Original Article
Syncytial Giant-Cell Hepatitis — Sporadic Hepatitis with Distinctive Pathological Features, a Severe Clinical Course, and Paramyxoviral Features
N Engl J Med 1991; 324:455-460February 14, 1991
- Abstract
- Abstract
Background and Methods.
We describe a new form of hepatitis, occurring in 10 patients over a period of six years, characterized clinically by manifestations of severe hepatitis, histologically by large syncytial giant hepatocytes, and ultrastructurally by intracytoplasmic structures consistent with paramyxoviral nucleocapsids.
Results.
The patients ranged in age from 5 months to 41 years. The tentative clinical diagnosis before biopsy was non-A, non-B hepatitis in five patients and autoimmune chronic active hepatitis in the others. Five patients underwent liver transplantation; the others died.
The diagnosis of syncytial giant-cell hepatitis was established pathologically. The liver cords were replaced in all 10 patients by syncytial giant cells with up to 30 nuclei. In 8 of the 10 the cytoplasm contained pleomorphic particles of 150 to 250 μm, filamentous strands, and particles of 14 to 17 nm with peripherally disposed spikes resembling paramyxoviral nucleocapsids. Structures resembling degenerated forms were found in the other two patients. One of two chimpanzees injected with a liver homogenate from the index patient had an increase in the titer of paramyxoviral antibodies, probably an anamnestic reaction to previous paramyxoviral infection, suggesting that a paramyxoviral antigen but not viable virus was present in the liver homogenate.
Conclusions.
Although further virologic studies will be required for precise classification, we believe that paramyxoviruses should be considered in patients with severe sporadic hepatitis. (N Engl J Med 1991; 324:455–60.)
Media in This Article
Figure 1
Biopsy Specimen Showing Syncytial Giant Cells in Continuity with Normal Liver Cells in the Hepatic Cords.Figure 2
Micrograph of Giant Cells at High Magnification.Article Activity
- Article
IN this paper, we describe 10 patients seen over a six-year period with acute and chronic hepatitis in whom liver-biopsy specimens were characterized by the presence of giant multinucleated syncytial hepatocytes. Giant cells are a common pathological finding in liver disorders in infants and very young children, but they are not common in adults. Large syncytial giant hepatocytes have rarely been described in patients at any age, and their association with intracytoplasmic structures consistent with paramyxoviral nucleocapsids, found in 8 of the 10 cases reported here, has never to our knowledge been described. The clinical and pathological features of this condition are presented here, together with preliminary virologic results in two chimpanzees injected with a homogenate of liver tissue from the index patient.
Case Reports
Index Patient
The index patient (Patient 10) was a 32-year-old female physical-education teacher in whom acute icteric hepatitis developed in November 1985. Markers for hepatitis A and B were negative, and the case was diagnosed as non-A, non-B hepatitis. By February 1986 the jaundice had resolved, but the serum aspartate aminotransferase level remained elevated at 270 U per liter. The patient returned to work until the end of the school year. During the summer, she began to tire while exercising, and fluctuating jaundice developed. She had no history of jaundice, transfusions, or contact with sick persons. Her only travel outside Canada was to Nassau, Bahamas, in March 1985.
On examination, a few spider nevi were seen. The liver was not enlarged, and the spleen was not palpable. There was no ascites or edema. The results of initial investigations were as follows: the serum bilirubin level was 57 μmol per liter; aspartate aminotransferase, 844 U per liter; alanine aminotransferase, 910 U per liter; alkaline phosphatase, 118 U per liter; albumin, 41 g per liter; and globulin, 55 g per liter. Immunoglobulins were diffusely increased, and the prothrombin time was 12 seconds (control value, 11). Viral serologic tests for hepatitis A and B, Epstein–Barr virus, toxoplasmosis, human immunodeficiency virus (HIV), and cytomegalovirus were negative. Serum samples subsequently tested for hepatitis C were also negative. The hemogloblin level was 116 g per liter, the white-cell count 4.9×109 per liter, and the platelet count 210×109 per liter. The serum ceruloplasmin level, the serum iron level, the total iron-binding capacity, and the level of alpha1-antitrypsin were all within the normal range. The results of immunoserologic studies showed the samples to be positive for antinuclear antibody and anti–smooth-muscle antibody (titer, 1:80) and negative for anti—mitochondrial antibody and rheumatoid factor, with normal levels of C3 and C4.
The patient was admitted to the hospital for a liver biopsy, which revealed syncytial giant cells and chronic hepatitis. The biopsy specimen was submitted for electron-microscopical studies and also for viral culture. Because of the findings on light microscopy, notably syncytial giant cells and ultrastructural features (see below), complement-fixing antibodies to the paramyxovirus group of viruses were sought. Tests for parainfluenza viruses 1 and 2, measles, and mumps were negative (titer, ≤l:2). The titer of complementfixing antibody to parainfluenza 3 was 1:16. The patient was discharged.
From October to December 1986, she returned to teaching but was advised not to undertake strenuous exercise. The results of liver-function tests remained stable (serum bilirubin level, 60 μmol per liter; aspartate aminotransferase, 410 U per liter; alanine aminotransferase, 210 U per liter; and alkaline phosphatase, 140 U per liter). By January 1987 the patient had become increasingly tired, with increased anemia and jaundice, and hepatosplenomegaly and ascites had developed. Investigation revealed a serum bilirubin level of 310 μmol per liter, levels of aspartate and alanine aminotransferase >2000 U per liter, a prothrombin time of 23 seconds, and an albumin level of 30 g per liter. She was admitted to the hospital for a transjugular liver biopsy, which showed the formation of more syncytial giant cells, now in columns. The results of weekly serologic tests for paramyxoviruses including measles were normal. While the patient was awaiting a liver transplant, an erythematous macular rash typical of measles developed, and the measles-antibody titer rose transiently to 1:160. The attack lasted only two to three days, and the rash then faded and the antibody titer returned to normal. Liver transplantation was performed on March 25, 1987. After a complicated postoperative course, the patient was discharged well six weeks later. There was no recurrence of disease in the transplant.
First Liver Biopsy
On light microscopy, the liver cords in the first liver-biopsy specimen were occupied by syncytial giant cells (Fig. 1Figure 1
Biopsy Specimen Showing Syncytial Giant Cells in Continuity with Normal Liver Cells in the Hepatic Cords. and 2Figure 2Micrograph of Giant Cells at High Magnification.). The giant cells were much larger than those seen in neonatal hepatitis and had 3 to 20 centrally placed nuclei and a very large volume of cytoplasm. The cytoplasm frequently had the appearance of ground glass and was deeply acidophilic. Centrally, the cytoplasm also contained many brown granules of various sizes, some containing biliary pigment. The remaining hepatocytes had various degrees of ballooning degeneration and focal necrosis. Bridging necrosis was prominent. Cholestasis was prominent and was within both cells and the canalicular and ductal lumina. The portal and periportal regions had been infiltrated by cells producing chronic inflammation, predominantly lymphocytes.Second Liver Biopsy
The patient's second biopsy sample was small and again had numerous syncytial giant cells, but fibrosis and nodular regenerative changes were also evident. The biopsy specimen was interpreted as showing more advanced chronic hepatitis with features of syncytial giant cells and early cirrhosis.
Liver at Transplantation
On gross examination at transplantation, the liver was uniformly dark green externally and weighed 1100 g. Its cut surface showed two morphologic patterns: near the capsule and in the center of the liver the parenchyma was finely nodular and cirrhotic; in between, large regions were retracted and smooth. More than 50 percent of the hepatocytes were lost, and many remaining hepatocytes showed degenerative changes. On microscopical examination the liver showed prominent piecemeal necrosis, fibrosis, nodules, syncytial giant cells, cholestasis with bile plugs and lakes, and bile-ductular proliferation.
Electron Microscopy
Of special interest in these biopsy specimens were the syncytial giant cells. They had obvious hepatocellular features, with a great abundance of cellular organelles typical of hepatocytes. Remnants of plasma membranes often ended abruptly in the cytoplasm. Intracytoplasmic bile canaliculi were also seen. The peripheral cytoplasm contained large numbers of mitochondria and an abundance of smooth membranes, which explained the appearance of ground glass histologically. Some of the membranes were interspersed with glycogen particles forming glycogen-membrane arrays or glycogen bodies. The nuclei had peripherally condensed chromatin, but no inclusions were seen. The cytoplasmic granules seen histologically were secondary lysosomes and pleomorphic membranous formations (Fig. 3Figure 3
Electron Micrographs of Syncytial Giant Cells Showing Viral Particles.A). Associated with the membranes were pleomorphic spherical particles of 150 to 250 nm and filamentous structures (Fig. 3B). In some areas the filamentous structures had a uniform crystalline arrangement that on sectioning was 14 to 17 nm in diameter, with peripherally disposed spikes (Fig. 3C). The size and ultrastructural morphologic features of these particles were typical of the nucleocapsids of paramyxoviruses. They were most numerous in the central part of the syncytial giant cells. In selected areas, the apparent budding of viral particles from membranes was noted. Viral components were frequently seen within lysosomes. The electron-microscopical findings were similar in all but two of the patients we describe; in those two, only degenerated forms were identified.virologic Studies
Approximately 4 g of frozen liver tissue obtained from the surgically removed liver of Patient 10 at transplantation and subsequently stored at —80°C for 14 months was ground with sterile sand in a mortar and pestle and suspended in Hanks' balanced salt solution with 10 percent fetal-calf serum to form a 10 percent suspension. After low-speed centrifugation to clarify the preparation, it was frozen at —80°C. This material was used for serologic and virologic studies and for the inoculation of chimpanzees. Two juvenile male chimpanzees, 32 and 26 months of age, were each inoculated intravenously with 1 ml of liver suspension. The chimpanzees were housed and maintained in a fully accredited facility, as previously described.1 The protocol for this experiment was reviewed by the appropriate animal-care and animal-use committees. Serum samples and liver-biopsy specimens were obtained before inoculation and weekly for 17 weeks; serum samples were obtained biweekly for another 4 weeks.
In neither animal was there biochemical or histologic evidence of hepatitis or serologic evidence of infection with hepatitis A virus, hepatitis B virus, or hepatitis C virus. However, one chimpanzee (1384) had a strong serologic response to two paramyxoviruses, measles virus and parainfluenza 4, when tested by complement fixation (Fig. 4Figure 4
Titers of Complement-Fixing Antibodies to Paramyxoviruses and Liver Homogenate in Chimpanzee 1384.). In addition, the animal had complement-fixation antibodies to an antigen or antigens in the 10 percent liver suspension used for inoculation as well as in a liver suspension from a normal chimpanzee. Hemagglutinating antibodies to sheep red cells also developed in the chimpanzee. Antibody responses to other paramyxoviral antigens (parainfluenza 1, 2, and 3 and mumps virus) were negative. The chimpanzee had previously been infected experimentally with respiratory syncytial virus and had an essentially unchanging anti—respiratory syncytial virus titer throughout the experiment. The pattern of antibody responses was typical of an anamnestic (recall) response. Antibody was first detected on day 7 after inoculation, peaked on approximately day 14, and returned to lower levels relatively quickly. The hemagglutinating response to sheep red cells was very similar to the complement-fixation response to measles (data not shown). Hemagglutinating responses to other red cells (from guinea pig, chicken, rhesus monkey, and African green monkey) were negative or equivocal. Serum samples obtained from the chimpanzee on days 7, 14, and 30 were fractionated into IgM and IgG classes by chromatography on Quik-sep System-II columns (Isolab, Akron, Ohio). All the antiviral and hemagglutinating activity was found in the IgG fraction, further evidence of an anamnestic response. In contrast, the other chimpanzee (1410) did not have antibodies to any of the antigens tested.When the 10 percent liver homogenates from the patient and the normal chimpanzee were tested against reference antiserum to paramyxoviruses by complement fixation, no differences were found. We could not detect paramyxoviral antigens in the liver from Patient 10 by serologic means.
The liver suspension was inoculated into Hep-2 and LLC cell cultures in an attempt to recover a paramyxovirus. The cultures were examined for syncytia and underwent hemadsorption with guinea pig red cells weekly for three weeks. Neither of the cultures revealed any evidence of a hemadsorbent or syncytia-producing transmissible agent.
Case Histories and Pathological Findings
The index patient has been described in detail, since the findings in her case are representative of those in a group of 10 patients (Tables 1Table 1
Clinical Characteristics of the Patients. and 2Table 2
Histopathological and Electron-Microscopical Findings on Initial Liver Biopsy.*). The patients ranged in age from 5 months to 41 years. Three presented with subacute hepatic failure that was thought to be of viral origin, but as in all the cases, serologic virologic markers were negative. Five patients had positive serologic markers for autoantibodies, and two had autoimmune hemolytic anemia. None of the patients tested were HIV-positive. Only 1 of the 10 patients had a history of measles (Patient 3). Three patients (Patients 2, 4, and 6) had been immunized against measles. Specific serologic testing for measles was performed only in the index patient. Only the index patient had a rash. Specific tests for immunodeficiency were not performed. The working clinical diagnosis before biopsy was non-A, non-B hepatitis in five patients and autoimmune chronic active hepatitis in the others. Five patients were treated by liver transplantation and survived; the others died. Disease did not recur in any of the transplanted livers. Pathological features of the liver were diagnostic in each instance and established the diagnosis of syncytial giant-cell hepatitis.The hallmark of the condition is the presence of syncytial giant cells replacing the liver-cell cords. The syncytial cells in the biopsy samples conformed to the reticular framework of the cord and showed a marked predilection for the zone 3 (centrilobular) region of the liver. The syncytial giant cells were large and contained many nuclei (commonly up to 30) within a single large cytoplasmic body. They were easily recognized on light microscopy. In some instances, the syncytial cells crossed the sinusoids to form syncytial masses with neighboring cords. Dying syncytial cells had nuclear pyknosis or karyorrhexis and infiltration with neutrophils. Bridging necrosis was common, occurring most frequently in the areas where the syncytial giant cells were most numerous; linear areas of necrosis were frequently bordered by syncytial giant cells. Other histopathological findings were typical of severe acute and chronic viral hepatitis: cholestasis, mononuclear-cell aggregation, ballooning of cells, loss of hepatocytes, and portal and periportal inflammation.
Using the peroxidase–antiperoxidase technique, we performed a battery of immunohistochemical-staining tests for paramyxoviruses, including parainfluenza 1, 2, and 3, measles virus, respiratory syncytial virus, and distemper virus. Lung tissue with giant cells and known viral particles from patients who had died of measles pneumonia and respiratory syncytial virus pneumonia served as controls. The only stain that was equivocally positive was the immunoperoxidase reaction with canine distemper, but it was not strong enough to be definitive. All the other stains were negative.
Discussion
We have described 10 patients with an unusual form of giant-cell hepatitis associated with a severe clinical course resulting in acute or chronic hepatic necrosis, which in these cases ended in either death or liver transplantation. On electron microscopy, structures resembling the nucleocapsids of paramyxoviruses were seen in 8 of the 10 cases.
Giant cells constitute evidence of a nonspecific reaction in infants and children with liver disorders including neonatal hepatitis, biliary atresia,2 3 4 5 and chronic active hepatitis with autoimmune hemolytic anemia and circulating immune complexes.6 In older children and adults, giant cells are infrequently seen in association with autoimmune features7 8 9 and drug reactions.10 A report from Austria has described six patients with postinfantile giant-cell hepatitis of unknown cause; we would interpret the biopsy findings in that report as indicating syncytial giant cells.8 Similarly, in another case of non-A, non-B giant-cell hepatitis, we would interpret what were described as "microtubular aggregates" as paramyxovirions.11 HIV infection may be associated with giant cells in the liver,12 but several of our patients were tested for HIV and were negative.
Fusion of cells to form syncytial giant cells is a pathologic feature of paramyxoviruses. In measles pneumonitis, for instance, syncytial giant cells are found in the alveolar walls of the lung,13 , 14 and giant cells (Warthin—Finkeldey cells) may also be found in lymphatic tissue.15 Cell fusion is part of the basic pathobiology of this family of viruses, which fuse with the cell membrane.
Our virologic studies suggest that the liver homogenate obtained from the index patient with syncytial-cell hepatitis at transplantation may have contained paramyxoviral antigens to which chimpanzee 1384, but not chimpanzee 1410, had previously been exposed. Chimpanzee 1384 had an anamnestic antibody response not only to paramyxoviral antigens but also to an antigen in both the liver homogenate and normal liver and to sheep erythrocytes. Neither chimpanzee had any evidence of hepatitis, and paramyxoviruses were not isolated in cell culture, suggesting that the putative viral antigen was noninfectious. It is likely that paramyxoviral antigen was present in the liver homogenate, but not viable viral particles. Long preservation at — 80°C may have inactivated the virus.
The serologic data do not permit the identification of the putative paramyxovirus. Serologic cross-reactions, especially on complement fixation, are common among the paramyxoviruses, particularly among the parainfluenza viruses, viruses of the mumpsNewcastle disease group, and those of the measlesdistemper—rinderpest complex.16 , 17 Such serologic cross-reactivity is most likely to occur after repeated exposure to paramyxoviruses. Chimpanzee 1384 had been exposed to respiratory syncytial virus as part of a previous study of experimental transmission, but there was no marked serologic response to this more distantly related paramyxovirus. There was no serologic evidence of previous exposure to other paramyxoviruses on the moderately sensitive complement-fixation test, but captive chimpanzees, like humans, are exposed to many respiratory viruses at one time or another. The complement-fixation antibody found in chimpanzee 1384 was considered evidence of an anamnestic reaction, as in a previous study with hepatitis B antigen.18
Elevated levels of antibodies to viruses, especially paramyxoviruses, have been reported in patients with chronic hepatitis, autoimmune diseases, and multiple sclerosis.19 20 21 22 23 Although an etiologic association has been suggested in some cases, it has also been pointed out that one paramyxovirus, measles virus, shares antigens with cellular vimentin24 and host-cell stress protein,25 a probable example of molecular mimicry. However, genomic sequences of measles virus have been detected by hybridization in some cases of multiple sclerosis.26 The importance of elevated levels of antibodies to paramyxoviruses and other viruses in autoimmune and other chronic diseases thus remains unexplained.
The paramyxoviruses are a large family of viruses. Most are pathogenic to animals, but some are human pathogens. Paramyxovirus virions are usually 150-to-250-nm spheroids, with frequent variant forms ranging from 100 to 700 nm. Nucleocapsids have a diameter of 12 to 17 nm and have surface projections.27 The particles identified by electron microscopy in the syncytial giant cells in this report had precisely these measurements. Moreover, the nucleocapsids are frequently associated with membranes within the cell from which they appear to be budding.28
Measles hepatitis is a well-known entity. In one study it occurred in 80 percent of 65 young patients.29 The liver disease was typically mild and transitory, resolving completely in all cases.29 Histologic examination of the liver has been reported to produce only nonspecific findings, with nuclear vacuolation and leukocytes in the sinusoids and no giant cells; on electron microscopy there were no viral particles.30 There are a number of case reports of measles hepatitis,31 32 33 34 35 including a recent thorough discussion of the topic.36 In fatal pediatric measles that has been documented pathologically, the disease has occurred predominantly but not solely in immunocompromised children.15 , 24 25 26 , 37 38 39 There was no evidence in 9 of our 10 patients of immune deficiency, immunosuppression, or other underlying predisposing factors.
An important question is whether this condition is measles or another paramyxoviral hepatitis. It is well known that measles virus can produce other than classic lesions, as in subacute sclerosing panencephalitis40 and vaccine-related atypical measles. It is also known that the virus can persist in tissues long after the clinical disease has subsided36 , 41 and that persisting measles viral genome has been found in lymphocytes of patients with autoimmune chronic active hepatitis.42 However, stains of the liver sections with antimeasles antibodies were negative in this study. Precise classification of this virus will require molecular studies; since the measles virus has been cloned43 and sequence homology within the morbilliviruses is known,44 classification should be possible.
The fusion of hepatocytes, the finding of paramyxoviral nucleocapsids in the fused hepatocytes, their association with membranes, and the anamnestic reaction in the chimpanzee all point to a paramyxoviral cause of syncytial giant-cell hepatitis. We conclude that syncytial giant-cell hepatitis is a heretofore unrecognized form of paramyxoviral infection that is severe and for which the prognosis is poor.
Supported by a grant (MT-0785) from the Medical Research Council of Canada to Dr. Phillips.
We are indebted to Mrs. Doris Wong, National Institute of Allergy and Infectious Diseases, for excellent technical assistance.
Source Information
From the Departments of Pathology (M.J.P., S.P., J.P.), Microbiology (M.P.), Pediatrics (E.R.), and Surgery (R.A.S.), Hospital for Sick Children, Toronto, and the University of Toronto; the Departments of Medicine (L.M.B., G.A.L.), Pathology (R.C.), and Surgery (P.D.G., B.L.), Toronto General Hospital, and the University of Toronto; and the Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. (R.H.P.). Address reprint requests to Dr. Phillips at the Department of Pathology, Hospital for Sick Children, 555 University Ave., Toronto, ON M5G 1×8, Canada.
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