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Hækkuð blóðfita

Hækkuð blóðfita. Gunnar Sigurðsson prófessor Kennsla 4. árs læknanema 23. nóvember 2005. Hækkuð blóðfita (hyperlipoproteinemiur). Áhersluatriði: Helstu lipoprotein og hlutverk þeirra. Megindrættir í lipoprotein physiology. Tengsl við sjúkdóma, sérstaklega æðakölkun.

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Hækkuð blóðfita

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  1. Hækkuð blóðfita Gunnar Sigurðsson prófessor Kennsla 4. árs læknanema 23. nóvember 2005

  2. Hækkuð blóðfita (hyperlipoproteinemiur) Áhersluatriði: • Helstu lipoprotein og hlutverk þeirra. • Megindrættir í lipoprotein physiology. • Tengsl við sjúkdóma, sérstaklega æðakölkun. • Undirliggjandi orsakir fyrir hækkaðri blóðfitu og erfðaþættir. • Hvenær er ástæða til að mæla blóðfitur? • Hvenær er ástæða til að lækka blóðfitur? • Helstu atriði í meðferð.

  3. Structure of Lipoproteins Free cholesterol Phospholipid Triglyceride Cholesteryl ester Apolipoprotein

  4. Types of Lipoprotein Particles • Triglyceride-rich lipoproteins • Chylomicrons • Very low-density lipoprotein (VLDL) • Cholesterol-rich lipoproteins • Low-density lipoprotein (LDL) • High-density lipoprotein (HDL)

  5. The Physiologic Role of Cholesterol • Cholesterol is required for normal biologic function • Component of all cell membranes • Precursor of other steroids • Cortisol • Progesterone • Estrogen • Testosterone • Bile acids • Excess cholesterol can result in • Coronary heart disease (CHD) • Xanthomas Adapted from Saladin KS. Anatomy and Physiology. 2nd ed. Boston: McGraw-Hill, 2001; Jones PH et al. In Hurst’s The Heart. Arteries and Veins. 9th ed. New York: McGraw-Hill, 1998:1553-1581; Ginsberg HN, Goldberg IJ. In Harrison’s Principles of Internal Medicine. 14th ed. New York: McGraw-Hill, 1998:2138-2149.

  6. Overview of Cholesterol Transport

  7. Reiknað LDL-kólesteról (Friedewald’s formúla) • mmol/L = heildarkól. – HDL-kól. – (þríglyseríðar) 2.2 • mg/dl = heildarkól. – HDL-kól. – (þríglyseríðar) 5 • kólesteról: 1 mmol/L = 38.7 mg/dl • þríglyseríðar: 1 mmol/L = 88.5 mg/dl Þessa nálgunaraðferð er ekki unnt að nota ef þríglyseríðar eru mjög háir eða meir en 5 mmol/L

  8. Samkvæmt rannsóknum á eineggja tvíburum ákvarðast kólesterólgildi einstaklingsins nokkurn veginn að hálfu leyti af erfðaþáttum og að hálfu af umhverfisþáttum.

  9. Mismunandi mataræði skýrir að stórum hluta mismun á meðalgildi heilla þjóða, t.d. Finna og Japana.

  10. Heterozygotar hafa einungis helming eðlilegra LDL-viðtaka og þar af leiðandi hækkar LDL-kólesteról utan frumna. Kólesteról þeirra er því oftast verulega hækkað. Homozygotar hafa enga eðlilega LDL-viðtaka og margfalda hækkun á kólesteróli í blóði.

  11. Sérkennandi klínísk teikn í F.H. eru útfellingar á kólesteróli í sinar, sérstaklega hásinar og handarsinar (tendinous xanthomata). Þær koma þó ekki fyrr en á miðjum aldri og einungis ef kólesteról helst hátt. Þær hverfa oft við meðferð.

  12. Xanthelasmata palpebrarum sjást oft við hækkun á blóðfitu hver sem undirliggjandi orsök er. Hverfur oftast við blóðfitulækkandi meðferð eftir um það bil 12 mánuði.

  13. Ef arcus senilis er til staðar fyrir fimmtugt er vert að mæla blóðfitur.

  14. Tvær mikilvægustu gerðirnar af arfbundinni hækkun á blóðfitu

  15. Selective screening for hyperlipidemia • First-degree relatives of patients with hyperlipidemia • Precence of xanthomas or xanthelasma in patient of first-degree relative • Family history of coronary artery disease before age 50 (men) or 60 (women) • Corneal arcus before age 50 Skimun fyrir kólesteróli, HDL-kólesteróli og þríglyseríðum er alla vega réttlætanleg og mikilvæg þegar þessir þættir eru til staðar.

  16. GENERAL CLASSIFICATION OF HYPERLIPIDAEMIAS Hyperlipidaemia Detected at initial Examination Repeat Serum Lipid Determination Cholesterol Normal to Severely Elevated: Hypertriglyceridaemia Hypercholesterolaemia: Triglyceride Normal Hypercholesterolaemia: Hypertriglyceridaemia Vert er að gera sér grein fyrir hvort bæði kólesteról og þríglyseríðar sé hækkað eða einungis kólesteról. Það skiptir máli upp á meðferð. Undirliggjandi orsakir einnig oft aðrar.

  17. Útiloka verður aðrar (secunderar) ástæður fyrir hækkun á blóðfitu, sérstaklega TSH við kólesterólhækkun (hypothyr.), diabetes og alkóhól við hækkun á þríglyseríðum.

  18. Elevated Cholesterol Is a Risk Factor for Cardiovascular Disease • Elevated serum cholesterol is associated with increased risk of • CHD and MI • Re-infarction • Stroke • CVD Mortality • All-cause • CHD • Stroke Multiple Risk Factor Intervention Trial (n=350,977) 50 40 30 CVD mortality rate* 20 10 0 <160 160–199 200–239 >240 Serum cholesterol (mg/dl) *Crude death rate (per 10,000 persons/years) CVD = cardiovascular disease Adapted from Kannel WB Am J Cardiol 1995;76:69C-77C; Anderson KM et al JAMA 1987;257:2176-2180; Kannel WB et al Ann Intern Med 1971;74:1-12; Neaton JD et al Arch Intern Med 1992;152:1490-1500.

  19. Vert er fyrir lækna að kunna almennar og einfaldar ráðleggingar um mataræði sem lækkar kólesterólgildi að jafnaði um 10%, sumir svara betur, en aðrir síður, sérstaklega þeir sem hafa LDL-viðtakagalla (F.H.).

  20. LDL-C Lowering With Statins: Reduced CHD Events Secondary Prevention 4S-PL Primary Prevention 25 LIPID-PL 20 4S-Rx 15 CARE-PL Events (%) CARE-Rx WOSCOPS-PL 10 LIPID-Rx WOSCOPS-Rx 5 AFCAPS-Rx AFCAPS-PL 0 50 70 90 110 130 150 170 190 210 LDL Cholesterol (mg/dL) Adapted from Illingworth DR. Med Clin North Am. 2000;84:23-42.

  21. Benefits of Cholesterol Lowering Meta-analysis of 38 primary and secondary intervention trials -0.0 -0.2 -0.4 Mortality log odds ratio -0.6 Total mortality (p=0.004) CHD mortality (p=0.012) -0.8 -1.0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 % in cholesterol reduction (Adapted from Gould AL, et al.,1998)

  22. European Guidelines for CVD Prevention: Lipid Management Treatment Goals Patient group LDL-C Total-C General population <115 mg/dl <190 mg/dl (3 mmol/L) (5 mmol/L) Clinical CVD <100 mg/dl <175 mg/dl (2.5 mmol/L) (4.5 mmol/L) Diabetes <100 mg/dl <175 mg/dl (2.5 mmol/L) (4.5 mmol/L) Adapted from DeBacker C et al Eur Heart J 2003;24:1601–1610.

  23. Mechanism of Action of Statins: Cholesterol Synthesis Pathway acetyl CoA HMG-CoA synthase HMG-CoA HMG-CoA reductase Statins X mevalonic acid mevalonate pyrophosphate isopentenyl pyrophosphate geranyl pyrophosphate ubiquinones dolichols farnesyl pyrophosphate Squalene synthase squalene cholesterol

  24. Statin-lyfin eru tekin upp í lifur og þar er aðalverkun þeirra á LDL-kólesteról.

  25. Effects of Statins on Lipids LDL cholesterol % change HDL cholesterol % change Triglycerides % change atorvastatin simvastatin pravastatin lovastatin fluvastatin -50 -41 -34 -34 -24 +6 +12 +12 +8.6 +8 -29 -18 -24 -16 -10 Daily dose of 40 mg of each drug (Adapted from Knopp 1999)

  26. Currently Available Pharmacologic Agents • HMG-CoA reductase inhibitors • Inhibit cholesterol synthesis • Increase LDL receptors • Decrease LDL-C by 25–40% • Decrease VLDL-C • Bile acid–binding resins • Interrupt enterohepatic bile acid circulation • Increase LDL-C receptors • Decrease LDL-C by 20–30% • Decrease VLDL-C • Increase HDL-C Ginsberg HN, Goldberg IJ. In Harrison’s Principles of Internal Medicine. 14th ed. New York: McGraw-Hill, 1998:2138-2149.

  27. Cholesterol Management: Other Agents • Bile acid–binding resins • Interrupt enterohepatic bile acid circulation •  LDL-C by 20–30%,  VLDL-C,  HDL-C,  TG • Nicotinic acid (niacin) • Inhibits lipoprotein secretion •  LDL-C by 15–25%,  VLDL-C by 25–35%,  HDL-C • Fibric acid derivatives • Induce lipoprotein lipolysis,  LDL-C removal,  HDL production and reverse cholesterol transport •  TG by 25–40%,  HDL-C,  or  LDL-C VLDL-C = very-low-density lipoprotein cholesterol; HDL-C = high-density lipoprotein cholesterol; TG = triglycerides Adapted from Ginsberg HN, Goldberg IJ. In Harrison’s Principles of Internal Medicine. 14th ed. New York: McGraw-Hill, 1998:2138-2149; Illingworth DR Med Clin North Am 2000;84:23-42;Staels B et al Circulation 1998;98:2088-2093.

  28. Two Sources of Cholesterol Dietary cholesterol(~300–700 mg/day) Fecal bile acids and neutral sterols Intestine Biliarycholesterol(~1000 mg/day) ~700 mg/day Liver Synthesis(~800 mg/day) Extrahepatictissues Adapted from Champe PC, Harvey RA. Biochemistry. 2nd ed. Philadelphia: Lippincott Raven, 1994; Glew RH. In Textbook of Biochemistry with Clinical Correlations. 5th ed. New York: Wiley-Liss, 2002:728-777; Ginsberg HN, Goldberg IJ. In Harrison’s Principles of Internal Medicine. 14th ed. New York: McGraw-Hill, 1998:2138-2149; Shepherd J Eur Heart J Suppl 2001;3(suppl E):E2-E5; Hopfer U. In Textbook of Biochemistry with Clinical Correlations. 5th ed. New York: Wiley-Liss, 2002:1082-1150.

  29. Biochemical Targets for Cholesterol Control: Absorption Biliarycholesterol Dietarycholesterol ACAT inhibitor ABCA1 Stanols Sterols Synthetic saponins Neomycin Surformer Sucrose polyester Ezetimibe MTP inhibitor MTP=microsomal triglyceride transfer protein Adapted from Champe PC, Harvey RA Lippincott’s Illustrated Reviews:Biochemistry. 2nd ed. Philadelphia: Lippincott-Raven, 1994; Miettinen TA Int J Clin Pract 2001;55(10):710-716; Brown WV Am J Cardiol 2001;87(suppl 5A):23B-27B.

  30. Ezetimibe: A New Cholesterol Absorption Inhibitor • First of a new class of drugs with unique mechanism of action • Targets intestinal absorption of dietary and biliary cholesterol • Inhibits absorption of dietary and biliary cholesterol • Reduces plasma LDL-C • May be useful as monotherapy for patients intolerant or nonresponsive to statins • In co-administration therapy with statins • Inhibits cholesterol absorption in the intestine and biosynthesis in the liver (dual inhibition) • Achieves lipid reductions greater than those with statins alone • Favorable safety profile shown in clinical trials • May reduce need for dosage adjustments of the statin Adapted from Leitersdorf E Eur Heart J Suppl 2001;3(suppl E):E17-E23; Miettinen TA Int J Clin Pract 2001;55:710-716; Stein E Eur Heart J Suppl 2001;3(suppl E):E11-E16.

  31. Ezetimibe Co-administered with Statins: Easier Control of LDL-C • One-step co-administration of ezetimibe equivalent to three-step statin titration 80 mg 20 mg 40 mg Three-step titration Statin 10 mg + Ezetimibe 10 mg One-step co-administration Statin 10 mg 0 10 20 30 40 50 60 % reduction in LDL-C Adapted from Stein E Eur Heart J Suppl 2001;3(suppl E):E11-E16.

  32. HDL Cholesterol • Low HDL cholesterol is a strong independent predictor of CHD1 • The lower the HDL cholesterol level the higher the risk for atherosclerosis and CHD2 • Low HDL is defined categorically as a level < 40 mg/dL (a change from < 35 mg/dL in ATP II)1 • HDL cholesterol tends to be low when triglycerides are high2 1. NCEP, Adult Treatment Panel III. JAMA. 2001;285:2486-2497. 2. Wood D, et al. Atherosclerosis. 1998;140:199-270.

  33. Lipoproteins: HDL Nascent HDL Liver Free cholesterol (C) C PERIPHERAL TISSUES HDL receptor Lecithin: cholesterol acyltransferase Cholesterol ester + Apo HDL HDL=high-density lipoprotein Adapted from Champe PC, Harvey RA. Biochemistry. 2nd ed. Philadelphia: Lippincott-Raven, 1994.

  34. Triglycerides • Recent data suggest that elevated triglycerides are an independent risk factor for CHD • Normal triglyceride levels: <150 mg/dL • Borderline-high triglycerides: 150 to 199 mg/dL • High triglycerides: 200 to 499 mg/dL • Very high triglycerides: (500 mg/dL) increase pancreatitis risk • Initial aim of therapy is prevention of acute pancreatitis NCEP, Adult Treatment Panel III. JAMA. 2001;285:2486-2497.

  35. Þríglyseríðar Æskileg gildi <2 mmol/L. Hækkaðir þríglyseríðar eru sjálfstæður áhættuþáttur fyrir æðakölkun enda þótt sú áhætta sé minni en af kólesteróli.

  36. VLDL og chylomicron eru það stór mólekúl að þau valda gruggugu sermi sem hækkun á LDL-kólesteróli gerir ekki. Þríglyseríðar þessa sjúklings voru meir en 20 mmol/L. Hann kom inn vegna acute abdomen. Hver er líklegasta orsökin?

  37. Veruleg hækkun á þríglyseríðum í blóði getur leitt til fituútfellinga í húð (tuberous xanthomata). Hverfa fljótt við meðferð.

  38. Meðferð við hækkun á þríglyseríðum • Útiloka og meðhöndla sekunder orsakir: • Alkóhól • Sykursýki • Lyf o.fl. • Meðferð: • Megrun • Statín-lyf • Fibrate-lyf (pparagonists)

  39. Lipoprotein - (a) er undirflokkur á LDL. (a) er skylt plasminogeni en hlutverk óþekkt. Virðist vera atherogent. Magn ákvarðast af erfðum. Lækkar ekki við statin-lyfjagjöf.

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