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1.
New treatments and therapeutic targets for IBS and other functional bowel disorders.
Simrén, M, Tack, J
Nature reviews. Gastroenterology & hepatology. 2018;(10):589-605
Abstract
Functional bowel disorders (FBDs) are a spectrum of disorders characterized by combinations of symptoms attributable to the lower gastrointestinal tract. Most current first-line therapies for IBS and other FBDs target the predominant symptom and mainly affect one symptom in the symptom complex. Additional broadly effective treatment alternatives targeting the entire symptom complex are needed. New drugs for FBDs (such as lubiprostone, linaclotide, plecanatide, prucalopride, eluxadoline and rifaximin) target key mechanisms in the pathophysiology of these disorders and improve both the abnormal bowel habit and other key symptoms, such as abdominal pain and bloating. The current development of new treatment alternatives is focusing on different aspects of the complex pathophysiology of IBS and other FBDs: gut microenvironment (via diet and modulation of gut microbiota), enterohepatic circulation of bile acids, gastrointestinal secretion, motility and sensation, gut-brain interactions, gut barrier function and the immune system within the gastrointestinal tract. Studies also suggest that personalized treatment of IBS and other FBDs is possible using various diagnostic markers.
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2.
Erythromycin versus metoclopramide for post-pyloric spiral nasoenteric tube placement: a randomized non-inferiority trial.
Hu, B, Ouyang, X, Lei, L, Sun, C, Chi, R, Guo, J, Guo, W, Zhang, Y, Li, Y, Huang, D, et al
Intensive care medicine. 2018;(12):2174-2182
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Abstract
PURPOSE To determine whether erythromycin is non-inferior to metoclopramide in facilitating post-pyloric placement of self-propelled spiral nasoenteric tubes (NETs) in critically ill patients. METHODS A prospective, multicenter, open-label, parallel, and non-inferiority randomized controlled trial was conducted comparing erythromycin with metoclopramide in facilitating post-pyloric placement of spiral NETs in critically ill patients admitted to intensive care units (ICUs) of eight tertiary hospitals in China. The primary outcome was procedure success defined as post-pyloric placement (spiral NETs reached the first portion of the duodenum or beyond confirmed by abdominal radiography 24 h after tube insertion). RESULTS A total of 5688 patients were admitted to the ICUs. Of these, in 355 patients there was a plan to insert a nasoenteric feeding tube, of whom 332 were randomized, with 167 patients assigned to the erythromycin group and 165 patients assigned to the metoclopramide group. The success rate of post-pyloric placement was 57.5% (96/167) in the erythromycin group, as compared with 50.3% (83/165) in the metoclopramide group (a difference of 7.2%, 95% CI - 3.5% to 17.9%), in the intention-to-treat analysis, not including the prespecified margin of - 10% for non-inferiority. The success rates of post-D1 (reaching the second portion of the duodenum or beyond), post-D2 (reaching the third portion of the duodenum or beyond), post-D3 (reaching the fourth portion of the duodenum or beyond), and proximal jejunum placement and the incidence of any adverse events were not significantly different between the groups. CONCLUSIONS Erythromycin is non-inferior to metoclopramide in facilitating post-pyloric placement of spiral NETs in critically ill patients. The success rates of post-D1, post-D2, post-D3, and proximal jejunum placement were not significantly different.
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Advances in glucagon like peptide-2 therapy. physiology, current indications and future directions.
Sigalet, DL
Seminars in pediatric surgery. 2018;(4):237-241
Abstract
The treatment paradigm for pediatric patients with short bowel syndrome (SBS) and intestinal failure (IF) has changed significantly over recent years; the development of dedicated IF teams, refinements in PN and surgical treatments have greatly improved survival. The majority of SBS patients undergo intestinal adaptation such that nutrient absorption from enteral feeds increases and the child can come off of PN. This "adaptation" or upregulation in nutrient absorptive capacity is still poorly understood; the enteric hormone Glucagon like peptide 2 (GLP-2) appears to be a key regulator in this process. The development of Teduglutide, a long acting GLP-2 ligand as a therapy to specifically enhance adaptation has been anticipated as a further shift in the paradigm. This article reviews the physiology of GLP-2 with an emphasis on the known or potential roles in infants and children with SBS and IF. The results and implications of the present studies and approved indications for GLP-2 and its ligands are discussed. Finally, the potential future uses of GLP-2 ligands in the pediatric population are considered.
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An FXR Agonist Reduces Bile Acid Synthesis Independently of Increases in FGF19 in Healthy Volunteers.
Al-Khaifi, A, Rudling, M, Angelin, B
Gastroenterology. 2018;(4):1012-1016
Abstract
Bile acid (BA) synthesis is regulated through suppression of hepatic cholesterol 7α-hydroxylase via farnesoid X receptor (FXR) activation in hepatocytes and/or enterocytes; in enterocytes, this process requires FGF19 signaling. To study these pathways, we quantified markers of BA synthesis (7α-hydroxy-4-cholesten-3-one [C4]) and cholesterol production (lathosterol), fibroblast growth factor (FGF)19, and BAs in serum from healthy male volunteers given 1 oral dose of the nonsteroidal FXR agonist Px-102 (0.15 mg/kg, 0.3 mg/kg, 0.6 mg/kg, 1.12 mg/kg, 2.25 mg/kg, 3.38 mg/kg, or 4.5 mg/kg). After 8 hours, serum levels of C4 decreased by 80% in volunteers given 0.15 mg/kg, whereas serum levels of FGF19 were unchanged. Serum levels of FGF19 increased significantly, in a dose-dependent manner, in volunteers given >0.3 mg/kg Px-102, up to as much as 1600%, whereas C4 levels remained significantly reduced (by >80%). For all doses, FGF19 levels returned to normal 24 hours after administration of Px-102. Serum levels of C4 decreased before levels of FGF19 levels increased, and were still reduced by 95% 24 hours after the highest dose (4.5 mg/kg) of Px-102, even though levels of FGF19 had returned to baseline. Our findings indicate that activation of hepatic FXR is able to suppress BA synthesis, independent of FGF19.
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Interventions for preventing distal intestinal obstruction syndrome (DIOS) in cystic fibrosis.
Green, J, Gilchrist, FJ, Carroll, W
The Cochrane database of systematic reviews. 2018;(6):CD012619
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Abstract
BACKGROUND Cystic fibrosis (CF) is the most common, life-limiting, genetically inherited disease. It affects multiple organs, particularly the respiratory system. However, gastrointestinal problems such as constipation and distal intestinal obstruction syndrome (DIOS) are also important and well-recognised complications in CF. They share similar symptoms e.g. bloating, abdominal pain, but are distinct conditions. Constipation occurs when there is gradual faecal impaction of the colon, but DIOS occurs when there is an accumulation of faeces and sticky mucus, forming a mass in the distal part of the small intestine. The mass may partially block the intestine (incomplete DIOS) or completely block the intestine (complete DIOS). Symptoms of DIOS can affect quality of life and other aspects of CF health, such as airway clearance, exercise, sleep and nutritional status. Treatment of constipation and prevention of complete bowel obstruction are required for gastrointestinal management in CF. However, many different strategies are used in clinical practice and there is a lack of consensus. The importance of this topic was highlighted in a recent research priority setting exercise by the James Lind Alliance. OBJECTIVES To evaluate the effectiveness and safety of laxative agents of differing types for preventing DIOS (complete and incomplete) in children and adults with CF. SEARCH METHODS We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Date of search: 22 May 2018.We also searched online trial registries. Date of last search: 10 June 2018. SELECTION CRITERIA Randomised and quasi-randomised controlled parallel trials comparing laxative therapy for preventing DIOS (including osmotic agents, stimulants, mucolytics and substances with more than one action) at any dose to placebo, no treatment or an alternative laxative therapy, in people of any age with pancreatic sufficient or insufficient CF and any stage of lung disease. Randomised cross-over trials were judged on an individual basis. DATA COLLECTION AND ANALYSIS Two authors independently assessed trials for inclusion, extracted outcome data and performed a risk of bias assessment for the included data. We judged the quality of the evidence using GRADE criteria. MAIN RESULTS We included one cross-over trial (17 participants) with a duration of 12 months, in which participants were randomly allocated to either cisapride (a gastro-prokinetic agent) or placebo for six months each. The trial had an unclear risk of bias for most domains but had a high risk of reporting bias.Radiograph scores revealed no difference in occurrence of DIOS between cisapride and placebo (narrative report, no data provided). There were no adverse effects. Symptom scores were the only secondary outcome within the review that were reported. Total gastrointestinal symptom scores favoured cisapride with a statistically significant mean difference (MD) of -7.60 (95% confidence interval (CI) -14.73 to -0.47). There was no significant difference at six months between cisapride and placebo for abdominal distension, MD -0.90 (95% CI -2.39 to 0.59) or abdominal pain, MD -0.4 (95% CI -2.05 to 1.25). The global symptom scores (whether individuals felt better or worse) were reported in the paper to favour cisapride and be statistically significant (P < 0.05).We assessed the available data to be very low quality. There was a great deal of missing data from the included trial and the investigators failed to report numerical data for many outcomes. The overall risk of bias of the trial was unclear and it had a high risk for reporting bias. There was also indirectness; the trial drug (cisapride) has since been removed from the market in several countries due to adverse effects, thus it has no current applicability for preventing DIOS. The included trial also had very few participants, which downgraded the quality a further level for precision. AUTHORS' CONCLUSIONS There is an absence of evidence for interventions for the prevention of DIOS. As there was only one included trial, we could not perform a meta-analysis of the data. Furthermore, the included trial compared a prokinetic agent (cisapride) that is no longer licensed for use in a number of countries due to the risk of serious cardiac events, a finding that came to light after the trial was conducted. Therefore, the limited findings from the trial are not applicable in current clinical practice.Overall, a great deal more research needs to be undertaken on gastrointestinal complications in CF, as this is a very poorly studied area compared to respiratory complications in CF.
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Insights into medical management of pediatric intestinal failure.
Oliveira, SB, Cole, CR
Seminars in pediatric surgery. 2018;(4):256-260
Abstract
Medical management of children with Intestinal failure continues to evolve. The development of specialized teams focused on the management of these children has made the most significant impact in improving outcomes. Medical management strategies are centered on the provision of adequate fluid electrolytes and calories to allow for appropriate growth and neurological development. Enteral therapy and drugs are required to enhance bowel adaptation while parenteral nutrition is the main source of nutrients, electrolytes and fluid. Modification in parenteral nutrition with the availability of lipid alternatives are contributing to decreasing incidence of Intestinal failure associated liver disease. Utilization of patient centered central line care bundles has also significantly contributed to the decrease in morbidity and mortality. This review provides insight into the current medical therapy available for managing intestinal failure in children.
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Redefining "bowel regimen": Pharmacologic strategies and nutritional considerations in the management of small bowel fistulas.
Parli, SE, Pfeifer, C, Oyler, DR, Magnuson, B, Procter, LD
American journal of surgery. 2018;(2):351-358
Abstract
Enterocutaneous fistulae (ECF) and enteroatmospheric fistulae (EAF) are difficult complications that primarily arise after abdominal surgical procedures. Development of an ECF or EAF carries significant mortality and morbidity. Effective management of patients with these disease states requires a multidisciplinary approach, which includes surgical, pharmacotherapeutic, and nutritional interventions. This review focuses on the medical and nutritional management of ECF/EAF, providing background on drug agents and nutritional strategies that may be helpful in reducing effluent volume, optimizing fistula healing, and maintaining nutritional health.
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Nutritional Interventions in Chronic Intestinal Pseudoobstruction.
Kirby, DF, Raheem, SA, Corrigan, ML
Gastroenterology clinics of North America. 2018;(1):209-218
Abstract
Although chronic intestinal pseudo-obstruction (CIPO) is a rare disorder, it presents a wide spectrum of severity that ranges from abdominal bloating to severe gastrointestinal dysfunction. In the worst cases, patients may become dependent upon artificial nutrition via parenteral nutrition or choose to have an intestinal transplant. However, whatever the severity, a patient's quality of life can be seriously compromised. This article defines the disorder and discusses the spectrum of disease and challenges to providing adequate nutrition to help improve a patient's quality of life.
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Reduction of Parenteral Nutrition and Hydration Support and Safety With Long-Term Teduglutide Treatment in Patients With Short Bowel Syndrome-Associated Intestinal Failure: STEPS-3 Study.
Seidner, DL, Fujioka, K, Boullata, JI, Iyer, K, Lee, HM, Ziegler, TR
Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition. 2018;(4):520-527
Abstract
BACKGROUND Patients with intestinal failure associated with short bowel syndrome (SBS-IF) require parenteral support (PS) to maintain fluid balance or nutrition. Teduglutide (TED) reduced PS requirements in patients with SBS-IF in the randomized, placebo (PBO)-controlled STEPS study (NCT00798967) and its 2-year, open-label extension, STEPS-2 (NCT00930644). METHODS STEPS-3 (NCT01560403), a 1-year, open-label extension study in patients with SBS-IF who completed STEPS-2, further monitored the safety and efficacy of TED (0.05 mg/kg/day). Baseline was the start of TED treatment, in either STEPS or STEPS-2. At the end of STEPS-3, patients treated with TED in both STEPS and STEPS-2 (TED-TED) received TED for ≤42 months, and patients treated with TED only in STEPS-2 (no TED treatment [NT]/PBO-TED) received TED for ≤36 months. RESULTS Fourteen patients enrolled (TED-TED, n = 5; NT/PBO-TED, n = 9) and 13 completed STEPS-3. At the last dosing visit, mean (SD) PS was reduced from baseline by 9.8 (14.4 [50%]) and 3.9 (2.8 [48%]) L/week in TED-TED and NT/PBO-TED, respectively. Mean (SD) PS infusions decreased by 3.0 (4.6) and 2.1 (2.2) days per week from baseline in TED-TED and NT/PBO-TED, respectively. Two patients achieved PS independence; 2 additional patients who achieved independence in STEPS-2 maintained enteral autonomy throughout STEPS-3. All patients reported ≥1 treatment-emergent adverse event (TEAE); 3 patients had TEAEs that were reported as treatment related. No patient had a treatment-related treatment-emergent serious AE. CONCLUSIONS Long-term TED treatment yielded a safety profile consistent with previous studies, sustained efficacy, and a further decline in PS requirements.
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Infant cholestasis patient with a novel missense mutation in the AKR1D1 gene successfully treated by early adequate supplementation with chenodeoxycholic acid: A case report and review of the literature.
Wang, HH, Wen, FQ, Dai, DL, Wang, JS, Zhao, J, Setchell, KD, Shi, LN, Zhou, SM, Liu, SX, Yang, QH
World journal of gastroenterology. 2018;(35):4086-4092
Abstract
Steroid 5β-reductase [aldo-keto reductase family 1 member D1 (AKR1D1)] is essential for bile acid biosynthesis. Bile acid deficiency caused by genetic defects in AKR1D1 leads to life-threatening neonatal hepatitis and cholestasis. There is still limited experience regarding the treatment of this disease. We describe an infant who presented with hyperbilirubinemia and coagulopathy but normal bile acid and γ-glutamyltransferase. Gene analysis was performed using genomic DNA from peripheral lymphocytes from the patient, his parents, and his elder brother. The patient was compound heterozygous for c.919C>T in exon 8 and exhibited a loss of heterozygosity of the AKR1D1 gene, which led to an amino acid substitution of arginine by cysteine at amino acid position 307 (p.R307C). Based on these mutations, the patient was confirmed to have primary 5β-reductase deficiency. Ursodeoxycholic acid (UDCA) treatment did not have any effect on the patient. However, when we changed to chenodeoxycholic acid (CDCA) treatment, his symptoms and laboratory tests gradually improved. It is therefore crucial to supplement with an adequate dose of CDCA early to improve clinical symptoms and to normalize laboratory tests.