MD FRCPC FACP CCD ECNU Associate Professor and Consultant Medicine Endocrinology Department of Medicine King Saud University Lipid Transport LPLApo C2 Rader DJ Daugherty A Nature 2008 451904913 ID: 1048627
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1. Dyslipidemia(Med-3)Dr Anwar A Jammah, MD, FRCPC, FACP, CCD, ECNU.Associate Professor and Consultant Medicine, EndocrinologyDepartment of Medicine, King Saud University
2. Lipid TransportLPL/Apo C2Rader DJ, Daugherty, A Nature 2008; 451:904-913
3. The story of lipidsChylomicrons transport fats from the intestinal mucosa to the liverIn the liver, the chylomicrons release triglycerides and some cholesterol and become low-density lipoproteins (LDL).LDL then carries fat and cholesterol to the body’s cells.High-density lipoproteins (HDL) carry fat and cholesterol back to the liver for excretion.
4. The story of lipids (cont.)When oxidized LDL cholesterol gets high, atheroma formation in the walls of arteries occurs, which causes atherosclerosis.HDL cholesterol is able to go and remove cholesterol from the atheroma.Atherogenic cholesterol → LDL, VLDL, IDL
5. Atherosclerosis
6. Lipid TransportLPL/Apo C2Rader DJ, Daugherty, A Nature 2008; 451:904-913
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10. Atherogenic ParticlesMEASUREMENTS:TG-rich lipoproteinsVLDLVLDLRIDLLDLSmall,denseLDL
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12. A-IHDL and Reverse Cholesterol TransportLiverCECEFCLCATFCBileSR-BIABCA1MacrophageMature HDLNascent HDLA-IFCCEFC
13. Plasma lipoproteinsTypeSourceMajor lipidApoproteinsELFOAthero-genicityChylomicronsGutDietary TGsA-I, B-48, C-I, C-III, Eno mobility–(pancreatitis)VLDLLiverEndogenous TGsB-100, E, C-II, C-III, Pre-β+IDLVLDL remnantCh esters, TGsB-100, C-III, ESlow pre- β+LDLVLDL, IDLCh estersB-100β+++HDLGut, liverCh esters, PLsA-I, A-II, C-II, C-III, D, Eαanti-atherogenic
14. Hereditary Causes of HyperlipidemiaFamilial HypercholesterolemiaCodominant genetic disorder, coccurs in heterozygous formOccurs in 1 in 500 individualsMutation in LDL receptor, resulting in elevated levels of LDL at birth and throughout lifeHigh risk for atherosclerosis, tendon xanthomas (75% of patients), tuberous xanthomas and xanthelasmas of eyes. Familial Combined HyperlipidemiaAutosomal dominantIncreased secretions of VLDLsDysbetalipoproteinemiaAffects 1 in 10,000Results in apo E2, a binding-defective form of apoE (which usually plays important role in catabolism of chylomicron and VLDL)Increased risk for atherosclerosis, peripheral vascular diseaseTuberous xanthomas, striae palmaris
15. Fredrickson classification of hyperlipidemiasPhenotypeLipoprotein(s) elevatedPlasma cholesterolPlasma TGsAthero-genicityRel. freq.TreatmentIChylomicronsNorm. to –pancreatitis<1%Diet controlIIaLDLNorm.+++10%Bile acid sequestrants, statins, niacinIIbLDL and VLDL+++40%Statins, niacin, fibratesIIIIDL+++<1%FibratesIVVLDLNorm. to +45%Niacin, fibratesVVLDL and chylomicrons to +pancreatitis 5%Niacin, fibrates
16. Primary hypercholesterolemiasDisorderGenetic defectInheritancePrevalenceClinical featuresFamilial hyper-cholesterolemia LDL receptor dominantheteroz.:1/5005% of MIs <60 yrhomoz.: 1/1 millionpremature CAD (ages 30–50) TC: 7-13 mMCAD before age 18TC > 13 mMFamilial defectiveapo B-100apo B-100dominant1/700premature CADTC: 7-13 mMPolygenic hypercholesterolemiamultiple defects and mechanismsvariablecommon 10% of MIs <60 yrpremature CADTC: 6.5-9 mMFamilial hyper-alphalipoproteinemiaunknownvariablerareless CHD, longer lifeelevated HDL
17. Primary hypertriglyceridemiasDisorderGenetic defectInheritancePrevalenceClinical featuresLPL deficiencyendothelial LPL recessiverare1/1 millionhepatosplenomegalyabd. cramps, pancreatitisTG: > 8.5 mMApo C-II deficiencyApo C-IIrecessiverare1/1 millionabd. cramps, pancreatitisTG: > 8.5 mMFamilial hyper-triglyceridemiaunknownenhanced hepatic TG-productiondominant1/100abd. cramps, pancreatitisTG: 2.3-6 mM
18. Primary mixed hyperlipidemiasDisorderGenetic defectInheritancePrevalenceClinical featuresFamilial dysbeta-lipoproteinemiaApo Ehigh VLDL, chylo.recessiverarely dominant1/5000premature CADTC: 6.5 -13 mMTG: 2.8 – 5.6 mMFamilial combinedunknownhigh Apo B-100dominant1/50 – 1/100 15% of MIs <60 yrpremature CADTC: 6.5 -13 mMTG: 2.8 – 8.5 mM
19. Dietary sources of CholesterolType of FatMain SourceEffect on Cholesterol levelsMonounsaturatedOlives, olive oil, canola oil, peanut oil, cashews, almonds, peanuts and most other nuts; avocadosLowers LDL, Raises HDLPolyunsaturatedCorn, soybean, safflower and cottonseed oil; fishLowers LDL, Raises HDLSaturatedWhole milk, butter, cheese, and ice cream; red meat; chocolate; coconuts, coconut milk, coconut oil , egg yolks, chicken skinRaises both LDL and HDLTransMost margarines; vegetable shortening; partially hydrogenated vegetable oil; deep-fried chips; many fast foods; most commercial baked goods Raises LDL
20. Causes of Hyperlipidemia DietHypothyroidismNephrotic syndromeAnorexia nervosaObstructive liver diseaseObesityDiabetes mellitusPregnancy Obstructive liver diseaseAcute heaptitisSystemic lupus erythematoususAIDS (protease inhibitors)
21. DisorderVLDLLDLHDLMechanismDiabetes mellitus↑ ↑ ↑↑↓VLDL production ↑,LPL ↓, altered LDLHypothyroidism↑↑ ↑ ↑↓LDL-rec.↓, LPL ↓Obesity↑ ↑↑↓VLDL production ↑Anorexia-↑ ↑-bile secretion ↓, LDL catab. ↓Nephrotic sy↑ ↑↑ ↑ ↑↓Apo B-100 ↑ LPL ↓ LDL-rec. ↓Uremia, dialysis↑ ↑ ↑-↓LPL ↓, HTGL ↓ (inhibitors ↑)Pregnancy↑ ↑↑ ↑↑oestrogen ↑VLDL production ↑, LPL ↓Biliary obstructionPBC--↓Lp-X ↑ ↑no CAD; xanthomasAlcohol↑ ↑chylomicr. ↑-↑dep. on dose, diet, geneticsSecondary hyperlipidemias
22. Checking lipidsNonfasting lipid panelmeasures HDL and total cholesterolFasting lipid panelMeasures HDL, total cholesterol and triglyceridesLDL cholesterol is calculated:LDL cholesterol = total cholesterol – (HDL + triglycerides/5)
23. When to check lipid panel Different RecommendationsAdult Treatment Panel (ATP III) of the National Cholesterol Education Program (NCEP)Beginning at age 20: obtain a fasting (9 to 12 hour) serum lipid profile consisting of total cholesterol, LDL, HDL and triglyceridesRepeat testing every 5 years for acceptable values
24. United States Preventative Services Task ForceWomen aged 45 years and older, and men ages 35 years and older undergo screening with a total and HDL cholesterol every 5 years. If total cholesterol > 200 or HDL <40, then a fasting panel should be obtainedCholesterol screening should begin at 20 years in patients with a history of multiple cardiovascular risk factors, diabetes, or family history of either elevated cholesteral levels or premature cardiovascular disease.
25. Treatment TargetsLDL: To prevent coronary heart disease outcomes (myocardial infarction and coronary death)Non LDL( TC/HDL): To prevent coronary heart disease outcomes (myocardial infarction and coronary death)Triglyceride: To prevent pancreatitis and may be coronary heart disease outcomes (myocardial infarction and coronary death)
26. LDL and Non-LDL(HDL/TC)Risk Assessment Tool for Estimating 10-year Risk of Developing Hard CHD (Myocardial Infarction and Coronary Death)Framingham Heart Study to estimate 10-year risk for coronary heart disease outcomeshttp://hp2010.nhlbihin.net/atpiii/CALCULATOR.asp?usertype=profAge LDL-C T. CholHDL-C Blood PressureDiabetesSmoking
27. Adult Treatment Panel III Guidelines for Treatment of Hyperlipidemia Risk Category Begin Lifestyle Changes If: Consider Drug Therapy If: LDL Goal High: CAD or CAD equivalents (10-yr risk > 20%)LDL ≥ 2.58 mMLDL ≥ 2.58 mM(drug optional if < 2.58 mM)< 2.58 mM;< 1.8 mM optionalModerate high: ≥ 2 risk factors with 10-yr risk 10 to 20%*LDL ≥ 3.36 mMLDL ≥ 3.36 mM< 3.36 mM; < 2.58 mM optionalModerate: ≥ 2 risk factors with 10-yr risk < 10%*LDL ≥ 3.36 mMLDL ≥ 4.13 mM< 3.36 mM; < 2.58 mM optionalLower: 0–1 risk factorLDL ≥ 4.13 mMLDL ≥ 4.91 mM (drug optional if 4.13–4.88 mM)< 4.13 mM*For 10-yr risk, see Framingham risk tables
28. Canadian New Guideline
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30. http://clincalc.com/Cardiology/ASCVD/PooledCohort.aspx
31. Intensity of Statin Therapy in primary and secondary prevention
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33. Treatment of HyperlipidemiaLifestyle modificationLow-cholesterol dietExercise
34. Medications for HyperlipidemiaDrug ClassAgentsEffects (% change)Side EffectsHMG CoA reductase inhibitorsStatinsLDL (18-55), HDL (5-15) Triglycerides (7-30)Myopathy, increased liver enzymesCholesterol absorption inhibitorEzetimibe LDL( 14-18), HDL (1-3)Triglyceride (2)Headache, GI distressNicotinic AcidLDL (15-30), HDL (15-35) Triglyceride (20-50)Flushing, Hyperglycemia,Hyperuricemia, GI distress, hepatotoxicityFibric AcidsGemfibrozilFenofibrateLDL (5-20), HDL (10-20)Triglyceride (20-50)Dyspepsia, gallstones, myopathyBile Acid sequestrantsCholestyramine LDL HDLNo change in triglyceridesGI distress, constipation, decreased absorption of other drugs
35. MI = myocardial infarction.Adapted with permission from Robinson JG et al. J Am Coll Cardiol. 2005;46:1855–1862.
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39. George Yuan, Khalid Z. Al-Shali, Robert A. HegeleCMAJ • April 10, 2007 • 176(8)
40. STATIN Safety recommendations Conditions that could predispose pts to statin side effect:Impaired renal or hepatic functionHistory of previous statin intolerance or muscle disorderAge >75yUnexplained ALT elevation > 3x ULNHistory of hemorrhagic strokeAsian ancestry
41. STATIN Safety recommendations Check baseline ALT prior initiating the statin (Grade B)Check LFTs if patient develops Symptoms of hepatic dysfunction (Grade E)If 2 consecutive LDL <40, Consider decreasing the statin dose (Grade C, weak recommendation)It may be harmful to initiate simvastatin 80mg, or increase the dose of simvastatin to 80mg (Grade B)
42. Case 162 year old AA male Total cholesterol: 140Low HDL: 35SBP: 130 mmHgNot taking anti-hypertensive medicationsNon-diabeticNon-smokerCalculated 10 yr risk of ASCVD : 9.1%
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44. Moderate to high intensity statin
45. Case 250 year old white femaleTotal cholesterol 180HDL: 50SBP: 130taking anti-hTN meds+diabetic+smokerCalculated 10 yr ASCVD: 9.8%
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47. high intensity statin
48. Case 348 yo white femaleTotal cholesterol 180HDL: 55SBP: 130Not taking anti-hTN meds+diabeticNon-smokerCalculated 10 yr risk ASCVD : 1.8%
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50. Moderate intensity statin
51. Case 422 yo white maleLDL: 195SBP: 120Not taking anti-hTN medsNon-diabeticNon-smoker
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53. High intensity statin
54. Case 566 yo white female High Total cholesterol: 230HDL: 55SBP: 150taking anti-hTN medsNon-diabeticNon-smokerCalculated 10 yr risk of ASCVD : 2.0 %
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56. Statin therapy NOT recommended
57. Take Home MessageRather than LDL–C or non-HDL– C targets, new guideline uses the intensity of statin therapy as the goal of treatment.Know the 4 Statin Benefit Groups:Individuals with clinical ASCVDIndividuals with primary elevations of LDL–C ≥190 mg/dL Individuals 40 to 75 years of age with diabetes and LDL–C 70 to189 mg/dL without clinical ASCVDIndividuals without clinical ASCVD or diabetes who are 40 to 75 years of age with LDL–C 70 to 189 mg/dL and have an estimated 10-year ASCVD risk of 7.5% or higher. (using the Pooled Cohort Equations for ASCVD risk prediction)
58. THANK YOU ALLdrjammah@gmail.comSee you in 5th year MED-441 Course