Homocysteine: Really Not a Crystal Ball

Former Visiting Professor Patrick Holford is still Head of Science and Education at Biocare so presumably they must believe that he enhances their reputation and scientific credibility with his advocacy of tests such as those for homocysteine (Hcy) levels and recommendations that people with high levels (as defined by him) should lower it by taking various supplements (see related reading).

According to Holford and Dr James Braly, Hcy is:

[l]ike a chemical crystal ball, it reveals exactly what we should be doing to guarantee our future health…your H score predicts your risk of more than 100 diseases and medical conditions-including increased risk of premature death from all common causes.

HolfordWatch has covered the extravagant claims relating to the clinical benefits of reducing homocysteine levels with supplements on several occasions. Recent trials emphasise that there is still no substantial evidence to support such recommendations for the general, asymptomatic population.

We need to update our section on Hcy but, in the interim, for those parties who are interested, we list some recent papers about Hcy and humans. We preface this with the fine advice from Vasan.

Regardless of the purpose for its use, a new biomarker will be of clinical value only if it is accurate, it is reproducibly obtained in a standardized fashion, it is acceptable to the patient, it is easy to interpret by clinicians, it has high sensitivity and high specificity for the outcome it is expected to identify, it explains a reasonable proportion of the outcome independent of established predictors consistently in multiple studies, and there are data to suggest that knowledge of biomarker levels changes management.

Vasan RS. (2006) Biomarkers of cardiovascular disease: molecular basis and practical considerations. Circulation 113: 2335-2362

As you glance through the following studies, recall that it is possible to reduce Hcy levels but there has not, as yet, been any demonstrable clinical primary outcome such as a reduction in death by CVD following a prior incident. In the absence of such findings it is possible that Hcy is an interesting biomarker that is associated with a variety of conditions or underlying systemic inflammation but that reducing it does not have a clinical impact.

Albert CM, Cook NR, Gaziano JM, Zaharris E, MacFadyen J, Danielson E, Buring JE, and Manson JE. Effect of Folic Acid and B Vitamins on Risk of Cardiovascular Events and Total Mortality Among Women at High Risk for Cardiovascular Disease. JAMA, May, 2008; vol 299(17): pp. 2027-2036.
The women who participated in the study were US health professionals aged 42 years or older. Participants had either a history of cardiovascular disease or 3 or more coronary risk factors; the trial follow-up extended for 7.3 years, which is substantially longer than many previous trials. They were randomised to a combination pill of B vitamins recommended for lowering Hcy levels or a placebo. Although the pill was successful in reducing Hcy levels there was no significant clinical benefit such as a reduction in major cardiovascular events.

In summary…a combination pill of 2.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg vitamin B12 had no beneficial or adverse effects on a combined outcome of total major cardiovascular events in a high-risk population of women with prior cardiovascular disease or 3 or more coronary risk factors over 7.3 years of follow-up. Our results are consistent with prior randomized trials performed primarily among men with established vascular disease3 and do not support the use of folic acid and B vitamin supplements as preventive interventions for CVD in these high-risk–fortified populations.

This trial involved a significant number of women without prior cardiovascular disease (n=1950) but it was comparatively underpowered to be confident about the outcome for primary prevention of major cardiovascular events. However, does the outcome of this match the hyperbolic description of Hcy as a crystal ball?

Ray JG. Hyperhomocysteinemia: no longer a consideration in the management of venous thromboembolism. Curr Opin Pulm Med. 2008 Sep;14(5):369-73.
Ray looks at the evidence for the answers to 4 questions. One of the questions is “Does lowering plasma homocysteine alter the risk of venous thromboembolism?”. However, although it is possible to lower Hcy levels by the supplementation of various vitamins and formulations, “two randomized placebo-controlled trials have failed to show a significant reduction in the risk of venous thromboembolism by lowering plasma homocysteine”.

Celik T, Iyisoy A, Yuksel UC, Isik E. Homocysteine-lowering vitamins and cardiovascular mortality: are they really effective? Int J Cardiol. 2008 Aug 29;128(3):432-3.
The authors consider current data obtained from prospective outcome studies, and conclude that, for the present, it is premature to support the use of homocysteine-lowering vitamins including folic acid in patients with established coronary artery disease in order to improve cardiovascular outcomes.

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. JAMA. 2008 Aug 20;300(7):795-804.
This trial did not find an effect of treatment with folic acid/vitamin B(12) or vitamin B(6) on total mortality or cardiovascular events. The findings do not support the use of B vitamins as secondary prevention in patients with coronary artery disease. Medscape elaborates but the message remains the same: Don’t End It With WENBIT — Details Needed on B Vitamins, Stroke, and Cancer. (Free registration.)

Observational studies have reported associations between circulating total homocysteine concentration and the risk for cardiovascular disease and stroke. Because oral administration of folic acid can lower plasma total homocysteine levels, numerous trials have investigated whether cardiovascular disease could be prevented by homocysteine-lowering therapy. However, so far, none of the larger published trials has reported any effect of homocysteine lowering on the risk for cardiovascular disease or total mortality rates.

This trial didn’t change anything: it looks like you can use vitamins to lower Hcy levels but to no useful clinical outcome.

Maron BA, Loscalzo J. The Treatment of Hyperhomocysteinemia. Annu Rev Med. 2008 Aug 19.
This has it every way suggesting that the lack of clinical results from the trial suggest the need for identifying sub-groups for whom this is relevant: however, the authors suggest that this ranges from those who might be interested in primary prevention of atherothrombotic disease in individuals at low or intermediate risk, or those with severe hyperhomocysteinemia.

Numerous epidemiological reports have established hyperhomocysteinemia as an independent risk factor for cardiovascular disease, cerebrovascular disease, dementia-type disorders, and osteoporosis-associated fractures. Although combined folic acid and B-vitamin therapy substantially reduces homocysteine levels, results from randomized placebo-controlled clinical trials testing the effect of vitamin therapy on outcome in these diseases have generally fallen short of expectations.

Purnell C, Gao S, Callahan CM, Hendrie HC. Cardiovascular Risk Factors and Incident Alzheimer Disease: A Systematic Review of the Literature. Alzheimer Dis Assoc Disord. 2008 Aug 13.
The clinical literature is mixed but despite a diligent search there is a lack of a clear finding.

In this review, the evidence that single clinically defined cardiovascular risk factors are significantly associated with incident AD is inconsistent at best. The strength of the association of cardiovascular risk factors and AD can be influenced greatly by changing the parameters of measurement of risk factors and by identifying interactions between the factors.

Mashavi M, Hanah R, Boaz M, Gavish D, Matas Z, Fux A, Shargorodsky M. Effect of homocysteine-lowering therapy on arterial elasticity and metabolic parameters in metformin-treated diabetic patients. Atherosclerosis. 2008 Aug;199(2):362-7.
Metformin increases levels of Hcy: the experimental study involved an n=60.

Hcy-lowering therapy improved small arterial elasticity in diabetic patients treated with high dose of metformin. The improvement was associated with a decrease in Hcy as well as an increase in folic acid and vitamin B12. These findings suggest that Hcy-lowering may have beneficial vascular effect in metformin-treated diabetic patients.

Interesting. However, it remains to be see if there is a significant difference in primary clinical outcomes rather than surrogate end-points.

Kamphuis MH, Geerlings MI, Grobbee DE, Kromhout D. Dietary intake of B(6-9-12) vitamins, serum homocysteine levels and their association with depressive symptoms: the Zutphen Elderly Study.

Low B-vitamin status and high levels of serum homocysteine are found in depressed inpatients, but results of population-based studies of this association are inconclusive. We investigated whether a low dietary intake of B(6-9-12) vitamins and high levels of serum homocysteine are associated with depressive symptoms in elderly men…
Our results do not support the hypothesis that a low dietary intake of B(6-9-12) vitamins and high levels of serum homocysteine are related to depression in healthy elderly men.

Kim JM, Stewart R, Kim SW, Shin IS, Yang SJ, Shin HY, Yoon JS. Changes in folate, vitamin B12 and homocysteine associated with incident dementia. J Neurol Neurosurg Psychiatry. 2008 Aug;79(8):864-8.

Prospective findings have not been consistent for folate, vitamin B(12) and homocysteine concentrations as predictors of dementia. This study aimed to investigate both baseline concentrations of folate, vitamin B(12) and homocysteine and changes in these concentrations as predictors/correlates of incident dementia…
Only baseline lower folate concentrations predicted incident dementia. The onset of dementia was significantly associated with an exaggerated decline in folate, a weaker increase in vitamin B(12) concentrations and an exaggerated increase in homocysteine concentrations over the follow-up period. These associations were reduced following adjustment for weight change over the same period.

Potter K, Hankey GJ, Green DJ, Eikelboom JW, Arnolda LF. Homocysteine or renal impairment: which is the real cardiovascular risk factor? Arterioscler Thromb Vasc Biol. 2008 Jun;28(6):1158-64.
The authors evaluated whether adjustment for renal function eliminates the relationship between total plasma homocysteine (tHcy) and vascular risk, assessed by carotid intima medial thickness (CIMT) and flow-mediated dilation (FMD) of the brachial artery. They assessed the cross-sectional data from 173 stroke patients who were treated with B-vitamins (folic acid 2 mg, vitamin B(6) 25 mg, and vitamin B(12) 0.5 mg) or placebo in a randomized double-blinded trial to test the relationships between posttreatment tHcy, cystatin C (a marker of glomerular filtration rate), estimated glomerular filtration rate (eGFR, Modification of Diet in Renal Disease equation) creatinine, CIMT, and FMD. The authors concluded:

Adjusting for renal function eliminates the relationship between tHcy and CIMT and FMD, supporting the hypothesis that elevated tHcy is a marker for renal impairment rather than an independent cardiovascular risk factor. [Emphasis added.]

Potter K. Homocysteine and cardiovascular disease: should we treat? Clin Biochem Rev. 2008 Feb;29(1):27-30.
Earlier this year Potter wrote about the vexed issue of treatment.

recent results, added to earlier data, suggest that moderately elevated tHcy is a risk marker for vascular disease rather than a causal risk factor. B-vitamin treatment modifies the marker without reducing the underlying risk. However, the homocysteine hypothesis is not yet disproved. Most large trials have enrolled subjects with existing vascular disease, with end-stage renal failure or with multiple risk factors for atherosclerosis. B-vitamins may prove more effective if treatment is begun prior to the development of clinically evident disease, although this has yet to be demonstrated…

An abrupt increase in colorectal cancer rates followed the introduction of mandatory food fortification with folic acid in both the USA and Canada, and recent epidemiological data suggests that individuals who take B-vitamin supplements may be at increased risk of breast, prostate and colorectal tumours.35–39 This new evidence may prompt homocysteine-lowering trialists to re-analyse their data for cancer outcomes.

Several large homocysteine-lowering trials are still ongoing and will provide additional data on the safety and efficacy of long-term B-vitamin supplementation.15,17,40,41 A meta-analysis including data from more than fifty thousand trial participants is planned and will have adequate power to clearly determine whether lowering tHcy reduces vascular event rates.42 Currently, however, there is no evidence to support B-vitamin treatment in patients at risk of cardiovascular disease.

Currently, it seems like there is no clear clinical evidence to support the notion that lowering raised homocysteine levels actually results in a significant clinical outcome. Even at a recent homocysteine conference, the general consensus was:

The results of ongoing randomized controlled intervention trials must be available before screening for and treatment of hyperhomocysteinemia can be recommended for the apparently healthy general population.

Dr Eva Lonn’s editorial in JAMA addresses the implications of a newly-published trial that looked at the clinical outcomes for women who took B vitamins to reduce their Hcy levels (full text currently available): Effect of Folic Acid and B Vitamins on Risk of Cardiovascular Events and Total Mortality Among Women at High Risk for Cardiovascular Disease (above). Lonn provides a thoughtful editorial that gives an overview of the history of the heady potential of the therapeutic manipulation of homocysteine levels: Homocysteine-Lowering B Vitamin Therapy in Cardiovascular Prevention—Wrong Again? However, as she points out, the optimism has not been justified for the general population.

While the experimental and epidemiological evidence does indeed support a plausible role for homocysteine lowering in CVD prevention in the population at large (as opposed to a limited role in rare genetic disorders), overzealous interpretations of such data have led to extrapolations and unjustified early enthusiasm…

Two obvious questions arise: why did the B vitamin homocysteine-lowering trials conducted to date not demonstrate clinical benefits and is there a role for additional trials or should researchers close yet another chapter, which seemed promising but failed to deliver. The answers to these questions are complex…However, it is possible that the treatment truly has no effect on vascular risk…

In conclusion, B vitamin supplements cannot currently be recommended for the prevention of CVD events (with the exception of rare genetic disorders) and there is no role for routine screening for elevated homocysteine levels. However, ongoing clinical research should provide further evidence on whether there may be any role for homocysteine-lowering B vitamin supplements in CVD prevention and for the overall importance of homocysteine as a CVD risk factor.

One obvious caveat is that the outcomes from the above trials might be different for a population that is not well-nourished or for countries where there is no fortification of common foodstuffs with folic acid (as mentioned in WENBIT).

On a side-note, we have seen frequent claims that Hcy levels are monitored routinely as part of healthcare in Germany, we would be grateful for any information or pointers to Eurostat analyses or similar that comment on whether this translates into improved clinical outcomes.

Folic acid supplements have clear benefits for some demographics such as women who may conceive or are in the first trimester of pregnancy. However, for other segments of the population, where there is routine fortification of foodstuffs, there are some concerns that excess supplementation with folic acid might be associated with an increase in colon cancer.[1][2] Dr Steve Murphy advocates personalised medicine but as a Gene Sherpa argues that lowering homocysteine hasn’t had the expected clinical effects and that there are some groups for whom the recommended vitamin supplementation is contra-indicated.

Hcy does not seem to meet Vasan’s criteria for a practical and useful biomarker. Overall, it does not seem as if Hcy testing and therapeutic intervention by supplementation is ready to go mainstream for the general population. The hype seems to run ahead of the evidence for the clinical benefits of reducing Hcy levels, particularly when the recommended supplementation and sequence of testing and re-testing to tweak supplementation levels may cost from £500-£1000 per person, per annum. [a]


[a] Regular homocysteine tests (as recommended 2-3 times a year to establish your baseline levels and tweak/maintain them with vitamin supplements) cost money; from around £70-75 per test. The recommended Connect supplement is cheaper than the previously-touted H-Factors and will cost from £24.95 for 90 days to £24.95 for 30 days, depending on the recommended dose. There is no information about the bioavailability of the contents, so I don’t know if it is appropriate to expect your GP or Practice Nurse to advise you on your Connect dosage; you might need to pay to consult a nutritionist or similar. A nutritionist might base his/her recommendations on an inappropriate interpretation of research and some unsupported beliefs. It should be noted that Holford typically recommends that all targeted supplements like this are taken alongside his usual basic recommendations that work out at around £5.68 per person, per day for an adult.

You may well be comforted at the thought that your homocysteine levels are low or within bounds; however, it might be helpful if you are confident that there is good quality research to support the value of this. So, be aware that you might spend between £700-1000 per year and successfully lower your homocysteine levels but still have raised blood pressure and no reduction in your risk for primary clinical outcomes such as a major CVD event.


[1] Cole BF, Baron JA, Sandler RS, Haile RW, Ahnen DJ, Bresalier RS, McKeown-Eyssen G, Summers RW, Rothstein RI, Burke CA, Snover DC, Church TR, Allen JI, Robertson DJ, Beck GJ, Bond JH, Byers T, Mandel JS, Mott LA, Pearson LH, Barry EL, Rees JR, Marcon N, Saibil F, Ueland PM, Greenberg ER; Polyp Prevention Study Group. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA. 2007 June; vol 297(21): pp. 2351-9.
[2] Ulrich, C.M. and Potter, J.D. Folate and Cancer—Timing Is Everything. JAMA. 2007 June; vol 297: pp 2408-2409.

Related Reading

Never Mind the Research Quality, Feel the Fear: Justifying Homocysteine Tests
Homocysteine: Helpful or Hoax Asks Patrick Holford
How Relevant Are Holford’s Claims About Homocysteine Levels? Part 1
How Relevant Are Holford’s Claims About Homocysteine Levels? Part 2
Patrick Holford, Alzheimer’s Disease, Homocysteine Tests and Supplements
Polypills or Vitamins for Homocysteine and Cardiovascular Risks: the Hype is Ahead of the Evidence
Gene Sherpa on homocysteine




Filed under Holford, home test, homocysteine, patrick holford, supplements

4 responses to “Homocysteine: Really Not a Crystal Ball

  1. Kelseigh

    Is there something weird about your RSS? I’m subscribed to the BPSBD feed, and I keep getting multiple copies of your posts. Everyone else’s comes in fine, but I keep getting old messages from yours. Sometimes four or five copies of posts going back about a week and a half.

  2. Claire

    The American Heart Association seems to share your reticence about the utility of hyc testing and supplementation.

  3. Claire

    Not sure how solid this is, given the source, but thought it might be of interest in this context.

  4. Pingback: Patrick Holford Promotes His Apocryphal Homocysteine Gospel in The News of the World « Holford Watch: Patrick Holford, nutritionism and bad science

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