International Journal of Laboratory Hematology

The Official journal of the International Society for Laboratory Hematology

ORIGINAL ARTICLE

INTERNAT IONAL JOURNAL OF LABORATO RY HEMATO LOGY

Vitamin B12 and folate deficiency: should we use a different

cutoff value for hematologic disorders?
B. TOPRAK, H. Z. YALCIN, A. COLAK

Department of Clinical
Biochemistry, Tepecik Training
and Research Hospital, Izmir,
Turkey
Correspondence:
Burak Toprak, Department of
Clinical Biochemistry, Tepecik
Training and Research Hospital,
Gaziler Cad., No:468, Yenisehir,
Izmir 35183, Turkey.
Tel.: +90-232-4696969;
Fax: +90-232-4330756;
E-mail: beiot@hotmail.com
doi:10.1111/ijlh.12158

Received 27 August 2013;

accepted for publication 12 September 2013
Keywords
Anemia, B12, cutoff value,
folate, macrocytosis

S U M M A RY
Introduction: Anemia and macrocytosis are well-defined expected
hematologic findings of vitamin B12 and folate deficiency; however, some previous studies did not show a significant association
of subnormal B12 with anemia and macrocytosis.
Methods: We retrospectively analyzed 17 713 laboratory patient
records to evaluate vitamin B12 and folate levels in relation to
anemia and macrocytosis.
Results: In an age- and sex-adjusted logistic regression model, low
B12 status but not marginal B12 status was significantly associated
with anemia [ORs respectively, 1.291 (95% CI, 1.1821.410),
1.022 (95% CI, 0.9431.108)] and macrocytosis [ORs, respectively,
3.853 (95% CI, 3.1214.756), 1.031 (95% CI, 0.7701.381)]. Also
low folate status but not marginal folate status was significantly
associated with anemia [adjusted ORs, respectively, 1.819 (95% CI,
1.3722.411), 1.101 (95% CI, 0.9311.301)] and macrocytosis
[adjusted ORs, respectively, 2.945 (95% CI, 1.7474.965), 1.228
(95% CI, 0.7951.898)].
Conclusion: Our results show that increased anemia and macrocytosis are observed at values below commonly used B12 lower-reference thresholds. Determining a hematologic cutoff value may help
physicians in clinical practice.

INTRODUCTION
Vitamin B12 and folate are important cofactors in the
DNA synthesis. Deficiency of both of these water soluble vitamins is frequent health problems particularly
in the elderly [1, 2]. Common causes of cobalamin
deficiency are food-cobalamin malabsorbtion, pernicious anemia, and dietary deficiency [36]. A number
of biomarkers have been used for cobalamin deficiency diagnosis, including serum cobalamin,
2013 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2014, 36, 409414

methylmalonic acid (MMA), homocystein, and holotranscobalamin II. The most common biomarker used
for diagnosis is serum cobalamin. Older studies used
lower cobalamin cutoff values <90 pM (121 pg/mL)
for defining deficiency [7]. The cutoff value <148 pM
(200 pg/mL) was frequently used, and WHO suggested <150 pM (203 pg/mL) as a cutoff for defining
deficiency [8]. Utility of more sensitive biomarkers
MMA and homocystein showed that many patients
with normal cobalamin levels may be deficient;
409

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B. TOPRAK, H. Z. YALCIN AND A. COLAK | VITAMIN B12 AND FOLATE DEFICIENCY

therefore, usage of higher cobalamin cutoff values

was suggested by some authors for improvement of
sensitivity [9]. Vitamin B12 deficiency is associated
with hematologic and neurologic abnormalities.
Hematologic manifestations of cobalamin deficiency
include anemia, macrocytosis, pancytopenia and neutrophil hypersegmentation [1014]. The effect of
cobalamin deficiency on hematopoiesis is documented
in the literature [15, 16], and the association between
pernicious anemia and cobalamin deficiency is well
known, but studies about hematologic response to
B12 treatment is inconsistent [10, 1724]. Some studies failed to demonstrate a significant hematologic
response to cobalamin therapy [1722].
The reasons for folate deficiency are reduced
intake, malabsorbtion, increased metabolism, and
increased requirements. Folate deficiency is associated
with megaloblastic anemia mood disorders and neural
tube defects [25]. The lower limit of the reference
range for serum folate is usually set at about 6.8 nM
(3 ng/mL) [26]. Some studies defined <5 nM (2.2 ng/
mL) as low folate and 57 nM (2.23.1 ng/mL) as borderline folate [2, 27]. It was reported that folic acid
supplementation reduces megaloblastic anemia risk
but have no impact on anemia and hemoglobin levels
[28]. Studies about hematologic response to folate
therapy in those without megaloblastic anemia and
with low folate levels are limited.
In this study, we aimed to investigate vitamin B12
and folate levels in relation to anemia and
macrocytosis.

M AT E R I A L S A N D M E T H O D S
We retrospectively analyzed serum folate, vitamin
B12, hemoglobin and MCV records of 1885 years
aged outpatients attending Tepecik Training and
Research Hospital during the period January 2007
December 2011. Only first results of the patients were
included in the study to exclude patients taking cobalamin or folate therapy. Four parameters investigated
were ordered by physicians in a 1-week period. The
results of 17 713 patients were included in the analysis. Tepecik Training and Research Hospital Ethics
Committee approved the study.
Serum vitamin B12 and folate were measured on
Immulite XPI 2000 system (Siemens Healthcare Diagnostics, Eschborn, Germany). MCV and hemoglobin

were measured using LH 750 hematology analyzer

(Beckman Coulter, Miami, FL, USA). Vitamin B12
levels were classified as low (150 pg/mL), marginal
(151200 pg/mL) and normal (>200 pg/mL). Folate
levels were classified as low (2.2 ng/mL), marginal
(2.23 ng/mL) and normal (>3 ng/mL). World Health
Organization criteria (hemoglobin <12 g/dL for women
and <13 g/dL for men) were used to define anemia
[29]. MCV > 100 fL was defined as macrocytosis.
Data analyses were performed using SPSS 17 software (SPSS Inc., Chicago, IL). P < 0.05 was considered statistically significant. Logistic regression was
used to estimate ORs for anemia and macrocytosis.
B12 > 200 pg/mL (148 pM) and folate >3 ng/mL
(6.8 nM) were considered as reference and age- and
gender-adjusted ORs of marginal and low b12, and
folate status for anemia and macrocytosis was estimated. To investigate the effect of age on vitamin B12
and folate deficiency, age groups (1850, 5160,
6170, 7180, 8085) were generated. ORs of age
groups for low cobalamin and folate status were estimated using logistic regression analyses. The age
group 1850 was reference.

R E S U LT S
A total of 17 713 vitamin B12, folate, hemoglobin,
and MCV results were investigated. There were
12 870 female and 4843 male subjects. The results
show that 14.7% of the subjects have vitamin
B12 150 pg/mL (111 pM) and 34.1% have vitamin
B12 200 pg/mL (148 pM). Only 1.1% of the subjects
have folate 2.2 ng/mL (5 nM) and 4.7% have folate
3.0 ng/mL (6.8 nM). There were 35% anemic subjects, and 2.5% of the subjects have macrocytosis
(Table 1).
In an age- and sex-adjusted logistic regression
model, low B12 status but not marginal B12 status
was significantly associated with anemia [ORs, respectively, 1.291 (95% CI, 1.1821.410), 1.022 (95% CI,
0.9431.108)] and macrocytosis [ORs, respectively,
3.853 (95% CI, 3.1214.756), 1.031 (95% CI, 0.770
1.381)]. Low B12 status and marginal B12 status were
significantly related to male sex [age-adjusted ORs,
respectively, 1.300 (95% CI, 1.1831.427), 1.134
(95% CI, 1.0411.237)] (Table 2).
Also low folate status but not marginal folate status
was significantly associated with anemia [adjusted
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B. TOPRAK, H. Z. YALCIN AND A. COLAK | VITAMIN B12 AND FOLATE DEFICIENCY

DISCUSSION

Table 1. Characteristics of the study

N = 17 713
Age (mean  SD)
Sex
Male
Female
Vitamin b12
<150 pg/mL
<200 pg/mL
Folate
<2.2 ng/mL
<3.0 ng/mL
Anemia
Hemoglobin (mean  SD)
Macrocytosis
Mean cell volume (mean  SD)

411

49  18
27.3%
72.7%
14.7%
34.1%
1.1%
4.7%
35%
12.60  2.05
2.5%
84.7  9.8

ORs, respectively, 1.819 (95% CI, 1.3722.411), 1.101

(95% CI, 0.9311.301)] and macrocytosis [adjusted
ORs, respectively, 2.945 (95% CI, 1.7474.965), 1.228
(95% CI, 0.7951.898)]. Both low and marginal folate
status were related to male sex [age-adjusted ORs,
respectively, 2.026 (95% CI, 1.7202.386), 1.804
(95% CI, 1.3502.409)] (Table 3).
Age over 70 was significantly associated with low
vitamin B12 status [ORs, 1.338 (95% CI, 1.183
1.513) for 7180 age group, 1.500 (95% CI, 1.221
1.843) for 8185 age group] and low folate status
[ORs, 1.725 (95% CI, 1.1872.507) for 7180 age
group, 2.705 (95% CI, 1.6064.556) for 8185 age
group] (Table 4).

In this study, we evaluated vitamin B12 and folate

levels in relation to anemia and macrocytosis which
are major hematologic manifestations of vitamin B12
and folate deficiency. Our data showed that low b12
status was significantly associated with increased anemia and macrocytosis, but marginal B12 status was
not associated with increased anemia and macrocytosis. Although it is well known that vitamin b12 deficiency causes pernicious anemia, observational
studies reported inconsistent results about vitamin
b12 deficiency and anemia relation [3033]. Moreover, intervention studies investigating response to
vitamin b12 treatment reported conflicting results
[1721, 23, 24]. Some of the studies did not demonstrate a significant hemoglobin increase and MCV
decrease to vitamin b12 therapy. The data of previous intervention studies show that subjects who
responded to vitamin b12 treatment with an elevation of hemoglobin or decrease of MCV have lower
vitamin b12 levels than nonresponders [17, 19, 23].
This evidence is consistent with our finding. Marginal vitamin B12 status (151200 pg/mL) has very
limited nonsignificant effect on anemia and macrocytosis. This suggests that the appropriate vitamin B12
cutoff value to expect hematologic consequences as
anemia or macrocytosis is lower than the frequently
used cutoff 200 pg/mL (148 pM). This also may
explain the inconsistency between intervention studies. Studies that included subjects with very low

Table 2. Anemia and macrocytosis in the three vitamin B12 groups

Vitamin B12 status

Male
Anemia
Macrocytosis

Marginal
(n = 3439)

Low
(n = 2599)

Normal
(n = 11 675)
(%)

(%)

OR (95% CI)

(%)

OR (95% CI)

26.1
34.2
1.7

28
34.3
1.8

1.134 (1.0411.237)*
1.022 (0.9431.108)
1.031 (0.7701.381)

0.004
0.595
0.835

32.1
39.5
6.9

1.300 (1.1831.427)
1.291 (1.1821.410)
3.853 (3.1214.756)

<0.001
<0.001
<0.001

Normal B12 status was reference. Normal B12 (>200 pg/mL); marginal B12 (151200 pg/mL); low B12 (<151 pg/mL).
*Adjusted for age.
Adjusted for age and sex.
Anemia: hemoglobin <13 g/dL (men) <12 g/dL (women).
Macrocytosis: MCV > 100 fL.

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B. TOPRAK, H. Z. YALCIN AND A. COLAK | VITAMIN B12 AND FOLATE DEFICIENCY

Table 3. Anemia and macrocytosis in the three folate groups

Folate status
Normal
(n = 16 872)
(%)
Male
Anemia
Macrocytosis

26.6
34.8
2.4

Marginal
(n = 640)

Low
(n = 201)

(%)

OR (95% CI)

(%)

OR (95% CI)

42
35
3.6

2.026 (1.7202.386)*
1.101 (0.9311.301)
1.228 (0.7951.898)

<0.001
0.262
0.355

40.8
47.3
8.5

1.804 (1.3502.409)*
1.819 (1.3722.411)
2.945 (1.7474.965)

<0.001
<0.001
<0.001

Normal folate status was reference. Normal folate (>3 ng/mL); marginal folate (2.23 ng/mL); low folate (<2.2 ng/mL).
*Adjusted for age.
Adjusted for age and sex.
Anemia: hemoglobin <13 g/dL (men) <12 g/dL (women).
Macrocytosis: MCV > 100 fL.

Table 4. Low folate and vitamin B12 status in different age groups
Low vitamin B12

Low folate

Age

OR (95% CI)

OR (95% CI)

1850
5160
6170
7180
8185

13.8
14.2
14.4
17.7
19.4

1.0
1.033
1.048
1.338
1.500

1
0.8
1
1.7
2.7

1.0
0.815
0.959
1.725
2.705

(0.9151.167)
(0.9231.189)
(1.1831.513)**
(1.2211.843)**

(0.5171.286)
(0.6131.503)
(1.1872.507)*
(1.6064.556)**

Age group 1850 was reference.

*P < 0.05.
**P < 0.001.

vitamin b12 levels demonstrated significant response

to cobalamin therapy. Possibly subjects with subnormal or marginal vitamin b12 levels did not showed
any hematologic response to therapy and caused
some studies to report nonsignificant results. Diagnosing vitamin B12 deficiency may be a complicated
issue in some patients. Anemia and macrocytosis are
often absent in cobalamin deficiency; in addition,
deficiency may be subtle or only with minor
neuropsychiatric symptoms [3436]. MMA and homocystein are sensitive biomarkers and may be
increased in many patients with normal and subnormal vitamin B12 concentrations. Using a higher cutoff (>200 pg/mL) value for defining deficiency is
useful for diagnosing patients with neuropsychiatric
disorders or elevated MMA and homocystein concentrations, but we think that the cutoff value for hematologic disorders should be different and lower

from the value which is useful for diagnosing subtle

deficiency states. Anemia is a frequently encountered
problem in medical practice. The major causes of
anemia are iron deficiency and chronic inflammation
[37]. To determine whether anemia is caused by
cobalamin deficiency or not may be problematic. In
clinical practice, a subject with anemia and subnormal vitamin B12 concentrations may be regarded as
vitamin b12 deficiency anemia although the underlying cause was different in many cases. Using a
higher cutoff value may lead to an overdiagnosis of
vitamin B12 deficiency and an increase in the number of misdiagnosed anemic patients. We think that
laboratories should provide a hematologic cutoff
value to expect anemia and macrocytosis and a different higher cutoff value for subtle or neurologic
deficiency states. Cascade testing was proposed by
some authors [19, 26]. We agree with cascade testing
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B. TOPRAK, H. Z. YALCIN AND A. COLAK | VITAMIN B12 AND FOLATE DEFICIENCY

approach, but that approach did not define a distinct

hematologic cutoff value.
Low folate status but not marginal folate status was
significantly associated with anemia and macrocytoses.
In the present study, odds ratios of marginal folate
status for anemia and macrocytosis were higher than
marginal vitamin b12 status. Intervention studies
about hematologic response to folate therapy in subjects with subnormal folate concentrations are limited.
We think that there is not enough evidence to determine a hematologic cutoff for folate deficiency. The
usage of higher folate cutoff values may improve
sensitivity to detect deficiency.
We found that age over 70 was significantly associated with low vitamin B12 and folate status. Our
results are consistent with several studies which
reported that vitamin b12 deficiency and folate
deficiency were related with increasing age [1, 2, 38].
This retrospective study has some limitations.
Firstly, medical history of the subjects was not available; therefore, confounding factors may exist. Our
results reflect an outpatient population, and it is not

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