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Homocysteine is an intermediate formed during the metabolism of the essential sulfur-containing amino acid methionine. Homocysteine concentration rises progressively with age in men and women, making it an important risk factor for cardiovascular disease.
The causes are still under study, but likely culprits include clinical or subclinical folate and B vitamin deficiencies and possibly renal dysfunction. The association between adverse cardiovascular events and plasma homocysteine persists in older populations.
In women, homocysteine levels increase after menopause and may be related to decreased estrogen concentrations. Folic acid supplementation decreases homocysteine concentration, but coadministration of vitamin B12 may be needed to prevent irreversible neurologic damage.
Moustapha A, Robinson K. Homocysteine: An emerging age-related cardiovascular risk factor. Geriatrics 1999; 54 (April):49-63
During the past few years, numerous important studies have shown an association between higher-than-normal plasma homocysteine levels and coronary and other vascular diseases, thus helping confirm the molecule's role as an independent risk factor for cardiovascular disease. Several of these studies have shown that homocysteine levels are elevated in older persons and are correlated with an increased incidence of cardiovascular events.
To provide an overview for the primary care physician, this article reviews the prevalence and causes of hyperhomocysteinemiathe presence of excess homocysteine in the plasmawith particular focus on older populations. The association of high homocysteine with cardiovascular disease and possible therapeutic strategies are also discussed.
HOMOCYSTEINE METABOLISM
Homocysteine is the demethylated derivative of methionine,(FN1,2) an essential amino acid derived from dietary and recycled endogenous proteins. Normally, approximately 50% of intracellular homocysteine is remethylated to methionine through two remethylation pathways
Homocysteine may also be transsulfurated to cystathionine, a
reaction catalyzed by the vitamin B6 (pyridoxal 5'-phosphate)
dependent cystathionine [beta]-synthase. Cystathionine, in turn,
is a source of cysteine, which is required for the synthesis
of many major biological compounds, including glutathione, the
most important intracellular thiol. Ultimately, cystathionine
and other sulfur-containing amino acids are metabolized to water
and sulphate and are excreted in the urine.
Approximately 80% of total plasma homocysteine is bound to albumin
by a disulfide bridge. Unbound homocysteine species exist mainly
as homocysteine-cysteine or homocysteine-homocysteine (homocystine)
disulfides. Only 1% of all circulating homocysteine exists as
truly free homocysteine. Total homocysteine (tHcy) describes
the sum of all these free and protein-bound biochemical homocysteine
species.
In normal subjects, the mean value for plasma tHcy is about 10[mu]mol/L, and the 95th percentile is about 16 [mu]mol/L. Values are about 10% higher in men compared with women(FN2) and concentrations rise progressively in both genders with age. Hyperhomocysteinemia is characterized as moderate (16 to 30 [mu]mol/L), intermediate (31 to 100 [mu]mol/L), and severe (>100 [mu]mol/L).(FN3) At present, no therapeutic targets for homocysteine levels have been established. Based on the current data, however, a target level of less than 10 [mu]mol/L is practical for patients at increased risk for cardiovascular disease.(FN3) Homocysteine measurements should be obtained while a patient is in the fasting state.
Factors that affect tHcy. In general, the most common acquired causes of increased plasma tHcy concentrations are probably absolute or relative deficiencies of folate and other B vitamins and renal failure (table 1). This is particularly true in older persons.
Other clinical conditions that may cause high tHcy levels include malignancies (breast and ovarian carcinomas, according to laboratory studies) and psoriasis. Hypothyroidism and various pharmacologic agents may also be responsible for elevated tHcy concentrations.(FN1)
Genetic deficiencies account for probably only a fraction of the elevated levels seen in the general population or in patients with vascular disease. Deficiency in cystathionine [beta]-synthase is the most common genetic basis for homocystinuria, a disorder characterized by extremely elevated tHcy levels and premature cardiovascular disease. Other genetic causes of increased tHcy include absence, or defects of, methylenetetrahydrofolate reductase (MTHFR) and methionine synthase. This includes the relatively common thermolabile variant form of MTHFR, seen in approximately 15% of the Caucasian population. This variant form may be associated with hyperhomocysteinemia, especially in the presence of low folate levels.(FN1,2)
High risk populations.
Persons likely to harbor high tHcy levels include those with a strong family history for atherosclerosis and those with arterial occlusive diseases, particularly in the absence of other risk factors.(FN3) High tHcy levels also are associated with advanced age, hypothyroidism, systemic lupus erythematosus, and certain medications, including nicotinic acid, theophylline, and L-dopa.(FN3)
HOMOCYSTEINE AND AGE
Several studies(FN4-10) have established a correlation between tHcy and age and showed that plasma tHcy levels increase in older populations with and without cardiovascular disease. In addition, abnormalities of folate, vitamin B12, and vitamin B6, appear to play a major role in the pathogenesis of increased tHcy levels in older persons.(FN6,7,11)
In healthy middle-aged and older subjects, Brattström et al showed that plasma folate and vitamin B12 are the major determinants of plasma tHcy and that users of multivitamins had lower levels than nonusers. Selhub et al(FN6) also demonstrated a strong nonlinear association between tHcy and the dietary intake of folate and vitamin B6 and the plasma concentrations of folate, vitamin B6, and vitamin B12 in a group of older participants in the Framingham Heart Study. Similarly, in the New Mexico Aging Process Study, folate and vitamin B12 were both significant determinants of tHcy concentrations.
Furthermore, although by standard laboratory criteria folate and vitamin B12 levels in most older persons register in the normal range, recent studies have suggested that some of these individuals manifest subclinical and tissue deficiencies, as proven by elevated levels of the metabolites tHcy and methylmalonic acid. The concentrations of both of these are now emerging as more sensitive and specific indicators of folate and vitamin B12 deficiencies at the tissue level. Using elevated tHcy and methylmalonic acid as criteria, approximately 7 and 12% of older patients were vitamin B12 deficient in the New Mexico Aging Process Study and the Framingham study, respectively. Moreover, the incidence of folate deficiency may be higher than previously believed.
Vitamin B12 deficiency. Causes of vitamin B12 deficiency in older persons remain unclear. Autoimmune processes such as pernicious anemia may play a minor role.(FN12) Possible mechanisms include low dietary intake, bacterial intestinal overgrowth, and gastric atrophy with decreased acid and pepsin secretion that impairs liberation of vitamin B12 from food.
Age-related decline in cystathionine [beta]-synthase, and other enzymes involved in homocysteine metabolism can potentially result in increased plasma tHcy in older persons. The progressive deterioration of kidney function with age may also provide an additional explanation for the correlation between age and increased plasma tHcy levels. The mechanisms behind the high plasma tHcy associated with kidney dysfunction are unclear and cannot be explained by decreased renal uptake. It may be related to altered non-renalpossibly hepaticmetabolism in the presence of renal failure.
MENOPAUSE AND HOMOCYSTEINE
Plasma tHcy levels increase in postmenopausal women compared with premenopausal women, although not consistently. Discrepancies could be due to different sample sizes, variations in study populations, methods of diagnosis of menopause, or assay procedures. For example, total homocysteine was measured in some studies, whereas the free form or homocysteine-cysteine mixed disulfide was measured in others.
The lower tHcy levels seen in premenopausal women may be attributed to more efficient handling of methionine through the trans-sulfuration or the remethylation pathway. Higher levels of plasma estrogens may also account for the lower plasma tHcy seen in these subjects. In a study by Wouters et al,(FN14) post methionine total plasma homocysteine strongly and negatively correlated to serum 17[beta]-estradiol in pre- but not postmenopausal women. Plasma tHcy is reduced during pregnancy, a condition characterized by increased estrogen levels.
The higher tHcy levels in postmenopausal women may play a role in the pathogenesis of increased incidence of adverse cardiovascular events seen after menopause. Hormone replacement therapy with combined estrogen and progesterone or progesterone alone lowers plasma tHcy in healthy pre- and postmenopausal women and could help reduce this risk.
VASCULAR DISEASE
Vascular complications are common in homocystinuria and provided the rationale for Wilcken and Wilcken to study higher homocysteine levels in patients with coronary artery disease (CAD).(FN21) Since then, many but not all studies(FN1,2) have confirmed the association of elevations of tHcy concentrations in all types of vascular disease, including CAD, aortic atherosclerosis, stroke, peripheral vascular disease, and venous thrombosis.
The association between adverse cardiovascular events and high plasma tHcy levels persists in older persons. In one case control study,(FN8) patients age 65 and older with CAD had higher tHcy concentrations than similarly aged healthy subjects (14.5 ± 5.1 [mu]mol/L versus 11.9 ± 3.5 [mu]mol/L). Similar results were obtained in a study by Aronow et al, where elevated plasma tHcy levels (>17 [mu]mol/L) were seen in 43% of older men with coronary disease versus 15% without it. Results were similar for women in the study. In another report by Aronow et al,(FN23) elevated plasma tHcy levels were observed in 45% of older men exhibiting 40 to 100% extracranial carotid artery stenosis versus 20% of older men with 0 to 39% extracranial carotid artery stenosis.
In a study by Selhub et al(FN24) involving older subjects from the Framingham Heart Study, the odds ratio for extracranial carotid artery stenosis of >=25% was 2.0 (95% confidence interval, 1.4 to 2.9) for subjects with the highest plasma tHcy concentrations (>=14.4 [mu]mol/L) compared with those with the lowest concentrations (<=9.1 [mu]mol/ L), after adjustment for other risk factors. Elevated plasma tHcy levels also are associated with isolated systolic hypertension in older patients.
POSSIBLE MECHANISMS OF VASCULAR DAMAGE
Possible mechanisms, if any, of hyperhomocysteinemia-induced vascular damage remain unclear. The major focus of current studies is on the endothelium and to a lesser extent on platelets and clotting factors as the sites of initiation of vascular damage.
In vitro studies have shown that homocysteine exerts direct endothelial cytotoxicity at higher than normal levels. Oxidation of homocysteine may also lead to the formation of hydrogen peroxide, which may play a role in endothelial cell damage.
In a recent in vivo study in monkeys, diet-induced hyperhomocysteinemia was associated with altered endothelium-dependent vascular function. Meanwhile, a clinical study in humans showed that homocysteine may also cause inhibition of endothelium-dependent flow-mediated dilation, suggesting inhibition of nitric oxide. Other proposed mechanisms that could lead to thrombosis include inhibited synthesis of prostacyclin, decreased platelet survival, increased factor V expression, inactivation of endothelial anti-coagulant protein C, or disruption of the processing and secretion of von Willebrand factor.
FOLIC ACID SUPPLEMENTATION
Folic acid supplementation reduces tHcy levels in normal subjects and in patients with vascular disease. It may be used alone or in combination with vitamin B12 and vitamin B6. Dosing levels and vitamin combinations remain unclear although one study showed that a mean supplementation of 0.5 to 5.7 mg/d folic acid may produce a 25% reduction in homocysteine concentration.
Benefits.
Naurath et al(FN27) have shown that IM injections combining 1 mg folic acid, 1.1 mg vitamin B12, and 5 mg vitamin B6 normalized elevated tHcy levels in a population of institutionalized older persons who had no overt chronic renal failure. Elevated tHcy concentrations returned to normal in 92% of the vitamin group compared with 20% of the placebo group. Lower doses of folic acid may also be useful in older persons. For example, Brönstrup et al(FN28) reduced tHcy by 15% in healthy older subjects using daily supplements of combination folic acid, 400 mg; vitamin B12, 4 mg; and vitamin B6, 2 mg, administered orally for 4 weeks. Another study showed that IM hydroxocobalamin supplementation alone lowered tHcy concentrations significantly in healthy older subjects with low cobalamin levels.(FN29) Folic acid supplementation was also shown to reduce homocysteine-cysteine mixed disulfide in postmenopausal women.
Risks.
Although folate supplementation may provide a benefit by lowering tHcy, it also poses a special hazard in older persons. A high folate intake may mask the development of megaloblastic anemia characteristic of patients with vitamin B12 deficiency. Delay in the diagnosis of vitamin B12 deficiency may lead to irreversible neurologic damage clinically manifested as cognitive impairment, diminished position and vibratory sensation, and sensory peripheral neuropathy.
Tucker et al evaluated the effects of the recent increase in folate fortification (140 [mu]g per 100 g) of cereals and grain products and found that the benefit of decreasing tHcy may outweigh any potential risks of masked low vitamin B12 concentration. Nonetheless, it may still be prudent to check vitamin B12 and/or methylmalonic acid levels in older patients at risk of deficiency before initiation of treatment and perhaps also during follow-up. Appropriate investigation and correction of any deficiency may help prevent the occurrence of irreversible neurologic damage.
Although folic acid may lower tHcy concentrations, as yet there is no evidence from randomized trials that this improves clinical outcomes. Controlled intervention studies of folic acid supplements in patients with vascular disease are in progress to assess the role of vitamin therapy in the management of patients with atherosclerosis.
CONCLUSION
A high plasma total homocysteine concentration is an independent risk factor for atherosclerosis in older persons. The causes for elevated tHcy concentrations are complex and are likely related to suboptimal vitamin status and kidney dysfunction. The mechanism, if any, by which high plasma homocysteine may cause vascular damage remains unclear but is possibly due to endothelial damage.
Pending definitive results from clinical trials, it is advisable to screen for tHcy only in older patients determined to be at high risk for ardiovascular disease. That is:
Although homocysteine screening can be costly, Medicare will reimburse for it in some cases.
If changes in diet do not produce significant decreases in patients whose tHcy levels are high, then supplementation with folic acid and vitamin B12 could be initiated. The dose and combination remain unclear, but 1 mg/d of folic acid and 500 mg/d of vitamin B12 given orally should provide adequate and safe intervention. Older persons at risk are also advised to consume adequate amounts of fruits and vegetables. Intervention studies using vitamin supplements with clinical outcomes as endpoints are in progress.
ADDED MATERIAL
ALI MOUSTAPHA, MD
KILLIAN ROBINSON, MD
Dr. Moustapha is a cardiology fellow, department of cardiology, University of Texas at Houston. Dr. Robinson is staff cardiologist, department of cardiology, The Cleveland Clinic Foundation, Cleveland, OH.
TABLE 1 Causes of hyperhomocysteinemia
INHERITED
Transsulfuration disorders
Cysthathione ss-synthase deficiency (rare)
Remethylation disorders
Defects of vitamin B12 transport (rare)
Defects of vitamin B12 coenzyme synthesis (rare)
Defects of methionine synthase (rare)
Defects or deficiency (rare) of 5, 10 methylenetetrahydrofolate reductase
ACQUIRED
Vitamin deficiencies
Vitamin B12
Folate
Vitamin B6
Renal failure
Hypothyroidism
Acute lymphoblastic leukemia
Psoriasis
Drugs
Methotrexate (an inhibitor of dihydrofolate reductase)
Phenytoin and carbamazepine (antagonists of folate)
Nitrous oxide (an inactivator of methionine synthase)
Methylxanthines (inhibits vitamin B6)
Nicotinic acid (mechanism unknown)
Source: Prepared for GERIATRICS by Ali Moustapha, MD, and Killian
Robinson, MD
ALI MOUSTAPHA; KILLIAN ROBINSON, Homocysteine: An emerging age-related cardiovascular risk factor. Vol. 54, Geriatrics, 04-01-1999.
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