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ORIGINAL RESEARCH COMMUNICATION |
1 From the Divisions of Gastroenterology and Nutrition (JT, JIS, BSZ, and VAS), Biostatistics and Data Management Core (RFI), and Child Development and Rehabilitation Medicine (MY and YD), The Childrens Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, and the Department of Bioscience and Biotechnology, Drexel University, Philadelphia, PA (IEO)
2 Supported by the NIH (HL 57448 and HL 744326), the General Clinical Research Center (RR00240), and the Nutrition Center at Childrens Hospital of Philadelphia. JT was supported in part by the Maternal and Child Health Bureau (T73MC00051) and the NIH (T32-HL07443-26). 3 Address reprint requests to J Trabulsi, Divisions of Gastroenterology and Nutrition, The Childrens Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104. E-mail: trabulsi{at}email.chop.edu.
| ABSTRACT |
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Objective: Our objective was to characterize energy balance and the reporting accuracy of dietary intake in children with CF by evaluating the relations between energy intake (EI), energy expenditure (EE), fecal energy loss, nutritional status, and growth.
Design: The subjects were participants of a 24-mo prospective study of children 610 y of age with CF and PI. EE, EI, fecal energy loss, and anthropometric measures were obtained at baseline and at 24 mo.
Results: The children (n = 69) had suboptimal growth at baseline (
± SD: weight-for-age z score, 0.53 ± 1.19; adjusted height-for-age z score, 0.67 ± 1.06; body mass index z score, 0.29 ± 1.12), and these variables remained suboptimal at 24 mo. The median ratios of EI to EE at baseline and 24 mo were 1.15 and 1.18, respectively, which decreased to 1.09 and 1.10, respectively, when adjusted for fecal energy loss (EIFL:EE). At baseline, 7% of subjects were underreporters, 64% were accurate reporters, and 23% were overreporters of energy intake; the percentages were similar at 24 mo.
Conclusions: Although EIFL:EE ratios were higher than expected at both baseline and 24 mo, this cohort showed only age-appropriate weight gain. Self-reported dietary intake data at the individual level should be interpreted with caution, and weight gain velocity may serve as an objective measure of long-term energy balance.
Key Words: Cystic fibrosis children energy intake energy expenditure doubly labeled water fecal fat
| INTRODUCTION |
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Despite interventions such as the use of enzyme therapy, enteral supplements, and nutritional counseling to maximize nutritional status, undernutrition and suboptimal growth remain common findings in children with CF (9-11). Data from the CF Registry show that
16% of persons with CF <20 y of age fall below the 5th percentile for weight, and 15% fall below the 5th percentile for height (1) compared with US growth standards (12). The poor weight and growth status observed in children with CF suggests a chronic negative balance between energy intake (EI) and energy expenditure (EE). Children require a positive balance to meet energy requirements to sustain a pattern of normal growth, development, and physical activity.
To plan effective malnutrition prevention and treatment interventions for children with CF, an understanding of energy balance is required. Energy balance includes EI, EE, energy loss in stool due to maldigestion and malabsorption, and energy storage or tissue accretion in children. Some investigators found that total EE was higher in infants (13, 14) and preadolescent children (15, 16) with CF than in healthy control subjects, whereas others did not (17-20). Preadolescent children with CF were found to have a greater EI (measured as kcal/d and as kcal/kg body wt) than age-matched control subjects (21-24). With respect to energy losses in stool,
85% of persons with CF have exocrine pancreatic insufficiency (PI) (25), which, despite exogenous pancreatic enzyme replacement therapy, generally leads to variable rates of persistent malabsorption and energy loss in stool (21, 26-29).
To our knowledge, no studies have measured all aspects of the energy balance equation (EE, EI, fecal energy loss, and energy storage), both simultaneously and longitudinally, in children with CF. Furthermore, a thorough assessment of energy balance must take into account the accuracy of reported dietary intake, and few studies to date have explored the effect of a chronic disease on the reporting accuracy of dietary intake in children, especially one in which nutritional status and growth are negatively affected. We therefore sought to characterize energy balance and reporting accuracy in children with CF and PI by evaluating the relations between EI, EE, fecal energy loss, nutritional status, and growth, with the belief that improved knowledge of energy balance and reporting accuracy will lead to more effective strategies to prevent and treat malnutrition.
| SUBJECTS AND METHODS |
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Mothers education and household income measures
Information regarding the mothers education and household income was obtained by questionnaire at baseline. For the purpose of this study, the mothers education was classified as those who had completed some college or technical training or less or those who had obtained an undergraduate college diploma or more. Total household income was reported in $5000 increments from <$10 000 to >$75 000 (15 categories). For the purpose of this study, households were classified as those with an annual income <$75 000 or
$75 000.
Anthropometric measures
Weight and height were measured at all study visits (baseline and 6, 12, 18, and 24 mo) with the use of standard techniques (30) and a scale accurate to 0.1 kg (Scaletronix, White Plain, NY) and a stadiometer accurate to 0.1 cm (Holtain, Crymych, United Kingdom), and body mass index (BMI; in kg/m2) was calculated. Parental height, determined by measurement or recall, was collected for both biologic parents and was used to obtain a midparent height (31). The midparent height and the subjects height were then used to calculate adjusted height. Weight, adjusted height, and BMI values were compared with National Center for Health Statistics reference standards and z scores for weight-for-age (WAZ), adjusted height-for-age (AHAZ), and body mass index (BMIZ) were computed (12). Upper arm circumference was measured with a flexible plastic measuring tape (Ross Laboratories, Columbus, OH), and a skinfold caliper (Holtain, Crymych, United Kingdom) was used to measure tricep, bicep, subscapular, and suprailiac skinfold thicknesses on the right side. Total upper arm muscle and fat areas were calculated (32), and z scores for upper arm muscle area (UAMAZ) and upper arm fat area (UAFAZ) were computed (33).
Dietary measures
A 7-d weighed food record was completed at the baseline and 24-mo visits. Detailed verbal and written instructions for measuring and recording intake were given, and the subjects were provided with measuring cups, spoons, and a digital food scale for use at home. Parents were encouraged to maintain the childs usual dietary practices. A registered dietitian reviewed the completed diet records and queried the family for missing or additional information when necessary. Diet records were analyzed by using computerized software (NDS; Nutrition Data System, Minneapolis, MN).
Total energy expenditure measures
At the baseline and 24-mo visits, TEE was measured with the doubly labeled water (DLW) technique (34). The DLW technique requires subjects to ingest water enriched with the isotopes deuterium and oxygen-18. These isotopes equilibrate with body water and as a part of routine metabolism are eliminated from the body over time. Oxygen-18 is eliminated as part of both water and carbon dioxide, and deuterium is eliminated via water. The difference in the elimination rates of these isotopes is a measure of carbon dioxide production, which can then be converted to EE via standard indirect calorimetry equations (35). TEE measured by the DLW method accounts for the energy cost of basal metabolic rate, physical activity, theromoregulation, and tissue accretion. In children, energy storage or tissue accretion is added to total EE to calculate total energy requirements (36). The DLW protocol used in this study was as follows. After collection of a baseline urine sample, subjects received a DLW dose consisting of 0.14 g 2H2O (99.8 atom% excess; Sigma Aldrich, Milwaukee, WI) and 0.3 g H218O (10 atom% excess; ICON Services, Summitt, NJ) per kg estimated TBW. Preweighed absorbent cloth was used to collect any spillage of the dose and was then reweighed to quantify dose loss. Subjects collected the second and third daily voids on postdose days 1, 7, 10, and 14. Samples were stored frozen until analyzed in the CHOP Mass Spectrometry Core Laboratory.
Isotopic enrichment of urine specimens was determined with a ThermoQuest Finnigan Delta Plus isotope ratio mass spectrometer (ThermoQuest Finnigan, San Jose, CA). Before mass spectrometer analysis, urine samples were treated with 20 mg activated charcoal, mixed by vortex for 10 s, and filtered through a 0.45-µm filter (Millipore Corporation, Billerica, MA). For deuterium analysis, water was reduced to hydrogen gas via the automated injection of 1.0 µL sample into a quartz tube packed with chromium metal (100200 mesh) maintained at 850 °C. For each specimen, 5 measurements of isotopic enrichment and 5 measurements of a standard reference gas of hydrogen were obtained. All measurements were expressed as the mean ± SD of the 5 analyses. The CV within samples was <0.5%. After correction for triprotium ion, the data were expressed as parts per million (
) relative to standard mean oceanic water (SMOW). For oxygen-18 analysis, the sample was placed in a gas bench analyzer, and a defined volume of gas (0.3% CO2/99.7% He) was injected into the sample vial. A period of 18 h was allowed for equilibration of the water and carbon dioxide at room temperature (
22 °C). The sample was then injected into a gas chromatography column held isothermally at 28 °C. For each specimen, a total of 13 measurements was made, 9 of which pertained to the unknown urine specimen and an additional 4 to the reference gas. All measurements were expressed as the mean of the 9 analyses as parts per million (
) relative to SMOW.
TEE was measured over a 9-d period (baseline mean: 9.3 ± 0.6 d; 24-mo mean: 9.2 ± 0.9 d). Isotope dilution spaces (kg) were determined with the slope intercept method and the equations of Coward and Cole (37) and were 1.036 ± 0.026 and 1.033 ± 0.020 at the baseline and 24-mo time points, respectively. Total body water was calculated as the average of the deuterium and oxygen-18 dilution spaces corrected for in vivo isotope exchange (38). The rate of carbon dioxide production was computed from the difference in elimination rate of the isotopes (34) by using the 2-point method with urine samples from day 1 (second and third voids) and day 7 or 10 (second and third voids). An assumed respiratory quotient of 0.86 (38) was used, and EE was calculated by using the modified Weir equation (39). The analytic error for TEE (kcal/d) measures in our laboratory is 4.7%.
Pulmonary, stool, and genotype measures
Pulmonary and stool measures were obtained at the baseline and 12- and 24-mo visits. Clinical status was rated by the method of Shwachman and Kulczycki (40). Pulmonary function was evaluated by using standard methods for spirometry and plethysmography, and the values were compared with reference values (41, 42). A 72-h stool sample was collected at the baseline and 24-mo visits for fecal fat analysis. The subjects were provided standardized instructions and kits for collecting stool and were instructed to maintain their usual enzyme regimen. Stool specimens were stored frozen until analyzed. Fat content was determined by using a gravimetric method (Mayo Medical Laboratories, Rochester, MN). The coefficient of absorption was calculated from a 7-d weighed food record and 72-h stool collection (43). Fecal fat energy loss was determined from the 72-h stool collection. Grams of fecal fat loss were multiplied by 9 kcal/g to determine fecal fat energy loss (kcal/d). Random stool samples were obtained at a protocol hospital visit for fecal elastase (FE) analysis. Specimens were stored at 20 °C and analyzed with an enzyme-linked immunosorbent assay FE kit (ScheBo Biotech, Gieseen, Germany). For the purposes of this study, subjects with
15 µg FE/g stool were classified as having residual pancreatic activity and those with <15 µg FE/g stool were classified as pancreatic insufficient. Genotype was obtained from the subjects medical records when available. When unknown, a blood sample was submitted for genotype analysis (Genzyme Genetics, Pittsburgh, PA). For the purposes of this study, subjects were categorized as either homozygous or heterozygous for the
F508 mutation versus "other." Other mutations included both identified non-
F508 mutations and unknown mutations.
Accuracy of reported energy intake
The ratio of reported EI from the diet record minus fecal fat energy loss (FL), to measured EE by DLW (EIFL:EE) was used to categorize subjects as accurate reporters, underreporters, or overreporters of EI. An EI:EE ratio of 1.01 to 1.02 was expected, because the energy needs for growth are estimated to be 12% greater than EE (44). The subjects whose EIFL:EE ratio was within the 95% confidence limit of the expected ratio were categorized as accurate reporters, whereas those below or above the 95% confidence limit were categorized as underreporters and overreporters, respectively. The 95% confidence limits were defined as follows:
![]() | (1) |
Statistical analysis
Initially, all variables were tested for normality. The variables age, weight, fecal fat, and weight gain were significant (chi-square test, P < 0.05) with respect to skewness and kurtosis; hence, nonparametric methods were used to analyze these variables. The following description is divided into 3 subsections based on the type of data presented: clinical characteristics, energy balance, and reporting accuracy. Within each subsection, data are first presented using descriptive statistics such as means and SDs, followed by a discussion of all inferential models tested.
For data related to clinical characteristics (Table 1
) and energy balance (Table 2
), sex x time interactions were explored across 2 specific observation periods (baseline and 24 mo). For data related to reporting accuracy (Table 3
), reporting accuracy x time interactions were explored across the same 2 observation periods (baseline and 24 mo). Longitudinal mixed-effects models were used to test for interactions. Where no significant sex x time (Tables 1
and 2
) or reporting accuracy x time (Table 3
) interactions were observed, main-effect models were tested to better understand the significance of any observed difference between males and females or between reporting accuracy groups over time. Mixed-effects models have the added benefit of incorporating incomplete data across both time points (46). Additionally, with respect to reporting accuracy (Table 3
), differences in nutrition and disease variables between accurate reporters and overreporters of EI were examined at baseline by using either a Students t test or chi-square test for continuous and categorical outcome variables, respectively. Underreporters were not included in these statistical analyses because of the small sample size.
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= 0.007. | RESULTS |
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89% of the subjects were homozygous or heterozygous for the
F508 mutation, 88% had PI (<15 µg FE/g stool), 42% had a mother with a college diploma or more education, and 41% had an annual household income of
$75 000 (data not shown).
Clinical characteristics
The clinical characteristics of the subjects are presented by study visit and sex (Table 1
). Baseline growth and nutritional status measures showed suboptimal growth status as indicated by negative scores for WAZ, AHAZ, BMIZ, UAMAZ, and UAFAZ; WAZ, AHAZ, and UAFAZ remained suboptimal at 24 mo. No significant sex x time interactions were found for any of the variables in Table 1
. For the group as a whole, a significant difference was found between baseline and 24 mo for weight and UAMAZ, which increased over the 24-mo study period, and for FEV1 and Shwachman score, which decreased over the study period.
Energy balance
Energy balance measures in Table 2
are presented as medians and 25th and 75th percentiles. No significant sex x time interactions were found for any of the variables in Table 2
. For the group as a whole, a significant difference was found between baseline and 24-mo for EE, EI, and fat intake, all of which increased over the study period. The median EI:EE ratio for all subjects was 1.15 at baseline and 1.18 at 24 mo. When fecal fat energy loss was accounted for (EIFL:EE), the ratio decreased to 1.09 and 1.10 at baseline and 24 mo, respectively.
Reporting accuracy
The subjects were categorized on the basis of the reporting accuracy of dietary intake (Table 3
) by using the 95% CI for the expected EIFL:EE ratio: the within-subject CV for EI (CVwEI) was 20% at both baseline and 24 mo; a repeat measure of EE was not conducted, but the within-subject CV for EE (CVwEE) derived from studies with repeat DLW measures was 8.2% (48) and was used in this analysis; and the correlation between EE and EIFL was 0.59 at baseline and 0.48 at 24 mo. Thus, the EIFL:EE ratios were as follows: <0.80 for underreporters of EI,
0.80 and <1.23 for accurate reporters, and
1.23 for overreporters. At baseline, 7% of the subjects were underreporters of EI, 64% were accurate reporters, and 23% were overreporters; 24 mo later, 3% of the subjects were underreporters of EI, 59% were accurate reporters, and 28% were overreporters. Given the low number of subjects in the underreporters group, underreporters were not included in further statistical analyses. Of the 44 subjects with TEE and EI data at both baseline and 24 mo, 26 (57%) had the same reporting accuracy classification at both baseline and 24 mo (data not shown). Significant reporting accuracy by time interactions was not found for any of the variables in Table 3
. For the group as a whole, a statistically significant decrease in Shwachman score was observed over time. Significant differences at baseline between the accurate reporters and overreporters of EI were not found for any of the variables in Table 3
when the significance criterion was adjusted for multiplicity (
adj = 0.002).
| DISCUSSION |
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As reflected in the negative WAZ and HAZ z scores at baseline, the preadolescent children with CF and PI in the present study had suboptimal growth at enrollment, which indicated that a persistent period of negative energy balance occurred before the ages of 6.0 to 8.9 y. Throughout the 24-mo study period, the cohort gained weight at a rate similar to that of healthy children, 8 g/d (49), which indicated that they were in a state of positive energy balance sufficient to support age-appropriate, but not catch-up, weight gain. We explored the sex x time interactions with respect to clinical characteristics and energy balance over time and found no significant relations. To further our understanding of energy balance in this cohort, we looked to measures of EE, EI, and energy loss.
The TEE measures in our cohort can be compared with only one previous study of TEE in similarly aged children with CF (15). This earlier study, in which TEE was also measured by DLW, found a higher TEE in children with CF than in children with healthy control children. Additionally, the children in the previous study had a higher daily EE than did the children in the current study; however, these children were also heavier and taller than our cohort. TEE was measured in other age groups of individuals with CF and compared with that in healthy control subjects (13, 14, 17, 19, 20). These studies yielded conflicting results as to whether persons with CF have a higher TEE than do their healthy counterparts.
The median fecal fat loss in our cohort was within the range of that found in other studies of similarly aged children with CF and PI (15, 26, 28, 29, 50). Previous studies have reported fecal fat losses ranging from 8 to 17 g/d in children with CF compared with losses ranging from only 2 to 4 g/d in control children (26, 28, 50). Our subjects with CF and PI lost from 4 to 26 g/d of fat in stool, which corresponds to an energy loss of
36 to 234 kcal/d. Two previous studies of fecal energy loss in children with CF measured other sources of energy loss, such as nitrogen and bacteria (26, 50). Murphy et al (26) found that preadolescent children with CF lost a mean of 9.9 ± 1.2 g fat, 2.5 ± 0.5 g N, and 13.4 ± 2.1 g bacteria daily, for a total fecal energy loss of 228 kcal/d, which was significantly greater than the fecal energy loss of 68 kcal/d in control children, (26). Because our measure of fecal loss accounted for only fat malabsorption, it is expected that the average total energy loss in stool for our children was greater.
Our measure of EI was based on self-report by weighed food record. The ability of some children and their caregivers to accurately report EI has come into question (51-56). In healthy children of a similar age with a normal BMI, EI has been reported within 5% of measured EE (51, 52), but as children become older (>10 y of age) (51, 52) or as BMI increases (54-56), EI is increasingly underreported. Conversely, a study of undernourished children with cerebral palsy found that EI determined by diet record was grossly overreported (44 to 54%) compared with that reported by control subjects (57). In adults, underreporting of EI was related to psychosocial factors, such as social desirability (58, 59) and eating restraint (59, 60), but these factors were not evaluated in children. In our cohort of nonoverweight, 6to11-y-old children with a chronic disease and nutritional risks, the median ratio of EI:EE was greater than the expected ratio of 1.01 to 1.02 at both baseline and 24 mo. In children with CF, the relation between EI and EE may be confounded by excessive energy loss in stool. When fecal fat energy loss was accounted for (EIFL:EE), the median EIFL:EE ratio decreased, but was still greater than that expected given the rate of weight gain observed, which suggested overreporting of EI in some children.
Further exploration into reporting accuracy in children with CF required evaluation of intraindividual variation in EI and EE. Absolute agreement between EI and EE was not expected, rather EI:EE ratios within 95% confidence limits of the mean were used to define underreporters, accurate reporters, and overreporters of EI. Although most of the children and caregivers in this cohort accurately reported EI,
25% of the children with CF overreported EI. This finding is consistent with the observation that the overreporters had a more positive EIFL:EE ratio (30% greater for overreporters than for accurate reporters), yet the overreporters did not show a concomitant greater weight gain than did the accurate reporters. An examination of subject and caregiver attributes that could be used to identify reporting accuracy status provided little insight into characteristics that may be used to identify misreporters. No significant baseline differences in age, weight, BMI, disease status, sex, mothers education, or household income between accurate reporters and overreporters of EI were observed. Last, only 57% of the subjects were classified into the same reporting accuracy category at both baseline and 24 mo, which indicated that reporting accuracy was transient over time in this cohort.
Another issue to consider with respect to reporting accuracy in this cohort was the instrument used to assess dietary intake. The food record is a prospective method, and it has been shown that the act of recording intake may lead to changes in usual food intake during the record-keeping period (61). In a disease such as CF, in which growth and nutrition status are related to outcome and nutrition counseling is an early and integral component of comprehensive care, some individuals may feel pressure to consume more energy. Thus, the children in our cohort may have consumed more energy than they normally would for the duration of the record-keeping period but were unable to sustain the increased intake during the entire 24-mo study; this resulted in age-appropriate, but not catch-up, weight-gain velocity.
In summary, this study of energy balance and reporting accuracy in preadolescents with CF and PI found that suboptimal growth and nutritional status were present at the onset and conclusion of the 24-mo study. The lack of change in WAZ and AHAZ indicated a state of positive energy balance sufficient to allow for an age-appropriate, but not catch-up rate of, weight gain or height in children with a growth deficit. The elevated EIFL:EE ratios showed that
25% of the children and their caregivers overreported EI and only 5% underreported EI. Additionally, the classification of reporting accuracy was not stable over time within all subjects. Overreporting of EI was not related to current growth and disease status; however, overreporting may delay the diagnosis of inadequate EI and possibly lead to declines in growth and pulmonary status over time.
The findings of this study suggest a weakness of the diet record at the individual level in young children with a nutrition-related disease and serve as a cautionary note to clinicians and researchers. Evaluation of energy balance with an objective measure, such as weight-gain velocity, is likely more reliable and useful in clinical care than is the use of a diet record. Future studies are needed to determine whether children with CF overreport intake when using retrospective diet assessment methods such as the 24-h dietary recall. Finally, studies are needed to confirm the observation of misreporting of EI in children with CF and in persons with other disease conditions in which nutritional status and growth are affected and emphasized as a component of routine care.
| ACKNOWLEDGMENTS |
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BSZ and VAS designed the study. BSZ, VAS, and JIS collected the data. MY, YD, JT, IEO, and VAS conducted the mass spectrometry analysis and interpreted the data. JT, JIS, RFI, and VAS conducted the data analysis. JT, JIS, and VAS wrote the manuscript. RFI, IEO, MY, YD, and BSZ critically revised the manuscript for intellectual content. None of the authors had a conflict of interest regarding any aspect of this research.
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