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European Journal of Clinical Nutrition (2009) 63, 18–30
& 2009 Macmillan Publishers Limited All rights reserved 0954-3007/09 $32.00
www.nature.com/ejcn
ORIGINAL ARTICLE
Dietary intake and status of folate and vitamin B12
and their association with homocysteine and
cardiovascular disease in European populations
RAM Dhonukshe-Rutten1, JHM de Vries1, A de Bree2, N van der Put2, WA van Staveren1 and
LCPGM de Groot1
1
Department of Human Nutrition, Wageningen University, Netherlands and 2Unilever Food and Health Research Institute,
Vlaardingen, Netherlands
Background/Objectives: Folate and vitamin B12 have been suggested to play a role in chronic diseases like cardiovascular
diseases. The objectives are to give an overview of the actual intake and status of folate and vitamin B12 in general populations in
Europe, and to evaluate these in view of the current vitamin recommendations and the homocysteine concentration.
Methods: Searches in Medline with ‘folic acid’, ‘folate’ and ‘vitamin B12’, ‘B12’ or ‘cobalamin’ as key words were combined
with the names of the European countries. Populations between 18 and 65 years were included.
Results: Sixty-three articles reporting on studies from 15 European countries were selected. Low folate intakes were observed in
Norway, Sweden, Denmark and the Netherlands. Low intakes of vitamin B12 were not common and only seen in one small
Greek study. In the countries with a low intake of folate, the recommended levels were generally not achieved, which was also
reflected in the folate status. Vitamin B12 intake was not strongly associated with the vitamin B12 status, which can explain why
in the Netherlands and Germany the vitamin B12 status was inadequate, despite sufficient intake levels. In countries with a low
folate intake in particular, the Hcy concentration was higher than ideal.
Conclusions: Populations from the Nordic countries, the Netherlands, Germany and Greece may need to improve their intakes
of folic acid, B12 or both to either meet the recommendations or to optimize their statuses. This could be achieved via a food-
based approach, food fortification or supplements.
European Journal of Clinical Nutrition (2009) 63, 18–30; doi:10.1038/sj.ejcn.1602897; published online 12 September 2007
Keywords: folic acid; folate; vitamin B12; homocysteine; vascular disease
Introduction explained via homocysteine (Hcy), though conclusive trial
evidence of lowering Hcy is still required to have sufficient
Much attention has been given to B-vitamins, in particular power to detect plausible differences in risk at convincing
to folate and vitamin B12, because of their potential levels of significance (Anonymous, 2006).
influence on cardiovascular diseases (CVD) (Folsom et al., Folate is present in a wide range of foods such as
1998; Rimm et al., 1998; Eikelboom et al., 1999; Chambers vegetables, bread, dairy products, liver and fruits. Folic acid
et al., 2001; Schnyder et al., 2001; Voutilainen et al., 2001, is the synthetic form of folate present in supplements and in
2004), cognitive function (Selhub et al., 2000; Malouf et al., fortified foods. Foods rich in vitamin B12 are dairy products,
2003; Tucker et al., 2005) and bone health (McLean et al., meat, liver, fish, eggs and shellfish. Supplementation with
2004; van Meurs et al., 2004; Sato et al., 2005). The link folic acid and vitamin B12 can reduce Hcy concentrations by
between these B-vitamins and CVD is suggested to be, partly, approximately 32% in the general population (Anonymous,
2005; Verhoef and de Groot, 2005).
The important role that folate and vitamin B12 could play in
Correspondence: Dr RAM Dhonukshe-Rutten, Department of Human health maintenance has triggered our interest in the adequacy of
Nutrition, Wageningen University, PO Box 8129, NL-6700 EV Wageningen, the status of these B vitamins. We evaluated (1) the actual dietary
Netherlands.
intake of folate and vitamin B12 and (2) the actual folate,
E-mail: rosalie.dhonukshe-rutten@wur.nl
Received 12 October 2006; revised 20 June 2007; accepted 18 July 2007; vitamin B12 and Hcy status in European populations, taking into
published online 12 September 2007 account the recommended intakes and the association with Hcy.Dietary intake and status of folate and vitamin B12 in European populations
RAM Dhonukshe-Rutten et al
19
Methods in pg ml1 were converted into pmol l1 by multiplying with
0.738. Homocysteine levels in fasting blood samples were
Literature search mainly determined with the high-performance liquid chro-
A computerized MEDLINE search, from January 1990 matography method. In case another method, the fluores-
through December 2005, was used to identify (English) cence polarization immunoassay (IMx) method, was used to
papers that reported on folate or vitamin B12 intake or status determine Hcy concentration, then it is mentioned in the
in general population-based samples. The key words ‘folic footnote of the related table.
acid’, ‘folate’ and ‘vitamin B12’, ‘B12’ or ‘cobalamin’ were
combined with the names of the European countries in the
search. As our main interest was the intake and status of Correlations of folate, vitamin B12 and homocysteine
folate and vitamin B12, we did not include a search term for Information on correlations or associations between intake
‘homocysteine’. We included Hcy status only when data on or status of folate, vitamin B12 and Hcy are presented only
Hcy status were available in the identified articles. In when this information was provided in the articles.
addition, we checked reference lists for additional relevant A total of 49 articles reported on dietary intake (Table 1) or
studies. Authors were approached in case we were not able to status (Table 2) in 15 European countries. Twenty-nine
obtain their articles (n ¼ 12). articles from 12 countries were identified, which provided
information on intake of folate and/or vitamin B12. Thirty
articles from 13 countries provided information on status of
Study populations folate and/or vitamin B12. Only 10 articles reported on both
Articles dealing with European populations older than or intake and status.
equal to 18 years, and younger than or equal to 65 years were Several articles reported on the same study populations;
included. A few exceptions were made when studies articles providing the least information were excluded from
concerned broader age groups (for example, 25–74 years). this review.
Only studies containing data of more than 100 apparently
healthy adults (men or women) were included. For case–
control studies (such as cancer studies), only data from Results
control groups were used. Studies focussing on pregnant or
lactating women or on people from non-European origin Intake of folate
(because of their different dietary pattern) were not included. Average folate intake ranged from 205 to 431 mg day1 in the
Studies that a priori divided subjects by specific character- diet of men and from 186 to 465 mg day1 in women (Table 1).
istics such as smoking status or genetic polymorphisms were The range of mean folate intake in the studies that combined
not included. Finally, when a paper did not clearly define the the intake of men and women was smaller: 190–290 mg day1
study group, it was not included. (eight studies).
In general, men had a higher mean folate intake than
women within studies. Based on data of Schroder et al.
Assessment of dietary intake and status (2004), it could be postulated that men and women have
No specific selection criteria were used regarding the more similar intake levels when intakes are adjusted for
assessment methods to select the papers of interest. Thus, energy intake.
different dietary methods are reported in this paper, includ- No clear North–South gradient in the intakes of folate was
ing dietary records (2, 3, 4 or 7 days), 24 h recalls, dietary observed across Europe. Most favourable intakes
histories and food frequency questionnaires. In principle, (4350 mg day1) were observed in two study populations in
data on B-vitamin intake originating from the diet itself are the United Kingdom (Kirk et al., 1999; Davey et al., 2003;
shown, and not from supplements. When the method of Cade et al., 2004). Moderate folate intakes (250–350 mg day1)
dietary assessment was not clearly described, the study was were observed in Finland, Ireland, Germany, France, Italy,
not included. Several studies did not provide information on Spain (except for the study of Planells et al., 2003) and
the method used for determination of folate and vitamin Greece. Low intakes (o250 mg day1) were observed in
B12 in the food composition tables. Norway, Sweden, Denmark, The Netherlands and in one
Most studies determined folate and vitamin B12 status by Spanish study (Planells et al., 2003).
radio(immuno)assay, by IMx or by using microbiological
assays on microtitre plates with a chloramphenicol-resistant
strain of Lactobacillus casei and a colistin sulphate-resistant Intake of vitamin B12
strain of Lactobacillus leichmanni, for folate and vitamin B12 Average vitamin B12 intake ranged from 0.4 to 11.0 mg day1
respectively. When the microbiological method was used, in the diet of men and from 0.5 to 7.1 mg day1 in women
this is indicated in the footnote of the related table. Folate (Table 1). After excluding the low intake of vegans, it ranged
status given in ng ml1 were converted into nmol l1 by from 2.6 to 11.0 mg day1 in men and from 2.5 to 7.1 mg day1
multiplying with 2.266. Vitamin B12 concentrations given in women. Vitamin B12 intake in studies of men and women
European Journal of Clinical Nutrition20
European Journal of Clinical Nutrition Table 1 Dietary intake of folate and vitamin B12 in general European populations
Country, reference Dietary Age (mean n Sex Folate in Vitamin B12 in Remarks
Dietary intake and status of folate and vitamin B12 in European populations
assessment or range) mg day1(s.d. or mg day1 (s.d. or
range) range)
Finland
Hartman et al. (2001) FFQ 50–69 300 M 331 (100) 11.0 (4.5) ATBC study, controls
Alfthan et al. (2003) 24 h 25–74 318 M 275 10.5 FINRISK study.
325 F 230 7.4 Data for vitamin B12 are estimated based on a diet
containing 2500 kcal day1 for men and 2000
kcal day1 for women.
Tolmunen et al. (2004) 4d 42–60 2313 M 256 (76) 9.5 (9.5) KIHD study
Norway
Brevik et al. (2005) FFQ 47–49 1216 M 240 (80) Hordaland Homocysteine Study; includes intake from
supplements and minus the loss from cooking
1622 F 209 (69)
RAM Dhonukshe-Rutten et al
Sweden
Van Guelpen et al. (2005) FFQ 30, 40, 50, 671 MF 242 (201, 299)a 5.7 (4.1, 7.9)a Northern Sweden Health and Disease Cohort, 55%
60 men
Denmark
Friis et al. (1997) 4d 20–29 122 F 241 (83) 4.3 (2.1)
United Kingdom
Kirk et al. (1999) FFQ 33–72 5413 F 371 (141) 5.4 (3.5) UKWCS, non-supplement users
Brunner et al. (2001) 7d 39–61 457 M 266 (85) Whitehall II
403 F 229 (68)
Davey et al. (2003) FFQ 35–69 6951 M 329 (102) 7.3 (3.9) Meat-eaters
22962 F 321 (100) 7.0 (3.3)
1500 M 358 (117) 5.0 (2.9) Fish-eaters
6931 F 346 (113) 4.9 (2.8)
3748 M 367 (120) 2.6 (1.4) Vegetarians
12347 F 350 (121) 2.5 (1.3)
770 M 431 (162) 0.4 (0.6) Vegans
1342 F 412 (158) 0.5 (0.7)
Cade et al. (2004) FFQ 35–69 35372 F 404 (146) Total sample UKWCS
24738 F 397 (142) Meat-eaters
870 F 465 (176) Oily fish-eaters
3286 F 416 (143) Other fish-eaters
6478 F 416 (154) Vegetarians
Roddam et al. (2005) 7d 50–64 12221 F 253 4 Million Women Study
Wilmink et al. (2004) FFQ 450 306 M 324 (99) 6.8 (3.7)
Prynne et al. (2005) 5 d food diary 53 562 M 311 (302, 317) 6.3 (5.9, 6.6) British Birth Cohort
691 F 257 (252, 265) 5.1 (4.7, 5.3)
Ireland
O’Brien et al. (2001) 7 d food diary 18–35 253 M 339 (135) 5.0 (2.5) The North/South Ireland Food Consumption Survey
269 F 247 (120) 3.6 (3.1)
36–50 236 M 339 (128) 5.6 (4.3)
286 F 267 (141) 4.5 (4.3)
51–64 173 M 314 (115) 5.8 (4.4)
162 F 268 (182) 4.2 (3.0)Table 1 Continued
Country, reference Dietary Age (mean n Sex Folate in Vitamin B12 in Remarks
assessment or range) mg day1(s.d. or mg day1 (s.d. or
range) range)
Netherlands
Botterweck et al. (2000) FFQ 55–69 3123 MF 290 (77) NLCS
Konings et al. (2001) 2d 16–92 4691 MF 192 (112) Dutch National Food Consumption Survey, non-
supplement users
de Bree et al. (2001a) FFQ 20–65 1275 M 239 (73) 5.7 (2.8) MORGEN study
1160 F 192 (54) 4.3 (2.1)
van den Donk et al. (2005) FFQ 18–75 709 MF 190 (53) 4.5 (2.0) POLIEP study, controls, 38% men
Germany
Beitz et al. (2002) DH 18–79 1763 M 276 (271, 279) 7.2 (7.0, 7.3) Also data available on % below reference
2267 F 229 (227, 233) 4.7 (4.6, 4.8)
Wolters et al. (2003) 3d 60–70 178 F 318 (96) 5.1 (3.3)
Thorand et al. (1998) Questionnaire 39–74 106 F 213 (68, 553) Controls of the (Berlin) EURAMIC study
Mensink and Beitz (2004) FFQ 18–79 581 M 302 (291, 314) 9.0 (8.6, 9.4) East Germany
815 F 281 (248, 313) 6.0 (5.6, 6.4)
1182 M 314 (307, 320) 7.7 (7.4, 7.9) West Germany
1452 F 305 (286, 324) 5.6 (5.3, 5.8)
France
Mennen et al. (2002) 6 times 24 h 45–60 310 M 306 (88) 7.5 (5.0) French supplementation with antioxidant vitamins and
minerals study
35–60 306 F 268 (92) 6.3 (4.5)
RAM Dhonukshe-Rutten et al
Dietary intake and status of folate and vitamin B12 in European populations
Italy
Sofi et al. (2005) FFQ 20–60 211 M 345 (140)
309 F 339 (121)
Spain
Schroder et al. (2004) 3d 25–34 120 M 242 5.0
134 F 266 4.9
35–44 149 M 278 5.1
163 F 291 4.9
45–54 152 M 279 5.5
174 F 295 4.8
55–64 177 M 294 5.6
191 F 288 4.8
Planells et al. (2003) 2d 25–60 1816 M 205 (117) 7.2 (8.7)
1712 F 197 (105) 5.7 (7.2)
25–39 1836 MF 197 (120) 6.4 (8.1)
40–49 780 MF 207 (124) 6.7 (8.1)
50–60 912 MF 211 (112) 6.3 (8.2)
Aranceta et al. (2001) 24 h 25–60 4728 M 267 (108) 9.5 (8.5) Regional population nutrition surveys at different
European Journal of Clinical Nutrition
places in Spain
5480 F 252 (103) 7.1 (7.1)
Henriquez et al. (2004) FFQ 18–75 601 MF 248.5 (239.0, 258.4) 43% men
Greece
Vrentzos et al. (2004) 3d 40–77 152 MF 254 (68, 1105) 2.2 (0.1, 18.7) 83% men
Abbreviations: DH, dietary history; FFQ, food frequency questionnaire; FI, fat intake questionnaire; 24 h, 24-h dietary record; 4 d, 4-day food record.
a
Interquartile range.
21Dietary intake and status of folate and vitamin B12 in European populations
RAM Dhonukshe-Rutten et al
22
Table 2 National and international recommendations of folate and Vitamin B12 intake was above the country-specific
vitamin B12 recommendations for all countries, except for the Greek
Country, reference Folate (mg day1) Vitamin B12 (mg day1) population and the vegetarians in the United Kingdom.
Finland 300 2
Norway 300 2 Status of folate, vitamin B12 and homocysteine
Sweden 300 2
Folate status ranged from 6.3 to 20.1 nmol l1 (Table 3). No
Denmark 300 2
United Kingdom 200 1.5 obvious differences existed in status indicators between men
Ireland 300 1.4 and women. Within countries most studies revealed a
Netherlands 300 2.8 comparable folate status, except for three studies in Sweden,
Germany 400 3
which uncovered large differences in average folate status
France 300 2.4
Italy 200 2 ranging from 7.2 to 17.9 nmol l1.
Spain 200 2 We define a folate status lower than 10 nmol l1 as ‘low’, a
Greece 200 2.4 status between 10 and 15 nmol l1 as ‘moderate’ and a status
European Union 200 2.4
above 15 nmol l1 as ‘favourable’. Favourable levels were
Reference: Scientific Committee on Food (SCF, 2003). observed in one Swedish study (Wahlin et al., 2002), and in
the United Kingdom, Germany and Spain. A moderate folate
status was observed in Finland, Ireland, the Czech Republic,
Portugal and Italy. A low status was found in Norway,
together ranged from 2.2 to 6.7 mg day1 (four studies). Sweden (Hultdin et al., 2005; Van Guelpen et al., 2005),
Similar to folate, within studies men tended to have a higher Netherlands and Greece.
vitamin B12 intake than women. Vitamin B12 levels ranged from 222 to 460 pmol l1. Most
Although no clear North–South gradient in the intakes of studies showed vitamin B12 concentrations around
vitamin B12 can be observed in the European countries, the 350 pmol l1. No clear differences were present between
highest intakes of vitamin B12 were observed consistently in men and women.
three Finnish studies and the lowest intake of vitamin B12 On average, the vitamin B12 status of the study popula-
(o2.5 mg day1) was found in Greece (Vrentzos et al., 2004). tions in Finland, Norway, Sweden, the United Kingdom and
In Sweden, Germany, France and Spain the mean vitamin Spain were favourable (4350 pmol l1). Vitamin B12 levels
B12 intake was high (45 mg day1) as well. Note however, in Swedish and Greek studies indicated a moderate status
that in Sweden and France only one study was available. (300–350 pmol l1). Finally, a marginal average vitamin B12
Countries with moderate-to-high (2.5–5 mg day1) intakes status (o300 pmol l1) occurred in study populations from
were Denmark, Ireland and The Netherlands. The popula- the Netherlands, Germany, in one Czech study (Vesela et al.,
tions in the United Kingdom had a large variance in vitamin 2005) and in one Italian study (Sofi et al., 2005).
B12 intake which was mainly due to the type of diet; vitamin Homocysteine levels differed to a great extent between
B12 intake decreased by following a more vegetarian diet. countries: from 7.1 to 14.8 mmol l1. Overall, Hcy levels were
Overall, the English had a moderate-to-high vitamin B12 consistently higher in men than in women within the
intake. same studies. Fasting plasma Hcy concentrations below
15 mmol l1 are generally regarded as ‘normal’, whereas
concentrations above 15 mmol l1 are considered as ‘elevated’
(Refsum et al., 2004). Concentrations below 10 mmol l1 are
Meeting the national recommendations? seen as ‘ideal’. Only two countries presented an ideal average
Within Europe, different recommendations defined as Hcy concentration: Ireland and Portugal, but only one study
recommended daily allowances or adequate intakes, exist was available for each country (Brown et al., 2003; Castro
for folate and vitamin B12 intake (Table 2). Recommenda- et al., 2003). Other populations with Hcy concentrations
tions vary between 200 and 400 mg day1 for folate and close to 10 mmol l1 were Norway, the United Kingdom,
between 1.4 and 3.0 mg day1 for vitamin B12 (SCF, 2003). Germany, Czech Republic, France and Spain. In Finland and
In Finland, the United Kingdom, Ireland, France, Italy, Italy, Hcy concentration varied greatly. The higher Hcy
Spain and Greece, study populations had a mean folate concentration in the Finnish ATBC study was because the
intake at or above their respective national recommenda- cohort consisted of male smokers (Hartman et al., 2001). The
tions. In Norway, Sweden, Denmark, Netherlands and highest Hcy concentrations, close to 15 mmol l1, were seen
Germany, mean folate intake levels were lower than the in the Netherlands and Sweden.
recommendations. It is important to notice that even when
the population mean intake equals the recommended
intake, this still means that many (in case of a normal Intake reflected in status
distribution: 50%) people do not achieve the recommended We examined whether intake of folate and vitamin B12 is
intake level. reflected in its status (Table 4). Folate intake was repeatedly
European Journal of Clinical NutritionTable 3 Status of homocysteine, folate and vitamin B12 in general European populations
Country, reference Age (mean or n Sex Plasma/serum Serum vitamin B12 Serum/plasma Hcy Comments
range) folate in in pmol l1 (s.d. or in mmol l1 (s.d. or
nmol l1 (s.d. range) range)
or range)
Finland
Voutilainen et al. (2004) 46–64 749 M 10.5 (3.9) 10.8 (3.4) KIHD study; no acute coronary event
Alfthan et al. (2003) 25–74 318 M 14.6 (6.6) 371 (132) 11.3 (3.6) FINRISK study
325 F 14.3 (8.6) 391 (164) 9.2 (2.8)
Hartman et al. (2001) 50–69 300 M 9.7 (4.1)z 460 (152) 13.4 (7.0) ATBC study, controls
Norway
Nurk et al. (2004)a 41–42 1658 M 6.7 (0.1) 370 (3) 10.3 (9.0, 12.0)b Hordaland Homocysteine study
2058 F 6.9 (0.1) 337 (3) 8.8 (7.6, 10.5)b
65–67 1461 M 6.8 (0.1) 360 (7) 11.9 (10.1, 13.9)b
1854 F 7.8 (0.1) 391 (9) 10.6 (9.1, 12.5)b
Brevik et al. (2005)a 47–49 1216 M 7.3 (3.9) 10.8 (3.5) Hordaland Homocysteine Study
1622 F 8.5 (6.1) 9.1 (3.4)
Christensen et al. (1999) 45–75 103 MF 10.9 (3.0) 70.9% men
Sweden
Hultdin et al. (2005)d 40, 50, 60 514 M 8.8 (5.3) 300 (104) 13.2 (7.3) Northern Sweden Health and Disease Cohort
Wahlin et al. (2002) 35–80 961 MF 17.9 (10.9) 313 (136) 47% men
35, 40 197 MF 332 (112)
40, 45 194 MF 325 (110)
45, 60 194 MF 310 (104)
Van Guelpen et al. (2005) 30, 40, 50, 60 671 MF 7.2 (5.0, 9.9)b 316 (256, 388)b Northern Sweden Health and Disease Cohort, 55%
men (median)
RAM Dhonukshe-Rutten et al
Dietary intake and status of folate and vitamin B12 in European populations
United Kingdom
Chambers et al. (2000) 35–60 507 M 16.0 (7.6) 357 (158) 10.2 (2.9)
Ireland
Brown et al. (2003) 20–26 357 M 12.7 (3.2, 21.3) 8.9 (4.2, 44.6) Young Hearts Population
29–53 565 M 10.9 (3.4, 45.3) 7.1 (1.6, 58.5) Industrial Workers Population (different methods for
Hcy analyses than in YHP)
Netherlands
Melse-Boonstra et al. (2002)a 20–65 1275 M 8.4 (4.2) MORGEN study
1160 F 8.1 (4.0)
de Bree et al. (2001b) 20–65 1493 M 14.6 (6.1) MORGEN study
1532 F 13.1 (4.6)
de Bree et al. (2003a) 20–65 2051 MF 7.4 (2.4, 22.4) 284 (102, 638) 13.6 (7.8, 39.5) MORGEN study, 53% men
Verhoef et al. (1997) 25–65 100 MF 248 (97) 12.5 (5.7) 74% men
Durga et al. (2005) 50–70 801 MF 12 (10, 15) 289 (242, 264) 13.8 (12.8, 15.4) 72% men
Germany
European Journal of Clinical Nutrition
Rauh et al. (2001) 26–50 172 F 16.5 (7.7)c 345 (106)c 9.2 (3.3)
Wolters et al. (2003)d 60–70 178 F 20.1 (6.7) 290 (98) 9.9 (2.4)
Dierkes et al. (2001) 40–65 189 M 17.1 (10.1, 26.1) 222 (131, 399) 10.8 (7.4, 17.6)
40–65 147 F 16.4 (10.6, 30.0) 230 (125, 447) 9.0 (5.9, 14.1)
Czech
Mayer et al. (2001) 35–65 292 M 13.6 (0.2)c 359 (9)
251 F 14.5 (0.5)c 397 (14)
2324
European Journal of Clinical Nutrition Table 3 Continued
Dietary intake and status of folate and vitamin B12 in European populations
Country, reference Age (mean or n Sex Plasma/serum Serum vitamin B12 Serum/plasma Hcy Comments
range) folate in in pmol l1 (s.d. or in mmol l1 (s.d. or
nmol l1 (s.d. range) range)
or range)
Country, reference Age (mean or n Sex Plasma/serum Serum vitamin B12 Serum/plasma Hcy Comments
range) folate in in pmol l1 (s.d. or in mmol l1 (s.d. or
nmol l1 (s.d. range) range)
or range)
Vesela et al. (2005) 18–65 511 MF 14 (10.6, 17.7) 278 (215, 364) 9.6 (8.2, 11.3) Healthy folate non-users, 47% male, 53% female
France
Mennen et al. (2002)a 35–40 232 F 8.1 (7.7, 8.4) French supplementation with antioxidant vitamins and
minerals study
RAM Dhonukshe-Rutten et al
40–45 302 F 8.6 (8.3, 8.9)
45–50 343 M 10.4 (10.0, 10.7)
45–50 290 F 8.7 (8.4, 9.1)
50–55 290 M 11.1 (10.7, 11.5)
50–55 213 F 9.3 (9.0, 9.7)
55–60 281 M 11.1 (10.7, 11.5)
55–60 146 F 9.2 (8.7, 9.6)
Italy
Cafolla et al. (2000) 20–60 99 M 10.7 (3.6) 434 (174) Blood donors
102 F 11.3 (3.0) 422 (162)
Sofi et al. (2005)d 20–60 211 M 11.8 (5.7)c 281 (131)c 11.2 (4.3, 70.6)
309 F 12.7 (5.9) 294 (141)c 9.5 (5.2, 27)
Girelli et al. (2003) 57.5 (13) 222 MF 13 (12.3, 13.9) 304 (290, 319) 14.7 (14, 15.5) No coronary atherosclerotic disease, 64% men
Spain
Planells et al. (2003) 25–60 183 M 14.7 (14.7)c 367 (367)c
201 F 16.6 (16.6) 376 (376)c
25–39 194 MF 15.9 (8.2) 396 (173)c
40–49 74 MF 15.4 (7.0) 314 (145)c
50–60 116 MF 15.6 (8.8) 364 (183)c
Reyes-Engel et al. (2002)d 25–50 194 MF 10.4 (2.1)
51–75 198 MF 11.4 (3.6)
Henriquez et al. (2004) 18–75 601 MF 17.8 (17.3, 18.2) 326 (313, 339) 43% men
Portugal
Castro et al. (2003)d 20–69 117 MF 14.8 (15.4, 18.2) 8.8 (8.6, 9.6)
Greece
Vrentzos et al. (2004)d 40–77 152 MF 7.9 (2.4, 15.5) 326 (91, 835) 12.5 (6.6, 44.7) Controls, 83% men
Abbreviation: Hcy, homocysteine.
a
Microbiological method was used to determine folate and vitamin B12 concentrations.
b
Interquartile range.
c
Converted from ng ml1 into nmol l1.
d
Fluorescence polarization immunoassay (IMx) method was used to determine homocysteine concentration.Dietary intake and status of folate and vitamin B12 in European populations
RAM Dhonukshe-Rutten et al
25
Table 4 Associations between folate and vitamin B12 intake and status data, and with homocysteine concentrations
Folate Vitamin B12
Intake ¼ status Intake-Hcy Status-Hcy Intake-status Intake-Hcy Status-Hcy
Alfthan et al. (2003) N/A Inverse trend* 0.23* N/A N/A 0.16*
Glynn et al. (1996) 0.22* N/A N/A N/A N/A N/A
Hartman et al. (2001) 0.26 N/A 0.32* 0.10 N/A 0.20*
Breviket al. (2005) 0.13* 0.37* N/A N/A N/A N/A
Hultdin et al. (2005) N/A N/A 0.46* N/A N/A 0.23*
Van Guelpen et al. (2005) 0.24* N/A 0.43* -0.01 N/A 0.22*
Wolters et al. (2003) 0.20* N/A 0.42* N/A N/A 0.21*
Rauh et al. (2001) N/A N/A 0.56* N/A N/A 0.49*
Girelli et al. (1998) N/A N/A 0.38* N/A N/A 0.25
Planells et al. (2003) N/A N/A N/A 0.15* N/A N/A
de Bree et al. (2001a) N/A Inverse trend* N/A N/A Inverse trend* N/A
Mennen et al. (2002) Positive trend* N/A Inverse trend* N/A N/A Inverse trend
Sofi et al. (2005) Positive trend* N/A Inverse trend* No association N/A Inverse trend*
Abbreviation: Hcy, homocysteine.
*Po0.01.
N/A: data not available.
significant but weakly correlated with folate status with B-vitamins is adequate. Inadequate folate intakes were seen
rB0.2 (Po0.01). Significant positive associations were also in Norway, Sweden, Denmark and Netherlands; intakes were
found in two other studies (Mennen et al., 2002; Sofi et al., below 250 mg day1 and for Netherlands even below
2005) according to trend analysis (by quartiles) and linear 200 mg day1. Not surprisingly, the national recommenda-
regression analysis. tions for folate were not achieved in these countries. This
Three studies reported inverse associations between folate was also the case with Germany, but the recommendation in
intake and Hcy status; Brevik et al. (2005) calculated a this country is set at a higher level, that is 400 vs
correlation of 0.37 (Po0.01), Alfthan et al. (2003) and de 300 mg day1 in Norway, Sweden, Denmark and Netherlands.
Bree et al. (2001a) found inverse significant associations The low folate intake levels were reflected in a low folate
(P for trend) in tertiles and quintiles, respectively. status within the same study populations (de Bree et al.,
An inverse association between folate status and Hcy levels 2001a, 2003a; Brevik et al., 2005; Van Guelpen et al., 2005).
was consistently reported in the majority of the studies. The However, studies with data on folate status but not on
correlations varied between 0.23 and 0.56. Also, Mennen intake, supported the notion that folate status in the above-
et al. (2002) and Sofi et al. (2005), observed significant mentioned countries was low (Nurk et al., 2004; Hultdin
associations within their trend analysis (Po0.0001). et al., 2005). As a result, the Hcy levels in the Netherlands
Rarely, vitamin B12 intake was strongly correlated with and Sweden were also relatively high.
vitamin B12 status. Sofi et al. (2005) did not observe The intake of vitamin B12 was in general adequate, with
significant associations between vitamin B12 intake and the exceptions of intake in British vegans (Davey et al., 2003)
Hcy status in their linear regression analysis. In none of the and in a small Greek study population (Vrentzos et al., 2004).
studies the correlation of vitamin B12 intake with Hcy status Yet the Greek did not have an inadequately low vitamin B12
was assessed. de Bree et al. (2001a) performed a P-test for status. Likewise, the mean intake level of vitamin B12 in the
trend: Hcy status was inversely associated with vitamin B12 Netherlands and Germany lay far above the recommended
intake per quintile (Po0.001). level; nevertheless, the vitamin B12 status in these countries
Vitamin B12 correlated consistently and significantly was inadequate. The absence of a clear cut relation between
inversely with Hcy; with correlations between 0.16 and vitamin B12 intake and status is also illustrated by the data
0.49. Also Mennen et al. (2002) and Sofi et al. (2005) in Table 4. The relatively low vitamin B12 status in Dutch
observed associations within their trend analysis (respec- subjects could also have contributed to the somewhat higher
tively P ¼ 0.06 and 0.01). Hcy concentrations in this country. Reasons for no associa-
tion of vitamin B12 intake and status have to do with the
Discussion many causes of vitamin B12 malabsorption. Malabsorption is
mainly present in elderly people (Baik and Russell, 1999).
Main findings Moreover, because vitamin B12 is the best stored of all
We reviewed intakes and status of folate, vitamin B12 and vitamins, with enough stores to last 3–5 years in a normal
Hcy in general populations (p65 years) from 15 European replete subject, there is no association between its intake and
countries to evaluate whether intake and status of these status in adults.
European Journal of Clinical NutritionDietary intake and status of folate and vitamin B12 in European populations
RAM Dhonukshe-Rutten et al
26
Differences within countries are partly explained by the X800 mg day1 is typically required to achieve the maximal
fact that some populations consisted solely of women (for reduction in plasma Hcy concentrations (Anonymous,
example, Roddam et al., 2005) and others solely of men (for 2005). Daily doses of 400 mg day1 are associated with 90%
example, Wilmink et al., 2004). Men had in general a higher of the maximum reduction in blood Hcy concentrations
intake of folate and vitamin B12 than women, an effect that (van Oort et al., 2003; Anonymous, 2005).
is probably reduced when corrections for energy intake are Also vitamin B12 recommendations are re-evaluated for a
applied (Schroder et al., 2004). Explaining differences potential adjustment towards a higher level, especially for
between countries remains speculative, but is probably elderly (465 years), as deficiencies mainly occur in this
mainly due to the type of diet. This is clearly illustrated in group (Baik and Russell, 1999). Although this age group was
a British study where meat-eaters had lower intakes of folate beyond the scope of this article, it is illustrative that doses
than vegetarians and vegans (Davey et al., 2003). Another 4200 times greater than the recommended dietary allow-
study in the United Kingdom also showed slightly higher ance are required to obtain a normal vitamin B12 status in
intakes of folate in vegetarians and fish-eaters than in meat- elderly people (Eussen et al., 2005). These high doses, which
eaters. Considering vitamin B12, the opposite occurred with ensure passive absorption (in humans), might be required for
lower vitamin B12 intakes in fish-eaters, vegetarians and elderly with (mild) vitamin B12 deficiency or with absorp-
vegans as compared to meat-eaters (Cade et al., 2004). tion problems and are attainable with supplements rather
than with food (such as meat and dairy products). It is less
certain whether such high doses are also required for a
Value of these intake data general adult population, as Bor et al. (2006) showed that a
When intake figures are compared between countries, it daily intake of 6 mg was sufficient to normalize all vitamin
should be realized that methodological differences between B12-related variables in 98 Danish postmenopausal women.
studies are a source of variation in folate intake. The several
methods used to collect dietary information have their own
advantages and disadvantages, which can potentially have Extrapolations
led to an over- or underestimation of the habitual intake It is important to discuss to what extent these data can be
(McNulty, 1995). Moreover, the nutrient databases could generalized to the ‘European population’. First, for this
differ from each other. The low folate and vitamin B12 intake inventory, as many studies as possible were identified that
observed in some study populations could be due to a contained relevant data. We did not include data of large
genuine low intake or to a nutrient database which has lower national surveys because these surveys in general do not
values for folate and vitamin B12 contents in food products have data on biochemical markers of intake, which would
(because of different analysis methods) than databases in complicate relating intake data to status data within a
other countries. country. We are aware that there is probably more informa-
Furthermore, data based on long-term habitual consump- tion available on folate and vitamin B12 data in the original
tion provide more stable intake estimates than data based on language of the European countries. The question remains
short-term intake (Cameron and Van Staveren, 1988). Only a whether this information has the same quality (which was
few studies in this review estimated the dietary intake with a one of the criteria for the articles to be included in this
single 24-h dietary record. When we compare these dietary review) as articles published in scientific, English-written,
intakes with the other studies within the same country, the peer-reviewed journals. Moreover, the articles we reviewed
intakes seem to be similar. are accessible for everybody. Second, despite our efforts, the
final number of included studies was 63 of which only 13
studies contained information on both intake and status.
Judging adequacy Third, we collected information from general, apparently
While comparing intakes with national and international healthy study populations and from control groups in cohort
recommendations, we have to be aware that recommenda- or case–control studies. Especially, the latter group makes it
tions are calculated to be sufficient to meet the basic nutrient more complicated to be able to generalize our findings.
requirements of nearly all individuals in the group (mean þ 2 Moreover, the selection of a general population, existing of
s.d.). The recommendations are not set to achieve optimal volunteers, could have led to an inclusion of a more healthy
health effects, for this goal, higher levels may be required. population because volunteers generally follow a more
Currently, the labelling reference value for folate, as set by favourable lifestyle profile (Verschuren et al., 1993). Further-
the Scientific Committee on Food, is 200 mg day1. Only more, we selected studies with study samples of larger than
Italy, Spain and Greece agree with this level. All other 100 people. This number of subjects is arbritary and there-
countries use a recommended level of 300 or even fore it remains questionable whether some of the included
400 mg day1. Presently, folate recommendations are under studies are indeed too small to represent a certain country.
debate in several European countries partly because higher Therefore we should be genuinely cautious and may rely
intakes might be required to obtain low Hcy concentrations. more on the national food composition surveys mainly
For example, a meta-analysis showed that folic acid of published in the original language of the countries. Using a
European Journal of Clinical NutritionDietary intake and status of folate and vitamin B12 in European populations
RAM Dhonukshe-Rutten et al
27
true random sample of the European population would been raised on the effectiveness of folate and vitamin B12
almost certainly result in higher prevalence of low folate and supplementation on CVD as outcome measure. The first
vitamin B12 intake and status, and high Hcy status. Fourth, results came from the Vitamin Intervention for Stroke
an important problem with estimating the folate and Prevention (VISP) trial (Toole et al., 2004), the Norwegian
vitamin B12 intake is the lack and unreliability of the folate Vitamin trial (NORVIT) (Bonaa et al., 2006) and the Heart
and vitamin B12 content data in food composition tables. Outcomes Prevention Evaluation 2 study (HOPE) (Lonn
This problem can lead to an underestimation of the actual et al., 2006). Supplements combining folic acid and vitamins
intake (Black et al., 1985). Finally, differences exist not only B6 and B12 did not reduce the risk of major (recurrent)
between laboratories but also between methods used for vascular outcomes in patients with (cardio)vascular disease.
determination of folate, vitamin B12 and Hcy status. As In the NORVIT trial, folic acid and vitamin B12 treatment
described in the Methods section, three methods were used was even associated with a nonsignificant increase in risk of
for determination of folate and vitamin B12 concentrations. recurrent myocardial infarction, stroke or sudden death.
Bolann et al. (2000) did not find a significant bias for serum Positive findings were observed in a subgroup of patients in
cobalamin values, so cobalamin values from different studies the VISP trial. In these patients, who were not already taking
can readily be compared with each other. The judgment of B12 supplements and not having B12 malabsorption or renal
cobalamin status remains however controversial because for failure, survival was improved (Spence et al., 2005). Also in
example, a ‘low’ cobalamin value may not represent a the HOPE-2 trial, fewer incidents of stroke occurred in the
metabolic-deficient cobalamin status. Therefore, it would treatment group compared to the placebo group. Never-
be better to judge cobalamin concentrations in combination theless, these studies have been performed in patients, and
with elevated methylmalonic acid and/or Hcy concentra- therefore conclusions cannot be generalized to the healthy
tions (Klee, 2000). For folate, the IMx method gave 6% population. The strength of association of Hcy with risk of
higher results than the radioassay method. Two methods CVD may be weaker than had previously been believed
were used for determination of Hcy concentrations. These (2006).
differences in method are known to influence the measure- Examining the studies included in this review, only 10
ment of Hcy levels (Pfeiffer et al., 2000; Caliskan et al., 2001; studies reported on associations of folate, vitamin B12 and
Zappacosta et al., 2002). Moreover, serum yields slightly Hcy with CVDs (Verhoef et al., 1997; Girelli et al., 1998, 2003;
higher Hcy values than plasma, while optimally collected Christensen et al., 1999; Chambers et al., 2000; de Bree et al.,
ethylenediaminetetraacetic acid or heparin plasma gives 2003b; Nurk et al., 2004; Voutilainen et al., 2004; Vrentzos
identical results and citrated plasma yields lower Hcy values et al., 2004; Durga et al., 2005; Van Guelpen et al., 2005).
(Refsum et al., 2004). Homocysteine status was positively associated with several
We did not observe a North–South gradient in intake or outcome measures of CVD in 8 out of 10 studies. Folate and
status of folate, vitamin B12 and Hcy, while de Bree et al. vitamin B12 were less often investigated in association to
(1997), who studied folate intake in national food consump- CVD, respectively in six and three studies. The findings were
tion surveys, observed a North–South gradient with lower not consistent but tended to go into the direction of an
folate intakes in the Northern countries. Differences in folate inverse association of folate intake or status with CVD and
intake may have partly reflected differences in dietary habits no association of vitamin B12 intake or status with CVD.
among European countries, with the Mediterranean diet
providing more folate-rich foods. The national food con-
sumption surveys may better reflect the dietary habits across What can be done about low intake/status?
European countries than the studies we included in this As indicated in this review, several European countries do
review. not have adequate folate and vitamin B12 intakes with
respect to the recommendations, and also with respect to the
status of these B-vitamins and Hcy concentration. To achieve
Folate, vitamin B12, homocysteine and cardiovascular diseases health benefits, intakes should probably be higher than the
Folate, vitamin B12 and Hcy are believed to play a role in the recommendations. Several approaches to increase the intake
development of CVD. Cohort and case–cohort studies of folate and vitamin B12 are possible (Finglas et al., 2006);
suggest that low intake and low levels of serum or (a) a food-based approach which includes a healthy lifestyle
erythrocyte folate, independent of Hcy concentrations, are consisting of a diet rich in green leafy vegetables (rich in
associated with vascular disease morbidity and mortality. folate and betaine), meat and dairy products (rich in vitamin
Data from several but not all prospective studies showed a B12), together with a moderate coffee and protein intake. It
reduced risk of CVD and stroke associated with high folate should also be emphasized to select foods with high folate
intake or blood concentrations (see for an overview Eikel- content and advice should be given which household
boom et al., 1999; Schwammenthal and Tanne, 2004). preparation method can be used (McKillop et al., 2002).
A meta-analysis has found that a 2.6 mmol l1 higher Hcy Different processing treatments can influence the bioacces-
was associated with a 13% (95% CI 8–19%) increase in risk of sibility of folate from vegetables. Freezing and high-pressure
CVD (Anonymous, 2002). However, recently some doubt has treatments are promising approaches for improving the
European Journal of Clinical NutritionDietary intake and status of folate and vitamin B12 in European populations
RAM Dhonukshe-Rutten et al
28
bioaccessibility of folate from vegetables. (b) Consumption Conflict of interest
of food products rich in folate and vitamin B12 or by food None declared.
fortification. Different types of food fortification exist: (1)
biofortification by traditional breeding methods or genetic
modification; and (2) food fortification by industry in
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