Clinical features affecting final adult height in patients with pediatric-onset Crohn's disease.

BACKGROUND: Growth failure is a recognized complication of pediatric-onset Crohn's disease, but there are few data on final adult height. OBJECTIVE: Our purpose with this work was to determine adult height and the clinical features that influence long-term growth impairment. METHODS: We retrospectively studied 123 patients with Crohn's disease (65 male and 58 female) who had reached adult height. All of the case subjects were diagnosed before age 16.0 years. Heights were converted to SD scores and univariate analysis performed of factors postulated to influence final height, that is, interval from onset of symptoms to diagnosis, prepubertal onset of symptoms, gender, jejunal disease present at diagnosis, systemic steroid therapy, intestinal surgery, and midparental height SD scores. Significant univariate factors were additional analyzed in regression models. RESULTS: Mean height deficit at diagnosis was -0.50 SD scores, which improved to -0.29 SD scores at final height. Mean final height compared with target height, calculated from parental height, was -2.4 cm (range: -20.0 to 9.0 cm). Nineteen percent of the case subjects achieved a final height >8.0 cm below target height. The length of the interval between symptom onset and diagnosis correlated negatively with height SD scores at diagnosis. Height SD scores at diagnosis were related to final height SD scores, independent of midparental height. The presence of jejunal disease was negatively related to final height. CONCLUSIONS: Mean final adult height showed a modest deficit compared with target height, but in one fifth of patients, final height was significantly less than target height. Earlier diagnosis and improved treatment of jejunal disease would be likely to improve final height.

Intestinal inflammation-induced growth retardation acts through IL-6 in rats and depends on the -174 IL-6 G/C polymorphism in children.

Inflammatory diseases frequently impair linear growth. Crohn's disease inhibits growth in up to one third of affected children. In rats with trinitrobenzenesulphonic acid-induced colitis, 40% of growth impairment is attributable to inflammation, with the rest being due to undernutrition. In transgenic mice without inflammation, raised IL-6 retards growth, suppressing insulin-like growth factor (IGF)-I. We hypothesized that IL-6, induced by intestinal inflammation, suppresses growth and inhibits IGF-I expression. Therefore, an anti-IL-6 Ab was given to rats with trinitrobenzene-sulphonic acid colitis. The Ab did not improve nutrient intake or decrease inflammation compared with untreated disease controls, but it significantly restored linear growth (P = 0.023) and increased IGF-I (P = 0.05). In humans, the IL-6 -174 G/C promoter polymorphism affects IL-6 transcription, with the GG genotype inducing the greatest IL-6 levels. Because IL-6 is increased in Crohn's disease, we further hypothesized that growth failure would vary with the IL-6 -174 genotype. At diagnosis, among 153 children with Crohn's disease, those with the IL-6 GG genotype were more growth-retarded than those with the GC or CC genotypes (height SD score, -0.51 vs. -0.10; P = 0.031). Also, the patients with the IL-6 GG genotype had higher circulating levels of C-reactive protein, an IL-6-induced product (36 vs. 18 mg/dl, P = 0.028). However, their risk of developing Crohn's disease was similar to other genotypes when compared with 351 healthy controls (P = 0.7). Thus, the IL-6 -174 genotype mediates growth failure in children with Crohn's disease.

Inhibition of tumour necrosis factor-alpha and interleukin 6 production by mononuclear cells following dietary fish-oil supplementation in healthy men and response to antioxidant co-supplementation.

Increased dietary consumption of the n-3 polyunsaturated fatty acids (PUFA) eicosapentaenoic acid (20 : 5n-3; EPA) and docosahexaenoic acid (22 : 6n-6; DHA) is associated with their incorporation into circulating phospholipid and increased production of lipid peroxide metabolites. The relationship between peripheral blood mononuclear cell (PBMC) function, n-3 PUFA intake and antioxidant co-supplementation is poorly defined. We therefore investigated tumour necrosis factor (TNF)-alpha and interleukin (IL) 6 production by PBMC and phospholipid fatty acid composition in plasma and erythrocytes of healthy male subjects (n 16) receiving supplemental intakes of 0.3, 1.0 and 2.0 g EPA+DHA/d, as consecutive 4-week courses. All subjects were randomised in a double-blind manner to receive a concurrent antioxidant supplement (200 microg Se, 3 mg Mn, 30 mg D-alpha-tocopheryl succinate, 90 mg ascorbic acid, 450 microg vitamin A (beta-carotene and retinol)) or placebo. There was a positive dose-dependent relationship between dietary n-3 PUFA intake and EPA and DHA incorporation into plasma phosphatidylcholine and erythrocyte phosphatidylethanolamine, with a tendency towards a plateau at higher levels of intake. Production of TNF-alpha and IL-6 by PBMC decreased with increasing n-3 PUFA intake but tended towards a 'U-shaped' dose response. Both responses appeared to be augmented by antioxidant co-supplementation at intermediate supplementary n-3 PUFA intakes. Thus, increased dietary n-3 PUFA consumption resulted in defined but contrasting patterns of modulation of phospholipid fatty acid composition and PBMC function, which were further influenced by antioxidant intake.

Prostaglandin E2 production and T cell function after fish-oil supplementation: response to antioxidant cosupplementation.

BACKGROUND: Prostaglandin E(2) (PGE(2)) inhibits lymphocyte proliferation and the production of interferon-gamma (IFN-gamma) by peripheral blood mononuclear cells, but the effect of PGE(2) on interleukin 4 (IL-4) production is unclear. Fish oil, which contains eicosapentaenoic and docosahexaenoic acids, inhibits production of PGE(2). The effects of fish oil on lymphocyte proliferation and production of IFN-gamma and IL-4 are unclear and may be influenced by the availability of antioxidants. OBJECTIVE: We investigated the effect of dietary fish oil with and without antioxidant cosupplementation on lymphocyte proliferation and the production of PGE(2), IFN-gamma, and IL-4 by peripheral blood mononuclear cells. DESIGN: Sixteen healthy men received dietary fish-oil supplements providing 0.3, 1, and 2 g eicosapentaenoic acid plus docosahexaenoic acid/d for 4 consecutive weeks each (total of 12 wk). All subjects were randomly assigned to daily cosupplementation with either antioxidants (200 microg Se, 3 mg Mn, 30 mg RRR-alpha-tocopheryl succinate, 90 mg ascorbic acid, 450 micro g vitamin A) or placebo. RESULTS: Fish-oil supplementation decreased PGE(2) production and increased IFN-gamma production and lymphocyte proliferation from baseline values. Cosupplementation with antioxidants did not affect cytokine production or lymphocyte proliferation. CONCLUSION: Dietary fish oil modulates production of IFN-gamma and lymphocyte proliferation in a manner consistent with decreased production of PGE(2), but this effect is not modified by antioxidant cosupplementation.

Delayed puberty associated with inflammatory bowel disease.

Delayed puberty frequently complicates the clinical course of young patients with inflammatory bowel disease, more often in Crohn's disease than ulcerative colitis. Undernutrition has been thought to be the main reason for delayed puberty in these patients. However, puberty may be delayed despite a normal nutritional status. Observations in patients with inflammatory bowel disease and in rats with experimental colitis suggest that inflammatory mediators may have a direct adverse influence, independent of undernutrition, on the onset and progression of puberty. Serum androgens are consistently reported to be reduced in patients with delayed puberty and inflammatory bowel disease. This reduction is not necessarily secondary to a reduction in gonadotrophins as serum concentrations of gonadotrophins have been reported to be normal or even increased in some studies. Management of delayed puberty involves calorie supplements to correct undernutrition and treatment of inflammation. Observations in boys with delayed puberty and controlled studies in experimental models of intestinal inflammation suggest that testosterone therapy can accelerate puberty.

Endothelin in human inflammatory bowel disease: comparison to rat trinitrobenzenesulphonic acid-induced colitis.

There have been suggestions that endothelins (ET-1, ET-2, ET-3) are involved in the pathogenesis of human inflammatory bowel disease (IBD). Furthermore, the non-selective endothelin receptor antagonist, bosentan, ameliorates colonic inflammation in TNBS colitis in rats. However, no studies have measured the tissue expression and release of endothelins in human IBD in direct comparison to experimental TNBS colitis. Mucosal biopsies were obtained from 114 patients (42 Crohn's colitis, 35 ulcerative colitis and 37 normal) and compared to whole colonic segments from rats with TNBS colitis. ET-1/2 levels were reduced in human IBD but greatly increased in experimental TNBS colitis. RT-PCR indicated ET-2 was the predominant endothelin isoform in human IBD whereas ET-1 prevailed in the TNBS model. No associations were found between human IBD and tissue expression, content or release of ET-1/2. Our study shows, therefore, that unlike TNBS colitis in rats, in which ET-1/2 levels are greatly elevated and ET receptor antagonists are efficacious, there is no significant link between endothelins and human IBD.

Anorexia in a rat model of colitis: interaction of interleukin-1 and hypothalamic serotonin.

BACKGROUND AND AIMS: Anorexia induced by experimental colitis in rats is mediated, in part, by increased release of serotonin (5-HT) from the hypothalamic paraventricular nucleus (PVN). In this model, anorexia is attenuated by treatment with an interleukin-1 (IL)-1 receptor antagonist (ra). However, a functional link between central IL-1 receptors and 5-HT release remains unproven. We have tested the hypothesis that anorexia associated with experimental colitis is mediated by IL-1 induced release of 5-HT. METHODS: In vivo 5-HT release in the PVN was measured in rats with 2,4,6-trinitrobenzenesulphonic acid (TNBS)-induced colitis, treated with intracerebroventricular infusion of IL-1ra or vehicle treated controls. The effect of inhibition of tumour necrosis factor-alpha on food intake and PVN 5-HT release in TNBS-colitis was also tested. RESULTS: In rats with TNBS-induced colitis, intracerebroventricular infusion of IL-1ra resulted in a 18-fold reduction in PVN 5-HT release compared to vehicle-treated controls. This was associated with a significant increase in food intake in IL-1ra treated rats. In contrast intracerebroventricular administration of anti-tumour necrosis factor antibodies had no effect on either PVN 5-HT release or food intake in rats with TNBS-induced colitis. CONCLUSIONS: In animals with TNBS-colitis, anorexia is mediated, in part, by the stimulatory effect of IL-1 on medial hypothalamic 5-HT.