What is the diagnosis and treatment approach for familial hypercholesterolemia?

Diagnosis of Familial Hypercholesterolemia

Familial hypercholesterolemia should be diagnosed using country-specific phenotypic criteria (such as Dutch Lipid Clinic Network or Simon Broome criteria) combined with genetic testing whenever feasible to confirm the diagnosis and enable cascade screening of family members. 1

Diagnostic Approach

Initial Screening and Detection

• Measure LDL-cholesterol using age-specific, sex-specific, and country-specific thresholds above the 95th percentile to screen for index cases 2
• Non-fasting samples may be used for initial screening, though the Friedewald equation should be used with caution 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 rather than calculated values 1

Clinical Diagnostic Criteria

In adults, apply either the Dutch Lipid Clinic Network or Simon Broome criteria, which are the most widely validated methods internationally 1, 3. These criteria combine:

• Elevated LDL-cholesterol levels (typically ≥190 mg/dL or ≥4.9 mmol/L) 2
• Family history of premature coronary artery disease (men <55 years, women <60 years) or elevated cholesterol in first-degree relatives 3
• Physical stigmata: tendon xanthomas (especially Achilles tendon), xanthelasma palpebrarum, premature corneal arcus (<45 years) 1, 4

Critical caveat: Adjust LDL-cholesterol values for concurrent lipid-lowering medications (statins, ezetimibe, PCSK9 inhibitors) when making the phenotypic diagnosis, particularly if no reliable pretreatment value is available 1. If the diagnosis remains uncertain, repeat LDL-cholesterol measurement after full recovery from any acute illness 1.

Genetic Testing

Genetic testing is the most accurate diagnostic method and should be performed in all suspected cases to identify pathogenic variants in LDLR, APOB, and PCSK9 genes 1, 3. This approach:

• Provides definitive diagnosis when a pathogenic variant is identified 1
• Enables cascade testing of family members, which is highly cost-effective 3
• Guides treatment decisions, particularly in patients with moderately elevated LDL-cholesterol without clear clinical indicators 1

After identifying a pathogenic variant in the index case, offer cascade genetic testing for that specific variant to all first-degree relatives, then extend to second-degree and third-degree relatives 1, 3.

Important limitation: A pathogenic variant may not be found in all clinically diagnosed FH cases due to polygenic hypercholesterolemia or currently unidentified variants 3. The absence of a genetic finding does not exclude FH if clinical criteria are met.

Pediatric Considerations

• For children with suspected homozygous FH (physical stigmata or both parents with FH), test as early as possible—at newborn stage or by age 2 years—using LDL-cholesterol measurement followed by genetic confirmation 1
• For children at risk of heterozygous FH, screen at age 5 years or older, or as early as age 2 years if there is a strong family history of premature cardiovascular disease 1

Additional Laboratory Tests

• Apolipoprotein B (apoB) measurement may be useful in patients with hypertriglyceridemia, as it estimates the number of atherogenic particles 2
• Lipoprotein(a) testing should be considered in those with family history of premature cardiovascular disease 2

Common Pitfalls to Avoid

• Failing to adjust for lipid-lowering medications leads to underdiagnosis, as treated LDL-cholesterol values may appear falsely normal 1
• Using the Friedewald equation when triglycerides exceed 400 mg/dL produces inaccurate LDL-cholesterol calculations; always use direct assay in this setting 1, 2
• Overlooking secondary causes of hypercholesterolemia, particularly hypothyroidism in patients with autoimmune conditions like Hashimoto's thyroiditis, which can elevate LDL-cholesterol independently of FH 5
• Dismissing the diagnosis in the absence of physical stigmata, as many FH patients, especially younger individuals, may not yet have developed xanthomas or corneal arcus 4

Treatment Implications

Once FH is diagnosed, all patients require aggressive cholesterol-lowering therapy regardless of current atherosclerosis status, as lifetime cardiovascular risk remains extremely high 3. Treatment should begin with high-intensity statins, adding ezetimibe and PCSK9 inhibitors as needed to achieve LDL-cholesterol goals 3, 6, 7. For homozygous FH or treatment-resistant heterozygous FH with established cardiovascular disease, consider LDL apheresis 3, 8.