Autoimmune hepatitis (AIH) is a chronic liver disease of unknown aetiology which may affect any patient irrespective of age, sex, and ethnicity. At baseline, the clinical spectrum of the disease varies largely from asymptomatic cases to acute liver failure with massive hepatocyte necrosis. The aim of these EASL guidelines is to provide updated guidance on the diagnosis and management of AIH both in adults and children. Updated guidance on the management of patients with variants and specific forms of AIH is also provided, as is detailed guidance on the management of AIH-associated cirrhosis, including surveillance for portal hypertension and hepatocellular carcinoma, as well as liver transplantation in decompensated cirrhosis.

Autoimmune hepatitis (AIH) is a chronic liver disease, characterized by elevated levels of transaminases, immunoglobulin G, and positive autoantibodies. The disease course is dynamic and presents heterogeneous disease manifestations at diagnosis. This review summarizes the issues regarding the treatment and monitoring of AIH in adult patients. Glucocorticoids and azathioprine are the first line of treatment. Alternative first-line treatments include budesonide or mycophenolate mofetil (MMF). Although no randomized controlled trials have been performed, MMF, cyclosporine, tacrolimus, 6-mercaptopurine, 6-thioguanine, allopurinol, sirolimus, everolimus, infliximab, or rituximab have been attempted in patients not responding to or intolerant to first-line treatments. Most patients require life-long special monitoring, with or without maintenance treatment.

Autoimmune hepatitis (AIH) is an immune-mediated chronic inflammatory liver disease, characterized by hypergammaglobulinemia, the presence of specific autoantibodies, and typical abnormalities in liver histology. Prompt diagnosis and initiation of immunosuppressive treatment are necessary for both chronic and acute onset AIH to prevent progression to end-stage liver disease or fatal liver failure. However, the diagnosis of AIH is challenging mainly because of its heterogeneous clinical, serological and pathological features. Although portal lymphoplasmacytosis and interface hepatitis are the most typical histological features of AIH, many other histological features can be observed in AIH, including emperipolesis, hepatocyte rosettes, and Kupffer cell hyaline globules. Recent studies have questioned emperipolesis and hepatocyte rosette formation as typical features of AIH, and atypical clinical and histological presentations have also been recognized. This led an international working group to propose the modified AIH diagnostic criteria. However, it is well recognized that there are no pathognomonic characteristics that can be used to diagnose AIH and careful clinicopathological correlation is required to arrive at the correct diagnosis. The aim of this review is to summarize the histological features of AIH, its varied histopathologic spectrum, recent updates and major differential diagnoses in routine clinical practice.

In order to develop immune tolerant to the fetal, maternal immune system will have some modification comparing to the time before pregnancy. Immune tolerance starts and develops at the maternal placental interface. In innate immunity, decidual natural killer (dNK) cells, macrophages and dendritic cells play a key role in immue tolerance. In adaptive immunity, a moderate increase of number and immune inhibition function of regulatory T cells (Treg) are essential for immune tolerance. The trophoblast cells and immune cells expressing indoleamine 2,3-dioxygenase (IDO), the trophoblast cells expressing HLA-G, and Th1/Th2 shifting to Th2 dominant and Th17/Treg shifting to Treg domiant are in favor of maternal fetal immune tolerance. Steroids (estrogen and progesterone) and human chorionic gonadotropin (HCG) also participate in immune tolerance by inducing Treg cells or upregulating immunosuppressive cytokines. Most of the patients with chronic HBV infection are in the "HBV immune tolerance period" before pregnancy, and the liver disease is relatively stable during pregnancy. In chronic HBV infection women, after delivery, the relative immunosuppression in vivo is reversed, and Th1 is dominant in Th1/Th2 and Th17 is dominant in Th17/Treg balance. After delivery, the number of Treg decrease and NK cells increase in quantity and cytotoxicity in peripheral blood. Liver NK cells may cause liver inflammation through a non-antigen specific mechanism. After delivery, the number of CD8+ T cells will increase and HBV specific T cell response recovers from the disfunction in pregnancy. Under the background of postpartum inflammation, the rapid decrease of cortisol after delivery, and especially the enhancement of HBV specific T cell response induced by HBV DNA and cytokines, are the main reasons for postpartum hepatitis. HBeAg positive, especially HBeAg<700 S/CO, and HBV DNA>3-5Log10IU/ml are risk factors for postpartum hepatitis. Antiviral treatment in late pregnancy can reduce the incidence of mother to child transmission (MTCT) in chronic HBV infection women. Chronic HBV infection women have hepatitis both during pregnancy and more often in 12 weeks postpartum. It is generally agreed that postpartum hepatitis is mild symptoms and self-limited. Delaying drug withdrawal to 48 weeks can increase the seroconversion rate of HBeAg in delivery women with elevated alanine aminotransferase (ALT) in pregnancy.

Recommendations for drug withdrawal in patients with autoimmune hepatitis (AIH) in longstanding remission are conflicting and rely on retrospective data. We prospectively investigated the predictive value of histological normalisation for successful treatment withdrawal in AIH patients.

Non-cirrhotic patients with established AIH and complete biochemical remission (normalisation of serum alanine aminotransferase [ALT] or aspartate aminotransferase [AST] and immunoglobulin G [IgG]) of at least 2 years were biopsied. Immunosuppressive therapy was only withdrawn in patients with histological normalisation (histological activity index [HAI] ≤3) with a minimum follow-up of 12 months.

A total of 17 patients in biochemical remission for at least 2 years were included. Persistent histological inflammatory activity (HAI >3) precluded drug withdrawal in five patients. These had higher values of ALT (25 vs. 16 U/L; p = 0.01) and AST (26 vs. 22 U/L; p = 0.01) compared with patients in histological remission. Immunosuppressive medication was withdrawn in 12 patients; eight (67%, C.I. 40-93% p = 0.4) remained in remission during a median follow-up of 62 months (range: 13-75 months); and four (33%, C.I. 7-60% p = 0.4) required reinstitution of therapy after 1, 6, 11, and 40 months, all without clinical signs of disease progression or hepatic decompensation. No predictors of relapse were identified.

Two-thirds of the patients who prove to have histological normalisation after at least 2 years of biochemical remission achieve treatment-free remission. Although patient numbers were small and results should be interpreted with caution, these findings support a liver biopsy prior to drug withdrawal.

Initial treatment of autoimmune hepatitis (AIH) with prednisolone ± azathioprine is based on randomised controlled trials. Many patients receive long-term immunosuppressive treatment to prevent disease relapse; this strategy has a weaker evidence base.

To consider whether immunosuppressive treatment (IST) withdrawal in AIH is justified and to develop a rationale for patient selection.

We reviewed published papers between 1972 and 2018, which addressed the outcomes of IST withdrawal and/or complications of IST in AIH.

(1) AIH relapse rates after withdrawal of IST vary between 25% and 100%. There is heterogeneity in these studies regarding relapse definition, IST duration prior to withdrawal and criteria for biochemical and histological remission prior to withdrawal. (2) Factors associated with relapse following IST withdrawal include: (a) absence of an identifiable initial disease trigger, (b) presence of other autoimmune diseases, (c) longer time to biochemical remission and (d) elevated serum transaminases on treatment withdrawal. Reports of associations between relapse and age, IST duration and failure of histological remission have been inconsistent. (3) Continued IST reduces risk of AIH relapse over at least 5 years. However, there is no evidence that routine (as opposed to selective) long-term IST improves disease outcome. (4) Patients with AIH have an increased risk of extrahepatic cancer, notably non-melanoma skin cancer, to which long-term IST may contribute. Long-term corticosteroid therapy is associated with weight gain, low-trauma fractures, diabetes and possibly vascular disease.

While further studies are needed, evidence supports a strategy of IST withdrawal in some patients with AIH who have achieved remission.

Predniso(lo)ne, alone or in combination with azathioprine, is the standard-of-care (SOC) therapy for autoimmune hepatitis (AIH). However, the SOC therapy is poorly tolerated or does not control disease activity in up to 20% of patients. We assessed the efficacy of mycophenolate mofetil (MMF) and tacrolimus as second-line therapy for patients with AIH.

We performed a retrospective study of data (from 19 centers in Europe, the United States, Canada, and China) from 201 patients with AIH who received second-line therapy (121 received MMF and 80 received tacrolimus), for a median of 62 months (range, 6-190 mo). Patients were categorized according to their response to SOC. Patients in group 1 (n = 108) had a complete response to the SOC, but were switched to second-line therapy as a result of side effects of predniso(lo)ne or azathioprine, whereas patients in group 2 (n = 93) had not responded to SOC.

There was no significant difference in the proportion of patients with a complete response to MMF (69.4%) vs tacrolimus (72.5%) (P = .639). In group 1, MMF and tacrolimus maintained a biochemical remission in 91.9% and 94.1% of patients, respectively (P = .682). Significantly more group 2 patients given tacrolimus compared with MMF had a complete response (56.5% vs 34%, respectively; P = .029) There were similar proportions of liver-related deaths or liver transplantation among patients given MMF (13.2%) vs tacrolimus (10.3%) (log-rank, P = .472). Ten patients receiving MMF (8.3%) and 10 patients receiving tacrolimus (12.5%) developed side effects that required therapy withdrawal.

Long-term therapy with MMF or tacrolimus generally was well tolerated by patients with AIH. The agents were equally effective in previous complete responders who did not tolerate SOC therapy. Tacrolimus led to a complete response in a greater proportion of previous nonresponder patients compared with MMF.

Beyond available guidelines, therapy of autoimmune hepatitis (AIH) shows wide variation among physicians. We compared two regimens for treatment naive AIH: one recommended protocol with an initial prednisolone dose of 30 mg/day and our own 40 mg/day prednisolone with a slow dose tapering protocol. We analyzed the safety, response rates, and outcomes for two groups of treated patients.

We retrospectively evaluated data of 71 AIH patients including, group I (n = 32, prednisone 30 mg/day) and group II (n = 39, prednisone 40 mg/day). All patients also received azathioprine.

The frequency of complete biochemical response was significantly higher in group II than in group I (69.2 vs. 43.8%, p = 0.031) after 3 months of therapy, but not after 6 and 12 months (79.5 vs. 59.4%, p = 0.065 and 89.5 vs. 80.6%, p = 0.30). In patients with severe interface hepatitis, the complete response rates were significantly higher in group II than in group I after 3 (63.6 vs. 23.1%, p = 0.02) and 6 months (72.7 vs. 38.5%, p = 0.046), but not after 12 months of therapy (86.4 vs. 69.2%, p = 0.221). Relapses were observed in 50% of group I and in 35.9% of group II during maintenance therapy (p = 0.23). Overall survival was significantly better in group II than in group I (100 vs. 87.5%, log-rank, p = 0.048). No severe steroid-related side effects were observed in either group.

Our real-world experience suggests that an initial prednisolone dose of 40 mg/day with a slower tapering protocol induces earlier biochemical response, tends to result in less relapses during maintenance, and is associated with a better disease outcome.

In autoimmune hepatitis (AIH), relapse rates as high as 90% have been reported after treatment withdrawal. We therefore investigated, whether longer duration of treatment and proper patient selection could increase the long-term success rates after treatment withdrawal.

Following our previously published experience, treatment withdrawal was considered when biochemical remission was maintained under immunosuppressive monotherapy for at least 2 years. Remission was defined as repeatedly normal serum aminotransferase levels as well as normal IgG levels.

Out of 288 patients with well-defined AIH, 28 patients were included. Median duration of treatment was 48.5 months (range 35-179) and a sustained remission was observed for 45 months (range 24-111). All patients were in remission on immunosuppressive monotherapy for a minimum of 2 years before treatment was withdrawn. Using this strict approach, 15 patients (54%) remained in long-term remission after a median of 28 months follow-up (range 17-57) and 13 patients (46%) required reinstitution of treatment. Higher ALT and IgG levels - although within the normal range in all patients--were associated with the time to relapse. All patients who remained in remission had ALT levels less than half the ULN and IgG levels not higher than 12 g/L at the time of treatment withdrawal.

Proper patient selection including a sustained complete biochemical remission on immunosuppressive monotherapy for a minimum of 2 years can markedly improve the success rates of treatment withdrawal. The interpretation of aminotransferase and IgG levels within the normal range could aid in predicting the risk of relapse.

Autoimmune hepatitis is characterized by increased serum aminotransferase levels, autoantibodies, hypergammaglobulinemia, and interface hepatitis. Presentation can be acute, severe (fulminant), asymptomatic, or chronic. Diagnosis requires multiple findings and exclusion of similar diseases. Treatment with prednisone or prednisolone with azathioprine is recommended. Budesonide with azathioprine has normalized laboratory test with few side effects, but histologic resolution, durability of response, and target population are uncertain. Progressive worsening, incomplete improvement, drug intolerance, and relapse after drug withdrawal are suboptimal outcomes. Calcineurin inhibitors and mycophenolate mofetil are salvage agents in small series and liver transplantation is effective for liver failure.

Corticosteroids alone or in combination with azathioprine are the mainstay therapies of autoimmune hepatitis. Suboptimal responses (treatment failure, partial response, drug toxicity), frequent relapse after drug withdrawal, and the emergence of alternative immunosuppressive medications have fueled the pursuit of new treatments. The goals of this review are to present current management strategies and evolving interventions.

PubMed searches from 1970 - 2014 provide the bases for this review. Corticosteroid regimens should be administered until resolution of symptoms, laboratory tests, and liver tissue abnormalities. Treatment failure warrants high doses of the original regimen, and relapse warrants re-treatment followed by long-term maintenance with azathioprine. The calcineurin inhibitors, budesonide, and mycophenolate mofetil are evolving as frontline therapies, and they may be considered as salvage therapies with the exception of budesonide. Rapamycin, rituximab, and infliximab have also rescued refractory patients but experiences are limited. Anti-oxidants, recombinant molecules, mAbs, and modulators of critical cell populations are key prospects.

Autoimmune hepatitis must be managed by multiple medications that supplement or supplant current regimens depending on the clinical situation. Rescue therapies will emerge as adjunctive interventions to minimize tissue damage (prevent fibrosis and hepatocyte apoptosis) and improve immune tolerance (regulatory T cell manipulations).

Autoimmune hepatitis can be rendered treatment-free, but the difficulty, frequency and risks associated with the pursuit of this outcome are unclear.

To describe the frequency that autoimmune hepatitis can be rendered treatment-free, identify the features that characterise these patients, examine the pathogenic pathways that may sustain or terminate the disease and indicate management protocols that can obtain this result.

Studies cited in Pub Med from 1972-2014 for autoimmune hepatitis, treatment, relapse, remission and outcome were selected.

The frequency of a treatment-free state varies from 19% to 40% in patients observed for ≥3 years after drug withdrawal. Complete laboratory resolution and reversion to normal liver tissue prior to drug withdrawal favours this response. The development of cirrhosis during therapy may increase treatment-dependence. Persistent liver damage and the generation of neo-antigens during the apoptosis of hepatocytes may perpetuate the disease. Genetic and age-related effects on the vigour of the immune response may also contribute. Reversion to normal liver tissue is achieved in only 22% of patients during conventional corticosteroid therapy, and the emerging pharmacological and biological interventions may improve this frequency. A management strategy designed to achieve a treatment-free state accommodates all candidates for this outcome, and it can be modified to a long-term maintenance strategy as warranted by the clinical response.

Permanent drug withdrawal is a treatment outcome that is desirable and achievable in patients with autoimmune hepatitis. Normalisation of liver tests and liver tissue during treatment enhances this occurrence.

Chronic liver inflammation drives hepatic fibrosis, and current immunosuppressive, anti-inflammatory, and anti-viral therapies can weaken this driver. Hepatic fibrosis is reversed, stabilized, or prevented in 57%-79% of patients by conventional treatment regimens, mainly by their anti-inflammatory actions. Responses, however, are commonly incomplete and inconsistently achieved. The fibrotic mechanisms associated with liver inflammation have been clarified, and anti-fibrotic agents promise to improve outcomes as adjunctive therapies. Hepatitis C virus and immune-mediated responses can activate hepatic stellate cells by increasing oxidative stress within hepatocytes. Angiotensin can be synthesized by activated hepatic stellate cells and promote the production of reactive oxygen species. Anti-oxidants (N-acetylcysteine, S-adenosyl-L-methionine, and vitamin E) and angiotensin inhibitors (losartin) have had anti-fibrotic actions in preliminary human studies, and they may emerge as supplemental therapies. Anti-fibrotic agents presage a new era of supplemental treatment for chronic liver disease.

Consensus guidelines aid in the diagnosis and management of autoimmune hepatitis, but they are frequently based on low-quality clinical evidence, conflicting experiences and divergent opinions. Recommendations may be weak, discrepant or non-existent at critical decision points.

To identify the decision points where guidelines are weak or non-existent and review the evidence essential in the decision process.

Full-text articles published in English using the keyword 'autoimmune hepatitis' were identified by PubMed from 1972 to 2013. Personal experience and investigations in autoimmune hepatitis also identified important contributions.

Seventy per cent of the guidelines developed by the American Association for the Study of Liver Diseases and 48% of those proposed by the British Society of Gastroenterology are based on low-quality evidence, conflicting experiences or divergent opinions. The key uncertainties in diagnosis relate to the timing of liver biopsy, recognising acute severe (fulminant) disease, interpreting coincidental nonclassical histological changes, accommodating atypical or deficient features in non-White patients, differentiating drug-induced from classical disease and identifying overlap syndromes. The key uncertainties in management relate to pre-treatment testing for thiopurine methyltransferase activity, treating asymptomatic mild disease, determining treatment end points, managing suboptimal responses, incorporating nonstandard medications as front-line and salvage agents, using azathioprine in pregnancy and instituting surveillance for hepatocellular carcinoma.

Consensus guidelines are fraught with uncertainties in the diagnosis and management of autoimmune hepatitis. Each decision point must counterbalance the current available evidence and tailor the application of this evidence to the individual patient.

Corticosteroid treatment for autoimmune hepatitis has been shown by randomised controlled clinical trials to ameliorate symptoms, normalise liver tests, improve histological findings and extend survival. Nevertheless, suboptimal responses to corticosteroid treatment still occur.

To describe the current definitions, frequencies, clinical relevance and treatment options for suboptimal responses, and to discuss alternative medications that have been used off-label for these occurrences.

Literature search was made for full-text papers published in English using the keyword 'autoimmune hepatitis'. Authors' personal experience and investigational studies also helped to identify important contributions to the literature.

Suboptimal responses to standard therapy include treatment failure (7%), incomplete response (14%), drug toxicity (13%) and relapse after drug withdrawal (50-86%). The probability of a suboptimal response prior to treatment is higher in young patients and in patients with a severe presentation, jaundice, high MELD score at diagnosis, multilobular necrosis or cirrhosis, antibodies to soluble liver antigen, or inability to improve by clinical indices within two weeks or by MELD score within 7 days of conventional corticosteroid treatment. Management strategies have been developed for the adverse responses and nonstandard drugs, including mycophenolate mofetil, budesonide, ciclosporin, tacrolimus, sirolimus and rituximab, are emerging as rescue therapies or alternative frontline agents.

Once diagnosed, the suboptimal response should be treated by a highly individualised and well-monitored regimen, preferentially using first-line therapy. Nonstandard drugs warrant consideration as salvage or second-line therapies.

Autoimmune hepatitis can recur or appear de novo after liver transplantation, and it can result in hepatic fibrosis, graft loss, and re-transplantation. The goals of this review are to describe the prevalence, manifestations, putative pathogenic mechanisms, outcomes, and management of these occurrences. Autoimmune hepatitis recurs in 8-12 % of transplanted patients at 1 year and 36-68 % at 5 years. Recurrence may be asymptomatic and detected only by surveillance liver test abnormalities or protocol liver tissue examination. Autoantibodies that characterized the original disease, hypergammaglobulinemia, increased serum immunoglobulin G level, and histological findings of interface hepatitis, lymphoplasmacytic infiltration, perivenular hepatocyte necrosis, pseudo-rosetting, and acidophil bodies typify recurrence. Premature corticosteroid withdrawal and pre-transplant severity of the original disease are possible risk factors. De novo autoimmune hepatitis occurs in 1-7 % of patients 0.1-9 years after transplantation, especially in children. The appearance of autoantibodies may herald its emergence, and antibodies to glutathione-S-transferase T1 have been predictive of the disease. Recurrent disease may reflect recruitment of residual memory T lymphocytes and host-specific genetic predispositions, whereas de novo disease may reflect an allo-antigenic immune response and molecular mimicries that override self-tolerance. Treatment should be appropriate for autoimmune hepatitis and not based on anti-rejection drugs. Corticosteroid therapy alone or combined with azathioprine is the essential treatment. The substitution of mycophenolate mofetil for azathioprine and switch of the calcineurin inhibitor or its replacement with rapamycin have also been used for refractory disease. Re-transplantation has been necessary in 8-23 %.

Current treatment strategies for autoimmune hepatitis are complicated by frequent relapse after drug withdrawal, medication intolerance, and refractory disease. The objective of this review is to describe advances that have improved treatment outcomes by defining the optimum objectives of initial therapy, managing relapse more effectively, identifying problematic patients early, and incorporating the new pharmacological interventions that have emerged as frontline and salvage therapies. Initial corticosteroid treatment should be continued until serum aminotransferase, γ-globulin, and immunoglobulin G levels are normal, and maintenance of this improvement for 3-8 months before liver tissue assessment. Improvement to normal liver tissue is the ideal histological result that justifies drug withdrawal, but it is achievable in only 22 % of patients. Minimum portal hepatitis, inactive cirrhosis, or minimally active cirrhosis is the most common treatment end point. Relapse after drug withdrawal warrants institution of a long-term maintenance regimen, preferably with azathioprine. Mathematical models can identify problematic adult patients early, as also can clinical phenotype (age ≤ 30 years and HLA DRB1 03), rapidity of treatment response (≤ 24 months), presence of antibodies to soluble liver antigen, and non-white ethnicity. The calcineurin inhibitors (cyclosporine and tacrolimus) can be effective in steroid-refractory disease; mycophenolate mofetil can be corticosteroid-sparing and effective for azathioprine intolerance; budesonide combined with azathioprine can be effective for treatment-naïve, non-cirrhotic patients. Standard treatment regimens for autoimmune hepatitis can be upgraded without adjustments that require major new expertise.

Autoimmune hepatitis (AIH) is characterized by chronic inflammation of the liver, interface hepatitis (based on histologic examination), hypergammaglobulinemia, and production of autoantibodies. Many clinical and basic science studies have provided important insights into the pathogenesis and treatment of AIH. Transgenic mice that express human antigens and develop autoantibodies, liver-infiltrating CD4(+) T cells, liver inflammation, and fibrosis have been developed as models of AIH. AIH has been associated with autoantibodies against members of the cytochrome P450 superfamily of enzymes, transfer RNA selenocysteine synthase, formiminotransferase cyclodeaminase, and the uridine diphosphate glucuronosyltransferases, whereas alleles such as DRB1*0301 and DRB1*0401 are genetic risk factors in white North American and northern European populations. Deficiencies in the number and function of CD4(+)CD25(+) (regulatory) T cells disrupt immune homeostasis and might be corrected as a therapeutic strategy. Treatment can be improved by continuing corticosteroid therapy until normal liver test results and normal liver tissue are within normal limits, instituting ancillary therapies to prevent drug-related side effects, identifying problematic patients early, and providing long-term maintenance therapy after patients experience a first relapse. Calcineurin inhibitors and mycophenolate mofetil are potential salvage therapies, and reagents such as recombinant interleukin-10, abatacept, and CD3-specific antibodies are feasible as therapeutics. Liver transplantation is an effective salvage therapy, even in the elderly, and AIH must be considered in all patients with graft dysfunction after liver transplantation. Identification of the key defects in immune homeostasis and antigen targets will direct new therapies.