Hyperhomocysteinaemia

In plasma, 70–80% of homocysteine is bound to
plasma proteins, chiefl y albumin; only about 1% circulates
as free homocysteine. The remaining 20–30%
circulates as homocysteine disulphide (homocystine)
or as the mixed disulphide, homocysteine–cysteine.
Plasma homocysteine assays measure total homocysteine,
which is the sum of the homocysteine moieties
present in all of the above forms. Because variable
changes in plasma homocysteine concentration have
been observed post-prandially, it is customary to obtain
measurements in the fasting state. Normal levels
of fasting plasma homocysteine are considered to be
between 5 and 15 μmol L–1. Higher fasting values are
classifi ed arbitrarily as moderate (16–30), intermediate
(31–100) and severe (>100 μmol L–1) hyperhomocysteinaemia.
The methionine loading test has been
used to accentuate abnormalities of the homocysteine
metabolic pathways. The test measures fasting plasma
homocysteine before and 2 hours after an oral dose
of methionine (100 mg per kg body weight). An elevated
post-loading homocysteine level indicates an
abnormality.
Hyperhomocysteinaemia can result from inherited
defects in enzymes necessary for either trans-sulphuration
or remethylation and from acquired defi ciencies
in vitamin coenzymes. Renal insuffi ciency can
also lead to hyperhomocysteinaemia. Subclinical
folate defi ciency is commonly associated with hyperhomocysteinaemia,
presumably because of decreased
remethylation of homocysteine. Kang et al. (1987)
found elevated total homocysteine levels in 84% of
subjects with subnormal folate levels. The mean homocysteine
level in the low-folate subjects was about
four-fold greater than the mean level in the control
subjects.
An association between mild hyperhomocysteinaemia
and increased risk of occlusive vascular disease in
the coronary, cerebral and peripheral arteries has been
demonstrated in case-control (Selhub et al., 1995; European
Concerted Action Project, 1997) and prospective
(Stampfer et al., 1992; Arneson et al., 1995; Perry
et al., 1995) studies. Plasma homocysteine concentration
is a strong predictor of mortality in patients with
angiographically confi rmed coronary artery disease
(Nygard et al., 1997). Whether hyperhomocysteinaemia
is a causal risk factor for the disease or simply
a marker of another prothrombotic risk factor(s) is
debatable (Kuller & Evans, 1998).
Up to 30% of patients with coronary artery disease
had homocysteine elevations that were 10–50%
greater than the level observed among normal subjects
(Clarke et al., 1991). Subjects with hyperhomocysteinaemia
have a two-fold to three-fold increase in
risk of developing cardiovascular disease or venous
thrombosis (den Heijer et al., 1998). In vitro studies
have shown that high concentrations of homocysteine
can promote a prothrombotic state at the luminal surface
of the blood vessel (Lentz, 1998). An association
between impaired endothelium-dependent vasodilation
and hyperhomocysteinaemia was demonstrated
in children with homozygous homocystinuria (Celermajer
et al., 1993), in monkeys fed a methionine-enriched
diet (Lentz et al., 1996), in methionine-loaded
healthy humans (Bellamy et al., 1998; Chambers et
al., 1998) and in non-induced hyperhomocysteinaemic
healthy middle-aged (Woo et al., 1997) and
elderly (Tawakol et al., 1997) humans. In healthy
human subjects, even physiological increments in
plasma homocysteine following oral administration
of methionine or an animal protein meal impaired
endothelium-dependent vasodilatation (Chambers et
al., 1999a). Plasma homocysteine concentration can
be decreased by dietary supplementation with folic
acid, which suggests that hyperhomocysteinaemia
may be a treatable risk factor for vascular disease.