BACKGROUND:Adalimumab is efficacious therapy for adults with Crohn's disease (CD). AIM:To summarise the United Kingdom and Republic of Ireland paediatric adalimumab experience. METHODS:British Society of Paediatric Gastroenterology, Hepatology and Nutrition (BSPGHAN) members with Inflammatory Bowel Disease (IBD) patients <18 years old commencing adalimumab with at least 4 weeks follow-up. Patient demographics and details of treatment were then collected. Response and remission was assessed using the Paediatric Crohn's Disease Activity Index (PCDAI)/Physicians Global Assessment (PGA). RESULTS:Seventy-two patients [70 CD, 1 ulcerative colitis (UC), 1 IBD unclassified (IBDU)] from 19 paediatric-centres received adalimumab at a median age of 14.8 (IQR 3.1, range 6.1-17.8) years; 66/70 CD (94%) had previously received infliximab. A dose of 80 mg then 40 mg was used for induction in 41(59%) and 40 mg fortnightly for maintenance in 61 (90%). Remission rates were 24%, 58% and 41% at 1, 6 and 12 months, respectively. Overall 43 (61%) went into remission at some point, with 24 (35%) requiring escalation of therapy. Remission rates were higher in those on concomitant immunosuppression cf. those not on immunosuppression [34/46 (74%) vs. 9/24 (37%), respectively, (χ(2) 8.8, P=0.003)]. There were 15 adverse events (21%) including four (6%) serious adverse events with two sepsis related deaths in patients who were also on immunosuppression and home parenteral nutrition (3% mortality rate). CONCLUSIONS:Adalimumab is useful in treatment of refractory paediatric patients with a remission rate of 61%. This treatment benefit should be balanced against side effects, including in this study a 3% mortality rate.

OBJECTIVE:To systematically review the evidence base for the medical (pharmaceutical and nutritional) treatment of paediatric inflammatory bowel disease. METHODS:Key clinical questions were formulated regarding different treatment modalities used in the treatment of paediatric (not adult-onset) IBD, in particular the induction and maintenance of remission in Crohn disease and ulcerative colitis. Electronic searches were performed from January 1966 to December 2006, using the electronic search strategy of the Cochrane IBD group. Details of papers were entered on a dedicated database, reviewed in abstract form, and disseminated in full for appraisal. Clinical guidelines were appraised using the AGREE instrument and all other relevant papers were appraised using Scottish Intercollegiate Guidelines Network methodology, with evidence levels given to all papers. RESULTS:A total of 6285 papers were identified, of which 1255 involved children; these were entered on the database. After critical appraisal, only 103 publications met our criteria as evidence on medical treatment of paediatric IBD. We identified 3 clinical guidelines, 1 systematic review, and 16 randomised controlled trials; all were of variable quality, with none getting the highest methodological scores. CONCLUSIONS:This is the first comprehensive review of the evidence base for the treatment of paediatric IBD, highlighting the paucity of trials of high methodological quality. As a result, the development of clinical guidelines for managing children and young people with IBD must be consensus based, informed by the best-available evidence from the paediatric literature and high-quality data from the adult IBD literature, together with the clinical expertise and multidisciplinary experience of paediatric IBD experts.

BACKGROUND & AIMS:Trichohepatoenteric syndrome (THES) is an autosomal-recessive disorder characterized by life-threatening diarrhea in infancy, immunodeficiency, liver disease, trichorrhexis nodosa, facial dysmorphism, hypopigmentation, and cardiac defects. We attempted to characterize the phenotype and elucidate the molecular basis of THES. METHODS:Twelve patients with classic THES from 11 families had detailed phenotyping. Autozygosity mapping was undertaken in 8 patients from consanguineous families using 250,000 single nucleotide polymorphism arrays and linked regions evaluated using microsatellite markers. Linkage was confirmed to one region from which candidate genes were analyzed. The effect of mutations on protein production and/or localization in hepatocytes and intestinal epithelial cells from affected patients was characterized by immunohistochemistry. RESULTS:Previously unrecognized platelet abnormalities (reduced platelet alpha-granules, unusual stimulated alpha granule content release, abnormal lipid inclusions, abnormal platelet canalicular system, and reduced number of microtubules) were identified. The THES locus was mapped to 5q14.3-5q21.2. Sequencing of candidate genes showed mutations in TTC37, which encodes the uncharacterized tetratricopeptide repeat protein, thespin. Bioinformatic analysis suggested thespin to be involved in protein-protein interactions or chaperone. Preliminary studies of enterocyte brush-border ion transporter proteins (sodium hydrogen exchanger 2, sodium hydrogen exchanger 3, aquaporin 7, sodium iodide symporter, and hydrogen potassium adenosine triphosphatase [ATPase]) showed reduced expression or mislocalization in all THES patients with different profiles for each. In contrast the basolateral localization of Na/K ATPase was not altered. CONCLUSIONS:THES is caused by mutations in TTC37. TTC37 mutations have a multisystem effect, which may be owing to abnormal stability and/or intracellular localization of TTC37 target proteins.

Aims: The aims of this study were to describe the prevalence and clinical features of diabetes in hereditary haemochromatosis (HH), with particular emphasis to how this has changed since the introduction of genetic testing in 1996.Subjects and methods: Two hundred and thirty-seven patients were diagnosed with HH (based on elevated iron indices and liver biopsy or genetic testing) by a single physician, and all biochemical and clinical data recorded from diagnosis to the end of the study.Results: The prevalence of diabetes (21.9%) was lower than most previously published studies. There was a significantly greater prevalence of diabetes and cirrhosis in those diagnosed before the introduction of genetic testing, p < 0.001. The type of genetic mutation for HH, degree of ferritin elevation at diagnosis, or the presence of cirrhosis was not predictive for the development of diabetes. Iron depletion did not result in an improvement in glycaemic control or reduction in insulin requirements in the majority of patients.Conclusions: This is one of the largest published series of diabetes in HH. Because the occurrence of diabetes in patients with HH reduces life expectancy, our finding of a lower prevalence of diabetes is expected to translate into a greater survival rate in these patients. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

OBJECTIVE:Although azathioprine usually is reserved for inflammatory bowel disease that proves difficult to control, routine early use has recently been advocated for children with Crohn disease. However, this practice carries with it an increased risk of adverse reactions. The objective of this study was to look for characteristics at first presentation that may identify those likely to benefit from early azathioprine.PATIENTS AND METHODS:Study setting was a tertiary pediatric gastroenterology department. Retrospective cohort study of 156 children (93 Crohn disease, 47 ulcerative colitis, 16 indeterminate colitis), comparing characteristics at presentation in those who did and did not eventually require azathioprine. Azathioprine was reserved for patients with frequent relapses and steroid dependence/resistance. Twenty variables were examined, including patient and disease characteristics and initial treatment response. These were analysed using Kaplan-Meier survival curves, log-rank tests, and Cox proportional hazard regression.RESULTS:Median follow-up was 3.9 years (range 0.5-10.6 years). Azathioprine was used in 36% with Crohn disease and 40% with ulcerative colitis. Median time to commencing azathioprine was 14 months (range 3-77.5 months). Multifactorial analysis revealed an association with endoscopic colitis severity in Crohn disease (P < 0.02). However, only 50% with severe Crohn colitis actually needed azathioprine. There was an association with need for intravenous corticosteroids for induction of remission in Crohn disease (P < 0.006) and ulcerative colitis (P < 0.05). Of these patients, 75% required azathioprine.CONCLUSIONS:These findings support the early use of azathioprine in children who require intravenous corticosteroids to induce initial remission. No other characteristics examined were of clinical utility in predicting need for azathioprine.

We report a case of megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS), occurring in association with mydriasis, in a female infant born to consanguineous Asian parents. This association has not previously been reported and is of interest because mydriasis has been found in a murine MMIHS model produced by knockout of the genes coding for the alpha3 subunit or the beta2 and beta4 subunits of the neuronal nicotinic acetylcholine receptor. This may provide an important clue to the genetic basis of MMIHS in humans.

Background: Active Crohn's disease can be treated using liquid diet therapy (LDT), but non-adherence may limit success, necessitating corticosteroid therapy. Whole-protein polymeric formula (PF) seems to be much more palatable than amino acid-based elemental formula (EF) and thus may significantly improve adherence to LDT. Aim: To compare adherence to LDT using PF versus EF. Methods: Success in completing a 6-week course of LDT, need for nasogastric tube administration of formula and use of LDT for relapses were compared between children presenting with active disease and treated with EF (n = 53) and children given PF (n = 45). Results: Remission rates were similar (EF 64%, 95% CI 51 to 77 vs PF 51%, 95% CI 37 to 66; p>0.15). 72% (95% CI 60 to 84) given EF completed the initial course of LDT compared with 58% (95% CI 44 to 72) given PF (p = 0.15). Of those failing to complete the initial course, 13% on EF and 16% on PF gave up by choice (non-adherence), the remainder stopping due to treatment failure. Nasogastric administration was more frequent with EF (55%, 95% CI 42 to 68) compared to PF (31%, 95% CI 17 to 45) (p = 0.02). Among those treated successfully at first presentation, LDT was used for 28% of relapses in the EF group (95% CI 12 to 44) and 39% in the PF group (95% CI 19 to 59) (p>0.2) over the next year. Conclusion: PF did not effect adherence to LDT but was associated with significantly reduced need for nasogastric tube administration of formula.

BACKGROUND:Little data exist on immunosuppressive drug absorption in children with short bowel syndrome and intestinal failure associated liver disease (SBS-IFALD).AIM:To evaluate the absorption of immunosuppressive medications in children with SBS-IFALD undergoing isolated liver transplantation (iLTx).METHODS:A retrospective review was performed in children with SBS-IFALD undergoing LTx and comparison made with weight, age-matched children undergoing iLTX (extra-hepatic biliary atresia (EHBA) and normal intestinal length and function).RESULTS:Seven children with SBS-IFALD undergoing iLTx (median residual bowel length, 60 cm, range 40-80) were compared with 15 children undergoing LTx for EHBA. SBS-IFALD children had significantly lower trough tacrolimus levels at three months (5.8 vs. 7.9 ng/mL, p<0.05) and six months (5.0 vs. 8.0 ng/mL, p<0.05), but equivalent levels at 12 months after iLTx. The median calculated dose-normalized concentrations indicated that systemic availability of tacrolimus was comparable in two groups at 3, 6, 12 months (33.1 vs. 23.3; 42.4 vs. 36; 51 vs. 52.9) despite the differences in enteral function. The incidence of acute rejection was 1/7 (SBS-IFALD) and 10/15 (EHBA) group (p = 0.06).CONCLUSION:Children with SBS-IFALD demonstrated adequate absorption of oral tacrolimus without significant acute rejection rate after iLTx suggesting that modification of immunosuppression is not necessary.

BACKGROUND AND AIMS:Total enteral nutrition (TEN) with a liquid formula can suppress gut inflammation and induce remission in active Crohn's disease. The mechanism is obscure. Studies have suggested that long term nutritional supplementation with a liquid formula (partial enteral nutrition (PEN)) may also suppress inflammation and prevent relapse. The aim of this study was to compare PEN with conventional TEN in active Crohn's disease. PATIENTS AND METHODS:Fifty children with a paediatric Crohn's disease activity index (PCDAI)>20 were randomly assigned to receive 50% (PEN) or 100% (TEN) of their energy requirement as elemental formula for six weeks. The PEN group was encouraged to eat an unrestricted diet while those receiving TEN were not allowed to eat. The primary outcome was achievement of remission (PCDAI<10). Secondary analyses of changes in erythrocyte sedimentation rate (ESR), C reactive protein, albumin, and platelets were performed to look for evidence of anti-inflammatory effects. RESULTS:Remission rate with PEN was lower than with TEN (15% v 42%; p=0.035). Although PCDAI fell in both groups (p=0.001 for both), the reduction was greater with TEN (p=0.005). Moreover, the fall in PCDAI with PEN was due to symptomatic and nutritional benefits. With both treatments there were significant improvements in relation to abdominal pain, "sense of wellbeing", and nutritional status. However, only TEN led to a reduction in diarrhoea (p=0.02), an increase in haemoglobin and albumin, and a fall in platelets and ESR. CONCLUSIONS:TEN suppresses inflammation in active Crohn's disease but PEN does not. This suggests that long term nutritional supplementation, although beneficial to some patients, is unlikely to suppress inflammation and so prevent disease relapse.

ABSTRACT Enteropathogenic Escherichia coli (EPEC) strains deliver effector proteins Tir, EspB, Map, EspF, EspH, and EspG into host cells to induce brush border remodeling and produce attaching and effacing (A/E) lesions on small intestinal enterocytes. In this study, the role of individual EPEC effectors in brush border remodeling and A/E lesion formation was investigated with an in vitro human small intestinal organ culture model of EPEC infection and specific effector mutants. tir, map, espB, and espH mutants produced “footprint” phenotypes due to close bacterial adhesion but subsequent loss of bacteria; an espB mutant and other type III secretion system mutants induced a “noneffacing footprint” associated with intact brush border microvilli, whereas a tir mutant was able to efface microvilli resulting in an “effacing footprint”; map and espH mutants produced A/E lesions, but loss of bacteria resulted in a “pedestal footprint.” An espF mutant produced typical A/E lesions without associated microvillous elongation. An espG mutant was indistinguishable from the wild type. These observations indicate that Tir, Map, EspF, and EspH effectors play a role in brush border remodeling and production of mature A/E lesions.

AIMS:To determine the reliability of a panel of blood tests in screening for ulcerative colitis and Crohn's disease.METHODS:The subjects were 153 children referred to a paediatric gastroenterology department with possible inflammatory bowel disease (IBD). Of these, 103 were found to have IBD (Crohn's disease 60, ulcerative colitis 37, indeterminate colitis 6). The 50 without IBD formed the controls. Blood tests evaluated included haemoglobin, platelet count, ESR, CRP, and albumin. Receiver operating characteristic curves were used where possible to determine optimal threshold values. Binary logistic regression analysis was used to investigate the five screening tests in combination, and a stepwise method was used to find the best test combination.RESULTS:The optimal screening strategy used a combination of haemoglobin and platelet count and "1 of 2 abnormal" as the criterion for positivity. This was associated with a sensitivity of 90.8% (95% CI 83.3 to 95.7%), a specificity of 80.0% (95% CI 65.7 to 89.8%), and positive and negative predictive values of 94.4% and 75.9% respectively.CONCLUSIONS:Haemoglobin and platelet count provide a useful screening test combination for patients with suspected IBD. These tests are not completely reliable however. If clinical suspicion is high further investigations are required.

Gastro-oesophageal reflux is a common phenomenon in infancy, and medical intervention is usually unnecessary. If reflux causes illness, it is referred to as ‘gastro-oesophageal reflux disease’. Such patients require investigation and treatment. This review considers the epidemiology, aetiology, pathophysiology and clinical effects of gastro-oesophageal reflux disease. The role of various investigations and the choice of therapeutic strategy are discussed.

Objective To evaluate Tc-99m-HMPAO leukocyte scintigraphy as an investigation for inflammatory bowel disease (IBD).Study design Scintigraphy was performed in 95 children undergoing investigation for 11311 in a tertiary Gastroenterology Department. Diagnosis was based on conventional investigations including small bowel barium contrast radiology (BCR), upper gastrointestinal endoscopy (UGIE), colonoscopy, and endoscopic biopsy (the "gold standards"). IBD was confirmed-in 73 (57 Crohn's disease; 10 ulcerative colitis; 6 indeterminate colitis) and excluded in 22 (controls). Scintigraphy was (1) evaluated as a screening test, (2) compared with individual conventional tests, (3) assessed for each gut segment.Results Screening test: sensitivity 0.75 (95% CI, 0.63-0.85), specificity 0.82 (95% CI, 0.59-0.94), PPV 0.93, NPV 0.5. Comparison with BCR: sensitivity 0.87 (95% CI, 0.72-0.96), specificity 0.57 (95% CI, 0.39-0.73), PPV 0.69, NPV 0.2. Comparison with UGIE: specificity 0.9 (95% CI, 0.79-0.96), NPV 0.13 (sensitivity and PPV unavailable). Comparison with colonoscopy: sensitivity 0.57 (95% CI, 0.41-0.73), specificity 0.71 (95% CI, 0.54-0.85), PPV 0.71, NPV 0.42. Comparison with biopsies paralleled that with endoscopy. False negatives were especially common (NPV : 0.2) in the proximal gut.Conclusions Tc-99m-HMPAO leukocyte scintigraphy should not be relied on as a screening test for IBD because false egative results are common. This method is especially unreliable at detecting disease in the proximal gut.

Confirmation of the diagnosis of coeliac disease requires unequivocal evidence of recovery on a gluten‐free diet. The lactose H 2 breath test is a non‐invasive technique for detecting lactose malabsorption, and this may occur in untreated coeliac disease. The utility of this test was investigated in objectively confirming a response to gluten exclusion. The study included 44 children from 0.9 to 14.75 y of age (median 3.2) with coeliac disease. Five children were asymptomatic, being identified through coeliac antibody screening. Breath tests were performed prior to dietary treatment. If positive, they were repeated at 4‐wk intervals following gluten exclusion. Overall, 21/44 (48%) children had positive breath tests at presentation. In 18/21 children on a gluten‐free diet, this became negative after 4 wk (86%) and in all the children by 8 wk. In two children with positive tests at 4 wk, problems with dietary adherence were identified. A positive test before treatment was not associated with significant differences in individual symptoms, height, weight and body mass index standard deviation scores, serum haemoglobin or albumin. However, no positive results were found in the asymptomatic patients ( p = 0.05). Lactose malabsorption was associated with earlier age of presentation ( p = 0.008). Conclusion : The lactose H 2 breath test objectively confirms a response to gluten exclusion. In selected cases it can help confirm a diagnosis of coeliac disease. However, the test tends to be less informative in asymptomatic patients, and in older children.

BACKGROUND:Upper gastrointestinal endoscopic biopsies often show histologic abnormalities in Crohn disease. Consequently, it has been proposed that routine endoscopy could help to distinguish Crohn disease from ulcerative colitis. Surprisingly, however, recent case reports and an uncontrolled study suggested that similar abnormalities may occur in ulcerative colitis. Therefore, a blinded, controlled study was performed.METHODS:Esophageal, gastric antral, and duodenal biopsies from children with Crohn disease (n = 28) and ulcerative colitis (n = 14) were compared with those from controls undergoing endoscopy for suspected reflux esophagitis (n = 22). Two pathologists, unaware of patient identity and diagnosis, agreed on a consensus report. Severity of inflammation was scored semiquantitatively. Helicobacter pylori colonization was an exclusion criterion.RESULTS:Inflammation was reported as follows: esophagitis: controls 91%; Crohn disease: 72%; ulcerative colitis: 50%; gastritis: controls: 27%; Crohn disease: 92% (P < 0.001); ulcerative colitis: 69%; duodenitis: controls: 9%; Crohn disease: 33%; ulcerative colitis: 23%. In Crohn disease, granulomas were noted in 40% of patients (P = 0.001). Duodenal cryptitis was noted in 26% of patients with Crohn disease but not ulcerative colitis. In one patient with ulcerative colitis, neutrophilic infiltration of gastric glands was seen. Abnormalities seen in Crohn disease and ulcerative colitis included gastroduodenal ulceration (Crohn disease, 7%; ulcerative colitis, 8%), villus atrophy (Crohn disease, 11%; ulcerative colitis, 15%), and increased intraepithelial lymphocytes (Crohn disease, 15%; ulcerative colitis, 31% [P < 0.05]). None of these abnormalities was noted in the controls.CONCLUSION:Although the presence of granulomas can support a diagnosis of Crohn disease, severe inflammation and other abnormalities occur in the proximal gastrointestinal tract in Crohn disease and ulcerative colitis.

Short bowel syndrome is the most common cause of ‘intestinal failure’ in childhood. It usually follows extensive surgical resection of the small intestine. The most common causes include necrotizing enterocolitis, congenital atresias, gastroschisis and volvulus. Expert management of parenteral feeding is crucial. In the early post-operative phase, avoidance of fluid, electrolyte and mineral imbalances is important. Management of enteral feeding should be based on an understanding of the underlying pathophysiology, and should take account of the specific anatomic details in individual patients. ‘Intestinal adaptation’ eventually allows many children to recover and to dispense with parenteral nutrition. Enteral feeding is an essential factor in promoting the adaptive response. The management of short bowel syndrome is complex and should be undertaken by an experienced multi-disciplinary team.

OBJECTIVETo investigate the use of 99mTc-HMPAO (hexamethyl propylene amine oxime) leucocyte scintigraphy as a non-invasive screening test for inflammatory bowel disease.PATIENTS10 children with suspected Crohn's disease, in whom routine investigation using barium contrast radiology, upper gastrointestinal endoscopy, colonoscopy, and mucosal biopsies had identified severe gastroduodenal and/or jejunal involvement.DESIGN99mTc-HMPAO leucocyte scintigraphic studies performed in each of these cases were assessed by a radiologist who was blinded to the disease distribution.RESULTSIn nine cases there was no scintigraphic evidence of inflammation in the proximal gastrointestinal tract. The 10th child had both gastroduodenal and jejunal involvement, but scintigraphy only revealed faint jejunal positivity.CONCLUSIONS99mTc-HMPAO leucocyte scintigraphy should not be depended upon as a screening test for Crohn's disease. False negative results are likely in cases with Crohn's disease confined to the proximal gastrointestinal tract.

In the 1970s several reports highlighted the long delay in diagnosis often experienced by children with Crohn's disease. In recent years this disorder has attracted much publicity, and many believe that the incidence has increased substantially. The aim of this investigation was to determine whether heightened awareness had shortened the interval to diagnosis, improved clinical management and reduced morbidity. A retrospective study was therefore carried out on 112 children with inflammatory bowel disease (64 Crohn's disease, 41 ulcerative colitis, 7 indeterminate colitis) referred to a paediatric gastroenterology department in the UK between 1994 and 1998. In Crohn's disease the median interval to diagnosis was 47 wk (maximum 7 y). In those without diarrhoea this was longer (66 vs 28 wk; p = 0.005). In ulcerative colitis the median interval was 20 wk (maximum 3 y). Even in severe colitis the median interval was 5.5 wk (range 3-9 wk) and 4 required urgent colectomy soon after referral. Many with unrecognized Crohn's disease had undergone inappropriate treatments, such as growth hormone or psychiatric therapy. Nineteen (17%) had undergone endoscopic investigations in adult units prior to referral. Malnutrition was equally common in Crohn's disease and ulcerative colitis (11%). Short stature was present in 19% with Crohn's disease. and 5% with ulcerative colitis, and was severe in 8% with Crohn's disease. There was a significant correlation between symptom duration and the degree of growth impairment present (r(s) = -0.4: p = 0.004).Conclusion: This study suggests that late diagnosis and inappropriate investigation and management are still significant problems.

Failure to recognise secretory diarrhoea leads to inappropriate gastrointestinal investigations, delayed diagnosis of a vipoma, and avoidable morbidity