Undernutrition in childhood: Clinically based assessment tools and biological markers: Where are we and where should we go?

Despite its association with poor clinical outcomes and increased hospital costs, as of today undernutrition still goes undetected in paediatric hospitals. The reported prevalence of undernutrition in paediatric patients varies considerably. This disparity is partly due to the diversity of methods for its detection and assessment, as well as to the lack of consensus regarding its definition. Several methods, based on varied combinations of morphology characteristics, estimated nutritional intakes and medical conditions have been developed during the last 25 years. However, these tools suffer from poor sensitivity and selectivity particularly in acute conditions. Also while having their own merit, these tools mainly view malnutrition from the energy standpoint, disregarding assessment of specific micronutrients such as minerals and vitamins. In this position paper we make the point that in the era of personalized medicine, present technology offers the possibility of going beyond the traditional nutritional tools for assessing patients' status, and propose the measurement of selected micronutrients and allied metabolic markers in nutritional workup schemes adapted to each clinical condition.

Is there a relationship between vitamin D nutritional status and metabolic syndrome in childhood acute lymphoblastic leukemia survivors? A PETALE study.

BACKGROUND: Treatment of childhood acute lymphoblastic leukemia (cALL) has reached unprecedented success leading to survival rates reaching 90%. This is regrettably linked to increased risk of developing long-term health-related sequels into early adulthood. OBJECTIVE: This study aims at assessing the relationship between the vitamin D status and metabolic biomarkers in PETALE, a well-characterized cohort of cALL survivors. RESULTS: We demonstrate that 15.9% of the study participants exhibited 3 or more metabolic syndrome (MetS) risk factors. We also show a direct relationship between s25OHD3 and plasma HDL-Cholesterol concentrations in female but not male participants. CONCLUSION: Our data, from a metabolically well-described cohort, support a modest role for vitamin D in lipid metabolism in childhood leukemia survivors. The major outcome of this study is the strong association between HDL-Cholesterol concentration and s25OHD3 only in female subjects, thereby conveying vitamin D a gender-specific cardio-protective effect. cALL survivors represent a population at higher risk for secondary diseases. For this reason thorough nutritional evaluation, including vitamin D should be part of the regular follow-up.

Vitamin D nutritional status and bone turnover markers in childhood acute lymphoblastic leukemia survivors: A PETALE study.

BACKGROUND: The remarkable progress in the treatment of childhood acute lymphoblastic leukemia (cALL) has led to a survival rate reaching 90%. This success story is unfortunately linked to increased risk of impaired skeletal mass accumulation during childhood and adolescence, predisposing the patients to osteoporosis and pathological fractures at adulthood. OBJECTIVE: This study aims at characterizing the vitamin D status and bone health biomarkers in a well-characterized cohort of cALL survivors. RESULTS: Food frequency questionnaires reveal that (i) the total vitamin D intake varies greatly (44-2132 IU/d), (ii) only 16.8% of the participants consume vitamin D supplements, and (iii) 74% of survivors' intakes are below the Recommended Daily Intakes (400 IU/d). For the 42 participants taking vitamin D supplements, the median (2.5-97.5%iles) intake is 600 IU/d (21.2-1972 IU/d). Sixteen participants are vitamin D deficient (<30 nM) and 66 insufficient (≥30 - <50 nM). Serum 24,25(OH)2D3 concentrations are directly related to those of 25OHD3, and those of 3-epi-25OHD3 below the Lower Limit of Quantification in most samples. The participants' serum concentrations of cross-linked C-telopeptide of type-I collagen and intact amino-terminal pro-peptide of type-I collagen decrease steadily with age, leveling at adulthood, and are at all times higher in males. CONCLUSION: The present study shows that the prevalence of vitamin D insufficiency or deficiency is not greater in cALL survivors compared to the general Canadian population despite low vitamin D food and supplement intakes. Furthermore, there seem to be no overt imbalance in the gender- and age-adjusted serum bone turnover marker concentrations.

Data for the measurement of serum vitamin D metabolites in childhood acute lymphoblastic leukemia survivors.

This article describes data related to a companion research paper entitled "Vitamin D nutritional status and bone turnover biomarkers in childhood acute lymphoblastic leukemia (cALL) survivors." (Delvin et al., submitted for publication) [1]. Various methods for the measurement of serum 25OHD3, the accepted biomarker for assessing vitamin D nutritional status, have been described (Le Goff et al., 2015; Jensen et al., 2016) [2], [3]. This article describes a novel mass spectrometry-QTOF method for the quantification of circulating 25OHD3, 3-epi-25OHD3 and 24,25(OH)2D3. It provides the description of the extraction, chromatography and mass spectrometry protocols, a sample of mass spectra obtained from standards and extracted serum, and a comparison with another HPLC-MS/MS (Jensen et al., 2016) [3] method for the measurement of serum concentrations of 25OHD3.

Pediatric Obesity and Cardiometabolic Disorders: Risk Factors and Biomarkers.

Obesity remains the most prevailing disorder in childhood males and females worldwide. Its high prevalence markedly predisposes children to insulin resistance, hypertension, hyperlipidemia and liver disorders while enhancing the risk of type 2 diabetes and cardiovascular diseases. In this review, the relationship of obesity with genetic and environmental factors will be described and the underlined causes will briefly be reported. As obesity in children constitutes an increasingly health concern, important potential biomarkers have been discussed for the diagnosis, treatment and follow-up of the wide range of overweight-related complications. Awareness about the applicability and limitations of these preventive and predictive biomarkers will intensify the research and medical efforts for new developments in order to efficiently struggle against childhood obesity.

Erratum: (1) Pediatric Obesity and Cardiometabolic Disorders: Risk Factors and Biomarkers.

[This corrects the article on p. 6 in vol. 28, PMID: 28439216.].

Data in support for the measurement of serum 25-hydroxyvitamin D (25OHD) by tandem mass spectrometry.

This article provides data and a method related to a research paper entitled "Assessing vitamin D nutritional status: is capillary blood adequate?" (Jensen et al., 2016) [1]. Circulating 25OHD, the accepted biomarker of the vitamin D nutritional status, is routinely measured by automated immunoassays, that although may be performed in hospital central laboratories, often suffer from a lack of specificity with regards to the different vitamin D metabolites, "Measurement of circulating 25-hydroxyvitamin D: a historical review" (Le Goff et al., 2015) [2]. Mass spectrometry offers this specificity. This article describes the performance of an in-house tandem mass spectrometry method for the individual measurement of 25OHD3, 25OHD2 and 3-épi-25OHD3.

Assessing vitamin D nutritional status: Is capillary blood adequate?

BACKGROUND: Venous blood is the usual sample for measuring various biomarkers, including 25-hydroxyvitamin D (25OHD). However, it can prove challenging in infants and young children. Hence the finger-prick capillary collection is an alternative, being a relatively simple procedure perceived to be less invasive. We elected to validate the use of capillary blood sampling for 25OHD quantification by liquid chromatography tandem-mass spectrometry (LC/MS-MS). METHODS: Venous and capillary blood samples were simultaneously collected from 15 preschool-aged children with asthma 10days after receiving 100,000IU of vitamin-D3 or placebo and 20 apparently healthy adult volunteers. 25OHD was measured by an in-house LC/MS-MS method. RESULTS: The venous 25OHD values varied between 23 and 255nmol/l. The venous and capillary blood total 25OHD concentrations highly correlated (r(2)=0.9963). The mean difference (bias) of capillary blood 25OHD compared to venous blood was 2.0 (95% CI: -7.5, 11.5) nmol/l. CONCLUSION: Our study demonstrates excellent agreement with no evidence of a clinically important bias between venous and capillary serum 25OHD concentrations measured by LC/MS-MS over a wide range of values. Under those conditions, capillary blood is therefore adequate for the measurement of 25OHD.

Measurement of circulating 25-hydroxyvitamin D: A historical review.

The constantly increasing requests for the measurement of serum 25-hydroxyvitamin D over the last years has led reagent manufacturers to market different automated and semi-automated methods, that being unfortunately not fully harmonized, yield different results. Liquid chromatography coupled to tandem mass spectrometry (LC/MS2) has more recently been introduced. This approach allows the distinction between the two forms of 25-hydroxyvitamin D and to measure other metabolites. This approach also requires harmonization to curtail the differences between the different analytical methods. To meet this requirement, the American National Institutes of Health (NIH), the Centre for Disease Control and Prevention (CDC) in Atlanta, the National Institute of Standards and Technology (NIST) and the vitamin D Reference laboratory of Ghent University have pooled their expertise to develop a standardization program. This article reviews the main elements and the difficulties of the automated and semi-automated methods for 25-hydroxyvitamin D, from sample preparation to the analytical phase, as well as those related to mass spectrometry. It also emphasizes the need for standardization to better define the clinical decision thresholds of vitamin D nutritional status.

Plotting transcutaneous bilirubin measurements on specific transcutaneous nomogram results in better prediction of significant hyperbilirubinemia in healthy term and near-term newborns: a pilot study.

BACKGROUND: The American Academy of Pediatrics has recommended a systematic assessment before discharge for the risk of severe hyperbilirubinemia. Plotting total serum bilirubin (TSB) or transcutaneous bilirubin (TcB) on a TSB hour-specific nomogram is proposed as a tool for laboratory evaluation. OBJECTIVES: The aim of this study was to compare the predictive characteristics, particularly the incidence of false negative rate (FNR), of the practice of plotting TcB values on the TSB hour-specific risk nomogram versus on transcutaneous nomogram. METHODS: Paired TSB and TcB measurements were conducted on 141 newborns. Risk of developing significant hyperbilirubinemia was defined as infants with bilirubin level ≥ 75% on TSB or ≥ 95% on TcB nomogram. TSB values, plotted on the TSB nomogram of Bhutani et al. [Pediatrics 1999;103:6-14], were used as reference. TcB values were plotted on the TSB nomogram and on the transcutaneous nomograms of Maisels and Kring [Pediatrics 2006;117:1169-1173] and Fouzas et al. [Pediatrics 2010;125:e52-e57]. RESULTS: Plotting TcB measurements on a TSB nomogram resulted in a trend towards a higher FNR when compared to Maisels' and Fouzas' nomograms (18.0/1,000 compared to 10.2/1,000 and 8.6/1,000 respectively). Although not statistically significant, plotting TcB on transcutaneous nomogram resulted in better predictive values with the Fouzas' nomogram, having the best sensitivity (90.0%) and specificity (87.79%) as well as the highest positive (35.97%) and negative (99.14%) predictive value. CONCLUSION: Plotting TcB on a TSB nomogram may result in increased rate of FNR and decreased predictive characteristics. The practice of plotting TcB on a TSB nomogram needs further evaluation.

Higher vitamin D intake is needed to achieve serum 25(OH)D levels greater than 50 nmol/l in Québec youth at high risk of obesity.

BACKGROUND/OBJECTIVES: Vitamin D levels are often observed to be low in Canadian youth, despite the mandatory fortification of fluid milk. We identified modifiable correlates of plasma vitamin D concentrations to inform public health efforts to remediate low-vitamin D status. SUBJECTS/METHODS: We recruited 159 children aged 8-11 years, who were at at high risk of obesity, non-systematically during different seasons. Vitamin D status was assessed by measuring plasma 25-hydroxyvitamin D (25(OH)D) using a radioimmunoassay. Dietary intake, including vitamin supplements, was measured using three dietitian-administered 24 h diet recalls. Fat mass was measured by dual energy X-ray absorptiometry. Accelerometers were worn for 7 days to estimate physical activity. Independent correlates of plasma 25(OH)D concentrations were identified using multiple regression in an analysis controlling for season of measurement. RESULTS: Approximately, 7% of youth had hypovitaminosis D (25(OH)D ≤37.5 nmol/l) during winter and spring when vitamin D levels are at their nadir. Only 55% of participants had vitamin D levels, which the Institute of Medicine considers optimal (25(OH)D >50 nmol/l). The mean dietary vitamin D intake, 6.6 mcg, was well below current recommendations set at 15 mcg. A serving increase in milk consumption and a s.d. increase in physical activity were associated with only a 2.9 and 2.1 nmol/l increase in plasma 25(OH)D, respectively. There was no association between 25(OH)D and adiposity. CONCLUSIONS: Our results indicate the challenges of obtaining adequate vitamin D intake from the current food supply to support a level of 25(OD)D >50 nmol/l.

Point of care testing: transcutaneous bilirubinometry in neonates.

Physicians taking care of infants in the first days of life are often faced with neonatal jaundice, especially in an era where post-partum discharge occurs earlier and assessment of newborn bilirubinemia status is required prior to discharge. The Canadian Pediatric Society and the American Academy of Pediatrics have developed and published guidelines for the diagnosis and management of hyperbilirubinemia in newborns. Point of care testing refers to any test performed outside of laboratory by clinical personnel and close to the site of patient care. Based on a summary of multiple reports during the last twenty years, we realize that devices which provide a non-invasive transcutaneous bilirubin (TcB) measurement have proven to be very useful as screening tools and provide a valid estimate of the total serum bilirubin level (TSB). Published data suggest that these devices provide measurements within 30-50 micromol/L of the TSB levels and can replace laboratory measurement particularly when TSB levels are less than 260 micromol/L. At the present time, in the literature, evidence is insufficient to abandon neonatal serum bilirubin testing and replace it with TcB. Any measurement, TSB or TcB, has potential for error. However, we have evidence that TcB, can help avoiding potential errors associated with even visual assessment of jaundice and may be useful as screening device to detect significant jaundice and decrease a large number of unnecessary skin punctures. The current manuscript is based on a careful comprehensive literature review concerning neonatal hyperbilirubinemia. We consider that this manuscript will help clinicians and laboratory professionals in the management of neonatal jaundice.

Modulation of intestinal cholesterol absorption by high glucose levels: impact on cholesterol transporters, regulatory enzymes, and transcription factors.

Growing evidence suggests that the small intestine may contribute to excessive postprandial lipemia, which is highly prevalent in insulin-resistant/Type 2 diabetic individuals and substantially increases the risk of cardiovascular disease. The aim of the present study was to determine the role of high glucose levels on intestinal cholesterol absorption, cholesterol transporter expression, enzymes controlling cholesterol homeostasis, and the status of transcription factors. To this end, we employed highly differentiated and polarized cells (20 days of culture), plated on permeable polycarbonate filters. In the presence of [(14)C]cholesterol, glucose at 25 mM stimulated cholesterol uptake compared with Caco-2/15 cells supplemented with 5 mM glucose (P < 0.04). Because combination of 5 mM glucose with 20 mM of the structurally related mannitol or sorbitol did not change cholesterol uptake, we conclude that extracellular glucose concentration is uniquely involved in the regulation of intestinal cholesterol transport. The high concentration of glucose enhanced the protein expression of the critical cholesterol transporter NPC1L1 and that of CD36 (P < 0.02) and concomitantly decreased SR-BI protein mass (P < 0.02). No significant changes were observed in the protein expression of ABCA1 and ABCG8, which act as efflux pumps favoring cholesterol export out of absorptive cells. At the same time, 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity was decreased (P < 0.007), whereas ACAT activity remained unchanged. Finally, increases were noted in the transcription factors LXR-alpha, LXR-beta, PPAR-beta, and PPAR-gamma along with a drop in the protein expression of SREBP-2. Collectively, our data indicate that glucose at high concentrations may regulate intestinal cholesterol transport and metabolism in Caco-2/15 cells, thus suggesting a potential influence on the cholesterol absorption process in Type 2 diabetes.

[Is it justifiable to administrate vitamin A, E and D for 6 months in the premature infants?]. / Est-il légitime d'administrer des vitamines liposolubles (A, E et D) chez le prématuré pendant 6 mois?

UNLABELLED: Information on the vitamin A and E nutritional status in preterm infants is scarce. POPULATION AND METHODS: In the present prospective and longitudinal study, we measured the plasma concentrations of vitamins A, E, D and of retinol binding protein (RBP) in preterm infants (32-34 weeks of gestation) at birth, and verified whether oral supplementation with these 3 vitamins for 1, 3 and 6 months affected their plasma concentrations. The 17 consecutively recruited premature infants received daily 3000 IU of vitamin A, 5 mg of vitamin E and 1000 IU of vitamin D. RESULTS: At birth, premature infants exhibited a low plasma concentrations of vitamin A (0.66 [0.41-0.96]) micromol/l, vitamin E (8.1 [4.2-16.9] micromol/l), RBP (0.45 [0.22-0.71] micromol/l) and 25 hydroxyvitamine D (25 OHD) (20 [20-40] nmol/l). Plasma vitamin A, E , D and RBP concentrations increased with time, but vitamin A at 1, 3 and 6 months did not attain values considered normal in term infants or adolescents. At 6 months, the plasma 25 OHD was at 92 (71-116) nmol/l, a concentration considered normal and non-toxic. CONCLUSION: We recommend to increase oral administration of vitamin A to 5000 IU/day, at least for the first month of life and, thereafter to administer 3000 IU for 5 months. As for vitamin E and vitamin D, the doses used in this study are sufficient but should be administered for 6 months.

Asymmetrical regulation of scavenger receptor class B type I by apical and basolateral stimuli using Caco-2 cells.

Cholesterol uptake and the mechanisms that regulate cholesterol translocation from the intestinal lumen into enterocytes remain for the most part unclear. Since scavenger receptor class B type I (SR-BI) has been suggested to play a role in cholesterol absorption, we investigated cellular SR-BI modulation by various potential effectors administered in both apical and basolateral sides of Caco-2 cells. With differentiation, Caco-2 cells increased SR-BI protein expression. Western blot analysis showed the ability of cholesterol and oxysterols in both cell compartments to reduce SR-BI protein expression. Among the n-3, n-6, and n-9 fatty acid families, only eicosapentaenoic acid was able to lower SR-BI protein expression on both sides, whereas apical alpha-linolenic acid decreased SR-BI abundance and basolateral arachidonic acid (AA) raised it. Epidermal growth factor and growth hormone, either in the apical or basolateral medium, diminished SR-BI cellular content, while insulin displayed the same effect only on the basolateral side. In the presence of proinflammatory agents (LPS, TNF-alpha, IFN-gamma), Caco-2 cells exhibited differential behavior. SR-BI was downregulated by lipopolysaccharide on both sides. Finally, WY-14643 fibrate diminished SR-BI protein expression when it was added to the apical medium. Biotinylation studies in response to selected stimuli revealed that regulatory modifications in SR-BI protein expression occurred for the most part at the apical cell surface irrespective of the effector location. Our data indicate that various effectors supplied to the apical and basolateral compartments may impact on SR-BI at the apical membrane, thus suggesting potential regulation of intestinal cholesterol absorption and distribution in various intracellular pools.

[Evaluation of transcutaneous bilirubin measurement and agreement with bilirubinemia]. / Evaluation de la mesure transcutanée de la bilirubine et concordance avec la mesure sur sang total et plasma.

Evaluation of the neonates for jaundice and kernicterus is indispensable when early hospital discharge has become standard practice. Transcutaneous bilirubin (TcB) measurement is an advantageous option because of its non-invasive nature and the possibility of its use near the patient. The point of care device BiliCheck has been compared in numerous instances to serum bilirubin. However, its clinical utility remains a subject of discussion. We have compared total blood bilirubin (TBB) concentrations to TcB values using the BiliCheck in newborns at 48 +/- 12 hours of life, at the time of discharge when they have lost weight. One hundred and ninety-six term neonates were initially included into the study. Transcutaneous bilirubin could be compared to whole blood bilirubin for 178 of them. Methods were compared by linear regression analysis and by the non-parametric Bland and Altman method. The correlation between BiliCheck and whole blood bilirubin was adequate (r(2): 0.7768). However, the Bland-Altman analysis revealed a 95% CI of -50.4 to 47.5 micromol/L. Transcutaneous bilirubin was also compared to a measure on plasma in a sub-group of 53 infants, the correlation was 0.7749 with a 95% CI of -35.8 to 46.5 micromol/L. Comparing total blood bilirubin with plasma bilirubin in 35 patients, we observed a similar results with a correlation of 0.7583 and a 95% CI of -34.6 to 40.7 micromol/L. Finally, the extent of weight loss observed in our group of patients had little influence and did not affect the agreement between the 2 approaches. We conclude that the BiliCheck may be used to monitor bilirubin in term neonates at 48 hours of life even with a weight loss. Clinicians have however to be conscious of the limit of the precision of the measures both for the BiliCheck and the laboratory methods.

Natremia of healthy term newborns at 48 h of life: influence of feeding patterns.

OBJECTIVES: To describe natremia in healthy term newborns and determine whether there is a relationship between blood sodium and feeding patterns. METHODS: All normal newborns, admitted to the nursery between January and March 2004 were eligible for this prospective cohort study. Inclusion criteria were: > or =37 weeks of gestational age, birth weight > or =2500 g, Apgar scores > or =7 at 5 and 10 min and normal physical examination. A capillary blood sample was taken at 48+/-12 h of life. RESULTS: Blood samples from 126 newborns were analyzed. Mean gestational age was 39.6 weeks, birth weight was 3414 g and weight loss at 48 h of life was 6.5% of birth weight. Mean capillary blood sodium was 141 mmol/L (SD 3.4). Exclusively, breast-fed newborns had statistically higher mean blood sodium (141 mmol/L, SD 3.0) than the non-exclusively breast-fed+formula fed group (139 mmol /L, SD 3.7). There was a significant linear association between blood sodium and the quantity of milk supplements received as well as between blood sodium and weight loss. CONCLUSIONS: Most newborns have blood sodium values within a narrower range than previously described in the literature. We also demonstrate that the exclusively breast-fed infants appear to have marginally but statistically higher values of blood sodium than non-exclusively breast-fed and formula-fed infants.

Overproduction of intestinal lipoprotein containing apolipoprotein B-48 in Psammomys obesus: impact of dietary n-3 fatty acids.

AIMS/HYPOTHESIS: Emerging evidence underscores the important role of the small intestine in the pathogenesis of dyslipidaemia in insulin resistance and type 2 diabetes. We therefore tested the hypothesis that n-3 fatty acids improve the various events governing intra-enterocyte lipid transport in Psammomys obesus gerbils, a model of nutritionally induced metabolic syndrome. MATERIALS AND METHODS: Experiments were carried out on Psammomys obesus gerbils that were assigned to an isocaloric control diet and a diet rich in fish oil for 6 weeks. RESULTS: Increased dietary intake of fish oil lowered body weight and improved hyperglycaemia and hyperinsulinaemia. It simultaneously decreased de novo intestinal lipogenesis and lipid esterification of the major lipid classes, e.g. triglycerides, phospholipids and cholesteryl esters, particularly in insulin-resistant and diabetic animals. Accordingly, lessened activity of monoacylglycerol and diacylglycerol acyltransferase was recorded. As assessed in cultured jejunal explants incubated with either [(14)C]-oleic acid or [(35)S]-methionine, fish oil feeding resulted in diminished triglyceride-rich lipoprotein assembly and apolipoprotein (apo) B-48 biogenesis, respectively. The mechanisms did not involve apo B-48 transcription or alter the gene expression and activity of the critical microsomal triglyceride transfer protein. Rather, the suppressed production of apo B-48 by n-3 fatty acids was associated with intracellular proteasome-mediated posttranslational downregulation in insulin-resistant and diabetic animals. CONCLUSIONS/INTERPRETATION: Our data highlight the beneficial impact of n-3 fatty acids on adverse effects of the metabolic syndrome and emphasise their influence on intestinal lipid transport, an effect which may limit postprandial lipaemia and the risk of atherosclerosis.