Is Vitamin B12 Deficiency a Risk Factor for

Cardiovascular Disease in Vegetarians?

Roman Pawlak, PhD, RD

The goal of this paper is to describe the role of vitamin B12 deficiency in cardiovascular disease
development among vegetarians. Vegetarians have a high prevalence of vitamin B12 deficiency.
Deficiency of this vitamin is associated with a variety of atherogenic processes that are mainly, but
not exclusively, due to vitamin B12 deficiency–induced hyperhomocysteinemia. Each 5-μmol/L
increase above 10 μmol/L of serum homocysteine is associated with a 20% increased risk of
circulatory health problems. Mean homocysteine concentration 410 μmol/L among vegetarians
was reported in 32 of 34 reports. Macrocytosis associated with vitamin B12 deficiency is also
associated with fatal and non-fatal coronary disease, myocardial infarction, stroke, and other
circulatory health problems. Compared with non-vegetarians, vegetarians have an improved profile
of the traditional cardiovascular disease risk factors, including serum lipids, blood pressure, serum
glucose concentration, and weight status. However, not all studies that assessed cardiovascular
disease incidence among vegetarians reported a protective effect. Among studies that did show a
lower prevalence of circulatory health problems, the effect was not as pronounced as expected, which
may be a result of poor vitamin B12 status due to a vegetarian diet. Vitamin B12 deficiency may
negate the cardiovascular disease prevention benefits of vegetarian diets. In order to further reduce
the risk of cardiovascular disease, vegetarians should be advised to use vitamin B12 supplements.
(Am J Prev Med 2015;48(6):e11–e26) & 2015 American Journal of Preventive Medicine

Introduction vegetarians than non-vegetarians are overweight or

obese.6 In general, fewer vegetarians smoke or abuse

H
eart disease is the leading cause of mortality
alcohol, and they eat more fruits and vegetables com-
worldwide, causing more than 17 million deaths
pared with non-vegetarians.9–11 Additionally, recent
annually, which accounts for 31% of all mortal-
findings have shown that vegetarian diets improve
ities (32% among women and 27% among men).1,2
markers of inflammation such as C-reactive protein,
Vegetarian diets are protective against some chronic
reduce oxidative stress, and protect against plaque
health conditions. Vegetarian diets are devoid of all flesh
formation.9 The profile of the traditional heart disease
foods, but may include eggs (ovo-vegetarian); milk and
risk factors is especially beneficial among vegans. Based
dairy products (lacto-vegetarian [LV]); or eggs, milk, and
on these factors alone, vegan individuals should exhibit
dairy (lacto-ovo-vegetarian [LOV]). A vegan diet does
the lowest risk of circulatory health problems.
not contain meats, fish, or poultry and does not contain
Interestingly, the improved heart disease risk factors in
any products of animal origin (milk, dairy, and eggs).
vegetarians compared with non-vegetarians do not
These diets improve many modifiable risk factors for
always translate into a lower risk of incidence of and
heart disease, including serum lipid profile, serum
mortality from circulatory diseases. Studies that did find
glucose concentration, and systolic and diastolic blood
a lower prevalence of and mortality from circulatory
pressure.3–8 Consequently, fewer vegetarians than non-
health conditions among vegetarians did not always
vegetarians are diagnosed with hyperlipidemia, hyper-
report substantial benefits, as should have been expected
glycemia, and hypertension. Furthermore, fewer
based on the impact of vegetarian diets on cardiovascular
disease (CVD) risk factors. The death rate ratio from
From the Department of Nutrition Science, East Carolina University,
Greenville, North Carolina ischemic heart disease (IHD) among vegetarians in
Address correspondence to: Roman Pawlak PhD, RD, Department of comparison with non-vegetarians ranged from 0.45
Nutrition Science, East Carolina University, Rivers West 337, Greenville (95% CI¼0.22, 0.95) for German vegetarians included
NC 27858. E-mail: pawlakr@ecu.edu.
0749-3797/$36.00 in the Heidelberg Study to 0.97 (95% CI¼0.78, 1.21)
http://dx.doi.org/10.1016/j.amepre.2015.02.009 among the European Prospective Investigation into

& 2015 American Journal of Preventive Medicine  Published by Elsevier Inc. Am J Prev Med 2015;48(6):e11–e26 e11
e12 Pawlak / Am J Prev Med 2015;48(6):e11–e26
Cancer and Nutrition (EPIC)-Oxford participants
reported by Key et al.9 When data on all circulatory
death rate ratios and cerebrovascular disease death ratios
were analyzed, some cohorts actually reported higher
rates among vegetarians, including vegans, compared
with non-vegetarians.12,13 Although vegetarians seem to
have a lower risk of circulatory health problems, it must
be concluded that vegetarian diets are not as protective as
would be assumed based on the pattern of the CVD
traditional risk factors, data were not adjusted for a
sufficient number of confounding factors, or that other
factors may negate any or some protective effect
of these diets on serum lipids, serum glucose, blood
pressure, and weight status.
Although plant foods provide a variety of nutrients,
including antioxidant vitamins and phytochemicals as
well as dietary fiber, they provide no (in the case of a
vegan diet) or inadequate amounts of vitamin B12.
Vitamin B12 deficiency leads to hyperhomocysteinemia.
Elevated homocysteine (Hcy) is associated with arterial
endothelial dysfunction and is considered an independ-
ent risk factor for CVD.14 Although other nutritional
deficiencies reported among vegetarians may contribute
to the circulatory health problems (e.g., inadequate
serum vitamin D, eicosapentaenoic and docosahexaenoic
acids), the magnitude of the reported prevalence of
vitamin B12 deficiency and the variety of associated
pathologic processes may cause this deficiency to be the
single most important factor in explaining the disap-
pointing findings of CVD prevalence among vegetarians.
The goal of the current paper is to describe the role of
vitamin B12 deficiency in CVD development. The objec-
tives are to (1) describe the association between Hcy and
heart disease; (2) provide an overview of the prevalence
of hyperhomocysteinemia among vegetarians; (3) review
vitamin B12 status among vegetarians; (4) discuss the
impact of B12 on Hcy in vegetarians; (5) describe the role
of Hcy in atherogenesis; and (6) examine the role of red
blood cell (RBC) distribution width (RDW) and mean
corpuscular volume (MCV) in circulatory health
problems.
Homocysteine and Heart Disease
Perhaps the most important way that low vitamin B12
status increases risk of CVD is via its role in Hcy
metabolism. Hyperhomocysteinemia was hypothesized
to play a role in atherogenesis 46 years ago. In 1969,
McClully15 described a case of an infant’s death with
homocystinuria, cystathioninuria, and methylmalonic
aciduria due to an abnormal vitamin B12 status.
He noted that the arterial atherosclerotic lesions were
similar to those developed by children with progressive
arterial disease that results from the lack of normal
activity of cystathionine synthetase. He concluded that
the common vascular changes found in these children
were a result of elevated concentrations of Hcy or its
derivatives.16
A number of publications have supported McClully’s
hypothesis. Jacobsen17 proposed that an Hcy concen-
tration of 10–15 mmol/L is a substantial CVD risk factor
and that this risk should be considered as a continuum:
the higher the concentration, the higher the risk. Jacob-
son’s conclusion is consistent with findings from the
Framingham study, where an increased risk of carotid
stenosis was reported at Hcy concentrations of 9.1–11.3
μmol/L among men and 11.4–14.3 μmol/L among
women.18 The meta-analysis of the Homocysteine Stud-
ies Collaboration group evaluated the impact of Hcy on
ischemic heart disease and stroke based on 30 prospec-
tive and retrospective studies.14 After adjustment for
heart disease risk factors, lowering Hcy by 25% or 3
μmol/L was associated with a statistically significant
(11%) lower risk of IHD and a 19% lower risk of stroke.
Humphrey and colleagues19 conducted another meta-
analysis to assess the effect of Hcy on coronary heart
disease risk. They included 31 studies (eight prospective
cohort studies and 23 nested case-control studies). The
combined effect for each 5-μmol/L increase in Hcy
concentration yielded a significantly (18%) higher risk
of coronary events, independent of the traditional risk
factors. Consequently, these authors suggested that for
each 5-μmol/L increase in plasma Hcy, there is a
corresponding 20% increase in the risk of coronary heart
disease that is independent of traditional heart disease
risk factors.19
Prevalence of Hyperhomocysteinemia
Among Vegetarians
The prevalence of hyperhomocysteinemia depends on
several factors, including the serum concentration
defined as normal, age, gender, presence/absence of
circulatory health conditions, and presence/absence of
vegetarianism. In the Third National Health and Nutri-
tion Examination Survey, hyperhomocysteinemia was
defined as concentration of at least 11.4 μmol/L for male
participants and at least 10.4 μmol/L for female partic-
ipants.20 In this study, the reported prevalence of high
Hcy concentration varied by age and gender, with the
lowest prevalence reported for female adolescents (aged
12–19 years, 7.9%) and the highest reported for elderly
women (aged Z60 years, 46.5%). In the Framingham
cohort, Selhub18 reported hyperhomocysteinemia as a
risk factor for extracranial carotid artery stenosis in at
least 25% of the sample. Pruefer et al.20 suggested that
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 Pawlak / Am J Prev Med 2015;48(6):e11–e26
hyperhomocysteinemia is found in 9%–15% of the
general population and about 40% of individuals with
coronary or cerebrovascular disease.21
Almost without exception, studies that compared Hcy
concentrations among vegetarians with non-vegetarians
reported a higher serum mean total Hcy (tHcy) concen-
tration among the former, with the highest concentration
found among vegans.22 Similarly, vegetarians, especially
vegans, consistently show a higher prevalence of hyper-
homocysteinemia.22 In the review of Elmadfa and
Singer,22 nine of ten comparisons of tHcy concentrations
between vegetarians and non-vegetarians showed a
higher concentration among vegetarians. All four com-
parisons between vegans and vegetarians showed higher
concentrations among vegans. Obersby and colleagues23
published a meta-analysis of total Hcy concentration
among vegetarians (LOVs, LVs, and vegans) in compar-
ison with non-vegetarians. They identified 17 studies (six
cohort and 11 case-control) with 3,230 participants. The
mean (SD) Hcy concentration among vegetarians based
on 15 studies was 13.91 (3.5) μmol/L, that among vegans
based on nine studies was 16.41 (4.8) μmol/L. Non-
vegetarians had the lowest mean tHcy concentration, at
11.3 (2.89) μmol/L.23 Data included in Table 1 show the
prevalence of hyperhomocysteinemia among vegetarians,
which ranges from 12% (hyperhomocysteinemia defined
as serum tHcy 415 μmol/L) in LV and LOV from
Germany to 78% (hyperhomocysteinemia defined as
serum tHcy 412 μmol/L) among vegetarians from
Slovakia. Of the 20 samples that assessed the prevalence
of hyperhomocysteinemia among vegetarians, 13
reported a prevalence higher than 50% of the sample,
ranging from 52% to 78%. Furthermore, only two (one of
which was for semi-vegetarians) of 34 reports of the
mean Hcy concentration were o10 μmol/L (Table 1).
Thus, research findings suggest that (1) vegetarians have
a higher Hcy concentration compared with non-vegeta-
rians; (2) the prevalence of hyperhomocysteinemia
among vegetarians is higher than that among non-
vegetarians; and (3) the prevalence of hyperhomocystei-
nemia among vegetarians may actually be higher than
that among non-vegetarians already diagnosed with
heart disease.
Vitamin B12 Status Among Vegetarians
Almost universally, research findings show a poor
vitamin B12 status among vegetarians, regardless of the
type of biochemical assessment. The earliest reports of
vitamin B12 deficiency among vegetarians from India
were published in 1960.24 The earliest reports on a
deficiency among vegetarian members of the Seventh-
Day Adventist Church were published in 1970s.25 The
June 2015
e13
most recent results showed a deficiency among 62% of
pregnant women, 25% to almost 86% of children, 21%–
41% of adolescents, and 11%–90% of the elderly.26
Fifteen of 26 reports, among the 18 studies, reported
either elevated serum or urinary methylmalonic acid in
50% or more of their respective samples. The prevalence
of B12 deficiency is summarized in Tables 1 and 2.
Homocysteine in Vegetarians Is Affected
Mainly by Vitamin B12 Status
Homocysteine is a sulfur-containing amino acid that is
synthesized in the metabolism of the dietary amino acid
methionine. Hcy undergoes metabolism via one of two
pathways: remethylation to methionine by either methio-
nine synthetase or methylene tetrahydrofolate reductase
enzymes, or trans-sulfuration via cystathionine β-
synthase enzyme. Vitamins B12 and folate are required
for the first pathway and vitamin B6 is needed for the
latter (Figure 1). Consequently, a high intake of methio-
nine and low folate, vitamin B12, or vitamin B6 status may
result in hyperhomocysteinemia.
In the U.S. and a number of other countries, following
studies that documented the effectiveness of folic acid in
preventing neural tube defects, some grain and other
products have been fortified with folic acid. This public
health measure increased the overall intake of folic acid
and improved RBC folate concentration. The higher
folate status in the post-fortification era has also been
associated with a reduction in Hcy concentration. Studies
have also shown that in the post-fortification era, vitamin
B12 is the predominant cause of hyperhomocysteinemia.
Green and Miller,27 based on a study with 1,096
participants aged Z60 years, showed that when three
different criteria of vitamin B12 deficiency were taken
into account (o148 pmol/L, holotranscobalamin o35
pmol/L, creatinine 4115 mmol/L), 50.8% of those with
hyperhomocysteinemia were diagnosed with B12 defi-
ciency. By contrast, only 1.1% of hyperhomocysteinemia
participants had an RBC folate concentration o365
nmol/L (indicative of folate deficiency). Only 0.3% of
the risk for hyperhomocysteinemia was attributed to
RBC folate o365 nmol/L, whereas 29.7%, 36.4%,
and 41.5% of the attributable risk was related to
serum vitamin B12 o148 pmol/L, holotranscobalamin
o35 pmol/L, and creatinine 4115 mmol/L, respectively.
They concluded that in the post-fortification
period, vitamin B12 is the dominant risk factor for
hyperhomocysteinemia.27
The hypothesis that the Hcy concentration is affected
mainly by vitamin B12 status in groups of high folate
consumers is supported by findings from other studies.
Waldmann et al.28 assessed cardiovascular risk factors
 e14
Table 1. Homocysteine Concentration and Prevalence of Hyperhomocysteinemia Among Vegetarian Adults

Vitamin B12
Diet length of deficiency Prevalence of
Study Country Sample (number and age) adherence criteria B12 deficiency Vitamin B12 status

Hyperhomocysteinemia defined as Z or 4 15 lmol/L

Refsum et al. (2001) 29
India N¼78 (LV: n¼77; vegans: n¼1); age Not reported 415 76% 22
range 27–55 years
Herrmann et al. (2001)30 Germany N¼41 (LV/LOV: n¼34, M age¼22 years Criteria of inclusion: 415 LV/LOV: 12% LV/LOV: 11.0
[range 19.5–49.3]; vegans: n¼7, M 41 year of Vegans: 57% Vegans: 15.2
age¼22 years [range 19–30]) constant dietary
pattern
Bissoli et al. (2002)31 Italy N¼45 (vegans: n¼31, M 5 years 415 53.3% All vegetarians: 23.9⫾21.3
age¼45.8⫾15.8 years, LV: n¼14, M Vegans: 26.9⫾24.1

Pawlak / Am J Prev Med 2015;48(6):e11–e26

age¼48.5⫾14.5 years) LV: 17.4⫾11.1

Karabudak et al. (2008)32 Turkey N¼26 Turkish women (SV: n¼7; LOV: Diet duration Z15 34.6% 12.6⫾5.97
n¼9; LV: n¼10); M age 29.0⫾8.84 years 10.5⫾6.77
(range 20–50)
Naik et al. (2013)33 India N¼51 LV (men: n¼15; women: n¼36); Not reported Z15 65% 21.1
M age¼27.6 years (range 26– 30)
Huang et al. (2003)34 Taiwan N¼37 (vegans: n¼3; nLV: n¼18, LOV: M¼5.6 years (from Z15.0 21.6% 13.2
n¼16) M age¼28.9 years (range 27.1– 1.3 to 19 years)
30.7)
Hyperhomocysteinemia defined as Z or 412 lmol/L
Krivosikova et al. Slovakia N¼141 LOV; “Long-term”—no Z12.0 78% 16.5⫾5.6
(2010)35 M age¼41.9 years (range 20–70) details/definition
Herrmann et al. (2003)36 Germany N¼95 LV/LOV: n¼66; M age¼48 years Criteria of inclusion: 412 LV-LOV: 38% LV/LOV: 10.6 (6.4, 27.7)
Netherlands (range 24–75), and vegans: n¼29; M 41 year of Vegans: 67% Vegans: 12.8 (5.9, 57.1)
age¼37 years (range 15–64) constant dietary
pattern
Elmadfa et al. (2009)22 Austria N¼78 (vegans: n¼42 and LOV: n¼36; Not reported 412 Vegans: 66% Not reported
age not reported Vegetarians: 52%
Herrmann et al. (2005)37 Germany N¼164 LV/LOV: n¼114, M age¼50 Not reported 412 Vegans: 62% LV/LOV: 10.9
years (range 35–71) and vegans: n¼50, LV/LOV: not Vegans: 13.0
M age¼44 years (range 20–66) reported
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Majchrzak et al. (2006)38 Austria N¼78; vegan: n¼42, M age¼30.7⫾9.9 67% of vegetarians Z12 Vegan: 65.9% Vegan men: 15.72⫾5.94;
and LOV: n¼36, M age¼34.2⫾13.6 and vegans LOV: 52.8% vegan women:
followed their own 17.25⫾10.06
diet for at least 5 LOV men: ¼17.01⫾6.47;
LOV women: 12.80⫾4.56

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June 2015

Table 1. Homocysteine Concentration and Prevalence of Hyperhomocysteinemia Among Vegetarian Adults (continued)

Vitamin B12
Diet length of deficiency Prevalence of
Study Country Sample (number and age) adherence criteria B12 deficiency Vitamin B12 status

Geisel et al. (2005)39 Germany N¼71 LV/LOV: n¼48 M age¼53 years Criteria of inclusion: 412 45% LV/LOV: 11.1
(range 21–75) and vegans: n¼23, M 41 year of (range 6.3–21.8)
age¼51 years (range 28–76) constant dietary Vegans ¼ 13.0
pattern (range 5.5–38.0)
Obeid et al. (2002)40 Germany N¼113 LV/LOV: n¼64, Vegan: n¼29, Not reported 412 36% for the LV/LOV: 10.5;
Netherlands SV: n¼20), M (SD) age¼46 (15) entire sample Vegans¼12.8
SV¼8.7

Herrmann et al. (2003)41 Germany, N¼111; M age¼46 (18–73) Not reported 412 36% 10.4
Netherlands

Pawlak / Am J Prev Med 2015;48(6):e11–e26

Hyperhomocysteinemia defined as 410 lmol/L
Waldmann et al. (2005) 28
Germany N¼154 vegans (strict vegans: n¼98, M M diet duration 410 Strict vegans: Strict vegans: 13.3
age 43.4⫾15.4; and moderate vegans: 7.70⫾6.40 – strict 71.1%; 57.1% (range 5.97–82.0)
n¼56), M age 45.7⫾14.2 years 5.06⫾4.03 – Moderate vegans: 11.1
moderate (range 3.60–25.7)
No specified definition of hyperhomocysteinemia
42
Herrmann et al. (2009) Germany, n¼54 LV/LOV from Germany M age 50 Criteria of inclusion: Not reported Not reported LV/LOV: from
Oman years, n¼23 Vegans from Germany M Z2 year of Germany: 14.4
age¼45 years, and n¼19, Indian LOV M constant dietary Vegans from
age¼45 years pattern Germany: 15.9
Indian LOV: 14.0
Mezzano et al. (1999)43 Chile N¼26 LV/LOV: n¼23 and vegans: n¼3; 41 year Not reported Not reported 13.5
women: n¼14 and men: n¼12) M
age¼39⫾12.7 years
Hung et al. (2002)44 Taiwan, N¼45 LV women; age range 31–45 Not reported Not reported Not reported 11.20⫾4.27
Buddhist years
Su et al. (2006)45 Taiwan N¼57 healthy postmenopausal women M diet duration¼ Not reported Not reported 11.0⫾3.3
(vegan: n¼51 and vegetarian: n¼6); M 10.4⫾4.2
age¼59.2⫾6.4 years
Chen et al. (2008)46 Taiwan N¼99; M age 51.24⫾8.88 years Not reported Not reported Not reported 10.97⫾6.69
47 b
Su et al. (2011) N¼49 healthy postmenopausal LOV M diet duration¼ Not reported Not reported 10.8⫾3.2
women; M age¼58.6⫾6.0 years 10.8⫾6.0 years
Haddad et al. (1999)48 U.S. N¼25 vegans; age range 20–60 years; 9 4.2 years Not reported Not reported 7.9
used B12 supplements þ 4 used
multivitamin supplements

LOV, lacto-ovo-vegetarians; LV, lacto-vegetarians; SV, semi-vegetarians.

e15
 e16
Table 2. Vitamin B12 Status Among Vegetarian Adults

Vitamin B12
Diet length of deficiency Prevalence of
Study Country Sample (Number, and age) adherence criteria B12 deficiency Vitamin B12 status

Methylmalonic acid
Refsum India N¼78 (LV: n¼77; vegans: n¼1), age range Not reported MMA4260 nmol/L 75% M MMA¼0.53 μmol/L
et al. 27–55 years
(2001)29
Herrmann Germany N¼41 (LV/LOV: n¼34, M age¼22 years [range Criteria of inclusion: 41 MMA4271 nmol/L LV/LOV: 32% LV/LOV: M MMA¼205
et al. 19.5–49.3]; vegans: n¼7, M age¼22 years year of constant dietary Vegans: 43% Vegans: M MMA¼246
(2001)30 [range 19–30]) pattern
Herrmann Germany, N¼95 LV/LOV: n¼66, M age¼48 years (range Criteria of inclusion: 41 MMA4271 nmol/L LV/LOV: 68% LV/LOV: M serum B12¼192
et al. Netherlands 24–75), and vegans: n¼29, M age¼37 years year of constant dietary Vegan: 83% (range 127–450)

Pawlak / Am J Prev Med 2015;48(6):e11–e26

(2003)36 (range 15–64) pattern Vegans: M serum B12¼148
(range 99–314) pmol/L

Obeid et al. Germany, N¼113 LV/LOV: n¼64, vegan: n¼29, Not reported MMA4271 58% for the entire LV/LOV: M serum B12¼192
(2002)40 Netherlands SV: n¼20), M (SD) age¼46 (15) sample pmol/L, MMA¼355 nmol/L
Vegans: M serum B12¼148
pmol/L, MMA¼708 nmol/L
SV: M serum B12¼218 pmol/
L, MMA¼206 nmol/L
Herrmann Germany, N¼111; M age¼46 (18–73) Not reported MMA4271 nmol/L 60% M MMA¼356 nmol/L
et al. Netherlands
(2003)41
Haddad U.S. N¼25 vegans, age range 20–60 years; 9 used 4.2 years MMA4376 nmol/L 20% M MMA¼316 nmol/L
et al. B12 supplements þ 4 used multivitamin
(1999)48 supplements
Herrmann Germany N¼164 LV/LOV: n¼114, M age¼50 years Not reported MMA (value not LV/LOV:57% LV/LOV: M MMA¼308 pmol/L
et al. (range 35–71) and vegans: n¼50, M age¼44 specified) Vegans:74% Vegans: M MMA¼698
(2005)37 years (range 20–66)
HoloTC
Refsum India N¼78 (LV: n¼77; vegans: n¼1), age range Not reported HoloTC IIo35 76% M holoTC II¼19.0 pmol/L
et al. 27–55 years pmol/L
(2001)29
Herrmann Germany, N¼95 Criteria of inclusion: 41 HoloTC IIo35 LV/LOV: 77%, LV/LOV: M serum B12¼192
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et al. Netherlands LV/LOV: n¼66, M age¼48 years (range 24– year of constant dietary pmol/L vegan: 92% (range 127–450)
(2003)36 75), and vegans: n¼29; M age¼37 years pattern Vegans: M serum B12¼148
(range (range 99–314) pmol/L
15–64)

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June 2015

Table 2. Vitamin B12 Status Among Vegetarian Adults (continued)

Vitamin B12
Diet length of deficiency Prevalence of
Study Country Sample (Number, and age) adherence criteria B12 deficiency Vitamin B12 status

Herrmann Germany N¼164 LV/LOV: n¼114, M age¼50 years Not reported HoloTC IIo35 LV/LOV: 61% LV/LOV: M holoTC
et al. (range 35–71); and vegans: n¼50, M age¼44 pmol/L Vegans: 76% II¼31 pmol/L
(2005)37 years (range 20–66) Vegans: M holoTC
II¼13 pmol/L
Herrmann Germany N¼111; M age¼46 (18–73) Not reported HoloTC IIo35 72% M holoTC II¼23 pmol/L
et al. Netherlands pmol/L
(2003)41
Status assessed by both MMA and holoTC

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Geisel et al. Germany N¼71 LV/LOV: n¼48 M age¼53 years (range Criteria of inclusion: 41 Both present: 58% LV/LOV: M serum B12¼180
(2005)39 21–75) and vegans: n¼23, M age¼51 years year of constant dietary HoloTC IIo35 pmol/L; HoloTC II¼40 pmol/
(range 28–76) pattern pmol/L and L; M MMA¼273
MMA4271 nmol/L Vegans: M serum B12¼145
pmol/L; HoloTC II¼22 pmol/
L; M MMA¼695

Herrmann Germany n¼54 LV/LOV from Germany, M age 50 years; Criteria of inclusion: Z2 Both present: German LV/LOV: from Germany:
et al. Oman n¼23 vegans from Germany, M age¼45 years; year of constant dietary holoTCo35 pmol/ vegetarians¼66%
(2009)42 and n¼19 LOV from India, M age¼45 years pattern L and MMA4271 Indian HoloTC II¼22; MMA¼424 n/
nmol/L vegetarians¼69% mol/L; M serum
B12¼163 pmol/L
Vegans: HoloTC II¼20;
MMA¼727 n/mol/L; M serum
B12¼138 pmol/L
Indian LOV: HoloTC II¼18;
MMA¼723 n/mol/L; M serum
B12¼107 pmol/L
Serum Vitamin B12
Refsum India N¼78 (LV: n¼77; vegans: n¼1), age range 27– Not reported Serum B12o150 60% M serum B12¼124 pmol/L
et al. 55 years pmol/L
(2001)29
Naik et al. India N¼51 LV (men: n¼15 women: n¼36); M Not reported Serum B12o148 56.9% M serum B12¼130 pmol/L; M
(2013)33 age¼27.6 years (range 26–30) pmol/L holoTC II¼19.6
Waldmann Germany N¼154 vegans (strict vegans: n¼98, M age M diet duration Serum B12o250 Strict Strict vegan: M serum
et al. 43.4⫾15.4 and moderate vegans: n¼56), M 7.70⫾6.40 – strict pmol/L vegan¼86.5% B12¼130 pmol/L
(2005)28 age 45.7⫾14.2 years 5.06⫾4.03 – moderate Moderate Moderate vegans: M serum
vegans¼69.1% B12¼187 pmol/L

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e17
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Table 2. Vitamin B12 Status Among Vegetarian Adults (continued)

Vitamin B12
Diet length of deficiency Prevalence of
Study Country Sample (Number, and age) adherence criteria B12 deficiency Vitamin B12 status

Mezzano Chile N¼26 (LV/LOV: n¼23, and vegans: n¼3; 41 year First criteria: serum First M serum B12¼166⫾89 pg/
et al. women: n¼14 and men: n¼12) M B12o100 pg/mL criteria¼26.9% mL
(1999)43 age¼39⫾12.7 years Second criteria: Second
serum criteria¼80.8%
B12o200 pg/mL
Haddad U.S. N¼25 vegans; age range 20–60 years; 9 used 4.2 years Serum B12o150 12% M serum B12¼312 pmol/L
et al. B12 supplements þ 4 used multivitamin pmol/L
(1999)48 supplements
Herrmann Germany N¼41 (LV/LOV: n¼34, M age¼22 years [range Criteria of inclusion: 41 Serum B12o156 LV/LOV: 6% LV/LOV: M serum
B12¼253pmol/L

Pawlak / Am J Prev Med 2015;48(6):e11–e26

et al. 19.5–49.3]; vegans: n¼7, M age¼22 years year of constant dietary pmol/L Vegans: 14%
(2001)30 [range 19–30]) pattern Vegans: M serum
B12¼217pmol/L
Bissoli et al. Italy N¼45 (vegans: n¼31, M age¼45.8⫾15.8 5 years Serum B12o127 Vegans: 47.8% M serum B12¼171.2⫾73.6
(2002)31 years; LV: n¼14, M age¼48.5⫾14.5 years) pmol/L LV: 33.3% pmol/L
Karabudak Turkey N¼26 Turkish women (SV: n¼7, LOV: n¼9, LV: Diet duration Serum B12o150 26.9% M serum
et al. n¼10), M age 29.0⫾8.84 years (range 20–50) 10.5⫾6.77 pmol/L B12¼200.5⫾137.28 pmol/L
(2008)32
Krivosikova Slovakia N¼141 LOV; M age¼41.9 years (range 20–70) “Long-term”—no details/ Serum B12r220 47% M serum B12¼246.9⫾161.3
et al. definition pmol/L pmol/L
(2010)35
Elmadfa Austria N¼78 (vegans: n¼42 and LOV: n¼36); age not Not reported Serumo110 Vegans¼2.4% Not reported
et al. reported pmol/L
(2009)22
Majchrzak Austria N¼78 (vegan: n¼42, M age¼30.7⫾9.9; and 67% of vegetarians and Serum B12o110 LOV¼0% LOV: M serum
et al. LOV: n¼36, M age¼34.2⫾13.6) vegans followed their pmol/L Vegan¼2.4% B12¼238.54⫾99.1 pmol/L
(2006)38 own diet for at least 5 Vegans: M
years B12¼203.17⫾101.5 pmol/L

Herrmann Germany, N¼111; M age¼46 (18–73) Not reported Serum B12o156 30% M serum B12¼156 pmol/L
et al. Netherlands pmol/L
(2003)41
B12 status without reported deficiency criteria or deficiency rate
www.ajpmonline.org

Hung et al. Taiwan, N¼45 LV women Not reported Not reported Not reported M serum
(2002)44 Buddhist Age range 31–45 years B12¼207.7⫾127.1 pmol/L

(continued on next page)

 Pawlak / Am J Prev Med 2015;48(6):e11–e26 e19
among 154 German vegans. The group was divided into

M serum B12¼265.2⫾179.3

M serum B12¼273.4⫾184.8

M serum B12¼191.8 pmol/L

strict and moderate (a maximum of 5% of the ingested

Vitamin B12 status

energy was derived from eggs, milk, or dairy products)
vegans. Elevated Hcy concentrations (410 μmol/L) were

range 164.0–220.0
present in 71.1% of strict vegans and 57.1% of moderate
vegans. Neither RBC folate nor vitamin B6 predicted Hcy
concentration. Vitamin B12 was the only predictor of Hcy

pmol/L

pmol/L
concentration among these participants (r’s¼–0.684,
po0.001, vs r’s¼0.033, po0.689, for RBC folate; r’s¼
–0.08, po0.342 for vitamin B6). Hcy concentration 410
μmol/L was found among 66% of the study participants
B12 deficiency
Prevalence of

Not reported

Not reported

Not reported
(combined strict and moderate vegans), of which 67%
had a serum B12 concentration of o150 pmol/L and 93%
had a concentration o250 pmol/L. Similar findings were
reported by Herrmann and colleagues36: Folate defi-
ciency, defined as serum folate o7 nmol/L, was not
found among any of the 66 LVs or LOVs or among the 29
Vitamin B12
deficiency

vegans. They did, however, find vitamin B12 to be the

criteria

Not reported

Not reported

Not reported

strongest predictor of Hcy (β coefficient for holotransco-

HoloTC II, holotranscobalamin; LOV, lacto-ovo-vegetarians; LV, lacto-vegetarians; MMA, methylmalonic acid; SV, semi-vegetarians.

balamin II¼–0.237, po0.001).

Karabudak et al.32 found a similar association between
vitamin B12 (regression correlation¼–0.969, po0.001)
but not folate (regression correlation¼0.004, po0.488)
M¼5.6 years (from 1.3

and serum Hcy among 26 Turkish women (mean [SD]

duration¼10.4⫾4.2

duration¼10.8⫾6.0
Diet length of
adherence

age¼29.0 [8.84] years). Serum vitamin B12 among 26

vegetarians from Chile was associated with Hcy in a
to 19 years)

study conducted by Mezzano and colleagues43 (Spear-

man correlation for serum B12¼–0.46, p¼0.017). They
M diet

M diet

years

did not find statistically significant correlations between

Hcy and serum folate (r¼–0.03, p¼not significant [NS]);
N¼57 healthy postmenopausal women (vegan:

N¼49 healthy postmenopausal LOV women, M

pyridoxal-5-phosphate (B6) (r¼0.27, p¼NS); or creati-

N¼37 (vegans: n¼3, LV: n¼18, LOV: n¼16)

nine (r¼0.27, p¼NS).

Table 2. Vitamin B12 Status Among Vegetarian Adults (continued)

Serum vitamin B12 concentration was the most sig-

Sample (Number, and age)

M age¼28.9 years (range 27.1–30.7)

nificant predictor of Hcy among the 31 vegans and 14

vegetarians (r¼–0.776, po0.001) included in a study of
Bissoli et al.31 The correlation between serum folate was
n¼51 and vegetarian: n¼6);

much weaker (r¼–0.34, po0.05). These authors also

M age¼59.2⫾6.4 years

concluded that their results supported the hypothesis

age¼58.6⫾6.0 years

that poor vitamin B12 status appears to explain hyper-

homocysteinemia among vegetarians.

Homocysteine and Atherogenesis

Studies have documented several mechanisms for the
role of hyperhomocysteinemia in atherogenesis, includ-
Country

ing auto-oxidation of Hcy, which leads to synthesis of

Taiwan

Taiwan

compounds associated with the initiation of atherogenic

processes, such as superoxide, hydrogen peroxide, super-
oxide anion, and hydroxyl radicals.49 These compounds
Huang et al.

have been implicated in atherogenesis via oxidation of

(2006)45

(2011)47

(2003)34
Su et al.

Su et al.

low-density lipoprotein, suppression of nitric oxide syn-

Study

thesis, arterial stiffness, endothelial inflammation, and

foam cell formation.49,50 Chronic hyperhomocysteinemia

June 2015
e20 Pawlak / Am J Prev Med 2015;48(6):e11–e26
Figure 1. Pathway of homocysteine metabolism.
reduces the activity of superoxide dismutase, an enzyme
that is important in the dismutation of superoxide
radicals.51 Elevated serum Hcy concentrations result
in suppression of endothelium-derived nitric oxide
synthesis. Nitric oxide plays a critical role in CVD
development by several mechanisms, including vaso-
anticonstricting and vaso-antiaggregating effects.52
Van Campenhout and colleagues53 found that Hcy is
present in advanced atheromas. They further docu-
mented a positive association between total Hcy concen-
tration and severity of aortic calcification. Mahalle et al.54
reported a negative association between vitamin B12 and
a positive association between Hcy and triglycerides, very
low-density lipoprotein, and C-reactive protein, respec-
tively. They also found a positive association of B12 and
an inverse association of total Hcy with high-density
lipoprotein.
The link between hyperhomocysteinemia and CVD is
supported by six of seven recent meta-analyses.18,19,55–59
These meta-analyses included data from prospective and
case-control studies.18,19 They also included data on the
impact of Hcy lowering on intima-media thickness and
flow-mediated vasodilation.55,56,59
Vitamin B12, Red Blood Cell Distribution
Width, Mean Corpuscular Volume, and
Circulatory Health Problems
In addition to vitamin B12 deficiency–induced hyper-
homocysteinemia, deficiency of this nutrient may
increase the risk of circulatory health problems via its
role in macrocytosis. Elevated MCV and RDW are
symptoms of vitamin B12 deficiency. RDW has been
associated with several circulatory problems. Tonelli and
colleagues60 reported a significantly increased risk of fatal
coronary disease and nonfatal myocardial infarction (8%
increase in risk for each 1% increase in RDW); stroke
(20% increase for each 1% increase in RDW); and
symptomatic heart failure (15% increase for each 1%
increase in RDW). Dabbah et al.61 found a progressively
increased risk of death among patients with acute
myocardial infarction with each of the higher quintiles
of RDW compared to the lowest quintile. The risk among
the extreme quintiles was 2.8 (95% CI¼1.6, 4.7, p for
trendo0.0001). RDW has been associated with morbid-
ity and mortality among heart failure patients from the
North American Candesartan in Heart Failure: Assess-
ment of Reduction in Mortality and Morbidity
(CHARM) Program (hazard ratio¼1.17 per 1-SD
increase, po0.001) and the Duke Databank (hazard
ratio¼1.29 per 1-SD increase, po0.001) cohorts.62
Petal and colleagues63 reported an increased death
from CVD for each quintile of RDW among individuals
aged Z45 years who participated in the 1988–1994
National Health and Nutrition Examination Survey.
The risk for the fifth quintile compared to the first
quintile was 2.9, 2.5, and 2.1, respectively, for each of the
three reported statistical models (Model 1 adjusted for
age, sex, and ethnicity; Model 2 additionally adjusted for
education, BMI, smoking status, hospitalizations, renal
function, hemoglobin concentration, MCV, and C-
reactive protein; and Model 3 additionally adjusted for
iron, folate, and vitamin B12 deficiency risk factors).
Mueller et al.64 showed an increased risk of peripheral
artery disease among patients with elevated MCV.
Discussion
The available data strongly support the hypothesis that
hyperhomocysteinemia is associated with atherogenesis.
Although Hcy concentration is a function of several
nutrients, the data equally strongly support that among
individuals with low methionine, adequate vitamin B6,
and high folate intake, low vitamin B12 status is the main
predictor of hyperhomocysteinemia.28 Furthermore, low
vitamin B12 status may increase the mortality and
morbidity from CVD due to factors other than hyper-
homocysteinemia, such as elevated RDW and MCV.
www.ajpmonline.org
 Pawlak / Am J Prev Med 2015;48(6):e11–e26
Consequently, vegetarians with low vitamin B12 status
are predisposed to developing circulatory health prob-
lems regardless of their favorable profile of traditional
heart disease risk factors. In fact, because of their low risk
of CVD mediated by traditional risk factors, it may be
correct to suggest that low vitamin B12 status and
hyperhomocysteinemia may play an even bigger role in
developing circulatory problems among vegetarians
compared with their non-vegetarian counterparts.
Although vegetarians do show a modest reduction in
CVD (Table 3), the described research findings support
the hypothesis that the compromised vitamin B12 status
that leads to hyperhomocysteinemia, elevated RDW, and
MCV largely negates these benefits.23
The hypothesis that low vitamin B12 and hyperhomo-
cysteinemia are risk factors for CVD is supported by data
from vegan individuals.12,28 Vegans consistently have
been shown to have the lowest vitamin B12 status and
highest Hcy concentration. At the same time, data show
that vegans have the best profile of all traditional risk
factors (serum glucose concentration, blood pressure,
serum lipids, and weight status). Yet, though some
studies have shown a reduced risk of circulatory health
problems among vegans compared with non-vegetarians,
other studies have reported a higher risk of CVD among
vegans compared with LOV and even non-vegetarians
(Table 3).12,28
Results of six of seven recent meta-analyses support
the association between hyperhomocysteinemia and
increased risk of CVD.18,19,55–59 However, only one of
two meta-analyses of randomized trials that assessed the
impact of Hcy lowering on CVD events supports the
association.58,59 Several explanations have been suggested
for the lack of reduction in CVD outcomes in interven-
tional studies with reduced Hcy concentration. Is it
possible that folic acid, B12, and vitamin B6 supplements
carry an undetermined adverse effect that negates any
benefits associated with Hcy reduction?65 Is it possible
that folic acid supplements stimulate cell proliferation
and plaque formation? Would the results of interven-
tional studies be different if the intervention to lower Hcy
concentration with folic acid would consist of adequate
food folate intake rather than synthetic folic acid? Is it
possible that Hcy concentration is a surrogate for another
causative agent?65
Taking a closer look at the individual studies included
in the meta-analysis of Clarke and colleagues66–72 may
also, at least in part, explain the lack of reduction in CVD
events. Folic acid supplementation was included in each
of the studies as the intervention agent. Although
reduction in Hcy concentration was reported among
the intervention group(s) in each of the groups that used
folic acid and B12 supplements, in only two of these
June 2015
e21
studies the post-intervention mean Hcy concentration
was substantially lower than 10 μmol/L; in two of them
it was about 10 μmol/L, and in two it was higher than
10 μmol/L. As stated previously, Jacobsen17 proposed
that an Hcy concentration of 10–15 mmol/L constitutes a
substantial CVD risk factor and that this risk should be
considered as a continuum: the higher the concentration,
the higher the risk. If Jacobsen were correct, the post-
intervention mean Hcy concentration in a bulk of the
participants of these studies would have been too high to
expect any reduction in CVD outcomes. Thus, results of
the trials that did not show improvements/reduction in
CVD outcomes in secondary prevention among high-
risk individuals may at least in part be attributed to
inadequate intervention results in terms of post-
intervention Hcy concentration. Although the meta-
analysis of Clarke et al.59 did not find a statistically
significant improvement in cardiovascular event occur-
rence or mortality within the median of 5 years of using
folic acid supplements to lower Hcy concentration (these
studies also used B12 supplements), ample evidence exists
to support a conclusion that hyperhomocysteinemia
promotes oxidative stress, inflammation, thrombosis,
endothelial dysfunction, and cell proliferation and thus
should be considered an atherogenic agent.59,60
Herrmann and colleagues36 suggested that their find-
ings, which showed the association between vitamin B12
and hyperhomocysteinemia, support the following rec-
ommendations: (1) to screen all vegetarians for vitamin
B12 deficiency and (2) that all vegetarians, regardless of
the type of vegetarian diet they adhere to, use vitamin B12
supplements. Taking an adequate dose of supplemental
vitamin B12 would virtually eliminate a deficiency among
vegetarians. Furthermore, findings reported by Kwok
et al.73 showed that 500 μg/day B12 supplementation for
12 weeks used by asymptomatic vegetarians not only
statistically significantly increased serum B12 (mean
baseline serum B12¼134.0 pmol/L vs 379.6 pmol/L at
12 weeks, p¼0.0001) and reduced Hcy (mean baseline
Hcy¼16.7 μmol/L vs 11.3 μmol/L at 12 weeks, p¼0.01)
concentrations but also improved flow-mediated dilation
of the brachial artery and intima–media thickness of the
carotid artery.
Unfortunately, recommending taking B12 supplements
may meet opposition among vegetarians because mis-
conceptions regarding this nutrient are prevalent. Many
individuals still hold on to the old myth that deficiency of
this vitamin is rare and occurs only in a small proportion
of vegans. This myth is accepted not only by some
vegetarians but also by some researchers.74 Future studies
with vegetarians should focus on identifying ways of
convincing vegetarians to routinely take vitamin B12
supplements in order to prevent a deficiency.
 e22
Table 3. Incidence and Mortality of Cardiovascular Disease, Ischemic Heart Disease, and Stroke Among Vegetarians and Non-Vegetarians

Incidence/prevalence vegetarians and/or vegan versus

Reference Country Study design non-vegetarians

Circulatory/cardiovascular disease
Key et al. United Kingdom EPIC-Oxford Study; N¼55,041 (32% vegetarians); age range¼20–89 DRR for all circulatory deaths¼0.93 (95% CI¼0.65, 1.32)
(2003)13 years
Key et al. United Kingdom EPIC-Oxford Study; N¼47,254; age range¼20–89 years DRR for circulatory diseases¼0.97 (95% CI¼0.78, 1.21)
(2009)75
Orlich et al. North America Adventist Health Study-2; N¼73,308; vegans: n¼5,548 and LOV: DHR for CVD:
(2013)12 n¼21,177; Vegans¼0.91 (95% CI¼0.71, 1.16); vegan men¼0.58 (95% CI¼0.38,
M age: vegans¼57.9 years; LOV¼57.5 years; non-vegetarians¼55.9 0.89), vegan women¼1.18 (95% CI¼0.88, 1.60)
years LOV¼0.90 (95% CI¼0.76, 1.06); LOV men¼0.77 (95% CI¼0.59,

Pawlak / Am J Prev Med 2015;48(6):e11–e26

0.99), LOV women¼0.99 (95% CI¼0.81, 1.22)

IHD
Key et al. United Kingdom Health Food Shoppers Study N¼10,736 (43% vegetarians) DRR for IHD mortality¼0.85 (95% CI¼0.71, 1.01)
(2003)13
Key et al. United Kingdom Oxford Vegetarian Study; N¼11,045 (42% vegetarians) DRR for IHD mortality¼0.86 (95% CI¼0.67, 1.12)
(2003)13
Key et al. United Kingdom EPIC-Oxford Study; N¼55,041 (32% vegetarians); participants’ age range: DRR for IHD mortality¼0.75 (95% CI¼0.41, 1.37)
(2003)13 20–89 years
Crowe United Kingdom EPIC-Oxford Study; N¼44,561 (34% vegetarians), age Z20 years Hazard ratio¼0.68 (95% CI¼0.58, 0.81); the cumulative probability of
et al. IHD between ages 50 and 70 years was 6.8% for non-vegetarians
(2013)76 compared with 4.6% for vegetarians
Key et al. United Kingdom EPIC-Oxford Study; N¼47,254; age range: 20–89 years DRR¼0.83 (95% CI¼0.59, 1.18)
(2009)75
Key et al. U.S. Adventist Mortality Study DRR¼0.748 (95% CI¼0.63, 0.88)
(1999)9 N¼24,538; vegetarians: n¼10,258
Key et al. United Kingdom Health Food Shoppers Study N¼9,878; vegetarians: n¼3,790 DRR¼0.97 (95% CI¼0.81, 1.16)
(1999)9
Key et al. U.S. Adventist Health Study; N¼28,952; vegetarians: n¼8,003 DRR in AHS¼0.62 (95% CI¼0.53, 0.73)
(1999)9
www.ajpmonline.org

Key et al. Germany Heidelberg Study N¼1,757; vegetarians: n¼1,083 DRR¼0.45 (95% CI¼0.22, 0.95)
(1999)9
Key et al. United Kingdom Oxford Vegetarian Study; N¼11,047; vegetarians: n¼4,674 DRR¼0.90 (95% CI¼0.68, 1.20)
(1999)9

(continued on next page)

June 2015

Table 3. Incidence and Mortality of Cardiovascular Disease, Ischemic Heart Disease, and Stroke Among Vegetarians and Non-Vegetarians (continued)

Incidence/prevalence vegetarians and/or vegan versus

Reference Country Study design non-vegetarians

Key et al. U.S., United Combined effect of five studies Adventist Mortality Study, Health Food DRR¼0.93 (95% CI¼0.62, 0.94)
(1999)9 Kingdom, Shoppers Study, Adventist Health Study, Heidelberg Study, and Oxford
Germany Vegetarian Study; N¼76,172; vegetarians: n¼27,808
Orlich et al. North America Adventist Health Study-2; N¼73,308; vegans: n¼5,548 and LOV: Hazard ratio:
(2013)12 n¼21,177 Vegans¼0.90 (95% CI¼0.60, 1.33); vegan men¼0.45 (95% CI¼0.21,
M age; vegans¼57.9 years; vegetarians¼57.5 years; non- 0.94), vegan women¼1.39 (95% CI¼0.87, 2.24)
vegetarians¼55.9 years LOV¼0.82 (95% CI¼0.62, 1.06); LOV men¼0.76 (95% CI¼0.52, 1.12)

Pawlak / Am J Prev Med 2015;48(6):e11–e26

Vegan woman¼0.85 (95% CI¼0.59, 1.22)

Cerebrovascular disease
Key et al. United Kingdom EPIC-Oxford Study; N¼55,041 (32% vegetarians); participants’ age range: DRR¼1.13 (95% CI¼0.65, 1.96)
(2003)13 20–89 years
Key et al. United Kingdom EPIC-Oxford Study DRR¼1.10 (95% CI¼0.77, 1.58)
(2009)75 N¼47,254
Key et al. U.S. Adventist Mortality Study; N¼24,538; vegetarians: n¼10,258 DRR¼0.65 (95% CI¼ 0.48, 0.87)
(1999)9
Key et al. United Kingdom Health Food Shoppers Study N¼9,878; vegetarians: n¼3,790 DRR¼0.99 (95% CI¼0.78, 1.26)
(1999)9
Key et al. U.S. Adventist Health Study; N¼28,952; vegetarians: n¼8,003 DRR¼0.93 (95% CI¼0.73, 1.19)
(1999)9
Key et al. Germany Heidelberg Study; N¼1,757; vegetarians: n¼1,083 DRR¼1.69 (95% CI¼0.69, 4.15)
(1999)9
Key et al. United Kingdom Oxford Vegetarian Study; N¼11,047; vegetarians: n¼4,674 DRR¼1.17 (95% CI¼0.76, 1.80)
(1999)9
Key et al. U.S., United Combined effect of five studies Adventist Mortality Study, Health Food DRR¼0.93 (95% CI¼0.74, 1.17)
(1999)9 Kingdom, Shoppers Study, Adventist Health Study, Heidelberg Study, and Oxford
Germany Vegetarian Study; N¼76,172; vegetarians: n¼27,808

CVD, cardiovascular disease; DHR, death hazard ratio; DRR, death rate ratio; EPIC, European Prospective Investigation into Cancer and Nutrition; IHD, ischemic heart disease; LOV, lacto-ovo-vegetarian.

e23
e24 Pawlak / Am J Prev Med 2015;48(6):e11–e26
Limitations
This study represents a non-systematic review of the
literature and, therefore, may not have included all
pertinent studies. To the author’s knowledge, no study
to date has assessed the risk of CVD incidence or
mortality among vegetarians based on vitamin B12 status.
Only one published study assessed the impact of improv-
ing vitamin B12 status of vegetarians via the use of
vitamin B12 supplements on CVD indices.73 Based on
available studies, it is not possible to assess how much of
the potential risk for CVD in vegetarians may be
accounted for by inadequate vitamin B12 status. Any
potential cardio-protective benefits of improved vitamin
B12 status needs to be confirmed in additional studies.
Conclusions
Although vegetarians have an improved profile of tradi-
tional heart disease risk factors in comparison to non-
vegetarians, available findings show only a modest
decrease in CVD prevalence. The low status of vitamin
B12 among vegetarians that results in hyperhomocystei-
nemia, elevated RDW, and MCV predisposes them to
CVD development and may negate the benefits associ-
ated with their traditional risk factor profile. Health
professionals should find ways to convince vegetarians
of the importance of improving their vitamin B12
concentration.11,26
No financial disclosures were reported by the author of
this paper.
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