Association between bridging therapy and posttransplant outcomes in patients with HCC within Milan criteria: A systematic review and meta-analysis.

Liver transplantation is the curative therapy of choice for patients with early-stage HCC. Locoregional therapies are often employed as a bridge to reduce the risk of waitlist dropout; however, their association with posttransplant outcomes is unclear. We conducted a systematic review using Ovid MEDLINE and EMBASE to identify studies published between database inception and August 2, 2023, which reported posttransplant recurrence-free survival and overall survival among patients transplanted for HCC within Milan criteria, stratified by receipt of bridging therapy. Pooled HRs were calculated for each outcome using the DerSimonian and Laird method for a random-effects model. We identified 38 studies, including 19,671 patients who received and 20,148 patients who did not receive bridging therapy. Bridging therapy was not associated with significant differences in recurrence-free survival (pooled HR: 0.91, 95% CI: 0.77-1.08; I2 =39%) or overall survival (pooled HR: 1.09, 95% CI: 0.95-1.24; I2 =47%). Results were relatively consistent across subgroups, including geographic location and study period. Studies were discordant regarding the differential strength of association by pretreatment tumor burden and pathologic response, but potential benefits of locoregional therapy were mitigated in those who received 3 or more treatments. Adverse events were reported in a minority of studies, but when reported occurred in 6%-15% of the patients. Few studies reported loss to follow-up and most had a risk of residual confounding. Bridging therapy is not associated with improvements in posttransplant recurrence-free or overall survival among patients with HCC within Milan criteria. The risk-benefit ratio of bridging therapy likely differs based on the risk of waitlist dropout.

Racial and Ethnic Disparities in Liver Transplantation for Alcohol-associated Liver Diseases in the United States.

BACKGROUND: Emerging data suggest disparities exist in liver transplantation (LT) for alcohol-associated liver disease (ALD). As the incidence of ALD increases, we aimed to characterize recent trends in ALD LT frequency and outcomes, including racial and ethnic disparities. METHODS: Using United Network for Organ Sharing/Organ Procurement and Transplantation Network data (2015 through 2021), we evaluated LT frequency, waitlist mortality, and graft survival among US adults with ALD (alcohol-associated hepatitis [AH] and alcohol-associated cirrhosis [AAC]) stratified by race and ethnicity. We used adjusted competing-risk regression analysis to evaluate waitlist outcomes, Kaplan-Meier analysis to illustrate graft survival, and Cox proportional hazards modeling to identify factors associated with graft survival. RESULTS: There were 1211 AH and 26 526 AAC new LT waitlist additions, with 970 AH and 15 522 AAC LTs performed. Compared with non-Hispanic White patients (NHWs) with AAC, higher hazards of waitlist death were observed for Hispanic (subdistribution hazard ratio [SHR] = 1.23, 95% confidence interval [CI]: 1.16-1.32), Asian (SHR = 1.22, 95% CI:1. 01-1.47), and American Indian/Alaskan Native (SHR = 1.42, 95% CI: 1.15-1.76) candidates. Similarly, significantly higher graft failures were observed in non-Hispanic Black (HR = 1.32, 95% CI: 1.09-1.61) and American Indian/Alaskan Native (HR = 1.65, 95% CI: 1.15-2.38) patients with AAC than NHWs. We did not observe differences in waitlist or post-LT outcomes by race or ethnicity in AH, although analyses were limited by small subgroups. CONCLUSIONS: Significant racial and ethnic disparities exist for ALD LT frequency and outcomes in the United States. Compared with NHWs, racial and ethnic minorities with AAC experience increased risk of waitlist mortality and graft failure. Efforts are needed to identify determinants for LT disparities in ALD that can inform intervention strategies.

Increasing practice and acceptable outcomes of high-MELD living donor liver transplantation in the USA.

Recent deceased-donor allocation changes in the United States may have increased high-Model for End-Stage Liver Disease (MELD) living donor liver transplantation (LDLT); however, outcomes in these patients remain poorly defined. We aimed to examine the impact of the MELD score on LDLT outcomes. Using UNOS data (January 1, 2010-December 31, 2021), LDLT recipients were identified and stratified into low-MELD (<15), intermediate-MELD (15-24), and high-MELD (≥25) groups. We compared outcomes between MELD-stratified LDLT groups and between MELD-stratified LDLT and donation after brain death liver transplantation recipients. We used Kaplan-Meier analysis to compare graft survival rates and multivariable Cox proportional hazards modeling to identify factors associated with graft outcomes. Of 3558 LDLTs, 1605 (45.1%) were low-MELD, 1616 (45.4%) intermediate-MELD, and 337 (9.5%) high-MELD. Over the study period, the annual number of LDLTs increased from 282 to 569, and the proportion of high-MELD LDLTs increased from 3.9% to 7.7%. Graft survival was significantly higher in low-MELD versus high-MELD LDLT recipients (adjusted HR = 1.36, 95% CI: 1.03-1.79); however, 5-year survival exceeded 70.0% in both groups. We observed no significant difference in graft survival between high-MELD LDLT and high-MELD donation after brain death liver transplantation recipients (adjusted HR: 1.25, 95% CI:0.99-1.58), with a 5-year survival of 71.5% and 77.3%, respectively. Low LDLT center volume (<3 LDLTs/year) and recipient life support requirement were both associated with inferior graft outcomes among high-MELD LDLT recipients. While higher MELD scores confer graft failure risk in LDLT, high-MELD LDLT outcomes are acceptable with similar outcomes to MELD-stratified donation after brain death liver transplantation recipients. Future practice guidance should consider the expansion of LDLT recommendations to high-MELD recipients in centers with expertise to help reduce donor shortage.

Biliary atresia and liver transplantation in the United States: A contemporary analysis.

BACKGROUND: Biliary atresia (BA) remains the number one indication for paediatric liver transplantation (LT) worldwide but is an uncommon indication for older LT recipients. The impact of recent donor allocation changes, pervasive organ shortage and evolving LT practices on the BA LT population is unknown. METHODS: We identified patients who underwent LT between January 2010 and December 2021 using the UNOS database. We compared clinical outcomes between patients with BA and those with non-BA cholestatic liver disease. Groups were stratified by age, <12 years (allocated via PELD system) and ≥12 years (allocated via MELD system). Waitlist outcomes were compared using competing-risk regression analysis, graft survival rates were compared using Kaplan-Meier time-to-event analysis and Cox proportional hazards modelling provided adjusted estimates. RESULTS: There were 2754 BA LT waitlist additions and 2206 BA LTs (1937 <12 years [younger], 269 ≥12 years [older]). There were no differences in waitlist mortality between BA and non-BA cholestatic patients. Among BA LT recipients, there were 441 (20.0%) living-donor liver transplantations (LDLT) and 611 (27.7%) split deceased-donor LTs. Five-year graft survival was significantly higher among BA versus non-BA cholestatic patients in the older group (88.3% vs. 79.5%, p < .01) but not younger group (89.3% vs. 89.5%). Among BA LT recipients, improved graft outcomes were associated with LDLT (vs. split LT: HR: 2, 95% CI: 1.03-3.91) and higher transplant volume (volume >100 vs. <40 BA LTs: HR: 3.41, 95% CI: 1.87-6.2). CONCLUSION: Liver transplant outcomes among BA patients are excellent, with LDLT and higher transplant centre volume associated with optimal graft outcomes.

Liver Transplantation in Elderly Recipients: Is Age Just a Number?

BACKGROUND: The proportion of older patients on the liver transplant waitlist continues to increase. With limited existing data to guide liver transplant evaluation of elderly patients, we aimed to study selection practices and outcomes of patients ≥70 years old. We hypothesized that 1-year patient and graft survival would not differ between appropriately selected elderly patients and those who are younger. METHODS: All patients referred for liver transplantation between 2018 and 2020 were stratified into elderly (age ≥70) and young (age <70) cohorts. Evaluation data pertaining to medical, surgical, and psychosocial risk assessment were reviewed. Recipient characteristics and post-operative outcomes, primarily 1-year graft and patient survival, were compared, with a median follow-up of 16.4 months. RESULTS: 322 patients underwent transplant out of 2331 referred. Elderly patients represented 230 of these referrals and 20 underwent transplant. The most common reasons for denial of elderly patients were multiple medical comorbidities (49%), cardiac risk (15%) and psychosocial barriers (13%). The median MELD of elderly recipients was lower (19 vs 24, P = .02), and proportion of hepatocellular carcinoma was higher (60% vs 23%, P < .001). There was no difference in 1-year graft (elderly 90.9% vs young 93.3%, P = .72) or patient survival (elderly 90.9% vs young 94.7%, P = .88). DISCUSSION: Liver transplant outcomes and survival are not affected by advanced age in carefully evaluated and selected recipients. Age should not be considered an absolute contraindication for liver transplant referral. Efforts should be made to develop guidelines for risk stratification and donor-recipient matching that optimize outcomes in elderly patients.

High Neutrophil-Lymphocyte Ratio and Delta Neutrophil-Lymphocyte Ratio Are Associated with Increased Mortality in Patients with Hepatocellular Cancer.

BACKGROUND: The neutrophil-lymphocyte ratio (NLR) has been proposed as a prognostic biomarker for cirrhosis and non-liver malignancies. We aimed to evaluate the prognostic value of NLR in a diverse cohort of patients with hepatocellular carcinoma (HCC). METHODS: We performed a retrospective study of patients diagnosed with HCC between 2008 and 2017 at two large US health systems. We used Cox proportional hazard and multivariable ordinal logistic regression models to identify factors associated with overall survival and response to first HCC treatment, respectively. Primary variables of interest were baseline NLR and delta NLR, defined as the difference between pre- and post-treatment NLR. RESULTS: Among 1019 HCC patients, baseline NLR was < 5 in 815 (80.0%) and ≥ 5 in 204 (20.0%). Patients with NLR ≥ 5 had a higher proportion of infiltrative tumors (36.2% vs 22.3%), macrovascular invasion (39.6% vs 25.5%), metastatic disease (20.6% vs 11.4%), and AFP > 200 ng/mL (45.6% vs 33.8%). Baseline NLR ≥ 5 was independently associated with higher mortality (median survival 4.3 vs 15.1 months; adjusted HR 1.70, 95%CI 1.41-2.06), with differences in survival consistent across BCLC stages. After adjusting for baseline covariates including NLR, delta NLR > 0.26 was also independently associated with increased mortality (HR 1.42, 95%CI 1.14-1.78). In a secondary analysis, high NLR was associated with lower odds of response to HCC treatment (20.2% vs 31.6%; adjusted OR 0.55, 95%CI 0.32-0.95). CONCLUSIONS: In a large Western cohort of patients with HCC, high baseline NLR and delta NLR were independent predictors of mortality. IMPACT: NLR is an inexpensive test that may be a useful component of future HCC prognostic models.

Short-term liver transplant outcomes from SARS-CoV-2 lower respiratory tract NAT positive donors.

On April 2021, the United States Organ Procurement and Transplantation Executive Committee approved the "lower respiratory SARS-CoV-2 testing for lung donors" emergency policy upon recommendation from the Ad Hoc Disease Transmission Advisory Committee. This policy requires that all lung donors be tested for SARS-CoV-2 in a lower respiratory specimen by nucleic acid test (NAT) and that the results be available before the lungs are transplanted. The overarching goal of the emergency policy was to minimize the risk of donor-derived COVID-19 to lung recipients. However, an unintended consequence of the policy was the emergence of a new population of potential donors: the SARS-CoV-2 lower respiratory tract (LRT) NAT positive donor. We describe the use of two SARS-CoV-2 LRT NAT positive liver donors without a known history of COVID-19 infection with adequate short-term outcomes. The recipients did not have a prior history of COVID-19, nor did they receive monoclonal antibodies post-transplantation; one was unvaccinated. If the safety and long-term outcomes from SARS-CoV-2 LRT NAT positive donors are confirmed in larger studies, this strategy represents a promising way to increase the pool for organ donation.

Survey of Liver Transplantation Practices for Severe Acute Alcoholic Hepatitis.

Liver transplantation (LT) has a demonstrated survival benefit in select patients with severe acute alcoholic hepatitis (SAH) who do not respond to steroids, but prior studies suggest low adoption among US LT centers. Our study explored current perceptions and practice patterns of LT for SAH in the United States. We administered a Web-based survey to medical directors of US LT centers between May and October of 2017 to characterize practice patterns and perceptions of LT for SAH. We obtained responses from 45 (41.3%) of 109 surveyed centers, representing all 11 (100%) United Network for Organ Sharing regions. Half (n = 23; 51.1%) reported performing at least 1 LT for SAH, although most (n = 19; 82.6%) of those had performed ≤5 LTs for that indication. Centers expressed near consensus for selection criteria, requiring strong social support (100%), no prior presentations with SAH (91.3%), absence of a severe coexisting psychiatric disorder (91.3%), and official psychosocial evaluation (87.0%). Reported posttransplant survival of SAH patients was excellent, with 17 (73.9%) centers reporting 1-year posttransplant survival exceeding 90%. Among centers that had not performed LT for SAH, the most commonly cited reason was perceived high risk of alcohol relapse. In conclusion, our data demonstrate that LT is increasingly adopted as a therapeutic intervention for patients with SAH and that careful selection allows for excellent 1-year posttransplant survival. Despite this, nearly half of US centers do not perform LT for this indication due to perceived high risk of alcohol relapse. Our data support the use of LT for well-selected patients with SAH.

Racial and Ethnic Disparities in Nonalcoholic Fatty Liver Disease Prevalence, Severity, and Outcomes in the United States: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the United States, affecting 75-100 million Americans. However, the disease burden may not be equally distributed among races or ethnicities. We conducted a systematic review and meta-analysis to characterize racial and ethnic disparities in NAFLD prevalence, severity, and prognosis. METHODS: We searched MEDLINE, EMBASE, and Cochrane databases through August 2016 for studies that reported NAFLD prevalence in population-based or high-risk cohorts, NAFLD severity including presence of nonalcoholic steatohepatitis (NASH) and significant fibrosis, and NAFLD prognosis including development of cirrhosis complications and mortality. Pooled relative risks, according to race and ethnicity, were calculated for each outcome using the DerSimonian and Laird method for a random-effects model. RESULTS: We identified 34 studies comprising 368,569 unique patients that characterized disparities in NAFLD prevalence, severity, or prognosis. NAFLD prevalence was highest in Hispanics, intermediate in Whites, and lowest in Blacks, although differences between groups were smaller in high-risk cohorts (range 47.6%-55.5%) than population-based cohorts (range, 13.0%-22.9%). Among patients with NAFLD, risk of NASH was higher in Hispanics (relative risk, 1.09; 95% CI, 0.98-1.21) and lower in Blacks (relative risk, 0.72; 95% CI, 0.60-0.87) than Whites. However, the proportion of patients with significant fibrosis did not significantly differ among racial or ethnic groups. Data were limited and discordant on racial or ethnic disparities in outcomes of patients with NAFLD. CONCLUSIONS: In a systematic review and meta-analysis, we found significant racial and ethnic disparities in NAFLD prevalence and severity in the United States, with the highest burden in Hispanics and lowest burden in Blacks. However, data are discordant on racial or ethnic differences in outcomes of patients with NAFLD.

Novel Application of Extracorporeal Photopheresis as Treatment of Graft-versus-Host Disease Following Liver Transplantation.

A 48-year-old man with hepatitis C virus (HCV) cirrhosis complicated by hepatocellular carcinoma underwent liver transplantation. His course was complicated by fever, diarrhea, abdominal pain, and pancytopenia. He developed a diffuse erythematous rash, which progressed to erythroderma. Biopsies of the colon and skin were consistent with acute graft-versus-host disease. Donor-derived lymphocytes were present in the peripheral blood. The patient was treated with corticosteroids and cyclosporine; however, he had minimal response to intensive immunosuppressive therapy. Extracorporeal photopheresis was initiated as a salvage therapy. He had a dramatic response, and his rash, diarrhea, and pancytopenia resolved. He is maintained on minimal immunosuppression 24 months later.

Liver disease in pregnancy.

Changes in the liver biochemical profile are normal in pregnancy. However, up to 3% to 5% of all pregnancies are complicated by liver dysfunction. It is important that liver disease during pregnancy is recognized because early diagnosis may improve maternal and fetal outcomes, with resultant decreased morbidity and mortality. Liver diseases that occur in pregnancy can be divided into 3 different groups: liver diseases that are unique to pregnancy, liver diseases that are not unique to pregnancy but can be revealed or exacerbated by pregnancy, and liver diseases that are unrelated to but occur coincidentally during pregnancy.

XIAP: cell death regulation meets copper homeostasis.

X-linked inhibitor of apoptosis (XIAP), traditionally known as an anti-apoptotic protein, has recently been shown to be involved in copper homeostasis. XIAP promotes the ubiquitination and degradation of COMMD1, a protein that promotes the efflux of copper from the cell. Through its effects on COMMD1, XIAP can regulate copper export from the cell and potentially represents an additional intracellular sensor for copper levels. XIAP binds copper directly and undergoes a substantial conformational change in the copper-bound state. This in turn destabilizes XIAP, resulting in lowered steady-state levels of the protein. Furthermore, copper-bound XIAP is unable to inhibit caspases and cells that express this form of the protein exhibit increased rates of cell death in response to apoptotic stimuli. These events take place in the setting of excess intracellular copper accumulation as seen in copper toxicosis disorders such as Wilson's disease and establish a new relationship between copper levels and the regulation of cell death via XIAP. These findings raise important questions about the role of XIAP in the development of copper toxicosis disorders and may point to XIAP as a potential therapeutic target in these disease states.

XIAP Is a copper binding protein deregulated in Wilson's disease and other copper toxicosis disorders.

X-linked inhibitor of apoptosis (XIAP), known primarily for its caspase inhibitory properties, has recently been shown to interact with and regulate the levels of COMMD1, a protein associated with a form of canine copper toxicosis. Here, we describe a role for XIAP in copper metabolism. We find that XIAP levels are greatly reduced by intracellular copper accumulation in Wilson's disease and other copper toxicosis disorders and in cells cultured under high copper conditions. Elevated copper levels result in a profound, reversible conformational change in XIAP due to the direct binding of copper to XIAP, which accelerates its degradation and significantly decreases its ability to inhibit caspase-3. This results in a lowering of the apoptotic threshold, sensitizing the cell to apoptosis. These data provide an unsuspected link between copper homeostasis and the regulation of cell death through XIAP and may contribute to the pathophysiology of copper toxicosis disorders.