Endocrinol Metab.  2017 Mar;32(1):36-40. 10.3803/EnM.2017.32.1.36.

Update on Familial Hypercholesterolemia: Diagnosis, Cardiovascular Risk, and Novel Therapeutics

• Lee SH

• KMID: 2413284
• DOI: http://doi.org/10.3803/EnM.2017.32.1.36

Abstract

In recent studies, the reported prevalence of heterozygous familial hypercholesterolemia (FH) has been higher than in previous reports. Although cascade genetic screening is a good option for efficient identification of affected patients, diagnosis using only clinical criteria is more common in real clinical practice. Cardiovascular risk is much higher in FH patients due to longstanding low density lipoprotein cholesterol (LDL-C) burden and is also influenced by other risk factors. Although guidelines emphasize aggressive LDL-C reduction, the majority of patients cannot reach the LDL-C goal by conventional pharmacotherapy. Novel therapeutics such as proprotein convertase subtilisin/kexin type 9 inhibitors have shown strong lipid lowering efficacy and are expected to improve treatment results in FH patients.

Keyword

Hyperlipoproteinemia type II; Genetics; Coronary disease; Hydroxymethylglutaryl-CoA reductase inhibitors; PCSK9 protein, human

MeSH Terms

Cholesterol, LDL
Coronary Disease
Diagnosis*
Drug Therapy
Genetic Testing
Genetics
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Hyperlipoproteinemia Type II*
Prevalence
Proprotein Convertases
Risk Factors
Cholesterol, LDL
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Proprotein Convertases

Figure

• 

  Fig. 1 Low density lipoprotein cholesterol (LDL-C) burden in individuals with or without familial hypercholesterolemia (FH) as function of the onset of statin therapy. Adapted from Nordestgaard et al. [7], with permission from Oxford University Press. CHD, coronary heart disease; HDL-C, high density lipoprotein cholesterol.

Reference

1. Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS, 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. 2013; 34:3478–3900a. PMID: 23956253.

2. Talmud PJ, Shah S, Whittall R, Futema M, Howard P, Cooper JA, 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; 381:1293–1301. PMID: 23433573.

3. Austin MA, Hutter CM, Zimmern RL, Humphries SE. Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review. Am J Epidemiol. 2004; 160:407–420. PMID: 15321837.

4. Benn M, Watts GF, Tybjaerg-Hansen A, Nordestgaard BG. Mutations causative of familial hypercholesterolaemia: screening of 98 098 individuals from the Copenhagen General Population Study estimated a prevalence of 1 in 217. Eur Heart J. 2016; 37:1384–1394. PMID: 26908947.

5. de Ferranti SD, Rodday AM, Mendelson MM, Wong JB, Leslie LK, Sheldrick RC. Prevalence of familial hypercholesterolemia in the 1999 to 2012 United States National Health and Nutrition Examination Surveys (NHANES). Circulation. 2016; 133:1067–1072. PMID: 26976914.

6. Marks D, Thorogood M, Neil HA, Humphries SE. A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia. Atherosclerosis. 2003; 168:1–14. PMID: 12732381.

7. Hovingh GK, Davidson MH, Kastelein JJ, O'Connor AM. Diagnosis and treatment of familial hypercholesterolaemia. Eur Heart J. 2013; 34:962–971. PMID: 23416791.

8. Harada-Shiba M, Arai H, Oikawa S, Ohta T, Okada T, Okamura T, et al. Guidelines for the management of familial hypercholesterolemia. J Atheroscler Thromb. 2012; 19:1043–1060. PMID: 23095242.

9. Soutar AK, Naoumova RP. Mechanisms of disease: genetic causes of familial hypercholesterolemia. Nat Clin Pract Cardiovasc Med. 2007; 4:214–225. PMID: 17380167.

10. Stein EA, Raal FJ. Polygenic familial hypercholesterolaemia: does it matter? Lancet. 2013; 381:1255–1257. PMID: 23433574.

11. Cuchel M, Bruckert E, Ginsberg HN, Raal FJ, Santos RD, Hegele RA, 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. 2014; 35:2146–2157. PMID: 25053660.

12. McCrindle BW, Gidding SS. What should be the screening strategy for familial hypercholesterolemia? N Engl J Med. 2016; 375:1685–1686. PMID: 27783919.

13. Hovingh GK, Kastelein JJ. Diagnosis and management of individuals with heterozygous familial hypercholesterolemia: too late and too little. Circulation. 2016; 134:710–712. PMID: 27601557.

14. Perez de Isla L, Alonso R, Mata N, Saltijeral A, Muniz O, Rubio-Marin P, 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. 2016; 36:2004–2010. PMID: 27444203.

15. Khera AV, Won HH, Peloso GM, Lawson KS, Bartz TM, Deng X, et al. Diagnostic yield and clinical utility of sequencing familial hypercholesterolemia genes in patients with severe hypercholesterolemia. J Am Coll Cardiol. 2016; 67:2578–2589. PMID: 27050191.

16. Watts GF, Sullivan DR, Poplawski N, van Bockxmeer F, Hamilton-Craig I, Clifton PM, et al. Familial hypercholesterolaemia: a model of care for Australasia. Atheroscler Suppl. 2011; 12:221–263. PMID: 21917530.

17. Gidding SS, Champagne MA, de Ferranti SD, Defesche J, Ito MK, Knowles JW, et al. The agenda for familial hypercholesterolemia: a scientific statement from the American Heart Association. Circulation. 2015; 132:2167–2192. PMID: 26510694.

18. 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; 29:2625–2633. PMID: 18840879.

19. Vuorio A, Docherty KF, Humphries SE, Kuoppala J, Kovanen PT. Statin treatment of children with familial hypercholesterolemia: trying to balance incomplete evidence of long-term safety and clinical accountability: are we approaching a consensus? Atherosclerosis. 2013; 226:315–320. PMID: 23141908.

20. Wiegman A, Gidding SS, Watts GF, Chapman MJ, Ginsberg HN, Cuchel M, et al. Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment. Eur Heart J. 2015; 36:2425–2437. PMID: 26009596.

21. Lozano P, Henrikson NB, Dunn J, Morrison CC, Nguyen M, Blasi PR, 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. 2016; 316:645–655. PMID: 27532919.

22. Ajufo E, Rader DJ. Recent advances in the pharmacological management of hypercholesterolaemia. Lancet Diabetes Endocrinol. 2016; 4:436–446. PMID: 27012540.

23. Santos RD, Gidding SS, Hegele RA, Cuchel MA, Barter PJ, Watts GF, 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. 2016; 4:850–861. PMID: 27246162.

24. Kazi DS, Moran AE, Coxson PG, Penko J, Ollendorf DA, Pearson SD, et al. Cost-effectiveness of PCSK9 inhibitor therapy in patients with heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease. JAMA. 2016; 316:743–753. PMID: 27533159.

25. Zhou M, Zhao D. Familial hypercholesterolemia in Asian populations. J Atheroscler Thromb. 2016; 23:539–549. PMID: 27075771.

26. Shin DG, Han SM, Kim DI, Rhee MY, Lee BK, Ahn YK, et al. Clinical features of familial hypercholesterolemia in Korea: predictors of pathogenic mutations and coronary artery disease. A study supported by the Korean Society of Lipidology and Atherosclerosis. Atherosclerosis. 2015; 243:53–58. PMID: 26343872.

27. Lee SH. Characteristics and vascular complications of familial hypercholesterolemia in Korea. J Atheroscler Thromb. 2016; 23:532–538. PMID: 26947601.