Pediatric Liver Transplant Survival in Alagille Syndrome Is Comparable to Biliary Atresia-A Linked Database Analysis.

OBJECTIVES: This study aims to report liver transplantation (LT) outcomes and cardiac disease manifestations in children with Alagille Syndrome (ALGS) in a contemporary cohort. METHODS: This project used a novel linkage between the Scientific Registry of Transplant Recipients and Pediatric Health Information System databases. All children ≤21 years undergoing a first LT were identified (2002-2018). The presence of ALGS was identified using Scientific Registry of Transplant Recipients diagnosis coding. Subjects with ALGS were age-matched 1:2 to LT recipients with biliary atresia (BA). The Kaplan-Meier method and log-rank test were used to compare patient and graft survival between groups. RESULTS: A total of 156 LT recipients with ALGS were identified and matched to a control group of 312 LT recipients with BA. Children with ALGS were more likely to have an associated diagnosis of congenital heart disease (80.7% vs 16.4%; P = 0.001) compared with children with BA with 40 (25.6%) children with AGS requiring cardiac intervention (catheter or surgical) either before or after LT. Those patients with ALGS had a higher creatinine, laboratory MELD, and PELD scores before LT. No difference was observed regarding patient or graft survival between children with ALGS and children with BA ( P = 0.08 and P = 0.27, respectively). CONCLUSIONS: Despite increased rate of congenital heart defects and cardiac interventions, higher creatinine, and higher laboratory MELD/PELD scores at time of transplant, this study demonstrates that there is no difference in either patient or graft survival between patients with ALGS and BA.

Liver Transplantation in Children with Urea Cycle Disorders: The Importance of Minimizing Waiting Time.

Liver transplantation (LT) for children with urea cycle disorders (UCDs) is capable of correcting the enzymatic defect and preventing progressive neurologic injury. We describe the characteristics and outcomes of pediatric LT recipients with UCDs. We identified all pediatric (<18 years) LT candidates with UCDs in the United Network for Organ Sharing (UNOS) database (February 2002 to September 2020). Multivariable Cox and logistic regression were used to determine risk factors for graft loss and cognitive delay, respectively. Of 424 patients, 1.9% (8/424) experienced waitlist mortality and 95.0% underwent LT (403/424). The most frequently encountered UCDs in our cohort were ornithine transcarbamylase deficiency (46.2%), citrullinemia (20.3%), and argininosuccinic aciduria (ASA; 12.9%). The 1-, 3-, and 5-year graft survival rates were 90.4%, 86.3%, and 85.2%, respectively. Multivariable analysis showed a decreased risk of graft loss with increasing weight at LT (adjusted hazard ratio [aHR], 0.96; 95% confidence interval [CI], 0.94-0.99; P = 0.02), male sex (aHR, 0.49; 95% CI, 0.28-0.85; P = 0.01), and ASA diagnosis (aHR, 0.29; 95% CI, 0.09-0.98; P = 0.047), when adjusting for location (intensive care/hospital/home) and graft type (both P ≥ 0.65). In multivariable logistic regression, waitlist time (adjusted odds ratio [aOR], 1.10; 95% CI, 1.02-1.17; P = 0.009) and male sex (aOR, 1.71; 95% CI, 1.02-2.88; P = 0.04) were associated with increased odds of long-term cognitive delay. Waitlist duration is associated with a long-term risk of cognitive delay. Given excellent long-term outcomes, early LT evaluation should be considered in all children with UCDs to prevent progressive neurologic injury and optimize cognitive outcomes.

Mortality Determinants in Children with Biliary Atresia Awaiting Liver Transplantation.

OBJECTIVE: To determine risk factors for waitlist mortality in children with biliary atresia listed for liver transplantation. STUDY DESIGN: There were 2704 children with biliary atresia (<12 years of age) listed for a first liver transplant (2002-2018) in the United Network for Organ Sharing database. Fine-Gray regression models for competing risks analysis (main risk = waitlist mortality/delisting owing to too sick; competing risk = liver transplantation) were implemented to identify risk factors for waitlist mortality. RESULTS: The median waitlist time was 83 days (IQR, 34-191). The cumulative incidence of waitlist mortality was 5.2%. In multivariable analysis (n = 2253), increasing bilirubin level (P < .001), portal vein thrombosis (P = .03), and ventilator dependence (P < .001) at listing were associated with a higher risk, whereas weight ≥10 kg at listing (P = .009) was associated with a lower risk of waitlist mortality. When ascites at listing was included in multivariable analysis (n = 1376), it was associated with a higher risk for the composite outcome (P = .03). Encephalopathy at listing was not associated with waitlist mortality (n = 1376; P = .15). CONCLUSIONS: These parameters can be used to more objectively prioritize children with biliary atresia awaiting liver transplantation and identify children with biliary atresia-related end-stage liver disease at high-risk of mortality.

Sofosbuvir and Ribavirin Therapy for Children Aged 3 to <12 Years With Hepatitis C Virus Genotype 2 or 3 Infection.

Currently, the only approved hepatitis C virus (HCV) treatment for children aged <12 years is pegylated interferon plus ribavirin. In an open-label study, we evaluated the safety and efficacy of sofosbuvir plus ribavirin for 12 weeks in children aged 3 to <12 years chronically infected with genotype 2 or for 24 weeks in patients with genotype 3. Patients aged 3 to <6 years weighing <17 kg received sofosbuvir 150 mg, and patients aged 3 to <6 years weighing ≥17 kg and all patients aged 6 to <12 years received sofosbuvir 200 mg once daily. Intensive pharmacokinetic sampling conducted in each age group confirmed the appropriateness of sofosbuvir doses. For all patients, ribavirin dosing was determined by baseline weight (up to 1,400 mg/day, two divided doses). The primary efficacy endpoint was sustained virologic response 12 weeks after therapy (SVR12). Fifty-four patients were enrolled (41 aged 6 to <12 years and 13 aged 3 to <6 years). Most were treatment naïve (98%) and infected perinatally (94%). All but one patient achieved SVR12 (53/54, 98%; 95% confidence interval, 90%-100%). The patient who did not achieve SVR12 was a 4-year-old who discontinued treatment after 3 days because of "abnormal drug taste." The most commonly reported adverse events in patients aged 6 to <12 years were vomiting (32%) and headache (29%), and those in patients aged 3 to <6 years were vomiting (46%) and diarrhea (39%). One 3-year-old patient had a serious adverse event of accidental ribavirin overdose requiring hospitalization for monitoring; this patient completed treatment and achieved SVR12. Conclusion: Sofosbuvir plus ribavirin was well tolerated and highly effective in children aged 3 to <12 years with chronic HCV genotype 2 or 3 infection.

Safety and Efficacy of Ledipasvir-Sofosbuvir With or Without Ribavirin for Chronic Hepatitis C in Children Ages 6-11.

Currently, there are no interferon-free treatments available for hepatitis C virus (HCV)-infected patients younger than 12 years. We evaluated the safety and effectiveness of the all-oral regimen ledipasvir-sofosbuvir ± ribavirin in HCV-infected children aged 6 to <12 years. In an open-label study, patients aged 6 to <12 years received ledipasvir 45 mg-sofosbuvir 200 mg as two fixed-dose combination tablets 22.5/100 mg once daily, with or without ribavirin, for 12 or 24 weeks, depending on HCV genotype and cirrhosis status. The primary efficacy endpoint was sustained virologic response 12 weeks after therapy (SVR12). Twelve patients underwent intensive pharmacokinetic sampling to confirm the appropriateness of the ledipasvir and sofosbuvir dosages. Ninety-two patients were enrolled (88 genotype 1, 2 genotype 3, and 2 genotype 4), with a median age of 9 years (range, 6-11). Most were perinatally infected (97%) and treatment-naive (78%). Two were confirmed to have cirrhosis, while the degree of fibrosis was unknown in 55 patients. The overall SVR12 rate was 99% (91/92; 95% confidence interval, 94%-100%). The single patient not reaching SVR relapsed 4 weeks after completing 12 weeks of treatment. The most common adverse events were headache and pyrexia. One patient had three serious adverse events, which were considered to be not related to study treatment: tooth abscess, abdominal pain, and gastroenteritis. The area under the concentration-time curve and maximum concentration values for sofosbuvir, its primary metabolite GS-331007, and ledipasvir were within predefined pharmacokinetic equivalence boundaries (50%-200%) compared to values in adults in phase 2/3 of the ledipasvir and sofosbuvir studies. Conclusion: Ledipasvir-sofosbuvir was well tolerated and highly effective in children 6 to <12 years old with chronic HCV.

Enhancing Recovery After Kasai Portoenterostomy With Epidural Analgesia.

BACKGROUND: Biliary atresia (BA) is a rare obstructive cholangiopathy that presents in early infancy. The Kasai portoenterostomy (PE) improves survival with the native liver. Epidural analgesia is an appealing option to control pain in this fragile patient population, yet its safety, efficacy, and potential benefits remain unproven. METHODS: Patients undergoing PE for BA between 2001 and 2016 at a single institution were identified by ICD codes. Preoperative laboratories, procedure details, and recovery outcomes were reviewed retrospectively. Outcomes of interest were need for postoperative mechanical ventilation, pain scores, normalized opioid administration, return of bowel function, and length of hospital stay after PE. RESULTS: Of 47 infants undergoing PE for BA, 25 received epidural analgesia, and 22 did not. Infants with epidurals received less systemic opioids over the first 96 h postoperatively than those without (P < 0.001). Epidurals were associated with lower pain scores between 6 and 30 h postoperatively (P = 0.01 to 0.04), during which the highest median 6-h interval pain score was 0.2 (IQR 0-1.3) for patients with epidurals yet 2.1 (IQR 1.2-3.3) for patients without. Patients with epidurals (88%, n = 22) were more commonly extubated before leaving the operating room than those without (59%, n = 13; P = 0.02). No significant difference was observed in time to first bowel movement (P = 0.48) or first oral feed (P = 0.81). However, infants with epidurals had shorter hospital stays after PE than those without (6 d [IQR 5-7] versus 8 d [IQR 6.3-11], P = 0.01). No major complications were associated with epidural catheters. CONCLUSIONS: Epidural analgesia in patients undergoing PE for BA appears safe and effectively controls pain while minimizing the need for systemic opioids. Reduced need for mechanical ventilation postoperatively and shortened hospital stays serve as further evidence for using epidurals to enhance recovery after PE.

Expanding analytic possibilities in pediatric solid organ transplantation through linkage of administrative and clinical registry databases.

Database linkage is a common strategy to expand analytic possibilities. Our group recently completed a linkage between the SRTR and PHIS databases for pediatric heart transplant recipients. The aim of this project was to expand the linkage between SRTR and PHIS to include liver, kidney, lung, heart-lung, and small bowel transplants. All patients (<21 years) who underwent liver, kidney, lung, heart-lung, or small bowel transplant were identified from the PHIS database using APR-DRG codes (2002-2018). Linkage was performed in a stepwise approach using indirect identifiers. Hospital costs were estimated based on hospital charges and cost-to-charge ratios, inflated to 2018 dollars and described by transplant type. A total of 14 061 patients overlapped between databases. Of these, 13 388 (95.2%) were uniquely linked. Linkage success ranged from 92.6% to 97.8% by organ system. A total of 12 940 (92%) patients had complete cost data. Hospitalization costs were greatest for patients undergoing small bowel transplantation with a median cost of $734 454 (IQR $336 174 - $1 504 167), followed by heart $565 386 (IQR $352 813 - $999 216), heart-lung $471 573 (IQR $328 523 - 992 438), lung $303 536 (IQR $215 383 - $612 749), liver $200 448 (IQR $130 880 - $357 897), and kidney transplant $94 796 (IQR $73 157 -$131 040). We report a robust linkage between the SRTR and PHIS databases, providing an invaluable tool to assess resource utilization in solid organ transplant recipients. Our analysis provides contemporary cost data for pediatric solid organ transplantation from the largest US sample reported to date. It also provides a platform for expanded analyses in the pediatric transplant population.

Clinical Practice Approach to Nonalcoholic Fatty Liver Disease by Pediatric Gastroenterologists in the United States.

OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is common; however, no information is available on how pediatric gastroenterologists in the United States manage NAFLD. Therefore, study objectives were to understand how pediatric gastroenterologists in the US approach the management of NAFLD, and to identify barriers to care for children with NAFLD. METHODS: We performed structured one-on-one interviews to ascertain each individual pediatric gastroenterologist's approach to the management of NAFLD in children. Responses were recorded from open-ended questions regarding screening for comorbidities, recommendations regarding nutrition, physical activity, medications, and perceived barriers to care. RESULTS: Response rate was 72.0% (486/675). Mean number of patients examined per week was 3 (standard deviation [SD] 3.5). Dietary intervention was recommended by 98.4% of pediatric gastroenterologists. Notably, 18 different dietary recommendations were reported. A majority of physicians provided targets for exercise frequency (72.6%, mean 5.6 days/wk, SD 1.6) and duration (69.9%, mean 40.2 minutes/session, SD 16.4). Medications were prescribed by 50.6%. Almost one-half of physicians (47.5%) screened for type 2 diabetes, dyslipidemia, and hypertension. Providers who spent more than 25 minutes at the initial visit were more likely to screen for comorbidities (P = 0.003). Barriers to care were reported by 92.8% with 29.0% reporting ≥3 barriers. CONCLUSIONS: The majority of US pediatric gastroenterologists regularly encounter children with NAFLD. Varied recommendations regarding diet and exercise highlight the need for prospective clinical trials. NAFLD requires a multidimensional approach with adequate resources in the home, community, and clinical setting.

Mutations in the human UBR1 gene and the associated phenotypic spectrum.

Johanson-Blizzard syndrome (JBS) is a rare, autosomal recessive disorder characterized by exocrine pancreatic insufficiency, typical facial features, dental anomalies, hypothyroidism, sensorineural hearing loss, scalp defects, urogenital and anorectal anomalies, short stature, and cognitive impairment of variable degree. This syndrome is caused by a defect of the E3 ubiquitin ligase UBR1, which is part of the proteolytic N-end rule pathway. Herein, we review previously reported (n = 29) and a total of 31 novel UBR1 mutations in relation to the associated phenotype in patients from 50 unrelated families. Mutation types include nonsense, frameshift, splice site, missense, and small in-frame deletions consistent with the hypothesis that loss of UBR1 protein function is the molecular basis of JBS. There is an association of missense mutations and small in-frame deletions with milder physical abnormalities and a normal intellectual capacity, thus suggesting that at least some of these may represent hypomorphic UBR1 alleles. The review of clinical data of a large number of molecularly confirmed JBS cases allows us to define minimal clinical criteria for the diagnosis of JBS. For all previously reported and novel UBR1 mutations together with their clinical data, a mutation database has been established at LOVD.

Clinical and Histopathologic Characteristics of Acute Severe Hepatitis Associated With Human Herpesvirus 6 Infection.

Acute severe hepatitis associated with active human herpesvirus 6 (HHV-6) infection is a rare life-threatening condition with unclear clinical course and histopathology. In this study, we retrospectively analyzed 5 patients with indeterminate acute severe hepatitis found to have active hepatic HHV-6 infection during care. All patients were previously healthy children presenting with a nonspecific prodrome. Four developed acute liver failure (ALF) and 3 received liver transplantation. The explanted livers and biopsies demonstrated a centrilobular pattern of necroinflammation characterized by moderate to marked central perivenulitis and confluent centrilobular to panlobular necrosis in 4 cases, accompanied by marked hepatocellular swelling and milder portal inflammation in 3. Central perivenulitis was more prominent in comparison to a control of group of ALF without HHV-6 (P=0.01). When compared with the children with acute severe hepatitis associated with adenovirus encountered in the recent outbreak, both central perivenulitis and centrilobular necrosis were significant predictors for association with HHV-6 (P<0.01). Liver immunohistochemistry detected HHV-6 structural protein in biliary epithelium in all cases and a predominance of CD8+ T cells in the perivenular inflammatory infiltrate. Among the 4 patients with ALF, one received early anti-HHV-6 therapy and had transplant-free survival, while the other 3 received either general prophylactic antiviral treatment only (n=2) or late anti-HHV-6 therapy (n=1) and needed liver transplantation. Our findings were similar to those in previously reported cases. In summary, acute severe hepatitis associated with HHV-6 tends to affect children, progress to ALF, and exhibit characteristic centrilobular necroinflammation which likely represents an immune-mediated process.

Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-B.

Cornelia de Lange syndrome (CdLS; OMIM 122470) is a dominantly inherited multisystem developmental disorder characterized by growth and cognitive retardation; abnormalities of the upper limbs; gastroesophageal dysfunction; cardiac, ophthalmologic and genitourinary anomalies; hirsutism; and characteristic facial features. Genital anomalies, pyloric stenosis, congenital diaphragmatic hernias, cardiac septal defects, hearing loss and autistic and self-injurious tendencies also frequently occur. Prevalence is estimated to be as high as 1 in 10,000 (ref. 4). We carried out genome-wide linkage exclusion analysis in 12 families with CdLS and identified four candidate regions, of which chromosome 5p13.1 gave the highest multipoint lod score of 2.7. This information, together with the previous identification of a child with CdLS with a de novo t(5;13)(p13.1;q12.1) translocation, allowed delineation of a 1.1-Mb critical region on chromosome 5 for the gene mutated in CdLS. We identified mutations in one gene in this region, which we named NIPBL, in four sporadic and two familial cases of CdLS. We characterized the genomic structure of NIPBL and found that it is widely expressed in fetal and adult tissues. The fly homolog of NIPBL, Nipped-B, facilitates enhancer-promoter communication and regulates Notch signaling and other developmental pathways in Drosophila melanogaster.

Clinicopathologic Features of Severe Acute Hepatitis Associated With Adenovirus Infection in Children.

A recent increase in reports of severe acute hepatitis of unknown etiology in children is under investigation. Although adenovirus has been frequently detected, its role remains unclear, and systematic histopathologic analysis is lacking. We conducted a retrospective study of 11 children hospitalized between October 2021 and May 2022 with unexplained acute hepatitis and concurrent adenovirus infection. Liver biopsies collected shortly after admission demonstrated moderately to severely active hepatitis in 8/11 (73%) cases, characterized by marked portal mixed inflammation, moderate-to-severe interface activity, and milder lobular inflammation. Clusters of plasma cells were present in 6/11 (55%) cases, mimicking autoimmune hepatitis. Semiquantitative scoring of 17 discrete histologic features found that greater degrees of portal inflammation, interface activity, bile duct injury, bile ductular reaction, lobular inflammation, Kupffer cell activation, and hepatocyte focal necrosis were significantly more common in these cases in comparison to the control group of unexplained acute severe hepatitis without adenovirus infection. Liver biopsy immunohistochemistry was negative for adenovirus in all cases. Polymerase chain reaction testing of liver tissue was positive for the enteric adenovirus serotypes 41 (species F) in 10/11 (91%) cases. An immunoprofile study of hepatic infiltrating lymphocytes in 1 patient revealed the presence of large numbers of CD3 + and CD4 + lymphocytes. Nine patients received supportive treatment without steroids and recovered without the need for liver transplantation. In summary, liver injury in children with severe acute hepatitis and adenovirus infection is characterized by a hepatitic pattern that resembles severe autoimmune hepatitis and may represent an immune-mediated process associated with viral infection.

Ciliated hepatic foregut cysts in children.

Ciliated hepatic foregut cyst (CHFC) is a rare foregut developmental malformation usually diagnosed in adulthood; however, rare cases have been reported in the pediatric population. CHFC can transform into a squamous cell carcinoma resulting in death despite surgical resection of the isolated malignancy. We report the presentation, evaluation, and surgical management of a symptomatic 17-year-old girl found to have a 6.5 x 4.5 cm CHFC and suggest that all patients with suspected CHFC undergo prompt evaluation and complete cyst excision.

Population-Based Analysis of Hepatocellular Carcinoma in Children: Identifying Optimal Surgical Treatment.

BACKGROUND: Hepatocellular carcinoma (HCC) constitutes 0.5% of childhood malignancies and exhibits poor prognosis. Complete tumor extirpation either by partial liver resection (LR) or liver transplantation (LT) is the only curative treatment. Due to the poor initial outcomes of LT, LR has remained the mainstay of treatment for all but select children fulfilling the Milan criteria (originally designed for adults). METHODS: We conducted a retrospective cohort study of pediatric HCC patients (younger than 18 years of age) registered in the Surveillance, Epidemiology, and End Results database between 2004 and 2015. Survival analysis was performed by means of Kaplan-Meier methods, 2-sided stratified log-rank tests, and Cox regression models. RESULTS: Of 127 children with HCC, 46 did not undergo operation (36.2%), 32 underwent LT (25.2%), and 49 underwent LR (38.6%). Using the Kaplan-Meier method, the 5-year cancer-specific survival (CSS) rates for LT and LR were 87% and 63%, respectively. LT exhibited superior CSS vs LR (log-rank, p = 0.007). For T1 stage, LT showed equivalent CSS compared with LR (log-rank, p = 0.23), and for T2 and T3 stage, LT exhibited superior CSS (log-rank, p = 0.047 and p = 0.01, respectively). On multivariable Cox regression analysis, T3/T4 stage (adjusted hazard ratio 13.63; 95% CI, 2.9 to 64.07; p = 0.001), and LR (adjusted hazard ratio 7.51; 95% CI, 2.07 to 27.29; p = 0.002) were found to be independently associated with cancer-specific mortality. Fibrolamellar histology and lymph node status were not found to be associated with mortality. CONCLUSIONS: Our findings suggest that children diagnosed with nonmetastatic advanced-stage HCC have a favorable prognosis after LT compared with LR. Early inclusion of an LT consultation after the initial diagnosis is warranted, especially in children with unresectable HCC or when complete tumor extirpation with LR is not feasible.

Liver Fibrosis Associated With Crigler-Najjar Syndrome in a Compound Heterozygote: A Case Report.

Crigler-Najjar syndrome is a hereditary unconjugated hyperbilirubinemia. Two forms of the disease are recognized. Type I is more severe and results in kernicterus if left untreated, and Type II is less severe and responds to phenobarbital. While Crigler-Najjar syndrome is thought by many to have normal liver histology, few reports of the liver pathology exist. Herein, we present a 19-year-old patient with Crigler-Najjar who underwent liver transplantation. The liver showed marked canalicular cholestasis with portal and variable, delicate, bridging fibrosis. Correlation of the patient's genetic test results and clinical phenotype is presented.

Gastrointestinal manifestations of mitochondrial disease.

Although non-specific gastrointestinal and hepatic symptoms are commonly found in most mitochondrial disorders, they are among the cardinal manifestations of several primary mitochondrial diseases, such as: mitochondrial neurogastrointestinal encephalomyopathy; mitochondrial DNA depletion syndrome; Alpers syndrome; and Pearson syndrome. Management of these heterogeneous disorders includes the empiric supplementation with various "mitochondrial cocktails," supportive therapies, and avoidance of drugs and conditions known to have a detrimental effect on the respiratory chain. There is a great need for improved methods of treatment and controlled clinical trials of existing therapies. Liver transplantation is successful in acquired cases; however neuromuscular involvement in primary mitochondrial disorders should be a contraindication for liver transplantation.

NIPBL mutational analysis in 120 individuals with Cornelia de Lange syndrome and evaluation of genotype-phenotype correlations.

The Cornelia de Lange syndrome (CdLS) is a multisystem developmental disorder characterized by facial dysmorphia, upper-extremity malformations, hirsutism, cardiac defects, growth and cognitive retardation, and gastrointestinal abnormalities. Both missense and protein-truncating mutations in NIPBL, the human homolog of the Drosophila melanogaster Nipped-B gene, have recently been reported to cause CdLS. The function of NIPBL in mammals is unknown. The Drosophila Nipped-B protein facilitates long-range enhancer-promoter interactions and plays a role in Notch signaling and other developmental pathways, as well as being involved in mitotic sister-chromatid cohesion. We report the spectrum and distribution of NIPBL mutations in a large well-characterized cohort of individuals with CdLS. Mutations were found in 56 (47%) of 120 unrelated individuals with sporadic or familial CdLS. Statistically significant phenotypic differences between mutation-positive and mutation-negative individuals were identified. Analysis also suggested a trend toward a milder phenotype in individuals with missense mutations than in those with other types of mutations.