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