Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis
BMJ 2002; 325 doi: https://doi.org/10.1136/bmj.325.7374.1202 (Published 23 November 2002) Cite this as: BMJ 2002;325:1202
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Pre-test assessment to determine appropriateness of pre-travel genetic screening for thrombosis risk
Dear Editor
I agree with Dr Richard Fiddian-Green that additional measurements
indicating the likelihood of expression of a genetic alteration associated
with thromboembolism would greatly improve the predictive value of genetic
testing (1). At present the co-existence of genetic and environmental risk
factors, together with a family history or previous deep vein thrombosis
(DVT) episode, are considered when individuals are categorized in low,
moderate, high, or very high risk subgroups, similar to the risk
stratification applying to patients under assessment for surgery (2).
Inclusion of an exercise and decompression hypoxia stress test would be
valuable for interpretation of genetic test results and might indeed
determine the most appropriate preventative strategy. This approach will
be valuable in a formal research program but due to logistical constraints
incorporation in a large scale screening program would be difficult.
To prevent possible psychological harm as a consequence of pre-
clinical genetic testing for thrombosis risk (3), we designed a pre-test
assessment form to determine the appropriateness of genetic testing in
healthy individuals. This is done in the form of a questionnaire-based
survey (table 1) and those individuals who agree with any of the first two
statements are strongly advised against genetic testing.
TABLE 1. Questionnaire-based survey - agree / uncertain / disagree? Pre-test assessment 1.Having a genetic predisposition for a modifiable genetic condition, in this case DVT, will make me anxious 2.I will fear the future if I have an increased risk of thrombosis due to the presence of both genetic and environmental risk factors 3.I believe that people should be told of their risk of disease 4.A positive test result does not mean that I will develop DVT, because the expression of a specific gene is influenced by external factors 5.The test procedure includes only the most prevalent risk factors and therefore a negative test result does not exclude the possibility of a future episode of DVT Positive test result 1.I wish I did not know that I have a genetic predisposition for thrombosis 2.My well-being has diminished after gene mutations implicated in DVT have been identified in my genetic material 3.I am satisfied to know that I have a genetic predisposition for DVT, because I can do something to reduce the risk 4.I believe that my family should be screened for genetic risk factors of DVT Negative test result 1.I am convinced that I will not suffer DVT in future 2.I wish I did not know that I test negative for the most common genetic causes of DVT, because it does not exclude the possibility of other risk factors and gives me a false sense of assurance 3.I would like to participate in a research project aimed at the identification of other known or unknown risk factors for DVT and will provide written consent for further analysis
To date genetic screening for thrombosis risk using our multiplex
assay including three mutations (4) has only been performed in patients
with strong clinical indications of hypercoagulability referred by their
doctors, and not in healthy individuals. In fact, even in these cases we
have not reported on the presence or absence of the MTHFR 677C/T
polymorphism although it is included in the multiplex assay, because of
the fact that the role of this mutation in DVT was controversial (5). We
accepted that this was clarified in the study of Wald et al. (6) and can
now be routinely included as part of a thrombophilia assessment, as
indicated by Ray et al. (5) provided that more compelling data become
available on the role of the MTHFR mutation. The debate that followed
further emphasised the importance of providing a clear interpretation of
the genetic test result with reference to data available in the
literature.
The number of travellers who suffer DVT is relatively small, but
individual cases remain an important consideration. Just yesterday an
example came under my attention of a 23-year old female who started to use
oral contraceptives before she got married and died of thromboembolism on
her honeymoon shortly after leaving the airplane. I believe that increased
awareness of the association between prolonged immobility and venous
thromboembolism is of utmost importance if mortality from this cause is to
be decreased. The availability of a genetic screening service for
thrombosis risk contributes to increased awareness among the general
population, irrespective of whether genetic testing is requested or not.
References
1.Fiddian-Green FG. Pre-travel screening for thromboembolism. BMJ online,
30 Dec 2002.
2.Turpie AGG, Chin BSP, Lip GYH. Venous thromboembolism: pathophysiology,
clinical features, and prevention. BMJ 2002; 325: 887-890.
3.Ray JG. Pre-travel screening may be harmful. BMJ online, 30 Dec 2002
4.Kotze MJ. Pre-travel screening to identify genetic factors predisposing
to thrombosis. BMJ online, 27 Dec 2002.
5.Ray JG, Shmorgun D, Chan WS. Common C677T polymorphism of the
methylenetetrahydrofolate reductase gene and the risk of venous
thromboembolism: meta-analysis of 31 studies. Pathophysiol Haemost Thromb
2002; 32: 51-58.
6.Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease:
evidence on causality from a meta-analysis. BMJ 2002; 325: 1-7.
Competing interests:
MK is a shareholder in Genecare Molecular Genetics and derives income from providing genetic testing
Competing interests: TABLE 1. Questionnaire-based survey - agree / uncertain / disagree?Pre-test assessment1.Having a genetic predisposition for a modifiable genetic condition, in this case DVT, will make me anxious2.I will fear the future if I have an increased risk of thrombosis due to the presence of both genetic and environmental risk factors3.I believe that people should be told of their risk of disease4.A positive test result does not mean that I will develop DVT, because the expression of a specific gene is influenced by external factors 5.The test procedure includes only the most prevalent risk factors and therefore a negative test result does not exclude the possibility of a future episode of DVTPositive test result1.I wish I did not know that I have a genetic predisposition for thrombosis2.My well-being has diminished after gene mutations implicated in DVT havebeen identified in my genetic material3.I am satisfied to know that I have a genetic predisposition for DVT, because I can do something to reduce the risk4.I believe that my family should be screened for genetic risk factors of DVTNegative test result1.I am convinced that I will not suffer DVT in future2.I wish I did not know that I test negative for the most common genetic causes of DVT, because it does not exclude the possibility of other risk factors and gives me a false sense of assurance3.I would like to participate in a research project aimed at the identification of other known or unknown risk factors for DVT and will provide written consent for further analysis
Wald et al report a significantly higher risk of both ischaemic
heart disease and deep vein thrombosis (with or without pulmonary
embolism) in people with the MTHFR mutation (1). It has also been
reported that the risk of death in patients with coronary artery disease
(2) and that the severity of pulmonary embolism (3) increase as the level
of uric acid in serum increases. A common denominator appears to be a
rise in blood lactate caused by a systemic anaerobiosis.
Dysoxia may be defined as a state in which ATP pools are being partly
or wholly maintained by anaerobic metabolism (4,5). It is a state in
which protons accumulate in proportion with the number of molecules of ATP
whose hydrolysis cannot reversed by ATP resynthesis by oxidative
phosphorylation. It is also a state in which protons accumulate in
proportion with the degree of ATP degradation. The generation of ATP in
anaerobic metabolism occurs in part by residual oxidative phosphorylation.
It is also generated in the Embden-Meyerhoff pathway to the degree it is
able to run in the absence of oxidative phosphorylation by the conversion
of pyruvate to lactate and by the resynthesis of ATP from ADP catalysed
by adenylate kinase.
The severity of the tissue acidosis produced from the unreversed ATP
hydrolysis is offset by the proton needed to covert pyruvate into
lactate. As the development of a tissue acidosis is not inhibited by
inhibiting the generation of lactate with iodoacetate in vitro the
intracellular accumulation of lactate per se does not appear to be the
principle cause of the tissue acidosis as often supposed. The blood
lactate rises and arterial pH falls with reperfusion/oxygenation such as
that occurring when the aortic cross clamp is removed in the course of a
cardiovascular operation. The blood lactate rises and the pH falls because
of the washout of lactate and the tissue carbon dioxide generated by the
buffering of protons released by unreversed ATP hydrolysis. The fall in
arterial pH may be compounded by conversion of lactate back into pyruvate
in preparation for the resynthesis of ATP by mitochondrial oxidative
phosphorylation. Hence the misleading term “lactic acidosis”.
The fall in tissue pH caused by the unreversed ATP hydrolysis in
anaerobiosis is in effect a measure of a fall in adenylate energy charge
or more specifically a fall in protonmotive energy charge for ATP
resynthesis is driven by the protonmotive force established by the pH
gradient generated by the electron transport chain across the
mitochondrial membrane (6). [ATP]/[ADP] is maintained by the adenylate
kinase reaction long after the pH falls and [AMP] the lactate rise and is,
thus, an insensitive index of the presence or absence and degree of
anaerobiosis present.. The fall in tissue pH, and by inference the
accompanying rise in ionised calcium, accounts for some 90% of the
enzymatic adaptation to anaerobiosis including translational, membrane
channel and neuronal spike arrest (7).
The degree of this enzymatic adaptation in anaerobiosis, which
incorporates the enzymatic reactions catalysing ATP regeneration in
addition to those catalysing ATP utilisation, change inversely as the
adenylate energy charge falls from 1.0 to 0 intersecting at a “metabolic
equilibrium” point. By inference a similar relationship exists between
the protonmotive energy charge or the degree of dysoxia present and the
enzymatic adaptation to anaerobiosis.
One of the enzymatic adaptations to anaerobiosis and its accomanying
fall in tissue pH and rise in ionised calcium is the conversion of
xanthine dehydrogenase to xanthine oxidase catalysed by the calcium-
induced activation of protease and accompanying increase in serum uric
acid (8).
The lactate that rises in blood upon reperfusion/oxygenation is said
to compete with uric acid for secretion into the renal tubules thus
increasing the likelihood of a rise in uric acid concentration in serum.
The metabolic degradation products of alcohol appear to cause a rise in
uric acid concentration in serum by the same mechanism (6,8). Since a rise
in serum uric acid will, in accordance with the law of mass action impair
the degradation of AMP into adenosine, hyoxanthine and xanthine adenosine
concentrations can be expected to also rise. In which case the
degradation of adenosylhomecysteine into adenosine and homocysteine will
be impaired and the concentration of adenylhomocysteine in blood may rise.
With the resumption of mitochondrial oxidative phosphorylation
homocysteine levels in blood can be expected , therefore, to rise from the
increased levels in adenylhomocysteine.
The efficiency of homocysteine thiolactone metabolism declines with
age and may explain the decreased formation of adenosyl methionine in
aging and loss of thioretinaco ozonide from membranes of aging cells (9).
It is possible that this putative cause of an increase in homocysteine
levels is one of the many enzymatic adaptations to anerobiosis. The free
base of homocysteine thiolactone appears to be responsible for many of the
noxious effects of homocysteine including mitochondrial dysfunction and
apoptosis. Thus anaerobiosis might induce a rise homocysteine in
addition to inducing a rise in blood lactate and uric acid.
The stress of a systemic anaerobiosis may induce a release of
catecholamines, CRH from the hypothalamus, ACTH from the pituitary and
cortisol from the adrenals. This may be accompanied by an increase in
glycogenolsis, lipolysis, blood cholesterol and low density lipoproteins,
and insulin resistance. (80% of the cholesterol from which steroid
hormones including cortisol are synthesised are contained with the low
density lipoproteins). It has also been proposed that thromboembolism
might be the product of a systemic anaerobiosis (10). The possibility
exists, therefore, that many of the risk factors for cardiovascular
diseases might be products of a systemic anaeobiosis and not the causes of
the diseases as is commonly supposed (11).
1. Homocysteine and cardiovascular disease: evidence on causality
from a meta-analysis David S Wald, Malcolm Law, and Joan K Morris
BMJ 2002; 325: 1202-1206
2. Bickel C, Rupprecht HJ, Blankenberg S, Rippin G, Hafner G, Daunhauer A,
Hofmann KP, Meyer J. Serum uric acid as an independent predictor of
mortality in patients with angiographically proven coronary artery
disease.
Am J Cardiol. 2002 Jan 1;89(1):12-7.
3. Shimizu Y, Nagaya N, Satoh T, Uematsu M, Kyotani S, Sakamaki F,
Nakanishi N, Miyatake K. Serum uric acid level increases in proportion to
the severity of pulmonary thromboembolism.
Circ J. 2002 Jun;66(6):571-5.
4. Fiddian-Green RG. Gastric intramucosal pH, tissue oxygenation and acid-
base balance.
Br J Anaesth. 1995 May;74(5):591-606. Review.
5. Fiddian-Green RG. Monitoring of tissue pH: the critical measurement.
Chest. 1999 Dec;116(6):1839-41.
6. Garrett, Anderson. Biochemistry, Second edition, Saunders College
Publishing, Orlando, Florida, 1999.
7. Hochachka PA, Somero GW. Biochemical adaptation. Oxford University
Press, New York, NY, 2002.
8. Halliwell B, Gutteridge JMC. Free radicals in biology and medicine.
Oxford University Press, Oxford, Third edition, 1999.
9. Homocysteine causes mitochondrial dysfunction Richard G Fiddian-Green
bmj.com/cgi/eletters/325/7374/1202#27538, 2 Dec 2002
10. Re: pre-travel screening for thromboembolism Richard G Fiddian-Green
bmj.com/cgi/eletters/325/7374/1202#28242, 28 Dec 2002
11. Homocysteine, folic acid, uric acid, ATP and free radical scavenging
Richard G Fiddian-Green (19 December 2002)
Competing interests:
None declared
Competing interests: No competing interests
Dear Editor:
Re. Dr. Kotze's appeal to my letter arguing that "preventive"
thrombophilia screening among travelers can be life saving, and that
pending litigation in Australia may drive us to consider this even more.
I respond with the following: 1) Civil litigation about cramped
seating on airplanes is another matter altogether, and it does not provide
us with the onus to consider thrombophilia screening; 2) there is no
evidence to screen prospective long-haul travelers for venous
thromboembolism or thrombophilia markers -- in fact, it may be dangerous,
as mentioned in my last letter. Once there is decent evidence to support
doing so, I will reconsider my stance; 3) "primum non nocere" is meant to
be an inner guiding voice among clinicians, whose main message includes
not creating a way of making money off of patients, however cheaply or
efficiently, without first proving to them (and to ourselves) that we can
improve their lives, or prevent misery.
Joel G Ray, MD FRCPC MSc
Competing interests:
None declared
Competing interests: No competing interests
It is the expression of a rogue gene rather than the presence of a
rogue gene per se that would appear to be of most importance in the
pathogenesis of diseases.
Our data suggests that a fall in endothelial pH caused by unreversed
ATP hydrolysis or more likely a rise in endothelial ADP are likely to be
the critical events most likely to induce rogue gene expression in the
genesis of deep vein thrombosis (1). A fall in ADP is a late event and
indicates the presence of a severe inadequacy of mitochondrial oxidative
phosphorylation. It is accompanied by a proportionally large fall in
tissue pH. Factors most likely to induce thromboembolism during a long
flight are, therefore, likely to be in order of importance a fall in
ambient pO2, dehydration and immobility.
Pre-flight screening, if it is appropriate (2) might be best
achieved by including an exercise (3) or better yet a decompression
hypoxia stress test using either gastric intramucosal measurements or
possibly the endothelial pH derived in a representative leg vein as end-
points. It is in theory possible to measure the intra-endothelial pCO2
and indeed pO2 indirectly and to derive the intra-endothelial pH from this
pCO2 and the arterial or possibly the venous bicarbonate as in gastric
tonometry.
A formal prospective determination of the risk factors for
thromboembolism in a study incorporating these measurements in addition to
screening for gene mutations (4) might generate the information necessary
to determine the most appropriate screening tests, if any, to use for pre
-travel screening.
1. Unreversed ATP hydrolysis: the initiating endothelial event?
Richard G Fiddian-Green
bmj.com/cgi/eletters/325/7369/887#26445, 22 Oct 2002
2. Testing travellers for MTHFR TT is absurd Joel G Ray bmj.com, 21 Dec
2002
3. Kolkman JJ, Groeneveld AB, van der Berg FG, Rauwerda JA, Meuwissen SG.
Increased gastric PCO2 during exercise is indicative of gastric ischaemia:
a tonometric study.
Gut. 1999 Feb;44(2):163-7.
4. Pre-travel screening to identify genetic factors predisposing to
thrombosis Maritha J Kotze bmj.com, 27 Dec 2002
Competing interests:
None declared
Competing interests: No competing interests
Dear Editor:
Dr Ray states in his response to my letter of 26 November 2002 that the absolute risk of thrombosis in travellers is very low. Nevertheless, individuals with hypercoagulability are at increased risk of deep vein thrombosis and its potentially lethal complications. Forewarned is forearmed, and persons in whom risk factors have been identified will be empowered to make choices concerning personal preventative measures. This information may simply reinforce the importance of periodic stretching during long-distance travel, or the avoidance of excess alcohol and sedation, and the maintenance of adequate hydration. Awareness of a potential risk and attention to these avoidance techniques may be lifesaving.
Dr Ray expresses concern about the financial aspects of the screening service, stating that Dr Kotze's "company's tests can together cost several hundred US dollars". This is not the case since we screen simultaneously for the three gene mutations included in our test procedure by using a multiplex polymerase chain reaction-based assay which costs R993.30 (approximately US$114.00 at the current rand-dollar exchange rate), with the result available within 24 hours. This is less than half the cost for a less comprehensive pre-travel screening service offered at a laboratory in the USA at a fee of US $245, with a turn around time of 4-10 working days. Our test result is provided within the context of other environmental and genetic risk factors that may be present or absent.
Class action litigation by air travellers who have suffered deep vein thrombosis is pending in Australia. The findings of the court may well be relevant to the ongoing debate on the issue of hypercoagulability screening.
Competing interests:
MK is a shareholder in Genecare Molecular Genetics and derives income from providing genetic testing
Competing interests: No competing interests
Dear Editor:
I read the BMJ electronic letter by Maritha J Kotze, in response to
my letter stating that MTHFR testing among most individuals with VTE is
not necessary.
I do not agree with Dr. Kotze that individuals planning to travel
long distance should be screened for 1 or more thrombophilia factors. This
is a dangerous concept because:
1) The absolute risk of VTE with travel is very very low.
2) The studies that examined the risk of VTE with travel often
included those who had also traveled by land -- should they too be
screened? Would we then include truck drivers as well? What distance
defines a "greater danger"?
3) The MTHFR TT polymorphism is very common (10% prevalence), so
that, with screening, one would generate many false-positives, in the
sense that most of these individuals will not develop VTE, even if they
are not prophylaxed.
4) One opens up a whole can of worms about testing family members if
an individual is found to be MTHFR TT -- what counseling should they
receive? Might that that be psychologically harmful, by creating
unnecessary worry?
5) There are many thrombophilia factors that have yet to be
discovered, so that one might give a falase sense of assurance to those
whose thrombophilia screen is negative -- that they are somehow at "lower
risk" of VTE during a long-haul flight.
6) Should we not simply encourage ALL individuals planning long-haul
travel to periodically stretch their legs, remain hydrated, stand up, and
even walk? The answer is: "Of course."
7) Among those with Factor V Leiden and/or MTHFR 677 TT, what therapy
should they receive if long-haul travel is planned: warfarin, ASA,
heparin, LMWH, compression stockings? What evidence is there to support
such an expensive and invasive approach?
7) I am concerned that a privately run company, which
Dr. Kotze represents, stands to gain much by promoting ideas that have not
yet been supported by even decent quality scientific evidence. Her
company's tests can together cost several hundred US dollars for each
customer ("Blood: DNA Extraction -- 270.90 Rand" and "Blood: Genotype
analysis per PCR -- 361.20 Rand"), as listed on their website
(http://www.genecare.co.za/other.html)
Joel G. Ray, MD FRCPC MSc
Department of Medicine
Sunnybrook and Women's College Health Sciences Centre, University of
Toronto
Competing interests:
None declared
Competing interests: No competing interests
To the editor,
Wald et al. (1) in their large meta-analysis reported the MTHFR 677TT
polymorphism to be associated with a 1.29-fold (95%CI 1.08 to 1.54)
increased risk on venous thrombosis, based on a meta-analysis of 26
studies. We would like to make some additional remarks on this finding.
In our opinion, the overview of these studies is not completely
correct. The data that represent the control group of the study of Salden
et al. (2) are not those of the controls but data of another patient
group. Using this original control group yielded a crude odds ratio of
1.17 instead of 1.09 found by Wald et al. (1). Also the study of Fujimura
et al. (3) for which Wald et al. selected a subgroup of patients. This in
our opinion should have been the total patient population, yielding an
odds ratio of 1.88 instead of 2.00.
Furthermore, there might have been some studies included that had
better been left out (4-6) while other articles that were not included in
our opinion are eligible (7-12). The study by Legnani et al. (4), for
example, uses only patients with thrombophilic conditions and the study by
Rintelen et al. (6) uses subjects with factor V Leiden as cases. The
estimated odds ratios in our opinion, to much reflect interactions of risk
factors instead of the isolated effect of MTHFR on the risk of venous
thrombosis.
The main point we want to make is to be careful for the
interpretation that MTHFR is indeed a risk factor for venous thrombosis.
Although Wald et al. mentioned the possibility of publication bias, we
feel it is important to realise that the largest studies in this meta-
analysis (Brown et al.(13), Kluijtmans et al. (14)) did not find the MTHFR
677TT polymorphism to be a risk factor for venous thrombosis.
Therefore, we find that the risk for venous thrombosis associated
with this MTHFR polymorphism needs further investigation, preferably by
conducting large individual studies.
References
1. Wald DS, Law M, Morris J. Homocysteine and cardiovascular disease:
evidence on causality from a meta-analysis. BMJ 2002; 325: 1-7.
2. Salden A, Keeney S, Hay CRM, Cumming AM. The C677T MTHFR variant
and the risk of venous thrombosis. Br J Haematol 1997; 99: 472.
3. Fujimura H, Kawasaki T, Sakata T, Ariyoshi H, Kato H, Monden M et
al. Common C677T polymorphism in the methylenetetrahydrofolate reductase
gene increases the risk for deep vein thrombosis in patients with
predisposition of thrombophilia. Thromb Res 2000;98:1-8.
4. Legnani C, Palareti G, Grauso F, Sassi S, Grossi G, Piazzi S,
Bernardi F, Marchetti G, Ferraresi P, Coccheri S. Hyperhomocyst(e)inemia
and a common methylenetetrahydrofolate reductase mutation (Ala223Val
MTHFR) in patients with inherited thrombophilic coagulation defects.
Arterioscler Thromb Vasc Biol 1997;17:2924-9.
5. Rintelen C, Mannhalter C, Lechner K, Eichinger S, Kyrle PA,
Papagiannopoulos M, Schneider B, Pabinger I. No evidence for an increased
risk of venous thrombosis in patients with factor V Leiden by the
homozygous 677 C to T mutation in the methylenetetrahydrofolate-reductase
gene. Blood Coagul Fibrinolysis 1999;10:101-5.
6. Philipp CS, Dilley A, Saidi P, Evatt B, Austin H, Zawadsky J, et
al. Deletion polymorphism in the angiotensin-converting enzyme gene as a
thrombophilic risk factor after hip arthroplasty. Thromb Haemost
1998;80:869-873.
7. De Stefano V, Chiusolo P, Paciaroni K, Serra FG, Voso MT,
Casorelli I et al. Prevalence of the 677C to T mutation in the
methylenetetrahydrofolate reductase gene in Italian patients with venous
thrombotic disease. Thromb Haemost 1998; 79: 686-687.
8. Gaustadnes M, Rüdiger N, Møller J, Rasmussen K, Bjerregaard Larsen
T, Ingerslev J. Thrombophilic predisposition in stroke and venous
thromboembolism in Danish patients. Blood Coag Fibrinol 1999; 10: 251-259.
9. Gemmati D, Serino ML, Trivellato C, Fiorini S, Scapoli GL. C677T
substitution in the methylenetetrahydrofolate reductase gene as a risk
factor for venous thrombosis and arterial disease in selected patients.
Haematologica 1999; 84:824-828.
10. Lin J-S, Shen M-C, Tsai W, Lin B. The prevalence of C677T
mutation in the methylenetetrahydrofolate reductase gene and its
association with venous thrombophilia in Taiwanese Chinese. Thromb Res
2000; 97: 89-94.
11. Hsu L-A, Ko Y-L , Wang S-M, Chang C-J, Hsu T-S, Chiang C-W et al.
The C677T mutation of the methylenetetrahydrofolate reductase gene is not
associated with the risk of coronary artery disease or venous thrombosis
among Chinese in Taiwan. Hum Hered 2001; 51: 41-45.
12. Hanson NQ, Aras Ö, Yang F, Tsai MY. C677T and A1298C
polymorphisms of the methylenetetrahydrofolate reductase gene: Incidence
and effect of combined genotypes on plasma fasting and post-methionine
load homocysteine in vascular disease. Clin Chem 2001; 47: 661-666.
13. Brown K, Luddington R, Baglin T. Effect of the MTHFRC677T variant
on risk of venous thromboembolism: interaction with factor V Leiden and
prothrombin (F2G20210A) mutations. Br J Haematol 1998; 103: 42-44.
14. Kluijtmans LAJ, den Heijer M, Reitsma PH, Heil SG, Blom HJ,
Rosendaal FR. Thermolabile methylenetetrahydrofolate reductase and factor
V Leiden in the risk of deep-vein thrombosis. Thromb Haemost 1998; 79: 254
-258.
Competing interests:
None declared
Competing interests: No competing interests
Wald and colleagues present their findings of a causal association
between serum homocysteine and cardiovascular disease (CVD)(1), based on a
meta-analysis of the methylenetetrahydrofolate reductase (MTHFR) studies
and prospective studies of serum homocysteine and disease risk.
Furthermore, they suggest that by increasing folic acid intake this
cardiovascular risk could be reduced.
Although a mutation in the MTHFR enzyme may lead to fasting
hyperhomocysteinaemia (HHcy), increased cardiovascular risk is not
associated with the mutation per se. The high frequency (~30%) of post-
methionine load HHcy that occurs in patients with CVD would suggest non-
genetic factors as a major cause of HHcy. However, the risk of
cardiovascular risk may increase in those individuals with a genetic cause
of HHcy with concomitantly low folate levels, an example of a gene-
environment interaction.
Several 'environmental' factors determine serum homocysteine levels
and cardiovascular risk, including for example, chronic disease states,
hormonal factors, and physical inactivity, the latter being identified
more so especially in adolescence (2). Diabetes and obesity, are major
risk factors for CVD, with individuals being insulin resistant and having
a relative HHcy; improving insulin resistance lowers serum homocysteine.
Lifestyle intervention, such as exercise improves insulin sensitivity and
has many benefits for health and CVD morbidity and mortality. Recently,
walking (150 minutes per week) has been shown to be associated with
substantial reduction (58%) in the incidence of type 2 diabetes
mellitus(3). More recently, prospective data indicate that both walking
and vigorous exercise are associated with substantial reductions in the
incidence of cardiovascular events (4). The exact mechanism(s) remain
unclear.
We recently reported the effects of a six-month exercise programme on
plasma total homocysteine levels (5),in young overweight or obese women
[age (mean ± SD) 30.6 ± 6.6 years, body mass index (BMI): 35.49 ± 7.57
kg/m²] with polycystic ovary syndrome (PCOS), who have a clustering of
cardiovascular risk factors. Subjects were invited to take up sustained
brisk walking, and by the sixth week walked an equivalent to 30 min per
day. All walking was in addition to any normal habitual activity. Compared
to baseline, there was a statistically significant decrease in plasma
total homocysteine concentrations (27%; p<_0.001 and="and" whr="whr" a="a" significant="significant" increase="increase" in="in" aerobic="aerobic" capacity="capacity" vo2max5.="vo2max5." p="p"/> Wald et al(1), conclude that "a decrease in serum homocysteine of 3
micromol/L (achievable by daily intake of about 0.8 mg folic acid) should
reduce risk of ischaemic heart disease by 16%, deep vein thrombosis by
25%, and stroke by 24%." The clinical translation of our findings (5),
that brisk walking (30 min per day) decreased plasma homocysteine levels
by an average of 2.7 micromol/L, could enhance the conclusion by Wald et
al. It is also important to emphasise that exercise has health benefits
beyond a reduction in plasma homocysteine and is particularly relevant
given physical inactivity is increasing and diabetes and obesity are
becoming a global health problem.
References 1. Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ 2002; 325:1202-9.
2. Kimm SY, Glynn NW, Kriska AM, Barton BA, Kronsberg SS, Daniels SR, et al. Decline in physical activity in black girls and white girls during adolescence. N Engl J Med 2002; 347:709-15.
3. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346:393-403.
4. Manson JE, Greenland P, LaCroix AZ, Stefanick ML, Mouton CP, Oberman A, et al. Walking compared with vigorous exercise for the prevention of cardiovascular events in women. N Engl J Med 2002; 347:716- 25.
5. Randeva HS, Lewandowski KC, Drzewoski J, Brooke-Wavell K, O'Callaghan C, Czupryniak L, Hillhouse EW, Prelevic GM. Exercise decreases plasma total homocysteine in overweight young women with polycystic ovary syndrome. J Clin Endocrinol Metab 2002; 87:4496-501.
Competing interests: None declared
Competing interests: No competing interests
Folic acid is a potent inhibitor of xanthine oxidase (1) and is said
to be a “free radical scavenger” (2) in addition to being necessary for
the enzymatic catalysation of the disposal of homocysteine. Thus the
beneficial effect of folic acid on outcome reported in this study might
have been due to the preservation of ATP stores, to the inhibition of free
radical generation, and/or to the scavenging of free radicals (3) rather
than to the reduction in the concentrations of homocysteine in serum (4).
The professional and especially the lay press is full of reports of
the allegedly beneficial effects of antioxidants including polyphenols in
red wine. Despite these enthusiastic reports the evidence suggesting that
any benefical effect is due to the scavenging of free radicals generated
in anaerobiosis rather than to the preservation of ATP by preventing loss
of uric acid in urine is highly questionable (3). Consider further the
effects of ethanol.
Ethanol increases the uric acid concentrations, supposedly another
free radical scavenger (5). The increasing levels of uric acid are
accompanied by a decrease in 8-OHdG levels, a marker of DNA damage. This
evidence is consistent with that from patients with acute ischemic strokes
in whom there is a 12% increase in the odds of good clinical outcome for
each milligram per deciliter increase of serum uric acid (6).
Whilst these data are consistent with the view that beneficial
effects of red wine might be due to free radical scavenging of with
polyphenols or uric acid, the law of mass action dictates that any
increase in uric acid concentration in anerobiosis must be accompanied by
a decrease in the rate of ATP degradation into uric acid being catalysed
by the conversion of xanthine dehydrogenase to xanthine oxidase. This
should be especially so if the increase in uric acid is due to an
impairment of renal excretion. Indeed familial gout, which may be due to
an impairment of uric acid secretion, has lower serum triglyceride, total
cholesterol, and percentage of hypertension than nonfamilial gout controls
(7).
The recent identification of the F2-isoprostanes as oxidative
products of arachidonic acid has provided a reliable measure of in vivo
lipid peroxidation, or free radical damage (8). As no reduction in lipid
peroxidation occurs following red or white wine consumption any protective
effects of wine drinking on cardiovascular disease would seem unlikely to
be related to inhibition of lipid oxidation by the scavenging of free
radicals.
Antioxidants reduce the incidence of organ failure and shorten ICU
length of stay in critically ill surgical patients (9). The development
of organ dysfunction and extended ICU stay appears, however, to be
accompanied by an impairment ATP resynthesis by oxidative phosphorylation
and can be prevented by preventing its development (10). Given the very
large number of compounds said to be anitoxidants and the multiplicity of
their actions, the possibility that any clinical benefit induced by the
taking of antioxidants might be due to an accompanied and unappreciated
preservation of ATP stores rather than the scavenging free radicals needs
to be seriously considered.
Cytochrome oxidase, complex IV in the respiratory chain in
mitochondria, does not appear to cause any appreciable damage in healthy
subjects even though it too is said in textbooks of biochemistry to
generate free radicals in the absence of aneobiosis during healthy
resynthesis of ATP by oxidative phosphorylation. Indeed the damage
occurring in rexoygenation/reperfusion would appear to be always
accompanied by some degree of ATP degradation from unreversed ATP
hydrolysis which is turn is accompanied by an abnormal fall in tissue pH
and rise in cytosolic calcium.
The free radicals released, the fall in tissue pH and the rise in
cytosolic calcium seen in anaerobiosis may all open the permeability
transition pores. This dissipates the protonmotive force upon which ATP
resynthesis depends and thereby uncouples oxidative phosphorylation
compounding the depletion of ATP stores present and hence the likelihood
of cellular apoptosis and necrosis, organ dysfunctions and failures.
Before it can be concluded that free radicals are even partly the
cause of the cellular damage seen in ischaemia/reperfusion it would seem
that it would have to be shown that their allegedly harmful effects are
independent of those induced by the fall in pH and rise in cytosolic
calcium. The harmful effects of homocysteine need to be reconsidered in
the same context.
The prevailing view that free radicals cause tissue damage and that
antioxidants, and even catalase, superoxide dismutase and glutathione
perioxidases, prevents free radical-induced injury might be invalid.
1. Spector T, Ferone R. Folic acid does not inactivate xanthine
oxidase.
J Biol Chem. 1984 Sep 10;259(17):10784-6.
2. Joshi R, Adhikari S, Patro BS, Chattopadhyay S, Mukherjee T. Free
radical scavenging behavior of folic acid: evidence for possible
antioxidant activity.
Free Radic Biol Med. 2001 Jun 15;30(12):1390-9.
3. Fiddian-Green RG. Homocysteine, ATP degradation and free radical
release.
bmj.com/cgi/eletters/325/7374/1202#27916, 17 Dec 2002
4. David S Wald, Malcolm Law, and Joan K Morris Homocysteine and
cardiovascular disease: evidence on causality from a meta-analysis.
BMJ 2002; 325: 1202-1206
5. Yoshida R, Shioji I, Kishida A, Ogawa Y. Moderate alcohol consumption
reduces urinary 8-hydroxydeoxyguanosine by inducing of uric acid.
Ind Health. 2001 Oct;39(4):322-9.
6. Chamorro A, Obach V, Cervera A, Revilla M, Deulofeu R, Aponte JH.
Prognostic significance of uric acid serum concentration in patients with
acute ischemic stroke.
Stroke. 2002 Apr;33(4):1048-52.
7. Chen SY, Chen CL, Shen ML, Kamatani N. Clinical features of familial
gout and effects of probable genetic association between gout and its
related disorders.
Metabolism. 2001 Oct;50(10):1203-7.
8. Abu-Amsha Caccetta R, Burke V, Mori TA, Beilin LJ, Puddey IB, Croft KD.
Red wine polyphenols, in the absence of alcohol, reduce lipid peroxidative
stress in smoking subjects.
Free Radic Biol Med. 2001 Mar 15;30(6):636-42.
9. Nathens AB, Neff MJ, Jurkovich GJ, Klotz P, Farver K, Ruzinski JT,
Radella F, Garcia I, Maier RV. Randomized, prospective trial of
antioxidant supplementation in critically ill surgical patients.
Ann Surg. 2002 Dec;236(6):814-22
10. Fiddian-Green RG. Gastric intramucosal pH, tissue oxygenation and acid
-base balance.
Br J Anaesth. 1995 May;74(5):591-606. Review.
Competing interests:
None declared
Competing interests: No competing interests
Role of renal impairment.
It has been stated that the MTHFR mutation is an important contributor to an elevated homocysteine in the population. Actually there are at least 3 gene culprits and 3 vitamin deficiency states that can lead to hyperhomocysteinemia in addition to a multitude of drugs.
However, anecdotally, I must say that far and away the single most important contributor to very high homocysteines as seen in my practice has been renal impairment (mild to severe degrees). It is well known that patients with renal impairment (mild to severe degrees) have greatly increased risks of atherosclerosis (on the order of 10-20-fold increases), and that the kidney clears homocysteine from the body (hence the term homozygous homocystinuria). Perhaps, homocysteine is one of the contributors to vascular disease in this population.
On lowering homocysteine in the renally impaired, the literature conflicts. There are some studies that showed that very high doses of B vitamins are necessary, and others show partial and incomplete lowering with megadoses. A colleague in London Ontario has suggested Betaine and is currently studying its effect in the dialysis population. I personally use high doses of B vitamins: Folic acid 10 mg, B6 50 mg, and B12 1000 mcg daily, in those with renal impairment, particularly those with advanced CRF.
Competing interests:
I invariably order fasting homocysteines in my patients.
Competing interests: No competing interests