Arq Bras CardiolabcArquivos Brasileiros de CardiologiaArq. Bras. Cardiol.0066-782X1678-4170Sociedade Brasileira de Cardiologia - SBCJGLtFtVbzqfQ3cYXyhdt9LqS0066-782X201800160058510.5935/abc.20180193Short EditorialPredictors of Family Recruitment in a Program of Genetic Cascade Screening for Familial HypercholesterolemiaIzarMaria Cristina de OliveiraFonsecaFrancisco Antonio HelfensteinUniversidade Federal de São PauloEscola Paulista de MedicinaSão PauloSPBrazilDisciplina de Cardiologia - Escola Paulista de Medicina - Universidade Federal de São Paulo, São Paulo, SP - BrazilMailing Address: Maria Cristina de Oliveira Izar, Rua Loefgren, 1350. Postal Code 04040-001, Vila Clementino, São Paulo, SP - Brazil. E-mail: mcoizar@terra.com.br; mcoizar@cardiol.br1020181114585586This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.KeywordsHyperlipoproteinemia Type II/geneticLipid Metabolism DisordersHyperlipoproteinemia/prevention &controlFamily Health Strategy
Familial hypercholesterolemia (FH) is a common inherited disease affecting lipid metabolism; it is associated with lifelong exposure to high levels of LDL-cholesterol, and premature atherosclerotic cardiovascular disease. FH imposes an enormous burden on patients and their relatives, due to years of life lost, and particularly, for not being diagnosed as an entity.1
In spite of the high LDL-cholesterol and even after an atherosclerotic event, a large proportion of individuals with FH remains undiagnosed.2,3 Criteria for diagnosing FH are based on clinical findings, family history, LDL-cholesterol levels, and genetic testing (Simon Broome or Dutch Lipid Clinic Network), or on the LDL-cholesterol levels alone (US MED PED).4 However, FH phenotypes can vary, and the lack of physical signs (15-30% of patients with genetic diagnosis of FH present xanthomas or corneal arcus, and 5% have xanthelasma) can contribute for the underdiagnosis of FH. 5-7
Genetic testing using a panel that includes FH-causing genes (LDLR, APOB, PCSK9, and LDLRAP-1) is the best approach to identify probands.1,4 When cascade screening is proposed to a family with a confirmed genetic case of FH, the costs for this screening program are much lower and are considered a cost-effective intervention, enabling early diagnosis and treatment of the affected relatives. One problem with cascade screening is how to have a high proportion of relatives adhering to the screening program.8-11
Silva-Souza, et al.,12 in the article entitled Predictors of Family Recruitment in a Program of Genetic Cascade Screening for Familial Hypercholesterolemia identified the best predictors of genetic family screening, using characteristics derived from their probands.12 From January 2011 to July 2015, 183 probands (confirmed for FH by genetic testing) had their 1st degree family members recruited for the cascade program. The response variable was the number of relatives that adhered to the recruitment.13 Study variables were derived from clinical and socioeconomic characteristics of the index cases. A linear negative binomial regression model was used to test predictors. Reference origin from the site of cascade screening vs. tertiary prevention, LDL-cholesterol in the proband, and family history were independent predictors for a higher number of recruited subjects.
There are a number of reasons that would reinforce the need and the importance to adhere to a genetic cascade screening program. The costs are lower than when a proband is diagnosed,10 it is a predictor of coronary disease,14 adherence to lipid-lowering drugs can be enhanced, and the treatment can be initiated earlier in life.14 A structured follow-up of the screened individuals should be performed to assure early and continuous treatment. Most concerns related to lack of adherence to screening are related to patient/relatives education, and physician inertia. Strategies to address these issues and mitigate the burden of atherosclerotic disease in this population should be developed.
Short Editorial regarding the article: Predictors of Family Enrollment in a Genetic Cascade Screening Program for Familial Hypercholesterolemia
References1 Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: Guidance for clinicians to prevent coronary heart disease. Eur Heart J. 2013;34(45):3478-90a.NordestgaardBGChapmanMJHumphriesSEGinsbergHNMasanaLDescampsOSFamilial hypercholesterolaemia is underdiagnosed and undertreated in the general population: Guidance for clinicians to prevent coronary heart diseaseEur Heart J201334453478390a2 Brænne I, Kleinecke M, Reiz B, Graf E, Strom T, Wieland T, et al. Systematic analysis of variants related to familial hypercholesterolemia in families with premature myocardial infarction. Eur J Hum Genet 2016;24(2):191-7.BrænneIKleineckeMReizBGrafEStromTWielandTSystematic analysis of variants related to familial hypercholesterolemia in families with premature myocardial infarctionEur J Hum Genet20162421911973 Abul-Husn NS, Manickam K, Jones LK, Wright EA, Hartzel DN, Gonzaga-Jauregui C, et al. Genetic identification of familial hypercholesterolemia within a single U.S. health care system. Science. 2016;354(6319):piiaaf7000.Abul-HusnNSManickamKJonesLKWrightEAHartzelDNGonzaga-JaureguiCGenetic identification of familial hypercholesterolemia within a single U.S. health care systemScience20163546319piiaaf7000piiaaf70004 Santos RD, Gagliardi AC, Xavier HT, Casella Filho A, Araujo DB, Cesena FY, et al. [First Brazilian Guidelines for Familial Hypercholesterolemia]. Arq Bras Cardiol. 2012;99(2 Suppl 2):1-28.SantosRDGagliardiACXavierHTCasellaAFilhoAraujoDBCesenaFYFirst Brazilian Guidelines for Familial HypercholesterolemiaArq Bras Cardiol2012992Suppl 21285 Perez de Isla L, Alonso R, Mata N, Fernández-Pérez C, Muñiz O, Díaz-Díaz JL, et al. Predicting cardiovascular events in familial hypercholesterolemia: the SAFEHEART Registry (Spanish Familial Hypercholesterolemia Cohort Study). Circulation. 2017;135(22):2133-44.Perez de IslaLAlonsoRMataNFernández-PérezCMuñizODíaz-DíazJLPredicting cardiovascular events in familial hypercholesterolemia: the SAFEHEART Registry (Spanish Familial Hypercholesterolemia Cohort Study)Circulation201713522213321446 Perez de Isla L, Alonso R, Watts GF, Mata N, Saltijeral Cerezo A, Muñiz O, et al. Attainment of LDL-cholesterol treatment goals in patients with familial hypercholesterolemia: 5-year SAFEHEART registry follow-up. J Am Coll Cardiol. 2016;67(11):1278-85.Perez de IslaLAlonsoRWattsGFMataNSaltijeral CerezoAMuñizOAttainment of LDL-cholesterol treatment goals in patients with familial hypercholesterolemia: 5-year SAFEHEART registry follow-upJ Am Coll Cardiol20166711127812857 Leren TP. Cascade genetic screening for familial hypercholesterolemia. Clin Genet. 2004;66(6):483-7.LerenTPCascade genetic screening for familial hypercholesterolemiaClin Genet20046664834878 Santos RD, Bourbon M, Alonso R, Cuevas A, Vásquez-Cárdenas A, Pereira AC, et al. Clinical and molecular aspects of familial hypercholesterolemia in Ibero-American countries. J Clin Lipidol. 2016;11(1):160-6.SantosRDBourbonMAlonsoRCuevasAVásquez-CárdenasAPereiraACClinical and molecular aspects of familial hypercholesterolemia in Ibero-American countriesJ Clin Lipidol20161111601669 Henderson R, O’Kane M, McGilligan V, Watterson S. The genetics and screening of familial hypercholesterolaemia. J Biomed Sci. 2016 Apr 16;23:39.HendersonRO’KaneMMcGilliganVWattersonSThe genetics and screening of familial hypercholesterolaemiaJ Biomed Sci1604201623393910 Kerr M, Pears R, Miedzybrodzka Z, Haralambos K, Cather M, Watson M, et al. Cost effectiveness of cascade testing for familial hypercholesterolaemia, based on data from familial hypercholesterolaemia services in the UK. Eur Heart J. 2017;38(23):1832-9.KerrMPearsRMiedzybrodzkaZHaralambosKCatherMWatsonMCost effectiveness of cascade testing for familial hypercholesterolaemia, based on data from familial hypercholesterolaemia services in the UKEur Heart J201738231832183911 Lázaro P, Pérez de Isla L, Watts GF, Alonso R, Norman R, Muñiz O, et al. Cost-effectiveness of a cascade screening program for the early detection of familial hypercholesterolemia. J Clin Lipidol. 2017;11(1):260-71.LázaroPPérez de IslaLWattsGFAlonsoRNormanRMuñizOCost-effectiveness of a cascade screening program for the early detection of familial hypercholesterolemiaJ Clin Lipidol201711126027112 Silva PRS, Jannes CE, Oliveira TGM, Gómez LMG, Krieger JE, Santos RD, et al. Predictors of Family Enrollment in a Genetic Cascade Screening Program for Familial Hypercholesterolemia. Arq Bras Cardiol. 2018; 111(4):578-584.SilvaPRSJannesCEOliveiraTGMGómezLMGKriegerJESantosRDPredictors of Family Enrollment in a Genetic Cascade Screening Program for Familial HypercholesterolemiaArq Bras Cardiol2018111457858413 Khera AV, Won HH, Peloso GM, awson KS, Bartz TM, Deng X, et al. Diagnostic yield and clinical utility of sequencing familial hypercholesterolemia genes in patients with severe hypercholesterolemia. J Am Coll Cardiol .2016;67(22):2578-89.KheraAVWonHHPelosoGMawsonKSBartzTMDengXDiagnostic yield and clinical utility of sequencing familial hypercholesterolemia genes in patients with severe hypercholesterolemiaJ Am Coll Cardiol201667222578258914 Kassner U, Wuhle-Demuth M, Missala I, Humphries SE, Steinhagen-Thiessen E, Demuth I. Clinical utility gene card for: hyper- lipoproteinemia, type II. Eur J Hum Genet. 2014;22(7) doi:10.10338/ejhg.2013.271. Epub 2013 Nov 20KassnerUWuhle-DemuthMMissalaIHumphriesSESteinhagen-ThiessenEDemuthIClinical utility gene card for: hyper- lipoproteinemia, type IIEur J Hum Genet201422710.10338/ejhg.2013.271Epub 2013 Nov 20MinieditorialPreditores de Recrutamento Familiar em um Programa de Rastreamento Genético em Cascata para Hipercolesterolemia FamiliarIzarMaria Cristina de OliveiraFonsecaFrancisco Antonio HelfensteinDisciplina de Cardiologia - Escola Paulista de Medicina - Universidade Federal de São Paulo, São Paulo, SP - BrasilCorrespondência: Maria Cristina de Oliveira Izar, Rua Loefgren, 1350. CEP 04040-001, Vila Clementino, São Paulo, SP - Brasil. E-mail: mcoizar@terra.com.br; mcoizar@cardiol.brPalavras-chaveHipercolesterolemia Tipo II/genéticaTranstornos do Metabolismo LipídicoHipercolesterolemia/tratamento preventivoEstratégia Saúde da Família
A hipercolesterolemia familiar (HF) é uma doença hereditária comum que afeta o metabolismo lipídico; está associada a exposição prolongada a níveis altos de LDL-colesterol e doença cardiovascular aterosclerótica prematura. A HF tem uma carga grande sobre os pacientes e seus parentes, devido aos anos de vida perdidos e, especialmente, por não ser diagnosticada como uma entidade.1
Apesar dos níveis altos de LDL-colesterol e mesmo após um evento aterosclerótico, uma grande proporção de indivíduos com HF permanece sem diagnóstico.2,3 Os critérios para o diagnóstico de HF são baseados em achados clínicos, história familiar, níveis de LDL-colesterol e exames genéticos (Simon Broome ou Dutch Lipid Clinic Network), ou nos níveis isolados de LDL-colesterol (US MED PED).4 No entanto, os fenótipos de HF podem variar, e a ausência de sinais físicos (15-30% dos pacientes com diagnóstico genético de HF apresentam xantomas ou arcos corneanos, e 5% possuem xantelasma) podem contribuir para o subdiagnóstico da HF.5-7
O exame genético com uso de um painel que inclui genes causadores de HF (LDLR, APOB, PCSK9 e LDLRAP-1) é a melhor abordagem para identificar caso - índice.1,4 Quando a triagem em cascata é proposta para uma família com um caso genético confirmado de HF, os custos desse programa de rastreamento são muito menores e são considerados uma intervenção custo-efetiva, que possibilita o diagnóstico e tratamento precoces dos familiares acometidos. Um problema com o rastreamento em cascata é como ter uma alta proporção de parentes aderindo ao programa de rastreamento.8-11
Silva-Souza, et al.,12 no artigo intitulado Preditores de Recrutamento Familiar em um Programa de Triagem Genética em Cascata para Hipercolesterolemia Familiar, identificaram os melhores preditores de triagem genética familiar, usando características derivadas de seus probandos.12 De janeiro de 2011 a julho de 2015, 183 probandos (confirmados para HF por exames genéticos) tiveram seus familiares de 1º grau recrutados para o programa em cascata. A variável de resposta foi o número de parentes que aderiram ao recrutamento.13 Variáveis do estudo foram produzidas a partir de características clínicas e socioeconômicas dos casos índice. Um modelo de regressão binomial linear negativo foi utilizado para testar os preditores. A origem de referência do local da triagem em cascata versus prevenção terciária, o colesterol LDL no caso-índicee a história familiar foram preditores independentes para um número maior de indivíduos recrutados.
Há uma série de razões que reforçariam a necessidade e a importância de aderir a um programa de triagem genética em cascata. Os custos são menores do que quando um caso-índice é diagnosticado,10 é um preditor de doença coronariana,14 a adesão a fármacos hipolipemiantes pode ser aumentada, e o tratamento pode ser iniciado mais cedo na vida.14 Um acompanhamento estruturado dos indivíduos triados deve ser realizado para garantir tratamento precoce e contínuo. A maioria das preocupações relacionadas com a falta de adesão ao rastreamento está relacionada com a educação do paciente/parentes e com a inércia do médico. Estratégias para abordar essas questões e reduzir o ônus da doença aterosclerótica nessa população devem ser desenvolvidas.
Minieditorial referente ao artigo: Preditores de Recrutamento Familiar em um Programa de Rastreamento Genético em Cascata para Hipercolesterolemia Familiar