Familial hypercholesterolemia (FH) is an autosomal-dominant inherited disorder that is often underdiagnosed and undertreated. FH is characterized by a lifelong exposure to high levels of low-density lipoprotein cholesterol (LDL-C), which causes early and accelerated atherogenesis. Patients with genetically defined FH have a risk of coronary heart disease that is >10-fold than that of the general population, and a 3-fold increased risk of cardiovascular disease at the same LDL-C level.1 The relative cardiovascular risk patients with FH is highest between the ages of 25 and 40 years.2 FH can be clinically controlled when treated early: children receiving treatment have a much lower cardiovascular risk than their parents treated in adulthood.3 The prevalence of FH has been estimated at 1:300,4,5 with <5% of cases being detected in childhood. This amounts to over 500,000 children and 2,000,000 adults with undiagnosed FH in Europe, with only a small proportion receiving lipid-lowering treatment.

Several approaches have been established in different countries to improve the detection of FH: screening of entire populations (universal screening); screening of family members following identification of an index case (cascade screening); screening of LDL-C levels whenever available and genetic testing if possible at the time of premature heart attack or during other health-care measures (opportunistic screening); and a combination of any or all of these methods.6, 7, 8, 9, 10 When attached to existing public health programs, a combination of universal and reverse cascade screening was shown to be especially promising and cost-effective.7 In this approach, children are screened either through stand-alone programs or within the framework of routine health initiatives and any case of suspected or confirmed FH triggers family screening.

While these general principles are widely accepted, there is ongoing debate regarding the optimal lipid measure (total cholesterol [TC], LDL-C, or non-high-density lipoprotein cholesterol [non-HDL-C]) and their cut-off values for an elevated probability of diagnosing FH, the optimal age of screening in children, and the role of genetic testing.11 In cascade screening, family history alone is not a reliable indicator for pediatric FH12 and a combined approach of universal screening in children, including genetic testing with subsequent reverse cascade screening in relatives, may be more efficient.8,11

Despite the need for such programs, only a few pediatric screening programs exist in Europe.8,9 In 2004, following the alarming results of a pivotal epidemiological study published in 2003,13 Slovakia initiated a universal mandatory national TC screening for all children nearing their 11th and 17th birthdays, based on the Methodological Instruction of the Ministry of Health 13010/2004. TC is measured in all children and a threshold level of 188 mg/dL (4.85 mmol/L)1 is used to stratify care for hypercholesterolemic children.13 This cut-off level differs from the 201 mg/dL (5.2 mmol/L) used in the United States National Cholesterol Education Programme Adult Treatment Panel III (NECP ATPIII).14 Children with a TC level of 188–209 mg/dL (4.85–5.4 mmol/L) with a negative family history are followed up by a pediatrician. High-risk children and adolescents (those with ≥1 cardiovascular risk factor) are referred to the second level of care (specialists) or, if familial hyperlipoproteinemia is suspected, directly to the third level (specialists in the treatment of metabolic disorders in children, which are part of the “Make Early Diagnosis to Prevent Early Deaths” [MEDPED] network). These specialists provide a stratification of cardiovascular risk with a detailed genealogical examination of first-degree relatives (siblings, parents, and grandparents) and conduct laboratory sampling with family members. Based on these examinations, they conduct a classification and differential diagnosis of dyslipidemia or FH and initiate treatment.

MEDPED is an international project focusing on serious genetic disorders of lipid metabolism and was founded by Roger Williams in 1989.15 In 2002, the Slovak Association of Atherosclerosis (SAA) established the nonprofit foundation “Heart of the Family,” which is fully involved in the organization of the local MEDPED initiative. It is a part of the international ScreenPro FH initiative (http://screenprofh.com/about/structure/slovakia/) and also participates in the FH Studies Collaboration, led by the European Atherosclerosis Society.16 MEDPED has demonstrated its effectiveness in detecting patients at risk of FH in the region. An analysis of data from eight centers participating in the Slovak MEDPED registry reported that FH diagnosis was based on testing for genetic variants in 48.2% of patients and clinical criteria in 51.8% of patients (Dutch Lipid Clinic Network [DLCN] criteria: 32.7%, Simon Broome criteria: 11.6%, US MEDPED criteria: 7.5%).17 Another study of patients from the Slovak MEDPED registry18 included 235 probands with a clinical diagnosis of FH (methodology modified from van Aalst-Cohen et al.19), i.e. LDL-C or TC above the 95th percentile for age and sex, and met at least one of the following criteria: a) evidence of hyperlipidemia in a first-degree relative, b) evidence of CVD before the age of 65 years in the patient or a first-degree relative, c) presence of xanthoma or corneal arcus in the patient or a relative. Among these patients with clinical FH, APOB mutation was detected in 6% (14/235) and LDLR mutation in 38% (89/235); hence, 44% of patients with clinical FH were confirmed to have genetic mutations.

The Slovak National Health Information Center has reported that 94.1% of 6–14-year-old children and 71.7% of 15–18-year-old adolescents underwent a preventive examination during 2019–2020.20 The effectiveness of this program in identifying individuals with FH via reverse cascade screening has not been systematically assessed. Therefore, this study aimed to estimate the proportion of FH cases among parents of children with elevated TC levels identified during the national mandatory universal TC screening.