A 44-year-old male presents to your clinic to establish care. He is asymptomatic but reports that he has first-degree relatives with a history of coronary artery disease, some of whom required coronary artery bypass surgery in their fourth decade of life. Physical exam is unremarkable apart from a body-mass index of 33 kg/m². Labs are notable for a calculated low-density lipoprotein (LDL)-cholesterol (LDL-C) of 284 mg/dL. What are some important considerations in the management of this patient?

Familial Hypercholesterolemia: Prevalence and Pathophysiology, and Screening

Familial hypercholesterolemia (FH) is the most common monogenic disorder, affecting an estimated 1:250 people worldwide.^1-3 FH is caused by inherited autosomal-dominant defects of LDL metabolism (Table 1).^4-7 There are three major genetic loci linked to FH, with the majority (approximately 88%) of cases due to mutations in the LDL receptor (LDLR) gene. The fundamental pathophysiologic hallmark of FH is accelerated atherosclerosis due to the cumulative lifetime exposure to high concentrations of circulating LDL. Although the prevalence of FH in the general population is substantial, only about 15% to 20% of affected patients receive a formal diagnosis.⁴ Patients with untreated heterozygous FH are at approximately 10-20-fold increased risk for premature coronary artery disease (CAD).^4,8 This risk can be reduced to that of the general population with appropriate recognition and treatment of FH.^4,6,7,9

Universal screening at 9-11 years of age for elevated LDL-C is recommended by multiple organizations. LDL-C level greater than 190 mg/dL or LDL-C greater than 160 mg/dL coupled with a family history of premature CAD should prompt further evaluation for FH.^6,7,10 Table 2 outlines recent North American and European screening guidelines that should prompt suspicion for FH.^11,12

Diagnosis and Genetic Testing

FH remains a clinical diagnosis but can be confirmed by genetic testing. North American and European diagnostic schema incorporate various aspects of family history, presence of physical exam findings, LDL-C levels, and/or genetic testing to categorize patients as to their probability of having FH (Table 3). Genetic testing for FH includes testing for pathogenic variants in three primary genes: LDLR, APOB, and PCSK9. The FH Foundation recommends genetic testing in patients with definitive or probable FH along with cascade screening of first degree relatives.¹³ The presence of a causal genetic mutation carries significant risk that compounds the elevation in LDL-C. For example, when referenced to patients with LDL-C ≤ 130 mg/dL, FH patients with LDL-C>190 mg/dL had a twenty-two-fold higher risk of CAD (OR 22.3, 95%CI 10.7-53.2).¹⁴

There are important caveats in the molecular diagnosis of FH. Individuals with a clinical diagnosis of definite FH are found to harbor causal mutations only 60-80% of the time. This observation may be explained due to mutations in established genes that have yet to be discovered, novel FH genes, or presence of an FH phenocopy.¹³ Additional challenges of genetic testing include genetic discrimination for possible life and long-term care insurance. Potential advantages of genetic testing include formal confirmation of a diagnosis of FH as well as the ability to facilitate cascade genetic screening.

Cardiovascular Risk Stratification

Although there are many putative clinical and laboratory markers that can provide incremental prognostic information, refining risk stratification with measures of subclinical coronary atherosclerosis in asymptomatic FH individuals appears to be the most promising. It is important to clarify that the role of atherosclerosis imaging in FH is quite different than its routine use in the general population. All adult patients with FH should receive lifestyle counseling and high intensity statin therapy independent of additional testing; statin therapy should be started at the lowest dose in children and titrated upwards.¹⁵ However, within the context of FH, the utility of atherosclerosis imaging is to identify individuals who may be eligible for more aggressive management approaches above and beyond therapeutic lifestyle changes and statin therapy.

Imaging Techniques

Imaging modalities that have been studied in patients with FH include carotid intima-media thickness (cIMT), coronary artery calcium (CAC) scoring, and coronary computed tomography angiography (CCTA).

With respect to cIMT, pediatric FH patients have higher cIMT values as compared to age-matched controls with normal lipid levels, suggesting utility as a non-invasive marker of ASCVD risk.¹⁶ Indeed, pediatric FH patients who were started on statins and followed over 20 years had decreased progression of cIMT and fewer cardiovascular events in comparison to their parents.¹⁷ Despite this observation, cIMT has not been shown to correlate with vascular disease in the aorta or coronaries in FH patients.^18,19

Given robust improvements in discrimination, calibration, and net reclassification in the general population, CAC scoring has been evaluated in FH populations for further ASCVD risk stratification.²⁰ In a prospective study by Miname et al, 206 asymptomatic molecularly confirmed individuals with heterozygous FH were followed for a median of 3.7 years to evaluate CAC as a predictor of ASCVD events. Among patients with a CAC score of 0 (n= 101, 49%), no ASCVD events were observed. Higher CAC scores correlated with an increased incidence of major adverse cardiovascular events. In adjusted models, CAC was found to be an independent predictor of ASCVD events.²¹ Additionally, these same investigators calculated a vascular age with the standard Framingham Risk, [vascular age-Framingham Risk Score (vaFRS)]. Patients with higher vaFRS demonstrated markedly elevated CVD risk: all 15 subjects who suffered ASCVD events had a vaFRS>20%.

Lastly, CCTA has also been shown to help risk stratify asymptomatic patients with FH. Advanced disease on CCTA correlated to the estimated cardiovascular risk evaluated by the SAFEHEART risk equation.²² Findings such as coronary calcium, the sum of stenosis, and plaque composition sum all correlated with estimated cardiovascular risk.²³ Among 101 Japanese patients with FH, increasing coronary plaque burden as demonstrated by CCTA was significantly associated with future coronary events.²²

Given the heterogeneous expression of the FH phenotype, selective use of coronary vessel imaging in the form of CAC scoring or CCTA offer a promising method of risk stratification, despite the inherently high baseline risk of this population.

Clinical Management of Familial Hypercholesterolemia

While therapeutic lifestyle changes are paramount in all individuals, these efforts alone may not decrease LDL-C to an adequate level in those with FH. High-intensity statin therapy should be initiated in all adult patients with goal LDL-C reductions ≥50% and/or achieved LDL-C <100 mg/dL in those without ASCVD.^6,7,9,24 Stepwise intensification of pharmacotherapy should be initiated in all patients who fail to achieve LDL-C reductions and those with additional risk factors such as smoking, family history of premature ASCVD, and Lp(a) ≥50mg/dL.⁷ Ezetimibe is recommended as the second-line adjunctive therapy and is associated with LDL-C reductions of 20-24% above and beyond what is achieved with statin therapy. If combination therapy with maximally tolerated statin and ezetimibe fails to adequately reduce LDL-C, a PCSK9 inhibitor should be considered.^6,11

PCSK9 inhibitors rapidly reduce LDL-C by 60% in individuals with heterozygous FH.^25-27 Alirocumab and evolocumab are both approved by the FDA for use in individuals with heterozygous FH and are well tolerated.²⁸ Evolocumab is also approved for individuals with homozygous FH. Most individuals with FH can achieve adequate LDL-C and cardiovascular risk reduction given these advances in therapeutic management.²⁹

For individuals with FH who fail to achieve adequate LDL-C reduction with maximal medical therapy, LDL apheresis may be an option. Apheresis is an extracorporeal therapy that can selectively remove LDL and Lp(a) particles from circulation and has been shown to prevent and slow progression of CAD.^30-34 The US Food and Drug Administration set criteria for initiation of LDL apheresis in 1997 with eligible patients defined as those with homozygous FH and LDL-C ≥ 500mg/dL, heterozygous FH and LDL-C ≥ 200mg/dL in the presence of CAD, or heterozygous FH and LDL-C ≥ 300mg/dL in absence of CAD.³³ Apheresis results in an immediate decrease in ApoB-containing lipoproteins, with an acute LDL-C reduction of nearly 60%.³³ LDL apheresis has extended the lifespan of homozygous patients to over 50 years.³²

Conclusion

FH is an underdiagnosed yet treatable disorder. Recognizing FH is of utmost importance due to the high risk of premature CAD and major adverse cardiovascular events. After diagnosis of an index case, there is a mandate to perform cascade lipid and/or genetic screening of all first-degree relatives.

Our patient has probable FH according to the Dutch Lipid Clinic and Simon Broom Register diagnostic criteria. In addition to emphasizing the importance of therapeutic lifestyle changes, high intensity statin therapy should be recommended. The potential value of genetic testing should be discussed with referral to a certified genetic counselor if the patient is amenable. His first-degree relatives should also be evaluated for FH. If high-intensity statin therapy fails to decrease his LDL-C by 50% or more (or attain and LDL-C <100 mg/dL), then addition of non-statin therapy should be recommended, starting with ezetimibe. If after three months of combination therapy, LDL-C reduction is still inadequate, a PCSK9 inhibitor may be considered. Alternatively, CAC testing can be discussed, and if performed, the absence of CAC may argue against the addition of a PCSK9 inhibitor, at least in the short term. With appropriate monitoring and LDL-C reduction, our patient's ASCVD risk can be decreased substantially.

References

1. 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;34:3478-90a.
2. Sjouke B, Kusters DM, Kindt I, et al. Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: prevalence, genotype-phenotype relationship, and clinical outcome. Eur Heart J 2015;36:560-65.
3. Watts GF, Gidding S, Wierzbicki AS, et al. Integrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation. Int J Cardiol 2014;171:309-15.
4. Bilen O, Pokharel Y, Ballantyne CM. Genetic testing in hyperlipidemia. Cardiol Clin 2015;33:267-75.
5. Bouhairie VE, Goldberg AC. Familial hypercholesterolemia. Cardiol Clin 2015;33:169-79.
6. 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.
7. Goldberg AC, Hopkins PN, Toth PP, 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:S1-8.
8. Watts GF, Lewis B, Sullivan DR. Familial hypercholesterolemia: a missed opportunity in preventive medicine. Nat Clin Pract Cardiovasc Med 2007;4:404-05.
9. Santos RD, Gidding SS, Hegele RA, 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;4:850-61.
10. Singh S, Bittner V. Familial hypercholesterolemia--epidemiology, diagnosis, and screening. Curr Atheroscler Rep 2015;17:482.
11. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019;73:3168-3209.
12. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2020;41:111-88.
13. Sturm AC, Knowles JW, Gidding SS, et al. Clinical genetic testing for familial hypercholesterolemia: JACC Scientific Expert Panel. J Am Coll Cardiol 2018;72:662-80.
14. 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.
15. Wiegman A, Gidding SS, Watts GF, et al. Familial hypercholesterolæmia in children and adolescents: gaining decades of life by optimizing detection and treatment. Eur Heart J 2015;36:2425-37.
16. Wiegman A, De Groot E, Hutten BA, et al. Arterial intima-media thickness in children heterozygous for familial hypercholesterolaemia. Lancet 2004;363:369-70.
17. Luirink IK, Wiegman A, Kusters DM, et al. 20-Year follow-up of statins in children with familial hypercholesterolemia. N Engl J Med 2019;381:1547-56.
18. Miname MH, Santos RD. Reducing cardiovascular risk in patients with familial hypercholesterolemia: risk prediction and lipid management. Prog Cardiovasc Dis 2019;62:414-22.
19. Martinez LRC, Miname MH, Bortolotto LA, et al. No correlation and low agreement of imaging and inflammatory atherosclerosis' markers in familial hypercholesterolemia. Atherosclerosis 2008;200:83-88.
20. Greenland P, Blaha MJ, Budoff MJ, Erbel R, Watson KE. Coronary calcium score and cardiovascular risk. J Am Coll Cardiol 2018;72:434-47.
21. Miname MH, Bittencourt MS, Moraes SR, et al. Coronary artery calcium and cardiovascular events in patients with familial hypercholesterolemia receiving standard lipid-lowering therapy. JACC Cardiovasc Imaging 2019;12:1797-1804.
22. Tada H, Kawashiri MA, Okada H, et al. Assessment of coronary atherosclerosis in patients with familial hypercholesterolemia by coronary computed tomography angiography. Am J Cardiol 2015;115:724-29.
23. Pérez de Isla L, Alonso R, Muñiz-Grijalvo O, et al. Coronary computed tomographic angiography findings and their therapeutic implications in asymptomatic patients with familial hypercholesterolemia. Lessons from the SAFEHEART study. J Clin Lipidol 2018;12:948-57.
24. Parizo J, Sarraju A, Knowles JW. Novel therapies for familial hypercholesterolemia. Curr Treat Options Cardiovasc Med 2016;18:64.
25. Raal FJ, Stein EA, Dufour R, et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet 2015;385:331-40.
26. Raal F, Scott R, Somaratne R, et al. Low-density lipoprotein cholesterol-lowering effects of AMG 145, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: the reduction of LDL-C with PCSK9 Inhibition in heterozygous familial hypercholesterolemia disorder (RUTHERFORD) randomized trial. Circulation 2012;126:2408-17.
27. Kastelein JJP, Ginsberg HN, Langslet G, et al. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur Heart J 2015;36:2996-3003.
28. Hovingh GK, Raal FJ, Dent R, et al. Long-term safety, tolerability, and efficacy of evolocumab in patients with heterozygous familial hypercholesterolemia. J Clin Lipidol 2017;11:1448-57.
29. Karatasakis A, Danek BA, Karacsonyi J, et al. Effect of PCSK9 inhibitors on clinical outcomes in patients with hypercholesterolemia: a meta-analysis of 35 randomized controlled trials. J Am Heart Assoc 2017;6:e006910.
30. Thompson GR, HEART-UK LDL Apheresis Working Group. Recommendations for the use of LDL apheresis. Atherosclerosis 2008;198:247-55.
31. Thompson GR. LDL apheresis. Atherosclerosis. 2003;167:1-13.
32. Thompson GR, Catapano A, Saheb S, et al. Severe hypercholesterolaemia: therapeutic goals and eligibility criteria for LDL apheresis in Europe. Curr Opin Lipidol 2010;21:492-8.
33. Moriarty PM, Hemphill L. Lipoprotein Apheresis. Cardiol Clin 2015;33:197-208.
34. Kitano Y, Thompson GR. Randomized trial of LDL apheresis to treat coronary artery disease in familial hypercholesterolemia. J Japan Soc Blood Transfus 1992;38:188.

Clinical Topics: Dyslipidemia, Noninvasive Imaging, Prevention, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Nonstatins, Novel Agents, Primary Hyperlipidemia, Statins, Echocardiography/Ultrasound

Keywords: Primary Prevention, Hyperlipoproteinemia Type II, Cholesterol, LDL, Coronary Artery Disease, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Carotid Intima-Media Thickness, Calcium, PCSK9 protein, human, Proprotein Convertase 9, Prevalence, Prospective Studies, Body Mass Index, Prognosis, Constriction, Pathologic, Insurance, Long-Term Care

< Back to Listings