Familial hypercholesterolemia (FH) is an autosomal dominant disorder primarily driven by mutations in three genes—LDLR, APOB, and PCSK9—which result in increased levels of circulating LDL cholesterol (LDL-C).¹ Heterozygous FH is a common, morbid condition that affects roughly one in 250 people of European descent and, if untreated, significantly increases the risk of premature atherosclerotic cardiovascular disease (ASCVD).^2-4

The recent advent of registry-related studies of the FH population have helped characterize the current diagnostic and therapeutic landscape of FH care. In the United States, FH is often diagnosed late in life after the development of ASCVD and is undertreated. A 2016 cross-sectional analysis of 1,295 patients with heterozygous FH enrolled in the Cascade Screening for Awareness and Detection of FH (CASCADE-FH) registry demonstrated that patients were diagnosed at a median age of 47 years and only 25% achieved LDL-C ≤100 mg/dL. Not surprisingly, rates of ASCVD were very high: 47% of men and 29% of women had prevalent ASCVD at an average age of 47 and 55, respectively.⁵ Other registry-related studies in Spain,^6,7 Brazil,⁸ Norway,^9,10 and Canada have demonstrated similar treatment gaps and rates of premature ASCVD in their respective FH populations.¹¹ Nevertheless, when used appropriately, statins have been shown to curb ASCVD risk in FH.^12,13

A closer examination of the CASCADE-FH registry data has also identified certain sex and racial/ethnic disparities in the care of FH. In a recent study,¹⁴ women with FH were found to be less likely to receive appropriate statin therapy and less likely to achieve goal LDL-C reduction (≤100 mg/dL or ≥50% reduction from pretreatment LDL-C) than their male counterparts. Asians and blacks were also noted to be less likely to achieve goal LDL-C reduction compared to whites. As the authors in this study suggested, these disparities may be related to poor access to health care and unintentional biases leading to later diagnosis and less aggressive treatment.

For years, the diagnosis of FH has been based on clinical criteria such as the Simon Broome and Dutch Lipid Clinic Network criteria, which determine the likelihood of FH based on variables such as cholesterol levels, physical exam findings (i.e., tendon xanthomas, corneal arcus), personal/family history of premature ASCVD, and genetic mutational analysis if available. However, it has become clear through registry studies in the US and Spain that physical stigmata of FH are less frequently found even in genetically proven cases.^5,6,15 Therefore, the 2015 American Heart Association scientific statement on FH as well as the Canadian guidelines recommend a simpler classification for screening for potential heterozygous FH: LDL-C ≥190 mg/dL in adults with a first-degree relative similarly affected or with premature ASCVD or with positive genetic testing for an LDL-C raising gene defect.^1,16 Both of these methods are designed to identify patients with the FH phenotype who are at higher risk for premature ASCVD.

In addition, registry data and other large studies have highlighted the importance of understanding the relationship between the genetic basis of FH and its clinical phenotype. For example, a recent study found that among patients with LDL-C ≥190 mg/dL, those who had no FH mutation had a six-fold increase in ASCVD risk over a control group with LDL ≤130 mg/dL while those with an FH mutation (which constituted <2% of patients with LDL-C ≥190 mg/dL) had a 22-fold increase in ASCVD risk over the same control group.¹⁷ This suggests that the simple classification techniques we use may not effectively distinguish FH from polygenic hypercholesterolemia and lack important prognostic information. Other studies have shown that the clinical severity of FH differs based on the type of driver mutation (i.e., loss of function vs. missense mutation) and affected gene.^3,18,19

While registry data has taught us a great deal about current FH care, we are still limited by our finite knowledge of genetic drivers of FH and limited cataloguing of known mutation variants responsible for FH.¹⁵ The public at large is also unaware of the dangers of FH. One sign of progress is the inclusion of specific FH codes in the International Classification of Diseases, 10th Revision, which is an important step in ensuring accurate diagnosis of FH and facilitating future clinical FH research.²⁰ With cascade screening of family members of index patients with known FH and the use of widespread genetic testing, we hope to be able to better understand the genotype-phenotype relationship in FH. When coupled with continued education of patients and providers, this will enable us to accurately diagnose, risk stratify, and treat patients with FH, changing the narrative for this otherwise under-recognized population.

References

1. Gidding SS, Champagne MA, de Ferranti SD, et al. The agenda for familial hypercholesterolemia: a scientific statement from the American Heart Association. Circulation 2015;132:2167-92.
2. 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;37:1384-94.
3. Do R, Stitziel NO, Won HH, et al. Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature 2015;518:102-6.
4. Stone NJ, Levy RI, Fredrickson DS, Verter J. Coronary artery disease in 116 kindred with familial type II hyperlipoproteinemia. Circulation 1974;49:476-88.
5. deGorma EM, Ahmad ZS, O'Brien EC, et al. Treatment gaps in adults with heterozygous familial hypercholesterolemia in the United States: data from the CASCADE-FH Registry. Circ Cardiovasc Genet 2016;9:240-9.
6. Perez de Isla L, Alonso R, Mata N, 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;36:2004-10.
7. Perez de Isla L, Alonso R, Watts GF, et al. Attainment of LDL-cholesterol treatment goals in patients with familial hypercholesterolemia: 5-year SAFEHEART registry follow-up. J Am Coll Cardiol 2016;67:1278-85.
8. Silva PR, Jannes CE, Marsiglia JD, Krieger JE, Santos RD, Pereira AC. Predictors of cardiovascular events after one year of molecular screening for familial hypercholesterolemia. Atherosclerosis 2016;250:144-50.
9. Mundal L, Veierod MB, Halvorsen T, et al. Cardiovascular disease in patients with genotyped familial hypercholesterolemia in Norway during 1994-2009, a registry study. Eur J Prev Cardiol 2016;23:1962-9.
10. Mundal L, Igland J, Ose L, et al. Cardiovascular disease mortality in patients with genetically verified familial hypercholesterolemia in Norway during 1992-2013. Eur J Prev Cardiol 2017;24:137-44.
11. Brunham LR, Cermakova L, Lee T, et al. Contemporary trends in the management and otucomes of patients with familial hypercholesterolemia in Canada: a prospective observational study. Can J Cardiol 2017;33:385-92.
12. Versmissen J, Oosterveer DM, Yazdanpanah M, et al. Efficacy of statins in familial hypercholesterolaemia: a long term cohort study. BMJ 2008;337:a2423.
13. Neil A, Cooper J, Betteridge J, 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;29:2625-33.
14. Amrock SM, Duell PB, Knickebine T, et al. Health disparities among adult patients with a phenotypic diagnosis of familial hypercholesterolemia in the CASCADE-FH patient registry. Atherosclerosis 2017;267:19-26.
15. Kindt I, Mata P, Knowles JW. The role of registries and genetic databases in familial hypercholesterolemia. Curr Opin Lipidol 2017;28:152-60.
16. Genest J, Hegele RA, Bergeron J, et al. Canadian Cardiovascular Society position statement on familial hypercholesterolemia. Can J Cardiol 2014;30:1471-81.
17. Khera AV, Won HH, Peloso GM, et al. Diagnostic yield and clinical utility of sequencing familial hypercholesterolemia genes in patients with severe hypercholesterolemia. J Am Coll Cardiol 2016;67:2578-89.
18. Soutar AK, Naoumova RP. Mechanisms of disease: genetic causes of familial hypercholesterolemia. Nat Clin Pract Cardiovasc Med 2007;4:214-25.
19. Abul-Husn NS, Manickam K, Jones LK, et al. Genetic identification of familial hypercholesterolemia within a single U.S. healthcare system. Science 2016;354.
20. Rodriguez F, Knowles JW. Enough evidence, time to act! Circulation 2016;134:20-3.

Keywords: Hyperlipoproteinemia Type II, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Arcus Senilis, Cholesterol, LDL, Cross-Sectional Studies, Hypercholesterolemia, American Heart Association, Control Groups, Mutation, Missense, International Classification of Diseases, Prognosis, Prevalence, Heterozygote, Ethnic Groups, Risk, Registries, Genetic Testing, Phenotype, Xanthomatosis, Cardiovascular Diseases, Health Services Accessibility, Tendons, Apolipoproteins B, Primary Prevention, Secondary Prevention

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