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Familial hypercholesterolaemia

Familial hypercholesterolaemia ( FH ) is a genetic disorder affecting the metabolism of low density lipoprotein ( LDL ) particles leading to high LDL cholesterol levels maintained over time and higher risk of cardiovascular disease early in life ( )


Brown and Goldstein for the first time explained the molecular basis of FH about 3 decades ago which provided the basis of link between LDL and CV disease due to atherosclerosis FH is amongst the commonest inherited metabolic disorder Prevalence of FH is estimated to be between 1 in 200-500 The prevalence is more common in persons with established coronary heart disease ( ie frequent disorder in patients with ACS ) It is widely believed that FH is more prevalent than considered historically with an overall prevalence rate of 1:200-300 individuals in the general population The prevalence also varies among populations and regions based on factors as detection methods , criteria ,availability of genetic testing & intrinsic characteristic of different populations


What happens – Mutations in 4 genes have been found with the LDL receptor being the most common Inheritance is autosomal dominant ( most cases ) with homozygous suffering with double the LDL cholesterol levels in comparison to heterozygotes Mutation in LDL-receptor ( LDR ) gene leads to the plasma accumulation of cholesterol ester-laden LDL particles ( impaired LDL clearance ) LDL receptors is the most common Proprotein convertase subtilin/kexin 9 ( PCSK9 ) Apolipoprotein B( Apo B ) Low density lipoprotein receptor adaptor protein ( LDLRAP )


Mutation spectrum is wide and new variants are being constantly reported It has also been reported that about 20% of FH patients diagnosed using clinical criteria do not have identifiable causative mutations ( ie mutation negative ) Autosomal recessive inheritance is rare.



Heterozygous – Most common Caused by an inherited mutation from one parent only CVD typically develops before the age of 55 yrs in men and before the age of 60 yrs in women.


Homozygous -Rare and severe form affecting approximately 1 in 1,000,000 individuals ( extremely raised LDL ) Happens when the person inherits the gene mutation from both parents Manifests early in life typically before the age of 20 yrs.


First degree relative- A persons biological parents , brothers ,sisters and children.


Second degree relatives – Biological grandparent , grandchild, uncle , aunt , niece , nephew , half sister or half brother.


Third degree relatives – Biological great grandparent , great grand child , great aunt , great uncle , first cousin , grand nephew or grand niece


Cascade testing – Used to identify people at risl of genetic condition by family tracing.


Tendon xanthomata – Clinically identifiable nodularity / thickening due to infiltration with lipid laden histiocytes. They can be seen commonly on Achilles tendon and on the back of hands , elbows and knees.


Why important – Dysregulated lipid metabolism Imparts significantly higher CVD risk particularly coronary artery disease In heterozygous FH the cumulative risk of CHD by the age of 60 yrs without treatment is atleast 50 % in men and about 30 % in women Patients are exposed to elevated LDL-C concentrations from birth -> accelerated atherosclerotic CV disease.


If FH is suspected – Do not use the conventional CV risk stratification algorithms for e.g QRISK2 which are based on general population and would significantly underestimate the lifetime CVD risk in patients with FH.


FH remains mostly underdiagnosed and untreated – most patients are diagnosed at the time of the 1st coronary event Untreated FH patients have a dramatically increased lifetime risk of CHD which can be 20 fold higher than that in the general population It is estimated that < 10 % of patients worldwide with FH have been diagnosed Children and young adults have to gain most from treatment and left untreated will develop CHD early in life HoFH patients can develop CHD very early in life and can die before age 20 without treatment.


Untreated FH carries a high risk of early CVD and death , early recognition and treatment is vital.


Diagnosis -Most patients asymptomatic until an event happens Occasionally visible signs like tendon xanthomata may be noted The rare HoFH may present in childhood with present with xanthelasmas , tendon xanthomas and corneal arcus.


Lipid profile – total cholesterol > than 7.5 mmol / L OR personal or family h/o premature CAD – which is if the person has suffered with an event before 60 or a 1st degree relative.


Check records – young people <30 with total cholesterol > 7.5 mmol/L and 30 or older with total cholesterol > 9.0 mmol/l


Secondary cause – Consider what else can alter the lipid profile and exclude causes as diabetes mellitus , obesity , excess alcohol consumption , untreated hypothyroidism and some medications as thiazide diuretics.


Homozygous – Adults- consider a diagnosis of HeFH in adults with a LDL-C conc of > 13 mmol/ L Children / young people if LDL-C conc of > 11 mmol ‘l.


NICE recommends that you should measure LDL-C twice if you are considering FH as biological and analytical variability can happen.


Different diagnostic systems are available , they may differ slightly but their prediction value is generally similar
 Simon Broome system ( recommended by NICE ) Dutch Lipid Clinic Network Criteria Japanese FH diagnostic criteria.


Refer all suspected cases to FH specialist service for DNA testing is they meet the Simon Broome citeria Cascade screening – for FH screening and targeted strategy to detect FH mutation and identify new FH index cases.


Children at risk of HoFH- at risk because of 2 affected parents or presence of clinical signs
 ( HoFH is very rare )


Children 0-10 1 affected parent NICE recommends DNA testing.


Management – Early diagnosis and treatment significantly improves prognosis Statins ( with or without ezetimibe ) are the mainstay of treatment and are effective FH patients may need higher doses of statins , more potent statins The strategy is to reduce the LDL – cholesterol levels as the prognosis of FH largely depends on the magnitude of LDL-C lowering The goal is to reduce LDL-C by 50 % from baseline level Newer more potent LDL-C lowering therapies are employed in those with more severe phenotypes.


Lifestyle modification – forms the basis of management interventions include advice on smoking , regular physical exercise , dietary recommendations.


Statins – first line reduce mortality even in receptor negative patients use greatest potency statin at the maximum tolerated dose.


Ezetimibie -if statins not tolerated or in combination when statin alone is inadequate.


PCSK9 inhibitor – injectable monoclonal antibodies that bind to PCSK9 and decrease the turnover of LDL receptors leading to a decrease in LDL-C levels.


Other novel therapies – Lomitapide – microsomal transfer protein Mipomersen – oligonucleotide inhibitor of apolipoprotein B-100 synthesis ( antisense inhibitor )


If everything else fails – Apheresis ( filtration like process ) Orthoptic liver transplantation.


  1. David T W Lui, Alan C H Lee, Kathryn C B Tan, Management of Familial Hypercholesterolemia: Current Status and Future Perspectives, Journal of the Endocrine Society, Volume 5, Issue 1, January 2021, bvaa122,
  2. Robinson JG. Management of familial hypercholesterolemia: a review of the recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Manag Care Pharm. 2013 Mar;19(2):139-49. doi: 10.18553/jmcp.2013.19.2.139. PMID: 23461430. ( Abstract )
  3. Lambert, Cameron T et al. “Current Treatment of Familial Hypercholesterolaemia.” European cardiology vol. 9,2 (2014): 76-81. doi:10.15420/ecr.2014.9.2.76
  4. Santos, Raul D.a,b Screening and management of familial hypercholesterolemia, Current Opinion in Cardiology: September 2019 – Volume 34 – Issue 5 – p 526-530 doi: 10.1097/HCO.0000000000000660 ( Abstract )
  5. Prescriber – Diagnosis and management of familial hypercholesterolemia ELIZABETH HUGHES, PATRICK J TWOMEY, SIMON WILLIAMS AND TERRY MCCORMACK Diagnosis and management of familial hypercholesterolaemia – PrescriberPrescriber

  6. Hypercholesterolaemia familial CKS NHS Hypercholesterolaemia – familial | Health topics A to Z | CKS | NICE
  7. Humphries, S E et al. “Coronary heart disease mortality in treated familial hypercholesterolaemia: Update of the UK Simon Broome FH register.” Atherosclerosis vol. 274 (2018): 41-46. doi:10.1016/j.atherosclerosis.2018.04.040
  8. NICE

    Familial hypercholesterolaemia: identification and management Clinical guideline [CG71]Published date:  Last updated: 

  9. Liyanage KE, Burnett JR, Hooper AJ, van Bockxmeer FM. Familial hypercholesterolemia: epidemiology, Neolithic origins and modern geographic distribution. Crit Rev Clin Lab Sci. 2011 Jan-Feb;48(1):1-18. doi: 10.3109/10408363.2011.565585. PMID: 21657943. ( Abstract )
  10. Prevalence and management of familial hypercholesterolemia in patients with coronary artery disease: The heredity survey Pompilio Faggiano ,Angela Pirillo ,Raffaele Griffo ,Pierluigi Temporelli ,Alberico L. Catapano ,On behalf ofCentro Studi e Formazione – Italian Association for Cardiovascular Prevention and Rehabilitation ( Abstract ) Prevalence and management of familial hypercholesterolemia in patients with coronary artery disease: The heredity survey – International Journal of Cardiology

  11. Singh, S., Bittner, V. Familial Hypercholesterolemia—Epidemiology, Diagnosis, and Screening. Curr Atheroscler Rep 17, 3 (2015). ( Abstract )
  12. Worldwide Prevalence of Familial Hypercholesterolemia American College of Cardiology Worldwide Prevalence of Familial Hypercholesterolemia – American College of Cardiology (
  13. Wang, Y., Li, Y., Liu, X. et al. The prevalence and related factors of familial hypercholesterolemia in rural population of China using Chinese modified Dutch Lipid Clinic Network definition. BMC Public Health 19, 837 (2019).


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