Treatment with probucol of children with familial hypercholesterolaemia

Nine children with familial hypercholesterolaemia, age range 2 to 12 years, were treated with a low cholesterol diet and probucol (10 mg/kg/day). The year before, the children received, as only treatment, a low fat-cholesterol diet. During this period their mean plasma total cholesterol level fell from 8.2 +/- 1.45 mmol/l to 7.17 +/- 0.84 mmol/l (12.6%). This level was further reduced to 5.92 +/- 0.63 mmol/l (17.1%) after the addition of probucol. Plasma high density lipoprotein cholesterol levels were lowered in absolute terms but not in relation to total cholesterol. No apparent side effects were observed. However, the use of probucol should be restricted for the moment to severe cases of hypercholesterolaemia as the long-term excretion of the drug in children is not yet known.     

Cholesterol screening and family history of vascular disease

Hypercholesterolaemia is a major risk factor for the development of coronary heart disease (CHD). Early detection and management of hypercholesterolaemia could retard the atherosclerotic process. Given that CHD and hypercholesterolaemia cluster within families, a screening strategy based on a family history of vascular disease has been advocated. Serum total cholesterol concentrations were measured in a random stratified sample of 1012 children aged from 12-15 years old participating in a coronary risk factor surveillance study in Northern Ireland. Information about vascular disease in close family members was obtained by means of a questionnaire. The study population was divided into two groups according to total cholesterol values: (i) normal, < 5.2 mmol/l (n = 822) and (ii) raised, > or = 5.2 mmol/l (n = 190). A family history identified 63 out of 190 individuals with hypercholesterolaemia yielding a sensitivity of 33.2% and specificity of 71.5%. Our data indicated that a strategy whereby only children from high risk families are screened for hypercholesterolaemia is ineffective. While primary prevention emphasising a healthy diet for all is essential, the role of universal screening deserves further appraisal.     

Cholesterol screening and family history of vascular disease.

Hypercholesterolaemia is a major risk factor for the development of coronary heart disease (CHD). Early detection and management of hypercholesterolaemia could retard the atherosclerotic process. Given that CHD and hypercholesterolaemia cluster within families, a screening strategy based on a family history of vascular disease has been advocated. Serum total cholesterol concentrations were measured in a random stratified sample of 1012 children aged from 12-15 years old participating in a coronary risk factor surveillance study in Northern Ireland. Information about vascular disease in close family members was obtained by means of a questionnaire. The study population was divided into two groups according to total cholesterol values: (i) normal, < 5.2 mmol/l (n = 822) and (ii) raised, > or = 5.2 mmol/l (n = 190). A family history identified 63 out of 190 individuals with hypercholesterolaemia yielding a sensitivity of 33.2% and specificity of 71.5%. Our data indicated that a strategy whereby only children from high risk families are screened for hypercholesterolaemia is ineffective. While primary prevention emphasising a healthy diet for all is essential, the role of universal screening deserves further appraisal.     

SCREENING OF CORD BLOOD LOW-DENSITY-LIPOPROTEIN CHOLESTEROL IN THE DIAGNOSIS OF FAMILIAL HYPERCHOLESTEROLAEMIA: A STUDY OF 2000 INFANTS

Abstract. A prospective follow-up study of infants selected by cord blood total cholesterol (TC) and low-density-lipoprotein cholesterol (LDL-C) levels from 2000 consecutive live births was undertaken to reassess the role of cord blood screening in the diagnosis of familial hypercholesterolaemia (FH). Mean values for serum cholesterol were (mmol/l ± S.D.): TC, 1.83 ± 0.56; LDL-C, 0.90 ± 0.49; HDL-C, 0.70 ± 0.33; TG, 0.38 ± 0.16. Seventy-three of 117 infants who had had a cord TC and/or LDL-C >95th percentile, and 373 control group children (cord TC and/or LDL-C >95th percentile) were followed up at age 3–12 months. Six of the 117 were hypercholesterolaemic (HC), and one child had an HC parent: positive detection rate ≥0.05%; false positive rate ≥3.7%. Four control-group children were HC and had an HC parent; false negative rate ≥1.1%. With the possible exception of detecting FH in a child with a known affected parent, cord blood screening appears to be unreliable for the diagnosis of FH.     

Individualized dietary counselling of families: serum cholesterol concentration and growth of children aged 7–13 months

We studied the effect of a change in dietary fat composition on serum total and high-density lipoprotein cholesterol and growth in healthy infants between 7 and 13 months of age. The intervention families ( n = 22) received individualized dietary counselling when the infant was 7, 8 and 10 months of age. The intervention diet was designed to have a fat content of 35–45 E%, of total energy intake in infants aged 7–12 months and 30–35 E% after 12 months of age. The ratio of saturated to monounsaturated to polyunsaturated fatty acids was designed to be 1:1:1. The children in the control group ( n = 23) were given no specific advice on the fat composition of the diet. Intake of polyunsaturated fatty acids was significantly higher in the intervention group than in the controls (5.9 E% versus 3.6 E%, p < 0.05). Serum total cholesterol concentration decreased significantly in the intervention group during the study from 4.16± 0.41 mmol/l to 3.86 ± 0,48 mmol/l ( p < 0.05). The infants of both groups grew like average Finnish children. Modification of dietary fat composition, as widely recommended for adults and older children to prevent coronary heart disease, decreases cholesterol values in infants without affecting their normal growth.     

冠心病家族史儿童脂质三角的研究

目的：了解有冠心病(CHD)家族史儿童脂质三角［低密度脂蛋白-胆固醇(LDL-C),高密度脂蛋白-胆固醇(HDL-C)和甘油三脂(TG)］有无异常。方法：对83例有冠心病家族史的儿童检测血浆TG,LDL-C和HDL-C浓度,计算LDL-C/HDL-C,以无CHD家族史的健康儿童作为对照。结果：与对照组比较,有CHD家族史的儿童血TG,LDL-C浓度明显增高［(1.46±0.63) mmol/L vs (0.84±0.43) mmol/L,(2.09±1.13) mmol/L vs (0.96±0.87) mmol/L］,HDL-C水平降低［(1.48±0.48) mmol/L vs (1.72±0.53) mmol/L］,LDL-C/HDL-C升高(1.71±1.29 vs 0.96±0.68)(P1.7 mmol/L及LDL-C/HDL-C>2.5的发生率明显增高(20.5% vs 1.2%)(P均0.05)。有早发CHD家族史的儿童血TG,LDL-C水平［(1.86±0.63),(3.12±1.32) mmol/L］高于无早发CHD家族史儿童［(1.34±0.58),(1.79±0.87) mmol/L］及对照组［(0.84±0.43),(0.96±0.87) mmol/L］。有早发CHD家族史者LDL-C/HDL-C(2.85±1.21)高于无早发家族史组(1.37±1.11)和对照组(0.96±0.68)(P均<0.01),HDL-C水平［(1.11±0.26) mmol/L］低于无早发家族史者［(1.59±0.47) mmol/L］和对照组［(1.72±0.53) mmol/L］。脂质三角异常发生率(52.6%)高于无早发家族史组(10.9%)和对照组(1.2%)(P<0.01)。结论：有CHD家族史的儿童存在脂质三角异常,以有早发CHD家族史儿童明显。提示儿童期脂质三角异常与CHD家族史关系密切,有CHD家族史儿童成年后发生CHD的危险性显著增高。     

Influence of dietary intervention on growth in children with hypercholesterolaemia

Aim: To determine whether a moderately reduced fat diet affects longitudinal growth in children with hypercholesterolaemia with a mean duration of 7.42 ± 1.93 y. Methods: Subjects with hypercholesterolaemia, total cholesterol above 5.18 mmol/L and LDL-cholesterol above 3.49 mmol/L (n = 144; 69 males and 75 females) from 2 to 13 y of age were studied. Patients were seen in our outpatient department for regular health check-ups. Weight and height were measured every year. At the same time, cholesterol, triglycerides, LDL-C, HDL-C, A-apoprotein and B-apoprotein levels were analysed. Furthermore, degrees of compliance at 1 mo, 6 mo and each year after starting the dietary treatment were determined. Results: No significant change in height or weight was found after fat restriction. In contrast, significant reductions in total cholesterol, LDL cholesterol and B-apoprotein levels of 19%, 24% and 14%, respectively, were detected. Finally, no significant differences were seen in HDL-cholesterol, A-apoprotein or triglycerides.

Conclusions: These data support the hypothesis that growth is not influenced by moderate fat restriction in healthy children who otherwise have normal nutrition.     

Lipid and apolipoprotein levels and enteral nutrition in very low-birth-weight preterm infants

Lipid, lipoprotein cholesterol and apolipoprotein A-I, A-II and B levels were determined in 10 very low-birth-weight (birth weight 1279 ±144 g; gestational age 29.2±1.2 weeks, mean ± SD) preterm infants on postnatal days 3, 10 and 21. Feeding with pooled human milk began on day 3 ± 1 and by day 10 all infants were exclusively enterally fed. Both triglyceride and total cholesterol levels increased significantly from day 3 to day 10 (0.84 ± 0.28 versus 1.53 ± 0.72 and 2.42 ± 0.47 versus 3.24 ± 0.80, mmol/l, respectively) ( p <0.01); thereafter no further increase was observed. The increase in total cholesterol level was primarily due to a significant enhancement of very low-density lipoprotein and low-density lipoprotein cholesterol (1.52±.34 versus 2.29 ± 0.73 mmol/l, p <0.01). Apo A-I, A-II and B levels did not change between day 3 and day 10. From day 10 to day 21, however, a significant increase in apo A-I concentration was noted (0.57±.20 versus 0.87 ± 0.17 g/l, p <0.01), whereas apo A-II levels increased significantly from day 3 to 21 (0.15 ± 0.03 versus 0.27 ± 0.08 g/l, p<0.01). No change in apo B level was seen.     

Lipid and apolipoprotein levels and enteral nutrition in very low-birth-weight preterm infants

Lipid, lipoprotein cholesterol and apolipoprotein A-I, A-II and B levels were determined in 10 very low-birth-weight (birth weight 1279 ± 144 g; gestational age 29.2 ± 1.2 weeks, mean ± SD) preterm infants on postnatal days 3, 10 and 21. Feeding with pooled human milk began on day 3 ± 1 and by day 10 all infants were exclusively enterally fed. Both triglyceride and total cholesterol levels increased significantly from day 3 to day 10 (0.84 ± 0.28 versus 1.53 ± 0.72 and 2.42 ± 0.47 versus 3.24 ± 0.80, mmol/l, respectively) ( p <0.01); thereafter no further increase was observed. The increase in total cholesterol level was primarily due to a significant enhancement of very low-density lipoprotein and low-density lipoprotein cholesterol (1.52 ± 0.34 versus 2.29 ± 0.73 mmol/l, p< 0.01). Apo A-I, A-II and B levels did not change between day 3 and day 10. From day 10 to day 21, however, a significant increase in apo A-I concentration was noted (0.57 ± 0.20 versus 0.87 ± 0.17 g/l, p< 0.01), whereas apo A-II levels increased significantly from day 3 to 21 (0.15 ± 0.03 versus 0.27 ± 0.08 g/l, p<0.01). No change in apo B level was seen.     

Response to drugs and diet in a compound heterozygote for familial hypercholesterolaemia

A boy with a total plasma cholesterol concentration of 20.9 mmol/l which fell significantly with a low fat diet, cholestyramine and simvastatin, was shown to have two different mutations in the low density lipoprotein receptor gene, demonstrating that some patients with homozygous familial hypercholesterolaemia show a good lipid lowering response to treatment.     

Response to drugs and diet in a compound heterozygote for familial hypercholesterolaemia.

A boy with a total plasma cholesterol concentration of 20.9 mmol/l which fell significantly with a low fat diet, cholestyramine and simvastatin, was shown to have two different mutations in the low density lipoprotein receptor gene, demonstrating that some patients with homozygous familial hypercholesterolaemia show a good lipid lowering response to treatment.     

Lipid profiles in Polish adolescents from high- and low-risk families: tracking unfavourable lipid levels over a one-year period

In a country with a high cardiovascular mortality rate, lipid profiles were studied in 929 adolescents (440 from affected and 489 from non-affected families for cardiovascular disease and hypercholesterolaemia). In 334 children with elevated or borderline total cholesterol level, lipid profiles were re-measured after a 1-y period. In boys from affected families, in contrast to boys from non-affected families, significantly higher total cholesterol levels (4.36 +/- 0.81 vs 4.19 +/- 0.78 mmol/L, p < 0.05) and LDL-C level (2.1 +/- 0.72 vs 1.89 +/- 0.79 mmol/L, p < 0.05) and significantly lower HDL-cholesterol levels (1.81 +/- 0.34 vs 1.93 +/- 0.38 mmol/L, p < 0.05) were found. The odds ratio for being in the most unfavourable decile for LDL-cholesterol was significantly higher for girls from affected families (2.17, p = 0.02). A relatively high HDL-C level as well as a favourable TC/HDL-C ratio was demonstrated in all groups, being lowest in boys from affected families. A significant correlation was found between baseline lipids and their values re-measured after 1 y. It is concluded that (1) adolescents with a positive family history are at increased risk for unfavourable lipid profile, (2) adolescents with elevated total cholesterol and LDL-cholesterol levels remain hypercholesterolaemic after a 1-y period and are therefore candidates for further biochemical and clinical monitoring, and (3) children with elevated total cholesterol may not be at high risk for cardiovascular disease owing to the favourable TC/HDL-C ratio. The study results do not indicate that general cholesterol screening in Polish adolescents is necessary, as the proportion of children with elevated LDL-cholesterol is relatively low.     

Follow up study on children with dyslipidaemia detected by mass screening at 18 months of age: effect of 12 months dietary treatment

The present study was done to evaluate the effect of short-term dietary therapy on 148 dyslipidaemic children (24 familial hypercholesterolaemia, 105 non-familial hypercholesterolaemia and 19 hypertriglyceridaemia), detected by mass screening in children at 18 months of age. In the model diet used for treatment, 15% of the total calories were obtained from protein, 27% from fat and 57% from carbohydrate. Cholesterol intake was set at <200 mg/day and the ratio of polyunsaturated to saturated fatty acid (P/S ratio) was 1.2. When compared to the composition of the diet ingested by the dyslipidaemic children, only the P/S ratio changed from 0.7 to 1.2. During 12 months treatment, levels of total cholesterol, low density lipoproteins cholesterol and apoB decreased by 10%–15% in children with familial and non-familial hypercholesterolaemia. There was no significant change in the levels of high density lipoproteins. In 19 children with hypertriglyceridaemia, the intake of carbohydrate was limited to 55% of the total calories consumed and after 12 months of treatment, triglyceride levels reverted to normal. Throughout the study period, apprimately 70% of the children on this dietary therapy were seen in our clinics every 3–6 months and physical development was within normal ranges. These results, taken together, indicate that dietary therapy can be effective for correcting dyslipidaemia, even in young children.     

瘦素受体基因20外显子突变对儿童脂质代谢影响的临床研究(英文)

目的：探讨瘦素受体基因(LEPR)第20外显子突变对脂质代谢的影响及肥胖儿童基因型与血脂的关系。方法：用聚合酶链反应限制性片段长度多态性(PCRRFLP)方法及聚丙烯酰胺凝胶电泳分析20外显子的基因突变频率,并测定单纯型肥胖儿童(102例)和健康儿童(81例)血清中甘油三脂(TG)、总胆固醇(TC)、高密度脂蛋白(HDL)和低密度脂蛋白(LDL)水平。两组分别测量身高、体重,计算体重指数(BMI)及脂肪百分比。结果：肥胖儿童瘦素受体基因的20外显子经PCRRFLP及聚丙烯酰胺凝胶电泳分析,检测出3种基因型G/G,G/A和A/A型。肥胖儿童20外显子3057位G→A突变频率较健康儿童增高(P<0.05)。A/A基因型的肥胖儿童其血清TG(1.8±0.5mmol/Lvs1.0±0.4mmol/L,P<0.01)、BMI(33±5kg/m2vs25±4kg/m2,P<0.05)水平和脂肪百分比(30±8vs20±3,P<0.01)均明显高于G/G基因型者,而血清HDL水平则低于后者(1.08±0.23mmol/Lvs1.38±0.22mmol/L,P<0.01)。G/A型肥胖儿童,除其血清TG浓度高于G/G基因型者外(1.6±0.4mmol/Lvs1.0±0.4mmol/L,P<0.05),余各项指标均与另外两种基因型无明显差别。心电图检查显示部分A/A型血脂增高儿童有ST段和T波改变。结论：单纯型肥胖儿童瘦素受体基因第20外显子存在基因多态性,且该多态性明显影响肥胖儿童的脂质代谢及体脂分布。该研究为临床上开展对肥胖儿童的早期干预提供了理论依据。     

Circulating lipids and glycaemic control in insulin dependent diabetic children

The prevalence of dyslipidaemia in children with insulin dependent diabetes mellitus (IDDM) and its relation to glycaemic control was studied in a group of 51 diabetic children and a control population of 132 schoolchildren. The prevalence of dyslipidaemia in the fasting state was increased in the diabetic group (39%) compared with control subjects (17%). Serum cholesterol concentration alone was raised in 25% of diabetic subjects while serum cholesterol and triglycerides were raised in 14%, compared with 16% and 0.7% respectively in control subjects. Serum total cholesterol (5.1 v 4.5 mmol/l), low density lipoprotein cholesterol (3.2 v 2.6 mmol/l), non-esterified fatty acids (0.91 v 0.50 mmol/l), and triglycerides (0.94 v 0.76 mmol/l) were higher in diabetic children. Serum total cholesterol, triglycerides, and apolipoprotein (apo)B concentrations increased with worsening control, while serum high density lipoprotein cholesterol and apoA-I concentrations were unaltered. There were also positive correlations between glycated haemoglobin and total cholesterol, triglycerides, and apoB in diabetic children. Thus, abnormalities in circulating lipids are common in young subjects with IDDM but largely disappear if blood glucose concentrations are reasonably controlled.     

Circulating lipids and glycaemic control in insulin dependent diabetic children.

The prevalence of dyslipidaemia in children with insulin dependent diabetes mellitus (IDDM) and its relation to glycaemic control was studied in a group of 51 diabetic children and a control population of 132 schoolchildren. The prevalence of dyslipidaemia in the fasting state was increased in the diabetic group (39%) compared with control subjects (17%). Serum cholesterol concentration alone was raised in 25% of diabetic subjects while serum cholesterol and triglycerides were raised in 14%, compared with 16% and 0.7% respectively in control subjects. Serum total cholesterol (5.1 v 4.5 mmol/l), low density lipoprotein cholesterol (3.2 v 2.6 mmol/l), non-esterified fatty acids (0.91 v 0.50 mmol/l), and triglycerides (0.94 v 0.76 mmol/l) were higher in diabetic children. Serum total cholesterol, triglycerides, and apolipoprotein (apo)B concentrations increased with worsening control, while serum high density lipoprotein cholesterol and apoA-I concentrations were unaltered. There were also positive correlations between glycated haemoglobin and total cholesterol, triglycerides, and apoB in diabetic children. Thus, abnormalities in circulating lipids are common in young subjects with IDDM but largely disappear if blood glucose concentrations are reasonably controlled.     

Hypercholesterolaemia treated by soybean protein diet.

After a period of stabilisation on a controlled low lipid low cholesterol diet with animal proteins a group of 16 children with familial hypercholesterolaemia were given a textured soybean protein based diet, with a similar fat composition. All the children had a highly significant reduction in total cholesterol, averaging -21.8% against the baseline after eight weeks. Compliance became less strict afterwards, but more than half of the patients have regularly continued the diet and results have been maintained for one year. Minimal changes were noted in triglyceridaemia and in high density lipoprotein cholesterol concentrations, which showed a slight rise only at the end of treatment. The children''s growth during the trial was normal. In view of the psychological difficulties of prescribing treatment with drugs to children with severe hypercholesterolaemia before puberty and of the relative ineffectiveness of standard low lipid diets in this condition the soybean protein diet may offer a satisfactory alternative.     

Lipid and lipoprotein profiles in children with familial hypercholesterolaemia: effects of therapy

In 71 children with familial hypercholesterolaemia the effect of dietary and/or medical treatment was evaluated. Initial total cholesterol and low density lipoprotein (LDL)-cholesterol levels were significantly lower in children who were consecutively treated by diet (Step-One-Diet) than in those who received additional medication. By dietary treatment, the median total cholesterol level (236.5 mg/dl; range 210–510 mg/dl) was reduced by 7.4% and the median LDL-cholesterol level (162 mg/dl; range 126–423 mg/dl) by 9.9%. By dietary and medical therapy, the median total cholesterol level (330 mg/dl; range 270–424 mg/dl) was reduced by 29.7% and the median LDL-cholesterol level (263 mg/dl; 192–333 mg/dl) by 25.9%. High density lipoprotein (HDL)-cholesterol and HDL 3 remained unchanged. HDL 2 showed a significant decrease of 15.6% up to 27 mg/dl (13–42 mg/dl) on medical treatment. Apolipoprotein A I levels did not change during therapy. Initial apolipoprotein B levels were significantly higher in children who were treated by diet and medication and were reduced by 28.9% by combined therapy. In 28 patients (39.4%) an excess of lipoprotein (a) was detected. Regarding the apolipoprotein E phenotype, 32.2% of the patients carried the risk gene ɛ4 in a hetero- or homozygous form. Conclusion Early dietary and/or medical treatment in hypercholesterolaemic children significantly ameliorates the lipoprotein status. The pretherapy lipoprotein status seems to prognosticate the effectiveness of therapy. Received: 16 April 1997 / Accepted in revised form: 27 May 1998     

Screening for familial hyper-beta-lipoproteinaemia in children in hospital.

1510 plasma cholesterol estimations were made in 1391 children admitted to hospital as part of a biochemical profile. Babies under 1 year and children known to have familial hyperlipoproteinaemia were excluded. The mean concentration was 4-28 mmol/l +/- 1-04 (1 SD) (165-3 mg/100 ml +/- 38-6), and levels exceeded 5-93 mmol/l (229 mg/100 ml) in 68 children. Repeat estimations on 55 of these children showed 34 still to have values greater than 5-93 mmol/l and family studies were performed in 19 of these. In 8 children hypercholesterolaemia was secondary and no familial lipoprotein disorder was present. Familial hyper-beta-lipoproteinaemia (FH) was diagnosed in 3 children and in 2 of the families there was a history of early ischaemic heart disease. In 2 children the diagnosis was in doubt. In the remaining 6 children FH and secondary hyperlipoproteinaemia were excluded so the hypercholesterolaemia was presumably environmentally induced, possibly in association with polygenic inheritance. In the present state of knowledge screening of the childhood population for FH by means of plasma cholesterol determinations cannot be recommended. Studies of lipoproteins should, however, be made in children from families known to have FH or early coronary heart disease.     

Long Term Effects of a High Protein Diet on Glucose Metabolism After Early Postnatal Malnutrition in Rats with Intrauterine Growth Retardation

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