Pediatric reference intervals for lipids and apolipoproteins on the VITROS 5,1 FS Chemistry System

doi:10.1016/j.clinbiochem.2006.06.012

Clinical Biochemistry

Volume 39, Issue 10, October 2006, Pages 978-983

https://doi.org/10.1016/j.clinbiochem.2006.06.012 Get rights and content

Abstract

Objectives:

Lipid biomarkers are integral in the assessment of dyslipidemia and cardiovascular risk, conditions that have become increasingly prevalent in pediatric populations. A comprehensive set of pediatric reference intervals for traditional or recently established lipid analytes is not currently available.

Design and methods:

525 outpatient samples from a pediatric population were categorized into five age groups ranging from 0 to 20 years of age. Groups were further partitioned by gender. Serum or plasma samples were analyzed on the VITROS 5,1 FS Chemistry System for cholesterol and triglycerides by dry-film methods, direct HDL-C and LDL-C by selective detergent elimination, and apolipoproteins AI and B by immunoturbidimetry. Reference intervals were established by non-parametric methods at the 2.5th and 97.5th percentiles.

Results:

Lipid levels show age- and gender-related differences, particularly during the first year of life and in young adults following puberty. Concentrations of total cholesterol, LDL-C, and apo B were lowest in the 12 months after birth and remained relatively constant throughout childhood, but decreased for males in early adulthood. Triglyceride levels increased gradually throughout childhood and adolescence, and along with cholesterol, the upper limits of these intervals exceeded the recommended concentrations of lipid levels in children. For HDL-C and apo AI, no age- or sex-related differences were found until after puberty when values for males decreased slightly.

Conclusions:

Our current reference intervals in children and adolescents provide an important update for lipid markers and suggest earlier incidence of hypercholesterolemia when compared to previous ranges. Increased profiling of lipids is anticipated, and these will aid in the early assessment of cardiovascular risk in pediatric populations.

Introduction

In adults, the utility of lipid biomarkers has evolved from traditional reference intervals to defined dyslipidemic states with emphasis placed on risk reduction of cardiovascular events, diabetes, and their co-morbidities. Reference to established marker levels like cholesterol, triglycerides, HDL-cholesterol (HDL-C), and LDL-cholesterol (LDL-C) is frequently made in major clinical practice guidelines and position statements [1], [2], [3]. Despite the recent and widespread recognition that changes in these lipid-related risk factors begin in childhood, our understanding of normal and abnormal values in the pediatric population remains limited. Although the National Cholesterol Education Program (NCEP) made recommendations on the cholesterol levels in children and adolescents [4], screening of youth remains controversial and reference intervals are needed in the interpretation of laboratory results. Furthermore, several new and emerging markers have moved from the research setting into the clinical laboratories. For example apo AI and apo B have demonstrated utility in major studies which may enhance and potentially exceed the value of traditional markers [5].

Childhood dyslipidemia has become a highly important health concern due to its association with increased risk for cardiovascular disease and the metabolic syndrome with consequent occurrence of cardiovascular mortality and type 2 diabetes later on in adulthood, respectively. The existence of an obesity epidemic in children and adolescents is now well appreciated [6], [7], [8], and childhood obesity is commonly associated with dyslipidemia [9]. From large population studies such as the Bogalusa Heart Study and others, cardiovascular risk factors traditionally applied to the adult population are apparent in children and young adults which are strongly associated with the development of atherosclerotic disease [10], [11], [12]. Moreover, dyslipidemia is among various factors that cluster with obesity and insulin resistance states in the criteria that define the metabolic syndrome [13], and epidemiological studies indicate that the biochemical changes in the lipid profile and glycemic control originate during childhood [14].

In a recent review by Mansoub et al. [15], a gap analysis of reference intervals for the pediatric population for several established and emerging biomarkers was presented. In the present study, we have established reference intervals on a new clinical chemistry platform (VITROS 5,1 FS) for five age groups covering 0–20 years of age from an outpatient population for six biochemical lipid markers (cholesterol, triglycerides, HDL-C, LDL-C, apo AI and apo B) for the assessment of these levels in children and young adults.

Section snippets

Subject selection and sample collection

Serum or plasma was obtained from leftover specimens from an outpatient population deemed to lack the presence of a metabolic illness. For children and adolescents, this included dentistry, orthopedic, and plastic surgery patients and patients undergoing elective surgeries, while neonatal and infant samples were from elective surgeries, orthopedic, dermatology, and infectious disease clinics. Serum and heparin plasma samples were collected from plastic tubes or syringes without gel over a

Results and discussion

Reference intervals for serum (or plasma) lipid biomarkers determined on the VITROS 5,1 FS Chemistry System are summarized in Table 1and Fig. 1. The number of samples for each reference interval depended on the availability of leftover laboratory specimens from presumptive healthy outpatients for each analyte. No statistical differences in the mean or variance were found between males and females for the age groups spanning 1–14 years. While differences in the mean existed for some analytes in

Acknowledgments

P.M.Y. is supported by the Sanford Jackson Fellowship at The Hospital for Sick Children. This work was supported by a research grant from Ortho-Clinical Diagnostics, USA.

References (39)

A.D. Sniderman et al.
Apolipoproteins versus lipids as indices of coronary risk and as targets for statin treatment
Lancet
(2003)
A. Fagot-Campagna et al.
Type 2 diabetes among North American children and adolescents: an epidemiologic review and a public health perspective
J. Pediatr.
(2000)
R.H. Eckel et al.
The metabolic syndrome
Lancet
(2005)
J. Steinberger et al.
Adiposity in childhood predicts obesity and insulin resistance in young adulthood
J. Pediatr.
(2001)
B.A. Kottke et al.
Levels of lipids, lipoproteins, and apolipoproteins in a defined population
Mayo Clin. Proc.
(1991)
J.P. van Wijk et al.
Normal ranges of non-fasting triglycerides in healthy Dutch males and females
Clin. Chim. Acta
(2003)
S. Baroni et al.
Serum apolipoprotein A1, B, CII, CIII, E, and lipoprotein (a) levels in children
Clin. Biochem.
(1996)
O. Gozlan et al.
Lipoprotein levels in newborns and adolescents
Clin. Biochem.
(1994)
O.P. Soldin et al.
Serum iron, ferritin, transferrin, total iron binding capacity, hs-CRP, LDL cholesterol and magnesium in children; new reference intervals using the Dade Dimension Clinical Chemistry System
Clin. Chim. Acta
(2004)
P.S. Horn et al.
Reference intervals: an update
Clin. Chim. Acta
(2003)

P.O. Kwiterovich et al.

Comparison of the plasma levels of apolipoproteins B and A-1, and other risk factors in men and women with premature coronary artery disease

Am. J. Cardiol.

(1992)

E.J. Schaefer et al.

Effects of age, gender, and menopausal status on plasma low density lipoprotein cholesterol and apolipoprotein B levels in the Framingham Offspring Study

J. Lipid Res.

(1994)

Executive summary of the third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III)

JAMA

(2001)

J. Genest et al.

Recommendations for the management of dyslipidemia and the prevention of cardiovascular disease: summary of the 2003 update

CMAJ

(2003)

S.M. Grundy et al.

Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines

Circulation

(2004)

American Academy of Pediatrics

National cholesterol education program: report of the expert panel on blood cholesterol levels in children and adolescents

Pediatrics

(1992)

R.P. Troiano et al.

Overweight children and adolescents: description, epidemiology, and demographics

Pediatrics

(1998)

S.R. Daniels et al.

Overweight in children and adolescents: pathophysiology, consequences, prevention, and treatment

Circulation

(2005)

M.I. Goran et al.

Abdominal obesity and cardiovascular risk in children

Coron. Artery Dis.

(1998)

Cited by (38)

Evaluation of Lipid Profile in Children Born to Female Transplant Recipients
2020, Transplantation Proceedings
Being aware of the nephro- and hepatotoxic effects of most immunosuppressants, assessing their potential effects on the health of the offspring is an important aspect of deliberate family planning after organ transplantation.
The aim of the study was to evaluate the influence of immunosuppressive drugs used by pregnant women after kidney or liver transplantation on the lipid profile of their children.
Ninety-one children born to mothers after kidney or liver transplantation (study group) and 91 children of healthy mothers from the control group (control group) were included in the study. Transplant donors received immunosuppressive treatment in monotherapy or combination regimens during pregnancy. The study compared lipidogram values including total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglycerides. The lipidogram was analyzed depending on the following 3 most commonly used immunosuppressive regimens: study group 1: CI (calcineurin inhibitors); study group 2: CI + GCs (glucocorticosteroids); and study group 3: CI + GCs + AZA (azathioprine).
There were no significant differences between study group and control group in mean total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglyceride levels (P > .05). In each of the studied subgroups, at least 1 abnormal lipidogram fraction was noted. Frequency of these deviations in study group 1, study group 2, and study group 3 were 31%, 57%, and 26%, respectively. However, no statistically significant differences were found between these obtained results (P > .05).
Prenatal exposure to immunosuppressants taken by the mother after liver or kidney transplantation does not appear to significantly affect the occurrence of lipid disorders in these children.
Lipid alterations in adolescents with early-onset psychosis may be independent of antipsychotic medication
2020, Schizophrenia Research
Citation Excerpt :
In addition, adjunctive omega-3 dietary supplements have been suggested to have stage-specific effects, with more positive effects observed in the treatment in earlier stages, and progressively diminishing efficacy in later stages of patients with SCZ (Chen et al., 2015). The lipid alterations we found here did not exceed clinical cutoff limits according to child and adolescent reference charts (Yip et al., 2006), but more patients than HC had lipid levels above the 50th percentile. These findings are important with regard to increased CVD risk in adulthood, as exposure to increased blood lipid levels at a young age leads to the earlier progression of arterial atherosclerotic lesions (Nordestgaard et al., 2013).
Dyslipidemia and insulin resistance (HOMA-IR) are cardiovascular risk factors prevalent in patients with psychosis. Whether these factors are intrinsic or affected by lifestyle or antipsychotic medication (AP) is unclear. Therefore, we investigated lipid profiles, HOMA-IR, and psychotic phenotypes in patients aged 12–18 years with early-onset psychosis (EOP) with and without AP exposure.
We measured fasting total cholesterol (TC), high-density lipoprotein cholesterol (HDLC), triglycerides (TG), insulin, and glucose in patients with EOP (n = 39) and healthy controls (HC) (n = 66). Diet information was not available. Negative symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). We used univariate analysis of variance to compare TC/HDL-C ratios and TG and HOMA-IR values, controlling for body mass index (BMI) and AP exposure. We assessed the explained variance of having EOP using multiple regression analysis.
Patients with and without AP exposure had significantly higher TC/HDL-C (p = 0.003, p = 0.029) and TG values (p < 0.001, p = 0.021) than HC. Significantly increased HOMA-IR scores were found only in AP-exposed patients (p = 0.037). EOP significantly increased the explained variance for TC/HDL-C and TG, but not for HOMA-IR. Patients with a PANSS negative score > 21 had significantly higher levels of TG than those with low scores (p = 0.032).
Our results suggest that lipid alterations predate AP treatment in adolescents with EOP. Higher levels of negative symptoms and AP further increase metabolic risk. The preliminary findings propose that subclinical dyslipidemia may be intrinsic to EOP.
CLSI-based transference of CALIPER pediatric reference intervals to Beckman Coulter AU biochemical assays
2015, Clinical Biochemistry
Citation Excerpt :
In an effort to address this important evidence gap, the CALIPER (Canadian Laboratory Initiative on Pediatric Reference Intervals) project was established as a collaborative initiative between several pediatric centers across Canada [10,11]. In 2006, the CALIPER project released the first pilot data describing pediatric reference intervals for several basic chemistry analytes [12]. Since then, CALIPER has produced a comprehensive database of pediatric reference intervals for many specialty immunoassay and chemistry analytes [1,11,13–21], and has effectively filled many of the previous gaps in pediatric reference intervals [10,11].
The CALIPER program has established a comprehensive database of pediatric reference intervals using largely the Abbott ARCHITECT biochemical assays. To expand clinical application of CALIPER reference standards, the present study is aimed at transferring CALIPER reference intervals from the Abbott ARCHITECT to Beckman Coulter AU assays.
Transference of CALIPER reference intervals was performed based on the CLSI guidelines C28-A3 and EP9-A2. The new reference intervals were directly verified using up to 100 reference samples from the healthy CALIPER cohort.
We found a strong correlation between Abbott ARCHITECT and Beckman Coulter AU biochemical assays, allowing the transference of the vast majority (94%; 30 out of 32 assays) of CALIPER reference intervals previously established using Abbott assays. Transferred reference intervals were, in general, similar to previously published CALIPER reference intervals, with some exceptions. Most of the transferred reference intervals were sex-specific and were verified using healthy reference samples from the CALIPER biobank based on CLSI criteria. It is important to note that the comparisons performed between the Abbott and Beckman Coulter assays make no assumptions as to assay accuracy or which system is more correct/accurate.
The majority of CALIPER reference intervals were transferrable to Beckman Coulter AU assays, allowing the establishment of a new database of pediatric reference intervals. This further expands the utility of the CALIPER database to clinical laboratories using the AU assays; however, each laboratory should validate these intervals for their analytical platform and local population as recommended by the CLSI.
Insulin resistance and endothelial function in children and adolescents
2014, International Journal of Cardiology
Citation Excerpt :
Blood glucose, insulin, total cholesterol (TC), high (HDL) and low (LDL) density lipoprotein cholesterol, triglycerides (TG) and C-reactive protein (CRP) were measured after overnight fasting in all subjects. Values of TC, LDL, HDL and TG were considered in the normal range if within the 5th and the 95th percentile [17]. An oral glucose (1.75 g/kg) tolerance test (OGTT) was performed in obese subjects recording basal levels of blood glucose and insulin and after 120 min.
Insulin resistance (IR) impairs cellular response to insulin due to a dysfunction in glucose metabolism, associated with an increased cardiovascular risk. The aim of our study was to investigate the relationship among homeostasis model assessment index (HOMA index), endothelial function and vascular morphology in order to better stratify cardiovascular risk in children and adolescents.
A total of 150 children and adolescents (55 pre-pubertal, mean age 10.4 ± 3.1 years) were enrolled. Anthropometric [body mass index (BMI), waist circumference (WC)], laboratory [blood lipids, inflammatory markers, insulinemia, glycemia], HOMA index and ultrasound parameters [flow-mediated dilatation (FMD), common carotid intima–media thickness (cIMT) and antero-posterior diameter of infra-renal abdominal aorta (APAO)] were assessed.
cIMT was positively related to age (r = 0.274, p < 0.01), BMI (r = 0.318, p < 0.01), WC (r = 0.315, p < 0.01) and triglycerides (r = 0.230, p < 0.01). APAO measurements showed a linear positive correlation with age (r = 0.435, p < 0.01), BMI (r = 0.505, p < 0.01), WC (r = 0.487, p < 0.01), triglycerides (r = 0.280, p < 0.01), C-reactive protein (r = 0.209, p < 0.05), fasting insulin (r = 0.378, p < 0.01) and HOMA index (r = 0.345, p < 0.01). FMD was inversely related to age (r = − 0.251, p < 0.01), rough BMI (r = − 0.318, p < 0.01), WC (r = − 0.340, p < 0.01), fasting insulin (r = − 0.281, p < 0.01) and HOMA index (r = − 0.282, p < 0.01). Multiple regression analysis found no influence of HOMA index on APAO and cIMT. HOMA index was an independent predictor for brachial artery FMD worsening after the statistical adjustment.
HOMA index increase induced a worsening in endothelial function since childhood.
Development of paediatric biochemistry centile charts as a complement to laboratory reference intervals
2014, Pathology
Age-specific paediatric reference intervals are used in interpretation of laboratory results. However, interpretation may be problematic when a child just crosses an age bracket and the difference between the original and the subsequent age-specific reference interval is large. Moreover, details about the physiological changes with age may be masked. For the 12 months ending 30 September 2013, results of 16 common clinical biochemistry tests of ambulatory paediatric patients aged 0-19, requested by primary care physicians, were retrospectively collected in a large pathology service, and used to construct smoothed centile charts using a penalised maximum likelihood method. From the developed centile charts, the concentrations of sodium, bicarbonate, creatinine, urate, total protein, and albumin all increased with increasing age of the children. In contrast, the concentrations of potassium, chloride, anion gap, calcium, phosphate and lactate dehydrogenase decreased with increasing age of the children. Changes in the concentrations of urea, alkaline phosphatase, glucose, and total cholesterol varied by age. Generally, the boys and girls shared similar trend patterns until 10-15 years of age, when variations in the age of onset of puberty and development caused the trends of some biochemical measures to differ. The paediatric biochemistry centile charts are intuitive tools to use. They complement age-specific reference intervals in the tracking, interpretation and discussion of laboratory results. They also enhance the understanding of underlying physiological changes in biochemistry in children.
Repeat antenatal steroid exposure and later blood pressure, arterial stiffness, and metabolic profile
2013, Journal of Pediatrics
Citation Excerpt :
From these analyses, we calculated HDL/LDL-ratio and Apo B/Apo A1-ratio. Cut-offs for deviating laboratory values were defined as cholesterol >4.89/5.88 mmol/L (men/women, respectively), triglycerides >2.07/2.35 mmol/L, HDL <0.6/0.74 mmol/L, LDL >3.02/3.62 mmol/L, Apo A1 <0.85/0.96 g/L, and Apo B >1.02/1.17 g/L.27 Homeostatic model assessment (HOMA) is a method for assessing insulin resistance (IR) from basal fasting glucose and insulin.28 HOMA-IR was calculated using a HOMA calculator (http://www.dtu.ox.ac.uk/homacalculator/index.php).
To determine the relationship between repeat courses of antenatal corticosteroids (ACS) and risk factors for cardiovascular disease in adolescents and young adults.
We assessed body mass index, blood pressure, arterial stiffness, blood lipids, and insulin resistance (IR) in a Swedish population-based cohort (n = 100) at a median age of 18 (range 14-26) years. Fifty-eight subjects (36 males) had been exposed to 2-9 weekly courses of antenatal betamethasone and 42 (23 males) were unexposed subjects matched for age, sex, and gestational age (GA).
There were no significant differences between the groups regarding body mass index, systolic or diastolic blood pressures, arterial stiffness measured by augmentation index, blood lipids, IR, or morning cortisol levels either in simple regression or in multivariable models. However, more subjects with elevated augmentation index had been exposed to repeat courses of ACS (n = 7) compared with unexposed subjects (n =1, P = .06), and glucose, insulin, and IR correlated inversely to GA at start of ACS (P < .01).
Repeat courses of ACS did not correlate to adverse cardiovascular risk profile in adolescence and young adulthood, but long-standing effects on the arterial tree and glucose metabolism, the latter dependent on GA at ACS exposure, cannot be excluded. These observations have clinical implications for the ongoing discussion on short-term benefits and long-term safety of repeat ACS treatment.

View all citing articles on Scopus

¹: Current address: Toronto Medical Laboratories, University Health Network, 200 Elizabeth Street, 3ES-412, Toronto, ON, Canada M5G 2C4. Fax: +1 416 586 1426.

View full text

Pediatric reference intervals for lipids and apolipoproteins on the VITROS 5,1 FS Chemistry System

Abstract

Objectives:

Design and methods:

Results:

Conclusions:

Introduction

Section snippets

Subject selection and sample collection

Results and discussion

Acknowledgments

Lancet

J. Pediatr.

Lancet

J. Pediatr.

Mayo Clin. Proc.

Clin. Chim. Acta

Clin. Biochem.

Clin. Biochem.

Clin. Chim. Acta

Clin. Chim. Acta

Am. J. Cardiol.

J. Lipid Res.

Executive summary of the third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III)

JAMA

Recommendations for the management of dyslipidemia and the prevention of cardiovascular disease: summary of the 2003 update

CMAJ

Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines

Circulation

National cholesterol education program: report of the expert panel on blood cholesterol levels in children and adolescents

Pediatrics

Overweight children and adolescents: description, epidemiology, and demographics

Pediatrics

Overweight in children and adolescents: pathophysiology, consequences, prevention, and treatment

Circulation

Abdominal obesity and cardiovascular risk in children

Coron. Artery Dis.