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The Severe Hypercholesterolemia Phenotype: Genes and Beyond.


Pendyal A15, Fazio S16.


Endotext [Internet]. South Dartmouth (MA):, Inc.; 2000-.
2015 Nov 16.

Author information

Research Professor, Cell and Molecular Biology, College of the Environment and Life Sciences, University of Rhode Island, Kingston, RI
Department of Paediatrics, National University of Athens, Athens, Greece
Associate Professor of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Ohio State University
Professor of Medicine, University of California - San Francisco, CA; Staff Physician and Chief of the Endocrine Clinic, San Francisco VA Medical Center, San Francisco, CA
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, University of Mississippi Medical Center, Jackson, MS
Co-Centre Head, Department of Endocrinology, Barts and the London School of Medicine, London, England
Director of Clinical Research, Prince Henry's Institute, Clayton, Victoria, Australia; Consultant Endocrinologist, Monash Medical Centre, Melbourne, Australia
Professor of Pediatrics, Professor of Genetics and Genomic Sciences, and Director of the Adrenal Steroid Disorders Program, Mount Sinai School of Medicine, New York, NY; Associate Dean for Clinical Research, Herbert Wertheim College of Medicine, Florida International University, Miami, FL
Professor of Medicine, Knight Cardiovascular Institute and the Division of Endocrinology, Oregon Health and Science University, Portland, OR
Executive Director, American Society for Reproductive Medicine in Birmingham, Alabama; Volunteer Clinical Professor, Department of Obstetrics and Gynecology, University of Alabama, Birmingham, AL
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
Professor of Medicine and Director, Strelitz Diabetes Center, Eastern Virginia Medical School, Norfolk, VA
Fellow, Cardiovascular Medicine, 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


Genetic disorders resulting in hypercholesterolemia comprise autosomal dominant hypercholesterolemia (ADH), as well as other rare conditions such as autosomal recessive hypercholesterolemia. All of these disorders cause profound elevations in LDL cholesterol (LDL-C) and, as a result, greatly increased risk of incident cardiovascular disease (CVD). Genetic loci involved in ADH include LDLR (which codes for the LDL receptor, whose dysfunction causes Familial Hypercholesterolemia, or FH), APOB (which codes for apoB-100, the major protein component of LDL), and PCSK9 (which codes for PCSK9, the circulatory protein that terminates the lifecycle of the LDLR). Importantly, a large percentage of people with a severe hypercholesterolemic phenotype do not possess a readily identifiable gene defect. Thus, identification of a specific genetic substrate is not a necessary condition for the diagnosis of a genetic hypercholesterolemia. Several formal diagnostic criteria exist for familial hypercholesterolemia; they involve 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, niacin, and fibrates. Few patients with extreme and unresponsive elevations in LDL will need invasive therapies such as lipoprotein apheresis. Novel agents for the treatment of severe hypercholesterolemia include microsomal triglyceride transfer protein (MTP) inhibitors, apoB-100 antisense oligonucleotides (ASOs), and monoclonal antibodies against PCSK9. The FDA has just approved two PCSK9 inhibitors, alirocumab and evolocumab, for use in addition to diet and maximally tolerated statin therapy in adult patients with heterozygous familial hypercholesterolemia or those with clinical CAD who require additional LDL-C lowering. For complete coverage of this and all related areas of endocrinology, please see our free web-book,

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