Availability of living donor optimizes timing of liver transplant in high-risk waitlisted cirrhosis patients.

Liver transplant (LT) candidates have become older and frailer, with growing Non-alcoholic steatohepatitis (NASH) and comorbid disease burden in recent years, predisposing them for poor waitlist outcomes. We aimed to evaluate the impact of access to living donor liver transplantation (LDLT) in waitlisted patients at highest risk of dropout. We reviewed all adult patients with decompensated cirrhosis listed for LT from November 2012 to December 2018. Patients with a potential living donor (pLD) available were identified. Survival analyses with Cox Proportional Hazards models and time to LT with Competing risk models were performed followed by prediction model development. Out of 860 patients who met inclusion criteria, 360 (41.8%) had a pLD identified and 496 (57.6%) underwent LT, out of which 170 (34.2%) were LDLT. The benefit of pLD was evident for all, but patients with moderate to severe frailty at listing (interaction p = 0.03), height <160 cm (interaction p = 0.03), and Model for end stage liver disease (MELD)-Na score <20 (interaction p < 0.0001) especially benefited. Our prediction model identified patients at highest risk of dropout while waiting for deceased donor and most benefiting of pLD (time-dependent area under the receiver operating characteristic curve 0.82). Access to LDLT in a transplant program can optimize the timing of transplant for the increasingly older, frail patient population with comorbidities who are at highest risk of dropout.

Divergent trajectories of lean vs obese non-alcoholic steatohepatitis patients from listing to post-transplant: A retrospective cohort study.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) cirrhosis is the second most common indication for liver transplantation (LT). The role of body mass index (BMI) on outcomes of NASH cirrhosis has been conflicting. AIM: To compare the longitudinal trajectories of patients with lean vs obese NASH cirrhosis, from listing up to post-transplant, having adjusted their BMI for ascites. METHODS: We retrospectively reviewed all adult NASH patients listed for LT in our program from 2012 to 2019. Fine-Gray Competing Risk analyses and Cox Proportional-Hazard Models were performed to examine the cumulative incidence of transplant and survival outcomes respectively. RESULTS: Out of 265 NASH cirrhosis listed patients, 176 were included. Median age was 61.0 years; 46% were females. 111 patients underwent LT. Obese robust patients had better waitlist survival [hazard ratio (HR): 0.12; 95%CI: 0.05-0.29, P < 0.0001] with higher instantaneous rate of transplant (HR: 5.71; 95%CI: 1.26-25.9, P = 0.02). Lean NASH patients had a substantially higher risk of graft loss within 90 d post-LT (1.2% vs 13.8%, P = 0.032) and death post-LT (2.4% vs 17.2%, P = 0.029). 1- 3- and 5-year graft survival was poor for lean NASH (78.6%, 77.3% and 41.7% vs 98.6%, 96% and 85% respectively). Overall patient survival post-LT was significantly worse in lean NASH (HR: 0.17; 95%CI: 0.03-0.86, P = 0.0142) with 83% lower instantaneous rate of death in obese group. CONCLUSION: Although lean NASH is considered to be more benign than obese NASH, our study suggests a paradoxical correlation of lean NASH with waitlist outcomes, and graft and patient survival post-LT.

Autologous Hematopoietic Stem Cell Transplantation for Liver Transplant Recipients With Recurrent Primary Sclerosing Cholangitis: A Pilot Study.

BACKGROUND: Primary sclerosing cholangitis (PSC) is an indication for liver transplantation, but recurrence after liver transplantation is associated with poor outcomes often requiring repeat transplantation. We investigated whether autologous hematopoietic stem cell transplantation (aHSCT) could be used to stop progression of recurrent PSC and promote operational tolerance. METHODS: Twelve patients with recurrent PSC were fully evaluated and 5 were selected for aHSCT. Autologous hematopoietic stem cells were collected, purified by CD34 immunomagnetic selection, and cryopreserved. Immunoablation using busulfan, cyclophosphamide, and rabbit antithymocyte globulin was followed by aHSCT. The primary endpoint of the study was the establishment of operational tolerance defined as lack of biochemical, histologic, and clinical evidence of rejection while off immunosuppression at 2 y post-aHSCT. RESULTS: Two of the 5 patients achieved operational tolerance with no clinical or histologic evidence of PSC progression or allorejection. A third patient developed sinusoidal obstruction syndrome following aHSCT requiring repeat liver transplantation but has no evidence of PSC recurrence while on sirolimus monotherapy now >3 y after aHSCT. A fourth patient was weaned off immunosuppression but died 212 d after aHSCT from pericardial constriction. A fifth patient died from multiorgan failure. Immunosuppression-free allograft acceptance was associated with deletion of T-cell clones, loss of autoantibodies, and increases in regulatory T cells, transitional B cells, and programmed cell death protein-1 expressing CD8+ T cells in the 2 long-term survivors. CONCLUSIONS: Although operational tolerance occurred following aHSCT, the high morbidity and mortality observed render this specific protocol unsuitable for clinical adoption.

Results of Early Transplantation for Alcohol-Related Cirrhosis: Integrated Addiction Treatment With Low Rate of Relapse.

BACKGROUND & AIMS: In 2018, our team initiated a prospective pilot program to challenge the paradigm of the "6-month rule" of abstinence for patients with alcohol-related liver disease (ALD) requiring transplant. Our pilot involved an in-depth examination of patients' alcohol use, social support, and psychiatric comorbidity, as well as the provision of pre- and post-transplantation addiction treatment. METHODS: Patients with ALD were assessed for inclusion in the pilot by a multidisciplinary team. Relapse prevention therapy was provided directly to all patients deemed to meet the program's inclusion criteria. Random biomarker testing for alcohol was used pre and post transplantation. RESULTS: We received 703 referrals from May 1, 2018 to October 31, 2020. After fulfilling the program's criteria, 101 patients (14%) were listed for transplantation and 44 (6.2%) received transplants. There were no significant differences in survival rates between those receiving transplants through the pilot program compared with a control group with more than 6 months of abstinence (P = .07). Three patients returned to alcohol use during an average post-transplantation follow-up period of 339 days. In a multivariate analysis, younger age and lower Model for End-Stage Liver Disease scores at listing were associated with an increased likelihood of a return to alcohol use (P < .05); length of abstinence was not a predictor. CONCLUSIONS: Our prospective program provided direct monitoring and relapse prevention treatment for patients with ALD and with less than 6 months of abstinence and resulted in a reduction of post-transplantation return to drinking. This pilot study provides a framework for the future of more equitable transplant care.

Sex Disparity in Liver Transplant and Access to Living Donation.

Importance: The Model for End-stage Liver Disease (MELD)-based organ allocation system has significantly decreased mortality on the transplant waiting list for patients with end-stage liver disease. However, women have remained at a disadvantage with respect to access to deceased donor liver transplant (DDLT) even after introduction of the MELD score for organ allocation. Objective: To determine whether availability of living donation in a transplant program can offset inequity in liver transplant (LT) allocation for women. Design, Setting, and Participants: This cohort study retrospectively analyzed adult patients listed for LT at the University Health Network in Toronto, Ontario, Canada. Patients included had a potential living donor (pLD) at the moment of listing. This study was performed from November 13, 2012, to May 31, 2019. A total of 1289 listed patients (830 men; 459 women) were analyzed during the study period. Main Outcomes and Measures: This study performed survival analysis and competing-risk analysis to delineate how access to livers from living donors was associated with events in women vs men on the transplant waiting list (LT, death, or dropout). Results: Of 1289 included patients, 459 (35.6%) were women, and the mean (SD) age was 56.1 (10.0) years at assessment and listing. A total of 783 of 1289 listed patients underwent LT. Among those with no pLD at assessment, there was a higher median (range) Model for End-stage Liver Disease incorporating sodium levels (MELD-Na) score at listing (22 [6-50] vs 19 [6-50]; P < .001) and at LT (27 [6-49] vs 20 [6-52]; P < .001) in women receiving DDLT. Women were at a significant disadvantage without a pLD (hazard ratio [HR], 1.29; 95% CI, 1.04-1.60; P = .01); there was no difference in access to LT with availability of a pLD (HR, 0.93; 95% CI, 0.76,-1.14; P = .44). The instantaneous rate of receiving a transplant in men with a pLD was 1.39 times higher than men who did not have a pLD (HR, 1.39; 95% CI; P < .001) and the instantaneous rate of receiving a transplant in women with a pLD was 1.92 times higher than in women who did not (HR, 1.92; 95% CI, 1.51-2.44; P < .001). The HR was 1.38 times higher in women compared with men across the MELD-Na score strata (HR, 1.38; 95% CI, 1.03-1.84; P = .03) and 2.04 times higher when the MELD-Na score was less than 20 (HR, 2.04; 95% CI, 1.31-3.14; P = .001). Conclusions and Relevance: These study findings suggest that women can overcome the complex problem of allocation inequity with access to livers from living donors. Women with access only to DDLT were much more unwell than men independent of liver disease at the time of listing, dropout, or LT. Therefore, the wider availability of living donation liver transplant would be helpful in addressing the sex disparity in access to LT in the current MELD-Na era.

Early Allograft Dysfunction After Liver Transplantation With Donation After Circulatory Death and Brain Death Grafts: Does the Donor Type Matter?

BACKGROUND: Early allograft dysfunction (EAD) after liver transplantation has been associated with long-term reduced graft and patient survival. METHODS: In this single-center cohort study, we aimed to compare incidence, risk factors, and outcomes in liver transplant recipients who developed EAD. Patients who received donation after circulatory death (DCD) or donation after brain death (DBD) grafts between January 2007 and December 2017 were included. EAD was defined as bilirubin of ≥10 mg/dL (171 µmol/L) or an international normalized ratio of ≥1.6 on postoperative day 7 or transaminases >2000 U\L in the first-week posttransplantation as previously described. RESULTS: In our cohort of 1068 patients, incidence of EAD was 44%. EAD occurred more frequently in the DCD versus DBD group (71% versus 41%, P < 0.01). Overall, recipients who developed EAD showed a significantly lower graft and patient survival at 1, 3, and 5 y after transplantation (all P < 0.05). This was also the case for recipients of DBD grafts. However, for recipients of DCD grafts, patient and graft survival were not affected by the presence of EAD. For recipients of DBD grafts, donor age, body mass index (BMI) and gender, recipient BMI and model for end-stage liver disease score and warm and cold ischemia time were associated with EAD. For DCD recipients, donor BMI and cold ischemia time were associated with EAD. CONCLUSIONS: In our cohort study, EAD resulted in reduced long-term patient and graft survival only for DBD recipients but not for DCD recipients. Predictive markers for EAD were dependent on the donor type.

The Impact of Primary Liver Disease and Social Determinants in a Mixed Donor Liver Transplant Program: A Single-Center Analysis.

Organ allocation in liver transplantation (LT) remains imperfect. Periodic center reviews ensure programs transparently evaluate the impact of practice on access to transplantation, reflecting, in particular, patient (primary disease, social determinants) and program (deceased versus live donation) factors. Adult Ontario residents waitlisted for first LT at Toronto General Hospital from November 2012 to May 2019 were reviewed. Analyses were performed between distance to transplant center, income, education level, population density and primary liver disease, with LT, deceased donor liver transplant (DDLT), living donor liver transplant (LDLT), and delisting. Of 1735 listed patients, 549 were delisted (32%), while 1071 were transplanted (62%), with 819 DDLT recipients (76%) and 252 LDLT recipients (24%), while 115 (7%) remained actively listed at data census. On univariate analysis, DDLT recipients lived 30% closer (median 39.7 versus 60.6 km; P < 0.001), lived in more populous areas (median 8501.0 versus 6868.5 people in a 1-km radius; P < 0.001), and resided in households that annually earned 10% less (median $92,643.17 versus $102,820.89 Canadian dollars; P < 0.001) compared with LDLT recipients. These findings with population density and income differences between DDLT versus LDLT receival remained significant on multivariate modeling even when accounting for primary liver disease. Primary liver disease was a statistically significant factor on multivariate analyses in LT receival (P = 0.001) as well as DDLT versus LDLT receival (P < 0.001). Of patients listed for end-stage liver disease, more patients with autoimmune cholestatic liver diseases received LDLT (34%-41%) than DDLT (27%-30%); this contrasted with patients with noncholestatic diseases LDLT (8%-19%) versus DDLT (37%-59%) receival (P < 0.001). Review of transplant allocation in a large mixed-donor North American liver transplant program demonstrates how patient social determinants and primary liver disease etiology continue to be significantly associated with ultimate transplantation.

Single-Center North American Experience of Liver Transplantation in Autoimmune Hepatitis: Infrequent Indication but Good Outcomes for Patients.

BACKGROUND AND AIMS: A 40% risk of disease recurrence post-liver transplantation (LT) for autoimmune hepatitis (AIH) has been previously reported. Risk factors for recurrence and its impact on long-term patient outcome are poorly defined. We aimed to assess prevalence, time to disease recurrence, as well as patient and graft survival in patients with recurrent AIH (rAIH) versus those without recurrence. METHODS: Single-center retrospective study of adult recipients who underwent LT for AIH between January 2007 and December 2017. Patients with AIH overlap syndromes were excluded. RESULTS: A total of 1436 LTs were performed during the study period, of whom 46 (3%) for AIH. Eight patients had AIH overlap syndromes and were excluded. Patients were followed up for 4.4 ± 3.4 years and mean age at LT was 46.8 years. Average transplant MELD (Model for End-Stage Liver Disease) score was 24.9. About 21% of patients (8 of 38) were transplanted for acute onset of AIH; 66% of patients (n = 25) received a deceased donor liver graft, and 34% a living donor organ. rAIH occurred in 7.8% (n = 3/38) of recipients. Time to recurrence was 1.6, 12.2 and 60.7 months. Patient and graft survival in patients without recurrence was 88.6% and 82.8% in 5 years, whereas in those with rAIH, it was 66.7%, respectively. CONCLUSION: Although AIH recurs post-LT, our data indicate a lower recurrence rate when compared to the literature and excellent patient and graft survival.

Liver transplantation in adult polycystic liver disease: the Ontario experience.

BACKGROUND: Liver transplantation (LT) remains the curative treatment for symptomatic Polycystic Liver Disease (PCLD) patients and is associated with excellent survival rates. The aim of the study is to review the Ontario experience in LT for PCLD. METHODS: A retrospective study was performed from pre-existing LT databases from the LT Units at Toronto General Hospital and London Health Sciences Center, which are the two LT programs in Ontario, Canada. This database contains demographic, clinical parameters and follow-up of all patients transplanted for PCLD. Data was extracted for patients who underwent LT between January 2000-April 2017 and included follow up until December 31st, 2018. RESULTS: A total of 3560 patients underwent LT, of whom 51 (1.4%) had PCLD and met inclusion criteria. 43 (84%) of these patients were female. The median physiologic Model for End Stage Liver Disease (MELD-Na) score at time of referral was 13 (IQR = 7-22), however all patients required MELD-Na exception points to receive LT. The median age of transplant was 62 years (IQR = 59-64) for male vs. 52 (IQR = 45-56) for female patients. 33 (65%) of our cohort had PCLD while 9 (17.5%) had ADPKD and 9 (17.5%) had both diseases. 39 (76%) had LT due to symptoms of mass effect, while 8 (16%) had portal hypertensive complications. After a median follow-up of 6.3 (IQR = 2.9-12.5) years, the probability of survival was 96% (95% CI: 90%, 100%). Log-rank test, comparing survival analysis between males and females did not show a statistically significant difference (p = 0.26). CONCLUSION: Most patients underwent LT for PCLD due to symptoms of mass effect with women being more likely than men to undergo LT. LT for PCLD had excellent long-term survival.

Living donor liver paired exchange: A North American first.

Paired organ exchange can be used to circumvent living donor-recipient ABO incompatibilities. Herein, we present the first case of successful liver paired exchange in North America. This 2-way swap required 4 simultaneous operations: 2 living donor hepatectomies and 2 living donor liver transplants. A nondirected anonymous living donor gift initiated this domino exchange, alleviating an ABO incompatibility in the other donor-recipient pair. With careful attention to ethical and logistical issues, paired liver exchange is a feasible option to expand the donor pool for incompatible living liver donor-recipient pairs.

Outcomes of Highly Selected Live Donors With a Future Liver Remnant Less Than or Equal to 30%: A Matched Cohort Study.

BACKGROUND: The main concern with live donor liver transplantation (LDLT) is the risk to the donor. Given the potential risk of liver insufficiency, most centers will only accept candidates with future liver remnants (FLR) >30%. We aimed to compare postoperative outcomes of donors who underwent LDLT with FLR ≤30% and >30%. METHODS: Adults who underwent right hepatectomy for LDLT between 2000 and 2018 were analyzed. Remnant liver volumes were estimated using hepatic volumetry. To adjust for between-group differences, donors with FLR ≤30% and >30% were matched 1:2 based on baseline characteristics. Postoperative complications including liver dysfunction were compared between the groups. RESULTS: A total of 604 live donors were identified, 28 (4.6%) of whom had a FLR ≤30%. Twenty-eight cases were successfully matched with 56 controls; the matched cohorts were mostly similar in terms of donor and graft characteristics. The calculated median FLR was 29.8 (range, 28.0-30.0) and 35.2 (range, 30.1-68.1) in each respective group. Median follow-up was 36.5 mo (interquartile range, 11.8-66.1). Postoperative outcomes were similar between groups. No difference was observed in overall complication rates (FLR ≤30%: 32.1% versus FLR >30%: 28.6%; odds ratio [OR], 1.22; 95% confidence interval [CI], 0.46-3.27) or major complication rates (FLR ≤30%: 14.3% versus FLR >30%: 14.3%; OR, 1.17; 95% CI, 0.33-4.10). Posthepatectomy liver failure was rare, and no difference was observed (FLR ≤30%: 3.6% versus FLR >30%: 3.6%; OR, 1.09; 95% CI, 0.11-11.1). CONCLUSION: A calculated FLR between 28% and 30% on its own should not represent a formal contraindication for live donation.

Management of primary hepatic malignancies during the COVID-19 pandemic: recommendations for risk mitigation from a multidisciplinary perspective.

Around the world, recommendations for cancer treatment are being adapted in real time in response to the pandemic of COVID-19. We, as a multidisciplinary team, reviewed the standard management options, according to the Barcelona Clinic Liver Cancer classification system, for hepatocellular carcinoma. We propose treatment recommendations related to COVID-19 for the different stages of hepatocellular carcinoma (ie, 0, A, B, and C), specifically in relation to surgery, locoregional therapies, and systemic therapy. We suggest potential strategies to modify risk during the pandemic and aid multidisciplinary treatment decision making. We also review the multidisciplinary management of intrahepatic cholangiocarcinoma as a potentially curable and incurable diagnosis in the setting of COVID-19.

The Impact of Direct-acting Antivirals on Overall Mortality and Tumoral Recurrence in Patients With Hepatocellular Carcinoma Listed for Liver Transplantation: An International Multicenter Study.

BACKGROUND: There is a lack of data on the use of direct-acting antivirals (DAA) on the risk of death and tumoral recurrence in patients with hepatitis C virus (HCV) and hepatocellular carcinoma (HCC) listed for liver transplantation (LT). We aimed to assess the impact of antiviral treatment on mortality and HCC recurrence patients with HCC-HCV. METHODS: This was a retrospective multicenter study of patients with HCC-HCV listed for LT from 2005 to 2015. Patients were divided according to the antiviral treatment received after HCC diagnosis: DAA, interferon (IFN), or no antiviral. Intention-to-treat overall survival and HCC recurrence incidence were compared by the Kaplan-Meier method. Multivariable regression analysis was performed to identify risk factors for outcomes. RESULTS: A total of 1012 HCV-HCC patients were listed for LT during the study period. The median follow-up was 4.0 (interquartile range = 2.3-6.7) years. Mortality was 5.6 (95% confidence interval [CI], 4.3-7.2), 13.1 (95% CI, 11.0-15.7), and 6.2 (95% CI, 5.4-7.2) deaths per 100 person-year among patients treated with DAA, IFN, and antiviral naïve, respectively (P < 0.001). Of the 875 HCV-HCC transplant recipients, the 5-year recurrence-free survival was 93.4%, 84.8%, 73.9% for the pre-LT DAA, pre-LT IFN, and antiviral naïve groups, respectively (P < 0.001). After multivariable regression, the use of pre-LT DAA was not associated to risk of recurrence (hazard ratio = 0.44 [95% CI, 0.19-1.00]). Post-LT DAA was not related to increased risk of recurrence (hazard ratio = 0.62 [95% CI, 0.33-1.16]). CONCLUSIONS: In this multicenter intent-to-treat study, DAA therapy was not found to be a risk factor for mortality or HCC recurrence after adjusting for potential confounders.

Liver stiffness and thrombin generation in compensated cirrhosis.

BACKGROUND: Decompensated cirrhosis is associated with coagulation abnormalities that can increase the risk of thrombosis and bleeding. It is unclear precisely when these abnormalities arise and whether they are exacerbated as compensated cirrhosis progresses. Transient elastography using FibroScan generates liver stiffness measurements (LSM) that associate with portal hypertension, clinical outcomes and provides prognostic information at an earlier stage than traditional liver function scores eg, MELD score. OBJECTIVE: To characterize thrombin generation in patients with compensated cirrhosis and to determine whether parameters of coagulation change throughout compensated cirrhosis, staged using LSM. PATIENTS/METHODS: Blood samples were collected from well-compensated cirrhotic patients n = 61, All Child Pugh A stage) attending the Mater Misericordiae University Hospital, Ireland. Comprehensive clinical staging of liver disease, including LSM, was performed. Tissue Factor-stimulated thrombin generation was measured by calibrated automated thrombography. RESULTS: Using LSM to stage well-compensated cirrhotic patients, we demonstrate a significant decrease in the rate of propagation, the rate of attenuation, and total thrombin generation as LSM increase. LSM correlated with endogenous thrombin potential, peak thrombin generation, the rate of propagation, and the rate of attenuation. This association between thrombin generation and LSM was still evident in sub-analyses excluding patients with ongoing alcohol use, active HCV infection, or a history of decompensation. In contrast, there was no significant correlation between thrombin generation, prothrombin times, Child-Pugh scores, or MELD scores. CONCLUSION: Liver stiffness measurements identify differences in parameters of thrombin generation within a cohort of compensated cirrhotic patients before changes in clotting times occur.

The Impact of Preexisting and Post-transplant Diabetes Mellitus on Outcomes Following Liver Transplantation.

BACKGROUND: Diabetes mellitus (DM) is said to adversely affect transplant outcomes. The aim of this study was to investigate the impact of pre-existing and new-onset DM on liver transplantation (LT) recipients. METHODS: A single-center retrospective analysis of prospectively collected data of LT recipients (1990-2015) was undertaken. RESULTS: Of the 2209 patients, 13% (n = 298) had Pre-DM, 16% (n = 362) developed post-transplant diabetes mellitus (PTDM), 5% (n = 118) developed transient hyperglycemia (t-HG) post-LT, and 65% (n = 1431) never developed DM (no DM). Baseline clinical characteristics of patients with PTDM were similar to that of patients with Pre-DM. Incidence of PTDM peaked during the first year (87%) and plateaued thereafter. On multivariate analysis (Bonferroni-corrected), nonalcoholic fatty liver disease and the use of tacrolimus and sirolimus were independently associated with PTDM development. Both Pre-DM and PTDM patients had satisfactory and comparable glycemic control throughout the follow-up period. Those who developed t-HG seem to have a unique characteristic compared with others. Overall, 9%, 5%, and 8% of patients developed end-stage renal disease (ESRD), major cardiovascular event (mCVE), and de novo cancer, respectively. Both Pre-DM and PTDM did not adversely affect patient survival, retransplantation, or de novo cancer. The risks of ESRD and mCVE were significantly higher in patients with Pre-DM followed by PTDM and no DM. CONCLUSIONS: In this largest nonregistry study, patients with Pre-DM and PTDM share similar baseline clinical characteristics. Pre-DM increases the risk of ESRD and mCVE; however, patient survival was comparable to those with PTDM and without diabetes. Understanding the impact of PTDM would need prolonged follow-up.