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Hyperlipidemia for USMLE Step 2

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Hyperlipidemia for the USMLE Step 2 Exam
Hyperlipidemia, characterized by elevated blood lipid levels (e.g., cholesterol, triglycerides), is a major risk factor for atherosclerotic cardiovascular disease (ASCVD), which includes coronary artery disease, stroke, and peripheral artery disease. Management focuses primarily on lowering low-density lipoprotein (LDL) cholesterol to reduce ASCVD risk.
Types of Lipoproteins and Their Roles
  • Low-Density Lipoprotein (LDL): Known as “bad cholesterol,” LDL carries cholesterol to peripheral tissues and contributes to plaque formation in arteries, increasing ASCVD risk. Lowering LDL levels is the main target of therapy.
  • High-Density Lipoprotein (HDL): “Good cholesterol” that helps transport cholesterol from peripheral tissues to the liver for excretion, providing some protection against atherosclerosis.
  • Triglycerides (TG): Elevated triglycerides increase the risk of pancreatitis and, when associated with high LDL or low HDL, contribute to cardiovascular risk.
Classification of Hyperlipidemia
Primary (Genetic) Hyperlipidemia
  • Familial Hypercholesterolemia (FH): An autosomal dominant disorder leading to high LDL levels due to mutations in LDL receptors or apolipoprotein B, increasing early ASCVD risk.
  • Familial Combined Hyperlipidemia: Characterized by elevated LDL and triglycerides; often presents in families with premature ASCVD.
  • Polygenic Hypercholesterolemia: Results from multiple gene interactions causing moderately elevated LDL levels.
Secondary (Acquired) Hyperlipidemia
  • Dietary and Lifestyle Factors: High intake of saturated and trans fats, obesity, and sedentary lifestyle can increase cholesterol and triglycerides.
  • Medical Conditions: Diabetes, hypothyroidism, chronic kidney disease, and liver disease are common contributors.
  • Medications: Drugs like corticosteroids, beta-blockers, and thiazide diuretics can elevate lipid levels.
Screening and Risk Assessment
  • Screening: Baseline lipid panel at age 20, repeated every 4–6 years in low-risk individuals; more frequent testing in those with ASCVD risk factors.
  • High-Risk Populations: Annual screening in patients with diabetes or a family history of early ASCVD; also consider screening in patients with chronic kidney disease or chronic inflammatory conditions.
  • ASCVD Risk Score: Uses age, sex, blood pressure, cholesterol levels, smoking status, and diabetes to estimate 10-year ASCVD risk, guiding treatment intensity.
Management of Hyperlipidemia
Lifestyle Modifications
  • Diet: A heart-healthy diet, such as the Mediterranean or DASH diet, is encouraged, emphasizing fruits, vegetables, whole grains, and reduced intake of saturated fats.
  • Exercise: Moderate-intensity aerobic exercise (150 minutes per week) improves lipid profiles, especially raising HDL and lowering triglycerides.
  • Weight Loss: Reducing weight improves LDL and triglycerides, particularly beneficial in overweight or obese patients.
  • Smoking Cessation: Increases HDL and reduces ASCVD risk.
Pharmacologic Therapy
Statins
  • Mechanism: Statins inhibit HMG-CoA reductase, reducing cholesterol synthesis and increasing LDL receptor expression in the liver, which lowers circulating LDL levels.
  • Indications: First-line for patients with elevated ASCVD risk, diabetes, or established ASCVD.
  • Intensity:
    • High-Intensity Statins: Atorvastatin (40–80 mg), rosuvastatin (20–40 mg) for patients requiring ≥50% LDL reduction.
    • Moderate-Intensity Statins: Lower doses of atorvastatin or rosuvastatin, or simvastatin for patients 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 small intestine, leading to reduced hepatic cholesterol stores and lower circulating LDL levels.
  • Use: Commonly added to statins in patients not achieving LDL goals or who cannot tolerate high-intensity statins.
PCSK9 Inhibitors
  • Mechanism: Monoclonal antibodies (e.g., alirocumab, evolocumab) that inhibit PCSK9, a protein that decreases LDL receptor availability, thus enhancing LDL clearance.
  • Use: Primarily for familial hypercholesterolemia or in high-risk ASCVD patients requiring additional LDL reduction beyond statin therapy.
Fibrates
  • Mechanism: Activate PPAR-α, increasing lipoprotein lipase activity and lowering triglycerides.
  • Use: Primarily for hypertriglyceridemia (triglycerides >500 mg/dL) to prevent pancreatitis.
  • Side Effects: Risk of myopathy, especially when combined with statins.
Key Points
  • LDL Reduction: Primary goal in hyperlipidemia management, with statins as first-line therapy.
  • Lifestyle Modifications: Essential for all patients, emphasizing diet, physical activity, and smoking cessation.
  • Statin Therapy: High- and moderate-intensity statins are chosen based on ASCVD risk, with liver function monitoring for side effects.
  • Adjunctive Therapy: Ezetimibe and PCSK9 inhibitors may be added if LDL targets are not met with statins alone.
  • Triglyceride Management: Fibrates are used for severe hypertriglyceridemia to reduce pancreatitis risk.
  • Risk-Based Treatment: The 10-year ASCVD risk score helps guide statin therapy and preventive measures in primary prevention.

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