Cytopathic Liver Injury in Acute Delta Virus Hepatitis

Transcription

1 GASTROENTEROLOGY 1987;92; CASE REPORT Cytopathic Liver Injury in Acute Delta Virus Hepatitis JAY H. LEFKOWITCH, HOWARD GOLDSTEIN, ROBERT YATTO, and MICHAEL A. GERBER Departments of Pathology, College of Physicians and Surgeons of Columbia University, New York, New York; Good Samaritan Hospital, Suffern, New York; City Hospital Center at Elmhurst and Mount Sinai School of Medicine, New York, New York Hepatitis 8-virus (the 8-agent) is now recognized as a cause of acute hepatitis, fulminant hepatitis, chronic hepatitis, and cirrhosis in hepatitis B surface antigen-positive hosts. This report describes the clinical course and liver biopsy histopathology of acute 8-hepatitis in a young American woman with presumed chronic hepatitis B infection. The liver biopsy specimen features included severe cytotoxic and cytopathic hepatocellular damage, small droplet vacuolar liver cell degeneration, and few parenchymal inflammatory cells, lesions resembling epidemic 8-hepatitis in Venezuelan Indians and experimental chimpanzee 8-superinfection. This case suggests that this form of cytopathic liver injury is an important morphologic expression of 8-virus hepatitis that deserves wider diagnostic recognition. The 8-agent, also known as hepatitis 8-virus (HDV), was discovered in 1977 by Rizzetto and colleagues (1) and is a defective nm ribonucleic acid virus that requires helper functions of the hepatitis B virus (HBV) for replication and infection. The structure of HDV includes 8-antigel} and its ribonucleic acid genome enclosed in a coat of hepatitis B surface antigen (HBsAg) borrowed from HBV (2,3). Modes of HDV infection include acute coinfection by HDV and HBV; acute HDV superinfection of patients with chronic HBV infection; and chronic HDV infection in patients with chronic HBV infection (2,3). Recent morphologic studies indicate that in susceptible populations with HBV infection, concurrent infection by HDV may result in fulminant hepatitis (4,5) or worsening of chronic hepatitis and progression to cirrhosis (6). In addition, a study of epidemic HDV Received March 13, Accepted October 3, Address requests for reprints to; Dr. Jay H. Lefkowitch, Department of Pathology, College of Physicians and Surgeons, 630 West 168th Street, New York, New York by the American Gastroenterological Association /871$3.50 infection in Venezuelan Indians has suggested that hepatocellular injury is due to a cytopathic effect by HDV, consisting of small-droplet steatosis, vacuolization of hepatocytes, and focal necrosis without evidence of lymphocytotoxicity (7,8). We describe the features of acute 8-hepatitis in a young woman with HBV infection whose liver biopsy specimen showed distinctive cytopathic hepatocellular damage resembling that seen in epidemic Venezuelan hepatitis D. Case Report Clinical History A 23-yr-old female cleaning aide was admitted with complaints of weakness, nausea, and vomiting. Four days before admission she sought medical attention for complaints of myalgia, anorexia, and nausea, and was diagnosed as having influenza. She used four to six acetaminophen tablets daily for 3 days before admission. Further medical attention was sought for progressing weakness, cola-colored urine, and pale stools. There was no history of exposure to unusual cleaning agents at work, including carbon tetrachloride. The patient used no alcohol or drugs and had no recent injections or past blood transfusions. She had had sexual relations with a known intravenous drug user for several months. Past history was significant for lymphadenopathy and hypergammaglobulinemia first noted 2 yr before admission. A lymph node biopsy done 1 yr before admission showed benign follicular hyperplasia. On admission, her temperature was 37.8 C and she was jaundiced. There was soft tissue swelling sub mentally and an old scar from the prior lymph node biopsy, with two small palpable cervical nodes. The right upper quadrant was tender to palpation with the liver edge felt 5 em below the right costal margin. The spleen was not felt, and there were no stigmata of chronic liver disease, peripheral edema, or evidence of intravenous injections. Abbreviations used in this paper; HBV, hepatitis B virus; HOV, hepatitis 8-virus.

2 May 1987 DELTA HEPATITIS 1263 Initial blood tests showed a white blood cell count of 6400 per mm 3 with 61% polymorphonuclear leukocytes, 3% bands, 29% lymphocytes, 7% monocytes, and a hematocrit of Additional studies included a prothrombin time of 11.5 s, total bilirubin of 26.2 mg/dl, alkaline phosphatase of 150 IU/L (normal ), aspartate aminotransferase of 3860 lull (normal 7-40), alanine aminotransferase of 2300 lull (normal 7-40), total protein of 7.4 g/dl, albumin of 2.2 g/dl, blood urea nitrogen of 71 mg/dl, and creatinine of 9.7 mg/dl. Results of serologic tests for hepatitis on admission included positive HBsAg, antibody to surface antigen (anti-hbs), hepatitis Be antigen, and antibody to hepatitis B core antigen (anti-hbc). Antibodies to hepatitis A virus were not detectable. Percutaneous liver biopsy performed on the third hospital day showed features of an acute hepatitis (Figure la and B). Portal tracts contained lymphocytes and plasma cells (Figure la). Swollen hepatocytes demonstrated hydropic and rarefied cytoplasm with small vacuoles of apparent fat, suggestive of severe "toxic" hepatocellular damage (Figure lb). Scattered coagulative necrosis of hepatocytes, characterized by acidophilic clumping of the cytoplasm and intrasinusoidal acidophilic bodies, was also present. There was moderate canalicular cholestasis. In most areas, damaged hepatocytes were not associated with significant numbers of mononuclear inflammatory cells; only few intrasinusoidallymphocytes could be identified (Figure lb). This appearance was in distinct contrast to the histopathologic changes of typical acute HBV infection (9-11) in which generalized hepatocyte disarray, swelling, and acidophilic degeneration are associated with prominent intralobular infiltrates of lymphocytes (Figure lc and D). Because these unusual biopsy features suggested the possibility of infection by the 8-agent, specific staining of the liver biopsy tissue for 8-antigen and serum testing for antibody to HDV (anti-a) were undertaken. Paraffin sections of the liver biopsy tissue were stained by an avidinbiotin-peroxidase complex method for 8-antigen (12,13)' hepatitis B core antigen (HBcAg), and HBsAg using the proper controls as described previously (14). Scattered hepatocyte nuclei showed the pre(ience of 8-antigen (Figure 2), whereas HBcAg and HBsAg were not detected. Shikata's orcein stain for HBsAg (15) was also negative. Serum anti-a was not detectable at that time. Peritoneal dialysis was begun on the second hospital day as the patient remained anuric. However, by the eighth hospital day blood urea nitrogen had risen to 54 mg/dl and creatinine had risen to 14.6 mg/dl. Hemodialysis was begun, but was limited by a hypotensive episode, with subsequent respiratory distress. Physical examination revealed a harsh precordial friction rub. Echocardiogram confirmed a pericardial effusion, and an emergency pericardiotomy with evacuation of 800 ml of blood and clots was performed. The hospital course was one of slow improvement. Urine output returned (with proteinuria) and aminotransferase elevations resolved in the first 2 wk. On the 16th hospital day pancreatitis developed, with serum amylase of 1545 IUIL (normal ). Sonogram of the abdomen showed diffuse pancreatic edema, but no gallstones or dilated ducts. The patient responded to conservative therapy, and was discharged 34 days after admission with an aspartate aminotransferase of 118 lull, alanine aminotransferase of 34 lull, total bilirubin of 3.2 mg/dl, alkaline phosphatase of 431 IU/L, total protein of 6.9 g/dl, albumin of 2.5 g/dl, blood urea nitrogen of 31 mg/dl, and creatinine of 4.4 mg/dl. Repeat serologic tests 8 mo later showed positive antibody to hepatitis B e antigen, anti-hbs, immunoglobulin G anti-hbc, and anti-a. Hepatitis B surface antigen, hepatitis B e antigen and immunoglobulin M anti-hbc were not detectable. The patient's sexual partner developed serologically confirmed hepatitis B -4 wk after the onset of the patient's disease. His illness required no hospitalization. Discussion Pathologic studies of human liver disease in 8-hepatitis are now coming of age because of wider availability of serologic tests for this infection and because of interest stimulated by investigations of epidemics such as that in Venezuelan Indians (7,8). Published reports to date stress the potential severity of liver disease once HDV infection develops in the HBsAg-positive host (4-8). The cytopathic form of liver damage described in our patient, with prominence of microvesicular steatosis and few parenchymal inflammatory cells, was an unexpected and distinctive histologic finding in a patient whose initial serologic profile on admission had only suggested infection by HBV. Similar, though not identical, histologic features were described in the reports on epidemic Venezuelan 8-hepatitis as well as in a chronic HBV -carrier chimpanzee with experimentally introduced acute 8-hepatitis (16), but they were not cited in several major studies from centers in the United States (4-6,14). Moreover, Rizzetto and colleagues (17) have commented on the relative rarity of this morphologic expression of HDV infection in their Italian patients, suggesting that a different nutritional background in the Venezuelan subjects was related to their distinctive histopathologic lesions. The purpose of our report is to bring attention to these unusual liver biopsy features that first caused us to suspect 8-virus infection. We are uncertain of the nutritional or other factors that may have contributed to this histopathologic picture. It might represent only one aspect of the morphologic spectrum of 8-hepatitis. Alternatively, it could be postulated that several variants of 8-agent exist that produce different hepatic lesions. In any event, it is notable that such biopsy changes may be seen in patients from metropolitan areas of the United States. Recognition of this pathologic picture should prove to be important and useful as further introduction of 8-infection in segments of the U.S. population

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4 May 1987 DELTA HEPATITIS 1265 Figure 1. A and B. Liver biopsy specimen from patient with acute 5-hepatitis and HBV infection. A. The portal tract (P) contains a mild infiltrate of lymphocytes and plasma cells. Conspicuous hepatocyte cytotoxic changes and vacuolar degeneration are seen in the parenchyma which shows few inflammatory cells. B. Cytoplasmic vacuoles of presumed fat (large arrow) and scattered acidophilic bodies (short arrow) are present. Note the paucity of mononuclear inflammatory cells (open arrows]. C and D. Liver biopsy specimen from patient with acute HBV infection alone. (This reference case, randomly selected from our biopsy file of "acute hepatitis B," was a 36-yr-old man with jaundice, acute HBsAg-positive hepatitis, and 20-fold serum aminotransferase elevations. Immunohistochemical stains for 5-antigen, HBsAg, and hepatitis B core antigen and orcein stain for HBsAg were negative.) C. In comparison to A, note the abundant mononuclear cells within the iobular parenchyma. Hepatocytes undergoing acidophilic degeneration are present (arrow), but the severe liver cell rarefaction and cytotoxic changes are not apparent. D. Parenchymal disarray, hepatocyte swelling, and acidophilic body formation (arrow) are present. Numerous lymphocytes are visible adjacent to hepatocytes. Liver cell damage appears less severe than in B. (Hematoxylin and eosin stain;,a, x 100; B, x 400; C, x 100; D, x400.) «occurs (18), particularly among drug addicts and their sexual partners (14,18)' as in our patient. The serologic data regarding this patient's HBV and HDV infections require clarification. We believe that the positive admission serum tests for HBsAg, hepatitis B e antigen, and anti-hbc combined with the liver biopsy histopathology and nuclear staining for 5-antigen are consistent with an acute 5-super- Figure 2. Positive staining (black) for 5-antigen in several hepatocyte nuclei (arrows) in liver biopsy specimen from patient with acute 5-hepatitis and HBV infection. (Paraffin section stained with specific antiserum to 5- antigen by the avidin-biolin-peroxidase complex method; no counterstain; x 380.) infection of a chronic HBV carrier. Subfractionation of the anti-hbc to identify an immunoglobulin M antibody was unfortunately not requested at the time of admission, thereby precluding documentation of an acute co-infection by HBV and HDV. The significance of the positive anti-hbs concomitant with HBsAg must be considered uncertain, particularly because the specific anti-hbs ratio units and antigenic determinants of the HBsAg were not obtained. On the other hand, the absence of antibody to 5- antigen on admission (despite positive staining for 5-antigen in the liver biopsy) is not unexpected; 5-antigen in liver tissue may be the only marker of HDV infection in the florid stage of acute IS-hepatitis (17). Indeed, the patient's anti-is test became positive later in the clinical course. The case can therlilfore he made that this patient had an underlying mild form of chronic HBV infection (such as chronic persistent hepatitis), features of which were not identifiable once the striking changes of acute 5-hepatitis were superimposed. The presence of underlying chronic liver disease is supported by this patient's low level of albumin (2.2 g/dl) on admission, although undocumented proteinuria before admission might also have contributed to this finding. As far as the pathogenesis of this patient's renal failure is concerned, the issue of HBV -related immune complex disease might be raised (19), but there is insufficient data by which to corroborate this hypothesis. In regard to the development of acute pancreatitis in the setting of severe hepatitis, a number of etiologic factors have been proposed, including viral infection and shock (20). References 1. Rizzetto M. Canese MG. AricQ S. et al. Immunofluorescence detection of a new antigen-antibody system (delta/anti-delta) associated with hepatitis B virus in liver and serum of HBsAg carriers. Gut 1977;18: Ri zzetto M. The delta agent. Hepatology 1983;3: Rizzetto M. Verme G. Delta hepatitis-present status. Hepatol (Arnst) 1985;1: Govindarajan S. Chin KP. Redeker AG. Peters RL. Fulminant B viral hepatitis: role of delta agent. Gastroenterology 1984;86:

5 1266 LEFKOWITCH ET AL. GASTROENTEROLOGY Vol. 92, No.5, Part 1 5. Govindarajan S, DeCock KM, Peters RL. Morphologic and immunohistochemicai features of fulminant delta hepatitis. Hum Pathol 1985;16: Kanel GC, Govindarajan S, Peters RL. Chronic delta infection and liver biopsy changes in chronic active hepatitis B. Ann Intern Med 1984;101: Hadler SC, DeMonzon M, Ponzetto A, et al. Delta virus infection and severe hepatitis. An epidemic in the Yucpa Indians of Venezuela. Ann Intern Med 1984;10: Popper H, Thung SN, Gerber MA, et al. Histologic studies of severe delta agent infection in Venezuelan Indians. Hepato logy 1983;3: Okuno T, Sano A, Deguchi T, et al. Pathology of acute hepatitis A in humans. Comparison with acute hepatitis B. Am J Clin Pathol 1984;81: Abe H, Ikejiri N, Sata M, et al. Histological findings of the liver in viral hepatitis A. A comparison with hepatitis type B. Acta Hepatol Jpn 1981;22: Popper H, Dienstag JL, Feinstone SM, Alter HJ, Purcell RH. Lessons from the patholdgy of viral hepatitis in chimpanzees. In: Bianchi L, Gerok W, Sickinger K, Stalder GA, eds. Virus and the liver. Boston: MTP Press, 1980: Rizzetto M, Hoyer B, Canese MG, et al. Delta antigen: the association of delta antigen with hepatitis B surface antigen and ribonucleic acid in the serum of delta infected chimpanzees. Proc Natl Acad Sci USA 1980;77: Rizzetto M, Canese MG, Gerin JL, et al. Transmission of hepatitis B virus-associated delta antigen to chimpanzees. J Infect Dis 1980;141: Thung SN, Gerber MA. Immunohistochemical study of delta antigen in an American metropolitan population. Liver 1983;3: Shikata T, Uzawa T, Yoshiwara N, Akatsuka T, Yamazaki S. Staining methods of Australia antigen in paraffin sectiondetection of cytoplasmic inclusion bodies. Jpn J Exp Med 1974;44: Govindarajan S, Fields HA, Humphrey CD, Margolis HS. Pathologic and ultrastructural changes of acute and chronic delta hepatitis in an experimentally infected chimpanzee. Am J Pathol 1986;122: Rizzetto M, Verme G, Gerin JL, Purcell RH. Hepatitis delta virus disease. In: Popper H, Schaffner F, eds. Progress in liver diseases. Volume VIII. New York: Grune & Stratton, 1986: Nishioka NS, Dienstag JL. Delta hepatitis. A new scourge? N Engl J Med 1985;312: Dienstag JL. Hepatitis B as an immune complex disease. Semin Liver Dis 1981;1: Sherlock S. Diseases of the liver and biliary system. 7th ed. London: Blackwell Scientific, 1985:114.