ARTICLE IN PRESS+ModelCLINRE-581; No. of Pages 4

Clinics and Research in Hepatology and Gastroenterology (2014) xxx, xxx—xxx

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MINI REVIEW

Autoimmune liver disease: Noveltiesin management

Nedim Hadzica,∗, Loreto Hierrob

a Pediatric Centre for Hepatology, Gastroenterology and Nutrition, King’s College Hospital, Denmark Hill,London, UKb Pediatric Liver Service, La Paz Children’s University Hospital, Madrid, Spain

Summary Autoimmune liver disease is the second commonest cause of chronic liver diseasein teenagers. There are several forms including autoimmune hepatitis, autoimmune scleros-ing cholangitis, primary sclerosing cholangitis and various overlap syndromes, classified on thebasis of different serum antibody profiles, histological features and appearances on cholan-giography. Treatment with immunosupressants is usually effective, but often required mediumto 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 transplantationis a possible option, although risk of recurrence in the grafted liver remains lifelong.© 2014 Published by Elsevier Masson SAS.

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Introduction

Autoimmune liver disease (AILD) is a chronic conditioncaused by immune mediated auto-aggressive inflammatoryreaction in genetically susceptible individuals [1]. JuvenileAILD could be divided into:

Please cite this article in press as: Hadzic N, Hierro L. AutoimHepatol Gastroenterol (2014), http://dx.doi.org/10.1016/j.cli

• autoimmune hepatitis (AIH);• autoimmune sclerosing cholangitis (AISC), where histo-

logical injury is predominantly aimed at parenchymal

∗ Corresponding author. Tel.: +44 2032994120;fax: +44 2032994228.

E-mail address: nedim.hadzic@kcl.ac.uk (N. Hadzic).

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http://dx.doi.org/10.1016/j.clinre.2014.03.0152210-7401/© 2014 Published by Elsevier Masson SAS.

or biliary components of the liver micro-architecture,respectively [2].

Clinical distinction is not always simple due to overlap-ing clinical and histological features; thus, cholangiographys often needed for differentiation [3]. Accurate diagnosiss relevant not for the immediate management, which isractically identical, but more for prognostication as AISCppears to be more resistant to treatment and has worserognosis [2]. Evolution from AIH to AISC has been docu-ented both in paediatric and adult patients [4,5]. Some

uthors use term AISC/overlap syndrome to highlight thesembiguous histological and radiological features [6]. A term

mune liver disease: Novelties in management. Clin Resnre.2014.03.015

‘primary sclerosing cholangitis’’ in paediatric literature issually reserved for the disease where no autoantibodiesould be detected and where the inflammatory componentay have been burnt out [4].

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AILD is the second most common cause of chronic liverisease after non-alcoholic fatty liver disease in the sec-nd decade of life. Recent US study reported respectiverevalence of PSC, ASC, and AIH to be 1.5, 0.6 and 3.0ases per 100,000 children [7]. Diagnostic criteria includeypergammaglobulinaemia, presence of organ-specific andrgan-nonspecific autoantibodies, characteristic histologi-al features and favourable response to immunosuppression1,2]. The original scoring system designed for researchnd use in adults appears applicable for juvenile AILD [8]nd has recently been simplified [9]. Diagnostic work upncludes laboratory investigations, ultrasonography, liveriopsy and cholangiography. On clinical examination stig-ata of chronic liver disease such as palmar erythema,

pider naevi and splenomegaly are often evident. A briefnfectious prodrome can be sometimes observed. Presencef other autoimmune conditions is often noted in the fam-ly history [6]. In addition to radiological features of chroniciver disease, abdominal ultrasonography often reveals peri-ortal lymphadenopathy.

athogenesis

IH has a strong female prevalence. According to the pres-nce of different autoantibodies it could be divided in type

[antinuclear (ANA) and/or anti-smooth muscle (SMA) anti-odies] and type II [anti-liver-kidney-microsomal 1 (LKM-1)nd/or liver cytosol-1 (LC-1) antibodies] [10,11]. Type II AIHsually presents earlier in childhood, runs a more aggressivelinical course and more often can be associated with otherutoimmune conditions such as diabetes mellitus, coeliacisease, thyroid and other endocrine disorders. Anti-solubleiver antigen (SLA) antibodies can be detected in all formsf AILD, possibly indicating more severe forms [12]. Theres some debate whether rare conditions, usually responsiveo immune suppression, such as infantile giant cell hepati-is associated with Coombs-positive haemolytic anaemia anderonegative autoimmune hepatitis represent a part of thepectrum of juvenile AILD.

AISC is diagnosed on cholangiography [13]. Histor-cally, direct methods, such as endoscopic retrogradeholangio-pancreatography (ERCP) or percutaneous tran-hepatic cholangiography (PTC) have been used, butechnological advances in magnetic resonance cholangio-ancreatography (MRCP) have established this non-invasiveethod as a gold diagnostic standard for paediatric patients

n recent years [14]. Term ‘‘small-bile-duct disease’’ is usedor chronic liver conditions with features of chronic cholan-iopathy in the liver biopsy, but normal cholangiography4]. In addition to the standard autoantibodies, childrenith AISC appear also to have increased prevalence of anti-eutrophil cytoplasmic antibodies (ANCA). There is a stronget unexplained epidemiological association with severalhronic inflammatory bowel conditions, including ulcerativeolitis and Crohn disease [15].

The pathogenic mechanisms for AILD are complex andnclude genetic susceptibility such as possession of several

Please cite this article in press as: Hadzic N, Hierro L. AutoiHepatol Gastroenterol (2014), http://dx.doi.org/10.1016/j.cli

pecific HLA alleles (for example B8/DR3 and DR4) [16]. Theuto-aggressive immune responses, executed by interactionetween T-regulatory lymphocytes and plasma cells, areimed at specific and nonspecific antigenic targets, possibly

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licited by mechanism of ‘‘molecular mimicry’’, wherehose antigenic targets are shared between environmentalriggers such as viruses or some drugs, and epitopes on theomponents of the liver cell [4,17]. The classical histologicaleatures include portal and periportal inflammatory infil-rate with frequent plasma cells, interface hepatitis witherivenular cell necrosis and different degrees of chronicnflammation ranging from mild fibrosis to establishedirrhotic change. If the presentation of AILD is acute, areasf parenchymal collapse and cholestasis may be observed.

anagement

he conventional treatment of AILD includes inductionf biochemical remission by prednisolone or prednisone2 mg/kg/d, not exceeding 60 mg/d) alone or in combina-ion with azathioprine (up to 2 mg/kg/d) or mycophenolateofetyl (up to 40 mg/kg/d). To avoid side effects the steroidose is reduced to a maintenance of 5—7.5 mg/day over—6 weeks [2,4]. Ursodeoxycholic acid (20—25 mg/kg/d)mproves biochemical abnormalities in AISC, whereas theole of immunosuppression in modifying the natural his-ory of AISC is not very well documented. Mycophenolateofetyl can be used as additional immunosuppressant where

zathioprine is not tolerated or had no effect [18]. Usef cyclosporine or tacrolimus in exceptional cases is pos-ible, but should not be indefinite, i.e. must be limited to

months, due to their considerable long-term side effects19].

De novo autoimmune hepatitis is a form of liver graftysfunction, clinically reminiscent of AIH, where aberrantmmune responses related to chronic use of calcineurinnhibitors are probably operational [20]. This disorder devel-ps in both children and adults transplanted for non-immuneediated conditions in the absence of other documented

auses of liver graft dysfunction. The pathogenic mecha-isms are yet to be definitely established, but emergencef auto-reactive T cells due to abnormal intrathymic anderipheral clonal deletion mechanisms and mismatch inxpression of glutathione-S-transferase T1 have been pro-osed to play a role [10,19]. The treatment is similar to thereatment of classical autoimmune hepatitis, but one groupeported beneficial effect of conversion to rapamycin [21].

ovel approaches to management

udenoside is an alternative steroid which has hepatic firstass clearance of > 90% and theoretically represents a drughich could achieve much better efficacy with less sideffects. A recent prospective randomised controlled cross-ver open label study in adults with AILD demonstrated thatver 6 months 60% of the non-cirrhotic patients given budes-nide (3 mg tds or bd) have achieved biochemical responses compared with 38.8% of those on initial dose of 40 mg/dayf prednisolone. In addition, they all also have received aza-hioprine (1—2 mg/kg/day) [22]. The side effects have beenignificantly fewer in the budenoside arm, including in par-

mmune liver disease: Novelties in management. Clin Resnre.2014.03.015

icular the second, open label phase when all patients wereonverted to budenoside [22]. However, in the paediatricranch of the same study [23] the results were not that con-incingly different, as budenoside showed similar efficacy

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Autoimmune liver disease: Novelties in management

and side effects to standard tapered dose of steroids in indu-cing biochemical remission [23]. It is worth emphasizing thatthe dose reduction of prednisolone was not directed by thebiochemical response. The weight gain, however, was con-siderably reduced in the budenoside cohort [23]. Possibleexplanations for the discrepancy between the budenosideresponse in adults and children may be in more florid inflam-matory component at presentation and higher prevalence ofcirrhosis and AISC variant, known to confer a poorer prog-nosis, in the juvenile AILD.

Clinical observation that oral vancomycin could improvebiochemical and histological features of autoimmune scle-rosing cholangitis [24] was recently tested in a small pilotstudy in adults [25]. Both low dose and high dose oralvancomycin 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 vancomycinwere compared with oral metronidazole and faired bet-ter in terms of side effects [25]. The positive impact ispresumably achieved through not only modification of gutmicroflora via attenuation of lipopolysaccharide-inducedactivation of proinflammatory cytokine pathways, but alsoby direct effects on number and function of T-regulatorycells [26]. This emerging new information with potentialclinical relevance needs to be tested in a larger number ofchildren from different centres.

Although the conventional treatment is reasonably effec-tive in majority of patients with juvenile AILD, novelmanipulations of immune response are required to improvemanagement of difficult-to-treat patients or the ones whodevelop considerable side effects. These approaches, forexample, could include directly targeting presumed patho-genetic mechanisms using monoclonal antibodies againstB-cells (anti-CD20), or promoting restoration of immunetolerance to specific liver-derived antigens by ex vivo manip-ulation of T-regulatory cells.

Withdrawal of treatment

Important question in management of AISC is a length oftreatment. Most centres would intend to treat children long-term due to fear of relapses and their cumulative effects onworsening liver injury. On the other hand, there is a consid-erable pressure from the parents and children to attemptstopping the treatment due to perceived fear of long-termside effects of the medications. Recently, one small studyreported that weaning of immune suppression is possible inapproximately 42% of patients within 5 years of diagnosis,particularly the ones who are non-cirrhotic, p-ANCA nega-tive and had no coagulopathy or history of other non-hepaticautoimmune disorders [27]. This percentage appears consid-erably higher than the one reported in early studies [6].

Conclusion

AILD is one the commonest causes of chronic liver diseasein childhood. There are immunological and clinical similari-

Please cite this article in press as: Hadzic N, Hierro L. AutoimHepatol Gastroenterol (2014), http://dx.doi.org/10.1016/j.cli

ties between juvenile and adult form of the disease, but alsoimportant differences in response to the immunosuppressivetreatment. Early-onset forms of AISC have more florid his-tological and immunological features suggesting that more

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ggressive approach could potentially modify biochemicalesponse and natural history. Liver transplantation is possi-le, but recurrence rate is high.

isclosure of interest

he authors declare that they have no conflicts of interestoncerning this article.

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