What causes hyperlipidemia?

Causes of Hyperlipidemia

Hyperlipidemia is caused by a combination of genetic factors, secondary medical conditions, lifestyle factors, and medications, with the most common causes being genetic predisposition and poor lifestyle habits.

Primary (Genetic) Causes

Familial Hypercholesterolemia (FH)

• Autosomal dominant inherited disorder affecting approximately 1 in 500 people of European descent 1
• Characterized by very high LDL cholesterol levels (usually 5-10 mmol/L or 200-400 mg/dL) 1
• Most commonly caused by mutations in:
  • LDL receptor gene (LDLR) - approximately 700 different mutations identified 1
  • Apolipoprotein B 100 gene (APOB) - affects approximately 3% of FH patients 1
  • Protein convertase subtilisin/kexin type 9 (PCSK9) gene 1

Familial Combined Hyperlipidemia (FCH)

• More common than FH, with a prevalence of approximately 1 in 100 1
• More polygenic/multifactorial than FH 1
• Associated with the upstream regulatory factor 1 (USF1) gene, a major controller of lipid and glucose homeostasis 1
• Characterized by elevated LDL cholesterol and/or triglycerides 1

Other Genetic Disorders

• Familial hypertriglyceridemia
• Familial HDL deficiency syndromes 1
• Multifactorial chylomicronemia syndrome - 40-60 times more prevalent than monogenic conditions 1

Secondary Causes

Medical Conditions

• Diabetes mellitus - poorly controlled diabetes significantly influences plasma lipid levels and can exacerbate hypertriglyceridemia 1
• Hypothyroidism - most common secondary cause after dietary factors 2
• Cushing's syndrome 1
• Liver diseases 1, 2
• Kidney diseases 1, 2
• Obesity - especially visceral adiposity which exposes the liver to higher levels of free fatty acids 1
• Lipodystrophy - both inherited and acquired forms 1
• HIV-associated dyslipidemic lipodystrophy 1

Medications

• Corticosteroids - can cause secondary dyslipidemia 1, 2
• Estrogens and oral contraceptives - can elevate triglycerides 3, 2
• Beta-blockers - raise triglycerides and lower HDL-C 2
• Thiazide diuretics - short-term usage raises cholesterol, triglycerides, and LDL-C 2
• Retinoids (isotretinoin and etretinate) 1, 2
• Cyclosporin - raises LDL-C and lipoprotein(a) 1, 2
• Antipsychotics 4

Lifestyle Factors

• Excessive alcohol consumption - major contributor to hypertriglyceridemia 1, 2
• Poor diet - especially diets high in saturated fats, refined carbohydrates, and added sugars 4, 2
• Sedentary lifestyle - lack of physical activity 4
• Obesity - particularly central obesity with BMI >30 kg/m² 1

Pathophysiological Mechanisms

Hyperlipidemia can result from:

1. Increased production of lipoproteins

   • Seen in obesity, insulin resistance, and excessive alcohol consumption

2. Impaired clearance of lipoproteins

   • Genetic defects in lipoprotein metabolism
   • Secondary conditions affecting clearance pathways

3. Combined mechanisms

   • Most cases involve both increased production and decreased clearance

Clinical Approach to Determining Cause

1. Rule out secondary causes first:

   • Check for diabetes, hypothyroidism, alcohol use, renal/liver disease
   • Review medication list for potential contributors
   • Assess BMI and body fat distribution

2. Evaluate for genetic causes:

   • Family history of premature cardiovascular disease
   • Very high lipid levels (total cholesterol >8 mmol/L or >320 mg/dL)
   • Physical signs (xanthomas, xanthelasmas)
   • Consider genetic testing in suspected familial disorders

3. Consider mixed etiology:

   • Most cases of hyperlipidemia result from genetic susceptibility combined with environmental triggers
   • Multiple genetic variants can increase risk for hyperlipidemia, while environmental factors can force expression of the dyslipidemic phenotype 5

Important Clinical Considerations

• Patients with familial hypercholesterolemia should be aggressively treated with statins at a young age due to high cardiovascular risk 1
• Secondary causes of hyperlipidemia can exacerbate underlying primary disorders, potentially leading to severe complications like pancreatitis 2
• Fasting lipid testing is preferred when diagnosing metabolic syndrome, identifying lipid disorders in those with family history, assessing treatment adherence, or identifying those at risk for hypertriglyceridemia-induced pancreatitis 1
• Cascade testing of family members is recommended for patients with suspected familial hypercholesterolemia 1

Remember that most cases of hyperlipidemia are polygenic and often coexist with non-genetic conditions, representing a complex interaction between genetic susceptibility and environmental factors 5.