Hyperhomocysteinemia and Venous Thrombosis: A Meta-analysis

Abstract

Hyperhomocysteinemia is an established risk factor for atherosclerosis and vascular disease. Until the early nineties the relationship with venous thrombosis was controversial. At this moment ten case-control studies on venous thrombosis are published. We performed a meta-analysis of these reports.
We performed a MEDLINE-search from 1984 through June 1997 on the keywords “homocysteine” or “hyperhomocysteinemia” and “venous thrombosis”, which yielded ten eligible case-control studies.
We found a pooled estimate of the odds ratio of 2.5 (95% CI 1.8-3.5) for a fasting plasma homocysteine concentration above the 95th percentile or mean plus two standard deviations calculated from the distribution of the respective control groups. For the post-methionine increase in homocysteine concentration we found a pooled estimate of 2.6 (95% CI 1.6-4.4).
These data from case-control studies support hyperhomocysteinemia as a risk factor for venous thrombosis. Further research should focus on the pathophysiology of this relationship and on the clinical effects of reducing homocysteine levels by vitamin supplementation.

Full text

Thromb
Haemost
1998;
80:
874-7
©
1998
Schattauer
Verlag.
Stuttgart
Hyperhomocysteinemia
and
Venous
Thrombosis:
A
Meta-analysis
Martin
den
Heijer1,
Frits
R.
Rosendaal2,
Henk
J.
Blom3,
Wim
B. J.
Gerrits1,
Gerard
M. J.
Bös1
From
the
Department
of
Hematology,
Leyenburg
Hospital,
The
Hague,
2Department
of
Clinical
Epidemiology
and
Department
of
Hematology,
University
Hospital Leiden,
3Laboratory
of
Paediatrics
and
Neurology,
University
Hospital
Nijmegen,The
Netherlands
Summary
•
Hyperhomocysteinemia
is an
established
risk
factor
for
atheroscle-
rosis
and
vascular
disease.
Until
the
early
nineties
the
relationship
with
venous
thrombosis
was
controversial.
At
this
moment
ten
case-control
studies
on
venous thrombosis
are
published.
We
performed
a
meta-
analysis
of
these reports.
We
performed
a
MEDLINE-search
from
1984
through
June 1997
on
the
keywords
"homocysteine"
or
"hyperhomocysteinemia"
and
"venous
thrombosis",
which
yielded
ten
eligible
case-control
studies.
We
found
a
pooled
estimate
of the
odds ratio
of 2.5
(95%
CI
1.8-3.5)
for
a
fasting plasma homocysteine
concentration
above
the
95th
percen-
tile
or
mean
plus
two
Standard
deviations
calculated
from
the
distribu-
tion
of the
respective
control
groups.
For the
post-methionine
increase
in
homocysteine
concentration
we
found
a
pooled estimate
of 2.6
(95%
CI1.6-4.4).
These data from case-control studies support hyperhomocystein-
emia
äs
a
risk factor
for
venous thrombosis.
Further
research
should
focus
on the
pathophysiology
of
this
relationship
and on the
clinical
effects
of
reducing
homocysteine
levels
by
vitamin supplementation.
Introduction
Homocysteine
is an
amino
acid,
which
was
discovered
in
1932
by
Vigneaud
äs
a
product
of
transmethylation
of
methionine,
an
essential
amino
acid
(1).
In the
early
sixties
Carlson
et
al.
äs
well
äs
Gerritsen
et
al.
found
very
high
levels
of the
disulphate homocystine
in the
urine
(homocystinuria)
of
some infants with mental retardation
(2-4).
In
1964
Mudd
and
colleagues reported
the
absence
of
cystathionine-ß-synthase
activity
in the
liver
of a
subject with homocystinuria (5). Because
ho-
mocystinuria
was
found
to be
associated
with vascular
disease
at
young
age.
it was
supposed, that
also
the
carrier
state
for
homocystinuria
might
be a
risk
factor
for
vascular
disease.
This
carrier state
was
thought
to be
identical with mildly
elevated
homocysteine levels, par-
ticularly
after
methionine
loading.
Up to
now, more than
thirty
case-
control
studies
have been published which show
an
increased
risk for
vascular
disease
due
to
hyperhomocysteinemia (6).
Present addresses:
Dr.
Gerard
M. J.
Bös
is
presently
a
fellow
of the
Dutch
Cancer
Foundation.
Correspondence
to:
Martin
den
Heijer. Department
of
Internal Medicine,
University
Hospital Nijmegen, PO-Box
9101,
6500
HB
Nijmegen,
The
Netherlands
-
Tel.:
+31 24
3614782;
FAX
Number.
+31 24
3541734;
e-mail:
m.denheijer@AlG.AZN.NL
Although
Mudd reported
äs
early
äs
1985 that
51% of the
vascular
events
in
severe
homocystinuria were
of
venous
origin
(7),
the
first
studies
on the
relation
between mild
hyperhomocysteinemia
and
venous thrombosis were
not
published
until
1991
(8,9).
From 1991
to
now.in
total
eight
case-control
studies
are
published,
which
are
subject
of
the
present review.
Methods
We
performed
a
MEDLINE-search
from
1984
through June
1998
on
the
keywords "homocysteine"
or
"hyperhomocysteinemia"
and
"venous
thrombosis".
We
found
a
total
of
117
articles
of
which
12
contain data from
case-control studies
on
venous thrombosis (8-19).
Two
papers reported
the
same
study
(8,10).
One
study
concerned
only
women
using
oral
contraceptives
and
reported only mean homocysteine concentrations
(l 1).
Therefore this study
was
not
included
in the
meta-analysis.
Also
the
follow-up
study
of
Kyrie
et al.
was
left
out
because
this
study
concerned
the risk of
recurrent
venous
thrombosis after
a first
event (20).
We
derived
the
numbers
of
cases
and
control subjects with
and
without
hyperhomocysteinemia
from the ten
remaining
studies. Hyperhomocystein-
emia
was
defined according
to the
reported study
äs
a
plasma homocysteine con-
centration above
the
95th
percentile
or
mean plus
2 (or
2.7) times
the
Standard
deviation
calculated
from
the
distribution
of the
respective control groups (for
the
study
of
Simioni only data about
the
90th
percentile were available).
Be-
cause
most
studies with
the
methionine loading
lest
used post-methionine
in-
crease
in
homocysteine
concentration
rather than absolute
values
we
reanalysed
one
study
on
recurrent venous thrombosis
in
terms
of
homocysteine increase
(13).
We
calculated
(unmatched)
odds
ratlos
for
each
of the
studies
with corre-
sponding
confidence
intervals.
using
Woolf's
method.
A
pooled estimate
was
calculated
by a
Mantel-Haenszel
method.
This
meth-
od was
used because
two
studies
had no
subjects
with
hyperhomocysteinemia
in
their
control
group.
So, for
these
studies
no
individual
odds
ratio
could
be
calculated.
The
confidence intervals
of the
Mantel-Haenszel
estimates
were
calculated
by
using
the
method
of
Robms
(21).
We
also tested
for
homogeneity
äs
reported
by
Greenland
(22). This
lest
could
only
be
applied
to
those
studies
for
which odds
ratios
can
be
calculated. Therefore
we
left
out two
studies with
no
control subjects with hyperhomocysteinemia.
Results
Ten
studies examined
the
relationship between hyperhomocystein-
emia
and
venous thrombosis
(Table
1). The
odds ratios
for the
fasting
state
äs
well
äs
after methionine loading
are
shown
in
Fig.
1.
In
1991
Bienvenu
et al.
(8,10)
found
elevated
homocysteine
levels
in
a
group
of 17
patients with venous thrombosis compared
to 49
con-
trol
subjects.
The
same study
was
published
in
English
language
in
1993 with
23
patients
and 49
control subjects.
The
patient group includ-
ed
patients with rare
presentations
of
venous thrombosis
äs
Budd-
874

odds
ratio
(CI9S%)
den
Heijer
et
al.:
Homocysteine
and
Venous
Thrombosis
den
Heijer
(16)
All
"
Brattstrom
(9)
Falcon
(12)
den
Heijer
(13)
Amundsen
(14)
Cattaneo
(17)
All
*
.
·
.-_
100
0,1
B
1
10 100
odds ratio
(CI95%)
Fig.
l
A, B The
odds ratios
accordmg
to
elevated fastmg homocysteine levels
(A) or
elevated
post-methionine
homocysteine increase
(B) in
case-control studies
on
venous thrombosis.
Two
studies (10,
12) are
left
out
in
the figure on
fasting
homocysteine
levels
because
no
odds
ratios
could
be
calculated
Chiari
syndrome,
central
retinal
vein
occlusion
and
mesenterical
venous
thrombosis.
Brattstrom
et
al.
(9)
reported
no
significant
difference
in
mean
plas-
ma
homocysteine between patients
with
venous thrombosis
and
con-
trols
in a
small
series
of 42
patients
and 42
controls. Interestingly,
from
their
data
on
post-methiomne
increase
a
3-fold
elevated risk
of
hyper-
homocysteinemia
for
thrombosis could
be
calculated,
which
remained
non-significant
likely
due to the
small sample size.
In
1994
Falcon
et al.
reported hyperhomocysteinemia
äs
a risk
factor
for
thrombosis
occumng
before
the age of
forty
(12).
They
studied
patients with
one or
more episodes
of
venous thrombosis including
cerebral vein thrombosis (and excluding other
thrombophilic
disor-
ders),
and
healthy control subjects
from
the
hospital
staff.
They report-
ed a
difference
in
homocysteine
level
between cases
and
controls
par-
ticularly
after methionine loading.
In
1995
we
found hyperhomocys-
teinemia
to be a
risk factor
for
recurrent
venous thrombosis
in
patients
between
20 and 70
years
of age
when
compared
to
controls from
the
general population (13).
Other studies, published
in
1995
are the
study
of
Amundsen
et
al.,
who
found
no
significant difference
in
mean homocysteine
in 35 pa-
tients (age
less
than
56)
with deep-vein thrombosis
and 39
controls (14)
and the
study
of
Fermo
et al. who
found
significantly
higher prevalence
of
hyperhomocysteinemia
in 107
patients with venous thrombosis
be-
fore
the age of 45
compared with
60
healthy persons
(15).
They also
found
an
increased
recurrence
rate
in
patients with hyperhomocystein-
emia.
In
1996,
we
reported
a
population-based
case-control study
in pa-
tients
with
a
first,
objectively
confirmed,
episode
of
deep-vein
throm-
bosis
and
control subjects
of the
general population (16).
Another
pop-
ulation-based study
was
published
by
Cattaneo
et al. who
studied
89 pa-
tients with
a
first
episode
of
deep-vein thrombosis
and 89 age and sex
matched controls (17). Both studies found
an
increased risk
for
venous
thrombosis
due to
hyperhomocysteinemia.
Simioni
et al.
published
a
study
in 60
patients with proven
DVT and
äs
control subjects patients
who
were
referred
to the
hospital because
of
clinically suspected
DVT but had
normal venograms; they found
an
odds
Table
l
Characteristics
of ten
studies
on
hyperhomocysteinemia
and
venous thombosis
First
author
Bienvenu"
IIJ
Brattstrom"
Falcon"
den
Heijer'J
Amundsen"
Fermo'"
den
Heijer'0
Cattaneo"
Simioni'0
Ridker"
Kind
of
Ihrom-bosis
(age)
VT
(<60)
DVT/PE
(<50)
VT
(<50)
DVT/PE
(20-90)
DVT
(<66)
VT
(<45)
DVT
(16-70)
DVT
DVT
DVT
Number
of
thrombotic
episodes
?
1
1
2
1
1
1
1
1
1
cui-off
pomt
mean
+2 7 SD
mean
-f
2 SD
mean
+
2 SD
951h
perc»
mean
+
2 SD
95th
perc
951h
perc
951h
perc
90tn
perc
951h
perc
Fastmg
(F) /
Post-load
(P)
F
F
P
F
P
F
P
F
P
F
P
FH
F
P
F
?
Cases
«ilh
HH/
total
cases
7/23
4/42
6/42
7/80
14/79
24/185
15/185
2/35
2/35
10/107
11/58
28/269
7/89
7/89
15/60
10/145
Controls
with
HH/
total
controls
0/49
3/42
2/43
0/51
1/40
10/220
11/220
1/39
1/39
3/60
3/60
13/269
4/89
4/89
17/148
29/646
*
denved
irom
original
dala
HH=
hypertiomocyslßinemta
DVT=
deep-νβιη
thrombosis
H
m
this
study
non-fastmg
samptes
were
use·
VT^
all
kinds
of
venous
thrombosis
PE=
pulmonary
embolism

Thromb
Haemost
1998;
80:
874-7
ratio
of 2.6
(18). Ridker
et
al.
investigated
homocysteine
levels
in the
Physicians'
Health Study
in 145 men who
subsequently
developed
venous
thromboembolism
and 646 men
free
of
cardiovascular
disease
(19).
They concluded that hyperhomocysteinemia
was
associated
with
idiopathic
venous
thrombosis
but not
with
venous
thrombosis
of any
cause.
So,
eight studies
found
hyperhomocysteinemia
to be a
risk
factor
for
venous
thrombosis
and two
studies
reported
no
relationship
between
hyperhomocysteinemia
and
venous
thrombosis.
The
other
Fig.
l
shows
that
all
studies
from
which
an
odds
ratio
could
be
calculated,
have
point
estimates
of the
odds
ratio
above
l .4. The
pooled estimate
for the
fast-
ing
homocysteine
levels
of all
eight
studies
is 2.5
(95%CI
1.8-3.5).
For
the
post-methionine
increase
in
homocysteine
concentration
we
found
a
pooled
estimate
of 2.6
(95%
CI
1.6-4.4).
The
test
for
homogeneity
-
which
was
restricted
to
those studies
for
which odds ratios could
be
cal-
culated
- did not
reach
significance
for
either
the
fasting
homocysteine
level
(χ2
=
2.23,
p
>0.9,
df = 7)
äs
well
äs
for the
post-load
homocys-
teine increase
(χ2
=
3.36,
p
>0.5,
df = 5); the
distribution
of the
effect
measures over
the
studies,
äs
shown
in
Figs.
1A and 1B,
also
does
not
point
to
heterogeneity
of
effect.
Discussion
The
pooled estimates
for
fasting homocysteine
and
post-methionine
increase
confirm
the
conclusion
of
most
-
except
of
two
(9,14)
-
stud-
ies
that hyperhomocysteinemia
is a risk
factor
for
venous thrombosis.
Notably,
the
odds ratios calculated
for
these
two
studies
are
very
simi-
lar
to the
pooled
estimate.
The
negative conclusions
of
these
two
stud-
ies are
based
on
comparing
mean
homocysteine levels
in
patients
and
control
subjects
and not on
odds
ratios
äs
estimates
of risk.
Two
studies
are yet
published which provide prospective data.
The
study
of
Ridker
et al.
showed
that subjects with
increased
homocysteine
levels
are at
increased risk
for
future
venous thromboembolism
(19).
Kyrie
et al.
reported
that
patients
who
already suffered from
deep-vein
thrombosis
had a
higher risk
for
recurrences
if
they
had
elevated homo-
cysteine levels
(20).
These
two
studies strengthen
the
hypothesis
that
homocysteine
is
causally associated with venous thrombosis.
The
pooled estimates
for
both
the
fasting homocysteine level
and the
post-methionine homocysteine increase
are
very
similar.
It
is
believed
that
fasting homocysteine levels
are
more associated with remethyla-
tion defects
while
post-load increase
of
homocysteine
are
more asso-
ciated with transsulfuration defects.
The
similarity
in
odds ratios does
not
point
out
whether
venous thrombosis
is
more associated with
re-
methylation
defects
or
transsulfuration
defects.
The
question whether
patients
with venous thrombosis should
underwent
a
methionine
load-
ing
test
or
that
measurement
of
fasting homocysteine
would
be
enough
could
not be
answered
on the
base
of
this
meta-analysis
because
we
have
no
Information about
the
correlation
between
fasting
homocys-
teine concentrations
and
post-load homocysteine
increase.
Despite this epidemiological evidence
for the
relationship between
hyperhomocysteinemia
and
venous
thrombosis,
little
is
known
about
its
pathophysiology.
A
magnitude
of
possible mechanisms
is
proposed
with
respect
to
vascular disease, which have been reviewed
by
several
authors
(23-25). Many
of
these proposed mechanisms with respect
to
arterial
vascular disease
may
be
applied
to
venous thrombosis
äs
well.
However, most hypotheses
are
based
on in
vitro
experiments
using very
high
and
unphysiological concentrations
of
homocysteine.
The
clinical relevance
of the
fmding
that
hyperhomocysteinemia
is a
risk
factor
for
venous thrombosis depends mainly
on its
treatability
by
vitamin
supplementation.
Especially
folic
acid
has
a
strong homocys-
teine
lowering
effect
(26-27). However,
no
data
on
clinical
Intervention
studies
are yet
available
and it
cannot
be
ruled
out
that homocysteine
is
an
epiphenomen
with
respect
to
thrombosis,
in
which case
vitamin
supplementation would probably
be
ineffective
(28).
In
conclusion, there
is
increasing evidence that mild hyperhomocys-
teinemia
is a risk
factor
for
venous thrombosis. Further
research
should
focus
on the
pathophysiology
of
thrombosis
in
hyperhomocysteinemia
and on the
clinical
effects
of
homocysteine lowering
by
means
of
vita-
min
supplementation
äs
well
äs
on the
interaction
of
this very common
abnormality
with pther genetic
or
acquired thrombogenic defects.
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Accepted after resubmission August
20,1998
ENDOCRINOLOGY
E
D
K.Munii
The
Thyroid
and
:
iiaivtwii.Ai^JO-Mn-zv;1;.·,?.;;:^·:.^1.::·..·'^.,:
$^&®$$&&$$'$\
Pinchera/Mann/Hostalek
(Hrsg.)
The
Thyroid
and Age
1998.
410pages,
37figures,
50
tables,
paperback
DM69-/öS504-/sFr63-
ISBN
3-7945-1867-5
Prevalence,
clinical
manifestations
and
therapeutic
requirements
of
thyroid
dis-
orders
greafly
differ
during
the
course
of
life.
There
is a
variety
of
diagnostic
and
therapeutic
problems
in
pregnant
women
which
are
relevant
not
only
for
the
endocrinologist,
but
also
for the
pediatrician
and the
gynecologist.
The
development
of the
fetal
thyroid
and the
pathogenesis
of
genetic
diseases
are
only partly understood. Screening
for
thyroid diseases
in the
newborn
and
early
treatment
are
offen
inconsequentially
performed.
In
puberty,
early diagnosis
and
prevention
of
thyroid diseases
are of
tremendous
socio-economical
relevance,
äs
most
goiters develop
at
this
age.
In
adults,
iodine
deficiency remains
a
world-wide
risk
that
is
responsible
for
morbidity
resulting
from
nodular
goiter
and
thyroid
autonomy.
Iodine
excess
is
a
common cause
of
iatrogenic
thyroid
disorders.
Thyroid
diseases
in the
elderly
are
offen
unrecognized
and may
substan-
tially contribute
to
morbidity
and
mortalily.
It
is the aim of
this
book
to
focus
fhe
attention
on age
dependent aspects
of
thyroid
diseases
and
their
specific diagnosis
and
treatment.
F.
K.
Schattauer
Publishing
Co.
Stuttgart
- New
York
Distributors:
United
States
and
Canada:
John
Wiley
&
Sons,
Inc.,
Wiley-Liss
Division,
605
Third
Avenue,
New
York,
NY
101
58-0012/USA
UK,
Eire,
Spain,
France,
The
Netherlands
and
South
Africa:
Brilish
Medical
Journal,
BMA
House,
Travistock
Square,
London
WC1H
9JR