What is the pathophysiology of familial hypercholesterolemia (FH)?

Updated: Oct 04, 2021
  • Author: Mose July, MD, CCD; Chief Editor: Romesh Khardori, MD, PhD, FACP  more...
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FH is a disorder of absent or grossly malfunctioning low-density lipoprotein (LDL) receptors. The LDL receptor gene is located on the short arm of chromosome 19, and the protein is composed of 860 amino acids. It is the primary determinant of hepatic LDL uptake, which normally processes approximately 70% of circulating LDL. Two ligands on LDL bind to the receptor, apolipoprotein B-100 (apoB-100) and apoE. The LDL receptor also binds another ligand, apoE, and is, therefore, more accurately termed the B,E receptor. ApoE is found on most lipoproteins other than LDL, including very low-density lipoprotein (VLDL) and chylomicrons and their remnants, intermediate-density lipoprotein (IDL), and a subclass of high-density lipoprotein (HDL). The LDL receptor binds apoE with higher affinity than apoB-100, and some mutations in the receptor may spare uptake of LDL by allowing binding to apoE. [16, 17, 18]

Goldstein and Brown discovered the LDL receptor and determined that FH was caused by an autosomal dominant mutation. [19, 20] Since then, more than 1700 mutations have been identified, with 79% of of them probably expressed as a hypercholesterolemic phenotype. Defects in the genes encoding apoB and proprotein convertase subtilisin/kexin type 9 (PCSK9) are responsible for approximately 5% and less than 1% of FH cases, respectively. [13] LDL receptor function varies from nonexistent up to about 25% of normal receptor activity. [21]

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