Introduction

Members of the Banff Panel on Liver Allograft Pathology have recently arrived at a consensus grading system for acute liver allograft rejection (Hepatology 25(3), 658-663 (1997) ). It is based on pre-existing systems that were shown to be scientifically correct, simple, reproducible and prognostically significant. At the 1996 Banff Conference on Allograft Pathology, the topic of chronic rejection was addressed. The goal was to develop an international consensus grading/staging system similar to acute rejection. After several presentations and much discussion, members of the liver panel came to two major conclusions: 1) chronic rejection can be reliably recognized in liver allograft biopsies, before the criterion of 50% bile duct loss has been met; and 2) it is uncertain whether a form of chronic rejection exists that can closely resemble chronic hepatitis with interface activity and end in cirrhosis. However, the group was hesitant about making specific recommendations to the community at large, because of an incomplete recognition/understanding of precursor lesions and natural history of the chronic rejection. Thus, an agreement was made to undertake an initial multicenter study, the goal of which would be to document the evolution of chronic rejection.

Goals

1. Document the temporal evolution of chronic rejection in serial liver allograft biopsies that were taken from allografts that failed from chronic rejection.
2. Attempt to identify particular lesions in the evolution of CR that might eventually be useful in predicting which patients will respond to medical therapy and those who may not respond.

Exclusion Criteria

1. All patients who are HCV or HBV positive at the time of transplantation, or who acquire HBV or HCV after transplantation will be excluded. While it is known that patients who are HCV or HBV positive can still develop chronic rejection, it is difficult to ascribe particular changes to either viral infection or to the chronic rejection process.
2. Specimens obtained at the time of autopsy will be excluded: a) it is not always clear whether chronic rejection alone led to the patient's demise; and b) tissue fixation and morphology may be suboptimal.
3. All allografts failing less than one week after transplantation will be excluded. This will avoid unnecessary examination of failed allografts where chronic rejection can be excluded on a temporal basis.
4. All non-primary allografts will be excluded, since chronic rejection is known to recur in subsequent allografts and such patients may not be typical of those who experience CR for the first time.
5. All allografts failing from technical complications, such as hepatic artery thrombosis, venous obstruction, obstructive cholangiopathy(unless related to chronic rejection), will be excluded.

1. All allografts in which chronic rejection was verified at the time of retransplantation, based on the criteria of obliterative arteriopathy affecting at least some of the peri-hilar arteries and/or the presence of bile duct loss involving at least 50% of ducts.
2. All allografts in which the cause of graft failure has no explanation other than rejection.

Methods

1. All failed allografts/patients which have met the criteria will be assigned a unique local ID number known only to that center. This number will be used to trace the individual cases. No names, social security numbers or other publicly accessible identification should be used. This will add an additional level of confidentiality and security to the study.
2. All pre-failure biopsy specimens from the above allografts will be assigned a unique specimen ID#, again known only to the center. This number will be used to trace individual biopsy specimens.
3. All pre-failure biopsy and failed allograft specimens should be reviewed by the participating pathologists and the gross and histopathological fields listed in the data entry form should be completed.
4. The reason(s)(i.e. Entry Criteria) for including samples from this particular patient should be entered.
5. All other general demographic and histopathological data should be checked and verified for accuracy. When the data form is complete, it should be submitted to TPIS, as per instructions included with the data entry form .

Statistical Analysis

Quality Control Issues

A significant concern in such a multicenter study is the collection of common data and the reproducbility of the readings (i.e. are we all seeing the same things). Therefore, the minimum amount of data collected should equal those parameters listed on the data entry form . Those of you who wish to collect more data, are welcome to do so.

Unless self-explanatory, a linked image showing an example of a pertinent score will be provided. For example, if you want to see what mild portal inflammation looks like, you will be able to refer to the Web-based resource document, complete with images. This should be available within the next week.

Data Analysis and Reporting

The intent of the multicenter study is to collect enough cases so that a meaningful analysis of chronic rejection can be undertaken, which might not be possible at individual centers. Participation in the study however, does not preclude any of the participating centers from separate study and publication of their own data. Each center will have access to their own data for modifications and analysis. During the study, access to the complete data set will be initially limited to TPIS administrators, who will periodically inform the participating centers of progress and number of cases entered. At the closure of data collection, the goals of the study will be addressed by those willing to contribute to data analysis. At this point, I am unsure whether our computer support personnel will be able to enable the participants to analyze the complete data set over the internet. Regardless, any publication from the group will have to be approved my a majority of the participating centers.