Winita Hardikar

Asian Pacific Association for the Study of the Liver consensus statements on the diagnosis, management and treatment of hepatitis C virus infection.

Co-chairs: GW McCaughan, Royal Prince Alfred Hospital, University of Sydney, Sydney, Australia M Omata, Tokyo University Hospital, Tokyo, Japan Faculty Members: D Amarapurkar, Bombay Hospital, Mumbai, India S Bowden, Victorian Infectious Diseases Reference Laboratories, Melbourne, Australia WC Chow, Singapore General Hospital, Singapore A Chutaputti, Pramongkutklao Hospital, Bangkok, Thailand G Dore, National Center in HIV Epidemiology and Clinical Research, Sydney, Australia E Gane, NZ Liver Transplant Unit, Auckland, New Zealand R Guan, Mount Elizabeth Medical Center, Singapore SS Hamid, The Aga Khan University, Karachi, Pakistan W Hardikar, Royal Children’s Hospital, Melbourne, Australia CK Hui, Queen Mary Hospital, University of Hong Kong, Hong Kong, China W Jafri, The Aga Khan University, Karachi, Pakistan J-D Jia, Beijing Friendship Hospital, Capital Medical University, Beijing, China M-Y Lai, National Taiwan University Hospital, Taiwan L Wei, Peking University Peoples Hospital, Beijing, China N Leung, The Chinese University of Hong Kong, Hong Kong, China T Piratvisuth, Prince of Songkla University, Hat Yai, Thailand S Sarin, GB Pant Hospital, Delhi, India J Sollano, University Santo Tomas Hospital, Manilla, Philippines R Tateishi, University of Tokyo Hospital, Tokyo Japan

NOTCH2 mutations in Alagille syndrome

Background Alagille syndrome (ALGS) is a dominant, multisystem disorder caused by mutations in the Jagged1 (JAG1) ligand in 94% of patients, and in the NOTCH2 receptor in <1%. There are only two NOTCH2 families reported to date. This study hypothesised that additional NOTCH2 mutations would be present in patients with clinical features of ALGS without a JAG1 mutation. Methods The study screened a cohort of JAG1-negative individuals with clinical features suggestive or diagnostic of ALGS for NOTCH2 mutations. Results Eight individuals with novel NOTCH2 mutations (six missense, one splicing, and one non-sense mutation) were identified. Three of these patients met classic criteria for ALGS and five patients only had a subset of features. The mutations were distributed across the extracellular (N=5) and intracellular domains (N=3) of the protein. Functional analysis of four missense, one nonsense, and one splicing mutation demonstrated decreased Notch signalling of these proteins. Subjects with NOTCH2 mutations demonstrated highly variable expressivity of the affected systems, as with JAG1 individuals. Liver involvement was universal in NOTCH2 probands and they had a similar prevalence of ophthalmologic and renal anomalies to JAG1 patients. There was a trend towards less cardiac involvement in the NOTCH2 group (60% vs 100% in JAG1). NOTCH2 (+) probands exhibited a significantly decreased penetrance of vertebral abnormalities (10%) and facial features (20%) when compared to the JAG1 (+) cohort. Conclusions This work confirms the importance of NOTCH2 as a second disease gene in ALGS and expands the repertoire of the NOTCH2 related disease phenotype.

Helicobacter pylori and recurrent abdominal pain in children

Recurrent abdominal pain is one of the most common presentations to pediatricians; yet an organic etiology can be found in only 10% of cases. Because infection with Helicobacter pylori in adults and children results in gastritis, a causative role for the organism has been postulated. To investigate this theory, we conducted a prospective case-control study in children with recurrent abdominal pain using serum H. pylori IgG antibodies measured by an enzyme immunoabsorbent assay. Age, sex, ethnicity, and socioeconomic status were adjusted in the statistical model. Five subjects (5.1%) and 14 controls (14.3%) had raised serum IgG antibodies to H. pylori (adjusted OR, 0.21; 95% confidence interval, 0.05, 0.85). The negative association between H. pylori and recurrent abdominal pain indicates that this organism is unlikely to have an important etiologic role in this disorder.

Cell‐mediated rejection results in allograft loss after liver cell transplantation

Liver cell transplantation in humans has been impeded by invariable loss of the graft. It is unclear whether graft loss is due to an immune response against donor hepatocytes. Transplantation with ABO‐matched liver cells was performed in a patient with Crigler‐Najjar type 1. After successful engraftment, there was a gradual loss of graft function. Solid‐phase enzyme immunoassay testing and cell‐complement cytotoxicity assays detecting preformed antibodies directed toward class I and/or class II human leukocyte antigen (HLA) molecules were negative. In contrast, a striking host alloresponse to either the HLA‐B39 or C7 antigen was found, suggesting that a vigorous response to a defined mismatched HLA antigen contributed to graft loss in our patient. This study provides evidence that a T‐cell–mediated immune mechanism could be responsible for human liver cell transplant graft loss. This finding warrants confirmation in future liver cell transplants in humans. Liver Transpl 14:688–694, 2008.

Evaluation of the pediatric patient for liver transplantation: 2014 practice guideline by the american association for the study of liver diseases, american society of transplantation and the north american society for pediatric gastroenterology, hepatology and nutrition

Current American Association for the Study of Liver Diseases (AASLD) liver transplant evaluation guidelines include both adult and pediatric patients. While pediatric liver transplants account for 7.8% of all liver transplants in the United States, sufficient differences between pediatric and adult patients seeking liver transplantation (LT) now require independent, yet complementary documents. This document will focus on pediatric issues at each level of the evaluation process. Disease categories suitable for referral to a pediatric LT program are similar to adults: acute liver failure, autoimmune, cholestasis, metabolic or genetic, oncologic, vascular, and infectious. However, specific etiologies and outcomes differ widely from adult patients, justifying independent pediatric guidelines. Data supporting our recommendations are based on a Medline search of the English language literature from 1997 to the present. Intended for use by physicians, these recommendations suggest preferred approaches to the diagnostic, therapeutic, and preventive aspects of care. They are intended to be flexible, in contrast to standards of care, which are inflexible policies to be followed in every case. Specific recommendations are based on relevant published information. To more fully characterize the available evidence supporting the recommendations, the AASLD Practice Guidelines Committee has adopted the classification used by the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) workgroup with minor modifications (Table 1). The classifications and recommendations are based on three categories: the source of evidence in levels I through III; the Abbreviations: ALF, acute liver failure; GRADE, Grading of Recommendation Assessment, Development, and Evaluation; HB, hepatoblastoma; HCC, hepatocellular carcinoma; HPE, hepatoportoenterostomy; LT, liver transplantation; OTPN, Organ Procurement and Transplantation Network; PFIC, progressive familial intrahepatic cholestasis; TIPS, transjugular intrahepatic portosystemic shunt. From the Department of Pediatrics, University of Pittsburgh School of Medicine; Division of Pediatric Gastroenterology, Hepatology and Nutrition, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA; Department of Pediatrics, University of Toronto; Division of Pediatric Gastroenterology, Hepatology and Nutrition, SickKids Transplant and Regenerative Medicine Center, Hospital for Sick Children, Toronto, Canada; Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Emory University School of Medicine; Children’s Healthcare of Atlanta, Atlanta, GA; Department of Pediatrics, Division of Pediatric Gastroenterology and Hepatology, Yale School of Medicine, New Haven, CT; Department of Paediatrics, University of Melbourne; Department of Gastroenterology, Royal Children’s Hospital, Melbourne, Australia; Department of Surgery, Section of Transplantation and Immunology, Yale School of Medicine, New Haven, CT; Department of Surgery, University of Pittsburgh School of Medicine; Division of Pediatric Transplantation, Hillman Center for Pediatric Transplantation, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA. Financial support to develop this practice guideline was provided by the American Association for the Study of Liver Diseases. All AASLD Practice Guidelines are updated annually. If you are viewing a Practice Guideline that is more than 12 months old, please visit www.aasld.org for an update in the material. Received April 22, 2014; accepted April 22, 2014. Address reprint requests to: Robert H. Squires, M.D., Professor of Pediatrics, University of Pittsburgh, Children’s Hospital of Pittsburgh of UPMC, 4401 Penn Ave., Pittsburgh, PA 15224. E-mail: squiresr@upmc.edu Copyright VC 2014 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27191 Potential conflict of interest: Dr. Romero received grants from Bristol-Myers Squibb.

The development of food allergy after liver transplantation

The acquisition of new food allergy after orthotopic liver transplantation is now a well described phenomenon, mainly reported in children. The etiology of this phenomenon is at present unclear, but has been ascribed by some to tacrolimus treatment. Here we report a case of liver transplant acquired food allergy (LTAFA) in a child who received a split liver graft. The case is remarkable for the absence of new food allergy in the adult recipient of the same graft. This suggests that host‐specific factors play an important role in the development of food allergy after liver transplantation, and emphasizes the predisposition that children have toward this phenomenon. Possible mechanisms underlying the development of food allergy after liver transplantation are discussed. In conclusion, tacrolimus treatment alone cannot account for LTAFA. Host factors such as the maturity of immune regulatory mechanisms are likely to play a critical role in the development of new food allergy after a liver transplant. (Liver Transpl 2005;11:326–330.)

Long-term outcome of vertically acquired and post-transfusion hepatitis C infection in children

Background and Aim:  To determine the natural history of perinatally acquired hepatitis C virus (HCV) infection, clinical and laboratory outcomes among 31 children with HCV infection were retrospectively reviewed. Fifteen children had acquired HCV by blood transfusion (BT) prior to 6 months of age and 16 had vertically acquired (VT) HCV.

Long‐term outcome of autoimmune hepatitis in children

Autoimmune hepatitis (AIH) is a chronic disease of unknown etiology, which usually progresses to cirrhosis if not diagnosed and treated promptly. Data on long‐term follow up in children with AIH are scant. The aim of this study is to assess the long‐term outcome of autoimmune hepatitis in children with respect to clinical and laboratory features at presentation.

Altered FXR signalling is associated with bile acid dysmetabolism in short bowel syndrome-associated liver disease

BACKGROUND & AIMS Despite the mortality associated with liver disease observed in patients with short bowel syndrome (SBS), mechanisms underlying the development of SBS-associated liver disease (SBS-ALD) are poorly understood. This study examines the impact of bacterially-mediated bile acid (BA) dysmetabolism on farnesoid X receptor (FXR) signalling pathways and clinical outcome in a piglet model of SBS-ALD. METHODS 4-week old piglets underwent 75% small bowel resection (SBR) or sham operation. Liver histology and hepatic inflammatory gene expression were examined. Abundance of BA biotransforming bacteria was determined and metabolomic studies detailed the alterations in BA composition of stool, portal serum and bile samples. Gene expression of intestinal and hepatic FXR target genes and small heterodimer partner (SHP) transrepression targets were assessed. RESULTS Histological evidence of SBS-ALD included liver bile duct proliferation, hepatocyte ballooning and fibrosis. Inflammatory gene expression was increased. Microbiota changes included a 10-fold decrease in Clostridium and a two-fold decrease in Bacteroides in SBS-ALD piglets. BA composition was altered and reflected a primary BA dominant composition. Intestinal and hepatic regulation of BA synthesis was characterised by a blunted intestinal FXR activation response and a failure of SHP to repress key hepatic targets. CONCLUSIONS We propose a pathological scenario in which microbial dysbiosis following SBR results in significant BA dysmetabolism and consequent outcomes including steatorrhoea, persistent diarrhoea and liver damage. Furthermore alterations in BA composition may have contributed to the observed disturbance in FXR-mediated signalling pathways. These findings provide an insight into the complex mechanisms mediating the development of liver disease in patients with SBS.

Sixty-year study of incidence of childhood ulcerative colitis finds eleven-fold increase beginning in 1990s.

Background:We sought to define the point at which a recently noted marked increase in the incidence of ulcerative colitis (UC) had occurred in children in Victoria, Australia. Methods:A 60-year retrospective review (1950-2009) of children age 16 years or less diagnosed with UC in the state’s major pediatric centers was performed. Results:In all, 342 children were diagnosed with UC (male to female ratio of 1.25:1.0, median age 10.9 years, interquartile range [IQR] 7.0, 13.2). The overall median annual incidence of UC was 0.36/105 children ⩽16 years of age (IQR 0.18, 0.66). The number of reported cases increased by 11-fold during the study period (P < 0.001). This marked increase appeared to occur from the early 1990s and has yet to plateau. Children diagnosed during the last two decades were older at diagnosis (median 10 years vs. 11.6, P < 0.0001), and had higher weight- and height-for-age z scores than those diagnosed during the first 40 years (mean weight-for-age [standard deviation] 1950−1989: −0.80 [1.56] vs. 1990–2009: −0.11 [1.17], P < 0.001; mean height-for-age 1950–1989: −0.50 [1.15] vs. 1990–2009: –0.13 [1.12], P < 0.05). More recently diagnosed children also had more extensive disease (1950–1989: 52% vs. 1990–2009: 71%, P < 0.01). Conclusions:The incidence of UC has increased markedly in Victorian children since 1990. Although some of this change may be attributable to earlier diagnosis, it is unlikely that this can provide a complete explanation for this still-increasing condition.