Cirrhosis and hepatocellular carcinoma (HCC) are long-term complications of chronic liver disease (CLD). In this large multi-ancestry genome-wide association study of all-cause cirrhosis (35,481 cases, 2.36M controls) and HCC (6,680 cases, 1.76M controls), we identified 27 loci associated with cirrhosis (10 novel) and 11 with HCC (three novel). Three novel cirrhosis loci were replicated in independent cohorts (e.g. FGF21, RPTOR, and IFNL3/4). Fifteen cirrhosis loci exhibited differential effects on cirrhosis risk via underlying etiologies, and six HCC loci influenced HCC risk indirectly via cirrhosis. In a gene-burden analysis of rare variants from whole-genome sequencing data in the VA Million Veteran Program (n=102,677), we identified GSTA5 as a novel cirrhosis-associated gene, while APOB and ATP9B were associated with and replicated for HCC. A high genetic risk score for cirrhosis was associated with a nearly doubled risk of CLD progressing to cirrhosis (HR=1.94, P=2x10-68) and of cirrhosis progressing to HCC (HR=1.65, P=7x10-08). Finally, among individuals with chronic hepatitis C who underwent antiviral therapy, cirrhosis risk was modified by variants in PNPLA3, IFNL3/4, and CD81 following pegylated interferon-α therapy, and by APOE lead variant following direct-acting antiviral therapy. These findings provide new insights into the complex genetic architecture of CLD progression with potential clinical and therapeutic implications.

Kidney dysfunction is associated with decreased survival in liver transplant (LT) candidates, yet serum creatinine (sCr) is a poor surrogate for glomerular filtration rate (GFR) in this population. Serum cystatin C (CysC) may provide a more accurate assessment of kidney function and predict outcomes. We performed a multicenter prospective cohort study of consecutive candidates for LT. CysC was obtained at LT evaluation (n = 244), and a subset underwent simultaneous I-125-iothalamate clearance for measured GFR (mGFR) assessment (n = 137). Patients were followed to assess the need for pre-LT renal replacement therapy, simultaneous liver and kidney transplant, and survival. Estimated GFR (eGFR) based on MDRD-4, GRAIL, Royal Free Hospital Cirrhosis GFR, and the CKD-EPI equations was assessed for bias, precision, and accuracy in reference to mGFR. Receiver operator characteristic (AUROC) and competing risk survival analyses were performed. CysC more accurately discriminated mGFR than sCr at thresholds of <= 60 and <= 30 mL/min/1.73 m(2) with AUROC 0.92 (p = 0.005) and 0.96 (p=0.01), respectively. All eGFR equations overestimated GFR, especially among females (p < 0.05). The GRAIL equation demonstrated the least bias, while CKD-EPI-cystatin C was associated with the greatest precision and lowest frequency of GFR overestimation. Among 165 recipients of LT, CysC discriminated pre-LT renal replacement therapy and the need for simultaneous liver and kidney transplant with AUROC of 0.70 and 0.85, respectively. Cumulative incidence of death, accounting for LT as a competing event, increased with CysC (p = 0.002) but was not observed with sCr overall or among subgroups (p = NS). CysC more accurately predicts thresholds of mGFR than sCr in candidates for LT. Elevated CysC discriminates pre-LT renal replacement therapy and simultaneous liver and kidney transplant and is strongly associated with survival in contrast with sCr. CysC is a promising tool to improve prognostication among candidates for LT.

Background:Acute cellular rejection (ACR) remains a common complication causing significant morbidity post-liver transplantation. Non-human leukocyte antigen (non-HLA) mismatches were associated with an increased risk of ACR in kidney transplantation. Therefore, we hypothesized that donor-recipient non-HLA genetic mismatch is associated with increased ACR incidence post-liver transplantation.Methods:We conducted an international multicenter case-control genome-wide association study of donor-recipient liver transplant pairs in 3 independent cohorts, totaling 1846 pairs. To assess genetic mismatch burden, we calculated sum scores for single-nucleotide polymorphism (SNP) mismatch based on all non-HLA functional SNPs, specifically SNPs coding for transmembrane or secreted proteins as they more likely affect the immune system. We analyzed the association between the non-HLA mismatch scores and ACR in a multivariable Cox regression model per cohort, followed by a weighted meta-analysis.Results:During the first year post-transplantation, 90 of 689 (13%), 161 of 720 (22%), and 48 of 437 (11%) recipients experienced ACR in cohorts 1-3, respectively. Weighted meta-analyses showed that higher mismatch in functional non-HLA SNPs was associated with an increased incidence of ACR (HR 5.99; 95% CI: 1.39-20.08; p=0.011). Moreover, we found a larger effect of mismatch in SNPs coding for transmembrane or secreted proteins on ACR (HR 7.54; 95% CI 1.95-28.79; p=0.003). Sensitivity analyses showed that imputed HLA mismatch did not affect the associations between both non-HLA mismatch scores and ACR.Conclusions:Donor-recipient mismatch of functional non-HLA SNPs overall and, especially, of SNPs encoding transmembrane or secreted proteins correlated with 1-year ACR post-liver transplantation. Identifying high-risk immunological burdens between pairs may prevent early graft rejection and aid in personalizing immunosuppressive therapy. Future studies are, however, needed to validate our findings using a genotyped HLA cohort.

The long-term (>5 y) outcomes following liver transplantation (LT) have not been extensively reported. The aim was to evaluate outcomes of LT recipients who have survived the first 5 years. A multicenter retrospective analysis of prospectively collected data from 3 high volume LT centers (Dallas-USA, Birmingham-UK, and Barcelona-Spain) was undertaken. All adult patients, who underwent LT since the inception of the program to December 31, 2010, and survived at least 5 years since their LT were included. Patient survival was the primary outcome. A total of 3682 patients who survived at least 5 years following LT (long-term survivors) were included. Overall, median age at LT was 52 years (IQR 44–58); 53.1% were males; and 84.6% were Caucasians. A total of 49.4% (n=1820) died during a follow-up period of 36,828 person-years (mean follow-up 10 y). A total of 80.2% (n=1460) of all deaths were premature deaths. Age-standardized all-cause mortality as compared to general population was 3 times higher for males and 5 times higher for females. On adjusted analysis, besides older recipients and older donors, predictors of long-term mortality were malignancy, cardiovascular disease, and dialysis. Implementation of strategies such as noninvasive cancer screening, minimizing immunosuppression, and intensive primary/secondary cardiovascular prevention could further improve survival.

Donation after circulatory death (DCD) donors now represent over 30% of the deceased donor pool in the United States. Compared to donation after brain death, DCD is less likely to result in transplantation. For each potential donor whose organs cannot be utilized for transplantation (ie, dry run), fees are associated with the attempted donation, which add to the overall costs of organ acquisition. To better characterize the true costs of DCD liver acquisition, we performed a cost comparison of the fees associated with organ acquisition for DCD versus donation after brain death at a single transplant institute that comprises 2 liver transplant centers. Cost, recipient, and transportation data for all cases, including fees associated with liver acquisition from July 1, 2019, to October 31, 2021, were collected. We found that the total cost of DCD liver acquisition per liver transplant was $15,029 more than that for donation after brain death donation, with 18% of the costs of the DCD transplant attributed to dry runs. Overall, the costs associated with DCD transplantation accounted for 34.5% of the total organ acquisition costs; however, DCD transplantation accounted for 30.3% of the transplantation volume. Because the expansion of DCD is essential to increasing the availability of liver grafts for transplantation, strategies need to be implemented to decrease the costs associated with dry runs, including using local recovery, transferring donors to hospitals close to transplant centers, and performing more prerecovery organ analysis. Moreover, these strategies are needed to ensure that financial disincentives to DCD procurement and utilization do not reverse the gains made by expanding the organ donor pool using machine perfusion technologies.

Despite a significant increase in utilization over the past decade, the number of donation after circulatory death (DCD) organs that are procured and transplanted in the United States (US) remains well below its potential. There is still room for expansion, as utilizing DCD organs to the fullest extent is currently the most viable solution to the persistent mismatch between supply and demand in transplantation. We convened a multidisciplinary transplantation summit to examine various aspects of DCD, with faculty members from around the world with clinical and academic interest in DCD donation and transplantation, including abdominal and cardiothoracic surgeons, organ procurement organization directors, hepatologists, and gastroenterologists. The conference focused on identifying barriers to DCD organ utilization and strategies to overcome these barriers. We divide the barriers to DCD utilization into three mains categories: (I) policy and process variation; (II) logistical and transportation challenges; and (III) higher risk perceptions related to DCD outcomes. For each barrier, we proposed a variety of solutions, providing an overview of the status of DCD donation in the US and suggestions on how to increase the use of DCD. There is a specific focus on ex situ machine perfusion, normothermic regional perfusion, and other opportunities to expand DCD utilization without negatively impacting recipient outcomes.

1Division of Gastroenterology and Hepatology, Baylor Medical Center, Dallas, Texas, USA 2Transplant, Baylor Medical Center, Dallas, Texas, USA 3Transplant, Baylor All Saints Medical Center at Fort Worth, Fort Worth, Texas, USA Abbreviations: LI-RADS, Liver Reporting & Data System; MELD, Model for End-Stage Liver Disease; MMaT−3, median MELD at transplant minus 3. Correspondence Shivang Mehta, Transplant, Baylor All Saints Medical Center, Ste 515, 1250 8th Ave., Fort Worth, TX 76104, USA. Email: [email protected]

Candidates for multivisceral transplant (MVT) have experienced decreased access to transplant in recent years. Using Organ Procurement and Transplantation Network data, transplant and waiting list outcomes for MVT (ie, liver-intestine, liver-intestine-pancreas, and liver-intestine-kidney-pancreas) candidates listed between February 4, 2018, and February 3, 2022, were analyzed, including model for end-stage liver disease/pediatric end-stage liver disease and exception scores by era (before and after acuity circle [AC] implementation on February 4, 2020) and age group (pediatric and adult). Of 284 MVT waitlist registrations (45.6% pediatric), fewer had exception points at listing post-AC compared to pre-AC (10.0% vs 19.1%), and they were less likely to receive transplant (19.1% vs 35.9% at 90 days; 35.7% vs 57.2% at 1 year). Of 177 MVT recipients, exception points at transplant were more common post-AC compared to pre-AC (30.8% vs 20.2%). Postpolicy, adult MVT candidates were more likely to be removed due to death/too sick compared with liver-alone candidates (13.5% vs 5.6% at 90 days; 24.2% vs 9.8% at 1 year), whereas no excess waitlist mortality was observed among pediatric MVT candidates. Under current allocation policy, multivisceral candidates experience inferior waitlist outcomes compared with liver-alone candidates. Clarification of guidance around submission and approval of multivisceral exception requests may help improve their access to transplantation and achieve equity between multivisceral and liver-alone candidates on the liver transplant waiting list.

The exception point system for liver allocation in the United States allows for additional waitlist priority for candidates where the Model for End-Stage Liver Disease or Pediatric End-stage Liver Disease does not effectively represent their urgency or need for a transplant. In May 2019, the review process for liver exception cases transitioned from 11 Regional Review Boards (RRBs) to 1 National Liver Review Board (NLRB), intended to increase consistency nationwide, improve efficiency, and balance transplant access for candidates with and without exception scores. This report provides a review of liver exception request and review practices, waitlist outcomes, and transplant activity in the first 2 years after implementation of the NLRB and acuity circle–based distribution in the United States. We compared initial and extension exception request forms submitted from May 13, 2017 to May 13, 2019 (prepolicy or RRB era) to the period from February 4, 2020 to February 3, 2022 (postpolicy or NLRB era). During this time, the NLRB reviewed 10,083 initial exception requests and 12,686 extension requests. Notable postpolicy highlights include (1) an increase in the proportion of initial and extension requests that were automatically approved instead of manually reviewed; (2) a decrease in the overall approval rates of initial exception requests (87.8% for adult HCC, 64.3% for adult other diagnoses, and 71.5% for pediatric); and (3) reduction in the time from exception request submission to adjudication to a median of 3.73 days. The proportions of waitlist registration and deceased donor liver transplants for patients with exception scores decreased, and waitlist outcomes between patients with and without exception scores are now comparable. Implementation of the NLRB improved efficiency, reduced case workloads, and standardized criteria for exception cases, with similar waitlist outcomes between patients with and without exception scores and improved equity in terms of access to liver transplants.

1Baylor All Saints Medical Center at Fort Worth, Transplant, Fort Worth, Texas, USA 2Baylor Medical Center, Transplant, Dallas, Texas, USA Abbreviations: Cr, creatinine; GFR, glomerular filtration rate; MELD, Model for End-Stage Liver Disease; OPTN, Organ Procurement and Transplantation Network. Correspondence James Trotter, Baylor Medical Center, 3500 Gaston Avenue 4 Roberts, Transplant, Dallas, Texas 75246, USA. Email: [email protected]

In patients with severe acute alcohol-related hepatitis not responding to medical therapy, early liver transplantation (LT) represents the only effective therapy and, when performed within strict and well-defined protocols, it is associated with a clear survival benefit and acceptable rates of return to alcohol use after transplantation. However, there is still high variability in access to LT for patients with severe alcohol-related hepatitis, mainly due to a persistent overemphasis in the pre-LT evaluation on duration of pre-transplant abstinence and the stigma that patients with alcohol-related liver disease often experience, leading to marked inequity of access to this potentially lifesaving procedure and negative health outcomes. Therefore, there is an increasing need for prospective multicentre studies focusing on pre-transplant selection practices and on better interventions to treat alcohol use disorder after LT.

BACKGROUND & AIMS:Obeticholic acid (OCA) is a first-in-class farnesoid X receptor agonist and antifibrotic agent in development for the treatment of pre-cirrhotic liver fibrosis due to non-alcoholic steatohepatitis (NASH). We aimed to validate the original 18-month liver biopsy analysis from the phase III REGENERATE trial of OCA for the treatment of NASH with a consensus panel analysis, provide additional histology data in a larger population, and evaluate safety from >8,000 total patient-years' exposure with nearly 1,000 participants receiving study drug for >4 years. METHODS:Digitized whole-slide images were evaluated independently by panels of three pathologists using the NASH Clinical Research Network scoring system. Primary endpoints were (1) ≥1 stage improvement in fibrosis with no worsening of NASH or (2) NASH resolution with no worsening of fibrosis. Safety was assessed by laboratory values and adverse events. RESULTS:Prespecified efficacy analyses included 931 participants. The proportion of participants achieving a ≥1 stage improvement in fibrosis with no worsening of NASH was 22.4% for OCA 25 mg vs. 9.6% for placebo (p <0.0001). More participants receiving OCA 25 mg vs. placebo achieved NASH resolution with no worsening of fibrosis (6.5% vs. 3.5%, respectively; p = 0.093). Histology data in a larger population of 1,607 participants supported these results. Safety data included 2,477 participants. The incidence of treatment-emergent adverse events (TEAEs), serious TEAEs, and deaths was not substantively different across treatment groups. Pruritus was the most common TEAE. Rates of adjudicated hepatic, renal, and cardiovascular events were low and similar across treatment groups. CONCLUSIONS:These results confirm the antifibrotic effect of OCA 25 mg. OCA was generally well tolerated over long-term dosing. These data support a positive benefit:risk profile in patients with pre-cirrhotic liver fibrosis due to NASH. IMPACT AND IMPLICATIONS:Patients with non-alcoholic steatohepatitis (NASH) often have liver scarring (fibrosis), which causes an increased risk of liver-related illness and death. Preventing progression of fibrosis to cirrhosis or reversing fibrosis are the main goals of drug development for NASH. In this clinical trial of obeticholic acid (OCA) in patients with NASH (REGENERATE), we reaffirmed our previous results demonstrating that OCA was superior to placebo in improving fibrosis using a more rigorous consensus panel analysis of liver biopsies taken at month 18. We also showed that OCA treatment resulted in dose-dependent reductions of serum liver biochemistries and liver stiffness measurements compared with placebo, even in participants in whom histologic fibrosis did not change at 18 months, providing evidence that the benefit of OCA extends beyond what is captured by the ordinal NASH CRN scoring system. OCA was well tolerated with a favorable safety profile supporting a positive benefit: risk profile in patients with pre-cirrhotic liver fibrosis due to NASH.

1Baylor All Saints Medical Center at Fort Worth, Transplant, 1400 8th Avenue, Fort Worth, Texas 76101-0031, United States 2Baylor Medical Center, 3500 Gaston Avenue 4 Roberts, Transplant, Dallas, Texas 75246, United States List of abbreviations: HCC, hepatocellular carcinoma; LI-RADS, Liver Reporting & Data System; LRT, locoregional therapy; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; MMaT, median MELD at transplant; OPTN, Organ Procurement and Transplantation Network. Correspondence Shivang Mehta Baylor All Saints Medical Center at Fort Worth. Email: [email protected]

IntroductionLiving donor liver transplantation (LDLT) is a promising option for mitigating the deceased donor organ shortage and reducing waitlist mortality. Despite excellent outcomes and data supporting expanding candidate indications for LDLT, broader uptake throughout the United States has yet to occur. MethodsIn response to this, the American Society of Transplantation hosted a virtual consensus conference (October 18-19, 2021), bringing together relevant experts with the aim of identifying barriers to broader implementation and making recommendations regarding strategies to address these barriers. In this report, we summarize the findings relevant to the selection and engagement of both the LDLT candidate and living donor. Utilizing a modified Delphi approach, barrier and strategy statements were developed, refined, and voted on for overall barrier importance and potential impact and feasibility of the strategy to address said barrier. ResultsBarriers identified fell into three general categories: 1) awareness, acceptance, and engagement across patients (potential candidates and donors), providers, and institutions, 2) data gaps and lack of standardization in candidate and donor selection, and 3) data gaps regarding post-living liver donation outcomes and resource needs. ConclusionsStrategies to address barriers included efforts toward education and engagement across populations, rigorous and collaborative research, and institutional commitment and resources.

1Baylor All Saints Medical Center at Fort Worth, Fort Worth, Texas, USA 2Baylor Medical Center, Dallas, Texas, USA Correspondence James F. Trotter, Hepatology Section, Baylor Medical Center, 3500 Gaston Avenue 4 Roberts, Transplant, Dallas, TX 75246, USA. E-mail: [email protected] Abbreviations: DCD, donor by cardiac death; OPTN, Organ Procurement Transplantation Network.

Liver allocation and prioritization are perhaps the most important factors impacting the survival of patients with cirrhosis before and after listing. For listed patients, the decisions about prioritizing patients may increase organ access and enhance their survival. For example, acuity circle allocation has increased the transplant rate and reduced waiting list mortality for the sickest patients.1 For unlisted patients with cirrhosis, the specific criteria for listing and assignment of a Model for End-Stage Liver Disease (MELD) score exception may alter their access to a donor organ. A patient with compensated cirrhosis (with a low MELD score) with hepatopulmonary syndrome may receive a MELD exception score of median MELD minus 3 points based on their arterial blood gas (pCO2 <60). Therefore, the providers caring for patients with cirrhosis and liver transplant candidates must have comprehensive knowledge of the specific criteria for liver allocation and prioritization to manage these complex patients most efficiently. Since these criteria are constantly changing, we thought the readership of the Journal would benefit from a series of articles highlighting the most important recent changes. The United Network for Organ Sharing (UNOS) Liver and Intestine Committee is primarily responsible for developing the criteria for liver allocation. The process for making these changes starts with a concept that is reviewed and developed usually over many months. Thereafter, a proposal is put forward for public comment after its review in the regional meetings across the country. Based on the feedback from the public comment, the policy proposal is frequently amended, sent to the UNOS Board over the following 6 months, and then ultimately approved. Implementation of policy changes may occur immediately or take up to a year depending on their complexity. As allocation has become more complicated over the years, changes are occurring faster and faster. In the past 3 years, the basic framework for liver allocation and prioritization has changed twice (introduction of the National Liver Review Board for adjudication of MELD exception scores and acuity circle liver allocation). With the codification of the criteria for MELD exception scores, the UNOS Liver and Intestine Committee has begun to systematically review and update the criteria for each MELD exception. Consequently, keeping abreast of these important and clinically relevant changes in liver allocation is increasingly difficult. Therefore, the purpose of this series of articles is to summarize ongoing changes in liver allocation which have been developed in the Liver Committee. We hope that these will provide a useful resource to our clinicians who care for patients with cirrhosis but may not be involved in transplantation as well as an adjunct to all the more detailed information available on the UNOS website for all of our readership.