Familial Hypercholesterolemia Children Research Articles

Quality of life, anxiety and concerns among statin‐treated children with familial hypercholesterolaemia and their parents.

Aim: To assess the quality of life, anxiety and concerns among statin‐treated children with familial hypercholesterolaemia (FH) and their parents. Methods: 69 FH children on statin therapy and 87 parents (51 families) participated in this study. Quality of life of the children, and anxiety levels of both the children and their parents, were investigated using self‐report questionnaires. In addition, a questionnaire was designed to evaluate FH‐specific concerns of these children and their parents on six different topics: 1, knowledge about FH; 2, experience of the disease; 3, family communication; 4, screening; 5, diet; and 6, experience of medication therapy. Results: FH children and their parents reported no problems with regard to quality of life and anxiety. In contrast, the FH survey showed specific FH‐related concerns. One‐third of the children thought that FH can be cured, and 44% of the children suffered from the fact they have FH, but taking medication makes them feel safer (62%). The majority of the children kept a low cholesterol diet and more than 50% took care not to eat too much fat. Almost 38% of the parents experienced FH as a burden to their family and 79% suffered because their child had FH. Conclusion: These findings show that statin‐treated children with FH and their parents did not report affected psychosocial functioning, but did show specific FH‐related concerns.

The Apolipoprotein ε4 Allele Confers Additional Risk in Children with Familial Hypercholesterolemia

Children with familial hypercholesterolemia (FH) exhibit substantial variance of LDL cholesterol. In previous studies, family members of children with FH were included, which may have influenced results. To avoid such bias, we studied phenotype in 450 unrelated children with FH and in 154 affected sib-pairs. In known families with classical FH, diagnosis was based on plasma LDL cholesterol above the age- and gender-specific 95th percentile. Girls had 0.47 +/- 0.15 mmol/L higher LDL cholesterol, compared with boys (p = 0.002). Also in girls, HDL cholesterol increased by 0.07 +/- 0.03 mmol/L per 5 y (pfor trend = 0.005); this age effect was not observed in boys. The distribution of apolipoprotein (apo) E genotypes was not significantly different between probands, their paired affected siblings, or a Dutch control population. Carriers with or without one epsilon4 allele had similar LDL and HDL cholesterol levels. Within the affected sib-pairs, the epsilon4 allele explained 72.4% of the variance of HDL cholesterol levels (-0.15 mmol/L, 95% confidence interval -0.24 to -0.05, p = 0.003). The effect of apoE4 on HDL cholesterol differed with an analysis based on probands or on affected sib-pairs. The affected sib-pair model used adjustment for shared environment, type of LDL receptor gene mutation, and a proportion of additional genetic factors and may, therefore, be more accurate in estimating effects of risk factors on complex traits. We conclude that the epsilon4 allele was associated with lower HDL cholesterol levels in an affected sib-pair analysis, which strongly suggests that apoE4 influences HDL cholesterol levels in FH children. Moreover, the strong association suggests that apoE4 carries an additional disadvantage for FH children.

Hyperlipidemia in HIV-infected children treated with protease inhibitors: relevance for cardiovascular diseases.

Cases of severely hypercholesterolemic HIV-infected children taking protease inhibitors (PIs) have been reported. Because high cholesterol levels (> or =15 mmol/L), as seen in homozygous familial hypercholesterolemia (FH), may lead to heart disease in childhood, the authors performed a systematic retrospective survey of all plasma lipid levels recorded for children who had received ritonavir or nelfinavir between 1995 and 2001 in Switzerland. Administration of PIs was associated with a significant increase in plasma cholesterol levels, which was more pronounced for those given ritonavir (from 3.3 +/- 0.7 mmol/L, n = 5 to 6.3 +/- 2.8 mmol/L, n = 19 [mean +/- SD]; p =.03) than for nelfinavir (from 3.0 +/- 0.7 mmol/L, n = 11 to 4.9 +/- 1.0 mmol/L, n = 30; p = <.001). Cholesterol levels exceeded 10.0 mmol/L in 3 of 49 (6%) PI-treated children and culminated at 13.8 mmol/L. Plasma cholesterol levels in PI-treated children were comparable with levels reported for heterozygous FH children but were all lower than in homozygous FH children. Because heterozygous FH patients usually develop heart disease in middle age, the authors conclude that the risk for heart disease in PI-treated children is minimal. Long-term monitoring of these children, however, will be necessary.

Hyperlipidemia in HIV-Infected Children Treated With Protease Inhibitors: Relevance for Cardiovascular Diseases

Cases of severely hypercholesterolemic HIV-infected children taking protease inhibitors (PIs) have been reported. Because high cholesterol levels (≥15 mmol/L), as seen in homozygous familial hypercholesterolemia (FH), may lead to heart disease in childhood, the authors performed a systematic retrospective survey of all plasma lipid levels recorded for children who had received ritonavir or nelfinavir between 1995 and 2001 in Switzerland. Administration of PIs was associated with a significant increase in plasma cholesterol levels, which was more pronounced for those given ritonavir (from 3.3 ± 0.7 mmol/L, n = 5 to 6.3 ± 2.8 mmol/L, n = 19 [mean ± SD]; p = .03) than for nelfinavir (from 3.0 ± 0.7 mmol/L, n = 11 to 4.9 ± 1.0 mmol/L, n = 30; p = < .001). Cholesterol levels exceeded 10.0 mmol/L in 3 of 49 (6%) PI-treated children and culminated at 13.8 mmol/L. Plasma cholesterol levels in PI-treated children were comparable with levels reported for heterozygous FH children but were all lower than in homozygous FH children. Because heterozygous FH patients usually develop heart disease in middle age, the authors conclude that the risk for heart disease in PI-treated children is minimal. Long-term monitoring of these children, however, will be necessary.

Family history of cardiovascular events and endothelial dysfunction in children with familial hypercholesterolemia

Objectives: in patients with familial hypercholesterolemia (FH), the propensity towards atherosclerosis may vary considerably. In the general population, a positive family history is associated with an increased risk for cardiovascular events. Since endothelial dysfunction is predictive for future cardiovascular events, we evaluated whether FH-children with a positive family history of premature cardiovascular disease have more pronounced endothelial dysfunction compared to children with a negative family history. Study design: 50 FH children, 10–18 years, participated in this study. Thirty-one children had a positive family history for cardiovascular events (fh +) and 19 children had no events in the family (fh −). Nineteen matched siblings participated as controls. Endothelial function was assessed by testing the flow mediated dilatation (FMD) of the brachial artery. Results: baseline characteristics were comparable for fh +, fh − and controls. Lipid levels were significantly higher in FH children. In FH, FMD was impaired compared to controls (11.7±4.4 vs. 15.6±6.8%, P<0.03). In addition, FMD was significantly lower in fh + compared to fh − (10.7±9.9 vs. 13.3±4.6%, P<0.05). Conclusion: In FH-children, endothelial function is impaired compared to matched controls. This impairment is most pronounced in FH children with a positive family history of premature cardiovascular disease.

Reduced susceptibility of low density lipoprotein to lipid peroxidation after cholestyramine treatment in heterozygous familial hypercholesterolemic children

Cholestyramine treatment in children with heterozygous familial hypercholesterolemia (FHHe) can interfere with fat absorption from the intestinal tract, and has the potential to decrease the absorption of fat-soluble vitamins. The aim of this study was to examine the effect of cholestyramine treatment on the levels of the fat soluble vitamins (vitamin E, β-carotene and lycopene) in LDL, on the glutathione system and on the susceptibility of LDL to oxidation in FHHe children. Patients were 16 children (seven girls, nine boys), age 14±4 years, non-smokers. Plasma LDL level before cholestyramine treatment but after dietary treatment was 239±50 mg% with no secondary cause for hypercholesterolemia. A control group was comprised of ten children (seven girls, three boys), age 14±4 years with plasma LDL level of 100±14 mg%. Blood was drawn from 16 FHHe children and five control children after fasting for 14 h. Thereafter cholestyramine treatment was begun in the patient group, at a dose of 8 g/day for 2 months. At the end of this period the dose was increased to 12–16 g/day for an additional 2 months. After 4 months from the beginning of the treatment, blood was drawn again. Plasma LDL cholesterol decreased after treatment by 14% (from 239±67 mg% before treatment to 205±55 mg% after treatment, P=0.07). Malondialdehyde (MDA) levels measured by thiobarbituric reactive substances (TBARS) assay in LDL at the end of oxidation were 30% higher in FHHe children in comparison to controls ( P=0.02). After treatment TBARS levels in LDL (after in vitro oxidation) from FHHe children were decreased by 23% ( P=0.02). Vitamin E levels in LDL from FHHe children after treatment were decreased by 65%, while β-carotene and lycopene contents in LDL, paradoxically increased by 90 and 102%, respectively. In red blood cells (RBC), glutathione peroxidase (GPx) and glutathione transferase (GTf) activities were decreased by 29 and 24%, respectively, while glutathione reductase activity, total and oxidized glutathione contents from FHHe children did not change after cholestyramine treatment. LDL was more prone to oxidation in FHHe children than in controls, when measured by TBARS levels after LDL oxidation (with 10 μM CuSO 4). Cholestyramine treatment for 4 months normalized LDL susceptibility to oxidation measured by TBARS levels, despite the decrease in vitamin E content in LDL from treated FHHe children. This is presumably due to the increased LDL content of β-carotene and lycopene after treatment. GPx and GTf activities decreased after treatment, presumably due to the drop in oxidative stress within the RBCs, in parallel to the decreased LDL tendency to oxidation. Cholestyramine treatment in FHHe children has an overall antioxidant effect on LDL.

Determinants of lipid level variability in French-Canadian children with familial hypercholesterolemia.

The wide variability in the biochemical expression of familial hypercholesterolemia (FH) is only partly explained by mutational heterogeneity in the low density lipoprotein receptor (LDLR) gene. In the current study, we measured this biochemical variability in a group of children heterozygous for the >15-kb LDLR gene deletion (n=67) and examined the contribution of apolipoprotein (apo) E and B allelic variations to this phenotypic variability. Variances of total cholesterol (TC), LDL-C, and apoB concentrations and of the ratio of TC to high density lipoprotein cholesterol (HDL-C) were increased in FH subjects compared with controls. However, after taking the means into account, the coefficients of variation showed that the variability of LDL-C and apoB concentrations was smaller for FH than for controls and that the variability of TC and of the ratio TC to HDL-C was similar between both groups. The epsilon2/3 genotype was associated with lower mean TC, LDL-C, and apoB concentrations in FH. The magnitude of this effect was smaller in controls than in FH. Indeed, the percentages of total variance of TC, LDL-C, and apoB attributable to the apoE locus were 19.9%, 18.1%, and 11.8%, respectively, in FH cases and 5.9%, 7.4%, and 6.0%, respectively, in controls. We did not detect any effect of the apoB insertion/deletion polymorphism on lipid traits in FH children. However, in controls, we observed a strong interaction between apoE and apoB genotypes on apoB concentrations and on TC to HDL-C ratios. Our study reemphasizes the important role of apoE in lipid metabolism and illustrates that the effects of allelic variations on lipid traits are context dependent.

An update on familial hypercholesterolaemia

A report of a World Health Organization consultation on familial hypercholesterolaemia (FH) was recently presented in Geneva. The report provides an update on several aspects of FH such as the molecular basis, DNA diagnosis, clinical criteria for the diagnosis, treatment of FH adults and children, the role of diet, psychosocial aspects of FH, contacting and helping relatives with FH and gives suggestions for government cooperation. The report is reviewed here.

Heterozygous familial hypercholesterolemia in children: low-density lipoprotein receptor mutational analysis and variation in the expression of plasma lipoprotein-lipid concentrations

The phenotypic expression of heterozygous familial hypercholesterolemia (FH) is variable from biochemical and clinical standpoints and several genetic and environmental factors could contribute to explain this variability. We have compared, in a cohort of 266 heterozygous FH children and adolescents (1–19 years), the variation in plasma lipoprotein-lipid levels among patients defined by three mutations in the low density lipoprotein receptor (LDLR) gene. Comparison of the plasma total and LDL-cholesterol (LDL-C) levels among the three mutation groups revealed significant differences. Plasma total and LDL-C levels were significantly higher ( P < 0.05) in the group bearing the French-Canadian Δ > 15 kb null allele mutation (8.17 ± 1.45 and 6.58 ± 1.42 mmol/l) and in the group with the defective allele C646Y missense mutation (8.18 ± 1.53 and 6.65 ± 1.50 mmol/l) compared to the group with the defective allele W66G missense mutation (7.19 ± 1.23 and 5.62 ± 1.16 mmol/l). Comparisons of other lipoprotein-lipid parameters between FH heterozygotes and normolipemic ( n = 120) children indicated that all mutation groups had significantly ( P = 0.0001) lower plasma HDL-cholesterol (HDL-C) levels and a higher total cholesterol (TC) to HDL-C ratio ( P < 0.05). Among FH heterozygote groups, the W66G group had the lowest TC to HDL-C ratio. Multivariate analyses revealed that in FH heterozygotes as well as in controls, HDL-C levels contributed to a greater proportion of the variation in TC to HDL-C ratio than TC. In order to examine the age effect, control and FH heterozygote Δ > 15 kb groups were then subdivided into four groups (1–4; 5–8; 9–13, and 14–19 years). The variation in HDL-C and triglycerides with age in heterozygous FH children showed a pattern which was similar to the one noted in the control group. In conclusion, the present study demonstrated that the overall contribution of age to variation in the lipoprotein profile of heterozygous FH children is similar to the effect observed among healthy children. The effect of LDLR gene in FH is dominant and there was no difference in plasma TC and LDL-C due to gender. Finally, this study indicates that the LDLR gene type mutations are a modulator of the magnitude of the increase in plasma TC and LDL-C levels noted among FH heterozygote children.

113. Thrombogenic factors in heterozygous familial hypercholesterolemic children and their siblings

113. Thrombogenic factors in heterozygous familial hypercholesterolemic children and their siblings

Hemorheological profile in patients with cardiovascular risk factors.

In order to find out whether hemorheological alterations precede the atherosclerotic lesions and could constitute an atherothrombotic risk factor, we studied the hemorheological profile in 150 healthy normotensive offspring whose parents were diagnosed as having essential hypertension WHO I-II grade and in another group of 40 children with familial hypercholesterolemia (FH) but without vascular atherosclerosis lesions, whose parents also suffer from FH. In offspring of hypertensive individuals, a significant increase in the fibrinogen level with respect to the control group was found both in males and females. In addition, only the female offspring showed a higher leucocyte count. FH children showed increased erythrocyte aggregation and increased plasma viscosity with respect to the control group. The fact that the rheological alterations appear prior to the development of the vascular lesion suggests that they could play a role in the pathogenesis of the atherosclerotic process.

Sonography in the detection of achilles tendon xanthomata in children with familial hypercholesterolaemia.

Patients with heterozygous familial hypercholesterolaemia (FH) are at high risk for the development of coronary artery disease. Achilles tendon xanthomata are often the first clinical manifestation of FH, but are seldom palpable earlier than during the third decade. Twenty-one FH children aged 3-18 years underwent high-frequency ultrasound examination of the achilles tendon. Hypoechoic infiltration of the normal tendon structure was demonstrated in 8 of 21 (38%) of the FH children. The findings were similar in boys and girls. Control subjects (n = 68) aged 1-25 years had no sonographically detectable tendon abnormalities. The thickness of the achilles tendon of the FH children was (mean +/- SD) 7.1 +/- 1.5 mm (range 5-10 mm). The respective values for the controls were 5.8 +/- 1.0 mm (3-7 mm. We conclude that ultrasound examination sensitively detects cholesterol accumulation in the achilles tendon of FH children before tendon xanthomata are clinically evident.

Hypocholesterolemic effects of mixture Da Huai on experimental rats and treatment of a homozygous FH child

This study observes the hypocholesterolemic effects of Mixture Da Huai — a drug of enhancing monocyte macrophage system — on experimental rats, and the treatment of a homozygous familial hypercholesterolemia (FH) child. The results show that TC, VLDL-C and LDL-C in Mixture Da Huai group were significantly reduced and HDL-C was significantly increased. Fractional clearance rates for 125I-GLC-LDL, and the 125I-GLD-LDL uptake of rat peritoneal macrophages were significantly increased. Excretions of total sterol and acidic sterol in feces were also increased. After treatment for 3 months, serum TC and LDL-C of a homozygous FH child were significantly decreased. Tendon and cutaneous xanthomas were limited. This study indicates that by promoting the monocyte macrophage system to degrade LDL, a promising prevention and treatment of hypercholesterolemia and atherosclerosis might be provided, especially in the treatment of homozygous FH.

Identification and treatment of heterozygous familial hypercholesterolemia in children and adolescents

Heterozygous familial hypercholesterolemia (FH) is completely expressed at birth and early in childhood by significant elevations in plasma total and tow density lipoprotein (LDL) cholesterol levels. High density lipoprotein cholesterol can be low in such FH children; the triglyceride levels are usually within the normal range. Screening of children for heterozygous FH using a LDL cholesterol level is reasonably efficient in families with known FH, but for general population screening, the LDL cholesterol level is often too nonspecific. Screening of offspring with a positive family history of premature coronary artery disease will provide a panoply of different lipoprotein phenotypes, reflecting the presence of other genetic conditions, including familial combined hyperlipidemia. Guidelines have been developed by the National Cholesterol Education Program (NCEP) Expert Panel on Blood Cholesterol levels in Children and Adolescents to assist in the evaluation and treatment of children with high LDL cholesterol levels. Although heterozygous FH probably counts for ≤5% of premature coronary artery disease, its identification and treatment are important, because FH often causes marked premature coronary artery disease early in adulthood, and can be successfully treated with a combined dietary and drug approach.

小児期家族性高コレステロール血症ヘテロ接合体の検討およびコレスチラミン投与の臨床効果

小児期家族性高コレステロール血症ヘテロ接合体の検討およびコレスチラミン投与の臨床効果

Pharmacologic and Surgical Treatment of Dyslipidemic Children and Adolescents

A wide variety of treatment modalities have been used in children with dyslipidemias to reduce the concentrations of atherogenic lipoprotein particles. Most of the published experience has focused upon children with familial hypercholesterolemia (FH). A variety of pharmacologic regimens have been utilized with variable degrees of success. The bile acid sequestrants colestipol and cholestyramine, lovastatin, pantethine, paraminosalicylic acid, and fenofibrate have all been successful in reducing total blood cholesterol concentrations by 18-24% in hypercholesterolemic children. Of these medications, only the bile acid sequestrants are not absorbed into the circulation. This theoretic advantage is paralled by long-term safety studies which indicate the absence of serious adverse effects with bile acid sequestrant therapy. Therefore, the bile acid sequestrants represent the drugs of choice in treating severely dyslipidemic children. In selected cases of profoundly dyslipidemic children, other therapeutic strategies have been utilized. Most of these efforts have been directed in the treatment of the child homozygous for FH. Despite the lipid lowering effects of partial ileal bypass surgery in hypercholesterolemic adults, homozygous familial hypercholesterolemic children are not adequately treated by this approach. Portacaval shunt has reduced the total cholesterol concentrations by 20-35% in homozygous FH children without having a negative impact on growth and development. These children have, however, gone on to develop atherosclerotic cardiovascular disease despite therapy. Liver transplantation has led to virtual normalization of the plasma lipoprotein concentrations in 3 children homozygous for familial hypercholesterolemia, and there is evidence for regression of vascular lesions in the coronary arteries in one of these children. However, considering the expense, the difficulty in posttransplantation management, and the irreversible nature of the therapy, liver transplantation should be reserved as the therapy of last resort for homozygous FH. The best therapy for FH homozygotes is the frequent removal of the atherogenic lipoproteins by one of the several apheresis procedures currently available. Total plasma exchange, immunoadsorption, membrane filtration, dextran sulfate adsorption, and heparin extracorporeal precipitation have all been used successfully in significantly reducing the concentrations of total and low-density lipoprotein cholesterol. Studies currently under way will more extensively evaluate the long-term safety as well as the efficacy of apheresis procedures.

Cardiovascular findings in familial hypercholesterolemic children.

Four child patients (1 male and 3 females) with homozygous familial hypercholesterolemia (FH) were examined. They were 4y4m to 9y8m of age on admission. A female patient at age 5y7m on admission had already experienced anginal attacks. Ischemic change was found on exercise ECG in 2 patients. Grade 1/6 to 3/6 (Levine) systolic ejection type murmur was audible in all patients. Cardiac catheterization was carried out in all patients. Supravalvular aortic stenosis was found and so-called atherosclerotic wall thickening was also noticed in 3 of them. Narrowing of the coronary arteries was found in only 1 patient who complained of anginal pain. Supravalvular aortic stenosis was more prevalent than coronary artery disorders in FH children and this lesion was also detected by echocardiography. Therefore, follow-up by echocardiography seems to be very useful in assessing the progression of atherosclerosis in patients with severe hypercholesterolemia.

The hypolipidemic effect of locust bean gum food products in familial hypercholesterolemic adults and children

Seventeen adults and 11 children, a group of 18 familial hypercholesterolemic (FHC) and 10 normal subjects, were fed products with and without locust bean gum (LBG) (8 to 30 g/day) to assess the hypolipidemic effect of LBG. Identical food products with and without LBG were consumed by two groups (A and B) of arbitrarily assigned patients using a cross-over design. Plasma cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, very low-density lipoprotein cholesterol and triglycerides were measured at 2-wk intervals and compared to control feeding periods. In group A, FHC C decreased 10% and LDL-C 11%, normal subjects decreased C 6% and LDL-C 10% (p < 0.001). In group B, FHC C decreased 17% and LDL-C 19%, normal subjects decreased cholesterol 11%, and LDL-C 6% (p < 0.001). Cholesterol and LDL-C were lowered in FHC children in both groups. High-density lipoprotein/LDL ratios increased in both groups. The use of food products with LBG in children and adults is a unique approach to treating FHC. LBG food acceptance was good, and there were no significant side effects. LBG in food products appears to be an effective, safe approach to controlling hyperlipidemia.

Cholesterol excretion studies in familial hypercholesterolemic children and their normolipidemic siblings

Twenty children ages 3 to 17 yr, eight with normal lipids and 12 with familial hypercholesterolemia were studied on a metabolic unit for 14 days to evaluate fecal bile acid and fecal neutral sterol excretion. The diet contained a moderately low cholesterol content, 180 to 200 mg/day. Stools were collected in three separate, 3-day pools. Fecal bile acids and fecal neutral sterols were measured using two stool markers and thin-layer, and gas-liquid chromatography techniques. Fecal neutral sterol and fecal bile acid excretion were the same for normal and familial hypercholesterolemic children on a mg/kg basis. Fecal neutral sterols in familial hypercholesterolemic children decreased with age, p less than 0.001; fecal bile acid excretion also appeared to decrease with age, but less significantly, p less than 0.07. Although the familial hypercholesterolemic children have significantly increased plasma and potentially elevated tissue or total body cholesterol, the excretion of fecal bile acids and fecal neutral sterols did not differ between familial hypercholesterolemic and normal children.

Changes in plasma lipid and lipoprotein fractions after alteration in dietary cholesterol, polyunsaturated, saturated, and total fat in free-living normal and hypercholesterolemic children

To assess the effects of dietary cholesterol and the amount and type of fat on plasma lipid and lipoproteins, nutrient intakes were altered sequentially over 15 months in 11 normal children and 12 children with heterozygous familial hypercholesterolemia. After a 3-month base-line assessment period, on an ad libitum diet, the following diets were given sequentially for three months each: dietary cholesterol greater than 450 mg/day, total fat less than 35% of total calories, and polyunsaturated fat to saturated fat ratio (P/S) greater than 1.5 (diet 1); dietary cholesterol less than 160 mg/day, total fat less than 35% total calories and P/S greater than 1.5 (diet 2); dietary cholesterol less than 160 mg/day, total fat 40% total calories P/S = 1 (diet 3), and dietary cholesterol greater than 450 mg/day total fat greater than 40% total calories, P/S less than 0.04 (diet 4). In normal and familial hypercholesterolemic children the high dietary P/S ratio lowered total and low-density lipoprotein cholesterol in the presence of high dietary cholesterol; sharp reductions in dietary cholesterol lowered the total and low-density lipoprotein cholesterol slightly in familial hypercholesterolemia subjects when P/S was high. High-density lipoprotein cholesterol was not affected by large changes in dietary cholesterol or amount or type of fat. Sustained dietary alteration which significantly lowers total and low-density lipoprotein cholesterol with commercially available products is achievable and practical in free-living children.