Autoimmune hepatitis in children and adolescents: clinical study, diagnosis and therapeutic response

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1 /02/78-04/309 Jornal de Pediatria Copyright 2002 by Sociedade Brasileira de Pediatria Jornal de Pediatria - Vol. 78, Nº4, ORIGINAL ARTICLE Autoimmune hepatitis in children and adolescents: clinical study, diagnosis and therapeutic response Alexandre R. Ferreira 1, Mariza L.V. Roquete 2, Francisco J. Penna 3, Nivaldo H. Toppa 4 Abstract Objective: the aim of this study was to evaluate the clinical, laboratory and histopathological characteristics and the response to immunosuppression in children and adolescents with autoimmune hepatitis (AIH). Methods: the present research is a descriptive study consisting of 39 children and adolescents with AIH who receive care at the Department of Pediatric Gastroenterology of Hospital das Clínicas (UFMG) from 1986 to Results: children s age ranged from 1.6 to 17 years (mean 8.7 ± 3.49), most of them were females (87.2%). There were three types of clinical presentations: chronic (53.9%), acute (41%), and serious hepatic failure (5.1%). The most relevant laboratory parameters were the aminotransferases and g-globulin increase. Antinuclear antibodies were positive in 66.7% of the patients, while smooth muscle antibodies were positive in 52.8% and anti-lkm1 in 3% of the patients. In the histopathology the most important findings were the piecemeal necrosis (93.7%), moderate to severe portal inflammation (78.1%), definitive or incomplete cirrhosis (76.9%), absence of lesion of biliary ducts (93.7%) and presence of rosettes (90.6%). During the treatment, 77.8% obtained complete resolution, associated to side effects in 27.8% of them. Seven patients died (17.9%). During the treatment there was significant z score reduction (P< 0.05) for height/age. Conclusions: after carrying out this study, we observed that the typical characteristics of AIH were: female sex, several clinical presentations, increased aminotransferase, and hypergammaglobulinemia. Histopathology showed a predominance of incipient and/or definitive cirrhosis associated with moderate to severe portal inflammation and piecemeal necrosis. Treatment using corticosteroids and azathioprine, turned out to be effective. However, the reduction in the height/age z score probably represents an adverse effect of corticoid treatment. J Pediatr (Rio J) 2002; 78 (4): : autoimmune hepatitis, children, treatment, clinical, histopathology. 1. Physician, Specialist in Pediatric Gastroenterology, Universidade Federal de Minas Gerais (UFMG). Master s Degree in Medicine (Pediatrics). 2. Assistant Professor, Department of Pediatrics, School of Medicine, UFMG. Coordinator of the Subunit of Hepatology, Unit of Pediatric Gastroenterology, Hospital das Clínicas, UFMG. Master s Degree in Medicine (Pediatrics). 3. Professor, Department of Pediatrics, School of Medicine, UFMG. 4. PhD in Medicine (Pathology). Manuscript received Oct Accepted for publication Jun Introduction Autoimmune hepatitis (AIH) is a form of chronic hepatitis that affects patients who have lost their immunological tolerance to liver-specific antigens. 1-6 The diagnosis is based on clinical and laboratory findings, and on the exclusion of other causes of chronic liver disease. AIH is more frequent in women and is associated with 309

2 310 Jornal de Pediatria - Vol. 78, Nº4, 2002 Autoimmune hepatitis in children and adolescents:... - Ferreira AR et alii hypergammaglobulinemia and other autoimmune disorders in patients themselves and in their first-degree relatives. 7 It is more common among individuals with HLA B8, DR3, DR4 histocompatibility antigens and with serum autoantibodies: antinuclear antibodies (ANA), liver-kidney antimicrosome type I antibodies (anti-lkm1), anti-smooth muscle antibodies (ASMA), anti-soluble liver antigen antibodies (anti-sla), antiasialoglycoprotein receptor antibodies (Anti-ASGPR) and anti-liver specific lipoprotein antibodies (anti-lsp). 3,7-11 An important criterion for diagnosis is the prompt response to the treatment with corticosteroids and immunosuppressants. 3,7 The age for diagnosis ranges between six months and seventy-five years. AIH is rare before the age of two years, but its frequency increases after that, reaching its maximum between ten and thirty years. 12 The manifestations of AIH comprise a broad clinical spectrum: asymptomatic individuals with abnormal lab results, clinical symptoms similar to those of acute viral hepatitis and hepatic insufficiency. 2 The high levels of aminotransferase and hypergammaglobulinemia are the most common lab findings. 7,13 On liver histopathology, the presence of periportal or periseptal piecemeal necrosis, lymphoplasma cell infiltrate with a great number of plasmocytes and formation of rosettes 7 are suggestive of AIH. The treatment is based on the use of prednisone or prednisone associated with azathioprine and is aimed at clinical remission, maintenance of aminotransferases at normal level or not twice higher than the reference value, and reduction of inflammatory infiltrate within the liver. 9,10,13-15 The response, which is achieved by more than two thirds of the patients, is characterized by the improvement of symptoms and reduction of aminotransferase levels. Histological improvement occurs later on. Some patients do not respond to treatment and might require liver transplantation. 13 Most publications on AIH report experiments with adults; however, there are a few publications on children and adolescents with AIH. 2,7,11,16-21 Therefore, it is important to publish the results of our experience of approximately twelve years with children and adolescents at the unit of pediatric gastroenterology of Hospital das Clínicas, Universidade Federal de Minas Gerais (UFMG), with the aim of analyzing the following aspects: (a) clinical status, lab and histopathological findings; (b) clinical outcome after the treatment with immunosuppressants, with evaluation of response and relapses during treatment; (c) complications caused by the treatment with immunosuppressants; (d) survival rate and anthropometric evolution of patients. Patients and methods The present article is a descriptive study that includes the retrospective and prospective assessment of patients with AIH treated between January 1986 and September The retrospective assessment consisted in analyzing the medical records of cases diagnosed until August 1996, while the prospective assessment included patients after August The diagnosis was established according to the International Autoimmune Hepatitis Group, published in 1993, 9 and revised in 1999; 15 patients with definitive or probable diagnosis were included. Thirty-nine children and adolescents were included. Of these patients, 35 (89.7%) had definitive diagnosis and four (10.3%) had a probable diagnosis. Investigation was carried out in order to rule out other chronic liver diseases. Clinical signs were classified into three forms: acute form, similar to the symptoms of acute viral hepatitis; chronic form (presence of adynamia, anorexia, ascites, hepatomegaly, intermittent jaundice, splenomegaly); and severe liver failure, which resembles fulminant liver failure. AIH was classified into: type I, in case of positive ANA and/ or ASMA; and type II, when anti-lkm1 was positive. The patients with negative autoantibodies were not classified into any type. The lab exams assessed the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AP); serum bilirubins, plasma proteins with electrophoretic fractionation; quantitative and qualitative determination of antinuclear antibodies (ANA), anti-smooth muscle antibodies (ASMA) and anti-liver kidney microsome type I antibodies (anti-lkm1), which were submitted to indirect immunofluorescence (IIF). The reference values were: ALT and AST - 15 to 35 U/L, gammaglobulin to 1.5 g/dl. The histopathological examination of the liver was carried out by means of the protocol based on the criteria modified by Knodell et al., 22 and Ishak et al. 23 The treatment consisted of a combination of prednisone and azathioprine, given at 1 to 2 mg/kg/day (maximum 60 mg/day) and 1.5 mg/kg/day (maximum 100 mg/day), respectively. The first reassessment was made on the sixth week, when the dose of prednisone was reduced by half; the subsequent reassessments were made every eight weeks, with a 5-mg reduction of the dose of prednisone, up to 5 mg/ day, keeping the patient in clinical and laboratory remission. The initial dose of azathioprine was maintained. For the patients who revealed leukopenia (leukocyte count less than 3,000) and/or reduced platelet count (less than 50,000) at the beginning of the treatment, only prednisone was used; azathioprine was added after these problems were solved; otherwise, only prednisone was maintained. Treatment response was assessed according to the criteria established by the International Autoimmune Hepatitis Group, published in (Table 1). The Epi-Info version was used for statistical analysis. The assessment of anthropometric data was obtained through Epi-Info (Epinut) program, with z score values for weight/age and height/age, using NCHS (The National Center for Health Statistics) reference values. 24

3 Autoimmune hepatitis in children and adolescents:... - Ferreira AR et alii Jornal de Pediatria - Vol. 78, Nº4, Table 1 - Definition of treatment response Response Definition Complete Symptoms improvement, with at least 50% improvement rate regarding the liver function in the first month of treatment. The levels of aminotransferases kept two-fold below the upper limit of normality in six months, during the reductions towards the maintenance therapy Partial Symptoms improvement and at least 50% improvement of the liver function during the first two years of treatment, with progressive reductions. Aminotranspherases levels above the reference values after one year of treatment Absence Liver function with improvement of 50% above the of response initial values during the first or second month. However, it does not reach normal function, with absence of improvement in the next six months, if the dose of corticosteroids is increased or if the symptoms disappear Treatment Patient s clinical status has a progressive failure deterioration, in spite of the improvement in some parameters of the disease Liver function: aminotransferases, total bilirrubin, gammaglobulin or IgG; 50% improverment = the alteration of parameters (towards normal function) of 50% of the difference between the initial value and the upper limit of normality. Source: Johnson & McFarlane, Student t test was used to compare the means. The comparison of the distribution of the variable was analyzed by Fisher s exact (two-tailed) test and chi-square test (Yates ). A significance level less than 0.05 was considered significant (P < 0.05). The study was approved by the Ethics Committee of Hospital das Clínicas, Universidade Federal de Minas Gerais (UFMG). Results Among 39 patients, 34 were females (87.2%), aged between 1.6 and 17 years (mean: 8.7; standard deviation (SD) ± 3.49) at the time of admission. The chronic form of AIH was observed in 21/39 patients (53.9%); the acute form affected 16/39 (41%); and severe liver failure was detected in two cases (5.1%). Among the 39 patients, 35 (89.7%) were classified as having type I AIH, one patient (2.6%) presented type II AIH, and the autoantibodies were negative in three patients (7.7%). The major laboratory findings in the diagnosis of AIH were: elevation of ALT (mean 377 U/L; SD 351) and AST (mean 523 U/L; SD 485); and hypergammaglobulinemia (mean 3 g/dl; SD 1.25). The antinuclear antibodies (ANA) were positive in 26/39 patients (66.7%) with titers between 1:40 and 1:5,120 (mean 1:390 ± 1:1,022); the ASMA were positive in 19/36 patients (52.8%), with titers between 1:20 and 1:5,120 (mean 1:828 ± 1:1,222); and the anti- LKM1 were positive in 1/33 patient (3%), with a titer of 1:160. The autoantibodies were negative in three patients (7.6%). The presence of ASMA and anti-lkm1 was not detected in six patients; all the patients had a definitive diagnosis. The main results of the histopathological analysis were piecemeal necrosis (93.7%), moderate to severe portal inflammation (78.1%), complete and/or incomplete cirrhosis (76.9%), absence of lesions to bile ducts (93.7%) and formation of rosettes (90.6%) (Table 2). The determination of histopathological grades was possible in 32 of 39 patients diagnosed with AIH due to the fragmentation of the obtained material, with a low number of portal spaces. Treatment response was assessed in 36 patients. Complete response was observed in 77.8% of the patients, partial response in 8.3%, noncompliance in 11.1%, and insufficient follow-up time for the assessment of therapeutic response in one patient (Table 3). Treatment response was not assessed in three cases- one patient died before starting the treatment and two patients did not follow the treatment. Some complications occurred in the assessment of 36 patients submitted to drug therapy. These drug-related complications required that the treatment be interrupted or that the dose be readjusted in 27.8% of the patients (three cases of sepsis, two of leukopenia, one of subcapsular cataract, one of gastrointestinal disorder, one of pancytopenia, one of diabetes mellitus and one of encephalopathy). The z score for height/age suffered a statistically significant reduction (P<0.05) from the first to the fifth year of treatment (Table 4). Table 2 - Histological data Histopathological analysis, according to the clinical presentation of patients with AIH, at the unit of pediatric gastroenterology of Hospital das Clínicas, Universidade Federal de Minas Gerais (UFMG) Clinical presentation Acute Chronic Liver Total failure Cirrhosis Incomplete 04 / / / 39 Complete 08 / / 21 2 / 2 22 / 39 Fibrosis 04 / / / 39 Piecemeal necrosis 15 / / / 32 Portal inflammation Mild 2 / / / 32 Moderate 7 / / / 32 Severe 6 / / / 32 Absence of lesions 14 / / / 32 to bile ducts Lymphoid follicles 03 / / / 32 Steatosis 02 / / / 32

4 312 Jornal de Pediatria - Vol. 78, Nº4, 2002 Autoimmune hepatitis in children and adolescents:... - Ferreira AR et alii Table 3 - Treatment Treatment assessment, according to the clinical presentation of patients with AIH, at the unit of pediatric gastroenterology of Hospital das Clínicas, Universidade Federal de Minas Gerais (UFMG) Clinical presentation Acute Chronic Liver Total failure Treatment response Complete 14 / / / 36 Partial 01 / / 19 1 / 1 03 / 36 Failure 01 / / / 36 Short period 01/19 01 / 36 of assessment Complications 03/16 06/19 1 / 1 10 / 36 Treatment Prednisone and Azathioprine 10 / / / 36 Prednisone 02 / / 19 1 / 1 08 / 36 Prednisone after Azathioprine 04 / / / 36 The follow-up period of the 39 patients ranged from 3.9 to months, mean of 47 ± 34.8 months. Seven patients (17.9%) died and two patients (5.1%) quit after 14.7 and 75.5 months of follow-up. The length of treatment of six patients who died ranged between 2.8 and months, mean of 37.6 (±16.3). Discussion AIH is a rare childhood disease; therefore, there are few studies carried out with children. 2,7,11,16-21 The prevalence of AIH among female children and adults (60 to 75%) is a common finding. 2,21,25,26 The disease can have different forms: asymptomatic individual with isolated elevation of aminotransferases; insidious, sometimes oscillating, clinical course; similar to acute hepatitis or to fulminant liver failure. An undistinguishable clinical status of acute viral hepatitis can be the initial manifestation in 40 to 70% of the patients with AIH. 2,11,20,21 The laboratory findings that suggest AIH are hypergammaglobulinemia, elevated titers of autoantibodies and enhanced activity of aminotransferases. Lab exams are essential in ruling out other causes of chronic liver diseases. 7,9,11,17-21 The presence of autoantibodies is important for the diagnosis of autoimmune hepatitis; however, their absence is not enough to rule out the disease. These autoantibodies are the major findings of autoimmune hepatitis, but are rare in healthy children; for this reason, titers as low as 1:20 are considered significant to the diagnosis of AIH in pediatric patients. 10 Positive ANA in pediatric studies range from 27.6% to 38.4%, 11,21,27 whereas ASMA range between 50% and 76.6%. 11,21 The anti- LKM1 is an autoantibody that characterizes AIH type II, and is highly positive in pediatric patients. 2,11 The negativity for ANA, ASMA and anti-lkm1 is reported in the literature in 20 to 30% of the cases of AIH. 9,28 Histopathological lesions found in AIH can vary, depending on the level and stage of the disease, and are not essential for the diagnosis and implementation of treatment, as occurs with other clinical and laboratory parameters. The presence of complete or incomplete cirrhosis is the most common finding at diagnosis, with a frequency of 59% to 100% among pediatric patients. 2,7,21 Piecemeal necrosis was evident in 93.7% of our patients, compared to literature data, which show a prevalence of up to 100%. 11,17,18 This type of necrosis can also be found in chronic hepatitis associated with drugs and virus and in primary biliary cirrhosis. 29,30 The inflammatory infiltrate in the portal tract Table 4 - Assessment of the difference of z score for height/age during the treatment of patients wit AIH at the unit of pediatric gastroenterology of Hospital das Clínicas, Universidade Federal de Minas Gerais (UFMG) Length of n. of Mean Mean Difference Difference (P) treatment patients z score for z score for between z score z score (years) for height* height in periods for height for height * Mean z score for height/age in the beginning of the treatment Mean z score for height/age at the end of the period of treatment (years) Difference between z score for height/age in the beginning and at the end of the treatment (years) P value of the difference of z score for height/age before the treatment with respect to each year after the beginning of the treatmen (P value)

5 Autoimmune hepatitis in children and adolescents:... - Ferreira AR et alii Jornal de Pediatria - Vol. 78, Nº4, is one of the most frequent findings in AIH, and it could be the only histological abnormality observed. The lesions to bile ducts are more frequent in primary sclerosing cholangitis, 11,21 whereas steatosis and lymphoid follicles are more common in chronic hepatitis C and, less frequently, in AIH. 31 Therapy response is assessed through the improvement of signs and symptoms, improvement of the levels of liver inflammation on lab exams and improvement of the liver synthesis function. Histopathology can be used to assess the progression of the patient during therapy, although remission of the inflammatory activity occurs at a later stage and is not associated with biochemical improvement. 32 We obtained good results from the therapy used. Our results are in agreement with those reported in the literature, with a complete response of 65 to 80%. 2,7,11,33,35 The presence of side effects, such as cushingoid facies and weight gain, can be observed in all patients. Since these side effects are tolerable, the treatment does not have to be discontinued. 21,25 More severe complications that required reducing or discontinuing medication were observed in 27.8% of our patients. Porta 11 reported low frequency of side effects associated with the use of corticoids on alternate days. Maggiore et al. 2 detected complications in 35.5% of the cases. The frequency of deaths in pediatric studies ranges from 9.7 to 20%,2,7,11,21 data that are similar to those found among our patients. Clark & Fitzgerald assessed children diagnosed with chronic active hepatitis and found an increased growth speed in those who were receiving corticosteroids on alternate days and slow growth in those who received them every day. 34 Porta 11 used corticosteroids on alternate days, but did not find any significant difference in relation to weight-height development, whereas Maggiore et al. 18 reported reduced growth speed in children during initial corticosteroid therapy, followed by speed recovery when prednisone was administered on alternate days, or when the dose was gradually reduced. We observed a reduction of the z score for height/age during treatment. This reduction could be associated with the daily use of corticoids; however, this hypothesis should be carefully analyzed, since the type of study used does not allow for generalized conclusions. Our conclusion is that AIH is predominant among female individuals, with different forms of presentation (acute, chronic, and severe liver failure). The histopathological examination revealed moderate to severe portal inflammation, and cirrhosis was the most frequent finding. Lab results showing elevated activity of aminotransferases, presence of hypergammaglobulinemia and of autoantibodies are commonly observed. The diagnosis should be based upon this set of data and upon therapeutic response. The treatment scheme used by us showed good results, with a considerable percentage of complications, which made us reconsider the current daily use of corticosteroids. References 1. Maddrey WC. Subdivisions of autoimmune chronic active hepatitis. Hepatology 1987;7: Maggiore G, Veber F, Bermard O, Hadchouel M, Homberg JC, Alvarez F, et al. Autoimmune hepatitis associated with anti-actin antibodies in children and adolescents. J Pediatr Gastroenterol Nutr 1993;17: Payne JA. Chronic hepatitis: pathogenesis and treatment. Dis Mon 1988;34: Porta G, Bonfa E, Miura IK, Pugliese RS, Cossermelli W, Oliveira RM. Chronic active hepatitis associated with anti-liverkidney microsome antibody type 1. Arq Gastroenterol 1988; 25: Zetterman RK. Chronic hepatitis: is it persistent, active, or just chronic? Am J Gastroenterol 1993;88: Desmet VJ, Gerver M, Hoofnagle JH, Manns M, Scheuer PJ. Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology 1994;19: Maggiore G, Bernard O, Homberg JC, Hadchouel M, Alvarez F, Hadchouel P, et al. Liver disease associated with anti-liverkidney microsome antibody in children. J Pediatr 1986;108: Maggiore G, Porta G, Bernard O, Hadchouel M, Alvarez F, Homberg JC, et al. Autoimmune hepatitis with initial presentation as acute hepatic failure in young children. J Pediatr 1990;116: Johnson PJ, McFarlane IG. Meeting report: International Autoimmune Hepatitis Group. Hepatology 1993;18: Mieli-Vergani G, Vergani D. Progress in pediatric autoimmune hepatitis. Semin Liver Dis 1994;14: Porta G. Hepatite auto-imune na infância: análise clínicolaboratorial, histológica e evolutiva.: Faculdade de Medicina, Universidade de São Paulo: São Paulo; Vento S, Garofano T, Di Perri G, Dolci L, Concia E, Basseti D. Identification of hepatitis A virus as a trigger for auto-immune chronic hepatitis type 1 in susceptible individuals. Lancet 1991;337: Mieli-Vergani G, Lobo-Yeo A, McFarlane BM, McFarlane IG, Mowat AP, Vergani D. Different immune mechanisms leading to autoimmunity in primary sclerosing cholangitis and autoimmune chronic active hepatitis of childhood. Hepatology 1989;9: Johson PJ, McFarlane IG. Chronic active hepatitis. Gut 1991; Supl: 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: Dubois RS, Silverman A. 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6 314 Jornal de Pediatria - Vol. 78, Nº4, 2002 Autoimmune hepatitis in children and adolescents:... - Ferreira AR et alii 22. Knodell RG, Ishak KG, Black WC, Chen TS, Graig R, Kaplowitz N, et al. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology 1981;1: Ishak K, Baptista A, Bianchi L, Callea F, Groote JD, Gudat F, et al. Histological grading and staging of chronic hepatitis. J Hepatol 1995;22: Dean AG, Dean JA, Culombier D, Brendel KA, Smith DC, Burton A, et al. Epi-Info, version 6; a word processing, database, and statistics program for epidemiology on microcomputers. Centers of Disease Control and Prevention, Atlanta, Georgia; Czaja AJ. Treatment of autoimmune hepatitis. In: Krawitt EL, Wiesner RH, Nishioka M, editores. Autoimmune liver diseases. 2nd ed. Amsterdam: Elsevier; 1998.p Porta G, Gayotto LCC, Alvarez F. Anti-liver-kidney microsome antibody-positive autoimmune hepatitis presenting as fulminant liver failure. J Gastroenterol Nutrit 1990;11: Czaja AJ, Carpenter HA, Santrach PJ, Moore SB. Genetic predisposition for the immunological features of chronic active hepatitis. Hepatology 1993;18: Meyer Zum Buschenfelde KH. Autoimmune hepatitis definition-classification-histopathology-immunopathogenesis. Virchows Arch 1996;429: Popper H, Geller SA. Pathogenetic considerations in the histologic diagnosis of drug-induced injury. In: Fenoglio CM, Wolff M, editores. Progress in Surgical Pathology vol. III. Mansson: New York; p Wright R. Drug-induced chronic hepatitis. Springer Seminars in Immunopatholgy 1980;3: Batts KP, Ludwig J. Histopathology of autoimmune hepatitis. In: Krawitt EL, Wiesner RH, Nishioka M, editores. Autoimmune liver diseases. 2nd ed. Amsterdam: Elsevier; 1998.p Maddrey WC, Combes B. Therapeutic concepts for the management of idiopathic autoimmune chronic hepatitis. Semin Liver Dis 1991;11: Czaja AJ, Cassani F, Cataleta M, Valentini P, Bianchi FB. Antinuclear antibodies and patterns of nuclear immunofluorescence in type 1 autoimmune hepatitis. Dig Dis Sci 1997;42: Clark JH, Fitzgerald JF. Effect of exogenous corticosteroid therapy on growth in children with HBsAg-negative chronic aggressive hepatitis. J Pediatr Gastroenterol Nutr 1984;3:72-6. Correspondence: Dr. Alexandre Rodrigues Ferreira Rua Mônica, apto. 201 CEP Sete Lagoas, MG, Brazil Phone: alexfer@net.em.com.br