How to diagnose and treat familial hypercholesterolemia?

How to Diagnose Familial Hypercholesterolemia

Diagnose FH using a combined phenotypic and genetic approach: start with clinical criteria (Dutch Lipid Clinic Network or Simon Broome) based on elevated LDL-cholesterol, family history, and physical stigmata, then confirm with genetic testing when feasible. 1

Initial Phenotypic Diagnosis

LDL-Cholesterol Measurement

• Measure LDL-cholesterol using age-specific, sex-specific, and country-specific thresholds above the 95th percentile for the population to screen for index cases 1
• Non-fasting samples may be used for initial screening, though the Friedewald equation should be used with caution due to hypertriglyceridemia interference 1
• 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
• Adjust LDL-cholesterol values for concurrent lipid-lowering medications (statins, ezetimibe, PCSK9 inhibitors) if pretreatment values are unavailable 1
• Repeat measurement after full recovery from acute illness if diagnosis is uncertain, as acute conditions can alter LDL-cholesterol levels 1

Clinical Diagnostic Criteria

• Apply the Dutch Lipid Clinic Network or Simon Broome criteria in adults as the most widely validated phenotypic diagnostic tools 1, 2
• Alternative internationally accepted criteria include US MED-PED, Japanese, and Canadian criteria 1
• Clinical diagnosis requires elevated LDL-cholesterol combined with family history of premature cardiovascular disease and/or physical stigmata 2, 3

Physical Examination Findings

• Look for tendon xanthomas (most specific for FH, particularly on Achilles tendons and extensor tendons of hands) 1, 4
• Examine for xanthelasma palpebrarum (yellowish plaques on eyelids) 1, 4
• Check for premature corneal arcus (arcus cornealis before age 45 years) 1, 4
• Assess for cutaneous xanthomas and planar xanthomas 1, 4

Family History Assessment

• Obtain a three-generation family medical history focusing on premature cardiovascular disease (men <55 years, women <60 years) 1, 5
• Document elevated cholesterol levels in family members 2, 5
• Record any known FH diagnoses in relatives 5

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 and/or family history 1
• Consider genetic testing in individuals with probable phenotypic FH 1
• May consider genetic testing in possible FH cases when information is incomplete and results would affect clinical management 1

Testing Methodology

• 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 1

Interpretation of Genetic Results

• Classify and report variants according to ACMG, AMP, or ClinGen FH Variant Curation Expert Panel guidelines 1
• Do not exclude FH if a pathogenic variant is not detected, particularly when clinical phenotype is strongly suggestive, as undetected genetic variants may be responsible 1, 2
• Polygenic scores for hypercholesterolemia are not yet fully standardized and should be used with caution 1, 2

Genetic Counseling

• Offer pre-test and post-test genetic counseling to all individuals suspected of having FH 1
• Counseling should include three-generation family history, risk assessment, family-based care planning, and psychological assessment 1
• Provide pre-conception counseling to all couples, especially if both partners have or are suspected to have FH 1

Age-Specific Diagnostic Approaches

Children and Adolescents

• 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 1
• 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
• Use age-specific and sex-specific LDL-cholesterol thresholds for diagnosis 1, 5
• Consider FH highly probable in children with untreated LDL-cholesterol >4.9 mmol/L with parental history of high LDL-cholesterol or premature cardiovascular disease 5

Homozygous FH Diagnosis

• Diagnose homozygous FH if untreated LDL-cholesterol >10 mmol/L with physical stigmata before age 10 and/or both parents with FH 5
• Genetic confirmation should follow clinical diagnosis 1, 5
• Rule out sitosterolemia and cerebrotendinous xanthomatosis, which can present similarly 5

Cascade Testing of Family Members

Genetic Cascade Testing

• After identifying a pathogenic variant in the proband, offer cascade genetic testing for that specific variant to all first-degree relatives 1
• 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
• Offer cascade genetic testing to at-risk children at the earliest opportunity if a parent has an identified FH-causing variant 1

Phenotypic Cascade Testing

• When genetic testing is not feasible, use age-specific, sex-specific, and country-specific LDL-cholesterol thresholds for phenotypic diagnosis in relatives 1
• Clinical tools for diagnosing probands (Dutch Lipid Clinic Network, Simon Broome) are not valid for cascade testing of relatives 1
• Follow the same sequential approach: first-degree, then second-degree, then third-degree relatives 1

Screening Strategies

Multiple Approaches

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

Selective Screening

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

Opportunistic Screening

• Use LDL-cholesterol >4.9 mmol/L (≥190 mg/dL) as a trigger for FH evaluation in community settings 1, 6
• 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

Universal Screening

• Consider universal screening in children and adolescents using age-specific and sex-specific LDL-cholesterol criteria, followed by reverse cascade testing to parents 1
• Genome-based population screening of adults may be considered but requires careful implementation 1

Common Pitfalls and Caveats

• Clinical characterization alone cannot distinguish between genetic FH and polygenic/environmental hypercholesterolemia—there is considerable overlap in LDL-cholesterol values between groups with and without LDLR mutations 7
• Hypertriglyceridemia significantly interferes with Friedewald equation accuracy; always use direct LDL-cholesterol measurement when triglycerides exceed 4.5 mmol/L 1, 6
• Statin therapy complicates phenotypic diagnosis; adjust LDL-cholesterol values upward (typically multiply by 1.43 for moderate-intensity statins, 1.67 for high-intensity statins) 1
• Physical stigmata (xanthomas, corneal arcus) are highly specific but insensitive—their absence does not exclude FH 4
• Genetic testing may not identify a pathogenic variant in all clinically diagnosed FH cases due to polygenic hypercholesterolemia or unidentified variants 1, 2
• Digital health record searches should be implemented to systematically detect index cases in community care settings 1