TY - JOUR
T1 - The severe hypercholesterolemia phenotype
T2 - Clinical diagnosis, management, and emerging therapies
AU - Sniderman, Allan D.
AU - Tsimikas, Sotirios
AU - Fazio, Sergio
N1 - Funding Information:
Dr. Tsimikas is supported by National Institutes of Health/National Heart, Lung, and Blood Institute grants R01-HL119828 , R01-HL093767 , and P01-HL055798 ; has received royalties from patents held by the University of California; has received research grants from Pfizer, ISIS, and Genentech; and is a consultant to ISIS, Genzyme, and Sanofi. Dr. Fazio is supported by NIH/NHLBI grants R01-HL106845 and R01-HL57986 ; has received research grants from ISIS, Merck, Pfizer, and Amarin; and is a consultant for Merck, Roche, Kowa, Sanofi, Gilead, Aegerion, Genzyme, and Amarin. Dr. Sniderman has received honoraria from Merck and Genzyme.
PY - 2014/5/20
Y1 - 2014/5/20
N2 - The severe hypercholesterolemia phenotype includes all patients with marked elevation of low-density lipoprotein cholesterol (LDL-C) levels. The most common cause is autosomal dominant hypercholesterolemia, an inherited disorder caused by mutations either in LDL receptor, apolipoprotein B (APOB), or proprotein convertase subtilisin kexin type 9 (PCSK9) genes. However, it is now known that many subjects with severe inherited hypercholesterolemia have no defects in these genes. These cases are caused either by mutations in genes yet to be identified or are consequences of polygenic, epigenetic, or acquired defects. Because the clinical consequences of extreme hypercholesterolemia are the same no matter the cause, the focus should be on the identification of subjects with severe hypercholesterolemia, followed by phenotypic screening of family members. Genetic screening is not necessary to diagnose or initiate treatment for the severe hypercholesterolemia phenotype. Management of severe hypercholesterolemia is based on risk factor modification and use of multiple lipid-lowering medications. Lipoprotein apheresis is indicated for coronary artery disease (CAD) patients taking maximally tolerated therapy and with LDL-C levels >200 mg/dl (>300 mg/dl if without CAD). A microsomal triglyceride transfer protein inhibitor and an antisense oligonucleotide against APOB have recently been approved for use in subjects with clinically diagnosed homozygous familial hypercholesterolemia. PCSK9 inhibitors, currently in phase II and III trials, lower LDL-C up to an additional 70% in the setting of maximally tolerated medical therapy and have the potential to reduce LDL-C to <70 mg/dl in most patients. Early identification of affected individuals and aggressive treatment should significantly reduce the burden of cardiovascular disease in society.
AB - The severe hypercholesterolemia phenotype includes all patients with marked elevation of low-density lipoprotein cholesterol (LDL-C) levels. The most common cause is autosomal dominant hypercholesterolemia, an inherited disorder caused by mutations either in LDL receptor, apolipoprotein B (APOB), or proprotein convertase subtilisin kexin type 9 (PCSK9) genes. However, it is now known that many subjects with severe inherited hypercholesterolemia have no defects in these genes. These cases are caused either by mutations in genes yet to be identified or are consequences of polygenic, epigenetic, or acquired defects. Because the clinical consequences of extreme hypercholesterolemia are the same no matter the cause, the focus should be on the identification of subjects with severe hypercholesterolemia, followed by phenotypic screening of family members. Genetic screening is not necessary to diagnose or initiate treatment for the severe hypercholesterolemia phenotype. Management of severe hypercholesterolemia is based on risk factor modification and use of multiple lipid-lowering medications. Lipoprotein apheresis is indicated for coronary artery disease (CAD) patients taking maximally tolerated therapy and with LDL-C levels >200 mg/dl (>300 mg/dl if without CAD). A microsomal triglyceride transfer protein inhibitor and an antisense oligonucleotide against APOB have recently been approved for use in subjects with clinically diagnosed homozygous familial hypercholesterolemia. PCSK9 inhibitors, currently in phase II and III trials, lower LDL-C up to an additional 70% in the setting of maximally tolerated medical therapy and have the potential to reduce LDL-C to <70 mg/dl in most patients. Early identification of affected individuals and aggressive treatment should significantly reduce the burden of cardiovascular disease in society.
KW - LDL receptor
KW - familial hypercholesterolemia
KW - genetics
KW - lipoproteins
KW - statins
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U2 - 10.1016/j.jacc.2014.01.060
DO - 10.1016/j.jacc.2014.01.060
M3 - Review article
C2 - 24632267
AN - SCOPUS:84900832381
SN - 0735-1097
VL - 63
SP - 1935
EP - 1947
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 19
ER -