A Case of Adult Autoimmune Hepatitis with Histological Features of Giant Cell Hepatitis

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1 CASE REPORT A Case of Adult Autoimmune Hepatitis with Histological Features of Giant Cell Hepatitis Hiroki Hayashi 1, Ryoichi Narita 1, Masaaki Hiura 1, Shintaro Abe 1, Akinari Tabaru 1, Akihide Tanimoto 2,3, Yasuyuki Sasaguri 2 and Masaru Harada 1 Abstract Giant cell hepatitis is rare in adult patients. This form of hepatitis shows fast progression to cirrhosis. A 65-year-old woman was admitted to our hospital with jaundice. She was negative for hepatitis virus markers and positive for antinuclear antibodies. We diagnosed her as autoimmune hepatitis. Liver biopsy findings revealed typical features of interface hepatitis and giant cell hepatitis. Giant cells were positive for keratin 8/18, but not for keratin 19, keratin 7 or Ki-67. These results suggest that giant cell formation is associated with the fusion of matured hepatocytes rather than the active proliferation of immature cells. Key words: autoimmune hepatitis, giant cell hepatitis, keratin, Ki-67 () () Introduction Giant cell hepatitis is commonly found in various neonatal and infantile liver diseases, but is rarely found in the post-infantile period (1). This form of hepatitis is generally thought to be a non-specific pattern of liver injury that can result from many different causes. In adults, giant cell formation represents an idiosyncratic response to various hepatic stimuli including viral infections (paramyxovirus, hepatitis B virus, hepatitis C virus, human immunodeficiency virus, and Epstein-Barr virus infection), drugs (methotrexate, 6-mercaptopurine, p-aminosalicylic acid, clomethacin, vinyl chlorpromazine), and autoimmune disease (hypoparathyroidism, and Graves disease) (2). In one of the larger series to date, autoimmune diseases were the most common clinical association (2, 3). In this report, we present a case of post-infantile giant cell hepatitis (PGCH) associated with autoimmune hepatitis (AIH). The actual mechanism of giant cell transformation of the hepatocyte is not known; possibilities include fusion of individual cells to form a syncytium and failure of the cytoplasm to divide at the time of nuclear division (2). We investigated the hepatocyte proliferation rate in this patient, using an anti Ki-67 antibody. We also evaluated the expression of keratin8/18, keratin7 and keratin19 in the liver tissue. Case Report Subject was a 65-year-old woman who had enjoyed good health until 2008, at which time she developed general fatigue and jaundice. She was referred and admitted to our hospital. The patient had not been taking any medication or supplement before the onset of her illness, and risk factors for viral hepatitis were absent. She did not drink alcohol. Physical examination on admission showed deep jaundice. There was no ascites or leg edema. Liver and spleen were not palpable. The laboratory data on admission is shown in Table 1. Ultrasonography and computerized tomography of the abdomen showed hepatomegaly of the liver without focal masses. On the eighth hospital day a liver biopsy was performed. The liver biopsy specimens showed numerous multinucleated hepatocyte transformations with severe inflammatory cell infiltration in the expanded portal areas and irregularly Third Department of Internal Medicine, University of Occupational and Environmental Health, Japan, School of Medicine, Japan, Department of Pathology and Cell Biology, University of Occupational and Environmental Health, Japan, School of Medicine, Japan and Department of Molecular and Cellular Pathology, Kagoshima University Graduate School of Medical and Dental Sciences, Japan Received for publication June 9, 2010; Accepted for publication October 25, 2010 Correspondence to Dr. Ryoichi Narita, r-narita@med.uoeh-u.ac.jp 315

2 Table 1. Laboratory Findings on Admission Hematology FBS 109 mg/dl WBC 5400/ L Viral marker RBC / L IgM-HA Ab ( ) Hb 14.0 g/dl HBsAg ( ) Plt / L HBcAb ( ) Coagulation IgM-HBcAb ( ) PT 61.2% HBV-DNA ( ) APTT 31.1 sec HCV Ab ( ) Fibrinogen 158 mg/dl HCV-RNA ( ) FDP 1.3 g/ml EB VCA IgM ( ) AT 60% EB VCA IgG ( ) ESR 21/h EBNA antibody ( ) Chemistry Cytomegalo IgM ( ) TP 6.7 g/dl Cytomegalo IgG ( ) Alb 3.1 g/dl Immunology -glb 1.73 g/dl CRP 0.77 mg/dl T-bil 33.6 mg/dl IgA 401 mg/dl D-bil 21.4 mg/dl IgG 2,018 mg/dl ZTT 17.3 KU IgM 84 mg/dl TTT 20.6 MU ANA 1,280 AST 867 IU/L AMA 66 ALT 838 IU/L LE test ( ) LDH 360 IU/L ads-dnaab ( ) ALP 425 IU/L RF ( ) BUN 11.0 mg/dl Anti-SS-A/Ro-Ab ( ) Cre 0.64 mg/dl Anti-SS-B/LA-Ab ( ) TG 465 mg/dl Anti-LKM-1-Ab ( ) T Chol 194 mg/dl HGF 0.86 ng/ml ESR, erythrocyte sedimentation rate; WBC, white blood cell; RBC, red blood cell; Hb hemoglobin; Ht hematocrite; Plt, platelet; PT, prothrombin; APTT, activated partial thromboplastin time; Alb, alubumin; TG, triglyceride; T chol, total cholesterol; FBS, fasting blood sugar; EB, Epstein-Barr; VCA, viral captid antigen; EBNA, anti-ebv nuclear antigen; AMA, antimitochondrial antibody; ads-dnaab, anti-double-strand DNA antibody; RF, rheumatoid factor; LKM-1, liver/kidney microsome type 1; HGF, hepatocyte growth factor. Figure 1. Histological findings of liver biopsy (Hematoxylin and Eosin staining) (a) The liver showed severe infiltration of inflammatory cells, piecemeal necrosis and mild fibrosis (Hematoxylin and Eosin staining 4). The inset photo is a high magnification. (b) There were many multinucleated giant cells with infiltration of plasma lymphocytes in zones 2-3. Giant cell transformation containing up to 11 nucleoli/cell (arrow) (Hematoxylin and Eosin staining 100). extending fibrosis (Fig. 1). These characteristic histological observations and the laboratory data led us to make a diagnosis of AIH with giant cell transformation. Immunohistological studies were performed. Although Ki- 67 was positive in 20% of the hepatocyte nuclei, it was negative in the giant cell nuclei (Fig. 2a). Giant cells were 316

3 Figure 2. Immunohistological staining of the liver biopsy specimen. (a) Giant cells without Ki-67 staining (arrows) were seen. Note that some adjacent mononuclear hepatocytes show strong Ki-67 staining (arrowheads) (reactivity approximately 20%). (b) Giant cells were diffusely stained for keratin 8/18. (c) Giant cells were negative for keratin 19 (arrows). (d) Giant cells were negative for keratin 7 (arrows). strongly stained with keratin8/18 as compared with ordinary hepatocytes (Fig. 2b). Giant cells were not stained with keratin7 or keratin19 (Fig. 2c, d). According to the revised scoring system proposed by the International Autoimmune Hepatitis Group, we diagnosed the patient as definite AIH (4). She was started on 60 mg prednisolone daily. She responded to corticosteroid therapy and the liver dysfunction immediately improved (Fig. 3). A second liver biopsy performed 1 month later showed that the lobular inflammation and giant cell formation had substantially decreased as compared to the findings at the first biopsy. The clinical remission continued for about 2 years. Discussion Hepatitis with multinucleated giant cells in the liver tissue is called giant cell hepatitis, and is often seen in neonatal viral hepatitis and biliary atresia (1). By contrast, giant cells are rarely found in adult liver diseases. Giant cell transformation of hepatocytes can be seen in a wide variety of inflammatory and cholestatic liver diseases in adults and appears to be an unusual but non-specific pattern of liver injury. Etiologic factors implicated include drugs, and viruses (hepatitis A, hepatitis B and hepatitis C (5), Epstein-Barr virus, variant A of human herpesvirus 6 (6) and paramyxoviruses (7, 8) and AIH (3)). The prognosis depends on the underlying liver disease (9). The present patient had not received any drugs or toxic agents, and viral disease did not appear to be responsible for the associated giant cell hepatitis in this case. She had antinuclear antibodies and responded well to treatment with corticosteroids. Therefore, she had definite AIH. In the case of AIH, multinucleated giant cells are likely observed in the acute type or chronic type with exacerbation (10). Typical clinical features are a prolonged clinical course, severe cholestasis, and progression to cirrhosis within a few months (11). In the present case, prolonged treatment with corticosteroids was effective. The present results confirmed the previously reported finding that corticosteroid treatment was effective in reducing the number of giant hepatocytes (9, 12, 13). In this case, anti-mitochondrial antibody (AMA) was positive. Whether AMA is a secondary response to an ongoing hepatocytic injury or a primary disorder that initiates the damage and giant cell transformation remains unclear (14). The mechanism of giant cell formation is still unknown. It was reported that cellular derangement due to rapid cell death and regeneration led to the formation of multinucleated giant cells (2). Multinucleated cell formation is reported to be the result of degenerative cell fusion (15). It is also reported to be the result of cell fusion because mitotic figures have never been observed (16). Fusion of mononuclear hepatocytes and nuclear proliferation without cell division are 317

4 Figure 3. Clinical course: total bilirubin (T-Bil), alanine aminotransferase (ALT), prothrombin activity reached (PT%), antinuclear antibodies (ANA) and immunoglobulin G (IgG) in association with use of prednisolone (PSL) and ursodeoxycholic acid (UDCA). the two prevailing pathogenic hypotheses (16). We performed immunohistochemical analysis using MIB- 1, a monoclonal antibody raised against the recombinant part of the Ki-67 antigen that reacts with cells in all phases of the cell cycle except the G0 (resting) phase (17). In the present case, giant cells were not positive for Ki-67, as is also the case in infant giant cell hepatitis (18). Therefore, the proliferation potency of giant cells was low and the giant cells were not actively dividing, suggesting that nuclear division is a less likely explanation for the giant cell formation. In addition, giant cells were strongly positive for keratin 8/18 and were not positive for keratin7 or keratin 19. Hepatocytes positive for keratin 8/18 represent mature hepatocytes, and intermingled hepatocytes negative for keratin 8/ 18 may represent regenerative hepatocytes. This finding suggests that these cells are of hepatocytic origin and are highly differentiated. Therefore our report suggests that the fusion of hepatocytes may be the mechanism of giant cell formationinpgch. In conclusion, we described a case of PGCH associated with AIH. Immunohistological findings indicated that the giant cells in this case are not regenerative cells, that they are not formed by amitotic division of nuclei in syncytia, and that fusion of highly differentiated hepatocytes is a probable mechanism of the formation of giant cells. The authors state that they have no Conflict of Interest(COI). References 1. Schaffner F, Popper H. Morphologic studies in neonatal cholestasis with emphasis on giant cells. Ann N Y Acad Sci 111: , Devaney K, Goodman ZD, Ishak KG. Postinfantile giant-cell transformation in hepatitis. Hepatology 16: , Thijs JC, Bosma A, Henzen-Logmans SC, Meuwissen SG. Postinfantile giant cell hepatitis in a patient with multiple autoimmune features. Am J Gastroenterol 80: , Johnson PJ, McFarlane IG. Meeting report: International Autoimmune Hepatitis Group. Hepatology 18: , Micchelli ST, Thomas D, Boitnott JK, Torbenson M. Hepatic giant cells in hepatitis C virus (HCV) mono-infection and HCV/HIV co-infection. J Clin Pathol 61: , Potenza L, Luppi M, Barozzi P, et al. HHV-6A in syncytial giantcell hepatitis. N Engl J Med 359: , Fimmel CJ, Guo L, Compans RW, et al. A case of syncytial giant cell hepatitis with features of a paramyxoviral infection. Am J Gastroenterol 93: , Phillips MJ, Blendis LM, Poucell S, et al. Syncytial giant-cell hepatitis. Sporadic hepatitis with distinctive pathological features, a severe clinical course, and paramyxoviral features. N Engl J Med 324: , Labowitz J, Finklestein S, Rabinovitz M. Postinfantile giant cell hepatitis complicating ulcerative colitis: a case report and review of the literature. Am J Gastroenterol 96: , Iwai M, Jo M, Ishii M, Mori T, Harada Y. Comparison of clinical features and liver histology in acute and chronic autoimmune hepatitis. Hepatol Res 38: , Koskinas J, Deutsch M, Papaioannou C, Kafiri G, Hadziyannis S. Post-infantile giant cell hepatitis associated with autoimmune hepatitis and polyarteritis nodosa. Scand J Gastroenterol 37: , Ben-Ari Z, Broida E, Monselise Y, et al. Syncytial giant-cell hepatitis due to autoimmune hepatitis type II (LKM1+) presenting as subfulminant hepatitis. Am J Gastroenterol 95: , Protzer U, Dienes HP, Bianchi L, et al. Post-infantile giant cell hepatitis in patients with primary sclerosing cholangitis and autoimmune hepatitis. Liver 16: , Rabinovitz M, Demetris AJ. Postinfantile giant cell hepatitis associated with anti-m2 mitochondrial antibodies. Gastroenterology 107: , Kumar A, Minuk GY. Postinfantile giant cell hepatitis in associa- 318

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