Familial hypercholesterolaemia


Familial hypercholesterolaemia is a common inherited disorder characterized by abnormally elevated serum levels of low-density lipoprotein (LDL) cholesterol from birth, which in time can lead to cardiovascular disease (CVD). Most cases are caused by autosomal dominant mutations in LDLR, which encodes the LDL receptor, although mutations in other genes coding for proteins involved in cholesterol metabolism or LDLR function and processing, such as APOB and PCSK9, can also be causative, although less frequently. Several sets of diagnostic criteria for familial hypercholesterolaemia are available; common diagnostic features are an elevated LDL cholesterol level and a family history of hypercholesterolaemia or (premature) CVD. DNA-based methods to identify the underlying genetic defect are desirable but not essential for diagnosis. Cascade screening can contribute to early diagnosis of the disease in family members of an affected individual, which is crucial because familial hypercholesterolaemia can be asymptomatic for decades. Clinical severity depends on the nature of the gene that harbours the causative mutation, among other factors, and is further modulated by the type of mutation. Lifelong LDL cholesterol-lowering treatment substantially improves CVD-free survival and longevity. Statins are the first-line therapy, but additional drugs, such as ezetimibe, bile acid sequestrants, PCSK9 inhibitors and other emerging therapies, are often required.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Survival rates of patients with familial hypercholesterolaemia.
Figure 2: Basic pathways in LDL particle synthesis and LDLR-mediated uptake.
Figure 3: Tendinous xanthomas on the hands and Achilles tendon in patients with heterozygous familial hypercholesterolaemia.
Figure 4: Arcus cornealis and xanthelasmata in patients with heterozygous familial hypercholesterolaemia.
Figure 5: Basic schematic procedure of clinical cascade screening.
Figure 6: Severe familial hypercholesterolaemia criteria and treatment goals according to the International Atherosclerosis Society expert panel*.


  1. 1

    Goldstein, J. L., Hobbs, H. H. & Brown, M. S. in The Metabolic annd Molecular Bases of Inherited Disease (eds Scriver, C. R., Beaudet, A., Valle, D. & Sly, W. S. ) 2863–2913 (McGraw-Hill, 2001).

  2. 2

    Scientific Steering Committee on behalf of the Simon Broome Register Group. Risk of fatal coronary heart disease in familial hypercholesterolaemia. BMJ 303, 893–896 (1991).This paper describes the widely used Simon Broome clinical criteria for diagnosis of heterozygous familial hypercholesterolaemia.

  3. 3

    Umans-Eckenhausen, M. A., Defesche, J. C., Sijbrands, E. J., Scheerder, R. L. & Kastelein, J. J. Review of first 5 years of screening for familial hypercholesterolaemia in the Netherlands. Lancet 357, 165–168 (2001).This paper defines the widely used DLCN criteria for diagnosis of heterozygous familial hypercholesterolaemia.

  4. 4

    Williams, R. R. et al. Diagnosing heterozygous familial hypercholesterolemia using new practical criteria validated by molecular genetics. Am. J. Cardiol. 72, 171–176 (1993).

  5. 5

    Genest, J. G. et al. Canadian Cardiovascular Society position statement on familial hypercholesterolemia. Can. J. Cardiol. 30, 1471–1481 (2014).

  6. 6

    Nordestgaard, B. G. et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur. Heart J. 34, 3478–3490 (2013).This article offers the definitive European Atherosclerosis Society position statement on major clinical and cardiovascular implications of heterozygous familial hypercholesterolaemia.

  7. 7

    Gidding, S. S. et al. The agenda for familial hypercholesterolemia: a scientific statement from the American Heart Association. Circulation 132, 2167–2192 (2015).This article offers the definitive American Heart Association position statement on several clinical and cardiovascular implications of heterozygous familial hypercholesterolaemia.

  8. 8

    Cuchel, M. et al. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur. Heart J. 35, 2146–2157 (2014).This expert opinion consensus document focuses on numerous pressing issues specific to homozygous familial hypercholesterolaemia.

  9. 9

    Versmissen, J. et al. Efficacy of statins in familial hypercholesterolaemia: a long term cohort study. BMJ 337, a2423 (2008).

  10. 10

    Nordestgaard, B. G. & Benn, M. Genetic testing for familial hypercholesterolaemia is essential in individuals with high LDL cholesterol: who does it in the world? Eur. Heart J. 38, 1580–1583 (2017).

  11. 11

    Benn, M., Watts, G. F., Tybjaerg-Hansen, A. & Nordestgaard, B. G. Familial hypercholesterolemia in the Danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication. J. Clin. Endocrinol. Metab. 97, 3956–3964 (2012).

  12. 12

    Watts, G. F. et al. Prevalence and treatment of familial hypercholesterolaemia in Australian communities. Intl J.Cardiol. 185, 69–71 (2015).

  13. 13

    Shi, Z. et al. Familial hypercholesterolemia in China: prevalence and evidence of underdetection and undertreatment in a community population. Intl J.Cardiol. 174, 834–836 (2014).

  14. 14

    Sjouke, B. et al. Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: prevalence, genotype-phenotype relationship, and clinical outcome. Eur. Heart J. 36, 560–565 (2015).

  15. 15

    Lansberg, P. J., Tuzgol, S., van de Ree, M. A., Defesche, J. C. & Kastelein, J. J. Higher prevalence of familial hypercholesterolemia than expected in adult patients of four family practices in Netherlands [Dutch]. Ned. Tijdschr. Geneeskd. 144, 1437–1440 (2000).

  16. 16

    Marks, D., Thorogood, M., Neil, H. A. & Humphries, S. E. A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia. Atherosclerosis 168, 1–14 (2003).

  17. 17

    Steyn, K. et al. Estimation of the prevalence of familial hypercholesterolaemia in a rural Afrikaner community by direct screening for three Afrikaner founder low density lipoprotein receptor gene mutations. Hum. Genet. 98, 479–484 (1996).

  18. 18

    Marais, A. D., Firth, J. C. & Blom, D. J. Familial hypercholesterolemia in South Africa. Semin. Vasc. Med. 4, 93–95 (2004).

  19. 19

    Moorjani, S. et al. Homozygous familial hypercholesterolemia among French Canadians in Quebec Province. Arteriosclerosis 9, 211–216 (1989).

  20. 20

    Der Kaloustian, V. M., Naffah, J. & Loiselet, J. Genetic diseases in Lebanon. Am. J. Med. Genet. 7, 187–203 (1980).

  21. 21

    Miller, P. E. et al. Screening and advanced lipid phenotyping in familial hypercholesterolemia: the Very Large Database of Lipids Study-17 (VLDL-17). J. Clin. Lipidol. 9, 676–683 (2015).

  22. 22

    Varvel, S. A. et al. Familial hypercholesterolemia prevalence of 1.5% in a clinical database of 542,214 patients: refined risk stratification using apoB:LDL-C ratio [abstract]. J. Clin. Lipidol. 9, 103 (2015).

  23. 23

    De Backer, G. et al. Prevalence and management of familial hypercholesterolaemia in coronary patients: an analysis of EUROASPIRE IV, a study of the European Society of Cardiology. Atherosclerosis 241, 169–175 (2015).

  24. 24

    Do, R. et al. Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature 518, 102–106 (2015).

  25. 25

    Pérez de Isla, L. et al. Coronary heart disease, peripheral arterial disease, and stroke in familial hypercholesterolaemia: insights from the SAFEHEART registry (Spanish Familial Hypercholesterolaemia Cohort Study). Arterioscler. Thromb. Vasc. Biol. 36, 2004–2010 (2016).

  26. 26

    Wiegman, A. et al. Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment. Eur. Heart J. 36, 2425–2437 (2015).This expert opinion consensus document focuses on issues and challenges specific to familial hypercholesterolaemia in children and adolescents.

  27. 27

    Besseling, J., Kastelein, J. J., Defesche, J. C., Hutten, B. A. & Hovingh, G. K. Association between familial hypercholesterolemia and prevalence of type 2 diabetes mellitus. J. Am. Med. Assoc. 313, 1029–1036 (2015).

  28. 28

    Eapen, D. J. Valiani, K., Reddy, S. & Sperling, L. Management of familial hypercholesterolemia during pregnancy: case series and discussion. J. Clin. Lipidol. 6, 88–91 (2012).

  29. 29

    Raal, F. J. & Santos, R. D. Homozygous familial hypercholesterolemia: current perspectives on diagnosis and treatment. Atherosclerosis 223, 262–268 (2012).

  30. 30

    Raal, F. J. et al. Reduction in mortality in subjects with homozygous familial hypercholesterolemia associated with advances in lipid-lowering therapy. Circulation 124, 2202–2207 (2011).

  31. 31

    Nanchen, D. et al. Prognosis of patients with familial hypercholesterolemia after acute coronary syndromes. Circulation 134, 698–709 (2016).

  32. 32

    Khera, A. V. et al. Diagnostic yield and clinical utility of sequencing familial hypercholesterolemia genes in patients with severe hypercholesterolemia. J. Am. Coll. Cardiol. 67, 2578–2589 (2016).

  33. 33

    Goldstein, J. L. & Brown, M. S. The LDL receptor. Arterioscler. Thromb. Vasc. Biol. 29, 431–438 (2009).This retrospective paper provides a firsthand account of the history of the Nobel Prize-winning discovery of the LDLR and the process of receptor-mediated endocytosis.

  34. 34

    Huijgen, R. et al. Assessment of carotid atherosclerosis in normocholesterolemic individuals with proven mutations in the low-density lipoprotein receptor or apolipoprotein B genes. Circ. Cardiovasc. Genet. 4, 413–417 (2011).

  35. 35

    Hegele, R. A. Plasma lipoproteins: genetic influences and clinical implications. Nat. Rev. Genet. 10, 109–121 (2009).

  36. 36

    Stroes, E. S., Koomans, H. A., de Bruin, T. W. & Rabelink, T. J. Vascular function in the forearm of hypercholesterolaemic patients off and on lipid-lowering medication. Lancet 346, 467–471 (1995).

  37. 37

    Moore, K. J. et al. Loss of receptor-mediated lipid uptake via scavenger receptor A or CD36 pathways does not ameliorate atherosclerosis in hyperlipidemic mice. J. Clin. Invest. 115, 2192–2201 (2005).

  38. 38

    Lusis, A. J. Atherosclerosis. Nature 407, 233–241 (2000).

  39. 39

    Liyanage, K. E., Burnett, J. R., Hooper, A. J. & van Bockxmeer, F. M. Familial hypercholesterolemia: epidemiology, Neolithic origins and modern geographic distribution. Crit. Rev. Clin. Lab. Sci. 48, 1–18 (2011).

  40. 40

    Bourbon, M., Alves, A. C. & Sijbrands, E. J. Low-density lipoprotein receptor mutational analysis in diagnosis of familial hypercholesterolemia. Curr. Opin. Lipidol. 28, 120–129 (2017).

  41. 41

    Moorjani, S. et al. Mutations of low-density-lipoprotein-receptor gene, variation in plasma cholesterol, and expression of coronary heart disease in homozygous familial hypercholesterolaemia. Lancet 341, 1303–1306 (1993).

  42. 42

    Jansen, A. C., van, W. S., Defesche, J. C. & Kastelein, J. J. Phenotypic variability in familial hypercholesterolaemia: an update. Curr. Opin. Lipidol. 13, 165–171 (2002).

  43. 43

    Wang, J., Ban, M. R. & Hegele, R. A. Multiplex ligation-dependent probe amplification of LDLR enhances molecular diagnosis of familial hypercholesterolemia. J. Lipid Res. 46, 366–372 (2005).

  44. 44

    Santos, R. D. & Maranhao, R. C. What is new in familial hypercholesterolemia? Curr. Opin. Lipidol. 25, 183–188 (2014).

  45. 45

    Andersen, L. H., Miserez, A. R., Ahmad, Z. & Andersen, R. L. Familial defective apolipoprotein B-100: a review. J. Clin. Lipidol. 10, 1297–1302 (2016).

  46. 46

    Abifadel, M. et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat. Genet. 34 154–156 (2003).

  47. 47

    Hopkins, P. N. et al. Characterization of autosomal dominant hypercholesterolemia caused by PCSK9 gain of function mutations and its specific treatment with alirocumab, a PCSK9 monoclonal antibody. Circ. Cardiovasc. Genet. 8, 823–831 (2015).

  48. 48

    Awan, Z. et al. APOE p. Leu167del mutation in familial hypercholesterolemia. Atherosclerosis 231, 218–222 (2013).

  49. 49

    Fouchier, S. W. et al. Mutations in STAP1 are associated with autosomal dominant hypercholesterolemia. Circ. Res. 115, 552–555 (2014).

  50. 50

    Fellin, R., Arca, M., Zuliani, G., Calandra, S. & Bertolini, S. The history of Autosomal Recessive Hypercholesterolemia (ARH). From clinical observations to gene identification. Gene 555, 23–32 (2014).

  51. 51

    Rios, J., Stein, E., Shendure, J., Hobbs, H. H. & Cohen, J. C. Identification by whole-genome resequencing of gene defect responsible for severe hypercholesterolemia. Hum. Molec. Genet. 19, 4313–4318 (2010).

  52. 52

    Stitziel, N. O. et al. Exome sequencing and directed clinical phenotyping diagnose cholesterol ester storage disease presenting as autosomal recessive hypercholesterolemia. Arterioscler. Thromb. Vasc. Biol. 33, 2909–2914 (2013).

  53. 53

    Patel, S. B. Recent advances in understanding the STSL locus and ABCG5/ABCG8 biology. Curr. Opin. Lipidol. 25, 169–175 (2014).

  54. 54

    Fouchier, S. W. & Defesche, J. C. Lysosomal acid lipase A and the hypercholesterolaemic phenotype. Curr. Opin. Lipidol. 24, 332–338 (2013).

  55. 55

    Talmud, P. J. et al. Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study. Lancet 381, 1293–1301 (2013).This manuscript reports the initial observation that a substantial proportion of individuals who seem to have heterozygous familial hypercholesterolaemia on clinical grounds in fact have polygenic hypercholesterolaemia due to multiple inherited small genetic effects.

  56. 56

    Global Lipids Genetics Consortium et al. Discovery and refinement of loci associated with lipid levels. Nat. Genet. 45, 1274–1283 (2013).

  57. 57

    Futema, M. et al. Refinement of variant selection for the LDL cholesterol genetic risk score in the diagnosis of the polygenic form of clinical familial hypercholesterolemia and replication in samples from 6 countries. Clin. Chem. 61, 231–238 (2015).

  58. 58

    Wang, J. et al. Polygenic versus monogenic causes of hypercholesterolemia ascertained clinically. Arterioscler. Thromb. Vasc. Biol. 36, 2439–2445 (2016).

  59. 59

    Santos, R. D. et al. Defining severe familial hypercholesterolaemia and the implications for clinical management: a consensus statement from the International Atherosclerosis Society Severe Familial Hypercholesterolemia Panel. Lancet Diabetes Endocrinol. 4, 850–861 (2016).This paper provides advice pertinent to individuals who are on the severe end of the clinical spectrum of familial hypercholesterolaemia, particularly severely affected patients with heterozygous familial hypercholesterolaemia.

  60. 60

    ICD List. ICD-10 Diagnosis Code E78.01: Familial hypercholesterolemia. ICD Listhttp://icdlist.com/icd-10/E78.01 (2017).

  61. 61

    Brahm, A. J. & Hegele, R. A. Combined hyperlipidemia: familial but not (usually) monogenic. Curr. Opin. Lipidol. 27, 131–140 (2016).

  62. 62

    Haralambos, K. et al. Clinical experience of scoring criteria for Familial Hypercholesterolaemia (FH) genetic testing in Wales. Atherosclerosis 240, 190–196 (2015).

  63. 63

    Weng, S. F., Kai, J., Andrew Neil, H., Humphries, S. E. & Qureshi, N. Improving identification of familial hypercholesterolaemia in primary care: derivation and validation of the familial hypercholesterolaemia case ascertainment tool (FAMCAT). Atherosclerosis 238, 336–343 (2015).

  64. 64

    Iacocca, M. A. & Hegele, R. A. Recent advances in genetic testing for familial hypercholesterolemia. Expert Rev. Mol. Diagn. 17, 641–651 (2017).

  65. 65

    Santos, R. D. Familial hypercholesterolaemia: beware of lipoprotein(a). Lancet Diabetes Endocrinol. 4, 553–555 (2016).

  66. 66

    Langsted, A., Kamstrup, P. R., Benn, M., Tybjaerg-Hansen, A. & Nordestgaard, B. G. High lipoprotein(a) as a possible cause of clinical familial hypercholesterolaemia: a prospective cohort study. Lancet Diabetes Endocrinol. 4, 577–587 (2016).

  67. 67

    Paquette, M. et al. Cardiovascular disease in familial hypercholesterolemia: validation and refinement of the Montreal-FH-SCORE. J. Clin. Lipidol. 11, 1161–1167 (2017).

  68. 68

    Lyceum CME Inc. Framingham Risk Score: Risk assessment tool for estimating a patient's 10-year risk of developing cardiovascular disease. Patient Monitoring and Support: CVD Risk Checkhttps://www.cvdriskchecksecure.com/framinghamriskscore.aspx (2013).

  69. 69

    Pérez de Isla, L. et. al. Predicting cardiovascular events in familial hypercholesterolemia: the SAFEHEART registry (Spanish Familial Hypercholesterolemia Cohort Study). Circulation 135, 2133–2144 (2017).

  70. 70

    deGoma, E. M. et al. Treatment gaps in adults with heterozygous familial hypercholesterolemia in the United States: data from the CASCADE-familial hypercholesterolemia registry. Circ. Cardiovasc. Genet. 9, 240–249 (2016).

  71. 71

    Wierzbicki, A. S., Humphries, S. E. & Minhas, R. Familial hypercholesterolaemia: summary of NICE guidance. BMJ 337, a1095 (2008).

  72. 72

    EAS Familial Hypercholesterolaemia Studies Collaboration et al. Pooling and expanding registries of familial hypercholesterolaemia to assess gaps in care and improve disease management and outcomes: rationale and design of the global EAS Familial Hypercholesterolaemia Studies Collaboration. Atheroscler. Suppl. 22, 1–32 (2016).

  73. 73

    Andersen, R. & Andersen, L. Examining barriers to cascade screening for familial hypercholesterolemia in the United States. J. Clin. Lipidol. 10, 225–227 (2016).

  74. 74

    Kusters, D. M. et al. Paediatric screening for hypercholesterolaemia in Europe. Arch. Dis. Child. 97, 272–276 (2012).

  75. 75

    Lozano, P. et al. Lipid screening in childhood and adolescence for detection of familial hypercholesterolemia: evidence report and systematic review for the US Preventive Services Task Force. JAMA 316, 645–655 (2016).

  76. 76

    Bell, D. A. et al. Effectiveness of genetic cascade screening for familial hypercholesterolaemia using a centrally co-ordinated clinical service: an Australian experience. Atherosclerosis 239, 93–100 (2015).

  77. 77

    Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents. Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents: summary report. Pediatrics 128 (Suppl. 5), S213–S256 (2011).

  78. 78

    Klancar, G. et al. Universal screening for familial hypercholesterolemia in children. J. Am. Coll. Cardiol. 66, 1250–1257 (2015).

  79. 79

    Wald, D. S. et al. Child-parent familial hypercholesterolemia screening in primary care. N. Engl. J. Med. 375, 1628–1637 (2016).This paper validates the utility of case finding in familial hypercholesterolaemia by child and parent lipid screening in primary care practices at routine child immunization visits.

  80. 80

    Besseling, J., Hovingh, G. K., Huijgen, R., Kastelein, J. J. & Hutten, B. A. Statins in familial hypercholesterolemia: consequences for coronary artery disease and all-cause mortality. J. Am. Coll. Cardiol. 68, 252–260 (2016).

  81. 81

    Gryn, S. E. & Hegele, R. A. New oral agents for treating dyslipidemia. Curr. Opin. Lipidol. 27, 579–584 (2016).

  82. 82

    Schonewille, M., de Boer, J. F. & Groen, A. K. Bile salts in control of lipid metabolism. Curr. Opin. Lipidol. 27, 295–301 (2016).

  83. 83

    Cupido, A. J., Reeskamp, L. F. & Kastelein, J. J. P. Novel lipid modifying drugs to lower LDL cholesterol. Curr. Opin. Lipidol. 28, 367–373 (2017).This is a state-of-the-art review of the medications available for the management of hypercholesterolaemia.

  84. 84

    Kastelein, J. J. et al. Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 monoclonal antibody alirocumab versus placebo in patients with heterozygous familial hypercholesterolemia. J. Clin. Lipidol. 11, 195–203.e4 (2017).

  85. 85

    Raal, F. J. et al. Long-term treatment with evolocumab added to conventional drug therapy, with or without apheresis, in patients with homozygous familial hypercholesterolaemia: an interim subset analysis of the open-label TAUSSIG study. Lancet Diabetes Endocrinol. 5, 280–290 (2017).

  86. 86

    Robinson, J. G. & Goldberg, A. C. Treatment of adults with familial hypercholesterolemia and evidence for treatment: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J. Clin. Lipidol 5, S18–S29 (2011).

  87. 87

    Smit, J. W., Bar, P. R., Geerdink, R. A. & Erkelens, D. W. Heterozygous familial hypercholesterolaemia is associated with pathological exercise-induced leakage of muscle proteins, which is not aggravated by simvastatin therapy. Eur. J. Clin. Invest. 25, 79–84 (1995).

  88. 88

    Sbrana, F. et al. Statin intolerance in heterozygous familial hypercolesterolemia with cardiovascular disease: after PCSK-9 antibodies what else? Eur. J. Prev. Cardiol. 24, 1528–1531 (2017).

  89. 89

    Stroes, E. S. et al. Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur. Heart J. 36, 1012–1022 (2015).This review of the mechanisms and management strategies of statin intolerance provides important clinical guidance, as statin intolerance is observed among many patients with familial hypercholesterolaemia.

  90. 90

    Mancini, G. B. et al. Diagnosis, prevention, and management of statin adverse effects and intolerance: Canadian Working Group Consensus update. Can. J. Cardiol. 29, 1553–1568 (2013).

  91. 91

    Amundsen, A. L. et al. Marked changes in plasma lipids and lipoproteins during pregnancy in women with familial hypercholesterolemia. Atherosclerosis 189, 451–457 (2006).

  92. 92

    Robinson, J. G. et al. Determining when to add nonstatin therapy: a quantitative approach. J. Am. Coll. Cardiol. 68, 2412–2421 (2016).

  93. 93

    Raal, F. J. et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet 385, 331–340 (2015).

  94. 94

    Tonstad, S., Knudtzon, J., Sivertsen, M., Refsum, H. & Ose, L. Efficacy and safety of cholestyramine therapy in peripubertal and prepubertal children with familial hypercholesterolemia. J. Pediatr. 129, 42–49 (1996).

  95. 95

    Hegele, R. A. et al. Nonstatin low-density lipoprotein-lowering therapy and cardiovascular risk reduction — statement from ATVB council. Arterioscler. Thromb. Vasc. Biol. 35, 2269–2280 (2015).

  96. 96

    Kastelein, J. J. et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N. Engl. J. Med. 358, 1431–1443 (2008).

  97. 97

    Huijgen, R. et al. Colesevelam added to combination therapy with a statin and ezetimibe in patients with familial hypercholesterolemia: a 12-week, multicenter, randomized, double-blind, controlled trial. Clin. Ther. 32, 615–625 (2010).

  98. 98

    Qian, L. J. et al. Therapeutic efficacy and safety of PCSK9-monoclonal antibodies on familial hypercholesterolemia and statin-intolerant patients: a meta-analysis of 15 randomized controlled trials. Sci. Rep. 7, 238 (2017).

  99. 99

    Landmesser, U. et al. European Society of Cardiology/European Atherosclerosis Society Task Force consensus statement on proprotein convertase subtilisin/kexin type 9 inhibitors: practical guidance for use in patients at very high cardiovascular risk. Eur. Heart J. 38, 2245–2255 (2017).

  100. 100

    Orringer, C. E. et al. Update on the use of PCSK9 inhibitors in adults: recommendations from an Expert Panel of the National Lipid Association. J. Clin. Lipidol. 11, 880–890 (2017).

  101. 101

    Sabatine, M. S. et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N. Engl. J. Med. 376, 1713–1172 (2017).

  102. 102

    Ridker, P. M. et al. Cardiovascular efficacy and safety of bococizumab in high-risk patients. N. Engl. J. Med. 376, 1527–1539 (2017).

  103. 103

    Santos, R. D. Phenotype versus genotype in severe familial hypercholesterolemia: what matters most for the clinician? Curr. Opin. Lipidol. 28, 130–135 (2017).

  104. 104

    Wierzbicki, A. S. & Watts, G. F. The hinterland of familial hypercholesterolaemia: what do we not know? Curr. Opin. Lipidol. 26, 475–483 (2015).

  105. 105

    Watts, G. F. et al. Integrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation. Intl J. Cardiol. 171, 309–325 (2014).

  106. 106

    Ito, M. K., McGowan, M. P. & Moriarty, P. M. Management of familial hypercholesterolemias in adult patients: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J. Clin. Lipidol 5, S38–S45 (2011).

  107. 107

    Smilde, T. J. et al. Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomised, double-blind trial. Lancet 357, 577–581 (2001).

  108. 108

    National Institute for Health and Care Excellence. Ezetimibe for treating primary heterozygous-familial and non-familial hypercholesterolaemia. NICE technology appraisal guidance [TA385]. NICEhttps://www.nice.org.uk/guidance/ta385 (2016).

  109. 109

    Cannon, C. P. et al. Ezetimibe added to statin therapy after acute coronary syndromes. N. Engl. J. Med. 372, 2387–2397 (2015).

  110. 110

    Maher, V. M. et al. Effects of lowering elevated LDL cholesterol on the cardiovascular risk of lipoprotein(a). JAMA 274, 1771–1774 (1995).

  111. 111

    Ference, B. A. et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur. Heart J. 38, 2459–2472 (2017).This comprehensive review lays out the arguments supporting a direct causative role in atherogenesis for LDL cholesterol.

  112. 112

    Raal, F. J. et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet 385, 341–350 (2015).

  113. 113

    Gagne, C., Gaudet, D. & Bruckert, E. Efficacy and safety of ezetimibe coadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia. Circulation 105, 2469–2475 (2002).

  114. 114

    Moutafis, C. D., Simons, L. A., Myant, N. B., Adams, P. W. & Wynn, V. The effect of cholestyramine on the faecal excretion of bile acids and neutral steroids in familial hypercholesterolaemia. Atherosclerosis 26, 329–334 (1977).

  115. 115

    Thompson, G. R. The evidence-base for the efficacy of lipoprotein apheresis in combating cardiovascular disease. Atheroscler. Suppl. 14, 67–70 (2013).

  116. 116

    Wang, A. et al. Systematic review of low-density lipoprotein cholesterol apheresis for the treatment of familial hypercholesterolemia. J. Am. Heart Assoc. 5, e003294 (2016).

  117. 117

    Thompson, G. R. et al. Familial Hypercholesterolaemia Regression Study: a randomised trial of low-density-lipoprotein apheresis. Lancet 345, 811–816 (1995).

  118. 118

    Wang, L. R., & Hegele, R. A. Genetics for the identification of lipid targets beyond PCSK9. Can. J. Cardiol. 33, 334–342 (2017).

  119. 119

    Raal, F. J. et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet 375, 998–1006 (2010).

  120. 120

    Cuchel, M. et al. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet 381, 40–46 (2013).

  121. 121

    Blom, D. J. et al. Long-term efficacy and safety of the microsomal triglyceride transfer protein inhibitor lomitapide in patients with homozygous familial hypercholesterolemia. Circulation 136, 332–335 (2017).

  122. 122

    Daniels, S. R., Gidding, S. S. & de Ferranti, S. D. Pediatric aspects of familial hypercholesterolemias: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J. Clin. Lipidol. 5, S30–S37 (2011).

  123. 123

    Stein, E. A. et al. Efficacy of rosuvastatin in children with homozygous familial hypercholesterolemia and association with underlying genetic mutations. J. Am. Coll. Cardiol. 70, 1162–1170 (2017).

  124. 124

    Frich, J. C., Ose, L., Malterud, K. & Fugelli, P. Perceived vulnerability to heart disease in patients with familial hypercholesterolemia: a qualitative interview study. Ann. Fam. Med. 4, 198–204 (2006).

  125. 125

    Claassen, L., Henneman, L., van der Weijden, T., Marteau, T. M. & Timmermans, D. R. Being at risk for cardiovascular disease: perceptions and preventive behavior in people with and without a known genetic predisposition. Psychol. Health. Med. 17, 511–521 (2012).

  126. 126

    Agard, A., Bolmsjo, I. A., Hermeren, G. & Wahlstom, J. Familial hypercholesterolemia: ethical, practical and psychological problems from the perspective of patients. Patient Educ. Couns. 57, 162–167 (2005).

  127. 127

    Graesdal, A. et al. Apheresis in homozygous familial hypercholesterolemia: the results of a follow-up of all Norwegian patients with homozygous familial hypercholesterolemia. J. Clin. Lipidol. 6, 331–339 (2012).

  128. 128

    Sturm, A. C. Cardiovascular cascade genetic testing: exploring the role of direct contact and technology. Front. Cardiovasc. Med. 3, 11 (2016).This article reviews the process and provides tips on procedures and implementation of cascade screening, which is very effective in ascertaining new patients with familial hypercholesterolaemia.

  129. 129

    Aatre, R. D. & Day, S. M. Psychological issues in genetic testing for inherited cardiovascular diseases. Circ. Cardiovasc. Genet. 4, 81–90 (2011).

  130. 130

    Homsma, S. J., Huijgen, R., Middeldorp, S., Sijbrands, E. J. & Kastelein, J. J. Molecular screening for familial hypercholesterolaemia: consequences for life and disability insurance. Eur. J. Hum. Genet. 16, 14–17 (2008).

  131. 131

    Huijgen, R. et al. Improved access to life insurance after genetic diagnosis of familial hypercholesterolaemia: cross-sectional postal questionnaire study. Eur. J. Hum. Genet. 20, 722–728 (2012).

  132. 132

    Perak, A. M. et al. Long-term risk of atherosclerotic cardiovascular disease in US adults with the familial hypercholesterolemia phenotype. Circulation 134, 9–19 (2016).

  133. 133

    Paquette, M., Dufour, R. & Baass, A. The Montreal-familial hypercholesterolemia-SCORE: A new score to predict cardiovascular events in familial hypercholesterolemia. J. Clin. Lipidol. 11, 80–86 (2017).

  134. 134

    Hegele, R. A. et al. Targeted next-generation sequencing in monogenic dyslipidemias. Curr. Opin. Lipidol. 26, 103–113 (2015).

  135. 135

    van der Graaf, A. et al. Familial defective apolipoprotein B and familial hypobetalipoproteinemia in one family: two neutralizing mutations. Ann. Intern. Med. 148, 712–714 (2008).

  136. 136

    Wittekoek, M. E. et al. A common mutation in the lipoprotein lipase gene (N291S) alters the lipoprotein phenotype and risk for cardiovascular disease in patients with familial hypercholesterolemia. Circulation 97, 729–735 (1998).

  137. 137

    Wierzbicki, A. S. & Grant, P. Drugs for hypercholesterolaemia - from statins to pro-protein convertase subtilisin kexin 9 (PCSK9) inhibition. Clin. Med. 16, 353–357 (2016).This is another state-of-the-art review of current medications available for the management of hypercholesterolaemia.

  138. 138

    Ray, K. K. et al. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N. Engl. J. Med. 376, 1430–1440 (2017).

  139. 139

    Turner, T. & Stein, E. A. Non-statin treatments for managing LDL cholesterol and their outcomes. Clin. Ther. 37, 2751–2769 (2015).

  140. 140

    Galabova, G. et al. Peptide-based anti-PCSK9 vaccines — an approach for long-term LDLc management. PLoS ONE 9, e114469 (2014).

  141. 141

    The HPS3-TIMI55-REVEAL Collaborative Group. Effects of anacetrapib in patients with atherosclerotic vascular disease (REVEAL). N. Engl. J. Med. 377, 1217–1227 (2017).

  142. 142

    Kassim, S. H. et al. Adeno-associated virus serotype 8 gene therapy leads to significant lowering of plasma cholesterol levels in humanized mouse models of homozygous and heterozygous familial hypercholesterolemia. Hum. Gene Ther. 24, 19–26 (2013).

  143. 143

    Somanathan, S. et al. AAV vectors expressing LDLR gain-of-function variants demonstrate increased efficacy in mouse models of familial hypercholesterolemia. Circ. Res. 115, 591–599 (2014).

  144. 144

    Nherera, L., Marks, D., Minhas, R., Thorogood, M. & Humphries, S. E. Probabilistic cost-effectiveness analysis of cascade screening for familial hypercholesterolaemia using alternative diagnostic and identification strategies. Heart 97, 1175–1181 (2011).

  145. 145

    Ademi, Z. et al. Cascade screening based on genetic testing is cost-effective: evidence for the implementation of models of care for familial hypercholesterolemia. J. Clin. Lipidol. 8, 390–400 (2014).

  146. 146

    Alfonsi, J. E., Hegele, R. A. & Gryn, S. E. Pharmacogenetics of lipid-lowering agents: precision or indecision medicine? Curr. Atheroscler. Rep. 18, 24 (2016).

  147. 147

    Dequeker, J., Muls, E. & Leenders, K. Xanthelasma and lipoma in Leonardo da Vinci's Mona Lisa. Isr. Med. Assoc. J. 6, 505–506 (2004).

  148. 148

    Ose, L. The real code of Leonardo da Vinci. Curr. Cardiol. Rev. 4, 60–62 (2008).

  149. 149

    Erkelens, D. W. & Sherwood, L. M. Familial hypercholesterolaemia, tendinous xanthomas, and Frans Hals. JAMA 262, 2092 (1989).

  150. 150

    Fagge, C. H. Xanthomatous diseases of the skin. Trans Pathol. Soc. 24, 242–250 (1873).

  151. 151

    Muller, C. Xanthoma, hypercholesterolaemia, angina pectoris. Acta Med. Scand. 89, 75–84 (1938).

  152. 152

    Wilkinson, C. F., Hand, E. A. & Fliegelman, F. T. Essential familial hypercholesterolaemia. Ann. Intern. Med. 29, 671–676 (1948).

  153. 153

    Khachadurian, A. K. The inheritance of essential familial hypercholesterolaemia. Am. J. Med. 37, 402–407 (1964).

  154. 154

    Goldstein, J. L. & Brown, M. S. Familial hypercholesterolaemia: identification of a defect in the regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity associated with overproduction of cholesterol. Proc. Natl Acad. Sci. USA 70, 2804–2808 (1973).

  155. 155

    Brown, M. S. & Goldstein, J. L. Expression of the familial hypercholesterolaemia gene in heterozygotes: mechanism for a dominant disorder in man. Science 185, 61–63 (1974).

  156. 156

    Anderson, R. G., Goldstein, J. L. & Brown, M. S. Localization of low density lipoprotein receptors on plasma membrane of normal human fibroblasts and their absence in cells from a familial hypercholesterolaemia homozygote. Proc. Natl Acad. Sci. USA 73, 2434–2438 (1976).

  157. 157

    Brown, M. S. & Goldstein, J. L. A receptor-mediated pathway for cholesterol homeostasis. Science 232, 34–47 (1986).

  158. 158

    Endo, A., Kuroda, M. & Tsujita, Y. ML-236A, ML-236B, and ML-236C, new inhibitors of cholesterogenesis produced by Penicillium citrinium. J. Antibiot. 29, 1346–1348 (1976).

  159. 159

    Santos, R. D. Cascade screening in familial hypercholesterolemia: advancing forward. J. Atheroscler. Thromb. 22, 869–880 (2015).

Download references

Author information

Introduction (J.C.D. and R.A.H.); Epidemiology (A.S.W.); Mechanisms/pathophysiology (R.A.H. and J.C.D.); Diagnosis, screening and prevention (R.A.H., R.D.S. and J.C.D.); Management (A.S.W., R.A.H. and S.S.G.); Quality of life (S.S.G. and M.H.-S.); Outlook (M.H.-S. and R.A.H.); Overview of the Primer (J.C.D. and R.A.H).

Correspondence to Joep C. Defesche or Robert A. Hegele.

Ethics declarations

Competing interests

S.S.G. acts as a consultant for RegenXbio. M.H.-S. acts as a consultant for Aegerion, receives research funding from Amgen, Astellas, Sanofi and MSD and has received speaker fees from Amgen, Astellas, Astra Zeneca, Sanofi, Boehringer Ingelheim, Otsuka and Daiichi-Sankyo. R.A.H. acts as a consultant for and is on the advisory board of Acasti, Aegerion, Amgen, Boston Heart Diagnostics, Cerenis, Medpace, Pfizer, Regeneron, Sanofi and Valeant. R.S.D. acts as a consultant for Amgen, Biolab, Boehringer Ingelheim, Eli Lilly, Merck, NovoNordisk, Pfizer and Sanofi/Regeneron and has received speaker fees from Amgen, Astra Zeneca and Sanofi/Regeneron. J.C.D. and A.S.W. declare no competing interests.

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Defesche, J., Gidding, S., Harada-Shiba, M. et al. Familial hypercholesterolaemia. Nat Rev Dis Primers 3, 17093 (2017). https://doi.org/10.1038/nrdp.2017.93

Download citation

Further reading