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Phenotypes of A mechanisc 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 Mechanisc understanding leads to correct diagnosis ² Idenficaon of secondary genec mechanisms is important ² Treatment selecon is based on phenotype

Metabolism of VLDL and LDL Liver Capillary 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

² Primary causes: Impairment of lipoprotein lipase, ApoC-II, ApoA-V, LMF-1, GPIHBP, inhibion by Apo C-III ² Secondary Causes: Ø deficiency Ø Gammopathies, monoclonal and polyclonal ² Risk: Acute pancreas ² Management: Very low diet, no IV fat emulsions

MODERATELY ELEVATED TRIGLYCERIDES WITH NORMAL LDL

² Primary Causes: Genec disorders of moderate severity ² Secondary causes: , , alcohol, sepsis, HIV, nephrosis, medicaons, gammopathies, ² Risk: Arteriosclerosis, fay liver ² Management: PPAR alpha agonists, , 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

² Primary Cause: Unknown, highly penetrant genec factors. ² Prevalence: 1-2 percent of North American populaon. ² Risk: High risk of ² Management: Drug combinaons, stans, Zea 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 (Accumulaon of remnant )

² Cause: Homozygous Apo E-2, or other ligand-incompetent Apo E ² Risk: Arteriosclerosis, aorc aneurysm ² Management: Stans, 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 Genec Causes: 1) Familial 2) Ligand defecve hypercholesterolemia 3) Autosomal recessive hypercholesterolemia 4) PCSK9 gain of funcon mutaons ² Secondary causes: , gammopathies, early nephrosis, cholestasis ² Risk: Arteriosclerosis ² Management: Stans, Zea, niacin, (PCSK9, MTP inhibion)

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HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA

² Causes: Genec ² Risk: Very aggressive arteriosclerosis ² Management: Stan, if any receptor acvity; Zea, apheresis, ansense RNA vs apoB-100, MTP inhibion

Phytosterolemia

² Cause: Genec defects in plant sterol transporter (ABCG5, ABCG8) ² Risk: Arteriosclerosis ² Management: Zea, 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: Genec ² Secondary: Hypothyroidism, inflammaon (nephrosis) ² Risk: Arteriosclerosis ² Management: ASA, reduce LDL, niacin, (PCSK9 inhibion)

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LDL DEFICIENCY

Abetalipoproteinemia: ² Genec cause: Mutaons in MTP ² Risk: Tocopherol deficiency, renal and neuropathic disorders

Hypobetalipoproteinemia: ² Genec causes: Mutaons in ApoB-100, other ² Gammopathies ² Management: Moderate tocopherol supplementaon

HYPOALPHALIPOPROTEINEMIA HDL DEFICIENCY ² Primary causes: Ø Ø Lecithin- 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

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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 degradaon De novo synthesis of apo A-I Preβ -1 HDL liver and intesne A-I

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