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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Liver Transpl. Author manuscript; available in PMC 2014 June 10.
Published in final edited form as:
PMCID: PMC4050662

Recurrent Primary Biliary Cirrhosis: Peritransplant Factors and Ursodeoxycholic Acid Treatment Post-Liver Transplant


Primary biliary cirrhosis (PBC) recurs after orthotopic liver transplantation (OLT) in up to one-third of patients. These patients are typically asymptomatic, can be identified by abnormal liver biochemistries, and have evidence of histologic recurrence on liver biopsy. The effect of treatment on recurrence has not been determined. This pilot study evaluates the factors associated with recurrent PBC and describes our experience using ursodeoxycholic acid treatment in this patient population. Forty-eight patients with PBC were followed for at least 1 yr post-OLT, and 27 patients (56%) developed abnormal serum alkaline phosphatase. Seventeen patients (35%) had evidence of recurrent PBC by liver biopsy. Patients with recurrent PBC had a trend toward longer warm ischemia times and more episodes of acute cellular rejection in the first year posttransplant, but this was not significant in multivariate analysis. Donor or recipient age, donor and recipient cytomegalovirus status, and dose of immunosuppression did not correlate with recurrence of PBC. Those patients diagnosed with recurrent PBC were placed on ursodeoxycholic acid, 15 mg/kg daily, with improvement in serum alkaline phosphatase in the majority. In conclusion, recurrent PBC is not infrequent post-OLT, and ursodeoxycholic acid can be used with some benefit post-OLT. Treatment effects on long-term survival are not known.

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease involving immune-mediated destruction of interlobular and septal bile ducts. The clinical presentation varies depending upon the stage of disease from asymptomatic disease to pruritus, fatigue, jaundice, and end-stage liver disease. The laboratory diagnosis includes elevated levels of serum alkaline phosphatase and immunoglobulin M (IgM), positive antimitochondrial antibodies (AMA), and a consistent liver biopsy. Ursodeoxycholic acid (UDCA) is the only Food and Drug Administration-approved treatment for PBC. UDCA is thought to decrease toxic hydrophobic bile acids, to stabilize cell membranes, and to have immunomodulatory properties.15 Though controversy exists regarding whether treatment improves survival free of transplant,612 there is evidence to show that UDCA improves symptoms, delays early histologic progression of disease, and may prevent cirrhosis.1317 Liver transplant remains the gold standard for treatment of end-stage liver disease, and long-term survival post-orthotopic liver transplant (OLT) is excellent.18,19 Recurrent PBC, as diagnosed by standard histologic characteristics, has been shown to occur in 17–30% of transplanted patients.18,2023 However the effect of UDCA treatment in patients with recurrent disease is unknown. The aim of this report is to describe our experience using UDCA to treat patients with recurrent PBC and to correlate peritransplant factors associated with disease recurrence.

Patients and Methods

All patients who were transplanted for PBC were identified from the 511 patients transplanted at Washington University between 1985 and 1997. Those patients transplanted for PBC were then followed prospectively from 1995 for development of abnormal serum alkaline phosphatase. As per standard posttransplant protocol, all patients had monthly liver biochemistries and were biopsied 1 yr post-liver transplant and whenever abnormal serum liver tests were noted. Patients were tested yearly for AMA and quantitative IgM. AMA was reported by serial dilution, and mean results are described as numerals for each dilution (1 = 1:20, 2 = 1:40, 3 = 1:80, etc). Peritransplant data were also collected on age, gender, cytomegalovirus status, and human leukocyte antigen (HLA) of donors and recipients; warm ischemic time of the transplant procedure; the type and amount of immunosuppression received; and the number of rejection episodes occurring posttransplant.

Cases of recurrent PBC were defined by a previously described histologic classification based on a portal tract mononuclear cell inflammatory infiltrate, lymphoid aggregates, epithelioid granulomata, and bile duct damage.20,24 Patients were classified as definite (three of four characteristics), probable (two of four), or nondiagnostic but consistent with recurrent PBC without evidence of acute rejection. These patients were then offered treatment with UDCA (15 mg/kg daily), and their liver tests were monitored every 3 months. The protocol for this study was approved by the Human Studies Committee at Washington University School of Medicine.

Statistical tests were two-sided t-tests with unequal variance for peritransplant characteristics. Dichotomous variables (HLA) were run with Fisher’s exact test because of the small sample size and sparse cells. Multicovariate analysis considered all peritransplant characteristics. Analyses were performed in SAS 8.2 (SAS Institute, Cary, NC). We did not adjust for multiple comparisons in this exploratory analysis.


Five hundred and eleven patients were transplanted between 1985 and 1997; 56 had a diagnosis of PBC. Six of these patients died within 90 days posttransplantation. Forty-eight patients were followed for at least 1 yr posttransplant (range 1–12 yr, mean 4.2). All 48 patients had elevated serum alkaline phosphatase pre-transplantation, with a mean of 592 ± 494 IU/L (normal <126 IU/L). Forty-five patients were female (94%), 46 were Caucasian (96%), and the mean age at transplant was 53.3 ± 14 yr (range 34–74).

Serum Alkaline Phosphatase

Post-liver transplantation, 27 patients (56%) had an elevated serum alkaline phosphatase. Ten patients did not meet criteria for recurrent PBC: four had transient elevations, three of which were due to biliary strictures; one had acute cellular rejection; one died of acute leukemia; one died of recurrent biliary disease 6 yr post-liver transplantation without a liver biopsy; one refused follow-up; and two did not have a liver biopsy because of patient or physician choice. The remaining 17 patients (35.4%) with abnormal serum alkaline phosphatase had a liver biopsy consistent with recurrent PBC and form the subject of this report. On liver biopsy, four had definite recurrent PBC (8% of total), 11 had probable recurrence (23%), and two were nondiagnostic but consistent with recurrent PBC (4%). In patients with recurrent PBC, the mean time to abnormal alkaline phosphatase was 40 ± 34 months. The mean of the highest serum alkaline phosphatase noted in those with recurrent PBC was 244 ± 93 IU/ml. Figure 1 shows mean serum alkaline phosphatase levels after liver transplantation in all PBC patients who underwent liver transplantation, those transplanted PBC patients whose serum alkaline phosphatase remained normal, and those diagnosed with recurrent PBC. All patients had normal serum albumin and bilirubin (data not shown).

Figure 1
Comparison of serum alkaline phosphatase (mean ± standard error) in all transplanted PBC patients (▲), those with recurrent PBC (■), and those PBC patients in whom SAP remained normal post-liver transplantation (●).

Peritransplant Characteristics

Peritransplant characteristics were evaluated to determine any factors associated with development of recurrent PBC. Table 1 compares all patients transplanted with a diagnosis of PBC, patients who developed recurrent PBC, and patients whose serum alkaline phosphatase remained normal post-liver transplantation. There were no differences in age of donor or recipient between the groups or in the prevalence of cytomegalovirus in the donor or recipient. The warm ischemia time was higher at 59.2 ± 19.0 min for those who developed recurrent PBC than for those in whom the alkaline phosphatase remained normal post-liver transplantation, 50.0 ± 8.7 min (P = 0.14).

Table 1
Peritransplant Characteristics Between All Transplanted Patients, Those With Recurrent PBC, and Those With Normal Serum Alkaline Phosphatase

AMA were elevated in 92% of patients pretransplant, and mean titers were not significantly different post-liver transplantation. Eighty-two percent of patients with recurrent PBC and 63% of those without recurrent PBC had documented persistence of AMA post-liver transplantation. While there was no difference between pre- and post-OLT titers, more patients with recurrent PBC had persistence of AMA post-OLT (94% compared to 64% of those with normal alkaline phosphatase, P < 0.04). Serum IgM was significantly elevated pretransplantation in all subjects and was not significantly different between those with normal alkaline phosphatase and those with recurrent PBC post-transplantation, although there was a tendency toward higher IgM post-OLT in those who developed recurrent PBC. In those patients with recurrent PBC, there was a higher percentage of donor DR3 and recipient DR4 than in those who maintained normal serum alkaline phosphatase (P < 0.055, Fisher’s exact test; Table 1). None of the recipients with recurrent PBC patients had DR3, but six recipients received DR3-positive donors. Four patients with recurrent PBC had donor DR3 and recipient DR4 mismatches, and no patient with normal alkaline phosphatase post-OLT had a donor DR3 and recipient DR4 mismatch.


The majority of patients transplanted for PBC received prednisone- (89%) and cyclosporine- (77%) based therapy. Of the eight patients who received tacrolimus, six developed recurrent PBC, with a median time to abnormal alkaline phosphatase of 4.5 yr. The remaining 11 patients with recurrent PBC received cyclosporine with a median time to abnormal alkaline phosphatase of 3 yr. During the first year post-liver transplantation, there was no difference between the groups in the mean prednisone or cyclosporine dose. However, those with recurrent PBC trended toward a higher number of rejection episodes during the first year post-OLT (P < 0.07). When multivariate analysis was performed on all peritransplant factors, only DR3 was significant at P = 0.046.

Treatment with UDCA

All patients were asymptomatic post-OLT except for two patients with mild pruritus. Those patients with recurrent PBC were offered therapy with UDCA, and one refused. Sixteen patients initiated treatment: one patient did not tolerate treatment due to worsening of pruritus, the second patient did not take his medication, and a third was noncompliant briefly after 6 months of treatment. Figure 2 depicts serum alkaline phosphatase in the 14 patients who took medication for more than 1 month, excluding the first two patients noted above. All patients were followed on therapy for a mean of 18 ± 11 months (range 3 months-3 yr). Overall, 75% of patients had improvement in serum alkaline phosphatase, with a mean decrease of 111 ± 157 IU/L. Of those patients who received UDCA for more than 1 month, 86% had improvement of their serum alkaline phosphatase. Of the 14 patients who received at least 1 month of therapy, biopsies were definitive in three, probable in nine, and consistent with recurrent PBC without evidence of rejection in two. Unfortunately, no patients had a repeat liver biopsy. There were two patients who did not have a response to UDCA with lowering of serum alkaline phosphatase: both had “definitive” recurrent PBC on biopsy and were diagnosed 5 yr after OLT. One other patient who had “probable” recurrent PBC, which was diagnosed 4 yr post-OLT, took UDCA inconsistently during the first 6 months but responded when she restarted UDCA.

Figure 2
Individual serum alkaline phosphatase after initiation of treatment with UDCA. Individual patients are marked with different lines. One patient (■) was noncompliant with her medication briefly after 3 months of therapy but resumed UDCA at 6 months. ...


UDCA is a safe, well-tolerated drug that has been shown to improve quality of life and symptoms of fatigue and pruritus in patients with PBC.25,26 However, there are no randomized controlled studies that address the efficacy of UDCA in recurrence of PBC post-liver transplantation. This pilot study describes our experience treating patients with elevated serum alkaline phosphatase and compatible liver biopsies for recurrent PBC with UDCA. Given that patients with early histologic disease in the native organ are the most likely to benefit from treatment by delaying disease progression and since early-stage fibrosis can occur within 2–6 yr of diagnosis,13,1517,27 we sought to identify and treat patients early in the course of recurrent disease. Our data illustrate that the majority of patients had improvement in serum alkaline phosphatase with UDCA therapy and that treatment was well tolerated. However, without follow-up biopsies, histologic benefit is unknown.

Serum alkaline phosphatase levels were used to identify potential patients at risk for disease recurrence because obtaining routine liver biopsies becomes increasingly difficult as length of follow-up increases, due to both patient preferences and logistics. We recognize that we may have underestimated the proportion of our cohort who had recurrence as some of our patients with abnormal serum alkaline phosphatase were not evaluated nor were patients with normal serum alkaline phosphatase biopsied except at the first year after liver transplantation. Although an abnormal serum alkaline phosphatase is required for the diagnosis of PBC in the nontransplant patient, recent data from the Mayo Clinic suggest one-half to one-third of patients with recurrence will have normal chemistries.23 Other potential serologic markers like serum bilirubin and albumin, which may have superior correlation to outcomes like histologic state or disease prognosis,17,28 become elevated at later stages of disease, therefore limiting their effectiveness in early patient identification. AMA have been shown to be an early finding in patients who subsequently develop disease; however, the AMA titer has not been shown to reflect disease progression.29 In our study, more recurrent PBC patients had persistence of AMA post-OLT, although the titers were not higher, in keeping with other studies.

The second focus of our study was to evaluate factors that could be related to disease recurrence. While exploratory studies may find peritransplant characteristics associated with recurrent PBC, these characteristics may not be significant in more rigorous testing. However, pilot studies can be used to identify possible factors of importance for further study. Population-based and familial studies of PBC suggest a genetic susceptibility; however, the only major histocompatibility class II allele with consistent association in PBC is the HLA DR8 allele.3037 HLA DR3 is associated with many other autoimmune diseases; however, its role in PBC is less well established, although the extended haplotype B8, DR3, DQA1*0501, and DQB1*0201 has been associated.31,35 Most studies suggest that PBC is genetically heterogeneous. Our data showed an increased mismatch of donor DR3 and recipient DR4 in patients with recurrent PBC. Whether this mismatch led to higher alloantigen reactivity is not known and should be evaluated in larger studies.

Controversy exists over whether the type of immunosuppression used affects the rate of disease recurrence after transplant.22,3840 Although only a limited number of patients in our study were receiving tacrolimus, the majority did develop recurrent disease, with an odds ratio of 2.5, which is in agreement with an odds ratio of 2.73 from recent data by Neuberger et al.38 The patients with recurrent PBC in the study had an increased number of rejection episodes despite equal dosing of prednisone and cyclosporine. Rejection has not been associated with an increased incidence of recurrent disease in PBC; however, acute rejection appears to correlate with recurrence in patients transplanted with hepatitis C virus.41,42 Whether this increase in rejection was associated with DR3-DR4 mismatch is not known. There is no evidence that these class II antigens have a higher incidence of rejection.

In summary, we found recurrent PBC in 35% of patients. These subjects did respond to UDCA during short-term follow-up. The benefit of long-term UDCA treatment is unknown. Careful monitoring of abnormal liver function tests and biopsy to evaluate for recurrent disease are warranted in subjects transplanted for PBC.


The authors thank Janet Andersen, ScD, at Harvard School of Pubic Health for expert statistical assistance.


primary biliary cirrhosis
immunoglobulin M
antimitochondrial antibodies
ursodeoxycholic acid
orthotopic liver transplantation
human leukocyte antigen


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