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Hyperhomocysteinemia and vascular disease
(Portuguese PDF version)

Marília Duarte Brandão Panico*

*Supervisor of the course on angiology, School of Medicine, Universidade do Estado do Rio de Janeiro, Brazil.

J Vasc Br 2004;3(1):3-4

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Among the risk factors for vascular diseases, hyperhomocysteinemia is currently considered to be the most important one. Besides favoring the formation of atheromatous plaques in elastic and muscular arteries, it can also cause both arterial and venous thrombosis, affecting vessels of any diameter.

Medical literature is rich in showing the relevance of such a metabolic dysfunction, which leads to severe health problems and to a miserable quality of life for patients. Hyperhomocysteinemia may be secondary to genetic mutations, causing functional defects in the enzymes involved in the process, or to nutritional deficiency in terms of the cofactors.

Homozygous individuals present homocystinuria and plasma homocysteine levels higher than 100 µmol/l. Its several signs appear in childhood and, in most cases, the patient dies at the end of the first decade of life or in adolescence due to vascular complications of early atherosclerosis.

Although severe hyperhomocysteinemia is rare, the moderate form (15 to 30 µmol/l), which affects patients with heterozygosity for N⁵, N¹⁰ methylenetetrahydrofolate reductase (MTHFR) mutation, is present among 38% of Canadians of French descent,¹ and among 5% to 7% of the world population.² Both in the moderate and intermediate forms (30 to 100 µmol/l), patients remain asymptomatic until the third or fourth decades of life, when they present thrombotic episodes. Deep venous thrombosis is the most frequent complication. From the fourth or fifth decade of life onwards, patients present with symptoms of atherosclerosis, and 42% of them present with cerebrovascular diseases. The incidence of peripheral vascular disease is 28% and that of coronary vascular disease is 30%.³

The article of Stahlke et al. (published in this issue) evidences that, when there are conditions for the elevation of plasma homocysteine levels, premature endothelial injuries occur. In their study, the histological sections of the aortas of rabbits fed with an overload of methionine presented foam cells two months after the beginning of the diet.

There are several hypotheses to explain how elevated plasma homocysteine levels trigger the mechanism for the formation of atherosclerotic plaques (Table 1).

Table 1 - Hyperhomocysteinemia can alter endothelial metabolism, inducing an oxidative stress, which is the starting point for the formation of atheromatous plaques

Effect	Consequence
Increased oxidative stress, inhibiting the formation of endothelial nitric oxide	Vasoconstriction
Formation of hydrogen superoxide and peroxide radicals	Endothelial injury
Oxidation of LDL (low-density lipoprotein) in subendothelium Increased activity of macrophages	Uptake of oxidized LDL by activated macrophages, forming foam cells
Induced proliferation of smooth muscle cells	Migration to subendothelial layer, atheromatous plaque increases
Activation of platelets	Platelet adhesion and aggregation, forming platelet thrombus in the areas of endothelial injury

The mechanisms that cause venous thrombosis are described in Table 2.

Table 2 - All consequences of hyperhomocysteinemia occur at the same time but, given that the effects over the coagulation cascade are immediate, venous thrombosis is the most frequent complication

Effect	Consequence
Decreased thrombomodulin expression	Decreased activation of proteins C and S
Decreased activation of antithrombin III	Reduced control over activation of thrombin
Impaired binding of plasminogen tissue factor to its receptor	Reduced activation of fibrinolysis

McCully² affirmed that the ideal plasma homocysteine level is below 10 µmol/l. Providing evidences for such statement, Nygärd et al.⁴ found that patients with plasma homocysteine levels of 15 µmol/l have an associated mean mortality rate 1.6 higher than patients with the levels below 10 µmol/l. An elevation of 5 µmol/l in plasma homocysteine is associated with an increase of 1.7 in the relative risk for coronary ischemia, of 1.5 for cerebrovascular disease and, in the case of peripheral arterial disease, the increase in the relative risk reaches 6.8. Such high values evidence the importance of screening vascular patients for this disorder, no matter their age.

On the other hand, Stampfer⁵ found that two thirds of the cases of hyperhomocysteinemia are secondary to low concentrations of one or more cofactors, which are fundamental for remethylation (vitamin B12 and folic acid), transforming homocysteine again in methionine, and for transsulfuration (vitamin B6), transforming homocysteine in cysteine.

According to such findings, it is believed that an adult subject may not carry the mutation which leads to such metabolic dysfunction or may not have disorders which lead to an increase in plasma homocysteine (such as hypothyroidism, some neoplasias, renal insufficiency, etc.), but nevertheless develop thromboses. Subjects who do not have a healthy diet or even those whose diets include only a restricted amount of meat (such as vegetarians) may have elevated plasma homocysteine levels (even for short periods of time), causing oxidative stress or leading to the development of venous thrombosis. Following the antiphospholipid antibody syndrome, the elevation of homocysteine levels is the most frequent risk factor for venous thrombosis among women and its prevalence increases with age. After menopause, plasma levels are even higher. It is usual that elderly patients have difficulty absorbing vitamin B12, causing pernicious anemia and also moderate elevation of homocysteine levels. Men with plasma levels 12% above the limit which is considered normal (15 µmol/l) have three times more chance of having a myocardial infarction than those with levels below 10 µmol/l, even controlling for other risk factors.¹

Vitamin supplementation usually lowers or normalizes homocysteine levels when the disorder is secondary to deficiency of the cofactors or when the patient is heterozygous for MTHFR mutation. The minimum dose of folic acid or pyridoxine needed is still to be determined. For most cases, an intake of 1 to 5 mg of folic acid/day and vitamins B6 e B12 is usually effective.⁶ The levels reach normal values 4 to 6 weeks after the beginning of the treatment. Depending on the cause, the patient must remain under treatment for an undetermined period of time.

In the case of one homozygous patient we are treating in our hospital (she is now 17 years-old), we managed to lower her plasma homocysteine level from 357 µmol/l to 50 µmol/l. Along with a daily intake of large doses of cofactors, she is also being treated with anticoagulant therapy because she had several episodes of venous thrombosis (the last one in the inferior vena cava, when she was 14 years-old.) She has bilateral femoropopliteal occlusion, which remains unaltered up to the present moment. Despite ectopia lentis (which was surgically corrected) and the neurological deficit after the beginning of a continuous treatment with vitamin supplementation and anticoagulant therapy (when she was 14 years-old), the patient had her quality of life improved and was able to return to school.

It is still uncertain whether the normalization or lowering of plasma homocysteine levels will impact on the incidence and development of vascular diseases.

REFERENCES

1. Arruda VR, von Zuben PM, Chiaparini LC, Annichino-Bizzacchi JM, Costa FF. The mutation Ala677-->Val in the methylene tetrahydrofolate reductase gene: a risk factor for arterial disease and venous thrombosis. Thromb Haemost 1997;77(5):818-21.

2. McCully KS. Homocysteine and vascular disease. Nat Med 1996;56:111-28.

3. Clarke R, Daly L, Robinson K, Naughten E, Cahalane S, Fowler B, et al. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med 1991;324(17):1149-55.

4. Nygard O, Nordrehaug JE, Refsum H, Ueland PM, Farstad M, Vollset SE. Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med 1997;337:230-6.

5. Stampfer MJ, Malinow MR, Willett WC, Newcomer LM, Upson B, Ullmann D, et al. A prospective study of plasma homocyst(e)ine and risk factor of myocardial infarction in US Physicians. JAMA 1992;268:877-81.

6. Saltzman E, Mason JB, Jacques PF, Selhub J, Salem D, Schaefer EJ, et al. B vitamin supplementation lowers homocysteine levels in heart disease. Clin Res 1994;42:172A.