RECURRENCE OF PRIMARY BILIARY CIRRHOSIS, AUTOIMMUNE CHOLANGITIS AND PRIMARY SCLEROSING CHOLANGITIS AFTER LIVER TRANSPLANTATION

PRIMARY BILIARY CIRRHOSIS, PRIMARY SCLEROSING CHOLANGITIS, AND ADULT CHOLANGIOPATHIES

1089-3261/98 $8.00

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RECURRENCE OF PRIMARY BILIARY CIRRHOSIS, AUTOIMMUNE CHOLANGITIS AND PRIMARY SCLEROSING CHOLANGITIS AFTER LIVER TRANSPLANTATION Kenneth P. Batts, MD, and Xuedong Wang, MD, PhD

Liver transplantation as a common therapeutic modality is still a relatively recent phenomenon; therefore, our understanding of the incidence and significance of disease recurrence after orthotopic liver transplantation (OLT) remains in evolution. Although identification in liver tissue of hepatitis B, delta antigens, and hepatitis C RNA5can be readily accomplished using immunohistochemical and polymerase chain reaction techniques, respectively, the recurrence of liver disease of putative autoimmune pathogenesis (primary biliary cirrhosis [PBC], autoimmune cholangitis, and primary sclerosing cholangitis [PSC]) is not as convincingly documented. Each of the autoimmune diseases can show overlap histological features with rejection, chronic viral hepatitis, drug reactions and, particularly in the case of PSC, ischemic cholangitis or other causes of large-duct biliary damage. Furthermore, because early recurrent disease is generally unaccompanied by symptoms and autoimmune serological markers often persist after OLT, it is difficult to detect recurrence

From the Department of Laboratory Medicine and Pathology, Mayo Clinic; and the Mayo Medical School, Rochester, Minnesota (KPB); and the Department of Pathology, Lorna Linda University Medical Center, Lorna Linda, California (XW)

CLINICS IN LIVER DISEASE VOLUME 2 * NUMBER 2 * MAY 1998

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clinically. Nonetheless, there is growing evidence that autoimmune biliary disease can recur in hepatic allografts. PRIMARY BlLlARY CIRRHOSIS

PBC is a chronic, progressive, cholestatic liver disease characterized histologically by the granulomatous destruction of intrahepatic bile ducts, periportal hepatitis with piecemeal necrosis, and eventual cirrhosis. OLT has proven to be an effective treatment in the advanced stage of the disease.15 While the issue of recurrence of PBC following liver transplantation has been controversial, there is considerable evidence that PBC can recur in hepatic allografts. The hallmark lesion of PBC in the nontransplant setting is the presence of epithelioid cells centered around septa1 or interlobular bile ducts with evidence of bile duct damage and destruction, known as granulomatous duct destruction or the florid duct lesion. Signs of bile duct damage also include destruction of the basement membrane and swelling, pyknosis or loss of biliary epithelial cells. In addition, PBC also demonstrates nonspecific features such as portal and periportal chronic inflammatory infiltrates, lymphocytic bile duct destruction, ductopenia, and unexplained noncaseating granulomas. Eventually biliary-type cirrhosis may result, characterized by bridging fibrosis, irregular garlandshaped regenerative nodules and cholate stasis changes in periseptal hepatocytes (hepatocellular swelling, copper accumulation, and variable Mallory's hyaline) (Table 1). Successful documentation of recurrent PBC post-transplantation has been difficult. Early recurrence may be asymptomatic and if symptoms do develop the clinical distinction from other forms of graft dysfunction may be impossible. Antimitochondrial antibodies (AMA) persist in serum in the majority of patients; therefore, identification of these is not helpful. Furthermore, mild elevations in serum alkaline phosphatase and gammaglutamyl transpeptidase levels are common post-OLT and, therefore, not of much use in detection of recurrent PBC. As a result, histologic examination of liver biopsy specimens has come to play a major role in identification of recurrent PBC. Unfortunately, the majority of characteristic histologic findings of PBC can also be seen in other conditions affecting allografts such as acute or chronic rejection, viral hepatitis, drug effects, and ischemia. Allograft rejection, in particular, shares in common with PBC portal inflammation, lymphocytic cholangitis, and potential duct loss (see Table l),making histologic documentation of putative recurrent PBC difficult. Furthermore, the immunosuppressive drugs given after transplantation could potentially modify the histologic manifestations of PBC.8,16, 25, 36, 37 It is generally felt that the most specific criterion for recurrent PBC is the observation of the hallmark histologic lesion of PBC, the florid duct lesion (Fig. 1).Even this lesion is not entirely specific, however, as hepatitis C can rarely be associated with granulomatous duct destruction

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Table 1. HISTOLOGIC FEATURES OF PBC, PSC, AND POST-OLT MIMICS Histologic Features Florid duct lesion Fibrous obliterative lesion Cholangiectasis Cholangitic abscesses Lymphocytic cholangitis Ductopenia Ductular proliferation Portal inflammation Cholate stasis changes Granulomas Endotheliitis

PBC*

PSC

+

-

+ + + + + + -

Acute Chronic Ischemic HCV** Rejection Rejection Cholangitis rare

Other

rare

-

rare

-

+ +

infection drug

+ + + + +

+

-

-

rare

-

-

-

+

drug

+

-

drug

-

-

-

?

rare

-

-

?

drug drug

-

"Autoimmune cholangitis will show similar features ""Hepatitis C virus

Figure 1. Recurrent primary biliary cirrhosis after liver transplantation. This characteristic florid duct lesion was noted in a routine (protocol) biopsy 4 years post orthotopic liver transplantation. The bile duct (asterisk) shows both lymphocytic cholangitis and granulomatous duct destruction (florid duct lesion), the latter is located eccentrically to the left of the bile duct (hematoxylin-eosin,original magnification x 240).

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indistinguishable from primary biliary ~irrhosis.~, 12, l9 Rarely, ischemic cholangitis may produce florid-duct-like lesions (Fig. 2). Nonetheless, in our experience nearly all florid duct lesions observed post-transplantation have been in patients transplanted for PBC. In 1982, Neuberger et a1 first reported the development of a syndrome suggestive of recurrent PBC in three patients, using both clinical and histologic criteria.26This group's experience was updated in 1989, with putative, recurrent PBC noted in 9 of 10 patients and tissue available more than one year post-transplant.28Histologic criteria regarded as PBC-like included ductular proliferation, lymphocytic aggregates, breaks in the basement membranes of bile ducts, copper-associated protein in the absence of cholestasis, paucity of bile ducts, and granulomas. Florid duct lesions were not reported, however, and therefore the specificity of the evidence for recurrence of PBC remained debatable. In the late 1980's and 1990, little support for recurrent PBC was generated and a number of articles were published that failed to identify disease recurrence', 7, 9, 11, 16, z9; however, these studies had relatively few PBC patients with long-term histologic follow-up. One of these studies reported 76 patients transplanted for PBC but only 34% had a clinical follow-up over 1 year, and only two of the eight biopsy specimens reported had been obtained over 1 year post-transplant." Interestingly, another of these studies does describe a 2-year post-OLT biopsy specimen from a patient transplanted for PBC that showed nonsuppurative

Figure 2. Ischemic cholangitis posttransplant, mimicking florid duct lesion of primary biliary cirrhosis. This allograft was excised thirteen months post-OLT for multiple ischemic large duct strictures. This peripheral bile duct shows atrophic epithelium with a periductal granulomatous reaction, perhaps reacting to extruded bile. As opposed to the true florid duct lesion of Figure 1, there is no lymphocytic cholangitis evident (hematoxylin-eosin, original magnification x 140).

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RECURRENCE OF PBC AND PSC AFTER LIVER TRANSPLANTATION

destructive cholangitis, although the authors attributed this to cellular rejection.16 In 1990, Dietze et a1 described two patients with putative recurrent PBC at 6 and 12 months post-transplant as manifested by ”typical histological features of bile duct damage and development of granulomas.”1°More detailed reports with larger series illustrating florid duct lesions post-transplant appeared in 1993 by Hubscher et a1 from the United Kingdomz0and Balan et a1 from the United States.2Hubscher et a1 noted findings suggestive of recurrent PBC in 13 of 83 patients (16%) who had post-transplant biopsy specimens taken at least 12 months posttransplant, with a mean follow-up of 18 months for the PBC and control groups combined (Table 2). Criteria regarded as suggestive of recurrent PBC were a combination of portal inflammation, lymphoid aggregates, epithelioid granulomas, and bile duct damage. In two patients, granulomatous duct destruction was evident. In the study by Balan et al, the presence of granulomatous duct destruction was regarded as the sole criterion for recurrence of PBC.2 In biopsy specimens from patients transplanted for PBC with tissue available at least 12 months posttransplant, 5 of 60 patients (8%) had florid duct lesions noted between 2 and 6 years after transplantation, the mean follow-up being 3.3 years (see Table 2). Recurrent PBC may be independent of the immunosuppressive regimen. In 1993, recurrence of PBC was noted in two patients being maintained on tacrolimus immunosuppression, in contrast to the cyclosporine-based regimen used in most other reports.38 In a 1994 study, Gouw et a1 failed to find convincing evidence of recurrent PBC in 19 patients with yearly protocol biopsies and a mean post-transplant follow-up of 5 years (range 1 to 11 years).14 They concluded that there were no distinctive histologic features for recurrent PBC, however they did find portal granulomas as well as mild bile duct damage in the third year biopsy specimens from two PBC patients, accompanied by normal liver tests and no clinical symptoms. The reasons for the disparate results in previous studies investigating PBC recurrence after liver transplantation are probably multifactorial and are related to variably stringent criteria for recurrent disease, the Table 2. FREQUENCY OF RECURRENT PBC POST TRANSPLANTATION: A SUMMARY OF RECENT POSITIVE STUDIES

Author

Date

Time to Recurrence Mean Flu Post-OLT Frequency (months) (months)

Hubscher et al Balan Van De Water et al

1993 1993 1996

13/83(16%) 5/60(8%) 8/38(21%)

Data from references 3, 20, 34.

48 39 32

12-61 24-72 8-48

Criteria Florid Duct Lesion X X X

Other X

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BATTS & WANG

number of biopsy samples available for review, the number of PBC patients examined, and the length of follow-up. In our experience, it is not uncommon for biopsy specimens subsequent to those with florid duct lesions to be normal or near-normal, suggesting that the lesions are likely quite patchy in early stages. Furthermore, it is characteristic that portal tracts adjacent to those harboring florid duct lesions such as illustrated in Figure 1 are completely normal. While this reinforces the concept of patchiness, it is also helpful in distinguishing recurrent PBC from the rare examples of recurrent hepatitis C with granulomas as hepatitis C tends to affect most portal tracts in a more or less uniform fashion. An alternative approach to the problem of nonspecificity of histologic criteria for recurrent PBC would be the identification of a specific marker for PBC that develops early in the course of the disease and is not affected by immunosuppressive medications. One potential marker is a well characterized monoclonal antibody, C355.1, that reacts with the immunodominant mitochondria1 autoantigen of PBC (PDC-E2) by producing intense apical staining of bile duct epithelium (BDE) specifically in liver sections of patients with PBC. Using this antibody, Van de Water et a1 performed immunohistochemical and histological analysis of serial liver biopsies of 67 patients pre- and post-OLT, including 38 selected patients with PBC (some of which were reported by Balm et a12 earlier) and 29 non-PBC liver disease controls.35They found that intense C355.1 staining was present in approximately 90% of pretransplant or explant specimens from patients with PBC. Subsequently, 74% (28 of 38) of these patients developed intense apical staining of the BDE with mAb C355.1 after transplantation, regardless of the histologic findings; none of the 29 control cases stained positively. Moreover, 28% of the 28 positive patients had histologic features consistent with disease recurrence, and an additional 32% had nonspecific portal infiltrates. In addition, 50% of the C355.1 positive patients with disease recurrence had cholestatic laboratory values at the time of biopsy. There were no patients in this study documented with histologic recurrence that were negative for C355.1. Therefore, there appears to be immunohistochemical evidence that supports the concept of recurrence of PBC following OLT. This staining may be antibody dependent, however, as Neuberger noted that polyclonal anti-E2 antisera reacted similarly with PBC and normal control The implications of a PBC-specific staining pattern in the bile ducts of patients following transplantation are unknown; however, the recurrence of PBC following transplantation is strongly suggested by the correlation between C355.1 staining and the histologic data. Summary There is considerable evidence to support the histologic recurrence of PBC following OLT (see Table 2). The incidence of recurrent PBC

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post-OLT, as defined by characteristic histologic lesions, is probably in the 8% to 16% range at 2 to 5 years, although this incidence will likely increase with longer follow-up and acquisition of additional biopsy specimens. Recurrent PBC is generally documented at least 1 year after liver transplantation, although we have seen examples as early as 4 months post-transplant. Based on the data accumulated thus far, however, recurrence is unlikely to be a frequent cause of early (i.e., <5 years) graft dysfunction or loss and significant clinical manifestations related to the disease are very uncommon. Whether disease recurrence will have an impact on patient or graft survival over a longer period of follow-up remains to be determined, but the disease course will likely be influenced by a number of factors including the immunosuppressive regimen used and the age of the patient. The data suggest, however, that the latency period for disease expression in PBC may be very long.

AUTOIMMUNE CHOLANGITIS

In the nontransplant setting, approximately 5% to 10% of patients when judged by standard clinical, biochemical and histological parameters have a disease which has all the characteristics of PBC except they lack the classical serological hallmark, AMA. The AMA-negative patients may be a heterogeneous group. Michieletti reported that 3 out of 20 AMA-negative PBC patients by immunofluorescence had falsely negative results upon further testing with enzyme linked immunosorbent assay (ELISA) and immunoblotting specific for components of the M2 most likely reflecting either low or fluctuating titers of AMA. In the majority of AMA-negative PBC patients other autoantibodies such as antinuclear antibody (ANA) or antismooth muscle antibody (ASMA) are present. The terms ”primary autoimmune ~holangitis,”~~ “autoimmune cholangiopathy,”6 and ”autoimmune ~holangitis”’~ have been applied to this disease. It remains unclear as to whether a significant difference exists between AMA-positive PBC and autoimmune cholangitis; therefore, some authors prefer retaining the term ”AMA-negative PBC” for the latter.13 This entity is discussed in greater detail in the autoimmune cholangitis article of this issue. It is not well documented whether the absence of AMA portends a different post-OLT outcome when comparing autoimmune cholangitis (AMA-negative) to PBC. Kim et a1 identified OLT recipients who had clinical, radiologic and histologic features compatible with PBC.21Their pretransplant AMA status was determined, and each AMA-negative patient was paired with two AMA-positive patients. In their experience with nine patients who met the criteria for a diagnosis of autoimmune cholangitis, one (11%) developed convincing features of recurrent disease in the graft at 4 and 6 years following OLT, an incidence similar to those shown in Table 2. Despite the histologic findings, however, the patient remains well with normal liver biochemistries at 7 years of follow-up.

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BATTS & WANG

We have recently observed another probable florid duct lesion 4 months post-OLT in a patient transplanted for AMA-negative PBC (Fig. 3). In summary, in the nontransplant setting patients with AMA-negative PBC share many disease characteristics with their AMA-positive counterparts. While experiences are very limited, AMA-negative patients may be as prone to recurrence as the AMA-positive patients. PRIMARY SCLEROSING CHOLANGITIS

PSC is a disorder characterized by nonspecific inflammatory fibrosis in the wall of the biliary tree leading to irregular stenosis and ectasia, of usually both the intrahepatic and extrahepatic bile ducts. In the nontransplant setting, the diagnosis of PSC is based on the combination of clinical and laboratory data, radiographic appearance of the bile ducts, and supportive histologic features. The pathognomonic histologic feature of PSC, fibrous obliterative cholangitis, is rarely seen in biopsy specimens. While the diagnosis of PSC generally can be made with certainty based on radiographic findings in a patient with the appropriate clinical setting and compatible histopathology, the radiographic lesions of PSC are not specific and have been reported to occur in patients with ische-

Figure 3. Putative recurrent autoimmune cholangitis 4 months after liver transplant. Dense portal inflammation and ill-defined granuloma (arrowheads) and lymphocytic cholangitis (arrow) are evident. Although suggestive of recurrent autoimmune cholangitis, the absence of unequivocal granulomatous duct destruction precludes a definitive diagnosis of such. Helpful circumstantial evidence to support this includes the other portal tracts in the specimen being fairly normal, the absence of acute rejection changes or endotheliitis elsewhere in this specimen, stable levels of liver-related enzymes, and absence of evidence for hepatitis C or biliary ischemia (hematoxylin-eosin,original magnification, x 140).

RECURRENCE OF I’BC AND PSC AFTER LIVER TRANSPLANTATION

429

mia, cirrhosis, hepatocellular carcinoma, polycystic liver disease, meta34 static liver disease and in HIV-associated ~holangiopathy.~~,

Histopathology In the nontransplant setting, the distinctive histologic feature of the bile duct lesion in PSC is a fibro-obliterative one characterized by an onion skin type of periductal fibrosis around medium-sized or larger bile ducts, with degeneration and atrophy of the epithelial lining and eventual replacement of the bile duct by fibrous cords. These lesions, accompanied by reduced numbers of interlobular bile ducts and appropriate clinical and radiographic findings, are virtually diagnostic of PSC; however, because of the large size of the ducts involved, the lesions are rarely identified in needle biopsy specimens. The early fibro-obliterative lesions are not pathognomonic for PSC, as biliary obstruction and, most importantly, ischemic cholangitis4,23 (Fig. 4) can produce similar lesions. Cholangiectases and cholangitic abscesses are other characteristic lesions of PSC. These are caused by focal destruction of the biliary epithelium of larger ducts, resulting in saccular dilatation of the bile duct, inspissation of bile, bile infarcts, and potentially superinfection with cholangitic abscesses. Like fibrous-obliterative lesions, however, these lesions rarely are seen in needle biopsies of the liver, and therefore

Figure 4. Fibrous cholangitis after liver transplantation-ischemic cholangitis mimicking primary sclerosing cholangitis. In this case, well-documented biliaty ischemia was present. The central scarred area (arrows) in the center of this field likely represents remnants of an atrophic bile duct. In the nontransplant setting, lesions such as this are near-pathognomonic of primary sclerosing cholangitis (hematoxylin-eosin, original magnification x 42.5).

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are of limited use in this setting. Furthermore, identical lesions can be seen in ischemic cholangitis4,23 (Figs. 5 and 6). The remaining histologic lesions of PSC are similar to those seen in PBC (see Table 1).In early-stage disease one will note variable portal and periportal inflammation, ductular proliferation, lymphocytic cholangitis, ductopenia, and little lobular damage. In later stages, biliary-type bridging fibrosis and garland-shaped regenerative nodules will be present with prominent ductopenia, variable ductular proliferation, and cholate stasis changes in periseptal hepatocytes as described in PBC; however, the majority of these features can be mimicked by a variety of diseases affecting allografts (see Table 1). Clinical Aspects The clinical features of PSC are reviewed in detail elsewhere in this issue. Cholangiography plays a major diagnostic role in PSC, as the majority of patients will demonstrate characteristic alterations of the intrahepatic or extrahepatic biliary system, usually both. Typical findings include irregular strictures and beading, diverticular outpouchings, cholangiectases, and later an attenuated pattern simulating a pruned tree. Documenting putative recurrent PSC post-OLT is difficult radiographically, however, as PSC-like lesions have been reported in association

Figure 5. Post-liver-transplant cholangiectasis in ischemic cholangitis, mimicking primary sclerosing cholangitis. This markedly dilated bile duct with concentric fibrosis and inflammation mimics the cholangiectases, which are typical of primary sclerosing cholangitis in the nontransplant setting. In this case, the patient had not been transplanted for PSC, and well-documented diffuse biliary ischemia was present (hematoxylin-eosin, original magnification x 425).

RECURRENCE OF PBC AND PSC A F E R LIVER TRANSPLANTATION

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Figure 6. Cholangiectasis post-liver-transplantation in ischemic cholangitis, mimicking primary sclerosing cholangitis. This markedly ectatic duct shows disrupted epithelium resulting in denudation (small arrow) resulting in fibrosis and inflammation of the wall and collections of bilious debris in the lumen (large arrows). Lesions such as this are typical of primary sclerosing cholangitis in the nontransplant setting (hematoxylin-eosin, original magnification x42.5).

with hepatic artery thrombosis, prolonged cold ischemia time, use of ABO-incompatible allografts, chronic rejection, and preservation-related ischemia.3O In the absence of a specific test for PSC, the best evidence that PSC may recur post-OLT is based on an increase in frequency of PSC-like cholangiographic or histologic lesions in series of cases rather than in individual case reports. In 1988, Lemt et a1 reported the development of PSC-like lesions in 1 of 55 patients transplanted because of PSC." Although suggestive of recurrent disease, the authors concluded in a second report that the bile duct strictures were not caused by recurrent PSC.18 The largest study in which the frequency of post-OLT strictures in patients with PSC has been examined involved reviewing cholangiograms from 687 allografts in 643 patients. All had choledochojejunostomy (Roux-en-Y) biliary anastomoses; 112 of the allografts were placed in 100 PSC patients with the remaining cases serving as contro1s.31 It was noted that PSC patients were more likely than controls to develop intrahepatic, nonanastomotic strictures (27% versus 13%, p = .0005) and extrahepatic nonanastomotic strictures (6% versus 2%, p = .008); however, no difference in frequency of anastomotic strictures was noted (l8Y0 versus 15%, p = .381). When the data were corrected for hepatic artery occlusion, the frequency of intrahepatic strictures in the PSC group was 18% versus 9% in the non-PSC group. Patients were not

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BA'ITS&WANG

matched for the presence of chronic rejection, ABO-incompatibility, or cold ischemia time, all of which influence the frequency of post-OLT strictures. The same group later examined the issue of recurrence of PSC from another perspective, comparing in a blinded fashion the cholangiographic appearance of post-OLT strictures in 32 patients transplanted for PSC versus a control group of non-PSC patients with While the location, number, and length of strictures and ductal dilatation were similar in the two groups, mural irregularities and diverticulumlike outpouchings occurred more frequently in PSC patients. Histologic Perspectives

Harrison et all7studied the issue of recurrent PSC from a histologic perspective, comparing histologic material taken at least 6 months postOLT from 22 patients transplanted for PSC, using as controls 185 nonPSC, noncholedochojejunostomysubjects (non-PSC controls) and 22 nonPSC, choledochojejunostomypatients (Roux controls). When comparing the PSC patients with non-PSC controls, biopsy specimens from the former group were more likely to show biliary obstruction changes (27% versus 8%, p < O.OOOl), fibrous cholangitis (24% versus 1%,p < 0.001), and fibro-obliterative lesions (6% versus O%, p < 0.001). When PSC patients were compared with Roux controls, fibrous cholangitis was more likely in the PSC group (24% versus 3%, p = 0.05); small patient numbers may have contributed to no differences being found in biliary obstruction and fibro-obliterative lesions. The authors did not attempt to correlate their biopsy findings with cholangiography. Finally, in our own unpublished experience, we have occasionally observed convincing post-OLT cholangiographic or histologic (Fig. 7) evidence of recurrent PSC in the absence of known risk factors for strictures or biliary atrophy.

Summary The diagnosis of putative recurrent PSC post-OLT is based on nonspecific radiographic and pathologic findings and can be very difficult in an individual case, requiring the reasonable exclusion of immunologic (chronic rejection, ABO mismatch), preservation, vascular, or infectious insults that may mimic recurrent PSC. While the issue of recurrent PSC has not been entirely settled, there is emerging cholangiographic and histologic data from controlled series that suggest that PSC does recur. The recurrence seems to be in the form of nonanastomotic intrahepatic and extrahepatic strictures and the frequency is probably in the 20% to 25% range at 3 to 5 years. Further follow-up is necessary to determine the clinical and laboratory manifestations of recurrent PSC, the longterm incidence, and the effects (if any) on survival.

RECURRENCE OF PBC AND FSC AFTER LIVER TRANSPLANTATION

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Figure 7. Putative recurrent primary sclerosing cholangitis 2 years after liver transplantation. The concentric periductal fibrosis (arrow), periportal and bridging fibrosis, and ductular proliferation, in the context of PSC-like cholangiographic abnormalities and no risk factors for ischemic cholangitis, would be compatible with recurrent primary sclerosing cholangitis (hematoxylin-eosin,original magnification x 133).

CONCLUSION

Given the usually prolonged natural history of primary biliary cirrhosis, autoimmune cholangitis, and primary sclerosing cholangitis, and the relatively recent introduction of orthotopic liver transplantation, our understanding of post-OLT recurrence of these autoimmune diseases has been slow to evolve. Present data suggest that after OLT patients with PBC will have persistence of serum antimitochondrial antibodies, develop histologic lesions suggestive of recurrent PBC with a frequency in the 8% to 16% range at 2 to 5 years post-OLT, but will demonstrate little if any symptomatic disease as a consequence. While data are extremely limited, autoimmune cholangitis patients will likely have a similar post-transplant course (without AMA). Recurrence of PSC remains the most controversial; however, PSC patients probably develop nonanastomotic intrahepatic and extrahepatic strictures more frequently than non-PSC patients, with a frequency in the 20% to 25% range at 3 to 5 years. With longer patient follow-up and additional studies it is hoped that our understanding of recurrent autoimmune biliary diseases will grow considerably. References 1. Anonymous. Is PBC cured by liver transplantation? Lancet 337272-273, 1991 2. Balan V, Batts KP, Porayko MK, et al: Histological evidence for recurrence of primary biliary cirrhosis after liver transplantation. Hepatology 18:1392-1398, 1993

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3. Balm V, Batts KP, Porayko MK, et a1 Granulomatous destruction of bile ducts after liver transplantation. PBC Recurrence of HCV Infection: The Author’s Reply (letter). Hepatology 21:1767, 1995 4. Batts KP: Ischemic cholangitis. Mayo Clin Proc (in press) 5. Bonilla Guerrero R, Batts KP, Brandhagen DJ, et a1 Effects of formalin fixation and prolonged block storage on detection of hepatitis C virus RNA in liver tissue. Diagnostic Molecular Pathology 6277-281, 1997 6. Ben-An Z, Dhillon AP, Sherlock S: Autoimmune cholangiopathy: Part of the spectrum of autoimmune chronic active hepatitis. Hepatology 18:lO-15, 1993 7. Buist LJ, Hubscher SG,Vickers C, et al: Does liver transplantation cure primary biliary cirrhosis? Transplant Proc 21:2402, 1989 8. Christensen E, Neuberger J, Crowe J, et al: Beneficial effect of azathioprine and prediction of prognosis in primary biliary cirrhosis. Final results of an international trial. Gastroenterology 89:1084-1091, 1985 9. Demetris AJ, Markus BH, Esquivel C, et al: Pathologic analysis of liver transplantation for primary biliary cirrhosis. Hepatology 8:939-947, 1988 10. Dietze 0, Vogel W, Margreiter R, et al: Early recurrence of primary biliary cirrhosis after liver transplantation (letter). Gastroenterology 981106-1107, 1990 11. Esquivel CO, Van Thiel DH, Demetris AJ, et al: Transplantation for primary biliary cirrhosis. Gastroenterology 941207-1216, 1988 12. Farges 0, Sebagh M, Reynes J, Bismuth H: Granulomatous destruction of bile ducts after liver transplantation, PBC recurrence or HCV infection? Hepatology 21:17651767, 1995 13. Goodman ZD, McNally PR, Davis DR, et al: Autoimmune cholangitis: A variant of primary biliary cirrhosis. Clinicopathologic and serologic correlations in 200 cases. Dig Dis Sci 40:1232-1242, 1995 14. Gouw ASH, Haagsma EB, Manns M, et al: Is there recurrence of primary biliary cirrhosis after liver transplantation? A clinicopathologic study in long-term survivors. J Hepatol20500-507,1994 15. Grambsch PM, Dickson ER, Wiesner RH, et al: Application of the Mayo primary biliary cirrhosis survival model to Mayo liver transplant patients. Mayo Clinic Proceedings M699-704, 1989 16. Haagsma EB, Manns M, Klein R, et al: Subtypes of antimitochondrial antibodies in primary biliary cirrhosis before and after orthotopic liver transplantation. Hepatology 7129-133, 1987 17. Harrison RF, Davies MH, Neuberger JM, et al: Fibrous and obliterative cholangitis in liver allografts: evidence of recurrent primary sclerosing cholangitis? Hepatology 20:356-361, 1994 18. Hartman GG, Gordon R, Lerut JA et al: Intrahepatic bile duct strictures in a liver allograft recipient mimicking recurrent primary sclerosing cholangitis. Transplant Int 4191-192, 1991 19. Hoso M, Nakanuma Y, Kwano M, et al: Granulomatous cholangitis in chronic hepatitis C: A new diagnostic problem in liver pathology. Pathology International 46301-305, 1996 20. Hubscher SG, Elias E, Buchels JA, et al: Primary biliary cirrhosis. Histological evidence of disease recurrence after liver transplantation. J Hepatol 18173-184, 1993 21. Kim WR, Poterucha JJ,Jorgensen RA, et al: Does antimitochondrial antibody status affect response to treatment in patients with primary biliary cirrhosis?: Outcomes of ursodeoxycholic acid therapy and liver transplantation. Hepatology 26:22-26, 1997 22. Lerut J, Demetris AJ, Stieber AC, et al: Intrahepatic bile duct strictures after human orthotopic liver transplantation. Recurrence of primary sclerosing cholangitis or unusual presentation of allograft rejection? Transplant Int 1:127-130, 1988 23. Ludwig J, Batts KP, MacCarty R L Ischemic cholangitis in hepatic allograft. Mayo Clin Proc 67519-526, 1992 24. Michieletti P, Wanless IR, Katz A, et al: Antimitochondrial antibody negative primary biliary cirrhosis: A distinct syndrome of autoimmune cholangitis. Gut 35:260-265, 1994 25. Mitchison HC, Bassendine MF, Malcolm AJ, et a1 A pilot, double-blind, controlled 1-

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year trial of prednisolone treatment in primary biliary cirrhosis: Hepatic improvement but greater bone loss. Hepatology 10:420429, 1989 26. Neuberger J, Portmann B, Macdougall BR, et al: Recurrence of primary biliary cirrhosis after liver transplantation. N Engl J Med 3061-4, 1982 27. Neuberger J, Wallace L, Joplin R, et al: Hepatic distribution of E2 component of pyruvate dehydrogenase complex after transplantation. Hepatology 22:798-801, 1995 28. Polson RJ, Portmann B, Neuberger J, et al: Evidence for disease recurrence after liver transplantation for primary biliary cirrhosis. Clinical and histologic follow-up studies. Gastroenterology 97715-725, 1989 29. Samuel D, Gugenheim J, Mentha G, et al: Liver transplantation for primary biliary cirrhosis. Transplant Proc 221497-1498, 1990 30. Sebagh M, Farges 0, Kalil A, et al: Sclerosing cholangitis following human orthotopic transplantation. Am J Surg Path 1981-90,1995 31. Sheng R, Zajko AB, Campbell WL, et al: Biliary strictures in hepatic transplants: prevalence and types in patients with primary sclerosing cholangitis vs those with other liver diseases. AJR Am J Roentgenol 161997-300, 1993 32. Sheng R, Campbell WL, Zajko AB, et al: Cholangiographic features of biliary strictures after liver transplantation for primary sclerosing cholangitis: Evidence of recurrent disease. AJR Am J Roentgenol 166(5):1109-1113, 1996 33. Taylor SL, Dean PJ, Rely C A Primary autoimmune cholangitis. An alternative to antimitochondrial antibody-negative primary biliary cirrhosis. Am J Surg Pathol18:9199, 1994 34. Terada T, Nakanuma Y Intrahepatic cholangiographic appearance simulating primary sclerosing cholangitis in several hepatobiliary disease: A postmortem cholangiographic and histopathological study in 154 livers at autopsy. Hepatology 2275-81, 1995 35. Van de Water J, Gerson LB, Ferrell LD, et al: Immunohistochemical evidence of disease recurrence following liver transplantation for primary biliary cirrhosis. Hepatology 24(5):1079-1084, 1996 36. Wiesner RH, Grambsch PM, Lindor KD, et al: Clinical and statistical analyses of new and evolving therapies for primary biliary cirrhosis (Review). Hepatology 8:668-676, 1988 37. Wiesner RH, Ludwig J, Lindor KD, et al: A controlled trial of cyclosporine in the treatment of primary biliary cirrhosis. N Engl J Med 322:1419-1424, 1990 38. Wong PY, Portmann B, OGrady JG, et al: Recurrence of primary biliary cirrhosis after liver transplantation following FK506-based immunosuppression. J Hepatol 17284287, 1993

Address reprint requests to Kenneth P. Batts, MD Division of Anatomic Pathology Mayo Clinic 200 First Street, SW Rochester, MN 55905