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Several large trials have examined the reduction of total homocysteine levels as secondary stroke prevention in patients with vascular disease. In the Vitamin Intervention for Stroke Prevention (VI...

Large randomized, controlled trials of total homocysteine-lowering therapy for the potential reduction of cardiovascular disease outcomes are ongoing in the United States and Canada. These trials are the Vitamin Intervention for Stroke Prevention (VISP) trial, the Women's Antioxidant Cardiovascular Disease Study (WACS), and the Heart Outcomes Prevention Evaluation (HOPE-2). However, the dramatic effect of policies mandating fortification of cereal grain flour products with folic acid may reduce the statistical power of these trials. All three trials assume that the active treatment groups will achieve the same mean effects of total homocysteine-lowering therapy as those reported in the absence of folic acid-fortified cereal grain flour. This paper examines this assumption using data from studies of total homocysteine-lowering therapy in U.S. and Canadian patients with cardiovascular disease who were exposed to products made with folic acid-fortified cereal grain flour. These data showed that the VISP trial, HOPE-2, and WACS will probably achieve only approximately 20% to 25% of the projected treatment effects of mean total homocysteine-lowering therapy (1.0 to 1.5 micromol/L vs. 4.0 to 6.0 micromol/L). As a result, all three trials will be substantially underpowered to test the specific hypotheses of total homocysteine-lowering therapy identified a priori. In contrast, renal transplant recipients have a persistent excess prevalence of hyperhomocysteinemia in the era of fortification but remain very responsive to supraphysiologic doses of folic acid-based supplementation (mean reduction in total homocysteine level, 5.0 to 6.0 micromol/L). Therefore, unlike other populations with normal renal function that are at high risk for cardiovascular disease but are profoundly affected by fortification efforts, renal transplant recipients continue to merit serious consideration for a controlled trial of the "homocysteine hypothesis."

Elevated plasma total homocysteine level has been associated with cardiovascular disease in many studies, mostly in Europe and North America. Data on persons from other areas and on associations with overall mortality are sparse.To determine the relation of plasma homocysteine level to all-cause and cause-specific mortality.Prospective observational study with 9- to 11-year follow-up.A free-living, multiethnic Jewish population in western Jerusalem, Israel.1788 residents of Jerusalem (808 men and 980 women) who were at least 50 years of age and were examined between 1985 and 1987 as part of the Kiryat Yovel Community Health Study.Nonfasting plasma homocysteine level was determined in frozen stored samples. Deaths during follow-up were identified by linkage with the national population registry.Plasma homocysteine levels exceeded 14 micromol/L in 28% of men and 20% of women. During the study period, 405 deaths occurred. In multivariate Cox models that controlled for possible confounders, a nonmonotonic increase in mortality hazard ratios was associated with ascending quintile of homocysteine level: 1.0, 1.4, 1.3, 1.5, and 2.0 (P0.001 for trend). The relation was similar for cardiovascular and noncardiovascular causes of death (excluding cancer). The association was weaker when deaths that occurred during the first 5 years of follow-up were excluded; corresponding hazard ratios for ascending quintile of homocysteine level were 1.0, 1.0, 1.2, 1.1, and 1.6 (P = 0.063 for trend). Age- and sex-adjusted percentages of deaths "attributable" to elevated plasma homocysteine level (or = 14 micromol/L) were 12.5% (95% CI, 6.7% to 18.8%) for all deaths, 16.0% (CI, 7.2% to 25.6%) for deaths during the first 5 years of follow-up, and 8.3% (CI, 1.5% to 16.1%) for later deaths.A mildly to moderately elevated nonfasting plasma homocysteine level is a substantial risk marker for death from all causes. The association seems to be stronger during the first 5 years of follow-up.

Total homocysteine levels are associated with arteriosclerotic outcomes.To determine whether total homocysteine levels predict incident stroke in elderly persons.Prospective population-based cohort study with 9.9 years of follow-up.Framingham, Massachusetts.1947 Framingham Study participants (1158 women and 789 men; mean age +/- SD, 70 +/- 7 years).Baseline total homocysteine levels and 9.9-year stroke incidence.The quartiles of nonfasting total homocysteine levels were as follows: quartile 1, 4.13 to 9.25 micromol/L; quartile 2, 9.26 to 11.43 micromol/L; quartile 3, 11.44 to 14.23 micromol/L; quartile 4, 14.24 to 219.84 micromol/L. During follow-up, 165 incident strokes occurred. In proportional hazards models adjusted for age, sex, systolic blood pressure, diabetes, smoking, and history of atrial fibrillation and coronary heart disease, relative risk (RR) estimates comparing quartile 1 with the other three quartiles were as follows: quartile 2 compared with quartile 1--RR, 1.32 (95% CI, 0.81 to 2.14); quartile 3 compared with quartile 1--RR, 1.44 (CI, 0.89 to 2.34); quartile 4 compared with quartile 1--RR, 1.82 (CI, 1.14 to 2.91). The linear trend across the quartiles was significant (P0.001).Nonfasting total homocysteine levels are an independent risk factor for incident stroke in elderly persons.

Upper reference limits for serum total homocysteine concentration increased with age and were higher for male participants than for female participants at all ages. In most cases, high homocysteine...

Background: Stable renal transplant recipients have an excess prevalence of hyperhomocysteinemia, which is a risk factor for arteriosclerosis. Objective: To determine the effect of treatment with 1) vitamin B 6 or 2) folic acid plus vitamin B 12 on fasting and post-methionine-loading plasma total homocysteine levels in renal transplant recipients. Design: Block-randomized, placebo-controlled, 2 x 2 factorial study. Setting: University-affiliated transplantation program. Patients: 29 clinically stable renal transplant recipients. Intervention: Patients were randomly assigned to one of four regimens: placebo (n = 8); vitamin B 6 , 50 mg/d (n = 7); folic acid, 5 mg/d, and vitamin B 12 , 0.4 mg/d (n = 7); or vitamin B 6 , 50 mg/d, folic acid, 5 mg/d, and vitamin B 12, 0.4 mg/d (n = 7). Measurements: Fasting and 2-hour post-methionine-loading plasma total homocysteine levels. Results: Vitamin B 6 treatment resulted in a 22.1% reduction in geometric-mean post-methionine-loading increases in plasma total homocysteine levels (P = 0.042), and folic acid plus vitamin B 12 treatment caused a 26.2% reduction in geometric-mean fasting plasma total homocysteine levels (P = 0.027). These results occurred after adjustment for age; sex; and pretreatment levels of total homocysteine, B vitamins, and creatinine. Conclusions: Vitamin B 6 should be added to the combination of folic acid and vitamin B 12 for effective reduction of both post-methionine-loading and fasting plasma total homocysteine levels in renal transplant recipients.

A 44-year-old woman with diarrhea, weight loss, and a small-bowel biopsy consistent with adult celiac disease failed to improve on a gluten-free diet. Despite in-hospital supervision at two university medical centers and addition of corticosteroid therapy, diarrhea and wegith loss continued, resulting in life-threatening nutritional depletion. She was transferred to the University of Chicago and made full nutritional recovery with total parenteral nutrition. Exploratory laparotomy showed no abnormality except the flat intestinal mucosal lesion. Diarrhea recurred when a gluten-free diet was resumed. When the patient ate egg, chicken, or tuna alone, severe diarrhea, hypotension, cyanosis, and shock occurred. When these foods--along with gluten--were eliminated from the diet, the patient returned to oral nutrition and made a full clinical recovery. In patients with refractory sprue deletion of other dietary proteins in addition to gluten, as in the present patient, may be lifesaving.

Excerpt Although medicine has long sought methods to study fecal fat without studying feces, the 72-hour stool collection for quantitative determination of fecal fat (1) remains the gold standard f...