Evaluation of Familial Hyperlipoproteinemia
Genetic testing should be your primary diagnostic approach whenever possible, identifying pathogenic variants in LDLR, APOB, PCSK9, or LDLRAP1 genes, but if unavailable, use validated phenotypic criteria (Dutch Lipid Clinic Network, Simon Broome, or Canadian criteria) combined with fasting LDL-cholesterol measurements on two separate occasions after excluding secondary causes. 1
Diagnostic Algorithm
Step 1: Initial Laboratory Assessment
Measure fasting LDL-cholesterol on two separate occasions (>2 weeks but <3 months apart). This is essential because single measurements are unreliable 1. If the patient is already on lipid-lowering therapy, you must adjust the LDL-cholesterol value upward to estimate the untreated level, or ideally obtain a reliable pretreatment value 1.
Critical thresholds to recognize:
- Adults: LDL-C >5.0 mmol/L (>190 mg/dL) suggests possible FH
- Children/adolescents: LDL-C >4.9 mmol/L (>190 mg/dL) is highly probable FH with positive family history 1
- Homozygous FH: LDL-C >10 mmol/L (>400 mg/dL) with physical stigmata before age 10 1
Step 2: Exclude Secondary Causes
You must rule out secondary hyperlipidemias before diagnosing FH 1. Order:
- TSH (hypothyroidism)
- Glucose and HbA1c (diabetes)
- Creatinine, urea, urinalysis for protein (nephrotic syndrome, chronic kidney disease)
- Liver function tests (biliary cirrhosis, hepatic disease)
- Review medications (antiretroviral agents, immunosuppressants)
This step is non-negotiable—secondary causes are more common than primary FH and can mimic the phenotype 2.
Step 3: Apply Phenotypic Diagnostic Criteria (If Genetic Testing Unavailable)
For adults, use country-specific validated criteria 1:
- Dutch Lipid Clinic Network criteria (most widely used internationally)
- Simon Broome criteria
- Canadian criteria 3
- MED-PED, AHA, or Japanese criteria
These incorporate:
- LDL-cholesterol levels
- Family history of premature ASCVD (men <55 years, women <60 years)
- Personal history of premature ASCVD
- Physical examination findings (tendon xanthomas, arcus cornealis)
Important caveat: Adult phenotypic criteria (like Dutch Lipid Clinic Network) should NOT be used in children or for cascade testing 1. They will misclassify pediatric cases.
Step 4: Physical Examination for Stigmata
Look specifically for:
- Tendon xanthomas (Achilles tendons, extensor tendons of hands)—consider imaging-based detection of subclinical Achilles tendon xanthomas to increase diagnostic accuracy 1
- Arcus cornealis before age 45
- Xanthelasma palpebrarum
- Cutaneous xanthomas (in severe/homozygous cases)
Note that with early statin treatment, physical stigmata may be absent even in true FH, making diagnosis more challenging 1.
Step 5: Family History Assessment
Document:
- First-degree relatives with elevated LDL-cholesterol
- Premature ASCVD in family (men <55 years, women <60 years)
- Known FH diagnosis in family members
- Consanguinity (increases homozygous FH risk)
Step 6: Genetic Testing (Preferred Approach)
Genetic testing should be offered to all suspected FH patients, especially when cascade testing is planned 1. Test for pathogenic variants in:
- LDLR (most common, 70-80% of genetic FH)
- APOB (1-5% of cases)
- PCSK9 (up to 3% of cases)
- LDLRAP1 (rare, autosomal recessive)
Critical point: A negative genetic test does NOT exclude FH 1. The phenotype may result from:
- Polygenic hypercholesterolemia (multiple small-effect variants)
- Variants of uncertain significance
- Undetected variants (complex rearrangements, noncoding regions)
- Rare genes not routinely tested (STAP1, APOE, LIPA)
Conversely, genetic confirmation provides:
- Definitive diagnosis for cascade screening
- Improved risk stratification (genetic FH carries 22-fold increased ASCVD risk vs 6-fold for phenotypic hypercholesterolemia alone) 3
- Enhanced treatment adherence
- Access to specialized therapies
Step 7: Pediatric-Specific Considerations
Highly probable FH in children requires 1:
- Untreated LDL-C >4.9 mmol/L (>190 mg/dL) on two occasions, AND
- Parental history of high LDL-C, premature ASCVD, or positive genetic test
Probable FH in children includes lower thresholds with positive family history:
- LDL-C >4.0 mmol/L (>160 mg/dL) with parental high cholesterol/premature ASCVD
- LDL-C >3.5 mmol/L (>135 mg/dL) with parent having pathogenic FH variant
Children should be evaluated by a pediatric lipid specialist when possible 1.
Step 8: Homozygous FH Recognition
Suspect homozygous FH when 1:
- Untreated LDL-C >10 mmol/L (>400 mg/dL) on two occasions, PLUS
- Physical stigmata (xanthomas, arcus) before age 10, OR
- Both parents have LDL-C consistent with heterozygous FH
Immediately refer to a specialist center—homozygous FH requires aggressive intervention including lipoprotein apheresis, often started by age 5-8 years 4.
Step 9: Additional Testing
Consider measuring:
- Lipoprotein(a) [Lp(a)]—frequently elevated in FH and contributes independent cardiovascular risk 5
- Triglycerides—if >400 mg/dL (4.7 mmol/L), standard LDL-C calculations are unreliable; use lipoprotein electrophoresis 2
- ApoB levels—may help differentiate FH from polygenic hypercholesterolemia
Common Pitfalls to Avoid
Don't diagnose FH based on a single LDL-C measurement—always confirm with repeat testing 1
Don't forget to adjust for lipid-lowering medications—failure to account for statin/ezetimibe/PCSK9 inhibitor effects leads to underdiagnosis 1
Don't use adult criteria in children—this causes misclassification 1
Don't exclude FH based on negative genetic testing alone—30-50% of clinical FH cases have no identifiable monogenic variant 3
Don't overlook secondary causes—hypothyroidism and nephrotic syndrome are common mimics 1
Cascade Screening
Once FH is diagnosed in an index case, systematically screen all first-degree relatives using:
- Genetic testing (if proband has identified variant)—most cost-effective approach 3, 6
- Age-specific, sex-specific LDL-C thresholds (if genetic testing unavailable) 1
This identifies 50% of additional FH cases among relatives and is the most efficient detection strategy 3, 7.