Familial Hypercholesterolemia (FH)
Definition
Familial hypercholesterolemia (FH) is a common autosomal codominant genetic disorder characterised by severely elevated LDL-C from birth due to impaired LDL receptor function. It is the most prevalent monogenic cause of premature ASCVD. Heterozygous FH (HeFH) affects 1 in 250–300 individuals (~20 million in the US); homozygous FH (HoFH) is rare (~1:300,000). Up to 90% of affected individuals are undiagnosed.
Key Concepts
Epidemiology and Genetics
- HeFH affects 1 in 250–300 (comparable to type 1 diabetes prevalence) sources/lipid-aha-2026 (very high)
- Associated with 2–4× higher risk of premature ASCVD; affects up to 20% of adults with premature MI
- Most common causative genes: LDLR (LDL receptor, ~70–80%), APOB (apolipoprotein B), PCSK9 (gain-of-function), LDLRAP1 (autosomal recessive FH)
- Elevated Lp(a) is common in FH (ascertainment bias — high Lp(a) increases clinical recognition); FH itself does not cause elevated Lp(a)
Diagnosis and Screening
- FH phenotype: LDL-C ≥190 mg/dL (4.9 mmol/L) in adults (may be lower in children)
- Clinical diagnosis supported by Dutch Lipid Clinic Network (DLCN) or Simon Broome criteria (family history, physical signs such as tendon xanthomas/corneal arcus)
- Genetic panel testing for FH (LDLR, APOB, PCSK9, LDLRAP1 pathogenic/likely pathogenic variants): COR 2a in adults with LDL-C ≥190 mg/dL without secondary cause; COR 2a in children/adolescents with clinical FH presentation sources/lipid-aha-2026 (very high)
- AHA 2020 FH genetic testing criteria (Table 4): (sources/genetic-test-aha-2020 — high)
- Testing should be offered: (1) Children with persistent LDL-C ≥160 mg/dL or adults with LDL-C ≥190 mg/dL (no secondary cause) plus ≥1 first-degree relative with similar LDL-C or premature CAD, or when family history is unavailable; (2) Children with LDL-C ≥190 mg/dL or adults with LDL-C ≥250 mg/dL (no secondary cause), even without a positive family history
- Testing may be considered: (1) Children with LDL-C ≥160 mg/dL + parent LDL-C ≥190 mg/dL or family history of hypercholesterolemia + premature CAD; (2) Adults without pre-treatment LDL-C data but with personal premature CAD and family history of both hypercholesterolemia and premature CAD; (3) Adults with LDL-C ≥160 mg/dL + family history of hypercholesterolemia and premature CAD (personal or family history)
- Premature CAD thresholds: males ≤55 years, females ≤65 years
- Genetic confirmation identifies higher-risk individuals within the LDL-C ≥190 mg/dL group
- Lipid screening from age ≥2 y if family history of FH (cascade screening): identifies FH early for lifestyle and pharmacotherapy sources/lipid-aha-2026 (very high)
Risk Assessment Caveat
- PREVENT-ASCVD equations (and PCE) should NOT be used in HeFH (COR 3: Harm) — standard equations vastly underestimate lifetime ASCVD risk because they were not derived in FH populations sources/lipid-aha-2026 (very high)
- Lifetime cumulative LDL-C exposure (cholesterol-years concept) drives ASCVD risk; FH starts at birth
Treatment Goals — LDL-C Targets by Clinical Context
| HeFH Scenario | LDL-C Goal | Non-HDL-C Goal | Agents |
|---|---|---|---|
| No ASCVD, no additional risk factors, no coronary calcification | <100 mg/dL | <130 mg/dL | Maximally tolerated statin + ezetimibe/PCSK9 mAb/bempedoic acid (COR 1) |
| HeFH confirmed (clinical or genetic) OR additional risk factors OR coronary calcification, no ASCVD | <70 mg/dL | <100 mg/dL | Statin + ezetimibe/PCSK9 mAb/bempedoic acid (COR 1) |
| Clinical ASCVD | <55 mg/dL | <85 mg/dL | Statin + ezetimibe/PCSK9 mAb/bempedoic acid (COR 1) |
| LDL-C ≥100 mg/dL on max statin ± ezetimibe | Intensify to goals | — | Add inclisiran (COR 2a) |
HoFH (Homozygous FH) — Special Considerations
- Very severe hypercholesterolemia (LDL-C often 400–1000+ mg/dL); LDL receptor function near zero
- Standard statin therapy has limited effect (LDL receptor-dependent mechanism)
- PCSK9 mAbs: 21–31% LDL-C reduction only in HoFH (vs 45–64% in HeFH/general) due to near-absent LDLR
- Evinacumab (ANGPTL3 mAb, IV every 4 weeks): LDL receptor-independent mechanism; ~49% LDL-C reduction
- ACC/AHA 2026: COR 2b in HoFH with LDL-C ≥100 mg/dL on max statin + ezetimibe + PCSK9 mAb sources/lipid-aha-2026 (very high)
- ESC 2025: COR IIa B — should be considered in HoFH patients aged ≥5 years not at LDL-C goal despite maximum lipid-lowering therapy (ELIPSE HoFH trial + paediatric extension) sources/lipid-esc-2025 (very high)
- ESC recommendation is broader (IIa vs 2b) and explicitly includes paediatric patients ≥5 years; ACC/AHA 2026 recommendation is restricted to adults with LDL-C still ≥100 mg/dL on triple therapy
- Lomitapide (MTTP inhibitor): 40–50% LDL-C reduction; available through REMS program only; hepatotoxicity risk; daily fat-soluble vitamin supplements required
- Lipoprotein apheresis: available for refractory HoFH/HeFH with high Lp(a) ≥60 mg/dL + CAD/PAD
Statin Therapy in FH
- High-intensity statin is first-line; should be started early (children with FH from age 8–10 y in most guidelines)
- Paediatric statin RCTs show safety and LDL-C lowering in short/medium term; long-term follow-up of 1 RCT showed reduced premature ASCVD sources/lipid-aha-2026 (very high)
- Most HeFH patients will require statin + ezetimibe ± PCSK9 inhibitor to reach LDL-C <70 mg/dL
Cascade Screening
- After index case identified: screen all first- and second-degree relatives with fasting lipid profile (COR 2a)
- Can be performed from age ≥2 years for early adoption of lifestyle and timely pharmacotherapy
- "Reverse cascade screening" — screening relatives of FH probands identifies other affected family members and may be cost-effective
- Genetic testing improves cascade yield (vs lipid testing alone)
DTC-GT for FH — Emerging Role
- DTC genetic testing panels include the key FH genes: LDLR, APOB, PCSK9, LDLRAP1; these have ClinGen definitive/strong evidence and are ACMG SF v3.2 actionable secondary findings (sources/consumer-genetictest-aha-2025 — high)
- Gene-first FH screening is likely cost-effective in US adults ≤50 years — this represents one of the stronger clinical utility arguments for DTC-GT in cardiovascular medicine; however confirmatory CLIA-certified testing remains recommended before management changes (sources/consumer-genetictest-aha-2025 — high)
- DTC-GT for FH uses SNP-chip genotyping, which captures common known variants but not all novel LDLR mutations — a negative DTC result does NOT exclude FH in a patient with LDL-C ≥190 mg/dL (sources/consumer-genetictest-aha-2025 — high)
- GINA 2008 protects against genetic discrimination in health insurance but NOT life, disability, or long-term care insurance — relevant when FH identified through DTC-GT channels (sources/consumer-genetictest-aha-2025 — high)
- For comprehensive DTC-GT framework, see concepts/DTC-Genetic-Testing
Referral to Lipid Specialist
- All patients with diagnosed or suspected FH
- HeFH not achieving treatment targets on maximally tolerated statin + nonstatin therapy
- HeFH with statin-attributed side effects on ≥2 statins including at lowest dose
- HoFH (always)
Contradictions / Open Questions
- Debate on when to start statins in children with FH: ACC/AHA recommends age 8–10 in US guidelines; some European guidelines more aggressive (from age 6–8); concerns about very long-term statin safety in children vs magnitude of cumulative LDL-C benefit
- Whether genetic vs phenotypic FH diagnosis changes management beyond risk stratification: genetics identifies higher-risk subset within LDL-C ≥190 mg/dL group, but treatment goals are identical in most cases
- HoFH: emerging RNA-based therapies (siRNA targeting PCSK9, ANGPTL3, or APOB) may eventually replace current complex regimens — not yet guideline-incorporated
- Evinacumab COR discordance (HoFH): ESC 2025 COR IIa B (consider in HoFH ≥5 y not at LDL-C goal on max therapy) vs ACC/AHA 2026 COR 2b (weaker — HoFH with LDL-C ≥100 mg/dL on max statin + ezetimibe + PCSK9 mAb). ESC also extends indication to paediatric patients ≥5 years explicitly sources/lipid-esc-2025 sources/lipid-aha-2026 (both very high)
Connections
- Related to concepts/Dyslipidemia-Management — FH is the most severe LDL-C disorder requiring most intensive treatment
- Related to concepts/ASCVD-Risk-Assessment — PREVENT equations specifically contraindicated in FH
- Related to concepts/Lipoprotein-a — elevated Lp(a) common in FH; multiplicative risk if both present
- Related to concepts/DTC-Genetic-Testing — LDLR/APOB/PCSK9 in DTC panels; gene-first FH screening cost-effectiveness
- Related to sources/genetic-test-aha-2020 — FH genetic testing criteria Table 4; cascade screening recommendations