Pneumatosis Intestinalis in Children With Intestinal Failure: The Result of Intestinal Stress From Enteral Feeding?

OBJECTIVE: The incidence and significance of pneumatosis intestinalis (PI) in children with a diagnosis of intestinal failure is not well understood. The aim of this study was to identify clinical and anatomical factors associated with the imaging findings of PI in patients with intestinal failure. METHODS: We performed a retrospective review of all children with a diagnosis of intestinal failure at Children's Hospital Colorado between January 2019 and April 2022. Patients were stratified and compared based on the incidence of PI on abdominal imaging. Differences were compared using 2-sample Wilcoxon tests, chi-square, or Fisher exact tests. RESULTS: There were 111 patients identified with a diagnosis of intestinal failure and 30.6% (34) developed at least 1 instance of PI. There were no differences in etiology of intestinal failure or anatomy between those who developed PI and those who did not. Patients who developed PI, were less likely to be on total parental nutrition (60.6% vs 98.6%, P < 0.001) and more likely to be receiving any form of enteral feeds (87.9% vs 66.2%, P = 0.035) or tube feeds (75.8% vs 44.2%, P = 0.0045). Of the children with PI, 30.3% (10) were undergoing an enteral feed advancement at time of PI development. Three patients with PI underwent laparotomy for PI treatment, 2 of which were negative laparotomies. CONCLUSIONS: The development of PI in children with intestinal failure is likely a benign finding. It is associated with enteral feeding and may be due to increased intestinal stress.

Gastrostomy Button Placement in Infants With Cyanotic Versus Acyanotic Congenital Heart Disease.

BACKGROUND: Infants with congenital heart disease (CHD) may exhibit increased metabolic demands, and many will undergo placement of a gastrostomy to achieve adequate nutritional intake. There is a paucity of data, however, comparing the operative risks and overall complications of gastrostomy placement in cyanotic versus acyanotic infants with CHD. We hypothesized that patients with cyanotic CHD would have a higher rate of gastrostomy-associated complications than infants with acyanotic CHD. METHODS: We retrospectively reviewed patients who underwent gastrostomy button placement after cardiac surgery for CHD between 2013 and 2018. Patients were stratified into cyanotic CHD and acyanotic CHD cohorts. Patient data were extracted from the Society of Thoracic Surgeons database and merged with clinical data related to gastrostomy placement and complications from chart review. Unadjusted analyses were used to find covariates associated with cyanotic CHD and acyanotic CHD, using a t-test or Wilcoxon rank-sum test for continuous data, depending on normalcy, and χ2 or Fisher's exact tests for categorical data depending on the distribution. RESULTS: There were 257 infants with CHD who underwent gastrostomy placement during the study period, of which 86 had cyanotic CHD. There were no significant differences in baseline weight or preoperative albumin levels between the two groups. Patients with cyanotic CHD had a lower incidence of comorbid syndromes (P = 0.0001), higher Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery scores (P < 0.0001), and higher postoperative mortality rate (P = 0.0189). There was a higher rate of granulation tissue formation in patients with acyanotic CHD (48.5% versus 22.1%, P < 0.0001). There were no differences in other gastrostomy button-related complications, including leakage, wound infection, or dislodgement. CONCLUSIONS: Patients with acyanotic CHD demonstrated a higher incidence of granulation tissue. We found no difference in gastrostomy-specific complication rates between the two groups, with the notable exception of granulation tissue formation. Based on this study, the diagnosis of cyanotic CHD does not increase the risk of gastrostomy-related complications.

Management of Central Venous Access in Children With Intestinal Failure: A Position Paper From the NASPGHAN Intestinal Rehabilitation Special Interest Group.

ABSTRACT: Intestinal failure requires the placement and maintenance of a long-term central venous catheter for the provision of fluids and/or nutrients. Complications associated with this access contribute to significant morbidity and mortality, while the loss of access is an increasingly common reason for intestinal transplant referral. As more emphasis has been placed on the prevention of central line-associated bloodstream infections and new technologies have developed, care for central lines has improved; however, because care has evolved independently in local centers, care of central venous access varies significantly in this vulnerable population. The present position paper from the Intestinal Failure Special Interest Group of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) reviews current evidence and provides recommendations for central line management in children with intestinal failure.

The Nissen Unwrapped: Predictors and Outcomes of Nissen Fundoplication in Congenital Heart Disease.

BACKGROUND: Infants with congenital heart disease (CHD) often require the placement of a gastrostomy button to ensure proper nutrition. Some also require a Nissen fundoplication (NF) to further improve nutrition capabilities in the setting of reflux, however, the clinical and diagnostic imaging characteristics that support NF are variable. The aims of this study were as follows: (1) identify the factors associated with NF in patients with CHD and (2) determine the incidence of NF complications in patients with CHD. METHODS: All patients with CHD who underwent cardiac repair and subsequent creation of a gastrostomy at a single institution between 6/1/2013 and 9/1/2018 were included. We then identified which patients underwent NF. RESULTS: Two-hundred fifty-seven CHD patients who had a gastrostomy button placed after CHD repair, with 17% undergoing a simultaneous NF or an NF at a later time. The presence of acyanotic heart disease, neurologic comorbidities, and vocal cord dysfunction was not univariately associated with a higher likelihood of NF. On multivariable model, only prematurity was significantly associated with NF (P = 0.022). Abnormal findings on imaging studies (upper gastrointestinal series, gastric emptying studies, motility studies, upper endoscopies, swallow studies, and pH probe studies) were not associated with an NF (all P's > 0.05). The overall complication rate was 23%. CONCLUSIONS: Prematurity was the only factor associated with an NF. Surprisingly, cyanotic heart disease, neurologic comorbidities, age at first cardiac surgery, and vocal cord dysfunction were not associated with an NF. We identified an area for quality improvement at our institution given the lack of standardized work-up for the NF in this high-risk population.

Evaluating the yield of gastrointestinal testing in pediatric patients in aerodigestive clinic.

OBJECTIVE: To improve understanding of the interrelatedness of airway and esophageal diagnoses by evaluating the yield of procedural and radiographic testing of the gastrointestinal tract in children with airway conditions by their referring diagnoses in a pediatric aerodigestive clinic. METHODS: A retrospective chart review of all 325 patients seen in the aerodigestive program from 2010 to 2013 was performed in a single academic medical center. Demographics and results from esophagogastroduodenoscopies with biopsies (EGD), upper gastrointestinal fluoroscopy studies (UGI), and pH multichannel intraluminal impedance probe (pH-MII) performed within 30 days of the clinic visit were evaluated according to presenting diagnoses. RESULTS: Mean patient age was 3.15 years (range 0.15-24 years) and 41.2% were born premature. 189/325 (58.1%) were on acid suppression. A total of 295 EGD, 193 pH-MII, and 54 UGI were performed. The most common diagnosis with an abnormal pH-MII was asthma. The most common diagnoses with an abnormal EGD were feeding difficulty and tracheal esophageal fistula/ esophageal atresia (TEF/EA). EGDs were normal in 188/295 (63.7%), while 39/295 (13.2%) demonstrated esophagitis, and 22/295 (7.5%) had >15 esophageal eosinophils per high power field. The majority of pH-MII (144/193 [74.6%]) and UGI (47/54 [87%]) were normal. CONCLUSIONS: Children with feeding difficulty, TEF/EA, and asthma were the mostly likely to have a histologic abnormality on EGD or an abnormal pH-MII. The majority of children were previously prescribed acid suppression medication and had a referring diagnosis of gastroesophageal reflux disease but were subsequently found to have normal evaluation. Prospective studies are needed to optimize care of this population.

Follow-Up Survey on Functionality of Nutrition Documentation and Ordering Nutrition Therapy in Currently Available Electronic Health Record Systems.

BACKGROUND: This is a follow-up survey to reassess the safety and efficacy of nutrition content in the available electronic health record (EHR) systems. MATERIALS AND METHODS: Members of the American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.), American Society for Nutrition, and the Academy for Nutrition and Dietetics were asked to participate in an online survey. The survey included questions from a 2012 EHR survey on the safety and efficacy in 5 nutrition content areas as well as questions from previous 2003 and 2011 A.S.P.E.N. parenteral nutrition (PN) surveys. RESULTS: Percent of respondents using an EHR and using the EHR for less than 1 year increased between 2012 and 2014 (86%-94%, P < .05; 11%-16%, P < .05, respectively). However, there was no improvement in the safety and efficacy of the 5 nutrition content areas, with a significant decrease in 2 of these areas, ordering oral nutrition supplements and ordering PN. The top-rated EHR vendors had a higher average favorable response rate in regards to safety and efficacy in the nutrition content areas but even the top-rated EHR vendor had only a 60% average in favorable responses. Reported use of electronic PN ordering and a direct interface between the EHR and the automated compounding device (ACD) significantly increased from 2003 to 2011 to 2014 (29% to 33% to 63% and 16% to 19% to 28%, respectively, P < .05). CONCLUSIONS: This is a call to action to nutrition support clinicians, societies, and organizations to proactively be involved in initiatives to educate clinicians and collaborate with EHR vendors to enhance the EHR systems to improve the safety and efficacy of providing nutrition therapy in hospitalized patients.

Multidisciplinary care of children with repaired esophageal atresia and tracheoesophageal fistula.

OBJECTIVES: Children with congenital esophageal atresia with tracheoesophageal fistula (TEF) require complex medical and surgical care, but few guidelines exist to guide the long term care of this population. The purpose of this study is to describe the findings and initial management of a comprehensive aerodigestive team in order to understand the ongoing needs of children with repaired TEF. METHODS: A retrospective chart review was performed on children with TEF who were seen in the multidisciplinary Aerodigestive Clinic at Children's Hospital Colorado. Diagnostic studies were ordered based on physician discretion. RESULTS: Twenty-nine children with TEF were evaluated (mean age 3.8 years) between 2010 and 2014. All children had symptoms attributed to breathing, swallowing, and digestive difficulties. Less than half of the children had seen a pulmonary or gastrointestinal specialist in the past year. Tracheomalacia was diagnosed in all children who had a bronchoscopy (23/23), and the presence of dysphagia was correlated with severe tracheomalacia. 7/25 children who had a swallow study had aspiration. 7/25 children had a diagnosis of active reflux despite current management. Four patients were diagnosed with bronchiectasis as a result of the multidisciplinary evaluation. CONCLUSION: Although all children had persistent aerodigestive symptoms, over 50% had not been seen by an appropriate subspecialist in the year prior to the clinic visit. The multidisciplinary evaluation resulted in new diagnoses of bronchiectasis and active reflux, which can both lead to long-term morbidity and mortality. Children with TEF require evaluation by multiple subspecialists to manage not only current symptoms but also long term risks. Ongoing care should be guided by protocols based on known risks. Pediatr Pulmonol. 2016;51:576-581. © 2015 Wiley Periodicals, Inc.

Rectal biopsies for Hirschsprung disease: Patient characteristics by diagnosis and attending specialty.

PURPOSE: Hirschsprung disease (HD) is diagnosed with rectal biopsy. At our institution two services perform these biopsies: pediatric surgery and gastroenterology. Our objective was to review our institutional experience with rectal biopsies to diagnose HD and compare patients and outcomes between the two services. METHODS: We reviewed all children undergoing a rectal biopsy for the evaluation of HD at our institution over a 10-year period. Comparisons were made using multiple logistic regression models. RESULTS: We identified 518 children who underwent rectal biopsy for evaluation of HD; 451/518 (87%) were adequate and 56/518 (11%) were positive for HD. A positive biopsy was more likely with delayed passage of meconium (p<0.001), obstructive symptoms (p<0.001), trisomy 21 (p<0.001), full-term gestation (p=0.03), and male gender (p=0.02). Pediatric surgeons biopsied younger patients with more classic symptoms for HD compared to gastroenterologists. Pediatric surgeons were more likely to take adequate (OR 6.0, 95% CI 2.9-12.4, p<0.001) and positive biopsies (OR 6.7 95% CI 2.1-21.2, p=0.001) compared to gastroenterologists. CONCLUSION: Infants with classic symptoms can reliably be diagnosed with HD by a pediatric surgeon. The work up for HD in older children with constipation should be a collaborative effort between pediatric surgery and gastroenterology.

Unsedated transnasal esophagoscopy for monitoring therapy in pediatric eosinophilic esophagitis.

BACKGROUND AND AIMS: Unsedated transnasal endoscopy (TNE) is safer and less costly than sedated EGD. The aim of this study was to evaluate the performance of TNE with biopsies in monitoring the esophageal mucosa of pediatric patients with eosinophilic esophagitis. METHODS: Patients between 8 and 17 years of age with eosinophilic esophagitis and their parents were enrolled. Unsedated TNE was performed. A 2.8-mm (1.2-mm channel) or a 4-mm flexible bronchoscope (2-mm channel) was used, and esophageal biopsy specimens were obtained. Biopsy specimen analysis, duration, adverse events, and billing charges of TNE were assessed. Immediately after TNE and a minimum of 2 weeks later, a modified Group Health Association of America 9 survey and a preference questionnaire were completed, respectively. RESULTS: Twenty-one of 22 enrolled patients underwent TNE. TNE was performed with no serious adverse events. Histopathological analysis revealed 0 eosinophils per high-power field (n = 12), fewer than 15 eosinophils per high-power field (n = 4), and more than 15 eosinophils per high-power field (n = 5). The total epithelial surface area of mucosal biopsy samples from either TNE Forceps (1.2 mm or 2 mm biopsy channel forceps) compared with those obtained during the subject's previous EGD by using standard endoscopic forceps was not statistically different (P = .308 [1.2 mm]/P = .492 [2 mm]). All parents and 76.2% of subjects would undergo the TNE again. TNE was preferred over EGD by 85.7% of parents and 52.4% of subjects. The modified Group Health Association of America 9 survey revealed a high degree of satisfaction (average, 43.19 ± 2.6; maximum score, 45). Charges associated with TNE were 60.1% lower than for previous EGDs. CONCLUSIONS: Unsedated TNE is an effective, lower-cost procedure for monitoring the esophageal mucosa of children with eosinophilic esophagitis.

Predictors of Enteral Autonomy in Children with Intestinal Failure: A Multicenter Cohort Study.

OBJECTIVES: In a large cohort of children with intestinal failure (IF), we sought to determine the cumulative incidence of achieving enteral autonomy and identify patient and institutional characteristics associated with enteral autonomy. STUDY DESIGN: A multicenter, retrospective cohort analysis from the Pediatric Intestinal Failure Consortium was performed. IF was defined as severe congenital or acquired gastrointestinal diseases during infancy with dependence on parenteral nutrition (PN) >60 days. Enteral autonomy was defined as PN discontinuation >3 months. RESULTS: A total of 272 infants were followed for a median (IQR) of 33.5 (16.2-51.5) months. Enteral autonomy was achieved in 118 (43%); 36 (13%) remained PN dependent and 118 (43%) patients died or underwent transplantation. Multivariable analysis identified necrotizing enterocolitis (NEC; OR 2.42, 95% CI 1.33-4.47), care at an IF site without an associated intestinal transplantation program (OR 2.73, 95% CI 1.56-4.78), and an intact ileocecal valve (OR 2.80, 95% CI 1.63-4.83) as independent risk factors for enteral autonomy. A second model (n = 144) that included only patients with intraoperatively measured residual small bowel length found NEC (OR 3.44, 95% CI 1.36-8.71), care at a nonintestinal transplantation center (OR 6.56, 95% CI 2.53-16.98), and residual small bowel length (OR 1.04 cm, 95% CI 1.02-1.06 cm) to be independently associated with enteral autonomy. CONCLUSIONS: A substantial proportion of infants with IF can achieve enteral autonomy. Underlying NEC, preserved ileocecal valve, and longer bowel length are associated with achieving enteral autonomy. It is likely that variations in institutional practices and referral patterns also affect outcomes in children with IF.

Race affects outcome among infants with intestinal failure.

OBJECTIVE: Intestinal failure (IF) is a rare, devastating condition associated with significant morbidity and mortality. We sought to determine whether ethnic and racial differences were associated with patient survival and likelihood of receiving an intestinal transplant in a contemporary cohort of children with IF. METHODS: This was an analysis of a multicenter cohort study with data collected from chart review conducted by the Pediatric Intestinal Failure Consortium. Entry criteria included infants ≤ 12 months receiving parenteral nutrition (PN) for ≥ 60 continuous days and studied for at least 2 years. Outcomes included death and intestinal transplantation (ITx). Race and ethnicity were recorded as they were in the medical record. For purposes of statistical comparisons and regression modeling, categories of race were consolidated into "white" and "nonwhite" children. RESULTS: Of 272 subjects enrolled, 204 white and 46 nonwhite children were available for analysis. The 48-month cumulative incidence probability of death without ITx was 0.40 for nonwhite and 0.16 for white children (P < 0.001); the cumulative incidence probability of ITx was 0.07 for nonwhite versus 0.31 for white children (P = 0.003). The associations between race and outcomes remained after accounting for low birth weight, diagnosis, and being seen at a transplant center. CONCLUSIONS: Race is associated with death and receiving an ITx in a large cohort of children with IF. This study highlights the need to investigate reasons for this apparent racial disparity in outcome among children with IF.

Natural history of pediatric intestinal failure: initial report from the Pediatric Intestinal Failure Consortium.

OBJECTIVE: To characterize the natural history of intestinal failure (IF) among 14 pediatric centers during the intestinal transplantation era. STUDY DESIGN: The Pediatric Intestinal Failure Consortium performed a retrospective analysis of clinical and outcome data for a multicenter cohort of infants with IF. Entry criteria included infants <12 months receiving parenteral nutrition (PN) for >60 continuous days. Enteral autonomy was defined as discontinuation of PN for >3 consecutive months. Values are presented as median (25th, 75th percentiles) or as number (%). RESULTS: 272 infants with a gestational age of 34 weeks (30, 36) and birth weight of 2.1 kg (1.2, 2.7) were followed for 25.7 months (11.2, 40.9). Residual small bowel length in 144 patients was 41 cm (25.0, 65.5). Diagnoses were necrotizing enterocolitis (71, 26%), gastroschisis (44, 16%), atresia (27, 10%), volvulus (24, 9%), combinations of these diagnoses (46, 17%), aganglionosis (11, 4%), and other single or multiple diagnoses (48, 18%). Prescribed medications included oral antibiotics (207, 76%), H2 blockers (187, 69%), and proton pump inhibitors (156, 57%). Enteral feeding approaches varied among centers; 19% of the cohort received human milk. The cohort experienced 8.9 new catheter-related blood stream infections per 1000 catheter days. The cumulative incidences for enteral autonomy, death, and intestinal transplantation were 47%, 27%, and 26%, respectively. Enteral autonomy continued into the fifth year after study entry. CONCLUSIONS: Children with IF endure significant mortality and morbidity. Enteral autonomy may require years to achieve. Improved medical, nutritional, and surgical management may reduce time on PN, mortality, and need for transplantation.

Laparoscopic suture rectopexy for full-thickness anorectal prolapse in children: an effective outpatient procedure.

BACKGROUND/PURPOSE: Our approach to full-thickness anorectal prolapse has transitioned to laparoscopic suture rectopexy (LSRP). The purpose of this study was to describe the indications, technique, and postoperative outcomes for LSRP. METHODS: Rectopexy was performed using 3 or 4 laparoscopic ports. Redundant rectum was retracted from the pelvis, and the posterior rectal wall was secured to the sacral promontory using 3 permanent sutures. RESULTS: Nineteen children (7 girls) underwent LSRP from March 2003 to January 2008. Mean age was 6.2 ± 3.6 years. Three patients had prior perineal operations: 2 sacrococcygeal teratoma resections and 1 pull-through for Hirschsprung disease. One patient had cystic fibrosis, and another had Prader-Willi syndrome. The remaining children had either chronic constipation or idiopathic prolapse. All patients were treated preoperatively with laxatives. Two patients received antegrade continent enemas. Length of stay was 1 ± 0.8 days, with only the first 5 patients admitted to the hospital. The patient with Prader-Willi syndrome had a full-thickness recurrence (5%) owing to obsessive-compulsive behavior. Partial mucosal prolapse occurred in 2 patients. There were no other complications. CONCLUSIONS: Laparoscopic suture rectopexy is an effective minimally invasive method to treat full-thickness rectal prolapse in children from various etiologies. It can be performed as an outpatient procedure with minimal morbidity and low recurrence rate (5%).

Clinical assessment of the child with intestinal failure.

The management of the child with intestinal failure is complex, and it is developing into a multispecialty field of its own led by expert teams of both transplant and nontransplant surgeons, gastroenterologists, and dieticians. Patients are at risk for medical, surgical, and nutritional complications that should be anticipated so that they can be prevented or managed appropriately. Catheter associated infections and intestinal failure associated liver diseases are important complications that impact the likelihood of bowel adaptation and long-term survival. The clinical assessment of a pediatric intestinal failure patient should include evaluation of the child within the context of recognized prognostic factors.

Failure of resolution of portal fibrosis during omega-3 fatty acid lipid emulsion therapy in two patients with irreversible intestinal failure.

Parenteral omega-3 fatty acid lipid emulsions have been evaluated for their potential role in reversing intestinal failure-associated liver disease. We report our experience using Omegaven in 2 patients with irreversible intestinal failure and intestinal failure-associated liver disease. Despite biochemical and histologic improvement in cholestasis, both patients had persisting, significant portal fibrosis on liver biopsy.

First successful antegrade single-balloon enteroscopy in a 3-year-old with occult GI bleeding.

BACKGROUND: Balloon enteroscopy is an emerging technique to allow access to the small intestine for both diagnostic and therapeutic purposes. To date, there have been few published data documenting the safety and efficacy of balloon enteroscopy in small children. OBJECTIVE: To describe our experience with single-balloon enteroscopy (SBE) in a 37-month-old toddler with occult GI bleeding. DESIGN: A single case report. SETTING: A free-standing, academic children's hospital in Denver, Colorado. PATIENT: The patient was a 37-month-old, 13.5-kg toddler with persistent heme-positive stools, severe microcytic anemia, and hypoalbuminemia. Previous workup was significant for eosinophilic inflammation in the antrum and a video capsule study showing erythematous lesions in the small bowel. INTERVENTION: An antegrade SBE was performed with the child under general endotracheal anesthesia, with biopsy specimens obtained from identified lesions in the jejunum and ileum. MAIN OUTCOME MEASUREMENTS: Complications and successful treatment of symptoms were the primary endpoints. RESULTS: The procedure was performed successfully in 85 minutes, passing an estimated 200 cm beyond the pylorus, without complications. Identification of the lesions as consistent with eosinophilic enteropathy led to successful treatment with an elimination diet and corticosteroids. LIMITATIONS: The primary limitation of this study is that it is a single case report. Therefore, it is difficult to make a generalized statement regarding the safety and efficacy of balloon enteroscopy in toddlers of this size. CONCLUSIONS: Antegrade SBE can be a well-tolerated and effective procedure to evaluate occult GI bleeding in children as young as 3 years of age. Further study is needed to better establish safety parameters for balloon enteroscopy in small pediatric patients.

Hepatic veno-occlusive disease and human herpes virus 7 infection in primary agammaglobulinemia.

Hepatobiliary disease has been described in Bruton's x-linked agammaglobulinemia; however, veno-occlusive disease has not been reported in this setting. We report a case of end-stage liver disease in a patient with x-linked agammaglobulinemia who was found to have VOD and evidence of human herpes virus 7 infection in the explanted liver after transplantation.

Resistance of young rat hepatic mitochondria to bile acid-induced permeability transition: potential role of alpha-tocopherol.

Retention of bile acids within the liver is a primary factor in the pathogenesis of cholestatic liver disorders, which are more common in human infants. The objective of this study was to evaluate developmental changes in mitochondrial factors involved in bile acid-induced hepatocyte injury. Hepatic mitochondria from adult rats (aged 9 wk) underwent a mitochondrial permeability transition (MPT) and release of cytochrome c upon exposure to glycochenodeoxycholic acid. In contrast, mitochondria from young rats (age 6-36 d) were resistant to MPT induction and cytochrome c release. Neither mitochondrial levels of MPT-associated proteins (voltage-dependent anion channel, cyclophilin D, or adenine nucleotide translocase), Bcl-2 family proteins, nor antioxidant enzymes explained this resistance. Mitochondria from young rats contained 2- to 3-fold higher alpha-tocopherol (alpha-TH). In vivo alpha-TH enrichment of adult hepatic mitochondria increased their MPT resistance. Tetra-linoleoyl cardiolipin (TL-CL), the primary molecular species of CL, was reduced in mitochondria of the young rat; however, enrichment with CL and TL-CL only modestly increased their MPT susceptibility. In conclusion, we observed an unexpected resistance in young rats to bile acid induction of mitochondrial cell death pathways, which may be related to developmental differences in membrane composition.

Subcutaneous vitamin E ameliorates liver injury in an in vivo model of steatocholestasis.

UNLABELLED: Several genetic metabolic liver diseases share the pathological features of combined steatosis and cholestasis, or steatocholestasis. The aims of this study were to develop and characterize an in vivo model for steatocholestasis and to evaluate the effects of an antioxidant treatment on liver injury, oxidative stress, and mitochondrial perturbations in this model. Obese and lean Zucker rats received intravenous (IV) injections of glycochenodeoxycholic acid (GCDC) and were killed 4 hours later. Liver enzymes were measured; the liver histology was assessed, and hepatic mitochondria were analyzed for mitochondrial lipid peroxidation. In separate experiments, rats received daily injections of subcutaneous (SQ) vitamin E before GCDC infusion. Bile acid-induced injury (serum AST and ALT and liver histology) was more severe in the obese rats than in the lean rats, characterized predominantly by extensive cell necrosis with minimal evidence of apoptosis. SQ vitamin E provided significant protection against IV GCDC-induced hepatic injury, in vitro GCDC-induced permeability transition, and cytochrome C and apoptosis-inducing factor release from isolated mitochondria. CONCLUSION: Steatosis sensitizes the liver to bile acid-induced necrotic hepatocyte injury, which is responsive to vitamin E therapy.