Introduction

Atherosclerotic Cardiovascular Disease (ASCVD) remains among the leading causes of death in the United States (U.S.) [1]. In 2019 alone, excluding heart failure, hospitalizations in the U.S. for coronary atherosclerosis or acute myocardial infarction cost over $112.8 billion [2]. In a search for etiologies, the Framingham Heart research group found, in 1961, that high blood cholesterol levels were associated with an increased likelihood of coronary artery disease [3]. Over 55 years later, the European Atherosclerosis Society became the first major professional society to declare that cumulative exposure to low-density lipoprotein cholesterol (LDL-C) causes ASCVD. The group noted that “long-term exposure to lower LDL-C is associated with up to a three-fold greater proportional reduction in the risk of cardiovascular disease per unit reduction in LDL-C, when compared with shorter-term treatment with a statin started later in life after atherosclerosis has developed” [4]. That observation provides adequate justification for “primordial prevention” of atherosclerosis. Stary identified “advanced” atherosclerotic lesions of the coronary arteries of nearly 10% of general population 12-14-year-olds [5]. However, there is compelling evidence that, when LDL-C levels are exceptionally high, atherosclerosis is even more prevalent at younger ages [6].

Among the causes of moderate-to-severe hypercholesterolemia are several monogenic disorders [7]. At an estimated prevalence among U.S. adolescents of 1:237, the most common is inherited co-dominantly and known as Familial Hypercholesterolemia (FH) [8]. If untreated, the significantly elevated LDL-C levels of patients with FH predispose them to a much higher—and much expedited—risk of major adverse cardiovascular events (MACE) compared to the general population [9,10,11,12,13,14,15,16]. Worse subclinical vascular health has even been shown among heterozygous FH populations (versus non-FH siblings) among children under 8 years old [17].

FH is, however, treatable, and there is an expanding array of options available for children with hypercholesterolemia. In recent years, the U.S. Food and Drug Administration has approved the use, by children, of pitavastatin (2019), evolocumab (2021), and evinacumab (2021, updated 2023). According to ClinicalTrials.gov, prospective pediatric trials of lomitapide or inclisiran are ongoing. While data on the long-term risks and benefits of newer drugs being initiated in childhood have not yet been published, 20-year follow-up data on pravastatin usage by heterozygous FH patients beginning in middle childhood have been encouraging [18]. The American Heart Association has endorsed the use of statins in children with heterozygous FH as young as 8-10 years old [19, 20]. Statin initiation in adulthood has not yet eliminated the excess event risk of FH, making early detection and treatment of FH highly important [9,10,11]. Whether newer lipid-lowering drugs or combination therapies, initiated in adulthood, will mitigate the excess risk of FH remains unknown. However, the cost of such approaches often limits their use in primary and secondary prevention. Early detection and treatment of FH, starting in childhood, may significantly reduce the need for more costly and aggressive lipid-lowering therapy in adulthood. It is estimated that only 31.1% of those with FH have been identified in the U.S., and the rate of FH identification remains poor worldwide [21••].

As the most prevalent single-gene disorder in humans—causing substantial, yet easily mitigatable, hazards—FH has long attracted interest as a target for screening [22]. In 1989, the American Academy of Pediatrics (AAP) proposed expanding selective pediatric cholesterol screening to the clinical realm—a notion soon clarified and championed by the National Cholesterol Education Program (NCEP) [23, 24]. In 2011, the National Heart, Lung, and Blood Institute (NHLBI) presented a more ambitious proposal: that universal screening of U.S. youth should occur at 9-11 years old [25], in addition to selective screening at other ages based on risk factors. The NHLBI guideline was embraced by the AAP, as well as many other U.S. professional societies. We summarize existing guidelines for pediatric cholesterol screening in Table 1. However, the NHLBI’s recommendation for universal cholesterol screening in childhood has not been widely accepted or integrated into routine clinical practice. A review of over 60,000 well-child visits from three large datasets demonstrated no overall change in the rate of cholesterol screening among children 9-11 years old after the release of the 2011 NHLBI guidelines [31]. As says the U.S. Preventive Services Task Force (USPSTF), “Recent studies investigating screening practices in large U.S. health care organizations have found universal screening rates of 2 to 9 percent in children between 9 and 11 years of age” [26]. Troublingly, missed cholesterol screenings often have been intentional. In two recent surveys of U.S. pediatricians, nearly half of the respondents reported regularly omitting screening patients for hypercholesterolemia, believing that universal cholesterol screening is “not appropriate” [32, 33]. The Lown Institute’s Right Care Alliance Children’s Health Council has even ranked routine cholesterol screenings among their “top five ‘don’t’ recommendations” for child healthcare [34]. In this review, we examine what is currently known about the beliefs and practices of healthcare providers regarding the potential benefits/limitations/harms of universal cholesterol screening in childhood (Table 2). We also propose ways of increasing such screening rates to improve healthcare outcomes for youth at risk for premature cardiovascular disease (Table 3).

Table 1 Overview of select major U.S. pediatric cholesterol screening guidelines for all populations
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Table 2 Why Universal Pediatric Hypercholesterolemia Screening?
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Table 3 Cholesterol Screening in Youth: Barriers & Opportunities
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Barriers & Solutions

A Misperception that Targeted Screening is Sufficient to Identify at-risk Children

The presence of obesity, chronic kidney disease, Kawasaki disease, Human Immunodeficiency Virus infection, cardiomyopathy, an endocrinopathy, or a transplanted heart has been shown to correlate with a higher likelihood of a child undergoing cholesterol screening [35,36,37,38]. Although many of those factors are important causes of hyperlipidemia among children, FH exists independent of those factors, thus sneaking “under the radar” despite its insidious harm.

In 1991, the NCEP proposed principally family-history-based criteria for screening children selectively for hypercholesterolemia in clinical practice [24]. It is conceivable that many healthcare professionals mistake the now-antiquated NCEP guideline as a current care standard. That such a misunderstanding may exist is suggested by a recent national survey having found that 30% of pediatricians felt that a review of family history is “sufficient to identify familial dyslipidemias” [33]. Moreover, in a survey of family physicians, most respondents reported screening pediatric patients for hypercholesterolemia only selectively, with a family history of hypercholesterolemia, heart attack, or stroke among the biggest measured influencers favoring screening [39].

Unfortunately, in practice, family histories are often incompletely known. The demonstrated consequence is that selective pediatric cholesterol screening approaches that rely on family history miss a vital share of children with hypercholesterolemia [40,41,42]. In the U.S., just 2 in 5 young adults—the demographic that predominates as parents to young children—self-report having undergone a cholesterol screening in the preceding 5 years. Moreover, only 1 in 5 young adults in the U.S. who have hypercholesterolemia have awareness of their hypercholesterolemia [43]. Such numbers strongly suggest an implementation problem under a paradigm of family-history-driven selective pediatric cholesterol screening. “Cascade screening” refers to the practice of screening for a given disease the relatives (usually progeny) of those diagnosed with the disease. Though efforts to understand and deepen family tracing in cascade-based cholesterol screening approaches, including outreach to ask adult specialists to promote cholesterol screening of the children of their hypercholesterolemic patients may usefully boost identification of pediatric FH, the USPSTF has noted that “rigorous cascade screening is not currently implementable in the United States due to HIPAA and lack of current infrastructure” [26, 44,45,46,47,48,49]. Moreover, population health modeling demonstrates that “Cascade testing is not [alone] a suitable method of population screening for FH, because a separate method of systematically identifying new FH index cases is required to achieve a reasonable level of FH detection in the population” [50].

The cost-effectiveness of universal versus selective cholesterol screening remains a topic of active debate. Proponents of biochemical cascade screening for FH may cite studies demonstrating that such screening can be cost-effective in the U.S. [51]. However, one recent pediatric-testing model contends that 126,000 extra 10-year-olds per year in the U.S. would be diagnosed with hyperlipidemia (including 8,000 extra children diagnosed with severe hypercholesterolemia, 7,000 of whom promptly would qualify for a lipid-lowering prescription) utilizing a strategy of universal, versus selective, screening. The cost per diet-refractory severe hypercholesterolemia case detected predictably rises with universal, versus selective, cholesterol testing. However, it increases only to $12,590 per case identified through universal screening—a meager expense compared to the decades of cost spent on individuals with ASCVD [52].

Guideline-Based Barriers

Much of the divide between proponents and opponents of universal childhood cholesterol screening falls along medical specialty lines. Compared to pediatricians, family practitioners more often oppose universal childhood cholesterol screening [39]. That difference may be due substantially to perceived conflicts amongst competing professional society traditions, philosophies of care, and guidelines [53]. While the American Academy of Pediatrics leans toward an activist modus operandi, the American Academy of Family Physicians openly acknowledges hewing closely on medical policy matters to the clinical assessments of the conservative USPSTF. Indeed, in regard to the concept of pediatric cholesterol screenings, the website of the American Academy of Family Physicians (AAFP) explicitly states that “The AAFP supports … USPSTF… recommendations on this topic” [54]. However, although the USPSTF has released several meticulously-curated evidence reviews on pediatric cholesterol screenings, no summary statement from the USPSTF officially contains any actual recommendation on the subject. Its most recent “final” assessment, from 2016, and its just-published draft-released evidence review both state that there is “insufficient evidence” for the USPSTF to issue any practice recommendation, perpetuating ambiguity about how—or even whether—the AAFP endorses cholesterol screening should proceed in the pediatric population [26, 28]. Some sources have misinterpreted the USPSTF’s most recent final determination as advising against pediatric cholesterol screenings [55]. At the least, many family practitioners have interpreted the USPSTF’s ambivalence as extending permission to direct their attention toward other medical issues. However, such an approach yields noticeably narrower testing guidance across the hypercholesterolemia care age spectrum [56].

In some data sets, cholesterol screening rates among children 9-11 years old declined following the release of the USPSTF’s 2016 statement on pediatric lipid screening [53]. That has been tragic for patients whose FH has gone undetected and whose lives may be shortened by decades—and that pattern likely will repeat in the aftermath of the USPSTF’s meticulous, but misguided, 2023 literature summary. A June 22, 2023 Medline search for ((pediatr$ or children) and (cholesterol or lipid or dyslipid$ or hyperlipid$ or hypercholesterol$) and (screening or detecting or identification or finding or sensitiv$)).ti,ab.—excluding review and non-English articles—returned 2,363 articles. However, in their recently released 314 page report on pediatric cholesterol screening, the USPSTF report’s authors—only one of whom is a physician—found no study adequate to address either of its self-framed “Key Questions” containing the word “screening.” Most troublingly, as others have suggested of past USPSTF statements, the USPSTF’s Key Questions on childhood cholesterol screening are inveterately unanswerable practically [57,58,59,60,61].

In its latest iteration, the USPSTF asks whether screening children for FH or multifactorial dyslipidemia delays or reduces the incidence of health outcomes or improves intermediate outcomes [26]. To satisfy such an inquiry for FH, a prospective trial would need to cholesterol-screen >12,000 U.S. ten-year-olds (to find 50 with FH at a 1:237 prevalence) and >>12,000 previously-unscreened U.S. twenty-year-olds (necessitating >>13,000 chart reviews, assuming a 9% cholesterol screening rate among ten-year-olds) to find 50 with FH, follow for a decade the subjects enrolling at ten years old, and compare differences in the carotid intimal-medial thickness (CIMT) between the two groups at twenty years old. Alternatively, one could scour the medical records of 133,000 U.S. twenty-year-olds to find 50 who were diagnosed biochemically with FH at ten years old (assuming a 1:237 FH prevalence, discovered at a 9% screening rate) plus >>12,000 U.S. twenty-year-olds who were not screened for hypercholesterolemia at ten years old (again necessitating >>13,000 chart reviews). Those >>12,000 twenty-year-olds would need to be screened for FH (~50 of whom will, in fact, have had FH all along). CIMT could then be compared between the two groups. Because of the higher prevalence of multifactorial dyslipidemia, smaller, but analogous, studies could be undertaken in pursuit of a justification for childhood lipid screening. However, given multifactorial dyslipidemia’s more modest hypercholesterolemia, a clinically-meaningful difference between groups might be harder to demonstrate. Moreover, valid objections could be raised that the subjects first identified as having multifactorial dyslipidemia at twenty years old might not have had stable multifactorial dyslipidemia since they were ten years old. In practice, then, it is highly unlikely that any of those studies ever will be done. Like a hamster in its cage, the USPSTF spins its wheel perpetually, while getting nowhere. The USPSTF is apparently satisfied with that outcome, but we—family practitioners included—should not be. The rubber can reach the road by a different tact, such as a systematic application of evidence on pediatric cholesterol screening to Wilson and Jungner’s classic screening principles [62].

The length and complexity of guidelines and test interpretation can also hinder guideline adoption. What was asked of the primary care community in the official summary figures for the 2011 NHLBI recommendations spanned one-and-a-half daunting journal pages, failed to define separately primary care and subspecialist roles in pediatric cholesterol screening and care, and encouraged two fasting lipid profiles prior to intervention [25]. In a survey, one-third of pediatricians admitted a lack of comfort with interpreting a lipid profile, citing that as a barrier to screening. Additionally, 90% noted that the need for fasting discourages cholesterol screening [33]. Some also report that achieving comprehensively the tasks recommended within the ever-growing AAP’s Bright Futures’ periodicity schedule is unrealistically ambitious in the limited time that practices allot to well visits—obliging omissions [63,64,65]. A primary care physician commented to one of the authors of this paper (TCD) that he felt it necessary to concentrate well-child care “on what might kill…[his] patients in the next year.” Viewed through that lens, childhood cholesterol screening may register to primary care providers (PCPs) as a low priority even when they endorse hypercholesterolemia’s long-term public health significance [33, 39, 66••, 67].

While the reasons for patient and parent refusals of blood collections have not been explored academically, traditional venipuncture requires painful needle sticks, and most children and 20-50% of adolescents fear needles—an understandable barrier to cholesterol screening efforts [68, 69]. No other laboratory blood testing routinely is recommended by the AAP for patients anywhere close to 9-11 years old. Last, but not least, PCPs also report reluctance to inconvenience their patients to seek cholesterol care from subspecialists when the current NHLBI-guideline-recommended lipid level threshold for further investigation (non-HDL ≥145 mg/dL) affords only 38% specificity in the identification of patients who require prescription pharmacotherapy [70, 71]. Indeed, half of the pediatricians responding to one survey “agreed or strongly agreed that ‘screening all children for high cholesterol will lead to unnecessary and costly follow-up’” [33].

Guidelines-Based Solutions

Sensible solutions do exist, and there is growing evidence of their efficacy. Multiple studies have shown practical equivalency between fasting and nonfasting clinical cholesterol level results for initial screening [72,73,74,75]. It is uncommon for hypertriglyceridemia to interfere seriously with hypercholesterolemia care at the screening and diagnostic stages [76,77,78,79]. Even in the rare instance when hypertriglyceridemia is marked, new formulas for calculating LDL-C levels are helping to sharpen what diagnostic insights may still be gleaned [80, 81]. Given what is known about nonfasting cholesterol screening, the 2018 “multisociety” guidelines on cholesterol explicitly state, “Nonfasting lipid parameters are similar to fasting ones, and screening with a nonfasting non–HDL-C is a reasonable approach to population screening in childhood” [19].

Explicit encouragement of point-of-care testing in support of childhood cholesterol screening may also enhance compliance rates. Such technologies yield results that clinicians can present within minutes—obviating a need for post-visit outreach by PCPs or their schedulers. At least two point-of-care systems for cholesterol testing are already available commercially in the U.S.. They require no more than a single drop of a patient’s blood to produce results—enabling lancet-based testing to supplant venipuncture-based testing for cholesterol screens. Both point-of-care systems can yield insurance-reimbursable results at break-even or even slightly-profitable levels. One of the systems can even result only total and HDL cholesterol levels—simplifying the task of interpreting lipid profiles.

An evidence-based response to the problem of pediatric cholesterol screening occurring as an isolated blood test demands both historical and modern insights. Citing a 2007 systematic evidence review by the USPSTF that “the optimal age and frequency of testing” children universally for hypercholesterolemia had not yet been established, the NHLBI’s 2011 report proposed completing universal screening of children for hypercholesterolemia by specifically 9-11 years old as “a stable time for lipid assessment in children” before most children enter puberty (within which, total cholesterol and LDL-C levels were known to dip). Further justification for highlighting cholesterol screening at 9-11 years old was uncredited in the guideline [42, 70]. However, both Stary’s evidence of advanced coronary atherosclerosis arising just beyond the 9-11 age window and accumulating evidence of statin safety and effectiveness among patients at least 10 years old likely influenced the NHLBI’s choice [5, 70]. Nevertheless, despite an originally “grade D” evidence rating for the 9-11 years old universal screening window, that window was endorsed as official policy by the AAP while still in pre-print, integrated into the AAP’s Bright Futures program’s “periodicity schedule” in 2014, and echoed by guidelines from the National Lipid Association in 2015, American Association of Clinical Endocrinologists and American College of Endocrinology in 2017, and the latest “multi-society” guidelines on blood cholesterol management in 2018 [19, 27, 29, 30, 70, 82].

However, not long after the USPSTF closed its 2007 systematic evidence review, Starr and colleagues demonstrated substantially greater discriminatory ability—between individuals genetically-positive versus genetically-negative for FH—from blood LDL-C measurements when the subjects tested were, for instance, <15 versus 45-54 years old [83]. Wald and colleagues contemporarily refined that concept in a meta-analysis. They generated receiver operating characteristic curves of FH detection rates plotted against false-positive rates for total cholesterol and LDL-C as measured from subjects of various age brackets. Whether relying upon total cholesterol or LDL-C, they showed the greatest discriminatory capability between subjects with versus without FH when the subjects being blood tested were 1-9 years old versus any other age group tested (newborns, 10-19-year-olds, and 3 adult cohorts). That finding held regardless of sex, defining FH clinically or genetically, or whether subjects were recruited from lipid clinics or mass screenings. Wald’s group also noted, “Within the 1-9 year age group, the screening performance seemed to peak at between 1 and 2 years of age” [84]. From that discovery arose the screening technique for FH index-case-finding today known as “child-parent screening,” in which 1-2-year-olds are screened universally for FH, and the relatives of toddlers diagnosed with FH are next offered testing [84,85,86,87]. Importantly, Wald and colleagues have demonstrated empirically, in a large trial, that child-parent screening efficiently identifies FH cases [86].

Notions of testing children’s blood cholesterol levels in early toddlerhood may be unfamiliar to many PCPs, as no major U.S. guideline has ever endorsed testing cholesterol levels among patients so young. However, there has long been evidence that children’s blood cholesterol levels stabilize by the end of infancy—albeit no younger [88,89,90]. Wald and Martin have summarized several compelling arguments for screening toddlers for hypercholesterolemia. Among their reasons, such timing of pediatric cholesterol screening would: facilitate the premorbid detection of children with homozygous FH, aid the early initiation of “heart healthy” diets for patients with a genetic predisposition for hypercholesterolemia, and facilitate detecting parents with FH before they have incurred or succumbed to MACE [91, 92]. Moreover, screening for lead exposure and anemia already occurs in the U.S. at 1 and 2 years old, the window recommended by Wald and colleagues for pediatric cholesterol screening [63, 84]. Universal screening for anemia at approximately one year of age is supported by the AAP’s Committee on Nutrition [93]. Blood lead level assessment is Federally mandated in the U.S. for all Medicaid-insured 1- and 2-year-olds outside Arizona (where targeted lead screening is permitted), with roughly 40% of U.S. children currently enrolled with Medicaid [94, 95]. Piggybacking of cholesterol screening onto anemia or lead screening manifestly may enhance pediatric cholesterol screening rates and even bolster anemia or lead screening rates by compounding justification for a routine blood draw in toddlerhood.

Last, but not least, although further refinement of cholesterol cutpoints warranting investigation may likely be useful if U.S. guidelines evolve toward targeting pediatric cholesterol screening to toddlerhood, Zawacki and colleagues helpfully have suggested more stringent non-HDL-C cutpoints for determining which 9-11 years old patients warrant further evaluation for hypercholesterolemia. Notably, applying the higher cutpoints recommended by Zawacki and colleagues—which could eventually secure guideline endorsement—would still flag 99% of standard-risk children and 95% of children otherwise at an elevated ASCVD risk who warrant antihyperlipidemic pharmacotherapy while enhancing specificity in the standard-risk group to 96% [71]. The test specificity among children in the group otherwise-at-risk for ASCVD would also improve, to 55%. Though the latter specificity improvement is less robust, that subset of children has other traditional ASCVD risk factors and arguably has greater cause to see a preventive subspecialist irrespective of the child’s cholesterol level [96••]. It is reasonable to anticipate that screening performance like that should engender more enthusiasm than current standards from PCPs reluctant to over-refer their patients to subspecialists.

Systems-Based Barriers and Solutions

One systems-based barrier to pediatric lipid screening has been the local inaccessibility of pediatric lipidologists. For instance, roughly one-third of pediatricians confess a lack of comfort in providing appropriate dietary counseling to manage hypercholesterolemia, >95% express doubt about their abilities to motivate patient compliance with appropriate lifestyle changes, and nearly 90% admit discomfort with prescribing statins to children [33]. Such findings should motivate lipidologists to engage further with our trainees at all levels—and with our legislators in support of telehealth offerings. Telemedicine cholesterol care can yield outcomes non-inferior to in-clinic care [97].

Inconsistent health insurance coverage for pediatric cholesterol screening has understandably impeded some screening [32, 39, 66]. Happily, under the Affordable Care Act, all Healthcare Marketplace health insurance plans are mandated to absorb fully the cost of preventive healthcare services recommended under the AAP’s Bright Futures program [98, 99]. Furthermore, Tricare Basic, Select, and Prime health plans for U.S. military families fully cover the cost of one lipid profile for children 9-11 years old [100]. Vitally, all Medicaid and CHIP programs at least cover “for cause” lipid panel testing throughout childhood. However, even in 2023, universal childhood cholesterol screening is still not universally reimbursable. Minors in the District of Columbia and only 42 states who are insured through Medicaid or CHIP are guaranteed no-cost Early and Periodic Screening, Diagnosis, and Treatment care coverage, including universal cholesterol screening by middle childhood. However, with Medicaid being administered at the state level, children covered under its plans in Alabama, Delaware, Massachusetts, Minnesota, Missouri, Rhode Island, Utah, and Wisconsin lack policy coverage for universal cholesterol screening [98, 99, 101,102,103]. Lobbying of policymakers in those states is a clear and present need.

Conclusions

The USPSTF is now completing its second systematic review of evidence regarding what value may reside in routine pediatric cholesterol screening since the 2011 release of the NHLBI’s guideline on the same subject. Its recently-released draft statement indicates that incongruity between USPSTF and NHLBI guidance will sow misunderstanding and missed screening opportunities [25, 26]. Meanwhile, outside of cholesterol screening’s inclusion in the Bright Futures program’s periodicity schedule, the AAP has not commented on pediatric cholesterol screenings since 2012 [82]. With the AAP being the US’s most authoritative professional body on pediatric healthcare, we encourage the Academy to recruit knowledgeable lipidologists to produce the next generation of pediatric cholesterol screening guidelines. Universal cholesterol screening of children is vital. However, given the poor acceptance of past recommendations in that vein, we urge that those called to the task would not merely recapitulate what has not worked. Instead, they should seek out avenues for garnering the enthusiastic support of all PCPs. We do not possess all the light regarding the ideal way to screen children for hypercholesterolemia, but we hope these remarks will at least point in productive directions. Our responsibility to children with hypercholesterolemia is too great for us to shirk from seeking solutions in all corners. We would do well to adopt the attitude exemplified when U.S. Marines officer Oliver Smith famously told a Time magazine reporter during the Korean War’s losing Chosin Reservoir Campaign: "Retreat, hell! We're not retreating, we're just advancing in a different direction" [104]!