ArticlePDF Available


Background: Vitamin B12 deficiency is associated with hematological, neurological, and cardiovascular consequences. Epidemiologic data on these related illnesses indicate gender differences. Methods: A cross-sectional study was designed to examine gender differences in vitamin B12 deficiency among a healthy population. Data from healthy individuals 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 supplements 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.
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 @
© 2018 S. Karger AG, Basel
DOI: 10.1159/000488326
Albumin · Cobalamin · Gender · Sex · Vitamin B12
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
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].
Downloaded by:
Tel Aviv Ichilov - Sourasky Medical Ctr - 11/19/2019 2:10:31 PM
Ann Nutr Metab 2018;72:265–271
DOI: 10.1159/000488326
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.
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
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.
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-
Downloaded by:
Tel Aviv Ichilov - Sourasky Medical Ctr - 11/19/2019 2:10:31 PM
Vitamin B12 Deficiency and Gender
Ann Nutr Metab 2018;72:265–271
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)
(≥206 pmol/L; n= 6,098)
(<206 pmol/L; n= 1,865)
p value
Gender, n (%) <0.001
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 0.025
eGFR*, mL/min/1.73 m297.35±13.65 97.87±13.51 95.63±13.98 <0.001
Hemoglobin, g/dL 14.35±1.34 14.32±1.29 14.46±1.48 <0.001
MCV, fL 85.84±7.00 85.96±6.98 85.47±7.00 0.009
Transferrin saturation** 31.37±12.06 31.56±12.08 30.78±11.96 0.015
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 <0.001
Uric acid, mg/dL 5.50±1.39 5.46±1.39 5.64±1.40 <0.001
Homocysteine, μmol/L 11.69±5.64 10.92±4.11 14.23±8.50 <0.001
Folate, nmol/L 19.37±8.26 20.06±8.47 17.10±7.07 <0.001
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 <0.001
Triglycerides, mg/dL 123.17±80.65 120.01±76.60 133.48±91.99 <0.001
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).
Statistically 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.
Downloaded by:
Tel Aviv Ichilov - Sourasky Medical Ctr - 11/19/2019 2:10:31 PM
Ann Nutr Metab 2018;72:265–271
DOI: 10.1159/000488326
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–
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
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 1.28–1.68
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 0.72–0.93
Hyperhomocysteinemia (>15.0 μmol/L) 3.26 2.79–3.81
Folate deficiency (<12.2 nmol/L) 1.20 1.05–1.39
Albumin, g/dL 0.42 0.33–0.52
Transferrin saturation*0.47 0.30–0.76
ᵠStatistically significant determinant.
* Transferrin saturation = (serum iron/[serum transferrin *
1.25]) * 100.
BMI, body mass index; eGFR, estimated glomerular filtration
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)
aAdjusted for age, BMI, eGFR status, hyperhomocysteinemia, and folate deficiency.
bAdjusted for age, BMI, eGFR status, hyperhomocysteinemia, folate deficiency, and albumin.
cAdjusted for age, BMI, eGFR status, hyperhomocysteinemia, folate deficiency, albumin, and transferrin saturation.
dIndividuals with normal homocysteine and folate levels (n= 5,926), adjusted for age, BMI, eGFR status, albumin, and transferrin
eNon-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.
Downloaded by:
Tel Aviv Ichilov - Sourasky Medical Ctr - 11/19/2019 2:10:31 PM
Vitamin B12 Deficiency and Gender
Ann Nutr Metab 2018;72:265–271
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-
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-
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
Downloaded by:
Tel Aviv Ichilov - Sourasky Medical Ctr - 11/19/2019 2:10:31 PM
Ann Nutr Metab 2018;72:265–271
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
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-
Disclosure Statement
The authors have no conflicts of interest to disclose.
1 Green R, Allen L, Bjørke-Monsen A, et al: Vi-
tamin B12 deficiency. Nat Rev Dis Prim 2017;
3: 17040.
2 Pawlak R, Lester SE, Babatunde T: The preva-
lence of cobalamin deficiency among vegetar-
ians assessed by serum vitamin B12: a review
of literature. Eur J Clin Nutr 2014; 68: 541–
3 Solomon LR: Disorders of cobalamin (vita-
min B12) metabolism: emerging concepts in
pathophysiology, diagnosis and treatment.
Blood Rev 2007; 21: 113–130.
4 Gamble MV, Liu X, Ahsan H, et al: Folate and
arsenic metabolism: a double-blind, placebo-
controlled folic acid-supplementation trial in
Bangladesh. Am J Clin Nutr 2006; 84: 1093–
5 Pawlak R: Is vitamin B12 deficiency a risk fac-
tor for cardiovascular disease in vegetarians?
Am J Prev Med 2015; 48:e11–e26.
6 Oertelt-Prigione S, Regitz-Zagrosek V: Sex
and Gender Aspects in Clinical Medicine.
London, Springer, 2011.
7 EUGenMed Cardiovascular Clinical Study
Group, Regitz-Zagrosek V, Oertelt-Prigione
S, et al: Gender in cardiovascular diseases:
impact on clinical manifestations, manage-
ment, and outcomes. Eur Heart J 2016; 37:
8 Kim YH, Kim NH, Jung MH, Kim HJ: Sex
differences in metabolic risk indicator of de-
mentia in an elderly urban Korean popula-
tion: a community-based cross-sectional
study. Geriatr Gerontol Int 2017; 17: 2136–
9 Neu SC, Pa J, Kukull W, et al: Apolipoprotein
E genotype and sex risk factors for alzheimer
disease: a meta-analysis. JAMA Neurol 2017;
74: 1178–1189.
10 Fagot D, Chicherio C, Albinet CT, André N,
Audiffren M: The impact of physical activity
and sex differences on intraindividual vari-
ability in inhibitory performance in older
adults. Neuropsychol Dev Cogn B Aging
Neuropsychol Cogn 2017: 1–23.
11 den Elzen W, van der Weele GM, Gussekloo
J, Westendorp RG, Assendelft WJ: Subnormal
vitamin B12 concentrations and anaemia in
older people: a systematic review. BMC Geri-
atr 2010; 10: 42.
12 Stabler S: Vitamin B12 deficiency. N Engl J
Med 2013; 368: 149–160.
13 Kasper DL, Fauci AS, Houser SL, Longo DL,
Jameson JL, Loscalzo J: Harrison’s Principles
of Internal Medicine, (ed 19). New york, Mc-
Graw-Hill Education, 2015.
14 Chui C, Lau FY, Wong R, et al: Vitamin B12
deficiency – need for a new guideline. Nutri-
tion 2001; 17: 917–920.
15 Morris MS, Jacques PF, Rosenberg IH, Selhub
J: Folate and vitamin B-12 status in relation to
anemia, macrocytosis, and cognitive impair-
ment in older Americans in the age of folic
acid fortification. Am J Clin Nutr 2007; 85:
16 Smith AD, Refsum H, Bottiglieri T, et al: Ho-
mocysteine and dementia: an international
consensus statement. J Alzheimers Dis 2018;
62: 561–570.
17 Levey AS, Stevens LA, Schmid CH, et al: A
new equation to estimate glomerular filtra-
tion rate. Ann Intern Med 2009; 150: 604–
18 Kalantar-Zadeh K, Kleiner M, Dunne E, Lee
GH, Luft FC: A modified quantitative subjec-
tive global assessment of nutrition for dialysis
patients. Nephrol Dial Transplant 1999; 14:
19 El-Khateeb M, Khader Y, Batieha A, et al: Vi-
tamin B12 deficiency in Jordan: a population-
based study. Ann Nutr Metab 2014; 64: 101–
20 Carmel R: Current concepts in cobalamin de-
ficiency. Annu Rev Med 2000; 51: 357–375.
21 Miranti EH, Stolzenberg-Solomon R, Wein-
stein SJ, et al: Low vitamin B12 increases risk
of gastric cancer: a prospective study of one-
carbon metabolism nutrients and risk of up-
per gastrointestinal tract cancer. Int J Cancer
2017; 141: 1120–1129.
22 Pan Y, Liu Y, Guo H, et al: Associations be-
tween folate and vitamin B12 levels and in-
flammatory bowel disease: a meta-analysis.
Nutrients 2017; 9:pii:E382.
23 Green PH, Cellier C: Celiac disease. N Engl J
Med 2007; 357: 1731–1743.
24 Shamir R, Lerner A, Shinar E, et al: The use of
a single serological marker underestimates
the prevalence of celiac disease in Israel: a
study of blood donors. Am J Gastroenterol
2002; 97: 2589–2594.
25 Israeli E, Hershcovici T, Grotto I, Rouach Z,
Branski D, Goldin E: Prevalence of celiac dis-
ease in an adult Jewish population in Israel. Isr
Med Assoc J 2010; 12: 266–269.
26 The 2014 Social Survey: Consumerism
and Environmental Considerations. Cent
Bur Stat Isr. 2016.
27 Herrmann W, Schorr H, Obeid R, Geisel J:
Vitamin B-12 status, particularly holotrans-
cobalamin II and methylmalonic acid con-
centrations, and hyperhomocysteinemia in
vegetarians. Am J Clin Nutr 2003; 78: 131–
28 Schüpbach R, Wegmüller R, Berguerand C,
Bui M, Herter-Aeberli I: Micronutrient status
and intake in omnivores, vegetarians and veg-
ans in Switzerland. Eur J Nutr 2017; 56: 283–
29 Morris MS, Jacques PF, Selhub J, Rosenberg
IH: Total homocysteine and estrogen status
indicators in the Third National Health and
Nutrition Examination Survey. Am J Epide-
miol 2000; 152: 140–148.
Downloaded by:
Tel Aviv Ichilov - Sourasky Medical Ctr - 11/19/2019 2:10:31 PM
Vitamin B12 Deficiency and Gender
Ann Nutr Metab 2018;72:265–271
DOI: 10.1159/000488326
30 Smolders RG, de Meer K, Kenemans P, Jakobs
C, Kulik W, van der Mooren MJ: Oral estra-
diol decreases plasma homocysteine, vitamin
B6, and albumin in postmenopausal women
but does not change the whole-body homo-
cysteine remethylation and transmethylation
flux. J Clin Endocrinol Metab 2005; 90: 2218–
31 Carmel R, Howard JM, Green R, Jacobsen
DW, Azen C: Hormone replacement therapy
and cobalamin status in elderly women. Am J
Clin Nutr 1996; 64: 856–859.
32 Wilson SM, Bivins BN, Russell KA, Bailey LB:
Oral contraceptive use: impact on folate, vita-
min B6, and vitamin B12 status. Nutr Rev 2011;
69: 572–583.
33 Mühlberg W, Sieber C: Sarcopenia and frailty in
geriatric patients: implications for training and
prevention. Z Gerontol Geriatr 2004; 37: 2–8.
34 Bulut EA, Soysal P, Aydin AE, Dokuzlar O,
Kocyigit SE, Isik AT: Vitamin B12 deficiency
might be related to sarcopenia in older adults.
Exp Gerontol 2017; 95: 136–140.
35 Carmel R, Vasireddy H, Aurangzeb I, George
K: High serum cobalamin levels in the clinical
setting – clinical associations and holo-trans-
cobalamin changes. Clin Lab Haematol 2001;
23: 365–371.
36 McMahon GM, Hwang SJ, Tanner RM, et al:
The association between vitamin B12, albu-
minuria and reduced kidney function: an ob-
servational cohort study. BMC Nephrol 2015;
16: 7.
37 Tanaka T, Scheet P, Giusti B, et al: Genome-
wide association study of vitamin B6, vita-
min B12, folate, and homocysteine blood
concentrations. Am J Hum Genet 2009; 84:
38 Tanwar VS, Chand MP, Kumar J, et al: Com-
mon variant in FUT2 gene is associated with
levels of vitamin B(12) in Indian population.
Gene 2013; 515: 224–228.
39 Mohrenweiser HW, Tsujimoto S, Gordon L,
Olsen AS: Regions of sex-specific hypo- and
hyper-recombination Identified through In-
tegration of 180 genetic markers into the met-
ric physical map of human chromosome 19.
Genomics 1998; 47: 153–162.
40 Ji Y, Song Y, Wang Q, et al: Sex-specific as-
sociation of SH2B3 and SMARCA4 poly-
morphisms with coronary artery disease
susceptibility. Oncotarget 2017; 8: 59397–
41 Raval AD, Thakker D, Rangoonwala AN, Gor
D, Walia R: Vitamin B and its derivatives for
diabetic kidney disease. Cochrane Database
Syst Rev 2015; 1:CD009403.
Downloaded by:
Tel Aviv Ichilov - Sourasky Medical Ctr - 11/19/2019 2:10:31 PM
... Margalit et al in 2018 investigated 7,963 healthy individuals and found that men had a greater tendency for deficiency compared to women with an OR of 2.26. 23 Alvarez et al in 2016 also had a similar result that diabetic men who are on metformin are at higher risk for Vitamin B12 deficiency than women. 24 However, one study reported a greater tendency for Vitamin B12 deficiency among women because of the concomitant deficiency in holotranscobalamin, which is a protein that delivers cobalamin to the tissues and is considered a more sensitive diagnostic marker for cobalamin deficiency. ...
Full-text available
Background and Aim: The association between Vitamin B12 deficiency and metformin use among Type 2 diabetic patients (T2DM) were reported. We wanted to determine the prevalence of Vitamin B12 deficiency among T2DM patients who were on metformin seen in our institution. Methods: We conducted a retrospective medical records review of Saudi patients diagnosed with Type 2 Diabetes Mellitus patient aged between 30-50 years who visited the Primary Care Center of Security Forces Hospital in Riyadh, Saudi Arabia during the last two years 2018-2019. Results: A total of 289 T2DM patients, 161 (55.7%) males and 128 (44.3%) females with a mean age of 44.66 ± 4.49 years were included in the study. The mean Vitamin B12 level was 296.68 ± 114.79 pg/mL. There were 12 patients (4.2%) with Vitamin B12 deficiency, and the remaining 277 patients (95.8%) had normal Vitamin B12 level. The mean (SD) Vitamin B12 level of males was significantly higher among males than females (311.75 ± 115.34 pg/mL versus 277.72 ± 111.68 pg/mL, p=0.012). There was no significant difference in the mean (SD) Vitamin B12 level among patients <50 years old and patients ≥50 years old (292.40 ± 111.82 pg/mL versus 324.08 ± 130.52 pg/mL, p=0.109). Conclusion: In summary, we found 19.72% prevalence of Vitamin B12 deficiency among patients seen at th e family medicine clinics with 40.14% of our patients in the borderline Vitamin B12 status. Contrary to other previous studies, we found that females are more at risk for Vitamin B12 deficiency in this region. This study suggests the importance of measuring the Vitamin B12 levels of women especially and improve their Vitamin B12 status.
... Poor intake or malabsorption were the two main causes of micronutrient deficiency in specific patient groups: vitamin A deficiency in children; thiamine deficiency in women of reproductive age; and vitamin B12 deficiency in men. In part, these age and sex differences reflect the differing nutritional demands and prevalence of micronutrient deficiencies among men, women and children in general: globally, children are most at risk of vitamin A deficiency because they have higher vitamin A requirements [76]; thiamine requirements increase during pregnancy and lactation [77], and vitamin B12 deficiency is more prevalent among men [78]. Hence, there may be physiological factors underlying these interactions between age, sex and nutrition. ...
Full-text available
Idiopathic intracranial hypertension (IIH) is a neurological disorder characterised by optic disc swelling secondary to raised intracranial pressure (ICP) of unknown cause. Obesity is the most established and prevalent risk factor in developed countries. As obesogenic diets are high in calories and nutrient-poor, there may be associated nutritional deficiencies that contribute to the clinical presentation of IIH. Yet none, aside from iron deficiency, are currently included in the inclusion or exclusion criteria for the diagnosis of IIH. Our primary aim was to determine which micronutrient deficiencies, aside from iron deficiency, could present with optic disc swelling associated with or without intracranial hypertension that could potentially meet current IIH diagnostic criteria. To this end, we conducted a systematic search of articles published between 1 January 1980 and 18 December 2020 reporting cases of optic disc swelling associated with micronutrient deficiencies. In total, 65 cases met the eligibility criteria from initial searches: all were case reports and case series with a high risk of bias. Our findings suggest that patients with IIH or unexplained optic disc swelling ought to be screened, investigated, and treated for associated micronutrient deficiencies in vitamin A, B1 and B12; and weight loss interventions in IIH patients ought to promote better nutrition in addition to overall calorie restriction.
... There is a bias in preclinical studies that use mostly male mice [8,9], which means clinical pharmaceutical findings favor better outcomes in males [10,11]. However, the impact of vitamin B12 deficiency on stroke outcome on males does need to be investigated, and clinical data have shown that males are more susceptible to vitamin B12 deficiencies [50]. Furthermore, in our study, we measured the levels of total homocysteine in plasma and liver, as well as methylmalonic acid in cecum tissue, both of which are markers of a dietary deficiency of vitamin B12 [38]. ...
Full-text available
A vitamin B12 deficiency (vit. B12 def.) is common in the elderly, because of changes in metabolism. Clinical studies have reported that a vit. B12 def. results in worse outcome after stroke, and the mechanisms through which a vit. B12 def. changes the brain requires further investigation. This study investigated the role of vit. B12 def. on stroke outcome and mechanisms using aged female mice. Eighteen-month-old females were put on a control or vit. B12 def. diet for 4 weeks, after which an ischemic stroke was induced in the sensorimotor cortex. After damage, motor function was measured, the animals were euthanized, and tissues were collected for analysis. Vit. B12 def. animals had increased levels of total homocysteine in plasma and liver, and choline levels were also increased in the liver. Vit. B12 def. animals had larger damage volume in brain tissue and more apoptosis. The cecum tissue pathway analysis showed dysfunction in B12 transport. The analysis of mitochondrial metabolomics in brain tissue showed reduced levels of metabolites involved in the TCA cycle in vit. B12 def. animals. Motor function after stroke was impaired in vit. B12 def. animals. A dietary vit. B12 def. impairs motor function through increased apoptosis and changes in mitochondrial metabolism in brain tissue.
... Genetic polymorphism within the local population can be a reason for an association of gender with vitamin B12 levels. [17] In our study, mean vitamin B12 level was significantly higher in females (339 pg/ml) than males (289 pg/ml). The frequency of hyperhomocysteinemia is significantly higher in males. ...
Purpose: To evaluate Vitamin B12 levels in healthcare professionals at a tertiary eyecare centre in India. Methods: This was a cross-sectional study conducted among healthcare professionals working at a tertiary eyecare centre in India. The sample included 2,374 employees. Chemiluminescent immunoassay method (reference range, 211-911 pg/ml) was used to assess serum vitamin B12 levels. Effect of age and gender was analyzed in vitamin B12 normal and vitamin B12 deficient groups. To evaluate risk factors, questions related to vitamin B12 deficiency were asked to the study participants in a survey. Results: The mean age of employees was 29.2 ± 0.7 years. Around 26% of them were vitamin B12 deficient. The proportion of males in the vitamin B12 deficient group (61.2%) was significantly higher (P < 0.0001) than that of the vitamin B12 normal group (44.9%). There was no effect of age on vitamin B12 levels in both vitamin B12 normal and vitamin B12 deficient groups. Mean vitamin B12 levels in males (289.1 ± 22.2 pg/ml) was significantly lower (P < 0.0001) than that of females (338.7 ± 30.0 pg/ml). Conclusion: This is the first such study on eyecare professionals. One-fourth of the eyecare professionals were vitamin B12 deficient. The proportion of males was higher in the vitamin B12 deficiency group. Males had lower vitamin B12 levels than females. Annual blood tests for vitamin B12 are recommended for timely diagnosis and management of vitamin B12 deficiency, particularly in males.
... Vitamin B12 deficiency with MTF is rarely symptomatic; it is linked to a reduction in the intestinal absorption of cobalamin and can be reversed by the discontinuation of MTF or with oral B12 supplementation. Men have lower vitamin B12 levels compared to women [62]. In a study of patients with T2DM (without a control group), higher doses of MTF and male sex were factors associated with lower levels of vitamin B12 [63]. ...
Full-text available
Metformin (MTF) occupies a major and fundamental position in the therapeutic management of type 2 diabetes mellitus (T2DM). Gender differences in some effects and actions of MTF have been reported. Women are usually prescribed lower MTF doses compared to men and report more gastrointestinal side effects. The incidence of cardiovascular events in women on MTF has been found to be lower to that of men on MTF. Despite some promising results with MTF regarding pregnancy rates in women with PCOS, the management of gestational diabetes, cancer prevention or adjunctive cancer treatment and COVID-19, most robust meta-analyses have yet to confirm such beneficial effects.
... The 14-days supplementation period resulted in a significant increase in the serum vitamin B12 concentration for both males and females; with higher levels for females compared to males. While we did not assess the possible reasons for this difference, other studies have suggested genderbased differences in vitamin B12 related metabolism [14,15]. ...
Full-text available
Background This study examined the effect of vitamin B12 supplementation on sleep parameters of latency, total sleep time, wake-after-sleep onset, total time in bed and sleep efficiency in healthy adults. Methods This quasi-experimental pre-test, post-test design recruited adults 25-50 years old, with normal vitamin B12 levels. Sleep parameters were assessed using Phillips Respironics Actiwatch-2® on non-dominant wrist from Monday to Thursday for four weeks. Pre-supplementation data was collected for the first two weeks; then participants started 3mg pre-packaged cyanocobalamin supplements daily for 14 days. Post-supplementation data was collected for weeks three and four. Serum was collected by venipuncture at the beginning and end of the study for vitamin B12 assay. Descriptive statistics involved median and interquartile range [IQR]. A comparison of the sleep parameters before and after cyanocobalamin supplementation was done using non-parametric inferential analysis. Results Fourteen healthy adult participants completed the study; nine females and five males with median age of 37[17] years and a normal range of serum vitamin B12 level (169-695pmol/L). Median serum vitamin B12 level was significantly elevated following supplementation (355[217] to 961[679]) pmol/L; p=0.020); but there was no change in any of the sleep parameters measured. Spearman’s rho correlation analysis showed no correlation between serum vitamin B12 levels and the sleep parameters for pre-supplementation and post-supplementation weeks. Conclusion Two weeks of cyanocobalamin supplementation (3mg/day) resulted in the expected increase in serum vitamin B12 levels in healthy adults but did not influence their sleep wake activity.
... Only two studies compared postoperative concentrations between gender groups (Louw et al. 1992;Blomberg Jensen et al. 2018). Given the established differences in vitamin bioavailability and pharmacokinetics between gender groups (AlQuaiz et al. 2018;Blanchard 1991;Margalit et al. 2018) and variability in stress responses (Verma, Balhara, and Gupta 2011), studies should consider gender as a key factor influencing postoperative concentrations. Additionally, a number of studies consisted of sample sizes below 15 patients, with no reporting of sample size calculations. ...
Given the rise in worldwide chronic diseases, supplemented by an aging population, the volume of global major surgeries, encompassing cardiac and orthopedic procedures is anticipated to surge significantly. Surgical trauma can be accompanied by numerous postoperative complications and metabolic changes. The present review summarized the results from studies assessing the effects of orthopedic and cardiovascular surgery on vitamin concentrations, in addition to exploring the possible mechanisms associated with changes in concentrations. Studies have revealed a potentially severe depletion in plasma/serum concentrations of numerous vitamins following these surgeries acutely. Vitamins C, D and B1 appear particularly vulnerable to significant depletions, with vitamin C and D depletions consistently transpiring into inadequate and deficient concentrations, respectively. The possible multifactorial mechanisms impacting postoperative vitamin concentrations include changes in hemodilution and vitamin utilization, redistribution, circulatory transport and absorption. For a majority of vitamins, there has been a lack of investigation into the effects of both, cardiac and orthopedic surgery. Additionally, studies were predominantly restricted to short-term postoperative investigations, primarily performed within the first postoperative week of surgery. Overall, results indicated that further examination is necessary to determine the severity and clinical significance of the possible depletions in vitamin concentrations that ensue cardiovascular and orthopedic surgery.
Research suggests that high intake of supplemental vitamin B12 may be associated with increased risk of cancer, with some evidence that this association may vary by gender and smoking status. This investigation evaluates if similar patterns in association are observed for data for 11,757 adults from the National Health and Nutrition Examination Survey (1999-2006). Survey-weighted multivariable-adjusted linear regression was used to evaluate the association between regular B12 supplement use and log-transformed serum B12 levels. Persons taking vitamin B12 through a multivitamin/multimineral (MVMM) had a median supplemental intake of 12 mcg/day (Q1: 6, Q3: 25), compared to 100 mcg/day (Q1: 22, Q3: 500) for persons reporting supplemental B12 intake through a MVMM-exclusive source. MVMM users had a geometric mean serum B12 26% (95% CI: 23%-30%) higher than nonusers, whereas MVMM-exclusive users’ geometric mean was 61% (95% CI: 53%-70%) higher than nonusers (p-trend < 0.001). Although a positive trend (p-trend < 0.001) was observed for both men and women, the association was stronger among women (p-interaction < 0.001). No interaction was observed for smoking status (p-interaction = 0.45). B12 supplementation is associated with higher levels of serum B12, with significant interaction by gender but not smoking. Further work is needed to better understand the interplay of B12 and gender.
Full-text available
Identification of modifiable risk factors provides a crucial approach to the prevention of dementia. Nutritional or nutrient-dependent risk factors are especially important because dietary modifications or use of dietary supplements may lower the risk factor level. One such risk factor is a raised concentration of the biomarker plasma total homocysteine, which reflects the functional status of three B vitamins (folate, vitamins B12, B6). A group of experts reviewed literature evidence from the last 20 years. We here present a Consensus Statement, based on the Bradford Hill criteria, and conclude that elevated plasma total homocysteine is a modifiable risk factor for development of cognitive decline, dementia, and Alzheimer's disease in older persons. In a variety of clinical studies, the relative risk of dementia in elderly people for moderately raised homocysteine (within the normal range) ranges from 1.15 to 2.5, and the Population Attributable risk ranges from 4.3 to 31%. Intervention trials in elderly with cognitive impairment show that homocysteine-lowering treatment with B vitamins markedly slows the rate of whole and regional brain atrophy and also slows cognitive decline. The findings are consistent with moderately raised plasma total homocysteine (>11 μmol/L), which is common in the elderly, being one of the causes of age-related cognitive decline and dementia. Thus, the public health significance of raised tHcy in the elderly should not be underestimated, since it is easy, inexpensive, and safe to treat with B vitamins. Further trials are needed to see whether B vitamin treatment will slow, or prevent, conversion to dementia in people at risk of cognitive decline or dementia.
Full-text available
It is well-known that processing speed and executive functions decline with advancing age. However, physical activity (PA) has a positive impact on cognitive performances in aging, specifically for inhibition. Less is known concerning intraindividual variability (iiV) in reaction times. This study aims to investigate the influence of PA and sex differences on iiV in inhibitory performance during aging. Healthy adults were divided into active and sedentary groups according to PA level. To analyse iiV in reaction times, individual mean, standard deviation and the ex-Gaussian parameters were considered. An interaction between activity level and sex was revealed, sedentary females being slower and more variable than sedentary men. No sex differences were found in the active groups. These results indicate that the negative impact of sedentariness on cognitive performance in older age is stronger for females. The present findings underline the need to consider sex differences in active aging approaches.
Full-text available
Importance: It is unclear whether female carriers of the apolipoprotein E (APOE) ε4 allele are at greater risk of developing Alzheimer disease (AD) than men, and the sex-dependent association of mild cognitive impairment (MCI) and APOE has not been established. Objective: To determine how sex and APOE genotype affect the risks for developing MCI and AD. Data sources: Twenty-seven independent research studies in the Global Alzheimer's Association Interactive Network with data on nearly 58 000 participants. Study selection: Non-Hispanic white individuals with clinical diagnostic and APOE genotype data. Data extraction and synthesis: Homogeneous data sets were pooled in case-control analyses, and logistic regression models were used to compute risks. Main outcomes and measures: Age-adjusted odds ratios (ORs) and 95% confidence intervals for developing MCI and AD were calculated for men and women across APOE genotypes. Results: Participants were men and women between ages 55 and 85 years. Across data sets most participants were white, and for many participants, racial/ethnic information was either not collected or not known. Men (OR, 3.09; 95% CI, 2.79-3.42) and women (OR, 3.31; CI, 3.03-3.61) with the APOE ε3/ε4 genotype from ages 55 to 85 years did not show a difference in AD risk; however, women had an increased risk compared with men between the ages of 65 and 75 years (women, OR, 4.37; 95% CI, 3.82-5.00; men, OR, 3.14; 95% CI, 2.68-3.67; P = .002). Men with APOE ε3/ε4 had an increased risk of AD compared with men with APOE ε3/ε3. The APOE ε2/ε3 genotype conferred a protective effect on women (OR, 0.51; 95% CI, 0.43-0.61) decreasing their risk of AD more (P value = .01) than men (OR, 0.71; 95% CI, 0.60-0.85). There was no difference between men with APOE ε3/ε4 (OR, 1.55; 95% CI, 1.36-1.76) and women (OR, 1.60; 95% CI, 1.43-1.81) in their risk of developing MCI between the ages of 55 and 85 years, but women had an increased risk between 55 and 70 years (women, OR, 1.43; 95% CI, 1.19-1.73; men, OR, 1.07; 95% CI, 0.87-1.30; P = .05). There were no significant differences between men and women in their risks for converting from MCI to AD between the ages of 55 and 85 years. Individuals with APOE ε4/ε4 showed increased risks vs individuals with ε3/ε4, but no significant differences between men and women with ε4/ε4 were seen. Conclusions and relevance: Contrary to long-standing views, men and women with the APOE ε3/ε4 genotype have nearly the same odds of developing AD from age 55 to 85 years, but women have an increased risk at younger ages.
Full-text available
To determine whether sex differences affect the association between genetic polymorphisms and coronary artery disease (CAD) in the Chinese Han population, we conducted a study comparing the frequency of SH2B3 and SMARCA4 variants in 456 CAD patients (291 men, 165 women) and 685 age-matched controls (385 men, 300 women). Ten single nucleotide polymorphisms (SNPs) in SH2B3 and SMARCA4 were genotyped using MassARRAY technology. Allelic and genotypic models and haplotype frequencies were compared between groups. Logistic regression was used to estimate the CAD risk associated with the genotypes. We found that the “A” alleles in both rs11879293 and rs12232780 of SMARCA4 were associated with CAD risk in men (p = 0.036 and p = 0.001, respectively). The genetic model showed that SH2B3 was associated with CAD susceptibility in both women and men, while SMARCA4 was associated with reduced odds of CAD in men. SH2B3 haplotypes were associated with decreased CAD risk in women (p = 0.007) and increased CAD risk in men (p = 0.047). By providing evidence for the sex-related association between SH2B3 and SMARCA4 gene variants and CAD susceptibility in the Chinese Han population, this study may help define useful diagnostic and preventive markers for these patients.
Full-text available
Vitamin B12 (B12; also known as cobalamin) is a B vitamin that has an important role in cellular metabolism, especially in DNA synthesis, methylation and mitochondrial metabolism. Clinical B12 deficiency with classic haematological and neurological manifestations is relatively uncommon. However, subclinical deficiency affects between 2.5% and 26% of the general population depending on the definition used, although the clinical relevance is unclear. B12 deficiency can affect individuals at all ages, but most particularly elderly individuals. Infants, children, adolescents and women of reproductive age are also at high risk of deficiency in populations where dietary intake of B12‑containing animal-derived foods is restricted. Deficiency is caused by either inadequate intake, inadequate bioavailability or malabsorption. Disruption of B12 transport in the blood, or impaired cellular uptake or metabolism causes an intracellular deficiency. Diagnostic biomarkers for B12 status include decreased levels of circulating total B12 and transcobalamin-bound B12, and abnormally increased levels of homocysteine and methylmalonic acid. However, the exact cut-offs to classify clinical and subclinical deficiency remain debated. Management depends on B12 supplementation, either via high-dose oral routes or via parenteral administration. This Primer describes the current knowledge surrounding B12 deficiency, and highlights improvements in diagnostic methods as well as shifting concepts about the prevalence, causes and manifestations of B12 deficiency.
Full-text available
Background: Inflammatory bowel disease (IBD) patients may be at risk of vitamin B12 and folate insufficiencies, as these micronutrients are absorbed in the small intestine, which is affected by IBD. However, a consensus has not been reached on the association between IBD and serum folate and vitamin B12 concentrations. Methods: In this study, a comprehensive search of multiple databases was performed to identify studies focused on the association between IBD and serum folate and vitamin B12 concentrations. Studies that compared serum folate and vitamin B12 concentrations between IBD and control patients were selected for inclusion in the meta-analysis. Results: The main outcome was the mean difference in serum folate and vitamin B12 concentrations between IBD and control patients. Our findings indicated that the average serum folate concentration in IBD patients was significantly lower than that in control patients, whereas the mean serum vitamin B12 concentration did not differ between IBD patients and controls. In addition, the average serum folate concentration in patients with ulcerative colitis (UC) but not Crohn's disease (CD) was significantly lower than that in controls. This meta-analysis identified a significant relationship between low serum folate concentration and IBD. Conclusions: Our findings suggest IBD may be linked with folate deficiency, although the results do not indicate causation. Thus, providing supplements of folate and vitamin B12 to IBD patients may improve their nutritional status and prevent other diseases.
Previous studies have found associations between one-carbon metabolism nutrients and risk of several cancers, but little is known regarding upper gastrointestinal tract (UGI) cancer. We analyzed pre-diagnostic serum concentrations of several one-carbon metabolism nutrients (vitamin B12, folate, vitamin B6, riboflavin, and homocysteine) in a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study of male smokers, which was undertaken in Finland between 1985 and 1988. We conducted a nested case-control study including 127 non-cardia gastric adenocarcinoma (NCGA), 41 esophago-gastric junctional adenocarcinoma (EGJA), and 60 esophageal squamous cell carcinoma (ESCC) incident cases identified within ATBC. Controls were matched to cases on age, date of serum collection, and follow-up time. One-carbon nutrient concentrations were measured in fasting serum samples collected at baseline (up to 17 years prior to cancer diagnosis). Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional logistic regression. Lower pre-diagnostic vitamin B12 concentrations at baseline were associated with a 5.8-fold increased risk of NCGA (95% CI = 2.7 to 12.6 for lowest compared to highest quartile, p-trend < 0.001). This association remained in participants who developed cancer more than 10 years after blood collection, and after restricting the analysis to participants with clinically normal serum vitamin B12 (>300 pmol/L). In contrast, pepsinogen I, a known serologic marker of gastric atrophy, was not associated with NCGA in this population. As vitamin B12 absorption requires intact gastric mucosa to produce acid and intrinsic factor, our findings suggest vitamin B12 as a possible serologic marker for the atrophic gastritis that precedes NCGA, one more strongly associated with subsequent NCGA than pepsinogen. This article is protected by copyright. All rights reserved.
Sarcopenia and dynapenia are related to repeated falls, mobility restriction, depression, frailty, increased mortality and morbidity. The aim of this study is to evaluate the relationship between vitamin B12 deficiency and sarcopenia in older adults. 403 patients, who attended to outpatient clinic and underwent comprehensive geriatric assessment, were included study. All cases' skeletal muscle mass (SMM), walking speed and hand grip strength were recorded by bioimpedance, 4 meter walking test and hand dynamometer respectively. The diagnosis of sarcopenia was defined according to the criteria of the European Working Group on Sarcopenia in Older People. Sarcopenia was accepted low SMM with low handgrip strength or low physical performance. Dynapenia was defined as handgrip strength < 30 kg (men) and < 20 kg (women). The prevalence of sarcopenia and dynapenia was 24.8% and 32.0%, respectively. In the patients with sarcopenia, mean age, osteoporosis and frailty were higher, and MMSE, and instrumental ADL scores were lower than the patients without sarcopenia (p < 0.05). The frequency of sarcopenia and dynapenia were 31.6% and 35.4%, respectively, in patients with vitamin B12 levels < 400 pg/mL. In addition lean body mass, total skeletal mass and skeletal muscle mass index were lower in the patients with vitamin B12 levels < 400 pg/mL compared to higher than 400 pg/mL (p < 0.05). Sarcopenia, which results in lots of negative clinical outcomes in older adults, might be related to vitamin B12 deficiency. Therefore, these patients should be periodically examined for vitamin B12 deficiency due to the potential negative clinical outcomes such as sarcopenia in older adults.
Aim: The aim of the present study was to evaluate the age-specific prevalence of dementia, and develop a metabolic risk indicator for dementia according to sex. Methods: This cross-sectional study was carried out from September 2007 through December 2012 with 19 935 elderly participants in metropolitan Seoul, Korea. Multiphase assessments were used to measure metabolic risk factors and confirm dementia according to sex. Specifically, multivariate logistic regression analyses were used to identify how elderly men and women differed in regard to metabolic risk indicators of dementia. Results: The adjusted prevalence rates of dementia in elderly Seoul residents were estimated at 4.9%, 6.1% and 5.6% in men, women and the overall population, respectively. Stroke conferred an odds ratio of 5.14 (95% CI 3.91-6.77) and 2.55 (95% CI 2.01-3.25) in men and women, respectively. Additionally, within the female population, diabetes mellitus conferred an odds ratio of 1.29 (95% CI 1.09-1.53), whereas alcohol consumption conferred an odds ratio of 0.77 (95% CI 0.61-0.97). Conclusions: Stroke played a primary role as a metabolic risk indicator of dementia in elderly men, while diabetes mellitus and alcohol abstinence were important metabolic risk factors in elderly women. Taken together, the data show that when designing preventative measures against dementia based on metabolic risk, sex needs to be taken into account. Geriatr Gerontol Int 2017; ••: ••-••.