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Pediatric cholestatic liver diseases are rare conditions that can result from multiple specific underlying etiologies. Among the most common etiologies of pediatric cholestatic liver diseases are biliary atresia, Alagille syndrome (ALGS), and inherited disorders of bile acid transport. These diseases are characterized by episodic or chronic unremitting cholestasis. Due to the chronicity of these conditions, it is imperative to optimize medical management to improve patient quality of life, provide nutritional support, and reduce bile acid toxicity in efforts to slow disease progression. Cholestatic liver diseases remain the leading cause of pediatric liver transplantation, as many underlying disease etiologies have no curative medical therapies. In the present review, we provide an update on the nutritional, medical, and surgical management of pediatric cholestatic liver diseases. As recent advances have occurred in the field with the addition of ileal bile acid transporter (IBAT) inhibitors, we also review the results from prospective clinical trials, including their strengths and limitations. While recent clinical trials have demonstrated improved pruritus using IBAT inhibitors in ALGS and progressive familial intrahepatic cholestasis, establishing medical therapies proven to slow disease progression remains an area of unmet need., (© 2025 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Cirrhotic cardiomyopathy is a complication of cirrhosis resulting in cardiac dysfunction. It remains poorly characterized in children. The aim of this study was to assess relationship of pre-liver transplant (LT) conventional and novel parameters of biventricular function with post-LT clinical course. This is a retrospective study of pre-LT echocardiograms performed on patients < 18 years of age with cirrhosis at a single center, who received a LT. Demographic, clinical, and echocardiographic data were collected. Speckle tracking echocardiography (STE) analysis was performed by a single observer using TomTec system. Descriptive data were expressed as mean (SD) and number (%). The relationship between clinical data and echocardiographic variables were assessed using Spearman correlation coefficient. Significance was set at < 0.05. Thirty-five patients (median age 6.5; IQR 14.2 years) underwent LT between 2010 and 2020. Pre-LT diagnosis was biliary atresia in 14 (40%) patients and 7 (20%) patients were listed as status 1A/1B. Their median natural pediatric/model end-stage liver disease score was 13 (IQR 9). Their pre-LT echocardiogram showed normal left ventricular systolic (LV) function by ejection fraction and strain parameters. Right ventricular (RV) function was abnormal in 74% of patients as measured by RV GLS (23 ± 3%). There was correlation between echocardiographic parameters with pre-transplant clinical disease and post-operative LT course (length of stay and duration of mechanical ventilation). Children undergoing liver transplant have RV dysfunction as evidenced by abnormal RV GLS on STE. There is echocardiographic parameter correlation between clinical liver disease and post-LT clinical course. This evidence highlights the importance of using novel technology like STE in assessment of children undergoing evaluation for liver transplant., Competing Interests: Declarations. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s).)

Importance: Acute liver failure (ALF) carries significant morbidity and mortality, for both pediatric and adult patients. Albumin dialysis via the molecular adsorbent recirculating system (MARS) is a form of extracorporeal liver support (ELS) that can reduce hepatic encephalopathy (HE), a main driver of mortality in ALF. However, data on MARS and its benefit on mortality have been inconsistent., Objectives: We sought to report our experiences and patient outcomes from the first 2 years of operation of a new ELS program, within an established pediatric liver transplantation center., Design Setting and Participants: Retrospective review of outcomes in pediatric and adult patients treated with MARS therapy for ALF, from 2021 to 2022., Main Outcomes and Measures: Outcomes included reduction in HE and biochemical markers of ALF after MARS therapy, survival, and transplant-free survival. Comparisons were made via Wilcoxon signed-rank test., Results: Five pediatric and two adult patients underwent MARS for ALF. Ages ranged from 2 to 29 years. Overall, 21 MARS runs were performed (median 3 runs per patient, 12.4 hr per run [interquartile range, IQR 10.1-17]). Overall survival was 85.7%, and transplant-free survival was 71.4%. There was a statistically significant reduction in HE score with MARS therapy (median 3 [IQR 3-4] to 1 [IQR 0-1], p = 0.03), and in ALF biomarkers including ammonia (256 µL/dL [195-265] to 75 µL/dL [58-101], p = 0.02), aspartate aminotransferase (6,362 U/L [920-8,305] to 212 U/L [72-431], p = 0.02), alanine aminotransferase (8,362 U/L [3,866-9,189] to 953 U/L [437-1,351], p = 0.02), and international normalized ratio (4.5 [3.3-6.7] to 1.3 [1.2-1.4], p = 0.02)., Conclusions and Relevance: MARS therapy for ALF was well tolerated by both pediatric and adult patients, and resulted in significant improvement in clinical and biochemical parameters. We demonstrated encouraging overall and transplant-free survival, suggesting that early initiation of MARS with relatively long and frequent cycle times may be of significant benefit to ALF patients, and is worthy of additional study in larger cohorts., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Background: Biliary atresia (BA) remains the most common indication for pediatric liver transplantation. Early diagnosis is essential for a favorable long-term prognosis for patients with BA. Preliminary data suggests that measurement of direct bilirubin (DB) in newborns may be an effective screening tool for neonatal cholestasis, particularly BA, allowing for early referral and diagnosis. The objective of our study was to establish a cutoff DB value to predict diagnosis of cholestatic liver disease (CLD) with high sensitivity and specificity, as well as, to evaluate whether newborns with elevated DB received appropriate follow-up in our health system., Methods: Baseline data were collected on infants born between 2016 and 2019 who had serum total bilirubin and DB drawn in the nursery, and who continued to follow in our health system. Sensitivity, specificity, and positive and negative predictive values were examined using cutoff values of 0.5, 0.6, and 0.7 mg/dL for identifying infants at risk for CLD. Patients' charts were reviewed to note whether they had follow-up levels drawn by their pediatrician or by the hepatology team within 2 months of age and whether they were diagnosed with CLD., Results: Serum total bilirubin and DB levels were drawn from 11 965 infants during their hospitalizations. Three infants from this cohort were diagnosed with CLD: 2 with BA and 1 with Alagille syndrome. DB cutoff values of 0.5, 0.6, and 0.7 mg/dL had sensitivity of 100% and specificity of 96.83% (95% confidence interval [CI], 96.69%-97.53%), 99.08% (95% CI, 98.81%-99.30%), and 99.63% (95% CI, 99.4%-99.7%), respectively. Given that a DB of 0.6 mg/dL had a sensitivity of 100% and specificity of 99%, this value was chosen as the cutoff value to monitor for DB follow-up and diagnosis of CLD. Out of 60 infants who met criteria for DB ≥0.6 mg/dL, only 15 (25%) had a repeat level drawn after nursery discharge; 3 (5%) were eventually diagnosed with CLD., Conclusions: A DB cutoff value of 0.6 mg/dL yielded high sensitivity and specificity for identifying patients with CLD. All 3 patients diagnosed with CLD had elevated DB at hospital discharge. The data revealed that the majority (75%) of eligible newborns did not receive follow-up for their elevated DB in the outpatient setting., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background: Adult SOT recipients with COVID-19 have higher mortality rates when compared to general population. There is paucity of data on outcomes in pediatric SOT recipients., Methods: This is a cross-sectional study investigating the prevalence of COVID-19 infection and outcomes in pediatric SOT (heart, liver, and kidney) recipients. We extracted demographic and clinical characteristics and COVID-19 testing (PCR or [Ab] test) results from medical records. Clinical characteristics were compared between patients who were positive for COVID-19 (PCR or Ab) and those who did not, using Mann-Whitney, Student's t test, or chi-square test. p value <.05 was statistically significant., Results: A total of 108 SOT recipients with a median age of 13.1 (8.4, 17.8) years and median 4.2 (2.7, 7.9) years from transplant were checked for COVID-19 via a PCR or Ab test. A positive PCR was confirmed in 10 patients (9.3%), while 12 patients (11.1%) were positive for COVID-19 Ab. The patients who tested positive in our cohort were 9/50 (18%) heart, 6/68 (8.8%) kidney, and 7/50 (14%) liver transplant recipients. There were no differences in the clinical characteristics between patients with and without COVID-19 infection. All patients were either asymptomatic (50%) or had self-limiting symptoms. No changes were made to the immunosuppressive regimen. Only one patient was hospitalized and none had an oxygen requirement., Conclusions: In our cohort of pediatric SOT recipients, COVID-19 infection was asymptomatic or mild. This data may aid clinicians in counseling patients and families in this increased-risk population., (© 2021 Wiley Periodicals LLC.)

Background and Aims: Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) associated acute liver injury (ALI) has been linked to poor outcomes in adults. Here we compare characteristics in children with elevated ALT (E-ALT) in two distinct manifestations of the infection, multisystem inflammatory syndrome-children (MIS-C) and coronavirus disease 2019 (COVID-19)., Methods: This is a retrospective study of patients ≤21 years of age with positive for SARS-CoV-2 PCR. E-ALT was defined as alanine aminotransferase (ALT) > 40 U/L. Bivariate analysis and multivariable logistic regression were obtained to describe differences in children with and without E-ALT in COVID-19 and MIS-C., Results: E-ALT was detected in 36% of the 291 patients; 31% with COVID-19, and 51% with MIS-C. E-ALT in COVID-19 was associated with obesity (P < .001), immunocompromised status (P = .04), and chronic liver disease (P = .01). In the regression models, E-ALT in COVID-19 was associated with higher c-reactive protein (OR 1.08, P = .01) after adjusting for common independent predictors. Children with E-ALT and MIS-C were more often boys (P = .001), Hispanic (P = .04), or Black (P < .001). In MIS-C, male gender (OR 5.3, P = .02) and Black race (OR 4.4, P = .04) were associated with increased odds of E-ALT. Children with E-ALT in both cohorts had significantly higher multiorgan dysfunction, longer hospitalization, and ICU stay. Children with MIS-C had 2.3-fold increased risk of E-ALT compared to COVID-19. No association was found between E-ALT and mortality., Conclusion: E-ALT with SARS-CoV-2 presents as elevated transaminases without hepatic synthetic dysfunction. Patients with either manifestation of SARS-CoV-2 infection and E-ALT experienced more severe disease., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Increased mortality risk because of 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 1 patient died. Bivariable logistic-regression analysis found that patients with nonalcoholic fatty LD (NAFLD) (odds ratio [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., (Copyright © 2021 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Objectives: The relationship between vitamin D deficiency (VDD) and pediatric nonalcoholic fatty liver disease (NAFLD) remains uncertain due to conflicting results and few studies with histologic endpoints. We therefore used multiple imaging and histologic NAFLD endpoints to more comprehensively assess the association between VDD and NAFLD in a large pediatric population., Methods: Data were obtained from an ongoing pediatric NAFLD study in Bronx, NY. Briefly, overweight and obese children aged 2-18 years with alanine aminotransferase (ALT) levels ≥ 35 U/L were serially enrolled. Liver biopsy was obtained in accordance with clinical guidelines. All participants had liver imaging, namely, controlled attenuation parameter (CAP; Echosens, France) to assess steatosis and, to assess fibrosis, vibration controlled transient elastography (VCTE; FibroScan™, Echosens, France) and acoustic radiation force impulse (ARFI; Philips, Netherlands) imaging. Levels of 25-hydroxyvitamin D were measured serologically., Results: N=276 (88%) of 315 participants had 25-OH vitamin D results, of whom 241 (87%) were Hispanic, 199 (72%) were male, and 92 (33%) underwent liver biopsy. VDD was univariately associated with high waist circumference (p=0.004), high-density lipoprotein level (p=0.01), season (p=0.009), and CAP score (p=0.01). In multivariate analysis, only waist circumference (p=0.0002) and biopsy inflammation grade (p=0.03) were associated with VDD, though the latter had not approximated statistical significance in univariate analysis (p=0.56). There was no association between VDD and hepatic steatosis, ballooning, NAFLD Activity Score, ARFI or VCTE elasticity scores., Conclusions: VDD was not associated with NAFLD defined by imaging and histologic endpoints, except for a possible relation with histologic inflammation grade.

Liver abnormalities in severe acute respiratory syndrome-coronavirus 2 infection, including hepatitis and cholestasis, have been observed in adults and are associated with worse outcomes. We describe 2 adolescents with cholestasis and hepatitis with mild presentation of severe acute respiratory syndrome-coronavirus 2 lacking typical symptoms. Our intention is to raise index of suspicion for testing and protective equipment use., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Pediatric liver transplant recipients are at risk of developing graft fibrosis which can affect patient survival. VCTE is a non-invasive tool that measures LSM and has been shown to correlate with hepatic fibrosis. The aim of this study was to therefore evaluate the ability of LSM to predict fibrosis in pediatric liver transplant recipients with different graft types. We performed a cross-sectional study evaluating LSM of 28 pediatric liver transplant recipients who underwent a total of 20 liver biopsies within 1 month of LSM. LSM was compared to liver histology as well as graft type: WL or PL. The median LSM of all post-transplant patients was 5.6 kPa (range = 2.7-18.3). There was a statistically significant correlation between LSM and METAVIR fibrosis score (P = .001) and LAF score (P < .001). There was no difference in LSM between graft type (P = .088). The AUROC curve for LSM predicting any significant fibrosis (F ≥ 2) was 0.863. A cutoff value of 7.25 had a sensitivity of 71%, specificity of 100%, NPV of 87%, and PPV of 100% for significant fibrosis. LSM by VCTE is feasible in pediatric liver transplant recipients regardless of graft type. We found a significant correlation between LSM and hepatic fibrosis and established a cutoff value that may help determine which patients warrant further evaluation for graft fibrosis., (© 2020 Wiley Periodicals LLC.)

Background: Children with sickle cell disease (SCD) are at risk of liver injury because of sickle cell hepatopathy and iron overload from chronic transfusions (CT). The authors examine the association between iron overload and liver stiffness measurement (LSM) by vibration controlled transient elastography (VCTE), which has been shown to correlate with fibrosis., Methods: Patients 21 years of age and less with SCD had VCTE performed; those who received CT underwent magnetic resonance imaging T2* for iron quantification., Results: The authors enrolled 42 patients, 17 (40%) of whom received CT. There was no difference in LSM between patients who underwent CT (5.5±1.5 kPa) and those who did not (5.2±2.3 kPa) (P=0.923). There was no correlation between iron quantification and LSM (r=-0.077, P=0.769). However, children 12 years of age and older had abnormal LSM when compared with a reference range (P=0.013)., Conclusion: VCTE is a noninvasive technology that is feasible in children with SCD. LSM values were elevated in older children but did not correlate with iron overload, suggesting that fibrosis may not be affected by iron overload alone. Though additional data are needed, LSM may be a useful test for the progression of liver disease in SCD regardless of iron burden.

One cause of neonatal cholestasis (NC) is paucity of intrahepatic bile ducts which can be associated with Alagille syndrome or non- syndromic. Alagille syndrome is caused by autosomal dominant mutations in the Notch signaling pathway ligand Jagged1 in 94% of patients and mutations in the NOTCH2 receptor in <1% of patients. This is a retrospective case series studying infants with neonatal cholestasis found to have variants of unknown significance (VOUS) in NOTCH2 . Sorting intolerant from tolerant (SIFT) and polymorphism phenotyping (PolyPhen) were utilized to predict a damaging effect. Five infants with NC without other features of Alagille syndrome were found to have one copy of a VOUS in NOTCH2 , predicted to be damaging by SIFT and PolyPhen. Our cases support the notion that NOTCH2 mutations may result in hypoplastic biliary system. Further characterization of these variants is important to assist with our clinical approach to NC., Competing Interests: Conflict of interest the authors declare no potential conflict of interest., (©Copyright: the Author(s), 2019.)

Background: Nonalcoholic fatty liver disease (NAFLD) is strongly associated with obesity and is the most common liver disease in the developed world. In children with suspected NAFLD, present guidelines suggest consideration of alternative diagnoses via extensive blood testing, though the yield of this work up is unknown. Furthermore, the gold standard diagnostic test for NAFLD remains liver biopsy, making the development of non-invasive tests critically important., Objectives: Our objectives are: 1) to determine the accuracy of elastography and multiple serum biomarkers - each assessed individually and as algorithms (including those previously tested in adults) - for the diagnosis of nonalcoholic steatohepatitis (NASH) and early fibrosis in children and (2) to examine the utility of extensive testing for rare alternative diagnoses in overweight or obese children with elevated alanine aminotransferase (ALT) suspected to have NAFLD., Design: This is an ongoing, cross-sectional study in children 2-18 years of age with up to 2 years of prospective follow up. Eligible patients are asymptomatic, overweight or obese, and have an ALT ≥35 U/L upon enrollment. Two forms of elastography are obtained serially along with anthropometric data and routine laboratory tests. Elastography and serum biomarkers are also performed immediately prior to any clinically-indicated biopsy., Methods: Between April 2015 and April 2018, 193 children have been enrolled in this ongoing study and 71 have undergone liver biopsy. Here we carefully report the rationale, methodology, and preliminary data for this study., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Neonatal liver disease is an important source of morbidity in the pediatric population. The manifestation of liver disease in young infants may be different than in older patients, and there are a number of diagnoses that are unique to this age group. Familiarity with these entities is important as imaging plays a key role in the diagnostic workup, and prompt diagnosis is necessary to prevent complications. This article reviews the spectrum of liver pathologies that can manifest in the first 6 months of life and is intended to educate the general radiologist who may be faced with interpretation of neonatal liver imaging. Categories of disease that will be reviewed include cholestatic diseases, tumors, vascular anomalies, and acquired diseases. The authors will also review optimization of ultrasonography (US) and magnetic resonance imaging of the liver and present a systematic method for interpretation of neonatal liver US findings in the context of clinical and laboratory findings. © RSNA, 2017.

Background and Objectives: Failure to attend pediatric outpatient endoscopic procedures leads to inefficient use of resources, longer wait-list times, and delay in diagnoses. The causes for pediatric endoscopy nonattendance are not well studied. The aim of the study was to identify factors associated with failure to attend endoscopic procedures and to assess the value of quality improvement (QI) interventions implemented to improve pediatric endoscopy attendance., Methods: This was a continuous QI project. We collected nonattendance data from November 2011 to November 2013. Information collected included procedure type, age, sex, time on the waiting list, history of previous procedures, and reason for nonattendance. The following QI interventions were implemented sequentially: an appointment reminder letter, a telephone call 1 week before procedure, and creation of an electronic medical note dedicated to endoscopy appointment. Pareto charts and statistical process control charts were used for analysis., Results: From November 2011 to November 2013, we were able to decrease nonattendance from 17% to 11% (P = 0.005). No-show rate was reduced from 5% to 0.9% (P = 0.00001). There was no significant difference between attendees and nonattendees in relation to sex, age, or having a previous procedure. Longer waiting time (33 vs 26 days) was associated with increased risk for nonattendance (P = 0.0007). The most common causes for nonattendance were illness (31.5%), followed by caregiver/patients who no longer wanted the procedure (17.7%), and patients who improved (12.9%)., Conclusions: Applying QI methods and tools improved pediatric endoscopy attendance. Longer wait time for endoscopic procedures is associated with nonattendance. Given the increased pediatric endoscopy demand, strategies should be implemented to reduce wait time for pediatric endoscopy.

Pediatric liver transplantation has matured into a well-established, highly successful treatment for advanced pediatric liver disease. Recent 1-year success rates range from 85% to 95%. This unprecedented achievement is the result of careful selection criteria and optimal timing of transplantation, technical advances in surgical technique, and improved treatment following transplant. This report highlights many recent published findings representing advances that have led to current successful approaches.