Prevalence Of Heterozygous Familial Hypercholesterolemia Research Articles

Abstract 4136799: Disparities in Diagnosis and Treatment of Heterozygous Familial Hypercholesterolemia

Introduction: The prevalence of heterozygous familial hypercholesterolemia (HeFH) is 1:250. Untreated individuals have up to a 20-fold increased risk for premature coronary artery disease (CAD). In adults, low socioeconomic status (SES) individuals, bear a disproportionate share of the CAD burden. In this context, we sought to examine the association of social determinants of health and age at HeFH diagnosis and treatment. Methods: We performed a retrospective single-center study of children with HeFH who presented to the Lipid Heart Clinic at the Children’s Hospital of Philadelphia (2012-2022). The primary outcome was age at HeFH diagnosis. The secondary outcome was age at statin initiation. Multivariable linear regression models were used to examine the association between the primary exposure of interest, Child Opportunity Index (COI) and the outcomes. Secondary exposures included race, ethnicity, health insurance, and primary language. To explore potential referral bias, we compared the COI of the study cohort to that of the institution’s catchment area, defined as within a two-hour drive of the primary clinic. Results: We evaluated 577 patients. The median age at presentation was 12 (9, 14) years and the median LDL-C was 199 (169, 235) mg/dL; 58% were prescribed a statin with a median age of statin initiation of 13 (10, 15) years. The median COI for the cohort was 84 (62, 95). There was no association between COI, ethnicity, health insurance, or primary language and the age at HeFH diagnosis or statin initiation. On multivariable analysis, black race was associated with older age at HeFH diagnosis compared to white race (adjusted estimate 1.2 +/- 0.49 yrs, p = 0.014). There was no difference in age at statin initiation by race. Higher LDL-C, male sex, and lower BMI percentile were associated with younger age at statin initiation. The COI distribution of the study cohort was significantly different than that of the catchment area (p < 0.001). 70% of the study cohort were of high and very high COI compared to 57% of the catchment area. Conclusion: Black race was associated with older age at HeFH diagnosis, however, there were no disparities in age at statin initiation. The COI of the cohort was significantly higher than that of the catchment area suggesting that low COI populations are under-referred for HeFH evaluation. Future efforts should focus on improving barriers to universal screening and identifying obstacles to HeFH diagnosis and referrals.

Familijarna hiperholesterolemija i kaskadni skrining za detekciju novih pacijenata

Familial Hypercholesterolemia (FH) is a metabolic disorder that is inherited in an autosomal dominant manner and is characterized by elevated cholesterol levels and the development of premature atherosclerotic cardiovascular disease (ASCVD). The prevalence of heterozygous FH is 1 in 250-500 individuals, while the prevalence of homozygous FH is 1 in a million. The molecular basis of this condition involves mutations in the genes encoding the LDL receptor (Low-Density Lipoprotein Receptor, LDLR), Apolipoprotein B (ApoB), or Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) enzyme. In patients with FH, laboratory analyses are dominated by elevated levels of low-density lipoprotein cholesterol (LDL-C) above the 95th percentile for age and gender, with most commonly normal values of high-density lipoprotein cholesterol (HDL-C) in very low-density lipoprotein cholesterol (VLDL-C), and triglycerides. The gold standard for diagnosing FH is genetic analysis and mutation detection, but it is often inaccessible due to economic reasons. Today, the diagnosis is made by applying a scoring system within well-validated questionnaires, which assess the probability of FH based on the simultaneous analysis of personal and family history, clinical findings of tendon xanthomas or corneal arcus, as well as biochemical analysis of the lipid profile. Despite clear diagnostic recommendations for FH, there is an extremely low rate of diagnosis of these patients, even in developed healthcare systems, as well as a low rate of treatment. A large number of unrecognized FH patients, along with a significantly increased risk of cardiovascular diseases in untreated young FH patients, have prompted global efforts to diagnose the disease earlier and reduce complications through appropriate treatment. Cascade screening in the detection of new patients involves analyzing the relatives, first-, second-, and third-degree, of patients with known FH (index case, proband). Upon identifying a new case, that individual becomes the new proband, and their relatives are analyzed in subsequent cascades. There are three basic models of cascade screening: clinical, genetic, and hybrid models. Currently, selective clinical cascade screening is most commonly applied. Selective cascade screening detects the disease in individuals at high risk of its manifestation. The expert consensus panel recommends a hybrid model, where genetic testing is performed in all patients with definite or probable FH, and in cascade screening, both cholesterol levels and genetic analysis are continued in their high-risk relatives. Adequate detection of FH patients and timely treatment significantly reduce their cardiovascular morbidity and mortality, justifying the implementation of cascade screening. Conducting screening through routine clinical practice does not yield satisfactory results. Therefore, it is necessary to organize a screening program at the national level, including the establishment of lipidology centers and the provision of genetic screening and genetic counseling services.

The Prevalence of Heterozygous Familial Hypercholesterolemia among Adult Filipino Patients with Dyslipidemia at Universidad de Santa Isabel Health Services Department: An Observational Descriptive Prospective Study

The Prevalence of Heterozygous Familial Hypercholesterolemia among Adult Filipino Patients with Dyslipidemia at Universidad de Santa Isabel Health Services Department: An Observational Descriptive Prospective Study

Familial Hypercholesterolemia Prevalence Among Ethnicities-Systematic Review and Meta-Analysis.

Background: Heterozygous familial hypercholesterolemia (FH) is a common genetic disorder leading to premature cardiovascular disease and death as a result of lifelong high plasma low-density lipoprotein cholesterol levels, if not treated early in life. The prevalence of FH varies between countries because of founder effects, use of different diagnostic criteria, and screening strategies. However, little is known about differences in FH prevalence according to ethnicity. We aimed to investigate the ethnic distribution of FH in diverse populations and estimate the prevalence of FH according to ethnicity. Methods: We performed a systematic review and meta-analysis, searching PubMed and Web of Science for studies presenting data on the prevalence of heterozygous FH among different ethnicities in non-founder populations. Studies with more than 100 individuals, relevant data on prevalence, ethnicity, and using the Dutch Lipid Clinical Network Criteria, Simon Broome, Making Early Diagnosis Prevents Early Death, genetic screening, or comparable diagnostic criteria were considered eligible for inclusion. Results: Eleven general population studies and two patient studies were included in a systematic review and 11 general population studies in a random-effects meta-analysis. The overall pooled FH prevalence was 0.33% or 1:303 in 1,169,879 individuals (95% confidence interval: 0.26–0:40%; 1:385–1:250). Included studies presented data on six ethnicities: black, Latino, white, Asian, brown, and mixed/other. Pooled prevalence was estimated for each group. The highest prevalence observed was 0.52% or 1:192 among blacks (0.34–0.69%; 1:294–1:145) and 0.48% or 1:208 among browns (0.31–0.74%; 1:323–1:135) while the lowest pooled prevalence was 0.25% or 1:400 among Asians (0.15–0.35; 1:500–1:286). The prevalence was 0.37% or 1:270 among Latino (0.24–0.69%; 1:417–1:145), 0.31% or 1:323 among white (0.24–0.41%; 1:417–1:244), and 0.32% or 1:313 among mixed/other individuals (0.13–0.52%; 1:769–1:192). Conclusion: The estimated FH prevalence displays a variation across ethnicity, ranging from 0.25% (1:400) to 0.52% (1:192), with the highest prevalence seen among the black and brown and the lowest among the Asian individuals. The differences observed suggest that targeted screening among subpopulations may increase the identification of cases and thus the opportunity for prevention.

Prevalence of heterozygous familial hypercholesterolemia in patients with established atherosclerotic disease in the Colombian northeast

Background and Aims: The aim of the study was to establish the prevalence of Heterozygous familial hypercholesterolemia (HeFH) in patients with established atherosclerotic coronary and/or cerebrovascular disease, since in Colombia there are no such data nor data on the number of patients with established cardiovascular disease with this condition.

The prevalence of heterozygous familial hypercholesterolemia in selected regions of the Russian federation

The prevalence of heterozygous familial hypercholesterolemia in selected regions of the Russian federation

The Prevalence of Familial Hypercholesterolemia (FH) in Chinese Patients With Acute Myocardial Infarction (AMI): Data From Chinese Acute Myocardial Infarction (CAMI) Registry

Background: The prevalence of familial hypercholesterolemia (FH) in the patients with acute myocardial infarction (AMI) in China is unclear.Materials and Methods: In China Acute Myocardial Infarction (CAMI) Registry, 13,002 patients with age 18–80 were consecutively enrolled with first-onset AMI who were naïve to statin before admission from January 1st, 2013 to October 31st, 2014. According to Dutch Lipid Clinical Network Criteria (DLCNC), the patients were divided to heterozygous familial hypercholesterolemia (HeFH) (definite/probable HeFH, possible HeFH) or non-HeFH group.Results: The number of the patients in the three groups was as following, 62 in definite/probable HeFH group, 484 in possible HeFH group, 12,456 in non-HeFH group. The prevalence of HeFH is 4.2% (including 0.47% of definite/probable HeFH, 3.73% of possible FH). The average age of onset of first-time AMI was 54 ± 12, 56 ± 12, 63 ± 12 years old (p < 0.0001) in definite/probable HeFH group, possible HeFH group and non-HeFH group, respectively. The percentage of Killip III or above (8.1 vs. 4.3 vs. 6.3%, p = 0.1629), cardiac arrest (1.6 vs. 0.6 vs. 0.9%, p = 0.6990), and TIMI 0–2 grade after primary percutaneous cardiac intervention (PCI) (0 vs. 6.8 vs. 4.3%, p = 0.5866) was not significantly different in definite/probable HeFH group, possible HeFH group and non-HeFH group, respectively.Conclusions: The prevalence of HeFH in Chinese patients with AMI is 4.2%. The patients were significantly younger in HeFH group, when compared with those with non-HeFH. However, no significant differences were found in the severity of clinical manifestations in both HeFH and non-HeFH group.

Prevalence of Familial Hypercholesterolemia Among the General Population and Patients With Atherosclerotic Cardiovascular Disease: A Systematic Review and Meta-Analysis.

Contemporary studies suggest that familial hypercholesterolemia (FH) is more frequent than previously reported and increasingly recognized as affecting individuals of all ethnicities and across many regions of the world. Precise estimation of its global prevalence and prevalence across World Health Organization regions is needed to inform policies aiming at early detection and atherosclerotic cardiovascular disease (ASCVD) prevention. The present study aims to provide a comprehensive assessment and more reliable estimation of the prevalence of FH than hitherto possible in the general population (GP) and among patients with ASCVD. We performed a systematic review and meta-analysis including studies reporting on the prevalence of heterozygous FH in the GP or among those with ASCVD. Studies reporting gene founder effects and focused on homozygous FH were excluded. The search was conducted through Medline, Embase, Cochrane, and Global Health, without time or language restrictions. A random-effects model was applied to estimate the overall pooled prevalence of FH in the general and ASCVD populations separately and by World Health Organization regions. From 3225 articles, 42 studies from the GP and 20 from populations with ASCVD were eligible, reporting on 7 297 363 individuals/24 636 cases of FH and 48 158 patients/2827 cases of FH, respectively. More than 60% of the studies were from Europe. Use of the Dutch Lipid Clinic Network criteria was the commonest diagnostic method. Within the GP, the overall pooled prevalence of FH was 1:311 (95% CI, 1:250-1:397; similar between children [1:364] and adults [1:303], P=0.60; across World Health Organization regions where data were available, P=0.29; and between population-based and electronic health records-based studies, P=0.82). Studies with ≤10 000 participants reported a higher prevalence (1:200-289) compared with larger cohorts (1:365-407; P<0.001). The pooled prevalence among those with ASCVD was 18-fold higher than in the GP (1:17 [95% CI, 1:12-1:24]), driven mainly by coronary artery disease (1:16; [95% CI, 1:12-1:23]). Between-study heterogeneity was large (I2>95%). Tests assessing bias were nonsignificant (P>0.3). With an overall prevalence of 1:311, FH is among the commonest genetic disorders in the GP, similarly present across different regions of the world, and is more frequent among those with ASCVD. The present results support the advocacy for the institution of public health policies, including screening programs, to identify FH early and to prevent its global burden.

Statins for children with familial hypercholesterolemia.

Familial hypercholesterolemia is one of the most common inherited metabolic diseases and is an autosomal dominant disorder meaning heterozygotes, or carriers, are affected. Those who are homozygous have severe disease. The average worldwide prevalence of heterozygous familial hypercholesterolemia is at least 1 in 500, although recent genetic epidemiological data from Denmark and next generation sequencing data suggest the frequency may be closer to 1 in 250. Diagnosis of familial hypercholesterolemia in children is based on elevated total cholesterol and low-density lipoprotein cholesterol levels or DNA-based analysis, or both. Coronary atherosclerosis has been detected in men with heterozygous familial hypercholesterolemia as young as 17 years old and in women with heterozygous familial hypercholesterolemia at 25 years old. Since the clinical complications of atherosclerosis occur prematurely, especially in men, lifelong treatment, started in childhood, is needed to reduce the risk of cardiovascular disease. In children with the disease, diet was the cornerstone of treatment but the addition of lipid-lowering medications has resulted in a significant improvement in treatment. Anion exchange resins, such as cholestyramine and colestipol, were found to be effective, but they are poorly tolerated. Since the 1990s studies carried out on children aged 6 to 17 years with heterozygous familial hypercholesterolemia have demonstrated significant reductions in their serum total and low-density lipoprotein cholesterol levels. While statins seem to be safe and well-tolerated in children, their long-term safety in this age group is not firmly established. This is an update of a previously published version of this Cochane Review. To assess the effectiveness and safety of statins in children with heterozygous familial hypercholesterolemia. Relevant studies were identified from the Group's Inborn Errors and Metabolism Trials Register and Medline. Date of most recent search: 04 November 2019. Randomized and controlled clinical studies including participants up to 18 years old, comparing a statin to placebo or to diet alone. Two authors independently assessed studies for inclusion and extracted data. We found 26 potentially eligible studies, of which we included nine randomized placebo-controlled studies (1177 participants). In general, the intervention and follow-up time was short (median 24 weeks; range from six weeks to two years). Statins reduced the mean low-density lipoprotein cholesterol concentration at all time points (high-quality evidence). There may be little or no difference in liver function (serum aspartate and alanine aminotransferase, as well as creatinine kinase concentrations) between treated and placebo groups at any time point (low-quality evidence). There may be little or no difference in myopathy (as measured in change in creatinine levels) (low-quality evidence) or clinical adverse events (moderate-quality evidence) with statins compared to placebo. One study on simvastatin showed that this may slightly improve flow-mediated dilatation of the brachial artery (low-quality evidence), and on pravastatin for two years may have induced a regression in carotid intima media thickness (low-quality evidence). No studies reported rhabdomyolysis (degeneration of skeletal muscle tissue) or death due to rhabdomyolysis, quality of life or compliance to study medication. Statin treatment is an effective lipid-lowering therapy in children with familial hypercholesterolemia. Few or no safety issues were identified. Statin treatment seems to be safe in the short term, but long-term safety remains unknown. Children treated with statins should be carefully monitored and followed up by their pediatricians and their care transferred to an adult lipidologist once they reach 18 years of age. Large long-term randomized controlled trials are needed to establish the long-term safety issues of statins.

CC1 COST-EFFECTIVENESS OF SCREENING AND TREATING CHILDREN WITH FAMILIAL HYPERCHOLESTEROLEMIA EARLY IN LIFE FROM A DUTCH HEALTHCARE PERSPECTIVE

Studies have shown that atherosclerosis in heterozygous familial hypercholesterolemia (HeFH) starts at birth and is reversible in childhood. Hitherto no economic evaluation has shown the impact of screening and early treatment in children with HeFH. We investigated the impact and cost-effectiveness of offering screening and preventive treatment to children with HeFH from the perspective of the Dutch healthcare. Screening and preventive treatment with statins was modelled to simulate the progression of ten-year olds suspected of having HeFH over a lifetime. The model consisted of three health states (alive without coronary heart disease (CHD), alive with CHD, and dead). The prevalence of HeFH in this target population was 54.13%, and the sensitivity and specificity of testing was 100%. The decision tree consisted of confirmation and immediate treatment with statins, and the comparator was usual care. Mendellian-Randomisation-Analysis data was used to understand the lifelong exposure to elevated low-density-lipoprotein- cholesterol. Costs and outcome data was sourced from the Dutch registry and other published sources. Cost-effectiveness was defined as below €20,000/QALY (quality-adjusted life years) gained, using incremental cost-effectiveness ratios (ICERs), compared with usual care. All future benefits and costs were discounted annually by 1.5% and 4% respectively. Screening and early treatment at age 10 years compared with usual care would save 4.22 life years gained (LYG) and 4.13 QALYs per person (undiscounted). Discounted results showed that an initiation of treatment at age 10 years compared with usual care was predicted to achieve 2.18 LYG and 2.22 QALYs gained per person, at an additional cost of €8,617. These equated to ICERs of €3957 per LYG gained and €3880 per QALY gained. Screening and initiation of statins in children with HeHF from age 10 years is highly cost-effective over a lifetime. Our findings and conclusion are conditional on the assumptions inherent in our health economic model.

P848Prevalence and Prognosis of Familial Hypercholesterolemia (FH) with Acute Myocardial Infarction (AMI) in China: Chinese Acute Myocardial Infarction (CAMI) Registry

Abstract Background The prevalence and prognosis of familial hypercholesterolemia (FH) with acute myocardial infarction (AMI) in China is unclear. Purpose To invistigate the prevalence and prognosis of familial hypercholesterolemia (FH) with acute myocardial infarction (AMI) in China. Methods In China Acute Myocardial Infarction (CAMI) Registry, 13,002 patients with age 18–80 were consecutively enrolled with first-onset acute myocardial infarction who were naïve to statin before admission from Januanry 1st, 2013 to October 31st, 2014. According to Dutch Lipid Clinical Network Criteria (DLCNC), the patients were divided to heterozygous familial hypercholesterolemia (HeFH) (definite or probable HeFH, possible HeFH) or no HeFH group. All the patients were followed up (average follow-up period, 24 months) and composite major adverse cardiovascular events (ENDPOINT) were recorded which were defined as all-cause death, non-fatal myocardial reinfarction and stroke. Cox regression was performed to analyze the difference of composite endpoint occurrence between HeFH group and no HeFH group. Results The number of the patients in the three groups was as following, 62 in definite or probable HeFH group, 484 in possible HeFH group, 12456 in no HeFH group. The prevalence of HeFH is 4.2% (including 0.47% of definite or probable HeFH, 3.73% of possible FH). The average age of onset of first-time AMI was 54±12,56±12,63±12 years old (p&lt;0.0001) in definite or probable HeFH group, possible HeFH group and no HeFH group, respectively. The percentage of Killip III or above (8.1% vs 4.3% vs 6.3%, p=0.1629), cardiac arrest (1.6% vs 0.6% vs 0.9%, p=0.6990), and TIMI 0–2 grade after primary percutaneous cardiac intervention (PCI) (0% vs 6.8% vs 4.3%, p=0.5866) was not significantly different in definite or probable HeFH group, possible HeFH group and no HeFH group, respectively. After Cox proportional analysis adjusting multiple factors, the rate of composite endpoint during follow-up period was not significantly different (definite or probable HeFH group vs no HeFH group, HR 0. 853, 95% CI 0.381–1.910, p=0.699, possible HeFH group vs no HeFH group, HR1.076, 95% CI 0.795–1.458, p=0.635). The prognosis of FH with AMI in China Conclusions In CAMI Registry, the prevalence of HeFH was 4.2%, the diagnosis of HeFH was not a dependent risk factor for the rate of composite cardiovascular events.

Prediction of Familial Hypercholesterolemia in Patients at High Atherosclerotic Cardiovascular Disease Risk Using a Recently Validated Algorithm

BackgroundThe prevalence of heterozygous familial hypercholesterolemia (FH) is 1 of 250 in the general population and approximately 1 of 125 in patients with atherosclerotic cardiovascular disease (ASCVD), yet only a minority are diagnosed. The diagnostic criteria for FH rely on a point system using low-density lipoprotein cholesterol (LDL-C), family history, cutaneous manifestations, and molecular diagnosis. The aim of the present study was to determine the prevalence of FH in the Relating Evidence to Achieve Cholesterol Targets (REACT) registry. MethodsPatients were enrolled as ASCVD (n = 86) or FH (n = 109) and with an LDL-C level > 3.0 mmol/L despite maximally tolerated statin therapy. FH was diagnosed clinically using a validated clinical application integrating an imputation for baseline (untreated) LDL-C levels. ResultsThere were 109 men and 86 women with a mean age of 63 ± 12 years. Diabetes (29.7%), hypertension (62.1%), smoking (37.9%), and family history of premature ASCVD (59.5%) were common. On-treatment LDL-C was 4.26 ± 0.94 mmol/L. On the basis of the dose and type of statin ± ezetimibe, imputed baseline LDL-C was 7.04 ± 2.90 mmol/L. A diagnosis of probable/definite FH was found in 54.7%, 49.5%, and 61.5% of patients according to the Simon Broome, Dutch Lipid Clinic Network criteria, and the new Canadian FH definition, respectively. Of note, 40% of patients in the ASCVD inclusion subgroup had probable or definite FH. ConclusionsOur study reveals that a substantial proportion of patients with ASCVD whose LDL-C levels are > 3.0 mmol/L despite maximally tolerated statins have heterozygous FH. Clinicians should consider using the recently described algorithm to assess the possibility of FH in this high-risk population.

Functional analysis of new variants at the low-density lipoprotein receptor associated with familial hypercholesterolemia.

Familial hypercholesterolemia is an autosomal dominant disease of lipid metabolism caused by defects in the genes LDLR, APOB, and PCSK9. The prevalence of heterozygous familial hypercholesterolemia (HeFH) is estimated between 1/200 and 1/250. Early detection of patients with FH allows initiation of treatment, thus reducing the risk of coronary heart disease. In this study, we performed in vitro characterization of new LDLR variants found in our patients. Genetic analysis was performed by Next Generation Sequencing using a customized panel of 198 genes in DNA samples of 516 subjects with a clinical diagnosis of probable or definitive FH. All new LDLR variants found in our patients were functionally validated in CHO-ldlA7 cells. The LDLR activity was measured by flow cytometry and LDLR expression was detected by immunofluorescence. Seven new variants at LDLR were tested: c.518 G>C;p.(Cys173Ser), c.[684 G>T;694 G>T];p.[Glu228Asp;Ala232Ser], c.926C>A;p.(Pro309His), c.1261A>G;p.(Ser421Gly), c.1594T>A;p.(Tyr532Asn), and c.2138delC;p.(Thr713Lysfs*17). We classified all variants as pathogenic except p.(Ser421Gly) and p.(Ala232Ser). The functional in vitro characterization of rare variants at the LDLR is a useful tool to classify the new variants. This approach allows us to confirm the genetic diagnosis of FH, avoiding the classification as "uncertain significant variants", and therefore, carry out cascade family screening.

Prevalence of heterozygous familial hypercholesterolemia and combined hyperlipidemia phenotype in very young survivors of myocardial infarction and their association with the severity of atheromatous burden

Heterozygous familial hypercholesterolemia (HeFH) and combined hyperlipidemia (CHL) phenotype are associated with premature myocardial infarction (MI). To assess the prevalence of HeFH and CHL phenotype among young survivors of MI and compare patients' characteristics with these 2 lipid disorders. We recruited 382 young survivors of MI (≤40years). Fasting lipids, lipoprotein(a) [Lp(a)], apolipoprotein A-1, and apolipoprotein B (apoB) levels were determined. Using the Dutch Lipid Clinic Network (DLCN) algorithm, patients having definite or probable HeFH were identified. Patients with apoB levels >120mg/dL and triglyceride levels >170mg/dL (1.92mmol/L) [>90th percentile of 326 age and sex-matched healthy controls] were classified as having CHL phenotype. Common carotid artery intima-media thickness (CCA-IMT) was measured by B-mode ultrasonography. Eighty-one patients (21.2%) had definite/probable HeFH and 62 (16.2%) had CHL phenotype. Twenty-three patients fulfilled the criteria for both HeFH and CHL phenotype and were removed from further comparisons. Patients with HeFH (n=58) had higher levels of total cholesterol, low-density lipoprotein (LDL)-cholesterol, Lp(a), and apoB, whereas patients with CHL phenotype (n=39) had higher levels of triglycerides and lower high-density lipoprotein (HDL)-cholesterol levels. The prevalence of metabolic syndrome was higher in patients with CHL phenotype compared to those with HeFH (67.0% vs 16.4%, P<.001). Patients with HeFH had more extensive coronary artery disease (3-vessel disease: 36.2% vs 12.8%, P=.011) and greater right CCA-IMT (0.67±0.11mm vs 0.56±0.09mm, P<.001) and left CCA-IMT (0.68±0.10mm vs 0.56±0.08mm, P<.001) compared to CHL phenotype patients. Both HeFH and CHL phenotype are common among patients with premature MI. CHL phenotype compared to HeFH is associated with less atheromatous burden in coronary and carotid arteries at the time of first MI.

Detection of the benign c.2579C>T (p.A860V) variant of the LDLR gene in a pedigree-based genetic analysis of familial hypercholesterolemia

More than 2500 variants of the low-density lipoprotein receptor (LDLR) gene have been reported in familial hypercholesterolemia (FH). However, the effects of these variants on the pathophysiology of FH have not been fully clarified. Our aim was to examine whether the c.2579C>T (p.A860V) variant of the LDLR gene affects the phenotype of FH. We present 2 index cases harboring biallelic LDLR variants, including the c.2579C>T (p.A860V) variant, which is defined as having uncertain significance in ClinVar. Genetic analysis was performed for coding regions of the LDLR and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes in 2 families. Detailed clinical and biochemical data were gathered from family members. In one family, the index case involved a patient who harbored biallelic A860V and c.1528-1529insA (p.T510Nfs) LDLR variants and had 8 children; the affected children had the p.T510Nfs variant, and the unaffected children had the A860V variant. In another family, the patient involved in the index case and his sister had biallelic A860V and c.1845+2T>C LDLR variants. There was no difference in FH phenotype between these siblings and their relatives who were heterozygous for the c.1845+2T>C variant. In addition, the allele frequency of the A860V variant (0.0062/0.0095) in the Japanese population, as indicated by 2 databases, was higher than expected based on the prevalence of heterozygous FH in the Japanese population (0.002-0.005). This is the first report to show using pedigree-based genetic analysis that the A860V variant of the LDLR gene is a benign variant.

Severe xanthomatosis in heterozygous familial hypercholesterolemia

Familial hypercholesterolemia is a genetic lipoprotein disorder characterized by elevated plasma low-density lipoprotein cholesterol level, (tendinous xanthomas, xanthelasmas, and premature arcus corneus) and early onset atherosclerotic cardiovascular disease. Familial hypercholesterolemia is caused by mutations in the low-density lipoprotein receptor, apolipoprotein B or proprotein convertase subtilisin/kexin type 9 genes. Rare mutations in low-density lipoprotein receptor adapter protein 1, APOE p.Leu167del or lysosomal acid lipase genes can mimic FH. The prevalence of heterozygous familial hypercholesterolemia is estimated to be 1/250 worldwide, although some populations with founder effects show a higher prevalence. The rare homozygous form has an estimated prevalence of 0.000004 or 1/250,000 and is characterized by markedly elevated low-density lipoprotein cholesterol, skin manifestations (planar xanthomas, tendinous xanthomas) in childhood and extremely premature atherosclerotic cardiovascular disease. While tendinous xanthomas are considered pathognomonic for familial hypercholesterolemia, they can also be found in rare diseases, including sitosterolemia. Here, we report a case of severe tendinous xanthomatosis with heterozygous familial hypercholesterolemia due to the low-density lipoprotein receptor del >15 kb mutation. The phenotypic expression of the disease is out of proportion with the genetic diagnosis or biochemical measurements. We report the case of 51-year-old woman of French-Canadian origin diagnosed with heterozygous familial hypercholesterolemia since age 12. She presented with hypercholesterolemia with total cholesterol 7.6 mmol/L, with an imputed low-density lipoprotein cholesterol level of 6.5 mmol/L. She had extensive tendinous xanthomas of the Achilles tendons, knees, elbows and metacarpophalangeal joints. Because of cosmetic disfigurement, she had multiple excisions of Achilles, knee and elbow xanthomas, albeit with rapid recurrence. Our patient has a significant family history of lung cancer and other autoimmune diseases associated with familial hypercholesterolemia and xanthoma. Lipid-lowering therapy was started, at age 12; which included initially cholestyramine, then changed to statin and ezetimibe. Eventually, evolocumab was added. Despite trying different lipid-lowering therapy, there has been no noticeable decrease in the size of the xanthomas. Our patient has severe xanthomatosis out of proportion with the genetic diagnosis or biochemical measurements. Her xanthomatosis did not improve by pharmacological therapy consisting of statins and evolocumab despite a 50% reduction in low-density lipoprotein cholesterol. It is likely that the patient presented here has a second genetic disorder that leads to extensive xanthomatosis.

Abstract 9: Alirocumab Prior Authorization Approval and Prescription Fill Rates Among Medicare Advantage Patients in a Large US Managed Care Plan

Introduction: Alirocumab is a proprotein convertase subtilisin/ kexin type 9 (PCSK9) inhibitor approved as an adjunct to diet and maximally tolerated statin therapy for treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease who require additional lowering of LDL-cholesterol. Barriers to possession, including therapy cost and cost-sharing implications, may contribute to low utilization of this therapy. Objective: To explore differences in demographic and clinical characteristics between patients with prior authorization (PA) approvals or denials for alirocumab as evidenced through filled alirocumab prescription claims. Methods: A retrospective claims-based database analysis of patients with a Medicare Advantage Prescription Drug (MAPD) plan was conducted to identify patients with evidence of a PA approval for alirocumab. Among the group of patients with a PA for alirocumab, the pharmacy claims database was searched for evidence of a corresponding prescription claim within 30 days following the first PA request (index date). The analysis was stratified by evidence of Federal low income subsidy (LIS) support, a program that provides extra assistance with prescription drug costs for eligible individuals whose income and resources are limited, and/ or dual eligibility (DE) status, eligible for Medicare and Medicaid, (LIS/DE) at index. Results: A total of 2,098 MAPD patients meeting study inclusion/exclusion criteria and with a PA for alirocumab were identified between March 1, 2016 and February 28, 2017. Non-LIS/DE patients comprised approximately 82% of the eligible population (n=1,730). There were several notable differences in baseline demographics between the non-LIS/DE vs. the LIS/DE cohorts with an approved PA claim, including Deyo-Charlson Comorbidity Index (2.2 vs. 3.0), prevalence of diabetes mellitus (39.2% vs. 54.7%), and prevalence of HeFH (11.8% vs. 15.6%). While the percentage of patients with an approved PA was similar between the LIS/DE and non-LIS/DE cohorts, 88.9% and 91.2%, respectively, substantially more patients in the LIS/DE cohort had evidence of alirocumab possession based on a paid claim (60.6%) vs. those in the non-LIS/DE cohort (17.3%). Conclusion: Although a high percentage of MAPD patients had evidence of an approved PA, there were notable differences in clinical and demographic characteristics between those with and without LIS/ DE status. Further, the proportion of patients with an approved PA and a paid prescription claim differed markedly amongst MAPD patients with and without LIS/DE status, suggesting further research is needed to understand potential barriers to obtaining PCSK9i therapy.

Genetics of familial hypercholesterolemia in patients recruited from epidemiological study

Aim: Familial hypercholesterolemia (FH) is an autosomal-dominant disorder caused by mutations in 1 of 3 genes. A definitive diagnosis of FH can be made by the demonstration of a pathogenic mutation. The prevalence of heterozygous FH is 0.2%–0.5%, which is now considered to be underestimated. In the patients who are mutation negative, the clinical phenotype can be associated with an accumulation of common small-effect LDL cholesterol (LDL-C)-raising alleles. The aims of the study were to investigate the genetic causes of high LDL-C levels in patients with familial hypercholesterolemia identified in epidemiological study.

The prevalence of heterozygous familial hypercholesterolemia in the Russian Federation: A substudy of the ESSE-Rf

The prevalence of heterozygous familial hypercholesterolemia in the Russian Federation: A substudy of the ESSE-Rf

Statins for children with familial hypercholesterolemia.

Familial hypercholesterolemia is one of the most common inherited metabolic diseases and is an autosomal dominant disorder meaning heterozygotes, or carriers, are affected. Those who are homozygous have severe disease. The average worldwide prevalence of heterozygous familial hypercholesterolemia is at least 1 in 500, although recent genetic epidemiological data from Denmark and next generation sequencing data suggest the frequency may be closer to 1 in 250. Diagnosis of familial hypercholesterolemia in children is based on elevated total cholesterol and low-density lipoprotein cholesterol levels or DNA-based analysis, or both. Coronary atherosclerosis has been detected in men with heterozygous familial hypercholesterolemia as young as 17 years old and in women with heterozygous familial hypercholesterolemia at 25 years old. Since the clinical complications of atherosclerosis occur prematurely, especially in men, lifelong treatment, started in childhood, is needed to reduce the risk of cardiovascular disease. In children with the disease, diet was the cornerstone of treatment but the addition of lipid-lowering medications has resulted in a significant improvement in treatment. Anion exchange resins, such as cholestyramine and colestipol, were found to be effective, but they are poorly tolerated. Since the 1990s studies carried out on children aged 6 to 17 years with heterozygous familial hypercholesterolemia have demonstrated significant reductions in their serum total and low-density lipoprotein cholesterol levels. While statins seem to be safe and well-tolerated in children, their long-term safety in this age group is not firmly established. This is an update of a previously published version of this Cochane Review. To assess the effectiveness and safety of statins in children with heterozygous familial hypercholesterolemia. Relevant studies were identified from the Group's Inborn Errors and Metabolism Trials Register and Medline.Date of most recent search: 20 February 2017. Randomized and controlled clinical studies including participants up to 18 years old, comparing a statin to placebo or to diet alone. Two authors independently assessed studies for inclusion and extracted data. We found 26 potentially eligible studies, of which we included nine randomized placebo-controlled studies (1177 participants). In general, the intervention and follow-up time was short (median 24 weeks; range from six weeks to two years). Statins reduced the mean low-density lipoprotein cholesterol concentration at all time points (moderate quality evidence). Serum aspartate and alanine aminotransferase, as well as creatinine kinase concentrations, did not differ between treated and placebo groups at any time point (low quality evidence). The risks of myopathy (low quality evidence) and clinical adverse events (moderate quality evidence) were very low and also similar in both groups. In one study simvastatin was shown to improve flow-mediated dilatation of the brachial artery (low quality evidence), and in another study treatment with pravastatin for two years induced a significant regression in carotid intima media thickness (low quality evidence). Statin treatment is an effective lipid-lowering therapy in children with familial hypercholesterolemia. No significant safety issues were identified. Statin treatment seems to be safe in the short term, but long-term safety remains unknown. Children treated with statins should be carefully monitored and followed up by their pediatricians and their care transferred to an adult lipidologist once they reach 18 years of age. Large long-term randomized controlled trials are needed to establish the long-term safety issues of statins.