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Familial Hypercholesterolemia: Genes and Beyond.


Warden BA22, Fazio S23, Shapiro MD24.


Endotext [Internet]. South Dartmouth (MA):, Inc.; 2000-.
2018 Dec 24.

Author information

Professor of Medicine, University of California, San Francisco, CA
Chief of Medicine at the University of Washington Medical Center and Professor and Vice Chair of the Department of Medicine, University of Washington
Pediatric Endocrinologist and Associate Research Physician in the Skeletal Diseases and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health
Professor of Pediatrics and Endocrinology, Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, "Aghia Sophia" Children's Hospital, Athens, Greece
Associate Professor of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Ohio State University
Professor of Endocrinology and Director of the Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, UK
Distinguished Professor of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA; Associate Chief, Endocrinology and Diabetes Division and Director, Endocrine Clinic, West Los Angeles VA Medical Center, Los Angeles, CA
Professor of General Medicine-Endocrinology, First Department of Propaedeutic Internal Medicine, Laiko University Hospital, Athens, Greece
Head of the Medicover MVZ Oldenburg; affiliated with the Carl von Ossietzky University and the Technical University of Dresden
Professor of Medicine and Chief of the Division of Endocrinology, Diabetology and Metabolism, University of Lausanne, Switzerland
Professor of Endocrinology and Metabolism, Centre Lead for Endocrinology and Deputy Institute Director, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, England
Director of Clinical Research, Hudson Institute of Medical Research; Consultant Endocrinologist, Monash Medical Centre, Melbourne, Australia
Dammert Professor of Gerontology and Director, Division of Geriatric Medicine and Director of the Division of Endocrinology, Saint Louis University Medical Center
Professor of Pediatrics, Professor of Genetics and Genomic Sciences, and Chief of the Adrenal Steroid Disorders Program, Icahn School of Medicine, Mount Sinai School of Medicine, New York, NY
Associate Professor of Medicine and Epidemiology, University of Colorado Anschutz Medical Campus
Professor of Medicine, Knight Cardiovascular Institute and the Division of Endocrinology, and Associate Director, Bob and Charlee Moore Institute for Nutrition and Wellness, Oregon Health and Science University, Portland, OR
Professor and Chair, Department of Obstetrics and Gynecology, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, MI
Director of the Endocrine/Bone Disease Program, John Wayne Cancer Institute at Saint John’s Health Center, Santa Monica, CA; Clinical Professor of Medicine, UCLA School of Medicine, Los Angeles, CA
Director of the Diabetes Care Center and Associate Professor of Medicine, University of Washington Medical Center, Seattle, WA
Murray Waitzer Endowed Chair for Diabetes Research, Professor of Medicine/Pathology/Neurobiology, Director of Research and Neuroendocrine Unit Division of Endocrine and Metabolic Disorders, Eastern Virginia Medical School, Norfolk, VA
Endowed Chair, Cardiovascular Health and Risk Prevention, Pediatric Endocrinology and Diabetes, Cook Children's Medical Center, Fort Worth, TX
Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239
The William and Sonja Connor Chair of Preventive Cardiology, Professor of Medicine and Physiology & Pharmacology, Knight Cardiovascular Institute, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239
Associate Professor of Medicine and Radiology, Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239


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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