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Journal ArticleDOI

Advances, gaps and opportunities in the detection of familial hypercholesterolemia: overview of current and future screening and detection methods.

01 Dec 2020-Current Opinion in Lipidology (Ovid Technologies (Wolters Kluwer Health))-Vol. 31, Iss: 6, pp 347-355
TL;DR: Investigation of familial hypercholesterolemia can be enhanced by optimizing current diagnostic algorithms, probing electronic health records with novel information technologies and integrating universal screening of children with cascade testing of parents and other relatives.
Abstract: Purpose of review Studies reaffirm that familial hypercholesterolemia is more prevalent than initially considered, with a population frequency of approximately one in 300. The majority of patients remains unidentified. This warrants critical evaluation of existing screening methods and exploration of novel methods of detection. Recent findings New public policy recommendations on the detection of familial hypercholesterolemia have been made by a global community of experts and advocates. Phenotypic tools for diagnosing index cases remain inaccurate. Genetic testing is the gold standard for familial hypercholesterolemia and a new international position statement has been published. Correction of LDL cholesterol (LDL-C) for the cholesterol content of lipoprotein(a) [Lp(a)] may increase the precision of the phenotypic diagnosis of familial hypercholesterolemia. Cascade cotesting for familial hypercholesterolemia and elevated Lp(a) levels provides a new opportunity to stratify risk in families. Digital technology and machine learning methods, coupled with clinical alert and decision support systems, lead the way in more efficient approaches for detecting and managing index cases. Universal screening of children, combined with child-parent cascade testing, appears to be the most effective method for underpinning a population strategy for maximizing the detection of familial hypercholesterolemia. Summary Detection of familial hypercholesterolemia can be enhanced by optimizing current diagnostic algorithms, probing electronic health records with novel information technologies and integrating universal screening of children with cascade testing of parents and other relatives.
Citations
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01 Jan 2015
TL;DR: Familial Hypercholesterolaemia (FH) is the commonest autosomal inherited condition affecting man and it is caused by mutation in one of three genes, encoding the low-density lipoprotein======(LDL) receptor, or the gene for apolipoprotein B (which is the major protein component of the LDL particle), or in the gene======coding for PCSK9.
Abstract: Familial Hypercholesterolaemia (FH) is the commonest autosomal co-dominantly inherited condition affecting man It is caused by mutation in one of three genes, encoding the low-density lipoprotein (LDL) receptor, or the gene for apolipoprotein B (which is the major protein component of the LDL particle), or in the gene coding for PCSK9 (which is involved in the degradation of the LDLreceptor during its cellular recycling) These mutations result in impaired LDL metabolism, leading to life-long elevations in LDLcholesterol (LDL-C) and development of premature atherosclerotic cardiovascular disease (ASCVD) [1e3] If left untreated, the relative risk of premature coronary artery disease is significantly higher in heterozygous patients than unaffected individuals, with most untreated homozygotes developing ASCVD before the age of 20 and generally not surviving past 30 years Although early detection and treatment with statins and other LDL-C lowering therapies can improve survival, FH remains widely underdiagnosed and undertreated , thereby representing a major global public health challenge

115 citations

Journal ArticleDOI
TL;DR: In this paper, a review of advances on several aspects of lipoprotein(a) which are reviewed in the present article is presented, including molar concentration, apo(a)-IoF isoform size or variants within the LPA gene.

31 citations

Posted ContentDOI
14 May 2021
TL;DR: In this paper, the authors explored the acceptability, appropriateness, and feasibility of automated screening approaches utilizing existing health data to identify those who require subsequent diagnostic evaluation for familial hypercholesterolemia (FH) and family communication methods including chatbots and direct contact to communicate information about inherited risk for FH.
Abstract: Guided by the Conceptual Model of Implementation Research, we explored the acceptability, appropriateness, and feasibility of: (1) automated screening approaches utilizing existing health data to identify those who require subsequent diagnostic evaluation for familial hypercholesterolemia (FH) and (2) family communication methods including chatbots and direct contact to communicate information about inherited risk for FH. Focus groups were conducted with 22 individuals with FH (2 groups) and 20 clinicians (3 groups). These were recorded, transcribed, and analyzed using deductive (coded to implementation outcomes) and inductive (themes based on focus group discussions) methods. All stakeholders described these initiatives as: (1) acceptable and appropriate to identify individuals with FH and communicate risk with at-risk relatives; and (2) feasible to implement in current practice. Stakeholders cited current initiatives, outside of FH (e.g., pneumonia protocols, colon cancer and breast cancer screenings), that gave them confidence for successful implementation. Stakeholders described perceived obstacles, such as nonfamiliarity with FH, that could hinder implementation and potential solutions to improve systematic uptake of these initiatives. Automated health data screening, chatbots, and direct contact approaches may be useful for patients and clinicians to improve FH diagnosis and cascade screening.

9 citations


Cites background from "Advances, gaps and opportunities in..."

  • ...of reasons for underdiagnosis of FH, including lack of systematic cholesterol screening in children and adults and a lack of awareness about FH among healthcare clinicians [5-8]....

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Journal ArticleDOI
TL;DR: In this paper, the authors explored the acceptability, appropriateness, and feasibility of automated screening approaches utilizing existing health data to identify those who require subsequent diagnostic evaluation for familial hypercholesterolemia (FH) and family communication methods including chatbots and direct contact to communicate information about inherited risk for FH.
Abstract: Guided by the Conceptual Model of Implementation Research, we explored the acceptability, appropriateness, and feasibility of: (1) automated screening approaches utilizing existing health data to identify those who require subsequent diagnostic evaluation for familial hypercholesterolemia (FH) and (2) family communication methods including chatbots and direct contact to communicate information about inherited risk for FH. Focus groups were conducted with 22 individuals with FH (2 groups) and 20 clinicians (3 groups). These were recorded, transcribed, and analyzed using deductive (coded to implementation outcomes) and inductive (themes based on focus group discussions) methods. All stakeholders described these initiatives as: (1) acceptable and appropriate to identify individuals with FH and communicate risk with at-risk relatives; and (2) feasible to implement in current practice. Stakeholders cited current initiatives, outside of FH (e.g., pneumonia protocols, colon cancer and breast cancer screenings), that gave them confidence for successful implementation. Stakeholders described perceived obstacles, such as nonfamiliarity with FH, that could hinder implementation and potential solutions to improve systematic uptake of these initiatives. Automated health data screening, chatbots, and direct contact approaches may be useful for patients and clinicians to improve FH diagnosis and cascade screening.

9 citations

Journal ArticleDOI
TL;DR: In this paper , the authors investigated the detection of new cases of elevated Lp(a) during cascade testing of relatives of probands with a definite diagnosis of FH and elevated plasma lipoprotein (Lp) (≥50 mg/dL).

8 citations

References
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Journal ArticleDOI
TL;DR: There is an urgent worldwide need for diagnostic screening together with early and aggressive treatment of this extremely high-risk condition, familial hypercholesterolaemia.
Abstract: Aims The first aim was to critically evaluate the extent to which familial hypercholesterolaemia (FH) is underdiagnosed and undertreated. The second aim was to provide guidance for screening and treatment of FH, in order to prevent coronary heart disease (CHD). Methods and results Of the theoretical estimated prevalence of 1/500 for heterozygous FH, <1% are diagnosed in most countries. Recently, direct screening in a Northern European general population diagnosed approximately 1/200 with heterozygous FH. All reported studies document failure to achieve recommended LDL cholesterol targets in a large proportion of individuals with FH, and up to 13-fold increased risk of CHD. Based on prevalences between 1/500 and 1/200, between 14 and 34 million individuals worldwide have FH. We recommend that children, adults, and families should be screened for FH if a person or family member presents with FH, a plasma cholesterol level in an adult ≥8 mmol/L(≥310 mg/dL) or a child ≥6 mmol/L(≥230 mg/dL), premature CHD, tendon xanthomas, or sudden premature cardiac death. In FH, low-density lipoprotein cholesterol targets are <3.5 mmol/L(<135 mg/dL) for children, <2.5 mmol/L(<100 mg/dL) for adults, and <1.8 mmol/L(<70 mg/dL) for adults with known CHD or diabetes. In addition to lifestyle and dietary counselling, treatment priorities are (i) in children, statins, ezetimibe, and bile acid binding resins, and (ii) in adults, maximal potent statin dose, ezetimibe, and bile acid binding resins. Lipoprotein apheresis can be offered in homozygotes and in treatment-resistant heterozygotes with CHD. Conclusion Owing to severe underdiagnosis and undertreatment of FH, there is an urgent worldwide need for diagnostic screening together with early and aggressive treatment of this extremely high-risk condition.

2,039 citations

Journal ArticleDOI
TL;DR: In an analysis of participants with serial lipid measurements over many years, FH mutation carriers had higher cumulative exposure to LDL cholesterol than noncarriers and within any stratum of observed LDL cholesterol, risk of CAD was higher among FH mutations carriers than non carriers.

681 citations


"Advances, gaps and opportunities in..." refers background in this paper

  • ...acterized by life-long elevation of LDL cholesterol (LDL-C), resulting in an up to 25-fold higher atherosclerotic cardiovascular disease (ASCVD) risk in familial hypercholesterolemia patients compared with individuals with normal LDL-C levels [1]....

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

581 citations


"Advances, gaps and opportunities in..." refers background in this paper

  • ...In children, phenotypic diagnosis of familial hypercholesterolemia is based on an LDL-C of at least 5 mmol/l, or an LDL-C of at least 4 mmol/l with family history of premature CAD and/or high baseline cholesterol in one parent [14]....

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  • ...The applicability of current diagnostic tools in children varies; the DLCN criteria are not valid in children, while the Simon Broome criteria have specific LDL-C cut-offs with an LDL-C threshold of 4 mmol/l in children with familial hypercholesterolemia aged less than 10 years [14]....

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Journal ArticleDOI
TL;DR: Drug discovery has linked enhancement of LDL receptor function to LDL-C lowering and successful prevention of ischemic heart disease, first with statins and now with newer drugs that affect LDL receptors function in other ways, including those that impair PCSK9 regulation of LDL receptors recycling.
Abstract: Familial hypercholesterolemia (FH) is an autosomal-dominant genetic disease present in all racial and ethnic groups and has long been recognized as a cause of premature atherosclerotic coronary heart disease.1–3 Heterozygous FH has the highest prevalence of genetic defects that cause significant premature mortality (≈1:200 to 1:500 or higher in founder populations). The genetic basis of the disorder, impaired functioning of the low-density lipoprotein (LDL) receptor, was first recognized by Goldstein and Brown4 in their Nobel Prize–winning work. Studies of LDL receptor function have identified additional mechanisms for the pathogenesis of FH (defects in apolipoprotein [apo] B impairing binding with the LDL receptor and gain-of-function mutations in proprotein convertase subtulisin/kexin type 9 [PCSK9] that enhance LDL receptor degradation). FH leads to elevated LDL concentrations, with levels in heterozygous FH generally in untreated adults >190 mg/dL LDL cholesterol (LDL-C) and in untreated children or adolescents >160 mg/dL LDL-C. Long-term exposure to elevated plasma concentrations of LDL-C begins in utero, leading in heterozygotes to premature ischemic heart disease in mid adulthood and in homozygotes to ischemic heart disease in childhood or early adulthood. In those who meet clinical definitions of FH based on LDL-C levels and family history, genetic testing identifies mutations in most children and a large percentage of adults.5,6 Complementing these cell biology discoveries has been drug discovery that has linked enhancement of LDL receptor function to LDL-C lowering and successful prevention of ischemic heart disease, first with statins and now with newer drugs that affect LDL receptor function in other ways, including those that impair PCSK9 regulation of LDL receptor recycling.7 The natural history of FH, the natural history of genetic disorders that lead to lifelong low LDL-C, and the dramatic improvement in life expectancy created by effective cholesterol lowering provide the …

500 citations


"Advances, gaps and opportunities in..." refers background in this paper

  • ...The American Heart Association (AHA) criteria define a similar clinical classification of familial hypercholesterolemia [19], whereby heterozygous familial hypercholesterolemia is defined as a positive family history of elevated cholesterol or premature CAD and LDL-C of at least 4 mmol/l in a child or at least 5 mmol/l in an adult confirmed on two occasions [19]....

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Journal ArticleDOI
TL;DR: Targeted family screening with DNA analysis proved to be highly effective in identifying patients with hypercholesterolaemia and most of the identified patients sought treatment and were successfully started on cholesterol-lowering treatment to lower the risk of premature CVD.

439 citations


"Advances, gaps and opportunities in..." refers background in this paper

  • ...6. deGoma EM, Ahmad ZS, O’Brien EC, et al. Treatment gaps in adults with heterozygous familial hypercholesterolemia in the United States: data from the CASCADE-FH Registry....

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  • ...The American Heart Association (AHA) criteria define a similar clinical classification of familial hypercholesterolemia [19], whereby heterozygous familial hypercholesterolemia is defined as a positive family history of elevated cholesterol or premature CAD and LDL-C of at least 4 mmol/l in a child or at least 5 mmol/l in an adult confirmed on two occasions [19]....

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  • ...Patients admitted to the CCU with ACS or previously documented CAD should be routinely screened for familial hypercholesterolemia after Copyright © 2020 Wolters Kluwer H 350 www.co-lipidology.com which cascade testing of relatives should be initiated....

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  • ...Familial hypercholesterolemia is the most common monogenic cause of premature coronary artery disease (CAD)....

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  • ...Source of data: Dutch national expertise ce from [55,58]....

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