Complication Of Liver Transplantation Research Articles

Icaritin attenuates ischemia–reperfusion injury by anti-inflammation, anti-oxidative stress, and anti-autophagy in mouse liver

BackgroundHepatic ischemia–reperfusion (IR) injury is a major complication of liver transplantation and gravely affects patient prognosis. Icaritin (ICT), the primary plasma metabolite of icariin (ICA), plays a critical role in anti-inflammatory and immunomodulatory processes. However, the role of ICT in hepatic IR injury remains largely undefined. In this study, we aimed to elucidate the role of ICT in hepatic IR injury. MethodsWe established hepatic IR injury models in animals, as well as an oxygen-glucose deprivation/reperfusion (OGD/R) cell model. Liver injury in vivo was assessed by measuring serum alanine aminotransferase (ALT) levels, necrotic areas by liver histology and local hepatic inflammatory responses. For in vitro analyses, we implemented flow-cytometric and western blot analyses, transmission electron microscopy, and an mRFP-GFP-LC3 adenovirus reporter assay to assess the effects of ICT on OGD/R injury in AML12 and THLE-2 cell lines. Signaling pathways were explored in vitro and in vivo to identify possible mechanisms underlying ICT action in hepatic IR injury. ResultsCompared to the mouse model group, ICT preconditioning considerably protected the liver against IR stress, and diminished the levels of necrosis/apoptosis and inflammation-related cytokines. In additional studies, ICT treatment dramatically boosted the expression ratios of p-PI3K/PI3K, p-AKT/AKT, and p-mTOR/mTOR proteins in hepatic cells following OGD/R damage. We also applied LY294002 (a PI3K inhibitor) and RAPA (rapamycin, an mTOR inhibitor), which blocked the protective effects of ICT in hepatocytes subjected to OGD/R. ConclusionThis study indicates that ICT attenuates ischemia–reperfusion injury by exerting anti-inflammation, anti-oxidative stress, and anti-autophagy effects, as demonstrated in mouse livers. We thus posit that ICT could have therapeutic potential for the treatment of hepatic IR injury.

Pneumonia promotes pulmonary metastasis of HCC after transplantation via VEGF regulated PI3K/AKT/Cas-9 signaling and angiogenesis

Aim: Pneumonia is the most frequent early postoperative complication in liver transplantation (LT) recipients. Inflammation may provide a favorable environment for tumor implantation, so we aimed to evaluate the impact of pneumonia on pulmonary metastasis of hepatocellular carcinoma (HCC) and reveal its underlying mechanism. Methods: A training cohort with 234 LT recipients were recorded and analyzed. Using the propensity-score method, we matched covariates between patients with and without pneumonia. A model for predicting pulmonary metastasis was built and validated in an independent validating cohort containing 179 subjects. A mouse model was built to mimic HCC pulmonary metastasis. The potential pathway was revealed by cytokine array analysis and validated in vitro . Results: Pneumonia was an independent risk factor for pulmonary metastasis in liver transplant recipients. It promoted pulmonary metastasis in both the clinical setting and the mouse model. In vitro , LPS-stimulated VEGF secretion from macrophages in the lung significantly reduced cell apoptosis and activated PI3K/AKT/cas-9 signaling. Administration of VEGF receptor2 inhibitor Vatalanib could reduce metastasis and improve prognosis in pneumonia mice. Conclusion: Pneumonia promotes HCC pulmonary metastasis by activating PI3K/AKT/Cas-9 signaling in HCC cells via macrophage-originated VEGF. Vatalanib might be efficient in reducing HCC pulmonary metastasis in liver transplant recipients with pneumonia.

Erratum: Role of Interventional Radiology in the Management of Liver Transplant Complications in Children

Erratum: Role of Interventional Radiology in the Management of Liver Transplant Complications in Children

The type, duration, and severity of pretransplant kidney injury predict prolonged kidney dysfunction after liver transplantation.

Chronic kidney disease (CKD) is a major complication of liver transplantation (LT) associated with substantial morbidity and mortality. Knowing the drivers of post-LT kidney dysfunction-with a granular focus on the type, duration, and severity of pre-LT kidney disease-can highlight intervention opportunities and inform dual-organ allocation policies. We retrospectively analyzed predictors of safety net kidney after liver transplant (KALT) eligibility and kidney replacement therapy (KRT) for > 14 days after LT. Among 557 recipients of adult deceased-donor LT, 49% had normal kidney function, 25% had acute kidney injury (AKI), and 25% had CKD±AKI at the time of LT. A total of 36 (6.5%) qualified for KALT and 63 (11%) required KRT > 14 days. In univariable analysis, factors associated with KALT eligibility and KRT > 14 days, respectively, included stage 3 AKI (OR 7.87; OR 7.06), CKD±AKI (OR 4.58; OR 4.22), CKD III-V duration (OR 1.10 per week; OR 1.06 per week), and increasing CKD stage (stage III: OR 3.90, IV: OR 5.24, V: OR 16.8; stage III: OR 2.23, IV: OR 3.62, V: OR 19.4). AKI stage I-II and AKI duration in the absence of CKD were not associated with the outcomes. Pre-LT KRT had a robust impact on KALT eligibility (OR 4.00 per week) and prolonged post-LT KRT (OR 5.22 per week), with 19.8% of patients who received any pre-LT KRT ultimately qualifying for KALT. Eligibility for KALT was similar between those who received 0 days and ≤ 14 days of KRT after LT (2.1% vs. 2.9%, p = 0.53). In conclusion, the type, duration, and severity of pre-LT kidney dysfunction have unique impacts on post-LT kidney-related morbidity, and future research must use these novel classifications to study mitigation strategies.

The type, duration, and severity of pretransplant kidney injury predict prolonged kidney dysfunction after liver transplantation.

Chronic kidney disease (CKD) is a major complication of liver transplantation (LT) associated with substantial morbidity and mortality. Knowing the drivers of post-LT kidney dysfunction-with a granular focus on the type, duration, and severity of pre-LT kidney disease-can highlight intervention opportunities and inform dual-organ allocation policies. We retrospectively analyzed predictors of safety net kidney after liver transplant (KALT) eligibility and kidney replacement therapy (KRT) for > 14 days after LT. Among 557 recipients of adult deceased-donor LT, 49% had normal kidney function, 25% had acute kidney injury (AKI), and 25% had CKD±AKI at the time of LT. A total of 36 (6.5%) qualified for KALT and 63 (11%) required KRT > 14 days. In univariable analysis, factors associated with KALT eligibility and KRT > 14 days, respectively, included stage 3 AKI (OR 7.87; OR 7.06), CKD±AKI (OR 4.58; OR 4.22), CKD III-V duration (OR 1.10 per week; OR 1.06 per week), and increasing CKD stage (stage III: OR 3.90, IV: OR 5.24, V: OR 16.8; stage III: OR 2.23, IV: OR 3.62, V: OR 19.4). AKI stage I-II and AKI duration in the absence of CKD were not associated with the outcomes. Pre-LT KRT had a robust impact on KALT eligibility (OR 4.00 per week) and prolonged post-LT KRT (OR 5.22 per week), with 19.8% of patients who received any pre-LT KRT ultimately qualifying for KALT. Eligibility for KALT was similar between those who received 0 days and ≤ 14 days of KRT after LT (2.1% vs. 2.9%, p = 0.53). In conclusion, the type, duration, and severity of pre-LT kidney dysfunction have unique impacts on post-LT kidney-related morbidity, and future research must use these novel classifications to study mitigation strategies.

Role of Interventional Radiology in the Management of Liver Transplant Complications in Children

AbstractLiver transplantation (LT) is a common solid organ transplant in the pediatric population. The common indications for LT, as well as its complications, differ between adults and children. This difference necessitates unique pediatric interventional radiology (IR) interventions. This article focuses on unique vascular complications occurring post-pediatric LT and highlights the importance of IR in their management. It explores IR's involvement in the workup of patients' pre-LT and management of complications following portosystemic shunts. We discuss advantages and disadvantages of different access routes as well as the prevalence, clinical picture, diagnosis, and management of complications after pediatric LT. These complications encompass portal vein stenosis, portal vein thrombosis, hepatic artery stenosis, hepatic artery thrombosis, hepatic artery pseudoaneurysm, arterioportal fistula, hepatic vein stenosis, and inferior vena cava stenosis. The choice of endovascular technique for a clinical indication depends on vascular anatomy, time since LT, and patient-specific factors. Transsplenic access is a useful alternative to transhepatic or transjugular access. The decision to place a stent in a child is influenced by the expected growth of the child and risk of focal narrowing at stent edge (because of recipient growth). Technical challenges in pediatric patient management, including uncooperative patients and sedation issues, must be considered. Pediatric LT complications can present with significant challenges in the posttransplant care of recipients and may lead to serious morbidity and graft failure if not managed effectively. IR techniques like balloon angioplasty, stent placement, thrombolysis, and embolization have demonstrated success in treating these complications, improving patient outcomes, and reducing long-term morbidity and mortality. By enhancing the understanding of medical practitioners and interventional radiologists about complex vascular complications, this article aims to contribute to better posttransplant care and improved outcomes for LT in pediatric populations. Continued collaboration between specialties and research will advance the field of pediatric LT and IR, to create even more effective treatment strategies.

Donor and recipient genetics: Implications for the development of posttransplant diabetes mellitus

Posttransplant diabetes mellitus (PTDM) is a prevalent complication of liver transplantation and is associated with cardiometabolic complications. We studied the consequences of genetic effects of liver donors and recipients on PTDM outcomes, focusing on the diverse genetic pathways related to insulin that play a role in the development of PTDM. One thousand one hundred fifteen liver transplant recipients without a pretransplant diagnosis of type 2 diabetes mellitus (T2D) and their paired donors recruited from 2 transplant centers had polygenic risk scores (PRS) for T2D, insulin secretion, and insulin sensitivity calculated. Among recipients in the highest T2D-PRS quintile, donor T2D-PRS did not contribute significantly to PTDM. However, in recipients with the lowest T2D genetic risk, donor livers with the highest T2D-PRS contributed to the development of PTDM (OR [95% CI] = 3.79 [1.10-13.1], P = .035). Recipient risk was linked to factors associated with insulin secretion (OR [95% CI] = 0.85 [0.74-0.98], P = .02), while donor livers contributed to PTDM via gene pathways involved in insulin sensitivity (OR [95% CI] = 0.86 [0.75-0.99], P = .03). Recipient and donor PRS independently and collectively serve as predictors of PTDM onset. The genetically influenced biological pathways in recipients primarily pertain to insulin secretion, whereas the genetic makeup of donors exerts an influence on insulin sensitivity.

Median Arcuate Ligament Syndrome (MALS) in Hepato-Pancreato-Biliary Surgery: A Narrative Review and Proposed Management Algorithm.

Median arcuate ligament syndrome (MALS) is an uncommon condition characterized by the compression of the celiac trunk by the median arcuate ligament. Due to the anatomical proximity to the foregut, MALS has significant implications in hepato-pancreato-biliary (HPB) surgery. It can pose complications in pancreatoduodenectomy and orthotopic liver transplantation, where the collateral arterial supply from the superior mesenteric artery is often disrupted. The estimated prevalence of MALS in HPB surgery is approximately 10%. Overall, there is consensus for a cautious approach to MALS when embarking on complex foregut surgery, with a low threshold for intraoperative median arcuate ligament release or hepatic artery reconstruction. The role of endovascular intervention in the management of MALS prior to HPB surgery continues to evolve, but more evidence is required to establish its efficacy. Recognizing the existing literature gap concerning optimal management in this population, we describe our tertiary center experience as a clinical algorithm to facilitate decision-making. Research question: What is the significance and management of median arcuate ligament syndrome in patients undergoing hepato-pancreato-biliary surgery?

The Role of Frequent Screening or Diagnostic Testing of Serum Cryptococcal Antigen in Liver Transplant Recipients: A Descriptive Epidemiology.

Cryptococcosis is a notable infectious complication of liver transplantation. Currently, there is no recommendation for screening serum cryptococcal antigen (CrAg) levels in solid organ transplant recipients. We aimed to explore the role of serum CrAg in liver transplant recipients at an institution where posttransplant serum CrAg has been widely tested. This retrospective study was conducted at a tertiary care center in Japan. All liver transplant recipients with serum CrAg measured either for screening or for diagnostic testing at least once after transplantation between April 2005 and March 2022 were included. For participants with either a positive CrAg test result or positive culture for Cryptococcus, we manually reviewed clinical manifestations, management, and prognosis from the medical records. During the study period, 12 885 serum CrAg tests (median, 16 tests per patient) were performed in 468 liver transplant recipients. The 1-year posttransplant incidence of positive serum CrAg test results and culture-proven cryptococcosis was 1.9% (9/468) and 0.6% (3/468), respectively. No patient with persistently negative serum CrAg test results showed growth of Cryptococcus in culture. Four patients had clinical manifestations consistent with cryptococcosis, of whom 2 (50.0%) started antifungal therapy promptly based on a positive serum CrAg test result. In contrast, 5 patients had no clinical manifestations. Three of the 5 (60.0%) patients did not receive antifungal therapy and remained free of clinical manifestations. Serum CrAg test was more sensitive than culture among liver transplant recipients and prompted early diagnosis and antifungal therapy in symptomatic patients. However, serial screening of serum CrAg in asymptomatic patients may be of little value, with the potential for false-positive results.

Incidence, epidemiology, and outcomes of acute allograft rejection following liver transplantation in Australia.

Acute allograft rejection is a well-known complication of liver transplantation (LT). The incidence, epidemiology, and outcomes of acute rejection have not been well described in Australia. We retrospectively studied consecutive adults who underwent deceased donor LT at a single center between 2010 and 2020. Donor and recipient data at the time of LT and recipient outcomes were collected from a prospective LT database. Liver biopsy reports were reviewed, and only a graft's first instance of biopsy-proven acute rejection was analyzed. During the study period, 796 liver transplants were performed in 770 patients. Biopsy-proven rejection occurred in 34.9% of transplants. There were no significant changes in the incidence of rejection over time (linear trend p =0.11). The median time to the first episode of rejection was 71 days after LT: 2.2% hyperacute, 50.4% early (≤90d), and 47.5% late rejection (>90d). Independent risk factors for rejection were younger recipient age at transplant (aHR 0.98 per year increase, 95% CI: 0.97-1.00, p =0.01), and ABO-incompatible grafts (aHR 2.55 vs. ABO-compatible, 95% CI: 1.27-5.09, p <0.01) while simultaneous multiorgan transplants were protective (aHR 0.21 vs. LT only, 95% CI: 0.08-0.58, p <0.01). Development of acute rejection (both early and late) was independently associated with significantly reduced graft (aHR 3.13, 95% CI: 2.21-4.42, p <0.001) and patient survival (aHR 3.42, 95% CI: 2.35-4.98, p <0.001). In this 11-year Australian study, acute LT rejection occurred in 35%, with independent risk factors of younger recipient age and ABO-incompatible transplant, while having a simultaneous multiorgan transplant was protective. Acute rejection was independently associated with reduced graft and patient survival after adjustment for other factors.

A rare complication of pediatric liver transplantation: Post-transplant diaphragmatic hernia.

Acquired post-transplant diaphragmatic hernia (PTDH) is a rare complication of liver transplantation (LT) in children. We aimed to present our experience in PTDH, and a possible causative background is discussed. Medical records of patients who had undergone diaphragmatic repair following LT between 2015 and 2023 were reviewed. Demographic information, details of primary diseases necessitating LT, transplantation techniques, and clinical findings associated with PTDH were evaluated. There were seven patients with PTDH. Median age at transplantation was 69 (range: 9-200) months. Five patients received a left lateral sector, one patient had a right lobe, and one had a left lobe graft. Time between LT and PTDH was 9 (2-123) months. One patient who was diagnosed in the postoperative 10th year was asymptomatic. Respiratory distress and abdominal pain were the main symptoms among all. All patients underwent laparotomy, and primary repair was performed in six patients, and one patient required mesh repair because of a large defect. Small intestine herniated in most cases. There were two complicated cases with perforation of the stomach and colonic volvulus. There is no recurrence or long-term complications for the median 60 (20-119) month follow-up period. PTDH is a rare but serious complication. Majority of symptomatic cases present within the first postoperative year, whereas some late-presenting cases may not be symptomatic. Inadvertent injury to the inferior phrenic vasculatures due to excessive use of cauterization for control of hemostasis may be a plausible explanation in those cases.

A new method to predict venous complications in pediatric liver transplantation: Evaluation of splenic parameters by ultrasonography.

Venous complications after pediatric liver transplantation seriously affect the survival rate of patients and grafts. At present, the diagnostic indicators have not been unified. Venous complications may cause portal hypertension, which may lead to splenomegaly and splenic vein dilatation. Therefore, the changes in spleen may be closely related to the venous complications. The purpose of this study was to explore the relationship between ultrasonic splenic parameters and venous complications and to study whether these splenic parameters can be used for the diagnosis of venous complications. We retrospectively included pediatric patients who underwent liver transplantation and collected ultrasonic spleen parameters before, and then 1-3 days, 1-3 weeks, 1-3 months, and 4-12 months after liver transplantation. We observed whether there were portal vein or hepatic vein complications within 1 year after liver transplantation. Among 109 pediatric patients after liver transplantation included in our study, 11 of them suffered from portal vein complications and nine hepatic vein complications. Spleen transverse diameter, spleen longitudinal diameter, spleen portal vein diameter, spleen index, spleen transverse diameter ratio, spleen longitudinal diameter ratio, and spleen index ratio were independent risk factors of venous complications. The accuracy of spleen transverse diameter (AUROC: 0.73), spleen index (AUROC: 0.70), spleen transverse diameter ratio (AUROC: 0.71), and spleen index ratio (AUROC: 0.72) in predicting venous complications were higher than other ones. Ultrasonic examination is a common follow-up method for pediatric patients after liver transplantation and the application of ultrasonic spleen parameters may be helpful to monitor venous complications.

Intraoperative kidney replacement therapy in acute liver failure.

Paediatric acute liver failure (PALF) is often characterised by its rapidity of onset and potential for significant morbidity and even mortality. Patients often develop multiorgan dysfunction/failure, including severe acute kidney injury (AKI). Whilst the management of PALF focuses on complications of hepatic dysfunction, the associated kidney impairment can significantly affect patient outcomes. Severe AKI requiring continuous kidney replacement therapy (CKRT) is a common complication of both PALF and liver transplantation. In both scenarios, the need for CKRT is a poor prognostic indicator. In adults, AKI has been shown to complicate ALF in 25-50% of cases. In PALF, the incidence of AKI is often higher compared to other critically ill paediatric ICU populations, with reports of up to 40% in some observational studies. Furthermore, those presenting with AKI regularly have a more severe grade of PALF at presentation. Observational studies in the paediatric population corroborate this, though data are not as robust-mainly reflecting single-centre cohorts. Perioperative benefits of CKRT include helping to clear water-soluble toxins such as ammonia, balancing electrolytes, preventing fluid overload, and managing raised intracranial pressure. As liver transplantation often takes 6-10h, it is proposed that these benefits could be extended to the intraoperative period, avoiding any hiatus. Intraoperative CKRT (IoCKRT) has been shown to be practicable, safe and may help sicker recipients tolerate the operation with outcomes analogous with less ill patients not requiring IoCKRT. Here, we provide a comprehensive guide describing the rationale, practicalities, and current evidence base surrounding IoCKRT during transplantation in the paediatric population.

Association of donor hepatectomy time with liver transplantation outcomes: A multicenter retrospective study.

Prolonged donor hepatectomy time may be implicated in early and late complications of liver transplantation. To evaluate the impact of donor hepatectomy time on outcomes of liver transplant recipients, mainly early allograft dysfunction. This multicenter retrospective study included brain-dead donors and adult liver graft recipients. Donor-recipient matching was obtained through a crossover list. Clinical and laboratory data were recorded for both donors and recipients. Donor hepatectomy, cold ischemia, and warm ischemia times were recorded. Primary outcome was early allograft dysfunction. Secondary outcomes included need for retransplantation, length of intensive care unit and hospital stay, and patient and graft survival at 12 months. From January 2019 to December 2021, a total of 243 patients underwent a liver transplant from a brain-dead donor. Of these, 57 (25%) developed early allograft dysfunction. The median donor hepatectomy time was 29 (23-40) min. Patients with early allograft dysfunction had a median hepatectomy time of 25 (22-38) min, whereas those without it had a median time of 30 (24-40) min (P = 0.126). Donor hepatectomy time was not associated with early allograft dysfunction, graft survival, or patient survival following liver transplantation.

Bulk and single-cell RNA sequencing analysis with 101 machine learning combinations reveal neutrophil extracellular trap involvement in hepatic ischemia-reperfusion injury and early allograft dysfunction

BackgroundHepatic ischaemia–reperfusion injury (HIRI) is a major clinical concern during the perioperative period and is closely associated with early allograft dysfunction (EAD), acute rejection (AR) and long-term graft survival. Neutrophil extracellular traps (NETs) are extracellular structures formed by the release of decondensed chromatin and granular proteins following neutrophil stimulation. There is growing evidence that NETs are involved in the progression of various liver transplantation complications, including ischaemia–reperfusion injury (IRI). This study aimed to comprehensively analyse the expression patterns of NET-related genes (NRGs) in HIRI, identify HIRI subtypes with distinct characteristics, and develop a reliable EAD prediction model. MethodsMicroarray, bulk RNA-seq, and single-cell sequencing datasets were obtained from the GEO database. Initially, differentially expressed NRGs (DE-NRGs) were identified using differential gene expression analyses. We then utilised a non-negative matrix factorisation (NMF) algorithm to classify HIRI samples. Subsequently, we employed machine learning algorithms to screen the hub NRGs related to EAD and developed an EAD prediction model based on these hub NRGs. Concurrently, we assessed the expression patterns of hub NRGs at the single-cell level using the HIRI. Additionally, we validated C5AR1 expression and its effect on HIRI and NETs formation in a rat orthotopic liver transplantation (OLT) model. ResultsIn this study, we identified 11 DE-NRGs in the HIRI context. Based on these 11 DE-NRGs, HIRI samples were classified into two distinct clusters. Cluster1 exhibited a low expression of DE-NRGs, minimal neutrophil infiltration, mild inflammation, and a low incidence of EAD. Conversely, Cluster2 displayed the opposite phenotype, with an activated inflammatory subtype and a higher incidence of EAD. Furthermore, an EAD prediction model was developed using the four hub NRGs associated with EAD. Based on risk scores, HIRI samples were classified into high- and low-risk groups. The OLT model confirmed substantial upregulation of C5AR1 expression in the liver tissue, accompanied by increased formation of NETs. Treatment with a C5AR1 antagonist improved liver function, reduced tissue inflammation, and decreased NETs formation. ConclusionsThis study distinguished two apparent HIRI subtypes, established a predictive model for EAD, and validated the effect of C5AR1 on HIRI. These findings provide novel perspectives for the development of advanced clinical strategies to enhance the outcomes of liver transplant recipients.

O-sialoglycoprotein Endopeptidase (OSGEP) Suppresses Hepatic Ischemia-Reperfusion Injury-Induced Ferroptosis Through Modulating the MEK/ERK Signaling Pathway.

Hepatic ischemia-reperfusion injury (HIRI) was widely accepted as a critical complication of liver resection and transplantation. A growing body of evidence suggested that O-sialoglycoprotein endopeptidase (OSGEP) was involved in cell proliferation and mitochondrial metabolism. However, whether OSGEP could mediate the pathogenesis of HIRI has still remained unclarified. This study investigated whether OSGEP could be protective against HIRI and elucidated the potential mechanisms. The OSGEP expression level was detected in cases undergoing ischemia-related hepatectomy and a stable oxygen-glucose deprivation/reoxygenation (OGD/R) condition in hepG2 cells. Additionally, it was attempted to establish a mouse model of HIRI, thus, the function and mechanism of OSGEP could be analyzed. At one day after hepatectomy, the negative association of OSGEP expression level with the elevated serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) was noted. Moreover, it was attempted to carry out gain- and loss-of-function analyses of OSGEP in hepG2 cells to reveal its influences on OGD/R-induced injury and relevant signaling pathways. The findings suggested that OSGEP overexpression significantly protected hepG2 cells against ferroptotic cell death, while OSGEP consumption had opposite effects. Consistent with in vitro studies, OSGEP deficiency exacerbated liver functions and ferroptoticcell death in a mouse model of HIRI. The results also revealed that OSGEP mediated the progression of HIRI by regulating the MEK/ERK signaling pathway. Rescue experiments indicated that ERK1/2 knockdown or overexpression reversed the effects of OSGEP overexpression or knockdown on hepG2 cells under OGD/R condition. Taken together, the findings demonstrated that OSGEP could contribute to alleviate HIRI by mediating the MEK-ERK signaling pathway, which may serve as a potential prognostic marker and a therapeutic target for HIRI.

RAMP1 Protects Hepatocytes against Ischemia-reperfusion Injury by Inhibiting the ERK/YAP Pathway.

Hepatic ischemia-reperfusion injury (HIRI) is a prevalent complication of liver transplantation, partial hepatectomy, and severe infection, necessitating the development of more effective clinical strategies. Receptor activity-modifying protein 1 (RAMP1), a member of the G protein-coupled receptor adapter family, has been implicated in numerous physiological and pathological processes. The study aimed to investigate the pathogenesis of RAMP1 in HIRI. We established a 70% liver ischemia-reperfusion model in RAMP1 knockout (KO) and wild-type mice. Liver and blood samples were collected after 0, 6, and 24 h of hypoxia/reperfusion. Liver histological and serological analyses were performed to evaluate liver damage. We also conducted in-vitro and in-vivo experiments to explore the molecular mechanism underlying RAMP1 function. Liver injury was exacerbated in RAMP1-KO mice compared with the sham group, as evidenced by increased cell death and elevated serum transaminase and inflammation levels. HIRI was promoted in RAMP1-KO mice via the induction of hepatocyte apoptosis and inhibition of proliferation. The absence of RAMP1 led to increased activation of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway and yes-associated protein (YAP) phosphorylation, ultimately promoting apoptosis. SCH772984, an ERK/MAPK phosphorylation inhibitor, and PY-60, a YAP phosphorylation inhibitor, reduced apoptosis in in-vitro and in-vivo experiments. Our findings suggest that RAMP1 protects against HIRI by inhibiting ERK and YAP phosphorylation signal transduction, highlighting its potential as a therapeutic target for HIRI and providing a new avenue for intervention.

Endothelial YAP/TEAD1-CXCL17 signaling recruits myeloid-derived suppressor cells against liver ischemia-reperfusion injury.

Liver ischemia-reperfusion injury (IRI) is a common complication of liver transplantation and hepatectomy, and causes acute liver dysfunction and even organ failure. Myeloid-derived suppressor cells (MDSCs) accumulate and play immunosuppressive function in cancers and inflammation. However, the role of MDSCs in liver IRI has not been defined. We enrolled recipients receiving orthotopic liver transplantation (OLT) and obtained the pre-OLT/post-OLT blood and liver samples. The proportions of MDSCs were significantly elevated after OLT and negatively associated with liver damage. In single-cell RNA-sequencing analysis of liver samples during OLT, two cell clusters with MDSC-like phenotypes were identified and showed maturation and infiltration in post-OLT livers. In mice model, liver IRI mobilized MDSCs and promoted their infiltration in damaged liver, and intrahepatic MDSCs possessed with enhanced immunosuppressive function by up-regulation of STAT3 signaling. Under treatment with αGr-1 antibody or adoptive transfer MDSCs to change the proportion of MDSCs in vivo, we found that intrahepatic MDSCs alleviated liver IRI-induced inflammation and damage by inhibiting M1 macrophage polarization. Mechanistically, bulk RNA-sequencing analysis and in vivo experiments verified that CXCL17 was upregulated by YAP/TEAD1 signaling and subsequently recruited MDSCs via binding with GPR35 during liver IRI. Moreover, hepatic endothelial cells were the major cells responsible for CXCL17 expression in injured livers, among which hypoxia-reoxygenation stimulation activated YAP/TEAD1 complex to promote CXCL17 transcription. Endothelial YAP/TEAD1-CXCL17 signaling recruited MDSCs to attenuate liver IRI, providing evidence of a therapeutic potential for managing IRI in liver surgery.

Intraoperative vascular air embolism and intracardiac thrombosis complicating liver transplantation: a case report

BackgroundIntracardiac thrombus and vascular air embolism represent rare complications in the context of orthotopic liver transplantation. While isolated reports exist for intracardiac thrombus and vascular air embolism during orthotopic liver transplantation, this report presents the first documentation of their simultaneous occurrence in this surgical setting.Case presentationThis case report outlines the clinical course of a 60-year-old white female patient with end-stage liver disease complicated by portal hypertension, ascites, and hepatocellular carcinoma. The patient underwent orthotopic liver transplantation and encountered concurrent intraoperative complications involving intracardiac thrombus and vascular air embolism. Transesophageal echocardiography revealed the presence of air in the left ventricle and a thrombus in the right atrium and ventricle. Successful management ensued, incorporating hemodynamic support, anticoagulation, and thrombolytic therapy, culminating in the patient’s discharge after a week.ConclusionsThis report highlights the potential for simultaneous intraoperative complications during orthotopic liver transplantation, manifesting at any phase of the surgery. It underscores the critical importance of vigilant monitoring throughout orthotopic liver transplantation to promptly identify and effectively address these rare yet potentially catastrophic complications.

Hypercholesterolemia Is Associated With Dysregulation of Lipid Metabolism and Poor Prognosis in Primary Biliary Cholangitis

Hypercholesterolemia is frequently diagnosed in patients with primary biliary cholangitis (PBC). However, its association with the prognosis and lipid metabolism is unknown. In this study, we aimed to investigate the prognostic value of baseline total cholesterol (TC) levels in PBC and characterized the associated lipid metabolism. Five hundred and thirty-one patients with PBC without prior cirrhosis-related complications were randomly divided into the derivation and validation cohorts at a ratio of 7:3. Complete clinical data were obtained and analyzed. The endpoints were defined as liver-related death, liver transplantation, and cirrhosis-related complications. Lipidomics was performed in 89 patients and 28 healthy controls. Baseline TC was independently associated with poor liver-related outcomes, and adjusted C-statistics were 0.80 (95% confidence interval [CI]: 0.74-0.85) and 0.88 (95% CI: 0.78-0.91) in the derivation and validation cohorts, respectively. The predictive ability of TC for disease outcomes was stable over time and comparable with the Globe score. The 200mg/dL cut-off optimally divided patients into low- and high-TC groups. A combination of TC and Globe score provided a more accurate stratification of patients into risk subgroups. Lipidomics indicated an up-regulation of lipid families in high-TC patients. Pathway analysis of 66 up-regulated lipids revealed the dysregulation of glycerophospholipid and sphingolipid metabolism in high-TC patients, which were associated with poor liver-related outcomes. Our results indicate that patients with PBC having baseline TC levels above 200 mg/dL have unique lipidome characteristics and are at a higher risk of poor liver-related outcomes.