What is the recommended approach to diagnose familial hypercholesterolemia?

How to Test for Familial Hypercholesterolemia

The diagnosis of FH should be made using a combination of LDL-cholesterol measurement (the cornerstone test), clinical diagnostic criteria (Dutch Lipid Clinic Network or Simon Broome), and genetic testing to confirm the diagnosis and enable cascade screening of family members. 1, 2

Initial Laboratory Testing

LDL-Cholesterol Measurement

• Obtain a fasting lipid profile including total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglycerides as the initial screening test. 2
• Use age-specific, sex-specific, and country-specific LDL-cholesterol concentrations above the 95th percentile to screen for index cases. 2
• Measure LDL-cholesterol on at least two separate occasions to establish baseline levels and confirm the diagnosis. 3
• Non-fasting samples may be acceptable for screening, though the Friedewald equation should be used cautiously due to interference from hypertriglyceridemia. 2

Adjustments for Accurate Measurement

• If triglycerides exceed 4.5 mmol/L (400 mg/dL), use direct LDL-cholesterol assay rather than calculated values, as the Friedewald formula becomes unreliable. 1, 2
• Adjust LDL-cholesterol concentrations for concurrent use of statins, ezetimibe, PCSK9 inhibitors, and other lipid-lowering therapies when phenotypically screening for FH. 1, 2
• Repeat LDL-cholesterol measurement after full recovery from acute illness if the diagnosis is in doubt, as acute conditions can temporarily alter lipid levels. 1, 2

Clinical Diagnostic Criteria

Adults

• Apply the Dutch Lipid Clinic Network or Simon Broome criteria, which incorporate LDL-cholesterol levels, family history of premature ASCVD, personal history of premature ASCVD, and physical examination findings. 1, 4
• Look for physical stigmata including tendon xanthomas (particularly Achilles tendon), xanthelasma palpebrarum, premature arcus cornealis, and planar xanthomas. 1, 3
• Document family history focusing on premature cardiovascular disease (men <55 years, women <60 years), elevated cholesterol levels in relatives, and known FH diagnoses in family members. 3

Children

• Screen children at risk of heterozygous FH using LDL-cholesterol at or after age 5, or as early as age 2 in those with strong family history of premature ASCVD. 2
• Consider FH highly probable in children with untreated LDL-cholesterol >4.9 mmol/L (190 mg/dL) with parental history of high LDL-cholesterol, premature ASCVD, or positive genetic test for FH. 3
• For suspected homozygous FH, test as early as possible (at newborn stage or by 2 years of age), diagnosing if untreated LDL-cholesterol >10 mmol/L with physical stigmata before age 10 and/or both parents with FH. 2, 3

Genetic Testing

When to Perform Genetic Testing

• Genetic testing is the most accurate way to diagnose FH and should be performed in all suspected cases to confirm diagnosis, enable cascade testing of family members, and guide treatment decisions. 1, 4
• Offer genetic testing to potential index cases who are most likely to have a pathogenic variant based on clinical criteria, or to patients where a variant could influence treatment recommendations. 1
• Test for pathogenic variants in the three most common causative genes: LDLR, APOB, and PCSK9. 4, 3

Cascade Testing Strategy

• After identifying a pathogenic variant in the proband, offer cascade genetic testing for the specific variant to all first-degree relatives, followed by second-degree and third-degree relatives. 2, 4
• Known familial variant testing should be initially offered to all first-degree relatives of a proband with an identified mutation. 2
• Provide pre-test and post-test genetic counseling to all patients and at-risk relatives as an integral component of testing. 4

Important Limitations

• A negative genetic test does not exclude FH if clinical features are strongly suggestive, as pathogenic variants may not be found in all clinically diagnosed cases due to polygenic hypercholesterolemia or unidentified variants. 4, 3
• Genetic testing is currently underutilized due to costs, inadequate clinical skills in genomic medicine, genetic privacy concerns, and limited availability of genetic counseling services. 4

Additional Laboratory Tests

Supplementary Measurements

• Measure apolipoprotein B (apoB) in patients with hypertriglyceridemia, as it provides an estimate of the number of atherogenic lipoprotein particles and remains accurate in non-fasting states. 2
• Test lipoprotein(a) [Lp(a)] in those with a family history of premature ASCVD or personal history of ASCVD not explained by major risk factors. 2

Exclusion of Secondary Causes

• Exclude secondary causes of hypercholesterolemia including hypothyroidism, renal failure, and other metabolic disorders before confirming FH diagnosis. 3
• Rule out sitosterolaemia and cerebrotendinous xanthomatosis in children, which can present similarly to homozygous FH. 3

Screening Strategies for Case Detection

Multiple Approaches

• Use multiple screening strategies (selective, opportunistic, and/or universal) to detect index cases with FH. 2
• Target selective screening to adults with premature ASCVD and a family history of premature ASCVD and/or hypercholesterolemia. 2
• Implement opportunistic screening using LDL-cholesterol ≥190 mg/dL (≥4.9 mmol/L) to detect cases in the community. 2
• Consider universal screening using age-specific and sex-specific criteria for LDL-cholesterol in children and adolescents. 2

Digital and Alert Systems

• Use digital technologies to search electronic health records to enable systematic detection of index cases, particularly in community care settings. 1
• Implement alerts and interpretive comments on laboratory reports of standard lipid profiles to enable case detection, emphasizing the need for formal diagnosis and referral. 1

Common Pitfalls to Avoid

• Do not rely solely on calculated LDL-cholesterol when triglycerides are elevated above 4.5 mmol/L (400 mg/dL); always use direct measurement in these cases. 1, 2
• Do not diagnose FH based on a single lipid measurement, especially during acute illness or without accounting for lipid-lowering medications. 1, 2
• Do not assume a negative genetic test rules out FH when clinical criteria are strongly suggestive. 4, 3
• Do not overlook the importance of cascade testing once an index case is identified, as this is highly cost-effective for detecting additional affected family members. 4