**2. Epidemiology**

**1. Introduction**

60 Cholesterol Lowering Therapies and Drugs

destruction of LDLRs [2, 3].

are generally normal [4].

Familialhypercholesterolemia (FH)is anautosomal codominantgeneticdisorderoflipoprotein metabolism,usually causedbymutations inthe low‐density lipoprotein(LDL)receptor(*LDLR*) gene or other genes that affect LDLR function. Patients can be heterozygous (HeFH) with one mutatedallele,homozygous (HoFH) withtwo identicalmutations, or compoundheterozygous with different mutations in each allele [1]. Patients with HoFH have either a complete absence or marked impairment (i.e., 2–30% activity) in LDLR function [1]. There are a number of defects in lipid metabolism among patients with FH that include reduced LDLR‐mediated catabolism of LDL, impairment of apolipoprotein B (apo B)‐mediated clearance of LDL, and increased proprotein convertase subtilisin/kexin type 9 (PCSK9) levels, which mediates posttranslational

Since the reduction of LDLRs in HoFH is more pronounced than that seen with HeFH, hypercholesterolemia is usually more severe in HoFH than in HeFH and is characterized by very high serum levels of total cholesterol and LDL‐cholesterol (LDL‐C). Levels of LDL‐C are typically above 500 mg/dL and total cholesterol levels range from 650 to 1000 mg/dL when HoFH is untreated, whereas LDL‐C levels are typically greater than 300 mg/dL when treated [2–5]. High‐density lipoprotein cholesterol (HDL‐C) is often decreased and triglyceride levels

**Figure 1.** Cumulative LDL exposure in patients with FH [8, 9]. Modified from Horton et al. 2009 [9].

The severe lipid abnormalities associated with HoFH result in accelerated atherosclerosis, accelerated cardiovascular disease (CVD), and an increased risk of cardiac events and early death. It is estimated that CVD risk is increased by up to 20‐fold in untreated patients and still

The exact prevalence rate of HoFH is unknown. Although the prevalence is historically estimated to be approximately 1 in 1 million [7], this likely underestimates true prevalence rates. More recent estimates, based on surveys of unselected general populations that found a prevalence of HeFH of 1 in ∼200 or 1 in 244, suggest a prevalence of 1 in 160,000 to 1 in 300,000 for HoFH [10]. Founder mutations that reduce genetic variation can influence the prevalence in certain racial groups or geographic locations, resulting in increased prevalence in certain groups (e.g., French Canadian, the Netherlands, Lebanese, Hokuriku district of Japan, South African Afrikaners) [11–15]. National programs that include patient registries and cascade screening have been useful for identifying patients and facilitating treatments.
