Management of Familial Hypercholesterolemia: Current Status and Future Perspectives

Abstract

Familial hypercholesterolemia (FH) is the most common monogenic disorder associated with premature atherosclerotic cardiovascular disease. Early diagnosis and effective treatment can significantly improve prognosis. Recent advances in the field of lipid metabolism have shed light on the molecular defects in FH and new therapeutic options have emerged. A search of PubMed database up to March 2020 was performed for this review using the following keywords: “familial hypercholesterolemia”, “diagnosis”, “management”, “guideline”, “consensus”, “genetics”, “screening”, “lipid lowering agents”. The prevalence rate of heterozygous FH is approximately 1 in 200 to 250 and FH is underdiagnosed and undertreated in many parts of the world. Diagnostic criteria have been developed to aid the clinical diagnosis of FH. Genetic testing is now available but not widely used. Cascade screening is recommended to identify affected family members and the benefits of early interventions are clear. Treatment strategy and target is currently based on LDL cholesterol levels as the prognosis of FH largely depends on the magnitude of LDL cholesterol lowering that can be achieved by lipid-lowering therapies. Statins with or without ezetimibe are the mainstay of treatment and are cost-effective. Addition of newer medications like PCSK9 inhibitors is able to further lower LDL cholesterol levels substantially but the cost is high. Lipoprotein apheresis is indicated in homozygous FH or severe heterozygous FH patients with inadequate response to cholesterol-lowering therapies. In conclusion, FH is a common treatable genetic disorder and although our understanding of this disease has improved, many challenges still remain for its optimal management.

Pharmacogenomics Variability of Lipid-Lowering Therapies in Familial Hypercholesterolemia

“…Furthermore, the secretion of ApoB-containing lipoproteins, LDL, and very-low-density lipoprotein (VLDL), as well as triglycerides from hepatocytes, may also be lowered via statins [ 11 ]. The lifelong overburden of high cholesterol makes patients with FH highly susceptible to the risk of CVD and significantly reduces their life expectancy [ 2 ]. Although statins robustly diminish cholesterol in addition to CVD morbidity and mortality by 20–30% in normal individuals, their efficacy is predominantly weaker in FH subjects [ 5 ].…”

“…Based on the knowledge of pathological genetic mutations involved in the intrinsic or extrinsic cholesterol pathways, therapeutic research has discovered novel strategies with unique mechanisms that substantially enhance the management of dyslipidemia. Gene-based medicines are categorized into integrated genomic replacement treatment that inserts healthy genes to replace pathological mutants, modification of gene expression, and transcription that target coding or noncoding RNAs to alter singling or splicing mechanisms and, ultimately genome modification to insert or delete a specific genetic sequence [ 2 ]. Gene therapy showed potent and persistent reduction of LDL-C and elevation of LDLR expression in homozygous FH by restoring the functional hepatic LDL-C elimination [ 89 ].…”

“…Familial hypercholesterolemia (FH) is the most common and first acquired pathology of lipoprotein metabolism to be characterized genetically and clinically [ 1 ]. It is identified by elevated levels of absolute low-density lipoprotein cholesterol (LDL-C) in the blood, early-onset of atherosclerotic cardiovascular diseases (ASCVD), fat accumulation in external tissues, and tendon and cutaneous xanthomas [ 2 ]. Globally, heterozygous FH afflicts around one in 250–500 individuals, with a more noticeable predominence in special communities, including the Christian Lebanese, French-Canadian, Finnish, and Afrikaner [ 3 ].…”

A Novel LDLR variant in a Ukrainian Patient: A Case Report and Overview of the Disease-Causing LDLR Variants Associated to Familial Hypercholesterolemia

“…Genetic testing should include at least 3 main genes: the LDL-receptor (LDLR) gene, accounting for over 90% of the cases, the apolipoprotein B-100 (APOB) gene, accounting for 5 to 10% of the cases, and the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene accounting for up to 3% of the cases [9]. In addition, other genes as APOE, LDLR adaptor protein 1 (LDLRAP1) and signal-transducing adaptor family member 1 (STAP1) genes should be considered as rare causes of autosomal dominant/recessive FH forms [10].…”

“…However, the diagnostic performance of any genetic test can vary greatly depending on the population studied and the NGS platform used. In this context, the mutation detection rate is also higher when genetic testing is performed in patients with a clear suspicion of FH [9].…”