Dyslipidemia

Dyslipidemia Definition

• Dyslipidemia is defined as high total cholesterol, low HDL cholesterol, high LDL cholesterol, or high triglycerides, or a combination.
• It plays a major role in atherosclerosis and plaque formation, leading to coronary heart disease (CHD) and other forms of atherosclerotic cardiovascular disease (ASCVD).
• CHD is a leading cause of death and disability in adults.

Pathophysiology

• Cholesterol is essential for cell walls and hormones.
• Cholesterol, triglycerides, and phospholipids travel in the blood as lipoproteins (Chylomicrons, VLDL, IDL, LDL, HDL).
• Total cholesterol measures all cholesterol in the major lipoproteins. LDL cholesterol can be estimated by the Friedewald equation (total cholesterol - (HDL + triglycerides/5) or (total cholesterol - (HDL + triglycerides/2.2)).
• This formula is inaccurate if triglycerides are over 400mg/dL (4.52mmol/L), if chylomicrons are present, or if the patient has familial dysbetalipoproteinemia, in which case direct measurement is necessary.
• Cholesterol biosynthesis is regulated by existing cholesterol levels; higher intake leads to less production in the liver.
• HMG-CoA reductase is the enzyme in cholesterol production (the target of statins).

Pathophysiology (continued)

• High total and LDL cholesterol, and low HDL cholesterol contribute to CHD development.
• CHD can lead to angina, myocardial infarction, stroke, peripheral arterial disease, and even death.
• Repeated injury to atherosclerotic plaque leads to a fibrous cap over the core of lipids, collagen, calcium, and inflammatory cells.
• Primary dyslipidemias result from genetic defects impacting cholesterol metabolism, like hypercholesterolemia, hypertriglyceridemia, combined hyperlipidemia, or disorders of HDL metabolism. These elevate cholesterol risk.
• Secondary dyslipidemia can occur from medications like progestins, thiazides, glucocorticoids, etc.

Clinical Presentation

• Dyslipidemia is usually asymptomatic.
• Corneal arcus and xanthomas may appear in patients with genetic disorders and high LDL cholesterol (> 250 mg/dL).
• Symptomatic patients might experience chest pain, palpitations, sweating, anxiety, shortness of breath, abdominal pain, speech/movement difficulties, or loss of consciousness.
• Physical signs may include cutaneous xanthomas, high blood pressure, and increased BMI/waist size.

Diagnosis

• Adults over 20 should undergo lipid panels (fasting required) every 5 years.
• Non-fasting lipid panels are suitable for risk assessment.
• If triglycerides are high in a non-fasting sample, a fasting lipid panel may be needed for accurate LDL cholesterol assessment.
• Children between 2 and 20 with family history of early CHD or high cholesterol should be screened.
• Elevated non-HDL cholesterol or LDL cholesterol above target levels (for those above 40 to 75 years without diabetes) require assessing ASCVD risk.
• Triglyceride levels > 150mg/dL and HDL < 40mg/dL (men) or < 50mg/dL (women) are also evaluated.

Diagnosis (further considerations)

• History and physical exam are key for evaluating cardiovascular risk factors.
• Patients should be assessed for secondary causes (e.g., pancreatitis, kidney/liver disease, peripheral vascular disease), symptoms (e.g., xanthomas, abdominal pain), and family history of lipid disorders.
• Normal/desirable values for cholesterol, triglycerides, HDL, and LDL are provided in a table, and should be consulted when assessing parameters.

Non-Pharmacological Therapy

• Begin therapeutic lifestyle changes (TLCs) at the first visit: dietary changes, weight loss, increased physical activity, cessation of smoking, and managing hypertension.
• Dietary modifications include reducing total fat, saturated fat, and cholesterol intake, increasing soluble fiber (oat, bran, pectin). Dietary supplementation with fish oil can decrease triglycerides and VLDL-C but may not effect LDL/total cholesterol. Plant sterols may also lower LDL (6-15%).

Pharmacologic Therapy

• HMG-CoA reductase inhibitors (statins): inhibit cholesterol biosynthesis, increasing LDL receptor expression and reducing LDL levels.
• Combinations with drugs like ezetimibe (inhibits cholesterol absorption) further reduce cholesterol levels.
• Other medications like fibrates (gemfibrozil, fenofibrate, clofibrate) lower VLDL, often with less effect on LDL.
• Bile acid resins (cholestyramine, colestipol, colesevelam) sequesters bile acids, and increase LDL receptor production and reducing LDL.
• Nicotinic acid (niacin) can reduce VLDL and increase HDL.
• Fish oil supplementation can decrease triglycerides, LDL, and VLDL, increasing HDL.
• Mipomersen (an apolipoprotein B-100 synthesis inhibitor) is indicated for homozygous familial hypercholesterolemia.
• Lomitapide (an MTP inhibitor) lowers LDL, total cholesterol, apolipoprotein B, and non-HDL cholesterol, useful in homozygous familial hypercholesterolemia.

Treatment Recommendations

• Total daily fat intake should be 10-25% of calories.
• Primary hypercholesterolemia (familial hypercholesterolemia, familial combined dyslipidemia) uses statins, niacin or ezetimibe.
• Combined hyperlipidemia can be addressed by statins, niacin, and/or gemfibrozil
• In cases of low HDL cholesterol, primary focus remains LDL reduction, along with lifestyle measures like weight loss, increased activity, and smoking cessation.
• Fibrates and niacin may be used if response to lifestyle alone is insufficient.