TGFß1 single-nucleotide polymorphism C-509T alters mucosal cell function in pediatric eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) is a chronic Th2 antigen-driven disorder associated with tissue remodeling. Inflammation and remodeling lead to esophageal rigidity, strictures, and dysphagia. TGFß1 drives esophageal remodeling including epithelial barrier dysfunction and subepithelial fibrosis. A functional SNP in the TGFß1 gene that increases its transcription (C-509T) is associated with elevated numbers of esophageal TGFß1-expressing cells. We utilized esophageal biopsies and fibroblasts from TT-genotype EoE children to understand if TGFß1 influenced fibroblast and epithelial cell function in vivo. Genotype TT EoE esophageal fibroblasts had higher baseline TGFß1, collagen1α1, periostin, and MMP2 (p < 0.05) gene expression and distinct contractile properties compared with CC genotype (n = 6 subjects per genotype). In vitro TGFß1 exposure caused greater induction of target gene expression in genotype CC fibroblasts (p < 0.05). Esophageal biopsies from TT-genotype subjects had significantly less epithelial membrane-bound E-cadherin (p < 0.01) and wider cluster distribution at nanometer resolution. TGFß1 treatment of stratified primary human esophageal epithelial cells and spheroids disrupted transepithelial resistance (p < 0.001) and E-cadherin localization (p < 0.0001). A TGFß1-receptor-I inhibitor improved TGFß1-mediated E-cadherin mislocalization. These data suggest that EoE severity can depend on genotypic differences that increase in vivo exposure to TGFß1. TGFß1 inhibition may be a useful therapy in subsets of EoE patients.

Enteric-coated cysteamine for the treatment of paediatric non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a common cause of liver disease in children. Hepatic fat accumulation and oxidative stress contribute to its pathogenesis. Cysteamine bitartrate readily traverses cellular membranes and is a potent antioxidant. AIM: To evaluate the safety and efficacy of enteric-coated (EC) cysteamine in children with NAFLD. METHOD: Children, aged ≥10 y, meeting screening criteria with biopsy-proven NAFLD and serum ALT ≥60 IU/L, received twice-daily EC-cysteamine for 24 weeks. Monthly ALT, AST, body mass index (BMI) and gastrointestinal symptom scores were measured. Subjects with >50% reduction or normalisation of ALT achieved the primary endpoint. RESULTS: Of the 13 children enrolled (mean age 14.0 years), 11 completed EC-cysteamine therapy (mean dose 15.2 mg/kg/day) and were included in the final analysis. For these 11 subjects, the mean ALT levels at baseline and 24 weeks were 120.2 and 55 IU/L respectively (P = 0.002), and the AST levels were 60 and 36 IU/L respectively (P = 0.007). The primary endpoint was reached in 7 and normalisation (≤40 IU/L) of ALT in 5. After 24 week therapy, mean adiponectin levels increased (P = 0.009) and CK-18 fragment levels decreased (P = 0.013), insulin levels remained unchanged (P = 0.99). Mean leptin levels were decreased in responders (P = 0.044). Mean BMI was 34.5 at baseline and 34.2 kg/m(2) after treatment (P = 0.35). Mean symptom scores at baseline (1.1) and at 24 weeks (0.7) were similar. No major adverse events were reported. CONCLUSIONS: Enteric-coated cysteamine reduces ALT and AST levels in children with NAFLD without reduction in body mass index. Further studies will evaluate optimal cysteamine therapeutic dose and effect on liver histology in NAFLD (Clinicaltrials.gov protocol ID: 07-1699).

Resolution of remodeling in eosinophilic esophagitis correlates with epithelial response to topical corticosteroids.

BACKGROUND: Esophageal remodeling occurs in eosinophilic esophagitis (EE) patients but whether the components of remodeling in the subepithelium are reversible by administration of topical oral corticosteroids is unknown. METHODS: We quantitated the degree of lamina propria remodeling in esophageal biopsies obtained before and after at least 3 months of therapy with budesonide in 16 pediatric EE subjects. In addition, we investigated whether corticosteroid therapy modulated vascular activation (expression of VCAM-1; level of interstitial edema), TGFbeta(1) activation (levels of TGFbeta(1), phosphorylated Smad2/3), and performed a pilot analysis of a polymorphism in the TGFbeta(1) promoter in relation to EE subjects who had reduced remodeling with budesonide therapy. RESULTS: EE subjects were stratified based on the presence (n = 9) or absence (n = 7) of decreased epithelial eosinophilia following budesonide. Patients with residual eosinophil counts of

Dysfunction of the longitudinal muscles of the oesophagus in eosinophilic oesophagitis.

BACKGROUND: Oesophageal motility, as measured by manometry, is normal in the majority of patients with eosinophilic oesophagitis (EO). However, manometry measures only the circular muscle function of the oesophagus. The goal of the present study was to assess circular and longitudinal muscle function during peristalsis in patients with EO. METHODS: Ultrasound imaging and manometry were simultaneously acquired during swallow-induced peristalsis in patients with EO and controls to measure the longitudinal muscle and circular muscle contraction, respectively. A probe with an ultrasound transducer was positioned 2 cm and then 10 cm above the lower oesophageal sphincter and five, 5 ml water swallows were recorded before and after edrophonium. RESULTS: There is no difference in the incidence of swallow-induced peristalsis and manometric pressures (a marker of circular muscle contraction) between controls and patients with EO. However, changes in the muscle thickness (a marker of longitudinal muscle contraction) are markedly diminished in patients with EO, at both 2 and 10 cm above the lower oesophageal sphincter. The longitudinal muscle response to edrophonium is markedly blunted in patients with EO. Normal subjects demonstrate synchrony between the circular and longitudinal muscle contraction during peristalsis that is affected by edrophonium. On the other hand, patients with EO demonstrate mild asynchrony of circular and longitudinal muscle contraction during swallow-induced contractions that is not altered by edrophonium. CONCLUSIONS: In patients with EO, there is selective dysfunction of the longitudinal muscle contraction during peristalsis. It is proposed that the longitudinal muscle dysfunction in EO may contribute to dysphagia.

Peptic ulcer disease in children.

A peptic ulcer in a child looks the same as it does in an adult, and many of the aetiologies of peptic ulcer disease in children are similar to those in adults. However, there are many differences between children and adults, especially in the areas of clinical presentation, the prevalences of different types of ulcer disease, and the prevalence of complications of ulcer disease. Therefore the approach to diagnosis and management in children is often at variance with that in adults. One important example is the approach to suspected Helicobacter pylori (H. pylori) disease in children, in which consensus groups have advised a considerably different approach in children. While the chapter deals with the full range of peptic ulcer disease in children, the focus is on those aspects in which there are differences between adults and children.

Spectrum of gastritis in celiac disease in childhood.

Celiac disease (CD) may cause changes throughout the gastrointestinal tract. The pathology is best described in the distal duodenum and jejunum. It is also associated with lymphocytic gastritis (LG) and varioliform gastritis in adults and children, but the histologic spectrum in the gastric biopsy and the clinical implications are undefined. In this report we relate our experience with the clinical, endoscopic, and histologic changes in gastric biopsies in CD in childhood. Slides (hematoxylin and eosin stained) were reviewed from 33 celiac children, 5 having had more than 1 gastric biopsy during a 7-year period. Gastric intraepithelial lymphocyte (IEL) counts were compared with those of 10 histologically normal controls (normal range, 1-7 IEL/100 antral or body epithelial cells) and 10 nonceliac chronic gastritis (CG) biopsies without H. pylori (normal range, 1-19 IEL/100 antral cells), noting changes in the epithelium and lamina propria (LP). LG was present in 29/33 initial biopsy sets. Fifteen of 29 showed LG/CG. The IEL number was greater in LG/CG than in LG only (27.2 +/- 9.3, n = 14 vs. 18.6 +/- 13.4, n = 15 in the antrum; 23.5 +/- 2.8, n = 4 vs. 13.0 +/- 8.4 in the body). In CD the difference between these mean values and those of normal and nonceliac CG controls was statistically significant. In CG/LG the inflammatory infiltrate was predominantly diffuse/superficial in the LP; mucin depletion was noted in 11/15. The IELs were in the LG/CG range in two CG controls. The IELs were normal at follow-up in five cases. There were no statistically significant differences between the groups with respect to clinical parameters or gastric endoscopic findings. No child had varioliform gastritis. We conclude that in CD children, the stomach is endoscopically unremarkable but may show LG, or LG/CG with or without mucin depletion, or occasionally appear normal. Gastric histology returned to normal with gluten withdrawal. Normal gastric histology is not typical, but does not exclude CD.

Esophageal stenosis in children.

This article focuses on the special features of esophageal stenosis which pertain to children. In order to focus on stenoses intrinsic to the esophagus, esophageal stenosis due to extrinsic compression is excluded. While the causes of esophageal stenosis may be grouped as either congenital or acquired, congenital causes account for less than 5% of cases.

Recombinant human erythropoietin for treatment of anemia of chronic disease in children with Crohn's disease.

We evaluated the efficacy and safety of and compliance with rH-EPO (150 U/kg three times a week subcutaneously for up to 12 weeks) for treatment of anemia in childhood Crohn's disease (n = 4). The mean hemoglobin level before rH-EPO therapy was 109 gm/L (10.9 gm/dl) (range, 103 to 115 gm/L). The mean hemoglobin level in the three compliant children increased to 138 gm/L (13.8 gm/dl) after treatment. Response time for the correction of anemia ranged from 6 to 12 weeks (mean, 9.5 weeks). Resolution of symptoms of lethargy, poor appetite, and irritability occurred with correction of the anemia. The only adverse effect observed was transient local pain at the injection site.

Effective 2-wk therapy for Helicobacter pylori disease in children.

UNLABELLED: Successful eradication of Helicobacter pylori infection in children has required long treatment regimens that may result in noncompliance with failure to eradicate this organism. Despite full compliance with shorter therapeutic regimens, such as amoxycillin and omeprazole for 2 wk, the H. pylori eradication rate is poor in children. OBJECTIVES: The aim of this study was to evaluate the efficacy of, and compliance with, a 2-wk treatment with metronidazole, omeprazole, and clarithromycin in eradicating H. pylori disease in children. METHODS: Over a 15-month period, children diagnosed to be H. pylori positive by Steiner's stain of gastric antral biopsy specimens were treated with metronidazole, omeprazole, and clarithromycin. Follow-up upper GI endoscopy was performed 6-8 wk after completion of therapy. RESULTS: Of 15 patients with H. pylori-positive antral gastritis, 11 had duodenal ulcer disease; three patients with severe abdominal pain and one with vomiting had H. pylori gastritis only. H. pylori eradication was seen in 11 of 11 (100%) patients with duodenal ulcer disease and in three of four (75%) with gastritis only; the overall success rate was 93%. Duodenal ulcer disease healed when H. pylori was eradicated in all but one patient, who at presentation had a penetrating ulcer with a duodenobiliary fistula. Fourteen of 15 patients (93%) were fully compliant, and no adverse reactions were reported. CONCLUSIONS: Two weeks of therapy with metronidazole, omeprazole, and clarithromycin is effective H. pylori therapy in children. It is well tolerated, and full compliance can be achieved.

Constipation and reversible urinary tract abnormalities.

Urinary tract anomalies were prospectively investigated with ultrasound in 29 children with functional constipation. These children were compared before and after treatment with 451 age matched healthy controls without constipation. The bladder residue and upper renal tract dilatation after micturition were significantly increased in the group with constipation and improved after treatment.