Expression of GH/IGF-1 Axis Compounds in Moderate-Severe Crohn's Disease: Role of Mucosal Inflammation and Anti TNF-α Treatment

Abstract

AIM: Growth failure in children and adolescents, weight loss and catabolism in adults, are well known features of active Crohn's disease (CD). Increasing evidence shows that these features may be due to growth hormone (GH) resistance caused by persistent chronic inflammation. Aim of this study was to evaluate, in CD patients, a possible peripheral GHresistance (intestinal mucosa), and eventual modifications following anti TNF-α treatment. MATERIALS AND METHODS: 9 patients (5 F, median age 42.2 years, range 19-67) with moderate-severe active CD (CDAI>220), consecutively scheduled to receive three infliximab infusions at a dose of 5 mg/kg for induction of remission, were studied. Biopsy specimens from normal appearing duodenal mucosa were collected, in the 2 weeks prior to the first and after the third infusion. Confocal and real time PCR analysis of insulin-like growth factor 1 (IGF-1), activated signal transducer and activator of transcription protein 5 (phosphoSTAT5) and suppressor of cytokine signalling protein 3 (SOCS-3) were carried out and normalised to GAP, 18S and H3 referring genes. Four dyspeptic patients (2 F, median age 39 years, range 24-57), who underwent upper endoscopy with duodenal biopsy sampling, represented our control group. Differences between CD patients and controls were analysed by one-way ANOVA and REST-coupled ANOVA analysis. RESULTS: In CD patients, a significant inverse correlation was found when comparing phospho-STAT5 levels with CDAI (r=-0.71; p=0.003). Confocal analysis showed a significant decrease in phospho-STAT5 immunoreactivity in sections from CD patients, compared to controls (p<0.001). After treatment, phospho-STAT5 levels significantly increased (p<0.001). Molecular data for phospho-STAT5 were in keeping with biochemical findings. At baseline, compared with controls, in CD patients, the PCR analysis of IGF-1, showed a trend towards a decrease, while SOCS3 showed a trend towards an increase. Following treatment, SOCS-3 and IGF-1 target genes showed a trend toward a decrease and an increase, respectively. Nevertheless, following infliximab induction treatment, IGF-1, phospho-STAT5 and SOCS-3 levels did not reach those of the control group. CONCLUSION: The present study underline the effect of inflammation on the growth hormone axis not only at the level of hepatic metabolism, but also in the intestinal mucosa, since biologic agents able to inhibit pro-inflammatory cytokines, in particular TNF-α, the main inflammatory mediator, reverse growth hormone resistance. These therapeutic approaches could prevent the onset of those clinical conditions with a negative impact on child growth and quality of life of adults.