Banff Schema for Grading Liver Allograft Rejection: Utility in Clinical Practice

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1 Banff Schema for Grading Liver Allograft Rejection: Utility in Clinical Practice Donald G. Ormonde,* W. Bastiaan de Boer, Anthony Kierath, Roger Bell, Keith B. Shilkin, Anthony K. House, Gary P. Jeffrey,*, and William D. Reed* ORIGINAL ARTICLES An accurate and functional system for grading acute liver allograft rejection is important for patient management, research, and communication. The Banff schema is a consensus document designed to provide an internationally accepted standard for this purpose. The aim of this study is to determine if application of the Banff schema would significantly alter the grading of acute liver allograft rejection compared with the Birmingham system. One hundred twenty-four post liver transplantation biopsies performed by the Western Australian Liver Transplantation Service between 99 and 997 were retrospectively analyzed by a pathologist and a hepatologist. Each was supplied with a brief clinical history before applying the Banff and Birmingham criteria. Results were compared with each other and to the diagnosis made at the time of the biopsy, which was based on the European grading system. Rejection was diagnosed by the reviewers in 6 of 4 biopsy specimens according to the criteria of Snover. The Banff schema and Birmingham system agreed on the grade of rejection in of the 6 biopsy specimens. The Banff schema elevated the grade of rejection in 9 specimens by an increment of one. In no instance did the Banff schema reduce the grade. Comparison between the Banff schema and diagnosis made at the time of biopsy showed agreement in 9 specimens, whereas the Banff schema elevated the grade in 5 specimens and reduced the grade in specimens. In comparison to the Birmingham system, the Banff schema elevated the grade of liver allograft rejection in the majority of biopsy specimens, and this has the potential to alter clinical management with the adoption of the Banff schema or if the systems are used interchangeably. Copyright 999 by the American Association for the Study of Liver Diseases L iver transplantation is now widely accepted as effective treatment for end-stage liver disease. Despite improving immunosuppression, acute allograft rejection still occurs in approximately 60% of the patients and is associated with significant morbidity. Although there is no gold standard for the diagnosis of rejection, interpretation of the liver biopsy specimen remains fundamental, and there is evidence that the histological severity of rejection may have implications for patient management and outcome. 4,5 Therefore, the use of a reliable and reproducible system to grade acute liver allograft rejection is important for appropriate patient management and follow-up, as well as effective research and communication. A well-designed grading system should be scientifically correct, simple to apply, clinically useful, and reproducible both within and between observers. Certain histological features have been shown to be of prognostic value 6 and therefore should be incorporated into the system. A number of different grading systems based on semiquantitative assessments have been in use, including the Pittsburgh 7 and Minnesota 6 systems, but such systems include features that are poorly reproducible and do not discriminate well. 8-0 Other grading systems include the National Institute of Diabetes and Digestive and Kidney Diseases system, which uses a more Gestalt assessment of overall severity, 4 and the Birmingham system, 0 which is a semiquantitative analysis of the three main features of rejection. Another system is the European grading system, which involves grading the features of rejection in much the same way as the Birmingham system and From the Departments of *Medicine and Surgery, The University of Western Australia; PathCentre, Queen Elizabeth II Medical Centre; and the Western Australian Liver Transplantation Service, Sir Charles Gairdner Hospital, Perth, Western Australia. Supported in part by the Sir Charles Gairdner Hospital Research Fund, Perth, Western Australia. Address reprint requests to Gary P. Jeffrey, MBBS, FRACP, MD, Department of Medicine, The University of Western Australia, 4th floor, G Block, Queen Elizabeth II Medical Center, Verdun St, Nedlands, Western Australia Copyright 999 by the American Association for the Study of Liver Diseases 074-0/99/ $.00/0 Liver Transplantation and Surgery, Vol 5, No 4 ( July), 999: pp

2 6 Ormonde et al combining the results to produce an overall rejection grade. The Royal Free Hospital system is also similar to the Birmingham system, but places greater emphasis on the presence of eosinophils. In an attempt to overcome some of the weaknesses of these different systems and develop an internationally acceptable standard, members of an international consensus panel met in Banff, Canada, and developed the Banff schema. 8 This schema is composed of two parts, the global assessment (GA) and the rejection activity index (RAI). The GA is a verbal grading based on the overall appearance of the biopsy specimen and is particularly weighted by the severity of portal tract inflammation. The RAI grades the severity of portal inflammation, bile duct damage, and venous endothelial damage, each with a score of 0 to, giving a total score of 0 to 9. This analysis provides a score that is converted to a rejection grade from nil to severe. In this retrospective analysis, the Birmingham system was used because of its popularity in Europe, detailed nature, and similarity to the European system semiquantitative analysis and Banff schema RAI. The contributors to the Banff schema proposed it should become the international standard for grading acute liver allograft rejection. The aim of this study is to determine if application of this new schema would significantly alter the grading of liver allograft rejection compared with the Birmingham system and therefore influence clinical practice. Materials and Methods Table. Banff Schema: Grading of Acute Liver Allograft Rejection Global Assessment Criteria Indeterminate Portal inflammatory infiltrate that fails to meet the criteria for the diagnosis of acute rejection. Mild Rejection infiltrate in a minority of triads that is generally mild and confined within the portal spaces. Moderate Rejection infiltrate expanding most or all of the triads. Severe As above for moderate, with spillover into periportal areas and moderate to severe perivenular inflammation that extends into the hepatic parenchyma and is associated with perivenular hepatocyte necrosis. NOTE. Global assessment of rejection grade made on a review of the biopsy specimen and after the diagnosis of rejection has been established. We reviewed 4 liver core biopsy specimens from 6 adult liver transplant recipients, 50 who underwent transplantation by the Western Australian Liver Transplantation Service (WALTS) between July 99 and December 997 and who underwent transplantation elsewhere. Of those who underwent transplantation by the WALTS, 48 patients underwent transplantation between July 994 and December 997. All patients received perioperative immunosuppression that consisted of hydrocortisone, 00 mg intravenously twice daily; cyclosporine, mg/kg intravenously twice daily; and azathioprine, to mg/kg. Basic demographic data were collected on these patients, as well as their indications for transplantation. For each biopsy specimen, three levels were stained with haematoxylin and eosin and routine special stains were available, including reticulin, Perl s Prussian blue, Masson s trichrome, and periodic acid Schiff with and without diastase. A single center prepared all slides. All biopsy specimens were reviewed and retrospectively graded using both the Banff schema (Tables and ) and the Birmingham system (Table ) by a hepatologist (D.G.O) and pathologist (W.B.deB), who arrived at a consensus on the grade. The reviewers were supplied with a brief clinical history, including the time of the biopsy posttransplantation. When applying the Banff schema, a grade of nil rejection was scored if rejection was not present according to the diagnostic criteria of Snover. 6, Case notes were reviewed to determine the grade of rejection assigned at the time of biopsy, and this was termed the WALTS grade. The WALTS grade had been diagnosed by a number of different pathologists with varying degrees of experience in the reporting of posttransplantation liver biopsy specimens. These pathologists primarily used a summary of the European grading system (Table 4) provided in the original report by Hubscher. 0 Although this system involves grading the features of rejection in much the same way as the Birmingham system, the pathological opinion based on this system was summarized as a verbal conclusion without reference to the score of points. Two main comparisons were then performed, the first between the Banff schema and the Birmingham system and the second between the Banff schema and the WALTS grade. For each main comparison, the number of biopsy specimens for which the grade agreed, number in which the Banff schema elevated or decreased the grade, and degree of change were analyzed. In addition, to detect any major discrepancies in the diagnosis of rejection, the data were analyzed to determine the number of biopsy specimens for which the

3 Clinical Application of Banff Schema 6 Table. Banff Schema: Rejection Activity Index Category Criteria Score Portal inflammation Bile duct inflammation/ damage Venous endothelial inflammation Mostly lymphocytic inflammation involving but not noticeably expanding a minority of the triads Expansion of most or all of the triads by a mixed infiltrate containing lymphocytes with occasional blasts, neutrophils, and eosinophils. Marked expansion of most or all of the triads by a mixed infiltrate containing numerous blasts and eosinophils with inflammatory spillover into the periportal parenchyma. A minority of the ducts are cuffed and infiltrated by inflammatory cells and show only mild reactive changes, such as increased nuclear-cytoplasmic ratio of the epithelial cells. Most or all of the ducts infiltrated by inflammatory cells. More than an occasional duct shows degenerative changes, such as nuclear pleomorphism, disordered polarity, and cytoplasmic vacuolation of the epithelium. As above for, with most or all of the ducts showing degenerative changes or focal luminal disruption. Subendothelial lymphocytic infiltration involving some, but not a majority of the portal and/or hepatic venules. Subendothelial infiltration involving most or all of the portal and/or hepatic venules. As above for, with moderate or severe perivenular inflammation that extends into the perivenular parenchyma and is associated with perivenular hepatocyte necrosis. NOTE. Total score sum of components. Criteria that can be used to score liver allograft biopsy specimens with acute rejection as defined by the World Gastroenterology Consensus Document. Category Portal inflammation Bile duct damage Venous endothelial inflammation Table. Birmingham System No. of Portal Tracts Involved/Density of Inflammatory/ Cellular Composition No portal tracts involved. Some portal tracts involved with a light inflammation composed of mainly lymphocytes and other mononuclear cells. Most portal tracts with moderate inflammation composed of mononuclear cells with polymorphs (neutrophils blast cells). All portal tracts involved with a dense inflammation composed of mixed blast cells and often numerous eosinophils. No portal tracts involved. Occasional ducts cuffed by inflammatory cells. Little inflammatory infiltration. Several ducts cuffed and focally infiltrated by inflammatory cells. May be associated with epithelial, degenerative changes (nuclear pleomorphism, cytoplasmic vacuolation, disordered polarity). Most ducts show inflammatory infiltration. Morphological damage to biliary epithelium conspicuous and may include focal disruption and/or focal duct loss. No portal tracts involved. Focal attachment of lymphoid cells to endothelial surface. Subendothelial infiltration not prominent. More extensive lymphoid attachment with subendothelial infiltration conspicuous. Extensive subendothelial infiltration with lifting and focal disruption prominent. Score NOTE. The grading system scores for the three main histological features are added to provide a final rejection score. This is then converted to a histological grade as follows: 0-, no rejection;, borderline; 4-5, mild rejection; 6-7, moderate rejection; 8-9, severe rejection

4 64 Ormonde et al Table 4. European Grading System for Acute Liver Allograft Rejection Grade (mild) Grade (moderate) Grade (severe) Portal inflammatory changes are generally mild and patchily distributed. Bile duct damage and venous endothelial inflammation are both mild. Portal inflammatory changes are more severe and widespread. Bile duct damage and venous endothelial inflammation are both conspicuous. All three classic features of rejection are present to a marked degree. They may be accompanied by additional periportal, sinusoidal, parenchymal, or vascular changes as outlined in notes. NOTE. The severity of () portal inflammation, () bile duct damage, and () venous endothelial inflammation are graded on a scale of 0 none to severe and are then collated to provide a final rejection grade. In some cases, additional features seen inconsistently in acute rejection (e.g., portal inflammatory spillover, sinusoidal endotheliitis, parenchymal inflammation necrosis, arteritis) may be used to upgrade the severity of acute rejection. systems disagreed about the presence or absence of rejection. Three months after liver transplantation, a number of hepatic inflammatory complications become more common. To determine if this influenced the agreement for each comparison, all biopsy specimens were allocated to group I if performed within months of liver transplantation or group II if performed months or after. The degree of agreement about rejection grading between systems was measured using a chance-corrected agreement index ( ) calculated for each main comparison. assumes the value 0 if the agreement is no better than that expected by chance. When maximal agreement exists, is equal to, and is less than 0 when the amount of agreement is less than chance. Between 0 and, greater than 0.7 represents excellent agreement; 0.5 to 0.7, good agreement; 0. to 0.5, moderate agreement; 0. to 0., fair agreement; and less than 0., poor agreement. A Chi-squared test was performed to determine if the time of biopsy posttransplantation ( or months) significantly affected the degree of agreement between the two systems under comparison. A probability value less than.05 was required to disprove the null hypothesis that the timing of biopsy posttransplantation did not affect agreement. Results Patient Characteristics The 6 patients included men and 9 women with a mean age of 46 years (range, 5 to 66 years).indications for transplantation are listed in Table 5. Banff Schema and Birmingham System Comparison According to the criteria of Snover et al, acute rejection was present in 6 of 4 posttransplantation liver biopsy specimens. Analysis of these 6 biopsy specimens determined the grade of rejection was the same in biopsy specimens when the Banff schema was compared with the Birmingham system (Table 6). Of these biopsy specimens, the grade of rejection was indeterminate in, mild in, moderate in 6, and severe in. In the remaining 9 biopsy specimens, the Banff schema elevated the grade of rejection by an increment of one. It increased the grade of rejection from nil to indeterminate in 6 specimens, indeterminate to mild in 9 specimens, mild to moderate in specimens, and moderate to severe in specimens. Based on these data, for chance-corrected agreement between the Banff and Birmingham systems was (confidence intervals, 0.9 to 0.6), which indicated moderate agreement. Table 5. Indications for Transplantation No. of Indication Patients Autoimmune hepatitis Primary biliary cirrhosis 0 Alcohol 9 Hepatitis C cirrhosis 7 Primary sclerosing cholangitis 6 Hepatitis B cirrhosis Haemochromatosis/hepatitis C -Antitrypsin deficiency Haemochromatosis/ -antitrypsin deficiency Haemochromatosis/alcohol Hepatitis B and C cirrhosis Hepatitis C/alcohol Primary biliary cirrhosis/hepatitis C Wilson s disease Budd-Chiari syndrome Caroli s disease Fulminant hepatic failure Total 6

5 Clinical Application of Banff Schema 65 Table 6. Banff Versus Birmingham Comparison of Grading Banff Schema When the reviewers applied the Birmingham system to the other 6 biopsy specimens, they agreed rejection was absent in all. There was no biopsy specimen in which rejection was considered definitely present by one system but not present by the other. Analysis of the results regarding the time of biopsy posttransplantation showed that of the biopsy specimens in which the grade agreed, 5 specimens were from group I and 7 specimens were from group II. Of the 9 specimens in which the grade was elevated, were from group I and 6 from group II (P.66). When a comparison was made between the Banff schema RAI and Birmingham system score, the total was the same in 05 specimens. The Birmingham score was higher by one point in 7 specimens and by points in specimens. Banff Schema and WALTS Grade Comparison The Banff schema and WALTS grade agreed on the grade of rejection in 9 of the 6 biopsy specimens with acute rejection (Table 7). The rejection grade was indeterminate in 5 of these specimens, mild in 9, moderate in, and severe in 4. Analysis of the remaining biopsy specimens found that the Banff schema compared with the WALTS grade elevated the severity of rejection in 5 specimens and reduced the severity in 7 specimens. In those 5 specimens in which the grade was elevated, the grade changed from nil to indeterminate in 6, indeterminate to mild in, indeterminate to moderate in, mild to moderate in 5, and moderate to severe in. In those 7 biopsy specimens in which the severity of rejection was reduced, the grade changed from moderate to indeterminate in and mild to indeterminate in 6. for chance-corrected agreement between the Banff and WALTS diagnoses was 0.56, with confidence intervals of 0.45 to 0.67, which indicated good agreement. Of the 6 biopsy specimens in which the reviewers believed rejection was absent, the WALTS grade agreed in 47 specimens. In the other 6 specimens, the original diagnosis was indeterminate in 0 and mild rejection in 6. When all 4 biopsy specimens were considered, the grade was reduced in by the Banff schema. There were six biopsy specimens in which the WALTS pathologists diagnosed rejection as definitely present (all mild rejection) when the Banff schema had diagnosed rejection as absent. According to the reviewers, these biopsy specimens did not show sufficient criteria for the diagnosis of rejection by the criteria of Snover. Analysis of the results regarding the time of biopsy showed that of the 9 biopsy specimens in which there was agreement, 6 were from group I and from group II. Of the in which there was disagreement, were from group I and 0 from group II (P.). Discussion Table 7. Banff Versus WALTS Comparison of Grading Banff Schema Comparison of the Banff schema and Birmingham system clearly showed a significant and systematic difference in the way the two systems graded acute liver allograft rejection. The Banff schema elevated the grade of rejection in 9 of 6 biopsy specimens with rejection and reduced it in none compared with the Birmingham system. The reason for this difference can be attributed to the different struc- Nil Indeterminate Mild Moderate Severe Birmingham Nil 6 6 Indeterminate 9 Mild Moderate 6 Severe NOTE. Kappa 0.495; SE (confidence interval, 0.9 to 0.60). Nil Indeterminate Mild Moderate Severe Walts Nil 47 6 Indeterminate 0 5 Mild Moderate Severe 4 NOTE. Kappa 0.56; SE 0.05 (confidence interval, 0.45 to 0.67).

6 66 Ormonde et al ture of the two systems. Once the presence of rejection has been established, the Banff schema relies on a global assessment for the grade, which is largely based on the severity of portal inflammation. All grades apart from severe are assessed on this feature alone. In comparison with this, the Birmingham system is semiquantitative, with an equal emphasis on inflammation, bile duct damage, and endothelialitis, requiring a total score of 4 before definite rejection is present. Therefore, any specimen in which portal inflammation is the predominant feature might be graded more highly by the Banff schema than the Birmingham system. For example, a biopsy specimen with a significant infiltrate in most or all of the portal tracts would be graded moderate according to the Banff schema global assessment. The same biopsy specimen graded by the Birmingham system might score points for portal tract inflammation and would require a further 4 points for bile duct damage and endothelialitis to reach the total of 6 points required for a moderate grading. This trend toward elevation of the grade, based primarily on the severity of portal tract inflammation, was reflected throughout all grades from indeterminate to moderate. In contrast, the Banff schema RAI is evenly weighted for all three histological features and therefore does not incorporate the same bias as the global assessment. This is supported by our comparison, which showed close agreement between the Banff RAI and Birmingham score, which might be expected because of the similar nature of the criteria used. In all specimens in which there was disagreement, the Birmingham score was higher. Despite this, the Banff schema GA grading was systematically more severe. The difference noted between the RAI and Birmingham score relates primarily to differences in the descriptions used to score all three features. For portal inflammation, unlike the Birmingham system, the RAI requires inflammatory spillover to score points. For bile duct damage, the RAI requires involvement of most or all ducts to score points, whereas the Birmingham system only requires several. For endothelial inflammation, the Birmingham system attributes one point for focal attachment, which is not an accredited feature in the RAI. In addition, the Birmingham system only requires more extensive lymphoid attachment to score points, whereas the RAI requires most or all venules to be involved. It is implied in the Banff consensus paper, in the section entitled Clinicopathological Correlation and Treatment of Acute Rejection, that an RAI of 4 or less may indicate mild rejection and 6 or greater may indicate moderate or severe rejection, but a formal alignment of the RAI with the GA grade was not made. It was recommended that the Banff RAI criteria be routinely used, but it is not clear if the RAI should also help grade the rejection or solely provide a score for use in patient follow-up and research. To exclude any systematic difference in rejection grading between the GA and RAI, a series of 50 transplant biopsy specimens were scored using both methods by Demetris et al. 8 No significant difference between the grades determined by each method was found (data not shown). Three months after liver transplantation, a number of hepatic inflammatory complications become more common, including recurrent or de novo viral hepatitis 4,5 and recurrent autoimmune disease. 6-8 As a result, diagnosis of rejection after months might be more complicated. 9 The results of this study found that the timing of the biopsy after transplantation did not influence the degree of agreement between the systems under comparison. Because both the Banff schema and the Birmingham system were applied here in a retrospective fashion, it allowed for a direct comparison of the two systems free from the influence of such variables as the amount of clinical information provided and the experience of the pathologist assessing the biopsy specimen. To address some of these issues, a comparison was made between the Banff schema and WALTS grade. In this comparison, the grade was elevated by the Banff schema in 5 specimens and reduced in specimens. Sixteen of those specimens were cases in which rejection was not present according to the reviewers. This represented a difference between the authors and the original reporting pathologists in the diagnosis of rejection and not a difference between the grading systems. Demetris et al suggested there is significant variation between pathologists in their interpretation of rejection biopsy specimens, particularly among the less experienced. The WALTS reporting was performed by a number of pathologists with varying experience who may have tended to interpret minor changes as significant and therefore diagnostic of rejection. Demetris et al reported a score between 0.5 and 0.68 for interrater agreement in the diagnosis of acute rejection when it was considered

7 Clinical Application of Banff Schema 67 diagnostic or indeterminate. This range corresponds closely to the of 0.56 calculated for our comparison between the Banff schema and WALTS grade. These results highlight the subjectivity of histopathological interpretation, particularly when based on overall diagnostic impression, and supports minimizing the number of pathologists involved in the interpretation of post liver transplantation biopsy specimens. It is important to determine if these differences might be clinically relevant. In hepatology units in which histologically mild rejection is not treated, the tendency of the Banff schema to elevate the grade of rejection from mild to moderate would need to be taken into consideration, particularly given that of the biopsy specimens graded mild by the Birmingham system were elevated to a grade of moderate by the Banff schema. Data taken from protocol biopsy specimens have shown that despite the presence of histopathological evidence of rejection, clinically apparent graft dysfunction may be absent, 0 and these cases may not require treatment. 5 Klopmaker et al showed a 5% incidence of histopathological rejection on -week protocol biopsy specimens. In these studies, the grading of rejection was based on informal use of the Snover criteria 0, or the Birmingham system. 5 Approximately two thirds of these patients were not treated for rejection and did not show any difference in end points compared with the treated group. Despite this, there is a lack of consensus on how best to manage mild rejection. 8 In contrast, it is widely accepted that clinically evident rejection should be treated irrespective of the histological grade. In this setting, the most important distinction is whether histological rejection is definitely present or absent. When the Banff and Birmingham systems were compared on this analysis, there were no cases diagnosed as definite rejection by one system and as absent by the other. It is important to note that the comparison between these systems was not intended to determine the better system. Because there is no gold standard for the diagnosis and grading of rejection, it would be impossible to attempt such a determination. Instead, these comparisons were performed to highlight the systematic differences between these systems. In conclusion, use of the Banff schema elevated the grade of rejection compared with the Birmingham system. This increase in grade was predictable according to the structure of the two systems. Despite these differences, there is still moderate to excellent agreement between the two systems, particularly in determining whether rejection was present or absent. Because these differences are reproducible and systematic, it would appear reasonable to use the Banff schema provided the characteristics of its application are recognized. Knowledge of the schema s tendency to elevate the level of rejection compared with semiquantitative systems will be important when adopting this new system and when therapeutic decisions are based on the grading of rejection. References. O Grady J. Clinical economics review: Liver transplantation. Aliment Pharmacol Ther 997;: Wiesner RH. Advances in diagnosis, prevention, and management of hepatic allograft rejection. Clin Chem 994;40: Demetris A, Belle S, Hart J, Lewin K, Ludwig J, Snover DC, et al. Intraobserver and interobserver variation in the histopathological assessment of liver allograft rejection. Transplantation 99;4: Demetris A, Seaberg E, Batts K, Ferrel LD, Ludwig J, Markin RS, et al. Reliability and predictive value of the National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database nomenclature and grading system for cellular rejection of liver allografts. Hepatology 995;: Dousset B, Hubscher SG, Padbury RT, Gunson BK, Buckels JA, Mayer AD, et al. Acute liver allograft rejection Is treatment always necessary? Transplantation 99;55: Snover D, Freese D, Sharp H, Bloomer J, Najarian JS, Ascher NL. An analysis of the use of biopsy in determining the outcome of rejection. Am J Surg Pathol 987;: Demetris A, Qian S, Sun H, Fung J. Liver allograft rejection: An overview of morphologic findings. Am J Surg Pathol 990;: Demetris A, Batts K, Dhillon A, Wight D, Williams J, Yamabe H. Banff schema for grading liver allograft rejection: An international consensus document. Hepatology 997;5: Hubscher SG. Histological findings in liver allograft rejection New insights into the pathogenesis of hepatocellular damage in liver allografts. Histopathology 99;8: Hubscher S. Diagnosis and grading of liver allograft rejection: A European perspective. Transplant Proc 996;8: Gupta S, Hudson M, Burroughs A, Morris R, Scheuer P, Dhillon A. Grading of cellular rejection after orthotopic liver transplantation. Hepatology 995;:46-57.

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