Familial hypercholesterolaemia (FH) is an autosomal co-dominant disorder that markedly raises plasma low-density lipoprotein-cholesterol (LDL-C) concentration, causing premature atherosclerotic coronary artery disease (CAD). FH has recently come under intense focus and, although there is general consensus in recent international guidelines regarding diagnosis and treatment, there is debate about the value of genetic studies. Genetic testing can be cost-effective as part of cascade screening in dedicated centres, but the full mutation spectrum responsible for FH has not been established in many populations, and its use in primary care is not at present logistically feasible. Whether using genetic testing or not, cholesterol screening of family members of index patients with an abnormally raised LDL-C must be used to determine the need for early treatment to prevent the development of CAD. The metabolic defects in FH extend beyond LDL, and may affect triacylglycerol-rich and high-density lipoproteins, lipoprotein(a) and oxidative stress. Achievement of the recommended targets for LDL-C with current treatments is difficult, but this may be resolved by new drug therapies. Lipoprotein apheresis remains an effective treatment for severe FH and, although expensive, it costs less than the two recently introduced orphan drugs (lomitapide and mipomersen) for homozygous FH. Recent advances in understanding of the biology of proprotein convertase subtilisin/kexin type 9 (PCSK9) have further elucidated the regulation of lipoprotein metabolism and led to new drugs for effectively treating hypercholesterolaemia in FH and related conditions, as well as for treating many patients with statin intolerance. The mechanisms of action of PCSK9 inhibitors on lipoprotein metabolism and atherosclerosis, as well as their impact on cardiovascular outcomes and cost-effectiveness, remain to be established.
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Review Article|
April 15 2015
Recent advances in the understanding and care of familial hypercholesterolaemia: significance of the biology and therapeutic regulation of proprotein convertase subtilisin/kexin type 9
Michael M. Page;
Michael M. Page
*Lipid Disorders Clinic, Cardiovascular Medicine, Royal Perth Hospital, Perth, Australia
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Claudia Stefanutti;
Claudia Stefanutti
†Extracorporeal Therapeutic Techniques Unit–Lipid Clinic and Atherosclerosis Prevention Centre, Department of Molecular Medicine, Sapienza University of Rome, Umberto I Hospital, Rome, Italy
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Allan Sniderman;
Allan Sniderman
‡Division of Cardiology, McGill University, Montréal, Québec, Canada
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Gerald F. Watts
Gerald F. Watts
1
*Lipid Disorders Clinic, Cardiovascular Medicine, Royal Perth Hospital, Perth, Australia
§School of Medicine and Pharmacology, University of Western Australia, Perth, Australia
Correspondence: Professor G.F. Watts (email [email protected])
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Publisher: Portland Press Ltd
Received:
November 19 2014
Revision Received:
February 12 2015
Accepted:
February 20 2015
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2015 Biochemical Society
2015
Clin Sci (Lond) (2015) 129 (1): 63–79.
Article history
Received:
November 19 2014
Revision Received:
February 12 2015
Accepted:
February 20 2015
Citation
Michael M. Page, Claudia Stefanutti, Allan Sniderman, Gerald F. Watts; Recent advances in the understanding and care of familial hypercholesterolaemia: significance of the biology and therapeutic regulation of proprotein convertase subtilisin/kexin type 9. Clin Sci (Lond) 1 July 2015; 129 (1): 63–79. doi: https://doi.org/10.1042/CS20140755
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