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Paulina B, Kuczkowska J, Areshchanka Y, Banach W, Rzepka J, Kudliński B, Rzepka R. Acute Liver Failure During Early Pregnancy-Case Report and Review of Literature. J Clin Med 2025; 14:2028. [PMID: 40142836 PMCID: PMC11942626 DOI: 10.3390/jcm14062028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2025] [Revised: 03/07/2025] [Accepted: 03/14/2025] [Indexed: 03/28/2025] Open
Abstract
Background/Objectives: This article presents the case of a 31-year-old primigravida who experienced acute liver failure in the 23rd week of pregnancy, along with a review of the literature on this rare condition during pregnancy. The purpose of this publication is to highlight the diagnostic and therapeutic challenges associated with acute liver failure in pregnant women. Methods: The patient presented with jaundice, pruritus, and dark-colored urine. Laboratory tests revealed a significant increase in aminotransferase, bilirubin, and bile acid levels, suggesting liver problems; however, due to the patient's rapidly deteriorating condition and test results, autoimmune hepatitis was considered. Viral infections and other causes of liver damage were excluded. No clear diagnosis was established. The patient was administered ursodeoxycholic acid and due to her worsening condition, a cesarean section was performed at 23 weeks of gestation. After delivery, the patient's condition improved, although she did experience cardiac arrest during hospitalization. The patient was discharged with a diagnosis of acute liver failure in the course of an overlap syndrome of autoimmune hepatitis and primary cholangitis or intrahepatic cholestasis of pregnancy. No abnormalities were noted during a follow-up visit 6 weeks after delivery. Despite a detailed case analysis, a final diagnosis was not established, which complicates planning for future pregnancies. Discussion: Several liver conditions can occur during pregnancy, including intrahepatic cholestasis of pregnancy, primary biliary cholangitis, and autoimmune hepatitis. Diagnosing these conditions can be challenging due to overlapping symptoms and metabolic and immunological adaptations during pregnancy that can affect the course of liver diseases. Rapid intervention is crucial to protect the health of both the mother and the fetus. Conclusions: In summary, this article aims to increase awareness of the complexities surrounding acute liver failure during pregnancy, highlighting the diagnostic challenges and importance of prompt medical intervention for the well-being of both the mother and the child. This paper aims to provide a comprehensive overview of the complexities surrounding acute liver failure during pregnancy, aiming to improve the understanding, diagnosis, and management of this condition.
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Affiliation(s)
- Banach Paulina
- Department of Gynecology and Obstetrics, Collegium Medicum, University of Zielona Góra, 65417 Zielona Góra, Poland; (B.P.); (J.K.); (Y.A.)
| | - Justyna Kuczkowska
- Department of Gynecology and Obstetrics, Collegium Medicum, University of Zielona Góra, 65417 Zielona Góra, Poland; (B.P.); (J.K.); (Y.A.)
| | - Yulia Areshchanka
- Department of Gynecology and Obstetrics, Collegium Medicum, University of Zielona Góra, 65417 Zielona Góra, Poland; (B.P.); (J.K.); (Y.A.)
| | - Weronika Banach
- Poznan University of Medical Sciences, 61701 Poznań, Poland;
| | - Jakub Rzepka
- Poznan University of Medical Sciences, 61701 Poznań, Poland;
| | - Bartosz Kudliński
- Department of Anesthesiology, Intensive Care and Emergency Medicine, Collegium Medicum, University of Zielona Góra, 65417 Zielona Góra, Poland;
| | - Rafał Rzepka
- Department of Gynecology and Obstetrics, Collegium Medicum, University of Zielona Góra, 65417 Zielona Góra, Poland; (B.P.); (J.K.); (Y.A.)
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Mercado LA, Gil-Lopez F, Chirila RM, Harnois DM. Autoimmune Hepatitis: A Diagnostic and Therapeutic Overview. Diagnostics (Basel) 2024; 14:382. [PMID: 38396421 PMCID: PMC10887775 DOI: 10.3390/diagnostics14040382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 02/02/2024] [Accepted: 02/06/2024] [Indexed: 02/25/2024] Open
Abstract
Autoimmune hepatitis is an immune-mediated inflammatory condition of the liver of undetermined cause that affects both sexes, all ages, races, and ethnicities. Its clinical presentation can be very broad, from having an asymptomatic and silent course to presenting as acute hepatitis, cirrhosis, and acute liver failure potentially requiring liver transplantation. The diagnosis is based on histological abnormalities (interface hepatitis), characteristic clinical and laboratory findings (increased aspartate aminotransferase, alanine aminotransferase, and serum IgG concentration), and the presence of one or more characteristic autoantibodies. The large heterogeneity of these clinical, biochemical, and histological findings can sometimes make a timely and proper diagnosis a difficult task. Treatment seeks to achieve remission of the disease and prevent further progression of liver disease. First-line therapy includes high-dose corticosteroids, which are later tapered to decrease side effects, and azathioprine. In the presence of azathioprine intolerance or a poor response to the standard of care, second-line therapy needs to be considered, including mycophenolate mofetil. AIH remains a diagnostic and therapeutic challenge, and a further understanding of the pathophysiological pathways of the disease and the implementation of randomized controlled trials are needed.
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Affiliation(s)
- Lydia A. Mercado
- Department of Liver Transplant, Mayo Clinic Florida, Jacksonville, FL 32224, USA
| | - Fernando Gil-Lopez
- Department of Liver Transplant, Mayo Clinic Florida, Jacksonville, FL 32224, USA
| | - Razvan M. Chirila
- Department of General Internal Medicine, Mayo Clinic Florida, Jacksonville, FL 32224, USA;
| | - Denise M. Harnois
- Department of Liver Transplant, Mayo Clinic Florida, Jacksonville, FL 32224, USA
- Department of Gastroenterology and Hepatology, Mayo Clinic Florida, Jacksonville, FL 32224, USA
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3
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KASL clinical practice guidelines for management of autoimmune hepatitis 2022. Clin Mol Hepatol 2023; 29:542-592. [PMID: 37137334 PMCID: PMC10366804 DOI: 10.3350/cmh.2023.0087] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 03/27/2023] [Accepted: 04/03/2023] [Indexed: 05/05/2023] Open
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Vimalesvaran S, Samyn M, Dhawan A. Liver disease in adolescents. Arch Dis Child 2023; 108:427-432. [PMID: 36167480 DOI: 10.1136/archdischild-2021-323647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 09/19/2022] [Indexed: 11/04/2022]
Abstract
In this article, we discuss common liver diseases in the adolescent population. We describe the initial evaluation of an adolescent presenting with new-onset liver enzyme abnormalities, based on the clinical history and physical examination. The management approach to the adolescent with liver disease is exemplified, including monitoring for adherence, risk-taking behaviours and focusing on psychosocial aspects of their care. Finally, we highlight the challenges of caring for the adolescent patient and the importance of addressing not only the liver disease but, more importantly, the holistic approach towards their management.
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Affiliation(s)
- Sunitha Vimalesvaran
- Paediatric Liver, Gastroenterology and Nutrition Centre, King's College Hospital NHS Foundation Trust, London, UK
| | - Marianne Samyn
- Paediatric Liver, Gastroenterology and Nutrition Centre, King's College Hospital NHS Foundation Trust, London, UK
| | - Anil Dhawan
- Paediatric Liver, Gastroenterology and Nutrition Centre, King's College Hospital NHS Foundation Trust, London, UK
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5
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Khartade PB, Taksande A, Meshram R, Uke P. An Uncommon Presentation of Autoimmune Hepatitis in a Child With Thalassemia Trait. Cureus 2023; 15:e38964. [PMID: 37313112 PMCID: PMC10259484 DOI: 10.7759/cureus.38964] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Accepted: 05/13/2023] [Indexed: 06/15/2023] Open
Abstract
Autoimmune hepatitis (AIH) is quite rare in children. AIH is classified into two types based on the presence of autoantibodies: type 1 and type 2. The presentation of AIH varies, ranging from asymptomatic to acute or chronic hepatitis and occasionally fulminant liver failure. It can present at any age. In 20% of AIH cases, other autoimmune disorders might be present, such as diabetes mellitus and arthritis. A high index of suspicion is required for the early diagnosis of this condition. Pediatricians should consider the possibility of AIH in patients with jaundice once common causes are ruled out. The diagnosis is done on the basis of the presence of typical autoantibody titer, liver biopsy findings, and response to immunosuppressive medications. Some AIH patients may not respond to immunosuppressive therapy and may need a liver transplant. We present a case of a 12-year-old male child with thalassemia trait who was diagnosed with AIH.
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Affiliation(s)
| | - Amar Taksande
- Paediatrics, Jawaharlal Nehru Medical College, Sawangi Meghe, Wardha, IND
| | - Revat Meshram
- Paediatrics, Jawaharlal Nehru Medical College, Sawangi Meghe, Wardha, IND
| | - Punam Uke
- Paediatrics, Jawaharlal Nehru Medical College, Sawangi Meghe, Wardha, IND
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Subramanian K, Paul S, Libby A, Patterson J, Arterbery A, Knight J, Castaldi C, Wang G, Avitzur Y, Martinez M, Lobritto S, Deng Y, Geliang G, Kroemer A, Fishbein T, Mason A, Dominguez-Villar M, Mariappan M, Ekong UD. HERV1-env Induces Unfolded Protein Response Activation in Autoimmune Liver Disease: A Potential Mechanism for Regulatory T Cell Dysfunction. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2023; 210:732-744. [PMID: 36722941 PMCID: PMC10691554 DOI: 10.4049/jimmunol.2100186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 01/12/2023] [Indexed: 02/02/2023]
Abstract
Regulatory T cells (Tregs) are not terminally differentiated but can acquire effector properties. Here we report an increased expression of human endogenous retrovirus 1 (HERV1-env) proteins in Tregs of patients with de novo autoimmune hepatitis and autoimmune hepatitis, which induces endoplasmic reticulum (ER) stress. HERV1-env-triggered ER stress activates all three branches (IRE1, ATF6, and PERK) of the unfolded protein response (UPR). Our coimmunoprecipitation studies show an interaction between HERV1-env proteins and the ATF6 branch of the UPR. The activated form of ATF6α activates the expression of RORC and STAT3 by binding to promoter sequences and induces IL-17A production. Silencing of HERV1-env results in recovery of Treg suppressive function. These findings identify ER stress and UPR activation as key factors driving Treg plasticity (species: human).
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Affiliation(s)
- Kumar Subramanian
- Department of Surgery, Georgetown University School of Medicine, Washington, DC, USA
| | - Saikat Paul
- Department of Surgery, Georgetown University School of Medicine, Washington, DC, USA
| | - Andrew Libby
- Dept of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, DC
| | - Jordan Patterson
- Division of Gastroenterology, University of Alberta, Edmonton, AB, Canada
| | - Adam Arterbery
- Pediatric Gastroenterology and Hepatology, Yale University, New Haven, CT, USA
| | - James Knight
- Yale Center for Genome Analysis, Yale School of Medicine, New Haven, CT, USA
| | | | - Guilin Wang
- Yale Center for Genome Analysis, Yale School of Medicine, New Haven, CT, USA
| | - Yaron Avitzur
- Division of Gastroenterology, Hepatology, and Nutrition, Hospital for Sick Children, Toronto, ON, Canada
| | - Mercedes Martinez
- Pediatric Gastroenterology, Hepatology, and Nutrition, Columbia University, New York, NY, USA
| | - Steve Lobritto
- Pediatric Gastroenterology, Hepatology, and Nutrition, Columbia University, New York, NY, USA
| | - Yanhong Deng
- Yale Center for Analytical Sciences, New Haven, CT, USA
| | - Gan Geliang
- Yale Center for Analytical Sciences, New Haven, CT, USA
| | - Alexander Kroemer
- Department of Surgery, Georgetown University School of Medicine, Washington, DC, USA
| | - Thomas Fishbein
- Department of Surgery, Georgetown University School of Medicine, Washington, DC, USA
| | - Andrew Mason
- Division of Gastroenterology, University of Alberta, Edmonton, AB, Canada
| | | | | | - Udeme D. Ekong
- Pediatric Gastroenterology and Hepatology, Yale University, New Haven, CT, USA
- Department of Surgery, Georgetown University School of Medicine, Washington, DC, USA
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Ozdogan E, Arikan C. Liver fibrosis in children: a comprehensive review of mechanisms, diagnosis, and therapy. Clin Exp Pediatr 2023; 66:110-124. [PMID: 36550776 PMCID: PMC9989719 DOI: 10.3345/cep.2022.00367] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Accepted: 09/14/2022] [Indexed: 12/23/2022] Open
Abstract
Chronic liver disease incidence is increasing among children worldwide due to a multitude of epidemiological changes. Most of these chronic insults to the pediatric liver progress to fibrosis and cirrhosis to different degrees. Liver and immune physiology differs significantly in children from adults. Because most of pediatric liver diseases have no definitive therapy, a better understanding of population and disease-specific fibrogenesis is mandatory. Furthermore, fibrosis development has prognostic significance and often guide treatment. Evaluation of liver fibrosis continues to rely on the gold-standard liver biopsy. However, many high-quality studies put forward the high diagnostic accuracy of numerous diagnostic modalities in this setting. Herein, we summarize and discuss the recent literature on fibrogenesis with an emphasis on pediatric physiology along with a detailed outline of disease-specific signatures, noninvasive diagnostic modalities, and the potential for antifibrotic therapies.
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Affiliation(s)
- Elif Ozdogan
- Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA
| | - Cigdem Arikan
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Koc University School of Medicine, Istanbul, Turkey
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Xi D, Lin H, Shah AA. Overview of autoimmune liver disease: Prevalence, risk factors, and role of autoantibodies. Clin Liver Dis (Hoboken) 2022; 20:111-115. [PMID: 36245681 PMCID: PMC9549306 DOI: 10.1002/cld.1227] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 04/18/2022] [Accepted: 04/20/2022] [Indexed: 02/04/2023] Open
Abstract
Content available: Author Interview and Audio Recording.
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Affiliation(s)
- Dong Xi
- Division of GastroenterologyDoernbecher Children's HospitalOregon Health & Science UniversityPortlandOregonUSA
| | - Henry Lin
- Division of GastroenterologyDoernbecher Children's HospitalOregon Health & Science UniversityPortlandOregonUSA
| | - Amit A. Shah
- Division of Gastroenterology, Hepatology, & NutritionChildren's Hospital of Philadelphia and Perelman School of Medicine at the University of PennsylvaniaPhiladelphiaPennsylvaniaUSA
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Shin E, Schwarz KB, Jones-Brando LV, Florea LD, Sabunciyan S, Wood LD, Yolken RH. Expression of HLA and Autoimmune Pathway Genes in Liver Biopsies of Young Subjects With Autoimmune Hepatitis Type 1. J Pediatr Gastroenterol Nutr 2022; 75:269-275. [PMID: 35759748 PMCID: PMC9365252 DOI: 10.1097/mpg.0000000000003538] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 05/18/2022] [Indexed: 12/10/2022]
Abstract
OBJECTIVES To test the hypothesis that autoimmune hepatitis (AIH type I) in young subjects is due to genetic differences in proinflammatory genes responding to viral triggers in patients and controls. METHODS Intrahepatic gene expression was compared between AIH type I (n = 24, age 9-30 years) patients (hereafter referred to as the AIH group) and controls (n = 21, age 4-25 years). RNA sequencing was performed on complementary DNA (cDNA) libraries made from total RNA extracted from formalin-fixed paraffin-embedded (FFPE) liver biopsy samples. Gene expression levels were quantified, and differentially expressed genes were functionally analyzed. Pathway analysis was performed using the databases Kyoto Encyclopedia of Genes and Genomes (KEGG) and PANTHER. The remaining sequences were mapped to the RefSeq complete set of viral genomes. RESULTS Differential gene analysis identified 181 genes that were significantly differentially expressed (136 upregulated in the AIH group). Autoimmune pathway genes such as CD19 and CD20 which are important in B cell regulation and maturation as well as, CD8 and LY9 , which are T-cell related, were upregulated in our AIH group. Genes implicated in AIH pathogenesis including CXCL10 , which is thought to be associated with AIH severity and progression, complement genes ( C1QA, C1QB , and C1QC ), and human leucocyte antigen ( HLA ) genes ( HLA-DRB1, HLA-DRA, HLA-B , and HLA-C ) were upregulated in samples from the AIH group. Specific viral etiologies were not found. CONCLUSIONS Unbiased next-generation sequencing and differential gene expression analysis of the AIH group has not only added support for the role of B cells in the pathogenesis and treatment of AIH but also has introduced potential new therapeutic targets: CXCL10 (anti- CXCL10 ) and several complement system-related genes.
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Affiliation(s)
- Emilia Shin
- From the Pediatrics, Johns Hopkins Medical Institutions, Baltimore, MD
| | | | | | - Liliana D. Florea
- the Genetic Medicine, Johns Hopkins Medical Institutions, Baltimore, MD
| | - Sarven Sabunciyan
- From the Pediatrics, Johns Hopkins Medical Institutions, Baltimore, MD
| | | | - Robert H. Yolken
- From the Pediatrics, Johns Hopkins Medical Institutions, Baltimore, MD
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Hercun J, Willems P, Bilodeau M, Vincent C, Alvarez F. Long-Term Follow-Up into Adulthood of Pediatric-Onset Primary Sclerosing Cholangitis and Autoimmune Sclerosing Cholangitis. JPGN REPORTS 2022; 3:e220. [PMID: 37168634 PMCID: PMC10158455 DOI: 10.1097/pg9.0000000000000220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 05/03/2022] [Indexed: 05/13/2023]
Abstract
UNLABELLED Studies on pediatric patients with primary sclerosing cholangitis (PSC) have been limited by short follow-up and inconsistent classification of pediatric patients with autoimmune hepatitis-sclerosing cholangitis overlap (AIC). We conducted a retrospective study of patients diagnosed with AIC or PSC during childhood with extension of follow-up into adulthood. METHODS We reviewed records of patients followed for PSC or AIC between 1998 and 2019 at a pediatric referral center. Features at diagnosis, biochemical and liver-related outcomes (cholangitis, liver transplant, and cirrhosis) were compared. RESULTS Forty patients (27 PSC, 13 AIC) were followed for 92 months on average (standard deviation 79 months) with extension into adulthood in 52.5%; 70% had associated inflammatory bowel disease (IBD). The proportion of patients with significant fibrosis and abnormal baseline liver tests (serum bilirubin and transaminase levels) were similar in both groups. One year postdiagnosis, 55% (15/27) of PSC patients had normal liver tests versus only 15% (2/13) in the AIC group (P = 0.02). During follow-up, more liver-related events occurred in the AIC group (69% versus 27%, hazard ratio [HR] = 3.7 [95% confidence interval (CI): 1.4-10] P = 0.01). Baseline elevated serum bilirubin levels (HR = 5.3 [95% CI: 1.7-16.9] P = 0.005) and elevated transaminase levels at 1 year (HR = 9.09 [95% CI: 1.18-66.7) P = 0.03) were predictive of liver-related events, while having IBD was not (HR = 0.48 (95% CI: 0.15-1.5) P = 0.22). CONCLUSIONS Pediatric patients with AIC and PSC presented at a similar fibrosis stage, however, with a more severe hepatitis in AIC. In this cohort, AIC was associated with more liver-related events, primarily driven by a higher rate of cirrhosis compared with PSC; transplant rates were similar.
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Affiliation(s)
- Julian Hercun
- From the Liver Unit, Centre hospitalier de l’Université de Montréal, Montréal, Canada
| | - Philippe Willems
- From the Liver Unit, Centre hospitalier de l’Université de Montréal, Montréal, Canada
| | - Marc Bilodeau
- From the Liver Unit, Centre hospitalier de l’Université de Montréal, Montréal, Canada
| | - Catherine Vincent
- From the Liver Unit, Centre hospitalier de l’Université de Montréal, Montréal, Canada
| | - Fernando Alvarez
- Department of Gastroenterology, Hepatology and Nutrition, Centre Hospitalier Universitaire Sainte-Justine, Montréal, Canada
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11
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Hepatic manifestations of systemic disease: an imaging-based review. Pediatr Radiol 2022; 52:852-864. [PMID: 34797394 DOI: 10.1007/s00247-021-05222-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Revised: 08/28/2021] [Accepted: 10/05/2021] [Indexed: 10/19/2022]
Abstract
The liver is responsible for many processes that maintain human metabolic homeostasis and can be affected by several pediatric systemic diseases. In this manuscript, we explore key pathological findings and imaging features across multiple modalities of a spectrum of congenital, metabolic and autoimmune disorders. Strengthening the radiologists' knowledge regarding potential hepatic manifestations of these systemic diseases will ultimately lead to improved care for pediatric patients.
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12
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Liu M, Zhang H, Zhang L, Liu X, Zhou S, Wang X, Zhong W, Zhang J, Wang B, Zhao J, Zhou L. RIP3 blockade prevents immune-mediated hepatitis through a myeloid-derived suppressor cell dependent mechanism. Int J Biol Sci 2022; 18:199-213. [PMID: 34975327 PMCID: PMC8692153 DOI: 10.7150/ijbs.65402] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 10/16/2021] [Indexed: 12/13/2022] Open
Abstract
Autoimmune hepatitis (AIH) is an immune-mediated chronic inflammatory liver disease, and its pathogenesis is not fully understood. Our previous study discovered that receptor interacting protein kinase 3 (RIP3) is correlated with serum transaminase levels in AIH patients. However, its role and underlying mechanism in AIH are poorly understood. Here, we detected the increased expression and activation of RIP3 in livers of patients and animal models with AIH. The inhibition of RIP3 kinase by GSK872 prevented concanavalin A (ConA)-induced immune-mediated hepatitis (IMH) by reduced hepatic proinflammatory cytokines and immune cells including Th17 cells and macrophages. Further experiments revealed that RIP3 inhibition resulted in an increase in CD11b+Gr1+ myeloid-derived suppressor cells (MDSCs) with immunoregulatory properties in the liver, spleen, and peripheral blood. Moreover, the depletion of Gr-1+ MDSCs abrogated the protective effect and immune suppression function of GSK872 in ConA-induced IMH. Altogether, our data demonstrate that RIP3 blockade prevents ConA-induced IMH through promoting MDSCs infiltration. Inhibition of RIP3 kinase may be a novel therapeutic avenue for AIH treatment.
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Affiliation(s)
- Man Liu
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China.,Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Hongxia Zhang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Lu Zhang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Xin Liu
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Simin Zhou
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Xiaoyi Wang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Weilong Zhong
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Jie Zhang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Bangmao Wang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Jingwen Zhao
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Lu Zhou
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China.,Department of Gastroenterology and Hepatology, People's Hospital of Hetian District, Xinjiang Uygur Autonomous Region, China
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13
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Mogahed E, El-Karaksy H, Zaki H, Abdullatif H. Autoimmune hepatitis in Egyptian children: A single center experience. Int J Immunopathol Pharmacol 2022; 36:20587384211073265. [PMID: 35231187 PMCID: PMC8894955 DOI: 10.1177/20587384211073265] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 11/30/2021] [Accepted: 12/21/2021] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND AND AIM Autoimmune hepatitis (AIH) has variable clinical manifestations and should be considered in the diagnostic work-up of any patient with cryptogenic liver disease. The aim of the study was to determine the clinical, biochemical, histopathological characteristics and treatment outcome of AIH in Egyptian children. PATIENTS AND METHODS This observational study was conducted at the Pediatric Hepatology Unit at Cairo University Pediatric Hospital, Egypt. All children (<18 years of age) presenting from 2009 to 2016 with established diagnosis of AIH were included. Medical history, clinical examination, and results of investigations were retrieved from patients' files. The main outcome measures included the rate of remission, relapses, and mortality. RESULTS The study included 34 children with AIH. Twenty patients (58%) presented with chronic liver disease. There was a history of concomitant autoimmune diseases in 5 patients. Transaminases were elevated in all patients. There was synthetic dysfunction in 58%. Twenty-four patients (70.5%) had AIH-1, while nine patients (26.4%) had AIH-2 and one patient (2.9%) had autoantibody negative AIH. Piecemeal necrosis was observed in the liver biopsy of 79% of our cohort. Approximately 80% achieved biochemical remission (88% received combined therapy of prednisolone and azathioprine). About half of the patients developed relapses. One patient died of liver cell failure. CONCLUSION In children with liver disease, a diagnosis of AIH should be considered. In those patients, AIH-1 is more common than AIH-2. Prednisolone monotherapy or combined with azathioprine could achieve remission, but relapse is still common. Treatment non-adherence is the main risk factor for relapse.
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Affiliation(s)
- Engy Mogahed
- Department of Pediatrics, Kasr Alainy Medical School, Cairo University, Cairo, Egypt
| | - Hanaa El-Karaksy
- Department of Pediatrics, Kasr Alainy Medical School, Cairo University, Cairo, Egypt
| | - Heba Zaki
- Department of Pediatrics, Kasr Alainy Medical School, Cairo University, Cairo, Egypt
| | - Hala Abdullatif
- Department of Pediatrics, Kasr Alainy Medical School, Cairo University, Cairo, Egypt
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14
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Ma Y, Su H, Yuksel M, Longhi MS, McPhail M, Wang P, Bansal S, Wong GW, Graham J, Yang L, Thompson R, Doherty DG, Hadzic N, Zen Y, Quaglia A, Henghan M, Samyn M, Vergani D, Mieli-Vergani G. Human Leukocyte Antigen Profile Predicts Severity of Autoimmune Liver Disease in Children of European Ancestry. Hepatology 2021; 74:2032-2046. [PMID: 33971035 PMCID: PMC8463472 DOI: 10.1002/hep.31893] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 04/03/2021] [Accepted: 04/28/2021] [Indexed: 02/05/2023]
Abstract
BACKGROUND AND AIMS Genetic predisposition to autoimmune hepatitis (AIH) in adults is associated with possession of human leukocyte antigen (HLA) class I (A*01, B*08) and class II (DRB1*03, -04, -07, or -13) alleles, depending on geographic region. Juvenile autoimmune liver disease (AILD) comprises AIH-1, AIH-2, and autoimmune sclerosing cholangitis (ASC), which are phenotypically different from their adult counterparts. We aimed to define the relationship between HLA profile and disease course, severity, and outcome in juvenile AILD. APPROACH AND RESULTS We studied 236 children of European ancestry (152 female [64%], median age 11.15 years, range 0.8-17), including 100 with AIH-1, 59 with AIH-2, and 77 with ASC. The follow-up period was from 1977 to June 2019 (median 14.5 years). Class I and II HLA genotyping was performed using PCR/sequence-specific primers. HLA B*08, -DRB1*03, and the A1-B8-DR3 haplotype impart predisposition to all three forms of AILD. Homozygosity for DRB1*03 represented the strongest risk factor (8.8). HLA DRB1*04, which independently confers susceptibility to AIH in adults, was infrequent in AIH-1 and ASC, suggesting protection; and DRB1*15 (DR15) was protective against all forms of AILD. Distinct HLA class II alleles predispose to the different subgroups of juvenile AILD: DRB1*03 to AIH-1, DRB1*13 to ASC, and DRB1*07 to AIH-2. Possession of homozygous DRB1*03 or of DRB1*13 is associated with fibrosis at disease onset, and possession of these two genes in addition to DRB1*07 is associated with a more severe disease in all three subgroups. CONCLUSIONS Unique HLA profiles are seen in each subgroup of juvenile AILD. HLA genotype might be useful in predicting responsiveness to immunosuppressive treatment and course.
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Affiliation(s)
- Yun Ma
- Institute of Liver Studies, MowatLabs, Department of Inflammation Biology, School of Immunology & Microbial Sciences, Faculty of Liver Sciences and Medicine, King’s College London, London, UK
| | - Habin Su
- Institute of Liver Studies, MowatLabs, Department of Inflammation Biology, School of Immunology & Microbial Sciences, Faculty of Liver Sciences and Medicine, King’s College London, London, UK,Department of Liver Disease of Chinese PLA General Hospital, the Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Muhammed Yuksel
- Institute of Liver Studies, MowatLabs, Department of Inflammation Biology, School of Immunology & Microbial Sciences, Faculty of Liver Sciences and Medicine, King’s College London, London, UK,Koc University Research Centre for Translational Medicine (KUTTAM), Istanbul, Turkey
| | - Maria Serena Longhi
- Institute of Liver Studies, MowatLabs, Department of Inflammation Biology, School of Immunology & Microbial Sciences, Faculty of Liver Sciences and Medicine, King’s College London, London, UK,Department of Anesthesia, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA
| | - Mark McPhail
- Institute of Liver Studies, MowatLabs, Department of Inflammation Biology, School of Immunology & Microbial Sciences, Faculty of Liver Sciences and Medicine, King’s College London, London, UK
| | - Pengyun Wang
- Institute of Liver Studies, MowatLabs, Department of Inflammation Biology, School of Immunology & Microbial Sciences, Faculty of Liver Sciences and Medicine, King’s College London, London, UK
| | - Sanjay Bansal
- Paediatric Liver, GI and Nutrition Centre, King’s College Hospital, Denmark Hill, London, UK
| | - Guan-Wee Wong
- Institute of Liver Studies, MowatLabs, Department of Inflammation Biology, School of Immunology & Microbial Sciences, Faculty of Liver Sciences and Medicine, King’s College London, London, UK,Department of Medicine, Ng Teng Fong General Hospital, 1 Jurong East Street, Singapore 609606
| | - Jonathon Graham
- Institute of Liver Studies, MowatLabs, Department of Inflammation Biology, School of Immunology & Microbial Sciences, Faculty of Liver Sciences and Medicine, King’s College London, London, UK
| | - Li Yang
- Department of Gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Richard Thompson
- Institute of Liver Studies, MowatLabs, Department of Inflammation Biology, School of Immunology & Microbial Sciences, Faculty of Liver Sciences and Medicine, King’s College London, London, UK,Paediatric Liver, GI and Nutrition Centre, King’s College Hospital, Denmark Hill, London, UK
| | - Derek G. Doherty
- Division of Immunology, School of Medicine, Trinity College Dublin, Dublin, Ireland
| | - Nedim Hadzic
- Paediatric Liver, GI and Nutrition Centre, King’s College Hospital, Denmark Hill, London, UK
| | - Yoh Zen
- Institute of Liver Studies, MowatLabs, Department of Inflammation Biology, School of Immunology & Microbial Sciences, Faculty of Liver Sciences and Medicine, King’s College London, London, UK
| | - Alberto Quaglia
- Institute of Liver Studies, MowatLabs, Department of Inflammation Biology, School of Immunology & Microbial Sciences, Faculty of Liver Sciences and Medicine, King’s College London, London, UK,Department of Cellular Pathology, Royal Free London NHS Foundation Trust, UCL Cancer Institute, Research Department of Pathology, London, UK
| | - Michael Henghan
- Institute of Liver Studies, MowatLabs, Department of Inflammation Biology, School of Immunology & Microbial Sciences, Faculty of Liver Sciences and Medicine, King’s College London, London, UK
| | - Marianne Samyn
- Paediatric Liver, GI and Nutrition Centre, King’s College Hospital, Denmark Hill, London, UK
| | - Diego Vergani
- Institute of Liver Studies, MowatLabs, Department of Inflammation Biology, School of Immunology & Microbial Sciences, Faculty of Liver Sciences and Medicine, King’s College London, London, UK
| | - Giorgina Mieli-Vergani
- Institute of Liver Studies, MowatLabs, Department of Inflammation Biology, School of Immunology & Microbial Sciences, Faculty of Liver Sciences and Medicine, King’s College London, London, UK,Paediatric Liver, GI and Nutrition Centre, King’s College Hospital, Denmark Hill, London, UK
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Abstract
BACKGROUND Seronegative autoimmune hepatitis (AIH) is a diagnostic challenge with unclear prognosis. This study describes the features and outcomes of seronegative AIH in children. PATIENTS AND METHODS Patients under 18 years of age, who had been diagnosed with AIH between April 2014 and April 2020, were retrospectively evaluated. Seronegative AIH was identified by the absence of the three conventional non-organ-specific autoantibodies (anti-nuclear antibody [ANA], anti-smooth muscle antibody [ASMA], and anti-liver kidney microsomal [anti-LKM] type 1 antibody), alongside the characteristic AIH liver histopathology and a positive response to immunosuppressive therapy in the absence of other liver diseases. RESULTS The study included 54 patients with AIH. 15 (27.77%) were seronegative at the time of diagnosis. 13 of the 15 seronegative patients presented with acute hepatitis or acute liver failure (ALF). Mean follow-up duration was 27.48 months in seronegative patients. Two seronegative patients had lymphocytopenia on admission, and, although the liver disease improved after corticosteroid treatment, they developed aplastic anemia (AA). Other seronegative patients responded well to immunosuppressive therapy. CONCLUSIONS Patients with seronegative AIH present frequently with acute hepatitis or ALF. AIH diagnosis can be confirmed by observing the effects of corticosteroid therapy in seronegative patients with characteristic AIH liver histopathological features. However, the presence of lymphocytopenia in seronegative patients is a sign of bone marrow failure.
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Yanny B, Grewal JK, Vaswani VK. Celiac Disease and the Liver. DIAGNOSIS AND MANAGEMENT OF GLUTEN-ASSOCIATED DISORDERS 2021:27-40. [DOI: 10.1007/978-3-030-56722-4_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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17
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Rahim MN, Miquel R, Heneghan MA. Approach to the patient with acute severe autoimmune hepatitis. JHEP Rep 2020; 2:100149. [PMID: 32995712 PMCID: PMC7509236 DOI: 10.1016/j.jhepr.2020.100149] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 07/09/2020] [Accepted: 07/15/2020] [Indexed: 12/11/2022] Open
Abstract
Autoimmune hepatitis is associated with varied clinical presentations and natural history, as well as somewhat unpredictable treatment responses. Understanding how to stratify patients who require further escalation of therapy will help clinicians manage these patients. The presentation of acute severe autoimmune hepatitis (AS-AIH) is relatively uncommon, although its prevalence is potentially greater than currently perceived. Previous studies consist of small retrospective single-centre series and are not directly comparable due to the diversity of presentations, disease definitions and non-standardised treatment regimens. We define AS-AIH as those who present acutely with AIH and are icteric with an international normalised ratio ≥1.5 and no evidence of hepatic encephalopathy. Those with hepatic encephalopathy should be defined as having AS-AIH with acute liver failure. In this review, we provide a structured practical approach for diagnosing and managing this unique group of patients.
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Key Words
- ACLF, acute-on-chronic liver failure
- AIH, autoimmune hepatitis
- ALF, acute liver failure
- ALI, acute liver injury
- ALT, alanine aminotransferase
- ANA, anti-nuclear antibody
- AS-AIH, acute severe autoimmune hepatitis
- ASMA, anti-smooth muscle antibody
- AST, aspartate aminotransferase
- AUROC, analysis of area under the receiver operator characteristic curve
- Acute liver failure
- Acute severe presentation
- Autoimmune hepatitis
- CT, computed tomography
- Corticosteroids
- DILI, drug-induced liver injury
- EBV, Epstein-Barr virus
- HE, hepatic encephalopathy
- HLA, human leukocyte antigen
- IAIHG, International Autoimmune Hepatitis Group
- INR, international normalised ratio
- LT, liver transplantation
- Liver transplantation
- MELD, model for end-stage liver disease
- MELD-Na, model for end-stage liver disease-sodium
- MHN, massive hepatic necrosis
- NAC, N-acetylcysteine
- PT, prothrombin time
- UKELD, United Kingdom end-stage liver disease
- USALF, United States Acute Liver Failure
- anti-LC-1, anti-liver cytosol-1
- anti-LKM, anti-liver kidney microsomal
- anti-SLA/LP, anti-soluble liver antigen/liver pancreas
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Affiliation(s)
- Mussarat N. Rahim
- Institute of Liver Studies, King's College Hospital, London, SE5 9RS, UK
| | - Rosa Miquel
- Liver Histopathology Laboratory, King's College Hospital, London, SE5 9RS, UK
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18
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Ee LC. Liver disease in the older child. J Paediatr Child Health 2020; 56:1702-1707. [PMID: 33197971 DOI: 10.1111/jpc.14708] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2019] [Revised: 09/07/2019] [Accepted: 11/07/2019] [Indexed: 11/30/2022]
Abstract
Liver disease in children tends to present either as: (i) an acute hepatitis with or without jaundice; (ii) incidental finding of abnormal liver function tests; or (iii) from a complication of portal hypertension with either haematemesis and/or incidental splenomegaly. Acute hepatitis may result from acute infection, prescribed or other drugs, ischaemia or vascular causes, autoimmune hepatitis, or idiopathic liver failure. Non-alcoholic fatty liver disease is now the most likely reason for abnormal liver function tests but medications, metabolic disease, cholangiopathy and non-liver causes should be considered. Autoimmune hepatitis and alpha-1-antitrypsin deficiency are the most likely causes of insidious liver disease. An international normalised ratio uncorrected by vitamin K reflects the severity of liver synthetic dysfunction, but not propensity to bleed. Creatine kinase helps to differentiate muscle from liver disease in patients with raised transaminases. Doppler ultrasound of hepatic vasculature is useful when assessing splenomegaly to differentiate extra-hepatic portal hypertension from inherent liver disease.
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Affiliation(s)
- Looi C Ee
- Department of Gastroenterology, Hepatology and Liver Transplant, Queensland Children's Hospital, Brisbane, Queensland, Australia
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19
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Autoimmune Hepatitis in Children: Prednisone Plus Azathioprine Versus Cyclosporine: A Randomized Trial. J Pediatr Gastroenterol Nutr 2020; 71:376-380. [PMID: 32520828 DOI: 10.1097/mpg.0000000000002776] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
OBJECTIVE The aim of this study was to find the outcome and adverse effects of 2 initial treatments in children with autoimmune hepatitis, prednisone (PRED) plus azathioprine (AZA) versus cyclosporine (CsA). STUDY DESIGN Between December 2008 and February 2012, 50 consecutive patients were centrally randomized to 1 of 2 treatment arms. Group 1: PRED was indicated at a dose of 1 to 2 mg · kg · day (up to 60 mg/day) and AZA at a dose of 1 to 2 mg · kg · day. Group 2: CsA was administered at a dose of 4 mg · kg · day orally divided into 2 doses. After remission, all patients were given a combination of PRED at 0.3 to 0.5 mg · kg · day and AZA at 1 to 2 mg · kg · day. Children presenting liver failure were placed on a triple immunosuppressive regimen if this condition persisted after 1 week of treatment, after liver function normalization they were switched back to their initial scheme. RESULTS A total of 26 patients received PRED-AZA and 24 CsA. Both treatments showed similar initial results in effectiveness and safety, although remission was achieved earlier with PRED-AZA: 8.6 versus CsA: 13.6 weeks (P < 0.0081). All children recovered liver function in a mean time of 32 ± 26 days. Cushingoid syndrome was more frequently observed with PRED-AZA (P < 0.001) and gingival hypertrophy with CsA (P < 0.001). A significant increase in body mass index was observed in all patients from initial treatment to remission, being greater with PRED-AZA. CONCLUSIONS Similar outcomes were obtained with PRED plus AZA or CsA treatments. Either therapeutic strategy could be used according to the particular characteristics of each patient. Triple immunosuppression was beneficial in patients with liver failure at onset.
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21
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Yassin S, De Lacy R, Pillay K, Goddard E. Characteristics and Outcomes of Autoimmune Hepatitis from a Tertiary Paediatric Centre, Cape Town, South Africa. J Trop Pediatr 2020; 66:448-457. [PMID: 31943108 DOI: 10.1093/tropej/fmz088] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
OBJECTIVES To describe the clinical characteristics, biochemical and histological features, outcomes and predictors of prognosis of children with autoimmune hepatitis (AIH) from a paediatric centre in South Africa. METHODS Thirty-nine children diagnosed with AIH at Red Cross War Memorial Children's Hospital between 2005 and 2015 were included. Relevant patient's data were retrieved from the hospital's medical records and database. Liver biopsy slides were reviewed. Ethical approval was obtained. Data were analysed using SPSS. RESULTS Females were 29 (74%). Mean age at presentation was 7.27 ± 3.35 years and the mean follow-up was 4.5 ± 2.4 years. Jaundice was present in 97% of patients at presentation. An acute presentation was observed in 26 (67%) even though cirrhosis was detected in 22 (56%). Autoantibody screening was completed in 35 patients, 20 (57%) were AIH-1, 1 (3%) was AIH-2 and 14 (40%) were seronegative AIH. Of the 25 patients who underwent magnetic resonance cholangiography 17 (68%) had associated autoimmune sclerosing cholangitis. The remission rate was 79%. However, 11 children relapsed later. One child required liver transplantation and one demised. Seronegative and seropositive patients have comparable characteristics and outcomes. While a higher alanine transaminase (ALT) level at presentation is a significant predictor of remission, a lower ALT level and cirrhosis are significant risk factors for unfavourable outcome. Overall survival rate was 97%. CONCLUSION AIH responds well to therapy with excellent survival. Hence, it should be considered in any child presenting with viral screen negative hepatitis and start therapy timeously to prevent disease progression.
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Affiliation(s)
- Sawsan Yassin
- Division of Paediatric Gastroenterology, Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital/University of Cape Town, Cape Town 7700, South Africa
| | - Ronalda De Lacy
- Division of Paediatric Gastroenterology, Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital/University of Cape Town, Cape Town 7700, South Africa
| | - Komala Pillay
- Division of Paediatric Pathology, Red Cross War Memorial Children's Hospital University of Cape Town National Health Laboratory Services, Cape Town 7700, South Africa
| | - Elizabeth Goddard
- Division of Paediatric Gastroenterology, Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital/University of Cape Town, Cape Town 7700, South Africa
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22
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Smolka V, Tkachyk O, Ehrmann J, Karaskova E, Zapalka M, Volejnikova J. Acute onset of autoimmune hepatitis in children and adolescents. Hepatobiliary Pancreat Dis Int 2020; 19:17-21. [PMID: 31474443 DOI: 10.1016/j.hbpd.2019.08.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Accepted: 08/15/2019] [Indexed: 02/05/2023]
Abstract
BACKGROUND Autoimmune hepatitis (AIH) is a rare progressive liver disease, which manifests as acute hepatitis in 40%-50% of pediatric cases. This refers predominantly to spontaneous exacerbations of previously unrecognized subclinical AIH with laboratory and histological signs of chronic hepatitis, or to acute exacerbations of known chronic disease. Only a few of these patients fulfill criteria for acute liver failure (ALF). METHODS Forty children diagnosed with AIH in our center between 2000 and 2018 were included in this study. All of them fulfilled revised diagnostic criteria of the International Autoimmune Hepatitis Group (IAIHG) for probable or confirmed AIH, and other etiologies of liver diseases were excluded. Patients were divided into two groups: acute AIH (A-AIH) or chronic AIH (C-AIH). RESULTS Acute onset of AIH occurred in 19/40 children (48%). Six of them fulfilled the criteria of ALF with coagulopathy and encephalopathy. Five of 6 children with ALF suffered from exacerbation of previously undiagnosed chronic AIH, among which 4 children were histologically confirmed as micronodular cirrhosis. The remaining one patient had fulminant AIH with centrilobular necrosis, but no histological signs of previous chronic liver damage. We observed significantly lower levels of albumin, higher levels of aminotransferases, bilirubin, INR, IgG, higher IAIHG score and more severe histological findings in A-AIH than in C-AIH. No differences in patient age and presence of autoantibodies were observed between A-AIH and C-AIH. All children, including those with ALF and cirrhosis, were treated with corticosteroids, and are alive and achieved AIH remission. Liver transplant was not indicated in any patient. CONCLUSION Rapid and accurate diagnosis of A-AIH may be difficult. However, timely start of immunosuppressive therapy improves prognosis and decreases number of indicated liver transplantations in children with AIH.
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Affiliation(s)
- Vratislav Smolka
- Department of Pediatrics, Faculty of Medicine and Dentistry, Palacky University and University Hospital Olomouc, I. P. Pavlova 185/6, Olomouc 779 00, Czech Republic.
| | - Oksana Tkachyk
- Department of Pediatrics, Faculty of Medicine and Dentistry, Palacky University and University Hospital Olomouc, I. P. Pavlova 185/6, Olomouc 779 00, Czech Republic
| | - Jiri Ehrmann
- Department of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacky University and University Hospital Olomouc, I. P. Pavlova 185/6, Olomouc 779 00, Czech Republic
| | - Eva Karaskova
- Department of Pediatrics, Faculty of Medicine and Dentistry, Palacky University and University Hospital Olomouc, I. P. Pavlova 185/6, Olomouc 779 00, Czech Republic
| | - Martin Zapalka
- Department of Pediatrics, Faculty of Medicine and Dentistry, Palacky University and University Hospital Olomouc, I. P. Pavlova 185/6, Olomouc 779 00, Czech Republic
| | - Jana Volejnikova
- Department of Pediatrics, Faculty of Medicine and Dentistry, Palacky University and University Hospital Olomouc, I. P. Pavlova 185/6, Olomouc 779 00, Czech Republic
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23
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Alsayed MAL, Elbeah SM, El-Desoky MM, Elziny SM, Megahed A. Polymorphism in Macrophage Migration Inhibitory Factor -173GC in Pediatric Patients with Autoimmune Hepatitis. Pediatr Gastroenterol Hepatol Nutr 2020; 23:63-71. [PMID: 31988876 PMCID: PMC6966214 DOI: 10.5223/pghn.2020.23.1.63] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Accepted: 09/13/2019] [Indexed: 12/12/2022] Open
Abstract
PURPOSE Autoimmune hepatitis (AIH) is a chronic disease that may lead to cirrhosis. The immunopathogenesis of AIH is not fully understood and it mainly involves T-cell mediated mechanism. Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that promotes T cell response and its polymorphism may serve as a severity marker of AIH. No previous study has considered investigating MIF polymorphism in children with AIH. METHODS Forty-two children with definite diagnosis of AIH were enrolled along with 100 age and sex matched controls. All participants were tested for polymorphism at -173GC (rs755622) of MIF gene. All patients received the standard protocol of steroid plus azathioprine to achieve remission. Liver biopsy was performed at time of diagnosis for all patients and only 18 of them underwent a second biopsy after treatment. RESULTS No statistically significant differences in the frequency of the genotypes GG and GC or in allele distribution were found in both patient and control groups (p=0.590, 0.640 respectively). Initial alanine aminotransferase (ALT) levels at the time of presentation was significantly higher in the GC group than GG group (p=0.020). GC genotype significantly correlated with disease relapse (r=0.41, p=0.007). Regression of necroinflammation and the fibrosis score in the second liver biopsy was statistically significant in the GG group (p<0.0001, p=0.010 respectively). CONCLUSION MIF -173GC polymorphism is associated with clinically significant markers of pediatric AIH, including increased initial serum ALT levels, may help predict necroinflammatory/fibrosis regression effectively, following immunosuppressive treatment.
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Affiliation(s)
- Mona Abdel Latif Alsayed
- Pediatric Gastroenterology and Hepatology Unit, Mansoura University Children's Hospital, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Shymaa Mohsen Elbeah
- Biochemistry Department, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Manal M El-Desoky
- Biochemistry Department, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Shereen Magdy Elziny
- Pediatric Gastroenterology and Hepatology Unit, Mansoura University Children's Hospital, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Ahmed Megahed
- Pediatric Gastroenterology and Hepatology Unit, Mansoura University Children's Hospital, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Egypt
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24
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Minkoff NZ, Buzzi K, Williamson AK, Hagmann SHF. Case Report: Acute Hepatitis E in a Pediatric Traveler Presenting with Features of Autoimmune Hepatitis: A Diagnostic and Therapeutic Challenge. Am J Trop Med Hyg 2019; 100:155-158. [PMID: 30350777 DOI: 10.4269/ajtmh.18-0640] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Hepatitis E virus (HEV) is globally the most common cause of acute viral hepatitis. In industrialized countries, HEV infection can be seen in travelers returning from hyperendemic countries or in individuals at risk for autochthonous infection due to zoonotic exposure. Hepatitis E virus infection is often unrecognized and at times misdiagnosed because of nonspecific findings that can overlap with other causes of hepatitis, including autoimmune hepatitis (AIH). Although most cases of acute HEV infection resolve spontaneously and do not require treatment, life-threatening acute liver failure may occur in some cases. We discuss the case of an 8-year-old boy returning from Bangladesh with progressive acute liver injury and a clinical profile suggestive of AIH, who showed a favorable response to corticosteroid treatment before the diagnosis of an acute HEV infection could be established.
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Affiliation(s)
- Nathan Z Minkoff
- Department of Pediatrics, Steven and Alexandra Cohen Children's Medical Center, Northwell Health, New Hyde Park, New York
| | - Kate Buzzi
- Division of Pediatric Gastroenterology, Steven and Alexandra Cohen Children's Medical Center, Northwell Health, New Hyde Park, New York.,Department of Pediatrics, Steven and Alexandra Cohen Children's Medical Center, Northwell Health, New Hyde Park, New York.,Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York
| | - Alex K Williamson
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York.,Department of Pathology, Steven and Alexandra Cohen Children's Medical Center, Northwell Health, New Hyde Park, New York
| | - Stefan H F Hagmann
- Department of Pediatrics, Steven and Alexandra Cohen Children's Medical Center, Northwell Health, New Hyde Park, New York.,Division of Pediatric Infectious Diseases, Steven and Alexandra Cohen Children's Medical Center, Northwell Health, New Hyde Park, New York.,Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York
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25
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Arcos-Machancoses JV, Molera Busoms C, Julio Tatis E, Bovo MV, Quintero Bernabeu J, Juampérez Goñi J, Crujeiras Martínez V, Martín de Carpi J. Development and validation of a new simplified diagnostic scoring system for pediatric autoimmune hepatitis. Dig Liver Dis 2019; 51:1308-1313. [PMID: 30928421 DOI: 10.1016/j.dld.2019.02.018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Revised: 02/25/2019] [Accepted: 02/25/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND Children with autoimmune hepatitis (AIH) often exhibit particular features. Accordingly, seven pediatric-specific criteria have been proposed. AIM To develop a prediction model based on them, transform it into a scoring system and study its accuracy. METHODS A cohort of children under study for liver disease was consecutively selected. AIH diagnosis was based on classical criteria. Already proposed pediatric criteria were recorded. The best possible regression model was selected, and the beta coefficient of each criterion was translated into a whole number (points). Total scores were obtained following the points system and the best cut-off was calculated. Subsequently, accuracy of the diagnostic score was studied in the validation set. RESULTS Among 212 included patients, 100 had AIH. The score included 5 criteria: autoantibodies (0-2 points), hypergammaglobulinemia, exclusion of viral hepatitis, exclusion of Wilson's disease (1 point each) and liver histology (3 points). In addition, a normal cholangiogram is mandatory. The validation set was formed of 70 patients (24 with AIH). In this subsample, a score of ≥6 renders a sensitivity/specificity of 95.8%/100%. The area under the receiver operating characteristic curve was 97.1%. CONCLUSION Pediatric-specific criteria for the diagnosis of AIH can be reliably used as a scoring system.
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Affiliation(s)
| | - Cristina Molera Busoms
- Sant Joan de Déu Hospital (HSJD), Department of Pediatric Gastroenterology, Hepatology and Nutrition, Barcelona, Spain; HSJD-HVH Comprehensive Unit of Complex Hepatology and Pediatric Liver Transplantation, Barcelona, Spain.
| | - Ecaterina Julio Tatis
- Sant Joan de Déu Hospital (HSJD), Department of Pediatric Gastroenterology, Hepatology and Nutrition, Barcelona, Spain.
| | - María Victoria Bovo
- Sant Joan de Déu Hospital (HSJD), Department of Pediatric Gastroenterology, Hepatology and Nutrition, Barcelona, Spain.
| | - Jesús Quintero Bernabeu
- Vall d'Hebron Hospital (HVH), Department of Pediatric Gastroenterology, Hepatology and Nutrition, Barcelona, Spain; HSJD-HVH Comprehensive Unit of Complex Hepatology and Pediatric Liver Transplantation, Barcelona, Spain.
| | - Javier Juampérez Goñi
- Vall d'Hebron Hospital (HVH), Department of Pediatric Gastroenterology, Hepatology and Nutrition, Barcelona, Spain; HSJD-HVH Comprehensive Unit of Complex Hepatology and Pediatric Liver Transplantation, Barcelona, Spain.
| | - Vanessa Crujeiras Martínez
- University Hospital Complex of Santiago de Compostela, Department of Pediatric Gastroenterology, Hepatology and Nutrition, Spain.
| | - Javier Martín de Carpi
- Sant Joan de Déu Hospital (HSJD), Department of Pediatric Gastroenterology, Hepatology and Nutrition, Barcelona, Spain; HSJD-HVH Comprehensive Unit of Complex Hepatology and Pediatric Liver Transplantation, Barcelona, Spain.
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Singh SK, Poddar U, Mishra R, Srivastava A, Yachha SK. Ascitic fluid infection in children with liver disease: time to change empirical antibiotic policy. Hepatol Int 2019; 14:138-144. [PMID: 31290071 DOI: 10.1007/s12072-019-09968-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2019] [Accepted: 06/27/2019] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND AIMS Recent years have shown a rise in occurrence of multidrug resistant ascitic fluid infection (AFI) including resistant to third generation cephalosporins. Our aim was to find the prevalence, antibiotics resistance and outcome of AFI in children with liver disease. METHODS Children (≤ 18 years) with liver disease-related ascites were prospectively enrolled from April 2015 to October 2017. Based on the results of ascitic fluid examination and culture, patients were classified as having AFI [spontaneous bacterial peritonitis (SBP), culture negative neutrocytic ascites (CNNA) and monomicrobial non-neutrocytic bacterascites (MNB)] and no-AFI. AFI diagnosed after 48 h of index hospitalization was considered as nosocomial. RESULTS We enrolled 194 children with a median age of 85 [2-216] months. Chronic liver disease was the commonest etiology (153, 79%). AFI was present in 60 (31%) children [SBP (n = 13), CNNA (n = 39), MNB (n = 8)] of which 53% were nosocomial and resulted in high in-hospital mortality. Gram-negative bacilli dominated the ascitic fluid culture (12/21, 57%) and 10/12 (83%) of them were extended spectrum beta-lactamases (ESBL) producers. Six (60%) ESBL producers were sensitive to cefoperazone-sulbactam and 70% to carbapenems. Child-Pugh-Turcotte (CPT) score of ≥ 11 independently determined in-hospital mortality in children with AFI. CONCLUSIONS AFI was found in 31% children with liver disease and almost half of them were nosocomial resulting in high mortality. ESBL producing Gram-negative bacteria were the most frequently isolated organisms. Cefoperazone-sulbactam or carbapenems may be useful empirical antibiotics in nosocomial setting. Children with AFI and CPT score ≥ 11 should be evaluated for liver transplantation.
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Affiliation(s)
- Sumit Kumar Singh
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, 226014, India
| | - Ujjal Poddar
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, 226014, India.
| | - Richa Mishra
- Department of Microbiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226014, India
| | - Anshu Srivastava
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, 226014, India
| | - Surender Kumar Yachha
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, 226014, India
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de Boer YS, Gerussi A, van den Brand FF, Wong GW, Halliday N, Liberal R, Drenth JPH, Thorburn D, Bouma G, Heneghan MA. Association Between Black Race and Presentation and Liver-Related Outcomes of Patients With Autoimmune Hepatitis. Clin Gastroenterol Hepatol 2019; 17:1616-1624.e2. [PMID: 30471454 DOI: 10.1016/j.cgh.2018.11.028] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Revised: 11/01/2018] [Accepted: 11/06/2018] [Indexed: 02/06/2023]
Abstract
INTRODUCTION & AIMS Small studies have found that black patients with autoimmune hepatitis (AIH) present with more aggressive disease. We aimed to characterize the presentation and outcome in black and white patients with AIH. METHODS We performed a retrospective study, collecting information from databases of patients with AIH attending the Institute of Liver studies at King's College Hospital, London (1971-October 2015, the Royal Free Hospital, London (1982 through December 2016) and the multicenter Dutch Autoimmune Hepatitis Study Group cohort (2006-August 2016). We identified 88 black patients with AIH and we compared their clinical characteristics and outcomes to 897 white patients with AIH. RESULTS Black patients presented at a younger age (median 38 years vs 45 years) (P = .007), had higher IgG levels (mean 31.0 mg/dL vs 27.5 mg/dL) (P = .04), but there were no significant differences between groups in auto-antibody profiles, International AIH Group scores, or sex distribution of disease. A higher proportion of black patients had systemic lupus erythematosus (10%) than white patients (2%) (P ≤ .001). There was no significant difference in proportions of patients with a response to standard therapy (86% for black patients vs 91% for white patients; P = .20) or in rate of relapse (57% vs 50%; P = .3). Despite this, black patients had an increased risk of liver transplantation and liver-related death (hazard ratio 2.4, 95% confidence interval, 1.4-4.0; P < .001). Overall mortality was similar between the two groups. CONCLUSION In a comparison of black and white patients with AIH in Europe, we found that black patients present at a younger age, have higher levels of IgG levels, and a greater proportion have SLE. We also found black patients to have a greater risk of liver transplantation and liver-related mortality, indicating more aggressive disease.
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Affiliation(s)
- Ynto S de Boer
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers - VU University Medical Center, Amsterdam, the Netherlands; Institute of Liver Studies, King's College Hospital, Denmark Hill, London, London, United Kingdom
| | - Alessio Gerussi
- Sheila Sherlock Liver Centre and UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, United Kingdom; Department of Medicine, University of Udine, Udine, Italy
| | - Floris F van den Brand
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers - VU University Medical Center, Amsterdam, the Netherlands
| | - Guan-Wee Wong
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London, London, United Kingdom
| | - Neil Halliday
- Sheila Sherlock Liver Centre and UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, United Kingdom; Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London, Royal Free Hospital, London, United Kingdom
| | - Rodrigo Liberal
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London, London, United Kingdom
| | - Joost P H Drenth
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Douglas Thorburn
- Sheila Sherlock Liver Centre and UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, United Kingdom
| | - Gerd Bouma
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers - VU University Medical Center, Amsterdam, the Netherlands
| | - Michael A Heneghan
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London, London, United Kingdom.
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Doycheva I, Watt KD, Gulamhusein AF. Autoimmune hepatitis: Current and future therapeutic options. Liver Int 2019; 39:1002-1013. [PMID: 30716203 DOI: 10.1111/liv.14062] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2018] [Revised: 01/13/2019] [Accepted: 01/17/2019] [Indexed: 02/13/2023]
Abstract
Autoimmune hepatitis (AIH) is a rare immune-mediated liver disease with few major advances in treatment options over the last several decades. Available options are effective in most patients albeit are imprecise in their mechanisms. Novel and more tolerable induction regimens and alternative options for management of patients intolerant or with suboptimal response to traditional therapies including in the post-transplant setting remain an important unmet need. This review aims to summarize recent data on pharmacological options and investigational drugs in development for patients with AIH. Standard therapy using prednisone with or without azathioprine remains the mainstay of therapy and is effective in most patients. Budesonide may be considered for induction in early disease and in those with mild fibrosis, but has not been approved for maintenance therapy. Mycophenolate mofetil (MMF) in combination with steroids might be an alternative first-line therapy, but results from a randomized trial are awaited. MMF as a second-line maintenance agent has moderate efficacy though more frequent adverse events in patients with cirrhosis may be seen. Tacrolimus may be an equally effective second-line option particularly in non-responders, but data remain limited. Management of recurrent AIH post-liver transplantation remains controversial with insufficient data to support long-term steroid use. Moving forward, expanding the scope of therapeutic options to include biologics including B-cell depleting agents may be a promising step. Recent insights in understanding the pathogenesis of AIH could serve as a basis for future therapies, including the elucidation of different immunoregulatory pathways and the potential role of the intestinal microbiome.
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Affiliation(s)
- Iliana Doycheva
- Division of Gastroenterology and Hepatology, Medical University, Sofia, Bulgaria
| | - Kymberly D Watt
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Aliya F Gulamhusein
- Toronto Centre for Liver Disease, Division of Gastroenterology and Hepatology, University Health Network, Toronto, ON, Canada
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Di Giorgio A, D'Adda A, Marseglia A, Sonzogni A, Licini L, Nicastro E, D'Antiga L. Biliary features in liver histology of children with autoimmune liver disease. Hepatol Int 2019; 13:510-518. [PMID: 31069759 DOI: 10.1007/s12072-019-09948-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Accepted: 04/20/2019] [Indexed: 12/23/2022]
Abstract
OBJECTIVES AND STUDY Various degrees of biliary changes are considered to be part of the histological picture of children with pediatrics autoimmune liver disease (AILD), but the literature is scarce and confusing. We aimed to describe the characteristics of children with AILD (autoimmune hepatitis, AIH, and autoimmune sclerosing cholangitis, ASC) focusing on the prevalence and type of biliary abnormalities on initial biopsy to see whether ASC was predictable on histological ground. METHODS The files of children diagnosed with AILD were reviewed. The Ishak score was used to grade inflammation and fibrosis on biopsy; a biliary score was built to grade bile duct injury. Demographic, laboratory and histological features at diagnosis were reported and compared between the two groups (AIH vs ASC). RESULTS Forty-one patients were diagnosed with AIH (n = 24), ASC (n = 13) and PSC (n = 4) between 2009 and 2018. Twenty-nine patients [F = 76%, AIH = 20, ASC = 9, median age at diagnosis 11.7 (range 2.2-17.8)] were included in the study; 12 (4 with PSC) were excluded. Prevalence of inflammatory bowel disease was higher in ASC group (56% vs 10% in AIH, p < 0.05). On histology 17% had cirrhosis. The grade of biliopathy with AILD was moderate in 72% and severe in 31%, and overall more prominent in ASC (p = 0.031). The inflammation of the bile ducts was classified as "multifocal" or "diffuse" mainly in ASC patients (89% vs 45% in AIH, p = 0.043). Periductular fibrosis was reported in 52% of AILD patients, with a higher mean score in ASC group (p < 0.05). However, ductular reaction, biliary metaplasia and granulomatous cholangitis were equally reported in AIH and ASC, providing no clear-cut for the distinction of the two entities in the global histological evaluation. CONCLUSIONS Majority of patients with pediatrics AILD have "moderate" or "severe" features of biliopathy; AIH and ASC are not easily distinguishable on histological ground at diagnosis, and therefore, the cholangiogram remains the only effective tool to differentiate patients with AIH from those with ASC. Further prospective studies are needed to better define histological biliary features in AILD, assess if the biliopathy responds to immunosuppressive treatment and evaluate its impact on long-term outcome.
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Affiliation(s)
- Angelo Di Giorgio
- Paediatric Hepatology, Gastroenterology and Transplantation, Hospital Papa Giovanni XXIII, Piazza Oms 1, 24127, Bergamo, Italy.
| | - A D'Adda
- Paediatric Hepatology, Gastroenterology and Transplantation, Hospital Papa Giovanni XXIII, Piazza Oms 1, 24127, Bergamo, Italy
| | - A Marseglia
- Paediatric Hepatology, Gastroenterology and Transplantation, Hospital Papa Giovanni XXIII, Piazza Oms 1, 24127, Bergamo, Italy
| | - A Sonzogni
- Liver Pathology, Hospital Papa Giovanni XXIII, Bergamo, Italy
| | - L Licini
- Liver Pathology, Hospital Papa Giovanni XXIII, Bergamo, Italy
| | - E Nicastro
- Paediatric Hepatology, Gastroenterology and Transplantation, Hospital Papa Giovanni XXIII, Piazza Oms 1, 24127, Bergamo, Italy
| | - L D'Antiga
- Paediatric Hepatology, Gastroenterology and Transplantation, Hospital Papa Giovanni XXIII, Piazza Oms 1, 24127, Bergamo, Italy
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30
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Wehrman A, Waisbourd-Zinman O, Shah A, Hilmara D, Lin H, Rand EB. Steroid Free Treatment of Autoimmune Hepatitis in Selected Children. J Pediatr 2019; 207:244-247. [PMID: 30723013 DOI: 10.1016/j.jpeds.2018.12.070] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Revised: 12/10/2018] [Accepted: 12/31/2018] [Indexed: 12/29/2022]
Abstract
Current guidelines recommend steroids for induction of remission in all children diagnosed with autoimmune hepatitis regardless of the clinical presentation. In this report, we describe our experience in treating selected asymptomatic children with autoimmune hepatitis using a steroid-free regimen; this treatment strategy was safe and effective in inducing remission.
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Affiliation(s)
- Andrew Wehrman
- Children's Hospital of Philadelphia, Division of Gastroenterology, Hepatology, and Nutrition, Philadelphia, PA
| | - Orith Waisbourd-Zinman
- Children's Hospital of Philadelphia, Division of Gastroenterology, Hepatology, and Nutrition, Philadelphia, PA; Schneider Children's Medical Center of Israel, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Amit Shah
- Children's Hospital of Philadelphia, Division of Gastroenterology, Hepatology, and Nutrition, Philadelphia, PA
| | - Didja Hilmara
- College of Arts and Sciences, University of Pennsylvania, Philadelphia, PA
| | - Henry Lin
- Children's Hospital of Philadelphia, Division of Gastroenterology, Hepatology, and Nutrition, Philadelphia, PA
| | - Elizabeth B Rand
- Children's Hospital of Philadelphia, Division of Gastroenterology, Hepatology, and Nutrition, Philadelphia, PA.
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31
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Arcos-Machancoses JV, Molera Busoms C, Julio Tatis E, Bovo MV, Martín de Carpi J. Accuracy of the Simplified Criteria for Autoimmune Hepatitis in Children: Systematic Review and Decision Analysis. J Clin Exp Hepatol 2019; 9:147-155. [PMID: 31024195 PMCID: PMC6477136 DOI: 10.1016/j.jceh.2018.10.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Accepted: 10/30/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND/OBJECTIVES Several studies have been conducted on the accuracy of simplified criteria for autoimmune hepatitis that were presented in 2008 as an alternative to original criteria. Our purpose is to summarize the evidence available regarding their accuracy in children and to carry out a basic clinical decision analysis based on it. METHODS Electronic and manual searches were performed with keywords related to diagnostic validity terms. Data from included studies were extracted, and summary estimates of accuracy measures were calculated. An effect model was chosen depending on heterogeneity, and the presence of publication bias was also studied. Therapeutic threshold was calculated based on the already published data. Through a Bayesian approach, simplified criteria's clinical utility was simulated, taking into account the meta-analyzed indicators and several assumptions on the prevalence of autoimmune hepatitis. RESULTS The search yielded 166 studies, four of which were finally included, providing a total population of 437 patients. Pooled sensitivity and specificity of the simplified criteria for the diagnosis of autoimmune hepatitis in children was 77% and 95%, respectively, with a diagnostic odds ratio of 67. No evidence of publication bias was found. For prevalences ranging from 8.5 to 85.7, the predictive value of either a positive or a negative result moved beyond the therapeutic threshold (estimated at 56%). CONCLUSIONS The simplified criteria show high specificity and moderate sensitivity for the diagnosis of autoimmune hepatitis in children. A positive result can justify starting a therapeutic assay, but a negative result does not seem sufficient to rule out this condition.
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Affiliation(s)
- José V. Arcos-Machancoses
- Address for correspondence: J. V. Arcos-Machancoses, Sant Joan de Déu Hospital, Barcelona. Department of Pediatric Gastroenterology, Hepatology and Nutrition. Passeig de Sant Joan de Déu, 2, 08950 Esplugues de Llobregat, Barcelona (Catalonia), Spain.
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32
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Juvenile autoimmune hepatitis: A comprehensive review. J Autoimmun 2018; 95:69-76. [DOI: 10.1016/j.jaut.2018.10.007] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2018] [Accepted: 10/13/2018] [Indexed: 12/12/2022]
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Costaguta A, González A, Pochettino S, Trotta L, Vicentín R, Wagener M. Incidence and Clinical Features of Autoimmune Hepatitis in the Province of Santa Fe (Argentina). J Pediatr Gastroenterol Nutr 2018; 67:e107-e110. [PMID: 30095578 DOI: 10.1097/mpg.0000000000002122] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJETIVES The aim of the study is to investigate the incidence and clinical features of autoimmune hepatitis (AIH) in children from the province of Santa Fe, Argentina, for 10 years. METHODS From the records of all of the pediatric hepatologists in the province of Santa Fe, Argentina, we reviewed the clinical charts of patients <18 years who were diagnosed with AIH (simplified score >6 points) and followed between January 2003 and December 2013. Population data were extracted from the 2010 national census. Values were expressed as percentages and median ± interquartile range. Mann-Whitney U test was used for comparison between the groups. RESULTS Sixty-seven patients fulfilled inclusion criteria, from which 11 (16%) were later reclassified as having "autoimmune sclerosing cholangitis" according to biochemical, histological, and radiological findings. A final sample of 56 patients (39 F) with AIH was analyzed, giving an annual incidence of 0.56/100,000. Median age at presentation was 8 (5.7-11) years, and the median follow-up was 4 (2-7) years. Type 1 AIH was diagnosed in 89%. An acute presentation was observed in 53%, while 13 (23%) showed cirrhosis on initial biopsy. Prednisone (87%) and azathioprine (60%) were the most common drugs prescribed. At the end of follow-up, 53/56 (95%) were alive, including 4 patients (7%) who underwent liver transplantation. CONCLUSIONS AIH has an estimated incidence of 0.56/100,000 per year in children from the province of Santa Fe (Argentina). Overall survival rate was 95%. A subgroup of patients diagnosed as AIH develops predominant biliary disease and should be better classified as autoimmune sclerosing cholangitis.
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Affiliation(s)
| | | | | | - Liliana Trotta
- Division of Hepatology, Hospital de Niños, Santa Fe (SF), Argentina
| | - Rosalía Vicentín
- Division of Hepatology, Hospital de Niños, Santa Fe (SF), Argentina
| | - Marta Wagener
- Division of Hepatology, Hospital de Niños, Santa Fe (SF), Argentina
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Terziroli Beretta-Piccoli B, Mieli-Vergani G, Vergani D. The clinical usage and definition of autoantibodies in immune-mediated liver disease: A comprehensive overview. J Autoimmun 2018; 95:144-158. [DOI: 10.1016/j.jaut.2018.10.004] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Revised: 10/09/2018] [Accepted: 10/11/2018] [Indexed: 02/06/2023]
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Arterbery AS, Yao J, Ling A, Avitzur Y, Martinez M, Lobritto S, Deng Y, Geliang G, Mehta S, Wang G, Knight J, Ekong UD. Inflammasome Priming Mediated via Toll-Like Receptors 2 and 4, Induces Th1-Like Regulatory T Cells in De Novo Autoimmune Hepatitis. Front Immunol 2018; 9:1612. [PMID: 30072988 PMCID: PMC6060440 DOI: 10.3389/fimmu.2018.01612] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Accepted: 06/28/2018] [Indexed: 12/13/2022] Open
Abstract
De novo autoimmune hepatitis (DAIH) is an important cause of late allograft dysfunction following liver transplantation, but its cause and underlying pathogenesis remains unclear. We sought to identify specific innate and adaptive immune mechanisms driving the pro-inflammatory cytokine secreting regulatory T cell (Treg) phenotype in DAIH and determine if modulation of these pathways could resolve the inflammatory milieu observed in the livers of patients with DAIH. Here, we demonstrate toll-like receptors (TLRs) 2- and 4-mediated inflammasome activation in CD14++ monocytes, a finding that is key to maintaining dysfunctional Tregs in patients with DAIH. Furthermore, silencing of TLR 2 and 4 in CD14++ monocytes prevented activation of the inflammasome and significantly decreased IFN-γ production by FOXP3+ Tregs. We also observed significantly increase in expression of tumor necrosis factor α-induced protein 3 (TNFAIP3), a negative regulator of the NLRP3 Inflammasome, in monocytes/macrophages of liver transplant subjects who have normal allograft function and do not have DAIH. TNFAIP3 expression was virtually absent in monocytes/macrophages of patients with DAIH. Our findings suggest that autoimmunity in DAIH is promoted by CD14++ monocytes predominantly through activation of inflammatory signaling pathways.
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Affiliation(s)
- Adam S. Arterbery
- Pediatric Gastroenterology and Hepatology, Yale University, New Haven, CT, United States
| | - Jie Yao
- Pediatric Gastroenterology and Hepatology, Yale University, New Haven, CT, United States
| | - Andrew Ling
- Pediatric Gastroenterology and Hepatology, Yale University, New Haven, CT, United States
| | - Yaron Avitzur
- Gastroenterology, Hepatology, and Nutrition, Hospital for Sick Children, Toronto, ON, Canada
| | - Mercedes Martinez
- Pediatric Gastroenterology, Hepatology, and Nutrition, Columbia University, New York, NY, United States
| | - Steven Lobritto
- Pediatric Gastroenterology, Hepatology, and Nutrition, Columbia University, New York, NY, United States
| | - Yanhong Deng
- Yale Center for Analytical Sciences, New Haven, CT, United States
| | - Gan Geliang
- Yale Center for Analytical Sciences, New Haven, CT, United States
| | - Sameet Mehta
- Yale Center for Genome Analysis, Yale School of Medicine, New Haven, CT, United States
| | - Guilin Wang
- Yale Center for Genome Analysis, Yale School of Medicine, New Haven, CT, United States
| | - James Knight
- Yale Center for Genome Analysis, Yale School of Medicine, New Haven, CT, United States
| | - Udeme D. Ekong
- Pediatric Gastroenterology and Hepatology, Yale University, New Haven, CT, United States
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Dyson JK, Beuers U, Jones DEJ, Lohse AW, Hudson M. Primary sclerosing cholangitis. Lancet 2018; 391:2547-2559. [PMID: 29452711 DOI: 10.1016/s0140-6736(18)30300-3] [Citation(s) in RCA: 273] [Impact Index Per Article: 39.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2016] [Revised: 11/24/2017] [Accepted: 01/03/2018] [Indexed: 12/13/2022]
Abstract
Primary sclerosing cholangitis is a rare, chronic cholestatic liver disease characterised by intrahepatic or extrahepatic stricturing, or both, with bile duct fibrosis. Inflammation and fibrosis of bile ducts and the liver are followed by impaired bile formation or flow and progressive liver dysfunction. Patients might be asymptomatic at presentation or might have pruritus, fatigue, right upper quadrant pain, recurrent cholangitis, or sequelae of portal hypertension. The key diagnostic elements are cholestatic liver biochemistry and bile duct stricturing on cholangiography. Genetic and environmental factors are important in the cause of the disease, with the intestinal microbiome increasingly thought to play a pathogenetic role. Approximately 70% of patients have concurrent inflammatory bowel disease and patients require colonoscopic screening and surveillance. Primary sclerosing cholangitis is associated with increased malignancy risk and surveillance strategies for early cholangiocarcinoma detection are limited. No single drug has been proven to improve transplant-free survival. Liver transplantation is effective for advanced disease but at least 25% of patients develop recurrent disease in the graft.
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Affiliation(s)
- Jessica K Dyson
- Department of Hepatology, Newcastle upon Tyne Hospitals NHS Foundation Trust and Institute of Cellular Medicine, Newcastle University, Newcastle, UK.
| | - Ulrich Beuers
- Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - David E J Jones
- Department of Hepatology, Newcastle upon Tyne Hospitals NHS Foundation Trust and Institute of Cellular Medicine, Newcastle University, Newcastle, UK
| | - Ansgar W Lohse
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Mark Hudson
- Department of Hepatology, Newcastle upon Tyne Hospitals NHS Foundation Trust and Institute of Cellular Medicine, Newcastle University, Newcastle, UK
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Abstract
OBJECTIVES The aim of this study was to evaluate the effect of autoimmune hepatitis (AIH) on the quality of life of children and adolescents and to identify which variables effect health-related quality of life (HRQoL). METHODS The Pediatric Quality of Life Inventory 4.0 (PedsQL 4.0) was used to evaluate HRQoL. In addition, a questionnaire was applied which included signs, symptoms, and use of medications. RESULTS A total of 43 patients (mean age, 15.0 ± 3.9 years; 65.1% girls; 90.7% with type 1 AIH) was evaluated. Advanced liver disease was present in 30.2%, and 18.6% had sclerosing cholangitis. Treatment was effective in 93.1% of patients. The lowest HRQoL scores were associated with the school (67.7), emotional (68.2), and psychosocial (75.5) domains. Compared with healthy children, patients presented lower scores on the total, psychosocial, emotional, and school domains (P < 0.05). The presence of symptoms (β = 0.39, P < 0.01), extrahepatic autoimmune diseases (β = 0.27, P < 0.05), and a dislike of taking medication (β = 0.40, P < 0.01) negatively affected the psychosocial PedsQL 4.0 score, and the presence of symptoms (β = 0.40, P < 0.01) negatively affected the total PedsQL 4.0 score. CONCLUSIONS AIH has a significant and negative effect on HRQoL among children and adolescents. The presence of symptoms, extrahepatic autoimmune diseases, and a dislike of taking medication were associated with the worsening of HRQoL. Providers should work with professionals trained to improve QoL to help improve treatment adherence and disease outcomes.
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Arcos-Machancoses JV, Molera Busoms C, Julio Tatis E, Victoria Bovo M, Quintero Bernabeu J, Juampérez Goñi J, Crujeiras Martínez V, Martin de Carpi J. Accuracy of the 2008 Simplified Criteria for the Diagnosis of Autoimmune Hepatitis in Children. Pediatr Gastroenterol Hepatol Nutr 2018; 21:118-126. [PMID: 29713609 PMCID: PMC5915689 DOI: 10.5223/pghn.2018.21.2.118] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Revised: 11/28/2017] [Accepted: 12/18/2017] [Indexed: 02/07/2023] Open
Abstract
PURPOSE Classical criteria for diagnosis of autoimmune hepatitis (AIH) are intended as research tool and are difficult to apply at patient's bedside. We aimed to study the accuracy of simplified criteria and the concordance with the expert diagnosis based on the original criteria. METHODS A cohort of children under study for liver disorder was selected through consecutive sampling to obtain the prevalence of AIH within the group of differential diagnoses. AIH was defined, based on classical criteria, through committee review of medical reports. Validity indicators of the simplified criteria were obtained in an intention to diagnose approach. Optimal cut-off and the area under the receiver operating characteristic (ROC) curve were calculated. RESULTS Out of 212 cases reviewed, 47.2% were AIH. For the optimal cut-off (6 points), the simplified criteria showed a sensitivity of 72.0% and a specificity of 96.4%, with a 94.7% positive and a 79.4% negative predictive value. The area under the ROC curve was 94.3%. There was a good agreement in the pre-treatment concordance between the classical and the simplified criteria (kappa index, 0.775). CONCLUSION Simplified criteria provide a moderate sensitivity for the diagnosis of AIH, but may help in indicating treatment in cases under suspicion with 6 or more points.
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Affiliation(s)
| | - Cristina Molera Busoms
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Sant Joan de Déu Hospital (SJDH), Barcelona, Spain.,SJDH-VHH Comprehensive Unit of Complex Hepatology and Pediatric Liver Transplantation, Barcelona, Spain
| | - Ecaterina Julio Tatis
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Sant Joan de Déu Hospital (SJDH), Barcelona, Spain
| | - María Victoria Bovo
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Sant Joan de Déu Hospital (SJDH), Barcelona, Spain
| | - Jesús Quintero Bernabeu
- Department of Pediatric Gastroenterology and Hepatology, Vall d'Hebron Hospital (VHH), Barcelona, Spain.,SJDH-VHH Comprehensive Unit of Complex Hepatology and Pediatric Liver Transplantation, Barcelona, Spain
| | - Javier Juampérez Goñi
- Department of Pediatric Gastroenterology and Hepatology, Vall d'Hebron Hospital (VHH), Barcelona, Spain.,SJDH-VHH Comprehensive Unit of Complex Hepatology and Pediatric Liver Transplantation, Barcelona, Spain
| | - Vanessa Crujeiras Martínez
- Department of Pediatric Gastroenterology and Hepatology, University Hospital Complex of Santiago de Compostela, Santiago de Compostela, Spain
| | - Javier Martin de Carpi
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Sant Joan de Déu Hospital (SJDH), Barcelona, Spain.,SJDH-VHH Comprehensive Unit of Complex Hepatology and Pediatric Liver Transplantation, Barcelona, Spain
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de Boer YS, Liberal R, Vergani D, Mieli-Vergani G. Real-world management of juvenile autoimmune liver disease. United European Gastroenterol J 2018; 6:1032-1038. [PMID: 30228891 PMCID: PMC6137590 DOI: 10.1177/2050640618768922] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2018] [Accepted: 03/12/2018] [Indexed: 02/06/2023] Open
Abstract
Background and aims Juvenile autoimmune liver disease (JAILD) includes paediatric forms of autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (ASC). Since evidence is scarce, there are currently no evidence-based management guidelines for juvenile AIH. This survey was carried out amongst the paediatric members of the International AIH Group (IAIHG) to describe their practices in the management of JAILD. Methods An online survey questionnaire was distributed to members of the IAIHG with active practice (https://www.surveymonkey.de/r/Juvenile_AILD). The questionnaire consisted of four clinical scenarios on different presentations of AIH. Results Fifty-eight surveys were sent to the IAIHG members, out of which 43 (74%, 22 countries, four continents) were returned. None reported budesonide as a first-line induction agent for the acute presentation of AIH. Sixteen (37%) routinely perform liver biopsy at three years of biochemical remission. Thirty-five respondents (81%) perform magnetic resonance cholangiography (MRC) at presentation. Ciclosporin is the most widely used second-line agent (number of patients treated = ∼360, 21 centres). Mycophenolate mofetil (n = ∼225, 31 centres), tacrolimus (n = ∼130, 21 centres) and sirolimus (n = ∼5, 3 centres) are less often reported. Rescue therapy with infliximab and rituximab has been tried in eight centres (n = ∼19) and nine centres (n = ∼16), respectively. Conclusions Prednisolone remains the preferred first-line induction agent in JAILD. MRC at presentation is performed by the large majority of participants. Participants reported a wide variation in performing liver biopsy for therapy evaluation during follow-up. Within the paediatric members of the IAIHG there is considerable experience with second-line therapeutic agents.
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Affiliation(s)
- Y S de Boer
- Department of Gastroenterology and Hepatology, VU University Medical Center, The Netherlands
| | - R Liberal
- Institute of Liver Studies, King's College London, UK
| | - D Vergani
- Institute of Liver Studies, King's College London, UK
| | - G Mieli-Vergani
- Institute of Liver Studies, King's College London, UK.,Paediatric Liver, GI and Nutrition Centre, King's College Hospital, UK
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Mieli-Vergani G, Vergani D, Baumann U, Czubkowski P, Debray D, Dezsofi A, Fischler B, Gupte G, Hierro L, Indolfi G, Jahnel J, Smets F, Verkade HJ, Hadžić N. Diagnosis and Management of Pediatric Autoimmune Liver Disease: ESPGHAN Hepatology Committee Position Statement. J Pediatr Gastroenterol Nutr 2018; 66:345-360. [PMID: 29356770 DOI: 10.1097/mpg.0000000000001801] [Citation(s) in RCA: 192] [Impact Index Per Article: 27.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Paediatric autoimmune liver disease is characterized by inflammatory liver histology, circulating autoantibodies, and increased levels of IgG, in the absence of a known etiology. Three conditions have a likely autoimmune pathogenesis: autoimmune hepatitis (AIH), autoimmune sclerosing cholangitis, and de novo AIH after liver transplantation. Two types of pediatric AIH are recognized according to seropositivity for smooth muscle and/or antinuclear antibody (AIH-1) or liver kidney microsomal type 1 and/or anti-liver cytosol type 1 antibodies (AIH-2).Pertinent issues addressing the diagnosis, treatment, and long-term follow-up were formulated by a core group of ESPGHAN members. They have commissioned the first authors with execution of this project. Initially, they have performed a systematic literature search on MEDLINE, ResearchGate, and Mendeley databases during the last 30 years and produced a document focusing on prospective and retrospective studies in children. The ESPGHAN core group and ESPGHAN Hepatology Committee members voted on each recommendation, using a formal voting technique.
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Affiliation(s)
| | - Diego Vergani
- MowatLabs, Paediatric Liver, GI & Nutrition Centre, King's College Hospital, London, UK
| | - Ulrich Baumann
- Pädiatrische Gastroenterologie und Hepatologie, Medizinische Hochschule, Hannover, Germany
| | - Piotr Czubkowski
- Department of Gastroenterology, Hepatology, Nutrition Disturbances and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland
| | - Dominique Debray
- Pediatric Hepatology Unit, AP-HP-Hôpital Necker Enfants Malades, Paris, France
| | - Antal Dezsofi
- First Department of Paediatrics, Semmelweis University, Budapest, Hungary
| | - Björn Fischler
- Department of Pediatrics, Karolinska University Hospital, CLINTEC, Karolinska Institutet, Stockholm, Sweden
| | - Girish Gupte
- Liver Unit (Including Small Bowel Transplantation), Department of Gastroenterology and Nutrition, Birmingham Children's Hospital, Birmingham, UK
| | - Loreto Hierro
- Hospital Infantil Universitario La Paz, Madrid, Spain
| | - Giuseppe Indolfi
- Paediatric and Liver Unit, Meyer Children's University Hospital of Florence, Firenze, Italy
| | - Jörg Jahnel
- Division of General Pediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
| | - Françoise Smets
- UCL, Cliniques Universitaires Saint-Luc, Pediatric Gastroenterology and Hepatology, Brussels, Belgium
| | - Henkjan J Verkade
- Dept of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, Groningen, the Netherlands
| | - Nedim Hadžić
- MowatLabs, Paediatric Liver, GI & Nutrition Centre, King's College Hospital, London, UK
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41
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Autoimmune Hepatitis and Autoimmune Hepatitis Overlap With Sclerosing Cholangitis: Immunophenotype Markers in Children and Adolescents. J Pediatr Gastroenterol Nutr 2018; 66:204-211. [PMID: 29045346 DOI: 10.1097/mpg.0000000000001783] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
OBJECTIVE The pathophysiology of autoimmune hepatitis (AIH) may involve the activation of immune cells and changes in the expression of cellular markers. The aim of the present study was to characterize the immunophenotype markers of lymphocytes and monocytes in the peripheral blood of children and adolescents with type 1 AIH and AIH overlap with sclerosing cholangitis (overlap syndrome [OS]). METHODS This is a cross-sectional study of 20 children and adolescents diagnosed with type 1 AIH and 19 with OS. Fifteen healthy subjects were included as controls. Flow cytometric analysis was used to identify markers of inflammation and autoimmunity. RESULTS The total number of CD4 T cells was higher in the AIH patients compared with the controls. The number of CD4 T cells expressing CCR3 and CD28 was higher in the AIH group than in the control group. CD45RO was more highly expressed in the AIH group, whereas CD45RA was more highly expressed in the OS group. In regard to CD8 T lymphocytes, the CCR3 expression was higher in both groups of patients. Patients with OS had the highest expression of CD45RA and CD25. In monocytes, human leukocyte antigen DR (HLA-DR) was less expressed in both groups of patients. CONCLUSIONS Complex phenotype features may be involved in the pathophysiology of AIH, accounting for changes in immune system regulation mechanisms. In conclusion, even after good response to treatment, patients still have immune activity signals at the cellular level.
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42
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Characteristics of autoimmune hepatitis in a sample of Egyptian children. EGYPTIAN PEDIATRIC ASSOCIATION GAZETTE 2017. [DOI: 10.1016/j.epag.2017.11.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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43
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Terziroli Beretta-Piccoli B, Invernizzi P, Gershwin ME, Mainetti C. Skin Manifestations Associated with Autoimmune Liver Diseases: a Systematic Review. Clin Rev Allergy Immunol 2017; 53:394-412. [DOI: 10.1007/s12016-017-8649-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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44
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Zizzo AN, Jimenez-Rivera C, Kim J, Schreiber RA, Ling SC, Yap J, Critch J, Ahmed N, Alvarez F, Kamath BM. A national retrospective study of paediatric end-stage liver disease as a predictor of change to second-line therapy in children with autoimmune hepatitis. Liver Int 2017; 37:1562-1570. [PMID: 28199778 DOI: 10.1111/liv.13387] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2016] [Accepted: 02/05/2017] [Indexed: 12/24/2022]
Abstract
BACKGROUND & AIMS Adult studies of autoimmune hepatitis (AIH) have shown that the model of end-stage liver disease is associated with resistance to first-line treatment. Using a multicentre retrospective database, we sought to determine if the paediatric end-stage liver disease (PELD) score would similarly predict treatment resistance in paediatric AIH. METHODS One hundred and seventy-one children from 13 Canadian centres who fulfilled the International Autoimmune Hepatitis Group (IAIHG) criteria were included and assessed for change to second-line therapy within 24 months of primary treatment onset. Those with PSC overlap at presentation, or missing data on the PELD variables were excluded. PELD was calculated for all remaining patients. Univariate analysis and receiver-operator characteristic (ROC) curves were performed to determine the predictive ability of the PELD score to change to second-line therapy. RESULTS A total of 103 children were included with median age of 11 years (range 2-17). Mean PELD was -2.51±8.58. Second-line therapy was used within 24 months of diagnosis in 13 patients. Univariate analysis revealed that change to second-line therapy was associated with higher PELD (P=.028) and internal normalized ratio (INR) (P=.011). ROC curves for PELD and its individual components were performed. The strength of association was strongest with INR (AUC 0.72; CI: 0.58-0.86) although the composite PELD score also showed some predictive ability (AUC 0.67; CI: 0.52-0.81). CONCLUSION In this paediatric AIH cohort, higher PELD at presentation predicted change to second-line therapy within the first 2 years of follow-up. INR appeared to be the main contributor to that association.
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Affiliation(s)
- Andréanne N Zizzo
- Division of Gastroenterology, Department of Paediatrics, London Children's Hospital, Western University, London, ON, Canada
| | - Carolina Jimenez-Rivera
- Division of Gastroenterology, Hepatology and Nutrition, Department of Paediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON, Canada
| | - Joseph Kim
- Department of Medicine, University Health Network, University of Toronto, Toronto, ON, Canada
| | - Richard A Schreiber
- Division of Paediatric Gastroenterology, Hepatology and Nutrition, Department of Paediatrics, University of British Columbia, Vancouver, BC, Canada.,Child and Family Research Institute, Vancouver, BC, Canada
| | - Simon C Ling
- Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, ON, Canada.,Department of Paediatrics, University of Toronto, Toronto, ON, Canada
| | - Jason Yap
- Division of Paediatric Gastroenterology and Nutrition, Department of Paediatrics, University of Alberta, Edmonton, AB, Canada
| | - Jeff Critch
- Department of Paediatrics, Faculty of Medicine, Memorial University, St. John's, NL, Canada
| | - Najma Ahmed
- Division of Paediatric Gastroenterology and Nutrition, Montreal Children's Hospital, McGill University, Montreal, QC, Canada
| | - Fernando Alvarez
- Division of Gastroenterology, Hepatology and Nutrition, Department of Paediatrics, Hôpital Sainte-Justine, Université de Montréal, Montreal, QC, Canada
| | - Binita M Kamath
- Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, ON, Canada.,Department of Paediatrics, University of Toronto, Toronto, ON, Canada
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Di Giorgio A, Sonzogni A, Piccichè A, Alessio G, Bonanomi E, Colledan M, D'Antiga L. Successful management of acute liver failure in Italian children: A 16-year experience at a referral centre for paediatric liver transplantation. Dig Liver Dis 2017; 49:1139-1145. [PMID: 28663066 DOI: 10.1016/j.dld.2017.05.026] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Revised: 04/18/2017] [Accepted: 05/30/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND Identifying the causes of acute liver failure (ALF) and predictors of death or liver transplantation (LTX) is crucial to decide its management. We aimed to describe features and outcome of ALF in Italian children. METHODS Retrospective review of cases presenting between 1996-2012. ALF was defined by high transaminases, INR ≥2.0 regardless of hepatic encephalopathy (HE), no evidence of underlying chronic liver disease. RESULTS 55 children (median age 2.6 years, range 0.1-15.1; M/F=31/24) had ALF due to autoimmune hepatitis (AIH) in 10 (18%), metabolic disorders in 9 (17%), paracetamol overdose in 6 (11%), mushroom poisoning in 3 (5%), viral infection in 1 (2%), indeterminate in 26 (47%); 25/55 recovered with supportive management (45%); 28/55 underwent LTX and 2 died on the waiting list (55%). On multivariate analysis severity of HE grade 3-4 and bilirubin ≥12mg/dl were independent predictors of death or LTX (p<0.05). After a median follow up of 4 years (range 2-15.0 years) the overall survival rate was 93%. CONCLUSION Children with ALF can be managed successfully with combined medical treatment and transplantation, warranting a survival rate similar to children transplanted because of chronic conditions. In our cohort of patients severe HE and high bilirubin on admission were independent predictors of the need of LTX.
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Affiliation(s)
- A Di Giorgio
- Paediatric Hepatology, Gastroenterology and Transplantation, Hospital Papa Giovanni XXIII Bergamo, Italy
| | - A Sonzogni
- Liver and Transplant Pathology, Hospital Papa Giovanni XXIII Bergamo, Italy
| | - A Piccichè
- Hospital Management, Hospital Papa Giovanni XXIII Bergamo, Italy
| | - G Alessio
- Laboratory Medicine, Hospital Papa Giovanni XXIII Bergamo, Italy
| | - E Bonanomi
- Paediatric Intensive Care Unit, Hospital Papa Giovanni XXIII Bergamo, Italy
| | - M Colledan
- General Surgery and Transplantation, Hospital Papa Giovanni XXIII Bergamo, Italy
| | - L D'Antiga
- Paediatric Hepatology, Gastroenterology and Transplantation, Hospital Papa Giovanni XXIII Bergamo, Italy.
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46
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Terziroli Beretta-Piccoli B, Mieli-Vergani G, Vergani D. Autoimmune hepatitis: Standard treatment and systematic review of alternative treatments. World J Gastroenterol 2017; 23:6030-6048. [PMID: 28970719 PMCID: PMC5597495 DOI: 10.3748/wjg.v23.i33.6030] [Citation(s) in RCA: 85] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Revised: 07/18/2017] [Accepted: 08/02/2017] [Indexed: 02/06/2023] Open
Abstract
Autoimmune hepatitis is a rare chronic inflammatory liver disease, affecting all ages, characterised by elevated transaminase and immunoglobulin G levels, positive autoantibodies, interface hepatitis at liver histology and good response to immunosuppressive treatment. If untreated, it has a poor prognosis. The aim of this review is to summarize the evidence for standard treatment and to provide a systematic review on alternative treatments for adults and children. Standard treatment is based on steroids and azathioprine, and leads to disease remission in 80%-90% of patients. Alternative first line treatment has been attempted with budesonide or cyclosporine, but their superiority compared to standard treatment remains to be demonstrated. Second-line treatments are needed for patients not responding or intolerant to standard treatment. No randomized controlled trials have been performed for second-line options. Mycophenolate mofetil is the most widely used second-line drug, and has good efficacy particularly for patients intolerant to azathioprine, but has the major disadvantage of being teratogenic. Only few and heterogeneous data on cyclosporine, tacrolimus, everolimus and sirolimus are available. More recently, experience with the anti-tumour necrosis factor-alpha infliximab and the anti-CD20 rituximab has been published, with ambivalent results; these agents may have severe side-effects and their use should be restricted to specialized centres. Clinical trials with new therapeutic options are ongoing.
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Affiliation(s)
| | - Giorgina Mieli-Vergani
- Paediatric Liver, GI and Nutrition Centre, MowatLabs, King’s College Hospital, Denmark Hill, London SE5 9RS, United Kingdom
| | - Diego Vergani
- Institute of Liver Studies, MowatLabs, King’s College Hospital, Denmark Hill, London SE5 9RS, United Kingdom
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47
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Jarasvaraparn C, Imran H, Siddiqui A, Wilson F, Gremse DA. Association of autoimmune hepatitis type 1 in a child with Evans syndrome. World J Hepatol 2017; 9:1008-1012. [PMID: 28878866 PMCID: PMC5569276 DOI: 10.4254/wjh.v9.i23.1008] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Revised: 04/26/2017] [Accepted: 07/10/2017] [Indexed: 02/06/2023] Open
Abstract
Autoimmune hepatitis (AIH) is a progressive liver disease that is often associated with extrahepatic autoimmune disorders. Evans syndrome (ES) is a rare autoimmune disorder, which is characterized by immune thrombocytopenia and autoimmune hemolytic anemia. Association of AIH with ES is rare, especially in children. We report a 3-year-old female with a past medical history of ES who presented with jaundice and significant transaminitis due to AIH type 1. She required multiple treatments with steroids as well as azathioprine, intravenous immunoglobulin and a course of rituximab.
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48
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Mycophenolate mofetil embryopathy: A newly recognized teratogenic syndrome. Eur J Med Genet 2017; 60:16-21. [DOI: 10.1016/j.ejmg.2016.09.014] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2016] [Accepted: 09/12/2016] [Indexed: 01/25/2023]
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49
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Yuksel M, Xiao X, Tai N, Vijay M, Gülden E, Beland K, Lapierre P, Alvarez F, Hu Z, Colle I, Ma Y, Wen L. The induction of autoimmune hepatitis in the human leucocyte antigen-DR4 non-obese diabetic mice autoimmune hepatitis mouse model. Clin Exp Immunol 2016; 186:164-176. [PMID: 27414259 DOI: 10.1111/cei.12843] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/12/2016] [Indexed: 12/17/2022] Open
Abstract
Autoimmune hepatitis (AIH) is a chronic liver disease characterized by progressive inflammation, female preponderance and seropositivity for autoantibodies such as anti-smooth muscle actin and/or anti-nuclear, anti-liver kidney microsomal type 1 (anti-LKM1) and anti-liver cytosol type 1 (anti-LC1) in more than 80% of cases. AIH is linked strongly to several major histocompatibility complex (MHC) alleles, including human leucocyte antigen (HLA)-DR3, -DR7 and -DR13. HLA-DR4 has the second strongest association with adult AIH, after HLA-DR3. We investigated the role of HLA-DR4 in the development of AIH by immunization of HLA-DR4 (DR4) transgenic non-obese diabetic (NOD) mice with DNA coding for human CYP2D6/FTCD fusion autoantigen. Immunization of DR4 mice leads to sustained mild liver injury, as assessed biochemically by elevated alanine aminotransferase, histologically by interface hepatitis, plasma cell infiltration and mild fibrosis and immunologically by the development of anti-LKM1/anti-LC1 antibodies. In addition, livers from DR4 mice had fewer regulatory T cells (Tregs ), which had decreased programmed death (PD)-1 expression. Splenic Tregs from these mice also showed impaired inhibitory capacity. Furthermore, DR4 expression enhanced the activation status of CD8+ T cells, macrophages and dendritic cells in naive DR4 mice compared to naive wild-type (WT) NOD mice. Our results demonstrate that HLA-DR4 is a susceptibility factor for the development of AIH. Impaired suppressive function of Tregs and reduced PD-1 expression may result in spontaneous activation of key immune cell subsets, such as antigen-presenting cells and CD8+ T effectors, facilitating the induction of AIH and persistent liver damage.
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Affiliation(s)
- M Yuksel
- Section of Endocrinology, Yale University School of Medicine, New Haven, USA.,Department of Hepatology and Gastroenterology, Ghent University Hospital, Belgium.,Institute of Liver Studies and Transplantation, King's College London Faculty of Life Sciences and Medicine, King's College Hospital, London, UK
| | - X Xiao
- Section of Endocrinology, Yale University School of Medicine, New Haven, USA.,Department of Nephrology, Qilu Hospital, Shandong University, China
| | - N Tai
- Section of Endocrinology, Yale University School of Medicine, New Haven, USA
| | - Manakkat Vijay
- Section of Endocrinology, Yale University School of Medicine, New Haven, USA.,Institute of Liver Studies and Transplantation, King's College London Faculty of Life Sciences and Medicine, King's College Hospital, London, UK
| | - E Gülden
- Section of Endocrinology, Yale University School of Medicine, New Haven, USA
| | - K Beland
- Division of Gastroenterology, Hepatology and Nutrition, Sainte-Justine University Hospital, Montreal, Canada
| | - P Lapierre
- Immunovirology Laboratory, Institut National De La Recherche Scientifique, INRS-Institut Armand-Frappier, Laval, Québec, Canada
| | - F Alvarez
- Division of Gastroenterology, Hepatology and Nutrition, Sainte-Justine University Hospital, Montreal, Canada
| | - Z Hu
- Department of Nephrology, Qilu Hospital, Shandong University, China
| | - I Colle
- Department of Hepatology and Gastroenterology, Ghent University Hospital, Belgium
| | - Y Ma
- Institute of Liver Studies and Transplantation, King's College London Faculty of Life Sciences and Medicine, King's College Hospital, London, UK
| | - L Wen
- Section of Endocrinology, Yale University School of Medicine, New Haven, USA.
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50
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Liberal R, Krawitt EL, Vierling JM, Manns MP, Mieli-Vergani G, Vergani D. Cutting edge issues in autoimmune hepatitis. J Autoimmun 2016; 75:6-19. [PMID: 27502148 DOI: 10.1016/j.jaut.2016.07.005] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Revised: 07/06/2016] [Accepted: 07/10/2016] [Indexed: 12/14/2022]
Abstract
Autoimmune hepatitis (AIH) is a severe liver disease affecting all age groups worldwide. Novel basic and clinical aspects of AIH, addressed at a Monothematic Conference in London in September 2015, are highlighted in this review. The diagnosis of AIH relies upon detection of characteristic autoantibodies, hypergammaglobulinemia, and interface hepatitis on liver histology. The International Autoimmune Hepatitis Group (IAIHG) has devised diagnostic scoring systems to help in comparative studies and clinical practice. AIH arises in a genetically predisposed host, when yet unknown triggers - such an encounter with a pathogen - lead to a T cell-mediated immune response targeting liver autoantigens. This immune response is inadequately controlled because regulatory mechanisms are impaired. The mainstay of treatment for AIH is immunosuppression, which should be instituted as soon as the diagnosis is made. Standard treatment regimens include relatively high doses of predniso(lo)ne, which are tapered gradually as azathioprine is introduced. Recent guidelines have described newer treatment regimens and have tightened the goal of therapy to complete normalization of biochemical, serological and histological parameters. Mycophenolate mofetil, calcineurin inhibitors, mTOR inhibitors and biological agents are potential salvage therapies, but should be reserved for selected non-responsive patients and administered only in experienced centers. Liver transplantation is a life-saving option for those patients who progress to end-stage liver disease. Further dissection of cellular and molecular pathways involved in AIH pathogenesis is likely to lead to the discovery of novel, tailored and better tolerated therapies.
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Affiliation(s)
- Rodrigo Liberal
- Institute of Liver Studies, King's College Hospital, London, UK
| | - Edward L Krawitt
- Department of Medicine, Dartmouth College, Hanover, NH, USA; Department of Medicine, University of Vermont, Burlington, VT, USA
| | - John M Vierling
- Departments of Medicine and Surgery, Baylor College of Medicine, Baylor-St Luke's Medical Center, Houston, TX, USA
| | | | - Giorgina Mieli-Vergani
- Institute of Liver Studies, King's College Hospital, London, UK; Paediatric Liver, GI & Nutrition Centre, King's College Hospital, London, UK
| | - Diego Vergani
- Institute of Liver Studies, King's College Hospital, London, UK.
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