Treatment of mild hyperhomocysteinemia in vascular disease patients.

Abstract

Mild hyperhomocysteinemia is recognized as a risk factor for premature arteriosclerotic disease. A few vitamins and other substances have been reported to reduce blood homocysteine levels, but normalization of elevated blood homocysteine concentrations with any of these substances has not been reported. Therefore, we screened 421 patients suffering from premature peripheral or cerebral occlusive arterial disease by oral methionine loading tests for the presence of mild hyperhomocysteinemia. Thirty-three percent of patients with peripheral and 20% of patients with cerebral occlusive arterial disease were identified with mild hyperhomocysteinemia (14% of the men, 34% of the premenopausal women, and 26% of the postmenopausal women). Mildly hyperhomocysteinemic patients were administered vitamin B 6 250 mg daily. After 6 weeks methionine loading tests were again assessed to evaluate the effect of treatment. Patients with nonnormalized C lassic homocystinuria, due to homozygosity for cystathionine synthase (CS) deficiency, is characterized by severe accumulation of homocysteine in the blood and tissues. The incidence of this hereditary dysfunction varies geographically and is estimated as 1:200 000 worldwide.1 Homocystinuria is generally considered to cause premature arteriosclerosis and thromboembolism. It is treated with high-dose administration of vitamin B 6 , the active form of which, pyridoxal phosphate, functions as a cofactor in the conversion of homocysteine to cystathionine (Fig 1). The marked homocysteine-lowering effect of vitamin B 6 is attributable to its stimulation of the residual activity of the cystathionine synthase enzyme.14 Additionally, folic acid and betaine, both involved in the remethylation of homocysteine into methionine, can lower or even normalize elevated homocysteine levels in patients who respond poorly or not at all to vitamin B 6 treatment. 13 The incidence of vascular accidents is significantly reduced after initiating homocysteine-lowering treatment, revealing the clinically beneficial effect of such intervention in homozygous patients. 4 Mild hyperhomocysteinemia, with homocysteine concentrations equivalent to those found in individuals heterozygous for CS deficiency, is characterized by Received September 30, 1993; revision accepted November 22, 1993.From the Department of Medicine, Division of Endocrinology (D.G.F., G.H.J.B., P.W.C.K.), and the Department of Pediatrics (H.J.B., F.J.M.T.) of the University Hospital Nijmegen, Nijmegen, the Netherlands.Reprint requests to Dr G.HJ. Boers, Department of Medicine, University Hospital Nijmegen, Post Box 9101, 6500 HB Nijmegen, the Netherlands. homocysteine concentrations were further treated with vitamin B 6 250 mg daily and/or folic acid 5 mg daily and/or betaine 6 g daily, solely or in any combination. Vitamin B 6 treatment normalized the afterload homocysteine concentration in 56% of the treated patients (71% of the men, 45% of the premenopausal women, and 88% of the postmenopausal women). Further treatment resulted in a n...

Impairment of Lipid Metabolism Due to Deficiency of Pyridoxal-5-phosphate and/or Activated Immune system: its Interpretation

“…Our results of lipid deviations demonstrated in this study after addition of P-5-P to normal rat liver homogenate and to P-5-Pdeficient rat liver homogenate further support this conclusion. It is affirmed also by the normalization of homocysteine accumulation in the blood of patients with drug-induced homocysteinaemia after supplementary treatment with vitamin B6 and/or folic acid together with betaine (27,69) while this treatment was ineffective in healthy individuals (27).…”

Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease

“…[32][33][34] Renal insufficiency or nutritional deficiencies of B vitamins required for homocysteine metabolism, namely folic acid, vitamin B6 (pyridoxal phosphate), and/or vitamin B12 (methylcobalamin), also cause HHcy. 35,36 It is estimated that inadequate intake of vitamins accounts for two-thirds of all cases of HHcy. 36 Although vitamin supplementation has been shown to be effective in lowering plasma homocysteine levels, it remains to be determined if the risk of cardiovascular disease is decreased.…”

“…Various ex vivo studies using vascular tissues have implicated HHcy in causing abnormal vascular relaxation responses by inducing the intracellular production of superoxide. [67][68][69] Superoxide is believed to react with endothelial nitric oxide to yield peroxynitrite, thereby limiting the normal vasodilation response. 70,71 Both superoxide and peroxynitrite contribute to the modification of tissues, resulting in the generation of lipid peroxides and in the case of peroxynitrite, the modification of proteins by tyrosine nitration and the formation of 3-nitrotyrosine.…”

Lipid peroxidation and susceptibility of low‐density lipoprotein to in vitro oxidation in hyperhomocysteinaemia

“…last 10 years it has become evident that mild hyperhomocysteinaemia is also an independent risk factor for vascular disease [2][3][4][5][6][7][8], and very recently it has been shown to be a risk factor for obstetric complications such as recurrent spontaneous abortion, gross placen tal infarcts and neural-tube defects [9,10]. Both severe and mild hyperhomocysteinaemia can be effectively treated with simple regimens o f vitamin Bfn folate and bctaine [3,11]. Mudd at al.…”