What causes Xanthelasma in a middle-aged to elderly woman with a normal lipid panel?

Causes of Xanthelasma with Normal Lipid Panel

Even when lipid panels appear normal, xanthelasma can occur due to familial hypercholesterolemia (FH), histiocytic disorders like Erdheim-Chester Disease, lipodystrophy syndromes, or subtle lipoprotein abnormalities not captured by standard testing.

Familial Hypercholesterolemia (FH) - Most Important Consideration

You must actively screen for FH even with apparently "normal" lipids, as xanthelasma is a clinical indicator that should prompt genetic and advanced lipid testing. 1

• Standard lipid panels can miss FH if the patient is on cholesterol-lowering medications (statins, ezetimibe, PCSK9 inhibitors) or has recently recovered from acute illness, both of which artificially lower LDL-cholesterol 1
• LDL-cholesterol concentrations should be adjusted for medication use when phenotypically screening for FH; if diagnosis is uncertain, repeat testing after full recovery from illness 1
• Xanthelasma palpebrarum is specifically listed as a clinical sign warranting FH evaluation by ophthalmologists and optometrists, even before lipid abnormalities are confirmed 1
• The Friedewald equation can underestimate LDL-cholesterol in patients with hypertriglyceridemia >400 mg/dL, potentially masking FH 1
• Genetic testing is the gold standard for FH diagnosis and should be pursued when clinical signs like xanthelasma are present, regardless of current lipid values 1

Erdheim-Chester Disease (ECD) - Critical Rare Diagnosis

Xanthelasma occurs in 25-33% of ECD patients and may be the presenting sign of this potentially fatal histiocytic neoplasm. 1, 2

• ECD presents with xanthelasma-like yellow eyelid plaques that are clinically indistinguishable from lipid-related xanthelasma 1
• This is a multisystem disease affecting bone (bilateral symmetric long bone involvement), cardiovascular system ("coated aorta"), retroperitoneum ("hairy kidney"), and CNS 1
• Shave biopsy of xanthelasma is the least invasive diagnostic procedure when ECD is suspected 2
• Consider ECD when xanthelasma occurs with: bone pain, diabetes insipidus, exophthalmos, cardiovascular symptoms, or constitutional symptoms 1
• Baseline evaluation should include CT chest/abdomen/pelvis, brain MRI, cardiac MRI, and FDG-PET if ECD is suspected 1

Rosai-Dorfman Disease (RDD) - Another Histiocytic Disorder

RDD can present with xanthomatous papules around the orbits in up to 50% of patients with cutaneous involvement. 1

• Presents as red-to-brown macules, papules, or xanthomatous lesions around eyelids and malar region 1
• Unlike ECD, RDD more commonly presents with painless lymphadenopathy and is less frequently multisystem 1
• Histologic confirmation is required as clinical features overlap with other conditions 1

Lipodystrophy Syndromes

Both inherited and acquired lipodystrophy can cause xanthelasma despite normal or near-normal standard lipid panels. 1, 3

HIV-Associated Lipodystrophy

• Occurs as complication of antiretroviral therapy, particularly protease inhibitors 3
• Characterized by fat redistribution with increased triglyceride content in VLDL, LDL, and HDL 1, 3
• Risk factors include increased HIV duration, high viral load, and low CD4 counts before HAART 3
• Always obtain HIV history and antiretroviral medication exposure 3

Inherited Lipodystrophy

• Familial partial lipodystrophy (Dunnigan variety) causes severe hypertriglyceridemia and can present with xanthomas 1
• Congenital generalized lipodystrophy presents with severe hypertriglyceridemia and eruptive xanthomas 1
• Mechanisms include decreased fat storage capacity and delayed clearance of triglyceride-rich lipoproteins 1

Subtle Lipoprotein Abnormalities Not Detected by Standard Testing

Standard lipid panels may miss important abnormalities that cause xanthelasma. 4, 5, 6

• Elevated VLDL-cholesterol and LDL-cholesterol with low HDL-cholesterol can occur even when total cholesterol appears "normal" 5, 6
• Low HDL-cholesterol/LDL-cholesterol ratios are significantly associated with xanthelasma, even in normolipidemic patients 6
• 50% of xanthelasma patients have dyslipidemia, but this means 50% have apparently normal lipids by standard criteria 4
• Consider measuring: apolipoprotein B, lipoprotein(a), direct LDL-cholesterol assay, and advanced lipoprotein particle analysis 1

Other Endocrine and Metabolic Causes

Diabetes Mellitus

• Type 2 diabetes causes hypertriglyceridemia with low HDL-cholesterol and small dense LDL particles 1
• Poor glycemic control increases hepatic VLDL production and impairs chylomicron clearance 1
• Screen for diabetes in all xanthelasma patients 1

Hypothyroidism

• Can cause secondary dyslipidemia and xanthelasma 1
• Obtain thyroid function tests in all xanthelasma patients 2

Clinical Algorithm for Xanthelasma with "Normal" Lipids

1. Verify lipid panel accuracy:

   • Obtain fasting lipid panel if not already done 1
   • Calculate non-HDL cholesterol and HDL/LDL ratio 5, 6
   • If on lipid-lowering medications, adjust LDL-cholesterol upward or obtain pre-treatment values 1
   • Consider direct LDL-cholesterol assay if triglycerides >400 mg/dL 1

2. Screen for FH:

   • Apply Dutch Lipid Clinic Network or Simon Broome criteria 1
   • Examine for other stigmata: tendon xanthomas, premature arcus cornealis 1
   • Obtain detailed family history of premature cardiovascular disease 1
   • Pursue genetic testing if clinical suspicion exists 1

3. Evaluate for systemic diseases:

   • Obtain thyroid function tests 2
   • Screen for diabetes (HbA1c, fasting glucose) 1
   • HIV testing with detailed antiretroviral history 3
   • Consider histiocytic disorders if systemic symptoms present 1

4. Consider biopsy if:

   • Atypical presentation or distribution 2
   • Systemic symptoms suggesting ECD or RDD 1, 2
   • No identifiable lipid or metabolic abnormality 2

Critical Pitfalls to Avoid

• Never dismiss xanthelasma as purely cosmetic without thorough metabolic and genetic evaluation 1, 4
• Don't rely solely on total cholesterol and triglycerides; examine HDL, LDL, and their ratios 5, 6
• Remember that lipid-lowering medications mask FH; always adjust for treatment effect 1
• Consider life-threatening diagnoses like ECD, especially with multisystem symptoms 1
• Standard lipid panels miss 50% of metabolic abnormalities in xanthelasma patients 4, 5