Pathology of Acute Hepatitis A in Humans

Transcription

1 Pathology of Acute Hepatitis A in Humans Comparison with Acute Hepatitis B TADAO OKUNO,.D., ATSUSHI SANO,.D., TAKESHI DEGUCHI,.D., YOSHINORI KATSUA,.D., TAKESHI OGASAWARA,.D., TAKESHI OKANOUE,.D., AND TATSURO TAKINO,.D. Little is known about the pathologic characteristics of viral hepatitis A in humans. The authors compared the histologic features in liver biopsy specimens taken within 3 days of the onset of illness from 15 patients with hepatitis A and 14 patients with acute hepatitis B. In both hepatitis A and B, liver cell damage and necrosis were diffusely located, with accentuation in the centrilobular and midzonal areas in which ballooning degeneration and variation in cytoplasmic staining quality were observed frequently. One case of epidemic hepatitis A showed prominent periportal liver cell necrosis with inconspicuous centrilobular liver cell alterations. Kupffer cell mobilization was mild in hepatitis A, but more striking in hepatitis B. The portal inflammation was more pronounced and rich in plasma cells in hepatitis A than in hepatitis B. In summary, there were no major differences in the pathologic features of acute hepatitis A and B as sampled within 3 days of the onset of illness. (Key words: Hepatitis A; Hepatitis, viral; Liver biopsy) Am J Clin Pathol 1984; 81: THE ORPHOLOGIC CHANGES of acute viral hepatitis have been described in detail. 2,4,9,1-12 In recent years, hepatitis A and B have been differentiated serologically from each other. However, little is known about the pathologic characteristics of hepatitis A in humans, compared with acute hepatitis B, and there is no consensus about its histologic characteristics. Tanikawa' 3 states that the morphologic changes of the liver in a natural outbreak of hepatitis A in primary school children were similar to those of hepatitis A in chimpanzees. Recently, Abe and co-workers' also stressed that acute hepatitis A in human adults was characterized by conspicuous mononuclear inflammatory cell infiltration of the portal tracts with frequent disruption of the limiting plate, periportal hepatocyte necrosis, and virtual sparing of the centrilobular parenchyma. However, other observers have emphasized histologic similarities in acute hepatitis A and B, rather than differences. The purpose of this paper is to describe the pathologic changes in liver biopsy specimens from 15 patients with acute hepatitis A, identified as hep- Received January 25,1983; received revised manuscript and accepted for publication August 29, Address reprint requests to Dr. Okuno: Third Department of Internal edicine, Kyoto Prefectural University of edicine, Kawaramachi, Hirokoji-Agaru, Kamikyo-ku, Kyoto, 62, Japan. Third Department of Internal edicine, Kyoto Prefectural University of edicine, Kyoto, Japan atitis A by positive Ig-anti-HAV, compared with those of 14 patients with acute hepatitis B. aterials and ethods One hundred ninety-four patients with a diagnosis of acute viral hepatitis were hospitalized in the Third Department of Internal edicine, Kyoto Prefectural University Hospital, during the 6-year period from 1975 to 198. These 194 were classified serologically into 62 cases of hepatitis A, 5 of hepatitis B, and 82 of non-a, non- B hepatitis. Liver biopsy samples were obtained in 1 of these 194 patients, in most within 6 days after the onset of illness, because all patients were asked to consent to liver biopsy, but only 1 patients agreed to the procedure. In order to evaluate the morphologic differences between acute hepatitis A and B, 29 cases were selected from these 1 biopsied cases, on the basis that liver biopsy was performed within 3 days of the onset of illness. All of these patients had neither known previous exposure to hepatotoxins nor consumption of more than 6 g of ethanol a day. Sera taken at the time of admission and during the period of follow-up were stored at 2 C before testing. HBsAg and anti-hbs were detected by radioimmunoassay (Austria II and Ausab, respectively, Abott Laboratories, North Chicago, IL). Anti-HBc was detected by CORAB kit (Abott Laboratories). Ig-anti- HAV was detected by HAVAB- radioimmunoassay kit (Abott Laboratories). Hepatitis A infection was identified by positive Ig-anti-HAV in the absence of HBsAg and anti-hbc in serum. Hepatitis B infection was identified by positive HBsAg in the acute phase serum with disappearance of HBsAg during convalescence. Liver function tests were measured by routine laboratory methods at weekly intervals for the period of follow-up. Liver biopsy was carried out using a enghini or Vim-Silverman needle. Tissue was fixed in neutral formalin, embedded in paraffin and sectioned at 5-/*m intervals. Paraffin sec- 162 Downloaded from on 17 August 218

2 Vol. 81 -No. 2 PATHOLOGY O ACUTE HEPATITIS A IN HUANS Table 1. Summary of Clinical Data in Acute Viral Hepatitis A and B 163 Acute hepatitis A Acute hepatitis B Student's /-test Number of cases Age (yr) ±SD Sex ale/emale Days to biopsy* ±SD Liver function testsf T. Bilirubin (mg/dl) SGOT (KU)t SGPT (KU) Alkaline phosphatase (KAU)H 7-GTP (mu/ml)" TTT (U)tt Ig (mg/dl) ± 8.7 1/ ± ± ± ± ± ± ± ± ± / ± ± ± ± ± ± ± 2.7 P <.2 P <.5 NS P<.\ P <.2 NS NS P<.\ * After the onset of illness. t Data on admission. t KU: Karmen Units (reference range 12 31). KU: Karmen Units (reference range 3 ~ 33). 11 KAU: King-Armstrong Units (reference range 4 1). * Reference range 4 mu/ml. tt Reference range.2 ~- 4 U. ft Reference range 7 17 mg/dl. tions from liver biopsy samples were stained by standard methods including hematoxylin and eosin, silver -impregnation for reticulin fibers, and asson's trichrome stain. Before analysis of the clinical and laboratory data, all liver biopsy sections were coded and then blindly reviewed by one of the authors (T.O.). Histologic assessment was made in a semiquantitative manner, using a -3 scale ( = absent, 1 = mild, 2 = moderate, 3 = severe) for the following parameters: Liver cell swelling, necrosis, inflammatory cell infiltration (periportal, midzonal, and central), lobular distribution of lesions, Kupffer cell mobilization, cholestasis, portal inflammation, and portal fibrosis. or statistical evaluation, Student's est was used. Results Clinical data are shown in Table 1. The mean age of 15 patients with hepatitis A (1 men and five women) was 33.3 years (range, years), and that of 14 patients with hepatitis B (11 men and three women) 43.8 years (range, years). The mean number of days to biopsy after the onset of illness was 18.6 days in patients with hepatitis A, and 24.2 days in patients with hepatitis B. The levels of serum total bilirubin, alkaline phosphatase, and 7-GTP were not significantly different in hepatitis A and B. SGOT and SGPT were statistically higher in hepatitis B than in hepatitis A (P <.1 and <.2, respectively). However, thymol turbidity test (TTT) was Table 2. Histologic indings in 15 Cases of Viral Hepatitis A with Liver Biopsy Performed within 3 Days of the Onset of Illness Case Number Sex Age (yr) Days to Biopsy after Onset Parenchymal Changes Periportal idzonal Central Kupffer Cell obilization Cholestasis Portal Changes Inflammation ibrosis II The degree of histologic abnormality was graded from to. Downloaded from on 17 August 218

3 164 OKUNO ET AL. A.J.C.P. ebruary 1984 Table 3. Histologic indings in 14 Cases of Acute Viral Hepatitis B with Liver Biopsy Performed within 3 Days of the Onset of Illness Case Number Sex Age (yr) Days to Biopsy after Onset Parenchymal changes Periportal idzonal Central Kupffer Cell obilization Cholestasis Portal Changes Inflammation ibrosis i+ i+ i+ The degree of histologic abnormality was graded from to. significantly higher in hepatitis A than in hepatitis B (P <.1) and Ig showed much higher values in hepatitis A than normal. Histologic features are summarized in Tables 2 and 3. In both hepatitis A and B, liver cell damage and necrosis were diffusely located, with accentuation in centrilobular IG. 1. Viral hepatitis A (case 3). There is prominent lobular disarray with liver cell swelling and focal liver cell necrosis. The lobular disarray is more prominent in the centrilobular area. The central vein is shown by arrow heads. The portal tract shown by arrows is heavily infiltrated and enlarged, with some irregularity of its border. Hematoxylin and eosin (original magnification X2). Downloaded from on 17 August 218

4 lg. 2. Same case as in igure I. A (upper) is a higher magnification of the centnlobular area, showing marked liver cell swelling and focal liver cell necrosis. Kupffer cell mobilization is not prominent. Hematoxylin and eosin (original magnification X1). B (lower) is a higher magnification of the portal tract, heavily infiltrated by lymphocytes and plasma cells, shown in the inset. The limiting plate is mildly disrupted. Hematoxylin and eosin (original magnification X5); Inset: Hematoxylin and eosin (original magnification X2). Downloaded from on 17 August 218

5 IG. 3. Viral hepatitis A (case 9). A (upper). The portal tract is moderately infiltrated. There is prominent periportal liver cell alteration with disruption of the limiting plate. There is bridging necrosis extending downwards from the portal tract at the center of the field and also a focus of confluent necrosis in the upper right hand corner. Hematoxylin and eosin (original magnification X25). B (lower). Centrilobular liver cell swelling, necrosis, and Kupffer cell mobilization are inconspicuous. A small portal tract is seen aboveright.cv; central vein. Hematoxylin and eosin (original magnification X25). Downloaded from on 17 August 218

6 IG. 4. Acute viral hepatitis B (case 2). A (upper). The central midzonal areas show prominent lobular disarray, liver cell necrosis, and Kupffer cell mobilization. Compare with igure 1A. Hematoxylin and eosin (original magnification X5). B (lower). The small portal tract is mildly infiltrated by mononuclear cells. There is no disruption of the limiting plate. Hematoxylin and eosin (original magnification X5). Downloaded from on 17 August 218

7 168 OKUNO ET AL. AJ.C.P. ebruary 1984 IG. 5. Central-portal bridging necrosis in viral hepatitis A. The portal tract (P) is infiltrated by mononuclear cells. The centrilobular area (C) shows a wide area of parenchymal necrosis accompanied by inflammatory cell infiltration that extends to the portal tract. Hematoxylin and eosin (original magnification X5). and midzonal areas (igs. 1 and 2) in which ballooning degeneration and variation in cytoplasmic staining quality were observed frequently. The one exception among the examples of hepatitis A was in case 9, biopsied 2 days after the onset of illness. In this patient, there were prominent periportal liver cell alterations (ig. 3A), but centrilobular liver cell swelling and necrosis were sparse (ig. 3B). This patient was involved in a hepatitis A outbreak in Kyoto, whereas the others had sporadic hepatitis A. In hepatitis B, liver cell alterations were diffuse, but less in the periportal areas in most cases (ig. 4). Kupffer cell mobilization was mild in hepatitis A, but more striking in hepatitis B. Cholestasis was noted in three cases each of hepatitis A and hepatitis B. Portal inflammation was more pronounced in hepatitis A (igs. 2 and 3), and the inflammatory infiltrate in the portal tracts was rich in plasma cells (ig. 2B). ild to moderate portal fibrosis was observed in five cases of hepatitis A and three cases of hepatitis B. In some cases of both hepatitis A and B there was bridging hepatic necrosis linking centrilobular and portal areas (ig. 5). Clinical recovery was complete Downloaded from on 17 August 218 and liver function tests returned to normal in all patients. No patients appeared to develop chronic hepatitis. Discussion In the present study, the morphologic features of acute hepatitis A and B were similar to those of acute viral hepatitis described previously. 2,4,9112 However, some differences between hepatitis A and B were observed. Kupffer cell mobilization was more striking in hepatitis B than in hepatitis A. By contrast, portal inflammation was pronounced and rich in plasma cells in hepatitis A. One patient with hepatitis A was exceptional in showing the conspicuous periportal inflammation with sparing of centrilobular liver cells reported in the literature in chimpanzees 31 and in humans. 1,15 Our findings are not completely in agreement with those of Abe and colleagues' in so far as we found diffuse parenchymal damage in most patients. However, the cases studied by Abe and associates' were all of epidemic hepatitis A, whereas all but one of ours were sporadic, and the patients were

8 Vol. 81 -No. 2 PATHOLOGY O ACUTE HEPATITIS A IN HUANS 169 much younger than those in the present study. urthermore, liver biopsies were performed much earlier in their study than in ours. Teixeira and co-workers' 5 studied liver biopsy specimens taken between 2 and 27 weeks from onset in 17 patients with hepatitis A and found considerable centrilobular liver cell damage, inflammation, and cholestasis in many of their biopsy samples, as well as periportal inflammation and abundant plasma cells in some. Their findings are thus broadly similar to ours. Tanaka and colleagues' 4 also studied liver biopsy sections in seven patients with epidemic hepatitis A, and four patients with sporadic hepatitis A. In their study, liver tissue samples were taken between 4 and 37 days after onset of jaundice. The earlier specimens taken 4, 6, 7, and 8 days after onset of jaundice revealed prominent portal inflammation and diffuse lobular alteration manifested by hydropic degeneration and coagulation necrosis, not only in periportal but also in centrilobular areas, whereas later tissues showed less conspicuous portal inflammation, but still hydropic degeneration and spotty necrosis in centrilobular areas. A recent experimental study has demonstrated that hepatitis A virus (HAV) antigen-containing hepatocytes were localized in periportal areas in enterally inoculated hepatitis A in marmosets. 5 However, intravenous inoculation of HAV in chimpanzees 6,8 and marmosets 7 has shown random but uniform distribution of HAV antigen in hepatocytes without any preference for pericentral or periportal areas. Conclusions regarding similarities or differences in the pathologic features of hepatitis A in humans and chimpanzees are therefore hazardous, because the inoculum size and route of HAV infection may not be comparable, although basic morphologic patterns are similar. Acknowledgments. The authors are grateful to Professor P. J. Scheuer, Department of Histopathology of the Royal ree Hospital for his helpful discussion and reviewing the manuscript, and to iss Kagumi Yuasa for typing the manuscript. References 1. Abe H, Beninger PR, Ikejiri N, Setoyama H, Sata, Tanikawa K: Light microscopic findings of liver biopsy specimens from patients with hepatitis type A and comparison with type B. Gastroenterology 1982; 82: Desmet VJ, DeGroote J: Histological diagnosis of viral hepatitis. In: Viral Hepatitis. Edited by Tygstrup N. Philadelphia, W. B. Saunders, 1974, pp Dienstag JL, Popper H, Purcell RH: The pathology of viral hepatitis types A and B in chimpanzees. A comparison. Am J Pathol 1976; 85: Ishak KG: Light microscopic morphology of viral hepatitis. Am J Clin Pathol 1976; 65: Krawczynki KK, Bradley DW, urphy BL, et al: Pathogenetic aspects of hepatitis A virus infection in enterally inoculated marmosets. Am J Clin Pathol 1981; 76: athiesen LR, einstone S, Purcell RH, Wagner JA: Detection of hepatitis A antigen by immunofluorescence. Infect Immun 1977; 18: athiesen LR, Drucker J, Lorenz D, et al: Localization of hepatitis A antigen in marmoset organs during acute infection with hepatitis A virus. J Infect Dis 1978; 138: urphy BL, aynord JE, Bradley DW, et al: Immunofluorescence of hepatitis A virus antigen in chimpanzees. Infect Immun 1978; 21: Peters RL: Viral hepatitis: a pathologic spectrum. Am J ed Sci 1975;27: Popper H: The pathology of viral hepatitis. Can ed Assoc J 1972; 16: Popper H, Dienstag JL, einstone S, Alter HJ, Purcell RH: The pathology of viral hepatitis in chimpanzees. Virchows Arch A Pathol Anat Histol 198; 387: Smetana H: The histopathology of viral hepatitis by needle biopsy. Gastroenterology 1954; 26: Tanikawa K: Acute viral hepatitis. Type A hepatitis. Its epidemiology, clinical pictures and pathologic changes of the liver. Gastroenterol Jpn 1979; 14: Tanaka T, Tanaka I, Koga, et al: orphological findings of acute hepatitis A. Acta Hepatol Jpn 1981; 22: Teixeira R Jr., Weller IVD, urray A, et al: The pathology of hepatitis A in man. Liver 1982; 2:53-6 Downloaded from on 17 August 218