Natural history of liver disease in a large international cohort of children with Alagille syndrome: Results from the GALA study.

BACKGROUND AND AIMS: Alagille syndrome (ALGS) is a multisystem disorder, characterized by cholestasis. Existing outcome data are largely derived from tertiary centers, and real-world data are lacking. This study aimed to elucidate the natural history of liver disease in a contemporary, international cohort of children with ALGS. APPROACH AND RESULTS: This was a multicenter retrospective study of children with a clinically and/or genetically confirmed ALGS diagnosis, born between January 1997 and August 2019. Native liver survival (NLS) and event-free survival rates were assessed. Cox models were constructed to identify early biochemical predictors of clinically evident portal hypertension (CEPH) and NLS. In total, 1433 children (57% male) from 67 centers in 29 countries were included. The 10 and 18-year NLS rates were 54.4% and 40.3%. By 10 and 18 years, 51.5% and 66.0% of children with ALGS experienced ≥1 adverse liver-related event (CEPH, transplant, or death). Children (>6 and ≤12 months) with median total bilirubin (TB) levels between ≥5.0 and <10.0 mg/dl had a 4.1-fold (95% confidence interval [CI], 1.6-10.8), and those ≥10.0 mg/dl had an 8.0-fold (95% CI, 3.4-18.4) increased risk of developing CEPH compared with those <5.0 mg/dl. Median TB levels between ≥5.0 and <10.0 mg/dl and >10.0 mg/dl were associated with a 4.8 (95% CI, 2.4-9.7) and 15.6 (95% CI, 8.7-28.2) increased risk of transplantation relative to <5.0 mg/dl. Median TB <5.0 mg/dl were associated with higher NLS rates relative to ≥5.0 mg/dl, with 79% reaching adulthood with native liver ( p < 0.001). CONCLUSIONS: In this large international cohort of ALGS, only 40.3% of children reach adulthood with their native liver. A TB <5.0 mg/dl between 6 and 12 months of age is associated with better hepatic outcomes. These thresholds provide clinicians with an objective tool to assist with clinical decision-making and in the evaluation of therapies.

Update on the diagnosis and management of neonatal intrahepatic cholestasis caused by citrin deficiency: Expert review on behalf of the Asian Pan-Pacific Society for Pediatric Gastroenterology, Hepatology, and Nutrition.

Citrin deficiency is an autosomal recessive metabolic liver disease caused by mutations in the SLC25A13 gene. The disease typically presents with cholestasis, elevated liver enzymes, hyperammonemia, hypercitrullinemia, and fatty liver in young infants, resulting in a phenotype known as "neonatal intrahepatic cholestasis caused by citrin deficiency" (NICCD). The diagnosis relies on clinical manifestation, biochemical evidence of hypercitrullinemia, and identifying mutations in the SLC25A13 gene. Several common mutations have been found in patients of East Asian background. The mainstay treatment is nutritional therapy in early infancy utilizing a lactose-free and medium-chain triglyceride formula. This approach leads to the majority of patients recovering liver function by 1 year of age. Some patients may remain asymptomatic or undiagnosed, but a small proportion of cases can progress to cirrhosis and liver failure, necessitating liver transplantation. Recently, advancements in newborn screening methods have improved the age of diagnosis. Early diagnosis and timely management improve patient outcomes. Further studies are needed to elucidate the long-term follow-up of NICCD patients into adolescence and adulthood.

Management and monitoring of pediatric inflammatory bowel disease in the Asia-Pacific region: A position paper by the Asian Pan-Pacific Society for Pediatric Gastroenterology, Hepatology, and Nutrition (APPSPGHAN) PIBD Working Group: Surgical management, disease monitoring, and special considerations.

Disease phenotype of pediatric inflammatory bowel disease (PIBD) in children from the Asia-Pacific region differs from that of children from the West. Many parts of Asia are endemic for tuberculosis, making diagnosis and management of pediatric Crohn's disease a challenge. Current available guidelines, mainly from Europe and North America, may not be completely applicable to clinicians caring for children with PIBD in Asia due to differences in disease characteristics and regional resource constraints. This position paper is an initiative from the Asian Pan-Pacific Society for Pediatric Gastroenterology, Hepatology and Nutrition (APPSPGHAN) that aims to provide an up-to-date, evidence-based approach to PIBD in the Asia-Pacific region. A group of pediatric gastroenterologists with a special interest in PIBD performed an extensive literature search covering epidemiology, disease characteristics and natural history, management, and monitoring. Attention was paid to publications from the region with special consideration to a resource-limited setting. This current position paper deals with surgical management, disease monitoring, immunization, bone health, and nutritional issues of PIBD in Asia. A special section on differentiating pediatric Crohn's disease from tuberculosis in children is included. This position paper provides a useful guide to clinicians in the surgical management, disease monitoring, and various health issues in children with IBD in Asia-Pacific region.

Impact of Trainee Involvement on Pediatric ERCP Procedures: Results From the Pediatric ERCP Initiative.

This study examines the role of trainee involvement with pediatric endoscopic retrograde cholangiopancreatography (ERCP) and whether it affects the procedure's success, post-procedural adverse outcomes, and duration. A secondary analysis of the Pediatric ERCP Database Initiative, an international database, was performed. Consecutive ERCPs on children <19 years of age from 18 centers were entered prospectively into the database. In total 1124 ERCPs were entered into the database, of which 320 (28%) were performed by trainees. The results showed that the presence of trainees did not impact technical success ( P = 0.65) or adverse events rates ( P = 0.43). Rates of post-ERCP pancreatitis, pain, and bleeding were similar between groups ( P > 0.05). Fewer cases involving trainees were in the top quartile (>58 minutes) of procedural time (19% vs 26%; P = 0.02). Overall, our findings indicate trainee involvement in pediatric ERCP is safe.

Pediatric ERCP in the Setting of Acute Pancreatitis: A Secondary Analysis of an International Multicenter Cohort Study.

Previous studies have demonstrated the safety of performing endoscopic retrograde cholangiopancreatography (ERCP) in the pediatric population; however, few have addressed the outcomes of children undergoing ERCP during acute pancreatitis (AP). We hypothesize that ERCP performed in the setting of AP can be executed with similar technical success and adverse event profiles to those in pediatric patients without pancreatitis. Using the Pediatric ERCP Database Initiative, a multi-national and multi-institutional prospectively collected dataset, we analyzed 1124 ERCPs. One hundred and ninety-four (17%) of these procedures were performed in the setting of AP. There were no difference in the procedure success rate, procedure time, cannulation time, fluoroscopy time, or American Society of Anesthesiology class despite patients with AP having higher American Society of Gastrointestinal Endoscopy grading difficulty scores. This study suggests that ERCP can be safely and efficiently performed in pediatric patients with AP when appropriately indicated.

Recent Improvement in Survival Outcomes and Reappraisal of Prognostic Factors in Pediatric Living Donor Liver Transplantation.

Living donor liver transplantation (LDLT) is a significant advancement for the treatment of children with end-stage liver disease given the shortage of deceased donors. The ultimate goal of pediatric LDLT is to achieve complete donor safety and zero recipient mortality. We conducted a retrospective, single-center assessment of the outcomes as well as the clinical factors that may influence graft and patient survival after primary LDLTs performed between 1994 and 2020. A Cox proportional hazards model was used for multivariate analyses. The trends for independent prognostic factors were analyzed according to the following treatment eras: 1, 1994 to 2002; 2, 2003 to 2011; and 3, 2012 to 2020. Primary LDLTs were performed on 287 children during the study period. Biliary atresia (BA; 52%), acute liver failure (ALF; 26%), and monogenic liver disease (11%) were the leading indications. There were 45 graft losses (16%) and 27 patient deaths (7%) in this population during the study period. During era 1 (n = 81), the cumulative survival rates at 1 and 5 years after LDLT were 90.1% and 81.5% for patients and 86.4% and 77.8% for grafts, respectively. During era 2 (n = 113), the corresponding rates were 92.9% and 92% for patients and 89.4% and 86.7% for grafts, respectively. During era 3 (n = 93), the corresponding rates were 100% and 98.6% for patients and 98.9% and 95.4% for grafts, respectively. In the multivariate analyses, primary diagnosis ALF, bloodstream infection, posttransplant lymphoproliferative disease, and chronic rejection were found to be negative prognostic indicators for patient survival. Based on generalized care guidelines and center-oriented experiences, comprehensive advances in appropriate donor selection, refinement of surgical techniques, and meticulous medical management may eventually realize a zero-mortality rate in pediatric LDLT.

Recurrence of Primary Sclerosing Cholangitis After Liver Transplant in Children: An International Observational Study.

BACKGROUND AND AIMS: Recurrent primary sclerosing cholangitis (rPSC) following liver transplant (LT) has a negative impact on graft and patient survival; little is known about risk factors for rPSC or disease course in children. APPROACH AND RESULTS: We retrospectively evaluated risk factors for rPSC in 140 children from the Pediatric PSC Consortium, a multicenter international registry. Recipients underwent LT for PSC and had >90 days of follow-up. The primary outcome, rPSC, was defined using Graziadei criteria. Median follow-up after LT was 3 years (interquartile range 1.1-6.1). rPSC occurred in 36 children, representing 10% and 27% of the subjects at 2 years and 5 years following LT, respectively. Subjects with rPSC were younger at LT (12.9 vs. 16.2 years), had faster progression from PSC diagnosis to LT (2.5 vs. 4.1 years), and had higher alanine aminotransferase (112 vs. 66 IU/L) at LT (all P < 0.01). Inflammatory bowel disease was more prevalent in the rPSC group (86% vs. 66%; P = 0.025). After LT, rPSC subjects had more episodes of biopsy-proved acute rejection (mean 3 vs. 1; P < 0.001), and higher prevalence of steroid-refractory rejection (41% vs. 20%; P = 0.04). In those with rPSC, 43% developed complications of portal hypertension, were relisted for LT, or died within 2 years of the diagnosis. Mortality was higher in the rPSC group (11.1% vs. 2.9%; P = 0.05). CONCLUSIONS: The incidence of rPSC in this cohort was higher than previously reported, and was associated with increased morbidity and mortality. Patients with rPSC appeared to have a more aggressive, immune-reactive phenotype. These findings underscore the need to understand the immune mechanisms of rPSC, to lay the foundation for developing new therapies and improve outcomes in this challenging population.

The Sclerosing Cholangitis Outcomes in Pediatrics (SCOPE) Index: A Prognostic Tool for Children.

BACKGROUND AND AIMS: Disease progression in children with primary sclerosing cholangitis (PSC) is variable. Prognostic and risk-stratification tools exist for adult-onset PSC, but not for children. We aimed to create a tool that accounts for the biochemical and phenotypic features and early disease stage of pediatric PSC. APPROACH AND RESULTS: We used retrospective data from the Pediatric PSC Consortium. The training cohort contained 1,012 patients from 40 centers. We generated a multivariate risk index (Sclerosing Cholangitis Outcomes in Pediatrics [SCOPE] index) that contained total bilirubin, albumin, platelet count, gamma glutamyltransferase, and cholangiography to predict a primary outcome of liver transplantation or death (TD) and a broader secondary outcome that included portal hypertensive, biliary, and cancer complications termed hepatobiliary complications (HBCs). The model stratified patients as low, medium, or high risk based on progression to TD at rates of <1%, 3%, and 9% annually and to HBCs at rates of 2%, 6%, and 13% annually, respectively (P < 0.001). C-statistics to discriminate outcomes at 1 and 5 years were 0.95 and 0.82 for TD and 0.80 and 0.76 for HBCs, respectively. Baseline hepatic fibrosis stage was worse with increasing risk score, with extensive fibrosis in 8% of the lowest versus 100% with the highest risk index (P < 0.001). The model was validated in 240 children from 11 additional centers and performed well. CONCLUSIONS: The SCOPE index is a pediatric-specific prognostic tool for PSC. It uses routinely obtained, objective data to predict a complicated clinical course. It correlates strongly with biopsy-proven liver fibrosis. SCOPE can be used with families for shared decision making on clinical care based on a patient's individual risk, and to account for variable disease progression when designing future clinical trials.

Usability of intraoperative cine-portogram during liver transplantation in young pediatric patients with biliary atresia.

BACKGROUND: Pediatric patients with biliary atresia (BA) often present liver cirrhosis-associated portal hypertension and portal vein (PV) hypoplasia. For successful liver transplantation (LT), it is essential to maintain sufficient PV inflow through stenosis-free PV reconstruction with effective ligation of collateral veins. The aim of this study was to assess the clinical usability of intraoperative cine-portogram (IOCP) in young pediatric patients who underwent LT for BA. METHODS: Medical records of pediatric patients younger than 10 years who underwent primary LT for BA from 2018 to 2020 were reviewed. RESULTS: A total of 31 patients had undergone Kasai portoenterostomy soon after birth. Their median ages at Kasai portoenterostomy and LT were 1 and 11 months, respectively. Types of LT were living-donor LT in 13, deceased-donor split LT in 15, and deceased-donor whole LT in three patients. PV interposition using an iliac vein homograft was performed in 28 patients receiving partial liver grafts. Side-to-side PV unification venoplasty was performed in three patients undergoing whole LT. All patients underwent ligation of collateral veins. IOCP was performed in 6 (19.4%) patients. Four showed no or faint residual venous collaterals. Collateral vein embolization and endovascular stenting were performed in one patient each. PV insufficiency-free survival rate was 100% at 1 year and 93.8% at 3 years. All patients are currently alive with a median follow-up period of 23 months. CONCLUSIONS: Intraoperative cine-portogram can be a useful method for identification and embolization of residual portosystemic collateral veins in young pediatric patients who undergo LT for biliary atresia.

Medical Management of Pediatric Inflammatory Bowel Disease (PIBD) in the Asia Pacific Region: A Position Paper by the Asian Pan-Pacific Society for Pediatric Gastroenterology, Hepatology, and Nutrition (APPSPGHAN) PIBD Working Group.

Pediatric inflammatory bowel disease (PIBD) is rising rapidly in many industrialised and affluent areas in the Asia Pacific region. Current available guidelines, mainly from Europe and North America, may not be completely applicable to clinicians caring for children with PIBD in this region due to differences in disease characteristics and regional resources constraints. This position paper is an initiative from the Asian Pan-Pacific Society for Pediatric Gastroenterology, Hepatology and Nutrition (APPSPGHAN) with the aim of providing an up-to-date, evidence-based approach to PIBD in the Asia Pacific region, taking into consideration the unique disease characteristics and financial resources available in this region. A group of pediatric gastroenterologists with special interest in PIBD performed an extensive literature search covering epidemiology, disease characteristics and natural history, management and monitoring. Gastrointestinal infections, including tuberculosis, need to be excluded before diagnosing IBD. In some populations in Asia, the Nudix Hydrolase 15 (NUD15) gene is a better predictor of leukopenia induced by azathioprine than thiopurine-S-methyltransferase (TPMT). The main considerations in the use of biologics in the Asia Pacific region are high cost, ease of access, and potential infectious risk, especially tuberculosis. Conclusion: This position paper provides a useful guide to clinicians in the medical management of children with PIBD in the Asia Pacific region.

Predictors of Prolonged Fluoroscopy Exposure in Pediatric Endoscopic Retrograde Cholangiopancreatography: Results From the Large Pediatric Endoscopic Retrograde Cholangiopancreatography Database Initiative Multicenter Cohort.

BACKGROUND AND AIMS: Ionizing radiation exposure during endoscopic retrograde cholangiopancreatography (ERCP) is an important quality issue especially in children. We aim to identify factors associated with extended fluoroscopy time (FT) in children undergoing ERCP. METHODS: ERCP on children <18 years from 15 centers were entered prospectively into a REDCap database from May 2014 until May 2018. Data were retrospectively evaluated for outcome and quality measures. A univariate and step-wise linear regression analysis was performed to identify factors associated with increased FT. RESULTS: 1073 ERCPs performed in 816 unique patients met inclusion criteria. Median age was 12.2 years (interquartile range [IQR] 9.3-15.8). 767 (71%) patients had native papillae. The median FT was 120 seconds (IQR 60-240). Factors associated with increased FT included procedures performed on patients with chronic pancreatitis, ERCPs with American Society of Gastrointestinal Endoscopy (ASGE) difficulty grade >3, ERCPs performed by pediatric gastroenterologist (GI) with adult GI supervision, and ERCPs performed at non-free standing children's hospitals. Hispanic ethnicity was the only factor associated with lower FT. CONCLUSION: Several factors were associated with prolonged FTs in pediatric ERCP that differed from adult studies. This underscores that adult quality indicators cannot always be translated to pediatric patients. This data can better identify children with higher risk for radiation exposure and improve quality outcomes during pediatric ERCP.

Technical Outcomes in Pediatric Endoscopic Retrograde Cholangiopancreatography: Data from an International Collaborative.

OBJECTIVES: Endoscopic retrograde cholangiopancreatography (ERCP) in adults has been extensively studied through multicenter prospective studies. Similar pediatric studies are lacking. The Pediatric ERCP Database Initiative (PEDI) is a multicenter collaborative aiming to evaluate the indications and technical outcomes in pediatric ERCPs. METHODS: In this prospective cohort study, data were recorded for pediatric ERCPs performed across 15 centers. A pre-procedure, procedure, 2-week post-procedure follow-up, and adverse event form were completed for each ERCP performed. Univariate and stepwise linear regression was performed to identify factors associated with technically successful procedures and adverse events. RESULTS: A total of 1124 ERCPs were performed on 857 patients from May 1, 2014 to May 1, 2018. The median age was 13.5 years [interquartile range (IQR) 9.0-15.7]. Procedures were technically successful in the majority of cases (90.5%) with success more commonly encountered for procedures with biliary indications [odds ratio (OR) 4.2] and less commonly encountered for native papilla anatomy (OR 0.4) and in children <3 years (OR 0.3). Cannulation was more often successful with biliary cannulation (95.9%) compared to pancreatic cannulation via the major papilla (89.6%, P < 0.0001) or minor papilla (71.2%, P < 0.0005). The most commonly identified adverse events included post-ERCP pancreatitis (5%), pain not related to post-ERCP pancreatitis (1.8%), and bleeding (1.2%). Risk factors for the development of each were identified. CONCLUSIONS: This large prospective study demonstrates that ERCP is reliable and safe in the pediatric population. It highlights the utility of PEDI in evaluating the technical outcomes of pediatric ERCPs and demonstrates the potential of PEDI for future studies in pediatric ERCPs.

Shift to a Younger Age and Regional Differences in Inflammatory Bowel Disease in Korea: Using Healthcare Administrative Data.

BACKGROUND: Research using healthcare administrative data with a validated algorithm can reveal the real-world data of rare diseases. AIMS: We investigated an accurate algorithm for detecting incident cases of inflammatory bowel disease (IBD) from healthcare data and analyzed the nationwide population-based epidemiological features in Korea. METHODS: Healthcare data from Songpa-Kangdong districts in Seoul were extracted from the National Health Insurance Service and analyzed to identify the best algorithm reflecting the cohort data. The most accurate criterion was applied to the entire database for further analysis. RESULTS: With the selected working criteria, 37,555 incident cases of IBD (Crohn's Disease [CD], 13,130; ulcerative colitis [UC], 24,425) were identified from 2005 to 2016. The male-to-female ratio was 2.5:1 for CD and 1.4:1 for UC. Over 12 years, the annual standardized incidence rate (SIR) per 100,000 people increased from 1.6 to 2.7 and 3.8 to 4.3 for CD and UC, respectively. The peak age at diagnosis of UC shifted from 55-59 years to 20-24 years, whereas that of CD shifted from 19 to 17 years. The SIR of CD was higher in metropolitan areas than in non-metropolitan areas. CONCLUSIONS: This nationwide population-based epidemiologic study of Korean IBD revealed a gradual increase in the incidence rates and a notable shift toward younger age at diagnosis. Males were predominant in both CD and UC. There was an urban-rural difference in the SIR of CD.

Multiplex gene targeting in the mouse embryo using a Cas9-Cpf1 hybrid guide RNA.

CRISPR-Cas systems, including Cas9 and Cpf1 (Cas12a), are promising tools for generating gene knockout mouse models. Unlike Cas9, Cpf1 can generate multiple crRNAs from a single concatemeric crRNA precursor, which is favorable for multiplex gene editing. Recently, a hybrid guide RNA (hgRNA) system employing both Cas9 and Cpf1 was developed for multiplex gene editing. As the crRNA of Cpf1 was linked to the 3' end of the sgRNA for Cas9, it can be split into separate guide RNAs by Cpf1. To examine whether this Cas9-Cpf1 hybrid system is suitable for multiplex gene knockouts in the mouse embryo, we generated an hgRNA that simultaneously targets the mouse Il10ra gene by Cas9 and mouse Dr3 (or Tnfrsf25, death receptor3) gene by Cpf1. The expression of hgRNA from a single promoter induced significant indels at each gene in cultured mouse cells upon the co-expression of both Cas9 and Cpf1. Interestingly, the hgRNA exhibited comparable Cas9-mediated indel activity without Cpf1 expression. Similarly, when the hgRNA was co-microinjected with both Cas9 and Cpf1 mRNAs into mouse zygotes at the pronuclear stage, founder mice were generated harboring mutations in both the Il10ra and Dr3 genes. However, when Cas9 mRNA was used alone without Cpf1 mRNA, the mouse Il10ra gene targeting was significantly decreased. These results indicate that the hgRNA system is a possible tool for multiplex gene targeting in the mouse embryo.

Predictive Prenatal Diagnosis for Infantile-onset Inflammatory Bowel Disease Because of Interleukin-10 Signalling Defects.

OBJECTIVES: Advances in genetic technologies provide opportunities for patient care and ethical challenges. Clinical care of patients with rare Mendelian disorders is often at the forefront of those developments. Whereas in classical polygenic inflammatory bowel disease (IBD), the predictive value of genetic variants is very low, predictive prenatal genetic diagnosis can inform families at high risk of severe genetic disorders. Patients with IL-10 signalling defects because of pathogenic variants in IL10RA, Il10RB, and IL10 develop severe infantile onset inflammatory bowel disease that is completely penetrant and has a high morbidity and substantial mortality despite treatment. METHODS: We performed a survey among tertiary specialist paediatric centers of 10 countries on the utilization of predictive prenatal genetic diagnosis in IL-10 signalling defects. We retrospectively report prenatal genetics in a series of 8 families. RESULTS: International variation in legislation, guidelines, expert opinion, as well as cultural and religious background of families and clinicians results in variable utilization of preimplantation and prenatal genetic testing for IL-10 signalling defects. Eleven referrals for prenatal diagnosis for IL-10 signalling defects were identified across 4 countries. We report on 8 families who underwent prenatal preimplantation monogenic testing after in vitro fertilization (n = 2) and/or by amniocentesis/chorion villus sampling (n = 6). A genetic diagnosis was established in 1 foetus and excluded in 7 foetuses (all IL10RA variants). CONCLUSIONS: Prenatal genetic testing for IL10R-defects is feasible, yet the legal and ethical considerations are complex and controversial. In some countries, predictive genetics for IL-10-related signalling defects is entering clinical practice.

Growth, puberty, and bone health in children and adolescents with inflammatory bowel disease.

BACKGROUND: Endocrine complications such as impaired growth, delayed puberty, and low bone mineral density (BMD) can be associated with inflammatory bowel disease (IBD) in children and adolescents. This study was performed to investigate the frequency, characteristics, and outcomes of endocrine complications of IBD in children and adolescents. METHODS: This study included 127 patients with IBD diagnosed before 18 years of age [117 with Crohn disease (CD) and 10 with ulcerative colitis (UC)]. Growth profiles, pubertal status, 25-hydroxyvitamin D3 [25(OH)D3] levels, and BMD were reviewed retrospectively. RESULTS: Short stature was observed in 14 of 127 (11.0 %) with a mean height-SDS of -2.31 ± 0.72. During a 2-year follow-up period, height-SDS did not significantly improve, while weight-SDS significantly improved. Among 109 patients who were older than 13 (girls) or 14 (boys) years of age during the study period, 11 patients (10.1 %) showed delayed puberty, which was associated with low weight-SDS. Vitamin D deficiency was documented in 81.7 % (94/115) with the average 25(OH)D3 level of 14.5 ± 7.0 ng/mL. Lumbar BMD Z-score was below - 2 SDS in 25 of 119 patients (21.0 %). Height-SDS, weight-SDS, and body mass index (BMI)-SDS were lower in patients with osteoporosis than those without osteoporosis. When pediatric CD activity index scores were high (≥ 30), weight-SDS, BMI-SDS, insulin-like growth factor 1 (IGF-1)-SDS, and testosterone levels were significantly decreased. CONCLUSIONS: Vitamin D deficiency and osteoporosis are common in pediatric IBD patients. As disease severity deteriorates, weight-SDS, IGF-1-SDS, and testosterone levels were decreased. Optimal pubertal development is necessary for bone health.

Assessment of native liver fibrosis using ultrasound elastography and serological fibrosis indices in children with biliary atresia after the Kasai procedure.

BACKGROUND: Validated non-invasive examinations are necessary to monitor liver fibrosis in children with biliary atresia (BA) after the Kasai procedure. PURPOSE: To evaluate the diagnostic accuracy of two-dimensional shear wave elastography (2D-SWE), transient elastography (TE), and the serologic biomarkers of aspartate transaminase-to-platelet ratio index (APRI) and Fibrosis-4 (FIB-4) score for evaluating native liver fibrosis in children with BA. MATERIAL AND METHODS: We retrospectively reviewed same-day 2D-SWE and TE liver stiffness (LS) measurements of 63 patients with BA who underwent the Kasai procedure. The APRI and FIB-4 score were computed. Hepatic fibrosis was categorized into three clinical categories based on the ultrasound (US) hepatic morphology and clinical manifestations of liver cirrhosis: I, pre-cirrhotic liver state (n = 15); II, US and/or clinical signs of liver cirrhosis with compensated liver function (n = 27); and III, liver cirrhosis with decompensated liver function (n = 21). We compared area under the receiver operating characteristic curve (AUC) data among 2D-SWE, TE, APRI, and FIB-4 score. Combined evaluation of serologic fibrosis indices and US elastography was conducted and AUCs of combinations were analyzed. RESULTS: 2D-SWE, TE, APRI, and FIB-4 score showed good to excellent diagnostic accuracy for differentiating clinical categories (AUCs 0.779-0.955). AUC values were significantly increased after adding TE to FIB-4 score for detecting liver cirrhosis (P = 0.02). CONCLUSION: 2D-SWE, TE, APRI, and FIB-4 score are accurate non-invasive markers for monitoring native liver fibrosis in patients with BA. Combined use of serologic markers and US elastography could yield more accurate diagnoses of liver fibrosis than serologic markers alone.

Epstein-Barr viral load monitoring for diagnosing post-transplant lymphoproliferative disorder in pediatric liver transplant recipients.

This study aimed to investigate the incidence of PTLD in pediatric liver transplant recipients and the risk factors for the development of PTLD. We also determined clinically useful quantitative EBV PCR parameters for aiding in the diagnosis of EBV-associated PTLD in the pediatric liver transplant recipients at our institute. We reviewed children < 18 years old who had undergone liver transplantations and quantitative analysis of whole blood EBV load at our institute from January 2006 to March 2015. A total of 142 liver transplant recipients were included, and their median age was 1.5 years. Clinically significant high-level EBV DNAemia ≥ 10 000 copies/mL at least twice was observed in 53.5% and PTLD occurred in 9.9%. Among PTLD group, graft failure and mortality rate were as high as 21.4% and 14.3%, respectively. Deceased donor, presence of high-level EBV DNAemia, and primary CMV infection following transplant were associated with an increased risk for PTLD in the multivariate analysis. The peak titer at 10 875 copies/mL could be used as a cutoff value with a sensitivity of 92.9% and a specificity of 37.9%; the rate of increase in EBV load suggested a sensitivity of 64.3% and a specificity of 70.9% at the cutoff value of 44 000 copies/mL/week. In conclusion, the incidence of PTLD following liver transplant in children was as high as 10%. PTLD is associated with significant morbidity and mortality. Close monitoring of EBV DNAemia is crucial for the early diagnosis and proper treatment of PTLD in pediatric liver transplant recipients.

Development of a Prognostic Score to Predict Mortality in Patients With Pediatric Acute Liver Failure.

OBJECTIVES: This study aims to develop a new prognostic score based on changes in serial laboratory data from patients with pediatric acute liver failure (PALF). METHODS: We retrospectively reviewed data on 146 patients with PALF at the Seoul National University Children Hospital (SNUCH) and the Asan Medical Center (AMC). Daily morning laboratory records were obtained for up to 7 days after diagnosis of PALF: total bilirubin (TB) (mg/dL), international normalized ratio for prothrombin time (INR) at enrolment; peak TB, peak INR, peak ammonia (µmol/L); the difference between the peak TB and TB at enrollment (ie, Δpeak TB), the difference between the peak INR and INR at enrollment (ie, Δpeak INR), the maximum change in serial TB (ie, Δdaily TB), the maximum change in serial INR level (ie, Δdaily INR). We assigned nontransplanted patients in SNUCH and AMC to derivation and validation cohorts, respectively. RESULTS: Δpeak TB, Δdaily TB, Δpeak INR, and Δdaily INR were significantly higher in the nonsurvival group. We developed a new score that can predict mortality in nontransplanted patients (derivation cohort n = 42, validation cohort n = 33). PALF-Delta score (PALF-Ds) = [0.232 × Δpeak TB (mg/dL)] + [2.263 × Δdaily INR] + [0.013 × peak ammonia (µmol/L)] - 4.498. The score yielded AUC 0.918 in the derivation cohort (sensitivity 81%, specificity 91%) and AUC 0.947 in the validation cohort (sensitivity 100%, specificity 89%). CONCLUSION: A prognostic scoring system using the change of TB/INR may be useful for predicting mortality in patients with PALF.

Assessing the Validity of Adult-derived Prognostic Models for Primary Sclerosing Cholangitis Outcomes in Children.

BACKGROUND: Natural history models for primary sclerosing cholangitis (PSC) are derived from adult patient data, but have never been validated in children. It is unclear how accurate such models are for children with PSC. METHODS: We utilized the pediatric PSC consortium database to assess the Revised Mayo Clinic, Amsterdam-Oxford, and Boberg models. We calculated the risk stratum and predicted survival for each patient within each model using patient data at PSC diagnosis, and compared it with observed survival. We evaluated model fit using the c-statistic. RESULTS: Model fit was good at 1 year (c-statistics 0.93, 0.87, 0.82) and fair at 10 years (0.78, 0.75, 0.69) in the Mayo, Boberg, and Amsterdam-Oxford models, respectively. The Mayo model correctly classified most children as low risk, whereas the Amsterdam-Oxford model incorrectly classified most as high risk. All of the models underestimated survival of patients classified as high risk. Albumin, bilirubin, AST, and platelets were most associated with outcomes. Autoimmune hepatitis was more prevalent in higher risk groups, and over-weighting of AST in these patients accounted for the observed versus predicted survival discrepancy. CONCLUSIONS: All 3 models offered good short-term discrimination of outcomes but only fair long-term discrimination. None of the models account for the high prevalence of features of autoimmune hepatitis overlap in children and the associated elevated aminotransferases. A pediatric-specific model is needed. AST, bilirubin, albumin, and platelets will be important predictors, but must be weighted to account for the unique features of PSC in children.