Phenotypes of Dyslipidemia A mechanis8c approach to management. Disclosures. Consultant FGH Research Funding Synageva, Inc.

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1 Phenotypes of Dyslipidemia A mechanis8c approach to management John P. Kane, M.D., Ph.D. Professor of Medicine University of alifornia, San Francisco Disclosures onsultant FGH Research Funding Synageva, Inc. 1

selec8on is based on phenotype Liver Parenchymal ell Metabolism of VLDL and

2 Phenotypes of Dyslipidemia Mechanis8c understanding leads to correct diagnosis Iden8fica8on of secondary gene8c mechanisms is important Treatment selec8on is based on phenotype Liver Parenchymal ell Metabolism of VLDL and LDL Lipoprotein Lipase apillary wall Golgi apparatus VLDL E Remnant Peripheral ell E LDL 2

3 VERY HIGH TRIGLYERIDES Primary causes: Impairment of lipoprotein lipase, Apo- II, ApoA- V, LMF- 1, GPIHBP, inhibi8on by Apo - III Secondary auses: Ø Insulin deficiency Ø Gammopathies, monoclonal and polyclonal Risk: Acute pancrea88s Management: Very low fat diet, no IV fat emulsions MODERATELY ELEVATED TRIGLYERIDES WITH NORMAL LDL Primary auses: Gene8c disorders of moderate severity Secondary causes: Diabetes, obesity, alcohol, sepsis, HIV, nephrosis, medica8ons, gammopathies, lipodystrophy Risk: Arteriosclerosis, fa[y liver Management: PPAR alpha agonists, niacin, omega3, decrease alcohol, treat diabetes, obesity 3

4 Liver Parenchymal ell Metabolism of VLDL and LDL Lipoprotein Lipase apillary wall Golgi apparatus VLDL E Remnant Peripheral ell E LDL ombined Hyperlipidemia Primary ause: Unknown, highly penetrant gene8c factors. Prevalence: 1-2 percent of North American popula8on. Risk: High risk of atherosclerosis Management: Drug combina8ons, sta8ns, Ze8a plus PPAR alpha agonists Treat: Diabetes, obesity 4

5 Liver Parenchymal ell Metabolism of VLDL and LDL Lipoprotein Lipase apillary wall Golgi apparatus VLDL E Remnant Peripheral ell E LDL DYSBETALIPOPROTEINEMIA (Accumula8on of remnant lipoproteins) ause: Homozygous Apo E- 2, or other ligand- incompetent Apo E Risk: Arteriosclerosis, aor8c aneurysm Management: Sta8ns, niacin 5

6 Liver Parenchymal ell Metabolism of VLDL and LDL Lipoprotein Lipase apillary wall Golgi apparatus VLDL E Remnant Peripheral ell E LDL ISOLATED ELEVATION OF LDL Gene8c auses: 1) Familial hypercholesterolemia 2) Ligand defec8ve hypercholesterolemia 3) Autosomal recessive hypercholesterolemia 4) PSK9 gain of func8on muta8ons Secondary causes: Hypothyroidism, gammopathies, early nephrosis, cholestasis Risk: Arteriosclerosis Management: Sta8ns, Ze8a, niacin, (PSK9, MTP inhibi8on) 6

7 HOMOZYGOUS FAMILIAL HYPERHOLESTEROLEMIA auses: Gene8c Risk: Very aggressive arteriosclerosis Management: Sta8n, if any receptor ac8vity; Ze8a, apheresis, an8sense RNA vs apo, MTP inhibi8on Phytosterolemia ause: Gene8c defects in plant sterol transporter (ABG5, ABG8) Risk: Arteriosclerosis Management: Ze8a, low phytosterol diet 7

8 Lp(a) Lipoprotein NH 2 n s IV IV s IV V Apo Protease X ELEVATED Lp(a) auses: Gene8c Secondary: Hypothyroidism, inflamma8on (nephrosis) Risk: Arteriosclerosis Management: ASA, reduce LDL, niacin, (PSK9 inhibi8on) 8

9 LDL DEFIIENY Abetalipoproteinemia: Gene8c cause: Muta8ons in MTP Risk: Tocopherol deficiency, re8nal and neuropathic disorders Hypobetalipoproteinemia: Gene8c causes: Muta8ons in Apo, other Gammopathies Management: Moderate tocopherol supplementa8on HYPOALPHALIPOPROTEINEMIA HDL DEFIIENY Primary causes: Ø Tangier Disease Ø Lecithin- cholesterol acyl transferase deficiency Ø Muta8ons in Apo A- I, other Secondary: Gammopathy, leukemia, (high triglycerides) Risk: Arteriosclerosis Management: Some cases respond to niacin 9

Free holesterol SR- BI Liver PLTP Removal and degradadon A-I

10 PreBeta-1 HDL Metabolism A-I LAT Large spherical (alpha) HDL A-I ETP hylos VLDL IDL LDL Peripheral ell ABA1 Transporter Free holesterol SR- BI Liver PLTP Removal and degradadon A-I Preβ - 1 HDL A-I De novo synthesis of apo A- I liver and intesdne 10

ATP III (Adult Treatment Panel III) CLASSIFICATION C IN ADULTS

ATP III (Adult Treatment Panel III) CLASSIFICATION C IN ADULTS LABORATORY AND RISK FACTORS OF ATHEROSCLEROSIS S R. Mohammadi Biochemist (Ph.D.) Faculty member of Medical Faculty RISK FACTORS FOR CHD Clinical Risk Factors Laboratory Risk Factors MAJOR CLINICAL RISK