Tag Archives: james braly

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). Continue reading

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Polypills or Vitamins for Homocysteine and Cardiovascular Risks: the Hype is Ahead of the Evidence

You may have experienced déjà vu over the last few days if you’ve been reading excited accounts about polypills for the over-55s (there was a lot of Oh Brave New World about the potential for polypills in 2003). The claims are that polypills will prevent 100,000 premature deaths a year and also prevent up to 80% of heart attacks and strokes. The polypills will contain a cholesterol-reducing statin; three types of medicine to lower blood pressure (thiazide, aspirin and beta-blockers); and folic acid to reduce levels of homocysteine (Hcy). Continue reading

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How Relevant Are Holford’s Claims About Homocysteine Levels? Part 2

Patrick Holford gives a remarkable overview of history to support his claims for the value of homocysteine testing in helping you “to eliminate your risk of ever having a heart attack”. He swoops from autopsies on egyptian mummies to unsubstantiated opinions on the prevalence of heart disease in late 19th century America via some mangled statistics on the risk of premature death from cardiovascular disease in the UK, before alighting on a study of restenosis to justify his claims.

One of the most common surgical procedures for those with coronary artery disease is angioplasty. It involves inserting catheter tubing containing a small balloon into arteries around the heart. The balloon is inflated to flatten deposits of atherosclerotic plaques blocking the artery, so blood can once again flow to the heart.

Like bypass surgery, angioplasty is often not a permanent cure, and after surgery the arteries may reclog in the treated area – a very undesirable condition called restenosis…

Restenosis of the coronaries is much more likely if your H score is high, according to research at the Swiss Cardiovascular Centre in Bern. (4) In a nutshell, this means the higher your H score, the faster your coronary arteries will narrow again after surgery, so there’s little point having an angioplasty without testing for and treating high homocysteine.

Unfortunately, this is only part of the story; the role of homocysteine levels in predicting restenosis is not that straightforward. Holford has frequently expressed his concern about the mis-citing of research literature and possible suppression of inconvenient findings, so it seems appropriate to look at the research literature for homocysteine and restenosis in a little more detail to see if he is representing the literature in an evenhanded way.

Back in 2000, Dr. Steven Miner and his colleagues published an interesting study into possible correlations between homocysteine concentrations and restenosis following angioplasty. This was a well-designed, prospective study. The authors were confident in their conclusion that raised homocysteine levels do not predict the likelihood of restenosis.

The range of plasma homocysteine concentrations in this study is consistent with that seen in other studies,[refs] as is the trend toward an increased mean homocysteine concentration in homozygotes for the MTHFR 677T genotype.[ref] However, ours is the first published study to investigate the possible correlation between homocysteine concentrations and restenosis after PTCA and clearly shows the absence of any positive correlation. This lack of effect is apparent in patients undergoing PTCA alone and in with those receiving adjuvant stenting. No threshold effect is apparent. The adequate sample size, near complete follow-up, and the trend toward a negative correlation makes the possibility of a false-negative study extremely unlikely. [Emphasis added.]

There are several other studies that do not find a signficant relationship for homocysteine and restenosis:

2002 Relation of homocysteine, vitamin B(12), and folate to coronary in-stent restenosis “These results suggest that homocysteine, folate, and vitamin B(12) are not related to the angiographically determined rate of coronary in-stent restenosis after 6 months.”

2005 Clinician Update Homocysteine and Its Effects on In-Stent Restenosis cites a number of earlier clinical trials that fail to show a relationship between high homocysteine levels and restenosis. They note that several trials are in progress and conclude: “Until complete results of these studies become available, screening for hyperhomocystinemia in patients undergoing coronary stenting is only recommended in the case of premature atherosclerotic disease (patients homocysteine-lowering therapy might have a deleterious effect in patients treated with stent implantation“. [Emphasis added.]

2006 A prospective patient observational study of the role of hyperhomocysteinemia in restenosis in patients undergoing infrainguinal angioplasty or bypass procedures. “This study does not support the hypothesis that HHCy is associated with an increased risk of restenosis after vascular intervention.”

2006 Effect of folic acid supplementation on risk of cardiovascular diseases: a meta-analysis of randomized controlled trials. This is one of the studies that Holford acknowledges and disputes; however, the authors conclude: “Folic acid supplementation has not been shown to reduce risk of cardiovascular diseases or all-cause mortality among participants with prior history of vascular disease. Several ongoing trials with large sample sizes might provide a definitive answer to this important clinical and public health question”.

2006 Efficacy of folic acid therapy for prevention of in-stent restenosis: a randomized clinical trial. “Treatment with folic acid does not decrease the rate of restenosis and need for revascularization of the target lesion after stent-percutaneous coronary angioplasty.”

2006 Post-interventional homocysteine levels: failure as a predictive biomarker of in-stent restenosis. “[W]e hypothesise that homocysteine may not serve as a safe and independent biomarker of in-stent restenosis after a six months period following percutaneous coronary stenting.”

Holford uses a restenosis study that is not validated by other researchers to assemble a supporting platform of evidence to demonstrate the value of widespread testing of homocysteine levels.

Holford and Braly claim that homocysteine levels are a “chemical crystal ball”. It would be profoundly useful and cost-effective if homocysteine levels were capable of predicting the need for restenosis or could function as a simple index of your current and future health. Unfortunately, it doesn’t seem as if a homocysteine test can bear the mantle of so much responsibility: there isn’t even a consensus of opinion as to whether or not it has a predictive role for restenosis although the evidence is increasingly against it.

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 H Factors vitamin supplement will cost from £41.60 for 90 days to £41.60 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 H Factors 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.

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. In subsequent parts of the review of Holford’s claims for homocysteine, we will look at trials that report that homocysteine levels can be reduced by vitamin supplementation but that this has no affect on clinical outcomes; e.g., you might spend between £700-1000 per year and successfully lower your homocysteine levels but still have raised blood pressure.

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How Relevant Are Holford’s Claims About Homocysteine Levels? Part 1

Patrick Holford and Dr. James Braly wrote a book about homocysteine and assert that it is “the best single indicator of whether you are likely to live long or die young: The H-Factor Solution. According to Holford and Braly, homocysteine 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.

Holford and Braly’s claims for the value of homocysteine are extraordinary. However, the proof that Holford offers is less impressive; particularly against the background of an article about homocysteine and coronary vascular disease (CVD) in which he substantially overstates the risk of premature death from CVD.

You might expect that any claims would be based on a balanced overview of all the research literature about homocysteine: any causal links to clinical conditions; its predictive value; whether it is possible to lower homocysteine levels with a therapeutic intervention; whether lowering homocysteine levels reduces the risk of disease, or poor outcomes in disease. I can’t comment on the book, but Holford does not do this in relevant articles on his website.

Holford is enthusiastic about the homocysteine test. The test is a significant part of his claims that you can follow his advice and learn How to Eliminate Your Risk of Ever Having a Heart Attack. I should emphasise that your homocysteine level is not a diagnostic test: it is not something like a cardiac enzyme study that can determine whether you’ve recently had a heart attack. If it’s not diagnostic, is it predictive? Does this test tell you something about your risk profile that is more meaningful than other sources of information such as a physical examination alongside a detailed family history? According to Holford:

[t]he single greatest risk of a heart attack comes from having a high homocysteine level. Homocysteine is a naturally-occurring protein that’s found in the blood. If you’ve had a heart attack, the chances that you have an unacceptably high homocysteine score (over 9 units) are well above 50 per cent. About 30 per cent of you will have a level above 15 units, which is very high. Very conservatively, I estimate that at least 8 million people in Britain have dangerously high homocysteine, increasing their risk of a heart attack by at least 50 per cent.

I’m going to go out on a limb and say that your “single greatest risk of a heart attack” is whether or not you’ve already had a heart attack, followed by your age (67% of deaths from CHD occur in those aged 75 and above figures calculated from British Heart Foundation statistics report (pdf)). I’m also going to say that there are some conditions, such as familial hyperlipidaemia that would raise a red flag and should be fully investigated before considering the need for a homocysteine test.

Gene Sherpa, Dr. Steve Murphy, provides fascinating insights into the role of genetics in personalised medicine. He emphasises the research that shows time and again that a good family clinical history is the best and cheapest genetic risk assessment that trumps most offerings from a direct-to-consumer testing service. He has recently commented on the importance of family history when estimating the risk of stroke. Murphy outlines research into a genetic variation that might affect homocysteine/folate/one carbon metabolism and raises questions about whether vitamin status plays a role. This might look like a showcase example of the need for nutrigenomics: how the appropriate diet and supplements can reduce risks attributable to individual variation. However, Murphy cautions that all is not as it seems:

  1. Homocysteine is only poorly linked to heart disease in asymptomatic patients
  2. There is some literature which states that B vitamin supplementation in patients with prior heart attack can cause WORSE outcomes.
  3. This is a replicated study, but not on a heterogeneous population………..

Basing his advice on the current state of knowledge, Murphy counsels that people who have already had a heart attack should not supplement B vitamins.

The following are some of the causes or proposed correlates of elevated homocysteine levels:

  1. defect in the transsulfuration pathway / deficiency in cystathionine B-synthase
  2. defect in the remethylation pathway / defective methylcobalamin synthesis or abnormality in MTHFR
  3. Proposed sources of abnormalities
    1. genetic predisposition

    2. genetic predisposition exacerbated by co-morbid conditions and/or nutritional and environmental factors:
      1. abnormal MTHFR
      2. chronic renal failure
      3. hypothyroidism
      4. methotrexate therapy
      5. oral contraceptive use
      6. malignancies of breast, ovary, and psoriasis
      7. smoking
      8. high alcohol consumption
      9. age

For most of these, you would need a skilled interpretation of your homocysteine levels alongside your clinical history: it might be very unwise to self-medicate to adjust homocysteine levels without allowing for relevant clinical details.

If the question about homocysteine measurement is, “For the general population, does this test tell you something about your risk profile for heart attacks that is more meaningful than other sources of information such as a physical examination alongside a detailed medical and family history?”, the answer would seem to be “No”. Holford and Braly may well have been right when they likened homocysteine to a “chemical crystal ball”; it is a matter of judgment for readers to decide whether or not they consider a “crystal ball” to be a reliable source of information.

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Homocysteine: Helpful or Hoax Asks Patrick Holford

I was disappointed in the quality of evidence that Patrick Holford put forward to support his claims that we could learn, How to Eliminate Your Risk of Ever Having a Heart Attack. Since then, I’ve been reading through the intervention trials that have experimented with lowering homocysteine levels through supplementation etc. and whether they have succeeded in lowering those levels, but not the incidence of clinical disease. Ultimately, it is more relevant to consider whether you have decreased the incidence of disease or reduced its severity rather than concentrating on a particular measurement. When you alter a particular measurement such as a cholesterol or homocysteine level, but you don’t reduce the incidence of (say) heart attacks or strokes, then it raises the suspicion that you have identified a false surrogate endpoint.

So, I was more than a little interested when I came across Holford’s article, Homocysteine: Helpful or Hoax? I don’t fully agree with his conclusions but it is a shame that he doesn’t link to this less dogmatic article from the one where he claims that

Lowering your H score…dramatically reduces the risk of death from all causes, not just heart attacks.

Holford is aware of trials that don’t support his conclusions and discusses those results with particular reference to the objections made by Dr. Helga Refsum. This discussion does, of course, include the use of a rhetorical device:

So was this a cover-up of the sort all too common with inconvenient findings in drug trials?

Somewhere in there, the fine nuance of Refsum’s arguments is lost. Holford quotes Refsum:

If we are going to optimise treatment for heart disease patients we need to discover what works for them and what doesn’t…The problem is that the trials so far are too small to come forward with definite advice.

It could also be argued that the trials, so far, are insufficient to support Holford’s broad recommendation for testing and supplementation in asymptomatic individuals.

In the light of his recent objections and comments about folate fortification (here and here), it is worth mentioning that Holford quotes Refsum on this:

The business of folate fortification…may also be affecting the results. Since it was introduced, stroke rates in North America have dropped significantly – by 10% in the USA and by 15% in Canada. “Translated into British terms,” says Dr Refsum, “those figures suggest that adding folate to the diet could actually save more than 5000 lives a year.” [Emphasis added.]

There is considerably more to say on the matter but it may well be premature (at best) to recommend that large-scale homocysteine screening and ‘corrective’ supplementation would “eliminate your risk of ever having a heart attack”. The evidence isn’t satisfactory or sufficient for people who have already had heart attacks and it has certainly not been adequately established for people who are asymptomatic. Helpful or hoax – who knows? Overhyped on the basis of current evidence – that’s a different question.

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Never Mind the Research Quality, Feel the Fear: Justifying Homocysteine Tests

I was recently trying to make sense of Patrick Holford’s support for homocysteine testing and his remarkable confidence in his own guidance: How to Eliminate Your Risk of Ever Having a Heart Attack. One of the irritations about reading Holford’s material is that it’s like being pecked by a hummingbird, darting from one assertion to another so rapidly that it’s difficult to get a “Huh?” in edgewise. It is usually very difficult to review Holford’s claims because he doesn’t provide references in his web articles although his text is dense with implied footnotes, scientific papers and reference texts. For this piece, I shall concentrate on Holford’s inappropriate interpretation of official statistics for cardiovascular disease and some simple mathematical errors.

Patrick Holford doesn’t seem to write in a rhetorical style other than one modelled after Cassandra and her prophecies of doom. Fortunately, Patrick Holford has a solution for most modern ills that he warns us about, and, usefully, it is typically available from his associated site, Health Products for Life. A recent example of this is, Are you being electrified? in which Holford guides us through the horrors of being immersed in electromagnetic radiation and advises us on various protective measures including the purchase of an Electrosmog detector that he sells.

Holford assures us that he does his research. Not only did he run an electrosmog detector around his own home:

[n]ext, I did additional research. I read well-respected medical journals. I looked into safety regulations in a wide variety of countries, including the UK, the United States, Russia, Sweden, Switzerland and New Zealand. I also delved into the technological and biotech publications.

After all that impressive array of research into electromagnetic radiation, it is a little disappointing that Holford only provided 10 references but that is better than his usual practice.

To return to the issue of homocysteine testing. I should probably state upfront that I don’t believe that it is currently possible to eliminate your risk of having a heart attack; it may be possible and even practical to reduce it but not to eliminate it. Socio-economic factors are widely reported to have a significant role in cardiovascular disease; as do race, gender, age, smoking, co-morbid diseases such as diabetes and family history (the British Heart Foundation statistics report gives a good overview of some of these factors). Research scientists and epidemiologists have worked very hard to discover whether there are dietary or pharmacological interventions that can overcome the impact of all of these contributory factors, but so far, there are not.

Holford has a hummingbird approach to proving his alarming claim that “[h]eart attacks and strokes have reached epidemic proportions”. He darts here and there, throwing in assertions from ancient history, the late nineteenth century and modern cultural comparisons, all without citing any references.

Britons, for example, have approximately nine times as much heart disease by middle age as the Japanese, although this difference is starting to narrow as the Japanese adopt more Western diets and lifestyles. But it wasn’t always this way.

Autopsies performed on mummified Egyptians who died in 3000 BC show signs of deposits in the arteries but no actual blockages that would result in a stroke or heart attack. Fast forward a few thousand years to 1890, where according to American health records, the incidence per 100,000 people of heart attacks was near zero. By 1970, however, that incidence had risen to 340 deaths per 100,000.

It’s a tremendous amount of work to track down all of these vague references (some of which I suspected to be wrong) so I concentrated on the assertions that I could readily check. E.g.:

[a]lmost one in two men and women die from heart attacks or strokes…In Britain, a quarter of a million people die prematurely every year from heart attack or stroke”.

No, they don’t; both of these statements are wrong. I know this because I read the same British Heart Foundation statistics report on which these assertions are probably based. Chapter 1 (pdf) of the British Heart Foundation (BHF) report summarises the mortality statistics.

Diseases of the heart and circulatory system (cardiovascular disease or CVD) are the main cause of death in the UK and account for just over 216,000 deaths in 2004. More than 1 in 3 people (37%) die of CVD

CVD is one of the main cause of premature death in the UK (death before the age of 75). 32% of premature deaths in men and 24% of premature deaths in women are from CVD…CVD caused just under 60,000 premature deaths in the UK in 2004.

It’s a considerable stretch to interpret 37% as “[a]lmost one in two”. The total number of deaths from CVD is a “quarter of a million”; the number of premature deaths that involve CVD is “just under 60,000”. There is no room for complacency, but the figures are lower than the alarming ones that Holford stated.

It’s bad enough when Holford misreports figures that are clearly stated in the BHF text; it becomes more embarrassing/awkward when he seems to interpret some of the data tables. E.g., Holford writes, “a quarter of all deaths from heart attack occur in people under the age of 65”. No, they don’t; not according to my calculations. At least, not according to Table 1.2 of the BHF report and some basic arithmetic which should surely be well within the attention grasp and number-handling skills of someone awash with the fish oil capsules that Holford recommends on a regular basis. Heart attacks are typically classified as coronary heart disease or CHD: I have reproduced these data from Table 1.2 of the report.

Deaths from CHD by sex and age, 2004, United Kingdom
All ages

Under 35

35-44

45-54

55-64

65-74

75 & over

Men

58,555

136

850

3,041

7,369

14,149

33,010

Women

47,287

36

196

610

2,006

6,634

37,805

Total

105,842

172

1,046

3,651

9,375

20,783

70,815


I don’t take fish oil supplements but it seems to me you can add the total number of deaths in the final two columns and subtract this new figure from the number of total deaths to calculate the number of deaths from CHD in the under-65s. From there, it should be a straightforward calculation to estimate whether it is accurate to say that “a quarter of all deaths from heart attack occur in people under the age of 65”.

The number of CHD deaths in people over the age of 65:
20,783+70,815=91,598
We need to subtract this number from the total number of deaths from CHD to obtain the number of people who died under the age of 65:
105,842-91,598=14,244
It doesn’t even need arithmetic skills, just estimation, to know that if 14,244 deaths from CHD occur in the under-65s, this is not even close to “a quarter” of 105,842. The percentage is 13.5.

Holford is wrong when he claims that, “a quarter of all deaths from heart attack occur in people under the age of 65”: according to the BHF figures, an accurate estimate of the number is 13.5%. I did Holford the courtesy of running various permutations of the numbers such as men only (19.5%), or calculating the numbers for all deaths from diseases of the circulatory system rather than just CHD (11%) but none of the numbers come out at anything approaching “a quarter”.

I shall spare you the reading around that I did on the issue of autopsies in egyptian mummies but I will say that only the very wealthy could afford the elaborate funeral rites of mummification, so this might skew the results. Further, it seems as if life expectancy was somewhere between the ages of 30-40 and it is possible that tuberculosis and various other endemic diseases killed many of these people. This post is not the appropriate place to counter the implication that it is only people with ‘blockages’ who experience fatal heart attacks or strokes: consider coronary artery spasm which can occur in arteries that appear normal; or sudden cardiac arrest that arises from an unsuspected abnormality.

I scouted about for information about heart disease and late 19th century America. Last year, the New York Times published an overview of some fascinating research into the history of some chronic diseases: So Big and Healthy Grandpa Wouldn’t Even Know You.

The biggest surprise emerging from the new studies is that many chronic ailments like heart disease, lung disease and arthritis are occurring an average of 10 to 25 years later than they used to. There is also less disability among older people today, according to a federal study that directly measures it. And that is not just because medical treatments like cataract surgery keep people functioning. Human bodies are simply not breaking down the way they did before…

Scientists used to say that the reason people are living so long these days is that medicine is keeping them alive, though debilitated. But studies like one Dr. Fogel directs, of Union Army veterans, have led many to rethink that notion.

The study involves a random sample of about 50,000 Union Army veterans. Dr. Fogel compared those men, the first generation to reach age 65 in the 20th century, with people born more recently…

Instead of inferring health from causes of death on death certificates, Dr. Fogel and his colleagues looked at health throughout life. They used the daily military history of each regiment in which each veteran served, which showed who was sick and for how long; census manuscripts; public health records; pension records; doctors’ certificates showing the results of periodic examinations of the pensioners; and death certificates.

They discovered that almost everyone of the Civil War generation was plagued by life-sapping illnesses, suffering for decades. And these were not some unusual subset of American men — 65 percent of the male population ages 18 to 25 signed up to serve in the Union Army. “They presumably thought they were fit enough to serve,” Dr. Fogel said…

After the war ended, as the veterans entered middle age, they were rarely spared chronic ailments…

Eighty percent had heart disease by the time they were 60, compared with less than 50 percent today.

The studies by Fogel and others do not directly contradict Holford’s assertions about heart disease in the late nineteenth century but they do highlight some relevant facts that might question the evidence base for his assertions.

In another post, I shall address the issue of whether your H-score and homocysteine tests are proxy measures for CVD risk or established causal factors in disease. I’ll look at the intervention trials that have experimented with lowering homocysteine levels through supplementation etc. and whether they have succeeded in lowering those levels, but not the incidence of clinical disease. Ultimately, it is more relevant to consider whether you have decreased the incidence of disease or reduced its severity rather than concentrating on a particular measurement. When you alter a particular measurement such as a cholesterol or homocysteine level, but you don’t reduce the incidence of (say) heart attacks or strokes, then it raises the suspicion that you have identified a false surrogate endpoint.

Holford might “read well-respected journals”, but when one considers the mangling of the straightforward BHF report, he doesn’t always seem to manage to distil or communicate the facts in an accurate and transparent way. This might lead a reader to consider whether Holford’s summary of the research evidence in support of homocysteine tests and supplementation is an accurate reflection of the literature and sufficiently strong to support his recommendations or his claims that you can “eliminate your risk of ever having a heart attack”.

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