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Year : 2012  |  Volume : 55  |  Issue : 1  |  Page : 22-27
Histological and immunohistochemical features in fatal acute fulminant hepatitis E

1 Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
2 Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
3 Department of Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India

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Date of Web Publication11-Apr-2012


Background: Hepatitis E is being increasingly recognized as an emerging infection in developed countries. Data on histological findings and nature of inflammatory cell infiltrate in liver in this disease are quite sparse. Aims: This study was planned to study the histological features and the type of inflammatory infiltrate in liver biopsies of patients with acute fulminant hepatitis E. Materials and Methods: We retrieved postmortem liver biopsies of 11 Indian patients with fulminant hepatitis E, and compared these with biopsies from seven patients with fulminant hepatitis B. Results : Biopsies from acute fulminant hepatitis E showed varying degrees of hepatocyte necrosis, mixed portal and lobular inflammation, accompanied by bile ductular proliferation, lymphocytic cholangitis, Kupffer cell prominence, cholestasis, apoptotic bodies, pseudo-rosette formation, steatosis, and presence of plasma cells in portal tracts. Interface hepatitis was more frequent in acute hepatitis B than in acute hepatitis E (100% vs 20%; P<0.05). These findings differ from those reported in cases with autochthonous hepatitis E in Europe. On immunohistochemistry, lymphocyte infiltrate consisted predominantly of CD3 + T cells in both hepatitis E and hepatitis B; these cells contained a predominant cytotoxic (CD8 + ) cell subpopulation in 81.8% of cases with hepatitis E and in 50% of cases with hepatitis B. Conclusion: Our findings suggest that histological changes in HEV infection may vary with geographical location because of prevalent HEV genotypes, and that CD8 + lymphocytes play a role in HEV-induced liver injury.

Keywords: Acute hepatitis E, acute hepatitis B, immunohistochemistry, liver histology, T lymphocytes

How to cite this article:
Agrawal V, Goel A, Rawat A, Naik S, Aggarwal R. Histological and immunohistochemical features in fatal acute fulminant hepatitis E. Indian J Pathol Microbiol 2012;55:22-7

How to cite this URL:
Agrawal V, Goel A, Rawat A, Naik S, Aggarwal R. Histological and immunohistochemical features in fatal acute fulminant hepatitis E. Indian J Pathol Microbiol [serial online] 2012 [cited 2022 Jul 4];55:22-7. Available from: https://www.ijpmonline.org/text.asp?2012/55/1/22/94849

   Introduction Top

Hepatitis E is a major health problem in several developing countries and is emerging as a possible zoonotic disease in several developed countries. [1] The disease is most often in the form of an acute self-limited hepatitis. In some persons, the illness is more severe and presents as acute liver failure with a high mortality rate. The latter outcome is more common when infection occurs in pregnant women. [2] The infection is endemic in south, south-east, and central Asia, the Middle East, parts of Africa, and Mexico. [1],[2],[3],[4],[5] In India, hepatitis E virus (HEV) infection is particularly common and has accounted for several large outbreaks, [2],[3],[4] 50% to 70% of cases with sporadic viral hepatitis, and a large proportion of cases with acute liver failure. [6],[7],[8],[9],[10]

Four HEV genotypes are known; of these, genotypes 1 and 2 cause human disease in endemic areas and do not infect animals. [11] In contrast, genotypes 3 and 4 predominantly infect animal species with occasional zoonotic transmission to humans, mainly in areas where HEV infection is not endemic, and mostly affect elderly persons with other coexistent diseases. [1],[11]

During acute viral hepatitis, liver biopsy, an invasive procedure with a risk of internal bleeding, is usually not indicated. Literature on histological changes in liver in HEV infection is therefore limited, with only occasional small case series having been reported. Most of these have been from developed countries where HEV infection is infrequent. [12],[13] The reports from developing countries, where the disease is endemic, are from outbreaks in India, namely in New Delhi during 1955-1956 and in Kashmir during 1978-1979, and from an outbreak in Accra, Ghana during 1962-1963. [2],[14],[15] Since the disease in these areas appears to be different from that in the developed world, there is need for more data on the subject. [1]

Data on cellular responses and characteristics of intrahepatic immune cells in patients with hepatitis E are sparse. A recent study suggests the role of cytotoxic T-cells and natural killer (NK) cells in the immunopathogenesis of HEV infection. [16]

Aggarwal et al. [17] have previously shown that peripheral blood mononuclear cells from patients with hepatitis E have significant proliferation on in vitro stimulation with recombinant HEV open reading frame 2 protein, which codes for a 660-amino acid viral capsid protein. In another report, Srivastava et al. [18] described alterations in the number and activity of NK cells.

In this study, we retrospectively retrieved post-mortem liver biopsy tissue from patients dying of HEV-associated acute liver failure, and evaluated morphological changes and nature of inflammatory cell infiltrate in the liver using histological and immunohistochemical techniques, respectively. The findings were compared with those in biopsies from patients with acute liver failure due to hepatitis B virus (HBV) infection.

   Materials and Methods Top


Liver biopsies from 11 patients diagnosed as acute given failure due to hepatitis E between June 2000 and May 2006 were included in the study. All patients had presented with acute liver failure and biopsies had been collected postmortem. Acute hepatitis E had been diagnosed based on characteristic clinical picture, biochemical findings, and detection of IgM anti-HEV antibodies using an enzyme immunoassay (Genelabs or MP Diagnostics, Singapore), and absence of serological markers for hepatitis A (IgM anti-HAV) and hepatitis B (hepatitis B surface antigen). Liver biopsies obtained from seven patients diagnosed as acute hepatitis B presenting with acute hepatic failure were also studied as a comparison group. All patients with acute hepatitis B had detectable HBsAg and IgM anti-HBc in their serum.

Laboratory Methods

Paraffin blocks of liver biopsies were retrieved from our archives. Formalin-fixed paraffin-embedded tissue was sectioned at 2 to 4 μm thickness and stained with hematoxylin and eosin, reticulin, and Masson's trichrome stains. Parenchymal heptocytic necrosis was graded as absent, spotty necrosis, bridging necrosis, multilobular necrosis, or panlobular confluent necrosis. Ballooning degeneration of hepatocytes, multinucleation, Councilman bodies, bile duct damage, Kupffer cell prominence, intracytoplasmic hepatocytic, and intracanalicular cholestasis were recorded as present or absent. Interface hepatitis, portal and lobular inflammation, ductular proliferation, portal plasma cells, and steatosis were graded using a semi-quantitative scale as absent (grade 0), mild (1), moderate (2), and severe (3). Fibrosis was graded as none (grade 0), portal (1), portal with incomplete septa (2), bridging (3), and cirrhosis (4).

Immunohistochemistry was performed on formalin-fixed, paraffin-embedded liver sections in all 11 cases with fulminant hepatitis E and six with fulminant hepatitis B; one case with hepatitis B could not be evaluated because of lack of adequate tissue. In brief, biopsies were stained with primary antibodies for a pan-T-lymphocyte marker (polyclonal rabbit anti-human CD3 [prediluted, Dako, Glostrup, Denmark]) and for a marker of cytotoxic T-lymphocytes (monoclonal mouse anti-human CD8 [clone C8/144B, prediluted; Dako]). A streptavidin-biotin peroxidase method with diaminobenzidine (DAB; Dako) as chromogen was used to detect the bound antibodies. Two consecutive sections from each biopsy specimen were selected for immunohistochemistry.

A semi-quantitative estimate of proportion of portal lymphocytes expressing CD3 (T-cells) was performed in each case; <10% (grade 0), 10%-50% (grade 1), >50%-80% (grade 2), and >80% (grade 3). CD8 immunostaining was scored on the basis of percentage of CD3-positive cells expressing CD8, using the same scale.

Sections from a lymph node with reactive hyperplasia and from healthy duodenal mucosa were used as positive controls for CD3 and CD8, respectively.

Statistical Analysis

Chi-square test was used for inter-group comparisons.

   Results Top

Clinical Features

Clinical details of the fulminant HEV (n=11) and fulminant HBV (n=7) patients studied are shown in [Table 1]. There was no significant difference in clinical and biochemical parameters between the two groups.
Table 1: Clinical features of patients with fulminant hepatitis E and fulminant hepatitis B

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Histological Features

Fulminant hepatitis E

Histological features in biopsies from patients with acute liver failure due to HEV infection are summarized in [Table 2]. Of the 11 cases studied, one showed panlobular confluent necrosis with complete loss of liver parenchyma precluding further assessment; histological features could therefore be assessed in only 10 biopsies.
Table 2: Histology findings in postmortem liver biopsies from patients with fulminant hepatitis E as compared with those from fulminant hepatitis B

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All biopsies showed features of acute hepatitis with variable degrees of portal and lobular inflammation, consisting of polymorphs and lymphocytes, and spotty or confluent necrosis [Figure 1]. Ballooning degeneration of hepatocytes was observed in seven cases, and apoptotic Councilman bodies were identified in nine cases. Portal inflammation was seen in all cases, and was graded as mild (3/10) or moderate (7/10). In addition, portal tracts showed mild (grade 1) plasma cell infiltration in two cases, bile ductular proliferation in nine cases, and associated periductal lymphocytic infiltration with degenerative changes in the ductal epithelium in five cases. Two biopsies showed mild to moderate interface hepatitis. Nine biopsies showed both intracytoplasmic and intracanalicular cholestasis. Hepatocyte rosette formation was seen in seven cases, whereas multinucleated cells were not seen. Kupffer cells were prominent in all biopsies. None biopsies showed bridging fibrosis, cirrhosis, epithelioid granulomas, glycogenated nuclei, or Mallory hyaline.
Figure 1: Liver histology in acute fulminant hepatitis E showing hepatocytic necrosis, canalicular cholestasis (open arrow), rosette formation (closed arrow), and mononuclear inflammatory cell infiltrate in portal tract (Hematoxylin and eosin, × 200)

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Fulminant hepatitis B

Evaluation of histological features was possible in five biopsies, since two biopsies showed panlobular confluent necrosis with no viable liver parenchyma. Histological features are summarized in [Table 2]. All biopsies had features of acute hepatitis with portal and lobular inflammation composed of polymorphs and lymphocytes and spotty, bridging, or confluent necrosis. Interface hepatitis was present in all biopsies. Four of the five cases had bile ductular proliferation; however, only one had bile duct damage characterized by lymphocytic infiltration and degenerative changes in bile duct epithelium. Kupffer cells were prominent in all the biopsies from HBV-infected persons. Intracytoplasmic and intracanalicular cholestasis were seen in four cases each. Hepatocytic rosettes and multinucleate hepatocytes were found in only one case each. None of the cases had bridging fibrosis or cirrhosis. Epithelioid granulomas, glycogenated nuclei, or Mallory hyaline were not seen.

Interface hepatitis was significantly more frequent in biopsies from patients with HBV infection than in those with HEV infection (P=0.010) [Figure 2]a-b. Ballooning degeneration of hepatocytes, presence of apoptotic bodies, pseudo-rosette formation, steatosis, and portal plasma cells were more prominent in HEV infection than in HBV infection, but the difference was not significant.
Figure 2: Liver histology in acute fulminant hepatitis E (a) showing portal tract inflammation with minimal spill-over of mononuclear inflammation into the adjacent hepatic parenchyma (interface hepatitis) as compared with moderate spill-over (arrows) in acute fulminant hepatitis B (b) (Hematoxylin and eosin, × 400)

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Hepatitis E

Immunohistochemistry for CD3 revealed that T-lymphocytes were the predominant portal inflammatory cell in nine cases (grade 2); in the remaining two cases, these comprised 10% to 50% of all lymphocytes (grade 1) [Figure 3]a. No case had grade 0 or grade 3 immunostaining for CD3 cells.

Of the nine biopsies with grade 2 CD3 T-lymphocyte infiltration, seven had grade 2 CD8 cell infiltration and two had grade 1 infiltration with these cells [Figure 3]b. Both the cases with grade 1 T lymphocyte infiltration had grade 2 staining for CD8-positive lymphocytes.
Figure 3: Immunohistochemistry in liver biopsy from a patient with fatal acute fulminant hepatitis E with (a) CD3 immunostain showing T lymphocytes as the predominant portal inflammatory cells (70%-80% [grade 2]), and (b) CD8 immunostain showing cytotoxic T lymphocytes (20%-30% [grade 1]) (both diaminobenzidine, × 200)

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Hepatitis B

Of the six cases in whom immunohistochemistry was done, T lymphocytes (CD3 positive) were the predominant portal inflammatory cells in four cases (grade 2); in the remaining two cases, CD3 cell infiltration was scored as grade 1, comprising 10% to 50% of all lymphocytes. In three cases with grade 2 T cell infiltration, CD8 cells comprised 10% to 50% of all T lymphocytes (grade 1). In the remaining case with grade 2 T cell infiltration and both the cases with grade 1 T cell infiltration, CD8-positive cytotoxic T cells were the predominant T lymphocytes (grade 2).

   Discussion Top

We retrospectively studied histological features in post-mortem liver biopsies from 11 and seven patients with fulminant hepatitis E and fulminant hepatitis B, respectively. Biopsies in both groups showed varying degrees of hepatocyte necrosis, and mixed portal and lobular inflammation, accompanied by bile ductular proliferation, lymphocytic cholangitis, Kupffer cell prominence, cholestasis, apoptotic bodies, pseudo-rosettes, and steatosis. Interface hepatitis was significantly more frequent in acute fatal hepatitis B than in acute fatal hepatitis E. Using immunohistochemistry, T lymphocytes were a predominant component of lymphocyte infiltrate in both fulminant hepatitis E and fulminant hepatitis B. In addition, cytotoxic CD8 cells were the predominant T lymphocyte subpopulation in most (9/11, 82%) cases with acute liver failure due to hepatitis E.

Information on histological features of acute hepatitis E is limited to occasional studies of epidemic hepatitis E from India and Ghana, or from cases of sporadic hepatitis E in the west. [2],[12],[13],[14],[15],[19] The current report is one of the largest series on histological features in fulminant hepatitis caused by sporadic HEV infection. We also present data on immunophenotype characterization of inflammatory cells in acute hepatitis E.

Previous studies have described focal to confluent hepatocytic necrosis, apoptosis, and lobular and portal inflammatory cell infiltrates on liver histology in acute hepatitis E. In a study on 11 sporadic cases of acute hepatitis E from South-West France, Peron et al. [12] found histological features of acute hepatitis with necroinflammatory activity and a mixed inflammatory cell infiltrate composed predominantly of neutrophils in all cases. Five of their 11 cases had confluent hepatocytic necrosis. Malcolm et al.,[13] in a study of four cases of acute hepatitis E from Europe, reported focal hepatocytic necrosis, apoptotic hepatocytes, and a mixed portal and lobular inflammatory cell infiltrate. They reported preferential localization of polymorphs at the portal-hepatocyte interface, and that of lymphocytes and plasma cells centrally in portal tracts in three cases of locally acquired acute hepatitis E; in comparison, an "imported" case associated with travel to China, an endemic area, showed portal inflammation with no such localization of lymphocytes and plasma cells. [12] These authors also reported a predilection of hepatocyte necrosis to be located in the perivenular acinar zone 3 in cases with autochthonous (locally-acquired) HEV infection. [13] We observed variable hepatocytic necrosis, and a portal and lobular mixed inflammatory cell infiltrate in all our cases. The marked prominence of hepatocytic necrosis in our study is possibly because we studied liver biopsies collected post-mortem in patients with severe fatal hepatitis E. We found no particular zonal distribution of the portal infiltrate or hepatocytic necrosis. Similar histological features have been described in reports of outbreaks of hepatitis E from geographical regions where this disease is endemic, including Delhi, India (1955-56), Kashmir, India (1978-79), and Ghana in West Africa. [2],[14],[15]

Cholestatic features have been variably described in acute hepatitis E in cases from Europe, as also in those from endemic regions. Malcolm et al. reported canalicular and cytoplasmic cholestasis in all of their four cases. [13] Furthermore, they found mixed cholangiolitis in all the three locally acquired cases, but not in the "imported endemic" case. Peron et al. [12] found prominent neutrophilic cholangitis in 82% and cholestasis in 73% cases. The studies during epidemics in India have reported prominence of cholestatic features. [2],[14] In the Delhi epidemic, Gupta and Smetana [14] described cholestatic features in 67% of liver biopsies from patients with severe and fatal hepatitis. In the current series, we found lymphocytic cholangitis and cholangiolitis in 50% of biopsies and cholestasis in 90% of biopsies from patients with fulminant hepatitis E. The report from Ghana, West Africa described presence of cholestasis in 63% of cases. [15]

Hepatocyte pseudo-rosette formation was observed in 70% of biopsies in the current series. This finding has been uncommon in sporadic cases from the West, but has been common in the studies from endemic regions. [12],[13] Studies during outbreaks of hepatitis E in India reported frequent occurrence of "gland-like arrangement" and "gland-like transformation" of hepatocytes, respectively. [1],[5] Similar distinctive features characterized by glandular transformation were described in 72% of cases in the study from West Africa. [13] In contrast, Peron et al. [12] described pseudo-glandular pattern as an uncommon feature and Malcolm et al. [13] found hepatocyte rosette formation only in the "imported endemic" case.

Prominence of Kupffer cells, as seen in our study, has been reported in studies from Europe as well as those from India and West Africa. [1],[5],[11],[12],[13] However, Malcolm et al. [13] reported preferential presence of Kupffer cell aggregates in acinar zone 3 in the three cases in whom infection was acquired in Europe. This zonal distribution of Kupffer cells has not been described in other studies, and was not found in our cases.

Peron et al. [12] reported interface hepatitis in two of their 11 cases (18%) of HEV infection. The authors suggested that this finding may indicate an associated autoimmune hepatitis in these two cases. [12] We found mild interface hepatitis in two of ten (20%) biopsies from fulminant hepatitis E; however, this feature was significantly more frequently biopsies from fulminant HBV infection (100%).

Our study highlights the differences in histological findings between sporadic cases in Europe, and those in disease-endemic regions. These differences are similar to those observed between autochthonous and travel-associated cases of HEV infection reported from Europe. We believe that differences in genotypes of the infecting virus could account for these histological differences. HEV genotypes 1 and 2 are prevalent in regions where HEV infection is endemic, such as India and Africa. [1],[11] In comparison, sporadic human cases in Europe have all been due to zoonotic transmission of genotype 3 HEV. [1] Infection with genotype 3 HEV has been shown to be associated with a milder disease, and occurs mostly in elderly men with co-existent other diseases, suggesting that the genotype 3 virus isolates may be relatively less virulent. [1] Both humoral and cellular immune responses can play a role in the pathogenesis of viral infections. In hepatitis B virus and hepatitis C virus infections, cellular immune responses have been shown to be important for elimination of the infecting virus, as also in the causation of host tissue injury. We have previously reported evidence of lymphoproliferative T-cell responses in patients with acute hepatitis E, and have mapped T cell epitopes in the capsid protein of the HEV. [17] However, in another study, we were unable to show any change in the number of HEV-specific cytokine-producing activated (CD69 positive) CD8 + T cells in the peripheral blood of patients with acute hepatitis E. [18] In a more recent study, we have found a lower frequency of HEV-specific CD4 + T cells in the peripheral blood of patients with fulminant hepatitis E than in those with uncomplicated disease. [20]

Data on the nature of inflammatory responses in livers of patients with acute hepatitis E are scant. In a recent study, Prabhu et al. [16] have demonstrated the presence of CD8 + T cells in liver biopsies of HEV-induced acute liver failure. They also found significant higher counts of CD56 + cells in acute liver failure caused by hepatitis E as compared with that caused by acute hepatitis A, B, or C. [16] Findings in the current study support a role for CD8 + cells in the causation of liver injury, even though the studies on peripheral blood failed to show an increased activation of these cells.

In conclusion, liver biopsies from patients with fatal acute hepatitis E in our study showed acute hepatocyte necrosis and liver inflammation of varying degrees, hepatocyte pseudo-rosettes, cholestasis, bile ductular proliferation, and lymphocytic cholangitis and Kupffer cell prominence. These features more closely resembled those previously reported from patients with acute hepatitis E in disease-endemic regions than in those reported from sporadic cases in non-endemic developed countries. These differences may be related to differences in prevalent genotypes in these regions and the severity of clinical disease. In addition, biopsies from patients with acute hepatitis E showed a predominance of cytotoxic T-lymphocytes in the inflammatory infiltrate, suggesting a role for these cells in liver injury induced by HEV.

   References Top

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Correspondence Address:
Vinita Agrawal
Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226 014, Uttar Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0377-4929.94849

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  [Table 1], [Table 2]

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