Hyperlipidemia for USMLE Step 1
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Hyperlipidemia for the USMLE Step 1 Exam
Overview of Hyperlipidemia
Hyperlipidemia is characterized by elevated blood lipid levels, particularly total cholesterol, low-density lipoprotein (LDL), and triglycerides. It is a major risk factor for atherosclerotic cardiovascular disease (ASCVD), including coronary artery disease, stroke, and peripheral artery disease. Hyperlipidemia may be primary (genetic) or secondary to lifestyle and other medical conditions.
Lipoprotein Types and Functions
- Low-Density Lipoprotein (LDL): Often termed “bad cholesterol,” LDL transports cholesterol to peripheral tissues, where it can deposit in arterial walls and contribute to atherosclerosis. Lowering LDL levels is the primary goal in hyperlipidemia management.
- High-Density Lipoprotein (HDL): Known as “good cholesterol,” HDL helps transport cholesterol from peripheral tissues back to the liver for excretion, providing a protective effect against atherosclerosis.
- Triglycerides (TG): High triglycerides are associated with an increased risk of pancreatitis and, in combination with high LDL or low HDL, may contribute to cardiovascular disease.
Primary (Genetic) Hyperlipidemia
- Familial Hypercholesterolemia (FH): An autosomal dominant disorder leading to high LDL levels due to defective LDL receptors or apolipoprotein B mutations.
- Familial Combined Hyperlipidemia: Elevation of both LDL and triglycerides, often seen in families with premature ASCVD.
- Polygenic Hypercholesterolemia: Multiple genetic factors contribute to moderately elevated LDL levels.
Secondary (Acquired) Hyperlipidemia
- Dietary and Lifestyle Factors: High intake of saturated and trans fats, obesity, and sedentary lifestyle increase cholesterol and triglycerides.
- Medical Conditions: Diabetes, hypothyroidism, chronic kidney disease, and liver disease are common causes.
- Medications: Certain drugs like corticosteroids, thiazide diuretics, and beta-blockers can elevate lipid levels.
Screening and Risk Assessment
- General Population: Baseline lipid screening is recommended for adults starting at age 20 and repeated every 4–6 years, with more frequent screening in those with risk factors.
- High-Risk Populations: Patients with diabetes, chronic kidney disease, or a strong family history of early ASCVD should be screened more frequently.
- ASCVD Risk Score: A 10-year risk calculator that includes age, gender, cholesterol levels, blood pressure, smoking status, and diabetes to guide treatment intensity.
Management of Hyperlipidemia
Lifestyle Modifications
- Diet: Emphasize a heart-healthy diet, such as the Mediterranean or DASH diet, with low saturated fats, high fiber, and plenty of fruits and vegetables.
- Exercise: Regular aerobic activity (150 minutes per week) can help improve HDL levels and lower triglycerides.
- Weight Management: Weight reduction improves overall lipid profiles, particularly lowering triglycerides.
- Smoking Cessation: Smoking is a risk factor for ASCVD and can reduce HDL levels, so cessation is encouraged.
Pharmacologic Therapy
Statins
- Mechanism: Statins inhibit HMG-CoA reductase, the enzyme responsible for cholesterol synthesis, thereby reducing LDL levels and upregulating LDL receptors in the liver.
- Indications: Statins are first-line treatment in patients with high ASCVD risk or established ASCVD.
- Intensity:
- High-Intensity Statins: Atorvastatin (40–80 mg) and rosuvastatin (20–40 mg) achieve ≥50% reduction in LDL.
- Moderate-Intensity Statins: Lower doses of atorvastatin or rosuvastatin or simvastatin, for patients with moderate ASCVD risk or statin intolerance.
- Side Effects: Myopathy, elevated liver enzymes; routine liver function tests are recommended initially.
Ezetimibe
- Mechanism: Inhibits intestinal absorption of cholesterol, reducing hepatic cholesterol stores and lowering LDL levels.
- Use: Often added to statins in patients not achieving LDL goals or those with statin intolerance.
PCSK9 Inhibitors
- Mechanism: Monoclonal antibodies (e.g., alirocumab, evolocumab) that inhibit PCSK9, a protein that reduces LDL receptor availability, thereby enhancing LDL clearance.
- Use: Primarily for familial hypercholesterolemia or high-risk ASCVD patients requiring further LDL reduction beyond statin therapy.
Fibrates
- Mechanism: Activate peroxisome proliferator-activated receptor alpha (PPAR-α), increasing lipoprotein lipase activity and reducing triglyceride levels.
- Use: Mainly for hypertriglyceridemia (TG >500 mg/dL) to reduce the risk of pancreatitis.
- Side Effects: Risk of myopathy, especially when combined with statins.
Niacin
- Mechanism: Decreases hepatic VLDL synthesis, lowering triglycerides and slightly raising HDL levels.
- Use: Limited due to side effects; may be used in patients intolerant to other therapies.
- Side Effects: Flushing, hyperglycemia, and hepatotoxicity limit its use.
Key Points
- LDL Reduction: The primary target in hyperlipidemia management, with statins as the first-line treatment.
- Lifestyle Modifications: Essential for all patients, including a healthy diet, regular exercise, and smoking cessation.
- Statins: High- and moderate-intensity statins are used based on ASCVD risk, with monitoring for myopathy and liver function.
- Adjunctive Therapy: Ezetimibe and PCSK9 inhibitors may be added if LDL goals are not met with statins alone.
- Triglyceride Management: Fibrates are indicated for severe hypertriglyceridemia (>500 mg/dL) to prevent pancreatitis.
- Risk Assessment: The 10-year ASCVD risk score guides treatment decisions for primary prevention.