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Blood, Vol. 96 No. 3 (August 1), 2000:
pp. 823-833
REVIEW ARTICLE
Erythropoietin, iron, and erythropoiesis
Lawrence T. Goodnough,
Barry Skikne, and
Carlo Brugnara
From the Departments of Medicine and Pathology and Immunology,
Washington University School of Medicine, St. Louis, MO; the Department
of Medicine, University of Kansas Medical Center, Kansas City, KS; and
the Departments of Laboratory Medicine and Pathology, Children's
Hospital, Harvard Medical School, Boston, MA.
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Abstract |
Recent knowledge gained regarding the relationship between
erythropoietin, iron, and erythropoiesis in patients with blood loss
anemia, with or without recombinant human erythropoietin therapy, has
implications for patient management. Under conditions of significant
blood loss, erythropoietin therapy, or both, iron-restricted erythropoiesis is evident, even in the presence of storage iron and iron oral supplementation. Intravenous iron therapy in renal dialysis patients undergoing erythropoietin therapy can produce hematologic responses with serum ferritin levels up to 400 µg/L, indicating that traditional biochemical markers of storage iron in
patients with anemia caused by chronic disease are unhelpful in the
assessment of iron status. Newer measurements of erythrocyte and
reticulocyte indices using automated counters show promise in the
evaluation of iron-restricted erythropoiesis. Assays for serum
erythropoietin and the transferrin receptor are valuable tools for
clinical research, but their roles in routine clinical practice remain
undefined. The availability of safer intravenous iron
preparations allows for carefully controlled studies of their value
in patients undergoing erythropoietin therapy or experiencing blood loss, or both.
(Blood. 2000;96:823-833)
© 2000 by The American Society of Hematology.
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Introduction |
Several clinical settings have served as "natural experiments"
that have furthered our understanding of the relationship between erythropoietin, iron, and the erythropoietic response to anemia in
humans. In a review nearly 20 years ago, Finch1 summarized the knowledge gained primarily from studies of healthy
persons, patients with hereditary hemolytic anemias, and
patients with hemochromatosis. Under conditions of basal erythropoiesis
in normal subjects, plasma iron turnover (as an index of marrow
erythropoietic response) is little affected, whether transferrin
saturation ranges from very low to very high levels. In contrast, the
erythropoietic response in patients with congenital hemolytic anemia,
in whom erythropoiesis is chronically raised as much as 6 times over
basal levels,2 is affected (and limited) by serum iron
levels and by transferrin saturation.3 Patients with
hemochromatosis who underwent serial phlebotomy were observed to mount
erythropoietic responses as much as 8 times over basal rates,
attributed to the maintenance of very high serum iron and transferrin
saturation levels in these patients,4 whereas healthy
persons have been shown to have difficulty providing
sufficient iron to support rates of erythropoiesis more than 3 times
basal rates.5 These observations led Finch6 to
identify a "relative iron deficiency" state that occurs when
increased erythron iron requirements exceed the available supply of
iron, even in the presence of storage iron. The recent practice of
multiple phlebotomies through autologous blood donation in patients who
are scheduled for elective surgery is also a natural experiment in
blood loss anemia. This review summarizes insight gained in the past 20 years regarding the relationship between erythropoietin, iron, and
erythropoiesis in patients with anemia, along with implications for
patient management.
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Blood loss anemia through autologous phlebotomy |
Erythropoiesis mediated by endogenous erythropoietin
Patients undergoing autologous blood phlebotomy may donate 10.5 mL/kg (450 ± 45 mL) blood as often as twice a week until 72 hours
before surgery.7 Under routine conditions, patients usually donate once a week.8 Oral iron supplements are routinely
prescribed. This iatrogenic blood loss is accompanied by a response in
endogenous erythropoietin levels that, though increased significantly
over basal levels, remain within the range of normal (4-26 µm/mL).9 The erythropoietic response that occurs under
these conditions is modest.8,10 A summary of selected
prospective, controlled trials11-16 of patients undergoing
phlebotomy is presented in Table 1. Calculated estimates
of red blood cell (RBC) volume expansion (erythropoiesis in excess of
basal rates) were determined17; 220 to 351 mL (11% to 19%
RBC expansion,11,12 or the equivalent to 1 to 1.75 U
blood18) are produced in excess of basal erythropoiesis, defining the efficacy of this blood conservation practice.
For patients subjected to more aggressive (up to 2 U a week)
phlebotomy, the endogenous erythropoietin response is more
substantial.13-16 In one clinical trial,14 a
linear-logarithmic relationship was demonstrated between change in
hemoglobin level and erythropoietin response,19 predicted
previously by phlebotomy experiments in normal subjects.20
Erythropoietin-mediated erythropoiesis in this setting is 397 to 568 mL
(19% to 26% RBC expansion,13-16 or the equivalent of 2 to
3 U blood18).
Erythropoiesis mediated by erythropoietin therapy
Clinical trials have demonstrated a dose-response relationship
between erythropoietin and red blood cell expansion.16 A study of "very low" dose erythropoietin therapy in autologous blood donors found that 400 U/kg administered over a 2-week interval resulted in clinically significant erythropoiesis.21 Table
2 details red cell volume expansion in 134 patients treated with erythropoietin therapy during aggressive blood
phlebotomy,14-16,22,23 ranging from 358 to 1764 mL (28% to
79% RBC expansion) over 25 to 35 days, or the equivalent of 2 to 9 U
blood.18 The range in response (erythropoiesis) to dose
(erythropoietin) is not related to patient gender or
age,24,25 suggesting that patient-specific factors such as
accompanying chronic disease, iron-restricted erythropoiesis, or other
factors that normally cause the wide distribution of the hemoglobin
level account for the variability in erythropoietic response to
erythropoietin.
Studies in patients with the anemia of chronic disease
(osteoarthritis26-28 or rheumatoid
arthritis29,30) are summarized in Table
3. Red cell volume expansion ranged from
157 to 353 mL (11% to 24%) for endogenous erythropoietin-mediated
erythropoiesis and 268 to 673 mL (21% to 44%) with erythropoietin
therapy. These erythropoietic responses are indistinguishable from
those in patients with anemia from blood loss alone, noted in Tables 1
and 2. A study of 17 patients with inflammatory bowel disease treated with erythropoietin and oral iron therapy demonstrated a similar response, with an estimated 20% increase in red cell volume over that
in placebo-treated patients.31
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Iron-restricted erythropoiesis and iron therapy |
Blood loss and the endogenous erythropoietin response
Erythropoiesis in response to aggressive autologous
phlebotomy through endogenous erythropoietin has been estimated to
increase by approximately 3 times.16,32 As illustrated in
Figure 1, panel A, no relationship exists
between basal iron stores and this magnitude of erythropoiesis,
suggesting that serum iron and transferrin saturation for erythron
requirements are adequately maintained by storage
iron.13-16 Little or no benefit to oral iron supplementation was found in 2 studies,13,33 whereas a
third study12 found some benefit (Table 1). Intravenous
iron supplementation is of no value in enhancing erythropoiesis under
these conditions.12,13
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| Fig 1.
Initial storage iron and red blood cell volume expansion.
(A) Relationship between initial storage iron (mg) and red blood cell
volume expansion (mL/kg) in patients undergoing aggressive phlebotomy,
without erythropoietin therapy. Based on data from reference 32. Linear
regression analysis (not shown) demonstrated no significant correlation
(r = 0.06; P = .67). (B) Relationship between
initial storage iron (mg) and red blood cell volume expansion
(mL/kg) in patients undergoing aggressive phlebotomy, with
erythropoietin therapy. Linear regression analysis demonstrated a
significant correlation (r = 0.6; P = .02). Reprinted
with permission.32
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Blood loss and erythropoietin therapy
With enhanced erythropoiesis during erythropoietin therapy,
iron-restricted erythropoiesis occurs even in patients with measurable storage iron (Figure 1B). Despite an 8-fold increase in
gastrointestinal iron absorption,34 serum ferritin and
transferrin saturation levels decline up to 50% with erythropoietin
therapy.35 A 4-fold increase in erythropoietic activity is
accompanied by declining reticulocyte counts and the appearance of
hypochromic red cells by the second week of erythropoietin
therapy.23,36 The superior erythropoietic response in a
patient with hemochromatosis further suggests iron-restricted
erythropoiesis in patients treated with erythropoietin (Table
2).23
Basal red cell precursor mass is also a limiting factor. Half-maximal
hemoglobin synthesis can be achieved by as few as 50 molecules of
erythropoietin per target cell. This means that the high levels of
serum erythropoietin present initially after parenteral injection are
not entirely used for erythropoiesis.37-39 The biologic response is, therefore, maximal at lower levels than the erythropoietin concentration required to saturate all erythropoietin-binding sites.
Consistent with this, reticulocyte responses in healthy subjects peak
after a single erythropoietin dose of 1800 U/kg,40 and
storage iron is mobilized more effectively after multiple-dose regimens
than after single-dose regimens.41 A 72-hour interval between erythropoietin administrations is superior to a 24-hour interval.42 Erythropoietin therapy stimulates the gradual
expansion of erythroblast mass,43 so that acute demands for
erythropoiesis are met by an influx from pre-erythroid colony forming
unit (CFU-E) pools, and chronic demands (eg, chronic hemolytic anemia)
are met by an amplified pool of later erythroid precursors. Expansion and maturation of erythroid precursor cells are, therefore, limiting factors in the erythropoietic response to acute blood loss anemia and
in treatment strategies using larger erythropoietin dosages. In a study
of escalating (400%) erythropoietin dose administered to patients
undergoing aggressive phlebotomy, the marrow erythropoietic index
increased from 2.9 times (with endogenous erythropoietin stimulation) to 3.6 times over basal rates of erythropoiesis, representing only a 58% increase in erythropoiesis (Figure
2). Emerging growth factors, such as novel
erythropoiesis-stimulating protein,44 may have different
pharmacokinetics regarding dose and response related to longer plasma
residence time and erythron expansion.
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| Fig 2.
Erythropoietic response, as reflected in the bone marrow
erythropoietic index, in 4 cohorts of autologous donors treated with
placebo or escalating doses of erythropoietin therapy.
(U/kg, given for 6 doses over 3 weeks.) Erythropoietic response (mL/kg
per day) was estimated for each treatment group, according to the
formula: bone marrow erythropoietic index = [RBC expansion] + [baseline RBC production] = [baseline RBC production]. Based on
data from Goodnough et al.16
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Blood loss and iron therapy
Whether iron-restricted erythropoiesis is clinically important in
patients with blood loss anemia is detailed in Table
4.27,32 No differences in
erythropoiesis stimulated by endogenous erythropoietin alone were seen
between patients with or without measurable storage iron, in which the
mean red blood cell expansion was 20% and 22%, respectively, in one
study32 and 23% and 24%, respectively, in another
study.27 When patients were administered erythropoietin therapy, those without measurable storage iron had reductions in
erythropoiesis compared to patients with storage iron that reached
statistical significance in one study (P < .05)27
but not another (P = .07).32 These studies indicate
that oral iron supplementation is sufficient for endogenous
erythropoietin-mediated RBC expansion but may not be sufficient to
prevent iron-restricted erythropoiesis during erythropoietin
therapy.
Intravenous iron can allow up to a 5-fold erythropoietic response to
significant blood loss anemia in healthy
persons.3,45 A greater rate of hemoglobin
production is probably not possible unless red marrow expands into
yellow marrow space, as is seen in hereditary anemias.2,45
One limitation to intravenous iron therapy in patients not undergoing
erythropoietin therapy may be that much of the administered iron is
transported into the reticuloendothelial system as storage iron, where
it is less readily available for erythropoiesis.46 For
iron-deficient patients, 50% of intravenous iron is incorporated into
hemoglobin within 3 to 4 weeks,47 whereas for patients with
anemia of chronic disease or renal failure, intravenous iron is less
rapidly mobilized from the reticuloendothelial system.48
The value of intravenous iron administration in patients undergoing
erythropoietin therapy is not established. In one clinical trial,26 significantly greater erythropoietic responses
were seen with intravenous iron therapy than with oral iron
supplementation only (Table 3). However, a recent study28
found no difference in red cell production between oral iron and
intravenous iron therapy in patients before orthopedic surgery. Another
study found that intravenous iron supplementation was not accompanied
by a corresponding erythropoietic response to increasing doses of
erythropoietin therapy; a 2-fold increase in erythropoietin dose was
associated with only a 32% increase in red cell
production,22 similar to the dose-response relationship
using oral iron supplementation.16 Intravenous iron
administered to normal subjects treated with erythropoietin abolished
the marked reduction in serum ferritin and increased the reticulocyte
hemoglobin content (a measure in g/L of the hemoglobin contained in all
reticulocytes); however, the total number of reticulocytes generated in
8 days after therapy was not affected.49 Finally,
perisurgical exposure to allogeneic blood is not different for
autologous blood donors with or without measurable storage iron,
regardless of oral27,32 or intravenous iron28
administration. The current status of intravenous iron therapy in
patients with blood loss anemia is summarized in Table 5.50-55
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Anemia of chronic renal failure or chronic disease |
The success of erythropoietin therapy in correcting the anemia of
chronic renal failure has led to substantial clinical experience and
knowledge in erythropoietin, iron metabolism, and erythropoiesis in
this setting.52,56 A distinguishing characteristic of the anemia in patients undergoing chronic renal dialysis is the presence of
a normal mean corpuscular volume (MCV) in 85% of the patients and
hypochromia in 96% of the patients.57 Hyporesponsiveness to erythropoietin therapy is a common phenomenon in these
patients58,59 because of a variety of co-morbid conditions,
particularly aluminum toxicity and iron deficiency.
Anemic patients undergoing dialysis may have suboptimal responses to
oral iron therapy for several reasons. Under basal conditions, their
absorption levels of food iron and therapeutic oral iron are similar to
levels in normal subjects.60 During erythropoietin therapy,
the absorption of iron increases as much as 5 times.61 Nevertheless, external iron loss, including loss from hemodialysis and
blood testing, exceed gastrointestinal iron absorption.52 Poor compliance because of gastrointestinal symptoms is problematic, and significantly reduced iron absorption may occur with some newer
iron formulations.62 Iron-restricted erythropoiesis is evident by clinical responses to ascorbate supplementation, thought to
facilitate the release of iron from reticuloendothelial stores and
increased iron use by erythrons,59 and by the success of intravenous iron therapy in reducing erythropoietin
dosage.56
Because anemia is a determinant of life expectancy in patients on
dialysis for chronic disease,57,63 intravenous iron
administration has become standard therapy for many patients receiving
erythropoietin therapy.64 Dialysis patients treated with
intravenous iron (100 mg twice a week) achieved a 46% reduction in
erythropoietin dosage, required to maintain hematocrit levels between
30% and 34%, compared with patients supplemented with oral
iron.56 In a study of patients with chronic renal failure
but not on dialysis,53 two thirds of patients who were
unresponsive to oral iron responded to weekly intravenous iron therapy.
Improved erythropoiesis occurred despite initial serum ferritin levels
as high as 400 µg/L,65 indicating that biochemical
markers of storage iron are not helpful in evaluating iron-restricted erythropoiesis.
The effect of intravenous iron therapy in patients with the anemia of
chronic disease undergoing erythropoietin therapy is shown in Table 3.
Patients with osteoarthritis and measurable storage iron doubled their
red cell expansion, from a range of 21% to 22% (with oral iron) to
40% to 43% with intravenous iron.26 Intravenous iron
therapy in iron-deficient patients with inflammatory bowel disease also
resulted in improved responses to erythropoietin therapy55
compared with a similar patient group who received oral iron
supplementation.31 The clinical response to intravenous iron may be attributed to the salutary effect of erythropoietin on iron
mobilization from the reticuloendothelial system into red cell
precursors.66 The risk/benefit profile of intravenous iron
is controversial in anemic patients on renal
dialysis59,63,64,67 and in patients with anemia of chronic
disease.68 Nevertheless, clinical settings in which the
effect of intravenous iron therapy on erythropoiesis is beneficial, not
beneficial, or undefined (investigational) are summarized in Table
5.
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Laboratory evaluation |
Iron, transferrin, and transferrin saturation
The diagnosis of iron deficiency is traditionally based on a
combination of parameters, including iron metabolism and hematologic indices.69-73 Technical and biologic issues limit the
usefulness of these assays in the clinical setting,74-78
and the value of iron, transferrin, and transferrin saturation is
limited to uncomplicated iron deficiency. During repeated phlebotomy,
there is little change in iron levels until iron stores are exhausted,
after which iron declines to below 50 µg/dL.69 Once iron
stores are depleted, transferrin increases linearly to approximately
400 µg/L. Transferrin saturation, therefore, falls below 16% only
when iron stores are exhausted, in contrast to erythropoietin
therapy-induced erythropoiesis, in which iron saturation falls even in
the presence of storage iron.71 Hence, the detection of
iron-restricted erythropoiesis during erythropoietin
therapy6,35,41,71-73 poses additional challenges.
Ferritin
Ferritin is widely used as a marker of iron
storage,79-81 with a log relationship between serum
ferritin and liver iron (measured with magnetic spectrophotometry) and
with a cutoff of 15 µg/L indicating absent iron stores in normal
persons.82-84 However, 1 study found that 25% of women
with no stainable bone marrow iron had serum ferritin levels above the
15 µg/L cutoff.85 Ferritin levels are elevated in
conditions such as hyperthyroidism, inflammation/infection, hepatocellular disease, malignancies, alcohol consumption, and oral
contraceptives.86 A cutoff level of 30 µg/L87
to 40 µg/L88 for anemic patients is desirable to provide
optimal diagnostic efficiency (positive predictive values of 92%
to 98%, respectively), even without clinical evidence of
infection or inflammation.
Subjects treated with erythropoietin exhibit a rapid decrease in
ferritin to levels 50% to 75% below baseline.34,49,89 Ferritin also decreased rapidly after intravenous iron administration in normal subjects treated with erythropoietin.49 Under
these conditions, ferritin most likely reflects the iron content of a
smaller, more labile pool in equilibrium with erythropoietic compartment and storage iron. Many patients have underlying disorders with "inappropriately high" serum ferritin levels. Two thirds of
patients on renal dialysis respond to intravenous iron therapy; their
mean ferritin levels of 94 µg/L and mean transferrin saturations of
22% are no different from those of patients not responsive to
intravenous iron.65 This has led to suggested
guidelines54 and algorithms90 for anemic
patients with renal failure, in whom ferritin levels of less than 200 µg/L alone or less than 400 µg/L with a transferrin saturation less
than 20% are used to determine the need for intravenous iron
therapy90; only at transferrin saturations greater than
50% or ferritin levels in excess of 800 µg/L are these patients
considered unlikely to benefit from iron therapy.54
Among patients with the anemia of cancer who are treated with
erythropoietin, ferritin levels greater than 400 µg/L correctly predicted lack of response in 88%, whereas levels less than 400 µg/L
correctly predicted response in 75%.91 However, several studies have failed to show a role for ferritin in predicting response
to erythropoietin or in identifying functional iron deficiency in
patients with cancer-related anemia.92-94 It is reasonable
to assume that ferritin levels lower than 200 µg/L would predict response to intravenous iron in most patients receiving erythropoietin.
Erythrocyte ferritin and zinc protoporphyrin
Some studies have advocated a role for erythrocyte ferritin, rather
than serum ferritin, in detecting iron deficiency in patients with
anemia of chronic disorders.95-98 However, this difficult assay is insensitive to dynamic changes and becomes abnormally low only
after most of the red cell population has been replaced by
iron-deficient erythrocytes. A similar limitation of the zinc protoporphyrin measurement is that a significant proportion of the red
cell pool must contain new red blood cells produced under iron-restricted conditions.99 Furthermore, the zinc
protoporphyrin measurement is sensitive to interference by drug and
plasma components.100 Zinc protoporphyrin, therefore, has
little value in identifying iron-restricted
erythropoiesis.101
Erythrocyte indices
Erythropoietin therapy in patients on dialysis is associated with
the progressive appearance of hypochromic, microcytic
erythrocytes.102 Values exceeding 10% (normally less than
2.5%) are compatible with iron-restricted
erythropoiesis.54 Hypochromic erythrocytes are observed
when erythropoietin is administered to normal subjects undergoing
multiple phlebotomies,89 but not when it is administered to
a patient with hereditary hemochromatosis treated
similarly.23 Erythrocyte indices are helpful for monitoring
iron status and the need for iron supplementation during erythropoietin
therapy for the anemia of chronic renal failure.103-106
Hypochromic erythrocytes also increase in patients with increased
numbers of normal reticulocytes and young red cells. Therefore, the
value of this assay has been questioned.107-109
Reticulocyte parameters
Because reticulocytes are normally released from the marrow 18 to 36 hours before their final maturation into erythrocytes, they provide a
real-time assessment of the functional state of erythropoiesis.
However, in the early phases of stimulated erythropoiesis, changes in
absolute reticulocyte counts reflect the release from marrow of
immature reticulocytes rather than the true expansion of
erythropoiesis.45,48,110,111 It has been suggested that a
response to erythropoietin can be assessed by measuring hemoglobin and
reticulocyte counts after 4 weeks of therapy; a change in hemoglobin
level by more than 1.0 g/dL or a change in absolute reticulocyte count
by more than 40 × 109/L could indicate that the
patient is a responder to erythropoietin therapy.93,112,113
Flow cytometric analysis of reticulocytes allows precise measurements
of reticulocyte cell volume (MCVr), hemoglobin concentration (CHCMr),
and hemoglobin content (CHr).114,115 In normal subjects, erythropoietin therapy induces an increase in MCVr and a decrease in
CHCMr.43 Normal subjects treated with erythropoietin with baseline serum ferritin levels greater than 100 µg/L produce almost no hypochromic reticulocytes. Iron-restricted erythropoiesis is detected at an earlier stage if reticulocyte parameters rather than red
cell indices are used.89,111,116,117
CHr has been studied in patients on dialysis. CHr demonstrated 100%
sensitivity and 80% specificity and was a more accurate predictor of
response to iron therapy than serum ferritin, transferrin saturation,
or percentage hypochromic erythrocytes.107 Another study
showed that a baseline CHr of less than 28 pg had 78% sensitivity and
71% specificity for detecting iron-restricted erythropoiesis, compared
with 50% and 39% for traditional biochemical measures.118 In dialysis patients treated with erythropoietin, CHr increases during
intravenous iron therapy, indicating value as an early indicator of
iron-restricted erythropoiesis,119 even with normal serum
ferritin or transferrin saturation.120
Measurements of total reticulocyte hemoglobin, an integrated index
derived from the absolute reticulocyte count and the CHr,121 showed that reticulocyte-hemoglobin levels are much higher in subjects treated with intravenous iron.49 Moreover, in
patients undergoing cardiac surgery, the administration of intravenous iron along with erythropoietin therapy abolishes the production of
hypochromic reticulocytes, and CHr remains within the normal range.122 A recent study123 concluded that CHr
was the strongest predictor of iron deficiency in children, and it
should be considered an alternative to standard iron studies for the
diagnosis of iron deficiency.
Another reticulocyte parameter now provided by automated analyzers is
the immature reticulocyte fraction. Because it is sensitive to
leukocyte interference124 and is difficult to
standardize,125,126 its clinical use has been limited. The
immature reticulocyte fraction reflects the degree of erythropoiesis,
but it is not indicative of iron-restricted
erythropoiesis.127,128
Transferrin receptor
The soluble transferrin receptor (TfR) is derived primarily from red
cell precursor normoblasts129 and provides an estimate of
the erythroid compartment mass. Both enhanced erythropoiesis and iron
deficiency elevate TfR.129,130 Endogenous
erythropoietin-mediated erythropoiesis through phlebotomy minimally
influences TfR until iron-restricted erythropoiesis occurs, as
illustrated in Figure 3.69
Serum ferritin is the most sensitive and specific index of iron status
when there are residual iron stores, whereas TfR is most sensitive in
the presence of iron-restricted erythropoiesis.88
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| Fig 3.
Endogenous erythropoietin-mediated erythropoiesis by
phlebotomy minimally influences serum transferrin receptor (TfR) until
iron-restricted erythropoiesis occurs.
Serial determinations of TfR during phlebotomy in 3 subjects with
initial iron stores of 107 mg ( ), 335 ( ), and 1,102 mg ( ).
Reprinted with permission.69
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In a study of 43 healthy, nonanemic adult women, 17 (40%) had
significant changes in TfR in response to oral iron therapy, indicating
the presence of subclinical iron deficiency.131 In another
study, 25% of patients undergoing routine ferritin tests, who were
also studied for TfR measurements, were categorized as iron deficient
by TfR (more than 2.8 mg/L) but not by ferritin (more than 12 µg/L).88 These values could represent iron-replete persons with increased erythropoiesis or iron-deficient patients with
acute-phase increases of ferritin values. The clinical usefulness of
the TfR may be limited to the subset of ill patients in whom iron
deficiency is suspected but whose ferritin values are normal or
raised,88 seen commonly in the anemia of chronic disease; numerous studies69,87,88,132-134 have shown TfR to be of
value in differentiating iron-deficiency anemia (in which TfR is
usually increased) from the anemia of chronic disease (in which TfR is usually normal). Meaningful comparisons of studies of TFR are difficult
because of differences resulting from the reagents used.
The value of TfR in predicting the response to erythropoietin therapy
and the adequacy of iron availability is modest. Although lower
baseline or low-normal TfR levels predict the initial response to
erythropoietin therapy in patients on dialysis,135 other
studies have shown little predictive value for this assay in patients receiving erythropoietin because serum TfR values above normal are
observed in iron deficiency and during erythropoietin-induced expansion
of erythropoietic activity.136 The combination of TfR measurements, serum ferritin, and automated reticulocyte counts may be
predictive of an erythropoietic response to increased erythropoietin dosage or of the need to ensure adequate iron replacement, such as by
the intravenous administration of iron.137,138 Further studies are required to delineate the clinical usefulness of TfR measurements in these settings.
Erythropoietin assay
A classification of anemias has been proposed around the concept of
adequate or inadequate erythropoietin response to degree of
anemia139-141; patients with iron-deficiency or chronic
hemolytic anemia would comprise the reference
populations.142-144 The correlation between the percentage
of patients showing an "inadequate" erythropoietin response to
anemia and the percentage of patients responding to erythropoietin
therapy (according to the author's criteria) can be illustrated
(Figure 4) for several diseases, with a
range in response to myelodysplastic syndromes,145 multiple
myeloma,146 and rheumatoid arthritis.147
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| Fig 4.
Correlation between the percentage of patients showing
inadequate erythropoietin response to anemia and the percentage
responding to erythropoietin therapy (according to the authors'
criteria).
Numbers are derived directly or are calculated from reported data. ARF,
anemia of renal failure; RA, anemia of rheumatoid arthritis; HIV,
anemia in patients with human immunodeficiency virus; MM, anemia in
multiple myeloma; Cancer, anemia of cancer; MDS/MMM, anemia in
myelodysplastic syndromes and myelofibrosis with myeloid metaplasia.
Reprinted with permission.141
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There are several problems with the use of erythropoietin levels in the
management of patients. The interpretation of an erythropoietin level
must take into account the degree of anemia at the time of measurement.
Commercial assay results do not take this into consideration; hence,
clinicians must have some familiarity with mathematical corrections,
such as observed/predicted ratios.141 A retrospective
analysis of erythropoietin therapy in anemic patients with cancer not
undergoing chemotherapy148 found that pre-treatment erythropoietin levels of less than 200 mU/mL were correlated with red
cell response to erythropoietin therapy. Subsequent analyses, however,
have found that erythropoietin levels are not predictive for response
in cancer patients undergoing chemotherapy.149,150 Because
almost all anemic patients with cancer or on renal dialysis have
erythropoietin levels that are inadequate for the degree of
anemia,141 measuring erythropoietin levels is not useful in these settings. Furthermore, guidelines recommend that erythropoietin therapy be instituted before hemoglobin levels fall below 10 g/L, a
level at which interpretation of erythropoietin level is not valid.141 The erythropoietin assay may be most useful as a
determinant of response to therapy in certain patients, such as those
with myelodysplasia.145
The proliferative state of bone marrow erythroid cells affects
erythropoietin levels,151 as does iron
status,152 hemolysis,153 and
chemotherapy-induced endothelial damage.154 TfR has helped in the understanding of the relationship between hemoglobin level and
serum erythropoietin. As illustrated in Figure
5, a patient with pure red cell aplasia and
a markedly elevated erythropoietin level was administered
erythropoietin therapy for 4 weeks. Before hemoglobin level increased,
the erythropoietin level decreased because erythroid activity measured
by TfR reappeared. The increased plasma clearance of erythropoietin is
probably related to an influx of early RBC precursors into CFU-E from
primitive erythroid burst-forming units (BFU-E). CFU-E has a higher
concentration of erythropoietin receptors than BFU-E,39 so
late BFU-E through the proerythroblast stage defines the narrow
window of erythroid cellular compartment that is erythropoietin
responsive.151
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| Fig 5.
Time course of hemoglobin (Hb) level, serum
erythropoietin level (sEpo), and serum transferrin receptor (sTfR) in a
patient with pure red cell aplasia (PRCA) responding to treatment.
The patient was treated with erythropoietin at a dose of 150 U/kg per
day subcutaneously, 5 days a week; dosage was reduced to 3 weekly
administrations when Hb level achieved 12 g/dL, and treatment was
discontinued after 8 weeks. Reprinted with permission.151
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A recent study of anemic children with systemic-onset juvenile chronic
arthritis found that erythropoietin levels were appropriate for the
degree of anemia. Variable iron status, measured by TfR levels,
accounted for variations in hemoglobin levels, and intravenous iron
therapy resulted in the normalization of TfR levels.155 Another study in children with cancer found that TfR levels were inappropriately low for the degree of anemia, and a highly significant correlation between the logarithms of erythropoietin and hemoglobin levels was identified.156 The report concluded that anemia
in children with cancer results from decreased erythropoietic activity, in contrast to anemia in adults with cancer.142 The anemia
of chronic inflammatory disease is particularly multifactorial, caused not only by impaired erythropoietin response but also by defective iron
supply to the erythron, along with inflammatory cytokine-mediated suppression of the erythropoietic response to
erythropoietin.157,158 To effectively evaluate erythroid
activity, an assay of TfR and mathematical correction of the
erythropoietin level would be necessary,151 but this is not
practical for clinical evaluation and patient management.
In summary, pre-therapy laboratory evaluation of erythropoietin, iron,
or erythropoiesis in anemic patients may no longer be always
appropriate. Rather, the epidemiology (ie, clinical setting) of the
anemia may suggest a therapeutic trial of iron or erythropoietin
therapy, with post-therapy laboratory evaluation determining the
response. One example of this approach is the empiric use of oral iron
therapy in otherwise well anemic, menstruating women, in which a
follow-up blood count may serve as the sole laboratory assay. A second
example is patients with chronic renal failure who remain anemic
despite erythropoietin therapy and in whom an empiric trial of
intravenous iron is recommended despite apparent laboratory evidence of
storage iron. Follow-up transferrin saturations, serum ferritin, and
blood counts then determine when intravenous iron therapy can be
modified or withdrawn.54 Hematologic parameters are
emerging as promising alternatives to biochemical markers in evaluating
iron-restricted erythropoiesis.
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Clinical management: iron therapy strategies |
With significant on-going iron losses, oral iron supplementation is
not enough to correct iron-deficient erythropoiesis. Patients on renal
dialysis have such blood losses, and intravenous iron therapy allows
the correction of anemia through the use of lower erythropoietin
doses.54,159 Another role for intravenous iron therapy is
in bloodless medical treatment and bloodless surgery for patients who
decline blood transfusions because of religious beliefs.50
These patients include pregnant women and patients with dysfunctional
uterine bleeding who are scheduled for hysterectomy.51
Intravenous iron therapy has been closely scrutinized for risks and
adverse events. Imferon (iron dextran BP, Merrill-Dow, Cincinnati, OH) was previously approved for parenteral
use.160 This product was associated with a 0.6% risk of
anaphylactoid reactions and a 1.7% risk of severe serum sickness-like
reactions characterized by fever, arthralgias, and
myalgias.161 Delayed reactions of up to 30% and severe
reactions of 5.3% were subsequently described. They were attributed to
changes in manufacturing processes,162 and this product was
withdrawn from use.
InFed (iron dextran USP; Schein Pharm, Florham Park, NJ) has been
approved for parenteral (intramuscular or intravenous) use in the
United States. InFed (Schein Pharm) administered intravenously during
dialysis is associated with significant adverse reactions in 4.7% of
patients, of which 0.7% are serious or life threatening and another
1.7% are characterized as anaphylactoid.163 The prevalence of these reactions does not differ among patients receiving low-dose (100 mg) or higher-dose (250-500 mg) infusions.164 A recent
review reported 196 incidences of allergy/anaphylaxis from iron dextran between 1976 and 1996, of which 31 (15.8%) were fatal.165
Safety aspects of parenteral iron dextran, ferric gluconate, and iron
saccharate have been scrutinized.166-168 Iron saccharate is
available in Europe but not in the United States. Ferric gluconate has
been available in Europe for more than 20 years and was approved for
intravenous use in the United States in 1999 (Ferrlecit; Schein Pharm)
in patients on renal dialysis. Dosage is limited to 125 mg infused over
1 hour at each administration. The number of allergic reactions (3.3 episodes per million doses) is lower than that from iron dextran (8.7 episodes per million doses), and the safety profile is substantially
better; among 74 severe adverse events reported from 1976 to 1996, there were no deaths.165
Adverse events associated with ferric gluconate include hypotension,
rash, and chest or abdominal pain, with an incidence of 1.3% for
serious reactions.170,171 Intravenous iron therapy can
cause a clinical syndrome (nausea, facial reddening, and hypotension) that may be attributed to acute iron toxicity caused by oversaturation (more than 100%) of transferrin172 or nonspecific drug
toxicity.173 The increased erythropoietic effect (4.5 to
5.5 times basal) of intravenous iron dextran (with an estimated
half-life of 60 hours) is transient and lasts 7 to 10 days, after which
the remaining iron is sequestered in the reticuloendothelial system and
erythropoiesis returns to basal rates.3 Iron measurements
and intravenous iron therapy are optimal at 2-week intervals.
A dose-response relationship between erythropoietin and erythropoiesis
that is affected favorably by intravenous iron has important
implications for erythropoietin dosage and cost.174 The
current total recommended erythropoietin dose for patients scheduled
for elective surgery175 ranges from 1800 U/kg176 to 4200 U/kg,177,178 which for a 70-kg
patient would cost $1300 to $3000.179 However, an economic
analysis of erythropoietin therapy in patients undergoing orthopedic
surgery concluded that even the lower recommended dosage is not cost
effective.180 Intravenous iron may potentiate the
erythropoietic response in erythropoietin therapy by improving
functional iron deficiency.
A multicenter trial in dialysis patients, designed to achieve normal
(more than 42%) or low (more than 30%) hematocrits with a combination
of erythropoietin therapy and intravenous iron (dextran USP)
supplementation, was halted because of increased mortality in the high
hematocrit cohort.63 These patients experienced a decline
in dialysis adequacy and received intravenous iron in greater
quantities than those in the low hematocrit group. Debated links
between iron stores and morbidity or mortality rates include a
predisposition to infection,181,182 increased death from
infection183 in dialysis patients, and detrimental coronary
outcomes in men.184-186 An accompanying
editorial187 to a U.S. study of ferric
gluconate170 concluded that its role in the management of
anemia from renal disease was unclear until its relative efficacy,
tolerability, and cost effectiveness is established. However, another
editorial64 accompanying the target hematocrit
study63 concluded that for patients with anemia of chronic
renal disease, intravenous iron is recommended to reach target
hematocrit goals of 33% to 36%. The current status of intravenous
iron therapy for patients who are unresponsive to oral iron or in whom
it is malabsorbed along with opportunities for investigationare
presented in Table 5.
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Conclusion |
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Top
Abstract
Introduction