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Reticulocyte Hemoglobin Content (Ret He): A Simple Tool for Evaluation of

Iron Status in Childhood Cancer

Article  in  Journal of Pediatric Hematology/Oncology · December 2019

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 ORIGINAL ARTICLE
Reticulocyte Hemoglobin Content (Ret He): A Simple Tool for
Evaluation of Iron Status in Childhood Cancer
Azza A. Tantawy, MD,* Iman A. Ragab, MD,* Eman A. Ismail, MD,†
Fatma S.E. Ebeid, MD, MRCPCH,* and Ramadan M. Al-Bshkar, MBBCh*
Background: Cancer-related anemia is a common complication of
cancer and its treatment that may be mediated by nutritional defi-
ciency or inflammatory cytokines inhibiting erythropoiesis.
Aim: We evaluated the value of reticulocyte hemoglobin content
(Ret He) as a marker of iron availability for erythropoiesis in
childhood cancer and the impact of oral iron supplementation on
hematologic parameters in patients with low Ret He.
Materials and Methods: This prospective study included 100
pediatric patients with cancer on chemotherapy who were screened
for the presence of anemia. Patients with anemia underwent testing
for complete blood count including Ret He on Sysmex XE 2100 and
assessment of reticulocyte count, serum iron, serum ferritin, trans-
ferrin saturation, total iron-binding capacity, and C-reactive pro-
tein. Patients were classified according to their level of Ret He into
normal or low Ret He using a cutoff level of 28 pg. Patients with
low Ret He were subjected to 6 weeks’ treatment with oral ion and
were followed up with complete blood count and iron profile.
Results: Thirty-one (77.5%) patients had normal Ret He, and 9
(22.5%) had low Ret He. Ret He was positively correlated with red
cell indices, but not with iron parameters. After oral iron supple-
mentation, a significant increase in hemoglobin, reticulocyte count,
and iron was found.
Conclusions: We suggest that Ret He could be used as an easy and
affordable tool for the assessment of iron deficiency anemia in
childhood cancer during chemotherapy treatment. A trial of oral
iron in patients with low Ret He may be useful to correct the
associated anemia.
Key Words: childhood cancer, reticulocyte hemoglobin content,
iron status, anemia, iron therapy
(J Pediatr Hematol Oncol 2020;42:e147–e151)
A nemia is a prevalent complication in patients with cancer
who are treated with chemotherapy.1 The European Cancer
Anemia Survey, a large prospective survey conducted in 24
European countries, demonstrated that the prevalence of anemia
was 51% for adult patients receiving chemotherapy2 and,
although trial and recommendation in the adult population are
numerous, pediatric recommendations are very limited.3,4
Cancer-related anemia may be related to true versus
functional iron deficiency.5 True iron deficiency may be
related to nutritional problems in such children,6 while functional
Received for publication April 24, 2019; accepted November 26, 2019.
From the Departments of *Pediatrics; and †Clinical Pathology, Faculty
of Medicine, Ain Shams University, Cairo, Egypt.
The authors declare no conflict of interest.
Reprints: Iman A. Ragab, MD, Hematology-Oncology Unit, Abbas-
seya Square, Pediatric Hospital, Ain Shams University, Cairo
11566, Egypt (e-mails: hragab68@hotmail.com; hragab68@med.
asu.edu.eg).
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
J Pediatr Hematol Oncol  Volume 42, Number 3, April 2020
Copyright r 2019 Wolters Kluwer Health, Inc. All rights reserved.
iron deficiency may be mediated by inflammatory cytokines that
have a direct inhibitory effect on erythropoiesis and may inhibit
the production of erythropoietin.7 Among the common treat-
ments are erythropoietin-stimulating agents (ESAs). However,
they are not frequently used in children, and treatment response is
reached in about half of adults. Concomitant iron treatment in
anemic patients with cancer is underused, as compared with
dialysis patients,8 and it may exaggerate the lack of availability
of iron.
It is important to find a way to discriminate between
iron deficiency anemia (IDA) and anemia induced by an
acute-phase response, that is, anemia of chronic disease.9
Direct measurement of the reticulocyte hemoglobin content
(Ret He on autoanalyzers from Sysmex or hemoglobin
content [CHr] on ADVIA) provides useful information for
the diagnosis and treatment of iron-deficient states.10 Ret
He is used to detect iron deficiency because reticulocytes
exist in the circulation for only 1 to 2 days.11 A decrease in
Ret He precedes a similar decrease in erythrocytes and is an
early and reliable indicator of IDA.12,13 Thus, the CHr of
reticulocytes provides an evaluation of the bone marrow
activity, reflecting the balance between iron and erythropoiesis.12
However, biochemical markers measure iron supply for the bone
marrow and are only indirect indicators of the balance between
iron and erythropoiesis.11
The usefulness of Ret He in monitoring erythropoietic
function is indicated in the evaluation of iron status in
hemodialysis patients,14,15 in the diagnosis of iron deficiency
in children and elderly anemic patients,9,10,12,16 and in the
diagnosis and treatment of various hematologic disorders.17,18
Ret He, not being affected by acute-phase responses, is also an
early indicator of functional iron deficiency in patients treated
with ESAs.19 The use of Ret He in the evaluation of iron defi-
ciency has been reported in a cancer care setting among adults.20
Therefore, this study aimed to evaluate Ret He as a marker for
iron availability for erythropoiesis among children and adoles-
cents with cancer on chemotherapy and assess the impact of oral
iron supplementation on hematologic parameters in patients with
low Ret He.
MATERIALS AND METHODS
This was an open-label prospective trial conducted at
Ain Shams University, Pediatric Haematology-Oncology
Unit. One hundred children and adolescents, below 18 years of
age, who had cancer on chemotherapy (acute lymphoblastic
leukemia in maintenance chemotherapy phase) and who were
regularly attending the clinic were screened for the presence of
anemia. Patients with hemoglobin level <11 g/dL and those
planned for at least a further 3 months’ period of systemic
chemotherapy were enrolled. Informed consent was obtained
from each patient or control or their legal guardians before
enrollment in the study. This study was approved by the local
www.jpho-online.com | e147
Tantawy et al
ethical committee of Ain Shams University and is in accordance
with the Helsinki Declaration of 2008.
Patients with bone marrow malignant infiltration and not
in remission, having refractory disease and a life expectancy
<3 months, hepatitis C infection, fever due to infection, or those
admitted to hospital or who had received blood transfusion
3 months before the study were excluded from the study.
Data collected from hospital records included age, sex,
type and date of cancer diagnosis, age at the start of treat-
ment, treatment protocol and duration, and anthropometric
parameters at diagnosis. Patients who underwent an initial
clinical assessment for symptoms suggestive of anemia (fatigue,
tachycardia, palpitations, and poor concentration) and its signs
(pallor, hyperdynamic circulation, anorexia, pica, irritability,
fatigue, tachycardia, epithelial changes in nails and hair, and
gastrointestinal complaints) were evaluated. Performance sta-
tus was assessed using the Lansky scale. It is used to assess
patients younger than 16 years in a score of 10 to 100 that best
represents the activity status at a specific time point, wherein
100 represents fully active and 10 represents completely dis-
abled and not even involved in the passive play.21
Baseline laboratory tests included complete blood count
including Ret He on Sysmex XE 2100 (Sysmex, Kobe, Japan).
The threshold used in the diagnostic plot for Ret He was the
same for measurements with analyzers from ADVIA (Siemens
Diagnostics, Germany). A cutoff level for Ret He of 28 pg was
considered.11,18 Reticulocyte count was assessed. Serum iron
and total iron-binding capacity (TIBC) were measured on
AU680 (Beckman Coulter Inc., Brea, CA), and transferrin
saturation (Tsat) was calculated. Serum ferritin was performed
on Cobas e 411 (Roche Diagnostics, Mannheim, Germany).
To exclude infection, high-sensitivity C-reactive protein levels
were measured using Cobas Integra 800 (Roche Diagnostics).
The recruited patients were classified according to the
level of Ret He into 2 groups; group 1 comprised patients
with Ret He <28 pg (low Ret He), and group 2 comprised
patients with Ret He ≥ 28 pg (normal Ret He). Patients with
low Ret He was then allocated to treatment with oral iron
sulfate 6 mg/kg/d for 6 weeks (Fig. 1). Patients who had to be
transfused during the study were considered nonresponders; their
laboratory data were excluded from this analysis. Patients who
had any change of the used chemotherapeutic drugs, significant
infection, or drug-related severe myelosuppression during
FIGURE 1. CONSORT flow diagram for the enrolled anemic pediatric patients with cancer on chemotherapy. Ret He indicates retic-
ulocyte hemoglobin content.
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J Pediatr Hematol Oncol  Volume 42, Number 3, April 2020
the study period were also excluded to avoid any disease or
chemotherapy-related differences. After treatment, patients were
subjected to clinical assessment to review their symptoms/signs
and to follow-up laboratory investigations that included complete
blood count, reticulocyte count, and iron profile.
Sample Size
The sample size was calculated using the PASS version 11
program, setting the type-1 error (α) at 0.05 and confidence
interval width at 0.12 (margin of error 6%). Results from a pre-
vious study18 showed that IDA was present in 9.4% of patients
with cancer on chemotherapy. Calculation according to these
values produced a sample size of 91 cases that was approximated
to 100 to take into consideration the drop-out rate.
Statistical Analysis
Data were collected, coded, and entered into the Statistical
Package for Social Science (IBM SPSS) version 20 (IBM
Corporation, Armonk, NY). Kolmogorov-Smirnov test was
used to examine the normality of numerical data distribution.
When the data were skewed, they were presented as the median
and interquartile range (IQR), and between-group differences
were compared nonparametrically using the Mann-Whitney
U test. The Wilcoxon signed-rank test was used for within-
group (paired) comparisons. Qualitative data were presented as
number and percentage, and differences between groups were
compared using the χ2 test. The receiver operating characteristic
(ROC) curve was used to determine the best cutoff value of
mean corpuscular volume (MCV) with the highest balanced
sensitivity and specificity. Spearman correlation test was used
to assess the association between 2 nonparametric variables.
Multivariable linear regression analysis was used to assess
the relation between Ret He and other laboratory variables. All
P values were 2-sided. P-value of <0.05 was considered stat-
istically significant in all analyses.
RESULTS
Of 100 pediatric patients with acute lymphoblastic
leukemia in the maintenance chemotherapy phase screened
for the presence of anemia, 40 patients had hemoglobin
<11 g/dL at the screening time (range, 8.2 to 10.9 g/dL).
There were 22 male individuals (55%) and 18 female indi-
viduals (45%) with a median age of 5.1 years (IQR, 3 to 7 y).
J Pediatr Hematol Oncol  Volume 42, Number 3, April 2020 Ret He for Assessing IDA in Childhood Cancer

TABLE 1. Complete Blood Count, Reticulocyte Count, and Iron Profile in Relation to Reticulocyte Hemoglobin Content Before and After
Treatment With Oral Iron Therapy in Pediatric Patients With Cancer on Chemotherapy
Normal Ret He Low Ret He (Before Low Ret He (After
(N = 31) Treatment) (N = 9) Treatment) (N = 9) P

Between Normal Between Before and

Variables Median IQR Median IQR Median IQR and Low Ret He After Treatment
WBC count (×109/L) 4.2 3.2-5.8 4.1 3.4-6.2 4.0 3.3-5.9 0.776 0.618
Neutrophil count (×109/L) 2.4 1.9-3.2 2.9 2.1-3.5 2.8 1.8-3.3 0.307 0.528
Lymphocytic count (×109/L) 2.5 2.1-3.2 2.1 2-3.2 3.0 2.2-3.5 0.651 0.165
RBC count (×1012/L) 4 3.5-4.6 5 3.7-5.2 4.7 4.2-5.6 0.131 0.345
Hemoglobin (g/dL) 10 9.3-10.3 9.5 9-10 12 11.4-12.9 0.144 0.028
MCV (fL) 87 79.8-90.2 73 72-87 78 71-91.3 0.043 0.752
MCH (pg) 35 30-36.3 28.5 27.8-32.3 32 29-35 0.022 0.012
MCHC (pg/dL) 33 32-33.3 29 28-32 33.7 30-34.8 0.046 0.044
RDW (%) 13.8 11-19.3 14 12-16.5 12.5 10.8-14.3 0.673 0.076
Reticulocyte count (%) 1.5 1.2-2.2 1.4 0.7-1.7 2.2 2.1-2.4 0.801 0.043
Serum iron (μg/dL) 119 99-145 86 34-100.5 100 77.5-132 0.007 0.017
TIBC (μg/dL) 170 127-198 276 226.3-307.8 215.5 90.5-229.8 < 0.001 0.028
Serum ferritin (μg/L) 757 418-1279 265 163-1019 352 247-1148 < 0.001 0.014
Transferrin saturation (%) 66 45-181 33 16-57 47 28.8-58.8 0.018 0.025
Data were expressed as median and IQR wherein the Mann-Whitney test was used for comparisons.
IQR indicates interquartile range; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; MCV, mean corpuscular
volume; RBC, red blood cell; RDW, red cell distribution width; Ret He, reticulocyte hemoglobin content; TIBC, total iron-binding capacity; WBC, white
blood cell.

Thirty-one patients (77.5%) had Ret He ≥ 28 pg. They
included 12 female individuals and 19 male individuals with a
median age of 4 years (IQR, 3 to 6 y). The 9 patients (22.5%)
with Ret He <28 pg (6 male individuals and 3 female individuals)
had a median age of 3.5 years (IQR, 2 to 7 y) (Fig. 1). There was
no significant difference between patients with Ret He ≥ or
<28 pg as regards age or sex (P > 0.05).
As shown in Table 1, patients with low Ret He had
significantly lower levels of MCV, mean corpuscular hemoglobin
(MCH), mean corpuscular hemoglobin concentration (MCHC),
serum iron, serum ferritin, and Tsat, and they had higher TIBC
compared with patients with normal Ret He. ROC curve analysis
showed that the cutoff value of 78 fL could differentiate patients
with low and normal Ret He with 77% sensitivity and 82%
specificity.
The 9 patients who had low Ret He received oral iron
supplementation for 6 weeks with no adverse effects and
showed a significant increase in median Lansky perform-
ance score of 80 (IQR, 77.5 to 90) after iron therapy com-
pared with the pre-iron therapy of 65 (IQR, 60 to 72.5);
P-value of 0.024. Moreover, hemoglobin level, MCH,
MCHC, reticulocyte count, serum iron, ferritin, and Tsat
were significantly higher, while TIBC was lower after iron
therapy compared with baseline levels.
There were significant positive correlations between
Ret He and hemoglobin (r = 0.512, P = 0.001), MCV (r = 0.489,
P = 0.002) (Fig. 2), MCH (r = 0.416, P = 0.008), and MCHC
(r = 0.443, P = 0.005), whereas parameters of iron profile were
not correlated with Ret He (P > 0.05). Multivariable linear
regression analysis included all significantly correlated variables

FIGURE 2. Correlation between reticulocyte hemoglobin content (Ret He) and hematologic indices. A, Hemoglobin. B, Mean corpus-
cular volume (MCV).

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Tantawy et al
TABLE 2. Multivariable Linear Regression Analysis for
Independent Variables Affecting Ret He in Pediatric Patients With
Cancer on Chemotherapy
Unstandardized Standardized
Coefficients Coefficients
Variables B SE β P
Constant 28.995 7.924 — 0.001
Hemoglobin 1.712 0.594 0.299 0.007
(g/dL)
MCV (fL) 0.301 0.086 0.524 0.001
MCH (pg) 0.113 0.108 0.125 0.306
MCHC (pg/dL) 0.652 0.298 0.276 0.035
MCH indicates mean corpuscular hemoglobin; MCHC, mean corpus-
cular hemoglobin concentration; MCV, mean corpuscular volume; Ret He,
reticulocyte hemoglobin content.
with Ret He in the studied patients before iron therapy and
showed that hemoglobin level, MCV, and MCHC were the
significant independent variables related to Ret He (Table 2).
DISCUSSION
Inadequate iron supply is a major component in the
pathogenesis of anemia in patients with cancer,22 and its defi-
ciency is a frequent complication, particularly in those under-
going chemotherapy.23 It correlates with poor performance status
in adult patients with cancer.2 Consequently, we evaluated an
easy and financially affordable tool to assess the iron status in
children with cancer. We found that 22.5% of our patients with
cancer and anemia had low Ret He. The estimated prevalence of
insufficient iron availability in patients with cancer ranges from
19% to 63%.2,22,23 A literature review reported a 29% to 60%
prevalence of iron deficiency in patients with cancer using dif-
ferent definitions in various studies.22
Standard biochemical tests of iron metabolism, such as
serum iron, ferritin, and transferrin, are affected by the
acute-phase response.20,24 In patients with deficient red
cell hemoglobinization but no acute-phase response, iron-
deficient erythropoiesis was indicated by serum ferritin and
soluble transferrin receptor/ferritin index values <20.8 and
> 1.5 μg/L, respectively. Corresponding values in patients with
acute-phase responses were <61.7 and > 0.8 μg/L, respectively,
in 1 study.11
Ret He reflects the recent functional availability of iron for
erythropoiesis.20,25 Therefore, it has been proposed as a surrogate
marker for iron status.26 Ret He is available in real-time as
part of automated reticulocyte analysis, and its measurement is
not affected by physiologic interferences, except in cases of
thalassemia27 and macrocytosis/megaloblastosis.13
Previous studies that performed an ROC curve analysis
to define a cutoff value for Ret He were in patients with iron
deficiency, and they classified patients on the basis of iron
parameters and then determined a cutoff value to differentiate
patients with IDA versus the iron-deficient group or healthy
controls.9,10,15,16 However, in cancer patients, there is no stand-
ardization of iron parameters because they are totally affected by
the malignancy itself and its complications. Therefore, we used an
established cutoff for Ret He to evaluate it as a simple marker
away from iron parameters. There are controversies about
Ret He or CHr cutoff level diagnostic for iron deficiency.
A cutoff level ranging between 25 and 32 pg has been used
in different studies,11,16,18 but the cutoff <28 pg has been
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J Pediatr Hematol Oncol  Volume 42, Number 3, April 2020
reported in several studies with balanced sensitivity and
specificity.13,18,20 Children with CHr > 29 pg have virtually
zero probability of being iron-deficient.28
According to Ret He cutoff <28 pg, we found that the 9
patients with low Ret He had significantly lower levels of
hematologic indices and iron profile compared with patients
with normal Ret He. MCV was not the best marker to
define iron deficiency in anemia of childhood cancer due to
limited sensitivity and specificity. Ret He was correlated to
red blood cell indices but not to iron profile. This further
suggests that iron parameters are not sensitive in anemic
patients with cancer. Park et al29 reported that consistent
with common belief, cancer anemia seems to be closely
related to the inflammatory process according to higher
ferritin, CRP, and hepcidin levels in this population. How-
ever, iron deficiency and/or iron-restricted erythropoiesis
also contributes considerably to the pathogenesis of anemia
in patients with cancer.29
Toki et al16 examined the correlation between Ret He
and markers of iron metabolism in patients with true iron
deficiency. They showed the efficacy of Ret He for diagnosis
of IDA and the usefulness for monitoring drug iron admin-
istration. Ret He correlated positively with serum iron and
Tsat, and it correlated negatively with TIBC and serum
transferrin receptors. There was no correlation between Ret
He and serum ferritin when all patients were included in the
analysis; however, analysis of groups according to their iron
status revealed a positive correlation between Ret He and
serum ferritin in patients with iron deficiency. Furthermore,
Ret He changed in parallel with changes in hemoglobin
during iron administration for iron-deficient anemic patients.
Different recommendations for the treatment of anemia
during chemotherapy are ESAs and/or intravenous iron.30 The
goal of iron therapy is to safely and effectively correct anemia
in patients with either absolute iron deficiency or functional
iron deficiency.31 Hedenus et al32 performed a randomized
controlled trial to investigate the effect of a single dose of
ferrous carboxymaltose without concomitant ESAs’ therapy
and found that it resulted in significantly increased hemoglobin
levels, which were maintained for at least 8 weeks in patients
with cancer receiving antineoplastic therapy; however, hyper-
sensitivity is a major concern for intravenous iron.33
With the high prevalence of iron deficiency in the
Egyptian population, we tried an oral iron replacement in
patients with low Ret He during chemotherapy. The Lansky
performance scale was used to assess the functional status
and activity of studied patients. Iron deficiency is well
known to affect both the brain34 and physical activities.35
We found a significant improvement in the performance
status after iron therapy with increased hemoglobin level
and reticulocyte count denoting that nutrient deficiency,
especially iron, should be considered in children developing
anemia during chemotherapy treatment.36
Study Limitations
The small number of patients with low Ret He is a
limiting factor. The inclusion of a larger number of patients
would have allowed further randomization of patients with
low Ret He for receiving oral iron therapy or not. Although
hepcidin activity is increased in the setting of inflammation,
the lack of assessment of hepcidin in this study is another
limiting factor.
In conclusion, Ret He could be used as an easy and
affordable tool for assessment of IDA in children with
cancer during chemotherapy treatment, and it is a more
J Pediatr Hematol Oncol  Volume 42, Number 3, April 2020
reasonable assay compared with the conventional iron
profile in which the inflammatory conditions associated with
cancer can impact. A trial of oral iron in patients with low
Ret He may be useful to correct the associated anemia.
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