The Diagnosis and Grading of Acute Liver Allograft Rejection Overview
Acute (cellular) rejection most commonly presents between 5 and 30 days after transplantation and 60% or more of all episodes occur within the first 6 weeks(1). The overall frequency varies with the baseline immunosuppression regimen, ranging between 30 and 70%. Acute rejection is more common in inadequately immunosuppressed and pediatric recipients, patients with a positive crossmatch and in recipients with donor DR mismatches. Female patients and those individuals with autoimmune disorders also show a higher frequency of acute rejection in some studies.
As the time after transplantation increases, acute rejection becomes less common. In fact, in patients who survive for more than one year after transplantation, acute rejection accounts for less than 30% of all causes of allograft dysfunction. More common causes of late allograft dysfunction include recurrence of viral or autoimmune liver disease, de novo viral hepatitis and obstructive cholangiopathy. Therefore, simply knowing the time after transplantation when the biopsy was obtained and the original liver disease contribute greatly to the evaluation of a liver allograft biopsy.
Clinical findings are often absent in early or mild acute rejection, although in late or severe cases, fever as well as enlargement, cyanosis, and tenderness of the allograft frequently occur(1). Bile drainage from a T tube often becomes thin and pale and the flow is decreased. Occasionally, ascites develops because of liver swelling, increased intrahepatic pressure and increased production of lymphatic fluid. Liver dysfunction is usually manifest as concomitant nonselective elevations of some or all of the standard liver injury tests, including total bilirubin, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, and alkaline phosphatase(1). Peripheral blood leukocytosis and eosinophilia are also frequently present. The diagnosis of acute rejection is suspected on clinical grounds and confirmed by examination of a core needle biopsy(1).
The histopathological diagnosis of acute rejection is based on three main histopathologic features(1): 1) mixed, but predominantly mononuclear portal inflammation, containing blastic or activated lymphocytes, neutrophils and eosinophils; 2) subendothelial inflammation of portal and/or terminal hepatic veins; and 3) bile duct inflammation and damage. The portal and perivenular localization of the inflammation are likely related to the presence of donor dendritic cells at these sites, which trigger the rejection reaction. An International Panel recently agreed that the minimal findings needed to establish the diagnosis of acute rejection are at least two of the above histopathologic features along with biochemical evidence of liver damage(1). The diagnosis is strengthened if > 50% of the ducts are damaged or if unequivocal endotheliitis of portal or terminal hepatic vein branches can be identified(1). Each of these features is shown in detail in the accompanying internet-based images used to illustrate the grading of acute rejection.
Once the diagnosis of acute rejection has been established, grading of the severity of acute rejection is based on Banff Schema for liver allograft rejection(2). This international consensus grading scheme was developed by a panel of expert histopathologists and clinical physicians who represent most of the large liver transplant centers throughout the world. Conceptually, the Banff Schema is based on the overall severity of inflammation, combined with morphological evidence of rejection-related ischemia, which is the final common pathway of allograft failure from acute rejection. The pathologist first renders a descriptive (indeterminate, mild moderate, severe) grading of rejection, which is based on an overall evaluation of the parameters listed in the criteria for the schema. Subsequently, a semi-quantitative evaluation can be carried out when necessary. The semi-quantitative evaluation is based on separately evaluating the severity of the three histopathological findings used to establish the diagnosis: portal inflammation; bile duct damage; and venous endothelial inflammation. Each of these parameters are subjectively scored on a scale of 0 - 3 using the criteria given in the Rejection Activity Index(RAI), table. Then, the scores for each component are added together for a final rejection score, or RAI, much like the Hepatitis Activity Index, first popularized by Knodell(5).
In general, the severity and extent of the portal inflammation are used to distinguish between mild and moderate acute rejection, whereas the presence of perivenular inflammation and accompanying necrosis is the critical lesion that distinguishes severe acute rejection from the lower grades. A more detailed description of the finer points of grading acute rejection is provided in the appropriate sections.
If more than one inflammatory condition is affecting the allograft (e.g. acute rejection and viral hepatitis), it is extremely difficult, if not impossible, to apportion the relative severity of the injury patterns with the RAI. However, it is left to the discretion of the pathologist to determine if separate analysis of the severity of each pathologic entity can be achieved. Click here for a typical example of a consultation case with that showed changes of both recurrent hepatitis and rejection.
For historical interest, it is worth mentioning that the Banff Schema is based on the National Institute of Diabetes and Digestive and Kidney Diseases grading system(3), and the European system(4), which in turn, are based on concepts derived from still earlier systems.
It should be emphasized again, that application of the Banff Schema already presupposes that the diagnosis of acute rejection has been established, based on the histopathological findings listed above.
The following series of photomicrographs illustrate typical examples of the various histopathological features used to grade acute liver allograft rejection into the categories of "indeterminate", "mild", "moderate" and "severe" acute rejection. These internet-based photomicrographs can be used as a "yardstick" and referred to when grading individual biopsy specimens showing acute liver allograft rejection.