Familial hypercholesterolaemia

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Familial hypercholesterolaemia is usually autosomal dominant and most often reflects impaired LDL receptor pathway function. LDL cholesterol is elevated from birth, so cumulative arterial exposure is far greater than the same concentration first acquired in later life. Heterozygous disease is common enough to appear in every general practice; homozygous or compound disease is rare and much more severe.

Clinical diagnosis integrates untreated cholesterol, family history, premature coronary disease, tendon signs and genetics. Secondary causes such as hypothyroidism, nephrotic syndrome, cholestatic liver disease and poorly controlled diabetes must be assessed, but their presence does not exclude inherited disease. A negative genetic panel also does not erase a strong clinical phenotype because not every causal variant is detected.

The family is part of the intervention. Specialist services construct a pedigree, obtain consent and contact relatives through governed pathways. Cascade testing can identify an asymptomatic child or sibling decades before a first infarction. Confidentiality matters: clinicians should support the index patient to share information and use approved services rather than independently disclosing a result to relatives without lawful justification.

Key points

Suspect FH in adults with total cholesterol above 7.5 mmol/L or a personal or family history of premature coronary heart disease, after secondary causes are excluded.
Use Simon Broome or Dutch Lipid Clinic Network criteria in primary care; do not invent a diagnosis from one lipid value alone.
Tendon xanthomata in the patient or a first- or second-degree relative strongly support FH; corneal arcus in a young person is a clue but not diagnostic alone.
Obtain at least two LDL measurements because biological and analytical variation can alter classification, while not delaying treatment in very high-risk disease.
Do not use QRISK to decide whether to treat FH: lifelong LDL exposure creates risk that a ten-year calculator can seriously underestimate.
Refer for DNA testing when clinical criteria support FH; once a pathogenic family variant is known, cascade testing should use that variant rather than cholesterol alone.
Each first-degree relative of a person with heterozygous autosomal-dominant FH has approximately a one-in-two chance of inheriting the variant.
Offer a high-intensity statin aiming for at least a 50% LDL reduction from untreated baseline, then add ezetimibe and specialist therapies when needed.
Children at risk should enter the specialist family pathway, with testing generally completed by age ten and treatment led by clinicians experienced in paediatric FH.
Discuss contraception and pregnancy early; NICE advises stopping lipid-modifying medicines three months before attempting conception and throughout pregnancy and breastfeeding, with specialist exceptions planned individually.
Lifestyle reduces total cardiovascular risk but cannot correct monogenic LDL-receptor dysfunction; never withhold effective medicine because diet is already healthy.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Autosomal dominant LDL-pathway defect

An inherited defect, most often affecting LDL receptor pathway function, reduces clearance and exposes arteries to raised LDL cholesterol from birth.

Severe biallelic disease

Homozygous or compound inheritance produces much lower residual LDL clearance and a substantially earlier, more severe cardiovascular phenotype.

Clinically strong but test-negative phenotype

Current genetic panels do not identify every causal variant, so untreated cholesterol, tendon signs and premature family disease remain important when testing is negative.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
LDL clearance is impaired
Reduced receptor-pathway activity allows circulating LDL particles to remain in plasma for longer and reach markedly raised concentrations.
2
Arterial exposure accumulates
Because elevation begins in childhood, cumulative LDL burden is far greater than the same concentration acquired only in later adult life.
3
Atherosclerotic plaques develop early
LDL retention and inflammation within arterial walls accelerate coronary and other atherosclerotic disease, sometimes before conventional risk scores appear alarming.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Marked untreated LDL

Persistent LDL above 4.9 mmol/L or total cholesterol above 7.5 in an adult is compatible with Simon Broome thresholds and warrants family and secondary-cause assessment.

Tendon xanthomata

Firm cholesterol deposits in Achilles, extensor hand or other tendons in the patient or close relative are highly suggestive; distinguish them from xanthelasma, nodules and ordinary tendon thickening.

Premature coronary history

Myocardial infarction, revascularisation or sudden coronary death at an unexpectedly young age in the patient or family strengthens a clinical FH score and referral need.

Affected childRed flag

A child with high cholesterol plus an affected parent may have heterozygous FH; very early xanthomata or extreme values raise homozygous disease and demand urgent paediatric lipid care.

Homozygous phenotypeRed flag

Extremely high LDL from childhood, cutaneous or tendon xanthomata before adolescence, aortic-root disease or two affected parents suggests biallelic disease requiring specialist drugs or apheresis.

Pregnancy planning

A person taking lipid-lowering treatment who wants pregnancy needs planned withdrawal and specialist risk review rather than discovering exposure after conception or losing years of follow-up.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Two untreated or best-estimate LDL cholesterol measurementsFirst step
Why
Confirm persistent magnitude and support validated clinical criteria.
Interpretation and limitations
Use pretreatment values where available; total cholesterol above 7.5 or LDL above 4.9 mmol/L meets the adult cholesterol component of Simon Broome but does not alone prove FH.
02
Simon Broome or Dutch Lipid Clinic Network score
Why
Combine cholesterol, examination and family history reproducibly.
Interpretation and limitations
Definite or possible categories guide specialist referral and genetic testing; document ages and relationships precisely because vague 'heart disease in family' is insufficient.
03
TSH, glucose, liver, renal and urine protein assessment
Why
Exclude common secondary drivers of very high LDL cholesterol.
Interpretation and limitations
Correct hypothyroidism, nephrotic syndrome, cholestasis or dysglycaemia and remeasure, while retaining FH concern when phenotype or family evidence remains strong.
04
Molecular genetic testing
Why
Confirm a causal variant and enable accurate family cascade testing.
Interpretation and limitations
A pathogenic LDLR-pathway variant confirms FH; a negative panel does not exclude clinically diagnosed polygenic or undetected inherited hypercholesterolaemia.
05
Pedigree and cascade testing
Why
Identify relatives with the familial variant before cardiovascular disease appears.
Interpretation and limitations
Use the known family DNA variant where available; cholesterol-only thresholds are less precise and should not replace the approved cascade service.
06
Cardiovascular disease assessment
Why
Identify symptomatic or subclinical consequences that change treatment intensity.
Interpretation and limitations
Investigate chest pain, exertional symptoms, murmurs and vascular signs through standard pathways; routine imaging of every asymptomatic adult is specialist- and risk-dependent.
07
Lipoprotein(a) in specialist risk refinement
Why
Identify an additional inherited atherogenic factor that can amplify premature risk.
Interpretation and limitations
A high value strengthens risk management but is not the diagnostic test for FH; concentration is largely inherited and usually needs only one credible measurement.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Polygenic hypercholesterolaemia

Multiple common variants and lifestyle factors can raise LDL without a clear dominant pedigree or pathogenic single-gene result.

Hypothyroidism

Low thyroid hormone reduces lipid clearance and can mimic or amplify inherited disease; thyroid testing helps identify this reversible contributor.

Nephrotic syndrome

Heavy proteinuria, oedema and low albumin distinguish renal protein-loss-associated dyslipidaemia from an isolated familial LDL phenotype.

Cholestatic liver disease

Cholestasis can markedly alter cholesterol measurements, with liver symptoms and biochemical abnormalities pointing away from a primary LDL-receptor disorder.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01Case findingRecognise possible FHFirst stepAn adult has marked cholesterol elevation or premature coronary family history.

1Retrieve the highest untreated lipid values, repeat a full profile, examine Achilles and hand tendons and build a three-generation pedigree with ages at coronary events.
2Exclude secondary causes and apply Simon Broome or Dutch criteria, remembering that a standard cardiovascular risk score must not determine treatment eligibility.
3Refer eligible cases to a lipid or FH service for genetic counselling, DNA testing and a coordinated cascade plan while beginning appropriate LDL lowering.

02LDL treatmentHalve lifelong LDL exposureHeterozygous FH is clinically or genetically diagnosed in an adult.

1Offer the highest suitable high-intensity statin after baseline liver, medicine-interaction and pregnancy review, aiming for at least 50% LDL reduction from untreated baseline.
2Check response and adherence, maximise the tolerated statin, then add ezetimibe when the goal is not reached or statin intensity is limited.
3Refer for PCSK9-directed treatment, inclisiran, bempedoic-acid or apheresis assessment according to vascular risk, residual LDL and live NICE commissioning criteria.

03CascadeFind affected relatives safelyA pathogenic variant or strong index diagnosis is established.

1Explain autosomal-dominant risk, obtain a pedigree and support the patient with accurate written information to share through the governed cascade-testing service.
2Offer variant testing to first-degree relatives and extend through affected branches, using age-appropriate paediatric services and consent or assent processes.
3Start prevention promptly in affected relatives and release unaffected variant-negative relatives from unnecessary lifelong lipid surveillance for that familial mutation.

04Reproductive carePlan treatment around pregnancyA person with FH may conceive, is planning pregnancy or is pregnant.

1Discuss contraception during routine reviews and arrange lipid-obstetric consultation before conception, including current NICE advice on stopping lipid medicines three months beforehand.
2Avoid ordinary statin, ezetimibe and injectable lipid therapy during pregnancy and breastfeeding unless a specialist determines an exceptional product-specific plan for extreme risk.
3Restart effective treatment promptly after the pregnancy and feeding plan permits, documenting the gap and preserving family cascade care during the interruption.

Key medicines and prescribing safety3 treatments · regimens, roles and cautions

First-line lifelong reduction of cumulative LDL exposure and premature atherosclerotic cardiovascular risk.

High-intensity atorvastatin for heterozygous FH

Start with a suitable high-intensity once-daily dose, commonly atorvastatin 20 to 80 mg according to baseline LDL, age, interactions and tolerability, then titrate toward at least 50% LDL reduction.

Review liver status, strong CYP3A4 interactions, grapefruit and muscle symptoms. Stop three months before planned conception under NICE FH guidance and avoid pregnancy or breastfeeding unless specialist advice changes the plan.

Adds LDL lowering when statin alone cannot achieve the FH reduction goal.

Ezetimibe add-on therapy

Take 10 mg orally once daily with the maximally tolerated statin, or alone when statin treatment is contraindicated or genuinely not tolerated under the NICE pathway.

Check hepatic function when combined with statin and review ciclosporin, biliary disease and reproductive plans. A modest response does not replace adherence assessment or specialist escalation for very high LDL.

Provides major additional LDL lowering in selected high-risk heterozygous or homozygous disease.

PCSK9 inhibitor, inclisiran or advanced therapy

Use the current product-specific injection or infusion schedule only after a specialist confirms FH phenotype, residual LDL, vascular-risk category and NICE commissioning eligibility.

Thresholds and routes differ among agents and jurisdictions; verify background therapy, pregnancy, injection reactions and follow-up ownership. Homozygous FH may require apheresis or specialised agents beyond ordinary formularies.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Premature coronary disease

Lifelong LDL exposure accelerates coronary atherosclerosis, causing angina, myocardial infarction or revascularisation at an unusually young age.

Other arterial disease

The same lifelong atherosclerotic exposure can affect cerebral and peripheral arteries, adding stroke and limb-ischaemia risk alongside premature coronary disease.

Unrecognised familial disease

Without cascade assessment, asymptomatic children and siblings may remain untreated through decades of cumulative arterial exposure.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Repeat lipid profile and liver transaminases two to three months after starting or changing treatment, calculating percentage LDL reduction from the best untreated baseline.
Review adherence, injection access, interactions and adverse effects before escalating; FH treatment gaps add to lifelong LDL burden even when the patient feels well.
Ask about chest pain, exertional limitation, cerebrovascular symptoms and smoking at follow-up, managing every modifiable cardiovascular factor rather than LDL in isolation.
Update the pedigree when relatives have events, results or children, and confirm that cascade referrals reached the correct family branch without breaching confidentiality.
For children, follow growth, puberty, liver, muscle and lipid response in the specialist paediatric service with age-appropriate shared decisions.
Review contraception and conception timing regularly, plan treatment withdrawal in advance and ensure a named date for postpartum restart.
Maintain specialist surveillance for homozygous disease, aortic-root involvement, apheresis and advanced drug toxicity according to the tertiary-centre protocol.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Exposure begins at birth

A young adult with modest ten-year QRISK can still have decades of damaging LDL exposure, which is why conventional risk calculators should not gate FH treatment.

Xanthelasma is not xanthoma

Eyelid cholesterol plaques are nonspecific; tendon xanthomata within Achilles or hand extensors carry much stronger diagnostic weight in Simon Broome assessment.

Negative genetics is not normal lipids

Current panels do not find every cause. A convincing clinical phenotype still needs prevention even when no reportable monogenic variant is identified.

One diagnosis prevents many events

Identifying an index case can lead to testing and early treatment across generations, making pedigree work a therapeutic intervention rather than paperwork.

Lifestyle cannot repair LDLR

Healthy eating and activity reduce total vascular risk but rarely lower monogenic LDL enough; praising lifestyle must not become a reason to defer medicine.

11Common pitfallsFrequent interpretation and management errors.

01
Using QRISK to reassure a young adult with probable FH.
02
Diagnosing FH from one cholesterol value without secondary-cause assessment.
03
Mistaking xanthelasma for diagnostic tendon xanthomata.
04
Stopping investigation because a genetic panel is negative despite a strong phenotype.
05
Treating only the index patient and omitting cascade referral.
06
Waiting for symptoms before testing children in an affected family.
07
Accepting a small LDL fall without checking adherence or aiming for at least 50% reduction.
08
Discovering statin exposure after conception because reproductive counselling was never revisited.