Heterozygous Familial Hypercholesterolemia

Actionability Adult Summary Report

Secondary Findings in Adult Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Mode(s) of Inheritance: Autosomal Codominant
• Literature Search: 05/08/2018
• Curation Status: Released (2.0.1)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
No assertions found.

Actionability Assertion Rationale

• This topic was initially scored prior to development of the process for making actionability assertions. The Actionability Working Group decided to defer making an assertion until after the topic could be reviewed through the update process.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Clinical cardiovascular events / Oral hypercholesterolemia treatment to FH appropriate goal	2	3C	3A	3	11CA

Severity of Outcome

Prevalence of the Genetic Condition

The prevalence of heterozygous familial hypercholesterolemia (HeFH) is most commonly estimated at 1:200-500, though estimates from 1/67 to 1/1000 have been reported. HeFH has been estimated to affect between 14 and 34 million individuals worldwide.

Clinical Features (Signs / symptoms)

HeFH is associated with a lifelong elevation of serum low-density lipoprotein cholesterol (LDL-C) with levels generally 350-550 mg/dL. The major clinical manifestations of FH result from prolonged exposure to high levels of LDL-C leading to the development of atherosclerotic lesions in the heart, brain, and peripheral arteries. This leads to an increased risk of cardiovascular disease (CVD), most commonly coronary artery disease (CAD). Symptoms of ischemia may occur due the restriction of blood flow; however, acute complications such as myocardial infarction (MI) and sudden cardiac death can occur as the first manifestations of CVD. Other manifestations may include xanthomas around the eyelids and within tendons of the elbows, hands, knees, and feet and corneal arcus.

Natural History (Important subgroups & survival / recovery)

If left untreated, men and women with HeFH typically develop CAD by ages 55 and 60, respectively. On average, individuals with HeFH experience their first coronary event at age 42, 20 years younger than the general population. Statins have changed the prognosis of FH such that the rates of cardiovascular (CV) events are equal to the general population after 10 years of treatment. HeFH patients with tendon xanthomas have higher risk of CVD compared to FH patients without xanthomas (OR=3.20, 95% CI: 2.12-4.82).

Likelihood of Outcome

Mode of Inheritance

Autosomal Codominant

Prevalence of Genetic Variants

1-2 in 500

Population screening of 50,762 individuals in a US health care system identified pathogenic variants associated with FH in 1:256 in unselected individuals; however, this may be an overestimate as it was based on screening within a single health care delivery system.

Tier 5

Penetrance (Includes any high-risk racial or ethnic subgroups)

>= 40 %

Based on studies of individuals selected based on clinical criteria in the pre-statin era, untreated males are at 50% risk for a fatal or non-fatal coronary event by age 50 years, and women are at 30% risk by 60 years.

Tier 3

Unknown

Incomplete penetrance is noted for those heterozygous for a APOB pathogenic variant.

Tier 3

>= 40 %

Recent findings suggest that only 73% of those with a heterozygous LDLR pathogenic variant have an LDL level >130 mg/dL, suggesting lower penetrance than previously proposed.

Tier 3

>= 40 %

While penetrance up to 90% is noted for some pathogenic variants in PCSK9, the penetrance for other PCSK9 pathogenic variants remains largely unknown.

Tier 3

>= 40 %

In a US health-system based screening study of individuals with a pathogenic variant associated with FH, 44.7% would have been judged unlikely to have a diagnosis of FH based on Dutch Lipid Clinic Criteria without information about their pathogenic variant.

Tier 5

Relative Risk (Includes any high-risk racial or ethnic subgroups)

>3

In a Danish population-based study of patients with FH (selected on clinical criteria) versus non-FH patients, the odds ratios for CAD were 10.3 (95% CI: 7.8–13.8) and 13.2 (95% CI: 10.0–17.4) in subjects treated and not treated with lipid-lowering therapy, respectively.

Tier 1

>3

In an analysis of 12 existing observational studies (N=26,025), individuals high LDL cholesterol (≥190 mg/dl) had six-fold higher risk for CAD (OR: 6.0; 95% CI: 5.2–6.9) compared to those without a high LDL. When limited those with high LDL cholesterol and an FH pathogenic variant, there was a twenty-two-fold increased risk (OR: 22.3; 95% CI: 10.7–53.2).

Tier 3

>3

Within a US health-system based screening study individuals with an FH variant had a higher risk of CAD (OR: 2.6, 95%CI: 2.0-3.5) and premature CAD (OR: 3.7, 95% CI: 2.6 to 5.2).

Tier 5

Expressivity

Despite this high risk of CVD compared with unaffected individuals, the clinical course of atherosclerotic cardiovascular disease in FH subjects is variable.

Tier 4

Intervention Effectiveness

Patient Management

The initial treatment for individuals with FH, irrespective of their calculated cardiovascular risk, should be a high intensity statin with an aim of a reduction of at least 50% in LDL-C concentration from baseline. Statin treatment is lifelong. No studies have examined the use of statins vs placebo in adults with FH. However, high and moderate quality RCTs from populations without FH have found that high-intensity statins reduce non-fatal MI (RR: 0.46, 95% CI: 0.37-0.59). Statins have also been shown to have a small (non-clinically important) effect on reducing 5-year all cause (RR: 0.90, 95% CI: 0.80-1.00), CV mortality (RR: 0.73, 95% CI: 0.61-0.88), and stroke (RR: 0.80, 95% CI: 0.70-0.91).

Tier 1

Based on a meta-analysis of 4 observational studies, individuals with HeFH in the pre-statin era exhibited a higher risk for stroke compared with the general population (OR: 7.66, 95% CI: 6.06-9.68, p<0.01) but a lower odds for stroke following the generalization of statin therapy (OR: 0.25, 95% CI: 0.18-0.36, p<0.01).

Tier 1

Ezetimibe monotherapy is recommended as an option for treating primary HeFH in adults in whom initial statin therapy is contraindicated. No trials of ezetimibe in individuals with FH have been published. An RCT (IMPROVE-IT trial) of ezetimibe plus simvastatin vs simvastatin alone in 18,144 patients with stabilized acute coronary syndrome found a 6.4% relative risk reduction at 6 years a composite of cardiovascular death, major coronary event, or non-fatal stroke compared with simvastatin alone (HR: 0.94, 95% CI: 0.89-0.99).

Tier 1

Adults with FH and contraindications to statin or ezetimibe should be offered a referral to a specialist with expertise in FH for consideration for treatment with either a bile acid sequestrant (resin) or a fibrate. RCTs have found that bile acid sequestrants (2 RCTs, N= 248 with FH) and fibrates (2 RCTs, N= 208 with FH) can results in similar reductions in LDL-C and total cholesterol compared to placebo as treatment with statins.

Tier 1

PCSK9 inhibitors may be considered in HeFH, particularly in patients for whom a statin is contraindicated.

Tier 1

Four RCTs (N=598) found a mean decrease in LDL-C of 8-57% (Alirocumab) and 44-61% (Evolocumab) compared to placebo in HeFH individuals already on a high-dose statin plus ezetimibe in 12 weeks.

Tier 1

Healthcare professionals should offer adults with FH a referral to specialists with expertise in FH and cardiology if they are assessed to be at very high risk of a coronary event base on: established or suspected CHD, family history of premature CHD, or two or more other CV risk factors.

Tier 2

Given that asymptomatic coronary disease may not be detected without routine investigation. In individual instances, an ECG should be considered as a baseline investigation for adults with FH. However, evidence is lacking regarding clinical outcomes based on routine investigation.

Tier 2

Lifestyle advice should be provided as a component of medical management, and not a substitute for lipid-modifying drug therapy, including: individualized nutritional advice and physical activity advice, limiting alcohol consumption, stress reduction, and support for weight loss in line with national guidance for the general population. The aim of these interventions is not to lower LDL-C, but to confer a cardioprotective effect. However, there is no evidence that these interventions improve clinical outcomes in adults with FH.

Tier 2

Shared care arrangements, to include expertise in cardiology and obstetrics, should be made for women with FH who are considering pregnancy or are pregnant, including: assessment of CHD risk, particularly to exclude aortic stenosis.

Tier 2

Surveillance

All people with FH should be offered a regularly structured review that is carried out at least annual including an update of family pedigree, changes in CHD status of relatives, assessment of any symptoms of CHD, smoking status, fasting lipid profile, discussion about concordance with medication, possible side effects of treatment, and changes in lifestyle or lipid-modifying drug therapy that may be required.

Tier 2

Circumstances to Avoid

Individuals with FH should be strongly discouraged from smoking or advised to stop smoking given the greatly increased risk for CHD.

Tier 2

Nature of Intervention

Nature of Intervention

Interventions for HeFH include: surveillance (echocardiogram), clinical monitoring, and medication. Statins have possible adverse events of elevated liver enzymes, myopathy, and potential fetal teratogenicity. Adverse reactions with ezetimibe monotherapy are generally gastrointestinal and usually mild, when taken with a statin adverse events may include: elevated liver enzymes, headache, and myalgia. Trials of PCSK9 inhibitors indicate that there is no significant difference in the frequency of adverse events compared to those on placebo.

Context: Adult

Chance to Escape Clinical Detection

HeFH is often unrecognized until the inaugural cardiovascular event due to inconsistent screening practices and general unawareness regarding the diagnosis.

Context: Adult

Tier 4

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers

References List

Abul-Husn NS, Manickam K, Jones LK, Wright EA, Hartzel DN, Gonzaga-Jauregui C, O'Dushlaine C, Leader JB, Lester Kirchner H, Lindbuchler DM, Barr ML, Giovanni MA, Ritchie MD, Overton JD, Reid JG, Metpally RP, Wardeh AH, Borecki IB, Yancopoulos GD, Baras A, Shuldiner AR, Gottesman O, Ledbetter DH, Carey DJ, Dewey FE, Murray MF. (2016) Genetic identification of familial hypercholesterolemia within a single U.S. health care system. Science (New York, N.Y.). 354(6319).

Barkas F, Elisaf M, Milionis H. (2015) Statins decrease the risk of stroke in individuals with heterozygous familial hypercholesterolemia: A systematic review and meta-analysis. Atherosclerosis. 243(1):60-4.

Catapano AL, Graham I, De Backer G, Wiklund O, Chapman MJ, Drexel H, Hoes AW, Jennings CS, Landmesser U, Pedersen TR, Reiner Z, Riccardi G, Taskinen MR, Tokgozoglu L, Verschuren WM, Vlachopoulos C, Wood DA, Zamorano JL. (2016) 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias: The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) Developed with the special contribution of the European Assocciation for Cardiovascular Prevention & Rehabilitation (EACPR). Atherosclerosis. 253:281-344.

Cuchel M, Bruckert E, Ginsberg HN, Raal FJ, Santos RD, Hegele RA, Kuivenhoven JA, Nordestgaard BG, Descamps OS, Steinhagen-Thiessen E, Tybjaerg-Hansen A, Watts GF, Averna M, Boileau C, Boren J, Catapano AL, Defesche JC, Hovingh GK, Humphries SE, Kovanen PT, Masana L, Pajukanta P, Parhofer KG, Ray KK, Stalenhoef AF, Stroes E, Taskinen MR, Wiegman A, Wiklund O, Chapman MJ. (2014) 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. European heart journal. 35(32):2146-57.

E Youngblom, JW Knowles. Familial Hypercholesterolemia. (2014) . In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK174884/

Genest J, Hegele RA, Bergeron J, Brophy J, Carpentier A, Couture P, Davignon J, Dufour R, Frohlich J, Gaudet D, Gupta M, Krisnamoorthy P, Mancini J, McCrindle B, Raggi P, Ruel I, St-Pierre J. (2014) Canadian Cardiovascular Society position statement on familial hypercholesterolemia. The Canadian journal of cardiology. 30(12):1471-81.

Gidding SS, Champagne MA, de Ferranti SD, Defesche J, Ito MK, Knowles JW, McCrindle B, Raal F, Rader D, Santos RD, Lopes-Virella M, Watts GF, Wierzbicki AS. (2015) The Agenda for Familial Hypercholesterolemia: A Scientific Statement From the American Heart Association. Circulation. 132(22):2167-92.

Goldberg AC, Hopkins PN, Toth PP, Ballantyne CM, Rader DJ, Robinson JG, Daniels SR, Gidding SS, de Ferranti SD, Ito MK, McGowan MP, Moriarty PM, Cromwell WC, Ross JL, Ziajka PE. (2011) Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. Journal of clinical lipidology. 5(3 Suppl):S1-8.

Jellinger PS, Handelsman Y, Rosenblit PD, Bloomgarden ZT, Fonseca VA, Garber AJ, Grunberger G, Guerin CK, Bell DSH, Mechanick JI, Pessah-Pollack R, Wyne K, Smith D, Brinton EA, Fazio S, Davidson M, Zangeneh F, Bush MA. (2017) AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY GUIDELINES FOR MANAGEMENT OF DYSLIPIDEMIA AND PREVENTION OF CARDIOVASCULAR DISEASE - EXECUTIVE SUMMARYComplete Appendix to Guidelines available at http://journals.aace.com. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 23(4):479-497.

Lloyd-Jones DM, Morris PB, Ballantyne CM, Birtcher KK, Daly DD Jr, DePalma SM, Minissian MB, Orringer CE, Smith SC Jr. (2016) 2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: A Report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. Journal of the American College of Cardiology. 68(1):92-125.

McDonagh M, Peterson K, Holzhammer B, Fazio S. (2016) A Systematic Review of PCSK9 Inhibitors Alirocumab and Evolocumab. Journal of managed care & specialty pharmacy. 22(6):641-653q.

National Institute for Health and Care Excellence. Ezetimibe for treating primary heterozygous-familial and non-familial hypercholesterolaemia. (2016) Accessed: 2018-05-08. URL: https://www.nice.org.uk/guidance/ta385

National Institute for Health and Care Excellence. Familial hypercholesterolaemia: identification and management. (2019) Accessed: 2018-05-08. URL: https://www.nice.org.uk/guidance/cg71

Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS, Wiklund O, Hegele RA, Raal FJ, Defesche JC, Wiegman A, Santos RD, Watts GF, Parhofer KG, Hovingh GK, Kovanen PT, Boileau C, Averna M, Boren J, Bruckert E, Catapano AL, Kuivenhoven JA, Pajukanta P, Ray K, Stalenhoef AF, Stroes E, Taskinen MR, Tybjaerg-Hansen A. (2013) 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. European heart journal. 34(45):3478-90a.

Oosterveer DM, Versmissen J, Yazdanpanah M, Hamza TH, Sijbrands EJ. (2009) Differences in characteristics and risk of cardiovascular disease in familial hypercholesterolemia patients with and without tendon xanthomas: a systematic review and meta-analysis. Atherosclerosis. 207(2):311-7.

Rynkiewicz A, Cybulska B, Banach M, Filipiak K, Guzik T, Idzior-Walus B, Imiela J, Jankowski P, Klosiewicz-Latoszek L, Limon J, Mysliwiec M, Opolski G, Steciwko A, Stepinska J, Zdrojewski T. (2013) Management of familial heterozygous hypercholesterolemia: Position Paper of the Polish Lipid Expert Forum. Journal of clinical lipidology. 7(3):217-21.

Scottish Intercollegiate Guidelines Network. Risk estimation and the prevention of cardiovascular disease.. (2017) Accessed: 2018-05-08. URL: http://www.sign.ac.uk/assets/sign149.pdf

The Royal Australian College of General Practitioners. Guidelines for preventive activities in general practice. 9th edn.. (2016) Accessed: 2018-05-08. URL: https://www.racgp.org.au/download/Documents/Guidelines/Redbook9/17048-Red-Book-9th-Edition.pdf

Wang A, Richhariya A, Gandra SR, Calimlim B, Kim L, Quek RG, Nordyke RJ, Toth PP. (2016) Systematic Review of Low-Density Lipoprotein Cholesterol Apheresis for the Treatment of Familial Hypercholesterolemia. Journal of the American Heart Association. 5(7).

Watts GF, Gidding S, Wierzbicki AS, Toth PP, Alonso R, Brown WV, Bruckert E, Defesche J, Lin KK, Livingston M, Mata P, Parhofer KG, Raal FJ, Santos RD, Sijbrands EJ, Simpson WG, Sullivan DR, Susekov AV, Tomlinson B, Wiegman A, Yamashita S, Kastelein JJ. (2015) Integrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation. European journal of preventive cardiology. 22(7):849-54.

Wong B, Kruse G, Kutikova L, Ray KK, Mata P, Bruckert E. (2016) Cardiovascular Disease Risk Associated With Familial Hypercholesterolemia: A Systematic Review of the Literature. Clinical therapeutics. 38(7):1696-709.