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Results for “Familial hypercholesterolaemia”

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At least 19 recordsLinked to original sources
PubMed1975

Plasma exchange in the management of homozygous familial hypercholesterolaemia.

Two young women with homozygous familial hypercholesterolaemia and coronary and aortic atheroma were treated by repeated plasma exchange, using a continuous-flow blood-cell separator, for 4 and 8 months. A pronounced reduction in plasma cholesterol and low-density lipoprotein (L.D.L.) concentrations was achieved by exchanging each patient's plasma with cholesterol-free plasma protein fraction (B.P.), at 3-weekly intervals on an outpatient basis. By pre-labelling the patients' cholesterol with 14-C and comparing the specific activity of the cholesterol in adipose tissue with that in plasma, evidence was obtained of an influx of tissue cholesterol into plasma after each exchange. There was no side-effects and both patients lost their angina. Plasma exchange offers a new and practical approach to the long-term management of this lethal disorder and may also provide information about the possible reversibility of human atheroma.

Adult↗
PubMed1979

Reversible abnormalities of low density lipoprotein composition in familial hypercholesterolaemia.

Low density lipoprotein (LDL) composition was analysed in twenty-one patients with familial hypercholesterolaemia, including six homozygotes. By comparison with nineteen controls the patients' LDL had an increased ratio of cholesterol:phospholipid and a decreased ratio of lecithin:sphingomyelin; these changes were more marked in homozygotes than in heterozygotes. Treatment of sevel patients with plasma exchange temporarily resulted in near-normalization of the composition of their LDL. These results suggest that abnormalities of LDL composition in familial hypercholesterolaemia are secondary to hypocatabolism of LDL, which prolongs the half-life of LDL and thus increases the mean age of the population of particles circulating in plasma.

Blood Transfusion↗
PubMed1977

Dose-effect relation of cholestryamine in children and young adults with familial hypercholesterolaemia.

Twenty children and young adults with familial hypercholesterolaemia (F.H.), on a diet low in cholesterol and high in polyunsaturated fats, were treated with cholestyramine in a metabolic unit to determine the decrease in plasma cholesterol and low-density lipoprotein (L.D.L.) cholesterol in relation to drug dosage, pretreatment concentrations of cholesterol and L.D.L. cholesterol, and body-weight. When the dose of cholestyramine was increased in thirteen patients by 1 g/day up to 16 g/day, given twice daily, cholesterol and L.D.L. cholesterol fell within the normal range in eleven subjects (average dose, 7 g/day), and the response was directly proportional (P less than less than 0-001) to the pretreatment concentrations of cholesterol (r = 0-89) and L.D.L. cholesterol (r = 0-93) but did not correlate with body-weight. Plasma total cholesterol and L.D.L. cholesterol continued to fall and concentrations reached a plateau after which additional cholestyramine had no further effect (average dose, 11 g/day). The L.D.L. cholesterol regression line successfully predicted the dose required to reduce L.D.L. cholesterol concentrations in seven other patients. There was a significant decrease in mean serum-folate in female patients. It was concluded that the minimum effective dose of cholestyramine in young patients with F.H. can be predicted from the pretreatment plasma total and L.D.L. cholesterol and may be given twice daily.

Administration, Oral↗
PubMed1977

Non-stedy-state studies of low-density-liproprotein turnover in familial hypercholesterolaemia.

1. The non-steady-state turnover of low-density lipoprotein (LDL), labelled in its apoprotein moiety (apo-B) with 131I, was determined in four patients with familial hypercholesterolaemia, three of them homozygotes. 2. The fractional and absolute catabolic rates (FCR and ACR) of LDL-apo-B were determined by relating the excretion of radioactivity, measured in urine in vitro and by whole-body counter in vivo, to plasma radioactivity and to LDL specific radioactivity respectively. 3. The FCR remained relatively constant, even after marked reduction of LDL pool size by means of plasma exchange. This confirms the existence of an intrinsic defect in LDL catabolism in familial hypercholesterolaemia. 4. LDL-apo-B synthesis, determined by summing the ACR and the daily increment in plasma LDL, was much higher in the three homozygotes than in the one heterozygote, in whom the synthetic rate was normal. 5. These results illustrate the usefulness of combining plasma exchange and whole-body radioactivy counting as a means of examining the relationship between the turnover and pool size of a 131I-labelled protein, such as LDL.

Adolescent↗
PubMed1979

Treatment of familial hypercholesterolaemia by partial ileal bypass.

Ten patients with heterozygous familial hypercholesterolaemia (Fredrickson type II) were treated by the operation of partial ileal bypass. Postoperatively, serum cholesterol levels fell by an average of 34% (P less than 0.005), and the decrease was satisfactorily sustained over a period of 12-30 months. Angina and xanthomas also improved in some patients. Postoperatively all patients experienced considerable diarrhoea, which lessened with time. Other complications of surgery included abdominal distension and cramps, colonic dilatation, sepsis and intestinal obstruction. It is concluded that partial ileal bypass significantly lowers serum cholesterol levels, but that in view of the complications the operation should be offered only to carefully selected patients who are intolerant of or unresponsive to conservative measures.

Adult↗
PubMed1976

A new approach to the management of familial hypercholesterolaemia: Removal of plasma-cholesterol based on the principle of affinity chromatography.

Reduction of plasma-cholesterol by the removal of low-density lipoproteins (L.D.L.) in an extracorporeal system is described as a possible approach in the treatment of familial hypercholesterolaemia. L.D.L. were removed from the blood by their interaction with heparin linked to agarose beads in the presence of calcium ions. Plasma-L.D.L. was markedly decreased in two patients with heterozygous familial hypercholesterolaemia. The technique is specific for the removal of L.D.L., as the concentration of high-density lipoproteins was not affected. The treatment was well tolerated by all three subjects (i.e., two hypercholesterolaemic patients and a normal volunteer), and there were no undesirable effects. Several haematological parameters, clinical-chemistry tests, including serum enzymes, and immunoelectrophoresis of plasma proteins were all unaffected by the treatment.

Calcium↗
PubMed2026

Genetic screening of children for familial hypercholesterolaemia: the VRONI study.

BACKGROUND AND AIMS: The role of genetic testing as part of universal screening programmes for familial hypercholesterolaemia (FH) in children is not well defined. Here, a two-step approach to identify children carrying FH-causing variants was investigated. METHODS: In this study from Southern Germany, paediatricians were invited to offer FH screening to all children aged 4.8-14.9 years at routine paediatric examinations. The FH screening programme began in September 2020 in Bavaria and has involved up to 480 paediatricians. It included biochemical and genetic testing using 0.2 mL of blood taken from a fingertip. In case of low-density lipoprotein cholesterol (LDL-C) serum concentration ≥3.36 mmol/L (≥130 mg/dL), FH-causing variants were determined in the same sample with a focused panel covering most frequent variants (n = 48) and sequencing of relevant genes. RESULTS: Out of 25 431 children screened so far, 1689 children had an LDL-C ≥ 3.36 mmol/L (>130 mg/dL), which defined this concentration as the 93rd percentile. Pathogenic variants were identified by the focused panel in 157 and by next-generation sequencing in 283 children, respectively. While 17% (283/1670) of all genetically analysed children tested positive, the fraction of individuals with FH-causing variants increased across the spectrum of LDL-C serum concentrations from 4.7% (23/492) at 3.36-3.49 mmol/L (130-135 mg/dL) to 78.6% (81/103) above 5.17 mmol/L (200 mg/dL). Overall, the prevalence of FH-causing variants was high (1:90). One reason was a founder variant (n = 63) within the LDLR gene, found 40 times more frequent than European average. The analysis of recruitment data revealed significant ascertainment bias, with lower recruitment rate practices exhibiting higher prevalence. After adjustment for the bias using a generalized linear mixed model, the predicted prevalence was 1 in 163 (0.61%), which is highly consistent with large-scale genomic benchmarks as gnomAD (1:165, n = 622 057) and the UK Biobank (1:176, n = 48 741). CONCLUSIONS: The prevalence of FH determined in this study is significantly higher than previously published estimates (∼1:250), highlighting the importance of this condition for public health and supporting calls for a national paediatric screening programme, given the availability of effective treatment options. For children between 5 and 15 years, biochemical screening is an effective way to select patients for genetic testing, with sequencing of candidate genes being superior to variant screening. In summary, the VRONI study demonstrates the feasibility and efficacy of a combined biochemical and genetic screening for FH in children.

Humans↗
PubMed1979

Changes in cholesterol metabolism with dietary cholesterol in children with familial hypercholesterolaemia.

1. Possible defects in cholesterol metabolism were sought in children with familial hypercholesterolaemia. 2. In nine affected children (eight heterozygotes and one homozygote) and in five healthy children, cholesterol synthesis and bile acid synthesis were determined from the excretion of steroids in the faeces during a low cholesterol diet. Cholesterol synthesis of 10.1 +/- 4.4 mg day-1 kg-1 in the hypercholesterolaemic children was similar to that in these and other normal children. Mean bile acid synthesis of 4.0 +/- 2.1 mg day-1 kg-1 also resembled normal values though three severely affected heterozygotes excreted substantially less. 3. The response to 4 weeks' additional 450 mg of dietary cholesterol/day led to variable changes in the plasma cholesterol and in the sterol balance. On average the affected children showed a rise in plasma cholesterol which resembled that in healthy subjects. The sterol balance fell in most, suggesting a reduction in cholesterol synthesis, which is the normal response to dietary cholesterol. 4. The response to dietary cholesterol was therefore at least qualitatively similar in the hypercholesterolaemic children to that reported in healthy subjects.

Adolescent↗
PubMed1975

Effects of intravenous hyperalimentation of plasma-lipoproteins in severe familial hypercholesterolaemia.

The plasma-lipoprotein response to intravenous hyperalimentation was studied in three patients with severe familial hypercholesterolaemia. Hyperalimentation substantially lowered plasma concentrations of cholesterol, low-density lipoproteins (L.D.L.P.), and high-density lipoproteins. The chemical composition of L.D.L.P. did not change. Triglyceride levels increased slightly in two patients and decreased in the third. Turnover of radiolabelled L.D.L.P. was disturbed as L.D.L.P. concentration fell but then returned to normal. The mechanism by which intravenous hyperalimentation rapidly lowers plasma-cholesterol in severe hypercholesterolaemia is unknown.

Adolescent↗
PubMed1975

A new type of familial hypercholesterolaemia.

Two members of a family (proband and daughter) with hypercholesterolaemia have an abnormal low-density lipoprotein which fails to suppress the activity of a rate-determining enzyme for cholesterol biosynthesis (3-hydroxy-3-methyl glutaryl-CoA reductase) in leucocytes of the patients and controls. However, the proband's leucocytes are inhibited by lipoproteins from other sources demonstrating that the mechanism for cellular regulation of the enzyme is intact. This mutant lipoprotein may have a role in the production of hypercholesterolaemia.

Adult↗
PubMed1978

Prenatal diagnosis of homozygous familial hypercholesterolaemia. Expression of a genetic receptor disease in utero.

Cultured amniotic-fluid cells from a fetus at risk for homozygous familial hypercholesterolaemia (F.H.) almost completely lacked cell-surface receptors for plasma low-density lipoprotein (L.D.L.), as evidenced by direct measurement of binding, uptake, and degradation of 125I-L.D.L. Functional consequences of L.D.L. binding to the receptor--i.e., suppression of 3-hydroxy-3-methylglutaryl coenzyme A reductase and stimulation of cholesterol esterification--were proportionately reduced when compared with results in cultured amniotic cells from two control fetuses. On the basis of these findings, homozygous F.H. was diagnosed and the pregnancy was terminated at the 20th week. The diagnosis of homozygous F.H. was confirmed by a serum-cholesterol of the aborted fetus of 279 mg/dl, a value 9 times the mean of four control fetuses of similar gestational age. More than 80% of the serum-cholesterol of the affected fetus was contained within L.D.L. Prenatal diagnosis of homozygous F.H. now seems practical; moreover, the finding of a raised serum-L.D.L. in the affected fetus indicates that the L.D.L. receptor is normally functional as early as the 20th week of fetal life.

Adult↗
PubMed1979

Metabolism of apolipoprotein B-containing lipoproteins in familial hypercholesterolaemia: effects of plasma exchange.

The turnover of apolipoprotein B (apo B) in very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and low density lipoprotein (LDL) was investigated in 2 homozygous and 3 heterozygous patients with familial hypercholesterolaemia. The effects of a marked reduction in plasma LDL concentration, brought about by plasma exchange, upon apo B turnover were studied in 4 patients. Specific activity-time curves for the the plasma apo B after intravenous radioactive VLDL before plasma exchange indicated that in the heterozygotes all IDL-apo B was derived from VLDL and all LDL-apo B was derived from IDL, but the curves from the homozygotes showed that a significant fraction of the LDL in the plasma was not derived from IDL. Plasma exchange did not increase the rates of synthesis of LDL-apo B or VLDL-apo B and had no significant effect on the precursor--product relationship between IDL-apo B and LDL-apo B in heterozygous or homozygous patients. These findings provide no support for the hypothesis that apo B synthesis is controlled by the plasma LDL.

Apolipoproteins↗
PubMedDate not supplied

Compactin inhibits cholesterol synthesis in lymphocytes and intestinal mucosa from patients with familial hypercholesterolaemia.

Compactin (2000 nmol/l), a potent competitive inhibitor of the rate-determinign enzyme for cholesterol synthesis (3-hydroxy-3-methyl-glutaryl coenzyme-A reductase), inhibited by about 90% cholesterol synthesis from 14C-acetate in isolated lymphocytes from healthy control and from patients heterozygous for familial hypercholesterolaemia (F.H.). In isolated intestinal mucosa, a physiologically important tissue for cholesterol synthesis, compactin (2000 nmol/l) suppressed cholesterol synthesis by approximately 50% in controls and F.H. patients. Compactin or its derivatives may prove to be useful in the treatment of hypercholesterolaemia.

Acetates↗
PubMed1979

Screening of cord blood low-density-lipoprotein cholesterol in the diagnosis of familial hypercholesterolaemia: a study of 2000 infants.

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 greater than 95th percentile, and 373 control group children (cord TC and/or LDL-C less than 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 greater than or equal to 0.05%; false positive rate greater than or equal to 3.7%. Four control-group children were HC and had an HC parent; false negative rate greater than or equal to 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.

Adolescent↗
PubMed1979

Regulation of sterol synthesis in leukaemic blast cells: a defect resembling familial hypercholesterolaemia.

Leucocytes from normal subjects and from patients with acute myeloblastic leukaemia incubated for 9 h in the absence of lipoproteins increased their rate of sterol biosynthesis from [2-14C]acetate threefold. Subsequent addition of complete serum, low density lipoprotein or cholesterol in a non-lipoprotein form suppressed sterol synthesis in leucocytes from normal subjects. In contrast, complete serum or low density lipoprotein totally failed to suppress sterol synthesis in leukaemic blast cells. However, when these cells were incubated with cholesterol in a non-lipoprotein form suppression of sterol synthesis occurred as in normal leucocytes. These results suggest that leukaemic blast cells behave like cells from patients with familial hypercholesterolaemia in showing failure of regulation of sterol synthesis by low density lipoprotein.

Humans↗
PubMed1977

Cholestyramine and ileal by-pass in the treatment of familial hypercholesterolaemia.

A comparison was made of the therapeutic effectiveness of cholestyramine and an ileal by-pass operation as hypocholesterolaemic measures in thirteen patients with familial xanthomatotic type II hypercholesterolaemia. Serum cholesterol and faecal steroids were measured before and at the end of a 10 day course of cholestyramine (32 g/day), and subsequently after an ileal by-pass operation. The mean decrease in serum cholesterol caused by cholestyramine (-17%) was significantly less than that caused by the surgical procedure (-33%). The increase in faecal steroid excretion, mainly as bile acids, was lower with cholestyramine (1.261 g/day) than after the ileal exclusion (2.176 g/day) and a positive correlation was found between the decrease in serum cholesterol and the increase in the faecal elimination of steroids of cholesterol origin. However, even though the increase in faecal steroids with cholestyramine was positively correlated with that resulting from ileal by-pass, the correlation between the corresponding changes in serum cholesterol level was not significant. The findings indicate that ileal by-pass decreases serum cholesterol and increases faecal elimination of cholesterol more effectively than cholestyramine, and that the decrease in the serum cholesterol level induced by ileal exclusion is not consistently predictable by the serum cholesterol response to the preceding cholestyramine treatment.

Adult↗
PubMed1978

[A comparative study of colestipol and colestyramine in children and adolescents with familial hypercholesterolaemia (author's transl)].

Plasma lipids and lipoproteins were studied in 20 children and adolescents with familial hypercholesterolemia during the administration of two anion exchange resins. All the patients' cholesterol levels had been stabilized by treatment with a cholesterol-lowering diet for at least 12 months. Colestyramin (0.6 g per kg body weight) or Colestipol (0.5 g per kg body weight) were given for eight weeks each in a cross-over design. In 6 children, the study had to be terminated due to gastrointestinal problems. Cholesterol, triglycerides and phospholipids were determined serially in whole serum and in isolated lipoprotein fractions. Apolipoprotein-B was determined by radial immunodiffusion in whole serum and in the LDL-fraction. Total plasma cholesterol and LDL cholesterol were lowered by about 25% from initial values of 290 mg/100 ml and 230 mg/100 ml, respectively and Apo-B was lowered by 20%. Low HDL-cholesterol levels in the patients remained decreased during therapy. Triglyceride and phospholipid levels were not affected by treatment. Efficacy, tolerance and side-effects were similar with both Colestyramin and Colestipol.

Adolescent↗