Paediatric autoimmune liver disease
- 1Paediatric Liver, GI and Nutrition Centre, King's College London School of Medicine at King's College Hospital, London, UK
- 2Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, London, UK
- Correspondence to Professor Giorgina Mieli-Vergani, Department of Paediatric Liver, GI and Nutrition Centre, King's College Hospital, Denmark Hill, London SE5 9RS, UK;
- Received 10 April 2013
- Revised 30 July 2013
- Accepted 2 August 2013
- Published Online First 3 September 2013
Autoimmune liver disorders in childhood include autoimmune hepatitis (AIH) and AIH/sclerosing cholangitis overlap syndrome (henceforth referred to as autoimmune sclerosing cholangitis, ASC). These inflammatory liver disorders are characterised histologically by interface hepatitis, biochemically by elevated transaminase levels, and serologically by autoantibodies and increased levels of immunoglobulin G. AIH is particularly aggressive in children and progresses rapidly unless immunosuppressive treatment is started promptly. With appropriate treatment, 80% of patients achieve remission and long-term survival. For non-responders and difficult-to-treat patients, novel and more effective therapeutic approaches are sought. ASC responds to the same treatment used for AIH in regards to parenchymal inflammation, but bile duct disease progresses in about 50% of cases, leading to a worse prognosis and a higher liver transplantation requirement; moreover, it has a high recurrence rate after transplant. Progression of liver disease and recurrence after transplant are more common in patients with associated poorly controlled inflammatory bowel disease. Though the mechanisms underlying the pathogenesis of liver autoimmunity are not fully understood, genetic and environmental factors are likely to be involved. A deeper understanding of the pathogenesis of these conditions will contribute to the development of novel treatments, aimed ultimately at the restoration of tolerance to liver-derived antigens.
Autoimmune liver diseases (AILD) are progressive disorders characterised by high levels of transaminases and immunoglobulin G (IgG), positive autoantibodies and interface hepatitis on histology (figure 1), in the absence of a known aetiology. The cause of the autoimmune attack is unknown, but genetic and environmental factors are involved.1
In paediatrics, two types of AILD are recognised: classical autoimmune hepatitis (AIH) and the AIH-sclerosing cholangitis overlap syndrome (autoimmune sclerosing cholangitis, ASC). This review will concentrate on personal experience acquired over three decades in the largest supraregional paediatric hepatology referral centre in the UK. We have observed a marked increase in juvenile AILD over the last two decades, their incidence being 2.3% in the 1990s and 12% in the 2000s out of ∼500 new referrals/year.
AILD presentation is non-specific: as prompt treatment is life-saving, AILD should be suspected and investigated in all children with liver disease not ascribable to more common pathologies.
In children/adolescents AIH often presents acutely and has an aggressive course. AIH responds well to immunosuppressive treatment, which should be instituted as soon as the diagnosis is made, as, if untreated, AIH progresses to liver failure requiring transplantation.2
Two types of AIH are recognised: type 1 AIH (AIH-1), positive for antinuclear (ANA) and/or smooth muscle antibodies (SMA), and type 2 AIH (AIH-2), positive for liver/kidney microsomal type 1 (anti-LKM-1) and/or antiliver cytosol type 1 (anti-LC-1) autoantibodies.3 While AIH-1 affects children and adults, AIH-2 is predominantly a paediatric condition.
The epidemiology of childhood AIH is unknown, but AIH-1, accounting for ∼60% of cases, often presents around puberty, whereas AIH-2 tends to affect younger children, even infants.4 ,5 AIH-2 presents more commonly with fulminant hepatic failure compared with AIH-1, and tends to have higher serum bilirubin and transaminase levels. Excluding the fulminant presentation, a severely impaired hepatic synthetic function, as assessed by the presence of prolonged prothrombin time and hypoalbuminemia, is more common in AIH-1 than in AIH-2; 80% of patients have elevated IgG levels, but normal IgG cannot exclude the diagnosis of AIH. Partial IgA deficiency is more common in AIH-2 than in AIH-1.4 The severity of interface hepatitis at diagnosis is similar in both types, but cirrhosis on initial biopsy is more frequent in AIH-1, suggesting a more chronic disease course.4
In AIH-1 and AIH-2, presence of autoantibodies to soluble liver antigen (SLA),6 heralds a more severe disease course with frequent relapses. Importantly, a small proportion of AIH patients are positive only for anti-SLA. It is therefore important to request this autoantibody, which is tested in specialised laboratories. Autoantibody-negative AIH responsive to immunosuppression has been reported in adults, but its prevalence and clinical characteristics in children remain to be defined.7
AIH is three times more frequent in females than males.2 ,4 ,5 A family history of autoimmune diseases is present in 40% of cases,4 and at least 20% of AIH patients have or develop concomitant autoimmune conditions,4 including thyroiditis, inflammatory bowel disease (IBD), insulin-dependent diabetes, vitiligo, nephrotic syndrome, hypoparathyroidism and Addison disease, the latter two being observed particularly in AIH-2 or in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal-dystrophy (APECED).8
In 40%, the presentation mimics an acute viral hepatitis (non-specific symptoms of malaise, nausea/vomiting, anorexia, and abdominal pain, followed by jaundice, dark urine and pale stools). Some children, particularly those who are anti-LKM-1-positive, develop acute liver failure with grades II–IV hepatic encephalopathy within 2–8 weeks from the onset of symptoms.
In 25–40%, the onset is insidious, with progressive fatigue, relapsing jaundice, headache, anorexia, amenorrhoea, and weight loss, lasting for several months, and even years, before diagnosis.
In 10%, there is no history of jaundice, and the disease presents with complications of portal hypertension, such as upper gastrointestinal bleeding or hypersplenism.
The disease course can be fluctuating, with flares and spontaneous remissions, occasionally resulting in delayed referral and diagnosis. Most children, however, on physical examination have clinical signs of chronic liver disease, including cutaneous stigmata (spider naevi, palmar erythema, leukonychia, striae), firm liver and splenomegaly. At ultrasound, the liver parenchyma is often nodular and heterogeneous.9
Autoimmune sclerosing cholangitis
Sclerosing cholangitis is an uncommon disorder, characterised by chronic inflammation and fibrosis of the intrahepatic and/or extrahepatic bile ducts. When bile duct damage is detectable histologically, but cholangiography is normal, a diagnosis of ‘small duct disease’ is made. In childhood, sclerosing cholangitis may occur as an individual disease or may develop in association with a wide variety of disorders. The term primary sclerosing cholangitis (PSC), used in adult patients, is not accurate to describe paediatric sclerosing colangitis: ‘primary’ denotes ignorance about aetiology and pathogenesis, while in paediatrics there are well-defined forms of sclerosing cholangitis.10–14 In the neonatal period, pathological features of severe sclerosing cholangitis characterise biliary atresia as well as neonatal sclerosing cholangitis, a condition inherited in an autosomal recessive manner.15 Some other inherited diseases and immunological defects may produce a clinical picture similar to adult PSC. For example, mild to moderate defects in the ABCB4 (MDR3) gene are a likely cause of a number of cases of small duct PSC in children and adults16 ,17 and sclerosing cholangitis may complicate a wide variety of disorders, including primary and secondary immunodeficiencies, Langerhans cell histiocytosis, psoriasis, cystic fibrosis, reticulum cell sarcoma and sickle cell anaemia. Moreover, an overlap syndrome between AIH and sclerosing cholangitis (ASC), is significantly more common in children than in adults.10 In only a relatively small number of paediatric patients, sclerosing cholangitis occurs without any of the above defining features. The term of PSC would be better confined to the latter, as different types of sclerosing cholangitis respond to different therapeutic managements.
ASC is characterised by florid autoimmune features, positive autoantibodies, especially ANA and SMA, hypergammaglobulinemia, and interface hepatitis on liver biopsy.2 ,10 Since these features are shared with AIH, and alkaline phosphatase (AP) or gamma glutamyl transpeptidase (GGT) levels are often not elevated at disease onset, the diagnosis of ASC relies on cholangiographic studies. In a 16-year prospective study, during which all children with serological and histological features of AILD underwent liver biopsy, sigmoidoscopy and cholangiography at presentation,10 approximately half were found to have bile duct changes characteristic of sclerosing cholangitis (figure 2), and were therefore diagnosed with ASC. Importantly, a quarter of children with ASC had no histological features pointing to bile duct involvement despite abnormal cholangiograms. Virtually all ASC patients were seropositive for ANA and/or SMA. By contrast with AIH, which is predominantly a disease of females, ASC affects, similarly, boys and girls.10
The mode of presentation of ASC is similar to that of AIH-1, although an association with IBD is more common in ASC (45%) than AIH-1 (20%). Of note, in the prospective study, only one-third of the children with IBD had bowel symptoms, while the others were diagnosed because of surveillance sigmoidoscopy. At presentation, liver function tests—including GGT levels, which are a more reliable indicator of cholestasis than AP in growing children/adolescents, in whom AP often reflects bone growth—do not discriminate between AIH and ASC, though the AP/aspartate aminotransferase ratio is significantly higher in ASC (table 2). Notably, atypical perinuclear anti-neutrophil cytoplasmic antibody (atypical pANCA, also termed peripheral anti-nuclear neutrophil antibodies (pANNA)) positivity is present in 74% of children with ASC but only 45% of those with AIH-1 and 11% of those with AIH-2.10 Clinical, laboratory and histological features of AIH-1, AIH-2 and ASC are compared in table 1.
In the prospective study, AIH evolved to ASC in one patient, suggesting that these conditions are likely to be part of the same nosological spectrum.10
Though ‘small duct disease’ is reported rarely in paediatric series, in a recent study,14 where cholangiography was mainly performed by magnetic resonance (MRCP), no radiological biliary involvement was detected despite histological evidence of sclerosing cholangitis in a high proportion (36%) of patients, some of whom had autoimmune features. Whether this finding is due to a lower sensitivity of the MRCP compared to retrograde cholangiopancreatography in detecting biliary changes remains to be verified.
Possession of the human leukocyte antigen (HLA) DRB1*03 is associated with AIH-1 in paediatric patients in northern Europe.4 ,18 ,19 By contrast with adult patients, possession of DRB1*04 does not predispose to AIH in childhood, and can even exert a protective role.4 AIH-2 is associated with possession of DRB1*07 or DRB1*03.20 In South America, possession of the HLA DRB1*1301 allele, which predisposes to paediatric AIH-1 in that geographical area, is also associated with persistent infection with the endemic hepatitis A virus.21 ,22
Paediatric patients with AIH, whether anti-LKM1-positive or ANA/SMA-positive, have genetically determined isolated partial deficiency of the HLA class III complement component C4.23
AIH-2 can be associated with APECED, an autosomal-recessive monogenic disorder in which liver disease is present in some 20% of cases.8
In the UK, susceptibility to ASC is conferred by the possession of the HLA DRB1*1301 allele.24
A diagnostic scoring system has been developed by the International Autoimmune Hepatitis Group (IAIHG), based on positive and negative criteria, the latter including infection with hepatitis B or C virus, Wilson disease and alcohol consumption.25 ,26 Liver biopsy is necessary to establish diagnosis and assess the extent of liver damage. The typical histological picture is interface hepatitis, characterised by a dense mononuclear and plasma-cell infiltration of the portal areas, expanding into the liver lobule and damaging the hepatocytes at the periphery of the lobule with erosion of the limiting plate (figure 1). In addition to this typical histological pattern, other positive criteria include elevated serum transaminase and IgG levels, and the presence of ANA, SMA anti-LKM-1, anti-LC-1 and/or anti-SLA.
The IAIHG scoring system is complex and was originally devised for research purposes. A simplified IAIHG scoring system, suitable for clinical application, is based on autoantibody seropositivity, elevated IgG, interface hepatitis and exclusion of viral hepatitis.27 Neither scoring system is, however, suited to juvenile AIH, where diagnostically relevant autoantibodies have titres lower than the cut-off value considered positive in adults. Thus, as healthy adults may show reactivity on rodent tissue substrate by immunofluorescence at the conventional starting serum dilution of 1/10, the arbitrary dilution of 1/40 is considered clinically significant by the IAIHG. By contrast, healthy children are rarely autoantibody positive, therefore, titres of 1/20 for ANA and SMA and 1/10 for anti-LKM-1 and anti-LC-1 are clinically relevant. The laboratory should report any level of positivity ≥1/10 in children, and the attending physician should interpret the result within the clinical context.7
Neither the original nor the simplified IAIHG systems distinguish between AIH and ASC, which can only be differentiated if a cholangiogram is performed at presentation. Criteria for the diagnosis of childhood autoimmune liver disease are shown in the box.
Criteria for the diagnosis of autoimmune liver disease in childhood
Positivity for circulating autoantibodies
ANA and/or SMA (titre ≥1:20)=AIH-1 or ASC
Anti-LKM-1 (titre ≥1:10)=AIH-2
Elevated immunoglobulin G (in 80% of cases)
Exclusion of viral hepatitis
Exlusion of Wilson disease
Exclusion of non-alcholic steatohepatitis
Normal=AIH or ‘small duct disease’
AIH, autoimmune hepatitis; ASC, autoimmune sclerosing cholangitis; ANA, antinuclear antibodies; SMA, antismooth muscle antibodies; anti-LKM-1, antiliver kidney microsomal type 1 antibody; anti-LC-1, antiliver cytosol type antibody.
Remission is defined as clinical recovery, return to normal of transaminase and IgG levels, negative or low autoantibody titre by immunofluorescence (≤1:20 for ANA and SMA; ≤1:10 for anti-LKM-1) and histological resolution of inflammation.28 Clinical and biochemical remission does not equate histological resolution, the histological response lagging behind the biochemical response.29 An improvement of portal inflammation is observed in up to 95% of AIH cases after ∼4 years of treatment and is accompanied by improved fibrosis scores.29 Relapse during treatment (ie, increased serum aminotransferase levels after remission has been achieved) is common, affecting about 40% of patients and requiring a temporary increase in immunosuppression.4 An important contributor to relapse is non-adherence, particularly in adolescents.30 In more aggressive cases, the risk of relapse is higher if steroids are administered on an alternate-day schedule, which is often instituted with the aim to reduce negative effects on the child's growth. In fact, small daily doses are more efficient in maintaining disease control while minimising the need for high-dose steroid pulses during relapse (with consequent more severe side effects) and do not affect final height.31
AIH and ASC respond well to immunosuppression, and treatment should be initiated promptly to avoid progression of disease. The goal of treatment is to improve symptoms, induce remission, reduce or eliminate liver inflammation, and prolong survival.28 The rapidity and degree of the response depends on disease severity at presentation. In AIH, though cirrhosis is reported in 40–80% of children at diagnosis, progression to end-stage liver disease requiring liver transplantation is rare, most children remaining clinically stable, with a good quality of life on long-term treatment.4 ,32 With the exception of a fulminant presentation with encephalopathy, where liver transplant is usually required, AIH and ASC respond satisfactorily to immunosuppressive treatment whatever the degree of liver impairment, with a reported remission rate >80%.28 However, the long-term prognosis is worse in ASC, where bile duct disease progresses despite treatment in 50% of cases.10
The conventional treatment of childhood AIH consists of prednisolone (or prednisone) at 2 mg/kg/day (maximum 60 mg/day), gradually decreased over 4–8 weeks, in parallel with the declining transaminase levels, towards a maintenance dose of 2.5–5 mg/day, depending on age and weight.28 ,33 Within the initial 2 months of treatment, an 80% decrease in transaminase levels is commonly achieved, but complete normalisation can take several months.4 During the first 6–8 weeks of treatment, liver function tests should be performed weekly to allow dose adjustments that avoid severe steroid side effects.28 At our centre, azathioprine is added as a steroid sparing agent when the transaminase levels stop decreasing on prednisolone alone or, rarely, in the presence of serious steroid side effects (eg, psychosis). Azathioprine is used at a starting dose of 0.5 mg/kg/day, which in the absence of signs of toxicity is increased up to a maximum of 2.0–2.5 mg/kg/day until biochemical control of the disease is achieved. Centres differ in terms of the time at which azathioprine is used; in some it is added in all cases at a dose of 0.5–2 mg/kg/day after a few weeks of steroid treatment, and in others a combination of steroids and azathioprine is used from the outset. However, caution is recommended, particularly in patients with severe jaundice, given the hepatotoxic properties of azathioprine. Regardless of the initial choice of treatment protocol, 80% of patients eventually require the addition of azathioprine.28 Another possible side effect of this drug is a dose-related, generally reversible, depression of bone marrow function, most frequently expressed as leukopoenia, but sometimes as anaemia and thrombocytopoenia and rarely as agranulocytosis, pancytopoenia and aplastic anaemia. These complications occur particularly in patients predisposed to myelotoxicity, such as those with thiopurine methyltranferase (TPMT) deficiency and renal or hepatic insufficiency. Measurement of the TPMT activity level has been advocated to predict azathioprine metabolism and toxicity before the initiation of azathioprine therapy,34 although only patients with near-zero erythrocyte concentrations of TPMT activity are at risk of myelosuppression during azathioprine treatment.34 ,35 Thus, determination of the enzyme activity is warranted only when there is pretreatment or intratreatment cytopoenia, or the need for particularly high doses of azathioprine.35 Maintenance with azathioprine monotherapy has been advocated once remission is achieved,36 but whether this is effective long-term and weather it offers any benefit on possible side effects compared with low dose prednisolone/azathioprine maintenance is unclear.
Cyclosporine-A has been used in naive patients, mainly with AIH-1, alone for 6 months, followed by the addition of prednisone and azathioprine; cyclosporine was discontinued 1 month later, and children were maintained on prednisone and azathioprine.37 Using this approach, however, the 1-year remission rate is worse than with standard treatment. Whether this protocol has any advantage over standard treatment should be investigated in controlled studies.
Budesonide has been compared to prednisone, both in combination with azathioprine, in a large European controlled trial in naive or relapsing adult and paediatric AIH patients.38 Budesonide is an attractive alternative to predniso(lo)ne, as it has a hepatic first-pass clearance of >90% of oral dose and fewer side effects, although it cannot be used in cirrhotic patients, who represent a large proportion of AIH cases. However, the results within the paediatric cohort of this study are disappointing, with similarly low remission rates in the budesonide/azthioprine and prednisone/azathioprine arms (15.8% and 14.8% after 6 months of treatment and 50% and 41.7% after 12 months of treatment, respectively).39 The poor response rate to prednisolone/azathioprine in this study compared with that observed with standard treatment (80–90%) is likely to depend on the low fixed initial dose of prednisone, decreased by protocol and not according to response, used in the trial.40 Despite this, budesonide could be a valid alternative in selected non-cirrhotic patients at risk of adverse steroid side effects.
Treatment of refractory cases
Mycophenolate mofetil (MMF) is a purine antagonist that selectively inhibits proliferation of activated lymphocytes but is not dependent on TPMT activity.41 Side effects include headache, diarrhoea, nausea, dizziness, hair loss and neutropoenia.28 MMF has been successfully used in association with predniso(lo)ne in those children (up to 10%) resistant to standard immunosuppression or intolerant to azathioprine.42
Calcineurin inhibitors, cyclosporine and tacrolimus, have been used as a rescue treatment for difficult-to-treat cases of AIH. As large studies in this subgroup of patients are lacking, they should be used with caution.28
Autoimmune sclerosing cholangitis
ASC responds to the same immunosuppressive treatment used for AIH when treatment is initiated early. Abnormal liver function tests generally resolve within a few months of treatment, although medium-term to long-term prognosis is worse than that of AIH because bile duct disease continues to progress despite treatment in ∼50% of patients.10 Ursodeoxycholic acid at a dose of 15–20 mg/kg/day is usually added to the conventional AIH treatment regimen in ASC, but whether this actually helps arrest the progression of bile duct disease remains to be established. ASC is commonly associated with IBD which should be investigated even in the absence of symptoms and appropriately treated, as progression of bile duct disease is associated with persistent intestinal inflammatory damage. Flares up of liver disease often follow exacerbations of intestinal manifestations.10
Duration of treatment and prognosis
The optimal duration of immunosuppressive treatment for AIH is unknown, but treatment withdrawal is successful only in the presence of histological resolution of inflammation. Hence, cessation of treatment can be considered when there is no inflammatory activity on liver biopsy after 1–2 years of normal liver function tests, normal IgG levels and negative or low titre autoantibodies. In our centre, treatment withdrawal is never considered within 3 years of diagnosis or during/immediately before puberty, when relapses are more common. In AIH-1, but not AIH-2, some 20% of juvenile patients can successfully and permanently stop treatment.4 Long-term treatment, therefore, is required for the majority, and patients/parents should be counselled accordingly. Response to treatment of AIH and ASC patients can be monitored by assessing IgG levels and autoantibody titres, the fluctuation of which correlates with disease activity.43
For children with AIH who respond to immunosuppressive treatment, prognosis is good, with the majority surviving long term with an excellent quality of life on low-dose medication. However, progression to end-stage liver disease requiring liver transplantation, despite treatment, has been reported 8–14 years after diagnosis in 8.5%.4 The medium-term to long-term prognosis of children with ASC is worse because of the progression of bile duct damage in 50% of cases.10 ,44
Approximately 10% of children with AIH and 20% of those with ASC require liver transplantation. Liver transplantation is indicated in patients who present with fulminant hepatic failure (with encephalopathy) and in those who develop end-stage liver disease despite treatment. After transplantation, recurrent AIH has been described in ∼20% of cases45 and recurrent ASC in ∼70%.44 ,45 Diagnosis of recurrence is based on biochemical abnormalities, seropositivity for autoantibodies, interface hepatitis on histology, steroid dependence and, for ASC, the presence of cholangiopathy. Recurrence of ASC after transplant is more common in the presence of active IBD. Recurrence may even appear years after transplantation, therefore, steroid-based immunosuppression should be maintained at a higher dose than that used for patients transplanted for non-AILD.45
In the late 1990s, it was observed that AIH can arise de novo after liver transplantation in children who had not been transplanted for autoimmune liver disease. Characteristic of this condition is a histological picture of interface hepatitis and multilobular collapse associated with increased IgG levels and positive autoantibodies. These include ANA, SMA and classical anti-LKM-1, but also atypical anti-LKM-1, staining the renal tubules but not the liver. After the original report,46 de novo AIH following liver transplant has been confirmed by several studies in adult and paediatric patients,47–49 and has been reported to be more frequent in steroid-free antirejection regimens.50 ,51 Importantly, treatment with prednisolone and azathioprine using the same schedule for classical AIH, concomitant with reduction of the calcineurin inhibitor dose, is highly effective in de novo AIH, leading to excellent graft and patient survival. It is of interest that these patients do not respond satisfactorily to the standard antirejection treatment schedule, making it essential to reach an early diagnosis to avoid graft loss. Rapamycin has been reported to be effective in difficult-to-treat patients.52 Whether the liver damage observed in these patients is a form of rejection or the consequence of an autoimmune injury possibly triggered by drugs or viral infection, remains to be established. There are several non-mutually exclusive explanations as to why autoimmunity and AIH may arise de novo in patients transplanted for non-autoimmune conditions. Besides autoantigen release from the damaged tissue, molecular mimicry might be involved, where immune responses to external pathogens become directed towards structurally similar self-components.53 Moreover, calcineurin inhibitors may interfere with the maturation of T-cells and/or with the function of regulatory T-cells (T-regs), with consequent emergence and activation of auto-aggressive T-cell clones.54–58
Over the past two decades, the incidence of juvenile AILD has markedly increased. Whether this is due to a real increase in the number of cases or is due to better awareness of the disease is unclear. It is important to consider AILD in the differential diagnosis of any increase in liver enzyme levels. When more common causes of liver disease are excluded, early referral to specialised centres is warranted, as with prompt immunosuppressive treatment, the prognosis for patients with AIH is excellent, with symptom-free long-term survival in the majority. The prognosis of ASC is worse, with a higher requirement for transplantation in the medium term, and a greater risk of disease recurrence after grafting. The immunosuppressive regimens currently available for AILD are non-specific and may have unpleasant side effects. Parents and patients should be counselled that treatment is long term, and that adherence to therapy is essential to maintain remission, avoiding progression of liver damage during relapse episodes. Tasks for the future include devising novel treatments aimed at arresting, specifically, liver autoaggression or, ideally, at reinstating tolerance.59
Contributors GMV and DV have equally contributed in writing this review.
Competing interests None.
Provenance and peer review Commissioned; externally peer reviewed.