Lee, Jessica J.*; Mitchell, Paul D.†; Hood, Helen C.*; Grand, Richard J.*; Cohen, Laurie E.‡
Linear growth impairment, which occurs commonly in pediatric-onset inflammatory bowel disease (IBD), has been attributed to nutritional, hormonal, genetic, and disease-related factors, including inflammation and chronic corticosteroid use. Although most patients achieve normal height by adulthood (1–3), some remain permanently stunted (4,5). It has not yet been possible to predict which patients are at risk for this lifelong complication.
Insulin-like growth factor 1 (IGF-1) is the primary mediator of growth hormone (GH) action (6). The biological half-life of IGF-1 is the longest among the hormones of the GH axis, and its level does not fluctuate as GH does (7). More than 90% of circulating IGF-1 forms a 150-kDa complex with IGF-binding protein-3 (IGFBP-3), 1 of the 6 binding proteins that modulate the availability of IGF-1 at the tissue level (8). Serum IGF-1 has been reported to be lower in children with IBD and height-for-age z score (HAZ) <−2.0 (9). Because studies have reported decreased IGF-1 but normal levels of GH secretion in patients with IBD (10–12), a finding of relatively low serum IGF-1 in children with IBD and short stature has pointed to the possibility of a state of GH resistance (6). We hypothesized that patients with IBD and permanent growth impairment would have lower serum levels of IGF-1 and IGFBP-3 than those with temporary growth impairment.
Most studies investigating the hormones of GH axis in patients with IBD combined IGF-1 and IGFBP-3 levels across all age and sex groups; however, a proper interpretation of the results should incorporate age- and sex-matched reference ranges (7). To our knowledge, no studies have evaluated IGF-1 and IGFBP-3 levels in growth-impaired patients with IBD who eventually catch-up growth as adults (temporary growth impairment) and those who do not (permanent growth impairment).
The primary objective of this pilot study was to compare IGF-1, IGF-1-for-age z scores, IGFBP-3, and IGFBP-3-for-age z scores in the 3 groups of pediatric patients with IBD: those with permanent growth impairment, those who had temporary growth impairment, and those with normal growth. We also assessed available inflammatory markers (erythrocyte sedimentation rate [ESR], C-reactive protein [CRP], and interleukin-6 [IL-6] nutritional assessments (serum albumin levels, weight-for-age z scores, and BMI z scores), and corticosteroid exposure, because these factors have been shown to influence the IGF-1 and IGFBP-3 levels (10,13–17).
Patients and Data Collection
We retrospectively identified patients (54 boys and girls) from the Division of Gastroenterology and Nutrition at Boston Children's Hospital (BCH) who met the following inclusion criteria: diagnosed with Crohn disease or ulcerative colitis before the age of 16 based on clinical, endoscopic, histopathologic, and radiographic studies (18); had blood samples drawn for measurement of IGF-1, IGFBP-3, and IL-6 on the same day as a height measurement; and had available subsequent final adult stature data. Patients who had received recombinant human growth hormone therapy were excluded. We retrospectively collected demographic and clinical information relevant to IBD from medical records, including age, sex, age at IBD diagnosis, disease location, pharmacological treatment, nutritional supplementation, and history of IBD-related surgery. We also collected height measurements obtained from a wall-mounted Holtain stadiometer in the gastroenterology and nutrition clinic at BCH. Heights were converted to standard deviation scores (z scores) using the National Center for Health Statistics reference values. For those who were >20 years of age at the time of adult height measurement, heights were converted to z scores calculated for sex-matched individuals who were 20 years of age.
Growth impairment was defined as the HAZ <−1.64 (equivalent to <5th percentile on the growth curve) at the time of blood draw (19,20). Patients were divided into the following 3 growth categories:
1. No growth impairment (HAZ ≥ −1.64 both at the time of initial height measurement/blood draw and adult height measurement)
2. Temporary growth impairment (HAZ <−1.64 at the time of initial height measurement/blood draw, but HAZ ≥ −1.64 at the time of adult height measurement)
3. Permanent growth impairment (HAZ < −1.64 both at the time of initial height measurement/blood draw and adult height measurement).
When available, we recorded albumin, ESR, and CRP from the time of initial height measurement/blood draw, as well as the Pediatric Crohn's Disease Activity Index (21) and Pediatric Ulcerative Colitis Activity Index (22) scores. The Committee on Clinical Investigation (CCI) at Boston Children's Hospital approved the study protocol.
Serum samples obtained at the time of initial study visit were frozen within 30 minutes of the collection and stored at −80°C until analysis. The IGF-1 level was determined using the enzyme-linked immunosorbent assay kit by Immunodiagnostic Systems (Fountain Hills, AZ). Upon request, Immunodiagnostic Systems provided age, sex, and IGF-1 levels of control patients they used to calculate the age-stratified normal reference ranges. Based on calculated means and standard deviations within each sex and age group, we computed the median IGF-1 level and the IGF-1-for-age z score. The IGFBP-3 level was determined using the automated chemiluminescent assay system by IMMULITE, Diagnostic Products Corp (Los Angeles, CA). We used the published age-stratified reference ranges for IGFBP-3 (23).
IGF-1 in patients with IBD was compared with reference ranges for control patients in the form of z scores, stratified by sex and categorical age (9–11, 12–14, and 15–19 years). The paired difference of IGF-1 obtained at the initial study visit and the median reference value was evaluated with a signed-rank test. A Kruskal-Wallis test was used for the Pediatric Ulcerative Colitis Activity Index score and CRP, for which the sample size was smaller because of missing data (<25 patients). Highly skewed continuous variables were normalized by transforming the data using Blom normal scores (24). Between-group comparisons among 3 or more groups were made only if the omnibus F test was significant (P < 0.05), where the P values were adjusted for multiple comparisons using the Bonferroni method. All of the tests were 2-sided with significance level P < 0.05. The data analysis was performed with SAS/STAT software, version 9.2 of the SAS System for Windows (SAS Institute, Cary, NC).
Growth Impairment Status of Study Patients
At the time of initial study visit, 20 (37%) patients were determined to have growth impairment (HAZ < −1.64). By adulthood (mean age 21.3 ± 2.0), 11 (20%) patients were no longer growth impaired (adult HAZ ≥ −1.64), whereas 9 (17%) patients remained permanently stunted (adult HAZ < −1.64, Fig. 1). Patients who did not present with growth impairment at the initial visit did not subsequently develop growth impairment as they aged.
Demographic and Clinical Characteristics Based on Growth Impairment Status
Table 1 summarizes demographic and clinical characteristics at the time of initial visit, stratified by the growth impairment status at adulthood. The majority of patients were boys (67%) and had their first study visit at 16 ± 2 years. There was no substantial difference among the 3 groups with regard to ages at the initial study visit or at the adult study visit. Although HAZ were similar between patients with temporary and permanent growth impairment during the initial study visit (−2.07 ± 0.46 and −2.30 ± 0.67, respectively; P = 1.00), they were significantly different during the adult study visit (−0.94 ± 0.73 and −2.46 ± 0.57, respectively; P = 0.0003).
Patients were diagnosed at similar ages (mean age of 13 ± 3 years), and did not have substantial difference in disease duration at the time of initial study visit. There were 45 and 9 patients with Crohn disease and ulcerative colitis, respectively; there was no notable difference in disease distribution among the groups. Although the median Pediatric Crohn's Disease Activity Index scores were different among the 3 groups, the difference in scores between temporary and permanent growth impairment was not significant.
Overall, markers of inflammation, such as ESR, CRP, and IL-6, trended higher in patients with temporary growth impairment compared with those with no or permanent growth impairment. The patients with temporary growth impairment also had lower serum albumin levels, weight-for-age z scores, and BMI z scores at initial study visit, suggesting undernutrition. There was no correlation between serum albumin and IGF-1 z scores (Spearman correlation coefficient 0.14, P = 0.35).
A higher proportion of patients with permanent growth impairment received corticosteroid therapy at the initial study visit compared with the patients with normal growth; however, the duration of treatment before the initial study visit was not statistically different across the growth impairment groups. Although some patients with no or temporary growth impairment were receiving biologic therapy, no patient in the permanently growth-impaired group was receiving biologic therapy at the time of initial study visit. A larger proportion of patients with temporary growth impairment received nutritional supplementation compared with the other 2 growth groups. A history of IBD-related surgery did not predict growth impairment status in adulthood.
IGF-1 and IGFBP-3 Based on Growth Impairment Status
IGF-1 levels of the patients with IBD were first compared with the reference population, then across the 3 growth groups. Figure 2 shows serum IGF-1 levels for each patient plotted against sex- and age-stratified reference values. In general, patients with IBD had lower IGF-1 levels than the median IGF-1 levels of the reference population. A majority of the patients (55%) with permanent or temporary growth impairment had IGF-1 levels that were below the minimum reference range, compared with 32% among patients with no growth impairment. This difference was not statistically significant, however.
Although numerical median values of IGF-1 and IGF-1-for-age z scores were consistently lower in the permanently growth-impaired group compared with the temporarily growth-impaired and nongrowth-impaired groups (Table 2), we found no statistically significant differences among the groups. Despite lower levels of inflammatory markers and no obvious evidence to suggest acute nutritional deficit, the patients with permanent growth impairment had lower IGF-1-for-age z scores compared with those with the temporary growth impairment. We did not observe any association between IGF-1 level and type of IBD (data not shown). There was no substantial difference in IGFBP-3 or IGFBP-3-for-age z scores between the groups.
This pilot study demonstrated that children with IBD and permanent growth impairment have numerically lower IGF-1-for-age z scores at the initial growth assessment compared with those with temporary growth impairment. In fact, patients with temporary growth impairment had IGF-1-for-age z scores that were numerically similar to those without the evidence of growth impairment. Our results suggest that differences in IGF-1-for-age z scores may help distinguish the patients with IBD who are likely to have permanent growth impairment from those whose growth impairment is likely to be temporary.
The studies have emphasized the role of undernutrition in the suppression of IGF-1 production (10,16), and have noted associations between lower IGF-1 levels and inflammation and prolonged steroid therapy (14,25). Furthermore, serum levels of IGF-1 and its major carrier IGFBP-3 have been shown to be low in the patients with IBD and relapsing disease presenting with elevated serum levels of ESR, CRP, and IL-6 (13,15,17).
To our knowledge, this is the first study to compare differences in sex- and age-matched IGF-1 and IGFBP-3 z scores of patients with IBD with temporary and permanent growth impairment. Our data suggest that patients without growth impairment during the initial visit do not subsequently develop growth impairment, which is reassuring and consistent with a previous report (20). Although patients with temporary growth impairment demonstrated evidence of higher disease activity (based on elevated ESR, CRP, and IL-6 levels), undernutrition (based on lower weight-for-age z scores, BMI z scores, and serum albumin), and longer exposure to corticosteroids, all of which have been previously reported to be associated with lower IGF-1 levels, we did not observe a similar correlation in our cohort. In fact, the temporarily growth-impaired group had similar levels of IGF-1 and IGF-1-for-age z scores to the nongrowth-impaired counterparts with inactive disease. IGFBP-3-for-age z scores did not differ substantially among the 3 growth groups, reducing the likelihood that low levels of IGF-1 were caused by the low levels of its carriers. These findings suggest that inflammation, undernutrition, and corticosteroid exposure do not fully explain lower IGF-1 and IGFBP-3 levels seen in children with IBD and linear growth impairment.
One of the limitations of our study was its small size, similar to most published studies investigating IGF-1 levels in patients with IBD. Unlike most other studies, however, our study accounted for differences in IGF-1 levels by age and sex. Interpretation of these results without proper age- and sex-related reference data can be misleading (7). A larger study incorporating all pediatric age groups with detailed information on caloric intake, growth velocity, Tanner staging, and parental heights would better elucidate the differences in IGF-1 and IGFBP-3 levels in patients with IBD with temporary or permanent growth impairment.
The intent of this article is not to provide a specific direction regarding clinical care, but to point out an area of research that requires further attention. If IGF-1 levels continue to track in the low range in patients with IBD with impaired growth in the absence of active inflammation or nutritional deficit, clinicians should keep in mind that these patients may be at risk for permanent growth impairment. Although serum IGFBP-3 levels trended lower in patients with permanent growth impairment compared with those with temporary growth impairment, the sex- and age-matched z scores did not demonstrate the same trend.
In conclusion, lower serum levels of IGF-1 and IGFBP-3, in the absence of significant inflammation and malnutrition, may represent early signs of permanent stunting in children with IBD presenting with growth impairment. Furthermore, inflammation, undernutrition, and corticosteroid exposure do not seem to adequately explain lower IGF-1 and IGFBP-3 levels in growth-impaired children with IBD. A larger prospective study is needed to better elucidate the role of growth-related hormones in identifying patients at risk for permanent growth impairment.
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