MedSearchGraphRAG
6 quiz questions available for this topicTake Quiz

Hypercholesterolaemia - familial

SNOMED: 238079002886 words•Updated 03/03/2026
💡

Exam Tips

  • In OSCE/viva, think FH when there is very high LDL-C plus family history of premature CHD; do not rely on symptoms because many patients are initially asymptomatic.
  • Tendon xanthomata are the highest-yield physical sign for FH and are more specific than xanthelasma; inspect Achilles and extensor tendons carefully (See figure: Achilles tendon xanthomata in lipid clinic teaching atlases).
  • State that secondary causes must be excluded before confirming primary FH, and mention TSH, HbA1c/glucose, renal and liver tests explicitly.
  • For children at genetic risk, mention early specialist referral and DNA-based cascade testing by age 10 (or earlier in high-risk families).
  • Always include statin safety in management answers: pregnancy contraindication, baseline LFTs, myopathy counselling, and major interaction checks.

Definition

Familial hypercholesterolaemia (FH) is a genetic disorder of LDL-cholesterol clearance that causes markedly raised LDL from birth and lifelong arterial cholesterol exposure. It is usually autosomal dominant (heterozygous FH), while homozygous FH is much rarer and presents earlier with more severe disease. Untreated FH greatly accelerates atherosclerosis and premature coronary disease.

Pathophysiology

Most FH is caused by loss-of-function variants in LDLR, reducing hepatic uptake of circulating LDL particles. Less commonly, APOB variants impair LDL binding to the LDL receptor, and gain-of-function PCSK9 variants increase receptor degradation; all mechanisms raise plasma LDL-C and increase subendothelial ApoB particle retention. Persistent LDL infiltration drives endothelial dysfunction, inflammation, foam-cell formation, and progressive atheromatous plaque development in coronary, cerebrovascular, and peripheral arterial beds. Homozygous FH has minimal residual receptor activity, so LDL levels are extreme and vascular disease may appear in childhood.

Risk Factors

  • First-degree relative with FH or premature coronary heart disease
  • Autosomal dominant inheritance pattern (50% transmission risk to children/siblings from an affected parent)
  • Very high untreated cholesterol (for example total cholesterol >7.5 mmol/L in adults; LDL-C >10 mmol/L suggests possible homozygous disease)
  • Male sex (overall higher ASCVD risk in many cohorts), though young women with FH also show excess early cardiovascular morbidity
  • Elevated lipoprotein(a)
  • Smoking, hypertension, diabetes, chronic kidney disease, obesity, sedentary lifestyle, and poor medication adherence increase cardiovascular risk on top of FH biology

Clinical Features

Symptoms

  • Often asymptomatic until cardiovascular disease develops
  • Exertional chest pain or acute coronary syndrome at a younger-than-expected age
  • Exertional calf pain (intermittent claudication) from peripheral arterial disease
  • Possible transient ischaemic attack or stroke symptoms in advanced atherosclerotic disease
  • Family history of premature myocardial infarction, revascularisation, or sudden cardiac death

Signs

  • Tendon xanthomata (classically Achilles or extensor tendons of hands/knuckles); highly suggestive of FH
  • Premature corneal arcus (especially if seen in younger adults)
  • Xanthelasma (supportive but less specific)
  • Clinical evidence of premature atherosclerotic disease (for example carotid bruit, reduced peripheral pulses)

Investigations

Fasting or non-fasting lipid profile (repeat LDL-C on two occasions):Persistently raised LDL-C; severe elevations raise suspicion of FH, and very high LDL-C supports possible homozygous FH
Total cholesterol screening thresholds in primary care case-finding:Adults with total cholesterol >7.5 mmol/L (or >9.0 mmol/L if age >=30 in systematic searches) warrant FH assessment
FH clinical scoring (Simon Broome or Dutch Lipid Clinic Network criteria):Classifies likelihood as possible/probable/definite FH and supports referral decisions
Secondary cause screen:Check TSH, HbA1c/glucose, renal profile, liver function, urine protein, medication/alcohol history to exclude or treat secondary dyslipidaemia
Genetic testing (index case and cascade testing of relatives):Pathogenic variant in LDLR/APOB/PCSK9 (or rarer genes) confirms inherited cause and enables family detection
Cardiovascular risk/target-organ assessment:Baseline ECG and assessment for established ASCVD; specialist imaging may be used in severe or symptomatic cases
Lipoprotein(a):Elevated Lp(a) identifies additional inherited atherothrombotic risk

Management

Lifestyle Modifications

  • Heart-healthy diet with reduced saturated/trans fats and increased fibre/unsaturated fats
  • Regular aerobic physical activity and weight optimisation
  • Smoking cessation and alcohol moderation
  • Aggressive management of coexisting risk factors (blood pressure, diabetes, CKD)
  • Structured adherence support and family-based counselling
  • Specialist referral for all clinically diagnosed FH, with cascade testing of first-degree relatives

Pharmacological Treatment

High-intensity statins (first-line)

  • Atorvastatin 20 mg once daily initially, titrate up (commonly to 40-80 mg once daily)
  • Rosuvastatin 10-20 mg once daily (up to 40 mg once daily in specialist care)

Use maximally tolerated high-intensity therapy to achieve substantial LDL-C reduction. Contraindicated in pregnancy and active liver disease; avoid in breastfeeding. Check baseline liver enzymes, assess for myopathy symptoms, and review interactions (for example macrolides, azoles, ciclosporin, some calcium-channel blockers, and high grapefruit intake with atorvastatin).

Cholesterol absorption inhibitor

  • Ezetimibe 10 mg once daily

Add if LDL-C remains above target on maximally tolerated statin, or use when statin is not tolerated. Generally well tolerated; monitor liver enzymes if combined with statin.

PCSK9 pathway therapies (specialist initiation)

  • Alirocumab 75 mg subcutaneously every 2 weeks, increased to 150 mg every 2 weeks if needed
  • Evolocumab 140 mg subcutaneously every 2 weeks or 420 mg monthly
  • Inclisiran 284 mg subcutaneously on day 1, at 3 months, then every 6 months

Consider in severe heterozygous FH or established ASCVD when LDL-C remains high despite maximal oral therapy, and in homozygous FH according to specialist criteria. Main cautions are hypersensitivity and injection-site reactions; ensure shared-care follow-up.

Other oral LDL-lowering options in statin intolerance (specialist/commissioning dependent)

  • Bempedoic acid 180 mg once daily (alone or with ezetimibe where appropriate)

Useful when statins are contraindicated or not tolerated. Caution in history of gout or tendon disorders; can increase uric acid and has rare tendon injury risk.

Surgical / Interventional

  • LDL apheresis for selected severe cases (especially homozygous FH or refractory severe heterozygous FH under specialist lipid services)
  • Rarely, liver transplantation in extreme refractory homozygous FH

Complications

  • Premature coronary heart disease (stable angina, myocardial infarction, acute coronary syndrome)
  • Ischaemic stroke or transient ischaemic attack
  • Peripheral arterial disease
  • Erectile dysfunction as a vascular manifestation
  • Early cardiovascular death, particularly in untreated severe disease

Prognosis

Prognosis is strongly treatment-dependent. Without treatment, young adults with FH have a very large excess risk of fatal coronary disease, and homozygous FH can cause cardiovascular events in childhood or adolescence. Early diagnosis, family cascade testing, and prompt intensive LDL-lowering therapy can reduce risk substantially, with many treated heterozygous patients approaching population life expectancy.

Sources & References

💊BNF Drug References(3)

✅NICE Guidelines(1)

📖Textbook References(20)

  • David Randall PhD MRCP (Editor), John Booth PhD MRCP (Editor), K - Kumar and Clark's Clinical Medicine (2025, American Elsevier Publishing Co.) - libgen.li.pdf(pp. 554)[context]
  • David Randall PhD MRCP (Editor), John Booth PhD MRCP (Editor), K - Kumar and Clark's Clinical Medicine (2025, American Elsevier Publishing Co.) - libgen.li.pdf(pp. 555)[context]
  • David Randall PhD MRCP (Editor), John Booth PhD MRCP (Editor), K - Kumar and Clark's Clinical Medicine (2025, American Elsevier Publishing Co.) - libgen.li.pdf(pp. 1160)[context]
  • David Randall PhD MRCP (Editor), John Booth PhD MRCP (Editor), K - Kumar and Clark's Clinical Medicine (2025, American Elsevier Publishing Co.) - libgen.li.pdf(pp. 1834)[context]
  • David Randall PhD MRCP (Editor), John Booth PhD MRCP (Editor), K - Kumar and Clark's Clinical Medicine (2025, American Elsevier Publishing Co.) - libgen.li.pdf(pp. 554)[context]
  • David Randall PhD MRCP (Editor), John Booth PhD MRCP (Editor), K - Kumar and Clark's Clinical Medicine (2025, American Elsevier Publishing Co.) - libgen.li.pdf(pp. 1833)[context]
  • David Randall PhD MRCP (Editor), John Booth PhD MRCP (Editor), K - Kumar and Clark's Clinical Medicine (2025, American Elsevier Publishing Co.) - libgen.li.pdf(pp. 553, 554)[context]
  • David Randall PhD MRCP (Editor), John Booth PhD MRCP (Editor), K - Kumar and Clark's Clinical Medicine (2025, American Elsevier Publishing Co.) - libgen.li.pdf(pp. 555)[context]
  • David Randall PhD MRCP (Editor), John Booth PhD MRCP (Editor), K - Kumar and Clark's Clinical Medicine (2025, American Elsevier Publishing Co.) - libgen.li.pdf(pp. 551)[context]
  • David Randall PhD MRCP (Editor), John Booth PhD MRCP (Editor), K - Kumar and Clark's Clinical Medicine (2025, American Elsevier Publishing Co.) - libgen.li.pdf(pp. 558)[context]
  • David Randall PhD MRCP (Editor), John Booth PhD MRCP (Editor), K - Kumar and Clark's Clinical Medicine (2025, American Elsevier Publishing Co.) - libgen.li.pdf(pp. 1160)[context]
  • David Randall PhD MRCP (Editor), John Booth PhD MRCP (Editor), K - Kumar and Clark's Clinical Medicine (2025, American Elsevier Publishing Co.) - libgen.li.pdf(pp. 480)[context]
  • David Randall PhD MRCP (Editor), John Booth PhD MRCP (Editor), K - Kumar and Clark's Clinical Medicine (2025, American Elsevier Publishing Co.) - libgen.li.pdf(pp. 1831)[context]
  • David Randall PhD MRCP (Editor), John Booth PhD MRCP (Editor), K - Kumar and Clark's Clinical Medicine (2025, American Elsevier Publishing Co.) - libgen.li.pdf(pp. 555)[context]
  • David Randall PhD MRCP (Editor), John Booth PhD MRCP (Editor), K - Kumar and Clark's Clinical Medicine (2025, American Elsevier Publishing Co.) - libgen.li.pdf(pp. 558)[context]
  • David Randall PhD MRCP (Editor), John Booth PhD MRCP (Editor), K - Kumar and Clark's Clinical Medicine (2025, American Elsevier Publishing Co.) - libgen.li.pdf(pp. 561)[context]
  • David Randall PhD MRCP (Editor), John Booth PhD MRCP (Editor), K - Kumar and Clark's Clinical Medicine (2025, American Elsevier Publishing Co.) - libgen.li.pdf(pp. 1833)[context]
  • David Randall PhD MRCP (Editor), John Booth PhD MRCP (Editor), K - Kumar and Clark's Clinical Medicine (2025, American Elsevier Publishing Co.) - libgen.li.pdf(pp. 1818)[context]
  • Guyton and Hall Textbook of Medical Physiology (John E. Hall, Michael E. Hall) (Z-Library).pdf(pp. 851)[context]
  • Guyton and Hall Textbook of Medical Physiology (John E. Hall, Michael E. Hall) (Z-Library).pdf(pp. 851)[context]

Sources

Test Your Knowledge

6 quiz questions available for this topic

Start Quiz