Clinical Chemistry 45: 1826-1832, 1999;
(Clinical Chemistry. 1999;45:1826-1832.)
© 1999 American Association for Clinical Chemistry, Inc.
Dried Plasma Spot Measurements of Ferritin and Transferrin Receptor for Assessing Iron Status
Carol H. Flowersa and
James D. Cook
Department of Medicine, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160-7402.
Portions of this work were presented at Exp Bio `99, April 17–21,
1999, Washington, DC, and have been published as an abstract: Flowers
CH, Cook JD. Plasma spotted onto filter paper for the assessment of
iron status. FASEB J 1999;13:A265.
a Author for correspondence. Fax 913-588-7031; e-mail cflowers{at}kumc.edu
 |
Abstract
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Background: Efforts to reduce the high global prevalence of
nutritional anemia require the use of both reliable laboratory assays
to distinguish iron deficiency from other causes of anemia and
cost-effective methods for collection of blood specimens under field
conditions. The suitability of using small plasma samples spotted and
dried on filter paper for measurements of plasma ferritin and
transferrin receptor was evaluated in the present study.
Methods: Blood specimens obtained from 73 male and 83 female
subjects (19–40 years) representing a wide range of iron status were
used to perform parallel measurements of plasma ferritin and
transferrin receptor on whole plasma and spotted plasma samples.
Results: Ratio plots, evaluating the acceptability and precision
of the spot method in ferritin and transferrin receptor assays, showed
the expected proportion of data points within the 95% prediction
interval. In the composite group of 156 subjects, both the whole plasma
and plasma spot methods gave a geometric mean transferrin
receptor/ferritin ratio of 18. The regression equation for the ratio
was logy = 1.045 logx -
0.05126; r = 0.986; P <0.0001. The
ratio of transferrin receptor/ferritin determined from plasma spots
correctly identified all 12 subjects with iron deficiency anemia
compared with 11 of the 12 for whole plasma measurements.
Conclusions: Measurements of ferritin and transferrin receptor on
plasma spotted and dried on filter paper are comparable to whole plasma
values for the identification of iron deficiency anemia. The use of
dried plasma spots will facilitate the collection, storage, and
transport of samples in epidemiological studies of anemia
prevalence.
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Introduction
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It has been estimated that approximately one-quarter of the
world's population, or more than one billion people, are anemic and
that the cause in more than one-half of these individuals is iron
deficiency (1). A variety of approaches for controlling iron
deficiency anemia
(IDA)1
have been proposed, including iron supplementation, food
fortification, nutrition education, reducing intestinal parasites, and
improving the bioavailability of dietary iron (2). Because
of the subtle manifestations of iron lack, the choice of a particular
intervention strategy and the assessment of its effectiveness are
heavily dependent on laboratory methods that will identify IDA
specifically and distinguish it from other causes of anemia that may be
encountered in prevalence surveys. The majority of traditional
measurements of iron status, such as serum iron, iron-binding capacity,
and red cell indices, require venous blood because of the relatively
large sample volumes required for these assays. In recent years, highly
sensitive and specific assays of iron status, such as those for plasma
ferritin and plasma transferrin receptor (TfR), have been developed
that require only a few microliters of sample and are, therefore,
readily performed on blood specimens obtained by finger-stick rather
than venous sampling (3)(4). These assays would
become even more effective if techniques were used that improved the
cost and efficiency of processing, transporting, and storage of
specimens obtained under field conditions.
An important evolving technology in the handling of blood specimens
obtained in epidemiological studies is the use of small volumes of
blood or plasma dried on filter paper. This approach has been used
effectively for detecting iodine deficiency
(5)(6) and for evaluating vitamin A status by
assay of retinol-binding protein (7). A spot method using
dried serum for ferritin measurements was reported recently
(8). In another recent study, the use of dried whole-blood
spots for tandem measurements of ferritin and TfR was evaluated
(9) and was highly reliable for identifying IDA. However,
the contribution of erythrocyte ferritin diminished the sensitivity of
whole blood compared with plasma for detecting milder iron deficiency
without anemia (ID). The purpose of the present investigation was to
assess the suitability of using dried plasma spots rather than whole
blood for tandem measurements of plasma ferritin and TfR to assess iron
status.
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Materials and Methods
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study population
Venous blood samples were obtained from 73 men and 83 women
ranging in age from 19 to 40 years (mean, 25 years). All subjects
without anemia were considered in good health. Separation into two
degrees of severity of iron deficiency was based on the hematocrit and
plasma ferritin concentration as follows: ID was considered present in
subjects with a plasma ferritin 
12 µg/L and a hematocrit 
37% in
women or 40% in men (10), whereas IDA was defined by the
same plasma ferritin criteria and a hematocrit <37% in women or
<40% in men. All specimens were obtained according to procedures
approved by the Human Subjects Committee of the University of Kansas
Medical Center.
laboratory methods
Blood was collected into Vacutainer Tubes containing EDTA as the
anticoagulant. After the microhematocrit was measured in duplicate, the
blood was centrifuged to remove red cells and 25 µL of plasma was
spotted in duplicate onto filter paper (filter paper no. 903;
Schleicher & Schuell) and dried at room temperature for at least 3
h. The plasma spot samples were stored at 4 °C for up to 3 weeks in
sealed plastic bags containing 10 g of calcium sulfate (Drierite;
W.A. Hammond Drierite) as a desiccant, until the day of assay. The
Drierite was contained within a porous pouch constructed in our
laboratory, as commercially available packets did not have sufficient
desiccating capacity. The remaining volume of plasma was stored in
microcentrifuge tubes at -30 °C.
Measurements on the eluted plasma spot samples and thawed whole plasma
from each subject were performed in the same immunoassay. To prepare
the plasma spot samples for assay, the entire spot was cut from the
filter paper and transferred to a conical microcentrifuge tube. One
milliliter of phosphate-buffered saline, pH 7.2 containing 0.5
mL/L Tween 20 (PBS-t) was then added. The tube was sealed and
placed on an end-over-end rotator for 2 h at 4 °C. Prior
studies on 10 replicate samples of whole blood demonstrated an elution
efficiency for measurements of ferritin and TfR ranging from 93% to
97% with a mean of 95% ± 0.01% (9).
Plasma ferritin and TfR were measured by ELISA using monoclonal
antibodies as both capture and indicator antibodies. For the ferritin
determination, 200 µL of the plasma spot eluate or whole plasma
diluted 1:20 in PBS-t was transferred to a microtiter plate, coated
previously with anti-ferritin antibody in 0.2 mol/L carbonate buffer at
pH 9.6, and incubated for 2 h at room temperature as described
previously (3). After the wells were washed with PBS-t, 200
µL of horseradish peroxidase-conjugated antiferritin antibody in
PBS-t containing 10 g/L bovine serum albumin was added to each
well and incubated an additional 2 h. The plate was again washed
with PBS-t, and after the addition of 200 µL of
3,3',5,5'tetramethylbenzidine substrate, the plate was incubated
for 30 min in the dark. The reaction was stopped with 50 µL of 2.5
mol/L sulfuric acid, and the absorbance was measured at 450 nm with a
Bio-Tek EL808 microplate reader (Bio-Tek Instruments). Ferritin values
were determined using a calibration curve constructed with known
concentrations of purified human liver ferritin plotted against the
absorbance. The purified calibrators were calibrated against the WHO
reference standard obtained from the National Bureau of Standards
(11). The TfR was assayed by a similar protocol using two
monoclonal antibodies to TfR and using intact transferrin receptor
purified from human placenta as the calibrator (4).
To determine the stability of dried spots under different storage
temperatures, plasma from 10 subjects was spotted onto filter paper in
three sets of four spots. Each set was stored at a different
temperature in zipsealed plastic bags containing Drierite in the
previously described desiccant pouches. Previous studies have shown
that desiccation is vital to the stability of the proteins during
storage (9). One set was stored at ambient temperature
(22–25 °C), the second at 4 °C, and the third at 37 °C. On
days 0, 7, 14, and 28, the spots were cut from the filter paper,
eluted as described above, and assayed for ferritin and TfR.
statistical analysis
The variability and precision of the whole plasma and plasma spot
methods for the measurement of ferritin and TfR were evaluated using
ratio plots as described by Andersen et al. (12). The
mean ratios were calculated by dividing the plasma spot values by the
whole plasma values, and the distribution of the ratios was plotted.
The total assay variances of the whole plasma and plasma spot
measurements for ferritin and TfR were calculated as the sum of the
within-assay variance, determined from 70 triplicate measurements
performed in the same assay, and the between-assay variance, calculated
from 30 triplicate measurements assayed on different days. The
within-subject variability was calculated on measurements obtained from
three different samples from each of 30 subjects, drawn on separate
days at 2-week intervals. Paired results were evaluated using the 95%
prediction interval (13). The acceptability of the plasma
spot method was evaluated according to analytical quality
specifications for imprecision as proposed by Cotlove et al.
(14).
Because of skewed distributions, statistical analyses on ferritin, TfR,
and TfR/ferritin values were performed on log-transformed data. The
difference between various laboratory values in normal ID, and
IDA subjects was assessed by ANOVA followed by comparisons between the
groups with the Scheffé test. Least-squares regression analysis
of log plasma spot vs log whole plasma values was used to compare
ferritin, TfR, and TfR/ferritin. Correlation was evaluated by the
Pearson product-moment. Statistical calculations were performed using
the Abstat statistical program (Anderson Bell).
|
Results
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The stability of plasma spotted onto filter paper during storage,
as assessed by assay of ferritin and TfR, is shown in Table 1
. There was no loss with either measurement when samples were
stored at 4 °C. At ambient temperature, the ferritin values were
constant with 4 weeks of storage, but the TfR values fell at day 14 and
28 by 7% and 11%, respectively. Higher losses occurred with storage
at 37 °C. The ferritin and TfR values declined by 22% and 21%,
respectively, at 7 days and by 51% and 56% at 14 days. These results
indicate that plasma spot samples can be stored with desiccant at an
ambient temperature <25 °C for up to 14 days and for at least 4
weeks at 4 °C without substantial loss of activity.
Of the 156 participants in the study, 124 had normal iron
status, 20 had ID, and 12 had IDA. The group with normal iron status
was composed of 55 women and 69 men who had mean hematocrit values of
42.3% ± 2.4% and 45.7% ± 2.3%, respectively, and geometric mean
plasma ferritin values of 64.6 µg/L (± 1 SD, 36.5–115.9 µg/L) and
30.2 µg/L (16.2–56.4 µg/L), respectively. The ID group was
composed of 18 women and 2 men. The composite mean hematocrit in these
subjects was 42.3% ± 2.0% and the geometric mean plasma ferritin was
7.2 µg/L (± 1 SD, 4.0–12.7 µg/L). Ten of the 12 individuals with
IDA were women. The mean hematocrit in the total group was 31.7% ±
4.4%, and the geometric mean plasma ferritin was 4.3 µg/L (± 1 SD,
2.6–6.9 µg/L). The composite geometric mean whole plasma ferritin
was 30.4 µg/L compared with of 46.5, 7.2, and 4.3 µg/L in normal,
ID, and IDA subjects, respectively (Table 2
).
For plasma spot ferritin measurements, the CVs for the within-,
between-, and total-assay variability were 7.1%, 11%, and 13%
(CVS), respectively. For whole plasma
measurements the within-, between-, and total-assay CVs were 4.9%,
9.2%, and 10% (CVP), respectively. Based on the
sum of the total variances for whole plasma and plasma spot ferritin,
the 95% prediction interval was 0.9268 ± 0.312 (12)
(Fig. 1
). Seven data points out of 156 were outside the prediction
interval, which is within the acceptance limits of analytical
imprecision. All of these data points were below the cutoff value of 12
µg/L for IDA, where a larger variation would be expected. The
within-subject variability of 18% obtained by our laboratory was the
same as that reported previously by Cooper and Zlotkin (15).
Applying the alternative acceptability criterion for imprecision as
described by Cotlove et al. (14), we calculated a value of
17% compared with the total analytical CV of 17%.
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Figure 1. Ratio plot comparing the results of plasma ferritin using
plasma spot and whole plasma measurements.
The mean ratio of paired samples is 0.93 and is shown as the
solid line. The dashed lines indicate the
95% prediction interval based on the sum of the total assay variances
and determined by the following formula: ratio ±
1.99(CVS2 +
CVP2)1/2 x ratio, where
CVS is the total CV for the spot method and
CVP is the total CV for the whole plasma method.
|
|
Regression analysis gave a high correlation between whole plasma and
plasma spot measurements. However, in the composite group, the plasma
spot ferritin values were significantly lower than whole plasma
(P <0.001). The paper ferritin measurements averaged 9%
less thanwhole plasma in the composite sample but varied from 7% less
in normal subjects to 12% and 21% less in ID and IDA subjects,
respectively. This trend to a greater disparity at lower ferritin
values is seen in Fig. 2
, although the absolute difference in plasma ferritin values
below 10 µg/L was <1 µg/L. These lower values are presumably the
result of incomplete elution of proteins.
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Figure 2. Relationship between log ferritin values obtained on dried
plasma spot and whole plasma samples.
The solid line represents the regression equation:
logy = 1.050 logx - 0.1146;
r = 0.987; P <0.0001. The
dashed line is the line of identity.
|
|
Similar findings were observed with TfR measurements. For plasma spot
TfR measurements, the within-, between-, and total-assay CVs were
3.3%, 7.9%, and 8.5% (CVS), respectively. For
whole plasma TfR measurements, the within-, between-, and total-assay
CVs were 3.8%, 6.8%, and 7.8% (CVP),
respectively. Based on the sum of the total variances for whole plasma
and plasma spot TfR, the 95% prediction interval was 0.9212 ±
0.211 (Fig. 3
). Nine data points were outside the 95% prediction interval a
compared with the predicted number of eight. The within-subject
variability for TfR was 10%, similar to 13% reported previously
(15). Applying the acceptability criterion for imprecision,
we calculated a value of 9.2%, compared with the total analytical CV
of 11%.
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Figure 3. Ratio plot comparing the results of plasma TfR using
plasma spot and whole plasma methods.
The mean ratio of paired samples is 0.92 and is shown as the
solid line. The dashed lines indicate the
95% prediction interval based on the sum of the total assay variances
and determined by the formula: ratio ±
1.99(CVS2 +
CVP2)1/2 x ratio, where
CVS is the total CV for the spot method and
CVP is the total CV for the plasma method.
|
|
Regression analysis yielded a high correlation between whole plasma and
plasma spot values (Fig. 4
). As in the case of ferritin determinations, plasma spot TfR
measurements were consistently lower than whole plasma values, with a
mean disparity in the composite group of 8% (P <0.001).
However, in contrast to ferritin measurements, greater differences
occurred at high rather than low TfR values. The geometric mean plasma
TfR of 5.2 mg/L in normal subjects (Table 2
) was similar to the
mean of 5.7 mg/L reported previously (4). The mean plasma
TfR in ID was identical to the mean in normal subjects and remained
within the normal range in all subjects with ID (Fig. 5
A). There was minimal overlap between normal subjects and the
increased whole plasma values observed in subjects with IDA; the value
in one normal subject fell within the range of IDA and the value in one
IDA subject fell within the range of normals. The degree of overlap in
plasma spot TfR values between normal and IDA subjects was roughly
similar to that observed with whole plasma measurements (Fig. 5B
).
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Figure 4. Relationship between log TfR values obtained on dried
plasma spot and whole plasma samples.
The solid line represents the regression equation:
logy = 0.9131 logx + 0.0287; r
= 0.985; P <0.0001. The dashed line is
the line of identity.
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Figure 5. Assay values for plasma spot TfR (A) and
whole plasma TfR (B).
The values are separated into three groups: normal,
ID, and IDA.
|
|
The major advantage of including TfR measurements in studies of anemia
prevalence and cause is the ability to distinguish between IDA and the
anemia of chronic disease (ACD), using the ratio of TfR/ferritin
(16)(17)(18). It was, therefore, of interest to assess the
correspondence in this index when based on whole plasma and
plasma spot measurements. Because the ferritin falls with iron
depletion whereas the TfR increases, the disparities observed between
whole plasma and plasma spot values of the ferritin and TfR were offset
when calculating the ratio (19). This produced identical
values of 11 for the ratio in normal subjects and only minor
differences of 73 and 77 in ID subjects and 333 and 384 in subjects
with IDA (Table 2
). The similarity between whole plasma and plasma spot
results was again reflected in a high correlation by regression
analysis (Fig. 6
). The ability to identify IDA with the TfR/ferritin ratio was
comparable in whole plasma and plasma spot measurements (Fig. 7
). Neither measurement showed any overlap between normal
and IDA subjects. The ratios in subjects with ID demonstrated a similar
degree of overlap between normal subjects and those with IDA when based
on whole plasma or plasma spot determinations.
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Figure 6. Relationship between log TfR/ferritin ratios obtained from
plasma spot and whole plasma samples.
The solid line represents the regression equation:
logy = 1.043 logx + 0.05126;
r = 0.986; P <0.0001. The
dashed line is the line of identity.
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Figure 7. Calculated TfR/ferritin ratios for plasma spot
(A) and whole plasma (B) samples.
Values are separated into three groups: normal,
ID, and IDA.
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|
Discussion
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One type of anemia that is often confused with IDA in prevalence
studies is ACD, which results from the impaired stimulation of red cell
production associated with a wide spectrum of infectious or
inflammatory illnesses. Several laboratory measurements that are used
to identify IDA, such as mean corpuscular volume, transferrin
saturation, and erythrocyte protoporphyrin concentration, are affected
similarly in IDA and ACD. This problem is often circumvented by
including plasma ferritin determinations, which are a reliable index of
IDA when a low value is detected in the presence of anemia. However,
the plasma ferritin concentration is increased in the presence of
inflammation or infection and therefore cannot reliably identify
concurrent IDA. There is mounting evidence that chronic disease with or
without iron deficiency accounts for a large proportion of the anemia
detected in certain developing countries. For example, in a recent
study of 93 anemic pregnant women living in Malawi, less than one-half
were found to have IDA (20).
The usual clinical method for identifying IDA when chronic illness is
common is to perform a bone marrow examination to detect the presence
or absence of stainable iron (21). This approach clearly is
impractical for large epidemiological studies. The measurement of
plasma TfR recently has emerged as a suitable alternative, especially
when performed in conjunction with plasma ferritin measurements. In a
recent clinical study, 129 patients with anemia underwent a diagnostic
bone marrow examination to determine the cause (18). There
were 48 patients with IDA, 64 with ACD, and 17 with both. Plasma TfR
was more reliable than plasma ferritin in distinguishing the cause of
anemia, but the optimal index was the TfR/ferritin ratio. The ratio
correctly identified all patients with either IDA or ACD and, with the
exception of a single patient, correctly identified the presence of IDA
in the 17 patients with concurrent infection or inflammation. If
confirmed in other studies, tandem measurements of plasma TfR and
ferritin will be a valuable addition to studies of anemia prevalence.
The present study was undertaken to determine whether dried plasma
spots can be used for measurements of plasma TfR and ferritin in
prevalence studies. Because of the small volume of specimen required
for these assays, blood can be obtained by finger-stick sampling. The
transportation and storage of specimens can be simplified when studies
are performed in rural areas without access to proper laboratory
facilities. We observed in the present study that spotted paper samples
could be stored at 4 °C for at least 4 weeks before assay when
sealed in plastic bags containing desiccant. Prior studies using dried
whole-blood spots demonstrated that storage up to 1 year at 4 °C
with desiccation does not lead to deterioration of the samples or loss
of protein activity. Because loss of ferritin and TfR activity can
occur at higher temperatures, it seems unwise to transport samples by
regular mail during summer months.
In a prior investigation, we evaluated the use of whole blood spotted
onto filter paper for measurements of TfR and ferritin (9).
The whole blood TfR concentration was nearly identical to plasma TfR
when corrections were made for the displacement of plasma by red cells
in the whole blood, but the whole blood ferritin concentration was
threefold higher than the plasma ferritin concentration because of the
contribution of erythrocyte ferritin. Despite the reduced utility of
the ferritin determination, the TfR/ferritin ratio in whole-blood spots
was able to correctly identify all 10 individuals with IDA. As in the
present investigation, subjects with ID but no anemia had TfR/ferritin
ratios that were intermediate between normal subjects and those with
IDA.
The choice between using whole blood or plasma for dried paper spots
depends on several considerations. The preparation of paper samples in
the field is easier with whole blood than with plasma because blood can
be spotted directly onto the filter paper, whereas plasma must obtained
either by centrifugation or by allowing samples to stand long enough
for the separation of red cells. On the other hand, an important
advantage of using plasma rather than blood is the highly predictable
relationship in ferritin determinations. In populations with a
relatively low prevalence of ID or IDA, the assessment of iron reserves
based on ferritin measurements is less reliable with whole blood than
with plasma. This consideration is less important in regions where the
prevalence of anemia is high because the separation between normal
individuals and those with IDA is similar when either whole-blood or
plasma spots are used. It should be emphasized, however, that subjects
with ACD, with or without concurrent IDA, were not included in the
prior evaluation of dried whole-blood spots (9) or in the
present study of dried plasma spots. It will be important to
compare these approaches in a setting where the prevalence of ACD and
IDA is high and can be distinguished clearly by a concurrent bone
marrow examination.
|
Footnotes
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1 Nonstandard abbreviations: IDA, iron deficiency anemia; TfR, transferrin receptor; ID, iron deficiency without anemia; PBS-t, phosphate-buffered saline + 0.5 mL/L Tween 20; CVS, total assay variance for plasma spot method; CVP, total assay variance for whole plasma method; and ACD, anemia of chronic disease. 
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Abstract
Introduction
