This form of rejection refers to a type of cellular rejection that occurs several months after transplantation and may show different histologic features as compared with typical ACR described earlier. Alternative names include centrizonal/parenchymal rejection, hepatitic variant of rejection, or atypical rejection. It is characterized by a hepatitic pattern of liver injury and can mimic hepatitis closely [7, 8]. Perivenular inflammation (central perivenulitis) is commonly seen, which may or may not be associated with centrilobular hepatocyte injury and necrosis (Fig. 5.8). Late acute rejection is considered a diagnosis of exclusion, and complete serologic studies (including rare forms of viral hepatitis such as hepatitis E) must be performed to rule out other etiologies of hepatitis. Of note, hepatitis E is an uncommon but increasingly recognized cause of acute and chronic hepatitis in the developed countries and should be considered in any post–liver transplant patient with a hepatitic pattern of injury. In general however, if central perivenulitis is present in less than 50 % of the lobules, the diagnosis of late acute rejection is favored [9].

PCH is an immune-mediated post-transplant histologic pattern of injury. It is characterized by the presence of plasma cell–rich portal and lobular inflammatory infiltrates, including central perivenulitis, which closely resembles autoimmune hepatitis in the native liver (Fig. 5.9) [10]. While the pathophysiology is somewhat unclear, PCH is generally considered a form of rejection and is a negative prognostic factor for graft and patient outcomes. Patients with this pattern of injury are more likely to be resistant to increased immunosuppression and have an increased risk of fibrosis and graft loss [11–13].

In comparison to other solid organ transplants (such as heart, lung, and kidney) in which CR may affect 30–50 % of allograft recipients, CR affects only 3–5 % of liver transplant recipients. Although late CR is considered an irreversible, progressive disease that leads to graft loss, early CR is considered potentially reversible [14]. Early CR is identified by degenerative changes of the biliary epithelium, even before duct loss. These include uneven spacing of biliary epithelial cells, loss of nuclear polarity, and increased cytoplasmic eosinophilia (Fig. 5.10). Late CR is characterized by bile duct loss involving greater than 50 % of portal tracts (Fig. 5.11). Other lobular features that may be seen in later phases of CR include clusters of pigmented foamy macrophages, canalicular cholestasis, pericentral hepatocyte atrophy, and/or ballooning and perivenular fibrosis (Figs. 5.12, 5.13, and 5.14). While foam cell obliterative arteriopathy is the characteristic feature of CR, this finding is only rarely seen in needle core biopsies (Fig. 5.15). The minimum diagnostic criteria for histopathologic diagnosis of CR are defined as follows [15]: (1) the presence of bile duct atrophy/senescence affecting most of the bile ducts, with or without bile duct loss (early CR), (2) foam cell obliterative arteriopathy (OA) with accumulation of foamy, lipid-laden histiocytes within the myointimal layer, or (3) loss of interlobular bile ducts in at least 50 % of the portal tracts (late CR).

AMR is becoming increasingly recognized in liver allografts. However, it remains a controversial area because its diagnostic criteria and histologic features have not been fully established. In general, AMR may be considered if other etiologies of allograft dysfunction have been excluded and if donor-specific antibodies (DSAs) are discovered in the patient’s serum. Histologic features that have been reported include portal edema and neutrophilic inflammation with ductular reaction (i.e., features similar to those of bile duct obstruction), hepatocellular necrosis (i.e., features of ischemic injury) as well as portal vein endothelial cell hypertrophy, portal eosinophilia, and eosinophilic central venulitis (Fig. 5.16). Diffuse C4d deposition in the portal vein and sinusoids, demonstrated by immunohistochemistry and/or immunofluorescence, has been described in cases with clinical suspicion of AMR in the presence of DSAs (Fig. 5.17) [16–18]. However, the C4d stain remains a nonspecific stain, and its clinical utility remains unclear because positivity has also been reported in cases of ACR, CR, recurrent hepatitis B and C, biliary obstruction, vascular thrombosis, and even normal allograft livers [19]. The Banff schema consensus guidelines for diagnosis of AMR and C4d interpretation in liver allograft are expected to be released in the near future.