phytosterols and Hyperlipoproteinemia-Type-II

The purpose of this review was to summarize important and updated information on sitosterolemia. Sitosterolemia is an inherited lipid disorder consisting of high levels of plasma plant sterols. This sterol storage condition is caused by biallelic loss-of-function genetic variants in either ABCG5 or ABCG8, leading to increased intestinal absorption and decreased hepatic excretion of plant sterols. Clinically, patients with sitosterolemia usually exhibit xanthomatosis, high levels of plasma cholesterol, and premature atherosclerotic disease, but presentation can be highly heterogeneous. Therefore, recognition of this condition requires a high level of suspicion, with confirmation upon genetic diagnosis or through measurement of plasma phytosterols. Treatment of sitosterolemia with both a plant sterol-restricted diet and the intestinal cholesterol absorption inhibitor ezetimibe can reduce efficiently the levels of plasma plant sterols, consisting in the first-line therapy for this disease.. Since hypercholesterolemia is often present in individuals with sitosterolemia, it is important to search for genetic variants in ABCG5 and ABCG8 in patients with clinical criteria for familial hypercholesterolemia (FH), but no variants in FH implicated genes. Indeed, recent studies have suggested that genetic variants in ABCG5/ABCG8 can mimic FH, and even when in heterozygosis, they may potentially exacerbate the phenotype of patients with severe dyslipidemia. Sitosterolemia is a genetic lipid disorder characterized by increased circulating levels of plant sterols and clinically manifested by xanthomatosis, hematologic disorders, and early atherosclerosis. Awareness about this condition, a rare, but commonly underdiagnosed and yet treatable cause of premature atherosclerotic disease, is imperative.

Topics: Atherosclerosis; Cholesterol; Humans; Hypercholesterolemia; Hyperlipoproteinemia Type II; Intestinal Diseases; Lipid Metabolism, Inborn Errors; Phytosterols; Xanthomatosis

Inherited hypercholesterolemias include monogenic and polygenic disorders, which can be very rare (eg, cerebrotendinous xanthomatosis (CTX)) or relatively common (eg, familial combined hyperlipidemia [FCH]). In this review, we discuss familial hypercholesterolemia (FH), FH-mimics (eg, polygenic hypercholesterolemia [PH], FCH, sitosterolemia), and other inherited forms of hypercholesterolemia (eg, hyper-lipoprotein(a) levels [hyper-Lp(a)]). The prevalence, genetics, and management of inherited hypercholesterolemias are described and selected guidelines summarized.

Topics: Humans; Hypercholesterolemia; Hyperlipoproteinemia Type II; Intestinal Diseases; Lipid Metabolism, Inborn Errors; Phytosterols

Familial hypercholesterolemia has long been considered a monogenic disorder. However, recent advances in genetic analyses have revealed various forms of this disorder, including polygenic and oligogenic familial hypercholesterolemia. We review the current understanding of the genetic background of this disease.. Mutations in multiple alleles responsible for low-density lipoprotein regulation could contribute to the development of familial hypercholesterolemia, especially among patients with mutation-negative familial hypercholesterolemia. In oligogenic familial hypercholesterolemia, multiple rare genetic variations contributed to more severe familial hypercholesterolemia.. Familial hypercholesterolemia is a relatively common 'genetic' disorder associated with an extremely high risk of developing coronary artery disease. In addition to monogenic familial hypercholesterolemia, different types of familial hypercholesterolemia, including polygenic and oligogenic familial hypercholesterolemia, exist and have varying degrees of severity. Clinical and genetic assessments for familial hypercholesterolemia and clinical risk stratifications should be performed for accurate diagnosis, as should cascade screening and risk stratification for the offspring of affected patients.

Topics: Animals; Humans; Hypercholesterolemia; Hyperlipoproteinemia Type II; Intestinal Diseases; Lipid Metabolism, Inborn Errors; Phytosterols; Risk Assessment

Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated low-density lipoprotein (LDL) cholesterol and premature cardiovascular disease, with a prevalence of approximately 1 in 200-500 for heterozygotes in North America and Europe. Monogenic FH is largely attributed to mutations in the LDLR, APOB, and PCSK9 genes. Differential diagnosis is critical to distinguish FH from conditions with phenotypically similar presentations to ensure appropriate therapeutic management and genetic counseling. Accurate diagnosis requires careful phenotyping based on clinical and biochemical presentation, validated by genetic testing. Recent investigations to discover additional genetic loci associated with extreme hypercholesterolemia using known FH families and population studies have met with limited success. Here, we provide a brief overview of the genetic determinants, differential diagnosis, genetic testing, and counseling of FH genetics.

Topics: Apolipoprotein B-100; Cholesterol Ester Storage Disease; Diagnosis, Differential; Genetic Counseling; Genetic Predisposition to Disease; Genetic Testing; Humans; Hypercholesterolemia; Hyperlipoproteinemia Type II; Intestinal Diseases; Lipid Metabolism, Inborn Errors; Phytosterols; Proprotein Convertase 9; Proprotein Convertases; Receptors, LDL; Serine Endopeptidases; Xanthomatosis, Cerebrotendinous

A cholesterol-lowering diet and several other dietary interventions have been suggested as a management approach either independently or as an adjuvant to drug therapy in children and adults with familial hypercholesterolaemia (FH). However, a consensus has yet to be reached on the most appropriate dietary treatment. Plant sterols are commonly used in FH although patients may know them by other names like phytosterols or stanols.. To examine whether a cholesterol-lowering diet is more effective in reducing ischaemic heart disease and lowering cholesterol than no dietary intervention in children and adults with familial hypercholesterolaemia. Further, to compare the efficacy of supplementing a cholesterol-lowering diet with either omega-3 fatty acids, soya proteins, plant sterols or plant stanols.. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Inborn Errors of Metabolism Trials Register, which is compiled from electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (updated with each new issue of The Cochrane Library), quarterly searches of MEDLINE and the prospective handsearching of one journal - Journal of Inherited Metabolic Disease. Most recent search of the Group's Inborn Errors of Metabolism Trials Register: 22 August 2013. We also searched PubMed to 05 February 2012.. Randomised controlled trials, both published and unpublished, where a cholesterol-lowering diet in children and adults with familial hypercholesterolaemia has been compared to other forms of dietary treatment or to no dietary intervention were included.. Two authors independently assessed the trial eligibility and risk of bias and one extracted the data, with independent verification of data extraction by a colleague.. In the 2014 update of the review, 15 trials have been included, with a total of 453 participants across seven comparison groups. The included trials had either a low or unclear risk of bias for most of the parameters used for risk assessment. Only short-term outcomes could be assessed due to the short duration of follow up in the included trials. None of the primary outcomes, (incidence of ischaemic heart disease, number of deaths and age at death) were evaluated in any of the included trials. No significant differences were noted for the majority of secondary outcomes for any of the planned comparisons. However, a significant difference was found for the following comparisons and outcomes: for the comparison between plant sterols and cholesterol-lowering diet (in favour of plant sterols), total cholesterol levels, mean difference 0.30 mmol/l (95% confidence interval 0.12 to 0.48); decreased serum LDL cholesterol, mean difference -0.60 mmol/l (95% CI -0.89 to -0.31). Fasting serum HDL cholesterol levels were elevated, mean difference -0.04 mmol/l (95% CI -0.11 to 0.03) and serum triglyceride concentration was reduced, mean difference -0.03 mmol/l (95% CI -0.15 to -0.09), although these changes were not statistically significant. Similarly, guar gum when given as an add on therapy to bezafibrate reduced total cholesterol and LDL levels as compared to bezafibrate alone.. No conclusions can be made about the effectiveness of a cholesterol-lowering diet, or any of the other dietary interventions suggested for familial hypercholesterolaemia, for the primary outcomes: evidence and incidence of ischaemic heart disease, number of deaths and age at death,due to the lack of data on these. Large, parallel, randomised controlled trials are needed to investigate the effectiveness of a cholesterol-lowering diet and the addition of omega-3 fatty acids, plant sterols or stanols, soya protein, dietary fibers to a cholesterol-lowering diet.

Topics: Adult; Child; Cross-Over Studies; Diet, Fat-Restricted; Fatty Acids, Omega-3; Humans; Hyperlipoproteinemia Type II; Phytosterols; Randomized Controlled Trials as Topic; Soybean Proteins

Recommendations about the use of plant stanol/sterol esters have not been updated since 2001. There have been many developments in medicines for lipid-lowering since 2001. In this review, the use of margarines containing stanol or sterol esters, to lower LDL cholesterol is considered in the 2011 setting. Firstly, there is a brief overview of the effects of the stanols/sterols on LDL cholesterol, which shows that these agents have a modest ability to lower LDL cholesterol, and are not effective in all conditions. Secondly, the relevance of the stanols/sterols in 2010/1 is questioned, given they have not been shown to reduce clinical endpoints, and have no effects on HDL cholesterol or triglyceride levels. Finally, there is a section comparing the stanols/sterols with the present day prescription lipid lowering medicines. Prescription drugs (statins, ezetimibe, and niacin) have a much greater ability to lower LDL cholesterol than the stanol/sterol esters, and also increase levels of HDL cholesterol and decrease levels of triglycerides. The statins and niacin have been shown to reduce cardiovascular clinical endpoints. Except in borderline normo/hypercholesterolemia, prescription drugs should be preferred to stanol/sterol esters for lowering LDL cholesterol in 2011.

Topics: Anticholesteremic Agents; Azetidines; Cardiovascular Diseases; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus; Ezetimibe; Fibric Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hyperlipoproteinemia Type II; Intestinal Diseases; Lipid Metabolism, Inborn Errors; Margarine; Micronutrients; Niacin; Phytosterols; Sitosterols; Triglycerides

A cholesterol-lowering diet and several other dietary interventions have been suggested as a management approach either independently or as an adjuvant to drug therapy in children and adults with familial hypercholesterolemia. However, a consensus has yet to be reached on the most appropriate dietary treatment.. To examine whether a cholesterol-lowering diet is more effective in reducing ischaemic heart disease and lowering cholesterol than no dietary intervention in children and adults with familial hypercholesterolaemia. Further, to compare the efficacy of supplementing a cholesterol-lowering diet with either omega-3 fatty acids, soya proteins, plant sterols or plant stanols.. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Inborn Errors of Metabolism Trials Register.Most recent search of the Group's Inborn Errors of Metabolism Trials Register: 09 October 2009.We also searched PubMed till 01 June 2008.. Randomised controlled trials, both published and unpublished, where a cholesterol-lowering diet in children and adults with familial hypercholesterolaemia has been compared to other forms of dietary treatment or to no dietary intervention were included.. Two authors independently assessed the trial eligibility and methodological quality and one extracted the data, with independent verification of data extraction by a colleague.. In the present update, four new trials have been added making eleven trials with a total of 331 participants eligible for inclusion. Only short-term outcomes could be assessed due to the short duration of follow up in the included studies. None of the primary outcomes, (incidence of ischaemic heart disease, number of deaths and age at death) were evaluated in any of the included studies. No significant difference was noted for the majority of secondary outcomes for any of the planned comparisons. However, a significant difference was found only for the following comparison and outcome: total cholesterol levels for the comparison between plant sterols and cholesterol-lowering diet, mean difference 0.70 (95% confidence interval 0.19 to 1.21).. No conclusions can be made about the effectiveness of a cholesterol-lowering diet, or any of the other dietary interventions suggested for familial hypercholesterolaemia, due to the lack of adequate data. Large, parallel, randomised controlled trials are needed to investigate the effectiveness of a cholesterol-lowering diet and the addition of omega-3 fatty acids, plant sterols or stanols, soya protein to a cholesterol-lowering diet.

Topics: Adult; Child; Cross-Over Studies; Diet, Fat-Restricted; Fatty Acids, Omega-3; Humans; Hyperlipoproteinemia Type II; Phytosterols; Randomized Controlled Trials as Topic; Soybean Proteins

To-date, reviews regarding the cholesterol lowering capacity of phytosterols/stanols have focused on normo- and hypercholesterolemic (HC) subjects. Familial hypercholestrolemia (FH) is characterized by very high low-density lipoprotein cholesterol (LDL-C) concentrations and is considered a world public health problem due to the high incidence of premature coronary heart disease (CHD) in these patients.. To conduct a systematic review that investigates the efficacy of phytosterols/stanols in lowering total cholesterol (TC) and LDL-C concentrations in FH subjects.. Randomized controlled intervention trials with the primary objective to investigate the effects of phytosterols/stanols on lipid concentrations in FH subjects were identified through selected international journal databases and reference lists of relevant publications. Two researchers extracted data from each identified trial and only trials of sufficient quality (e.g. controlled, randomized, double-blind, good compliance, sufficient statistical power) were included in the review. The main outcome measures were differences between treatment and control groups for LDL-C, TC, high-density lipoprotein cholesterol (HDL-C) and triacylglycerol (TG).. Six out of 13 studies were of sufficient quality. Two were excluded from the meta-analysis because the sterols were administered in the granulate form at very high dosages (12 g/day and 24 g/day) compared to the other studies that used fat spreads as vehicle with dosages ranging from 1.6-2.8 g/day. The subjects were heterozygous, aged 2-69 years with baseline TC and LDL-C concentrations of +/-7 mmol/L and +/-5.4 mmol/L, respectively. The duration of the studies ranged from 4 weeks to 3 months. Fat spreads enriched with 2.3 +/- 0.5 g phytosterols/stanols per day significantly reduced TC from 7 to 11% with a mean decrease of 0.65 mmol/L [95% CI -0.88, -0.42 mmol/L], p < 0.00001 and LDL-C from 10-15% with a mean decrease of 0.64 mmol/L [95% CI -0.86, -0.43 mmol/L], p < 0.00001 in 6.5 +/- 1.9 weeks compared to control treatment, without any adverse effects. TG and HDL-C concentrations were not affected.. Phytosterols/stanols may offer an effective adjunct to the cholesterol lowering treatment strategy of FH patients.

Topics: Adolescent; Adult; Aged; Anticholesteremic Agents; Child; Child, Preschool; Cholesterol; Cholesterol, LDL; Dietary Fats; Female; Food, Fortified; Humans; Hyperlipoproteinemia Type II; Male; Middle Aged; Phytosterols; Treatment Outcome

Plant sterol and stanol esters each have similar additive effects in lowering low-density lipoprotein cholesterol when combined with statins. They differ in that plasma plant sterols increase when plant sterol esters are used for this purpose, especially in patients with familial hypercholesterolemia, but decrease when plant stanol esters are used.

Topics: Cholesterol, LDL; Drug Interactions; Drug Therapy, Combination; Humans; Hyperlipoproteinemia Type II; Phytosterols; Phytotherapy; Randomized Controlled Trials as Topic; Sitosterols; Treatment Outcome

Topics: Anticholesteremic Agents; Drug Monitoring; Ezetimibe, Simvastatin Drug Combination; Female; Humans; Hyperlipoproteinemia Type II; Lipid Metabolism; Male; Middle Aged; Phytosterols; Simvastatin; Treatment Outcome

Subjects with increased cholesterol absorption might benefit more from statin therapy combined with a cholesterol absorption inhibitor. We assessed whether baseline cholesterol absorption markers were associated with response to ezetimibe/simvastatin therapy, in terms of LDL-cholesterol (LDL-C) lowering and cholesterol absorption inhibition, in patients with familial hypercholesterolemia (FH). In a posthoc analysis of the two-year ENHANCE trial, we assessed baseline cholesterol-adjusted campesterol (campesterol/TC) and sitosterol/TC ratios in 591 FH patients. Associations with LDL-C changes and changes in cholesterol absorption markers were evaluated by multiple regression analysis. No association was observed between baseline markers of cholesterol absorption and the extent of LDL-C response to ezetimibe/simvastatin therapy (beta = 0.020, P = 0.587 for campesterol/TC and beta<0.001, P = 0.992 for sitosterol/TC). Ezetimibe/simvastatin treatment reduced campesterol levels by 68% and sitosterol levels by 62%; reductions were most pronounced in subjects with the highest cholesterol absorption markers at baseline, the so-called high absorbers (P < 0.001). Baseline cholesterol absorption status does not determine LDL-C lowering response to ezetimibe/simvastatin therapy in FH, despite more pronounced cholesterol absorption inhibition in high absorbers. Hence, these data do not support the use of baseline absorption markers as a tool to determine optimal cholesterol lowering strategy in FH patients. However, due to the exploratory nature of any posthoc analysis, these results warrant further prospective evaluation in different populations.

Topics: Adult; Aged; Anticholesteremic Agents; Azetidines; Biomarkers; Cholesterol; Cholesterol, LDL; Double-Blind Method; Drug Therapy, Combination; Ezetimibe; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipoproteinemia Type II; Intestinal Absorption; Male; Middle Aged; Phytosterols; Simvastatin; Sitosterols; Statistics as Topic

Familial hypercholesterolemia (FH) is associated with a high risk of coronary heart disease. Pharmacological treatment and diet are both essential for the management of FH. Foods rich in plant sterols (PS) may play an important role in the treatment of patients with these disorders.. To test the effect of the intake of PS on low-density lipoprotein (LDL) concentration, endothelial function (EF) and LDL particle size in 30 patients with FH.. Randomized and crossover dietary intervention study.. Tertiary outpatient care.. Thirty-eight were recruited, but only 30 were subjected to four low-fat dietary intervention periods, each of 4 weeks.. Each intervention had a different content of cholesterol (<150 or 300 mg/day) and sitosterol (<1 or 2 g/day). Lipid response, EF and LDL particle size were analysed after the intervention.. Plasma sitosterol/cholesterol ratio was higher during both plant sterol-rich periods than during the low plant sterols periods. Basal sitosterol concentrations predicted the LDL-cholesterol response during the intake of plant sterol-enriched diets. The change in LDL-cholesterol was significantly greater in subjects in the upper and intermediate tertiles of basal plasma sitosterol concentrations (-21+/-8 mg/dl, P=0.03; -19+/-7 mg/dl, P=0.04, respectively) than in subjects in the lower tertile (8+/-5 mg/dl) when they changed from a low cholesterol diet to a low cholesterol plus plant sterol diet.. Our study demonstrates that basal sitosterol values can predict hypolipidemic response in patients with FH.

Topics: Adult; Cholesterol, LDL; Combined Modality Therapy; Cross-Over Studies; Diet, Fat-Restricted; Endothelium, Vascular; Female; Humans; Hyperlipoproteinemia Type II; Hypolipidemic Agents; Male; Particle Size; Phytosterols; Predictive Value of Tests; Sitosterols; Treatment Outcome

To assess causes for insufficient cholesterol-lowering response to pravastatin and plant stanol esters in children with heterozygous familial hypercholesterolemia (HeFH).. Nine of 16 children with HeFH who had not reached normocholesterolemia (< or =194 mg/dL [< or =5 mmol/L]) by 1 year after treatment (40 mg pravastatin and plant stanol ester) were called nonresponders. The 7 remaining children were responders. Serum noncholesterol sterol ratios (10(2) x mmol/mol of cholesterol), surrogate estimates of cholesterol absorption (cholestanol, campesterol, sitosterol) and synthesis (desmosterol and lathosterol), were studied at study baseline (on plant stanol esters) and during combination therapy with pravastatin and plant stanol esters.. Pravastatin decreased the serum levels of cholesterol and cholesterol synthesis markers, and increased the ratios of cholesterol absorption markers. Compared with the responders, the nonresponders had higher study baseline (on plant stanol esters) serum cholesterol concentrations (299 +/- 39 vs 251 +/- 35 mg/dL [7.7 +/- 1.0 vs 6.5 +/- 0.9 mmol/L]; P <.001) and higher respective ratios of campesterol (371 +/- 99 vs 277 +/- 67 10(2) x mmol/mol of cholesterol; P = .049) and sitosterol (176 +/- 37 vs 126 +/- 24 10(2) x mmol/mol of cholesterol; P = .008). The higher the ratio of cholestanol at study baseline, the smaller the 1-year percent reduction in cholesterol (r = .556; P = .025).. Pravastatin treatment increases the markers of cholesterol absorption and decreases those of cholesterol synthesis in HeFH during simultaneous inhibition of cholesterol absorption. Combined inhibition of cholesterol absorption and synthesis may not normalize serum lipids in those patients with the highest cholesterol levels, especially if signs of enhanced cholesterol absorption are detectable.

Topics: Adolescent; Anticholesteremic Agents; Child; Cholestanol; Cholesterol; Desmosterol; Female; Heterozygote; Humans; Hyperlipoproteinemia Type II; Male; Phytosterols; Pravastatin; Sitosterols; Triglycerides

To examine the effect of plant stanols on lipids and endothelial function in pre-pubertal children with familial hypercholesterolemia (FH).. Children with FH (n=42), aged 7-12 years, were enrolled in a double-blind crossover trial, in which they consumed 500 mL of a low-fat yogurt enriched with 2.0 g of plant stanols and 500 mL of a low-fat placebo yogurt for 4 weeks, separated by a 6-week washout period. Lipid profiles and endothelial function were assessed after both consumption periods. Endothelial function was measured as flow-mediated dilation (FMD) of the brachial artery.. This daily intake of 2.0 g of stanols significantly decreased the levels of total cholesterol (TC) by 7.5% and low-density lipoprotein cholesterol (LDL-C) by 9.2% as compared with placebo. High-density lipoprotein cholesterol and triglyceride levels remained unaltered. The reduction of LDL-C levels did not improve FMD, which was 10.5%+/-5.1% after plant stanol consumption and 10.6%+/-5.0% after placebo consumption, respectively (P=.852).. This study demonstrates that plant stanols reduce LDL-C levels in children with FH without improving endothelial function.

Topics: Anticholesteremic Agents; Child; Cholesterol; Cholesterol, LDL; Cross-Over Studies; Double-Blind Method; Endothelium, Vascular; Female; Humans; Hyperlipoproteinemia Type II; Male; Phytosterols; Triglycerides; Vasodilation

Published data suggest that the cholesterol-lowering effect of dietary plant sterol esters is less marked in longer-term than in short-term studies, whereas plant stanol esters maintain their efficacy. To investigate this further, healthy subjects and patients with familial hypercholesterolemia (FH) receiving statins were randomized to receive plant sterol ester 1.6 g/day or plant stanol ester 1.6 g/day or 2.6 g/day for 2 months. There was no difference among the 3 groups in the pooled low-density lipoprotein (LDL)-lowering response of FH patients and healthy subjects, but the effect of plant sterol diminished at 2 months and was not significantly different from baseline. This was accompanied by increases in serum plant sterols and a significant decrease in 7alpha-hydroxy-4-cholesten-3-one, a marker of bile acid synthesis, especially in FH patients not taking bile acid sequestrants. In contrast, plant stanol esters lowered significantly both LDL cholesterol and plant sterols at 2 months and had no effect on bile acid synthesis. Slight decreases in serum lipid-soluble antioxidants occurred with both plant sterol and stanol esters. Our findings suggest that absorption of dietary plant sterols downregulates bile acid synthesis, which attenuates their cholesterol-lowering efficacy. We conclude that plant stanol esters are preferable for the long-term management of hypercholesterolemia.

Topics: Bile Acids and Salts; Cholesterol, LDL; Down-Regulation; Drug Administration Schedule; Female; Humans; Hyperlipoproteinemia Type II; Male; Middle Aged; Phytosterols; Phytotherapy; Placebos; Sitosterols; Treatment Outcome

While plant stanols are known to upregulate low density lipoprotein (LDL) receptors, we studied the effects of plant stanol (STA) and sterol (STE) ester spreads on triglyceride-rich lipoprotein (TRL) removal in statin-treated patients with familial hypercholesterolemia (FH) using intravenous Intralipid-squalene fat tolerance test.. Five patients consumed STA and STE in a randomized, crossover study for 4 weeks. TRL removal was studied at baseline and at the end of both periods. Serum, chylomicron (CM), and very low density lipoprotein lipids, squalene, and plant sterols were measured.. LDL cholesterol was decreased by both spreads (15-16%, p<0.05). Plant sterol concentrations were doubled in serum and CM by STE vs. STA. After the injection of Intralipid, CM squalene and sitosterol, but not triglycerides (TG), reached higher peak levels (and area under the incremental curve (AUIC) of squalene) by both spreads than at baseline. Despite different plant sterol concentrations by STE vs. STA, the incremental curves for plant sterols were similar by the spreads.. Despite the retarded removal of TRL lipids by STA and STE in the statin-treated subjects with FH, improvement of the fasting lipid profile was suggested important in consideration of combination of cholesterol absorption inhibitor with statins even in FH.

Topics: Absorption; Adult; Cholesterol; Cholesterol, LDL; Cross-Over Studies; Double-Blind Method; Fat Emulsions, Intravenous; Female; Humans; Hyperlipoproteinemia Type II; Lipids; Male; Phytosterols; Sitosterols; Squalene; Triglycerides

To study the compliance and changes in plasma lipids, plant sterols, fat-soluble vitamins and carotenoids in children and parents with familial hypercholesterolemia (FH) consuming a plant sterol ester-enriched (PSE) spread.. A 26-week open-label follow-up of children who had previously been studied in a controlled cross-over design. The parents were also included in the open-label arm of the study.. Outpatient clinic for treatment of hyperlipidemia.. A total of 37 children (7-13 y) and 20 parents (32-51 y) diagnosed with 'definite' or 'possible' heterozygous FH. In all, 19 of the parents, but no children, used statins. All were patients at the Lipid Clinic, National Hospital in Oslo.. Subjects were recommended to eat 20 g/day of PSE spread as part of their lipid-lowering diet.. The mean intake of PSE spread was 13.7 and 16.5 g/days in the children and parents, respectively, corresponding to 1.2 and 1.5 g of plant sterols. Plasma total cholesterol decreased by 9.1% in both children (P<0.001) and parents (P=0.002). The corresponding decreases in LDL cholesterol were 11.4% (P<0.001) and 11.0% (P=0.012). Increases in serum lathosterol, campesterol and sitosterol, adjusted for total cholesterol, were observed in the children (31, 96, 48%, respectively, P<0.001) at the end of the controlled cross-over period. In the parents, serum campesterol and sitosterol, adjusted for total cholesterol, increased by 92 and 39%, respectively (P< 0.001). Lipid-adjusted serum alpha- and beta-carotene decreased by 17.4% (P=0.008) and 10.9% (P=0.018), respectively, in the children at the end of the controlled PSE period, but increased again during the follow-up. In the parents, serum alpha- and beta-carotene concentrations were unchanged, while serum lutein and lycopene decreased by 7.3% (P=0.037) and 14.6% (P=0.044), respectively.. Sustained efficacy of cholesterol reduction and long-term compliance of PSE intake were demonstrated in this study.

Topics: Adolescent; Adult; Carotenoids; Child; Cholesterol; Cross-Over Studies; Female; Humans; Hyperlipoproteinemia Type II; Lipids; Male; Margarine; Middle Aged; Patient Compliance; Phytosterols; Sitosterols; Treatment Outcome

To compare the cholesterol-lowering efficacy and other metabolic effects of plant sterol and stanol esters, both of which are commonly used in the dietary management of hypercholesterolaemia.. The cholesterol-lowering efficacy of equivalent intakes of sterol and stanol esters and of different intakes of stanol esters were compared at 1 and 2 months, both in normal subjects and treated patients with familial hypercholesterolaemia. Systemic effects were assessed by measuring serum levels of plant sterols and of lathosterol and 7alpha-hydroxy-cholestenone, indices of sterol absorption and of cholesterol and bile acid synthesis respectively. There were no significant differences during the study between 1.6g daily of sterol and stanol esters in reducing total cholesterol (by 3-7%) or low density lipoprotein cholesterol (by 4-8%), nor between 1.6 and 2.6 g daily of stanol. However, the cholesterol-lowering effect of plant sterol esters was attenuated between 1 and 2 months. This was accompanied by increased serum plant sterols and decreased levels of 7alpha-hydroxy-cholestenone, especially in statin-treated hypercholesterolaemic patients not taking bile acid sequestrants.. These findings suggest that absorption of dietary plant sterols suppressed bile acid synthesis, thereby diminishing their cholesterol-lowering efficacy. In contrast, plant stanols reduced plant sterol absorption and maintained their cholesterol-lowering efficacy.

Topics: Adult; Analysis of Variance; Cholesterol, HDL; Cholesterol, LDL; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Hyperlipoproteinemia Type II; Male; Margarine; Middle Aged; Phytosterols; Probability; Treatment Outcome

Twelve obligate heterozygotes from two kindreds were ascertained through phytosterolemic probands homozygous for molecular defects in the ATP binding cassette (ABC) half transporter, ABCG8. The response of these heterozygotes to a Step 1 diet low in fat, saturated fat, and cholesterol, and to 2.2 g daily of plant sterols (as esters) was determined in Protocol I (16 weeks) and Protocol II (28 weeks) during three consecutive feeding periods: Step 1/placebo spread; Step 1/plant sterol spread; and Step 1/placebo spread (washout). At baseline, half the heterozygotes had moderate dyslipidemia and one-third had mildly elevated campesterol and sitosterol levels. On the Step 1/placebo spread, mean LDL cholesterol decreased significantly, 11.2% in Protocol I (n = 12), and 16.0% in Protocol II (n = 7). Substitution with plant sterol spread produced a significant treatment effect on LDL levels in Protocols I and II. Conversely, the mean levels of campesterol and sitosterol increased 119% and 54%, respectively, during the use of plant sterol spread for 6 weeks in Protocol I, an effect mirrored for 12 weeks in Protocol II. During the placebo spread washouts, LDL levels increased, while those of plant sterols decreased to baseline levels in both protocols. In conclusion, phytosterolemic heterozygotes respond well to a Step 1 diet, and their response to a plant sterol ester challenge appears similar to that observed in normals.

Topics: Adolescent; Adult; Aged; Carotenoids; Child; Cholesterol; Diet, Fat-Restricted; Heterozygote; Humans; Hyperlipoproteinemia Type II; Lipids; Middle Aged; Phytosterols; Placebos; Sitosterols; Vitamins

In adults with familial hypercholesterolaemia (FH), cholesterol lowering with statins has been shown to improve the endothelial function, a hallmark of early atherogenesis. Currently, therapeutic options for treating high cholesterol levels in FH children are limited. Plant sterols safely and effectively reduce serum cholesterol concentrations by inhibiting cholesterol absorption. Therefore, we evaluated the effect of plant sterols on cholesterol and vascular function in prepubertal children with FH. We included 41 children (5-12 years old) with FH in a double-blind crossover trial using spreads containing 2.3 g of plant sterols (mainly sitosterol and campesterol) per 15 g spread and a placebo spread for a 4-week period, separated by a 6-week washout period. Lipid levels and endothelial function were assessed after both 4-week treatment periods. Endothelial function was assessed as flow-mediated dilation (FMD) of the brachial artery using a wall tracking system. Data were compared to those of 20 healthy controls. Intake of 2.3 g plant sterols per day decreased total cholesterol (-11%) and low-density cholesterol (-14%) as compared to placebo spread in FH children. FH children treated with placebo spread were characterized by an impaired FMD compared to healthy control children (7.2% +/- 3.4% versus 10.1% +/- 4.2%, p < 0.005). However, the reduction of LDL in FH children did not improve FMD (placebo: 7.2% +/- 3.4% versus plant sterols: 7.7% +/- 4.1%). In conclusion, the present study shows a clear reduction of LDL cholesterol by plant sterol treatment. However, short-term plant sterol treatment does not improve the endothelial function in FH children.

Topics: Brachial Artery; Child; Cholesterol; Cholesterol, LDL; Cross-Over Studies; Double-Blind Method; Endothelium, Vascular; Humans; Hyperlipoproteinemia Type II; Phytosterols; Puberty; Regional Blood Flow; Vasodilation

Naturally occurring plant sterol esters (SEs) favorably affect serum cholesterol concentrations in humans and could aid in the treatment of children with familial hypercholesterolemia (FH).. We studied the effect of SE-enriched spread on serum lipids, lipoproteins, carotenoids, fat-soluble vitamins, and physiologic variables in children with FH aged 7-12 y.. In a randomized, double-blind crossover study comprising two 8-wk interventions, 38 children with FH consumed 18.2 +/- 1.5 g SE spread/d, corresponding to 1.60 +/- 0.13 g SEs, or a control spread. Blood samples were analyzed at the start and end of each diet period.. Plasma LDL-cholesterol concentrations decreased by 10.2% (P = 0.003) during the SE period compared with the control period. Total cholesterol and apolipoprotein B concentrations were reduced by 7.4% (P = 0.007 and P = 0.020, respectively) during the SE period. No changes were observed in HDL cholesterol, triacylglycerol, or apolipoprotein A-I. Serum concentration of lipid-adjusted lycopene decreased by 8.1% (P = 0.015) in the SE period, with no changes in the other carotenoids. Lipid-adjusted retinol and alpha-tocopherol concentrations increased by 15.6% (P < 0.001) and 7.1% (P = 0.027), respectively. There was an increase (16.8%, P = 0.04) in alanine transaminase in the SE period, but this was explained by a significantly lower starting concentration in the SE period than in the control period. The children consumed a recommended American Heart Association Step I diet during both intervention periods.. A daily intake of 1.6 g SEs induces an additional reduction in LDL-cholesterol concentrations in children with FH consuming a recommended diet.

Topics: Carotenoids; Child; Cholesterol; Double-Blind Method; Female; Humans; Hyperlipoproteinemia Type II; Male; Phytosterols

Sitosterolemia is a rare autosomal recessive disorder caused by homozygous or compound heterozygous variants in. From 443 familial hypercholesterolemia index cases, 260 were negative for familial hypercholesterolemia genes and were sequenced for the. Testing genes associated with sitosterolemia in the molecular routine workflow of a familial hypercholesterolemia cascade screening program allowed the precise diagnosis of sitosterolemia in a substantial number of patients with varying LDL-C levels and high incidence of early atherosclerotic cardiovascular disease and hematologic abnormalities.

Topics: Adolescent; Adult; ATP Binding Cassette Transporter, Subfamily G, Member 5; ATP Binding Cassette Transporter, Subfamily G, Member 8; Cardiovascular Diseases; Cholesterol; Cholesterol, LDL; Female; Humans; Hypercholesterolemia; Hyperlipoproteinemia Type II; Intestinal Diseases; Lipid Metabolism, Inborn Errors; Lipoproteins; Male; Middle Aged; Phytosterols; Young Adult

Sitosterolemia (STSL) is an extremely rare genetic disease. Xanthomas as the first symptom are frequently misinterpreted as familial hypercholesterolemia (FH) in children. Inappropriate treatment may deteriorate the condition of STSL.. To present the clinical and laboratory characteristics of xanthomatous children diagnosed with sitosterolemia in comparison with childhood FH with xanthomas.. We summarized and compared the clinical characteristics of STSL and FH patients with xanthomas as the first manifestations and investigated the different indicators between the STSL and FH groups, as well as their diagnostic values for STSL.. Two tertiary pediatric endocrinology departments contributed ten STSL cases. Five of the STSL patients (50%) experienced mild anemia, whereas two (20%) had vascular complications. The xanthomas of the STSL group displayed morphologies comparable to those of the FH group. There were ten cases of homozygous FH (HoFH) with xanthomas as the predominant symptom of the control group who had no anemia. The serum cholesterol (Chol) levels of the STSL and FH groups were 12.57 (9.55 ~ 14.62) mmol/L and 17.45 (16.04 ~ 21.47) mmol/L, respectively (p value 0.002). The serum low-density lipoprotein cholesterol (LDL-c) levels of the STSL and FH groups were 9.26 ± 2.71 mmol/L and 14.58 ± 4.08 mmol/L, respectively (p value 0.003). Meanwhile, the mean platelet volume (MPV) levels of the STSL and FH groups were 11.00 (9.79 ~ 12.53) fl. and 8.95 (8.88 ~ 12.28) fl., respectively (p value 0.009). The anemia proportions of the STSL and FH groups were 50% and 0%, respectively (p value 0.033). The AUC values of Chol, LDL-c, MPV, hemoglobin (Hb) for the diagnosis of STSL were 0.910, 0.886, 0.869, 0.879, respectively. Chol ≤ 15.41 mmol/L, LDL-c ≤ 13.22 mmol/L, MPV ≥ 9.05 fl., or Hb≤120 g/L were the best thresholds for diagnosing STSL with childhood xanthomas.. The xanthoma morphology of STSL patients resembles that of FH patients. Xanthomas as the initial symptom of a child with Chol ≤ 15.41 mmol/L, LDL-c≤13.22 mmol/L, MPV ≥ 9.05 fl., or Hb≤120 g/L, he was most likely to have STSL.

Topics: Child; Cholesterol; Cholesterol, LDL; Humans; Hypercholesterolemia; Hyperlipoproteinemia Type II; Intestinal Diseases; Lipid Metabolism, Inborn Errors; Male; Phytosterols; Xanthomatosis

Sitosterolemia is caused by homozygous or compound heterozygous gene mutations in either ATP-binding cassette subfamily G member 5 (ABCG5) or 8 (ABCG8). Since ABCG5 and ABCG8 play pivotal roles in the excretion of neutral sterols into feces and bile, patients with sitosterolemia present elevated levels of serum plant sterols and in some cases also hypercholesterolemia. A 48-year-old woman was referred to our hospital for hypercholesterolemia. She had been misdiagnosed with familial hypercholesterolemia at the age of 20 and her serum low-density lipoprotein cholesterol (LDL-C) levels had remained about 200-300 mg/dL at the former clinic. Although the treatment of hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors was ineffective, her serum LDL-C levels were normalized by ezetimibe, a cholesterol transporter inhibitor. We noticed that her serum sitosterol and campesterol levels were relatively high. Targeted analysis sequencing identified a novel heterozygous ABCG5 variant (c.203A>T; p.Ile68Asn) in the patient, whereas no mutations were found in low-density lipoprotein receptor (LDLR), proprotein convertase subtilisin/kexin type 9 (PCSK9), or Niemann-Pick C1-like intracellular cholesterol transporter 1 (NPC1L1). While sitosterolemia is a rare disease, a recent study has reported that the incidence of loss-of-function mutation in the ABCG5 or ABCG8 gene is higher than we thought at 1 in 220 individuals. The present case suggests that serum plant sterol levels should be examined and ezetimibe treatment should be considered in patients with hypercholesterolemia who are resistant to HMG-CoA reductase inhibitors.

Topics: Anticholesteremic Agents; ATP Binding Cassette Transporter, Subfamily G, Member 5; Cholesterol; Cholesterol, LDL; Diagnostic Errors; Ezetimibe; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hyperlipoproteinemia Type II; Intestinal Diseases; Lipid Metabolism, Inborn Errors; Lipoproteins; Loss of Function Mutation; Middle Aged; Phytosterols; Sitosterols; Treatment Failure

Sitosterolemia is an extremely rare, autosomal recessive disease characterized by high plasma cholesterols and plant sterols because of increased absorption of dietary cholesterols and sterols from the intestine, and decreased excretion from biliary tract. Previous study indicated that sitosterolemic patients might be vulnerable to post-prandial hyperlipidemia, including high remnant-like lipoprotein particles (RLP) level. Here we evaluate whether a loading dietary fat increases a post-prandial RLP cholesterol level in sitosterolemic patients compared to heterozygous familial hypercholesterolemic patients (FH).. We recruit total of 20 patients: 5 patients with homozygous sitosterolemia, 5 patients with heterozygous sitosterolemia, and 10 patients with heterozygous FH as controls from May 2015 to March 2018 at Kanazawa University Hospital, Japan. All patients receive Oral Fat Tolerance Test (OFTT) cream (50 g/body surface area square meter, orally only once, and the cream includes 34% of fat, 74 mg of cholesterol, and rich in palmitic and oleic acids. The primary endpoint is the change of a RLP cholesterol level after OFTT cream loading between sitosterolemia and FH. We measure them at baseline, and 2, 4, and 6 hours after the oral fat loading.. This is the first study to evaluate whether sitosterolemia patients have a higher post-prandial RLP cholesterol level compared to heterozygous FH patients.. The result may become an additional evidence to restrict dietary cholesterols for sitosterolemia. This study is registered at University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN ID: UMIN000020330).

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Cholesterol; Dietary Fats; Female; Follow-Up Studies; Humans; Hypercholesterolemia; Hyperlipoproteinemia Type II; Intestinal Diseases; Japan; Lipid Metabolism, Inborn Errors; Lipoproteins; Male; Middle Aged; Phytosterols; Postprandial Period; Prognosis; Triglycerides; Young Adult

A young girl, age 8.5 years, presented with profound hypercholesterolemia and early xanthomatosis, suggesting homozygous familial (or type II) hypercholesterolemia. The patient's low density lipoprotein (LDL) receptor function and parental lipoprotein profiles were determined to be normal, prompting revision of the initial diagnosis to pseudohomozygous familial hypercholesterolemia. When she subsequently presented with giant platelets, the case was presented to colleagues on an electronic mailing list. It was recommended that plasma and sterol analysis be performed, which led to a diagnosis of sitosterolemia. The presentation of profound hypercholesterolomia in childhood that ultimately is not attributed as due to homozygous or compound heterozygous defects in the LDL receptor gene has been termed pseudohomozygous familial (or type II) hypercholesterolemia (PHT2HC). Patients diagnosed with PHT2HC subsequently confirmed to have sitosterolemia have been previously reported only rarely. The challenge of achieving accurate specific diagnosis and appropriate workup for these conditions in children is discussed in the context of this rare case and review of the historical literature concerning these conditions.

Topics: Blood Platelets; Child; Diagnosis, Differential; Female; Homozygote; Humans; Hypercholesterolemia; Hyperlipoproteinemia Type II; Intestinal Diseases; Lipid Metabolism, Inborn Errors; Phytosterols; Receptors, LDL; Sterols; Treatment Outcome; Xanthomatosis

Current guidelines strongly recommend the identification of genetic forms of hypercholesterolemia (HC) during childhood.The usefulness of non-cholesterol sterols (NCS) in the diagnosis of genetic HC has not been fully explored. Plasma NCS were measured by gas chromatography/mass spectrometry (GC/MS) in 113 children with hypercholesterolemia affected by: autosomal dominant hypercholesterolemia (ADH), familial combined hyperlipidemia(FCHL), polygenic hypercholesterolemia (PHC), and in 79 controls to evaluate: i) plasma NCS profile in different genetic HC and ii) the usefulness of NCS for the diagnosis of HC beyond current clinical criteria. ADH was characterized by raised lathosterol/total cholesterol (TC) and reduced phytosterols/TC ratios, indicative of increased cholesterol synthesis. FCHL showed a slight increase of lathosterol/TC ratio, whereas PHC showed increased phytosterols/TC ratios, indicative of increased cholesterol absorption. In a post hoc discriminant analysis of patients with HC, lipid values correctly classified the 73% (14 of 19) of ADH, whereas the inclusion of plasma sterols allowed the correct identification of all 19 patients with ADH. FCHL was not differentiated from PHC (62 versus 69%).In conclusion, NCS measurement showed that cholesterol plasma levels are related to the cholesterol synthesis in ADH and to cholesterol absorption in PHC. NCS improve the detection of ADH in pediatric patients, whereas FCHL diagnosis is not improved.

Topics: Adolescent; Biomarkers; Case-Control Studies; Child; Cholesterol; Discriminant Analysis; Female; Gas Chromatography-Mass Spectrometry; Genetic Predisposition to Disease; Humans; Hyperlipidemia, Familial Combined; Hyperlipoproteinemia Type II; Italy; Male; Multifactorial Inheritance; Phytosterols; Predictive Value of Tests; Sitosterols; Sterols

Dietary recommendations are the first step of children hypercholesterolemia's management, whatever its level and its mechanism. The authors review the scientific justifications for these recommendations, and particularly the effects on plasma LDL-cholesterol of the different dietary fatty acids, of fibers and plant sterols. They point out the diet's aim and principles and they give consumption indicators and practical advice.

Topics: Child; Diet; Dietary Fiber; Fatty Acids; Humans; Hyperlipoproteinemia Type II; Phytosterols

Foods containing plant sterol or stanol esters can be beneficial in lowering LDL-cholesterol concentration, a major risk factor for CVD. The present study examined whether high dietary intake of rapeseed oil (RSO) derived plant sterol and stanol esters is associated with increased levels of these components in brain tissue of homozygous and heterozygous Watanabe rabbits, an animal model for familial hypercholesterolemia. Homozygous animals received either a standard diet, RSO stanol or RSO sterol ester while heterozygous animals were additionally fed with 2 g cholesterol/kg to the respective diet form for 120 d (n 9 for each group). Concentrations of cholesterol, its precursor lathosterol, plant sterols and stanols in brain and additionally in liver and plasma were determined by highly sensitive GC-MS. High-dose intake of RSO derived plant sterols and stanols resulted in increased levels of these components in plasma and liver. In brain a limited uptake of plant sterols and stanols was proven, indicating that these compounds passed the blood-brain barrier and may be retained in the brain tissue of Watanabe rabbits. Plant stanol ester feeding lowered plant sterol levels in brain, liver, and plasma. Cholesterol synthesis in brain, indicated by lathosterol, a local surrogate cholesterol synthesis marker, does not seem to be affected by plant sterol or stanol ester feeding. We conclude that high dose intake of plant sterol and stanol esters in Watanabe rabbits results in elevated concentrations of these components not only in the periphery but also in the central nervous system.

Topics: Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Blood-Brain Barrier; Brain; Cholesterol; Disease Models, Animal; Fatty Acids, Monounsaturated; Female; Heterozygote; Homozygote; Hyperlipoproteinemia Type II; Liver; Male; Phytosterols; Plant Oils; Rabbits; Rapeseed Oil; Sitosterols

We studied the concentrations and ratios to cholesterol of noncholesterol sterols reflecting absorption (eg, campesterol) or synthesis (eg, lathosterol) of cholesterol off and on plant sterol and stanol ester spreads in serum and in different lipoproteins of a family with familial hypercholesterolemia, including heterozygous parents receiving no treatment and their homozygous offspring undergoing long-term treatment with statins and apheresis. Serum cholesterol levels were similar in the homozygous and heterozygous individuals, but the concentrations of sterols reflecting cholesterol absorption were as much as 10 times greater in the homozygous child than in the heterozygous parents, whereas the respective markers of cholesterol synthesis only tended to be higher. About 70% of squalene in the homozygous individual (60% in the heterozygous family members) and 85% to 90% of noncholesterol sterols (60%-80% in the heterozygous subjects) were transported by low-density lipoprotein. The ratios of absorption sterols to cholesterol were higher in high-density lipoprotein (HDL) than in very low-density lipoprotein (VLDL), whereas those of synthesis markers and plant stanols were highest in VLDL. The ratios of absorption sterols in serum were mostly lower than those in HDL but higher than in VLDL, whereas the ratios of synthesis sterols in serum were lower than they were in VLDL. Both spreads reduced serum total cholesterol by about 14% in the heterozygous family members and 9% in the homozygous individual. The sterol ester spread increased serum plant sterol concentrations (eg, campesterol in the homozygous family member increased from 5 to 9 mg/dL) and the ratios to cholesterol, but the stanol ester spread decreased them. Plant sterol esters seemed to similarly decrease serum cholesterol in this family with familial hypercholesterolemia, but the clinical role of increased plant sterol concentrations, almost doubled in the LDL of homozygous individuals, is not known.

Topics: Adult; Blood Component Removal; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Dietary Fats; Double-Blind Method; Female; Heterozygote; Homozygote; Humans; Hyperlipoproteinemia Type II; Hypolipidemic Agents; Male; Margarine; Middle Aged; Phytosterols; Sitosterols; Squalene; Triglycerides

Squalene and noncholesterol sterols, e.g. lathosterol and plant sterols, the respective markers of cholesterol synthesis and absorption, are transported with cholesterol in serum lipoproteins. Their concentrations and ratios to cholesterol in serum and lipoproteins have not been carefully compared, especially in children and in marked hypercholesterolemia. Thus, we measured these variables with gas-liquid chromatography in 18 children with and 29 without familial hypercholesterolemia, all aged 5-17 y. Concentrations of most noncholesterol sterols were higher in serum, LDL, and intermediate density lipoprotein in the children with than those without familial hypercholesterolemia. Despite accumulation of noncholesterol sterols mainly in LDL (75% in familial hypercholesterolemia and 55% in non-familial hypercholesterolemia, p < 0.001), their ratios were mostly similar in serum and lipoproteins of the two groups. The ratios of squalene and lathosterol were higher in VLDL and intermediate density lipoprotein, whereas in LDL that of lathosterol was lower than the respective serum values in both groups. Absorption marker sterol ratios were highest in HDL in both groups. Thus, even though the ratios of noncholesterol sterols to cholesterol in serum reflect, in general, synthesis and absorption of cholesterol, their ratios in different lipoproteins could give additional information of cholesterol metabolism.

Topics: Adolescent; Apolipoproteins E; Child; Child, Preschool; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Cholesterol, VLDL; Female; Heterozygote; Humans; Hyperlipoproteinemia Type II; Lipoproteins; Male; Phenotype; Phytosterols; Squalene

1. We administered the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor pravastatin at a daily dose of 1 mg kg(-1) body weight to cholesterol-fed (0.03%) heterozygous Watanabe heritable hyperlipidaemic rabbits, an animal model for heterozygous familial hypercholesterolaemia. 2. After 12 months of cholesterol treatment, immunohistochemistry with the monoclonal antibody 9D9 was used to detect hepatic low density lipoprotein (LDL) receptors, which were quantified by densitometry. In addition we determined LDL receptor mRNA by competitive reverse transcriptase polymerase chain reaction. The cholesterol precursor lathosterol and the plant sterol campesterol were analysed by gas-liquid chromatography. 3. The drug reduced total plasma cholesterol levels by 51% (P=0.04), when compared to the control group. Unexpectedly, hepatic LDL receptor density and mRNA showed no significant differences between the groups. Total plasma levels of lathosterol and campesterol also revealed no significant differences between the groups, if expressed relative to plasma cholesterol. 4. The findings suggest that mechanisms other than induced hepatic LDL receptors are responsible for the cholesterol-lowering effect of pravastatin in this animal model. We propose a reduced cholesterol absorption efficiency compatible with similar campesterol levels between both groups observed in our study.

Topics: Animals; Anticholesteremic Agents; Cholesterol; Cholesterol, Dietary; Heterozygote; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipoproteinemia Type II; Immunohistochemistry; Intestinal Absorption; Liver; Phytosterols; Polymerase Chain Reaction; Pravastatin; Rabbits; Receptors, LDL; RNA, Messenger

This study was undertaken to compare the ability of two plant sterols to reduce serum levels of lipids and to compare their mechanism of action in nine children with severe familial hypercholesterolemia (total and low-density lipoprotein cholesterol concentrations averaged 9.57 mmol/L (370 mg/dl) and 7.87 mmol/L (301 mg/dl)). After a 3-month strict diet, the children were given sitosterol pastils (2 gm three times a day) for 3 months, followed by a 7-month course of sitostanol (0.5 gm three times a day). Serum lipoprotein levels and serum concentrations of campesterol and sitosterol were determined in all nine children, and the fecal excretion of neutral and acidic sterols were determined in seven children at the end of each therapeutic regimen. Sitosterol reduced low-density lipoprotein cholesterol levels by 20% (p < 0.01); sitostanol reduced low-density lipoprotein cholesterol levels by 33% after 3 months and 29% after 7 months (p < 0.01 compared with diet; p < 0.05 compared with sitosterol). Although sitosterol did not alter serum concentrations of campesterol and sitosterol, a significant reduction did occur during sitostanol therapy (-47% and -51%, respectively; p < 0.01). Fecal excretion of neutral sterols increased from 6.7 mg/kg per day during the control period to 9.7 mg/kg per day during sitosterol administration (p < 0.05), and to 12.6 mg/kg per day during sitostanol administration (p < 0.05 compared with diet and sitosterol periods), indicating an increase in the inhibition of intestinal cholesterol absorption. All children completed the study and no obvious side effects occurred. The data indicate that sitostanol, even with a dose four-fold lower than that of sitosterol, was significantly more effective in reducing elevated levels of low-density lipoprotein cholesterol, and the reduction in serum lipid levels was of the same magnitude as that observed with systemic lipid-lowering drugs. These results suggest that sitostanol, a nonabsorbable plant sterol, could be the drug of choice for treating familial hypercholesterolemia in childhood.

Topics: Adolescent; Alanine Transaminase; Alkaline Phosphatase; Apolipoproteins B; Carotenoids; Child; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Feces; Female; Heterozygote; Humans; Hyperlipoproteinemia Type II; Male; Phytosterols; Sitosterols; Sterols

The hypocholesterolaemic effect of pravastatin 40 mg and lovastatin 40 mg daily has been compared in patients with familial hypercholesterolaemia (FH). Administration of the two drugs was separated by a three-month washout period. The reduction in total serum cholesterol after 1,2 and 4 weeks of treatment was similar after pravastatin (-23%, -32% and -32%) and lovastatin (-23%, -30% and -31%). The serum concentrations of LDL cholesterol were similarly reduced, whilst triglycerides, other lipoproteins, cholestanol and squalene were not altered. The reductions in the serum levels of the cholesterol precursor sterols, delta 8-cholesterol, desmosterol and lathosterol were not significantly different after either drug. The lack of difference suggests that cholesterol synthesis was equally inhibited by the two agents. In addition, the serum content of the plant sterols campesterol and sitosterol tended to be equally increased. The comparability of the increases suggests that the absorption and biliary elimination of the two sterols were equally affected by the two statins. Thus, no difference was found between the effects of pravastatin and lovastatin on the serum levels and metabolic precursors of cholesterol in FH during four weeks of treatment.

Topics: Adult; Aged; Cholesterol; Cholesterol, LDL; Desmosterol; Female; Humans; Hyperlipoproteinemia Type II; Isomerism; Lovastatin; Male; Middle Aged; Phytosterols; Pravastatin; Sitosterols; Triglycerides

To assess relationships of serum phytosterols (plant sterols [P]) to serum cholesterol (C), P were measured by gas-liquid chromatography (GLC) in 595 hypercholesterolemics (top C quintile in screening of 3,472 self-referred subjects). A second specific aim was to determine whether high serum P would track over time and whether they would predict familial aggregation of high C, high low-density lipoprotein cholesterol (LDLC), high apolipoprotein (apo) B, and increased premature coronary heart disease (CHD) in hyperphytosterolemic probands and their first-degree relatives. Mean +/- (SD) C was 260 +/- 56 mg/dL, campesterol (CAMP) was 2.10 +/- 1.6 micrograms/mL, stigmasterol (STIG) 1.71 +/- 1.67, sitosterol (SIT) 2.98 +/- 1.61, and total P 6.79 +/- 3.66 micrograms/mL. Serum C correlated with CAMP (r = .15, P less than or equal to .001), STIG (r = .10, P less than or equal to .02), SIT (r = .34, P less than or equal to .0001), and total P (r = .29, P less than or equal to .0001). High serum CAMP and STIG were associated with a personal or family history of CHD in subjects less than or equal to age 55 years (premature CHD). In 21 hyperphytosterolemic probands who initially had at least one P at or above the 95th percentile and a second P at or above the 75th percentile, P were remeasured 2 years later. Initial and 2-year follow-up CAMP, STIG, and SIT did not differ (P greater than .7). Initial and follow-up CAMP were correlated (r = .47, P = .03).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aging; Cholesterol; Coronary Disease; Cyclic AMP; Female; Follow-Up Studies; Humans; Hyperlipoproteinemia Type II; Lipids; Lipoproteins; Male; Phytosterols; Sex Characteristics

Topics: Biopsy, Needle; Cells, Cultured; Child; Cholesterol; Fibroblasts; Homozygote; Hong Kong; Humans; Hyperlipoproteinemia Type II; Male; Phytosterols; Skin; Xanthogranuloma, Juvenile

We measured the serum lathosterol level, a reflection of the rate of whole body cholesterol synthesis, in 15 patients with manifest type III hyperlipoproteinemia (HLP), in 20 subjects with apolipoprotein (apo) E2/2 phenotype, but without type III HLP, in 21 patients with type IIA and 10 patients with type IIB HLP. A group of 100 subjects with apo E3/3 phenotype served as reference. Using ANCOVA, lathosterol was adjusted for serum cholesterol and triglyceride concentrations, since these parameters were found to independently correlate with lathosterol. The adjusted means (+/- SEM), in mumol/L, in these groups were 12.9 +/- 1.1, 8.2 +/- 1.1, 4.8 +/- 0.9, 9.8 +/- 1.4, and 7.8 +/- 0.4, respectively. Type III HLP patients had significantly higher lathosterol levels than all other groups except type IIB HLP. In addition, lathosterol was significantly lower in type IIA patients than in all other groups. The serum levels of plant sterols, used as a reflection of cholesterol absorption, did not differ among the various groups after adjustment for serum cholesterol. These findings suggest that an overproduction of cholesterol is one factor discriminating E2/2 homozygotes with type III HLP from those without the disease.

Topics: Analysis of Variance; Apolipoprotein E2; Apolipoproteins E; Cholesterol; Humans; Hyperlipoproteinemia Type II; Hyperlipoproteinemia Type III; Isomerism; Phenotype; Phytosterols; Sitosterols

Serum cholesterol precursor levels and plant sterol were related to parameters of cholesterol metabolism in 22 patients with heterozygous familial hypercholesterolemia. The serum levels of cholesterol precursor sterols were inversely related to fractional absorption of dietary cholesterol and subsequently positively to overall cholesterol synthesis. The serum plant sterol levels, on the contrary, were significantly associated with fractional cholesterol absorption and negatively with overall cholesterol synthesis. These results were confirmed also with multivariate analyses. Fecal lanosterol, a cholesterol precursor, was related positively to cholesterol synthesis measured by sterol balance and serum precursors and negatively to serum plant sterols. The serum precursor and plant sterol levels were inversely significantly related to each other, indicating that the higher cholesterol absorption efficiency the higher are the serum plant sterol levels and the lower the precursor sterol contents and the overall cholesterol synthesis.

Topics: Cholesterol; Female; Humans; Hyperlipoproteinemia Type II; Intestinal Absorption; Lipids; Lipoproteins; Male; Middle Aged; Phytosterols

Factors regulating the metabolism of plant sterols (sitosterol and campesterol) and their serum levels were studied in sixteen patients with heterozygous familial hypercholesterolemia. Eight patients had undergone an ileal bypass operation, resulting in slight fat and severe bile acid malabsorption and in lowered serum cholesterol concentration, but normal fractional cholesterol absorption. Serum plant sterol concentrations (mg/dl) were similar in the two groups, but expressed per milligram of cholesterol were higher in the operated patients. Fecal excretion (equal with intake) and biliary secretion (reflecting absorption) of the plant sterols were similar in the two groups and were significantly correlated with the serum plant sterol content, which also correlated positively with the fractional cholesterol absorption in the control but not in the operated group. The estimated fractional absorption of the plant sterols was similar in the two groups, but that of sitosterol (3.5%) was lower than that of campesterol (9.1%). Our study shows that serum plant sterols are associated with fractional cholesterol absorption even in patients with familial hypercholesterolemia. However, after ileal exclusion dietary intake of the plant sterols is the main regulator of their serum levels.

Topics: Bile Acids and Salts; Cholesterol; Female; Humans; Hyperlipoproteinemia Type II; Ileum; Intestinal Absorption; Jejunoileal Bypass; Male; Middle Aged; Phytosterols; Sitosterols

Topics: Child, Preschool; Diagnosis, Differential; Female; Humans; Hypercholesterolemia; Hyperlipoproteinemia Type II; Lipid Metabolism, Inborn Errors; Phytosterols; Xanthomatosis

We evaluated the large dose effect of the purified unsaponifiable fraction of soybean (PUFS) given over 24 weeks to 19 patients with primary types IIa and IIb hyperlipoproteinemia. The percent reduction of plasma cholesterol in types IIa and IIb were 13.2% and 11.5%, respectively. PUFS significantly reduced LDL cholesterol levels, but had little affect on VLDL or HDL cholesterol. The triglyceride/cholesterol ratio in HDL fraction was also significantly reduced, suggesting that PUFS plays a role in the catabolism of HDL. PUFS contained tocopherol and unsaturated fatty acid. The relative impact of the individual components could not be assessed directly, however, it seemed reasonable to conclude that the hypo-cholesterolemic effect of PUFS results from a summation effect of plant sterols, tocopherols and unsaturated fatty acids.

Topics: Cholesterol; Cholesterol, LDL; Female; Glycine max; Humans; Hyperlipoproteinemia Type II; Hypolipidemic Agents; Male; Phytosterols; Triglycerides

The death of a 13-year-old boy from coronary atherosclerosis prompted the study of an Amish family. Five of his twelve sibs had tendon and tuberous xanthomas, and increased plasma plant sterols, particularly beta-sitosterol. The plasma level of the major apoprotein of low density lipoprotein (LDL), the B protein, was very high (mean 173 mg/dl) in these five sibs, while the LDL cholesterol level was moderately increased (209 mg/dl). Four other sibs and both parents had an increased LDL B protein level with a normal or mildly raised plasma total and LDL cholesterol level (hyperapobeta-lipoproteinaemia). Evidence for coronary artery disease was found in both parents and three xanthomatous sibs. The original family with beta-sitosterolaemia and xanthomatosis, described in 1974, was re-examined. The proband and her sister had persistent phytosterolaemia and normocholesterolaemia but increased LDL B protein levels. Both parents, two uncles, and three of four grandparents had increased LDL B protein levels and normal total and LDL cholesterol levels. The proband's father had atypical angina pectoris. People with the full syndrome (phytosterolaemia, xanthomas, and hyperapobetalipoproteinaemia) are most probably homozygous for a mutant allele. An increased LDL B protein level permits the identification of heterozygotes in these families, even though in the fasting state they show no phytosterolaemia. The homozygote and probably the heterozygote are at increased risk for cardiovascular atherosclerotic disease.

Topics: Adolescent; Adult; Coronary Disease; Female; Heterozygote; Homozygote; Humans; Hyperlipoproteinemia Type II; Lipoproteins, LDL; Male; Pedigree; Phytosterols; Xanthogranuloma, Juvenile

A patient with phytosterolemia and type IIa hyperlipoproteinemia with tuberous xanthomas is described. The plant sterols, beta-sitosterol, campesterol, and stigmasterol, were identified in plasma and the xanthomas; to our knowledge, this is the first case of phytosterolemia and xanthomatosis in a Japanese.

Topics: Child, Preschool; Humans; Hyperlipoproteinemia Type II; Male; Phytosterols; Xanthomatosis

Topics: Cholesterol; Cholesterol, Dietary; Dietary Fats; Fatty Acids; Fatty Acids, Unsaturated; Female; Humans; Hyperlipoproteinemia Type II; Infant, Newborn; Lactation; Lipid Metabolism; Lipids; Milk, Human; Phytosterols; Pregnancy; Time Factors

Topics: Cholesterol; Humans; Hyperlipoproteinemia Type II; Phytosterols; Steroids