A 37-year-old Caucasian man presents to clinic to establish care. At age 18 years, he was diagnosed with homozygous familial hypercholesterolemia (HoFH) after his father died suddenly of a massive myocardial infarction at age 42 years. Two paternal uncles also died suddenly at ages 39 and 45 years. At that time, his low-density lipoprotein cholesterol (LDL-C) was 530 mg/dL, and he was started on a statin and advised to initiate LDL-C apheresis. He notes that he stopped the statin after seven months because "he did not like the way it made him feel." He also discontinued apheresis because it required a 3.5-hour drive each way to reach an academic medical center, and his health insurance only covered approximately 30% of the cost. Despite much encouragement, he rejected the possibility of liver transplantation. He stopped following up with a physician. At age 35 years, he sustained an inferior wall myocardial infarction. On cardiac catheterization, he was found to have diffuse multivessel disease with an 80% obstruction in his left main coronary artery, a 75% obstruction in his proximal circumflex artery, and a completely occluded right coronary artery at approximately the middle portion of the vessel. He underwent a three-vessel coronary artery bypass without complication.
FH can be attributed to abnormalities in which of the following?
Show Answer
The correct answer is: F. Answers A, B, C, and D are correct.
FH is among the most common genetic disorders.1,2 It is inherited in an autosomal dominant manner. The incidence of FH varies from population to population, with a variety of founder effects. The incidence of heterozygous FH (HeFH) and HoFH are, in general, one in 500 and one in one million or so, respectively. FH is due to severe impairments in capacity to clear LDL-C from the systemic circulation and has multiple etiologies. The classic and most common etiology for HoFH is from either the null expression of the LDL-R or expression of a severely defective LDL-R, which greatly diminishes the ability to take up LDL particles (LDL-P) into the hepatocyte.3,4 Over 1,700 mutations in LDL-R have been catalogued, and the number is increasing rapidly.
Apoprotein B100 (ApoB100) is the molecular conduit through which LDL-P binds to the LDL-R. Genetic defects in ApoB are associated with reduced affinity for the LDL-R and decreased clearance of LDL-P (familial defective ApoB100).5 In order for the LDL-R/LDL-P complex to undergo uptake into hepatocytes, they must concentrate in clathrin-coated pits along the hepatocyte membrane, a process potentiated by adaptor protein-1. Loss of function polymorphisms in LDLRAP1 also lead to hypercholesterolemia secondary to reduced LDL-P uptake, a condition known as autosomal recessive hypercholesterolemia.6,7
PCSK9 is a molecule that regulates expression of the LDL-R.8 The LDL-R/LDL-P complex binds PCSK9, which targets the complex for proteolytic destruction in the lysosome. If the LDL-R/LDL-P complex does not bind PCSK9, once the LDL-P dissociates from LDL-R within the hepatocyte cytosol, it gets recycled to the cell surface to reinitiate another cycle of LDL-P uptake.9 Increased expression of PCSK9 leads to reduced surface expression of LDL-R and large elevations in LDL-C and LDL-P. In contrast, loss of function polymorphisms in PCSK9 are associated with reduced risk for coronary artery disease (CAD)-related events.10
Niemann Pick C1-like 1 protein (NPC1L1) is responsible for pumping cholesterol and plant sterols (phytosterols) into jejunal enterocytes.11 Under normal circumstances the cholesterol is incorporated into chylomicrons, which are then secreted into the perimesenteric lymphatics and then into the central circulation via the thoracic duct. The phytosterols (e.g., campesterol, lanosterol, beta-sitosterol) are pumped back out into the gut lumen for elimination by the ABCG5/G8 sterol transporter. Beta-sitosterolemia can mimic FH. In beta-sitosterolemia, ABCG5/G8 is defective and there is reduced capacity to translocate phytosterols back into the gut lumen.12 In this scenario, patients also develop xanthomas and premature onset CAD because the phytosterols at high concentration are atherogenic.
References
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