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Nastasio S, Mosca A, Alterio T, Sciveres M, Maggiore G. Juvenile Autoimmune Hepatitis: Recent Advances in Diagnosis, Management and Long-Term Outcome. Diagnostics (Basel) 2023; 13:2753. [PMID: 37685291 PMCID: PMC10486972 DOI: 10.3390/diagnostics13172753] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 08/11/2023] [Accepted: 08/13/2023] [Indexed: 09/10/2023] Open
Abstract
Juvenile autoimmune hepatitis (JAIH) is severe immune-mediated necro-inflammatory disease of the liver with spontaneous progression to cirrhosis and liver failure if left untreated. The diagnosis is based on the combination of clinical, laboratory and histological findings. Prothrombin ratio is a useful prognostic factor to identify patients who will most likely require a liver transplant by adolescence or early adulthood. JAIH treatment consists of immune suppression and should be started promptly at diagnosis to halt inflammatory liver damage and ultimately prevent fibrosis and progression to end-stage liver disease. The risk of relapse is high especially in the setting of poor treatment compliance. Recent evidence however suggests that treatment discontinuation is possible after a prolonged period of normal aminotransferase activity without the need for liver biopsy prior to withdrawal.
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Affiliation(s)
- Silvia Nastasio
- Division of Gastroenterology, Hepatology & Nutrition, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115, USA;
| | - Antonella Mosca
- Hepatogastroenterology, Rehabilitative Nutrition, Digestive Endoscopy and Liver Transplant Unit, ERN RARE LIVER, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; (A.M.); (T.A.)
| | - Tommaso Alterio
- Hepatogastroenterology, Rehabilitative Nutrition, Digestive Endoscopy and Liver Transplant Unit, ERN RARE LIVER, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; (A.M.); (T.A.)
| | - Marco Sciveres
- Pediatric Department and Transplantation, ISMETT, 90133 Palermo, Italy;
| | - Giuseppe Maggiore
- Hepatogastroenterology, Rehabilitative Nutrition, Digestive Endoscopy and Liver Transplant Unit, ERN RARE LIVER, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; (A.M.); (T.A.)
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Maggiore G, Bernard O, Mosca A, Ballot E, Johanet C, Jacquemin E. Long-term outcomes of patients with type 1 or 2 autoimmune hepatitis presenting in childhood. J Hepatol 2023; 78:979-988. [PMID: 36708813 DOI: 10.1016/j.jhep.2023.01.013] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 12/14/2022] [Accepted: 01/12/2023] [Indexed: 01/26/2023]
Abstract
BACKGROUND & AIMS In children with autoimmune hepatitis, uncertainties include outcomes associated with type 2 hepatitis, the possibility of and criteria for attempting withdrawal of treatment, and long-term outcomes. We report our experience on these issues. METHODS From 1973 to 2002, 117 children with type 1 (n = 65) or type 2 (n = 52) hepatitis, excluding fulminant hepatitis, were treated, primarily with prednisone and azathioprine. Median follow-up was 20 years in survivors. RESULTS Normalisation of aminotransferases and prothrombin ratio were observed in 93% and 84% of children, respectively; sustained remission after treatment withdrawal was recorded in 24% of the entire population, with a median follow-up of 7 years. Sustained treatment-free remission was obtained in 11 of 24 children with follow-ups of 4-22 years based on durable normalisation of aminotransferases (without histological assessment). Gastrointestinal bleeding from varices and the emergence of extrahepatic autoimmune disorders occurred in 10 and 22 patients, respectively. Liver transplantation was performed in 23 patients at a median age of 21 years. The 30-year probabilities of overall and native liver survival were 81% and 61%, respectively. No differences were observed between type 1 and 2 hepatitis for any of the component parts of outcome. In the multivariate analysis, a persistent abnormal prothrombin ratio was associated with worse probabilities of overall and native liver survival. CONCLUSIONS In terms of liver outcome, type 2 hepatitis is not different from type 1. Withdrawal of treatment is possible without prior liver histology. A persistent abnormal prothrombin ratio identifies patients who will require liver transplantation in adolescence or early adulthood. IMPACT AND IMPLICATIONS In children with autoimmune hepatitis, there are conflicting reports on the differences in outcome between type 1 and type 2 hepatitis, and on the possibility of treatment withdrawal, before which liver histology is required; data concerning >10-year overall and native liver survival rates are limited. In this study, we found no differences in outcomes between type 1 and 2 hepatitis; a durable treatment-free state was achieved in 19% of all patients throughout childhood and early adulthood, and in 45% of children for whom treatment withdrawal was attempted without prior liver histology; prothrombin was found to be predictive of 30-year overall and native liver survival. The results allow for a less-strict approach to treatment withdrawal in children, avoiding the risks of a liver biopsy, and they provide a tool to help anticipate the need for liver transplantation before complications occur.
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Affiliation(s)
- Giuseppe Maggiore
- Hepatogastroenterology, Rehabilitative Nutrition, Digestive Endoscopy and Liver Transplant Unit, ERN RARE LIVER, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
| | - Olivier Bernard
- Paediatric Hepatology and Liver Transplantation Unit, National Reference Centre for Inflammatory Biliary Diseases and Autoimmune Hepatitis, FILFOIE, ERN RARE LIVER, Bicetre Hospital, APHP, University Paris-Saclay, Le Kremlin-Bicetre, France
| | - Antonella Mosca
- Hepatogastroenterology, Rehabilitative Nutrition, Digestive Endoscopy and Liver Transplant Unit, ERN RARE LIVER, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Eric Ballot
- Laboratory of Autoimmunity, Department of Immunology, St Antoine Hospital, APHP, Sorbonne University, Paris, France
| | - Catherine Johanet
- Laboratory of Autoimmunity, Department of Immunology, St Antoine Hospital, APHP, Sorbonne University, Paris, France
| | - Emmanuel Jacquemin
- Paediatric Hepatology and Liver Transplantation Unit, National Reference Centre for Inflammatory Biliary Diseases and Autoimmune Hepatitis, FILFOIE, ERN RARE LIVER, Bicetre Hospital, APHP, University Paris-Saclay, Le Kremlin-Bicetre, France; Inserm U1193, Hepatinov, University Paris-Saclay, Orsay, France
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Nastasio S, Sciveres M, Matarazzo L, Malaventura C, Cirillo F, Riva S, Maggiore G. Long-term follow-up of children and young adults with autoimmune hepatitis treated with cyclosporine. Dig Liver Dis 2019; 51:712-718. [PMID: 30502231 DOI: 10.1016/j.dld.2018.10.018] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Revised: 10/22/2018] [Accepted: 10/24/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Cyclosporine (CSA) is an alternative treatment for autoimmune hepatitis (AIH), however, its unknown long-term safety and efficacy have limited its use. AIMS Examine the long-term outcome of children and young adults with AIH treated with CSA for at least 4 years. METHODS Twenty patients were included in this retrospective study: 15 with classical AIH and 5 with autoimmune hepatitis/autoimmune sclerosing cholangitis overlap syndrome (ASC). CSA was administered as first (12 patients) or second-line (8 patients) treatment, alone or in combination with azathioprine or mycophenolate mofetil and/or prednisone. RESULTS CSA determined initial clinical and biochemical remission in all patients. At the end of follow-up (median 8.6; range 4-20.4 years), all patients are alive with their native liver; 15 in complete remission (75%), 2 with incomplete response to treatment and 3 listed for liver transplant. Side effects were mild and transitory after dose tapering or, in 1 case, after CSA withdrawal. Hypertrichosis and moderate gingival hyperplasia were the most frequent. Two patients presented mild transient glomerular filtration rate (GFR) reduction. Median GFR at the beginning and end of treatment was not statistically different for all patients. CONCLUSIONS CSA was effective and safe in the long-term treatment of our cohort of patients with AIH, tailoring the treatment remains key-points during CSA administration.
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Affiliation(s)
- Silvia Nastasio
- Division of Gastroenterology, Hepatology, & Nutrition, Boston Children's Hospital, Boston, MA, USA
| | - Marco Sciveres
- Pediatric Hepatology and Liver Transplantation, ISMETT UPMC Palermo, Palermo, Italy
| | | | - Cristina Malaventura
- Section of Pediatrics, Department of Medical Sciences, University of Ferrara, University Hospital Arcispedale Sant'Anna, Ferrara, Italy
| | - Francesco Cirillo
- Pediatric Hepatology and Liver Transplantation, ISMETT UPMC Palermo, Palermo, Italy
| | - Silvia Riva
- Pediatric Hepatology and Liver Transplantation, ISMETT UPMC Palermo, Palermo, Italy
| | - Giuseppe Maggiore
- Pediatric Hepatology and Liver Transplantation, ISMETT UPMC Palermo, Palermo, Italy; Section of Pediatrics, Department of Medical Sciences, University of Ferrara, University Hospital Arcispedale Sant'Anna, Ferrara, Italy.
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Maggiore G, Nastasio S, Sciveres M. Juvenile autoimmune hepatitis: Spectrum of the disease. World J Hepatol 2014; 6:464-476. [PMID: 25067998 PMCID: PMC4110538 DOI: 10.4254/wjh.v6.i7.464] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2013] [Revised: 03/19/2014] [Accepted: 05/29/2014] [Indexed: 02/06/2023] Open
Abstract
Juvenile autoimmune hepatitis (JAIH) is a progressive inflammatory liver disease, affecting mainly young girls, from infancy to late adolescence, characterized by active liver damage, as shown by high serum activity of aminotransferases, by elevated immunoglobulin G levels, high titers of serum non organ-specific and organ-specific autoantibodies, and by interface hepatitis on liver biopsy. It is a multifactorial disease of unknown etiology in which environmental factors act as a trigger in genetically predisposed individuals. Two types of JAIH are identified according to the autoantibody panel detected at diagnosis: AIH-1, characterized by the presence of anti-smooth muscle antibody and/or antinuclear antibody and AIH-2, by anti-liver-kidney microsomal antibody type 1 and/or by the presence of anti-liver cytosol type 1 antibody. Epidemiological distribution, genetic markers, clinical presentation and pattern of serum cytokines differentiate the two types of AIH suggesting possible pathogenetic mechanisms. The most effective therapy for AIH is pharmacological suppression of the immune response. Treatment should be started as soon as the diagnosis is made to avoid severe liver damage and progression of fibrosis. The aim of this review is to outline the most significant and peculiar features of JAIH, based largely on our own personal database and on a review of current literature.
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Bridoux-Henno L, Maggiore G, Johanet C, Fabre M, Vajro P, Dommergues JP, Reinert P, Bernard O. Features and outcome of autoimmune hepatitis type 2 presenting with isolated positivity for anti-liver cytosol antibody. Clin Gastroenterol Hepatol 2004; 2:825-30. [PMID: 15354284 DOI: 10.1016/s1542-3565(04)00354-4] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS Autoimmune hepatitis (AIH) type 2 is identified by the presence in the serum of anti-liver/kidney microsome type 1 autoantibody. Anti-liver cytosol autoantibody has been reported in children with autoimmune liver disorders mostly in association with anti-liver/kidney microsome reactivity. However, its role as a sole marker of AIH type 2 is debated. We describe here a series of 18 children and adolescents (15 girls, 3 boys) with AIH with serum anti-liver cytosol type 1 (aLC1) as the only autoimmune marker. METHODS A retrospective review was conducted from 3 pediatric hepatology units of all children with an autoimmune liver disease associated with aLC1 as found by immunofluorescence and/or immunodiffusion or immunoblotting. RESULTS Age at first symptoms ranged from 11 months to 14 years; 12 children presented with acute hepatitis, 1 with progressive jaundice, and 5 were asymptomatic. Anti-liver/kidney microsome, antimitochondria, and anti-actin autoantibodies were not detected. Signs of cirrhosis were present in 11 children. Immunosuppressive treatment was effective in all except 2 children who had subfulminant hepatic failure and who required liver transplantation. Sixteen patients (14 with their native liver) currently are alive; 14 patients still are on immunosuppressive therapy after 1 to 22 years. According to the international scoring system for the diagnosis of AIH, 16 patients corresponded to a definite diagnosis and 2 corresponded to a probable diagnosis. CONCLUSIONS The presence of aLC1 in children with acute or chronic liver disease of unknown origin strongly supports a diagnosis of AIH and is an indication for early immunosuppressive therapy.
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Affiliation(s)
- Laure Bridoux-Henno
- Service d'Hépatologie Pédiatrique, Hôpital de Bicêtre, Le Kremlin Bicêtre, France
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Abstract
AIH, ASC, and de novo AIH after liver transplantation are childhood liver diseases of an autoimmune nature. The mode of presentation of AIH in childhood is variable, and the disease should be suspected and excluded in all children presenting with symptoms and signs of prolonged or severe acute liver disease. Although corticosteroids are effective in all types of childhood AIH, patients with LKM1 have a higher frequency of acute hepatic failure and relapse after corticosteroid withdrawal than do patients with ANA/SMA. ASC occurs commonly in the absence of inflammatory bowel disease, requires cholangiography for diagnosis, and improves during corticosteroid therapy. The development of AIH de novo in children who undergo liver transplantation for nonautoimmune liver disease may reflect interference with the maturation of T cells by immunosuppressive drugs.
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Abstract
BACKGROUND AND AIM Autoimmune hepatitis (AIH) is a chronic disease of unknown etiology, which usually progresses to cirrhosis if not diagnosed and treated promptly. Data on long-term follow up in children with AIH are scant. The aim of this study is to assess the long-term outcome of autoimmune hepatitis in children with respect to clinical and laboratory features at presentation. METHODS Data were extracted from the medical records of patients presenting over a 28-year period (1972-2000) to the Royal Children's Hospital, Melbourne, Australia. Additional information was obtained by interviewing patients, and their current physicians. Of the 30 patients (22 females, mean age 9 years) identified, 18 had type I, three had type II, four had autoimmune-polyendocrinopathy syndrome type 1, one had infantile giant-cell hepatitis associated with Coomb's-positive hemolytic anemia, and four were seronegative (antinuclear antibody (ANA), smooth muscle antibody (SMA) and liver-kidney microsomal antibody (LKM)). RESULTS Clinical features at presentation included hepatomegaly (86%), jaundice (66%) and splenomegaly (50%). Initial investigations revealed a median serum bilirubin level of 55 micromol/L (range 6-425), median aspartate aminotransferase level of 678 IU (range 70-2548), and abnormal clotting in 33% of patients. Liver biopsies were performed on all patients at presentation and 11 showed cirrhosis (36%). The mean follow-up period was 10.0 +/- 7.8 years with 43% being followed for > 10 years. Only two patients died and one required transplantation. Fourteen (50%) patients continue to be on low dose prednisolone with azathioprine, two (7%) are on prednisolone alone, and six (21%) are on no therapy. When the cirrhotic and non-cirrhotic patients were compared, the albumin level at presentation was significantly lower in the cirrhotic group (P=0.01). Of the patients who were cirrhotic at presentation, six (54%) remain compensated with a mean follow-up period of 8 years. All 24 patients currently under follow up are engaged in age-appropriate activities including school, part- or full-time work. CONCLUSION Autoimmune hepatitis has a favorable long-term outcome with a transplant-free survival rate of 90% over a mean period of 10.0 +/- 7.8 years (range: 0.5-23), and a normal or near-normal lifestyle irrespective of presenting clinical, laboratory or histological features.
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Affiliation(s)
- O I Saadah
- Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital, Melbourne, Victoria, Australia
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Herzog D, Rasquin-Weber AM, Debray D, Alvarez F. Subfulminant hepatic failure in autoimmune hepatitis type 1: an unusual form of presentation. J Hepatol 1997; 27:578-82. [PMID: 9314137 DOI: 10.1016/s0168-8278(97)80364-9] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Autoimmune hepatitis type 1 is known to progress insidiously and in many cases cirrhosis is already established at the first presentation of symptoms. It affects mostly females, with peaks of incidence around 10 and 50 years of age. Subfulminant hepatic failure is an unusual initial form of presentation of AIH type 1 and it was observed in three post-pubertal female patients. Rapid disease evolution or no response to immunosuppressive therapy led to liver transplantation in all patients. Two did not have cirrhosis, and the third had focal cirrhosis. The occurrence of the unusual subfulminant form of autoimmune hepatitis in three latepubertal girls (Tanner V) suggests that estrogen may play a role in the severity of the disease.
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Affiliation(s)
- D Herzog
- Department of Pediatrics, Sainte-Justine Hospital, University of Montreal, Canada
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Launay V, Gottrand F, Michaud L, Masy E, Turck D, Farriaux JP. [Autoimmune hepatitis treated with cyclosporin revealed by acute hepatocellular failure]. Arch Pediatr 1997; 4:40-3. [PMID: 9084707 DOI: 10.1016/s0929-693x(97)84306-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Autoimmune hepatitis (AIH), usually chronic hepatitis, can be revealed by an acute episode of hepatic failure not easily treatable. CASE REPORT A 4 year-old boy presented with severe acute hepatic failure (AHF) without hypergammaglobulinemia, revealing AIH. A triple immunosuppressive treatment (prednisolone, azathioprine, ciclosporine) was started when clinical and biological signs worsened (prothrombin time 18%, factor V 32%). Liver functions significantly improved within 10 days, although complications due to intensive immunosuppression occurred (Candida septicemia). CONCLUSION AIH must be evocated in each case of AHF. Some observations of AIH treated with ciclosporine are published but protocols of its administration are variable: ciclosporine is used alone or associated with other drugs, in first intention or secondarily, when the classical treatment is contra-indicated or fails. Controlled studies are needed to precise ciclosporine indications in AIH and to propose the best protocol.
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Affiliation(s)
- V Launay
- Service de pédiatrie, hôpital Claude-Huriez, Lille, France
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Peeters S, Blecker U, De Valck J, Goossens A, Hautekeete M, Devis G, Vandenplas Y. Asymptomatic autoimmune chronic active hepatitis in a male adolescent. Eur J Pediatr 1993; 152:107-9. [PMID: 8444216 DOI: 10.1007/bf02072484] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
We report a 12-year-old boy presenting with smooth muscle antibody-positive auto-immune chronic active hepatitis. Suspicion of the diagnosis arose after a routine blood test which revealed abnormal liver function tests. In spite of the presence of cirrhosis and patchy necrosis on liver biopsy, our patient never showed any clinical feature of impaired liver function. This observation demonstrates that auto-immune hepatitis may exist for a long time before clinical symptoms appear and probably explains why some cases of auto-immune hepatitis finally present as fulminant liver failure.
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Affiliation(s)
- S Peeters
- Department of Paediatrics, Vrije Universiteit Brussel, Belgium
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Maggiore G, Porta G, Bernard O, Hadchouel M, Alvarez F, Homberg JC, Alagille D. Autoimmune hepatitis with initial presentation as acute hepatic failure in young children. J Pediatr 1990; 116:280-2. [PMID: 2299503 DOI: 10.1016/s0022-3476(05)82892-6] [Citation(s) in RCA: 43] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Affiliation(s)
- G Maggiore
- Département de Pédiatrie, INSERM U56, Hôpital de Bicêtre, Paris, France
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