Disorders of lipids and lipoprotein metabolism Vladimír Soška Department of Clinical Biochemistry Dyslipidemia in the population 0 20 40 60 80 100 25 - 34 35 - 44 45 - 54 55 - 64 0 20 40 60 80 100 25 - 34 35 - 44 45 - 54 55 - 64 Men Women Age % % TC > 5.0 or HDL-ch. < 1.0 or LDL-ch. > 3.0 or TG > 2 mmol/l or treatment with hypolidemic drugs Age LP particles Lipoprotein(a) • LDL particle + apolipoprotein(a) • Apolipoprotein(a) • Structure similar to plasminogen • Inhibition of fibrinolysis • ↑ risk of artery occlusion (thrombosis) Lipoprotein(a) • Physiological concentration: • < 75 nmol/l (0,3 g/l) Apolipoprotein B • Surfice of the VLDL, LDL particles • 1 particle = 1 molecule of apo B • Number of apo B = number of LDL + VLDL particles • Function: binding of the LDL-particles to the LDL-receptorvs Low risk people Moderate risk people High risk people Very high risk people LDL-Ch < 3,0 < 2,6 < 1,8 < 1,4 Target levels of LDL-cholesterol (mmol/l) Guidelines exist to help CV risk estimation Piepoli MF et al. Eur Heart J 2016;37:2315–2381. Very high risk High risk Moderate risk Low risk Subjects with any 1 of: • CVD • T2DM, or T1DM + target organ damage • Severe CKD (GFR <30mL/min/1.73m2) • SCORE relative risk estimate ≥10% Subjects with: • Markedly elevated single risk factors, such as cholesterol >8 mmol/L or BP >180/110mmHg • Most other people with DM • Moderate CKD (GFR 30–59mL/min/1.73m2) • SCORE ≥5% and <10% SCORE ≥1 and <5% at 10 years • Many middle-aged subjects belong to this category SCORE <1% and no qualifiers • ESC/EAS guidelines stratify risk using various criteria, including SCORE – Relative risk calculated using tables that take into account sex, smoking status, SBP and cholesterol Optimal levels of blood lipids HDL-Ch M > 1,0 mmol/l F > 1,2 mmol/l Tg M < 1,7 mmol/l F < 1,7 mmol/l How to decrease LDL-cholesterol? Lifestyle management How to decrease triglycerides? How to elevate HDL-cholesterol? Weight reduction and blood lipids 1 kg of weight 2 - 3% triglycerides 1 % total and LDL cholesterol 2 - 3 % HDL cholesterol = = = Etiology of dyslipidemia Life-style Other diseases Genetic Hypercholesterolemia Combined DLP Hypertriglyceridemia Fenotype of DLP Therapeutic classification of DLP • Hypercholesterolemia • Hypertriglyceridemia • Mixed hyperlipidemia • Primary (inherent) DLP • Secondary DLP Secondary DLP • Endocrine diseases • Liver diseases • Kidney diseases • Drugs-induced DLP • Toxonutritive DLP • DLP induced by environmental influences DLP due to endocrine diseases • Diabetes mellitus • Undercontrolled • Hypothyreoidism • Hyperfunction of suprarenal glands • Cushing disease • Pregnancy (physiological DLP) DM a DLP 0 10 20 30 40 50 60 0 5 10 15 20 25 30 Glykémie (mmol/l) Triglyceridy(mmol/l) • Cholestasis • Primary biliary cirrhosis • Parenchyma liver disease • Hepatitis (no steatosis) DLP due to hepatic diseases • Nephrotic syndrome • Chronic renal failure • Haemodialysis, peritoneal dialysis • Renal transplantation DLP due to renal diseases Drugs-induced DLP • Immunosuppressive • Cyclosporine A • Corticosteroides • Retinoids • Antihypertenzive drugs • High doses of • Thiazid diuretics, non-selective β-blockers Toxonutritive DLPs: alcohol • Alcohol increases blood lipids !!! • This effect is dose-dependent • Individual sensitivity to the alcohol • This type of DLP is not atherogenic • Leading cause of secondary DLP resistant to the therapy Alcohol and lipids Ethanol → acetaldehyde → AcetylCoA → FA→ Tg → VLDL • The higher alcohol intake, the higher blood lipid level  Tg, TC DLP induced by the life style • Food • High intake of saturated fats, sugar • Fructose • Alcohol • Smoking • ↓ HDL-Ch, ↑ LDL-cholesterol • Physical inactivity • ↓ HDL-Ch, ↑ Tg Primary DLP (genetic DLP) • Hypercholesterolemia • Familial hypercholesterolemia • Polygenic HCH • Hypertriglyceridemia • Familial HTg • Mixed DLP • Familial combined DLP Familial hypercholesterolemia • Cause • Defective LDL-receptor gene • Defective apo B gene • Frequency: 1: 500 (heterozygote form) • Heredity: autosomal dominant • Pathophysiology: ↓ catabolism of LDL • Lab: chol. 9-15 mmol/l • Physiological level of Tg, HDL-ch) • Premature CHD • Xantomatosis - relative rare 0 0 0 0 3 3 32 17 37 30 67 52 46 50 33 33 0 10 20 30 40 50 60 70 0 - 9 10-19 20 - 29 30-39 40 - 49 50-59 60 - 69 70-79 men women Thompson et al., 1989 %populationwithCHD CHD in heterozygotes FH věk Familial hypercholesterolaemia patients reach LDL-C threshold levels for CHD at an early age Cuchel et al. Eur Heart J 2014;35:2146–2157. Nordestgaard et al. Eur Heart J 2013;34:3478–3490. Without FH 55 years 12.5 years 35 years Heterozygous FHHomozygous FH 0 Age in years CumulativeLDL-C(mmol) 200 150 100 50 0 Threshold for CHD 603 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 mmol/L mg/dL LDL-C 10 13 15 390 500 580 0 5 0 190 Early or high-intensity lipid lowering in FH patients delays onset of CHD Nordestgaard et al. Eur Heart J 2013;34:3478–3490. 0 0 Age in years CumulativeLDL-C(mmol) 200 150 100 50 Threshold for CHD 603 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 Without FH 55 years 35 years Heterozygous FH 12.5 years Homozygous FH 48 years Start high dose statin 53 years Start low dose statin Untreated FH is associated with poor prognosis Versmissen et al. BMJ 2008;337:a2423. Follow up (years) CumulativeCHD-freesurvival(%) N = 1537 No statin treatment N = 413 Statin treatment Non-pharmacology treatment of DLP • Stop smoking !!! • Regular physical activity • Weight loss • If overweight or obesity • Diet • ↓ saturated FA, sugar (fructose), trans-FA • ↑ vegetable, fruits, unsaturated FA, fiber Pharmacotherapy of DLP Decrease of LDL cholesterol Statins Ezetimibe Resins PCSK9-inhibitors Decrease of triglycerides Elevation fo HDL cholesterol Fibrates Low risk people Moderate risk people High risk people Very high risk people LDL-Ch < 3,0 < 2,6 < 1,8 < 1,4 Apo B g/l < 1,0 < 0,8 < 0,65 Non HDL-ch. < 3,8 < 3,4 < 2,6 < 2,2 Target levels of non HDL-chol. (mmol/l)