Genetic disorders resulting in familial hypercholesterolemia (FH) include autosomal dominant hypercholesterolemia (ADH), polygenic hypercholesterolemia, as well as other rare conditions such as autosomal recessive hypercholesterolemia (ARH). All of these disorders cause elevations in low-density lipoprotein (LDL)-cholesterol (LDL-C) and, as a result, greatly increase the risk of cardiovascular disease (CVD). Genetic loci involved in ADH include the LDLR, which codes for the LDL receptor (LDLR), APOB, which codes for apolipoprotein B-100 (apoB-100), the major protein component of LDL, PCSK9, which codes for Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9), the low abundance circulatory protein that terminates the lifecycle of the LDLR, apolipoprotein E (APOE), which synthesizes the main protein of triglyceride rich lipoproteins, and signal transducing adaptor family member 1 (STAP1), who’s function in cholesterol homeostasis remains largely unknown. Importantly, a large percentage of people with the severe hypercholesterolemic phenotype do not possess a readily identifiable gene defect and many likely have polygenic hypercholesterolemia. Thus, identification of a specific genetic pathologic variant is not a necessary condition for the diagnosis of a genetic hypercholesterolemia. Several formal diagnostic criteria exist for FH and include lipid levels, family history, personal history, physical exam findings, and genetic testing. As all individuals with severe hypercholesterolemia are at high risk for CVD, treatment is centered on dietary and lifestyle modifications and early institution of lipid-lowering pharmacotherapy. Treatment should initially be statin-based, but most patients require adjunctive medications such as ezetimibe and PCSK9 inhibitors. Three large cardiovascular outcome trials have recently shown a reduction in atherosclerotic CVD when ezetimibe or PCSK9 inhibitors were added to a background of statin therapy and consequently have assisted in shaping international guidelines and consensus recommendations. A few patients with extreme and unresponsive elevations in LDL-C will require more aggressive therapies such as lipoprotein apheresis or the use of novel agents for the treatment of severe hypercholesterolemia such as microsomal triglyceride transfer protein (MTP) inhibitors and apoB-100 antisense oligonucleotides. For complete coverage of this and all related areas of endocrinology, please see our free web-book,
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