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Recurrence of primary biliary cirrhosis after liver transplantation: Histologic estimate of incidence and natural history
Recurrence of Primary Biliary Cirrhosis After Liver Transplantation: Histologic Estimate of Incidence and Natural History Pamela B. Sylvestre,* Kenneth P. Batts,* Lawrence J. Burgart,* John J. Poterucha,† and Russell H. Wiesner† The goals of this study were to determine the rate of recurrent primary biliary cirrhosis (PBC) after orthotopic liver transplantation (OLT) based on strict morphologic criteria and to evaluate histologic progression of recurrent PBC over time. Strict criteria for PBC recurrence were established as the presence of a florid duct lesion or destructive lymphocytic cholangitis within a dense portal infiltrate. Of the 784 OLTs performed at the Mayo Clinic during the first 12 years of the program, 100 met criteria for the PBC study group, and 35 met criteria for the control group. Strict histologic criteria for recurrent PBC were observed in 17 of 100 (17%) study patients (14 with florid duct lesion, 3 with destructive lymphocytic cholangitis within dense portal infiltrate). Mean follow-up for the PBC group was 4.7 years (range, 1.0 to 13.8). Mean time to recurrence was 3.7 years (median, 3.1; range, 0.3 to 7.9). In those who met strict criteria for recurrent PBC, 2 of 17 progressed to septal fibrosis (stage 3). No florid duct lesions, destructive lymphocytic cholangitis, or septal fibrosis were observed in the control group. Other less specific morphologic features of PBC (portal infiltrates, plasma cells, dense lymphoplasmacytic infiltrates, and lymphocytic cholangitis) were also evaluated in the course of this study. Based on strict criteria, a conservative histologic estimate of the rate of recurrent PBC is 17% with a mean of 4.7 years of follow-up. When criteria for histologic recurrence are expanded to include moderate lymphocytic cholangitis with lymphoplasmacytic portal infiltrate, the recurrence rate of PBC is estimated as 26%. (Liver Transpl 2003;9:1086-1093.)
P
rimary biliary cirrhosis (PBC) is a chronic, nonsuppurative cholangitic liver disease, with progressive loss of interlobular and septal bile ducts that may result in a biliary type of cirrhosis. PBC principally affects middle-aged women. Substantial evidence points to an
From the *Division of Anatomic Pathology and †Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, MN. Address reprint requests to Pamela B. Sylvestre, MD, 1211 Union Ave, Suite 300, Memphis, TN 38104. Telephone: 901-726-7182; FAX: 901-276-5474; E-mail: [email protected] Copyright © 2003 by the American Association for the Study of Liver Diseases 1527-6465/03/0910-0012$30.00/0 doi:10.1053/jlts.2003.50213
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autoimmune mechanism, with antimitochondrial antibodies being present in the vast majority of patients.1-5 The recurrence of PBC in liver allografts was first reported from the King’s College Liver Unit in 1982.6 Since that time, a number of studies7-11 have supported the concept of recurrent PBC posttransplantation, most often through the recognition of granulomatous bile duct destruction, a lesion thought to be near-pathognomonic of PBC. Clinically recognized disease, however, has rarely been reported in studies that report histologic recurrence.12,13 A single putative example of stage 4 (cirrhotic) PBC in an orthotopic liver transplant was reported by Hubscher et al.14 In 1993, a prior study at our institution reported an 8% rate (5 of 60 patients) of recurrent PBC status after orthotopic liver transplantation (OLT) based on a mean follow-up of 3.3 years (range, 1 to 7.2).15 The recurrence rate was based on the histologic presence of a florid duct lesion (granulomatous bile duct destruction). Given the protracted nature of PBC progression, we revisited this issue with longer follow-up and a larger patient group. In this study, we hoped to gain additional insight into the incidence and natural history of recurrent PBC by obtaining follow-up data on our previously reported cohort of PBC cases from 1993 as well as examining our subsequent experience with PBC patients undergoing OLT. The specific objectives of this study were to (1) determine the incidence of histologically recurrent PBC and (2) evaluate histologic progression of recurrent PBC based on the development of fibrosis (stage) over time. Other less specific morphologic features of PBC (portal infiltrates, plasma cells, dense lymphoplasmacytic infiltrates, and lymphocytic cholangitis) were also evaluated in the course of this study.
Patients and Methods At the Mayo Clinic, post-OLT protocol biopsy samples have traditionally been obtained at 1 week, 3 weeks (1985 to 1996 only), 4 months, and 1 year, and at 1- to 2-year intervals thereafter. Samples are also taken during episodes of suspected
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graft dysfunction. The research proposal and design was reviewed and approved by the Mayo Clinic Institutional Review Board as specified by both federal regulations and local institutional policy.
Study and Control Group The study group was composed of all patients who underwent transplantation for PBC at the Mayo Clinic during the first 12 years of the liver transplantation program (March 1985 to March 1997) who had ⱖ4 months of histologic follow-up. Exclusion criteria included a history of malignancy, chronic hepatitis B or C (pre- or post-OLT), and metabolic disease in the donor liver. The control group consisted of patients who underwent transplantation over the same time frame for diseases that were unlikely to recur (excluded were chronic viral hepatitis, alcoholic cirrhosis, and chronic biliary disease). Hematoxylin and eosin–stained sections of all liver biopsy samples taken at ⱖ5 weeks post-OLT were retrospectively reviewed from both the control group and the study group by a single pathologist (P.B.S.) who was blinded to the primary disease process in the native liver and to clinical information regarding patients’ posttransplantation courses. A total of 679 liver biopsies from the study group were reviewed, with a mean number of 6.8 biopsies per patient (range, 2 to 13).
Histologic Recurrence and Progression PBC recurrence was defined as the presence of a florid duct lesion (granulomatous bile duct destruction), as shown in Figure 1, or destructive lymphocytic cholangitis within a dense portal infiltrate (in the absence of features of acute cellular rejection), as shown in Figure 2. Histologic progression was assessed using Masson trichrome-stained slides and staged as 0 (no fibrosis), 1 (fibrous portal expansion), 2 (periportal fibrosis), 3 (septal fibrosis), and 4 (septal fibrosis plus nodular regeneration).
Other Potential Histologic Markers of Disease Recurrence Other less specific morphologic features of PBC were also noted in the course of this study. Specifically, the presence of a mononuclear portal infiltrate, plasma cells, a dense lymphoplasmacytic infiltrate, and moderate lymphocytic cholangitis (without evidence of acute cellular rejection) were each independently evaluated as potential markers for recurrent PBC. Semiquantification of plasma cells was performed, evaluated on routine hematoxylin and eosin–stained sections. The presence of ⱖ4 plasma cells within a portal tract was a distinguishing threshold. A dense lymphoplasmacytic infiltrate was defined as a mononuclear infiltrate containing ⱖ4 plasma cells that filled at least one of the portal tracts with or without expansion of the portal tract.
Figure 1. Florid duct lesion (granulomatous cholangitis) as a marker of recurrent primary biliary cirrhosis after orthotopic liver transplantation.
Results Patient Groups Of the 784 patients undergoing primary liver transplantation during the study period, 127 had a pre-OLT diagnosis of PBC, that had been confirmed through review of the explanted liver. One hundred of these patients (79%) met criteria for the study group. Twentyseven were excluded for the following reasons: less than 4 months of follow-up, n ⫽ 16; developed chronic viral hepatitis post-OLT, n ⫽ 7; received a liver allograft from donor with alpha-1 antitrypsin deficiency, n ⫽ 1; concomitant hepatocellular carcinoma in explanted liver, n ⫽ 2; bone marrow disease, n ⫽ 1. The control group was composed of all patients who underwent transplantation over the same period for metabolic, toxic, or genetic conditions unlikely to recur. The control group consisted of 35 patients who underwent transplantation for the following conditions: alpha-1 antitrypsin deficiency, n ⫽ 17; amyloidosis, n ⫽ 3; oxalosis, n ⫽ 3; drug-associated fulminant failure, n ⫽ 1; polycystic disease, n ⫽ 2; Wilson disease,
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Recurrence Rate Florid duct lesions were identified in 14 of 100 patient (14%) of the PBC group. Three of the 14 florid duct lesions were identified ⬎7.2 years post-OLT (the maximum follow-up time of the previous study). Destructive lymphocytic cholangitis within a dense portal infiltrate (in the absence of features of acute cellular rejection) was identified in an additional 3 patients from the PBC study group. Neither florid duct lesions nor destructive lymphocytic cholangitis within a dense portal infiltrate were noted in controls. Collectively, strict criteria for histologic recurrence of PBC were met in 17 of 100 patients (17%) of PBC study group. The mean time to first recurrence was 3.7 years, with a median of 3.1 years and range of 0.3 to 7.9 years. Compared with the control group, this conservative estimate of recurrent PBC is statistically significant, with a P value of ⬍.0001. Fourteen of the 17 duct lesions meeting strict diagnostic criteria for recurrent PBC were identified in protocol biopsies. As noted in Figure 3 and Table 1, the first identification of these destructive bile duct lesions is fairly evenly spread out across time. Figure 2. Destructive lymphocytic cholangitis within a dense portal infiltrate as a marker of recurrent primary biliary cirrhosis after orthotopic liver transplantation.
n ⫽ 5; hereditary hemochromatosis, n ⫽ 5. The mean follow-up in the PBC group was 4.7 years (range, 1.0 to 13.8) and in the control group was 3.6 years (range, 0.9 to 11.3).
Biochemical Analysis for Recurrence Biochemical analysis was available for 14 of the 17 PBC patients at the time when strict histologic evidence of recurrent PBC (as defined as the presence of a florid duct lesion or destructive lymphocytic cholangitis within a dense portal infiltrate) was first identified. At the time of the first diagnostic lesion of recurrent disease, the alkaline phosphatase was known to be elevated in 8 of these patients (57%), with values ranging from
Figure 3. The first identification of the diagnostic lesion of recurrent primary biliary cirrhosis, as defined by the presence of a florid duct lesion or destructive lymphocytic cholangitis within a dense portal infiltrate, is plotted (as vertical bars) against time status after orthotopic liver transplantation. Plotted in the background (as a dashed line) is the at-risk patient pool, consisting of all patients still undergoing follow-up at our institution without a prior diagnosis of histologic recurrence of PBC.
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Recurrence of PBC After Liver Transplantation
Table 1. Recurrent Primary Biliary Cirrhosis: Year of First Florid Duct Lesion or Destructive Lymphocytic Cholangitis Seen in Liver Allograft Biopsies
OLT 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Calendar Year of OLT
Calendar Year in Which First Diagnostic Lesion Is Seen
Years post-OLT at Time of First Diagnostic Lesion
Protocol (P) or Nonprotocol (NP) Biopsy
Total Number of Biopsies Reviewed for the Given Patient
1986 1987 1988 1988 1988 1988 1990 1990 1991 1992 1993 1993 1994 1994 1996 1996 1997
1990 1994 1992 1995 1991 1990 1996 1998 1992 1995 1995 1995 1996 1999 1999 1999 1997
4.50 7.21 4.17 7.23 3.06 1.25 6.08 7.92 1.75 3.00 1.50 2.00 2.17 5.00 3.17 2.96 0.33
P P P P P NP NP P P P NP P P P P P P
8 11 9 11 13 7 9 6 6 6 10 7 5 9 3 3 5
NOTE. The first identification of the diagnostic lesion of recurrent primary biliary cirrhosis (as defined by the presence of a florid duct lesion or destructive lymphocytic cholangitis within a dense portal infiltrate) is fairly evenly spread out across time. Fourteen of the 17 duct lesions meeting strict diagnostic criteria for recurrent PBC were identified in protocol biopsies.
117 to 434 (reference range, 81 to 251 U/L) as noted in Table 2. Fibrosis In analyzing histologic progression, the PBC patients who at any point in time had histologic evidence of recurrent disease (based on strict criteria defined as either a florid duct lesion or destructive lymphocytic cholangitis within a dense portal infiltrate) were compared with the control patient population. The maximum degree of fibrosis observed for each group is shown in Tables 2 and 3. Among the PBC patients who met strict criteria of recurrent disease, 8 of 17 patients (47%) had at least periportal fibrosis (stage 2 fibrosis) with a mean follow-up of 5.9 years, whereas in the control population, 7 of 35 patients (20%) had periportal fibrosis with a mean follow-up of 3.3 years. Two of the 17 PBC patients with histologic recurrence and none of the control patients had developed septal fibrosis (stage 3 fibrosis) during the study period. No evidence of septal fibrosis with regenerative nodules (stage 4 fibrosis) was seen in either patient population.
Other Potential Histologic Markers of Disease Recurrence Less specific but potentially more sensitive markers of recurrent PBC were also evaluated in the course of this study, as summarized in Table 4. Portal infiltrates. Almost all (96%) of the PBC patients showed a minimum of mild portal inflammation in at least one portal tract, as compared with 74% of the control group. In the PBC study group, 58% showed a dense portal mononuclear infiltrate in at least one portal tract, compared with 31% of patients in the control group. Plasma cells. Semiquantification of plasma cells showed 37% of the PBC patients with ⱖ4 plasma cells within ⱖ1 portal tract, irrespective of the density of the inflammatory infiltrate, as compared with 6% in the control group. Dense lymphoplasmacytic infiltrate. A dense lymphoplasmacytic infiltrate (defined as a mononuclear infiltrate that filled at least one of the portal tracts, with or without expansion of the portal tract, containing ⱖ4 plasma cells) was observed in 29% of PBC patients, as
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Table 2. Patient Profile With Liver Biopsies Showing Histologic Recurrence of PBC Status After Orthotopic Liver Transplantation
Patient 1 2 3 4 5 6 7
8 9 10 11 12 13 14 15 16 17
Time Post-OLT (y) 4.50 7.21 8.33* 4.17 7.23 3.06 11.00* 1.25 6.08 6.31* 6.83* 7.92 1.75 5.67* 3.00 4.00* 1.50 2.13* 2.00 2.17 5.00 3.17 2.96 0.33
Florid Duct Lesion X X X X X X
X X X
Destructive Lymphocytic Cholangitis Within Dense Portal Infiltrate
X
X X X X X X X X X
X X X X X X X X
X X
Alkaline Phosphatase (U/L)
Last Follow-Up Biopsy (y)
Time From First Lesion to Last Follow-Up Biopsy (y)
Maximum Stage of Fibrosis (Scale 0-4)
208 Unavailable 283 117 267 178 910 Unavailable 279 387 1351 410 279 565 353 516 376 288 294 434 Unavailable 228 183 158
4.5 8.33
0 1.12
2 0
9.15 11.06 11.08
4.98 2.83 7.94
1 2 2
1.38 8.33
0.13 2.23
1 2
7.92 5.75
0.00 4.00
3 2
7.00
4.00
3
3.25
2.75
1
5.00 5.33 5.00 3.17 2.96 1.00
3.00 3.18 0.00 0.00 0.00 0.67
1 2 1 1 1 1
NOTE. Profile of patients in PBC study group meeting strict criteria for histologic recurrence, as defined by the presence of either a florid duct lesion or dense portal infiltrate with destructive lymphocytic cholangitis. Seven patients had a repeat occurrence of a diagnostic lesion, as noted by an asterisk (*). Histologic progression was measured by stage of fibrosis. *Repeat occurrence of diagnostic lesion for histologic recurrent PBC.
compared with none (0%) of the control patients. Six of the 17 PBC patients who met strict criteria for recurrence showed the presence of a dense lymphoplasmacytic infiltrate before identification of a florid duct lesion or destructive lymphocytic cholangitis. Moderate lymphocytic cholangitis. Moderate lymphocytic cholangitis (unaccompanied by endotheliitis or other features suggestive of acute cellular rejection) was seen in 14 (14%) PBC patients who did not meet strict criteria for disease recurrence and in none (0%) of the control group patients. Nine of these 14 PBC patients had a concomitant dense lymphoplasmacytic infiltrate (as defined above) within the same biopsy.
Discussion Since 1982, several studies have supported the concept of recurrent PBC posttransplantation. In 1993, Hub-
scher et al reported histologic features suggestive of recurrent PBC in 13 of 83 patients (16%) who underwent transplantation for PBC 12 to 100 months postOLT.14 In 2001, a large single-center study from Birmingham, UK, reported histologic evidence of recurrent disease in 68 of 400 patients (17%) who underwent transplantation for PBC with a mean time between the diagnosis of recurrence and OLT of 36 months.11 Khettry et al recently reported 8 of 43 patients (18.6%) who underwent transplantation for PBC with a liver allograft biopsy containing a florid duct lesion indicative of recurrent PBC, with median time of recurrence after OLT of 4 years.16 Similar to that of Khettry et al, our experience showed a recurrence rate of 17% based on strict histologic criteria, with a mean time to recurrence of 3.7 years. In a prior study performed at our institution, serum antimitochondrial antibody (AMA) titers did not pre-
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Table 3. Degree of Fibrosis in Control Patients Status Post Orthotopic Liver Transplantation OLT Number
Last Follow-Up Biopsy (y)
Maximum Stage of Fibrosis (Scale 0-4)
2.00 7.92 11.25 0.54 4.00 5.08 5.08 3.23 5.00 7.08 6.38 5.92 5.08 3.08 3.48 1.38 1.13 3.00 4.88 3.00 1.00 2.00 3.00 0.90 0.88 3.00 0.92 2.88 2.38 3.08 3.08 2.75 0.92 1.00 1.13
1 1 2 2 1 0 2 2 0 0 0 1 0 0 1 1 0 1 1 1 2 1 2 2 0 1 1 1 0 1 0 0 1 0 1
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35
NOTE. Stage of fibrosis observed in orthotopic liver transplant biopsies in control patients.
dict histologic recurrence, and therefore was not included as a part of this study; however, because of expressed interest by several reviewers, a retrospective look at AMA status was performed. Of the 17 patients diagnosed with recurrent PBC based on strict histologic criteria, 13 patients had detectable AMA at some time postoperatively. One of these 13 patients was AMAnegative at the time of the diagnostic lesion but was previously AMA-positive postoperatively on several prior occasions, and 1 patient was AMA-negative 7 months after the diagnostic histologic lesion (no AMA study was performed at the time of the diagnostic histopathologic lesion) with subsequent detectable AMA. No AMA was detected in 2 of the 17 patients postoperatively during the study period, and no postoperative AMA data were available for 2 patients. Of the 83 patients within the PBC study group who were not diagnosed with recurrent PBC based on strict histologic criteria, 69 had detectable AMA at some time postoperatively, no AMA was detected postoperatively for 9 patients, and no postoperative AMA data were available on 5 patients. As showed in the prior study from this institution, serum AMA titers do not predict histologic recurrence of PBC. Liver biopsy remains the gold standard for diagnosis. PBC is an insidious process with nonuniform involvement of the portal tracts, particularly with early and mild recurrence; therefore, because of sampling variation, florid duct lesions or destructive lymphocytic cholangitis may not be seen in random core needle biopsy samples. Less specific findings may be all that is represented in the sample, while more classic histologic changes exist elsewhere within the unsampled liver. This study addresses the spectrum of findings within a liver allograft biopsy that can be attributed to recurrent PBC. Clinicians should consider possible recurrence when interpreting liver function tests and histology.
Table 4. Incidence of Other Potential Histologic Markers of Recurrent Primary Biliary Cirrhosis
Study Groups PBC (n ⫽ 100) Control (n ⫽ 35) P value
Dense Mononuclear Moderate Lymphocytic Portal Inflammation Dense Mononuclear ⱖ4 Plasma Cells Infiltrate With ⱖ4 Cholangitis, Florid Duct Within ⱖ1 Portal Infiltrate Within ⱖ1 Within ⱖ1 Portal Plasma Cells Within Lesion, or Destructive Tract Portal Tract Tract ⱖ1 Portal Tract Lymphocytic Cholangitis 96% 74% ⬍.001
58% 31% ⬍.005
37% 6% ⬍.0005
29% 0% ⬍.0001
29% 0% ⬍.0001
NOTE. Summarized is the incidence of potential markers of recurrent primary biliary cirrhosis observed within the PBC study group and contrasted against the incidence in the control group. When criteria for histologic recurrence are expanded to include moderate lymphocytic cholangitis combined with lymphoplasmacytic portal infiltrate, the recurrence rate of PBC is estimated as 26%.
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The potential effect of immunosuppression regimens on the recurrence of PBC was not reviewed in the course of this study and will be the subject of future research.
Conclusion Based on strict morphologic criteria of either the presence of a florid duct lesion or destructive lymphocytic cholangitis within a dense portal infiltrate, a conservative histologic estimate of the rate of recurrent PBC is 17% with 4.7 years of mean follow-up. Given longer follow-up, florid duct lesions, the hallmark histologic lesion of PBC, were identified in an additional 6% of hepatic liver allografts over our previous PBC study. With longer follow-up from the previous study, the recurrence rate based on strict criteria has increased, a trend that may continue as this population matures. Approximately one half to one third of the patients diagnosed with histologic recurrence of PBC (by a florid duct lesion or destructive lymphocytic cholangitis within a dense portal infiltrate) did not have an abnormal alkaline phosphatase level at the time of the first lesion, showing that biochemical analysis of alkaline phosphatase is not a sensitive marker of histologic recurrence. Although the risk of recurrent PBC in OLT has been well established in this and other studies, the risk of histologic progression to advanced fibrosis has not been well established. During the study period, only 2 of 17 patients with recurrent PBC based on strict histologic criteria showed histologic progression to septal fibrosis (stage 3). Given the protracted nature of PBC progression and the relatively limited OLT follow-up periods, longer post-OLT follow-up will be required to assess the clinical significance of recurrent PBC. Several less specific but potentially more sensitive histologic markers of recurrent PBC were also evaluated in the course of this study. Moderate lymphocytic cholangitis and dense lymphoplasmacytic infiltrate have each been shown to occur frequently in liver allografts of PBC patients and not in controls. When criteria for histologic recurrence are expanded to include moderate lymphocytic cholangitis with concomitant lymphoplasmacytic infiltrate (without evidence of acute cellular rejection), the histologic rate of recurrent PBC is estimated as 26%. When moderate lymphocytic cholangitis is alone added as a criterion, the estimated incidence of recurrent PBC is increased from the baseline of 17% to 31%. Dense lymphoplasmacytic infiltrates were significantly more common in liver allo-
grafts in PBC patients than controls. Using the presence of a florid duct lesion, destructive lymphocytic cholangitis within a dense portal infiltrate, or dense lymphoplasmacytic infiltrate as a marker of PBC, the post-OLT recurrence rate of PBC is estimated as 35%. This figure represents approximately twice the rate as compared with the conservative histologic estimate of recurrent PBC based strictly on the presence of a florid duct lesion or destructive lymphocytic cholangitis within a dense portal infiltrate. Likely, the most valuable point to be drawn by evaluation of these other potential less specific histologic markers of recurrent PBC is that their incidence is significantly higher in liver allografts of PBC patients than controls, with recurrent PBC being a reasonable explanation for their occurrence.
References 1. Portmann B, Popper H, Neuberger J, Williams R. Sequential and diagnostic features in primary biliary cirrhosis based on serial histologic study in 209 patients. Gastroenterology 1985;88: 1777-1790. 2. Bernuau D, Feldmann G, Degott C, Gisselrecht C. Ultrastructural lesions of bile ducts in primary biliary cirrhosis. Hum Pathol 1981;12:782-793. 3. Wiesner RH, Grambsch PM, Lindor KD, Ludwig J, Dickson ER. Clinical and statistical analysis of new and evolving therapies for primary biliary cirrhosis. Hepatology 1988;8:668-676. 4. Pape GR, Spengler U, Hoffman RM, Jung MC. Pathogenesis of primary biliary cirrhosis. New aspects of the role of T lymphocytes. In: Krawitt EL, Wiesner RH, eds. Autoimmune Liver Diseases. New York: Raven Press; 1991: 43-62. 5. Batts KP, Ludwig J. Histopathology of autoimmune chronic active hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis. In: Krawitt EL, Wiesner RH, eds. Autoimmune Liver Diseases. New York: Raven Press; 1991: 75-92. 6. Neuberger J, Portmann B, MacDougall BRD, Calne RY, Williams R. Recurrence of primary biliary cirrhosis after liver transplantation. N Engl J Med 1982;306:1-4. 7. Van de Water J, Gerson LB, Ferrell LD, Lake JR, Coppel RL, Batts KP, et al. Immunohistochemical evidence of disease recurrence after liver transplantation for primary biliary cirrhosis. Hepatology 1996;24:1079-1084. 8. Sebagh M, Farges O, Dubel L, Samuel D, Bismuth H, Reynes M. Histological features predictive of recurrence of primary biliary cirrhosis after liver transplantation. Transplantation 1998; 65:1328-1333. 9. Dmitrewski J, Hubscher SG, Mayer AD, Neuberger JM. Recurrence of primary biliary cirrhosis in the liver allograft: the effect of immunosuppression. J Hepatol 1996;24:253-257. 10. Wong PY, Portmann B, O’Grady JG, Devlin JJ, Hegarty JE, Tan KC, Williams R. Recurrence of primary biliary cirrhosis after liver transplantation after FK506-based immunosuppression. J Hepatol 1993;17:284-287. 11. Liermann Garcia RF, Evangelista Garcia C, McMaster P, Neuberger J. Transplantation for primary biliary cirrhosis: Retrospective analysis of 400 patients in a single center. Hepatology 2001;33:22-27.
Recurrence of PBC After Liver Transplantation
12. Knoop M, Bechstein WO, Schrem H, Lobeck H, Hopf U, Neuhaus P. Clinical significance of recurrent primary biliary cirrhosis after liver transplantation. Transpl Int 1996;9(suppl 1):S115-119. 13. Polson RJ, Portmann B, Neuberger J, Calne RY, Williams R. Evidence for disease recurrence after liver transplantation for primary biliary cirrhosis. Clinical and histologic follow-up studies. Gastroenterology 1989;97:715-725. 14. Hubscher SG, Buckels JAC, Elias E, Mayer AD, McMaster P,
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Neuberger JM. Does primary biliary cirrhosis recur after liver transplantation [abstract]? Hepatology 1992;16:545. 15. Balan V, Batts KP, Porayko MK, Krom RAF, Ludwig J, Wiesner RH. Histologic evidence for recurrence of primary biliary cirrhosis after liver transplantation. Hepatology 1993;18:1392-1398. 16. Khettry U, Anand N, Faul PN, Lewis WD, Pomfret EA, Pomposelli J, et al. Liver transplantation for primary biliary cirrhosis: A long-term pathologic study. Liver Transpl 2003; 9:87-96.
P
rimary biliary cirrhosis (PBC) is a chronic, nonsuppurative cholangitic liver disease, with progressive loss of interlobular and septal bile ducts that may result in a biliary type of cirrhosis. PBC principally affects middle-aged women. Substantial evidence points to an
From the *Division of Anatomic Pathology and †Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, MN. Address reprint requests to Pamela B. Sylvestre, MD, 1211 Union Ave, Suite 300, Memphis, TN 38104. Telephone: 901-726-7182; FAX: 901-276-5474; E-mail: [email protected] Copyright © 2003 by the American Association for the Study of Liver Diseases 1527-6465/03/0910-0012$30.00/0 doi:10.1053/jlts.2003.50213
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autoimmune mechanism, with antimitochondrial antibodies being present in the vast majority of patients.1-5 The recurrence of PBC in liver allografts was first reported from the King’s College Liver Unit in 1982.6 Since that time, a number of studies7-11 have supported the concept of recurrent PBC posttransplantation, most often through the recognition of granulomatous bile duct destruction, a lesion thought to be near-pathognomonic of PBC. Clinically recognized disease, however, has rarely been reported in studies that report histologic recurrence.12,13 A single putative example of stage 4 (cirrhotic) PBC in an orthotopic liver transplant was reported by Hubscher et al.14 In 1993, a prior study at our institution reported an 8% rate (5 of 60 patients) of recurrent PBC status after orthotopic liver transplantation (OLT) based on a mean follow-up of 3.3 years (range, 1 to 7.2).15 The recurrence rate was based on the histologic presence of a florid duct lesion (granulomatous bile duct destruction). Given the protracted nature of PBC progression, we revisited this issue with longer follow-up and a larger patient group. In this study, we hoped to gain additional insight into the incidence and natural history of recurrent PBC by obtaining follow-up data on our previously reported cohort of PBC cases from 1993 as well as examining our subsequent experience with PBC patients undergoing OLT. The specific objectives of this study were to (1) determine the incidence of histologically recurrent PBC and (2) evaluate histologic progression of recurrent PBC based on the development of fibrosis (stage) over time. Other less specific morphologic features of PBC (portal infiltrates, plasma cells, dense lymphoplasmacytic infiltrates, and lymphocytic cholangitis) were also evaluated in the course of this study.
Patients and Methods At the Mayo Clinic, post-OLT protocol biopsy samples have traditionally been obtained at 1 week, 3 weeks (1985 to 1996 only), 4 months, and 1 year, and at 1- to 2-year intervals thereafter. Samples are also taken during episodes of suspected
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graft dysfunction. The research proposal and design was reviewed and approved by the Mayo Clinic Institutional Review Board as specified by both federal regulations and local institutional policy.
Study and Control Group The study group was composed of all patients who underwent transplantation for PBC at the Mayo Clinic during the first 12 years of the liver transplantation program (March 1985 to March 1997) who had ⱖ4 months of histologic follow-up. Exclusion criteria included a history of malignancy, chronic hepatitis B or C (pre- or post-OLT), and metabolic disease in the donor liver. The control group consisted of patients who underwent transplantation over the same time frame for diseases that were unlikely to recur (excluded were chronic viral hepatitis, alcoholic cirrhosis, and chronic biliary disease). Hematoxylin and eosin–stained sections of all liver biopsy samples taken at ⱖ5 weeks post-OLT were retrospectively reviewed from both the control group and the study group by a single pathologist (P.B.S.) who was blinded to the primary disease process in the native liver and to clinical information regarding patients’ posttransplantation courses. A total of 679 liver biopsies from the study group were reviewed, with a mean number of 6.8 biopsies per patient (range, 2 to 13).
Histologic Recurrence and Progression PBC recurrence was defined as the presence of a florid duct lesion (granulomatous bile duct destruction), as shown in Figure 1, or destructive lymphocytic cholangitis within a dense portal infiltrate (in the absence of features of acute cellular rejection), as shown in Figure 2. Histologic progression was assessed using Masson trichrome-stained slides and staged as 0 (no fibrosis), 1 (fibrous portal expansion), 2 (periportal fibrosis), 3 (septal fibrosis), and 4 (septal fibrosis plus nodular regeneration).
Other Potential Histologic Markers of Disease Recurrence Other less specific morphologic features of PBC were also noted in the course of this study. Specifically, the presence of a mononuclear portal infiltrate, plasma cells, a dense lymphoplasmacytic infiltrate, and moderate lymphocytic cholangitis (without evidence of acute cellular rejection) were each independently evaluated as potential markers for recurrent PBC. Semiquantification of plasma cells was performed, evaluated on routine hematoxylin and eosin–stained sections. The presence of ⱖ4 plasma cells within a portal tract was a distinguishing threshold. A dense lymphoplasmacytic infiltrate was defined as a mononuclear infiltrate containing ⱖ4 plasma cells that filled at least one of the portal tracts with or without expansion of the portal tract.
Figure 1. Florid duct lesion (granulomatous cholangitis) as a marker of recurrent primary biliary cirrhosis after orthotopic liver transplantation.
Results Patient Groups Of the 784 patients undergoing primary liver transplantation during the study period, 127 had a pre-OLT diagnosis of PBC, that had been confirmed through review of the explanted liver. One hundred of these patients (79%) met criteria for the study group. Twentyseven were excluded for the following reasons: less than 4 months of follow-up, n ⫽ 16; developed chronic viral hepatitis post-OLT, n ⫽ 7; received a liver allograft from donor with alpha-1 antitrypsin deficiency, n ⫽ 1; concomitant hepatocellular carcinoma in explanted liver, n ⫽ 2; bone marrow disease, n ⫽ 1. The control group was composed of all patients who underwent transplantation over the same period for metabolic, toxic, or genetic conditions unlikely to recur. The control group consisted of 35 patients who underwent transplantation for the following conditions: alpha-1 antitrypsin deficiency, n ⫽ 17; amyloidosis, n ⫽ 3; oxalosis, n ⫽ 3; drug-associated fulminant failure, n ⫽ 1; polycystic disease, n ⫽ 2; Wilson disease,
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Recurrence Rate Florid duct lesions were identified in 14 of 100 patient (14%) of the PBC group. Three of the 14 florid duct lesions were identified ⬎7.2 years post-OLT (the maximum follow-up time of the previous study). Destructive lymphocytic cholangitis within a dense portal infiltrate (in the absence of features of acute cellular rejection) was identified in an additional 3 patients from the PBC study group. Neither florid duct lesions nor destructive lymphocytic cholangitis within a dense portal infiltrate were noted in controls. Collectively, strict criteria for histologic recurrence of PBC were met in 17 of 100 patients (17%) of PBC study group. The mean time to first recurrence was 3.7 years, with a median of 3.1 years and range of 0.3 to 7.9 years. Compared with the control group, this conservative estimate of recurrent PBC is statistically significant, with a P value of ⬍.0001. Fourteen of the 17 duct lesions meeting strict diagnostic criteria for recurrent PBC were identified in protocol biopsies. As noted in Figure 3 and Table 1, the first identification of these destructive bile duct lesions is fairly evenly spread out across time. Figure 2. Destructive lymphocytic cholangitis within a dense portal infiltrate as a marker of recurrent primary biliary cirrhosis after orthotopic liver transplantation.
n ⫽ 5; hereditary hemochromatosis, n ⫽ 5. The mean follow-up in the PBC group was 4.7 years (range, 1.0 to 13.8) and in the control group was 3.6 years (range, 0.9 to 11.3).
Biochemical Analysis for Recurrence Biochemical analysis was available for 14 of the 17 PBC patients at the time when strict histologic evidence of recurrent PBC (as defined as the presence of a florid duct lesion or destructive lymphocytic cholangitis within a dense portal infiltrate) was first identified. At the time of the first diagnostic lesion of recurrent disease, the alkaline phosphatase was known to be elevated in 8 of these patients (57%), with values ranging from
Figure 3. The first identification of the diagnostic lesion of recurrent primary biliary cirrhosis, as defined by the presence of a florid duct lesion or destructive lymphocytic cholangitis within a dense portal infiltrate, is plotted (as vertical bars) against time status after orthotopic liver transplantation. Plotted in the background (as a dashed line) is the at-risk patient pool, consisting of all patients still undergoing follow-up at our institution without a prior diagnosis of histologic recurrence of PBC.
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Table 1. Recurrent Primary Biliary Cirrhosis: Year of First Florid Duct Lesion or Destructive Lymphocytic Cholangitis Seen in Liver Allograft Biopsies
OLT 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Calendar Year of OLT
Calendar Year in Which First Diagnostic Lesion Is Seen
Years post-OLT at Time of First Diagnostic Lesion
Protocol (P) or Nonprotocol (NP) Biopsy
Total Number of Biopsies Reviewed for the Given Patient
1986 1987 1988 1988 1988 1988 1990 1990 1991 1992 1993 1993 1994 1994 1996 1996 1997
1990 1994 1992 1995 1991 1990 1996 1998 1992 1995 1995 1995 1996 1999 1999 1999 1997
4.50 7.21 4.17 7.23 3.06 1.25 6.08 7.92 1.75 3.00 1.50 2.00 2.17 5.00 3.17 2.96 0.33
P P P P P NP NP P P P NP P P P P P P
8 11 9 11 13 7 9 6 6 6 10 7 5 9 3 3 5
NOTE. The first identification of the diagnostic lesion of recurrent primary biliary cirrhosis (as defined by the presence of a florid duct lesion or destructive lymphocytic cholangitis within a dense portal infiltrate) is fairly evenly spread out across time. Fourteen of the 17 duct lesions meeting strict diagnostic criteria for recurrent PBC were identified in protocol biopsies.
117 to 434 (reference range, 81 to 251 U/L) as noted in Table 2. Fibrosis In analyzing histologic progression, the PBC patients who at any point in time had histologic evidence of recurrent disease (based on strict criteria defined as either a florid duct lesion or destructive lymphocytic cholangitis within a dense portal infiltrate) were compared with the control patient population. The maximum degree of fibrosis observed for each group is shown in Tables 2 and 3. Among the PBC patients who met strict criteria of recurrent disease, 8 of 17 patients (47%) had at least periportal fibrosis (stage 2 fibrosis) with a mean follow-up of 5.9 years, whereas in the control population, 7 of 35 patients (20%) had periportal fibrosis with a mean follow-up of 3.3 years. Two of the 17 PBC patients with histologic recurrence and none of the control patients had developed septal fibrosis (stage 3 fibrosis) during the study period. No evidence of septal fibrosis with regenerative nodules (stage 4 fibrosis) was seen in either patient population.
Other Potential Histologic Markers of Disease Recurrence Less specific but potentially more sensitive markers of recurrent PBC were also evaluated in the course of this study, as summarized in Table 4. Portal infiltrates. Almost all (96%) of the PBC patients showed a minimum of mild portal inflammation in at least one portal tract, as compared with 74% of the control group. In the PBC study group, 58% showed a dense portal mononuclear infiltrate in at least one portal tract, compared with 31% of patients in the control group. Plasma cells. Semiquantification of plasma cells showed 37% of the PBC patients with ⱖ4 plasma cells within ⱖ1 portal tract, irrespective of the density of the inflammatory infiltrate, as compared with 6% in the control group. Dense lymphoplasmacytic infiltrate. A dense lymphoplasmacytic infiltrate (defined as a mononuclear infiltrate that filled at least one of the portal tracts, with or without expansion of the portal tract, containing ⱖ4 plasma cells) was observed in 29% of PBC patients, as
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Table 2. Patient Profile With Liver Biopsies Showing Histologic Recurrence of PBC Status After Orthotopic Liver Transplantation
Patient 1 2 3 4 5 6 7
8 9 10 11 12 13 14 15 16 17
Time Post-OLT (y) 4.50 7.21 8.33* 4.17 7.23 3.06 11.00* 1.25 6.08 6.31* 6.83* 7.92 1.75 5.67* 3.00 4.00* 1.50 2.13* 2.00 2.17 5.00 3.17 2.96 0.33
Florid Duct Lesion X X X X X X
X X X
Destructive Lymphocytic Cholangitis Within Dense Portal Infiltrate
X
X X X X X X X X X
X X X X X X X X
X X
Alkaline Phosphatase (U/L)
Last Follow-Up Biopsy (y)
Time From First Lesion to Last Follow-Up Biopsy (y)
Maximum Stage of Fibrosis (Scale 0-4)
208 Unavailable 283 117 267 178 910 Unavailable 279 387 1351 410 279 565 353 516 376 288 294 434 Unavailable 228 183 158
4.5 8.33
0 1.12
2 0
9.15 11.06 11.08
4.98 2.83 7.94
1 2 2
1.38 8.33
0.13 2.23
1 2
7.92 5.75
0.00 4.00
3 2
7.00
4.00
3
3.25
2.75
1
5.00 5.33 5.00 3.17 2.96 1.00
3.00 3.18 0.00 0.00 0.00 0.67
1 2 1 1 1 1
NOTE. Profile of patients in PBC study group meeting strict criteria for histologic recurrence, as defined by the presence of either a florid duct lesion or dense portal infiltrate with destructive lymphocytic cholangitis. Seven patients had a repeat occurrence of a diagnostic lesion, as noted by an asterisk (*). Histologic progression was measured by stage of fibrosis. *Repeat occurrence of diagnostic lesion for histologic recurrent PBC.
compared with none (0%) of the control patients. Six of the 17 PBC patients who met strict criteria for recurrence showed the presence of a dense lymphoplasmacytic infiltrate before identification of a florid duct lesion or destructive lymphocytic cholangitis. Moderate lymphocytic cholangitis. Moderate lymphocytic cholangitis (unaccompanied by endotheliitis or other features suggestive of acute cellular rejection) was seen in 14 (14%) PBC patients who did not meet strict criteria for disease recurrence and in none (0%) of the control group patients. Nine of these 14 PBC patients had a concomitant dense lymphoplasmacytic infiltrate (as defined above) within the same biopsy.
Discussion Since 1982, several studies have supported the concept of recurrent PBC posttransplantation. In 1993, Hub-
scher et al reported histologic features suggestive of recurrent PBC in 13 of 83 patients (16%) who underwent transplantation for PBC 12 to 100 months postOLT.14 In 2001, a large single-center study from Birmingham, UK, reported histologic evidence of recurrent disease in 68 of 400 patients (17%) who underwent transplantation for PBC with a mean time between the diagnosis of recurrence and OLT of 36 months.11 Khettry et al recently reported 8 of 43 patients (18.6%) who underwent transplantation for PBC with a liver allograft biopsy containing a florid duct lesion indicative of recurrent PBC, with median time of recurrence after OLT of 4 years.16 Similar to that of Khettry et al, our experience showed a recurrence rate of 17% based on strict histologic criteria, with a mean time to recurrence of 3.7 years. In a prior study performed at our institution, serum antimitochondrial antibody (AMA) titers did not pre-
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Table 3. Degree of Fibrosis in Control Patients Status Post Orthotopic Liver Transplantation OLT Number
Last Follow-Up Biopsy (y)
Maximum Stage of Fibrosis (Scale 0-4)
2.00 7.92 11.25 0.54 4.00 5.08 5.08 3.23 5.00 7.08 6.38 5.92 5.08 3.08 3.48 1.38 1.13 3.00 4.88 3.00 1.00 2.00 3.00 0.90 0.88 3.00 0.92 2.88 2.38 3.08 3.08 2.75 0.92 1.00 1.13
1 1 2 2 1 0 2 2 0 0 0 1 0 0 1 1 0 1 1 1 2 1 2 2 0 1 1 1 0 1 0 0 1 0 1
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35
NOTE. Stage of fibrosis observed in orthotopic liver transplant biopsies in control patients.
dict histologic recurrence, and therefore was not included as a part of this study; however, because of expressed interest by several reviewers, a retrospective look at AMA status was performed. Of the 17 patients diagnosed with recurrent PBC based on strict histologic criteria, 13 patients had detectable AMA at some time postoperatively. One of these 13 patients was AMAnegative at the time of the diagnostic lesion but was previously AMA-positive postoperatively on several prior occasions, and 1 patient was AMA-negative 7 months after the diagnostic histologic lesion (no AMA study was performed at the time of the diagnostic histopathologic lesion) with subsequent detectable AMA. No AMA was detected in 2 of the 17 patients postoperatively during the study period, and no postoperative AMA data were available for 2 patients. Of the 83 patients within the PBC study group who were not diagnosed with recurrent PBC based on strict histologic criteria, 69 had detectable AMA at some time postoperatively, no AMA was detected postoperatively for 9 patients, and no postoperative AMA data were available on 5 patients. As showed in the prior study from this institution, serum AMA titers do not predict histologic recurrence of PBC. Liver biopsy remains the gold standard for diagnosis. PBC is an insidious process with nonuniform involvement of the portal tracts, particularly with early and mild recurrence; therefore, because of sampling variation, florid duct lesions or destructive lymphocytic cholangitis may not be seen in random core needle biopsy samples. Less specific findings may be all that is represented in the sample, while more classic histologic changes exist elsewhere within the unsampled liver. This study addresses the spectrum of findings within a liver allograft biopsy that can be attributed to recurrent PBC. Clinicians should consider possible recurrence when interpreting liver function tests and histology.
Table 4. Incidence of Other Potential Histologic Markers of Recurrent Primary Biliary Cirrhosis
Study Groups PBC (n ⫽ 100) Control (n ⫽ 35) P value
Dense Mononuclear Moderate Lymphocytic Portal Inflammation Dense Mononuclear ⱖ4 Plasma Cells Infiltrate With ⱖ4 Cholangitis, Florid Duct Within ⱖ1 Portal Infiltrate Within ⱖ1 Within ⱖ1 Portal Plasma Cells Within Lesion, or Destructive Tract Portal Tract Tract ⱖ1 Portal Tract Lymphocytic Cholangitis 96% 74% ⬍.001
58% 31% ⬍.005
37% 6% ⬍.0005
29% 0% ⬍.0001
29% 0% ⬍.0001
NOTE. Summarized is the incidence of potential markers of recurrent primary biliary cirrhosis observed within the PBC study group and contrasted against the incidence in the control group. When criteria for histologic recurrence are expanded to include moderate lymphocytic cholangitis combined with lymphoplasmacytic portal infiltrate, the recurrence rate of PBC is estimated as 26%.
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The potential effect of immunosuppression regimens on the recurrence of PBC was not reviewed in the course of this study and will be the subject of future research.
Conclusion Based on strict morphologic criteria of either the presence of a florid duct lesion or destructive lymphocytic cholangitis within a dense portal infiltrate, a conservative histologic estimate of the rate of recurrent PBC is 17% with 4.7 years of mean follow-up. Given longer follow-up, florid duct lesions, the hallmark histologic lesion of PBC, were identified in an additional 6% of hepatic liver allografts over our previous PBC study. With longer follow-up from the previous study, the recurrence rate based on strict criteria has increased, a trend that may continue as this population matures. Approximately one half to one third of the patients diagnosed with histologic recurrence of PBC (by a florid duct lesion or destructive lymphocytic cholangitis within a dense portal infiltrate) did not have an abnormal alkaline phosphatase level at the time of the first lesion, showing that biochemical analysis of alkaline phosphatase is not a sensitive marker of histologic recurrence. Although the risk of recurrent PBC in OLT has been well established in this and other studies, the risk of histologic progression to advanced fibrosis has not been well established. During the study period, only 2 of 17 patients with recurrent PBC based on strict histologic criteria showed histologic progression to septal fibrosis (stage 3). Given the protracted nature of PBC progression and the relatively limited OLT follow-up periods, longer post-OLT follow-up will be required to assess the clinical significance of recurrent PBC. Several less specific but potentially more sensitive histologic markers of recurrent PBC were also evaluated in the course of this study. Moderate lymphocytic cholangitis and dense lymphoplasmacytic infiltrate have each been shown to occur frequently in liver allografts of PBC patients and not in controls. When criteria for histologic recurrence are expanded to include moderate lymphocytic cholangitis with concomitant lymphoplasmacytic infiltrate (without evidence of acute cellular rejection), the histologic rate of recurrent PBC is estimated as 26%. When moderate lymphocytic cholangitis is alone added as a criterion, the estimated incidence of recurrent PBC is increased from the baseline of 17% to 31%. Dense lymphoplasmacytic infiltrates were significantly more common in liver allo-
grafts in PBC patients than controls. Using the presence of a florid duct lesion, destructive lymphocytic cholangitis within a dense portal infiltrate, or dense lymphoplasmacytic infiltrate as a marker of PBC, the post-OLT recurrence rate of PBC is estimated as 35%. This figure represents approximately twice the rate as compared with the conservative histologic estimate of recurrent PBC based strictly on the presence of a florid duct lesion or destructive lymphocytic cholangitis within a dense portal infiltrate. Likely, the most valuable point to be drawn by evaluation of these other potential less specific histologic markers of recurrent PBC is that their incidence is significantly higher in liver allografts of PBC patients than controls, with recurrent PBC being a reasonable explanation for their occurrence.
References 1. Portmann B, Popper H, Neuberger J, Williams R. Sequential and diagnostic features in primary biliary cirrhosis based on serial histologic study in 209 patients. Gastroenterology 1985;88: 1777-1790. 2. Bernuau D, Feldmann G, Degott C, Gisselrecht C. Ultrastructural lesions of bile ducts in primary biliary cirrhosis. Hum Pathol 1981;12:782-793. 3. Wiesner RH, Grambsch PM, Lindor KD, Ludwig J, Dickson ER. Clinical and statistical analysis of new and evolving therapies for primary biliary cirrhosis. Hepatology 1988;8:668-676. 4. Pape GR, Spengler U, Hoffman RM, Jung MC. Pathogenesis of primary biliary cirrhosis. New aspects of the role of T lymphocytes. In: Krawitt EL, Wiesner RH, eds. Autoimmune Liver Diseases. New York: Raven Press; 1991: 43-62. 5. Batts KP, Ludwig J. Histopathology of autoimmune chronic active hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis. In: Krawitt EL, Wiesner RH, eds. Autoimmune Liver Diseases. New York: Raven Press; 1991: 75-92. 6. Neuberger J, Portmann B, MacDougall BRD, Calne RY, Williams R. Recurrence of primary biliary cirrhosis after liver transplantation. N Engl J Med 1982;306:1-4. 7. Van de Water J, Gerson LB, Ferrell LD, Lake JR, Coppel RL, Batts KP, et al. Immunohistochemical evidence of disease recurrence after liver transplantation for primary biliary cirrhosis. Hepatology 1996;24:1079-1084. 8. Sebagh M, Farges O, Dubel L, Samuel D, Bismuth H, Reynes M. Histological features predictive of recurrence of primary biliary cirrhosis after liver transplantation. Transplantation 1998; 65:1328-1333. 9. Dmitrewski J, Hubscher SG, Mayer AD, Neuberger JM. Recurrence of primary biliary cirrhosis in the liver allograft: the effect of immunosuppression. J Hepatol 1996;24:253-257. 10. Wong PY, Portmann B, O’Grady JG, Devlin JJ, Hegarty JE, Tan KC, Williams R. Recurrence of primary biliary cirrhosis after liver transplantation after FK506-based immunosuppression. J Hepatol 1993;17:284-287. 11. Liermann Garcia RF, Evangelista Garcia C, McMaster P, Neuberger J. Transplantation for primary biliary cirrhosis: Retrospective analysis of 400 patients in a single center. Hepatology 2001;33:22-27.
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12. Knoop M, Bechstein WO, Schrem H, Lobeck H, Hopf U, Neuhaus P. Clinical significance of recurrent primary biliary cirrhosis after liver transplantation. Transpl Int 1996;9(suppl 1):S115-119. 13. Polson RJ, Portmann B, Neuberger J, Calne RY, Williams R. Evidence for disease recurrence after liver transplantation for primary biliary cirrhosis. Clinical and histologic follow-up studies. Gastroenterology 1989;97:715-725. 14. Hubscher SG, Buckels JAC, Elias E, Mayer AD, McMaster P,
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Neuberger JM. Does primary biliary cirrhosis recur after liver transplantation [abstract]? Hepatology 1992;16:545. 15. Balan V, Batts KP, Porayko MK, Krom RAF, Ludwig J, Wiesner RH. Histologic evidence for recurrence of primary biliary cirrhosis after liver transplantation. Hepatology 1993;18:1392-1398. 16. Khettry U, Anand N, Faul PN, Lewis WD, Pomfret EA, Pomposelli J, et al. Liver transplantation for primary biliary cirrhosis: A long-term pathologic study. Liver Transpl 2003; 9:87-96.