Familial Hypercholesterolemia: Genes and Beyond

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, and apolipoprotein E (APOE), which synthesizes the main protein of triglyceride rich lipoproteins. 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 blocking monoclonal antibodies. Three large cardiovascular outcome trials have shown a reduction in atherosclerotic CVD when ezetimibe or PCSK9 blocking monoclonal antibodies were added to a background of statin therapy and consequently have assisted in shaping international guidelines and consensus recommendations. Novel therapeutics recently developed, include: inclisiran – a small interfering ribonucleic acid (siRNA)-based gene-silencing technology that inhibits PCSK9 production (approved in the European Union only thus far), bempedoic acid – an inhibitor of adenosine triphosphate (ATP)-citrate lyase (FDA approved for heterozygous FH and patients with prior CVD and elevated LDL-C), and evinacumab – a fully human monoclonal antibody inhibiting angiopoietin-like 3 (ANGPTL3) (FDA approved for homozygous FH only). Patients with extreme and unresponsive elevations in LDL-C will require more aggressive therapies such as lipoprotein apheresis and agents for the treatment of severe hypercholesterolemia such as microsomal triglyceride transfer protein (MTP) inhibitors and evinacumab. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG .