Folic acid supplement decreases the homocysteine increasing effect of filtered coffee. A randomised placebo-controlled study

European Journal of Clinical Nutrition volume 57, pages1411–1417(2003)Cite this article

Abstract

Objective: Elevated levels of plasma total homocysteine (tHcy) are identified as independent risk factors for coronary heart disease and for fetal neural tube defects. tHcy levels are negatively associated with folic acid, pyridoxine and cobalamine, and positively associated with coffee consumption and smoking. A total of 600 ml of filtered coffee results in a tHcy increase that 200 μg of folic acid or 40 mg of pyridoxine supplementation might eliminate.

Design: Randomised, blinded study with two consecutive trial periods.

Setting: Free living population. Volunteers.

Subjects: A total of 121 healthy, nonsmoking men and women (78%) aged 29–65 y.

Interventions: (1) A coffee-free period of 3 weeks, (2) 600 ml coffee/day and a supplement of 200 μg folic acid/day or placebo for 4 weeks, (3) 3-week coffee-free period, (4) 600 ml coffee/day and 40 mg pyridoxine/day or placebo for 4 weeks.

Main outcome measures: The difference between the change in tHcy in the supplement group and the change in tHcy in the placebo group during the 4-week trial period.

Results: Coffee abstention resulted in a tHcy decrease of 1.04 μmol/l for the whole group. In the subsequent coffee period, a further decrease of 0.17 μmol/l was observed in the folic acid group whereas an increase of 1.26 μmol/l was observed in the placebo group, the difference was 1.43 μmol/l (95% CI: 0.80, 2.07). Pyridoxine supplement had no impact on tHcy levels.

Conclusions: Supplementation of 200 μg folic acid/day eliminates the tHcy increasing effect of 600 ml filtered coffee in subjects not already on folic acid supplements. A supplement of 40 mg pyridoxine/day does not have the same effect.

Sponsorship: None.

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Introduction

Elevated concentrations of the endogenous sulphur amino compound, homocysteine (total homocysteine, tHcy), have been identified as an independent risk factor for coronary heart disease (Clarke et al, 1991; Boushey et al, 1995; Ueland et al, 2000), recurrent early spontaneous abortions (Wouters et al, 1993; Goddijn-Wessel et al, 1996; Nelen et al, 2000), neural tube defects (Vollset et al, 2000a, 2000b; Refsum, 2001) as well as other reproductive and fetal hazards (Leeda et al, 1998; Sorensen et al, 1999). The levels of plasma and serum tHcy are increased not only in folate deficiency, but also at folate levels in the lower reference range (Jacobsen et al, 1994). tHcy levels are also depending upon the availability of the other B-vitamins, pyridoxine (vitamin B6) and cobalamine (vitamin B12). These associations are reflected in population studies such as the Hordaland Homocysteine Study where the major determinants for tHcy variation were age, sex, smoking, dietary folic acid intake, vitamin supplements and coffee consumption (Nygard et al, 1995). The relation between coffee and tHcy has been observed in a number of cross-sectional studies around the world and the effect of coffee on tHcy varies between 0.8 and 1.3 μmol/l for a change in coffee consumption of three to four cups (Stolzenberg-Solomon et al, 1999; Jacques et al, 2001; Saw et al, 2001), and 1.1–2.3 μmol/l for a difference of 6–9 cups/day (Nygard et al, 1997; Oshaug et al, 1998; de Bree et al, 2001). A causal role of coffee intake has been shown in three published intervention studies (Grubben et al, 2000; Urgert et al, 2000; Christensen et al, 2001). Grubben et al (2000) demonstrated that very high doses of unfiltered coffee increased the levels of tHcy by 1.2 μmol/l, whereas a more recent study showed that abstaining from filtered brewed coffee was associated with a decrease in the serum tHcy by 1.08 μmol/l (Christensen et al, 2001). Urgert showed that 1 l of filtered coffee/daily for 3–4 weeks resulted in a tHcy increment of 1.5 μmol/l (Urgert et al, 2000). These consistent findings across both the cross-sectional and the intervention studies suggest that coffee does play an important role on determining the tHcy level.

At this stage, no biological mechanism is known that could explain why the intake of coffee may affect the concentrations of tHcy. The fact that both filtered and unfiltered coffee are associated in a dose–response manner with tHcy makes diterpenes (which are occurring at higher concentrations in unfiltered coffee, Bak, 1990) a less likely causal factor. These consistent findings also raised the question whether it is possible to reduce the coffee-induced tHcy increase by agents known to reduce homocysteine such as folic acid or pyridoxine (Mansoor et al, 1999; Wald et al, 2001).

A randomised placebo-controlled intervention study was therefore undertaken to assess whether a given dose of folic acid (200 μg) or pyridoxine supplements (40 mg) might eliminate the total homocysteine raising effect of 600 ml (four cups) of filtered brewed coffee, a commonly used dose in coffee-consuming populations (Nygard et al, 1997; Christensen et al, 2001; de Bree et al, 2001).

Subjects and methods

Trial design and estimation of magnitude of effects and number of participants

The study was organised as a prospective, blinded controlled, study with two consecutive trial periods, starting with folic acid supplements during the first period followed by pyridoxine in the next period (Figure 1). The participants were randomly allocated to either placebo or active supplementation in each trial period. Prior to both the trial periods and randomisation, a washout period of 3 weeks of coffee abstention was inserted. The main outcome or effect variable was plasma total homocysteine and the effect was assessed as the difference between the first measurement after the coffee-free washout period and the measurement after 4 weeks on coffee+folic acid or coffee+placebo and coffee+pyridoxine/placebo, respectively. The difference between the coffee+folic acid group and the coffee+placebo group was expected to be 1.50 μmol/l or greater, and standard deviation 0.5, an assumption based on earlier intervention studies (Grubben et al, 2000; Urgert et al, 2000; Christensen et al, 2001). With a power of 80% (80% probability for detecting this difference if it is there) and a significance level of 0.05, 80 subjects were needed to assess this effect. Trial duration of 3–4 weeks has previously been shown to be sufficient to get an effect of coffee on tHcy (Grubben et al, 2000; Urgert et al, 2000; Christensen et al, 2001).

Figure 1

Study design.

Full size image

Pilot study and dosage of pyridoxine and folic acid supplements

In total, 10 healthy women took part in a pilot study for 3 weeks to determine the dose of pyridoxine in the main study. Five persons were given 40 mg/day of pyridoxine and five persons were given 80 mg/day. There were no differences in tHcy changes between the two groups. Tablets of 40 mg were easily available and hence, for this practical reason, were used. These doses correspond with previous intervention studies using 25–50 mg (den Heijer et al, 1998; Bosy-Westphal et al, 2001; van Guldener and Stehouwer, 2001).

There was a decrease in s-folate for all 10 participants in the pilot study, which corresponds to the studies of Mansoor (1999) and Bosy-Westphal (2001).

The dosage of folic acid supplement was set to 200 μg/day, which corresponds to a change in homocysteine levels of 0.1–2.5 μmol dependent on initial tHcy levels (Wald et al, 2001). The current recommendation of folic acid in Sweden is 300 μg/day for the general population, and 400 μg for pregnant women (Swedish Recommended Allowances, 1997).

Subjects and procedure

Participants were recruited by advertising in Gothenburg's major newspaper. Inclusion criteria were age range 30–65 y, free from clinically recognised chronic diseases, such as cardiovascular diseases, cancer, renal disorders, liver disease and diabetes mellitus. The participants were required to be free from antiepileptic or cholesterol-lowering drugs, and free from vitamin B supplements. They had been using coffee on a regular basis for at least 5 y and were currently nonsmokers (at least for the last 6 months).

Subsequent to the first coffee abstaining period of 3 weeks (the washout period), the participants were instructed to drink 600 ml (four cups) of filtered brewed coffee/day and received a supplement of either 200 μg of folic acid/day or placebo for a 4-week period. The coffee was provided so that all were exposed to the same brand and quality of filtered brewed coffee.

After this trial period and following another 3 weeks of coffee abstention, the participants were again asked to take up drinking four cups of coffee/day and were given a supplement of 40 mg pyridoxine/day or placebo for another 4-week period.

Any divergence from the four cups was reported. The participants were allowed to drink tea and other caffeine-containing beverages during the coffee-free periods.

The randomisation procedure was carried out by a third part not associated to the study. Randomisation to the pyridoxine trial was made independently of the folic acid trial randomisation; thus, participants who received active substance in the folic acid trial period had equal chance of being allocated to the active or placebo group in the pyridoxine trial period.

Effect variables

The blood samples were analysed for plasma homocysteine and folate concentrations in serum. Nonfasting blood samples were drawn at inclusion and at 3, 7, 10 and 14 weeks after start of the trial. Plasma was prepared from EDTA-blood within 2 h after storage at 4°C, whereas serum was prepared from centrifuged blood without additives after storage at room temperature. Prior to analysis, prepared serum and plasma were stored at −70°C for up to 2 months.

Plasma tHcy was determined by the Abbott IMX homocysteine assay (Abbot Laboratories, Abbot Park, IL, USA). Folate concentrations were analysed by the ADVIA Centaur System. Biochemical measurements of pyridoxine status were not available. Body mass index (BMI; kg/m2) was recorded once during the study. Blood pressure was recorded by manual devices. EKG and heart rate was recorded on all five visits.

Dietary survey

Dietary habits with special emphasis on folic acid- and pyridoxine-containing food were assessed by a food frequency questionnaire throughout the trial. The questionnaire was based upon a Norwegian version (Nes et al, 1992). The purpose of the food frequency questionnaire was to demonstrate whether the intake of folic acid- and pyridoxine-containing food items did differ between the coffee+active and the coffee+placebo groups, or changed during the study period. The first interview aimed at assessing the food frequency intake. During the four subsequent interviews, the participants were asked if they had changed their food habits in relation to the baseline examination.

Statistical methods

All analyses were performed using the SAS© software. The statistical significance of the differences was assessed by Student's t-test. P-values <0.05 were considered statistically significant. 95 % confidence intervals (CI) were calculated and are presented.

Results

Of the 156 persons who responded to the advertisement, 124 fulfilled the inclusion criteria and were able to participate in the study. Three persons decided to withdraw during the study, leaving a total of 121 participants. One person was not able to take part during the folic acid trial and five persons were not able to take part in the pyridoxine trial, resulting in 120 participants in the folic acid trial and 116 in the pyridoxine trial.

Average coffee intake prior to the study was 3.9 cups/day (s.d. 1.83) for the 121 participants. Table 1 shows the effect of the two 3-week period of coffee abstention (washout) for all participants. Plasma homocysteine decreased by 1.04 μmol/l (95% CI: −1.45, −0.62) in the first coffee abstention period. Both plasma homocysteine and serum folate decreased significantly during the second coffee abstention period and returned to levels close to those seen at the end of the first period of coffee abstention.

Table 1 Mean levels and differences of tHcy, folate, blood pressure and heart rate after the 3 weeks periods of coffee abstention prior to the folic acid trial (week 0 to week 3, n=120) and prior to the pyridoxine trial (week 7 to week 10, n=116)
Full size table

Age, sex and the mean levels of the effect variables after randomisation for the folic acid trial are given in Table 2. There were no important differences between the two groups. During the 4 weeks of coffee exposure, plasma homocysteine concentrations in the coffee+placebo group increased by 1.26 μmol/l, whereas a decrease of 0.17 μmol/l was observed in the coffee+folic acid group resulting in a difference of 1.43 μmol/l (95% CI: 0.80, 2.07) between the groups. Table 3 shows the results of the pyridoxine trial. There were no differences in age, sex and effect variables between the coffee+pyridoxine and the coffee+placebo groups after randomisation. The supplementation with pyridoxine had no effect on the plasma homocysteine concentrations after 4 weeks on 600 ml of coffee/day. Serum folate was increased by 0.86 nmol/l in the coffee +pyridoxine group and 4.72 nmol/l in the coffee+placebo group, resulting in a difference of 3.86 nmol/l (95% CI: 1.93, 5.79).

Table 2 Mean levels of tHcy, folate, blood pressure, heart rate, BMI, age and sex after randomisation in the folic acid triala
Full size table
Table 3 Mean levels of tHcy, folate, blood pressure, heart rate, BMI, age and sex after randomisation in the pyridoxine triala
Full size table

The dietary survey showed that the intake of folic acid- and pyridoxine-containing food did not differ between the active and placebo groups during both the trial periods, apart from the intake of orange juice and raspberry, which was higher in the coffee+folic acid group at baseline. Six persons reported coffee consumption during the coffee abstention period in the folic acid trial (mean 1.8 cups/period) and four persons reported coffee consumption in the pyridoxine trial (mean 0.7 cups/period). The following variables concerning coffee consumption and compliance were registered: cups of coffee during the coffee abstention and coffee consumption periods, number of days on or off coffee, and number of pills during these periods. None of these variables differed between the active and the placebo groups in the two trial periods.

Discussion

Our study showed that 3 weeks of coffee abstention was associated with a tHcy decrease of 1. 04 μmol/l among non smoking regular coffee drinkers, drinking on average 3.9 cups of coffee/day and not already taking vitamin B supplements. During the subsequent randomised controlled trial, a 4-week period with 600 ml filtered coffee a day was associated with an increase in plasma tHcy levels by 1.26 μmol/l among those who received an inactive substance, whereas a further decrease of 0.17 μmol/l was observed among those receiving 200 μg of folic acid. Thus, a total difference of 1.43 μmol/l was observed between the coffee+folic acid group and the coffee+placebo group. Pyridoxine supplement did not, however, show a similar effect. The higher serum folate levels of week 7 are because of the folate supplementation given to half of the participants during the preceding 4 weeks. The increased serum folate levels in the coffee+placebo group during the pyridoxine trial period were surprising, and we are so far inclined to explain this as chance.

The observed effects of coffee on plasma tHcy support previous relations from cross-sectional studies and trials, in which it was shown that coffee abstention will decrease plasma homocysteine concentrations or that coffee exposure will increase the levels (Nygard et al, 1997; Oshaug et al, 1998; Stolzenberg-Solomon et al, 1999; Grubben et al, 2000; Urgert et al, 2000; Christensen et al, 2001; de Bree et al 2001; Jacques et al 2001; Koehler et al, 2001; Saw et al, 2001). The observed decline in tHcy corresponds to the results of Christensen et al (2001), who showed that coffee abstention of 6 weeks was associated with a 1.08 μmol reduction in tHcy levels. The plasma tHcy concentrations increased by 1.26 μmol following another 4 weeks of renewed coffee consumption in the present study. This can be compared to Grubben et al (2000), who showed that 1 l unfiltered coffee/day for 2 weeks increased the tHcy levels by 1.2 μmol/l and Urgert et al (2000), who demonstrated that a 4-week period of coffee abstention resulted in a tHcy levels decrease of 1.3 μmol/l, whereas 1 l/day of filtered coffee for 4 weeks increased the tHcy with 1.5 μmol/l.

The strengths of the present study are that it was a blinded, randomised study, planned and performed with a specific hypothesis based upon previous studies on the same issue. The major weakness of the study is the pyridoxine branch and the problems in determining an adequate dosage of pyridoxine.

Our study demonstrated that folate supplement of 200 μg, in subjects not already taking folic acid supplements, reduced the homocysteine raising effect of coffee in healthy nonsmoking persons by 1.43 μmol/l, whereas pyridoxine supplement did not have any effect. The effect of 200 μg folate on plasma tHcy levels is similar to what was observed in a recent intervention trial by Wald et al (2001), who investigated the effect of different folic acid doses on tHcy levels.

These consistent findings from both cross-sectional studies and trials imply that substances in coffee interfere with the methionine metabolism.

Three different chemical factors, chlorogenic acid (Olthof et al, 2001), diterpenes (Grubben et al, 2000) and caffeine (Nygard et al, 1997; Grubben et al, 2000; de Bree et al, 2001), have been suggested as biologically active substances responsible for the coffee–homocysteine association. The possible role of chlorogenic acid suggested by Olthof et al (2001) has to be corroborated by other studies. Diterpenes are, as mentioned above, unlikely candidates as the effects on tHcy levels are seen both with filtered and unfiltered coffee, which differ considerably with regard to the content of diterpenes (Bak, 1990). At present, caffeine seems a more likely candidate (Nygard et al, 1997; Grubben et al, 2000; de Bree et al, 2001). This is also suggested by the findings in the Hordaland Homocysteine study (Nygard et al, 1997) and the study of Jacques et al (2001), where the use of decaffeinated coffee not was shown to be related to the tHcy concentration. The other cross-sectional studies (Stolzenberg-Solomon et al, 1999; de Bree et al, 2001; Koehler et al, 2001; Saw et al, 2001) report no information about intake of decaffeinated coffee.

The amount of caffeine in tea is approximately half of that of coffee. The Hordaland Homocysteine study showed a weak increasing effect of tHcy associated with tea drinking, suggesting that the tHcy reductions might have been even larger if both coffee and tea were restricted (Nygard et al, 1997).

The lack of effect of pyridoxine supplementation is difficult to explain. It may be because of a very low dosage (40 mg) of pyridoxine (Mansoor et al, 1999), or that an effect of pyridoxine of this dosage is effective only when given together with folic acid and cobalamine (Ubbink et al, 1994), or chance.

There are three main public health concerns with regard to increased plasma homocysteine levels: increased risk of cardiovascular diseases (Clarke et al, 1991; Boushey et al, 1995; Ueland et al, 2000), reproductive hazards (Wouters et al, 1993; Goddijn-Wessel et al, 1996; Leeda et al, 1998; Sorensen et al, 1999; Nelen et al, 2000; Vollset et al, 2000a, 2000b; Refsum, 2001) and the possible association to cognitive disorders (Clarke et al, 1998; McCaddon et al, 2001; Seshadri et al, 2002). The effect of increased plasma homocysteine levels on certain reproductive hazards is currently accepted as causal, whereas the effect on coronary heart disease is still under investigation and awaits the results of intervention studies (Ubbink & Delport, 2000; Ueland et al, 2000). The association between tHcy and reproductive hazards is, however, well established and confined not only to high tHcy levels, but also to the central tHcy (5–15 μmol/l) distribution (Vollset et al, 2000a, 2000b). Whether the coffee–tHcy association has any effect on reproductive hazards is by no means established. The coffee–tHcy association is on the other hand remarkably consistent, as demonstrated by six published cross-sectional studies (Nygard et al, 1997; Oshaug et al, 1998; Stolzenberg-Solomon et al, 1999; de Bree et al, 2001; Jacques et al, 2001; Saw et al, 2001) comprising altogether 22 485 subjects, and four intervention studies (Grubben et al, 2000; Urgert et al, 2000; Christensen et al, 2001) including the present. The true relation between tHcy and cognitive disorders is not clarified and awaits the results of further prospective studies and trials (Smith, 2002).

References

  1. Bak A (1990): Coffee and Cardiovascular Risk; An Epidemiological Study. Rotterdam: Erasmus Univerisity.

    Google Scholar 

  2. Bosy-Westphal A, Holzapfel A, Czech N & Müller MJ (2001): Plasma folate but not vitamin B(12) or homocysteine concentrations are reduced after short-term vitamin B(6) supplementation. Ann. Nutr. Metab. 45, 255–258.

    CAS  Article  Google Scholar 

  3. Boushey CJ, Beresford SA, Omenn GS & Motulsky AG (1995): A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA 274, 1049–1057.

    CAS  Article  Google Scholar 

  4. Christensen B, Mosdol A, Retterstol L, Landaas S & Thelle DS (2001): Abstention from filtered coffee reduces the concentrations of plasma homocysteine and serum cholesterol—a randomized controlled trial. Am. J. Clin. Nutr. 74, 302–307.

    CAS  Article  Google Scholar 

  5. Clarke R, Daly L, Robinson K, Naughten E, Cahalane S, Fowler B & Graham I (1991): Hyperhomocysteinemia: an independent risk factor for vascular disease. N. Engl. J. Med. 324, 1149–1155.

    CAS  Article  Google Scholar 

  6. Clarke R, Smith AD, Jobst KA, Refsum H, Sutton L & Ueland PM (1998): Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch. Neurol. 55, 1449–1455.

    CAS  Article  Google Scholar 

  7. de Bree A, Verschuren WM, Blom HJ & Kromhout D (2001): Lifestyle factors and plasma homocysteine concentrations in a general population sample. Am. J. Epidemiol. 154, 150–154.

    CAS  Article  Google Scholar 

  8. den Heijer M, Brouwer IA, Bos GM, Blom HJ, van der Put NM, Spaans AP, Rosendaal FR, Thomas CM, Haak HL, Wijermans PW & Gerrits WB (1998): Vitamin supplementation reduces blood homocysteine levels: a controlled trial in patients with venous thrombosis and healthy volunteers. Arterioscler. Thromb. Vasc. Biol. 18, 356–361.

    CAS  Article  Google Scholar 

  9. Goddijn-Wessel TA, Wouters MG, van de Molen EF, Spuijbroek MD, Steegers-Theunissen RP, Blom HJ, Boers GH & Eskers TK (1996): Hyperhomocysteinemia: a risk factor for placental abruption or infarction. Eur. J. Obstet. Gynecol. Reprod. Biol. 66, 23–29.

    CAS  Article  Google Scholar 

  10. Grubben MJ, Boers GH, Blom HJ, Broekhuizen R, de Jong R, van Rijt L, de Ruijter E, Swinkels DW, Nagengast FM & Katan MB (2000): Unfiltered coffee increases plasma homocysteine concentrations in healthy volunteers: a randomized trial. Am. J. Clin. Nutr. 71, 480–484.

    CAS  Article  Google Scholar 

  11. Jacobsen DW, Gatautis VJ, Green R, Robinson K, Savon SR, Secic M, Ji J, Otto JM & Taylor LM Jr (1994): Rapid HPLC determination of total homocysteine and other thiols in serum and plasma: sex differences and correlation with cobalamine and folate concentrations in healthy subjects. Clin. Chem. 40, 873–881.

    CAS  PubMed  Google Scholar 

  12. Jacques PF, Bostom AG, Wilson PW, Rich S, Rosenberg IH & Selhub J (2001): Determinants of plasma total homocysteine concentration in the Framingham Offspring cohort. Am. J. Clin. Nutr. 73, 613–621.

    CAS  Article  Google Scholar 

  13. Koehler KM, Baumgartner RN, Garry PJ, Allen RH, Stabler SP & Rimm EB (2001): Association of folate intake and serum homocysteine in elderly persons according to vitamin supplementation and alcohol use. Am. J. Clin. Nutr. 73, 628–637.

    CAS  Article  Google Scholar 

  14. Leeda M, Riyazi N, de Vries JI, Jakobs C, van Geijn HP & Dekker GA (1998): Effects of folic acid and vitamin B6 supplementation on women with hyperhomocysteinemia and a history of preeclampsia or fetal growth restriction. Am. J. Obstet. Gynecol. 179, 135–139.

    CAS  Article  Google Scholar 

  15. Mansoor MA, Kristensen O, Hervig T, Bates CJ, Pentieva K, Vefring H, Osland A, Berge T, Drablos PA, Hetland O & Rolfsen S (1999): Plasma total homocysteine response to oral doses of folic acid and pyridoxine hydrochloride (vitamin B6) in healthy individuals. Oral doses of vitamin B6 reduce concentrations of serum folate. Scand. J. Clin. Lab. Invest. 59, 139–146.

    CAS  Article  Google Scholar 

  16. McCaddon A, Hudson P, Davies G, Hughes A, Williams JH & Wilkinson C (2001): Homocysteine and cognitive decline in healthy elderly. Dement. Geriatr. Cogn. Disord. 12, 309–313.

    CAS  Article  Google Scholar 

  17. Nelen WL, Blom HJ, Steegers EA, den Heijer M, Thomas CM & Eskes TK (2000): Homocysteine and folate levels as risk factors for recurrent early pregnancy loss. Obstet. Gynecol. 95, 519–524.

    CAS  PubMed  Google Scholar 

  18. Nes M, Frost Andersen L, Solvoll K, Sandstad B, Hustvedt BE, Løvø A & Drevon CA (1992): Accuracy of a quantitative food frequency questionnaire applied in elderly Norwegian women. Eur. J. Clin. Nutr. 46, 809–821.

    CAS  PubMed  Google Scholar 

  19. Nygard O, Vollset SE, Refsum H, Stensvold I, Tverdal Å, Nordrehaug JE, Ueland M & Kvale G (1995): Total plasma homocysteine and cardiovascular risk profile. The Hordaland Homocysteine Study. JAMA 274, 1526–1533.

    CAS  Article  Google Scholar 

  20. Nygard O, Refsum H, Ueland PM, Stensvold I, Nordrehaug JE, Kvale G & Vollset SE (1997): Coffee consumption and plasma total homocysteine: The Hordaland Homocysteine Study. Am. J. Clin. Nutr. 65, 136–143.

    CAS  Article  Google Scholar 

  21. Olthof MR, Hollman PC, Zock PL & Katan MB (2001): Consumption of high doses of chlorogenic acid, present in coffee, or of black tea increases plasma total homocysteine concentrations in humans. Am. J. Clin. Nutr. 73, 532–538.

    CAS  Article  Google Scholar 

  22. Oshaug A, Bugge KH & Refsum H (1998): Diet, an independent determinant for plasma total homocysteine. A cross sectional study of Norwegian workers on platforms in the North Sea. Eur. J. Clin. Nutr. 52, 7–11.

    CAS  Article  Google Scholar 

  23. Refsum H (2001): Folate, vitamin B12 and homocysteine in relation to birth defects and pregnancy outcome. Br. J. Nutr. 85(Suppl 2), S109–S113.

    CAS  Article  Google Scholar 

  24. Saw SM, Yuan JM, Ong CN, Arakawa K, Lee HP, Coetzee GA & Yu MC (2001): Genetic, dietary, and other lifestyle determinants of plasma homocysteine concentrations in middle-aged and older Chinese men and women in Singapore. Am. J. Clin. Nutr. 73, 232–239.

    CAS  Article  Google Scholar 

  25. Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D'Agostino RB, Wilson PW & Wolf PA (2002): Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N. Eng. J. Med. 346, 476–483.

    CAS  Article  Google Scholar 

  26. Smith D (2002): Homocysteine, B vitamins, and cognitive deficit in the elderly. Am. J. Clin. Nutr. 75, 785–786.

    CAS  Article  Google Scholar 

  27. Stolzenberg-Solomon RZ, Miller ER III, Maguire MG, Selhub J & Appel LJ (1999): Association of dietary protein intake and coffee consumption with serum homocysteine concentrations in an older population. Am. J. Clin. Nutr. 69, 467–475.

    CAS  Article  Google Scholar 

  28. Sorensen TK, Malinow MR, Williams MA, King IB & Luthy DA (1999): Elevated second-trimester serum homocyst(e)ine levels and subsequent risk of preeclampsia. Gynecol. Obstet. Invest. 48, 98–103.

    CAS  Article  Google Scholar 

  29. Svenska Näringsrekommendationer (Swedish recommended dietary allowances) (1997): National Food Administration, Uppsala.

  30. Ubbink JB, Vermaak WJ, van der Merwe A, Becker PJ, Delport R & Potgieter HC (1994): Vitamin requirements for the treatment of hyperhomocysteinemia in humans. J. Nutr. 124, 1927–1933.

    CAS  Article  Google Scholar 

  31. Ubbink JB & Delport R (2000): Homocysteine as atherothrombotic agent: is the bark worse than the bite? Nutrition 16, 672–674.

    CAS  Article  Google Scholar 

  32. Ueland PM, Refsum H, Beresford SA & Vollset SE (2000): The controversy over homocysteine and cardiovascular risk. Am. J. Clin. Nutr. 72, 324–332.

    CAS  Article  Google Scholar 

  33. Urgert R, van Vliet T, Zock PL & Katan MB (2000): Heavy coffee consumption and plasma homocysteine: a randomized controlled trial in healthy volunteers. Am. J. Clin. Nutr. 72, 1107–1110.

    CAS  Article  Google Scholar 

  34. van Guldener C & Stehouwer CD (2001): Homocysteine-lowering tretment: an overview. Expert. Opin. Pharmacol. 2, 1449–1460.

    CAS  Article  Google Scholar 

  35. Vollset SE, Nygard O, Refsum H & Ueland PM (2000a): Coffee and homocysteine. Am. J. Clin. Nutr. 71, 403–404.

    CAS  Article  Google Scholar 

  36. Vollset SE, Refsum H, Irgens LM, Emblem RM, Tverdal A, Gjessing HK, Monsen AL & Ueland PM (2000b): Plasma total homocysteine, pregnancy complications, and adverse pregnancy outcomes: the Hordaland Homocysteine study. Am. J. Clin. Nutr. 71, 962–968.

    CAS  Article  Google Scholar 

  37. Wald DS, Bishop L, Wald NJ, Law M, Hennessy E, Weir D, McPartlin J & Scott J (2001): Randomized trial of folic acid supplementation and serum homocysteine levels. Arch. Intern. Med. 161, 695–700.

    CAS  Article  Google Scholar 

  38. Wouters MG, Boers GH, Blom HJ, Trijbels FJ, Thomas CM, Borm GF, Steegers-Theunissen RP & Eskes TK (1993): Hyperhomocysteinemia: a risk factor in women with unexplained recurrent early pregnancy loss. Fertil. Steril. 60, 820–825.

    CAS  Article  Google Scholar 

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Acknowledgements

We thank the volunteers for their participation, Lisbeth Jakobsson and Monica Eriksson for research assistance and Georg Lappas for help with statistical calculations.

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  1. Department of Medicine, Cardiovascular Institute, Sahlgrenska University Hospital/Östra, Göteborg, Sweden

    E Strandhagen & D S Thelle

  2. Department of Clinical Chemistry, Ullevål University Hospital, Oslo, Norway

    S Landaas

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  2. S Landaas
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  3. D S Thelle
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Correspondence to E Strandhagen.

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Strandhagen, E., Landaas, S. & Thelle, D. Folic acid supplement decreases the homocysteine increasing effect of filtered coffee. A randomised placebo-controlled study. Eur J Clin Nutr 57, 1411–1417 (2003). https://doi.org/10.1038/sj.ejcn.1601703

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Keywords

  • controlled study
  • filtered coffee
  • homocysteine
  • folic acid
  • pyridoxine

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