Body height in paediatric inflammatory bowel diseases: A structural equation model analysis.

BACKGROUND: Linear growth restriction is a unique feature of paediatric inflammatory bowel diseases (IBD), and reduced insulin-like growth factor (IGF-1) is a major determinant of short stature. We aimed to assess factors influencing somatic height in children suffering from IBD. MATERIALS AND METHODS: This was a retrospective, cross-sectional study conducted after approval by Institutional authorities. Anthropometric data, disease-related factors, biochemical and clinical indices of inflammation and endocrine parameters were recorded and considered as explanatory covariates. A structural equation model analysis was utilized. Somatic height was the outcome of interest, and possible associations of explanatory covariates directly or through the mediation effect of IGF-1 were assessed. RESULTS: Systemic inflammation, as expressed by high-sensitivity intereukin-6 (IL-6), and nutritional status described by body mass index (BMI) were the pathways that significantly affected stature through the mediation effect of IGF-1. Cortisol showed a direct, positive and independent of IGF-1 association with height. CONCLUSIONS: Insulin-like growth factor-1 is a key player in the process that results in impaired linear growth. Malnutrition and systemic inflammation have a restrictive action on growth by reducing circulating IGF-1. The positive relation of serum cortisol to height could correspond to suppressed pituitary-adrenal axis due to long-term use of glucocorticoids.

The prevalence of Helicobacter pylori gastritis in newly diagnosed children with inflammatory bowel disease.

BACKGROUND: Recent studies have shown that patients with inflammatory bowel disease (IBD) are less likely to be infected with Helicobacter pylori compared with non-IBD patients. We aimed to study the prevalence of H. pylori-positive and H. pylori-negative gastritis in newly diagnosed children with IBD in comparison to those with non-IBD in Greece. MATERIALS AND METHODS: All children who underwent first esophagogastroduodenal endoscopy between 2002 and 2011 were retrospectively included. Four groups were studied: patients with Crohn's disease (CD), ulcerative colitis (UC), IBD unclassified (IBDU), and non-IBD individuals (non-IBD). Helicobacter pylori infection was defined by positive culture or by positive histology and CLO test. Those children with negative or not available culture and only one positive test (histology or CLO) were further evaluated by urea breath test, and the positives were also included in the infected group. RESULTS: We studied 159 patients with IBD (66 CD, 34 UC, and 59 IBDU) and 1209 patients in non-IBD individuals. Helicobacter pylori gastritis was less frequent in the IBD group (3.8% vs 13.2% in the control group, p < .001), whereas IBD patients were significantly older than non-IBD children (p < .001). Children with H. pylori-negative gastritis were 3.3 times more likely to belong in the IBD group compared with H. pylori-positive patients (p = .006). CONCLUSIONS: Occurrence of H. pylori gastritis is less frequent in children with IBD compared with controls. Our study confirms an inverse association between H. pylori and IBD. Future studies are needed to distinguish between a true protective role of H. pylori and a confounding effect due to previous antibiotic use in children with IBD.

Circulating leptin and adiponectin and their relation to glucose metabolism in children with Crohn's disease and ulcerative colitis.

BACKGROUND: Crohn's disease (CD) and ulcerative colitis (UC) result in metabolic consequences. We assessed circulating leptin and adiponectin concentrations and examined their relations to glucose metabolism in children with CD and UC. METHODS: Circulating morning fasting concentrations of leptin, adiponectin, glucose, and insulin were measured in 32 children with CD and 18 children with UC. Insulin resistance (IR) and ß-cell function were evaluated by the updated homeostatic model assessments (HOMA2-IR and HOMA2-B). RESULTS: Leptin was positively related to BMI z-scores overall and in the CD and the UC subgroups (P < 0.001). A negative correlation between leptin and disease activity was observed in the entire population (P = 0.034) and in the UC (P = 0.03) group. None of the assessed parameters was related to adiponectin. Fourteen percent of the participants were insulin resistant (15.6% in the CD group and 11.1% in the UC group), significantly more than expected (P < 0.001). Leptin was associated with HOMA2-IR (overall: r = 0.29, P = 0.045). Pathway analysis suggested that, overall, disease activity and BMI significantly affect leptin, which in turn is the only correlate of HOMA2-IR. CONCLUSION: Disease activity was significantly and inversely related to leptin in children with inflammatory bowel disease (IBD). A significant proportion of the patients had increased IR, which is positively related to circulating leptin.

Investigative MRI cholangiopancreatography for primary sclerosing cholangitis-type lesions in children with IBD.

OBJECTIVES: The aim of the study was to estimate the frequency of primary sclerosing cholangitis (PSC)-type lesions in children with inflammatory bowel disease (IBD) by means of magnetic resonance cholangiopancreatography (MRCP), and to investigate the association between a series of easily applicable data on the one hand and the presentation of such lesions at MRCP on the other hand. METHODS: Collected demographic, laboratory, and magnetic resonance enterography data from the records of 73 children with IBD were cross-sectionally related to the MRCP-based diagnosis. RESULTS: Around the time of MRCP, the distribution of IBD subtypes was 64.4%, 24.7%, and 11% for Crohn disease, indeterminate colitis, and ulcerative colitis, respectively. A total of 11 patients (15.1%) were identified with PSC-type lesions. Demographic and magnetic resonance enterography data were unrelated to the MRCP outcome. Biochemical abnormalities were of low prevalence (<50%) among patients with PSC. The abnormality prevalences of aspartate transaminase, alanine transaminase, and γ-glutamyl transferase were significantly higher in the PSC group, both at initial diagnosis of IBD and at the time of MRCP. Less-consistent results were documented for bilirubin and alkaline phosphatase, especially at initial diagnosis of IBD. CONCLUSIONS: The abnormality prevalences of aspartate transaminase, alanine transaminase, and γ-glutamyl transferase were significantly higher in the PSC group. Nevertheless, PSC-type lesions frequently occur in pediatric IBD, even if the biochemical profile is hardly indicative of this probability.

Acute gastrointestinal graft-versus-host disease in pediatric patients: serum albumin on day 5 from initiation of therapy correlates with nonrelapse mortality and overall survival.

The aim of the present study was to identify factors associated with the risk of development of gastrointestinal acute graft-versus-host disease (GI-aGVHD), as well as to evaluate the impact of various baseline parameters on response to treatment, nonrelapse mortality (NRM), and overall survival (OS) in pediatric patients with GI-aGVHD after allogeneic hematopoietic stem cell transplantation (allo-SCT). We retrospectively analyzed 300 pediatric patients who underwent allo-SCT from HLA-matched related or volunteer unrelated donors in our institution. GI tract involvement was observed in 46 out of 133 patients with aGVHD grade II-IV. Severe aGVHD (grade III-IV) was more frequently observed among patients with GI-aGVHD in comparison with patients without GI involvement (P < .001). Treatment with steroids resulted in durable responses in 22/46 patients; 14 additional patients responded to salvage therapy, whereas 10 were refractory to all treatments administered. Using Cox regression analysis, we observed that serum albumin level ≥ 3 mg/dL on day 5 after the initiation of therapy with steroids was statistically significantly associated with decreased hazard of NRM and improved OS (P = .021 and P = .026, respectively). In our study, serum albumin level, early (+ day 5) after the onset of steroids in patients with GI-aGVHD, was a predictor of treatment outcome. Prospective randomized trials need to be performed to verify the predictive significance of serum albumin and the need for early intensification of immunosuppressive treatment.

Stressful life events and psychosocial correlates of pediatric inflammatory bowel disease activity.

AIM: To investigate the association of psychiatric and psychosocial correlates with inflammatory bowel disease (IBD) activity in children and adolescents. METHODS: A total of 85 pediatric IBD patients (in remission or active state of the disease) and their parents completed a series of questionnaires and semi-structured interviews measuring life events, depression, anxiety, family dysfunction, and parent mental health. Differences between the remission and the IBD active group and the association of any significant variable with the disease activity state were examined. RESULTS: Parents of children being in active state of the disease reported more life events (P = 0.005) and stressful life events (P = 0.048) during the past year and more mental health symptoms (P < 0.001), while the children themselves reported higher levels of anxiety symptoms (P = 0.017) compared to the remission group. In the logistic regression multivariate analysis, the only predictor which had a significant positive effect on the probability of the patients being in active state was parent mental health symptoms (OR = 4.8; 95%CI: 1.2-25.8). CONCLUSION: Life events, child anxiety and parent mental health symptoms may be important correlates of pediatric IBD activity and targets of thorough assessment and treatment.

Dental Caries and Periodontal Disease in Children and Adolescents with Inflammatory Bowel Disease: A Case-Control Study.

BACKGROUND: Previous reports have demonstrated a higher prevalence of dental caries and periodontal disease in adults with inflammatory bowel disease (IBD), but similar data in children and adolescents do not exist. The aim of the study was to evaluate the status of dental caries, oral hygiene, gingival status and periodontal treatment needs of children with IBD. METHODS: In this case-control study, 55 children on remission from a single outpatient IBD clinic, aged 4 to 18 years (12.27 ± 3.67 yr) and 55 matched systemically healthy controls of a dental practice were assessed prospectively. The evaluation included medical history, dental questionnaire in both groups, and previous and current medical therapy of children with IBD. Additionally, the decayed, missing, and filled tooth (dmf-t or DMF-T), simplified gingival, plaque control record and community periodontal treatment needs indices were evaluated. RESULTS: Children with IBD compared with controls had a statistically significant (P < 0.001) higher dmf-t (2.95 versus 0.91) or DMF-T (5.81 versus 2.04) index and a higher gingival inflammation (simplified gingival, 40% versus 24%) although the respectively dental plaque index showed no significant difference (plaque control record, 42% versus 41%). Also, the community periodontal treatment needs was significantly higher compared with controls (P < 0.001); most of the patients with IBD needed treatment of gingivitis (47% versus 4%), and none of them had healthy periodontium (0% versus 69%). CONCLUSIONS: The results of this case-control study demonstrate a higher frequency of dental caries, more clinical signs of gingival inflammation, and increased periodontal treatment needs in children and adolescents with IBD despite similar oral hygiene status.

Pediatric inflammatory bowel disease in Greece: 30-years experience of a single center.

BACKGROUND: Significant advances have been made in the care of children with inflammatory bowel disease (IBD). We aimed to describe the trends during the last 3 decades in the clinical presentation, management, and outcome of pediatric IBD at a single center. METHODS: Medical records of children with IBD referred to a pediatric gastroenterology unit from January 1981 to December 2011 were reviewed retrospectively. RESULTS: A total of 483 children were diagnosed with IBD, with mean age at diagnosis of 9.6 years (range 6 months - 18 years). Ulcerative colitis (UC) was diagnosed in 267 (55.2%), Crohn's disease (CD) in 167 (34.5%), and IBD unclassified (IBDU) in 49 (10.1%). Children with UC and IBDU were younger than those with CD [mean age at diagnosis 9.2, 8.9, and 10.5 years respectively; P (UC vs. CD)<0.01 and P (IBDU vs. CD)=0.028]. Patients received 5-ASA (96.6%), steroids (77.0%), thiopurines (50.2%), biological agents (14%), and 10% underwent surgical intervention. The cohort was divided into three subgroups according to the date of diagnosis; Group A: 1981-1989, Group B: 1990-1999, and Group C: 2000-2011. During the last two decades a significant increase in CD (Group A 18.5%, Group B 23.8%, Group C 48.8%; P<0.01) compared with the first decade with parallel decrease in UC (Group A 79.6%, Group B 71.9%, Group C 33.2%; P<0.001) was observed. CONCLUSIONS: Most children received 5-ASA, steroids, and immunomodulators. Patients with UC and IBDU were younger than those with CD. A significant increase in CD with parallel decrease in UC during the last decade was found.

The value of focally enhanced gastritis in the diagnosis of pediatric inflammatory bowel diseases.

BACKGROUND AND AIMS: Focally enhanced gastritis (FEG) has been suggested as a diagnostic marker for patients with Crohn's disease. In this study we evaluated the prevalence of FEG in children with inflammatory bowel diseases (IBD) and assessed the ability of FEG to distinguish IBD from non-IBD patients. METHODS: A retrospective study of the children who underwent esophagogastroduodenal endoscopy (EGD) during 2004-2011 was performed, after excluding individuals with H. pylori infection and celiac disease. Two groups were studied: patients with IBD (IBD group, n=185) and non-IBD patients who underwent endoscopy of the upper gastrointestinal tract for various abdominal complaints (non-IBD group, n=684). Relation of FEG to age and gender was also assessed. RESULTS: FEG was found significantly more frequently among children with IBD (35.7% vs 3.4%, respectively, p<0.001). Children with FEG were 15.4 times more likely to have IBD than to belong in the non-IBD group. All types of IBD had significantly higher frequencies of FEG compared to non-IBD individuals (Crohn's disease: 54.1%, ulcerative colitis: 21.6%, IBD unclassified: 18.4%, all three comparisons with the non-IBD group: p-values<0.001). FEG positivity was more common in females compared to males with Crohn's disease and ulcerative colitis and in children younger than 2 years in the IBD-unspecified group. FEG achieved a sensitivity of 35.7% and specificity of 96.6% in distinguishing between IBD from non-IBD patients. CONCLUSIONS: FEG has significantly higher prevalence in children with IBD, particularly Crohn's disease and can be a valuable supporting finding in cases of indefinite diagnosis.

Thiopurine methyltransferase genotype and thiopurine S-methyltransferase activity in Greek children with inflammatory bowel disease.

BACKGROUND: Azathioprine (AZA) and 6-mercaptopurine (6MP) are used in the treatment of pediatric inflammatory bowel disease (IBD). Genetic variations in thiopurine S-methyltranfarase (TPMT) gene have been correlated with enzyme activity and with the occurrence of adverse events to AZA and 6MP. The aim of the present study was to examine the sensitivity and specificity of TPMT genotyping for TPMT enzymatic activity, reducing harm from thiopurine by pretesting, and the association of thiopurine toxicity with TPMT status in children with IBD. METHODS: TPMT red blood cell (RBC) activity was measured by using a radiochemical method and genotype was determined for the TPMT alleles *2, *3A, *3B and *3C in 108 thiopurinetreated pediatric IBD patients with a mean age of 11.3 years (range 3-16). RESULTS: Significant TPMT activity differences between wild-type and heterozygous and homozygous mutated subjects were observed. We divided TPMT activity into three categories according to frequency distribution: low (16.67%), intermediate (25.92%) and high (57.41%). The whole population included a total of 77.78% of homozygous wild-type subjects, 15.74% heterozygous variants, 1.85% homozygous variants and five (4.63%) compound heterozygous variant TPMT*3B/*3C. The overall concordance rate between TPMT genotypes and phenotypes was 88.2%. Seven carriers of at least one variant allele and low or intermediate TPMT activity developed adverse effects. CONCLUSIONS: Our findings suggest that carriers of at least one variant allele and both intermediate and absent TPMT activity have an increased risk of developing thiopurine-induced myelotoxicity compared with individuals with normal genotype and TPMT activity.

Association of TNF and FcγRΙΙΙA gene polymorphisms with differential response to infliximab in a Greek cohort of Crohn's disease patients.

BACKGROUND AND AIM: Infliximab (IFX) has revolutionized the treatment of patients with Crohn's disease (CD). However, a significant proportion of patients may fail to respond primarily or lose response over time. The genetic background of a particular individual may partially explain differences in responsiveness to anti-TNFα therapy. The aim of this study was to investigate whether polymorphisms in the promoter region of the TNF and FcγRΙΙΙA gene are associated with response to IFX in patients with CD. METHODS: We investigated the following single nucleotide polymorphisms in the promoter region of the TNF gene (-238 G/A, -308 G/A, and -857 C/T) and the -158 V/F polymorphism in the FcγRΙΙΙA gene in a cohort of 79 adults and 27 children, who were all Greek patients with CD. These polymorphisms were determined using PCR-RFLP or allele-specific PCR. RESULTS: Regarding the 106 patients included in the study, 68 (64.15%) were classified as complete and 25 (23.58%) as partial responders to IFX, while 13 (12.26%) patients were primary non responders. There were no significant differences in the frequencies of the various TNF and FcγRΙΙΙA genotypes among complete, partial responders or primary non responders. CONCLUSION: These results suggest that TNF and FcγRΙΙΙA genotypes did not affect the response to IFX in this cohort of Greek patients with CD.

NOD2/CARD15, ATG16L1 and IL23R gene polymorphisms and childhood-onset of Crohn's disease.

AIM: To assess whether the polymorphisms of NOD2/CARD15, autophagy-related 16-like 1 (ATG16L1), and interleukin-23 receptor (IL23R) genes play a more critical role in the susceptibility of childhood-onset than in adult-onset Crohn's disease (CD). METHODS: Polymorphisms R702W, G908R, and 3020insC of NOD2/CARD15; rs2241880 A/G of ATG16L1, and rs11209026 (R381Q) of IL23R gene were assessed in 110 childhood-onset CD, 364 adult-onset CD, and 539 healthy individuals. Analysis of polymorphisms R702W, G908R, and 3020insC of NOD2/CARD15 genotyping was performed by allele specific polymerase chain reaction (PCR) or by PCR-restriction fragment length polymorphism analysis. The polymorphisms rs2241880 A/G of the ATG16L1, and rs11209026 (R381Q) of the IL23R gene in the children's cohort were genotyped by PCR and melting curve analysis whereas adult group genotyping was performed using the Affymetrix Genome-Wide Human SNP Array 5.0 (500K). RESULTS: The 3020insC allele in NOD2/CARD15 was significantly higher in childhood than in adult-onset CD (P = 0.0067). Association with at least 1 NOD2/CARD15 variant was specific for ileal disease (with or without colonic involvement). Even if the frequency of G allele of the rs2241880 ATG16L1 polymorphism was increased in both paediatric and adult CD patients compared to controls (P = 0.017 and P = 0.001, respectively), no difference was observed between the childhood and the adult cohort. The rare Q allele of IL23R rs11209026 polymorphism was underrepresented in both paediatric and adult CD cases (P = 0.0018 and P = 0.04, respectively) and no difference was observed between the childhood and the adult cohort. The presence of the rs2241880 ATG16L1 and rs11209026 IL23R polymorphisms did not influence disease phenotype. CONCLUSION: Polymorphism 3020insC in NOD2/CARD15 occurs statistically significantly more often in patients with childhood-onset CD than in patients with adult-onset CD. The ATG16L1 and IL23R variants are associated with susceptibility to CD, but not early-onset disease.

Erythropoietin levels in children and adolescents with inflammatory bowel disease.

Iron deficiency anemia (IDA) and anemia of chronic disease (CDA) are often encountered in patients with inflammatory bowel disease (IBD). Inadequate intake or loss of iron is a clear cause of IDA, but mechanisms of CDA induction are multifactorial and involve erythropoiesis disturbance due to circulating inflammation mediators. The authors investigated erythropoietin (Epo) levels in children and adolescents with IBD and correlated them to disease activity, with the aim of gaining an improved understanding of the role of Epo in CDA. Thirty-three patients with IBD were examined (18 boys, 15 girls) ages 4 to 15 years (median 11 years). Two study groups related to the disease activity were formed: group A, those with active disease (n = 21), and group B, those in remission (n = 12). Epo levels were measured using a two-site chemiluminescence immunoassay. Predictive Epo values in response to the degree of anemia were calculated by the equation: logEpo = (3.48 - 0.20) x Hb. According to the results, CDA anemia was present only in patients with active disease. These patients also had a significantly higher possibility of altered Epo levels than expected compared with patients with inactive disease (16/21 vs. 4/12, P < 0.05). It was also interesting that most of the patients with anomalous Epo concentrations presented with an elevated Epo value compared with that expected from the calculation (14/20). It seems that disturbed Epo concentrations are correlated with disease activity in children and adolescents with IBD. It is possible that failure of the bone marrow to respond to increased Epo levels leads to further incremental response. These in turn lead to the high Epo concentrations detected in most of the authors' patients. Impaired Epo production is another mechanism of CDA development and is the one mainly expressed in patients with low Epo values.