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Familial hypercholesterolemia: clinical reports, molecular genetics and differential diagnosis


Authors: Michal Vrablík 1;  Lucie Schwarzová 1;  Tomáš Freiberger 1;  Lukáš Tichý 2;  Richard Češka 1
Authors‘ workplace: Centrum preventivní kardiologie III. interní kliniky 1. LF UK a VFN, Praha 1;  Genetická laboratoř, Centrum kardiovaskulární a transplantační chirurgie, Brno 2
Published in: AtheroRev 2016; 1(1): 19-27
Category: Reviews

Overview

Recent studies have revealed the prevalence of familial hypercholesterolemia (FH) is approximately twice higher than previously estimated and, thus, the disease affects one in 250 persons from the general population. Therefore FH remains the most frequent inherited metabolic disorder. Due to the genetic defect LDL-cholesterol accumulates both in the plasma and tissues leading to premature and accelerated atherosclerosis. Untreated patients with FH might suffer myocardial infarction in the third or fourth decade, one third of these events being fatal. The disease is under­diagnosed and undertreated worldwide. The most effective way to identify FH patients is so called cascade screening in affected families. Early diagnosis and treatment significantly contribute to lowering of CVD risk. The treatment is based on lifestyle changes complemented with a maximal dose of statin. In case target LDL-cholesterol values are not reached a statin-ezetimibe combination is recommended. In the nearest future we will be able to use novel therapies (particularly PCSK9 inhibitors). These compounds together with MTP inhibitor lomitapide (indicated for homozygous and severe heterozygous FH) will bring up to 80 % of patients to their LDL-cholesterol targets.

Key words:
familial hypercholesterolemia – differential diagnosis – genetics – cardiovascular risk – cascade screening


Sources

1. Lai CQ, Parnell LD, Ordovas JM. The APOA1/C3/A4/A5 gene cluster, lipid metabolism and cardiovascular disease risk. Curr Opin Lipidol 2005; 16(2): 153–166.

2. Goldstein JL, Hobbs HH, Brown MS. Familial hypercholesterolemia. In: Scriver, CR, Beaudet AL, Sly WS et al. The metabolic and molecular bases of inherited disease. 4 voll. 8th ed. McGraw-Hill: New York 2001: 2863–2914. ISBN 978–0071163361.

3. Marks D, Thorogood M, Neil HA et al. A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia. Athero­sclerosis 2003; 168(1):1–14.

4. Hobbs HH, Brown MS, Goldstein JL. Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. Hum Mutat 1992; 1(6): 445–466.

5. Hegele RA. Monogenic dyslipidemias: window on determinants of plasma lipoprotein metabolism. Am J Hum Genet 2001; 69(6): 1161–1177.

6. Rader DJ, Cohen J, Hobbs HH. Monogenic hypercholesterolemia: new insights in pathogenesis and treatment. J Clin Invest 2003; 111(12): 1795–1803.

7. Innerarity TL, Weisgraber KH, Arnold KS et al. Familial defective apolipoprotein B-100: low density lipoproteins with abnormal receptor binding. Proc Natl Acad Sci USA 1987; 84(19): 6919–6923.

8. Cohen JC, Boerwinkle E, Mosley TH Jr et al. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006; 354(12): 1264–1272.

9. 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(11): 3956–3964.

10. Cuchel M, Bruckert E, Ginsberg HN 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 2012; 35(32): 2146–2157.

11. Nordestgaard BG, Chapman MJ, Humphries SE et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease. Eur Heart J 2013; 34(45):3478–3490a.

12. Šamánek M, Urbanová Z. Hodnoty cholesterolu a triglyceridů a jejich vývoj mezi druhým a sedmnáctým rokem. Čas Lék Čes 1997; 136(12): 380–385.

13. Hansen PS, Rudinger N, Tybjerg-Hansen A et al. Detection of the apoB-3500 mutation (glutamine for arginine) by gene amplification and cleavage with MspI. J Lipid Res 1991; 32(7): 1229–1233.

14. Tichý L, Freiberger T, Zapletalová P et al. The molecular basis of familial hypercholesterolemia in the Czech Republic: Spectrum of LDLR mutations and genotype-phenotype correlations. Atherosclerosis 2012; 223(2): 401–408.

15. Hartgers ML, Ray KK, Hovingh GK. New Approaches in Detection and Treatment of Familial Hypercholesterolemia. Curr Cardiol Rep 2015; 17(12): 109.

16. Hegele RA, Ban MR, Cao H et al. Targeted next-generation sequencing in monogenic dyslipidemias. Curr Op Lipidol 2015; 26(2): 103–113.

17. Vandrovcova J, Thomas ERA, Atanur SS et al. The use of next-generation sequencing in clinical diagnosis of famolial hypercholesterolemia. Genet Med 2013; 15(12): 948–957.

18. Hansel B, Carrie´ A, Brun-Druc N et al. Premature atherosclerosis is not systematic in phytosterolemic patients: severe hypercholesterolemia as a confounding factor in five subjects. Atherosclerosis 2014; 234(1):162–168.

19. Kidambi S, Patel SB. Sitosterolaemia: pathophysiology, clinical presentation and laboratory diagnosis. J Clin Pathol 2008; 61(5): 588–594.

20. Bernstein DL, Hulkova H, Bialer MG et al. Cholesteryl ester storage disease: review of the findings in 135 reported patients with an underdiagnosed disease. J Hepatol 2013; 58(6): 1230–1243.

21. Burton BK, Balwani M, Feillet F et al. A phase 3 trial of sebelipase alfa in lysosomal acid lipase deficiency. N Engl J Med 2015; 373(11): 1010–1020.

22. 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): 1293–1301.

23. Knoblauch H, Bauerfeind A, Krahenbuhl C et al. Common haplotypes in five genes influence genetic variance of LDL and HDL cholesterol in the general population. Hum Mol Genet 2002; 11(12): 1477–1485.

24. Soška V, Vaverková H, Vrablík M et al. Stanovisko výboru ČSAT k doporučením ESC/EAS pro diagnostiku a léčbu dyslipidemií z roku 2011. DMEV 2013; 16(1): 24–29.

25. Vrablík M, Freiberger T, Bláha V et al. Souhrn konsenzu panelu expertů European Atherosclerosis Society k otázce diagnostiky a klinickému vedení nemocných s familiární hypercholesterolemií. Pracovní skupina České společnosti pro aterosklerózu. Hypertenze a KV prevence 2015; 4(2): 44–48. Dostupné z WWW: http://www.hypertension.cz/sqlcache/hypertenze-02–2015.pdf.

26. Vrablík M, Češka R, Bláha V et al. Souhrn konsenzu panelu expertů European Atherosclerosis Society k otázce diagnostiky a klinickému vedení nemocných s homozygotní formou familiární hypercholesterolemie. Hypertenze a KV prevence 2015; 4(1): 54–56. Dostupné z WWW: http://www.hypertension.cz/sqlcache/csh-2015–1-web.pdf.

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Angiology Diabetology Internal medicine Cardiology General practitioner for adults
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