Features of Autoimmune Hepatitis in Egyptian Children

Transcription

1 Med. J. Cairo Univ., Vol. 78, No. 1, March: , Features of Autoimmune Hepatitis in Egyptian Children NEHAL EL-KOOFY, M.D.; MONA FAHMY, M.D.*; MONA AZIZ, M.D.**; AHMAD EL-HENNAWY, M.D.*** and HANAA EL-KARAKSY, M.D. The Departments of Pediatrics*, Clinical Pathology** and Pathology***, Faculty of Medicine, Cairo University and the Department of Pediatrics, Research Institute of Ophthalmology, Egypt. Abstract Background and Aim: Autoimmune hepatitis (AIH) is a progressive inflammatory liver disorder mainly affecting female and its diagnosis is based on a series of positive and negative criteria. The aim of this study is to define the clinical, biochemical features and the response to immunosuppression in children with AIH and also to compare the performance of the International Autoimmune Hepatitis Group (IAIHG) revised original scoring system and the simplified scoring system. Patients and Methods: Data of 30 children (22 female and 8 male) with AIH have been analyzed for their clinical, serological, histological profile and their response to treatment. We also re-analyzed their clinical features using the IAIHG revised original scoring system and the simplified scoring system. Results: The median age at diagnosis was 8 years (range, 3-12 years). Clinical features at presentation included jaundice (90%), hepatomegaly (80%), splenomegaly (43%), pallor (10%), lower limb edema (6.6%) and ascites (3%). Acute hepatic like illness was the first presentation in (66.7%). Initial laboratory investigation revealed high serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and serum immunoglobulin G (IgG) in all patients. Antinuclear antibodies (ANAs), anti-smooth muscle antibody (SMA), anti-soluble liver antigen (SLA), and perinuclear antineutrophil cytoplasmic antibodies (pncan) were positive in 36.7%, 86.7%, 16.6%, 30% patients respectively. No patient was seropositive for anti-liver kidney microsome antibody (anti- LKM). Liver biopsy was performed in 26 patients. Interface hepatitis was present in 77% patients, rosette formation in 34.6%, biliary changes in 69%, and lymphoblastic infiltrates in all patients. Cirrhosis was present in 30.8% patients and fibrosis in 96% patients. All patients received steroids as the initial therapy and in 22 of them azathioprine was added to start steroid withdrawal. Complete response to treatment was observed in 33.3% patients; partial response in 10%, and 56.7% had relapses. The sensitivity of original revised scoring system was 100% versus 88.5% for the simplified scoring system for diagnosis AIH among our patients. Concordance between the original revised and the simplified scores for a probable or definite diagnosis of AIH was 38.5% and 19.2%, respectively. Correspondence to: Dr. Ahmad Y. Rezk, Nehal El-Koofy, Pediatr. Dept., Fac. of Medicine, Cairo Univ., Cairo, Egypt. Conclusion: Survival in AIH apparently good with early diagnosis and treatment. The revised original score system performed better among our patients than the simplified score system. Key Words: Children Autoimmune hepatitis Autoantibodies IAIHG score system. Introduction AUTOIMMUNE hepatitis (AIH) is a progressive inflammatory liver disorder mainly affecting females. It is characterized serologically by high levels of transaminases and immunoglobulin (Ig) G, and the presence of autoantibodies; and characterized histologically by interface hepatitis, in the absence of a known etiology [1]. Two types of AIH are recognized: AIH type 1, which also affects adults, is characterized by the presence of smooth muscle antibody (SMA) and/or antinuclear antibodies (ANAs); AIH type 2, which is mainly a pediatric condition, is positive for antibodies to liver-kidney microsome type 1 (anti-lkm) [2] and/ or anti-liver cytosol type 1 (anti-lc 1) [3]. Percutaneous liver biopsy should be performed for grading and staging, as well as for therapeutic monitoring. Interface hepatitis, lymphocytic/lymphoplasmocytic infiltrates in portal tracts and extending into the lobule, emperipolesis (active penetration by one cell into and through a larger cell), and hepatic rosette formation were regarded as typical for the diagnosis of AIH [4]. AIH is a remarkably well treatable chronic liver disease [5]. It is exquisitely responsive to immunosuppression. The rapidity and degree of response depends on the disease severity at presentation. All types of presentation apart from fulminate hepatic failure with encephalopathy, respond to stander treatment with prednisolone with or without azathioprine [6]. 107

2 108 Features of Autoimmune Hepatitis in Egyptian Children Two sets of diagnostic criteria have been developed to help standardize the diagnosis of AIH. The earliest criteria were developed by the International Autoimmune Hepatitis Group (IAIHG) in 1993 [7] and revived to 15 parameters in 1999 [8]. Though these criteria have been produced mainly for research purposes, they have been validated also in clinical practice. They provided clinical guidelines for the definite and probable diagnosis of AIH and a scoring system that allowed assessment of the strength of the diagnosis. The revised original scoring system could be applied before or after corticosteroid treatment [8]. Because these criteria are complex, the IAIHG developed a simplified scoring system based on four components and twelve possible grades. The included parameters were represented by autoantibody titer, IgG levels, liver histology, and exclusion of viral hepatitis. The authors reached 88% sensitivity and 97% specificity with score ^!6 and 8 1 % sensitivity and 99% specificity with a score ^!7 [9]. The aim of our study is to define the clinical, biochemical features and the response to immunosuppression in children with AIH presenting to the Pediatric Hepatology Unit, Cairo University; between 2000 and We also compared the performance of the revised original scoring system and the simplified scoring system. Patients and Methods We retrospectively reviewed the records of 30 AIH children presenting to the Pediatric Hepatology Unit, Cairo University Children s Hospital, between 2000 and The diagnosis of AIH was made by clinical, immunological, and histological examination. All the patients had the following: A- Clinical examination. B- Laboratory tests: 1- Liver function tests [aspartate aminotransferase (AST), alanine aminotransferase (ALT), Alkaline phosphatase, total bilirubin, serum protein, serum albumin, prothrombin time (PT)]. 2- Serum immunoglobulins concenterations (IgG, IgM, IgA). 3- Quantitative and qualitative determination of ANA, SMA, AMA and anti-lkm. Additional two antibodies were performed in order to apply it to IAIHG revised original criteria: Anti-soluble liver antigen (SLA). Antineutrophil cytoplasmic antibodies (ANCAs): These antibodies could give either a cytoplasmic (canca) or a perinuclear (panca). These two antibodies were performed for 16 patients before treatment and 14 patients on immunosuppressive therapy. C- Abdominal ultrasonography. D- Liver biopsy. Tests for ANA, SMA, AMA and anti-lkm, were done using immunofluorescence assay (Bio- Rad KallestadTM Rat Liver/Kidney/Stomach Slides, Catalog No /29001). Tests for ANCA were done using immunofluoresence assay (Bio-Rad Complete ANCA Kit, Catalog No ). Tests for SLA were done using ELISA (Quanta Lite TM SLA). To exclude other cause of liver diseases, all the patients had the following: 1- Hepatitis B surface antigen (HBsAg), hepatitis B core amtibody (HBcAb). 2- Hepatitis C antibody (HCVAb) (if antibody tested positive we further confirmed by HCV- RNA). 3- In patients with acute hepatitis like, hepatitis A IgM was done. 4- Work up for Wilson s disease (serum ceruloplasmin, 24 hour urinary copper before and after penicillamine, Keyser-Fleischer rings). 5- Alpha- 1 -antitrypsin. Liver biopsy was performed for 26 out of 30 patients (because of coagulopathy). All patients were initially treated with prednisone (1 to 2mg/kg/day; maximum 60mg/day). This was gradually tapered by 5mg every 1-2 weeks depending upon the clinical symptoms and AST and ALT activity. Azathioprine (1 to 2mg/kg/day; maximum 100 mg/day) was administered with prednisone if an increase in AST or ALT level was observed on tapered dose or the amount of steroid had to be reduced because of significant side effects. Remission was defined as the absence of clinical symptoms and a normal AST and ALT on a minimum of two occasions at least a month apart, a relapse as an at least two-fold increase in AST or ALT with or without recurrence of symptoms. We applying retrospectively the IAIHG revised original scoring system in 1999 [8] and also the

3 Nehal El-Koofy, et al. 109 simplified scoring system [9] to our patients. According to revised original system, scores of before institution of therapy define "probable" and >15 indicate definite AIH, and when outcome of treatment is included, the corresponding values are and >17 respectively. In the simplified system, a score of 6 (8 being maximum) equates to probable "AIH" whereas a score of 7 or above denotes "definite AIH". Statistical analysis was performed using the SPSS program version 11 (SPSS Inc, Chicago, IL). The nonparametric Mann-Whitney U test was used for data that are not normally distributed. p<0.05 was considered statistically significant. Results were expressed as medians and ranges. Results The clinical features at presentation are summarized in Table (1). Among 30 patients, 22 (73.3%) were female and 8 (26.7%) were male. Age at diagnosis range from 3 to 12 years (median 8 years). Age was not significantly differed between male and female (8 ±3.4 vs 7.5 ±2.5 years, p>0.05). The most frequent symptom and sign was jaundice. Eight patients had concurrent autoimmune diseases (6 female): three patients had systemic lupus erythematosus, two patients had celiac, and one patient each had inflammatory bowel disease, insulin dependent diabetes mellitus, and idiopathic thrombocytopenic purpura. Table (1): Clinical features at presentation in 30 patients with AIH. Variable Number of patients 30 Age (year) median (range) 8 (3-12) Female n (%) 22 (73.3) Symptoms n (%): Jaundice 27 (90) Bleeding 18 (60) Abdominal distension 17 (56.6) Fever 11 (36.6) Anorexia 8 (26.6) Fatigue 7 (23.3) Weight loss 5 (16.6) Examination n (%): Jaundice 27 (90) Pallor Hepatomegaly 3 (10) 24 (80) Splenomegaly Lower limb edema 13 (43.3) 2 (6.6) Ascites 1 (3.3) Associated autoimmune disorders n (%): Systemic lupus erythematosus 3 (10) Celiac disease 2 (6.6) Insulin dependent diabetes 1 (3.3) Inflammatory bowel disease 1 (3.3) Idiopathic thrombocytopenic purpura 1 (3.3) Autoimmune disorders in first degree relatives n (%): AIH 1 (3.3) Vitiligo 1 (3.3) At the time of presentation all the patients had increased levels of ALT ( folds), AST ( folds), and IgG ( folds) above upper limits of normal. Serum IgM and IgA levels had increased in 7 (23.3%) and 14 (46.6%) patients respectively. Serum alkaline phosphatase and GGT levels were normal in 7 (23.3%) and 9 (30%) respectively. Liver function tests and immunoglobulins were not significantly differed between male and female (Table 2). Table (2): Comparison of laboratory variables between male and female. Variable Total bilirubin (mg/di) Male N = 8 Median (range) Female N = 22 Median (range) p value 4.95 ( ) 3 ( ) NS AST (IU/L) 445 ( ) 431 ( ) NS ALT (IU/L) 187 ( ) 220 ( ) NS GGT (IU/L) 71 (37-428) 112 (33-416) NS AP (IU/L) 396 ( ) 693 ( ) NS Total protein (g/di) 7.3 ( ) 7.25 ( ) NS Albumin (g/di) 3.2 ( ) 3.35 ( ) NS PC (%) 70 (70-75) 60 (26-100) NS IgG (mg/di) 3084 ( ) 3043 ( ) NS IgM (mg/di) 104 (92-428) 183 (85-423) NS IgA (mg/di) ( ) (21-464) NS NS: non-significant All patients were negative for HBsAg, and HBcAb. Two patients were positive for anti-hcv antibody but negative for HCV-RNA by PCR. HAV IgM was done for 20 patients presenting with acute hepatic illness, it was negative in all of them. At presentation, 11 (36.7%) patients were positive for ANA, 26 (86.7%) for SMA, 5 (16.6%) for SLA and 9 (30%) for panca. Nine patients were positive for both ANA and SMA; two for ANA alone and 17 positive for SMA alone. ANA titer range from 1:40 to 1:320 (median 1:40) and the median SMA titer was 1:80 (range 1:40-1:2560). One patient was negative for all autoantibodies except panca. None of our patients were positive for anti-lkm. Table (3) illustrates the prevalence of autoantibodies among male and female.

4 110 Features of Autoimmune Hepatitis in Egyptian Children Table (3): Prevalence of autoantibodies among female and male AIH patients. Variables Criteria Female N=22 Definite diagnosis AIH Probable diagnosis AIH Male N=8 ANA 11 (36.7) 0 (0) SMA 19 (86.4) 6 (75) anti-lkm 0 (0) 0 (0) SLA 5 (22.7) 0 (0) panca 6 (27.3) 3 (37.5) Liver biopsies were performed in 26 patients. Interface hepatitis was present in 20 (77%) patients, rosette formation in nine (34.6%), biliary changes in 18 (69%), lymphoblastic infiltrates in all patients. Cirrhosis was present in 8 (30.8%) and fibrosis in 25 (96%). By applying retrospectively the revised original scoring system of the IAIHG, all patients (26) who satisfied the codifined clinical criteria for AIH, having either definite (n= 15) or probable (n= 11) AIH. In contrast, the simplified scoring system made the diagnosis of definite (n= 13) and probable (n=10) AIH less frequently (88.5% versus 100%) (Table 4). Table (4): Comparison of the revised original and the simplified IAIHG criteria in 26 patients. Nondiagnostic Revised original criteria 15 (57.7) 11 (42.3) 0 (0) Simplified criteria 13 (50) 10 (38.5) 3 (11.5) The frequency of definite diagnosis was greater by the revised original scoring system than by the simplified scoring system (57.7% versus 50%), and three (11.5%) patients had been graded as probable AIH according to the revised original system, had non diagnostic scores using the simplified scoring system. Of the 15 patients graded as definite AIH using the revised original scoring system, 5 (33%) were classified as probable using the simplified system. Of the 1 1 patients with probable AIH using the revised original scoring system, 6 were classified as definite (n=3) or no AIH (n=3) using the simplified system. Concordance between the original revised and the simplified scores for a definite diagnosis was 38.5% (n=10) and for a probable diagnosis was 19.2% (n=5). Discordant diagnosis of AIH were rendering in 11 (42.3%) patients. All patients received steroids as the initial therapy and in 22 of them azathioprine was added to start withdrawal. At time of writing this manu- script, nine (30%) patients were on prednisone alone, fifteen (50%) patients were on prednisone and azathioprine, and six (20%) patients were on azathioprine alone. Complete response to treatment was observed in 10 (33.3%) patients, partial response in 3 (10%), and 17 (56.7%) had relapses. Discussion Autoimmune liver disease has been described to have a female preponderance [5], which is about 4:1 in some reports [10,11,12]. In the present study 73% was female. The increased female propensity for immune reactivity and autoimmune hepatitis, however, dose not imply increased disease severity and poor prognosis [13,14]. Twenty (66.7%) patients were presenting with acute hepatitis like illness in the present study. Gregorio et al. reported the occurrence of acute symptoms, similar to viral hepatitis, in over 50% of patients and only one third of patients had a history of hepatic symptoms of more than 6 months. Thus, the mode of presentation of AIH is variable and the disease should be suspected and excluded in all children presenting with symptoms and signs of prolonged or severe liver disease [2]. In AIH, female patients have reported to have a higher frequency of concurrent autoimmune diseases at the time of diagnosis than male patients [2,15,16,17]. The same finding was reported in the present study (6/8). However, Miyake et al. [18] reported that male and female had the same frequency of symptomatic concurrent autoimmune diseases. Diagnosis of AIH is based on a series of positive and negative criteria [7,8]. Serum IgG was elevated and also ANA and/or SMA titer was high in all patients, but none had anti-lkm autoantibody positive in the present study at presentation. Positive ANA in pediatric studies range from 27.6% to 38.4% [2,19,20], whereas SMA range between 50% and 76.6% [2,19]. The anti-lkm is an autoantibody that characterizes AIH type 2, and is highly positive in pediatric patients [19,21]. None of our patients were diagnosed type 2 AIH. Absence of the autoantibodies conventionally used for diagnosis (ANA, SMA or anti-lkm) at presentation should not exclude the diagnosis of AIH and follow-up of these antibodies are essential. Gregorio et al. [2] reported three patients who were positive for liverspecific autoantibodies only at the onset of the disease but become positive for ANA, SMA, or anti-lkm at follow-up. Other autoantibodies less commonly tested but of diagnostic importance in pediatric AIH include

5 Nehal El-Koofy, et al. 111 those to ANCA and SLA. Five (16.7%) patients in the present study were also positive for SLA in addition to ANA and/or SMA antibodies. In both types of AIH, a more severe disease course and a higher tendency to relapse are associated with the possession of antibodies to SLA which are present in approximately half of the patients with AIH type 1 or 2 at diagnosis [22]. In the present study 30% of our patients were positive for panca and it was the only positive autoantibody in one patient. Many patients with AIH type 1 (50%-96%) are panca seropositive while, interestingly, most with AIH type 2 are negative [23-26]. Detection of panca can act as an additional pointer towered the diagnosis of AIH, particularly in the absence of other autoantibodies [27]. Liver biopsy is necessary to establish the diagnosis of AIH. Although the histological appearance of AIH is characteristic, there is no specific histological feature that can be used to prove the diagnosis [28]. Interface hepatitis was evident in 77% of our patients and cirrhosis in 31%. The presence of complete or incomplete cirrhosis is the most common finding at diagnosis, with a frequency of 59% to 100% among pediatric patients [2,21,29]. High prevalence up to 100% of interface hepatitis was reported by many authors [19,30,31]. The goals of treatment are to abate liver inflammation, induce remission, improve symptoms, and prolong survival [32]. In present study, treatment with prednisone and/or azathioprine was effective in abating the inflammatory process in 33% of our patients, as assessed by a return to normal levels of both AST and ALT. In the Kings experience, successful long-term withdrawal of treatment was achieved in 20% of patients with AIH type 1, but in none with AIH type 2 [2]. Porta et al. [19] reported a complete response for 61% of 36 children. Fifty percent of our patients were on prednisone and azathioprine, and 20% was on azathioprine alone. Sustained remission, achieved with prednisone and azathioprine, can be maintained with azathioprine alone in some children with AIH type 1, akin to the experience in adults, but not in AIH type 2 [33]. In the present study, 56.7% had relapsed. Relapse while on treatment is common, occurring in about 40% of the patients and requiring a temporary increase of the steroid dose [34]. Few studies have reported on the use of IAIHG scoring system in pediatric patients with chronic immune hepatobiliary disease. In the present study the sensitivity of revised original scoring system was 100% versus 88.5% for the simplified scoring system and the concordance for definite or probable diagnosis of AIH was 38.5% and 19.2%, respectively. Czaja compared the performance of the revised original scoring system and the simplified scoring system [35]. He found a somewhat smaller sensitivity for the diagnosis of AIH in the simplified scoring system (100% in the original versus 95% in the simplified). Yeoman et al. [36] found a concordance between the original revised and the simplified scores for probable or definite diagnosis of AIH was 90% and 61 %, respectively. In addition, Czaja [35] and Yeoman et al. [36] also reported that the simplified criteria perform less well in patients with atypical features. Muratori et al. [37] tested the simplified diagnostic score in a well-characterized patient group and determined an overall sensitivity and specificity with a score >_6 of 91.8% and 94.3%, respectively and with a score >_7 of 87.1% and 99.6%, respectively. A limitation of both scoring systems, however, is that they have been produced for adult patients and do not take into account the peculiarities of AIH in children. 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