Histological behaviour of chronic hepatitis in patients treated with alpha interferon.

To evaluate the histological effects of alpha Interferon (IFN) therapy, serial liver biopsy specimens from 30 patients with chronic hepatitis were studied. The biopsies were examined using a scoring system. After 12 mths of IFN therapy responders were 8 out of 11 HBV infected patients, 10 out of 12 HCV infected patients and only 1 out of 7 patients with cryptogenetic hepatitis. As spontaneous improvement of hepatic changes is infrequent, our data indicate that in terms of histological patterns interferon therapy is effective in chronic viral hepatitis.     

Histological features of sclerosing cholangitis in patients with chronic ulcerative colitis.

Primary sclerosing cholangitis was diagnosed radiologically in 16 of 681 patients (2.2%) with chronic ulcerative colitis in a follow up study at the gastroenterology unit in Oxford. On the basis of established histological criteria, the liver biopsy was considered diagnostic in only half of the cases. The histological findings in these cases were therefore reassessed to determine whether the accuracy of biopsy diagnosis could be improved. The most common specific histological feature was periductal concentric fibrosis of small interlobular bile ducts, even in the absence of inflammation. Other common features were bile ductular proliferation associated with diminution or absence of interlobular bile ducts. Degeneration of bile duct epithelium and diffuse infiltration of portal tracts by mononuclear cells and polymorphonuclear leucocytes were accompanying features. Piecemeal necrosis without rosette formation was found in about half the biopsies. When all these features were considered together a biopsy diagnosis of primary sclerosing cholangitis was established in 14 of 16 cases.     

Changes in the expression of major histocompatibility complex class II antigens in liver allograft rejection

The expression of major histocompatibility complex (MHC) class II antigens was studied in human liver grafts by immunohistochemical staining with monoclonal antibodies to HLA-DR, HLA-DP, and HLA-DQ antigens. Staining was carried out on frozen sections from 13 normal livers, used as controls, and 85 post-transplant specimens in six histological categories: acute rejection (n = 25); chronic rejection (n = 21); massive haemorrhagic necrosis (n = 2); resolving acute rejection (n = 10); non-rejection complications--pure cholestasis, ischaemia, biliary obstruction (n = 23); and stable graft function greater than 1 year post-transplantation (n = 4). Staining was graded semi-quantitatively on a scale of 0-3+ in bile ducts, hepatocytes, and vascular endothelium. Expression of class II antigens was increased in bile ducts, hepatocytes, and vascular endothelium in all of the post-transplant groups compared with controls. The degree of expression of HLA-DR and HLA-DP in bile ducts and vascular endothelium was significantly greater in cases of rejection than in the non-rejection groups. These observations suggest that increased class II antigen expression may be important in the pathogenesis of immune-mediated bile duct and endothelial damage in liver allografts. Immunohistochemical staining for class II antigens in post-transplant biopsies may also be useful as an adjunct to conventional histological diagnosis.     

Progression of autoimmune damage in primary biliary cirrhosis: an immunohistochemical study

Aberrant MHC Class II antigen expression and the nature of the infiltrating lymphoid cells were studied by immunohistochemical techniques in liver biopsies from 37 patients with Primary biliary cirrhosis (PBC) (11 histological stage I, 13 stage II-III, 13 stage IV) and 15 patients with chronic non autoimmune liver disease. Bile duct epithelial cells expressed HLA-DR, DP and DQ antigens in biopsies from patients with early (Stage I) PBC and less frequently in the late cirrhotic phases of the disease (Stage IV); these observations support the hypothesis that induction of Class II antigens on epithelial cells may be involved in initiating autoimmune responses towards bile duct components. The presence of cytotoxic/suppressor T cells around the bile ducts in Stage I suggests a role for cell mediated destruction of the ducts at this early stage. The nature of the chronic inflammatory cell infiltrate in the portal tracts, periportal areas and lobular parenchyma does not establish the mechanism(s) involved in disease progression. However, the lack of Class II antigen expression on hepatocytes is compatible with the hypothesis that hepatocellular damage is non-specific and may be secondary to the initial bile duct injury.     

Secondary sclerosing cholangitis after intensive care unit treatment: clues to the histopathological differential diagnosis

Secondary sclerosing cholangitis (SSC) is a chronic cholestatic disorder caused by mechanical, infectious, toxic, or ischemic factors. A new variant of SSC occurring after long-term treatment in intensive care units (ICU) has been recently described and characterized from the clinical point of view. The aim of this study was the histomorphological characterization of ICU-treatment-related SSC (ICU-SSC) and the definition of histological changes occurring over time based on the morphological findings. Liver biopsies of ten patients affected by ICU-SSC obtained at different time points (1.5 to 57 months) after the initial injury were analyzed. The main morphological alterations included degenerative changes of portal bile ducts, portal edema, inflammation, and fibrosis as well as biliary interface activity and bilirubinostasis. Perivenular necroses and bile infarcts were found in eight and six patients, respectively. Bile duct loss was not observed. No correlation between morphological features of biopsies and liver chemistry tests or outcome could be established. Based on the morphological observation, a possible disease-progression model starting with an initial damage of portal bile ducts (primary insult) with associated portal/periportal changes (inflammation, ductular reaction) and resulting in secondary parenchymal changes is proposed.     

Hepatic histology of patients with HIV infection and chronic hepatitis C treated with interferon.

AIMS: To evaluate the histological changes seen in liver biopsies after interferon (IFN) treatment in patients with chronic hepatitis C and human immunodeficiency virus (HIV) infection. METHODS: Twenty four intravenous drug users with chronic hepatitis C were investigated histologically before beginning a 12 month course of IFN treatment and 18 months later. Twelve were HIV positive, without opportunistic or other viral infections (group A), and 12 were HIV negative (group B). RESULTS: According to alanine amino-transferase concentrations, four sustained responders and eight non-responders were found in group A; six sustained responders, five relapsers, and one non-responder were found in group B. HCV RNA became negative in one sustained responder of group A and in the six sustained responders of group B. When histological findings of biopsies performed before therapy and 18 months later were compared, no significant changes in the mean value of Knodell's index and subindices were found in group A, whereas in group B Knodell's index, piecemeal necrosis, and focal hepatocellular necrosis decreased significantly. CONCLUSIONS: In chronic hepatitis C, coinfection with HIV showed a tendency towards a lower response to IFN, although this did not reach statistical significance; however, none of the HIV positive patients developed cirrhosis during the follow up and this should be considered in clinical management of such patients.     

Increased expression of nuclear envelope gp210 antigen in small bile ducts in primary biliary cirrhosis

The sustained antibody response to nuclear envelope gp210 antigen indicates a group of primary biliary cirrhosis (PBC) patients at high risk for the progression to end-stage hepatic failure. To address this issue, we immunohistochemically studied the expression of gp210 antigen in needle liver biopsy specimens from PBC patients using a monoclonal antibody specific for gp210 antigen. The specimens from autoimmune hepatitis (AIH), chronic viral hepatitis B (CHB) and C (CHC) patients served as disease controls. The expression of gp210 antigen was apparently increased on the nuclear envelope of biliary epithelial cells (BECs) of small bile ducts in almost all specimens from PBC. In contrast, the expression of gp210 antigen was negative in BECs of small bile ducts in normal liver, while relatively weak anti-gp210 immunostaining was observed in AIH, CHC and CHB. In addition, the degree of gp210 expression in BECs of small bile ducts was positively correlated to that of portal inflammation, interface hepatitis and lobular inflammation in PBC. These results indicate that the increased expression of gp210 in small bile ducts, which is probably associated with damage to BECs by inflammation, is possibly involved in autoimmune response to gp210 leading to the progression to end-stage hepatic failure in PBC.     

CD10 immunostaining of bile canaliculi in liver biopsies: change of staining pattern with the development of cirrhosis

AIMS: This study was prompted by published observations concerning the absence of normal bile canalicular CD10 staining in some cases of primary liver cell carcinoma. Our aim was to investigate the possibility that this loss of staining occurs prior to the development of cancer. METHODS AND RESULTS: The study comprised 164 liver biopsies, including 96 from patients with hepatitis C infection of various grades and stages including nine cases with cirrhosis, 24 other cases of cirrhosis of other aetiology, five cases of primary liver carcinoma, 12 cases of metastatic carcinoma, as well as biopsies with a variety of other liver diseases. CD10 was demonstrated in paraffin sections using the avidin-biotin immunoperoxidase technique. In hepatitis C cases, a significant loss of the canalicular pattern was seen in four out of 41 (10%) biopsies with stages 0-1 compared with 25 out of 55 (45%) with stages 2-6 (P < 0.001). There was also a significant difference (P < 0.001) between biopsies with stage 2-3 and those with stage 4-6, where marked pattern loss was seen in 9/37 (24%) and 16/18 (89%), respectively. Marked loss of the pattern was also seen in 16 out of the 24 (67%) other cirrhotic biopsies, as well as in cases with severe lobular inflammation and cholestasis and liver cell dysplasia and carcinoma. In hepatitis C biopsies, no relationship was noted between the reduction in the canalicular pattern and the necroinflammatory score. CONCLUSIONS: CD10-stained bile canalicular pattern in liver biopsies is preserved in cases with mild fibrosis and inflammation, but it becomes increasingly reduced with the advance of fibrosis or the presence of severe lobular inflammation or extensive metastases. Further investigations into the relationship between the changes in CD10 staining pattern and liver function tests may be useful in explaining test results.     

Qualitative and quantitative differences between bile ducts in chronic hepatitis and in primary biliary cirrhosis

AIM: Lymphocytic infiltration in the portal triads usually conceals the detection--in haematoxylin and eosin (H&E) stained sections--of bile ducts in two liver diseases: chronic hepatitis and primary biliary cirrhosis. The aim was to assess the number and the characteristics of the bile ducts in those diseases with the aid of an antibody to cytokeratin 7 (CK7). METHODS: Consecutive sections from 99 liver biopsies were stained with H&E and anti-CK7. RESULTS: In H&E sections the total number of central bile ducts in the triads was 52 in primary biliary cirrhosis (n = 37), 69 in chronic hepatitis (n = 43), and 30 in miscellaneous cases (n = 19). Using anti-CK7, the number of central bile ducts was 276 in primary biliary cirrhosis, 348 in chronic hepatitis, and 96 in miscellaneous cases. Central bile ducts with lumen were found in 93.0% of chronic hepatitis cases and in 89.5% of the miscellaneous cases, but in only 13.5% of the primary biliary cirrhosis cases. Peripheral bile ducts in groups of > or = 4/triad were found in all cases of chronic hepatitis (100%) and in 75.7% primary biliary cirrhosis cases, but only in 10.5% of the miscellaneous cases. In 21.6% of primary biliary cirrhosis cases, no bile ducts (central and/or peripheral) were present. CONCLUSIONS: Anti-CK7 detects bile ducts in the triads that are concealed by chronic inflammatory cells. Central and peripheral bile ducts in groups of > or = 4 were significantly more common in primary biliary cirrhosis and chronic hepatitis than in other liver diseases. The lack of lumen in central bile ducts, as well as the absence of central and/or peripheral bile ducts in CK7 stained liver sections, seem to be valuable additional parameters in the differential diagnosis between primary biliary cirrhosis and chronic hepatitis.     

The histopathological features of asymptomatic hepatitis C virus-antibody positive blood donors

Since the introduction of screening for hepatitis C virus (HCV) in donated blood, the risk of contracting post-transfusion hepatitis has been greatly reduced and the test has led to the recognition of asymptomatic blood donors positive for anti-HCV antibodies. Following confirmation of the HCV status with second generation RIBA testing followed by counselling, 55 patients had full investigations, including liver biopsy. These were classified by the traditional chronic hepatitis system and were graded according to the Knodell and Scheuer histological activity indices. Seven of the biopsies were normal (12%), apart from minor degrees of steatosis in two. Eleven cases (20%) were in the chronic lobular hepatitis category without portal inflammation, while 37 cases showed portal inflammation, including 20 (36%) cases where chronic persistent hepatitis was the predominant feature and 17 cases (31%) where there was chronic active hepatitis with piecemeal necrosis. Features which have previously been described in chronic HCV-associated hepatitis were noted: portal lymphoid aggregates (58%), lymphoid follicles with germinal centres (15%), bile duct damage (11%), lobular inflammation (80%), sinusoidal mononuclear cell infiltration (26%), acidophil body formation (11%), and steatosis (47%). Fibrosis was present in 46% of cases but was generally of mild degree; 9% of biopsies demonstrated bridging fibrosis but no cases of cirrhosis were present. Even though serum transaminase levels correlated well with the presence of chronic hepatitis and with the Scheuer and Knodell activity indices, a proportion of patients with significant liver damage had normal transaminase levels, and this study suggests the need for liver biopsy in the evaluation of asymptomatic HCV-positive blood donors.     

BILE DUCTAL AND DUCTULAR CHANGES OF THE LIVERS IN THE RENAL ALLOGRAFTED PATIENTS

Nine liver biopsies from six renal allografted patients suffering from liver injury were examined by light and electron microscope and immunostaining. The patients had never been on liver dysfunction prior to renal transplantation and after renal transplanatation had been administered azathioprine continuously. These patients had shown HBs antigen negative sera. Three of these patients restored normal liver function after withdrawal of azathioprine. Accordingly, the liver diseases of the three were supposedly caused by azathioprine. The liver biopsies of six patients were histologically diagnosed as follows: chronic active hepatitis with severe cholestasis (1 patient), liver cirrhosis with cholestasis (1 patient), acute hepatitis (1 patient), and mild hepatitis (3 patients). The common pathological findings of six patients were degeneration of interlobular bile ducts and ductules, as well as degeneration of liver cells, and mild to moderate inflammatory cell infiltration of portal tracts and sinusoids. The degeneration of bile ductal and ductular cells were classified into two types: light microscopical finding showed vacuolar or eosinophilic cytoplasm and electron microscopic compatible findings showed hydropic cytoplasm scant of free ribosome and organelles, or dense cytoplasm rich in free ribosome and degenerated organelles. The basement membranes of interlobular bile ducts and ductules were always preserved.     

Bile ductal and ductular changes of the livers in the renal allografted patients

Nine liver biopsies from six renal allografted patients suffering from liver injury were examined by light and electron microscope and immunostaining. The patients had never been on liver dysfunction prior to renal transplantation and after renal transplantation had been administered azathioprine continuously. These patients had shown HBs antigen negative sera. Three of these patients restored normal liver function after withdrawal of azathioprine. Accordingly, the liver diseases of the three were supposedly caused by azathioprine. The liver biopsies of six patients were histologically diagnosed as follows: chronic active hepatitis with severe cholestasis (1 patient), liver cirrhosis with cholestasis (1 patient), acute hepatitis (1 patient), and mild hepatitis (3 patients). The common pathological findings of six patients were degeneration of interlobular bile ducts and ductules, as well as degeneration of liver cells, and mild to moderate inflammatory cell infiltration of portal tracts and sinusoids. The degeneration of bile ductal and ductular cells were classified into two types: light microscopical finding showed vacuolar or eosinophilic cytoplasm and electron microscopic compatible findings showed hydropic cytoplasm scant of free ribosome and organelles, or dense cytoplasm rich in free ribosome and degenerated organelles. The basement membranes of interlobular bile ducts and ductules were always preserved.     

Expression of cytokeratin 7 and 20 in pathological conditions of the bile tract

Expression of cytokeratin 7 (CK7) and cytokeratin 20 (CK20) helps to establish the origin of biliary and metastatic carcinomas. We investigated the expression of CK7 and CK20 in inflammatory, metaplastic and neoplastic conditions of the bile ducts, and evaluated possible relationships between the CK expression pattern and extrahepatic bile duct/gallbladder carcinomas (EBDCs) or intrahepatic bile duct carcinomas (IBDCs). We used immunohistochemistry for the investigation of 48 formalin-fixed, paraffin-embedded specimens grouped as: A) lithiasic or inflamed surgically resected extrahepatic bile ducts/gallbladders: all were CK7+/CK20+; B) percutaneous liver biopsies from patients with chronic hepatitis C primary biliary cirrhosis and primary sclerosing cholangitis: all were CK7+/CK20-; C) EBDCs: all were CK7+/CK20+, except for two cases which were CK7-/CK20-; D) IBDCs: all were CK7+/CK20-, except for one case showing CK20 positivity. Metaplastic changes were seen only among specimens in groups A and C: in these cases, CK20 was either focally or diffusely expressed. Our study suggests that the expression of cytokeratins under specific stimuli can be different from normal tissues, and that sometimes CK20 expression can be related to and precede the occurrence of metaplastic alterations.     

Histologic changes in Chinese patients with chronic hepatitis B virus infection after interferon-alpha therapy.

To evaluate the histologic effects of interferon-alpha (IFN alpha) therapy on chronic hepatitis B virus (HBV) infection, a semiquantitative study using a modified Knodell's numeric histologic scoring system was performed on paired pre- and post-treatment liver biopsy specimens from 127 adult Chinese patients from two trials of IFN alpha therapy (IFN alpha, n = 86; control, n = 41). The effects of IFN alpha therapy on the hepatic expression of HBV antigens were also determined using immunohistochemical analysis. Serologic response with clearance of HBV e antigen (n = 18) was associated with reduction in lobular activity, periportal piecemeal necrosis, portal inflammation, and total histologic scores. Loss of HBV e antigen also was associated with a reduction in the amount of HBV core antigen in the hepatocytes. In contrast, there was an increase in hepatic expression of HBV surface antigen after IFN alpha therapy. Patients who lost HBV e antigen with IFN alpha therapy were characterized by more severe initial periportal piecemeal necrosis before treatment. These data indicate that (1) serologic response is associated with a reduction in hepatic HBV replication and an improvement in hepatic histology, and (2) patients with severe periportal piecemeal necrosis respond more favorably to IFN alpha therapy.     

Epithelioid cell granulomas in chronic hepatitis C: immunohistochemical character and histological marker of favourable response to interferon-α therapy

Aims : The clinicopathological significance of intrahepatic epithelioid cell granulomas in chronic hepatitis C was determined.  

Method and results

Granulomatous lesions were surveyed in 542 liver biopsy specimens and were immunohistochemically examined. We also tested whether this lesion is a marker of response to interferon-α therapy in chronic hepatitis C. Granulomatous lesions in hepatic lobules and/or portal tracts were identified in 11/542 (2%) cases with chronic hepatitis C. Granulomas were positive for HLA-DR and β2-microglobulin, and were surrounded by T-cells. Among them, three chronic hepatitis C cases showed portal granulomas with mild biliary epithelial damage. Bile ducts showing mild epithelial damage in chronic hepatitis C were positive for β2-microglobulin, but negative for HLA-DR, while both antigens were frequently expressed in damaged bile ducts in primary biliary cirrhosis (PBC). All five cases of chronic hepatitis C with granulomas who had interferon-α therapy and were followed up and were found to have responded well.  

Conclusion

Granulomas showed the same immunohistochemical phenotypes, though the expression of HLA-DR on bile ducts in PBC but not in chronic hepatitis C suggests a different pathogenesis. Granulomas may predict a favourable response to interferon-α therapy in chronic hepatitis C.     

Apoptosis of bile duct epithelial cells in hepatic allograft rejection

Liver biopsy remains the 'gold standard' for monitoring rejection in liver transplant patients. Portal inflammation, bile duct damage and endothelialitis are recognized features of hepatic allograft rejection. The pathogenesis of the bile duct injury during rejection, however, remains unclear. To define the mechanism of bile duct damage, we studied the light- and electronmicroscopic appearance of hepatic tissue from selected patients in whom allograft failure was solely due to rejection. Of the 25 orthotopic liver transplant rejection cases examined, 17 were mild, seven were moderate and one was severe rejection. Light microscopy examination of the damaged bile duct epithelium revealed evidence of apoptosis which was confirmed by electronmicroscopy. Furthermore, there appeared to be a positive correlation between the grade of rejection and the number of apoptotic cells. Also included in the study were 13 cases of chronic active hepatitis and 10 normal livers which showed the least apoptotic cells. We conclude that the identification of apoptotic cells in damaged bile ducts in allograft biopsies might be helpful in the diagnosis of rejection and in assessment of the severity of rejection.     

Histopathology of graft versus host disease of the liver

AIMS: To analyse the histological features of 33 patients (48 biopsy specimens) with a clinicopathological diagnosis of graft vs. host disease of the liver (L-GVHD). RESULTS: The time of biopsy post-haematopoietic stem cell transplantation (HSCT) ranged from 22 to 1082 days (median 144 days). Bile duct damage (BDD) was present in all biopsies except one. The bile duct to portal ratio ranged from 0.3 to 1 (median 0.8). Moderate/severe lobular hepatitis was present in 11 biopsies. Endotheliitis was present in four biopsies (8%). The majority of the biopsies showed none [25 (52%)] or mild [17 (35%)] fibrosis. The only significant difference between biopsies earlier ("acute") or later ("chronic" GVHD) than 100 days post-HSCT was the presence of portal inflammation in the "chronic" GVHD group. CONCLUSION: BDD is the predominant change in L-GVHD. In about a quarter of biopsies the appearance may be of a lobular hepatitis. L-GVHD is not a fibrogenic process. The significance of separating acute versus chronic L-GVHD based on a cut-off of 100 days post-HSCT is questionable. Further studies are needed to understand the relationships between the mechanisms of BDD, bile duct loss and regeneration.     

In situ characterization of the cell-surface antigens of the mononuclear cell infiltrate and bile duct epithelium in primary biliary cirrhosis

To analyze the tissue distribution of mononuclear cells and HLA antigens in primary biliary cirrhosis, we studied liver biopsies of 12 patients at different stages of the disease, using the avidin-biotin-peroxidase technique and monoclonal antibodies directed against T and B lymphocytes, T-cell subsets, macrophages, NK/K cells, dendritic cells, and HLA class I and II antigens. To evaluate the proportion of activated T cells we used anti-interleukin-2-receptor antibodies and a double-staining technique for T cells and class II HLA antigens. In all biopsies activated T cells predominated in the portal areas and around the damaged bile ducts. T4 cells almost always outnumbered T8 cells. While B cells, NK/K cells, and dendritic cells were always scarce, macrophages constituted about 30% of the cellular infiltrate. Biliary epithelium, which normally expresses HLA class I antigens, displayed mainly HLA class II antigens. The predominance of T4 cells around the bile ducts, which express class II antigens, suggests that class II-restricted T4 lymphocytes may mediate liver damage in primary biliary cirrhosis.     

Immunohistochemical detection of collagen type III and IV in relation with transformation of Ito cells in liver sinusoids of patients with reactive biliary hepatitis.

Reactive biliary hepatitis is a defined morphological entity, which is a result of chronic diseases of the gall bladder, biliary ducts or pancreas. The aim of the present study was to describe the morphology of reactive biliary hepatitis and its significance for progression of liver fibrosis, and in particular Ito cell (fat storing cell) transformation and occurrence of collagen type III and IV in the liver. Liver tissue from 19 patients with reactive biliary hepatitis was investigated light microscopically and immunohistochemically. Histologically, the liver showed features of mild to severe portal and lobular inflammation. The number of Ito cells increased periportally and pericentrally. Deposition of collagen type III and IV was increased in portal tracts, septa and perisinusoidal spaces, mainly in periportal zones of the lobules. Ultrastructurally, collagen type III immunoreactive fibrillar networks were found to be increased in the space of Disse around transitional cells. Collagen type IV immunoreactive deposits were detected around newly proliferating bile ducts in portal stroma and in the space of Disse. Ito cells were mainly transformed into transitional and myofibroblast-like cells. We discuss here the role of Ito cells and certain cytokines in the process of fibrosis of the liver in the course of reactive biliary hepatitis. It is proposed that bile acid retention in bile ducts during non-specific reactive inflammation or a gut endotoxin may cause transformation of Ito cells and increased collagen type III and IV in this type of hepatitis.     

The role of liver biopsy in evaluating acute allograft dysfunction following liver transplantation: a clinical histologic correlation of 34 liver transplants

One hundred six liver biopsy specimens from 34 orthotopic liver transplant (OLT) patients were examined and the histologic findings correlated with the clinical course of the patients to determine if specific morphologic patterns were associated with specific causes of acute allograft dysfunction. The principle causes of allograft injury in these patients appeared to be acute rejection and ischemic injury, with rarer cases of viral infection and biliary obstruction. Graft rejection causing transient liver dysfunction was associated with a mixed inflammatory infiltrate in the portal tracts and involving the interlobular bile ducts. Rejection resulting in severe, persistent dysfunction was associated with destruction and loss of the interlobular bile ducts or portal inflammation, followed by acute centrilobular hepatocyte necrosis. Ischemic liver injury was characterized by hepatocyte ballooning and/or hepatocyte necrosis. Ischemic injury causing transient graft dysfunction demonstrated focal, limited areas of hepatocyte necrosis or transient centrilobular hepatocyte ballooning. Severe ischemic injury resulting in persistent dysfunction caused diffuse hepatocyte necrosis or centrilobular ballooning followed by centrilobular hepatocyte loss and severe cholestasis with evidence of bile duct epithelial injury. The histologic patterns observed were not pathognomonic; radiologic studies, bile cultures, and other laboratory tests were necessary to rule out biliary or vascular obstruction and bacterial cholangitis. However, liver biopsies, especially serial biopsies, were helpful in suggesting the probable cause of liver dysfunction and in predicting subsequent allograft recovery or failure.