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In: Vitamin B: New Research ISBN 978-1-60021-782-1
Editor: Charlyn M. Elliot, pp. 121-137 © 2008 Nova Science Publishers, Inc.
Nephrology and Dialysis Unit, Vimercate Hospital, Vimercate, Italy.
High total plasma homocysteine levels are detected not only in patients with
homocystinuria, a recessively inherited disease, but also in patients with renal failure,
hypothyroidism, and methyltetrahydrofolate reductase polymorphism. The most
important clinical signs of high plasma homocysteine values are thromboembolic
vascular occlusions of arteries and veins, cerebral impairment, osteoporosis, and
displacement of the lens. Cardiovascular disease is the primary reason of morbidity and
mortality in the general population, and it represents about 50% of the causes of
mortality of the patients with chronic renal failure. Folic acid, vitamin B6 and vitamin
B12, lower hyperhomocysteinemia acting on remethylation and transsulphuration
pathway. Vitamin B treatments don't often normalize plasma homocysteine levels, but
long-term effects of vitamin B therapy are effective in reducing the life-threatening
vascular risk of homocystinuric patients. Hyperhomocysteinemia is detected in patients
with chronic renal failure, and especially in patients with stage 5 of chronic kidney
disease. Clinical observational studies have shown different results about the effects of
high plasma homocysteine levels on cardiovascular disease in dialysis patients. In fact,
cardiovascular mortality has been associated not only with hyperhomocysteinemia, but
also in some studies with hypohomocysteinemia. These contrasting data are probably due
to the strict relationship between homocysteine and malnutrition-inflammation markers.
Dialysis patients are frequently affected by malnutrition-inflammation-atherosclerosis
syndrome, and consequently this severe clinical condition can interfere with
homocysteine levels. I and my coworkers recently observed in a prospective clinical trial
that hemodialysis patients, submitted to vitamin B treatment, with low homocysteine
levels and high protein catabolic rate show a significantly higher survival rate as
compared with the other three subgroups. Prospective clinical studies, evaluating
homocysteine-lowering vitamin B therapy on cardiovascular events in patients with mild
hyperhomocysteinemia, have recently shown no clinical benefits. These results could be
misleading because a part of patients had normal homocysteine levels, follow-up time
may have been too short, and confounding factors has not been considered. To
Keywords: homocysteine, folic acid, vitamin B, cardiovascular disease.
About 50 years ago homocysteine’s story begins: just on 1955 Vincent du Vigneaud, an
American scientist born in Chicago on 18th May 1901, won the Nobel Prize in Chemistry. He
Homocystinuria and high plasma homocysteine concentrations were first described in the
60s. In 1962 Carson et al. [2] discovered homocysteine in the urine of subjects with cerebral
atherosclerosis in patients with homocystinuria and high homocysteine levels.
Homocystinuria is a recessively inherited disease due to cystathionine beta-synthase
deficiency. Cystathionine beta-synthase catalyzes the first step in the transsulfuration process,
promoting the condensation of homocysteine with serine to form cystathionine. The
biochemical data of this rare metabolic inborn error are: hyperhomocysteinemia with 10
times higher levels than normal, hypermethioninemia, hypocysteinemia; while the clinical
findings are: thromboembolic vascular occlusion of arteries and veins, cerebral impairment,
osteoporosis, skeletal abnormalities, displacement of the lens.
In the last ten years the scientific interest for homocysteine and vitamin B therapy is
highly increased because of its strict relationship with cardiovascular events. This paper
shows the hottest news regarding the effects of homocysteine-lowering vitamin B therapy on
cardiovascular events, exploring the intriguing puzzle of homocysteine.
Homocysteine is a small, 135 Da, sulfur amino acid. Plasma homocysteine is chiefly
bound to albumin, but it exists also as free, non protein-bound, form. Total plasma
homocysteine includes all homocysteine fractions, both protein-bound and free.
Homocysteine is achieved from methionine’s demethylation, and it is then converted either to
Vitamin B Treatment and Cardiovascular Events in Hyperhomocysteinemic Patients 123
cysteine through the transsulfuration pathway or to methionine through the remethylation
process. In the transsulfuration pathway homocysteine is metabolised to cystathionine in a
reaction, requiring vitamin B6, catalysed by cystathionine beta-synthase; while, in the
remethylation process homocysteine acquires a methyl group either from 5-
methyltetrahydrofolate with a vitamin B12 dependent reaction, or from betaine (Figure 1).
Figure 1. Homocysteine metabolic pathway.
The human cystathionine beta-synthase gene is on chromosome 21, and therefore
patients with trisomy 21 have greater than normal enzyme activity and as a result lower than
normal total homocysteine [4]. Diabetic patients have decreased homocysteine values
because cystathionine beta-synthase activity is increased by the reduced levels of insulin and
by the high levels of counter regulatory hormones such as glucagon and glucocorticoids [5].
Also the enzyme 5,10-methylene-tetrahydrofolate reductase (MTHFR), which reduces
5,10-methylene-tetrahydrofolate to 5-methyl-tetrahydrofolate, may have a reduced activity
due to genetic mutations, and as a result a specific susceptibility to folic acid insufficiency,
high total plasma homocysteine levels, and an increased risk for cardiovascular events [6].
Total plasma homocysteine levels are related to sex and age: young men usually have
higher homocysteine values than women of the same age, but after fertility period this gender
difference disappears probably because the positive effect of estrogens [7] promptly goes
away with menopause; while the age-related increase of plasma homocysteine levels is
probably linked to the physiologic reduction of renal function. High homocysteine levels are
frequently detected in end-stage renal disease patients. Plasma homocysteine values rise as
renal function declines, and total homocysteine levels fall in patients after renal
transplantation [8], suggesting that renal mechanisms are at least partly responsible for the
increase of homocysteine among individuals with renal impairment [9]. High plasma
homocysteine levels in patients with renal failure don’t directly depend on impaired renal
excretion because, first, protein-bound form is not filtered and, second, almost all filtered free
fraction is submitted to proximal tubular reabsorption. The most apt hypothesis is the increase
of uremic toxins that may lead to impairment of enzymes related to homocysteine
metabolism. Methionine transmethylation and homocysteine remethylation are decreased in
patients with renal failure compared to healthy subjects, in contrast, whole body
homocysteine transsulfuration appears to be unaffected when corrected for variation in the
B6 vitamin status [10]. Vitamin B11, isolated from spinach leaves and called folate from the
Latin “folium” [11], is the most important determinant of plasma total homocysteine. Folate
therapy increases homocysteine remethylation and methionine transmethylation, and almost
certainly indirectly stimulates cystathionine beta-synthase [12] improving transsulfuration,
but not sufficiently to normalize homocysteine in the major part of end-stage renal disease
Total plasma homocysteine levels depend also on thyroid state: hypothyroidism is
associated with low and hyperthyroidism with high glomerular filtration rate, which in turn is
strictly related to plasma total homocysteine [14]. Therefore total homocysteine is decreased
in hyperthyroidism, and increased in hypothyroidism. Furthermore, in hypothyroidism
hormone replacement therapy normalizes homocysteine levels [15].
Plasma total homocysteine exists essentially as the protein-bound form, with albumin
being the main homocysteine-binding protein, and this is showed by a positive relationship
between plasma total homocysteine and serum albumin in end-stage renal disease patients.
Another important finding in these patients is the positive correlation between plasma total
homocysteine and serum creatinine, even stronger than that seen with serum albumin. This
finding may strengthen a nutritional factor of total homocysteine, but it could also be the
result of the metabolic association between total homocysteine and serum creatinine. In fact,
homocysteine [16]. Plasma total homocysteine may be a nutritional marker in maintenance
dialysis patients, and this nutritional feature may explain its reverse association with
mortality rate in some studies [17].
Diabetic patients on dialysis have higher homocysteine levels than diabetic patients with
normal renal function, but lower than dialysis patients with other nephropathies [18].
Many drugs may influence plasma total homocysteine levels. Methotrexate, “classical
antifolate” used in the treatment of cancer, as well as for other conditions such as rheumatoid
arthritis and psoriasis, interrupts the function of folate’s methyl transfer. Treatment protocols
with methotrexate can induce an acute state of folate depletion which may lead to significant
treatment-related toxicity. Both folate and folinic acid reduce methotrexate toxicity, and
decrease methotrexate-induced hyperhomocysteinemia. The efficacy of methotrexate
probably decreases slightly, but the benefit outweighs the risk. Folate supplementation
should, therefore, be routinely prescribed to every patient taking low-dose methotrexate [19].
Phenytoin, phenobarbital and primidone are also associated with high plasma total
homocysteine and low folate levels, whereas valproate does not influence folic acid and
homocysteine [20]. Moreover, both Parkinson’s disease patients treated with L-dopa and
asthma patients treated with theophylline show high homocysteine levels because in the first
Vitamin B Treatment and Cardiovascular Events in Hyperhomocysteinemic Patients 125
ones most likely the breakdown of L-dopa by catechol-O-methyltransferase results in
increased homocysteine formation [21], and in the second ones theophylline, a pyridoxal
kinase antagonist, causes vitamin B6 deficiency, impaired transsulfuration and therefore high
homocysteine levels [22]. Conversely estrogens lower homocysteine levels, but the
mechanism behind this observation is unclear. Estrogen-induced lowering of homocysteine
levels is probably not linked to transmethylation, remethylation, and transsulfuration
pathways, but due to a change in albumin metabolism. Furthermore, it is noteworthy to
remember that the influence of anticalcineurin drugs on homocysteine levels is controversial.
Homocysteine levels are closely related with serum creatinine both in cyclosporine and in
tacrolimus treated patients; the latter ones have lower homocysteine levels because they show
Table 1 summarizes the effects of drugs and diseases on homocysteine levels.
Table 1. Drugs and diseases affecting total plasma homocysteine levels
Drugs and diseases homocysteine
Total plasma homocysteine concentrations have a strong inverse correlation with serum
folate values. Folic acid supplementation is an effective therapy to normalize total plasma
homocysteine levels in patients with occlusive vascular disease and without renal failure [23].
On the contrary, high “pharmacological” doses of folate lower, but rarely normalize total
hemodialysis, treated with folic acid, have total plasma homocysteine levels higher than the
upper normal limit, and that folate treatment with 15 mg per day is not better than 5 mg per
day in lowering total plasma homocysteine levels. Folate supplementation with higher doses,
equal to 30 or 60 mg per day, is not more useful than 15 mg per day in reducing high total
plasma homocysteine levels [25]. Moreover, it has been observed that the supplementation
with folate and betaine does not further reduce total plasma homocysteine values [26],
suggestive of a betaine-dependent remethylation not stimulated by exogenous betaine when
patients are just submitted to folate therapy; and also that the homocysteine-lowering effect
of i.v. folinic acid, oral folinic acid and oral folic acid is similar [27], suggesting that high
total plasma homocysteine levels are not due to abnormal folate metabolism.
We recently detected in a 6-months prospective trial [28] that vitamin B therapy,
including folate 5 mg p.o. per day, vitamin B12 1 mg i.m. per week, and vitamin B6 300 mg
p.o. per day, largely reduces total plasma homocysteine levels, normalizing these values in
more than 70% of end-stage renal disease patient on peritoneal dialysis. We chose to add
high doses of vitamin B12 and vitamin B6 to standard folate therapy because:
1. the remethylation of homocysteine to methionine needs vitamin B12 as enzymatic
2. the folate supplementation reduces the dependency of homocysteine on folate with a
shift in dependency from folate to vitamin B12 [29];
3. the transsulfuration of homocysteine to cystathionine needs vitamin B6 as enzymatic
4. vitamin B6 deficiency, usually found in dialysis patients, contributes to impaired
The literature’s data tell us that there are no known severe side effects concerning folate
therapy; and, furthermore, the upper level of 1 mg per day of folic acid recommended dose
[30] is due to the possible risk of concealing anemia in the case of vitamin B12 deficiency.
Also for vitamin B12 supplementation, there are no known side effects, and apparently
neither upper limits of intake. Vitamin B6 is important, when added to vitamin B12 and
folate, to reduce hyperhomocysteinemia; but single high doses of vitamin B6 are
unsuccessful to lower high total plasma homocysteine levels. Moreover, contrary to folate
and vitamin B12, there is a safe upper limit for long-term vitamin B6 supplementation that is
equal to 50-100 mg per day. Table 2 shows the different doses of vitamin B therapy in the
homocysteine-lowering trials with a long-term follow-up period.
Total plasma homocysteine concentrations of end-stage renal disease patients may be
also improved with dialysis therapy. The standard low-flux bicarbonate dialysis removes
about 30% of the pre-dialysis total plasma homocysteine concentration and, as expected,
homocysteine reduction rate during this type of hemodialysis is lower than that of creatinine,
according to its protein binding. Total plasma homocysteine levels do not rise for at least 8
hours after standard low-flux dialysis in contrast to plasma creatinine concentration [31], and
Vitamin B Treatment and Cardiovascular Events in Hyperhomocysteinemic Patients 127
plasma homocysteine levels have a postdialytic slight decrease, considering patients on high
flux dialysis [32]. This interdialytic homocysteine curve is fitting with the thinking that
dialysis treatment may remove uraemic toxins with inhibitory activities against one or more
enzymes of the remethylation or transsulphuration pathway. The high-flux dialysis membrane
should perform this removal with greater efficiency. High-flux dialysers with high capacity to
eliminate large uraemic substances, but without excessive leakage of useful proteins such as
albumin, show an intradialytic higher homocysteine-lowering rate, about 40% compared to
30% with low-flux membrane, and pre-dialysis total plasma homocysteine values are slightly,
but not significantly, lower in end-stage renal disease patients treated with high-flux
membranes as compared to patients submitted to low flux dialysers during a follow-up time
of 3 months [33]. The high-flux advanced polysulphone dialysers with high clearance of
larger uraemic toxins, but non-albumin-leaking, do not improve homocysteine clearance
compared to high-flux standard polysulphone membranes, confirming that the large part of
uraemic toxins affecting homocysteine metabolism are protein-bound or have a molecular
mainly by removing large molecular weight solutes able to affect the homocysteine
metabolism [35,36,37]. Also the hemodiafiltration with endogenous reinfusion and the
internal hemodiafiltration have high homocysteine-lowering power [38] similar to superflux
membranes. End-stage renal disease patients submitted to pre-dilution on-line hemofiltration
[39], nocturnal hemodialysis six or seven nights per week [40], and peritoneal dialysis
[41,28] show a significantly lower pre-dialysis total plasma homocysteine levels as compared
to patients on standard low-flux hemodialysis, because the first removes larger molecular
weight solutes, and the others have a shorter interdialytic period which permits a less
restricted diet. Indeed, total plasma homocysteine concentrations are not efficiently decreased
by peritoneal dialysis because its dialytic removal via the peritoneal membrane is inefficient
owing to its high protein-bound fraction [42] and, therefore, the reason of lower total plasma
homocysteine levels in end-stage renal disease patients on peritoneal dialysis as compared to
patients on standard hemodialysis is in theory due to the continuous treatment which gives
the chance to the patients having a diet with more fruit and vegetable.
Table 2. Vitamin B doses, net changes of homocysteine from baseline levels, and relative
risk for stroke in the long-term homocysteine-lowering trials
Journal First Author B6 Folate B12 Δ homocysteine RR Stroke
Blood Purif Righetti M [58] 5mg -15.1 0.55
JACC Zoungas S [74] 15mg -2.4 0.45
N Engl J Med HOPE-2 Inv. [69] 50mg 2.5mg 1mg -3.2 0.76
N Engl J Med Bǿnaa KH [68] 40mg 0.8mg 0.4mg -3.8 0.91
JAMA Toole JF [66] 25mg 2.5mg 0.4mg -2.1 1.04
End-stage renal disease patients on maintenance haemodialyis, submitted to intravenous
N-acetylcysteine, showed post-dialysis lower plasma homocysteine levels and better pulse
pressure values as compared with untreated haemodialysis patients [43,44]. Scholze A et al.
[43] demonstrated not only that patients submitted to 5 g acetylcysteine in 5% glucose
solution for 4 hours during a single haemodialysis session had total plasma homocysteine
levels markedly reduced (about 90%, with post-dialysis homocysteine values equal to 2
micromoles/liter) beyond the effects of haemodialysis alone; but also they observed an
improvement of endothelial function. The high homocysteine-lowering effect of intravenous
acetylcysteine is probably due to a quick displacement of homocysteine from protein-binding
sites, allowing an increased rate of homocysteine available for clearance by haemodialysis,
considering its small size. On the contrary, oral administration of acetylcysteine showed only
a 20% of homocysteine-lowering as compared to no homocysteine-reduction in the placebo
group [45]; and, unfortunately, a randomised controlled trial by Tepel M et al. [46] showing a
significant lowering of composite cardiovascular end-points in haemodialysis patients
submitted to acetylcysteine, 600 mg BID orally, did not analyze the effects on plasma
haemorrhagic cystitis caused by cyclofosfamide and other cancer-fighting drugs, on total
plasma homocysteine levels in hemodialysis patients. The intra-dialytic mesna
supplementation at the dose of 5 mg per Kg caused, lowering homocysteine’s protein-bound
fraction, a higher decrease (about 55%) of total plasma homocysteine levels as compared to
hemodialysis alone (about 35%). Table 3 summarizes homocysteine-lowering treatments.
Table 3. Homocysteine-lowering treatments in end-stage renal disease patients
Righetti M [24] 5mg FA 5mg FA is similar to 15mg, only about 10% of pts with
final normal homocysteine values
Righetti M [28] 5mg FA, 250mg B6,
Multivitamin B therapy is better than FA alone, about
70% of pts with final normal homocysteine values
Righetti M [38] HDF High intra-dialytic homocysteine-lowering rate, about
40-50%, in pts on I-HDF, OL-HDF, HFR; better than
30% in pts on standard thrice weekly HD
Moustapha A [41] PD Homocysteine levels are lower in pts on PD as compared
Friedman AN [40] Every-day HD Homocysteine levels are lower in pts on every-day HD
as compared with pts on thrice weekly HD
Scholze A [43] N-acetylcysteine IV N-acetylcysteine therapy improves intra-dialytic
High total plasma homocysteine values cause endothelial damages through several
mechanisms, usually not exclusive [48]. Homocysteine can change the release or activity of
anti-inflammatory, vasoactive agents like adenosine and nitric oxide. High homocysteine
levels are linked to impaired vasodilation and decreased nitric oxide production by
endothelial nitric oxide synthase, due both to arginine transport alterations that reduce
Vitamin B Treatment and Cardiovascular Events in Hyperhomocysteinemic Patients 129
cellular uptake of L-arginine and to the increase of asymmetric dimethylarginine, an
endogenous inhibitor of nitric oxide synthase, with consequent rise of superoxide anion
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