Original ArticleLong term follow-up of children with familial hypercholesterolemia and relatively normal LDL-cholesterol at diagnosis
Introduction
Familial hypercholesterolemia (FH) is an inherited disease primarily caused by mutations in one of three genes; low-density lipoprotein (LDL) receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin/kexin type 9 (PCSK9), leading to elevated plasma cholesterol from the first years of life and increased risk of atherosclerotic cardiovascular disease among both sexes.1 Early diagnosis and treatment from 8 to 10 years of age is strongly recommended to reduce cardiovascular disease risk. In clinical screening programs a cut-off of LDL-cholesterol (LDL-C) of more than 4.0 mmol/L (~160 mg/dL)2 has been suggested for suspecting an FH diagnosis.3 In families with a known FH mutation, genetic testing of family members (cascade screening) is the most reliable and cost-effective method to identify affected individuals and is recommended by the EAS Consensus Panel.1,2 Although the majority of children who carry an FH mutation have elevated cholesterol levels, we previously reported that approximately 8% may have relatively normal cholesterol levels at time of diagnosis.4 It has been questioned whether these children can be considered to have true FH, and if they need follow-up at lipid clinics and later statin treament.5,6 No data currently exists on whether these children with relatively normal LDL-C levels, but carrying an FH mutation, actually need follow-up and statin treatment. In a short pilot study we reported that 11 out of 25 children with relatively normal pretreatment LDL-C had increased cholesterol levels during 3.8 years of follow-up.4
In the present study, we further investigate the clinical significance of carrying an FH mutation with relatively normal LDL-C levels in a larger cohort and with longer follow-up.
Section snippets
Methods
Children (≤18 years) with genetically verified FH (“likely pathogenic” or “pathogenic” mutation according to the guidelines published by the American College of Medical Genetics7), and who were followed-up at the Lipid Clinic, Oslo University Hospital, Oslo, Norway (1990–2018) and the Cardiovascular Genetics Center and the Sophia Children's Hospital of the Erasmus MC Rotterdam, the Netherlands (1993–2018), were included in the study. Part of the study sample and details on data collection, have
Characteristics
Out of 742 children with genetically verified FH, 109 children (15%) had pretreatment LDL-C ≤ 4.1 mmol/L (~160 mg/dL) of which 49 (6.6%) had LDL-C ≤ 3.5 mmol/L (~130 mg/dL). Pretreatment LDL-C was measured at age 11.8 (3.9) years.
Follow-up and statin treatment
Among the 109 children with LDL-C ≤ 4.1 mmol/L (~160 mg/dL), 78 (71.6%) were initiated on statins during follow-up. Age of statin start was 16.0 (4.4) years. Patients were followed 8.2 (5.2) years (Table 1). Pretreatment LDL-C was 3.6 (0.4) mmol/L and latest follow-up
Discussion
This is the first study to investigate the long-term clinical significance of carrying an FH mutation in children with relatively normal LDL-C levels at diagnosis. More than 70% of these children were initiated on statins during follow-up. These findings might even underestimate the need for statin treatment in follow-up since mean age at end of follow-up of the children, not initiated on statins, was only 14.4 years. Pretreatment LDL-C levels ≥3.5 mmol/L (~130 mg/dL) has been suggested as
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Cited by (2)
Integrated guidance to enhance the care of children and adolescents with familial hypercholesterolaemia: Practical advice for the community clinician
2022, Journal of Paediatrics and Child HealthGenetic Analysis of Japanese Children Clinically Diagnosed with Familial Hypercholesterolemia
2022, Journal of Atherosclerosis and Thrombosis
Funding: This study was supported by the University of Oslo, Oslo, Norway, the Norwegian National Advisory Unit on FH, Oslo University Hospital, Oslo, Norway, the Throne-Holst Foundation for Nutrition Research, Oslo, Norway and the South-Eastern Regional Health Authority, Oslo, Norway.
Conflict of interest: Dr. Bogsrud has received research grants and/or personal fees from Amgen, Sanofi, MSD, Boehringer Ingelheim, Mills DA and Kaneka, none of which are related to the content of this manuscript. Dr. Retterstøl has received research grants and/or personal fees from Amgen, Mills DA, the Directorate for Health in Norway, The Norwegian Medical Association, Sanofi, Chiesi, Takeda, Bayer, MSD, none of which are related to the content of this manuscript. Dr Roeters van Lennep reports honoraria from Akcea and grants from Aegerion/Amryt none of which are related to the content of this manuscript. Dr. Langslet reports lecture and advisory board fees from Amgen, Sanofi and Boehringer. Dr. Holven reports grants and/or personal fees from Tine SA, Mills DA, Olympic Seafood, Amgen, Sanofi, Kaneka and Pronova, none of which are related to the content of this manuscript. Msc. Johansen and dr. Narverud have no financial relationships relevant to disclose.
Authors' contribution: AKJ, MPB, and KBH conceived and designed research; AKJ, MPB, JRvL, IN, GL, KR and KBH conducted research; AKJ and KBH performed statistical analyses; all authors interpreted results; AKJ, MPB, and KBH were responsible for drafting the manuscript and were responsible for final content; all authors read, critically revised, and approved the final manuscript.