What is the recommended workup and treatment for a patient with suspected familial hypercholesterolemia (high cholesterol due to genetic disorder)?

Familial Hypercholesterolemia Workup

Initial Diagnostic Approach

The workup for suspected familial hypercholesterolemia (FH) should begin with measurement of LDL-cholesterol on at least two separate occasions (ideally fasting), followed by formal diagnosis using phenotypic criteria and genetic testing when feasible. 1

Lipid Profile Assessment

• Measure LDL-cholesterol on two separate occasions (>2 weeks but <3 months apart) to establish baseline levels, accounting for any cholesterol-lowering medications currently in use 1
• Non-fasting samples may be used for screening, but the Friedewald equation should be used cautiously if triglycerides are elevated 1
• If triglycerides exceed 400 mg/dL (4.5 mmol/L), re-screen with a 12-hour fasting sample and measure LDL-cholesterol using a direct assay 1
• Adjust LDL-cholesterol values for concurrent use of statins, ezetimibe, or PCSK9 inhibitors if a reliable pretreatment value is unavailable 1
• If acute illness is present, repeat LDL-cholesterol measurement after full recovery, as acute illness can affect lipid levels 1

Phenotypic Diagnosis in Adults

Apply country-specific or internationally recognized phenotypic criteria (Dutch Lipid Clinic Network or Simon Broome criteria) that incorporate: 1

• LDL-cholesterol levels: Untreated LDL-C ≥190 mg/dL (≥4.9 mmol/L) strongly suggests FH 2
• Family history: Premature cardiovascular disease in first-degree relatives (men <55 years, women <60 years) or documented high LDL-cholesterol in relatives 1
• Physical examination findings: Tendon xanthomas (especially Achilles tendon), xanthelasma palpebrarum, premature corneal arcus (<45 years) 1, 3

Phenotypic Diagnosis in Children

For children aged 5 years and older at risk of heterozygous FH, consider diagnosis highly probable if: 1, 4

• Untreated LDL-cholesterol >190 mg/dL (>4.9 mmol/L) on two occasions AND parental history of high LDL-cholesterol, premature ASCVD, or positive genetic test for FH 1, 4
• For children with suspected homozygous FH (both parents with FH or physical stigmata present), test as early as possible—at newborn stage or by 2 years of age 1

Exclude Secondary Causes

Before confirming FH diagnosis, systematically exclude secondary causes of hypercholesterolemia: 1, 4

• Hypothyroidism (check TSH, free T4)
• Nephrotic syndrome or chronic kidney disease (urinalysis, creatinine, albumin)
• Obstructive liver disease (liver function tests)
• Medications (thiazides, beta-blockers, oral estrogens, corticosteroids, protease inhibitors)
• Poorly controlled diabetes mellitus
• Excessive alcohol intake

Genetic Testing

Genetic testing should be offered to all individuals with strong clinical suspicion of FH (definite or highly probable phenotypic diagnosis) and is the most accurate diagnostic method. 1

Testing Methodology

• Use targeted next-generation sequencing in an accredited laboratory covering all exons and exon-intron boundaries of: 1
  • LDLR (LDL receptor gene—most common)
  • APOB (apolipoprotein B gene)
  • PCSK9 (proprotein convertase subtilisin/kexin type 9 gene)
  • LDLRAP1 (LDL receptor adaptor protein 1 gene)
• Include analysis for deletions and duplications in LDLR 1
• Variants should be classified according to ACMG/AMP or ClinGen FH Variant Curation Expert Panel guidelines 1

Important Caveats About Genetic Testing

• A negative genetic test does not exclude FH if the clinical phenotype is strongly suggestive, as undetected genetic variants or polygenic hypercholesterolemia may be responsible 1, 2
• Genetic testing is currently underutilized due to cost, limited availability, and inadequate genetic counseling services 2
• Polygenic scores are not yet fully standardized and should be used with caution 1

Genetic Counseling

Pre-test and post-test genetic counseling should be offered to all patients, including: 1

• Three-generation family medical history
• Risk and psychological assessment
• Discussion of cascade testing implications
• Pre-conception counseling if both partners have or are suspected to have FH 1

Cascade Testing of Family Members

After identifying an index case, systematically offer testing to all first-degree relatives, then extend to second- and third-degree relatives. 1

Cascade Testing Approach

• If a pathogenic variant is identified: Offer cascade genetic testing for the specific familial variant to all first-degree relatives 1
• If genetic testing is unavailable: Use phenotypic cascade testing with age-specific, sex-specific LDL-cholesterol thresholds (note: Dutch Lipid Clinic Network and Simon Broome criteria are NOT valid for cascade testing of relatives) 1
• For children of affected parents: Offer cascade genetic testing at the earliest opportunity, ideally at age 5 years or older (or as early as 2 years with strong family history of premature ASCVD) 1
• Consider "reverse" cascade testing from child to parents when a child is identified as the index case 1

Physical Examination Findings

Systematically examine for physical stigmata that increase diagnostic certainty: 1, 3

• Tendon xanthomas: Especially Achilles tendon thickening, extensor tendons of hands (highly specific for FH) 3
• Xanthelasma palpebrarum: Yellowish plaques on eyelids (less specific but suggestive) 1, 3
• Corneal arcus: Premature arcus cornealis before age 45 years 1, 3
• Planar xanthomas: Particularly in homozygous FH 1
• Imaging-based detection of subclinical Achilles tendon xanthomas may increase diagnostic specificity 1

Specialist Referral

All patients with confirmed or highly suspected FH should be referred to or discussed with a lipid specialist for management planning, especially: 2

• All homozygous FH cases (require specialized center care) 1
• Heterozygous FH cases not achieving treatment goals on maximum tolerated therapy 2
• Cases requiring genetic confirmation and cascade testing coordination 2

Common Pitfalls to Avoid

• Do not rely solely on LDL-cholesterol levels without considering family history and physical findings—phenotypic criteria provide better diagnostic accuracy 1
• Do not use proband diagnostic criteria (Dutch Lipid Clinic Network, Simon Broome) for cascade testing of relatives—use age-specific LDL-cholesterol thresholds instead 1
• Do not exclude FH based on negative genetic testing alone if clinical phenotype is strongly suggestive 1
• Do not forget to adjust LDL-cholesterol values for concurrent lipid-lowering medications when making phenotypic diagnosis 1
• Do not overlook secondary causes of hypercholesterolemia before confirming FH diagnosis 1, 4