Autoimmune hepatitis - Journal of Hepatology

Review

Autoimmune hepatitis Ansgar W. Lohse1,⇑, Giorgina Mieli-Vergani2 1

Department of Medicine, University Medical Centre Hamburg-Eppendorf, Germany; 2Institute of Liver Studies, King’s College London School of Medicine at King’s College Hospital, London, UK

Autoimmune hepatitis was one of the first liver diseases for which an effective treatment was developed and the benefit proven by randomized controlled trials. Nonetheless, both the diagnosis and the treatment of autoimmune hepatitis remain full of challenges. The clinical spectrum is very wide, ranging from subclinical non-progressive disease to fulminant hepatic failure. Diagnostic criteria based on elevation of IgG, demonstration of characteristic autoantibodies, and histological features of hepatitis in the absence of viral disease are very helpful. However, in some patients, diagnosis remains a clinical challenge. Adequately dosed steroids are the mainstay of remission induction treatment, while remission maintenance is best achieved by azathioprine. Therapeutic alternatives are required in a small group of patients responding insufficiently to these drugs or intolerant to their side effects. Ó 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Introduction Autoimmune hepatitis (AIH) was described as a disease often severely affecting young women well before viral hepatitis markers could reliably distinguish viral from non-viral liver disease [1–3]. The serological demonstration of anti-nuclear antibodies (ANA) and antibodies to double-stranded DNA (dsDNA) lead to the term ‘‘lupoid hepatitis’’ [4,5]. A good response to steroids was observed early on and saved the lives of patients as soon as the disease was recognized as an autoimmune condition [6]. Three landmark clinical controlled trials in the 70s established the life-saving value of corticosteroids in the treatment of patients with ‘‘HBsAg-negative hepatitis’’ [7–11]. In addition, to establishing the value of immunosuppression in autoimmune hepatitis, these were some of the earliest controlled clinical trials, thus advancing clinical science well beyond hepatology. The present review will mainly concentrate on clinical issues.

Keywords: Autoimmunity; Immunosuppression; Prednisolone; Azathioprine; Budesonide. Received 1 October 2010; received in revised form 7 December 2010; accepted 8 December 2010 ⇑ Corresponding author. Address: Department of Medicine, University Medical Centre Hamburg Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. Tel.: +49 7410 53910; fax: +49 7410 58531. E-mail address: [email protected] (A.W. Lohse).

Epidemiology Autoimmune hepatitis occurs in all races and in all geographical areas [12,13]. As it is a relatively rare disease, there are few reliable epidemiological data published. The few data available suggest a prevalence of at least 1:10,000 both in Caucasians and in Japanese [14,15]. However, the subclinical character of the disease in a considerable proportion of patients makes it likely that the true frequency is considerably higher. Regional and racial differences have not been studied systematically. Large groups of patients have been reported from regions as diverse as South America, Alaska, Scandinavia and Australia. In Asia most reports come from Japan [15]. AIH was long thought to be very uncommon in China, but with more refined diagnostic work-up of patients, AIH is increasingly being reported in that country [16,17]. In textbooks, AIH is described as a disease of young women, the patient group in which the disease was initially reported. A female predilection has been confirmed in almost all studies with a female to male ratio of around 3:1 across the world. The age of manifestation of AIH varies greatly from as early as the first year of life up until the eighties [13,18,19]. As in many other autoimmune diseases, both the median and the mean age of initial disease presentation are in the forties. In children, the mean age of onset for AIH type 1 is between 10 and 11 years of age and for AIH type 2 is between 6 and 7 years of age. The universal occurrence of AIH, the very wide age range of primary disease manifestation and the involvement of both sexes means that autoimmune hepatitis needs to be considered in the differential diagnosis of any patient with laboratory evidence of liver disease.

Clinical presentation The clinical manifestations of autoimmune hepatitis are varied [12,13]. About a third of the patients come to clinical attention with an acute icteric hepatitis, occasionally even with fulminant hepatic failure [20–22]. The majority of patients have milder and some even subclinical disease. They may come to clinical attention because of non-specific symptoms such as generalized fatigue. In addition, many patients experience arthralgias without arthritis and this may lead to a systematic work-up. Increasingly AIH is diagnosed in patients who show elevated liver function tests on routine medical tests. At least a third of patients have already cirrhosis at presentation, indicating that the disease has gone unrecognized for a considerable period of time prior to diagnosis. Even in

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Review the group of patients presenting with acute disease, liver biopsy often shows signs of advanced fibrosis or cirrhosis. Acute icteric hepatitis is more common in children and young adults, and it is particularly in this age group that fulminant hepatic failure may develop [13]. Nonetheless, even patients in their seventies can present with fulminant hepatitis and subacute liver failure, and in these rapid diagnosis and treatment is critical. A high index of suspicion is important. A characteristic feature in some patients is an acute relapsing course. Untreated acute autoimmune hepatitis does not inevitably lead to immediate liver failure, but the majority of patients, if not diagnosed or for other reasons not treated, will experience a spontaneous partial recovery, sometimes even a complete normalization of liver function tests. However, histological disease activity usually persists and another acute exacerbation is usually experienced within a few months. Others progress to a chronic hepatitis, mostly with a fluctuating course. Patients with acute autoimmune hepatitis or an acute flare are almost invariably icteric with a pronounced degree of jaundice. Most of these patients also report general symptoms such as malaise, fatigue, loss of appetite and, as mentioned above, arthralgias. For many patients, this latter symptom is a parameter of disease activity, which can be helpful in the clinical management. In patients with biochemical remission, persistence of arthralgia usually suggests persistence of inflammatory activity in the liver, as can be demonstrated by liver biopsy. On clinical examination signs of chronic liver disease may be detectable. Palmar erythema is present not only in association with cirrhosis. In some patients it may disappear with successful immunosuppressive therapy. The liver may be palpable as enlarged, and sometimes swollen and tender. In advanced disease, nodularity may be palpable. As autoimmune hepatitis has a genetic predisposition, and like other autoimmune diseases is associated with a variety of autoimmune conditions [23–32], both family and personal history should be taken carefully. Table 1 lists the conditions most frequently described in association with autoimmune hepatitis. Like in most autoimmune disorders, the manifestation of different autoimmune diseases in the same patient is usually sequential and only rarely simultaneous. A number of patients with AIH presents late with cirrhosis, at times decompensated. Many of them are diagnosed as having ‘‘cryptogenic cirrhosis’’ and in the past AIH was the most common cause of cryptogenic cirrhosis. Earlier diagnosis and treatment of AIH patients on the one hand and an increasing number of patients with non-alcoholic steatohepatitis (NASH) have made the latter diagnosis the most common cause of cryptogenic cirrhosis, but AIH remains second.

Pathogenesis Autoimmune hepatitis carries all features of an autoimmune disease: genetic predisposition, association with other autoimmune diseases, spontaneous disease fluctuations, autoantibodies, and auto-reactive T-cells, inflammatory infiltrate, and a good response to immunosuppression. As in other autoimmune diseases, the etiology is not understood, nor the factors that may trigger a flare, and those that may lead to spontaneous remissions in some patients.

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Table 1. Extrahepatic disorders associated with autoimmune hepatitis. List of autoimmune or immune mediated diseases that have been described in patients with autoimmune hepatitis [22–32]. The strongest association is found with thyroiditis.

Thyroiditis (Hashimoto) Vitiligo Ulcerative colitis Celiac disease Type 1 diabetes mellitus Systemic lupus erythematosus Rheumatoid arthritis Mixed connective tissue disease Hyperthyroidism (Graves´ disease) Panniculitis Sjögren´s syndrome Mononeuritis Urticaria pigmentosa Sweet´s syndrome Glomerulonephritis Polyglandular autoimmune syndrome, type I Idiopathic thrombocytopenic purpura Hemolytic anemia Polymyositis Uveitis

The genetic predisposition is demonstrated best by the HLAassociation of the disease. Different HLA-subtypes contribute different relative risks in different ethnic groups. In Caucasians the extended HLA haplotypes DRB1⁄0301 and DRB1⁄0401 are strongly associated with the disease and found in more than half of the patients, while the haplotype DRB1⁄1501 appears to be protective [33–36]. In Japan the DRB1⁄0405 haplotype is the dominant association, while in South America children with AIH show an association with DRB1⁄1301 and less so with DRB1⁄0301 and adults with DRB1⁄0405 [34,37], like in Japan [34,38]. The strength of the HLA-associations and the frequent association with DRB1⁄ alleles with some common features across the world suggest that peptide binding to the antigen-presenting parts of the HLA-molecules and presentation of specific peptides to HLA-class II restricted CD4+ T-lymphocytes are crucial to the pathogenesis of autoimmune hepatitis [34,39]. Various other genetic associations have been described in AIH, but most of these have only been studied in relatively small groups of patients, and often have not been confirmed by other studies [34]. These associations have all been with genetic polymorphisms of immune response genes that further support the immunopathogenesis of the disease. This is also corroborated by the demonstration of autoreactive T-cells and their dysregulation [40–42]. There is strong experimental evidence that under normal circumstances the liver is an organ of immunological tolerance due to several regulatory mechanisms including tolerogenic antigen presentation and secretion of modulatory cytokines such as interleukin 10 and transforming growth factor b [43,44]. Breaking of

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JOURNAL OF HEPATOLOGY self-tolerance in the liver may therefore be more difficult than in other organs [44]. These mechanisms may account for the relative rarity of autoimmune liver disease and for the observed spontaneous fluctuation of disease activity. On the other hand, once tolerance is broken, the presence of pro-inflammatory cytokines and activated immune cells may contribute to progression and perpetuation of damage. A number of animal models of autoimmune hepatitis have demonstrated that tolerance can be broken in the liver, albeit not as easily as in some other organs [45–49]. These models allow testing pathogenic mechanisms and new therapeutic approaches, though no experimental model mimics precisely human autoimmune hepatitis as yet.

Diagnosis The heterogeneity of the clinical presentation can make it difficult to diagnose autoimmune hepatitis, and even in very experienced hands the diagnosis at times may remain uncertain. Diagnosis rests primarily on a high index of suspicion. Autoimmune hepatitis should be considered in any patient with elevated liver enzymes and in any patient with cirrhosis. In 1993 the International Autoimmune Hepatitis Group devised a scoring system to help the standardization of patient populations in scientific publications [50]. This scoring system, revised in 1999 [51], has also been applied by some to daily clinical practice, for which it had not been primarily designed nor tested, and found to be very cumbersome. In 2008 the International Autoimmune Hepatitis Group suggested a simplified scoring system for clinical practice, which is useful in most cases [52] (Table 2). Diagnosis rests on four features: hypergammaglobulinaemia, autoantibodies, histology and absence of viral hepatitis. Hypergammaglobulinaemia is the cheapest of these screening tests, the most characteristic finding being a selective elevation of IgG with normal levels of IgA and IgM. As the range for normal IgG levels is wide, difficulty arises in those AIH patients who physiolog-

Table 2. Simplified diagnostic criteria (2008) of the international autoimmune hepatitis group [42].

Points Autoantibodies

IgG (or gamma-globulius) Liver histology* Absence of viral hepatitis

ANA or SMA or LKM >1:40

1

ANA or SMA or LKM >1:80 SLA/LP Positive (>20 units)

2

Upper normal limit

1

>1.10 times normal limit

2

Compatible with AIH

1

Typical for AIH

2

Yes No

2 0

Definite autoimmune hepatitis (AIH): P7; probable AIH: P6. ANA, antinuclear antibody; SLA, soluble liver antigen; IgG, immunoglobulin G; AIH, autoimmune hepatitis. ⁄ Typical: (1) Interface hepatitis, lymphocytic/lymphoplasmacytic infiltrates in portal tracts and extending in the lobule; (2) emperipolesis (active penetration by one cell into and through larger cell); (3) hepatic rosette formation. Compatible: Chronic hepatitis with lymphoctic infiltration without features considered typical. Atypical: Showing signs of another diagnosis like NAFLD.

ically have low baseline levels of IgG. These patients usually have significantly increased IgG levels during phases of disease activity, but this increase may remain within the normal range. Probably because of this 5–10% of AIH patients are reported to have normal IgG levels at diagnosis. Most of these patients have low or even very low levels after induction of remission. IgG levels are not only of help in making the diagnosis, but are also very helpful in monitoring disease activity during treatment. Autoantibodies are a hallmark of autoimmune hepatitis and constitute an important part of the diagnostic work-up [53,54]. However, there is no simple autoantibody test that can answer all questions. Anti-nuclear antibodies (ANA) and smooth-muscle antibodies (SMA) are not disease specific [53,54]. Antibodies to liver–kidney microsomes (LKM) are also not disease-specific, and, although present in about a third of the children with AIH, occur in only a small fraction of adult patients [53]. Only SLA/LPautoantibodies are disease-specific, and therefore of high diagnostic value, but can only be detected by commercial assays in upto 30% of AIH patients [55]. For SLA/LP-autoantibodies [56] and LKM-autoantibodies [57] the molecular identity of the antibody targets has been identified and this has allowed the development of highly specific immunoassays. Both ANA and SMA are heterogeneous and are best detected by immunofluorescence [53] – a diagnostic technique coming somewhat out of fashion in large commercial laboratories in the US, because it is time-consuming and requires experienced technicians and laboratory physicians. Nonetheless, the presence of autoantibodies, their titers and their specificities are important clues and sometimes the critical component in making a diagnosis of autoimmune hepatitis. Immunofluorescence testing on murine tissue sections remains the gold standard for the detection of ANA and SMA. ANA fluorescence pattern, which in AIH is usually homogeneous, should be further characterized using Hep2 cells [54]. Similarly, testing for anti-actin may increase sensitivity and specificity of SMA for AIH [58–60]. Histology is considered a necessary prerequisite for making a diagnosis of autoimmune hepatitis [43,52]. There are some histological features that are highly suggestive of the diagnosis, but like hypergammaglobulinaemia and autoantibodies (except for SLA/LP probably), histology is not diagnostic in itself [61]. The revised scoring system distinguishes histology ‘‘compatible with AIH’’, scoring as 1 point, from histology ‘‘typical for AIH’’, scoring as 2 points. Compatible with AIH is almost any hepatitic picture not suggestive of non-alcoholic steatohepatitis (NASH) or druginduced inflammation. Increasingly, it is important to distinguish AIH from NASH, and in a few patients both conditions may coexist [62]. ANA and SMA are found, usually at low titers, in up to a third of patients with NASH [63,64]. Especially in NASH cirrhosis in elderly women, hypergammaglobulinaemia and autoantibodies can lead to diagnostic confusion, making histological examination essential for a correct diagnosis [62]. Characteristic features suggesting typical AIH include interface hepatitis, portal and periportal inflammation, presence of plasma cells, rosetting of hepatocytes, and emperipolesis (Fig. 1). Most patients with autoimmune hepatitis have complications of chronic inflammation, including fibrosis, at presentation, and about a third of them are already cirrhotic. In children, this proportion seems to be even higher [13,65]. Only patients with very acute presentation may lack features of previous chronic hepatitis and fibrosis. Cirrhosis in autoimmune hepatitis is often irregular and macronodular, and may easily be overlooked by

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Review

Fig. 1. Histology of autoimmune hepatitis. Biopsy specimen of a patient with typical features of active autoimmune hepatitis sees as piecemeal necroses, interface hepatitis, rosette formation and plasma cell enrichment (provided by Dr. A. Quaas, Institute of Pathology, University Medical Centre Hamburg-Eppendorf).

percutaneous liver biopsy (Fig. 2). Laparoscopy, a minimally invasive technique with the currently available very small diameter endoscopes, is helpful in making a diagnosis of cirrhosis in autoimmune hepatitis, as cirrhosis may be overlooked in up to 40% of cases without macroscopic assessment of the liver [66–69]. Diagnosis of cirrhosis may influence the choice and dose of the immunosuppressive agents prescribed, has prognostic implications, and forms the basis for regular screening for complications of cirrhosis, such as esophageal varices or hepatocellular carcinoma. Absence of viral hepatitis was generally thought to be a prerequisite for making a diagnosis of autoimmune hepatitis, but in a few patients viral and autoimmune hepatitis may co-exist. This is particularly relevant in countries with a high prevalence of viral hepatitis, where a diagnosis of AIH may be entirely overlooked in viral hepatitis infected patients. Untreated AIH has usually a much more severe course and poorer prognosis than chronic viral hepatitis B or C, and therefore it is important to be able to make a diagnosis of AIH in such patients. However, both chronic hepatitis B and hepatitis C virus infection may induce elevation of IgG and

Fig. 2. Macroscopic aspect of autoimmune cirrhosis. Typical macro modular cirrhosis of a patient with autoimmune hepatitis diagnosed at a relatively advanced stage.

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development of autoantibodies. Criteria for AIH in these patients should therefore be very strict. The revised simplified scoring system allows the diagnosis of AIH in these patients only in the presence of high IgG levels and high titer autoantibodies as well as a typical histology, which should be reviewed by an expert liver histopathologist [52,70]. Long-term follow up of these patients is required to formulate recommendations. Two subgroups of patients may be missed by standard diagnostic criteria and require special attention: 1. Acute and fulminant autoimmune hepatitis; 2. Pediatric autoimmune hepatitis. In acute or fulminant autoimmune hepatitis, hypergammaglobulinaemia, and autoantibodies may not be present at the time of clinical presentation. Most of these patients go on to develop significant titers of autoantibodies and high IgG levels, but diagnosis and institution of immunosuppression need to take place immediately. In these patients liver biopsy, which is essential for the diagnosis of AIH, may be difficult to perform because of severe coagulopathy and, if performed, may present a further challenge: in severe acute AIH there may be centrilobular lesions and necrosis mimicking drug-induced liver injury [71,72]. Severe drug-induced hypersensitivity hepatitis, however, usually responds to high dose steroids in the same fashion as severe acute autoimmune hepatitis, and thus the differential diagnosis may be not so relevant if immunosuppression is started without delay [56,73]. The course of the disease will later allow differentiation between autoimmune and drug-induced disease: patients with drug-induced hepatitis will not relapse after withdrawal of immunosuppressive therapy (in the absence of the offending drug), while autoimmune hepatitis patients will relapse [73]. In addition, most autoimmune hepatitis patients show a fluctuation of IgG levels in parallel to transaminase levels and eventually become autoantibody positive. In pediatric patients it is crucial to use very low cut-off levels for the definition of autoantibodies [13,44]. Titers as low as 1:10 for LKM autoantibody and 1:20 for ANA and SMA are pathological in young children. Cut-off values for SLA/LP have not been evaluated for children. Despite limitations inherent in any diagnostic score, several studies have by now confirmed the value of the score, which appears to serve well in clinical practice [17,70,74–76].

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JOURNAL OF HEPATOLOGY Standard treatment Three randomized trials in the seventies showed unequivocally the survival benefit of corticosteroid treatment in patients with what was then called HBsAg-negative chronic active hepatitis [7–11]. Most patients studied in these trials probably did have autoimmune hepatitis, but, well over a decade prior to the discovery of the hepatitis C virus, it is conceivable that some of them had chronic viral hepatitis C. The exclusion of these patients from the analysis would probably show an even more dramatic therapeutic benefit of steroid treatment. The trials were landmark studies for both clinical hepatology and for the development of randomized controlled trials as evidence basis for novel treatments. In addition, the trials document impressively the dismal prognosis of untreated symptomatic autoimmune hepatitis, the five year survival rate being below 25% in untreated patients versus 80% in those treated with corticosteroids [11]. While the evidence for treating symptomatic and jaundiced patients with AIH is unequivocal, there is ongoing discussion about the need to treat mild and asymptomatic disease. We believe that reports of the risk of progression even in patients with mild disease activity during treatment, and the risk of acute and hyper-acute flares in untreated patients are strong arguments for treatment of almost all patients in an individually tailored fashion. In addition, the demonstration of the presence of the strongly pro-fibrogenic cytokine transforming growth factor b (TGFb) within the liver inflammatory infiltrate also in AIH patients with mild disease, stresses the importance of trying to suppress the tissue inflammatory activity even when laboratory values are normal or near normal [77]. The immunosuppression schedule depends on the severity of the disease, age and co-morbidities of the patient, and, somewhat non-scientifically, on the school of thought of the treating (or recommending) physicians. The recently published AASLD practice guidelines recommend either an initial dose of 30 mg prednisone combined with 1–2 mg of azathioprine per day, or monotherapy with prednisone at a starting dose of 40–60 mg daily in adults [78]. For children, a dose of 1–2 mg/kg prednisone up to a daily dose of 60 mg is recommended in combination with azathioprine (1–2 mg/kg) or 6-mercaptopurine (1.5 mg/kg). However, as azathioprine is hepatotoxic, particularly in jaundiced patients with decompensated disease, it is advisable that these patients are treated with high dose steroids first and azathioprine is added later after partial disease control is achieved and jaundice has subsided. The adult recommendations are very much based on the doses used in the Mayo clinic trial of corticosteroid treatment [9] and can thus be considered evidence based. On the other hand, many experts have been initiating treatment in adults like in children with 1 mg/kg body weight of prednisone or prednisolone and achieved excellent results [13,79,80]. Higher starting doses, we believe, induce remission more quickly and help to spare steroids in the long run. A typical treatment schedule is shown in Table 3. Using this approach we have been able to induce complete remission, defined as normal transaminase levels, in 91.2% of patients within six months, and incomplete remission, defined as transaminase levels below twice the upper limit of normal, in 98.1% of patients [79]. As steroid side-effects tend to be few and only transient, depending on the time period during which a dose of more than 7.5–10 mg per day is used, it seems sensible to reduce steroids below this dose as quickly as possible. Reduction can be achieved much faster when higher doses are given at the beginning.

Table 3. Treatment schedule. Recommended treatment schedule for adult patients (e.g. 70Kg) with newly diagnosed autoimmune hepatitis. Lower initial prednisolone doses can be used in cases of mild to moderate disease, or in early flare-ups after treatment reduction or tapering out of immunosuppressives. Dose reduction schedules need to be adapted to individual response and side-effect patterns.

Week

Prednisolone (mg/d)

1

70 ( = 1 mg/kg body weight)

Azathioprine (mg/d)

2

60

50

3

50

50

4

40

100*

5 6

30 25

100 100

7 8+9

20 15

100 100

10 + 11 from week 12

12.5 10

100 100

When transaminases reach normal levels, reduction of prednisolone to 7.5 mg/d, and after 3 months to 5 mg/d, tapering out at 3 months intervals depending on individual assessment of risk and response. ⁄ Weight adapted dose of 1-1.5 mg/kg body weight.

The debate regarding the correct starting dose of steroids would ideally be solved by a randomized controlled trial, but it is unlikely that it will be possible to perform such a study. Careful case series and analysis of the results in centers using theses different approaches will therefore need to be undertaken to give further guidance. This also applies to the question of the ideal maintenance therapy. It has long been shown that while steroids are the drug of choice for induction of remission, azathioprine is the drug of choice for the maintenance of remission [81]. The optimal dose of azathioprine is also a matter of debate. A careful trial by the King’s College group demonstrated the effectiveness of maintenance with azathioprine alone [81], while a second trial showed that steroid withdrawal is better achieved when azathioprine is given at the dose of 2 mg/kg body weight [82]. However, the tumor rate in this trial was relatively high [83]; because of this, a maintenance dose of 1–1.5 mg/kg of azathioprine in combination with low-dose steroids has been recommended in those patients that fail to reach or maintain complete remission on low-dose azathioprine monotherapy. The most reasonable approach is probably to tailor treatment according to the individual patient depending on whether the risk of steroid side-effects is higher than the risk of long-term higher azathioprine doses, or vice versa. Fig. 3 shows a treatment algorithm. If the diagnosis of AIH is not yet definite, steroids should be given as monotherapy and the response pattern and relapse rate used as diagnostic test (Fig. 4). Budesonide is presently receiving considerable attention as an alternative to prednisone or prednisolone in the treatment of autoimmune hepatitis. First reports were somewhat contradictory, but a large randomized trial, in fact the largest ever to be undertaken in AIH, has given encouraging results [84]. In this European multicenter trial, treatment starting with 40 mg prednisone and weekly dose reduction was compared to 3  3 mg/day budesonide with reduction only upon response. Remission at

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Review Definite AIH

Induction Therapya)

Response

Complete Remissionb)

Maintenance therapy d) 3-12 months

Insufficient Response

Incomplete Remissionc)

Increase steroids (i.v.?)

Increase Immunosuppression

Insufficient Response

Complete Remission

Incomplete Remission

Alternative Immunosuppressants

Trial of steroid withdrawal Liver Biopsy e) Maintained Remission >3 years

Trial of complete treatment withdrawal Fig. 3. Management algorithm for patients with definite autoimmune hepatitis. (a) Induction therapy with initially prednisolone, usually 1 mg/kg/d and azathioprine 1 mg/kg/d according to Table 1. (b) Complete remission is defined as both AST and ALT as well as IgG below the upper limit of normal. (c) Incomplete remission is defined as improvement of AST/ALT within 2 the upper limit of normal, or normalization of AST and ALT without complete normalization of IgG. (d) Maintenance therapy usually with 1–1.5 mg/kg azathioprine and 5–7.5 mg prednisolone therapy. (e) Liver biopsy in patients with incomplete remission should exclude alternate diagnoses (such as azathioprine hepatotoxicity), and should assess the inflammatory activity (hepatitis activity index HAI): HAI scores of more than 5 suggest progressive disease and should lead to increased or alternative immunosuppression, while at lower scores reduction of immunosuppressants can be tried according to individual risk variables. (f) Most experts recommend a liver biopsy prior to a trial of treatment withdrawal. Treatment withdrawal should not be tried, if there remains significant histological disease activity. In patients with intermittent relapses, treatment should also be maintained long-term.

6 months was achieved in 60% of the budesonide group, but in only 38.8% of the prednisone group [84]. Remission induction thus was clearly below that reported in series starting with higher doses of prednisolone. Nonetheless, this trial seems to suggest, that budesonide can be an alternative in patients in whom steroid side-effects are expected to be a problem. Importantly, patients with cirrhosis were excluded from this study, because budesonide is contraindicated in cirrhosis as the first pass effect in the liver is bypassed in many cirrhotic patients, and complications have been described [85]. As cirrhosis is present in about a third of patients at diagnosis, budesonide is not an option for these patients. The role that budesonide may play in other patients will need to be defined in the future. In addition, the trial suggests that standard recommendations of prednisone treatment are suboptimal, as the dose is too low for many patients.

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Management of autoimmune hepatitis requires careful follow-up and strict adherence to treatment by both patients and treating physicians [86]. Therapy should aim at the complete normalization of transaminase levels. Importantly, IgG levels correlate quite closely with histological disease activity, and normalization of IgG should similarly be aimed for [87]. When both transaminase and IgG levels are normal, the histological disease activity is at most mild to minimal, while if either IgG or transaminase levels are abnormal, about 50% of patients still have significant inflammatory activity on biopsy, defined as a histological activity index (HAI) score of 6 or more [87]. Follow-up biopsies may be particularly helpful in these patients to guide immunosuppressive therapy (Fig. 3). Alternatively immunosuppression can be intensified in these patients, if well tolerated, and the effect on the biochemical disease parameters measured.

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JOURNAL OF HEPATOLOGY Propable or possible AIH

1 mg/kg prednisolone

Response (= AIH likely)

Non-response

Taper steroids

Consider alternative diagnoses

Relapse

Remission

Definite AIH

Withdraw steroids and observe closely >1year

No relapse

AIH unlikely

Fig. 4. Management algorithm for patients with suspected autoimmune hepatitis. A good response to treatment supports the diagnoses, relapse upon dose reduction is further strong evidence.

Follow-up biopsies are also generally recommended before considering cessation of therapy [88]. Cessation of therapy will be considered in all patients, and is a question patients will repeatedly ask. However, many, if not most, patients require life-long therapy. This certainly applies to all those who continue to have inflammatory activity despite adequately dosed immunosuppression. During the reduction of immunosuppression, especially following steroid withdrawal, about half of the patients experience a flare, demonstrating the necessity of longer term therapy [79]. In patients in stable remission on azathioprine monotherapy, a trial of treatment withdrawal can be undertaken. The chance of a successful drug withdrawal depends on the length of treatment and stable remission. A minimum of three years of treatment appears to be best [88]. Some authors recommend biopsy prior to withdrawal, and do not attempt withdrawal in patients with continued histological activity. This approach, however, may not suit all patients. For some it may be justified to carefully withdraw therapy in a stepwise fashion with close

(monthly) laboratory follow-up. If reactivation of disease is recognized early and treatment reinstituted quickly, than lower doses of steroids (usually 0.5 mg/kg) will suffice, and remission is usually reached rapidly. Even patients in stable remission off therapy should be followed up regularly, because reemergence of the disease can occur any time, even decades after stable remission. Prognosis of treated autoimmune hepatitis is good [79]. Some centers report normal life expectancy rates, but there may be a patient selection bias. In particular some patients with early severe disease progress rapidly despite immunosuppression and require liver transplantation. Moreover, patients presenting with already advanced cirrhosis or liver failure may die in the early phase of treatment because of infectious complications related to immunosuppression. The experience of the attending physician is also likely to influence the prognosis, but there are no published data on this effect. Finally, patient’s adherence to treatment is of paramount importance.

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Review Pregnancy Autoimmune hepatitis affects mainly young females, raising the question of pregnancy in this disease. Several centers have collected their data and tried to come to some recommendations on the basis of these observations [89–91]. Even though these types of studies inevitably leave a considerable amount of uncertainty due to the limited number of patients and their observational character, the message is encouragingly uniform: pregnancy in AIH is generally safe for both mother and child. There seems to be a somewhat higher rate of (mostly early) miscarriage, but this seems to be unrelated to the treatment being given [89–91]. Azathioprine, even though being a class D drug of uncertain safely in pregnancy, was not related to miscarriage or other pregnancy complications. AIH activity is often observed to be milder during pregnancy, as has also been described for other autoimmune diseases, and this may allow tapering of immunosuppression especially during the early stages. However, occasional flares up to fulminant liver failure can occur during pregnancy, therefore immunosuppression should be upheld at a reasonable level that has been individually assessed for each patient. In addition, post-partum flares of the disease are frequent, and we recommend increasing the steroid dose shortly before the expected date of delivery, and to monitor liver enzymes and IgG levels closely in the weeks following delivery.

Difficult to treat patients Most, but not all patients respond very well to treatment. Nonresponse, intolerance of the drug or drug side-effects may lead to management problems in AIH. Furthermore, patients with AIH and features of sclerosing cholangitis or primary biliary cirrhosis (overlap syndromes) may present a therapeutic challenge. Finally, co-morbidities may limit therapeutic options and thus influence management of autoimmune hepatitis. Non-response Response to immunosuppression in AIH is so universal that it is considered to be a diagnostic criterion. Thus, non-response should question the diagnosis, and perhaps adherence to treatment (Fig. 4). Nonetheless, a few patients show an insufficient response to standard immunosuppression, and some show reactivation during reduction of steroid doses at levels higher than can be tolerated. Therapeutic management of these cases can be challenging. Due to the relative rarity of this situation, only a few case series have been published that can guide treatment. Initially, intravenous prednisolone at doses of 100 mg daily or more may be required in a few aggressive cases with severe jaundice, as these may also suffer from malabsorption. In patients intolerant to azathioprine, mycophenolate mofetil seems to be a relatively good alternative [92–94]. It appears to be of very limited efficacy in patients with an insufficient response to azathioprine [95], but experience in children is more favorable than in adults [96]. In these patients stronger immunosuppressive agents appear to be required, and good results have been reported with cyclophosphamide [97], methotrexate [98], cyclosporine [99], tacrolimus [94,100] and infliximab [101]. No comparative data are available. The decision should thus be based on local and personal expertise.

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It appears that the calcineurin inhibitors cyclosporine and tacrolimus are efficient agents, but like in other autoimmune diseases they are not immunomodulatory, and therefore tend to require permanent treatment, while immunomodulatory agents such as cyclophosphamide or infliximab may allow reduction of immunosuppression over time. Specific studies on second line treatment for difficult to treat patients are needed. Non-compliance Compliance is rarely a problem in acute disease, but can be a problem during follow-up. A particularly difficult to manage group are pediatric patients entering puberty [13]. Non adherence to treatment is particularly frequent in adolescents, who do not accept treatment side effects and deny their disease in an attempt to be ‘normal’, with consequent high relapse rate, at times leading to liver failure [86]. Like in other chronic diseases, during puberty management requires careful motivation of the patients and their parents, which is better achieved in specialized transition services with a multidisciplinary approach, including pediatric and adult hepatologists, psychologists and nurse specialists. Drug intolerance Intolerance to azathioprine occurs in 3–5% of patients and is of an idiosyncratic nature [79]. Intolerance manifests itself within a few weeks, and mostly during the very first days of treatment. It is important to recognize intolerance and stop the drug immediately, which usually results in the resolution of symptoms within a couple of days. If in doubt, re-exposure should be attempted with a low dose, which in case of true intolerance will lead to rapid reemergence of symptoms. In patients intolerant to azathioprine, mycophenolate mofetil appears to be a good alternative with a long-term response rate around 70% and should be the first choice drug in patients intolerant to azathioprine. Other alternatives are steroid monotherapy in patients with mild disease and little steroid risk factors, or any of the immunosuppressives used also in non-responders, i.e. methotrexate, cyclophosphamide, calcineurin inhibitors or infliximab. Overlap syndromes Patients with clinical, laboratory, and histological features of both autoimmune hepatitis and one of the cholestatic liver diseases primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC) have often been labeled as suffering from overlap syndromes [102]. This term is probably misleading as very rarely there is a true overlap of the two conditions, but most patients suffer from active or aggressive forms of PBC [103] or PSC [104]. In children particularly, however, this secondary aggressive hepatitic picture can be so dominant that patients mostly manifest initially as typical autoimmune hepatitis [105]. This has lead to the term autoimmune sclerosing cholangitis for these children [105]. The parenchymal liver disease in autoimmune sclerosing cholangitis responds satisfactorily to the same immunosuppression schedule used for AIH, with the addition of medium dose ursodeoxycholic acid (15 mg/kg/day), though in some 50% of patients the bile duct disease progresses [105]. At the other end of the spectrum, about 10–20% of adult patients with

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JOURNAL OF HEPATOLOGY PBC have an insufficient response to treatment with ursodeoxycholic acid and have been shown to benefit from usually low dose prednisolone therapy [106]. It remains controversial to what extent these patients should be considered as suffering from autoimmune hepatitis [102]. Nonetheless, since the very poor prognosis of untreated autoimmune hepatitis and the excellent response to immunosuppression seem to apply similarly to these patients with secondary autoimmune hepatitis, immunosuppressive treatment should be guided by the same principles as in straightforward autoimmune hepatitis [103,106]. In hepatitic forms of PBC (in the past PBC/AIH overlap) it is usually sufficient to treat with doses of steroids lower than in classical autoimmune hepatitis, and many patients can be kept very successfully on low dose azathioprine in the long term, not requiring corticosteroids. In hepatitic forms of PSC (autoimmune sclerosing cholangitis and/ or AIH/PSC overlap) immunosuppression is often required in the same fashion as in AIH, but response tends to be incomplete, and the disease progresses, albeit more slowly, despite immunosuppressive therapy, resulting in the eventual need for liver transplantation in the majority of affected patients [107].

Hepatocellular carcinoma It was long thought that in autoimmune liver diseases the risk of hepatocellular carcinoma (HCC) is negligible. However, recent reports of HCC in both PBC and AIH have highlighted that this presumption can no longer be upheld [108–110]. The relative rarity of AIH makes it impossible to evaluate reliably the incidence of HCC in AIH cirrhosis, but as several cases of HCC in AIH cirrhosis have been reported from a variety of centers, it appears reasonable to include AIH cirrhosis among the conditions justifying regular ultrasound screening for the development of neoplastic foci. Ultrasound evaluation can be difficult as AIH is associated with macronodular cirrhosis, thus making it hard to distinguish regenerative nodules from neoplastic nodules. Patterns on contrast ultrasound and other imaging techniques can help, but occasionally biopsy may be required. In view of the need of regular ultrasound examinations of cirrhotic patients with AIH, it is important to make a diagnosis of cirrhosis in a timely fashion.

Role of liver transplantation Liver transplantation is only rarely required for patients with autoimmune hepatitis, but is more common in children, who present more often with fulminant hepatitis, than in adults. Main reasons for transplantation are fulminant disease not responding to steroids quickly enough, progression due to (intermittent) non-compliance, and long-term progression despite adequate treatment in initially already advanced cirrhosis. In fulminant disease steroids need to be given as early as possible, usually before the diagnosis is finally confirmed, in order to give the patient a chance of recovery. We would recommend 100 mg i.v. daily for these patients. Unless there is a clear-cut response within the first 14 days, it is probably better to proceed with transplantation in eligible patients than to hope longer for a good response [111]. Prolonged high-dose immunosuppression in a patient with liver failure leads to a very high risk of infectious complications, which may endanger the results of emergency

transplantation. Antibiotic prophylaxis during high-dose immunosuppression in these patients is recommended. In children presenting with acute liver failure (INR >2) and encephalopathy grade II–IV, transplantation is usually the only therapeutic option. For those children with acute liver failure without encephalopathy, prednisolone at the dose of 2 mg/kg/ day, rapidly decreased according to biochemical response over 6–8 weeks to a dose of 5–10 mg daily, is usually effective in achieving remission. In patients deteriorating because of non-adherence, the decision to proceed to transplantation can be most challenging, as strict adherence to treatment is essential for the success of liver transplantation. As this question arises mostly in adolescents and young adults, most centers would give the patient one chance with a new liver, but close follow up with strong psychological input is essential post surgery. Patients with advanced cirrhosis at initial presentation may progress to end stage liver disease despite adequate immunosuppression and adherence to treatment. In these, transplantation is a good option, with altogether good results. Manipulation of immunosuppression to achieve both rejection prevention and prevention of AIH recurrence needs to be considered. The risk of recurrence of AIH seems to be particularly high in those patients transplanted when the disease is active, and therefore post-transplant treatment should aim both at suppression of rejection and suppression of AIH [112]. In these patients low dose steroids (5 mg daily) should be continued indefinitely and azathioprine, a drug out of fashion in the liver transplant community, should be combined with standard calcineurin inhibitors. MMF can be used as an alternative. Recurrent AIH, reported in some 20% of cases [113], may occur even years after grafting and is diagnosed on the basis of biochemical abnormalities, presence of autoantibodies, interface hepatitis on liver histology and/or steroid dependence. Additionally, a form of graft dysfunction called de novo AIH, associated with positive autoantibodies, high IgG, histological features of interface hepatitis has been described in 6–10% of patients transplanted for non autoimmune disorders [114]. This condition does not respond satisfactorily to anti-rejection regimens, but only to the standard treatment for AIH [114], or, in resistant cases, to rapamycin [115]. The European transplant registry shows that the results in AIH overall are fairly good, but not as good as they are in PBC, infectious complications being a frequent reason for an untoward outcome [116].

Future outlook After many decades of research into autoimmune hepatitis, like in other autoimmune diseases, we still do not know what causes the disease process. Identifying cause and trigger of the inflammatory process would not only greatly advance our understanding, but help in the design of more specific and more effective immune interventions. Animal models provide clues, and the complexity of immune regulation in the liver is beginning to become unraveled [43]. At the same time, advances in the immunotherapy of other more common and more severe autoimmune diseases, such as multiple sclerosis or rheumatoid arthritis, need to be transferred to autoimmune hepatitis. Specialized centers across the

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Review world should collaborate in clinical trials, particularly in regard to difficult-to-treat patients. At the same time, we need to increase the awareness that autoimmune hepatitis should be considered in the differential diagnosis of any elevation of liver enzymes, and that it is important to adapt immunosuppressive therapy to the individual needs of our patients. The great advances of the past should benefit the many patients as yet undiagnosed or undertreated. In addition to the scientific challenge of understanding the cause of this enigmatic disease, the biggest challenge is educational: to recognize and diagnose AIH, and treat it skillfully.

Key Points 1 Autoimmune Hepatitis (AIH) can affect patients of all age groups The peak age at first manifestation is between 40 and 50, but manifestations in young childhood are also common AIH is more common in women (female : male ratio 3 : 1). Children and younger adults often have an acute disease onset Subclinical and asymptomatic disease is common, AIH therefore needs to be considered in the differential diagnosis of all patients with elevated liver enzymes

Key Points 2 Diagnosis is based on four major criteria: elevated IgG levels (or total gamma globulins) characteristic autoantibodies histological features of hepatitis absence of viral hepatitis Response to immunosuppression is characteristic and supports the diagnosis

Key Points 3 Corticosteroids are the drug of choice for remission induction in AIH Higher starting doses allow more rapid steroid tapering and result in faster remission Remission is defined by normal transaminase and IgG levels, or by histology showing no more than minimal inflammatory activity; this should always be the therapeutic aim Azathioprine is the drug of choice for maintenance of remission. In patients intolerant to azathioprine, other imunosuppressants, preferably mycophenolate mofetil, should be tried Failure to reach stable remission should question the diagnosis After reaching remission, steroids might be cautiously tapered out Maintenance immunosuppression (usually azathioprine) should be given for a minimum of three years

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