A. Jake Demetris
University of Pittsburgh Medical Center
Chronic rejection has been defined as an immunological injury to the liver allograft, which usually
evolves from severe or persistent acute rejection, and results in potentially irreversible damage to the
bile ducts, arteries and veins
. It currently affects about 3-5 % liver allograft
recipients by 5 years after transplantation, which is a dramatic decrease since the 1980's when the
incidence was 15-20 %  . The decline is probably attributable to better recognition and
control of acute and the early phases of chronic rejection, combined with the unique immunological
properties of liver allografts and the remarkable ability of the liver to regenerate without fibrosis
. Nevertheless, chronic rejection has not been entirely eliminated and is still an
important cause of late liver allograft dysfunction and failure
The term "chronic" technically implies a time parameter, but none is intended  , because
chronic rejection often occurs within several months after transplantation and allograft failure
typically occurs within the first year after transplantation
. In contrast to
other vascularized allografts, the incidence of chronic rejection in the liver does not appear to
increase with time after transplantation
. There is, however, a small group of
patients with late onset chronic rejection. These patients usually suffer from complications of
over-immunosuppression and the baseline drugs are often decreased or discontinued altogether because of
immunosuppression-related complications  . Older terms for chronic rejection such as
"vanishing bile duct syndrome", or "ductopenic rejection" are fading from use, because bile duct loss is
now recognized as just one histopathologic feature of chronic rejection
Risk factors for the development of CR have generally been divided into two general categories. The
first and most important are "alloantigen-dependent", immunological or rejection-related factors,
including the number and severity of acute rejection episodes
. In cyclosporine-
treated cohorts, late onset acute rejection episodes
; younger recipient
; male-to-female sex mismatch; a primary diagnosis of autoimmune hepatitis or biliary
disease  ; baseline immunosuppression
, interactions between HLA-DR3,
TNF-2 status and CMV infection  , and non-Caucasian recipient race
all been associated with an increased risk of developing chronic rejection. The role of
histocompatibility differences is still controversial
, as is the effect of CMV
. In a large Tacrolimus-treated cohort, many of the matching
factors were not a significant risk factor for chronic rejection, but the influence of the number and
severity of acute rejection episodes remained  . Non-alloantigen-dependent or
"non-immunological" risk factors that contribute to the development of chronic rejection include donor
age > 40 years  .
Chronic rejection usually evolves from severe or multiple recurrent and uncontrolled acute
. 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
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
. The cumulative damage results in enhanced biliary epithelial cell
senescence  , which manifests as distinct cytologic changes recognizable on routine light
microscopy and enhanced expression of nuclear p21 without Ki-67 labeling  . These changes
precede bile duct loss
. 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.
. 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  , excess production of pro-fibrogenic cytokines
 , loss or change of the supporting architecture theory  , and "premature
senescence" of epithelial cells
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.
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 . There are three typical clinical settings: 1)
the endstage of unresolved acute rejection; 2) after multiple episodes of acute rejection
; and 3) evolving indolently without preceding clinically recognized
episodes of acute rejection
. 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 .
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 .
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
. Transition from acute to chronic rejection may be marked by persistent
elevation of alanine aminotransferase and total bilirubin that presage allograft failure
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  that presage bile duct loss
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 .
The early phase of chronic rejection in the centrilobular regions is characterized by subendothelial
and perivenular mononuclear inflammation
. This is accompanied by perivenular hepatocyte
dropout, and an accumulation of pigment-laden macrophages and mild perivenular fibrosis
. Spotty acidophilic necrosis of hepatocytes, or so-called "transitional hepatitis"
may occur during evolution from early to late stages of chronic rejection  .
Late stage CR in the portal tracts can manifest as bile duct, which at times can also be accompanied
by arteriolar loss
. 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
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
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
. However, well-developed cirrhosis from chronic rejection is unusual
 until the very late stages when venous obliteration leads to areas of parenchyma
extinction  . True "regenerative" nodules are uncommon, perhaps because the combination of
venous and arterial obliteration blunts any regenerative response  .
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
. 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 .
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
, 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 
. 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  .
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 .
Table 1. Features of early and late chronic liver allograft rejection (Adapted from  ).
|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
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|
|Large perihilar bile ducts ||Inflammation damage and focal foam cell deposition ||Mural fibrosis|
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
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.
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 . 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
. 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 . In other cases, isolated ductopenia involving
less than 50% of the portal tracts can be seen without significant elevations of liver injury tests
. 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
Isolated perivenular fibrosis can be caused by mechanical outflow obstruction, adverse
drug reactions  and all of the non-rejection causes of veno-occlusive disease and
Budd-Chiari syndrome in native livers .
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.
- Terminology for hepatic allograft rejection. International Working Party. Hepatology 1995, 22:648-654.
- Freese DK, Snover DC, Sharp HL, Gross CR, Savick SK, Payne WD: Chronic rejection after liver transplantation: a study of clinical, histopathological and immunological features. Hepatology 1991, 13:882-891.
- Hubscher SG, Buckels JA, Elias E, McMaster P, Neuberger J: Vanishing bile-duct syndrome following liver transplantation--is it reversible? Transplantation 1991, 51:1004-1010.
- Blakolmer K, Seaberg EC, Batts K, Ferrell L, Markin R, Wiesner R, Detre K, Demetris A: Analysis of the reversibility of chronic liver allograft rejection implications for a staging schema. Am J Surg Pathol 1999, 23:1328-1339.
- Blakolmer K, Jain A, Ruppert K, Gray E, Duquesnoy R, Murase N, Starzl TE, Fung JJ, Demetris AJ: Chronic liver allograft rejection in a population treated primarily with tacrolimus as baseline immunosuppression: long-term follow-up and evaluation of features for histopathological staging. Transplantation 2000, 69:2330-2336.
- Quaglia AF, Del Vecchio Blanco G, Greaves R, Burroughs AK, Dhillon AP: Development of ductopaenic liver allograft rejection includes a "hepatitic" phase prior to duct loss. J Hepatol 2000, 33:773-780
- Demetris A, Adams D, Bellamy C, Blakolmer K, Clouston A, Dhillon AP, Fung J, Gouw A, Gustafsson B, Haga H, Harrison D, Hart J, Hubscher S, Jaffe R, Khettry U, Lassman C, Lewin K, Martinez O, Nakazawa Y, Neil D, Pappo O, Parizhskaya M, Randhawa P, Rasoul-Rockenschaub S, Reinholt F, Reynes M, Robert M, Tsamandas A, Wanless I, Wiesner R, Wernerson A, Wrba F, Wyatt J, Yamabe H: Update of the International Banff Schema for Liver Allograft Rejection: working recommendations for the histopathologic staging and reporting of chronic rejection. An International Panel. Hepatology 2000, 31:792-799.
- Demetris AJ, Murase N, Lee RG, Randhawa P, Zeevi A, Pham S, Duquesnoy R, Fung JJ, Starzl TE: Chronic rejection. A general overview of histopathology and pathophysiology with emphasis on liver, heart and intestinal allografts. Ann Transplant 1997, 2:27-44
- Starzl TE, Todo S, Fung J, Demetris AJ, Venkataramman R, Jain A: FK 506 for liver, kidney, and pancreas transplantation. Lancet 1989, 2:1000-1004.
- Demetris AJ, Fung JJ, Todo S, Banner B, Zerbe T, Sysyn G, Starzl TE: Pathologic observations in human allograft recipients treated with FK 506. Transplant Proc 1990, 22:25-34.
- Pirsch JD, Kalayoglu M, Hafez GR, D'Alessandro AM, Sollinger HW, Belzer FD: Evidence that the vanishing bile duct syndrome is vanishing. Transplantation 1990, 49:1015-1018.
- Wiesner RH, Ludwig J, van Hoek B, Krom RA: Current concepts in cell-mediated hepatic allograft rejection leading to ductopenia and liver failure. Hepatology 1991, 14:721-729
- Starzl TE, Demetris AJ, Murase N, Ildstad S, Ricordi C, Trucco M: Cell migration, chimerism, and graft acceptance. Lancet 1992, 339:1579-1582.
- Ascher NL, Lake JR, Emond J, Roberts J: Liver transplantation for hepatitis C virus-related cirrhosis. Hepatology 1994, 20:24S-27S
- Sher LS, Cosenza CA, Michel J, Makowka L, Miller CM, Schwartz ME, Busuttil R, McDiarmid S, Burdick JF, Klein AS, Esquivel C, Klintmalm G, Levy M, Roberts JP, Lake JR, Kalayoglu M, D'Alessandro AM, Gordon RD, Stieber AC, Shaw BW, Jr., Thistlethwaite JR, Whittington P, Wiesner RH, Porayko M, Cosimi AB, et al.: Efficacy of tacrolimus as rescue therapy for chronic rejection in orthotopic liver transplantation: a report of the U.S. Multicenter Liver Study Group. Transplantation 1997, 64:258-263
- Quiroga J, Colina I, Demetris AJ, Starzl TE, Van Thiel DH: Cause and timing of first allograft failure in orthotopic liver transplantation: a study of 177 consecutive patients. Hepatology 1991, 14:1054-1062.
- Backman L, Gibbs J, Levy M, McMillan R, Holman M, Husberg B, Goldstein R, Gonwa TA, Klintmalm G: Causes of late graft loss after liver transplantation. Transplantation 1993, 55:1078-1082
- Pappo O, Ramos H, Starzl TE, Fung JJ, Demetris AJ: Structural integrity and identification of causes of liver allograft dysfunction occurring more than 5 years after transplantation. Am J Surg Pathol 1995, 19:192-206.
- Slapak GI, Saxena R, Portmann B, Gane E, Devlin J, Calne R, Williams R: Graft and systemic disease in long-term survivors of liver transplantation. Hepatology 1997, 25:195-202.
- Starzl TE, Marchioro TL, Porter KA: Experimental and clinical observations after homotransplantation of the whole liver. Rev Int Hepatol 1965, 15:1447-1480
- Porte RJ, Ploeg RJ, Hansen B, van Bockel JH, Thorogood J, Persijn GG, Hermans J, Terpstra OT: Long-term graft survival after liver transplantation in the UW era: late effects of cold ischemia and primary dysfunction. European Multicentre Study Group. Transpl Int 1998, 11 Suppl 1:S164-167
- Ludwig J, Wiesner RH, Batts KP, Perkins JD, Krom RA: The acute vanishing bile duct syndrome (acute irreversible rejection) after orthotopic liver transplantation. Hepatology 1987, 7:476-483.
- Lowes JR, Hubscher SG, Neuberger JM: Chronic rejection of the liver allograft. Gastroenterol Clin North Am 1993, 22:401-420.
- Hoek BV, Wiesner R, Krom R, al e: Severe ductopenic rejection following liver transplantation: Incidence, time of onset, risk factors, treatment and outcome. Semin Liver Dis 1992, 12:41-50
- Neil DA, Hubscher SG: Histologic and biochemical changes during the evolution of chronic rejection of liver allografts. Hepatology 2002, 35:639-651
- Demetris AJ, Ruppert K, Dvorchik I, Jain A, Minervini M, Nalesnik MA, Randhawa P, Wu T, Zeevi A, Abu-Elmagd K, Eghtesad B, Fontes P, Cacciarelli T, Marsh W, Geller D, Fung JJ: Real-time monitoring of acute liver-allograft rejection using the Banff schema. Transplantation 2002, 74:1290-1296
- Candinas D, Gunson BK, Nightingale P, Hubscher S, McMaster P, Neuberger JM: Sex mismatch as a risk factor for chronic rejection of liver allografts. Lancet 1995, 346:1117-1121.
- Farges O, Nocci Kalil A, Sebagh M, Reynes M, Bismuth H: Low incidence of chronic rejection in patients experiencing histological acute rejection without simultaneous impairment in liver function tests. Transplant Proc 1995, 27:1142-1143.
- Anand AC, Hubscher SG, Gunson BK, McMaster P, Neuberger JM: Timing, significance, and prognosis of late acute liver allograft rejection. Transplantation 1995, 60:1098-1103.
- Halloran PF, Melk A, Barth C: Rethinking chronic allograft nephropathy: the concept of accelerated senescence. J Am Soc Nephrol 1999, 10:167-181
- Evans PC, Smith S, Hirschfield G, Rigopoulou E, Wreghitt TG, Wight DG, Taylor CJ, Alexander GJ: Recipient HLA-DR3, tumour necrosis factor-alpha promoter allele-2 (tumour necrosis factor-2) and cytomegalovirus infection are interrelated risk factors for chronic rejection of liver grafts. J Hepatol 2001, 34:711-715
- Devlin JJ, O'Grady JG, Tan KC, Calne RY, Williams R: Ethnic variations in patient and graft survival after liver transplantation. Identification of a new risk factor for chronic allograft rejection. Transplantation 1993, 56:1381-1384.
- Gupta P, Hart J, Cronin D, Kelly S, Millis JM, Brady L: Risk factors for chronic rejection after pediatric liver transplantation. Transplantation 2001, 72:1098-1102
- Batts KP, Moore SB, Perkins JD, Wiesner RH, Grambsch PM, Krom RA: Influence of positive lymphocyte crossmatch and HLA mismatching on vanishing bile duct syndrome in human liver allografts. Transplantation 1988, 45:376-379.
- Donaldson PT, Alexander GJ, O'Grady J, Neuberger J, Portmann B, Thick M, Davis H, Calne RY, Williams R: Evidence for an immune response to HLA class I antigens in the vanishing-bileduct syndrome after liver transplantation. Lancet 1987, 1:945-951.
- Donaldson PT, Thomson LJ, Heads A, Underhill JA, Vaughan RW, Rolando N, Williams R: IgG donor-specific crossmatches are not associated with graft rejection or poor graft survival after liver transplantation. An assessment by cytotoxicity and flow cytometry. Transplantation 1995, 60:1016-1023.
- Manez R, White LT, Linden P, Kusne S, Martin M, Kramer D, Demetris AJ, Van Thiel DH, Starzl TE, Duquesnoy RJ: The influence of HLA matching on cytomegalovirus hepatitis and chronic rejection after liver transplantation. Transplantation 1993, 55:1067-1071.
- Paya CV, Wiesner RH, Hermans PE, Larson-Keller JJ, Ilstrup DM, Krom RA, Moore SB, Ludwig J, Smith TF: Lack of association between cytomegalovirus infection, HLA matching and the vanishing bile duct syndrome after liver transplantation. Hepatology 1992, 16:66-70.
- Wiesner RH, Demetris AJ, Belle SH, Seaberg EC, Lake JR, Zetterman RK, Everhart J, Detre KM: Acute hepatic allograft rejection: incidence, risk factors, and impact on outcome. Hepatology 1998, 28:638-645.
- Lautenschlager I, Hockerstedt K, Jalanko H, Loginov R, Salmela K, Taskinen E, Ahonen J: Persistent cytomegalovirus in liver allografts with chronic rejection. Hepatology 1997, 25:190-194
- Nakazawa Y, Jonsson JR, Walker NI, Kerlin P, Steadman C, Lynch SV, Strong RW, Clouston AD: Fibrous obliterative lesions of veins contribute to progressive fibrosis in chronic liver allograft rejection. Hepatology 2000, 32:1240-1247.
- Oguma S, Belle S, Starzl TE, Demetris AJ: A histometric analysis of chronically rejected human liver allografts: insights into the mechanisms of bile duct loss: direct immunologic and ischemic factors. Hepatology 1989, 9:204-209.
- Oguma S, Zerbe T, Banner B, Belle S, Starzl TE, Demetris AJ: Chronic liver allograft rejection and obliterative arteriopathy: possible pathogenic mechanisms. Transplant Proc 1989, 21:2203-2207.
- Matsumoto Y, McCaughan GW, Painter DM, Bishop GA: Evidence that portal tract microvascular destruction precedes bile duct loss in human liver allograft rejection. Transplantation 1993, 56:69-75.
- Lunz JG, 3rd, Contrucci S, Ruppert K, Murase N, Fung JJ, Starzl TE, Demetris AJ: Replicative senescence of biliary epithelial cells precedes bile duct loss in chronic liver allograft rejection: increased expression of p21(WAF1/Cip1) as a disease marker and the influence of immunosuppressive drugs. Am J Pathol 2001, 158:1379-1390
- Ross R: - Rous-Whipple Award Lecture. Atherosclerosis: a defense mechanism gone awry. [Review] [139 refs]. American Journal of Pathology 1993, 143:987-1002
- Ross R: - The pathogenesis of atherosclerosis: a perspective for the 1990s. [Review] [127 refs]. Nature 1993, 362:801-809
- Oguma S, Banner B, Zerbe T, Starzl T, Demetris AJ: Participation of dendritic cells in vascular lesions of chronic rejection of human allografts. Lancet 1988, 2:933-936.
- Demetris AJ, Murase N, Ye Q, Galvao FH, Richert C, Saad R, Pham S, Duquesnoy RJ, Zeevi A, Fung JJ, Starzl TE: Analysis of chronic rejection and obliterative arteriopathy. Possible contributions of donor antigen-presenting cells and lymphatic disruption. Am J Pathol 1997, 150:563-578.
- Paul LC: Chronic allograft nephropathy: An update. Kidney Int 1999, 56:783-793
- Fennell RH, Jr.: Ductular damage in liver transplant rejection: its similarity to that of primary biliary cirrhosis and graft-versus-host disease. Pathol Annu 1981, 16:289-294.
- Grond J, Gouw AS, Poppema S, al. e: Chronic rejection in liver transplants: A histopathologic analysis of failed grafts and antecedent serial biopsies. Transplant Proc 1986, 18:128-135
- Vierling JM, Fennell RH, Jr.: Histopathology of early and late human hepatic allograft rejection: evidence of progressive destruction of interlobular bile ducts. Hepatology 1985, 5:1076-1082.
- Portmann B, Neuberger J, Williams R: Intrahepatic bile duct lesions. Liver Transplantation: The Cambridge-Kings College Hospital Experience. Edited by Calne R. New York, Grune & Stratton, 1983, pp 279-287
- Wight DA: Chronic liver transplant rejection: definition and diagnosis. Transplant Proc 1996, 28:465-467
- Neil DA, Adams DH, Gunson B, Hubscher SG: Is chronic rejection of liver transplants different from graft arteriosclerosis of kidney and heart transplants? Transplant Proc 1997, 29:2539-2540.
- Demetris AJ, Seaberg EC, Batts KP, Ferrell L, Lee RG, Markin R, Detre KM: Chronic liver allograft rejection: a National Institute of Diabetes and Digestive and Kidney Diseases interinstitutional study analyzing the reliability of current criteria and proposal of an expanded definition. National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database. Am J Surg Pathol 1998, 22:28-39.
- Demetris AJ, Fung JJ, Todo S, McCauley J, Jain A, Takaya S, Alessiani M, Abu-Elmagd K, Van Thiel DH, Starzl TE: Conversion of liver allograft recipients from cyclosporine to FK506 immunosuppressive therapy--a clinicopathologic study of 96 patients. Transplantation 1992, 53:1056-1062.
- Demetris AJ, Fung JJ, Todo S, McCauley J, Jain A, Takaya S, Alessiani M, Abu-Elmagd K, Van Thiel DH, Starzl TE: FK 506 used as rescue therapy for human liver allograft recipients. Transplant Proc 1991, 23:3005-3006.
- Popper H, Kent G, Stein R: Ductular cell reaction in the liver in hepatic injury. J Mt Sinai Hosp 1957, 24:551-556
- Popper H: The relation of mesenchymal cell products to hepatic epithelial systems. [Review]. Progress in Liver Diseases 1990, 9:27-38
- Demetris AJ: Immunopathology of the Human Biliary Tree. Biliary and Pancreatic Ductal Epithelia. Pathobiology and Pathophysiology. Edited by Sirica AE, Longnecker DS. New York, Marcel Dekker, Inc, 1997, pp 127-180
- Kemnitz J, Gubernatis G, Bunzendahl H, Ringe B, Pichlmayr R, Georgii A: Criteria for the histopathological classification of liver allograft rejection and their clinical relevance. Transplant Proc 1989, 21:2208-2210
- Wanless I: Physioanatomic Considerations. Diseases of the Liver. Edited by Schiff ER, Sorrell MF, Maddrey WC. Philadelphia, Lippincott Williams & Wilkins, 1999, pp 3-37
- Wight D: Pathology of rejection. Liver Transplantation: The Cambridge-King's College Hospital Experience. Edited by Calne R. New York, Grune & Stratton, 1983, pp 247-277
- Porter KA: Pathology of liver transplantation. Transplant Rev 1969, 2:129-170
- Demetris AJ, Zerbe T, Banner B: Morphology of solid organ allograft arteriopathy: identification of proliferating intimal cell populations. Transplant Proc 1989, 21:3667-3669.
- Demetris AJ, Markus BH, Burnham J, Nalesnik M, Gordon RD, Makowka L, Starzl TE: Antibody deposition in liver allografts with chronic rejection. Transplant Proc 1987, 19:121-125.
- Crawford AR, Lin XZ, Crawford JM: The normal adult human liver biopsy: a quantitative reference standard. Hepatology 1998, 28:323-331
- Demetris AJ, Lasky S, Van Thiel DH, Starzl TE, Whiteside T: Induction of DR/IA antigens in human liver allografts. An immunocytochemical and clinicopathologic analysis of twenty failed grafts. Transplantation 1985, 40:504-509.
- Hubscher SG, Elias E, Buckels JA, Mayer AD, McMaster P, Neuberger JM: Primary biliary cirrhosis. Histological evidence of disease recurrence after liver transplantation. J Hepatol 1993, 18:173-184.
- White RM, Zajko AB, Demetris AJ, Bron KM, Dekker A, Starzl TE: Liver transplant rejection: angiographic findings in 35 patients. AJR Am J Roentgenol 1987, 148:1095-1098.
- Devlin J, Page AC, O'Grady J, Portmann B, Karani J, Williams R: Angiographically determined arteriopathy in liver graft dysfunction and survival. J Hepatol 1993, 18:68-73.
- Ludwig J: Classification and terminology of hepatic allograft rejection: whither bound? Mayo Clin Proc 1989, 64:676-679.
- Dhillon AP, Burroughs AK, Hudson M, Shah N, Rolles K, Scheuer PJ: Hepatic venular stenosis after orthotopic liver transplantation. Hepatology 1994, 19:106-111.
- Pathology of the Liver. Edited by MacSween RN, Burt AD, Portmann B, Ishak K, Scheuer PJ, Anthony PP. Philadelphia, Churchill Livingstone, 2002, pp 982