Family History Of Hypercholesterolemia Research Articles

Knowledge of Metabolic Syndrome Among Third and Sixth Year Medical Students in Saudi Arabia.

Metabolic syndrome has become a public health challenge, and its prevalence is increasing among young adults. Little is known about the knowledge of medical students about this syndrome. The study aimed to assess the level of knowledge of the medical students about conditions relevant to metabolic syndrome. A cross-sectional survey was administered using a self-administered questionnaire to students in a medical college in Saudi Arabia. The survey was divided into four sections: diabetes, adiposity, hypertension, and hypercholesterolemia. Students' responses were gathered and interpreted as adequate knowledge (81-100%), moderate knowledge (51-80%), and low knowledge (≤50%). Independent samples t-test and Chi-square tests were done to examine the association between students' knowledge with the academic year (thirdand sixth years). The level of significance was set at 0.05. There were a total of 224 respondents, 102 (46%) from the third year and 122 (54%) from the sixth year. More than 70% of students correctly identified symptoms, complications, and risk factors of diabetes, adiposity, and hypertension, and 90% were aware of different types of diabetes. There were some false beliefs held by students such as 91% of third-year students believed that fatigue is a frequent symptom of high serum cholesterol compared to 70% of sixth-year students (p <0.001). Likewise, 36% of students falsely identified liposuction as the best possible treatment in adiposity therapy. The sixth year of study and family history of hypercholesterolemia was found to be positively associated with a higher knowledge score for most categories. The study concludes that the student's knowledge about conditions relevant to metabolic syndrome can be enhanced and preventative measures can be implemented to raise awareness about the syndrome.

A Family History of Hypercholesterolemia - the Role of Genetics

A Family History of Hypercholesterolemia - the Role of Genetics Abstract. Genetic testing is rarely used in Switzerland to confirm the clinical diagnosis of familial hypercholesterolemia. However, cascade genetic testing from an index case is recommended by the guidelines. By describing a patient and his family with severe hypercholesterolemia, we discuss the benefits, risks and barriers regarding the implementation of genetics for familial hypercholesterolemia. Family screening with genetic testing could become a standard of care for severe hypercholesterolemia.

Clinical analysis of 4 children with hereditary hypercholesterolemia

Objective: To investigate the clinical characteristics of hereditary hypercholesterolemia in childhood. Methods: The clinical data including general conditions, clinical manifestations, laboratory tests, and genetic testing results of 4 children with hereditary hypercholesterolemia who admitted to Henan Children's Hospital from January 2020 to December 2020 were retrospectively analyzed. Results: There were 4 female children aged 5.5,1.5,6.3,3.1 years, all presented with skin xanthoxoma as the chief complaint. Plasma total cholesterol (range 11.8 to 20.9 mmol/L) and low density lipoprotein-cholesterol (range 8.2 to 13.7 mmol/L) were significantly elevated. The serum β-glutamate levels in case 1 (241.2 μmol/L) and case 2 (164.2 μmol/L) increased significantly. Genetic analysis revealed compound heterozygous variants of ABCG8 gene in case 1 and ABCG5 gene in case 2 who were diagnosed with sitosterolemia. Case 3 and 4 who all had family history of hypercholesterolemia and compound heterozygous variants of LDLR gene were diagnosed with familial hypercholesterolemia. After diet treatment, the blood lipids returned normal and the skin xanoma subsided in case 1 and 2. In case 3 and 4, the blood lipids gradually decreased after diet and rosuvastatin treatment. Conclusions: Xanthomatosis is the common clinical manifestation of sitosterolemia and familial hypercholesterolemia. Family history, blood plant sterol profile, genetic variation, and changes in blood lipids after early dietary treatment are helpful for disease identification.

Unveiling Compound Heterozygous Familial Hypercholesterolemia

Lead Author's Financial Disclosures Nothing to disclose. Study Funding None. Background/Synopsis A 38-year-old female with a history of hypercholesterolemia as well as a family history of hypercholesterolemia in mother diagnosed at age 68 and in young daughter at age 11 is referred for further evaluation and management of hypercholesterolemia. Objective/Purpose To review the role of genetic testing in management of severe hypercholesterolemia. Methods In addition to routine clinical care, genetic testing was completed by Invitae using gene sequencing and deletion/duplication analysis with next generation sequencing technology (NGS). Results A 38-year-old female has been treated since age 20, when she was first found to have high cholesterol. She is referred for further evaluation after her 11-year-old daughter is noted to have high cholesterol. Invitae Familial Hypercholesterolemia Panel identified a LDLR: c.1027 G>A (p.Gly343Ser) pathogenic variant and LDLR: c.1880 C>T (p.Ala627Val) variant of uncertain significance (VUS). Conclusions Familial hypercholesterolemia (FH) is the most common inherited cardiovascular disease, with a prevalence of 1 in 311, characterized by significantly elevated LDL cholesterol (LDL-C) and responsible for up to 2%-3% of heart attacks in individuals younger than age 60 years. In fact, men with FH who are untreated have a 50% chance of having a coronary event by age 50 and untreated women have a 30% risk by age 60. FH is caused by pathogenic (disease-causing) variants in four major genes: APOB, LDLR, LDLRAP1, PCSK9. The severity of the LDL-C elevation can be determined by the specific variant's impact on LDL-receptor activity and function, and/or the impact from other genes that raise and/or lower the LDL-C. Pathogenic variants in the APOB and PCSK9 and additional LDLR variants may be present as well and are described as double heterozygotes if different genes are affected, compound heterozygotes if different alleles in the same gene are affected, or homozygous if 2 copies of the pathogenic variant is found. In our clinical case, genetic testing revealed a pathogenic variant in the LDLR gene, c.1027 G>A (p.Gly343Ser). This gene is responsible for effective transport of LDL cholesterol into the cell, when defective leads to build up of the un-transported cholesterol in blood vessels. In addition to the pathogenic LDLR variant, a VUS in the LDLR gene, c.1880 C>T (p.Ala627Val) was identified. Variants are of uncertain significance generally do not have evidence to determine pathogenicity with little to no direct impact on phenotype. For now, our patient should be considered heterozygous FH based upon the single pathogenic variant. However, given the supporting evidence and expectation that the VUS is likely pathogenic, we did advise her that the genetic description may change to compound heterozygous depending upon database expansion. Of note, the underrepresentation of this variant in existing databases may reflect sampling bias. Our patient is of Afro-Caribbean (Haitian) heritage, which is a population that has been underrepresented in medical studies. Nothing to disclose.

Phenotypic and genotypic characterization of familial hypercholesterolemia in French adult and pediatric populations

BackgroundFamilial hypercholesterolemia (FH) is the most common genetic disorder associated with a high risk for premature atherosclerotic cardiovascular disease attributable to increased levels of LDL-cholesterol (LDL-C) from birth. FH is both underdiagnosed and undertreated. ObjectiveWe describe the clinical, biological, and genetic characteristics of 147 patients in France with clinical FH (including a group of 26 subjects aged < 20 years); we explore how best to detect patients with monogenic FH. MethodsWe retrospectively reviewed all available data on patients undergoing genetic tests for FH from 2009 to 2019. FH diagnoses were based on the Dutch Lipid Clinics Network (DLCN) scores of adults, and elevated LDL-C levels in subjects < 20 years of age. We evaluated LDLR, APOB, and PCSK9 status. ResultsThe mutations of adults (in 25.6% of all adults) were associated with DLCN scores indicating “possible FH,” "probable FH, and “definitive FH” at rates of 4%, 16%, and 53%, respectively. The areas under the ROC curves of the DLCN score and the maximum LDL-C level did not differ (p = 0.32). We found that the pediatric group evidenced more monogenic etiologies (77%, increasing to 91% when an elevated LDL-C level was combined with a family history of hypercholesterolemia and/or premature coronary artery disease). ConclusionDiagnosis of monogenic FH may be optimized by screening children in terms of their LDL-C levels, associated with reverse-cascade screening of relatives when the children serve as index cases.

Upholding trust in therapeutic trials and evidence-based medicine: need for full disclosure of data, crowdsourcing data analysis and independent review?

An active 74-year-old woman with hypertension and a family history of hypercholesterolaemia was referred for evaluation of chest pain and underwent coronary angiography. Low-density lipoprotein (LDL) cholesterol was 270 mg/dL....

Integrated Guidance for Enhancing the Care of Familial Hypercholesterolaemia in Australia

Familial hypercholesterolaemia (FH) is a dominant and highly penetrant monogenic disorder present from birth that markedly elevates plasma low-density lipoprotein (LDL)-cholesterol concentration and, if untreated, leads to premature atherosclerosis and coronary artery disease (CAD). There are approximately 100,000 people with FH in Australia. However, an overwhelming majority of those affected remain undetected and inadequately treated, consistent with FH being a leading challenge for public health genomics. To further address the unmet need, we provide an updated guidance, presented as a series of systematically collated recommendations, on the care of patients and families with FH. These recommendations have been informed by an exponential growth in published works and new evidence over the last 5 years and are compatible with a contemporary global call to action on FH. Recommendations are given on the detection, diagnosis, assessment and management of FH in adults and children. Recommendations are also made on genetic testing and risk notification of biological relatives who should undergo cascade testing for FH. Guidance on management is based on the concepts of risk re-stratification, adherence to heart healthy lifestyles, treatment of non-cholesterol risk factors, and safe and appropriate use of LDL-cholesterol lowering therapies, including statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors and lipoprotein apheresis. Broad recommendations are also provided for the organisation and development of health care services. Recommendations on best practice need to be underpinned by good clinical judgment and shared decision making with patients and families. Models of care for FH need to be adapted to local and regional health care needs and available resources. A comprehensive and realistic implementation strategy, informed by further research, including assessments of cost-benefit, will be required to ensure that this new guidance benefits all Australian families with or at risk of FH.

Verification of Underlying Genetic Cause in a Cohort of Russian Patients with Familial Hypercholesterolemia Using Targeted Next Generation Sequencing.

Russian patients with familial hypercholesterolemia (FH) were screened for pathogenic mutations using targeted next generation sequencing. Genetic testing was performed in 52 probands with definite or probable FH based on the Dutch lipid clinic network criteria (DLCN score ≥ 6). Blood samples were studied by massive parallel sequencing (Illumina HiSeq 1500 platform) using a custom capture library related to dyslipidemia and premature atherosclerosis. Mutations considered to be responsible for monogenic FH were identified in 48% of the probands: 24 with mutations in the LDLR gene and two with a mutation in the APOB gene. There were 22 pathogenic/likely pathogenic mutations in LDLR, eight of which have not been previously described in the literature. Four patients with a clinical picture of homozygous FH had two heterozygous LDLR mutations. Although mutation-negative patients had highly elevated total cholesterol and low-density lipoprotein cholesterol levels, only half of them had a family history of hypercholesterolemia. With respect to heterozygous FH, mutation-positive patients had higher maximum total cholesterol levels (p = 0.01), more severe carotid atherosclerotic lesions, and a higher percentage of premature peripheral artery disease (p = 0.03) than mutation-negative ones. However, the number of patients who suffered from myocardial infarction was similar between the two groups.

Can erectile dysfunction severity predict left main and/or three-vessel disease in acute coronary syndrome patients?

Familial hypercholesterolemia is an Mendelian dominant disorder characterized by defects of the low density lipoprotein receptor (LDLR) that result in a defective removal of LDL from plasma, which promotes deposition of cholesterol in the skin (xanthelasma), tendons (xanthomas), and arteries (atherosclerosis).Diagnosis severe clinical phenotype FH with Dutch Lipid Clinic Network Criteria, encompassing history of premature ASCVD, tendon xanthomas, and a family history of hypercholesterolemia and premature ASCVD in relatives is rare in the Portuguese FH patients. There is a variability of the phenotype in FH individuals with clinical diagnosis or genetic mutation (carriers and patients) probably due to environmental factors in the last century, a Mediterranean diet, or a diet without fat food, trans fat food, no smoking, no sedentary life that can interfere with our metabolism, or are consequences of polygenic, epigenetic, acquired defects, modifiers genes and beta-globin asymptomatic carriers.We have several concepts/mechanisms in genetics that are transversal to hereditary diseases and common in FH, such as somatic mosaicism, germinal mosaicism, variable expression and variable penetrance of mutations.A negative blood genetic test result does not exclude FH, because the pathogenic LDLR mutation can be expressed only in the liver (a mutation in somatic tissue) or occasionally there is a vertical transmission from partner to future child by a mutation on germinal line - germinal mosaicism.Unlike north European countries, the most FH carriers and patients had less severe phenotypes, for example with have children and young adult carriers with LDL-R mutation had normal TC and LDL-C, old women had a milder phenotype without ASCVD events, tendon xanthomas are seen in <1% patients, and most homozygous FH patients are under combined therapy.

Relation between Blood pressure variability and Coronary Artery Remodeling Index in Normotensive Patients with Coronary artery disease: An Intravascular ultrasound Study

Familial hypercholesterolemia is an Mendelian dominant disorder characterized by defects of the low density lipoprotein receptor (LDLR) that result in a defective removal of LDL from plasma, which promotes deposition of cholesterol in the skin (xanthelasma), tendons (xanthomas), and arteries (atherosclerosis).Diagnosis severe clinical phenotype FH with Dutch Lipid Clinic Network Criteria, encompassing history of premature ASCVD, tendon xanthomas, and a family history of hypercholesterolemia and premature ASCVD in relatives is rare in the Portuguese FH patients. There is a variability of the phenotype in FH individuals with clinical diagnosis or genetic mutation (carriers and patients) probably due to environmental factors in the last century, a Mediterranean diet, or a diet without fat food, trans fat food, no smoking, no sedentary life that can interfere with our metabolism, or are consequences of polygenic, epigenetic, acquired defects, modifiers genes and beta-globin asymptomatic carriers.We have several concepts/mechanisms in genetics that are transversal to hereditary diseases and common in FH, such as somatic mosaicism, germinal mosaicism, variable expression and variable penetrance of mutations.A negative blood genetic test result does not exclude FH, because the pathogenic LDLR mutation can be expressed only in the liver (a mutation in somatic tissue) or occasionally there is a vertical transmission from partner to future child by a mutation on germinal line - germinal mosaicism.Unlike north European countries, the most FH carriers and patients had less severe phenotypes, for example with have children and young adult carriers with LDL-R mutation had normal TC and LDL-C, old women had a milder phenotype without ASCVD events, tendon xanthomas are seen in <1% patients, and most homozygous FH patients are under combined therapy.

SAT-086 A Rare Case of Cholestatic Liver Disease Causing Markedly Elevated LDL Successfully Managed with Plasmapheresis and Ursodeoxycholic Acid

Background Hypercholesterolemia (HC) in cholestatic liver disease commonly involves a high lipoprotein-X (LpX) and low LDL receptors. No evidence has been found to suggest the association of LpX with an increased risk of cardiovascular disease (CVD). Hence, lipid lowering therapy is unnecessary as HC improves with treatment of cholestasis, but plasmapheresis should be considered in markedly elevated LDL values given the uncertainty of short term complications. Clinical Case A 47-year-old man with HTN, DMT2, nephrotic syndrome secondary to DM glomerulosclerosis and CKD stage 3 was admitted for an NSTEMI and acute heart failure due to non-ischemic cardiomyopathy. On exam he had jaundice and hepatomegaly without xanthelasma or tendon xanthomas. Laboratory evaluation revealed elevated HDL 200 [35-75 mg/dl], LDL 2,182 [0-130 mg/dl] and triglyceride 326 [30-150 mg/dl] although his lipid panel four months ago was normal. He had no family history of HC or premature CAD. Interestingly, two months prior the patient was seen in GI clinic due to jaundice, pruritus, acholia and coluria. Work-up showed cholestasis with total bilirubin 5.2 [0.1-1.2 mg/dl], AST 148 [0-40 U/L], ALT 112 [5-25 U/L], alkaline phosphatase 1,874 [20-120 U/L] and GGT 2,307 [3-60 U/L]. Further evaluation was unrevealing with negative viral hepatitis serologies, antinuclear antibodies, anti-smooth muscle antibody, anti-mitochondrial antibody, ceruloplasmin, α-1antitrypsin. He underwent liver biopsy which demonstrated cholestatic hepatitis with advanced biliary fibrosis, lymphocytic cholangitis and perivenular infiltrate thought secondary to an atypical autoimmune cholangiopathy. Due to concern for hyperviscosity and potential CVD complications, two sessions of plasma exchange were performed with a rapid lowering of LDL to 661 mg/dL. He was given a dose of evolocumab and discharged on ursodeoxycholic acid with improvement in liver function and normalization of lipid panel within three weeks. His HC was presumed mainly from atypical autoimmune cholangiopathy. LpX was unlikely since his Apolipoprotein B was elevated at 239 [RR 52-109 mg/dl]. Once his liver function normalized, he was started on high intensity statin and ezetimibe due to an elevated CVD risk with a low ApoA 30 mg/dL [RR 94-176]. Conclusion This is a rare case of cholestatic liver disease causing markedly elevated LDL, successfully managed with plasma exchange and ursodeoxycholic acid with subsequent resolution of LDL abnormality.

Variable expression and penetrance in Portuguese families with Familial Hypercholesterolemia with mild phenotype

Familial hypercholesterolemia is an Mendelian dominant disorder characterized by defects of the low density lipoprotein receptor (LDLR) that result in a defective removal of LDL from plasma, which promotes deposition of cholesterol in the skin (xanthelasma), tendons (xanthomas), and arteries (atherosclerosis).Diagnosis severe clinical phenotype FH with Dutch Lipid Clinic Network Criteria, encompassing history of premature ASCVD, tendon xanthomas, and a family history of hypercholesterolemia and premature ASCVD in relatives is rare in the Portuguese FH patients. There is a variability of the phenotype in FH individuals with clinical diagnosis or genetic mutation (carriers and patients) probably due to environmental factors in the last century, a Mediterranean diet, or a diet without fat food, trans fat food, no smoking, no sedentary life that can interfere with our metabolism, or are consequences of polygenic, epigenetic, acquired defects, modifiers genes and beta-globin asymptomatic carriers.We have several concepts/mechanisms in genetics that are transversal to hereditary diseases and common in FH, such as somatic mosaicism, germinal mosaicism, variable expression and variable penetrance of mutations.A negative blood genetic test result does not exclude FH, because the pathogenic LDLR mutation can be expressed only in the liver (a mutation in somatic tissue) or occasionally there is a vertical transmission from partner to future child by a mutation on germinal line - germinal mosaicism.Unlike north European countries, the most FH carriers and patients had less severe phenotypes, for example with have children and young adult carriers with LDL-R mutation had normal TC and LDL-C, old women had a milder phenotype without ASCVD events, tendon xanthomas are seen in <1% patients, and most homozygous FH patients are under combined therapy.

A Japanese case of familial hypercholesterolemia with a novel mutation in the LDLR gene.

Familial hypercholesterolemia (FH, OMIM number #143890) is an autosomal dominant disorder, resulting in low-density lipoprotein (LDL) receptor dysfunction. The prevalence of FH is estimated to be approximately, 1 in 200 and 1 in 170,000 among heterozygotes and homozygotes, respectively (1). Since FH patients develop severe coronary-artery disease (CAD) due to hypercholesterolemia in early adult life, lipid-lowering treatments must be started at childhood (2). Although pediatric FH is clinically diagnosed based on the serum LDL cholesterol (LDL-C) levels and a family history of hypercholesterolemia, genetic analysis is useful for a definitive diagnosis, as it can predict the risk stratification of CAD (3, 4) and assist in early diagnosis and intervention, leading to improved prognosis. Here, we present a novel mutation in the LDLR gene, in a patient with heterozygous FH (HeFH).

Prevalence and sociodemographic correlates of cardiovascular risk factors among patients with hypertension in South African primary care.

To determine the prevalence and sociodemographic correlates of cardiovascular risk factors among patients with hypertension at Johan Heyns Community Health Centre, Sedibeng district, South Africa. A total of 328 participants were systematically sampled. A researcher-administered questionnaire collected information on: socio-demography, presence of diabetes, family history of hypercholesterolaemia, family history of fatal cardiovascular (CV) events, and engagement in physical activities. Other measurements included: blood pressure (BP), weight, height, abdominal circumference and electrocardiography (ECG). Data analysis included descriptive statistics, chi-squared test and regression analysis. Main outcome measures included the proportions of participants with each CV risk and their significant sociodemographic determinants. Participants' mean age was 57.7 years. Most participants were black (86.0%), female (79%) and pensioners (43.6%). The mean BP was 139/84 mmHg, and 60.7% had their BP controlled to targets. There was an average of 3.7 CV risk factors per participant and the prevalence of CV risk factors was: abdominal obesity (80.8%), physical inactivity (73.2%), diabetes (30.2%), alcohol use (28.0%), hypercholesterolaemia (26.5%), smoking (11.9%), past family history of fatal CV event (14.9%), and left ventricular hypertrophy (5.2%). Sociodemographic factors significantly associated with each CV risk factor were: obesity and being female (p = 0.00); alcohol use and young age (p = 0.00); smoking, being male and race other than black (p = 0.00 and p = 0.00, respectively); physical inactivity, being a pensioner and male (p = 0.02 and p = 0.02, respectively); diabetes and being male (p = 0.03); hypercholesterolaemia and race other than black (p = 0.03); family history of hypercholesterolaemia and race other than black (p = 0.00); and family history of fatal CV event and race other than black (p = 0.00). There is a high burden of CV risk factors among patients with hypertension in South African primary care, signifying a substantial risk of cardiovascular disease (CVD) in this setting. Interventions aimed at CVD risk reduction need to take cognisance of the sociodemographic correlates of CV risk factors.

Spectrum of low-density lipoprotein receptor (LDLR) mutations in a cohort of Sri Lankan patients with familial hypercholesterolemia \u2013 a preliminary report

BackgroundHypercholesterolemia is a major determinant of cardiovascular disease-associated morbidity and mortality. Mutations in the LDL-receptor (LDLR) gene are implicated in the majority of the cases with familial hypercholesterolemia (FH). However, the spectrum of mutations in the LDLR gene in Sri Lankan patients has not been investigated. The objective of this study was to report the frequency and spectrum of variants in LDLR in a cohort of Sri Lankan patients with FH.MethodsA series of consecutive patients with FH, diagnosed according to Modified Simon Broome criteria or Dutch Lipid Clinic Network criteria at the University Medical Unit, Colombo, were recruited. Clinical data was recorded. DNA was extracted from peripheral blood samples. The LDLR gene was screened for genetic variants by Sanger sequencing.ResultsA total of 27 patients [13 (48%) males, 14 (52%) females; age range 24–73 years] were tested. Clinical features found among these 27 patients were: xanthelasma in 5 (18.5%), corneal arcus in 1 (3.7%), coronary artery disease (CAD) in 10 (37%), and a family history of hypercholesterolemia and/or CAD in 24 (88.9%) patients. In the entire cohort, mean total cholesterol was 356.8 mg/dl (±66.4) and mean LDL-cholesterol was 250.3 mg/dl (±67.7). Sanger sequencing of the 27 patients resulted in the identification of known pathogenic missense mutations in 5 (18.5%) patients. Four were heterozygotes for 1 mutation each. They were c.682G > C in 2 patients, c.1720C > A in 1 patient, and c.1855 T > A in 1 patient. One patient with severe FH phenotypes was a compound heterozygote for one known mutation, c.2289G > T, and another missense variant, c.1670C > G (p.Thr557Ser), with unknown functional impact. This latter variant has not been reported in any other population previously.ConclusionsThe frequency of known mutations in the LDLR gene in this cohort of patients was markedly low compared to frequencies reported in other populations. This highlights the likelihood of a complex, polygenic inheritance of FH in Sri Lankan patients, indicating the need for a comprehensive genetic evaluation that includes the screening for mutations in other genes that cause FH, such as APOB, PCSK9, and LDLRAP1.

Familial hypercholesterolemia: experience from France.

We provide an overview of molecular diagnosis for familial hypercholesterolemia in France including descriptions of the mutational spectrum, polygenic susceptibility and perspectives for improvement in familial hypercholesterolemia diagnosis. Molecular testing for familial hypercholesterolemia is recommended for patients with a LDL-cholesterol level above 190 mg/dl (adults) associated with criteria related to personal and family history of hypercholesterolemia and premature cardiovascular disease. Among the 3381 index cases included with these characteristics in the French registry for familial hypercholesterolemia, 2054 underwent molecular diagnosis and 1150 (56%) were found to have mutations (93.5% in LDL Receptor (LDLR), 4.7% in apolipoprotein B and 1.8% in Proprotein convertase subtilisin/kexin type 9). A total of 416 different pathogenic variants were found in the LDLR gene. Based on gene score calculation, a polygenic origin may be suggested in 36% of nonmutated patients. Involvement of genetic counselors and education of healthcare professionals for genetics of familial hypercholesterolemia are underway with the aim of improving the efficiency of the diagnosis. Genetic cascade screening for familial hypercholesterolemia is currently implemented in France with the complexity to address the diversity of its molecular cause in index cases. Optimization of patient care pathways is critical to improve both the rate of diagnosis and the management of familial hypercholesterolemia patients.

Familial hypercholesterolaemia.

Familial hypercholesterolaemia is a common inherited disorder characterized by abnormally elevated serum levels of low-density lipoprotein (LDL) cholesterol from birth, which in time can lead to cardiovascular disease (CVD). Most cases are caused by autosomal dominant mutations in LDLR, which encodes the LDL receptor, although mutations in other genes coding for proteins involved in cholesterol metabolism or LDLR function and processing, such as APOB and PCSK9, can also be causative, although less frequently. Several sets of diagnostic criteria for familial hypercholesterolaemia are available; common diagnostic features are an elevated LDL cholesterol level and a family history of hypercholesterolaemia or (premature) CVD. DNA-based methods to identify the underlying genetic defect are desirable but not essential for diagnosis. Cascade screening can contribute to early diagnosis of the disease in family members of an affected individual, which is crucial because familial hypercholesterolaemia can be asymptomatic for decades. Clinical severity depends on the nature of the gene that harbours the causative mutation, among other factors, and is further modulated by the type of mutation. Lifelong LDL cholesterol-lowering treatment substantially improves CVD-free survival and longevity. Statins are the first-line therapy, but additional drugs, such as ezetimibe, bile acid sequestrants, PCSK9 inhibitors and other emerging therapies, are often required.

CaRe high – Cascade screening and registry for high cholesterol in Germany

IntroductionFamilial hypercholesterolemia (FH) is an inherited disorder of the LDL metabolism, leading to cardiovascular disease, even at young age. This risk can be significantly lowered by early diagnosis and treatment. About 270,000 patients affected in Germany are not diagnosed correctly and only a small number is treated properly. To improve FH diagnosis in the general population a cascade screening and registry data is warranted, yet missing in Germany. This project aims to fill this gap. MethodsStudy assistants approach physicians and lipid clinics to introduce the cascade screening and registry. The physicians identify potential FH patients and include them in the study. Patient data is acquired via questionnaires about medical history. Patients meeting at least two inclusion criteria (LDL-C >190 mg/dl or total cholesterol >290 mg/dl; tendon xanthomas; family history of hypercholesterolemia or early myocardial infarction) are included in the registry. Family members will be contacted and physicians get feedback about diagnosis and treatment options. Ethical approvals for all German states have been collected. ResultsSo far physicians, lipid clinics and patients within the Rhein-Neckar region, the Saarland, North-Rhine-Westphalia, Upper Bavaria, Bremen, Saxonia and Berlin have joined the study. We expect to include more than 3000 patients during the next two years. ConclusionAfter initial patient and data collection the project aims to improve FH-diagnosis and treatment. Utilizing registry data might advance diagnostic criteria and improve detection of FH and thus prevent CVD in this population.

Causative mutations and premature cardiovascular disease in patients with heterozygous familial hypercholesterolaemia.

Background Familial hypercholesterolemia is a common autosomal dominant disease, caused by mutations leading to elevated low-density lipoprotein (LDL) cholesterol and, if untreated, to premature cardiovascular disease. Methods Patients (young adults with a family history of hypercholesterolaemia or premature cardiovascular disease) with LDL cholesterol concentration ≥4.9 mmol/l, after excluding Familial Combined Hyperlipidaemia, were evaluated for causative mutations, Dutch Lipid Clinic Network score calculation and non-invasive ultrasound examination of carotid arteries. Results Of the 263 patients, 210 were heterozygotes for LDL receptor ( LDLR) mutations, four had APOB gene mutations, one PCSK9 gene mutation, while 48 had no evidence of mutations. Among 194 unrelated index cases 149 had mutations (77%). Among patients with LDLR mutations ( n = 145), there were five compound heterozygotes, 75 patients with null mutations and 65 with missense mutations. As many as 178 patients underwent a follow-up and treatment (statin ± ezetimibe), achieving a mean reduction of 49% in LDL cholesterol, with 21% of patients reaching the LDL goal of 2.6 mmol/l. In a multivariate analysis, carotid plaques, at ultrasound examination, were associated with the presence of genetic mutation ( p = 0.001), LDL cholesterol ( p < 0.001), Dutch Lipid Clinic Network score ( p < 0.001), independently of age, gender, smoking habits and systolic blood pressure. The presence of carotid plaque ( p = 0.017), LDL cholesterol ( p < 0.003), Dutch Lipid Clinic Network score ( p < 0.001) were independently associated with premature cardiovascular disease. Conclusions We identified patients with causative mutations in 82% of the cases under study. In addition to LDL cholesterol and Dutch Lipid Clinic Network score, carotid plaques in ultrasound evaluation provide direct evidence of premature vascular disease and are associated with high risk for cardiovascular events.

The Dilemma of Finding a Young Patient with a Raised Cholesterol Concentration

K.S., a 26-year-old male, presented to the lipid clinic at St George's Hospital in London with a baseline cholesterol concentration of 8.8 mmol/L (340 mg/dL) and a calculated LDL cholesterol concentration of 7.1 mmol/L (275 mg/L). On clinical examination, there were neither tendon xanthomas nor a family history of hypercholesterolemia or premature death from vascular disease. At this time, K.S. did not meet the Simon Broome criteria (Table 1) for possible familial hypercholesterolemia (FH),2 and because the patient had a body mass index of 31.5 kg/m2 (target <25), lifestyle modification was suggested and a review appointment ordered for 6 months. A carotid intima-medial thickness (CIMT) measurement was ordered to help assess vascular risk. The results showed no plaque, but a right CIMT of 0.6 mm and a left CIMT of 0.7 mm, which were both above the 97.5th percentile for his age and consistent with early atheromatous change. View this table: Table 1. Simon Broome criteria for the diagnosis of FH.a The following year, his younger brother (aged 23 years) presented with a raised cholesterol concentration of 9.6 mmol/L (371 mg/dL) and a calculated LDL cholesterol concentration of 7.7 mmol/L (298 mg/L). Because the brother had a first-degree relative with raised cholesterol, he met the Simon Broome criteria for possible FH and was investigated …