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Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis

BMJ 2002; 325 doi: (Published 23 November 2002) Cite this as: BMJ 2002;325:1202

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MTHFR gene mutation, methylmalonic acidosis, and exercise.

It is difficult to understand why a mutation in the gene coding for
the enzyme methylenetetrahydrofolate reductase (MTHFR) should be
associated with homocysteinaemia let alone an increased risk of
cardiovascular and neurological disorders (1) unless there is another
cause such as “lactic acidosis” (2). In the first place methionine
requirements can easily obtained from a normal diet. In the second place
the beneficial effect of folic acid supplements may not be related to
folic acid per se but to an additive which inhibits xanthine oxidase
(3,4). Consider this and other enzyme abnormalities in a broader metabolic
context including the effects of exercise.

The availability of homocysteine appears to be increased in
anaerobiosis by the hydrolysis of homocysteine-thiolactone. The
accompanying release of adenosine trapped by the homocysteine –thiolactone
increases the availability of adenosine for trapping as
adenosylhomeocysteine (5,6) and hence for ATP resynthesis and the
replenishment of adenine nucleotide pools once oxidative phosphorylation
resumes. An increase in availability of homocystine promotes the
synthesis of methionine, cysteine and succinyl CoA. Succinyl CoA is also
generated from alpha ketoglutatate in the Krebs cycle and from that
proprionic acid which is synthesised from other aminioacids and/or from
the beta oxidation of fatty acids. The likelihood of succinyl CoA being
synthesised from the degradation product of homocysteine, methylmalonyl
CoA, depends upon the concentration of methylmalonyl CoA, the
concentration of the enzyme methylmalonyl CoA mutase, and the availability
of the co-factor adenosylcobalamin. The adenosylcobalamin is synthesised
from uroporphyrogen III, which is also the substrate for porphyrin and
haeme synthesis, and which in turn is synthesised from succinyl CoA.

In the anaerobiosis induced by haemorrhagic shock myocardial tissue
lactate and succinyl CoA increase (7). The increase in succinyl CoA is
caused by an impairment of its utilisation as substrate in the Krebs cycle
to a degree that must be proportional with the degree of anaerobiosis or
dysoxia present (8). Tissue lactate increases not only because of an
impairment of mitochondrial oxidative phosphorylation but also because of
the catabolism of the cysteine derived from the catabolism of methionine
and homocysteine into pyruvate. The rise in blood lactate and
accompanying rise in the secretion of lactate into renal tubules appears
to impair the secretion of uric acid and may thus limit the rate and
degree of adenine nucleotide loss in urine. Hence the potential for an
increase in both uric acid and homocysteine in serum whenever the degree
of anaerobiosis or dysoxia becomes excessive.

Methylmalonic acidosis may cause the death of neonates and cause
neurological and mental disorders and even organ failures in adults. The
methylmalonic acidosis is caused by an impairment of the activity of the
enzyme methylmalonyl CoA mutase which catalyses the conversion of
methylmalonyl CoA into succinyl CoA. The dysfunction may either be
reversed by adenosylcobalamin or not. In those in whom it is not reversed
by adenosylcobalamin death occurs in infancy. In those in whom the
dysfunction is reversed by adenosylcobalamin neurological and mental
consequences and even organ failures may develop . The methylmalonic
acidosis is almost certainly primarily the product of unreversed ATP
hydrolysis induced by a fall in the availability of succinyl CoA not only
for the generation of ATP from oxidative phosphorylation synthesis but
also for the synthesis of the coenzyme adenosylcobalamin.

Porphyria may also cause neurological and mental diseases, such as
that in King George III, abdominal pain and organ failures and death from
the organ failures. In these conditions there is an accumulation of
aminolevulinic acid (ALA) in the mitochondria because it is not able to
pass into the cytosol to form uroporphyrogen III a substrate for
adenosylcobalamin synthesis. Thus the conversion of methylmalonyl CoA to
succinyl CoA may be impaired and methylmalonic acidosis develop. This
impairment of succinyl CoA synthesis is accompanied by an impairment of
porphyrin and haem synthesis. The law of mass action dictates that the
degradation of homocysteine will also be impaired thus favouring the
accumulation of homocysteine its conversion to methionine and the trapping
of adenine nucleotides as homocysteione-thiolactone and/or
adenosylhomocysteine. Thus hyperhomocysteinemia, hyperuricaemia, and the
inappropriate depletion of ATP pools are all favoured in the
methylmalonic acidosis caused by impaired function of the enzymes
methylmalonyl mutase and those responsible for porphyria.

Patients with the Lesch-Nyman syndrome develop hyperuricaemia, gout,
and neurological problems including spacticity, mental retardation and
self mutilation. The syndrome is caused by any one of some one hundred
abnormalities of the enzyme hyoxanthine-guanine-phosphoribosyl
transferase (HGPRTase) which catalyses adenine nucleotide salvage by
combining with phosphoribosylpyrophosphate (PRPP) to form IMP and Ppi. On
occasions the enzyme defect may reduce activity as much as 98% or even
100%. A relatively benign variant of the syndrome was caused by a change
in Km (9). The hyperuricaemia in the Lesch-Nyman syndrome is caused by an
excessive production of uric acid induced by the degradation of ATP.
Hyperhomocystienaemia may also occur because of the impairment of adenine
nucleotide salvage. This syndrome is, therefore, also characterised by an
inappropriate depletion of ATP pools and hence of metabolic energy for
cellular activities, organ dysfunctions and failures.

If the secretion of uric acid is indeed limited by the secretion of
lactate into renal tubules the generation of lactate in severe exercise,
both from the Emden-Meyerhoff pathway and from the degradation of the
cysteine derived from the homocystiene presumably released from the
homocysteine-thiolactone trap, may be one means of preserving adenine
nucleotide pools in athletes. The training of athletes is known to
increase the efficiency of mitochondrial oxidative phosphorylation (10) as
indeed may in ingestion of modest amounts of alcohol (11). From a
teleological perspective one would presume that any increase in efficiency
of mitochondrial oxidative phosphorylation might be accompanied by an
enhancement of the capacity to limit the losses of substrate for ATP
resynthesis in urine.

By impairing the conversion of homocysteine into methionine the
mutation in the MTHFR gene might cause an increase in homocysteine by
impairing its degradation into methionine. On the other hand homocysteine
synthesis from endogenous methionine is impaired. A rise in homocysteine
levels is, therefore, more likely to occur during anaerobiosis in these
patients. In addition to the release of homocysteine from the homocysteine
-thiolactone pool homocysteine catabolism into succinyl CoA is impaired
in anaerobiosis for the utilisation of succinyl CoA as a substrate in the
Krebs cycle is impaired t0o a degree determined by the degree of dysoxia
present. The beneficial effects of folic acid, the additive in which is a
potent inhibitor of xanthine oxidase, is consistent with this view for
xanthine oxidase appears to increase the rate of adenine nucleotide
depletion. But xanthine oxidase is only activated under abnormal
conditions including hypoxia and cytokine release. That folic acid has a
beneficial effect in patients with the mutation in the MTHFR gene implies,
therefore, that abnormal conditions prevail and that the increase in
homocysteine may indeed be the result rather than the primary or sole
cause of the cardiovascular and neurological diseases.

Folic acid rather than its additive might exert a beneficial effect
in patients with the mutation in the MTHFR gene by enhancing methionine
synthesis and hence the rate at which it is catabolised into homocysteine
and succinyl CoA. The increase in availability of succinyl CoA would, in
the presence of normal oxidative phosphorylation, tend to enhance the
salvage of adenine nucleotide. If, however, anaerobiosis were present pure
folic acid could not be expected to enhance ATP resynthesis or limit
further the adenine nucleotide in urine. Hence the suggestion that folic
acid can only be beneficial in patients who have an anaerobic energy
deficit (12). B12, on the other hand could be expected to be of benefit in
any patient who had developed a methylmalonic acidosis secondary to
competitive inhibition of the conversion of methylmalonyl CoA to succinyl
CoA by methylmalonyl Co A mutase by enhancing the synthesis of

A dietary deficiency in B12 but not in folic acid may cause
neurological disorders. The explanation for this may be that a B12
deficiency, but not a folic acid deficiency, may impair the resynthesis of
ATP by oxidative phosphorylation by limiting the availability of succinyl
CoA in the Krebs cycle and thereby cause a methylmalonic acidosis. The
beneficial effect which folic acid supplements have in preventing
neurological abnormalities in the newborn may be related to the ability
of the additive to inhibit xanthine oxidase and preserve adenine
nucleotide stores rather than an enhancement of methionine synthesis from
homocysteine. An metabolic energy deficit whatever its causes may indeed
be the primary cause of not only neurological disorders but also of
psychiatric disorders (13).

The HGPRTase gene is located on the Y chromosome and so the Lesch-
Nyman syndrome is confined to males. This is the second of two salvage
pathway for adenine nucleotides. That is the combining of adenine and PRPP
to form AMP. It is not clear from my readings whether adenosine has to be
converted into adenine to accommodate this pathway or whether it can as I
have presumed simply diffuse back into cells and recombine with Pi to form
AMP and hence ATP. In the absence of the HGPRT gene these must presumably
be the sole adenine nucleotide salvage pathways available to women. It
would seem, therefore, that men might be better adapted than women to
withstanding periodic exposures to severe anaerobiosis such as that
occurring with severe exercise. Men who exercise and drink in moderation
regularly may owe their protection against cardiovascular and neurological
diseases to their sex in addition to an acquired enhancement in their
capacity to preserve adenine nucleotide stores and replenish ATP by
mitochondrial oxidative phosphorylation (14,15).

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. "Lactic acidosis": the common denominator?
Richard G Fiddian-Green, 2 Jan 2003

3. Spector T, Ferone R. Folic acid does not inactivate xanthine oxidase. J
Biol Chem. 1984 Sep 10;259(17):10784-6.

4. Homocysteine, folic acid, uric acid, ATP and free radical scavenging
Richard G Fiddian-Green, 19 Dec

5. Homocysteine: an adenine nucleotide trap? Richard G Fiddian-Green (9
January 2003)

6. pH/calcium regulation of homocysteine metabolism Richard G Fiddian-
Green (10 January 2003)

7. Kline JA, Thornton LR, Lopaschuk GD, Barbee RW, Watts JA. Lactate
improves cardiac efficiency after hemorrhagic shock.
Shock. 2000 Aug;14(2):215-21.

8. Fiddian-Green RG. Gastric intramucosal pH, tissue oxygenation and acid-
base balance.
Br J Anaesth. 1995 May;74(5):591-606. Review.

9. Sorenson L, Benke PJ. Biochemical evidence of a distinct type of
primary gout. Nature 313:1122 n1967.

10. Baar K, Wende AR, Jones TE, Marison M, Nolte LA, Chen M, Kelly DP,
Holloszy JO. Adaptations of skeletal muscle to exercise: rapid increase in
the transcriptional coactivator PGC-1.
FASEB J. 2002 Dec;16(14):1879-86

11. Piquet MA, Nogueira V, Devin A, Sibille B, Filippi C, Fontaine E,
Roulet M, Rigoulet M, Leverve XM. Chronic ethanol ingestion increases
efficiency of oxidative phosphorylation in rat liver mitochondria. FEBS
Lett. 2000 Feb 25;468(2-3):239-42.

12. Homocysteine causes mitochondrial dysfunction Richard G Fiddian-Green, 2 Dec 2002

13. Madness, hyperhomocysteinemia, metabolic rate and body temperature
Richard G Fiddian-Green, 6 Jan

14. Tiger L. Nunc est bibendum. Wall Street Journal Europe, January 13,

15. Do port and red wine preserve ATP stores? Richard G Fiddian-Green, 16 Dec 2002

16. Exercise and plasma homocysteine Harpal S Randeva, Vivian Fonseca,
Professor, Medicine and Pharmacol, Tulane University, USA; Gordana M
Prelevic, Senior Lecturer, Reproductive Endocrinology, Royal Free&UCL,
UK (20 December 2002)

Competing interests:  
None declared

Competing interests: No competing interests

19 January 2003
Richard G Fiddian-Green