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Idiopathic neonatal hepatitis (INH) is a heterogeneous disease of undetermined cause. We report a retrospective histologic reevaluation of INH. Sixty patients with INH were reviewed along with 32 biliary atresia (BA) patients. Histologic findings, iron and fat deposits, giant cell transformation, portal fibrosis, and bile duct proliferation were semiquantitatively graded from 0 to 4+. Significant histologic findings were defined as > or =2+. Frequencies of patients with significant histologic findings in the INH group were compared with those of the BA group. Among the patients with significant histologic findings, those in the INH group had significantly less iron deposits (P < 0.01), portal fibrosis (P < 0.01), and bile duct proliferation (P < 0.01) than those of the BA group. A combination of significant hepatic macrovesicular steatosis and siderosis was observed in 10 INH patients but not in any BA patient (10/60 vs 0/32, P < 0.05). Without extensive treatment, the 10 INH patients all recovered, and hepatic abnormalities normalized by the age of 12 months. In conclusion, the present study showed that the recognition of hepatic siderosis is helpful to distinguish BA from INH and that in a subset of INH patients hepatic macrovesicular steatosis and siderosis occurs. [ABSTRACT FROM AUTHOR]

Choline is an essential nutrient, and its deficiency causes steatohepatitis. Dietary phosphatidylcholine (PC) is digested into lysoPC (LPC), glycerophosphocholine, and choline in the intestinal lumen and is the primary source of systemic choline. However, the major PC metabolites absorbed in the intestinal tract remain unidentified. ATP8B1 is a P4-ATPase phospholipid flippase expressed in the apical membrane of the epithelium. Here, we use intestinal epithelial cell (IEC)-specific Atp8b1-knockout (Atp8b1 IEC-KO ) mice. These mice progress to steatohepatitis by 4 weeks. Metabolomic analysis and cell-based assays show that loss of Atp8b1 in IEC causes LPC malabsorption and thereby hepatic choline deficiency. Feeding choline-supplemented diets to lactating mice achieves complete recovery from steatohepatitis in Atp8b1 IEC-KO mice. Analysis of samples from pediatric patients with ATP8B1 deficiency suggests its translational potential. This study indicates that Atp8b1 regulates hepatic choline levels through intestinal LPC absorption, encouraging the evaluation of choline supplementation therapy for steatohepatitis caused by ATP8B1 dysfunction., (© 2023. The Author(s).)

Inborn errors of the NF-κB pathways underlie various clinical phenotypes in humans. Heterozygous germline loss-of-expression and loss-of-function mutations in RELA underlie RELA haploinsufficiency, which results in TNF-dependent chronic mucocutaneous ulceration and autoimmune hematological disorders. We here report six patients from five families with additional autoinflammatory and autoimmune manifestations. These patients are heterozygous for RELA mutations, all of which are in the 3' segment of the gene and create a premature stop codon. Truncated and loss-of-function RelA proteins are expressed in the patients' cells and exert a dominant-negative effect. Enhanced expression of TLR7 and MYD88 mRNA in plasmacytoid dendritic cells (pDCs) and non-pDC myeloid cells results in enhanced TLR7-driven secretion of type I/III interferons (IFNs) and interferon-stimulated gene expression in patient-derived leukocytes. Dominant-negative mutations in RELA thus underlie a novel form of type I interferonopathy with systemic autoinflammatory and autoimmune manifestations due to excessive IFN production, probably triggered by otherwise non-pathogenic TLR ligands., (© 2023 Moriya et al.)

Background and Aims: Japan has experienced 8 waves of the coronavirus disease 2019 (COVID-19) outbreak over the past 3 years, resulting in an increasing number of deaths and incidence of severe infections. This study aimed to analyze the data from the Japanese inflammatory bowel disease (IBD) patients with COVID-19 registry (J-COSMOS) up to the eighth wave to investigate the clinical course of IBD patients with COVID-19 and factors contributing to disease severity., Methods: In this multicenter, observational, cohort study, we analyzed a cohort of 1308 IBD patients diagnosed with COVID-19, enrolled across 77 participating facilities in the J-COSMOS registry from June 2020 to December 2022. Data on age, sex, IBD (classification, treatment, and activity), and COVID-19 (symptoms, severity, and treatment) were analyzed., Results: The majority of patients (76%) were in clinical remission. According to the World Health Organization classification of COVID-19 severity, 98.4% of IBD patients had nonsevere disease, while 1.6% of patients had severe or critical disease. COVID-19 did not affect disease activity in most IBD patients. Stepwise logistic regression analysis revealed that high body mass index, and cerebrovascular disease were risk factors for severe COVID-19. Corticosteroids could affect COVID-19 severity, whereas anti-tumor necrosis factor α antibodies and thiopurines were associated with a reduced risk of severe COVID-19. No deaths were observed among IBD patients with COVID-19 registered in this cohort., Conclusion: The impact of COVID-19 on IBD disease activity and factors associated with COVID-19 severity were consistent with findings of previous reports. No deaths in Japanese patients with IBD were observed., (© 2023 The Authors.)

Background: Vedolizumab (VDZ) is a humanized monoclonal antibody that binds to α4β7 integrin expressed in T-lymphocytes and is gut selective. Few studies have evaluated the safety and efficacy of VDZ in pediatric ulcerative colitis (UC) patients, especially from Asia., Methods: A longitudinal multicenter retrospective study was conducted at 10 Japanese tertiary medical institutions. Patients aged ≤18 years old who received VDZ for UC between January 2019 and July 2021 were enrolled. Information on the clinical characteristics, prior/concomitant treatment, and safety during the observation period was collected., Results: The data obtained from 48 patients (males, n = 30; females, n = 18) were analyzed. The median age at VDZ induction was 14 (range 4-18) years old. VDZ was indicated in 73% of patients as switching from previous biologics due to primary failure, loss of response, and adverse events (AEs) and was the first biologic in 27%. Remission was achieved or maintained at weeks 14, 30, and 54 in 79.2%, 75.0%, and 65.8% of patients, respectively. There were no significant differences between the number of previous biologics exposures and VDZ effectiveness. The hematocrit, serum albumin concentrations, and erythrocyte sedimentation rate (ESR) at baseline differed significantly by VDZ effectiveness. Nine AEs, including infusion reaction, were noted in seven (14.3%) patients. There were no severe AEs related to VDZ administration., Conclusions: VDZ was safe and effective in children with UC. The hematocrit, albumin, and ESR at VDZ initiation might be predictors for VDZ effectiveness. VDZ may be an important option for pediatric patients and can be used as an alternative to immunomodulators., (© 2023 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Mothers of children with chronic hepatitis C virus (HCV) infection experience anxiety about the health of their children. In this study we assessed an impact of treating children with chronic HCV infection on the psychological burden of their mothers. This was a multicenter, questionnaire survey conducted at six institutions in Japan. A newly-developed questionnaire for this study was used to assess changes in the mothers' various concerns regarding HCV infection and thoughts about their child's HCV infection. Responses at the time of diagnosis and at the time of the survey were compared between mothers of children who had received treatment and those without treatment. Responses were received from 36 of 37 eligible mothers (11 and 25, non-treatment and treatment groups, respectively). All children in treatment group had successfully eliminated the virus. Mothers in both groups were psychologically stressed in various ways, including concern about their child's health in the present and future at the time of diagnosis, concern about school, employment, and marriage, concern about the behavior of others towards them and infecting others with HCV, and feelings of guilt regarding their child. These concerns were significantly lower in the present compared to at the time of diagnosis in treatment group, and the rate of decrease was significantly higher in treatment group compared to non-treatment group. Successful treatment greatly reduced mothers' concerns about their children's HCV infection, indicating that treatment during childhood is beneficial from the perspective of the mothers' psychological burden., (© 2022. The Author(s).)

Background: The spread of coronavirus disease 2019 (COVID-19) had a major impact on the health of people worldwide. The clinical background and clinical course of inflammatory bowel disease (IBD) among Japanese patients with COVID-19 remains unclear., Methods: This study is an observational cohort of Japanese IBD patients diagnosed with COVID-19. Data on age, sex, IBD (classification, treatment, and activity), COVID-19 symptoms and severity, and treatment of COVID-19 were analyzed., Results: From 72 participating facilities in Japan, 187 patients were registered from June 2020 to October 2021. The estimated incidence of COVID19 in Japanese IBD patients was 0.61%. The majority of IBD patients with COVID-19 (73%) were in clinical remission. According to the WHO classification regarding COVID-19 severity, 93% (172/184) of IBD patients had non-severe episodes, while 7% (12/184) were severe cases including serious conditions. 90.9% (165/187) of IBD patients with COVID-19 had no change in IBD disease activity. A logistic regression analysis stepwise method revealed that older age, higher body mass index (BMI), and steroid use were independent risk factors for COVID-19 severity. Six of nine patients who had COVID-19 after vaccination were receiving anti-tumor necrosis factor (TNF)-α antibodies., Conclusion: Age, BMI and steroid use were associated with COVID-19 severity in Japanese IBD patients., (© 2022. The Author(s).)

Background: Causes of early-onset inflammatory bowel disease (IBD) vary, and primary immunodeficiency diseases (PIDs) are associated with early-onset IBD as monogenic disorders., Aim: This review investigates the prevalence, clinical manifestation, genetic profile, and treatment of patients with early-onset IBD in Southeast and East Asia., Methods: A systemic review of articles reporting PID patients associated with early-onset IBD in Southeast and East Asia was conducted., Results: The prevalence of PID associated with IBD was higher than that reported in western nations, and the frequency of patients with bloody stools as an early symptom was relatively higher in monogenic diseases. A total 13 (12.0%) of 108 patients with early-onset IBD were diagnosed as PID by exome sequencing and targeted gene panel analysis in Japan, including four patients with XIAP , three with IL10RA , and two or one patient with other gene mutations. In addition, ten patients were reported as having IL-10 receptor alpha (IL-10RA) deficiency in China and Hong Kong. Allogeneic hematopoietic stem cell transplantation was performed in patients with X-linked inhibitor of apoptosis deficiency, IL-10RA deficiency, or other PID as a curative treatment, and the preferable outcome of reduced-intensity conditioning and complete resolution of IBD symptoms and dysbiosis were achieved., Conclusion: Comprehensive molecular diagnosis has been widely applied to screen for patients with PID-associated IBD in Southeast and East Asia. These results contributed to the awareness of monogenic PID in early-onset IBD patients and their differences in clinical manifestations and genetic profiles compared to the patients in western counties., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a past collaboration with the authors YS, TU, and TS., (Copyright © 2022 Sasahara, Uchida, Suzuki and Abukawa.)

Background: The first guidelines for care of pregnant women carrying the hepatitis C virus (HCV) and their infants were published in 2005 in Japan. Since then, evidence has gradually accumulated worldwide regarding the natural course and treatment of this condition and, especially in recent years, treatment for chronic hepatitis C in adult patients has made great progress. However, the clinical practice policy for children has not been standardized, and new clinical practice guidelines for children with mother-to-child (MTC) transmitted HCV infection have become necessary., Methods: In the development of the current guideline, we requested cooperation from The Japanese Society for Pediatric Infectious Diseases, The Japan Society of Hepatology, and the Japan Society of Obstetrics and Gynecology. The committee members were recommended and approved by each society to participate in developing the guidelines. The guideline was also created in accordance with the Minds Guide for Practice Guideline Development. The statements were prepared by consensus-building using the Delphi method, based on the comprehensively searched academic papers and guidelines. These articles were retrieved through searching the PubMed, Cochrane Library, and the Igaku Chuo Zasshi databases., Results: Eight clinical questions (CQs) with clinical statements were developed regarding etiology (CQs 1-3), diagnosis (CQs 4 and 5), and treatment (two CQs 6 and 7). In each statement, the consensus rate, evidence level, and recommendation level were determined., Conclusion: The guidelines will be helpful in the management of children with hepatitis C MTC transmission., (© 2022 Japan Pediatric Society.)

Background: Pediatric ulcerative colitis (UC) is more challenging to treat than adult UC. Qing-Dai therapy is effective in adults but reports of its efficacy in children are unavailable. We conducted a questionnaire survey on Qing-Dai use among pediatric patients with UC in Japan to determine its efficacy and safety., Methods: Questionnaires were sent to 31 high-volume centers treating pediatric patients with inflammatory bowel disease. The number of patients using Qing-Dai, short-term and long-term effects, and adverse events were assessed. A systematic review of studies on the efficacy and safety of Qing-Dai usage for UC was also performed., Results: Overall, 29/31 facilities (93.5%) responded, Qing-Dai was used in 107 patients with UC, and 84/107 patients (78.5%) initiated treatment. Within 6 months, 81/101 (80.2%) patients had clinical remission, while 59/92 (64.1%) patients had no relapse and 29/92 (31.5%) experienced only one to two relapses yearly. Eighty-seven percent of the patients underwent regular follow ups for adverse events, among whom one patient was diagnosed with pulmonary arterial hypertension (PAH), five with enteritis, and one with headache. In the systematic review, the clinical remission rate was 50-80%, and PAH was observed in 14 of 1,158 patients (1.2%)., Conclusions: Qing-Dai is highly effective in treating pediatric UC. However, Qing-Dai should be administered with caution as it may cause adverse events such as PAH., (© 2021 Japan Pediatric Society.)

Background: The mortality and risk factors of severe disease and death due to arterial and venous thromboembolism (ATE and VTE, respectively) in patients with inflammatory bowel disease (IBD) remain unclear, especially in Asia., Aims: This study aimed to reveal the mortality and risk factors of TE in IBD patients in Japan., Methods: In the primary surveillance, responses to questionnaires regarding the number of cases of severe TE and TE-associated death in IBD patients in a span of over the past 10 years were obtained from 32 institutions in Japan. In the secondary surveillance, detailed data about IBD patients with TE were collected. The characteristics, laboratory data, therapy status, and situation at the time of TE development were retrospectively collected, and the data were compared between the patients with and without severe TE and TE-associated death., Results: The incidence of TE was 1.89% among 31,940 IBD patients. The frequencies of severe TE and TE-associated mortality were 10.7% and 1.0% among the total IBD and TE with IBD patients, respectively. The only risk factor for severe ATE and ATE-associated death was ischemic heart disease. The independent risk factors for severe VTE and VTE-associated death were age (≤ 45 years old), the site of VTE, and disease severity, with anti-TNF therapy as a potential negative risk factor. Patients with severe VTE had a high risk of developing persistent VTE and sequelae., Conclusion: Unlike ATE, the incidence of VTE was comparable in Asian and Western countries. Therapeutic and prophylactic strategies for managing IBD-associated TE in Asia are urgently needed., (© 2021. The Author(s).)

Background and Aim: The implementation rates of pediatric gastrointestinal endoscopy are increasing with advancements in the devices used and pediatricians' skills. As part of the Japan Pediatric Endoscopy Study Group, we aimed to investigate the rates of pediatric gastrointestinal endoscopy use and the associated adverse events through a nationwide survey., Methods: A questionnaire was sent to 630 institutions in Japan. The numbers of pediatric gastrointestinal endoscopy cases and adverse events occurring during endoscopy, from April 2011 to March 2016, were investigated., Results: Responses were obtained from 445 facilities. The total number of pediatric gastrointestinal endoscopies was 37 447 and that of endoscopic examinations was 32 219 (86.0%), with esophagogastroduodenoscopy accounting for 18 484 cases; ileal colonoscopy, 11 936; endoscopic retrograde cholangiopancreatography, 389; wireless capsule endoscopy, 897; and balloon-assisted enteroscopy, 513. The number of endoscopic treatments was 5228, followed by balloon dilatation (1703), foreign body removal (989), and polypectomy (822); 201 adverse events (0.54%) occurred, 79 of which presented during endoscopic examination (0.25%). Eight serious perforations were noted in 0.0054% and 0.025% of those undergoing esophagogastroduodenoscopy and colonoscopy, respectively. Overall, 122 adverse events (2.33%) occurred in association with endoscopic treatment. One case of cardiopulmonary arrest occurred because of accidental extubation. However, no deaths occurred., Conclusion: Endoscopic examinations had a slightly higher adverse event rate, because of an increase in endoscopic retrograde cholangiopancreatography and small intestine enteroscopy, than that reported in previous studies, but the adverse event rate of endoscopic treatment did not increase., (© 2020 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Adenosine triphosphatase phospholipid transporting 8B1 (ATP8B1) deficiency, an ultrarare autosomal recessive liver disease, includes severe and mild clinical forms, referred to as progressive familial intrahepatic cholestasis type 1 (PFIC1) and benign recurrent intrahepatic cholestasis type 1 (BRIC1), respectively. There is currently no practical method for determining PFIC1 or BRIC1 at an early disease course phase. Herein, we assessed the feasibility of developing a diagnostic method for PFIC1 and BRIC1. A nationwide Japanese survey conducted since 2015 identified 25 patients with cholestasis with ATP8B1 mutations, 15 of whom agreed to participate in the study. Patients were divided for analysis into PFIC1 (n = 10) or BRIC1 (n = 5) based on their disease course. An in vitro mutagenesis assay to evaluate pathogenicity of ATP8B1 mutations suggested that residual ATP8B1 function in the patients could be used to identify clinical course. To assess their ATP8B1 function more simply, human peripheral blood monocyte-derived macrophages (HMDMs) were prepared from each patient and elicited into a subset of alternatively activated macrophages (M2c) by interleukin-10 (IL-10). This was based on our previous finding that ATP8B1 contributes to polarization of HMDMs into M2c. Flow cytometric analysis showed that expression of M2c-related surface markers cluster of differentiation (CD)14 and CD163 were 2.3-fold and 2.1-fold lower (95% confidence interval, 2.0-2.5 for CD14 and 1.7-2.4 for CD163), respectively, in patients with IL-10-treated HMDMs from PFIC1 compared with BRIC1. Conclusion : CD14 and CD163 expression levels in IL-10-treated HMDMs may facilitate diagnosis of PFIC1 or BRIC1 in patients with ATP8B1 deficiency., (© 2020 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of the American Association for the Study of Liver Diseases.)

Objectives: Causes of early-onset refractory diarrhea include exudative diarrhea associated with very early-onset inflammatory bowel diseases, osmotic or secretory diarrhea, and protein-losing enteropathy. Monogenic disorders are included in these diseases, yet a comprehensive genetic analysis has not been fully established., Methods: We established targeted gene panels covering all responsible genes for early-onset diarrhea. In total, 108 patients from 15 institutions were enrolled in this study. We collected clinical data from all patients. Seventy-three patients with exudative diarrhea, 4 with osmotic or secretory diarrhea and 8 with protein-losing enteropathy were subjected to genetic analysis., Results: A total of 15 out of the 108 enrolled patients (13.9%) were identified as monogenic. We identified 1 patient with RELA, 2 with TNFAIP3, 1 with CTLA4, 1 with SLCO2A1, 4 with XIAP, 3 with IL10RA, 1 with HPS1, 1 with FOXP3, and 1 with CYBB gene mutations. We also identified 1 patient with NFKB2 and 1 with TERT mutations from the gene panel for primary immunodeficiency syndromes. The patient with refractory diarrhea caused by heterozygous truncated RelA protein expression is the first case identified worldwide, and functional analysis revealed that the mutation affected nuclear factor kappa B signaling. Genotypes were significantly associated with the clinical and pathological findings in each patient., Conclusions: We identified variable monogenic diseases in the patients and found that genes responsible for primary immunodeficiency diseases were frequently involved in molecular pathogenesis. Comprehensive genetic analysis was useful for accurate molecular diagnosis, understanding of underlying pathogenesis, and selecting the optimal treatment for patients with early-onset refractory diarrhea.An infographic for this article is available at: http://links.lww.com/MPG/B853.

Smoking is a risk factor for adult-onset Crohn's disease (CD). Although passive smoking from family members is a major concern, especially in pediatric CD, the number of existing epidemiological studies is limited. This multicenter case-control study aimed to assess the effects of familial smoking on pediatric CD. We examined 22 pediatric CD cases and 135 controls. The subjects' mothers were given a self-administered questionnaire about family smoking before disease onset in the CD group or the corresponding period in the control group. Univariable logistic regression model was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), whereas dose-response relationship analyses were performed for more in-depth evaluations. Univariable analyses indicated that passive smoking from the mother (OR, 2.09; 95% CI, 0.61-7.10) was not a significant, but a candidate risk factor for developing pediatric CD. In contrast, the dose-response relationship analyses revealed that passive smoking from the mother (OR, 1.17; 95% CI, 1.04-1.31) was significantly associated with pediatric CD. Therefore, passive smoking from the mother may be predominantly associated with the development of pediatric CD. Further follow-up studies comprising environmental measurements of passive smoking exposure doses and genetic factors interaction analysis are necessary.

Background: To evaluate the role of colonoscopy in infants and young children and clarify the distribution of colonoscopy-requiring diseases in this age group., Methods: Cohorts of colonoscopies performed at three children's hospitals in Japan between April 2011 and March 2016 including infants and children younger than six years of age were retrospectively reviewed., Results: In total, 453 colonoscopies were performed in 276 infants and young children. Of these 275 (60.8%) were for diagnostic purposes, 177 (39.2%) were performed as follow-up, and one case was performed for treatment. The median patient age at the time of diagnostic colonoscopy was 2.49 years, and there was a male-to-female ratio of 1.72:1. Abnormal macroscopic and/or histopathological findings were noted in 212 (77.1%) cases. Of these, definite diagnoses were established for the presence of eosinophilic gastrointestinal disorders (EGIDs), inflammatory bowel disease (IBD), and polyp/polyposis in 23, 18.5, and 14% of patients, respectively. Among 51 IBD cases, ulcerative colitis, Crohn's disease, and IBD-unclassified were identified in 47.1, 33.3, and 7.8%, retrospectively via endoscopic examination. Of these, 11 (22%) were eventually diagnosed with monogenic diseases via genetic testing. Of those with rectal bleeding, EGIDs, polyps/polyposis, and IBD were found in 27, 19, and 18%, retrospectively. There were significantly more cases of EGIDs and fewer ones of IBD and polyps/polyposis in patients with rectal bleeding younger than two years of age. Furthermore, 68% of all follow-up colonoscopies were performed in children with IBD. There were no serious complications in our study cohort., Conclusion: We determined the role of colonoscopy in infants and young children. Diseases diagnosed using colonoscopy in this age group included IBD, EGIDs, and polyps/polyposis. The increasing trend of patients with IBD and EGIDs worldwide means that the role of colonoscopy in infants and younger children will be more important in the future.

Background: Chronic enteropathy associated with SLCO2A1 gene (CEAS) is a hereditary disease caused by mutations in the SLCO2A1 gene and characterized by multiple small intestinal ulcers of nonspecific histology. SLCO2A1 is also a causal gene of primary hypertrophic osteoarthropathy (PHO). However, little is known about the clinical features of CEAS or PHO., Methods: Sixty-five Japanese patients recruited by a nationwide survey of CEAS during 2012-2016 were enrolled in this present study. We reviewed the clinical information of the genetically confirmed CEAS patients., Results: We identified recessive SLCO2A1 mutations at 11 sites in 46 patients. Among the 46 patients genetically confirmed as CEAS, 13 were men and 33 were women. The median age at disease onset was 16.5 years, and parental consanguinity was present in 13 patients (28%). Anemia was present in 45 patients (98%), while a single patient experienced gross hematochezia. All patients showed relatively low inflammatory markers in blood tests (median CRP 0.20 mg/dl). The most frequently involved gastrointestinal site was the ileum (98%), although no patient had mucosal injuries in the terminal ileum. Mild digital clubbing or periostosis was found in 13 patients (28%), with five male patients fulfilling the major diagnostic criteria of PHO., Conclusions: The clinical features of CEAS are distinct from those of Crohn's disease. Genetic analysis of the SLCO2A1 gene is therefore recommended in patients clinically suspected of having CEAS.

Progressive familial intrahepatic cholestasis type 1 (PFIC1), a rare inherited recessive disease resulting from a genetic deficiency in ATP8B1, progresses to liver failure. Because of the difficulty of discriminating PFIC1 from other subtypes of PFIC based on its clinical and histological features and genome sequencing, an alternative method for diagnosing PFIC1 is desirable. Herein, we analyzed human peripheral blood monocyte-derived macrophages (HMDM) and found predominant expression of ATP8B1 in interleukin-10 (IL-10)-induced M2c, a subset of alternatively activated macrophages. SiRNA-mediated depletion of ATP8B1 in IL-10-treated HMDM markedly suppressed the expression of M2c-related surface markers and increased the side scatter (SSC) of M2c, likely via impairment of the IL-10/STAT3 signal transduction pathway. These phenotypic features were confirmed in IL-10-treated HMDM from four PFIC1 patients with disease-causing mutations in both alleles, but not in those from four patients with other subtypes of PFIC. This method identified three PFIC1 patients in a group of PFIC patients undiagnosed by genome sequencing, an identical diagnostic outcome to that achieved by analysis of liver specimens and in vitro mutagenesis studies. In conclusion, ATP8B1 deficiency caused incomplete polarization of HMDM into M2c. Phenotypic analysis of M2c helps to identify PFIC1 patients with no apparent disease-causing mutations in ATP8B1., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: It is necessary to evaluate the natural history of children with hepatitis B virus (HBV) infection in each country to consider their long-term management., Methods: A multi-center observational study of children with chronic HBV infection who were diagnosed at age ≤15 years was carried out in 18 hospitals in Japan., Results: We reviewed children with HBV infection including 381 with mother-to-child transmission (MTCT) and 154 with horizontal transmission, genotype C being the most prevalent virus genotype (83%). Children with horizontal transmission were more frequently infected with HBV genotype A or B and more likely to receive interferon therapy than those infected by MTCT. The HBeAg seroconversion rate at 15 years of age was 42% in the MTCT group and 38% in the horizontal group. It was lower in children with genotype C infection than in those infected with other genotypes (33 versus 45%). Hepatitis developed at any age but before 4 years of age the incidence was high in the horizontal group. At 3 years after the onset of the hepatitis, 26% of children with MTCT and 30% of those with horizontal transmission became inactive carriers. The incidences of hepatocellular carcinoma (HCC) at 30 years of age were 6% in the MTCT group and 11% in the horizontal group., Conclusions: Patients with childhood-onset HBV infection with MTCT and horizontal transmission developed hepatitis and seroconverted to anti-HBe at any age and had a lifetime risk of developing HCC.

We performed a Japanese nationwide survey of pediatric-onset chronic nonspecific multiple ulcers of the small intestine between January 2000 and July 2013 in 176 institutions of pediatric surgery or pediatric gastroenterology and clarified the clinical features associated with genetic abnormalities in the Solute Carrier Organic Anion Transporter Family, Member 2A1 (SLCO2A1) gene. A total of 4 cases (3 girls and 1 boy) were diagnosed in this series, which had to be differentiated from Crohn disease, Behçet disease, tuberculosis, or drug-induced enteropathy. Clinical symptoms appeared in infants and accurate diagnosis required several years. Medical therapies for inflammatory bowel disease were administered in all patients; however, 2 of the 4 patients had mutation in the SLCO2A1 gene which are responsible for primary hypertrophic osteoarthopathy, and underwent strictureplasty or ileal resection after long-term follow-up. Pediatric gastroenterologists should include this new entity in the differential diagnosis of small intestinal ulcers and inflammatory bowel disease.

Purpose: Pediatric inflammatory bowel disease (IBD) is a heterogeneous disorder caused by multiple factors. Although genetic and immunological analyses are required for a definitive diagnosis, no reports of a comprehensive genetic study of a Japanese population are available., Methods: In total, 35 Japanese patients <16 years of age suffering from IBD, including 27 patients aged <6 years with very early-onset IBD, were enrolled in this multicenter study. Exome and targeted gene panel sequencing was performed for all patients. Mutations in genes responsible for primary immunodeficiency diseases (PID) and clinical and immunological parameters were evaluated according to disease type., Results: We identified monogenic mutations in 5 of the 35 patients (14.3 %). We identified compound heterozygous and homozygous splice-site mutations in interleukin-10 receptor A (IL-10RA) in two patients, nonsense mutations in X-linked inhibitor of apoptosis protein (XIAP) in two patients, and a missense mutation in cytochrome b beta chain in one patient. Using assays for protein expression levels, IL-10 signaling, and cytokine production, we confirmed that the mutations resulted in loss of function. For each patient, genotype was significantly associated with clinical findings. We successfully treated a patient with a XIAP mutation by allogeneic cord blood hematopoietic stem cell transplantation, and his symptoms were ameliorated completely., Conclusions: Targeted sequencing and immunological analysis are useful for screening monogenic disorders and selecting curative therapies in pediatric patients with IBD. The genes responsible for PID are frequently involved in pediatric IBD and play critical roles in normal immune homeostasis in the gastrointestinal tract.