What are the diagnostic criteria for familial hypercholesterolemia in a patient with a family history of high cholesterol and cardiovascular disease?

Diagnostic Criteria for Familial Hypercholesterolemia

Familial hypercholesterolemia should be diagnosed using genetic testing whenever possible to identify pathogenic variants in LDLR, APOB, PCSK9, or LDLRAP1 genes, but when genetic testing is unavailable, use established phenotypic criteria such as the Dutch Lipid Clinic Network or Simon Broome criteria in adults, with specific LDL-cholesterol thresholds and family history requirements in children. 1

Genetic Diagnosis (Gold Standard)

Genetic testing provides the most accurate diagnosis and should be performed in all suspected cases. 1, 2

• Test for pathogenic variants in genes that impair the LDL receptor pathway: LDLR (most common), APOB, PCSK9, and LDLRAP1 1
• Use targeted next-generation sequencing of all exons and exon-intron boundaries of these genes 2
• Include analysis for deletions and duplications in LDLR 2
• Testing must be conducted in a certified laboratory using accredited methods 2
• Critical caveat: If the phenotype strongly suggests FH but genetic testing is negative, do not exclude FH—approximately 60% of clinically diagnosed FH patients do not have an identifiable monogenic mutation and may have polygenic hypercholesterolemia 1, 3

Phenotypic Diagnosis in Adults

When genetic testing is not feasible, use validated clinical criteria: 1

Dutch Lipid Clinic Network Criteria (Most Widely Used)

• LDL-cholesterol levels (untreated or adjusted for medication): 1, 2

  • ≥8.5 mmol/L (≥330 mg/dL): 8 points
  • 6.5-8.4 mmol/L (250-329 mg/dL): 5 points
  • 5.0-6.4 mmol/L (190-249 mg/dL): 3 points
  • 4.0-4.9 mmol/L (155-189 mg/dL): 1 point

• Family history: 1

  • First-degree relative with premature coronary artery disease (men <55 years, women <60 years) OR first-degree relative with LDL-C >95th percentile: 1 point
  • First-degree relative with tendon xanthomas and/or corneal arcus: 2 points

• Personal history: 1

  • Premature coronary artery disease: 2 points
  • Premature cerebral or peripheral vascular disease: 1 point

• Physical examination: 1

  • Tendon xanthomas: 6 points
  • Corneal arcus before age 45: 4 points

Scoring interpretation: ≥8 points = definite FH; 6-7 points = probable FH; 3-5 points = possible FH 1

Simon Broome Criteria (Alternative)

• Definite FH: Total cholesterol >7.5 mmol/L (>290 mg/dL) or LDL-C >4.9 mmol/L (>190 mg/dL) PLUS tendon xanthomas in patient or first/second-degree relative 1, 2
• Probable FH: Same cholesterol levels PLUS family history of premature coronary disease or elevated cholesterol in first-degree relative 1

Simplified Screening Approach

• LDL-C ≥190 mg/dL (≥4.9 mmol/L) in adults without secondary causes strongly suggests FH and warrants phenotypic screening of first-degree relatives 4, 2
• This single cut-off shows excellent sensitivity (84.9%) for identifying FH cases and is more practical than complex scoring systems 5

Phenotypic Diagnosis in Children and Adolescents

Do not use adult phenotypic criteria (Dutch Lipid Clinic Network or Simon Broome) in children—they are not validated for this population. 1

Highly Probable FH in Children

• Untreated LDL-C >4.9 mmol/L (>190 mg/dL) recorded on at least two occasions (fasting, >2 weeks but <3 months apart) 1
• PLUS parental history of high LDL-C levels, premature ASCVD, or positive genetic test for FH 1

Probable FH in Children

After excluding secondary causes: 1

• LDL-C >4.9 mmol/L (>190 mg/dL) on two occasions, even without parental history 1
• OR LDL-C >4.0 mmol/L (>160 mg/dL) on two occasions with parental history of high LDL-C or premature ASCVD 1
• OR LDL-C >3.5 mmol/L (>135 mg/dL) on two occasions with a parent having a pathogenic gene variant for FH 1

Timing of Testing in Children

• Test children with suspected homozygous FH (physical stigmata or both parents with FH) as early as possible—at newborn stage or by age 2 years 2
• 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 2

Essential Requirements for All Phenotypic Diagnoses

Exclude Secondary Causes

Before making a phenotypic diagnosis, rule out: 1

• Hypothyroidism
• Nephrotic syndrome
• Cholestatic liver disease
• Medications (thiazides, cyclosporine, glucocorticoids)
• Pregnancy
• Anorexia nervosa

LDL-Cholesterol Measurement Standards

• Measure LDL-C on at least two occasions 1
• Ideally use fasting samples (12-hour fast), though non-fasting may be used for initial screening 2
• If triglycerides >4.5 mmol/L (>400 mg/dL), obtain fasting sample and use direct LDL-C assay 2
• Adjust for concurrent lipid-lowering medications if pretreatment values unavailable 1, 2

Homozygous FH Diagnosis

• Untreated LDL-C >13 mmol/L (>500 mg/dL) or treated LDL-C >8 mmol/L (>300 mg/dL) 1
• PLUS cutaneous or tendon xanthomas before age 10 years 1
• OR elevated LDL-C consistent with heterozygous FH in both parents 1
• All patients with homozygous FH must be referred to a specialist center immediately 1

Cascade Testing After Index Case Identification

Once a pathogenic variant is identified in the proband: 1, 2

• Offer cascade genetic testing for that specific variant to all first-degree relatives 1, 2
• If first-degree relatives unavailable or decline, extend sequentially to second-degree and third-degree relatives 2
• Continue until all at-risk family members have been offered testing 2
• Cascade testing is highly cost-effective and enables early intervention 4

Common Pitfalls to Avoid

• Do not rely on DLCNS in routine clinical practice without complete data—studies show significant discrepancies between retrospective and on-site scoring, with a median of 3 out of 8 criteria unavailable 5
• Do not use coronary artery calcium scoring to exclude FH—young patients may have significant atherosclerotic burden without calcification 4
• Do not dismiss FH diagnosis based on negative genetic testing alone—polygenic hypercholesterolemia can present identically and requires similar aggressive treatment 3
• Do not forget to adjust LDL-C for concurrent statin therapy—failure to do so leads to underdiagnosis 1, 2
• Do not use Friedewald equation when triglycerides are elevated—it underestimates LDL-C 2