5/2/15 Phenotypes of Dyslipidemia A mechanis8c approach to management John P. Kane, M.D., Ph.D. Professor of Medicine University of California, San Francisco Disclosures • Consultant FGH • Research Funding Synageva, Inc. 1 5/2/15 Phenotypes of Dyslipidemia ² Mechanis8c understanding leads to correct diagnosis ² Iden8ficaon of secondary gene8c mechanisms is important ² Treatment selec8on is based on phenotype Metabolism of VLDL and LDL Liver Capillary Lipoprotein wall Parenchymal Cell Lipase Golgi B-100 apparatus C TG C C VLDL C Receptor TG Lysosome B-100 CE Peripheral Remnant Cell CE B-100 Lysosome LDL Receptor 2 5/2/15 VERY HIGH TRIGLYCERIDES ² Primary causes: Impairment of lipoprotein lipase, ApoC-II, ApoA-V, LMF-1, GPIHBP, inhibi8on by Apo C-III ² Secondary Causes: Ø Insulin deficiency Ø Gammopathies, monoclonal and polyclonal ² Risk: Acute pancrea8s ² Management: Very low fat diet, no IV fat emulsions MODERATELY ELEVATED TRIGLYCERIDES WITH NORMAL LDL ² Primary Causes: Gene8c disorders of moderate severity ² Secondary causes: Diabetes, obesity, alcohol, sepsis, HIV, nephrosis, medicaons, gammopathies, lipodystrophy ² Risk: Arteriosclerosis, fay liver ² Management: PPAR alpha agonists, niacin, omega3, decrease alcohol, treat diabetes, obesity 3 5/2/15 Metabolism of VLDL and LDL Liver Capillary Lipoprotein wall Parenchymal Cell Lipase Golgi B-100 apparatus C TG C C VLDL C Receptor TG Lysosome B-100 CE Peripheral Remnant Cell CE B-100 Lysosome LDL Receptor Combined Hyperlipidemia ² Primary Cause: Unknown, highly penetrant gene8c factors. ² Prevalence: 1-2 percent of North American populaon. ² Risk: High risk of atherosclerosis ² Management: Drug combinaons, stans, Zea plus PPAR alpha agonists ² Treat: Diabetes, obesity 4 5/2/15 Metabolism of VLDL and LDL Liver Capillary Lipoprotein wall Parenchymal Cell Lipase Golgi B-100 apparatus C TG C C VLDL C Receptor TG Lysosome B-100 CE Peripheral Remnant Cell CE B-100 Lysosome LDL Receptor DYSBETALIPOPROTEINEMIA (Accumulaon of remnant lipoproteins) ² Cause: Homozygous Apo E-2, or other ligand-incompetent Apo E ² Risk: Arteriosclerosis, aor8c aneurysm ² Management: Stans, niacin 5 5/2/15 Metabolism of VLDL and LDL Liver Capillary Lipoprotein wall Parenchymal Cell Lipase Golgi B-100 apparatus C TG C C VLDL C Receptor TG Lysosome B-100 CE Peripheral Remnant Cell CE B-100 Lysosome LDL Receptor ISOLATED ELEVATION OF LDL ² Gene8c Causes: 1) Familial hypercholesterolemia 2) Ligand defec8ve hypercholesterolemia 3) Autosomal recessive hypercholesterolemia 4) PCSK9 gain of func8on mutaons ² Secondary causes: Hypothyroidism, gammopathies, early nephrosis, cholestasis ² Risk: Arteriosclerosis ² Management: Stans, Zea, niacin, (PCSK9, MTP inhibi8on) 6 5/2/15 HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA ² Causes: Gene8c ² Risk: Very aggressive arteriosclerosis ² Management: Stan, if any receptor ac8vity; Zea, apheresis, an8sense RNA vs apoB-100, MTP inhibi8on Phytosterolemia ² Cause: Gene8c defects in plant sterol transporter (ABCG5, ABCG8) ² Risk: Arteriosclerosis ² Management: Zea, low phytosterol diet 7 5/2/15 Lp(a) Lipoprotein NH2 Protease n s X s IV IV IV V Apo B-100 … ELEVATED Lp(a) ² Causes: Gene8c ² Secondary: Hypothyroidism, inflammaon (nephrosis) ² Risk: Arteriosclerosis ² Management: ASA, reduce LDL, niacin, (PCSK9 inhibion) 8 5/2/15 LDL DEFICIENCY Abetalipoproteinemia: ² Gene8c cause: Mutaons in MTP ² Risk: Tocopherol deficiency, re8nal and neuropathic disorders Hypobetalipoproteinemia: ² Gene8c causes: Mutaons in ApoB-100, other ² Gammopathies ² Management: Moderate tocopherol supplementaon HYPOALPHALIPOPROTEINEMIA HDL DEFICIENCY ² Primary causes: Ø Tangier Disease Ø Lecithin-cholesterol acyl transferase deficiency Ø Mutaons in Apo A-I, other ² Secondary: Gammopathy, leukemia, (high triglycerides) ² Risk: Arteriosclerosis ² Management: Some cases respond to niacin 9 5/2/15 PreBeta-1 HDL Metabolism A-I Large CETP Chylos spherical VLDL (alpha) HDL IDL LDL LCAT A-I ABCA1 Transporter Free Cholesterol SR-BI Peripheral Cell Liver PLTP A-I Removal and degradaDon De novo synthesis of apo A-I Preβ -1 HDL liver and intesne A-I 10 .