Familial Hypercholesterolemia in Children and Adolescents | Ten Points to Remember

Wiegman A, Gidding SS, Watts GF, et al.
Familial Hypercholesterolaemia in Children and Adolescents: Gaining Decades of Life by Optimizing Detection and Treatment. Eur Heart J 2015;May 25:[Epub ahead of print].

The following are 10 points to remember about familial hypercholesterolemia (FH) in children and adolescents:

  1. FH is a common genetic cause of premature coronary heart disease (CHD). Both homozygous (HoFH) and heterozygous (HeFH) FH result in markedly reduced hepatic capacity to clear atherogenic cholesterol-rich low-density lipoproteins (LDLs) from the circulation.
  2. FH is most often caused by mutations in the LDL receptor (LDLR) gene, resulting in absent or dysfunctional receptors on the surface of hepatocytes, the principal site of LDL catabolism. Among a CHD-free control population, 1 in 217 carry a mutation in the gene encoding the LDLR and had LDL-C >190 mg/dl.
  3. More than 1,700 mutations in the LDLR gene on chromosome 19 have been identified, of which 79% are probably expressed as a hypercholesterolemic phenotype. Defects in the genes encoding apolipoprotein B (apoB) and proprotein convertase subtilisin/kexin type 9 (PCSK9) account for ~5% and <1% of FH cases. However, 5-30% of cases of phenotypic FH may arise from mutations in unidentified genes, or have a polygenic cause as distinct from a dominantly inherited disorder. An LDL-C >500 mg/dl is consistent with HoFH or may be a compound HeFH in which each parent has a different mutation in the LDLR or mutations in apoB or PCSK9 genes.
  4. In FH, attenuated clearance of plasma LDL-C by the LDLR leads to increased numbers of circulating LDL, which penetrate and then accumulate in the artery wall, become oxidatively modified, and subsequently initiate an inflammatory response, resulting in vascular injury and atherosclerotic plaque. The atherosclerotic process begins in the fetus. Additional factors in the lipoprotein profile in FH can increase atherosclerosis and CHD risk including lipoprotein (a) [Lp(a)] and triglyceride-rich lipoprotein remnants, and low levels of or dysfunctional HDL.
  5. A child of a parent with FH has a 50% probability of inheriting FH, thereby emphasizing the importance of a family pedigree to identify relatives for screening. After dietary intervention, any child with an LDL-C level ≥190 mg/dl has a high probability of genetically based FH. If there is a family history of premature CHD in close relatives and/or baseline high cholesterol in one parent, an LDL-C ≥160 mg/dl has a high probability of genetically based FH, and if a parent has HeFH, an LDL-C ≥130 mg/dl is likely to be HeFH.
  6. Genetic testing for those at risk or with the FH phenotype is recommended with genetic screening of children and adolescents in those with a parent or sibling with a mutation (not covered by payers in the United States). In the United States, universal screening at age 9-11 years has been recommended, in part because selective screening based on family history is not efficient in identifying children with LDL-C in the FH range.
  7. Children with HeFH should be treated with a fat-modified, heart-healthy diet at diagnosis, and begin statins at age 8-10 years. For children aged 8-10 years, LDL-C is ideally reduced by 50% from pretreatment levels. For children aged ≥10 years, especially if there are additional cardiovascular risk factors, including elevated Lp(a), the target LDL-C is <130 mg/dl. Addition of ezetimibe or a bile-acid sequestrant may be required to attain LDL-C goal. After starting treatment, lipid levels, weight, growth, physical and sexual development, and hepatic aminotransferases should be monitored.
  8. The use of carotid intima-media thickness and coronary artery calcium score by computed tomography is not recommended until evidence of its clinical utility is established.
  9. Counseling is recommended for all women considering pregnancy, especially when both prospective parents have FH, because of the 25% risk of having a child with HoFH. Statins should be discontinued 3 months before planned conception and during pregnancy and lactation. Bile-acid resins are the only safe agents for management of hypercholesterolemia during pregnancy and breast-feeding.
  10. In HoFH, treatment with a statin and ezetimibe must be started at diagnosis, albeit statins are not approved for those <6-8 years. Lipoprotein apheresis should be started as soon possible; and may be as early as age 2 years in specialized centers. Both approaches have delayed cardiovascular events and increased survival. Liver transplantation is increasingly considered as a therapeutic approach in difficult cases. Two new agents, oral lomitapide, a microsomal triglyceride transfer protein inhibitor, and injectable mipomersen, an antisense RNA therapy, both of which target hepatic production of atherogenic apoB-containing lipoproteins, were recently approved in the United States as adjunct therapy for HoFH in patients aged ≥18 and ≥12 years, respectively. Monoclonal antibody therapies to PCSK9 show the most promise, lowering both LDL-C and Lp(a).

Clinical Topics: Congenital Heart Disease and Pediatric Cardiology, Diabetes and Cardiometabolic Disease, Dyslipidemia, Noninvasive Imaging, Prevention, Vascular Medicine, CHD & Pediatrics and Arrhythmias, CHD & Pediatrics and Imaging, CHD & Pediatrics and Prevention, CHD & Pediatrics and Quality Improvement, Advanced Lipid Testing, Homozygous Familial Hypercholesterolemia, Lipid Metabolism, Nonstatins, Novel Agents, Primary Hyperlipidemia, Echocardiography/Ultrasound, Diet

Keywords: Adolescent, Apolipoproteins, Atherosclerosis, Bile, Cardiovascular Diseases, Child, Carotid Intima-Media Thickness, Cholesterol, Cholesterol, LDL, Chromosomes, Human, Pair 19, Coronary Disease, Counseling, Diet, Dyslipidemias, Genetic Testing, Hepatocytes, Hypercholesterolemia, Hyperlipoproteinemia Type II, Lipoprotein(a), Lipoproteins, Lipoproteins, LDL, Mutation, Plaque, Atherosclerotic, Phenotype, Primary Prevention, Proprotein Convertases, Receptors, LDL, Risk Factors, Subtilisins, Tomography, Transaminases, Triglycerides, Vascular System Injuries

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