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Autoimmune hepatitis

Open AccessPublished:December 15, 2010DOI:https://doi.org/10.1016/j.jhep.2010.12.012
      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.

      Keywords

      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 [

      Waldenstrom J. Leber, Blutproteine und Nahrungseiweiss. Dtsch Gesellsch Verdau Stoffwechselkr 1950;15:113.

      ,
      • Kunkel H.G.
      • Ahrens E.H.
      • Eisenmenger W.J.
      • et al.
      Extreme hypergammaglobulinemia in young women with liver disease of unknown etiology.
      ,
      • Bearn A.G.
      • Kunkel H.G.
      • Slater R.J.
      The problem of chronic liver disease in young women.
      ]. The serological demonstration of anti-nuclear antibodies (ANA) and antibodies to double-stranded DNA (dsDNA) lead to the term “lupoid hepatitis” [
      • Cowling D.C.
      • Mackay I.R.
      • Taft L.I.
      Lupoid hepatitis.
      ,
      • Joske R.A.
      • King W.E.
      The L.E.-cell phenomenon in active chronic viral hepatitis.
      ]. 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 [
      • Mackay I.R.
      • Wood I.J.
      The course and treatment of lupoid hepatitis.
      ]. Three landmark clinical controlled trials in the 70s established the life-saving value of corticosteroids in the treatment of patients with “HBsAg-negative hepatitis” [

      Copenhagen Study Group for Liver Diseases: effect of prednisone on the survival of patients with cirrhosis of the liver. Lancet 1969;1:119–121.

      ,
      • Cook G.C.
      • Mulligan R.
      • Sherlock S.
      Controlled prospective trial of corticosteroid therapy in active chronic hepatitis.
      ,
      • Soloway R.D.
      • Summerskill W.H.
      • Baggenstoss A.H.
      • Geall M.G.
      • Gitnićk G.L.
      • Elveback I.R.
      • et al.
      Clinical, biochemical, and histological remission of severe chronic active liver disease: a controlled study of treatments and early prognosis.
      ,
      • Murray-Lyon I.M.
      • Stern R.B.
      • Williams R.
      Controlled trial of prednisone and azathioprine in active chronic hepatitis.
      ,
      • Kirk A.P.
      • Jain S.
      • Pocock S.
      • Thomas H.C.
      • Sherlock S.
      Late results of the Royal Free Hospital prospective controlled trial of prednisolone therapy in hepatitis B surface antigen negative chronic active hepatitis.
      ]. 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.

      Epidemiology

      Autoimmune hepatitis occurs in all races and in all geographical areas [
      • Krawitt E.L.
      Autoimmune hepatitis.
      ,
      • Mieli-Vergani G.
      • Vergani D.
      Autoimmune paediatric liver disease.
      ]. 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 [
      • Boberg K.M.
      • Aadland E.
      • Jahnsen J.
      • Raknerud N.
      • Stiris M.
      • Bell H.
      Incidence and prevalence of primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis in a Norwegian population.
      ,
      • Toda G.
      • Zeniya M.
      • Watanabe F.
      • Imawari M.
      • Kiyosawa K.
      • Nishioka M.
      • et al.
      Present status of autoimmune hepatitis in Japan–correlating the characteristics with international criteria in an area with a high rate of HCV infection. Japanese National Study Group of Autoimmune Hepatitis.
      ]. 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 [
      • Toda G.
      • Zeniya M.
      • Watanabe F.
      • Imawari M.
      • Kiyosawa K.
      • Nishioka M.
      • et al.
      Present status of autoimmune hepatitis in Japan–correlating the characteristics with international criteria in an area with a high rate of HCV infection. Japanese National Study Group of Autoimmune Hepatitis.
      ]. 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 [
      • Lam K.C.
      • Lai C.L.
      • Wu P.C.
      • Todd D.
      Etiological spectrum of liver cirrhosis in the Chinese.
      ,
      • Qiu D.
      • Wang Q.
      • Wang H.
      • Xie Q.
      • Zang G.
      • Jiang H.
      • et al.
      Validation of the simplified criteria for diagnosis of autoimmune hepatitis in Chinese patients.
      ].
      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 [
      • Mieli-Vergani G.
      • Vergani D.
      Autoimmune paediatric liver disease.
      ,
      • Schramm C.
      • Kanzler S.
      • Galle P.R.
      Meyer zum Büschenfelde KH, Lohse AW.
      ,
      • Al-Chalabi T.
      • Boccato S.
      • Portmann B.C.
      • McFarlane I.G.
      • Heneghan M.A.
      Autoimmune hepatitis (AIH) in the elderly: a systematic retrospective analysis of a large group of consecutive patients with definite AIH followed at a tertiary referral centre.
      ]. 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 [
      • Krawitt E.L.
      Autoimmune hepatitis.
      ,
      • Mieli-Vergani G.
      • Vergani D.
      Autoimmune paediatric liver disease.
      ]. About a third of the patients come to clinical attention with an acute icteric hepatitis, occasionally even with fulminant hepatic failure [
      • Crapper R.M.
      • Bhathal P.S.
      • Mackay I.R.
      • Frazer I.H.
      ’Acute’ autoimmune hepatitis.
      ,
      • Amontree J.S.
      • Stuart T.D.
      • Bredfeldt J.E.
      Autoimmune chronic active hepatitis masquerading as acute hepatitis.
      ,
      • Czaja A.J.
      • Rakela J.
      • Ludwig J.
      Features reflective of early prognosis in corticosteroid-treated severe autoimmune chronic active hepatitis.
      ]. 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 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 [
      • Mieli-Vergani G.
      • Vergani D.
      Autoimmune paediatric liver disease.
      ]. 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 [
      • Czaja A.J.
      • Carpenter H.A.
      • Santrach P.J.
      • Moore S.B.
      Genetic predispositions for the immunological features of chronic active hepatitis.
      ,
      • Bittencourt P.L.
      • Farias A.Q.
      • Porta G.
      • Cançado E.L.
      • Miura I.
      • Pugliese R.
      • et al.
      Frequency of concurrent autoimmune disorders in patients with autoimmune hepatitis: effect of age, gender, and genetic background.
      ,
      • Caprai S.
      • Vajro P.
      • Ventura A.
      • Sciveres M.
      Maggiore G; SIGENP Study Group for Autoimmune Liver Disorders in Celiac Disease.
      ,
      • Perdigoto R.
      • Carpenter H.A.
      • Czaja A.J.
      Frequency and significance of chronic ulcerative colitis in severe corticosteroid-treated autoimmune hepatitis.
      ,
      • Bloom J.N.
      • Rabinowicz I.M.
      • Shulman S.T.
      Uveitis complicating autoimmune chronic active hepatitis.
      ,
      • Tomsic M.
      • Ferlan-Marolt V.
      • Kveder T.
      • Hojker S.
      • Rozman B.
      Mixed connective tissue disease associated with autoimmune hepatitis and thyroiditis.
      ,
      • Wada T.
      • Motoo Y.
      • Ohmizo R.
      • Terada T.
      • Nakanuma Y.
      Association of mixed connective tissue disease, Sjögren’s syndrome and autoimmune hepatitis: report of a case.
      ,
      • Sacher M.
      • Blümel P.
      • Thaler H.
      • Manns M.
      Chronic active hepatitis associated with vitiligo, nail dystrophy, alopecia and a new variant of LKM antibodies.
      ,
      • Luth S.
      • Birklein F.
      • Schramm C.
      • Herkel J.
      • Hennes E.
      • Muller-Forell W.
      • et al.
      Multiplex neuritis in a patient with autoimmune hepatitis: a case report.
      ,
      • Teufel A.
      • Weinmann A.
      • Kahaly G.J.
      • Centner C.
      • Piendl A.
      • Wörns M.
      • et al.
      Concurrent autoimmune diseases in patients with autoimmune hepatitis.
      ], 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.
      Table 1Extrahepatic disorders associated with autoimmune hepatitis. List of autoimmune or immune mediated diseases that have been described in patients with autoimmune hepatitis
      • Czaja A.J.
      • Rakela J.
      • Ludwig J.
      Features reflective of early prognosis in corticosteroid-treated severe autoimmune chronic active hepatitis.
      ,
      • Czaja A.J.
      • Carpenter H.A.
      • Santrach P.J.
      • Moore S.B.
      Genetic predispositions for the immunological features of chronic active hepatitis.
      ,
      • Bittencourt P.L.
      • Farias A.Q.
      • Porta G.
      • Cançado E.L.
      • Miura I.
      • Pugliese R.
      • et al.
      Frequency of concurrent autoimmune disorders in patients with autoimmune hepatitis: effect of age, gender, and genetic background.
      ,
      • Caprai S.
      • Vajro P.
      • Ventura A.
      • Sciveres M.
      Maggiore G; SIGENP Study Group for Autoimmune Liver Disorders in Celiac Disease.
      ,
      • Perdigoto R.
      • Carpenter H.A.
      • Czaja A.J.
      Frequency and significance of chronic ulcerative colitis in severe corticosteroid-treated autoimmune hepatitis.
      ,
      • Bloom J.N.
      • Rabinowicz I.M.
      • Shulman S.T.
      Uveitis complicating autoimmune chronic active hepatitis.
      ,
      • Tomsic M.
      • Ferlan-Marolt V.
      • Kveder T.
      • Hojker S.
      • Rozman B.
      Mixed connective tissue disease associated with autoimmune hepatitis and thyroiditis.
      ,
      • Wada T.
      • Motoo Y.
      • Ohmizo R.
      • Terada T.
      • Nakanuma Y.
      Association of mixed connective tissue disease, Sjögren’s syndrome and autoimmune hepatitis: report of a case.
      ,
      • Sacher M.
      • Blümel P.
      • Thaler H.
      • Manns M.
      Chronic active hepatitis associated with vitiligo, nail dystrophy, alopecia and a new variant of LKM antibodies.
      ,
      • Luth S.
      • Birklein F.
      • Schramm C.
      • Herkel J.
      • Hennes E.
      • Muller-Forell W.
      • et al.
      Multiplex neuritis in a patient with autoimmune hepatitis: a case report.
      ,
      • Teufel A.
      • Weinmann A.
      • Kahaly G.J.
      • Centner C.
      • Piendl A.
      • Wörns M.
      • et al.
      Concurrent autoimmune diseases in patients with autoimmune hepatitis.
      . The strongest association is found with thyroiditis.
      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.
      The genetic predisposition is demonstrated best by the HLA-association 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 [
      • Donaldson P.T.
      • Doherty D.G.
      • Hayllar K.M.
      • McFarlane I.G.
      • Johnson P.J.
      • Williams R.
      Susceptibility to autoimmune chronic active hepatitis: human leukocyte antigens DR4 and A1–B8-DR3 are independent risk factors.
      ,

      Donaldson PT. Role of genetics in immunopathogenesis. In: Dienes H-P, Leuschner U, Lohse AW, Manns MP, editors. Autoimmune liver disease. Springer and Falk Foundation e.V.; 2005. S. 127 Kap. 13.

      ,
      • Teufel A.
      • Wörns M.
      • Weinmann A.
      • Centner C.
      • Piendl A.
      • Lohse A.W.
      • et al.
      Genetic association of autoimmune hepatitis and human leucocyte antigen in German patients.
      ,
      • Czaja A.J.
      • Strettell M.D.
      • Thomson L.J.
      • Santrach P.J.
      • Moore S.B.
      • Donaldson P.T.
      • et al.
      Associations between alleles of the major histocompatibility complex and type 1 autoimmune hepatitis.
      ]. 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 [

      Donaldson PT. Role of genetics in immunopathogenesis. In: Dienes H-P, Leuschner U, Lohse AW, Manns MP, editors. Autoimmune liver disease. Springer and Falk Foundation e.V.; 2005. S. 127 Kap. 13.

      ,
      • Czaja A.J.
      • Souto E.O.
      • Bittencourt P.L.
      • Cancado E.L.
      • Porta G.
      • Goldberg A.C.
      • et al.
      Clinical distinctions and pathogenic implications of type 1 autoimmune hepatitis in Brazil and the United States.
      ], like in Japan [

      Donaldson PT. Role of genetics in immunopathogenesis. In: Dienes H-P, Leuschner U, Lohse AW, Manns MP, editors. Autoimmune liver disease. Springer and Falk Foundation e.V.; 2005. S. 127 Kap. 13.

      ,
      • Yoshizawa K.
      • Ota M.
      • Katsuyama Y.
      • Ichijo T.
      • Matsumoto A.
      • Tanaka E.
      • et al.
      Genetic analysis of the HLA region of Japanese patients with type 1 autoimmune hepatitis.
      ]. 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 [

      Donaldson PT. Role of genetics in immunopathogenesis. In: Dienes H-P, Leuschner U, Lohse AW, Manns MP, editors. Autoimmune liver disease. Springer and Falk Foundation e.V.; 2005. S. 127 Kap. 13.

      ,
      • Manabe K.
      • Hibberd M.L.
      • Donaldson P.T.
      • Underhill J.A.
      • Doherty D.G.
      • Demaine A.G.
      • et al.
      T-cell receptor constant beta germline gene polymorphisms and susceptibility to autoimmune hepatitis.
      ].
      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 [

      Donaldson PT. Role of genetics in immunopathogenesis. In: Dienes H-P, Leuschner U, Lohse AW, Manns MP, editors. Autoimmune liver disease. Springer and Falk Foundation e.V.; 2005. S. 127 Kap. 13.

      ]. 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 [
      • Löhr H.F.
      • Schlaak J.F.
      • Lohse A.W.
      • Böcher W.O.
      • Arenz M.
      • Gerken G.
      • et al.
      Autoreactive CD4+ LKM-specific and anticlonotypic T-cell responses in LKM-1 antibody-positive autoimmune hepatitis.
      ,
      • Longhi M.S.
      • Hussain M.J.
      • Mitry R.R.
      • Arora S.K.
      • Mieli-Vergani G.
      • Vergani D.
      • et al.
      Functional study of CD4+CD25+ regulatory T cells in health and autoimmune hepatitis.
      ,
      • Mix H.
      • Weiler-Normann C.
      • Thimme R.
      • Ahlenstiel G.
      • Shin E.C.
      • Herkel J.
      • et al.
      Identification of CD4 T-cell epitopes in soluble liver antigen/liver pancreas autoantigen in autoimmune hepatitis.
      ].
      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 β [
      • Lohse A.W.
      • Weiler-Normann C.
      • Tiegs G.
      Immune-mediated liver injury.
      ,
      • Meyer zum Büschenfelde K.H.
      • Lohse A.W.
      • Manns M.
      • Poralla T.
      Autoimmunity and liver disease.
      ]. Breaking of self-tolerance in the liver may therefore be more difficult than in other organs [
      • Meyer zum Büschenfelde K.H.
      • Lohse A.W.
      • Manns M.
      • Poralla T.
      Autoimmunity and liver disease.
      ]. 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 [
      • Lohse A.W.
      • Manns M.
      • Dienes H.P.
      • Meyer zum Büschenfelde K.H.
      • Cohen I.R.
      Experimental autoimmune hepatitis: disease induction, time course and T-cell reactivity.
      ,
      • Yamauchi K.
      • Yamaguchi N.
      • Furukawa T.
      • Takatsu K.
      • Nakanishi T.
      • Ishida K.
      • et al.
      A murine model of acute liver injury induced by human monoclonal autoantibody.
      ,
      • Holdener M.
      • Hintermann E.
      • Bayer M.
      • Rhode A.
      • Rodrigo E.
      • Hintereder G.
      • et al.
      Breaking tolerance to the natural human liver autoantigen cytochrome P450 2D6 by virus infection.
      ,
      • Zierden M.
      • Odenthal E.K.
      • Dienes H.P.
      Effects and regulation of autoreactive CD8(+) T cells in a transgenic mouse model of autoimmune hepatitis.
      ,
      • Christen U.
      • Hintermann E.
      • Jaeckel E.
      New animal models for autoimmune hepatitis.
      ]. 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 [
      • Johnson P.J.
      • McFarlane I.G.
      Meeting report: International Autoimmune Hepatitis Group.
      ]. This scoring system, revised in 1999 [
      • Alvarez F.
      • Berg P.A.
      • Bianchi F.B.
      • Bianchi L.
      • Burroughs A.K.
      • Cancado E.L.
      • et al.
      International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis.
      ], 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 [
      • Hennes E.M.
      • Zeniya M.
      • Czaja A.J.
      • Parés A.
      • Dalekos G.N.
      • Krawitt E.L.
      • et al.
      Eisenmann de Torres B, Galle PR, McFarlane I, Dienes HP, Lohse AW.
      ] (Table 2).
      Table 2Simplified diagnostic criteria (2008) of the international autoimmune hepatitis group
      • Mix H.
      • Weiler-Normann C.
      • Thimme R.
      • Ahlenstiel G.
      • Shin E.C.
      • Herkel J.
      • et al.
      Identification of CD4 T-cell epitopes in soluble liver antigen/liver pancreas autoantigen in autoimmune hepatitis.
      .
      Definite autoimmune hepatitis (AIH): ⩾7; probable AIH: ⩾6. 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.
      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 physiologically 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 [
      • Vergani D.
      • Alvarez F.
      • Bianchi F.B.
      • Cançado E.L.
      • Mackay I.R.
      • Manns M.P.
      • et al.
      Penner E; International Autoimmune Hepatitis Group.
      ,
      • Bogdanos D.P.
      • Mieli-Vergani G.
      • Vergani D.
      Autoantibodies and their antigens in autoimmune hepatitis.
      ]. 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 [
      • Vergani D.
      • Alvarez F.
      • Bianchi F.B.
      • Cançado E.L.
      • Mackay I.R.
      • Manns M.P.
      • et al.
      Penner E; International Autoimmune Hepatitis Group.
      ,
      • Bogdanos D.P.
      • Mieli-Vergani G.
      • Vergani D.
      Autoantibodies and their antigens in autoimmune hepatitis.
      ]. 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 [
      • Vergani D.
      • Alvarez F.
      • Bianchi F.B.
      • Cançado E.L.
      • Mackay I.R.
      • Manns M.P.
      • et al.
      Penner E; International Autoimmune Hepatitis Group.
      ]. Only SLA/LP-autoantibodies are disease-specific, and therefore of high diagnostic value, but can only be detected by commercial assays in upto 30% of AIH patients [
      • Baeres M.
      • Herkel J.
      • Czaja A.J.
      • Wies I.
      • Kanzler S.
      • Cancado E.L.
      • et al.
      Establishment of standardised SLA/LP immunoassays: specificity for autoimmune hepatitis, worldwide occurrence, and clinical characteristics.
      ]. For SLA/LP-autoantibodies [
      • Wies I.
      • Brunner S.
      • Henninger J.
      • Herkel J.
      • Kanzler S.
      • Meyer zum Büschenfelde K.H.
      • et al.
      Identification of target antigen for SLA/LP autoantibodies in autoimmune hepatitis.
      ] and LKM-autoantibodies [
      • Manns M.P.
      • Johnson E.F.
      • Griffin K.J.
      • Tan E.M.
      • Sullivan K.F.
      Major antigen of liver kidney microsomal autoantibodies in idiopathic autoimmune hepatitis is cytochrome P450db1.
      ] 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 [
      • Vergani D.
      • Alvarez F.
      • Bianchi F.B.
      • Cançado E.L.
      • Mackay I.R.
      • Manns M.P.
      • et al.
      Penner E; International Autoimmune Hepatitis Group.
      ] – 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 [
      • Bogdanos D.P.
      • Mieli-Vergani G.
      • Vergani D.
      Autoantibodies and their antigens in autoimmune hepatitis.
      ]. Similarly, testing for anti-actin may increase sensitivity and specificity of SMA for AIH [
      • Chretien-Leprince P.
      • Ballot E.
      • Andre C.
      • Olsson N.O.
      • Fabien N.
      • Escande A.
      • et al.
      Diagnostic value of anti-F-actin antibodies in a French multicenter study.
      ,
      • Czaja A.J.
      • Cassani F.
      • Cataleta M.
      • Valentini P.
      • Bianchi F.B.
      Frequency and significance of antibodies to actin in type 1 autoimmune hepatitis.
      ,
      • Frenzel C.
      • Herkel J.
      • Lüth S.
      • Galle P.R.
      • Schramm C.
      • Lohse A.W.
      Evaluation of F-actin ELISA for the diagnosis of autoimmune hepatitis.
      ].
      Histology is considered a necessary prerequisite for making a diagnosis of autoimmune hepatitis [
      • Lohse A.W.
      • Weiler-Normann C.
      • Tiegs G.
      Immune-mediated liver injury.
      ,
      • Hennes E.M.
      • Zeniya M.
      • Czaja A.J.
      • Parés A.
      • Dalekos G.N.
      • Krawitt E.L.
      • et al.
      Eisenmann de Torres B, Galle PR, McFarlane I, Dienes HP, Lohse AW.
      ]. 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 [
      • Dienes H.P.
      • Popper H.
      • Manns M.
      • Baumann W.
      • Thoenes W.
      • Meyer Zum Büschenfelde K.H.
      Histologic features in autoimmune hepatitis.
      ]. 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 drug-induced inflammation. Increasingly, it is important to distinguish AIH from NASH, and in a few patients both conditions may coexist [
      • Wiegard C.
      • Schramm C.
      • Lohse A.W.
      Scoring systems for the diagnosis of autoimmune hepatitis: past, present, and future.
      ]. ANA and SMA are found, usually at low titers, in up to a third of patients with NASH [
      • Loria P.
      • Lonardo A.
      • Leonardi F.
      • Fontana C.
      • Carulli L.
      • Verrone A.M.
      • et al.
      Non-organ-specific autoantibodies in nonalcoholic fatty liver disease: prevalence and correlates.
      ,
      • Cotler S.J.
      • Kanji K.
      • Keshavarzian A.
      • Jensen D.M.
      • Jakate S.
      Prevalence and significance of autoantibodies in patients with non-alcoholic steatohepatitis.
      ]. Especially in NASH cirrhosis in elderly women, hypergammaglobulinaemia and autoantibodies can lead to diagnostic confusion, making histological examination essential for a correct diagnosis [
      • Wiegard C.
      • Schramm C.
      • Lohse A.W.
      Scoring systems for the diagnosis of autoimmune hepatitis: past, present, and future.
      ]. Characteristic features suggesting typical AIH include interface hepatitis, portal and periportal inflammation, presence of plasma cells, rosetting of hepatocytes, and emperipolesis (Fig. 1).
      Figure thumbnail gr1
      Fig. 1Histology 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).
      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 [
      • Mieli-Vergani G.
      • Vergani D.
      Autoimmune paediatric liver disease.
      ,
      • Gregorio G.V.
      • Portmann B.
      • Reid F.
      • Donaldson P.T.
      • Doherty D.G.
      • McCartney M.
      • et al.
      Autoimmune hepatitis in childhood: a 20-year experience.
      ]. 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 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 [
      • Vajro P.
      • Hadchouel P.
      • Hadchouel M.
      • Bernard O.
      • Alagille D.
      Incidence of cirrhosis in children with chronic hepatitis.
      ,
      • Helmreich-Becker I.
      • Schirmacher P.
      • Denzer U.
      • Hensel A.
      • Meyer zum Büschenfelde K.H.
      • Lohse A.W.
      Minilaparoscopy in the diagnosis of cirrhosis: superiority in patients with Child-Pugh A and macronodular disease.
      ,
      • Poniachik J.
      • Bernstein D.E.
      • Reddy K.R.
      • Jeffers L.J.
      • Coelho-Little M.E.
      • Civantos F.
      • et al.
      The role of laparoscopy in the diagnosis of cirrhosis.
      ,
      • Denzer U.
      • Arnoldy A.
      • Kanzler S.
      • Galle P.R.
      • Dienes H.P.
      • Lohse A.W.
      Prospective randomized comparison of minilaparoscopy and percutaneous liver biopsy: diagnosis of cirrhosis and complications.
      ]. 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.
      Figure thumbnail gr2
      Fig. 2Macroscopic aspect of autoimmune cirrhosis. Typical macro modular cirrhosis of a patient with autoimmune hepatitis diagnosed at a relatively advanced stage.
      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 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 [
      • Hennes E.M.
      • Zeniya M.
      • Czaja A.J.
      • Parés A.
      • Dalekos G.N.
      • Krawitt E.L.
      • et al.
      Eisenmann de Torres B, Galle PR, McFarlane I, Dienes HP, Lohse AW.
      ,
      • Lohse A.W.
      Recognizing autoimmune hepatitis: scores help, but no more.
      ]. 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 [
      • Zen Y.
      • Notsumata K.
      • Tanaka N.
      • Nakanuma Y.
      Hepatic centrilobular zonal necrosis with positive antinuclear antibody: a unique subtype or early disease of autoimmune hepatitis?.
      ,
      • Hofer H.
      • Oesterreicher C.
      • Wrba F.
      • Ferenci P.
      • Penner E.
      Centrilobular necrosis in autoimmune hepatitis: a histological feature associated with acute clinical presentation.
      ]. 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 [
      • Wies I.
      • Brunner S.
      • Henninger J.
      • Herkel J.
      • Kanzler S.
      • Meyer zum Büschenfelde K.H.
      • et al.
      Identification of target antigen for SLA/LP autoantibodies in autoimmune hepatitis.
      ,
      • Björnsson E.
      • Talwalkar J.
      • Treeprasertsuk S.
      • Kamath P.S.
      • Takahashi N.
      • Sanderson S.
      • et al.
      Drug-induced autoimmune hepatitis: clinical characteristics and prognosis.
      ]. 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 [
      • Björnsson E.
      • Talwalkar J.
      • Treeprasertsuk S.
      • Kamath P.S.
      • Takahashi N.
      • Sanderson S.
      • et al.
      Drug-induced autoimmune hepatitis: clinical characteristics and prognosis.
      ]. 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 [
      • Mieli-Vergani G.
      • Vergani D.
      Autoimmune paediatric liver disease.
      ,
      • Meyer zum Büschenfelde K.H.
      • Lohse A.W.
      • Manns M.
      • Poralla T.
      Autoimmunity and liver disease.
      ]. 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 [
      • Qiu D.
      • Wang Q.
      • Wang H.
      • Xie Q.
      • Zang G.
      • Jiang H.
      • et al.
      Validation of the simplified criteria for diagnosis of autoimmune hepatitis in Chinese patients.
      ,
      • Lohse A.W.
      Recognizing autoimmune hepatitis: scores help, but no more.
      ,
      • Czaja A.J.
      Performance parameters of the diagnostic scoring systems for autoimmune hepatitis.
      ,
      • Gatselis N.K.
      • Zachou K.
      • Papamichalis P.
      • Koukoulis G.K.
      • Gabeta S.
      • Dalekos G.N.
      • et al.
      Comparison of simplified score with the revised original score for the diagnosis of autoimmune hepatitis: a new or a complementary diagnostic score?.
      ,
      • Muratori P.
      • Granito A.
      • Pappas G.
      • Muratori L.
      Validation of simplified diagnostic criteria for autoimmune hepatitis in Italian patients.
      ].

      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 [

      Copenhagen Study Group for Liver Diseases: effect of prednisone on the survival of patients with cirrhosis of the liver. Lancet 1969;1:119–121.

      ,
      • Cook G.C.
      • Mulligan R.
      • Sherlock S.
      Controlled prospective trial of corticosteroid therapy in active chronic hepatitis.
      ,
      • Soloway R.D.
      • Summerskill W.H.
      • Baggenstoss A.H.
      • Geall M.G.
      • Gitnićk G.L.
      • Elveback I.R.
      • et al.
      Clinical, biochemical, and histological remission of severe chronic active liver disease: a controlled study of treatments and early prognosis.
      ,
      • Murray-Lyon I.M.
      • Stern R.B.
      • Williams R.
      Controlled trial of prednisone and azathioprine in active chronic hepatitis.
      ,
      • Kirk A.P.
      • Jain S.
      • Pocock S.
      • Thomas H.C.
      • Sherlock S.
      Late results of the Royal Free Hospital prospective controlled trial of prednisolone therapy in hepatitis B surface antigen negative chronic active hepatitis.
      ]. 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 [
      • Kirk A.P.
      • Jain S.
      • Pocock S.
      • Thomas H.C.
      • Sherlock S.
      Late results of the Royal Free Hospital prospective controlled trial of prednisolone therapy in hepatitis B surface antigen negative chronic active hepatitis.
      ]. 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 β (TGFβ) 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 [
      • Bayer E.M.
      • Herr W.
      • Kanzler S.
      • Waldmann C.
      • Meyer Zum Büschenfelde K.H.
      • Dienes H.P.
      • et al.
      Transforming growth factor-beta1 in autoimmune hepatitis: correlation of liver tissue expression and serum levels with disease activity.
      ].
      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 [
      • Manns M.P.
      • Czaja A.J.
      • Gorham J.D.
      • Krawitt E.L.
      • Mieli-Vergani G.
      • Vergani D.
      • et al.
      American Association for the Study of Liver Diseases: diagnosis and management of autoimmune hepatitis.
      ]. 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 [
      • Soloway R.D.
      • Summerskill W.H.
      • Baggenstoss A.H.
      • Geall M.G.
      • Gitnićk G.L.
      • Elveback I.R.
      • et al.
      Clinical, biochemical, and histological remission of severe chronic active liver disease: a controlled study of treatments and early prognosis.
      ] 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 [
      • Mieli-Vergani G.
      • Vergani D.
      Autoimmune paediatric liver disease.
      ,
      • Kanzler S.
      • Galle P.R.
      Meyer zum Büschenfelde KH, Lohse AW. Long term management and prognosis of autoimmune hepatitis (AIH): a single centre experience.
      ,
      • Schramm C.
      • Weiler-Normann C.
      • Wiegard C.
      • Hellweg S.
      • Müller S.
      • Lohse A.W.
      Treatment response in patients with autoimmune hepatitis.
      ]. 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 [
      • Kanzler S.
      • Galle P.R.
      Meyer zum Büschenfelde KH, Lohse AW. Long term management and prognosis of autoimmune hepatitis (AIH): a single centre experience.
      ]. 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 3Treatment 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.
      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 [
      • Stellon A.J.
      • Keating J.J.
      • Johnson P.J.
      • McFarlane I.G.
      • Williams R.
      Maintenance of remission in autoimmune chronic active hepatitis with azathioprine after corticosteroid withdrawal.
      ]. 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 [
      • Stellon A.J.
      • Keating J.J.
      • Johnson P.J.
      • McFarlane I.G.
      • Williams R.
      Maintenance of remission in autoimmune chronic active hepatitis with azathioprine after corticosteroid withdrawal.
      ], while a second trial showed that steroid withdrawal is better achieved when azathioprine is given at the dose of 2 mg/kg body weight [
      • Johnson P.J.
      • McFarlane I.G.
      • Williams R.
      Azathioprine for long-term maintenance of remission in autoimmune hepatitis.
      ]. However, the tumor rate in this trial was relatively high [
      • Meyer zum Büschenfelde K.H.
      • Lohse A.W.
      Autoimmune hepatitis.
      ]; 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).
      Figure thumbnail gr3
      Fig. 3Management 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 . (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.
      Figure thumbnail gr4
      Fig. 4Management algorithm for patients with suspected autoimmune hepatitis. A good response to treatment supports the diagnoses, relapse upon dose reduction is further strong evidence.
      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 [
      • Manns M.P.
      • Woynarowski M.
      • Kreisel W.
      • Lurie Y.
      • Rust C.
      • Zuckerman E.
      • et al.
      European AIH-BUC-Study Group: budesonide induces remission more effectively than prednisone in a controlled trial of patients with autoimmune hepatitis.
      ]. 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 6 months was achieved in 60% of the budesonide group, but in only 38.8% of the prednisone group [
      • Manns M.P.
      • Woynarowski M.
      • Kreisel W.
      • Lurie Y.
      • Rust C.
      • Zuckerman E.
      • et al.
      European AIH-BUC-Study Group: budesonide induces remission more effectively than prednisone in a controlled trial of patients with autoimmune hepatitis.
      ]. 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 [
      • Hempfling W.
      • Grunhage F.
      • Dilger K.
      • Reichel C.
      • Beuers U.
      • Sauerbruch T.
      Pharmacokinetics and pharmacodynamic action of budesonide in early- and late-stage primary biliary cirrhosis.
      ]. 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.
      Management of autoimmune hepatitis requires careful follow-up and strict adherence to treatment by both patients and treating physicians [
      • Kerkar N.
      • Annunziato R.A.
      • Foley L.
      • Schmeidler J.
      • Rumbo C.
      • Emre S.
      • et al.
      J Pediatr: prospective analysis of nonadherence in autoimmune hepatitis: a common problem.
      ]. 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 [
      • Lüth S.
      • Herkel J.
      • Kanzler S.
      • Frenzel C.
      • Galle P.R.
      • Dienes H.P.
      • et al.
      Serologic markers compared with liver biopsy for monitoring disease activity in autoimmune hepatitis.
      ]. 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 [
      • Lüth S.
      • Herkel J.
      • Kanzler S.
      • Frenzel C.
      • Galle P.R.
      • Dienes H.P.
      • et al.
      Serologic markers compared with liver biopsy for monitoring disease activity in autoimmune hepatitis.
      ]. 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.
      Follow-up biopsies are also generally recommended before considering cessation of therapy [
      • Kanzler S.
      • Gerken G.
      • Löhr H.
      • Galle P.R.
      Meyer zum Büschenfelde KH, Lohse AW. Duration of immunosuppressive therapy in autoimmune hepatitis (AIH). J.
      ]. 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 [
      • Kanzler S.
      • Galle P.R.
      Meyer zum Büschenfelde KH, Lohse AW. Long term management and prognosis of autoimmune hepatitis (AIH): a single centre experience.
      ]. 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 [
      • Kanzler S.
      • Gerken G.
      • Löhr H.
      • Galle P.R.
      Meyer zum Büschenfelde KH, Lohse AW. Duration of immunosuppressive therapy in autoimmune hepatitis (AIH). J.
      ]. 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 [
      • Kanzler S.
      • Galle P.R.
      Meyer zum Büschenfelde KH, Lohse AW. Long term management and prognosis of autoimmune hepatitis (AIH): a single centre experience.
      ]. 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.

      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 [
      • Heneghan M.A.
      • Norris S.M.
      • O’Grady J.G.
      • Harrison P.M.
      • McFarlane I.G.
      Management and outcome of pregnancy in autoimmune hepatitis.
      ,
      • Schramm C.
      • Herkel J.
      • Beuers U.
      • Kanzler S.
      • Galle P.R.
      • Lohse A.W.
      Pregnancy in autoimmune hepatitis: outcome and risk factors.
      ,
      • Terrabuio D.R.
      • Abrantes-Lemos C.P.
      • Carrilho F.J.
      • Cançado E.L.
      Follow-up of pregnant women with autoimmune hepatitis: the disease behavior along with maternal and fetal outcomes.
      ]. 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 [
      • Heneghan M.A.
      • Norris S.M.
      • O’Grady J.G.
      • Harrison P.M.
      • McFarlane I.G.
      Management and outcome of pregnancy in autoimmune hepatitis.
      ,
      • Schramm C.
      • Herkel J.
      • Beuers U.
      • Kanzler S.
      • Galle P.R.
      • Lohse A.W.
      Pregnancy in autoimmune hepatitis: outcome and risk factors.
      ,
      • Terrabuio D.R.
      • Abrantes-Lemos C.P.
      • Carrilho F.J.
      • Cançado E.L.
      Follow-up of pregnant women with autoimmune hepatitis: the disease behavior along with maternal and fetal outcomes.
      ]. 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. Non-response, 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 [
      • Richardson P.D.
      • James P.D.
      • Ryder S.D.
      Mycophenolate mofetil for maintenance of remission in autoimmune hepatitis in patients resistant to or intolerant of azathioprine.
      ,
      • Devlin S.M.
      • Swain M.G.
      • Urbanski S.J.
      • Burak K.W.
      Mycophenolate mofetil for the treatment of autoimmune hepatitis in patients refractory to standard therapy.
      ,
      • Chatur N.
      • Ramji A.
      • Bain V.G.
      • Ma M.M.
      • Marotta P.J.
      • Ghent C.N.
      • et al.
      Transplant immunosuppressive agents in non-transplant chronic autoimmune hepatitis: the Canadian association for the study of liver (CASL) experience with mycophenolate mofetil and tacrolimus.
      ]. It appears to be of very limited efficacy in patients with an insufficient response to azathioprine [
      • Hennes E.M.
      • Oo Y.H.
      • Schramm C.
      • Denzer U.
      • Buggisch P.
      • Wiegard C.
      • et al.
      Mycophenolate Mofetil as Second Line Therapy in Autoimmune Hepatitis?.
      ], but experience in children is more favorable than in adults [
      • Aw M.M.
      • Dhawan A.
      • Samyn M.
      • Bargiota A.
      • Mieli-Vergani G.
      Mycophenolate mofetil as rescue treatment for autoimmune liver disease in children: a 5-year follow-up.
      ]. In these patients stronger immunosuppressive agents appear to be required, and good results have been reported with cyclophosphamide [
      • Kanzler S.
      • Gerken G.
      • Dienes H.P.
      • Meyer zum Büschenfelde K.H.
      • Lohse A.W.
      Cyclophosphamide as alternative immunosuppressive therapy for autoimmune hepatitis–report of three cases.
      ], methotrexate [
      • Burak K.W.
      • Urbanski S.J.
      • Swain M.G.
      Successful treatment of refractory type 1 autoimmune hepatitis with methotrexate.
      ], cyclosporine [
      • Alvarez F.
      • Ciocca M.
      • Cañero-Velasco C.
      • Ramonet M.
      • de Davila M.T.
      • Cuarterolo M.
      • et al.
      Short-term cyclosporine induces a remission of autoimmune hepatitis in children.
      ], tacrolimus [
      • Chatur N.
      • Ramji A.
      • Bain V.G.
      • Ma M.M.
      • Marotta P.J.
      • Ghent C.N.
      • et al.
      Transplant immunosuppressive agents in non-transplant chronic autoimmune hepatitis: the Canadian association for the study of liver (CASL) experience with mycophenolate mofetil and tacrolimus.
      ,
      • Van Thiel D.H.
      • Wright H.
      • Carroll P.
      • Abu-Elmagd K.
      • Rodriguez-Rilo H.
      • McMichael J.
      • et al.
      Tacrolimus: a potential new treatment for autoimmune chronic active hepatitis: results of an open-label preliminary trial.
      ] and infliximab [
      • Weiler-Normann C.
      • Wiegard C.
      • Schramm C.
      • Lohse A.W.
      A case of difficult-to-treat autoimmune hepatitis successfully managed by TNF-alpha blockade.
      ]. No comparative data are available. The decision should thus be based on local and personal expertise. 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 [
      • Mieli-Vergani G.
      • Vergani D.
      Autoimmune paediatric liver disease.
      ]. 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 [
      • Kerkar N.
      • Annunziato R.A.
      • Foley L.
      • Schmeidler J.
      • Rumbo C.
      • Emre S.
      • et al.
      J Pediatr: prospective analysis of nonadherence in autoimmune hepatitis: a common problem.
      ]. 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 [
      • Kanzler S.
      • Galle P.R.
      Meyer zum Büschenfelde KH, Lohse AW. Long term management and prognosis of autoimmune hepatitis (AIH): a single centre experience.
      ]. 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 [
      • Boberg K.M.
      • Chapman R.W.
      • Hirschfield G.M.
      • Lohse A.W.
      • Manns M.P.
      • Schrumpf E.
      • et al.
      ]. 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 [
      • Lohse A.W.
      • Meyer zum Büschenfelde K.H.
      • Franz B.
      • Kanzler S.
      • Gerken G.
      • Dienes H.P.
      Characterisation of the ’overlap syndrome’ of primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH) in genetically susceptible individuals.
      ] or PSC [
      • Boberg K.M.
      • Fausa O.
      • Haaland T.
      • Holter E.
      • Mellbye O.J.
      • Spurkland A.
      • et al.
      Features of autoimmune hepatitis in primary sclerosing cholangitis: an evaluation of 114 primary sclerosing cholangitis patients according to a scoring system for the diagnosis of autoimmune hepatitis.
      ]. In children particularly, however, this secondary aggressive hepatitic picture can be so dominant that patients mostly manifest initially as typical autoimmune hepatitis [
      • Gregorio G.V.
      • Portmann B.
      • Karani J.
      • Harrison P.
      • Donaldson P.T.
      • Vergani D.
      • et al.
      Autoimmune hepatitis/sclerosing cholangitis overlap syndrome in childhood: a 16-year prospective study.
      ]. This has lead to the term autoimmune sclerosing cholangitis for these children [
      • Gregorio G.V.
      • Portmann B.
      • Karani J.
      • Harrison P.
      • Donaldson P.T.
      • Vergani D.
      • et al.
      Autoimmune hepatitis/sclerosing cholangitis overlap syndrome in childhood: a 16-year prospective study.
      ]. 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 [
      • Gregorio G.V.
      • Portmann B.
      • Karani J.
      • Harrison P.
      • Donaldson P.T.
      • Vergani D.
      • et al.
      Autoimmune hepatitis/sclerosing cholangitis overlap syndrome in childhood: a 16-year prospective study.
      ]. At the other end of the spectrum, about 10–20% of adult patients with PBC have an insufficient response to treatment with ursodeoxycholic acid and have been shown to benefit from usually low dose prednisolone therapy [
      • Chazouilleres O.
      • Wendum D.
      • Serfaty L.
      • Montembault S.
      • Rosmorduc O.
      • Poupon R.
      Primary biliary cirrhosis-autoimmune hepatitis overlap syndrome: clinical features and response to therapy.
      ]. It remains controversial to what extent these patients should be considered as suffering from autoimmune hepatitis [
      • Boberg K.M.
      • Chapman R.W.
      • Hirschfield G.M.
      • Lohse A.W.
      • Manns M.P.
      • Schrumpf E.
      • et al.
      ]. 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 [
      • Lohse A.W.
      • Meyer zum Büschenfelde K.H.
      • Franz B.
      • Kanzler S.
      • Gerken G.
      • Dienes H.P.
      Characterisation of the ’overlap syndrome’ of primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH) in genetically susceptible individuals.
      ,
      • Chazouilleres O.
      • Wendum D.
      • Serfaty L.
      • Montembault S.
      • Rosmorduc O.
      • Poupon R.
      Primary biliary cirrhosis-autoimmune hepatitis overlap syndrome: clinical features and response to therapy.
      ]. 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 [
      • Lüth S.
      • Kanzler S.
      • Frenzel C.
      • Kasper H.U.
      • Dienes H.P.
      • Schramm C.
      • et al.
      Characteristics and long-term prognosis of the autoimmune hepatitis/primary sclerosing cholangitis overlap syndrome.
      ].

      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 [
      • Montano-Loza A.J.
      • Carpenter H.A.
      • Czaja A.J.
      Frequency, behavior, and prognostic implications of antimitochondrial antibodies in type 1 autoimmune hepatitis.
      ,
      • Teufel A.
      • Weinmann A.
      • Centner C.
      • Piendl A.
      • Lohse A.W.
      • Galle P.R.
      • et al.
      Hepatocellular carcinoma in patients with autoimmune hepatitis.
      ,
      • Yeoman A.D.
      • Al-Chalabi T.
      • Karani J.B.
      • Quaglia A.
      • Devlin J.
      • Mieli-Vergani G.
      • et al.
      Evaluation of risk factors in the development of hepatocellular carcinoma in autoimmune hepatitis: implications for follow-up and screening.
      ]. 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 [
      • Ichai P.
      • Duclos-Vallée J.C.
      • Guettier C.
      • Hamida S.B.
      • Antonini T.
      • Delvart V.
      • et al.
      Usefulness of corticosteroids for the treatment of severe and fulminant forms of autoimmune hepatitis.
      ]. 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 [
      • Milkiewicz P.
      • Hubscher S.G.
      • Skiba G.
      • Hathaway M.
      • Elias E.
      Recurrence of autoimmune hepatitis after liver transplantation.
      ]. 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 [
      • Duclos-Vallée J.C.
      • Sebagh M.
      • Rifai K.
      • Johanet C.
      • Ballot E.
      • Guettier C.
      • et al.
      A 10 year follow up study of patients transplanted for autoimmune hepatitis: histological recurrence precedes clinical and biochemical recurrence.
      ], 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 [
      • Mieli-Vergani G.
      • Vergani D.
      De novo autoimmune hepatitis after liver transplantation.
      ]. This condition does not respond satisfactorily to anti-rejection regimens, but only to the standard treatment for AIH [
      • Mieli-Vergani G.
      • Vergani D.
      De novo autoimmune hepatitis after liver transplantation.
      ], or, in resistant cases, to rapamycin [
      • Kerkar N.
      • Dugan C.
      • Rumbo C.
      • Morotti R.A.
      • Gondolesi G.
      • Shneider B.L.
      • et al.
      Rapamycin successfully treats post-transplant autoimmune hepatitis.
      ].
      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 [
      • Schramm C.
      • Bubenheim M.
      • Adam R.
      • Karam V.
      • Buckels J.
      • O’Grady J.G.
      • et al.
      European Liver Intestine Transplant Association: primary liver transplantation for autoimmune hepatitis: a comparative analysis of the European Liver Transplant Registry.
      ].

      Conflict of interest

      A.W. Lohse: Lecture fees and trial participation, Falk Pharma and MSD.
      G. Mieli-Vergani has nothing to disclose.

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