J.A. Gevers Leuven

The power of serum lathosterol concentration as an indicator of whole-body cholesterol synthesis was investigated in 47 human volunteers consuming two diets differing in fatty acid composition. The cholesterol balance (fecal excretion of neutral and acid steroids minus cholesterol intake) was strongly correlated with the serum level of total (free plus esterified) lathosterol and also with the ratio of serum lathosterol over serum cholesterol, both on a diet rich in polyunsaturated fatty acids (r = 0.74 for the ratio) and one containing mainly saturated fatty acids (r = 0.70 for the ratio). In a subgroup for which the serum levels of free lanosterol and other free methylsterols were also quantitated, the correlations of these levels (expressed relative to serum free cholesterol) with the cholesterol balance were lower than that found for total lathosterol (expressed relative to serum total cholesterol). A further corroboration was obtained by measuring the lathosterol/cholesterol ratio in 20 patients with familial hypercholesterolemia before and during treatment with the hydroxymethylglutaryl coenzyme A reductase inhibitor Mk-733. The ratio was lowered by 47% during drug treatment, suggesting a significant decrease of the cholesterol balance in these patients. We conclude, from the various indicators proposed to monitor whole-body cholesterol synthesis, that the lathosterol/cholesterol ratio in serum appears preferable with respect to indicative power and ease of quantitation.

Abstract There is accumulating evidence that oxidative modification of LDL is an important step in the process of atherogenesis and that antioxidants may protect LDL from oxidation. We and others have previously shown that ingestion of pharmacological doses of the antioxidant d,l -α-tocopherol (vitamin E), far above the recommended daily intake (ie, 12 to 15 IU/d for adults), increases the oxidation resistance of LDL. In this study, we ascertained the minimal supplementary dose of vitamin E necessary to protect LDL against oxidation in vitro. Twenty healthy volunteers (10 men and 10 women, aged 21 to 31 years) ingested consecutively 25, 50, 100, 200, 400, and 800 IU/d d,l -α-tocopherol acetate during six 2-week periods. No changes were observed in LDL triglyceride content, fatty acid composition of LDL, or LDL size during the intervention. Concentrations of α-tocopherol in plasma and LDL were both 1.2 times the baseline values after the first period (25 IU/d) and 2.6 and 2.2 times, respectively, after the last period (800 IU/d). There was a linear increase in LDL α-tocopherol levels up to an intake of 800 IU/d ( r =.79, P <.0001) and a good correlation between α-tocopherol in plasma and LDL ( r =.66, P <.0001). Simultaneously, the resistance of LDL to oxidation was elevated dose-dependently (+28% after the last period) and differed significantly from the baseline resistance time even after ingestion of only 25 IU/d. Correlation between α-tocopherol content of LDL and resistance time for all data was r =.57 ( P <.0001), whereas the correlation between plasma α-tocopherol and resistance time was r =.69 ( P <.0001). The rate of oxidation was decreased significantly at 400 and 800 IU/d (−13% and −17%, respectively). Baseline resistance time was not significantly different between men and women, but propagation rate was higher with LDL from men at baseline and after intake of 25 and 50 IU/d. Minor differences in LDL vitamin E levels and resistance time were found between men and women in response to vitamin E intake. Statistical evaluation of the relations between α-tocopherol content of LDL and resistance time in each of the 20 individual subjects showed strong and significant correlations for 14 individuals, indicating that vitamin E was the most important parameter that determined the oxidation resistance of LDL in these subjects. ANOVA indicated that LDL α-tocopherol content (47%) and interindividual variation (39%) were the most prominent parameters that contributed to the total variance in resistance time.

We previously reported that mortality due to ischaemic heart disease was lower in haemophilia patients than in the general male population. To support the hypothesis that this could be attributed to a protective effect of the clotting defect in haemophilia and not to differences in cardiovascular risk factors, we performed a second study. We examined 95 haemophilia patients for the presence of major risk factors for ischaemic heart disease and compared their risk factor profile with the data of epidemiologic surveys of the general Dutch population. Haemophilia patients had on average higher blood pressures than the comparison population, were more often hypertensive and used antihypertensive drugs twice as often. The mean serum cholesterol level of the patients was markedly lower than in the comparison population (4.8 versus 5.6 mmol/l, 95% confidence interval of the difference: 0.5-1.1 mmol/l). The risk factors were weighted into one theoretical risk ratio for ischaemic heart disease by application of logistic regression coefficients. The theoretical risk ratio based on the risk factor profile was 0.78. This risk ratio can only explain a moderate reduction in the incidence of ischaemic heart disease, much smaller than the mortality ratio of 0.20 we reported previously. Therefore these data support the hypothesis of a direct protective effect of haemophilia on the development of ischaemic heart disease.