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Phenotypes of Dyslipidemia A mechanis c 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.
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Phenotypes of Dyslipidemia
² Mechanis c understanding leads to correct diagnosis ² Iden fica on of secondary gene c mechanisms is important ² Treatment selec on 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
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VERY HIGH TRIGLYCERIDES
² Primary causes: Impairment of lipoprotein lipase, ApoC-II, ApoA-V, LMF-1, GPIHBP, inhibi on by Apo C-III ² Secondary Causes: Ø Insulin deficiency Ø Gammopathies, monoclonal and polyclonal ² Risk: Acute pancrea s ² Management: Very low fat diet, no IV fat emulsions
MODERATELY ELEVATED TRIGLYCERIDES WITH NORMAL LDL
² Primary Causes: Gene c disorders of moderate severity ² Secondary causes: Diabetes, obesity, alcohol, sepsis, HIV, nephrosis, medica ons, gammopathies, lipodystrophy ² Risk: Arteriosclerosis, fa y liver ² Management: PPAR alpha agonists, niacin, omega3, decrease alcohol, treat diabetes, obesity
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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 gene c factors. ² Prevalence: 1-2 percent of North American popula on. ² Risk: High risk of atherosclerosis ² Management: Drug combina ons, sta ns, Ze a plus PPAR alpha agonists ² Treat: Diabetes, obesity
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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 (Accumula on of remnant lipoproteins)
² Cause: Homozygous Apo E-2, or other ligand-incompetent Apo E ² Risk: Arteriosclerosis, aor c aneurysm ² Management: Sta ns, niacin
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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 Gene c Causes: 1) Familial hypercholesterolemia 2) Ligand defec ve hypercholesterolemia 3) Autosomal recessive hypercholesterolemia 4) PCSK9 gain of func on muta ons ² Secondary causes: Hypothyroidism, gammopathies, early nephrosis, cholestasis ² Risk: Arteriosclerosis ² Management: Sta ns, Ze a, niacin, (PCSK9, MTP inhibi on)
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HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA
² Causes: Gene c ² Risk: Very aggressive arteriosclerosis ² Management: Sta n, if any receptor ac vity; Ze a, apheresis, an sense RNA vs apoB-100, MTP inhibi on
Phytosterolemia
² Cause: Gene c defects in plant sterol transporter (ABCG5, ABCG8) ² Risk: Arteriosclerosis ² Management: Ze a, low phytosterol diet
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Lp(a) Lipoprotein
NH2 Protease n s X s IV IV IV V
Apo B-100 …
ELEVATED Lp(a)
² Causes: Gene c ² Secondary: Hypothyroidism, inflamma on (nephrosis) ² Risk: Arteriosclerosis ² Management: ASA, reduce LDL, niacin, (PCSK9 inhibi on)
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LDL DEFICIENCY
Abetalipoproteinemia: ² Gene c cause: Muta ons in MTP ² Risk: Tocopherol deficiency, re nal and neuropathic disorders
Hypobetalipoproteinemia: ² Gene c causes: Muta ons in ApoB-100, other ² Gammopathies ² Management: Moderate tocopherol supplementa on
HYPOALPHALIPOPROTEINEMIA HDL DEFICIENCY ² Primary causes: Ø Tangier Disease Ø Lecithin-cholesterol acyl transferase deficiency Ø Muta ons in Apo A-I, other ² Secondary: Gammopathy, leukemia, (high triglycerides) ² Risk: Arteriosclerosis ² Management: Some cases respond to niacin
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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 degrada on De novo synthesis of apo A-I Preβ -1 HDL liver and intes ne A-I
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