Hyperlipidemia
Hyperlipidemia
1. Introduction and Overview
Definition:
Hyperlipidemia refers to an abnormal increase in lipid levels in the blood, encompassing elevated levels of cholesterol, triglycerides, or both. It involves disruptions in lipid metabolism pathways, affecting lipoproteins such as low-density lipoprotein (LDL), high-density lipoprotein (HDL), and very low-density lipoprotein (VLDL).
Epidemiology:
• Global Prevalence: Hyperlipidemia affects approximately 39% of adults globally, contributing significantly to cardiovascular diseases (CVDs).
• Regional Statistics: Prevalence is higher in high-income countries due to sedentary lifestyles and diets rich in saturated fats, but rising rapidly in low- and middle-income countries.
• Age and Sex-Specific:
• More common in men during early adulthood.
• Postmenopausal women show increased prevalence due to hormonal changes.
Clinical Significance:
• Public Health Impact: Major modifiable risk factor for atherosclerotic cardiovascular diseases (ASCVD), including myocardial infarction and stroke.
• Morbidity and Mortality: Strongly associated with increased risk of coronary artery disease (CAD), accounting for significant global mortality.
2. Etiology
Primary Causes:
1. Genetic Factors:
• Familial Hypercholesterolemia (FH): Autosomal dominant disorder involving LDL receptor mutations.
• Familial Combined Hyperlipidemia (FCH): Polygenic disorder leading to mixed dyslipidemia.
• Apolipoprotein Defects: Mutations in APOB, APOE.
2. Congenital Causes:
• Lipoprotein lipase deficiency.
• Abetalipoproteinemia (rare).
Acquired Causes:
1. Diet-Related:
• High intake of trans fats, saturated fats, and cholesterol.
• Excessive alcohol leading to hypertriglyceridemia.
2. Toxin Exposure:
• Alcohol-induced hypertriglyceridemia.
Secondary Causes:
1. Endocrine Disorders:
• Hypothyroidism: Decreased LDL receptor activity.
• Diabetes Mellitus: Increased VLDL production and decreased HDL.
2. Drug-Induced:
• Corticosteroids, antiretroviral drugs, and thiazides.
3. Comorbidities:
• Chronic kidney disease, nephrotic syndrome.
Risk Factors:
1. Lifestyle-Related:
• Sedentary behavior, obesity, smoking.
2. Genetic Predisposition:
• Family history of premature ASCVD or dyslipidemia.
3. Environmental and Socioeconomic Factors:
• Urbanization, low physical activity.
3. Pathophysiology
Normal Metabolic Pathways:
• Cholesterol and triglycerides are transported in blood via lipoproteins (chylomicrons, VLDL, LDL, HDL).
• LDL delivers cholesterol to tissues; HDL removes excess cholesterol for excretion.
Disruption in Pathways:
• Key Enzymes/Proteins:
• Deficiency or dysfunction of LDL receptors in familial hypercholesterolemia.
• Impaired lipoprotein lipase activity in hypertriglyceridemia.
• Molecular Mechanisms:
• Accumulation of LDL in blood.
• Increased VLDL secretion in insulin resistance.
Systemic Effects:
• Accelerates atherosclerotic plaque formation.
• Leads to endothelial dysfunction, inflammation, and thrombosis.
Compensatory Mechanisms:
• Increased scavenger receptor activity on macrophages, promoting foam cell formation.
4. Clinical Features
Symptoms:
• Asymptomatic in early stages.
• Advanced stages:
• Angina or claudication due to atherosclerosis.
• Neurological symptoms in severe hypertriglyceridemia-induced pancreatitis.
Signs:
• Physical Examination Findings:
• Xanthomas (tendon xanthomas in FH).
• Xanthelasma (yellowish plaques near eyelids).
• Corneal arcus (lipid deposition in cornea).
Stages and Classification:
1. Fredrickson Classification:
• Type I: Hyperchylomicronemia.
• Type IIa: LDL hypercholesterolemia.
• Type IIb: Mixed dyslipidemia.
• Type III: Dysbetalipoproteinemia.
• Type IV: Hypertriglyceridemia.
• Type V: Mixed hyperlipidemia.
Differential Diagnosis:
• Conditions with Overlapping Features:
• Hypothyroidism.
• Lipodystrophies.
5. Diagnostic Approach
Clinical Evaluation:
• History:
• Family history of dyslipidemia, early CAD, or xanthomas.
• Dietary habits, alcohol consumption.
• Physical Examination:
• Look for xanthomas, hepatosplenomegaly.
Laboratory Investigations:
1. Biochemical Tests:
• Lipid profile: Total cholesterol, LDL, HDL, triglycerides.
• Non-HDL cholesterol and ApoB levels.
• Fasting glucose, HbA1c (for diabetes).
2. Genetic Testing:
• LDL receptor gene analysis in familial cases.
Imaging:
• Carotid intima-media thickness (CIMT).
• Coronary artery calcium (CAC) scoring.
Diagnostic Criteria:
• NCEP ATP III: LDL > 130 mg/dL, HDL < 40 mg/dL, or triglycerides > 150 mg/dL.
6. Management
Acute Management:
• Emergencies:
• Plasmapheresis in severe hypertriglyceridemia-induced pancreatitis.
• Insulin and glucose infusion for acute pancreatitis.
Chronic Management:
1. Dietary Modifications:
• Mediterranean diet, reduced saturated fat intake.
2. Medications:
• Statins: Atorvastatin, rosuvastatin (reduce LDL).
• Fibrates: Fenofibrate (reduce triglycerides).
• PCSK9 Inhibitors: Evolocumab, alirocumab.
• Omega-3 Fatty Acids: For triglyceride reduction.
3. Lifestyle Interventions:
• Regular physical activity, smoking cessation.
Monitoring and Follow-Up:
• Lipid profile every 4-12 weeks after therapy initiation, then yearly.
7. Prognosis
• Untreated hyperlipidemia leads to progressive ASCVD and premature death.
• Statin therapy reduces mortality by 25-30%.
8. Complications
1. Primary Disease-Related:
• CAD, ischemic stroke.
• Pancreatitis in severe hypertriglyceridemia.
2. Treatment-Related:
• Statin-induced myopathy, hepatotoxicity.
9. Prevention
• Primary Prevention:
• Early lipid screening in children of affected families.
• Lifestyle modifications.
• Secondary Prevention:
• Statin use in high-risk individuals.
• Tertiary Prevention:
• Regular follow-ups to prevent complications.
10. Patient Education
• Importance of adherence to therapy.
• Educate about dietary restrictions and exercise.
• Recognize symptoms of complications like chest pain.
11. Recent Research and Advances
• Development of RNA-based therapies (inclisiran).
• Trials on gene-editing for familial hypercholesterolemia.
12. Case Studies
1. Case Example:
• 45-year-old male with LDL of 190 mg/dL and tendon xanthomas. Diagnosed with FH, treated with high-dose statins and PCSK9 inhibitors.
13. References
• Harrison’s Principles of Internal Medicine, 21st Edition.
• NCEP ATP III Guidelines.
• WHO Global Health Observatory.