Organ Transplants From Deceased Donors With Primary Brain Tumors and Risk of Cancer Transmission.

Importance: Cancer transmission is a known risk for recipients of organ transplants. Many people wait a long time for a suitable transplant; some never receive one. Although patients with brain tumors may donate their organs, opinions vary on the risks involved. Objective: To determine the risk of cancer transmission associated with organ transplants from deceased donors with primary brain tumors. Key secondary objectives were to investigate the association that donor brain tumors have with organ usage and posttransplant survival. Design, Setting, and Participants: This was a cohort study in England and Scotland, conducted from January 1, 2000, to December 31, 2016, with follow-up to December 31, 2020. This study used linked data on deceased donors and solid organ transplant recipients with valid national patient identifier numbers from the UK Transplant Registry, the National Cancer Registration and Analysis Service (England), and the Scottish Cancer Registry. For secondary analyses, comparators were matched on factors that may influence the likelihood of organ usage or transplant failure. Statistical analysis of study data took place from October 1, 2021, to May 31, 2022. Exposures: A history of primary brain tumor in the organ donor, identified from all 3 data sources using disease codes. Main Outcomes and Measures: Transmission of brain tumor from the organ donor into the transplant recipient. Secondary outcomes were organ utilization (ie, transplant of an offered organ) and survival of kidney, liver, heart, and lung transplants and their recipients. Key covariates in donors with brain tumors were tumor grade and treatment history. Results: This study included a total of 282 donors (median [IQR] age, 42 [33-54] years; 154 females [55%]) with primary brain tumors and 887 transplants from them, 778 (88%) of which were analyzed for the primary outcome. There were 262 transplants from donors with high-grade tumors and 494 from donors with prior neurosurgical intervention or radiotherapy. Median (IQR) recipient age was 48 (35-58) years, and 476 (61%) were male. Among 83 posttransplant malignancies (excluding NMSC) that occurred over a median (IQR) of 6 (3-9) years in 79 recipients of transplants from donors with brain tumors, none were of a histological type matching the donor brain tumor. Transplant survival was equivalent to that of matched controls. Kidney, liver, and lung utilization were lower in donors with high-grade brain tumors compared with matched controls. Conclusions and Relevance: Results of this cohort study suggest that the risk of cancer transmission in transplants from deceased donors with primary brain tumors was lower than previously thought, even in the context of donors that are considered as higher risk. Long-term transplant outcomes are favorable. These results suggest that it may be possible to safely expand organ usage from this donor group.

Proximity to transplant center and outcome among liver transplant patients.

In the United States, distance from liver transplant center correlates with worsened outcomes; the effects of geography elsewhere are unassessed. We performed a national registry analysis of United Kingdom listings for liver transplantation (1995-2014) and assessed whether travel time to transplant center correlates with outcome. There were 11 188 listings assessed (8490 transplanted), with a median travel time to center of 60 minutes (range 36-86). Of the national population, 3.38 × 107 (55.1%) reside ≥60 minutes from a center, and 7.65 × 106 (12.5%) >119 minutes. After competing risk analysis, increasing travel time was associated with an increased risk of death after listing (subdistribution hazard ratios relative to <60 minutes of 1.33 for 60-119 and 1.27 for >119 minutes; P < 0.001) and reduced likelihood of transplantation or recovery (0.94 and 0.86; P < 0.001). Among those transplanted, travel time was not associated with retransplant-free survival (P = 0.532). We used our model to examine optimal placement of a new center and identify a single site with a total travel time reduction of ≈10%. Our findings of disparities in accessibility of liver transplantation showed worse outcomes following listing in those distant from their transplant center, and our description of a method to model a new center complement existing data and support similar analyses of other networks.

Pretreatment prediction of response to ursodeoxycholic acid in primary biliary cholangitis: development and validation of the UDCA Response Score.

BACKGROUND: Treatment guidelines recommend a stepwise approach to primary biliary cholangitis: all patients begin treatment with ursodeoxycholic acid (UDCA) monotherapy and those with an inadequate biochemical response after 12 months are subsequently considered for second-line therapies. However, as a result, patients at the highest risk can wait the longest for effective treatment. We determined whether UDCA response can be accurately predicted using pretreatment clinical parameters. METHODS: We did logistic regression analysis of pretreatment variables in a discovery cohort of patients in the UK with primary biliary cholangitis to derive the best-fitting model of UDCA response, defined as alkaline phosphatase less than 1·67 times the upper limit of normal (ULN), measured after 12 months of treatment with UDCA. We validated the model in an external cohort of patients with primary biliary cholangitis and treated with UDCA in Italy. Additionally, we assessed correlations between model predictions and key histological features, such as biliary injury and fibrosis, on liver biopsy samples. FINDINGS: 2703 participants diagnosed with primary biliary cholangitis between Jan 1, 1998, and May 31, 2015, were included in the UK-PBC cohort for derivation of the model. The following pretreatment parameters were associated with lower probability of UDCA response: higher alkaline phosphatase concentration (p<0·0001), higher total bilirubin concentration (p=0·0003), lower aminotransferase concentration (p=0·0012), younger age (p<0·0001), longer interval from diagnosis to the start of UDCA treatment (treatment time lag, p<0·0001), and worsening of alkaline phosphatase concentration from diagnosis (p<0·0001). Based on these variables, we derived a predictive score of UDCA response. In the external validation cohort, 460 patients diagnosed with primary biliary cholangitis were treated with UDCA, with follow-up data until May 31, 2016. In this validation cohort, the area under the receiver operating characteristic curve for the score was 0·83 (95% CI 0·79-0·87). In 20 liver biopsy samples from patients with primary biliary cholangitis, the UDCA response score was associated with ductular reaction (r=-0·556, p=0·0130) and intermediate hepatocytes (probability of response was 0·90 if intermediate hepatocytes were absent vs 0·51 if present). INTERPRETATION: We have derived and externally validated a model based on pretreatment variables that accurately predicts UDCA response. Association with histological features provides face validity. This model provides a basis to explore alternative approaches to treatment stratification in patients with primary biliary cholangitis. FUNDING: UK Medical Research Council and University of Milan-Bicocca.

Alcohol, Diet and Drug Use Preceding Alcoholic Hepatitis.

BACKGROUND: Alcoholic hepatitis (AH) is a severe manifestation of alcohol-related liver disease characterised by jaundice and liver failure. It is not known what might trigger an episode of AH. We interviewed patients to investigate changes in behaviour before the onset of AH. METHODS: Structured interviews were performed with patients with AH to examine their alcohol use, diet, drug use and smoking habit. Clinical and laboratory results were noted. Patients were followed up for 12 months after interview. RESULTS: Data from 39 patients was analysed. No single behavioural change occurred before the onset of jaundice, although reductions in alcohol and/or dietary intake were common. Reduction in alcohol use was seen to occur approximately 14 days before the onset of jaundice. Increased alcohol intake was not common. Clinical and laboratory data varied between types of behaviour changes, although these were not statistically significant. No changes in drug use or tobacco were reported before AH. Those who had not reduced alcohol intake or had increased their drinking had better survival. CONCLUSIONS: No single type of behaviour change is associated with AH. Contrary to previous assertions, increased alcohol intake was not common; in fact, participants were much more likely to have reduced their alcohol intake.

Practical Recommendations for Long-term Management of Modifiable Risks in Kidney and Liver Transplant Recipients: A Guidance Report and Clinical Checklist by the Consensus on Managing Modifiable Risk in Transplantation (COMMIT) Group.

Short-term patient and graft outcomes continue to improve after kidney and liver transplantation, with 1-year survival rates over 80%; however, improving longer-term outcomes remains a challenge. Improving the function of grafts and health of recipients would not only enhance quality and length of life, but would also reduce the need for retransplantation, and thus increase the number of organs available for transplant. The clinical transplant community needs to identify and manage those patient modifiable factors, to decrease the risk of graft failure, and improve longer-term outcomes.COMMIT was formed in 2015 and is composed of 20 leading kidney and liver transplant specialists from 9 countries across Europe. The group's remit is to provide expert guidance for the long-term management of kidney and liver transplant patients, with the aim of improving outcomes by minimizing modifiable risks associated with poor graft and patient survival posttransplant.The objective of this supplement is to provide specific, practical recommendations, through the discussion of current evidence and best practice, for the management of modifiable risks in those kidney and liver transplant patients who have survived the first postoperative year. In addition, the provision of a checklist increases the clinical utility and accessibility of these recommendations, by offering a systematic and efficient way to implement screening and monitoring of modifiable risks in the clinical setting.

International comparison of liver transplant programmes: differences in indications, donor and recipient selection and outcome between Italy and UK.

BACKGROUND & AIMS: Comparing liver transplant (LT) programmes internationally can improve outcomes by stimulating cross-national learning. Yet, comparison of crude outcomes, by using registry data, is limited by missing data, not allowing proper risk-adjustment for donor- and recipient-related factors. The objective of this study was to compare two European LT programmes based on high-quality national longitudinal databases prospectively collected in Italy and UK respectively. METHODS: We undertook a multicentre, international cohort study including all adults who underwent a first single organ LT in Italy (N = 1480) and the UK (N = 1003) between June 2007 and May 2009. RESULTS: Italian donors were much older compared to the UK ones. Hepatitis C virus infection and hepatocellular carcinoma had higher prevalence in the Italian cohort compared to the UK one (47.5% vs. 23.1%, and 47.2% vs. 17.1% respectively). Centres' volume differed significantly, with five centres out of seven in UK vs. only two out of 20 in Italy performing >60 transplants per year. No national strategies to drive the donor-recipient matching were identified in both countries. After appropriate adjustment, a higher risk of early transplant loss was identified in the Italian cohort, whereas no differences were found in the 3-year survival rates. CONCLUSIONS: International comparison of LT programmes provides the opportunity for benchmarking between heterogeneous healthcare systems and should ideally become a vital part of national quality assurance programmes. This requires the implementation of a standardized methodology for data collection to appropriately weigh each country's patient case-mix and donor and recipients risk factors.

Rapid dissemination of human T-lymphotropic virus type 1 during primary infection in transplant recipients.

BACKGROUND: Human T-lymphotropic virus type 1 (HTLV-1) infects an estimated 10 million persons globally with transmission resulting in lifelong infection. Disease, linked to high proviral load, occurs in a minority. In established infection HTLV-1 replicates through infectious spread and clonal expansion of infected lymphocytes. Little is known about acute HTLV-1 infection. The kinetics of early HTLV-1 infection, following transplantation-acquired infection in three recipients from one HTLV-1 infected donor, is reported. The recipients were treated with two HTLV-1 enzyme inhibitors 3 weeks post exposure following the detection of HTLV-1 provirus at low level in each recipient. HTLV-1 infection was serially monitored by serology, quantification of proviral load and HTLV-1 2LTR DNA circles and by HTLV-1 unique integration site analysis. RESULTS: HTLV-1 antibodies were first detected 16-39 days post-transplantation. HTLV-1 provirus was detected by PCR on day 16-23 and increased by 2-3 log by day 38-45 with a peak proviral doubling time of 1.4 days, after which steady state was reached. The rapid proviral load expansion was associated with high frequency of HTLV-1 2LTR DNA circles. The number of HTLV-1 unique integration sites was high compared with established HTLV-1 infection. Clonal expansion of infected cells was detected as early as day 37 with high initial oligoclonality index, consistent with early mitotic proliferation. CONCLUSIONS: In recipients infected through organ transplantation HTLV-1 disseminated rapidly despite early anti-HTLV-1 treatment. Proviral load set point was reached within 6 weeks. Seroconversion was not delayed. Unique integration site analysis and HTLV-1 2LTR DNA circles indicated early clonal expansion and high rate of infectious spread.

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.

UNLABELLED: The biochemical response to ursodeoxycholic acid (UDCA)--so-called "treatment response"--strongly predicts long-term outcome in primary biliary cholangitis (PBC). Several long-term prognostic models based solely on the treatment response have been developed that are widely used to risk stratify PBC patients and guide their management. However, they do not take other prognostic variables into account, such as the stage of the liver disease. We sought to improve existing long-term prognostic models of PBC using data from the UK-PBC Research Cohort. We performed Cox's proportional hazards regression analysis of diverse explanatory variables in a derivation cohort of 1,916 UDCA-treated participants. We used nonautomatic backward selection to derive the best-fitting Cox model, from which we derived a multivariable fractional polynomial model. We combined linear predictors and baseline survivor functions in equations to score the risk of a liver transplant or liver-related death occurring within 5, 10, or 15 years. We validated these risk scores in an independent cohort of 1,249 UDCA-treated participants. The best-fitting model consisted of the baseline albumin and platelet count, as well as the bilirubin, transaminases, and alkaline phosphatase, after 12 months of UDCA. In the validation cohort, the 5-, 10-, and 15-year risk scores were highly accurate (areas under the curve: >0.90). CONCLUSIONS: The prognosis of PBC patients can be accurately evaluated using the UK-PBC risk scores. They may be used to identify high-risk patients for closer monitoring and second-line therapies, as well as low-risk patients who could potentially be followed up in primary care.

Kidney donation after circulatory death (DCD): state of the art.

The use of kidneys from controlled donation after circulatory death (DCD) donors has the potential to markedly increase kidney transplants performed. However, this potential is not being realized because of concerns that DCD kidneys are inferior to those from donation after brain-death (DBD) donors. The United Kingdom has developed a large and successful controlled DCD kidney transplant program that has allowed for a substantial increase in kidney transplant numbers. Here we describe recent trends in DCD kidney donor activity in the United Kingdom, outline aspects of the donation process, and describe donor selection and allocation of DCD kidneys. Previous UK Transplant Registry analyses have shown that while DCD kidneys are more susceptible to cold ischemic injury and have a higher incidence of delayed graft function, short- and medium-term transplant outcomes are similar in recipients of kidneys from DCD and DBD donors. We present an updated, extended UK registry analysis showing that longer-term transplant outcomes in DCD donor kidneys are also similar to those for DBD donor kidneys, and that transplant outcomes for kidneys from expanded-criteria DCD donors are no less favorable than for expanded-criteria DBD donors. Accordingly, the selection criteria for use of kidneys from DCD donors should be the same as those used for DBD donors. The UK experience suggests that wider international development of DCD kidney transplantation programs will help address the global shortage of deceased donor kidneys for transplantation.

Improved access to histopathology using a digital system could increase the organ donor pool and improve allocation.

Improvements in digital slide scanners have reached a stage that digital whole slide images (WSIs) can be used for diagnostic purposes. A digital system for histopathology, analogous to the systems used in radiology, would allow the establishment of networks of subspecialist histopathologists to provide a regional, national or even international rota to support out of hours histopathology for emergency frozen sections, urgent paraffin sections and to generally improve efficiencies with the provision of histopathology services. Such a system would promote appropriate organ utilization by allowing rapid characterization of unexpected lesions in the donor to determine whether donation should occur and further characterization of the organ, such as the degree of fibrosis in the kidney or steatosis in the liver, to determine whether the organ should be used. If introduced across Europe, this would promote safe and effective exchange of organs and support a cost efficient use of pathologist expertise. This review article outlines current issues with the provision of an urgent out of hours histopathology service and focuses on how such a service has the potential to increase organ donors, improve allocation, sharing and the use of available donor organs.

Autoimmune liver disease, autoimmunity and liver transplantation.

Primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) represent the three major autoimmune liver diseases (AILD). PBC, PSC, and AIH are all complex disorders in that they result from the effects of multiple genes in combination with as yet unidentified environmental factors. Recent genome-wide association studies have identified numerous risk loci for PBC and PSC that host genes involved in innate or acquired immune responses. These loci may provide a clue as to the immune-based pathogenesis of AILD. Moreover, many significant risk loci for PBC and PSC are also risk loci for other autoimmune disorders, such type I diabetes, multiple sclerosis and rheumatoid arthritis, suggesting a shared genetic basis and possibly similar molecular pathways for diverse autoimmune conditions. There is no curative treatment for all three disorders, and a significant number of patients eventually progress to end-stage liver disease requiring liver transplantation (LT). LT in this context has a favourable overall outcome with current patient and graft survival exceeding 80% at 5years. Indications are as for other chronic liver disease although recent data suggest that while lethargy improves after transplantation, the effect is modest and variable so lethargy alone is not an indication. In contrast, pruritus rapidly responds. Cholangiocarcinoma, except under rigorous selection criteria, excludes LT because of the high risk of recurrence. All three conditions may recur after transplantation and are associated with a greater risk of both acute cellular and chronic ductopenic rejection. It is possible that a crosstalk between alloimmune and autoimmune response perpetuate each other. An immunological response toward self- or allo-antigens is well recognised after LT in patients transplanted for non-autoimmune indications and sometimes termed "de novo autoimmune hepatitis". Whether this is part of the spectrum of rejection or an autoimmune process is not clear. In this manuscript, we review novel findings about disease processes and mechanisms that lead to autoimmunity in the liver and their possible involvement in the immune response vs. the graft after LT.

Alcohol and substance abuse in solid-organ transplant recipients.

This review focuses on alcohol and substance abuse in the context of solid-organ transplantation. Alcohol and substance abuse are common and may lead to a need for solid-organ transplantation and may also contribute to significant physical and psychologic problems that impact upon the recipient. Damaging levels of alcohol intake can occur in the absence of dependence. Alcohol or substance abuse after transplantation is associated with poor medication compliance and this may increase risk of graft loss. Intravenous drug use is associated with increased risk of infections (especially secondary to opportunistic organisms-bacterial, viral, protozoal, and others-and such infections may be more severe in the immunosuppressed), but there is only anecdotal evidence that such behavior has a worse outcome in transplant recipients. Whereas previous alcohol excess and drug use in kidney recipients are both associated with a small but statistically significantly increased risk of adverse outcomes (hazard ratio, 1.16-1.56), alcohol use within recommended guidelines after transplantation appears safe and possibly beneficial. Robust data are lacking for other organs, but those available suggest that heart transplantation is safe in individuals with a history of alcohol or substance abuse. Health specialists in drug or alcohol addiction should carefully screen all potential transplant candidates for these conditions, and where there is evidence of dependency or abuse, effective psychologic and physical treatment should be offered. Studies have shown that interventions such as psychologic intervention have improved alcohol behavior in the context of liver transplantation. Although there are no comparable studies with other solid-organ recipients, it is reasonable to expect transferable outcomes.

Mental health disorders and solid-organ transplant recipients.

Depression affects up to 60% of solid-organ recipients and is independently associated with both mortality (hazard ratio for death of ~2) and de novo malignancy after transplantation, although the mechanism is not clear. Both pretransplantation psychosis and depression occurring more than 2 years after transplantation are associated with increased noncompliance and graft loss. It remains to be shown that effective treatment of depression is associated with improved outcomes and quality of life. Immunosuppressive drugs (especially corticosteroids and calcineurin inhibitors) and physiologic challenges can precipitate deterioration in mental health. All potential transplant candidates should be assessed for mental health problems and preexisting medical conditions that can mimic mental health problems, such as uremic, hepatic, or hypoxic encephalopathy, should be identified and treated appropriately. Expert mental health review of those with identified risk factors (such as previous suicide attempts, history of mental illness or noncompliance with medications) is advisable early in the transplant assessment process to mitigate risk and support the patient. Patients with mental health disorders, when adequately controlled and socially supported, have outcomes similar to the general transplant population. Therefore, exclusion from transplantation based on the diagnosis alone is neither ethically nor medically justified. However, it is ethically and clinically justifiable to deny access to transplantation to those who, despite full support, would have a quality of life that is unacceptable to the candidate or are likely to be noncompliant with treatment or follow-up, which would lead to graft loss.

The effect of liver transplantation on fatigue in patients with primary biliary cirrhosis: a prospective study.

BACKGROUND & AIMS: The role of liver transplantation (LT) for the relief of fatigue in patients with primary biliary cirrhosis (PBC) is unclear, and while many centers exclude fatigue as an indication for transplantation, there have been no studies to prospectively evaluate the impact of LT on fatigue. We aimed at assessing the severity of fatigue in LT candidates with PBC and the impact of LT on fatigue. METHODS: In a prospective, longitudinal study, we used the PBC-40 questionnaire in 49 adult patients with PBC at listing and at 6, 12, and 24 months after LT and in two sex- and age-matched cohorts of community controls and non-transplanted PBC patients. Correlation analysis was used to assess the relationship between liver function and fatigue. ANOVA was used to compare the variation of fatigue score before and after LT. RESULTS: There was no correlation between MELD and fatigue before LT (r(2)=0.01). Overall, the fatigue score after LT was substantially lower than before LT, falling from 40.7 ± 11.4 pre-transplant to 27.7 ± 9.5, 28.7 ± 10.1, 26.2 ± 10.1 (p<0.0001) at 6, 12, and 24 months after LT, respectively. The same improvement of fatigue was observed in both low-MELD (<17) and high-MELD (≥ 17) patients. Improvement in fatigue was also evident in the comparison with a "non-transplant PBC" control group (31.1 ± 11.6, p=0.03). However, 44% of the total cohort, and 47% of those with low-MELD, for whom the probability of dying of LT may be higher than that of dying without LT, had moderate to severe fatigue (defined as a fatigue score ≥ 29) at two years after LT. Moreover, fatigue scores at two years were higher in the transplant PBC cohort compared to a cohort of community controls (17.8 ± 5.9, p<0.0001). CONCLUSIONS: Liver transplantation is associated with improvement in fatigue in patients with PBC. However, a substantial proportion of patients continue to suffer from significant fatigue after two years. Whether the improvement is enough to justify organ allocation in patients with fatigue alone, without liver failure, is still an open issue. Certainly, in the era of organ shortage, with many patients dying waiting for a graft, this may not represent the optimal use of donated deceased organs.

Impact of primary biliary cirrhosis on perceived quality of life: the UK-PBC national study.

UNLABELLED: Primary biliary cirrhosis (PBC) has a complex clinical phenotype, with debate about the extent and specificity of frequently described systemic symptoms such as fatigue. The aim of this study was to use a national patient cohort of 2,353 patients recruited from all clinical centers in the UK to explore the impact of disease on perceived life quality. Clinical data regarding diagnosis, therapy, and biochemical status were collected and have been reported previously. Detailed symptom phenotyping using recognized and validated symptom assessment tools including the PBC-40 was also undertaken and is reported here. Perception of poor quality of life and impaired health status was common in PBC patients (35% and 46%, respectively) and more common than in an age-matched and sex-matched community control group (6% and 15%, P < 0.0001 for both). Fatigue and symptoms of social dysfunction were associated with impaired perceived quality of life using multivariate analysis. Fatigue was the symptom with the greatest impact. Depression was a significant factor, but appeared to be a manifestation of complex symptom burden rather than a primary event. Fatigue had its greatest impact on perceived quality of life when accompanied by symptoms of social dysfunction, suggesting that maintenance of social networks is critical for minimizing the impact of fatigue. CONCLUSION: The symptom burden in PBC, which is unrelated to disease severity or ursodeoxycholic acid response, is significant and complex and results in significant quality of life deficit. The complexity of symptom burden, and its lack of relation to disease severity and treatment response, suggest that specific approaches to symptom management are warranted that address both symptom biology and social impact.

The impact of liver transplantation on the phenotype of primary biliary cirrhosis patients in the UK-PBC cohort.

BACKGROUND & AIMS: Liver transplantation improves survival in end-stage primary biliary cirrhosis (PBC), but the benefit for systemic symptoms including fatigue is less clear. The aim of this study was to utilise the comprehensive UK-PBC Research Cohort, including 380 post-transplant patients and 2300 non-transplanted patients, to answer key questions regarding transplantation for PBC. METHODS: Cross-sectional study of post-transplant PBC patients and case-matched non-transplanted patients. Detailed clinical information was collected, together with patient systemic symptom impact data using validated assessment tools. RESULTS: Over 25% of patients in the transplant cohort were grafted within 2 years of PBC diagnosis suggesting advanced disease at presentation. Transplanted patients were significantly younger at presentation than non-transplanted (mean 7 years) and >35% of all patients in the UK-PBC cohort who presented under 50 years had already undergone liver transplantation at the study censor point (>50% were treatment failures (post-transplant or unresponsive to UDCA)). Systemic symptom severity (fatigue and cognitive symptoms) was identical in female post-transplant patients and matched non-transplanted controls and unrelated to disease recurrence or immunosuppression type. In males, symptoms were worse in transplanted than in non-transplanted patients. CONCLUSIONS: Age at presentation is a major risk factor for progression to transplant (as well as UDCA non-response) in PBC. Although both confirmatory longitudinal studies, and studies utilising objective as well as subjective measures of function, are needed if we are to address the question definitively, we found no evidence of improved systemic symptoms after liver transplantation in PBC and patients should be advised accordingly. Consideration needs to be given to enhancing rehabilitation approaches to improve function and life quality after liver transplant for PBC.