07 — Familial Hypercholesterolemia Pathway
Table of Contents
1.0 Overview
Familial hypercholesterolemia (FH) is an autosomal dominant disorder of LDL metabolism resulting in markedly elevated LDL-C from birth and premature atherosclerotic cardiovascular disease. FH is underdiagnosed — an estimated 1 in 250 individuals has heterozygous FH (HeFH), yet fewer than 10% are identified [1, 2].
This pathway provides a structured approach to FH suspicion, diagnosis, treatment, and cascade screening at The Sandusky Dyslipidemia Model clinic. See the FH Pathway Flowchart for a visual representation.
2.0 When to Suspect FH
FH should be suspected in any patient presenting with:
| Trigger | Details |
|---|---|
| 2.1 LDL-C ≥ 190 mg/dL in an adult | Without secondary causes (see 09 — Secondary Dyslipidemia) |
| 2.2 LDL-C ≥ 160 mg/dL with family history | First-degree relative with premature ASCVD or known FH |
| 2.3 Tendon xanthomas | Pathognomonic for FH (Achilles, extensor tendons of hands, patellar) |
| 2.4 Corneal arcus < 45 years | Suggestive of FH |
| 2.5 Family history of very high LDL-C | Multiple family members with LDL-C > 190 mg/dL |
| 2.6 Premature ASCVD with elevated LDL-C | Especially if onset < 55 years (male) or < 65 years (female) |
3.0 Clinical Diagnosis — Dutch Lipid Clinic Network (DLCN) Score
The DLCN score is the preferred clinical diagnostic tool for FH in this clinic [3]:
3.1 DLCN Criteria and Scoring
| Category | Criterion | Points |
|---|---|---|
| Family History | First-degree relative with known premature CVD (men < 55, women < 60) | 1 |
| First-degree relative with known LDL-C > 95th percentile | 1 | |
| First-degree relative with tendon xanthomas and/or corneal arcus | 2 | |
| Children < 18 years with LDL-C > 95th percentile | 2 | |
| Clinical History | Patient with premature CAD (men < 55, women < 60) | 2 |
| Patient with premature cerebral or peripheral vascular disease (men < 55, women < 60) | 1 | |
| Physical Exam | Tendon xanthomas | 6 |
| Corneal arcus < 45 years | 4 | |
| LDL-C (untreated) | ≥ 330 mg/dL (≥ 8.5 mmol/L) | 8 |
| 250–329 mg/dL (6.5–8.4 mmol/L) | 5 | |
| 190–249 mg/dL (5.0–6.4 mmol/L) | 3 | |
| 155–189 mg/dL (4.0–4.9 mmol/L) | 1 | |
| Genetic Testing | Functional mutation in LDLR, APOB, or PCSK9 | 8 |
Use the highest-scoring criterion in each category (scores within categories are not additive). The total score is the sum of the highest-scoring criterion from each of the five categories.
3.2 DLCN Score Interpretation
| Total Score | Diagnosis | Action |
|---|---|---|
| ≥ 8 | Definite FH | Confirm with genetic testing; initiate aggressive treatment; cascade screening |
| 6–7 | Probable FH | Strongly consider genetic testing; initiate treatment; cascade screening |
| 3–5 | Possible FH | Further evaluation; consider genetic testing; initiate treatment if risk warrants |
| < 3 | Unlikely FH | Standard dyslipidemia management |
4.0 Genetic Testing
4.1 Indications for Genetic Testing
| Indication | Notes |
|---|---|
| DLCN score ≥ 6 (probable or definite FH) | Confirms diagnosis; identifies specific mutation for cascade screening |
| DLCN score 3–5 with strong clinical suspicion | Provider discretion |
| LDL-C ≥ 250 mg/dL without secondary cause | Even without family history, genetic testing is informative |
| Family member with known FH mutation | Targeted cascade testing (see Section 5.0) |
4.2 Genes Tested
| Gene | Protein | Mechanism | Frequency |
|---|---|---|---|
| LDLR | LDL receptor | Loss-of-function → reduced LDL clearance | ~85–90% of FH mutations [1] |
| APOB | Apolipoprotein B-100 | Defective receptor binding → impaired LDL clearance | ~5–10% [1] |
| PCSK9 | PCSK9 | Gain-of-function → increased LDL receptor degradation | ~1–3% [1] |
| LDLRAP1 | LDL receptor adaptor protein 1 | Autosomal recessive FH (rare) | < 1% |
4.3 Testing Process
- Obtain informed consent — discuss implications for patient and family members
- Order FH genetic panel (e.g., Invitae FH Panel, GeneDx Cardiovascular Panel)
- Results typically available in 2–4 weeks
- If mutation identified: document in medical record; initiate cascade screening
- If no mutation identified (mutation-negative): does not exclude FH; clinical diagnosis with DLCN ≥ 6 is sufficient. Consider polygenic hypercholesterolemia.
5.0 Cascade Screening
Cascade screening identifies affected family members who may benefit from early treatment. It is the most cost-effective strategy for FH detection [4].
5.1 Who to Screen
| Relationship | Action |
|---|---|
| First-degree relatives (parents, siblings, children ≥ 18 years) | All should be offered screening |
| Second-degree relatives | Screen if first-degree relative is affected or unavailable |
| Children < 18 years | Refer to pediatric lipid specialist for evaluation |
5.2 Screening Method
| Scenario | Method |
|---|---|
| Known mutation in index patient | Targeted genetic testing for the specific mutation (most efficient) |
| No mutation identified in index patient | Lipid panel in family members; apply DLCN criteria |
5.3 Counseling for Index Patient
- Explain autosomal dominant inheritance (50% chance each first-degree relative is affected)
- Provide a brief written explanation for the patient to share with family members (see Patient Materials — FAQ)
- Offer to facilitate referrals for family members
- Children < 18 years should be referred to pediatric specialists
6.0 Treatment of Heterozygous FH (HeFH)
6.1 Treatment Goals
| Parameter | Target |
|---|---|
| LDL-C | < 70 mg/dL (< 55 mg/dL if ASCVD or additional high-risk features) |
| ApoB | < 80 mg/dL (< 65 mg/dL if ASCVD) |
| Percent LDL-C reduction | ≥ 50% from untreated baseline |
6.2 Treatment Approach
HeFH patients typically require multi-agent therapy to achieve targets:
| Step | Agent | Expected LDL-C Reduction |
|---|---|---|
| 1 | High-intensity statin (atorvastatin 80 mg or rosuvastatin 40 mg) | 50–55% |
| 2 | Add ezetimibe 10 mg | Additional 15–20% |
| 3 | Add PCSK9 inhibitor or inclisiran | Additional 50–60% |
| 4 | Consider adding bempedoic acid | Additional 15–25% |
6.3 Monitoring
- Lipid panel + ApoB every 4–8 weeks during titration
- Once at goal: every 3–6 months initially, then annually
- Screen for ASCVD with clinical assessment at each visit
7.0 Severe FH and Homozygous FH (HoFH)
7.1 Suspicion Criteria for HoFH
| Finding | Details |
|---|---|
| Untreated LDL-C > 400 mg/dL | Highly suggestive |
| LDL-C > 300 mg/dL despite high-intensity statin | Suggestive |
| Extensive xanthomas in childhood/young adulthood | Characteristic |
| Both parents with confirmed FH | Expected in offspring |
| Premature ASCVD (< 30 years) | HoFH patients develop ASCVD in childhood/adolescence |
7.2 Referral
Patients with suspected or confirmed HoFH should be referred to a tertiary lipid center with access to:
- LDL apheresis
- Lomitapide
- Evinacumab (anti-ANGPTL3 monoclonal antibody)
- Clinical trials for novel agents
This clinic initiates and optimizes pharmacotherapy (statin + ezetimibe + PCSK9i) while the referral is arranged.
8.0 Special Considerations
8.1 FH and Lipoprotein(a)
Approximately 30% of FH patients also have elevated Lp(a), which compounds their already elevated ASCVD risk [5]. All FH patients should have Lp(a) measured (typically done at initial assessment). Elevated Lp(a) in FH drives more aggressive treatment and closer surveillance.
8.2 FH and CAC Scoring
CAC scoring is generally not indicated in FH patients because:
- They already qualify for aggressive treatment regardless of CAC
- A CAC = 0 in a young FH patient does not justify withholding treatment (cumulative LDL-C exposure is the driver)
8.3 FH in Women of Childbearing Age
- Statins are contraindicated in pregnancy (FDA Category X)
- Discuss contraception and pregnancy planning
- If pregnancy is planned: discontinue statin ≥ 3 months before conception; may continue ezetimibe (Category C; limited data) per shared decision-making
- PCSK9 inhibitors: insufficient data in pregnancy; discontinue before conception
9.0 Version History
| Version | Date | Description |
|---|---|---|
| 1.0.0 | 2026-03-30 | Initial release |
References
- Defesche JC, Gidding SS, Harada-Shiba M, et al. Familial hypercholesterolaemia. Nat Rev Dis Primers. 2017;3:17093.
- Nordestgaard BG, Chapman MJ, Humphries SE, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population. Eur Heart J. 2013;34(45):3478–3490a.
- World Health Organization. Familial hypercholesterolaemia: report of a second WHO consultation. Geneva: WHO; 1999. (Dutch Lipid Clinic Network criteria)
- Knowles JW, Rader DJ, Khoury MJ. Cascade screening for familial hypercholesterolemia and the use of genetic testing. JAMA. 2017;318(4):381–382.
- Langsted A, Kamstrup PR, Benn M, et al. High lipoprotein(a) as a possible cause of clinical familial hypercholesterolaemia. Lancet Diabetes Endocrinol. 2016;4(5):377–386.