© 2001 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Renal Insufficiency, Vitamin B12 Status, and Population Attributable Risk for Mild Hyperhomocysteinemia Among Coronary Artery Disease Patients in the Era of Folic Acid–Fortified Cereal Grain Flour
From the Division of General Internal Medicine (G.L., A.G.B.), Memorial Hospital of Rhode Island, Providence, and the Tufts Jean Mayer USDA Human Nutrition Research Center on Aging (P.F.J., J.S., I.H.R., A.G.B.), Boston, Mass.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Abstract—Fortification of enriched cereal grain flour products with folic acid has drastically reduced the prevalence of deficient plasma folate status, a major determinant of plasma total homocysteine (tHcy) levels. We hypothesized that even more liberally defined "suboptimal" plasma folate status might no longer contribute importantly to the population attributable risk (PAR) for mild hyperhomocysteinemia, a putative atherothrombotic risk factor. We determined fasting plasma tHcy, folate, vitamin B12, and pyridoxal 5'-phosphate levels, along with serum creatinine and albumin levels, in 267 consecutive patients (aged 61±9 [mean±SD] years, 76.4% men and 26.6% women) with stable coronary artery disease (CAD) who were nonusers of vitamin supplements or had abstained from supplement use for at least 6 weeks before examination. Subjects were evaluated a minimum of 3 months after the implementation of flour fortification was largely completed. Relative risk estimates for the calculation of PAR were derived from a multivariable-adjusted logistic regression model with
12 µmol/L
tHcy as the dependent variable and with age, sex, pyridoxal
5'-phosphate (continuous), albumin (continuous), <5 ng/mL
folate, <250 pg/mL vitamin B12, and 1.3 mg/dL
creatinine as the independent variables. The prevalence
of 12 µmol/L plasma tHcy was 11.2% (30 of 267 patients). PAR
estimates (percentage) for 12 µmol/L tHcy were as follows: <5
ng/mL folate (<1%), <250 pg/mL vitamin B12
(24.5%), and 1.3 mg/dL creatinine (37.5%). In the era
of folic acid–fortified cereal grain flour, renal insufficiency and
suboptimal vitamin B12 status (but not folate
status) contribute importantly to the PAR for mild hyperhomocysteinemia
among patients with stable
CAD.
Key Words: coronary arteriosclerosis • renal function • homocysteine • determinants
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Ueland et al1 recently reported a meta-analysis of 14 prospective studies of the relationship between baseline total homocysteine (tHcy) levels and (primarily) coronary artery disease (CAD) outcomes in population-based cohorts; this meta-analysis was reported through the end of 1999. The aggregate relative risk estimate (from a total of 2786 cases) per 5 µmol/L change in tHcy concentration was 1.20 (95% CI 1.14 to 1.25). Nephrosclerosis, specifically renal arteriolar hyalinization,2 3 4 has been associated with systemic arteriosclerosis2 and clinical3 as well as subclinical CAD.4 There is a strong independent (inverse) association between glomerular filtration rate directly determined by either iohexol clearance5 6 or 51Cr-EDTA clearance7 and fasting tHcy levels, which encompasses glomerular filtration rates throughout the normative range. A surrogate for glomerular filtration rate8 and homocysteine generation,9 creatinine is a significant determinant of tHcy levels in CAD patients10 11 and general populations.12 In a population-based sample with predominantly normal renal function, fortification of enriched cereal grain flour products with folic acid drastically reduced the prevalence of deficient plasma folate status and mild hyperhomocysteinemia.13 These data contrast starkly with the very limited impact that this fortification policy has had on the prevalence of mild hyperhomocysteinemia among chronic renal transplant recipients,14 who serve as a valid model for the hyperhomocysteinemia of chronic renal insufficiency, in general.15 Moreover, renal function gauged as a simple creatinine determination is the major independent determinant of tHcy levels in each of these 2 patient groups with mild to moderate chronic renal insufficiency.14 15 In light of such collective findings,13 14 15 we hypothesized that even more liberally defined "suboptimal" plasma folate status might no longer contribute importantly to the population attributable risk (PAR) for mild hyperhomocysteinemia among stable CAD patients. Accordingly, we assessed fasting plasma tHcy and serum creatinine in conjunction with the other established determinants of tHcy levels (ie, age,16 sex,16 B-vitamin status,16 and albumin17 ) among 267 consecutive patients with clinically stable CAD, all of whom were examined at least 3 to 4 months after fortification of enriched cereal grain flour with folic acid was largely completed.13
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The institutional review board at Memorial Hospital of Rhode Island (Pawtucket) approved the study protocol, and all participants provided written informed consent. Study participants were 267 stable CAD patients (ie, they were studied at least 3 months after myocardial infarction or coronary angioplasty and/or at least 6 months after coronary artery bypass graft surgery). CAD status was confirmed by established 12-lead ECG and cardiac isoenzyme (ie, creatine phosphokinase-MB) criteria for definite myocardial infarction and/or unstable angina with angiographically proven
50%
stenosis of at least 1 major epicardial coronary
artery. Participants lived in the Pawtucket and Providence, RI,
metropolitan areas, and were examined between October 1997 and May
1999. Information regarding prior vitamin supplement use was obtained
by standardized interview, and subjects were either nonusers of
any supplements containing folic acid or had abstained from using such
supplements for at least 6 weeks by the time of their examination.
However, all participants were examined at least 3 to 4 months after
the widespread availability in New England (John Watson, Watson Foods,
New Haven, Conn, personal communication, 1998) of cereal grain
flour products fortified with folic acid at 140 µg per 100 g
flour.18 Overnight (10- to 14-hour) fasting blood samples were collected from each participant. Plasma tHcy levels were determined by high-performance liquid chromatography with fluorescence detection, and plasma pyridoxal 5'-phosphate (PLP) levels were measured by radioenzymatic (tyrosine decarboxylase) assay, as reported earlier.16 Plasma folate and vitamin B12 levels were measured by radioassay (Bio-Rad Quantaphase II). Serum creatinine levels (by Jaffe’s test) and albumin levels (by bromcresol method) were determined by using standard techniques adapted for automated clinical chemistry laboratory analyzers.
Descriptive data included arithmetic means with standard
deviations and complete ranges or geometric means with interquartile
and complete ranges for continuous variables and prevalences
(percentages) for discrete variables. The odds ratios (an estimate
of relative risk) for the calculation of PAR percentage
(PAR%)19 were derived from a
multivariable-adjusted logistic regression model with 12 µmol/L
tHcy as the dependent variable and age, sex, PLP (continuous),
albumin (continuous), <5 ng/mL folate, <250 pg/mL vitamin
B12, and 1.3 mg/dL creatinine as
the independent variables. The dichotomous cut points chosen for
mild hyperhomocysteinemia and mild renal insufficiency were
consistent with earlier operational
definitions.7 20 21
The dichotomous cut points chosen for suboptimal folate and vitamin
B12 status were deliberately selected to be
slightly above the most common clinically defined cut points for folate
deficiency and vitamin B12 deficiency of <3
ng/mL and <200 pg/mL, respectively. The dearth of US subjects with
clinically defined folate deficiency in the current era of folic
acid–fortified cereal grain flour figured prominently in our decision
regarding vitamin status cut
points.13 14 PAR%
estimates were calculated from the following formula:
PAR%={[prevalencerisk factor
(RR-1)]/[prevalencerisk factor
(RR-1)+1]}x100.19
Reported probability values were based on 2-tailed calculations, and
all statistical analyses were performed by using SYSTAT
(version 9.0) software.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Key subject characteristics, expressed as means, geometric means, percentages, and complete ranges, are depicted in Table 1
. Geometric mean fasting tHcy levels were greater in
the men (n=196) than in the women (n=71) at 8.5 versus 7.7 µmol/L,
respectively (P=0.007). The
prevalence of 12 µmol/L plasma tHcy was 11.2% (30 of the 267
patients). Logistic regression modeling was performed with 12
µmol/L tHcy as the dependent variable and age, sex, PLP
(continuous), albumin (continuous), <5 ng/mL folate, <250
pg/mL vitamin B12, and 1.3 mg/dL
creatinine as the potential explanatory variables.
Table 2 indicates the prevalence (percentage) of 1.3
mg/dL creatinine , <250 pg/mL vitamin
B12, and <5 ng/mL folate, as well as the
multivariable-adjusted relative risk estimates and PAR% for a 12
µmol/L fasting tHcy conferred by these 3 potential explanatory
variables. Stepwise forward selection and backward elimination
revealed that 1.3 mg/dL serum creatinine
(P=0.002) and <250 pg/mL
plasma vitamin B12
(P=0.008), but not <5 ng/mL
plasma folate (P=0.351), were
independently predictive of a 12 µmol/L fasting tHcy. PAR estimates
(percentage) for a 12 µmol/L tHcy, were as follows: <5 ng/mL
folate (<1%), <250 pg/mL vitamin B12
(24.5%), and 1.3 mg/dL creatinine
(37.5%).
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
All patients were examined at least several months after the widespread availability in southeast New England of cereal grain flour products (ie, all enriched wheat, corn, and rice flour products) fortified with folic acid at 140 µg/100 g of flour.18 Within a population-based sample of New England residents (ie, the Framingham Offspring cohort) who were nonusers of vitamin supplements, this fortification policy has doubled the plasma folate levels while reducing the prevalence of low folate levels (ie, <3 ng/mL) by >90% and the prevalence of >13 µmol/L fasting tHcy levels by nearly 50%.13 The very low point prevalence of <3 ng/mL plasma folate (ie, 4 [1.5%] of 267 patients) among the CAD patients examined in the present study is completely consistent with the prevalence of <3 ng/mL folate (1.0%, 95% CI 0.0% to 4.8%) among nonusers of supplements in the Framingham Offspring Study, who were similarly examined after the advent of fortification.13 Moreover, these results with respect to the current dearth of plasma folate deficiency in US populations are consistent with findings from Canadian general populations22 and CAD populations23 examined after the initiation of the same flour fortification policy in Canada. Improved, relatively "homogeneous" folate status secondary to cereal grain fortification may have contributed to the lack of association between plasma folate and fasting tHcy levels observed in the present study. In contrast, the median age of the CAD patient population (61 years) could have accentuated the impact of age-related decrements in renal function8 and vitamin B12 status24 on fasting plasma tHcy levels.
Persistent mild hyperhomocysteinemia is characteristic of patients with chronic renal insufficiency and end-stage renal disease.25 The etiology of this hyperhomocysteinemia remains unknown, although it has been hypothesized to result from the loss of intrarenal homocysteine metabolism26 and/or uremia-induced extrarenal defects in homocysteine metabolism.27 In conjunction with earlier reports,5 6 7 the present findings from clearly nonuremic subjects with, at most, only mild to moderate chronic renal insufficiency28 might suggest that intrarenal homocysteine metabolism is a major determinant of homocysteine levels. However, these data cannot rule out the possibility that subtle extrarenal defects in homocysteine metabolism that may accompany even such mild reductions in renal function could account for the resulting increases in tHcy levels.
In summary, ever since the advent of folic acid fortification of cereal grain flour, renal insufficiency and suboptimal vitamin B12 status, but not folate status, contribute importantly to the PAR for mild hyperhomocysteinemia among patients with stable CAD.
|
Acknowledgments |
|---|
Support for the work described was provided in part by National Heart, Lung, and Blood Institute grant RO1-HL-56908-01A1, the US Department of Agriculture, Agricultural Research Service agreement No.58-1950-9-001, and a grant from Roche Vitamin Division. We thank Evelyn Tolbert, BS, Marie Nadeau, MS, and Bonnie Souppa, BS, for their excellent technical assistance. This manuscript is dedicated to the memory of our friend and colleague, Dr Gintaras Liaugaudas.
|
Footnotes |
|---|
Reprint requests to Andrew G. Bostom, MD, MS, Division of General Internal Medicine, Memorial Hospital of Rhode Island, 111 Brewster St, Pawtucket, RI 02860.
The contents of this publication do not necessarily reflect the views or policies of the US Department of Agriculture, nor does mention of trade names, commercial products, or organizations imply indorsement by the US government.
Received November 21, 2001; accepted January 29, 2001.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Ueland PM, Refsum H, Beresford SAA, Vollset SE. The controversy over homocysteine and cardiovascular risk. Am J Clin Nutr. 2000;72:324–332.
2. Kasiske BL. Relationship between vascular disease and age-associated changes in the human kidney. Kidney Int. 1987;31:1153–1159.[Medline] [Order article via Infotrieve]
3. Tracy RE, Strong JP, Newman WP III, Malcolm GT, Oalmann MC, Guzman MA. Renovasculopathies of nephrosclerosis in relation to atherosclerosis at ages 25 to 54 years. Kidney Int. 1996;49:564–570.[Medline] [Order article via Infotrieve]
4. Tracy RE, Malcolm GT, Oalmann MC, Newman WP III, Guzman MA. Nephrosclerosis, glycohemoglobin, cholesterol, and smoking in subjects dying of coronary heart disease. Mod Pathol. 1994;7:301–309.[Medline] [Order article via Infotrieve]
5. Arnadottir M, Hultberg B, Nilsson-Ehle P, Thysell H. The effect of reduced glomerular filtration rate on plasma total homocysteine concentrations. Scand J Clin Lab Invest. 1996;56:41–46.[Medline] [Order article via Infotrieve]
6. Bostom AG, Kronenberg F, Gohh RY, Schwenger V, Ritz E, Selhub J. Proteinuria and total plasma homocysteine levels in chronic renal disease patients with a normal range serum creatinine: critical impact of true GFR. J Am Soc Nephrol. 2000;11:56A. Abstract.
7. Wollesen F, Brattstrom L, Refsum H, Ueland PM, Berglund L, Berne C. Plasma total homocysteine and cysteine in relation to GFR in diabetes. Kidney Int. 1999;55:1028–1035.[Medline] [Order article via Infotrieve]
8. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31–41.[Medline] [Order article via Infotrieve]
9. Mudd SH, Poole JR. Labile methyl balances for normal humans on various dietary regimens. Metabolism. 1975;24:721–735.[Medline] [Order article via Infotrieve]
10.
Pancharuniti
N, Lewis CA, Sauberlich HE, Perkins LL, Go RC, Alvarez JO, Macaluso M,
Acton RT, Copeland RB, Cousins AL. Plasma homocysteine, folate, and
vitamin B12 concentrations and risk for early-onset coronary
artery disease. Am J Clin
Nutr. 1994;59:940–948.
11.
Wu LL, Wu J,
Hunt SC, James BC, Vincent GM, Williams RR, Hopkins PN. Plasma
homocysteine as a risk factor for early familial coronary
artery disease. Clin Chem. 1994;40:552–561.
12. Brattstrom L, Lindgren A, Israelsson B, Anderson A, Hultberg B. Homocysteine and cysteine: determinants of plasma levels in middle-aged to elderly subjects. J Intern Med. 1994;236:633–641.[Medline] [Order article via Infotrieve]
13.
Jacques PF,
Selhub J, Bostom AG, Wilson PWF, Rosenberg IH. The effect of folic acid
fortification on plasma folate and total homocysteine concentrations.
N Engl J Med. 1999;340:1449–1454.
14. Bostom AG, Gohh RY, Liaugaudas G, Beaulieu AJ, Han H, Jacques PF, Dworkin L, Rosenberg IH, Selhub J. Prevalence of mild fasting hyperhomocysteinemia in renal transplant versus coronary artery disease patients after fortification of cereal grain flour with folic acid. Atherosclerosis. 1999;145:221–224.[Medline] [Order article via Infotrieve]
15. Bostom AG, Kronenberg F, Gohh RY, Schwenger V, Kuen E, Konig P, Kraatz G, Lhotta K, Mann JFE, Muller GA, et al. Chronic renal transplantation: a model for the hyperhomocysteinemia of renal insufficiency. Atherosclerosis. In press.
16.
Selhub J,
Jacques PF, Wilson PWF, Rush D, Rosenberg IH. Vitamin status and intake
as primary determinants of homocysteinemia in an elderly population.
JAMA. 1993;270:2693–2698.
17.
Lussier-Cacan
S, Xhignesse M, Piolot A, Selhub J, Davignon J, Genest J Jr. Plasma
total homocysteine in healthy subjects: sex-specific relation with
biological traits. Am J Clin
Nutr. 1996;64:587–593.
18. Food Standards: Amendment of Standards of Identity for Enriched Grain Products to Require Addition of Folic Acid. Washington, DC: Federal Register; 1996;61:8781–8797.
19. Hennekens CH, Buring JE. Epidemiology in Medicine. Boston, Mass: Little Brown and Co; 1987.
20.
Graham I,
Daly LE, Refsum HM, Robinson K, Brattstrom LE, Ueland PM, Palma-Reis
BJ, Boers GH, Sheahan RG, Israelsson B, et al. Plasma homocysteine as a
risk factor for vascular disease: the European Concerted Action
Project. JAMA. 1997;277:1775–1781.
21. Couchoud C, Pozet N, Labeeuw M, Pouteil-Noble C. Screening early renal failure: cut-off for serum creatinine as an indicator of renal impairment. Kidney Int. 1999;55:1878–1884.[Medline] [Order article via Infotrieve]
22. Ray JG, Cole DE, Boss SC. An Ontario-wide study of vitamin B12, serum folate, and red cell folate levels in relation to plasma homocysteine: is a preventable public health issue on the rise? Clin Biochem. 2000;33:337–343.[Medline] [Order article via Infotrieve]
23.
Title LM,
Cummings PM, Giddens K, Genest JJ, Nassar BA. Effect of folic acid and
antioxidant vitamins on endothelial function in
patients with coronary artery disease.
J Am Coll Cardiol. 2000;36:758–765.
24.
Lindenbaum
J, Rosenberg IH, Wilson PWF, Stabler SP, Allen RH. Prevalence of
cobalamin deficiency in the Framingham elderly population.
Am J Clin Nutr. 1994;60:2–11.
25.
Bostom AG,
Culleton B. Hyperhomocysteinemia in chronic renal disease.
J Am Soc Nephrol. 1999;10:891–900.
26. Bostom AG, Brosnan JT, Hall B, Nadeau MR, Selhub J. Net uptake of plasma homocysteine by the rat kidney in vivo. Atherosclerosis. 1995;116:59–62.[Medline] [Order article via Infotrieve]
27. van Guldener C, Donker AJ, Jakobs C, Teerlink T, de Meer K. No net renal extraction of homocysteine in fasting humans. Kidney Int. 1998;54:166–169.[Medline] [Order article via Infotrieve]
28. Hsu CY, Chertow GM. Chronic renal confusion: insufficiency, failure, dysfunction, or disease. Am J Kidney Dis. 2000;36:415–418. [Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  L. Hoey, J. Strain, and H. McNulty Studies of biomarker responses to intervention with vitamin B-12: a systematic review of randomized controlled trials Am. J. Clinical Nutrition, June 1, 2009; 89(6): 1981S - 1996S. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Ganji and M. R. Kafai Demographic, Lifestyle, and Health Characteristics and Serum B Vitamin Status Are Determinants of Plasma Total Homocysteine Concentration in the Post-Folic Acid Fortification Period, 1999-2004 J. Nutr., February 1, 2009; 139(2): 345 - 352. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Hoey, H. McNulty, N. Askin, A. Dunne, M. Ward, K. Pentieva, J. Strain, A. M Molloy, C. A Flynn, and J. M Scott Effect of a voluntary food fortification policy on folate, related B vitamin status, and homocysteine in healthy adults Am. J. Clinical Nutrition, November 1, 2007; 86(5): 1405 - 1413. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Bleys, E. R Miller III, R. Pastor-Barriuso, L. J Appel, and E. Guallar Vitamin-mineral supplementation and the progression of atherosclerosis: a meta-analysis of randomized controlled trials. Am. J. Clinical Nutrition, October 1, 2006; 84(4): 880 - 887. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. McNulty, L. R. C. Dowey, J.J. Strain, A. Dunne, M. Ward, A. M. Molloy, L. B. McAnena, J. P. Hughes, M. Hannon-Fletcher, and J. M. Scott Riboflavin Lowers Homocysteine in Individuals Homozygous for the MTHFR 677C->T Polymorphism Circulation, January 3, 2006; 113(1): 74 - 80. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Herrmann, H. Schorr, R. Obeid, and J. Geisel Vitamin B-12 status, particularly holotranscobalamin II and methylmalonic acid concentrations, and hyperhomocysteinemia in vegetarians Am. J. Clinical Nutrition, July 1, 2003; 78(1): 131 - 136. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Johnson, N. A Hawthorne, W. R Brackett, J. G Fischer, E. W Gunter, R. H Allen, and S. P Stabler Hyperhomocysteinemia and vitamin B-12 deficiency in elderly using Title IIIc nutrition services Am. J. Clinical Nutrition, January 1, 2003; 77(1): 211 - 220. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Carmel, R. Green, D. S. Rosenblatt, and D. Watkins Update on Cobalamin, Folate, and Homocysteine Hematology, January 1, 2003; 2003(1): 62 - 81. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Weiss, C. Keller, U. Hoffmann, and J. Loscalzo Endothelial dysfunction and atherothrombosis in mild hyperhomocysteinemia Vascular Medicine, August 1, 2002; 7(3): 227 - 239. [Abstract] [PDF]
|
|
|
|
 |
|
 D. V. Chirieac, T. A. Pearson, A. G. Bostom, B. Sharaf, N. Miele, G. Schnyder, and Z. G. Turi B Vitamins and Restenosis after Coronary Angioplasty N. Engl. J. Med., April 4, 2002; 346(14): 1093 - 1095. [Full Text] [PDF]
|
|
|
|
 |
|
 A. G. Bostom, P. F. Jacques, G. Liaugaudas, G. Rogers, I. H. Rosenberg, and J. Selhub Total Homocysteine Lowering Treatment Among Coronary Artery Disease Patients in the Era of Folic Acid-Fortified Cereal Grain Flour Arterioscler Thromb Vasc Biol, March 1, 2002; 22(3): 488 - 491. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||