Marco Gasparetto

Phenotype and disease course of early-onset pediatric inflammatory bowel disease.

Background:Early-onset (EO) pediatric inflammatory bowel diseases (IBD) seem to be more extensive than those with a later onset. To test this hypothesis, we examined the phenotype and disease course of patients with IBD diagnosis at 0 to 5 years, compared with the ranges 6 to 11 and 12 to 18 years. Methods:Anatomic locations and behaviors were assessed according to Paris classification in 506 consecutive patients: 224 Crohns disease, 245 ulcerative colitis, and 37 IBD-unclassified. Results:Eleven percent of patients were in the range 0 to 5 years, 39% in 6 to 11 years, and 50% in 12 to 18 years. Ulcerative colitis was the most frequent diagnosis in EO-IBD and in 6- to 11-year-old group, whereas Crohns disease was predominant in older children. A classification as IBD-unclassified was more common in the range 0 to 5 years compared with the other groups (P < 0.005). EO Crohns disease showed a more frequent isolated colonic (P < 0.005) and upper gastrointestinal involvement than later-onset disease. Sixty-two percent of the patients in the 0 to 5 years range had pancolonic ulcerative colitis, compared with 38% of 6 to 11 years (P = 0.02) and 31% of 12–18 years (P = 0.002) range. No statistical difference for family history for IBD was found in the 3-year age groups. Therapies at the diagnosis were similar for all children. However, at latest follow-up, a significantly higher proportion of younger children were under steroids compared with older groups (P < 0.05). Surgical risk did not differ according to age. Conclusions:EO-IBD exhibits an extensive phenotype and benefit from aggressive treatment strategies, although surgical risk is similar to later-onset disease. A family history for IBD is not common in EO disease.

Inflammatory bowel disease developing in paediatric and adult age.

Background and Objective: In recent decades, there has been a significant increase in the incidence of inflammatory bowel disease (IBD). It has yet to be established whether the manifestations of IBD are similar in paediatric and adult ages. The objective of this study was to compare the phenotypic expression of the disease between patients with childhood-onset IBD and adulthood-onset cases, all afferent to the same clinical centre. Patients and Methods: Descriptive and multivariate analyses were completed on retrospective and prospective data of paediatric-onset and adult-onset consecutive cases who were diagnosed and followed at the same tertiary referral hospital of the University of Padua, Italy, during a period of 14 years (1994–2008). Paediatric-onset patients were further divided into age brackets (0–5, 6–12, and 13–17 year-olds). Analyses were conducted using the SAS package, version 9.1 (SAS Institute Inc, Cary, NC). Results: Three hundred twelve patients were analysed. At disease onset, the manifestations which were more frequent among the 133 paediatric patients (50.4% with diagnosis of Crohn disease [CD], 43.6% with ulcerative colitis, and 6% with unclassified IBD) with respect to the adult-onset patients were perianal disease (12.8%) (P < 0.0001) and extraintestinal manifestations (14.3%) (P = 0.043). Among the 179 adult patients (55.3% with diagnosis of ulcerative colitis, 36.3% with CD, and 8.3% with unclassified IBD) instead, severe abdominal pain (P = 0.008), diarrhoea (P = 0.005), and anorexia (P < 0.0001) were more frequently observed. During the follow-up, the presence of extraintestinal manifestations (50.4%) (P = 0.005) and perianal disease (44.8% of the patients with childhood-onset CD) (P = 0.006) was observed more often in the paediatric-onset group. Conclusions: In our cases, the phenotypic expression of IBD developing in paediatric age differs from that seen in adults.

Highlights in IBD Epidemiology and Its Natural History in the Paediatric Age

Background. The number of patients of all age brackets diagnosed with Inflammatory Bowel Disease (IBD) has risen dramatically worldwide over the past 50 years. IBDs changing epidemiology suggests that environmental factors play a major role in modifying disease expression. Aim. To review studies carried out worldwide analyzing IBD epidemiology. Methods. A Medline search indicating as keywords “Inflammatory Bowel Disease,” “epidemiology,” “natural history,” “Crohns Disease,” “Ulcerative Colitis,” and “IBD Unclassified” was performed. A selection of clinical cohort and systematic review studies that were carried out between 2002 and 2013 was reviewed. Studies referring to an earlier date were also considered whenever the data were relevant to our review. Results. The current mean prevalence of IBD in the total population of Western countries is estimated at 1/1,000. The highest prevalence and incidence rates of IBD worldwide are reported from Canada. Just as urbanization and socioeconomic development, the incidence of IBD is rising in China. Conclusions. Multicenter national registers and international networks can provide information on IBD epidemiology and lead to hypotheses about its causes and possible management strategies. The rising trend in the diseases incidence in developing nations suggests that its epidemiological evolution is linked to industrialization and modern Westernized lifestyles.

Phenotypic and genotypic characterisation of inflammatory bowel disease presenting before the age of 2 years

Objectives: Inflammatory bowel disease [IBD] presenting in early childhood is extremely rare. More recently, progress has been made to identify children with monogenic forms of IBD predominantly presenting very early in life. In this study, we describe the heterogeneous phenotypes and genotypes of patients with IBD presenting before the age of 2 years and establish phenotypic features associated with underlying monogenicity. Methods: Phenotype data of 62 children with disease onset before the age of 2 years presenting over the past 20 years were reviewed. Children without previously established genetic diagnosis were prospectively recruited for next-generation sequencing. Results: In all, 62 patients [55% male] were identified. The median disease onset was 3 months of age (interquartile range [IQR]: 1 to 11). Conventional IBD classification only applied to 15 patients with Crohn’s disease [CD]-like [24%] and three with ulcerative colitis [UC]-like [5%] phenotype; 44 patients [71%] were diagnosed with otherwise unclassifiable IBD. Patients frequently required parenteral nutrition [40%], extensive immunosuppression [31%], haematopoietic stem-cell transplantation [29%], and abdominal surgery [19%]. In 31% of patients, underlying monogenic diseases were established [EPCAM, IL10, IL10RA, IL10RB, FOXP3, LRBA, SKIV2L, TTC37, TTC7A]. Phenotypic features significantly more prevalent in monogenic IBD were: consanguinity, disease onset before the 6th month of life, stunting, extensive intestinal disease and histological evidence of epithelial abnormalities. Conclusions: IBD in children with disease onset before the age of 2 years is frequently unclassifiable into Crohn’s disease and ulcerative colitis, particularly treatment resistant, and can be indistinguishable from monogenic diseases with IBD-like phenotype.

Helicobacter pylori Eradication Therapy: Current Availabilities

Background. Though Helicobacter pylori (HP) infections have progressively declined throughout most of the industrialized countries, a gradual increase in failure of HP eradication treatments is observed. Aim. To critically review evidence on the efficacy of the therapeutic availabilities for HP eradication, as yet. Methods. A selection of Clinical Trials, Systematic Reviews and Meta-analyses within the time period 2010–2012, was performed through a Medline search. Previous references were included when basically supporting the first selection. Results. An increasing rise in HP resistance rates for antimicrobial agents is currently observed. Further causes of HP treatment failure include polymorphisms of the CYP 2C19, an increased body mass index (BMI), smoking, poor compliance and re-infections. Alternative recent approaches to standard triple therapy have been attempted to increase the eradication rate, including bismuth-containing quadruple therapy, non-bismuth containing quadruple therapy, sequential therapy and levofloxacin-containing regimens. Conclusions. The main current aims should be the maintenance of a high eradication rate (>85%) of HP and the prevention of any increase in antimicrobial resistance. In the next future, the perspective of a tailored therapy could optimize eradication regimens within the different countries.

New screening tests enrich anti-transglutaminase results and support a highly sensitive two-test based strategy for celiac disease diagnosis.

BACKGROUND The identification of specific serological algorithms allowing the diagnosis of celiac disease (CD) is a new challenge for both the clinic and the laboratory. We compared the diagnostic accuracy of three new tests proposed for CD screening with that of the well established IgA tTG, and ascertained whether any combination of these tools might enhance accuracy in diagnosing CD. METHODS In sera from 329 CD and 374 control children, the following were assayed: IgA tTG; IgA/IgG, which identify tTG-gliadin complexes (Aeskulisa Celi Check and CeliCheck IgGA); IgA/IgG, which identify deamidated gliadin peptides and tTG (QUANTA Lite(TM) h-tTG/DGP Screen). RESULTS When specificity was set at 100%, the most sensitive index of CD was IgA tTG (75.7%, cut-off=100U), followed by QUANTA Lite(TM) h-tTG/DGP Screen (65.3%, cut-off 145U), Aeskulisa Celi Check (62.6%, cut-off 909U/mL) and CeliCheck IgGA (59.6%, cut-off 977U/mL). Three algorithms were obtained by combining IgA tTG with each of the new tests. The algorithm obtained by measuring IgA tTG and QUANTA Lite(TM) h-tTG/DGP Screen allowed the correct identification of CD in 78.7% of cases (negative predictive value=97.3%). CONCLUSIONS The two-test based strategy could be used for the cost effective diagnosis of CD.

DNA Methylation and Transcription Patterns in Intestinal Epithelial Cells From Pediatric Patients With Inflammatory Bowel Diseases Differentiate Disease Subtypes and Associate With Outcome.

Background & Aims We analyzed DNA methylation patterns and transcriptomes of primary intestinal epithelial cells (IEC) of children newly diagnosed with inflammatory bowel diseases (IBD) to learn more about pathogenesis. Methods We obtained mucosal biopsies (N = 236) collected from terminal ileum and ascending and sigmoid colons of children (median age 13 years) newly diagnosed with IBD (43 with Crohn’s disease [CD], 23 with ulcerative colitis [UC]), and 30 children without IBD (controls). Patients were recruited and managed at a hospital in the United Kingdom from 2013 through 2016. We also obtained biopsies collected at later stages from a subset of patients. IECs were purified and analyzed for genome-wide DNA methylation patterns and gene expression profiles. Adjacent microbiota were isolated from biopsies and analyzed by 16S gene sequencing. We generated intestinal organoid cultures from a subset of samples and genome-wide DNA methylation analysis was performed. Results We found gut segment-specific differences in DNA methylation and transcription profiles of IECs from children with IBD vs controls; some were independent of mucosal inflammation. Changes in gut microbiota between IBD and control groups were not as large and were difficult to assess because of large amounts of intra-individual variation. Only IECs from patients with CD had changes in DNA methylation and transcription patterns in terminal ileum epithelium, compared with controls. Colon epithelium from patients with CD and from patients with ulcerative colitis had distinct changes in DNA methylation and transcription patterns, compared with controls. In IECs from patients with IBD, changes in DNA methylation, compared with controls, were stable over time and were partially retained in ex-vivo organoid cultures. Statistical analyses of epithelial cell profiles allowed us to distinguish children with CD or UC from controls; profiles correlated with disease outcome parameters, such as the requirement for treatment with biologic agents. Conclusions We identified specific changes in DNA methylation and transcriptome patterns in IECs from pediatric patients with IBD compared with controls. These data indicate that IECs undergo changes during IBD development and could be involved in pathogenesis. Further analyses of primary IECs from patients with IBD could improve our understanding of the large variations in disease progression and outcomes.

The multidisciplinary health care team in the management of stenosis in Crohn's disease

Background Stricture formation is a common complication of Crohn’s disease (CD), occurring in approximately one-third of all patients with this condition. Our aim was to summarize the available epidemiology data on strictures in patients with CD, to outline the principal evidence on diagnostic imaging, and to provide an overview of the current knowledge on treatment strategies, including surgical and endoscopic options. Overall, the unifying theme of this narrative review is the multidisciplinary approach in the clinical management of patients with stricturing CD. Methods A Medline search was performed, using “Inflammatory Bowel Disease”, “stricture”, “Crohn’s Disease”, “Ulcerative Colitis”, “endoscopic balloon dilatation” and “strictureplasty” as keywords. A selection of clinical cohort studies and systematic reviews were reviewed. Results Strictures in CD are described as either inflammatory or fibrotic. They can occur de novo, at sites of bowel anastomosis or in the ileal pouch. CD-related strictures generally show a poor response to medical therapies, and surgical bowel resection or surgical strictureplasty are often required. Over the last three decades, the potential role of endoscopic balloon dilatation has grown in importance, and nowadays this technique is a valid option, complementary to surgery. Conclusion Patients with stricturing CD require complex clinical management, which benefits from a multidisciplinary approach: gastroenterologists, pediatricians, radiologists, surgeons, specialist nurses, and dieticians are among the health care providers involved in supporting these patients throughout diagnosis, prevention of complications, and treatment.

Chemiluminescence and ELISA-based serum assays for diagnosing and monitoring celiac disease in children: A comparative study

BACKGROUND Anti-transglutaminase (tTG) or anti-deamidated gliadin peptides (DGP) serum determination is the first step in diagnosing celiac disease (CD). Our aims were to: compare the performance of novel chemiluminescent tool in the detection of tTG and DGP (Q-Flash®, Inova) with that of the established ELISA (Q-Lite®, Inova) methods; identify the more reliable index for making a sound diagnosis and monitoring therapy. METHODS Using Q-Flash® and Q-Lite®, IgA and IgG class tTG and DGP were measured in the sera of 155 CD pediatric patients and 166 healthy age-matched controls. Forty-two of the patients had a follow-up one year after starting gluten free diet (GFD). RESULTS Q-Flash® IgA tTG, the more accurate (intra-assay CV for low, intermediate and high values: 2.2%, 1.6%, and 1.1%; inter-assay CV: 2.8%, 4%, and 3%), sensitive (96.1%) and specific (97%) test for diagnosing CD, was the only variable to be significantly correlated with CD at binary logistic regression analysis (r=0.263, p<0.0001, Exp(B)=1.0506, 95% CI=1.0286-1.0731). Q-Flash® IgA tTG or DGP screen were more accurate than Q-Lite® IgA tTG in monitoring CD patients on GFD (p=0.003). CONCLUSION Q- Flash® IgA tTG measurement is an extremely precise, sensitive and specific index for not only diagnosing CD, but also monitoring therapy.

Clinical features and risk factors of autoimmune liver involvement in pediatric inflammatory bowel disease

Objectives: Autoimmune liver disease is reported in up to 7.8% of children with inflammatory bowel disease. A distinct inflammatory bowel disease phenotype has been suggested in adults and in small pediatric cohorts. The aim of the study was to evaluate the features of inflammatory bowel disease associated with autoimmune liver diseases and to analyze the characteristics of the liver disease. Methods: Information on patients was obtained from the Italian Pediatric Inflammatory Bowel Disease Registry. Data of patients with and without autoimmune liver disease were compared. Results: Autoimmune liver disease was detected in 6.8% of the 677 patients enrolled and was significantly associated with the diagnosis of ulcerative colitis (83%), with pancolonic involvement (84%), and with perinuclear antineutrophil cytoplasmic antibody positivity (41%) (all Ps < 0.05). Autoimmune liver disease was defined as sclerosing cholangitis in 61% of the patients and as an overlap syndrome in 33%. Concomitant intra- and extrahepatic biliary involvement was reported in 61% of cases, whereas exclusive extrahepatic lesions were reported in 21%. Hepatobiliary complications were observed in 9% of the patients during follow-up. Conclusions: Autoimmune liver disease, especially sclerosing cholangitis, was significantly more common in patients with extensive ulcerative colitis. Although complications are relatively rare in the pediatric age, monitoring is recommended.