Dyslipidemia

Cholesterol Synthesis and Function

• Cholesterol is synthesized by all cells, primarily located in cell membranes.
• Approximately half of total cholesterol synthesis occurs in the liver.
• Cholesterol synthesis is an energy-intensive process, strictly regulated.
• In membranes, cholesterol interacts with neighboring lipids, regulating membrane rigidity, fluidity, and permeability.
• Cholesterol is a precursor to steroid hormones, starting with pregnenolone.

HDL Cholesterol and Atherosclerosis

• High-density lipoprotein (HDL) cholesterol has a protective effect against atherosclerosis and coronary artery disease.
• Lower HDL levels correlate with increased risk of atherosclerosis and coronary artery disease.
• High triglycerides often accompany low HDL levels.
• HDL's anti-atherogenic action involves two main mechanisms:
  • Reverse cholesterol transport (returning cholesterol from peripheral tissues to the liver).
  • Transferring cholesterol to other lipoproteins (VLDL, IDL, or LDL).

Genetic Cholesterol Disorders

• Familial hypercholesterolemia is a prevalent genetic disorder increasing the risk of atherosclerosis.
• This condition involves impaired LDL uptake, leading to elevated LDL cholesterol levels in the blood.
• This disorder plays a significant role in atherogenesis.
• Niemann-Pick type C disease features cholesterol accumulation within lysosomes.

Coronary Artery Disease Risk Factors

• Non-modifiable risk factors include age, sex, and family history of coronary artery disease (CAD).
• Modifiable risk factors include dyslipidemia (high LDL, high triglycerides, low HDL), smoking, hypertension, diabetes, obesity, and dietary factors.
• Elevated LDL cholesterol is the causal risk factor for atherosclerosis; other factors primarily accelerate the process.

Dyslipidemia

• Dyslipidemia is a group of metabolic disorders characterized by elevated pro-atherogenic and pro-coagulant lipoproteins (LDL, lipoprotein(a), triglycerides) or reduced anti-atherogenic HDL.
• Dyslipoproteinemia involves abnormalities in lipoprotein synthesis and/or degradation.
• Dyslipidemia types include hypercholesterolemia, hypertriacylglycerolemia, and combined hypertriacylglycerolemia.
• Dyslipoproteinemia and atherosclerosis can lead to various health issues, including coronary artery disease, cerebrovascular disease, and peripheral artery disease.

High-Risk Cardiovascular Patients

• High-risk patients for cardiovascular disease include those with existing CAD, PAD, stroke, transient ischemic attack (TIA), diabetes, familial hyperlipoproteinemia, or premature atherosclerosis in family members.
• Target LDL cholesterol levels vary based on risk:
  • Very high risk patients: <1.4 mM/L
  • High-risk patients: <1.8 mM/L
  • Moderate risk patients: <2.6 mM/L
  • Low-risk patients: <3 mM/L (normal).
• Triglycerides should be <1.7 mM/l.

Dyslipidemia Management

• Non-pharmacological management involves lifestyle modifications focused on weight reduction and increased physical activity.
• Pharmacological treatments include:
  • Statins (HMG-CoA reductase inhibitors): Inhibit liver cholesterol production, lowering VLDL, IDL, and LDL levels. Side effects include liver toxicity and rhabdomyolysis.
  • Ezetimibe: Inhibits dietary cholesterol absorption. Side effects include diarrhea.
  • Fibrates: Stimulate lipoprotein lipase, enhancing VLDL breakdown. Side effects include gallstones and hepatitis.
  • Bile acid sequestrants: Bind bile acids in the gut, driving more cholesterol use, and lowering LDL with potential side effects including fat malabsorption.
  • Niacin (nicotinic acid): In higher doses, it lowers VLDL and raises HDL levels. Side effects include hyperpigmentation and hyperuricemia.
  • PCSK9 inhibitors: monoclonal antibodies targeting PCSK9 for treating very high risk. This is an expensive treatment.