Rheumatology Advance Access published online on May 8, 2007
Rheumatology, doi:10.1093/rheumatology/kem108
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A comparison of autoimmune liver disease in juvenile and adult populations with systemic lupus erythematosus—a retrospective review of cases
Centre for Rheumatology, University College London Hospitals, 250 Euston Road, 3rd Floor Central Wing, London NW1 2PG, 1Great Ormond Street Hospital, Great Ormond Street, London WC1N 3JH and 2Whipps Cross University Hospital, Whipps Cross Road, Leytonstone, London E11 1NR, UK.
Correspondence to:
Prof. DA Isenberg, Centre for Rheumatology, University College London Hospitals, 250 Euston Rd, 3rd floor Central Wing, London NW1 2PG, UK. Email: d.isenberg{at}ucl.ac.uk
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Abstract |
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Objective. To compare the prevalence and type of autoimmune liver disease in adult and juvenile patients with systemic lupus erythematosus (SLE) in a large UK cohort.
Methods. A retrospective analysis was performed of patients attending the adult and juvenile lupus clinics at University College Hospital and Great Ormond Street Hospital, respectively, between January 1978 and December 2004. Patients with autoimmune liver disease were identified by searching an existing database (adults) and by case note review (juveniles). Histological diagnosis and autoantibody profile was noted and the time that had elapsed in months between the two diagnoses calculated.
Results. Of 377 adult patients and 92 juvenile patients, 5 and 9 respectively, had histologically confirmed autoimmune liver disease. This corresponds to a statistically significant (P < 0.001) greater prevalence in juvenile onset patients of 9.8% compared with 1.3% in adult patients. The juvenile patients were all positive for smooth muscle antibody and had histological changes consistent with autoimmune hepatitis. The adult patients had a variable antibody profile and one patient had histological changes consistent with primary biliary cirrhosis. In all of the juvenile patients, but notably in none of the adult patients, the liver disease predated the diagnosis of SLE (P < 0.001).
Conclusions. Our study confirms that autoimmune liver disease occurs infrequently in adult lupus patients but should be considered in a patient with persistent liver enzyme abnormalities. However, in our study there is a significantly higher prevalence in juvenile lupus patients. This association is previously unreported.
KEY WORDS: Systemic lupus erythematosus, Juvenile, Autoimmune hepatitis, Liver disease
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Introduction |
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Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disease associated with the production of autoantibodies. Although it has the potential to affect any organ, clinically significant hepatic involvement is considered to be uncommon in SLE and liver dysfunction is not included in the 1982 ARA revised diagnostic criteria [1, 2].
Hepatic disease is well recognized in lupus however [3]. A review of 238 patients in 1980 found 21% of patients fulfilled criteria for a diagnosis of liver disease and in 20% of these there was no cause attributable other than SLE [4]. Histological examination in lupus hepatitis usually reveals non-specific changes although autoimmune liver disease may be found rarely [5]. Interestingly, a recent retrospective review of 200 patients found only a 2.5% prevalence of abnormal liver enzyme tests [6] and this may be a reflection of effective disease control.
Of the SLE cases, 15–20% have onset in childhood or adolescence. Some differences in disease manifestation and course between adult and juvenile cohorts have emerged [7]. There is a higher male : female ratio, estimated at around 1 : 4.5 and the disease is more severe at onset in paediatric patients with higher rates of renal and neuropsychiatric disease. Renal disease is present in 61% of patients [8] and presentation is often atypical for example with abdominal pain (32%) which may result in further investigation by laparotomy [9]. There are higher rates of antibody expression. For example, antibodies to ribosomal P proteins which have been implicated in renal and neuropsychiatric disease occur in 16% of adult patients with SLE and 42% of patients with juvenile onset SLE [10]. These antibodies have also been associated with autoimmune hepatitis in a patient with lupus [11].
Most studies of the liver in lupus have been of adult patients with SLE and little is known about liver disease in juvenile patients although mild transient liver enzyme abnormalities are noted in up to 25% [8]. We work in a unique environment in the UK providing a clinical service to patients with lupus across all age ranges in an age appropriate fashion. We examined the cohorts to establish the prevalence and type of autoimmune liver disease and to identify any differences in clinical pattern between the adult and juvenile populations. We now report a striking difference in both the prevalence of autoimmune liver disease and in the sequence of when these conditions develop.
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Methods |
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The UCH adult cohort was established in 1978 and patients have been followed up regularly in the UCH/Middlesex specialist lupus clinic (average is 2–3 monthly). At this assessment as well as completing a BILAG form, the FBC, U&E, LFT, C3 and dsDNA antibody levels are measured. Patients with persistent liver enzyme abnormalities were referred to the department of hepatology for further evaluation including liver biopsy. A total of 401 adult patients have been under long-term review but in 24 cases the disease was diagnosed prior to the age of 16, the cut off we took to distinguish adult and paediatric onset. Patients in the juvenile cohort have been followed up since 1998. The BILAG system has been used to monitor disease activity since the mid-1980s.
This study focuses on all lupus patients followed up at University College London Hospital and at Great Ormond Street Hospital until December 2004. All patients satisfied the revised 1997 ACR criteria for a diagnosis of SLE.
A retrospective case note review was performed in the juvenile cohort (n = 74) at Great Ormond Street plus 18 from the adult cohort whose disease was diagnosed before age 16 and who were not already included in the juvenile cohort. An existing database of 377 adult patients was searched to identify those with autoimmune liver disease (AILD).
Antibody testing for antinuclear antibody (ANA) was performed by direct immunofluorescence using rat liver cells (a titre of 1:80 or above was considered positive). Anti-ENA and dsDNA antibodies and liver antibodies were tested using commercial ELISA kits (Shield Diagnostics, Dundee) following manufacturer's instructions.
The sequence of development of the diseases, the precise histological type of liver involvement and the number of months elapsing between the diagnoses of SLE and that of autoimmune hepatitis (AIH) was noted.
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Results |
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The results are summarized in Table 1.
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Of the 377 adult patients, 5 and of the 92 juvenile patients 9 had histologically confirmed AILD. This is equivalent to 1.3% prevalence in the adult population and 9.8% in the juvenile population and is a statistically significant difference (P < 0.001 Chi-square test).
All the juvenile patients had histological changes consistent with autoimmune hepatitis and were positive for smooth muscle antibody as well as ANA. The antibody profile in the adult patients was variable with two patients positive for anti-mitochondrial antibody and one patient had histologically confirmed primary biliary cirrhosis. All patients with liver disease were positive for ANA (adult cohort prevalence 96%). All five adult but only five of the nine juvenile patients were positive for dsDNA antibody (adult cohort prevalence 61%).
The five adult patients developed liver disease an average of 60 months after presenting with SLE (range 1–145 months). In contrast, in all nine juvenile patients the liver disease preceded the onset of SLE which developed an average of 22 months later (range 1–56 months) (P < 0.001 Fisher's exact test).
Review of the patients with liver disease with respect to activity in other organs or systems or the rate of acquisition of damage failed to demonstrate any major differences between these patients and those without AILD.
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Discussion |
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Our major findings in this study are the significantly higher prevalence of AILD in juvenile lupus patients compared with adult patients and the demonstration that the liver disease preceded the diagnosis of SLE in all the juvenile patients and none of the adult patients.
AILDs such as autoimmune hepatitis, primary biliary cirrhosis and primary sclerosing cholangitis are found uncommonly in patients with SLE. AIH was first described in the 1950s and has been known by a variety of terms including chronic active hepatitis, plasma cell hepatitis and lupoid hepatitis. The term ‘lupoid hepatitis’ arose in view of clinical and immunological similarities with SLE [12] but histological examination of the liver revealed specific changes only in patients with ‘lupoid hepatitis’ confirming that these were two distinct diseases [13]. More recently AIH has been subclassified according to antibody profile [14]. Type 1 AIH (classical or lupoid hepatitis) is characterized by positive ANA and anti-smooth muscle antibody (SMA) and a marked hypergammaglobulinaemia. Associated multisystem features seen in Type 1 AIH include facial rash, arthralgia, haematological disorder such as thrombocytopenia or haemolytic anaemia, fibrosing alveolitis and renal tubular acidosis. However, the classical renal disease and cerebral involvement seen in SLE does not occur in Type 1 AIH. Type 2 AIH is associated with anti-liver kidney microsome (LKM) antibodies and/or anti-liver cytosol antigens and appears to be more ‘organ-specific’. The diagnostic criteria for AIH have been revised several times and the most recent 1999 International Autoimmune Hepatitis Group Criteria [15] requires histological features of interface hepatitis, presence of autoantibodies and hypergammaglobulinaemia and exclusion of other causes of hepatitis.
Both Type 1 AIH and SLE are associated with antibodies to nuclear antigens and multisystem disease manifestations which may indicate shared pathogenetic processes [16]. However, the presence of disease associated antibodies may help delineate the underlying pathology. ANA is found in 70% of cases of Type 1 autoimmune hepatitis and 98% of SLE cases but SMA which is a sensitive marker for AIH occurs rarely in SLE and when present is suggestive of liver disease. Other antibodies such as anti-actin antibody and soluble liver antigen are more specific for AIH but less sensitive and in practice they are not usually assayed. Atypical perinuclear anti-neutrophil cytoplasmic antibodies (pANCA) are commonly found in Type 1 AIH but not SLE and may indicate AILD if present. Antibodies to dsDNA detected by the highly specific Crithidia luciliae assay have been found in 23% of patients with Type 1 AIH [17] challenging the view that this antibody is specific for SLE and potentially adding to the confusion in diagnosis. Therefore, in a patient with SLE and transaminitis obtaining histology is crucial in distinguishing AIH from lupus associated hepatitis [18].
In all but one of our patients with AILD the diagnosis was AIH. In Runyon's review of liver disease in lupus patients [4] AIH was confirmed in four cases (1.7%) which is a similar prevalence to our study. In a small number of adults therefore the two diseases co-exist. In our adult cohort all patients developed AILD subsequent to being diagnosed with SLE. However, in a report of five cases with diagnoses of AIH and SLE, two presented with AIH first and one presented with features of both diseases [19] and our findings therefore in this respect could theoretically be due to chance alone.
Previous studies of the liver in lupus have focused on adult-onset cases and little is known about the liver in juvenile SLE. Our study indicates a much higher prevalence of AILD in juvenile SLE patients compared with adults. The finding that the liver disease preceded the diagnosis of SLE suggests that children with AIH are at risk of developing SLE. However, in a review of 52 children with AIH over 20 yrs, 20% were found to have associated autoimmune diseases at presentation or following diagnosis of AIH but no child was reported to have developed SLE [20]. Although a patient with AIH and multisystem features may fulfil criteria for a diagnosis of SLE, our patients presented some time after the initial diagnosis of AIH with new clinical features consistent with a second diagnosis of SLE; therefore, this explanation for our data seems unlikely. The awareness of SLE in the paediatric community has greatly increased in the last decade as have links between paediatric rheumatology and hepatology units and this may explain our observations to some extent. It appears from our results however that juvenile patients with AIH do have a significant risk of developing SLE and the reason for this is unclear. It is our experience that in children the phenomenon of an autoimmune rheumatic disease ‘evolving’ into another is more commonly observed than in the adult population indicating that there may be differences in immune regulation between children and adults. In a patient with AILD who has genetic susceptibility for development of lupus it could be postulated that excessive antigen overload from hepatocyte damage may result in further immune system stimulation and dysregulation leading to the development of SLE. This may be more likely to occur in a child with an immature immune system.
In conclusion therefore, this study has highlighted an important and previously unreported difference between adult and juvenile patients with SLE and suggests an increased risk in juvenile patients with AIH of developing SLE. This may be secondary to a shared immunopathogenetic mechanism.
The authors have declared no conflicts of interest.
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