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FAMILIAL HYPERLIPIDEMIAS Julia Creider, PGY4 Endocrine OBJECTIVES Review lipid and lipoprotein classification and nomenclature Understand the pathways of cholesterol biosynthesis and metabolism Review primary disorders of hyper- and hypolipidemia Low-Density Lipoprotein (LDL) Triglycerides (TG) High-Density Lipoprotein (HDL) LIPIDS Group of naturally occurring molecules Biologically important lipids Free cholesterol Cholesterol esters (CE) Triglycerides (TG) Phospholipids Fat soluble vitamins (A, D, E, and K) Main biological functions include Storing energy Signaling Structural components of cell membranes LIPOPROTEINS Large macromolecular complexes that transport hydrophobic lipids surrounded by hydrophilic phospholipids and proteins LIPOPROTEINS Type Site of Origin Major Lipids Major Apolipoprotiens Chylomicrons (CM) Intestine 85% TG B48, A1, AIV CM Remnant Intestine 60% TG, 20% C B48, E VLDL Liver 55% TG, 20% C B100, E, C1, CII, CIII IDL From VLDL 35% C, 25% TG B100, E LDL From IDL 60% C, 5% TG HDL Liver, intestine, 25% PL, 20% C, A1, AII, C1, CII, plasma 5% TG (50% CIII, E protein) Lp(a) Liver 60% C, 5% TG B100 B100, (a) LIPOPROTEINS Lp(a) APOLIPOPROTEINS Protein component of lipoproteins Function Activate enzymes important to lipid metabolism Act as ligands for cell surface receptors Apolipoprotein Site of Synthesis Major Functions Structural protein of HDL Cofactor for LCAT Ligand for ABCA-1 and SR-B1 ApoA-1 Liver, intestine ApoA-II Liver ApoA-IV Intestine ApoA-V Liver Activator of LPL lipolysis ApoB-100 Liver Protein for VLDL, IDL, LDL ApoB-48 Intestine Inhibits apo-E binding to receptors Activator of LCAT Facilitates lipid secretion from intestine Protein for CMs ApoC-1 Liver Modulates apo-E mediated binding of remnants Activate LCAT ApoC-II Liver Cofactor for LPL ApoC-III Liver Remnant binding to receptors Inhibitor of LPL ApoE Liver, brain, skin, spleen, testes Apo(a) Liver Ligand for LDL & remnant receptor Reverse cholesterol transport Unknown RECEPTORS Low-Density Lipoprotein Receptor (LDLR) Present on cells throughout the body Mediates uptake of cholesterol-rich lipoproteins Requires specific proteins on lipoprotein surface ApoB-100 (LDL) ApoE (CM remnants, VLDL, IDL, and HDL) Number of LDLR on cell surface is tightly regulated by intracellular cholesterol content Low-Density Lipoprotein Receptor-Related Protein (LRP) Aka Remnant receptor Binds with high affinity to ApoE (CM remnants, VLDL) Does not bind LDL IMPORTANT ENZYMES Lipoprotein Lipase (LPL) Bound to capillary endothelial cells Mediates hydrolysis of TGs to release FFA from CMs and VLDL Requires ApoC-II as cofactor Activated by ApoA-V Inhibited by ApoC-III Activated by insulin in adipocytes Activated by glucagon and adrenaline in muscle and myocardial tissues IMPORTANT ENZYMES Hepatic Lipase (HL) Hydrolyzes TGs in final processing of CM remnants Completes processing of IDL to LDL Facilitates interaction of remnant lipoproteins with LRP for internalization by hepatocytes Participates in conversion of HDL2 back to HDL3 WHAT HAPPENS WHEN YOU EAT? (1) Brush boarder of epithelial cells of small intestine (duodenum and proximal jejunum) synthesize CMs from dietary fat and cholesterol CMs enter mesenteric lymph and are absorbed into general circulation by the thoracic duct Newly synthesized CMs have: ApoB-48 ApoA-1 ApoA-IV They acquire ApoE and C-apolipoproteins (primarily from HDL) WHAT HAPPENS WHEN YOU EAT? (2) LPL catalyzes release of FFAs from CM TG’s and converts them to CM remnants FFAs are: Stored in adipose tissue Oxidized as energy source Reutilized in hepatic lipoprotien TG synthesis (VLDL) Hepatic lipase helps in final preparation of CMs for uptake by hepatocytes CM remnants are rapidly cleared by the liver by either LDL or LRP receptors, mediated by ApoE ApoB-48 ApoA-1 ApoA-IV ApoE, C1, CII, CIII from HDL ApoB-48 ApoE VLDL Synthesized by the liver Production stimulated by increased delivery of FFA to hepatocytes Microsomal triglyceride transfer protein (MTP) Transfers TG and PL to nascent ApoB containing lipoproteins (ApoB-100, and B48) Deficiency of MTP causes Abetalipoproteinemia VLDL triglycerides are hydrolyzed by LPL and HL Converted to smaller particles that are increasingly rich in cholesterol IDL Metabolic product of VLDL catabolism by LPL Primary proteins are ApoE and ApoB-100 Fate: Further processed by LPL and HL to LDL Removed from plasma by the LDLR (uptake mediated by ApoE LDL 50% of VLDL makes it to LDL 70% of total plasma cholesterol is in LDL Major apolipoprotein is ApoB-100 Uptake by the LDLR is mediated by ApoB-100 Delivers cholesterol to cells B100, E, C1, CII, CIII B100, E B100 LIPID DISORDERS Previously classified according to Fredrickson phenotype Categorized by type of lipoprotein particle that accumulated in the blood Does not include HDL Not take into account cause Not distinguish between primary and secondary causes FREDRICKSON PHENOTYPES Phenotype Lipoprotein Lipid Elevation Type I CMs TG Type IIa LDL TC Type IIb LDL and VLDL TC and TG Type III IDL TC and TG Type IV VLDL TG Type V VLDL and CMs TC and TG PRIMARY DISORDERS OF HYPERLIPIDEMIA Increased Cholesterol Increased Cholesterol and Triglycerides Increased Triglycerides PRIMARY DISORDERS OF HYPERLIPIDEMIA Increased Cholesterol Familial Hypercholesterolemia (FH) Familial Defective Apolipoprotein B100 (FDB) Autosomal Recessive Hypercholesterolemia (ARH) Sitosterolemia Polygenic Hypercholesterolemia FAMILIAL HYPERCHOLESTEROLEMIA (FH) Autosomal dominant Caused by mutation in LDL receptor gene >900 described mutations Markedly elevated LDL (>95%ile) Heterozygous 1 in 500, homozygous 1 in 106 60-80, 000 Canadians French Canadian, Christian Lebanese, Dutch South Afrikaners ~5% of men with MI age < 60 High Risk of CAD if untreated > 60% men, > 30% women by age 60 Katz P. 2014. Lipid metabolism & clinical lipid disorders. WHEN TO CONSIDER FH Very high LDL (typically > 5.0 mmol/L) Personal history of early cardiovascular disease Typical physical findings: Xanthelasmas Arcus cornealis Tendon xanthomas Family history: Early cardiovascular disease Marked hyperlipidemia XANTHALASMAS ARCUS CORNEALIS TENDON XANTHOMAS HOMOZYGOUS FH Very rare, 1 in 106 Marked hypercholesterolemia from birth TC 15 – 25 mmol/L, LDL 14 - 25 mmol/L Symptomatic CHD < 10 years of age, MI as young as 18 months If untreated, usually die in 20’s of CHD Xanthomas, xanthelasma early in life Tuberous xanthomas Katz P. 2014. Lipid metabolism & clinical lipid disorders. SCREENING FOR FH 1. Targeted screening to identify FH index cases with at least 1 feature: Personal or family history of clinical stigmata or premature CVD Family history of significant hypercholesterolemia 2. Cascade screening to detect affected members Opportunistic screening should be done around time of cardiovascular event Canadian-specific cascade screening www.fhcanada.net CCS: Position Statement on FH. 2014 FH DIAGNOSIS Homozygous Suspect in child with TC > 12.9 or xanthomas Heterozygotes Primarily clinical diagnosis Family history very important Standard criteria have been suggested: Simon-Broome Criteria Dutch Lipid Clinic Criteria If family member has known FH and mutation can do cascade testing in family members Yuan G et al. 2006. CMAJ 17(8):1124 Yuan G et al. 2006. CMAJ 17(8):1124 FH DIAGNOSIS Yuan G et al. 2006. CMAJ 17(8):1124 WHEN TO DO GENETIC TESTING? Cases of diagnostic uncertainty Unavailable family history Borderline lipid levels Screened as possible or probable FH Will change management CCS: Position Statement on FH. 2014 TREATMENT OF FH Global risk factor assessment and management HTN, DM, smoking, obesity Homozygotes – plasmapharesis or LDL apheresis Heterozygotes – statins +/- other agents Ezetimibe, bile acid sequestrants, niacin Newer agents PSCK9 monoclonal antibodies Treatment goal is at least a 50% reduction in LDL or less than 2.0 mmol/L Feldman D et al. 2015. CurrAtherosclerRep 17(1):473. TREATMENT OF FH Feldman D et al. 2015. CurrAtherosclerRep 17(1):473. CHOLESTEROL BIOSYNTHESIS Cholesterol is either absorbed from diet or synthesized by cells in the body 3 molecules of acetate are condensed to form 3hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) HMG-CoA is converted to mevalonic acid by HMG-CoA reductase RATE LIMITING STEP Feedback regulation: intracellular cholesterol HMG-CoA reductase Cholesterol deficiency upregulate enzyme ENTEROHEPATIC CIRCULATION Either excreted as free cholesterol (FC) in bile or converted to bile acids (BA) 50% of FC and 97% of secreted BA are reabsorbed Reabsorbed cholesterol and BA regulate de novo cholesterol and bile acid synthesis in the liver 7-αHydroxylase RATE LIMITING STEP in BA synthesis Feedback regulation by recirculating BA Closely coupled to HMG-CoA reductase activity Statins: inhibit HMG CoA reductase decrease cholesterol upregulate LDL-R expression increased clearance of LDL-C Bile acid sequestrants: Decrease FC/BA reabsorption Ezetimibe: inhibit intestinal absorption Niacin: 1. Direct inhibition of DGAT2 2. Decrease lipolysis and FFA influx to liver 3. Increase ApoB catabolism PCSK9 Mullard A. 2012. Nature Rev Drug Discovery 11:817 FAMILIAL DEFECTIVE APOLIPOPROTEIN B100 Mutation in ApoB-100 that impairs its ability to bind to the LDL receptor Single mutation accounts for almost all cases Substitution of glutamine for arginine at aa3500 Phenotypically similar to FH Isolated elevated LDL Tendon xanthomas and xanthelasma Premature CVD Generally less severe Clear remnant particles through LDL receptor via ApoE Kronenberg HM et al. Williams Textbook of Endocrinology. 12th Ed AUTOSOMAL RECESSIVE HYPERCHOLESTEROLEMIA Mutation in ARH which encodes LDLR adaptor protein 1 Mediates endocytosis of LDL receptor in hepatocyte cells Very rare – described in Sardinia, Lebanon ✕ Soutar A. 2010. IUBMB Life. 62(2):125. SITOSTEROLEMIA Very rare autosomal recessive Mutations in Adenosine triphosphate binding cassette transporter (ABCG) 5 or 8 Function to remove passively absorbed plant sterols Leads to elevations of sitosterol and campesterol Presentation: Xanthomas Premature CHD Arthralgias, hemolysis, thrombocytopenia Requires liquid or gas chromatography to identify Treatment – restriction of dietary plant sterols and ezetimibe Othman R et al. 2013. Atherosclerosis. 231(2):291. POLYGENIC HYPERCHOLESTEROLEMIA A cholesterol value > 95th percentile for population Exclude other primary genetic causes by absence of tendon xanthomas and family history in ≤ 10% of first degree relatives Katz P. 2014. Lipid metabolism & clinical lipid disorders. PRIMARY DISORDERS OF HYPERLIPIDEMIA Increased Cholesterol and Triglyceride Familial Combined Hyperlipidemia Familial Dysbetalipoproteinemia FAMILIAL COMBINED HYPERLIPIDEMIA (FCH) Autosomal dominant Common disorder (5-7%) Unknown genetic cause, likely multiple genes Overproduction of ApoB VLDL, LDL or both Moderate elevations of cholesterol or TG or both Predominant lipid abnormality can vary among affected family member or a single person over time Kronenberg HM et al. Williams Textbook of Endocrinology. 12th Ed FAMILIAL COMBINED HYPERLIPIDEMIA (FCH) Clinically Overlapping features of metabolic syndrome Insulin resistance Obesity Hyperuricemia Low HDL No xanthomas Increased susceptibility to CHD 11% of male survivors of MI < age 60 Treatment Lifestyle – diet, exercise, weight loss Pharmacotherapy – targeted at specific lipid abnormality Kronenberg HM et al. Williams Textbook of Endocrinology. 12th Ed FAMILIAL DYSBETALIPOPROTEINEMIA/TYPE III HYPERLIPOPROTEINEMIA Mutations in ApoE Results in impaired binding of ApoE to lipoprotein receptors and accumulations of remnant particles (CM remnants and IDL) Moderate to severe TG and TC LDL reduced (cleared by LDL receptor via ApoB-100) Marais A et al. 2014.CritRevClinLabSci. 51(1):46. ApoB-48 ApoE B100, E × × B100 FAMILIAL DYSBETALIPOPROTEINEMIA/TYPE III HYPERLIPOPROTEINEMIA Typically autosomal recessive (rarely dominant) 1 in 10, 000 Majority are homozygous of ApoE-2 genotype ~ 1% population is ApoE2/E2, only 0.01% have type III Requires 2nd exacerbating metabolic factor Hypothyroidism, menopause, alcohol, diabetes Premature vascular disease (including PVD) Treatment Treat exacerbating factor Diet Fibrates +/- statins Marais A et al. 2014.CritRevClinLabSci. 51(1):46. PALMAR XANTHOMAS Yellowish plaques on palms – especially creases and flexural surface of fingers PRIMARY DISORDERS OF HYPERLIPIDEMIA Increased Triglceride Lipoprotein Lipase Deficiency Apolipoprotein CII Deficiency Familial hypertriglyceridemia LIPOPROTEIN LIPASE DEFICIENCY Autosomal recessive Mutation in the LPL gene Absence or inactivation of LPL protein Impaired clearance of TG-rich lipoproteins from plasma Accumulation of CMs and VLDL Chylomicronemia Syndrome Marked hypertriglyceridemia (TG >22.6 mmol/L) Recurrent abdominal pain /pancreatitis Rahalkar A et al. 2009.Can J Physiol Pharmacol. 87(3):151. LIPOPROTEIN LIPASE DEFICIENCY Usually present in infancy or childhood Clinically Eruptive xanthomas Lipemia retinalis Hepatosplenomegaly Neurological manifestations Dyspnea Biochemically Lipemic plasma Pseudohyponatremia Treatment – diet, fibrates Rahalkar A et al. 2009.Can J Physiol Pharmacol. 87(3):151. ERUPTIVE XANTHOMA LIPEMIA RETINALIS LIPEMIC PLASMA APOLIPOPROTEIN CII DEFICIENCY Rare autosomal recessive disorder (< 1 in 106) ApoC-II necessary cofactor for LPL activity Chylomicronemic syndrome similar to LPL deficiency Severely elevated TG Lipemic serum Recurrent pancreatitis/abdominal pain Eruptive xanthmoas and lipemia retinalis Absent ApoC-II on electrophoresis Treatment – diet, fibrates Katz P. 2014. Lipid metabolism & clinical lipid disorders. FAMILIAL HYPERTRIGLYCERIDEMIA Overproduction of VLDL with near normal ApoB production Typically TG 2.3-5.6 Normal LDL Often low HDL Must be present in half of 1st degree relatives to diagnose Eruptive xanthomas usually not present Obesity, insulin resistance common Exacerbating factors – hypothyroid, estrogen therapy, alcohol Uncertain if increase CHD risk Katz P. 2014. Lipid metabolism & clinical lipid disorders. HIGH-DENSITY LIPOPROTEIN (HDL) Redistribution of lipids among lipoproteins and cells by REVERSE CHOLESTEROL TRANSPORT: HDL acquires cholesterol from cells and transports it to other cells that require cholesterol or to the liver for excretion ORIGIN OF HDL 1. Liver makes ApoA-I phspholipid disc (nascent, pre-beta HDL) 2. Small intestine directly synthesizes small ApoA-I containing HDL particles 3. Derived from surface material (ApoA-I and PL) that comes from CM and VLDL during lipolysis by LPL ACQUISITION OF CHOLESTEROL BY HDL 1. Aqueous transfer from cells Free cholesterol moves by passive desorption from high concentration in membranes of cells with excess cholesterol to low concentration on HDL surface 2. Transport by a cell-surface binding proteins SR-B1 – transfers CEs through hydrophilic channel ABCA1 Binds ApoA-1 or a pre-beta HDL disc to the cell membrane and facilitates transfer of FC and PL from cell to HDL precursor ATP binding cassette transporters (ABCG1 and ABCG4) stimulate cholesterol efflux to mature HDL (HDL2 and HDL3) MATURATION OF HDL Nascent HDL particles (ApoA-I phospholipid discs) are excellent acceptors of excess cholesterol from cells or other lipoproteins Lecithin-cholesterol acyltransferase (LCAT) Converts free cholesterol to cholesterol esters (CEs) LCAT is activated by ApoA-I CEs are more hydrophobic, turn disc sphere (HDL3) HDL3 accepts and esterifies free cholesterol increases in size HDL2 FATE OF HDL2 1. 2. 3. 4. Reconverted to HDL3 by hepatic lipase Exchange CE for TG with VLDL, IDL, LDL and remnants via CETP which are then indirectly delivered to the liver and taken up by remnant receptor (MAJOR) Via SR-B1 receptor deposit CEs directly to liver, adrenal, gonads Is further enriched with CE and acquires ApoE becoming HDL1 thereby allowing interaction with LDL receptor allowing excretion of cholesterol by the liver (MINOR) PRIMARY DISORDERS OF HDL METABOLISM Disorder Mutant Gene AD vs Frequency AR HDL Corneal opacification Early vascular disease Familial Hypoalphalipoproteinemia Unknown AD ~1/400 0.5-0.8 No Yes Familial ApoA-I and ApoC-II deficiency ApoA-I or ApoC-II AR Rare <0.1 Yes Yes ApoA-I Milano ApoA-I AD Rare ~0.3 No No LCAT deficiency LCAT AR Rare <0.3 Yes Yes Fish-eye disease LCAT AR Rare <0.3 Yes No Tangier disease ABCA1 AR Rare <0.1 Yes Yes CETP deficiency CETP AR Rare >2.6 No No Katz P. 2014. Lipid metabolism & clinical lipid disorders. FAMILIAL HYPOALPHALIPOPROTEINEMIA HDL < 10% in men (<0.77 mmol/L), < 15% in women (<1.04 mmol/L) Normal LDL and TG Increased risk of premature CHD No characteristic findings Often family history Katz P. 2014. Lipid metabolism & clinical lipid disorders. APOLIPOPROTEIN A1 MUTATIONS Mutations in ApoA-I results in poor LCAT activation HDL < 0.3 Corneal opacities Increased CHD ApoA-I Milano rare variant of ApoA-I Autosomal dominant Low HDL Not associated with premature CHD Katz P. 2014. Lipid metabolism & clinical lipid disorders. LCAT DEFICIENCY Decreased esterification of cholesterol to cholesterol esters in HDL particles Free cholesterol accumulates on lipoprotein particles and in peripheral tissues Features Corneal opacities Normochromic anemia Renal failure Decreased HDL Increased free cholesterol Saeedi R et al. 2014. Clin Biochem. Aug:Epub FISH-EYE DISEASE Variant of LCAT deficiency Phenotype is less severe Able to esterfy cholesterol on ApoB-containing lipoproteins just not HDL Low HDL Corneal opacities No anemia, renal disease, or premature CHD Katz P. 2014. Lipid metabolism & clinical lipid disorders. TANGIER DISEASE Mutations in ABCA1 Loss of cholesterol efflux from cells such as macrophages massive accumulation of CEs Hypolipidemia Decreases in plasma HDL and LDL Features Orange tonsils Corneal opacities Hepatosplenomegaly Peripheral neuropathy Premature CHD Kolovou G et al. 2006. Curr Med Chem. 13(7):771. CHOLESTERYL ESTER TRANSFER PROTEIN (CETP) DEFICIENCY Diminished CETP activity Decreased transfer of CE from HDL to ApoB containing lipoproteins (VLDL, IDL, LDL) HDL increased More common in Japanese population Homozygotes have marked elevation of HDL (> 2.6 mmol/L) Effect on CHD risk is unclear Katz P. 2014. Lipid metabolism & clinical lipid disorders. OBJECTIVES Review lipid and lipoprotein classification and nomenclature Understand the pathways of cholesterol biosynthesis and metabolism Review primary disorders of hyper- and hypolipidemia Low-Density Lipoprotein (LDL) Triglycerides (TG) High-Density Lipoprotein (HDL) QUESTIONS? REFERENCES CCS: Position Statement on FH. 2014 Feldman D et al. 2015. CurrAtherosclerRep 17(1):473. Katz P. 2014. Lipid metabolism & clinical lipid disorders. CSEM. Kolovou G et al. 2006. Curr Med Chem. 13(7):771. Kronenberg HM et al. Williams Textbook of Endocrinology. 12th Ed Marais A et al. 2014.CritRevClinLabSci. 51(1):46. Mullard A. 2012. Nature Rev Drug Discovery 11:817. Othman R et al. 2013. Atherosclerosis. 231(2):291. Rahalkar A et al. 2009.Can J Physiol Pharmacol. 87(3):151. Saeedi R et al. 2014. Clin Biochem. Aug:Epub. Soutar A. 2010. IUBMB Life. 62(2):125. Yuan G et al. 2006. CMAJ 17(8):1124.
