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A 31-year-old male is referred for lipid management. The patient recently was diagnosed with multivessel coronary artery disease (CAD) and underwent 3-vessel bypass surgery. The patient's father experienced an acute myocardial infarction at age 39 years and required bypass surgery for management. The patient has no history of hypertension, diabetes, or tobacco use. Examination revealed a generally fit-appearing young man with bilateral tendon xanthomas. Preoperative fasting lipid panel was notable for total cholesterol 331 mg/dL, high-density lipoprotein (HDL) cholesterol 44 mg/dL, low-density lipoprotein (LDL) cholesterol 266 mg/dL, and triglycerides 104 mg/dL.

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1. What is the patient's primary lipid disorder?

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2. What is the patient's cholesterol treatment target, and what are his therapeutic options?

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Answers

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  1. Familial hypercholesterolemia (FH).

  2. LDL cholesterol <100 mg/dL; best treatment option is a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (“statin”).

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Lipids are sparingly soluble molecules that include cholesterol, fatty acids, and their derivatives. They are transported in the circulation by lipoprotein particles composed of proteins called apolipoproteins and phospholipids. Human plasma lipoproteins are classified into 5 major classes based on density: chylomicrons (least dense), very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), LDL, and HDL. A sixth class called lipoprotein(a) (Lp(a)) resembles LDL in lipid composition and has density that overlaps that of both LDL and HDL.

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There are 3 major lipid metabolic pathways. In the exogenous pathway, dietary long-chain fatty acids and cholesterol are esterified and assembled into chylomicrons as triglycerides and cholesterol esters, respectively. The primary structural protein on chylomicrons is apolipoprotein B48 (apo-B48). Chylomicrons are secreted into the lymphatic circulation by small bowel enterocytes and enter the venous circulation from the thoracic duct. Triglycerides are hydrolyzed to nonesterified fatty acids by the activity of the enzyme lipoprotein lipase (LPL), with apo-CII on chylomicrons serving as an essential cofactor. Triglyceride-depleted chylomicrons are called chylomicron remnants and are cleared by the LDL receptor–like protein (LRP) in an interaction with apo-E.

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Hepatic triglycerides and cholesterol esters are assembled into VLDL particles and secreted into the portal venous circulation in the endogenous lipid pathway. The main structural protein on VLDL particles is apo-B100, a high-affinity ligand for the LDL receptor. Triglycerides are hydrolyzed by LPL (with apo-CII as cofactor) to create triglyceride-depleted IDL. IDL can be cleared by binding to either LRP or LDL receptor or can undergo further delipidation by LPL to create cholesterol ester–enriched LDL particles. Apo-B100 is the only structural protein on LDL particles, and LDL is cleared by interaction of apo-B100 with LDL receptors expressed by liver and extrahepatic tissues.

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HDL is the key lipoprotein in the reverse cholesterol pathway. Nascent HDL is secreted from the liver and small intestines as small apo-AI-containing discs. The discs acquire free cholesterol from peripheral tissues through activity of the cholesterol efflux regulatory protein ABC1. Cholesterol is then esterified by the enzyme lecithin:cholesterol acyltransferase (LCAT), with apo-AI serving as cofactor. At this ...

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