**5. Treatment options**

of cases [7, 10, 17]. Mutations in this gene cause a reduction in LDLR activity and are associated

Secondary genes associated with HoFH include *APOB* (*MIM107730*), *PCSK9* (*MIM 607786*), and *LDLR‐adaptor protein 1* (*LDLRAP1*; *MIM 605747*) [8, 10, 17]. In addition to "true" HoFH, patients with HoFH can have compound heterozygous mutations (different mutations in each allele of the same gene) or double heterozygous mutations (mutations in two different genes affecting LDLR function) [7, 10]. The severity of the HoFH depends on residual LDLR activity. Irrespective of the underlying genetic defect, patients with HoFH are classified as either receptor negative (i.e., <2% residual activity) or receptor defective (i.e., 2–25% residual activity) [10]. The effect on LDL‐C concentrations is also related to genotype. Homozygous *LDLR*‐defective mutations are generally associated with the highest LDL‐C levels, followed by compound heterozygous *LDLR*‐defective + *LDLR‐*negative mutations, homozygous *LDLRAP1* or *LDLR*‐defective mutations, homozygous *APOB* or *PCKS9* gain‐of‐function mutation, and double heterozygous mutation [5, 10]. Metabolic defects include impaired LDL uptake (the most common functional defect), hepatic oversecretion of apo B, decreased catabolism of triglyceride‐rich lipoproteins, increased plasma levels of lipoprotein(a) (Lp(a)),

Since CV risk is related to the cumulative exposure to elevated lipids, early diagnosis is important for earlier treatment of HoFH to reduce CV risk. Although genetic testing can confirm FH, it is not well defined since genetic confirmation can be difficult to verify in some patients [10]. Indeed, genetic testing is generally not needed as the disease is primarily diagnosed via clinical and biochemical features [6–8, 10, 18]. A number of diagnostic criteria have been proposed [8], but they are typically based on family history (i.e., HeFH in both parents and/or premature CAD), the presence of physical manifestations (i.e., tendon xantho‐ mas, corneal arcus) at an early age, severely increased LDL‐C, and molecular diagnosis. Patients with HoFH generally have untreated LDL‐C levels >500 mg/dL (>13 mmol/L) or treated levels ≥300 mg/dL (≥7.76 mmol/L) [8]. However, not all patients (especially children) with HoFH have significantly elevated LDL‐C, with more than one‐half of Dutch children with HoFH having LDL‐C levels between 217 and 379 mg/dL (5.6–9.8 mmol/L) [10]. Patients with a suspected diagnosis of HoFH should typically be referred to a specialized center for proper

Since early detection of patients with HoFH is crucial for the prevention of CVD, targeted and cascade (i.e., identifying family members at risk) screening is recommended for the identifi‐ cation of new cases in adults [6, 7, 16, 19, 20]. Targeted screening to identify index cases is recommended for patients with hypercholesterolemia and at least one of the following features: personal/family history of xanthomas or premature CVD or family history of significant hypercholesterolemia or sudden premature cardiac death [6, 7]. Specific criteria in Europe (i.e., European Atherosclerosis Society [EAS]) are similar, but somewhat different than

with decreased clearance of LDL particles and increased LDL‐C levels.

and low levels of HDL‐C [10].

62 Cholesterol Lowering Therapies and Drugs

comprehensive management [6, 10].

**4. Diagnosis**

Given the severity of hypercholesterolemia with increased CV risk, HoFH requires intensive therapy. However, HoFH is often unresponsive to traditional treatment [20]. A number of societies and associations in the United States (American College of Cardiology/American Heart Association; National Lipid Association) [20, 23, 24], Europe (EAS; National Institute for Health and Care Excellence) [10, 25], and Canada (Canadian Cardiovascular Society) [6] have published guidelines on the treatment of HoFH. The primary target of treatment in these guidelines is the reduction of LDL‐C via a combination of lifestyle, antihyperlipidemic pharmacotherapy, and apheresis [6, 10, 20, 23, 26]. Since lipid‐lowering therapy is associated with a delayed onset of CVD and prolonged survival, early and aggressive therapy should be initiated as soon as possible [6, 10]. The EAS has recommended LDL‐C targets of <100 mg/dL (<2.5 mmol/L) in children and <70 mg/dL (<1.8 mmol/L) in adults [10].

Statins, the first line of pharmacotherapy to lowering cholesterol level, effectively lower LDL‐ C 10% to 25% in patients with HoFH [10, 26], and even more (approximately 50% reduction of LDL‐C) in those with HeFH [26]. The combination with ezetimibe (acholesterol absorption inhibitor) leads to additive 15–20% LDL‐C reductions [6, 10]. Other agents such as bile acid sequestrants, niacin, fibrates, and probucol can be considered. A clinical study of HoFH patients from South Africa found that statin use was associated with a 51% reduction in the risk of major CV events and a 66% reduction in the risk of death although the mean LDL‐C levels in the patients were only reduced 26% [27].

Because of very high LDL‐C levels in HoFH, its target level is extremely difficult to achieve though cholesterol has been reduced [10]. The inability of standard lipid‐lowering therapies to produce the necessary effect is further exacerbated by the fact that these agents work by increasing expression of LDLRs. Thus, lipoprotein apheresis should be considered in all patients with HoFH and should be initiated early. For example, the EAS guidelines recommend that apheresis should ideally be initiated by age 5 and not later than age 8 in children with HoFH [10]. Canadian guidelines recommend apheresis in adults with HoFH with LDL‐C >329 mg/dL (>8.5 mmol/L) and in children (weighing >15 kg or >7 years of age) with an LDL‐C >193 mg/dL (>5 mmol/L) [6]. LDL apheresis selectively removes LDL‐C without affecting immu‐ noglobulins or other proteins with reductions of approximately 60% [18]. However, a rapid

rebound in LDL‐C is seen with levels returning to baseline within 2 to 4 weeks [18, 20]. Although there are no randomized trials evaluating the effect of apheresis on clinical outcomes, there is clinical evidence that apheresis can contribute to regression and/or stabilization of atherosclerotic plaque [10]. Limitations to the use of apheresis include lack of availability in some locations, high cost, long procedure duration, and the need to maintain vascular access [4]. It is recommended that patients on apheresis undergo routine monitoring to assess carotid atherosclerosis (carotid ultrasound), progression of aortic valve/root disease (echocardiogra‐ phy), and progression of coronary atherosclerosis (stress exercise test) [6].
