Top

Published in:

01-02-2015 | New Drugs Approved for Homozygous FH (SS Virani, Section Editor)

Familial Hypercholesterolemia—Epidemiology, Diagnosis, and Screening

Authors: Siddharth Singh, Vera Bittner

Published in: Current Atherosclerosis Reports | Issue 2/2015

Abstract

Familial hypercholesterolemia is among the commonest inherited metabolic disorders and is characterized by severely elevated LDL cholesterol levels. Mutations in four genes have been noted in patients with familial hypercholesterolemia (FH): LDL receptor (most common), apolipoprotein B (Apo B), proprotein convertase subtilin/kexin 9 (PCSK9), and low-density lipoprotein receptor adaptor protein (LDLRAP). In most cases, inheritance is autosomal co-dominant with homozygotes having double the LDL cholesterol levels of heterozygotes. Autosomal recessive inheritance is rare. The prevalence of the heterozygous state has been estimated at 1 in 200 to 1 in 500 and of the homozygous state from 1 in 160,000 to 1 in 1,000, 000. Three formal diagnostic criteria have been proposed to diagnose FH in practice-MedPed, Simon Broome, and Dutch Lipid Clinic Network. The role of genetic testing and cascade screening among families is discussed in this review.

Khachadurian AK. The inheritance of essential familial hypercholesterolemia. Am J Med. 1964;37:402–7.PubMedCrossRef

Fredrickson DS, Lees RS. A system for phenotyping hyperlipoproteinemia. Circulation. 1965;31:321–7.PubMedCrossRef

Goldstein JL, Brown MS. Familial hypercholesterolemia: 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 U S A. 1973;70:2084–8.

4.•

Cuchel M, Bruckert E, Ginsberg HN, Raal FJ, Santos RD, Hegele RA, et al.; for the European Atherosclerosis Society Consensus Panel on Familial Hypercholesterolaemia. 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. 2014 Jul 22. Reviews genetics and clinical diagnosis of FH.

Goldstein JL, Schrott HG, Hazzard WR, Bierman EL, Motulsky AG. Hyperlipidemia in coronary heart disease. II. Genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia. J Clin Invest. 1973;52:1544–68.PubMedCentralPubMedCrossRef

Moorjani S, Roy M, Gagne C, et al. Homozygous familial hypercholesterolemia among French Canadians in Quebec Province. Arteriosclerosis. 1989;9:211–16.PubMedCrossRef

Seftel HC, Baker SG, Sandler MP, et al. A host of hypercholesterolaemic homozygotes in South Africa. Br Med J. 1980;281:633–6.PubMedCentralPubMedCrossRef

Leitersdorf E, Van Der Westhuyzen DR, Coetzee GA, Hobbs HH. Familial hypercholesterolemia in Afrikaner homozygotes. Two common low density lipoprotein receptor gene mutations cause familial hypercholesterolemia in Afrikaners. J Clin Invest. 1989;84:954–61.PubMedCentralPubMedCrossRef

Seftel HC, Baker SG, Jenkins T, Mendelsohn D. Prevalence of familial hypercholesterolemia in Johannesburg Jews. Am J Med Genet. 1989;34:545–7.PubMedCrossRef

10.

Slimane MN, Pousse H, Maatoug F, et al. Phenotypic expression of familial hypercholesterolaemia in central and southern Tunisia. Atherosclerosis. 1993;104:153–8.PubMedCrossRef

11.

Kontula K, Koivisto UM, Koivisto P, Turtola H. Molecular genetics of familial hypercholesterolaemia: common and rare mutations of the low density lipoprotein receptor gene. Ann Med. 1992;24(5):363–7.PubMedCrossRef

12.

Rubinsztein DC, van der Westhuyzen DR, Coetzee GA. Monogenic primary hypercholesterolaemia in South Africa. S Afr Med J. 1994;84:339–44.PubMed

13.

Betard C, Kessling AM, Roy M, Chamberland A, Lussier- Cacan S, Davignon J. Molecular genetic evidence for a founder effect in familial hypercholesterolemia among French Canadians. Hum Genet. 1992;88:529–39.PubMedCrossRef

14.

Benn M, Watts GF, Tybjaerg-Hansen A, Nordestgaard BG. Familial hypercholesterolemia in the Danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication. J Clin Endocrinol Metab. 2012;97:3956–64. In a community-based sample of 69,016 participants, the authors found that the prevalence of FH was 1 in 137 (much higher than commonly reported), and less than 50 % of sufferers were on lipid-lowering therapy.PubMedCrossRef

15.•

Sjouke B, Kusters DM, Kindt I, Besseling J, Defesche JC, Sijbrands EJ, Roeters van Lennep JE, Stalenhoef AF, Wiegman A, de Graaf J, Fouchier SW, Kastelein JJ, Hovingh GK. Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: prevalence, genotype-phenotype relationship, and clinical outcome. Eur Heart J. 2014 Feb 28. Authors provide recent estimate of homozygous FH from the Netherlands (1 in 300,000). Of 104, 682 individuals who underwent genetic testing, 49 had homozygous FH-20:20 were true homozygotes, 25 compound heterozygotes, and 4 homozygous for Apo B.

16.

Watts GF, Lewis B, Sullivan DR. Familial hypercholesterolemia: a missed opportunity in preventive medicine. Nat Clin Pract Cardiovasc Med. 2007;4:404–5.PubMedCrossRef

17.

Ozumi K, Tasaki H, Yamashita K, Tanaka S, Sasaguri T, Sasaguri Y, et al. Valvular and supravalvular aortic stenosis in heterozygous familial hypercholesterolemia, a case report. J Atheroscler Thromb. 2005;12(5):289–93.PubMedCrossRef

18.

Leren TP. Cascade genetic screening for familial hypercholesterolemia. Clin Genet. 2004;66:483–7.PubMedCrossRef

19.•

Goldberg AC, Hopkins PN, Toth PP, Ballantyne CM, Rader DJ, Robinson JG, et al. Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011;5(3):133–40. Reviews screening, diagnosis, and management of FH.PubMedCrossRef

20.

Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al. American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63(25):2889–934.PubMedCrossRef

21.

Goldstein JL, Brown MS. The LDL receptor locus and the genetics of familial hypercholesterolemia. Annu Rev Genet. 1979;13:259–89.PubMedCrossRef

22.

Pimstone SN, Sun XM, du Souich C, Frohlich JJ, Hayden MR, Soutar AK. Phenotypic variation in heterozygous familial hypercholesterolemia: a comparison of Chinese patients with the same or similar mutations in the LDL receptor gene in China or Canada. Arterioscler Thromb Vasc Biol. 1998;18:309–15.PubMedCrossRef

23.

Goldstein JL, Brown MS. Binding and degradation of low density lipoproteins by cultured human fibroblasts. Comparison of cells from a normal subject and from a patient with homozygous familial hypercholesterolemia. J Biol Chem. 1974;249:5153–62.PubMed

24.

Soutar AK, Naoumova RP. Mechanisms of disease: genetic causes of familial hypercholesterolemia. Nat Clin Pract Cardiovasc Med. 2007;4(4):214–25.PubMedCrossRef

25.

University College London Low Density Lipoprotein Familial Hypercholesterolemia Database. http://www.ucl.ac.uk/ldlr. Accessed 5 Sept 2014.

26.

Varret M, Abifadel M, Rabes JP, Boileau C. Genetic heterogeneity of autosomal dominant hypercholesterolemia. Clin Genet. 2008;73:1–13.PubMedCrossRef

27.

Myant NB, Forbes SA, Day IN, Gallagher J. Estimation of the age of the ancestral arginine3500 > glutamine mutation in human apoB-100. Genomics. 1997;45(1):78–87.PubMedCrossRef

28.

Tai DY, Pan JP, Lee-Chen GJ. Identification and haplotype analysis of apolipoprotein B-100 Arg3500–>Trp mutation in hyperlipidemic Chinese. Clin Chem. 1998;44:1659–65.PubMed

29.

Abifadel M, Varret M, Rabès JP, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003;34:154–6.PubMedCrossRef

30.

Cohen JC, Boerwinkle E, Mosley Jr TH, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354(12):1264–72.PubMedCrossRef

31.

Fouchier SW, Dallinga-Thie GM, Meijers JC, Zelcer N, Kastelein JJ, Defesche JC, et al. Mutations in STAP1 are associated with autosomal dominant hypercholesterolemia. Circ Res. 2014;115(6):552–5.PubMedCrossRef

32.

Khachadurian AK, Uthman SM. Experiences with the homozygous cases of familial hypercholesterolemia. A report of 52 patients. Nutr Metab. 1973;15:132–40.PubMedCrossRef

33.

Garcia CK, Wilund K, Arca M, Zuliani G, Fellin R, Maioli M, et al. Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein. Science. 2001;292(5520):1394–8.PubMedCrossRef

34.

Soutar AK, Naoumova RP, Traub LM. Genetics, clinical phenotype, and molecular cell biology of autosomal recessive hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2003;23(11):1963–70.PubMedCrossRef

35.•

Talmud PJ, Shah S, Whittall R, et al. Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study. Lancet. 2013;381(9874):1293–301. Using data from multiple sites, authors showed that mutation-negative FH patients had higher weighted LDL-gene score (derived using 12 common LDL-C-raising alleles) suggesting that single nucleotide polymorphisms may account for hyperlipidemia in mutation-negative patients and also explain variable penetrance seen with mutations.PubMedCrossRef

36.

Ferrieres J, Lambert J, Lussier-Cacan S, Davignon J. Coronary artery disease in heterozygous familial hypercholesterolemic patients with the same LDL receptor gene mutation. Circulation. 1995;92:290–95.PubMedCrossRef

37.•

Daniels SR, Gidding SS, de Ferranti SD. Pediatric aspects of familial hypercholesterolemias: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011;5:30–7. Reviews screening and diagnosis of FH in children and young adults.CrossRef

38.

Freedman DS, Srinivasan SR, Cresanta JL, Webber LS, Berenson GS. Cardiovascular risk factors from birth to 7 years of age: the Bogalusa Heart Study. Serum lipids and lipoproteins Pediatr. 1987;80(5 Pt 2):789–96.

39.

Vuorio AF, Turtola H, Kontula K. Neonatal diagnosis of familial hypercholesterolemia in newborns born to a parent with a molecularly defined heterozygous familial hypercholesterolemia. Arterioscler Thromb Vasc Biol. 1997;17(11):3332–7.PubMedCrossRef

40.

Kwiterovich Jr PO. Recognition and management of dyslipidemia in children and adolescents. J Clin Endocrinol Metab. 2008;93:4200–9.PubMedCrossRef

41.

Merkens LS, Myrie SB, Steiner RD, et al. Sitosterolemia. 2013 Apr 4. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2014. Available from: http://www.ncbi.nlm.nih.gov/books/NBK131810/

42.

Pullinger CR, Eng C, Salen G, Shefer S, Batta AK, Erickson SK, et al. Human cholesterol 7alpha-hydroxylase (CYP7A1) deficiency has a hypercholesterolemic phenotype. J Clin Invest. 2002;110(1):109–17.PubMedCentralPubMedCrossRef

43.

Fouchier SW, Defesche JC. Lysosomal acid lipase A and the hypercholesterolaemic phenotype. Curr Opin Lipidol. 2013;24(4):332–8.PubMedCrossRef

44.

Haacke H, Parwaresch MR. Spontaneous rupture of the Achilles tendon - a sign of hyperlipoproteinaemia (HLP) type II. Klin Wochenschr. 1979;57(8):397–400.PubMedCrossRef

45.

Sibley C, Stone NJ. Familial hypercholesterolemia: a challenge of diagnosis and therapy. Cleve Clin J Med. 2006;73(1):57–64.PubMedCrossRef

46.

Scientific Steering Committee on behalf of the Simon Broome Register Group. Risk of fatal coronary heart disease in familial hypercholesterolaemia. BMJ. 1991;303(6807):893–6.CrossRef

47.

World Health Organization. Familial hypercholesterolemia—report of a second WHO Consultation. Geneva, Switzerland: World Health Organization, 1999. (WHO publication no. WHO/HGN/FH/CONS/99.2).

48.

Williams RR, Hunt SC, Schumacher MC, Hegele RA, Leppert MF, Ludwig EH, et al. Diagnosing heterozygous familial hypercholesterolemia using new practical criteria validated by molecular genetics. Am J Cardiol. 1993;72(2):171–6.PubMedCrossRef

49.

Kraft HG, Lingenhel A, Raal FJ, Hohenegger M, Utermann G. Lipoprotein(a) in homozygous familial hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2000;20:522–8.PubMedCrossRef

50.

Alonso R, Andres E, Mata N, Fuentes-Jiménez F, Badimón L, López-Miranda J, et al. SAFEHEART Investigators. Lipoprotein(a) levels in familial hypercholesterolemia: an important predictor of cardiovascular disease independent of the type of LDL receptor mutation. J Am Coll Cardiol. 2014;63(19):1982–9.PubMedCrossRef

51.•

Leebmann J, Roeseler E, Julius U, Heigl F, Spitthoever R, Heutling D, et al. Pro (A) LiFe Study Group. Lipoprotein apheresis in patients with maximally tolerated lipid-lowering therapy, lipoprotein(A)-hyperlipoproteinemia, and progressive cardiovascular disease: prospective observational multicenter study. Circulation. 2013;128(24):2567–76.PubMedCrossRef

52.

Humphries SE, Whittall RA, Hubbart CS, Maplebeck S, Cooper JA, Soutar AK, Naoumova R, Thompson GR, Seed M, Durrington PN, Miller JP, Betteridge DJ, Neil HA; Simon Broome Familial Hyperlipidaemia Register Group and Scientific Steering Committee. Genetic causes of familial hypercholesterolaemia in patients in the UK: relation to plasma lipid levels and coronary heart disease risk. J Med Genet. 2006 Dec;43 (12):943–9. Erratum in: J Med Genet. 2010 Dec;47 (12):862. J Med Genet. 2009 Dec;46 (12):861

53.

Umans-Eckenhausen MA, Sijbrands EJ, Kastelein JJ, Defesche JC. Low-density lipoprotein receptor gene mutations and cardiovascular risk in a large genetic cascade screening population. Circulation. 2002;106(24):3031–6.PubMedCrossRef

54.

Hopkins PN, Toth PP, Ballantyne CM, Rader DJ, National Lipid Association Expert Panel on Familial Hypercholesterolemia. Familial hypercholesterolemias: prevalence, genetics, diagnosis and screening recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011Jun;5(3 Suppl):S9–17.

55.

Palacios L, Grandoso L, Cuevas N, Olano-Martin E, Martinez A, Tejedor D, et al. Molecular characterization of familial hypercholesterolemia in Spain. Atherosclerosis. 2012;221:137–42.PubMedCrossRef

56.

Herman K, Van Heyningen C, Wile D. Cascade screening for familial hypercholesterolaemia and its effectiveness in the prevention of vascular disease. Br J Diabet Vasc Dis. 2009;9:171–4.CrossRef

57.

DeMott, K, Nherera L, Shaw EJ, Minhas R, Humphries SE, Kathoria M, Ritchie G, Nunes V, Davies D, Lee P, McDowell I, Neil A, Qureshi N, Rowlands P, Seed M, Stracey H, Thorogood M, Watson M. Clinical guidelines and evidence review for familial hypercholesterolaemia: the identification and management of adults and children with familial hypercholesterolaemia. 2008. London: National Collaborating Centre for Primary Care and Royal College of General Practitioners

58.

Versmissen J, Oosterveer DM, Yazdanpanah M, Defesche JC, Basart DC, Liem AH, et al. Efficacy of statins in familial hypercholesterolaemia: a long term cohort study. BMJ. 2008;11.

59.

Neil A, Cooper J, Betteridge J, Capps N, McDowell I, Durrington P, et al. Reductions in all cause, cancer, and coronary mortality in statin-treated patients with heterozygous familial hypercholesterolaemia: a prospective registry study. Eur Heart J. 2008;29(21):2625–33.PubMedCentralPubMedCrossRef

60.

Kusters DM, Avis HJ, de Groot E, Wijburg FA, Kastelein JJ, Wiegman A, et al. Ten-year follow-up after initiation of statin therapy in children with familial hypercholesterolemia. JAMA. 2014;312(10):1055–7.PubMedCrossRef

61.

Schmidt HH, Hill S, Makariou EV, Feuerstein IM, Dugi KA, Hoeg JM. Relation of cholesterol-year score to severity of calcific atherosclerosis and tissue deposition in homozygous familial hypercholesterolemia. Am J Cardiol. 1996;77:575–80.PubMedCrossRef

62.

Thorsson B, Sigurdsson G, Gudnason V. Systematic family screening for familial hypercholesterolemia in Iceland. Arterioscler Thromb Vasc Biol. 2003;23:335–8.PubMedCrossRef

63.

Laurie AD, Scott RS, George PM. Genetic screening of patients with familial hypercholesterolaemia (FH): a New Zealand perspective. Atheroscler Suppl. 2004;5:13–5.PubMedCrossRef

64.

Leren TP, Manshaus T, Skovholt U, et al. Application of molecular genetics for diagnosing familial hypercholesterolemia in Norway: results from a family-based screening program. Semin Vasc Med. 2004;4:75–85.PubMedCrossRef

65.

Pocovi M, Civeira F, Alonso R, et al. Familial hypercholesterolemia in Spain: case-finding program, clinical and genetic aspects. Semin Vasc Med. 2004;4:67–74.PubMedCrossRef

66.

Nherera L, Marks D, Minhas R, Thorogood M, Humphries SE. Probabilistic cost-effectiveness analysis of cascade screening for familial hypercholesterolaemia using alternative diagnostic and identification strategies. Heart. 2011;97(14):1175–81.PubMedCrossRef

67.

Wald DS, Kasturiratne A, Godoy A, Ma L, Bestwick JP, Brewer N, et al. Child-parent screening for familial hypercholesterolemia. J Pediatr. 2011;159(5):865–7.PubMedCrossRef

68.

Vergotine J, Thiart R, Langenhoven E, Hillermann R, De Jong G, Kotze MJ. Prenatal diagnosis of familial hypercholesterolemia: importance of DNA analysis in the high-risk South African population. Genet Counsel. 2001;12:121–7.PubMed

Title: Familial Hypercholesterolemia—Epidemiology, Diagnosis, and Screening
Authors: Siddharth Singh
Vera Bittner
Publication date: 01-02-2015
Publisher: Springer US
Published in: Current Atherosclerosis Reports / Issue 2/2015
Print ISSN: 1523-3804
Electronic ISSN: 1534-6242
DOI: https://doi.org/10.1007/s11883-014-0482-5

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 2/2015

Female-Specific Factors for IHD: Across the Reproductive Lifespan

Percutaneous Versus Surgical Management of Lower Extremity Peripheral Artery Disease

Diagnosis and Management of Type II Myocardial Infarction: Increased Demand for a Limited Supply of Evidence

Epigenetic Reprogramming in Atherosclerosis

Non-traditional Dosing of Statins in Statin-Intolerant Patients—Is It Worth a Try?

A Review of Statin Use and Prostate Cancer

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials