Microscopically, mild preservation injuries are visible on biopsies taken 1 h after OLT as microvesicular steatosis with hepatocyte swelling, but these features are rapidly reversible. Conversely, the more severe forms of preservation injury are characterized microscopically by hepatocyte necrosis, especially in zone 3, with acidophilic bodies and/or zonal or confluent necrosis. The adjacent viable hepatocytes can show ballooning and mitotic activity. Bile duct degeneration is visible as a detachment of the biliocytes from the basement membrane and as a ductular reaction with ductular and lobular neutrophilic infiltrate [8, 9]. As a consequence, both intracellular and extracellular cholestases (with bile plugs) are common. Cholestasis, architectural lobular distortion, hepatocyte mitotic activity with nuclear polymorphism and ballooning, as well as histiocytosis in zone 3 can be seen several weeks after OLT.

In these early phases, the differential diagnosis includes acute infections, biliary complications, and antibody-mediated rejection. Cholangitis, bile duct obstruction, and reperfusion injury share predominant zone 3 damage, but cholangitis is commonly characterized by periductal oedema with neutrophilic granulocytes [9]. Interestingly, immunohistochemical positivity for C4d has been demonstrated in necrosis during reperfusion injury [10].

The histopathological modifications of “small-for-size” syndrome are commonly sorted into early, intermediate and late changes [11]. Starting from a few minutes after reperfusion, denudation of portal veins and sinusoids can be seen, resulting in haemorrhages in the periportal zone (zone 1), all consequences of portal hyperperfusion. In the more severe cases, ischaemic bile duct damage with lobular infarcts can be seen [9]. Intermediate features include hypertrophic changes in the endothelia, oedema and fibrosis, while the late changes comprise thrombosis and obliteration of the portal veins with recanalization, together with nodular regenerative hyperplasia and biliary stenosis.

Arterial vascular complications (see below).

At gross examination, the liver surface may be normal, while foci of cholestasis and/or necrosis can be seen in some cases. At histology, thrombosis of the hepatic artery leads to ischaemic necrosis of the bile ducts with epithelial denudation and bile leakage into the surrounding parenchyma. Lobular alterations, ranging from Councilman’s bodies to confluent hepatocytic necrosis, appear in the more severe and advanced cases. Prolonged arterial ischaemic injury can result in biliary strictures and fibrosis [12].

Post-transplant biliary complications histologically resemble the biliary disease of the native liver. Portal oedema and inflammation with neutrophilic granulocytes, resembling cholangitis, are common findings: the predominance of the neutrophilic infiltrate is very important in the differential diagnosis between post-OLT biliary complications and acute rejection. Cholestasis can be associated, while portal fibrosis and biliary cirrhosis represent the chronic evolution of this condition [12, 13].

The main histological features of ACR are portal inflammatory infiltrate, endothelialitis and bile duct aggression. The inflammatory infiltrate characterizing ACR is mainly portal and with a prevalent lymphocytic component, although macrophages and both neutrophilic and eosinophilic granulocytes can be seen. The lymphocytes are CD8-positive and show the morphology of activated (or frankly blastic) T cells [14]. Lymphocyte-mediated bile duct injury is always present, with intraepithelial lymphocytes and associated bile duct regressive and reactive changes such as cytoplasmic eosinophilia and/or vacuolation, prominent nucleoli and occasional apoptosis [15]. Endothelialitis is defined as the presence of inflammatory cells in the subendothelial layer of the graft vascular (mainly venous) structures [16]. It is an important diagnostic feature in ACR, albeit not a specific finding since it can be detected in other pathological conditions (e.g. HCV recurrent hepatitis, infections) [17].

Recurrent and de novo viral hepatitis (HCV, HBV, CMV, EBV), drug hepatitis, lymphoproliferative disorders and other disorders with a predominant inflammatory component. Clinical onset, serological and clinical data are mandatory for the differential diagnosis. The presence of a plasma cell component requires the differential diagnosis from plasmacellular HCV recurrent hepatitis or post-OLT autoimmune hepatitis: the role of plasma cells in acute rejection is still debated [18] (Fig. 11.6).