Recipient Survival among Living Donor vs. Deceased Donor Liver Transplants for Acute Liver Failure in the United States.

Objectives: Acute liver failure (ALF) is associated with high morbidity and mortality. Timely liver transplantation (LT) is the only universally accepted therapy for ALF that is non-responsive to medical therapy. Data regarding the use of living donor LT (LDLT) for this indication in the US is scarce. Materials and Methods: United Network of Organ Sharing/Organ Procurement and Transplantation Network (UNOS/OPTN) data from January 2002 to December 2020 were reviewed. Adult and pediatric recipients listed as status 1 were included. Demographics, clinical and laboratory data, and post-LT survival rates were compared for LDLT vs. DDLT recipients. Results: There were 180 LDLT (3.6%) and 4779 DDLT (96.4%) recipients with a diagnosis of ALF. The majority of recipients in the LDLT group were pediatric (n = 164, 91%) compared to the DDLT group (n = 1455, 30%), p < 0.001. In the pediatric-only group, post-LT survival was comparable between LDLT and DDLT recipients (p = 0.15). Five-year post-LT survival was higher for pediatric recipients compared to adults in the LDLT group (84.2% vs. 62.5%, respectively, p < 0.001) and the DDLT group (82.8% vs. 78.7%, respectively, p < 0.001). Adults had a higher hazard of death compared to pediatric recipients in the LDLT group (HR = 3.560, 95% CI 1.612-7.844, p = 0.002) and the DDLT group (HR = 1.472, 95% CI 1.290-1.679, p < 0.001). In multivariate analysis results, the type of LT and age group were not associated with higher post-LT mortality. Conclusions: In the US, LDLT constitutes 3.6% of LTs for ALF. In the pediatric-only group, post-LT survival was comparable between LDLT and DDLT recipients. Overall, there were superior post-LT outcomes for pediatric recipients compared to adults for LDLT and DDLT.

Primary biliary cholangitis drug evaluation and regulatory approval: Where do we go from here?

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease. The management landscape was transformed 20 years ago with the advent of Ursodeoxycholic Acid (UDCA). Up to 40% of patients do not, however, respond adequately to UDCA and therefore still remain at risk of disease progression to cirrhosis. The introduction of Obeticholic acid (OCA) as second-line therapy for patients failing UDCA has improved outcomes for PBC patients. There remains, however, a need for better treatments for higher risk patients. The greatest threat facing our efforts to improve treatment in PBC is, paradoxically, the regulatory approval model providing conditional marketing authorisation for new drugs based on biochemical markers on the condition that long-term, randomized placebo-controlled outcomes trials are performed to confirm efficacy. As demonstrated by the COBALT confirmatory study with OCA, it is difficult to retain patients in the required follow-on confirmatory placebo-controlled PBC outcomes trials when a licensed drug is commercially available. New PBC therapies in development such as the PPAR agonists, face even greater challenges in demonstrating outcomes benefit through randomized placebo-controlled studies once following conditional marketing authorisation, as there will be even more treatment options available. A recently published EMA Reflection Paper provides some guidance on the regulatory pathway to full approval but fails to recognise the importance of Real-World Data in providing evidence of outcomes benefit in rare diseases. Here we explore the impact of the EMA reflection paper on PBC therapy and offer pragmatic solutions for generating evidence of long-term outcomes through Real World data collection.

Adequate versus deep response to ursodeoxycholic acid in primary biliary cholangitis: To what extent and under what conditions is normal alkaline phosphatase level associated with complication-free survival gain?

BACKGROUND AND AIMS: Normal alkaline phosphatase (ALP) levels in ursodeoxycholic acid (UDCA)-treated patients with primary biliary cholangitis (PBC) are associated with better long-term outcome. However, second-line therapies are currently recommended only when ALP levels remain above 1.5 times the upper limit of normal (×ULN) after 12-month UDCA. We assessed whether, in patients considered good responders to UDCA, normal ALP levels were associated with significant survival gains. APPROACH AND RESULTS: We performed a retrospective cohort study of 1047 patients with PBC who attained an adequate response to UDCA according to Paris-2 criteria. Time to liver-related complications, liver transplantation, or death was assessed using adjusted restricted mean survival time (RMST) analysis. The overall incidence rate of events was 17.0 (95% CI: 13.7-21.1) per 1000 out of 4763.2 patient-years. On the whole population, normal serum ALP values (but not normal gamma-glutamyl transpeptidase (GGT), alanine aminotransferase (ALT), or aspartate aminotransferase (AST); or total bilirubin < 0.6 ×ULN) were associated with a significant absolute complication-free survival gain at 10 years (mean 7.6 months, 95% CI: 2.7 - 12.6 mo.; p = 0.003). In subgroup analysis, this association was significant in patients with a liver stiffness measurement ≥ 10 kPa and/or age ≤ 62 years, with a 10-year absolute complication-free survival gain of 52.8 months (95% CI: 45.7-59.9, p < 0.001) when these 2 conditions were met. CONCLUSIONS: PBC patients with an adequate response to UDCA and persistent ALP elevation between 1.1 and 1.5 ×ULN, particularly those with advanced fibrosis and/or who are sufficiently young, remain at risk of poor outcome. Further therapeutic efforts should be considered for these patients.

Influence of socioeconomic factors on liver transplant survival outcomes in patients with autoimmune liver disease in the United States.

INTRODUCTION AND OBJECTIVES: Autoimmune liver diseases (AILDs): autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) have different survival outcomes after liver transplant (LT). Outcomes are influenced by factors including disease burden, medical comorbidities, and socioeconomic variables. MATERIALS AND METHODS: Using the United Network for Organ Sharing database (UNOS), we identified 13,702 patients with AILDs listed for LT between 2002 and 2021. Outcomes of interest were waitlist removal, post-LT patient survival, and post- LT graft survival. A stepwise multivariate analysis was performed adjusting for transplant recipient gender, race, diabetes mellitus, model for end-stage liver disease (MELD) score, and additional social determinants including the presence of education, reliance on public insurance, working for income, and U.S. citizenship status. RESULTS: Lack of college education and having public insurance increased the risk of waitlist removal (HR, 1.13; 95 % CI, 1.05-1.23, and HR, 1.09; 95 % CI, 1.00-1.18; respectively), and negatively influenced post-LT patient survival (HR, 1.16; 95 % CI, 1.06-1.26, and HR, 1.15; 95 % CI, 1.06-1.25; respectively) and graft survival (HR, 1.13; 95 % CI, 1.05-1.23, and HR, 1.15; 95 % CI, 1.06-1.25; respectively). Not working for income proved to have the greatest detrimental impact on both patient survival (HR, 1.41; 95 % CI, 1.24-1.6) and graft survival (HR, 1.21; 95 % CI, 1.09-1.35). CONCLUSIONS: Our study highlights that lack of college education and public insurance have a detrimental impact on waitlist mortality, patient survival, and graft survival. Not working for income negatively affects post-LT survival outcomes. Not having U.S. citizenship does not affect survival outcomes in AILDs patients.

Silencing of aryl hydrocarbon receptor repressor restrains Th17 cell immunity in autoimmune hepatitis.

Th17-cells play a key role in the pathogenesis of autoimmune hepatitis (AIH). Dysregulation of Th17-cells in AIH is linked to defective response to aryl-hydrocarbon-receptor (AhR) activation. AhR modulates adaptive immunity and is regulated by aryl-hydrocarbon-receptor-repressor (AHRR), which inhibits AhR transcriptional activity. In this study, we investigated whether defective Th17-cell response to AhR derives from aberrant AHRR regulation in AIH. Th17-cells, obtained from the peripheral blood of AIH patients (n = 30) and healthy controls (n = 30) were exposed to AhR endogenous ligands, and their response assessed in the absence or presence of AHRR silencing. Therapeutic effects of AHRR blockade were tested in a model of Concanavalin-A (Con-A)-induced liver injury in humanized mice. AHRR was markedly upregulated in AIH Th17-cells, following exposure to l-kynurenine, an AhR endogenous ligand. In patients, silencing of AHRR boosted Th17-cell response to l-kynurenine, as reflected by increased levels of CYP1A1, the main gene controlled by AhR; and decreased IL17A expression. Blockade of AHRR limited the differentiation of naïve CD4-cells into Th17 lymphocytes; and modulated Th17-cell metabolic profile by increasing the levels of uridine via ATP depletion or pyrimidine salvage. Treatment with 2'-deoxy-2'-fluoro-d-arabinonucleic acid (FANA) oligonucleotides to silence human AHRR in vivo, reduced ALT levels, attenuated lymphocyte infiltration on histology, and heightened frequencies of regulatory immune subsets in NOD/scid/gamma mice, reconstituted with human CD4 cells, and exposed to Con-A. In conclusion, blockade of AHRR in AIH restores Th17-cell response to AHR, and limits Th17-cell differentiation through generation of uridine. In vivo, silencing of AHRR attenuates liver damage in NOD/scid/gamma mice. Blockade of AHRR might therefore represent a novel therapeutic strategy to modulate effector Th17-cell immunity and restore homeostasis in AIH.

Racial Disparities in Candidates for Hepatocellular Carcinoma Liver Transplant After 6-Month Wait Policy Change.

Importance: Racial disparities in liver transplant (LT) for hepatocellular carcinoma (HCC) may be associated with unequal access to life-saving treatment. Objective: To quantify racial disparities in LT for HCC and mortality after LT, adjusting for demographic, clinical, and socioeconomic factors. Design, Setting, and Participants: This cohort study was a retrospective analysis of United Network Organ Sharing/Organ Procurement Transplant Network (OPTN) data from 2003 to 2021. Participants were adult patients with HCC on the LT waiting list and those who received LT. Data were analyzed from March 2022 to September 2023. Exposures: Race and time before and after the 2015 OPTN policy change. Main Outcomes and Measures: Proportion of LT from wait-listed candidates, the proportion of waiting list removals, and mortality after LT. Results: Among 12 031 patients wait-listed for LT with HCC (mean [SD] age, 60.8 [7.4] years; 9054 [75.3%] male; 7234 [60.1%] White, 2590 [21.5%] Latinx/o/a, and 1172 [9.7%] Black or African American), this study found that after the 2015 model of end-stage liver disease (MELD) exception policy changes for HCC (era 2), the overall proportion of LT for HCC across all races decreased while the proportion of dropouts on the LT waiting list remained steady compared with patients who did not have HCC. In Kaplan-Meier analysis, Asian patients demonstrated the lowest dropout rates in both era 1 and era 2 (1-year dropout, 16% and 17%, respectively; P < .001). In contrast, Black or African American patients had the highest dropout rates in era 1 (1-year dropout, 24%), but comparable dropout rates (23%) with White patients (23%) and Latinx/o/a patients in era 2 (23%). In both eras, Asian patients had the highest survival after LT (5-year survival, 82% for era 1 and 86% for era 2), while Black or African American patients had the worst survival after LT (5-year survival, 71% for era 1 and 79% for era 2). In the multivariable analysis for HCC LT recipients, Black or African American race was associated with increased risk of mortality in both eras, compared with White race (HR for era 1, 1.17; 95% CI, 1.05-1.35; and HR for era 2, 1.31; 95% CI, 1.10-1.56). Conclusions and Relevance: This cohort study of LT candidates in the US found that after the 2015 MELD exception policy change for HCC, the proportion of LT for HCC had decreased for all races. Black or African American patients had worse outcomes after LT than other races. Further research is needed to identify the underlying causes of this disparity and develop strategies to improve outcomes for HCC LT candidates.

Two Decades of Liver Transplants for Primary Biliary Cholangitis: A Comparative Study of Living Donors vs. Deceased Donor Liver Transplantations.

Primary biliary cholangitis (PBC) prompts liver transplantation (LT) due to cholestasis, cirrhosis, and liver failure. Despite lower MELD scores, recent studies highlight higher PBC waitlist mortality, intensifying the need for alternative transplantation strategies. Living donor liver transplant (LDLT) has emerged as a solution to the organ shortage. This study compares LDLT and deceased donor liver transplant (DDLT) outcomes in PBC patients via retrospective analysis of the UNOS database (2002-2021). Patient survival, graft failure, and predictors were evaluated through Kaplan-Meier and Cox-proportional analyses. Among 3482 DDLTs and 468 LDLTs, LDLT showed superior patient survival (92.3%, 89.1%, 87.6%, 85.0%, 77.2% vs. 91.5%, 88.3%, 86.3%, 82.2%, 71.0%; respectively; p = 0.02) with no significant graft survival difference at 1-, 2-, 3-, 5-, and 10-years post-LT (91.0%, 88.0%, 85.7%, 83.0%, 75.4% vs. 90.5%, 87.4%, 85.3%, 81.3%, 70.0%; respectively; p = 0.06). Compared to DCD, LDLT showed superior patient and graft survival (p < 0.05). Younger male PBC recipients with a high BMI, diabetes, and dialysis history were associated with mortality and graft failure (p < 0.05). Our study showed that LDLT had superior patient survival to DDLT. Predictors of poor post-LT outcomes require further validation studies.

Racial, ethnic, and socioeconomic disparities impact post-liver transplant survival in patients with hepatocellular carcinoma.

INTRODUCTION AND OBJECTIVES: Liver transplantation can be a curative treatment for patients with hepatocellular carcinoma (HCC); however, the morbidity and mortality associated with HCC varies by socioeconomic status and race and ethnicity. Policies like Share 35 were implemented to ensure equitable access to organ transplants; however, their impacts are unclear. We aimed to characterize differences in post-liver transplant (LT) survival among patients with HCC, when considering race and ethnicity, income, and insurance type, and understand if these associations were impacted by Share 35. MATERIALS AND METHODS: We conducted a retrospective cohort study of 30,610 adult LT recipients with HCC. Data were obtained from the UNOS database. Survival analysis was carried out using Kaplan-Meier curves, and multivariate Cox regression analysis was used to calculate hazard ratios. RESULTS: Men (HR: 0.90 (95% CI: 0.85-0.95)), private insurance (HR: 0.91 (95% CI: 0.87-0.92)), and income (HR: 0.87 (95% CI: 0.83-0.92)) corresponded with higher post-LT survival, when adjusted for over 20 demographic and clinical characteristics (Table 2). African American or Black individuals were associated with lower post-LT survival (HR: 1.20 (95% CI: 1.12-1.28)), whereas. Asian (HR: 0.79 (95% CI: 0.71-0.88)) or Hispanic (HR: 0.86 (95% CI: 0.81-0.92)) individuals were associated with higher survival as compared with White individuals (Table 2). Many of these patterns held in the pre-Share 35 and Share 35 periods. CONCLUSIONS: Racial, ethnic, and socioeconomic disparities at time of transplant, such as private insurance and income, influence post-LT survival in patients with HCC. These patterns persist despite the passage of equitable access policies, such as Share 35.

Living-Donor Liver Transplant and Improved Post-Transplant Survival in Patients with Primary Sclerosing Cholangitis.

Primary sclerosing cholangitis (PSC) is the leading indication of liver transplantation (LT) among autoimmune liver disease patients. There is a scarcity of studies comparing survival outcomes between living-donor liver transplants (LDLT)s and deceased-donor liver transplants (DDLTs) in this population. Using the United Network for Organ Sharing database, we compared 4679 DDLTs and 805 LDLTs. Our outcome of interest was post-LT patient survival and post-LT graft survival. A stepwise multivariate analysis was performed, adjusting for recipient age, gender, diabetes mellitus, ascites, hepatic encephalopathy, cholangiocarcinoma, hepatocellular carcinoma, race, and the model for end-stage liver disease (MELD) score; donor' age and sex were also included to the analysis. According to univariate and multivariate analysis, LDLT had a patient and graft survival benefit compared to DDLT (HR, 0.77, 95% CI 0.65-0.92; p < 0.002). LDLT patient survival (95.2%, 92.6%, 90.1%, and 81.9%) and graft survival (94.1%, 91.1%, 88.5%, and 80.5%) at 1, 3, 5, and 10 years were significantly better than DDLT patient survival (93.2%, 87.6%, 83.3%, and 72.7%) and graft survival (92.1%, 86.5%, 82.1%, and 70.9%) (p < 0.001) in the same interval. Variables including donor and recipient age, male recipient gender, MELD score, diabetes mellitus, hepatocellular carcinoma, and cholangiocarcinoma were associated with mortality and graft failure in PSC patients. Interestingly, Asians were more protected than Whites (HR, 0.61; 95% CI, 0.35-0.99; p < 0.047), and cholangiocarcinoma was associated with the highest hazard of mortality (HR, 2.07; 95% CI, 1.71-2.50; p < 0.001) in multivariate analysis. LDLT in PSC patients were associated with greater post-transplant patient and graft survival compared to DDLT patients.

Management of Primary Biliary Cholangitis: Current Treatment and Future Perspectives.

Primary biliary cholangitis is an autoimmune cholestatic liver disease characterized by progressive destruction of bile ducts, which can ultimately progress to chronic liver disease and cirrhosis. Ursodeoxycholic acid and obeticholic acid are the only 2 Food and Drug Administration (FDA)-approved medications for primary biliary cholangitis. Unfortunately, up to 40% of patients with primary biliary cholangitis have an incomplete response to ursodeoxycholic acid, warranting an essential need for additional therapeutics. Peroxisome proliferator-activated receptor agonists have shown promising data supporting their use as disease-modifying therapies. Fibroblast growth factor-19 agonists, farnesoid X receptor agonists, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 3 inhibitors are additional agents under investigation as potential disease-modifying therapy. However, evidence supporting the use of certain novel therapies over others is sparse. There is a need for additional clinical trials as well as research aimed at the underlying pathophysiology of primary biliary cholangitis to discover additional therapeutic targets.

Pharmacological Therapy of Pruritus in Primary Biliary Cholangitis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

GOALS: We aim to summarize the current management of pruritus in primary biliary cholangitis (PBC) by evaluating the efficacy and safety of pharmacological therapies. BACKGROUND: Pruritus is a common symptom of PBC, and evidence regarding the most effective antipruritic agents available is lacking. New pharmacotherapy for PBC has shown promising antipruritic effects. STUDY: We performed a systematic literature review and meta-analysis including all available double-blind, randomized, placebo-controlled clinical trials that evaluated the efficacy of pharmacotherapy for the symptomatic management of pruritus in PBC. Pruritus was assessed as either a change from baseline or a postintervention score. RESULTS: We included 33 studies and 20 medications. Using the visual analog scale, cholestyramine did not significantly improve pruritus compared with placebo [standardized mean differences (SMD): -0.94, 95% CI: -2.05 to 0.17], whereas rifampin and nalfurafine hydrochloride both significantly improved pruritus (SMD: -3.29, 95% CI: -5.78 to -0.80; n=23 and SMD: -0.58, 95% CI: -1.04 to -0.12). In addition, Bezafibrate and linerixibat significantly improved pruritus (SMD: -1.05, 95% CI: -1.41 to -0.68; n=110 and SMD: -0.31, 95% CI: -0.62 to -0.04, respectively). This effect was also present within the subgroup analysis by pruritus scale, where both bezafibrate and linerixibat significantly improved pruritus compared with placebo (SMD: -1.09, 95% CI: -1.54 to -0.65; P <0.001; visual analog scale; as postintervention score and SMD: -0.31, 95% CI: -0.62 to -0.01; P =0.04; numeric rating scale; as a change from baseline score, respectively). CONCLUSIONS: Bezafibrate and Linerixibat are potential second-line antipruritic medications for PBC, particularly those with moderate to severe pruritus.

Factors Associated With Complete Pathologic Necrosis of Hepatocellular Carcinoma on Explant Evaluation After Locoregional Therapy: A National Analysis Using the UNOS Database.

BACKGROUND. Complete pathologic necrosis (CPN) is associated with improved survival in patients who undergo liver transplant (LT) after locoregional therapy (LRT) for hepatocellular carcinoma (HCC). OBJECTIVE. The purpose of this article was to identify patient, HCC, and transplant center characteristics associated with rates of CPN on explant evaluation using a large national sample of patients undergoing LT after LRT for HCC measuring 3 cm or smaller. METHODS. This retrospective study used data from the United Network for Organ Sharing database. The study included 6265 adults (median age, 62 years; 1505 women, 4760 men) who underwent LT after a single type of LRT (either transarterial chemoembolization [TACE], thermal ablation, or transarterial radioembolization [TARE]) for HCCs measuring 3 cm or smaller at one of 118 U.S. transplant centers from April 12, 2012, to March 31, 2020. Patients were classified as having CPN if explant evaluation showed 100% necrosis of all HCCs. Associations with CPN were explored. Centers were categorized into tertiles on the basis of center-level CPN rates, and tertiles were compared. RESULTS. LRT was performed by TACE in 69.5% (4352/6265), thermal ablation in 19.4% (1217/6265), and TARE in 11.1% (696/6265) of patients. CPN rate was 18.5% (805/4352) after TACE, 35.8% (436/1217) after thermal ablation, 33.6% (234/696) after TARE, and 23.5% (1475/6265) overall. In multivariable analysis incorporating age, sex, model for end-stage liver disease score, α-fetoprotein level before LRT, wait list time, number of HCCs, HCC size, and the transplant center (as a random factor), use of thermal ablation (OR, 2.19; 95% CI, 1.86-2.57; p < .001) or TARE (OR, 1.92; 95% CI, 1.57-2.36; p < .001), with TACE as reference, independently predicted greater likelihood of CPN. Center-level CPN rates ranged from 0.0% to 50.0%. With centers stratified by CPN rates, ablation was performed more frequently than TACE in 5.0% of centers in the first, 15.4% in the second, and 23.1% in the third tertiles (p = .07). CONCLUSION. CPN rate on explant evaluation was low. Thermal ablation or TARE, rather than TACE, was associated with higher likelihood of CPN in patient-level and center-level analyses. CLINICAL IMPACT. Findings from this large national sample support a potential role of thermal ablation or TARE for achieving CPN of HCC measuring 3 cm or smaller.

Waitlist and posttransplantation outcomes of lean individuals with nonalcoholic fatty liver disease.

Lean individuals with nonalcoholic fatty liver disease (NAFLD) represent a subset of patients with a distinct risk factor profile. We assessed the association between body mass index (BMI) on waitlist and postliver transplantation (LT) outcomes among these patients. We retrospectively analyzed the United Network for Organ Sharing data, including adult patients with NAFLD listed for LT between February 27, 2002, and June 30, 2020. We first used competing risk analyses to estimate the association of BMI with waitlist removal due to death or clinical deterioration. We then conducted Kaplan-Meier estimates and Cox regression models to determine the impact of weight change during the waiting list on all-cause mortality and graft failure after LT. Patients with normal weight (BMI 18.5-24.9 kg/m 2 ) suffered higher waitlist removal (adjusted subdistribution hazard ratio 1.26, 95% confidence interval [CI] 1.10-1.43; p = 0.001) compared with patients with obesity class I (BMI 30-34.9 kg/m 2 ). Those who remained at normal weight had higher all-cause mortality (adjusted hazard ratio [aHR] 1.61, 95% CI 1.32-1.96; p <0.001) and graft failure (aHR 1.57, 95% CI 1.32-1.88; p <0.001) than patients with stable obesity. Among patients with normal weight, those with the greatest weight increase (BMI gain ≥3 kg/m 2 ) had lower all-cause mortality (aHR 0.55, 95% CI 0.33-0.93; p = 0.03) and graft failure (aHR 0.49, 95% CI 0.30-0.81; p = 0.01) compared with patients with stable weight (BMI change ≤1 kg/m 2 ). Patients with NAFLD with normal weight have increased waitlist removal and those who remained at normal weight during the waitlist period have worse posttransplantation outcomes. Identifying and addressing factors influencing apparent healthy weight prior to LT are crucial to mitigate poor outcomes.

Liver Transplantation for Budd-Chiari Syndrome in the MELD Era.

To evaluate clinical characteristics and factors associated with survival among liver transplantation (LT) recipients with Budd-Chiari syndrome (BCS), with or without transjugular intrahepatic portosystemic shunt (TIPS), in the post-Model for End-stage Liver Disease era. Methods: We extracted data from the United Network for Organ Sharing database on all adult (≥18 y old) waitlisted candidates and recipients of LT with BCS in the United States between 2002 and 2019. Multivariable Cox regression was used to determine predictors of mortality and hazard ratios (HRs). Results: A total of 647 BCS patients were waitlisted between 2002 and 2019. BCS was an indication for LT in 378 (0.2%) of all adult LT recipients during the study period. Of BCS patients who received LT, approximately three-fourths (72.3%) were alive for up to 10 y. We found no significant difference in LT outcomes in BCS patients with or without TIPS. Longer length of hospital stay following LT (HR, 1.32; 95% confidence interval [CI], 1.19-1.47), Black/African American race (HR, 2.24; 95% CI, 1.38-3.64), diabetes (HR, 3.17; 95% CI, 1.62-6.21), donor risk index (HR, 1.44; 95% CI, 1.05-1.99), and lower albumin levels at the time of transplantation (HR, 0.66; 95% CI, 0.50-0.88) were negatively associated with survival after LT. Interestingly, neither the Model for End-stage Liver Disease nor prior TIPS showed a significant association with survival after LT. Conclusions: These findings demonstrate good comparable survival among TIPS versus no TIPS in LT recipients with BCS. The decision for TIPS versus LT should be individualized on a case-by-case basis.

Regional and National Trends of Adult Living Donor Liver Transplantation in the United States Over the Last Two Decades.

Background and Aims: Liver organ shortage remains a major health burden in the US, with more patients being waitlisted than the number of liver transplants (LTs) performed. This study investigated US national and regional trends in living donor LT (LDLT) and identified factors associated with recipient survival. Methods: We retrospectively analyzed LDLT recipients and donors from the United Network Organ Sharing/Organ Procurement Transplant Network database from 1998 until 2019 for clinical characteristics, demographic differences, and survival rate. National and regional trends in LDLT, recipient outcomes, and predictors of survival were analyzed. Results: Of the 223,571 candidates listed for an LT, 57.5% received an organ, of which only 4.2% were LDLTs. Annual adult LDLTs first peaked at 412 in 2001 but experienced a significant decline to 168 by 2009. LDLTs then gradually increased to 445 in 2019. Region 2 had the highest LDLT numbers (n=919), while region 1 had the highest proportion (11.1%). Overall, post-LT mortality was 21.4% among LDLT recipients. Post-LDLT survival rates after 1-, 5-, and 10-years were 92%, 87%, and 70%, respectively. Interval analysis (2004-2019) showed that patients undergoing LDLT in recent years had lower mortality than in earlier years (hazard ratio=0.81, 95% confidence interval=0.75-0.88). Conclusions: Following a substantial decline after a peak in 2001, the number of adult LDLTs steadily increased from 2011 to 2019. However, LDLTs still constitute the minority of the transplant pool in the US. Life-saving policies to increase the use of LDLTs, particularly in regions of high organ demand, should be implemented.

Liver stiffness measurement by vibration-controlled transient elastography improves outcome prediction in primary biliary cholangitis.

BACKGROUND & AIMS: Liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE) has been shown to predict outcomes of patients with primary biliary cholangitis (PBC) in small-size studies. We aimed to validate the prognostic value of LSM in a large cohort study. METHODS: We performed an international, multicentre, retrospective follow-up study of 3,985 patients with PBC seen at 23 centres in 12 countries. Eligibility criteria included at least 1 reliable LSM by VCTE and a follow-up ≥ 1 year. Independent derivation (n = 2,740) and validation (n = 568) cohorts were built. The primary endpoint was time to poor clinical outcomes defined as liver-related complications, liver transplantation, or death. Hazard ratios (HRs) with CIs were determined using a time-dependent multivariable Cox regression analysis. RESULTS: LSM was independently associated with poor clinical outcomes in the derivation (5,324 LSMs, mean follow-up 5.0 ± 3.1 years) and validation (1,470 LSMs, mean follow-up 5.0 ± 2.8 years) cohorts: adjusted HRs (95% CI) per additional kPa were 1.040 (1.026-1.054) and 1.042 (1.029-1.056), respectively (p <0.0001 for both). Adjusted C-statistics (95% CI) at baseline were 0.83 (0.79-0.87) and 0.92 (0.89-0.95), respectively. Between 5 and 30 kPa, the log-HR increased as a monotonic function of LSM. The predictive value of LSM was stable in time. LSM improved the prognostic ability of biochemical response criteria, fibrosis scores, and prognostic scores. The 8 kPa and 15 kPa cut-offs optimally separated low-, medium-, and high-risk groups. Forty percent of patients were at medium to high risk according to LSM. CONCLUSIONS: LSM by VCTE is a major, independent, validated predictor of PBC outcome. Its value as a surrogate endpoint for clinical benefit in PBC should be considered. LAY SUMMARY: Primary biliary cholangitis (PBC) is a chronic autoimmune disease, wherein the body's immune system mistakenly attacks the bile ducts. PBC progresses gradually, so surrogate markers (markers that predict clinically relevant outcomes like the need for a transplant or death long before the event occurs) are often needed to expedite the drug development and approval process. Herein, we show that liver stiffness measurement is a strong predictor of clinical outcomes and could be a useful surrogate endpoint in PBC trials.

Waitlist mortality in patients with autoimmune liver diseases.

INTRODUCTION AND OBJECTIVES: Autoimmune liver diseases such as autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis are the primary indication for ∼24% of total liver transplants. The liver transplant allocation system is currently based upon the Model for End-Stage Liver Disease and it often underestimates the severity of autoimmune liver diseases. We aim to compare the rate of adverse waitlist removal among patients with all autoimmune liver diseases and other indications for liver transplant in the Model for End-Stage Liver -Na era. MATERIALS AND METHODS: Using the United Network for Organ Sharing database, we identified all patients listed for liver transplant from 2016 to 2019. The outcome of interest was waitlist survival defined as the composite outcome of death or removal for clinical deterioration. Competing risk analysis was used to evaluate the waitlist survival. RESULTS: Patients with autoimmune hepatitis had a higher risk of being removed from the waitlist for death or clinical deterioration (SHR 1.37, 95% CI 1.08-1.72; P<0.007), followed by primary biliary cholangitis (SHR 1.34, 95% CI 1.07-1.68; P<0.011). CONCLUSIONS: High waitlist death or removal for clinical deterioration was observed in patients with PBC and AIH when compared to other etiologies. It may be useful to reassess the process of awarding MELD exception points to mitigate such disparity.

Long-Term Outcomes of Living Donor Versus Deceased Donor Liver Transplant for Hepatocellular Carcinoma in the United States.

OBJECTIVES: Although living donor liver transplant has become a vital treatment option in hepatocellular carcinoma, controversy remains on whether recurrence and survival rates are different versus deceased donor recipients. Here, we compared clinical characteristics and outcomes between recipients of living and deceased donor liver transplants for hepatocellular carcinoma in the United States. MATERIALS AND METHODS: Our comparisons used data from the United Network of Organ Sharing/Organ Procurement and Transplantation Network. RESULTS: There were 385 living donor and 25 274 deceased donor liver transplant recipients with diagnosis of hepatocellular carcinoma. Transplant list wait times of ≥6 months were more common in deceased donor(55.9%) versus living donor recipients (45.2%; P < .001). Both recipient groups were comparable with regard to alpha-fetoprotein level <200 ng/mL (P = .18). Only a small percentage in both groups had ≥3 total tumors (P = .73); both groups had similar low transplants outside of Milan criteria (P = .45). Overall, 1-, 5-, and 10-year overall survival rates for deceased versus living donor recipients were similar (91.2% vs 92%, 74% vs 76.4%, 58.9% vs 56.5%; P = .69). On multivariate analysis, Black/African American race/ethnicity was associated with worse outcomes than White race/ethnicity as reference (P < .001), whereas Hispanic and Asian race/ethnicity were more protected. Hepatitis C virus as liver disease etiology was associated with worse outcomes than other etiologies. Tumor characteristics, ≥3 lesions, tumor size, and higher alpha-fetoprotein levels were associated with worse outcomes. Living donor transplant was not associated with higher hazard of death. Among living donor recipients only, largest tumor size was associated with higher risk of death (P = .005). CONCLUSIONS: Survival was similarin between the living donor versus deceased donor recipients with hepatocellular carcinoma. With changes in Model for End-Stage Liver Disease exception policies for hepatocellular carcinoma in the United States, living donor transplant for hepatocellular carcinoma could expand the donor pool.

Cholestatic Liver Disease and Pregnancy: A Systematic Review and Meta-Analysis.

Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are two types of chronic cholestatic liver disease (CCLD). Little is known regarding the relationship between these conditions and pregnancy. We performed a systematic review and meta-analysis regarding the maternal and fetal outcomes amongst patients with a known diagnosis of PBC and PSC undergoing pregnancy. Our analysis shows that patients with PBC and PSC who undergo pregnancy are at an increased risk of pre-term delivery, as well as the development of new or worsening pruritus during pregnancy. Additionally, patients with PBC are at higher risk of undergoing a biochemical disease flare during the postpartum period compared to during pregnancy. However, there were no documented cases of maternal mortality or development of decompensated cirrhosis during pregnancy or the postpartum period.