Neurogenin-3 Enteric Endocrinopathy: A Rare Case of Pediatric Congenital Diarrhea and Diabetes Mellitus.

Disorders of intestinal enteroendocrine cells (EEC) are a rare cause of congenital diarrhea and diabetes. The gene NEUROG3 is essential in EEC differentiation, and mutations in this gene lead to a paucity of EEC in the intestine and pancreas, often presenting clinically as congenital diarrhea and diabetes mellitus. We present the earliest known diagnosis of NEUROG3-associated enteric endocrinopathy, which was identified on a neonatal diabetes genetic panel sent at 4 weeks of age. Our patient presented with severe diarrhea, malnutrition, electrolyte derangements, and neonatal diabetes. He was started on parenteral nutrition at 3 months of age for nutritional and hydration support and required long-acting insulin for his diabetes. We demonstrate significant reduction in EEC, including cells expressing glucagon-like peptide-1, in intestinal biopsies from our patient, raising the possibility that loss of glucagon-like peptide-1 contributes to NEUROG3-associated diarrhea and diabetes mellitus. This case advances our understanding of the presentation, diagnosis, and management of this rare disease.

Macrophage-derived IL-1ß/NF-κB signaling mediates parenteral nutrition-associated cholestasis.

In infants intolerant of enteral feeding because of intestinal disease, parenteral nutrition may be associated with cholestasis, which can progress to end-stage liver disease. Here we show the function of hepatic macrophages and phytosterols in parenteral nutrition-associated cholestasis (PNAC) pathogenesis using a mouse model that recapitulates the human pathophysiology and combines intestinal injury with parenteral nutrition. We combine genetic, molecular, and pharmacological approaches to identify an essential function of hepatic macrophages and IL-1ß in PNAC. Pharmacological antagonism of  IL-1 signaling or genetic deficiency in CCR2, caspase-1 and caspase-11, or IL-1 receptor (which binds both IL-1α and IL-1ß) prevents PNAC in mice. IL-1ß increases hepatocyte NF-κB signaling, which interferes with farnesoid X receptor and liver X receptor bonding to respective promoters of canalicular bile and sterol transporter genes (Abcc2, Abcb11, and Abcg5/8), resulting in transcriptional suppression and subsequent cholestasis. Thus, hepatic macrophages, IL-1ß, or NF-κB may be targets for restoring bile and sterol transport to treat PNAC.

Genetic Mutations in Pediatric Pancreatitis.

OBJECTIVES: The aim of our study was to describe the prevalence, characteristics, and outcomes of children with acute recurrent (ARP) or chronic (CP) pancreatitis with or without mutations in PRSS1, CFTR or SPINK1. METHODS: Retrospective chart review of children with ARP or CP with and without testing for PRSS1, CFTR, and SPINK1. Demographics, clinical features, management, and outcome were collected. Analysis of variance was used to compare continuous variables and χ or Fisher exact test for categorical variables. RESULTS: Ninety-one subjects with ARP (n = 77) or CP (n = 14) were identified and included in this study. Of these, 37 (41%) were male, 44 were white, and 30 were Hispanic. Thirty-three (36%) had at least 1 mutation identified (Pan-Mut): PRSS1 (7), CFTR (21), SPINK1 (3), SPINK/CFTR (2). Thirty-six were tested but had no mutation, and 22 were not tested. The Pan-Mut subjects were more likely to have a family history of pancreatitis but there were no differences in the clinical features, imaging or outcome. CONCLUSIONS: Mutations in CFTR, SPINK1 or PRSS1 are present in one third of pediatric ARP and CP with no other cause. No clinical features or outcomes differentiated between the Pan-Mut group and the no-mutation group. The Pan-Mut subjects were more likely to have a family history of pancreatitis. Pediatric ARP and CP without identified cause should undergo genetic testing.

Laparoscopic-Assisted Endoscopic Resection of a Gastric Leiomyoma.

Leiomyomas are infrequent benign intestinal tumors that can arise at any age and location within the gastrointestinal (GI) tract. These tumors can cause symptoms including abdominal pain, obstruction, intussusception, volvulus, GI bleeding, or amass and should be resected if symptomatic. Open surgical resection is considered the standard for removing these tumors. However, recent improvements in endoscopic and laparoscopic equipment have made it possible to utilize minimally invasive techniques of tumor removal including complete endoscopic resection or endoscopic-assisted laparoscopic resection. We present the case of an adolescent female with a large mass located at the gastroesophageal junction (GEJ) causing GI bleeding. Given the location of the mass near the GEJ and the morbidity associated with surgical resection, we performed laparoscopic-assisted complete endoscopic resection of tumor. In addition, this tumor had an unusual immunohistochemical-staining pattern, with focal expression of markers more often seen in GI stromal tumors, elucidating a gray area between these two tumor classes with potential implications for patient follow-up. Laparoscopic-assisted endoscopic resection of benign tumors is a useful technique that can be employed to facilitate resection of mucosal and subserosal masses near the GEJ with minimal morbidity.

Phytosterols promote liver injury and Kupffer cell activation in parenteral nutrition-associated liver disease.

Parenteral nutrition-associated liver disease (PNALD) is a serious complication of PN in infants who do not tolerate enteral feedings, especially those with acquired or congenital intestinal diseases. Yet, the mechanisms underlying PNALD are poorly understood. It has been suggested that a component of soy oil (SO) lipid emulsions in PN solutions, such as plant sterols (phytosterols), may be responsible for PNALD, and that use of fish oil (FO)-based lipid emulsions may be protective. We used a mouse model of PNALD combining PN infusion with intestinal injury to demonstrate that SO-based PN solution causes liver damage and hepatic macrophage activation and that PN solutions that are FO-based or devoid of all lipids prevent these processes. We have furthermore demonstrated that a factor in the SO lipid emulsions, stigmasterol, promotes cholestasis, liver injury, and liver macrophage activation in this model and that this effect may be mediated through suppression of canalicular bile transporter expression (Abcb11/BSEP, Abcc2/MRP2) via antagonism of the nuclear receptors Fxr and Lxr, and failure of up-regulation of the hepatic sterol exporters (Abcg5/g8/ABCG5/8). This study provides experimental evidence that plant sterols in lipid emulsions are a major factor responsible for PNALD and that the absence or reduction of plant sterols is one of the mechanisms for hepatic protection in infants receiving FO-based PN or lipid minimization PN treatment. Modification of lipid constituents in PN solutions is thus a promising strategy to reduce incidence and severity of PNALD.

Antibiotic exposure and room contamination among patients colonized with vancomycin-resistant enterococci.

OBJECTIVE: To determine whether total and antianaerobic antibiotic exposure increases the risk of room contamination among vancomycin-resistant enterococci (VRE)-colonized patients. DESIGN AND SETTING: A 14-month study in 2 intensive care units at an academic tertiary care hospital in Boston, Massachusetts. PATIENTS: All patients who acquired VRE or were VRE-colonized on admission and who had environmental cultures performed. METHODS: We performed weekly environmental cultures (2 sites per room) and considered a room to be contaminated if there was a VRE-positive environmental culture during the patient's stay. We determined risk factors for room contamination by use of the Cox proportional hazards model. RESULTS: Of 142 VRE-colonized patients, 35 (25%) had an associated VRE-positive environmental culture. Patients who contaminated their rooms were more likely to have diarrhea than those who did not contaminate their rooms (23 [66%] of 35 vs 41 [38%] of 107; P = .005) and more likely to have received antibiotics while VRE colonized (33 [94%] of 35 vs 86 [80%] of 107; P = .02). There was no significant difference in room contamination rates between patients exposed to antianaerobic regimens and patients exposed to nonantianaerobic regimens or between patients with and patients without diarrhea, but patients without any antibiotic exposure were unlikely to contaminate their rooms. Diarrhea and antibiotic use were strongly confounded; although two-thirds of room contamination occurred in rooms of patients with diarrhea, nearly all of these patients received antibiotics. In multivariable analysis, higher mean colonization pressure in the ICU increased the risk of room contamination (adjusted hazard ratio per 10% increase, 1.44 [95% confidence interval, 1.04-2.04]), whereas no antibiotic use during VRE colonization was protective (adjusted hazard ratio, 0.21 [95% confidence interval, 0.05-0.89]). CONCLUSIONS: Room contamination with VRE was associated with increased mean colonization pressure in the ICU and diarrhea in the VRE-colonized patient, whereas no use of any antibiotics during VRE colonization was protective.

Prior environmental contamination increases the risk of acquisition of vancomycin-resistant enterococci.

BACKGROUND: Patients colonized with vancomycin-resistant enterococci (VRE) frequently contaminate their environment, but the environmental role of VRE transmission remains controversial. METHODS: During a 14-month study in 2 intensive care units, weekly environmental and twice-weekly patient surveillance cultures were obtained. VRE acquisition was defined as a positive culture result >48 h after admission. To determine risk factors for VRE acquisition, Cox proportional hazards models using time-dependent covariates for colonization pressure and antibiotic exposure were examined. RESULTS: Of 1330 intensive care unit admissions, 638 patients were at risk for acquisition, and 50 patients (8%) acquired VRE. Factors associated with VRE acquisition included average colonization pressure (hazard ratio [HR], 1.4 per 10% increase; 95% confidence interval [CI], 1.2-1.8), mean number of antibiotics (HR, 1.7 per additional antibiotic; 95% CI, 1.2-2.5), leukemia (HR, 3.1; 95% CI, 1.2-7.8), a VRE-colonized prior room occupant (HR, 3.1; 95% CI, 1.6-5.8), any VRE-colonized room occupants within the previous 2 weeks (HR, 2.5; 95% CI, 1.3-4.8), and previous positive room culture results (HR, 3.4; 95% CI, 1.2-9.6). In separate multivariable analyses, a VRE-colonized prior room occupant (HR, 3.8; 95% CI, 2.0-7.4), any VRE-colonized room occupants within the previous 2 weeks (HR, 2.7; 95% CI, 1.4-5.3), and previous positive room culture results (HR, 4.4; 95% CI, 1.5-12.8) remained independent predictors of VRE acquisition, adjusted for colonization pressure and antibiotic exposure. CONCLUSIONS: We found that prior room contamination, whether measured via environmental cultures or prior room occupancy by VRE-colonized patients, was highly predictive of VRE acquisition. Increased attention to environmental disinfection is warranted.