The C677T mutation in the methylenetetrahydrofolate reductase gene predisposes to hyperhomocysteinemia in children with familial hypercholesterolemia treated with cholestyramine.

In children with familial hypercholesterolemia, heterozygosity and homozygosity for the C677T mutation in the methylenetetrahydrofolate reductase gene was associated with low serum folate and increased susceptibility to elevation of plasma total homocysteine during cholestyramine treatment. Because of the independent relationship between elevated plasma total homocysteine and cardiovascular disease, folate supplementation may be prudent in these children.

Fat-soluble vitamin levels in familial hypercholesterolemia.

OBJECTIVE: To examine serum levels of retinol, 25-hydroxyvitamin D, and alpha-tocopherol and their potential determinants in familial hypercholesterolemia (FH). SUBJECTS: Study 1: 151 boys and girls with FH aged 7 to 16 years who were following a lipid-reduced diet but not taking lipid-lowering drugs. Study 2: 87 boys and girls with FH, of whom 24 were taking bile acid-binding resins in addition to the diet, and 30 age- and sex-matched control subjects. DESIGN: Cross-sectional survey. SETTING: Lipid referral clinic. RESULTS: None of the subjects had suboptimal retinol or 25-hydroxyvitamin D levels. Only one girl had a low alpha-tocopherol level and alpha-tocopherol/lipid ratio. In multiple regression analysis, pubertal onset and gender were associated with retinol and 25-hydroxyvitamin D levels. The triglyceride level was positively related to level of retinol, and body mass index was inversely related to 25-hydroxyvitamin D level. Vitamin supplementation was positively related to 25-hydroxyvitamin D level and the alpha-tocopherol/lipid ratio. This ratio was lower in subjects whose total cholesterol level was above the median (8.0 mmol/L (310 mg/dl)) than in subjects whose cholesterol level was below the median (p = 0.01). In study 2, the alpha-tocopherol/lipid ratio in control subjects (median, 5.1 mumol/mmol) was higher than in subjects with FH who were not taking resins (median, 3.3 mumol/mmol; p < 0.05) but similar to the ratio in treated subjects (median, 5.4 mumol/mmol). CONCLUSIONS: Pubertal onset, gender, lipid levels, vitamin supplementation, and body mass index are significant predictors of fat-soluble vitamin levels in children with FH. Though children following a lipid-lowering diet have normal serum levels of fat-soluble vitamins, the alpha-tocopherol level does not appear to increase proportionately to the increase in cholesterol level. Treatment with resins may restore a normal alpha-tocopherol/lipid ratio.

Efficacy and safety of cholestyramine therapy in peripubertal and prepubertal children with familial hypercholesterolemia.

OBJECTIVE: To determine the efficacy and safety of cholestyramine therapy in young children with familial hypercholesterolemia. SUBJECTS: Boys aged 6 to 11 years (n = 57) and girls aged 6 to 10 years (n = 39) with familial hypercholesterolemia. DESIGN: After 1 year of a low-fat, low-cholesterol diet, children with low-density lipoprotein (LDL) cholesterol levels > or = 4.9 mmol/L (190 mg/di) or < or = 4.1 mmol/L (160 mg/dl) in the presence of familial premature cardiovascular disease were randomly assigned to a double-blind comparison of 8 gm cholestyramine (n = 36) and placebo (n = 36) for 1 year. OUTCOME MEASURES: The primary efficacy and safety outcomes were serum LDL cholesterol levels and height velocity, respectively. Secondary safety outcomes were erythrocyte folate, total plasma homocysteine, serum fat-soluble vitamins, and side effects. RESULTS: Twenty-two subjects in the cholestyramine group and 26 in the placebo group completed the 1-year study. Most withdrawals from the study were related to unpalatability of the study drug or placebo. The LDL cholesterol levels changed by -16.9% (95% confidence interval, -10.8% to -22.9%) in the cholestyramine group compared with 1.4% (95% confidence interval, -4.4% to 7.2%) in the placebo group. Mean height velocity standard deviation scores during 1 year for the children in the cholestyramine and the placebo groups who had not started puberty were 0.24 +/- 1.14 and 0.11 +/- 0.68, respectively (not significant). In the cholestyramine group, mean levels of 25-hydroxyvitamin D decreased. One girl had low folate and elevated homocysteine levels, and there was one case of intestinal obstruction caused by adhesions. CONCLUSIONS: Significant reductions in LDL cholesterol are achievable during treatment with cholestyramine in about half of eligible children. Growth is not adversely affected. Folate deficiency may occur, even with a low dose of cholestyramine, and vitamin D supplements should be considered. Caution should possibly be exercised in starting cholestyramine therapy within 3 months of abdominal surgery in children.