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.

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.

Pediatric living donor liver transplantation for biliary embryonal rhabdomyosarcoma: a case report of a case showing disease-free survival over 2 years.

Biliary rhabdomyosarcoma is a rare tumor, but it is still the most common tumor of the biliary tract in children. We report a case of a 6-year-old boy with biliary embryonal rhabdomyosarcoma and liver metastasis, which were treated with neoadjuvant and adjuvant chemotherapy combined with living donor liver transplantation (LDLT). Initial imaging studies showed a low-attenuation intraductal mass from the left hepatic duct to the intrapancreatic common bile duct with diffuse upstream dilatation of the intrahepatic duct and liver metastasis. Endoscopic biopsy revealed embryonal rhabdomyosarcoma. After tumor size reduction through neoadjuvant chemotherapy, LDLT was planned to remove the tumor completely. A left lateral section graft weighing 330 g was harvested from his 38-year-old mother and the graft-to-recipient weight ratio was 1.94%. Routine pediatric LDLT operation was performed with deep excavation of intrapancreatic distal bile duct. The explant liver showed minimal residual embryonal rhabdomyosarcoma with no lymph node metastasis. The patient recovered uneventfully from LDLT operation. Scheduled adjuvant chemotherapy was performed for 6 months. The patient is doing well without any evidence of tumor recurrence for 26 months after LDLT. In conclusion, liver transplantation could be an effective treatment for unresectable biliary rhabdomyosarcoma in children according to the location of tumor.

Living donor liver transplantation in an infant patient with progressive familial intrahepatic cholestasis along with hepatocellular carcinoma: a case report.

Progressive familial intrahepatic cholestasis (PFIC) is an autosomal recessive inherited disease requiring liver transplantation (LT). Hepatocellular carcinoma (HCC) is very rare in infants. We present a case of living donor LT using a left lateral section graft performed in a 7-month-old female infant diagnosed with PFIC type II and HCC. No mutation on ABCB11 gene was identified. Because of progressive deterioration of liver function, living donor LT with her mother's left lateral section graft was performed. Pretransplant serum alpha-fetoprotein (AFP) level was increased to 2,740 ng/mL, but HCC was not taken into account because of its rarity. The explant liver showed micronodular liver cirrhosis, multiple infantile hemangiomas and two HCCs of 0.7 cm and 0.3 cm in size. The patient recovered uneventfully from the LT operation. This patient has been regularly followed up with abdomen ultrasonography and AFP measurement every 6 months. The patient has been continually doing well for 8 years after the LT. In conclusion, LT is currently the only effective treatment for PFIC-associated end-stage liver diseases. HCC can develop at the cirrhotic liver of any cause, thus elevation of HCC tumor markers in pediatric patients is an important clue to perform further investigation before LT.

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.

The Pellino1-PKCθ Signaling Axis Is an Essential Target for Improving Antitumor CD8+ T-lymphocyte Function.

CD8+ T cells play an important role in the elimination of tumors. However, the underlying mechanisms involved in eliciting and maintaining effector responses in CD8+ T cells remain to be elucidated. Pellino1 (Peli1) is a receptor signal-responsive ubiquitin E3 ligase, which acts as a critical mediator for innate immunity. Here, we found that the risk of developing tumors was dependent on Peli1 expression. Peli1 was upregulated in CD8+ T cells among tumor-infiltrating lymphocytes (TIL). In contrast, a deficit of Peli1 enhanced the maintenance and effector function of CD8+ TILs. The development of Peli1-deficient CD8+ TILs prevented T-cell exhaustion and retained the hyperactivated states of T cells to eliminate tumors. We also found that Peli1 directly interacted with protein kinase C-theta (PKCθ), a central kinase in T-cell receptor downstream signal transduction, but whose role in tumor immunology remains unknown. Peli1 inhibited the PKCθ pathway by lysine 48-mediated ubiquitination degradation in CD8+ TILs. In summary, the Peli1-PKCθ signaling axis is a common inhibitory mechanism that prevents antitumor CD8+ T-cell function, and thus targeting Peli1 may be a useful therapeutic strategy for improving cytotoxic T-cell activity.

Clinical Characteristics and Long-term Outcomes of Pediatric Ulcerative Colitis: A Single-Center Experience in Korea.

Background/Aims: : Although pediatric ulcerative colitis (UC) has a different phenotype and clinical course than adult UC, its clinical features and outcomes are poorly defined, especially in Asian populations. This study investigated the clinical features and long-term outcomes of pediatric UC in a Korean population. Methods: We retrospectively analyzed 208 patients aged <18 years diagnosed with UC between 1987 and 2013. The patient characteristics at diagnosis according to the Paris classification and the clinical course were analyzed. Results: The male-to-female ratio was 1.3:1, and the median patient age was 15.5 years. At diagnosis, 28.8% of patients had proctitis (E1), 27.8%, left-sided colitis (E2); 5.2%, extensive colitis (E3); and 38.2%, pancolitis (E4). The cumulative probabilities of extension after 5, 10, 15, and 20 years were 32.7%, 40.4%, 52.5%, and 65.8%, respectively. Eighteen patients underwent colectomy, and three patients had colorectal cancer. The cumulative probabilities of colectomy after 5, 10, 15, and 20 years were 7.1%, 8.9%, 12.6%, and 15.6%, and those of colorectal cancer after 10, 15, and 20 years were 0%, 2.1%, and 12.0%, respectively. The disease extent, Pediatric Ulcerative Colitis Activity Index severity, and systemic corticosteroid therapy were significant risk factors for colectomy. The development of primary sclerosing cholangitis was significantly associated with colorectal cancer. Conclusions: This study provides detailed information on the disease phenotype and long-term clinical outcomes in a large cohort of Korean children with UC. They have extensive disease at diagnosis, a high rate of disease extension, and a low rate of cumulative colectomy.

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.

Liver transplantation in pediatric patients with progressive familial intrahepatic cholestasis: Single center experience of seven cases.

BACKGROUNDS/AIMS: Progressive familial intrahepatic cholestasis (PFIC) is an autosomal recessive inherited disease requiring liver transplantation (LT). The objective of this study was to investigate the clinicopathological features and posttransplant courses of seven LT recipients with PFIC. METHODS: This was a retrospective single-center study of patients with PFIC who underwent LT from January 2013 to June 2020. RESULTS: Two and five patients were diagnosed with PFIC type 1 and type 2, respectively. For all seven patients, age of PFIC onset was at birth. Jaundice was present in all cases. Mean pretransplant total and direct bilirubin levels were 16.1 ± 8.1 mg/dL and 12.4 ± 6.2 mg/dL, respectively. Median patient age and body weight at LT were 10 months and 7 kg, respectively. Types of donors were mothers of patients in four and deceased donors in three. All five patients with PFIC type 2 recovered uneventfully. One patient each with PFIC type 1 underwent retransplantation due to graft failure or died due to multi-organ failure. Overall graft and patient survival rates at five years were 66.7% and 83.3%, respectively. Bile salt export pump immunohistochemical staining showed normal canalicular expression in two patients with PFIC type 1, focal loss in two patients with PFIC type 2, and total loss in three patients with PFIC type 2. CONCLUSIONS: LT is currently the only effective treatment for PFIC-associated end-stage liver diseases. It is mandatory to perform regular follow-up due to the risk of complications including steatohepatitis, especially for patients with PFIC type 1.

Living donor liver transplantation in a pediatric patient with congenital absence of the portal vein.

Congenital absence of the portal vein (CAPV) is a rare venous malformation in which mesenteric venous blood drains directly into the systemic circulation. We report a case of pediatric living donor liver transplantation (LDLT) for CAPV combined with focal nodular hyperplasia (FNH) and hepatocellular adenoma. A 9-year-old girl who had been diagnosed with multiple FNH had CAPV. Her blood ammonia level was raised to 137 µg/dL. However, she did not complain of any symptoms. To treat CAPV and FNH, we decided to perform LDLT. The graft was a left liver graft from 39-year-old mother of the patient. Recipient hepatectomy was performed according to standard procedures of pediatric LDLT. Portal vein reconstruction was performed using interposition of an iliac vein homograft conduit to the superior mesenteric vein-splenic vein confluence. The CAPV-associated congenital splenorenal shunt was securely ligated. The pathology report of the explant liver showed a 2 cm-sized hepatocellular adenoma and multiple FNH lesions measuring up to 7.1 cm. The patient recovered uneventfully from the LDLT operation. The reconstructed portal vein was maintained well without any hemodynamic abnormalities. In conclusion, as CAPV patients can have various vascular anomalies, combined vascular anomalies should be thoroughly assessed before and during liver transplantation operation. The most effective reconstruction techniques should be used to achieve satisfactory results following liver transplantation.

Funneling venoplasty for anomalous graft left hepatic vein in living donor liver transplantation using a split left lateral section graft for an infant patient.

The left lateral section (LLS) can have an unusual variant left hepatic vein (LHV) anatomy. We present a case of customized funneling venoplasty of the graft LHV in a 22-month-old girl diagnosed with ornithine transcarbamylase deficiency undergoing deceased donor liver transplantation (LT) using a split LLS graft. The split LLS graft weighed 350 g, yielding a graft-to-recipient weight ratio of 3.2%. Notably, the graft LHV opening was located at the graft liver cut surface, which was only 1 cm in size and 2 cm away from the cephalad apex of the LLS graft. Since such a variant location of the small LHV opening was unsuitable for direct anastomosis, we performed a funneling venoplasty using an inferior vena cava fragment homograft obtained from the same donor. The graft implantation was performed according to standard procedures of infant split LT. Follow-up imaging studies showed no vascular complications. The patient recovered uneventfully from the LT operation. She had normal blood test findings, including normal ammonia level. She has been doing well for 6 months after the transplantation. In conclusion, our surgical technique using a funneling venoplasty enabled successful reconstruction of the anomalous graft LHV. Our results suggest that individualized reconstruction techniques should be applied to infant patients undergoing LT using a LLS graft with variant types of graft LHV anatomy.

Dextroplantation of a reduced left lateral section graft in an infant undergoing living donor liver transplantation.

Graft size matching is essential for successful liver transplantation in infant recipients. We present our technique of graft dextroplantation used in an infant who underwent living donor liver transplantation (LDLT) using a reduced left lateral section (LLS) graft. The patient was an 11-month-old female infant weighing 7.8 kg with hepatoblastoma. She was partially responsive to systemic chemotherapy. Thus, LDLT was performed to treat the tumor. The living donor was a 34-year-old mother of the patient. After non-anatomical size reduction, the weight of the reduced LLS graft was 235 g, with a graft-to-recipient weight ratio of 3.0%. Recipient hepatectomy was performed according to the standard procedures of pediatric LDLT. At the beginning of graft implantation, the graft was temporarily placed at the abdomen to determine the implantation location. The graft portal vein was anastomosed with an interposed external iliac vein homograft. As the liver graft was not too large and it was partially accommodated in the right subphrenic fossa, thus the abdominal wall wound was primarily closed. The patient recovered uneventfully. An imaging study revealed deep accommodation of the graft within the right subphrenic fossa. The patient has been doing well for six months without any vascular complications. This case suggests that dextroplantation of a reduced LLS graft can be a useful technical option for LDLT in infant patients.

Pediatric deceased donor liver transplantation with in situ size reduction for recipient-graft size matching.

We present a case of pediatric deceased donor liver transplantation using a reduced whole liver graft in a 25-month-old boy weighing 12.7 kg. After he had undergone Kasai portoenterostomy for biliary atresia, his general condition deteriorated progressively. He was enrolled on the waiting list for liver transplantation with Pediatric End-stage Liver Disease score of 15. The donor was a 51-monthold boy with body weight of 20 kg. The donor-to-recipient body weight ratio was 158%. The liver graft appeared to be larger than the recipient's abdominal cavity. Thus, we planned to do in situ size reduction. Recipient surgery was performed following standard procedures. We performed graft outflow vein reconstruction using a modified piggyback technique like the double inferior vena cava method. Since the portal vein was hypoplastic, a side-to-side anastomosis technique was used. We also performed intraoperative portogram to embolize venous collaterals. After completing the graft implantation, we found that the liver graft was too large to be accommodated within the abdomen. After in situ resection of the left lateral section parenchyma, we successfully performed primary closure of the abdominal wound. This patient experienced episodes of acute rejection. He has been doing well for four years after the transplantation.

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.

Third retransplantation using a whole liver graft for late graft failure from hepatic vein stent stenosis in a pediatric patient who underwent split liver retransplantation.

We present a case of third retransplantation using a whole liver graft in a 13-year-old girl who suffered graft failure and hepatopulmonary syndrome following split liver retransplantation with endovascular stenting of the hepatic and portal veins as an infant. She was diagnosed with biliary atresia-polysplenia syndrome, and thus underwent living donor liver transplantation from her mother at 9 months of age. The first liver graft failed due to stenosis of the portal vein. She underwent the second liver transplantation with a split left lateral section graft. Endovascular stenting was performed to the portal vein stenosis 2 months and hepatic vein stenosis 9 months after transplantation. During the next 9 years, 11 sessions of balloon angioplasty for hepatic vein stent stenosis were performed. Ten years after the second transplantation, she underwent third transplantation using a whole liver graft recovered from a 12-year-old-girl. The double inferior vena cava technique was used for outflow vein reconstruction. The graft portal vein was anastomosed with the stent-containing portal vein stump because it was not possible to remove the stent and the inner diameter of the portal vein stent was large enough. An aorto-hepatic jump graft was used for arterial reconstruction. The patient recovered slowly and is doing well for 6 months posttransplant. In conclusion, because stenting of the hepatic vein or portal vein can induce graft failure leading to late retransplantation, we emphasize secure vascular reconstruction to prevent endovascular stenting during LT in infants.

Recent improvement in survival outcomes and reappraisal of prognostic factors in hepatoblastoma.

BACKGROUND: Prognostic factors in hepatoblastoma need to be reevaluated considering the advances in treatment modalities. The study aimed to evaluate current outcomes of hepatoblastoma and reappraise the association of prognostic factors, including pre-treatment extent of tumor (PRETEXT) stage with annotation factors and Children's Hepatic tumors International Collaboration-Hepatoblastoma Stratification (CHIC-HS) system, with survival outcomes. METHODS: We evaluated 103 consecutive patients with hepatoblastoma retrospectively according to the treatment period based on the introduction of a liver transplantation program. RESULTS: The 5-year overall survival (OS), event-free survival (EFS), and transplant-free survival rates were 80.2%, 74.2%, and 61.8%, respectively. EFS and OS were improved significantly from 58.6% to 81.6% (P = 0.024) and from 58.6% to 90.8% (P < 0.001), respectively, in the late period (N = 74) compared with the early period (N = 29). The PRETEXT stage was significant or marginally significant for EFS and OS in the early period but not in the late period. The P, F, R, and C factors were significant for OS and EFS in the early period. However, in the late period, only the P factor was significant for OS, and the F and M factors were significant for EFS. The CHIC-HS system was significant or marginally significant for EFS in both the early and late periods; however, it was significant for OS only in the early period. CONCLUSION: Survival rates were significantly improved in children with hepatoblastoma, especially in those with advanced PRETEXT stages with positive annotation factors and in a high-risk CHIC-HS group. Prognostic factors had different clinical implications with evolved treatment modalities.

Risk Factors for Disease Behavior Evolution and Efficacy of Biologics in Reducing Progression in Pediatric Patients with Nonstricturing, Nonpenetrating Crohn's Disease at Diagnosis: A Single-Center Experience in Korea.

Background/Aims: : Recently, the treatment of Crohn's disease (CD) has changed to a treat-to-target strategy, in which disease progression is prevented with early intervention. We analyzed the long-term evolution of nonstricturing, nonpenetrating (B1) disease at diagnosis and factors related to disease evolution in pediatric CD. Methods: We retrospectively analyzed 402 patients between 2000 and 2013 who were younger than 18 years and had B1 disease at CD diagnosis. The median follow-up was 6.1 years (range, 1 to 13 years). The cumulative probabilities of developing stricturing (B2) or penetrating (B3) disease and associations between risk factors and disease behavior evolution were evaluated. Results: Among the 402 patients, 75 (18.7%) had B2 or B3 disease by the final follow-up. The cumulative probabilities of disease behavior evolution were 18.3%, 34.3%, and 50.9% at 5, 10, and 13 years, respectively. Patients whose disease progressed had an increased risk of intestinal resection (hazard ratio [HR], 3.61; 95% confidence interval [CI], 2.25 to 6.03; p<0.001). First-degree family history of inflammatory bowel disease (HR, 2.38; 95% CI, 1.07 to 5.28; p=0.032), isolated ileal involvement at diagnosis (HR, 7.55; 95% CI, 1.04 to 15.57; p=0.045), and positive anti-Saccharomyces cerevisiae antibody titers (HR, 2.10; 95% CI, 1.03 to 4.25; p=0.040) were associated with disease behavior evolution. Early treatment with biologics significantly reduced disease progression (HR, 0.46; 95% CI, 0.79 to 3.39; p=0.042). Conclusions: This study suggests that early aggressive therapy should be considered in B1 behavior pediatric CD patients with risk factors of disease evolution to improve long-term outcomes.

Interpretation of XIAP Variants of Uncertain Significance in Paediatric Patients with Refractory Crohn's Disease.

BACKGROUND AND AIMS: Mutations in XIAP can lead to the development of treatment-refractory severe paediatric Crohn's disease [CD], for which haematopoietic stem cell transplantation is the primary therapeutic option. The interpretation of variants of uncertain significance [VUSs] in XIAP needs to be scrutinized. METHODS: Targeted next-generation sequencing was performed for 33 male paediatric patients with refractory CD admitted at a tertiary referral hospital. To obtain functional data, biomolecular cell assays and supercomputing molecular dynamics simulations were performed. RESULTS: Nine unrelated male patients harboured hemizygous XIAP variants. Four known pathogenic variants and one novel pathogenic variant [p.Lys168Serfs*12] were identified in five patients, and two novel VUSs [p.Gly205del and p.Pro260Ser] and one known VUS [p.Glu350del] were identified in the remaining four. Among children with VUSs, only the subject with p.Gly205del exhibited defective NOD2 signalling. Using molecular dynamics simulation, we determined that the altered backbone torsional energy of C203 in XIAP of p.G205del was ~2 kcal/mol, suggesting loss of zinc binding in the mutant XIAP protein and poor coordination between the mutant XIAP and RIP2 proteins. Elevated auto-ubiquitination of zinc-depleted p.G205del XIAP protein resulted in XIAP protein deficiency. CONCLUSION: A high prevalence of XIAP deficiency was noted among children with refractory CD. Advanced functional studies decreased the subjectivity in the case-level interpretation of XIAP VUSs and directed consideration of haematopoietic stem cell transplantation.

Ability of Pelvic Magnetic Resonance Imaging to Predict Clinical Course of Perianal Fistula in Paediatric Crohn's Disease Patients.

BACKGROUND AND AIMS: Evidence is limited regarding clinical course and magnetic resonance imaging [MRI] features of perianal fistula [PAF] in Korean children with Crohn's disease [CD]. We investigated MRI features of PAF and associations with long-term outcomes. METHODS: We retrospectively analysed 243 patients with pelvic MRI for diagnosis of CD. Incidence of clinically evident PAF at diagnosis was determined, as were the proportions of patients with clinical failure [failure to achieve fistula healing within 1 year] and recurrence [new/recurrent PAF after fistula healing within 1 year]. Associations between outcomes and MRI features, specified in modified Van Assche index and MAGNIFI-CD, were evaluated. Associations between later development of clinically evident PAF and subclinical PAF detected on MRI at diagnosis were evaluated. RESULTS: Among 243 included patients, 108 [44.4%] and 76 [31.3%] had clinically evident and subclinical PAF at diagnosis, respectively; 66.4% of the patients with clinically evident PAF achieved fistula healing within 1 year, and 32.7% of those patients developed recurrence. Fistula length and dominant features of the tracts were associated with clinical failure, and fistula length was associated with recurrence. Clinically evident PAF developed in 17.0% of the patients without clinically evident PAF at diagnosis. We did not find statistically significant association between subclinical PAF and later development of clinically evident PAF [adjusted hazard ratio, 2.438; p = 0.15]. CONCLUSIONS: A considerable proportion of Korean paediatric CD patients had clinically evident and subclinical PAF. Fistula length and dominant feature of the tract on MRI are useful predictors of outcomes.