Familial hypercholesterolemia in adults: Overview
- Robert S Rosenson, MD
Robert S Rosenson, MD
- Section Editor — Lipids
- Professor of Medicine
- Mount Sinai School of Medicine
- Director, Cardiometabolic Disorders
- Mount Sinai Heart
- Paul Durrington, MD
Paul Durrington, MD
- Professor of Medicine
- Physician to Manchester Royal Infirmary
- University of Manchester
Familial hypercholesterolemia (FH) is the most common autosomal dominant genetic disease. The clinical syndrome (phenotype) is characterized by extremely elevated levels of low density lipoprotein cholesterol (LDL-C) and a propensity to early onset atherosclerotic cardiovascular disease. Homozygotes generally manifest disease in childhood. (See "Dyslipidemia in children: Definition, screening, and diagnosis", section on 'Familial hypercholesterolemia'.)
There are multiple definitions of FH in the literature. Some require the performance of genetic testing while others require very high levels of LDL-C with or without other clinical characteristics.
Other inherited lipid disorders are discussed separately. (See "Inherited disorders of LDL-cholesterol metabolism".)
This topic will focus on issues not related to the primary goal of therapy, which is to significantly lower LDL-C levels. Treatment is presented separately. (See "Familial hypercholesterolemia in adults: Treatment".)
Familial hypercholesterolemia (FH) is a genetic disease caused by functional mutations at one of three genetic loci. In the absence of genetic testing, which confirms one of these mutations, FH is defined based on clinical criteria. Many clinical definitions have been proposed with the following three representing the most commonly used :
- Benn M, Watts GF, Tybjærg-Hansen A, Nordestgaard BG. Mutations causative of familial hypercholesterolaemia: screening of 98 098 individuals from the Copenhagen General Population Study estimated a prevalence of 1 in 217. Eur Heart J 2016; 37:1384.
- Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014; 129:S1.
- Sjouke B, Kusters DM, Kindt I, et al. Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: prevalence, genotype-phenotype relationship, and clinical outcome. Eur Heart J 2015; 36:560.
- Khera AV, Won HH, Peloso GM, et al. Diagnostic Yield and Clinical Utility of Sequencing Familial Hypercholesterolemia Genes in Patients With Severe Hypercholesterolemia. J Am Coll Cardiol 2016; 67:2578.
- Austin MA, Hutter CM, Zimmern RL, Humphries SE. Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review. Am J Epidemiol 2004; 160:407.
- Fouchier SW, Dallinga-Thie GM, Meijers JC, et al. Mutations in STAP1 are associated with autosomal dominant hypercholesterolemia. Circ Res 2014; 115:552.
- Do R, Stitziel NO, Won HH, et al. Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature 2015; 518:102.
- Futema M, Shah S, Cooper JA, et al. Refinement of variant selection for the LDL cholesterol genetic risk score in the diagnosis of the polygenic form of clinical familial hypercholesterolemia and replication in samples from 6 countries. Clin Chem 2015; 61:231.
- Grossman M, Rader DJ, Muller DW, et al. A pilot study of ex vivo gene therapy for homozygous familial hypercholesterolaemia. Nat Med 1995; 1:1148.
- Hobbs HH, Russell DW, Brown MS, Goldstein JL. The LDL receptor locus in familial hypercholesterolemia: mutational analysis of a membrane protein. Annu Rev Genet 1990; 24:133.
- Ishibashi S, Brown MS, Goldstein JL, et al. Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery. J Clin Invest 1993; 92:883.
- Steinberg D, Parthasarathy S, Carew TE, et al. Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med 1989; 320:915.
- Guardamagna O, Restagno G, Rolfo E, et al. The type of LDLR gene mutation predicts cardiovascular risk in children with familial hypercholesterolemia. J Pediatr 2009; 155:199.
- Rader DJ, Cohen J, Hobbs HH. Monogenic hypercholesterolemia: new insights in pathogenesis and treatment. J Clin Invest 2003; 111:1795.
- Horton JD, Cohen JC, Hobbs HH. PCSK9: a convertase that coordinates LDL catabolism. J Lipid Res 2009; 50 Suppl:S172.
- Peterson AS, Fong LG, Young SG. PCSK9 function and physiology. J Lipid Res 2008; 49:1152.
- Abifadel M, Rabès JP, Devillers M, et al. Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease. Hum Mutat 2009; 30:520.
- Chen SN, Ballantyne CM, Gotto AM Jr, et al. A common PCSK9 haplotype, encompassing the E670G coding single nucleotide polymorphism, is a novel genetic marker for plasma low-density lipoprotein cholesterol levels and severity of coronary atherosclerosis. J Am Coll Cardiol 2005; 45:1611.
- Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006; 354:1264.
- Benn M, Nordestgaard BG, Grande P, et al. PCSK9 R46L, low-density lipoprotein cholesterol levels, and risk of ischemic heart disease: 3 independent studies and meta-analyses. J Am Coll Cardiol 2010; 55:2833.
- Dubuc G, Chamberland A, Wassef H, et al. Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 2004; 24:1454.
- Huijgen R, Boekholdt SM, Arsenault BJ, et al. Plasma PCSK9 levels and clinical outcomes in the TNT (Treating to New Targets) trial: a nested case-control study. J Am Coll Cardiol 2012; 59:1778.
- Stein EA, Mellis S, Yancopoulos GD, et al. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N Engl J Med 2012; 366:1108.
- Garcia CK, Wilund K, Arca M, et al. Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein. Science 2001; 292:1394.
- Defesche JC, Pricker KL, Hayden MR, et al. Familial defective apolipoprotein B-100 is clinically indistinguishable from familial hypercholesterolemia. Arch Intern Med 1993; 153:2349.
- Tybjaerg-Hansen A, Gallagher J, Vincent J, et al. Familial defective apolipoprotein B-100: detection in the United Kingdom and Scandinavia, and clinical characteristics of ten cases. Atherosclerosis 1990; 80:235.
- Tybjaerg-Hansen A, Steffensen R, Meinertz H, et al. Association of mutations in the apolipoprotein B gene with hypercholesterolemia and the risk of ischemic heart disease. N Engl J Med 1998; 338:1577.
- de Ferranti SD, Rodday AM, Mendelson MM, et al. Prevalence of Familial Hypercholesterolemia in the 1999 to 2012 United States National Health and Nutrition Examination Surveys (NHANES). Circulation 2016; 133:1067.
- Nordestgaard BG, Chapman MJ, Humphries SE, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J 2013; 34:3478.
- Benn M, Watts GF, Tybjaerg-Hansen A, Nordestgaard BG. Familial hypercholesterolemia in the danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication. J Clin Endocrinol Metab 2012; 97:3956.
- Steyn K, Goldberg YP, Kotze MJ, et al. Estimation of the prevalence of familial hypercholesterolaemia in a rural Afrikaner community by direct screening for three Afrikaner founder low density lipoprotein receptor gene mutations. Hum Genet 1996; 98:479.
- Couture P, Morissette J, Gaudet D, et al. Fine mapping of low-density lipoprotein receptor gene by genetic linkage on chromosome 19p13.1-p13.3 and study of the founder effect of four French Canadian low-density lipoprotein receptor gene mutations. Atherosclerosis 1999; 143:145.
- Nanchen D, Gencer B, Muller O, et al. Prognosis of Patients With Familial Hypercholesterolemia After Acute Coronary Syndromes. Circulation 2016; 134:698.
- Pang J, Poulter EB, Bell DA, et al. Frequency of familial hypercholesterolemia in patients with early-onset coronary artery disease admitted to a coronary care unit. J Clin Lipidol 2015; 9:703.
- Gidding SS, Bookstein LC, Chomka EV. Usefulness of electron beam tomography in adolescents and young adults with heterozygous familial hypercholesterolemia. Circulation 1998; 98:2580.
- Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents, National Heart, Lung, and Blood Institute. Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report. Pediatrics 2011; 128 Suppl 5:S213.
- Wiegman A, Gidding SS, Watts GF, et al. Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment. Eur Heart J 2015; 36:2425.
- Nanchen D, Gencer B, Auer R, et al. Prevalence and management of familial hypercholesterolaemia in patients with acute coronary syndromes. Eur Heart J 2015; 36:2438.
- Alonso R, Andres E, Mata N, et al. Lipoprotein(a) levels in familial hypercholesterolemia: an important predictor of cardiovascular disease independent of the type of LDL receptor mutation. J Am Coll Cardiol 2014; 63:1982.
- Wierzbicki AS, Humphries SE, Minhas R, Guideline Development Group. Familial hypercholesterolaemia: summary of NICE guidance. BMJ 2008; 337:a1095.
- Cuchel M, Bruckert E, Ginsberg HN, et al. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J 2014; 35:2146.
- Gregg RE, Connor WE, Lin DS, Brewer HB Jr. Abnormal metabolism of shellfish sterols in a patient with sitosterolemia and xanthomatosis. J Clin Invest 1986; 77:1864.
- Austin MA, Hutter CM, Zimmern RL, Humphries SE. Familial hypercholesterolemia and coronary heart disease: a HuGE association review. Am J Epidemiol 2004; 160:421.
- Stone NJ, Levy RI, Fredrickson DS, Verter J. Coronary artery disease in 116 kindred with familial type II hyperlipoproteinemia. Circulation 1974; 49:476.
- GENETIC CONSIDERATIONS
- Homozygotes versus heterozygotes
- LDL receptor genetic defects
- Mutations in the PCSK9 gene
- Familial defective apolipoprotein B-100
- VARIATION IN LDL-C
- CLINICAL PRESENTATION
- CLINICAL SUSPICION
- Differential diagnosis
- INDICATIONS FOR REFERRAL
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS