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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 8 (October 15), 1998:
pp. 2934-2939
Serum Transferrin Receptor and Transferrin Receptor-Ferritin Index
Identify Healthy Subjects With Subclinical Iron Deficits
By
Pauli Suominen,
Kari Punnonen,
Allan Rajamäki, and
Kerttu Irjala
From the Central Laboratory, Department of Clinical Chemistry and
Department of Hematology, Turku University Central Hospital, Turku,
Finland.
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ABSTRACT |
Despite the established utility of serum transferrin receptor
(sTfR), serum ferritin, and the sTfR/log ferritin ratio (TfR-F Index)
in the diagnosis of iron deficiency (ID) anemia, the numeric values of
these parameters, which are indicative of subclinical ID, remain to be
clearly defined. In this study, 65 apparently healthy nonanemic adults
(22 men and 43 women) were treated with 3 months of oral iron
supplementation to evaluate its effect on parameters reflecting iron
status and to determine the prevalence of subclinical iron deficiency
in apparently healthy adults. Significant supplementation-induced
changes were observed in sTfR, ferritin, and TfR-F Index values in
women, whereas in men, none of the studied parameters showed any
significant change. Iron-deficient erythropoiesis (IDE) was not
observed in men, but was found in 17 women (40%). Although individuals
with a compromised iron status may be represented in substantial
numbers in conventional reference populations, they can be readily
identified using sTfR, ferritin, and TfR-F Index determinations.
© 1998 by The American Society of Hematology.
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INTRODUCTION |
IRON DEFICIENCY (ID) is generally
acknowledged to be the single most common nutritional deficiency
worldwide. In developed countries, the prevalence of iron deficiency
anemia (IDA) has decreased rapidly during the past few decades, whereas
the prevalence of subclinical ID has remained
substantial.1-3 Subclinical ID is especially common in
children aged 1 to 3 years, in adolescents of both sexes, in women of
childbearing age, and in the elderly population.4-8 Because
current methods permit the accurate diagnosis of uncomplicated IDA, the
focus of clinical interest has shifted to the detection of subclinical
ID and to the distinction of ID from other entities in the differential
diagnosis of anemia.9
Both serum ferritin and serum transferrin receptor (sTfR) are known to
undergo a characteristic sequence of changes, as body iron stores
decrease from normal iron-replete levels to those found in IDA
(Fig 1).10-13 During the
depletion phase (stage I), in which sTfR concentration remains stable,
there is a progressive decrease in serum ferritin. When the storage
deficit is sufficient to restrict the synthesis of hemoglobin and other
functional iron compounds, iron-deficient erythropoiesis (IDE) ensues
(stage II). The only indicator of early IDE is the compensatorily
elevated sTfR concentration.14,15 Finally, IDA (stage III)
develops as the hemoglobin (Hb) concentration falls below the lower
limit of normal as a result of progressive depletion of the functional iron compartment.
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| Fig 1.
Phases of advancing ID. The gradual diminution of the
different iron compartments and the concomitant changes seen in the
laboratory analytes are presented schematically in relation to the
separate stages of advancing ID. Typical laboratory findings are
displayed separately for each stage, and the normal values of sTfR,
ferritin, and sTfR/log ferritin (TfR-F Index) are presented as 95%
reference intervals obtained from our study population of apparently
healthy adults after 3 months of oral iron supplementation. Normal Hb
concentrations are the reference values currently applied at the Turku
University Central Hospital (TUCH). The criteria used to define the
different stages of ID appear boxed. The prevalences of the different
subgroups with various degrees of ID in our study population before the
supplementation are presented as determined by these criteria.
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Establishing reliable reference values for ferritin and sTfR to study
subclinical ID has been challenging because of the strict concepts of
conventional reference values and because reference limits have
generally been designed to distinguish nonanemic subjects from patients
with IDA.16-22 Furthermore, definite exclusion of subclinical ID from reference populations has rarely been achieved by
methods other than bone marrow sampling or iron supplementation trials.23,24 To fully exploit the obvious potentials of
ferritin and sTfR assays in diagnosis of subclinical ID, their dynamic properties need to be examined over a wide range of iron status. Additionally, because serum ferritin reflects the storage iron compartment and sTfR reflects the functional iron compartment, these
two values can be combined into a ratio, which is reciprocally regulated. The special value of sTfR/ferritin ratio and the sTfR/log ferritin index (TfR-F Index) in the differential diagnosis of IDA has
already been documented.14,16-18,25 Reanalysis of the reference values for ferritin and sTfR would enable this derivative to
be used more accurately in definition of the entire range of body iron
stores.
We evaluated the effect of 3 months of oral iron supplementation on the
iron status of healthy nonanemic subjects as reflected by serum
transferrin receptor, serum ferritin, serum transferrin, serum iron,
and transferrin saturation levels. Subgroups with iron depletion were
identified in this population by using sTfR, ferritin, and the sTfR/log
ferritin ratio measurements. The results of this study define values of
sTfR and the sTfR-F Index useful in detecting subclinical ID.
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MATERIALS AND METHODS |
Subjects.
The protocol of this study was approved by the Joint Committee of
Ethics of the Turku University Central Hospital and the University of
Turku. Seventy-five apparently healthy volunteers (25 men and 50 women;
age range, 22 to 60 years) received 3 months of oral iron
supplementation with daily administration of 100 mg of elemental iron
as ferrous sulfate. Of the 75 individuals starting the supplementation
treatment, 3 men and 6 women (12.0%) withdrew from the trial
prematurely because of adverse gastrointestinal effects. One of the
female volunteers was found to be anemic (Hb, 113 g/L) and was
subsequently excluded from the trial. The exclusion criteria used were
the Hb concentrations used to define anemia in our hospital (128 g/L
for men and 117 g/L for women). Therefore, a total of 65 subjects (22 men and 43 women) succesfully completed the trial. Of these 43 women, 3 were postmenopausal.
Study design.
The iron status of the subjects was assessed at onset of the study
(sample A) by assaying a venous blood sample for Hb, hematocrit, mean
corpuscular hemoglobin, mean corpuscular volume, erythrocyte count,
reticulocyte count, serum ferritin, serum iron, serum transferrin, and
serum transferrin receptor (sTfR). The sTfR/log ferritin ratio (TfR-F
Index) and transferrin saturation levels were also determined. Similar
tests were also performed weeks after the discontinuation of
supplementation (sample B), a total of 14 weeks after its initiation. None of the subjects had regularly used iron supplements, and none had
dietary restrictions. The effect of a possible concomitant infection
was excluded in all of the subjects by assessing the white blood cell
count, erythrocyte sedimentation rate, and C-reactive protein both
before and after supplementation.
Diagnostic testing.
Blood counts were measured using an automated analyzer (Technicon H*2;
Technicon Instruments Corp, Tarrytown, NY). Serum transferrin receptor
assays were performed with a commercial kit using a monoclonal antibody
in a sandwich immunoezymometric assay (IEMA) format (IDeA; Orion
Diagnostica, Turku, Finland). The method has been described in detail
elsewhere.24 Serum ferritin (the reference range at our
hospital: 20 to 240 µg/L for men, 10 to 100 µg/L for women) was
measured using an automated time-resolved immunofluorometric assay
(Autodelfia, Wallac, Turku, Finland). Serum transferrin (reference
range, 1.75 to 3.13 g/L) was measured using a Behring Nephelometer
(Behringwerke AG, Marburg, Germany) together with antibodies obtained
from Dakopatts (Dakopatts, Glostrup, Denmark). The method was
calibrated using the IFCC calibrator (BCR CRM No. 470; Community Bureau
of Reference, Commission of the European Communities, Brussels,
Belgium). Serum iron (reference range, 10 to 40 µmol/L)
was measured using an Iron FZ assay (Hoffman-LaRoche, Basel,
Switzerland) based on a guanidine hydrochloride/Ferrozine reaction.
Transferrin saturation was calculated as described by Huebers and
Finch.26
Statistical analyses.
The 95% reference intervals for the various parameters as well as the
90% confidence intervals for the respective reference limits were
calculated using the GraphROC for Windows software package
(Veli Kairisto, Department of Clinical Chemistry, Turku University
Central Hospital, Turku, Finland).27 The distribution scattergram was visualized using Fig P Software (Fig P Software, Durham, NC). All P values were calculated by Student's
t-test using the Microsoft Windows for Workgroups software
package (Microsoft Corp, Redmond, WA).
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RESULTS |
In the group of women, 3 months of supplementation with ferrous sulfate
produced a highly significant change in sTfR, ferritin, and TfR-F
Index. There was only a modest, but statistically significant, change
in serum iron (data not shown) and transferrin saturation (Table 1). In the group of men, the
parameters reflecting iron status were not significantly altered.
Changes in the sTfR and the TfR-F Index mainly occurred in subjects in
which these values were elevated in the samples taken before
supplementation. Changes in ferritin were more variable, also occurring
in subjects considered to be iron-replete on the basis of
presupplementation testing. The distribution of the TfR-F Index was
narrowed most markedly. Differences between male and female subjects
before supplementation were seen in sTfR (P < .0003),
ferritin (P < .0005), and the TfR-F Index (P < .00001). After supplementation, the difference in sTfR values between
men and women was eliminated (P < .4). However, differences
remained in ferritin values (P < .001) and consequently in
the TfR-F Index (P < .02). The significant difference between men and women in Hb, hematocrit, and erythrocyte count (P < .00001) remained unaffected by supplementation. No
supplementation-induced changes or significant differences between men
and women were observed in values of transferrin, iron, and transferrin
saturation.
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Table 1.
Results Within Four Parameters of Iron Status Showing
Significant Differences Between Samples Obtained Before and After a
3-Month Oral Iron Supplementation
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The prevalence of the nonanemic stages of ID in our population was
studied retrospectively by comparing the individual values of the
separate parameters in the presupplementation samples (sample A) with
the respective 95% reference intervals calculated from results
obtained after supplementation (sample B)
(Table 2 and Fig 1). The decision limit of
ferritin was set at 22 µg/L, as this concentration represented the
lower limit of the 95% reference interval in the group of supplemented
men (90% confidence interval, 22 to 38 µg/L). Furthermore, the
range, which contained all subjects with elevated sTfR (>2.75 mg/L)
before supplementation was 4 to 21 µg/L
(Fig 2). Of the 65 subjects who completed
the trial, 25 were retrospectively judged to have had storage iron
depletion (stage I) or depletion of the functional compartment (IDE,
stage II) (Fig 1). Supplementation-induced changes in these 25 subjects were highly significant as judged by sTfR, ferritin, and TfR-F Index
(Table 1). Changes observed in other parameters indicative of iron
status, including transferrin saturation, were absent or variable (data
not shown).
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| Fig 2.
Distribution of ferritin in subjects with normal sTfR and
those with elevated sTfR. The ferritin concentrations of iron-replete
and iron-deplete (diminished or exhausted iron stores) subjects (sTfR
<2.75 mg/L) are compared with the corresponding values of subjects
with IDE, ie, depletion of the functional iron compartment (sTfR
>2.75 mg/L). The solid, horizontal line represents the ferritin
concentration of 22 µg/L, which we suggest to be used as a cutoff
value for clinically relevant depletion of the storage iron
compartment.
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DISCUSSION |
The transition from the normal iron-replete state to the development of
IDA entails two sequential processes (Fig 1): depletion of the storage
iron compartment (stage I), followed by its exhaustion and the
consequent initiation of depletion of the functional iron compartment
in the setting of continued iron loss (stage II). There are no
additional physiologic phenomena associated with the development of IDA
(stage III), which is merely a sequel of progressive depletion of the
functional compartment. Though the mechanisms linking the changes in
iron status to the consequent changes observed in the various
measurements have been well-documented,11-15,25,28-30 accurate assessment of the iron status in an individual patient requires that the normal values established for various parameters be
reexamined.
In this study, a population sample of apparently healthy, nonanemic
adults was subjected to 3 months of oral iron supplementation to
produce an iron-replete population. The samples obtained before supplementation (A) had values similar to those used to establish reference values for the various indices of iron
status.31-34 Samples drawn after supplementation (B) were
considered to represent the values of an iron-replete population. The
prevalence of the nonanemic stages of ID were studied retrospectively
by comparing the individual values of the separate parameters in the
presupplementation samples with the corresponding 95% reference
intervals from the postsupplementation samples. The effects of iron
supplementation on the various laboratory values reflecting iron status
were expected to be in agreement with findings from earlier studies and
reviews.13,35,36
Ferritin measurements have been used to differentiate between normality
and IDA, and the reference limits have been designed accordingly.
However, disagreement still remains on the value, which indicates
clinically relevant storage iron depletion. This is mainly due to the
fairly large physiologic variability occurring between individual
patients.5,28 The fact that ferritin is a known acute-phase
reactant also complicates its use as a marker of ID in acute or chronic
inflammatory diseases.28,37-44 To define the cut-off value
for ferritin indicative of storage iron depletion, comparison was made
of the the presupplementation ferritin and TfR levels observed in
normals and storage iron-deficient patients with those observed in
patients having IDE (Fig 2). The range of ferritin values in the 17 female subjects with IDE was found to be 4 to 21 µg/L, which suggests
that concentrations <22 µg/L could be used to define clinically
relevant storage depletion. The lower limit of the 95% reference
interval in our sample of supplemented men was also 22 µg/L. Thus,
this concentration can be used as a cut-off value for both men and
women.13
Regarding the postsupplementation samples, the 3 months of oral iron
supplementation produced a significant increase in ferritin concentrations in virtually all of the women, irrespective of their
initial iron status. Four of the 17 women with IDE and very low initial
ferritin concentrations emerged from the trial with ferritin
concentrations of 17 to 18 µg/L and normalized sTfR. Excluding these
four subjects, the lower limit of the 95% reference interval for women
in samples taken after supplementation was also 22 µg/L (90%
confidence interval, 21 to 24 µg/L). The restoration of the storage
compartment is known to be initiated only after the immediate demand
for iron is met and any losses of the functional compartment halted.
Therefore, the supplementation used in this study seems to have been
insufficient for complete replenishment of the iron deficit in subjects
with functional depletion.
The data from sTfR measurements give a clearer picture of functional
iron status than ferritin measurements. sTfR concentrations remain
unaffected by any active acute-phase reactants, which has made sTfR
measurement an attractive tool for the differential diagnosis of
IDA.16-18 Its day-to-day variation is more acceptable than
that of the conventionally used indices of functional iron status, such
as transferrin saturation.45 Although sTfR concentrations are known to reflect the degree of depletion of the functional compartment well before IDA develops, most clinical experience comes
from settings where reference limits have been set to diagnose ID in
patients already anemic. We wished to modify the normal range of sTfR
measurements to permit the detection of the inception of IDE. sTfR
concentrations exceeding 2.75 mg/L (90% confidence interval, 2.34 to
2.84 mg/L), but not 3.6 mg/L (90% confidence interval, 3.26 to 3.72 mg/L; measured using the IDeA method of Orion Diagnostica) were deemed
to define a subgroup of individuals having depletion of the functional
iron compartment leading to IDE. For comparison, in a previous
study,19 an sTfR concentration of 3.6 mg/L was identified
as an optimal cutoff value for IDA. Supplementation induced a
significant decrease in sTfR in all 17 women with initial values
>2.75 mg/L, whereas little change was seen in the other women or any
men with initial values <2.75 mg/L. This observation supports earlier
findings about the stability of sTfR, which does not begin to increase
until the development of true tissue ID. The difference in sTfR levels
between men and women completely disappeared during the study,
indicating that the initial difference might be explained by IDE
present only in the women of our population sample. Consequently, the
95% reference interval, as suggested by the results obtained after
supplementation, became narrower and virtually identical for both men
and women. This is in agreement with previous studies, which have found
similar sTfR concentrations in men and women.20,31,46 In
our population, therefore, the elevated presupplementation range of
sTfR was likely due to subclinical ID.
The sTfR/log ferritin ratio (TfR-F Index) has been shown to distinguish
between iron-replete and iron-deplete anemic patients effectively, yet
its value in diagnosing nonanemic ID remains to be
verified.16 In the present study, the
supplementation-induced change was made most apparent by using the
TfR-F Index, indicating that the nonanemic stages of ID are readily
detectable using this index. Similar supplementation-induced changes
have been observed by Simmons et al.36 The TfR-F Index can
distinguish storage iron depletion (stage I) from IDE (stage II), such
that separate decision limits could be derived in the present study: a
ratio of 1.8 (90% confidence interval, 1.55 to 1.99) or greater for storage iron depletion and 2.2 (90% confidence interval, 1.81 to 2.53)
or greater for IDE (Fig 1). One subject considered normal presented
with a combination of borderline normal values of ferritin (22 µg/L)
and sTfR (2.43 mg/L), but a slightly elevated TfR-F Index (1.81) in the
presupplementation sample. This might indicate that in borderline
cases, when the results of sTfR and ferritin assays are ambiguous, the
TfR-F Index is more sensitive in the detection of iron-deficient
states.
The role of the individual tests of serum iron, serum transferrin, and
transferrin saturation should be reevaluated because of their
unpredictable variability and relative
insensitivity.7,14,16,47,48 Our findings indicate that sTfR
measurement could replace these procedures in the routine testing of
ID, as the subclinical ID present in our study population remained
undetected by these other methods, and the changes induced by
supplementation were sporadic and inconsistent (Table 1).
This study was undertaken in an attempt to characterize the different
stages of ID by means of serum ferritin, sTfR, and TfR-F Index
determinations. A relatively large number of women of childbearing age
were intentionally enrolled to permit inclusion of a larger proportion
of potential subjects with subclinical ID. Therefore, the data
presented in this study offer limited epidemiologic information. In our
opinion, the presence of IDE could be disclosed by sTfR concentrations,
whereas Hb determination is applicable to the detection of IDA. The
detection of reduced ferritin concentrations, on the other hand, could
indicate an increased risk of progressive ID, and together with sTfR,
distinguish between the two subclinical phases of ID. In certain
situations, emphasizing the importance of sTfR rather than the Hb alone
in the diagnostic algorithm might contribute to a more effective
preventive approach: a clinically silent ID could be detected when the
need for compensatory mechanisms arises, ie, well before IDA develops.
The limited availability of dietary iron almost never seems to be the
only explanation for ID in older children, adult men, and
postmenopausal women. Therefore, further investigation is often
promptly indicated to disclose the underlying cause of ID. In certain
situations where an increase in iron requirements can be expected, it
might be useful to regard elevated sTfR concentrations as the
manifestation of true ID, as an elevated concentration represents IDE.
This use of sTfR measurement offers a particular advantage over
ferritin determination in physiologic conditions, in which depletion of
the storage compartment is highly prevalent, such as infancy, early
childhood, adolescence, and pregnancy. In these conditions, ferritin
concentrations are usually close to the limit of ID, and monitoring
sTfR would show differences in functional iron status more accurately.
The combined use of ferritin, sTfR, and Hb determinations, along with
the TfR-F Index, facilitates the accurate determination of the iron
status of any given patient. The clinical condition of the individual
patient, however, dictates which measurement should be emphasized for
the diagnosis of ID and whether the diagnosis of ID warrants
monitoring, dietary counseling, iron therapy, or other measures.
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FOOTNOTES |
Submitted December 29, 1997;
accepted June 5, 1998.
Address reprint requests to Pauli Suominen, MD, Central Laboratory,
Turku University Central Hospital, PL 52, FIN-20521, Turku, Finland;
e-mail: pausuo{at}utu.fi.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
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Abstract
Introduction
Abstract