The Dutch Lipid Clinic Network Criteria are most commonly used globally (Table 1) [5], and the Simon Broome criteria are also frequently used (Table 2) [13]. Currently, diagnosing FH based on these criteria seems most reasonable. Both criteria include LDL-C levels, physical findings such as tendon xanthoma, family history of premature CAD or severe hypercholesterolemia, and DNA mutations. A few countries have their own criteria for clinical diagnoses. In Canada and Japan, they analyzed models including LDL-C levels, clinical findings, and family history, and determined criteria with optimal sensitivity and specificity [14,15]. The Korean FH registry 2020 revealed that the rates of PV carriers were 50% to 64% when the patients were classified as definite or probable types by the Dutch or Simon Broome criteria [7]. Not surprisingly, the sensitivity and specificity were inversely correlated according to the criteria used. Thus, it may be less effective to identify patients when definite-type diagnostic criteria are applied. It is preferable to use criteria with high sensitivity for patient screening, whereas it is appropriate to use criteria with high specificity for cascade screening [16]. It may be helpful to choose diagnostic criteria flexibly according to diagnostic purpose.

Currently, Korean data for the unique diagnostic criteria of FH are insufficient. However, the Korean FH registry 2020 analyzed LDL-C distributions in the general population and patients with FH and reported cut-off values of total cholesterol and LDL-C of 250 and 177 mg/dL, respectively (Fig. 3A). For PV carriers, the cut-off values of total cholesterol and LDL-C with optimal sensitivity and specificity were 325 and 225 mg/dL, respectively (Fig. 3B) [7]. Therefore, these values may be used when screening FH or cascade screening within a family in Korea.

Although FH is a genetic disease, genetic testing is performed on a small number of individuals with suspected FH. Genetic testing is beneficial for (1) clearer diagnosis, (2) refining risk assessment and subsequent promotion of LLT, and (3) making cascade screening more efficient [17]. A recent study demonstrated that the cardiovascular risk of PV carriers is three times higher than that of those with similar physical signs but without PVs [18]. As previously mentioned, the prevalence of PV carriers can vary according to the type of clinical diagnosis. FH diagnosis cannot be ruled out when a person has an FH-compatible phenotype and family history, even if PVs are not identified in genetic testing. Such cases may be of polygenic origin, technical problems, autosomal recessive PVs of the LDLRAP1 gene, or a variant of a novel gene.

The target genes of FH genetic testing are LDLR, APOB, and PCSK9. Due to gradual cost reduction, many institutes recently examine these three genes using next-generation sequencing and deletion/duplication analysis. Similar to data from other countries, copy number variations are found in approximately 10% of PV carriers, but this type of PV requires multiplex ligation-dependent probe amplification or the TaqMan method for validation [7]. When a PV is identified, it is critical to properly interpret whether it is a causative variant. There are few databases on LDLR variants. The pathogenicity of the associated genes is classified according to the guidelines of the American College of Medical Genetics and Genomics and the Association of Molecular Pathology [19]. However, many reported variants are interpreted as variants of uncertain significance [20]. In such cases, variant functionality can be tested using co-segregation within the family (Fig. 4) [21].

Candidates for genetic testing usually include adults with LDL-C ≥ 190 mg/dL in the absence of other secondary causes, children or adolescents with LDL-C ≥ 160 mg/dL and a family history of premature CAD or severe hypercholesterolemia. As the cost is partly covered by the National Health Insurance Service (NHIS), further awareness and information on FH in health professionals seems to increase the clinical and genetic diagnosis rate of the patients.

Other secondary and primary hypercholesterolemia should also be ruled out. Secondary etiologies include hypothyroidism, nephrotic syndrome, cholestasis, acute intermittent porphyria, and pharmacological agents (e.g., thiazide and cyclosporine) [22]. The primary etiologies include sitosterolemia and familial combined hyperlipidemia. Sitosterolemia, a rare genetic disease, is accompanied by high levels of circulating plant sterols and is caused by loss-of-function mutations in ABCG5/8. This occurs in 1/200,000 people. LDL-C levels can vary but are very high in some affected individuals, such as children, and can be influenced by diet. Although confirmative diagnosis requires the identification of pathogenic mutations, lack of facility for sitosterol assay and genetic testing can be an obstacle [23]. Individuals with familial combined hyperlipidemia show high very-low-density lipoprotein and LDL-C levels and low HDL-C levels. The prevalence is 1/100 to 200. Familial hyperlipidemia is an important cause of premature CAD. Although the molecular background is uncertain, a polygenic cause is a plausible mechanism, and secondary factors can also affect the phenotype. Patients typically have total cholesterol of 200 to 400 mg/dL, triglyceride of 200 to 600 mg/dL, HDL-C of < 40 to 50 mg/dL and family history. To date, there is no standard definition of this disease, but the most common clues are simultaneous elevation of apoB (≥ 120 mg/dL) and triglycerides (≥ 133 mg/dL) [24].

Most international guidelines currently recommend maximal tolerable dose statins as the first-line therapy in patients with FH (Table 3) [5,29]. No randomized clinical trials have investigated the effects of statins in patients with FH. However, a cohort study from the Netherlands showed a 76% lower risk of coronary heart disease in patients with FH who received statin therapy at lower dose than the current guidelines [32]. In addition, a retrospective study from the Netherlands demonstrated a 50% reduction in CAD occurrence and mortality with moderate- to high-intensity statin therapy [33]. Furthermore, meta-analysis provides evidence of the benefits of intensive statin therapy [34].

The most recent guidelines recommend this agent as a second-line drug for LLT (Table 3). Ezetimibe, a cholesterol absorption inhibitor, reduces cardiovascular events when combined with a moderate-intensity statin [35]. Another study showed that a combination of statin and ezetimibe induced plaque regression compared to statin monotherapy [36]. Statin/ezetimibe combination results in strong LDL-C reduction (≥ 50% from the baseline) and is relatively safe tool of LLT [37].

These agents are recommended in patients with FH and are very high-risk when the LDL-C target is not achieved after the use of maximal tolerable dose statin/ezetimibe (Table 3). The results of the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) [38] and Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab (ODYSSEY-OUTCOMES) [39] studies showed the cardiovascular benefits of evolocumab and alirocumab, providing a scientific basis for anti-PCSK9 antibody use in patients with FH. The percentage reduction in LDL-C by these agents is not smaller than that in patients without FH [5]. These agents are also considered for patients who experience statin intolerance. However, it is more expensive than other oral agents, and it is difficult but important to determine appropriate LDL-C levels to start anti-PCSK9 antibodies in specific risk groups with consideration of cost-effectiveness [29,40,41].

The addition of this agent can be considered for severe hypercholesterolemia (Table 3). Although bile acid-binding resin has an LDL-C-lowering effect, its use is limited as there are no clinical outcome studies.

Mipomersen is an oligonucleotide derivative that binds apoB mRNA and inhibits the production of all apoB-containing lipoproteins. Its action is independent of LDLR expression and has been developed as an adjunct agent, particularly for patients with homozygous FH (HoFH). In these patients, mipomersen reduced LDL-C levels by 21%. Adverse events include injection site reactions, liver enzyme elevation, and increased hepatic fat content [42]. However, it is not currently available in Korea. Lomitapide, a microsomal triglyceride transfer protein inhibitor, reduces the assembly and secretion of apoB-containing lipoproteins in Golgi complex. Lomitapide reduces LDL-C by 38% to 50% in patients with HoFH [43]. It lowers LDL-C levels in an LDLR-independent manner and leads to the accumulation of hepatic triglycerides and hepatiosteatosis, and liver enzyme elevation. However, this agent is not available in Korea. Inclisiran, a synthetic small interfering RNA, inhibits PCSK9 synthesis and is highly effective at lowering LDL-C levels. In a clinical trial in HeFH, it reduced LDL-C by 48% compared to placebo, with a similar rate of adverse events [44]. A long dosing interval is expected to increase patient adherence. However, this agent is not yet available in Korea. Angiopoietin-like 3 (ANGPTL3) is a protein that inhibits lipoprotein- and endothelial lipase. Evinacumab is an antibody against ANGPTL3 that reduced LDL-C and triglyceride levels by up to 56% in patients with HeFH [45] and HoFH [46] in phase 2 and 3 clinical trials, respectively.

Lipoprotein apheresis is the method remove lipoproteins from the blood and it is important for patients whose lipid-lowering response is not sufficient to pharmacological agents. It has been occasionally used in patients with HoFH or severe HeFH. When applied, LDL-C decreases by 50% to 70%. However, owing to its invasiveness, the patient’s quality of life can be negatively affected [5].

Ideal targets are < 55 mg/dL in patients with ASCVD or major risk factors and < 70 mg/dL in those without ASCVD or risk factors [5]. However, achieving these targets is difficult in many cases even after 3-drug combination therapy [47], 50% reduction in LDL-C levels and < 70 mg/dL in patients with ASCVD or major risk factors and < 100 mg/dL in those without these conditions are recommended as realistic second best targets in many other guidelines [6,28,48]. In a study supported by the Korean Society of Lipid and Atherosclerosis analyzing individuals with severe hypercholesterolemia, those who achieved LDL-C < 100 mg/dL after statin therapy showed lower cardiovascular risk than those who did not [8].

The most well known diagnostic criteria for HoFH are from the consensus panel on FH of the European Atherosclerosis Society in 2014 [25]. It included DNA mutations, LDL-C levels, physical findings, and family history (Table 4). However, strict application of genetic diagnostic criteira can affect insurance benefits of pharmacological agents. Genetic analysis is considered to confirm the clinical diagnosis, facilitate testing of family members, and assist diagnosis where the clinical presentation is borderline between those of HoFH and HeFH [25,49].

Patients with suspected diagnoses need to be referred to a specialist for comprehensive management. Regular screening for CAD or aortic disease is recommended. Patients should undergo cardiovascular evaluation at diagnosis, with subsequent annual echocardiographic evaluation, stress testing, and, if available, computed tomography coronary angiography every 5 years. Emergency education is needed, and clinical assessment is recommended every 6 months.

Early detection of HoFH during childhood is crucial. The aim of treatment in HoFH is to start LLT as early as possible and obtain cholesterol levels as low as possible. The treatment targets are 100, 135, and 70 mg/dL in adults, children, and patients with ASCVD, respectively. Lifestyle modification, statin/ezetimibe, and lipoprotein apheresis (if available) are essential for treatment. Lipoprotein apheresis is recommended at the age of 5 years or at least 8 years. New therapeutics such as PCSK9 inhibitors, lomitapide, or mipomersen can be added. The Korean Food and Drug Administration approved PCSK9 inhibitors for HoFH, whereas mipomersen and lomitapide are not yet available in Korea. Evinacumab, an anti-ANGPTL3 antibody, has been approved in some countries for the treatment of HoFH. The control of other cardiovascular risk factors is important and aspirin needs to be considered.

Contraception and pregnancy are key issues in women with FH and should be appropriately discussed. Hormonal contraception is generally contraindicated, and other contraceptive methods are preferred. Women wishing to become pregnant need to be counseled and undergo cardiovascular assessments.

Lifestyle modifications for lipid control are recommended. Although some recent data have denied concerns regarding the teratogenicity of statins, minor effects on the fetal brain maturation cannot be ruled out [52]. Ongoing lipid-lowering drugs need be discontinued one to three months before conception or breastfeeding [6]. For women with severe FH, bile acid-binding resin and/or LDL apheresis can be considered [5]. However, there are no officially recommended LDL-C levels for starting drugs or targets.