Publications by authors named "Giorgina Mieli-Vergani"

207 Publications

Peginterferon Alfa-2a (40KD) Plus Lamivudine or Entecavir in Children with Immune-tolerant Chronic Hepatitis B.

J Pediatr Gastroenterol Nutr 2021 Mar 11. Epub 2021 Mar 11.

King's College London Faculty of Life Sciences & Medicine, London, United Kingdom Paediatric Liver, Gastrointestinal and Nutrition Centre, King's College Hospital NHS Foundation Trust, London, United Kingdom Children's Mercy Hospital, Kansas City, Kansas, United States Department of Pediatric Gastroenterology, Ankara University School of Medicine, Ankara, Turkey Liver Unit, Birmingham Women's & Children's Hospital and University of Birmingham, Birmingham, United Kingdom Roche Products Limited, Welwyn Garden City, United Kingdom Department of Pediatrics, Helios Medical Center Wuppertal, Witten-Herdecke University, Germany RochePharma Product Development Shanghai, Shanghai, China Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, United Kingdom.

Objective: Treatment guidelines for chronic hepatitis B (CHB) do not recommended antiviral therapy for patients in the immune-tolerant phase of the disease, which generally occurs in children who acquire hepatitis B virus (HBV) vertically and may last for decades. On the basis of promising results of a pilot study, we conducted a randomized, controlled, multicenter study to evaluate the efficacy and safety of antiviral therapy in children and adolescents with immune-tolerant CHB.

Methods: Fifty-nine children aged 3 to <18 years HBe antigen-positive with an HBV DNA titer >20000 IU/mL and persistently normal alanine aminotransferase levels were randomized to 56 weeks of antiviral therapy with an oral nucleoside analogue [entecavir or lamivudine], combined with subcutaneous peginterferon alfa-2a from week 8, or 80 weeks of untreated observation. The primary efficacy outcome was HBsAg loss 24 weeks post-treatment in the antiviral therapy group or at the end of observation in the control group.

Results: Enrollment was terminated after the results of two similar studies showed that similar antiviral regimens were ineffective in children and adults with immune-tolerant CHB. At 24 weeks post-treatment, one of 26 patients in the antiviral treatment group experienced HBsAg loss (vs none of 33 patients in the control group). No serious treatment-related adverse events were reported, and no patients discontinued treatment because of adverse events.

Conclusions: The antiviral regimen evaluated in this trial had an acceptable tolerability profile, but was ineffective in children and adolescents with immune-tolerant CHB.
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http://dx.doi.org/10.1097/MPG.0000000000003118DOI Listing
March 2021

Regulatory T cells in autoimmune hepatitis: an updated overview.

J Autoimmun 2021 May 27;119:102619. Epub 2021 Feb 27.

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, United Kingdom. Electronic address:

Regulatory T-cells (Tregs) are key players in the maintenance of immune homeostasis by preventing immune responses to self-antigens. Defects in Treg frequency and/or function result in overwhelming CD4 and CD8 T cell immune responses participating in the autoimmune attack. Perpetuation of autoimmune damage is also favored by Treg predisposition to acquire effector cell features upon exposure to a proinflammatory challenge. Treg impairment plays a permissive role in the initiation and perpetuation of autoimmune liver diseases, namely autoimmune hepatitis, primary biliary cholangitis and primary sclerosing cholangitis. In this Review, we outline studies reporting the role of Treg impairment in the pathogenesis of these conditions and discuss methods to restore Treg number and function either by generation/expansion in the test tube or through in vivo expansion upon administration of low dose IL-2. Challenges and caveats of these potential therapeutic strategies are also reviewed and discussed.
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http://dx.doi.org/10.1016/j.jaut.2021.102619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044040PMC
May 2021

ABCB4 variants in adult patients with cholestatic disease are frequent and underdiagnosed.

Dig Liver Dis 2021 Mar 31;53(3):329-344. Epub 2020 Dec 31.

Epatocentro Ticino, Lugano, Switzerland; Institute of Liver Studies, MowatLabs, King's College Hospital, Denmark Hill, London, United Kingdom. Electronic address:

Background: Heterozygous ABCB4 variants are not routinely tested in adults with cholestasis because of their supposed rarity and high costs.

Methods: Nineteen adult patients presenting with unexplained cholestasis, and/or recurrent gallstones were included; genotyping was not done in five due to lack of health insurance approval.

Results: heterozygous ABCB4 variants were identified in seven patients, followed by cascade testing of 12 family members: one patient underwent liver transplantation at age 40 for end-stage liver disease; one had compensated cirrhosis; all symptomatic adults had gallstones, including four with low phospholipid-associated cholelithiasis; four had intrahepatic cholestasis of pregnancy; all children and one 54-year old female were asymptomatic. Genotype: Families A and C: c.2211G>A (p.Ala737=) combined with c.959C>T (p.Ser320Phe) in one subject; Family B: c.1130T>C (p.Ile377Thr); Family D: large deletion removing ABCB4 exons 1-4 plus ABCB1, RUNDC3B, SLC25A40, DBF4, ADAM22 exons 1-3; Family E: c.1565T>C (p.Phe522Ser) ; Family F: c.1356+2T>C combined with c.217C>G (p.Leu73Val). All patients responded to ursodeoxycholic acid.

Conclusions: We found ABCB4 variants in half of the adults with unexplained cholestasis and/or recurrent gallstones presenting at our center, suggesting that this condition is underdiagnosed and undertreated, with serious consequences not only for the patients and their families, but also in terms of healthcare costs.
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http://dx.doi.org/10.1016/j.dld.2020.12.003DOI Listing
March 2021

Primary biliary cholangitis with normal alkaline phosphatase: A neglected clinical entity challenging current guidelines.

J Autoimmun 2021 Jan 20;116:102578. Epub 2020 Nov 20.

Paediatric Liver, GI and Nutrition Centre, MowatLabs, King's College London Faculty of Life Sciences & Medicine at King's College Hospital, Denmark Hill, London, SE5 9RS, United Kingdom.

Background & Aim: The diagnosis of primary biliary cholangitis (PBC), an uncommon immune-mediated cholestatic liver disease, is based on positive circulating anti-mitochondrial (AMA) and/or PBC-specific anti-nuclear autoantibodies (ANA), coupled with elevated serum alkaline phopsphatase (ALP) levels. Timely initiation of treatment with ursodeoxycholic acid prevents progression to cirrhosis and liver failure. We aimed at investigating liver histology in patients with normal ALP level and positive AMA and/or PBC-specific ANA.

Methods: We searched the Swiss PBC Cohort Study database, which includes subjects with positive PBC autoimmune serology and normal ALP levels, for patients who underwent a liver biopsy. Histological slides were centrally reviewed by an expert liver pathologist, and sera were centrally re-tested for AMA and ANA.

Results: 30 patients were included; 90% females, median age 53 (range 27-72) years. Twenty-four (80%) had liver histology typical for (n = 2), consistent with (n = 16) or suggestive of (n = 6) PBC, including three of four AMA-negative ANA-positive patients. Among 22 ursodeoxycholic acid treated patients, 14 had elevated GGT levels before treatment; a significant decrease of the median GGT level between pre- (1.46 x ULN) and post- (0.43 x ULN) treatment (p = 0.0018) was observed.

Conclusions: In our series, a high proportion of AMA positive patients with normal ALP levels have PBC. For the first time we show histological diagnosis of PBC in AMA-negative/PBC-specific ANA-positive subjects and the potential role of GGT as a biomarker in PBC patients with normal baseline ALP levels. Current guidelines for the diagnosis of PBC do not cover the whole extent of PBC presentation, with important clinical implications in terms of timely treatment initiation.
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http://dx.doi.org/10.1016/j.jaut.2020.102578DOI Listing
January 2021

A patient with primary biliary cholangitis, autoimmune hepatitis, and primary sclerosing cholangitis variant syndrome.

J Transl Autoimmun 2020 17;3:100033. Epub 2019 Dec 17.

Paediatric Liver, GI and Nutrition Centre, MowatLabs, King's College Hospital, London, UK.

Overlap between autoimmune hepatitis (AIH) and either primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC) is not rare and has extensively been reported. We herein report the first well documented case of triple overlap. A 68-year-old male patient presented with asymptomatic PBC including normal alkaline phosphatase serum level, developed AIH five years later, associated with magnetic resonance cholangiopancreatography biliary changes typical for PSC. Despite treatment with ursodeoxycholic acid and mycophenolate mofetil, owing to prednisone and azathioprine intolerance, he continued to have interface hepatitis and developed increasing fibrosis at follow-up liver biopsy. Our case report raises awareness for this rare and difficult to diagnose and treat clinical phenotype.
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http://dx.doi.org/10.1016/j.jtauto.2019.100033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388380PMC
December 2019

Seamless Management of Juvenile Autoimmune Liver Disease: Long-Term Medical and Social Outcome.

J Pediatr 2020 03 16;218:121-129.e3. Epub 2020 Jan 16.

Pediatric Liver, Gastrointestinal, and Nutrition Center, King's College Hospital, London, United Kingdom.

Objectives: To report baseline features and long-term medical/social outcomes of juvenile autoimmune liver disease, including autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (ASC), managed in a single tertiary center.

Study Design: Retrospective study of children diagnosed in 2000-2004 with AIH/ASC followed up to date. Patients with abnormal cholangiogram were classified as ASC. Presentation and outcome features were compared.

Results: Eighty-three children were included (42 female, median age 12.1 years [8.5-14.1 years], AIH = 54, ASC = 29). Most (65%) had antinuclear and/or anti-smooth muscle autoantibodies; 6% presented with acute liver failure; 29% had histologic evidence of cirrhosis. The 1999 and simplified International Autoimmune Hepatitis Group criteria failed to diagnose up to 26% of patients with AIH and 48% with ASC, and the proposed the European Society for Pediatric Gastroenterology, Hepatology and Nutrition criteria were accurate. Response to treatment was excellent with 95% achieving normal transaminase levels. During follow-up, 31% had at least 1 relapse episode; 3 patients with AIH developed cholangiopathy and 5 patients with ASC developed progressive bile duct injury. At last follow-up (median of 14.5 years, 10.4-16.8), 99% were alive, 11 underwent transplantation and 1 is listed for transplant. Five-, 10-, and 15-year transplant-free survival rates were 95%, 88%, and 83%; patients with ASC and those relapsing being more likely to require transplant. Social outcome was excellent with 93% in employment/education.

Conclusions: Seamless management of juvenile autoimmune liver disease leads to excellent clinical and social outcomes. Despite good response to immunosuppressive treatment, patients with ASC have a worse prognosis than those with AIH. Diagnostic models developed for adults are unsatisfactory to correctly diagnose juvenile autoimmune liver disease.
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http://dx.doi.org/10.1016/j.jpeds.2019.11.028DOI Listing
March 2020

The challenges of primary biliary cholangitis: What is new and what needs to be done.

J Autoimmun 2019 12 20;105:102328. Epub 2019 Sep 20.

Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, California, USA. Electronic address:

Primary Biliary Cholangitis (PBC) is an uncommon, chronic, cholangiopathy of autoimmune origin and unknown etiology characterized by positive anti-mitochondrial autoantibodies (AMA), female preponderance and progression to cirrhosis if left untreated. The diagnosis is based on AMA- or PBC-specific anti-nuclear antibody (ANA)-positivity in the presence of a cholestatic biochemical profile, histologic confirmation being mandatory only in seronegative cases. First-line treatment is ursodeoxycholic acid (UDCA), which is effective in preventing disease progression in about two thirds of the patients. The only approved second-line treatment is obeticholic acid. This article summarizes the most relevant conclusions of a meeting held in Lugano, Switzerland, from September 23rd-25th 2018, gathering basic and clinical scientists with various background from around the world to discuss the latest advances in PBC research. The meeting was dedicated to Ian Mackay, pioneer in the field of autoimmune liver diseases. The role of liver histology needs to be reconsidered: liver pathology consistent with PBC in AMA-positive individuals without biochemical cholestasis is increasingly reported, raising the question as to whether biochemical cholestasis is a reliable disease marker for both clinical practice and trials. The urgent need for new biomarkers, including more accurate markers of cholestasis, was also widely discussed during the meeting. Moreover, new insights in interactions of bile acids with biliary epithelia in PBC provide solid evidence of a role for impaired epithelial protection against potentially toxic hydrophobic bile acids, raising the fundamental question as to whether this bile acid-induced epithelial damage is the cause or the consequence of the autoimmune attack to the biliary epithelium. Strategies are needed to identify difficult-to-treat patients at an early disease stage, when new therapeutic approaches targeting immunologic pathways, in addition to bile acid-based therapies, may be effective. In conclusion, using interdisciplinary approaches, groundbreaking advances can be expected before long in respect to our understanding of the etiopathogenesis of PBC, with the ultimate aim of improving its treatment.
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http://dx.doi.org/10.1016/j.jaut.2019.102328DOI Listing
December 2019

Autoimmune liver serology before and after successful treatment of chronic hepatitis C by direct acting antiviral agents.

J Autoimmun 2019 08 30;102:89-95. Epub 2019 Apr 30.

DIMEC, University of Bologna, Bologna, Italy.

Background And Aims: Chronic hepatitis C virus (HCV) infection is associated with a wide range of immunopathological manifestations, which are significantly improved by successful interferon-based treatment. There is paucity of data on the impact of interferon-free HCV clearance on immunopathological manifestations, which might be expected to disappear more frequently as compared to what reported in interferon-induced HCV-clearance. We have investigated liver autoimmune serology before and after interferon-free clearance of HCV by treatment with direct acting antiviral agents (DAA).

Method: Patients within the Swiss Hepatitis C Cohort Study who underwent successful (SVR 12) HCV treatment with DAA were tested for autoimmune liver serology according to dedicated guidelines before and at least 6 months after end of treatment.

Results: A total of 235 patients were included; 62% males; median age 56 years; 27% with cirrhosis. Median time between end of DAA treatment and post-treatment serum sampling was 17 months. At least one autoantibody before treatment was found in 175 (74%) patients ; 32 (14%) were positive for 2 autoantibodies; no patient was positive for anti-SLA, anti-LC1 or typical AMA before or after DAA. ANA disappeared in 34%, SMA in 52% and anti-LKM1 in one of two patients after successful treatment, but, unexpectedly, one or more autoantibodies appeared in 27% of pre-treatment negative subjects.

Conclusion: HCV clearance by DAA is associated with autoantibody disappearance in more than one third of the patients who were positive before treatment. However, the majority of the patients remain autoantibody-positive and 27% of those who were negative before treatment developed autoantibodies after DAA-induced HCV clearance. These data confirm that HCV infection is associated with autoimmunity and show that the autoimmune imprint persists after viral clearance by DAA, suggesting that long-term follow-up may be warranted.
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http://dx.doi.org/10.1016/j.jaut.2019.04.019DOI Listing
August 2019

Chronic Cholangiopathy Associated with Primary Immune Deficiencies Can Be Resolved by Effective Hematopoietic Stem Cell Transplantation.

J Pediatr 2019 06 6;209:97-106.e2. Epub 2019 Mar 6.

Immunology Department, Great Ormond Street Hospital, London, United Kingdom.

Objectives: To investigate effects and outcome of hematopoietic stem cell transplantation (HSCT) on sclerosing cholangitis, in pediatric patients with different primary immunodeficiencies (PIDs).

Study Design: From databases in 2 tertiary centers for immunodeficiencies and liver disease, we have identified children with PIDs and sclerosing cholangitis, who have paired clinical, radiologic, and histologic information before and after HSCT and studied their clinical progress and outcome.

Results: Seven of 13 children (53.8%) died at a median interval of 4 months (range, 3 months-5 years) after HSCT. However, 6 surviving children (46.2%) with different PIDs and less severe cholangiopathies showed an improvement in markers of liver injury within months of successful unrelated reduced intensity conditioning HSCT. The repeated native liver biopsy, performed in 4 patients at a median of 96 (range, 4-144) months post-HSCT, showed a considerable improvement. Biochemical markers of liver function in the survivors completely normalized after a median of 13 months (range, 2-48). All patients continue to have a mildly dilated extrahepatic biliary system on ultrasonography with no intrahepatic ductal changes on magnetic resonance cholangiography after a follow-up of median 18 years (range, 2-20).

Conclusions: Effective HSCT has the potential to improve biochemical and histologic features of cholangiopathy in children with PIDs, presumably by clearance of chronic infection following establishment of immune competence. However, careful patient selection is critical as advanced liver injury is often associated with serious complications and mortality.
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http://dx.doi.org/10.1016/j.jpeds.2019.01.015DOI Listing
June 2019

The clinical usage and definition of autoantibodies in immune-mediated liver disease: A comprehensive overview.

J Autoimmun 2018 12 23;95:144-158. Epub 2018 Oct 23.

Institute of Liver Studies, MowatLabs, King's College Hospital, Denmark Hill, London, SE5 9RS, UK. Electronic address:

Autoimmune serology is key to the diagnosis and management of autoimmune liver diseases. Its correct use in clinical practice requires a basic knowledge of the laboratory techniques used for autoantibody detection. Indirect immunofluorescence (IIF) on triple rodent tissue is still the gold standard screening procedure for liver-relevant autoantibodies, while HEp2 cells and human ethanol-fixed neutrophils are used as substrates to characterize nuclear reactivities and to detect anti-neutrophil cytoplasm antibody, respectively. Assays based on purified or recombinant antigens are increasingly used, having the main advantage of being observer-independent and the disadvantage of detecting only autoantibodies whose antigenic target has been identified. The AIH-specific anti-soluble liver antigen antibody cannot be detected by IIF and a molecular-based assay should be used at the screening level. Since autoantibodies may be present in the context of viral hepatitides and other inflammatory liver diseases it is important to exclude these conditions before diagnosing autoimmune liver disease. Anti-nuclear antibody (ANA), most often with a homogeneous IIF pattern on HEp2 cells, characterizes type 1 autoimmune hepatitis (AIH), and is found in association with anti-smooth muscle antibody in about half of the cases. Two IIF ANA patterns are specific for primary biliary cholangitis, namely the rim-like/membranous pattern, and the multiple nuclear dots pattern. Anti-liver kidney microsomal antibody type 1 is the serological hallmark of type 2 AIH, often in association with anti-liver cytosol type 1 antibody. Atypical perinuclear anti-neutrophil antibody, referred to as perinuclear anti-neutrophil nuclear antibody, is frequently detected in primary sclerosing cholangitis, in AIH type 1 and in inflammatory bowel diseases. The anti-asiaglycoprotein receptor antibody is liver-specific but not disease-specific, and reliable commercial assays for its detection are lacking. Anti-mitochondrial antibody is the hallmark of primary biliary cholangitis (PBC), being disease-specific and present in about 95% of the PBC patients. Its incidental detection presages the future development of PBC.
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http://dx.doi.org/10.1016/j.jaut.2018.10.004DOI Listing
December 2018

Autoimmune sclerosing cholangitis: Evidence and open questions.

J Autoimmun 2018 12 23;95:15-25. Epub 2018 Oct 23.

Paediatric Liver, GI and Nutrition Centre, MowatLabs, King's College Hospital, London, UK.

Juvenile sclerosing cholangitis is a rare chronic hepatobiliary disorder characterized by inflammation of the intra- and/or extrahepatic bile ducts, bile duct dilatation, narrowing and obliteration, and, histologically, by inflammatory bile duct damage leading to periductular fibrosis. The diagnosis is based on endoscopic retrograde cholangiopancreatography or magnetic resonance cholangiopancreatography. In children, it may be associated to a variety of systemic and hepatic conditions: thus, the term "primary" sclerosing cholangitis should be reserved for the rare cases without a known cause. Small duct disease is diagnosed in the presence of histological features diagnostic of sclerosing cholangitis and normal cholangiography. Autoimmune sclerosing cholangitis (ASC) is a form of sclerosing cholangitis with strong autoimmune features overlapping with those of autoimmune hepatitis (AIH). It is a well-recognized nosological entity in paediatrics, where it accounts for the majority of sclerosing cholangitis cases. It is as prevalent as AIH in children, is equally frequent in males and females, half of the patients have concomitant inflammatory bowel disease, virtually all patients have raised immunoglobulin G levels and positive anti-nuclear and/or anti-smooth muscle antibodies. Half of the ASC patients respond well to standard immunosuppressive treatment for AIH with the addition of ursodeoxycholic acid, but the transplant rate is higher than in AIH, and post-transplant recurrence is frequent. A number of open questions remain: are ASC and AIH distinct entities or different manifestations of the same condition? What is the role of histology? Is small duct disease a specific entity? What is the relationship between ASC and adult primary sclerosing cholangitis? What is the role of inflammatory bowel disease? In addition, validated diagnostic criteria for ASC are needed.
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http://dx.doi.org/10.1016/j.jaut.2018.10.008DOI Listing
December 2018

Juvenile autoimmune hepatitis: A comprehensive review.

J Autoimmun 2018 12 19;95:69-76. Epub 2018 Oct 19.

Paediatric Liver, GI & Nutrition Centre, MowatLabs, King's College Hospital, London, UK.

Autoimmune hepatitis (AIH) is a rare, chronic disease that affects both adults and children, including infants. The disease is probably triggered by environmental factors in genetically predisposed individuals. The clinical presentation ranges from asymptomatic patients or patients with non-specific symptoms, such as fatigue, to fulminant liver failure, many children presenting with symptoms indistinguishable from those of acute hepatitis. Raised transaminase and immunoglobulin G (IgG) levels, in association with circulating autoantibodies, guide towards the diagnosis. The histological hallmark is interface hepatitis, which however is non-specific and may be absent. There are no bile duct changes on cholangiography. Presence of anti-nuclear antibody (ANA) and/or anti-smooth muscle antibody (SMA) is characteristic for type 1 AIH, whereas presence of anti-liver kidney microsomal type 1 (LKM1) antibody and/or anti-liver cytosol type 1 (LC1) antibody defines type 2 AIH. The latter accounts for about one third of the juvenile AIH cases, presents more acutely than type 1 AIH and is very rare in adults. Immunosuppressive therapy, based on steroids and azathioprine, is required, and in the vast majority of patients leads to clinical and biochemical remission, defined as absence of symptoms, normal transaminase and IgG levels, and negative or low-titer autoantibodies. In patients intolerant or non-responder to standard therapy, a number of second line drugs have been employed with variable results. For the rare cases who progress to end-stage liver disease, liver transplantation is life-saving, but recurrence of the disease is possible. A better understanding of the underlying pathogenic mechanisms will help to develop new, more effective and less toxic therapies, and to tailor treatment regimens to the individual patient.
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http://dx.doi.org/10.1016/j.jaut.2018.10.007DOI Listing
December 2018

Autoimmune liver disease serology in acute hepatitis E virus infection.

J Autoimmun 2018 11 7;94:1-6. Epub 2018 Jul 7.

DIMEC, University of Bologna, Bologna, Italy.

The etiology of autoimmune hepatitis (AIH) is unknown, though hepatotropic viruses may be potential triggers. Hepatitis E virus (HEV) infection, an increasingly recognized cause of acute hepatitis, has been misdiagnosed as AIH due to the occurrence of autoantibodies during its acute phase. It has also been suggested that HEV infection may lead to or unmask AIH. The HEV seroprevalence has been ascertained in patients with AIH, but the prevalence of AIH-related autoantibodies in patients with HEV infection has not been systematically tested. We aimed to investigate whether acute HEV infection is associated with the presence of AIH-relevant autoantibodies, following the liver autoimmune serology guidelines of the International AIH Group. We tested 48 patients with acute HEV infection. Half of them had at least one autoantibody, 17% two autoantibodies. Anti-nuclear antibody (ANA) were detected in 16 (33%), anti-smooth muscle antibody (SMA) in 10 (21%), and anti-neutrophil cytoplasmic antibody (ANCA) in 7 (14.6%). Of note, two patients showed SMA with VG or VGT patterns and five had ANA with homogeneous appearance, both being typical of AIH type 1. Other AIH-specific autoantibodies were negative. Atypical anti-mitochondrial antibody, without evidence of primary biliary cholangitis, was positive in one patient, disappearing at follow-up. Follow-up (median 12 months) serum was available from seven autoantibody positive patients: two became negative, while five remained positive, although no patient developed AIH to date. In conclusion, autoantibodies are frequently present during acute HEV infection, indicating that HEV should always be excluded before diagnosing AIH. Importantly, a minority of patients with acute hepatitis E develops AIH-specific autoantibodies, and, though they did not progress to autoimmune liver disease in the short-term, they warrant long-term monitoring.
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http://dx.doi.org/10.1016/j.jaut.2018.07.006DOI Listing
November 2018

The Role of Invariant NKT in Autoimmune Liver Disease: Can Vitamin D Act as an Immunomodulator?

Can J Gastroenterol Hepatol 2018 26;2018:8197937. Epub 2018 Jun 26.

Institute of Liver Studies, King's College London, Faculty of Life Sciences & Medicine at King's College Hospital, Denmark Hill, London, UK.

Natural killer T (NKT) cells are a distinct lineage of T cells which express both the T cell receptor (TCR) and natural killer (NK) cell markers. Invariant NKT (iNKT) cells bear an invariant TCR and recognize a small variety of glycolipid antigens presented by CD1d (nonclassical MHC-I). CD1d-restricted iNKT cells are regulators of immune responses and produce cytokines that may be proinflammatory (such as interferon-gamma (IFN-)) or anti-inflammatory (such as IL-4). iNKT cells also appear to play a role in B cell regulation and antibody production. Alpha-galactosylceramide (-GalCer), a derivative of the marine sponge, is a potent stimulator of iNKT cells and has been proposed as a therapeutic iNKT cell activator. Invariant NKT cells have been implicated in the development and perpetuation of several autoimmune diseases such as multiple sclerosis and systemic lupus erythematosus (SLE). Animal models of SLE have shown abnormalities in iNKT cells numbers and function, and an inverse correlation between the frequency of NKT cells and IgG levels has also been observed. The role of iNKT cells in autoimmune liver disease (AiLD) has not been extensively studied. This review discusses the current data with regard to iNKT cells function in AiLD, in addition to providing an overview of iNKT cells function in other autoimmune conditions and animal models. We also discuss data regarding the immunomodulatory effects of vitamin D on iNKT cells, which may serve as a potential therapeutic target, given that deficiencies in vitamin D have been reported in various autoimmune disorders.
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http://dx.doi.org/10.1155/2018/8197937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6038587PMC
March 2019

Outcomes of surgical management of familial intrahepatic cholestasis 1 and bile salt export protein deficiencies.

Hepatol Commun 2018 May 30;2(5):515-528. Epub 2018 Mar 30.

Institute of Liver Studies King's College London London United Kingdom.

Progressive familial intrahepatic cholestasis (PFIC) with normal circulating gamma-glutamyl transpeptidase levels can result from mutations in the gene (encoding familial intrahepatic cholestasis 1 [FIC1] deficiency) or the gene (bile salt export protein [BSEP] deficiency). We investigated the outcomes of partial external biliary diversion, ileal exclusion, and liver transplantation in these two conditions. We conducted a retrospective multicenter study of 42 patients with FIC1 deficiency (FIC1 patients) and 60 patients with BSEP deficiency (BSEP patients) who had undergone one or more surgical procedures (57 diversions, 6 exclusions, and 57 transplants). For surgeries performed prior to transplantation, BSEP patients were divided into two groups, BSEP-common (bearing common missense mutations D482G or E297G, with likely residual function) and BSEP-other. We evaluated clinical and biochemical outcomes in these patients. Overall, diversion improved biochemical parameters, pruritus, and growth, with substantial variation in individual response. BSEP-common or FIC1 patients survived longer after diversion without developing cirrhosis, being listed for or undergoing liver transplantation, or dying, compared to BSEP-other patients. Transplantation resolved cholestasis in all groups. However, FIC1 patients commonly developed hepatic steatosis, diarrhea, and/or pancreatic disease after transplant accompanied by biochemical abnormalities and often had continued poor growth. In BSEP patients with impaired growth, this generally improved after transplantation. Diversion can improve clinical and biochemical status in FIC1 and BSEP deficiencies, but outcomes differ depending on genetic etiology. For many patients, particularly BSEP-other, diversion is not a permanent solution and transplantation is required. Although transplantation resolves cholestasis in patients with FIC1 and BSEP deficiencies, the overall outcome remains unsatisfactory in many FIC1 patients; this is mainly due to extrahepatic manifestations. ( 2018;2:515-528).
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http://dx.doi.org/10.1002/hep4.1168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5944593PMC
May 2018

Should Giant Cell Hepatitis With Autoimmune Haemolythic Anaemia Be Considered a Paediatric Autoimmune Liver Disease?

J Pediatr Gastroenterol Nutr 2018 05;66(5):e138

MowatLabs, Paediatric Liver, GI & Nutrition Centre, King's College Hospital, London, UK.

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http://dx.doi.org/10.1097/MPG.0000000000001911DOI Listing
May 2018

Autoimmune hepatitis.

Nat Rev Dis Primers 2018 04 12;4:18017. Epub 2018 Apr 12.

Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, Alberta, Canada.

Autoimmune hepatitis (AIH) is a severe liver disease that affects children and adults worldwide. The diagnosis of AIH relies on increased serum transaminase and immunoglobulin G levels, presence of autoantibodies and interface hepatitis on liver histology. AIH arises in genetically predisposed individuals when a trigger, such as exposure to a virus, leads to a T cell-mediated autoimmune response directed against liver autoantigens; this immune response is permitted by inadequate regulatory immune control leading to a loss of tolerance. AIH responds favourably to immunosuppressive treatment, which should be started as soon as the diagnosis is made. Standard regimens include fairly high initial doses of corticosteroids (prednisone or prednisolone), which are tapered gradually as azathioprine is introduced. For those patients who do not respond to standard treatment, second-line drugs should be considered, including mycophenolate mofetil, calcineurin inhibitors, mechanistic target of rapamycin (mTOR) inhibitors and biologic agents, which should be administered only in specialized hepatology centres. Liver transplantation is a life-saving option for those who progress to end-stage liver disease, although AIH can recur or develop de novo after transplantation. In-depth investigation of immune pathways and analysis of changes to the intestinal microbiota should advance our knowledge of the pathogenesis of AIH and lead to novel, tailored and better tolerated therapies.
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http://dx.doi.org/10.1038/nrdp.2018.17DOI Listing
April 2018

Chapter 6. ESPGHAN's Contributions to Paediatric Hepatology.

J Pediatr Gastroenterol Nutr 2018 04;66 Suppl 1:S116

University of Birmingham and The Liver Unit, Birmingham Women's & Children's Hospital, Birmingham, UK.

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http://dx.doi.org/10.1097/MPG.0000000000001916DOI Listing
April 2018

Atovaquone/proguanil-induced autoimmune-like hepatitis.

Hepatol Commun 2017 06 8;1(4):293-298. Epub 2017 May 8.

Institute of Liver Studies King's College Hospital London United Kingdom.

We report a novel association between the commonly used antimalarial medication atovaquone/proguanil and drug-induced autoimmune-like hepatitis. The patient developed severe liver disease fulfilling biochemical, immunologic, and histologic criteria for the diagnosis of autoimmune hepatitis after the inadvertent rechallenge with the offending drug, which had caused self-limited hepatitic symptoms a year previously. Over a period of 18 months, the patient underwent two follow-up liver biopsies showing progressive resolution of the liver inflammation and achieved complete biochemical and immunologic remission on steroids. This remission persisted for 20 months following treatment withdrawal. : This well documented case raises awareness of the potential hepatotoxicity of atovaquone/proguanil. ( 2017;1:293-298).
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http://dx.doi.org/10.1002/hep4.1039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5721398PMC
June 2017

Diagnosis and Management of Pediatric Autoimmune Liver Disease: ESPGHAN Hepatology Committee Position Statement.

J Pediatr Gastroenterol Nutr 2018 02;66(2):345-360

MowatLabs, Paediatric Liver, GI & Nutrition Centre, King's College Hospital, London, UK.

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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http://dx.doi.org/10.1097/MPG.0000000000001801DOI Listing
February 2018

Serology in autoimmune hepatitis: A clinical-practice approach.

Eur J Intern Med 2018 02 19;48:35-43. Epub 2017 Oct 19.

Institute of Liver Studies, MowatLabs, King's College Hospital, Denmark Hill, London SE5 9RS, UK. Electronic address:

Serology is key to the diagnosis of autoimmune hepatitis (AIH). Clinicians need to be aware of which tests to request, how to interpret the laboratory reports, and be familiar with the laboratory methodology. If correctly tested, >95% of AIH patients show some serological reactivity. Indirect immunofluorescence on triple rodent tissue is recommended as first screening step, since it allows the detection of all liver-relevant autoantibodies, except for anti-soluble liver antigen (SLA) antibody, which needs to be detected by molecular based assays. The threshold of immunofluorescence positivity is a titer equal or exceeding 1/40, but for patients younger than 18years even lower titers are clinically significant. Anti-nuclear antibody (ANA) and/or anti-smooth muscle (SMA) antibody characterize type 1 AIH. ANA in AIH typically shows a homogeneous staining pattern on HEp2 cells, without any specific target antigen. Anti-SMA displays different staining patterns on indirect immunofluorescence: the vascular/glomerular (VG) and the vascular/glomerular/tubular (VGT) patterns are considered specific for AIH, whilst the V pattern can be found in a variety of diseases. Type 2 AIH, which is rare and affects mostly children/adolescents, is characterized by anti-liver kidney microsomal 1 and/or anti-liver cytosol 1 antibodies. The presence of anti-neutrophil cytoplasmic antibody (ANCA), particularly atypical p-ANCA (pANNA), points to the diagnosis of AIH, especially in absence of other autoantibodies. Since it is associated with sclerosing cholangitis and inflammatory bowel disease, these conditions have to be ruled out. The only antibody specific for AIH is anti-SLA, which is associated with a more severe disease course.
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http://dx.doi.org/10.1016/j.ejim.2017.10.006DOI Listing
February 2018

Autoimmune hepatitis: Standard treatment and systematic review of alternative treatments.

World J Gastroenterol 2017 Sep;23(33):6030-6048

Institute of Liver Studies, MowatLabs, King's College Hospital, Denmark Hill, London SE5 9RS, United Kingdom.

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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http://dx.doi.org/10.3748/wjg.v23.i33.6030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5597495PMC
September 2017

Anti-TNFα Treatment in Children and Adolescents With Combined Inflammatory Bowel Disease and Autoimmune Liver Disease.

J Pediatr Gastroenterol Nutr 2018 01;66(1):100-105

Paediatric Liver, GI and Nutrition Centre, Mowat Labs and Institute of Liver Studies, King's College Hospital, London, UK.

Objectives: Inflammatory bowel disease (IBD) and autoimmune liver disease (AILD) are closely associated, the former often dictating progression of the latter. Antibodies to tumor necrosis factor alpha (anti-TNFα) are effective in the management of IBD, but may cause liver injury.

Methods: Retrospective review of medical records of patients with juvenile AILD who received anti-TNFα for IBD to evaluate the safety and efficacy of anti-TNFα.

Results: Eleven patients (6 boys), ages 9 to 15 years (median 13 years) were identified. Ten had ulcerative colitis and 1 Crohn disease; 2 had autoimmune hepatitis type 1 and 9 autoimmune hepatitis-sclerosing cholangitis variant. All patients were started on infliximab (IFX, 5 mg/kg) and 2 required dose increase (10 mg/kg); 3 of 11 switched to adalimumab due to allergic reaction or nonresponse. Three received adalimumab after losing response or developing antibodies to IFX. Liver function tests (LFTs) improved in 5, 1 continued to have stably abnormal LFTs and 2 maintained normal LFTs. Patients on adalimumab showed stable or improved liver function compared to pretreatment status. Six of 8 treated with a full course of IFX maintained clinical remission of IBD for 6 months to 2.5 years; of the 6 patients treated with adalimumab, 1 sustained IBD clinical remission for 24 months, 2 achieved remission only after tacrolimus addition and 3 did not respond.

Conclusions: IBD in patients with AILD can be aggressive, requiring escalation to anti-TNFα or switching to other biologics. In this series, anti-TNFα did not impair liver function and improved gut disease in most of the patients, indicating that it can be beneficial and safe.
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http://dx.doi.org/10.1097/MPG.0000000000001759DOI Listing
January 2018

Autoimmunhepatitis: das Wichtigste für die Praxis.

Ther Umsch 2017 Jul;74(3):115-121

3 Paediatric Liver, GI and Nutrition Centre, King's College Hospital, MowatLabs, London.

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http://dx.doi.org/10.1024/0040-5930/a000894DOI Listing
July 2017

Autoimmune Liver Disease in Children with Sickle Cell Disease.

J Pediatr 2017 10 20;189:79-85.e2. Epub 2017 Jul 20.

Pediatric Liver, GI, and Nutrition Center, King's College Hospital, London, United Kingdom. Electronic address:

Objective: To assess the incidence, clinical features, and outcome of autoimmune liver disease (AILD) in patients with sickle cell disease (SCD).

Study Design: Single center retrospective review of patients with SCD with AILD referred between 1999 and 2015.

Results: Thirteen of 77 (17%) patients with SCD with hepatic dysfunction were diagnosed with AILD (median age 11, range, 3.4-16 years) with a female preponderance (77%). Acute hepatitis and insidious onset were the commonest presentations. Two patients (15%) presented with acute liver failure. In 2 patients (15%), parvovirus B19-induced transient red cell aplasia preceded the diagnosis of AILD. All patients were positive for antinuclear and/or smooth muscle autoantibodies. Six of 12 patients (50%) had cholangiopathy on cholangiogram suggesting autoimmune sclerosing cholangitis (ASC). Liver biopsy, performed in 11 patients without complications, showed interface hepatitis in 90%. Patients with AILD were treated with standard immunosuppression. After a median follow-up of 3.8 years (range, 0.2-14.3), 10 patients are alive (1 was transplanted 6.4 years after diagnosis); 2 are lost to follow-up; 1 died of subdural hemorrhage before starting treatment for AILD. Five (42%) achieved full and 4 (33%) partial biochemical remission. Ulcerative colitis, present in 4 patients (2 male patients, 3 with ASC) was diagnosed in 2 patients before and in 2 patients after the diagnosis of AILD.

Conclusions: AILD is not uncommon in patients with SCD, affecting mainly female patients and responding satisfactorily to immunosuppressive treatment. Liver biopsy is helpful in confirming the diagnosis and can be safely performed in the absence of acute vaso-occlusive sickling episodes. Ulcerative colitis is common in the presence of ASC.
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http://dx.doi.org/10.1016/j.jpeds.2017.06.035DOI Listing
October 2017

Regulatory T-cell conditioning endows activated effector T cells with suppressor function in autoimmune hepatitis/autoimmune sclerosing cholangitis.

Hepatology 2017 11 3;66(5):1570-1584. Epub 2017 Oct 3.

Department of Liver Studies, Division of Transplantation Immunology & Mucosal Biology, MRC Centre for Transplantation, Faculty of Life Sciences & Medicine, King's College London, London, UK.

Imbalance between T regulatory (Treg) and T effector (Teff) cells is likely to contribute to the induction and perpetuation of liver damage in autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (AISC) either through inability of Tregs to restrain proliferation and effector cytokine production by responders or through conversion of Tregs into T helper type 1 (Th1) or type 17 (Th17) effector lymphocytes. We investigated the effect of Treg skewing on the phenotypic and functional properties of CD4 CD127 CD25 cells, an activated subset of Teff, in 32 patients with AIH and 20 with AISC and in 36 healthy subjects. In AIH/AISC we noted a substantial increase in peripheral blood-derived CD4 CD127 CD25 cells that display a Th1/Th17 phenotypic profile, as reflected by heightened interferon gamma and interleukin 17 (IL-17) production as well as by high levels of T-bet and related orphan receptor 3 expression, which is strongly correlated with disease activity. CD4 CD127 CD25 cells are unresponsive to low-dose IL-2 and in patients have marked proliferative ability, further enhanced by stimulation with IL-7. CD4 CD127 CD25 cells obtained from CD4 cells exposed to Treg polarizing conditions display enhanced IL-10 production; up-regulate CD49b and LAG-3, markers of T regulatory 1 cells; and effectively suppress responder cell proliferation in both healthy subjects and AIH/AISC patients through a mechanism which is dependent on interferon gamma and IL-17. The suppressive function of CD4 CD127 CD25 cells is maintained upon proinflammatory challenge in healthy subjects but not in AIH/AISC.

Conclusion: Treg skewing confers activated Teff phenotypic and functional properties of T regulatory 1 cells in health and in AIH/AISC, though suppressive function is lost in patients upon proinflammatory challenge; protracted modulation of the inflammatory environment is required to attenuate the effector potential while boosting immunoregulatory properties in Teff. (Hepatology 2017;66:1570-1584).
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http://dx.doi.org/10.1002/hep.29307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5689077PMC
November 2017

The Riddle of Juvenile Sclerosing Cholangitis.

Hepatology 2017 08 26;66(2):315-317. Epub 2017 Jun 26.

Paediatric Liver, GI and Nutrition Centre, MowatLabs, Faculty of Life Sciences & Medicine at King's College Hospital, London, United Kingdom.

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http://dx.doi.org/10.1002/hep.29208DOI Listing
August 2017