Acute cellular rejection and its sequelae developing in a 42-year-old man after liver transplantation
Authors: M. Isabel Fiel, Thomas Schiano
Journal: Hepatology (2009)

A 42-year-old man with alcoholic liver disease underwent successful liver transplantation (LT) using a deceased donor. Both patient and donor were negative for antibody to cytomegalovirus (CMV), and the initial post-LT course was uneventful. Immunosuppression consisted of interleukin-2 antagonist induction as well as tacrolimus, mycophenolate mofetil, and corticosteroids. Corticosteroids were discontinued by month 3 and tacrolimus levels were maintained between 10-15 ng/mL, with infection prophylaxis discontinued 3 months after LT. Following an episode of viral gastroenteritis, the patient became jaundiced with the following laboratory values: alanine aminotransferase 980 U/L, aspartate aminotransferase 810 U/L, alkaline phosphatase 390 U/L, and total bilirubin 15.8 mg/dL. Viral serologies were negative. Abdominal imaging showed no biliary or vascular abnormalities and a liver biopsy was performed that demonstrated severe acute cellular rejection. CMV, cytomegalovirus; LT, liver transplantation. Figure 1 is a representative portal area from the biopsy showing severe inflammation consisting of a mixed infiltrate including eosinophils, plasma cells and lymphocytes, as well as endotheliitis (arrowheads) and bile duct damage (arrow). The patient received pulse corticosteroids as well as thymoglobulin with gradual improvement in the liver chemistry tests over a 3-week period. The tacrolimus dose was optimized and infection prophylaxis was resumed. However, shortly thereafter, the patient was hospitalized with worsening liver chemistry tests and decreasing hematologic indices. CMV as analyzed by polymerase chain reaction was found in high titer, and liver biopsy confirmed the presence of CMV hepatitis. Figure 2 is a representative field from the biopsy demonstrating a cell with the pathognomonic owl-eye nuclear inclusion body (arrow) and intracytoplasmic inclusions that are denoted by arrowheads. Antiviral treatment was initiated and the liver and hematologic abnormalities improved. Within 3 months, however, despite continuing immunosuppression with tacrolimus, mycophenolate and corticosteroids, the liver chemistry tests again worsened: alanine aminotransferase 125 U/L, aspartate aminotransferase 111 U/L, alkaline phosphatase 750 U/L, and total bilirubin 12.9 mg/dL. Another liver biopsy was performed which showed the loss of bile ducts in the majority of portal tracts. Figure 3 is a representative area showing lobular cholestasis and feathery degeneration (arrowhead) as well as a portal tract with an arteriole but without an accompanying bile duct (arrow). This is consistent with bile duct loss and indicative of chronic ductopenic rejection. Cytokeratin 7 immunostaining confirmed greater than 50% bile duct loss. Unfortunately, the patient eventually developed fungemia and expired. A postmortem examination was performed. Figure 4 is a section taken from the liver hilum showing almost total obliteration of the lumen of a hepatic artery by foamy macrophages (arrows) indicative of foam cell arteriopathy. Acute cellular rejection is diagnosed based on the degree of portal inflammation, bile duct damage, and venous endotheliitis.1 Post-LT CMV infection occurs more frequently in patients who have no previous exposure to CMV, especially in the setting of increased immunosuppression.2 Microabscesses are often seen along with the pathognomonic CMV inclusion bodies. These parenchymal neutrophilic abscesses were once thought to be specific for CMV hepatitis but are now known to also occur in the setting of other infections, graft ischemia, and biliary obstruction.3 Both severe acute cellular rejection and CMV infection may predispose to the development of chronic ductopenic rejection.4 Chronic rejection may lead to graft loss with patients most commonly dying from infection. It is characterized by progressive jaundice and obliterative arteriopathy. Cytokeratin staining can give a more accurate count of the degree of bile duct loss; greater than 50% loss is defined as ductopenia. Foam cell arteriopathy often affects larger vessels and is typically not seen on a needle biopsy. Chronic rejection can be classified as either early or late, based on bile duct degenerative changes and loss, hepatic arteriolar loss, and the degree of foam cell arteriopathy in larger arteries.5 Unexplained cholestasis unaccompanied by portal tract changes of biliary obstruction should prompt a careful assessment for subtle bile duct changes suggestive of early chronic rejection.3