What are the causes of xanthomas?

Causes of Xanthomas

Primary Lipid Disorders

Xanthomas result from lipid deposition in skin and subcutaneous tissue, most commonly caused by inherited or acquired dyslipidemias, with specific xanthoma types indicating distinct underlying metabolic abnormalities. 1, 2

Familial Hypercholesterolemia (FH)

• Tendinous and tuberous xanthomas are pathognomonic for familial hypercholesterolemia, an autosomal dominant disorder caused by pathogenic variants in LDLR, APOB, PCSK9, or LDLRAP1 genes that impair the LDL-receptor pathway 1, 3
• Homozygous FH presents with cutaneous or tendon xanthomas before age 10 years, along with untreated LDL-cholesterol >10 mmol/L (>400 mg/dL) 1
• Xanthelasma palpebrarum warrants FH evaluation even when standard lipid panels appear normal, as medication use or acute illness can artificially lower LDL-cholesterol concentrations 4
• Genetic testing is the gold standard for FH diagnosis when clinical signs like xanthomas are present, regardless of current lipid values 1, 4

Severe Hypertriglyceridemia

• Eruptive xanthomas indicate severe hypertriglyceridemia (typically >1000 mg/dL) and appear as sudden-onset, multiple red-to-yellow papules <5 mm on extensor surfaces and buttocks 1, 5, 6
• Associated with familial hypertriglyceridemia, diabetes mellitus, obesity, excessive alcohol intake, or rare genetic syndromes including LPL deficiency and apolipoprotein CII deficiency 1, 5, 6
• Eruptive xanthomas signal elevated risk for acute pancreatitis and type 2 diabetes mellitus, requiring urgent lipid-lowering intervention 6, 3

Type III Hyperlipoproteinemia (Dysbetalipoproteinemia)

• Palmar crease xanthomas (xanthoma striatum palmare) are pathognomonic for familial type III hyperlipoproteinemia, caused by homozygosity for apoE2 isoform with defective LDL receptor binding 1, 7, 2
• Tuboeruptive xanthomas also characteristic, typically appearing with near-equivalent cholesterol and triglyceride elevations 1
• Requires additional metabolic stressors (obesity, diabetes, hypothyroidism) for phenotypic expression 1, 7

Familial Combined Hyperlipidemia (FCHL)

• Multiple lipoprotein abnormalities due to hepatic overproduction of apoB-containing VLDL, IDL, and LDL 1
• Strongly represented in myocardial infarction survivors, particularly those <40 years old 1

Histiocytic Neoplasms

Erdheim-Chester Disease (ECD)

• Xanthelasma-like yellow eyelid plaques occur in 25-33% of ECD patients and may be the presenting sign of this potentially fatal histiocytic neoplasm 1, 4
• Clinically indistinguishable from lipid-related xanthelasma, requiring tissue diagnosis 4
• Consider ECD when xanthelasma occurs with bone pain, diabetes insipidus, exophthalmos, cardiovascular symptoms, or constitutional symptoms 1, 4
• Shave biopsy provides diagnostic tissue acquisition 4

Langerhans Cell Histiocytosis (LCH)

• Cutaneous manifestations include xanthomatous lesions appearing as red-to-purple nodules with yellowish hue 1
• May present with erythematous papular rash in groin, abdomen, chest, or back 1

Rosai-Dorfman Disease (RDD)

• Xanthomatous papules, nodules, and plaques occur in 50% of patients, typically around orbits or malar region 1

Secondary Metabolic Causes

Endocrine Disorders

• Hypothyroidism causes secondary dyslipidemia and xanthomas; thyroid function tests should be obtained in all xanthoma patients 4
• Type 2 diabetes mellitus causes hypertriglyceridemia with low HDL-cholesterol, leading to eruptive xanthomas through increased hepatic VLDL production and impaired chylomicron clearance 4, 6

Lipodystrophy Syndromes

• Both inherited and acquired lipodystrophy can cause xanthelasma despite normal standard lipid panels 4, 8
• Familial partial lipodystrophy (Dunnigan variety) causes severe hypertriglyceridemia and xanthomas 4, 8

Normolipemic Xanthomas

Paraproteinemia and Lymphoproliferative Disorders

• Diffuse plane xanthomas are frequently associated with paraproteinemia and lymphoproliferative disorders despite normal lipid profiles 2, 3

Critical Diagnostic Pitfalls

• Standard lipid panels can miss underlying disorders if patient is on cholesterol-lowering medications or has recently recovered from acute illness 4
• LDL-cholesterol concentrations must be adjusted for medication use when screening for FH 1, 4
• Verify lipid panel accuracy with direct LDL-cholesterol assay if triglycerides are elevated 4
• Screen for FH using Dutch Lipid Clinic Network or Simon Broome criteria, and pursue genetic testing if clinical suspicion exists 1, 4
• Evaluate for systemic diseases including thyroid function tests, diabetes screening, and histiocytic disorders if systemic symptoms present 4