Review of Homocysteine

By Antony Haynes BA,  Registered Nutritional Therapist

The word ‘homocysteine’ has entered the lexicon of familiar words over the past decade, at least for health practitioners, as has the term methylation, and the two are intimately connected.

What is Methylation?

Methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group, rather than a larger carbon chain, replacing a hydrogen atom. Methylation is catalysed by enzymes.

Methylation is involved in the regulation of gene expression, regulation of protein function, and RNA processing, and in the modification of heavy metals.

Homocysteine

This review is designed to tell you what homocysteine is, review evidence of its role in human disease, tell you what an ideal blood level is, briefly review its metabolism in our body and identify nutritional means by which to maintain optimal levels in order to protect our health from possible negative effects of too high a level. The vitamins involved in homocysteine metabolism are folic acid, vitamin B12 and vitamin B6. Betaine, aka trimethylglycine, is also involved.

The level of homocysteine in the plasma is increasingly being recognised as a risk factor for disease and seen as a predictor of potential health problems such as cardiovascular disease and Alzheimer’s. But, do we all need to get a test done? Do we all need to take the key B vitamins to lower our levels? I will address these questions.

What is homocysteine?

Homocysteine is a naturally occurring amino acid produced as part of the body’s methylation process, derived from methionine in the food we eat. It is an intermediary amino acid formed by the conversion of methionine to cysteine. The level of homocysteine is what matters, with the higher levels being more negative, according to numerous studies. However, there is some controversy in the research about its role in pathology.

What conditions is high homocysteine associated with?

Homocystinuria (a high level in the urine) or severe hyperhomocysteinemia (a high level in the blood) is a rare autosomal recessive disorder characterised by severe elevations in plasma and urine homocysteine concentrations.  Clinical manifestations of homocystinuria include developmental delay, osteoporosis, ocular abnormalities, thromboembolic disease, and severe premature atherosclerosis.

What conditions are moderately high levels of homocysteine associated with?

Less marked elevations in plasma homocysteine are much more common, occurring in 5 to 7 percent of the population. Although unassociated with the clinical stigmata of homocystinuria, mounting evidence suggests that moderate hyperhomocysteinemia is an independent risk factor for atherosclerotic vascular disease and for recurrent venous thromboembolism[1].

Who first brought homocysteine to our attention?

Dr Kilmer McKully has been the pioneer in research and for publicising the importance of homocysteine. After many years of research and commitment to the subject in the face of much criticism, he published his book ‘The Homocysteine Revolution: A Bold New Approach to the Prevention of Heart Disease’ in 1999. The focus on homocysteine and methylation has only increased since that time.

Mixed evidence

This being said, when one looks at the CV research when homocysteine has been lowered, there have been no benefits of improving CV risk[2],[3],[4],[5],[6],[7],[8]. Importantly, however, these studies did not use the active form of folate but rather folic acid alone or alongside vitamins B6 & B12 and this may be a vital variable when reviewing the relevance of the findings of these studies. This is due to the variations in the genetic expression of the enzymes, more of which shortly.

However, there are many research studies showing a definite link between homocysteine and cardiovascular disease and other conditions.

Very high homocysteine levels appear to be clearly associated with an increased risk of cardiovascular[9] and cerebrovascular disease and Alzheimer’s disease[10],[11],[12],[13]. However, homocysteine does not appear to be as important as other risk factors such as hypercholesterolemia, smoking, diabetes mellitus, and hypertension.

Yet, in a recent 2016 study, “CVD patients had significantly higher concentrations of homocysteine”, and this was also associated with a higher level of total oxidant stress (TOS), serum total lipids, high density lipoprotein-cholesterol (i.e. too low a level) and low density lipoprotein cholesterol (LDL-C) (i.e. too high a level)[14]. Additionally, in another 2016 study, the researchers concluded that “Homocysteine is an independent indicator of asymptomatic CAS, especially in patients with diabetes”[15].

In a 2015 meta-analysis by Li et al[16], it was acknowledged that numerous randomised controlled trials have investigated the efficacy of lowering homocysteine with folic acid supplementation for CVD risk, but conflicting results have been reported. They reviewed 30 randomised controlled trials involving 82 334 participants were included in the final analysis.

Their conclusions indicated a 10% lower risk of stroke and a 4% lower risk of overall CVD with folic acid supplementation. A greater benefit for CVD was observed among participants with lower plasma folate levels and without pre-existing CVD and in studies with larger decreases in homocysteine levels. Folic acid supplementation had no significant effect on risk of coronary heart disease.

An increased homocysteine level is associated with a higher risk of strokes. Carotid stenosis appears to have a graded response to increased levels of homocysteine. Increased carotid plaque thickness has been associated with high homocysteine and low B-12 levels.

In a 1999 study[17] by Yoo et al, both intracranial and extracranial vessels were studied by MR angiography and reported that homocysteine levels were higher in patients with 2- or 3-vessel stenoses than in those with 1-vessel stenosis.

The issue of whether homocysteine plays a causal role in cardiovascular disease or whether there is a non-causal association has additionally been addressed by meta-analyses that have looked at both prospective studies and MTHFR mutation studies.  Similar odds ratios for cardiovascular disease were found in both types of studies. The consistent odds ratios across studies that should have had distinct sources of bias and error argue in favour of a causal role for homocysteine.

In contrast, a subsequent meta-analysis of MTHFR mutation studies found no evidence of a causal relationship between homocysteine and coronary heart disease in studies of North American, European, and Australian populations, but did find such evidence in studies of Middle Eastern and Asian populations. The study found evidence of publication bias, and the authors felt the results could potentially be explained by such bias or by geographic variability in folate intake[18].

Elevations in the plasma homocysteine concentration can occur due to genetic defects in the enzymes involved in homocysteine metabolism, to nutritional deficiencies in vitamin cofactors, or to other factors including some chronic medical conditions and drugs.  Some drugs used in the treatment of hypercholesterolemia, such as fibrates and nicotinic acid, can raise homocysteine levels by approximately 30 percent; however, the clinical significance of this is uncertain. Cigarette smoking also may elevate homocysteine levels. Chronic kidney failure can increase homocysteine levels due to decreased renal removal and impaired metabolism[19].

Normal homocysteine concentrations range between 5 and 15 µmol/L.

Hyperhomocysteinemia has been classified by Kang et al (1992)[20] as follows:

• Moderate (15 to 30 µmol/L)
• Intermediate (30 to 100 µmol/L)
• Severe (>100 µmol/L)

Genetic Variations

Methylene tetrahydrofolate reductase (MTHFR) is the rate-limiting enzyme in the methyl cycle, and it is encoded by the MTHFR gene. Methylenetetrahydrofolate reductase catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a cosubstrate for homocysteine remethylation to methionine. Natural homozygous variations in this gene are common in healthy people. Although some variants have been reported to influence susceptibility to occlusive vascular disease, neural tube defects, Alzheimer’s disease and other forms of dementia, colon cancer, and acute leukaemia, findings from small early studies have not been reproduced. Some mutations in this gene are associated with MTHFR deficiency.

As already stated above, one thing that has not been fully analysed and appreciated in the above studies which offer differing strengths of connections with is the genetic variations within individuals as to how effective folic acid may be when the active folate is required for the methylation cycle to work properly.

Food first

A diet high in organic fruits and vegetables will also usually lower homocysteine levels. To maintain low plasma homocysteine concentration, people should be advised to increase their consumption of pulses, eggs, green leafy vegetables and fruits which are rich in B vitamins[21].

However, it has also been shown that a combination therapy with B vitamins – folate, vitamins B12 and B6 is an effective means to reduce elevated homocysteine levels in general people and in patients with myocardial infarction[22].

Lab testing for nutrients

To obtain a more accurate reflection of B12, folic acid and B6 status, additional testing may be worthwhile.  Methylmalonic acid (MMA), whether serum or urine is a far more sensitive indicator of B12 status; same with RBC folate.  Serum B6 is adequate.  Stop all supplements 72 hours before the test[23].

Summary

Homocysteine is now appreciated as a risk marker for cardiovascular disease and cerebrovascular diseases such as Alzheimer’s disease. However, there is mixed evidence of its impact on the development of these conditions. Folate and vitamins B12 and B6 and betaine can help to lower the risk of disease that has been associated with high homocysteine levels. A diet rich in leafy vegetables & other foods rich in folate provides sufficient folate for the majority of the population. However, there may be value in preventative supplementation, especially if the foods highlighted are not being consumed in sufficient amounts. A specific homocysteine test may be warranted to determine action.

Folate is not synthesised de novo by humans, therefore the daily requirements are met from the dietary intake of folic acid supplements or food rich in this vitamin. Folate deficiency could lead to numerous common health problems. Hyperhomocysteinemia and the possibility of malignancy developments are the long-term consequences of this deficit, albeit that there are contradictory findings on these claims.

Homocysteine can reasonably be seen to be an independent risk factor for heart disease as well as Alzheimer’s but, as with other individual markers such as cholesterol, needs to be viewed in the context with the widest array of markers available in order for intervention to be most appropriate for the health of the individual. Nonetheless, it is worth remembering the adage which states that “an ounce of prevention is worth a pound of cure”.

References

[1] McCully KS.  Homocysteine and vascular disease.  Nat Med. 1996;2(4):386.  (http://tinyurl.com/msgcoqq).

[2] Clarke R, Halsey J, Bennett D, Lewington S. Homocysteine and vascular disease: review of published results of the homocysteine-lowering trials. J Inherit Metab Dis. 2011 Feb;34(1):83-91. doi: 10.1007/s10545-010-9235-y. Epub 2010 Nov 11. View abstract

[3] Clarke R, Halsey J, Lewington S, Lonn E, Armitage J, Manson JE, Bønaa KH, Spence JD, Nygård O, Jamison R, Gaziano JM, Guarino P, Bennett D, Mir F, Peto R, Collins R; B-Vitamin Treatment Trialists’ Collaboration. Effects of lowering homocysteine levels with B vitamins on cardiovascular disease, cancer, and cause-specific mortality: Meta-analysis of 8 randomized trials involving 37 485 individuals. Arch Intern Med. 2010 Oct 11;170(18):1622-31. doi: 10.1001/archinternmed.2010.348. View abstract

[4] B-Vitamin Treatment Trialists’ Collaboration. Homocysteine-lowering trials for prevention of cardiovascular events: a review of the design and power of the large randomized trials. Am Heart J. 2006 Feb;151(2):282-7. View abstract

[5] Ebbing M, Bønaa KH, Arnesen E, Ueland PM, Nordrehaug JE, Rasmussen K, Njølstad I, Nilsen DW, Refsum H, Tverdal A, Vollset SE, Schirmer H, Bleie Ø, Steigen T, Midttun Ø, Fredriksen A, Pedersen ER, Nygård O. Combined analyses and extended follow-up of two randomized controlled homocysteine-lowering B-vitamin trials. J Intern Med. 2010 Oct;268(4):367-82. doi: 10.1111/j.1365-2796.2010.02259.x. View abstract

[6] Marcus J, Sarnak MJ, Menon V. Homocysteine lowering and cardiovascular disease risk: lost in translation. Can J Cardiol. 2007 Jul;23(9):707-10. View abstract

[7] Wierzbicki AS. Homocysteine and cardiovascular disease: a review of the evidence. Diab Vasc Dis Res. 2007 Jun;4(2):143-50. View abstract

[8] JAMA. 2008 Aug 20;300(7):795-804. doi: 10.1001/jama.300.7.795. Ebbing M, Bleie Ø, Ueland PM, Nordrehaug JE, Nilsen DW, Vollset SE, Refsum H, Pedersen EK, Nygård O. Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography: a randomized controlled trial. View abstract

[9] Kang SS, et al.  Hyperhomocyst(e)inemia as a risk factor for occlusive vascular disease. Annu Rev Nutr. 1992;12:279.  (http://tinyurl.com/p9d6hkw)

[10] Wu JT.  Circulating Homocysteine Is An Inflammation Marker And A Risk Factor of Life-Threatening Inflammatory Diseases.  J Biomed Lab Sci 2007 Vol 19 No 4.  (http://tinyurl.com/ktspr4l)

[11] Ravaglia G, et al.  Homocysteine and folate as risk factors for dementia and Alzheimer disease.  Am J Clin Nutr. 2005 Sep;82(3):636-43.  (http://tinyurl.com/k2y59w3)

[12] Hooshmand B, et al.  Homocysteine and holotranscobalamin and the risk of Alzheimer disease: a longitudinal study.  Neurology. 2010 Oct 19;75(16):1408-14. (http://tinyurl.com/o3tqm5n)

[13] Seshadri S.  Elevated plasma homocysteine levels: risk factor or risk marker for the development of dementia and Alzheimer’s disease?  J Alzheimers Dis. 2006 Aug;9(4):393-8.  (http://tinyurl.com/mmsrth9)

[14] Qasim M, Bukhari SA, Ghani MJ, Masoud MS, Huma T, Arshad M, Haque A, Ibrahim Z, Javed S, Rajoka MI. Relationship of oxidative stress with elevated level of DNA damage and homocysteine in cardiovascular disease patients. Pak J Pharm Sci. 2016 Nov;29(6(Suppl)):2297-2302. View abstract

[15] Jia J, Wang A, Wang J, Wu J, Yan X, Zhou Y, Chen S, Zhao X. Homocysteine and Its Relationship to Asymptomatic Carotid Stenosis in a Chinese Community Population. Sci Rep. 2016 Nov 21;6:37361. doi: 10.1038/srep37361. View abstract

[16] Li Y, Huang T, Zheng Y, Muka T, Troup J, Hu FB. Folic Acid Supplementation and the Risk of Cardiovascular Diseases: A Meta-Analysis of Randomized Controlled Trials. J Am Heart Assoc. 2016 Aug 15;5(8). pii: e003768. doi: 10.1161/JAHA.116.003768. View Full Paper

[17] Yoo JH, Chung CS, Kang SS. Relation of plasma homocyst(e)ine to cerebral infarction and cerebral atherosclerosis. Stroke. 1998 Dec;29(12):2478-83. View Full Paper

[18] Lewis SJ, et al.  Meta-analysis of MTHFR 677C->T polymorphism and coronary heart disease: does totality of evidence support causal role for homocysteine and preventive potential of folate?  BMJ. 2005;331(7524):1053.  (http://tinyurl.com/q94evu8)

[19] Desouza C, et al.  Drugs affecting homocysteine metabolism: impact on cardiovascular risk.  Drugs. 2002;62(4):605.  (http://tinyurl.com/qfxoso5)

[20] Kang SS, et al.  Hyperhomocyst(e)inemia as a risk factor for occlusive vascular disease. Annu Rev Nutr. 1992;12:279.  http://tinyurl.com/p9d6hkw 

[21] Krishnaswamy K, Lakshmi AV. Role of nutritional supplementation in reducing the levels of homocysteine. J Assoc Physicians India. 2002 May;50 Suppl:36-42. View abstract

[22] Krishnaswamy K, Lakshmi AV. Role of nutritional supplementation in reducing the levels of homocysteine. J Assoc Physicians India. 2002 May;50 Suppl:36-42. View abstract

[23] Vitamin B12 and Folate, The Test.  Lab Tests Online.  2013. (http://tinyurl.com/7xpqwlb).