Fractionated plasma N-glycan profiling of novel cohort of ATP6AP1-CDG subjects identifies phenotypic association.

ATP6AP1-CDG is an X-linked disorder typically characterized by hepatopathy, immunodeficiency, and an abnormal type II transferrin glycosylation pattern. Here, we present 11 new patients and clinical updates with biochemical characterization on one previously reported patient. We also document intrafamilial phenotypic variability and atypical presentations, expanding the symptomatology of ATP6AP1-CDG to include dystonia, hepatocellular carcinoma, and lysosomal abnormalities on hepatic histology. Three of our subjects received successful liver transplantation. We performed N-glycan profiling of total and fractionated plasma proteins for six patients and show associations with varying phenotypes, demonstrating potential diagnostic and prognostic value of fractionated N-glycan profiles. The aberrant N-linked glycosylation in purified transferrin and remaining plasma glycoprotein fractions normalized in one patient post hepatic transplant, while the increases of Man4GlcNAc2 and Man5GlcNAc2 in purified immunoglobulins persisted. Interestingly, in the single patient with isolated immune deficiency phenotype, elevated high-mannose glycans were detected on purified immunoglobulins without glycosylation abnormalities on transferrin or the remaining plasma glycoprotein fractions. Given the diverse and often tissue specific clinical presentations and the need of clinical management post hepatic transplant in ATP6AP1-CDG patients, these results demonstrate that fractionated plasma N-glycan profiling could be a valuable tool in diagnosis and disease monitoring.

Risk Factors for 30-Day Unplanned Readmission After Hepatectomy: Analysis of 438 Pediatric Patients from the ACS-NSQIP-P Database.

BACKGROUND: Hepatic resections are uncommon in children. Most studies reporting complications of these procedures and risk factors associated with unplanned readmissions are limited to retrospective data from single centers. We investigated risk factors for 30-day unplanned readmission after hepatectomy in children using the American College of Surgeons National Surgical Quality Improvement-Pediatric database. METHODS: The database was queried for patients aged 0-18 years who underwent hepatectomy for the treatment of liver lesions from 2012 to 2018. Chi-squared tests were performed to evaluate for potential risk factors for unplanned readmissions. A multivariate regression analysis was performed to identify independent predictors for unplanned 30-day readmissions. RESULTS: Among 438 children undergoing hepatectomy, 64 (14.6%) had unplanned readmissions. The median age of the hepatectomy cohort was 1 year (0-17); 55.5% were male. Patients readmitted had significantly higher rates of esophageal/gastric/intestinal disease (26.56% vs. 14.97%; p=0.022), current cancer (85.94% vs. 75.67%; p=0.012), and enteral and parenteral nutritional support (31.25% vs. 17.65%; p=0.011). Readmitted patients had significantly higher rates of perioperative blood transfusion (67.19% vs. 52.41%; p=0.028), organ/space surgical site infection (10.94% vs. 1.07%; p<.001), sepsis (15.63% vs. 3.74%; p<.001), and total parenteral nutrition at discharge (9.09% vs. 2.66%; p=0.041). Organ/space surgical site infection was an independent risk factor for unplanned readmission (OR=9.598, CI [2.070-44.513], p=0.004) by multivariable analysis. CONCLUSION: Unplanned readmissions after liver resection are frequent in pediatric patients. Organ/space surgical site infections may identify patients at increased risk for unplanned readmission. Strategies to reduce these complications may decrease morbidity and costs associated with unplanned readmissions.

Bone Fractures in Children With Cholestatic Liver Disease May Mimic Those Seen in Child Abuse.

ABSTRACT: Certain fractures in children are highly specific for child abuse. Metabolic bone disease frequently develops in patients with cholestatic liver disease (CLD); this can result in weakened bones and a predisposition to pathologic fractures. Fractures that occur in patients with rickets and osteopenia may mimic a bone response to inflicted injury, which in children raise the concern of child abuse. Here we report a series of 15 patients with CLD who developed pathologic fractures in the setting of metabolic bone disease. During initial evaluation, the caretakers of 5 of these 15 patients were reported to child protective services and investigated for child abuse. Pediatricians should be aware that children with CLD have an increased incidence of pathologic fractures, even after the cholestasis has resolved.

Concomitant tacrolimus and ketorolac therapy in pediatric liver transplant recipients: Teaching old dogma new tricks.

Nonsteroidal anti-inflammatory drugs (NSAIDs), such as ketorolac, are effective analgesic medications, but concerns for nephrotoxicity have limited their role for pain control following pediatric liver transplantation (LT). Calcineurin inhibitors (CNIs) and NSAIDs share a similar mechanism of nephrotoxicity, and concomitant administration is traditionally discouraged. A retrospective review of pediatric LT recipients was conducted between 1/1/2015 and 12/31/2019 at a single center. Patients were stratified based on receipt of ketorolac. The primary outcome was the incidence of acute kidney injury (AKI). Secondary outcomes included serum creatinine, urine output, estimated glomerular filtration rate, bleeding incidence, oral morphine milligram equivalents, and hospital length of stay (LOS). The incidence of AKI was similar between the two groups with 25.8% of patients in the ketorolac group versus 29.2% of patients in the nonketorolac group (p = .475) meeting criteria in the first 10 days post-transplant. Opioid requirements were less in the ketorolac group (p < .001), who also demonstrated shorter LOS compared with nonketorolac patients (p = .033). Concurrent CNI and ketorolac use did not result in an increased incidence of AKI in the early post-LT period and resulted in significantly lower opioid requirements along with a decreased hospital LOS.

A case of an Infant with SARS-CoV-2 hepatitis early after liver transplantation.

We present a case of a pediatric liver transplant recipient diagnosed with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection four days after receiving a living donor liver allograft from her mother. The recipient was a 6-month-old with end-stage liver disease due to biliary atresia and failed Kasai. The infant had an uncomplicated implantation, excellent graft function and down-trending liver enzymes until developing fevers, diarrhea, and moderate respiratory distress requiring non-invasive respiratory support. SARS-CoV-2 testing (nasal swab Polymerase Chain Reaction) was positive on post-operative day (POD) 4. Liver enzymes peaked ~1000 U/L (5-fold higher than the previous day) on POD 6. Histology demonstrated a mixed picture of moderate acute hepatitis and classical elements of mild to moderate acute cellular rejection. Her hepatitis and respiratory symptoms improved coincident with completing treatment with hydroxychloroquine, reduced immunosuppression, and intravenous gamma globulin (IVIG).

Role of Budesonide for the Treatment of Rejection in Pediatric Liver Transplantation.

INTRODUCTION: Corticosteroids are an integral part of liver transplant (LT) immunosuppression regimens but are often accompanied by many adverse effects. Budesonide is an oral corticosteroid with extensive (80%-90%) hepatic first-pass metabolism and minimal systemic absorption. The aim of this study was to examine the safety and efficacy of budesonide for management of acute cellular rejection (ACR) in pediatric LT recipients. METHODS: A retrospective descriptive analysis was performed for all pediatric patients who underwent LT at our center and were prescribed oral budesonide for the treatment of ACR. Alanine aminotransferase (ALT) values and documented adverse effects were reviewed. RESULTS: Twenty-nine patients were prescribed budesonide for the treatment of ACR; 65.5% with biopsy-proven acute rejection and 34.5% with presumed ACR. There was a significant decrease in ALT noted from the time of rejection when compared to values 1 month (P = 0.0011), 3 months (P = 0.0003), and 6 months (P = 0.0001) after treatment with budesonide. There was no difference noted between patient baseline ALT levels before rejection when compared to 1, 3, and 6 months posttreatment values suggesting resolution of rejection. Three patients required conversion from budesonide to systemic steroids. There were no discontinuations of budesonide secondary to adverse effects. CONCLUSION: Oral budesonide may be a promising alternative to systemic corticosteroids for the management of mild/moderate ACR and for empiric treatment of ACR in select pediatric LT recipients. Data from this study may provide the foundation for larger, prospective, multicenter trials to assess the effectiveness of budesonide in the treatment of ACR.

Nonalcoholic Fatty Liver Disease in Children: Unique Considerations and Challenges.

Nonalcoholic fatty liver disease (NAFLD) is increasing in prevalence in concert with the global epidemic of obesity and is being diagnosed at increasingly younger ages. The unique histologic features and early presentation of disease in pediatrics suggest that children and adults may differ with regard to etiopathogenesis, with children displaying a greater vulnerability to genetic and environmental factors. Of significant relevance to pediatrics, in utero and perinatal stressors may alter the lifelong health trajectory of a child, increasing the risk of NAFLD and other cardiometabolic diseases. The development and progression of disease in childhood is likely to carry increased risk of long-term morbidity. Novel biomarkers and therapeutic agents are needed to avoid the otherwise inevitable health and societal consequences of this rapidly expanding pediatric population.

MRI predictors of treatment response for perianal fistulizing Crohn disease in children and young adults.

BACKGROUND: Magnetic resonance imaging (MRI) is considered the imaging standard for diagnosis and characterization of perianal complications associated with Crohn disease in children and adults. OBJECTIVE: To define MRI criteria that could act as potential predictors of treatment response in fistulizing Crohn disease in children, in order to guide more informed study interpretation. MATERIALS AND METHODS: We performed a retrospective database query to identify all children and young adults with Crohn disease who underwent serial MRI studies for assessment of perianal symptoms between 2003 and 2010. We examined imaging features of perianal disease including fistula number, type and length, presence and size of associated abscess, and disease response/progression on follow-up MRI. We reviewed imaging studies and electronic medical records. Statistical analysis, including logistic regression, was performed to associate MR imaging features with treatment response and disease progression. RESULTS: We included 36 patients (22 male, 14 female; age range 8-21 years). Of these, 32 had a second MRI exam and 4 had clinical evidence of complete response, obviating the need for repeat imaging. Of the parameters analyzed, presence of abscess, type of fistula according to the Parks classification, and multiplicity were not predictors of treatment outcome. Maximum length of the dominant fistula and aggregate fistula length in the case of multiple fistulae were the best predictors of treatment outcome. Maximum fistula length <2.5 cm was a predictor of treatment response, while aggregate fistula length ≥2.5 cm was a predictor of disease progression. CONCLUSION: Perianal fistula length is an important imaging feature to assess on MRI of fistulizing Crohn disease.

Tissue-print and print-phoresis as platform technologies for the molecular analysis of human surgical specimens: mapping tumor invasion of the prostate capsule.

Molecular profiling of human biopsies and surgical specimens is frequently complicated by their inherent biological heterogeneity and by the need to conserve tissue for clinical diagnosis. We have developed a set of novel 'tissue print' and 'print-phoresis' technologies to facilitate tissue and tumor-marker profiling under these circumstances. Tissue printing transfers cells and extracellular matrix components from a tissue surface onto nitrocellulose membranes, generating a two-dimensional anatomical image on which molecular markers can be visualized by specific protein and RNA- and DNA-detection techniques. Print-phoresis is a complementary new electrophoresis method in which thin strips from the print are subjected to polyacrylamide gel electrophoresis, providing a straightforward interface between the tissue-print image and gel-based proteomic techniques. Here we have utilized these technologies to identify and characterize markers of tumor invasion of the prostate capsule, an event generally not apparent to the naked eye that may result in tumor at the surgical margins ('positive margins'). We have also shown that tissue-print technologies can provide a general platform for the generation of marker maps that can be superimposed directly onto histopathological and radiological images, permitting molecular identification and classification of individual malignant lesions.