What is the approach to diagnose familial hypercholesterolemia in a patient with a family history of cardiovascular disease and elevated low-density lipoprotein (LDL) cholesterol levels?

Diagnosis of Familial Hypercholesterolemia

Diagnose familial hypercholesterolemia using a combined phenotypic and genetic approach: start with clinical criteria based on elevated LDL-cholesterol (≥190 mg/dL in adults, ≥135-190 mg/dL in children depending on parental history), family history of premature cardiovascular disease, and physical stigmata, then confirm with genetic testing targeting LDLR, APOB, PCSK9, and LDLRAP1 genes. 1

Initial Laboratory Assessment

Measure LDL-cholesterol as the cornerstone diagnostic test:

• Obtain a fasting lipid profile including total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglycerides 2
• Use age-specific, sex-specific, and country-specific LDL-cholesterol thresholds above the 95th percentile to screen for index cases 1, 2
• Non-fasting samples are acceptable for initial screening, though the Friedewald equation should be used 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 1, 2
• Measure LDL-cholesterol on at least two separate occasions (>2 weeks but <3 months apart) to confirm diagnosis 3

Critical pitfall: If the patient is already on lipid-lowering therapy, adjust LDL-cholesterol values upward to estimate pretreatment levels—statins typically lower LDL-C by 30-50%, ezetimibe by 15-20%, and PCSK9 inhibitors by 50-60% 1, 2

Apply Clinical Diagnostic Criteria in Adults

Use the Dutch Lipid Clinic Network or Simon Broome criteria as the most widely validated phenotypic diagnostic tools: 1, 4

The Dutch Lipid Clinic Network scoring system assigns points for:

• LDL-cholesterol levels (≥190 mg/dL = 1 point; ≥250 mg/dL = 3 points; ≥330 mg/dL = 8 points)
• Family history of premature coronary disease or elevated LDL-C in first-degree relatives
• Personal history of premature coronary disease
• Physical examination findings (tendon xanthomas, corneal arcus before age 45)

A score ≥8 indicates "definite FH," 6-7 indicates "probable FH," and 3-5 indicates "possible FH" 1

Alternative internationally accepted criteria include US MED-PED, Japanese, and Canadian criteria, though these are less commonly used 1

Clinical Diagnostic Criteria in Children and Adolescents

Diagnose FH in children using age-specific LDL-cholesterol thresholds combined with parental history: 3

• Highly probable FH: Untreated LDL-cholesterol >4.9 mmol/L (>190 mg/dL) on at least two occasions PLUS parental history of high LDL-cholesterol, premature ASCVD, or positive genetic test for FH 3
• Probable FH: LDL-cholesterol >4.9 mmol/L (>190 mg/dL) even without parental history, OR LDL-cholesterol >4.0 mmol/L (>160 mg/dL) with parental history of high LDL-cholesterol or premature ASCVD, OR LDL-cholesterol >3.5 mmol/L (>135 mg/dL) with a parent having a pathogenic FH variant 3

Screen children at risk of heterozygous FH at or after age 5 years, or as early as age 2 in those with strong family history of premature cardiovascular disease 1, 2

For suspected homozygous FH (physical stigmata or both parents with FH), test as early as possible—at newborn stage or by age 2 years 1, 2

Exclude Secondary Causes of Hypercholesterolemia

Before confirming FH diagnosis, exclude or correct for secondary causes of elevated LDL-cholesterol: 3

• Hypothyroidism (check TSH)
• Nephrotic syndrome (check urinalysis for proteinuria, serum albumin)
• Cholestatic liver disease (check liver function tests)
• Medications (thiazide diuretics, beta-blockers, corticosteroids, isotretinoin)
• Pregnancy
• Anorexia nervosa
• Cushing's syndrome

Genetic Testing for Definitive Diagnosis

Perform genetic testing in all individuals with definite or highly probable phenotypic FH to confirm diagnosis and enable cascade testing: 3, 1

• Use targeted next-generation sequencing of all exons and exon-intron boundaries of LDLR, APOB, PCSK9, and LDLRAP1 genes 1
• Include analysis of exons in APOB encoding the LDLR ligand-binding region 1
• Perform analysis for deletions and duplications in LDLR 1
• Testing must be conducted in a certified laboratory using accredited methods 3, 1

Genetic testing is the most accurate diagnostic method and should be prioritized whenever feasible, particularly when phenotypic features are less obvious (such as in children), for planning long-term care, and for cascade testing of family members 3, 4

Important caveat: If the phenotype strongly suggests FH but genetic testing does not detect a pathogenic variant, do not exclude FH—this may represent polygenic hypercholesterolemia or an unidentified pathogenic variant 3, 4

Physical Examination Findings

Look for physical stigmata that increase diagnostic specificity: 3

• Tendon xanthomas (especially Achilles tendons, extensor tendons of hands)—most specific finding
• Corneal arcus before age 45 years
• Xanthelasma (less specific)

Consider imaging-based detection of subclinical Achilles tendon xanthomas using ultrasound or MRI to increase diagnostic accuracy 3

Cascade Testing of Family Members

After identifying a pathogenic variant in the proband, offer cascade genetic testing for that specific variant to all first-degree relatives: 1, 4

• If first-degree relatives are unavailable or decline testing, sequentially extend to second-degree and third-degree relatives 1
• Continue until all at-risk family members have been offered testing 1
• For relatives of phenotypically diagnosed patients without identified mutations, use phenotypic screening with LDL-cholesterol measurement 1

Cascade testing is highly cost-effective and crucial for early identification of affected family members before atherosclerosis develops 4

Screening Strategies for Case Detection

Implement multiple screening approaches simultaneously to maximize case detection: 1, 2

• Selective screening: Target adults with premature ASCVD (men <55 years, women <60 years) and family history of premature ASCVD 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
• Universal screening: Consider age-specific and sex-specific LDL-cholesterol criteria for children and adolescents 2
• Implement alerts and interpretive comments on laboratory lipid profile reports to enable case detection 1

Specialist Referral

Refer all patients with suspected or confirmed FH to a specialist center with expertise in lipidology, genetics, and ASCVD prevention for further assessment and care planning 4

This is particularly important for:

• Homozygous FH (requires immediate specialist referral) 3
• Treatment-resistant cases
• Genetic counseling and cascade testing coordination
• Complex treatment decisions including PCSK9 inhibitors or lipoprotein apheresis 4