LIVER TRANSPLANTATION: CURRENT MANAGEMENT 0039-6109/99 $8.00 + .OO AUTOIMMUNE LIVER DISEASES Recurrence After Liver Transplantation Vijayan Balan, ...

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AUTOIMMUNE LIVER DISEASES Recurrence After Liver Transplantation Vijayan Balan, MD, Kareem Abu-Elmagd, MD, PhD, and Anthony J. Demetris, MD

Orthotopic liver transplantation (OLTx) is now an effective therapeutic option for end-stage liver disease secondary to autoimmune liver diseases. The recurrence of the primary disorder in the grafted liver is a major concern. As the authors’ experience with OLTx increases and with long-term follow-up of these patients, recurrence of disease in the grafted liver is increasingly being recognized. Primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH) have all been reported to recur. RECURRENT PRIMARY BlLlARY CIRRHOSIS

The diagnosis of PBC in the pretransplant setting is based on clinical presentation, hepatic chemistries, and liver histology. In the initial stages, symptoms are nonspecific, and with disease progression, symptoms of chronic cholestasis, complications of portal hypertension, and decompensated liver disease develop. The hepatic chemistries reveal a cholestatic pattern with elevations in serum alkaline phosphatase and bilirubin. Hypergammaglobulinemia (IgM) and presence of antimitochondrial antibodies are characteristic of PBC. On liver histology, the diagnostic finding is the florid duct lesion or granulomatous bile duct destruction. After liver transplantation, the diagnosis of recurrent PBC in the

From the Thomas E. Starzl Transplantation Institute (KA-E, AJD) and the University of Pittsburgh School of Medicine (VB, KA-E, AJD), Pittsburgh, Pennsylvania




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liver allograft is difficult because many of the clinical features may be a result of other causes. For instance, pruritus caused by cholestasis may be secondary to medical or mechanical biliary complications. Cholestatic hepatic chemistries are often present after liver transplantation and may be related to bile duct abnormalities; medications, including cyclosporin and tacrolimus (FK506); sepsis; or rejection. Immunosuppressive agents may modify patterns of possible disease recurrence. Furthermore, immunosuppressive medications currently used following liver transplantation (i.e., azathioprine, corticosteroids, cyclosporine, and tacrolimus) have all been used in prospective trials in PBC patients and have shown to have an effect on PBC. Persistence of the immunologic abnormalities, such as elevated IgM, positive antimitochondrial antibody (AMA), and continuance or development of extrahepatic manifestations of PBC do not prove disease recurrence. Therefore, the diagnosis of recurrent disease depends mainly on histology. Histologic interpretation in the allograft can be difficult as immune processes in the graft can target bile ducts. For example, rejection, cytomegalovirus infection and hepatitis C are associated with bile duct damage; however, the use of strict histologic criteria, such as the demonstration of the florid duct lesions with bile duct damage and the presence of portal granulomas in the transplanted liver, is helpful in the diagnosis of recurrent PBC. In 1982, Neuberger and first reported the development of a syndrome suggestive of recurrent PBC after liver transplantation in three patients; their experience was later updated by Polson and colleague~ in~1989. ~ They reported on the features compatible with disease recurrence to be present in 9 of 10 patients with biopsies more than 1 year after liver transplantation. The diagnosis of recurrence was based on clinical and immunologic changes with histologic features suggestive disease recurrence. Histologic evidence of recurrent PBC included bile duct damage with lymphocytic infiltrate around irregular, enlarged portal tracts, development of septum formation, ductular proliferation, and the deposition of copper-associated protein in a periseptal distribution; however, these histologic findings are not diagnostic of PBC. In a study from the Mayo Clinic,' 60 consecutive patients with PBC with at least 1 year of follow-up after liver transplantation were studied. The immunosuppression regimen was either cyclosporine, prednisolone, and azathioprine or with FK506 and prednisolone. Hepatic biochemical parameters and protocol liver biopsy specimens were evaluated 1 week, 3 weeks, 4 months, and yearly after liver transplantation and with hepatic dysfunction. AMA and IgM levels were determined before liver transplantation, at 4 months, and yearly. Of the 72 patients grafted for PBC, 60 had survived for more than'l year. The mean follow-up was 3.3 years. At the time of the study, 55 of 60 (91%) patients had normal hepatic chemistries, including serum levels of alkaline phosphatase, bilirubin, alanine aminotransferase (ALT), and IgM. In addition, all patients had significant decreases in AMA titers and IgM levels at time of last followup. On histologic examination, 41 of 60 patients had a near-normal liver



histology. Of those with abnormal histology, five patients, 2 to 6 years after liver transplantation, had histologic features typical of a florid duct lesion, suggesting recurrent PBC. All five with the presence of portal granulomas were asymptomatic with normal hepatic chemistries. Two of five patients had persistent AMA. The human leukocyte antigen (HLA) status of the five patients with recurrent PBC showed that all five had at least a single match, three at class 1 loci (A1 A2 Bw38), one at class 2 (DR4),and one at both class 1 and class 2 loci (B51 DQWl). Subsequently, several other studies have also reported on recurrent PBC.4,12, 23, 27 In 1993, Hubscher and colleagues’* reported histologic features suggestive of recurrent disease in 13 PBC patients between 12 and 100 months after liver transplantation. The main diagnostic features were mononuclear cell portal inflammatory infiltrate, portal lymphoid aggregates, portal epithelioid granulomas and bile duct damage, ductopenia, ductular proliferation, portal fibrosis, and copper-associated protein deposition. Dietze4 also reported PBC recurrence in two of eight patients. The diagnosis of recurrence was based on histologic features of PBC in the allograft. Several other studies have failed to find evidence for recurrent PBC3,5-9, 25 Many of these studies failing to identify recurrence have relatively few PBC patients with long-term histologic follow-up. At present, recurrent PBC is not associated with significant clinical symptoms, and these patients at least in the short- to medium-term seem to have a good quality of life. Longer-term studies will help in defining the clinical relavence of PBC recurrence in the allograft. RECURRENT PRIMARY SCLEROSING CHOLANGITIS

The issue of recurrent PSC after liver transplantation is more complex than that of recurrent PBC because of a lack of a diagnostic gold standard in PSC. The diagnosis of PSC in the native liver is made by a combination of the following: imaging the biliary tree, clinical presentation, hepatic chemistries, and hepatic histology. As with PBC, the clinical presentation initially includes nonspecific symptoms and later signs of hepatic decompensation. PSC can occur alone; however, 70% of cases are associated with inflammatory bowel disease. A cholestatic pattern is typical of the hepatic chemistries. Autoantibodies in PSC are nonspecific and infrequent. Anticolon, antineutrophil nuclear, and antineutrophil cytoplasmic antibodies have been described in PSC; however, their association is variable and is not specific for PSC. The radiologic features are characteristic and exhibit diffuse strictures, beading, and dilatation of the intra- or extrahepatic bile ducts. Similar radiologic findings can also be seen in secondary sclerosing cholangitis as a result of sepsis, stones, or rejection and during the course of AIDS. The diagnostic histologic abnormality of PSC is the fibrous obliterative cholangitis that results in the replacement of bile ducts by fibrous scars with the appearance of concentric rings of fibrosis around bile


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ducts. There have been some reports suggesting similar features in secondary sclerosing cholangitis as well. After liver transplantation, imaging of the extrahepatic biliary tree is difficult because transplanted PSC patients have a Roux loop with removal of the recipient bile duct. These patients have increased incidence of biliary problems, such as anastomotic and nonanastomotic strictures, which can radiologically and histologically be consistent with PSC in the intrahepatic biliary tree. There are several reports of more frequent biliary complications in transplanted PSC patients than in patients transplanted for other indications.18,l9 These findings may be related to complications of the Roux-en-Y loop and are difficult to attribute to recurrent PSC. from the authors’ institution In 1991, Iwatsuki and colleag~es’~ initially found only 1 of 40 patients transplanted for PSC who had biochemical and radiologic features of recurrent PSC 1 year after liver transplantation. A more recent review of this subject from the authors’ institution by Sheng and colleagues1ohas found that radiologic findings resembling PSC occur more frequently in transplanted PSC patients than in patients receiving transplant for other diseases. A study group of 32 PSC grafts with biliary strictures was compared with a control group of 32 non-PSC grafts with strictures. Both groups were matched for the type of biliary anastomosis and for the time interval between transplantation and stricture diagnosis. The location, number, length of strictures, and ductal dilations were similar in the PSC and non-PSC groups; however, mural irregularities of bile ducts were present in 15 of 32 (47%) transplanted PSC patients versus 4 of 32 (13%) in the controls. Diverticulum-like outpouchings were seen in 6 of 32 (19%)transplanted PSC patients versus 1 of 32 (3%) controls. An overall resemblance to PSC was seen in 8 of 32 (25%) transplanted PSC patients versus 2 of 32 (6%) controls. These findings are highly suggestive of recurrent PSC. As for the histologic findings of recurrent PSC, Harrison and Hubscher suggested that the fibro-obliterative lesions (the ”onion skin” fibrosis) and the periductal lesions do occur in greater frequency in patients grafted for PSC than in those grafted for other conditions. In a review” of histologic material from a series of 22 transplanted PSC patients, 32% had biopsies showing features of biliary obstruction, 27% had periductal fibrosis, and 14% had the classic fibro-obliterativelesions. Of a control group of 22 patients transplanted for other diseases besides PSC but who had a Roux loop, 10% had features of biliary obstruction, 5% had periductal fibrosis, and no fibro-obliterative lesions were noted. Thus, the histologic features of PSC are more common in those with Roux loops, and the possibility of recurrent PSC in the allograft remains uncertain. Whether PSC recurs after liver transplantation remains inconclusive because of a considerable dilemma in making the diagnosis. In any case, if the PSC does recur, it seems to stay in an early stage so far. As with PBC, longer and careful follow-up is required to determine the issue of recurrent PSC.




Autoimmune hepatitis (AIH) is a diagnosis of exclusion and is made on the basis of hepatic chemistries, autoantibodies, and histology. Hepatic chemistries reveal elevations of serum aminotransferases. Several autoantibodies have been described in the various types of AIH and include antinuclear antibody, liver or kidney microsomal antibody class 1, and antiactin (smooth muscle). Liver histology shows features of a chronic hepatitis with a portal cell infiltrate consisting of plasma cells, piecemeal necrosis, and bridging. AIH promptly responds to corticosteroids. After liver transplantation, the diagnosis of recurrent AIH from acute rejection can be made easily by detecting elevated IgG levels and autoantibodies, characteristic of recurrent AIH. The first report of recurrence of autoimmune hepatitis was by Neuberger and colleagues22 in a female patient who developed clinical, biochemical, immunologic, and histologic features of recurrent AIH when corticosteroids were discontinued. Reintroduction of steroids resolved the abnormalities. Of interest, the recipient was HLA 88 DR3, whereas the donor was negative for both of these HLA antigens. In subsequent studies2Rfrom the authors’ institution based on a retrospective analysis of 43 transplanted AIH patients, 11 cases of recurrent AIH were reported. The diagnosis was made on the basis of histology. The recurrence was reported at a median of 18 months following transplantation, and all but one of the patients were female. Nine of the 11 patients were DR3 positive, and as with the initial patient, the graft was DR3 negative. Recurrence was not observed in those who had DR3-positive grafts. AIH can recur after liver transplantation and is readily controlled by increasing the dose of steroids. SUMMARY

PBC and AIH recur after OLTx. The recurrence of PSC is less clear. Recurrence of these diseases seems to be of relatively little importance in the short term; however, longer follow-up is required to address the significance of recurrent disease. Immunosuppression in these patients may alter the natural history of these entities in the post-transplant setting. References 1. Balan V, Batts K, Porayko M, et al: Histological evidence for recurrence of primary biliary cirrhosis after liver transplantation. Hepatology 18:1392-1398, 1993 2. Buist L, Hubscher SG, Vickers C, et al: Does liver transplantation cure primary biliary cirrhosis? Transplant Proc 212402, 1989 3. Demetris AJ, Markus BH, Esquivel C, et al: Pathologic analysis of liver transplantation for primary biliary cirrhosis. Hepatology 8:937-947, 1988 4. Dietze 0, Vogel W, Margreiter R: Primary biliary cirrhosis after liver transplantation. Transplant Proc 22:1501-1502, 1990 5. Esquivel C, Van Thiel D, Demetris A, et al: Transplantation for primary biliary cirrhosis. Gastroenterology 94:1207-1216, 1988 6. Fennel1 RH, Shikes R, Vierling J: Relationship of pretransplant hepatobiliary disease to bile duct damage occurring in the liver allograft. Hepatology 3534-89, 1983


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7. Gouw A, Haamna E, Manns M, et al: Is there recurrence of primarv biliarv cirrhosis after liver tranusplantation?J Hepatol 20:500-507, 1994 8. Haagsma EB, Manns M, Klein R, et al: Subtypes of antimitochondrial antibodies in primary biliary cirrhosis before and after liver transplantation. Hepatology 7129-133,1987 9. Hart J, Busuttil RW, Lewin KJ: Disease recurrence following liver transplantation. Am J Surg Pathol 14:79-91, 1990 10. Sheng R, Campbell WL, Zajko AB, et al: Cholangiographic features of biliary strictures after liver transplantation for primary sclerosing cholangitis: Evidence of recurrent disease. American Journal of Roentgenology 166:1109-1113, 1996 11. Harrison RF, Davis MH, NeuberEer JM, et al: Fibrous and obliterative cholangitis in liver allografts: Evidence of recurrent primary sclerosing cholangitis. Hepatoggy 201356-361. 1994 12. Hubscher S , Elias E, Buckels et al: Primary biliary cirrhosis: Histological evidence of disease recurrence after liver transplantation. J Hepatol 18:173-184, 1993 13. Iwatsuki S, Starzl T, Van Thiel D, et al: Liver transplantation for primary sclerosing cholangitis. Gastroenterology 90:1736, 1991 14. Joplin R, Lindsay JG, Johnson GD, et a1 Membrane dehydrolipoamide acetyl transferase (E2) on human biliary epithelial cells in PBC. Lancet 339:93-94, 1992 15. Kaplan MM: New strategies needed for treatment of PBC? Gastroenterology 104:651653, 1993 16. Klein R, Huizenga JR, Gips C, et a1 Antimitochondrial antibody profiles in patients with primary biliary cirrhosis before orthotopic liver transplantation and titers of antimitochondrial antibody subtypes after liver transplantation. J Hepatol 20:787-789, 1994 17. Lerut J, Zimmermann A, Gertsch P, et al: Chronic rejection and extrahepatic biliary obstruction 8 years after orthotopic liver transplantation with gallbladder conduit. HPB Surg 5:17-22, 1991 18. Letourneau JG, Day JL, Hunter DW, et al: Biliary complications after liver transplantation in patients with pre-existing sclerosing cholangitis. Radiology 167349-351, 1988 19. McEntee G, Wiesner R, Rosen C, et al: Comparative study of patients undergoing liver transplantation for primary sclerosing cholangitis and primary biliary cirrhosis. Transplant Proc 23:1563-1564, 1991 20. Mitchison HC, Bassendine MR, Hendrick A, et al: Positive antimitochondrial antibody but normal alkaline phosphatase: Is this primary biliary cirrhosis? Hepatology 6:12791284, 1986 21. Neuberger J, Portmann B, MacDougall B, et al: Recurrence of primary biliary cirrhosis after liver transplantation. N Engl J Med 306:14, 1982 22. Neuberger J, Portmann B, Calne R, et al: Recurrence of autoimmune chronic active hepatitis following orthotopic liver transplantation. Transplantation 37:363-365, 1984 23. Nsien EE, Silverman JF, Goodman 2: A 51-year-old woman with elevated liver enzymes seven months after liver transplantation for primary biliary cirrhosis. Semin Liver Dis 12:93-100, 1992 24. Polson R, Portmann B, Neuberger J, et al: Evidence for disease recurrence after liver transplantation for primary biliary cirrhosis. Gastroenterology 97715-725, 1989 25. Samuel D, Gugenheim J, Mehta G, et al: Liver transplantation for primary biliary cirrhosis. Transplant Proc 22:497498, 1990 26. Van Thiel DH, Gavaler J: Recurrent disease in patients with liver transplantation: When does it occur and how can we be sure? Hepatology 7:181-183, 1987 27. Wong PYN, Portmann B, OGrady J, et al: Recurrence of primary biliary cirrhosis after liver transplantation following FK506-based immunosuppression. J Hepatol 17284287, 1993 28. Wright HL, Bou-Abboud C, Hassanein T, et al: Disease recurrence following liver transplantation for autoimmune chronic active liver disease. Transplantation 53:136139, 1992 Address reprint requests to Vijayan Balan, MD University of Pittsburgh Medical Center 200 Lothrop Street Mezzanine C-Wing Pittsburgh, PA 15213