Diagnosis and Treatment of Heterozygous Familial Hypercholesterolemia

F amilial hypercholesterolemia (FH) is a common yet underdiagnosed autosomal dominant disorder that affects 1 in 220 individuals globally. FH is characterized by lifelong elevation of low-density lipoprotein cholesterol (LDL-C) and if untreated leads to early-onset atherosclerosis and increased risk of cardiovascular events. Affected men and women who are untreated have a 30% to 50% risk of a fatal or nonfatal cardiac event by ages 50 and 60 years, respectively. The most common causes of FH are pathogenic variants of the LDL receptor (LDL-R) gene, which are responsible for 85% to 90% of genetically confirmed FH. Pathogenic variants of the apolipoprotein (ApoB) gene, resulting in decreased binding of LDL to the LDL-R, or gain-of-function mutations in the gene for proprotein convertase subtilisin/kexin 9 (PCSK9), resulting in increased destruction of LDL-R, are responsible for 5% to 15% and 1% of cases of FH, respectively. Autosomal recessive FH, caused by homozygous mutations in the LDL-R adaptor protein-1, is associated with a mild homozygous FH (HoFH) phenotype and is beyond the scope of this review. With the exception of HoFH, FH is generally a silent disease. HoFH typically presents with pathognomonic physical findings in childhood, including xanthelasmas, tendon xanthomas, and corneal arcus. By contrast, in the Spanish Familial Hypercholesterolemia Cohort study, xanthomas and corneal arcus were present in <15% and 30% of patients with heterozygous FH (HeFH), respectively. However, the prevalence of these findings increases with age in untreated individuals. Elevated total cholesterol (240 mg/dL [6.2 mmol/L]) is found in up to 28.5 million (11.7%) of Americans over the age of 20 years. Coronary artery disease (CAD) and myocardial infarction (MI) are also very common cardiovascular conditions, with more than 1 million Americans estimated to have had an MI in 2018. Individuals with genetically confirmed FH account for only a small percentage of these cardiac events. In the US National Heart Lung and Blood Institute’s Exome Sequencing Project, only 2% of cases of premature MI in men <50 years and women <60 years of age were found to have a genetic defect in the LDL-R. However, as many as 20% of MIs in younger men (<45 years of age) have been attributed to FH. Given the broad range of causes of hypercholesterolemia and early-onset CAD, it is not surprising that FH is not always in the differential diagnosis for healthcare professionals when confronted with a patient presenting with early CAD. This represents a missed opportunity for the screening of family members (cascade screening) and the early initiation of potentially lifesaving therapies. It is crucial to consider the diagnosis of FH in children with LDL-C persistently >160 mg/dL (4.1 mmol/L), adults with LDL-C >190 mg/dL (4.9 mmol/L) (especially if there is a family history of early-onset CAD), and in all patients with early CAD. Given that FH is an autosomal dominant disorder, an individual who is heterozygous for FH has a 50% chance of passing the gene to his or her children. Homozygous individuals who have identical mutations in both alleles, compound heterozygotes who inherited different mutations in both alleles of the same gene, or double heterozygotes who have mutations in 2 different genes, will have offspring who are all obligate heterozygotes, assuming their partner does not have FH. This review will focus on HeFH and aims to highlight the differences between FH, which is present from birth, and hyperlipidemia secondary to suboptimal diet and lifestyle or other causes of acquired hyperlipidemia that develop later in life. Diagnostic tools and potential treatments for individuals with FH will also be discussed.