What is the mechanism of hypercholesterolemia?

Mechanisms of Hypercholesterolemia

Hypercholesterolemia results from an imbalance in cholesterol homeostasis, primarily due to genetic mutations affecting LDL receptor function, overproduction of lipoproteins, or environmental factors that impair cholesterol metabolism. 1

Primary Mechanisms of Hypercholesterolemia

Genetic Causes

1. Familial Hypercholesterolemia (FH)

   • Autosomal dominant disorder affecting approximately 1 in 200-500 people 2
   • Primary genetic mutations:
     • LDL receptor gene (LDLR) - Most common cause (~700 different mutations identified) 2
     • Apolipoprotein B gene (APOB) - Affects ~3% of FH patients 2
     • Proprotein convertase subtilisin/kexin type 9 (PCSK9) gene - Causes increased degradation of LDL receptors 2, 3
   • Severity depends on zygosity:
     • Heterozygous FH: LDL-C levels typically 2-3 times normal 2
     • Homozygous FH: More severe elevation, earlier cardiovascular manifestations 4

2. Familial Combined Hyperlipidemia (FCHL)

   • Characterized by elevated apolipoprotein B and variable lipid phenotypes
   • Associated with variants in APOA1/C3/A4/A5 cluster and USF1 gene 2
   • Strongly represented in survivors of myocardial infarction, especially under age 40 2

3. Familial Type III Hyperlipoproteinemia (Dysbetalipoproteinemia)

   • Accumulation of cholesterol-rich VLDL
   • Associated with homozygosity for the rare apoE2 isoform 2
   • Requires additional factors (obesity, diabetes, hypothyroidism) for phenotypic expression 2

Physiological Mechanisms

1. Impaired LDL Receptor Function

   • Reduced number or function of LDL receptors leads to decreased hepatic clearance of LDL particles 5
   • Results in prolonged circulation of LDL and increased plasma LDL-C levels 1

2. Increased Hepatic Production of Lipoproteins

   • Overproduction of VLDL and subsequently LDL by the liver 2
   • Common in FCHL and metabolic syndrome 2

3. Defective Cholesterol Absorption/Excretion

   • Increased intestinal cholesterol absorption via NPC1L1 transporter 6
   • Decreased biliary cholesterol excretion

Secondary Causes of Hypercholesterolemia

1. Metabolic Disorders

   • Hypothyroidism - Reduces LDL receptor expression and function 2
   • Diabetes mellitus - Particularly poorly controlled insulinopenic diabetes 2
   • Cushing's syndrome 2

2. Medications

   • Corticosteroids 2
   • Certain antipsychotics 2
   • Estrogens (oral) 2
   • Retinoids 2
   • Protease inhibitors 2
   • Beta-blockers (particularly non-selective) 2

3. Other Medical Conditions

   • Chronic kidney disease 2
   • Cholestatic liver disease 2
   • Pregnancy (especially third trimester) 2

Dietary and Lifestyle Factors

1. Diet High in Saturated Fat and Cholesterol

   • Decreases LDL receptor activity 1
   • Increases hepatic cholesterol synthesis 1

2. Obesity

   • Associated with slight elevations in LDL-C 2
   • More strongly related to elevated triglycerides and lower HDL-C 2
   • Exacerbates genetic predispositions to hypercholesterolemia 2, 1

Pathophysiological Consequences

1. Atherosclerotic Plaque Formation

   • Elevated LDL-C promotes endothelial dysfunction
   • LDL particles become oxidized and taken up by macrophages
   • Formation of foam cells and fatty streaks in arterial walls

2. Cardiovascular Risk

   • In untreated FH: 50% of men develop coronary artery disease by age 50 and 30% of women by age 60 2
   • Homozygous FH: cardiovascular events can occur in the first two decades of life 4

Clinical Implications

The understanding of these mechanisms has led to targeted therapeutic approaches:

1. HMG-CoA Reductase Inhibitors (Statins)

   • Inhibit cholesterol synthesis in the liver 5
   • Increase LDL receptor expression, enhancing LDL clearance 5

2. Cholesterol Absorption Inhibitors (Ezetimibe)

   • Block intestinal cholesterol absorption by inhibiting NPC1L1 transporter 6
   • Reduce hepatic cholesterol stores and increase LDL receptor expression 6

3. PCSK9 Inhibitors

   • Prevent PCSK9-mediated degradation of LDL receptors 3
   • Increase LDL receptor recycling and function

Key Considerations in Clinical Practice

• Early identification of genetic hypercholesterolemia is crucial, as cardiovascular risk begins in childhood 2
• Cascade screening of family members is recommended when FH is diagnosed 2
• Treatment approach should target the specific mechanism causing hypercholesterolemia
• Combination therapy may be necessary to address multiple pathways of cholesterol metabolism

Understanding these mechanisms allows for more precise diagnosis and targeted treatment strategies to reduce cardiovascular morbidity and mortality associated with hypercholesterolemia.