Homocysteine, the New Marker of Disease Risk - An Overview

Login or register to view PDF.
Abstract

Introduction
Butz and du Vigneaud first described homocysteine in 1932. This sulphur-containing amino acid is closely related to methionine and cysteine. Homocystinuria, a condition in which the homocysteine levels in blood and urine are very high, is caused by some severe enzyme defects. This condition was found to be associated with premature occlusive cardiovascular disease (CVD) and with mental retardation.
In 1969, McCully described the vascular pathology, including smooth muscle proliferation, progressive arterial stenosis and haemostatic changes found in such patients. A large number of epidemiological, case├óÔé¼ÔÇ£control and longitudinal studies have since demonstrated an association between moderately elevated homocysteine levels in the plasma or serum and pregnancy complications, neural tube defects, other birth defects, various neuropsychiatric disorders, cognitive impairment in the elderly and an increased mortality rate, in addition to vascular diseases. Research within the field has been very active during the last decade. About 1,000 scientific reports are now published annually.
This research has been made possible by the development of accurate methods for measuring homocysteine in plasma and serum. The recent introduction of enzyme immunoassays is a further step forward. Automated methods using standard immunoassay equipment have been introduced.

Pages

The One-carbon Metabolism
Homocysteine is an intermediate product of the one-carbon metabolism. All homocysteine found in mammals is formed during the metabolism of methionine in the methylation cycle (see Figure 1). Dietary methionine is used either for protein synthesis or the formation of S-adenosylmethionine (SAM), which contains a very reactive methyl group. This is transferred to a large variety of acceptor substrates, including nucleic acids (deoxyribonucleic acid (DNA) and ribonucleic acid), proteins, phospholipids, myelin, polysaccharides, choline, catecholamines and a large number of small molecules. SAM is the principal biological methyl group donor in the organism and the only donor in the central nervous system (CNS). S-adenosyl-l-homocysteine (SAH) is hydrolysed in a reversible reaction to homocysteine, which can be recycled to methionine and SAM or directed toward the transsulphuration pathway.

Figure 1: Homocysteine Metabolism

\\"

Three enzymes are involved directly in this metabolism: methionine synthase (MS); betaine homocysteine methyltransferase; and cystathionine ├Ä╦ø-synthase (CBS). Vitamin B12 is a co-factor to MS and vitamin B6 to CBS. Methyl tetrahydrofolate (methylTHF) is a substrate in the MS-mediated reaction. This reaction is also critical for the formation of the active folate forms required for purine and thymidine synthesis and thus for DNA synthesis and repair.

The majority of tissues, including the CNS, are entirely dependent on methyl groups derived from the MS-mediated recycling of homocysteine. This reaction is indirectly regulated by the activity of methyl-enetetrahydrofolate reductase (MTHFR), as this enzyme mediates the formation of methylTHF. This enzyme therefore has a strong, indirect influence on the remethylation of homocysteine. />/>/>

Pages

References

  1. Wilcken B, Bamforth F, Li Z et al., ├óÔé¼┼øGeographical and Ethnic Variation of the 677C├óÔÇá'T Allele of 5,10 Methylenetetrahydrofolate Reductase: Findings from over 7,000 Newborns from 16 Areas Worldwide├óÔé¼┼Ñ, J. Med. Genet., 40 (2003), pp. 619├óÔé¼ÔÇ£625.
  2. Nyg─é─ärd O et al., ├óÔé¼┼øMajor Lifestyle Determinants of Plasma Total Homocysteine Distribution: the Hordaland Homocysteine Study├óÔé¼┼Ñ, Am. J. Clin. Nutr., 67 (1998), section 2, pp. 263├óÔé¼ÔÇ£270.
  3. Jacques P F et al., ├óÔé¼┼øDeterminants of Plasma Total Homocysteine Concentration in the Framingham Offspring Cohort├óÔé¼┼Ñ, Am. J. Clin. Nutr., 73 (2001), pp. 613├óÔé¼ÔÇ£621.
  4. Willems F F et al., ├óÔé¼┼øCoronary Endothelial Function in Hyperhomocysteinemia: Improvement after Treatment with Folic Acid and Cobalamin in Patients with Coronary Artery Disease├óÔé¼┼Ñ, J. Am. College Cardiology, 40 (2002), pp. 766├óÔé¼ÔÇ£772.
  5. Schnyder G et al., ├óÔé¼┼øEffect of Homocysteine-lowering Therapy with Folic Acid, Vitamin B12 and Vitamin B6 on Clinical Outcome after Percutaneous Coronary Intervention. The Swiss Heart Study: a Randomised Controlled Trial├óÔé¼┼Ñ, JAMA, 228 (2002), pp. 973├óÔé¼ÔÇ£979.
  6. Schnyder G et al., ├óÔé¼┼øEffect of Homocysteine-lowering Therapy on Restenosis after Percutaneous Coronary Intervention for Narrowings in Small Coronary Arteries├óÔé¼┼Ñ, Am. J. Cardiology, 91 (2003), pp. 1,265├óÔé¼ÔÇ£1,269.
  7. Marcucci R et al., ├óÔé¼┼øVitamin Supplementation Reduces the Progression of Atherosclerosis in Hyperhomocysteinemic Renal-transplant Recipients├óÔé¼┼Ñ, Transplantation, 75 (2003), pp. 1,551├óÔé¼ÔÇ£1,555.
  8. The Homocysteine Studies Collaboration, ├óÔé¼┼øHomocysteine and Risk of Ischemic Heart Disease and Stroke ├óÔé¼ÔÇ£ a Metaanalysis├óÔé¼┼Ñ, JAMA, 288 (2002), pp. 2,015├óÔé¼ÔÇ£2,022.
  9. Klerk M et al., ├óÔé¼┼øMTHFR 677C>T Polymorphism and Risk of Coronary Heart Disease ├óÔé¼ÔÇ£ a Meta-analysis├óÔé¼┼Ñ, JAMA, 288 (2002), pp. 2,023├óÔé¼ÔÇ£2,032.
  10. Wald D S et al., ├óÔé¼┼øHomocysteine and Cardiovascular Disease: Evidence on Causality from Metaanalysis├óÔé¼┼Ñ, BMJ, 325 (2002), pp. 1,202├óÔé¼ÔÇ£1,206.
  11. Bautista L E et al., ├óÔé¼┼øTotal Plasma Homocysteine Level and Risk of Cardiovascular Disease ├óÔé¼ÔÇ£ a Meta-analysis of Prospective Cohort Studies├óÔé¼┼Ñ, J. Clin. Epidemiol., 55 (2002), pp. 882├óÔé¼ÔÇ£887.
  12. Selhub J et al., ├óÔé¼┼øB Vitamins, Homocysteine and Neurocognitive Function in the Elderly├óÔé¼┼Ñ, Am. J. Clin. Nutr., 71 (suppl) (2000), pp. 614S├óÔé¼ÔÇ£620S.
  13. Williams J H et al., ├óÔé¼┼øMinimal Hippocampal Width Relates to Plasma Homocysteine in Community-dwelling Older People├óÔé¼┼Ñ, Age and Ageing, 31 (2002), pp. 440├óÔé¼ÔÇ£444.
  14. Vermeer S E et al., ├óÔé¼┼øHomocysteine, Silent Brain Infarcts and White Matter Lesions: the Rotterdam Study├óÔé¼┼Ñ, Ann. Neurol., 51 (2002), pp. 285├óÔé¼ÔÇ£289.
  15. Clarke R et al., ├óÔé¼┼øFolate, Vitamin B12 and Serum Total Homocysteine Levels in Confirmed Alzheimer Disease├óÔé¼┼Ñ, Arch. Neurol., 55 (1998), pp. 1,449├óÔé¼ÔÇ£1,455.
  16. McCaddon A et al., ├óÔé¼┼øHomocysteine and Cognitive Decline in Healthy Elderly├óÔé¼┼Ñ, Dement. Geriatr. Disord., 12 (2001), pp. 309├óÔé¼ÔÇ£313.
  17. Seshadri S et al., ├óÔé¼┼øPlasma Homocysteine as a Risk Factor for Dementia and Alzheimers Disease├óÔé¼┼Ñ, New Engl. J. Med., 3446 (2002), pp. 476├óÔé¼ÔÇ£483.
  18. Mava M et al., ├óÔé¼┼øFolate, Vitamin B12 and Homocysteine in Major Depressive Disorder├óÔé¼┼Ñ, Am. J. Psych., 154 (1997) pp. 426├óÔé¼ÔÇ£428.
  19. Bottiglieri T et al., ├óÔé¼┼øHomocysteine, Folate, Methylation, and Monoamine Metabolism in Depression├óÔé¼┼Ñ, J. Neurol. Neurosurg. Psychiatry, 69 (2000), pp. 228├óÔé¼ÔÇ£232.
  20. Bjelland I et al., ├óÔé¼┼øFolate, Vitamin B12, Homocysteine, and the MTHFR 677C├óÔÇá'T Polymorphism in Anxiety and Depression├óÔé¼┼Ñ, Arch. Gen. Psychiatry, 60 (2003), pp. 618├óÔé¼ÔÇ£626.
  21. Alpert J E et al., ├óÔé¼┼øNutrition and Depression: Focus on Folate├óÔé¼┼Ñ, Review. Nutrition, 16 (2000), pp. 544├óÔé¼ÔÇ£546.
  22. Coppen A and Bailey J, ├óÔé¼┼øEnhancement of the Antidepressant Action of Fluoxetine by Folic Acid: a Randomised, Placebo-controlled Trial├óÔé¼┼Ñ, J. Affective Disorders, 60 (2000), pp. 121├óÔé¼ÔÇ£130.
  23. Alpert M et al., ├óÔé¼┼øPrediction of Treatment Response in Geriatric Depression from Baseline Folate Level: Interaction with an SSRI or a Tricyclic Antidepressant├óÔé¼┼Ñ, J. Clin. Psychopharmacol., 23 (2003), pp. 309├óÔé¼ÔÇ£313.
  24. Smithells R W et al., ├óÔé¼┼øVitamin Deficiencies and Neural Tube Defects├óÔé¼┼Ñ, Arch. Dis. Child., 51 (1976), pp. 944├óÔé¼ÔÇ£950.
  25. Kirke P et al., ├óÔé¼┼øMaternal Plasma Folate and Vitamin B12 are Independent Risk Factors for Neural Tube Defects├óÔé¼┼Ñ, Quarterly J. Med., 86 (1993), pp. 703├óÔé¼ÔÇ£708.
  26. Vollset S E et al., ├óÔé¼┼øPlasma Total Homocysteine, Pregnancy Complications and Adverse Pregnancy Outcome: the Hordaland Homocysteine Study├óÔé¼┼Ñ, Am. J. Clin. Nutr., 71 (2000), pp. 962├óÔé¼ÔÇ£968.
  27. Kalter H, ├óÔé¼┼øFolic Acid and Human Malformations: A Summary and Evaluation├óÔé¼┼Ñ, Reproductive Toxicology, 14 (2000), pp. 463├óÔé¼ÔÇ£476.
  28. Williams L J, Mai C T, Edmonds L D et al., ├óÔé¼┼øPrevalence of Spina Bifida and Anencephaly During the Transition to Mandatory Folic Acid Fortification in the United States├óÔé¼┼Ñ, Teratology, 66 (2002), pp. 33├óÔé¼ÔÇ£39.
  29. Persad V L, VandenHof M C, Dube J A et al., ├óÔé¼┼øIncidence of Open Neural Tube Defects in Nova Scotia after Folic Acid Fortification├óÔé¼┼Ñ, Canadian Medical Association J., 167 (2002), pp. 241├óÔé¼ÔÇ£245.
  30. Martin D C et al., ├óÔé¼┼øTime Dependency of Cognitive Recovery with Cobalamin Replacement: Report of a Pilot Study├óÔé¼┼Ñ, J. Am. Geriatr. Soc., 40 (1992), pp. 168├óÔé¼ÔÇ£172.
  31. Rasmussen K et al., ├óÔé¼┼øTotal Homocysteine Measurement in Clinical Practice├óÔé¼┼Ñ, Review. Ann. Clin. Biochem., 37 (2000), pp. 627├óÔé¼ÔÇ£648.
  32. Nyg─é─ärd O et al., ├óÔé¼┼øTotal Plasma Homocysteine and Cardiovascular Risk Profile. The Hordaland Homocysteine Study├óÔé¼┼Ñ, JAMA, 274 (1995), pp. 1,526├óÔé¼ÔÇ£1,533.
  33. Malinow M R et al., ├óÔé¼┼øHomocyst(e)ine, Diet and Cardiovascular Diseases. A Statement for Health Professionals from the Nutrition Committee, American Heart Association├óÔé¼┼Ñ, Circulation, 99 (1999), pp. 178-182.
  34. Nurk E et al., ├óÔé¼┼øPredictors of 6-years Change in Plasma Total Homocysteine: The Hordaland Study├óÔé¼┼Ñ, Homocysteine Metabolism, 3rd International Conference (1├óÔé¼ÔÇ£5 July 2001), abstract 99.
  35. Homocysteine Trialists™ Collaboration, ├óÔé¼┼øBlood Homocysteine Lowering with Folic Acid-based Supplements: A Systematic Overview of the Randomized Trials├óÔé¼┼Ñ, Neth. J. Med., abstract suppl., 52 (1998), section 33.
  36. Heaney R P, ├óÔé¼┼øLong-latency Deficiency Disease: Insights from Calcium and Vitamin D├óÔé¼┼Ñ, Am. J. Clin. Nutr., 78 (2003), pp. 912├óÔé¼ÔÇ£919.