scholarly journals Estimation of the prevalence of cholesteryl ester storage disorder in a cohort of patients with clinical features of familial hypercholesterolaemia

2018 ◽  
Vol 56 (1) ◽  
pp. 112-117
Author(s):  
Pauline Ashfield-Watt ◽  
Kate Haralambos ◽  
Rhiannon Edwards ◽  
Delyth Townsend ◽  
Rob Gingell ◽  
...  
Keyword(s):  
Cholesteryl Ester ◽  
Allele Frequency ◽  
Storage Disease ◽  
Familial Hypercholesterolaemia ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Splice Junction ◽  
European Population ◽  
Adult Patients ◽  
Routine Testing

Background and aim Familial hypercholesterolaemia is caused by variants in the low-density lipoprotein cholesterol metabolic pathway involving LDLR, APOB and PCSK9 genes. A national genetic testing service in Wales, UK has observed that no familial hypercholesterolaemia variant is found in almost 80% patients with the familial hypercholesterolaemia phenotype. It has recently been suggested that some adult patients with a familial hypercholesterolaemia phenotype may have cholesteryl ester storage disease which can also present as a mixed hyperlipidaemia. The commonest genetic cause of cholesteryl ester storage disease is an exon 8 splice junction variant in the LIPA gene (rs116928232, c.894G>A; E8SJM) previously found to have an allele frequency of 0.0011 (1 in 450 individuals) in a large European population. This study investigated the prevalence of the E8SJM in patients with a familial hypercholesterolaemia phenotype in Wales, UK. Method A total of 1203 patients with a clinical suspicion of familial hypercholesterolaemia but no familial hypercholesterolaemia variant were invited to participate. Of these, 668 patients provided informed written consent. Stored DNA samples from 663 patients were genotyped for the E8SJM variant. Results Three heterozygotes were identified (allele frequency 0.0023). Whole gene sequencing of the LIPA gene was undertaken in these three individuals, but no other variants were found. Therefore, there were no cholesteryl ester storage disease patients (homozygote or compound heterozygote) identified in this cohort. Conclusion The allele frequency 0.0023 (1 in 221 individuals) for the E8SJM variant was more prevalent in this cohort than in a European population study; however, no cholesteryl ester storage disease homozygotes were identified. We found no evidence to support routine testing for cholesteryl ester storage disease in adult patients with a familial hypercholesterolaemia phenotype.

Increased hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 in cholesteryl ester storage disease

1995 ◽  
Vol 41 (1) ◽  
pp. 111-114 ◽  
Author(s):  
M H Cummings ◽  
G F Watts
Keyword(s):  
Cholesteryl Ester ◽  
Apolipoprotein B ◽  
Storage Disease ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Mevalonic Acid ◽  
Secretion Rate ◽  
Gas Chromatography Mass Spectrometry ◽  
Very Low Density Lipoprotein ◽  
Low Density

Abstract Using a stable isotope method, we measured the hepatic secretion rate of very-low-density lipoprotein apolipoprotein B-100 (VLDL apoB) in a 26-year-old women who had dyslipidemia due to cholesteryl ester storage disease (CESD) and in five normolipidemic subjects. [1-13C]Leucine was administered by a primed constant intravenous infusion and the enrichment of VLDL apoB was determined by gas chromatography-mass spectrometry. The absolute secretion rate (ASR) of VLDL apoB in the patient was more than twice the mean ASR of the normolipidemic group (17.1 vs 8.0 +/- 0.8 mg/kg body wt. per day). The plasma mevalonic acid concentration, a measure of intrahepatic cholesterol synthesis, was also greater in the patient than in the normolipidemic subjects (8.3 vs 4.4 +/- 1.8 micrograms/L). The findings are consistent with the hypothesis that in CESD increased intrahepatic synthesis of cholesterol stimulates hepatic secretion of VLDL apoB and this may partly account for the dyslipidemia.

scholarly journals Cholesteryl Ester Transfer Protein Gene Polymorphisms and Longevity Syndrome

2010 ◽  
Vol 4 (1) ◽  
pp. 14-19 ◽  
Author(s):  
Genovefa Kolovou ◽  
Marianna Stamatelatou ◽  
Katherine Anagnostopoulou ◽  
Peggy Kostakou ◽  
Vana Kolovou ◽  
...  
Keyword(s):  
Cholesteryl Ester ◽  
Allele Frequency ◽  
Cholesteryl Ester Transfer Protein ◽  
Gene Polymorphisms ◽  
Ldl Cholesterol ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Transfer Protein ◽  
History Of

Purpose:High levels of high density lipoprotein (HDL) cholesterol are associated with a decreased risk of coronary heart disease (CHD). Subjects with high levels of HDL cholesterol (>70 mg/dl; 1.79 mmol/l) as well as high levels of low density lipoprotein (LDL) cholesterol, could represent a group with longevity syndrome (LS). Since HDL particles are influenced by cholesteryl ester transfer protein (CETP) activity, it is worth studying the CETP polymorphism. The aim of the study was to detect whether 2 genetic variants of the CETP are associated with the LS.Subjects and Methods:The study population consisted of 136 unrelated men and women with no personal and family history of CHD; 69 met the criteria for LS and 67 did not meet these criteria and had “normal” HDL cholesterol (>40 and <70 mg/dl; >1.03 and <1.79 mmol/l). All patients were genotyped for the TaqIB and I405V polymorphisms.Results:The B2 allele frequency of TaqIB polymorphism was higher in the LS in comparison with the non-LS group (p=0.03) whereas B1 allele frequency was higher in the non-LS group (p=0.03).Conclusions:Gene polymorphisms could help decide whether individuals who have increased levels of both LDL cholesterol and HDL cholesterol require treatment. Some of the prerequisites could include that subjects with LS should not only have very high levels of HDL cholesterol but also favorable gene polymorphisms. However, further investigations with a larger sample and including other gene polymorphisms, are needed.

scholarly journals Hydrolysis of cholesteryl ester in low density lipoprotein converts this lipoprotein to a liposome.

1992 ◽  
Vol 267 (7) ◽  
pp. 4992-4998
Author(s):  
F.F. Chao ◽  
E.J. Blanchette-Mackie ◽  
V.V. Tertov ◽  
S.I. Skarlatos ◽  
Y.J. Chen ◽  
...  
Keyword(s):  
Cholesteryl Ester ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Hydrolysis Of

scholarly journals 6th Hellenic Congress in Athens, of the Hellenic Atherosclerosis Society, on the 04-06 December 2014 Novel Pharmacologic Treatments of Familial Hypercholesterolaemia

2015 ◽  
Vol 9 (1) ◽  
pp. 73-77
Author(s):  
Athyros VG
Keyword(s):  
Familial Hypercholesterolaemia ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Automatic Device ◽  
Loss Of Function ◽  
Ldl Apheresis ◽  
Cvd Risk ◽  
Atherosclerosis Risk In Communities ◽  
Lipid Disorder ◽  
Pharmacologic Treatments

Familial hypercholesterolaemia (FH) is the most common inherited monogenic lipid disorder. It is caused by mutations of genes related to low density lipoprotein (LDL) receptors, apolipoprotein B or proprotein convertase subtilisin/kexin type 9 (PCSK9). Homozygous FH (HoFH; 1/400,000 births) is treated by LDL apheresis. Recently lomitapide has been used for the treatment of HoFH as a monotherapy or in addition to LDL apheresis. Heterozygous FH (HeFH), 1/250-1/200 births, is associated with an increased cardiovascular disease (CVD) risk. The main treatment for HeFH has been high doses of high intensity statins plus ezetimibe. However, this is not usually enough to attain LDL-C targets, especially in those with overt CVD or equivalents (LDL-C goal of<70 mg/dl). Data from the Atherosclerosis Risk in Communities study showed that loss of function mutations of PCSK9 were associated with a 28% lower LDL-C level and an 88% reduction in the risk of CVD in blacks, while in whites these numbers were 15% and 47%, respectively. This led to the development of technology to block PCSK9 with monoclonal human antibodies (e.g. evolocumab and alirocumab). These antibodies have been shown in phase II and III trials to be safe and to produce reductions in LDL-C levels by around 60% either as monotherapy or on top of optimal therapy with statins and ezetimibe. These antibodies are administered subcutaneously every 2 weeks with an automatic device. Anti-PCSK9 antibodies are expected to be licensed soon (? in 2015) and are considered by many as “the statins of the 21st century”.

scholarly journals Morphological characterization of the cholesteryl ester cycle in cultured mouse macrophage foam cells.

1983 ◽  
Vol 97 (4) ◽  
pp. 1156-1168 ◽  
Author(s):  
D J McGookey ◽  
R G Anderson
Keyword(s):  
Cholesteryl Ester ◽  
Lipase Activity ◽  
Lipid Droplets ◽  
Free Cholesterol ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
The Body ◽  
Cyclic Process ◽  
Low Density ◽  
Cholesteryl Esters

Mouse peritoneal macrophages can be induced to accumulate cholesteryl esters by incubating them in the presence of acetylated low density lipoprotein. The cholesteryl esters are sequestered in neutral lipid droplets that remain in the cell even when the acetylated low density lipoprotein is removed from the culture media. Previous biochemical studies have determined that the cholesterol component of cholesteryl ester droplets constantly turns over with a half time of 24 h by a cyclic process of de-esterification and re-esterification. We have used morphologic techniques to determine the spatial relationship of cholesteryl ester, free cholesterol, and lipase activity during normal turnover and when turnover is disrupted. Lipid droplets were surrounded by numerous 7.5-10.0-nm filaments; moreover, at focal sites on the margin of each droplet there were whorles of concentrically arranged membrane that penetrated the matrix. Histochemically detectable lipase activity was associated with these stacks of membrane. Using filipin as a light and electron microscopic probe for free cholesterol, we determined that a pool of free cholesterol was associated with each lipid droplet. Following incubation in the presence of the exogenous cholesterol acceptor, high density lipoprotein, the cholesteryl ester droplets disappeared and were replaced with lipid droplets of a different lipid composition. Inhibition of cholesterol esterification caused cholesteryl ester droplets to disappear and free cholesterol to accumulate in numerous myelin-like structures in the body of the cell.

Treatment of familial hypercholesterolaemia in children and adolescents in the last three decades

2013 ◽  
Vol 24 (3) ◽  
pp. 437-441 ◽  
Author(s):  
Avishay Elis ◽  
Rong Zhou ◽  
Evan A. Stein
Keyword(s):  
Children And Adolescents ◽  
Familial Hypercholesterolaemia ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Low Density ◽  
Low Density Lipoprotein Cholesterol ◽  
Cholesterol Levels ◽  
Heterozygous Familial Hypercholesterolaemia

AbstractBackground:This study evaluated the effectiveness of long-term intensive lipid-lowering therapy in children and adolescents with familial hypercholesterolaemia.Methods:The charts of 89 children and adolescents with heterozygous familial hypercholesterolaemia among ∼1000 patients treated from 1974 to 2008 were reviewed. Familial hypercholesterolaemia was defined as low-density lipoprotein cholesterol level >90th percentile in individuals with a history of familial hypercholesterolaemia.Results:Of the 89 patients, 51% were male; the mean age at diagnosis was 8 ± 4 years, and the mean follow-up was 13 ± 8 years. Baseline and most recent low-density lipoprotein cholesterol levels (mg/dl) under treatment were 250 ± 50 and 142 ± 49, respectively, reduced 43% from baseline (p < 0.0001). At the most recent visit, 39 patients received statin monotherapy, mainly atorvastatin or rosuvastatin, and 50 (56%) patients received combination therapy, mainly vytorin or rosuvastain/ezetimibe, 15 patients were >30 years of age, and none developed symptomatic cardiovascular disease or needed revascularisation.Conclusions:Long-term statin-based therapy can reduce low-density lipoprotein cholesterol levels in most children and adolescents with heterozygous familial hypercholesterolaemia and decrease cardiovascular risk significantly.

Application of the MCDA method for assessing new technologies for familial hypercholesterolaemia treatment

2021 ◽  
Vol 13 (1) ◽  
pp. 14-20
Author(s):  
Marisa Santos ◽  
◽  
Quenia Morais ◽  
Helena Cramer ◽  
Marcelo Assad ◽  
...  
Keyword(s):  
New Technologies ◽  
Familial Hypercholesterolaemia ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Cardiovascular Death ◽  
Hereditary Disease ◽  
New Drugs ◽  
Three Stages ◽  
Indirect Comparisons ◽  
Very High

Objective: Familial hypercholesterolaemia is a hereditary disease characterized by very high levels of low-density lipoprotein cholesterol and an elevated risk of early-onset cardiovascular disorders. New drugs provide alternatives for the treatment of patients with homozygous familial hypercholesterolaemia. The study aims to explore a practical application of multiple-criteria decision analysis on prioritization of new and emerging technologies for familial hypercholesterolaemia. Methods: The decision model was constructed using the MACBETH method. There were three stages: structuring the problem, measuring the performance of alternatives, and building the model. The weights for alternatives and levels were obtained by indirect comparisons, which evaluated the attractiveness of the performance levels of the criteria using the swing weights technique. Results: The drugs lomitapide, ezetimibe, evolocumab, and mipomersen were selected as alternatives for decision-making. “Cardiovascular Death”, “Stroke” and “Acute Myocardial Infarction” had the three most significant weights. The criteria with the lowest weights were “Comfort” and “LDL-C Reduction”. The top-ranked technology was evolocumab, with an overall score of 59.87, followed by ezetimibe, with a score of 37.21. Conclusion: How to apply the result of a higher score in the actual decisionmaking process still requires further studies. The case in question showed that evolocumab has more performance benefits than other drugs but with a cost approximately 50 times higher

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