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Homocysteine and heart disease: an update


Clinical bottom line

Studies support a link between cardiovascular disease and elevated levels of homocysteine in blood. The strength of the relationship remains, but is somewhat uncertain because different study architectures give different estimates.

The recognition that high levels of homocysteine are associated with heart disease started in the late 1960s when a pathologist in Boston encountered two children with homocystinuria, who, despite being very young, had advanced atherosclerosis, though the plaques contained no lipid. The pathologist concerned, Kilmer McCully, was given a hard time for putting forward the suggestion of a possible link between homocysteine and the formation of atheromatous plaque. Bandolier 57 summarised the evidence up to 1998. A new systematic review means that this topic is worth revisiting.


ES Ford et al. Homocyst(e)ine and cardiovascular disease: a systematic review of the evidence with special emphasis on case-control studies and nested case-control studies. International Journal of Epidemiology 2002 31: 59-70


The review used computer searches of three databases up to 1999 for papers relating homocysteine to cardiovascular disease, and additionally searched doctoral thesis abstracts for 1999. The search was limited to case-control, nested case-control and cohort studies of fatal and non-fatal cardiovascular and cerebrovascular disease. The outcome reported was the odds ratio for a 5 µmol/L change in homocysteine concentration for each of the studies.

Authors used a quality scoring system in which studies could score 0 to 10 (Table 1).

Table 1: Quality score for epidemiological studies



Study design
Cross-sectional study, series, or angiographic = 1
Case-control =2
nested case-control =3
Response rate
not given = 0
less than 75% =1
more than 75% = 2
Exclusion criteria
not given = 0
criteria specified = 1
Type of controls
hospital or mixed = 1
community = 2
Matching, adjustment for confounders
none = 0
any confounder = 1
age, smoking, hypertension, and cholesterol = 2


Coronary heart disease

There were 38 publications with 5,500 case subjects and 11,000 controls for coronary heart disease. The summary odds ratios for various studies are shown in Table 2. The result was significant for case-control studies, and in those in men and in women separately. There was a lower effect in studies scoring 7/10 or more on the scoring system compared with those scoring less than 7/10, but confidence intervals overlapped (Table 2).

Table 2: Summary odds ratios for a 5 µmol/L increase in homocysteine in coronary heart disease risk

Type of study

Number of studies

Odds ratio (95% CI)

Case-control, nested case-control


1.6 (1.4 to 1.7)

Men only


1.5 (1.3 to 1.6)

Women only


1.9 (1.3 to 2.9)

Higher quality studies

1.5 (1.2 to 1.8)

Lower quality studies

1.8 (1.5 to 2.0)

Cerebrovascular disease

There were 24 publications with 1,800 case subjects and 4,800 controls for cerebrovascular disease. The summary odds ratio was 2.0 (1.6 to 2.4).


One of the interesting things about this review is that it teases out some differences in the strength of the result depending on different designs, as an accompanying commentary points out [1], and as Figure 1 shows.

Figure 1: Association of a 5 µmol/L increase in homocysteine with the probability of heart disease or stroke


Where do we go from here? It is interesting that there is a bit of a difference, but with only two cohort studies, we probably should not get too excited. Clarke [1] tells us that there is an individual patient meta-analysis underway at Oxford, and that will tell us more.

Until then, the cautious among us will keep eating our greens and supplementing that with a multivitamin pill containing folate every day, just to be on the safe side.


  1. R Clarke. Commentary: an updated review of the published studies of homocysteine and cardiovascular disease. International Journal of Epidemiology 2002 31: 70-71.