Liver transplantation in primary biliary cholangitis (primary biliary cirrhosis) - UpToDate

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Liver transplantation in primary biliary cholangitis (primary biliary cirrhosis) - UpToDate

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Liver transplantation in primary biliary cholangitis (primary biliary cirrhosis) Authors: Steven Flamm, MD, Fredric D Gordon, MD, Raoul Poupon, MD Section Editor: Robert S Brown, Jr, MD, MPH Deputy Editor: Kristen M Robson, MD, MBA, FACG All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Aug 2019. | This topic last updated: Mar 22, 2019.

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 in recent years has declined slightly, possibly reflecting benefits of early treatment [1]. 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 [1]. 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 (primary biliary cirrhosis)" and "Overview of the treatment of primary biliary cholangitis (primary biliary cirrhosis)" and "Pathogenesis of primary biliary cholangitis (primary biliary cirrhosis)" and "Trials of ursodeoxycholic acid for the treatment 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 https://www.uptodate.com/contents/liver-transplantation-in-primary-biliary-cholangitis-primary-biliary-cirrhosis/print?search=CIRROSE HEPATIC…

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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, because the MELD score is used to prioritize patients for transplantation, it is often used to determine when to refer patients for transplantation. (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 and is increasing

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The serum albumin concentration is below 2.8 g/dL (28 g/L) and is decreasing

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Signs of decompensation or portal hypertension develop, such as ascites, variceal bleeding, coagulopathy malnutrition, or encephalopathy

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The patient has intractable pruritus

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The patient has recurrent, debilitating, nontraumatic bone fractures

Models based upon initial data — Findings on physical examination, laboratory data, and liver biopsy all have predictive value [2,4-7]. Among the factors at entry into the study that have been found to correlate with prognosis are age, the 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 [8]. 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) [3]. https://www.uptodate.com/contents/liver-transplantation-in-primary-biliary-cholangitis-primary-biliary-cirrhosis/print?search=CIRROSE HEPATIC…

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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 [9]. 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) [10].

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 [11]. 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 [3]. 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 [3]. 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".) 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 [13]. 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.)

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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, opiate 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 [14]. 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 [15]. 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 [11,16]. In a multicenter study including 785 patients, the rate of PBC recurrence at 5- and 10-years was 22 and 36 percent, respectively [11]. In an earlier report of 421 patients, recurrent PBC was observed in 8 percent of patients after five years, and 22 percent after 10 years [16]. Clinical significance — The clinical significance of recurrent disease is still being determined; however some data suggest that recurrence is associated with a higher risk of graft loss and lower patient survival [11,22,25]. Risk factors — The following factors are associated with increased risk for PBC recurrence after liver transplantation:

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Younger age at diagnosis or at transplantation – Younger age at diagnosis or at liver transplantation increases the risk of recurrence [11,26]. 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) [11].

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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 [11].

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Use of tacrolimus, sirolimus or mycophenolate mofetil – Immunosuppression with tacrolimus, sirolimus or mycophenolate mofetil has been associated with a higher risk of recurrence [11,23,25].

The use of cyclosporine may have a protective effect, although the data are mixed [11,25,27]. (See 'Prevention' below.) Prevention — Methods to prevent recurrence may include immunosuppression using cyclosporine rather than tacrolimus and giving ursodeoxycholic acid (UDCA) following liver transplantation [24,25]. We typically use UDCA following transplantation to prevent recurrence. In a retrospective series of 90 patients who underwent liver transplantation for PBC, 19 patients (21 percent) received preventive UDCA (10 to 15 mg/kg/day) [24]. Patients underwent protocol biopsies at 1, 5, 10, 15, 20, and 25 years or when clinically indicated (eg, because of abnormal liver blood tests). The use of preventive UDCA was associated with a decreased risk of recurrence (adjusted hazard ratio 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. Diagnosis — The diagnosis of recurrent PBC must be based upon histologic rather than serologic or biochemical findings. The following criteria have been proposed [28,29]: ●

Transplantation for PBC, and

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Persistence of antimitochondrial antibodies, and

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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 [30].

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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 [31,32]. Treatment — There are limited data to guide treatment of recurrent disease, although treatment with UDCA is reasonable. UDCA appears to improve biochemical tests [29], 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 [22]. Recurrent disease in patients with PBC following liver transplantation is not an indication for treatment with obeticholic acid. (See "Overview of the treatment of primary biliary cholangitis (primary biliary cirrhosis)", section on 'Obeticholic acid'.)

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".)

INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-toread materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) ●

Basics topic (see "Patient education: Primary biliary cholangitis (primary biliary cirrhosis) (The Basics)")

SUMMARY AND RECOMMENDATIONS

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Liver transplantation in primary biliary cholangitis (primary biliary cirrhosis) - UpToDate

Liver transplantation in primary biliary cholangitis (PBC) is prioritized using the Model for Endstage Liver Disease (MELD) score. (See "Model for End-stage Liver Disease (MELD)".)

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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 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 ●

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.)

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Resolution of symptoms related to PBC occurs at variable rates following liver transplantation. (See 'Effect of transplantation on symptoms' above.)

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Recurrent PBC after liver transplantation has been described in up to 36 percent of patients after 10 years of follow-up. Some data suggest that recurrence of disease may have a negative impact on graft and patient survival. (See 'Recurrence of PBC in the transplanted liver' above.)

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REFERENCES 1. Lee J, Belanger A, Doucette JT, et al. Transplantation trends in primary biliary cirrhosis. Clin Gastroenterol Hepatol 2007; 5:1313. 2. Wiesner RH, Porayko MK, Dickson ER, et al. Selection and timing of liver transplantation in primary biliary cirrhosis and primary sclerosing cholangitis. Hepatology 1992; 16:1290. 3. Markus BH, Dickson ER, Grambsch PM, et al. Efficacy of liver transplantation in patients with primary biliary cirrhosis. N Engl J Med 1989; 320:1709. 4. Dickson ER, Grambsch PM, Fleming TR, et al. Prognosis in primary biliary cirrhosis: model for decision making. Hepatology 1989; 10:1.

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5. Roll J, Boyer JL, Barry D, Klatskin G. The prognostic importance of clinical and histologic features in asymptomatic and symptomatic primary biliary cirrhosis. N Engl J Med 1983; 308:1. 6. Klion FM, Fabry TL, Palmer M, Schaffner F. Prediction of survival of patients with primary biliary cirrhosis. Examination of the Mayo Clinic model on a group of patients with known endpoint. Gastroenterology 1992; 102:310. 7. Goudie BM, Burt AD, Macfarlane GJ, et al. Risk factors and prognosis in primary biliary cirrhosis. Am J Gastroenterol 1989; 84:713. 8. Christensen E, Altman DG, Neuberger J, et al. Updating prognosis in primary biliary cirrhosis using a time-dependent Cox regression model. PBC1 and PBC2 trial groups. Gastroenterology 1993; 105:1865. 9. Lammers WJ, Hirschfield GM, Corpechot C, et al. Development and Validation of a Scoring System to Predict Outcomes of Patients With Primary Biliary Cirrhosis Receiving Ursodeoxycholic Acid Therapy. Gastroenterology 2015; 149:1804. 10. Carbone M, Sharp SJ, Flack S, et al. The UK-PBC risk scores: Derivation and validation of a scoring system for long-term prediction of end-stage liver disease in primary biliary cholangitis. Hepatology 2016; 63:930. 11. Montano-Loza AJ, Hansen BE, Corpechot C, et al. Factors Associated With Recurrence of Primary Biliary Cholangitis After Liver Transplantation and Effects on Graft and Patient Survival. Gastroenterology 2019; 156:96. 12. Kim WR, Lake JR, Smith JM, et al. OPTN/SRTR 2016 Annual Data Report: Liver. Am J Transplant 2018; 18 Suppl 1:172. 13. Rowe IA, Webb K, Gunson BK, et al. The impact of disease recurrence on graft survival following liver transplantation: a single centre experience. Transpl Int 2008; 21:459. 14. Carbone M, Bufton S, Monaco A, et al. The effect of liver transplantation on fatigue in patients with primary biliary cirrhosis: a prospective study. J Hepatol 2013; 59:490. 15. Pells G, Mells GF, Carbone M, et al. The impact of liver transplantation on the phenotype of primary biliary cirrhosis patients in the UK-PBC cohort. J Hepatol 2013; 59:67. 16. Abu-Elamgd K, Demetris J, Rakela J, et al. Transplantation for primary biliary cirrhosis: Recurrence and outcome in 421 patients (abstract). Hepatology 1997; 26:176A. 17. 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. https://www.uptodate.com/contents/liver-transplantation-in-primary-biliary-cholangitis-primary-biliary-cirrhosis/print?search=CIRROSE HEPATIC…

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Gastroenterology 1989; 97:715. 18. Balan V, Batts KP, Porayko MK, et al. Histological evidence for recurrence of primary biliary cirrhosis after liver transplantation. Hepatology 1993; 18:1392. 19. Esquivel CO, Van Thiel DH, Demetris AJ, et al. Transplantation for primary biliary cirrhosis. Gastroenterology 1988; 94:1207. 20. Tzakis AG, Carcassonne C, Todo S, et al. Liver transplantation for primary biliary cirrhosis. Semin Liver Dis 1989; 9:144. 21. Haagsma EB, Manns M, Klein R, et al. Subtypes of antimitochondrial antibodies in primary biliary cirrhosis before and after orthotopic liver transplantation. Hepatology 1987; 7:129. 22. Charatcharoenwitthaya P, Pimentel S, Talwalkar JA, et al. Long-term survival and impact of ursodeoxycholic acid treatment for recurrent primary biliary cirrhosis after liver transplantation. Liver Transpl 2007; 13:1236. 23. Neuberger J, Gunson B, Hubscher S, Nightingale P. Immunosuppression affects the rate of recurrent primary biliary cirrhosis after liver transplantation. Liver Transpl 2004; 10:488. 24. Bosch A, Dumortier J, Maucort-Boulch D, et al. Preventive administration of UDCA after liver transplantation for primary biliary cirrhosis is associated with a lower risk of disease recurrence. J Hepatol 2015; 63:1449. 25. Montano-Loza AJ, Wasilenko S, Bintner J, Mason AL. Cyclosporine A protects against primary biliary cirrhosis recurrence after liver transplantation. Am J Transplant 2010; 10:852. 26. Jacob DA, Neumann UP, Bahra M, et al. Long-term follow-up after recurrence of primary biliary cirrhosis after liver transplantation in 100 patients. Clin Transplant 2006; 20:211. 27. Egawa H, Sakisaka S, Teramukai S, et al. Long-Term Outcomes of Living-Donor Liver Transplantation for Primary Biliary Cirrhosis: A Japanese Multicenter Study. Am J Transplant 2016; 16:1248. 28. Hubscher SG, Elias E, Buckels JA, et al. Primary biliary cirrhosis. Histological evidence of disease recurrence after liver transplantation. J Hepatol 1993; 18:173. 29. Neuberger J. Recurrent primary biliary cirrhosis. Liver Transpl 2003; 9:539. 30. Slapak GI, Saxena R, Portmann B, et al. Graft and systemic disease in long-term survivors of liver transplantation. Hepatology 1997; 25:195. 31. Luettig B, Boeker KH, Schoessler W, et al. The antinuclear autoantibodies Sp100 and gp210 persist after orthotopic liver transplantation in patients with primary biliary cirrhosis. J Hepatol https://www.uptodate.com/contents/liver-transplantation-in-primary-biliary-cholangitis-primary-biliary-cirrhosis/print?search=CIRROSE HEPATIC…

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1998; 28:824. 32. Dubel L, Farges O, Bismuth H, et al. Kinetics of anti-M2 antibodies after liver transplantation for primary biliary cirrhosis. J Hepatol 1995; 23:674.

Topic 3609 Version 23.0

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GRAPHICS Mayo scoring system for predicting the need for liver transplantation in primary biliary cholangitis R = [0.871 x log e serum bilirubin (mg/dL)] - [2.53 x log e serum albumin (gm/dL)] + [0.039 x age (years)] + [2.38 x log e prothrombin time (seconds)] + [0.859 x edema score]

Edema score 0 = no edema 0.5 = diuretic-controlled edema 1.0 = diuretic-resisitant edema

Survival function [S(t)] 1 year = 0.970 2 years = 0.941 3 years = 0.883 4 years = 0.774 5 years = 0.721 6 years = 0.651

Calculated patient survival = S(t) exp(R - 5.07) Survival probability at one year = 0.970 exp(R - 5.07) Survival probability at three years = 0.883 exp(R - 5.07) Adapted from Dickson, ER, Grambsch, PM, Fleming, TR, et al, Hepatology 1989; 10:1, and Grambsch, PM, Dickson, ER, Kaplan, M, et al, Hepatology 1989; 10:846. Graphic 65783 Version 2.0

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Improved survival with liver transplantation in primary biliary cholangitis

Kaplan-Meier survival probabilities in 161 patients with primary biliary cholangitis treated with liver transplantation compared with the simulated survival in a "control" group calculated from the Mayo model. After six months, survival with transplantation exceeded that predicted with medical therapy alone. Data from Markus, BH, Dickson, ER, Grambsch, PM, et al, N Engl J Med 1989; 320:1709. Graphic 62006 Version 3.0

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Contributor Disclosures Steven Flamm, MD Grant/Research/Clinical Trial Support: Abbvie, Gilead (HCV). Speaker’s Bureau: Abbvie, Gilead, Merck (HCV). Consultant/Advisory Boards: Abbvie, Gilead, Merck (HCV). Fredric D Gordon, MD Grant/Research/Clinical Trial Support: Intercept Pharmaceuticals [Primary Biliary Cirrhosis (NASH) (obeticholic acid)]. Raoul Poupon, MD Consultant/Advisory Boards: Intercept Pharma. Robert S Brown, Jr, MD, MPH Grant/Research/Clinical Trial Support: Gilead; Bristol-Myers Squibb; AbbVie; Merck; Intercept [Hepatitis C, NALFD (various agents for HCV and NAFLD)]. Consultant/Advisory Boards: Gilead; BristolMyers Squibb; AbbVie; Merck; Intercept; Dova; Shionogi [Hepatitis B and C, PBC, cirrhosis (various directacting agents for HCV, therapies for PBC and thrombocytopenia)]. Kristen M Robson, MD, MBA, FACG Nothing to disclose Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy

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