GH Treatment for Growth Failure in Pediatric Patients with Crohn’s Disease
Heyman and colleagues studied the effects of growth hormone (GH) treatment (0.043 mg/kg/day; 0.3 mg/kg/week) on height velocity, body composition, and disease activity in a group of children and adolescents (mean age 12.6 ± 4.5 years; 6 males) with Crohn’s Disease (CD) and growth failure. All subjects had a confirmed endoscopic, histological, and/or radiographic diagnosis of CD and height below the 5th percentile for age with no evidence of catch-up growth (increase in height z-score of 0.5) for the year prior to GH therapy. Exclusion criteria included hepatic abnormalities, renal disease, history of non-compliance, and pre-existing scoliosis. Subjects were seen at baseline and every 3 months for 12 months for a history, physical assessment of anthropometric measurements, calculations of BMI and body fat mass, as well as laboratory studies to evaluate disease activity. Nutritional state, serum vitamin B12, iron levels, red blood cell, folate, plasma insulin-like growth factor (IGF)-I and IGF binding protein (IGFBP)-3 were measured at each visit and the CD activity was characterized using the Pediatric CD Activity Index (PCDAI). Bone age was determined by wrist radiography. Bone density and body composition were assessed using DEXA at the lumbar spine (L1 to L4) and hips. Age adjusted values were used for comparison and variation of z-scores. The comparison control group was gathered from the PEDI IBD Consortium Registry which included consecutively enrolled patients from 6 sites with inflammatory bowel disease; 989 children were identified as having CD. For each subject receiving GH, 3 comparison subjects with CD were retrospectively matched by age, sex, race, and height (at baseline). The patients in the control group were receiving standard treatment and nutritional supplementation for CD.
The study group had a mean bone age of 10.7 years with an average diagnosis of CD for 2.7 years, PCDAI of 21.9, a height z-score of –2.48, and a weight z-score of –1.88 with a previous year’s growth velocity of 2.8 cm/year. The control group had a similar age, and a mean height z-score of –1.8 with a mean weight z-score of –1.19. Each patient remained on his or her clinically indicated therapy for CD which included temporary total parenteral nutrition (TPN), elemental formula diet, or regular diet. All subjects consumed more than 85% of the RDA of calories for age. BMI did not increase significantly from baseline at 12 months, however DEXA scans at 1 year of GH treatment demonstrated an increase in mean lumbar z-scores and a decrease in mean percent body fat; the bone age increased by 0.97. IGF-I level increased from 249.4 ± 146.8 to 447.1 ± 242.6 at the end of treatment. Mean IGF-BP3 was within the range adjusted normal range. No significant changes in thyroid functions, or electrolytes were observed. Mean height velocity increased from 3 ± 1.39 cm/year at baseline to 8.32 ± 3.2 cm after 1 year of GH. Within the control group the mean height velocity was 3.98 ± 2.32 cm/year at baseline and 4.84 ± 2.85 cm/year after 1 year; this difference was significant. The height z-score increased by 0.76 and the weight z-score increased by 0.81 as compared with increases of 0.16 and 0 in the control group. The mean PCDAI was 21.9 at baseline and 13.1 after 1 year of treatment. No subject experienced any adverse reaction to GH. Two patients were excluded from the comparison, one of whom had a disease exacerbation requiring 2 hospitalizations during the 12 month study period and the other due to a lack of a matched comparison.
The authors stated that their data suggest that children with CD treated with GH experience increased height velocity and improved bone mineral density. There have been 10 other pediatric inflammatory bowel disease uncontrolled GH trials. Results from these studies have varied, but they have included small numbers of subjects and no disease controls. The authors noted that despite the increase in growth, there was no consistent clinical improvement in CD activity. Thus, it would appear that GH is not a primary treatment strategy for CD. They also noted the limitations of having used a retrospective comparison group and the small size of their study, which prohibited controlling for concomitant medications, including corticosteroids and other supplements. They concluded that a larger randomized trial of GH therapy in CD is needed.
The authors reported that growth impairment is seen in about 40% of pediatric patients with CD and that this often leads to short stature in adulthood. The possible etiology of this growth failure may include anorexia, inflammation, direct effects of cytokines on bone, GI nutrient losses, GH resistance with low IGF-I and other medications including corticosteroids. Of note, growth impairment may precede the onset of intestinal symptoms in CD.
Pediatric endocrinologists recognize the importance of looking for inflammatory bowel disease when evaluating children with short stature. Indeed CD is occasionally diagnosed during the evaluation for short stature prior to any GI symptoms. The authors clearly pointed out that other studies have shown variable results when GH is used to treat short stature and growth failure in CD and the limitations of those studies.
Studies of growth impairment in complex disease states such as CD may provide information on the importance of a variety of different disease processes associated with growth failure. In other words, are inflammatory processes critical or is the effect of cytokines on bones critical? Thus a study of a large number of individuals for whom assessments of these factors have been well characterized may lead to an important understanding of growth, not just in CD, but in other chronic disease processes.
William L. Clarke, MD