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Enzymes and Protein Markers |
1
Divisions of Laboratory Medicine and
2
Hematology, Departments of Pathology and Medicine, Washington University School of Medicine, St. Louis, MO 63110.
a Address correspondence to this author at: Division of Laboratory Medicine, Box 8118, 660 S. Euclid Ave., St. Louis, MO 63110. Fax 314-362-1461; e-mail mscott{at}labmed.wustl.edu.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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12 µg/L) had a sensitivity of 25% and a
specificity of 98%. However, the sensitivity and specificity of
ferritin could be improved to 92% and 98%, respectively, by using a
diagnostic cutoff value of 30 µg/L, resulting in a positive
predictive value of 92%. Ferritin and sTfR were also measured in 267
outpatient samples and 112 medical students. In the outpatient group,
the two tests agreed in 73% of the samples; however, 25% of the
samples had ferritin values >12 µg/L and increased sTfR. Among the
medical students, there was 91% agreement between the two tests, but
7% of the samples had ferritin 12 µg/L and normal sTfR. Together,
these data suggest that measurement of sTfR does not provide sufficient
additional information to ferritin to warrant routine use. However,
sTfR may be useful as an adjunct in the evaluation of anemic patients,
whose ferritin values may be increased as the result of an acute-phase
reaction. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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12 µg/L is a highly specific
indicator of iron deficiency (2). Other commonly used
laboratory tests such as serum iron, total iron-binding capacity, mean
corpuscular volume, and transferrin saturation provide little
additional diagnostic value over ferritin (3)(4)(5). However,
because ferritin is an acute-phase reactant, diagnosis of iron
deficiency in hospitalized or ill patients can be difficult, as such
patients may have normal or increased ferritin values even when iron
deficient. The low sensitivity of ferritin for iron deficiency in these
patients may require a bone marrow biopsy or a trial of iron therapy to
differentiate iron deficiency from other causes of anemia. Therefore,
it would be useful if a noninvasive laboratory test could accurately
predict the results of biopsy-proven iron deficiency. The soluble transferrin receptor (sTfR), a truncated form of the membrane-associated transferrin receptor (6)(7), has been reported to be a sensitive indicator of iron deficiency and is not an acute-phase reactant (8)(9)(10)(11). As such, it has been proposed as a laboratory test to identify iron deficiency in hospitalized and chronically ill patients and thus reduce the need for a bone marrow biopsy or trial of iron therapy (8)(9). Circulating concentrations of sTfR are proportional to cellular expression of the membrane-associated TfR (12)(13). Cellular expression of the TfR increases with increased cellular iron needs and cellular proliferation (12)(13). Because patients with aplastic anemia or bone marrow ablation have sTfR values ~40% of normal, erythroid precursors are believed to contribute ~60% of the sTfR in plasma. The increased sTfR concentration observed in patients with iron-deficient erythropoiesis reflects this abundant erythroid precursor expression (14)(15)(16). However, other conditions associated with erythroid hyperplasia, such as ß-thalassemia (16)(17) and autoimmune hemolytic anemia (14), also increase the sTfR concentration, suggesting that a high value will not always be specific for iron deficiency. We examined the sTfR and ferritin concentrations in a variety of clinical settings to compare their diagnostic performance in ill patients and in individuals presumed to be healthy.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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36% for
females and 39% for males as determined with a Model STKS Coulter
Counter. Five populations were examined. The nonanemic group consisted
of 103 nonanemic second-year medical students, out of 112 students who
had submitted anonymous samples as part of a pathology course, and 101
nonanemic adult outpatients with samples submitted previously for
routine clinical chemistry testing. The bone marrow group consisted of
54 anemic adult patients at our institution who were undergoing their
first bone marrow aspirate in which a serum or plasma sample was
available within 5 days of the bone marrow aspiration. The microcytic
anemia group consisted of plasma samples from 43 microcytic patients
(mean corpuscular volume <70 fl) whose samples were submitted for
hemoglobin electrophoresis. The medical student group consisted of all
112 samples from the medical students mentioned above. The routine
ferritin group consisted of 267 consecutive serum samples received by
the clinical chemistry laboratory for routine ferritin analysis.
Hematocrit determination was also requested in 225 of these patients,
and 194 (86%) were anemic.
Bone marrow aspirates.
Samples were collected in EDTA, and
coverslips were prepared and stained for iron with Prussian blue.
Positive and negative controls were performed with each sample. Samples
from patients whose bone marrow showed replacement of normal
hematopoietic elements with malignancy were excluded. At least three
spicules were examined in each sample, and stainable iron was
determined to be absent or present by a hematopathologist blinded to
the results of the sTfR and ferritin studies.
Immunoassays.
sTfR values were determined by using a
polyclonal sandwich immunoassay (R&D Systems, Minneapolis, MN). All
samples were tested in duplicate, and values reported are the means of
the duplicate analyses. In 16 of the total 577 samples tested,
duplicate values did not agree within 15% and were, therefore,
repeated in a subsequent assay. The mean values from the subsequent
assay are reported. Interassay precision was determined by assaying two
concentrations of control samples on each plate. Only plates where both
control sample values were within 2 SDs of the mean were used to
determine the values reported here. Results from 2 of 22 assay kits
were discarded because of unacceptable values for the control samples.
Interassay precision was 16.1% and 11.9% at 1.2 and 2.1 mg/L,
respectively (n = 20). Ferritin values were determined with either
the Chiron automated chemiluminescence system ferritin assay or the
Access immunoassay system ferritin assay from Beckman. Prior evaluation
of these two ferritin assays at our institution indicated that they
yield similar ferritin values (unpublished data).
Hemoglobin electrophoresis.
Samples were collected in tubes
containing EDTA, and an automated blood count was performed to
determine red blood cell indices. Hemolysates were prepared, and
alkaline and citrate agarose gel electrophoresis was performed
according to instructions provided by the manufacturer (Chiron).
Hemoglobin A2 was determined by anion-exchange column
chromatography (Helena Labs.), and hemoglobin F was determined by
alkaline denaturation (Chiron). Patients with microcytosis were
considered to have ß-thalassemia trait if the hemoglobin
A2 was >3.5% in the absence of marked anemia (hematocrit
<30%) and other hemoglobinopathies.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. The mean and SD for this population is 1.64 ± 0.47 mg/L,
which is similar to the manufacturer's stated normal mean of 1.54
± 0.43 mg/L obtained from screening 1000 apparently healthy individuals.
The mean and SD is 1.54 ± 0.43 mg/L for the 80 females and 1.69
± 0.50 mg/L for the 124 males. On the basis of these data, an sTfR value
of 2.8 mg/L (mean ± 2.5 SD) was set as the upper reference limit for
both sexes.
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The bone marrow biopsy group.
Five of the 54 anemic patients
had absent bone marrow iron stores. All five had sTfR values >2.8 mg/L
(Fig. 2
), suggesting that the sTfR is a sensitive indicator of iron
deficiency. However, 7 of the 49 patients with stainable iron in their
bone marrow aspirate also had sTfR values >2.8 mg/L, resulting in a
positive predictive value of only 42% in this population (Table 1
). Of these seven patients, two had megaloblastic changes
because of vitamin B12 deficiency, a condition known to be
associated with increased sTfR concentrations (18), and
one each had: myelofibrosis with marked extramedullary hematopoiesis;
Felty syndrome and pancytopenia; acquired immune deficiency syndrome
with non-Hodgkin lymphoma; metastatic endometrial leiomyosarcoma;
and systemic lupus erythematosus.
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Interestingly, only one of the five patients with absent bone marrow
iron stores had a ferritin value 12 µg/L (Fig. 2
), suggesting that
at this diagnostic limit (2), ferritin may be an
insensitive indicator of iron deficiency in acutely ill patients (Table 1
). However, all five of the iron-deficient patients in this group had
ferritin values 30 µg/L. If the diagnostic limit for ferritin is
raised to 30 µg/L, only one result is falsely positive (Fig. 2
), and
the positive predictive value for ferritin increases from 50% to 83%
(Table 1
). One patient with megaloblastic anemia had iron identified in
the marrow but had a low ferritin (8 µg/L) and an increased sTfR
(5.16 mg/L). An independent review of this patient's bone marrow
aspirate confirmed the presence of iron in erythroid precursor cells,
suggesting that both the ferritin and sTfR values were falsely
positive.
The microcytic anemia group.
Plasma ferritin and sTfR
concentrations were measured in 43 samples submitted for hemoglobin
electrophoresis from patients with a mean corpuscular volume <70 fL
(Fig. 3
). This population was chosen for study because nearly all
severely microcytic patients have either iron deficiency or a
ß-thalassemia. Thus, the diagnosis of iron deficiency is typically
not difficult based on clinical history and laboratory tests besides
ferritin and sTfR, such as hemoglobin typing and standard iron
chemistries. On the basis of these clinical criteria, iron deficiency
was determined to be the cause of the microcytic anemia in 26 patients
(23 females and 3 males) and was excluded in the remaining 17 patients
(9 females and 8 males). The sTfR was >2.8 mg/L in 23 of the 26
patients diagnosed as iron deficient, demonstrating a sensitivity of
88%. However, the sTfR value was also >2.8 mg/L for 6 of the 17
patients who were not clinically diagnosed as iron deficient,
indicating a specificity of 65% and a positive predictive value of
79% in this clinically defined population. Ferritin at a diagnostic
cutoff value of 12 µg/L was again less sensitive (73%) than sTfR
but had 100% specificity. Changing the upper diagnostic value to 30
µg/L provided 96% sensitivity yet maintained 100% specificity.
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Documented responses to iron therapy were available from eight of the
patients in this group (Fig. 3
). Seven patients had an increase in
hematocrit of >4% within 1 month of the initiation of iron therapy in
the absence of transfusion and were, therefore, clearly iron deficient.
The clinical history from one male with hypertension, renal
insufficiency, and hemoglobin AC clearly indicated that he was not iron
deficient, based on a documented failure to respond to iron therapy
over a 9-month period and subsequent bone marrow biopsy demonstrating
adequate iron stores. Among the documented iron-deficient patients,
primary diagnoses included sickle cell trait, 16-week pregnancy with
acute pyelonephritis, congestive heart failure, transient ischemic
attacks, systemic lupus erythematosus, uterine leiomyoma, and
rheumatoid arthritis. Among these seven patients, the sTfR was >2.8
mg/L in six but was <2.8 mg/L in the 16-week pregnant female. Ferritin
was <12 µg/L in only two of these seven but was <30 µg/L in six.
The one sTfR false negative had a ferritin of 13 µg/L, whereas one
iron-deficient patient had a ferritin of 113 µg/L but sTfR of 4.5
mg/L. Interestingly, this was a severe rheumatoid arthritis patient, a
condition known to increase ferritin as an acute-phase reactant.
Because response to iron therapy is considered a "gold standard"
for the diagnosis of iron deficiency, the data from these eight
patients were combined with that from the bone marrow biopsy group and
are presented in Table 1
. By using the combined data, the sTfR is more
sensitive (92%) than ferritin used with a diagnostic value of 12
µg/L but equivalent to ferritin used with a diagnostic value of 30
µg/L. In both cases, the ferritin is more specific than sTfR in these
well-defined populations.
The medical student group.
To examine the ability of ferritin
and sTfR to detect iron deficiency in a relatively healthy population,
we examined values in a population of 112 medical students (Fig. 4
, left). Nine of 52 (17%) female students were anemic at the
time of sampling. None of the 60 male students were anemic. The most
common cause of anemia in this population is presumed to be iron
deficiency, where the incidence is estimated to be as high as 20% in
women of child-bearing age (19)(20). Only two
of the nine anemic students had both sTfR >2.8 mg/L and ferritin 12
µg/L. The sTfR values were normal in the seven remaining anemic
female students. In contrast, four of nine had ferritin 12 µg/L,
and seven had ferritin 30 µg/L (Table 2
). An additional five female students with hematocrits >36%
had ferritin 12 µg/L, and one had sTfR of 3.0 mg/L. One nonanemic
male student had ferritin 12 µg/L, and one had sTfR of 4.5 mg/L
(Table 2
). All other 95 students had ferritin >12 µg/L and normal
sTfR values. If one assumes iron deficiency is the most common cause of
anemia in a "healthy" population, it appears that ferritin is more
sensitive than sTfR for screening purposes.
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The routine ferritin group.
To assess the diagnostic agreement
between diagnostic sTfR and ferritin values in a routine hospital
clinical laboratory environment, sTfR and ferritin values were compared
in samples from 267 patients submitted to the clinical chemistry
laboratory for ferritin analysis. Bone marrow samples, response to
iron, or other clinical information was not obtained from this
population. The sTfR and ferritin values were poorly correlated
(r = 0.228), and there was a considerable lack of
diagnostic agreement between the two assays (Fig. 4
, right panel). When
a ferritin of 12 µg/L is used as the diagnostic value, only 19
patients (7%) are classified as iron deficient by both tests, 68
(25%) as iron deficient by sTfR but not ferritin, and 5 (2%) by
ferritin but not sTfR. The remaining 175 patients (66%) are classified
as iron replete by both tests. Use of <30 µg/L ferritin as the
diagnostic value gave little improvement in diagnostic agreement.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Here we directly compared ferritin and sTfR in ill patients with independent documentation of iron status by bone marrow biopsy or response to iron therapy. In the patients with either bone marrow biopsy data or documented response to iron therapy, we found that sTfR is indeed a sensitive marker for iron deficiency, detecting 11 of 12 iron-deficient patients. However, 7 of 49 patients with stainable iron stores in their bone marrow and 1 patient who did not respond to iron therapy also had increased sTfR values, resulting in a specificity of 84% and a positive predictive value of only 58% in a population that is likely to be typical of the most difficult diagnostic environments for assessing iron status. Three of these eight patients with stainable iron had a known cause of increased erythropoiesis, resulting in the "false positive" sTfR values. Of the other five, one was diagnosed as anemia of chronic disease, and the remaining four had no identifiable reason for erythroid hyperplasia. Thus, interpretation of increased sTfR may be challenging, even in the absence of known causes of increased erythropoiesis.
The study of the microcytic anemia population was primarily retrospective, making it difficult to obtain objective iron status criteria for 35 of the 43 patients. Nevertheless, the results from these patients, i.e., clinical diagnoses and other laboratory data, support the findings from the above populations with documented iron status.
When ferritin was examined in these anemic populations, its specificity
was excellent (96–100%), but sensitivity was poor when a diagnostic
value of 12 µg/L was used. However, raising the diagnostic value to
30 µg/L made ferritin an almost perfect test. Although ferritin was
increased (115 µg/L) in one documented iron-deficient patient with
severe rheumatoid arthritis, it was <30 µg/L in iron-deficient
patients with diagnoses that included systemic lupus erythematosus,
adenocarcinoma of the lung, chronic liver disease, colon cancer, and
sepsis, all of which might be expected to cause an acute-phase increase
of ferritin. A diagnostic value of 30 µg/L for ferritin has also
been suggested by others (5)(22), and our data
support this in ill patients. Taken together, in these two populations,
ferritin alone was an adequate indicator of iron deficiency when a
diagnostic value of 30 µg/L was used. In all cases except the one
patient with severe rheumatoid arthritis, sTfR added little to the
information obtained from ferritin and might lead to overdiagnosis of
iron deficiency if identifiable causes of enhanced erythropoiesis are
not eliminated.
In the medical student group (Fig. 4
, left panel), the main area of
diagnostic disagreement between the ferritin and sTfR is in the lower
left quadrant of the plot, where 7 (all females) of 112 students had a
ferritin 12 µg/L and a normal sTfR. This observation in the
"healthy" population examined is distinctly different from that
seen in the other groups of patient samples studied, where very few
values were in this quadrant (Figs. 2
, 3
, and 4
, right panel). Because
serum ferritin is thought to reflect iron stores and sTfR the degree of
iron-deficient erythropoiesis (23), these students may
have depleted iron stores but have not yet begun iron-deficient
erythropoiesis. The presence of anemia (defined by hematocrit in Table 2
) in only two of these seven students is consistent with this
hypothesis, which is also suggested by other studies. Carriaga et al.
(24) studied a group of 176 women in the third trimester
of pregnancy and found that 66% of the 158 women with ferritin 12
µg/L had an sTfR value in the normal reference range. Because most of
the women in that study were taking iron supplements, they concluded
that the women had depleted iron stores but not iron-deficient
erythropoiesis. Furthermore, phlebotomy studies in healthy subjects
have demonstrated that sTfR remains normal until a tissue iron deficit
occurs (23), providing a basis for interpreting the data
from individuals with low ferritin and normal sTfR in this manner.
Here, all but two of the nine anemic female students had ferritin
values 30 µg/L, whereas only two had increased sTfR (Table 2
).
Thus, in an otherwise healthy population, ferritin appears to be a
sensitive and early indicator of iron deficiency and should be
considered the test of choice for assessing the need for iron therapy
in otherwise healthy females.
The sTfR concentrations determined in samples received for routine
ferritin analysis demonstrates that in a random, predominantly
outpatient population, a poor statistical correlation exists between
the values from the two assays (Fig. 4
, right panel) and that there is
a lack of diagnostic agreement between the two tests in 27% of these
patients. The former observation is not completely surprising, because
ferritin detects deficient iron stores, whereas sTfR detects increased
erythropoiesis. However, if both assays were perfect predictors of iron
deficiency, all of the data points would fall in either the upper left
(iron-deficient) or lower right (iron-replete) quadrants of the plot in
Fig. 4
, right panel. Most (73%) of the data points fall in one of
these two quadrants, but 25% are in the upper right quadrant (ferritin
>12 µg/L and sTfR >2.8 mg/L). These values may represent either
iron-replete patients who have increased erythropoiesis, such as a
patient with sickle cell disease who has received numerous red blood
cell transfusions, or patients with iron deficiency and an acute-phase
increase of the ferritin value. A physician educated in the strengths
and weaknesses of these two tests and familiar with the patient's
history could in all likelihood correctly determine many of the
patients in this quadrant to be iron deficient or replete without
further testing. Nevertheless, the preponderance of "ambiguous"
results, such as patients with ferritin values between 31 and 200
µg/L and increased sTfR, suggest that a bone marrow biopsy or a trial
of iron therapy might sometimes be necessary.
In conclusion, our findings are in agreement with those of
Pettersson et al. (10) in that the sTfR is not superior to
ferritin for the routine clinical evaluation of patients with suspected
iron deficiency. Furthermore, in two well-defined populations, we found
no evidence that sTfR provides additional information to that of
ferritin used with a diagnostic value of 30 µg/L. Finally, in the
small subset of patients clinically suspected to be iron depleted but
whose ferritin is increased by acute-phase reactions, a normal sTfR
would likely rule out iron deficiency, and an increased sTfR would be
useful if other causes of enhanced erythropoiesis can be eliminated.
Thus, we believe the utility of sTfR to be limited to a subset of ill
patients in whom iron deficiency is suspected but whose ferritin values
are normal.
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Acknowledgments |
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References |
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, females; 
, males.
), iron-replete females; (
),
iron-deficient females; (
