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CLINICAL IMPLICATIONS: Tezepelumab use for asthma successfully induced and sustained eosinophilic esophagitis remission and reversed its pathologic transcriptome. This case provides insight into the mechanistic underpinnings of type 2 inflammation in EoE and the clinical utility of targeting these pathways for treatment.
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BACKGROUND: Eosinophil accumulation is a main feature of eosinophilic gastritis (EoG) and is associated with its histologic diagnosis and pathology. However, a recent clinical trial has demonstrated that EoG endoscopic, noneosinophil histologic, and clinical features remain persistent despite complete eosinophil depletion. OBJECTIVE: Our aim was to examine gastric T-cell composition and associated cytokine levels of patients with EoG following benralizumab-induced eosinophil depletion versus following administration of placebo. METHODS: A cohort of subjects with EoG from a subset of subjects who participated in a recent phase 2 benralizumab trial was treated for 12 weeks with administration of 3 doses of benralizumab (anti-IL-5 receptor α antibody [n = 5]) or placebo (n = 4). Single-cell suspensions obtained by gastric biopsy were stimulated with phorbol 12,13-dibutyrate and ionomycin in the presence of brefeldin A and monensin. Harvested cells were fixed, stained, and analyzed by flow cytometry to examine T-cell populations and associated cytokines. RESULTS: Following benralizumab treatment but not placebo, blood and gastric eosinophil levels decreased 16-fold and 10-fold, respectively. Whereas histologic score and features were significantly decreased, no change was observed in endoscopic score and features. Following complete eosinophil depletion with benralizumab, gastric TH2 cell levels were 3-fold higher than the levels in the patients with EoG who were given placebo; and the levels of associated type 2 cytokine production of IL-4, IL-5, and IL-13 in the benralizumab-treated patients were, respectively, 4-, 5.5-, and 2.5-fold, higher than those in the placebo-treated patients. CONCLUSION: We have identified a putative positive feedback loop whereby eosinophil depletion results in a paradoxic increase in levels of TH2 cells and derived cytokines; this finding suggests an explanation for the limited success of eosinophil depletion as monotherapy in eosinophil-associated gastrointestinal disorders.
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BACKGROUND: Transnasal endoscopy (TNE) does not require general anesthesia, an attractive characteristic for monitoring eosinophilic esophagitis (EoE). We evaluated the adequacy of TNE-obtained esophageal biopsies using the EoE Histology Scoring System (EoEHSS). METHODS: The Cincinnati Center for Eosinophilic Disorders database was searched for esophageal biopsies obtained by the same endoscopist, using either TNE or conventional endoscopy (CE). Whole-slide biopsy images were evaluated. The Mann-Whitney test was used for median (interquartile range) values and Fisher exact test for categorical variables. P ≤ .05 was considered significant. RESULTS: Median age (P = .82) or height (P = .83) did not differ between TNE (n = 17) and CE (n = 17) groups. Although median largest piece size (mm2) differed between the groups (TNE: 0.59 (0.45, 0.86), CE: 2.24 (1.09, 2.82), P < .001), all 8 EoEHSS features were evaluated in each group; only 1 feature (lamina propria fibrosis) was missing in both groups (TNE: 19/34, CE: 11/34, P = .09). The median peak eosinophil count/high-power field differed (TNE: 3 (0, 29), CE: 16 (1, 66), P = .03), but overall grade (TNE: 0.17 (0.10, 0.29), CE: 0.22 (0.14, 0.46), P = .12), stage (TNE: 0.14 (0.10, 0.24), CE: 0.20 (0.10, 0.43), P = .15), and non-eosinophil-related individual EoEHSS scores did not differ. CONCLUSIONS: TNE- and CE-obtained esophageal biopsies are similarly sufficient for evaluation of key pathological features in EoE.
Subject(s)
Eosinophilic Esophagitis , Esophagus , Humans , Eosinophilic Esophagitis/pathology , Eosinophilic Esophagitis/diagnosis , Female , Male , Biopsy , Esophagus/pathology , Child , Adolescent , Esophagoscopy , Retrospective Studies , Child, Preschool , AdultABSTRACT
PURPOSE OF REVIEW: This review presents and summarizes the existing studies on the treatment goals and options for pediatric eosinophilic esophagitis utilizing rigorous peer-reviewed literature. RECENT FINDINGS: In addition to traditional treatments, emerging biologic therapies continue to evolve the approach to treating pediatric eosinophilic esophagitis. Well defined treatment goals will aid the continued development of new therapies. Further, innovative assessment tools have changed how the clinician is able to assess the effectiveness of therapies with a trend toward less invasive options. The management of pediatric eosinophilic esophagitis continues to evolve with the advent of both novel treatment options and assessment tools. Treatment choices, with benefits and risks involved, should be presented to families upon diagnosis and tailored towards the individual patient and likelihood of adherence and success. Biologic therapy for EoE presents an exciting option for both first line therapy and escalation for those with severe or unresponsive disease.
Subject(s)
Eosinophilic Esophagitis , Child , Humans , Eosinophilic Esophagitis/diagnosis , Eosinophilic Esophagitis/therapy , Biological TherapyABSTRACT
BACKGROUND: In eosinophilic gastrointestinal diseases, the role of eosinophils in disease pathogenesis and the effect of eosinophil depletion on patient outcomes are unclear. Benralizumab, an eosinophil-depleting monoclonal antibody that targets the interleukin-5 receptor α, might eliminate gastric tissue eosinophils and improve outcomes in eosinophilic gastritis. We aimed to assess the efficacy and safety of benralizumab in patients with eosinophilic gastritis. METHODS: We conducted a single-site, randomised, double-blind, placebo-controlled, phase 2 trial at Cincinnati Children's Hospital Medical Center (Cincinnati, OH, USA). Individuals aged 12-60 years with symptomatic, histologically active eosinophilic gastritis (peak gastric eosinophil count ≥30 eosinophils per high-power field [eos/hpf] in at least five hpfs) and blood eosinophilia (>500 eosinophils per µL [eos/µL]) were randomly assigned (1:1, block size of four) to benralizumab 30 mg or placebo, stratified by the use of glucocorticoids for gastric disease. Investigators, study staff, and study participants were masked to treatment assignment; statisticians were unmasked when analysing data. Treatments were administered subcutaneously once every 4 weeks for a 12-week double-blind period (three total injections). The primary endpoint was the proportion of patients who achieved histological remission (peak gastric eosinophil count <30 eos/hpf) at week 12. Key secondary endpoints were the changes from baseline to week 12 in peak gastric eosinophil count, blood eosinophil count, eosinophilic gastritis histology (total, inflammatory, and structural feature scores), Eosinophilic Gastritis Endoscopic Reference System (EG-REFS) score, and patient-reported outcome symptom measures (Severity of Dyspepsia Assessment [SODA] and Patient-Reported Outcome Measurement Information System [PROMIS] short-form questionnaire). After the 12-week double-blind period, patients were eligible for entry into two open-label extension (OLE) periods up to week 88, in which all patients received benralizumab. Efficacy was analysed in the intention-to-treat (ITT) population and safety was assessed in all patients who received at least one dose of study drug. The trial was registered on ClinicalTrials.gov, NCT03473977, and is completed. FINDINGS: Between April 23, 2018, and Jan 13, 2020, 34 patients were screened, and 26 were subsequently randomly assigned to benralizumab (n=13) or placebo (n=13) and included in the ITT and safety populations (mean age 19·5 years [SD 7·3]; 19 [73%] male patients and seven [27%] female patients). At week 12, ten (77% [95% CI 50 to 92]) of 13 patients who received benralizumab and one (8% [1 to 33]) of 13 who received placebo achieved histological remission (difference 69 percentage points [95% CI 32 to 85]; p=0·0010). Changes from baseline to week 12 were significantly greater in the benralizumab group versus the placebo group for peak gastric eosinophil counts (mean -137 eos/hpf [95% CI -186 to -88] vs -38 eos/hpf [-94 to 18]; p=0·0080), eosinophilic gastritis histology total score (mean -0·31 [-0·42 to -0·20] vs -0·02 [-0·16 to 0·12]; p=0·0016), histology inflammatory score (mean -0·46 [-0·60 to -0·31] vs -0·04 [-0·22 to 0·13]; p=0·0006), and blood eosinophil counts (median -1060 eos/µL [IQR -1740 to -830] vs -160 eos/µL [-710 to 120]; p=0·0044). Changes were not significantly different between the groups for eosinophilic gastritis histology structural score (mean -0·07 [95% CI -0·19 to 0·05] vs 0·03 [-0·09 to 0·15]; p=0·23), EG-REFS score (mean -1·0 [-2·3 to 0·3] vs -0·5 [-2·0 to 1·0]; p=0·62), or in patient-reported outcomes (SODA and PROMIS). During the double-blind period, treatment-emergent adverse events occurred in 11 (85%) of 13 patients in the benralizumab group and six (46%) of 13 in the placebo group; the most common treatment-emergent adverse events were headache (six [46%] vs two [15%] patients), nausea (three [23%] vs two [15%]), and vomiting (two [15%] vs three [23%]). There were no treatment-related deaths. Two patients had serious adverse events (dizziness and rhabdomyolysis in one patient; aspiration in one patient) during the OLE periods, which were considered unrelated to study treatment. INTERPRETATION: Benralizumab treatment induced histological remission, as defined by absence of tissue eosinophilia, in most patients with eosinophilic gastritis. However, the persistence of histological, endoscopic, and other features of the disease suggest a co-existing, eosinophil-independent pathogenic mechanism and the need for broader targeting of type 2 immunity. FUNDING: AstraZeneca and the Division of Intramural Research (National Institute of Allergy and Infectious Diseases, US National Institutes of Health).
Subject(s)
Asthma , Eosinophilia , United States , Child , Humans , Male , Female , Young Adult , Adult , Asthma/complications , Asthma/drug therapy , Disease Progression , Eosinophilia/drug therapyABSTRACT
BACKGROUND: Eosinophilic gastritis (EoG) associates with type 2 immunity. However, the type 2 cytokine cellular source, gastric T-cell composition, and gastric T-cell relationship (or relationships) with disease pathology remain understudied. OBJECTIVE: We defined gastric T-cell populations and their association with histologic and endoscopic EoG pathology. METHODS: Gastric biopsy samples (n = 6 EoG, n = 7 control) were subjected to histologic, endoscopic, and flow cytometry analyses. In a complementary cohort (n = 83 EoG), IL4, IL5, and IL13 mRNA levels were correlated with EoG pathologic parameters. RESULTS: Gastric biopsy samples contained CD3+ T cells that were mainly CD8+; the CD8/CD4 ratio was comparable in EoG and control biopsy samples (5.7 ± 3.0 and 4.3 ± 0.6, respectively; P = .28). Gastric regulatory T (CD3+CD4+FOXP3+) and TH2 (CD3+CD4+GATA3+) cell levels were increased in EoG versus controls (2-fold, P < .05 and 10-fold, P < .001, respectively) and correlated with gastric eosinophil levels (r = 0.63, P < .05 and r = 0.85, P < .001, respectively), endoscopic pathology (r = 0.56, P < .01; r = 0.84, P < .001, respectively), and histopathology (r = 0.72, P < .01; r = 0.82, P < .01, respectively). Cytokine-positive, most notably IL-4+, TH2 cell levels strongly correlated with histologic and endoscopic scores (r = 0.82, P < .0001 and r = 0.78, P < .0001, respectively). In an independent EoG cohort (n = 83), bulk gastric IL4, IL5, and IL13 mRNA levels correlated with histologic score (r = 0.22, P < .005; r = 0.54, P < .0001; and r = 0.36, P < .0001, respectively) and endoscopic score (r = 0.27, P < .001; r = 0.40, P < .0001; and r = 0.35, P < .0001, respectively). CONCLUSIONS: EoG is a TH2 cell-associated disease featuring increased gastric type 2 cytokine-producing CD3+CD4+GATA3+TH2 cells that strongly correlate with disease pathologies.
Subject(s)
Interleukin-13 , Interleukin-4 , Humans , Interleukin-5 , Cytokines , RNA, MessengerABSTRACT
PURPOSE OF REVIEW: This review will present what is known from recent research on the involvement of mast cells in eosinophilic esophagitis and identify questions requiring further investigation. RECENT FINDINGS: In the adults and children with eosinophilic esophagitis, there is increasing evidence that mastocytosis can persist, despite resolution of eosinophilia and is associated with persistent mucosal abnormalities and symptoms. Despite, treatment mast cells have an activated transcriptome. Mast cells likely contribute to epithelial barrier dysfunction, smooth muscle hypertrophy and contraction, and subepithelial fibrosis. It remains unclear whether targeting MCs alone has therapeutic efficacy to improve tissue damage. SUMMARY: Mast cells appear to play a key role in eosinophilic esophagitis and serve as a biomarker of mucosal healing in conjunction with eosinophils. Excessive mast cell activation likely contributes to tissue damage in eosinophilic esophagitis and need to be considered as a target of therapy along with eosinophils.
Subject(s)
Enteritis , Eosinophilic Esophagitis , Adult , Child , Eosinophilia , Eosinophilic Esophagitis/drug therapy , Eosinophils , Gastritis , Humans , Mast Cells/physiologyABSTRACT
BACKGROUND: Mast cells (MCs) are pleiotropic cells that accumulate in the esophagus of patients with eosinophilic esophagitis (EoE) and are thought to contribute to disease pathogenesis, yet their properties and functions in this organ are largely unknown. OBJECTIVES: This study aimed to perform a comprehensive molecular and spatial characterization of esophageal MCs in EoE. METHODS: Esophageal biopsies obtained from patients with active EoE, patients with EoE in histologic remission, and individuals with histologically normal esophageal biopsies and no history of esophageal disease (ie, control individuals) were subject to single-cell RNA sequencing, flow cytometry, and immunofluorescence analyses. RESULTS: This study probed 39,562 single esophageal cells by single-cell RNA sequencing; approximately 5% of these cells were MCs. Dynamic MC expansion was identified across disease states. During homeostasis, TPSAB1highAREGhigh resident MCs were mainly detected in the lamina propria and exhibited a quiescent phenotype. In patients with active EoE, resident MCs assumed an activated phenotype, and 2 additional proinflammatory MC populations emerged in the intraepithelial compartment, each linked to a proliferating MKI67high cluster. One proinflammatory activated MC population, marked as KIThighIL1RL1highFCER1Alow, was not detected in disease remission (termed "transient MC"), whereas the other population, marked as CMA1highCTSGhigh, was detected in disease remission where it maintained an activated state (termed "persistent MC"). MCs were prominent producers of esophageal IL-13 mRNA and protein, a key therapeutic target in EoE. CONCLUSIONS: Esophageal MCs comprise heterogeneous populations with transcriptional signatures associated with distinct spatial compartmentalization and EoE disease status. In active EoE, they assume a proinflammatory state and locally proliferate, and they remain activated and poised to reinitiate inflammation even during disease remission.
Subject(s)
Eosinophilic Esophagitis , Cell Proliferation , Eosinophilic Esophagitis/genetics , Eosinophilic Esophagitis/metabolism , Humans , Mast Cells/pathology , Sequence Analysis, RNAABSTRACT
BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) is a patchy disease of the esophagus with significant variability in intraepithelial eosinophilia. Three biopsies each from distal and proximal esophagus are recommended for identification of active EoE. Recent work suggests 3 biopsy sites are more optimal. We sought to evaluate 2-site vs 3-site esophageal biopsy combinations for utility to identify active EoE. METHODS: We prospectively obtained 3-site esophageal biopsies based on rigorous endoscopic measurements of the proximal, mid, and distal esophagus and gastroesophageal junction. Biopsies were reviewed by a pathologist, and those with at least 15 eosinophils per high-power field were considered active EoE. The sensitivity of one or more sites to identify active EoE was determined, and endoscopic measurements were correlated to height and age. RESULTS: Five hundred ninety-six endoscopies were performed in 217 patients; of these, 304 endoscopies in 167 patients had active EoE. Among the initial esophagogastroduodenoscopies with active EoE, distal biopsies had greater than 80% sensitivity, whereas mid and proximal biopsies had sensitivity of 65% and 62%, respectively, and distal + proximal biopsies had the highest diagnostic sensitivity for a 2-site combination. Among the 304 endoscopies with active EoE, 9 had focal eosinophilia restricted to the mid esophagus, and 8 were restricted to the proximal esophagus. For patients with multiple endoscopies with active EoE, nearly one fourth had reduced sites with eosinophilia at the second time point. Endoscopic measurements strongly correlated with height and age. CONCLUSIONS: This study supports endoscopic measurement-guided 3-site biopsies for optimal disease assessment of active EoE in children.
Subject(s)
Eosinophilic Esophagitis , Biopsy , Child , Enteritis , Eosinophilia , Eosinophils , Gastritis , HumansABSTRACT
OBJECTIVES: Mast cells (MCs) are increased in eosinophilic esophagitis (EoE). Endoscopic abnormalities, symptoms, and epithelial changes can persist after treatment despite a reduction of esophageal eosinophilia. It is unknown whether this could be due to persistent MC infiltration. We aimed to determine whether patients with histologically inactive (HI) EoE (defined as <15 eosinophils per high-powered field) with persistent symptoms, endoscopic, or epithelial abnormalities after treatment have increased MCs. METHODS: Secondary analysis of prospective data from 93 children with EoE undergoing post-treatment endoscopy between 2011 and 2015. Thirty-five non-EoE controls were included. Immunohistochemistry for tryptase, an MC marker, was performed on mid and distal esophageal biopsies. Total and degranulated intraepithelial MCs per high-powered field (MC/hpf) were quantified. Symptoms and endoscopic findings were recorded at time of endoscopy. MC/hpf were compared between HI-EoE and control, and among HI-EoE based on endoscopic and histologic findings, and symptoms. Nine clinical remission (CR) patients were identified, with absence of endoscopic abnormalities and symptoms. RESULTS: MC/hpf were increased in HI-EoE compared with control (17 ± 11 vs 8 ± 6, P < 0.0). Patients with persistent endoscopic abnormalities had increased total (20 ± 12 vs 13 ± 10, P = 0.001) and degranulated (8 ± 6 vs 5 ± 4, P = 0.002) MC/hpf, with no difference in eosinophils. MC/hpf predicted furrowing (odds ratio = 1.06, P = 0.01) and rings (odds ratio = 1.05, P = 0.03) after controlling for treatment type, proton-pump inhibitor, eosinophils, and duration of therapy. Patients with persistent basal zone hyperplasia and dilated intercellular spaces had increased MC/hpf. Eosinophils were weakly correlated with MC/hpf in the mid (r = 0.30, P < 0.001) and distal (r = 0.29, P < 0.001) esophagus. Clinical remission patients had lower MC/hpf compared with patients with persistent symptoms and/or endoscopic abnormalities. DISCUSSION: MC density is increased in patients with endoscopic and epithelial abnormalities, as well as a few symptoms, despite resolution of esophageal eosinophilia after treatment. This association warrants further study to ascertain whether MCs play an eosinophil independent role in EoE.
Subject(s)
Eosinophilic Esophagitis/pathology , Eosinophils/pathology , Mast Cells/pathology , Adolescent , Adrenal Cortex Hormones/therapeutic use , Child , Child, Preschool , Diet Therapy/methods , Edema/pathology , Eosinophilic Esophagitis/physiopathology , Eosinophilic Esophagitis/therapy , Esophagoscopy , Exudates and Transudates , Female , Humans , MaleSubject(s)
Esophagitis , Methamphetamine , Adolescent , Esophagitis/chemically induced , Female , Humans , Methamphetamine/adverse effectsABSTRACT
PURPOSE OF REVIEW: Pediatric foreign body ingestion is a common occurrence that presents a challenge both to pediatric gastroenterologists and primary care providers. Increasing prevalence of smaller, more technologically advanced toys in the household has resulted in an increased exposure to higher voltage batteries and powerful magnets that carry a high incidence of morbidity and mortality. This review highlights the latest findings regarding the patients at risk for button battery and magnet ingestions, the symptoms of presentation, and complications of these objects in contributing to long-standing gastrointestinal injury. RECENT FINDINGS: Button batteries may lead to esophageal injury within a few hours. Batteries retained in the esophagus are larger in diameter on average and size is associated with esophageal impaction as well as higher grade esophageal injury. Magnet ingestions, when multiple or with another metallic object, are often initially asymptomatic but may have acute worsening, and therefore warrant close monitoring. SUMMARY: Button battery and magnet ingestions have increased in incidence over the past two decades. Recent literature demonstrates that higher voltage, larger lithium button batteries, and prevalence of high-powered magnets can lead to significant morbidity. High suspicion, early referral, and removal may lead to improved outcomes.
Subject(s)
Burns, Chemical/diagnostic imaging , Burns, Chemical/etiology , Electric Power Supplies/adverse effects , Endoscopy, Digestive System , Foreign Bodies/diagnostic imaging , Magnets/adverse effects , Radiography , Child, Preschool , Eating , Esophagus/diagnostic imaging , Esophagus/injuries , Foreign Bodies/complications , Foreign Bodies/surgery , Gastrointestinal Tract/diagnostic imaging , Gastrointestinal Tract/injuries , Humans , Play and Playthings , Practice Guidelines as TopicABSTRACT
BACKGROUND & AIMS: The endoscopic reference score (EREFS) is used to determine severity of 5 endoscopic findings: edema, rings, exudates, furrows, and strictures. Little is known about the relationship between EREFSs and histologic markers of disease activity in children with eosinophilic esophagitis (EoE). We aimed to determine whether the EREFS can be used to identify children with EoE and how it changes with treatment. METHODS: We performed a prospective study of consecutive children (ages 2-17 years) undergoing diagnostic or post-treatment endoscopy scored real-time with EREFS from December 2012 through 2016. Findings from 192 diagnostic endoscopies and 229 post-treatment endoscopies were evaluated, from 371 children. Incident EoE cases were diagnosed based on 2011 consensus guidelines. Patients were treated with either elimination diet or topical steroids. Subjects who underwent endoscopy for symptoms of esophageal dysfunction but had normal esophageal findings from histology analysis were used as controls. EREFS and receiver operating characteristic curves were determined for incident EoE cases (n = 77) vs controls (n = 115), patients with active EoE (n = 101) vs inactive EoE after treatment (n = 128), and paired pre- and post-treatment cases of EoE (n = 85). Component and composite scores were correlated with eosinophilia. RESULTS: Visual detection of more than 1 esophageal abnormality during the diagnostic endoscopy identified children with EoE with 89.6% sensitivity and 87.9% specificity. EREFS correlated with peak level of eosinophilia (P < .001) at all esophageal levels. Children who responded to therapy had mean EREFSs of 0.5 compared to 2.4 in non-responders. In comparing pre-treatment vs post-treatment data from 85 patients, we found a significant reduction in the composite EREFS (from 2.4 to 0.7) (P < .001) among patients who responded to treatment; 92% of responders had a reduced EREFSs after treatment. EREFSs identified children with EoE with an area under the curve value (AUC) of 0.93. EREFSs identified children with active EoE following treatment with an AUC of 0.81 before treatment and an AUC of 0.79 after treatment. CONCLUSIONS: In a prospective study of children undergoing diagnostic or post-treatment endoscopy, we found the EREFS to accurately identify those with EoE. Children who responded to therapy had lower EREFS scores than non-responders. EREFSs can be used to measure outcomes of pediatric patients, in conjunction with histology findings, and assess treatments for children with EoE.
Subject(s)
Endoscopy/methods , Eosinophilic Esophagitis/diagnosis , Eosinophilic Esophagitis/pathology , Severity of Illness Index , Adolescent , Child , Child, Preschool , Eosinophilic Esophagitis/therapy , Female , Humans , Longitudinal Studies , Male , Prospective Studies , Sensitivity and SpecificityABSTRACT
UNLABELLED: Liver transplantation treats the hepatic affectation of UCDs; however, irreversible neurologic damage pretransplant is difficult to assess providing transplant teams with ethical dilemmas for liver transplantation. The purpose of our study was to determine whether pretransplant neuroimaging can predict developmental outcomes post-liver-transplant in children with UCDs. METHODS: Patients undergoing liver transplantation for UCDs at Cincinnati Children's Hospital Medical Center between 2002 and 2012 were identified. Neurologic assessments prior to and after transplantation were categorized into mild, moderate, or severe disability. Neuroimaging data were categorized into mild, moderate, or severe by a single pediatric neuroradiologist. RESULTS: Fifteen patients were identified of whom eight had neuroimaging prior to transplantation. Of the eight patients that had neuroimaging, four were categorized as severe, one moderate, and three no-to-mild delay. All four patients whose imaging was severe were found to have moderate-to-severe neurologic delay. Of the three patients with no-to-mild changes on neuroimaging two of three were found to have no-to-mild delay on developmental assessments after transplantation. CONCLUSION: Neuroimaging may be a helpful tool in determining developmental prognosis and outcomes post-liver-transplantation for UCDs. Further studies maybe needed to validate our preliminary findings.