Tacrolimus is the most commonly used immunosuppression drug after solid organ transplantation; however, its dosing is challenging due to substantial inter-individual variability, often resulting in blood levels that deviate from the target therapeutic range. We explored whether a dynamically customized, phenotypic-outcome-guided drug dosing method could improve maintenance of drug trough levels within pre-determined target ranges, focusing on tacrolimus immediately after liver transplantation. This single-center, partially blinded, completed clinical trial involved 62 adults undergoing liver transplantation, block randomized into parallel groups: standard-of-care (SOC) clinician-determined or Phenotypic Personalized Medicine (PPM)-guided tacrolimus dosing. The primary outcome was percentage of post-transplant days with large (>2 ng/mL) deviations from the target range. At trial completion, analysis found statistically significant improvement in the PPM group (n = 27): 24.2% of days showing large deviations compared to 38.4% in the SOC group (n = 29) (difference -14.2%, 95% CI: -26.7 to -1.5 %, P = 0.029) with no increase in adverse events. These results demonstrate that PPM-guided tacrolimus dosing more effectively maintains drug levels within the target range compared to SOC, suggesting a promising approach to improving drug dosing. The trial was registered at ClinicalTrials.gov with the identifier NCT03527238.

Liver transplantation (LT) is a curative treatment for end-stage liver disease. Anastomotic biliary strictures (ABSs) are more common in living donor LT (LDLT). However, the success rate of ERCP for ABSs remains unsatisfactory. In this study, we evaluated the efficacy of single-operator cholangioscopy (SOC) for ABS treatment in LDLT recipients where standard ERCP failed to access the stricture.

This prospective study included 40 LDLT patients undergoing ERCP with SOC (SpyGlass DS II; Boston Scientific Corp, Natick, Mass, USA) to treat ABSs when guidewire placement across the ABS was difficult during conventional ERCP (cannulation time >10 minutes) between October 2021 and May 2023. Our primary endpoint was technical success, defined as successful guidewire placement across the ABS and/or subsequent treatment. Secondary endpoints were rates of clinical success, adverse events, and reintervention.

The mean patient age was 59.7 ± 7.2 years, and the mean time from LDLT to the occurrence of ABS was 212 ± 230 days. Technical and clinical success were achieved in 92.5% (37/40) and 82.5% (33/40) of patients, respectively. The rates of post-ERCP cholangitis, pancreatitis, and bleeding were 10.0%, 15.0%, and 2.5%, respectively. Intestinal perforation did not occur, and all adverse events were mild in severity. Early stent migration within 1 month occurred in 2 patients (5.4%), and 4 patients (10.8%) required reintervention within 1 month.

This study shows the efficacy and safety of SOC-facilitated management for difficult ABSs in LDLT patients after failure of standard ERCP. (Clinical trial registration number: NCT05065125.).

The introduction of calcineurin inhibitors (CNIs) as the primary form of immunosuppression (IS) for liver transplantation (LT) in the late 1970s was a key in increasingly successful outcomes for transplantation over the past 3 decades. Despite the side effects of CNI which directly contribute to the long-term morbidity and mortality post-LT, they will remain the cornerstone of IS in the near future. Efforts to minimize exposure to CNI will require the application of blood and tissue biomarkers that accurately identify the extent of IS and risk of rejection for individual patients.

Organ injury is a major problem in liver transplant. Prolonged liver ischemia may result in ischemia/reperfusion injury (IRI), leading to inadequate activation of innate immunity. Hypothermic oxygenated machine perfusion (HOPE) of the graft emerges as a more physiologic method for liver preservation compared with static cold storage (SCS) by reducing IRI, which improves the quality of the graft. Despite being crucial, the immunological aspects of IRI in liver transplantation remained poorly explored.

We designed a pilot study to assess intrahepatic immune responses to HOPE compared with SCS (6 patients in each group). We explored immunologic and inflammatory pathways using both bulk RNA-sequencing and single-cell multiparametric flow cytometry analyses from liver biopsies performed on the graft before and after transplantation.

Despite a limited number of patients and heterogeneous effects on IRI, we observed immune changes in liver biopsies before and after organ storage and distinct functional modulations of intrahepatic immune cells from the transplanted liver that underwent SCS versus HOPE. A significant increase of infiltrated monocytes, conventional type 2 dendritic cells (cDC2s), and neutrophils ( P  < 0.05) and a trend toward reduced immune cell viability were observed after SCS but not after HOPE.

This pilot study did not allow us to conclude on IRI but showed that HOPE perfusion dampens liver infiltration of some innate immune cells. It reveals that the inclusion of additional transplanted patients and analysis of later time points after transplantation are needed to draw a definitive conclusion. However, it can guide future studies evaluating the development of new strategies to prevent IRI.

The neutrophil-lymphocyte ratio (NLR) is an easily calculable biomarker known to have a predictive value in cardiac disease, malignancy, and renal failure. However, it has not been studied before in chronic liver disease patients undergoing liver transplantation. We aimed to evaluate the role of the pre-transplantation NLR in predicting the prognosis of patients with chronic liver failure undergoing liver transplantation.

Data was retrospectively collected from 46 patients with chronic liver disease who underwent liver transplantation. The patients were divided into two groups. Group A had 23 patients who survived after liver transplantation. Group B had 23 patients who did not survive. NLR was calculated by dividing the percentage of neutrophils by the percentage of lymphocytes in peripheral blood. The NLR cut-off value was based on a receiver operating characteristic curve analysis. Postoperative complications were also noted.

Preoperative NLR of 3.46 can predict post-transplantation mortality, with the area under the curve (AUC) of 0.86, having a sensitivity of 86.96% and a specificity of 73.91%. NLR emerged as an independent predictor of mortality (hazard ratio (HR) = 4.1, p = 0.028) after adjusting for the Model for End-Stage Liver Disease-Sodium (MELD-Na), creatinine, and neutrophil count. A rising NLR trend was significantly associated with the development of postoperative complications like neurological disease (p < 0.001), coagulopathy (p = 0.004), and acute kidney injury (p = 0.043).

A high preoperative NLR is a predictor of poor outcomes in liver transplantation patients with chronic liver disease.

Cirrhosis is a disease with poor prognosis that requires the development of a novel therapeutic approach alternative to liver transplantation. In this study, we focused on the placenta and aimed to clarify the effects of human placental extract (HPE) on cirrhosis.

A mouse model of carbon tetrachloride-induced cirrhosis was used to evaluate the effect of HPE administration subcutaneously and compared with the control group (n = 8 for each group). In vitro and in vivo, real time-PCR and immunostaining were performed for HPE mechanistic analysis. Spatial transcriptomics was also performed for detailed analysis of the effect of HPE on cirrhosis.

HPE administration improved serum ALT levels compared to control mice. Furthermore, there was a decrease in the number of senescent cells in the liver and the mRNA levels of secrete senescence-associated secretory phenotype factors and Cdkn2a (p16). In vitro, HPE induced macrophage polarization to the anti-inflammatory M2 phenotype. Spatial transcriptomics was also performed to analyze the underlying anti-inflammatory mechanism. The results showed that HPE strongly polarized macrophages to the M2 phenotype, especially in macrophage-rich regions in the liver. Gene expression pathway analysis using spatial transcriptomics also revealed the possibility of improving senescent cell-derived inflammation via mitochondrial function.

HPE improves serum ALT levels via anti-inflammatory mechanisms in macrophages and senescent cells. HPE serves as a novel agent for cirrhosis treatment.

Liver transplantation is the treatment of choice in patients with chronic liver disease and acute liver failure of any etiology. Scales such as the Survival Outcome Following Transplantation (SOFT) score and the Balance of Risk (BAR) score can be used to predict survival. In this study, we compared these scales in the Mexican population.

A cross-sectional analytical study was carried out in a Mexican third-level transplant center. The MELD, SOFT, and BAR scales were adopted. The ROC curves of the three predictive scores were constructed, and the areas under the curve were obtained and compared. A bivariate analysis and Cox regression were performed. Finally, a survival analysis was performed using Kaplan-Meier curves.

We analyzed 123 liver transplant (LT) recipients. The bivariate analysis and Cox regression indicated that portal thrombosis, with an HR of 3.36 (IC 1.069-10.59, p = 0.038), and the number of red blood cells transfused, with an HR of 1.084 (CI 1.039-1.130, p < 0.000), were significantly associated with mortality. The receiver height was a protective factor, with an HR of 0.001 (CI 0.000-0.761, p = 0.041). Regarding the Pearson correlation analysis, the BAR scale had a coefficient of 0.199 (p = 0.032) for transfusion, while the SOFT scale's correlation coefficients for cold ischemia and transfusion were 0.236 (p = 0.011) and 0.274 (p = 0.003), respectively, all indicating weak correlations. The areas under the curve (AUCs) of MELD, SOFT, and BAR in predicting 3-month mortality were 0.495 (P = 0.94), 0.608 (p = 0.129), and 0.502 (p = 0.97), respectively. Finally, in the survival analysis using Kaplan-Meier curves, an estimated mean survival period of 71.52 months was obtained, with a survival rate of 89.3 % at 30 days and 81.1 % at five years.

In this study, it was found that all three scales were deficient in discriminating among the outcomes obtained in the Mexican population.

To evaluate the effect of perioperative probiotics or synbiotics on the incidence of postoperative infections following major liver surgery.

Meta-analysis.

PubMed, Embase, Scopus, and the Cochrane Library for relevant English-language studies published up to February 21st, 2024.

Randomized controlled trials evaluating perioperative probiotics or synbiotics for preventing postoperative infections in patients undergoing major liver surgery.

Outcomes included postoperative infection incidence, antibiotic therapy duration, length of stay in intensive care unit (ICU) and hospital. A random-effect model was adopted for the meta-analysis. The quality of included studies was evaluated using the Cochrane risk of bias tool.

Ten studies involving 588 patients were included. Pooled analyses revealed that perioperative probiotics or synbiotics significantly reduced postoperative infection incidence (RR 0.36, 95% CI [0.24-0.54], P < 0.0001, I2 = 6%) and antibiotic therapy duration (MD -2.82, 95% CI [-3.13 to -2.51], P < 0.001, I2 = 0%). No significant differences were observed in length of stay in ICU (MD -0.25, 95% CI [-0.84-0.34], P = 0.41, I2 = 64%) or length of stay in hospital (MD -1.25, 95% CI [-2.74-0.25], P = 0.10, I2 = 56%).

This meta-analysis suggests that perioperative administration of probiotics or synbiotics may reduce the incidence of postoperative infections and duration of antibiotic therapy. Their use as adjunctive therapy during the perioperative period could be considered for patients undergoing major liver surgery.

The creation of self-organizing liver organoids represents a significant, although modest, step toward addressing the ongoing organ shortage crisis in allogeneic liver transplantation. However, researchers have recognized that achieving a fully functional whole liver remains a distant goal, and the original ambition of organoid-based liver generation has been temporarily put on hold. Instead, liver organoids have revolutionized the field of hepatology, extending their influence into various domains of precision and molecular medicine. These 3D cultures, capable of replicating key features of human liver function and pathology, have opened new avenues for human-relevant disease modeling, CRISPR gene editing, and high-throughput drug screening that animal models cannot accomplish. Moreover, advancements in creating more complex systems have led to the development of multicellular assembloids, dynamic organoid-on-chip systems, and 3D bioprinting technologies. These innovations enable detailed modeling of liver microenvironments and complex tissue interactions. Progress in regenerative medicine and transplantation applications continues to evolve and strives to overcome the obstacles of biocompatibility and tumorigenecity. In this review, we examine the current state of liver organoid research by offering insights into where the field currently stands, and the pivotal developments that are shaping its future.

Despite technical and therapeutic advances, only 20-40% of patients with colorectal liver metastases (CRLM) have resectable disease. Historically, the remaining patients with unresectable, liver-only CRLM would receive palliative chemotherapy, with a median survival of 8 months.

Liver transplantation has emerged as a viable option for selected patients with CRLM. This advancement stems from improved understanding of tumour genomics and biology and better patient selection criteria. The results of recent prospective clinical trials have further ignited enthusiasm for liver transplantation as a viable therapeutic option. Living donor liver transplantation (LDLT) offers several advantages over deceased donor liver transplantation (DDLT) for this disease, including reduced wait-time and optimized timing and coordination of oncologic therapy. On-going LDLT clinical trials have demonstrated favourable outcomes as compared with other liver transplantation indications. However, there is no established consensus or standardization in the implementation of LDLT for CRLM, beyond trials and centre-specific protocols.

LDLT is an excellent therapeutic option in highly selected patients with CRLM. Refining prognostic factors and selection criteria will help to further optimize the utility and broaden the acceptance and implementation of LDLT for patients with CRLM.

Liver transplant (LT) is an effective treatment for hepatocellular carcinoma (HCC) in appropriately selected patients. Locoregional therapy (LRT) is often performed to extend a patient's eligibility for LT. Imaging has a modest sensitivity of approximately 40-77% for detecting pathologically viable HCC in post-LRT patients. The impact on overall survival (OS) and disease-free survival (DFS) is unclear. We hypothesize that Liver Imaging Reporting & Data Systems Treatment Response (LI-RADS TR) category is equivalently correlated with long-term survival and overall disease-free progression when compared to explant pathology findings. We additionally hypothesize that neoadjuvant LRT can improve OS and DFS in LT patients initially within MC.

Patients found to have HCC on explant between January 2005 and December 2021 were included. A total of 167 patients were divided into treatment (any pre-LT LRT except for Y-90 therapy) and control (no pre-LT LRT) groups. Of the patients who received pre-LT LRT, imaging studies were reviewed by two abdominal radiologists using 2018 LI-RADS criteria. Statistical analysis was performed using Kaplan-Meier survival curves and Cox proportional hazard models to assess OS and DFS.

No statistically significant difference in OS or DFS (p = 0.23 and p = 0.22 respectively) was initially found. Given significant difference in age between the groups (p < 0.0001), Cox proportional hazard models were used to adjust for age with statistical significance reached for better OS and DFS in the treatment group (p = 0.05 and p = 0.05 respectively). Contrary to our hypothesis, there was no difference between treatment response groups regarding overall survival or disease-free survival, presumably because of low number of HCC recurrences in our patient population (4%).

Despite not reaching statistical significance, LI-RADS TR categorization demonstrates a good interreader agreement (Kappa 0.6), helping radiologists feel comfortable that modest sensitivity of the LI-RADS TR treatment response category for detecting pathologically active malignancy does not confer a negative clinical outcome.

The Transplantation Society (TTS) has been presenting the Medawar Prize at its biennial Congresses since 1990 in recognition of Sir Peter Medawar's seminal contributions to organ transplantation. This prestigious award acknowledges individuals for their outstanding accomplishments in experimental and clinical transplantation. On September 25, 2024, I was honored to introduce Ronald W. Busuttil, M.D., Ph.D., as the 2024 Medawar Prize Laureate during the 30th TTS Congress in Istanbul, Turkey. This article highlights the remarkable achievements and critical milestones in Dr. Busuttil's over 40-year career in organ transplantation, which have profoundly advanced scientific knowledge and clinical practice, embodying the true spirit of this accolade.

Liver transplantation has been at the forefront of medical research, with efforts concentrated on understanding the intricate cellular and molecular dynamics involved this complex procedure. This body of work has chronicled critical clinical advancements, identified challenges, and highlighted progressive improvements in surgical practices. These concerted efforts have significantly contributed to the evolution and enhancement of liver transplantation, elevating it to its current level of sophistication. A successful liver transplant now demands an integrated, multidisciplinary approach that includes not only expanding the donor pool from deceased to living donors but also embracing advances in surgical methods, efficiently managing post-transplant complications, and, importantly, achieving operational tolerance. The latter, operational tolerance, is a state wherein the recipient's immune system is coaxed into accepting the transplanted organ without the long-term use of immunosuppressive drugs, thereby minimizing potential side effects, and improving quality of life. Understanding the critical immune mechanisms that aim to prevent graft rejection is essential from an immunological perspective. This review aims to highlight the crucial areas of host versus graft immune responses, making a clear distinction between organs received from living and deceased donors. It examines how these immune responses, both innate and adaptive, are initiated and proposes the exploration of molecular docking sites as a strategy to curb unwanted immune reactions. Additionally, this review explores the promising potential of biomarkers in predicting graft rejection, and emphasizes the importance of achieving tolerance and the continuous quest for innovative strategies to enhance the success and longevity of liver transplants.

In this article, we comment on an article published in a recent issue of the World Journal of Gastroenterology. We specifically focus on the roles of human leukocyte antigen (HLA) and donor-specific antibodies (DSAs) in pediatric liver transplantation (LT), as well as the relationship between immune rejection after LT and DSA. Currently, LT remains the standard of care for pediatric patients with end-stage liver disease or severe acute liver failure. However, acute and chronic rejection continues to be a significant cause of graft dysfunction and loss. HLA mismatch significantly reduces graft survival and increases the risk of acute rejection. Among them, D→R one-way mismatch at three loci was significantly related to graft-versus-host disease incidence after LT. The adverse impact of HLA-DSAs on LT recipients is already established. Therefore, the evaluation of HLA and DSA is crucial in pediatric LT.

Initial analysis of liver transplant biopsies in the INTERLIVER study (ClinicalTrials.gov; unique identifier NCT03193151) using rejection-associated transcripts failed to find an antibody-mediated rejection state (ie, rich in natural killer [NK] cells and with interferon-gamma effects). We recently developed an optimization strategy in lung transplants that isolated an NK cell-enriched rejection-like (NKRL) state that was molecularly distinct from T cell-mediated rejection (TCMR). Here we apply the same strategy to a liver transplant biopsy population.

We used this strategy to search for a molecular NKRL state in 765 consented liver transplant biopsies collected at participating international centers for gold-standard histology and molecular assessment by genome-wide microarrays. Validation through a training set-test set approach of an optimized selection of variables as inputs into unsupervised rejection classification identified an NKRL state in livers.

The full model classified 765 biopsies into the following molecular phenotypes, characterized by their gene expression: no-rejection 54%, TCMR 16%, NKRL 13%, and injury 16%. Top TCMR transcripts were expressed in effector T cells; top NKRL transcripts were almost exclusively expressed in NK cells; and both had increased interferon-γ-inducible transcripts, which were more pronounced in TCMR. Most TCMR biopsies had significant parenchymal injury, molecular fibrosis, and abnormal biochemistry. NKRL biopsies had no excess of injury, fibrosis, or biochemistry abnormalities.

Optimized rejection algorithms indicate that some liver transplants manifest an NKRL state that is well tolerated in the short term postbiopsy and with minimal injury and relatively normal biochemistry, while also underscoring the potential of TCMR to produce extensive parenchymal injury.

Background The passage of the Transplantation of Human Organs Act in 1994 banned the unethical trade in human kidneys and recognized heart beating brain death as a form of death. This enabled liver transplantation to be performed in India. We briefly recount the history of the Act's passage and describe, in some detail, the present status of the procedure. Methods We sent a questionnaire regarding liver transplant services via email to 400 members of the Liver Transplant Society of India requesting them to provide details on liver transplantation at their centres up to 2022. We received information on 3069 of 3920 transplants that had been performed in 2022. Results There were 183 registered centres who had performed a total of 3920 liver transplants, placing India in third position behind the USA (n=9528) and China (n=6053) while it performed the largest number of living donor liver transplants (n=3183) in the world. The most common indication for liver transplantation was non-alcoholic steatohepatitis (NASH)-related cirrhosis (20%). Our teams published 2449 PubMed indexed research papers and 384 foreign trainees came from 52 countries for training in liver transplantation. The concerns were the small numbers of deceased organ donation, the dominance of the private sector (96.7%), corruption in the form of kickbacks and false declarations of relationship and gender imbalance with only 22% women recipients receiving organs from men while 68% women donated their livers to men. Conclusion Liver transplantation has saved the lives of many Indians, made a major impact on Indian healthcare overall, and increased its reputation worldwide. There are problems which we hope will be tackled by increasing societal awareness.

Acute liver failure (ALF) is a fulminant clinical syndrome that usually leads to multiple organ failure and high mortality. Macrophages play a crucial role in the initiation, development, and recovery of ALF. Targeting macrophages through immunotherapy holds significant promise as a therapeutic strategy. These cells exhibit remarkable plasticity, enabling them to differentiate into various subtypes based on changes in their surrounding microenvironment. M1-type macrophages are associated with a pro-inflammatory phenotype and primarily rely predominantly on glycolysis. In contrast, M2-type macrophages, which are characterized by anti-inflammatory phenotype, predominantly obtain their energy from oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO). Shifting macrophage metabolism from glycolysis to OXPHOS inhibits M1 macrophage activation and promotes M2 macrophage activation, thereby exerting anti-inflammatory and reparative effects. This study elucidates the relationship between macrophage activation and glucose metabolism reprograming from an immunometabolism perspective. A comprehensive literature review revealed that several signaling pathways may regulate macrophage polarization through energy metabolism, including phosphatidyl-inositol 3-kinase/protein kinase B (PI3K/AKT), mammalian target of rapamycin (mTOR)/hypoxia-inducible factor 1α (HIF-1α), nuclear factor-κB (NF-κB), and AMP-activated protein kinase (AMPK), which exhibit crosstalk with one another. Additionally, we systematically reviewed several traditional Chinese medicine (TCM) monomers that can modulate glucose metabolism reprograming and influence the polarization states of M1 and M2 macrophages. This review aimed to provide valuable insights that could contribute to the development of new therapies or drugs for ALF.

Liver transplantation (LT) is an established life-saving procedure. The field of LT has changed in the past 10 years from several perspectives, with the expansion of indications, transplantation of patients with acute-on-chronic liver failure, evolution of transplant oncology, the use of donations after cardiac death, new surgical techniques, and prioritisation of recipients on the waiting list. In addition, the advent of organ perfusion machines, the recognition of new forms of rejection, and the attention paid to the transition from paediatric to adult patients, have all improved the management of LT recipients. The purpose of the EASL guidelines presented here is not to cover all aspects of LT but to focus on developments since the previous EASL guidelines published in 2016.

In the body, capillary beds fulfill the metabolic needs of cells by acting as the sites of diffusive transport for vital gasses and nutrients. In artificial tissues, replicating the scale and complexity of capillaries has proved challenging, especially in a three-dimensional context. In order to better develop thick artificial tissues, it will be necessary to recreate both the form and function of capillaries. Here we demonstrate a top-down method of patterning hydrogels using sacrificial templates formed from thermoresponsive microfibers whose size and architecture approach those of natural capillaries. Within the resulting microchannels, we cultured endothelial monolayers that remain viable for over three weeks and exhibited functional barrier properties. Additionally, we cultured endothelialized microchannels within hydrogels containing fibroblasts and characterized the viability of the co-cultures to demonstrate this approach's potential when applied to cell-laden hydrogels. This method represents a step forward in the evolution of artificial tissues and a path towards producing viable capillary-scale microvasculature for engineered organs.

Platelets not only participate in physiological hemostasis but also play a major role in liver ischemia-reperfusion injury, liver damage, tissue repair, and liver regeneration. A decrease in platelet count can lead to spontaneous bleeding, infection, and other complications that can seriously impact patient prognosis. Thrombocytopenia has been associated with increased complications after partial hepatectomy, although the effects of thrombocytopenia on patient outcomes remain unclear. Therefore, this study aimed to examine the impact of thrombocytopenia on short- and long-term prognosis following liver transplantation (LT).

This was a retrospective analysis comprising 234 adult liver transplant recipients and conducted from January 2019 to June 2022. Preoperative and postoperative daily platelet counts were recorded up to the 30th postoperative day (POD). We defined people with platelet counts <70 × 109/L as the low platelet group, and people with platelet counts >70 × 109/L as the high platelet group. Multivariate analysis was carried out to determine whether low perioperative platelet count was a risk factor for postoperative complications, graft failure, and patient survival.

Of the 234 patients analyzed in this study, approximately half (n = 112, 47.9%) developed persistent thrombocytopenia after LT. The most substantial decrease in platelet levels occurred on POD7. The cumulative survival rates at 1, 2, and 3 years in the high platelet group were higher than those in the low platelet group, 94%, 87%, and 85%, respectively, while those of the low platelet group were 84%, 78%, and 70% (P = .0014). In addition, the high platelet group had a lower incidence of biliary complications compared with the low platelet group (8% vs 19%, P = .020). At the same time, the high platelet group had a lower incidence of posttransplant lung infection (55% vs 75%, P = .040).

Thrombocytopenia is a common complication of LT. It indicates the severity of the postoperative course and is closely associated with patient survival. In particular, patients who undergo orthotopic liver transplantation (OLT) and have a platelet count <70 × 109/L on the POD7 have significant negative prognostic implications and should be further investigated.

The objectives of our study were to examine and compare patient and graft survival over a 5-year period across BMI groups, and examine immediate and short-term complications post-LT. This was a retrospective study that examined all liver transplants that occurred at our institution between January 2015-October 2022. Patients were divided into 4 BMI groups (n = 888): normal-overweight (BMI 18.5- 29.9 kg/m2), class I obesity (BMI 30-34.9 kg/m2), class II obesity (BMI 35-39.9 kg/m2), and class III obesity (BMI ≥40 kg/m2) patients. Kaplan Meier curves with the log rank test were created to assess survival outcomes and multivariate Cox regression analysis was performed. Patient and graft survival did not differ statistically between each BMI group. However, patient survival was significantly lower in patients with BMI ≥40 compared to patients with BMI <40. In multivariate analysis, BMI ≥40, admission to the ICU, and age were independent predictors of increased risk of mortality. Infection, arrhythmia, cardiac arrest, and myocardial infarction were more frequent immediate complications in the class III obesity group. Efforts to closely monitor patients with BMI ≥40 post LT to maximize survival are needed. Further studies are needed to improve post LT survival among patients with BMI ≥40.

Preserving organs at subzero temperatures with halted metabolic activity holds the potential to prolong preservation and expand the donor organ pool for transplant. Our group recently introduced partial freezing, a novel approach in high-subzero storage at -15 °C, enabling 5-day storage of rodent livers through precise control over ice nucleation and unfrozen fraction. However, increased vascular resistance and tissue edema suggested a need for improvements to extend viable preservation. Here, we describe an optimized partial freezing protocol with key optimizations, including an increased concentration of polyethylene glycol (PEG) to enhance membrane stability while minimizing shear stress during cryoprotectant unloading with an acclimation period and a maintained osmotic balance through an increase in bovine serum albumin (BSA). These approaches ensured the viability during preservation and recovery processes, promoting liver function and ensuring optimal preservation. This was evidenced by increased oxygen consumption, decreased vascular resistance, and edema. Ultimately, we show that using the optimized protocol, livers can be stored for 10 days with comparable vascular resistance and lactate levels to 5 days, outperforming the viability of time-matched static cold stored (SCS) livers as the current gold standard. This study represents a significant advancement in expanding organ availability through prolonged preservation, thereby revolutionizing transplant medicine.

Ischemia reperfusion injury represents a significant yet difficult to assess risk factor for short- and long-term graft impairment in human liver transplantation (LT). As a non-invasive, non-ionizing tool, hyperspectral imaging (HSI) is capable of correlating optical properties with organ microperfusion. Hence, we here performed a study of human liver allografts assessed by HSI for microperfusion and prediction of initial graft function.

Images of liver parenchyma of 37 human liver allografts were acquired at bench preparation, during normothermic machine perfusion (NMP), if applicable, and after reperfusion in the recipient. A specialized HSI acquisition software computed oxygen saturation (StO2), tissue hemoglobin indices (THI), near infrared perfusion indices (NIR), and tissue water indices (TWI). HSI parameters were analyzed for differences with regard to preservation technique, reperfusion sequence and presence of early allograft dysfunction (EAD).

Organ preservation was performed by means of NMP (n = 31) or static cold storage (SCS; n = 6). Patients' demographics, donor characteristics, presence of EAD (NMP 36.7% vs. SCS 50%, p = 0.6582), and HSI parameters were comparable between both groups of preservation method. In organs developing EAD, NIR at 1, 2, and 4 h NMP and after reperfusion in the recipient was significantly lower (1 h NMP: 18.6 [8.6-27.6] vs. 28.3 [22.5-39.4], p = 0.0468; 2 h NMP: 19.4 [8.7-30.4] vs. 37.1 [27.5-44.6], p = 0.0011; 4 h NMP: 26.0 [6.8-37.1] vs. 40.3 [32.3-49.9], p = 0.0080; reperfusion: 13.0 [11.5-34.3] vs. 30.6 [19.3-44.0], p = 0.0212).

HSI assessment of human liver allografts is feasible during organ preservation and in the recipient. NIR during NMP and after reperfusion might predict the onset of EAD. Larger trials are warranted for assessment of this novel technique in human LT.

Stem cell-related therapeutic technologies have garnered significant attention of the research community for their multi-faceted applications. To promote the therapeutic effects of stem cells, the strategies for cell microencapsulation in hydrogel microparticles have been widely explored, as the hydrogel microparticles have the potential to facilitate oxygen diffusion and nutrient transport alongside their ability to promote crucial cell-cell and cell-matrix interactions. Despite their significant promise, there is an acute shortage of automated, standardized, and reproducible platforms to further stem cell-related research. Microfluidics offers an intriguing platform to produce stem cell-laden hydrogel microparticles (SCHMs) owing to its ability to manipulate the fluids at the micrometer scale as well as precisely control the structure and composition of microparticles. In this review, the typical biomaterials and crosslinking methods for microfluidic encapsulation of stem cells as well as the progress in droplet-based microfluidics for the fabrication of SCHMs are outlined. Moreover, the important biomedical applications of SCHMs are highlighted, including regenerative medicine, tissue engineering, scale-up production of stem cells, and microenvironmental simulation for fundamental cell studies. Overall, microfluidics holds tremendous potential for enabling the production of diverse hydrogel microparticles and is worthy for various stem cell-related biomedical applications.

Ischemia-reperfusion injury (IRI) is an intrinsic risk associated with liver transplantation. Ex vivo hepatic machine perfusion (MP) is an emerging organ preservation technique that can mitigate IRI, especially in livers subjected to prolonged warm ischemia time (WIT). However, a method to quantify the biological response to WIT during MP has not been established. Previous studies used physiologically based pharmacokinetic (PBPK) modeling to demonstrate that a decrease in hepatic transport and biliary excretion of the tracer molecule sodium fluorescein (SF) could correlate with increasing WIT in situ. Furthermore, these studies proposed intracellular sequestration of the hepatocyte canalicular membrane transporter multidrug resistance-associated protein 2 (MRP2) leading to decreased MRP2 activity (maximal transport velocity; Vmax) as the potential mechanism for decreased biliary SF excretion. We adapted an extant PBPK model to account for ex vivo hepatic MP and fit a six-parameter version of this model to control time-course measurements of SF in MP perfusate and bile. We then identified parameters whose values were likely insensitive to changes in WIT and fixed them to generate a reduced model with only three unknown parameters. Finally, we fit the reduced model to each individual biological replicate SF time course with differing WIT, found the mean estimated value for each parameter, and compared them using a one-way ANOVA. We demonstrated that there was a significant decrease in the estimated value of Vmax for MRP2 at the 30-min WIT. These studies provide the foundation for future studies investigating real-time assessment of liver viability during ex vivo MP.NEW & NOTEWORTHY We developed a computational model of sodium fluorescein (SF) biliary excretion in ex vivo machine perfusion and used this model to assess changes in model parameters associated with the activity of MRP2, a hepatocyte membrane transporter, in response to increasing warm ischemia time. We found a significant decrease in the parameter value describing MRP2 activity, consistent with a role of decreased MRP2 function in ischemia-reperfusion injury leading to decreased secretion of SF into bile.

Lack of available organs poses a significant challenge in meeting the needs of patients with life-threatening liver disease who could benefit from liver transplantation (LT). Psychosocial vulnerability markers have been linked to post-transplant outcomes, raising questions about their use in patient selection. However, their incorporation into selection criteria raises concerns about health equity and potential discrimination. As a result, there is a pressing need to refine fair allocation systems that consider both clinical and psychosocial factors to ensure equitable access and optimize post-transplant outcomes. The Equitable Benefit Approach (EBA) proposed in this paper by the multidisciplinary group of clinical experts in LT from the Italian Society for the Study of the Liver seeks to address these concerns. It presents four procedural principles, the two allocative principles usually applied in transplantation (urgency and utility) and introduces a new one, the principle of health equity. The EBA aims to prioritize patients with the highest transplant benefit while addressing health inequalities. It emphasizes evidence-based decision-making and standardized assessment tools to reliably evaluate psychosocial risk factors. Implementing the EBA involves a multi-step process, including stakeholder engagement, prospective studies to validate its efficacy, development of institutional policies and algorithms, and ongoing monitoring and revision. By following these steps, health care providers can ensure that LT allocation decisions are transparent and responsive to evolving clinical and social contexts. Ultimately, the EBA should offer a comprehensive framework for fair patient selection in LT, considering both biomedical and psychosocial aspects.

Chylous ascites is caused by disruption of the lymphatic system, which is characterized by the accumulation of a turbid fluid containing high levels of triglycerides within the abdominal cavity. The two most common causes are cirrhosis and tuberculosis, and colon signer ring cell carcinoma (SRCC) due to the use of immunosuppressants is extremely rare in cirrhotic patients after liver transplantation, making it prone to misdiagnosis and missed diagnosis.

A 52-year-old man who underwent liver transplantation and was administered with immunosuppressants for 8 months was admitted with a 3-month history of progressive abdominal distention. Initially, based on lymphoscintigraphy and lymphangiography, lymphatic obstruction was considered, and cystellar chyli decompression with band lysis and external membrane stripping of the lymphatic duct was performed. However, his abdominal distention was persistent without resolution. Abdominal paracentesis revealed allogenic cells in the ascites, and immunohistochemistry analysis revealed adenocarcinoma cells with phenotypic features suggestive of a gastrointestinal origin. Gastrointestinal endoscopy was performed, and biopsy showed atypical signet ring cells in the ileocecal valve. The patient eventually died after a three-month follow-up due to progression of the tumor.

Colon SRCC, caused by immunosuppressants, is an unusual but un-neglected cause of chylous ascites.

Liver transplantation (LT) in Asia started comparatively early in 1964, just 1 year after Starzl's trail-blazing first attempt. Despite the quick start, LT was slow to develop in this region. Limited access to universal healthcare, lack of public understanding and support as well as the absence of strong legislation, on a backdrop of a wide range of diverse social, religious, economic and cultural background are all contributory factors. Through strong administrative efforts, the number of DDLTs in selected Asian countries has been slowly rising in recent years. However, Asians are generally still less likely to donate organs than Caucasians after death. The strong demand for LT with limited access to deceased organs has, therefore, led to constant need for innovation in LT this region, with the pioneering of various LDLT techniques and safe expansion of donor pool being driven primarily by Asian centers. Familiarity and the development of technical expertise in donor surgery have also resulted in Asian centers repeatedly pushing the boundaries on minimally invasive donor and recipient surgery. In this article, we focus on the past and present states of LT in Asia and explore the future trends of LT in this region.

Biliary atresia (BA) is a progressive fibroinflammatory disease affecting both the extrahepatic and intrahepatic bile ducts, potentially leading to chronic cholestasis and biliary cirrhosis. Despite its prevalence, the exact mechanisms behind BA development remain incompletely understood. Recent research suggests that the gut microbiota and its metabolites may play significant roles in BA development. This paper offers a comprehensive review of the changing characteristics of gut microbiota and their metabolites at different stages of BA in children. It discusses their influence on the host's inflammatory response, immune system, and bile acid metabolism. The review also explores the potential of gut microbiota and metabolites as a therapeutic target for BA, with interventions like butyrate and gut microbiota preparations showing promise in alleviating BA symptoms. While progress has been made, further research is necessary to untangle the complex interactions between gut microbiota and BA, paving the way for more effective prevention and treatment strategies for this challenging condition.

Liver transplantation (LT) has been an established treatment for end-staged liver disease for acute, chronic, metabolic diseases and liver cancer. Advanced surgical techniques, refined indications and contraindications for LT, improvements of donor selection, prognostic scorings system and immunosuppressive regimens have contributed to the improved outcomes of liver transplantation. The etiologies of cirrhosis have been shifting from viral hepatitis to metabolic associated fatty liver disease. New indications include peripheral or mass forming bile duct cancer, metastases from bowel cancers or neuroendocrine tumors. Resection and partial liver segments 2-3 transplantation with delayed total hepatectomy has been performed to the limited cases, which was the explored technique of auxiliary partial orthotopic LT. Minimally invasive donor hepatectomy (laparoscopic or robotic) has been increasingly done. In this review are described the recent pressing topics in LT.

Preserving organs at subzero temperatures with halted metabolic activity holds the potential to prolong preservation and expand the donor organ pool for transplant. Our group recently introduced partial freezing, a novel approach in high-subzero storage at -15°C, enabling 5 days storage of rodent livers through precise control over ice nucleation and unfrozen fraction. However, increased vascular resistance and tissue edema suggested a need for improvements to extend viable preservation. Here, we describe an optimized partial freezing protocol with key optimizations including increased concentration of propylene glycol to reduce ice recrystallization and maintained osmotic balance through an increase in bovine serum albumin, all while minimizing sheer stress during cryoprotectant unloading with an acclimation period. These approaches ensured the viability during preservation and recovery processes, promoting liver function and ensuring optimal preservation. This was evidenced by increased oxygen consumption, decreased vascular resistance and edema. Ultimately, we show that using the optimized protocol, livers can be stored for 10 days with comparable vascular resistance and lactate levels to 5 days, outperforming the viability of time-matched cold stored livers as the current gold standard. This study represents a significant advancement in expanding organ availability through prolonged preservation and thereby revolutionizing transplant medicine.

Hepatic stellate cells (HSCs) perform a significant function in liver regeneration (LR) by becoming active. We propose to investigate if activated HSCs enhance glycolysis via PFKFB3, an essential glycolytic regulator, and whether targeting this pathway could be beneficial for LR. The liver and isolated HSCs of mice subjected to 2/3 partial hepatectomy (PHx) exhibited a significant rise in PFKFB3 expression, as indicated by quantitative RT-PCR analyses and Western blotting. Also, the primary HSCs of mice subjected to PHx have a significant elevation of the glycolysis level. Knocking down PFKFB3 significantly diminished the enhancement of glycolysis by PDGF in human LX2 cells. The hepatocyte proliferation in mice treated with PHx was almost completely prevented when the PFKFB3 inhibitor 3PO was administered, emerging that PFKFB3 is essential in LR. Furthermore, there was a decline in mRNA expression of immediate early genes and proinflammatory cytokines. In terms of mechanism, both the p38 MAP kinase and ERK1/2 phosphorylation in LO2 cells and LO2 proliferation were significantly reduced by the conditioned medium (CM) obtained from LX2 cells with either PFKFB3 knockdown or inhibition. Compared to the control group, isolated hepatocytes from 3PO-treated mice showed decreased p38 MAP kinase and ERK1/2 phosphorylation and proliferation. Thus, LR after PHx involves the activation of PFKFB3 in HSCs, which enhances glycolysis and promotes lactate production, thereby facilitating hepatocyte proliferation via the p38/ERK MAPK signaling pathway.

To identify the mechanism underlying macrosteatosis (MaS)-related graft failure (GF) in liver transplantation (LT) by multi-omics network analysis. The transcriptome and metabolome were assayed in graft and recipient plasma in discovery (n = 68) and validation (n = 89) cohorts. Differentially expressed molecules were identified by MaS and GF status. Transcriptional regulatory networks were generated to explore the mechanism for MaS-related inferior post-transplant prognosis. The differentially expressed molecules associated with MaS and GF were enriched in ferroptosis and peroxisome-related pathways. Core features of MaS-related GF were presented on decreased transferrin and impaired anti-oxidative capacity dependent upon dysregulation of transcription factors hepatocyte nuclear factor 4A (HNF4A) and hypoxia-inducible factor 1A (HIF1A). Furthermore, miR-362-3p and miR-299-5p inhibited transferrin and HIF1A expression, respectively. Lower M2 macrophages but higher memory CD4 T cells were observed in MaS-related GF cases. These results were validated in clinical specimens and cellular models. Systemic analysis of multi-omics data depicted a panorama of biological pathways deregulated in MaS-related GF. Transcriptional regulatory networks centered on transferrin and anti-oxidant responses were associated with poor MaS graft quality, qualifying as potential targets to improve prognosis of patients after LT.

Cirrhosis remains a significant clinical challenge due to its poor prognosis and limited treatment options, creating a high unmet medical need for the development of novel therapies. In this study, we analyzed the effects of a novel approach to treat cirrhosis using platelet-rich plasma-derived extracellular vesicles (PRPEV) in mice.

PRPEV were collected from platelet-rich plasma using ultrafiltration, and their proteomes were analyzed. The carbon tetrachloride (CCl4)-induced cirrhosis model of mice was used to evaluate the effect of PRPEV administration and compared with the control group (n = 8). In vitro and in vivo mechanistic analyses of PRPEV administration were confirmed using real time-PCR and immunostaining.

Gene ontology analysis based on the proteome revealed that PRPEV contain many factors associated with EV and immune responses. In vitro, PRPEV polarize macrophages into an anti-inflammatory phenotype. Following PRPEV administration, there was a decrease in serum alanine aminotransferase levels and reduction in liver fibrosis, while mRNA levels of regenerative factors were upregulated and transforming growth factor β-1 was downregulated. Furthermore, the number of anti-inflammatory macrophages in the liver increased.

PRPEV may contribute to hepatocyte proliferation, anti-inflammation, and anti-fibrogenesis in the liver. This novel concept paves the way for cirrhosis treatment.

The liver, a complex and vital organ in the human body, is susceptible to various diseases, including metabolic disorders, acute hepatitis, cirrhosis, and hepatocellular carcinoma. In recent decades, these diseases have significantly contributed to global morbidity and mortality. Currently, liver transplantation remains the most effective treatment for hepatic disorders. Nucleic acid therapeutics offer a selective approach to disease treatment through diverse mechanisms, enabling the regulation of relevant genes and providing a novel therapeutic avenue for hepatic disorders. It is expected that nucleic acid drugs will emerge as the third generation of pharmaceuticals, succeeding small molecule drugs and antibody drugs. Lipid nanoparticles (LNPs) represent a crucial technology in the field of drug delivery and constitute a significant advancement in gene therapies. Nucleic acids encapsulated in LNPs are shielded from the degradation of enzymes and effectively delivered to cells, where they are released and regulate specific genes. This paper provides a comprehensive review of the structure, composition, and applications of LNPs in the treatment of hepatic disorders and offers insights into prospects and challenges in the future development of LNPs.

Liver transplantation is one of the most challenging areas in the medical field. Despite that, it has already been established as a standard treatment option, especially in decompensated cirrhosis and selected cases of hepatocellular carcinoma and acute liver failure. Complications due to graft rejection, including mortality and morbidity, have greatly improved over time due to better immunosuppressive agents and management protocols. Currently, immunosuppression in liver transplant patients makes use of the best possible combinations of effective agents to achieve optimal immunosuppression for long-term graft survival. Induction agents are no longer used routinely, and the aim is to provide minimal immunosuppression in the maintenance phase. Currently available immunosuppressive agents are mainly classified as biological and pharmacological agents. Though the protocols may vary among the centers and over time, the basics of effective use usually remain similar. Most protocols use the combination of multiple agents with different mechanisms of action to reduce the dose and minimize the side effects. Along with the improvement in operative and perioperative techniques, this art of immunosuppression has contributed to the recent progress made in the outcomes of liver transplants. In this review, we will discuss the various types of immunosuppressive agents currently in use, the different protocols of immunosuppression used, and the art of optimal use for achieving maximum immunosuppression without increasing toxicity. We will also discuss the practical aspects of various immunosuppression regimens, including drug monitoring, and briefly discuss the concepts of immunosuppression minimization and withdrawal.

Background: Acute rejection (AR) is the predominant form of rejection observed in liver transplantation and plays a crucial role in transplant immunology. This study aims to utilize bibliometric analysis to understand the status quo, hotspots, and future trends of research on AR after liver transplantation. Methods: We searched the Web of Science Core Collection (WoSCC) for studies on AR after liver transplantation published from 1988 to 2022. The Bibliometric Online Analysis Platform, VOSviewer, and CiteSpace were used for analysis of all extracted publications. Results: This study included 2,398 articles published in 456 journals by 12,568 authors from 1,965 institutions in 55 countries/regions. The United States and its affiliated institution, the University of Pittsburgh, were the most productive contributors. Transplantation (n = 12,435) was the most frequently cited journal. Neuhaus P (n = 38) was the highest output author, and Demetris AJ (n = 670) was the most co-cited author. The research hotspots of AR after liver transplantation include pathogenesis, immunosuppressive therapy, and prognosis. Emerging research directions include regulatory T cells, immunosuppression minimization, intra-patient variability (IPV) of tacrolimus, and novel non-invasive diagnostic markers. Conclusion: Our study utilized bibliometric methods to analyze the study of AR after liver transplantation over the past 35 years. With the prolonged survival of liver transplant recipients, the most active areas currently focus on individualized treatment and improving patient prognosis. Minimizing adverse reactions to immunosuppressive therapy while simultaneously avoiding an increase in the risk of AR remains a future research focus.

Liver transplantation is a highly complex and challenging field of clinical practice. Although it was originally developed in western countries, it has been further advanced in Asian countries through the use of living donor liver transplantation. This method of transplantation is the only available option in many countries in the Asia-Pacific region due to the lack of deceased organ donation. As a result of this clinical situation, there is a growing need for guidelines that are specific to the Asia-Pacific region. These guidelines provide comprehensive recommendations for evidence-based management throughout the entire process of liver transplantation, covering both deceased and living donor liver transplantation. In addition, the development of these guidelines has been a collaborative effort between medical professionals from various countries in the region. This has allowed for the inclusion of diverse perspectives and experiences, leading to a more comprehensive and effective set of guidelines.