Maralixibat in progressive familial intrahepatic cholestasis (MARCH-PFIC): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Progressive familial intrahepatic cholestasis (PFIC) is a group of autosomal recessive disorders, the most prevalent being BSEP deficiency, resulting in disrupted bile formation, cholestasis, and pruritus. Building on a previous phase 2 study, we aimed to evaluate the efficacy and safety of maralixibat-an ileal bile acid transporter inhibitor-in participants with all types of PFIC. METHODS: MARCH-PFIC was a multicentre, randomised, double-blind, placebo-controlled, phase 3 study conducted in 29 community and hospital centres across 16 countries in Europe, the Americas, and Asia. We recruited participants aged 1-17 years with PFIC with persistent pruritus (>6 months; average of ≥1·5 on morning Itch-Reported Outcome [Observer; ItchRO(Obs)] during the last 4 weeks of screening) and biochemical abnormalities or pathological evidence of progressive liver disease, or both. We defined three analysis cohorts. The BSEP (or primary) cohort included only those with biallelic, non-truncated BSEP deficiency without low or fluctuating serum bile acids or previous biliary surgery. The all-PFIC cohort combined the BSEP cohort with participants with biallelic FIC1, MDR3, TJP2, or MYO5B deficiencies without previous surgery but regardless of bile acids. The full cohort had no exclusions. Participants were randomly assigned (1:1) to receive oral maralixibat (starting dose 142·5 µg/kg, then escalated to 570 µg/kg) or placebo twice daily for 26 weeks. The primary endpoint was the mean change in average morning ItchRO(Obs) severity score between baseline and weeks 15-26 in the BSEP cohort. The key secondary efficacy endpoint was the mean change in total serum bile acids between baseline and the average of weeks 18, 22, and 26 in the BSEP cohort. Efficacy analyses were done in the intention-to-treat population (all those randomly assigned) and safety analyses were done in all participants who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, NCT03905330, and EudraCT, 2019-001211-22. FINDINGS: Between July 9, 2019, and March 4, 2022, 125 patients were screened, of whom 93 were randomly assigned to maralixibat (n=47; 14 in the BSEP cohort and 33 in the all-PFIC cohort) or placebo (n=46; 17 in the BSEP cohort and 31 in the all-PFIC cohort), received at least one dose of study drug, and were included in the intention-to-treat and safety populations. The median age was 3·0 years (IQR 2·0-7·0) and 51 (55%) of 93 participants were female and 42 (45%) were male. In the BSEP cohort, least-squares mean change from baseline in morning ItchRO(Obs) was -1·7 (95% CI -2·3 to -1·2) with maralixibat versus -0·6 (-1·1 to -0·1) with placebo, with a significant between-group difference of -1·1 (95% CI -1·8 to -0·3; p=0·0063). Least-squares mean change from baseline in total serum bile acids was -176 µmol/L (95% CI -257 to -94) for maralixibat versus 11 µmol/L (-58 to 80) for placebo, also representing a significant difference of -187 µmol/L (95% CI -293 to -80; p=0·0013). The most common adverse event was diarrhoea (27 [57%] of 47 patients on maralixibat vs nine [20%] of 46 patients on placebo; all mild or moderate and mostly transient). There were five (11%) participants with serious treatment-emergent adverse events in the maralixibat group versus three (7%) in the placebo group. No treatment-related deaths occurred. INTERPRETATION: Maralixibat improved pruritus and predictors of native liver survival in PFIC (eg, serum bile acids). Maralixibat represents a non-surgical, pharmacological option to interrupt the enterohepatic circulation and improve the standard of care in patients with PFIC. FUNDING: Mirum Pharmaceuticals.

Kinesin family member 12-related hepatopathy: A generally indolent disorder with elevated gamma-glutamyl-transferase activity.

Exome sequencing (ES) has identified biallelic kinesin family member 12 (KIF12) mutations as underlying neonatal cholestatic liver disease. We collected information on onset and progression of this entity. Among consecutively referred pediatric patients at our centers, diagnostic ES identified 4 patients with novel, biallelic KIF12 variants using the human GRCh38 reference sequence, as KIF12 remains incompletely annotated in the older reference sequence GRCh37. A review of these and of 21 reported patients with KIF12 variants found that presentation with elevated serum transaminase activity in the context of trivial respiratory infection, without clinical features of liver disease, was more common (n = 18) than manifest cholestatic disease progressing rapidly to liver transplantation (LT; n = 7). Onset of liver disease was at age <1 year in 15 patients; LT was more common in this group. Serum gamma-glutamyl transpeptidase activity (GGT) was elevated in all patients, and total bilirubin was elevated in 15 patients. Liver fibrosis or cirrhosis was present in 14 of 18 patients who were biopsied. The 16 different pathogenic variants and 11 different KIF12 genotypes found were not correlated with age of onset or progression to LT. Identification of biallelic pathogenic KIF12 variants distinguishes KIF12-related disease from other entities with elevated GGT.

Surgical versus Medical Management of Progressive Familial Intrahepatic Cholestasis-Case Compilation and Review of the Literature.

(1) Background: Progressive familial intrahepatic cholestasis (PFIC) is a rare cause of liver failure. Surgical biliary diversion (SBD) and ileal bile salt inhibitors (IBAT) can delay or prevent liver transplantation (LTX). A comparison of the two methodologies in the literature is lacking. The combination has not been investigated. (2) Methods: We performed a literature survey on medical and surgical treatments for PFIC and reviewed the charts of our patients with PFIC of a tertiary hospital. The end points of our analysis were a decrease in serum bile acid (sBA) levels, reduction of pruritus and delay or avoidance of (LTX). (3) Results: We included 17 case series on SBD with more than 5 patients and a total of 536 patients. External or internal SBD, either conventional or minimally invasive, can reduce pruritus and sBA, but not all PFIC types are suitable for SBD. Six publications described the use of two types of IBAT in PFIC with a total of 118 patients. Treatment response was dependent on genetic type and subtype. Patients with PFIC 2 (nt-BSEP) showed the best response to treatment. Four out of eleven PFIC patients underwent SBD at our centre, with two currently receiving IBAT. (4) Conclusions: Limited data on IBAT in selected patients with PFIC show safety and effectiveness, although surgical methods should still be considered as a successful bridging procedure. Further studies to evaluate a possible combination of IBAT and SBD in PFIC are warranted and treatment decision should be discussed in an interdisciplinary board.

The influence of liver transplantation on the interplay between gut microbiome and bile acid homeostasis in children with biliary atresia.

BACKGROUND: Biliary atresia (BA) causes neonatal cholestasis and rapidly progresses into cirrhosis if left untreated. Kasai portoenterostomy may delay cirrhosis. BA remains among the most common indications for liver transplantation (LT) during childhood. Liver function and gut microbiome are interconnected. Disturbed liver function and enterohepatic signaling influence microbial diversity. We, herein, investigate the impact of LT and reestablishment of bile flow on gut microbiome-bile acid homeostasis in children with BA before (pre, n = 10), 3 months (post3m, n = 12), 12 months (post12m, n = 9), and more than 24 months (post24 + m, n = 12) after LT. METHODS: We analyzed the intestinal microbiome of BA patients before and after LT by 16S-rRNA-sequencing and bioinformatics analyses, and serum primary and secondary bile acid levels. RESULTS: The gut microbiome in BA patients exhibits a markedly reduced alpha diversity in pre (p = 0.015) and post3m group (p = 0.044), and approximated healthy control groups at later timepoints post12m (p = 1.0) and post24 + m (p = 0.74). Beta diversity analysis showed overall community structure similarities of pre and post3m (p = 0.675), but both differed from the post24 + m (p < 0.001). Longitudinal analysis of the composition of the gut microbiome revealed the Klebsiella genus to show increased abundance in the post24 + m group compared with an age-matched control (p = 0.029). Secondary bile acid production increased 2+ years after LT (p = 0.03). Multivariable associations of microbial communities and clinical metadata reveal several significant associations of microbial genera with tacrolimus and mycophenolate mofetil-based immunosuppressive regimens. CONCLUSIONS: In children with BA, the gut microbiome shows strongly reduced diversity before and shortly after LT, and approximates healthy controls at later timepoints. Changes in diversity correlate with altered secondary bile acid synthesis at 2+ years and with the selection of different immunosuppressants.

Influence of age on gadoxetic acid disodium-induced transient respiratory motion artifacts in pediatric liver MRI.

PURPOSE: Gd-EOB-DTPA-enhanced liver MRI is frequently compromised by transient severe motion artifacts (TSM) in the arterial phase, which limits image interpretation for the detection and differentiation of focal liver lesions and for the recognition of the arterial vasculature before and after liver transplantation. The purpose of this study was to investigate which patient factors affect TSM in children who undergo Gd-EOB-DTPA-enhanced liver MRI and whether younger children are affected as much as adolescents. METHODS: One hundred and forty-eight patients (65 female, 83 male, 0.1-18.9 years old), who underwent 226 Gd-EOB-DTPA-enhanced MRIs were included retrospectively in this single-center study. The occurrence of TSM was assessed by three readers using a four-point Likert scale. The relation to age, gender, body mass index, indication for MRI, requirement for sedation, and MR repetition was investigated using uni- and multivariate logistic regression analysis. RESULTS: In Gd-EOB-DTPA-enhanced MRIs, TSM occurred in 24 examinations (10.6%). Patients with TSM were significantly older than patients without TSM (median 14.3 years; range 10.1-18.1 vs. 12.4 years; range 0.1-18.9, p<0.001). TSM never appeared under sedation. Thirty of 50 scans in patients younger than 10 years were without sedation. TSM were not observed in non-sedated patients younger than 10 years of age (p = 0.028). In a logistic regression analysis, age remained the only cofactor independently associated with the occurrence of TSM (hazard ratio 9.152, p = 0.049). CONCLUSION: TSM in Gd-EOB-DTPA-enhanced liver MRI do not appear in children under the age of 10 years.

Significance of validated symptom assessment versus breath testing for malabsorption after lactose load in children.

BACKGROUND AND OBJECTIVES: Lactose malabsorption and lactose-induced symptoms are poorly correlated, as shown by breath tests and various symptom assessment methods. Validated assessment is the key to overcome the limitations of biased symptom measurements. We characterized lactose-induced symptoms with the population-specific, validated paediatric carbohydrate perception questionnaire (pCPQ) and their correlation with the history of symptoms (HoS). METHODS: A total of 130 patients with functional gastrointestinal symptoms underwent a lactose hydrogen breath and tolerance test (LBTT) allowing for a diagnosis of malabsorption (M+) and lactose sensitivity (S+). HoS indicative of lactose-induced symptoms (abdominal pain, nausea, bloating, flatulence, diarrhoea) in the 4 weeks preceding the test was determined using a validated questionnaire. The pCPQ was used to score lactose-induced symptoms. MAIN RESULTS: The LBTT revealed 41 children (31.5%) with lactose malabsorption (M+), 56 (43.1%) with lactose sensitivity (S+) and 24 (18.5%) were M+/S+. Sensitivity correlated with HoS (P < 0.001), regardless of whether malabsorption was detectable. Malabsorption status did not correlate with HoS (NS). The odds of lactose sensitivity significantly increased when abdominal pain [odds ratio (OR) 3.5, confidence interval (CI) 1.6-7.8], nausea (OR 2.3, CI, 1.1-4.9) and flatulence (OR 3.1, CI 1.4-6.8) were reported in the 4 weeks preceding the LBTT. Symptoms after the lactose load were similar for M+/S+ and M-/S+, except for flatulence, which was more frequent in malabsorbers (P < 0.01). CONCLUSION: Our findings fit well with the emerging view of the important role of a validated symptom assessment after a lactose load. The determination of symptoms may be more relevant than malabsorption for the clinical outcomes of paediatric patients with lactose-related gastrointestinal symptoms.

Characteristics, management, and outcome of pediatric patients with post-transplant lymphoproliferative disease-A 20 years' experience from Austria.

BACKGROUND: Management of pediatric post-transplantation lymphoproliferative disorder (PTLD) after hematopoietic stem cell (HSCT) and solid organ transplantation (SOT) is challenging. AIM: This study of 34 PTLD patients up to 19-years old diagnosed in Austria from 2000 to 2018 aimed at assessing initial characteristics, therapy, response, and outcome as well as prognostic markers of this rare pediatric disease. METHODS AND RESULTS: A retrospective data analysis was performed. Types of allografts were kidney (n = 12), liver (n = 7), heart (n = 5), hematopoietic stem cells (n = 4), lungs (n = 2), multi-visceral (n = 2), small intestine (n = 1), and vessels (n = 1). Eighteen/34 were classified as monomorphic PTLD, with DLBCL accounting for 15 cases. Polymorphic disease occurred in nine, and non-destructive lesions in six cases. One patient had a non-classifiable PTLD. Thirteen/34 patients are surviving event-free in first remission (non-destructive, n = 4/6; polymorphic, n = 4/9; monomorphic, n = 6/18). Fourteen/34 patients lacked complete response to first-line therapy, of whom seven died. Four/34 patients relapsed, of whom two died. In 3/34 patients, death occurred as a first event. The 5-year overall and event-free survival rates were 64% ± 9% and 35% ± 9% for the whole cohort. Among all parameters analyzed, only malignant disease as the indication for transplantation had a significantly poor influence on survival. CONCLUSIONS: This study shows PTLD still to be a major cause of mortality following SOT or HSCT in children. A continued understanding of the molecular biology of the disease shall allow to decrease treatment intensity for lower risk patients and to identify patients who may benefit from newer therapy approaches to improve outcome and decrease morbidity.

Occurrence of autoimmune pancreatitis after chronic immune thrombocytopenia in a Caucasian adolescent.

Autoimmune pancreatitis is a rare, distinct and increasingly recognized form of chronic inflammatory pancreatic disease secondary to an underlying autoimmune mechanism. We report on a 14-year-old boy who developed autoimmune pancreatitis, while he was under treatment with eltrombopag for chronic immune thrombocytopenia. Therapy with corticosteroids resulted in complete remission of both. This is the first report on the co-occurrence of autoimmune pancreatitis and chronic immune thrombocytopenia in childhood, and clinicians should be aware of this rare association, because early diagnosis and therapy of autoimmune pancreatitis may prevent severe complications.

Relevance of Methane and Carbon Dioxide Evaluation in Breath Tests for Carbohydrate Malabsorption in a Paediatric Cohort.

OBJECTIVES: The relevance of methane measurement in breath tests for the detection of carbohydrate malabsorption in children is controversial. The need for correction for poor sample collection is disputed. We evaluated the relevance of methane/CO2 measurements for the diagnosis of paediatric carbohydrate malabsorption. METHODS: A total of 132 breath tests (fructose: n = 54; lactose: n = 78) were performed in 91 children/adolescents with functional abdominal complaints. Breath samples were collected and analysed for hydrogen, methane, and CO2. Malabsorption was defined by a net increase over baseline of ≥20 parts per million (ppm) for hydrogen, ≥5 to ≥12 ppm for methane, and ≥10 to ≥15 ppm for hydrogen-plus-methane. The diagnosis was made before and after the use of a CO2-based correction factor (5.5% as the numerator). Hydrogen-based test results were compared with results obtained with other cut-off values. RESULTS: Fifty-eight positive tests were obtained by hydrogen measurement (without CO2 correction). The addition of methane measurements did not significantly influence the test results (P > 0.05). Only under the use of extraordinary cut-offs (combined hydrogen-plus-methane smaller than ≥18 ppm) did the rate of malabsorbers increase significantly (P < 0.05). After CO2 correction, hydrogen ≥20 ppm was detected in 4 additional patients, but 1 patient lost the hydrogen-based diagnosis of malabsorption (Cohen kappa = 0.92). CONCLUSIONS: Methane measurement did not significantly affect the detection rate of carbohydrate malabsorbers in children/adolescents with functional abdominal complaints when established cut-offs are used. The use of CO2 correction altered the diagnosis of malabsorption in a minority of patients but did not significantly alter overall test results.

Golimumab in adolescents with Crohn's disease refractory to previous tumour necrosis factor antibody.

AIM: Anti-tumour necrosis factor (TNF)-α drugs are effective treatments for the management of moderate/severe Crohn's disease (CD), but treatment failure is common. In the treatment of paediatric CD, there are no data about the use of a third introduced subcutaneous TNF antibody golimumab. METHODS: We evaluated the efficacy of golimumab for adolescents with moderate/severe CD. Retrospective analyses were done in all 7 (5 girls) adolescents who received golimumab at a median age of 17 years for a median of 7.2 months. Paediatric Crohn's disease activity index (PCDAI), full blood count, inflammatory markers, use of corticosteroids and adverse events were recorded. RESULTS: With golimumab, 5 of the 7 children were PCDAI responders and 2 entered remission (PCDAI <10). Faecal calprotectin was significantly reduced after 4 weeks compared to baseline. Out of five children, steroid withdrawal was possible in one and steroid reduction in two cases. There were no serious side effects. CONCLUSION: In moderate/severe CD, golimumab induced clinical remission with PCDAI response. Golimumab may be an effective rescue therapy in refractory CD.

Development and validation of the paediatric Carbohydrate Perception Questionnaire (pCPQ), an instrument for the assessment of carbohydrate-induced gastrointestinal symptoms in the paediatric population.

BACKGROUND: There is an unmet need for a validated, test-specific symptom questionnaire to evaluate carbohydrate perception during breath tests. Our aim was to develop and validate a questionnaire for the assessment of symptoms after a provocative carbohydrate load. METHODS: After a literature search and initial focus group-style interviews, five relevant complaints were identified. Responses were given on a Likert-type faces scale with a language children use and understand. Reliability, validity and responsiveness to change were established by the implementation of the questionnaire during breath tests in 215 pediatric subjects. Correlation between the questionnaire and a medical interview by a pediatrician who was blinded to the results of the questionnaire (n = 19) was determined. KEY RESULTS: The questionnaire had good face and content validity (Lawshe ratio = 1). Intraclass correlation coefficients for test-retest reliability (n = 116) demonstrated good repeatability (P < .001), and effect sizes were small (Cohen's d < 0.15 for all symptoms). Convergent validity and discriminant validity were supported according to the multitrait-multimethod matrix method. The results obtained by the questionnaire correlated highly with the result of the medical interview (P < .001; Fisher's exact test). Cronbach's alpha was 0.81. Responsiveness was verified for the whole patient group and subgroups with medium to high effect sizes. CONCLUSIONS AND INFERENCES: The paediatric Carbohydrate Perception Questionnaire (pCPQ) is a simple, test-specific questionnaire for a pediatric population. It is a valid instrument with excellent psychometric properties to assess gastrointestinal symptoms after carbohydrate ingestion. The pCPQ can replace non-validated symptom assessment during carbohydrate breath tests and allows a standardized diagnosis of carbohydrate intolerance.

Publisher Correction: Human DEF6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant CTLA-4 homeostasis.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Human DEF6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant CTLA-4 homeostasis.

Immune responses need to be controlled tightly to prevent autoimmune diseases, yet underlying molecular mechanisms remain partially understood. Here, we identify biallelic mutations in three patients from two unrelated families in differentially expressed in FDCP6 homolog (DEF6) as the molecular cause of an inborn error of immunity with systemic autoimmunity. Patient T cells exhibit impaired regulation of CTLA-4 surface trafficking associated with reduced functional CTLA-4 availability, which is replicated in DEF6-knockout Jurkat cells. Mechanistically, we identify the small GTPase RAB11 as an interactor of the guanine nucleotide exchange factor DEF6, and find disrupted binding of mutant DEF6 to RAB11 as well as reduced RAB11+CTLA-4+ vesicles in DEF6-mutated cells. One of the patients has been treated with CTLA-4-Ig and achieved sustained remission. Collectively, we uncover DEF6 as player in immune homeostasis ensuring availability of the checkpoint protein CTLA-4 at T-cell surface, identifying a potential target for autoimmune and/or cancer therapy.

PD-L1 and PD1 expression in post-transplantation lymphoproliferative disease (PTLD) of childhood and adolescence: An inter- and intra-individual descriptive study covering the whole spectrum of PTLD categories.

Therapy of children with post-transplantation lymphoproliferative disorder (PTLD) after hematopoietic stem cell (HSCT) and solid organ transplantation (SOT) can be challenging. In this retrospective study, we investigated PD-L1 and PD1 expression in all PTLD categories of childhood and adolescence to see whether checkpoint inhibition with PD-L1/PD1 inhibitors may serve as a therapy option. We included 21 patients aged 19 years or younger (at date of transplant) with PTLD following SOT or HSCT having adequate tumor samples available (n = 29). Using immunohistochemistry, we evaluated PD-L1/PD1 expression on both tumor cells and cells of the microenvironment in all samples. Availability of consecutively matched tumor samples during 6 of 21 patients' disease courses also allowed an intra-individual assessment of PD-L1/PD1 expression. We observed lower PD-L1 and higher PD1 expression in non-destructive lesions, and higher PD-L1 and lower PD1 expression in polymorphic and, in particular, in monomorphic PTLD, mostly diffuse large B-cell lymphomas (DLBCL, n = 10/21). The amount of PD-L1- and PD1-positive cells changed in the opposite way in sequential biopsies of the same individual correlating well with the PTLD category. This is the first comprehensive pediatric study assessing PD-L1 and PD1 expression on tumor cells and in the microenvironment of PTLD including not only monomorphic, but also non-destructive early lesions. PD-L1 expression of the tumor cells inversely correlated with PD1 expression in surrounding tissues, with the highest expression in DLBCL. Since PTLD can be therapeutically challenging, our results indicate a potential efficacy of checkpoint inhibitors if standard immune- and/or chemotherapy fail or are impossible. We therefore recommend routine staining of PD-L1 and PD1 in all PTLD categories.

Vedolizumab use after failure of TNF-α antagonists in children and adolescents with inflammatory bowel disease.

BACKGROUND: Vedolizumab is safe and effective in adult patients with Crohn's disease (CD) and ulcerative colitis (UC); however, data in children with inflammatory bowel disease (IBD) are scarce. Therefore, we evaluated vedolizumab use in a cohort of Austrian paediatric patients with IBD. METHODS: Twelve patients (7 female; 7 CD; 5 UC), aged 8-17 years (median, 15 years), with severe IBD who received vedolizumab after tumour necrosis factor α antagonist treatment were retrospectively analysed. Clinical activity scores, relevant laboratory parameters, and auxological measures were obtained at infusion visits. RESULTS: In the CD group, 1/7 patient discontinued therapy due to a severe systemic allergic reaction; 1/7 and 2/7 patients achieved complete and partial response, respectively, at week 14; and 3/7 patients discontinued therapy due to a primary non-response or loss of response. In the UC group, complete clinical remission was achieved at weeks 2, 6, and 14 in 2/5, 1/5 and 1/5 patients respectively; partial response was observed in one patient at week 2. CD activity scores did not significantly change from baseline to week 38 (median 47.5 vs. 40 points, p = 1,0), while median UC activity scores changed from 70 to 5 points (p < 0,001). Substantial weight gain and increased albumin and haemoglobin levels were observed in both groups. CONCLUSION: These results demonstrate that vedolizumab can be an effective treatment for individual paediatric patients with IBD who are unresponsive, intolerant, or experience a loss of efficacy in other therapies. However, vedolizumab appears to be more effective in paediatric UC than in paediatric CD.

Correction to: Relationship Between Abdominal Symptoms and Fructose Ingestion in Children with Chronic Abdominal Pain.

The original version of this article unfortunately contained an error in a couple of reference citation in Discussion Section, paragraph 6. The reference citation number should be changed from [6] to [9] in the below sentences so that it reads.

Relationship Between Abdominal Symptoms and Fructose Ingestion in Children with Chronic Abdominal Pain.

BACKGROUND: Limited valid data are available regarding the association of fructose-induced symptoms, fructose malabsorption, and clinical symptoms. AIM: To develop a questionnaire for valid symptom assessment before and during a carbohydrate breath test and to correlate symptoms with fructose breath test results in children/adolescents with functional abdominal pain. METHODS: A Likert-type questionnaire assessing symptoms considered relevant for hydrogen breath test in children was developed and underwent initial validation. Fructose malabsorption was determined by increased breath hydrogen in 82 pediatric patients with functional abdominal pain disorders; fructose-induced symptoms were quantified by symptom score ≥2 and relevant symptom increase over baseline. The results were correlated with clinical symptoms. The time course of symptoms during the breath test was assessed. RESULTS: The questionnaire exhibited good psychometric properties in a standardized assessment of the severity of carbohydrate-related symptoms. A total of 40 % (n = 33) had malabsorption; symptoms were induced in 38 % (n = 31), but only 46 % (n = 15) with malabsorption were symptomatic. There was no significant correlation between fructose malabsorption and fructose-induced symptoms. Clinical symptoms correlated with symptoms evoked during the breath test (p < 0.001, r2 = 0.21) but not with malabsorption (NS). Malabsorbers did not differ from non-malabsorbers in terms of symptoms during breath test. Symptomatic patients had significantly higher pain and flatulence scores over the 9-h observation period (p < 0.01) than did nonsymptomatic patients; the meteorism score was higher after 90 min. CONCLUSIONS: Fructose-induced symptoms but not fructose malabsorption are related to increased abdominal symptoms and have distinct timing patterns.

Pediatric gastrointestinal endoscopy: European Society of Gastrointestinal Endoscopy (ESGE) and European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) Guideline Executive summary.

This Executive summary of the Guideline on pediatric gastrointestinal endoscopy from the European Society of Gastrointestinal Endoscopy (ESGE) and the European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) refers to infants, children, and adolescents aged 0 - 18 years. The areas covered include: indications for diagnostic and therapeutic esophagogastroduodenoscopy and ileocolonoscopy; endoscopy for foreign body ingestion; endoscopic management of corrosive ingestion and stricture/stenosis; upper and lower gastrointestinal bleeding; endoscopic retrograde cholangiopancreatography, and endoscopic ultrasonography. Percutaneous endoscopic gastrostomy and endoscopy specific to inflammatory bowel disease (IBD) have been dealt with in other Guidelines and are therefore not mentioned in this Guideline. Training and ongoing skill maintenance will be addressed in an imminent sister publication.

Coeliac disease in adolescence: Coping strategies and personality factors affecting compliance with gluten-free diet.

OBJECTIVES: Patients suffering from a chronic condition such as coeliac disease (CD) need to develop coping strategies in order to preserve emotional balance and psychosocial functioning while adhering to their obligatory life-long gluten free diet (GFD). However, this can be particularly challenging for adolescents and may lead to dietary transgressions. Little is currently known about the influence of coping strategies and personality factors on dietary compliance. This study aims to explore these factors for the first time in adolescents with biopsy-proven CD. STUDY DESIGN: We included 281 adolescents with CD and 95 healthy controls. We classified patients according to their GFD adherence status (adherent vs. non-adherent) and assessed coping strategies using the KIDCOPE and personality traits using the Junior-Temperament and Character Inventory (J-TCI). RESULTS: Adolescents with CD adherent to GFD used less emotional regulation and distraction as coping strategies than non-adherent patients. In terms of personality traits, adherent patients differed from non-adherent patients with respect to temperament, but not with respect to character, showing lower scores in novelty seeking, impulsivity and rule transgressions and higher scores in eagerness with work and perfectionism compared to non-adherent patients. No differences were found between healthy controls and adherent CD patients across these personality traits. CONCLUSIONS: Coping strategies and personality traits differ in adolescent patients with CD adherent to GFD from those not adherent, and may therefore relate to risk or protective factors in adherence. Targeting coping and temperament using psychological interventions may therefore be beneficial to support adolescents with CD and optimise their adherence to GFD.

Growth and bone health in paediatric patients with Crohn's disease receiving subcutaneous tumor necrosis factor antibody.

AIM: To study whether adalimumab (ADA) was associated with improvement in growth, bone mineral density (BMD) and bone metabolism. METHODS: In children with Crohn's disease (CD) there is a high prevalence of growth failure and reduced BMD. Treatment with infliximab is associated with an improvement in growth. Anthropometry, paediatric CD activity index (PCDAI), bone markers and BMD was measured in 18 patients (72% females) one year before and after start of ADA with a median age of 14.4 years (range: 5-19 years) at treatment start. Outcomes were indicators of growth with treatment as well as interval growth. RESULTS: Eleven (61%) children experienced catch-up growth after ADA. PCDAI significantly decreased from 52.1 ± 16 to 30.4 ± 23 (P ≤ 0.001). Post ADA, body mass index (BMI) standard deviation score (SDS) 0.1[range: 2.7-(-0.8)] vs -1 [range: 0.1-(-3.6)], P = 0.04 and ∆BMI SDS in children 0.3 [range: 0.7-(-0.2)] vs -1.1 [range: 1.2-(-2.3)], P = 0.01 in remission were significantly higher compared to those with moderate to severe inflammation. The main predictors for growth were 25-hydroxycholecalciferol and for bone mineralisation weight and height SDS. ADA had no significant influence on bone markers and BMD. CONCLUSION: Next to improvement of PCDAI, half of the children achieved a positive catch-up growth. A better nutritional status with improvement in BMI and weight is positive predictor for improved growth and bone mineralisation.