Pediatric Familial Hypercholesterolemia

Lifelong exposure to elevated low-density lipoprotein cholesterol (LDL-C) leads to premature coronary artery disease. Thus, early recognition of familial hypercholesterolemia (FH), a genetic condition that causes LDL receptor function to be impaired, is important. Recent publications from the European Atherosclerosis Society have indicated that FH is under-diagnosed and under-treated, emphasizing the critical importance of screening and beginning therapy at diagnosis for homozygotes and at age 8-10 years for heterozygotes.1-4 This Expert Analysis article recapitulates recent findings and recommendations.

Diagnosis and Screening

The phenotypic diagnosis of FH in children is established with two LDL-C levels (obtained at least 3 months apart) that are >190 mg/dl or >160 mg/dl, in the presence of a family history of severely elevated levels or premature coronary artery disease in a first-degree relative. If a parent has a documented FH gene mutation, then an LDL-C >130 mg/dl is sufficient. DNA testing confirms the diagnosis. Secondary causes of hypercholesterolemia, such as obstructive liver disease, hypothyroidism, or nephrotic syndrome should be ruled out.

Cascade screening of first-degree relatives of an index patient is the best way to identify cases. In the United States, universal cholesterol screening of children between ages 9-11 years has been recommended but has yet to be universally implemented.2 Because childhood LDL-C levels have the best discriminatory power for detecting FH, universal pediatric screening followed by reverse cascade parental testing, should theoretically allow for excellent case identification.

Based on studies of carotid intima media thickness, coronary artery calcium deposits, and extrapolations from observations of the Pathobiological Determinants of Atherosclerosis in Youth Study, accelerated atherosclerosis in FH likely develops late in the first or early in the second decade of life. A theoretical model has shown that treatment beginning at ages 8-10 years may be advantageous, as a treatment delay of even a decade results in excessive lifelong exposure to hypercholesterolemia.1


The goal of therapy is a 50% reduction in LDL-C levels, preferably to <130 mg/dl. If dietary and lifestyle modifications fail to achieve this, pharmacologic treatment with statins is recommended beginning at ages 8-10 years. Clinical trials are underway that include therapy for children as young as 6 years. Assessment of other cardiovascular risk factors, including measurement of lipoprotein(a) is recommended. Ezetimibe, an antilipemic agent that acts by decreasing intestinal absorption of cholesterol, may be added to the therapeutic regimen if necessary.5 Therapy before adulthood has been proven to be advantageous, as those who were treated from adolescence until age 30 years were event free, while 7% of parents had an event by that age.1 During medication initiation, LDL-C levels may be monitored every 3 months and, once stable, less frequently thereafter. In the absence of trials with patient follow-up longer than 10 years, clinicians should balance the risks and benefits of escalating treatment. It is important to monitor for muscle pain and liver dysfunction, as well as counsel against pregnancy for females on statin therapy.

Future Directions

While there is sufficient evidence to recommend treatment of FH in childhood, knowledge gaps exist in cost analysis, efficacy, long-term safety and outcome metrics. Evaluating the role of imaging in identifying subclinical atherosclerosis is important for risk stratification. Multidisciplinary, family-centric models of FH care that may vary by country or region, depending on available resources, should be established. Ideally, these clinical sites should include primary care providers, lipid specialists, cardiologists, nurses, dieticians, genetic counselors, pharmacists, and psychologists, depending on case complexity.


  1. 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;36:2425-37.
  2. National Health, Lung, and Blood Institute. Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents (NHLBI website). 2013. Available at: Accessed on 9/21/2015.
  3. Nordestgaard BG, Chapman MJ, Humphries SE, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: Consensus Statement of the European Atherosclerosis Society. Eur Heart J 2013;34:3478-3490a.
  4. Cuchel M, Bruckert E, Ginsberg HN, et al. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J 2014;35:2146-57.
  5. Vuorio A, Doherty KF, Humphries SE, Kuoppala J, Kovanen PT. Statin treatment of children with familial hypercholesterolemia - trying to balance incomplete evidence of long-term safety and clinical accountability: are we approaching a consensus? Atherosclerosis 2013;226:315-320

Clinical Topics: Congenital Heart Disease and Pediatric Cardiology, Dyslipidemia, Noninvasive Imaging, 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, Statins, Echocardiography/Ultrasound

Keywords: Adolescent, Atherosclerosis, Calcium, Cardiovascular Diseases, Carotid Intima-Media Thickness, Child, Cholesterol, Cholesterol, LDL, Coronary Artery Disease, DNA, Follow-Up Studies, Heterozygote, Homozygote, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypercholesterolemia, Hyperlipoproteinemia Type II, Hypothyroidism, Intestinal Absorption, Life Style, Lipoprotein(a), Lipoproteins, LDL, Liver Diseases, Models, Theoretical, Mutation, Myalgia, Nephrotic Syndrome, Nutritionists, Parents, Pharmacists, Primary Health Care, Receptors, LDL, Risk Assessment, Risk Factors, Specialization

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