Stage II: Summary Report Secondary Findings in Adults Non-diagnostic, excludes newborn screening & prenatal testing/screening Stage I Survey Update History Stage 2 Status (Adult):Complete (Actionability curation complete.)

Condition: Homozygous Familial Hypercholesterolemia
Narrative Description of Evidence
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Disorder
The frequency of homozygous familial hypercholesterolemia (HoFH) has historically been estimated to be 1/1,000,000. However, recent estimates are 1/160,000 to 1/300,000.
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Clinical Features
(Signs / symptoms)
The clinical features of HoFH are characterized by extensive xanthomas, premature and progressive cardiovascular disease (CVD), and total cholesterol >500 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. Severe aortic stenosis is common. Xanthomas around the tendons and interdigital folds may occur leading to tendinitis and joint pain.
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Natural History
(Important subgroups & survival / recovery)
Untreated, most individuals with HoFH develop severe coronary artery disease (CAD) and aortic stenosis before age 20 and die before age 30. HoFH patients who are LDLR-defective (2-25% residual enzyme activity) have a better prognosis than those who are receptor negative (<2% enzyme activity). Individuals may be initially asymptomatic, presenting only with cutaneous and tendinous xanthomas and possibly a cardiac murmur. Most individuals with HoFH experience their first coronary event as children or adolescents with angina pectoris, MI, and death being reported in early childhood.
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2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
Treatment for HoFH should be undertaken within a specialist center. (Tier 2)
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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 (but 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)
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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)
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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)
Evolocumab (a PCSK9 inhibitor) can be considered with background therapy in HoFH. Homozygotes, compound heterozygotes, or double heterozygotes with a gain of function PSCK9 allele are likely to respond well to PCSK9 inhibition. (Tier 2)
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One RCT (N=50) of individuals with HoFH found that Evolocumab lowered LDL-C 32% versus placebo in individuals already on a high-dose statin and ezetimibe in 12 weeks. (Tier 1)
Lomitapide and mipomersen might be considered as adjunctive treatment in patients with HoFH, particularly if apheresis is not available. In an open label trial of 29 HoFH patients, lomitapide in addition to apheresis was found to reduce LDL-C by 50%. Mipomersen resulted in reduction of 25% in LDL-C over placebo in a trial of 51 HoFH patients. (Tier 2)
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LDL-C apheresis should be offered for treatment of HoFH with initiation and based on the response to lipid-modifying drug therapy and the presence of CHD. (Tier 1)
A Systematic review of 7 pre-post observational studies of HoFH (N= 61) found mean reductions in LDL-C levels from 57-76%. Two of these studies (n=39) reported that after extended follow up, the mean reduction was around 34-36%. Data from 34 adults with FH receiving apheresis for an average of 2.5 years found that after apheresis individuals had a 3.2-fold decrease in CV events and over a 20-fold decrease in cardiovascular interventions. Subjectively individuals reported decreased episodes of angina symptoms and improved quality of life. (Tier 1)
Daily oral aspirin should be considered to prevent atherothrombosis. No studies of aspirin in FH were identified. In patients with HoFH who have not had a cardiovascular event, a net benefit of aspirin is a reasonable assumption because atheromatous disease is inevitable. (Tier 2)
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A meta-analysis of 6 primary prevention trials found aspirin, compared to placebo, reduced serious vascular events (RR: 0.88, 95% CI: 0.82-0.94), due mainly to a reduction in non-fatal MI (RR: 0.77, 95% CI: 0·67–0·89); the effect on stroke and mortality were not significant. Analysis of 16 secondary prevention trial found aspirin yielded a greater absolute reduction in serious vascular events (RR: 0.81, 95% CI: 0.75-0.87), stroke (RR: 0.81, 95% CI: 0.71-0.92), major coronary events (RR: 0.80, 95% CI: 0.73-0.88), and total mortality (RR: 0.90, 95% CI: 0.82-0.99). (Tier 1)
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)
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Patients should be taught “red flag” symptoms of CVD and acute coronary events. (Tier 2)
Psychological support (including family support) should be part of routine care. (Tier 2)
The lipid team should be involved if patients hospitalized. An alert card with contact details should be issued. (Tier 2)
Non-hormonal contraceptive techniques are recommended. Hormonal contraception is generally contraindicated for women with HoFH due to the risk of thrombosis. (Tier 2)
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Women should be advised that pregnancy in HoFH is hazardous due to the aggravation of hypercholesterolemia due to discontinuation of pharmacotherapy coupled with the effects of high levels of estrogen and progesterone on lipoprotein metabolism. Pre-conception, women should be referred to a cardiologist for a detailed cardiovascular assessment, including the aortic valve and root. (Tier 2)
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If HRT is provided for relief of postmenopausal symptoms, it should be taken in the lowest form of parenteral preparations, which have the lowest thrombotic risk. (Tier 2)
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)
Given the extremely high risk of early onset and rapid progression of CVD in HoFH, patients should be referred to a cardiologist and undergo comprehensive CV evaluation at diagnosis and repeated every 6 months with subsequent Doppler echocardiographic evaluation of the heart and aorta annually, stress testing and, if available, computed tomography coronary angiography every 5 years or more frequently if needed. (Tier 2)
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Family Management
No family management recommendations have been provided.
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)
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3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Codominant
Prevalence of Genetic Mutations
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)
Relative Risk
(Include any high risk racial or ethnic subgroups)
Most individuals with HoFH experience severe CAD by their mid-20s. (Tier 3)
An analysis of individuals identified from cascade screening in the identified 49 individuals with HoFH (20 were true homozygotes, 25 were compound heterozygotes). Within this population, 50% of the patients met the clinical criteria for HoFH (LDL-C .13.0 mmol/L) and 29% had a recorded history of a CVD event. (Tier 5)
No information related to relative risk was identified related HoFH.
Despite this high risk of CVD compared with unaffected individuals, the clinical course of atherosclerotic cardiovascular disease in FH subjects is variable. (Tier 4)
4. What is the Nature of the Intervention?
Nature of Intervention
Interventions for HoFH included: surveillance (biochemical and cardiac imaging), medication use, and apheresis. Statins have possible adverse events of elevated liver enzymes, myopathy, and potential fetal teratogenicity. Apheresis is a procedure in which either the plasma is separated from red blood cells before the physical removal of LDL-C or the LDL-C is directly removed from whole blood. Apheresis typically needs to be undertaken approximately every two weeks (though frequency can vary) and requires specialist administration and monitoring with the duration of the procedure ranging from 2 to >3 hours. Serious adverse events are rare, with the most common reactions being light-headedness, nausea/vomiting, hypotension, and chest pain. 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. The most frequently observed adverse events during use of lomitapide were gastrointestinal symptoms and liver fat accumulation. For mipomersen, the most frequently reported events were injection site reactions and increased liver fat accumulation. Aspirin can, in rare cases, lead to gastrointestinal and extracranial bleeds.
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5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
HoFH is typically diagnosed when considerable CAD has already developed. (Tier 4)

Final Consensus Scores
Outcome / Intervention Pair
Nature of the
Clinical cardiovascular events / Hypercholesterolemia treatment to FH appropriate goal
To see the scoring key, please go to:
Description of sources of evidence:
Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.
Reference List
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