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Hypercholesteronemia
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- 2. INTRODUCTION Lipoprotein disordersare clinically important due to the role in atherogenesis and the associated risk of atherosclerotic cardiovascular disease (ASCVD). For patients WITH known ASCVD (secondary prevention), cholesterol-lowering leads to a consistent reduction in cardiovascular mortality and cardiovascular events. Among patients WHITOUT cardiovascular disease (primary prevention), the data on reduction in atherosclerotic cardiovascular disease events with statin drugs is also well documented.
- 3. CHOLESTEROL ISTHE MOST CLINACALLY RELEVANT LIPID SUBSTANCES CONTRIBUTING TO ATHEROSCLEROSIS (LDL-C). Nearly 90% of patients with CHD have some form of dyslipidemia. Increased levels of LDL-C, remanent lipoproteins and Lp(a) and decreased levels of HDL-C have all been associated with an increased risk of premature vascular disease.
- 4. GENERAL PRINCIPLES Lipidsare sparingly soluble macromolecules that include cholesterol, fatty acids and their derivates. Plasma lipids are transported by lipoproteins particles composed of apoliproteins, phospholipids, free cholesterol, cholesterol esters and triglycerides. Human plasma lipoproteins are separated into five major classes based on density: Chylomicrons VLDL’s Intermidiate-density lipoproteins LDL’s HDL’s *A sixth class Lpa resembles LDL in lipid composition and has a density that overlaps LDL andb HDL.
- 5. Physical Properties ofPlasma Lipoproteins LIPOPROTEIN LIPID COMPOSITION ORIGIN Chylomicron TG 85%, Chol 3% Intestine VLDL TG 55%, Chol 20% Liver IDL TG 25%, Chol 35% Metabolic product of VLDL LDL TG 5%, Chol 60% Metabolic product of IDL HDL TG5%, Chol 20% Liver, Intestine Lp(a) TG5%, Chol 60% Liver
- 7. CHOLESTEROL METABOLISM Acetil-CoA Acetoacetyl-CoA HMG-CoA Mevalonate FarnesylPPi Squalene Lanosterol HMG-CoA Syntase CHOLESTEROL HMG-CoAReductase Cell membrane Vitamin D Bile salts Steroids (Adrenal,Ovaries, Testes Insuline Statins Glucagon cholesterol
- 8. Etiology Hypercholesterolemia canbe defined as a LDL-cholesterol greater than 190 mg/dL, greater than 160 mg/dL with one major risk factor, or greater than 130 mg/dL with two cardiovascular risk factors. The important risk factors include: Age; male 45 years or older, female 55 years or older A positive family history of premature atherosclerotic cardiovascular disease (younger than 55 years in a male and younger than 65yrs in a female) Hypertension Diabetes Smoking Low HDL-cholesterol levels (less than 40 mg/dl in male and less than 55 mg/dl in a female).
- 9. Most commoncause is Polygenic hypercholesterolemia which results from an interaction of unidentified genetic factors compounded by a sedentary lifestyle and an increased intake of saturated and trans-fatty acids. Secondary causes include: Hypothyroidism, Nephrotic syndrome, Cholestasis, Pregnancy, Certain drugs like Cyclosporine, Thiazide diuretics.
- 10. Lipid abnormality Primarydisorders Secondary disorders Hypercholesterolemia Polygenic, familial hypercholesterolemia, familial defective apo B-100; PCSK9gain of function mutation Hypothyroidism, nephrotic syndrome, anorexia nervosa. Hypertriglyceridemia Lipoprotein lipase deficiency, apo C II deficiency, familial hypertriglyceridemia, dysbetalipoproteinemia Diabetes mellitus, obesity, syndrome, alcohol use, oral estrogen,renal failure, hypothyroidism, lipodystrophies. Combined Familial comnined hyperlipodemia, dysbetalipoproteinemia Diabetes mellitus, obesity, syndrome, nephrotic syndrome, hypothyroidism, lipodystrophies Low HDL Familia hypoalphalipoproteinemia, Tangier disease (ABCA1 deficiency) apoA1mutations, lecithin-cholesterol acyktransferase deficiency. Diabetes mellitus, obesity, metaboloc syndrome, hypertriglyceridemia, smoking, anabolic steroids.
- 11. FAMILIAL HYPERCHOLESTEROLEMIA Classicalgenetic disorder due to mutations in the LDL-receptor gene resulting in LDL-C greater than 190 mg/dl in heterozygotes and greater than 450 mg/dl in homozygotes. This defect in the LDL receptor accounts for at least 85% of familial hypercholesterolemia.
- 12. Defective apolipoproteinB (most common with a mutation at position 3500) resulting in a loss of ligand binding to the LDL receptor A gain-of-function mutation in proprotein convertase subtilisin/kexin type 9 (PCSK9) gene leading to increased affinity of PCSK9 for the LDL- receptor
- 13. Epidemiology According tothe Center for Disease Control and Prevention (CDC), 73.5 million or 31.7% of adults in the United States have high levels of LDL-C and are at twice the risk for heart disease than people with normal levels. Only 48.1% are receiving treatment to lower LDL-C levels. Familial hypercholesterolemia has a prevalence of estimate of 1/250,000 as homozygous and 1/200-250 as a heterozygote. In certain populations such as the French Canadians, Lebanese, and Afrikaners it could be as high as 1/100. In the US, the highest level of LDL cholesterol occurs in Hispanic males, followed by African Americans and white males.
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- 15. CLINICAL CRITERIA Threesets of clinical criteria have been devised to identify patients with heterozygous familial hypercholesterolemia. Each is based on a combination of: Lipid levels, typically an LDL-C greater than 190 mg/dL Family history of premature coronary artery disease or familial hypercholesterolemia Clinical history Physical signs such as xanthelasma (cholesterol deposits in the skin of the eyelids); xanthoma (deposits in connective tissue in and around extensor tendons— pathognomonic for this disease) and arcus cornealis or corneal arcus (deposits along the corneal border)
- 16. Criteria Points Family history First-degreerelative with known premature atherosclerotic cardiovascular disease (age < 55 in men, age < 60 in women) or first- degree relative with LDL-C > 95th percentile 1 First-degree relative with tendon xanthomas or arcus cornealis, or child under age 18 with LDL-C > 95th percentile 2 Clinical history Premature coronary artery disease 2 Premature cerebral or peripheral vascular disease 1 Physical examination Tendon xanthomas 6 Arcus cornealis before age 45 4 LDL-C levels, mg/dL ≥ 330 8 250–329 5 190–249 3 155–189 1 DNA analysis Functional mutation in the LDLR, APOB, or PCSK9 gene 8 Interpretation Total Definite familial hypercholesterolemia > 8 Probable familial hypercholesterolemia 6–8 Possible familial hypercholesterolemia 3–5 Unlikely familial hypercholesterolemia < 3 The Dutch Lipid Clinic Network diagnostic criteria for familial hypercholesterolemia
- 17. Criterion Description A Totalcholesterol level > 290 mg/dL or LDL-C > 190 mg/dL in adults (age ≥ 16) Total cholesterol level > 260 mg/dL or LDL-C > 155 mg/dL in children (age < 16) B Tendon xanthomas in the patient or in a first- or second-degree relative C DNA-based evidence of a mutation in LDLR, APOB, or PCSK9 D Family history of myocardial infarction before age 50 in a second-degree relative, or before age 60 in a first- degree relative E Total cholesterol > 290 mg/dL in a first- or second-degree relative The Simon Broome diagnostic criteria for familial hypercholesterolemia Interpretation: “Definite” familial hypercholesterolemia requires criterion C by itself, or criterion A plus B; “probable” familial hypercholesterolemia requires either A plus D, or A plus E.
- 18. GENETIC TESTING ISTHE GOLD STANDARD Genetic testing is the gold standard for diagnosing familial hypercholesterolemia. Most of the known mutations are in LDLR, but APOB, PCSK9, and potentially other genes involved in LDL-C catabolism can also have mutations.
- 19. Patients hospitalizedfor an acute coronary syndrome or coronary revascularization should have a lipid panel obtained within 24 hours of admission if lipid levels are unknown Individuals with hyperlipidemia should be evaluated for potential secondary causes including hypothyroidism, DM, obstructive liver disease, chronic renal disease (nephrotic syndrome) and medications such as estrogens, progestins, anabolic steroids/androgens, corticosteroids, cyclosporine, retinoids, atypical antipsychotics and antiretrovirals.
- 20. SCREENING Screening forHypercholesterolemia should be done in all adults age 20 years or older Presence of diabetes Tobacco use Family history of cardiac disease Personal history of heart disease or peripheral vascular disease Obesity (BMI > 30) Hypertension
- 21. Screening is bestperformed with a lipid profile Total cholesterol LDL-C, HDL-C, and Triglycerides OBTEINED AFTER 12 HOUR FASTING If not fasting: Total cholesterol and HDL cholesterol be measured Non-HDL Cholesterol > 220 mg/dL may indicative of genetic or secondary cause. A fasting lipid panel is required if non-HDL Cholesterol is > 220mg/dL triglycerides > 500 mg/dL
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- 24. CHOLESTEROL METABOLISM Acetil-CoA Acetoacetyl-CoA HMG-CoA Mevalonate FarnesylPPi Squalene Lanosterol HMG-CoA Syntase CHOLESTEROL HMG-CoAReductase Cell membrane Vitamin D Bile salts Steroids (Adrenal,Ovaries, Testes Insuline Statins Glucagon cholesterol
- 25. Defective apolipoproteinB (most common with a mutation at position 3500) resulting in a loss of ligand binding to the LDL receptor A gain-of-function mutation in proprotein convertase subtilisin/kexin type 9 (PCSK9) gene leading to increased affinity of PCSK9 for the LDL- receptor
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- 27. DIET Adopt adiet that is high in fruits and vegetables Whole grains Fish Lean meat Low-fat dairy Legumes Nuts Lower intake of red meat Low intake of saturated and trans fats, sweets and sugary beverages
- 28. EXERCISE Aerobic and resistanceexercise recommended in all patients For all obese patients (body mas index > 30) and for overweight patients (body mass index > 25) who have additional risk factors, sustained weight loss of 3% to 5% or greater reduces ASCVD risk.
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- 30. Prior to thestart of treatment discuss with your patient: Potential for ASCVD risk reduction benefits Potential for adverse effects and drug-drug interactions Heart healthy lifestyle and management of other risk factors Patient preferences
- 31. Description of Lipid-LoweringMedications Drug Class Agents Mechanism of Action Lipoprotein Changes Statin •Atorvastatin •Fluvastatin •Lovastatin •Pitavastatin •Pravastatin •Rosuvastatin •Simvastatin Competitively inhibits HMG-CoA reductase to inhibit cholesterol synthesis in the liver, resulting in increased expression of LDL- receptors that accelerates uptake of LDL from blood to liver LDL-C: ↓ 18%–55% HDL-C: ↑ 5–15% TGs: ↓ 7–30% Cholesterol absorption inhibitor •Ezetimibe Blocks the Niemann-Pick C1-Like 1 receptor to inhibit absorption of cholesterol, leading to decreased delivery of intestinal cholesterol the liver reducing hepatic cholesterol stores and increasing cholesterol clearance from the blood LDL-C: ↓ 13%–20% HDL-C: ↑ 3%–5% TGs: ↓ 5%–11% Bile acid sequestrant •Colesevelam •Colestipol •Cholestyramine Binds intestinal bile acids, impeding reabsorption, upregulating cholesterol 7-α-hydroxylase, which increases conversion of cholesterol to bile acids with the increased cholesterol demand in the liver increasing hepatic LDLRs and increasing cholesterol clearance from the blood LDL-C: ↓ 15%–30% HDL-C: ↑ 3%–5% TGs: ↓ 0%–10% PCSK9 inhibitor •Alirocumab •Evolocumab Binds PCSK9, which normally binds to LDLRs to promote LDLR degradation (LDLR is the primary receptor that clears circulating LDL); by inhibiting PCSK9 binding to LDLRs, there are increased number of LDLRs and results in increased cholesterol removal LDL-C: ↓ 40%–72% HDL-C: ↑ 0%–10% TGs: ↓ 0%–17%
- 34. NEED TO KNOW!!! CLINICALASCVD CLINICAL ASCVD INCLUDES: Acute coronary syndromes History of MI Stable angina Arterial revascularization Stroke Transient Ischemic Attack Atherosclerotic peripheral arterial disease
- 35. HIGH INTENSITY (LDL >50%) MEDIUM INTENSITY (LDL 30%-49%) LOW INTENSITY (LDL <30%) Atorvastatin 40-80 mg Rosuvastatin 20-40 mg Atorvastatin 10-20 mg Fluvastatin 40 mg bid, 80 mg XL Lovastatin 40 mg Pitavastatin 1-4mg Pravastatin 40-80 mg Rosuvastatin 5-10 mg Simvastatin 20-40 mg Fluvastatin 20-40 mg Lovastatin 20 mg Pravastatin 10-20 mg Simvastatin10 mg Statin Therapy Regimens by Intensity • Secondary prevention is an indication for high intensity statin therapy. • If high-dose statin therapy is contraindicated or poorly tolerated or there are significant risk to high-intensity therapy (including age >75 years, the maximally tolerated statin therapy is an option. • In very-high-risk ASCVD, use LDL-C threshold of 70 mg/dL to consider addition of nonstatins to statins therapy. • If Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitor is considered add ezetimibe to maximal statin before start PCSK9 inhibitor
- 36. GUIDELANIES FOR THEMANAGEMENT OF HYPERCHOLESTEROLEMIA AMERICAN HEART ASSOCIATION / AMERICAN COLLEGE OF CARDIOLOGY EUROPEAN SOCIETY OF CARDIOLOGY / EUROPEAN ATHEROSCLEROTIC SOCIETY
- 37. Clinical ASCVD Age 21-75High-intensity Statin Age > 75 Moderate-intensity statin LDL-C > 190 High-Intensity statin LDL-C 70-189 Age 40-75 Y 10 Y ASCVD Risk > 7.5% Moderate- intensity Statin DM LDL-C 70-189 AGE 40-75 Y 10 Y ASCVD RISK > 7.5% High-intensity Statin 10 Y ASCVD RISK < 7.5% Moderate-intensity statin ACC/A HA
- 38. ESC/ EAS Score <1% LDL-C <100NO Intervention LDL-C 100-190 Lifestyle Intervention LDL-C >190 Consider Drug Treatment Score 1-5% LDL-C <100 Lifestyle intervention LDL-C >100 Consider Drug Treatment Score 5-10% Or high Risk LDL-C <100 Consider Drug Treatment LDL-C >100 Inmediate drug treatment Score > 10% or very high risk LDL-C <70 Consider drug treatment LDL-C >70 Inmediate drug treatment