How can I determine if I have familial hyperlipidemia?

How to Diagnose Familial Hyperlipidemia

Genetic testing for pathogenic variants in LDLR, APOB, PCSK9, or LDLRAP1 is the gold standard for diagnosing familial hypercholesterolemia (FH), and when genetic testing is not feasible, use validated phenotypic criteria (Dutch Lipid Clinic Network or Simon Broome) combined with elevated LDL-cholesterol levels measured on at least two occasions after excluding secondary causes. 1

Diagnostic Approach: A Stepwise Algorithm

Step 1: Measure LDL-Cholesterol Appropriately

• Obtain fasting lipid profile on two separate occasions (>2 weeks but <3 months apart) 1
• For adults with family history of premature ASCVD or suspected genetic hyperlipidemia, fasting samples are particularly important 2
• Document untreated LDL-C values; if already on therapy, adjust for cholesterol-lowering medication 1

Step 2: Apply Age-Specific LDL-C Thresholds

For Adults:

• Use validated phenotypic criteria (Dutch Lipid Clinic Network, Simon Broome, or country-specific criteria) 1
• These incorporate LDL-C levels, family history, physical findings, and personal history of premature ASCVD

For Children and Adolescents:

• Highly probable FH: Untreated LDL-C >190 mg/dL (>4.9 mmol/L) on two occasions plus parental history of high LDL-C, premature ASCVD, or positive genetic test 1
• Probable FH (after excluding secondary causes):
  • LDL-C >190 mg/dL even without parental history, OR
  • LDL-C >160 mg/dL with parental history of high LDL-C or premature ASCVD, OR
  • LDL-C >135 mg/dL with parent having pathogenic FH variant 1

Critical pitfall: Do NOT use adult phenotypic criteria (like Dutch Lipid Clinic Network) in children or for cascade testing—they are inappropriate for these populations 1

Step 3: Exclude Secondary Causes

Before diagnosing FH, rule out:

• Hypothyroidism
• Nephrotic syndrome
• Obstructive liver disease
• Medications that raise LDL-C
• Other metabolic conditions 1

Step 4: Look for Physical Stigmata

• Tendon xanthomas (Achilles tendon, extensor tendons of hands)
• Corneal arcus before age 45
• Xanthelasma
• Imaging-based detection of subclinical Achilles tendon xanthomas may increase diagnostic specificity 1

Step 5: Pursue Genetic Testing

When to order genetic testing:

• To confirm diagnosis when phenotype is less obvious (especially in children) 1
• Before initiating cascade screening of family members 1
• When planning long-term care 1
• Even if phenotype strongly suggests FH and genetic test is negative, do not exclude FH—some cases are polygenic or have unidentified variants 1

What to test: Look for pathogenic variants in LDLR, APOB, PCSK9, or LDLRAP1 1

Step 6: Consider Homozygous FH (Severe Form)

Suspect homozygous FH when:

• Untreated LDL-C >400 mg/dL (>10 mmol/L) on two occasions plus
• Physical stigmata (xanthomas, arcus) before age 10, OR
• Both parents have LDL-C consistent with heterozygous FH 1

Important: If genetic testing unavailable and parental history unclear, exclude sitosterolemia and cerebrotendinous xanthomatosis 1

Distinguishing FH from Familial Combined Hyperlipidemia (FCHL)

While the question asks about "familial hyperlipidemia" broadly, it's worth noting that FCHL is distinct from FH:

• FCHL shows variable lipid phenotypes (elevated cholesterol and/or triglycerides that fluctuate over time), elevated apoB, small dense LDL particles, and is polygenic 3, 4, 5
• FH shows consistently elevated LDL-C with identifiable monogenic mutations 1
• FCHL diagnosis is less consistent over time (only 74% stable over 5 years), whereas FH with genetic confirmation is definitive 3

Key Clinical Pearls

Genetic testing is underutilized but provides the most specific diagnosis, enables family cascade screening, and guides long-term management 1. The 2023 International Atherosclerosis Society guidelines give this a Class 1A recommendation—the highest level of evidence.

For cascade screening: Once an index case is confirmed (ideally genetically), screen first-degree relatives using age-specific, sex-specific LDL-C thresholds 1

Lipoprotein(a) and apoB: While not diagnostic for FH specifically, Lp(a) ≥50 mg/dL or apoB >130 mg/dL are risk-enhancing factors that support aggressive treatment 2