Hanoi, October 2016 Familial Hypercholesterole mia Maurice Choo, MD, FACC Prevalence of heterozygous FH in Asia ❖ Estimated prevalence based on frequency of 1:500 in population ❖ Assumes homogeneity of gene frequency in various populations ❖ Actual prevalence may be as high in 1:80 in some ethnic groups Familial hypercholesterolemia ❖ High LDL cholesterol from early childhood ❖ Cutaneous xanthomas and/or arthritic symptoms by 3rd decade of life ❖ Early onset and symptoms of coronary heart disease ❖ Autosomal disorder affecting 1:300-500 (heterozygotes) and 1:1,000,000 (homozygotes) persons in populations Familial hypercholesterolemia Genotypes ❖ LDL receptor (LDLR) genetic defects in most ❖ Familial defective apolipoprotein B-100 in 5% of cases ❖ Mutations in the PCSK9 gene in 1% of cases Diagnosis of heterozygous FH ❖ Clinical diagnosis if LDL cholesterol >330 mg/dL ❖ Or tendon xanthomas and LDL >95th percentile ❖ Before adulthood, suspect if LDL >200 mg/dL ❖ TG levels usually normal or mildly elevated ❖ Likely homozygous FH if LDL >600 mg/dL ❖ Confirmation using LDL receptor analysis ❖ Prevalence of heterozygotes is about 1:300-500 persons ❖ Prevalence of homozygotes is about 1:1,000,000 persons Main causes of secondary hypercholesterolemia ❖ Diabetes mellitus ❖ Hypothyroidism ❖ Hepatic disease ❖ Renal disease If identification of a cutaneous lesion is unclear, a biopsy can be performed Both xanthelasmas and the xanthomas of FH contain accumulations of cholesterol By contrast, eruptive xanthomas in patients with severe hypertriglyceridemia (levels >1000 mg/dL) contain triglycerides Xanthoma and xanthelasma Differential diagnosis of familial hypercholesterolemia ❖ Dysbetahyperlipoproteinemia (type III hyperlipidemia) ❖ Familial ligand defective apoB-100, familial defective apoB-100 ❖ Homozygous autosomal recessive hypercholesterolemia ❖ Sitosterolemia (phytosterolemia) Specialised tests for familial hypercholesterolemia ❖ Lipoprotein electrophoresis is expensive and is unnecessary for the diagnosis of FH If fasting lipid analysis reveals elevated triglyceride levels and the diagnosis of FH is in doubt, beta quantification (ultracentrifugation and electrophoresis) may be performed at a major lipid center ❖ LDL receptor analysis can be used to identify the specific LDL receptor defect This can only be performed at certain research laboratories and is expensive; and the results have no impact on management LDL receptor or apoB-100 studies can help distinguish heterozygous FH from the similar syndrome of familial defective apoB-100, but this finding would not alter treatment Imaging studies in familial hypercholesterolemia ❖ Annual echocardiogram and carotid ultrasonography ❖ MSCT coronary angiography every 3-5 years ❖ Stress myocardial perfusion imaging if indicated ❖ Others - aorta and arterial imaging Cholesterol mg/dL LDL mg/dL Homozygous familial hypercholesterolemia 800 600 400 200 2003 2004 Born Oct 1990 2005 2006 2007 2008 2009 2010 Died Sep 2010 Cholesterol LDLc TG Heterozygous familial hypercholesterolemia 400 MSCT coronary angiography normal in June 2015 300 Atorvastatin & Ezetimibe 200 100 2006 Born Feb 1996 2009 2013 2015 Cholesterol mg/dL LDL mg/dL TG mg/dL HDL mg/dL Heterozygous familial hypercholesterolemia 300 AMI and PCI, 1995 CABG, 2000 Recurrent ischemia, 2014 Diabetes mellitus, Type Hypertension Mild carotid artery disease 225 150 75 2007 Born Oct 1950 2009 2011 2013 2015 LDL targets in FH ❖ LDL