Publications by authors named "James E Squires"

51 Publications

SARS-CoV2 Infection in Children with Liver Transplant and Native Liver Disease: An International Observational Registry Study.

J Pediatr Gastroenterol Nutr 2021 Feb 16. Epub 2021 Feb 16.

Queen's University, Children's Hospital of Eastern Ontario, Kingston/Ontario/Canada, Ottawa/Ontario/Canada Stanford University , Stanford/CA/USA Hospital for Sick Children , Toronto/Ontario/Canada Fundacion Cardiofantil - Instituto de Cardiologia, Bogota/Columbia Texas Children's Hospital, Houston/TX/USA Children's Mercy - Kansas City, Kansas/MO/USA Children's Hospital at Montefiore, New York/NY/USA Children's Hospital of Philadelphia, Philadelphia/PA/USA Mount Sinai Hospital, New York/NY/USA University of Miami, Miami/FL/USA Emory University School of Medicine, Atlanta/GA/USA Ann & Robert H. Lurie Children's Hospital, Chicago/IL/USA UPMC Children's Hospital of Pittsburgh, Pittsburgh/PA/USA Hospital Italiano de Buenos Aires, Buenos Aires/Argentina Rocky Mountain Hospital for Children, Denver/CO/USA Primary Children's Hospital, Salt Lake City/UT/USA Children's Hospital Los Angeles, Los Angeles/CA/USA University of Chicago, Chicago/IL/USA Boston Children's Hospital, Boston/MA/USA University of California, San Francisco, San Francisco/CA/USA University of Maryland School of Medicine, Baltimore/MD/USA Johns Hopkins Hospital, , Baltimore/MD/USA University of Manitoba, Winnipeg/Manitoba/Canada Yale University School of Medicine, New Haven/CT/USA Medical College of Wisconsin, Milwaukee/WI/USA Children's Hospital and the Institute of Child Health , Lahore/Pakistan The First Affiliated Hospital of Wenzhou Medical University, Wenzhou/China Columbia University, New York/NY/USA.

Objective: Increased mortality risk due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV2) infection in adults with native liver disease (LD) and liver transplant (LT) is associated with advanced age and comorbid conditions. We aim to report outcomes for children with LD and LT enrolled in the NASPGHAN/SPLIT SARS-CoV2 registry.

Methods: In this multicenter observational cohort study, we collected data from 91 patients <21 years (LD 44, LT 47) with laboratory-confirmed SARS-CoV2 infection between April 21 and September 17, 2020.

Results: Patients with LD were more likely to require admission (70% vs 43% LT, p = 0.007) and pediatric intensive care unit (PICU) management (32% vs 4% LT, p = 0.001). Seven LD patients required mechanical ventilation (MV) and 2 patients died; no patients in the LT cohort died or required MV. Four LD patients presented in pediatric acute liver failure (PALF), 2 with concurrent multisystem inflammatory syndrome in children (MIS-C); all recovered without LT. Two LD patients had MIS-C alone and one patient died. Bivariable logistic-regression analysis found that patients with non-alcoholic fatty liver disease (NAFLD) (OR 5.6, p = 0.02) and LD (OR 6.1, p = 0.01, vs LT) had higher odds of severe disease (PICU, vasopressor support, MV, renal replacement therapy or death).

Conclusions: Although not directly comparable, LT recipients had lower odds of severe SARS-CoV2 infection (vs LD), despite immunosuppression burden. NAFLD patients reported to the registry had higher odds of severe SARS-CoV2 disease. Future controlled studies are needed to evaluate effective treatments and further stratify LD and LT patients with SARS-CoV2 infection.
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http://dx.doi.org/10.1097/MPG.0000000000003077DOI Listing
February 2021

A Learning Health System for Pediatric Liver Transplant: The Starzl Network for Excellence in Pediatric Transplantation.

J Pediatr Gastroenterol Nutr 2021 Mar;72(3):417-424

Hillman Center for Pediatric Transplantation, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA.

Objective: Learning health systems (LHS) integrate research, improvement, management, and patient care, such that every child receives "the right care at the right time...every time," that is, evidence-based, personalized medicine. Here, we report our efforts to establish a sustainable, productive, multicenter LHS focused on pediatric liver transplantation.

Methods: The Starzl Network for Excellence in Pediatric Transplantation (SNEPT) is the first multicenter effort by pediatric liver transplant families and providers to develop shared priorities and a shared agenda for innovation in clinical care. This report outlines SNEPT's structure, accomplishments, and challenges as an LHS.

Results: We prioritized 4 initial projects: immunosuppression, perioperative anticoagulation, quality of life, and transition of care. We shared center protocols/management to identify areas of practice variability between centers. We prioritized actionable items that address barriers to providing "the right care at the right time" to every pediatric liver transplant recipient: facilitating transparency of practice variation and the connection of practices to patient outcomes, harnessing existing datasets to reduce the burden of tracking outcomes, incorporating patient-reported outcomes into outcome metrics, and accelerating the implementation of knowledge into clinical practice. This has allowed us to strengthen collaborative relationships, design quality improvement projects, and collect pilot data for each of our priority projects.

Conclusions: The field of pediatric liver transplantation can be advanced through application of LHS principles. Going forward, SNEPT will continue to unite patient advocacy, big data, technology, and transplant thought leaders to deliver the best care, while developing new, scalable solutions to pediatric transplantation's most challenging problems.
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http://dx.doi.org/10.1097/MPG.0000000000002974DOI Listing
March 2021

Cost-Effectiveness of Primary Liver Transplantation Versus Hepatoportoenterostomy in the Management of Biliary Atresia in the United States.

Liver Transpl 2021 Jan 18. Epub 2021 Jan 18.

Division of General Internal Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA.

Biliary atresia (BA) is the leading indication to perform a pediatric liver transplantation (LT). Timely hepatoportoenterostomy (HPE) attempts to interrupt the natural history and allow for enteric bile flow; however, most patients who are treated with HPE require LT by the age of 10 years. We determined the cost-effectiveness of foregoing HPE to perform primary LT (pLT) in children with BA compared with standard-of-care HPE management. A Markov model was developed to simulate BA treatment over 10 years. Costs were measured in 2018 US dollars and effectiveness in life-years (LYs). The primary outcome was incremental cost-effectiveness ratio (ICER) between treatments. Model parameters were derived from the literature. In the base model, we assumed similar LT outcomes after HPE and pLT. Sensitivity analyses on all model parameters were performed, including a scenario in which pLT led to 100% patient and graft survival after LT. Children undergoing HPE accumulated $316,692 in costs and 8.17 LYs per patient. Children undergoing pLT accumulated $458,059 in costs and 8.24 LYs per patient, costing $1,869,164 per LY gained compared with HPE. With parameter variation over plausible ranges, only post-HPE and post-LT costs reduced the ICER below a typical threshold of $100,000 per LY gained. On probabilistic sensitivity analysis, 93% of iterations favored HPE at that threshold. With 100% patient and graft survival after pLT, pLT cost $283,478 per LY gained. HPE is more economically favorable than pLT for BA. pLT is unfavorable even with no graft or patient loss. The ability to predict those patients who may experience high costs after HPE or low costs after LT may help identify those patients for whom pLT could be considered.
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http://dx.doi.org/10.1002/lt.25984DOI Listing
January 2021

Molecular overview of progressive familial intrahepatic cholestasis.

World J Gastroenterol 2020 Dec;26(47):7470-7484

Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, United States.

Cholestasis is a clinical condition resulting from the imapairment of bile flow. This condition could be caused by defects of the hepatocytes, which are responsible for the complex process of bile formation and secretion, and/or caused by defects in the secretory machinery of cholangiocytes. Several mutations and pathways that lead to cholestasis have been described. Progressive familial intrahepatic cholestasis (PFIC) is a group of rare diseases caused by autosomal recessive mutations in the genes that encode proteins expressed mainly in the apical membrane of the hepatocytes. PFIC 1, also known as Byler's disease, is caused by mutations of the gene, which encodes the familial intrahepatic cholestasis 1 protein. PFIC 2 is characterized by the downregulation or absence of functional bile salt export pump (BSEP) expression variations in the gene. Mutations of the gene result in lower expression of the multidrug resistance class 3 glycoprotein, leading to the third type of PFIC. Newer variations of this disease have been described. Loss of function of the tight junction protein 2 protein results in PFIC 4, while mutations of the gene, which encodes farnesoid X receptor, an important transcription factor for bile formation, cause PFIC 5. A recently described type of PFIC is associated with a mutation in the gene, important for the trafficking of BSEP and hepatocyte membrane polarization. In this review, we provide a brief overview of the molecular mechanisms and clinical features associated with each type of PFIC based on peer reviewed journals published between 1993 and 2020.
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http://dx.doi.org/10.3748/wjg.v26.i47.7470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754551PMC
December 2020

50 Years Ago in TheJournalofPediatrics: The Unraveling of Hepatic Radioresistance and the Rise of Radiation-Induced Liver Disease.

J Pediatr 2021 01;228:43

Division of Pediatric Radiology, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania.

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http://dx.doi.org/10.1016/j.jpeds.2020.07.073DOI Listing
January 2021

Outcomes of Childhood Cholestasis in Alagille Syndrome: Results of a Multicenter Observational Study.

Hepatol Commun 2020 Mar 22;4(3):387-398. Epub 2020 Jan 22.

University of Colorado School of Medicine Children's Hospital Colorado Aurora CO.

Alagille syndrome (ALGS) is an autosomal dominant multisystem disorder with cholestasis as a defining clinical feature. We sought to characterize hepatic outcomes in a molecularly defined cohort of children with ALGS-related cholestasis. Two hundred and ninety-three participants with ALGS with native liver were enrolled. Participants entered the study at different ages and data were collected retrospectively prior to enrollment, and prospectively during the study course. Genetic analysis in 206 revealed mutations in 91% and mutations in 4%. Growth was impaired with mean height and weight -scores of <-1.0 at all ages. Regression analysis revealed that every 10 mg/dL increase in total bilirubin was associated with a decrease in height -score by 0.10 ( = 0.03) and weight -score by 0.15 ( = 0.007). Total bilirubin was higher for younger participants ( = 0.03) with a median of 6.9 mg/dL for those less than 1 year old compared with a median of 1.3 mg/dL for participants 13 years or older. The median gamma glutamyl transferase also dropped from 612 to 268 in the same age groups. After adjusting for age, there was substantial within-individual variation of alanine aminotransferase. By 20 years of age, 40% of participants had developed definite portal hypertension. Estimated liver transplant-free survival at the age of 18.5 years was 24%. : This is the largest multicenter natural history study of cholestasis in ALGS, demonstrating a previously underappreciated burden of liver disease with early profound cholestasis, a second wave of portal hypertension later in childhood, and less than 25% of patients reaching young adulthood with their native liver. These findings will promote optimization of ALGS management and development of clinically relevant endpoints for future therapeutic trials.
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http://dx.doi.org/10.1002/hep4.1468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049675PMC
March 2020

Nonfasted Liver Stiffness Correlates with Liver Disease Parameters and Portal Hypertension in Pediatric Cholestatic Liver Disease.

Hepatol Commun 2020 Nov 5;4(11):1694-1707. Epub 2020 Aug 5.

University of Michigan Ann Arbor MI USA.

Elastographic measurement of liver stiffness is of growing importance in the assessment of liver disease. Pediatric experiences with this technique are primarily single center and limited in scope. The Childhood Liver Disease Research Network provided a unique opportunity to assess elastography in a well-characterized multi-institutional cohort. Children with biliary atresia (BA), alpha-1 antitrypsin deficiency (A1ATD), or Alagille syndrome (ALGS) followed in a prospective longitudinal network study were eligible for enrollment in a prospective investigation of transient elastography (FibroScan). Studies were performed in participants who were nonfasted and nonsedated. Liver stiffness measurements (LSMs) were correlated with standard clinical and biochemical parameters of liver disease along with a research definition of clinically evident portal hypertension (CEPH) graded as absent, possible, or definite. Between November 2016 and August 2019, 550 participants with a mean age of 8.8 years were enrolled, 458 of whom had valid LSMs (BA, n = 254; A1ATD, n = 104; ALGS, n = 100). Invalid scans were more common in participants <2 years old. There was a positive correlation between LSM and total bilirubin, international normalized ratio (INR), aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT), GGT to platelet ratio (GPR), pediatric end-stage liver disease score, AST to platelet ratio index, and spleen size, and a negative correlation with albumin and platelet count in BA, with similar correlations for A1ATD (except AST, ALT, and albumin) and ALGS (except for INR, GGT, GPR, and ALT). Possible or definite CEPH was more common in BA compared to ALGS and A1ATD. LSM was greater in definite versus absent CEPH in all three diseases. Disease-specific clinical and biochemical characteristics of the different CEPH grades were observed. : It is feasible to obtain LSMs in children, especially over the age of 2 years. LSM correlates with liver parameters and portal hypertension, although disease-specific patterns exist.
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http://dx.doi.org/10.1002/hep4.1574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603532PMC
November 2020

Serum Matrix Metalloproteinase 7 Is a Diagnostic Biomarker of Biliary Injury and Fibrosis in Pediatric Autoimmune Liver Disease.

Hepatol Commun 2020 Nov 24;4(11):1680-1693. Epub 2020 Sep 24.

Division of Gastroenterology, Hepatology and Nutrition Cincinnati Children's Hospital Medical Center Cincinnati OH USA.

In autoimmune liver disease (AILD), including autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), and overlap syndrome of AIH and PSC (ASC), the presence of biliary injury portends a worse prognosis. We studied serum matrix metalloproteinase 7 (sMMP7) as a biomarker for pediatric sclerosing cholangitis (SC). We prospectively enrolled 54 children (median age, 16 years) with AILD (AIH, n = 26; ASC, n = 16; and PSC, n = 12) at our center. The sMMP7 concentrations were higher in patients with SC compared to those without cholangiopathy ( < 0.001). An sMMP7 concentration >23.7 ng/mL had a sensitivity and specificity of 79% and 96%, respectively, and outperformed alkaline phosphatase (ALP) and gamma-glutamyltransferase (GGT) in segregating patients with SC. Serum concentrations correlated with liver gene expression levels for ( = 0.70;  < 0.001). Using immunofluorescence, MMP7 was localized primarily to the cholangiocytes of patients with SC. In 46 subjects with liver biopsy available for blinded review, elevation in sMMP7 concentrations segregated with the presence of lymphocytic and neutrophilic cholangitis and periductal fibrosis and correlated with Ishak, Ludwig, and Nakanuma scoring systems. Liver stiffness measured by magnetic resonance elastography also correlated with sMMP7 concentrations ( = 0.56;  < 0.01). Using magnetic resonance cholangiopancreatography plus (MRCP+), sMMP7 in 34 patients correlated with the number of biliary dilatations ( = 0.54;  < 0.01) and strictures ( = 0.56;  < 0.01). MMP7 as a marker of biliary injury was validated in an independent cohort of children with ulcerative colitis. Higher sMMP7 concentrations also correlated with a history of SC-related complication. : MMP7 is a promising biomarker for pediatric SC that diagnostically outperforms ALP and GGT. sMMP7 may directly reflect biliary injury and fibrosis, the main drivers of disease progression in SC.
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http://dx.doi.org/10.1002/hep4.1589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603534PMC
November 2020

Living Related Liver Transplantation for Metabolic Liver Diseases in Children.

J Pediatr Gastroenterol Nutr 2021 Jan;72(1):11-17

Division of Gastroenterology, Hepatology and Nutrition.

Abstract: Metabolic liver diseases (MLDs) are a heterogeneous group of inherited conditions for which liver transplantation can provide definitive treatment. The limited availability of deceased donor organs means some who could benefit from transplant do not have this option. Living related liver transplant (LrLT) using relatives as donors has emerged as one solution to this problem. This technique is established worldwide, especially in Asian countries, with shorter waiting times and patient and graft survival rates equivalent to deceased donor liver transplantation. However, living donors are underutilized for MLDs in many western countries, possibly due to the fear of limited efficacy using heterozygous donors. We have reviewed the published literature and shown that the use of heterozygous donors for liver transplantation is safe for the majority of MLDs with excellent metabolic correction. The use of LrLT should be encouraged to complement deceased donor liver transplantation (DDLT) for treatment of MLDs.
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http://dx.doi.org/10.1097/MPG.0000000000002952DOI Listing
January 2021

Liver transplant for inherited metabolic disease among siblings.

Clin Transplant 2020 Nov 5;34(11):e14090. Epub 2020 Oct 5.

Hillman Center for Pediatric Transplantation, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.

Liver transplantation is a successful option for inherited metabolic disease yet little is published on the outcome among siblings. We report outcomes of siblings who have undergone liver transplantation for metabolic disease in a single program. Seventy-one siblings (35 males) from 33 individual families underwent liver transplantation since 1982. Outcomes were compared over three consecutive eras. Twenty-eight families had two siblings, four had three siblings, and one had four siblings. In half of families where dates of listing were known, siblings were listed simultaneously. Mean (SD) age at listing for the oldest and second sibling was 13.2 (7.1) and 9.8 (5.7) years, respectively (p < .01). In 18/33 families, the oldest sibling underwent transplantation first. Mean (SD) age at transplant fell from the oldest to second sibling from 12.9 (7.2) to 9.5 (6.3) years, respectively (p < .001). Ten-year patient survival was 83.5% which improved over the eras: era 1 (1982-1994) 65.0%, era 2 (1995-2007) 87.5%, and era 3 (2008-2019) 93.8%: p < .03. Sex, age at transplant, order of transplant, and presence of structural liver disease did not significantly impact survival. When siblings undergo liver transplant for inherited metabolic disease, later siblings are listed and transplanted at a significantly younger age.
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http://dx.doi.org/10.1111/ctr.14090DOI Listing
November 2020

Hepatitis C in 2020: A North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition Position Paper.

J Pediatr Gastroenterol Nutr 2020 09;71(3):407-417

Children's Hospital of Colorado, Digestive Health Institute, University of Colorado School of Medicine, Aurora, CO.

In 1989, a collaboration between the Centers for Disease Control (CDC) and a California biotechnology company identified the hepatitis C virus (HCV, formerly known as non-A, non-B hepatitis virus) as the causative agent in the epidemic of silent posttransfusion hepatitis resulting in cirrhosis. We now know that, the HCV genome is a 9.6 kb positive, single-stranded RNA. A single open reading frame encodes a 3011 amino acid residue polyprotein that undergoes proteolysis to yield 10 individual gene products, consisting of 3 structural proteins (core and envelope glycoproteins E1 and E2) and 7 nonstructural (NS) proteins (p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B), which participate in posttranslational proteolytic processing and replication of HCV genetic material. Less than 25 years later, a new class of medications, known as direct-acting antivirals (DAAs) which target these proteins, were introduced to treat HCV infection. These highly effective antiviral agents are now approved for use in children as young as 3 years of age and have demonstrated sustained virologic responses exceeding 90% in most genotypes. Although tremendous scientific progress has been made, the incidence of acute HCV infections has increased by 4-fold since 2005, compounded in the last decade by a surge in opioid and intravenous drug use. Unfortunately, awareness of this deadly hepatotropic virus among members of the lay public remains limited. Patient education, advocacy, and counseling must, therefore, complement the availability of curative treatments against HCV infection if this virus is to be eradicated.
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http://dx.doi.org/10.1097/MPG.0000000000002814DOI Listing
September 2020

Treatment of Hepatitis C: A New Paradigm toward Viral Eradication.

J Pediatr 2020 06;221:12-22.e1

Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital, Cincinnati, OH.

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http://dx.doi.org/10.1016/j.jpeds.2020.02.082DOI Listing
June 2020

Successful liver transplantation in short telomere syndromes without bone marrow failure due to DKC1 mutation.

Pediatr Transplant 2020 05 12;24(3):e13695. Epub 2020 Mar 12.

Division of Gastroenterology, Hepatology and Nutrition, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.

Short telomere syndromes are a heterogenous spectrum of disorders leading to premature cellular aging. These may involve bone marrow failure, adult-onset idiopathic pulmonary fibrosis, and liver disease, and classical entities such as dyskeratosis congenita. We report a patient who presented with common variable immunodeficiency at 3 years of age and autoimmune cytopenias at 8 years of age. He was found to have short telomeres, and genetic testing confirmed a hemizygous mutation NM_001363.4: c.-142C > G in DKC1 gene. He subsequently developed cirrhosis with severe portal hypertension and hepatopulmonary syndrome, prompting liver transplantation at 11 years of age. He remains well 10 years after transplant with no progression of bone marrow failure or progressive lung disease. In conclusion, short telomere syndromes should be considered as a potential cause of pediatric liver disease of unknown etiology, and in severe cases, isolated liver transplantation may be both appropriate and successful.
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http://dx.doi.org/10.1111/petr.13695DOI Listing
May 2020

New Tools for Screening Children With Portal Hypertension.

J Pediatr Gastroenterol Nutr 2019 12;69(6):639-640

Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh, PA.

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http://dx.doi.org/10.1097/MPG.0000000000002492DOI Listing
December 2019

When Considering Liver Transplant for Children with Glycogen Storage Disease 1b.

Authors:
James E Squires

Liver Transpl 2020 01;26(1):12-13

Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA.

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http://dx.doi.org/10.1002/lt.25688DOI Listing
January 2020

The use of urinary biomarkers to predict acute kidney injury in children after liver transplant.

Pediatr Transplant 2020 02 25;24(1):e13608. Epub 2019 Oct 25.

Division of Pediatric Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.

Background: AKI after pediatric liver transplantation is associated with increased morbidity and mortality. The role of urinary biomarkers for the prediction of AKI in pediatric patients after liver transplantation has not been previously reported. The primary objective of this prospective pilot study was to determine the predictive capabilities of urinary KIM-1, NGAL, TIMP-2, and IGFBP7 for diagnosing AKI.

Methods: Sixteen children undergoing liver transplantation were enrolled in the study over a 19-month time period. The Kidney Disease Improving Outcomes criteria for urine output and serum creatinine were used to define AKI. Predictive ability was evaluated using the area under the curve obtained by ROC analysis.

Results: AKI occurred in 6 (37.5%) of the patients between 2 and 4 days after transplant. There were no differences in any of the biomarkers prior to transplant. When obtained within 6 hours after transplant, the area under the ROC curve for predicting AKI was 0.758 (95% CI: 0.458-1.00) for KIM-1, 0.900 (95% CI: 0.724-1.00) for NGAL, and 0.933 (95% CI: 0.812-1.00) for the product of TIMP-2 and IGFBP7 ([TIMP-2]·[IGFBP7]).

Conclusions: Our results show that both NGAL and [TIMP-2]·[IGFBP7] provide significant discrimination for AKI risk following liver transplant in children. Larger studies are needed to determine the optimal time point for measuring these biomarkers and to validate our findings.
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http://dx.doi.org/10.1111/petr.13608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216780PMC
February 2020

Technique and outcome of domino liver transplantation from patients with maple syrup urine disease: Expanding the donor pool for live donor liver transplantation.

Clin Transplant 2019 11 6;33(11):e13721. Epub 2019 Oct 6.

Hillman Center for Pediatric Transplantation, Children's Hospital of Pittsburgh of UPMC, Thomas E. Starzl Transplant Institute, Pittsburgh, PA, USA.

Aim/background: Domino liver transplantation (DLT) using liver allografts from patients with metabolic disorders enhances organ utilization. Short- and long-term course and outcome of these patients can impact the decision to offer this procedure to patients, especially those with diseases that can potentially be cured with liver transplant. We reviewed the outcomes of DLT from maple syrup urine disease (MSUD) patients in our large academic pediatric and adult transplant program.

Methods: All patients receiving DLT were analyzed retrospectively with a minimum of one-year follow-up period for patient and donor characteristics, early and late postoperative complications and patient and graft survival with their MSUD donors in terms of age, weight, MELD/PELD scores, cold ischemia time, postoperative leucine levels, and peak ALT (alanine aminotransferase) levels during the first 48 postoperative hours.

Results: Between 2006 and May 2019, 21 patients underwent domino liver transplantation with live donor allografts from MSUD patients. Four patients transplanted for different metabolic diseases are focus of a separate report. Seventeen patients with minimum one-year follow-up period are reported herein. The indications were primary sclerosing cholangitis (PSC, n = 4), congenital hepatic fibrosis (CHF, n = 2), alpha-1 antitrypsin deficiency (A-1 ATD, n = 2), progressive familial intrahepatic cholestasis (PFIC, n = 2), cystic fibrosis (n = 1), primary biliary cirrhosis (PBC, n = 1), neonatal hepatitis (n = 1), embryonal sarcoma (n = 1), Caroli disease (n = 1), hepatocellular carcinoma (HCC, n = 1), and chronic rejection after liver transplantations for PSC (n = 1). All patients and grafts survived at median follow-up of 6.4 years (range 1.2-12.9 years). Median domino recipient age was 16.2 years (range 0.6-64.6 years) and median MSUD recipient age was 17.6 years (range 4.8-32.1 years). There were no vascular complications during the early postoperative period, one patient had portal vein thrombosis 3 years after DLT and a meso-Rex bypass was successfully performed. Small for size syndrome (SFSS) occurred in reduced left lobe DLT recipient and was managed successfully with conservative management. Biliary stricture developed in 2 patients and was resolved by stenting. Comparison between DLT and MSUD recipients' peak postoperative ALT results and PELD/MELD scores showed lower levels in DLT group (P-value <.05).

Conclusions: Patient and graft survival in DLT from MSUD donors was excellent at short- and long-term follow-up. Metabolic functions have been normal in all recipients on a normal unrestricted protein diet. Ischemia preservation injury based on peak ALT was significantly decreased in DLT recipients. Domino transplantation from pediatric and adult recipients with selected metabolic diseases should be increasingly considered as an excellent option and alternative to deceased donor transplantation, thereby expanding the living donor pool. This, to date, is the largest world experience in DLT utilizing livers from patients with MSUD.
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http://dx.doi.org/10.1111/ctr.13721DOI Listing
November 2019

Crigler-Najjar Syndrome Type 1: Pathophysiology, Natural History, and Therapeutic Frontier.

Hepatology 2020 Jun 5;71(6):1923-1939. Epub 2020 Feb 5.

Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA.

Background And Aims: We describe the pathophysiology, treatment, and outcome of Crigler-Najjar type 1 syndrome (CN1) in 28 UGT1A1 c.222C>A homozygotes followed for 520 aggregate patient-years.

Approach And Results: Unbound ("free") bilirubin (B ) was measured in patient sera to characterize the binding of unconjugated bilirubin (B ) to albumin (A) and validate their molar concentration ratio (B /A) as an index of neurological risk. Two custom phototherapy systems were constructed from affordable materials to provide high irradiance in the outpatient setting; light dose was titrated to keep B /A at least 30% below intravascular B binding capacity (i.e., B /A = 1.0). Categorical clinical outcomes were ascertained by chart review, and a measure (L ) was used to quantify liver fibrosis. Unbound bilirubin had a nonlinear relationship to B (R  = 0.71) and B /A (R  = 0.76), and B as a percentage of B correlated inversely to the bilirubin-albumin equilibrium association binding constant (R  = 0.69), which varied 10-fold among individuals. In newborns with CN1, unconjugated bilirubin increased 4.3 ± 1.1 mg/dL per day. Four (14%) neonates developed kernicterus between days 14 and 45 postnatal days of life; peak B  ≥ 30 mg/dL and B /A ≥ 1.0 mol:mol were equally predictive of perinatal brain injury (sensitivity 100%, specificity 93.3%, positive predictive value 88.0%), and starting phototherapy after age 13 days increased this risk 3.5-fold. Consistent phototherapy with 33-103 µW/cm •nm for 9.2 ± 1.1 hours/day kept B and B /A within safe limits throughout childhood, but B increased 0.46 mg/dL per year to reach dangerous concentrations by 18 years of age. Liver transplantation (n = 17) normalized B and eliminated phototherapy dependence. Liver explants showed fibrosis ranging from mild to severe.

Conclusion: Seven decades after its discovery, CN1 remains a morbid and potentially fatal disorder.
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http://dx.doi.org/10.1002/hep.30959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909716PMC
June 2020

Neurodevelopmental Outcomes in Preschool and School Aged Children With Biliary Atresia and Their Native Liver.

J Pediatr Gastroenterol Nutr 2020 01;70(1):79-86

Section of Pediatric GI, Hepatology and Nutrition, Children's Hospital Colorado and University of Colorado School of Medicine, Aurora, CO.

Objectives: The aim of the study was to assess neurodevelopmental outcomes among children with biliary atresia (BA) surviving with their native liver at ages 3 to 12 years and evaluate variables that associate with neurodevelopment.

Methods: Participants (ages 3-12 years) in a prospective, longitudinal, multicenter study underwent neurodevelopmental testing with Weschler Preschool and Primary Scale of Intelligence, 3rd edition (WPPSI-III, ages 3-5 years) and Weschler Intelligence Scale for Children, 4th edition (WISC-IV, ages 6-12 years). Continuous scores were analyzed using Kolmogorov-Smironov tests compared with a normal distribution (mean = 100 ± 15). Effect of covariates on Full-Scale Intelligence Quotient (FSIQ) was analyzed using linear regression.

Results: Ninety-three participants completed 164 WPPSI-III (mean age 3.9) and 51 WISC-IV (mean age 6.9) tests. WPPSI-III FSIQ (104 ± 14, P < 0.02), Verbal IQ (106 ± 14, P < 0.001), and General Language Composite (107 ± 16, P < 0.001) distributions were shifted higher compared with test norms. WISC-IV FSIQ (105 ± 12, P < 0.01), Perceptual Reasoning Index (107 ± 12, P < 0.01), and Processing Speed Index (105 ± 10, P < 0.02) also shifted upwards. In univariate and multivariable analysis, parent education (P < 0.01) was a significant predictor of FSIQ on WPPSI-III and positively associated with WISC-IV FSIQ. Male sex and higher total bilirubin and gamma glutamyl transferase (GGT) predicted lower WPPSI-III FSIQ. Portal hypertension was predictive of lower WISC-IV FSIQ.

Conclusions: This cohort of children with BA and native liver did not demonstrate higher prevalence of neurodevelopmental delays. Markers of advanced liver disease (higher total bilirubin and GGT for age ≤5 years; portal hypertension for age ≥6) correlate with lower FSIQ and may identify a vulnerable subset of patients who would benefit from intervention.
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http://dx.doi.org/10.1097/MPG.0000000000002489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934908PMC
January 2020

Disease burden of Crigler-Najjar syndrome: Systematic review and future perspectives.

J Gastroenterol Hepatol 2020 Apr 24;35(4):530-543. Epub 2019 Oct 24.

Audentes Therapeutics, San Francisco, CA, USA.

Background And Aim: Crigler-Najjar syndrome (CNS) results from biallelic mutations of UGT1A1 causing partial or total loss of uridine 5'-diphosphate glucuronyltransferase activity leading to unconjugated hyperbilirubinemia and its attendant risk for irreversible neurological injury (kernicterus). CNS is exceedingly rare and has been only partially characterized through relatively small studies, each comprising between two and 57 patients.

Methods: A systematic literature review was conducted to consolidate data on the patient, caregiver, and societal burden of CNS.

Results: Twenty-eight articles on clinical aspects of CNS were identified, but no published data on its humanistic or economic burden were found. In patients with complete UGT1A1 deficiency (type 1 CNS [CNS-I]), unconjugated bilirubin levels increase 3-6 mg/dL/day during the newborn period and reach neurologically dangerous levels between 5 and 14 days of age. Phototherapy is the mainstay of treatment but poses significant challenges to patients and their families. Despite consistent phototherapy, patients with CNS-I have worsening hyperbilirubinemia with advancing age. Liver transplantation is the only definitive therapy for CNS-I and is increasingly associated with excellent long-term survival but also incurs high costs, medical and surgical morbidities, and risks of immunosuppression.

Conclusions: Crigler-Najjar syndrome is associated with a substantial burden, even with existing standards of care. The development of novel disease-modifying therapies has the potential to reduce disease burden and improve the lives of CNS patients and their families.
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http://dx.doi.org/10.1111/jgh.14853DOI Listing
April 2020

Domino liver transplantation for select metabolic disorders: Expanding the living donor pool.

JIMD Rep 2019 Jul 19;48(1):83-89. Epub 2019 Jun 19.

Hillman Center for Pediatric Transplantation, Children's Hospital of Pittsburgh of UPMC Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine Pittsburgh Pennsylvania.

Domino liver transplantation (DLT) involves transplanting liver from a patient with metabolic disease into a patient with end-stage liver disease with the expectation that the recipient will not develop the metabolic syndrome or the recurrent syndrome will have minimal affect. The domino donor gets a deceased donor or a segment of live-donor liver through the deceased donor organ allocation system. Waitlist mortality for the domino recipient exceeds morbidity associated with getting the donor disease. Between 2015 and 2017, four patients with three metabolic disorders at UPMC Children's Hospital of Pittsburgh underwent DLT with domino allografts from maple syrup urine disease (MSUD) patients. These included patients with propionic acidemia (PA) (n = 1), Crigler-Najjar (CN) syndrome type-1 (n = 2), and carbamoyl phosphate synthetase deficiency (CPSD) (n = 1). Mean follow-up was 1.6 years (range 1.1-2.1 years). Total bilirubin levels normalized postoperatively in both CN patients and they maintain normal allograft function. The PA patient had normal to minimal elevations of isoleucine and leucine, and no other abnormalities on low protein diet supplemented with a low methionine and valine free formula. No metabolic crises have occurred. The patient with CPSD takes normal baby food. No elevation in ammonia levels have been observed in any of the patients. DLT for a select group of metabolic diseases alleviated the recipients of their metabolic defect with minimal evidence of transferrable-branched chain amino acid elevations or clinical MSUD despite increased protein intake. DLT using allografts with MSUD expands the live donor liver pool and should be considered for select metabolic diseases that may have a different enzymatic deficiency.
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http://dx.doi.org/10.1002/jmd2.12053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6606984PMC
July 2019

A learning health network for pediatric liver transplantation: Inaugural meeting report from the Starzl Network for Excellence in Pediatric Transplantation.

Pediatr Transplant 2019 09 22;23(6):e13528. Epub 2019 Jul 22.

Hillman Center for Pediatric Transplantation, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania.

Learning Health Networks (LHN) improve the well-being of populations by aligning clinical care specialists, technology experts, patients and patient advocates, and other thought leaders for continuous improvement and seamless care delivery. A novel LHN focused on pediatric transplantation, the Starzl Network for Excellence in Pediatric Transplantation (SNEPT), convened its inaugural meeting in September 2018. Clinical care team representatives, patients, and patient families/advocates partnered to take part in educational sessions, pain point exercises, and project identification workshops. Participants discussed the global impact of transplant from both a population and individual perspective, identifying challenges and opportunities where the Starzl Network could work to improve outcomes at scale across a variety of transplant-related conditions.
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http://dx.doi.org/10.1111/petr.13528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778726PMC
September 2019

A novel mutation in gene causing a milder ARC syndrome phenotype with prolonged survival.

JIMD Rep 2019 May 22;47(1):4-8. Epub 2019 Mar 22.

Pediatric Hepatology Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh Medical Center Pittsburgh Pennsylvania.

Introduction: ARC (arthrogryposis, renal dysfunction, and cholestasis) syndrome is an uncommon multisystem disorder that entails a very poor prognosis. It is caused by mutations in either or gene, both playing a key role in intracellular trafficking. We report two siblings born to first cousin parents with a novel mutation in who have both shown prolonged survival.

Cases Presentation: The index patient presented with bilateral hip dysplasia and arthrogryposis, failure to thrive, undernourishment, developmental delay, and low gamma-glutamyl transferase cholestasis. She at age 2 years underwent external biliary diversion with improvement in pruritus but liver disease continued to progress. She developed stomal bleeding at 7 years of age and liver biopsy displayed cirrhosis. Her 3-year-old sibling showed a similar trajectory as well as he had ichthyotic skin with excoriations. Their renal involvement was mild and stable. Genetic analysis in both patients revealed a novel homozygous mutation in NM_018668.4 ():c.1157A > C (p.His386Pro).

Conclusions: ARC syndrome is a severe disorder with few patients reported to survive beyond 12 months of age. This report discloses a novel mutation in the gene and describes a phenotype with prolonged survival, mild renal involvement, and progressive liver disease.
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http://dx.doi.org/10.1002/jmd2.12027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6498830PMC
May 2019

Expanding etiology of progressive familial intrahepatic cholestasis.

World J Hepatol 2019 May;11(5):450-463

Division of Gastroenterology, Hepatology, and Nutrition, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, United States.

Background: Progressive familial intrahepatic cholestasis (PFIC) refers to a disparate group of autosomal recessive disorders that are linked by the inability to appropriately form and excrete bile from hepatocytes, resulting in a hepatocellular form of cholestasis. While the diagnosis of such disorders had historically been based on pattern recognition of unremitting cholestasis without other identified molecular or anatomic cause, recent scientific advancements have uncovered multiple specific responsible proteins. The variety of identified defects has resulted in an ever-broadening phenotypic spectrum, ranging from traditional benign recurrent jaundice to progressive cholestasis and end-stage liver disease.

Aim: To review current data on defects in bile acid homeostasis, explore the expanding knowledge base of genetic based diseases in this field, and report disease characteristics and management.

Methods: We conducted a systemic review according to PRISMA guidelines. We performed a Medline/PubMed search in February-March 2019 for relevant articles relating to the understanding, diagnosis, and management of bile acid homeostasis with a focus on the family of diseases collectively known as PFIC. English only articles were accessed in full. The manual search included references of retrieved articles. We extracted data on disease characteristics, associations with other diseases, and treatment. Data was summarized and presented in text, figure, and table format.

Results: Genetic-based liver disease resulting in the inability to properly form and secrete bile constitute an important cause of morbidity and mortality in children and increasingly in adults. A growing number of PFIC have been described based on an expanded understanding of biliary transport mechanism defects and the development of a common phenotype.

Conclusion: We present a summary of current advances made in a number of areas relevant to both the classically described FIC1 (), BSEP (), and MDR3 () transporter deficiencies, as well as more recently described gene mutations -- TJP2 (), FXR (), MYO5B (), and others which expand the etiology and understanding of PFIC-related cholestatic diseases and bile transport.
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http://dx.doi.org/10.4254/wjh.v11.i5.450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547292PMC
May 2019

Corticosteroid Therapy for Indeterminate Pediatric Acute Liver Failure and Aplastic Anemia with Acute Hepatitis.

J Pediatr 2019 05 13;208:23-29. Epub 2019 Feb 13.

Department of Pediatrics, Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL.

Objective: To examine the characteristics and outcomes of a multicenter patient cohort with indeterminate pediatric acute liver failure (IND-PALF) and with aplastic anemia with acute hepatitis treated with corticosteroids.

Study Design: Retrospective study of patients age 1-17 years with IND-PALF and aplastic anemia with acute hepatitis who presented between 2009 and 2018 to 1 of 4 institutions and were treated with corticosteroids for presumed immune dysregulation.

Results: Of 28 patients with IND-PALF (median of 4.0 years of age [range 1-16] and 71% male) 71% (n = 20) were treated with 0.5-4 mg/kg/day of intravenous methylprednisolone, and 8 patients received 10 mg/kg/day followed by a taper. By 21 days postcorticosteroid initiation, 14 patients (50%) underwent liver transplantation, 13 patients (46%) recovered with their native liver, and 1 patient (4%) died. Patients who recovered with their native liver received a median of 139 days (range 19-749) of corticosteroid therapy, with a median of 12 days (range 1-240) to international normalized ratio ≤1.2. Patients with aplastic anemia with acute hepatitis (n = 6; median of 9.5 years of age [range 1-12], 83% male), received 1-2 mg/kg/day of methylprednisolone for a median of 100 days (range 63-183), and all recovered with their native liver. One patient with IND-PALF and 2 patients with aplastic anemia with acute hepatitis developed a serious infection within 90 days postcorticosteroid initiation.

Conclusions: Many patients with IND-PALF or aplastic anemia with acute hepatitis that were treated with corticosteroids improved, but survival with native liver may not be different from historical reports. A randomized controlled trial exploring the benefits and risks of steroid therapy is needed before it is adopted broadly.
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http://dx.doi.org/10.1016/j.jpeds.2018.12.042DOI Listing
May 2019

Evolving Trends in Liver Transplant for Metabolic Liver Disease in the United States.

Liver Transpl 2019 06 15;25(6):911-921. Epub 2019 Apr 15.

Hillman Center for Pediatric Transplantation, University of Pittsburgh, Pittsburgh, PA.

Indications for liver transplantation (LT) in metabolic disease are evolving. We reviewed the US experience with primary LT for metabolic disease in the Scientific Registry for Transplant Recipients (October 1987 to June 2017) to determine the following: temporal changes in indications, longterm outcomes, and factors predicting survival. Patients were grouped by the presence of structural liver disease (SLD) and whether the defect was confined to the liver. There were 5996 patients who underwent LT for metabolic disease, 2354 (39.3%) being children. LT for metabolic disease increased in children but not in adults. Children experienced a 6-fold increase in LT for metabolic disease without SLD. Indications for LT remained stable in adults. Living donor liver transplantation increased between era 1 and era 3 from 5.6% to 7.6% in children and 0% to 4.5% in adults. Patient and graft survival improved with time. The latest 5-year patient survival rates were 94.5% and 81.5% in children and adults, respectively. Outcomes were worse in adults and in those with extrahepatic disease (P < 0.01), whereas SLD did not affect outcomes. Survival improved with younger age at LT until age <2 years. On multivariate analysis, diagnostic category, inpatient status, age at LT, and transplant era significantly predicted outcomes in all ages with male sex predicting survival in childhood only. Children without structural disease were less likely to die awaiting LT and had improved post-LT survival compared with children with chronic liver disease. In conclusion, LT for metabolic disease is increasingly used for phenotypic correction in children; extrahepatic manifestations significantly impact survival at all ages; where indicated, transplantation should not be unnecessarily delayed; and the development of new allocation models may be required.
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http://dx.doi.org/10.1002/lt.25433DOI Listing
June 2019

Quality initiatives in pediatric transplantation.

Curr Opin Organ Transplant 2019 02;24(1):64-72

Department of Surgery, Hillman Center for Pediatric Transplantation, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Purpose Of Review: Pediatric transplantation faces unique challenges in implementing dynamic quality improvement measures because of proportionally smaller volumes compared to adults, logistics of being integrated successfully within larger or complex hospital systems, lack of adult-affiliated transplant centers, varying focus in prioritization of relevant outcome metrics, and potential lack of sufficient resources.

Recent Findings: To address these challenges, multiinstitutional collaborations have developed which have proven increasingly effective in driving awareness and quality improvement measures to supplement regulatory efforts in the pediatric population. Relevant work from the Pediatric Heart Transplant Society and Studies in Pediatric Liver Transplantation will be highlighted. The introduction of learning networks such as the Improving Renal Outcomes Collaborative and the Starzl Network for Excellence in Pediatric Transplantation have further focused on continuous learning initiatives in renal and liver transplantation using collaboration and patient informed measures.

Summary: Optimal transplant performance improvement is fully integrated into health delivery at all points of the patient pathway. Progress in performance improvement will require ongoing integration of big data solutions, improved patient engagement and technology solutions. VIDEO ABSTRACT:.
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http://dx.doi.org/10.1097/MOT.0000000000000595DOI Listing
February 2019

Molecular Mechanisms in Pediatric Cholestasis.

Gastroenterol Clin North Am 2018 12 28;47(4):921-937. Epub 2018 Sep 28.

Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Pittsburgh, One Children's Hospital Drive, 6th Floor FP, 4401 Penn Avenue, Pittsburgh, PA 15224, USA.

Pediatric cholestasis often results from mechanical obstruction of the biliary tract or dysfunction in the processes of forming and excreting bile. Various genetic defects with resulting molecular inaccuracies are increasingly being recognized, often with specific clinical characteristics. Identifying of the molecular abnormality can enable implementation of timely, appropriate treatment in some affected individuals and provide prognostic indicators for both families and care teams.
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http://dx.doi.org/10.1016/j.gtc.2018.07.014DOI Listing
December 2018

Acute Liver Failure: An Update.

Clin Liver Dis 2018 11 22;22(4):773-805. Epub 2018 Aug 22.

Department of Pediatric Gastroenterology and Hepatology, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh, 4401 Penn Avenue, Pittsburgh, PA 15224, USA.

Pediatric acute liver failure (PALF) is a dynamic, life-threatening condition of disparate etiology. Management of PALF is dependent on intensive collaborative clinical care and support. Proper recognition and treatment of common complications of liver failure are critical to optimizing outcomes. In parallel, investigations to identify underlying cause and the implementation of timely, appropriate treatment can be life-saving. Predicting patient outcome in the era of liver transplantation has been unfulfilling and better predictive models must be developed for proper stewardship of the limited resource of organ availability.
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http://dx.doi.org/10.1016/j.cld.2018.06.009DOI Listing
November 2018

Liver Transplantation for Propionic Acidemia and Methylmalonic Acidemia: Perioperative Management and Clinical Outcomes.

Liver Transpl 2018 09;24(9):1260-1270

Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA.

Propionic acidemia (PA) and methylmalonic acidemia (MMA) comprise the most common organic acidemias and account for profound morbidity in affected individuals. Although liver transplantation (LT) has emerged as a bulk enzyme-replacement strategy to stabilize metabolically fragile patients, it is not a metabolic cure because patients remain at risk for disease-related complications. We retrospectively studied LT and/or liver-kidney transplant in 9 patients with PA or MMA with additional focus on the optimization of metabolic control and management in the perioperative period. Metabolic crises were common before transplant. By implementing a strategy of carbohydrate minimization with gradual but early lipid and protein introduction, lactate levels significantly improved over the perioperative period (P < 0.001). Posttransplant metabolic improvement is demonstrated by improvements in serum glycine levels (for PA; P < 0.001 × 10 ), methylmalonic acid levels (for MMA; P < 0.001), and ammonia levels (for PA and MMA; P < 0.001). Dietary restriction remained after transplant. However, no further metabolic crises have occurred. Other disease-specific comorbidities such as renal dysfunction and cardiomyopathy stabilized and improved. In conclusion, transplant can provide a strategy for altering the natural history of PA and MMA providing stability to a rare but metabolically brittle population. Nutritional management is critical to optimize patient outcomes.
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http://dx.doi.org/10.1002/lt.25304DOI Listing
September 2018