Faculty Bibliography

BACKGROUND AND AIMS/OBJECTIVE:Liver transplant is a specialized treatment for a spectrum of indications that use a scarce resource. Transplant is guided by principles of justice, equity and benefit with a constant conflict between competing interests. Organs are a national resource with a goal of equitable distribution across sites. An AASLD guideline for the evaluation and selection of appropriate transplant candidates has been available since 2005. METHODS:A multidisciplinary writing group of liver transplant experts and a librarian convened over 24 months. The writing group reviewed the literature, generated guideline recommendations and rated the level of evidence for each recommendation based on the Oxford Center for Evidence-Based Medicine. The group categorized the strength of recommendations based on the level of evidence, risk-benefit ratio, and patient preferences. CONCLUSIONS:Liver transplant is a lifesaving procedure that should be offered to selected patients with clear indications and a reasonable prospect of benefit. The evaluation is designed to identify those in need, to outline hurdles to a successful outcome, and to develop an effective transplant plan. The goal of this document is to provide a template for this process.

Since the first kidney paired donation (KPD) transplant in the United States in 1999, the volume and scope of KPD has expanded substantially, accounting for nearly 20% of living donor kidney transplants in 2021-2022. Our review article discusses the practical and ethical issues specific to paired donor exchange that patients, transplant centers, and exchange programs commonly encounter. Access to paired donor exchange and education of candidates regarding the potential benefits, risks, and logistics of KPD are important considerations. Transplant centers and patients must consider practical issues including wait-times, allocation and matching strategies, assessment of organ quality, complex donors, cold ischemia time, and risks of broken chains. Protections available to donors from current KPD programs, the potential psychosocial effects, and the ethical concerns related to variable access and the proprietary nature of private exchange programs are also discussed. More detailed, timely data collection at a national level, and ability to merge national data with individual donor exchange registries will enable the analysis of the impact and outcomes of future trends in paired donation. KPD experience and key concepts may inform liver paired exchange, which has been employed internationally to expand living donor liver transplantation and is emerging in the United States.

With the increasing incidence of hepatocellular carcinoma (HCC) in both the United States and globally, the role of liver transplantation in management continues to be an area of active conversation as it is often considered the gold standard in the treatment of HCC. The use of living donor liver transplantation (LDLT) and the indications in the setting of malignancy, both generally and in HCC specifically, are frequently debated. In terms of both overall survival and recurrence-free survival, LDLT is at least equivalent to DDLT, especially when performed for disease within Milan criteria. Emerging and compelling evidence suggests that LDLT is superior to DDLT in treating HCC as there is a significant decrease in waitlist mortality. As the oncologic indications for liver transplantation continue to expand and the gap between organ demand and organ availability continues to worsen, high volumes centers should consider using LDLT to shrink the ever-expanding waitlist.

The impact of liver transplant allocation policy using acuity circles (ACs) on interactions between race and gender on waitlist mortality or receipt of deceased donor liver transplant (DDLT) is unknown. Using data from the United Network for Organ Sharing (UNOS), we examined adults listed for DDLT from April 3, 2017, to October 4, 2022 (30 months pre- and post-AC). Fine-Gray sub-distribution hazard model explored AC indicators by race and gender interactions and their effect on receipt of DDLT or waitlist mortality. Also explored was AC's impact on hepatocellular carcinoma (HCC) diagnosis and receipt of DDLT or waitlist mortality. 59 592 patients (30 202 pre-AC, 29 390 post-AC) included. For both receipt of DDLT and waitlist mortality, there were no 3-way (AC by race by gender) interactions, indicating that the effects of race and gender on DDLT or waitlist mortality were consistent pre- and post-AC. Irrespective of AC implementation, Black and Hispanic women were less likely to receive DDLT and had an increased risk of waitlist mortality compared to White women. White, Black, and Hispanic men had lower waitlist mortality risk and greater likelihood of receiving DDLT compared to their female race/ethnic counterparts. Patients with HCC had a significantly greater chance for DDLT than non-HCC, although post-AC this effect was attenuated. Patients with HCC were also at greater risk of waitlist mortality pre- and post-AC compared to those without HCC however, the waitlist mortality post-AC was attenuated only for those patients without HCC. To our knowledge, this is the first study to show the interaction of gender and race on waitlist mortality and access to transplantation since the implementation of AC, showing continued disparate outcomes for women both within and across racial groups.

BACKGROUND:Best practices in psychosocial evaluation and care of living donor candidates and donors are not well established. METHODS:We surveyed 195 living kidney donor (LKD) transplant centers in United States from October 2021 to April 2022 querying (1) composition of psychosocial teams, (2) evaluation processes including clinical tools and domains assessed, (3) selection criteria, and (4) psychosocial follow-up post-donation. RESULTS:We received 161 responses from 104 programs, representing 53% of active LKD programs and 67% of LKD transplant volume in 2019. Most respondents (63%) were social workers/independent living donor advocates. Over 90% of respondents indicated donor candidates with known mental health or substance use disorders were initially evaluated by the psychosocial team. Validated psychometric or transplant-specific tools were rarely utilized but domains assessed were consistent. Active suicidality, self-harm, and psychosis were considered absolute contraindications in >90% of programs. Active depression was absolute contraindication in 50% of programs; active anxiety disorder was excluded 27%. Conditions not contraindicated to donation include those in remission: anxiety (56%), depression (53%), and posttraumatic stress disorder (41%). There was acceptance of donor candidates using alcohol, tobacco, or cannabis recreationally, but not if pattern met criteria for active use disorder. Seventy-one percent of programs conducted post-donation psychosocial assessment and use local resources to support donors. CONCLUSIONS:There was variation in acceptance of donor candidates with mental health or substance use disorders. Although most programs conducted psychosocial screening post-donation, support is not standardized and unclear if adequate. Future studies are needed for consensus building among transplant centers to form guidelines for donor evaluation, acceptance, and support.

We surveyed living donor liver transplant programs in the United States to describe practices in the psychosocial evaluation of living donors focused on (1) composition of psychosocial team; (2) domains, workflow, and tools of the psychosocial assessment; (3) absolute and relative mental health-related contraindications to donation; and (4) postdonation psychosocial follow-up. We received 52 unique responses, representing 33 of 50 (66%) of active living donor liver transplant programs. Thirty-one (93.9%) provider teams included social workers, 22 (66.7%) psychiatrists, and 14 (42.4%) psychologists. Validated tools were rarely used, but domains assessed were consistent. Respondents rated active alcohol (93.8%), cocaine (96.8%), and opioid (96.8%) use disorder, as absolute contraindications to donation. Active suicidality (97%), self-injurious behavior (90.9%), eating disorders (87.9%), psychosis (84.8%), nonadherence (71.9%), and inability to cooperate with the evaluation team (78.1%) were absolute contraindications to donation. There were no statistically significant differences in absolute psychosocial contraindications to liver donation between geographical areas or between large and small programs. Programs conduct postdonation psychosocial follow-up (57.6%) or screening (39.4%), but routine follow-up of declined donors is rarely conducted (15.8%). Psychosocial evaluation of donor candidates is a multidisciplinary process. The structure of the psychosocial evaluation of donors is not uniform among programs though the domains assessed are consistent. Psychosocial contraindications to living liver donation vary among the transplant programs. Mental health follow-up of donor candidates is not standardized.

OBJECTIVE:To evaluate long-term oncologic outcomes of patients post-living donor liver transplantation (LDLT) within and outside standard transplantation selection criteria and the added value of the incorporation of the New York-California (NYCA) score. BACKGROUND:LDLT offers an opportunity to decrease the liver transplantation waitlist, reduce waitlist mortality, and expand selection criteria for patients with hepatocellular carcinoma (HCC). METHODS:Primary adult LDLT recipients between October 1999 and August 2019 were identified from a multicenter cohort of 12 North American centers. Posttransplantation and recurrence-free survival were evaluated using the Kaplan-Meier method. RESULTS:Three hundred sixty LDLTs were identified. Patients within Milan criteria (MC) at transplantation had a 1, 5, and 10-year posttransplantation survival of 90.9%, 78.5%, and 64.1% versus outside MC 90.4%, 68.6%, and 57.7% ( P = 0.20), respectively. For patients within the University of California San Francisco (UCSF) criteria, respective posttransplantation survival was 90.6%, 77.8%, and 65.0%, versus outside UCSF 92.1%, 63.8%, and 45.8% ( P = 0.08). Fifty-three (83%) patients classified as outside MC at transplantation would have been classified as either low or acceptable risk with the NYCA score. These patients had a 5-year overall survival of 72.2%. Similarly, 28(80%) patients classified as outside UCSF at transplantation would have been classified as a low or acceptable risk with a 5-year overall survival of 65.3%. CONCLUSIONS:Long-term survival is excellent for patients with HCC undergoing LDLT within and outside selection criteria, exceeding the minimum recommended 5-year rate of 60% proposed by consensus guidelines. The NYCA categorization offers insight into identifying a substantial proportion of patients with HCC outside the MC and the UCSF criteria who still achieve similar post-LDLT outcomes as patients within the criteria.

BACKGROUND:Whole-exome sequencing (WES) is an effective tool for diagnosis in patients who remain undiagnosed despite a comprehensive clinical work-up. While WES is being used increasingly in pediatrics and oncology, it remains underutilized in non-oncological adult medicine, including in patients with liver disease, in part based on the faulty premise that adults are unlikely to harbor rare genetic variants with large effect size. Here, we aim to assess the burden of rare genetic variants underlying liver disease in adults at two major tertiary referral academic medical centers. METHODS:WES analysis paired with comprehensive clinical evaluation was performed in fifty-two adult patients with liver disease of unknown etiology evaluated at two US tertiary academic health care centers. FINDINGS/RESULTS:Exome analysis uncovered a definitive or presumed diagnosis in 33% of patients (17/52) providing insight into their disease pathogenesis, with most of these patients (12/17) not having a known family history of liver disease. Our data shows that over two-thirds of undiagnosed liver disease patients attaining a genetic diagnosis were being evaluated for cholestasis or hepatic steatosis of unknown etiology. INTERPRETATION/CONCLUSIONS:This study reveals an underappreciated incidence and spectrum of genetic diseases presenting in adulthood and underscores the clinical value of incorporating exome sequencing in the evaluation and management of adults with liver disease of unknown etiology. FUNDING/BACKGROUND:S.V. is supported by the NIH/NIDDK (K08 DK113109 and R01 DK131033-01A1) and the Doris Duke Charitable Foundation Grant #2019081. This work was supported in part by NIH-funded Yale Liver Center, P30 DK34989.