Pharmacotherapies for Familial Hypercholesterolemia

Familial hypercholesterolemia (FH), an inherited genetic disorder characterized by significantly elevated low-density lipoprotein cholesterol (LDL-C) levels,¹ affects an estimated 620,000 Americans² and is generally underdiagnosed and undertreated.³ It can be heterozygous (HeFH) or homozygous (HoFH), although HeFH is the most common form, with a prevalence of 1 in every 200 people.¹

HoFH (typically associated with cholesterol elevations of 650-1000 mg/dl) is more serious than HeFH, in which individuals typically present with LDL-C concentrations of ~220 mg/dL.¹ Men and women with HeFH are diagnosed, on average, in the fourth and fifth decade of life respectively,⁴ while in HoFH, CVD develops at an average age of 20 years.⁵ The risks of coronary heart disease (CHD) in men and women respectively is 50% by age 50 years and 30% by age 60 years.⁶ These risks make early aggressive screening and management essential.

Screening, Diagnosis, and Clinical Features

Diagnosis of FH encompasses LDL-C levels, family history, physical findings and sometimes the results of genetic testing. High-risk individuals can be identified through eliciting information concerning a family history of hypercholesterolemia and premature CHD.¹ Universal screening, recommended by the National Lipid Association (NLA) should generally be conducted in children from 9 to 11 years old, and no later than 20 years in adults. However, in those with a suspicious family history, screening may be considered even in children as young as 2 years old.²

The NLA also recommends “cascade screening”—ie, the screening of all first-degree relatives of those diagnosed with FH.² Although genetic screening may confirm the diagnosis, a negative result should not rule it out or alter management.² (Tables 1 and 2).

Pathophysiology and Genetics

Several autosomal dominant mutations are typically responsible for FH. The most common is a mutation on chromosome 19, which is responsible for the expression of the low-density lipoprotein receptor (LDLR) gene, and accounts for over 95% of FH cases.¹

The gene that encodes apolipoprotein B (apo B-100), which is the lipoprotein responsible for enabling LDL-C to bind to the LDLR, can also be implicated. Even a single gene mutation can impede the binding of LDL-C to the LDLR, leading to reduced clearance of serum LDL-C. These mutations account for 2% to 5% of FH cases.⁷

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein of the serine protease family that is responsible for the degradation of LDLRs inside lysosomes. Decreased LDLRs results in diminished removal of plasma LDL-C. A mutation in the low-density lipoprotein receptor adaptor protein 1 (LDLRAP1) gene is very rare, accounting for less than 1% of FH cases.⁷