INTRODUCTIONChronic rejection (CR) is an indolent, but progressive form of allograft injury that is usually irreversible and eventually results in the failure of most vascularized solid organ allografts. It is the single most significant obstacle to morbidity-free long-term survival. By 5 years after transplantation, it affects as many as 30-50% of heart, lung, pancreas and kidney allograft recipients, but only 4-8% of patients who undergo liver replacement (1). Liver allografts also differ from other solid organs in that CR is potentially reversible. This quality that has been generally attributed to its unique immunobiological properties and the regenerative capacity of one of the main targets in CR, the bile ducts (2-5). Recent developments in the area of chronic liver allograft rejection include a proposal for a histopathological staging system and a greater understanding of why liver allografts are unusually resistant to CR (see below).
CLINICAL PRESENTATIONThe diagnosis of CR 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 (6). This usually occurs in 3 typical clinical settings: as the endstage of unresolved acute cellular rejection (ACR); after multiple episodes of ACR; and evolving indolently without preceding clinically recognized episodes of ACR (2, 3, 6-13). The first two of these usually occur early after transplantation, although a later onset is typically seen in inadequately immunosuppressed patients, either as a result of non-compliance or because of infectious, neoplastic or toxic complications of over-immunosuppression. 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, malnutrition, and hepatosplenomegaly are late findings presaging allograft failure(6) .
Standard liver injury tests abnormalities in a patient with CR usually show a progressive cholestatic pattern, with preferential elevation of gamma-glutamyl transpeptidase and alkaline phosphatase(6, 14, 15). The same pattern of liver injury test elevation can be seen with obstructive cholangiopathy and with cholestatic hepatitis(14). Therefore, cholangiography may be required in some cases to distinguish between CR and biliary obstruction, particularly since the latter can also cause small bile duct loss at the periphery of the liver. Findings in a core needle biopsy can easily distinguish between a cholestatic hepatitis and CR. The diagnosis of CR can also be supported by selective hepatic angiography, which shows pruning of the intrahepatic arteries with poor peripheral filling and segmental narrowing (6, 16-18).
RISK FACTORSRisk factors for the development of CR have generally been divided into two general categories, although the two are interdependent. The first and probably the most important set of risk factors have been lumped under the designation of "alloantigen-dependent", immunological or rejection-related factors. Among these, late onset and increased number of acute rejection episodes (2, 19, 20); younger recipient age (2); male-to-female sex mismatch; a primary diagnosis of autoimmune hepatitis or biliary disease (21-23); baseline immunosuppression (19, 24) and non-caucasian recipient race (2, 25) have all been associated with an increased risk of developing CR. The role of histocompatibility differences is still controversial (2, 22, 23, 25-31), as is the effect of CMV infection (2, 19, 22, 23, 30-32). Non-alloantigen-dependent or "non-immunological" risk factors that are also contribute to the development of CR include advanced donor age, pre-existing atherosclerosis in the donor organ, and prolonged cold ischemic time(1), but these have not been thoroughly studied in liver transplantation.
HISTOPATHOLOGICAL FEATURES AND PATHOPHYSIOLOGY OF CHRONIC LIVER ALLOGRAFT REJECTIONA number of investigators have contributed to the constellation of histopathological features that are now recognized as CR(1, 2, 5-8, 10-12, 15, 22, 26, 33-37). Most studies report very similar if not identical findings. Therefore, statements in the text below will not always referenced to a particular group.
As already mentioned, the diagnosis of CR is clinically suspected from the signs and symptoms listed above, and confirmed histopathologically, by recognizing the two principal features: obliterative arteriopathy (OA) , and severe damage and loss of small (< 60 microns) bile ducts (2, 3, 6, 7, 9-13, 38). Cases with either isolated bile duct loss or foam cell arteriopathy alone may occur, but usually both features are found together(13, 39). Unfortunately, arteries with pathognomonic changes are rarely present in needle biopsy specimens, and therefore what has been observed about OA in the liver has come from examination of failed allografts removed at the time of re-transplantation. Therefore, in biopsy specimens, significant weight is usually placed on damage and loss of small bile ducts, but ductopenia can be non-specific finding that occasionally occurs as a result of non-rejection-related complications(5, 15).
Until recently, the most widely used criteria defined CR as bile duct loss in more than 50% of the portal tracts (6, 13, 22, 23). However, an inter-institutional study recently showed that CR could be reliably identified in needle biopsy specimens on the basis of widespread biliary epithelial cell atrophy and pyknosis(15), with or without bile duct loss. Currently, in a biopsy specimen, the minimal diagnostic criteria for CR are a) the presence of bile duct atrophy/pyknosis, 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(2, 4-6, 9, 10, 15, 16, 22, 40, 41).
Bile duct loss is recognized by the presence of hepatic artery branches without accompanying bile ducts, or by the absence of both ducts and hepatic artery branches(6). The prevalence of bile duct loss is determined by calculating the ratio between the number of hepatic artery branches and the number of bile ducts within a portal tract. Normally, this ratio is greater than 0.7(11, 42, 43). The greater the number of portal tracts counted, the more likely the count is to be valid. Sometimes this will require the evaluation of several sequential biopsies. Recognition of portal tracts may be difficult in cases where the hepatic arterioles have also been destroyed(11, 38, 44). In such cases, reliance on other architectural landmarks, such as cholestasis, which is centrilobular predominant in CR can be helpful.
The early, potentially reversible, stage of CR is identified primarily by degenerative changes of the biliary epithelium, even before overt duct loss is detected. These include uneven spacing of individual epithelial cells , eosinophilic transformation of the cytoplasm , similar to that observed in primary biliary cirrhosis, and ducts only partially lined by epithelial cells. Portal inflammation is usually mild and ductulocentric, and consists of CD3+CD4+, and CD3+CD4- T cells, CD20+ B cells and CD68+ macrophages and plasma cells(45, 46). The presence of CD2+/CD8+ T-lymphocytes in contact with the degenerating biliary epithelial cells(47) and increased transcripts for TH1-type cytokines IL-2 and gamma-interferon, and the presence of granzyme B, indicate that cytotoxic effector cells are at least partially responsible for biliary epithelial cell damage (35, 45). However, TUNEL assays suggest that apoptosis is not a common pathway in the biliary epithelial cell damage(48).
As the disorder progresses, bile ducts loss affects a greater percentage of the portal tracts and biliary epithelial cells become difficult to identify. Special stains (e.g. trichrome, PAS-D, cytokeratin ) may be used to enhance their detection by highlighting the basement membrane or selectively staining the biliary epithelial cells, but generally the special stains are not needed(49). The smaller the duct, the more susceptible to damage and loss(11, 38). In most instances, bile duct loss is verified the presence of a portal tract containing a hepatic artery branch, without an accompanying bile duct, , which should be present within a distance of three times the shortest diameter of the artery in > 80% of portal tracts(11, 38, 42, 43). In very advanced cases, there is complete destruction of the small arterioles, peribiliary plexus (11, 38, 44) and the bile ducts, which results in a "scarred" appearance of the portal tract connective tissue.
Bile duct damage is caused by a combination of direct immunological damage as described above, combined with ductal ischemia because of destruction of the portal tract microvasculature and obliterative arteriopathy, and possibly interference with lymphatic drainage(11, 38, 44, 50). There are several possible non-exclusionary explanations for the preferential destruction of bile ducts: 1) the presence of a basement membrane, which could potentially play a role in migration, positioning and co-stimulation of T-cells; 2) an immunologically active antigenic profile of the biliary epithelial cells that is significantly different than other parenchymal cells, including class I and II MHC, and various adhesion and co-stimulatory molecules; and 3) the presence of nearby antigen presenting cells and lymphatics, that facilitate the functional role of these conduits in processing environmental antigen for local presentation and traffic to the regional lymph nodes. Thus, a ductulocentric immune response might be precipitated by environmental or autoantigens in an allograft, which creates inflammatory microenvironment, which has the potential to trigger a rejection reaction. Either reaction can compromise the structural integrity of the duct, and focally destroy the local microvasculature and lymphatic drainage, which in turn can ischemically damage the conduit and inhibit efficient antigen clearing. One could easily appreciate how this could lead to a vicious cycle, alternating between a persistent and inadequate response to environmental antigens/infections and allogeneic injury, resulting in a downward spiral of allograft structural integrity and function(51).
Despite the destruction of the bile ducts a ductular reaction (52-55) at the interface zone is unusual in CR. This might account for the observation that a well-developed cirrhosis from CR is unusual, although there are some case reports and descriptions to the contrary(33). More often, the fibrosis that develops in CR is preferentially detected in a perivenular distribution, which can result in central-to-central bridging fibrosis.
Foam cell arteriopathy can rarely be confirmed by a core needle biopsy, therefore, other "surrogate" features are often used to suggest the presence of obliterative arteriopathy. Features that suggest but do not prove the presence of foam cell arteriopathy include loss of arterioles and small arteries(< 20 microns) in > 20% of the portal tracts, centrilobular hepatocellular swelling, perivenular sclerosis, and centrilobular hepatocyte dropout.
Lobular changes commonly seen in CR include centrilobular hepatocanalicular cholestasis , intra-sinusoidal foam cell clusters , mild spotty acidophilic necrosis of hepatocytes, centrilobular hepatocyte atrophy and/or ballooning and perivenular sclerosis . Clusters of foamy macrophages are commonly seen in the sinusoids, although their presence may simply represent a non-specific response to cholestasis. The centrilobular degeneration and perivenular sclerosis may be related to either ischemia or damage from repeated bouts of "central venulitis" during acute rejection.
The diagnosis of CR is easier to establish in an explanted failed allograft. The presence of significant foam cell obliterative arteriopathy (OA) should be seen in at least some of the muscular arteries in the hilum. Arteries affected by OA show endothelial hypertrophy and luminal narrowing most commonly because of subintimal deposition of lipid-laden cells that are transformed macrophages and intimal and medial myocytes. Foamy macrophages can also be seen around bile ducts and veins in the connective tissue. Lymphohistiocytic intimal inflammation, smooth muscle cell proliferation, disruption of the elastic lamina, and periadventitial and intra-medial inflammation of medium-sized arteries may also be present. Occasionally, there is superimposed arterial thrombosis. Major hilar bile ducts may show sloughing of the epithelium, focal necrosis, intraluminal papillary hyperplasia of the epithelium, mural fibrosis and acute and chronic inflammation.
STAGING OF CHRONIC LIVER ALLOGRAFT REJECTIONIn acute rejection, graft damage can occur quickly within days or weeks, and graft failure occurs primarily because of ischemic necrosis of the organ. Therefore, histopathological grading of the severity of rejection is based primarily on the necro-inflammatory activity and evidence of acute vascular compromise. CR on the other hand, evolves more slowly in most cases over a period of months to years, and progresses through a predictable sequence of changes, making the process amenable to histopathological staging. In addition, several studies have shown that CR of a liver allograft is reversible to some extent(2, 3, 5, 15, 34, 41). This usually occurs before the duct loss, perivenular fibrosis or obliterative arteriopathy have become severe. Resolution of liver injury abnormalities and concomitant improvement of liver histology of CR has occurred in response to treatment with either an increase or change in immunosuppressive drugs(2, 3, 5, 15, 34, 41). In other cases, it appears to have occurred spontaneously (2, 3, 5, 15, 34, 41).
Most, if not all, patients who develop CR will experience one, or often more, episodes of acute rejection. In fact, CR evolves directly from inadequately controlled acute rejection episodes in up to 60% of patients who develop CR(2, 22, 23, 41). In the remaining patients, CR can develop more indolently, but even these have a documented history of acute rejection episodes. The transition from acute to the early stage of CR is accompanied by biliary epithelial cell atrophy/pyknosis involving a majority of the bile ducts, as described and illustrated above, and with or without bile duct loss in < 50 % of the portal tracts. Perivenular necrosis, hepatocellular swelling and hepatocanalicular cholestasis may be seen in the centrilobular regions, but perivenular fibrosis is not severe (bridging) and foam cell clusters are usually absent. Late CR is defined by bile duct loss involving 50 % or more of the portal tracts. Atrophy/pyknosis are usually seen in any remaining bile ducts and moderate tosevere perivenular fibrosis and foam cell clusters are present. The perivenular fibrosis is associated with an increase of extracellular matrix proteins fibronectin, tenascin, undulin, and collagen VI and an accumulation of alpha-actin-positive cells and TGF-b1-expressing macrophages (56). Severe obliterative arteriopathy is also present, but this is usually not detectable in needle biopsies taken from the periphery. The development of cirrhosis is unusual in our experience.
Several recent studies have chronicled the sequential changes associated with the development of CR and clinicopathological changes associated with either progression to allograft failure or recovery to normal or near normal liver injury tests and/or liver architecture (15, 41). Using strict clinical and histopathological criteria, which included the absence of biliary strictures or obstruction and other co-morbid conditions that might cause ductopenia, a cohort of 23/916 patients from the National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplant Database developed CR. Of these, 13 went on to graft failure from CR, whereas 10 recovered to normal or near normal liver injury tests and liver architecture. In 14 of these patients, CR evolved directly from acute rejection, as described above. In the remaining patients, CR evolved from the early to late phases over a period of time from a few days to a year (41). In contrast, recovery occurred over a period of time from several months to more than one year.
Histopathological findings associated with progression to allograft failure included bile duct loss in more than 50 % of the portal tracts, severe (bridging) perivenular fibrosis and foam cell clusters within the sinusoids (41). It should be noted however, that the histopathological features associated with progression to allograft failure or recovery overlapped, and there was no specific finding alone, which reliably predicted the outcome. More specifically, some patients with > 50 % bile duct loss recovered, whereas other patients with < 50 % bile duct loss went on to allograft failure.
In those who recovered, a "ductular reaction" at the interface zone has been described before and during clinical improvement (2, 3, 41). Whether the recovery of ducts is related to proliferation of residual ductal epithelium, maturation of liver progenitor cells, or metaplasia of periportal hepatocytes, is an intriguing question about liver growth and development.
FASCINATING ASPECTS OF CHRONIC LIVER ALLOGRAFT REJECTIONThere are two fascinating aspects of chronic liver allograft rejection: its potential reversibility (2, 3, 41), which is discussed above, under STAGING OF CR; and an appreciably lower incidence of CR compared to other vascularized allografts (1). In addition, experimental animal studies have also shown that a liver allograft can also protect other organs from the same donor from CR(50).
Resistance of liver allografts to CR can best be explained by the immunological theories of so called "hepatic tolerogenecity". They can be broadly separated into two general categories, based on whether emphasis is placed on the parenchymal or non-parenchymal portion of the liver, which in turn, results in: 1) deletion or 2) functional anergy in the responding T cell repertoire. Release of soluble donor MHC class I antigen from the allograft, supporting the importance of the parenchyma, cannot account for these observations, alone (57). Murine liver allografts are routinely accepted between strains of mice that show no difference between the class I loci, but are mismatched for class II (58). In addition, fully allogeneic liver allografts from class I or II MHC deficient mice, which do not shed soluble MHC antigens (58, 59), are also accepted without immunosuppression. Moreover, other organs also secrete soluble MHC antigens (60) but they are routinely rejected, and infusion of exogenous soluble MHC usually leads to only slight graft prolongation.
One potential explanation for the importance of the parenchyma relies on the concept that allogeneic hepatocytes provide only one of two signals needed for allogeneic lymphocyte activation (61). Lack of important co-stimulatory molecules is thought to result in the induction of anergy in the responding lymphocyte populations (61). However, when transgenic mice that aberrantly express the allogeneic MHC class I molecule H-2Kb (Kb) in the liver, using a metallothionein promoter (62), are crossed with a strain that develops CD8+ T cells specific for the Kb molecule, lymphocyte-mediated "autoimmune" liver damage can be induced under certain conditions. Interestingly, most of the CD8+ cells responsive to Kb were eliminated by the intense intrahepatic activation, but some of the liver continued to show chronic low grade inflammation (62). However, great care had to be taken to assure that alloantigen expression was limited to the liver (62). Interpretation of these complicated experiments is difficult, but it appears that the liver may be able to effect an activation-induced partial clonal deletion of allogeneic lymphocytes (62), as originally proposed by Kamada (63). This may represent a special circumstance, because alloantigen expression on other non-hematolymphoid cells such as pancreatic islets, does not lead to anergy (64), but to immunological "ignorance" (65), which is an important difference. Induction of true anergy may in fact, require presentation of antigen by professional antigen presenting cells.
It has been our contention that so called "hepatic tolerogenecity" is in large part, a result of hematolymphoid microchimerism (66-69) sustained by donor hematopoietic stem contained within the liver (70-72). The immunologic mechanisms involved in graft acceptance appear to be a non-deletional, active process that that requires donor antigen presenting cells(73). The details of the role of donor hematopoietic cells in organ allograft acceptance are described in detail elsewhere(73, 74).
DIFFERENTIAL DIAGNOSISCR is usually not difficult to recognize on the basis of the histopathological findings, but establishing the diagnosis with certainty often requires a thorough clinicopathological correlation and review of previous biopsies, which usually show a acute rejection with significant bile duct damage. The major problem areas are distinguishing: a) early CR from a normal or near normal biopsy(15); b) early CR from chronic hepatitis with bile duct damage; and c) determining whether CR or some other insult is responsible for the ductopenia or perivenular fibrosis, if present.
The first problem area, distinguishing early CR from a normal or near normal biopsy, can be minimized by paying close attention to liver injury tests and correlating them with the histopathological findings. Selective elevation of the "canalicular" enzymes, alkaline phosphatase and gamma glutamyl transpeptidase (ALP, GGTP), in an otherwise healthy long term liver allograft survivor should prompt the pathologist to look more closely at the integrity of the bile ducts and the number of portal tract sampled. If there are less than 6 - 8 portal tracts sampled, and there is no other explanation for the elevated GGTP and ALP, re-biopsy should be suggested. Conversely, widespread bile duct atrophy/pyknosis or bile duct loss without a significant (> 4X normal) elevation of ALP or GGTP is unusual, although it does happen on occasion(15).
The second problem area, distinguishing CR from chronic hepatitis is more difficult to resolve. Three separate issues contribute to this difficulty(15): 1) focal bile duct damage is often seen in chronic viral and autoimmune hepatitis; 2) "parenchymal-type" rejection, as originally proposed by Kemnitz et al(33), might be histopathologically indistinguishable from CR; and 3) CR and chronic hepatitis can co-exist(15). The first issue can be minimized by strict adherence to histopathological criteria. In chronic viral or autoimmune hepatitis, bile duct damage is limited to an occasional duct and rarely, if ever, results in significant bile duct loss. In contrast, small bile duct damage in CR involves a majority of the bile ducts, and is accompanied by atrophic changes in the biliary epithelium. It also frequently leads to bile duct loss. Conversely, interface activity accompanied by a type II ductular reaction is more common with chronic hepatitis than in CR. The second issue is more difficult to resolve and is currently the focus of several studies. Resolution of this problem will require long-term follow-up and close clinical correlation. However, it is somewhat reassuring that most large liver transplant programs are not reporting an increased incidence of unexplained cirrhosis in long term survivors, which might be expected from this type of rejection(14, 75). Lastly, the co-existence of chronic hepatitis and rejection is expected, since allograft inflammation induced by recurrent viral disease is associated with increased cytokines, which in turn, can up-regulate adhesion and major histocompatibility molecules involved in precipitating a rejection reaction. The key to identifying cases with both chronic hepatitis and CR is recognizing the features of hepatitis, along with bile duct damage that is more prevalent and severe than would be expected for chronic hepatitis alone.
Lastly, there are many potential causes of non-rejection-related ductopenia without arteriopathy in liver allograft recipients, as in the general population. One of the most common causes in an allograft is chronic obstructive cholangiopathy since bile duct obstruction and stricturing are relatively common long term complications, affecting from 10 - 20 % of long term survivors (14, 75). Adverse drug reaction, cytomegalovirus infection (30, 32, 76, 77) and arterial compromise are other, less common causes. Likewise, there are several causes of perivenular fibrosis, such as outflow obstruction and veno-occlusive disease because of adverse drug reactions. Again however, review of previous biopsies and clinical correlation will help to distinguish between these possibilities.
Typical examples of CR seen in consultation:
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