Hyperlipidemia for USMLE Step 3
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Hyperlipidemia for the USMLE Step 3 Exam
Overview of Hyperlipidemia
Hyperlipidemia is defined by elevated blood lipid levels, including total cholesterol, low-density lipoprotein (LDL), and triglycerides. It is a key risk factor for atherosclerotic cardiovascular disease (ASCVD), which encompasses coronary artery disease, stroke, and peripheral artery disease. Management focuses on lowering LDL to reduce cardiovascular risk.
Types of Lipoproteins and Their Roles
- Low-Density Lipoprotein (LDL): Known as “bad cholesterol,” LDL transports cholesterol to peripheral tissues, contributing to plaque formation and increased ASCVD risk. Lowering LDL is the primary goal in hyperlipidemia management.
- High-Density Lipoprotein (HDL): “Good cholesterol” that transports cholesterol from tissues to the liver for excretion, offering some cardiovascular protection.
- Triglycerides (TG): High levels increase the risk of pancreatitis and may also contribute to ASCVD when combined with high LDL or low HDL levels.
Classification of Hyperlipidemia
Primary (Genetic) Hyperlipidemia
- Familial Hypercholesterolemia (FH): An autosomal dominant disorder causing very high LDL levels due to defective LDL receptors or apolipoprotein B mutations, significantly increasing ASCVD risk.
- Familial Combined Hyperlipidemia: Elevated LDL and triglycerides, often leading to premature ASCVD in families.
- Polygenic Hypercholesterolemia: Multiple genes contribute to moderately elevated LDL levels.
Secondary (Acquired) Hyperlipidemia
- Lifestyle Factors: High intake of saturated fats, obesity, and physical inactivity increase cholesterol and triglycerides.
- Medical Conditions: Diabetes, hypothyroidism, chronic kidney disease, and liver disease can contribute to high lipid levels.
- Medications: Drugs like corticosteroids, thiazide diuretics, and beta-blockers may elevate lipid levels.
Screening and Risk Assessment
- Screening: Baseline lipid panel at age 20, with repeat testing every 4–6 years in low-risk individuals. High-risk patients should be screened more frequently.
- High-Risk Populations: Annual screening for patients with diabetes or family history of early ASCVD, and for those with chronic inflammatory conditions.
- ASCVD Risk Score: A 10-year risk assessment tool that uses age, sex, cholesterol, BP, smoking status, and diabetes to guide the intensity of lipid-lowering treatment.
Management of Hyperlipidemia
Lifestyle Modifications
- Diet: Encourage a heart-healthy diet such as the Mediterranean or DASH diet, high in fruits, vegetables, whole grains, and fiber, with limited saturated fats.
- Exercise: Regular aerobic exercise (150 minutes per week) is recommended to improve HDL and reduce triglycerides.
- Weight Reduction: Losing weight can improve LDL and triglyceride levels, especially beneficial in overweight patients.
- Smoking Cessation: Increases HDL and lowers cardiovascular risk.
Pharmacologic Therapy
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Statins
- Mechanism: Statins inhibit HMG-CoA reductase, decreasing cholesterol synthesis and increasing LDL receptor expression to lower LDL levels.
- Indications: First-line therapy for patients with high ASCVD risk, diabetes, or established ASCVD.
- Intensity:
- High-Intensity Statins: Atorvastatin (40–80 mg), rosuvastatin (20–40 mg) for patients requiring ≥50% reduction in LDL.
- Moderate-Intensity Statins: Lower doses of atorvastatin, rosuvastatin, or simvastatin for those with moderate ASCVD risk.
- Side Effects: Myopathy and elevated liver enzymes; liver function tests are recommended before starting therapy.
Ezetimibe
- Mechanism: Inhibits cholesterol absorption in the intestine, reducing LDL levels.
- Use: Often added to statin therapy in patients who do not meet LDL goals or cannot tolerate high-intensity statins.
PCSK9 Inhibitors
- Mechanism: Monoclonal antibodies (e.g., evolocumab, alirocumab) that inhibit PCSK9, a protein that degrades LDL receptors, enhancing LDL clearance.
- Use: For patients with familial hypercholesterolemia or high ASCVD risk requiring further LDL reduction beyond statins.
Fibrates
- Mechanism: Activate peroxisome proliferator-activated receptor alpha (PPAR-α), enhancing lipoprotein lipase activity to lower triglycerides.
- Use: Primarily for hypertriglyceridemia (TG >500 mg/dL) to reduce pancreatitis risk.
- Side Effects: Increased risk of myopathy, especially when combined with statins.
Key Points
- LDL Reduction: The primary goal in hyperlipidemia management, with statins as the first-line therapy.
- Lifestyle Modifications: Essential for all patients, emphasizing diet, exercise, and smoking cessation.
- Statins: High- and moderate-intensity statins are selected based on ASCVD risk, with monitoring for potential side effects.
- Adjunctive Therapy: Ezetimibe and PCSK9 inhibitors may be added if LDL targets are not met with statins alone.
- Triglyceride Management: Fibrates are indicated for severe hypertriglyceridemia to prevent pancreatitis.
- Risk-Based Approach: The 10-year ASCVD risk score guides the intensity of lipid-lowering therapy for primary prevention.