Albert Wiegman

Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society

Aims Homozygous familial hypercholesterolaemia (HoFH) is a rare life-threatening condition characterized by markedly elevated circulating levels of low-density lipoprotein cholesterol (LDL-C) and accelerated, premature atherosclerotic cardiovascular disease (ACVD). Given recent insights into the heterogeneity of genetic defects and clinical phenotype of HoFH, and the availability of new therapeutic options, this Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society (EAS) critically reviewed available data with the aim of providing clinical guidance for the recognition and management of HoFH. Methods and results Early diagnosis of HoFH and prompt initiation of diet and lipid-lowering therapy are critical. Genetic testing may provide a definitive diagnosis, but if unavailable, markedly elevated LDL-C levels together with cutaneous or tendon xanthomas before 10 years, or untreated elevated LDL-C levels consistent with heterozygous FH in both parents, are suggestive of HoFH. We recommend that patients with suspected HoFH are promptly referred to specialist centres for a comprehensive ACVD evaluation and clinical management. Lifestyle intervention and maximal statin therapy are the mainstays of treatment, ideally started in the first year of life or at an initial diagnosis, often with ezetimibe and other lipid-modifying therapy. As patients rarely achieve LDL-C targets, adjunctive lipoprotein apheresis is recommended where available, preferably started by age 5 and no later than 8 years. The number of therapeutic approaches has increased following approval of lomitapide and mipomersen for HoFH. Given the severity of ACVD, we recommend regular follow-up, including Doppler echocardiographic evaluation of the heart and aorta annually, stress testing and, if available, computed tomography coronary angiography every 5 years, or less if deemed necessary. Conclusion This EAS Consensus Panel highlights the need for early identification of HoFH patients, prompt referral to specialized centres, and early initiation of appropriate treatment. These recommendations offer guidance for a wide spectrum of clinicians who are often the first to identify patients with suspected HoFH.

Arterial intima-media thickness in children heterozygous for familial hypercholesterolaemia.

Patients with familial hypercholesterolaemia have severe coronary-artery disease early in adult life. Whether lipid-lowering treatment should be started in childhood remains to be established. We therefore assessed 201 children heterozygous for familial hypercholesterolaemia and 80 unaffected siblings (both age ranges 8-18 years) with B-mode ultrasound to measure carotid wall intima-media thickness. Mean combined carotid intima-media thickness of heterozygotes was significantly greater than that of unaffected siblings (0.494 mm [SD 0.051] vs 0.472 [SD 0.049], p=0.002). A significant deviation in intima-media thickness was noted from age 12 years in children with familial hypercholesterolaemia. Findings on multivariate analysis showed LDL cholesterol, age, and sex to be strong and independent predictors of intima-media thickness. Since raised LDL cholesterol concentrations can be lowered efficiently, clinical studies are needed to investigate long-term safety and effectiveness of statin treatment in children with familial hypercholesterolaemia.

Statin treatment in children with familial hypercholesterolemia - The younger, the better

Background— We previously demonstrated in a randomized placebo-controlled trial that 2-year pravastatin treatment induced a significant regression of carotid intima-media thickness (IMT) in 8- to 18-year-old children with familial hypercholesterolemia. Subsequently, we continued to follow up these children to explore the relation between the age of statin initiation and carotid IMT after follow-up on statin treatment. We also examined safety aspects of statin therapy during this long-term follow-up. Methods and Results— All 214 children who initially participated in the previous placebo-controlled study were eligible for the follow-up study. After completion of the placebo-controlled study, all children continued treatment with pravastatin 20 or 40 mg, depending on their age. Blood samples were taken on a regular basis for lipids and safety parameters, and a carotid IMT measurement was performed after an average treatment period of 4.5 years. Follow-up data for 186 children were available for the statistical analyses. Multivariate analyses revealed that age at statin initiation was an independent predictor for carotid IMT after follow-up with adjustment for carotid IMT at initiation of statin treatment, sex, and duration of treatment. Early initiation of statin treatment was associated with a subsequently smaller IMT. Furthermore, no serious laboratory adverse events were reported during follow-up, and statin treatment had no untoward effects on sexual maturation. Conclusions— These data indicate that early initiation of statin treatment delays the progression of carotid IMT in adolescents and young adults. The present study shows for the first time that early initiation of statin therapy in children with familial hypercholesterolemia might be beneficial in the prevention of atherosclerosis in adolescence.

Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment

Familial hypercholesterolaemia (FH) is a common genetic cause of premature coronary heart disease (CHD). Globally, one baby is born with FH every minute. If diagnosed and treated early in childhood, individuals with FH can have normal life expectancy. This consensus paper aims to improve awareness of the need for early detection and management of FH children. Familial hypercholesterolaemia is diagnosed either on phenotypic criteria, i.e. an elevated low-density lipoprotein cholesterol (LDL-C) level plus a family history of elevated LDL-C, premature coronary artery disease and/or genetic diagnosis, or positive genetic testing. Childhood is the optimal period for discrimination between FH and non-FH using LDL-C screening. An LDL-C ≥5 mmol/L (190 mg/dL), or an LDL-C ≥4 mmol/L (160 mg/dL) with family history of premature CHD and/or high baseline cholesterol in one parent, make the phenotypic diagnosis. If a parent has a genetic defect, the LDL-C cut-off for the child is ≥3.5 mmol/L (130 mg/dL). We recommend cascade screening of families using a combined phenotypic and genotypic strategy. In children, testing is recommended from age 5 years, or earlier if homozygous FH is suspected. A healthy lifestyle and statin treatment (from age 8 to 10 years) are the cornerstones of management of heterozygous FH. Target LDL-C is <3.5 mmol/L (130 mg/dL) if >10 years, or ideally 50% reduction from baseline if 8–10 years, especially with very high LDL-C, elevated lipoprotein(a), a family history of premature CHD or other cardiovascular risk factors, balanced against the long-term risk of treatment side effects. Identifying FH early and optimally lowering LDL-C over the lifespan reduces cumulative LDL-C burden and offers health and socioeconomic benefits. To drive policy change for timely detection and management, we call for further studies in the young. Increased awareness, early identification, and optimal treatment from childhood are critical to adding decades of healthy life for children and adolescents with FH.

Integrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation

Familial hypercholesterolaemia (FH) is a dominantly inherited disorder present from birth that markedly elevates plasma low-density lipoprotein (LDL) cholesterol and causes premature coronary heart disease. There are at least 20 million people with FH worldwide, but the majority remain undetected and current treatment is often suboptimal. To address this major gap in coronary prevention we present, from an international perspective, consensus-based guidance on the care of FH. The guidance was generated from seminars and workshops held at an international symposium. The recommendations focus on the detection, diagnosis, assessment and management of FH in adults and children, and set guidelines for clinical purposes. They also refer to best practice for cascade screening and risk notifying and testing families for FH, including use of genetic testing. Guidance on treatment is based on risk stratification, management of non-cholesterol risk factors, and safe and effective use of LDL lowering therapies. Recommendations are given on lipoprotein apheresis. The use of emerging therapies for FH is also foreshadowed. This international guidance acknowledges evidence gaps, but aims to make the best use of contemporary practice and technology to achieve the best outcomes for the care of FH. It should accordingly be employed to inform clinical judgement and be adjusted for country-specific and local health care needs and resources.

Family History and Cardiovascular Risk in Familial Hypercholesterolemia Data in More Than 1000 Children

Background—Elevated LDL cholesterol (LDL-C) levels in childhood predict cardiovascular disease (CVD) later in life. Familial hypercholesterolemia (FH) represents the paradigm of this relation. Methods and Results—The objectives of this study were to (1) establish the LDL-C level that provides the most accurate diagnosis of FH in children from families with known FH and (2) assess whether lipoprotein variation in these children is associated with premature CVD in relatives. Foremost, however, it was our objective to identify children with FH who are at high risk and in need of early intervention. A total of 1034 consecutive children from FH kindreds were investigated. First, LDL-C levels >3.50 mmol/L had a 0.98 post-test probability (95% CI, 0.96 to 0.99) of predicting the presence of an LDL receptor mutation. Second, children with FH in the highest LDL-C tertile (>6.23 mmol/L) had a 1.7-times higher incidence (95% CI, 1.24 to 2.36) of having a parent with FH suffering from premature CVD (P =0.001). In addition, such a parent was found 1.8 times more often (95% CI, 1.20 to 2.59) among children with FH who had HDL-C <1.00 mmol/L (P =0.004). Last, children with FH whose lipoprotein(a) was >300 mg/L had a 1.45-times higher incidence (95% CI, 0.99 to 2.13) of having a parent with FH suffering from premature CVD (P =0.05). Conclusions—In FH families, LDL-C levels allow accurate diagnosis of FH in childhood. Moreover, increased LDL-C and lipoprotein(a) and decreased HDL-C levels in children identify FH kindreds with the highest CVD risk.

Refinement of Variant Selection for the LDL Cholesterol Genetic Risk Score in the Diagnosis of the Polygenic Form of Clinical Familial Hypercholesterolemia and Replication in Samples from 6 Countries

BACKGROUND Familial hypercholesterolemia (FH) is an autosomal-dominant disorder caused by mutations in 1 of 3 genes. In the 60% of patients who are mutation negative, we have recently shown that the clinical phenotype can be associated with an accumulation of common small-effect LDL cholesterol (LDL-C)-raising alleles by use of a 12-single nucleotide polymorphism (12-SNP) score. The aims of the study were to improve the selection of SNPs and replicate the results in additional samples. METHODS We used ROC curves to determine the optimum number of LDL-C SNPs. For replication analysis, we genotyped patients with a clinical diagnosis of FH from 6 countries for 6 LDL-C-associated alleles. We compared the weighted SNP score among patients with no confirmed mutation (FH/M-), those with a mutation (FH/M+), and controls from a UK population sample (WHII). RESULTS Increasing the number of SNPs to 33 did not improve the ability of the score to discriminate between FH/M- and controls, whereas sequential removal of SNPs with smaller effects/lower frequency showed that a weighted score of 6 SNPs performed as well as the 12-SNP score. Metaanalysis of the weighted 6-SNP score, on the basis of polymorphisms in CELSR2 (cadherin, EGF LAG 7-pass G-type receptor 2), APOB (apolipoprotein B), ABCG5/8 [ATP-binding cassette, sub-family G (WHITE), member 5/8], LDLR (low density lipoprotein receptor), and APOE (apolipoprotein E) loci, in the independent FH/M- cohorts showed a consistently higher score in comparison to the WHII population (P < 2.2 × 10(-16)). Modeling in individuals with a 6-SNP score in the top three-fourths of the score distribution indicated a >95% likelihood of a polygenic explanation of their increased LDL-C. CONCLUSIONS A 6-SNP LDL-C score consistently distinguishes FH/M- patients from healthy individuals. The hypercholesterolemia in 88% of mutation-negative patients is likely to have a polygenic basis.

Ten-Year Follow-up After Initiation of Statin Therapy in Children With Familial Hypercholesterolemia

Ten-Year Follow-up After Initiation of Statin Therapy in Children With Familial Hypercholesterolemia Familial hypercholesterolemia (FH) is a prevalent (1:500 individuals) inherited disorder that strongly predisposes to premature atherosclerosis and subsequent cardiovascular disease.1 In children with FH, atherosclerosis progression is observed before puberty.2 Consequently, guidelines for FH treatment advocate initiation of statins in children as young as 8 years.3 However, longterm efficacy and safety data for statin therapy initiated during childhood do not exist. We followed up a cohort of children with FH receiving statin therapy until adulthood. Methods | We conducted a cohort study of 214 children heterozygous for FH, living in the Netherlands, aged 8 to 18 years, who were randomized between 1997 and 1999 into a singlecenter, 2-year, double-blind, placebo-controlled trial of pravastatin.4 Results showed a significant regression of carotid intima-media thickness (IMT) after statin treatment compared with placebo. After the trial, all children received pravastatin (20-40 mg/d) and were followed up until March 2011 along with 95 unaffected siblings. Patients were instructed to adhere to the Step 2 diet. During follow-up, several patients switched to other statins. After 10 years, all participants underwent a physical examination, fasted blood sample, assessment of family and medical history, including the occurrence of adverse events,

Molecular Basis of Autosomal Dominant Hypercholesterolemia Assessment in a Large Cohort of Hypercholesterolemic Children

Background— Autosomal dominant hypercholesterolemia (ADH) is characterized by elevated low-density lipoprotein cholesterol levels and premature cardiovascular disease. Mutations in the genes encoding for low-density lipoprotein receptor ( LDLR ), apolipoprotein B ( APOB ), and proprotein convertase subtilisin/kexin 9 ( PCSK9 ) underlie ADH. Nevertheless, a proportion of individuals who exhibit the ADH phenotype do not carry mutations in any of these 3 genes. Estimates of the percentage of such cases among the ADH phenotype vary widely. We therefore investigated a large pediatric population with an unequivocal ADH phenotype to assess the molecular basis of hereditary hypercholesterolemia and to define the percentage of individuals with unexplained dyslipidemia. Methods and Results— We enrolled individuals with low-density lipoprotein cholesterol levels above the 95th percentile for age and gender and an autosomal dominant inheritance pattern of hypercholesterolemia from a large referred pediatric cohort of 1430 children. We excluded children with thyroid dysfunction, nephrotic syndrome, autoimmune disease, liver disease, primary biliary cirrhosis, and obesity (body mass index >75th percentile for age and gender), as well as children referred via a cascade screening program and those from families with a known molecular diagnosis. Of the 269 children who remained after the exclusion criteria were applied, 255 (95%) carried a functional mutation ( LDLR , 95%; APOB , 5%). Conclusion— In the vast majority of children with an ADH phenotype, a causative mutation can be identified, strongly suggesting that most of the large-effect genes underlying ADH are known to date. # Clinical Perspective {#article-title-30}Background— Autosomal dominant hypercholesterolemia (ADH) is characterized by elevated low-density lipoprotein cholesterol levels and premature cardiovascular disease. Mutations in the genes encoding for low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9) underlie ADH. Nevertheless, a proportion of individuals who exhibit the ADH phenotype do not carry mutations in any of these 3 genes. Estimates of the percentage of such cases among the ADH phenotype vary widely. We therefore investigated a large pediatric population with an unequivocal ADH phenotype to assess the molecular basis of hereditary hypercholesterolemia and to define the percentage of individuals with unexplained dyslipidemia. Methods and Results— We enrolled individuals with low-density lipoprotein cholesterol levels above the 95th percentile for age and gender and an autosomal dominant inheritance pattern of hypercholesterolemia from a large referred pediatric cohort of 1430 children. We excluded children with thyroid dysfunction, nephrotic syndrome, autoimmune disease, liver disease, primary biliary cirrhosis, and obesity (body mass index >75th percentile for age and gender), as well as children referred via a cascade screening program and those from families with a known molecular diagnosis. Of the 269 children who remained after the exclusion criteria were applied, 255 (95%) carried a functional mutation (LDLR, 95%; APOB, 5%). Conclusion— In the vast majority of children with an ADH phenotype, a causative mutation can be identified, strongly suggesting that most of the large-effect genes underlying ADH are known to date.

Integrated guidance on the care of familial hypercholesterolemia from the International FH Foundation

Familial hypercholesterolemia (FH) is a dominantly inherited disorder present from birth that markedly elevates plasma low-density lipoprotein cholesterol and causes premature coronary heart disease. There are at least 20 million people with FH worldwide, but the majority remains undetected, and current treatment is often suboptimal. To address this major gap in coronary prevention we present, from an international perspective, consensus-based guidance on the care of FH. The guidance was generated from seminars and workshops held at an international symposium. The recommendations focus on the detection, diagnosis, assessment, and management of FH in adults and children and set guidelines for clinical purposes. They also refer to best practice for cascade screening and risk notifying and testing families for FH, including use of genetic testing. Guidance on treatment is based on risk stratification, management of noncholesterol risk factors, and the safe and effective use of low-density lipoprotein-lowering therapies. Recommendations are given on lipoprotein apheresis. The use of emerging therapies for FH is also foreshadowed. This international guidance acknowledges evidence gaps but aims to make the best use of contemporary practice and technology to achieve the best outcomes for the care of FH. It should accordingly be used to inform clinical judgment and be adjusted for country-specific and local healthcare needs and resources.