How can we improve advanced lipid testing for pediatrics?

In children, abnormal serum lipid levels are associated with dyslipidemia and increased risk of atherosclerotic cardiovascular disease in adulthood. Identification and management of dyslipidemia and other risks factors in early life is important for primary prevention for the disease. The high prevalence of childhood obesity in the US has increased concerns about the adverse effects of abnormal lipids in children, which prompted the National Heart Lung and Blood Institute (NHLBI) to include a strong recommendation for universal lipid screening in all children one time between the ages of 9-11 and a second universal screening between 17 and 21 years of age¹. This was followed by moderate level of evidence recommendation for universal screening in pediatrics in the AHA/ACC Cholesterol Clinical Practice Guidelines published in 2018². The NHLBI guidelines further highlight the importance of reporting lipid panel results with age-specific cutoffs established by the National Cholesterol Education Program (NCEP)³. Although the pediatric guidelines support the use of a routine lipid panel for screening, it is possible for the clinician to measure a few other parameters, including LDL particle number and size, using advanced lipoprotein tests such as lipoprotein analysis by Nuclear Magnetic Resonance Spectroscopy (NMR). Increased concentrations of small, dense low-density lipoprotein (LDL) particles, decreased high-density lipoprotein (HDL) particles, and increased triglyceride-rich lipoproteins have all been linked to atherosclerosis and CVD.

A review of specimens submitted to our laboratory revealed pediatric samples were being submitted for lipoprotein analysis by NMR for investigation of hyperlipidemia and abnormal weight gain. Subsequent audit of reference ranges for lipoprotein particle number and size available in online laboratory test menus from laboratories offering lipid analysis by NMR revealed the absence of pediatric cutoffs, leaving providers reliant on the adult cutoffs for clinical interpretation. Given the established difference in lipid levels in pediatrics and adults, use of adult cutoffs in children may result in misclassification of lipid status and underestimation or overestimation of dyslipidemia and CVD risk in children. Clinicians use provided reference intervals as a medical decision-making tool to interpret results and flag individuals who warrant additional follow-up or intervention. Therefore, the accuracy of applied reference intervals is critical to offer the best care for the patient. Establishment of pediatric reference intervals has long been challenging for the laboratory community because child development and growth can influence the concentration of many analytes, prompting a need for multiple age- and sex-specific partitions. Efforts such as the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) have established pediatric reference intervals for many common biochemical parameters; however, there is still a need to develop reference intervals for all tests that may be ordered on children, including lipoprotein analysis by NMR.

A recent study using lipoprotein NMR in adolescence found obese children had significantly higher LDL particle count and smaller HDL particles compared to normal weight children⁴, however, there are still no reference ranges for pediatrics, making interpretation of lipoprotein particles in children difficult. In the long term, we need to develop pediatric reference intervals for advanced lipid testing in children so that physicians are provided clinically interpretable results to aid in patient care and prevent future CVD risk. Until reference intervals can be established, it is important that labs make it very clear that reference ranges have not been established for pediatric patients, and results should be interpreted with caution.

References

1. Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents; National Heart, Lung, and Blood Institute. Pediatrics. 2011;128(Suppl 5):S213-56.
2. Writing Committee, Cholesterol Clinical Practice Guidelines. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: Executive summary. A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;139:e1046–e1081.
3. NCEP Expert Panel of Blood Cholesterol Levels in Children and Adolescents. National Cholesterol Education Program (NCEP): Highlights of the Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents. Pediatrics 1992;89:495-501.
4. Higgins V, Asgari S, Hamilton JK, Wolska A, Remaley AT, Hartmann B, Holst JJ, Adeli K. Postprandial Dyslipidemia, Hyperinsulinemia, and Impaired Gut Peptides/Bile Acids in Adolescents with Obesity. J Clin Endocrinol Metab. 2020;105(4):1228–1241.