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*Department of Pediatrics, S U M M A RY
Trondheim University Hospital,
Trondheim, Norway Introduction: Erythrocyte mean cell volume (MCV) is used clinically
†
Department of Clinical to classify anemia, and normal values may be used to exclude iron
Chemistry, Trondheim
University Hospital, Trondheim, deficiency. We have studied the diagnostic accuracy of MCV and
Norway the related measures mean cell hemoglobin (MCH) and mean cell
‡
Department of Immunology hemoglobin concentration (MCHC) in diagnosing empty iron stores
and Transfusion Medicine,
in children and young adults.
Trondheim University Hospital,
Trondheim, Norway Methods: Diagnostic accuracy of MCV, MCH, and MCHC was studied
by ROC curve analysis in 6443 ambulant patients aged 0.5–
Correspondence: 25 years, of which 476 were anemic. In all patients, blood hemoglo-
Ann Elisabeth Asberg, Depart- bin, MCV, MCH, and serum ferritin were measured in specimens
ment of pediatrics, St. Olavs
Hospital, 7006 Trondheim, sampled at the same time. MCHC was calculated as MCH divided by
Norway. MCV. The gold standard of empty iron stores was s-ferritin <10, 15,
Tel.: +47 72574846; or 20 lg/L. The cutoff limit of MCV giving 90% sensitivity in diag-
Fax: +47 72575501;
nosing serum ferritin <15 lg/L was constructed using quantile
E-mail: ann.asberg@stolav.no
regression.
doi:10.1111/ijlh.12132
Results: Generally, MCH was slightly more accurate than MCV and
MCHC. In the whole study population, the area under the ROC
Received 5 March 2013; curve was 0.68–0.93 for MCV, 0.73–0.96 for MCH, and 0.68–0.87
accepted for publication 9 July for MCHC; and 0.70–0.86, 0.71–0.89, and 0.68–0.88, respectively,
2013 in the anemic subpopulation. At the cutoff limits of MCV giving a
sensitivity of 90% at all ages in anemic patients, the specificity was
Keywords
about 50%.
Erythrocyte indexes,
hypochromic anemia, iron Conclusion: Mean cell hemoglobin, MCH, and MCHC are only mod-
deficiency anemia, mean cell erately accurate in diagnosing empty iron stores in children and
volume, mean corpuscular young adults, and normal values of these tests do not exclude
hemoglobin, mean corpuscular
empty iron stores in anemic patients.
hemoglobin concentration
98 © 2013 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2014, 36, 98–104
A. E.
ASBERG ET AL. | DIAGNOSTIC ACCURACY OF ERYTHROCYTE INDEXES 99
we have known for decades that it may very well be specimens on either Abbott CELL-DYN 4000, Siemens
normocytic [5]. In fact, the diagnostic accuracy of Bayer ADVIA 120 or ABX Micros 60, with reagents
mean cell volume (MCV) in diagnosing iron deficiency from the manufacturers. Sysmex XE-2100 was the
is fairly moderate in adults with anemia [6] and very main instrument; however, in certain cases, when
little investigated in children. In this study, we evalu- the main instrument did not yield valid results for
ated the diagnostic accuracy of MCV in diagnosing some parameters, another instrument would be used.
empty iron stores in Norwegian children and young The laboratory secured that b-hemoglobin, MCV, and
adults with and without anemia, using s-ferritin as the MCH from the different instruments were directly
gold standard. We compared the diagnostic accuracy of comparable, using fresh blood specimens analyzed on
MCV and the related measures mean cell hemoglobin Sysmex XE-2100 to calibrate the other instruments.
(MCH) and mean cell hemoglobin concentration Specimens from three patients were assayed on each
(MCHC). instrument every weekday to check agreement
between the instruments. On the Sysmex XE-2100,
b-hemoglobin was measured using the sodium lauryl
METHODS
sulfate (SLS)-hemoglobin method with a calibrator
traceable to the reference method recommended by
Population
the International Council for Standardization in Hae-
We used laboratory data from the Clinics of Laboratory matology (ICSH). B-hematocrit was measured using
Medicine at Trondheim University Hospital. These labo- the erythrocyte aperture–impedance pulse height
ratories serve nearly all inpatient and outpatient activi- detection method, MCV was calculated as b-hemato-
ties in the hospital and receive specimens from primary crit divided by blood erythrocyte particle concentra-
care physicians and other healthcare facilities for outpa- tion, MCH as b-hemoglobin divided by blood
tients in the County of Sør-Trøndelag. The hospital is a erythrocyte particle concentration, and MCHC as MCH
tertiary care centre for about 6 88 000 inhabitants and divided by MCV. MCV was calibrated with a calibrator
a secondary care centre for about 2 98 000 inhabitants. traceable to reference methods that follow the recom-
Specimens sent to the hospital for analysis are mostly mendations of ICSH and The Clinical and Laboratory
from primary care centers. Standards Institute (CLSI) standards for MCV. Using
We collected data between October 10, 2005, and Sysmex XE-2100, we have previously found MCV to
March 19, 2012, from ambulant patients that were be sufficiently stable in specimens kept at room tem-
<25 years old at the time of specimen sampling and perature (20 °C) for 14 h. If pre-analytical storage time
kept only records for patients with complete data sets exceeded 14 h, MCV was analyzed using the instru-
on serum ferritin (s-ferritin), blood hemoglobin ment ABX Micros 60. In this way, MCV could be reli-
(b-hemoglobin), MCV, and MCH analyzed in speci- ably analyzed in specimens kept at room temperature
mens sampled at the same time. Then all duplicate for up to 48 h. Between-day coefficients of variation
records were deleted, so that the data file only con- for b-hemoglobin, MCV, and MCH were 0.8% at
tained one (the oldest) record for each individual. 12.3 g/dL, 0.8% at 82 fL, and 0.9% at 28 pg/L, respec-
Finally, to secure that as many as possible of the tively. In classifying patients as anemic, we used the
records represented a new clinical event and not a following local b-hemoglobin lower reference limits
control situation, we deleted all records from 2005 (in g/dL) in healthy persons: 0–1 days, 14.5; 1–2 days,
and 2006. As a result, the record used for all patients 14.0; 2–7 days, 14.3; 1–2 weeks, 13.5; 2–4 weeks,
was the first record to satisfy the criteria since October 10.8; 1–2 months, 9.0; 2–12 months, 10.0; 1–4 years,
2005, so even for patients registered with a record 10.5; 4–8 years, 10.8; 8–14 years, 11.1; girls >14 years,
from January 2007, at least 14 months had gone. 11.7; boys >14 years, 13.4. For MCV, MCH, and
MCHC, we used the following local lower reference
limits in healthy persons: MCV (in fL): 0–5 days, 95;
Laboratory analysis
5 days-2 months, 87; 2–12 months, 72; 1–7 years, 75;
B-hemoglobin, MCV, and MCH were mostly analyzed 7–14 years, 77; >14 years 82. MCH (in pg): 0–7 days,
on Sysmex XE-2100 (Sysmex, Kobe, Japan) and few 31.0; 1–4 weeks, 28.0; 1–2 months, 29.0; 2–4 months,
© 2013 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2014, 36, 98–104
100 A. E.
ASBERG ET AL. | DIAGNOSTIC ACCURACY OF ERYTHROCYTE INDEXES
(32–35)
(32–35)
(32–35)
(32–36)
(32–36)
MCHC
24.1; 12–18 years, 25.0; >18 years, 27.1. MCHC (in g/
dL): 0–2 months, 25.8; 2 months-4 years, 27.1;
33
34
34
34
34
Table 1. Population characteristics for age groups of 5-year intervals. Median values are given for s-ferritin (lg/L), b-hemoglobin (b-Hb) (g/dL),
4–9 years, 30.6; 9–12 years, 31.2; >12 years, 31.7.
(23–29)
(25–30)
(25–31)
(26–32)
(27–32)
All biochemical analyses were carried out on a
MCH
Roche Modular P system (Roche Diagnostics GmbH,
27
28
28
30
30
Mannheim, Germany), with reagents from the manu-
facturer (s-ferritin, s-iron and s-transferrin and s-CRP)
(71–85)
(76–88)
(76–90)
(78–93)
(82–94)
and Diagnostic Systems GmbH, Holzheim, Germany
MCV
(s-CRP). S-ferritin was measured using a ‘sandwich’
79
82
84
87
88
immunological method with electrochemilumines-
cence detection. The calibrator was traceable to WHO
(10.6–13.4)
(11.5–14.3)
(11.9–15.1)
(13.0–16.6)
(13.7–16.9)
Ferritin 80/602 First International Standard. Between-
day coefficients of variation were 6.9% at 5.0 lg/L
B-Hb
and 4.1% at 50 lg/L.
12.1
12.8
13.5
14.8
15.2
All analyses were monitored using appropriate
internal and external quality control systems.
(20–191)
(35–318)
Males (n = 2450)
(12–94)
(14–84)
S-ferritin
(9–85)
MCV (fL), MCH (pg), and MCHC (g/dL). The number in parenthesis is 5 and 95 percentiles
Statistical analysis
120
26
34
37
67
The diagnostic accuracy of the various tests was stud-
189
352
508
667
734
ied using receiver operating characteristic (ROC) curve
n
analysis [7]. We did separate ROC curve analysis for
(31–35)
(32–35)
(32–35)
(31–35)
(32–35)
females and males, using different cutoff values of
MCHC
34
34
33
33
empty iron stores. These analyses were repeated in
the subgroup of anemic patients. We made 12 statisti-
(21–29)
(25–30)
(25–31)
(24–32)
(25–32)
cal comparisons between the diagnostic accuracy of
MCH
28
29
29
30
12 = 0.0042 as statistically significant. To investigate
the influence of age and gender on certain percentiles
(69–85)
(75–89)
(78–92)
(77–94)
(78–95)
of MCV in anemic patients, we used quantile regres-
MCV
83
85
88
89
(11.4–14.0)
(11.3–14.6)
(11.0–14.7)
(11.2–14.8)
12.1
12.9
13.3
13.3
13.3
(7–129)
(11–99)
S-ferritin
(8–82)
(8–94)
2012/160/REK midt).
26
33
32
33
38
R E S U LT S
107
289
601
1273
1723
15–19
20–24
0–4
5–9
© 2013 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2014, 36, 98–104
A. E.
ASBERG ET AL. | DIAGNOSTIC ACCURACY OF ERYTHROCYTE INDEXES 101
Table 2. The number of patients with anemia and s-ferritin below 10, 15, and 20 lg/L is given for age groups of 5-
year intervals. The number in parenthesis is percentages of total for each interval
Age Total Anemia 10 lg/L 15 lg/L 20 lg/L Total Anemia 10 lg/L 15 lg/L 20 lg/L
0–4 107 9 (8.4) 9 (8.4) 21 (19.6) 35 (32.7) 189 7 (3.7) 10 (5.3) 24 (12.7) 46 (24.3)
5–9 289 9 (3.1) 8 (2.8) 25 (8.7) 49 (17.0) 352 5 (1.4) 7 (2.0) 26 (7.4) 53 (15.1)
10–14 601 31 (5.2) 34 (5.7) 75 (12.5) 124 (20.6) 508 52 (10.2) 12 (2.4) 26 (5.1) 59 (11.6)
15–19 1273 127 (10.0) 134 (10.5) 215 (16.9) 334 (26.2) 667 56 (8.4) 12 (1.8) 23 (3.5) 32 (4.8)
20–24 1723 153 (8.9) 146 (8.5) 240 (13.9) 361 (21.0) 734 27 (3.7) 6 (0.8) 14 (1.9) 14 (1.9)
Table 3. Diagnostic accuracy of MCV, MCH, and MCHC in diagnosing empty iron stores in all 6443 patients
Females
<10 lg/L 331 3662 3993 0.810 0.857* 0.819
(0.782–0.838) (0.834–0.881) (0.794–0.845)
<15 lg/L 576 3417 0.741 0.787* 0.729
(0.718–0.765) (0.766–0.808) (0.705–0.754)
<20 lg/L 903 3090 0.680 0.725* 0.682
(0.660–0.702) (0.706–0.745) (0.661–0.703)
Males
<10 lg/L 47 2403 2450 0.929 0.959* 0.865
(0.902–0.956) (0.943–0.975) (0.804–0.926)
<15 lg/L 113 2337 0.805 0.847* 0.744
(0.760–0.851) (0.811–0.884) (0.697–0.791)
<20 lg/L 204 2246 0.804 0.834* 0.685
(0.774–0.834) (0.809–0.859) (0.645–0.724)
*The area under the ROC curve of MCH is statistically significantly larger than the area under the ROC curve of the
second most accurate test (P < 0.002).
of 1 321 patients with s-CRP <10 mg/L compared females and males, MCH had a statistically sign-
with 65 lg/L in the 139 patients with higher s-CRP ificantly larger area under the ROC curve than the
(P < 0.0001). Median s-ferritin was 40 lg/L in those second most accurate test (P < 0.002 for all compari-
4983 patients, where s-CRP was not measured, not sons). All tests showed a better diagnostic accuracy in
significantly different from the group with s-CRP males than in females. Table 4 gives corresponding
<10 mg/L (P = 0.19). S-creatinine was measured in results for the anemic subpopulation of 476 patients.
4565 patients and found to be normal in 4539 In this subpopulation, MCH showed better diagnostic
(99.4%). accuracy than the second most accurate test in all
Table 3 gives the area under the ROC curve of groups, but the differences did not reach statistical
MCV, MCH, and MCHC for three cutoff values of the significance.
gold-standard s-ferritin in the whole study population. In the anemic subpopulation of 476 patients, using
For all definitions of empty iron stores and in both the lower, age-specific reference limits as cutoff limits,
© 2013 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2014, 36, 98–104
102 A. E.
ASBERG ET AL. | DIAGNOSTIC ACCURACY OF ERYTHROCYTE INDEXES
Table 4. Diagnostic accuracy of MCV and MCH in diagnosing empty iron stores in the subgroup of 476 anemic
patients
Females
<10 lg/L 178 151 329 0.757 0.774 0.726
(0.702–0.811) (0.721–0.826) (0.671–0.780)
<15 lg/L 208 121 0.719 0.737 0.700
(0.659–0.780) (0.678–0.796) (0.643–0.758)
<20 lg/L 230 99 0.700 0.714 0.680
(0.633–0.768) (0.649–0.780) (0.618–0.742)
Males
<10 lg/L 29 118 147 0.856 0.894 0.881
(0.790–0.923) (0.843–0.946) (0.814–0.947)
<15 lg/L 40 107 0.790 0.823 0.805
(0.709–0.872) (0.745–0.902) (0.726–0.884)
<20 lg/L 49 98 0.766 0.792 0.756
(0.685–0.847) (0.714–0.870) (0.674–0.837)
© 2013 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2014, 36, 98–104
A. E.
ASBERG ET AL. | DIAGNOSTIC ACCURACY OF ERYTHROCYTE INDEXES 103
© 2013 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2014, 36, 98–104
104 A. E.
ASBERG ET AL. | DIAGNOSTIC ACCURACY OF ERYTHROCYTE INDEXES
the percentile functions of MCV in anemic patients. local lower b-hemoglobin reference limit of healthy
This choice was somewhat of a compromise, as we persons as cutoff limits to define anemia. These lim-
thought 10 lg/L might be too low (low sensitivity) and its may not be applicable in other populations and
20 lg/L might be too high (low specificity). Using bone health care systems.
marrow iron as the gold standard, Hallberg et al.[14] In conclusion, MCV, MCH, and MCHC are only
found that s-ferritin ≤15 ug/L was the optimal limit for moderately accurate in diagnosing empty iron stores
an assay calibrated against WHO Ferritin 80/602 First in children and young adults. These tests are no more
International Standard. accurate in anemic than in nonanemic patients. It
The findings in this clinical population may not should once again be pointed out that normal values
be transferable to other populations. First, the popu- of MCV, MCH, and MCHC do not exclude empty iron
lation is mostly northwest European, with a very stores in anemic patients.
low prevalence of thalassemia, so iron deficiency is
by far the most prevalent cause of microcytic
AC K N OW L E D G E M E N T S
anemia. In a population with an appreciable num-
ber of thalassemia, MCV, MCH, and MCHC may We thank Frode Width Gran for valuable assistance
show even lower accuracy. Secondly, we used the with data extraction.
© 2013 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2014, 36, 98–104
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