Past, Present, and Future of Familial Hypercholesterolemia Management

Abstract

Familial hypercholesterolemia (FH) is a monogenic form of severe hypercholesterolemia that, if left untreated, is associated with early onset of atherosclerosis. FH derives from genetic variants that lead to inefficient hepatic clearance of low-density lipoprotein (LDL) particles from the circulation. The FH phenotype is encountered in approximately 1 of every 300 people. The risk of atherosclerotic cardiovascular disease (ASCVD) is higher in those with FH than in normolipidemic individuals and in those with polygenic hypercholesterolemia. FH is usually diagnosed by clinical scores that consider hypercholesterolemia, family history of early ASCVD and hypercholesterolemia, and cutaneous stigmata. Genetic diagnosis is important and should be offered to individuals suspected of FH. Family cascade screening is important to identify asymptomatic hypercholesterolemic individuals. Despite the high risk of ASCVD, this risk is heterogenous in heterozygous FH and depends not only on high LDL cholesterol (LDL-C) but also on other risk biomarkers. Risk can be evaluated by considering biomarkers such as male sex, late-onset therapy (> age 40), LDL-C > 310 mg/dL, low high-density lipoprotein cholesterol, elevated lipoprotein(a), obesity, diabetes, and hypertension by using specific risk equations and by detecting subclinical coronary atherosclerosis. Statins are the main therapy for FH and change the natural history of ASCVD; however, most individuals persist with elevated LDL-C. PCSK9 inhibitors provide robust and safe LDL-C lowering in FH, although elevated costs preclude their widespread use. Newer therapies such as ANGPTL3 inhibitors add intensive LDL-C lowering for refractory forms of FH. Finally, while it is possible to normalize LDL-C in people with FH, the disease unfortunately is still severely underdiagnosed and undertreated.

Current Understanding on the Genetic Basis of Key Metabolic Disorders: A Review

“…Familial hypercholesterolemia (FH) is an inherited metabolic disorder that is characterized by deficiencies in the clearance of low-density lipoprotein (LDL) molecules from the liver, which, if left untreated, can lead to hypercholesterolemia. The FH phenotype has been encountered in approximately 1 of 300 individuals [ 67 ]. There has been an increase in scientific research in FH, which has been spearheaded by pharmaceutical companies in the areas of detection, diagnosis and treatment and 12 drugs have been approved and released in Europe, Japan, the United States and other regions of the world [ 68 ].…”

New Trends and Therapies for Familial Hypercholesterolemia

“…Most frequently (95% of cases), FH is caused by loss-of-function variants in the low-density lipoprotein receptor (LDLR) gene (LDLR) located on chromosome 19. Occasionally the phenotype may be caused by pathogenic variants in apolipoprotein B (APOB), gain-of-function variants in proprotein convertase subtilisin/kexin type 9 (PCSK9), LDL receptor adaptor protein (LDLRAP1) and apolipoprotein E genes (APOE) [17,18]. Recently, the STAP-1 (signal-transducing adaptor family member 1) gene was discarded as a cause of the FH phenotype [19].…”

“…LDLR is responsible for codifying the expression of LDL receptors on the extracellular surfaces of many types of cells, most important in hepatocytes, where they function to bind and internalize circulating LDL into cells for onward catabolism [17,18]. Loss-of-function variants in LDLR result in the reduced capacity of the cell-surface mechanism to bind and internalize circulating LDL particles and thereby lead to hypercholesterolemia.…”

“…In heterozygous FH, a single mutant allele of LDLR, APOB or PCSK9 is inherited from either of the parents carrying the genetic variant, while in homozygous FH, two variants are inherited, one from each parent [17,18], thereby following a co-dominant pattern. Consequently, individuals with homozygous FH typically present a more severe phenotype than heterozygous FH [3].…”

“…Given that the risk and severity of ASCVD in FH patients vary depending on the type of genetic defects [17,18] as well as other risk biomarkers [18], and considering the development of novel therapies, the treatment of FH patients is changing from generalized to individualized (tailored) approaches. The following part of the present review aims to evaluate the trends in the of therapies for FH.…”