Hélène Garnier-Lengliné

The efficacy of exclusive nutritional therapy in paediatric Crohn’s disease, comparing fractionated oral vs. continuous enteral feeding

Background  Nutritional therapy has an established role as induction therapy in paediatric Crohn’s disease. However, compliance is the main difficulty and may be greatly influenced by the administration route.

Tolerance and efficacy of azathioprine in pediatric Crohn's disease

Background: Thiopurines are considered first‐line immunomodulators for the prevention of relapse in moderate to severe pediatric Crohns disease (CD). Early introduction of thiopurines was shown in a pediatric trial to maintain steroid‐free remission in 90% of patients for 18 months. In the present study we analyzed the tolerance and efficacy of azathioprine (AZA) to maintain remission in a homogenous single‐center observational cohort of children with CD. Methods: In all, 105 pediatric CD patients (male/female 68/37) were retrospectively evaluated for the efficacy of AZA (doses 1.4–4 mg/kg) to maintain remission at 6, 12, 18, and 24 months of follow‐up. Overall, 93 children were included with active disease (pediatric Crohns disease activity index [PCDAI] >30), steroid/enteral‐nutrition dependency, or postileocecal resection. Remission was defined as PCDAI ≤10 without steroids. Patients requiring antitumor necrosis factor (TNF) medication, other immunomodulators, or surgery were considered to experience a relapse. Results: Based on PCDAI, steroid‐free remission was achieved in 56/93 (60.2%), 37/93 (39.8%), 31/93 (33.3%), and 29/93 (31.2%) at visits month (M)6, M12, M18, and M24, respectively. Within the first 4 weeks, AZA was stopped in 10/93 patients due to adverse reactions (pancreatitis, nausea, vomiting, skin reactions, general weakness), or not introduced due to low thiopurine methyl transferase (TPMT) activity (n = 3). No neutropenia occurred in patients with normal TPMT activity. Three infectious episodes were documented requiring temporary AZA suspension. Conclusions: AZA is efficacious in maintaining remission in pediatric CD patients, but to a lesser extent than previously suggested. The majority of patients who are in steroid‐free remission at 12 months remained in prolonged remission. Overall tolerance of AZA was excellent. Inflamm Bowel Dis 2011

Why are genetics important for nutrition? Lessons from epigenetic research.

Marked advances were made over the last decade in deciphering the molecular mechanisms on how external, nutritional factors can impact on the regulation of genes and ultimately their function without modification of the genetic code. This field of nutrigenomic research is literally exploding. With the understanding of epigenetic control mechanisms, such as DNA methylation, histone acetylation, methylation or phosphorylation, as well as the posttranscriptional regulation of gene expression via non-coding microRNA, many different experimental and analytic approaches were possible to elucidate how varying nutritional support might impact on specific functions, with short- and potently long-term effects. This review highlights the major principles of epigenetic control mechanisms and their link to particular nutritional influences. Epidemiological data, such as the Dutch famine studies, suggest that targeted nutritional intervention might be causative for long-term effects on health, such as the increased risk of cardiovascular diseases and metabolic syndrome in this cohort. However, to date most of the knowledge comes from experimental and animal data, which cannot be easily transferred to human situations. It is anticipated that within the next few years, major advances will be made to translate this knowledge of nutritional intervention on gene regulation and expression into health preventive programs.

Celiac disease in children

Celiac disease is an autoimmune enteropathy, triggered by ingestion of gluten in genetically predisposed individuals. Since the use of anti-transglutaminase and anti-endomysium antibodies in the early 1990s, two main groups of clinical presentation can be identified: patients with a symptomatic form of the disease, and patients with a pauci (a)-symptomatic form detected during the work-up of another autoimmune disease or due to a family history of celiac disease. The prevalence of both forms of the disease is currently estimated between 1/100 and 1/400. Classical form of the disease is characterized by occurrence of diarrhoea, failure to thrive, and abdominal bloating in young infants in the months following gluten introduction. Serological tests show high level of anti-transglutaminase and anti-endomysium antibodies. Until recently, the diagnosis required duodenal biopsies that show villous atrophy. HLA genotype can help for diagnosis: the absence of the HLA-DQ2 or DQ8 alleles has a high negative predictive value. European guidelines recently proposed to reconsider the need for systematic endoscopy in typical symptomatic forms with high level of anti-transglutaminase and positive anti-endomysium. These recommendations are being assessed now. Currently, the gluten-free diet remains the only effective treatment for celiac disease. Children with celiac disease have to exclude from their diet all products containing wheat, barley and rye. Gluten-free diet causes clinical remission within a few weeks, but normalization of the small bowel mucosa and negativity of anti-transglutaminase antibodies are obtained in several months or even years. Gluten-free diet is useful to obtain clinical assessment, but also to prevent long-term complications of celiac disease, mainly osteoporosis, other autoimmune diseases, decreased fertility and cancers.

Outcome of home parenteral nutrition in 251 children over a 14-y period: report of a single center.

BACKGROUND Parenteral nutrition (PN) is the main treatment for intestinal failure. OBJECTIVE We aimed to review the indications for home parenteral nutrition (HPN) in children and describe the outcome over a 14-y period from a single center. DESIGN We conducted a retrospective study that included all children who were referred to our institution and discharged while receiving HPN between 1 January 2000 and 31 December 2013. The indications for HPN were divided into primary digestive diseases (PDDs) and primary nondigestive diseases (PNDDs). We compared our results to a previous study that was performed in our unit from 1980 to 2000 and included 302 patients. RESULTS A total of 251 patients were included: 217 (86%) had a PDD. The mean ± SD age at HPN onset was 0.7 ± 0.3 y, with a mean duration of 1.9 ± 0.4 y. The indications for HPN were short bowel syndrome (SBS) (59%), PNDD (14%), congenital enteropathies (10%), chronic intestinal pseudo-obstruction syndromes (9%), inflammatory bowel diseases (5%), and other digestive diseases (3%). By 31 December 2013, 52% of children were weaned off of HPN, 9% of the PDD subgroup had intestinal transplantation, and 10% died mostly because of immune deficiency. The major complications of HPN were catheter-related bloodstream infections (CRBSIs) (1.7/1000 d of PN) and intestinal failure-associated liver disease (IFALD) (51 children; 20% of cohort). An increased rate of CRBSIs was observed compared with our previous study, but we saw a decreasing trend since 2012. No noteworthy deceleration of growth was observed in SBS children 6 mo after weaning off HPN. CONCLUSIONS SBS was the major indication for HPN in our cohort. IFALD and CRBSIs were potentially life-threatening problems. Nevertheless, complication rates were low, and deaths resulted mostly from the underlying disease.

Transforming Growth Factor and Intestinal Inflammation: The Role of Nutrition

The intestinal mucosa possesses a complex epithelial barrier and a well-organized local immune system, which both efficiently protect this internal-external surface against potential microbial aggressions while guaranteeing tolerance towards harmless bacteria or antigens (oral tolerance). There is good experimental evidence that the intestinal microbiota is a main driver for the development of the mucosal immune system. Any perturbations/changes of this interaction with the intestinal microbiota or the microbial colonization process may cause health problems with short- and eventually long-term consequences, such as suspected for allergic or dysimmune disorders. Dendritic cells (DC) play a key role in the initiation of immune responses. Immune responses elicited by intestinal DC differ markedly from those initiated by spleen-derived DC: while intestinal DC induce anti-inflammatory and tolerogenic responses to harmless antigens such as derived from the resident microflora or harmless food allergens, systemic immune activation yields in a strong inflammatory TH1/TH17 reaction to the same antigens. The recent discovery how DC functions are regulated and imprinted by the microenvironment (DC conditioning) will be discussed in this review. High concentrations of retinoic acid or vitamin D metabolites, thymic stromal lymphopoietin and/or transforming growth factor-β (TGF-β) activate signaling programs in DC that yield in priming of regulatory and anti-inflammatory T cell responses. TGF-β is one of the key factors implicated in intestinal immune regulation; it is produced by a large variety of cells in the intestinal mucosa, including intestinal epithelial cells, lymphocytes and monocytes/macrophages/DC. An important anti-inflammatory effect of TGF-β on the immune system is the promotion and generation of FOXP3-positive regulatory T cells in the intestinal compartment. There are first and encouraging data from the treatment of Crohns disease, an inflammatory GI condition, that targeted enteral therapy with optimized concentrations of immunoregulatory peptides, such as TGF-β, might of interest for the treatment of inflammatory disorders.

Monitoring of anti-transglutaminase autoantibodies in pediatric celiac disease using a sensitive radiobinding assay.

Objectives: The diagnosis of celiac disease (CD) is based on the histological identification of gluten-sensitive enteropathy and detection of anti-tissue transglutaminase antibodies (tTGA) and/or endomysial antibodies. Serial measurements of tTGA are now recommended as a follow-up strategy to monitor compliance with a gluten-free diet (GFD). We evaluated the performances of a quantitative radiobinding assay (RBA) of tTGA immunoglobulin A at diagnosis and during monitoring of GFD in pediatric CD. Methods: Eighty children with confirmed CD were selected. Levels of serum tTGA measured by RBA and a commercial enzyme-linked immunosorbent assay (ELISA) were compared at diagnosis. The relation between RBA-tTGA levels and histological damage was analyzed, as well as the time course of tTGA clearance during GFD. Results: Both RBA and ELISA showed high sensitivity and specificity for tTGA detection at diagnosis. There was no relation between RBA-tTGA levels at diagnosis and severity of mucosal damage. Upon initiation of GFD, the rate of RBA-tTGA positivity declined slower than that of endomysial antibodies positivity, with >50% of the children still tTGA positive at year 5; however, tTGA levels decreased rapidly during the first year of GFD and more slowly thereafter. Children who seroreverted had lower tTGA levels at diagnosis (2080±1554 cpm) than those who remained tTGA positive throughout follow-up (3688±1435 cpm). Conclusions: The high sensitivity of RBA is likely responsible for higher tTGA positivity rates during GFD than previously reported with ELISA. A decreasing trend for tTGA levels may represent a better surrogate marker of compliance with GFD than absolute normal tTGA levels.

Enteral Nutrition as Treatment Option for Crohn's Disease: In Kids Only?

Inflammatory bowel disorders (IBD) are characterized by chronic and recurrent inflammatory reactions of the intestinal mucosa resulting in progressing ulcerating lesions. Research over the past decade clearly identified in patients with Crohns disease (CD) a marked dysregulation of the intestinal microbiome (dysbiosis) as one trigger factor in these inflammatory processes, particularly in patients with a high genetic risk. When treating patients with CD, most drugs aim to control the inflammatory process (either by inhibiting inflammatory pathways or by reducing the activity of immune cells). Given the importance of the disturbed interaction between the microbiota and the host immune system, there might be a different therapeutic approach in targeting directly the intestinal microflora. There are good data to believe that the use of exclusive enteral nutrition (EEN) is one such option. Historically, enteral nutrition (EN) was used as supplemental nutritional therapy in CD patients with planned resection surgery. This treatment option showed unexpected and very powerful anti-inflammatory effects, and it was rapidly introduced as induction therapy for active CD. Several clinical trials and case series confirmed the efficacy of EN to induce remission in approximately 80% of patients equaling the potential of steroids. It is well established that EN has this strong anti-inflammatory potential only when given on an exclusive basis, without any additional food. This raises major compliance issues, probably one of the reasons why it is less used in adult patients. A recent study demonstrated that EEN has a specific effect on the intestinal microbiota, which is markedly different from steroid-induced remission, while all patients obtained complete clinical remission. These observations give a first basis for the understanding of the impact of EEN on dysbiosis in patients with CD.

Have serological tests changed the face of childhood coeliac disease? A retrospective cohort study

Objectives The aim of this study was to evaluate if the use of antitransglutaminase (tTG) and antiendomysium (EM) antibodies has modified the profile of coeliac disease (CD) in children. Design Retrospective cohort study. Setting Monocentric study, in one major tertiary centre in Paris. Two cohorts of patients were compared; the first included patients before the use of antibodies, and the second included patients after the use of antibodies. Participants All patients from the same physician diagnosed with a CD between 1976 and 1992 (historical cohort), and between 1994 and 2007, were included in the study. 56 patients were included in the historical cohort, 59 in the recent cohort. Primary and secondary outcome measures Clinical, biological and histological profiles at diagnosis have been studied. Results The recent cohort diagnosis of CD was based in 27% on a systematic screening (type I diabetes, n=10; CD in siblings, n=6). On comparison of CD patients in the historical to the recent cohort, the following significant differences were observed: Median age at diagnosis increased from 1 year to 2.7 years (p<0.0001). Patients in the historical cohort had more gastrointestinal symptoms (93% vs 63%, p=0.0001) and failure to thrive (98% vs 80%, p=0.0025). Nutritional deficiencies and morphological lesions were more severe in the historical cohort (90% subtotal or total villous atrophy vs 51%, p<0.0001). Differences observed between the two cohorts were mainly due to the presence of screened patients. Conclusions A new type of patients, with a paucisymptomatic or asymptomatic CD, has been identified using serological tests. Silent disease has been diagnosed by screening in a target population. In the other patients of the recent cohort, symptoms were similar but less severe than those observed before. Long-term risks of untreated silent CD are not well determined as yet, and have to be evaluated in prospective studies.