Familial hypercholesterolemia (FH) is a common genetic disorder with catastrophic long-term consequences. FH affects one in every 200–500 people, in whom insufficient low-density lipoprotein cholesterol (LDL-C) uptake by hepatocytes results in very high concentrations of serum LDL-C (e.g., ≥190 mg/dL) and an increased risk of premature atherosclerotic cardiovascular disease (ASCVD). Detecting and treating FH in youth may prevent future ASCVD, including acute myocardial infarction, ischemic cardiac arrest, and ischemic stroke. FH is currently 1 of only 3 Tier 1 conditions identified by the US Centers for Disease Control and Prevention as high priority for genomic screening in the general population. Current recommendations are to screen for lipid disorders of all types—including FH—starting at age 2 years if there is a family history or a medical condition that raises ASCVD risk (selective screening), and to test everyone for lipid disorders (universal screening) once between ages 9 and 11 years, and again once between 17 and 21 years. The emphasis in the USA to date has been to screen for lipid disorders in general; there are no recommendations to screen children specifically for FH. Despite the public health importance of FH, and guideline recommendations for pediatric lipid testing, FH screening is not widely performed in pediatric practice, genetic testing has not yet been integrated into screening, and broad pediatric FH screening approaches have not been formally evaluated in the USA.
Low rates of screening for FH in childhood are due in part to uncertainty about the long-term efficacy of statins and lifestyle interventions, and concern about known and unknown adverse effects with long-term statin exposure. For these reasons, some national guidelines advocate delaying FH screening until age 20 years or later. Alternative FH screening strategies include adding genetic testing for FH mutations to phenotypic screening in children, reverse cascade screening in the children of family members with FH, integrating FH screening into early routine pediatric wellness visits with vaccinations or lead screening. To discuss the implications of these and other approaches, 6 invited experts responded to the questions related to pediatric screening for FH. Perspectives were gathered on the topic of screening for FH in childhood from various stakeholders as a virtual roundtable with the panel of experts.
Screening children for lipid disorders has been advised for several decades, but FH screening is not explicitly recommended in the USA. Should children be screened specifically for FH vs general lipid screening, and if so, should all or a subset of children be screened?
Louis Vernacchio: When considering a recommendation for population-wide screening for any disorder, I start from the presumption that a relatively high level of evidence for the benefits of early identification and treatment should be required before such a recommendation is made. It is only recently, in my opinion, that a preponderance of evidence has emerged that identifying and treating FH in childhood does confer substantial long-term health benefits and thus I believe screening for FH makes sense. On the other hand, evidence for the benefits of identifying and treating lipid abnormalities other than FH during childhood is lacking, so a targeted approach to identifying FH specifically in childhood—and not incidentally identifying non-FH lipid abnormalities—would be the ideal. There will, however, always be trade-offs in terms of the accuracy, acceptability, and cost of the various screening approaches and the job of healthy policy makers is to balance those factors and recommend the most cost-effective overall approach.
As to the optimal age for screening, since the evidence for the benefits of pharmacological treatment for FH extends down to approximately 8 years of age, sometime in middle childhood would make the most sense. If a lipid panel is to be used as the screening test, screening before adolescence would be wise since it is known that hormonal changes in puberty complicate the interpretation of serum lipid values.
Tom Newman: Primary care clinicians face the challenging task of trying to address patient concerns and provide recommended preventive care within the limited time constraints of well child visits. Thus, it is important to critically evaluate preventive care recommendations to decide which ones to adopt. This necessarily involves estimating the costs and risks of following the recommendation, compared with the projected health benefit. Skeptical parents and clinicians may reasonably ask, “How many children need to be screened?,” “How many need to have regular fasting lipid panels?,” or “How many need to be put on diets or statins for how many years (causing how many cases of diabetes?) to prevent one cardiovascular death?” Proponents of screening have not provided answers to these essential questions. I think the benefit/harm balance for childhood screening for FH is more likely to be favorable than for general lipid screening (for which it almost certainly is not, at least as currently recommended). However, until I see credible analyses showing the projected benefits of starting screening in childhood exceed the risks and costs, I’m not prepared to tell clinicians they should screen any children.
If FH screening is negative/reassuring once, should children be screened for FH again at some point in the future?
Tom Newman: It depends what is meant by screening. If a parent has a molecular diagnosis of FH, the prior probability that the child is affected is 50%. In such a situation, depending on the sensitivity of the test, it may be worth repeat screening, especially if results are borderline or the family is worried. Outside of that situation (or similar situations with a very strong family history), because I am not yet convinced of the value of childhood lipid screening in general, I'm not inclined to recommend repeating it.
Barbara Howaniec: Yes, I would think that given the current recommendations to screen all children at 9–11 years and again at 17–21 years, it makes perfect sense to rescreen those with negative or reassuring initial screens. I think it would be advantageous to capture as many children with FH as soon as possible to initiate monitoring and treatment. At some point in the future, perhaps genetic screening of all children will be cost efficient to the point where we can capture all children with FH.
As a parent of 2 children, one of whom has FH, I would absolutely want my daughter retested for the presence of FH even though the original screening did not show high cholesterol. Fortunately, because my son is followed by the Preventive Cardiology team, I will have access to this testing simply by asking but it has never been suggested by our family practitioner.
Given FH has both a clinical definition, and also well described molecular defects, should the primary screen to identify FH be a lipid panel, a genetic test alone, or a tiered approach (lipid testing followed by genetic testing as indicated)?
Amit Khera: FH—as initially described—is an autosomal dominant disorder in which single mutations in the gene encoding the low-density lipoprotein receptors lead to impaired clearance of LDL-C from the circulation and increased risk of cardiovascular disease. Although a molecular definition of FH has always held considerable appeal, this definition was impractical because genetic testing was inaccessible. In its place, several groups developed diagnostics algorithms based on LDL-C, physical exam findings, and personal/family history—each of which serves a surrogate for the presence of a mutation.
At present, adopting a population level approach, I agree with current clinical guidelines that emphasize universal screening for hypercholesterolemia with a lipid panel starting in childhood, with subsequent consideration of genetic testing in those with severely increased values or a personal/family history suggestive of FH.
In the future, I do think we will move toward universal genetic testing for a range of important conditions, including FH. Potential benefits of this approach include increasing appreciation that—even for a given observed LDL-C—those with a FH variant have increased risk of cardiovascular disease (likely due to increased lifetime exposure), and identifying affected family members by cascade genetic screening. There is some literature to suggest that knowledge about genetic mutations may increase adherence with early and aggressive lipid-lowering therapy.
Tom Newman: I think the answer to this should be based on modeling that includes the accuracy and costs of the tests, and the costs (broadly defined) of false-positive and false-negative results.
If a lipid test is used to screen for FH, what lipid test should we use and what threshold(s) should be used to signal possible FH? If a tiered approach to FH screening is used, incorporating genetic testing, what lipid cut point should trigger genetic testing?
Steve Daniels: Lipid screening for children and adolescents should take place in primary care, and should be affordable and as simple as possible. Because health maintenance visits can occur at any time of day, fasting should not be required. For these reasons, measurement of non-HDL cholesterol is the most appropriate test for initial screening. This is calculated from the total and HDL cholesterol and is a good measure of atherogenic particles circulating in the blood. If non-HDL cholesterol is increased, then this should be confirmed by a fasting lipid profile that focuses specifically on the concentration of LDL-C. Historically, we have used a non-HDL cholesterol cutpoint of 145 mg/dL. While this cutpoint may be useful for other reasons, it is probably too low to use in screening for heterozygous FH and a non-HDL cholesterol cutpoint of 190 mg/dL would be a more appropriate screening cutpoint.
While genetic testing can be useful in making a specific genetic diagnosis, it is not clear that the results of genetic testing will change the clinical approach, which is focused on identifying markedly increased LDL-C and lowering it to reduce risk of future ASCVD.
Amit Khera: The optimal threshold for genetic testing is largely dependent on the cost of the genetic test and the perceived benefit of knowing genetic testing results over and above LDL-C concentrations themselves. Recent analyses from large cohort studies and health systems have established that even for those with severely increased LDL-C of >190 mg/dL, a pathogenic variant can be identified in fewer than 5% of individuals. This yield is substantially lower than prior studies that focused on patients referred to a lipid specialty clinic or with additional characteristics that suggest the presence of a mutation, such as exam findings or family history.
Additional research is needed to benchmark algorithms that predict the presence of a FH mutation for a given a set of laboratory values and clinical features, especially in geographically and ancestrally diverse populations. If well-calibrated, individuals or health systems can then make an informed decision regarding where in the probability distribution the estimated benefits of genetic testing outweigh the cost and potential harms.
Should genetic testing be performed for all patients with probable FH, or only for patients the “Gray Zone” (e.g., LDL-C 130–190 mg/dL) where the presence of an FH gene might alter medication recommendations?
Steve Daniels: I am not convinced that genetic testing is useful in the diagnosis and management of FH in most children and adolescents. At present, genetic testing is relatively expensive and not all pathologic genetic abnormalities have been identified. Thus, genetic testing will be inconclusive or noninformative for some patients and decisions regarding treatment are probably not improved by specific genetic information. The situation is likely different in adults where 2 patients with increased LDL-C, one with a genetic FH mutation and the other without, have meaningfully different levels of risk for ASCVD. The patient with the FH gene is at higher risk, presumably because they have had a lifetime of increased LDL-C where the patient without a genetic mutation will have had a shorter duration of increased LDL-C. For children and adolescents, the LDL-C at a young age has already been determined, so genetic information will be less useful in decision-making.
One area where genetic testing might be useful in children and adolescents is with patients with LDL-C in a gray zone between 130 and 190 mg/dL or between 160 and 190 mg/dL. In this range of LDL-C there will be some overlap between patients with heterozygous FH and those with increased LDL-C for other reasons. Whether the presence of a positive genetic test should alter the recommendation regarding medication for patients with LDL-C in this gray zone has not been proven one way or another. However, it might change the approach to follow up with closer surveillance, particularly for patients during puberty when the LDL-C may be temporarily lower, or the approach to testing other family members.
Barbara Howaniec: I am supportive of genetic testing for all patients with probable FH. If I had a child with only a slightly increased LDL, I would want the genetic testing done so that I would have a definitive answer regarding the presence of FH. I would find it less distressing than the potential need for serial testing to monitor concentrations. Is it necessary to even test a child with an extremely high value? Personally, I would, again, like the definite answer rather than an assumption. As a parent, if I knew that the genetic test was available and not done, I think I might wonder and want to see the testing. The only potential harm I can think of is related to access to the information. There have been several instances where biologic material submitted for genetic tests was used without consent as forensic evidence in unrelated settings. I would be concerned and wonder if this might be a deterrent to some parents.
What are the economic considerations when scaling up a pediatric national FH screening program?
Louis Vernacchio: Any universal screening recommendation will incur substantial costs to the healthcare system and the challenge is to obtain the most benefit at a reasonable cost. While genetic testing is ideal in terms of the accuracy of identifying FH, universal genetic testing at its current cost is unsupportable in the USA. More cost-effective alternatives such as universal screening with a relatively inexpensive serum lipid panel followed by genetic testing for those in the gray zone may be a more cost-reasonable alternative. It is important, however, to take into account the cost of follow-up testing, visits, and perhaps even treatment for abnormalities other than FH that may be discovered through lipid panel screening, and for which there is not good evidence of benefit.
Kirsten Bibbins-Domingo: The decision to scale up a national FH screening program should be based on whether such a program can be delivered in a cost-effective, equitable manner. When considering the cost effectiveness of such a program, relevant costs include those related to the screening test or tests and administering those tests to a large population, the treatments instituted among individuals who are identified as having FH, as well as treatments that result from overdiagnosis as a result of screening where benefits are not expected to accrue, and any costs of administering such a program. Of course, cost effectiveness would also account for savings that result from averting heart attacks or strokes by early detection and treatment among individuals with FH. The effectiveness of screening is a function of whether early detection and treatment improves health outcomes in the long-term—both in term of survival as well as quality of life. This effectiveness and safety of early statin therapy in FH is uncertain, though there is some suggestion of a reduction in premature cardiovascular disease in this high-risk population. Given the catastrophic consequences of undetected and untreated FH, it is plausible that screening would be cost effective. This needs to be formally evaluated. Because the cost of genetic testing and generic lipid-lowering therapies continues to decline, any formal cost effectiveness evaluation may need to updated periodically. Moreover, it is likely that some groups at higher risk of adverse outcomes are likely to derive a larger benefit, so that screening may be more cost effective in these populations.
Which brings us to the second consideration: we need to ensure that the scale-up occurs in a way that all communities benefit from screening and timely initiation of treatment. This may be particularly important if the populations at greatest risk of adverse outcomes include medically underserved populations.
Turning our attention to treatment, statins are recommended for treating FH because they are shown to have benefits well described in adults, reducing morbidity and mortality, and there are reassuring pediatric randomized clinical trial data on short- and medium-term safety and LDL-C lowering in childhood, and a long-term follow-up report of lower rates of ASCVD. Lifestyle modification has been shown to modestly lower LDL-C and has additional health benefits. How should we approach lifestyle modification in the treatment of this genetic lipid disorder?
Louis Vernacchio: Counseling on healthy lifestyle choices should be a continual part of pediatric preventive health care from infancy through adulthood. In cases of FH diagnosed in childhood, a more intensive approach to diet and physical activity counseling should probably be taken, likely in conjunction with a dietician trained in heart-healthy nutrition. However, it is clear from the literature that lifestyle modifications are likely to have only a modest effect on unhealthy lipid concentrations in those with FH and that pharmacologic treatment is necessary to reduce the very high risk of premature cardiovascular events. Also, I think we should be somewhat humbled by the rather checkered history of dietary advice from experts over the years and recognize the very powerful forces, such as the intensive marketing of unhealthy foods to children, that families confront in between their relatively infrequent contacts with the health care system.
Barbara Howaniec: The first step has to be the education and engagement of children and families. Ideally this should be started at the youngest age possible and should include both exercise and nutrition. I believe it can be best relayed to the children by peers who act as mentors. Obviously, this delivery would be most easily provided in higher populated areas but the COVID-19 pandemic has shown us that distant parts of our communities can be reached with technology. I would love to see exercise programs to get children moving and active from the youngest age possible—schedule the kids for weekly or bi-weekly exercise programs specifically suited for pediatric cardiac health. Provide incentives for the kids to attend and meet goals to motivate engagement.
Nutritional support needs to be given to both parent and child. Both need to understand the importance of diet in the treatment of their condition. I don’t believe a conventional nutrition consult in the hospital does this effectively. Families sit for a maximum of 45 minutes with a nutritionist and absorb maybe 10% of what they are told. This needs to be reiterated and backed up with ongoing education. Unfortunately, insurance companies rarely cover even a basic nutritional consult. After we got stuck with a large bill, we skipped all further nutritional counseling. Getting nutrition counseling should not be so difficult. These services need to be covered by insurance as part of preventive care. It is extremely important to the children and families to fully understand how their food choices will affect their health in life. In a perfect world we would provide each family with a cookbook of easy recipes for heart healthy, low cholesterol meals. Teenagers and young adults especially need this guidance to help them make difficult choices. What about cooking classes? This could be an amazing internship, public health dissertation topic or research opportunity, to investigate how direct engagement effect long-term outcomes for this population.
How should we approach the treatment of cases where there is genotype-phenotype mismatch, e.g., LDL-C is only moderately increased in an individual that is gene positive, or, LDL-C is substantially increased and the individual is gene negative?
Steve Daniels: The level of atherogenic lipid/lipoprotein particles circulating in the blood over time is the primary driver of the atherosclerotic process and can be measured in various ways, including ApoB, non-HDL-C, LDL-C, and other advanced lipid measures. Historically, we have focused clinically on the concentration of LDL-C for evaluation and a treatment decision. While some other approaches may better measure the risk of atherosclerosis, LDL-C has proved to be valuable in the clinical setting. There may be a range of concentration of LDL-C across individuals with heterozygous FH due to the impact of different genetic abnormalities on LDL-C receptor function, lifestyle, and other environmental factors. There may also be gene–gene interactions that, at present, are not well understood.
In the situation where there is a mismatch between genotype and phenotype, I would suggest that the concentration of LDL-C should drive decision-making, particularly when the clinical decision involves whether to use medication. When the LDL-C is substantially increased, but they are gene negative, a very likely possibility is that they have an FH gene variant not yet identified as pathologic. When patients have only moderately increased LDL-C and have genetic abnormality indicative of FH, they need to be followed closely throughout their lifetime and have lifestyle intervention. It is not clear, however, if or how decisions about the use of medication should be different based on the presence of a gene defect. They may have other genes that have a balancing impact on LDL-C that have not been identified and are associated with a lower lifetime risk of ASCVD. So, the LDL-C is a useful measure of the potential for development of atherosclerosis and CVD and should be used in clinical decision-making.
Amit Khera: The case of increased LDL-C with negative genetic testing is relatively common since these individuals represent up to 5% of the general adult population. Potential etiologies include a rare variant that is undetected or misclassified by current genetic testing strategies, a favorable common variant polygenic background, where the cumulative effects of many DNA beneficial variants offset the impact of a FH variant, or environmental/lifestyle influence. Although the clinical risk of these individuals is likely somewhat lower than those with both an increased LDL-C and a pathogenic FH variant, risk is still likely 5 times greater than the population average, and current clinical guidelines strongly encourage use of aggressive lipid-lowering therapy. Although cascade genetic screening—as traditionally considered—will not find a pathogenic FH variant in 50% of first-degree family members, cascade biochemical screening—where relatives have their LDL-C assessed—is still an important consideration to impact health of patient’s family members.
In the situation where LDL-C is normal or mildly increased and the individual tests positive for an FH pathogenic variant, the lack of a severely increased in LDL-C may be related to the genetic variant being milder, less damaging, the presence of other offsetting genetic factors, or environmental/lifestyle influence. Compared with noncarriers with same LDL, these individuals tend to have significantly higher risk of cardiovascular disease, suggesting that a lower threshold to initiate or intensify treatment compared to the general population may be appropriate. Moreover, these individuals’ family members may have significantly higher LDL-C even with the same variants, providing additional opportunity to identify high-risk family members via cascade screening.
Most research on FH has been conducted in white, primarily European populations, including characterization of genetic defects of FH. Given this, should we—how should we—think about FH screening and treatment differently in non-White ethnic minorities?
Louis Vernacchio: Unfortunately, minority populations continue to be under-represented in clinical research. While we should strive to correct this problem, we should also recognize that genetic variation among individuals generally outweighs that of population groups defined by social categories such as race and ethnicity. In the case of FH, while the preponderance of research has been conducted with individuals of European descent, evidence points to a very widespread distribution around the world of the common genetic defects that cause FH. It is unlikely, therefore, that screening and treatment protocols for FH would differ for minority populations in the USA relative to those of European descent. Furthermore, as medical science progresses farther down the path of precision medicine, we will hopefully be able to tailor treatments more specifically to individuals’ specific genetic profiles to achieve optimal health outcomes in FH and other disorders.
Kirsten Bibbins-Domingo: The majority of genetic studies in FH predominantly or exclusively enrolled individuals of European ancestry. We do not know of systematic differences in FH genotypes by race/ethnicity, but unfortunately the data on non-White populations remains limited. As a result, it is plausible and perhaps even likely that there may be differences in the optimal screening strategy (phenotype first vs genotype first) in different in populations. Equitable FH screening must begin with ensuring that the screening tests and overall screening strategy are effective in all populations who will be included in screening. The disparity in available evidence highlights the need to fund and perform studies related to FH in non-White populations, and to ensure that a diverse cohort is enrolled in future trials of FH screening and early treatment.
Nonstandard Abbreviations
FH, familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol; ASCVD, atherosclerotic cardiovascular disease.
Author Contributions
All authors confirmed they have contributed to the intellectual content of this paper and have met the following 4 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable for all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately investigated and resolved.
Authors’ Disclosures or Potential Conflicts of Interest
Upon manuscript submission, all authors completed the author disclosure form. Disclosures and/or potential conflicts of interest:
Employment or Leadership
None declared.
Consultant or Advisory Role
S.R. Daniels, Sanofi (Steering Committee) and Regeneron (Data Monitoring Committee); A.V. Khera, Sanofi, Amgen, Maze Therapeutics, Navitor Pharmaceuticals, Sarepta Therapeutics, Verve Therapeutics, Veritas International, Color Health, Third Rock Ventures.
Stock Ownership
None declared.
Honoraria
A.V. Khera, Illumina, MedGenome, Amgen, and the Novartis Institute for Biomedical Research.
Research Funding
S.D. de Ferranti, U.S. Department of Health and Human Services, National Institutes of Health, National Heart, Lung, and Blood Institute, R01HL141823; A.V. Khera, National Human Genome Research Institute grants 1K08HG010155 and 1U01HG011719, sponsored research agreements from the Novartis Institute for Biomedical Research and IBM Research; D.S. Kazi, NHLBI, Institute for Clinical and Economic Review.
Expert Testimony
None declared.
Patents
None declared.
Other Remuneration
S.D. de Ferranti, royalties from UpToDate.