randomized intervention trials that enrolled infants, schoolchildren, or pregnant women (total n = 1189, after excluding subjects with elevated C-reactive protein).

Results: The correlation coefficients between BI-ferritin and BI-TfR/ferritin were >0.95 for all studies. The kappa index ranged from 0.5 to 1.0. All of the sensitivities of BI-ferritin for identifying persons with low iron stores (defined as BI-TfR/ferritin < 0 mg/kg body wt) were >0.90. All of the specificities were >0.90 except the study of pregnant women (specificity = 0.66). The effect sizes of iron intervention trials were significantly greater for change in iron reserves estimated by BI-TfR/ferritin than by BI-ferritin in 2 studies with larger effect sizes (1.11 compared with 1.00 and 1.56 compared with 1.44, respectively; P < 0.05) and 1 study with medium effect size (0.70 compared with 0.57; P < 0.05). However, there were no significant differences between estimates of these effect sizes for 1 study with a medium effect size and 1 study with a smaller effect size (0.78 compared with 0.83 and 0.37 compared with 0.35, respectively; P > 0.2).

Conclusion: Plasma ferritin concentration alone provides a good approximation of total BI reserves, as estimated by BI-TfR/ferritin, on the basis of high correlation, sensitivity, and specificity among nonpregnant persons with unelevated C-reactive protein.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Iron deficiency is the micronutrient deficiency that is most commonly recognized around the world, and it results in anemia, impaired neurobehavioral performance, and decreased physical work capacity (1). Despite the increasing implementation of iron-supplementation and -fortification programs, anemia remains a common problem globally (2). To plan and manage intervention programs to control iron deficiency, appropriate indicators of iron status are needed (3, 4). Because of the relative simplicity and lower cost of measuring hemoglobin, the hemoglobin concentration, rather than direct indicators of iron status, is commonly used to estimate the prevalence of iron deficiency. However, the hemoglobin concentration is affected by factors besides iron status, such as malaria, other systemic infections, hemoglobinopathies, and other nutrient deficiencies. Moreover, mild iron deficiency may not result in anemia (1). Thus, more-sensitive and more-specific indicators of iron status are preferable.

Plasma ferritin concentration generally reflects total body iron (BI) stores in most persons (5). However, the acute phase response induced by infection or systemic inflammation can elevate plasma ferritin concentration independent of the iron stores (6). Furthermore, once iron stores are depleted, the plasma ferritin concentration does not quantitatively reflect further reductions of the tissue iron pool (7). In addition, there is concern about the use of ferritin as an indicator of iron status during pregnancy, because of its low specificity (8). Plasma transferrin receptor (TfR) concentrations are a quantitative indicator of total-body TfR mass (9, 10). The major advantage of TfR as an indicator is the possibility of estimating the magnitude of the functional iron deficit once iron stores are depleted (7). The ratio of TfR to ferritin (TfR/ferritin) was designed to evaluate changes in both stored iron and functional iron and was thought to be more useful than either TfR or ferritin alone. TfR/ferritin has been used to estimate BI stores in both children and adults (11). However, the high cost and the lack of standardization of the TfR assay so far have limited the applicability of the method.

Previous studies showed that plasma ferritin alone is a good indicator of BI stores when the ferritin concentration is above the generally accepted cutoff—ie, 12 µg/L (12, 13). However, it is not certain whether plasma ferritin concentration alone provides as suitable an estimation of BI stores as does TfR/ferritin across the full range of iron status and physiologic conditions. Thus, the goal of our present analyses was to compare plasma ferritin concentration alone with TfR/ferritin for estimating total BI stores, using data from 4 previously completed studies. BI stores can be measured both for population iron status assessment and for quantifying the change in iron stores in response to particular interventions, and therefore both applications were examined.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
The data were obtained from 4 randomized clinical trials carried out in 5 countries, as summarized in Table 1Go. In the Sweden-Honduras study (14), infants 4 mo of age were randomly assigned to receive 1) iron supplements [1 mg elemental Fe·kg body wt–1·d–1 as ferrous sulfate (Fer-In-Sol; Mead Johnson, Evansville, IN)] from 4 to 9 mo of age (4–9 group); 2) placebo from 4 to 6 mo of age and iron supplements [1 mg elemental Fe·kg body wt–1·d–1 as ferrous sulfate (Fer-In-Sol)] from 6 to 9 mo of age (6–9 group); or 3) placebo from 4 to 9 mo of age (placebo group). Venous blood was drawn at 4, 6, and 9 mo of age to assess iron status. In the Mexico study, mother-infant pairs were randomly assigned to have delayed or early umbilical cord clamping ({approx}2 min or {approx}10 s after delivery, respectively). Venous blood was obtained from the mothers at the time of delivery and from the infants at 6 mo of age to assess iron status (15). In the Ghana study, infants 6 mo old were randomly assigned to 1 of 3 daily micronutrient supplement groups: 1) Sprinkles (Ped-Med Ltd, Toronto, Canada; 12.5 mg elemental Fe/d as ferrous fumarate) (16); 2) Nutritabs (Laboratoires Pharmaceutiques Rodael SA, Bierne, France; 9 mg elemental Fe/d as ferrous sulfate) (17); or 3) Nutributter (Nutriset SA, Malaunay, France; 9 mg elemental Fe/d as ferrous sulfate) (18). Venous blood was collected at 6 and 12 mo of age from children enrolled in the intervention and at 12 mo of age from infants in a nonintervention comparison group (19). In the Senegal study, schoolchildren were assigned to one of the following treatments: 1) 30 mg Fe (as ferrous sulfate) + 200 µg folic acid/wk; 2) 60 mg Fe (as ferrous sulfate) + 400 µg folic acid/wk; 3) multiple micronutrients (including 30 mg Fe and 200 µg folic acid)/wk; or 4) a placebo weekly for 17–20 wk. Iron status was assessed at the end of the study (ED McLean, unpublished observations, 2005). In all studies, plasma ferritin, TfR and C-reactive protein (CRP) concentrations were measured.


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  		TABLE 1. Characteristics of subjects at each study site1

 
Subjects
The target sample sizes were calculated for the purposes of the original trials and were not calculated specifically for the present analyses. Because plasma ferritin is an acute phase protein, which becomes elevated in the presence of infections and systemic inflammation (6), we included in the main analyses only subjects with CRP < 10 mg/L (20).

Sample collection and laboratory analysis
Venous blood was collected in lithium heparin–or EDTA-coated tubes, and plasma separated from these samples was stored at –20 °C until analysis. Plasma ferritin concentrations were analyzed by using immunoradiometric assay kits (Coat-A-Count Ferritin IRMA; Diagnostic Products Corp, Los Angeles, CA). Plasma TfR concentrations were measured by using enzyme immunoassay kits (Ramco Laboratories Inc, Houston, TX). Both ferritin and TfR were analyzed in duplicate, and any samples with a high CV (CV > 15%) were repeated. CRP was analyzed by using radial immunodiffusion kits (The Binding Site, Birmingham, United Kingdom). Control materials were included in TfR and CRP kits. The average CV for CRP measurements in our laboratory was 1.6% (n = 123), and the between-day CV was 5.0% (n = 28) for the serum control samples provided by the manufacturer. Ferritin controls were obtained from Diagnostic Products Corp. The average CV for ferritin measurements in our laboratory was 7.4% (n = 20), and the between-day CV was 5.6% (n = 10) for the serum control samples (ferritin concentration = 33 µg/L) provided by the manufacturer. The average CV for TfR measurements in our laboratory was 5.8% (n = 62), and the between-day CV was 9.7% (n = 31) for the serum control samples (TfR concentration = 15.6 mg/L) provided by the manufacturer.

Statistical analysis
BI stores based on ferritin alone [BI-ferritin (mg/kg)] were calculated by using the following formulas (13): for infants (≤12 mo of age),

Formula 1(1)
and for pregnant women and older children,

Formula 2(2)
BI stores based on TfR/ferritin [BI-TfR/ferritin (mg/kg)] were calculated by using the following formula (4):

Formula 3(3)
Univariate distributions and measures of central tendency were examined for all variables. Both BI-ferritin and BI-TfR/ferritin were slightly skewed (most values for skewness and kurtosis were within –1 and 1). Paired Wilcoxon's tests were used to compare BI-ferritin and BI-TfR/ferritin within each study. Cross-tabulations and correlations were tested for each pair of BI-ferritin and BI-TfR/ferritin values across all studies to assess their agreement. BI stores < 0 mg/kg body wt were defined as low BI stores. McNemar's tests were used to measure agreement in the prevalence of low BI stores between BI-ferritin and BI-TfR/ferritin. To diagnose low BI stores, BI-TfR/ferritin was used as the reference technique, and both the sensitivity and specificity of BI-ferritin were calculated. Effect sizes of interventions on BI stores were calculated for the 3 studies that found a significantly different effect between intervention and control groups. First, the differences of BI between posttreatment and pretreatment measurements were calculated in the Sweden-Honduras study. Second, a general linear model of the difference in BI between the Sweden-Honduras, Mexico, and Ghana studies was built with treatment group as the independent variable. In the Ghana study, the 3 treatment groups were combined into 1 group, because there were no significant differences in BI among the 3 treatments (P > 0.9). Third, BI-ferritin and BI-TfR/ferritin were standardized by using the following formula:

Formula 4(4)
where MSE = mean square error. Then the differences between the BI-ferritin z score and the BI-TfR/ferritin z score in the treatment and control groups were compared by using t tests. SAS software (version 9.0; SAS Institute Inc, Cary, NC) was used in all the analyses, and scatter plots were drawn by using SIGMAPLOT software (version 9; Systat Software Inc. Richmond, CA).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The rates of elevated CRP ranged from 1.0% to 10.9% in all age groups across the 4 studies, except among the pregnant women in Mexico (23.6%) and 12 mo old infants in the Ghana study (13.6%) (Table 1Go). The subjects with elevated CRP were excluded from subsequent analyses. As shown in Table 1Go, iron status varied widely across study sites and age groups. The median plasma ferritin concentration was highest in younger infants (125 µg/L in 4-mo-old Swedish infants), intermediate in the older children (medians ranged from 24 to 76 µg/L) and lowest in the pregnant women (11 µg/L). By contrast, the median plasma TfR concentrations ranged from 4.5 mg/L among pregnant women to 8.0 mg/L among older children, and the median TfR/ferritin ranged from 1.8 in the younger infants to 2.6 in the pregnant women.

The median amounts of total BI reserves and the prevalence of low BI stores as estimated from BI-ferritin and BI-TfR/ferritin are shown by study and age group in Table 2Go. There were small, but statistically significant, differences between BI-ferritin and BI-TfR/ferritin in each age group, although the directions of the differences were not consistent among groups. There were no differences in the prevalence of low BI stores (<0 mg/kg body wt), as estimated by ferritin concentration alone or by TfR/ferritin, in any of the studies or age groups (P ≥ 0.05) except pregnant women, in whom BI-ferritin identified a significantly higher percentage with low BI stores (P < 0.001, Table 2Go). As shown in Figure 1Go, BI-ferritin and BI-TfR/ferritin were highly correlated (r > 0.95, P < 0.001) in all age groups.


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  		TABLE 2. Comparison of body iron (BI) stores as estimated by ferritin alone or the ratio of transferrin receptor to ferritin (TfR/ferritin) by age group in intervention trials1

 

Figure 1
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  		FIGURE 1.. A: Correlation between body iron (BI)-ferritin and the ratio of BI-transferrin receptor (TfR) to ferritin (BI-TfR/ferritin) in Swedish and Honduran infants at 4 mo of age. n = 226; r = 0.96, P < 0.001. B: Correlation between BI-ferritin and BI-TfR/ferritin in Swedish, Honduran, Mexican, and Ghanaian infants at 6 mo of age. n = 768; r = 0.96, P < 0.001. C: Correlation between BI-ferritin and BI-TfR/ferritin in Swedish and Honduran infants at 9 mo of age. n = 203; r = 0.96, P < 0.001. D: Correlation between BI-ferritin and BI-TfR/ferritin in Ghanaian infants at 12 mo of age. n = 293; r = 0.97, P < 0.001. E: Correlation between BI-ferritin and BI-TfR/ferritin among Senegalese schoolchildren (9–15 y old). n = 70; r = 0.96, P < 0.001. F: Correlation between BI-ferritin and BI-TfR/ferritin among pregnant Mexican women at term. n = 333; r = 0.96, P < 0.001.

 
The sensitivity and specificity of BI-ferritin for predicting low BI stores, as determined by BI-TfR/ferritin, were > 0.90 except in the group of pregnant women, in whom specificity was lower (specificity = 0.66) (Table 3Go). As shown in Table 4Go, there were either high or moderate levels of agreement between BI-ferritin and BI-TfR/ferritin in the different studies, as indicated by the kappa coefficients, which ranged from {approx}0.5 to 1.0 (P < 0.01).


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  		TABLE 3. Sensitivity and specificity of body iron (BI)-ferritin for identifying low BI stores1

 

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  		TABLE 4. Concordance between ferritin alone and the ratio of transferrin receptor to ferritin for identifying low body iron stores (<0 mg/kg body wt) by age group

 
To determine the ability of BI-ferritin to measure the effect of iron interventions, the effect sizes (ie, the differences between the respective treatment groups divided by their pooled SD) of 3 of the intervention trials in infants were compared by using data derived from both BI-ferritin and BI-TfR/ferritin. When there was a lower effect size [Mexico (0–6 mo)], there was no significant difference in the effect sizes measured by BI-ferritin and BI-TfR/ferritin (0.37 compared with 0.35, respectively; P > 0.2). When there was a medium effect size [Ghana (6–12 mo); Sweden and Honduras (4–6 mo)], the estimates of effect sizes derived from BI-TfR/ferritin were slightly but significantly greater than those derived from BI-ferritin in the Ghana study (0.70 compared with 0.57, respectively; P < 0.05), but there was no significant difference in the effect sizes measured by BI-ferritin and BI-TfR/ferritin in Sweden and Honduras (4–6 mo; 0.78 compared with 0.83, respectively; P > 0.2). When there was a larger effect size [Sweden and Honduras (6–9 mo and 4–9 mo)], the estimates of effect sizes derived from BI-TfR/ferritin were slightly but significantly greater than those derived from BI-ferritin (1.11 compared with 1.00 and 1.56 compared with1.44, respectively; P < 0.05) (Table 5Go). When analysis was stratified by initial iron status, BI-TfR/ferritin yielded a significantly greater effect size than did BI-ferritin only in the subgroup that had low BI stores at the beginning of the study (BI-TfR/ferritin < 0 mg/kg body wt) (2.04 compared with 1.47, respectively; P < 0.001). There were no significant differences within the subgroup whose BI-TfR/ferritin was initially >0 mg/kg body wt, even though the sample size was much larger in this latter group (1.00 compared with 0.95, respectively; P = 0.42) (Table 6Go).


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  		TABLE 5. Effect sizes of change in body iron (BI) stores after different interventions, estimated by using ferritin alone or the ratio of transferrin receptor to ferritin (TfR/ferritin)

 

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  		TABLE 6. Comparison of effect sizes for change in body iron (BI) stores after intervention between ferritin alone and the ratio of transferrin receptor to ferritin (TfR/ferritin) by initial iron stores1

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
These analyses indicate, that for most programmatically relevant purposes, total BI reserves (ie, iron status) can be measured as effectively by using plasma ferritin concentration alone as by using the more cumbersome and expensive method that relies on TfR/ferritin. Our results showed that the sensitivity of BI-ferritin was >0.9 for detecting low BI stores, which is the situation when ferritin alone may be expected to be a less sensitive indicator of iron status. In addition, there was no significant difference in effect sizes between BI-ferritin and BI-TfR/ferritin when the effect size of change in iron reserves following intervention was <0.5. In contrast, there were significant differences (except among 4–6-mo-old infants in Sweden and Honduras) in the estimated effect sizes when these were >0.5, mainly because these larger effect sizes occurred when initial iron stores were very low, and BI-TfR/ferritin probably provides a more accurate assessment of iron status under these conditions. Nevertheless, this discrepancy in the estimates of the magnitude of response to intervention is probably of less practical importance, because a large response (>0.5) was detectable with both indicators.

The generally high sensitivity and specificity of BI-ferritin indicate its ability to distinguish iron-deficient persons from those who are iron-replete in population assessment. The low specificity of BI-ferritin among pregnant women could be due to physiologic expansion of blood volume during pregnancy. According to previous studies, the plasma ferritin concentration falls dramatically during pregnancy even when women are supplemented with high doses of iron, but the concentration of TfR does not change (21, 22). Thus, TfR/ferritin would be greater, and apparent iron reserves from BI-TfR/ferritin as well as those from BI-ferritin would be less in pregnant women than in nonpregnant women. In other words, BI-TfR/ferritin and BI-ferritin both tend to underestimate the BI reserves during pregnancy, and any differential degree of underestimation may partially explain the low specificity of BI-ferritin.

Earlier studies consistently showed that ferritin has sensitivity and specificity similar to those of TfR/ferritin for distinguishing anemia with and without iron deficiency (23). Although some studies showed that TfR made a significant contribution to the detection of iron deficiency (24, 25), other studies showed that TfR did not improve the diagnosis of iron deficiency above ferritin alone (26, 27). The cost of BI-ferritin is much lower than the cost of BI-TfR/ferritin, which is an important consideration for population assessment.

The second purpose of determining BI stores is to evaluate the effect of iron-intervention programs or the effects of other mineral supplements on iron status. One previous review concluded, as the present study does, that ferritin is similar to BI-TfR/ferritin for determining the effect size of iron intervention trials (3). Several reports are also available on the effects of zinc supplements on iron status, and the results of these trials showed that ferritin performed as well as or better than TfR in detecting the effects (28-30).

A notable strength of the current analysis is the wide range of iron status among the studies that were included, which makes broader generalization possible. To further enhance the feasibility of applying BI-ferritin for population assessment, it may be possible to use a dried serum spot method to measure plasma ferritin concentrations in capillary blood (31).

There are a few limitations of using BI-ferritin to estimate BI stores. The most important one is that the ferritin concentration is affected by the acute phase reaction (eg, systemic inflammation and infection), thereby falsely elevating the estimate of BI stores. Nevertheless, BI-TfR/ferritin is also affected by these situations. In either case, it would be important to measure an acute phase protein to identify persons with systemic inflammation. In the present studies, CRP was elevated in only 10.8% of persons overall, and thus we were able to compare BI-ferritin and BI-TfR/ferritin in most persons in each population. However, even when subjects with elevated CRP were included in the analyses, the relation between BI-ferritin and BI-TfR/ferritin across study populations was very similar to that found when those subjects were excluded (data not shown). With all subjects included, the correlation coefficients between BI-ferritin and BI-TfR/ferritin were all >0.95. The kappa indexes still ranged from 0.5 to 1.0. All of the sensitivities of BI-ferritin were >0.90, and all of the specificities were >0.90 except in the study of pregnant women (specificity = 0.67). The effect size comparison results were also similar to those when subjects with elevated CRP were excluded.

We also examined the comparability of the 2 approaches separately for the subgroup of subjects with elevated CRP (data not shown). As expected, the median amounts of total BI reserves estimated by the 2 approaches for subjects with elevated CRP were significantly (P < 0.01) higher than those for the subjects without elevated CRP, except in the study of 4- and 9-mo-old infants (data not shown). However, the estimates using the 2 approaches were still highly correlated within this subgroup (r > 0.82). Because the number of persons in each of the cells was small, it was not appropriate to calculate the Kappa index, sensitivity or specificity. It should be noted that using CRP alone as a marker of infection or inflammation could have resulted in misclassification of some subjects. However, this is unlikely to have affected the above findings. A second potential limitation is that the magnitude of the plasma ferritin response to interventions may be less than expected during early infancy until 6–9 mo of age, although this may be more relevant for dietary interventions (32) than for iron supplementation (14, 33).

Overall, the high sensitivity and specificity of BI-ferritin make it an appropriate indicator by which to assess BI stores across a broad range of iron status. Because of its lower cost and the greater availability of reference material than with BI-TfR/ferritin, BI-ferritin is a suitable method for assessing iron status of populations and the response to iron intervention programs. At least one acute phase protein (such as CRP or an alternative biomarker) also should be measured to identify those persons whose plasma ferritin concentration may be falsely elevated by concurrent infection or inflammation.


   ACKNOWLEDGMENTS
 
We appreciate the statistical advice provided by Janet M Peerson (University of California, Davis).

The authors’ contributions were as follows—ZY, KGD, and KHB: the design of the study, analysis and interpretation of data, and preparation of the manuscript; KGD, BL, OH, CC, SA-A, EDM, RJC, MD, LHA, and KHB: the design, implementation, and analysis of the original clinical trials; and all authors: review and critique of the manuscript. None of the authors had a personal or financial conflict of interest.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Received for publication August 18, 2007. Accepted for publication March 5, 2008.




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E. E Ziegler, S. E Nelson, and J. M Jeter
Iron status of breastfed infants is improved equally by medicinal iron and iron-fortified cereal
Am. J. Clinical Nutrition, July 1, 2009; 90(1): 76 - 87.
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