Genetic susceptibility and genotype-phenotype association in 588 Danish children with inflammatory bowel disease.

AIM: To investigate the association between known inflammatory bowel disease (IBD)-associated genetic variants and development of paediatric IBD, and specific clinical sub-phenotypes. MATERIAL AND METHODS: In this case-control study we included IBD patients <18 years of age at diagnosis from the Danish National Patient Registry and healthy children <18 years of age were randomly selected from the Danish Central Office of Civil Registration. The latter had filled out a questionnaire regarding health status, and DNA was obtained from blood samples and the buccal mucosa. Patient files were retrieved and clinical information was extracted. DNA was obtained from Guthrie cards from the Danish National Neonatal Screening Biobank (PKU-biobanken) at Statens Serum Institut and from blood samples. RESULTS: A total of 588 IBD patients (244 Crohn's disease (CD), 318 ulcerative colitis (UC) and 26 IBD-unclassified (IBDU)) and 543 healthy controls were included. We found an association between CD and rs22411880 (ATG16L1, odds ratio (OR)=1.7 [1.1-1.7], p=0.003), rs5743289 (NOD2, OR=1.4 [1.1-1.9], p=0.009) and the paediatric specific rs1250550 (ZMIZ1, OR=0.7 [0.5-0.9], p=0.01). None of the investigated 41 SNPs were associated with disease localisation, medical treatment or surgery after correcting for multiple analyses. CONCLUSION: We found an association between CD and three previously published genetic variants and replicated the association with the paediatric specific ZMIZ1 gene. No Bonferroni corrected significant genotype-phenotype associations were found. For future studies aimed at finding predictors for disease course in (paediatric) IBD, it will be worthwhile to include a combination of genetic, clinical and serological markers.

Differences in phenotype and disease course in adult and paediatric inflammatory bowel disease--a population-based study.

BACKGROUND: Few studies have compared phenotype and disease course in children and adults with inflammatory bowel disease (IBD). AIM: To compare phenotype, treatment and disease course in children (<15 years) and adults (≥18 years) with IBD. METHODS: Two population-based cohorts comprising paediatric (2001-2006) and adult (2003-2004) patients from Copenhagen County and City were studied. RESULTS: Twenty children and 106 adults with ulcerative colitis (UC), and 29 children and 67 adults with Crohn's disease (CD) were included. Median follow-up time was 4.8 years (children) and 5.2 years (adults). Children with UC had more extensive disease compared to adult patients [14 (70%) vs. 20 (19%), P<0.001]. The risks of starting systemic steroid treatment and AZA/MP were higher for paediatric UC patients compared to adult UC patients; hazard ratio (HR): 3.1 (95% CI: 1.8-5.3) and HR: 2.5 (1.3-5-9), respectively. Steroid dependency was more frequent in paediatric than in adult UC patients [9 (45%) vs. 9 (8%), P<0.001]. Mild disease course was less frequent in children with UC compared to adult patients [7 (35%) vs. 76 (72%), P=0.002]. Paediatric and adult CD patients did not differ regarding treatment or disease course. Cumulative 5-year surgery rates for paediatric and adult patients were 5% and 9% for UC (N.S.) and 18% and 21% for CD (N.S.), respectively. CONCLUSIONS: Paediatric UC patients had more extensive disease, were more often treated with systemic steroids and AZA, had a higher frequency of steroid dependency and a more severe disease course compared to adult UC patients. No differences were found when comparing paediatric and adult CD patients.

Infliximab dependency in children with Crohn's disease.

BACKGROUND: Recently, infliximab dependency has been described. AIM: To assess frequency of ID in 82 consecutive Crohn's disease children treated with infliximab 2000-2006 and to describe clinical and genetic predictors of long-term infliximab response. METHODS: A phenotype model of infliximab dependency was used to assess treatment response: 'immediate outcome' (30 days after infliximab start)--complete/partial/no response. 'Long-term outcome': (i) prolonged response: maintenance of complete/partial response; (ii) infliximab dependency: relapse < or = 90 days after intended infliximab cessation requiring repeated infusions to regain complete/partial response or need of infliximab >12 months to sustain response. Polymorphisms TNF-308 A>G, TNF-857 C>T, Casp9 93 C>T, FasL-844 C>T, LTA 252 C>T and CARD15 (R702W, G908R, 1007fs) were analysed. RESULTS: Ninety-four per cent of children obtained complete/partial response. In long-term outcome, 22% maintained prolonged response, 12% had no response, while 66% became infliximab dependent. Perianal disease and no previous surgery were associated with infliximab dependency (OR 5.34, 95% CI: 1.24-22.55; OR 6.7, 95% CI: 1.67-26.61). No association was found with studied polymorphisms. The cumulative probability of surgery 50 months after starting infliximab was 10% in infliximab dependency, 30% in prolonged responders and 70% in nonresponders (P = 0.0002). CONCLUSIONS: Sixty-six per cent of children became infliximab dependent. Perianal disease and no surgery prior to infliximab were associated with infliximab dependency phenotype.

Granulocyte-monocyte adsorptive apheresis in pediatric inflammatory bowel disease: results, practical issues, safety, and future perspectives.

BACKGROUND: The purpose of the study was to collect data on granulocyte-monocyte adsorptive apheresis (GMA) for the treatment of corticosteroid-dependent (SD) or corticosteroid-resistant (SR) inflammatory bowel disease (IBD) in children from 3 Nordic countries to evaluate its efficacy and safety and to assess practical issues. METHODS: Retrospective data on 37 children treated with GMA were collected. In all, 22 children had ulcerative colitis (UC), 13 Crohn's disease (CD), and 2 had indeterminate colitis (IC). Their mean age was 13.2 years, range 5-17 years, and mean duration of disease was 2.4 years, range 1 month to 6 years. Indication for treatment in the UC group was SD in 11 cases, SR in 6 cases, and other reasons in 5 cases. The corresponding numbers in the CD group were SD in 8 cases, SR in 2 cases, and other reasons in 3 cases. In the IC group, 1 had SD and 1 was refractory to steroids, azathioprine, and infliximab. Efficacy was evaluated by severity indices: the Pediatric Ulcerative Colitis Activity Index (PUCAI) and the Pediatric Crohn's Disease Activity Index (PCDAI) and tapering of corticosteroids. RESULTS: PUCAI and PCDAI decreased significantly in both groups after 3 months (P = 0.0007, P = 0.025). The dosage of corticosteroid was significantly reduced in the UC group by the end of GMA (P = 0.004) and this response continued after 3 months. Relapse was seen in 2 patients with UC and 3 patients with CD after 3 months follow-up. CONCLUSIONS: GMA seems to be an effective and safe treatment in 81% of the SD or SR pediatric IBD patients, especially in those with UC.

Severe blue rubber bleb nevus syndrome in a neonate.

We report on a child with blue rubber bleb nevus syndrome (BRBNS) presenting during the first days of life with severe bleeding from the upper gastrointestinal tract. Medical treatment with methylprednisolone, cyklokapron, interferon 1 alpha and numerous blood transfusions were given to control bleeding during the first 3 years of life. Afterwards repeated endoscopic electrocoagulation were performed over a period of one year resulting in a termination of bleeding episodes. At ten years of age the patient developed spastic diplegia with slight walking disabilities, coordination and fine motor problems. The case is unique because 1) it is the first neonatal case with BRBNS and severe gastrointestinal bleeding; 2) the patient was successfully treated by endoscopic electrocoagulation; and 3) the long-term follow-up. The use of electrocoagulation appears to have been effective and ablation of the stomach could be avoided until now.

Response pattern recognition in paediatric Crohn's disease patients treated with enteral nutrition.

AIM: To describe the response pattern to enteral nutrition (EN) in paediatric patients with moderately to severely active Crohn's disease (CD). MATERIAL AND METHODS: A previously described method for assessment of response pattern to various treatments for CD was used. Patients who received EN during the 10-year period 1995-2005 were prospectively registered. Patient data, clinical outcome, time to relapse and subsequent need for treatment were extracted from the files. Four weeks treatment with polymeric ready-to-use liquid formula was given. The clinical outcome was assessed by pattern recognition of the disease course 30 days (immediate response) and 90 days (long-term response) after start of EN. RESULTS: Thirty-one patients (17/14 M/F), median age 14 years (range 7.5 -19.8 years), received 46 courses of EN. Thirty-seven courses (80%) were completed. Immediate response: twenty-five courses (67%) led to complete response (CR), 8 (22%) to partial response (PR) and in 4 courses (11%) no response (NR) was achieved. Long-term response: 21 courses (64%) led to prolonged response (PRO), defined as either maintenance of complete response (CR) or partial response (PR), while 12 courses (36%) were followed by loss of response (LR). The median time to relapse was 8.3 months (range 0.5-39 months). CONCLUSION: We found our model of response pattern to be a useful instrument for the description of results obtained during EN in children with CD.

Treatment of Helicobacter pylori in children with recurrent abdominal pain.

BACKGROUND: The role of Helicobacter pylori remains unclear in children with recurrent abdominal pain (RAP). In this study children with RAP were included in a double blind treatment study to elucidate whether symptoms disappear in children with a H. pylori infection and RAP, if the bacteria are eradicated. METHODS: Thirty-seven H. pylori-infected children aged 4.9-14.5 years (median 9.8 years) with RAP were included. H. pylori was identified by histology and culture. The children were treated with amoxicillin and metronidazole for 14 days. A re-endoscopy including biopsies for histology and culture was done at least one month after the end of treatment. Simple questions for symptoms were asked and blood for serology was repeated 3 and 6 months after the end of treatment. During the observation period the results of the re-endoscopy and the serology 3 and 6 months after the re-endoscopy were blinded for 23 patients and opened to 14 of the patients according to the choice of the families. RESULTS: The eradication rates were 81% (30/37) in the total group and 74% (17/23) in the blinded group. The IgG antibodies to H. pylori decreased significantly 3 (p =.03) as well as 6 months after end of treatment (p <.001) in children with successful eradication. The number of children with RAP decreased after examination and treatment and the well-being improved after 6 months in almost 95% of the children. However, no correlation was seen between eradication of H. pylori and disappearance of RAP, neither after 3 nor after 6 months' observation in the total group of patients (p =.94 and p =.90) or in the blinded group (p =.42 and p =.65). CONCLUSIONS: These results do not provide evidence for a causal relationship between RAP and H. pylori.

Different patterns of Helicobacter pylori adherence to gastric mucosa cells in children and adults. An ultrastructural study.

BACKGROUND: Infection with Helicobacter pylori in childhood may be the initiation of a lifelong coexistence between microorganisms and epithelial cells resulting in chronic inflammation. The adhesion pattern of H. pylori found in antral biopsies from a group of H. pylori-infected children with recurrent abdominal pain was compared with a group of H. pylori-infected adults suffering from dyspepsia, in an attempt to reveal differences in the type of adhesion. METHODS: The histology of antrum biopsies and the ultrastructure of adherent H. pylori in biopsies from 26 children (median age, 10.1 years) were compared with organisms in biopsies from 19 adults (median age, 54.4 years). RESULTS: More than 1000 adherent H. pylori were studied and divided into four types of adhesion: 1) contact to microvilli; 2) connection to the plasma membrane via filamentous material; 3) adhesive pedestal formation; and 4) abutting or making a depression in the plasma membrane. Contact to microvilli was significantly higher (69% versus 39%; P = 0.002) in children compared with adults and comprised two-thirds of all adherent organisms in children. The more intimate adhesion types as abutting or adhesive pedestals dominated in adults. CONCLUSIONS: These results indicate a change in contact types between H. pylori and gastric epithelial cells in adults compared with children and this may be a natural development in the lifelong infection of humans.

The prevalence and related symptomatology of Helicobacter pylori in children with recurrent abdominal pain.

The aim of the study was to assess and compare the IgG seroprevalence of H. pylori in children with recurrent abdominal pain with healthy children and to investigate the related symptoms. IgG antibodies against low-molecular weight H. pylori antigens were assessed in 438 children with recurrent abdominal pain and in 91 healthy controls. Sera with an ELISA unit-value above the cut-off level were confirmed by Western immunoblot. Only seropositive children with recurrent abdominal pain were examined by an oesophago-gastro-duodenoscopy. Symptomatology was recorded according to the localization of the abdominal pain, presence of pyrosis, nocturnal pain, relation of pain to meals and bowel irregularities. The seroprevalence was 21% (95% CI: 17-25%) in the children with recurrent abdominal pain and 10% (95% CI: 5-18%) in the healthy controls (p = 0.30). In seropositive children with RAP H. pylori was found in 46/66 by culture and histology. The presence of H. pylori was significantly associated with active or inactive chronic gastritis. The presence of H. pylori was associated with both parents being born in a country with a high prevalence and a low social class. Helicobacter pylori-positive children had more often pain related to meals than the H. pylori-negative children. No differences among the two groups were seen according to the levels of haemoglobin, leucocytes, thrombocytes, weight and height. In conclusion, the seroprevalence of H. pylori is comparable in children with recurrent abdominal pain and healthy children. No specific symptomatology was seen in H. pylori-positive children with RAP.

Abdominal ultrasonography in the diagnostic work-up in children with recurrent abdominal pain.

UNLABELLED: We report on our experience with routine abdominal ultrasonography in 120 children (aged 3-15 years) with recurrent abdominal pain, in order to determine the diagnostic value of this investigation. Eight children (7%) revealed sonographic abnormalities: gallbladder stone (n = 2), splenomegaly (n = 1) and urogenital abnormalities (n = 5). The recurrent abdominal pain could be explained by these findings in only two (may be three) cases. CONCLUSION: The diagnostic value of abdominal ultrasonography in unselected children with recurrent abdominal pain is low. However, the direct visualization of the abdominal structures as being normal may be helpful to the parents and the child in their understanding and acceptance of the benign nature of recurrent abdominal pain.

Helicobacter pylori infection in children with recurrent abdominal pain.

Helicobacter pylori was cultured and Helicobacter-like organisms (HLO) were seen in 6 (16%) of 37 children with recurrent abdominal pain. Five children had concomitant histological inflammation, but none had endoscopic changes. All 6 children demonstrated positive serology. Compared with the total group, they were more often from developing countries, larger families and lower social groups. Treatment with phenoxymethyl penicillin and colloidal bismuth subcitrate did not result in side effects or elevated serum levels of serum bismuth. Three children demonstrated metronidazole-resistant strains and the treatment of these children remained an unsolved problem. Among the 31 H. pylori/HLO negative children 8 (26%) demonstrated histological changes, 5 (16%) endoscopic changes and 11 (35%) had positive serology. In conclusion, pathological findings at upper gastrointestinal endoscopy are common in children with recurrent abdominal pain. Because of disconcordance between endoscopy, histology and culture, we recommend that biopsies should always be taken to clarify the diagnosis.

[Helicobacter pylori infection in children]. / Helicobacter pylori infektion hos børn.

Approximately 10 per cent of all schoolchildren have recurrent stomach pain, and 50 per cent of those referred to hospital for gastralgia can be expected to have persistent problems as adults. Some of these children might be helped by diagnosis and treatment. The lack of large controlled studies of the importance of H pylori in childhood needs to be remedied, with a view to diagnosis and treatment in the future.

Prevalence of hepatobiliary dysfunction in a regional group of patients with chronic inflammatory bowel disease.

A regional group of outpatients with chronic inflammatory bowel disease (ulcerative colitis, n = 396, and Crohn's disease, n = 125) was biochemically screened to estimate the prevalence of hepatobiliary dysfunction. Among the 396 patients with ulcerative colitis, 69 (17%; 95% confidence limits, 14-22%) had at least 1 abnormal laboratory value. Serum bilirubin was elevated in 5%, alkaline phosphatases in 8%, aspartate aminotransferases in 4%, and alanine aminotransferases in 8% of the patients. Two per cent had decreased plasma coagulation factors (2.7 and 10) and serum albumin. Further diagnositc evaluation consisting of ultrasonography, liver biopsy, and endoscopic retrograde cholangiography was performed in patients who had biochemical values more than twice the upper normal limit in two consecutive blood tests within a fortnight. Six patients (1%) fulfilled this criterion. Three patients had primary sclerosing cholangitis, of whom two were primarily diagnosed; one patient had cholangiocarcinoma also primarily diagnosed; and two patients were found to have alcoholic hepatic damage. Among the 125 patients with Crohn's disease, 38 (30%; 95% confidence limits, 23-38%) had at least 1 abnormal laboratory value. Serum bilirubin was elevated in 2%, alkaline phosphatases in 18%, asparetate aminotransferases in 3%, and alanine aminotransferases in 10% of the patients. One per cent had decreased plasma coagulation factors (2.7 and 10) and serum albumin concentrations. Three patients (2%) fulfilled the criteria for further evaluation as described above. One patient appeared to have epithelioid granuloma in the liver and one patient had alcoholic liver disease, whereas one patient refused further examination.(ABSTRACT TRUNCATED AT 250 WORDS)