Autoimmune hepatitis: an approach to disease understanding and management

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1 British Medical Bulletin, 2015, 114: doi: /bmb/ldv021 Advance Access Publication Date: 20 May 2015 Autoimmune hepatitis: an approach to disease understanding and management Margaret Corrigan, Gideon M. Hirschfield*, Ye H. Oo, and David H. Adams NIHR Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, UK *Correspondence address. Centre for Liver Research, University of Birmingham, Institute of Biomedical Research, Wolfson Drive, Birmingham B15 2TT, UK. Accepted 15 April 2015 Abstract Introduction: Autoimmune hepatitis is a chronic immune-mediated liver injury, frequently associated with progression to end-stage liver disease if untreated. Patients commonly present with hepatitis, positive immune serology, elevated immunoglobulins and compatible liver histology, in the absence of an alternative aetiology. Sources of data: Data for this review were obtained using PubMed. Areas of agreement: Disease usually responds to steroids and azathioprine, and appears to be a manifestation of autoimmune predisposition triggered in genetically susceptible individuals exposed to likely environmental challenges. We provide an up-to-date approach to disease understanding and management along with the clinical approach to diagnosis and current treatment suggestions. Areas of controversy: Controversies such as second line therapies and novel markers of disease activity are introduced. Growing points: Increased understanding of the immunoregulatory mechanisms behind autoimmune hepatitis has led to opportunities for new therapies. These are developed including a discussion of timely research studies relevant to future therapies for patients. Key words: autoimmune liver disease, immune mediated liver disease, prednisolone, azathioprine Introduction Autoimmune hepatitis (AIH) is a rare but important cause of liver morbidity and mortality. It is defined as a chronic immune-mediated liver injury, characterized in its classic form by lympho-plasmacytic hepatitis, autoantibodies, elevated immunoglobulins and steroid responsiveness along with an absence of recognized viral or metabolic liver disease. The aetiology of AIH The Author Published by Oxford University Press. All rights reserved. For permissions, please journals.permissions@oup.com

2 182 M. Corrigan et al., 2015, Vol. 114 remains unknown, but evidence suggests a coalescence of genetic susceptibility and environmental risks, which culminate in a loss of immune tolerance leading to T-cell-mediated destruction of hepatocytes. While local hepatic regulatory networks involving regulatory T cells are implicated in disease pathogenesis, animal models demonstrate that AIH may result from defective central immune tolerance. This has been demonstrated by the development of AIH in mice deficient in medullary thymic epithelial cells. 1 The spectrum of environmental triggers is likely to be broad as AIH syndromes have been associated with viral infections and drug toxicity. The pattern of clinical presentation spans benign chronic hepatitis and indolent disease through to fulminant liver failure. This suggests that, while there are common pathways to liver injury, AIH may encompass several distinct diseases. AIH occurs in all populations but has been reported as most frequent in Caucasian Western Europeans and North Americans with an estimated prevalence of 10 17/ As with many other forms of autoimmune disease, there is a documented female preponderance and a pan-age onset; initially described as a disease of younger women, presentation is now recognizedtobebroaderwithareportedmedianageof onset in the fifth decade 3 with men presenting at an earlier age than women. 4 Many patients will have another extra hepatic autoimmune disease; the most common being thyroiditis. 5 The presentation of AIH is highly variable. Onethird of patients present with an acute hepatitis with jaundice and right upper quadrant pain or occasionally fulminant hepatic failure. 6 The remainder are diagnosed either as the result of incidental findings on routine liver biochemistry tests in asymptomatic individuals or present with constitutional symptoms such as arthralgia, nausea and anorexia. Thirty per cent of patients will have cirrhosis at presentation 6 including a significant number who are asymptomatic. Fatigue is a frequent complaint for patients, which, albeit nonspecific, is recognized to impact on perceived qualityof-life indices. AIH is conveniently divided into two sub-types (Type 1 ANA/SMA positive and Type 2 LKM positive) largely based on immune serology and epidemiology. The term type 3 AIH is no longer used and probably represented an atypical presentation of type 1 disease. Table 1 details the main differences between the two patient groups. Disease diagnosis While there are a number of features that may point towards a diagnosis of AIH, there is no single pathognomonic test, reflecting the lack of knowledge about the underlying cause as well as the likelihood that AIH is an umbrella term for several diseases. AIH thus remains a diagnosis of exclusion, and proposed diagnostic criteria combine positive and negative features to indicate probability of disease. In some cases, treatment and assessment of response are required to support the Table 1 Serologic classification of autoimmune hepatitis Type 1 Type 2 Percentage of all AIH cases 80% 20% Geography Global More common in Northern Europe Gender (female : male) 4 : 1 9 : 1 Age Median age 40 years Median age 10 years Presentation Asymptomatic to fulminant More likely to be acute; can have fluctuating course; associated with IgA deficiency Serology ANA, anti SMA Anti LKM 1, anti LC 1 HLA association HLA DR3/DR4 HLA DR3/DR7 Prognosis Good More aggressive and classically harder to treat; rates of relapse are high ANA, anti-nuclear antibody; SMA, smooth muscle antibody; LKM, liver kidney microsomal; LC, liver cytosolic.

3 Autoimmune hepatitis, 2015, Vol diagnosis. In all cases, individual test results need to be interpreted carefully. In the patient presenting with acutely elevated serum transaminases, it is important to consider the full spectrum of liver diseases. In addition to viral infection and drug toxicity, the exclusion of alpha 1 antitrypsin deficiency, Wilson s disease, non-alcoholic steatohepatitis and alcohol excess is required. Druginduced autoimmune hepatitis is a well-recognized form of drug-induced liver injury, and unlike most classic drug reactions, the patient may have been on the offending drug for a number of months or years before presenting. Similarly, the exclusion of viral infection (including Hepatitis A, B, C and E as well as herpesviruses) is important, but there are welldescribed reports of viral infection triggering autoimmune hepatitis. Furthermore, some acute flares of AIH will resolve spontaneously and, even if a drug or viral trigger is suspected, the patient should be followed up: firstly, to ensure full clinical and biochemical resolution and, secondly, to monitor for relapse that is likely to occur after a few months if there is underlying AIH. The classical serologic pattern includes a positive anti-smooth muscle antibody (SMA) or anti-nuclear antibody in the case of type 1 AIH, or, in the case of type 2, positive anti-liver kidney microsomal antibody (LKM) 1 or anti-liver cytosolic 1. Anti-soluble liver antigen (SLA) antibodies are specific for autoimmune liver disease and were previously believed to define a distinct type 3 clinical syndrome. However, they can be present in AIH-1 and AIH-2 and are associated with a more severe clinical course. Adding to the diagnostic challenge, up to 20% of patients are antibody negative at presentation 7 while antimitochondrial antibodies (a feature typically associated with primary biliary cirrhosis/pbc) can be found in a similar proportion. These usually occur at a low titre <1 : 40 and do not necessarily indicate overlap with PBC. The utility of serology in diagnosing AIH is very dependent on the skill of the immunopathology laboratory and clinicians should frequent themselves with the techniques on offer within their own practice to interpret test results accurately. Antibody testing for specific AIH reactivity (e.g. anti- F-actin, anti-sla) can be very helpful in some settings, but is not easily accessible to nonspecialist centres. Another classical hallmark of AIH is a raised IgG level. However, for 5 10% of patients, IgG is normal although at the upper limit of the range. 6 Unless there is a very strong contraindication, a liver biopsy should be carried out in all patients with suspected autoimmune hepatitis to confirm the diagnosis and stage the disease. AIH is a lifelong disease usually requiring treatment with immunosupressants, and it is thus important that the diagnosis is as secure as possible. While there are no pathognomonic histological features, the presence of interface hepatitis, plasma cell infiltrate and hepatocyte rosetting is characteristic. In addition, histology may confirm or exclude alternative diagnoses by detecting viral inclusion bodies, malignant infiltration, biliary diseases, granulomatous hepatitis, etc. Histological appearances also allow for staging of disease and prognostication. These factors form the basis of the International Autoimmune Hepatitis Group (IAIHG) revised diagnostic criteria, which have a sensitivity of %. 7 However, they were designed principally as a research tool and emphasize the exclusion of biliary disease. More simplified criteria, applicable to clinical practice, have been developed which work well in non-specialist settings, assuming they are applied in the correct context. Using the simplified criteria, 8 a cut- off of 6 indicates probable AIH with a sensitivity of 88% and specificity of 97%, while a cut off of 7 indicates, so-called, definite AIH (Table 2). Non-invasive evaluation of liver disease severity by transient elastography is becoming increasingly frequent. In the context of autoimmune hepatitis, the precise utility of elastography remains to be demonstrated, and readings will reflect both active inflammatory activity as well as liver fibrosis. Thus, its utility may be both as a means to quantifying fibrosis (particularly in patients in remission) as well as to track patients on therapy, as disease is treated and inflammatory activity recedes. Management of autoimmune hepatitis Early data from trials of patients with what was then referred to variably as lupoid hepatitis, chronic

4 184 M. Corrigan et al., 2015, Vol. 114 Table 2 Simplified criteria for diagnosis of autoimmune hepatitis (Hennes et al.) 8 Variable Cut-off Points ANA or SMA 1 : 40 1 ANA or SMA 1:80 or LKM 1 : 40 2 or SLA Positive IgG >ULN 1 >1.10 ULN 2 Liver histology Compatible with AIH 1 Typical of AIH 2 Absence of viral hepatitis Yes 2 Maximum score for autoantibodies = 2. A cut-off of 6 indicates probable AIH while a cut-off of 7 indicates, so-called, definite AIH. active hepatitis or HBsAg negative chronic active hepatitis, highlight the poor prognosis of the condition without treatment. A follow-up study of patients presenting in the mid-1960s who were treated with steroids showed a 10-year survival of 63% in the treatment group compared with 27% in the control group (P = 0.03) with a median survival of 12.2 vs. 3.3 years. 9 Therapy prolongs life, and prednisolone is first line therapy for inducing remission of disease while azathioprine is first line for maintenance of remission. 10,11 Failure to use azathioprine is associated with poor outcomes in AIH. 12 Whom to treat All patients with AIH need follow-up and monitoring, and most patients, but not all, need treatment. The group who are left untreated largely consists of elderly patients with mild, indolent disease and/or significant co-morbidity, where risks of immunosuppression outweigh the benefits and the patient presenting with inactive cirrhosis who may not benefit from treatment. However, patients with cirrhosis in the presence of active inflammation may benefit significantly from immunosuppression with resolution of ascites and manifestations of liver failure; if in doubt, it is prudent to start a trial period of immunosuppression. British Society of Gastroenterology guidelines 2 suggest that treatment with immunosuppressive agents should be offered to all patients with AIH and moderate to severe inflammation evidenced by one or more of: AST >5 ULN, globulins >2 ULN, biopsy showing confluent necrosis. It should also be considered in those not meeting these criteria but who have evidence of cirrhosis on biopsy as well as young patients. The American Association for the Study of Liver Diseases guidelines 13 adopt a similar approach advising treatment for the following indications: AST >10 ULN, AST >5 ULN and gamma globulins >2 ULN, biopsy evidence of bridging necrosis/multilobular necrosis, incapacitating symptoms including fatigue and arthralgia. Both guidelines agree that for patients where the decision is made not to treat, there should be regular follow-up and monitoring for symptoms should continue. If blood tests remain abnormal after 2 3 years, re-biopsy should be considered. Several variations of initial treatment exist, and the precise algorithm is dependent on how the patient responds. Figure1 shows a proposed approach to treatment. Steroids and induction of remission An optimum dosing strategy remains poorly defined, and no trials have specifically compared prednisolone dosing. This reflects the fact that the disease is uncommon, heterogeneous and usually responds rapidly. The current recommended regimen in the UK is mg/day, although it might be more logical to dose according to patient weight with 1 mg/kg advocated as a starting dose by some. In the majority of patients, transaminases should start to fall after 2 weeks. Decisions regarding dose titration need to be individualized. Some give Prednisolone 20 mg per day for at least 2 3 months while others dose titrate in a more structured way; in most cases, the initial corticosteroid dose can be reduced after 3 4 weeks. However, asking for advice from specialist clinics if patients do not rapidly respond to treatment is sensible as few clinicians treat AIH in high volume. The duration of prednisolone therapy along with its dosing needs to be weighed against the risks associated especially in those with a history of poorly controlled diabetes, hypertension, psychosis or osteoporosis. Budesonide

5 Autoimmune hepatitis, 2015, Vol Fig. 1 Treatment approaches in autoimmune hepatitis. While guidelines do exist for treating autoimmune hepatitis, clinicians must be mindful of the heterogeneity of disease alongside the relative rareness of the condition. Approaches to treatment vary depending on the way clinicians balance the benefits of disease remission against the risks of powerful immunosuppressants. Fundamentally clinicians should personalize care to the patient and seek advice if patients do not respond well to first line interventions. is a theoretically attractive alternative to prednisolone for patients in whom it is important to minimize corticosteroid side effects, because it undergoes activation within the liver thereby reducing systemic side effects. Studies comparing its efficacy to that of prednisolone have revealed variable results, although the largest study to date which randomized just over 200 patients showed a clear benefit for budesonide over prednisolone when looking at remission and absence of corticosteroid side effects. 14 However, its use is limited by the fact that it is contraindicated in those with cirrhosis and portal hypertension. The risk of reducing corticosteroids too rapidly is reactivation of hepatitis sometimes referred to as a flare but probably reflects inadequate immunosuppresssion. Histological changes of acute hepatitis can persist for 6 months after transaminases have normalized, and it is rarely justified to repeat the liver biopsy before at least 12 months. Thus, corticosteroid dose titration should be done slowly and patients should expect to receive between 12 and 18 months of corticosteroid treatment assuming their disease is responsive. Guidelines for monitoring patients on long-term corticosteroids should be followed and, owing to the risk of steroid-related bone disease, patients should take calcium and vitamin D supplementation, after usually having a baseline bone density scan. However, the value of bone density scans in young adults is not clear, nor is the frequency with which scans should be repeated, although commonly repeat bone density

6 186 M. Corrigan et al., 2015, Vol. 114 measurement occurs at three yearly intervals. Of more relevance is individualized patient risk assessment (e.g. and discussion of bone health with appropriate osteoporosis experts. Most authorities recommend mg of calcium (total of diet and supplement) and international units of vitamin D daily. Blood glucose should also be monitored regularly to look for steroid precipitated diabetes mellitus. After 12 months of treatment with steroids, patients should be considered for screening for cataracts and glaucoma. Immunosuppression for maintenance Azathioprine is the drug of choice for maintenance of remissioninaih.theassociationwithhepatotoxicity means it is relatively contraindicated in the acutely jaundiced patient and is usually started a number of weeks after corticosteroids. This strategy also provides the physician with time to determine corticosteroid responsiveness, an important confirmatory diagnostic intervention in some patients, and to check thiopurine methyltransferase (TPMT) levels prior to commencing azathioprine treatment. Dosing strategies vary depending on country with US recommendations favouring 50 mg/day while UK and European recommendations favour a higher dose of mg/kg/day. Regardless of TPMT levels, some patients have an idiosyncratic intolerance to azathioprine, and ongoing use requires monitoring of full blood count and liver function tests. The azathioprine metabolite 6-mercaptopurine can also be used and is occasionally better tolerated than azathioprine. More so than measuring TPMT activity, dose monitoring of azathioprine/6-mercaptopurine by thioguanines and methylmercaptopurine nucleotide levels can be helpful in a subset of harder to treat patients. 15 Azathioprine is associated with increased sensitization to UV light and a markedly increased risk of squamous cell carcinoma of the skin, and patients should be advised to avoid strong sunlight and use sunscreens. A number of patients are unable to tolerate azathioprine due to side effects and an alternative in this case is mycophenolate mofetil (MMF): this second line agent is not more effective than azathioprine, but it has a clear role for patients intolerant of azathioprine or 6-mercaptopurine. 16 It is associated with nausea and abdominal pain in 20% of patients, but these can be reduced by splitting the dosing. All patients starting on immunosuppression should be tested for immunity to Hepatitis A and B and vaccinated if required. 2 Disease remission AASLD define remission as disappearance of symptoms, normalization of transaminases, bilirubin and gamma globulin and no ongoing activity on biopsy. 13 This definition is problematic for many reasons including the subjectivity of symptoms, the need to individualize risk and benefit, and the lack of consensus on the utility of follow-up liver biopsies. Practically, a fall to normal levels of transaminases and IgG is a good indicator of remission and can be used to monitor treatment response. Once remission has occurred, the goal is to maintain it using either low-dose corticosteroids and/or azathioprine. Many patients require lifelong treatment although, in a patient keen to stop treatment, risk of relapse can be predicted (see below). Most patients are treated for 3 5 years before consideration of stopping all therapy; cirrhotic patients should be counselled against stopping therapy. 6 Treatment cessation Disease relapse in classic AIH is so frequent that many do not offer any treatment withdrawal. However, the patterns of presentation can vary so much that there remain patients where it can be appropriate to consider cessation of all therapy, although this should only be done after careful assessment and with close monitoring to look for reactivation. Long-term follow-up studies suggest that prolonged treatment free periods vary between 19 and 40%. 17 When considering stopping treatment in patients with AIH, a number of factors need to be taken into account. Firstly, completeness of remission should be confirmed. 18 This requires normalization of biochemical and immunological parameters (transaminases, bilirubin and immunoglobulins) and histological proof of inactive disease on liver biopsy. A number of factors are predictive of relapse. Older patients without cirrhosis are more

7 Autoimmune hepatitis, 2015, Vol likely to sustain remission off treatment, as are those with type 1 disease, whereas relapse is almost inevitable for patients with type 2 AIH who should remain on treatment indefinitely. A longer time to initial treatment response as well as a shorter total length of time on treatment before withdrawal predict relapse. The presence of plasma cells and ongoing interface hepatitis in biopsy samples is also predictive of relapse if treatment is stopped. Stopping all therapy in a cirrhotic patient is rarely sensible: the risk and consequence of relapse usually far outweighs the benefit of stopping azathioprine. Controversies in AIH Corticosteroid dosage Corticosteroids are the most effective treatment of induction of remission in AIH patients. Its initial dosage varies with different guidelines but some advocate particularly high-dose therapy 19 (1 mg/kg dose of prednisolone). The lack of consensus on dose at initiation reflects a lack of more sophisticated immunologic markers of disease severity, alongside the heterogeneous presentation of patients. Relapse This is usually diagnosed based on biochemical and immunological findings with increasing transaminases and gamma globulins. Biopsy is not usually required, assuming the initial diagnosis and response to treatment were consistent with classic AIH. Fortunately, most patients who relapse will respond to reintroduction or increase of treatment. At this stage, lifelong maintenance therapy will usually be required, although the nature of any relapse, the severity of the underlying liver disease, and other patient factors such as side effects and preference need to be taken into account in reaching such a decision. Transplant for AIH There is a role for transplant both in the acute fulminant presentation and in the chronic cirrhotic with evidence of decompensated disease; steroid use in the acute setting can be complicated by an increased infection risk, but the benefits of a steroid response make it important to consider very carefully, and in consultation with a transplant centre, a trial of therapy should be given to all but the sickest patients. Overall, 10% of patients with AIH will require liver transplantation. 2 Post transplant, most patients will continue to have low-dose prednisolone and azathioprine or MMF as part of their immunosuppression regimen. However, recurrence rates at 5 years vary between 20 and 50% of transplants. Most can be managed with adjustment of immunosuppression and recurrence rarely necessitates re-grafting. Treatment failure More than 85% of patients respond to conventional treatment. Failure of treatment is defined as failure to normalize biochemistry, immunological profiles (IgG) or histological features while on standard treatment. Treatment failure may be a reflection of undertreatment of disease, poor compliance, overlap with biliary disease, the coexistence of other diseases particularly NAFLD or true resistant disease. Of concern is an understandable desire by clinicians and patients to taper steroids to reduce side effects, but this risks under treatment of initial disease, which is recognized to recover much slowly histologically than biochemically. A goal of future management is to develop better markers and definitions of treatment failure to allow more consistent and objective approaches to treatment. An important consideration, particularly in adolescent patients, is poor adherence to treatment, and every effort should be made to confirm that the patient is compliant with therapy and aware of the significant risks of treatment withdrawal. In patients who are truly resistant, repeat liver biopsy to confirm histological hallmarks of ongoing inflammation is valuable, as is evaluation of the biliary tree by MRCP to look for cholangiopathy that may develop in some patients with type 1 AIH, particularly young patients or those with concomitant inflammatory bowel disease, and is associated with treatment resistance. Therapy in the setting of true resistant disease is complicated but focuses on an intensification of steroid and azathioprine use. Alternative therapies may be considered (as below).

8 188 M. Corrigan et al., 2015, Vol. 114 Alternative immunosuppression AIH is a rare disease, and if a patient is not respondinginanoptimal way tofirst line therapy then referral to a clinic with an interest in autoimmune liver disease should be considered. Alternative immunosuppressive regimens are not evidence based. MMF (e.g. target dose of 2 3 g daily), tacrolimus (low-dose therapy to achieve trough levels of 5), ciclosporin and more recently monoclonal antibodies such a rituximab (two 1 g IV infusions spaced 2 weeks apart, followed by periodic maintenance therapy) and anti-tnf agents have all been identified as alternative treatments for patients who fail to respond to standard treatment. However, the studies are mostly small uncontrolled series, with varying inclusion criteria (true resistant disease differs to active disease from non-compliance, or progressive disease due to drug intolerance). The largest study of tacrolimus reported a 91% rate of biochemical remission in previously refractory patients 20 but consisted of only 11 patients while the largest series for ciclosporin contained 6 patients with refractory disease and reported biochemical remission in 83% of patients. 21 In addition, their use is limited by significant side effects in terms of renal impairment, neurotoxicity and hypertension. Rituximab efficacy had been studied in 12 patients 22 while infliximab (anti-tnf) had been used in resistant AIH, 23 but septic complications related to anti-tnf are a concern and highlight the need to define further the risk and benefits of this approach. Paradoxically, anti-tnf agents have also been reported in case series as triggers for autoimmune hepatitis. Overall, it is important to be clear that there is a limited evidence to guide treatment with any of these agents, and patients must be informed that inclusion in treatment algorithms is based on expert advice and is subject therefore to personal bias. Opportunities therefore exist for further study in this area, and better efforts at networked care. AIH with biliary features Overlap syndromes are a vexed area of autoimmune liver disease, and autoimmune hepatitis with overlapping features of primary biliary cirrhosis or primary sclerosing cholangitis is widely discussed. Overlap syndromes are defined as the presence of concurrent characteristics of two autoimmune conditions at the same time (concurrent) or during the course of the illness (sequential). Overlap syndromes are not disease entities in their own right. Recognizing that patients do have overlap presentations has not been the challenge to date; the challenge has been both agreeing definitions and determining the significance of overlap findings, and putting into context the descriptions of patients from case series. The frequency of overlap reported in different studies is therefore a factor of the definitions applied, as well as the enthusiasm to identify variant disease course. For PBC/AIH overlap, a French group has championed a pragmatic definition, 24 but it is not universally agreed that this reflects disease that needs different treatment. Furthermore in the context of PBC, UDCA treatment non-response is a confounder in the diagnosis of overlap: a hepatitic PBC is not necessarily the same as PBC/AIH overlap. Similarly, the challenge for PSC/AIH overlap is significant. Paediatric AIH is classically seen as a setting in which overlap is common, to the point that in some series 50% of children with AIH have cholangiopathy on direct biliary imaging. 25 This has coined the term autoimmune sclerosing cholangitis. It is however far from clear if this is a distinct disease (unlikely) or just a hepatitic presentation of PSC (more likely). In adults, it can be equally perplexing, with patients seemingly stable from AIH, developing late features of PSC. Treatment failure in AIH certainly must always account for the possibility of immune-mediated biliary injury as the underlying driving factor. Emerging areas in autoimmune hepatitis Dissecting further the underlying immunopathogenesis of disease is essential to help patients receive optimal treatment of autoimmune hepatitis. There are guidelines in progress to agree on initial steroid dose at diagnosis to achieve remission, although the enormous heterogeneity of presentation is always going to make a one size fits all approach to AIH management impossible. After achieving remission, manipulating the adaptive immune system with

9 Autoimmune hepatitis, 2015, Vol Fig. 2 Proposed immuno-pathogenesis of autoimmune hepatitis. T helper 1(Th1), T helper 17 (Th17) cells and cytotoxic CD8T lymphocytes, plasma cells and Regulatory T cells (Treg) are recruited to the liver via inflamed hepatic sinusoidal endothelium. Recruitment of these immune cells is mediated by the CXCR3 chemokine receptor, which is expressed on these immune cells. CXCR3 interacts with CXCR3 chemokines (CXCL9, 10, 11), which are expressed on inflamed hepatic sinusoidal endothelium. Granzyme B and Perforin secreted from Th1 and cytotoxic T cells and death ligand, CD95L interaction between T cells and death receptor, CD95, on the hepatocyte leads to hepatocyte apoptosis. IL-17 and IL-22 cytokines from Th17 cells lead to regeneration of hepatocytes. Regulatory T cells control T effector cells (Th1, Th17 and cytotoxic T cells) proliferation and cytokine secretion thus limiting ongoing hepatic injury. immunosuppressive medications such as azathioprine, MMF, tacrolimus, rituximab and anti-tnf needs to be based on more precise immunophenotyping using either blood or liver tissue. Although still at an early stage, new approaches using genomics, proteomics and metabolomics represent opportunities to understand disease at a deeper level, as well as to provide biomarkers that ultimately allow the clinician to personalize disease assessment and treatment in AIH. The HLA associations with disease have been known for some time, and more recently, genome-wide association studies have been reported in AIH, helping to identify non-hla risk loci. 26 Additionally current diagnostic scoring for AIH does not include individual immune cell subset surface markers or cytokines, and it is conceivable that such an approach could bring patients more sophistication to their treatment: certain immunological markers may better define treatment responders and resistant cohorts for example. The aetiology of autoimmune hepatitis is still unknown, and many groups are attempting to identify the causative antigens. T-cell receptor sequencing of regulatory and cytotoxic T cells and B cells may help in exploring triggering antigens. It is generally accepted that breakdown in self-tolerance leads to autoimmunity. 27 There is a fine balance of the regulatory and effector arms of the immune system to

10 190 M. Corrigan et al., 2015, Vol. 114 maintain immune homeostasis. The regulatory arm of the adaptive immune system includes regulatory T cells, myeloid derived suppressor cells and tolerogenic dendritic cells. Effector cell subsets comprise B cells, Th1, Th17, Th22 and cytotoxic T cells. To date, the majority of studies on immune mechanisms in AIH have been carried out on peripheral blood samples Although these correlation studies are helpful in understanding AIH, they do not fully represent the local environment at the site of inflammation in the liver, and studies on local environmental regulatory mechanisms are limited by access to tissue. 31,32 Dissecting immune cell interactions in the local microenvironment is however essential to understand the biology at a tissue level. Laboratory research utilizing normal and diseased human liver tissues and in vivo mouse models for mechanistic studies are ongoing to understand these aspects. (Fig. 2) Immune-directed therapies may be applied in a more targeted and informed manner once a more thorough understanding of the immunological mechanisms that lead to hepatocyte damage is achieved. This includes understanding the crosstalk of adaptive immune cells and antigen presenting cells at the level of the local microenvironment. The choice of T cells, B cells or cytokine-directed therapy might then be dependent on local and peripheral immunological profiles. There is a growing interest in regulatory T cells in autoimmune diseases including autoimmune hepatitis. Regulatory T cells control effector cells and maintain immunological peripheral tolerance and offer the opportunity for new therapeutic approaches either by their adoptive transfer or by activating them in vivo using for example low-dose interleukin-2 treatment. Conclusion AIH remains a rare but important chronic liver disease. Treatment can be effective for many, if the disease is diagnosed promptly and managed scrupulously, but a substantial minority of patients are in need of more refined approaches to therapy. In addition, patients would welcome therapies that have fewer side effects. Future opportunities to meet these unmet needs exist and will be based on better mechanistic insights into disease. Conflict of Interest statement The authors have no potential conflicts of interest. References 1. Bonito AJ, Aloman C, Fiel MI, et al. Medullary thymic epithelial cell depletion leads to autoimmune hepatitis. J Clin Invest 2013;123: Gleeson D, Heneghan MA, British Society of Gastroenterology. British Society of Gastroenterology (BSG) guidelines for management of autoimmune hepatitis. Gut 2011;60: Floreani A, Liberal R, Vergani D, et al. Autoimmune hepatitis: contrasts and comparisons in children and adults a comprehensive review. J Autoimmun 2013;46: Al-Chalabi T, Underhill JA, Portman BC, et al. Impact of gender on the long-term outcome and survival of patients with autoimmune hepatitis. J Hepatol 2008;48: Teufel A, Weinmann A, Kahaly GJ, et al. Concurrent autoimmune diseases in patients with autoimmune hepatitis. J Clin Gastroenterol 2010;44: Lohse AW, Mieli-Vergani G. Autoimmune hepatitis. J Hepatol 2011;55: Alvarez F, Berg PA, Bianchi FB, et al. International autoimmune hepatitis group report: review of criteria for diagnosis of autoimmune hepatitis. JHepatol1999;31: Hennes EM, Zeniya M, Czaja AJ, et al. Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology 2008;48: Kirk AP, Jain S, Pocock S, et al. Late results of the Royal Free Hospital prospective controlled trial of prednisolone therapy in Hepatits B surface antigen negative chronic active hepatitis. Gut 1980;21: Murray-Lyon I, Stern RB, Williams R. Controlled trial of prednisone and azathioprine in active chronic hepatitis. Lancet 1973;1: Stellon A, Keating J, Johnson P, et al. Maintenance of remission in autoimmune chronic active hepatitis with azathioprine after corticosteroid withdrawal. Hepatology 1988;8: Hoeroldt B, McFarlane E, Dube A, et al. Long term outcomes of patients with autoimmune hepatitis managed at a non transplant centre. Gastroenterology 2011;140: Manns MP, Czaja AJ, Gorham JD, et al. Diagnosis and management of autoimmune hepatitis. Hepatology 2010; 51: Manns MP, Woynarowski M, Kreisel W, et al. Budesonide induces remission more effectively than prednisone

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