Publications by authors named "Estella Alonso"

126 Publications

Applying an Age-Specific Definition to Better Characterize Etiologies and Outcomes in Neonatal Acute Liver Failure.

J Pediatr Gastroenterol Nutr 2021 Feb 24. Epub 2021 Feb 24.

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

Objective: Neonatal acute liver failure (ALF) is a rare disease with high mortality for which no standard age-specific definition exists. To advance the understanding of neonatal ALF we characterize the etiology, presenting features, treatment, and outcomes in infants within 1 month of life.

Methods: We performed a single-center 11-year retrospective chart review of neonates ≤ 30 days of life with ALF as defined by an INR of ≥ 2.0. Comparisons were made by etiology and survival with native liver. Estimated survival was performed using the Kaplan Meier method.

Results: Forty-three patients met inclusion criteria for neonatal ALF. Etiologies included viral infection (23%), gestational alloimmune liver disease with neonatal hemochromatosis (GALD-NH) (21%), cardiac-associated ischemia (16%), other ischemia (14%), genetic etiologies (9%), Trisomy 21 associated myelodysplasia (7%), hemophagocytic lymphohistiocytosis (HLH) (2%), and not identified (7%). Infants with viral etiologies had the highest alanine aminotransferase at presentation (1179 IU/L, IQR 683-1585 IU/L) in contrast to low levels in GALD-NH (23 IU/L, IQR 18-64 IU/L). Across all etiologies only 33% were alive at 1 year. Overall median survival was 74 days; 17 days for viral infection and 74 days for GALD-NH. Among laboratory values at presentation, alpha-fetoprotein was significantly higher in patients that survived with their native liver (p = 0.04).

Conclusions: Overall, outcome for neonatal ALF is poor. While initial laboratory values can differentiate viral infection or GALD-NH, further studies are needed to identify laboratory parameters that predict survival with native liver by etiology to ultimately improve patient outcomes.
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http://dx.doi.org/10.1097/MPG.0000000000003103DOI Listing
February 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

Modeling Outcomes in Children With Biliary Atresia With Native Liver After 2 Years of Age.

Hepatol Commun 2020 Dec 3;4(12):1824-1834. Epub 2020 Oct 3.

Emory University School of Medicine Atlanta GA.

Approximately 50% of infants with biliary atresia (BA) undergoing Kasai portoenterostomy show survival with native liver (SNL) at age 2 years. Predictors of disease progression after age 2 years are unknown, despite estimates of 20%-30% undergoing liver transplant (LT) between age 2 and 18 years. We sought to address this knowledge gap by developing prognostic models in participants of the multicenter prospective National Institutes of Health-supported Childhood Liver Disease Research Network. We extracted 14 clinical and biochemical variables at age 2 years to develop two models for future outcomes: 1) LT or death (LTD) and 2) first sentinel event (SE), either new onset ascites, hepatopulmonary syndrome (HPS), or gastrointestinal (GI) bleed. A total of 240 participants, enrolled between 2004 and 2017, were followed until a median age of 5.1 years (range, 2.0-13.3 years). Of these participants, 38 underwent LT (n = 37) or death (n = 1); cumulative incidence, 23.7% (95% confidence interval [CI], 16.2%-32.0%). Twenty-seven experienced either new-onset ascites (n = 13), HPS (n = 1), or GI bleed (n = 14). One participant had ascites and GI bleed concurrently; cumulative incidence, 21.5% (95% CI, 14.2%-29.8%) by age 10 years. The Cox proportional hazard model predicted risk of LTD, using total bilirubin, albumin, platelet count, and history of either ascites or cholangitis (BA LTD model), with a C-index of 0.88 (range, 0.86-0.89). A cause-specific hazard competing risk model predicted SE using platelet count and gamma glutamyltransferase levels (BA SE model) with a C-index of 0.81 (range, 0.80-0.84). Internal model validity was assessed using Harrell's C-index with cross-validation. Stratification using these models identified risk of poor outcomes in patients with BA SNL after age 2 years. The models may identify those who would benefit from enhanced clinical surveillance and prioritization in clinical trials.
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http://dx.doi.org/10.1002/hep4.1602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706301PMC
December 2020

Improvements in Disease Specific Health-Related Quality of Life of Pediatric Liver Transplant Recipients During Immunosuppression Withdrawal.

Liver Transpl 2020 Dec 6. Epub 2020 Dec 6.

Siragusa Transplantation Center, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.

Long-term immunosuppression leads to systemic complications affecting health-related quality of life in pediatric liver transplant recipients. We serially assessed health-related quality of life using PedsQL™ Generic, Multidimensional Fatigue, Family Impact, and Transplant modules as part of a multicenter prospective immunosuppression withdrawal trial between 2012-2018. Participants received a primary liver transplant ≥4 years ago, were on stable immunosuppression with normal liver tests and without rejection in the prior 2 years. Immunosuppression was withdrawn in 7 steps over 36-48 weeks. Health-related quality of life was assessed at regular intervals. The primary endpoint was change in disease-specific health-related quality of life measured by the PedsQL™ Transplant Module. Generic health related quality of life was measured by the PedsQL™ Generic module and was compared to an age and gender matched multi-center cohort. Of the 88 participants, 39 were male, median age was 11 years (range 8-13years) and time since transplant was 9 years (range 6-11years). Over 36 months, disease-specific health-related quality of life improved for all participants, while generic health-related quality of life was unchanged. Neither generic nor disease-specific health-related quality of life changed for the 35 participants who developed acute rejection during immunosuppression withdrawal. CONCLUSION: In the first of patient-reported outcome measures during immunosuppression withdrawal trial, we found improvements in disease-specific health-related quality of life in all participants and no lasting detrimental effects in those who experienced rejection.
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http://dx.doi.org/10.1002/lt.25963DOI Listing
December 2020

Dexmedetomidine leading to profound bradycardia in a pediatric liver transplant recipient.

Pediatr Transplant 2020 Oct 28:e13895. Epub 2020 Oct 28.

Department of Pediatrics, Northwestern University Feinberg School of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.

Dexmedetomidine, an α -agonist, is used in the PICU for its sedative properties as it minimally affects respiratory status. However, hemodynamic instability is one of its known side effects. There is limited published experience with its use in pediatric liver transplant. We present a case of a 9-month-old infant who received a deceased donor liver transplantation for biliary atresia and received an IV dexmedetomidine infusion for sedation starting at 20 hours post-operatively. The patient received an IV bolus of 0.08 mcg/kg followed by an increase to 1 mcg/kg/hour. She was also receiving a fentanyl infusion for sedation at the time of dexmedetomidine initiation. Approximately 3 hours after initiation, she developed bradycardia as low as 30 beats-per-minute with an associated sinus pause of 7 seconds. She was given chest compressions by the bedside nurse briefly before arousing and becoming agitated. Evaluation of other etiologies for the patient's bradycardia was unrevealing. Thus, bradycardia was attributed to dexmedetomidine therapy which was discontinued without recurrence. Hemodynamic instability, specifically bradycardia, is known to occur with dexmedetomidine administration. As this medication is primarily metabolized by the liver, its use immediately after transplantation, when liver function is still recovering, may be associated with an increased risk of side effects. Understanding risk factors for bradycardia and hemodynamic instability early after liver transplantation, particularly with dexmedetomidine, is critical to allow clinicians to identify the patients for higher risk for dexmedetomidine side effects.
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http://dx.doi.org/10.1111/petr.13895DOI Listing
October 2020

Response to: Recognizing Pediatric Acute-on-chronic Liver Failure: the Need of the Hour.

J Pediatr Gastroenterol Nutr 2021 Jan;72(1):e30

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

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http://dx.doi.org/10.1097/MPG.0000000000002935DOI Listing
January 2021

Activated CD8 T-cell Hepatitis in Children With Indeterminate Acute Liver Failure: Results From a Multicenter Cohort.

J Pediatr Gastroenterol Nutr 2020 12;71(6):713-719

Department of Pediatrics, Northwestern University.

Objectives: In many pediatric acute liver failure (PALF) cases, a diagnosis is not identified, and the etiology is indeterminate (IND-PALF). Our pilot study found dense CD8 T-cell infiltrates and increased T-cell clonality in liver specimens from IND-PALF patients. We aimed to validate these findings in a multicenter cohort with investigators blinded to diagnosis.

Methods: PALF Study Group registry subjects with IND-PALF (n = 37) and known diagnoses (DX-PALF) (n = 18), ages 1 to 17 years, with archived liver tissue were included. Liver tissue slides were stained for T cells (CD8 and CD4), B cells (CD20), macrophages (CD163), perforin, and tissue resident-memory T cells (Trm, CD103), and scored as minimal, moderate, or dense. Lymphocytes were isolated from frozen liver tissue for T-cell receptor beta (TCRβ) sequencing.

Results: Dense hepatic CD8 staining was found in significantly more IND-PALF (n = 29, 78%) compared with DX-PALF subjects (n = 5, 28%) (P = 0.001). IND-PALF subjects were more likely to have dense or moderate perforin (88% vs 50%, P = 0.03) and CD103 (82% vs 40%, P = 0.02) staining compared with DX-PALF subjects. TCRβ sequencing of 15 IND-PALF cases demonstrated increased clonal overlap compared with 6 DX-PALF cases (P = 0.002).

Conclusions: Dense infiltration of effector Trm CD8 T cells characterizes liver tissue from IND-PALF subjects. Increased clonality suggests the T-cell expansion is antigen(s)-driven as opposed to a nonspecific inflammatory response. These findings support CD8 staining as a new biomarker of the activated CD8 T-cell PALF phenotype. Future studies are needed to characterize potential antigens, host risk factors, and inflammatory pathways with the goal of developing targeted therapies.
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http://dx.doi.org/10.1097/MPG.0000000000002893DOI Listing
December 2020

Efficacy and Safety of Immunosuppression Withdrawal in Pediatric Liver Transplant Recipients: Moving Towards Personalized Management.

Hepatology 2020 Aug 12. Epub 2020 Aug 12.

Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA.

Background And Aims: Tolerance is transplantation's holy grail as it denotes allograft health without immunosuppression and its toxicities. Our aim was to determine, among stable long-term pediatric liver transplant recipients, the efficacy and safety of immunosuppression withdrawal to identify operational tolerance.

Approach And Results: We conducted a multi-center, single-arm trial of immunosuppression withdrawal over 36-48 weeks. Liver tests were monitored biweekly (year 1), monthly (year 2) and bimonthly (years 3-4). For-cause biopsies were done at investigators' discretion but mandated when alanine aminotransferase or gamma glutamyl transferase exceeded 100U/L. All subjects underwent final liver biopsy at trial end. The primary efficacy endpoint was operational tolerance, defined by strict biochemical and histological criteria 1 year after stopping immunosuppression. Among 88 subjects (median age 11 years; 39 boys; 57 deceased donor grafts), 33 (37.5%; 95%CI 27.4%, 48.5%) were operationally tolerant, 16 were non-tolerant by histology (met biochemical but failed histological criteria) and 39 were non-tolerant by rejection. Rejection, predicted by subtle liver inflammation in trial entry biopsies, typically (n=32) occurred at ≤32% of the trial entry immunosuppression dose and was treated with corticosteroids (n=32) and/or tacrolimus (n=38) with resolution (liver tests within 1.5X baseline) for all but 1 subject. No death, graft loss, or chronic, severe, or refractory rejection occurred. Neither fibrosis stage nor the expression level of a rejection gene set increased over 4 years for either tolerant or non-tolerant subjects.

Conclusions: Immunosuppression withdrawal showed that 37.5% of selected pediatric liver transplant recipients were operationally tolerant. Allograft histology did not deteriorate for either tolerant or non-tolerant subjects. The timing and reversibility of failed withdrawal justifies future trials exploring the efficacy, safety, and potential benefits of immunosuppression minimization.
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http://dx.doi.org/10.1002/hep.31520DOI Listing
August 2020

Unraveling the Relationship Between Itching, Scratch Scales, and Biomarkers in Children With Alagille Syndrome.

Hepatol Commun 2020 Jul 26;4(7):1012-1018. Epub 2020 May 26.

Baylor College of Medicine Texas Children's Hospital Houston TX.

Pruritus is a debilitating symptom for patients with Alagille syndrome (ALGS). In a previously reported trial of maralixibat, an investigational antipruritic agent, itching was assessed using a digital diary based on twice-daily caregiver observation of itching severity (Itch Reported Outcome, ItchRO[Observer]). The goal of this study was to characterize pruritus in participants with ALGS at baseline in this trial, as assessed by the ItchRO instrument and the physician-observed clinician scratch scale (CSS), relative to biomarkers putatively associated with pruritus and health-related quality of life assessment. Thirty-seven participants with ALGS (median age of 6 years; range 1-17 years) were enrolled. No association was identified between CSS and ItchRO(Obs) ( = 0.22,  = 0.2). Neither CSS nor ItchRO were associated with serum bile acids ( = -0.08,  = 0.6 for both) or autotaxin ( = 0.22,  = 0.2;  = 0.28,  = 0.12). There was no significant association between Pediatric Quality of Life Inventory total parent scores and CSS or ItchRO ( = -0.23,  = 0.2;  = -0.16,  = 0.36). There was a significant association between ItchRO and Multidimensional Fatigue Scale and Family Impact Module total scores (Pearson correlation coefficient -0.575,  = 0.0005; 0.504,  = 0.002). In exploratory analysis, selected questions relating to fatigue and sleep disturbance (n = 12) from Pediatric Quality of Life Inventory, Multidimensional Fatigue Scale, and Family Impact Module were correlated with pruritus scores; positive associations were identified. Itching scores did not correlate with each other, nor with putative serum biomarkers of pruritus, and further, did not correlate with quality of life. Hypothesis-generating analyses implicate sleep disturbance and fatigue as key associations with caregiver observations of itching. This is highly relevant to the selection of surrogate endpoints for clinical trials of pruritus therapies.
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http://dx.doi.org/10.1002/hep4.1522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327199PMC
July 2020

Health utility and quality of life in pediatric liver transplant recipients.

Pediatr Transplant 2020 06 26;24(4):e13720. Epub 2020 Apr 26.

Department of Pediatrics, Feinberg School of Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.

To measure HU and HRQOL in pediatric liver transplant (LT) recipients, a cross-sectional study of patient-parent dyads was conducted. Direct HU were assessed in 48 adolescents ≥12 years using SG and TTO techniques. Indirect HU were measured by Health Utility Index 2 and HUI3 for subjects ≥12 years and CHU9D for ≥7 years. Patients reported HRQOL using PedsQL™ GC and PedsQL™ TM. A total of 108 dyads participated (55.6% female; 73.2% Caucasian; 42.6% biliary atresia; 35.2% living donor; 37.0% Medicaid). Mean age at survey was 13.6 ± 3.5 years, and time from LT was 8.9 ± 4.9 years. 61.2% were on monotherapy, 25 (23.2%) had acute rejection within 3 years, and 15 (13.9%) had a biliary obstruction within 5 years. Mean indirect HU and HRQOL scores by child report were lower than norms (P < .001). LRD recipients had higher PedsQL™ GC, PedsQL™ TM, and HUI3 scores (P < .01). HU in pediatric LT recipients are lower than norms. Availability of HU scores for post-transplant health states will enable measurement of quality-adjusted life years for future comparative effectiveness studies.
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http://dx.doi.org/10.1111/petr.13720DOI Listing
June 2020

Four Biomarkers Linked to Activation of Cluster of Differentiation 8-Positive Lymphocytes Predict Clinical Outcomes in Pediatric Acute Liver Failure.

Hepatology 2021 Jan;73(1):233-246

Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh School of Medicine and Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, PA, USA.

Background And Aims: Immune dysregulation contributes to the pathogenesis of pediatric acute liver failure (PALF). Our aim was to identify immune activation markers (IAMs) in PALF that are associated with a distinct clinical phenotype and outcome.

Approach And Results: Among 47 PALF study participants, 12 IAMs collected ≤6 days after enrollment were measured by flow cytometry and IMMULITE assay on blood natural killer and cluster of differentiation 8-positive (CD8 ) lymphocytes and subjected to unsupervised hierarchical analyses. A derivation cohort using 4 of 12 IAMs which were available in all participants (percent perforin-positive and percent granzyme-positive CD8 cells, absolute number of CD8 cells, soluble interleukin-2 receptor level) were sufficient to define high (n = 10), medium (n = 15), and low IAM (n = 22) cohorts. High IAM was more frequent among those with indeterminate etiology than those with defined diagnoses (80% versus 20%, P < 0.001). High IAM was associated with higher peak serum total bilirubin levels than low IAM (median peak 21.7 versus 4.8 mg/dL, P < 0.001) and peak coma grades. The 21-day outcomes differed between groups, with liver transplantation more frequent in high IAM participants (62.5%) than those with medium (28.2%) or low IAM (4.8%) (P = 0.002); no deaths were reported. In an independent validation cohort (n = 71) enrolled in a prior study, segregation of IAM groups by etiology, initial biochemistries, and short-term outcomes was similar, although not statistically significant. High serum aminotransferases, total bilirubin levels, and leukopenia at study entry predicted a high immune activation profile.

Conclusion: Four circulating T-lymphocyte activation markers identify a subgroup of PALF participants with evidence of immune activation associated with a distinct clinical phenotype and liver transplantation; these biomarkers may identify PALF participants eligible for future clinical trials of early targeted immunosuppression.
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http://dx.doi.org/10.1002/hep.31271DOI Listing
January 2021

Admission Characteristics Identify Risk of Pediatric Acute-on-Chronic Liver Failure.

J Pediatr Gastroenterol Nutr 2020 06;70(6):783-788

Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago.

Objectives: Acute-on-chronic liver failure (ACLF) is well-studied in adults and characterized by decompensated cirrhosis, multi-organ failure, and early mortality. Studies of ACLF in children are limited. We sought to characterize the prevalence and clinical factors associated with pediatric ACLF (PACLF).

Methods: A retrospective review of children 3 months to 18 years listed for liver transplantation and hospitalized for decompensated cirrhosis between January 2007 and December 2017 at a single pediatric hospital. Primary outcome was the development of PACLF, characterized as failure of at least 1 extrahepatic organ (mechanical ventilation, renal replacement therapy, vasoactive medications, grade III/IV hepatic encephalopathy). Characteristics were recorded for each hospitalization.

Results: Sixty-six patients had 186 hospitalizations with mean age at admission 4.0 ± 5.6 years and diagnosis of biliary atresia (BA) in 65%. PACLF developed in 20 patients during 23 hospitalizations (12%) and respiratory failure was most common (17/23, 74%). Duration of intensive care unit stay, 13.1 ± 1.2 days versus 0.6 ± 0.6 days (P < 0.001) and length of stay, 24.3 ± 5.0 days versus 7.9 ± 1.9 days (P = 0.003) were longer in PACLF compared with non-PACLF. Mortality during PACLF hospitalizations was 22%. Clinical factors associated with PACLF were reported from a generalized linear mixed model and included increased admission creatinine (P < 0.0001), increased aspartate aminotransferase (AST) (P = 0.014), increased international normalized ration (INR) (P = 0.0015), and a positive blood culture (P = 0.007).

Conclusion: In this pediatric series, PACLF developed in 12% of hospitalizations and mortality was high. Admission creatinine, AST, INR, and presence of a positive blood culture were associated with PACLF development.
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http://dx.doi.org/10.1097/MPG.0000000000002695DOI Listing
June 2020

Heterogeneous Liver on Research Ultrasound Identifies Children with Cystic Fibrosis at High Risk of Advanced Liver Disease: Interim Results of a Prospective Observational Case-Controlled Study.

J Pediatr 2020 04 12;219:62-69.e4. Epub 2020 Feb 12.

Digestive Health Institute, Children's Hospital Colorado and Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO. Electronic address:

Objective: To assess if a heterogeneous pattern on research liver ultrasound examination can identify children at risk for advanced cystic fibrosis (CF) liver disease.

Study Design: Planned 4-year interim analysis of a 9-year multicenter, case-controlled cohort study (Prospective Study of Ultrasound to Predict Hepatic Cirrhosis in CF). Children with pancreatic insufficient CF aged 3-12 years without known cirrhosis, Burkholderia species infection, or short bowel syndrome underwent a screening research ultrasound examination. Participants with a heterogeneous liver ultrasound pattern were matched (by age, Pseudomonas infection status, and center) 1:2 with participants with a normal pattern. Clinical status and laboratory data were obtained annually and research ultrasound examinations biannually. The primary end point was the development of a nodular research ultrasound pattern, a surrogate for advanced CF liver disease.

Results: There were 722 participants who underwent screening research ultrasound examination, of which 65 were heterogeneous liver ultrasound pattern and 592 normal liver ultrasound pattern. The final cohort included 55 participants with a heterogeneous liver ultrasound pattern and 116 participants with a normal liver ultrasound pattern. All participants with at least 1 follow-up research ultrasound were included. There were no differences in age or sex between groups at entry. Alanine aminotransferase (42 ± 22 U/L vs 32 ± 19 U/L; P = .0033), gamma glutamyl transpeptidase (36 ± 34 U/L vs 15 ± 8 U/L; P < .001), and aspartate aminotransferase to platelet ratio index (0.7 ± 0.5 vs 0.4 ± 0.2; P < .0001) were higher in participants with a heterogeneous liver ultrasound pattern compared with participants with a normal liver ultrasound pattern. Participants with a heterogeneous liver ultrasound pattern had a 9.1-fold increased incidence (95% CI, 2.7-30.8; P = .0004) of nodular pattern vs a normal liver ultrasound pattern (23% in heterogeneous liver ultrasound pattern vs 2.6% in normal liver ultrasound pattern).

Conclusions: Research liver ultrasound examinations can identify children with CF at increased risk for developing advanced CF liver disease.
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http://dx.doi.org/10.1016/j.jpeds.2019.12.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7096278PMC
April 2020

The impact of caregiver post-traumatic stress and depressive symptoms on pediatric transplant outcomes.

Pediatr Transplant 2020 02 27;24(1):e13642. Epub 2019 Dec 27.

Icahn School of Medicine at Mount Sinai, New York, New York.

PTSS as well as symptoms of depression have been reported in children who experience a serious medical adversity as well as their caretakers. The adverse effects of PTSS, when experienced by the patients, on medical outcomes have been clearly documented. However, the impact of those symptoms, if any, when experienced by the caretakers on child outcomes has not been investigated prospectively. We evaluated whether caregiver PTSS and depression symptoms predict adherence to medications and medical outcomes in a prospective multisite study. Four hundred children participated in MALT. Caretaker PTSS were assessed by the IES and depressive symptoms by CES-D. During 2 years of follow-up, the MLVI was used to determine adherence. Centrally read, biopsy-confirmed organ rejection was the primary medical outcome. IES scores were not associated with either adherence or rejection outcomes. In contrast, there were significant correlations between CES-D (depression) scores and lower adherence, r = .13, P < .001, and a trend toward higher scores on the CES-D among those whose children had experienced rejection, 12.4 (SD = 10.9) versus 9.1 (SD = 8.6), P = .077. Caregivers' PTSS were not a risk factor for poor child outcomes in this cohort, whereas depression symptoms were associated with non-adherence and possibly increased rates of rejection. Further study can validate if caregivers' depression as opposed to PTSS confers greater risk and should be a focus during the clinical care of medically ill children.
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http://dx.doi.org/10.1111/petr.13642DOI Listing
February 2020

A Prospective Trial of Withdrawal and Reinstitution of Ursodeoxycholic Acid in Pediatric Primary Sclerosing Cholangitis.

Hepatol Commun 2019 Nov 29;3(11):1482-1495. Epub 2019 Aug 29.

Pediatrics Baylor College of Medicine Houston TX.

Ursodeoxycholic acid (UDCA) is commonly used to treat several liver disorders in adults and children, including primary sclerosing cholangitis (PSC) for which it is not U.S. Food and Drug Administration approved. UDCA treatment has an uncertain impact on disease outcomes and has been reported in high doses to be associated with worse outcome in adults with PSC. In this context, controlled withdrawal and reintroduction of UDCA in children with PSC were studied. Prior to study initiation, participants were required to have alanine aminotransferase (ALT) and gamma-glutamyl transpeptidase (GGT) <2 times the upper limit of normal on stable UDCA dosing. The study included four phases: I (stable dosing), II (50% UDCA reduction), III (UDCA discontinuation), IV (UDCA reintroduction), with a primary endpoint of change in ALT and GGT between phases I and III. We enrolled 27 participants (22 completed) between March 2011 and June 2016. Changes in mean ALT and GGT between phases I and III were ALT, +29.5 IU/L ( = 0.105) and GGT, +60.4 IU/L ( = 0.003). In 7 participants, ALT and GGT ≤29 IU/L did not rise above 29 IU/L (null response group). Eight participants had increases of ALT or GGT >100 IU/L (flare group). None developed elevated bilirubin. All flares responded to UDCA reinstitution. Serum GGT, interleukin-8, and tumor necrosis factor α levels were higher in the flare group at baseline. Liver biochemistries increased in children with PSC during controlled UDCA withdrawal; one third increased above 100 IU/L and one third remained normal during UDCA withdrawal. : The impact of prolonged UDCA use in childhood PSC and the significance of a biochemical flare are unclear. Further studies of the natural history and treatment of pediatric PSC and UDCA use are needed.
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http://dx.doi.org/10.1002/hep4.1421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824074PMC
November 2019

Health-Related Quality of Life and Cognitive Functioning in Pediatric Liver Transplant Recipients.

Liver Transpl 2020 01 6;26(1):45-56. Epub 2019 Nov 6.

Division of Gastroenterology, Hepatology and Nutrition, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL.

The goal of this work was to examine the change in health-related quality of life (HRQOL) and cognitive functioning from early childhood to adolescence in pediatric liver transplantation (LT) recipients. Patients were recruited from 8 North American centers through the Studies of Pediatric Liver Transplantation consortium. A total of 79 participants, ages 11-18 years, previously tested at age 5-6 years in the Functional Outcomes Group study were identified as surviving most recent LT by 2 years and in stable medical follow-up. The Pediatric Quality of Life 4.0 Generic Core Scale, Pediatric Quality of Life Cognitive Function Scale, and PROMIS Pediatric Cognitive Function tool were distributed to families electronically. Data were analyzed using repeated measures and paired t tests. Predictive variables were analyzed using univariate regression analysis. Of the 69 families contacted, 65 (94.2%) parents and 61 (88.4%) children completed surveys. Median age of participants was 16.1 years (range, 12.9-18.0 years), 55.4% were female, 33.8% were nonwhite, and 84.0% of primary caregivers had received at least some college education. Median age at LT was 1.1 years (range, 0.1-4.8 years). The majority of participants (86.2%) were not hospitalized in the last year. According to parents, adolescents had worse HRQOL and cognitive functioning compared with healthy children in all domains. Adolescents reported HRQOL similar to healthy children in all domains except psychosocial, school, and cognitive functioning (P = 0.02; P < 0.001; P = 0.04). Participants showed no improvement in HRQOL or cognitive functioning over time. For cognitive and school functioning, 60.0% and 50.8% of parents reported "poor" functioning, respectively (>1 standard deviation below the healthy mean). Deficits in HRQOL seem to persist in adolescence. Over half of adolescent LT recipients appear to be at risk for poor school and cognitive functioning, likely reflecting attention and executive function deficits.
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http://dx.doi.org/10.1002/lt.25634DOI Listing
January 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

A Pilot Study of a Screening Tool for Pediatric Minimal Hepatic Encephalopathy.

J Pediatr Gastroenterol Nutr 2019 12;69(6):655-661

Division of Gastroenterology, Hepatology & Nutrition.

Objectives: Despite the need for monitoring cognition for minimal hepatic encephalopathy (MHE) in children with portal hypertension, few screening methods exist. The Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric Perceived Cognitive Function (PedsPCF) item bank, a 43-item parent- and self-report questionnaire, could be a useful screening tool. This study aimed to evaluate the PedsPCF item bank as a screening tool and explore its correlation with other neurocognitive measures and clinical indicators of portal hypertension.

Methods: Pediatric patients with portal hypertension were recruited at Lurie Children's Liver Clinic. A short battery of neuropsychological tests tapping attention, executive functioning, and fine motor speed was administered along with surveys of cognitive functioning (PedsPCF, Behavior Rating Inventory of Executive Function; BRIEF) and quality of life (PROMIS Pediatric-25 Profile).

Results: Eighteen patients participated (ages 8--17). The PedsPCF correlated well with the BRIEF but did not correlate with neurocognitive testing. Qualitative heatmap analysis of the relationship between z-scores and clinical signs of portal hypertension suggests the PedsPCF is less sensitive than the BRIEF. The fine motor task (Grooved Pegboard) appears to offer the highest sensitivity of the tests administered and is also relatively quick and easy to administer.

Conclusions: Elements of the battery show promise in this small pilot sample. The BRIEF and the Grooved Pegboard may hold the most potential for screening in the clinical setting. Further study is necessary to examine this question in a larger multicenter sample.
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http://dx.doi.org/10.1097/MPG.0000000000002488DOI Listing
December 2019

Reply.

J Pediatr 2019 11 24;214:244-245. Epub 2019 Jul 24.

Northwestern University Feinberg School of Medicine and Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.

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http://dx.doi.org/10.1016/j.jpeds.2019.06.055DOI Listing
November 2019

Correlation of Immune Markers With Outcomes in Biliary Atresia Following Intravenous Immunoglobulin Therapy.

Hepatol Commun 2019 May 25;3(5):685-696. Epub 2019 Mar 25.

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

Biliary atresia is a progressive fibroinflammatory cholangiopathy of infancy that is associated with activation of innate and adaptive immune responses targeting bile ducts. A recently completed multicenter phase I/IIA trial of intravenous immunoglobulin in biliary atresia did not improve serum total bilirubin levels at 90 days after hepatoportoenterostomy or survival with the native liver at 1 year. A mechanistic aim of this trial was to determine if the peripheral blood immunophenotype was associated with clinical outcomes. Flow cytometry of peripheral blood cell markers (natural killer [NK], macrophage subsets, T- and B-cell subsets, regulatory T cells), neutrophils, and activation markers (clusters of differentiation [CD]38, CD69, CD86, human leukocyte antigen-DR isotype [HLA-DR]) was performed on 29 patients with biliary atresia at baseline and at 60, 90, 180, and 360 days after hepatoportoenterostomy. Plasma cytokines and neutrophil products were also measured. Spearman correlations of change of an immune marker from baseline to day 90 with change in serum bilirubin revealed that an increase in total bilirubin correlated with 1) increased percentage of HLA-DRCD38 NK cells and expression of NK cell activation markers CD69 and HLA-DR, 2) decreased percentage of regulatory T cells, and 3) increased interleukin (IL)-8 and associated neutrophil products (elastase and neutrophil extracellular traps). Cox modeling revealed that the change from baseline to day 60 of the percentage of HLA-DRCD38 NK cells and plasma IL-8 levels was associated with an increased risk of transplant or death by day 360. Poor outcomes in biliary atresia correlated with higher peripheral blood NK cells and IL-8 and lower regulatory T cells. Future studies should include immunotherapies targeting these pathways in order to protect the biliary tree from ongoing damage.
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http://dx.doi.org/10.1002/hep4.1332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492477PMC
May 2019

HMGB1 is a Central Driver of Dynamic Pro-inflammatory Networks in Pediatric Acute Liver Failure induced by Acetaminophen.

Sci Rep 2019 04 12;9(1):5971. Epub 2019 Apr 12.

Department of Surgery, University of Pittsburgh, Pittsburgh, PA, 15213, USA.

Acetaminophen (APAP) overdose (APAPo) is predominant in the NIH Pediatric Acute Liver Failure (PALF) Study. We assayed multiple inflammatory mediators in serial serum samples from 13 PALF survivors with APAPo + N-acetylcysteine (NAC, the frontline therapy for APAPo), 8 non-APAPo + NAC, 40 non-APAPo non-NAC, and 12 non-survivors. High Mobility Group Box 1 (HMGB1) was a dominant mediator in dynamic inflammation networks in all sub-groups, associated with a threshold network complexity event at d1-2 following enrollment that was exceeded in non-survivors vs. survivors. We thus hypothesized that differential HMGB1 network connectivity after day 2 is related to the putative threshold event in non-survivors. DyNA showed that HMGB1 is most connected in non-survivors on day 2-3, while no connections were observed in APAPo + NAC and non-APAPo + NAC survivors. Inflammatory dynamic networks, and in particular HMGB1 connectivity, were associated with the use of NAC in the context of APAPo. To recapitulate hepatocyte (HC) damage in vitro, primary C57BL/6 HC and HC-specific HMGB1-null HC were treated with APAP + NAC. Network phenotypes of survivors were recapitulated in C57BL/6 mouse HC and were greatly altered in HMGB1-null HC. HC HMGB1 may thus coordinate a pro-inflammatory program in PALF non-survivors (which is antagonized by NAC), while driving an anti-inflammatory/repair program in survivors.
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http://dx.doi.org/10.1038/s41598-019-42564-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461628PMC
April 2019

Cystic fibrosis and portal hypertension: Distal splenorenal shunt can prevent the need for future liver transplant.

J Pediatr Surg 2019 May 2;54(5):1076-1082. Epub 2019 Feb 2.

Division of Transplant Surgery, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. Electronic address:

Background: The management of portal hypertension (PHT) in children with well compensated cirrhosis and cystic fibrosis (CF) is controversial. We present our experience with distal splenorenal shunting (DSRS) for the treatment of PHT as an alternative to liver transplantation (LT).

Methods: Between 2008 and 2017, 5 CF children underwent a DSRS at a pediatric hepatobiliary and transplantation referral center. LT (n = 9) was reserved for patients with decompensated cirrhosis. Statistical analysis was done using the paired t-test (p < 0.05 considered significant).

Results: Mean PELD/MELD score was significantly lower for DSRS patients than LT (3 ± 6 vs 28 ± 4, p < 0.001). All 5 DSRS patients had grade III-IV varices. One bled prior to surgery. After DSRS, spleen size decreased significantly from 8.4 ± 1.5 cm to 4.4 ± 1.8 cm (p = 0.019). Mean platelet count remained stable (87.8 ± 48 to 91.8 ± 35, p = 0.9). There were no postoperative complications. No DSRS patient experienced variceal bleeding following shunt creation. Liver function tests remained stable in the DSRS group, and no patient required a liver transplant (median follow up 4.65 years, range 1.24-7.79).

Conclusions: Patients with cystic fibrosis who have well-compensated cirrhosis and symptomatic portal hypertension can be palliated with distal splenorenal shunting and do not need liver transplants. These patients can undergo shunting with minimal morbidity.

Type Of Study: Case series with no comparison group.

Level Of Evidence: IV.
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http://dx.doi.org/10.1016/j.jpedsurg.2019.01.035DOI Listing
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

A Phase I/IIa Trial of Intravenous Immunoglobulin Following Portoenterostomy in Biliary Atresia.

J Pediatr Gastroenterol Nutr 2019 04;68(4):495-501

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

Objectives: Biliary atresia (BA) is a progressive neonatal fibroinflammatory cholangiopathy. We hypothesized that intravenous immunoglobulin (IVIg) would be safe, feasible, acceptable, and efficacious for the treatment of BA. The primary objective of this study was to establish the feasibility, acceptability, and safety profile of IVIg administration after hepatoportoenterostomy (HPE) in BA. The secondary objective was to determine the treatment efficacy of IVIg based on good bile drainage and survival with the native liver.

Methods: A multicenter, prospective, open-labeled, phase I/IIA trial of IVIg was conducted, with 1 g/kg/dose of IVIg infused at 3-5, 30, and 60 days post-HPE, and subjects followed for 360 days post-HPE. Twenty-nine participants completed the study.

Results: Administration of IVIg infusions was feasible and acceptable in 79%. None of the serious adverse events (SAEs) were directly related to IVIg infusions; however, 90% of participants had an SAE. Compared with a historical placebo-arm group, there was no significant increase in the proportion of IVIg participants with a serum total bilirubin <1.5 mg/dL at 90, 180, or 360 days post-HPE. Survival with the native liver in the IVIg participants showed no significant benefit over the historical placebo arm, with a difference at 360 days of -11.9% (IVIg: 58.6%, placebo: 70.5%; 90% UCB: 2.1%; P > 0.05).

Conclusions: Although IVIg infusions in infants with BA post-HPE were feasible, acceptable and safe, there was no trend to lower bilirubin levels or improved 360-day survival with the native liver.

Clinical Trial: Safety Study of Intravenous Immunoglobulin Post-Portoenterostomy in Biliary Atresia; #NCT01854827.
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http://dx.doi.org/10.1097/MPG.0000000000002256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428610PMC
April 2019

Identification of Polycystic Kidney Disease 1 Like 1 Gene Variants in Children With Biliary Atresia Splenic Malformation Syndrome.

Hepatology 2019 09 21;70(3):899-910. Epub 2019 Mar 21.

Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA.

Biliary atresia (BA) is the most common cause of end-stage liver disease in children and the primary indication for pediatric liver transplantation, yet underlying etiologies remain unknown. Approximately 10% of infants affected by BA exhibit various laterality defects (heterotaxy) including splenic abnormalities and complex cardiac malformations-a distinctive subgroup commonly referred to as the biliary atresia splenic malformation (BASM) syndrome. We hypothesized that genetic factors linking laterality features with the etiopathogenesis of BA in BASM patients could be identified through whole-exome sequencing (WES) of an affected cohort. DNA specimens from 67 BASM subjects, including 58 patient-parent trios, from the National Institute of Diabetes and Digestive and Kidney Diseases-supported Childhood Liver Disease Research Network (ChiLDReN) underwent WES. Candidate gene variants derived from a prespecified set of 2,016 genes associated with ciliary dysgenesis and/or dysfunction or cholestasis were prioritized according to pathogenicity, population frequency, and mode of inheritance. Five BASM subjects harbored rare and potentially deleterious biallelic variants in polycystic kidney disease 1 like 1 (PKD1L1), a gene associated with ciliary calcium signaling and embryonic laterality determination in fish, mice, and humans. Heterozygous PKD1L1 variants were found in 3 additional subjects. Immunohistochemical analysis of liver from the one BASM subject available revealed decreased PKD1L1 expression in bile duct epithelium when compared to normal livers and livers affected by other noncholestatic diseases. Conclusion: WES identified biallelic and heterozygous PKD1L1 variants of interest in 8 BASM subjects from the ChiLDReN data set; the dual roles for PKD1L1 in laterality determination and ciliary function suggest that PKD1L1 is a biologically plausible, cholangiocyte-expressed candidate gene for the BASM syndrome.
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http://dx.doi.org/10.1002/hep.30515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642859PMC
September 2019

Impact of Steroid Therapy on Early Growth in Infants with Biliary Atresia: The Multicenter Steroids in Biliary Atresia Randomized Trial.

J Pediatr 2018 11 21;202:179-185.e4. Epub 2018 Sep 21.

Department of Surgery, University of Michigan Medical School, Ann Arbor, MI.

Objective: To investigate the impact of corticosteroid therapy on the growth of participants in the Steroids in Biliary Atresia Randomized Trial (START) conducted through the Childhood Liver Disease Research Network. The primary analysis in START indicated that steroids did not have a beneficial effect on drainage in a cohort of infants with biliary atresia. We hypothesized that steroids would have a detrimental effect on growth in these infants.

Study Design: A total of 140 infants were enrolled in START, with 70 randomized to each treatment arm: steroid and placebo. Length, weight, and head circumference were obtained at baseline and follow-up visits to 24 months of age.

Results: Patients treated with steroids had significantly lower length and head circumference z scores during the first 3 months post-hepatoportoenterostomy (HPE), and significantly lower weight until 12 months. Growth trajectories in the steroid and placebo arms differed significantly for length (P < .0001), weight (P = .009), and head circumference (P < .0001) with the largest impact noted for those with successful HPE. Growth trajectory for head circumference was significantly lower in patients treated with steroids irrespective of HPE status, but recovered during the second 6 months of life.

Conclusions: Steroid therapy following HPE in patients with biliary atresia is associated with impaired length, weight, and head circumference growth trajectories for at least 6 months post-HPE, especially impacting infants with successful bile drainage.

Trial Registration: ClinicalTrials.gov: NCT00294684.
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http://dx.doi.org/10.1016/j.jpeds.2018.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365098PMC
November 2018

Evidence of Chronic Allograft Injury in Liver Biopsies From Long-term Pediatric Recipients of Liver Transplants.

Gastroenterology 2018 12 23;155(6):1838-1851.e7. Epub 2018 Aug 23.

Institute of Liver Studies, King's College, London, London, United Kingdom.

Background & Aims: A substantial proportion of pediatric liver transplant recipients develop subclinical chronic allograft injury. We studied whether there are distinct patterns of injury based on histopathologic features and identified associated immunologic profiles.

Methods: We conducted a cross-sectional study of 157 stable, long-term pediatric recipients of transplanted livers (70 boys; > 6 years old at time of transplantation; mean, 8.9 ± 3.46 years after liver transplantation) who underwent liver biopsy analysis from August 13, 2012, through May 1, 2014. Participants had received livers from a living or deceased donor and had consistently normal results from liver tests. Liver biopsy specimens were scored by a central pathologist; an unsupervised hierarchical cluster analysis of histologic features was used to sort biopsy samples into 3 clusters. We conducted transcriptional and cytometric analyses of liver tissue samples and performed a systems biology analysis that incorporated clinical, serologic, histologic, and transcriptional data.

Results: The mean level of alanine aminotransferase in participants was 27.6 ± 14.57 U/L, and the mean level of γ-glutamyl transferase was 17.4 ± 7.93 U/L. Cluster 1 was characterized by interface activity (n = 34), cluster 2 was characterized by periportal or perivenular fibrosis without interface activity (n = 45), and cluster 3 had neither feature (n = 78). We identified a module of genes whose expression correlated with levels of alanine aminotransferase, class II donor-specific antibody, portal inflammation, interface activity, perivenular inflammation, portal and perivenular fibrosis, and cluster assignment. The module was enriched in genes that regulate T-cell-mediated rejection (TCMR) of liver and other transplanted organs. Functional pathway analysis showed overrepresentation of TCMR gene sets for cluster 1 but not clusters 2 or 3.

Conclusion: In an analysis of biopsies from an apparently homogeneous group of stable, long-term pediatric liver transplant recipients with consistently normal liver test results, we found evidence of chronic graft injury (inflammation and/or fibrosis). Biopsy samples with interface activity had a gene expression pattern associated with TCMR.
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http://dx.doi.org/10.1053/j.gastro.2018.08.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279538PMC
December 2018

Liver Transplant Listing in Pediatric Acute Liver Failure: Practices and Participant Characteristics.

Hepatology 2018 12 1;68(6):2338-2347. Epub 2018 Nov 1.

Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Pittsburgh School of Medicine and Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, PA.

Liver transplant (LT) decisions in pediatric acute liver failure (PALF) are complex. Three phases of the PALF registry, containing data on 1,144 participants over 15 years, were interrogated to characterize clinical features associated with listing status. A decrease in the cumulative incidence of listing (P < 0.005) and receiving (P < 0.05) LT occurred without an increase in the cumulative incidence of death (P = 0.67). Time to listing was constant and early (1 day; quartiles 1-3 = 0-2; P = 0.88). The most frequent reasons for not listing were "not sick enough" and "medically unsuitable." Participants listed for LT were more likely male, with coma grade scores >0; had higher international normalized ratio, bilirubin, lactate, and venous ammonia; and had lower peripheral lymphocytes and transaminase levels compared to those deemed "not sick enough." Participants listed versus those deemed "medically unsuitable" were older; had higher serum aminotransferase levels, bilirubin, platelets, and albumin; and had lower lactate, venous ammonia, and lymphocyte count. An indeterminate diagnosis was more prevalent in listed participants. Ventilator (23.8%) and vasopressor (9.2%) support occurred in a significant portion of listed participants but less frequently than in those who were not "medically suitable." Removal from the LT list was a rare event. Conclusion: The cumulative incidence of listing for and receiving LT decreased throughout the PALF study without an increase in the cumulative incidence of death. While all participants fulfilled entry criteria for PALF, significant differences were noted between participants listed for LT and those deemed "not sick enough" as well as those who were "medically unsuitable." Having an indeterminate diagnosis and a requirement for cardiopulmonary support appeared to influence decisions toward listing; optimizing listing decisions in PALF may reduce the frequency of LT without increasing the frequency of death.
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http://dx.doi.org/10.1002/hep.30116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6275095PMC
December 2018

Bone Density in Children With Chronic Liver Disease Correlates With Growth and Cholestasis.

Hepatology 2019 01 27;69(1):245-257. Epub 2018 Dec 27.

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

Osteopenia and bone fractures are significant causes of morbidity in children with cholestatic liver disease. Dual-energy X-ray absorptiometry (DXA) analysis was performed in children with intrahepatic cholestatic diseases who were enrolled in the Longitudinal Study of Genetic Causes of Intrahepatic Cholestasis in the Childhood Liver Disease Research Network. DXA was performed on participants aged >5 years (with native liver) diagnosed with bile acid synthetic disorder (BASD), alpha-1 antitrypsin deficiency (A1AT), chronic intrahepatic cholestasis (CIC), and Alagille syndrome (ALGS). Weight, height, and body mass index Z scores were lowest in CIC and ALGS. Total bilirubin (TB) and serum bile acids (SBA) were highest in ALGS. Bone mineral density (BMD) and bone mineral content (BMC) Z scores were significantly lower in CIC and ALGS than in BASD and A1AT (P < 0.001). After anthropometric adjustment, bone deficits persisted in CIC but were no longer noted in ALGS. In ALGS, height-adjusted and weight-adjusted subtotal BMD and BMC Z scores were negatively correlated with TB (P < 0.001) and SBA (P = 0.02). Mean height-adjusted and weight-adjusted subtotal BMC Z scores were lower in ALGS participants with a history of bone fractures. DXA measures did not correlate significantly with biliary diversion status. Conclusion: CIC patients had significant bone deficits that persisted after adjustment for height and weight and generally did not correlate with degree of cholestasis. In ALGS, low BMD and BMC reference Z scores were explained by poor growth. Anthropometrically adjusted DXA measures in ALGS correlate with markers of cholestasis and bone fracture history. Reduced bone density in this population is multifactorial and related to growth, degree of cholestasis, fracture vulnerability, and contribution of underlying genetic etiology.
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http://dx.doi.org/10.1002/hep.30196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324969PMC
January 2019

Liver Biopsy Can Be Safely Performed in Pediatric Acute Liver Failure to Aid in Diagnosis and Management.

J Pediatr Gastroenterol Nutr 2018 10;67(4):441-445

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

Objectives: Liver biopsy can be a valuable tool to help determine the etiology of pediatric acute liver failure (PALF), but is often not performed due to safety concerns. The primary aim was to describe the incidence of major complications after liver biopsy performed in the setting of PALF.

Methods: Medical records from 2006 to 2016 were reviewed. Patients age 0 to 17 years, who met criteria for PALF, and had a liver biopsy performed while their international normalized ratio (INR) was ≥1.5 were included.

Results: A total of 26 cases of liver biopsy in the setting of PALF were identified. The majority (n = 22, 85%) of patients had primary liver disease. Most biopsies (n = 17, 65%) were performed by the transjugular route, with 5 (19%) performed percutaneously under ultrasound guidance and 4 (15%) during a surgical procedure. Median INR before biopsy was 2.1 (IQR = 1.73-2.9). Blood products were given before or during the procedure in 23 (88%) cases. One patient (3.8%) had a major complication of biopsy-associated bleeding requiring a blood transfusion. An additional 3 patients had a hemoglobin decrease of 2.1 to 2.9 g/dL post-biopsy that was attributed to the procedure but no interventions were necessary. Biopsy results contributed to establishing a diagnosis in 62% (n = 16) of cases, and influenced treatment decisions in 9 of those cases.

Conclusions: Liver biopsy is safe in the majority of patients with PALF and associated with infrequent major complications. Clinicians should consider performing liver biopsy in this setting, especially when the transjugular approach is feasible, since findings may guide diagnosis and therapy.
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http://dx.doi.org/10.1097/MPG.0000000000002096DOI Listing
October 2018