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Clinical Transplantation


Is Chronic Rejection Part of the Disease Process?

Jeyarajah, D. Rohan1; Netto, George J.2; Lee, Stephen P.3; Testa, Giuliano1; Abbasoglu, Osman1; Husberg, Bo S.1; Levy, Marlon F.1; Goldstein, Robert M.1; Gonwa, Thomas A.4; Tillery, G. Weldon2; Crippin, Jeffrey S.5; Klintmalm, Goran B.1,6

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* Abbreviations: ACR, acute cellular rejection; CMV, cytomegalovirus; CR, chronic rejection; IBD, inflammatory bowel disease; OLTx, orthotopic liver transplant; PSC, primary sclerosing cholangitis; PTC, percutaneous transhepatic cholangiogram.

Orthotopic liver transplantation (OLTx*) has become an accepted treatment for primary sclerosing cholangitis (PSC) (1-9). The presence of the liver allograft in patients with a history of this disease provides a unique opportunity to study disease recurrence. Patients who received transplants for PSC have a higher incidence of biliary strictures and are at an increased risk for developing chronic rejection (CR) (10,11). Whether stricture formation and CR are manifestations of recurrent PSC has been debated extensively (11).

This study was designed to review the first 100 recipients of 118 liver allografts transplanted for the diagnosis of PSC. By examining clinical, pathologic, and radiographic data, we hoped to identify the differences, if any, between CR, recurrent PSC, and other clinical syndromes.


One hundred consecutive adult recipients of 118 OLTx for PSC from 1985 to 1995 were reviewed. The diagnosis of PSC was based on characteristic preoperative cholangiographic findings. A choledochojejunostomy was performed in each case. The minimal accepted patient follow-up was 12 months.

The following demographic items were studied: age, gender, time from diagnosis of PSC to OLTx, presence of inflammatory bowel disease (IBD), preoperative and postoperative malignancy, presence of HLA B8 and DR52, preoperative United Network for Organ Sharing status, donor/recipient blood group compatibility, cold ischemia time, presence of cholangiocarcinoma in the explanted liver, episodes of acute cellular rejection (ACR) (as defined by standard histologic criteria [12,13] and supporting biochemical enzyme elevation requiring institution of therapy), steroid-resistant ACR (as defined by a lack of histologic and biochemical response to steroid bolus/recycle therapy), OKT3-resistant ACR (as defined by a lack of histologic and biochemical response to OKT3 therapy, necessitating a switch in immunosuppression, usually from cyclosporine to tacrolimus), immunosuppressive regimen, number of clinically significant cytomegalovirus (CMV) infections requiring intravenous antiviral therapy, repeat transplantation rate, and patient and graft outcome.

The control group included all patients who received transplants at our center for diagnoses other than PSC, with a 1-year minimum follow-up. This group was further divided into those who did not develop CR (n=1153) and those who developed CR (n=51).

Cholangiographic studies for patients who developed either recurrent PSC or CR were examined by a single radiologist (S.P.L.) in a blinded fashion and graded according the scale shown in Table 1(14-17). Histopathologic specimens from patients in these same groups were reviewed in a blinded fashion by a single pathologist (G.J.N). A total of 10 explant specimens and 29 liver biopsy specimens were evaluated for 10 histologic parameters (Table 2). Each specimen was examined for the presence of obliterative arteriopathy, bile duct damage and loss, degree and extent of portal inflammation, portal fibrosis, hepatocyte degeneration, cholestasis, and the presence of bile duct scarring and/or concentric periductal lamellar fibrosis.

Table 1:
Radiographic schema for grading strictures in primary sclerosing cholangitis
Table 2:
Grading scale for histopathologic diagnosisa

Statistical analysis was performed using likelihood chi-square analysis and log-rank test for calculation of significance for groups. Three-way comparisons were checked using Bonferroni corrections. Kaplan-Meier survival curves were approximated using standard techniques. Pairwise comparisons were performed using the t test procedure.


Patient Groups

Based on the review of histopathologic, radiographic, laboratory, and clinical materials, it became apparent that patients receiving OLTx for the diagnosis of PSC had one of three possible outcomes and could be placed into the following groups.

Group A. Group A consisted of grafts in patients who received transplants for PSC with postOLTx biliary strictures demonstrated cholangiographically consistent with PSC (n=20). An additional patient did not have a percutaneous transhepatic cholangiogram (PTC) but had a liver biopsy suggestive of recurrent disease and was treated clinically as such. Hence, she was placed in this group. Mean time to diagnosis of recurrent PSC was 21.0±7.5 months from OLTx. Evidence of radiographic hepatic arterial flow was obtained in all cases to exclude the possibility of ischemic strictures. Doppler ultrasound studies documented presence of arterial flow in all the grafts in group A. Sixteen hepatic arteriograms were obtained. Hepatic arterial thrombosis with excellent collateral flow was seen in two patients, and another demonstrated hepatic arterial stenosis requiring revision. Postoperative study in this patient demonstrated excellent arterial flow. Analysis was performed with and without the three patients with arterial complications with similar results. The statistical results shown, however, exclude these three patients (n=18).

Group B. Group B consisted of patients who received transplants for PSC with histologic evidence of CR, as previously defined, (18,19) with supporting liver biochemical changes and clinical parameters (n=15). Mean time to diagnosis of CR was 5.0±3.3 months. Cholangiographic studies were available for eight patients, all of which were read as normal. In the other seven cases, hepatobiliary scintigraphy showed no evidence of biliary obstruction or impaired bile flow (data not shown).

Group C. Group C consisted of all patients who received transplants for PSC without subsequent histologic changes consistent with CR, cholestasis, or clinical changes suggestive of recurrent disease (n=82).

The following groups were sought from our database and used for comparison of graft and patient survival.

Group D. Group D consisted of patients who received OLTx for diagnoses other than PSC without CR (n=1153).

Group E. Group E consisted of patients who received OLTx for diagnoses other than PSC with CR (n=51).

Demographic Data

Results are presented in Table 3. Significant findings are summarized below.

Table 3:
A comparison of the demographic factors in patients transplanted for primary sclerosing cholangitis based on outcomea

Age. Mean age of the patients in group A was 41.0 (±10.1) years, group B was 43.3 (±11.7) years, and group C was 48.5 (±9.7) years (P=0.026, comparing all groups by Kruskal-Wallis test).

IBD. The overall incidence of IBD in those receiving OLTx for PSC was 73.0%, with ulcerative colitis in 60.9%, Crohn's disease in 8.7%, and nonspecific colitis in 3.5%. There was no significant difference in the specific type of IBD present in each group. However, when the patients were analyzed by the presence or absence of IBD, there was a significant difference in the three groups studied: group B had a significantly lower incidence of IBD than groups A or C (46.7% compared to 65.9% and 79.3%, respectively; P=0.035).

Donor DR52+. Significantly fewer patients in group A received grafts that were HLA DR52+, when compared to groups B and C (9.1% versus 75.0% and 62.7%, respectively; P=0.001).

ACR. Significantly more patients in groups A and B developed two or more episodes of ACR than those in C (55.6% and 60.0% compared with 31.7%; P=0.030).

CMV hepatitis. Significantly more patients in group A had CMV hepatitis, when compared to those in groups B and C (50.0% versus 20.0% and 14.6%, respectively- P=0.008).

Other parameters examined (not shown in Table 3) were as follows.

Blood group-compatible allograft. In total, 88.9%, 93.3%, and 93.8% of groups A, B, and C received blood group-identical donor grafts (P=0.79).

Cold ischemia time. Cold ischemia time for the liver allografts was 9.2 (±3.2) hr, 10.2 (±5.3) hr, and 9.8 (±3.8) hr for groups A, B, and C, respectively (P=0.78).

Immunosuppression. All patients in group A developed recurrent disease while receiving cyclosporine-based immunotherapy, the standard protocol until 1995. Fourteen (93.3%) of those in group B and 69 (84.2%) of those in group C had started on cyclosporine-based therapy (P=0.047, comparing all three groups). Cyclosporine was changed to tacrolimus in five (27.8%) patients in group A, three of which were for OKT3-resistant ACR, while seven (46.7%) of those in group B were switched to tacrolimus, two for resistant ACRs. The other reason for switching to tacrolimus from cyclosporine was in an attempt to reverse any component of CR. Seventy-two (61.0%) patients with grafts had received azathioprine at any time, while 7 (38.9%) of group A, 4 (26.7%) of group B, and 9 (11.0%) of group C received Cytoxan (P=0.018, comparing Cytoxan use in all three groups).

Steroid/OKT3-resistant ACR. Nine (50.0%), 6 (40.0%), and 26 (31.7%) of those in groups A, B, and C, respectively, developed steroid-resistant ACR (P=0.33). Two (11.1%), 3 (20.0%), and 18 (22.0%) of groups A, B, and C, respectively, developed OKT3-resistant ACR (P=0.55).

Radiographic Evaluation

PTC studies in 17 of 18 grafts in group A and 8 of 15 grafts in group B were reviewed and graded according to the scale shown in Table 1 (see Fig. 1). One (5.9%), seven (41.2%), one (5.9%), and eight (47.1%) of those in group A were classified as grade I, IIB, IIIA, and IV, respectively. It is interesting to note that there is a significant lack of sludge and biliary cast formation in patients with recurrent disease, when compared to other patients in our transplant population who develop ischemic biliary strictures. The presence of arterial flow to the allograft together with the lack of biliary sludge and casts leads us to believe that recurrent PSC is truly a separate entity to ischemic cholangiopathy. All eight of the PTC studies for those patients in group B were read as normal.

Figure 1:
Percutaneous transhepatic cholangiograms of patients with recurrent primary sclerosing cholangitis. Figure shows representative cholangiograms from two patients who developed recurrent PSC after OLTx. The classic findings of multiple strictures and diverticula illustrate the recurrence of the disease. Note the lack of sludge, which is characteristically seen in patients with ischemic cholangiopathy.

Histopathologic Findings

In general, specimens from groups A and B were histologically indistinguishable. The two groups showed no statistically significant differences in any of the parameters that we measured (see Table 2). Obliterative arteriopathy was present in cases that were clinically classified as recurrent PSC as well as in cases from group B, as shown in Figure 2. The same was true of bile duct scarring and concentric periductal lamellar fibrosis. No statistically significant difference in incidence of bile duct scarring (P=0.60) or obliterative arteriopathy (P=0.81) was seen between the two groups.

Figure 2:
Histology of patients who develop recurrent PSC and CR after OLTx for PSC shows overlap. Photomicrographs of histologic specimens from patients from group A and B are shown. Although, overall, there were no statistical differences between groups A and B in the histologic parameters studied, we show cases illustrating the classic findings of periductal lamellar fibrosis in PSC and obliterative arteriopathy in CR (panels A and B), respectively. However, changes of obliterative arteriopathy were also seen in patients clinically classified as recurrent PSC (panel C) and periductal lamellar fibrosis was seen in some patients with CR (panel D). (A) Concentric periductal lamellar fibrosis in a biopsy from a patient with recurrent PSC (group A). (B) Obliterative arteriopathy in an explant from a patient with CR (group B). (C) Obliterative arteriopathy in an explant from a patient with recurrent PSC (group A). (D) Concentric periductal lamellar fibrosis in an explant from a patient with CR (group B).

Patient Outcome

Repeat transplantation rate, 2- and 5-year patient outcomes, and 2- and 5-year graft outcomes are shown in Table 4. Kaplan-Meier curves are shown in Figures 3 and 4. As can be seen, repeat transplantation rates, graft survival, and patient survival were significantly different between groups A, B, and C.

Table 4:
Repeat transplantation rate, graft outcome, and patient outcomea
Figure 3:
Kaplan-Meier curves for graft survival.
Figure 4:
Kaplan-Meier curves for patient survival.


We have shown a 15.7% incidence of recurrent PSC and a 13.0% incidence of CR in our first 100 patients receiving 118 OLTx for the diagnosis of PSC. Moreover, we have clearly documented that, although recurrent PSC and CR have many histopathologic similarities, they behave very differently with respect to clinical outcome, with a poorer graft and patient survival in the latter group. This finding validates the model and demonstrates that recurrent PSC and CR are two separate clinical entities.

The definition of PSC is a difficult one, and as was mentioned earlier, cholangiographic findings are integral to the diagnosis, even in patients who did not receive transplants (1-9,14,16). In light of the difficulty in making the diagnosis of PSC in the native liver, documenting recurrent disease in those who received transplants for PSC is even more challenging. The presence of characteristic biliary strictures in the absence of an ischemic cholangiopathy is one way to define recurrence. These types of strictures rarely, if ever, develop in liver allografts in the absence of arterial thrombosis, prolonged ischemia time, or blood group incompatibility, and the exclusion of ischemic causes of biliary strictures makes our definition unique when compared to others (11-15). In addition, the lack of sludge and biliary casts differentiates recurrent PSC from ischemic cholangiopathy. We used this definition to classify patients as having recurrent disease, and, interestingly, the results demonstrate that this is an appropriate classification.

Transplant centers have faced the difficulty of differentiating recurrent PSC and CR (8,11). Although cholangiographic studies were not available for all patients classified as CR, there was no clear biochemical or clinical evidence suggestive of ductal strictures. In addition, most of the patients in the CR group had hepatobiliary scintigraphy that showed no biliary complications (data not shown). The PTCs available for the CR group were obtained in close temporal proximity to their diagnosis of CR, and these studies were unremarkable, suggesting that, even though there may be similarities on a histologic basis between recurrent PSC and CR, the latter patients do not form significant strictures. The difference between the two groups is further underlined by the fact that they clearly behave as very separate clinical entities, with a significantly worse patient and graft survival and earlier time to diagnosis for CR than for recurrent PSC.

The recurrence rate that we have found in this study is higher than that documented by the UCLA group (20). In their series, 1 of 36 patients (2.7%) who received transplants for PSC developed recurrent disease. A more recent analysis of 127 patients revealed a recurrence rate of 8.6% (21). In a similar series from Ascher et al. (8), 4 of 37 patients (11.0%) were thought to have developed recurrent PSC, while no patients were found to have recurrent PSC in the 41 patients reviewed by Kalayoglu et al. (22). Interestingly, CR was not documented in the latter two studies, while Busuttil et al. (20-22) had 2 of 36 cases (5.6%) and 6 of 127 cases (4.7%) more recently with CR. An Australian study looking at 19 patients who received transplants for PSC found a 15% incidence of CR (9). Our large cohort studied over a 10-year period demonstrates that recurrent PSC and CR are highly prevalent in this group.

Patients who eventually developed CR or recurrent disease after OLTx were younger than those who had a benign course. This finding has been suggested by Miki et al. in a much smaller study (23), and may suggest that earlier onset of this presumed immunologically-mediated disease may lead to a more aggressive form. Interestingly, there was no clear correlation with IBD status, in that there was actually a significantly lower incidence of IBD in the CR group. De novo PSC is found more frequently in those with IBD, but it appears that recurrent disease bears no correlation with IBD. Proposed immunological mechanisms of PSC have included theories that common epitopes are shared by colon and biliary epithelial elements, leading to a cross-reactivity of antibodies in these two sites (24). This mechanism would imply that recurrence should occur more frequently in those with IBD, but this is not confirmed in our data.

The overall incidence of HLAB8 and HLADR52 is 39.1% and 75.5%, respectively, in our cohort. The incidence in the natural control group, the donor population, showed 15.3% and 58.4%, respectively, confirming that B8 and DR52 are more commonly expressed in patients who have PSC (25-28). Interestingly, there was a lower incidence of DR52 in the grafts that eventually developed recurrent disease than in those that did not, suggesting that HLA represents a recipient-specific genetic predisposition to PSC and does not serve as an antigen for immune recognition.

The greater incidence of ACR in groups A and B suggests that immune attack of the biliary epithelium, which is always present in ACR, may increase autoimmune epitopes that can lead to ductal damage. The pathway in which this damage proceeds to recurrent disease, versus CR, is unclear. An alternative explanation might be that patients who develop recurrent PSC or CR have a "hyperresponsive" immune system and hence have an increased risk of developing ACR. In this way, it is possible that the increased ACR in these groups serves as a marker for aggressive disease. The increased incidence of CMV infection in the CR and recurrent PSC group again suggests that viral modulation of the immune repertoire may be involved in disease progression. Again, it is possible that a baseline hyperresponsiveness in those patients who develop recurrent disease could lead to a very exuberant response to the CMV virus, which results in clinically relevant liver injury.

The influence of immunosuppressive therapy on the disease process is an interesting one. Our results indicate that those who developed recurrent PSC or CR were more likely to have received cyclosporine-based therapy than those patients with PSC who did not develop either of these outcomes (P=0.047). One interpretation of this result may be that tacrolimus-based therapy might be beneficial in those who receive OLTx for PSC. However, we believe that one must be cautious in coming to this conclusion. Our protocol has changed in the last 5 years to begin primary tacrolimus therapy on all those patients receiving OLTx for PSC; hence, we do not have the follow-up to be sure that tacrolimus is truly beneficial in this group. In addition, the restrospective nature of this study leads to the confounding factor of comparing patients in a historical fashion.

Radiographically, 90% of patients with recurrent PSC show signs of at least intrahepatic disease, which is similar to the findings in de novo PSC (14,16,17). Histologically, there was significant overlap in the CR and recurrent PSC groups. The dichotomy presented with similarity in histology, and clear differences in PTC findings, between the recurrent PSC and the CR groups, is very interesting. Thus, PTC or endoscopic retrograde cholangiopancreatogram is necessary to distinguish between the two.

Patient and graft outcomes as shown in Figures 3 and 4, and Table 4 demonstrate the difference in the clinical behavior of CR and recurrent disease. The graft and patient outcomes support the notion that CR and recurrent PSC are two very different diseases. One factor that influences these curves is the time to development of CR or PSC: mean time to development of recurrent PSC is 21 months, while mean time to diagnosis of CR is 5 months. Again, this emphasizes the aggressive nature of the disease in those who develop CR, as opposed to the more indolent nature of recurrent PSC. The latter appears to closely follow the progression of de novo PSC, while the former is similar to non-PSC patients who develop CR.

In summary, we have proposed and validated a definition of recurrent PSC, and have shown a high rate of recurrent disease and CR in patients who have received OLTx for the diagnosis of PSC. Even though CR and recurrent PSC bear many similar histologic features, their clinical behavior demonstrates that they are separate entities. CR in PSC patients, although overrepresented, behaves much like CR in non-PSC patients. Recurrent disease tends to mimic the initial condition. Patients who received transplants for PSC need to be monitored carefully for recurrent disease or CR, and accurate diagnosis is essential in determining their appropriate treatment and prognosis.


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