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Original Paper
Ann Nutr Metab 2018;72:265–271
Vitamin B12 Deficiency and the Role of
Gender: A Cross-Sectional Study of a
Large Cohort
Ili Margalit
a Eytan Cohen
a, b Elad Goldberg
a, b Ilan Krause
a, b
a Department of Internal Medicine F-Recanati, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel;
b Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Received: December 7, 2017
Accepted after revision: March 12, 2018
Published online: March 29, 2018
Ili Margalit
Department of Internal Medicine F-Recanati
Rabin Medical Center, Beilinson Hospital, 39 Jabotinsky Road
IL–49100 Petah Tikva (Israel)
E-Mail ili.margalit @ mail.huji.ac.il
© 2018 S. Karger AG, Basel
E-Mail karger@karger.com
www.karger.com/anm
DOI: 10.1159/000488326
Keywords
Albumin · Cobalamin · Gender · Sex · Vitamin B12
Abstract
Background: Vitamin B12 deficiency is associated with he-
matological, neurological, and cardiovascular consequenc-
es. Epidemiologic data on these related illnesses indicate
gender differences. Methods: A cross-sectional study was
designed to examine gender differences in vitamin B12 de-
ficiency among a healthy population. Data from healthy in-
dividuals aged 18–65, who were provided with a routine
medical evaluation during 2000–2014, were retrieved from
the medical charts. Individuals with background illnesses
and those who had used medications or nutritional supple-
ments were excluded. Vitamin B12 deficiency was defined
by 2 cutoff values (206 and 140 pmol/L). The multivariate
analysis was adjusted for age, body mass index, estimated
glomerular filtration rate, hyperhomocysteinemia, folate
deficiency, albumin, and transferrin saturation. Sensitivity
analyses were implemented by excluding individuals with
anemia, hyperhomocysteinemia, or folate deficiency and by
age stratification. Results: In all, 7,963 individuals met the
inclusion criteria. Serum vitamin B12 mean levels were
312.36 and 284.31 pmol/L for women and men respectively
(p < 0.001). Deficiency prevalence was greater for men
(25.5%) in comparison with women (18.9%; p < 0.001). Men
were strongly associated with severe deficiency (adjusted
OR 2.26; 95% CI 1.43–3.56). Conclusions: Among the healthy
population, men are susceptible to vitamin B12 deficiency.
This can be explained by neither diet habits nor estrogen
effects. Genetic variations are therefore hypothesized to
play a role. © 2018 S. Karger AG, Basel
Introduction
The prevalence of vitamin B12 (cobalamin) deficiency
in the total population is estimated to be 2.9–25.7%, de-
pending on the cutoff value [1]. Elderly people, individu-
als with gastrointestinal disorders, and those following a
vegetarian or vegan diet have been identified as suscep-
tible populations [2].
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In addition to megaloblastic anemia, vitamin B12 de-
ficiency can lead to neurocognitive abnormalities, im-
mune dysfunction, and osteoporosis [3]. Furthermore,
vitamin B12 plays an important role in the one carbon
metabolism and its deficiency may lead to hyperhomo-
cysteinemia [4]. Vitamin B12 deficiency has been accord-
ingly associated with increased risk for cardiovascular
diseases, including coronary disease and stroke [5].
The role of gender in morbidity has been broadly dis-
cussed and is assumed to derive from both biological al-
terations and sociocultural aspects [6]. Men have been
shown to have an increased risk for cardiovascular events,
especially for acute coronary syndrome [7]. Women, on
the other hand, have been shown to be at a slightly higher
risk for various forms of cognitive impairments and de-
mentia [8–10]. These may be at least partially related to
vitamin B12 deficiency and raise the question regarding
the role of gender in vitamin B12 metabolism.
In the current study, we aimed to examine whether
gender has a role in vitamin B12 deficiency among non-
elderly adults, and to assess its possible contributors.
Methods
The study was designed as a cross-sectional, single-center
study, conducted in the Rabin Medical Center (RMC), a large pri-
mary-and-tertiary care, university-affiliated hospital, in Petah-
Tikva, Israel. RMC provides a comprehensive medical annual or
biannual medical evaluation for males and non-pregnant females.
During each visit, the patients undergo a thorough medical his-
tory intake, a physical examination, a broad range of blood and
urine tests, an ergometric stress testing, a chest radiogram, and a
lung functions test.
For the purpose of this study, the medical charts of individuals
with a documented serum vitamin B12 level were retrieved. In cas-
es of repeated visits, only the last one was extracted.
Healthy individuals aged 18–65 were included. Individuals with
any background illness were excluded. After a primary filtration
done on the basis of medical diagnoses, data were refined by imple-
menting a careful review. Individuals prescribed with medications
indicating the presence of a chronic illness and those taking vita-
mins or nutritional supplements of any sort were further omitted.
The extracted variables of interest included demographic de-
tails: age, sex, and body mass index; as well as laboratory parame-
ters: serum vitamin B12, homocysteine, and folic acid (FA) levels,
complete blood count including leucocyte differential count, cre-
atinine, fasting blood glucose, albumin, liver function tests, thy-
roid stimulating hormone and lipids profile.
Between May 2000 and May 2011, serum vitamin B12 and FA
levels were measured using Immulite® assay (Siemens). Between
May 2011 and by the end of the study, these were measured using
Architect® assay (Abbott). For both machines, measuring methods
were similar and reference levels were 138–781 pmol/L for serum
vitamin B12 and 7.0–46.4 nmol/L for serum FA. Serum homocys-
teine levels were measured using TDx® assay (Abbott) between
May 2000 and January 2005 and using AxSYM® assay (Abbott)
since then. For both machines, measuring methods of serum ho-
mocysteine were similar and reference levels were 5.0–20.0 μmol/L.
Different authors use slightly different cutoff values for the defi-
nition of vitamin B12 deficiency [1, 11]. However, it seems that a
cutoff value around 200 pmol/L has a relatively fair sensitivity and
specificity [12]. Two cutoff values were used to define vitamin B12
deficiency: a liberal cutoff with serum concentrations lower than 206
pmol/L [13] and a restrictive cutoff value with serum concentrations
lower than 140 pmol/L [14, 15], reflecting a deeper deficiency and a
greater specificity. In addition to its acceptance as a cutoff for defi-
nite deficiency, the 140 pmol/L cutoff is similar to our institutional
laboratory lower limit of reference range. Anemia was defined as
hemoglobin level ≤14.0 and ≤ 12.0 g/dL for men and women respec-
tively [13]. Hyperhomocysteinemia was defined as serum homocys-
teine levels of 15.0 μmol/L or higher [16]. Folate deficiency was de-
fined based on serum folate levels using a cutoff value of 12.2 nmol/L
or lower [13]. The renal function was evaluated using the Chronic
Kidney Disease Epidemiology Collaboration equation, treated as a
dichotomous variable with normal estimated glomerular filtration
rate (eGFR) defined as equal to 90 mL/min/1.73 m2 or higher [17].
Transferrin saturation was calculated as iron divided by iron-bind-
ing capacity (i.e., transferrin multiplied by 1.25) [18].
Statistical analyses included a univariate analysis implement-
ing Student’s t test and chi-square test for continuous and cate-
gorical variables respectively. A multivariate analysis conducted
implementing logistic regression models adjusted for universal
confounders and possible interfering factors. Sensitivity analyses
were thereafter carried out. As anemia may interfere with serum
components related to the consequences of vitamin B12 deficien-
cy, data were reanalyzed after an exclusion of individuals with
anemia. As homocysteine and folate share the biochemical path-
ways with vitamin B12, an additional analysis was implemented
after the exclusion of individuals with hyperhomocysteinemia or
follate deficiency. As gender differences are at least partially re-
lated to hormonal alterations, all analyses were repeated with
stratification to 2 age groups: before and after the age of 55 (by
which time menopause is certainly assumed for the entire female
population).
For all analyses, a p value of <0.05 was considered significant.
Statistical analysis was carried out using IBM SPSS version 23.
The study was approved by the Institutional Review Board.
Results
Between May 2000 and October 2014, 25,511 individ-
uals aged 18–65 underwent a routine evaluation in the
RMC. Of these, 14,440 had a documented serum vitamin
B12 level during their last visit. After excluding individu-
als with background illnesses, regular medications and
consumption of vitamins or other nutritional supple-
ments, 7,963 allegedly healthy individuals were included
for analysis.
Women’s mean vitamin B12 level was significantly
higher, measured 312.36 (SD 134.10) pmol/L for wom-
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DOI: 10.1159/000488326
en and 284.31 (SD 116.88) pmol/L for men (p< 0.001).
Of the total study population, 1,865 (23.4%) were iden-
tified with vitamin B12 deficiency using the 206 pmol/L
cutoff value, and 286 individuals (3.6%) were identified
with severe deficiency using the 140 pmol/L cutoff val-
ue. Patients’ characteristics and laboratory parameters
of interest are shown in Table 1. Men had a significant-
ly higher prevalence of vitamin B12 deficiency. Of the
men, 25.5 and 4.2% had serum vitamin B12 levels <206
and <140 pmol/L respectively; Of the women, 18.9 and
2.3% had serum vitamin B12 levels <206 and <140
pmol/L respectively (p< 0.001 for both comparisons).
Individuals with vitamin B12 deficiency had higher se-
rum homocysteine levels and lower folate levels. Their
albumin, eGFR, and transferrin saturation levels were
significantly lower, while their uric acid and hemoglo-
bin values were slightly higher. Individuals with vitamin
B12 deficiency also had lower high density lipoprotein
and higher triglyceride levels. Among the total study
population, albumin ranged 3.3–6.0 g/dL with a mean
level of 4.51 (SD 0.27) g/dL and mean levels of 4.56 and
4.40 g/dL for men and women respectively (p< 0.001).
These levels remained unchanged when analysis was re-
stricted to non-anemic individuals with normal homo-
cysteine and FA levels.
The results of the multivariate analysis are shown in
Table 2. Men were more likely than women to be diag-
nosed with vitamin B12 deficiency (OR 1.46, 95% CI
1.30–1.65 for all cases of deficiency; 1.82, 95% CI 1.36–
2.43 for severe deficiency). When adjusted for age, body
mass index, eGFR status, hyperhomocysteinemia, and fo-
late deficiency, the OR declined. However, the greater risk
for men remained significant. When further adjustments
additionally included both albumin and transferrin, OR
remained high, and the risk for severe vitamin B12 defi-
ciency was nearly twofold greater for men in comparison
to women.
When analysis was restricted to non-anemic individ-
uals with normal homocysteine and FA levels, the ad-
justed odds ratio for men raised to 1.60 (95% CI 1.35–
1.90) for all deficiency cases and to 2.26 (95% CI 1.43–
3.56) for severe deficiency cases. Data stratification
Table 1. Patients’ characteristics according to their serum vitamin B12 status. A cross-sectional study of 7,963 healthy adults who
underwent screening at Rabin Medical Center, 2000–2014
Serum vitamin B12 level Total
(n= 7,963)
Normal
(≥206 pmol/L; n= 6,098)
Deficiency
(<206 pmol/L; n= 1,865)
p value
Gender, n (%) <0.001ᵠ
Male 5,478 (100) 4,083 (74.5) 1,395 (25.5)
Female 2,485 (100) 2,015 (81.1) 470 (18.9)
Age, years 45.13±7.96 45.08±7.96 45.30±7.93 0.285
BMI, kg/m226.36±4.18 26.31±4.19 26.55±4.12 0.025ᵠ
eGFR*, mL/min/1.73 m297.35±13.65 97.87±13.51 95.63±13.98 <0.001ᵠ
Hemoglobin, g/dL 14.35±1.34 14.32±1.29 14.46±1.48 <0.001ᵠ
MCV, fL 85.84±7.00 85.96±6.98 85.47±7.00 0.009ᵠ
Transferrin saturation** 31.37±12.06 31.56±12.08 30.78±11.96 0.015ᵠ
Glucose, mg/dL 95.74±14.59 95.79±15.07 95.55±12.88 0.521
Albumin, g/dL 4.51±0.27 4.52±0.26 4.48±0.28 <0.001ᵠ
Uric acid, mg/dL 5.50±1.39 5.46±1.39 5.64±1.40 <0.001ᵠ
Homocysteine, μmol/L 11.69±5.64 10.92±4.11 14.23±8.50 <0.001ᵠ
Folate, nmol/L 19.37±8.26 20.06±8.47 17.10±7.07 <0.001ᵠ
TSH, μIU/L 1.90±1.64 1.90±1.44 1.92±2.18 0.708
Total cholesterol, mg/dL 199.29±36.79 199.47±36.70 198.72±37.06 0.443
HDL, mg/dL 51.55±12.57 52.26±12.77 49.22±11.60 <0.001ᵠ
Triglycerides, mg/dL 123.17±80.65 120.01±76.60 133.48±91.99 <0.001ᵠ
p value for differences between groups, calculated using Student t test for continuous variables and chi-square test for categorical
data. Unless stated otherwise, figures represent mean (SD).
ᵠStatistically significant difference.
*Calculated according to the Chronic Kidney Disease Epidemiology Collaboration equation.
**Transferrin saturation= (serum iron/[serum transferrin * 1.25]) * 100.
BMI, body mass index; eGFR, estimated glomerular filtration rate; MCV, mean corpuscular volume; TSH, thyroid stimulating hor-
mone; HDL, high density lipoprotein.
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according to age groups suggested that the excessive
risk for men to be diagnosed with vitamin B12 defi-
ciency was slightly greater before the age of 55 (OR
1.66, 95% CI 1.38–2.00). Among the older age group,
the results were not significant, but the point estimate
suggested a lesser risk for men (OR 1.35, 95% CI 0.87–
2.09).
Multivariable logistic regression analysis was estab-
lished with adjustments for possible confounders (Ta-
ble 3). As expected, hyperhomocysteinemia and folate
deficiency were significantly associated with vitamin
B12 deficiency. In addition, albumin was found as a de-
termining factor for vitamin B12 deficiency among
healthy individuals. With each rise of 1 gram of albu-
min, the risk for vitamin B12 deficiency declined by
58% (95% CI 48–67). Both transferrin saturation and
albumin level were negatively associated with vitamin
B12 deficiency. Normal renal function was also nega-
tively associated, although it had a lesser protective
contribution.
Discussion
In the current study, we found that vitamin B12 defi-
ciency is relatively common among the Middle Eastern
healthy population with a prevalence of 23%. The study
revealed that gender plays a role in vitamin B12 metabo-
lism, with a twofold greater risk for deficiency among
men, independent of anemia, folate, and homocysteine
status. Although the prevalence is similar to the level re-
ported in a neighboring Middle Eastern country, the gen-
der differences are surprising [19].
Diseases along the gastrointestinal tract may cause vi-
tamin B12 deficiency, by hampering normal food-cobal-
amin absorption. These include predominantly gastric
diseases such as Helicobacter pylori infection, atrophic
gastritis, gastric surgery [20], or cancer [21] but also in-
clude inflammatory bowel disease [22], diabetes mellitus,
Table 3. Determining factors for vitamin B12 deficiency (serum
level lower than 206 pmol/L). A cross-sectional study of 7,963
healthy adults who underwent screening at Rabin Medical Center,
2000–2014. OR adjusted using logistic regression
OR 95% CI
Gender, male 1.47 1.28–1.68ᵠ
Age, years 0.99 0.99–1.00
BMI, kg/m21.00 0.98–1.01
Normal eGFR (≥90 mL/min/1.73 m2) 0.82 0.72–0.93ᵠ
Hyperhomocysteinemia (>15.0 μmol/L) 3.26 2.79–3.81ᵠ
Folate deficiency (<12.2 nmol/L) 1.20 1.05–1.39ᵠ
Albumin, g/dL 0.42 0.33–0.52ᵠ
Transferrin saturation*0.47 0.30–0.76ᵠ
ᵠStatistically significant determinant.
* Transferrin saturation = (serum iron/[serum transferrin *
1.25]) * 100.
BMI, body mass index; eGFR, estimated glomerular filtration
rate.
Table 2. Male gender as a determining factor for vitamin B12 deficiency. A cross-sectional study of 7,963 healthy adults who underwent
screening at Rabin Medical Center, 2000–2014. OR with adjustments and sensitivity analyses using logistic regression models (95% CI)
Vitamin B12 deficiency <140 pmol/L <206 pmol/L
all participants all participants age <55 years age ≥55 years
Unadjusted 1.82 (1.36–2.43) 1.46 (1.30–1.65) 1.47 (1.30–1.67) 1.41 (1.00–1.98)
Model 1a1.33 (0.96–1.83) 1.18 (1.04–1.34) 1.18 (1.03–1.35) 1.20 (0.84–1.71)
Model 2b1.85 (1.32–2.60) 1.40 (1.23–1.60) 1.40 (1.21–1.61) 1.31 (0.91–1.88)
Model 3c2.02 (1.43–2.86) 1.47 (1.28–1.68) 1.44 (1.24–1.67) 1.48 (1.02–2.15)
Sensitivity analysis 1d2.05 (1.33–3.14) 1.56 (1.33–1.83) 1.61 (1.35–1.91) 1.32 (0.88–2.00)
Sensitivity analysis 2e2.26 (1.43–3.56) 1.60 (1.35–1.90) 1.66 (1.38–2.00) 1.35 (0.87–2.09)
aAdjusted for age, BMI, eGFR status, hyperhomocysteinemia, and folate deficiency.
bAdjusted for age, BMI, eGFR status, hyperhomocysteinemia, folate deficiency, and albumin.
cAdjusted for age, BMI, eGFR status, hyperhomocysteinemia, folate deficiency, albumin, and transferrin saturation.
dIndividuals with normal homocysteine and folate levels (n= 5,926), adjusted for age, BMI, eGFR status, albumin, and transferrin
saturation.
eNon-anemic individuals who have normal homocysteine and folate levels (n= 5,151), adjusted for age, BMI, eGFR status, albumin,
and transferrin saturation.
BMI, body mass index; eGFR, estimated glomerular filtration rate.
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DOI: 10.1159/000488326
or thyroid diseases [20]. As the current study encom-
passed a healthy population, it is unlikely that an underly-
ing significant disease could mediate the association be-
tween men and vitamin B12 deficiency. Celiac disease
may have a more concealing nature; however, it predom-
inantly affects women [23] and its local prevalence is low-
er than 1% [24, 25]. Therefore, it cannot explain the ob-
served phenomenon.
In 2014, 4.7% of the local population identified them-
selves as vegetarians (abstaining from consuming meat
and usually also fish) and an additional 1.7% identified
themselves as vegans (abstaining from consumption of
all animal-derived products). These rates reached 9.0%
for both diet styles among individuals with higher edu-
cation [26]. Individuals following either vegetarianism
or veganism are highly susceptible to vitamin B12 defi-
ciency [27]. It has been recently demonstrated that con-
sumption of a well-balanced diet including supple-
ments, as required, can potentially fulfill all nutritional
requirements [28]. Nonetheless, one may hypothesize
that the study included vegetarians or vegans who do
not consume supplements and are potentially at risk for
vitamin B12 deficiency. However, the rate of vegetarian
or vegan women is almost twice as higher than that of
men [26], suggesting that diet alone could not explain
the observed relationship between male gender and vi-
tamin B12 deficiency.
As most included individuals were adults younger
than 50 years, the stratification to age groups reduced the
statistical power in the older age group. Nonetheless, gen-
der differences at the risk for vitamin B12 deficiency,
tended to diminish with age. As menopause is almost cer-
tain at the age of 55, estrogen may play a protective role
against vitamin B12 deficiency. Higher estrogen status
was previously reported to be associated with decreased
serum homocysteine levels [29]. It was postulated that
estrogen decreases methionine levels by stimulating me-
thionine transamination, thus decreasing homocysteine
levels. Nonetheless, hormonal replacement therapy did
not alter serum vitamin B12 levels [30, 31]. Although sev-
eral studies reported that oral contraceptives decreased
serum vitamin B12 levels, there is currently no concrete
evidence for any such influence [32]. Even if endogenous
estrogen somehow plays a protective role, it seems that
the findings of the current study cannot be solely ex-
plained by estrogen. A further research on the role of es-
trogen in the one carbon metabolism is therefore war-
ranted.
In the current study, albumin was inversely associated
with vitamin B12 deficiency. It is well established that al-
bumin is positively associated with muscle mass [33]. It
was also established that vitamin B12 deficiency may lead
to sarcopenia [34]. This can explain the observed inverse
association between albumin and vitamin B12 deficiency,
although it is somewhat surprising, considering that the
study population was relatively young and healthy. In ad-
dition, albumin was also inversely associated with high
serum vitamin B12 levels (>664 pmol/L) [35]. The rela-
tionship between albumin and vitamin B12 may also be
mediated through Cubilin, an enzyme that facilitates
both the absorption of the B12-Intrinsinc factor complex
in the ileum and the reabsorption of the majority of the
filtered albumin from the urine [36]. The association be-
tween vitamin B12 and albumin awaits further clarifica-
tion.
Genetic factors may explain sex differences. Single
nucleotide polymorphism (SNP) in the gene fucosyl-
transferase 2 has been associated with vitamin B12 absorp-
tion and serum concentration [37]. It has been suggested
to interact with diet and to significantly contribute the
high prevalence of vitamin B12 deficiency in India [38].
The fucosyl-transferase 2 gene is located within chromo-
some 19, in which sex-specific probability for recombina-
tion has been shown [39]. Moreover, sex-related associa-
tions with SNPs have been recently demonstrated for cor-
onary artery disease, suggesting that a specific SNP could
influence each sex differently [40]. We therefore hypoth-
esize that genetic polymorphism within the local popula-
tion is likely to explain the observed association between
men and vitamin B12 deficiency. However, this is yet to be
examined in future genetic research.
The current study has several limitations. The cross-
sectional design hinders the ability to infer causality re-
garding the different determinants of vitamin B12 defi-
ciency. However, due to the inherent nature of sex, tem-
porality is not actually absent for the main examined
association. The direction of the association could there-
fore not be mistakenly interpreted. Additionally, repeat-
ed measurements generally have an added value in infer-
ring causation. However, the study focuses on inter-gen-
der relations, and these are not expected to change
significantly over time.
Nutrition is of utmost importance in regard to vitamin
B12 metabolism. Due to the retrospective nature of the
study, data on nutritional habits of the participants were
unavailable. Such data could have cast some light on the
mechanism for the observed gender differences. In addi-
tion, as data on medications and supplements consump-
tion was self-reported, a reporting bias might exist, that
is, individuals could potentially avoid disclosing their real
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DOI: 10.1159/000488326
intake. However, such a bias is expected to be insignifi-
cant, as the reporting bias for group B vitamin consump-
tion, was shown to be generally low [41].
Another limitation is related to the fact that the major-
ity of the examined population were white collar workers.
This homogeneity may diminish the study’s external va-
lidity. Yet, as the study demonstrated firm evidence for
gender differences, it is likely that these represent a phe-
nomenon prevailing beyond a specific socioeconomic
status.
To our knowledge, this study is the first to demon-
strate a strong association between gender and vitamin
B12 deficiency among the non-elderly healthy adult
population. Men were found more likely to be diagnosed
with both mild and severe vitamin B12 deficiency. The
causative mechanism for this phenomenon remains to
be determined, although genetic variations including
sex-related genetic expressions are likely to play an im-
portant role. Revealing the relations between gender and
vitamin B12 deficiency may contribute to the develop-
ment of screening guidelines, early identification of in-
dividuals at risk, and potentially to prevent its conse-
quences.
Disclosure Statement
The authors have no conflicts of interest to disclose.
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