What causes xanthomas?

Causes of Xanthomas

Xanthomas are primarily caused by underlying lipid metabolism disorders, with hypertriglyceridemia being the most common cause of eruptive xanthomas. 1

Primary Genetic Disorders

Severe Hypertriglyceridemia

• Familial Chylomicronemia Syndrome
  • Autosomal recessive disorders with very high triglycerides (>1000 mg/dL)
  • Caused by mutations in:
    • Lipoprotein lipase (LPL) deficiency
    • Apolipoprotein CII deficiency (cofactor for LPL)
    • Apolipoprotein AV mutations
    • GPIHBP1 mutations 1
  • Presents with eruptive xanthomas, lipemia retinalis, hepatosplenomegaly, and risk of pancreatitis

Familial Hypercholesterolemia

• Associated with tendinous xanthomas, particularly of the Achilles tendon
• Characterized by elevated LDL cholesterol levels 2

Familial Combined Hyperlipidemia (FCHL)

• Multiple lipoprotein abnormalities with elevated apolipoprotein B levels
• Characterized by increased production of apoB-containing lipoproteins 1, 3

Type III Dysbetalipoproteinemia (Familial)

• Defective apolipoprotein E (usually apoE2/E2 phenotype)
• Characterized by palmar xanthomas and tuberous xanthomas
• Near-equivalent cholesterol and triglyceride values 1

Secondary Causes

Metabolic Disorders

• Diabetes Mellitus
  • Poorly controlled diabetes leads to hypertriglyceridemia
  • Can cause eruptive xanthomas even as the first presenting symptom 4
  • Increased hepatic VLDL production and defective clearance of chylomicrons 1

Obesity

• Increases triglyceride levels through:
  • Increased visceral fat exposing liver to higher FFA levels
  • Impaired clearance of triglyceride-rich lipoproteins 1

Lipodystrophy

• Both inherited and acquired forms (including HIV-associated)
• Characterized by loss of adipose tissue and hypertriglyceridemia
• Can lead to eruptive xanthomas and pancreatitis 1

Other Secondary Factors

• Excessive alcohol consumption
• Hypothyroidism
• Medications (estrogens, retinoids, corticosteroids, antiretrovirals)
• Pregnancy 1

Clinical Presentation by Xanthoma Type

Eruptive Xanthomas

• Sudden crops of 1-4 mm yellow-orange papules
• Typically on extensor surfaces and buttocks
• Associated with severe hypertriglyceridemia (>1000 mg/dL) 5, 6
• Often the first sign of undiagnosed diabetes or severe hypertriglyceridemia 4

Tendinous Xanthomas

• Associated with familial hypercholesterolemia
• Commonly affect Achilles tendon 2, 7

Tuberous Xanthomas

• Associated with familial hypercholesterolemia and dysbetalipoproteinemia 1, 7

Palmar Xanthomas

• Characteristic of familial dysbetalipoproteinemia 1, 7

Xanthelasma

• Yellowish plaques around eyelids
• May be associated with normal lipid levels in 20-30% of cases 2

Diagnostic Approach

1. Complete fasting lipid profile

   • Triglycerides, total cholesterol, LDL, HDL
   • Fasting lipid testing is essential for accurate diagnosis 1

2. Screen for secondary causes

   • Diabetes (HbA1c, fasting glucose)
   • Thyroid function tests
   • Medication review
   • Alcohol consumption assessment 1

3. Family history assessment

   • Evaluate for familial lipid disorders
   • History of premature cardiovascular disease 1

Management Considerations

• Primary goal: Treat underlying lipid disorder to reduce morbidity and mortality
• For severe hypertriglyceridemia (>500 mg/dL), priority is lowering triglycerides to reduce pancreatitis risk 1
• Lifestyle modifications are foundational for all patients with hypertriglyceridemia 1
• Referral to a registered dietitian is strongly recommended 1
• Statins are not recommended specifically for xanthomas in Alagille syndrome but may be appropriate for other hyperlipidemia causes 1

Clinical Pearls

• Eruptive xanthomas can be misdiagnosed as other skin conditions (e.g., molluscum contagiosum) 5
• The appearance of xanthomas should prompt immediate evaluation of lipid metabolism disorders
• Xanthomas often resolve with successful treatment of the underlying metabolic disorder
• The specific type of xanthoma can provide clues to the underlying lipid disorder 7