From the Guidelines
Familial hypercholesterolemia (FH) is a co-dominant and highly penetrant monogenic disorder that markedly elevates LDL-cholesterol concentration from birth, leading to premature atherosclerotic cardiovascular disease (ASCVD) if left untreated. This condition is characterized by abnormally high levels of LDL cholesterol ("bad cholesterol") in the blood from birth, caused by mutations in genes that affect how the body processes cholesterol, most commonly the LDL receptor gene 1. People with FH have a significantly increased risk of developing early cardiovascular disease, including heart attacks and strokes, often decades earlier than the general population. The disorder exists in two forms: heterozygous FH (inherited from one parent), which is more common and less severe, and homozygous FH (inherited from both parents), which is rare but much more severe.
Key Characteristics of FH
- Elevated LDL-cholesterol concentration from birth
- Increased risk of premature atherosclerotic cardiovascular disease (ASCVD)
- Caused by mutations in genes that affect cholesterol processing, commonly the LDL receptor gene
- Exists in two forms: heterozygous and homozygous FH
Prevalence and Public Health Importance
- Affects up to 35 million people worldwide, with only 10% currently diagnosed 1
- Has substantial effects on public health, with an overall phenotypic frequency in the population of 1 in 311 1
Symptoms and Treatment
- Common symptoms include yellowish deposits of cholesterol in the skin or tendons (xanthomas), cholesterol deposits around the eyes (xanthelasmas), and a white ring around the cornea of the eye (corneal arcus) at a young age
- Treatment typically involves lifestyle modifications (heart-healthy diet, regular exercise, avoiding smoking) combined with cholesterol-lowering medications, such as statins, ezetimibe, and PCSK9 inhibitors 1 Early diagnosis and aggressive treatment are essential to reduce the risk of premature cardiovascular disease in affected individuals.
From the Research
Definition and Characteristics of Familial Hypercholesterolemia
- Familial hypercholesterolemia (FH) is an autosomal co-dominant genetic disorder characterized by elevated low-density lipoprotein cholesterol levels and increased risk for premature cardiovascular disease 2.
- It is also described as an autosomal dominant-inherited genetic disorder that leads to elevated blood cholesterol levels 3.
- FH is the most common genetic disorder in medicine, with a prevalence of 1/250, and is characterized by elevated low-density lipoprotein cholesterol (LDL-C) and an increased lifetime risk of atherosclerotic cardiovascular disease (ASCVD) 4.
Diagnosis and Identification
- The diagnosis of FH is based on algorithms that include LDL-C levels, physical manifestations, family history of high LDL-C and premature ASCVD, and genetic testing 4.
- Diagnostic scores such as Dutch Lipid Clinic Network criteria using clinical manifestations are helpful in identifying FH 5.
- DNA-based methods to identify the underlying genetic defect are desirable but not essential for diagnosis 6.
Treatment and Management
- High-intensity statins are the mainstay of treatment, which should be started as early as possible in homozygous FH and as soon as the diagnosis of heterozygous FH is made in adults 2.
- Combination therapy is often necessary in FH patients and can include the addition of ezetimibe and bile acid sequestrants 2.
- Lipoprotein apheresis is used when pharmacotherapy is inadequate, especially for those with homozygous FH and some patients with severe heterozygous FH 2.
- Emerging therapies such as LDL apheresis and novel therapeutic agents may be useful in patients with homozygous FH or treatment-resistant FH 3.
- Novel agents bempedoic acid, inclisiran, and evinacumab have expanded the treatment choices for some patients with FH 5.