Sue Rhee

Deficiency of Indoleamine 2,3-Dioxygenase Enhances Commensal-Induced Antibody Responses and Protects against Citrobacter rodentium-Induced Colitis

ABSTRACT Indoleamine 2,3-dioxygenase (IDO) is a negative regulator of lymphocyte responses that is expressed predominantly in macrophages and dendritic cells. We detected it at high levels in the small intestine and mesenteric lymph node of young adult mice, suggesting a role in intestinal immunity. Consistent with this idea, we found that IDO-deficient mice had elevated baseline levels of immunoglobulin A (IgA) and IgG in the serum and increased IgA in intestinal secretions. These abnormalities were corrected by a course of broad-spectrum oral antibiotics started at weaning, indicating that they were dependent on the intestinal microbiota. Kynurenine and picolinic acid, two IDO-generated metabolites of tryptophan, were able to inhibit lipopolysaccharide-induced antibody production by splenocytes in vitro, and kynurenine also induced B-cell apoptosis, findings that provide an explanation for the elevated Ig levels in animals lacking IDO. The intestinal secretions of IDO-deficient mice had elevated levels of IgA antibodies that cross-reacted with the gram-negative enteric bacterial pathogen Citrobacter rodentium. In keeping with the functional importance of this natural secretory IgA, the mutant animals were more resistant to intestinal colonization by Citrobacter, developed lower levels of serum Citrobacter-specific IgM and IgG antibodies following oral infection, and had significantly attenuated Citrobacter-induced colitis. Our observations point to an important role for IDO in the regulation of immunity to the gut commensal microbiota that has a significant impact on the response to intestinal pathogens.

Posttransplant metabolic syndrome in children and adolescents after liver transplantation: A systematic review†

During long‐term follow‐up, 18% to 67% of pediatric liver transplant recipients are overweight or obese, with rates varying by age and pretransplant weight status. A similar prevalence of posttransplant obesity has been seen in adults. Adults also develop posttransplant metabolic syndrome and, consequently, cardiovascular disease at rates that exceed the rates in age‐ and sex‐matched populations. Posttransplant metabolic syndrome has never been studied in pediatric liver transplant recipients, and this population is growing as transplant outcomes continue to improve. Here we systematically review the literature for each component of metabolic syndrome—obesity, hypertension, dyslipidemia, and glucose intolerance—in pediatric liver transplant recipients. Their rates of obesity are similar to the rates in children in the general US population. However, hypertension, dyslipidemia, and diabetes are more common than would be expected in transplant recipients according to age, sex, and obesity severity. Immunosuppressive medications are major contributors. The limitations of previous studies, including heterogeneous methods of diagnosis, follow‐up times, and immunosuppressive regimens, hinder the analysis of risk factors. Importantly, no studies have reported graft or patient outcomes associated with components of metabolic syndrome after pediatric liver transplantation. However, if the trends in children are similar to the trends seen in adults, these conditions may lead to significant long‐term morbidity. Further research on the prevalence, causes, and consequences of posttransplant metabolic syndrome in pediatric liver transplant recipients is needed and will ultimately help to improve long‐term outcomes. Liver Transpl, 2012.

Morphologic Findings in Progressive Familial Intrahepatic Cholestasis 2 (PFIC2): Correlation With Genetic and Immunohistochemical Studies

Progressive familial intrahepatic cholestasis, type 2 (PFIC2), characterized by cholestasis in infancy that may progress to cirrhosis, is caused by mutation in ABCB11, which encodes bile salt export pump (BSEP). We correlated histopathologic, immunohistochemical, and ultrastructural features in PFIC2 with specific mutations and clinical course. Twelve patients with clinical PFIC2 and ABCB11 mutations were identified, and 22 liver biopsy and explant specimens were assessed. All had hepatocellular cholestasis; most had canalicular bile plugs. At least 1 specimen from every patient had centrizonal/sinusoidal fibrosis, often with periportal fibrosis. Neonatal hepatitis-like features (inflammation, giant cells, necrosis) varied. In 2 of the 5 patients with paired specimens obtained >6 months apart, lobular and portal fibrosis worsened. Transmission electron microscopy (EM) in all 9 patients studied showed canalicular dilatation, microvilli loss, abnormal mitochondrial internal structure, and varying intracanalicular accumulation of finely granular bile. Canalicular staining for BSEP was absent in 10 patients and present in 2 patients, 1 of whom had intermittent symptoms. ABCB11 sequencing of all patients identified 6 novel and 10 previously described mutations, with nonsense, missense, and/or noncoding mutations in the 10 patients without immunohistochemically demonstrable BSEP. Missense and/or noncoding mutations were identified in the 2 patients with demonstrable BSEP, whose clinical course was more indolent. Mutations ending ABCB11 transcription appear linked, through hepatocellular necrosis and fibrosis, to worse outcome. In conclusion, light microscopy and electron microscopy findings in clinical PFIC2 can support diagnosis, but are variable and nonspecific. Therefore, no correlation between specific mutations and histopathology is yet possible.

Pediatric liver transplantation for urea cycle disorders and organic acidemias: United Network for Organ Sharing data for 2002‐2012

Decision making concerning liver transplantation is unique for children with urea cycle disorders (UCDs) and organic acidemias (OAs) because of their immediate high priority on the waiting list, which is not related to the severity of their disease. There are limited national outcome data on which recommendations about liver transplantation for UCDs or OAs can be based. This study was a retrospective analysis of United Network for Organ Sharing data for liver recipients who underwent transplantation at an age < 18 years in 2002‐2012. Repeat transplants were excluded. Among the pediatric liver transplants, 5.4% were liver‐only for UCDs/OAs. The proportion of transplants for UCDs/OAs increased from 4.3% in 2002‐2005 to 7.4% in 2010‐2012 (P < 0.001). Ninety‐six percent were deceased donor transplants, and 59% of these patients underwent transplantation at <2 years of age. Graft survival improved as the age at transplant increased (P = 0.04). Within 5 years after transplantation, the graft survival rate was 78% for children < 2 years old at transplant and 88% for children ≥ 2 years old at transplant (P = 0.06). Vascular thrombosis caused 44% of the graft losses, and 65% of these losses occurred in children < 2 years old. Patient survival also improved as the age at transplant increased: the 5‐year patient survival rate was 88% for children with UCDs/OAs who were <2 years old at transplant and 99% for children who were ≥2 years old at transplant (P = 0.006). At the last‐follow‐up (54 ± 34.4 months), children who underwent transplantation for UCDs/OAs were more likely to have cognitive and motor delays than children who underwent transplantation for other indications. Cognitive and motor delays for children with UCDs/OAs were associated with metabolic disorders, but they were not predicted by age or weight at transplant, sex, ethnicity, liver graft type (split versus whole), or hospitalization at transplant in univariate and multivariate analyses. In conclusion, most liver transplants for UCDs/OAs occur in early childhood. Further research on the benefits of early transplantation for patients with UCDs/OAs is needed because a younger age may increase posttransplant morbidity. Liver Transpl 20:89‐99, 2014.

Nonstandard Exception Requests Impact Outcomes for Pediatric Liver Transplant Candidates.

Nonstandard exceptions requests (NSERs), in which transplant centers appeal on a case‐by‐case basis for Pediatric End‐Stage Liver Disease/Mayo End‐Stage Liver Disease points, have been highly utilized for pediatric liver transplant candidates. We evaluated whether NSE outcomes are associated with waitlist and posttransplant mortality. United Network for Organ Sharing (UNOS) Scientific Registry of Transplant Recipients data on pediatric liver transplant candidates listed in 2009–2014 were analyzed after excluding those granted automatic UNOS exceptions. Of 2581 pediatric waitlist candidates, 44% had an NSE request. Of the 1134 children with NSERs, 93% were approved and 7% were denied. For children 2–18 years at listing, NSER denial increased the risk of waitlist mortality or removal for being too sick (subhazard ratio 2.99, 95% confidence interval [CI] 1.26–7.07, p = 0.01 in multivariate analysis). For children younger than 2 years, NSER denial did not impact waitlist mortality/removal. Children with NSER approved had reduced risk of graft loss 3 years posttransplant in univariate but not multivariable analysis (odds ratio 0.73, 95% CI 0.53–1.01, p = 06). Those with NSER denial had a higher risk of posttransplant death than those with no NSER (hazard ratio 2.43, 95% CI 0.99–5.95, p = 0.05, multivariable analysis), but NSER approval did not impact posttransplant death. Further research on NSER utilization in pediatric liver transplant is needed to optimize organ allocation and outcomes for children.

Shooting a moving target: use of real-time cine magnetic resonance imaging in assessment of the small bowel.

ABSTRACT The chronic nature of inflammatory bowel disease (IBD) creates a lifelong effect on the morbidity of children affected by the disease. The ability to confidently identify and characterize complications resulting from IBD in the pediatric patient is of critical importance. Magnetic resonance enterography (MRE) is especially valuable in the diagnostic assessment of IBD; however, precise elucidation of complications including strictures can be difficult with standard MRE sequences. The recent development of faster MRI pulse sequences provides rapid, real-time imaging of the intestinal tract. In this review, we describe how the addition of cine MRE confidently pinpoints areas of stricture, aids in lesion detection and diagnosis, and provides valuable information on intestinal motility.

Nonanesthesia magnetic resonance enterography in young children: feasibility, technique, and performance.

Objectives: The aim of the present study was to demonstrate the effectiveness and cost savings of a nonanesthesia approach to magnetic resonance enterography (MRE) in 14 young pediatric patients (age 4–7 years) with clinically suspected early-onset inflammatory bowel disease using an MRE protocol. Methods: MRE was performed using a combination of an abbreviated imaging protocol, magnetic resonance imaging video goggles, and Child Life Services support. MRE results were correlated with both colonoscopy and pathology results using Pearson correlation coefficient. Sensitivity, specificity, and positive and negative predictive values were calculated. Results: MRE was performed successfully in 13 of 14 patients (age range 4 years 0 months to 7 years 6 months). MRE findings matched with results in 12 of 13 patients in whom colonoscopy was successfully performed. Both MRE and colonoscopy demonstrated a high specificity (100%) and a positive predictive value (100%), but a low sensitivity (43%) and a negative predictive value (50%). Conclusions: MRE can be successfully performed in children ages 4 to 7 years using this approach. In addition to decreased risks to the child, the lack of anesthesia also offers a potential overall cost reduction.

Targeted MRI contrast agents for pediatric hepatobiliary disease.

ABSTRACT New options are available for the magnetic resonance imaging (MRI) assessment of pediatric hepatobiliary disease. This article describes the potential utility for MRI with contrast agents tailored for hepatobiliary imaging. MRI contrast agents that preferentially target the liver may be helpful in characterizing liver masses and bile duct abnormalities in select children. The imaging approach is noninvasive and relatively rapid to perform. It also provides anatomic and functional information and is a radiation-free alternative to other imaging strategies. This relatively new imaging procedure is placed in the context of more established imaging modalities. The pharmacokinetics, technical considerations, and potential applications of these hepatobiliary-specific contrast agents also are discussed.

Impact of the donor body mass index on the survival of pediatric liver transplant recipients and post-transplant obesity.

In adult liver transplant recipients, the donor body mass index (dBMI) is associated with posttransplant obesity but not with graft or patient survival. Because of the obesity epidemic in the United States and the already limited supply of liver donors, clarifying whether the dBMI affects pediatric outcomes is important. United Network for Organ Sharing data for pediatric liver transplants in the United States (1990‐2010) were evaluated. Data on transplants performed between 2004 and 2010 (n = 3788) were used for survival analyses with Kaplan‐Meier and Cox proportional hazards models and for posttransplant obesity analyses with generalized estimating equations. For children receiving adult donor livers, a dBMI of 25 to <35 kg/m2 was not associated with graft or patient survival in univariate or multivariate analyses. A dBMI ≥ 35 kg/m2 increased the risk of graft loss [hazard ratio (HR) = 2.54, 95% confidence interval (CI) = 1.29‐5.01, P = 0.007] and death (HR = 3.56, 95% CI = 1.64‐7.72, P = 0.001). For pediatric donors, the dBMI was not associated with graft loss or mortality in a univariate or multivariate analysis. An overweight or obese donor was not a risk factor for posttransplant obesity. Overweight and obesity are common among liver transplant donors. This analysis suggests that for adult donors, a body mass index (BMI) of 25 to <35 kg/m2 should not by itself be a contraindication to liver donation. Severe obesity (BMI ≥ 35 kg/m2) in adult donors increased the risk of graft loss and mortality, even after adjustments for recipient, donor, and transplant risk factors. Posttransplant obesity was not associated with the dBMI in this analysis. Further research is needed to clarify the impact of donor obesity on pediatric liver transplant recipients. Liver Transpl, 2012.

Detection of bowel inflammation with fused DWI/T2 images versus contrast-enhanced images in pediatric MR enterography with histopathologic correlation

PURPOSE To evaluate the fused, colorized diffusion weighted imaging (DWI) and anatomic T2 images compared to routine contrast-enhanced T1 images at pediatric magnetic resonance enterography (MRE). METHODS Fused, colorized DWI/T2 images were created from patients with magnetic resonance enterography (MRE) and colonoscopy/biopsy. Radiologists noted inflammation in five bowel segments (terminal ileum-rectosigmoid colon) on postcontrast images and DWI/T2 images. Test characteristics and agreement were calculated. RESULTS For 20 patients, sensitivity/specificity/positive predictive value (PPV)/negative predictive value (NPV) were 0.53/0.90/0.77/0.76 for DWI/T2 and 0.45/0.90/0.72/0.73 for postcontrast images. Intraobserver agreement was ҡ=0.45-0.73. Interobserver agreement was ҡ=0.53 for DWI/T2 and ҡ=0.63 for postcontrast images. CONCLUSION DWI/T2 images are similar in sensitivity/specificity to contrast-enhanced images and with moderate intra/interobserver reliability.