This paper presents the algorithm used in Lithuania to detect FH patients and initiate further screening. FH is now widely recognized as a public health care issue. Early detection and aggressive timely treatment of FH are highly important for preventing ASCVD caused by permanent exposure to increased LDL-C blood levels [20]. The currently used screening strategy in Lithuania is mainly based on opportunistic testing guided by increased LDL-C levels, followed by cascade screening of first-degree relatives when an index case of FH is detected. Cascade screening is the most commonly used FH screening model worldwide [21, 22]. The Lithuanian High Cardiovascular Risk (LitHir) primary prevention programme enables us to opportunistically access approximately 46% of Lithuanian middle-aged citizens every year and evaluate their cardiovascular risk. Therefore, LitHir provides a noteworthy possibility to detect a high percentage of patients with an FH-like phenotype who would otherwise most likely stay asymptomatic until a manifestation of a cardiovascular event. Studies have shown that FH causes atherosclerotic changes in the cardiovascular system as early as childhood, which further highlights the importance of early detection of FH [23]. In this study, the median age at FH diagnosis was 47 years, and 13% of the included patients were diagnosed with coronary artery disease, which is nearly twice the prevalence of CAD in the general Lithuanian population, which was 6.97% in 2022, as estimated based on data available from the Lithuanian Health Education and Disease Prevention Centre [24]. In contrast, in the The Copenhagen General Population Study, among the patients with FH, prevalence of CAD was found to be as high as 33% [25]. Concerning the high median age of FH diagnosis, findings from this study are compatible with those from other studies, especially as deGoma et al. in their study on CASCADE-FH Registry also found the median age of FH diagnosis to be 47 years [26]. At that point, at least some of the atherosclerotic damage may be irreversible. However, it has been proven that with adequate treatment beginning at an early age, the cardiovascular risk for FH patients may decrease to a level similar to that of the general population [27]. Furthermore, compared with men, women were significantly older at the time of FH diagnosis, with a median age at diagnosis difference of 10 years. One possible explanation is that the LitHir programme was available for women at a later age (from 50 to 65 years old) than for men (from 40 to 55 years old); in that way, it was biased against women, as it may have caused a delay in adequate treatment of FH. Since the end of 2023, this programme has been available for all Lithuanian citizens aged between 40 and 60 years. In addition, as the goal of FH screening is to prevent health impairment caused by dyslipidemia, an ideal screening program should also be focused on detecting FH patients before constant exposure to increased blood LDL-C levels occurs.

In this regard, universal screening for FH in children combined with cascade screening of first-degree relatives would probably be the most appealing model. However, the cost-effectiveness of universal FH screening is still controversial. Implementing a national universal screening model for FH is complicated, as the exact age at which children should be tested is uncertain—although FH may start affecting the cardiovascular system at an early age, unfortunately, neonatal testing for FH is not possible due to multiple factors affecting neonatal TC and LDL-C blood levels [5]. On the other hand, Slovenia is currently the only country that has implemented universal testing of children—they had success in testing preschool children at the age of 5 [22].

GPs are, in most cases, responsible for the first step of FH detection and should not be overlooked. Since cascade screening relies on index case detection, this algorithm is heavily dependent on the first medical contact (mostly GPs) performing and evaluating patients’ lipid profiles. However, several studies show that GPs across the world lack knowledge about FH and are frequently not aware of current guidelines about dyslipidemia management and cascade screening recommendations [12, 13]. Such gaps in GPs’ knowledge about FH may contribute to both the underdiagnosis and undertreatment of FH. Studies defining the situation in northeastern Europe as well as interventions to raise awareness of FH for not only specialists in lipidology but also GPs are needed.

Since multiple FH search strategies are employed in Lithuania, a great number of patients are screened for FH and consequently referred and consulted at the lipidology center (Fig. 5). As mentioned previously, FH is characterized by accelerated development of atherosclerosis, which eventually leads to (premature) CVD. Therefore, methodical in-depth evaluation of patients with an FH-like phenotype in tertiary lipidology centers is a key part of this screening program. The specialized lipidology unit is advantageous for patients for multiple reasons. First, the centralization of patients provides the opportunity to create a large database that encompasses real-world data about FH, which will undoubtedly improve the understanding of FH. Moreover, all tests and consultations required for both diagnosis and risk stratification can be performed in one location, with experienced specialists interpreting them. Some tests, which are a part of this algorithm, are not available in smaller outpatient settings. For example, echocardiography is of utmost importance in the evaluation of patients with FH since it has been proven that FH is associated with a greater incidence of aortic valve stenosis [28, 29]. Furthermore, vascular markers of early atherosclerosis, which are not routinely detected in most other healthcare institutions, are used for cardiovascular risk stratification, and a detailed analysis of these markers in the FH population in this study has been published previously [30].

Patients with FH are at increased risk of IHD and premature cardiovascular events. In this study, the DLCN category of clinical FH diagnosis was significantly related to CAD and premature CAD. However, recent findings from other studies suggest, that DLCN may not be an optimal predicting tool of CAD in FH [31]. On the other hand, the identification of the FH-related mutation was not significantly associated with a higher incidence of CAD or premature CAD; however, the tendency toward an association between positive mutation and CAD is evident. Several other studies have concluded that a positive mutation is associated with a greater risk of cardiovascular events [32, 33]. Therefore, the lack of statistical significance could be explained by the relatively small sample size.

It should be noted that this screening algorithm relies on current diagnostic methods for FH, the suitability of which has recently started to be questioned, particularly for the DLCN criteria. In this study, more than half of the analyzed patients were included in the possible FH diagnosis group according to the DLCN criteria, although their phenotype raised strong suspicion for clinicians. Furthermore, clinical and molecular diagnoses do not always correlate. For example, some patients with high DLCN scores may not have genetic mutations. It is possible that currently used tests are unable to detect them or that these patients might have a polygenic form of FH; however, this issue remains. On the other hand, patients with a mutation might have a much milder phenotype than those without a mutation, raising the question of whether genetic testing is necessary in patients with FH. Currently, genetic testing for FH is proven to be a cost-effective diagnostic method, despite common misconception that it is expensive and often limited in availability. A positive genetic test may help clinicians interpret the clinical risk of FH and even increase compliance between the patient and clinician [10].

As mentioned before, data collected from patients who signed a written consent form for enrollment in the Lithuanian FH long-term observation programme were also included in the EAS-FHCS international registry. A recent increase in interest in FH has led to several international systematic projects that collect and process data about FH, which is a major step in creating a better care system for patients with FH. These registries not only motivate FH patients to be monitored but also collect crucial, real-world practical data, highlighting gaps in the diagnosis, management, and follow-up of FH patients, which in turn produces information that will help in educating specialists on how to offer better management for affected patients – an important step forward.

Strengths of the study.

The implementation of a previously described FH screening algorithm allows an increase in the number of detected FH cases not only in the middle-aged Lithuanian population (participants in the LitHir programme) but also among younger patients, including children and adolescents.

The study is mainly based on the LitHir programme, which allows for opportunistic testing of suspected FH cases among a significant part of the middle-aged Lithuanian population. This screening strategy, together with cascade first-degree relatives screening, is believed to be the most cost-effective approach. Furthermore, the prevalence of CAD among different FH groups (clinically and/or molecularly diagnosed FH) has never been previously established nor in Lithuania, neither, to the best of knowledge, in other Eastern European countries.

Finally, the FH patient data gathered in this study are included not only in the Lithuanian long-term FH observation programme but also in the global FH registry (EAS FHSC). Notably, this is the only study from Lithuania participating in this project. This registry is crucial for better understanding country-specific FH peculiarities, reducing gaps in knowledge, and ultimately improving the care of FH patients.

There are several limitations to this study. First, there is still an enormous gap in general awareness about FH among the public and medical communities, and this gap is apparently greater in developing regions of the world, including Lithuania. This leads to a particularly small proportion of the FH population being diagnosed and adequately treated. Although the LitHir programme provides the opportunity to screen a large portion of the Lithuanian middle-aged population, it is also notable that such participation is still not active enough, as it still leaves a large part of the middle-aged Lithuanian population, not to mention the youth, unassessed. Additionally, due to attachment to LitHir, in many cases, this screening model relies heavily on patients’ own interest in their health since participation in LitHir is not obligatory. For most patients with FH, dyslipidemia is “silent” and does not cause any symptoms, which may result in some patients being reluctant to adhere to treatment or start treatment altogether. Unfortunately, despite all the efforts, the availability of genetic testing in Lithuania is still limited, as only 30% of patients were able to be tested for FH-causing mutations. Such barriers to screening should not be overlooked and should be addressed in the future.