scholarly journals Improving Familial Hypercholesterolemia Index Case Detection: Sequential Active Screening from Centralized Analytical Data

2021 ◽  
Vol 10 (4) ◽  
pp. 749
Author(s):  
Fernando Sabatel-Pérez ◽  
Joaquín Sánchez-Prieto ◽  
Víctor Manuel Becerra-Muñoz ◽  
Juan Horacio Alonso-Briales ◽  
Pedro Mata ◽  
...  
Keyword(s):  
Familial Hypercholesterolemia ◽  
Diagnostic Yield ◽  
Low Density Lipoprotein ◽  
Analytical Data ◽  
Genetic Diagnosis ◽  
Density Lipoprotein ◽  
Screening Strategy ◽  
Cascade Screening ◽  
Active Screening ◽  
Lipid Clinic

The majority of familial hypercholesterolemia index cases (FH-IC) remain underdiagnosed and undertreated because there are no well-defined strategies for the universal detection of FH. The aim of this study was to evaluate the diagnostic yield of an active screening for FH-IC based on centralized analytical data. From 2016 to 2019, a clinical screening of FH was performed on 469 subjects with severe hypercholesterolemia (low-density lipoprotein cholesterol ≥220 mg/dL), applying the Dutch Lipid Clinic Network (DLCN) criteria. All patients with a DLCN ≥ 6 were genetically tested, as were 10 patients with a DLCN of 3–5 points to compare the diagnostic yield between the two groups. FH was genetically confirmed in 57 of the 84 patients with DLCN ≥ 6, with a genetic diagnosis rate of 67.9% and an overall prevalence of 12.2% (95% confidence interval: 9.3% to 15.5%). Before inclusion in the study, only 36.8% (n = 21) of the patients with the FH mutation had been clinically diagnosed with FH; after genetic screening, FH detection increased 2.3-fold (p < 0.001). The sequential, active screening strategy for FH-IC increases the diagnostic yield for FH with a rational use of the available resources, which may facilitate the implementation of FH universal and family-based cascade screening strategies.

scholarly journals PCSK9 Inhibitors in a Statin-Intolerant Transgender Man With Heterozygous Familial Hypercholesterolemia: A Case Report

2019 ◽  
Vol 3 (8) ◽  
pp. 1461-1464 ◽  
Author(s):  
Carlo Pirazzi ◽  
Federica Tavaglione ◽  
Åsa Tivesten ◽  
Stefano Romeo
Keyword(s):  
Familial Hypercholesterolemia ◽  
Low Density Lipoprotein ◽  
Genetic Diagnosis ◽  
Density Lipoprotein ◽  
Statin Treatment ◽  
Lipoprotein Cholesterol ◽  
Pcsk9 Inhibitors ◽  
Pcsk9 Inhibitor ◽  
Lipid Clinic ◽  
High Doses

Abstract In female-to-male transgender individuals, testosterone is used to induce masculinization. Sex steroid therapy may increase circulating triglyceride and low-density lipoprotein cholesterol (LDL-C) levels and may decrease high-density lipoprotein cholesterol (HDL-C) levels, resulting in a more atherogenic lipid profile. These potentially adverse effects of androgen therapy may be exacerbated by the presence of familial hypercholesterolemia (FH). We describe the case of a transgender man with genetically diagnosed FH who was intolerant to statins and was started on a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor to control his lipoproteins more effectively. The 35-year-old female-to-male transgender individual was referred to our center with a history of elevated LDL-C levels. Despite treatment with high doses of high-potency statins and ezetimibe, he had never achieved a sustained reduction in LDL-C; his levels of LDL-C were fluctuating between 170 and 344 mg/dL (4.4 and 8.9 mmol/L). Moreover, he developed side effects to statins in the form of myalgia and discontinued statin treatment. At the Sahlgrenska Lipid Clinic, a genetic diagnosis of heterozygous FH was established, and PCSK9 inhibitor therapy was started. The patient’s LDL-C level has been reduced by approximately 40% for 23 months, and no adverse events have been reported.

scholarly journals Familial Hypercholesterolemia (FH) in Iran: Findings from the Four-Year FH Registry

2021 ◽  
Vol 2021 ◽  
pp. 1-6
Author(s):  
Golnaz Vaseghi ◽  
Marzieh Taheri ◽  
Kiyan Heshmat-Ghahdarijani ◽  
Mohammad Rayati ◽  
Sonia Zarfeshani ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Familial Hypercholesterolemia ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Degree Relative ◽  
Cascade Screening ◽  
Lipid Clinic ◽  
Premature Cardiovascular Disease ◽  
Dominant Disease ◽  
Laboratory Group

Background. Familial hypercholesterolemia (FH) is a common autosomal dominant disease. Its diagnosis in Iran was uncommon. Iran registry of FH (IRFH) has been started from 2017 from Isfahan. In this study, we report the four-year FH registry. Methods. The Iran FH registry is an ongoing study which is followed by a dynamic cohort. It has been started from 2017. The patients are selected from laboratories due to high cholesterol level and who have history of premature cardiovascular disease. The Dutch Lipid Clinic Network (DLCN) criteria are used for the detection of FH. Cascade screening is performed for detection of first-degree relative of patients. Results. Among the 997 individuals included in this registry, they were 522 (mean age 51.41 ± 12.91 year), 141 (mean age 51.66 ± 8.3 year), and 129 (mean age 41 ± 16.5 year) patients from laboratories, premature cardiovascular disease, and relatives, respectively. In total, 263 patients were diagnosed with probable or definite FH, and others were in the possible group. Low-density lipoprotein cholesterol (LDL) level was 141.42 ± 45.27   mg / dl in the laboratory group and 54.9% of patients were on LLT treatment. In patients with premature cardiovascular disease and FH, the LDL level was 91.93 ± 32.58 and was on LLT treatment. The LDL concentration in the first relative of FH patients was 152.88 ± 70.77 and 45.7% of them are on LLT therapy. Conclusions. Most of FH patients were underdiagnosed and undertreated before their inclusion in the IRFH. Cascade screening helps in the improvement of diagnosis.

Estimated Prevalence of Familial Hypercholesterolemia Among Egyptian Patients with Acute Coronary Syndromes; Analysis from The Cardiorisk Project

2021 ◽  
Vol 23 (Supplement_D) ◽  
Author(s):  
Ashraf Reda ◽  
Ahmed Bendary ◽  
Ahmed Shawky Elserafy ◽  
Elsayed Farag ◽  
Tamer Mostafa ◽  
...  
Keyword(s):  
Familial Hypercholesterolemia ◽  
Acute Coronary Syndromes ◽  
Total Population ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Cross Sectional ◽  
Lipid Clinic ◽  
Egyptian Patients ◽  
Coronary Syndromes ◽  
Premature Cad

Abstract Aims The prevalence of familial hypercholesterolemia (FH) in Egypt is largely un- known. We aimed to estimate the prevalence of FH among 3224 Egyptian patients with acute coronary syndromes enrolled from 2015 to 2018 in the nationwide cross- sectional cardioRisk project. Methods and Results We applied the Dutch Lipid Clinic criteria for the diagnosis of FH on the available data recorded for the patients enrolled in the CardioRisk project. Two main criteria were applied: the presence of premature CAD (given 2 points in the Dutch criteria), and the categorized low density lipoprotein cholesterol (LDL-C) lev- els (given 1, 3, 5, or 8 points in the Dutch criteria according to the level). From a total of 3224 patients, 2743 patients had available LDL-C levels. Among those patients, when applying the abovementioned 2 criteria, we estimated that 472 patients had at least ‘possible’ FH (17.2% of the total population). Specifically, 4 patients had ‘defi- nite’ FH (0.1%), 7 patients had ‘probable’ FH (0.25%), and 461 patients had ‘possi- ble’ FH (16.8%). Conclusion The estimated prevalence of at least ‘possible’ FH among Egyptian patients with ACS is 17%.

Abstract 14681: Comparative Study Between International Guidelines in Detecting Pediatric Familial Hypercholesterolemia Through a Unique Community Health System in Kagawa, Japan

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Keiji Matsunaga ◽  
Asako Mizobuchi ◽  
Hayato Tada ◽  
Tsuyoshi Sasaki ◽  
Yoshihiro Asano ◽  
...  
Keyword(s):  
Health System ◽  
Community Health ◽  
Familial Hypercholesterolemia ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Hereditary Disease ◽  
International Guidelines ◽  
Number Of Children ◽  
Lipid Clinic ◽  
Lipid Screening

Introduction: Familial hypercholesterolemia (FH) is an autosomal hereditary disease found in patients who have elevated low-density lipoprotein cholesterol (LDL-C) from birth. Early detection and treatment of FH during childhood potentially reduces the risk of premature cardiovascular events. In Kagawa prefecture, a unique community health system, involving three steps, has been conducted to prevent lifestyle-related diseases for 10-year-old children. This system includes universal lipid screening, selection by pediatricians, and next-generation sequencing (NGS) of FH-related genes in hospitals. The aim of this study is to compare 3 international guidelines to detect pediatric FH with this unique community health system in Kagawa. Methods: In Kagawa prefecture, the universal lipid screening of approximately 8,000 children at 10 years of age is performed annually, covering over 90% of the target group. After excluding secondary hypercholesterolemia, pediatric clinics introduced children with LDL-C >140mg/dL to 4 designated hospitals to perform NGS. We applied the guidelines of the Dutch Lipid Clinic Network (DLCN), Simon Broome (SB), and the Japanese Atherosclerosis Society (JAS) to children who received NGS in the unique community health system in Kagawa. Results: We performed NGS for 46 children from January 2018 to February 2020 (LDL-C 186.0±50.3 mg/dL; Male/F 27/19) and 26 (57%) had FH genetic mutations (23 LDL-R and 3 PCSK9 mutations). Seventeen children met FH criteria for DLCN (35%), 10 for Simon Broome (22%), and 11 for JAS (24%), respectively. The combination of NGS and either of the 3 guidelines increased the number of children diagnosed as FH up to 31 (67%). Conclusion: International guidelines detected only half of pediatric FH who were diagnosed by the unique community health system in Kagawa. Further investigation will be required to build an effective universal screening system for pediatric FH.

Differences in phenotype, genotype and cardiovascular events between patients with probable and definite heterozygous familial hypercholesterolemia

2019 ◽  
Vol 16 (6) ◽  
pp. 467-478
Author(s):  
Ye-Xuan Cao ◽  
Bing-Yang Zhou ◽  
Di Sun ◽  
Sha Li ◽  
Yuan-Lin Guo ◽  
...  
Keyword(s):  
Familial Hypercholesterolemia ◽  
Cardiovascular Events ◽  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Survival Rates ◽  
Gene Mutations ◽  
Density Lipoprotein ◽  
Heterozygous Familial Hypercholesterolemia ◽  
Lipid Clinic ◽  
Kaplan Meier

Aim: To investigated the potential differences between probable and definite heterozygous familial hypercholesterolemia (HeFH) patients diagnosed by Dutch Lipid Clinic Network criteria. Methods: Clinical characteristics, lipid profile, severity of coronary artery stenosis and gene mutations were compared. Kaplan–Meier curve was performed to evaluate the cardiovascular events. Results: Overall, 325 participants were included and divided into two groups: probable (n = 233) and definite HeFH (n = 92). Definite HeFH patients had higher low-density lipoprotein cholesterol (LDL-C), oxidized-LDL and proprotein convertase subtilisin/kexin 9 levels, and higher prevalence of tendon xanthomas. The incidence of genetic mutations was statistically higher in definite HeFH than probable HeFH patients. The coronary stenosis calculated by Gensini score was statistically severer in definite HeFH patients. The best LDL-C threshold for predicting mutations was 5.14 mmol/l. Definite HeFH had lower event-free survival rates. Conclusion: Definite HeFH patients had higher severity of phenotype and genotype, and higher risk of cardiovascular events.

scholarly journals Two Novel Disease-Causing Mutations in the LDLR of Familial Hypercholesterolemia

2021 ◽  
Vol 12 ◽  
Author(s):  
Haochang Hu ◽  
Tian Shu ◽  
Jun Ma ◽  
Ruoyu Chen ◽  
Jian Wang ◽  
...  
Keyword(s):  
Familial Hypercholesterolemia ◽  
High Throughput Sequencing ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Bioinformatic Analysis ◽  
Genetic Mutations ◽  
Missense Mutations ◽  
Autosomal Dominant Disorder ◽  
Lipid Clinic

As an autosomal dominant disorder, familial hypercholesterolemia (FH) is mainly caused by pathogenic mutations in lipid metabolism-related genes. The aim of this study is to investigate the genetic mutations in FH patients and verify their pathogenicity. First of all, a pedigree investigation was conducted in one family diagnosed with FH using the Dutch Lipid Clinic Network criteria. The high-throughput sequencing was performed on three family members to explore genetic mutations. The effects of low-density lipoprotein receptor (LDLR) variants on their expression levels and activity were further validated by silico analysis and functional studies. The results revealed that LDLC levels of the proband and his daughter were abnormally elevated. The whole-exome sequencing and Sanger sequencing were used to confirm that there were two LDLR missense mutations (LDLR c.226 G &gt; C, c.1003 G &gt; T) in this family. Bioinformatic analysis (Mutationtaster) indicated that these two mutations might be disease-causing variants. In vitro experiments suggested that LDLR c.226 G &gt; C and c.1003 G &gt; T could attenuate the uptake of Dil-LDL by LDLR. In conclusion, the LDLR c.226 G &gt; C and c.1003 G &gt; T variants might be pathogenic for FH by causing uptake dysfunction of the LDLR.

scholarly journals The Prevalence of Heterozygous Familial Hypercholesterolemia in Selected Regions of the Russian Federation: The FH-ESSE-RF Study

2021 ◽  
Vol 11 (6) ◽  
pp. 464
Author(s):  
Alexey N. Meshkov ◽  
Alexandra I. Ershova ◽  
Anna V. Kiseleva ◽  
Svetlana A. Shalnova ◽  
Oxana M. Drapkina ◽  
...  
Keyword(s):  
Familial Hypercholesterolemia ◽  
Russian Federation ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density Lipoprotein Cholesterol ◽  
Pcsk9 Inhibitor ◽  
Heterozygous Familial Hypercholesterolemia ◽  
Lipid Clinic ◽  
The Russian Federation ◽  
Artery Disease

Heterozygous familial hypercholesterolemia (HeFH) is one of the most common genetic conditions but remains substantially underdiagnosed. The aim of our study was to investigate the prevalence of HeFH in the population of 11 different regions of Russia. Individuals were selected from the Epidemiology of Cardiovascular Risk Factors and Diseases in Regions of the Russian Federation Study. All participants who had low-density lipoprotein cholesterol (LDL-C) higher than 4.9 mmol/L, or LDL-C lower than 4.9 mmol/L, but had statin therapy, were additionally examined by FH experts. FH was diagnosed using the Dutch Lipid Clinic Network criteria, incorporating genetic testing. HeFH prevalence was assessed for 18,142 participants. The prevalence of patients with definite or probable HeFH combined was 0.58% (1 in 173). A total of 16.1% of patients with definite or probable HeFH had tendon xanthomas; 36.2% had mutations in one of the three genes; 45.6% of FH patients had coronary artery disease; 63% of HeFH patients received statins; one patient received an additional PCSK9 inhibitor; no patients received ezetimibe. Only 3% of patients reached the LDL-C goal based on 2019 ESC/EAS guidelines. Underdiagnosis and undertreatment of FH in Russia underline the need for the intensification of FH detection with early and aggressive cholesterol-lowering treatment.

Abstract 16143: A Novel Clinical Prediction Model for Familial Hypercholesterolemia: Implementation of a Statin-correction Calculator to Enhance Diagnostic Yield

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Zahara A Kanji ◽  
Mohammad S Sheikh ◽  
Daniel Antwi-Amoabeng ◽  
Bryce H Beutler ◽  
Nageshwara Gullapalli ◽  
...  
Keyword(s):  
Statin Therapy ◽  
Familial Hypercholesterolemia ◽  
Diagnostic Yield ◽  
Genetic Disorder ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Clinical Criteria ◽  
Gene Testing ◽  
Whole Exome ◽  
Pre Treatment

Introduction: Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder. Individuals with FH have a 22-fold greater risk of early-onset cardiovascular disease as compared to the general population. Early identification of patients with FH is essential to prevent cardiovascular events. Diagnosis may be challenging however for individuals with underlying FH who are already receiving statin therapy, as criteria for FH rely on pre-treatment low-density lipoprotein (LDL) levels. We calculated pre-treatment LDL levels utilizing prior published literature by adjusting for serum LDL levels in patients receiving statins. This increased the diagnostic yield for gene-positive FH. Hypothesis: Integration of statin-correction calculator with the Dutch Lipid Clinical Criteria (DLCC) and Simon Broome Criteria (SBC) for FH will increase sensitivity to identify gene-positive FH. Methods: 29,797 participants enrolled in the Healthy Nevada Project underwent whole-exome gene testing. 126 had a FH variant; 37 of these participants were on statin therapy. A statin-correction calculator was utilized to predict patients' pre-treatment LDL levels. The likelihood of FH was assessed based on two versions of the DLCC and SBC: the standard versions and enhanced versions with integration of the statin-correction calculator (eDLCC and eSBC). The McNemar test was used to compare the sensitivity of DLCC and SBC with eDLCC and eSBC, respectively, in identifying gene-positive FH. Results: By adjusting LDL levels for statin usage, 70.24% and 24.32% of participants with a negative diagnosis of FH were reclassified to positive using eDLCC and eSBC (p=0.001 and 0.008, respectively). Conclusions: Integration of statin-correction calculator to correct LDL increases diagnostic yield for clinical FH.

scholarly journals Cascade screening for familial hypercholesterolemia-identification of the C308Y mutation in multiple family members and relatives for the first time in mainland China

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Weirong Jin ◽  
Qiuwang Zhang ◽  
Bei Wang ◽  
Lili Pan ◽  
Hongyou Qin ◽  
...  
Keyword(s):  
Dna Sequencing ◽  
Familial Hypercholesterolemia ◽  
Low Density Lipoprotein ◽  
Family Members ◽  
Mainland China ◽  
Density Lipoprotein ◽  
Low Density ◽  
Lipid Profiling ◽  
Cascade Screening ◽  
First Time

Abstract Background Familial hypercholesterolemia (FH), an autosomal dominant genetic disorder, is underdiagnosed and undertreated. The majority of FH cases are caused by low density lipoprotein receptor (LDL-R) gene mutations. The C308Y mutation in LDL-R results in approximately 70% loss of LDL-R activity, leading to the elevation of low density lipoprotein-cholesterol (LDL-C) and an increased risk of premature coronary heart disease (CHD). The aim of this study was to identify FH cases by cascade screening in family members and relatives of a 37-year old male with premature CHD and hypercholesterolemia. Methods Clinical exam, blood lipid profiling and genomic DNA sequencing of all exons of LDL-R were performed for the proband and his 14 family members and relatives. FH diagnosis was carried out using the Dutch Lipid Clinic Network (DLCN) criteria. Results Lipid profiling showed that 9 individuals, including the proband, had hypercholesterolemia. All these 9 subjects had a G > A substitution at nucleotide 986 in exon 7 resulting in the C308Y mutation as determined by DNA sequencing, and all those carrying the mutation were diagnosed as having definite FH under the DLCN criteria. However, most (7/9) did not have suggestive clinical manifestations of CHD. Conclusions The C308Y mutation was discovered in multiple family members and relatives for the first time in mainland China. Cascade screening is key for the confirmatory diagnosis of FH. Our hypothesis that the C308Y is a common variant in the population of Southern China origin warrants further validation by screening for the C308Y mutation in a large population.

scholarly journals Novel PCSK9 (Proprotein Convertase Subtilisin Kexin Type 9) Variants in Patients With Familial Hypercholesterolemia From Cape Town

2020 ◽  
Author(s):  
Roeland Huijgen ◽  
Dirk J. Blom ◽  
Merel L. Hartgers ◽  
Kévin Chemello ◽  
Asier Benito-Vicente ◽  
...  
Keyword(s):  
Familial Hypercholesterolemia ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Low Density ◽  
Proprotein Convertase ◽  
Low Density Lipoprotein Cholesterol ◽  
Cascade Screening ◽  
Gain Of Function

Objective: Familial hypercholesterolemia (FH) is characterized by elevated low-density lipoprotein-cholesterol and markedly increased cardiovascular risk. In patients with a genetic diagnosis, low-density lipoprotein receptor ( LDLR ) mutations account for >90% of cases, apolipoprotein B ( APOB ) mutations for ≈5% of cases, while proprotein convertase subtilisin kexin type 9 ( PCSK9 ) gain of function mutations are rare (<1% of cases). We aimed to evaluate the functional impact of several novel PCSK9 variants in a cohort of patients with FH by genetic cascade screening and in vitro functionality assays. Approach and Results: Patients with clinically diagnosed FH underwent genetic analysis of LDLR , and if negative, sequential testing of APOB and PCSK9 . We analyzed cosegregation of hypercholesterolemia with novel PCSK9 variants. Gain of function status was determined by in silico analyses and validated by in vitro functionality assays. Among 1055 persons with clinical FH, we identified nonsynonymous PCSK9 variants in 27 (2.6%) patients and 7 of these carried one of the 4 previously reported gain of function variants. In the remaining 20 patients with FH, we identified 7 novel PCSK9 variants. The G516V variant (c.1547G>T) was found in 5 index patients and cascade screening identified 15 additional carriers. Low-density lipoprotein-cholesterol levels were higher in these 15 carriers compared with the 27 noncarriers (236±73 versus 124±35 mg/dL; P< 0.001). In vitro studies demonstrated the pathogenicity of the G516V variant. Conclusions: In our study, 1.14% of cases with clinical FH were clearly attributable to pathogenic variants in PCSK9 . Pathogenicity is established beyond doubt for the G516V variant.

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