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Pediatric reference intervals for soluble transferrin receptor and transferrin receptor-ferritin index

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Recent studies showing an improved diagnosis of iron deficiency (ID) with soluble transferrin receptor (sTfR) and sTfR-ferritin index did not take into account the age-dependency of sTfR and ferritin. Moreover, there is a paucity of data on pediatric reference intervals for sTfR and sTfR-ferritin index. A study cohort of 436 apparently healthy children was analyzed to establish reference intervals for ferritin, transferrin, sTfR and sTfR-ferritin index. To account for age-dependency, standard deviation scores (Z-scores) for these markers were calculated. The association between these parameters and C-reactive protein (CRP) was analyzed. The Z-scores of ferritin, transferrin and sTfR had a significant association with CRP, whereas the Z-score of sTfR-ferritin did not correlate with CRP. The reference intervals of these parameters were reported. Among the different markers of ID, the Z-scores of sTfR, transferrin and ferritin, but not sTfR-ferritin index, associate with the inflammatory status.
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World J Pediatr, Vol 5 No 2 . May 15, 2009 . www.wjpch.com
122
World Journal of Pediatrics
Original article
Author Afliations: Department of Pediatrics, Children's Hospital, London
Health Science Centre, Schulich School of Medicine & Dentistry, University
of Western Ontario, 800 Commissioners Road East, London, Ontario N6A
7W9, Canada (Ooi CL, Sharma AP, Filler G); Department of Pathology and
Laboratory Medicine, Children's Hospital of Eastern Ontario, 401 Smyth
Road, Ottawa, Canada, K1H 8L1 (Lepage N); Sanquin Diagnostic Services,
Amsterdam, The Netherlands (Nieuwenhuys E)
Corresponding Author: Guido Filler, MD, PhD, FRCPC, Department of
Pediatrics, Children's Hospital, London Health Science Centre, London,
Ontario, Canada, N6A 5W9 (Tel: +1-519-685-8377; Fax: +1-519-685-8551;
Email: guido.ller@lhsc.on.ca)
doi:10.1007/s12519-009-0024-3
©2009, World J Pediatr. All rights reserved.
Background: Recent studies showing an improved
diagnosis of iron deciency (ID) with soluble transferrin
receptor (sTfR) and sTfR-ferritin index did not take
into account the age-dependency of sTfR and ferritin.
Moreover, there is a paucity of data on pediatric
reference intervals for sTfR and sTfR-ferritin index.
Methods: A study cohort of 436 apparently healthy
children was analyzed to establish reference intervals
for ferritin, transferrin, sTfR and sTfR-ferritin index.
To account for age-dependency, standard deviation
scores (Z-scores) for these markers were calculated. The
association between these parameters and C-reactive
protein (CRP) was analyzed.
Results: The Z-scores of ferritin, transferrin and
sTfR had a signicant association with CRP, whereas the
Z-score of sTfR-ferritin did not correlate with CRP. The
reference intervals of these parameters were reported.
Conclusion: Among the different markers of ID, the
Z-scores of sTfR, transferrin and ferritin, but not sTfR-
ferritin index, associate with the inammatory status.
World J Pediatr 2009;5(2):122-126
Key words: C-reactive protein;
ferritin;
reference interval;
soluble transferrin receptor;
soluble transferrin receptor-ferritin index;
transferrin
Introduction
Iron deciency (ID) is the most common nutritional
insufciency in the world.[1] It has been linked with
signicant auditory, visual, cognitive, behavioral,
motor and immune effects in children.[2] Marrow iron
estimation is the current gold standard to assess iron
status; however, its invasiveness limits its clinical
applicability.[2] Traditionally, serum ferritin, iron
and total iron binding capacity are used to diagnose
ID. The National Health and Nutrition Examination
Study III (NHANES III) denes ID based on the
presence of 2 of the following 3 parameters: ferritin
<10 μg/L, transferrin saturation <10% and erythrocyte
protoporphyrin >1.42 μmol/L.[3] Iron deciency anemia
is dened as ID plus hemoglobin <110 g/L.[3] The
presence of a concomitant inammation is recognized
as affecting the performance of these markers in
diagnosing ID.[4,5]
Serum soluble transferrin receptor (sTfR), a
monomer lacking 100 amino acids of the transferrin
receptor, is another relatively new marker to diagnose
ID.[6] A decrease in iron stores upregulates the
transferrin receptor, resulting in an increase in serum
sTfR levels.[4] Since there is an inverse relationship
between sTfR and ferritin in ID, different ratios based
on serum sTfR and ferritin levels have been proposed
to improve the performance over the either marker.[7-9]
Inammation can suppress erythropoiesis and
hamper the sTfR increase despite the presence of
ID.[10] Compared with ferritin and transferrin, sTfR
was found to have a better association with ID in
chronic infection,[11-13] acute infection,[14] and chronic
liver disorders.[15] In spite of a better association,
sTfR did not improve the diagnosis of ID in pregnant
women with HIV[16] or in general populations.[17,18]
Likewise, sTfR did not improve the diagnosis of ID
over full blood count and C-reactive protein (CRP) in
children with a high burden of infectious diseases.[19]
Moreover, serum sTfR has also been reported to have
an age-dependent increase in the childhood period.[16]
Currently available studies do not account for age-
dependency while assessing the relationship between
sTfR and inammation in children. The literature is
scarce on the pediatric reference intervals for sTfR and
Pediatric reference intervals for soluble transferrin
receptor and transferrin receptor-ferritin index
Cara Lianne Ooi, Nathalie Lepage, Ed Nieuwenhuys, Ajay Parkash Sharma, Guido Filler
London, Ontario, Canada
World J Pediatr, Vol 5 No 2 . May 15, 2009 . www.wjpch.com
123
Pediatric reference intervals for sTfR and sTfR-ferritin index
Original article
sTfR-ferritin index.
The objectives of this study were to establish
pediatric reference intervals for sTfR and sTfR-ferritin
index and to assess the relationship of CRP with the
Z-scores of sTfR, ferritin, transferrin and the sTfR-
ferritin index.
Methods
Two-hundred and sixty patients undergoing minor
elective surgeries, including hernia repair (n=33),
circumcision (n=8), hypospadia surgery (n=3),
orchidopexy (n=10), minor otolaryngologic surgery
(n=35), tonsillectomy and/or adenectomy (n=50), minor
ophthalmological operation (n=3), minor orthopedic
intervention (n=41), minor dental surgery (n=20)
and other surgeries (n=57), were identied from the
operative record lists at the Children's Hospital of
Eastern Ontario (CHEO) and approached by a study
nurse at the preoperative anesthesia assessment visit.
Written informed consent for the collection of limited
anthropometric data and blood sampling was obtained
from the parents or from the consenting-minor patients.
This cohort was augmented by 176 samples, stored at
-20°C, collected for a previous study.[20] Age, gender
and the type of surgery were recorded. CHEO's
institutional review board gave full approval for the
study.
sTfR was measured as previously described.[21]
Ferritin, transferrin and CRP were measured by
immunonephelometry using BN ProSpec® and the
corresponding Dade Behring reagents. The sTfR-
ferritin index was calculated as the ratio of sTfR
concentration in μg/mL over the log of ferritin
concentration in μg/L as previously described.[22]
Wherever possible, simple descriptive statistics was
used. Data were tested for normal distribution using the
D'Agostino Pearson omnibus normality test. Normally
distributed parameters were reported as mean ±
standard deviation (SD); otherwise, the median and the
2.5th and 97.5th percentiles were recorded. In order to
account for age-dependency, we calculated Z-scores
for all parameters based on the mean and standard
deviation of each age group. The Pearson's correlation
coefcient was used for normally distributed data;
otherwise, we used the Spearman's rank correlation
coefcient to test for a relationship between parameters.
All statistical analyses were performed using GraphPad
Prism for Windows version 4.01 (GraphPad Software
Inc., San Diego, CA, USA), with the exception of the
percentiles for the central 95% condence interval
for which SPSS for Windows version 14.0 (SPSS Inc.,
Chicago, IL, USA) was used.
Results
Four-hundred and thirty-six children (245 males, 191
females) aged 0.4 months to 18 years were studied. As
no statistical difference was found between genders for
all age groups in all parameters (P>0.05), the data were
pooled within the age categories.
Ferritin levels were high in the rst 6 months, had
a decreasing trend, with a nadir at 18 to 24 months, and
a subsequent gradual return to common adult levels in
adolescence. Transferrin and sTfR values also showed
variation in different age groups.
In most age groups, the data were normally
distributed for sTfR and transferrin, whereas the data
for ferritin were not normally distributed. In order to
report the reference intervals for all parameters, we
recorded the median and central 95% reference interval
as well as the mean ± SD (Table). All these parameters
clearly showed an age-dependency, with the non-
parametric Spearman's rank correlation coefcient of
0.2278 for ferritin, 0.3066 for transferrin and 0.2390 for
sTfR (P<0.0001).
To account for the age-dependency, we calculated
the Z-scores for ferritin, transferrin, sTfR and sTfR-
ferritin index. The slopes of the regression line between
the age and the Z-scores of ferritin, transferrin, sTfR,
and sTfR-ferritin index did not signicantly differ from
zero, indicating that the Z-score calculations introduced
no bias (P values between 0.70 and 0.96).
The level of CRP ranged from undetectable values
to a maximum of 37.06 mg/L. Although all the patients
in this study were asymptomatic and apparently
healthy, 17 (3.9%) of them had an elevated CRP level.
The distribution of elevated level of CRP was relatively
even among the age groups (range, 0.0%-12.8%). The
level of CRP was not normally distributed; therefore,
the relationship between CRP and the other parameters
was analyzed using the non-parametric Spearman's
rank correlation coefcient. Ferritin and transferrin
both correlated signicantly with CRP (Spearman's
rank, r=0.1283 and 0.1230; P<0.0085 and P<0.0116).
Interestingly, there was a signicant correlation
between CRP and sTfR (Spearman's rank, r=0.2390,
P<0.0001, Fig. 1), and also between CRP and sTfR
Z-score (Spearman's rank, r=0.2077, P<0.0001). CRP
did not have a signicant correlation with sTfR-ferritin
index (Spearman's rank, r=0.02790, P=0.5732, Fig. 2)
or with sTfR-ferritin index Z-score (Spearman's rank,
r=-0.01628, P=0.7424).
Discussion
The main objectives of this study were to establish
sTfR and sTfR-ferritin index reference intervals for the
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124
World Journal of Pediatrics
Original article
sTfR: soluble transferrin receptor.
Table. Pediatric reference intervals for transferrin, ferritin, soluble
transferrin receptor, and the soluble transferrin receptor-ferritin index
nMedian 2.5th
percentile
97.5th
percentile
Mean ± SD
0.4 to 6 months
Transferrin (g/L) 13 2.38 1.77 6.07 2.93±1.20
Ferritin (μg/L) 13 102.66 3.28 336.34 148.45±106.84
sTfR (mg/L) 13 1.52 1.26 3.17 1.78±0.58
sTfR/log(ferritin) 13 0.74 0.57 4.81 1.25±1.29
6 to 12 months
Transferrin (g/L) 17 2.82 1.04 3.83 2.74±0.65
Ferritin (μg/L) 17 31.61 5.04 56.55 29.31±14.51
sTfR (mg/L) 17 1.66 1.12 2.91 1.75±0.41
sTfR/log(ferritin) 17 1.22 0.81 2.96 1.36±0.57
12 to 18 months
Transferrin (g/L) 16 3.27 2.02 4.31 3.19±0.66
Ferritin (μg/L) 16 13.29 6.48 102.03 30.38±30.05
sTfR (mg/L) 16 1.89 1.37 2.52 1.90±0.39
sTfR/log(ferritin) 16 1.51 0.82 2.70 1.58±0.54
18 months to 2 years
Transferrin (g/L) 21 3.15 2.22 4.06 3.06±0.45
Ferritin (μg/L) 21 17.82 8.89 53.88 22.22±12.69
sTfR (mg/L) 20 1.72 1.33 2.93 1.82±0.39
sTfR/log(ferritin) 20 1.46 0.97 2.34 1.45±0.34
2 to 3 years
Transferrin (g/L) 47 2.73 1.96 4.26 2.83±0.52
Ferritin (μg/L) 47 17.36 2.55 81.29 21.80±15.74
sTfR (mg/L) 46 1.70 0.98 2.91 1.71±0.41
sTfR/log(ferritin) 46 1.32 0.65 5.55 1.61±1.01
3 to 4 years
Transferrin (g/L) 39 2.76 1.76 4.13 2.81±0.56
Ferritin (μg/L) 39 26.26 3.14 192.00 36.94±38.54
sTfR (mg/L) 38 1.57 1.08 2.55 1.63±0.34
sTfR/log(ferritin) 38 1.19 0.67 4.29 1.28±0.64
4 to 6 years
Transferrin (g/L) 76 2.69 2.04 4.78 2.88±0.72
Ferritin (μg/L) 76 23.98 5.26 108.98 31.34±23.48
sTfR (mg/L) 76 1.50 1.10 2.74 1.61±0.42
sTfR/log(ferritin) 76 1.12 0.69 2.34 1.22±0.41
6 to 9 years
Transferrin (g/L) 64 2.55 2.05 4.86 2.70±0.56
Ferritin (μg/L) 58 27.83 3.61 78.90 29.99±16.33
sTfR (mg/L) 64 1.40 0.93 2.63 1.50±0.37
sTfR/log(ferritin) 58 0.99 0.60 5.26 1.18±0.88
9 to 12 years
Transferrin (g/L) 44 2.64 1.86 4.19 2.70±0.51
Ferritin (μg/L) 44 31.29 4.84 242.21 40.20±38.71
sTfR (mg/L) 44 1.42 0.81 2.67 1.46±0.32
sTfR/log(ferritin) 44 0.94 0.35 2.27 1.03±0.35
12 to 18 years
Transferrin (g/L) 86 2.79 2.08 4.00 2.85±0.49
Ferritin (μg/L) 86 29.39 2.76 108.86 36.79±23.78
sTfR (mg/L) 85 1.34 0.91 1.91 1.37±0.24
sTfR/log(ferritin) 85 0.92 0.67 3.05 1.00±0.46
Fig. 2. The relationship between the soluble transferrin ferritin index [sTfR/
log(ferritin)] and C-reactive protein (CRP) in 436 apparently healthy
children. There was no signicant correlation between the two parameters.
sTfR/log(ferritin)
0.1 1 10 100
10
1
0
CRP (mg/L)
Fig. 1. The relationship between soluble transferrin receptor (sTfR)
concentration and C-reactive protein (CRP) in 436 apparently
healthy children. There was a signicant correlation between the two
parameters (Spearman's rank, r=0.2390, P<0.0001).
sTfR (mg/L)
0.1 1 10 100
3.0
2.5
2.0
1.5
1.0
0.0
CRP (mg/L)
new Dade Behring assay and to assess the relationship
of CRP with sTfR, ferritin, transferrin and sTfR-
ferritin index.
There is a paucity of data on pediatric reference
intervals for sTfR and sTfR-ferritin index. We are
unaware of any previous publications on pediatric
reference intervals for sTfR using the Dade Behring
assay. Kratovil et al[23] published age-dependent
reference intervals in 183 children, using the
Quantikine IVD sTfR Immunoassay kit. Their
reference ranges reported were 1.37-2.85 mg/L for 6 to
24 months, 1.05-3.05 mg/L for 2 to 6 years, 1.16-2.72
mg/L for 7 to 12 years, 0.97-2.60 mg/L for 13 to 17
years, and 0.84-2.32 mg/L for ≥18 years.[23] Our data
compared favorably with these reference intervals.
Additionally, we reported the reference ranges under
the age of 6 months, and expanded on other age groups
from a larger study cohort. Malope et al[22] reported
in a study with sTfR measured by enzyme-linked
immunosorbent assay a Log sTfR: ferritin ratio >2.55
for ID and <2.55 for anemia of inammation as the
World J Pediatr, Vol 5 No 2 . May 15, 2009 . www.wjpch.com
125
Pediatric reference intervals for sTfR and sTfR-ferritin index
Original article
cut-off to diagnose ID in children aged 1-6 years. Our
results have a reasonable agreement with their cut-
offs; however, we observed an age-dependency of
sTfR-ferritin index, similar to that of sTfR observed by
Kratovil et al.[23]
The utility of sTfR in diagnosing ID in the presence
of inammation has been debated lately. To evaluate
this issue further, we assessed the relationship of CRP
with sTfR and sTfR-ferritin index in apparently healthy
children. We also measured the traditional markers
of ID, transferrin and ferritin in our study cohort. To
improve on previous studies, we accounted for the age
dependency of these parameters by calculating their
Z-scores.
In our study sample, CRP had a signicant
association with ferritin as well as with transferrin.
Ferritin is a recognized positive acute phase reactant,
whereas inammation decreases transferrin production.
The ferritin peak observed in the rst 6 months was
consistent with previously reported high ferritin at
birth and early infancy.[24]
While assessing the effect of inammation on
sTfR, sTfR showed a positive association with CRP.
This association persisted even after accounting for
the age-dependency of sTfR. As is already known,
ID stimulates an increase in sTfR levels due to
the compensatory increase in erythropoiesis.[6-12]
Conversely, inammation can also decrease sTfR
production, thus lowering its serum level in rheumatoid
arthritis,[25] inammatory bowel disease,[26] and other
inammatory disorders.[27] A similar acute phase
reactant potential of sTf R was also reported in children
with a high load of infection and inammation.[18]
Because there is an opposing effect of ID and
inammation on sTfR production, the relative severity
of ID and inammation can affect the relationship
between sTfR and CRP in a study sample.
To explore this relationship further, we evaluated
the association between CRP and sTfR-ferritin index.
Based on an increase in sTfR level from stimulated
erythropoiesis and a decrease in ferritin levels with
reduced iron stores, an sTfR-ferritin ratio has been
proposed to be a better marker for ID than either sTfR
or ferritin alone.[27] In the presence of inammation,
the acute-phase decrease in sTfR level and an opposite
increase in serum ferritin can affect the diagnostic
accuracy of this ratio. In our study cohort, sTfR-ferritin
index did not have a signicant association with CRP,
even though CRP correlated signicantly with sTfR
and ferritin individually. Possibly this could be due to
the reverse direction of the change in sTfR and ferritin
with inammation. Previous studies have also shown
a better performance of sTfR-ferritin index over either
sTfR or ferritin in diagnosing ID in the presence
of inammation.[22,28] The statistically insignicant
association between sTfR-ferritin index and CRP, even
after calculating the respective Z-scores, was the novel
nding from our study. This observation suggests an
independence of sTfR-ferritin index from inammation
even after accounting for the age-dependency of these
variables.
Our study has a few limitations. Instead of a study
sample from the community at large, we enrolled our
subjects during a hospital visit. The inclusion prior
to an elective minor procedure minimized signicant
confounding from a major comorbidity on our
reference intervals. Otherwise, all included subjects
were clinically asymptomatic and the incidence of
elevated CRP was low (3.9%). Understandably, marrow
iron testing improves the quantication of the iron
status. Considering the primary focus of our study,
the lack of marrow iron quantication should not alter
the relative relationship among the studied ID indices
and CRP. The screening investigations also excluded
any suggestion of hemolysis to affect the sTfR levels.
Considering the selection of apparently healthy
children, our results cannot be extrapolated to the
inammatory states.
In summary, inammation associates signicantly
with sTfR, ferritin and transferrin in healthy children,
even after accounting for the age-dependency of these
variables. sTfR-ferritin index appears to be independent
from inammation. The applicability of our ndings
to the patients with inammatory conditions needs
further validation.
Funding: The study was supported by grants from Dade Behring
GmbH, Marburg, Germany and Dade Behring Inc., Mississauga,
ON, Canada.
Ethical approval: The Institutional Review Board of the
Children's Hospital of Eastern Ontariogave gave full approval for
the study.
Competing interest: None.
Contributors: Lepage N, Niewenhuys E and Filler G designed
and executed the study. Ooi CL and Filler G performed the
analysis and wrote the manuscript and it was critically edited
and revised by the other two co-authors. Sharma AP and Filler G
prepared the nal version.
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Received July 7, 2008
Accepted after revision February 19, 2009
... Roche Diagnostics. [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] Standardization has not been widely established and conversion of reference intervals between platforms is not possible. 16 Age intervals vary across studies, and evaluation of published data is complicated. ...
... In this study, we also set out to investigate associations of acute phase response, as measured by CRP, with sTfR. Studies in children with inflammatory conditions and infectious diseases are currently few and with contradictory results.11,32,33 Similarly to conclusions by Rohner et al,32 our data did not show sTfR to be associated with the acute phase response as assessed by CRP at 4 months or 12 months.There was, however, a significant association between sTfR and CRP at 48-96 hours which may be due to an increase in transferrin receptor expression by hypoxia induced by uterine contractions during normal labor. ...
Article
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Introduction Infant iron status assessments may be difficult to interpret due to infections. The soluble transferrin receptor (sTfR) has been suggested as a biomarker mainly unaffected by the acute phase response. Reference intervals reflecting dynamics of infant growth first year in life are not well established. Methods The sTfR and CRP concentrations were measured in samples from 451 term infants with the Roche Cobas platform in umbilical cord, at 48‐96 hours, 4 and 12 months. Reference values were constructed as the 2.5th and 97.5th percentiles. The relationship between CRP concentrations >1 mg/L and sTfR was tested by Kendall correlation. Results Reference intervals for girls and boys were 2.4‐9.5 mg/L at birth, 2.9‐8.4 mg/L at 48‐96 hours, 2.6‐5.7 mg/L at 4 months and 3.0‐6.3 mg/L at 12 months. No differences between sexes were observed except for at 4 months. sTfR did not covariate with CRP concentrations >1 mg/L except in 48‐96 hours samples. Conclusion This study reports reference intervals for sTfR from birth to 12 months of age in a large group of infants in a low‐risk area for iron deficiency. sTfR might add value to infant iron status diagnostics since no covariation with CRP was found at birth, at 4 months or at 12 months.
... Normal adult male and female levels in various studies have been found to range from 2.2 to 5.0 and 1.9 to 4.4 mg/l respectively[5,6]. Pediatric studies are few and most highlight relatively lower soluble transferrin receptor levels as compared to normal adults[7][8][9][10]. In present pilot study, we evaluated plasma soluble transferrin receptor levels in 40 healthy children (2–12 years) over a period of 6 months. ...
... In addition, levels were found to be even lower than those described in pediatric age group in various western studies. In a large cohort of 268 healthy children, Ooi et al.[7][11]and Choi et al.[12]also highlighted in their studies that soluble transferrin receptor ranges decrease with age from infants to adolescence age group. Tong et al.[13]in a study involving 110 infants found soluble transferrin receptor levels comparable to that of adults with a mean of 4.39 ± 1.70 mg/l. ...
Article
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Soluble serum transferrin receptor is derived from erythroid transferrin receptor expressed on surface of developing erythroid cells. It can be detected in blood using sensitive ELISA methodology and blood levels reflect physiological iron dependent erythropoiesis state in bone marrow. Normal adult levels vary from 2 to 5 mg/l. However, pediatric studies are few and describe normal ranges to the tune of 1.0–3.0 mg/l, which are relatively lower than that of adults. In present study 40 healthy children (2–12 years) were evaluated to establish normal soluble transferrin receptor range. The mean transferrin receptor levels were 0.39 mg/l with a range of 0.17–2.1 mg/l. The levels were low as compared to mean levels described in other studies from West and our country (4.39 and 2.0 mg/l respectively). Since, no internationally standard method for reporting and testing for transferrin receptor levels are yet available, hence it is imperative to establish normal control ranges in different population cohorts, especially in pediatric age group, to better interpret their levels in diagnostic context.
... Ferritin is difficult to interpret as an independent marker of iron status as it is an acute-phase reactant [6]. Production of transferrin is also affected by inflammation, although, in contrast to ferritin, inflammation decreases transferrin production, resulting in misleadingly elevated TSAT values [7]. ...
Article
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Background Anaemia is a common presenting feature among patients with chronic kidney disease (CKD) and associated with poor clinical outcomes. We evaluated the diagnostic validity of growth differentiation factor-15 (GDF-15) and hepcidin as it is not clear if they are useful as a biomarkers of anaemia among non-dialysis CKD egyptian patients. Method An analytical cross-sectional study was conducted among non-dialysis CKD patients ( n = 60) and apparently healthy controls ( n = 28) at Minia University maternity & children Hospital. Serum levels of GDF-15 and hepcidin were determined. Predictive logistic regression models were built and post estimation receiver operator characteristics were determined to evaluate diagnostic validity of hepcidin and GDF-15 for iron deficiency anaemia. Results Hepcidin and GDF-15 are significantly higher in cases than control p value (0.047 < 0.0001) respectively. The predictive value of diagnosing anaemia among CKD patients using hepcidin and GDF-15 was 72.0%, 70.0%. There was a weak negative correlation between hepcidin levels and glomerular filtration rate GFR ( r = -.175, p = 0.105) in CKD patients, and significant correlation between serum GDF-15 and haemoglobin ( r = -0.897, p < 0.0001), ferritin ( r = 0.489, P < 0.000), Iron ( r = -0.314, P = 0.002), CRP ( r = 0.409, P < 0.0001). Conclusion Hepcidin and GDF-15 is a potential biomarker for predicting anaemia connected with inflammation among CKD Egyptian patients.
... Production of transferrin is also affected by in ammation, although, in contrast to ferritin, in ammation decreases transferrin production, resulting in misleadingly elevated TSAT values [7]. ...
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Background Anaemia is a common presenting feature among patients with chronic kidney disease (CKD) and associated with poor clinical outcomes. We evaluated the diagnostic validity of growth differentiation factor-15 (GDF-15) and hepcidin as it is not clear if they are useful as a biomarkers of anaemia among non-dialysis CKD egyptian patients. Method An analytical cross-sectional study was conducted among non-dialysis CKD patients (n = 60) and apparently healthy controls (n = 28) at Minia University maternity & children Hospital. Serum levels of GDF-15 and hepcidin were determined. Predictive logistic regression models were built and post estimation receiver operator characteristics were determined to evaluate diagnostic validity of hepcidin and GDF-15 for iron deficiency anaemia. Results Hepcidin and GDF-15 are significantly higher in cases than control p value (0.047,<0.0001) respectively. The predictive value of diagnosing anaemia among CKD patients using hepcidin and GDF-15 was 72.0%, 70.0%.There was a weak negative correlation between hepcidin levels and glomerular filtration rate GFR (r-175 =, p = 0.105) in CKD patients, and significant correlation between serum GDF-15 and haemoglobin (r = -0.897, p < 0.0001), ferritin (r = 0.489, P < 0.000), Iron (r=-0.314, P = 0.002), CRP (r = 0.409, P < 0.0001). Conclusion Hepcidin and GDF-15 is a potential biomarker for predicting anaemia connected with inflammation among CKD Egyptian patients.
... 12 However, the above ratio has not been adequately studied in infants and children, and limited studies have been performed to determine its reference range and cutoff values for ID. 10,[12][13][14][15] In Greece, the prevalence of anemia, ID, and IDA is confounded by the high prevalence of heterozygous thalassemia and has not been well-studied during the last decade in infants and toddlers. The Thrace region is one of the least developed areas of Greece, with lower income than the rest of the country. ...
Article
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Background and Objectives: Iron deficiency (ID) is a major public health problem with high prevalence in early childhood. We assessed the prevalence of anemia, ID, and iron deficiency anemia (IDA) in healthy children of Thrace, Greece, its correlation with dietary factors, and evaluated the diagnostic performance of hematologic and biochemical markers of sideropenia. Patients and Methods: For 202 healthy children 1-5 years old, a questionnaire was filled out describing their nutritional habits during infancy and early childhood. Venous hemograms along with serum ferritin, TIBC, %TS, and CRP were obtained from all studied children. In a subset of 156 children, the concentration of sTfR was also determined. Results: Children with ID and IDA had significantly lower beef consumption than children without sideropenia (p=0.044). Using the WHO cut-off values of Hb
... It has advantages over other iron parameters (sTfR is unaffected by inflammation), but the non-standardisation of the measure is a major disadvantage. Despite this reservation, normal values have been published for healthy children and adolescents [12,29,37,45,46], as have cut-off values indicative of ID in adults [32,33] and children [3]. ...
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This cross-sectional study, conducted on a population-based representative sample, evaluates the usefulness of reticulocyte haemoglobin content (CHr), serum transferrin receptor (sTfR) and sTfR/log ferritin (sTfR-F index) to recognise iron deficiency (ID) without anaemia, provides specific cut-off points for age and gender, and proposes a new definition of ID. A total of 1239 healthy children and adolescents aged 1–16 years were included. Complete blood count, iron biomarkers, erythropoietin, C-reactive protein, CHr, sTfR, and sTfR-F index were determined. ROC curves were obtained and sensitivity, specificity, predictive values, likelihood ratios, and accuracy for each specific cut-off points were calculated. Seventy-three had ID without anaemia. Area under the curve for sTfR-F index, sTfR and CHr were 0.97 (CI95% 0.95–0.99), 0.87 (CI95% 0.82–0.92) and 0.68 (CI95% 0.61–0.74), respectively. The following cut-off points defined ID: sTfR-F Index > 1.5 (1–5 years and 12–16 years boys) and > 1.4 (6–11 years and 12–16 years girls); sTfR (mg/L) > 1.9 (1–5 years), > 1.8 (6–11 years), > 1.75 (12–16 years girls) and > 1.95 (12–16 years boys); and CHr (pg) < 27 (1–5 years) and < 28.5 (6–16 years).Conclusions: CHr, sTfR and the sTfR-F index are useful parameters to discriminate ID without anaemia in children and adolescents, and specific cut-off values have been established. The combination of these new markers offers an alternative definition of ID with suitable discriminatory power. What is Known: • In adults, reticulocyte haemoglobin content (CHr), serum transferrin receptor (sTfR) and sTfR/log ferritin index (sTfR-F index) have been evaluated and recognised as reliable indicators of iron deficiency (ID). • Clinical manifestations of ID may be present in stages prior to anaemia, and the diagnosis of ID without anaemia continues to pose problems. What is New: • CHr, sTfR and the sTfR-F index are useful parameters in diagnosis of ID in childhood and adolescence when anaemia is not present. • We propose a new strategy for the diagnosis of ID in childhood and adolescence, based on the combination of these measures, which offer greater discriminatory power than the classical parameters.
Article
Objectives Soluble transferrin receptor (sTfR) is a marker of both erythropoiesis and iron status and is considered useful for detecting iron deficiency, especially in inflammatory conditions, but reference intervals covering the entire pediatric age spectrum are lacking. Methods We studied 1,064 (48.5 % female) healthy children of the entire pediatric age spectrum to determine reference values and percentiles for sTfR and the ratio of sTfR to log-ferritin (sTfR-F index) using a standard immunoturbidimetric assay. Results Soluble TfR levels were highly age-specific, with a peak in infancy and a decline in adulthood, whereas the sTfR-F index was a rather constant parameter. There were positive linear relationships for sTfR with hemoglobin (Hb) (p=0.008) and transferrin (females p<0.001; males p=0.003). A negative association was observed between sTfR and ferritin in females (p<0.0001) and for transferrin saturation and mean corpuscular volume (MCV) in both sexes (both p<0.0001). We found a positive relationship between sTfR and body height, body mass index (BMI) and inflammatory markers (CrP p<0.0001; WBC p=0.0172), while sTfR-F index was not affected by inflammation. Conclusions Soluble TfR values appear to reflect the activity of infant erythropoiesis and to be modulated by inflammation and iron deficiency even in a healthy cohort.
Article
Objectives: To determine the prevalence of Iron Deficiency (ID) in children without clinical pallor using serum ferritin and the new parameters, soluble transferrin receptor (sTfR) & the ratio of sTfR/log10 serum ferritin (sTfR-F index), as suggested by WHO. Also to assess whether these new parameters could individually predict the presence of ID. Methods: Consecutive 230 healthy children aged 9-11 y without clinical pallor underwent estimation of Hemoglobin (Hb), C-Reactive Protein (CRP), serum ferritin, sTfR, and sTfR-F index levels in their blood. The abilities of the sTfR and sTfR-F index in predicting ID were determined by comparing with the gold standard (normal CRP and less serum ferritin), plotting Receiver-operating characteristic (ROC) curve, and noting the area under the curve (AUC). Results: The blood reports of 114 boys and 106 girls (total = 220) were available for analysis. Overall, 57 (31 girls, 26 boys) children had ID; among children with low CRP, 45 had ID, as suggested by low serum ferritin levels. Among children with high CRP, 12 had evidence of ID as evidenced by elevated sTfR and/or sTfR-F index. The positive predictive values of both sTfR and sTfR-F were low (32.9% and 35.9%, respectively) than the negative predictive values (85.6% and 95.3%, respectively). Conclusions: The proportion of children identified to have ID using serum ferritin, sTfR, and sTfR-index was 25.9%. sTfR and/or sTfR-F index are unlikely to be ideal individual predictors of ID.
Article
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Zinc supplementation reduces morbidity, but evidence suggests that excessive intakes may have negative health consequences. Current guidelines of upper limits (ULs) of zinc intake for young children are extrapolated from adult data. This systematic review (PROSPERO; registration no. CRD42020215187) aimed to determine the levels of zinc intake at which adverse effects are observed in young children. Studies reporting potential adverse effects of zinc intake in children aged 0–3 years were identified (from inception to August 2020) in MEDLINE, EMBASE and the Cochrane Library, with no limits on study design. Adverse clinical and physical effects of zinc intake were synthesized narratively, and meta-analyses of biochemical outcomes were conducted. Random effects models, forest plots were generated to examine the evidence by age category, dose, dose duration, chemical formula of zinc, and zinc vs placebo. The Joanna Briggs Institute Critical Appraisal Checklist, Cochrane Risk of Bias 2, and Grading of Recommendations Assessment, Development and Evaluation guideline (GRADE) were employed to assess risk of bias and to appraise the certainty of evidence. Fifty-eight studies assessed possible adverse effects of zinc doses ranging from 3 to 70 mg/d. Data from 39 studies contributed to meta-analyses. Zinc supplementation had an adverse effect on serum ferritin, plasma/serum copper concentration, sTfR, hemoglobin, hematocrit, and the odds of anemia in at least one of the subgroups investigated. Lactulose: mannitol ratio was improved with zinc supplementation, and no significant effect was observed on CRP, eSOD, ZPP and blood cholesterol and iron deficiency anemia. The certainty of the evidence, as assessed using GRADE, was very low to moderate. Although possible adverse effects of zinc supplementation were observed in some subgroups, it is unclear whether these findings are clinically important. The synthesized data can be used to undertake a dose-response analysis to update current guidelines of ULs of zinc intake for young children.
Article
Assessing iron status in a pediatric population is not easy, as it is based on parameters that undergo physiological variations in childhood and adolescence. Analysis of the reticulocyte hemoglobin content (CHr) to screen for iron deficiency may increase the accuracy of diagnosis, but, to date, reference values in healthy adolescents have not been adequately determined. A cross-sectional study was conducted on a population-based representative sample in the city of Almería (Spain), with 253 healthy non-iron-deficient (ID) subjects, aged 12 to 16 years. The mean CHr value was 31.6±1.3 pg. The CHr 2.5 percentile was 28.7 pg. There were no significant differences as regards age or sex. In the multivariate linear regression analysis, sex did not influence the variability of CHr, but it was related to age. CHr was influenced by hemoglobin and the Mentzer index, as well as by functional iron indicators such as erythrocyte protoporphyrin and serum transferrin receptor. These independent variables predicted two thirds of the variability in healthy adolescents (R=0.55). This study provides CHr reference ranges in healthy adolescents for use in clinical practice for the early detection of ID states. In populations with similar sociodemographic characteristics, values above the 2.5 percentile rule out ID, as values under the 2.5 percentile could be suggestive of functional ID.
Article
Despite the established utility of serum transferrin receptor (sTfR), serum ferritin, and the sTfR/log ferritin ratio (TfR-F Index) in the diagnosis of iron deficiency (ID) anemia, the numeric values of these parameters, which are indicative of subclinical ID, remain to be clearly defined. In this study, 65 apparently healthy nonanemic adults (22 men and 43 women) were treated with 3 months of oral iron supplementation to evaluate its effect on parameters reflecting iron status and to determine the prevalence of subclinical iron deficiency in apparently healthy adults. Significant supplementation-induced changes were observed in sTfR, ferritin, and TfR-F Index values in women, whereas in men, none of the studied parameters showed any significant change. Iron-deficient erythropoiesis (IDE) was not observed in men, but was found in 17 women (40%). Although individuals with a compromised iron status may be represented in substantial numbers in conventional reference populations, they can be readily identified using sTfR, ferritin, and TfR-F Index determinations. © 1998 by The American Society of Hematology.
Article
The objective of the study was to evaluate the diagnostic efficiency of laboratory tests, including serum transferrin receptor (TfR) measurements, in the diagnosis of iron depletion. The patient population consisted of 129 consecutive anemic patients at the University Hospital of Turku who were given a bone marrow examination. Of these patients, 48 had iron deficiency anemia (IDA), 64 anemia of chronic disease (ACD), and 17 patients had depleted iron stores and an infectious or an inflammatory condition (COMBI). Depletion of iron stores was defined as a complete absence of stainable iron in the bone marrow examination. Serum TfR concentrations were elevated in the vast majority of the IDA and COMBI patients, while in the ACD patients, the levels were within the reference limits reported earlier for healthy subjects. TfR measurement thus provided a reliable diagnosis of iron deficiency anemia (AUCROC 0.98). Serum ferritin measurement also distinguished between IDA patients and ACD patients. However, the optimal decision limit for evaluation of ferritin measurements was considerably above the conventional lower reference limits, complicating the interpretation of this parameter. Calculation of the ratio TfR/log ferritin (TfR-F Index) is a way of combining TfR and ferritin results. This ratio provided an outstanding parameter for the identification of patients with depleted iron stores (AUCROC 1.00). In anemic patients, TfR measurement is a valuable noninvasive tool for the diagnosis of iron depletion, and offers an attractive alternative to more conventional laboratory tests in the detection of depleted iron stores.
Article
Despite the established utility of serum transferrin receptor (sTfR), serum ferritin, and the sTfR/log ferritin ratio (TfR-F Index) in the diagnosis of iron deficiency (ID) anemia, the numeric values of these parameters, which are indicative of subclinical ID, remain to be clearly defined. In this study, 65 apparently healthy nonanemic adults (22 men and 43 women) were treated with 3 months of oral iron supplementation to evaluate its effect on parameters reflecting iron status and to determine the prevalence of subclinical iron deficiency in apparently healthy adults. Significant supplementation-induced changes were observed in sTfR, ferritin, and TfR-F Index values in women, whereas in men, none of the studied parameters showed any significant change. Iron-deficient erythropoiesis (IDE) was not observed in men, but was found in 17 women (40%). Although individuals with a compromised iron status may be represented in substantial numbers in conventional reference populations, they can be readily identified using sTfR, ferritin, and TfR-F Index determinations. © 1998 by The American Society of Hematology.
Article
The transferrin receptor plays a critical role in iron metabolism by precisely contrOlling the flow of transferrin iron into body cells. A soluble truncated form of the receptor can be detected in human serum using sensitive immunoassays, and the initial clinical experience with this new measurement indicates that it reflects the total body mass of tissue receptor. Serum receptor levels rise significantly with tissue iron deficiency and the heightened demand for iron associated with expansion of the erythroid marrow. The serum receptor provides a quantitative measure of functional iron deficiency and distinguishes the associated anemia from that of chronic disease. If iron deficiency is excluded, the serum receptor provides a quantitative measure of total erythropoiesis that is more sensitive and less invasive than bone marrow examination currently used to assess red cell precursor mass. Performed in conjunction with serum ferritin measurements, the serum receptor will be useful in establishing the true prevalence of iron deficiency anemia in population studies.
Article
Objective. —To determine the prevalence of iron deficiency and iron deficiency anemia in the US population.Design. —Nationally representative cross-sectional health examination survey that included venous blood measurements of iron status.Main Outcome Measures. —lron deficiency, defined as having an abnormal value for at least 2 of 3 laboratory tests of iron status (erythrocyte protoporphyrin, transferrin saturation, or serum ferritin); and iron deficiency anemia, defined as iron deficiency plus low hemoglobin.Participants. —A total of 24 894 persons aged 1 year and older examined in the third National Health and Nutrition Examination Survey (1988-1994).Results. —Nine percent of toddlers aged 1 to 2 years and 9% to 11% of adolescent girls and women of childbearing age were iron deficient; of these, iron deficiency anemia was found in 3% and 2% to 5%, respectively. These prevalences correspond to approximately 700000 toddlers and 7.8 million women with iron deficiency; of these, approximately 240 000 toddlers and 3.3 million women have iron deficiency anemia. Iron deficiency occurred in no more than 7% of older children or those older than 50 years, and in no more than 1% of teenage boys and young men. Among women of childbearing age, iron deficiency was more likely in those who are minority, low income, and multiparous.Conclusion. —lron deficiency and iron deficiency anemia are still relatively common in toddlers, adolescent girls, and women of childbearing age.
Article
Laboratory tests used in the diagnosis of iron status lack specificity in defining iron deficiency anaemia (IDA) and anaemia of inflammation (AI). The serum transferrin receptor (sTfR) may provide more information in this regard. The iron status of 561 pre-school children was determined and classified using the conventional measurements. The value of the concentration of sTfR, the ratio of sTfR (µg/ml) to LogSF (µg/l) (TfR-Index), and the Log of the ratio of sTfR (µg/l) to SF (µg/l) − (LogTfR:Fer ratio), in the classification of the iron status were determined by comparing their distributions across the classification of iron status. Although there were significant differences in sTfR and TfR-Index across the categories of iron status, there was considerable overlap. All subjects with iron deficiency had LogTfR:Fer ratio > 2·55, whereas in all subjects classified as AI it was < 2·55, thus clearly separating the two. The LogTfR:Fer ratio was not able to exclude IDA in the presence of inflammation. However, in cases of combined IDA and AI the LogTfR:Fer ratio was < 2·55 but increased to > 2·55 after resolution of the inflammation. This novel method of calculating the LogTfR:Fer ratio may provide a more precise classification of the iron status of children.
Article
Unlabelled: Iron studies are difficult to interpret in patients with chronic inflammatory states such as inflammatory bowel disease (IBD). Serum transferrin receptor (TfR) has been reported to be a reliable tool for the diagnosis of iron deficiency in adults. Our aim was to evaluate the role of serum TfR in diagnosing iron deficiency in children and adolescents with IBD. A total of 63 consecutive patients with IBD, aged 9 to 22 years (median 15 years), were tested for serum haemoglobin level, mean corpuscular volume (MCV), and serum iron, transferrin, ferritin and serum TfR levels. Those found to be anaemic were compared with seven age-matched subjects with iron deficiency anaemia (IDA) and 24 age-matched children without signs of anaemia or inflammation. Of the 63 patients with IBD, 26 had anaemia. Based on ferritin levels and MCV indices, anaemia was classified as IDA in 11 patients and as anaemia of chronic disease (ACD) in 15 patients. Mean serum TfR level in normal controls was 3.5 mg/l (range 1.2-8.2 mg/l). Mean (+/-SD) serum TfR levels were significantly lower in the IBD patients with ACD (5.3 +/- 2.3 mg/l) than in the IBD patients with IDA (8.2 +/- 3.1 mg/l) (P < 0.05). Serum TfR levels above 5 mg/l identified 10/11 IBD patients with IDA. The calculated TfR/ferritin ratio was 84 (range 17-367) for controls and 133 (range 6.4-1840) for IBD patients. A cut-off level of 350 (91% sensitivity, 100% specificity, 100% positive predictive value, 98% negative predictive value) was established for the diagnosis of IDA in IBD. Conclusion: The results suggest that serum transferrin receptor is a useful parameter for the diagnosis of iron deficiency in inflammatory bowel disease, in particular, the transferrin receptor/ferritin ratio with a cut-off level > or = 350.
Article
Transferrin receptors (TfRs) are the conventional pathway by which cells acquire iron for physiological requirements. Under iron-deficient conditions there is an increased concentration of surface TfR, especially on bone marrow erythroid precursors, as a mechanism to sequester needed iron. TfRs are also present in the circulation, and the circulating serum TfR (sTfR) level reflects total body TfR concentration. Under normal conditions erythroid precursors are the main source of sTfR. Disorders of the bone marrow with reduced erythroid precursors are associated with low sTfR levels. The sTfR concentration begins to rise early in iron deficiency with the onset of iron-deficient erythropoiesis, and continues to rise as iron-deficient erythropoiesis progressively worsens, prior to the development of anemia. The sTfR level does not increase in anemia of chronic inflammation, but is increased when anemia of chronic inflammation is combined with iron deficiency. The sTfR level is also increased in patients with expanded erythropoiesis, including hemolytic anemias, myelodysplastic syndromes, and use of erythropoietic stimulating agents. The ratio of sTfR/ferritin can be used to quantify the entire spectrum of iron status from positive iron stores through negative iron balance, and is particularly useful in evaluating iron status in population studies. The sTfR/log ferritin ratio is valuable for distinguishing anemia of chronic inflammation from iron deficiency anemia, whether the latter occurs alone or in combination with anemia of chronic inflammation.
Article
Recent studies have shown that the serum transferrin receptor is a sensitive, quantitative measure of tissue iron deficiency. This study was undertaken to determine the serum transferrin receptor's ability to distinguish iron-deficiency anemia from the anemia of chronic inflammation and to identify iron deficiency in patients with liver disease. The mean transferrin receptor level in 17 normal controls was 5.36 +/- 0.82 mg/L compared with 13.91 +/- 4.63 mg/L in 17 patients with iron-deficiency anemia (p less than 0.001). The mean serum receptor level was normal in all 20 patients with acute infection, including five with acute hepatitis, and was also normal in 8 of 10 anemic patients with chronic liver disease. Receptor levels were in the normal range in all but 4 of 41 patients with anemia of chronic disease. We conclude that unlike serum ferritin levels, which are disproportionately elevated in relation to iron stores in patients with inflammation or liver disease, the serum transferrin receptor level is not affected by these disorders and is therefore a reliable laboratory index of iron deficiency anemia.