+Model CLINRE-581; No. of Pages 4
ARTICLE IN PRESS
Clinics and Research in Hepatology and Gastroenterology (2014) xxx, xxx—xxx
Available online at
ScienceDirect www.sciencedirect.com
MINI REVIEW
Autoimmune liver disease: Novelties in management Nedim Hadzic a,∗, Loreto Hierro b a
Pediatric Centre for Hepatology, Gastroenterology and Nutrition, King’s College Hospital, Denmark Hill, London, UK b Pediatric Liver Service, La Paz Children’s University Hospital, Madrid, Spain
Summary Autoimmune liver disease is the second commonest cause of chronic liver disease in teenagers. There are several forms including autoimmune hepatitis, autoimmune sclerosing cholangitis, primary sclerosing cholangitis and various overlap syndromes, classified on the basis of different serum antibody profiles, histological features and appearances on cholangiography. Treatment with immunosupressants is usually effective, but often required medium to long-term, raising concerns about side effects and adherence to therapy. For a minority of children presenting in acute liver failure or with difficult-to-treat disease liver transplantation is a possible option, although risk of recurrence in the grafted liver remains lifelong. © 2014 Published by Elsevier Masson SAS.
Introduction Autoimmune liver disease (AILD) is a chronic condition caused by immune mediated auto-aggressive inflammatory reaction in genetically susceptible individuals [1]. Juvenile AILD could be divided into:
• autoimmune hepatitis (AIH); • autoimmune sclerosing cholangitis (AISC), where histological injury is predominantly aimed at parenchymal
∗ Corresponding author. Tel.: +44 2032994120; fax: +44 2032994228. E-mail address: [email protected] (N. Hadzic).
or biliary components of the liver micro-architecture, respectively [2]. Clinical distinction is not always simple due to overlapping clinical and histological features; thus, cholangiography is often needed for differentiation [3]. Accurate diagnosis is relevant not for the immediate management, which is practically identical, but more for prognostication as AISC appears to be more resistant to treatment and has worse prognosis [2]. Evolution from AIH to AISC has been documented both in paediatric and adult patients [4,5]. Some authors use term AISC/overlap syndrome to highlight these ambiguous histological and radiological features [6]. A term ‘‘primary sclerosing cholangitis’’ in paediatric literature is usually reserved for the disease where no autoantibodies could be detected and where the inflammatory component may have been burnt out [4].
http://dx.doi.org/10.1016/j.clinre.2014.03.015 2210-7401/© 2014 Published by Elsevier Masson SAS.
Please cite this article in press as: Hadzic N, Hierro L. Autoimmune liver disease: Novelties in management. Clin Res Hepatol Gastroenterol (2014), http://dx.doi.org/10.1016/j.clinre.2014.03.015
+Model CLINRE-581; No. of Pages 4
ARTICLE IN PRESS
2
N. Hadzic, L. Hierro
AILD is the second most common cause of chronic liver disease after non-alcoholic fatty liver disease in the second decade of life. Recent US study reported respective prevalence of PSC, ASC, and AIH to be 1.5, 0.6 and 3.0 cases per 100,000 children [7]. Diagnostic criteria include hypergammaglobulinaemia, presence of organ-specific and organ-nonspecific autoantibodies, characteristic histological features and favourable response to immunosuppression [1,2]. The original scoring system designed for research and use in adults appears applicable for juvenile AILD [8] and has recently been simplified [9]. Diagnostic work up includes laboratory investigations, ultrasonography, liver biopsy and cholangiography. On clinical examination stigmata of chronic liver disease such as palmar erythema, spider naevi and splenomegaly are often evident. A brief infectious prodrome can be sometimes observed. Presence of other autoimmune conditions is often noted in the family history [6]. In addition to radiological features of chronic liver disease, abdominal ultrasonography often reveals periportal lymphadenopathy.
Pathogenesis AIH has a strong female prevalence. According to the presence of different autoantibodies it could be divided in type I [antinuclear (ANA) and/or anti-smooth muscle (SMA) antibodies] and type II [anti-liver-kidney-microsomal 1 (LKM-1) and/or liver cytosol-1 (LC-1) antibodies] [10,11]. Type II AIH usually presents earlier in childhood, runs a more aggressive clinical course and more often can be associated with other autoimmune conditions such as diabetes mellitus, coeliac disease, thyroid and other endocrine disorders. Anti-soluble liver antigen (SLA) antibodies can be detected in all forms of AILD, possibly indicating more severe forms [12]. There is some debate whether rare conditions, usually responsive to immune suppression, such as infantile giant cell hepatitis associated with Coombs-positive haemolytic anaemia and seronegative autoimmune hepatitis represent a part of the spectrum of juvenile AILD. AISC is diagnosed on cholangiography [13]. Historically, direct methods, such as endoscopic retrograde cholangio-pancreatography (ERCP) or percutaneous transhepatic cholangiography (PTC) have been used, but technological advances in magnetic resonance cholangiopancreatography (MRCP) have established this non-invasive method as a gold diagnostic standard for paediatric patients in recent years [14]. Term ‘‘small-bile-duct disease’’ is used for chronic liver conditions with features of chronic cholangiopathy in the liver biopsy, but normal cholangiography [4]. In addition to the standard autoantibodies, children with AISC appear also to have increased prevalence of antineutrophil cytoplasmic antibodies (ANCA). There is a strong yet unexplained epidemiological association with several chronic inflammatory bowel conditions, including ulcerative colitis and Crohn disease [15]. The pathogenic mechanisms for AILD are complex and include genetic susceptibility such as possession of several specific HLA alleles (for example B8/DR3 and DR4) [16]. The auto-aggressive immune responses, executed by interaction between T-regulatory lymphocytes and plasma cells, are aimed at specific and nonspecific antigenic targets, possibly
elicited by mechanism of ‘‘molecular mimicry’’, where those antigenic targets are shared between environmental triggers such as viruses or some drugs, and epitopes on the components of the liver cell [4,17]. The classical histological features include portal and periportal inflammatory infiltrate with frequent plasma cells, interface hepatitis with perivenular cell necrosis and different degrees of chronic inflammation ranging from mild fibrosis to established cirrhotic change. If the presentation of AILD is acute, areas of parenchymal collapse and cholestasis may be observed.
Management The conventional treatment of AILD includes induction of biochemical remission by prednisolone or prednisone (2 mg/kg/d, not exceeding 60 mg/d) alone or in combination with azathioprine (up to 2 mg/kg/d) or mycophenolate mofetyl (up to 40 mg/kg/d). To avoid side effects the steroid dose is reduced to a maintenance of 5—7.5 mg/day over 4—6 weeks [2,4]. Ursodeoxycholic acid (20—25 mg/kg/d) improves biochemical abnormalities in AISC, whereas the role of immunosuppression in modifying the natural history of AISC is not very well documented. Mycophenolate mofetyl can be used as additional immunosuppressant where azathioprine is not tolerated or had no effect [18]. Use of cyclosporine or tacrolimus in exceptional cases is possible, but should not be indefinite, i.e. must be limited to 6 months, due to their considerable long-term side effects [19]. De novo autoimmune hepatitis is a form of liver graft dysfunction, clinically reminiscent of AIH, where aberrant immune responses related to chronic use of calcineurin inhibitors are probably operational [20]. This disorder develops in both children and adults transplanted for non-immune mediated conditions in the absence of other documented causes of liver graft dysfunction. The pathogenic mechanisms are yet to be definitely established, but emergence of auto-reactive T cells due to abnormal intrathymic and peripheral clonal deletion mechanisms and mismatch in expression of glutathione-S-transferase T1 have been proposed to play a role [10,19]. The treatment is similar to the treatment of classical autoimmune hepatitis, but one group reported beneficial effect of conversion to rapamycin [21].
Novel approaches to management Budenoside is an alternative steroid which has hepatic first pass clearance of > 90% and theoretically represents a drug which could achieve much better efficacy with less side effects. A recent prospective randomised controlled crossover open label study in adults with AILD demonstrated that over 6 months 60% of the non-cirrhotic patients given budesonide (3 mg tds or bd) have achieved biochemical response as compared with 38.8% of those on initial dose of 40 mg/day of prednisolone. In addition, they all also have received azathioprine (1—2 mg/kg/day) [22]. The side effects have been significantly fewer in the budenoside arm, including in particular the second, open label phase when all patients were converted to budenoside [22]. However, in the paediatric branch of the same study [23] the results were not that convincingly different, as budenoside showed similar efficacy
Please cite this article in press as: Hadzic N, Hierro L. Autoimmune liver disease: Novelties in management. Clin Res Hepatol Gastroenterol (2014), http://dx.doi.org/10.1016/j.clinre.2014.03.015
+Model CLINRE-581; No. of Pages 4
ARTICLE IN PRESS
Autoimmune liver disease: Novelties in management and side effects to standard tapered dose of steroids in inducing biochemical remission [23]. It is worth emphasizing that the dose reduction of prednisolone was not directed by the biochemical response. The weight gain, however, was considerably reduced in the budenoside cohort [23]. Possible explanations for the discrepancy between the budenoside response in adults and children may be in more florid inflammatory component at presentation and higher prevalence of cirrhosis and AISC variant, known to confer a poorer prognosis, in the juvenile AILD. Clinical observation that oral vancomycin could improve biochemical and histological features of autoimmune sclerosing cholangitis [24] was recently tested in a small pilot study in adults [25]. Both low dose and high dose oral vancomycin reduced serum levels of alkaline phosphatase, which was the primary end point at 12 weeks of treatment, but not of serum bilirubin. The effects of oral vancomycin were compared with oral metronidazole and faired better in terms of side effects [25]. The positive impact is presumably achieved through not only modification of gut microflora via attenuation of lipopolysaccharide-induced activation of proinflammatory cytokine pathways, but also by direct effects on number and function of T-regulatory cells [26]. This emerging new information with potential clinical relevance needs to be tested in a larger number of children from different centres. Although the conventional treatment is reasonably effective in majority of patients with juvenile AILD, novel manipulations of immune response are required to improve management of difficult-to-treat patients or the ones who develop considerable side effects. These approaches, for example, could include directly targeting presumed pathogenetic mechanisms using monoclonal antibodies against B-cells (anti-CD20), or promoting restoration of immune tolerance to specific liver-derived antigens by ex vivo manipulation of T-regulatory cells.
Withdrawal of treatment Important question in management of AISC is a length of treatment. Most centres would intend to treat children longterm due to fear of relapses and their cumulative effects on worsening liver injury. On the other hand, there is a considerable pressure from the parents and children to attempt stopping the treatment due to perceived fear of long-term side effects of the medications. Recently, one small study reported that weaning of immune suppression is possible in approximately 42% of patients within 5 years of diagnosis, particularly the ones who are non-cirrhotic, p-ANCA negative and had no coagulopathy or history of other non-hepatic autoimmune disorders [27]. This percentage appears considerably higher than the one reported in early studies [6].
Conclusion AILD is one the commonest causes of chronic liver disease in childhood. There are immunological and clinical similarities between juvenile and adult form of the disease, but also important differences in response to the immunosuppressive treatment. Early-onset forms of AISC have more florid histological and immunological features suggesting that more
3 aggressive approach could potentially modify biochemical response and natural history. Liver transplantation is possible, but recurrence rate is high.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
References [1] Alvarez F, Berg PA, Bianchi FB, Bianchi L, Burroughs AK, Cancado EL, et al. International Autoimmune Hepatitis Group report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol 1999;31:929—38. [2] Mieli-Vergani G, Heller S, Jara P, Vergani D, Chang MH, Fujisawa T, et al. Autoimmune hepatitis. J Pediatr Gastroenterol Nutr 2009;49:158—64. [3] Hiejima E, Komatsu H, Sogo T, Inui A, Fujisawa T. Utility of simplified criteria for the diagnosis of autoimmune hepatitis in children. J Pediatr Gastroenterol Nutr 2011;52:470—3. [4] Floreani A, Liberal R, Vergani D, Mieli-Vergani G. Autoimmune hepatitis: contrasts and comparisons in children and adults — a comprehensive review. J Autoimmun 2013;46:7—16. [5] Abdo AA, Bain VG, Kichian K, Lee SS. Evolution of autoimmune hepatitis to primary sclerosing cholangitis: a sequential syndrome. Hepatology 2002;36:1393—9. [6] Gregorio GV, Portmann B, Reid F, Donaldson PT, Doherty DG, McCartney M, et al. Autoimmune hepatitis in childhood: a 20year experience. Hepatology 1997;25:541—7. [7] Deneau M, Jensen MK, Holmen J, Williams MS, Book LS, Guthery SL. Primary sclerosing cholangitis, autoimmune hepatitis, and overlap in Utah children: epidemiology and natural history. Hepatology 2013;58:1392—400. [8] Ebbeson RL, Schreiber RA. Diagnosing autoimmune hepatitis in children: is the International Autoimmune Hepatitis Group scoring system useful? Clin Gastroenterol Hepatol 2004;10:935—40. [9] Hennes EM, Zeniya M, Czaja AJ, Pares A, Dalekos GN, Krawitt EL, et al. Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology 2008;48:169—76. [10] Homberg JC, Abuaf N, Bernard O, Islam S, Alvarez F, Khalil SH, et al. Chronic active hepatitis associated with anti-liver/kidney microsome antibody type 1: a second type of ‘‘autoimmune’’ hepatitis. Hepatology 1987;7:1333—9. [11] Liberal R, Longhi MS, Mieli-Vergani G, Vergani D. Pathogenesis of autoimmune hepatitis. Best Pract Res Clin Gastroenterol 2011;25:653—64. [12] Ma Y, Okamoto M, Thomas MG, Bogdanos DP, Lopes AR, Portmann B, et al. Antibodies to conformational epitopes of soluble liver antigen define a severe form of autoimmune liver disease. Hepatology 2002;35:658—64. [13] Debray D, Pariente D, Urvoas E, Hadchouel M, Bernard O. Sclerosing cholangitis in children. J Pediatr 1994;124:49—56. [14] Gregorio GV, Portmann B, Karani J, Harrison P, Donaldson PT, Vergani D, et al. Autoimmune hepatitis/sclerosing cholangitis overlap syndrome in childhood: a 16-year prospective study. Hepatology 2001;33:544—53. [15] Noble-Jamieson G, Heuschkel RB, Torrente F, Hadzic N, Zilbauer M. Colitis-associated sclerosing cholangitis in children: a single centre experience. J Crohns Colitis 2013;7:e414—8. [16] Czaja AJ, Donaldson PT. Genetic susceptibility for immune expression and liver cell injury in autoimmune hepatitis. Immunol Rev 2000;174:250—9. [17] Manns MP, Griffin KJ, Sullivan KF, Johnson EF. LKM1 autoantibodies recognize a short linear sequence in
Please cite this article in press as: Hadzic N, Hierro L. Autoimmune liver disease: Novelties in management. Clin Res Hepatol Gastroenterol (2014), http://dx.doi.org/10.1016/j.clinre.2014.03.015
+Model CLINRE-581; No. of Pages 4
ARTICLE IN PRESS
4
N. Hadzic, L. Hierro
[18]
[19]
[20]
[21]
[22]
P450IID6, a cytochrome P-450 monooxygenase. J Clin Invest 1991;88:1370—8. Aw MM, 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. J Hepatol 2009;51:156—60. Cuarterolo M, Ciocca M, Velasco CC, Ramonet M, González T, López S, et al. Follow-up of children with autoimmune hepatitis treated with cyclosporine. J Pediatr Gastroenterol Nutr 2006;43:635—9. Kerkar N, Hadzic N, Davies E, Portmann B, Donaldson PT, Rela M, et al. De novo autoimmune hepatitis after liver transplantation. Lancet 1998;351:409—13. Kerkar N, Dugan C, Rumbo C, Morotti RA, Gondolesi G, Shneider BL, et al. Rapamycin successfully treats post-transplant autoimmune hepatitis. Am J Transplant 2005;5:1085—9. Manns MP, Woynarowski M, Kreisel W, Lurie Y, Rust C, Zukerman E, et al. Budesonide induces remission more effectively than prednisone in a controlled trial of patients with autoimmune hepatitis. Gastroenterology 2010;139:1198—206.
[23] Woynarowski M, Nemeth A, Baruch Y, Koletzko S, Melter M, Rodeck B, et al. Budesonide versus prednisone with azathioprine for the treatment of autoimmune hepatitis in children and adolescents. J Pediatr 2013;163:1347—53. [24] Cox KL, Cox KM. Oral vancomycin: treatment of primary sclerosing cholangitis in children with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 1998;27:580—3. [25] Tabibian JH, Weeding E, Jorgensen RA, Petz JL, Keach JC, Talwalkar JA, et al. Randomised clinical trial: vancomycin or metronidazole in patients with primary sclerosing cholangitis — a pilot study. Aliment Pharmacol Ther 2013;37:604—12. [26] Abarbanel DN, Seki SM, Davies Y, Marlen N, Benavides JA, Cox K, et al. Immunomodulatory effect of vancomycin on Treg in pediatric inflammatory bowel disease and primary sclerosing cholangitis. J Clin Immunol 2013;33:397—406. [27] Deneau M, Book LS, Guthery SL, Jensen MK. Outcome after discontinuation of immunosuppression in children with autoimmune hepatitis: a population-based study. J Pediatr 2014;164(4):714—9.e2, http://dx.doi.org/10.1016/j.jpeds. 2013.12.008 [Epub 2014 Jan 11].
Please cite this article in press as: Hadzic N, Hierro L. Autoimmune liver disease: Novelties in management. Clin Res Hepatol Gastroenterol (2014), http://dx.doi.org/10.1016/j.clinre.2014.03.015
ARTICLE IN PRESS
Clinics and Research in Hepatology and Gastroenterology (2014) xxx, xxx—xxx
Available online at
ScienceDirect www.sciencedirect.com
MINI REVIEW
Autoimmune liver disease: Novelties in management Nedim Hadzic a,∗, Loreto Hierro b a
Pediatric Centre for Hepatology, Gastroenterology and Nutrition, King’s College Hospital, Denmark Hill, London, UK b Pediatric Liver Service, La Paz Children’s University Hospital, Madrid, Spain
Summary Autoimmune liver disease is the second commonest cause of chronic liver disease in teenagers. There are several forms including autoimmune hepatitis, autoimmune sclerosing cholangitis, primary sclerosing cholangitis and various overlap syndromes, classified on the basis of different serum antibody profiles, histological features and appearances on cholangiography. Treatment with immunosupressants is usually effective, but often required medium to long-term, raising concerns about side effects and adherence to therapy. For a minority of children presenting in acute liver failure or with difficult-to-treat disease liver transplantation is a possible option, although risk of recurrence in the grafted liver remains lifelong. © 2014 Published by Elsevier Masson SAS.
Introduction Autoimmune liver disease (AILD) is a chronic condition caused by immune mediated auto-aggressive inflammatory reaction in genetically susceptible individuals [1]. Juvenile AILD could be divided into:
• autoimmune hepatitis (AIH); • autoimmune sclerosing cholangitis (AISC), where histological injury is predominantly aimed at parenchymal
∗ Corresponding author. Tel.: +44 2032994120; fax: +44 2032994228. E-mail address: [email protected] (N. Hadzic).
or biliary components of the liver micro-architecture, respectively [2]. Clinical distinction is not always simple due to overlapping clinical and histological features; thus, cholangiography is often needed for differentiation [3]. Accurate diagnosis is relevant not for the immediate management, which is practically identical, but more for prognostication as AISC appears to be more resistant to treatment and has worse prognosis [2]. Evolution from AIH to AISC has been documented both in paediatric and adult patients [4,5]. Some authors use term AISC/overlap syndrome to highlight these ambiguous histological and radiological features [6]. A term ‘‘primary sclerosing cholangitis’’ in paediatric literature is usually reserved for the disease where no autoantibodies could be detected and where the inflammatory component may have been burnt out [4].
http://dx.doi.org/10.1016/j.clinre.2014.03.015 2210-7401/© 2014 Published by Elsevier Masson SAS.
Please cite this article in press as: Hadzic N, Hierro L. Autoimmune liver disease: Novelties in management. Clin Res Hepatol Gastroenterol (2014), http://dx.doi.org/10.1016/j.clinre.2014.03.015
+Model CLINRE-581; No. of Pages 4
ARTICLE IN PRESS
2
N. Hadzic, L. Hierro
AILD is the second most common cause of chronic liver disease after non-alcoholic fatty liver disease in the second decade of life. Recent US study reported respective prevalence of PSC, ASC, and AIH to be 1.5, 0.6 and 3.0 cases per 100,000 children [7]. Diagnostic criteria include hypergammaglobulinaemia, presence of organ-specific and organ-nonspecific autoantibodies, characteristic histological features and favourable response to immunosuppression [1,2]. The original scoring system designed for research and use in adults appears applicable for juvenile AILD [8] and has recently been simplified [9]. Diagnostic work up includes laboratory investigations, ultrasonography, liver biopsy and cholangiography. On clinical examination stigmata of chronic liver disease such as palmar erythema, spider naevi and splenomegaly are often evident. A brief infectious prodrome can be sometimes observed. Presence of other autoimmune conditions is often noted in the family history [6]. In addition to radiological features of chronic liver disease, abdominal ultrasonography often reveals periportal lymphadenopathy.
Pathogenesis AIH has a strong female prevalence. According to the presence of different autoantibodies it could be divided in type I [antinuclear (ANA) and/or anti-smooth muscle (SMA) antibodies] and type II [anti-liver-kidney-microsomal 1 (LKM-1) and/or liver cytosol-1 (LC-1) antibodies] [10,11]. Type II AIH usually presents earlier in childhood, runs a more aggressive clinical course and more often can be associated with other autoimmune conditions such as diabetes mellitus, coeliac disease, thyroid and other endocrine disorders. Anti-soluble liver antigen (SLA) antibodies can be detected in all forms of AILD, possibly indicating more severe forms [12]. There is some debate whether rare conditions, usually responsive to immune suppression, such as infantile giant cell hepatitis associated with Coombs-positive haemolytic anaemia and seronegative autoimmune hepatitis represent a part of the spectrum of juvenile AILD. AISC is diagnosed on cholangiography [13]. Historically, direct methods, such as endoscopic retrograde cholangio-pancreatography (ERCP) or percutaneous transhepatic cholangiography (PTC) have been used, but technological advances in magnetic resonance cholangiopancreatography (MRCP) have established this non-invasive method as a gold diagnostic standard for paediatric patients in recent years [14]. Term ‘‘small-bile-duct disease’’ is used for chronic liver conditions with features of chronic cholangiopathy in the liver biopsy, but normal cholangiography [4]. In addition to the standard autoantibodies, children with AISC appear also to have increased prevalence of antineutrophil cytoplasmic antibodies (ANCA). There is a strong yet unexplained epidemiological association with several chronic inflammatory bowel conditions, including ulcerative colitis and Crohn disease [15]. The pathogenic mechanisms for AILD are complex and include genetic susceptibility such as possession of several specific HLA alleles (for example B8/DR3 and DR4) [16]. The auto-aggressive immune responses, executed by interaction between T-regulatory lymphocytes and plasma cells, are aimed at specific and nonspecific antigenic targets, possibly
elicited by mechanism of ‘‘molecular mimicry’’, where those antigenic targets are shared between environmental triggers such as viruses or some drugs, and epitopes on the components of the liver cell [4,17]. The classical histological features include portal and periportal inflammatory infiltrate with frequent plasma cells, interface hepatitis with perivenular cell necrosis and different degrees of chronic inflammation ranging from mild fibrosis to established cirrhotic change. If the presentation of AILD is acute, areas of parenchymal collapse and cholestasis may be observed.
Management The conventional treatment of AILD includes induction of biochemical remission by prednisolone or prednisone (2 mg/kg/d, not exceeding 60 mg/d) alone or in combination with azathioprine (up to 2 mg/kg/d) or mycophenolate mofetyl (up to 40 mg/kg/d). To avoid side effects the steroid dose is reduced to a maintenance of 5—7.5 mg/day over 4—6 weeks [2,4]. Ursodeoxycholic acid (20—25 mg/kg/d) improves biochemical abnormalities in AISC, whereas the role of immunosuppression in modifying the natural history of AISC is not very well documented. Mycophenolate mofetyl can be used as additional immunosuppressant where azathioprine is not tolerated or had no effect [18]. Use of cyclosporine or tacrolimus in exceptional cases is possible, but should not be indefinite, i.e. must be limited to 6 months, due to their considerable long-term side effects [19]. De novo autoimmune hepatitis is a form of liver graft dysfunction, clinically reminiscent of AIH, where aberrant immune responses related to chronic use of calcineurin inhibitors are probably operational [20]. This disorder develops in both children and adults transplanted for non-immune mediated conditions in the absence of other documented causes of liver graft dysfunction. The pathogenic mechanisms are yet to be definitely established, but emergence of auto-reactive T cells due to abnormal intrathymic and peripheral clonal deletion mechanisms and mismatch in expression of glutathione-S-transferase T1 have been proposed to play a role [10,19]. The treatment is similar to the treatment of classical autoimmune hepatitis, but one group reported beneficial effect of conversion to rapamycin [21].
Novel approaches to management Budenoside is an alternative steroid which has hepatic first pass clearance of > 90% and theoretically represents a drug which could achieve much better efficacy with less side effects. A recent prospective randomised controlled crossover open label study in adults with AILD demonstrated that over 6 months 60% of the non-cirrhotic patients given budesonide (3 mg tds or bd) have achieved biochemical response as compared with 38.8% of those on initial dose of 40 mg/day of prednisolone. In addition, they all also have received azathioprine (1—2 mg/kg/day) [22]. The side effects have been significantly fewer in the budenoside arm, including in particular the second, open label phase when all patients were converted to budenoside [22]. However, in the paediatric branch of the same study [23] the results were not that convincingly different, as budenoside showed similar efficacy
Please cite this article in press as: Hadzic N, Hierro L. Autoimmune liver disease: Novelties in management. Clin Res Hepatol Gastroenterol (2014), http://dx.doi.org/10.1016/j.clinre.2014.03.015
+Model CLINRE-581; No. of Pages 4
ARTICLE IN PRESS
Autoimmune liver disease: Novelties in management and side effects to standard tapered dose of steroids in inducing biochemical remission [23]. It is worth emphasizing that the dose reduction of prednisolone was not directed by the biochemical response. The weight gain, however, was considerably reduced in the budenoside cohort [23]. Possible explanations for the discrepancy between the budenoside response in adults and children may be in more florid inflammatory component at presentation and higher prevalence of cirrhosis and AISC variant, known to confer a poorer prognosis, in the juvenile AILD. Clinical observation that oral vancomycin could improve biochemical and histological features of autoimmune sclerosing cholangitis [24] was recently tested in a small pilot study in adults [25]. Both low dose and high dose oral vancomycin reduced serum levels of alkaline phosphatase, which was the primary end point at 12 weeks of treatment, but not of serum bilirubin. The effects of oral vancomycin were compared with oral metronidazole and faired better in terms of side effects [25]. The positive impact is presumably achieved through not only modification of gut microflora via attenuation of lipopolysaccharide-induced activation of proinflammatory cytokine pathways, but also by direct effects on number and function of T-regulatory cells [26]. This emerging new information with potential clinical relevance needs to be tested in a larger number of children from different centres. Although the conventional treatment is reasonably effective in majority of patients with juvenile AILD, novel manipulations of immune response are required to improve management of difficult-to-treat patients or the ones who develop considerable side effects. These approaches, for example, could include directly targeting presumed pathogenetic mechanisms using monoclonal antibodies against B-cells (anti-CD20), or promoting restoration of immune tolerance to specific liver-derived antigens by ex vivo manipulation of T-regulatory cells.
Withdrawal of treatment Important question in management of AISC is a length of treatment. Most centres would intend to treat children longterm due to fear of relapses and their cumulative effects on worsening liver injury. On the other hand, there is a considerable pressure from the parents and children to attempt stopping the treatment due to perceived fear of long-term side effects of the medications. Recently, one small study reported that weaning of immune suppression is possible in approximately 42% of patients within 5 years of diagnosis, particularly the ones who are non-cirrhotic, p-ANCA negative and had no coagulopathy or history of other non-hepatic autoimmune disorders [27]. This percentage appears considerably higher than the one reported in early studies [6].
Conclusion AILD is one the commonest causes of chronic liver disease in childhood. There are immunological and clinical similarities between juvenile and adult form of the disease, but also important differences in response to the immunosuppressive treatment. Early-onset forms of AISC have more florid histological and immunological features suggesting that more
3 aggressive approach could potentially modify biochemical response and natural history. Liver transplantation is possible, but recurrence rate is high.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
References [1] Alvarez F, Berg PA, Bianchi FB, Bianchi L, Burroughs AK, Cancado EL, et al. International Autoimmune Hepatitis Group report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol 1999;31:929—38. [2] Mieli-Vergani G, Heller S, Jara P, Vergani D, Chang MH, Fujisawa T, et al. Autoimmune hepatitis. J Pediatr Gastroenterol Nutr 2009;49:158—64. [3] Hiejima E, Komatsu H, Sogo T, Inui A, Fujisawa T. Utility of simplified criteria for the diagnosis of autoimmune hepatitis in children. J Pediatr Gastroenterol Nutr 2011;52:470—3. [4] Floreani A, Liberal R, Vergani D, Mieli-Vergani G. Autoimmune hepatitis: contrasts and comparisons in children and adults — a comprehensive review. J Autoimmun 2013;46:7—16. [5] Abdo AA, Bain VG, Kichian K, Lee SS. Evolution of autoimmune hepatitis to primary sclerosing cholangitis: a sequential syndrome. Hepatology 2002;36:1393—9. [6] Gregorio GV, Portmann B, Reid F, Donaldson PT, Doherty DG, McCartney M, et al. Autoimmune hepatitis in childhood: a 20year experience. Hepatology 1997;25:541—7. [7] Deneau M, Jensen MK, Holmen J, Williams MS, Book LS, Guthery SL. Primary sclerosing cholangitis, autoimmune hepatitis, and overlap in Utah children: epidemiology and natural history. Hepatology 2013;58:1392—400. [8] Ebbeson RL, Schreiber RA. Diagnosing autoimmune hepatitis in children: is the International Autoimmune Hepatitis Group scoring system useful? Clin Gastroenterol Hepatol 2004;10:935—40. [9] Hennes EM, Zeniya M, Czaja AJ, Pares A, Dalekos GN, Krawitt EL, et al. Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology 2008;48:169—76. [10] Homberg JC, Abuaf N, Bernard O, Islam S, Alvarez F, Khalil SH, et al. Chronic active hepatitis associated with anti-liver/kidney microsome antibody type 1: a second type of ‘‘autoimmune’’ hepatitis. Hepatology 1987;7:1333—9. [11] Liberal R, Longhi MS, Mieli-Vergani G, Vergani D. Pathogenesis of autoimmune hepatitis. Best Pract Res Clin Gastroenterol 2011;25:653—64. [12] Ma Y, Okamoto M, Thomas MG, Bogdanos DP, Lopes AR, Portmann B, et al. Antibodies to conformational epitopes of soluble liver antigen define a severe form of autoimmune liver disease. Hepatology 2002;35:658—64. [13] Debray D, Pariente D, Urvoas E, Hadchouel M, Bernard O. Sclerosing cholangitis in children. J Pediatr 1994;124:49—56. [14] Gregorio GV, Portmann B, Karani J, Harrison P, Donaldson PT, Vergani D, et al. Autoimmune hepatitis/sclerosing cholangitis overlap syndrome in childhood: a 16-year prospective study. Hepatology 2001;33:544—53. [15] Noble-Jamieson G, Heuschkel RB, Torrente F, Hadzic N, Zilbauer M. Colitis-associated sclerosing cholangitis in children: a single centre experience. J Crohns Colitis 2013;7:e414—8. [16] Czaja AJ, Donaldson PT. Genetic susceptibility for immune expression and liver cell injury in autoimmune hepatitis. Immunol Rev 2000;174:250—9. [17] Manns MP, Griffin KJ, Sullivan KF, Johnson EF. LKM1 autoantibodies recognize a short linear sequence in
Please cite this article in press as: Hadzic N, Hierro L. Autoimmune liver disease: Novelties in management. Clin Res Hepatol Gastroenterol (2014), http://dx.doi.org/10.1016/j.clinre.2014.03.015
+Model CLINRE-581; No. of Pages 4
ARTICLE IN PRESS
4
N. Hadzic, L. Hierro
[18]
[19]
[20]
[21]
[22]
P450IID6, a cytochrome P-450 monooxygenase. J Clin Invest 1991;88:1370—8. Aw MM, 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. J Hepatol 2009;51:156—60. Cuarterolo M, Ciocca M, Velasco CC, Ramonet M, González T, López S, et al. Follow-up of children with autoimmune hepatitis treated with cyclosporine. J Pediatr Gastroenterol Nutr 2006;43:635—9. Kerkar N, Hadzic N, Davies E, Portmann B, Donaldson PT, Rela M, et al. De novo autoimmune hepatitis after liver transplantation. Lancet 1998;351:409—13. Kerkar N, Dugan C, Rumbo C, Morotti RA, Gondolesi G, Shneider BL, et al. Rapamycin successfully treats post-transplant autoimmune hepatitis. Am J Transplant 2005;5:1085—9. Manns MP, Woynarowski M, Kreisel W, Lurie Y, Rust C, Zukerman E, et al. Budesonide induces remission more effectively than prednisone in a controlled trial of patients with autoimmune hepatitis. Gastroenterology 2010;139:1198—206.
[23] Woynarowski M, Nemeth A, Baruch Y, Koletzko S, Melter M, Rodeck B, et al. Budesonide versus prednisone with azathioprine for the treatment of autoimmune hepatitis in children and adolescents. J Pediatr 2013;163:1347—53. [24] Cox KL, Cox KM. Oral vancomycin: treatment of primary sclerosing cholangitis in children with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 1998;27:580—3. [25] Tabibian JH, Weeding E, Jorgensen RA, Petz JL, Keach JC, Talwalkar JA, et al. Randomised clinical trial: vancomycin or metronidazole in patients with primary sclerosing cholangitis — a pilot study. Aliment Pharmacol Ther 2013;37:604—12. [26] Abarbanel DN, Seki SM, Davies Y, Marlen N, Benavides JA, Cox K, et al. Immunomodulatory effect of vancomycin on Treg in pediatric inflammatory bowel disease and primary sclerosing cholangitis. J Clin Immunol 2013;33:397—406. [27] Deneau M, Book LS, Guthery SL, Jensen MK. Outcome after discontinuation of immunosuppression in children with autoimmune hepatitis: a population-based study. J Pediatr 2014;164(4):714—9.e2, http://dx.doi.org/10.1016/j.jpeds. 2013.12.008 [Epub 2014 Jan 11].
Please cite this article in press as: Hadzic N, Hierro L. Autoimmune liver disease: Novelties in management. Clin Res Hepatol Gastroenterol (2014), http://dx.doi.org/10.1016/j.clinre.2014.03.015
