Journal of Pediatric Gastroenterology & Nutrition:
Original Articles: Gastroenterology
Assessment of Nutritional Status and Serum Leptin in Children With Inflammatory Bowel Disease
Aurangzeb, Brekhna*; Leach, Steven T†; Lemberg, Daniel A‡; Day, Andrew S†
*The Children's Hospital, Pakistan Institute of Medical Sciences, Islamabad, Pakistan
†School of Women's and Children's Health, University of New South Wales, Sydney
‡Department of Gastroenterology, Sydney Children's Hospital, Randwick, Sydney, NSW, Australia.
Received 1 May, 2010
Accepted 20 August, 2010
Address correspondence and reprint requests to Prof Andrew Day, Department of Paediatrics, University of Otago, Christchurch, Riccarton Avenue, Christchurch 8140, New Zealand (e-mail: firstname.lastname@example.org).
The authors report no conflicts of interest.
Objectives: Children with inflammatory bowel disease (IBD) commonly have altered nutrition and growth. Measurement of serum leptin may enhance other modalities to assess the nutritional state of children with IBD. The aim of the present study was to define the nutritional status of children with newly diagnosed IBD by measuring anthropometry and serum leptin levels.
Patients and Methods: Twenty-eight children newly diagnosed with IBD and 56 age- and sex-matched controls were enrolled prospectively. Anthropometry (weight, height, and body mass index [BMI] expressed as z scores) and serum leptin levels were measured.
Results: The children with IBD had lower mean BMI z scores and weight-for-age percentiles than controls (P = 0.05 and P = 0.01, respectively). The mean (standard deviation) serum leptin levels of the children with IBD were 2.4 (±1.9) pg/mL, compared with 5.2 (±4.6) pg/mL for controls (P = 0.01). The BMI percentile correlated positively with leptin levels in both groups. Following adjustment for BMI percentiles, serum leptin levels were lower in children with IBD than in controls (P = 0.02). Leptin levels did not correlate with serum markers of inflammation or disease activity scores.
Conclusions: Detailed and focused nutritional assessment should be an integral part of the management of all children with IBD. Children at the time of diagnosis of IBD have significant undernutrition and have lower serum leptin levels than controls. The inflammatory state in IBD appears not to alter leptin metabolism. Further study of the effect of leptin in IBD is required.
Ulcerative colitis (UC) and Crohn disease (CD) together comprise a clinically and genetically heterogeneous group of related disorders, considered collectively as inflammatory bowel disease (IBD) (1). Almost 25% of individuals with UC and CD have onset of the disease in childhood (2). IBD is becoming increasingly common, with rates in many countries rising recently, as emphasized in a recent review (3). This pattern has also been seen in Australia, with the incidence of CD in children from the state of Victoria increasing >10-fold to 2.0/100,000/year between 1971 and 2001 (4).
In childhood IBD, especially in CD, nutrition and growth may be affected, which can greatly affect disease status, quality of life, and future health and well-being. This is particularly an issue when children are diagnosed in adolescence or prepubertal years. Weight loss is present in 70% of children with CD and 34% with UC at diagnosis (5). In addition, up to 58% of children with IBD have linear growth failure (6). In hospitalized patients with IBD, malnutrition affects adversely the morbidity and mortality of the disease (7,8), whereas overall malnutrition negatively affects the general well-being of many children with CD (9).
Consequently, incorporating nutritional assessment into the initial and ongoing assessment of all children diagnosed with IBD may significantly improve health outcomes. Various anthropometric and biochemical markers are available to assess nutritional status (7,10). A combination of anthropometric measurements can be used to define the type and severity of malnutrition, whereas biochemical markers (eg, leptin as a marker of fat stores) can give an impression of fat mass (FM).
There are conflicting results in the literature about the role of leptin in IBD. Some researchers report that the level of leptin increases with inflammation (11–13), whereas others believe that leptin levels fall in this context (14). Some investigators propose that the level of leptin depends solely on the nutritional status of the individual, irrespective of the disease state (15). There is also controversy regarding the correlation between body mass index (BMI) and serum leptin levels in the context of IBD. Consequently, additional work exploring the role of serum leptin in IBD and its correlation with BMI is required. On the basis of this background, the present study was undertaken to investigate the nutritional status of children with newly diagnosed IBD and determine the relation between serum leptin and BMI in this group.
PATIENTS AND METHODS
The study population consisted of children ages 6 months to 16 years, who were referred to Sydney Children's Hospital, Randwick, Sydney, Australia, with clinical suspicion of IBD. The diagnosis of IBD and classification as CD or UC were based on the combination of clinical features and serological, endoscopic, colonoscopic, and histological findings (16,17). Children who could not be definitively classified as CD or UC were excluded. The location of disease at diagnosis was classified according to the Montreal system for both UC and CD (18). In all of the children with CD, disease activity was defined at diagnosis using the Pediatric Crohn Disease Activity Index (PCDAI) (19).
Children presenting to Sydney Children's Hospital for elective minor surgical or endoscopic procedures were enrolled prospectively as controls. Inclusion criterion for controls was no evidence of celiac disease or IBD (based on standard serological and histological features) or other underlying inflammatory or chronic disease. Exclusion criterion for both groups was presence of neurological disease or chromosomal abnormality or concurrent administration of parenteral nutrition or an existing gastrostomy.
All of the patients were enrolled before their procedure or operation. Informed consent was obtained from the parent if the child was younger than 16 years and from the child if older than 16 years, using a standard consent form. Ethics approval was obtained from the SESIAHS-ES research ethics committee.
At the time of enrollment, anthropometric measurements including weight, height, and BMI were performed for each child according to standard methods (20). The details of anthropometry and relevant clinical features were initially placed on a structured pro forma and later stored in a designated electronic database.
Measurement of Serum Leptin and Serum Inflammatory Markers
A blood sample was collected from all of the children enrolled in the study. Serum leptin levels were measured using a commercial immunoassay following the manufacturer's instructions (Duo system human leptin, R&D Systems, DY398; Minneapolis, MN). In addition, the results of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and albumin testing were obtained from each patient's medical records, when these tests had been conducted for clinical indications.
Data Management and Analysis
Data were analyzed with SPSS version 14 (SPSS Inc, Chicago, IL). The anthropometric measurements were converted into age- and sex-appropriate centiles using EpiInfo, which uses CDC 2000 charts (www.cdc.org/EpiInfo). These measurements were expressed as standard deviation (SD) scores (z score) to adjust for age and sex simultaneously. Descriptive analysis is presented as frequencies and percentages for categorical variables and mean with SD and median for continuous variables unless stated otherwise.
For comparison (univariate and bivariate analyses) between children with IBD and controls, χ2 test and Student t test were used. For categorical variables, χ2 test was used and 2-tailed P values were reported. For continuous variables, Student t test and, wherever appropriate, nonparametric test were used and 2-tailed P values were reported. Spearman correlation (presented as R2) was used to assess parametric data, and Pearson correlation (presented as R) was used to assess nonparametric data. Analysis of covariance was calculated for serum leptin levels and BMI. The significance level was set at 5%.
Twenty-eight children with IBD (23 with CD and 5 with UC) and 56 age- and sex-matched controls were recruited. Ten children with IBD were enrolled prospectively, and 18 children were included from a previous cohort (21). One child with inconclusive histological findings was excluded from the study because definitive diagnosis of IBD could not be made.
The children with IBD comprised 18 boys and 10 girls (Table 1). The mean age of children with IBD at the time of diagnosis was 9.4 years, ranging between 2.6 and 14.6 years. When considered in age categories, the most common age group at diagnosis was the 9- to 12-year-old group (43.3%) (Table 1). All 5 children with UC had E3 disease location. Seven children with CD had L2 disease (30%) and the remaining 16 children with CD had L3 disease (70%).
CRP, ESR, and albumin results were available in all 28 children diagnosed with IBD at the time of diagnosis. The mean CRP level was 16.7 ± 24.9 mg/mL, and the mean ESR was 30.7 ± 27.2 mm/hour. Albumin levels ranged between 20 and 44 g/L, with the mean value being 33.4 ± 6.4 g/L. The mean PCDAI score in the children with CD was 32.8, ranging from 10 to 70.
Six of the controls were recruited from minor surgical lists, where 50 had undergone an elective endoscopic procedure. These children were matched for age and sex to the study group. CRP levels were available for 15 of these children–all values were normal. ESR and albumin levels were not available in the control group.
Anthropometry of Children With IBD and Controls
The nutritional status of the children with IBD revealed that 3.6% children had height- and weight-for-age ≤2 SD, whereas 39.3% of children had height-for-age z score and weight-for-age z score between 0 and 2 z scores (Table 2). The mean height-for-age percentile of the children with IBD was 46.3, and the mean weight-for-age percentile was 34.9 (Table 3). The mean BMI percentile was 41.1. The mean height-for-age percentile of children with IBD did not differ from that in the control group (P = 0.83) (Table 3). The mean weight-for-age percentile of the 2 groups, however, differed significantly (33.9 for children with IBD and 54.2 for controls [P = 0.01]). Similarly, the mean BMI percentile for children with IBD was 41.1 as compared with 57.4 for controls (P = 0.03). Furthermore, the mean BMI z score of children with IBD was −0.8, whereas it was 0.2 for controls (P = 0.05) (Fig. 1). The minimum and maximum range of BMI z score for children with IBD was −3.3 to 1.5, whereas for controls it was −4.6 to 2.6. The mean weight-for-age percentile and BMI percentile and serum leptin levels differed between the 2 groups in boys (P values 0.004, 0.03, and 0.04, respectively) but not girls (P values 0.70, 0.50, and 0.05, respectively, Table 4).
Serum Leptin Levels
The mean (SD) serum leptin levels were lower for children with IBD than for control children (2.4 ± 1.9 vs 5.2 ± 4.6 pg/mL, P = 0.01, Table 3). The mean serum leptin in children with CD was 3.4 ± 1.7 as compared with 2.0 ± 2.0 in children with UC (P = 0.8). Furthermore, although the mean serum leptin level in boys with IBD was low (2.4 ± 2.1 pg/mL) compared with male controls (5.8 ± 5.5 pg/mL; P = 0.02), serum leptin levels were not different for girls (IBD 2.3 ± 1.5 pg/mL, controls 4.2 ± 2.1 pg/mL: P = 0.05).
Serum leptin levels were further analyzed by stratifying age of children into 4 age categories (Table 5). Although the mean serum leptin levels for children with IBD appeared to be smaller in each age group, this was only significant for the 0 to 4, 9 to 12, and older than 12 age groups, but was not significant for the 5- to 8-years-old age group (Table 4). Leptin levels were further analyzed according to BMI z score categories (Table 6). Serum leptin was only significantly different between IBD and control when BMI z score was in the range 1 to 2 SD (P = 0.008) and not for any other BMI z range. These data were further analyzed by correlating leptin and BMI for each group. BMI z score correlated with serum leptin level in children with IBD (Spearman correlation = 0.50, P = 0.001) and in control children (Spearman correlation = 0.622, P = 0.003). Analysis of covariance was undertaken to determine differences between the serum leptin levels and BMI correlation in IBD and controls. Using the general linear model and after adjusting for BMI percentiles, serum leptin levels remained higher in controls than in children with IBD (P = 0.02).
Correlation Between Inflammatory Markers, Disease Activity, and Leptin in Children With IBD
There were no correlations between serum leptin and CRP, ESR, albumin, or PCDAI in the children with IBD (data not shown: P > 0.05 in all cases).
The present study investigated the nutritional status of a group of children with IBD, with detailed anthropometry and serum leptin levels collected and then compared with values obtained from age- and sex-matched control children without IBD. The children with IBD were markedly undernourished and had low leptin levels that correlated positively with BMI. In this group of children with IBD, leptin levels did not correlate with the degree of inflammation, as defined by serum markers of inflammation.
This cohort of children diagnosed with IBD in the present study was similar to several previous reports of pediatric IBD and is likely representative of children with IBD. The mean age of the children in the present study was 9.4 years with a median of 10 years, similar to 2 previous series from Western Europe (22) and North America (23). Many children diagnosed with IBD present at prepubertal or peripubertal ages. This is a vulnerable age because the pubertal growth spurt is about to occur and the effect of the disease on the final growth of the individual is most marked. The effect of IBD on final height is most marked in children at Tanner stage 1 and 2 (24–26). There was also a male predominance in the present cohort, again similar to other reports (23). This is also relevant to a consideration of the nutritional effect of IBD because boys have later and longer puberty; hence, the effect of IBD on nutrition can be greater and more concerning.
The present study highlights the high rates of undernutrition in the children with IBD, in agreement with previous reports (27,28). Moreover, our results indicate that children with IBD were more wasted than stunted. This is in agreement with the findings of Azcue et al (28), who reported children with IBD to have significantly lower weight and ideal body weight compared with controls, but found no difference in height between IBD and controls. A further study, which included 104 patients with CD ages 4 to 25 years and compared with 233 controls, found that key anthropometric measurements (weight, height, and BMI) were significantly lower in CD compared with controls (29). In addition, several cross-sectional studies show that weight is affected more than height in children with IBD (22,27). Interestingly, it is pertinent to note that up to 5% of children diagnosed with IBD may present solely with growth failure (without other typical symptoms) (30). The markedly undernourished state in children with IBD favors reduced FM. A report of adolescent patients in apparent remission demonstrated significantly lower BMI than healthy controls, demonstrating lower body fat in children with IBD (31).
Corresponding to decreased BMI in IBD, serum leptin levels were also significantly lower in IBD than in matched controls. Further analysis by covariance analysis also showed that after adjusting for BMI percentiles, the serum leptin levels remained high in controls. In contrast, Hoppin et al (15) found no difference in serum leptin levels between children with IBD and controls and concluded that serum leptin levels depend on BMI and sex and not on disease activity or severity. Serum leptin levels are reflective of the body fat stores (32–34) and are lower in children with severe protein energy malnutrition (35). However, lower concentrations of serum leptin have been reported in several chronic diseases (32,36–39) and in other illnesses causing undernutrition, such as intrauterine growth retardation, untreated anorexia nervosa, and malnourishment in chronically ill elderly patients (37,40–42).
Interestingly, Hoppin et al (15) also report that children with UC in the lowermost BMI category had higher serum leptin levels than controls. The authors concluded that this may be a unique group in which inflammation causes an elevation of serum leptin levels independent of BMI (15). A limitation of the present study was that there were only 3 children with UC and 5 controls in the BMI <15th centile group. However, Tuzun et al (14) report that serum leptin is raised in adults with acute UC compared with healthy adults of similar age, sex, and BMI. Furthermore, serum leptin levels were higher in pancolonic disease compared with left-sided or distal colonic disease. The authors suggest that serum leptin may contribute to weight loss and anorexia in UC through a negative feedback signal to the hypothalamus to decrease appetite and food intake (14). Further animal studies also show that serum leptin levels increase with inflammation (11–13). These apparently conflicting results may be a further indication of the different inflammatory process in CD compared with UC.
Serum leptin levels were also assessed in different age groups and the different sexes. In healthy children, leptin levels increase with age until 10 years (43,44). After this age, levels fall in boys until the onset of puberty and then rise again. Children older than 12 years with IBD had significantly reduced leptin compared with controls. Furthermore, for this age group, mean BMI percentile scores were significantly lower in children with IBD compared with controls, yet there were no significant differences in either serum leptin levels or BMI percentile in lower age groups. In addition, the serum leptin level was assessed in detail for both sexes. The mean serum leptin level in boys with IBD was significantly lower compared with male controls; however, there was no difference between girls with IBD and female controls. This can be explained by a significant difference in the mean weight for age and BMI for boys with IBD compared with controls, whereas there was no difference in these measures for the girls. In a further study, girls with CD had higher serum leptin levels compared with boys, which could not be explained by BMI alone (15). It has been suggested that boys are affected by the disease process more than girls, despite the same stage of puberty, age at diagnosis, duration, and activity of disease (45). Similarly, other researchers have reported that the FM of men with IBD is affected more than in women with IBD (46). Thus, the nutritional status and leptin levels of male children of pubertal age are affected the most by IBD.
Several studies in adults have shown that serum leptin concentrations strongly correlate with FM and body weight in both normal and obese people (47–51). Furthermore, serum leptin concentrations correlate with adipose tissue in children (44,52–55). Additionally, our results show a correlation between serum leptin levels and BMI percentile both in controls and in children with IBD. However, contrary to these findings, Tuzun et al (14) reported that serum leptin levels did not correlate with BMI in adults with UC. This is the only study to our knowledge that has reported high serum leptin levels in patients with UC as compared with controls. However, in extremely malnourished children with fluid retention, BMI does not correlate with serum leptin levels because in this situation BMI does not adequately represent the body fat stores (56). Thus, serum leptin levels are a marker of body fat stores except in extremely undernourished states.
The strengths of the study are the detailed and focused assessment of the nutritional status of the children with newly diagnosed IBD presenting at an Australian tertiary hospital, in comparison with age- and sex-matched controls. In addition, serum leptin level in these children with IBD was evaluated in comparison with this control group. There are, however, potential limitations of the present study. First, Tanner staging was not completed, and therefore the pubertal and prepubertal stages were based solely on the age of the child. Having said this, the majority of the children in the present study were in a prepubertal age group. Second, the serum leptin level was analyzed and considered from the nutritional perspective. A detailed examination of correlations between serum leptin level and key inflammatory markers elevated in IBD would further enhance our understanding of the patterns of serum leptin level production in IBD. Lastly, the control group included in the present study did not comprise normal healthy individuals from the general population. The use of such a control group may have aided the interpretation of the data arising.
In conclusion, these children with IBD were significantly undernourished and had significantly lower serum leptin levels than controls. BMI correlated positively with serum leptin levels in children with IBD as well as in controls. Serum leptin levels are markedly reduced in boys with IBD in the prepubertal and pubertal period as compared with control boys. Detailed and focused nutritional assessment should be an integral part of the management of all of the children with IBD. Children with IBD at prepubertal and pubertal ages deserve particular attention to aspects of their nutritional status at and following their diagnosis.
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anthropometry; body mass index; inflammatory bowel disease; nutritional assessment; serum leptin
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