Search

Familial hypercholesterolaemia (FH) is commonly caused by mutations in the LDLR, APOB or PCSK9 genes, with untreated mean low density lipoprotein-cholesterol (LDL-C) concentrations being elevated in APOB mutation carriers, even higher in LDLR mutation and highest in those with a PCSK9 mutation. Here we examine this in children with FH from Norway, UK, The Netherlands, Belgium, Czech Republic, Austria, Portugal and Greece. Differences in characteristics and pre- and post-treatment lipid concentrations in those with different molecular causes were compared by standard statistical tests. Data were obtained from 2866 children, of whom 2531 (88%) carried a reported LDLR/APOB/PCSK9 variant. In all countries, the most common cause of FH was an LDLR mutation (79% of children, 297 different), but the prevalence of the APOB p.(Arg3527Gln) mutation varied significantly (ranging from 0% in Greece to 39% in Czech Republic, p < 2.2 × 10−16). The prevalence of a family history of premature CHD was significantly higher in children with an LDLR vs APOB mutation (16% vs 7% p= 0.0005). Compared to the LDLR mutation group, mean (±SD) concentrations of pre-treatment LDL-C were significantly lower in those with an APOB mutation (n = 2260 vs n = 264, 4.96 (1.08)mmol/l vs 5.88 (1.41)mmol/l, p < 2.2 × 10−16) and lowest in those with a PCSK9 mutation (n = 7, 4.71 (1.22)mmol/l). The most common cause of FH in children from eight European countries was an LDLR mutation, with the prevalence of the APOB p.(Arg3527Gln) mutation varying significantly across countries. In children, LDLR- FH is associated with higher concentrations of LDL-C and family history of CHD compared to those with APOB- FH. Image 1 • LDLR mutations are the most common cause of familial hypercholesterolaemia (FH) in children from 8 European countries. • Overall, 279 different LDLR mutations were found in 2531 FH children. • The frequency of APOB p.(Arg3527Gln) varied significantly over the 8 countries. • APOB -FH was less severe than LDLR -FH for low density lipoprotein-cholesterol (LDL-C) concentration and family onset of coronary heart disease (CHD). [ABSTRACT FROM AUTHOR]

The UK Simon Broome (SB) familial hypercholesterolaemia (FH) register previously reported 3-fold higher standardised mortality ratio for cardiovascular disease (CVD) in women compared to men from 2009 to 2015. Here we examined sex differences in CVD morbidity in FH by national linkage of the SB register with Hospital Episode Statistics (HES). Of 3553 FH individuals in the SB register (aged 20–79 years at registration), 2988 (52.5% women) had linked HES records. Standardised Morbidity Ratios (SMbR) compared to an age and sex-matched UK general practice population were calculated [95% confidence intervals] for first CVD hospitalisation in HES (a composite of coronary heart disease (CHD), myocardial infarction (MI), stable or unstable angina, stroke, TIA, peripheral vascular disease (PVD), heart failure, coronary revascularisation interventions). At registration, men had significantly (p < 0.001) higher prevalence of previous CHD (24.8% vs 17.6%), previous MI (13.2% vs 6.3%), and were commenced on lipid-lowering treatment at a younger age than women (37.5 years vs 42.3 years). The SMbR for composite CVD was 6.83 (6.33–7.37) in men and 7.55 (6.99–8.15) in women. In individuals aged 30–50 years, SMbR in women was 50% higher than in men (15.04 [12.98–17.42] vs 10.03 [9.01–11.17]). In individuals >50 years, SMbR was 33% higher in women than men (6.11 [5.57–6.70] vs 4.59 [4.08–5.15]). Excess CVD morbidity due to FH remains markedly elevated in women at all ages, but especially those aged 30–50 years. This highlights the need for earlier diagnosis and optimisation of lipid-lowering risk factor management for all FH patients, with particular attention to young women with FH. Image 1 • Males with familial hypercholesterolaemia (FH) had more cardiovascular disease (CVD) risk factors and were commenced on lipid-lowering therapy at a younger age, than females with FH. • Individuals with FH had excess rates of hospitalisations for CVD, compared to the general population of non-FH individuals. • Excess CVD morbidity due to FH was higher in women than men aged 30 years and over, but especially in those aged 30–50 years. [ABSTRACT FROM AUTHOR]

For children with heterozygous familial hypercholesterolaemia (HeFH), European guidelines recommend consideration of statin therapy by age 8–10 years for those with a low density lipoprotein cholesterol (LDL-C) >3.5 mmol/l, and dietary and lifestyle advice. Here we compare the characteristics and lipid levels in HeFH children from Norway, UK, Netherlands, Belgium, Czech Republic, Austria, Portugal and Greece. Fully-anonymized data were analysed at the London centre. Differences in registration and on treatment characteristics were compared by standard statistical tests. Data was obtained from 3064 children. The median age at diagnosis differed significantly between countries (range 3–11 years) reflecting differences in diagnostic strategies. Mean (SD) LDL-C at diagnosis was 5.70 (±1.4) mmol/l, with 88% having LDL-C>4.0 mmol/l. The proportion of children older than 10 years at follow-up who were receiving statins varied significantly (99% in Greece, 56% in UK), as did the proportion taking Ezetimibe (0% in UK, 78% in Greece). Overall, treatment reduced LDL-C by between 28 and 57%, however, in those >10 years, 23% of on-treatment children still had LDL-C>3.5 mmol/l and 66% of those not on a statin had LDL-C>3.5 mmol/l. The age of HeFH diagnosis in children varies significantly across 8 countries, as does the proportion of those >10 years being treated with statin and/or ezetimibe. Approximately a quarter of the treated children and almost three quarters of the untreated children older than 10 years still have LDL-C concentrations over 3.5 mmol/l. These data suggest that many children with FH are not receiving the full potential benefit of early identification and appropriate lipid-lowering treatment according to recommendations. Image 1 • The age of HeFH diagnosis varies significantly between 8 European countries. • The proportion of HeFH children being treated varies across 8 European countries. • A quarter of FH children on statins have LDL-C above the target (>3.5 mmol/L). • Many FH children are not getting the full benefit of early diagnosis and treatment. [ABSTRACT FROM AUTHOR]

In 2008, the National Institute of Health and Care Excellence in the UK recommended that patients undergoing lipoprotein apheresis (LA) should be included in an anonymised registry. The UK Lipoprotein Apheresis Registry was subsequently established in 2011. Between 2011 and 2017, data was entered retrospectively and prospectively by seven LA centres in the UK for 151 patients. Twenty-two patients were involved in a research study and were therefore excluded from the analysis. Observational data was analysed for the remaining 129 patients. Most patients had heterozygous familial hypercholesterolaemia (HeFH) (45.0%); 23.3% had homozygous FH (HoFH); 7.8% had hyper-lipoproteinaemia (a) (Lp(a)) and 24.0% had other forms of dyslipidaemia. Detailed treatment data is available for 63 patients relating to 348 years of LA treatment. The number of years of treatment per patient ranged from 1 to 15. The mean reduction in interval mean LDL-C from the pre-procedure baseline was 43.14%. The mean reduction in interval mean Lp(a) from baseline was 37.95%. The registry data also shows a 62.5% reduction in major adverse cardiovascular events (MACE) between the 2 years prior to, and the first 2 years following introduction of LA. The data generated by the UK Lipoprotein Apheresis Registry demonstrates that LA is a very efficient method of reducing LDL-C and Lp(a) and lowers the incidence rate of MACE. LA is an important tool in the management of selected patients with HoFH and drug-resistant dyslipidaemias. Image 1 • The UK Lipoprotein Apheresis (LA) Registry was established in 2011. • Between 2011 and 2017 data was entered retrospectively and prospectively by seven LA centres in the UK for 151 patients. • The mean reduction in interval mean LDL-C from the pre-procedure baseline was 43.14% and 37.95% for Lp(a). • There was a 62.5% reduction in major adverse cardiovascular events (MACE) following introduction of LA. [ABSTRACT FROM AUTHOR]

This consensus statement on the management of children and young people with heterozygous familial hypercholesterolaemia (FH) addresses management of paediatric FH in the UK, identified by cascade testing when a parent is diagnosed with FH and for those diagnosed following incidental lipid tests. Lifestyle and dietary advice appropriate for children with FH; suggested low density lipoprotein cholesterol (LDL-C) targets and the most appropriate lipid-lowering therapies to achieve these are discussed in this statement of care. Based on the population prevalence of FH as ~1/250 and the UK paediatric population, there are approximately 50,000 FH children under 18 years. Currently only about 550 of these children and young people have been identified and are under paediatric care. • Children with heterozygous familial hypercholesterolaemia (FH) should be managed by paediatric health professionals with expertise in FH. • Statin to be considered by the age of 10 years and use age appropriate target LDL-C level in children with FH. • Dietary and life style advice should begin in early childhood. • From the age of 14 years, consider joint review with adult lipidologist in transition clinic with transfer to adult lipid clinic at 16 to 18 years. [ABSTRACT FROM AUTHOR]

A phenocopy is an environmentally-defined phenotype that mimics another, genetically-determined phenotype. The severity of hypercholesterolaemia, extent of down regulation of LDL receptor expression and aortic root localisation of atherosclerosis in cholesterol-fed rabbits strikingly resemble the cardinal features of homozygous familial hypercholesterolaemia (FH) in humans, suggesting that the former is a phenocopy of the latter. This review compares the metabolic and pathological consequences of induced hypercholesterolaemia in rabbits with those of homozygous FH and contrasts their ease of reversibility on resumption of a normal diet with the refractoriness to lipid-lowering therapy of homozygotes, in whom major adverse cardiovascular events and survival depend upon the prevailing level of serum cholesterol. The monofactorial nature of the atherosclerosis in both situations corroborates Anitschkow's concept that “Cholesterin ist alles.” In contrast, atherosclerosis in heterozygous FH differs in several respects from that of homozygotes, notably the lack of aortic root involvement and in its multifactorial aetiology, with raised LDL cholesterol, male gender, low HDL cholesterol and raised lipoprotein (a) all contributing to its clinical expression. In angiographic trials of LDL-lowering therapy regression of coronary lesions was observed in FH heterozygotes whereas they progressed in non-FH subjects. Similarly, carotid artery plaques progressed less in FH heterozygotes than in non-FH subjects, in both instances despite FH patients having higher LDL cholesterol levels on treatment. These findings suggest that, compared with non-FH subjects, atherosclerotic lesions in FH heterozygotes may be hyper-responsive to LDL-lowering therapy, whereas treatment of homozygous FH remains a major challenge. [ABSTRACT FROM AUTHOR]

Background and aims Familial hypercholesterolaemia (FH) is underdiagnosed in children. In addition to lipid concentrations, lipoprotein particle quantity and quality could influence cardiovascular risk. We aimed to perform a comprehensive plasma lipid study, including lipoprotein particle number and size assessment by two-dimensional nuclear magnetic resonance (2D-1H-NMR), in children with FH compared to non-affected children and to evaluate the clinical value of these factors as subclinical atherosclerosis biomarkers. Methods One hundred eighty-three children participating in the broad “Hypercholesterolemia Early Detection Programme” (Decopin Project) were recruited. They were categorized as FH, if they had either a positive genetic test or clinical certainty, or as control children (CCh). Medical history, anthropometry and clinical variables were recorded. Standard biochemical measurements were performed. The lipoprotein profile was studied by 2D-1H-NMR. Carotid intima-media thickness (cIMT) was assessed by sonography in 177 children. Results FH children had a significant 36% increase in LDL particles. The small LDL fraction was increased by 33% compared to CCh. The relative relationship between large, medium and small LDL and the mean LDL particle size was similar between FH children and CCh. The total and small LDL particle numbers were directly associated with and contributed to the determination of the mean cIMT according to bivariate and multivariate analyses in FH children. Conclusions The higher cholesterol levels of FH children are due to an overall increased number of all LDL particle subclasses, including a notable 33% increase in small LDL. Total and small LDL particle number shows a good correlation with cIMT in FH children. [ABSTRACT FROM AUTHOR]

Background and aims Familial hypercholesterolaemia (FH) is a genetic disorder associated with significantly elevated plasma low-density lipoprotein cholesterol (LDL-C) and premature coronary heart disease (CHD). Optimal management of FH relies on early identification and treatment with statins alone or in combination with other lipid-lowering therapies. A lack of awareness of FH and its manifestations among primary care physicians and specialists has led to many individuals being misdiagnosed in the early stages of the disease, further increasing the risk of CHD and requiring much more intensive lipid-lowering strategies. Therefore, implementing clinical guidelines to optimise the diagnosis and treatment of FH is essential. Methods A working group of clinical experts managing FH patients in their daily practice collaborated in order to provide healthcare professionals with a practical evidence-based guide to streamline early diagnosis and treatment of FH. Results Following thorough evaluation of available data and clinical guidelines, the expert working group provided recommendations on how to detect patients with a suspicion of FH; criteria for clinical and genetic diagnoses of FH; how to assess atherosclerosis in primary care and identify patients at the highest risk; follow-up approaches for patients' families; the most optimal treatment combinations; and when to start lipid-lowering therapy in children with FH. Conclusions The expert working group placed great importance on an individualised approach in the management of FH and highlighted the unmet need for both improved education and communication with the laboratory for physicians when LDL-C levels are significantly elevated. Screening high-risk individuals, or cascade screening, is the most cost-effective way of identifying FH cases and initiating adequate statin therapy alone or in combination with other lipid-lowering therapies. In the case of severe FH, where plasma LDL-C levels remain high following maximum-tolerated statin and ezetimibe treatment, PCSK9 inhibitors should be considered. [ABSTRACT FROM AUTHOR]

Eur J Clin Invest 2010; 40 (2): 89–94 Background Few data are available on circulating mononuclear cells nuclear factor-kappa B (NF-kB) activity and plasma xanthine oxidase (XO) activity in heterozygous familial hypercholesterolaemia (FH). The goal of the study was to analyse circulating mononuclear cells NF-kB and plasma XO activities in FH patients. Materials and methods Thirty FH index patients and 30 normoglycaemic normocholesterolaemic controls matched by age, gender, body mass index, abdominal circumference and homeostasis model assessment index were studied. Plasma XO and inflammatory markers were measured by standard methods. NF-kB was assayed in circulating mononuclear cells. Results Familial hypercholesterolaemia patients showed a significantly higher NF-kB (75·0 ± 20·7 vs. 42·7 ± 16·8 relative luminiscence units) and XO (0·44 ± 0·13 vs. 0·32 ± 0·09 mU mL–1) activities than controls. In addition, interleukin-1, interleukin-6, high sensitivity C reactive protein (hsCRP) and oxidized LDL (LDL-ox) were also significantly higher in FH patients. In the total group (FH and controls), XO was significantly associated with LDL-cholesterol (LDL-C), apolipoprotein B (apoB), NF-kB and hsCPR, and NF-kB activity was significantly associated with XO, hsCPR, LDL-ox, LDL-C and apoB plasma values. Using multiple regression analysis, XO was independently associated with hsCPR and NF-kB, and NF-kB activity in circulating mononuclear cells was independently associated with apoB and LDL-ox plasma values. Conclusion Familial hypercholesterolaemia patients show increased activities of NF-kB and XO, and higher values of low grade inflammatory markers related to atherosclerosis. NF-kB activity was independently associated with apoB plasma values. These data could explain in part the high cardiovascular disease risk present in these patients. [ABSTRACT FROM AUTHOR]

Background While data are abundant on increased levels of inflammatory markers in adult patients with hypercholesterolaemia, such data in children are limited. Therefore, we sought to investigate the degree and character of inflammation in children with heterozygous familial hypercholesterolaemia (FH) by measuring levels of neopterin, high-sensitivity C-reactive protein (hsCRP), and soluble CD40 ligand (sCD40L). Materials and methods In the present study, we compared the concentration of inflammatory markers in children suffering from heterozygous FH ( n = 207) with those in unaffected siblings ( n = 84). Furthermore, we investigated the effect of 2-year treatment with pravastatin (20–40 mg qd) or placebo on plasma levels of those markers. Results Our main finding was that serum levels of neopterin and hsCRP were significantly higher in FH children compared with healthy siblings, whereas sCD40L was not. Body mass index and high-density lipoprotein cholesterol levels were significant independent predictors of hsCRP and neopterin. Furthermore, pravastatin therapy decreased neopterin, but not hsCRP and sCD40L, in the FH children, but these changes were not different from the placebo group. Conclusion These findings indicate low-grade monocyte/macrophage hyperactivity in the early stages of atherogenesis, but our findings also suggest that inflammation as well as anti-inflammatory effects of statins are less prominent features of atherosclerosis in FH children than in FH adults. [ABSTRACT FROM AUTHOR]

Abstract Background We have previously shown elevated fasting plasma concentrations of intestinal remnants, as reflected by apolipoprotein (apo) B-48 and remnant-like particle-cholesterol (RLP-C) in patients with heterozygous familial hypercholesterolaemia (FH). We now investigate the effect of an HMG-CoA reductase inhibitor (simvastatin) on chylomicron remnant metabolism using the measurement of fasting apoB-48 and RLP-C in FH patients after long- and short-term simvastatin therapy and after a wash-out period. We also piloted the response of a breath test, involving the measurement of the fractional catabolic rate (FCR) of an intravenously injected chylomicron remnant-like emulsion labeled with cholesteryl 13 C-oleate. Methods Fifteen FH patients were studied after > 6 months 40 mg day-1 simvastatin treatment (long-term), a wash-out period (4 weeks), and 4 weeks of simvastatin treatment (short-term). Apolipoprotein B-48 was determined by SDS-PAGE and Western blotting/enhanced chemiluminescence and RLP-C by an immunoseparation assay. The FCR of the chylomicron remnant-like emulsion was determined from the appearance of 13 CO2 in the breath and by multicompartmental mathematical modelling. Results Both long- and short-term treatment with simvastatin were associated with decreases in the plasma concentration of apoB-48 (P < 0·05) and RLP-C ( P < 0·001), but there was no significant change in the FCR of the emulsion. Conclusions We suggest that long- and short-term treatments with simvastatin have comparable effects in decreasing the plasma concentration of triglyceride-rich remnants in heterozygous FH, as measured by fasting apoB-48 and RLP-C. The mechanisms for this may involve decreased production of hepatic and possibly intestinal lipoproteins, and/or up-regulation of hepatic receptor clearance pathways, but these changes are apparently not associated with a change in remnant clearance as measured... [ABSTRACT FROM AUTHOR]