Pathophysiology
Chronic rejection usually evolves from severe or multiple recurrent and uncontrolled acute rejection episodes [4, 5, 25, 26] . Therefore, many of the immunologic mechanisms of injury discussed for acute rejection are likely to be relevant to chronic rejection. Instead of hepatocyte and biliary epithelial cell proliferation and architecturally correct repair, bile ducts are destroyed, perivenular and portal fibrosis develop, and arteries narrow [7, 41] .

The bile duct damage and loss in chronic rejection is due to a combination of direct immunological damage by the effector mechanisms of rejection and indirect ischemic damage because of obliterative arteriopathy, small artery/arteriolar loss, and destruction of the peri-biliary capillary plexus [42, 43, 44] . The cumulative damage results in enhanced biliary epithelial cell senescence [45] , which manifests as distinct cytologic changes recognizable on routine light microscopy and enhanced expression of nuclear p21 without Ki-67 labeling [45] . These changes precede bile duct loss [4, 7] . Any factors that can lessen the damage associated with acute rejection, such as treatment with increased immunosuppression, or foster non-fibrogenic repair reactions, have the potential to lessen the impact of chronic rejection.

In general, chronic rejection develops as a pathogenic "response to injury", similar to atherosclerosis. [46, 47, 48] . The basic algorithm is as follows:

Severe or persistent immunologic injury ® disruption of normal structure ® fibrogenic repair response ® parenchymal fibrosis, loss of bile ducts, and obliterative arteriopathy

Since livers usually recover completely without fibrosis from acute transient immunologic insults such as acute hepatitis, persistent immunologic damage is usually needed for the development of chronic rejection. Poor lymphatic drainage [49] , excess production of pro-fibrogenic cytokines [50] , loss or change of the supporting architecture theory [50] , and "premature senescence" of epithelial cells [30, 50] have been offered as explanations for a trendency toward the development of fibrosis in CR. All of the above hypotheses are likely to be valid to some extent and highlight mechanisms that contribute to various aspects of chronic rejection.

Clinical Presentation
A clinical diagnosis of chronic rejection is usually suspected in a patient with a history of acute rejection, who develops progressive cholestasis and an increase in canalicular enzymes that is unresponsive to anti-rejection treatment [1]. There are three typical clinical settings: 1) the endstage of unresolved acute rejection; 2) after multiple episodes of acute rejection [1, 2, 3, 4, 5, 6, 22, 25, 41, 42, 51, 52, 53, 54, 55] ; and 3) evolving indolently without preceding clinically recognized episodes of acute rejection [1, 2, 3, 4, 5, 6, 22, 25, 41, 42, 51, 52, 53, 54, 55, 56] . The first two scenarios are, by far, the most common and usually occur within the first year after transplantation. The last situation is relatively uncommon and may simply reflect inadequate monitoring. Late onset chronic rejection occurring more than one year after transplantation is typically seen in inadequately immunosuppressed patients, either as a result of non-compliance or because immunosuppression had to be lowered because of infectious, neoplastic or toxic complications of over-immunosuppression [5].

Unresolved or indolent rejection may become apparent only because of a persistent elevation of liver injury tests. If clinical symptoms are present, they usually resemble those of acute rejection, until allograft dysfunction becomes severe enough to cause jaundice. Biliary sludging or appearance of biliary strictures, hepatic infarcts, and finally loss of hepatic synthetic function, which can manifest as coagulopathy and malnutrition are other late findings presaging allograft failure [1].

Standard liver injury tests in patients with chronic rejection usually show a progressive cholestatic pattern, that manifests as preferential elevation of γ-glutamyl transpeptidase and alkaline phosphatase [1, 18, 57] . Transition from acute to chronic rejection may be marked by persistent elevation of alanine aminotransferase and total bilirubin that presage allograft failure [4, 5, 58] .

Histopathologic Findings and Staging
The portal tracts and perivenular regions are primarily affected by chronic rejection and changes seen in these areas are divided into "early" and "late" stages.

Portal tract changes in early chronic rejection include mild lymphocytic cholangitis, biliary epithelial cell senescence changes [45] that presage bile duct loss [3, 10, 58, 59] . These include eosinophilic transformation of the biliary epithelial cytoplasm; uneven nuclear spacing; syncithia formation; nuclear enlargement and hyperchromasia resembling cytological dysplasia; and ducts only partially lined by biliary epithelial cells. The senescent biliary epithelial cell stain positive for p21(WAF1/Cip1) (but not for Ki-67), an inhibitor of cell cycle progression that becomes upregulated in cells under severe stress or showing replicative senescence [45].

The early phase of chronic rejection in the centrilobular regions is characterized by subendothelial and perivenular mononuclear inflammation [7, 25] . This is accompanied by perivenular hepatocyte dropout, and an accumulation of pigment-laden macrophages and mild perivenular fibrosis [4, 5, 25, 41] . Spotty acidophilic necrosis of hepatocytes, or so-called "transitional hepatitis" may occur during evolution from early to late stages of chronic rejection [6] .

Late stage CR in the portal tracts can manifest as bile duct, which at times can also be accompanied by arteriolar loss [42, 43, 44] . When both bile duct and arterial loss are seen, recognizing and counting the portal tracts will ultimately depend on the subjective interpretation of the pathologist. Recognition of portal tracts in such cases should be based primarily on the location (cholestasis in chronic rejection is centrilobular), shape and internal structure of the connective tissue mesenchyme. Despite the destruction of the bile ducts, a ductular reaction [60, 61, 62] at the interface zone is unusual in chronic rejection, unless the liver is recovering from rejection. In such cases, a ductular reaction at the interface zone usually precedes the regrowth of bile ducts [2, 3, 4] .

Late CR in the centrilobular areas is characterized by severe (bridging) perivenular fibrosis with at least focal central-to-central or central-to-portal bridging and occasional obliteration of terminal hepatic venules [4, 5, 41] . However, well-developed cirrhosis from chronic rejection is unusual [63] until the very late stages when venous obliteration leads to areas of parenchyma extinction [41] . True "regenerative" nodules are uncommon, perhaps because the combination of venous and arterial obliteration blunts any regenerative response [64] .

Other common findings in late chronic rejection include perivenular hepatocyte ballooning and dropout; centrilobular hepatocanalicular cholestasis, nodular regenerative hyperplasia-like changes, and intra-sinusoidal foam cell clusters [1, 2, 23, 24, 42, 43, 51, 52, 53, 54, 65] . The clusters of foamy macrophages likely represent a non-specific response to cholestasis and therefore, alone, are not diagnostic of chronic rejection.

The final diagnosis of chronic rejection should be based on various combinations of the clinical, radiological, laboratory, and histopathological findings. In a biopsy specimen, the minimal diagnostic criteria for chronic rejection are: a) senescent changes, affecting a majority of the bile ducts, with or without bile duct loss; or b) convincing foam cell obliterative arteriopathy; or c) bile duct loss affecting greater than 50% of the portal tracts [7].

The diagnosis of chronic rejection is easier to establish in an explanted failed allograft and characteristic sequential changes that develop in the branches of the hepatic arterial tree can be appreciated. Arteriopathy is usually seen in at least some of the muscular arteries in the hilum [1, 2, 23, 24, 42, 43, 51, 52, 53, 54, 65, 66] , except in cases characterized by bile duct loss and/or perivenular fibrosis alone.

Sequential changes in the hepatic arterial tree include a progressive accumulation of t he foamy macrophages that triggers proliferation of donor-derived subintimal myofibroblasts [67] . In severely affected arteries, the entire wall can be completely replaced by foam cells or completely obliterated leading to arterial thrombosis and subsequent necrosis of the large bile ducts. This is followed by thinning of media as the arteries attempt to dilate and compensate for the reduced arterial flow. Eventually the foam cells are replaced by intimal myofibroblasts.

Other changes in the major hilar bile ducts include focal sloughing of the epithelium, papillary intraluminal hyperplasia, mural fibrosis and acute and chronic inflammation [68] . Foamy macrophages may also be seen around bile ducts and veins in the connective tissue.

Staging of chronic rejection (Table 1) assumes that the diagnosis has already been correctly established [7].

Table 1. Features of early and late chronic liver allograft rejection (Adapted from [7] ).

Structure	Early CR	Late CR
Small Bile Ducts (< 60 mm)	Bile duct loss in < 50% of portal tracts. Degenerative change involving a majority of ducts: eosinophilic transformation of the cytoplasm; nuclear hyperchromasia; uneven nuclear spacing; ducts only partially lined by biliary epithelial cells.	Loss in ≥ 50% of portal tracts. Degenerative changes in remaining bile ducts
Terminal hepatic venules and zone 3 hepatocytes	Intimal/lumenal inflammation Lytic zone 3 necrosis and inflammation Mild perivenular fibrosis	Focal obliteration Variable inflammation Severe perivenular fibrosis, defined as central-to-central bridging fibrosis.
Portal tract hepatic arterioles	Occasional loss involving < 25% of portal tracts.	Loss involving > 25 % of portal tracts.
Other	So-called "transition" hepatitis with spotty necrosis of hepatocytes	Sinusoidal foam cell accumulation; marked cholestasis
Large perihilar hepatic artery branches	Intimal inflammation, focal foam cell deposition without lumenal compromise	Lumenal narrowing by subintimal foam cells Fibrointimal proliferation
Large perihilar bile ducts	Inflammation damage and focal foam cell deposition	Mural fibrosis

Early chronic rejection implies that a significant potential for recovery exists if the insult can be controlled or removed. Late chronic rejection suggests that potential for recovery is limited, and perhaps retransplantation should be considered. However, more study is needed in this area because it is not well established that all patients sequentially proceed in an orderly fashion from the early to the late stage of chronic rejection. Some patients appear to persist in the acute/early stage for months or years, while others rapidly develop severe fibrosis and late changes. In addition, some cases show predominantly or exclusively either bile duct loss or foam cell arteriopathy alone, but usually both features are found together [7, 42, 55, 69] .

The decision to proceed with retransplantation should be based on both clinical and histopathologic parameters, such as progressive decline in synthetic function, superimposed hepatic artery thrombosis, and bile duct necrosis or biliary sludging. The important practical implication of chronic rejection staging is that the biopsy findings do not absolutely define a point of no return; they provide information about the likelihood of reversal. Thus, the histopathologic findings should be combined with a complete clinicopathologic evaluation before the decision to continue medical therapy or proceed with retransplantation.

Differential Diagnosis
Since arteries with pathognomonic changes are rarely present in needle biopsy specimens, considerable significance is placed on damage and loss of small bile ducts and perivenular fibrosis [7]. However, a similar pattern of duct injury and ductopenia can be as a result of non-rejection-related complications, such as obstructive cholangiopathy (including recurrent PSC), hepatic artery stricturing or thrombosis, adverse drug reactions, and CMV infection [57, 58, 70] . In cases of chronic rejection identified by biliary epithelial senescence or loss or perivenular fibrosis alone, other, non-rejection-related causes of ductal injury and loss or perivenular fibrosis, which histopathologically appear similar to chronic rejection, should be reasonably excluded. Bile duct loss in some portal tracts accompanied by a ductular reaction in other portal tracts should raise the suspicion of a biliary tract stricture. Cholangiography and/or angiography may be required in some case to distinguish between chronic rejection and biliary obstruction [58]. In other cases, isolated ductopenia involving less than 50% of the portal tracts can be seen without significant elevations of liver injury tests [4, 5, 71] . Whether these uncommon cases are an early phase of chronic rejection is uncertain. Selective hepatic angiography showing pruning of the intrahepatic arteries with poor peripheral filling and segmental narrowing can also be used to support the diagnosis of chronic rejection [1, 23, 72, 73, 74] .

Isolated perivenular fibrosis can be caused by mechanical outflow obstruction, adverse drug reactions [75] and all of the non-rejection causes of veno-occlusive disease and Budd-Chiari syndrome in native livers [76].

The safest approach to the diagnosis of chronic rejection in any setting is to review prior biopsies and closely correlate the histopathologic findings with the clinical course. The usual scenario is a history of severe or unresolved acute rejection preceding the development of histologic findings interpreted as chronic rejection.

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