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At least 19 recordsLinked to original sources

PubMed1975

Hypercholesterolaemia in primary cancer of the liver.

Hepatic synthesis of cholesterol in higher animals is normally markedly suppressed by dietary cholesterol. This feedback regulation has been shown to be absent in all experimental hepatomas studied, and also in the only 2 humans with primary hepatocellular cancer (PHC) who have been investigated. Another patient who presented with hypercholesterolaemia is described in whom cholesterogenesis in the tumour was not suppressed by cholesterol feeding. In order to determine the frequency with which hypercholesterolaemia occurs in PHC, serum cholesterol levels were measured in 132 Black patients with this tumour. Raised levels were found in 14 of the patients (11%). In only 2 of these was hypercholesterolaemia associated with obstructive jaundice.

Acetates↗

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↗

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↗

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↗

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↗

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

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

Selection of multiresistant coliforms by long-term treatment of hypercholesterolaemia with neomycin.

Patients with hypercholesterolaemia are often treated with the antimicrobial agent neomycin. Such treatment is potentially dangerous, however, as it may favour the emergence of multiresistant, R-factor-carrying, enteric bacteria among the intestinal flora. In 11 out of 14 patients who had received neomycin for three months to eight years most of the faecal coliforms were resistant to at least four antimicrobial drugs and capable of transferring this resistance to others. In contrast, only one out of nine patients who were treated with other lipid-lowering drugs had resistant bacteria in their faeces. Neomycin may cause multiresistant strains to emerge because, like tetracycline, it forms high concentrations in the gut. Long-term treatment of non-infectious conditions like hypercholesterolaemia with neomycin is potentially dangerous not only to the patient but also to the community because of the creation of a reservoir of multiresistant organisms.

Drug Resistance, Microbial↗

PubMed1975

Treatment of severe and mild hypercholesterolaemia with probucol and neomycin.

Administration of probucol to 23 patients with familial xanthomatotic hypercholesterolaemia reduced the serum cholesterol level during the 9-month study by 9%, while in 15 patients with less severe hypercholesterolaemia the decrease was on an average 15%. A reduction of more than 10% was obtained in 57% of the former and 80% of the latter subjects. In a double blind trial a greater reduction was obtained in serum cholesterol by probucol than by placebo. Neomycin lowered the serum cholesterol more effectively than probucol in subjects with severe type II abnormality and was at least equally effective in less severe type II patients. Probucol increased transiently the faecal bile acid and dietary cholesterol excretion, while neomycin enhanced the faecal elimination of cholesterol as neutral sterols.

Clinical Trials as Topic↗

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↗

PubMed1978

Regulation of cholesterol synthesis in the hyperlipoproteinaemias. Polymorphonuclear leucocyte abnormality specific to familial type II hypercholesterolaemia.

A simple procedure has been devised to give virtually pure preparations of polymorphonuclear leucocytes. This has permitted study of the regulation of cholesterol biosynthesis at cell level. Freshly isolated cells from donors with various forms of hyperlipoproteinaemia have been shown to have very low levels of cholesterol synthesis, presumably due to high circulating levels of apoprotein-B in donor plasma [1]. The activity of the rate-limiting enzyme for cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl coenzyme A reductase, rapidly increases as the cells are incubated in lipoprotein-deficient medium, until, by 12 h, cells from patients heterozygous for familial type IIa hypercholesterolaemia are clearly distinguished from other hyperlipoproteinaemias. The possible significance of this finding is discussed in relation to the causation and treatment of atherosclerotic disease.

Cells, Cultured↗

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↗

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↗

PubMed1975

Portacaval shunt in four patients with homozygous hypercholesterolaemia.

Four patients with homozygous hyperbetalipoproteinaemia who had proved resistant to intensive medical therapy have undergone portacaval shunt. During 3 weeks of total parenteral alimentation before the operation, the serum-cholesterol decreased significantly in each of the four patients. During the fat-emulsion phase of hyperalimentation, one patient experienced a rise in cholesterol. Postoperatively, the size of xanthomas decreased in all cases; serum-cholesterol levels rose above those achieved during hyperalimentation, and this rise continued for as long as 3 months before a further reduction was recorded. In patients with angina, this improved considerably; and in most cases bruits decreased in itensity. The results at this stage do not, however, suggest portacaval shunt for all patients with homozygous hypercholesterolaemia.

Adolescent↗

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↗

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↗

PubMed1976

The metabolism in vivo and in vitro of plasma low-density lipoprotein from a subject with inherited hypercholesterolaemia.

1. The metabolism in vivo and in vitro of an abnormal low-density lipoprotein (LDL) obtained from a patient with an inherited form of hypercholesterolaemia was compared with that of LDL obtained from a normal subject. 2. The rates of turnover of the apoprotein of the two types of LDL in a normal subject, and their uptake and catabolism by normal lymphocytes in vitro, were similar. 3. It is concluded that the abnormal behaviour of the patient's LDL may not be due to an abnormality in the apoprotein component.

Acacia↗

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↗