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Perspectives on Identifying and Treating Familial Hypercholesterolemia in Childhood

Year: 2021

Type: article

Abstract: 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. 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. 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. 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. 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. 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. 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. 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 and nutrition. I believe it can be to the children by who as this would be most provided in higher but the has us that of our communities can be with I would to see to children and from the youngest age the for or specifically for pediatric cardiac for the to and to needs to be given to both parent and need to the importance of diet in the treatment of their I believe a in the does this for a of with a and of what they are This needs to be and up with even a we with a large we all counseling should not be so need to be by as part of preventive It is extremely important to the children and families to how their choices will their health in life. In a perfect we would provide family with a of for heart low cholesterol and young adults especially need this to make about This be an public health topic or research to how engagement effect long-term outcomes for this population. Steve Daniels: The level of atherogenic particles circulating in the over time is the primary of the atherosclerotic and can be in various including LDL-C, and other lipid Historically, we have focused on the concentration of LDL-C for evaluation and a treatment While some other approaches may measure the risk of LDL-C has to be in the clinical There may be a range of concentration of LDL-C individuals with heterozygous FH due to the of different genetic abnormalities on LDL-C and other There may also be at present, are not well In the situation where there is a between and I would suggest that the concentration of LDL-C should particularly when the clinical decision involves whether to use When the LDL-C is substantially increased, but they are gene a very likely is that they have an FH gene variant not yet identified as When patients have only increased LDL-C and have genetic of FH, they need to be followed their lifetime and have lifestyle It is not however, if or how decisions about the use of medication should be different based on the presence of a gene may have other that have a on LDL-C that have not been identified and are with a lower lifetime risk of ASCVD. the LDL-C is a useful measure of the potential for of and and should be used in clinical decision-making. Amit Khera: The of increased LDL-C with negative genetic testing is relatively common since these individuals up to 5% of the general population. Potential include a variant that is undetected or by current genetic testing a favorable common variant where the effects of many the of a FH or Although the clinical risk of these individuals is likely somewhat lower than those with both an increased LDL-C and a pathogenic FH risk is likely than the population and current clinical guidelines use of aggressive lipid-lowering therapy. Although cascade genetic not find a pathogenic FH variant in of family cascade have their LDL-C an important consideration to health of family members. In the situation where LDL-C is or increased and the tests positive for an FH pathogenic the of a severely increased in LDL-C may be related to the genetic variant less the presence of other genetic or with with LDL, these individuals to have higher risk of cardiovascular that a lower threshold to initiate or treatment compared to the general population may be Moreover, these family members may have higher LDL-C even with the additional to high-risk family members cascade screening. Louis Vernacchio: populations to be in clinical While we should to this we should also recognize that genetic among individuals that of population groups by such as and In the of FH, the preponderance of research has been with individuals of evidence to a very distribution the of the common genetic that FH. It is that screening and treatment for FH would for populations in the USA to those of as medical down the of we will be to treatments more specifically to specific genetic to optimal health outcomes in FH and other Kirsten Bibbins-Domingo: The of genetic studies in FH or individuals of do not of in FH by but the on populations As a it is plausible and perhaps even likely that there may be in the optimal screening first in different in populations. FH screening with that the screening tests and overall screening are effective in all populations who will be in screening. The in available evidence the need to and studies related to FH in and to ensure that a diverse cohort is in future of FH screening and early treatment. FH, LDL-C, low-density lipoprotein ASCVD, atherosclerotic cardiovascular disease. confirmed they have to the of this and have the following to the and of or and interpretation of or the for of the and to be for all of the thus that questions related to the accuracy or of any part of the are and all the potential of and and the for of and of and and research from the for and for and from

Source: Clinical Chemistry

DOI: 10.1093/clinchem/hvab157