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Journal of Pediatric Gastroenterology & Nutrition:
Original Articles-Hepatology and Nutrition

Anti-Inflammatory and Growth-Stimulating Effects Precede Nutritional Restitution During Enteral Feeding in Crohn Disease

Bannerjee, Kaushik†; Camacho-Hübner, Cecilia†; Babinska, Katarzyna*; Dryhurst, Kay M.*; Edwards, Ray‡; Savage, Martin O.†; Sanderson, Ian R.*; Croft, Nicholas M.*

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Author Information

Departments of *Adult and Paediatric Gastroenterology, †Paediatric Endocrinology, and ‡NETRIA Unit, Barts and the London, Queen Mary's School of Medicine and Dentistry, University of London, London, United Kingdom.

Received: December 5, 2002; accepted: June 1, 2003.

Kay M. Dryhurst was supported by a grant from the Crohn's in Children Research Association. Nestlé, UK, contributed to the costs of the interleukin-6 assays.

Address correspondence and reprint requests to Dr. Nick M. Croft, Adult and Paediatric Gastroenterology, Barts and the London, Queen Mary's School of Medicine and Dentistry, St. Bartholomew's Hospital, London, EC1A 7BE, United Kingdom (e-mail: n.m.croft@mds.qmw.ac.uk).

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Abstract

Objectives: Exclusive enteral feeding reduces inflammation and improves well being, nutrition and growth in children with active Crohn disease. Whether improved growth and increases in growth-related proteins are a consequence of improved nutrition or a reduced inflammation is not known. This study was undertaken to test the hypothesis that changes in growth-related proteins are related to decreased inflammation, rather than improvement in nutritional status.

Methods: Twelve children with active Crohn disease treated for 6-weeks with exclusive enteral feeding were studied at days 0, 3, 7, 14, 21, 28, and 56. The Paediatric Crohn's Disease Activity Index (PCDAI), weight, triceps skinfold thickness, and midupper arm circumference were recorded. C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), interleukin-6 (IL-6), insulin-like growth factor (IGF-I), IGF-binding protein (IGFBP-3), and leptin were measured at each visit. Wilcoxon matched-pairs signed-rank test was used to compare day 0 with follow-up data.

Results: Significant improvements (P < 0.05) occurred by day 3 in inflammatory parameters (ESR, IL-6) and by day 7 in PCDAI, CRP, and IGF-I. These changes preceded any significant changes in nutritional parameters (weight-for-age Z score and midupper arm circumference day 14, triceps skinfold thickness day 21).

Conclusions: Early increases in IGF-I during treatment of Crohn disease are attributable to the anti-inflammatory effect of the enteral feed rather than nutritional restitution.

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INTRODUCTION

Impaired linear growth is common in children with active small bowel Crohn disease. Growth failure is present in as many as 50% of children at presentation, and as many as 90% are underweight (1). Growth failure in inflammatory bowel disease (IBD) has been attributed to undernutrition; however, the mechanisms have not been clearly defined (2–4).

Despite adequate nutrition, it is known that in some patients active disease is the sole cause of growth suppression. The pro-inflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor-alpha, and interferon-γ which originate in the inflamed bowel have been linked to growth suppression (5,6). Of particular interest is IL-6. Transgenic mice who overexpress IL-6 are growth retarded, with reduced circulating insulin-like growth factor I (IGF-I) and normal growth hormone despite normal food intake (7). In addition, in a rodent model of colitis, 40% of linear growth failure is a consequence of inflammatory processes, with 60% attributable to undernutrition (8). After immunoneutralizing IL-6 in this model, liver IGF-I messenger ribonucleic acid expression normalized and both plasma IGF-I and linear growth increased (9).

In children and adolescents with Crohn disease, prompt and sustained remission of the disease is necessary to ensure normal growth. Nutritional therapy is effective in inducing remission in small bowel Crohn disease (10). An early study in children showed that elemental formula was as effective as steroids in controlling disease and was associated with better linear growth compared to steroid treated patients (11). More palatable polymeric diets have been successfully used in both adults (12,13) and children (14).

Following introduction of exclusive enteral feeds, general well being, growth and inflammatory markers all improve. Beattie et al. (15) demonstrated that during 8 weeks of treatment with AL 110 (Nestlé, Croydon UK), a milk-based polymeric diet, there were decreases in inflammatory markers and increases in IGF-I and insulin-like growth factor binding protein (IGFBP-3) after 2 weeks. It is still not clear whether this early improvement is secondary to suppression of inflammatory processes or to the improvement in nutritional status. To confirm that reduction in inflammation and increase in growth factors are attributable to recovery of the nutritional status, nutritional parameters must be shown to change before (or at least coincident with) inflammatory and growth markers. The aim of this study was to test the hypothesis that changes in growth factors during treatment with enteral feedings are secondary to the suppression in inflammation (focusing on the IL-6 response), rather than to nutritional restitution.

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PATIENTS AND METHODS

The study was approved by the East London and City Health Authority research ethics committee. Written informed consent was obtained from the parents or guardians, and verbal consent was obtained from the patients.

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Patients

Twelve consecutive patients requiring enteral treatment for active Crohn disease were recruited from the Paediatric Inflammatory Bowel Disease clinic at Barts and the London NHS Trust. The diagnosis of Crohn disease had been confirmed by radiology, endoscopy, and histology according to an established protocol (16). The choice of enteral feeding as treatment for Crohn disease was made by senior clinicians in the outpatient department.

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Diet

A 6-week course of the polymeric formula AL 110 (Nestlé, Croydon UK) was prescribed and taken either orally or by nasogastric tube. The formula contained 1 calorie/mL, and the total calories given equalled the daily estimated average requirements for patient age. At the end of the course, foods were introduced during the subsequent 4 to 6 weeks, and the quantity of AL 110 was gradually reduced.

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Patient reviews

The children were reviewed at days 0, 3, 7, 14, 21, 28, and 56 days when blood samples were collected and clinical measurements were made. Serum samples were separated, aliquotted, and frozen at −20°C until assayed.

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Measurements

1. Disease activity was measured according to the Paediatric Crohn's Disease Activity Index (PCDAI) (17). PCDAI includes subjective patient historical information (30% of the total), physical examination findings (30%), laboratory assessment (20%), and data concerning weight gain or loss as well as height velocity (20%). A score of 0 to 10 corresponds with no disease activity; mild disease equals a score of 11 to 30, and score of 31 or greater represents moderate to severe disease activity (17).

2. Markers of inflammation Erythrocyte sedimentation rate and C-reactive protein were measured by routine laboratory assays. IL-6 was assayed using commercially available sandwich enzyme-linked immunosorbent assay (ELISA) (R&D Systems, Abingdon, UK).

3. Growth-related proteins Serum IGF-I was measured by radioimmunoassay after formic acid/acetone extraction, as previously described (18). Pharmacia (Stockholm, Sweden) kindly provided 125I iodinated recombinant human IGF-I. ELISA was used for the measurement of IGFBP-3 (OBI-Diagnostics Systems Laboratories, Upper Heyford, UK).

4. Nutritional and growth measurements. Height, weight, midupper arm circumference, and triceps skinfold thickness were measured by a single observer according to standard anthropometry techniques (19–21). Weight and height standard deviation scores were calculated using a software package (LGROW, Child Growth Foundation, London, United Kingdom) and are expressed as weight-for-age Z score (WAZ) and height-for-age Z score (HAZ), respectively. The BMI standard deviation score was calculated using an auxology calculator (Pfizer, Tadworth, UK). Pubertal staging was performed according to the criteria of Tanner (22). Serum leptin, which has been shown to positively correlate with the fat mass, was used as a serum marker of fat stores. Immunoreactive leptin was measured by radioimmunoassay (NETRIA Unit, St. Bartholomew's Hospital). The assay uses a sheep antihuman leptin, raised against recombinant human leptin (R&D Systems, Abingdon, UK), and 125-Iodine labeled human leptin prepared by the chloramine T method and purified by column chromatography (Sephadex G100 Amersham Biosciences, Chalfont St Giles, UK). Separation of antibody-bound fraction was by optimized second antibody/4% PEG solution (23). This assay detects leptin in plasma or serum with a sensitivity of 0.9 ng/mL. The inter- and intra-assay coefficients of variation were less than 10%.

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Statistical analysis

Day 0 data were compared with those of subsequent visits using the Wilcoxon matched-pairs signed-rank test; significant changes were defined as P values of less than 0.05. SPSS software package version 6.1 (SPSS Inc., Chicago, Illinois, U.S.A.) was used for all the statistical analysis.

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RESULTS

Children had moderate to severe Crohn disease at initiation of enteral feeds

Twelve (9 male and 3 female) patients with a median age of 12.8 years (range, 6.7–16.1 years) completed the course of treatment. Five were prepubertal (Tanner stage 1) and the remaining seven pubertal (Tanner stages 2–4). Five patients were newly diagnosed and 7 had disease in relapse. Four patients had small bowel disease exclusively, 6 had small bowel and colonic disease, and 2 had colonic disease alone. All 7 patients with disease in relapse at entry into the study were receiving mesalazine, and 1 was receiving a tapering dose of prednisolone plus azathioprine (at a stable dose of 2 mg/kg/d for the last 3 months).

All children had active Crohn disease as defined by a PCDAI greater than 10, with a median score of 36 (range, 22–52) in the moderate to severe range (Table 1). Medians for CRP and ESR also were raised (Table 1). The WAZ was −0.8, lower than the median HAZ of 0.06, suggesting that these children were relatively underweight for their age and height; this is consistent with a low body mass index standard deviation score of −1. IGF-I was at the lower limit of the normal range.

Table 1
Table 1
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Clinical and biochemical response to enteral feeding therapy

All children tolerated the feedings well and completed the course of AL 110 with an overall improvement of symptoms. Ten of the subjects took the formula orally, and 2 required nasogastric tubes. Most reported feeling better within 2 weeks of starting formula. Both the PCDAI and CRP decreased during the course of the study, with CRP showing a rapid decline during the first 7 days in some individuals (Fig. 1). The lowest median PCDAI was 10 (range, 2–22) at day 28; this was recorded at the same time as the greatest reduction in CRP and ESR (Fig. 2A). These responses were maintained until the end of the study period on day 56, 2 weeks after completion of the full enteral feeds. There were no significant changes in height-for-age Z score during the study, although this time period is too short to demonstrate significantly increased growth (data not shown).

Fig. 1
Fig. 1
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Fig. 2
Fig. 2
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Inflammatory markers, clinical score, and growth factors change before nutritional parameters

Figure 2 demonstrates the timing for all the parameters that changed during the study. ESR and IL-6 (Fig. 2A) were the first parameters to show a significant improvement which occurred as early as 3 days after commencing enteral diet. These were followed at day 7 by decreases in the PCDAI and CRP and an increase in the IGF-I (Fig. 2A). In contrast, none of the nutritional parameters (WAZ, midupper arm circumference, triceps skinfold thickness;Fig. 2B) significantly changed until day 14 or later. Although the median change in IGFBP-3 suggested an increase at 2 weeks of age, this was not significant (Fig. 2B). Leptin increased at only one measurement on day 21 (Fig. 2B).

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DISCUSSION

These studies show for the first time that reduction in inflammatory markers and IL-6, and an increase in IGF-I precede nutritional restitution in children with active Crohn disease treated with enteral feeds. Consistent with previous studies, all of our study children improved with AL 110 treatment both clinically and as measured by the PCDAI, and maintained some response to the end of the study period. (11,14). Although we found an increase in serum IGF-I, we did not find any differences in height-for-age Z scores during the study. Longer follow-up periods are required to establish significant improvements in growth. The IGF level of 162 μg/L in our subjects on day 0 was greater than that reported in a previous study (78 μg/L) (15). This was despite the similarity in ages in both groups. The explanation for the difference is that only 5 of 12 of our subjects were prepubertal (Tanner stage 1), whereas all but 1 were prepubertal in the earlier study. The peak increase of 100 μg/L in our study on day 56 was greater than that recorded in the earlier study (peak value 55 μg/L). A 100-μg/L increase is probably clinically relevant for growth; however, additional studies are required to confirm this impression.

Although inflammation markers may change rapidly once inflammation subside, a hypothesis suggesting that nutritional restitution is the primary cause for reduction in inflammation and increase in IGF-I must rely on demonstrating nutritional changes before or coincident with inflammatory changes. We have used standardized methods for measuring nutritional status and have not shown changes in these parameters until at least 1 week after changes in growth factors, clinical score, and serum inflammatory markers. It is possible that the nonsignificant change in WAZ at day 7 (Fig. 2B) could become significant with larger numbers; however, as a group there is no suggestion of change at day 3, by which time ESR and IL-6 were already significantly improved.

Other serum markers used as nutritional markers of protein turnover, such as retinol-binding protein and pre-albumin (transthyretin), have two major disadvantages and thus were not used in this study. First, they are proteins produced by hepatocytes and can be suppressed by the presence of inflammatory cytokines, which are raised during active disease (24–26). Second, in children treated for anorexia nervosa, IGF-1 increased in association with weight gain, but there was no change in retinol-binding protein and pre-albumin (transthyretin). These findings suggest that in noninflammatory malnutrition, weight changes occur before alterations in these proteins (27).

We used serum leptin as a marker of fat stores and did not shown any sustained change, although the initial level was low compared with adult levels. No age-matched control data are available. The one significant increase at 21 days did not correlate with the peak figures for other nutritional measures, such as WAZ, midupper arm circumference, and triceps skinfold thickness at 28 or 56 days. Leptin concentrations have been shown in children with IBD to be the same as those of healthy control subjects (28) and (in adults with IBD) to correlate with body fat and not increase during severe relapses (29). We cannot exclude the possibility that subtle nutritional changes (perhaps of micronutrients) caused some of the improvements we found in these subjects. Specific test results of the nutritional substance(s) under investigation would have to be identified and shown to change more rapidly than other, more-established nutritional measures during restitution of the nutritional state.

Our data suggest that reduction in inflammation leads to an increase in IGF-I, which may in turn lead to increased growth. Others have shown an improvement in growth in children with IBD after treatment with enteral feeding (3,11,30).

Because of the effects on growth in IL-6 transgenic mice, we focused on the IL-6 response and for the first time showed a dramatic and early reduction in serum levels after treatment with enteral diet. Raised serum IL-6 and a response after treatment with steroids have been demonstrated in adults with IBD (31). Possibly IGF-I increased as a result of a reduction in IL-6 and a consequent increase in hepatocyte-produced IGF-I. Similar arguments could be proposed for other pro-inflammatory cytokines, such as tumor necrosis factor-alpha and IL-1β, not measured in this study. Both of these have been shown to have growth-suppressing effects (32,33), to increase in active IBD (5,6,34), and decrease after treatment (34). The growth hormone/IGF-I growth axis also may be disrupted through alteration of both the concentration and the molecular composition of IGF binding proteins, including IGFBP-3. Although we did not find a significant change in the concentration of IGFBP-3, the levels trended upwards, as has been reported previously (15).

Understanding how enteral feeds reduce inflammation is of major pathophysiological importance in Crohn disease and has been reviewed previously (35). Early, more elemental diet plans were thought to be effective by minimizing the exposure of the mucosa to whole proteins; however, the effectiveness of polymeric diets including whole protein, such as that used in the current study, would make that explanation unlikely. The diet used in the current study contains transforming growth factor-beta (TGF-β), a constituent of bovine milk. The possibility that this may have some therapeutic effect has been raised (34) but is made less likely by other diets (e.g., Nutrison Standard, Nutricia, Trowbridge, UK) that do not contain TGF-β (EJ Kelly, personal communication) having been shown to be clinically effective (14).

In summary, we have shown that in children with Crohn disease being treated with exclusive enteral feeding, IGF-I rises on day 7 after or coincident with a reduction of inflammatory markers and overall disease activity. No significant changes in nutritional parameters were demonstrated until 1 week after these changes. These data suggest that exclusive enteral feeding can have a direct anti-inflammatory effect, preceding significant nutritional restitution contributing to improvement in the growth factor axis which may lead to improved linear growth.

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Acknowledgments:

The authors thank the patients and their parents for participating in this study. The authors also thank N. Jinanji and F. Miraki-Moud for excellent technical assistance.

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Back to Top | Article Outline
Keywords:

Crohn disease; Enteral feeding; Growth factors; Inflammation; Interleukin-6

© 2004 Lippincott Williams & Wilkins, Inc.

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