What is the pathophysiology of Familial Hypercholesterolemia (FH)?

From the Guidelines

Familial hypercholesterolemia (FH) is a genetic disorder characterized by abnormally high levels of low-density lipoprotein (LDL) cholesterol from birth, primarily due to mutations in genes responsible for LDL receptor function, leading to premature atherosclerosis and cardiovascular disease 1. The primary pathophysiology involves mutations in genes responsible for LDL receptor function, most commonly the LDLR gene which encodes the LDL receptor protein. These receptors normally remove LDL cholesterol from the bloodstream, but in FH, they are either reduced in number, completely absent, or functionally impaired. The most common mutation affects the LDLR gene (accounting for about 85-90% of cases), while less common mutations involve the APOB gene (which produces apolipoprotein B-100, the protein that binds LDL to its receptor) or the PCSK9 gene (which regulates LDL receptor degradation) 1. When LDL receptors don't function properly, LDL particles accumulate in the bloodstream, leading to premature atherosclerosis and cardiovascular disease. The condition follows an autosomal dominant inheritance pattern, meaning a person needs only one defective gene copy to develop the disorder. Homozygous FH (inheriting two defective genes) is much more severe than heterozygous FH (inheriting one defective gene), with LDL levels typically 2-3 times normal in heterozygous patients and 6-10 times normal in homozygous patients 1. This persistent elevation of LDL cholesterol from birth leads to cholesterol deposition in tendons (xanthomas), around the eyes (xanthelasmas), and most dangerously, in arterial walls, causing accelerated atherosclerosis and early cardiovascular events. Some key points to consider in the pathophysiology of FH include:

• The genetic basis of the disorder, with mutations in the LDLR, APOB, and PCSK9 genes being the most common causes 1
• The autosomal dominant inheritance pattern, meaning a person only needs one defective gene copy to develop the disorder 1
• The severity of the disorder, with homozygous FH being much more severe than heterozygous FH 1
• The importance of early diagnosis and treatment to prevent premature atherosclerosis and cardiovascular disease 1

From the Research

Pathophysiology of Familial Hypercholesterolemia

The pathophysiology of familial hypercholesterolemia (FH) is characterized by:

• Elevated low-density lipoprotein cholesterol (LDL-C) levels from birth, leading to premature cardiovascular disease 2, 3
• Mutations in the gene encoding the LDL receptor (LDLR), apolipoprotein B, the pro-protein convertase subtilisin/kexin 9 (PCSK9), and LDLR adaptor protein are the commonest abnormalities 2, 4, 5
• Impaired lipid metabolism, resulting in markedly elevated LDL-C levels and increased risk of atherosclerotic cardiovascular disease (ASCVD) 3, 6

Clinical Manifestations

The clinical manifestations of FH include:

• Premature coronary heart disease (CHD) 6
• Severely elevated total cholesterol and LDL cholesterol levels 6
• Tendon xanthomas 4
• Increased risk of ASCVD and premature deaths 3

Genetic Basis

The genetic basis of FH is attributed to:

• Mutations in the LDLR, APOB, and PCSK9 genes 4, 5
• Autosomal dominant inheritance pattern 6, 4
• Variable expression and penetrance of the genetic mutations 4

Diagnosis and Management

Diagnosis and management of FH involve:

• Clinical characteristics such as family history, lipid levels, and genetic testing 2, 3
• Early identification and treatment of patients, as well as screening of relatives 2, 3
• Statins as first-line therapy, with additional therapy with ezetimibe, bile acid sequestrants, and newer classes of pharmacotherapy as needed 2, 3