Definition and pathophysiology
Familial hypercholesterolaemia (FH) is an inherited disorder characterized by persistently elevated plasma low-density lipoprotein cholesterol (LDL-C) from early life and a consequent excess risk of premature atherosclerotic cardiovascular disease (ASCVD), particularly coronary artery disease (CAD).
FH results from pathogenic variants affecting proteins in the hepatic LDL-receptor pathway. Reduced cellular uptake and clearance of LDL leads to increased circulating LDL-C. The principal genetic mechanisms involve:
Loss-of-function variants in the LDL receptor gene, LDLR, which account for most cases.
Variants in APOB that impair apolipoprotein B binding to the LDL receptor.
Gain-of-function variants in PCSK9, which reduce recycling and surface availability of hepatic LDL receptors.
Rare biallelic variants in LDLRAP1, which impair LDL-receptor endocytosis and produce an FH-like phenotype.
Individuals with a single pathogenic variant have heterozygous FH (HeFH). Biallelic pathogenic variants cause homozygous FH (HoFH), which produces substantially higher LDL-C concentrations and much earlier, more severe clinical disease.
HeFH affects approximately 1 in 250–300 people and is the most common inherited metabolic disorder associated with premature cardiovascular disease. Prevalence is higher in populations with a founder effect. HoFH is much rarer, affecting approximately 1 in 250,000–350,000 individuals.
The lifelong exposure to high LDL-C is central to the disease burden. In untreated HeFH, CAD commonly develops during the third or fourth decade in males and approximately 10 years later in females. Untreated HoFH is associated with extensive premature and progressive ASCVD; CAD and aortic stenosis may occur before the age of 20 years, with death often occurring before age 30.
Clinical presentation and symptoms
Heterozygous familial hypercholesterolaemia
Many individuals with HeFH are asymptomatic until ASCVD develops. The clinical phenotype is driven principally by lifelong LDL-C elevation and may be discovered through:
Routine lipid testing showing severe hypercholesterolaemia.
A personal history of premature CAD, cerebral vascular disease or peripheral vascular disease.
A family history of premature myocardial infarction, vascular disease or marked hypercholesterolaemia.
Physical findings related to cholesterol deposition.
Untreated or inadequately treated patients may develop premature CAD. Symptoms therefore depend on the vascular territory involved and may include manifestations of coronary, cerebral or peripheral arterial disease, although the source material does not specify symptom patterns in detail.
Physical manifestations
Tendinous xanthomas, particularly over extensor tendons, are characteristic clinical manifestations of untreated FH and may develop when the disorder is not recognized early in life. Corneal arcus and xanthelasma can also occur, although they are less specific for FH. Corneal arcus is particularly informative when it occurs before age 45 years.
Homozygous familial hypercholesterolaemia
HoFH typically presents with:
Extensive cutaneous and tendon xanthomas.
Markedly elevated LDL-C.
Very premature, progressive ASCVD.
Premature aortic stenosis.
Cutaneous or tendon xanthomas before age 10 years are an important clue to HoFH, especially when both parents have untreated LDL-C levels compatible with HeFH.
Evaluation and physical examination
Assessment begins with systematic lipid screening and a careful clinical, medical, social and multigenerational family history. The evaluation should establish:
The magnitude of untreated LDL-C elevation.
The presence and age of onset of premature CAD or other vascular disease.
A history of myocardial infarction or raised cholesterol among relatives.
The presence of tendon xanthomas, corneal arcus and xanthelasma.
Potential secondary causes of hypercholesterolaemia.
The likelihood of a monogenic disorder and the need for family-based screening.
Physical examination should specifically assess the extensor tendons for xanthomas and inspect for corneal arcus and xanthelasma. Cardiovascular examination should be directed toward identifying clinical evidence of ASCVD and, in suspected HoFH, possible aortic valve disease; however, specific examination findings are not detailed in the source material.
Exclusion of secondary causes
An LDL-C concentration above 160 mg/dL should prompt measurement of thyroid-stimulating hormone to assess for hypothyroidism, with consideration of liver and kidney disease. More generally, secondary causes of dyslipidaemia should be sought before assigning the phenotype to a primary inherited lipid disorder.
Correct classification is important because the underlying genetic disorder may affect:
Prognostic assessment.
Choice and intensity of lipid-lowering treatment.
ASCVD risk estimation.
Screening and management of family members.
Diagnostic criteria
FH is principally a clinical diagnosis. Commonly used diagnostic frameworks include the Dutch Lipid Clinic Network criteria and the Simon Broome criteria. Genetic testing is recommended to identify causative variants and can strengthen diagnostic certainty, support earlier and more intensive treatment, and facilitate cascade screening.
Dutch Lipid Clinic Network criteria
The Dutch score incorporates family history, personal vascular history, physical findings, untreated LDL-C concentration and DNA analysis.
| Finding | Points |
|---|---|
| First-degree relative with premature coronary or vascular disease, or LDL-C above the 95th percentile | 1 |
| First-degree relative with tendon xanthomas and/or corneal arcus, or a child younger than 18 years with LDL-C above the 95th percentile | 2 |
| Premature CAD in the patient | 2 |
| Premature cerebral or peripheral vascular disease in the patient | 1 |
| Tendon xanthomas | 6 |
| Corneal arcus before age 45 years | 4 |
| Untreated LDL-C ≥8.5 mmol/L (≥325 mg/dL) | 8 |
| Untreated LDL-C 6.5–8.4 mmol/L (251–325 mg/dL) | 5 |
| Untreated LDL-C 5.0–6.4 mmol/L (191–250 mg/dL) | 3 |
| Untreated LDL-C 4.0–4.9 mmol/L (155–190 mg/dL) | 1 |
| Functional mutation in LDLR, APOB or PCSK9 | 8 |
Interpretation:
Definite FH: more than 8 points.
Probable FH: 6–8 points.
Possible FH: 3–5 points.
An untreated LDL-C above 4.9 mmol/L (190 mg/dL) requires careful assessment for FH. FH should also be considered at lower LDL-C concentrations when premature ASCVD or a relevant family history is present.
Simon Broome criteria
The Simon Broome framework combines lipid thresholds with clinical or genetic evidence.
| Category | Lipid criterion | Additional evidence |
|---|---|---|
| Definite FH | Total cholesterol >6.7 mmol/L or LDL-C >4.0 mmol/L in a child younger than 16 years; or total cholesterol >7.5 mmol/L or LDL-C >4.9 mmol/L in an adult | Tendon xanthomas in the patient or a qualifying relative, or DNA evidence of an LDLR mutation, familial defective apoB-100 or PCSK9 mutation |
| Possible FH | Same lipid thresholds | Family history of myocardial infarction before age 50 years in a second-degree relative or before age 60 years in a first-degree relative; or raised cholesterol in a qualifying first- or second-degree relative |
For the family-history cholesterol criterion, raised cholesterol is defined as greater than 7.5 mmol/L in an adult first- or second-degree relative, or greater than 6.7 mmol/L in a child or sibling younger than 16 years.
Genetic testing
Genetic testing should be considered or performed in suspected FH, particularly when the result may:
Confirm a clinical diagnosis.
Prompt earlier or more aggressive LDL-C lowering.
Permit targeted testing of relatives.
Improve recognition of affected family members.
The principal genes implicated in FH are LDLR, APOB, PCSK9 and, in rare recessive phenotypes, LDLRAP1. Genetic testing is not always affordable, and a negative result does not exclude clinically important hypercholesterolaemia. Individuals without an identified pathogenic variant, including those with polygenic hypercholesterolaemia, may still have substantial ASCVD risk and remain eligible for treatment.
Homozygous familial hypercholesterolaemia
HoFH should be suspected when untreated LDL-C is above 10 mmol/L, approximately 400 mg/dL, particularly in the presence of early xanthomas or compatible parental phenotypes.
| Diagnostic domain | Findings suggesting HoFH |
|---|---|
| LDL-C | Untreated LDL-C >10 mmol/L (> approximately 400 mg/dL) |
| Clinical features | Cutaneous or tendon xanthomas before age 10 years |
| Family phenotype | Untreated LDL-C levels compatible with HeFH in both parents |
| Genetic confirmation | Biallelic pathogenic or likely pathogenic variants involving LDLR, APOB, PCSK9 or LDLRAP1 |
Patients with suspected HoFH should be referred to specialist lipid centres.
Biomarkers and laboratory findings
The defining laboratory abnormality in HeFH is an LDL-C concentration above the 95th percentile for age and sex; in adults, the typical threshold is greater than 190 mg/dL (5.0 mmol/L). Untreated LDL-C is preferred for diagnostic scoring.
In HoFH, untreated LDL-C is generally greater than 400 mg/dL (10 mmol/L), although the diagnostic evaluation requires integration of lipid results, phenotype, family history and genetic findings.
Lipid assessment should be systematic and should distinguish the predominant lipoprotein abnormality. When LDL-C is elevated, secondary causes should be considered and evaluated. The source material specifically identifies thyroid-stimulating hormone testing for LDL-C above 160 mg/dL and consideration of liver or kidney disease.
No specific FH-related biomarker beyond the lipid profile and genetic findings is described in the source material.
Imaging and cardiovascular assessment
FH confers a high lifetime risk of ASCVD, particularly CAD. The source material emphasizes clinical history and physical examination for identifying premature coronary, cerebral or peripheral vascular disease but does not provide a specific imaging protocol or recommended modality for routine cardiovascular imaging in FH.
In HoFH, aortic stenosis is a recognized manifestation of the severe phenotype. The material does not specify an echocardiographic surveillance schedule or imaging thresholds.
Cascade screening and family management
Cascade screening is a central component of FH care. Once an index case is identified, first-degree relatives should be actively assessed. Screening may use:
Lipid measurement.
Clinical evaluation.
Targeted genetic testing when a familial pathogenic variant has been identified.
If a causative variant is known, relatives can undergo focused testing for that variant. If genetic testing is unavailable, declined or nondiagnostic, family assessment should rely on clinical screening and lipid analysis.
Cascade screening is important because FH is frequently underdiagnosed and undertreated, while early detection permits earlier initiation of LDL-C-lowering treatment. National screening programmes are also recommended to improve recognition across the population.
A multigenerational pedigree should document:
Family structure.
Diagnoses of hypercholesterolaemia and ASCVD.
Ages at onset of disease.
Causes and ages of death where known.
Relatives who may require lipid or genetic assessment.
Identification of FH in one family member should trigger assessment of relatives and continued family-based case finding as additional affected individuals are identified.
Treatment and management
General principles
The principal objectives are to reduce lifelong LDL-C exposure and prevent premature ASCVD. Treatment should begin as soon as possible after diagnosis. Management includes:
Lifestyle modification.
High-intensity statin therapy.
Addition of ezetimibe when LDL-C remains above the guideline-recommended goal.
Addition of a PCSK9 inhibitor in very-high-risk patients who remain above goal despite maximal tolerated statin therapy plus ezetimibe.
Specialist referral for HoFH and for severe or treatment-resistant disease.
Family-based cascade screening.
Early recognition and treatment may normalize life expectancy in FH, although the condition remains substantially underdiagnosed and undertreated.
Heterozygous familial hypercholesterolaemia
High-intensity statin therapy is recommended promptly after diagnosis. Ezetimibe should be added if the LDL-C target is not reached. In very-high-risk patients with FH, a PCSK9 inhibitor is recommended when the treatment goal remains unmet despite maximal tolerated statin therapy combined with ezetimibe.
The source material does not specify LDL-C goal values, individual statin doses, ezetimibe doses or PCSK9 inhibitor doses.
Homozygous familial hypercholesterolaemia
HoFH requires management in a specialist centre. Treatment should include lifestyle measures, statins and ezetimibe from the time of diagnosis.
Additional options include:
A PCSK9 inhibitor when residual LDL-receptor activity is present.
Lipoprotein apheresis when LDL-C is above 300 mg/dL (8 mmol/L).
Lomitapide or evinacumab, where available and accessible, when LDL-C remains above 115 mg/dL (3 mmol/L) despite therapy.
Liver transplantation as a last resort in progressive disease.
The source material does not provide doses, administration schedules or detailed safety-monitoring requirements for these treatments.
Pregnancy and lactation
Pregnancy produces substantial lipid changes, including approximate increases of:
LDL-C by 30–50%.
HDL cholesterol by 20–40%.
Triglycerides by 50–100%.
Routine reference ranges are therefore of limited usefulness during pregnancy.
Statins remain contraindicated during lactation. Continuing statin therapy during pregnancy may be considered in women with FH or established ASCVD, although the source material emphasizes the need for individualized management. Inadvertent conception while taking a statin does not require termination of pregnancy but should prompt close follow-up.
Bile acid sequestrants and LDL apheresis may be considered during pregnancy in women with FH. PCSK9 inhibitors and ezetimibe are not recommended during pregnancy because of insufficient clinical data. Bempedoic acid is strongly contraindicated, and contraception is recommended during its use.
Drugs and practical treatment considerations
| Treatment | Role described in the source material | Practical consideration |
|---|---|---|
| High-intensity statin | Initial treatment for HeFH; used from diagnosis in HoFH | Begin as soon as possible after diagnosis; use the maximal tolerated regimen |
| Ezetimibe | Added when LDL-C remains above the recommended goal despite statin therapy | Used with statin therapy; not recommended during pregnancy because of limited clinical data |
| PCSK9 inhibitor | Recommended for very-high-risk HeFH when maximal tolerated statin plus ezetimibe is insufficient; may help in HoFH when residual LDL-receptor activity exists | Not recommended during pregnancy because of insufficient clinical data |
| Lipoprotein apheresis | Considered in HoFH when LDL-C is >300 mg/dL (>8 mmol/L); may also be considered during pregnancy in FH | Specialist-centre treatment |
| Lomitapide | Considered in HoFH when LDL-C remains >115 mg/dL (>3 mmol/L) despite therapy, if available and accessible | Specialist use; no dose is provided |
| Evinacumab | Considered under the same HoFH circumstances as lomitapide, if available and accessible | Specialist use; no dose is provided |
| Bile acid sequestrants | May be considered during pregnancy in women with FH | No dose is provided |
| Bempedoic acid | Strongly contraindicated during pregnancy | Contraception is recommended during treatment |
Guideline recommendations
The source material supports the following recommendations:
Suspect FH in adults with untreated LDL-C above 4.9 mmol/L (190 mg/dL), particularly after secondary causes have been excluded.
Consider FH at lower LDL-C levels when premature ASCVD or a suggestive family history is present.
Use a validated clinical framework such as the Dutch Lipid Clinic Network or Simon Broome criteria.
Perform genetic testing to identify causative variants where feasible and clinically appropriate.
Initiate high-intensity statin therapy promptly after diagnosis.
Add ezetimibe if the LDL-C goal is not achieved.
Add a PCSK9 inhibitor in very-high-risk FH when maximal tolerated statin plus ezetimibe is inadequate.
Refer patients with suspected or confirmed HoFH to specialist lipid centres.
Consider lipoprotein apheresis in HoFH with LDL-C above 300 mg/dL (8 mmol/L).
Consider lomitapide or evinacumab in inadequately controlled HoFH when these treatments are available and accessible.
Implement cascade screening of family members of affected index cases.
Develop and support national screening programmes to improve early diagnosis.
During pregnancy, consider bile acid sequestrants or LDL apheresis when appropriate; avoid PCSK9 inhibitors and ezetimibe because of limited clinical data, and do not use bempedoic acid.
Prognosis and follow-up
Untreated HeFH is associated with premature CAD, with risk emerging particularly by the third to fourth decade in males and approximately a decade later in females. Early diagnosis and effective treatment may restore life expectancy toward normal.
HoFH carries a markedly worse prognosis. Untreated patients commonly develop CAD and aortic stenosis before age 20 years and may die before age 30. The severity of the phenotype requires specialist management and intensive, often combination, LDL-C-lowering therapy.
Follow-up should be longitudinal and should address:
LDL-C response to treatment.
Tolerance of lipid-lowering therapy.
Development or progression of ASCVD.
Need for treatment escalation.
Adherence to therapy and lifestyle measures.
Screening of relatives and completion of cascade testing.
Reassessment during pregnancy and lactation when relevant.
The source material does not specify treatment-monitoring intervals or a detailed schedule for cardiovascular imaging. Long-term management should nevertheless remain active because risk reflects cumulative LDL-C exposure and because FH is frequently recognized later than optimal.
