Heterozygosity for homocystinuria in premature peripheral and cerebral occlusive arterial disease: Boers GHJ, Smals AGH, Trijbels FJM, et al. N Engl J Med 1985; 313:709-15

Abstract

Homozygous homocystinuria is associated with premature atherosclerosis and early death from associated complications. Metabolic manipulation of animals with induction of homocystinemia has been used as a model of endothelial injury for atherosclerosis research. In this study the authors investigated homocysteine metabolism in 75 patients with symptomatic occlusive vascular disease, all of whom were less than 50 years of age. The severity and extent of disease were determined by appropriate arteriography and resulted in the classification of patients into three different anatomic patterns: peripheral vascular occlusive disease, coronary artery disease, and cerebrovascular disease—intracerebral and extracranial. A calculated oral dose of methionine was administered to all patients and serum levels of homocysteine subsequently determined. Criteria for positive testing that indicated heterozygous homocystinuria were developed and previously reported by the authors. Careful control for potential variables influencing the homocysteine pathway was used. None of the 25 patients with coronary artery disease had abnormal serum homocysteine levels after methionine loading. Of the 25 patients with peripheral arterial occlusive disease, seven (28%) had abnormal loading tests. All of these patients were women and represented 50% of the female cohort in this group. Most lesions in this group occurred in the abdominal aorta and visceral vessels. In the 25 patients with occlusive cerebrovascular disease, seven (28%) had abnormal methionine loading tests with no sex preponderance (four men and three women). Most lesions occurred in the intracerebral vessels with only one patient having disease in the extracranial carotid system. Corroboration of this abnormality in homocysteine metabolism was also obtained from in vitro measurement of cystathionine synthase activity in cultured fibroblasts from skin biopsy specimens. This procedures was performed only in patients in whom the oral loading test was unequivocally positive and was positive in 12 of the 14 patients (85%). Laboratory values of mean fasting glucose, mean fasting cholesterol, and mean fasting triglycerides were performed in all patients, with no statistically significant difference in distribution between patients with normal and abnormal methionine loading studies. Although homozygous homocystinuria is relatively rare, this study provides strong evidence to suggest that abnormalities of homocysteine metabolism either in the heterozygous form or others may be an important predisposing factor to the premature development of atherosclerosis in patients less than 50 years of age. The potential importance of this finding is significant in large part because this abnormality can be treated with folic acid or pyridoxine, both of which provide a relatively innocuous means of enhancing homocysteine use through alternate pathways.