Premature arteriosclerosis and thromboembolic events are well-known complications of homozygous homocystinuria due to cystathionine synthase deficiency. It is unknown whether heterozygosity for homocystinuria predisposes to premature vascular disease. We explored the frequency of excessive homocysteine accumulation after standardized methionine loading in 75 patients presenting with clinical signs of ischemic disease before the age of 50:25 with occlusive peripheral arterial disease, 25 with occlusive cerebrovascular disease, and 25 with myocardial infarction. In seven patients in each of the first two groups but in none of the patients in the third group, heterozygosity for homocystinuria was established on the basis of pathological homocysteinemia after methionine loading and cystathionine synthase deficiency in skin fibroblast cultures. Because the frequency of heterozygosity for homocystinuria in the normal population is 1 in 70 at the most, we conclude that this condition predisposes to the development of premature occlusive arterial disease, causing intermittent claudication, renovascular hypertension, and ischemic cerebrovascular disease.

Therapy with 131I is an effective alternative to surgery for elderly patients with a large, compressive multinodular goiter.

Plasma cortisol levels and modified Apache II (Apache IIm-stay) severity of disease scores were determined at weekly intervals in 159 patients who were treated for at least 7 days at the Critical Care Unit of our hospital. The mean (+/- SD) plasma cortisol level (0.60 +/- 0.28 mumol/l) was clearly elevated in these patients. The highest plasma cortisol levels were measured in patients treated with vasoactive drugs (0.76 +/- 0.39 mumol/l). Non-survivors (n = 36) had a significantly higher mean plasma cortisol level and Apache IIm-stay score than survivors (respectively 0.78 +/- 0.40 vs. 0.54 +/- 0.21 mumol/l; p less than 0.0003 and 12.6 +/- 4.8 vs. 7.3 +/- 4.1; p less than 0.0001). A significant correlation was found between the individual weekly plasma cortisol levels and the Apache IIm-stay scores (r = 0.41; p less than 0.0001), especially in the subgroup of patients, who never received glucocorticoids during their stay at the ICU (r = 0.51; p less than 0.0001). During the 14-month study period only two patients showed a clinical picture of adrenocortical insufficiency and a blunted response of cortisol to 0.25 mg synthetic ACTH(1-24). In conclusion, our data suggest that a high plasma cortisol level, like a high Apache IIm-stay score, indicates severity of disease and poor survival in critically ill patients. De novo adrenocortical insufficiency is rare and therefore routine screening of adrenocortical function is superfluous.

We measured bone mineral density (BMD) using dual-energy x-ray absorptiometry in 20 patients with Cushing's syndrome (CS) (14 preand 2 postmenopausal women, 4 men) before and in 18 of them also at regular intervals after surgical cure (median duration of follow-up, 36 months). In addition, in the premenopausal women with CS, fast ing blood samples and 2-h fasting urine samples for measurement of biochemical parameters of bone and collagen metabolism were col lected before and in 9 of them also at regular intervals during the first 2 yr after surgery. Marked osteopenia was present in'most patients with active CS (Z-scores: lumbar spine -1.45 ± 1,44 and femoral neck ~ 1.50 ± 1 .02; mean ± sd). No consistent change in BMD was observed at 3 and 6 months after surgery. Thereafter BMD increased consid erably in almost all patients. For the 15 patients with a follow-up of at least 1 yr, Z-scores at the last evaluation were -0.65 ± 1.27 for the lumbar spine and -0.98 ± 1.02 for the femoral neck (both/5 < 0.002 compared with pretreatment values). In the premenopausal patients, the increase in BMD both in the lumbar spine and in the femoral neck at 24 months was inversely correlated with age (r = -0.733, P < 0.03, and r ~ -0.667, P < 0.05, respectively). Serum levels of osteocalcin, bone alkaline phosphatase, carboxyterminal propeptide of type I pro

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...