Clinical Dyslipidemia Lecture Notes PDF

Clinical Dyslipidemia Sonia Rivera-Martinez, DO, FACOFP Associate Professor, Dept. of Family Medicine [email protected] Session Objectives Describe the main features for the different types of lipoprotein disorders and explain their role in disease Identify the main features for primary cau...

Clinical Dyslipidemia Sonia Rivera-Martinez, DO, FACOFP Associate Professor, Dept. of Family Medicine [email protected] Session Objectives Describe the main features for the different types of lipoprotein disorders and explain their role in disease Identify the main features for primary causes of dyslipidemia Examine the main features for secondary causes of dyslipidemia Correlate the presenting signs and symptoms with the different types of dyslipidemia disorders Explain the rationale for the different preventative strategies for dyslipidemia disorders and formulate a treatment plan based on the latest guidelines Source: Course Syllabus Dyslipidemia: Definition and Classification Dyslipidemia Definition: Disorders of lipoprotein metabolism Includes: Overproduction (Increase) Deficiency (Decrease) Source: Disorders of Lipoprotein Metabolism: Harrison’s Principles of Internal Medicine, 2022, 21th edition, Chapter 407 Lipoproteins - Role Lipoproteins Large macromolecular complexes composed of lipids and proteins Core of hydrophobic lipids Shell of hydrophilic lipids and proteins Needed for transport and absorption of cholesterol, triglycerides and fat-soluble vitamins Cholesterol – important component of cell membrane, bile acids and hormone Triglycerides – essential source energy supply Source: Disorders of Lipoprotein Metabolism: Harrison’s Principles of Internal Medicine, 2022, 21th edition, Chapter 407 Major Lipoprotein Classes Classified primarily by the lipid content per particle Chylomicrons – least dense lipoprotein (most lipid-rich) Very-low-density lipoprotein (VLDL) Intermediate-density lipoprotein (IDL) Low-density lipoprotein (LDL) High-density lipoprotein (HDL) – (least lipid content) Source: Disorders of Lipoprotein Metabolism: Harrison’s Principles of Internal Medicine, 2022, 21th edition, Chapter 407 Major Lipoprotein Classes Source: Disorders of Lipoprotein Metabolism: Harrison’s Principles of Internal Medicine, 2022, 21th edition, Chapter 407 Transport of Lipids Chylomicrons – involved in transport dietary lipids from the intestine to the periphery and liver Energy Storage VLDL, IDL, LDL – involved in transport of hepatic lipids to the periphery HDL – involved in transport of excess VLDL, IDL and LDL from the periphery back to the liver Source: Disorders of Lipoprotein Metabolism: Harrison’s Principles of Internal Medicine, 2022, 21th edition, Chapter 407 Lipid Transport: Exogenous and Endogenous Source: Disorders of Lipoprotein Metabolism: Harrison’s Principles of Internal Medicine, 2022, 21th edition, Chapter 407 Lipid Transport: HDL Reverse Cholesterol Transport Source: Disorders of Lipoprotein Metabolism: Harrison’s Principles of Internal Medicine, 2022, 21th edition, Chapter 407 Dyslipidemia – Role in Disease Dyslipidemia – Clinical Significance Dyslipidemias contribute to the development of atherosclerosis Coronary artery disease Peripheral vascular disease Cerebrovascular accidents Severe hypertriglyceridemia may lead to acute pancreatitis Critical element in non-alcoholic Source: Disorders of Lipoprotein Metabolism: Harrison’s Principles of Internal Medicine, 2022, 21th edition, Chapter 407 Lipoproteins and Atherosclerosis Atherosclerosis – Very common disease of the arteries caused by buildup of cholesterol plaques Macrophage and LDL accumulation eventually lead to formation of complex atheromas Complications: Ischemia, thrombus, emboli and aneurysms Symptoms: Angina, claudication or asymptomatic Source: Atlas of Atherosclerosis: Harrison’s Principles of Internal Medicine, 2022, 21 th edition, Chapter A10 Atherosclerosis Source: Cardiovascular Disorders: Heart Disease. In: Hammer GD, McPhee SJ. eds. Pathophysiology of Disease: An Introduction to Clinical Medicine, 8e. McGraw Hill; 2019. Risk Factors for Developing Atherosclerosis Age – increases with each decade of life Male gender Family history: Hypertension Diabetes Familial hypercholesterolemia Cigarette smoking Hypertension - both systolic and diastolic Hyperlipidemia - primarily elevated LDL and low HDL Diabetes Metabolic syndrome Source: Atlas of Atherosclerosis: Harrison’s Principles of Internal Medicine, 2022, 21 th edition, Chapter A10 Metabolic syndrome Group of risk factors Defined by three or more of the following five abnormalities: Fasting blood glucose > 100 mg/dl Blood pressure of at least 130/85 mm Hg Triglycerides > 150 mg/dl HDL level of < 40 mg/dl in men or < 50 mg/dl in women Waist circumference > 102 cm (40 in) in men or > 88 cm (35 in) in women Source: Metabolic Syndrome; Harrison’s Principles of Internal Medicine, 2022, 21 th edition, Chapter 408 Dyslipidemia: Etiology Primary causes of dyslipidemia Single or multiple gene mutations resulting in either: Overproduction or defective clearance of TG and LDL cholesterol Underproduction or excessive clearance of HDL Source: Dyslipidemia – Endocrine and Metabolic Disorders - Merck Manuals Professional Edition – Last full review/revision May 2023 by Michael H. Davidson, MD Primary causes of dyslipidemia Familial hypercholesterolemia Genetic defect: LDL receptor defect Diminished LDL clearance Inheritance: Co-dominant or complex with multiple gene involvement Prevalence: Heterozygotes 1/200 Homozygotes 1/250,000 - 1/1 million Heterozygotes: TC 250-500 mg/dl Premature CAD (Ages 30-50) – 5% of MI’s 500 mg/dl Premature CAD (Before age 18) Source: Dyslipidemia – Endocrine and Metabolic Disorders - Merck Manuals Professional Edition – Last full review/revision May 2023 by Michael H. Davidson, MD Primary causes of dyslipidemia Familial combined hyperlipidemia Genetic defect: Unknown, possible genetic multiple defects and mechanisms Inheritance: Autosomal dominant Prevalence: 1/50 to 1/100 Premature CAD 15% of MI’s in people < 60 yr Disproportionately elevated apoB TC 250-500 mg/dl TG 250-750 mg/dl Source: Dyslipidemia – Endocrine and Metabolic Disorders - Merck Manuals Professional Edition – Last full review/revision May 2023 by Michael H. Davidson, MD Primary causes of dyslipidemia Familial hypertriglyceridemia Genetic defect: Unknown, possible genetic multiple defects and mechanisms Inheritance: Autosomal dominant Prevalence: 1/500 Usually no symptoms or findings Absence of secondary causes TG: 200-500 mg/dl Source: Dyslipidemia – Endocrine and Metabolic Disorders - Merck Manuals Professional Edition – Last full review/revision May 2023 by Michael H. Davidson, MD Primary causes of dyslipidemia Familial defective apoB-100 Genetic defect: Apo B (LDL receptor- binding region defect) Diminished LDL clearance Inheritance: Autosomal dominant Prevalence: 1/700 Premature CAD, xanthomas, arcus corneae TC: 250-500 mg/dl Source: Dyslipidemia – Endocrine and Metabolic Disorders - Merck Manuals Professional Edition – Last full review/revision May 2023 by Michael H. Davidson, MD Primary causes of dyslipidemia Familial HDL deficiency Genetic defect: ABCA1 gene (ATP-binding cassette transporter A1 Inheritance: Autosomal dominant Prevalence: Rare Premature CAD Source: Dyslipidemia – Endocrine and Metabolic Disorders - Merck Manuals Professional Edition – Last full review/revision May 2023 by Michael H. Davidson, MD Secondary causes of dyslipidemia Secondary causes contribute to many cases of dyslipidemias in adults The most important secondary cause in developed countries is: A sedentary lifestyle with an excessive dietary intake of saturated fats, cholesterol, and trans fats. Source: Dyslipidemia – Endocrine and Metabolic Disorders - Merck Manuals Professional Edition – Last full review/revision May 2023 by Michael H. Davidson, MD Secondary causes of dyslipidemia Other common secondary causes include: Endocrine disorders: Diabetes mellitus, Insulin resistance, Cushing disease, Hypothyroidism, Hepatic disorders: Primary biliary cirrhosis, Other cholestatic liver diseases Renal disorders: Chronic kidney disease, Nephrotic syndrome Medications: Thiazides, β-blockers, Retinoids, Highly active antiretroviral agents, Estrogen and progestins, Glucocorticoids, Cyclosporine and Tacromilus Other: Diet, Alcohol overuse, Obesity Source: Dyslipidemia – Endocrine and Metabolic Disorders - Merck Manuals Professional Edition – Last full review/revision May 2023 by Michael H. Davidson, MD Secondary causes of dyslipidemia Diabetes Mellitus Significant secondary cause Atherogenic combination of: Elevated TG and LDL Low HDL Exacerbated by presence of obesity, physical inactivity and increase caloric intake Type 2 diabetics are especially at risk Source: Dyslipidemia – Endocrine and Metabolic Disorders - Merck Manuals Professional Edition – Last full review/revision May 2023 by Michael H. Davidson, MD Secondary causes of dyslipidemias Excessive hepatic production of VLDL Characterized by elevated fasting TG, Low HDL, variable levels of LDL Common causes: High carbohydrate diet Obesity and insulin resistance More free fatty acids are delivered from the adipose tissue to the liver Increased insulin levels promote increased fatty acid synthesis Nephrotic syndrome Cushing’s syndrome Source: Disorders of Lipoprotein Metabolism: Harrison’s Principles of Internal Medicine, 2022, 21th edition, Chapter 407 Secondary causes of dyslipidemias Alcohol overuse Causes excessive hepatic production of VLDL Inhibits hepatic oxidation of free fatty acids Promotes hepatic TG synthesis and VLDL secretion Raises plasma levels of HDL Consider in persons with combination of elevated TG and HDL Source: Disorders of Lipoprotein Metabolism: Harrison’s Principles of Internal Medicine, 2022, 21 th edition, Chapter 407 Secondary causes of dyslipidemias Impaired Lipolysis of TG-rich lipoprotein’s (TRL) Due to decreased LPL (Lipoprotein lipase activity Characterized by elevated fasting TG, Low HDL usually without elevations of LDL or apoB Common causes: Obesity and insulin resistance Source: Disorders of Lipoprotein Metabolism: Harrison’s Principles of Internal Medicine, 2022, 21th edition, Chapter 407 Secondary causes of dyslipidemias Impaired Hepatic Uptake of Lipoproteins containing ApoB Reduced LDL receptor activity Characterized by elevated LDL Common causes: Hypothyroidism Increased IDL and mild elevation of TG Chronic kidney disease Mild hypertriglyceridemia ( 1000 mg/dl) can cause acute pancreatitis Severe elevations of TGs can present with: Eruptive xanthomas over the trunk, back, elbows, buttocks, knees, hands and feet Severe hypertriglyceridemia (>2000 mg/dl) can present with: Lipemia retinalis Source: Dyslipidemia – Endocrine and Metabolic Disorders - Merck Manuals Professional Edition – Last full review/revision May 2023 by Michael H. Davidson, MD Signs and Symptoms High levels of LDL can present with: Arcus corneae Tendinosus xanthomas Xanthelasma Source: Dyslipidemia – Endocrine and Metabolic Disorders - Merck Manuals Professional Edition – Last full review/revision May 2023 by Michael H. Davidson, MD  Physical Exam Findings: Hypercholesterolemia Tendinosus xanthomas: Begins with tendons thickening at the lateral border Occur mainly in the extensor tendons of the hands, feet, elbows and knees. Tuberous xanthomas: Firm painless yellow or red nodules found over extensor aspects of limbs and buttocks Source: Dyslipidemia – Endocrine and Metabolic Disorders - Merck Manuals Professional Edition – Last full review/revision May 2023 by Michael H. Davidson, MD  Physical Exam Findings: Hypercholesterolemia Arcus corneae results from cholesterol infiltration of the corneal rim. Xanthelasmas are yellow cholesterol plaques that occur most commonly near the inner canthus usually of the upper eyelid. Source: Dyslipidemia – Endocrine and Metabolic Disorders - Merck Manuals Professional Edition – Last full review/revision May 2023 by Michael H. Davidson, MD Physical Exam Findings: Hypertriglyceridemia Eruptive xanthomas are painless, yellowish papules presenting as group lesions on the torso, elbows, chest and buttocks. Source: Dyslipidemia – Endocrine and Metabolic Disorders - Merck Manuals Professional Edition – Last full review/revision May 2023 by Michael H. Davidson, MD Dyslipidemia – Diagnosis Dyslipidemia – Clinical Manifestation Dyslipidemias may manifest as one of more of the following: Elevated total plasma cholesterol Elevated low-density lipoproteins (LDL) Elevated triglycerides (TGs) Decreased high-density lipoprotein (HDL) Source: Dyslipidemia – Endocrine and Metabolic Disorders - Merck Manuals Professional Edition – Last full review/revision May 2023 by Michael H. Davidson, MD  Diagnosis Dyslipidemia is diagnosed by measuring serum lipids Serum lipid profile Total cholesterol Triglycerides HDL cholesterol Calculated LDL cholesterol and VLDL cholesterol TC= VLDL + LDL + HDL Source: Dyslipidemia – Endocrine and Metabolic Disorders - Merck Manuals Professional Edition – Last full review/revision May 2023 by Michael H. Davidson, MD Serum Lipid Profile TC, TGs, and HDL cholesterol are measured directly TC values can vary by 10% and TGs by up to 25% day-to-day even in the absence of a disorder Patients should have all lipids measured while fasting (usually for 12 h) for maximum accuracy and consistency Testing should be postponed until after resolution of acute illness since: TG and lipoprotein levels increase, and cholesterol levels decrease in inflammatory states Source: Dyslipidemia – Endocrine and Metabolic Disorders - Merck Manuals Professional Edition – Last full review/revision May 2023 by Michael H. Davidson, MD LDL Cholesterol (calculated) LDL cholesterol = TC - [HDL + (TG/5)] This calculation is valid only when TGs are < 400 mg/dl and patients are fasting, because eating increases TGs Request a direct LDL measurement when TG’s are > 400 mg/dl Direct LDL measurements are not routinely necessary Source: Dyslipidemia – Endocrine and Metabolic Disorders - Merck Manuals Professional Edition – Last full review/revision May 2023 by Michael H. Davidson, MD  Screening for Dyslipidemia Universal screening using a fasting lipid profile should be done: No risk factors - Once for all children between age 9 and 11 or at 2 to 8 if children have a family history of severe hyperlipidemia or premature CAD Adults are screened at age 20 yr and every 5 years thereafter Assessment for cardiovascular risk factors should accompany the lipid measurements A definite age to discontinue screening has not been determined Source: Dyslipidemia – Endocrine and Metabolic Disorders - Merck Manuals Professional Edition – Last full review/revision May 2023 by Michael H. Davidson, MD Screening for secondary causes of dyslipidemia Patients with newly diagnosed dyslipidemia and/or when a component of the lipid profile has inexplicably changed for the worse Fasting glucose Liver enzymes Creatinine Thyroid-stimulating hormone (TSH) Urinary protein Once secondary causes ruled out attempt to determine primary cause of dyslipidemia Source: Dyslipidemia – Endocrine and Metabolic Disorders - Merck Manuals Professional Edition – Last full review/revision May 2023 by Michael H. Davidson, MD Dyslipidemias - Diagnosis of Primary Cause Chylomicronemia: Fasting plasma TG level > 1,000 mg/dl Familial chylomicronemia syndrome: Cholesterol to TG ratio > 10 At risk for acute pancreatitis Familial hypercholesterolemia: LDL levels are elevated in the absence of hypertriglyceridemia Clinical diagnosis Source: Disorders of Lipoprotein Metabolism: Harrison’s Principles of Internal Medicine, 2022, 21th edition, Chapter 407 Dyslipidemias – Diagnosis of Primary Cause Combined hyperlipidemia Elevation of TG, VLDL and LDL Ascertain the VLDL/TG ratio in plasma or direct LDL to determine if hyperlipidemia is due to: Accumulation of lipoprotein remnants (i.e. Familial dysbetalipoproteinemia) or An increase in both LDL and VLDL Measurement of apoB levels can help identify patients with Familial combined hyperlipidemia Source: Disorders of Lipoprotein Metabolism: Harrison’s Principles of Internal Medicine, 2022, 21th edition, Chapter 407 ACC/AHA Guidelines 2019 American College of Cardiology and American Heart Association Task Force Clinical Practice Guidelines https://doi.org/10.1161/CIR.0000000000000678 ACC/AHA Guidelines 2019 Main indication for dyslipidemia treatment is prevention of atherosclerotic cardiovascular disease (ASCVD) Acute coronary syndromes Stroke, transient ischemic attack Peripheral vascular disease Source: Dyslipidemia – Endocrine and Metabolic Disorders - Merck Manuals Professional Edition – Last full review/revision May 2023 by Michael H. Davidson, MD ACC/AHA Guidelines 2019 AHA/ACC recommends treatment with a statin for 4 groups of patients: Clinical atherosclerotic cardiovascular disease LDL cholesterol > 190 mg/dl Age 40 to 75 with diabetes and LDL cholesterol 70 to 189 mg/dl Age 40 to 75, LDL cholesterol 70 to 189 mg/dl and estimated 10-yr ASCVD > 7.5% Source: Dyslipidemia – Endocrine and Metabolic Disorders - Merck Manuals Professional Edition – Last full review/revision May 2023 by Michael H. Davidson, MD ACC/AHA Guidelines 2019 Risk of ASCVD is estimated using a risk calculator that takes into account: Sex Age Race Total and HDL cholesterol Systolic and diastolic BP Use of antihypertensives or statins Presence or absence of diabetes Smoker status Source: Dyslipidemia – Endocrine and Metabolic Disorders - Merck Manuals Professional Edition – Last full review/revision May 2023 by Michael H. Davidson, MD ACC/AHA Guidelines 2019 Other factors to consider to determine need for a statin: LDL cholesterol > 160 mg/dl Family history of premature CAD Onset < 55 yr in male 1st degree relative Onset < 65 yr in a female 1st degree relative High sensitivity C-reactive protein > 2 mg/L Coronary artery calcium score > 300 Agatson units (or > 75th percentile) Ankle-brachial BP index < 0.9 Increased lifetime risk (ACC/AHA risk calculator) Source: Dyslipidemia – Endocrine and Metabolic Disorders - Merck Manuals Professional Edition – Last full review/revision May 2023 by Michael H. Davidson, MD Dyslipidemia – Treatment Goals of Treatment of Lipoprotein Disorders Major goals: Prevention of CVD and related cardiovascular events Prevention of acute pancreatitis in patients with severe hypertriglyceridemia Source: Disorders of Lipoprotein Metabolism: Harrison’s Principles of Internal Medicine, 2022, 21th edition, Chapter 407 Treatment Plan for Lipoprotein Disorders Risk assessment for ASCVD Lifestyle changes- 1st line Exercise Dietary modification Elevated LDL: statins, bile acid sequestrants, ezetimibe, niacin, bempedoic acid, PSK9 monoclonal antibodies Elevated TG: Niacin, fibrates, omega-3- fatty acids Source: Dyslipidemia – Endocrine and Metabolic Disorders - Merck Manuals Professional Edition – Last full review/revision May 2023 by Michael H. Davidson, MD Management for Hypercholesterolemia Lifestyle: If obese - Reduce weight to ideal level Aerobic exercise Diet Reduce intake of: Saturated fats, Trans fats, Cholesterol Increase intake of: Fiber, Complex carbohydrates Source: Dyslipidemia – Endocrine and Metabolic Disorders - Merck Manuals Professional Edition – Last full review/revision May 2023 by Michael H. Davidson, MD Management of Hypercholesterolemia Statins are the treatment of choice for reduction of LDL cholesterol Reduction of cardiovascular risk is well supported by clinical trial data Statins = Hydroxymethylglutaryl Coenzyme A (HMG-CoA) Reductase Inhibitors Statins work by inhibiting the rate- limiting enzyme in cholesterol biosynthesis Significantly reduce LDL and have a modest HDL – raising effect Source: Dyslipidemia – Endocrine and Metabolic Disorders - Merck Manuals Professional Edition – Last full review/revision May 2023 by Michael H. Davidson, MD Management of Hypercholesterolemia Statins are mainly well tolerated Side effects: Dyspepsia Headaches Fatigue Muscle or joint pain Elevation of liver transaminase levels Need to closely monitor at least every 3 months Source: Disorders of Lipoprotein Metabolism: Harrison’s Principles of Internal Medicine, 2022, 21th edition, Chapter 407 Management of Hypertriglyceridemia Lifestyle: (First Line) If obese - Reduce weight to ideal level Aerobic exercise Dietary: Reduce intake of: Alcohol or preferably eliminate Simple carbohydrates Increase intake of: Omega-3-fatty acids (Marine fish) Diabetics: Tight control of glucose levels Source: Dyslipidemia – Endocrine and Metabolic Disorders - Merck Manuals Professional Edition – Last full review/revision August 2021 by Michael H. Davidson, MD Management of Hypertriglyceridemia Failed lifestyle management Initiate medications for patients with persistent TG levels > 500 mg/dl Fibric acid derivatives Side effects: Myopathy, gallstones, creatinine elevations Note: May raise LDL levels Omega 3 Fatty Acids Side effects: Dyspepsia Note: May prolong bleeding time Nicotinic Acid (Niacin) Side effects: Dyspepsia Note: May elevate uric acid and liver transaminase Source: Disorders of Lipoprotein Metabolism: Harrison’s Principles of Internal Medicine, 2022, 21th edition, Chapter 407 Summary Key Points Elevated lipid levels are a risk factor for atherosclerosis Causes of dyslipidemia include sedentary lifestyle with excessive dietary intake and or genetic abnormalities Diagnose using fasting serum lipid profile Screening tests should be done at age 9 to 11 Age 2 if there is strong family history of severe hyperlipidemia or premature CAD Screen adults every 5 years after age 20 Source: Dyslipidemia – Endocrine and Metabolic Disorders - Merck Manuals Professional Edition – Last full review/revision August 2021 by Michael H. Davidson, MD Core References Disorders of Lipoprotein Metabolism: Harrison’s Principles of Internal Medicine, 2022, 21th edition, Chapter 407 Dyslipidemia – Endocrine and Metabolic Disorders - Merck Manuals Professional Edition – Last full review/revision May 2023 by Michael H. Davidson,  Lecture Feedback Form: https://comresearchdata.nyit.edu/redcap/surveys/? s=HRCY448FWYXREL4R