440 likes | 759 Views
Dyslipidemias . SCHEME FOR LIPID TRANSPORT. Production / Catabolism = Number. Over- production Very common (? Cause). Decreased Catabolism Defective Receptor in FH (RARE). Cell receptors. Endogenous transport. Lipoprotein lipase. Hepatic lipase. LDL receptor. VLDL.
E N D
SCHEME FOR LIPID TRANSPORT Production / Catabolism = Number Over- production Very common (? Cause) Decreased Catabolism Defective Receptor in FH (RARE) Cell receptors Endogenous transport Lipoprotein lipase Hepatic lipase LDL receptor VLDL IDL LDL Lipoprotein lipase Exogenous transport chylomicrons remnants gut Remnant receptor Free cholesterol + phospholipids + C-apolipoproteins Nascent HDL Mature HDL Lecithin: cholesterol acyltransferase [circulating LDL] risk for atherosclerosis
GENETIC DYSLIPIDEMIAS I ApoB: II HDL III Lipoprotein Modifying Enzymes
GENETIC/METABOLIC CLASSIFICATION OF PRIMARY HYPERLIPIDAEMIAS
GENETIC/METABOLIC CAUSES OF PRIMARY HYPERLIPIDAEMIAS
Chylo ↑ ↓ ↓
Familial Lipoprotein Lipase Deficiency APO C-II DEFICIENCY LIPOPROTEIN LIPASE DEFICIENCY NORMAL CHYLOMICRON CHYLOMICRON CHYLOMICRON APO C-II APO C-II LIPOPROTEIN LIPASE LIPOPROTEIN LIPASE FFA FFA
CLINICAL FINDINGS IN Familial Lipoprotein Lipase Deficiency RECURRENT ACUTE PANCREATITIS ERUPTIVE XANTHOMAS RETINAL LIPEMIA HEPATOSPLENOMEGALY AUTOSOMAL RECESSIVE INHERITANCE (CONSANGUINITY COMMON)
DISORDERS OF LDL RECEPTORS: RARE • Familial hypercholesterolemia • (defective receptor) • Familial defective B100 • (defective ligand)
FH B Tg B Tg VLDL B B B B B B B B B B B B CE CE CE CE CE CE CE CE CE CE CE CE LDL LDL Clearance
IDL IDL Free Cholesterol Free Cholesterol HTGL Lysis Lysis B-100 Receptor LDL LDL B-100 Receptor PERIPHERAL CELLS LIVER
→ → ↑ ↑ ↑
Familial Combined Hyperlipidemia/ HyperapoB
PRODUCTION BREAKDOWN
Features of HyperapoB • Increased LDL particle number due • primarily to increased secretion of • hepatic B100 lipoprotein particles. • Often, but not always, many of the • LDL particles are smaller and denser • than normal.
HETEROGENEITY OF LDL B CE NORMAL FC CE Tg FC Tg PL B FC B CE FC CE Tg FH Tg PL B B CE CE FC Tg HYPERAPO B Tg FC PL PL
CII FH CI CIII Tg Tg Tg Tg Tg Tg Tg Tg Tg Tg CE CE CE CE CE CE CE CE CE CE E Tg Tg Tg Tg Tg Tg Tg Tg Tg CE CE CE CE CE CE CE CE CE
HyperapoB CII CII CI CI CIII CIII Tg Tg Tg Tg Tg Tg CE CE CE CE CE CE E E E E Tg CE Tg CE Tg Tg Tg Tg Tg Tg Tg Tg Tg CE CE CE CE CE CE CE CE CE
Interaction of apoB and LDL size as Determinants of CAD Risk 6.2 (p < 0.001) apoB Odds ratios for IHD 2.0 1.0 1.0 LDL peak particle diameter
HYPERAPO B IS • ASSOCIATED WITH: • SMOKING • MALE SEX • ABDOMINAL OBESITY • HYPERINSULINEMIA • OFFSPRING OF PARENTS WITH CAD
Principle I: VLDL synthesis and secretion is substrate driven.
Effect of Fatty Acid on Liver Cholesterol Synthesis 4HR pmol/min/mg
Direct Correlation between Cholesterol Synthesis and Hepatic Secretion of apoB 100 in Normolipidemic Subjects 15 10 5 Hepatic secretion ratio to VLDL apoB (mg/kg/day) 0 2 4 6 8 10 Plasma mevalonate concentration (ng/ml)
Principle II: What comes out depends on what went in. FA CHO
HDL ← ↓ ↑ ↑
COMMON GENETIC CAUSES OF HDL DEFICIENCY SECONDARY: 1. Familial Hypertriglyceridemia with Hypoalphalipoproteinemia (low apo A1) 2. Familial Combined Hyperlipidemia (Hyperapo B) with Hypoalphalipoproteinemia PRIMARY: Familial Hypoalphalipoproteinemia
FUNCTIONS OF HDL CHOLESTEROL ESTERS LCAT LCAT CHOLESTEROL LIVER PERIPHERAL CELLS NASCENT VLDL VLDL NASCENT CHYLOMICRON CHYLOMICRON HDL VLDL HDL CHYLOMICRON
RARE GENETIC CAUSES OF HDL DEFICIENCY Name Premature CAD Tangier disease + Apo A1, Clll, AlV deficiency ++ Apo A1, Cll deficiency +++ Apo A1 deficiency UK Apo A1 variants UK LCAT deficiency +
SECONDARY CAUSES OF DECREASED HDL • Hypertriglyceridemia • Obesity • Diabetes Mellitus • Cigarette smoking • Beta blockers • Liver cirrhosis
SECONDARY DYSLIPIDEMIAS AND DRUG EFFECTS ON LIPIDS
DISEASES CAUSING SECONDARY HYPERLIPIDAEMIA
LIPID ABNORMALITIES IN LIVER DISEASE
LIPID ABNORMALITIES IN RENAL DISEASE
DRUGS THAT CAN CAUSE SECONDARY HYPERLIPIDAEMIA DIURETICS BETA BLOCKERS ESTROGENS PROGESTERONE RETINOIDS CORTICOSTEROIDS MICROSOMAL ENZYME INDUCERS egPHENYTOIN