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Familial Hypercholesterolemia and Lipoprotein(a): History
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Please note this is an old version of this entry, which may differ significantly from the current revision.
Contributor: Amalia Despoina Koutsogianni ,
Petros Spyridonas Adamidis
, Fotios Barkas , Evangelos Liberopoulos , Ta-Chen Su , Shizuya Yamashita , George Liamis , Manfredi Rizzo

Familial hypercholesterolemia (FH) is the most frequent genetic disorder resulting in increased low-density lipoprotein cholesterol (LDL-C) levels from childhood, leading to premature atherosclerotic cardiovascular disease (ASCVD) if left untreated. FH diagnosis is based on clinical criteria and/or genetic testing and its prevalence is estimated as being up to 1:300,000–400,000 for the homozygous and ~1:200–300 for the heterozygous form. Apart from its late diagnosis, FH is also undertreated, despite the available lipid-lowering therapies. In addition, elevated lipoprotein(a) (Lp(a)) (>50 mg/dL; 120 nmol/L), mostly genetically determined, has been identified as an important cardiovascular risk factor with prevalence rate of ~20% in the general population. Novel Lp(a)-lowering therapies have been developed and their cardiovascular efficacy is investigated. 

  • familial hypercholesterolemia
  • lipoprotein(a)
  • cardiovascular disease
  • hypolipidemic treatment
  • cholesterol

1. Introduction

Familial hypercholesterolemia (FH) is caused by mutations in the genes involved in low-density lipoprotein (LDL) catabolism, and is related to premature atherosclerotic cardiovascular disease (ASCVD) [1]. Although available lipid-lowering therapies are effective in reducing LDL-C levels and cardiovascular risk in FH patients, the majority of these are diagnosed late or remain undertreated [2]. On the other hand, elevated lipoprotein(a) (Lp(a); hyperLp(a)), controlled mostly genetically by the LPA gene locus, is also associated with increased ASCVD risk [3][4]. Novel therapies targeting apolipoprotein(a), such as antisense oligonucleotide or silent RNAs, are effective in lowering Lp(a), but their cardiovascular benefit is yet to be determined [5]. A considerable proportion of patients with FH is diagnosed with high Lp(a) levels, but there is debate about whether these two entities are associated. A few studies have demonstrated a higher prevalence of hyperLp(a) in genetically or clinically diagnosed FH patients, but others suggest that a considerable proportion of these might have been misdiagnosed due to high Lp(a) levels [6][7][8]. Nevertheless, the co-existence of FH and hyperLp(a) seems to multiply the risk of ASCVD [6].

2. Familial Hypercholesterolemia

2.1. Definition and Prevalence of FH

FH prevalence varies depending on the definition used and population studied. Homozygous patients (HoFH) are rare, with an estimated worldwide prevalence of 1:300,000–400,000 [9], while heterozygous FH (HeFH) prevalence is estimated to be ~1:200–300 [10].

2.2. Genetics of FH

FH is mostly caused by functional mutations in the following genes: LDL receptor (LDLR), proprotein convertase subtilisin kexin 9 (PCSK9), apolipoprotein B (apoB), and LDLR adaptor protein 1 (LDLRAP1) [11]. Mutations in these genes may impair the LDLR-mediated catabolism of LDL by markedly reducing hepatic LDL clearance and leading to LDL-C accumulation [11]. Among FH patients, 85–90% exhibit mutations in LDLR, 2–4% in PCSK9, 1–12% in apoB, and only a few in LDLRAP1 genes [11][12][13][14].
Considering that FH is an autosomal dominant disorder inherited with a gene-dosing effect, homozygotes are more adversely affected than heterozygotes [9]. It should also be noted that most HoFH patients are compound heterozygotes [9]. This is attributed to a large number of distinct LDLR gene mutations [9]. Therefore, an adult with HoFH is more likely to have inherited genetic mutations in two different LDLRs [9]. True homozygosity more often occurs in cases of consanguineous union between two heterozygotes [9]. Of note, a high prevalence of a limited number of LDLR mutations may occur in a region due to the founder gene effect [9].

2.3. Clinical Presentation of FH

If left untreated, males and females with HeFH typically develop coronary heart disease (CHD) before the age of 55 and 60, respectively, while HoFH individuals develop CHD very early in life, and many will die before the age of 20 [15][16].
The characteristic lipid profile of FH patients consists of elevated total cholesterol and LDL-C (usually ≥190 mg/dL for HeFH or ≥500 mg/dL for HoFH) with normal high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) levels [15][16].

2.4. Diagnosis of FH

The diagnosis of HeFH is based on genetic testing or clinical criteria [17][18]. The most commonly used clinical criteria for HeFH are the Dutch Lipid Clinic Network (DLCN) which include patient family history for increased LDL-C levels, personal clinical history of premature ASCVD, the presence of tendon xanthomas, the presence of corneal arcus in a person < 45 years, patient LDL-C levels, and genetic testing, if available [13]. HoFH diagnosis is based on either genetic testing or an untreated/treated LDL-C > 500/300 mg/dL together with the presence of xanthomas before the age of 10 years or untreated LDL-C levels in both parents compatible with HeFH [13].
In the case of FH diagnosis, a screening cascade in all first-degree relatives is strongly recommended, including children beginning from the age of 2 years [10]. It is worth mentioning that, despite its well-documented high prevalence, <5% of those with FH have been diagnosed worldwide and the majority of those are diagnosed over 40 years old [2].

2.5. Prognosis and Treatment of FH

At any level of untreated LDL-C, the prognosis for HeFH patients is worse than individuals without FH [19]
Possible ASCVD predictors in FH patients include family ASCVD history, age, gender, smoking, hypertension, type 2 diabetes, hyperLp(a), as well as other potential risk modifiers [1]. These include genetic parameters beyond the traditional FH-causing mutations, parameters of HDL composition and function, inflammation, telomere length in somatic cells, oxidative stress, and hemostasis [1].
Concerning FH treatment, the European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) 2019 guidelines recommend an LDL-C target < 70 mg/dL (1.8 mmol/L) for FH patients without cardiovascular risk factors, and <55 mg/dL (1.4 mmol/L) for those with ASCVD or additional risk factors [10].
Maximally tolerated statin therapy ± ezetimibe is the cornerstone of treatment for FH patients [20]. Other therapeutic agents include PCSK9 inhibitors, bempedoic acid, and bile acid sequestrants [20][21]. In the case of HoFH, lomitapide, evinacumab, and lipoprotein apheresis are additional treatment options [20].

3. Lipoprotein(a)

3.1. Molecular Properties of Lp(a)

Lp(a) consists of an LDL-like particle, in which apoB-100 is linked by a single disulfide bridge to a unique plasminogen-like glycoprotein, known as apolipoprotein(a) (apo(a)) [3][4]. The LDL-like core constitutes a combination of triacylglycerols, phospholipids, and esterified/unesterified cholesterol surrounded by one molecule of apoB-100 [3][4]. Considering its formation, Lp(a) contributes to atherosclerosis, but also exerts inflammatory, oxidative, thrombotic, and antifibrinolytic properties [3][22][23].

3.2. Genetics of Lp(a)

About 90% of the Lp(a) level is autosomal dominantly inherited and strongly determined by a single gene, the LPA gene [23]. Most individuals express two distinct Lp(a) isoforms [23]. The LPA gene, located in chromosome 6q23, is evolutionarily derived from the plasminogen (PLG) gene and remains highly homologous to it [23][24][25][26]. The LPA gene, and thus apo(a), consists of two kringle domains: kringle V (KV) and kringle IV (KIV) [23][27]. KV is similar in apo(a) and plasminogen [23][27]. Although KIV is present only once in plasminogen, it is expressed in 10 different types in apo(a) [23][27]. Specifically, KIV contains one copy of KIV1 and KIV3–10, but variable copies of KIV2 (1 to >40 on each allele) [23][27]. KIV2 and its different repeats in apo(a) account for the high size apo(a) polymorphism and determine the size of each apo(a) isoform, its formation rate, and serum Lp(a) concentrations [26][27].

3.3. Definition and Prevalence of High Lp(a)

Plasma Lp(a) levels vary widely between individuals and are largely determined by apo(a) size [28]. There is an inverse relationship between the number of KIV2 repeats of apo(a) and Lp(a) levels in plasma [29]. Consequently, small apo(a) isoforms are related to hyperLp(a) [29]. The presence of the LPA single-nucleotide polymorphisms rs3798220 and rs10455872 is also associated with hyperLp(a) [30][31]. Lp(a) levels double over the first year of life in parallel with the apo(a) gene, which is fully expressed from the first or second year of life [32][33]. Afterwards, Lp(a) levels are stable over time and seem not to be affected by diet, physical activity, or other environmental factors [3][34]. Thus, Lp(a) is enough to be measured once, unless a secondary cause is suspected or specific treatment is instituted [3][34].
Lp(a) measurement is challenging in clinical practice [35]. There is substantial variability in assays, partly due to apo(a) structure and variability in K-IV repeats [35]. Ideally, clinical assays should use an antibody for a unique non-repetitive epitope in apo(a), to recognize each Lp(a) particle once and report levels as nmol/L [35]. On the other hand, Lp(a) values measured by assays based on polyclonal antibodies cannot be reported in molar units [35]. As a compromise, they approximate their findings by comparison with apo(a) isoform-insensitive reference methods that use molar units; in case this is impossible, Lp(a) values should be reported in mg/dL [35].
Traditional thresholds for hyperLp(a) are >30 mg/dL (>75 nmol/L), with about 20% of the general population having Lp(a) >50 mg/dL (>120 nmol/L) [3][35][36].
The cholesterol contained in Lp(a) particles cannot be separated from that in LDL particles and is thus totally reported as LDL-C concentration [35]. The analyses of isolated Lp(a) particles have shown so far that cholesterol accounts for 30–45% of Lp(a) mass concentration [35]. Therefore, it has been suggested that Lp(a)-cholesterol (Lp(a)-C) can be estimated by multiplying the Lp(a) mass by 0.3, whereas corrected LDL-C is equal to measured LDL-C minus Lp(a)-C [35]. However, this approach has limitations [35]. The direct measurement of Lp(a)-C relative to Lp(a) mass has shown inter- and intraindividual variation ranging from 6% to 60%, which may affect the prediction risk [35]. Therefore, the routine correction of LDL-C for Lp(a)-C is not strongly recommended [35].

3.4. Clinical Presentation of hyperLp(a)

The physiological role of Lp(a) is not thoroughly understood. Evidence from experimental, observational, and genetic studies has demonstrated that hyperLp(a) is an established risk factor for CHD, ischemic stroke, peripheral artery disease, heart failure, calcific aortic valve stenosis, and retinopathy in diabetic patients [3][34][35][37][38][39][40][41].
Recent guidelines recommend that Lp(a) levels should be measured at least once in each adult’s lifetime to identify those with hyperLp(a) [10]. Moreover, Lp(a) measurement should be considered in patients with personal or family history of premature ASCVD, and family history of high Lp(a) or FH [10][35]; premature atherosclerosis can be easily detected by endothelial dysfunction and early carotid lesions [42]. Screening for Lp(a) is also recommended in youth with a history of ischemic stroke and no other identifiable risk factors [35].

3.5. Available and Upcoming Therapies for hyperLp(a)

There are neither known nonpharmacologic methods nor any medications specifically approved for lowering Lp(a) levels [23]. However, some currently used therapeutic agents have a limited effect on Lp(a) [23]. Although low-saturated fat diets and statin therapy have been previously considered to raise Lp(a) levels by approximately 10–30% [4][23][43][44][45][46] a secondary analysis of the Familial Hypercholesterolemia Expert Forum (FAME) study including a Japanese nationwide cohort of FH patients has recently shown opposing results [47]. According to this analysis, the Lp(a) levels tended to lower in those under treatment (n = 399) after 2–4 years of follow-up compared with the baseline values [47].
On the other hand, lipoprotein apheresis is highly effective in reducing Lp(a) levels (25–40%) [4][23]. Similarly, fibrates, niacin, lomitapide, PCSK9 and cholesteryl transfer protein (CETP) inhibitors, aspirin, antibodies to interleukin-6, nutraceuticals, tibolone, and ezetimibe moderately decrease Lp(a) levels [4][23][48].
Novel medicines based on antisense oligonucleotides (ASOs) and small interfering RNAs (siRNA) technology are currently in clinical development [4][23][49][50]. Pelacarsen, an ASO, has shown much promise with reductions of up to 92.4% in Lp(a), olpasiran, a siRNA, reduced Lp(a) with observed maximal percent reductions of >90% in a phase I study, whereas the siRNA SLN360 also reduced plasma Lp(a) concentrations in a dose-dependent way [4][23][49][50].

This entry is adapted from the peer-reviewed paper 10.3390/metabo12111065

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