Post-liver Transplantation Research Articles

Challenges related to clinical decision-making in hepatocellular carcinoma recurrence post-liver transplantation: Is there a hope?

Hepatocellular carcinoma (HCC) is a common liver malignancy and represents a serious cause of cancer-related mortality and morbidity. One of the favourable curative surgical therapeutic options for HCC is liver transplantation (LT) in selected patients fulfilling the known standard Milan/University of California San Francisco criteria which have shown better outcomes and longer-term survival. Despite careful adherence to the strict HCC selection criteria for LT in different transplant centres, the recurrence rate still occurs which could negatively affect HCC patients' survival. Hence HCC recurrence post-LT could predict patients' survival and prognosis, depending on the exact timing of recurrence after LT (early or late), and whether intra/extrahepatic HCC recurrence. Several factors may aid in such a complication, particularly tumour-related criteria including larger sizes, higher grades or poor tumour differentiation, microvascular invasion, and elevated serum alpha-fetoprotein. Therefore, managing such cases is challenging, different therapeutic options have been proposed, including curative surgical and ablative treatments that have shown better outcomes, compared to the palliative locoregional and systemic therapies, which may be helpful in those with unresectable tumour burden. To handle all these issues in our review.

Long-term Outcomes Following Colectomy and Liver Transplantation for Inflammatory Bowel Disease with Primary Sclerosing Cholangitis.

To investigate the long-term outcomes of patients with combined primary sclerosing cholangitis/inflammatory bowel disease (PSC-IBD) undergoing both liver transplantation (LT) and total abdominal colectomy (TAC). The fraction of patients with PSC-IBD that require both LT and TAC is small, thereby limiting significant conclusions regarding long-term outcomes. Adult and pediatric patients from nine centers from the US IBD Surgery Collaborative who underwent staged LT and TAC for PSC-IBD were included. Long-term outcomes, including survival, were assessed. Among 127 patients, 66 underwent TAC-before-LT, with a median time from TAC to LT of 7.9 yrs, while 61 underwent LT-before-TAC, with a median time from LT to TAC of 4.4 years. Median patient survival post TAC was significantly worse in those undergoing LT-before-TAC (16.0 yrs vs. 42.6 yrs, P=0.007), while post LT survival was not impacted by the order of TAC and LT (21.6 yrs vs. 22.0 yrs, P=0.81). Patients undergoing TAC for medically refractory disease had a higher incidence of recurrent PSC (rPSC) (P=0.02) and biliary complications (0.09) compared to those undergoing TAC for oncologic indications. Definitive TAC reconstruction with either end ileostomy or ileal-pouch anal anastomosis (IPAA) did not impact post-LT or post-TAC outcomes. Long term survival in PSC-IBD was contingent upon progression to LT and was not impacted by the need for TAC. PSC-IBD patients undergoing TAC for medically refractory disease had a higher incidence of rPSC and biliary complications. The use of IPAA in PSC-IBD was a viable alternative to end ileostomy.

PAs and NPs in liver transplantation: Perceptions, implementation, and effect.

This study assessed the use and perceptions of physician associates/assistants (PAs) and NPs at liver transplant centers and sought to determine their financial effect. Leaders of liver transplant programs performing 25 or more transplants in 2020 were contacted to complete an 11-question survey about the role and effect of PAs and NPs in liver transplant. A single-center retrospective analysis compared length of stay (LOS) and readmission rates for primary liver transplants and simultaneous liver-kidney transplants before and after a dedicated PA team was established. Chi-square and t-test analyses were performed. The survey achieved a 77% response rate, and 98% of institutions reported using PAs and NPs. The single-center study found the mean LOS post-transplant was significantly shorter in the post-PA cohort (P = .0005). No significant difference was found in 30-day readmission rates. PAs and NPs are used broadly across the post-liver transplant care continuum. Using LOS as a surrogate financial marker suggests that a dedicated PA and NP team may contribute to cost savings.

Safety of acamprosate for alcohol use disorder after liver transplant: A pilot randomized controlled trial.

Acamprosate is a therapy for alcohol use disorder, but data on feasibility and safety in recipients of liver transplants are lacking. This was a single-center unblinded prospective pilot randomized controlled trial of adults (≥18y) with liver transplant for alcohol-associated liver disease enrolled between 2021 and 2023, who were randomized 2:1 to the intervention of acamprosate (666mg dose 3 times daily) or standard of care (SOC) over 14 weeks. Outcomes included safety (prevalence of adverse events [AEs]), feasibility (weekly survey response rate >60%), adherence (self-reported acamprosate use >60%), and efficacy (reduction in Penn Alcohol Craving Scale), and relapse-blood phosphatidylethanol (≥20ng/mL/reported alcohol use) evaluated by standardized weekly surveys. The efficacy analysis was done in both the intention-to-treat (excluding withdrawals before medication administration) and per-protocol population (excluding withdrawals/<4 weeks participation). Of 78 participants who were approached, 30 enrolled (19 acamprosate and 11 SOC) with similar baseline characteristics. Eight participants withdrew (6 acamprosate before medication administration and 2 SOC). AEs were similar between acamprosate and SOC groups (92.3% vs. 90.0%, p > 0.99), including grade 3 AEs (53.9% vs. 60.0%, p > 0.99) with no reported grade 4/5 AEs. Survey response rates were similar in acamprosate versus SOC groups (61.0% vs. 76.0%, p = 0.19), and 69.0% were acamprosate adherents. Baseline Penn Alcohol Craving Scale values were low with no difference by the group in median absolute change in Penn Alcohol Craving Scale for intention-to-treat (0, IQR: -4 to 0 vs. 0, IQR: 0-0, p = 0.32), and per-protocol analyses (-1, IQR: -6 to 0 vs. 0, IQR: -0 to 0, p = 0.36). There was no reported or biochemical evidence of alcohol relapse. In this pilot study, preliminary data suggest that acamprosate may be safe and feasible. These data can inform larger studies and clinician efforts to address alcohol use disorder in post-liver transplant care (ClinicalTrials.gov, Number: NCT06471686).

ECMO in severe hypoxemia post liver transplant for hepatopulmonary syndrome.

Hepatopulmonary syndrome (HPS) poses a significant challenge in liver transplant patients, affecting between 10% and 30% of candidates. Historically, HPS was considered a contraindication for liver transplantation due to its association with high mortality rates. However, recent studies have shown improvements in pulmonary function post-transplant, leading to the inclusion of these patients as candidates. Despite this progress, approximately one-fifth of liver transplant recipients develop severe postoperative hypoxia, further complicating their clinical course and contributing to increased mortality. The management of post-transplant HPS involves various strategies, including extracorporeal membrane oxygenation (ECMO), although its use remains infrequently reported. Theoretical models suggest that oxygenation typically improves within 10 days post-transplant, while resolution of HPS may take 6-12 months, making ECMO an attractive possibility as a bridge to recovery in this population. We present a case were ECMO was used in this context.

345.9: The mechanism research of intrahepatic glutamine metabolism promoting the differentiation of GARP Tregs to reshape the immune tolerance microenvironment post liver transplantation.

345.9: The mechanism research of intrahepatic glutamine metabolism promoting the differentiation of GARP Tregs to reshape the immune tolerance microenvironment post liver transplantation.

P.398: Evaluating post-liver transplantation outcomes in hepatorenal syndrome: Insights from a small volume center study.

P.398: Evaluating post-liver transplantation outcomes in hepatorenal syndrome: Insights from a small volume center study.

402.2: Association of macrovascular invasion and poor tumor differentiation on post-liver transplant outcomes in patients with hepatocellular carcinoma.

402.2: Association of macrovascular invasion and poor tumor differentiation on post-liver transplant outcomes in patients with hepatocellular carcinoma.

301.6: Comparison of polypropylene and dual mesh repair methods for incisional hernias post-liver transplantation: A retrospective cohort study.

301.6: Comparison of polypropylene and dual mesh repair methods for incisional hernias post-liver transplantation: A retrospective cohort study.

P.390: Impact of explant pathologic factors on hepatocellular carcinoma recurrence post-liver transplantation: Insights from a retrospective cohort study.

P.390: Impact of explant pathologic factors on hepatocellular carcinoma recurrence post-liver transplantation: Insights from a retrospective cohort study.

The clinical relevance of the new criteria for cirrhotic cardiomyopathy and future directions.

Cardiac dysfunction in patients with liver disease has been recognized since the 1950s. Initially attributed to shared risk factors, it is now evident that cardiac dysfunction in patients with cirrhosis can occur in the absence of known cardiac, i.e., coronary artery and valvular heart disease, and across all etiologies for cirrhosis. In 1996 this myocardial dysfunction was termed cirrhotic cardiomyopathy (CCM). The pathophysiologic mechanisms underlying CCM include impaired beta-adrenergic membrane function and circulating proinflammatory and cardiotoxic substances. In 2005, the first diagnostic criteria for CCM were introduced enabling greater sensitivity and accuracy of diagnosis. Since 2005, advancements in echocardiographic methods and better understanding of the pathophysiology of cardiac dysfunction in patients with cirrhosis necessitated revision of CCM criteria. Changes in CCM criteria included removal of blunted contractile or heart rate response on stress testing and addition of global longitudinal systolic strain. Refinement of criteria for diastolic dysfunction were also incorporated into the new diagnostic approach. Since 2020, the prevalence of the disorder and clinical considerations for pre-transplant, peritransplant, and post-transplant patients with cirrhosis have been further evaluated and CCM was found to adversely impact clinical outcomes during all three phases of care. Future research considerations should address the timing of universal echocardiographic screening for patients with cirrhosis, utility of biomarkers in aiding CCM diagnosis, impact of CCM on right heart function, and role of anti-remodeling agents post-liver transplant (post-LT).

Racial and ethnic disparities in post-liver transplant outcomes for patients with acute-on-chronic liver failure: An analysis of the UNOS database.

The incidence of hospitalisations related to acute-on-chronic liver failure (ACLF) is increasing. Liver transplantation (LT) remains the definitive treatment for the condition. To evaluate the influence of race and ethnicity on LT outcomes in ACLF. We conducted a retrospective analysis utilising LT data from the United Network for Organ Sharing (UNOS) database. White patients served as the control group and patients of other races were compared at each ACLF grade. The primary outcomes assessed were graft failure and all-cause mortality. Blacks exhibited a higher all-cause mortality (Grade 1: aHR 1.36, 95% CI 1.18-1.57, p < 0.001; Grade 2: aHR 1.27, 95% CI 1.08-1.48, p = 0.003; Grade 3: aHR 1.19, 95% CI 1.04-1.37, p = 0.01) and graft failure (Grade 1: aHR 2.05, 95% CI 1.58-2.67, p < 0.001; Grade 2: aHR 1.91, 95% CI 1.43-2.54, p < 0.001; Grade 3: aHR 1.50, 95% CI 1.15-1.96, p = 0.002). Hispanics experienced a lower all-cause mortality at grades 1 and 3 (Grade 1: aHR 0.83, 95% CI 0.72-0.96, p = 0.01; Grade 3: aHR 0.80, 95% CI 0.70-0.91, p < 0.001) and Asians with severe ACLF demonstrated decreased all-cause mortality (Grade 3: aHR 0.55, 95% CI 0.42-0.73, p < 0.001). Black patients experienced the poorest outcomes and Hispanic and Asian patients demonstrated more favourable outcomes compared to Whites.

Impact of Sarcopenia on Post-Liver Transplant Hospitalization: Insights From a South Asian Cohort

BackgroundSarcopenia's impact on post-liver transplant outcomes remains a subject of debate, with limited data from South Asia on its association with post-liver transplant hospital stays. This study aims to investigate sarcopenia's influence on post-transplant hospitalization duration in South Asians. MethodsIn this retrospective study, patients with liver cirrhosis who underwent living-donor liver transplantation at Shifa International Hospital in Islamabad, Pakistan, between January 2022 and January 2023 were included. Computed Tomography (CT) images were used to assess the skeletal muscle index (SMI). The areas of the psoas, erector spinae, multifidus, quadratus lumborum, rectus abdominis, transverse abdominis, and internal/external oblique muscles were quantified at the level of L3. The data was analyzed using SPSS v. 29.0 (IBM Chicago, IL). ResultsThere was a total of 84 patients. Mean age was 47.4 ± 12.0 years. There were 62 (73.8%) males and 22 (26.2%) females. Hepatitis C was noted in 36 (42.9%) patients. 22 (26.2%) patients had hepatocellular carcinoma. Sarcopenia was identified in 58 (69.0%) patients. No significant association was observed between sarcopenia and ICU or general floor stays. Regression analysis identified pre-transplant MELD-Na score as the sole significant factor associated with both ICU and total length of stay (p-value 0.002; p-value 0.009). ConclusionIn our population, sarcopenia did not correlate with post-transplant ICU or overall hospital stay. The pre-transplant MELD-Na score emerged as the most influential predictor of length of stay. Therefore, delaying liver transplant procedures based on muscle mass estimations may not be a practical clinical approach for South Asian patients.

Reappraisal of tacrolimus levels after liver transplant for HCC: A multicenter study toward personalized immunosuppression regimen.

Post-liver transplant (LT) immunosuppression is necessary to prevent rejection; however, a major consequence of this is tumor recurrence. Although recurrence is a concern after LT for patients with HCC, the oncologically optimal tacrolimus (FK) regimen is still unknown. This retrospective study included 1406 patients with HCC who underwent LT (2002-2019) at 4 US institutions using variable post-LT immunosuppression regimens. Receiver operating characteristic analyses were performed to investigate the influences of post-LT time-weighted average FK (TWA-FK) level on HCC recurrence. A competing risk analysis was employed to evaluate the prognostic influence of TWA-FK while adjusting for patient and tumor characteristics. The AUC for TWA-FK was greatest at 2 weeks (0.68), followed by 1 week (0.64) after LT. Importantly, this was consistently observed across the institutions despite immunosuppression regimen variability. In addition, the TWA-FK at 2 weeks was not associated with rejection within 6 months of LT. A competing risk regression analysis showed that TWA-FK at 2 weeks after LT is significantly associated with recurrence (HR: 1.31, 95% CI: 1.21-1.41, p < 0.001). The TWA-FK effect on recurrence varied depending on the exposure level and the individual's risk of recurrence, including vascular invasion and tumor morphology. Although previous studies have explored the influence of FK levels at 1-3 months after LT on HCC recurrence, this current study suggests that earlier time points and exposure levels must be evaluated. Each patient's oncological risk must also be considered in developing an individualized immunosuppression regimen.

MRI-serum-based score accurately identifies patients undergoing liver transplant without rejection avoiding the need for liver biopsy: A multisite European study.

Serum liver tests (serum tests) and histological assessment for T-cell-mediated rejection are essential for post-liver transplant monitoring. Liver biopsy carries a risk of complications that are preferably avoided in low-risk patients. Multiparametric magnetic resonance imaging (mpMRI) is a reliable noninvasive diagnostic method that quantifies liver disease activity and has prognostic utility. Our aim was to determine whether using mpMRI in combination with serum tests could noninvasively identify low-risk patients who underwent liver transplants who are eligible to avoid invasive liver biopsies. In a multicenter prospective study (RADIcAL2), including 131 adult and pediatric (children and adolescent) patients with previous liver transplants from the Netherlands, Portugal, and the United Kingdom, concomitant mpMRI and liver biopsies were performed. Biopsies were centrally read by 2 expert pathologists. T-cell-mediated rejection was assessed using the BANFF global assessment. Diagnostic accuracy to discriminate no rejection versus indeterminate or T-cell-mediated liver transplant rejection was performed using the area under the receiver operating characteristic curve. In this study, 52% of patients received a routine (protocol) biopsy, while 48% had a biopsy for suspicion of pathology. Thirty-eight percent of patients had no rejection, while 62% had either indeterminate (21%) or T-cell-mediated rejection (41%). However, there was a high interobserver variability (0 < Cohen's Kappa < 0.85) across all histology scores. The combined score of mpMRI and serum tests had area under the receiver operating characteristic curve 0.7 (negative predictive value 0.8) to identify those without either indeterminate or T-cell-mediated rejection. Combining both imaging and serum biomarkers into a composite biomarker (imaging and serum biomarkers) has the potential to monitor the liver graft to effectively risk stratify patients and identify those most likely to benefit from a noninvasive diagnostic approach, reducing the need for liver biopsy.

FXR agonist for post Liver transplantation cholestasis: A randomized open-labeled study- An Interim analysis

FXR agonist for post Liver transplantation cholestasis: A randomized open-labeled study- An Interim analysis

Impact of Religious Affiliation on Clinical Outcomes in Liver Transplant Patients.

While the impact of spirituality as it relates to quality of life post-liver transplant (LT) has been studied, there are limited data showing how religious affiliation impacts objective measures such as survival. The aim of the study is to investigate whether LT recipientswho identified as having a religious affiliation had better clinical outcomes when compared to LT recipientswho did not. Religious affiliation is obtained as part of general demographic information for patients within our institution (options of "choose not to disclose" and "no religious affiliation" are available). Subjects in this retrospective cohort study which conformed with the Declarations of Helsinki and Istanbul were separated into cohorts: LT recipientswho self-reported religious affiliation and LT recipients who did not. All LT recipients between March 2007 and September 2018 who had available information regarding their reported religion were included. Excluded patients included those who received a multi-organ transplant, underwent re-transplantation, received a partial liver graft, and identified as agnostic. Outcomes included 30-day readmission, death, and the composite outcome of re-transplantation/death. In an unadjusted analysis of 378 patients, there were no statistically significant differences between the two groups for 30-day readmission (OR=1.15, P=0.71), death (HR=0.63, P=0.19), or re-transplantation/death (HR=0.90, P=0.75). In multivariable analysis, adjusting for age at transplant and hospital admittance status when called for transplant, results were similar. We found no statistically significant difference in the outcomes measured between patients with and without self-reported religious affiliation. Further studies into the role of participation in religious activity and the impact of engagement with a religious community should be conducted in the future.

Effect of Immunosuppressive Regimens on Metabolic Dysfunction-associated Fatty Liver Disease Following Liver Transplantation

BackgroundMetabolic dysfunction-associated fatty liver disease has been linked to negative outcomes in patients with end stage liver disease following liver transplantation. However, the influence of immunosuppressive regimens on it has not been explored. MethodsA retrospective analysis was conducted using the preoperative and postoperative data from patients with end-stage liver disease. The study compared three different groups: tacrolimus-based group, sirolimus-based group, and combined tacrolimus and sirolimus-based regimens. Binary logistic regression analysis was employed to identify risk factors for metabolic dysfunction-associated fatty liver disease. ResultsA total of 171 patients participated in the study, consisting of 127 males and 44 females, with a mean age of 49.6 years. The prevalence of post-transplant metabolic dysfunction-associated fatty liver disease was 29.23%. Among the three groups, there were 111 liver transplant recipients in the tacrolimus-based group, 28 in the sirolimus-based group, and 32 in the combination group. A statistically significant difference was observed in the incidence of metabolic dysfunction-associated fatty liver disease (P < 0.05), whereas the other preoperative and postoperative parameters showed no significant differences. Multivariate analysis revealed that a low-calorie diet (95% confidence intervals: 0.15∼0.90, P = 0.021) and a combination of tacrolimus and sirolimus-based immunosuppressive regimen (95% confidence intervals: 1.01∼2.77, P = 0.046) were associated with lower risk of post-transplant metabolic dysfunction-associated fatty liver disease. ConclusionsOur study indicates that implementing a low-calorie diet and utilizing a combination of tacrolimus and sirolimus-based immunosuppressive regimen can effectively lower the risk of post-transplant metabolic dysfunction-associated fatty liver disease following liver transplantation.

Predictive performance of Metagenomic Next Generation Sequencing in early detection of post-liver transplantation infections

ObjectiveTo evaluate the predictive performance of metagenomic next-generation sequencing (mNGS) in identifying and predicting pulmonary infections following liver transplantation and to investigate its association with patient outcomes within the initial four-week post-transplantation period. MethodsWe retrospectively analyzed 41 liver transplant patients with suspected pulmonary infections from August 2022 to May 2023. Bronchoalveolar lavage fluid (BALF) samples were collected on the first postoperative day for metagenomic next generation sequencing (mNGS) and culture. The predictive capability of mNGS for subsequent infections was assessed by monitoring inflammatory biomarkers and comparing the detection rates with culture methods. Real-time Polymerase Chain Reaction (Rt-PCR) was used to monitor Human betaherpesvirus 5 (CMV) and Human parvovirus B19 (B19) weekly during a four-week postoperative period. Inflammatory biomarkers and blood coagulation function were evaluated on specific days throughout the first, third, fifth, and during four weeks following surgery. The study was conducted until August 2023 to evaluate the patients' prognostic survival outcome, classifying them into groups based on the mortality and survival. ResultsThe analysis included a total of 41 patients, comprising 32 males and 9 females, with an average age of 52 (47, 63) years. Within one week after liver transplantation, there were 7 cases of bacterial infections, 5 cases of fungal infections, 19 cases of mixed infections, 8 cases without any infection, and 2 cases with unidentified pathogen-associated infections. mNGS successfully predicted 39 (72 %) strains of pathogens, while culture-based methods only detected 28 (52 %) strains. Among the 8 patients diagnosed as non-infected, culture methods identified positive results in 4 cases (50 %), whereas mNGS yielded positive results in 7 cases (87.5 %). The detection rates of CMV and B19 by Rt-PCR within 4 weeks after liver transplantation were 61 % and 17 %, respectively (25/41, 7/41) among the patients. During the study period, a total of 9 patients succumbed while 32 patients survived. The death group and the survival group exhibited significant differences in CRP, HGB, and INR levels at specific monitoring time points. The proportion of CMV detection in blood was significantly higher in the death group compared to the surviving group. Elevated CRP level was identified as a prognostic risk factor. ConclusionsDespite the presence of false positives, mNGS still presents a potential advantage in predicting pulmonary infection pathogens following liver transplantation. Furthermore, the levels of CRP and CMV carrier status within four weeks post-surgery exhibit significant associations with patient survival and prognosis.

Antibody-mediated rejection in post-liver transplant clinical care: Are we there yet for timely diagnosis and treatment?

With improvements in medical management and surgical technique in the field of solid organ transplantation, many historically prominent causes of liver allograft injury have been ameliorated or, in the case of Hepatitis C virus, eliminated altogether. In this transformed clinical landscape, antibody-mediated rejection (AMR) has emerged as a defining barrier to maintenance of long-term liver allograft function. The liver's unique anatomy, high regenerative capacity, and tolerogenic immunological environment tend to mitigate the severest AMR manifestations. Consequently, the clinical importance of AMR in the liver has been recognized more slowly than for other solid organ allografts. Significant strides have been made in elucidating clinical and histopathologic features of acute and chronic liver AMR, with the Banff 2016 criteria among the most notable. However, current histopathologic definitions of AMR are lacking in sensitivity and specificity. C4d staining is an imperfect biological surrogate for antibody-mediated injury, and suffers from significant technical limitations. The frequent co-occurrence of T cell mediated rejection and non-immunologic allograft damage (including recurrence of primary disease) also hinders definitive identification of AMR and results in misattribution of its effects. The goal of this review is to summarize the current understanding of AMR in the context of liver transplantation, including risk factors, pathogenesis, and current diagnostic and treatment strategies. Potential directions of future research are also addressed.