What is the recommended evaluation and treatment approach for a patient with suspected familial hypercholesterolemia?

Evaluation for Familial Hypercholesterolemia

Initial Diagnostic Approach

Diagnose familial hypercholesterolemia (FH) using a combined phenotypic and genetic approach: start with clinical criteria based on elevated LDL-cholesterol, family history, and physical stigmata, then confirm with genetic testing. 1

Measure LDL-Cholesterol Levels

• Obtain LDL-cholesterol measurements on at least two separate occasions, ideally after fasting, to establish baseline levels 2
• Non-fasting samples may be used for initial screening, but use the Friedewald equation cautiously if triglycerides are elevated 1, 2
• If triglycerides exceed 400 mg/dL (4.5 mmol/L), obtain a 12-hour fasting sample and measure LDL-cholesterol using a direct assay 1, 2
• Adjust LDL-cholesterol values for concurrent lipid-lowering medications (statins, ezetimibe, PCSK9 inhibitors) if pretreatment values are unavailable 1

Apply Clinical Diagnostic Criteria

In adults, use the Dutch Lipid Clinic Network or Simon Broome criteria as the most widely validated phenotypic diagnostic tools. 1, 2

Key diagnostic thresholds in adults:

• Untreated LDL-cholesterol ≥190 mg/dL (≥4.9 mmol/L) strongly suggests FH and warrants further evaluation 1, 2
• Combine elevated LDL-cholesterol with family history of premature cardiovascular disease (men <55 years, women <60 years) 3
• Look for physical stigmata: tendon xanthomas (especially Achilles tendon), xanthelasma palpebrarum, and corneal arcus in individuals under age 45 3, 4

In children and adolescents:

• 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
• Consider probable FH with untreated LDL-cholesterol >190 mg/dL (>4.9 mmol/L) on at least two occasions, even without parental history 3
• Consider probable FH with untreated LDL-cholesterol >160 mg/dL (>4.0 mmol/L) on at least two occasions, with parental history of high LDL-cholesterol or premature cardiovascular disease 3
• Consider probable FH with untreated LDL-cholesterol >135 mg/dL (>3.5 mmol/L) on at least two occasions, with a parent having a pathogenic gene variant for FH 3

Critical pitfall: Do not use phenotypic criteria developed for adult index cases (such as Dutch Lipid Clinic Network criteria) in children or adolescents, or when undertaking cascade testing 3

Exclude Secondary Causes

Before diagnosing FH, exclude secondary causes of elevated LDL-cholesterol including:

• Hypothyroidism
• Nephrotic syndrome
• Obstructive liver disease
• Medications (thiazides, cyclosporine, glucocorticoids)
• Pregnancy 3

Genetic Testing

Perform genetic testing in all individuals with definite or highly probable phenotypic FH based on clinical and/or family history. 3, 1, 2

Testing Methodology

• Use targeted next-generation sequencing of all exons and exon-intron boundaries of LDLR, APOB, PCSK9, and LDLRAP1 genes 3, 1
• Include analysis of exons in APOB encoding the LDLR ligand-binding region 3, 1
• Perform analysis for deletions and duplications in LDLR 3, 1
• Testing must be conducted in a certified laboratory using accredited methods 3, 1
• Classify and report variants according to ACMG, AMP, or ClinGen FH Variant Curation Expert Panel guidelines 3

Genetic Counseling

• Offer genetic counseling before and after genetic testing to all individuals suspected of having FH 3
• Genetic counseling should include obtaining a three-generation family medical history, risk and psychological assessment, family-based care, enabling of cascade testing, and anticipatory guidance 3
• Pre-conception counseling should be offered to all couples, especially if both partners are known or suspected to have FH 3

Important caveat: If a pathogenic or likely pathogenic variant is not detected, do not exclude FH, particularly if the clinical phenotype is strongly suggestive, because the condition may result from undetected genetic variants 3

Cascade Testing of Family Members

After identifying a pathogenic variant in the proband, offer cascade genetic testing for that specific variant to all first-degree relatives. 3, 1, 2

Cascade Testing Algorithm

• Initially offer testing to all first-degree relatives (parents, siblings, children) 3
• If first-degree relatives are unavailable or decline testing, sequentially extend to second-degree relatives (grandparents, aunts, uncles, nieces, nephews) 3
• Then extend to third-degree relatives if needed 3
• Continue until all at-risk family members have been offered testing 3, 1
• Offer "reverse" cascade testing (from child to parents) when a child is identified as a proband with FH 3

When Genetic Testing Is Not Available

• Use phenotypic cascade testing with age-specific, sex-specific, and country-specific LDL-cholesterol concentrations 3
• Measure LDL-cholesterol ideally after fasting and on two occasions 3
• Follow the same sequential approach: first-degree, then second-degree, then third-degree relatives 3

Critical pitfall: Clinical tools for diagnosing FH probands (such as Dutch Lipid Clinic Network criteria and Simon Broome criteria) are not valid for cascade testing of relatives 3

Special Populations

Homozygous FH

• 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
• Diagnose phenotypic homozygous FH with untreated LDL-cholesterol >400 mg/dL (>10 mmol/L) on two occasions in the presence of physical stigmata before age 10 years and/or untreated LDL-cholesterol consistent with heterozygous FH in both parents 3
• Exclude sitosterolaemia and cerebrotendinous xanthomatosis if genetic testing is not available and family history is unclear 3

Polygenic Hypercholesterolemia

• Polygenic scores for hypercholesterolemia may be useful but are not yet fully standardized 3
• Use with caution when assessing the differential diagnosis of FH in clinical practice 3

Specialist Referral

Refer all patients with confirmed or highly suspected familial hypercholesterolemia to or discuss with a lipid specialist for management planning. 2, 5

• National and regional centers with expertise in lipidology, genetics, and atherosclerotic cardiovascular disease prevention should accept referrals and provide guidance 5
• A multidisciplinary team with expertise in FH should partner with primary care and include representation from appropriate specialty disciplines, including mental health care 5