INTRODUCTION — Liver transplantation can be successful in treating end-stage liver disease from primary biliary cholangitis (PBC; previously referred to as primary biliary cirrhosis). The total number of transplants performed for PBC has been declining slightly, possibly reflecting benefits of early treatment . Nevertheless, transplantation remains an important option in patients with progressive disease despite medical therapy. In the United States, the average age of patients undergoing transplantation for PBC is in the range of 53 to 55 years .
This topic will review issues related to patient selection for liver transplantation, the timing of transplantation, and transplantation outcomes in patients with PBC. Other issues related to the pathogenesis, clinical manifestations, diagnosis, and treatment of PBC are discussed elsewhere. (See "Clinical manifestations, diagnosis, and prognosis of primary biliary cholangitis" and "Overview of the management of primary biliary cholangitis" and "Pathogenesis of primary biliary cholangitis (primary biliary cirrhosis)".)
OPTIMAL TIME FOR TRANSPLANTATION — An important issue is to determine the optimal time to perform a liver transplantation. Many groups have developed models that use clinical variables to estimate patient survival. Three types of models have been developed: one based upon initial data on entry into the study; one that uses both initial and follow-up data; and one that is based on response to treatment. The Mayo model (table 1), which uses data from the initial evaluation, is most widely used, but because of individual patient variation, it does not replace the input of an experienced clinician [2,3]. The Mayo model can predict short- and long-term survival using current laboratory and clinical data. This tool can be used to anticipate liver failure, allowing the clinician to refer the patient for transplantation in a timely manner. Although these models are specific to survival in PBC, the MELD score is used to prioritize patients for transplantation and is often used to determine when to refer patients for transplant evaluation. (See "Model for End-stage Liver Disease (MELD)".)
In addition to considering the MELD score and Mayo model, we suggest that patients with PBC be referred for transplantation evaluation if one or more of the following is present:
●The plasma bilirubin concentration is greater than 5 mg/dL (85.5 micromol/L) and is increasing
●The serum albumin concentration is below 2.8 g/dL (28 g/L) and is decreasing
●Signs of decompensation or portal hypertension develop, such as ascites, variceal bleeding, coagulopathy malnutrition, or encephalopathy
●The patient has intractable pruritus
●The patient has recurrent, debilitating, nontraumatic bone fractures
Models based upon initial data — Some prognostic models are based on clinical features including physical examination findings, laboratory data, and liver biopsy because these characteristics have predictive value [2,4-7]. Additional factors that have been found to correlate with prognosis are age, plasma bilirubin and albumin concentrations, hepatomegaly, and the presence of cholestasis, portal fibrosis, or cirrhosis on biopsy [4,5].
A model developed at the Mayo Clinic does not require liver biopsy [2,6]. Survival could be predicted from the patient's age, plasma bilirubin and albumin concentrations, the prothrombin time, and the presence of edema (table 1).
These models are all based upon data obtained at a fixed time point and do not consider more dynamic data such as changes over time or the response to therapy. Models that incorporate these elements would likely more accurately reflect disease progression in individual patients.
Models based upon initial and follow-up data — Two time-dependent predictive models have been developed that use readily available markers and follow-up data to predict survival . These models therefore permit a change in the patient's condition to provide an updated prognosis. One uses the plasma albumin and bilirubin concentrations, the presence of ascites, a history of gastrointestinal bleeding, and age as important variables. The second uses the same variables and adds plasma immunoglobulin measurements and the presence of cirrhosis and central cholestasis on biopsy.
Both models were validated and were more accurate than the time-fixed models in predicting survival, particularly in the short term. They suggest that liver transplantation be undertaken when the estimated six-month survival is less than 80 percent. Six months is used as the cut-off since this is the time when survival after transplantation becomes better than survival without transplantation (assuming that an organ is available for transplantation within six months) (figure 1) .
Models based on treatment response — Prognostic models that incorporate data from patients on ursodeoxycholic acid (UDCA) have been developed and may be used to identify high risk patients who may benefit from closer monitoring or second line therapies [9,10]. For example, a risk score to predict transplant-free survival uses clinical and biochemical variables obtained after one year of UDCA therapy . Another model, the UK-Primary biliary cholangitis risk score for predicting end stage liver disease, contains both baseline variables (ie, albumin and platelet count) and variables after 12 months of UDCA therapy (ie, bilirubin, transaminases and alkaline phosphatase) .
OUTCOME AFTER LIVER TRANSPLANTATION — Excellent short- and long-term survival rates have been described following transplantation for PBC, and one-year survival rates of 90 to 95 percent are common at many medical centers [11,12]. In a multicenter study including 785 patients, survival rates at 5-, 10-, and 20-years were 90, 81, and 53 percent, respectively .
These results are significantly better than the predicted survival in nontransplanted patients derived from the models described above. A survival benefit has been demonstrated as early as three months after transplantation. As an example, one study monitored 161 patients with PBC after liver transplantation and compared the results to a simulated group of patients with the same diagnosis who were managed without transplantation . The three-month survival in this group was significantly higher than the predicted values in nontransplanted patients. The two-year survival was also higher with transplantation (74 versus 31 percent), a benefit that was seen in patients from all pretransplant risk groups (figure 1).
Although all patients with PBC benefit from liver transplantation, those who are chronically ill and malnourished prior to surgery do not do as well as those with less severe disease . The Mayo model (table 1) can help to identify high-risk patients. Unfortunately, the shortage of donor organs often limits transplantation to patients with advanced disease (and thus higher MELD scores), except for those with a suitable living donor. (See 'Models based upon initial data' above and "Model for End-stage Liver Disease (MELD)" and "Living donor liver transplantation in adults".)
As with transplantation for other liver diseases, a very small proportion of patients with PBC require a second transplantation, less than 2 percent in our experience. While recurrent PBC is not uncommon, in one series of patients with recurrent PBC following liver transplantation, only 5 percent lost their grafts . Most second transplants occur within the first month due to problems such as primary liver nonfunction, hepatic artery thrombosis, chronic rejection, acute rejection, and portal vein thrombosis, problems common to liver transplantation in general. This is an important issue because of the shortage in donor organs. (See 'Rate of recurrence' below.)
Effect of transplantation on symptoms — Resolution of symptoms related to PBC occurs at variable rates. Pruritus and complications of end-stage liver disease, such as encephalopathy, variceal bleeding, and hepatorenal syndrome are usually promptly reversed after transplantation. (See "Pruritus associated with cholestasis".)
Jaundice and ascites resolve somewhat more slowly, over a period of days to a few months. Splenomegaly usually persists, although the enlarged spleen may decrease slightly in size. Skin xanthomas also resolve within a few weeks. (See "Hypercholesterolemia in primary biliary cholangitis (primary biliary cirrhosis)".)
By contrast, it may take 12 to 18 months before improvement is seen in hepatic osteodystrophy, despite vitamin D and calcium supplementation. As a result, bone disease is a possible source of long-term morbidity (due to vertebral compression fractures, pain, opioid dependence, and immobility) despite successful liver transplantation. (See "Evaluation and treatment of low bone mass in primary biliary cholangitis (primary biliary cirrhosis)".)
Fatigue may improve in some patients following liver transplantation. In a study that analyzed 31 patients who received a liver transplantation for PBC, 89 percent of patients had moderate or severe fatigue prior to transplantation. Two years following transplantation, 44 percent reported moderate or severe fatigue . By contrast, in a study of 351 women and 29 men who underwent liver transplantation and equal numbers of matched controls, fatigue did not improve following transplantation in women and was worse following transplantation in men .
Recurrence of PBC in the transplanted liver — It is now generally accepted that PBC can recur following liver transplantation, although there was much initial debate [16-22].
Rate of recurrence — A precise estimate of the recurrence rate is uncertain since not all studies have used uniform criteria for defining recurrent PBC, and studies have had variable follow-up [11,16,23,24]. Two of the largest series with the longest follow-up (in which the diagnosis of recurrent PBC was based upon histologic features) probably represent the best available estimates [11,25]. In a multicenter cohort study of 571 patients who had liver transplantation for PBC and underwent at least one follow-up liver biopsy, the rates of PBC recurrence at 5 and 10 years were 18 and 31 percent, respectively . In another multicenter study including 785 patients, the rate of PBC recurrence at 5 and 10 years was 22 and 36 percent, respectively .
Impact on outcomes — Data have suggested that recurrence has been associated with a negative impact on graft and patient survival [11,22,26]. In a cohort study of 571 patients who had liver transplantation for PBC and had at least one follow-up liver biopsy, recurrence was associated with higher risk of graft loss (hazard ratio [HR] 1.96, 95% CI 1.45-2.65) and patient mortality (HR 1.93, 95% CI 1.42-2.63) compared with no recurrence .
Risk factors — The following factors are associated with increased risk for PBC recurrence after liver transplantation:
●Younger age at diagnosis or at transplantation – Younger age at diagnosis or at liver transplantation increases the risk of recurrence [11,27]. In a study of 785 patients with PBC, patients who were ≤50 years old at PBC diagnosis or were ≤60 years old at liver transplantation were more likely to have recurrence after transplantation (HR 1.79, 95% CI 1.36-2.36 and HR 1.39, 95% CI 1.02-1.90, respectively) .
●Elevation in alkaline phosphatase – Elevated alkaline phosphatase levels (beyond the upper limit of normal) at six and 12 months after liver transplantation have been associated with increased risk of recurrence .
Prevention — Strategies to prevent PBC recurrence include using ursodeoxycholic acid (UDCA) following liver transplantation and an immunosuppressive regimen containing cyclosporine (rather than tacrolimus) [24-26]. For most patients, we typically start UDCA (10 to 15 mg/kg/day in two divided doses) within two weeks following transplantation.
Data on the use of UDCA for preventing recurrence have been limited to observational studies but have suggested that UDCA was associated with better outcomes. In a cohort study including 780 patients who underwent liver transplantation for PBC and were followed for a median of 11 years, use of UDCA was associated with lower risk of histologic recurrence (adjusted HR [aHR] 0.41, 95% CI 0.28-0.61) and graft loss (aHR 0.33, 95% CI 0.13-0.82) compared with no UDCA . In addition, UDCA was associated with lower risk of liver-related death (aHR 0.46, 95% CI 0.22-98) and all-cause mortality (aHR 0.69, 95% 0.49-0.96). In a smaller retrospective series of 90 patients who underwent liver transplantation for PBC, 19 patients (21 percent) received preventive UDCA (10 to 15 mg/kg/day) . The use of UDCA was associated with a decreased risk of histologic recurrence (adjusted HR 0.32, 95% CI 0.11-0.91). The rates of recurrence for those who received UDCA were 11, 21, and 40 percent at 5, 10, and 15 years, respectively, whereas the recurrence rates for those who did not receive UDCA were 32, 53, and 70 percent, respectively.
The use of cyclosporine may have a protective effect, although the data are mixed [11,25,26,28]. Preliminary data have suggested that combining an immunosuppressive regimen containing cyclosporine with preventive UDCA has been associated with a complementary protective effect. In a cohort study including 780 patients who underwent liver transplantation for PBC and were followed for a median of 11 years, UDCA combined with cyclosporine was associated with lower risk of histologic recurrence compared with use of either agent alone (aHR 0.47, 95% CI 0.34-0.66) .
Diagnosis — The diagnosis of recurrent PBC must be based upon histologic rather than serologic or biochemical findings. The following criteria have been proposed [29,30]:
●Transplantation for PBC, and
●Persistence of antimitochondrial antibodies, and
●Liver histology showing the characteristic portal tract lesions (mononuclear inflammatory infiltrate, formation of lymphoid aggregates, epithelioid granulomas, bile duct damage). Definite recurrent PBC is present when three of the four portal tract lesions are present, whereas probable recurrence is diagnosed when two are present.
A cholestatic pattern of liver biochemical abnormalities is neither sensitive nor specific for recurrence. Cholestasis can arise from multiple causes in the transplant setting and not all patients with well documented histologic recurrence have cholestasis .
Similarly, the presence of antimitochondrial antibodies does not establish that recurrence is present or will develop. Antimitochondrial antibodies persist in most patients following transplantation, usually with a small and transient fall in their titer [32,33].
Treatment — There are limited data to guide treatment of recurrent disease, although treatment with UDCA is reasonable. UDCA appears to improve biochemical tests , but its effect on the natural history of recurrent PBC is uncertain. UDCA was not associated with improved patient and graft survival compared with untreated patients in a retrospective study involving 52 patients with recurrent PBC .
Recurrent disease in patients with PBC following liver transplantation is not an indication for treatment with obeticholic acid. (See "Overview of the management of primary biliary cholangitis", section on 'Subsequent therapy'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Primary biliary cholangitis" and "Society guideline links: Liver transplantation".)
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SUMMARY AND RECOMMENDATIONS
●Optimal time for liver transplantation – Liver transplantation in primary biliary cholangitis (PBC) is prioritized using the Model for End-stage Liver Disease (MELD) score. (See "Model for End-stage Liver Disease (MELD)".)
In addition to considering the MELD score, we suggest that patients with PBC be referred for liver transplantation evaluation if one or more of the following is present (see 'Optimal time for transplantation' above):
•The plasma bilirubin concentration is greater than 5 mg/dL (85.5 micromol/L) and is increasing
•The serum albumin concentration is below 2.8 g/dL (28 g/L) and is decreasing
•Signs of decompensation or portal hypertension develop, such as ascites, variceal bleeding, coagulopathy, malnutrition, or encephalopathy
•The patient has intractable pruritus
•The patient has recurrent, debilitating, nontraumatic bone fractures
●Outcomes – Excellent short- and long-term survival have been described following liver transplantation for PBC, and one-year survival rates of 90 to 95 percent are common at many medical centers. (See 'Outcome after liver transplantation' above.)
Resolution of symptoms related to PBC occurs at variable rates following liver transplantation. (See 'Effect of transplantation on symptoms' above.)
●Disease recurrence after liver transplantation – Recurrent PBC after liver transplantation has been described in up to 36 percent of patients after 10 years of follow-up. Data have suggested that recurrence of disease was associated with a negative impact on graft and patient survival. (See 'Recurrence of PBC in the transplanted liver' above.)
For most patients who undergo liver transplantation for PBC, we suggest therapy with ursodeoxycholic acid (UDCA) to prevent histologic recurrence rather than no pharmacologic intervention (Grade 2B). We typically use UDCA, 10 to 15 mg/kg/day, in two divided doses.
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