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

doi:10.1016/j.jpeds.2019.11.028

The Journal of Pediatrics

Volume 218, March 2020, Pages 121-129.e3

https://doi.org/10.1016/j.jpeds.2019.11.028 Get rights and content

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.

Section snippets

Methods

Data on all children with AILD diagnosed between 2000 and 2004 and followed-up to 2019 were collected, including demographic/clinical variables, signs/symptoms, biochemical/immunologic profile, histologic features, and immunosuppressive therapy.

Diagnosis of AILD was based on elevated transaminase levels, positive autoantibodies with or without elevation of IgG levels, compatible liver histology, and exclusion of other liver diseases (Table I; available at www.jpeds.com).⁸^,⁹ Cut-off titers ≥1:20

Results

Eighty-three patients (42 female) were diagnosed with AILD (Tables II and III). All were autoantibody-positive and underwent liver biopsy; 80 (97%) underwent cholangiography (median 3.4 months after presentation [2.0-5.8]). Patients without cholangiography included a 3.4-year-old boy with AIH-2 with fulminant hepatitis requiring liver transplantations; an 11.2-year-old girl with dermatomyositis, initially presenting with methotrexate-induced cholestasis and re-presenting 1 year later with ALF

Discussion

A seamless management of liver disease from pediatric to adult age has allowed us assessing the outcome of a large number of patients with AILD diagnosed in childhood. In contrast to published retrospective studies, all our patients were investigated from presentation to differentiate AIH from ASC, and all were treated following a single protocol. We report an excellent clinical and social outcome, 95% achieving normal transaminase levels on standard treatment with prednisolone ± azathioprine,

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Cited by (29)

Biliary disease progression in childhood onset autoimmune liver disease: A 30-year follow-up into adulthood
2024, JHEP Reports
Long-term follow-up studies of paediatric onset autoimmune liver disease (AILD) are invaluable in helping better understand the clinical course of disease. In day-to-day practice clinicians struggle with disease definitions whilst patients and parents lack clear prognostic information.
The clinical progression of 159 patients with childhood onset AILD between June 1990 and December 2013 was reviewed, capturing data up to adulthood (ending May 2021).
Presentation with autoimmune hepatitis (AIH) was dominant (n = 119); biliary presentations accounted for 25%. During follow up, biliary disease progression confirmed by cholangiography and/or liver histology was observed frequently: 19.8% (20/101) patients with childhood onset AIH type 1 (AIH-1) developed biliary features by adulthood and of these 50% phenotypically transitioned to primary sclerosing cholangitis (PSC); the remaining transitioned to an overlap disease phenotype. No patients with AIH type 2 developed biliary progression. Two-thirds of patients with overlap features (14/21) in childhood had phenotypically progressed to PSC by adulthood. Approximately 43% (6/14) of AIH-1 patients requiring a liver transplant in adulthood had explant evidence of biliary disease compared with 11% (1/9) in childhood, whereas 35.7% (5/14) of patients had histology diagnostic of PSC in their explant liver and 7.1% (1/14) had overlap features. All patients with biliary phenotypes (PSC, autoimmune sclerosing cholangitis, overlap) who required a transplant (n = 18) were found to have explant histology consistent with PSC. Twelve of 14 patients with biliary progression developed ulcerative colitis during follow-up with 92% progressing to PSC.
Three decades of follow-up demonstrated how children presenting with AILD had a significant risk of clinical transformation to PSC. Biliary progression was significantly associated with the development of inflammatory bowel disease.
Childhood onset autoimmune liver disease remains very impactful for patients and families. Disease nomenclature can however be confusing. Long-term follow up studies as children become adults is important to help understand how and why disease behaves over time. Understanding more about the long-term course of childhood autoimmune liver disease will help patients, families and doctors striving to improve care and reduce poor clinical outcomes. We followed over 150 patients with childhood onset autoimmune liver diseases into adulthood. We found that amongst patients with classical autoimmune hepatitis, 1 in 5 developed biliary disease over time, mostly consisting of primary sclerosing cholangitis. This was associated with developing inflammatory bowel disease. Our study design was retrospective and has relevant limitations. Defining phenotypes of autoimmune liver diseases is difficult and there is insufficient consensus, especially between adult and childhood physicians. Our data confirms the critical importance of careful long-term follow-up of patients, including safe transition to adult care, as well as robustly demonstrates, using real-world data, how disease nature can change over time. Our study affirms the need for investment in prospective cohort studies.
Liver and biliary disease in childhood
2023, Medicine (United Kingdom)
It is estimated that around 1000 children are diagnosed with liver disease in the UK, every year. Their presentation varies from acute to more insidious, often in the context of chronic liver disease. In acute settings, the liver disease can be so severe as to cause acute liver failure, a multisystemic disease requiring urgent referral to a specialized liver centre with access to intensive care support and liver transplantation. The clotting profile is the most sensitive marker of liver disease severity and should always be checked at presentation. Whereas infectious causes are common in this age group, other conditions such as autoimmune liver disease and Wilson disease must be excluded, and rarer, metabolic and genetic conditions considered. Children can develop acute cholestasis suggesting biliary obstruction related to intra- and/or extrahepatic pathologies. Presentation with complications of chronic liver disease, such as portal hypertension and failure of synthetic function, is less common but requires specialized care and consideration for liver transplantation.
Long-term outcomes of patients with type 1 or 2 autoimmune hepatitis presenting in childhood
2023, Journal of Hepatology
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.
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.
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.
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.
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.
Autoimmune serology testing in clinical practice: An updated roadmap for the diagnosis of autoimmune hepatitis
2023, European Journal of Internal Medicine
Citation Excerpt :
However, very few AIH-1 patients have isolated pANCA/ANNA and therefore, this autoantibody should be tested only in patients who are negative for ANA, SMA, and anti-SLA/LP. pANCA/ANNA has also been reported frequently in other immune-mediated diseases such as, primary sclerosing cholangitis (PSC), inflammatory bowel disease and autoimmune sclerosing cholangitis a specific AIH/PSC variant in children (Table 2) [45–47]. Anti-LKM antibodies include three isoforms: anti-LKM1, anti–liver kidney microsomal type2 (anti-LKM2), and anti-LKM3 [6,18,21,22,48].
Diagnosis of autoimmune hepatitis (AIH) is in most cases challenging for clinicians as there is not a single specific laboratory or histological marker to diagnose or exclude the presence of the disease. The clinical spectrum of AIH varies from completely asymptomatic to acute-severe or even rarely fulminant hepatic failure, while everybody can be affected irrespective of age, gender, and ethnicity. The old revised and the newer simplified diagnostic scores have been established by the International Autoimmune Hepatitis Group (IAIHG) in 1999 and 2008, respectively, which are based on several clinical, laboratory and histological parameters. Additionally, a thorough differential diagnosis from other diseases mimicking AIH is absolutely indicated. In this context, autoantibodies detection in patients with suspected AIH is mandatory -even though not pathognomonic- not only for AIH diagnosis but furthermore, for AIH classification (AIH-type 1 and AIH-type 2). Although autoimmune serology can be supportive of AIH diagnosis in ≥95% of cases if testing has been performed according to the IAIHG guidelines, this is not the case under real-life circumstances in routine clinical laboratories. Clinicians should be careful both for the importance of the required testing and how to interpret the results and therefore, they should communicate and discuss with the laboratory personnel to achieve the maximum benefit for the patient. Herein, a detailed and updated review of the diagnostic work-up for AIH diagnosis under real-life conditions is given to minimize the underestimation and misdiagnosis of AIH which can result in progression of the disease and unfavourable outcomes.
EASL Clinical Practice Guidelines on sclerosing cholangitis
2022, Journal of Hepatology
Recent Insights into Pediatric Primary Sclerosing Cholangitis
2022, Clinics in Liver Disease

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: The authors declare no conflicts of interest.

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Published by Elsevier Inc.

Original ArticleSeamless Management of Juvenile Autoimmune Liver Disease: Long-Term Medical and Social Outcome

Objectives

Study design

Results

Conclusions

Section snippets

Methods

Results

Discussion

Hepatology

J Hepatol

Hepatology

Gastroenterology

J Autoimmun

Hepatobiliary Pancreat Dis Int

Clin Gastroenterol Hepatol

Dig Liver Dis

Hepatology

J Hepatol

Diagnosis and management of pediatric autoimmune liver disease: ESPGHAN Hepatology Committee Position Statement

J Pediatr Gastroenterol Nutr

Primary sclerosing cholangitis, autoimmune hepatitis, and overlap in Utah children: epidemiology and natural history

Hepatology

Incidence and characteristics of autoimmune hepatitis

Pediatrics

Fulminant hepatic failure of autoimmune aetiology in children

J Pediatr Gastroenterol Nutr

Clinical characteristics and prognosis in children and adolescents with autoimmune hepatitis and overlap syndrome

J Pediatr Gastroenterol Nutr

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