What is new in familial hypercholesterolemia?

Area of Science:

• Cardiovascular Medicine
• Genetics
• Metabolic Disorders

Background:

• Familial hypercholesterolemia (FH) is a genetic disorder characterized by high levels of low-density lipoprotein cholesterol (LDL-C).
• It is a major cause of premature cardiovascular disease (CVD).
• Current understanding suggests FH is significantly underdiagnosed and undertreated.

Purpose of the Study:

• To review recent advancements in the diagnosis, etiology, metabolism, atherosclerosis risk factors, and treatment of FH.
• To highlight the prevalence and CVD risk associated with FH.
• To discuss novel diagnostic and therapeutic strategies.

Main Methods:

• Review of current literature on familial hypercholesterolemia.
• Analysis of recent findings on genetic diagnosis, lipoprotein metabolism, and atherosclerosis.
• Evaluation of emerging treatment options for LDL-C reduction.

Main Results:

• Heterozygous FH is more prevalent than previously estimated, conferring a 10-13 fold increased CVD risk.
• LDL receptor (LDLR) dysfunction leads to LDL-C accumulation, impacting other lipoprotein metabolisms.
• Next-generation sequencing improves molecular diagnosis, though ~40% of FH patients lack mutations in known genes (LDLR, APOB, PCSK9), suggesting polygenic causes.
• FH patients exhibit increased subclinical atherosclerosis, correlated with LDLR mutation severity.
• Newer and investigational medications show promise for CVD prevention in FH.

Conclusions:

• FH is common, underdiagnosed, and undertreated.
• Effective cascade screening programs are vital for identifying affected individuals.
• Early and intensive LDL-C lowering strategies can significantly alter the disease's natural history and prevent CVD.