Theoretical basics of clinical medicine - lipidology Ondrej Kyselak, M.D. Dept. of Clinical Biochemistry, St. Anne's University Hospital Brno Introduction, basic terms Dyslipidemia = deviation (↓/↑) in blood lipid values. General term, which includes: • Hypercholesterolemia • Hypertriglyceridemia … and less often: • Rare forms of dyslipidemia – familial hypercholesterolemia (FH) – dysbetalipoproteinemia (DBL) – familial deficit of lipoprotein lipase (LPLD) Part I. Metabolism of cholesterol Cholesterol Cholesterol • steroid structure Sources in human body: • own synthesis… enzyme HMG-CoA reductase (3-hydroxy-3-methylglutaryl coenzyme A reductase) • food intake Why do we need cholesterol? Many substances in our body are derived from cholesterol structure: • steroid hormones – androgens – testosterone – estrogens – estradiol – gestagens – progesteron • corticoids – mineralocorticoids (aldosterone) – glucocorticoids (cortisol, corticosterone) • vitamins (vit. D) • bile acids (cholic acid, deoxycholic acid) Cholesterol is a part of cell membrane as well. Why can be cholesterol dangerous? • atherosclerosis (complex process in attendance of immune system – foam cells, pro-inflammatory cytokines) • vessel injury by atherosclerotic plaques • CVD, MI, stroke, PAD How is cholesterol transported in the blood stream? • … by lipoprotein particles Depending on density we distinguish these groups of lipoproteins • Chylomicrons • VLDL particles (Very Low Density Lipoproteins) • IDL particles (Intermediate Density Lipoproteins) • LDL particles (Low Density Lipoproteins) • HDL particles (High Density Lipoproteins) LDL vs. HDL particles LDL particles • cholesterol rich ones • distribution of cholesterol to peripheral tissues • strongly proatherogenic – too much of LDL-C causes endothelial injury HDL particles • cholesterol poor ones • transport of cholesterol from periphery to liver, where cholesterol is metabolised Remember … molecule of cholesterol is still the same. Biological effect in organism is determined by the transport form (it depends in which type of lipoprotein particles – LDL/HDL the cholesterol is contained). Degradation of cholesterol Part II. Hypercholesterolemia Hypercholesterolemia Prevalence of hypercholesterolemia in the Czech Republic (T-CH ≥ 5,0 mmol/l) 53,9 % (without reference to gender) *) Cholesterol values are dependent on age and gender --- *) WHO: http://www.who.int/en/ Dyslipidemia in Czech 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 Males Females Age groupsAge groups % % T-CH. > 5.0 or HDL-ch. < 1.0 or LDL-ch. > 3.0 or TG > 2 mmol/l or lipid - lowering treatment Hypercholesterolemia Sub-type of dyslipidemia • pathologically increased blood level of cholesterol • risk factor of atherosclerosis and CVD 2 groups of dyslipidemia: • Polygenic • Monogenic (inherited) – severe DLP Polygenic hypercholesterolemia • the most common in population • influence of many genes with a small effect = genetic predisposition and environment (lifestyle) Reduce weight is sooo easy Familial hypercholesterolemia • monogenic type of DLP • frequency in population = 1:200 – 1:500 • mutation in DNA leads to defects in structures, which are responsible for cholesterol metabolism • genes for LDL receptor, apoB, PCSK9 • severe hypercholesterolemia – strongly proatherogenic • patients with these mutations reach cumulative dose of cholesterol very early – fatal MI, strokes in early age (-teens) • premature CVD in family history Defective LDLR / apoB in patients with FH Cumulative dose of LDL – C Part III. Triglycerides Triglycerides • Type of blood lipids • TGs contains glycerol esterified by fatty acids (FA) What are TGs good for? • energetic pool (FA are energy - rich substances). • the only way how to store FA (and energy contained in their structure) are TGs. Typical patients with hypertriglyceridemia are… Poorly compensated diabetics and patients with affected glucose metabolism – increased pool of glucose Patients with increased alcohol consumption • increased pool of acetyl-CoA = basic substance for lipid synthesis • high concentration of FA (used for synthesis of TGs) • alcoholic beverages (beer, wine) – highly caloric, provide substrate for synthesis of TGs. Patients with polygenic dyslipidemia Obese patients (abundance of energetic substrates) Clinical correlations of hypertriglyceridemia • slightly increased value of TGs (up to 10 - 11 mmol/l) = risk factor for CVD • very high serum TGs > 11 mmol/l = RF for acute pancreatitis*) • incidence of AP caused by hyperTG 40 cases / 100 000 adults and year (data from US)**) --- *) Kota SK, Jammula S. et al. Hypertriglyceridemia-induced recurrent acute pancreatitis: A case-based review Indian J Endocrinol Metab. 2012 Jan-Feb; 16(1): 141–143. **) Granger J, Remic k D., Acute pancreatitis: models, markers, and mediators. Shock. 2005 Dec;24 Suppl 1:45-51. Acute pancreatitis • very serious and acute situation! • strict diet without any lipids! • requires hospitalisation! Acute pancreatitis - Cullen´s sign - Grey-Turner´s sign Take home message Hypercholesterolemia • independent risk factor for CVD (MI, stroke, PAD) Hypertriglyceridemia • mild = RF for CVD • severe = RF for acute pancreatitis Part IV. Fatty acids FA – fatty acids • mostly part of triglycerides • source of energy • substrate for synthesis of many other substances FA can be divided into many groups Length of carbonaceous chain: • short chain FA • long chain FA – 12 and more carbons in chain Number of double bonds in chain: • SAFA (saturated FA) • MUFA (monounsaturated FA) • PUFA (polyunsaturated FA) Configuration of FA chain cis FA – plant lipids, oils trans FA – less often, milk lipids • toppings, chocolates , butter, beef. • strongly proatherogenic Cis x trans FA Synthesis in organism Essential FA: • we´re not able to synthetize • PUFA • fish, plant oils Non – essential FA • we can synthetize • SAFA, MUFA • animal lipids Sources of FA Sources of FA Part V. Atherosclerosis, CV risk Atherosclerosis • vessel disease • complex pathophysiological process (with participation of immune system, proinflammatory cytokines) Storage of cholesterol ↓ Calcification ↓ Increases rigidity of arterial wall Atherosclerosis Arterial obliteration by atherosclerotic plaques ↓ Plaque rupture, thrombocyte activation, thrombus ↓ Arterial occlusion ↓ Ischemia of tissues behind the occlusion ↓ Tissue infarction if the blood stream is not restored immediately Atherosclerosis Risk factors for atherosclerosis Bad lifestyle: • smoking • alcohol consumption • obesity • kidney disease • diabetes mellitus • hypertension • hypercholesterolemia Estimation of Cardiovascular risk • probability of fatal MI or stroke in 10 years • SCORE charts (Systematic COronary Risk Evaluation) • need to know: sex, smoking habits, age, systolic BP, T-CH value + other RF (individually adjusting CV risk) CV risk categories • Low CV risk (up to 1 %) • Intermediate CV risk (1-5 %) • High CV risk (5 – 10 %) • Very high CV risk (more than 10 %) The higher CV risk, the lower value of cholesterol is needed to be reached to protect arteries from the damage by atherosclerotic plaques. Smoking as a RF of CVD • Smoking is a psychiatric diagnosis (ICD, International Classification of Diseases: F17) • Health problem (CVD, lung cancer, infection of respiratory system, COPD, mental and physical addiction • Economic problem (price of cigarettes, costs for treatment of one smoker) • Social problem (smell, acceptation by non- smokers) Smoking and CV risk • Smokers have a double CV risk compared to non-smokers! • Abandon smoking is the basic key to lower the CV risk! Hypothyreosis and DLP Hypothyreosis can cause secondary DLP • Thyroidal hormones are involved into metabolism of nutrients in our body • Low values of thyroidal hormones can slow down metabolism of lipids. Part VI. How to diagnose DLP How to make a diagnosis • Anamnesis (premature CVD in family history) • Clinical examination (presence of clinical sings typical for DLP) • Laboratory exams (+DNA analysis) • Other methods (ultrasound of carotid arteries, ergometer, calcium score, coronarography) Anamnesis • Focused on premature CVD in family history (CVD in first – degree relatives before 55 years of age in males and before 60 years of age in females) Clinical signs of HLP Laboratory exams • fasting: 12 hrs. prior examination without meal, drink pure water • 3 days prior examination stop drinking alcohol, stop with any physical exercise • don´t smoke before taking the blood samples • use the pills (except of insulin → risk of hypoglycaemia) • first examination – patient should be without hypolipidemics to know origin values of lipids, • control examination – patient should take prescribed lipid lowering therapy regularly to see the effect of therapy • avoid to examine lipid values during acute disease Chylous serum Which parameters to examine • fasting plasma glucose • kidney parameters (urea, creatinine) • liver enzymes (AST, ALT, ALP, GGT) • lipid spectre (TCH, LDL-CH, HDL-CH, TG, apolipoprotein A, apolipoprotein B, non-HDL CH) • thyroidal parameters (TSH, peripheral hormones) DNA analysis In case of suspiction of an inherited DLP: • FH (genes for apoB, LDLR, PCSK9) • familial dysbetalipoproteinemia (apoE) • familial defective lipoprotein lipase (LPLD) Lipoprotein ultracentrifugation • enables to separate lipoprotein particles depending on different density given by lipid/protein ratio • with increasing density the size of lipoprotein particles is getting smaller • for this type of analysis is used very high gravity acceleration • used as a diagnostic method for dysbetalipoproteinemia Carotid ultrasound • carotid arteries are well accessible, it is not invasive • intima/media thickness, presence of atherosclerotic plaques (detection of subclinical atherosclerosis) • velocity and direction of the blood stream Ergometer • bicycle exercise • monitoring of ECG, BP • if ECG changes are present (arrhythmia, changes in ST segment), than arterial coronarography should be performed Selective coronarograpy • detecting occlusions / obstructions in coronary arteries, which can lead to coronary ischemia or myocardial infarction • with contrast liquid Advanced diagnostic technologies - IVUS • intravascular ultrasound • direct exploration of coronary arteries with using ultrasound probe • evaluating lumen of arteries, presence of atherosclerotic plaques, quality of coronary arteries Part VII. Target levels of cholesterol Guidelines Target levels of LDL-C • recommended by ESC/EAS guidelines 2016 • „safe“ values of LDL-C when progression of atherosclerosis is slowed down or stopped (in optimal case) LDL-C target levels The higher CV risk ↓ the higher probability of acute CVD (MI, stroke) ↓ more aggressive hypolipidemic treatment is needed to reach the low levels of LDL-C to protect arterial damage LDL-C goals (simplified) Low + intermediate CV risk • LDL-CH < 3,0 mmol/l High CV risk • LDL-CH < 2,6 mmol/l Very high CV risk • LDL-CH < 1,8 mmol/l Concept of treatment LDL-C: The lower, the better Part VIII. Therapeutic options, modifying CV risk, elimination of RFs Changes in lifestyle only (without LLT – lipid lowering therapy) • ESC/EAS guidelines: patients with CV risk < 5 % (without any other RFs, which would rise up the CV risk) • diet + physical activity, weight reduction Modifying CV risk, elimination of RFs We can affect: • Smoking – decrease CV risk up to 50 % • Hypertension (can be treated) • Cholesterol (can be decreased – with or without LLT) Other RFs: • DM (can be treated) • Hypothyreosis (can be treated) We can´t affect • Sex • Age • DNA (not yet) Smoking Why do I want to stop smoking? • because of me (health risk, social handicap, social isolation from non-smokers, financial burden) • because of the others (smell, health risk – passive smoking) Abandonment of smoking has usually higher impact than making cholesterol levels lower. Social isolation – „cage“ for smokers? Just choose your own way Diet recommendations Diet recommendations Reduce intake of: • saturated lipids (FA) (fried food, butter, chocolate topping, sweet creams, cakes…) …it contains lot of saturated FA, which are strongly proatherogenic • sugar (sweet bakery products, cookies, sweetened beverages!) Lipids in nutrition FA are rich of hydrogen (a lot of energy can be released from their structures) • need to receive essential FA from plant oils, which we are not able to synthetize by ourselves • reduce intake of animal lipids in general Sources of essential FA Plant oils: • flaxy • rapeseed • olive • others (sunflower, soya…) Olive oil is not so rich about essential FA. Physical activity Diet is very important part of lifestyle, but only diet is not enough. It is better to combine it with physical activity. Diet + physical activity = weight reduction, changing muscle/fat ratio in body Part IX. Lipid lowering therapy (LLT) LLT It doesn´t matter which kind of LLT is chosen, healthy diet and lifestyle + physical activity is essential for every patient with HLP. LLT is recommended for patients with CV risk (SCORE) ≥ 5 %, or in case of severe HLP (FH). Statins Fundamental drug for patients with hyperlipidemia • inhibitors of HMG-CoA reductase • decreasing own production of cholesterol in liver • many data about statins from clinical trials • effective and safe Statins Statin therapy, which makes LDL-C levels 1 mmol/l lower, decreases the CV risk in average by 20 - 25 %.*) --- *) Baigent C., Blackwell L., Emberson J. et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials. Lancet 2010; 376: 1670 - 81. Statin group of LLT • Atorva - statin • Simva - statin • Fluva - statin • Rosuva - statin • Prava - statin • Pitava - statin Ezetimibe Ezetimibe (Ezetrol®) • inhibitor of absorption of cholesterol from intestinal lumen to blood stream • can be used in patients who don´t tolerate statins • weak effect in monotherapy (cholesterol synthesis in liver is compensatory increased) • synergistic effect with statins (blocking two metabolic ways of cholesterol – synthesis + resorption from food) Ezetimibe IMPROVE-IT study • patients with acute coronary syndrome in personal history • by adding ezetimibe to statin, the level of LDL-C was decreased in average by 24 %. *) • combination of simvastatin + ezetimibe significantly decreased the risk of CV events *) --- *) Cannon CP., Blazing MA., Giugliano RP. et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med 2015;372:2387 - 97. Resins • bad taste • weak hypolipidemic effect • only for pregnant women and children with severe HLP (FH) • Cholestyramin (Vasosan P®) PCSK9 inhibitors PCSK9 = proprotein convertase subtilisin kexin type 9. Fully humanised antibodies against PCSK9 • evolocumab (Repatha®) • alirocumab (Praluent®) How does it work? PCSK9 inhibitors • decreasing LDL- C in average by 50 – 60 % *) • used in combination with statins • no adverse events known yet --- *) Whayne TF. Jr. PCSK9 inhibitors in the current management of atherosclerosis. Arch Cardiol Mex. 2016 Dec 27. How to use it? • subcutaneous injection once per 2-4 weeks • prefilled pen LLT for hypertriglyceridemia • fenofibrate • activator of PPAR – α (peroxisome proliferatoractivated receptor-alpha) • decreases levels of TGs by inhibition of their synthesis and increasing of their clearance • induces β – oxidation of FA and decreases their availability for synthesis of triglycerides and for VLDL particles • stimulates activity of LPL, which attacks TGs. • decreases risk of diabetic microangiopathy – benefit for patients with DM Polypills • 2 or more drugs in one pill • comfortable for patient, increases adherence to therapy Statins are available in combination with these drugs: • antihypertensives • fibrates Development of new drugs • Modifying production of LDL particles on the genetic level (silencing RNA – siRNA) Part X. Nutrition supplements Nutrition supplements • ω - 3 unsaturated FA • red yeast rice • plant sterols and stanols Part XI. The MedPed project MedPed project • Make early diagnosis to Prevent early deaths in MedicalPedigrees • active searching for patients with inherited HLP. Making diagnose, perform treatment • prevention of premature deaths due to acute cardiovascular events Thank you for your attention! Ondrej Kyselak, M.D. Dept. of Clinical Biochemistry, St. Anne's University Hospital Brno ondrej.kyselak@fnusa.cz