Whole Foods Introduction Associated With Symptomatic Anastomotic Ulceration in Children With Short Bowel Syndrome.

OBJECTIVES: Anastomotic ulceration (AU) is a rare but life-threatening complication of pediatric short bowel syndrome (SBS). AUs may be challenging to detect and refractory to treatment. This study aimed to identify features associated with symptomatic bleeding AUs in children with SBS and factors that may impact resolution of bleeding. The relationship between dietary changes and symptomatic anastomotic hemorrhage was also explored. METHODS: We conducted a retrospective chart review of 381 patients cared for in the Intestinal Rehabilitation Program at our center from 2013 to 2022. Patients with symptomatic AUs were identified based on at least 1 endoscopic procedure showing AUs and evidence of clinically significant gastrointestinal bleeding. We collected patient demographics, clinical characteristics, dietary history, radiologic imaging, and histopathology. We used descriptive statistics to identify patterns of presentation. RESULTS: AUs were identified in 22 patients who were followed for a median duration of 2.9 years after anastomotic ulcer identification. AUs uniformly evolved years after the initial anastomosis (median 3.2 years). Characteristics included bowel stricture (4/22), small bowel-colon anastomosis (19/22), partial colectomy (17/22), and an increase in whole foods fraction (12/18). Bleeding resolved with operative intervention in the majority with anastomotic stricture (3/4). Recurrent bleeding was common in those without stricture (13/18). In a subset of patients without stricture, whole food reduction was associated with improvement or resolution of bleeding (5/6). CONCLUSIONS: We observed a higher proportion of patients with AUs who responded to surgical intervention in the subset of children with definitive anastomotic strictures versus those without, suggesting that careful characterization of intestinal anatomy may be critical to predicting response to therapy. We also observed that bleeding from AU typically first manifested within 1 year of a shift from elemental or hydrolyzed enteral formula to a whole food-based diet (including commercial blenderized feeds), which may indicate that components of the enteral diet play a role in the pathogenesis of AU. Further studies are needed to validate these hypotheses.

Dietary fiber-based regulation of bile salt hydrolase activity in the gut microbiota and its relevance to human disease.

Complications of short bowel syndrome (SBS) include malabsorption and bacterial overgrowth, requiring prolonged dependence on parenteral nutrition (PN). We hypothesized that the intolerance of whole food in some SBS patients might be due to the effect of dietary fiber on the gut microbiome. Shotgun metagenomic sequencing and targeted metabolomics were performed using biospecimens collected from 55 children with SBS and a murine dietary fiber model. Bioinformatic analyses were performed on these datasets as well as from a healthy human dietary intervention study. Compared to healthy controls, the gut microbiota in SBS had lower diversity and increased Proteobacteria, a pattern most pronounced in children on PN and inversely correlated with whole food consumption. Whole food intake correlated with increased glycoside hydrolases (GH) and bile salt hydrolases (BSH) with reduced fecal conjugated bile acids suggesting that dietary fiber regulates BSH activity via GHs. Mechanistic evidence supporting this notion was generated via fecal and plasma bile acid profiling in a healthy human fiber-free dietary intervention study as well as in a dietary fiber mouse experiment. Gaussian mixture modeling of fecal bile acids was used to identify three clinically relevant SBS phenotypes. Dietary fiber is associated with bile acid deconjugation likely via an interaction between gut microbiota BSHs and GHs in the small intestine, which may lead to whole food intolerance in patients with SBS. This mechanism not only has potential utility in clinical phenotyping and targeted therapeutics in SBS based on bile acid metabolism but may have relevance to other intestinal disease states.

Impact of Pancreatic Enzymes on Enteral Fat and Nitrogen Absorption in Short Bowel Syndrome.

OBJECTIVES: Patients with short bowel syndrome (SBS) can have a high morbidity rate. To minimize morbidity, enteral autonomy is the primary goal in clinical management of patients with SBS. This is often difficult to achieve because of significant malabsorption. To date, there are limited therapies that improve absorption in patients with SBS. The impact of pancreatic enzyme replacement treatment on enteral absorption has not been studied in this population and was the primary aim of this study. SUBJECTS/METHODS: This was an interventional study in 11 subjects (6 pediatric subjects ages 4.0-17.9 years, 5 adult subjects 18-75 years) that compared enteral absorption in each subject before and after pancreatic enzyme medication (Creon). Coefficient of fat absorption (CFA) and coefficient of nitrogen absorption (CNA) were used as markers of enteral absorption of fat and protein, respectively. RESULTS: There was no statistically significant mean change in CFA and CNA before and after pancreatic enzyme medication therapy. Six subjects demonstrated an increase in CFA and 8 subjects demonstrated an increase in CNA after the use of pancreatic enzyme medication therapy. CONCLUSIONS: There was no statistically significant improvement in enteral fat and protein absorption in the cohort as a whole, though several subjects demonstrated an improvement. These results suggest that some patients with SBS may benefit from treatment with pancreatic enzymes. Further studies are needed to better evaluate the effect of pancreatic enzyme therapy on enteral absorption in subjects with SBS and to characterize factors that may predict a positive response.

Pathologic lower extremity fractures in children with Alagille syndrome.

OBJECTIVES: : In this retrospective study, we aimed to determine the incidence and distribution of fractures in patients with Alagille syndrome, 1 of the leading inherited causes of pediatric cholestatic liver disease. MATERIALS AND METHODS: : Surveys regarding growth, nutrition, and organ involvement were distributed to patient families in the Alagille Syndrome Alliance of the Children's Hospital of Philadelphia research database. Patients with a history of fracture were identified by their response to 1 question, and details characterizing each patient's medical, growth, and fracture history were obtained through chart review and telephone contact. RESULTS: : Twelve of 42 patients (28%) reported a total of 27 fractures. Patients experienced fractures at a mean age of 5 years, which contrasts with healthy children, in whom fracture incidence peaks in adolescence. Fractures occurred primarily in the lower extremity long bones (70%) and with little or no trauma (84%). Estimated incidence rate calculations yielded 399.6 total fractures per 10,000 person-years (95% confidence interval 206.5, 698.0) and 127.6 femur fractures per 10,000 person-years (95% confidence interval 42.4, 297.7). There were no differences in sex, age distribution, or organ system involvement between the fracture and no-fracture groups. CONCLUSIONS: : Children with Alagille syndrome may be at risk for pathologic fractures, which manifest at an early age and in a unique distribution favoring the lower extremity long bones. Although this preliminary study is limited by small sample size and potential ascertainment bias, the data suggest that larger studies are warranted to further characterize fracture risk and explore factors contributing to bone fragility in these children.

Lateral sinus thrombosis as a complication of otitis media: 10-year experience at the children's hospital of Philadelphia.

OBJECTIVES: Lateral sinus thrombosis is a rare intracranial complication of otitis media that is traditionally described in countries with poor access to medical care. Our goal was to describe the clinical presentation, management, and outcome of patients diagnosed with lateral sinus thrombosis in a US tertiary care center and to highlight the clinically relevant differences in presentation between these patients and those described in previous reports. PATIENTS AND METHODS: The medical charts of 13 patients diagnosed with otogenic lateral sinus thrombosis were reviewed. These patients were identified from a manual search of 156 subjects with International Classification of Diseases, Ninth Revision codes corresponding with a diagnosis of mastoiditis or thromboembolism over a 10-year period (1997-2007) at the Children's Hospital of Philadelphia. RESULTS: In contrast to previous reports in the literature, the majority of patients in this series exhibited cranial neuropathies and signs of raised intracranial pressure. Nearly all of the patients had a history of acute otitis media treated with antibiotics in the weeks preceding admission. However, many patients denied high fevers or active otomastoid symptoms, which are classically associated with lateral sinus thrombosis. The diagnosis was made in all of the children by using computed tomography and MRI/venography. Treatment strategies included myringotomy tube placement, simple mastoidectomy, intravenous antibiotics, and anticoagulation. Posthospitalization follow-up data revealed no significant long-term complications. CONCLUSION: Despite appropriate antibiotic therapy, lateral sinus thrombosis and other intracranial complications of otitis media are still a threat to children in the modern era. Neurologic, rather than otologic, symptoms may dominate the presentation of otogenic lateral sinus thrombosis. Thus, a high index of suspicion may be critical for ensuring timely diagnosis of this rare condition.

Bile duct proliferation in Jag1/fringe heterozygous mice identifies candidate modifiers of the Alagille syndrome hepatic phenotype.

UNLABELLED: Alagille syndrome (AGS) is a heterogeneous developmental disorder associated with bile duct paucity and various organ anomalies. The syndrome is caused by mutations in JAG1, which encodes a ligand in the Notch signaling pathway, in the majority of cases and mutations in the NOTCH2 receptor gene in less than 1% of patients. Although a wide array of JAG1 mutations have been identified in the AGS population, these mutational variants have not accounted for the wide phenotypic variability observed in patients with this syndrome. The Fringe genes encode glycosyltransferases, which modify Notch and alter ligand-receptor affinity. In this study, we analyzed double heterozygous mouse models to examine the Fringe genes as potential modifiers of the Notch-mediated hepatic phenotype observed in AGS. We generated mice that were haploinsufficient for both Jag1 and one of three paralogous Fringe genes: Lunatic (Lfng), Radical (Rfng), and Manic (Mfng). Adult Jag1(+/-)Lfng(+/-) and Jag1(+/-)Rfng(+/-) mouse livers exhibited widespread bile duct proliferation beginning at 5 weeks of age and persisting up to 1 year. The Jag1(+/-)Mfng(+/-) livers showed a subtle, yet significant increase in bile duct numbers and bile duct to portal tract ratios. These abnormalities were not observed in the newborn period. Despite the portal tract expansion by bile ducts, fibrosis was not increased and epithelial to mesenchymal transition was not shown in the affected portal tracts. CONCLUSION: Mice heterozygous for mutations in Jag1 and the Fringe genes display striking bile duct proliferation, which is not apparent at birth. These findings suggest that the Fringe genes may regulate postnatal bile duct growth and remodeling, and serve as candidate modifiers of the hepatic phenotype in AGS.

Transseptal suture to secure middle meatal spacers.

Middle meatal spacers are used by many sinus surgeons to aid postoperative care. Aspiration of a spacer is a concern. We demonstrate a novel method of securing spacers with a transseptal suture to prevent aspiration. We fashion each spacer from a powder-free, nonlatex glove finger that is packed with a Merocel sponge. The open end of the finger is closed with 2-0 Prolene sutures. For a bilateral procedure, the needle is left attached to one of the spacers. A spacer is placed in each ethmoid cavity, the attached needle is passed through the anterior cartilaginous septum, and the suture is tied to the suture on the opposite spacer. For unilateral procedures, the suture on the single spacer is passed to the contralateral side and tied on itself. One week later, the transseptal suture is cut and the spacers are removed. We performed this procedure on 78 patients who had undergone total ethmoidectomy. None of the spacers migrated during the 1 week they were in place. One patient complained of pain during removal of a spacer. During follow-up of 2 to 10 months, we found no evidence of injury to the septum at the site of the transseptal suture. We conclude that the transseptal suture is a safe and cosmetically superior method of securing middle meatal spacers.

Craniofacial resection of advanced juvenile nasopharyngeal angiofibroma.

OBJECTIVE: To describe the results of a craniofacial approach to resection of stage IIIB juvenile nasopharyngeal angiofibroma, performed by an integrated skull base surgical team. DESIGN: A retrospective case-series review was conducted with postoperative follow-up ranging from 28 to 63 months. SETTING: Operations were performed at a tertiary medical center. PATIENTS: A referred sample of 5 male patients, ranging in age from 10 to 23 years (mean, 15 years). INTERVENTIONS: All patients underwent resection of nasopharyngeal angiofibromas with intracranial extension. The procedure involved an infratemporal fossa approach via zygomatic osteotomy and subtemporal craniectomy. Anterior exposure was gained through a standard facial translocation. Dissection of the cavernous carotid artery was required in 3 patients. MAIN OUTCOME MEASURES: Intraoperative and postoperative morbidity. RESULTS: The average operating time was 12 hours 47 minutes. Estimated blood loss ranged from 700 to 1750 mL (mean, 1120 mL), with 2 patients requiring intraoperative transfusion. Patients were hospitalized for a mean duration of 5.6 days. Long-term morbidity includes facial dysesthesia, nasal crusting, and malodorous nasal discharge. No patients sustained stroke, oculomotor dysfunction, vision loss, or auditory impairment. At most recent follow-up, which ranges from 28 to 63 months, tumor recurrence has been confirmed in 1 patient. CONCLUSIONS: A combined craniofacial approach is appropriate for juvenile nasopharyngeal angiofibroma that extends intracranially. Complete tumor removal with acceptable morbidity can be expected.