Rejection can occur in the first days following transplantation, especially if induction immunosuppressive therapy is not used. The pattern of liver function test abnormalities varies and can be hepatocellular or cholestatic in nature. Diagnosis is made by liver biopsy since clinical signs and symptoms of rejection are extremely variable, non-specific, and unreliable (Table 9.20).

Rejection is a common phenomenon with at least 60 percent of liver transplant recipients having at least one episode. Acute cellular rejection usually occurs between the fourth and fourteenth day posttransplant with most episodes occurring within three months of transplantation. Some patients are asymptomatic while others may experience profound symptoms due to a failing liver allograft. The diagnosis of allograft rejection is confirmed by histologic examination of a liver biopsy. Classic histologic findings of acute cellular rejection include a portal infiltrate consisting of mixed inflammatory cells, where the presence of eosinophils

Table 9.20. Signs and symptoms of rejection

1. Fever

2. Decreased quality and quantity of bile

3. Elevation of the bilirubin and/or transaminase levels

4. Sense of ill being

5. Increased ascites can be diagnostic, as well as lymphocyte-mediated bile duct injury, and endothelialitis.(Fig. 9.5, Table 9.21)


Abnormality of liver function tests secondary to infection is most commonly secondary to viral infections which include cytomegalovirus (CMV) hepatitis, as well as recurrence of previous viral hepatitides. Recurrence of disease will be covered in the next section. CMV hepatitis is diagnosed by the presence of inclusion

Fig. 9.5. Hematoxylin and eosin stain of acute cellular rejection demonstrating a mixed portal infiltrate with many eosinophils, endothelialitis, and evidence of cellular-mediated bile duct disruption.

Table 9.21. Histologic determinants of acute cellular rejection

1. Portal infiltrate with mixed inflammatory cells

2. Bile duct injury

3. Endothelialitis

Grading of Acute Liver Allograft Rejection - Banff Criteria24

Grade Criteria

I (mild) Cellular infiltrate in a minority (< 50%) of the triads, that is generally mild, and confined within the portal spaces.

II (moderate) Cellular infiltrate, expanding most (> 50%) or all of the triads.

III (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.

Fig. 9.6. Immunoperoxidase stain of CMV hepatitis demonstrating an inclusion body with intranuclear staining for CMV and a surrounding cluster of polymorphonuclear cells.

bodies with clusters of polymorphonuclear cells (Fig. 9.6). These "clusters" represent the "footprints" of CMV. This evidence of tissue invasive disease is often associated with symptoms of fever, general malaise, myalgias, and diagnosis is corroborated with shell vial culture or positive antigenemia tests. Treatment consists of reduction in immunosuppression and antiviral agents such as ganciclovir. In addition to CMV infection, other bacterial and fungal systemic infections may result in a secondary abnormality in liver function tests associated primarily with a cholestatic pattern. These elevations are difficult to sort out and may require multiple diagnostic efforts. Finally infection of the liver secondary to abscess formation may occur resulting in abnormal liver function tests typically as a result of hepatic artery thrombosis. These can be bacterial and fungal in nature and can be diagnosed first with ultrasound, then CT scan, and finally angiography. ERCP may be helpful in delineating the extent of biliary duct disruption. If severe enough, these biliary tract complications may require retransplantation of the liver.

Recurrence of Native Disease

Recurrence of native disease consists most frequently of recurrence of viral infection such as hepatitis B and hepatitis C, as well as non-A, non-B, non-C hepatitis. Recurrence of hepatitis B is easy to diagnose with either serum markers or stains for surface antigen and core antigen on the biopsy. In contrast, recurrence of hepatitis C may be more difficult to differentiate histologically from other causes of liver abnormality such as rejection. Although there is some evidence that there may be a role for immune modulators and antiviral agents such as interferon and ribavirin in the prophylaxis and treatment of recurrent hepatitis C, the data are

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