What is the diagnostic approach for a patient with a suspected family history of familial hypercholesterolemia?

How to Test for Familial Hypercholesterolemia

Begin with measuring LDL-cholesterol using age-specific and sex-specific thresholds above the 95th percentile, then apply validated clinical diagnostic criteria (Dutch Lipid Clinic Network or Simon Broome), and confirm with genetic testing of LDLR, APOB, PCSK9, and LDLRAP1 genes in all cases meeting clinical criteria. 1

Initial Laboratory Testing

LDL-Cholesterol Measurement

• Measure LDL-cholesterol as the cornerstone diagnostic test, using age-specific, sex-specific, and country-specific thresholds above the 95th percentile for the population 1, 2
• Non-fasting samples are acceptable for initial screening, though use the Friedewald equation cautiously due to hypertriglyceridemia interference 1, 2
• If triglycerides exceed 4.5 mmol/L (>400 mg/dL), obtain a 12-hour fasting sample and measure LDL-cholesterol using a direct assay to avoid calculation errors 1, 2
• In adults, LDL-cholesterol ≥190 mg/dL (≥4.9 mmol/L) without secondary causes strongly suggests FH and should trigger formal evaluation 1, 3, 2

Medication Adjustment

• Adjust LDL-cholesterol values upward if the patient is on lipid-lowering medications (statins, ezetimibe, PCSK9 inhibitors) when pretreatment values are unavailable 1, 2
• This adjustment is critical for accurate phenotypic diagnosis in patients already receiving treatment 2

Clinical Diagnostic Criteria

Adults

• Apply the Dutch Lipid Clinic Network or Simon Broome criteria as the most widely validated phenotypic diagnostic tools 1, 3
• These criteria combine elevated LDL-cholesterol with family history of premature cardiovascular disease (men <55 years, women <60 years) and physical stigmata 1, 3
• Alternative internationally accepted criteria include US MED-PED, Japanese, and Canadian criteria, though these are less commonly used 1

Physical Examination Findings

• Look for tendon xanthomas (particularly on Achilles tendons and extensor tendons of hands), which are highly specific for FH 1, 4
• Examine for corneal arcus in individuals under age 45 years, which raises suspicion for FH 1, 4
• Check for xanthelasma (yellowish deposits around eyelids), though this is less specific than tendon xanthomas 4
• The presence of these physical signs should immediately prompt lipid testing and clinical scoring 4

Genetic Testing

When to Perform Genetic Testing

• Genetic testing should be performed in all individuals with definite or highly probable phenotypic FH based on clinical criteria and/or family history 1, 3
• Genetic testing is the most accurate diagnostic method and enables cascade testing of family members 3, 2

What Genes to Test

• Use targeted next-generation sequencing of all exons and exon-intron boundaries of LDLR, APOB, PCSK9, and LDLRAP1 genes 1
• Include specific analysis of exons in APOB encoding the LDLR ligand-binding region 1
• Perform analysis for deletions and duplications in LDLR, as these structural variants may be missed by standard sequencing 1
• Testing must be conducted in a certified laboratory using accredited methods 1

Genetic Counseling

• Pre-test and post-test genetic counseling should be offered to all patients and at-risk relatives as an integral component of testing 3

Age-Specific Diagnostic Approaches

Children with Suspected Homozygous FH

• Test as early as possible—at newborn stage or by age 2 years—if the child has physical stigmata or both parents have FH 1, 2

Children at Risk for Heterozygous FH

• Screen at or after age 5 years using age-specific and sex-specific LDL-cholesterol thresholds 1, 2
• Consider screening as early as age 2 in children with strong family history of premature cardiovascular disease 1, 2
• In children, diagnosis relies on elevated LDL-cholesterol plus positive family history of premature coronary disease or high LDL-cholesterol in at least one parent 3

Cascade Testing of Family Members

After Identifying a Pathogenic Variant

• Offer cascade genetic testing for the specific variant to all first-degree relatives of the proband 1, 3, 2
• If first-degree relatives are unavailable or decline testing, sequentially extend to second-degree and third-degree relatives 1, 3
• Continue until all at-risk family members have been offered testing 1
• This approach is highly cost-effective for identifying additional affected individuals 3

Screening Strategies

Multiple Approaches

• Use selective, opportunistic, and universal screening strategies simultaneously to maximize case detection 1, 2

Selective Screening

• Target adults with premature cardiovascular disease (coronary artery disease) and family history of premature cardiovascular disease and/or hypercholesterolemia 1, 2

Opportunistic Screening

• Use LDL-cholesterol >4.9 mmol/L (≥190 mg/dL) as a trigger for FH evaluation in community settings 1, 2
• Implement alerts and interpretive comments on laboratory lipid profile reports to enable case detection 1
• Screen patients presenting to dermatologists (before isotretinoin), rheumatologists/orthopedic surgeons (Achilles xanthomas), ophthalmologists (corneal arcus, xanthelasma), and pharmacists (point-of-care testing) 1

Additional Laboratory Tests

Supplementary Measurements

• Apolipoprotein B (apoB) measurement may be useful in patients with hypertriglyceridemia, as it provides an estimate of the number of atherogenic lipoprotein particles 2
• Lipoprotein(a) [Lp(a)] testing should be considered in those with family history of premature ASCVD or personal history of ASCVD not explained by major risk factors 2

Common Pitfalls and How to Avoid Them

Calculation Errors

• The Friedewald equation becomes unreliable when triglycerides exceed 400 mg/dL; always use direct LDL-cholesterol measurement in this scenario 1, 2

Acute Illness

• Repeat testing after recovery from acute illness if the diagnosis of FH is in doubt, as lipid levels can be transiently altered 2

Genetic Testing Limitations

• A pathogenic variant may not be found in all clinically diagnosed FH cases due to polygenic hypercholesterolemia or unidentified pathogenic variants 3
• Polygenic scores for hypercholesterolemia are not yet fully standardized and should be used with caution 3

Underutilization

• Genetic testing remains underutilized due to costs, inadequate clinical skills in genomic medicine, genetic privacy concerns, and limited availability of genetic counseling services 3

Specialist Referral

• All patients with suspected FH should be referred to or discussed with a relevant specialist (lipidology, genetics, ASCVD prevention) to plan further management 3
• National and regional centers with expertise should be established to accept referrals, as the complexity of FH management requires specialized knowledge beyond routine primary care 3