National universal screening in children may be more reliable in identifying familial hypercholesterolemia (FH) than selective screening based on family history, according to a study published Sept. 7 in the Journal of the American College of Cardiology.

Researchers examined 272 unrelated participants in Slovenia born between 1989 and 2009. Subjects had either total cholesterol >231.7 mg/dl or total cholesterol >193.1 mg/dl and a positive family history of premature cardiovascular disease. Serum total cholesterols levels at universal screening for hypercholesterolemia at age five and fasting lipid profile were measured at first admission to a tertiary pediatric outpatient clinic. Participants referred to the tertiary pediatric outpatient clinic were 7.3±3.1 years of age. A cardiovascular complications-positive family history was identified in 33.1 percent of participants.

Assuming the commonly reported FH incidence rate of 1 in 500, the predicted detection rate between 2009 and 2013 was 53.6 percent, reaching its peak in 2013 with an upper predicted detection rate of 96.3 percent. Assuming a greater incidence of 1 in 200, the upper estimated detection rate was only 38.5 percent. Of the total study population, 105 (38.6 percent) participants had heterozygous disease-causing variants in the LDL receptor (LDLR), 50 (18.4 percent) in apolipoprotein B (APOB), and none in PCSK9.

Additionally, nine novel disease-causing variants were identified, eight in the LDL receptor and one in APOB. In the remaining participants without disease-causing variants, 51 (18.7 percent) were carriers of the hypercholesterolemia-associated apolipoprotein E (APOE) E4 isoform and 66 (24.3 percent) had conditions that remained genetically undiagnosed. A cardiovascular complication-negative family history was associated with 48.6 percent, 60.0 percent, and 76.5 percent of patients with disease-causing or disease-associated variants in LDLR, APOB, or APOE E4 isoform, respectively. Relative risk of having a disease-causing genetic variant when a participant had a positive family history was 1.53 (RR: 1.529; 95 percent CI: 1.25 to 1.88; p = 0.0001).

The researchers, led by Gašper Klančar, BSc, of University Children’s Hospital, UMC Ljubljana, in Ljubljana, Slovenia, explain that while children were screened at five years, the fact that the mean referral age to a tertiary pediatric outpatient clinical 7.3 years of age indicates that additional education intervention to promote rapid referral may be required, along with a record of children not referred or whose parents refused referral. The authors add an additional benefit to screening all children is that once a child with FH is identified, 96 percent of parents with the disorder can be detected as well. All parents and older siblings from children identified as having FH in the study were referred for evaluation.

The study findings indicate that that only one-half of the total population was reached. Continuation and further improvements of screening and referral strategies will provide more data for the real FH incidence in this population and improve clinical algorithms in FH risk management. While the optimal age for a universal screening for hypercholesterolemia remains undetermined, the authors recommend intervention before pubertal age. They conclude that universal screening is more reliable for detecting FH than family history.

In an editorial comment accompanying the study, Stephen R. Daniels, MD, PhD, FACC, of the University of Colorado School of Medicine in Aurora, Colorado, writes that while these findings are important, “[m]ore evidence is required to determine the optimal approach to screening for children with FH. Experience with screening programs such as the one in Slovenia is useful, but well-designed prospective studies to evaluate the screening process will be even more important to provide the needed answers.” 

Keywords: Ambulatory Care Facilities, Apolipoproteins B, Apolipoproteins E, Cardiovascular Diseases, Heterozygote, Hypercholesterolemia, Hyperlipoproteinemia Type II, Protein Isoforms, Receptors, LDL, Risk Management

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