The Lancet ( IF 168.9 ) Pub Date : 2023-12-12 , DOI: 10.1016/s0140-6736(23)01842-1 Kanika Inamdar Dharmayat , Antonio J. Vallejo-Vaz , Christophe A.T. Stevens , Julia M. Brandts , Alexander R.M. Lyons , Urh Groselj , Marianne Abifadel , Carlos A. Aguilar-Salinas , Khalid Alhabib , Mutaz Alkhnifsawi , Wael Almahmeed , Fahad Alnouri , Rodrigo Alonso , Khalid Al-Rasadi , Tester F. Ashavaid , Maciej Banach , Sophie Béliard , Christoph Binder , Mafalda Bourbon , Krzysztof Chlebus , Pablo Corral , Diogo Cruz , Olivier S. Descamps , Euridiki Drogari , Ronen Durst , Marat V. Ezhov , Jacques Genest , Mariko Harada-Shiba , Kirsten B. Holven , Steve E. Humphries , Weerapan Khovidhunkit , Katarina Lalic , Ulrich Laufs , Evangelos Liberopoulos , Jeanine Roeters van Lennep , Marcos Miguel Lima-Martinez , Jie Lin , Vincent Maher , Winfried März , André R. Miserez , Olena Mitchenko , Hapizah Nawawi , Andrie G. Panayiotou , György Paragh , Arman Postadzhiyan , Ashraf Reda , Željko Reiner , Ximena Reyes , Fouzia Sadiq , Amirhossein Sahebkar , Heribert Schunkert , Aleksandr B. Shek , Eric Stroes , Ta-Chen Su , Tavintharan Subramaniam , Andrey Susekov , Alejandra Vázquez Cárdenas , Thanh Huong Truong , Alexandros D. Tselepis , Branislav Vohnout , Luya Wang , Shizuya Yamashita , Ahmad Al-Sarraf , Nasreen Al-Sayed , Kairat Davletov , Bambang Dwiputra , Dan Gaita , Meral Kayikcioglu , Gustavs Latkovskis , A. David Marais , Anne Thushara Matthias , Erkin Mirrakhimov , Børge G. Nordestgaard , Zaneta Petrulioniene , Belma Pojskic , Wilson Sadoh , Myra Tilney , Brian Tomlinson , Anne Tybjærg-Hansen , Margus Viigimaa , Alberico L. Catapano , Tomas Freiberger , G. Kees Hovingh , Pedro Mata , Handrean Soran , Frederick Raal , Gerald F. Watts , Laura Schreier , Virginia Bañares , Susanne Greber-Platzer , Margot Baumgartner-Kaut , Charlotte de Gier , Hans Dieplinger , Florian Höllerl , Reinhold Innerhofer , Daniela Karall , Julia Lischka , Bernhard Ludvik , Martin Mäser , Sabine Scholl-Bürgi , Alexandra Thajer , Hermann Toplak , Fabian Demeure , Ann Mertens , Jean-Luc Balligand , Xavier Stephenne , Etienne Sokal , Ivo Petrov , Assen Goudev , Fedya Nikolov , Snejana Tisheva , Yoto Yotov , Ivajlo Tzvetkov , Robert A Hegele , Daniel Gaudet , Liam Brunham , Isabelle Ruel , Brian McCrindle , Ada Cuevas , Dražen Perica , Phivos Symeonides , Efstratios Trogkanis , Andreas Kostis , Andreas Ioannou , Angeliki Mouzarou , Anthoula Georgiou , Andreas Stylianou , George Miltiadous , Paris Iacovides , Constantinos Deltas , Michal Vrablik , Zuzana Urbanova , Pavel Jesina , Lukas Tichy , Josef Hyanek , Jana Dvorakova , Jana Cepova , Josef Sykora , Kristyna Buresova , Michal Pipek , Eva Pistkova , Ivana Bartkova , Astrid S|ulakova , Lenka Toukalkova , Michaela Spenerova , Jan Maly , Marianne Benn , Ahmed Bendary , Atef Elbahry , Jean Ferrières , Dorota Ferrieres , Noel Peretti , Eric Bruckert , Antonio Gallo , René Valero , Florian Mourre , Karine Aouchiche , Rachel Reynaud , Patrick Tounian , Julie Lemale , Franck Boccara , Philippe Moulin , Sybil Charrières , Mathilde Di Filippo , Bertrand Cariou , François Paillard , Caroline Dourmap , Alain Pradignac , Bruno Verges , Isabelle Simoneau , Michel Farnier , Yves Cottin , Cecile Yelnik , Regis Hankard , François Schiele , Vincent Durlach , Ariane Sultan , Alain Carrié , Jean-Pierre Rabès , Veronika Sanin , Roland Schmieder , Sara Ates , Christos V. Rizos , Ioannis Skoumas , Konstantinos Tziomalos , Loukianos Rallidis , Vasileios Kotsis , Michalis Doumas , Emmanouil Skalidis , Genovefa Kolovou , Vana Kolovou , Anastasia Garoufi , Iosif Koutagiar , Georgios Polychronopoulos , Estela Kiouri , Christina Antza , Evangelos Zacharis , Achilleas Attilakos , George Sfikas , Charalambos Koumaras , Panagiotis Anagnostis , Georgia Anastasiou , George Liamis , Petros-Spyridon Adamidis , Haralambos Milionis , Vaia Lambadiari , Stella Stabouli , Theodosios Filippatos , Vicky Mollaki , Anastasia Tsaroumi , Frida Lamari , Pavlos Proyias , Mariann Harangi , Lakshmi Lavanya Reddy , Swarup A. V Shah , Chandrashekhar K. Ponde , Jamshed J. Dalal , Jitendra P.S. Sawhney , Ishwar C. Verma , Susan Hosseini , Tannaz Jamialahmadi , Mohammed Alareedh , Foaad Shaghee , Sabah Hasan Rhadi , Maryam Abduljalal , Sarmad Alfil , Huda Kareem , Hofit Cohen , Eran Leitersdorf , Daniel Schurr , Shoshi Shpitzen , Marcello Arca , Maurizio Averna , Stefano Bertolini , Sebastiano Calandra , Patrizia Tarugi , Manuela Casula , Federica Galimberti , Marta Gazzotti , Elena Olmastroni , Riccardo Sarzani , Claudio Ferri , Elena Repetti , Francesco Giorgino , Patrizia Suppressa , Antonio Carlo Bossi , Claudio Borghi , Sandro Muntoni , Francesco Cipollone , Roberto Scicali , Arturo Pujia , Angelina Passaro , Martina Berteotti , Valerio Pecchioli , Livia Pisciotta , Giuseppe Mandraffino , Fabio Pellegatta , Giuliana Mombelli , Adriana Branchi , Anna Maria Fiorenza , Cristina Pederiva , José Pablo Werba , Gianfranco Parati , Fabio Nascimbeni , Lorenzo Iughetti , Giuliana Fortunato , Raimondo Cavallaro , Gabriella Iannuzzo , Paolo Calabrò , Angelo Baldassare Cefalù , Maria Elena Capra , Alberto Zambon , Matteo Pirro , Francesco Sbrana , Chiara Trenti , Ilenia Minicocci , Massimo Federici , Maria Del Ben , Paola Sabrina Buonuomo , Simona Moffa , Antonio Pipolo , Nadia Citroni , Ornella Guardamagna , Salvatore Lia , Andrea Benso , Gianni Biolo Biolo , Lorenzo Maroni , Alessandro Lupi , Luca Bonanni , Elisabetta Rinaldi , Maria Grazia Zenti , Daisaku Masuda , Linda Mahfouz , Selim Jambart , Carine Ayoub , Youmna Ghaleb , Noor Alicezah Mohd Kasim , Noor Shafina Mohd Nor , Alyaa Al-Khateeb , Siti Hamimah Sheikh Abdul Kadir , Yung-An Chua , Aimi Zafira Razman , Sukma Azureen Nazli , Norashikin Mohd Ranai , Ahmad Zubaidi Abd Latif , María Teresa Magaña Torres , Roopa Mehta , Alexandro J. Martagon , Gabriela A. Galan Ramirez , Neftali Eduardo Antonio-Villa , Arsenio Vargas-Vazquez , Daniel Elias-Lopez , Gustavo Gonzalez Retana , Bethsabel Rodriguez Encinas , Jose J. Ceballos Macias , Alejandro Romero Zazueta , Rocio Martinez Alvarado , Julieta D. Morales Portano , Humberto Alvares Lopez , Leobardo Sauque-Reyna , Laura G. Gomez Herrera , Luis E. Simental Mendia , Humberto Garcia Aguilar , Elizabeth Ramirez Cooremans , Berenice Pe~na Aparicio , Victoria Mendoza Zubieta , Perla A. Carrillo Gonzalez , Aldo Ferreira-Hermosillo , Nacu Caracas Portilla , Guadalupe Jimenez Dominguez , Alinna Y. Ruiz Garcia , Hector E. Arriaga Cazares , Jesus R. Gonzalez Gonzalez , Carla V. Mendez Valencia , Francisco G. Padilla Padilla , Ramon Madriz Prado , Manuel O. De los Rios Ibarra , Ruy D. Arjona Villica~na , Karina J. Acevedo Rivera , Ricardo Allende Carrera , Jose A. Alvarez , Jose C. Amezcua Martinez , Manuel de los Reyes Barrera Bustillo , Gonzalo Carazo Vargas , Roberto Contreras Chacon , Mario H. Figueroa Andrade , Ashanty Flores Ortega , Hector Garcia Alcala , Laura E. Garcia de Leon , Berenice Garcia Guzman , Jose J. Gardu~no Garcia , Juan C. Garnica Cuellar , Jose R. Gomez Cruz , Anell Hernandez Garcia , Jesus R. Holguin Almada , Ursulo Juarez Herrera , Fabiola Lugo Sobrevilla , Eduardo Marquez Rodriguez , Cristina Martinez Sibaja , Alma B. Medrano Rodriguez , Jose C. Morales Oyervides , Daniel I. Perez Vazquez , Eduardo A. Reyes Rodriguez , Ma. Ludivina Robles Osorio , Juan Rosas Saucedo , Margarita Torres Tamayo , Luis A. Valdez Talavera , Luis E. Vera Arroyo , Eloy A. Zepeda Carrillo , Annette Galema-Boers , Albert Weigman , Martin P. Bogsrud , Munir Malik , Saeedullah Shah , Sabeen Abid Khan , Muhammad Asim Rana , Hijab Batool , Ewa Starostecka , Agnieszka Konopka , Joanna Lewek , Agata Bielecka-Dąbrowa , Agnieszka Gach , Jacek Jóźwiak , Marcin Pajkowski , Marzena Romanowska-Kocejko , Marta Żarczyńska-Buchowiecka , Marcin Hellman , Magdalena Chmara , Bartosz Wasąg , Aleksandra Parczewska , Natasza Gilis-Malinowska , Justyna Borowiec-Wolna , Aneta Stróżyk , Aleksandra Michalska-Grzonkowska , Izabela Chlebus , Mariola Kleinschmidt , Agnieszka Wojtecka , Tomasz Zdrojewski , Małgorzata Myśliwiec , Matylda Hennig , Ana Margarida Medeiros , Ana Catarina Alves , Ana Filipa Almeida , Andreia Lopes , António Guerra , Carla Bilhoto , Fernando Simões , Francisco Silva , Goreti Lobarinhas , Guida Gama , Isabel Palma , José Miguel Salgado , Luísa Diogo Matos , Márcio de Moura , Maria João Virtuoso , Mónica Tavares , Patrícia Ferreira , Patrícia Pais , Paula Garcia , Raquel Coelho , Raquel Ribeiro , Susana Correia , Dinara Sadykova , Evgenia Slastnikova , Dalal Alammari , Horia Ahmed Mawlawi , Atif Alsahari , Alia Abdullah Khudary , Nawal Lafi Alrowaily , Natasa Rajkovic , Ljiljana Popovic , Sandra Singh , Iva Rasulic , Ana Petakov , Nebojsa M. Lalic , Fabian Kok Peng , Rashida Farhan Vasanwala , Sreedharan Aravind Venkatesh , Katarina Raslova , Lubomira Fabryova , Jan Nociar , Jana Šaligova , Ludmila Potočňáková , Miriam Kozárová , Tibor Varga , Michaela Kadurova , Marianna Debreova , Peter Novodvorsky , Katarina Gonova , Alexander Klabnik , Ingrid Buganova , Tadej Battelino , Barbara Jenko Bizjan , Marusa Debeljak , Jernej Kovac , Matej Mlinaric , Neza Molk , Jaka Sikonja , Ursa Sustar , Katarina Trebusak Podkrajsek , Ovidio Muñiz-Grijalvo , Jose Luis Díaz-Díaz , Raimundo de Andrés , Francisco Fuentes-Jiménez , Dirk Blom , Eleonore B. Miserez , Janine L. Shipton , Poranee Ganokroj , Marta Futema , Uma Ramaswami , Rano B. Alieva , Khurshid G. Fozilov , Shavkat U. Khoshimov , Ulugbek I. Nizamov , Guzal J. Abdullaeva , Liliya E. Kan , Alisher A. Abdullaev , Daria V. Zakirova , Doan-Loi Do , Mai-Ngoc-Thi Nguyen , Ngoc-Thanh Kim , Thanh-Tung Le , Hong-An Le , Raul Santos , Kausik K. Ray
Background
Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies.
Methods
For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia.
Findings
Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8–13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05–6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50–75% of children and adolescents with familial hypercholesterolaemia not being identified.
Interpretation
Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life.
Funding
Pfizer, Amgen, Merck Sharp & Dohme, Sanofi–Aventis, Daiichi Sankyo, and Regeneron.
中文翻译：
48 个国家儿童和青少年的家族性高胆固醇血症：一项横断面研究
背景
全球每年大约有 450 000 名儿童出生时患有家族性高胆固醇血症，但只有 2·1% 的成人家族性高胆固醇血症在 18 岁之前通过目前的诊断方法被诊断出来，这些诊断方法来自于对成人的观察。我们的目的是描述患有杂合子家族性高胆固醇血症（HeFH）的儿童和青少年的特征，并了解当前识别和管理家族性高胆固醇血症的方法，为未来的公共卫生策略提供信息。
方法
在这项横断面研究中，我们评估了 2015 年 10 月 1 日至 2021 年 1 月 31 日期间进入家族性高胆固醇血症研究合作组织 (FHSC) 登记册时临床或基因诊断为 HeFH 的 18 岁以下儿童和青少年. 登记处的数据是从 48 个国家的 55 个区域或国家登记处收集的。依赖于家族性高胆固醇血症和疑似继发性高胆固醇血症的自我报告病史的诊断被排除在登记之外；未经治疗的低密度脂蛋白胆固醇 (LDL-C) 至少为 13·0 mmol/L 的患者被排除在本研究之外。数据按世卫组织区域、世界银行国家收入状况、年龄、诊断标准和指示病例状况进行总体评估。这项研究的主要结果是评估目前对患有家族性高胆固醇血症的儿童和青少年的识别和治疗。
发现
在 FHSC 登记的 63 093 名个体中，11 848 名 (18·8%) 是 18 岁以下患有 HeFH 的儿童或青少年，并被纳入本研究；11 476 例纳入个体中，女性 5756 例（50·2%），男性 5720 例（49·8%）。11 848 人中，有 372 人 (3·1%) 的性别数据缺失。登记时的中位年龄为 9·6 岁 (IQR 5·8–13·2)。11 235 名受试者中的 10 099 名 (89·9%) 经最终基因确诊为家族性高胆固醇血症，1136 名 (10·1%) 进行了临床诊断。11 848 人中有 613 人（5·2%）缺少基因确诊数据或临床诊断数据。基因诊断在高收入国家的儿童和青少年（10 202 人中的 9427 人 [92·4%]）中比非高收入国家的儿童和青少年（415 人中的 199 人[48·0%]）更常见。10 804 名儿童青少年中，3 414 名（31·6%）为指示病例。家族性高胆固醇血症相关的体征、心血管危险因素和心血管疾病并不常见，但在非高收入国家更为常见。10 428 名儿童或青少年中有 7557 名 (72·4%) 未服用降脂药物 (LLM)，且中位 LDL-C 为 5·00 mmol/L (IQR 4·05–6·08)。与基因诊断相比，使用未适应的成人临床标准并依赖于更极端的表型可能会导致 50-75% 的患有家族性高胆固醇血症的儿童和青少年未被识别。
解释
在患有家族性高胆固醇血症的成人中观察到的临床特征在患有家族性高胆固醇血症的儿童和青少年中并不常见，因此该年龄组的检测依赖于 LDL-C 的测量和基因确认。在无法进行基因检测的情况下，在生命最初几年增加 LDL-C 测量的可用性和使用可能有助于缩小目前患病率和检测之间的差距，从而增加组合法学硕士的使用，以在生命早期达到建议的 LDL-C 目标。
资金
辉瑞、安进、默沙东、赛诺菲-安万特、第一三共和再生元。
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