Systematic review provides evidence about the value of screening for FH in childhood

Lozano P, Henrikson NB, Dunn J, et al.
JAMA. 2016;316(6):645-655.

Background

Familial hypercholesterolaemia (FH) is characterised by highly elevated total cholesterol or LDL-C concentrations early in life, which, in turn, are associated with increased cardiovascular (CV) risk and mortality, especially in the age range of 20-39 [1,2]. Screening for FH and lipid-lowering treatment during childhood could reduce the future CV risk in these patients, however, the US Preventive Services Task Force (USPSTF) does not recommend routine screening for any lipid disorder, due to lack of evidence [3].
27 articles that met inclusion and quality criteria were included in this systematic review, that aimed to review the evidence regarding benefits and harms of screening and treating children and adolescents for heterozygous FH. 8 key questions on screening were formulated, but for several questions, no studies were identified that aimed to answer these.

Main results

• The diagnostic yield of screening for FH was reported to be 1.3 cases per 1000 screened in the CARDIAC project and 4.8 cases per 1000 screened in a Danish study [4,5].
• The benefits of treatment of FH in children and adolescents have been addressed by 13 studies, 8 of which were statin trials. LDL-C decreases of 20-40% were reported, including dose-response relationships for pravastatin and rosuvastatin [6,7]. Trials of non-statin medications in children and adolescents with FH reported LDL-C decreases ranging from 10% with colesevelam up to 38% with ezetimibe monotherapy [8-11].
• Possible harms of statin treatment in youth were assessed in 13 studies. No severe or permanent harms of statins were reported in FH patients, and statins were generally well tolerated [6,12-15]. One study reported decreased dehydroepiandrosterone sulfate levels by 10.3% in statin-treated males at 10-year follow-up, the clinical significance of which is unclear.
• Possible harms of FH treatment with other compounds: Cholestyramine and colestipol were associated with decreased vitamin D and folate concentrations compared with placebo, and homocysteine was increased in children treated with cholestyramine [8,9]. No marked laboratory abnormalities were associated with colesevelam, and ezetimibe monotherapy was not associated with serious adverse events or with different rates of adverse events compared with a control group [11].
• No evidence is available on the benefits or harms of FH screening in childhood, nor on the association of FH screening in childhood and delay or reduction of the incidence of hyperlipidaemia, atherosclerosis, myocardial infarction or stroke later in life.
• There are no data evaluating the long-term benefits or harms of starting lifestyle modifications and/or lipid-lowering treatment in childhood.

Conclusion

This systematic review shows that screening for FH in childhood leads to the identification of undiagnosed FH cases. No direct evidence was found on the relationship between screening and FH outcomes in childhood and adulthood. The available evidence suggests that lipid-lowering treatment of children with FH improves lipid levels up to 50%, with little evidence of harm. Several important questions around FH screening remain unanswered due to the lack of data, including regarding lifelong usage and long term outcomes of treatment in childhood.

Editorial comment [16]

Lipid screening during childhood and adolescence has been recommended by multiple associations as a strategy to identify FH. ‘Although FH is asymptomatic in youth, there is mounting evidence that if left untreated, heterozygous FH is associated with a higher risk of early atherosclerotic cardiovascular disease (ASCVD) such that as many as 25% of women and 50% of men will experience early heart disease. However, many children and adults with FH, who are at risk of early ASCVD, remain undiagnosed.’ Paediatric lipid screening can also identify other lipid disorders, such as combined dyslipidaemia often associated with obesity, which may have a genetic underpinning.
“Mounting evidence suggests that adolescence is a critical window in atherosclerosis development. Atherosclerosis in childhood is characterized by subclinical arterial thickening and vascular dysfunction but little calcification; even in high-risk youths with obesity and diabetes, mean
coronary artery calcium scores during adolescence are less than 10. Thus, younger age at initiation and longer duration of drug therapy have been associated with a better CIMT at 10 years of follow-up as demonstrated by no difference in rate of increase in CIMT between youths treated for FH compared with their nonaffected siblings.” Studies investigating CIMT in youths have not studied outcomes.
Potential harms associated with screening for dyslipidaemia may include overdiagnosis, since tracking of lipid levels into adulthood is imperfect, and not all young people with an isolated lipid elevation will develop ASCVD. Adverse effects may further include potential anxiety in the family and costs of follow-up testing and treatment, and cost/burden for the patient, parent, clinician and health care system. Long-term RCTs evaluating the cost effectiveness of various lipid screening and treatment approaches in childhood are lacking. Moreover, “The long-term adverse effects of lipid-lowering medications in children and adolescents remain undefined and the risk-benefit of long-term use of these medications must be rigorously assessed in longer-term studies.”
The authors conclude: “The USPSTF rightfully acknowledges that “clinical decisions involve more considerations than evidence alone.” Accordingly, when high-quality RCT data are lacking, clinicians who provide care for children and adolescents should make the best use of the available evidence to
make reasonable inferences that can inform decision-making for their patients and their families.”

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