Autoimmune hepatitis. Recent advances. Dominique-Charles VALLA

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1 Autoimmune hepatitis Recent advances Dominique-Charles VALLA The field of autoimmune hepatitis has been quite active since the last update on the topic at the Day of Hepatology of Beaujon Hospital in A simplified diagnostic score, better knowledge of some unusual forms, more solid criteria for remission and relapse, better understanding of prognostic factors, and especially improved therapeutic options are now available. The purpose of this chapter is to discuss these advances. The overlapping forms of autoimmune hepatitis with other liver or biliary diseases will not be discussed here. Diagnosis The autoimmune hepatitis is characterized by three elements: (a) a particular lesion, interface hepatitis, (b) the absence of other causes of this lesion (viral hepatitis, drug-induced hepatitis, Wilson s disease or alpha-1 antitrypsin deficiency); and (c) signs of autoimmunity (autoantibodies or other autoimmune diseases). Table 1. Simplified diagnostic criteria of autoimmune hepatitis Variable Cutoff Points ANA or SMA 1/40 1 ANA or SMA 1/80 and/or anti-lkm1 1/40 2 and/or anti-sla Positive IgG >ULN 1 >1.10 ULN 2 Liver biopsy Compatible 1 Typical 2 Absence of viral hepatitis Yes 2 Probable AIH > 6 Definite AIH > 7

2 A complex international score was established by the International Autoimmune Hepatitis Group (IAHG), in an essentially academic aim (1). Recently, simplified criteria, more easily used clinically have been developed in a group of 443 patients with or without AIH, and validated in an independent sample of 393 patients with or without AIH (2). These criteria are presented in Table 1. Excellent specificity of these simplified criteria were confirmed in a more recent study (3), however the sensitivity remains lower than the old criteria of IAHG particularly because neither other autoimmune diseases nor the HLA DR3 group were taken into consideration (3). In other words, a low simplified score implies the use of the more complex score of IAHG. ATYPICAL CLINICAL AND HISTOLOGICAL FORMS The autoimmune hepatitis is not exclusive to the young white woman, although it has long been considered the typical background. In addition, particular histological forms have been characterized, in which interface hepatitis is not the most significant lesion. Age The age of 40 years seems to distinguish 2 forms of autoimmune hepatitis corresponding to two incidence peaks: one around the age of 30 years, and the other towards the age of 55 years. The form of the older subjects is more frequent, always type 1; more frequently associated with HLA-DR4 group; characterized by a less acute presentation; more frequently associated with cirrhosis at the onset or during evolution; and less often associated with relapse. However, whatever the age group, the incidence of response to immunosuppressive treatment and serious side effects of treatment are equivalent (4-6). Race The autoimmune hepatitis occurring in the subjects of black race is generally more serious, particularly as they are male. Cirrhosis is more frequent at diagnosis, progression to fibrosis is faster, and the terminal stage of cirrhosis is reached more frequently (7, 8). Gender Men are clearly less exposed to autoimmune hepatitis, but they are not spared. There is no special semiology or progression of autoimmune hepatitis affecting men (9). Centrilobular form An individualized from where the initial lesions are located in the centrilobular region (necrosis with mononuclear inflammatory infiltrate, without steatohepatitis), while interface

3 hepatitis is absent or minimal. As a rule, typical lesions of the periportal region appear secondarily. This form has a good response to immunosuppressive therapy (10-12). The differential diagnosis of this form with acute drug-induced immunoallergic hepatitis is difficult. Form with giant cells Multinucleated hepatocytes, cholestasis, and a mononuclear inflammatory or eosinophilic infiltrate constitute the group of lesions which are referred to as giant cell hepatitis. The mechanisms of formation of multinucleated hepatocytes are not clarified. This syndrome is more common in infants than in adults. In adults, this syndrome is associated with a viral infection (EBV, CMV, HHV6, paramyxovirus, HCV, HEV) or drug toxicity in about half of the cases. In the other cases, it is often associated with autoimmune manifestations, can progress rapidly to cirrhosis or liver failure, and is sensitive to immunosuppressive therapy (13-16). Forms with antimitochondrial antibodies Antimitochondrial autoantibodies type M2 may be present (and sometimes isolated) in the absence of cholestasis (alkaline phosphatase <1.5 N) and histological signs of lymphocytic cholangitis. These forms do not exhibit an overlap with primary biliary cirrhosis and do not predict its subsequent development (17, 18). TREATMENT AND PROGNOSIS Definition of response criteria Although the reference remains the disappearance of necrotic and inflammatory lobular and portal lesions, a consensus seems to be acquired on a purely biochemical definition. Although a certain degree of heterogeneity persists, a growing consensus is emerging around the following definitions (19): - Complete (biochemical) remission: Persistently normal transaminases. - Partial remission: Transaminases <2 times the upper limit of normal (x ULN). - Relapse: Increase of transaminases to a value above the normal values after their normalization. - Failure of treatment: Stability or increase of transaminases.

4 These definitions are based on the very good relationship between the lesions of necrosis or lobular and periportal inflammation and transaminases on one hand (20, 21), and the overall progression of the disease on the other hand (22-24). Therefore, these definitions tend to substitute not only histological criteria of response, but also biochemical criteria used in studies of the Mayo Clinic (AST <2 x ULN for the remission and AST> 3 x ULN for the relapse). Natural history Few studies have been addressed to this subject because, as the benefit of immunosuppressive therapy has been firmly and formerly established, most of the patients are treated. The analysis of small series shows that a first attack may be followed by spontaneous remission, but the risk of a difficult to treat relapse is high in the following months. The long-term progression of these forms may be less favorable than that of the forms that are treated from the start (25, 26). Progression under immunosuppressive therapy It is now perfectly clear that the maintenance of prolonged remission is associated with a normal life expectancy after adjusting for age and sex (17, 27, 28). Prolonged remission can be maintained in more than 85% of patients either after discontinuation of immunosuppressive therapy (25-50% of patients), or through a maintenance treatment with low doses of immunosuppressive drugs (50-75% patients). As a result, overall life expectancy of patients with autoimmune hepatitis in general is excellent. It is also clear that the lesions of fibrosis and even cirrhosis may regress when remission is maintained (28-31). However, cirrhosis develops during treatment in 10 to 30% of cases according to the series. Relapse usually occurs during reduction or discontinuation of immunosuppressive therapy. Prognosis of relapse is not worse than those forms in which prolonged remission is maintained without treatment (32). The risk of hepatocellular carcinoma in the long term has been specified. It is about 0.5-1% per year. It concerns exclusively patients who developed cirrhosis, particularly those with severe portal hypertension. The role of prolonged immunosuppressive treatment remains to be elucidated (33, 34).

5 Prognostic factors of response to immunosuppressive treatment This involves the prediction of remission in response to the treatment of an attack, relapse during or at the discontinuation of maintenance therapy, and finally the occurrence of complications. - Prediction of remission. The high frequency of remission under immunosuppressive therapy (>85%) did not allow to study with good power the predictive factors of failure. In a study where the rate of treatment failure was 7% (14/214) factors associated with the failure were group HLA DRB1*03 (93% versus 53%), younger age (33 versus 48 years) and a higher initial bilirubinemia (68 versus 40 µmol/l). However, multivariate analysis showed that the score MELD alone, summarized the previous prognostic markers (35). Similar data were presented by another group (36). - Prediction of relapse. It was widely confirmed that abnormal transaminases and higher than normal serum -globulin or IgG are of value in predicting relapse during maintenance treatment or at its cessation (22). These two factors are largely but not completely redundant (22). More recent is the demonstration that a marked portal infiltration by plasma cells is also a powerful marker of risk of relapse (23, 37). This is probably redundant with the increase in -globulin or IgG. It was suggested that the duration of the remission under immunosuppressive therapy is also a major risk factor for relapse: in a recently published series, the risk of relapse was 33% after a successful treatment for more than 4 years, while it was 83% after treatment for 2-4 years and 90% after treatment for only 1-2 years (38). - Prediction of complications of advanced disease or death. These long-term complications are mainly related to the absence of prolonged complete response, in other words, the lack of persistent normalization of transaminases (22-24). The role of cirrhosis is much less clear whether it was present from the onset, or developed during progression: highly discordant data were reported on this subject without an evident explanation of divergence (17, 23). Therapeutic advances The principle of treatment of an attack by decreasing doses of immunosuppressives, followed by maintenance therapy once remission obtained was kept in all the recently published studies. The principle of treatment of attack by corticosteroids as a first choice was also conserved. Finally, the principle of combination with azathioprine to halve the dose of steroids - and hence their side effects - has only been followed in half of the patients included in most recent large series. Recent publications were addressed to the usefulness of

6 pharmacological tests to adjust the dose of azathioprine, rescue treatments in case of failure of conventional treatment and finally, the substitution of predniso(lo)ne with budesonide. Pharmacological tests and azathioprine Randomized controlled trials have clearly established that azathioprine (a) allows a reduction in corticosteroid dose while maintaining the efficacy of the treatment of attack, and (b) monotherapy at a dose of 2 mg/kg/day prevents relapse. However, these beneficial effects are limited by well-known side effects, gastrointestinal and hematological. By extension of studies performed in inflammatory bowel disease (IBD), several studies have investigated the relationship between genotype and phenotype of thiopurine methyl transferase (TMPT), or the concentration of metabolites 6-TGN, and the risk of toxicity or inefficacy of azathioprine (39-41). A poor relationship was observed between the phenotype or genotype of TPMT deficiency and manifestations of intolerance or inefficacy. Therefore, these determinations are not recommended. The monitoring must be carried out throughout the treatment using full blood count and transaminases. Failure of conventional treatment The failure of conventional treatment is rarely due to the inefficacy of treatment of an attack administered at the usual dose (predniso(lo)ne 0.5 mg/kg/day and azathioprine 1 mg/kg/day) and more often due to intolerance of treatment. The management of inefficacy has not been addressed in any robust clinical trial. Several options have been proposed (42-45): - Increasing doses of predniso(lo)ne 1 mg/kg/day, in combination with azathioprine 1 mg/kg/j until remission, then gradual reduction of corticosteroid; - Increasing the dose of azathioprine to 2 mg/kg/day, in combination with predniso(lo)ne 0.5 mg/kg/day until remission, then gradual reduction of corticosteroid; - Increasing both doses of azathioprine and predniso(lo)ne; - The addition of another immunosuppressant and decreasing the dose of corticosteroid and azathioprine from the start or once response is observed. The proposed immunosuppressants were tacrolimus, cyclosporine, mycophenolate mofetyl, methotrexate and cyclophosphamide. The efficacy of these attitudes has not really been evaluated. Such levels of immunosuppression pose a significant risk of opportunistic infections (pneumocystosis, aspergillosis, viral reactivations), and may be malignancy. These may, in themselves,

7 compromise liver transplantation. These potent immunosuppressive therapies can not be maintained unless under close monitoring, while preventing pneumocystosis, and provided that the efficacy is proven. The excellent efficacy and tolerability of budesonide (see below) made it probably the first choice in case of inefficacy of conventional treatment. Intolerance or containdication of azathioprine is easily managed by substitution by mycophenolate mophetyl. Although the side effects of these two products are close to each other (digestive and hematopoietic), there is no cross intolerance to these products. Intolerance or contraindication of predniso(lo)ne deserves a substitution by budesonide (see below). However, in patients with cirrhosis and portosystemic shunt, reduction or abolition of the first-pass effect should add prudence. The budesonide-azathioprine combination: standard treatment of attack A high scale controlled trial was presented to the last 2 annual EASL and AASLD conferences. Two hundred and three patients, never treated for autoimmune hepatitis, were included. They were randomly assigned for treatment with either budesonide, 3 mg 3 times/day until remission, then 3 mg 2 times/day; or prednisone 40 mg/day for 4 weeks, gradually reducing the dose to 10 mg/day for 2 months then 10 mg/day for 3 months. All patients received azathioprine, 1-2 mg/kg/day for 6 months. The main criterion ('complete response') was the complete normalization of transaminases in the absence of 6 characteristic complications of corticosteroid therapy (acne, cushingoid facies, buffalo hump, striae, diabetes and glaucoma). At 6 months, by intention-to-treat as well as per-protocol analysis, the criterion of success was achieved in 47% of patients treated with budesonide and only 18% of patients treated with prednisone (46). It should be noted that the benefit was due to both improved efficacy (biochemical remission 60% versus 39%) and lack of side effects (72% versus 47%). At the end of the first 6 months of treatment, all patients received budesonide alone, 3 mg 2 times/day. Six months later, a complete response (as defined above) was observed in 55% of cases, biochemical remission in 59% of cases, AST <2 x ULN in 93% of cases and lack of side effects in 93% of cases (47). The combination of azathioprine (1-2 mg/kg/day) and budesonide (3 mg 3 times/day, reduced to 3 mg 2 times/day once remission obtained) deserves to become the standard treatment of attack.

8 For maintenance treatment, a study comparing azathioprine alone and budesonide alone is necessary. Already, we can consider that budesonide at a dose of 3 mg 2 times/day is an interesting option in case of intolerance to azathioprine alone for maintenance treatment. CONCLUSIONS Simplified diagnostic criteria (autoantibodies, IgG, and liver biopsy) are highly specific for diagnosis of autoimmune hepatitis. When they are unhelpful, it is useful to use the modified criteria of AIHG. The diagnosis of autoimmune hepatitis is not surprising in a man, an elderly, or a black race subject. Differences in clinical manifestations or response to treatment between these different populations have no implications on managment. The isolated anti-mitochondrial type M2, without cholangitis or cholestasis, does not reflect a form of overlap. In the absence of viral infection or history of drug intake, giant multinucleated hepatocytes orient towards an autoimmune cause. Pure centrilobular lesions may constitute the initial lesions of autoimmune hepatitis. The two essential prognostic factors for autoimmune hepatitis are the complete normalization of transaminases and serum immunoglobulins. Therefore, these two criteria are the goal of treatment. The treatment of choice for induction of remission is the combination of budesonide and azathioprine for 6 months. The treatment of choice for the maintenance of remission is azathioprine. Mycophenolate mofetyl or budesonide (3 mg 2times/day) are effective options in case of intolerance to azathioprine. REFERENCES 1. Alvarez F, Berg PA, Bianchi FB, Bianchi L, Burroughs AK, Cancado EL, Chapman RW, et al. International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol 1999;31: Hennes EM, Zeniya M, Czaja AJ, Pares A, Dalekos GN, Krawitt EL, Bittencourt PL, et al. Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology 2008;48:

9 3. Czaja AJ. Performance parameters of the diagnostic scoring systems for autoimmune hepatitis. Hepatology 2008;48: Al-Chalabi T, Boccato S, Portmann BC, McFarlane IG, Heneghan MA. 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. J Hepatol 2006;45: Czaja AJ, Carpenter HA. Distinctive clinical phenotype and treatment outcome of type 1 autoimmune hepatitis in the elderly. Hepatology 2006;43: Schramm C, Kanzler S, zum Buschenfelde KH, Galle PR, Lohse AW. Autoimmune hepatitis in the elderly. Am J Gastroenterol 2001;96: Verma S, Torbenson M, Thuluvath PJ. The impact of ethnicity on the natural history of autoimmune hepatitis. Hepatology 2007;46: Lim KN, Casanova RL, Boyer TD, Bruno CJ. Autoimmune hepatitis in African Americans: presenting features and response to therapy. Am J Gastroenterol 2001;96: Czaja AJ, Donaldson PT. Gender effects and synergisms with histocompatibility leukocyte antigens in type 1 autoimmune hepatitis. Am J Gastroenterol 2002;97: Singh R, Nair S, Farr G, Mason A, Perrillo R. Acute autoimmune hepatitis presenting with centrizonal liver disease: case report and review of the literature. Am J Gastroenterol 2002;97: Pratt DS, Fawaz KA, Rabson A, Dellelis R, Kaplan MM. A novel histological lesion in glucocorticoid-responsive chronic hepatitis. Gastroenterology 1997;113: Te HS, Koukoulis G, Ganger DR. Autoimmune hepatitis: a histological variant associated with prominent centrilobular necrosis. Gut 1997;41: Tordjmann T, Grimbert S, Genestie C, Freymuth F, Guettier C, Callard P, Trinchet JC, et al. [Adult multi-nuclear cell hepatitis. A study in 17 patients]. Gastroenterol Clin Biol 1998;22: Anagnostopoulos GK, Margantinis G, Tsiakos S, Kostopoulos P, Grigoriadis K, Arvanitidis D. Postinfantile giant-cell hepatitis associated with ulcerative colitis and autoimmune hepatitis. J Gastroenterol Hepatol 2006;21: Harrison RA, Bahar A, Payne MM. Postinfantile giant cell hepatitis associated with long-term elevated transaminase levels in treated Graves' disease. Am J Med 2002;112: Ben-Ari Z, Broida E, Monselise Y, Kazatsker A, Baruch J, Pappo O, Skappa E, et al. Syncytial giant-cell hepatitis due to autoimmune hepatitis type II (LKM1+) presenting as subfulminant hepatitis. Am J Gastroenterol 2000;95: Feld JJ, Dinh H, Arenovich T, Marcus VA, Wanless IR, Heathcote EJ. Autoimmune hepatitis: effect of symptoms and cirrhosis on natural history and outcome. Hepatology 2005;42: Montano-Loza AJ, Carpenter HA, Czaja AJ. Frequency, behavior, and prognostic implications of antimitochondrial antibodies in type 1 autoimmune hepatitis. J Clin Gastroenterol 2008;42: Al-Chalabi T, Heneghan MA. Remission in autoimmune hepatitis: what is it, and can it ever be achieved? Am J Gastroenterol 2007;102: Czaja AJ, Wolf AM, Baggenstoss AH. Laboratory assessment of severe chronic active liver disease during and after corticosteroid therapy: correlation of serum transaminase and gamma globulin levels with histologic features. Gastroenterology 1981;80: Luth S, Herkel J, Kanzler S, Frenzel C, Galle PR, Dienes HP, Schramm C, et al. Serologic markers compared with liver biopsy for monitoring disease activity in autoimmune hepatitis. J Clin Gastroenterol 2008;42:

10 22. Montano-Loza AJ, Carpenter HA, Czaja AJ. Improving the end point of corticosteroid therapy in type 1 autoimmune hepatitis to reduce the frequency of relapse. Am J Gastroenterol 2007;102: Verma S, Gunuwan B, Mendler M, Govindrajan S, Redeker A. Factors predicting relapse and poor outcome in type I autoimmune hepatitis: role of cirrhosis development, patterns of transaminases during remission and plasma cell activity in the liver biopsy. Am J Gastroenterol 2004;99: Miyake Y, Iwasaki Y, Terada R, Takagi S, Okamaoto R, Ikeda H, Sakai N, et al. Persistent normalization of serum alanine aminotransferase levels improves the prognosis of type 1 autoimmune hepatitis. J Hepatol 2005;43: Dufour JF, Zimmermann M, Reichen J. Severe autoimmune hepatitis in patients with previous spontaneous recovery of a flare. J Hepatol 2002;37: Czaja AJ. Features and consequences of untreated type 1 autoimmune hepatitis. Liver Int Kanzler S, Lohr H, Gerken G, Galle PR, Lohse AW. Long-term management and prognosis of autoimmune hepatitis (AIH): a single center experience. Z Gastroenterol 2001;39: , Schvarcz R, Glaumann H, Weiland O. Survival and histological resolution of fibrosis in patients with autoimmune chronic active hepatitis. J Hepatol 1993;18: Czaja AJ, Carpenter HA. Decreased fibrosis during corticosteroid therapy of autoimmune hepatitis. J Hepatol 2004;40: Czaja AJ, Carpenter HA. Progressive fibrosis during corticosteroid therapy of autoimmune hepatitis. Hepatology 2004;39: Dufour JF, DeLellis R, Kaplan MM. Reversibility of hepatic fibrosis in autoimmune hepatitis. Ann Intern Med 1997;127: Czaja AJ, Menon KV, Carpenter HA. Sustained remission after corticosteroid therapy for type 1 autoimmune hepatitis: a retrospective analysis. Hepatology 2002;35: Montano-Loza AJ, Carpenter HA, Czaja AJ. Predictive factors for hepatocellular carcinoma in type 1 autoimmune hepatitis. Am J Gastroenterol 2008;103: Yeoman AD, Al-Chalabi T, Karani JB, Quaglia A, Devlin J, Mieli-Vergani G, Bomford A, et al. Evaluation of risk factors in the development of hepatocellular carcinoma in autoimmune hepatitis: Implications for follow-up and screening. Hepatology 2008;48: Montano-Loza AJ, Carpenter HA, Czaja AJ. Features associated with treatment failure in type 1 autoimmune hepatitis and predictive value of the model of end-stage liver disease. Hepatology 2007;46: Milkiewicz P, Ahmed M, Hathaway M, Elias E. Factors associated with progression of the disease before transplantation in patients with autoimmune hepatitis. Liver 1999;19: Czaja AJ, Carpenter HA. Histological features associated with relapse after corticosteroid withdrawal in type 1 autoimmune hepatitis. Liver Int 2003;23: Kanzler S, Gerken G, Lohr H, Galle PR, Meyer zum Buschenfelde KH, Lohse AW. Duration of immunosuppressive therapy in autoimmune hepatitis. J Hepatol 2001;34: Langley PG, Underhill J, Tredger JM, Norris S, McFarlane IG. Thiopurine methyltransferase phenotype and genotype in relation to azathioprine therapy in autoimmune hepatitis. J Hepatol 2002;37: Heneghan MA, Allan ML, Bornstein JD, Muir AJ, Tendler DA. Utility of thiopurine methyltransferase genotyping and phenotyping, and measurement of azathioprine metabolites in the management of patients with autoimmune hepatitis. J Hepatol 2006;45:

11 41. Czaja AJ, Carpenter HA. Thiopurine methyltransferase deficiency and azathioprine intolerance in autoimmune hepatitis. Dig Dis Sci 2006;51: Czaja AJ, Freese DK. Diagnosis and treatment of autoimmune hepatitis. Hepatology 2002;36: Manns MP, Strassburg CP. Autoimmune hepatitis: clinical challenges. Gastroenterology 2001;120: Heneghan MA, McFarlane IG. Current and novel immunosuppressive therapy for autoimmune hepatitis. Hepatology 2002;35: Krawitt EL. Autoimmune hepatitis. N Engl J Med 2006;354: Manns MP, Bahr M, Woynarowski M, Kreisel W, Oren R, Günther R, Hultcrantz RW, et al. Budesonide 3 mg tid is superior to prednisone in combination with azathioprine in the treatment of autoimmune hepatitis. J Hepatol 2008;48:S369-S Manns MP, Woynarowski M, kreisel W, Oren R, Rust C, Hultcrantz RW, Spengler U, et al. Budesonide 3mg bid in combination with azathioprine as maintenance treatment of autoimmune hepatitis - Final results of a large multicenter international trial. Hepatology 2008;48:376A-377A.