Pharmacological and Parenteral Nutrition-Based Interventions in Microvillus Inclusion Disease

Microvillus inclusion disease (MVID) is a rare inherited and invariably fatal enteropathy, characterized by severe intractable secretory diarrhea and nutrient malabsorption. No cure exists, and patients typically die during infancy because of treatment-related complications. The need for alternative treatment strategies is evident. Several pharmacological interventions with variable successes have been tried and reported for individual patients as part of their clinical care. Unfortunately, these interventions and their outcomes have remained hidden in case reports and have not been reviewed. Further, recent advances regarding MVID pathogenesis have shed new light on the outcomes of these pharmacological interventions and offer suggestions for future clinical research and trials. Hence, an inventory of reported pharmacological interventions in MVID, their rationales and outcomes, and a discussion of these in the light of current knowledge is opportune. Together with a discussion on MVID-specific pharmacokinetic, -dynamic, and -genetic concerns that pose unique challenges regarding pharmacological strategies, we envision that this paper will aid researchers and clinicians in their efforts to develop pharmacological interventions to combat this devastating disease

Effect of minimal enteral feeding on recovery in a methotrexate-induced gastrointestinal mucositis rat model

Patients suffering from gastrointestinal mucositis often receive parenteral nutrition as nutritional support. However, the absence of enteral nutrition might not be beneficial for the intestine. We aimed to determine the feasibility of minimal enteral feeding (MEF) administration in a methotrexate (MTX)-induced mucositis rat model and thereby determine the effect of MEF on recovery. Male Wistar rats were attached to swivel systems from day 1 to 5 after 45 mg/kg MTX IV injection. The MTX group continued ad libitum feeding, and the MTX + MEF group continued ad libitum feeding and received from day 1 to 5 continuously MEF. MEF consisted of 20 % of their normal caloric intake. We measured body weight, intake, and plasma citrulline. At day 10, the rats were terminated and villus and crypt length were measured. The administration of MEF caused no increased severity of mucositis phenotype, with comparable caloric intake, body weight, and plasma citrulline during mucositis. The recovery of plasma citrulline levels was not different between both groups. At day 7 and 8, the MTX + MEF group gained significantly more weight (p <0.05 and p <0.01, respectively), and at day 8 and 9 the total caloric intake was significantly increased (p <0.01 and p <0.05, respectively) compared to the MTX group. At day 10, the rats from the MTX + MEF group showed a significant increase in jejunal villus length compared to the MTX group (p <0.05). This is the first study in which the feasibility of MEF administration during chemotherapy-induced mucositis was determined. This study indicates that MEF administration is feasible during mucositis and suggests that MEF accelerates recovery after MTX-induced mucositis

The Role of a Nutrition Support Team in the Management of Intestinal Failure Patients

Parenteral nutrition (PN) is a complex and specialized form of nutrition support that has revolutionized the care for both pediatric and adult patients with acute and chronic intestinal failure (IF). This has led to the development of multidisciplinary teams focused on th

Myosin Vb and Rab11a regulate phosphorylation of ezrin in enterocytes

Microvilli at the apical surface of enterocytes allow the efficient absorption of nutrients in the intestine. Ezrin activation by its phosphorylation at T567 is important for microvilli development, but how such ezrin phosphorylation is controlled is not well understood. We demonstrate that a subset of kinases that phosphorylate ezrin closely co-distributes with apical recycling endosome marker Rab11a in the subapical domain. Expression of dominant-negative Rab11a mutant or depletion of the Rab11a-binding motor protein myosin Vb prevents the subapical enrichment of Rab11a and these kinases and inhibits ezrin phosphorylation and microvilli development, without affecting the polarized distribution of ezrin itself. We observe a similar loss of the subapical enrichment of Rab11a and the kinases and reduced phosphorylation of ezrin in microvillus inclusion disease, which is associated with MYO5B mutations, intestinal microvilli atrophy and malabsorption. Thus, part of the machinery for ezrin activation depends on recycling endosomes controlled by myosin Vb and Rab11a which, we propose, might act as subapical signaling platforms that enterocytes use to regulate development of microvilli and maintain human intestinal function

Feeding strategies in pediatric cancer patients with gastrointestinal mucositis:A multicenter prospective observational study and international survey

Introduction: Currently, there is no adequate prevention or treatment for both oral and gastrointestinal mucositis induced by chemotherapy and/or radiotherapy. Supportive care of symptoms plays a primary role during mucositis in the pediatric clinical setting. We aimed to get insight in the currently used feeding strategies in clinical practice in pediatric cancer patients with chemotherapy-induced mucositis. Methods: A prospective observational study was performed to identify feeding strategies after chemotherapy courses causing mucositis in almost all patients at the University Medical Center Groningen (UMCG), the Academic Medical Center Amsterdam (AMC), and the Princess Maxima Center Utrecht (PMC). Consecutive patients, aged 0-18 years, either diagnosed with B cell non-Hodgkin lymphoma (B-NHL) or scheduled for autologous stem cell transplantation (SCT) between April 2015 and September 2016 were included in this study. In addition to the observational study in the Netherlands, an international online questionnaire was conducted for pediatric oncology centers. Results: A total of 13 patients were included, after 21 chemotherapy courses. No nutritional support was administered after 23.8% courses, tube feeding after 19.0% of the courses, TPN in 19.0% of courses, and 38.1% received a combination of tube feeding and TPN. The international survey revealed that 63.2% of the centers administered tube feeding as first choice, 31.6% administered only TPN as first choice, and one center administered a combination as first choice. Conclusions: There is a variability in feeding strategies in the clinical practice both in the Netherlands as well as worldwide. This study is a basis for future studies in this important clinical field to develop clinical trials comparing tube feeding and TPN both in adult and pediatric patients

MYO5B, STX3, and STXBP2 mutations reveal a common disease mechanism that unifies a subset of congenital diarrheal disorders:A mutation update

Microvillus inclusion disease (MVID) is a rare but fatal autosomal recessive congenital diarrheal disorder caused by MYO5B mutations. In 2013, we launched an open-access registry for MVID patients and their MYO5B mutations (www.mvid-central.org). Since then, additional unique MYO5B mutations have been identified in MVID patients, but also in non-MVID patients. Animal models have been generated that formally prove the causality between MYO5B and MVID. Importantly, mutations in two other genes, STXBP2 and STX3, have since been associated with variants of MVID, shedding new light on the pathogenesis of this congenital diarrheal disorder. Here, we review these additional genes and their mutations. Furthermore, we discuss recent data from cell studies that indicate that the three genes are functionally linked and, therefore, may constitute a common disease mechanism that unifies a subset of phenotypically linked congenital diarrheal disorders. We present new data based on patient material to support this. To congregate existing and future information on MVID geno-/phenotypes, we have updated and expanded the MVID registry to include all currently known MVID-associated gene mutations, their demonstrated or predicted functional consequences, and associated clinical information.</p

Metabolic investigations prevent liver transplantation in two young children with citrullinemia type I

Acute liver failure may be caused by a variety of disorders including inborn errors of metabolism. In those cases, rapid metabolic investigations and adequate treatment may avoid the need for liver transplantation. We report two patients who presented with acute liver failure and were referred to our center for liver transplantation work-up. Urgent metabolic investigations revealed citrullinemia type I. Treatment for citrullinemia type I avoided the need for liver transplantation. Acute liver failure as a presentation of citrullinemia type I has not previously been reported in young children. Although acute liver failure has occasionally been described in other urea cycle disorders, these disorders may be underestimated as a cause. Timely diagnosis and treatment of these disorders may avoid liver transplantation and improve clinical outcome. Therefore, urea cycle disorders should be included in the differential diagnosis in young children presenting with acute liver failure

Risk analysis, diagnosis and management of gastrointestinal mucositis in pediatric cancer patients

Mucositis is a complex inflammatory reaction of the mucous membranes of the alimentary tract upon chemotherapy and radiotherapy treatment in oncology patients. Mucositis can be subdivided in oral and gastrointestinal mucositis (GI mucositis). The damage to the gastrointestinal tract compromises the intestinal function and thereby the nutritional status and the quality of life, and eventually affects survival. The literature on GI mucositis focuses mainly on adults. This review focuses on data available on GI mucositis in pediatric cancer patients. An evaluation of the clinical presentation and consequences of GI mucositis in children is outlined. The review summarizes key issues for clinicians with respect to risk analysis for developing mucositis and the diagnosis of this condition in children. Information on these issues is obtained from clinical trials in children and adults, and from animal models. Diagnostic tools and assessment of severity of GI mucositis in children is elaborated on. Furthermore, the clinical management of the symptoms and consequences of GI mucositis in children, with specific focus on nutritional support, are discussed. (C) 2014 Elsevier Ireland Ltd. All rights reserved