Hackl, Hubert

Background and Aims: Hypothermic oxygenated machine perfusion (HOPE) improves outcomes in orthotopic liver transplantation (OLT), but reliance on University of Wisconsin machine perfusion solution (UW-MPS) increases costs and logistical burden. Histidine-tryptophan-ketoglutarate (HTK) has potential as a single-solution alternative for HOPE. This study evaluated the safety and efficacy of HTK versus UW-MPS during HOPE. Methods: A retrospective, propensity score-matched cohort study including 46 patients who received donation after brain death (DBD) grafts that were preserved with HOPE at the Medical University of Vienna between May 2018 and October 2024 was conducted. A total of 23 patients received grafts perfused with HTK; another 23 patients transplanted with organs perfused with UW-MPS were matched based on recipient age and sodium model of end-stage liver disease score, donor age and sex, cold ischemia time, and perfusion time. Postoperative outcomes, perfusion parameters, and cost differences were assessed. Results: The HTK and UW-MPS cohorts demonstrated comparable perfusion dynamics and vascular resistance. While arterial pressure and flow were higher in the UW-MPS group, clinical outcomes—including early allograft dysfunction (47.8% each), ICU stay, and comprehensive complication index—were statistically similar. A trend toward fewer biliary complications (13.0% vs. 30.4%) and reduced hemodialysis requirement (17.4% vs. 30.4%) was observed in the HTK group. Use of HTK reduced perfusion-related costs by approximately EUR 560 per procedure. Conclusion: HTK is a viable alternative to UW-MPS during HOPE in OLT of DBD grafts, offering comparable short-term outcomes and relevant cost savings. Prospective studies are warranted to validate these findings and explore broader applications of single-solution perfusion strategies.

Portal hypertension is a key factor in posthepatectomy liver failure (PHLF). While preoperative liver function tests like APRI+ALBI assess liver function, they only partially reflect portal hypertension severity. Elevated von Willebrand factor antigen (vWF-Ag) indicates endothelial dysregulation and correlates with portal hypertension. Combining vWF-Ag with APRI+ALBI may enhance PHLF prediction. A total of 534 patients who underwent liver resection at Mayo Clinic Rochester (2020–2024) were analyzed for PHLF incidence, postoperative morbidity, and 90-day mortality. Predictive probability for PHLF was assessed using receiver operating characteristic analysis and validated in an external Austrian cohort of 283 patients (2008–2017). vWF-Ag was then integrated into the existing APRI+ALBI multivariable model. PHLF grade B/C was reported in 56 patients (10.5%). The 90-day mortality rate was 0.9% (n=5). Using 2 cutoffs (182%, 240%), vWF-Ag was found to be an independent predictive factor for PHLF grade B/C that remained statistically significant upon multivariable analysis. The combination of preoperative APRI+ALBI and vWF-Ag increased the positive predictive value to 27.9% for PHLF grade B/C in the APRI+ALBI high and vWF-Ag high group. Incorporation of vWF-Ag into the established APRI+ALBI-based multivariable model revealed a superior AUC of 0.772 for PHLF risk stratification and was successfully validated in an independent cohort (AUC=0.834). The combination of vWF-Ag with APRI+ALBI demonstrates a favorable predictive potential for PHLF risk assessment. We provide 2 pathways for clinical assessment: (1) a cutoff-based system and (2) a more complex multivariable model that can be calculated in a specifically designed smartphone application.

Post-hepatectomy liver failure (PHLF) remains a significant risk for patients undergoing partial hepatectomy (PHx). Reliable prognostic markers and treatments to enhance liver regeneration are lacking. Plasma nanoparticles, including lipoproteins, exosomes, and extracellular vesicles (EVs), can reflect systemic and tissue-wide proteostasis and stress, potentially aiding liver regeneration. However, their role in PHLF is still unknown. Methods: Our study included nine patients with hepatocellular carcinoma (HCC) undergoing PHx: three patients with PHLF, three patients undergoing the associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) procedure, and three matched controls without complications after PHx. Patient plasma was collected before PHx as well as 1 and 5 days after. EVs were isolated by ultracentrifugation, and extracted proteins were subjected to quantitative mass spectrometry using a super-SILAC mix prepared from primary and cancer cell lines. Results: We identified 2625 and quantified 2570 proteins in the EVs of PHx patients. Among these, 53 proteins were significantly upregulated and 32 were downregulated in patients with PHLF compared to those without PHLF. Furthermore, 110 proteins were upregulated and 78 were downregulated in PHLF patients compared to those undergoing ALPPS. The EV proteomic signature in PHLF indicates significant disruptions in protein translation, proteostasis, and intracellular vesicle biogenesis, as well as alterations in proteins involved in extracellular matrix (ECM) remodelling and the metabolic and cell cycle pathways, already present before PHx. Conclusions: Longitudinal proteomic analysis of the EVs circulating in the plasma of human patients undergoing PHx uncovers proteomic signatures associated with PHLF, which reflect dying hepatocytes and endothelial cells and were already present before PHx.

Liver resection (LR) is the primary treatment for hepatic tumors, yet posthepatectomy liver failure (PHLF) remains a significant concern. While the precise etiology of PHLF remains elusive, dysregulated inflammatory processes are pivotal. Therefore, we explored the theragnostic potential of extracellular high-mobility-group-box protein 1 (HMGB1), a key damage-associated molecular pattern (DAMP) released by hepatocytes, in liver recovery post LR in patients and animal models. Plasma from 96 LR patients and liver tissues from a subset of 24 LR patients were analyzed for HMGB1 levels, and associations with PHLF and liver injury markers were assessed. In a murine LR model, the HMGB1 inhibitor glycyrrhizin, was administered to assess its impact on liver regeneration. Furthermore, plasma levels of keratin-18 (K18) and cleaved cytokeratin-18 (ccK18) were quantified to assess suitability as predictive biomarkers for PHLF. Patients experiencing PHLF exhibited elevated levels of intrahepatic and circulating HMGB1, correlating with markers of liver injury. In a murine LR model, inhibition of HMGB1 improved liver function, reduced steatosis, enhanced regeneration and decreased hepatic cell death. Elevated levels of hepatic cell death markers K18 and ccK18 were detected in patients with PHLF and correlations with levels of circulating HMGB1 was observed. Our study underscores the therapeutic and predictive potential of HMGB1 in PHLF mitigation. Elevated HMGB1, K18, and ccK18 levels correlate with patient outcomes, highlighting their predictive significance. Targeting HMGB1 enhances liver regeneration in murine LR models, emphasizing its role in potential intervention and prediction strategies for liver surgery.

Objective and Background: Clinically significant posthepatectomy liver failure (PHLF B+C) remains the main cause of mortality after major hepatic resection. This study aimed to establish an aspartate aminotransferase to platelet ratio combined with an albumin-bilirubin grade (APRI+ALBI), based multivariable model (MVM) to predict PHLF and compare its performance to indocyanine green clearance (ICG-R15 or ICG-PDR) and albumin-ICG evaluation (ALICE). Methods: A total of 12,056 patients from the National Surgical Quality Improvement Program database were used to generate a MVM to predict PHLF B+C. The model was determined using stepwise backwards elimination. The performance of the model was tested using receiver operating characteristic curve analysis and validated in an international cohort of 2525 patients. In 620 patients, the APRI+ALBI MVM, trained in the National Surgical Quality Improvement Program cohort, was compared with the MVM’s based on other liver function tests (ICG clearance, ALICE) by comparing the areas under the curve (AUC). Results: A MVM including APRI+ALBI, age, sex, tumor type, and extent of resection was found to predict PHLF B+C with an AUC of 0.77, with comparable performance in the validation cohort (AUC: 0.74). In direct comparison with other MVM’s based on more expensive and time-consuming liver function tests (ICG clearance, ALICE), the APRI+ALBI MVM demonstrated equal predictive potential for PHLF B+C. A smartphone application for the calculation of the APRI+ALBI MVM was designed. Conclusion: Risk assessment through the APRI+ALBI MVM for PHLF B+C increases preoperative predictive accuracy and represents a universally available and cost-effective risk assessment before hepatectomy, facilitated by a freely available smartphone app.

Background and Aims Patients with cirrhosis on the liver transplant (LT) waiting list may die or be removed because of complications of portal hypertension (PH) or infections. von Willebrand factor antigen (vWF‐Ag) and C‐reactive protein (CRP) are simple, broadly available markers of these processes. Approach and Results We determined whether addition of vWF‐Ag and CRP to the Model for End‐Stage Liver Disease‐Sodium (MELD‐Na) score improves risk stratification of patients awaiting LT. CRP and vWF‐Ag at LT listing were assessed in two independent cohorts (Medical University of Vienna [exploration cohort] and Mayo Clinic Rochester [validation cohort]). Clinical characteristics, MELD‐Na, and mortality on the waiting list were recorded. Prediction of 3‐month waiting list mortality was assessed by receiver operating characteristics curve (ROC‐AUC). In order to explore potential mechanisms underlying the prognostic utility of vWF‐Ag and CRP in this setting, we evaluated their association with PH, bacterial translocation, systemic inflammation, and circulatory dysfunction. In the exploration cohort (n = 269) vWF‐Ag and CRP both improved the predictive value of MELD‐Na for 3‐month waitlist mortality and showed the highest predictive value when combined (AUC: MELD‐Na, 0.764; MELD‐Na + CRP, 0.790; MELD‐Na + vWF, 0.803; MELD‐Na + CRP + vWF‐Ag, 0.824). Results were confirmed in an independent validation cohort (n = 129; AUC: MELD‐Na, 0.677; MELD‐Na + CRP + vWF‐Ag, 0.882). vWF‐Ag was independently associated with PH and inflammatory biomarkers, whereas CRP closely, and MELD independently, correlated with biomarkers of bacterial translocation/inflammation. Conclusions The addition of vWF‐Ag and CRP—reflecting central pathophysiological mechanisms of PH, bacterial translocation, and inflammation, that are all drivers of mortality on the waiting list for LT—to the MELD‐Na score improves prediction of waitlist mortality. Using the vWFAg‐CRP‐MELD‐Na model for prioritizing organ allocation may improve prediction of waitlist mortality and decrease waitlist mortality.

Abstract Background Aspartate aminotransferase/platelet ratio index (APRI) and albumin–bilirubin grade (ALBI) are validated prognostic indices implicated as predictors of postoperative liver dysfunction after hepatic resection. The aim of this study was to evaluate the relevance of the combined APRI/ALBI score for postoperative clinically meaningful outcomes. Methods Patients undergoing hepatectomy were included from the American College of Surgeons National Surgical Quality Improvement Program database. The association between APRI/ALBI score and postoperative grade C liver dysfunction, liver dysfunction-associated and overall 30-day mortality was assessed. Results A total of 12 055 patients undergoing hepatic resection from 2014 to 2017 with preoperative blood values and detailed 30-day postoperative outcomes were included (exploration cohort: January 2014 to December 2016; validation cohort: 2017). In the exploration cohort (8538 patients), the combination of both scores (APRI/ALBI) was significantly associated with postoperative grade C liver dysfunction, 30-day mortality, and liver dysfunction-associated 30-day mortality, and was superior to either score alone. The association with postoperative 30-day mortality was confirmed in multivariable analysis. A predictive model was generated using the exploration cohort. The predicted incidence of events closely followed the observed incidence in the validation cohort (3517 patients). Subgroup analyses of tumour types were used to generate disease-specific risk models to assess risk in different clinical scenarios. These findings informed development of a smartphone application (https://tellaprialbi.37binary.com). Conclusion The predictive potential of the combined APRI/ALBI score for clinically relevant outcomes such as mortality was demonstrated. An evidence-based smartphone application will allow clinical translation and facilitation of risk assessment before hepatic resection using routine laboratory parameters.

Background and Aims Platelet‐stored serotonin critically affects liver regeneration in mice and humans. Selective serotonin reuptake inhibitors (SSRIs) and serotonin noradrenalin reuptake inhibitors (SNRIs) reduce intraplatelet serotonin. As SSRIs/SNRIs are now one of the most commonly prescribed drugs in the United States and Europe and given serotonin’s impact on liver regeneration, we evaluated whether perioperative use of SSRIs/SNRIs affects outcome after hepatic resection. Approach and Results Consecutive patients undergoing hepatic resection (n = 754) were retrospectively included from prospectively maintained databases from two European institutions. Further, an independent cohort of 495 patients from the United States was assessed to validate our exploratory findings. Perioperative intake of SSRIs/SNRIs was recorded, and patients were followed up for postoperative liver dysfunction (LD), morbidity, and mortality. Perioperative intraplatelet serotonin levels were significantly decreased in patients receiving SSRI/SNRI treatment. Patients treated with SSRIs/SNRIs showed a higher incidence of morbidity, severe morbidity, LD, and LD requiring intervention. Associations were confirmed in the independent validation cohort. Combined cohorts documented a significant increase in deleterious postoperative outcome (morbidity odds ratio [OR], 1.56; 95% confidence interval [CI], 1.07‐2.31; severe morbidity OR, 1.86; 95% CI, 1.22‐2.79; LD OR, 1.96; 95% CI, 1.23‐3.06; LD requiring intervention OR, 2.22; 95% CI, 1.03‐4.36). Further, multivariable analysis confirmed the independent association of SSRIs/SNRIs with postoperative LD, which was closely associated with postoperative 90‐day mortality and 1‐year overall survival. Conclusions We observed a significant association of perioperative SSRI/SNRI intake with adverse postoperative outcome after hepatic resection. This indicates that SSRIs/SNRIs should be avoided perioperatively in patients undergoing hepatic resections.