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• W2332002105 abstract "Chronic hepatitis is a histologically and clinically defined progressive liver disorder with a variety of etiologies (1). In addition to viral etiology—that is, hepatitis B, C, and D—autoimmune hepatitis plays an important role in liver disease. Autoimmune hepatitis is characterized by hypergammaglobulinemia, specific circulating antibodies, association with human leukocyte antigen (HLA) haplotype A1-B8-DR3 or DR4, and female predominance (2). Autoimmune hepatitis usually runs a chronic course; however, it may start with an episode of acute hepatitis (3) or it may be diagnosed in asymptomatic patients (4). Based on the serologic heterogeneity of autoantibodies, at least three subgroups of autoimmune hepatitis have been described (Table 1)(5). Antinuclear antibodies (ANAs) characterize classical autoimmune-type “lupoid” hepatitis (AIH-1) (6,7). Autoimmune hepatitis type 2 (AIH-2) is characterized by the presence of heterogeneous liver-kidney microsomal (LKM) antibodies (8,9). A third subgroup, type 3 (AIH-3), is associated with antibodies against a soluble liver antigen (10). Martini et al. found a liver-cytosol-specific autoantibody (anti-LC-1) in patients with chronic active AIH-2 (11). This antibody showed a characteristic immunofluorescence staining pattern sparing the cellular layer around the central veins of mouse and rat liver and recognized an antigenic peptide of 62 kDa in human and 58 kDa in rat (12). We report two pediatric patients with clinically asymptomatic autoimmune hepatitis associated with an autoantibody recognizing a 60-kDa protein in human liver microsomes and cytosol and a characteristic staining pattern of peripheral hepatocytes identical to that of the anti-LC-1 antibody. MATERIALS AND METHODS Serological determinations for hepatitis viruses A, B, and C, Epstein-Barr virus (EBV), and cytomegalovirus (CMV) were done with commercially available tests. Circulating antibodies were determined by standardized methods (13). Determination of LKM antibodies was performed by indirect immunofluorescence on rat liver and kidney tissue and confirmed by immunoblot with human liver microsomes (13,14). In immunofluorescence, LKM antibodies stain the whole liver lobule and the P3 portion of the proximal renal tubuli. Competitive enzyme-linked immunosorbent assays (ELISAs) for LKM-1 antibodies, LM antibody agent P450-IA2, and soluble liver antigen (SLA) were performed as previously described (15,16). CASE REPORTS Patient 1 A 10-year-old boy was transferred to the Dr. von Hauner'sches Kinderspital, Children's University Hospital, Munich, for evaluation of mildly elevated liver function tests. When the patient was 4 years old, his pediatrician had found on a routine examination an alanine aminotransferase (ALT) of 32 U/L (normal, <20) and aspartate aminotransferase (AST) of 38 U/L (normal, <20). During the following years, the transaminase activities fluctuated between 20 and 60 U/L. When the patient was eight years old, a splenomegaly was detected. Since early childhood he had been suffering from recurrent arthralgias although no objective inflammatory signs could be found. There was no specific drug history, nor was there a history of infection with a hepatotropic virus. Abnormal findings on physical examination included hypertrophied tonsil, cervical lymphadenopathy, and a palpable spleen. The liver measured 10 cm in the midclavicular line. Multiple laboratory investigations were performed. RBC and WBC were normal, and a differential WBC showed 11% eosinophils. The transaminase levels were 34 U/L for ALT and 39 U/L for AST. γ-Globulin levels were elevated to 24 g/L (normal, 6-16). The erythrocyte sedimentation rate (ESR) was elevated to 25 mm at 1 h and 56 mm at 2 h. IgE was elevated to 350 kU/L (normal, <100), and a prick test disclosed allergy against environmental allergens. No positive titers indicating hepatitis A, B, or C were detected. Absence of hepatitis C virus (HCV) infection was confirmed by polymerase chain reaction (PCR). EBV titers were positive for Epstein-Barr nuclear antigen (EBNA) and viral capsid antigen (VCA) IgG; CMV titers were negative. HLA phenotyping revealed the following antigens: A 1, 11, B 7, 8, BW 6, C 7, and DR 2, 3 DRw52, and DQw1, 2. Antibodies against double-stranded DNA, mitochondria, SLA, and smooth muscle as well as autoantibodies against thyroid, pancreatic islet cells, gastric cells, and adrenal cells were all negative. Positive titers (1:640) for liver microsomal antibodies were found by immunofluorescence. The serum stained periportal hepatocytes in contrast to LKM-1 antibodies, which homogenously stained the entire liver lobule (Fig. 1). Using a competitive ELISA for LKM-1 antibodies and an immunoblot with human liver microsomes, the serum showed no reactivity with LKM-1 antigen. The serum recognized a 60-kDa protein in immunoblot with a human liver microsomal and a human liver cytosolic fraction (Fig. 2). An anti-LC-1-positive reference serum (kindly provided by Dr. Homberg, Paris) revealed that the antibody recognized the LC-1 antigen described by Martini et al. (11) (data not shown). A liver biopsy disclosed chronic hepatitis. Therapy was initiated with prednisone, 2 mg/kg/day, and the patient developed transient but significant hepatomegaly, which resolved spontaneously. Azathioprine, 1.5 mg/kg/day, was added because of persistent inflammatory signs. Transaminase levels fell to normal (<20 U/L) and the titers of liver-specific microsomal antibodies disappeared shortly after the start of steroid therapy. Six months later, a second liver biopsy was performed, revealing septal fibrosis without evidence of chronic hepatitis. Four years later the patient remains on low-dose steroids (0.25 mg/kg/day) and is doing well, with no clinical or laboratory evidence of liver disease. There are no more arthralgias and the splenomegaly has disappeared. Patient 2 A 3-year-old girl had an acute illness characterized by fever, hepatosplenomegaly, and lymphadenopathy. Diagnostic workup revealed elevation of transaminase levels (ALT, 131 U/L; AST, 156 U/L) and a marked hypergammaglobulinema (IgG, 4,170 mg/dl; IgA, 121 mg/dl; IgM, 383 mg/dl). A blood count showed 10,500 WBC (34% granulocytes, 2% basophils, 62% lymphocytes, including Pfeiffer cells, and 2% monocytes). EBV serology was consistent with an acute EBV infection. After resolution of the acute EBV infection, elevated transaminase levels persisted for 6 months without further clinical symptoms, and the child was transferred to the University Children's Hospital at Freiburg, Germany, for further workup. Physical examination was completely normal. Transaminase levels were elevated (ALT, 115 U/L; AST, 140 U/L). IgG was 2,750 mg/dl, and a search for viral antibodies showed positive IgG titers for EBV VCA, EBNA, and CMV and negative titers for hepatitis A, B, and C. Additionally, HCV infection was ruled out by PCR. On rat liver sections, the serum gave an identical staining pattern on periportal hepatocytes as did the serum of patient 1. Western blot analysis revealed a 60-kDa protein recognized by the patient's serum (Fig. 2). A search for additional autoantibodies found none. Liver biopsy revealed chronic aggressive hepatitis with portal fibrosis. The patient was started on prednisone, 2 mg/kg, and the transaminase levels returned to normal within 4 weeks. Steroids were tapered rapidly, and the patient is well with a follow-up of 1 year. She remains on prednisone at 0.5 mg/kg. DISCUSSION We diagnosed two children with autoimmune hepatitis who did not present specific clinical symptoms pointing to liver disease. In both patients, elevated transaminase levels associated with hypergammaglobulinemia led to diagnosis. The presentation was in accordance with AIH-2, which is characterized by early onset in 50% of cases and also by the presence of LKM antibodies (11,17). In contrast to AIH-2 characterized by LKM antibodies, our patients had autoantibodies that predominantly stained periportal areas of rat liver and that differed slightly in molecular weight from cytochrome P450-2D6 and P450-1A2, two known integral proteins of the endoplasmic reticulum with a molecular weight of 50 kDa. In partial overlap with LKM-1 autoimmune hepatitis, a new antibody—anti-LC-1—was described by Martini et al. that recognizes a 60-kDa antigen (11). The molecular nature of the LC-1 autoantigen still awaits identification. The 60-kDa microsomal protein possibly belongs to the group of liver enzymes already identified as autoantigens in patients with inflammatory liver diseases, such as cytochrome P450-2D6 (13), P450-1A2 (18), P450-2C9 (19), and UDP glucuronosyl transferase (20). In contrast to original reports, the presence of anti-LC-1 antibodies does not seem to be specific for true autoimmune hepatitis since it has also been found in hepatitis C infection (21). The clinical characteristics and natural course of patients with anti-LC-1-positive autoimmune hepatitis are not yet well-established. A recent study by Han et al. could not identify distinct clinical features characterizing anti-LC-1-positive patients (22). Whether non- or oligosymptomatic LC-1-positive LKM-negative autoimmune hepatitis defines a new subtype remains to be shown. Our patients had a mild clinical course; however, severe hepatitis activity and progression to liver cirrhosis within 3 years after diagnosis has also been reported (11). The insidious onset of liver disease may herald severe irreversible autoimmune-mediated liver damage (23). Our cases underline the need for a rapid and precise diagnosis of autoimmune hepatitis and the quick institution of adequate immunosuppressive treatment to prevent liver failure.FIG. 1.: Immunofluorescence photomicrographs demonstrate the staining pattern on rat liver cryostat sections. A: Anti-LC-1 antibodies predominantly stain the peripheral hepatocytes of the liver lobule. B: LKM-1 antibodies homogenously stain the complete liver lobule.FIG. 2.: Immunoblot of human liver microsomes shows antigen reactivity of LC-1 sera of patients 1 and 2 against a 60-kDa antigen (lanes 1 and 2), reactivity of LKM-1 antibody against 50-kDa cytochrome P450-2D6 in serum from a patient with AIH-2 (lane 3), reactivity of LKM-3-positive serum from a patient with hepatitis D reacting with UDP glucuronosyl transferase (lane 4), reactivity of LKM-positive serum against a 59-kDa protein from a patient with hepatitis C (lane 5), and an anti-HCV-positive LKM-1-positive serum reacting with an additional 70-kDa protein (lane 6). Results with normal human serum (NHS) are shown in lane 7." @default.
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• W2332002105 title "Asymptomatic Autoimmune Hepatitis Associated with Anti-LC-1 Autoantibodies" @default.
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