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Although short-term machine perfusion (≤24 h) allows for resuscitation and viability assessment of high-risk donor livers, the donor organ shortage might be further remedied by long-term perfusion machines. Extended preservation of injured donor livers may allow reconditioning, repairing, and regeneration. This review summarizes the necessary requirements and challenges for long-term liver machine preservation, which requires integrating multiple core physiological functions to mimic the physiological environment inside the body. A pump simulates the heart in the perfusion system, including automatically controlled adjustment of flow and pressure settings. Oxygenation and ventilation are required to account for the absence of the lungs combined with continuous blood gas analysis. To avoid pressure necrosis and achieve heterogenic tissue perfusion during preservation, diaphragm movement should be simulated. An artificial kidney is required to remove waste products and control the perfusion solution's composition. The perfusate requires an oxygen carrier, but will also be challenged by coagulation and activation of the immune system. The role of the pancreas can be mimicked through closed-loop control of glucose concentrations by automatic injection of insulin or glucagon. Nutrients and bile salts, generally transported from the intestine to the liver, have to be supplemented when preserving livers long term. Especially for long-term perfusion, the container should allow maintenance of sterility. In summary, the main challenge to develop a long-term perfusion machine is to maintain the liver's homeostasis in a sterile, carefully controlled environment. Long-term machine preservation of human livers may allow organ regeneration and repair, thereby ultimately solving the shortage of donor livers.

Oxygenated ex situ machine perfusion of donor livers is an alternative for static cold preservation that can be performed at temperatures from 0 °C to 37 °C. Organ metabolism depends on oxygen to produce adenosine triphosphate and temperatures below 37 °C reduce the metabolic rate and oxygen requirements. The transport and delivery of oxygen in machine perfusion are key determinants in preserving organ viability and cellular function. Oxygen delivery is more challenging than carbon dioxide removal, and oxygenation of the perfusion fluid is temperature dependent. The maximal oxygen content of water-based solutions is inversely related to the temperature, while cellular oxygen demand correlates positively with temperature. Machine perfusion above 20 °C will therefore require an oxygen carrier to enable sufficient oxygen delivery to the liver. Human red blood cells are the most physiological oxygen carriers. Alternative artificial oxygen transporters are hemoglobin-based oxygen carriers, perfluorocarbons, and an extracellular oxygen carrier derived from a marine invertebrate. We describe the principles of oxygen transport, delivery, and consumption in machine perfusion for donor livers using different oxygen carrier-based perfusion solutions and we discuss the properties, advantages, and disadvantages of these carriers and their use.

Liver transplantation is the standard treatment for end-stage liver disease. However, due to the ongoing disparity between supply and demand for optimal donor organs, there is increasing usage of extended criteria donor organs, including steatotic liver grafts. To mitigate the increased risks associated with extended criteria donor livers, ex situ oxygenated machine perfusion (MP) has received increasing attention in recent years as an emerging platform for dynamic preservation, reconditioning, and viability assessment to increase organ utilization. MP can be applied at different temperatures. During hypothermic MP (4-12°C), liver metabolism is reduced, while oxygenation restores the intracellular levels of adenosine triphosphate. The liver is quickly "recharged" to support metabolism when at normothermia (35-37°C) and to ameliorate the detrimental effects of ischemia/reperfusion injury during transplantation. During normothermia, MP can be applied to assess hepatocellular and cholangiocellular viability. MP at hyperthermic (>38°C) temperatures (HyMP), however, remains relatively understudied. The liver is an important component in the regulation of core body temperature and, as such, displays significant physiological and metabolic changes in response to different temperatures. Hyperthermia may promote vasodilation, increase aerobic metabolism and induce production of protective molecules such as heat shock proteins. Therefore, HyMP could provide an attractive reconditioning strategy for steatotic livers. In this review, we describe current literature on the physiological and metabolic effects of the liver at hyperthermia for human, rodents, and pigs and provide a rationale for using therapeutic HyMP during isolated liver machine perfusion to recondition extended criteria donor livers, including steatotic livers, before transplantation.

Background: Lack of oxygen and biomechanical stimulation during static cold storage (SCS) of donor livers compromises endothelial cell function. We investigated the effect of end-ischemic oxygenated hypothermic machine perfusion (HMP) on endothelial cell function of extended criteria donor (ECD) livers., Methods: Eighteen livers, declined for transplantation, were transported to our center using static cold storage (SCS). After SCS, 6 livers underwent two hours of HMP, and subsequent normothermic machine perfusion (NMP) to assess viability. Twelve control livers underwent NMP immediately after SCS. mRNA expression of transcription factor Krüppel-like-factor 2 (KLF2), endothelial nitric oxide synthase (eNOS), and thrombomodulin (TM) was quantified by RT-PCR. Endothelial cell function and injury were assessed by nitric oxide (NO) production and release of TM into the perfusate., Results: In HMP livers, mRNA expression of KLF2 (p = 0.043), eNOS (p = 0.028), and TM (p = 0.028) increased significantly during NMP. In parallel, NO levels increased during NMP in HMP livers but not in controls. At the end of NMP cumulative TM release was significantly lower HMP livers, compared to controls (p = 0.028)., Conclusion: A short period of two hours oxygenated HMP restores endothelial cell viability after SCS and subsequent normothermic reoxygenation of ECD livers., (Copyright © 2017 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Ex vivo machine perfusion (MP) is a promising way to better preserve livers prior to transplantation. Currently, no methodology has a verified benefit over simple cold storage. Before becoming clinically feasible, MP requires validation in models that reliably predict human performance. Such a model has been found in porcine liver, whose physiological, anatomical, and immunological characteristics closely resemble the human liver. Since the 1930s, researchers have explored MP as preservation, but only recently have clinical trials been performed. Making this technology clinically available holds the promise of expanding the donor pool through more effective preservation of extended criteria donor (ECD) livers. MP promises to decrease delayed graft function, primary nonfunction, and biliary strictures, which are all common failure modes of transplanted ECD livers. Although hypothermic machine perfusion (HMP) has become the standard for kidney ex vivo preservation, the precise settings and clinical role for liver MP have not yet been established. In research, there are 2 schools of thought: normothermic machine perfusion, closely mimicking physiologic conditions, and HMP, to maximize preservation. Here, we review the literature for porcine ex vivo MP, with an aim to summarize perfusion settings and outcomes pertinent to the clinical establishment of MP. Liver Transplantation 23 679-695 2017 AASLD., (© 2017 by the American Association for the Study of Liver Diseases.)

This study investigates the relationship between blood group and waiting time until transplantation or death on the waiting list. All patients listed for liver transplantation in the Netherlands between 15 December 2006 and 31 December 2012, were included. Study variables were gender, age, year of listing, diagnosis, previous transplantations, blood group, urgency, and MELD score. Using a competing risks analysis, separate cumulative incidence curves were constructed for death on the waiting list and transplantation and used to evaluate outcomes.In 517 listings, the mean death rate per 100 patient-years was 10.4. A total of 375 (72.5% of all listings) were transplanted. Of all transplantations, 352 (93.9%) were ABO-identical and 23 (6.1%) ABO-compatible. The 5-year cumulative incidence of death was 11.2% (SE 1.4%), and of transplantation 72.5% (SE 2.0%). Patient blood group had no multivariate significant impact on the hazard of dying on the waiting list nor on transplantation. Age, MELD score, and urgency status were significantly related to the death on the waiting list and transplantation. More recent listing had higher probability of being transplanted. In the MELD era, patient blood group status does not have a significant impact on liver transplant waiting list mortality nor on waiting time for transplantation., (© 2016 Steunstichting ESOT.)

As donor organ shortages persist, functional machine perfusion is under investigation to improve preservation of the donor liver. The transplantation of donation after circulatory death (DCD) livers is limited by poor outcomes, but its application may be expanded by ex vivo repair and assessment of the organ before transplantation. Here we employed subnormothermic (21 °C) machine perfusion of discarded human livers combined with metabolomics to gain insight into metabolic recovery during machine perfusion. Improvements in energetic cofactors and redox shifts were observed, as well as reversal of ischemia-induced alterations in selected pathways, including lactate metabolism and increased TCA cycle intermediates. We next evaluated whether DCD livers with steatotic and severe ischemic injury could be discriminated from 'transplantable' DCD livers. Metabolomic profiling was able to cluster livers with similar metabolic patterns based on the degree of injury. Moreover, perfusion parameters combined with differences in metabolic factors suggest variable mechanisms that result in poor energy recovery in injured livers. We conclude that machine perfusion combined with metabolomics has significant potential as a clinical instrument for the assessment of preserved livers.

Background: Livers with moderate (30-60%) macrovesicular steatosis have been associated with poor outcome after transplantation. Aim of this study was to examine the outcome after transplantation of livers with moderate macrovesicular steatosis when the cold ischemia time (CIT) is kept very short., Methods: Postoperative outcome of 19 recipients of a moderate steatotic liver were compared with a matched control group of 95 recipients of a nonsteatotic liver graft (1:5 ratio). We studied graft/patient survival rates, incidences of primary nonfunction, postoperative complications (classified according to the Clavien-Dindo classification), first-week postoperative hepatic injury serum markers (AST/ALT), and liver function tests (PT time/bilirubin/lactate). In addition, we studied reversal of graft steatosis in follow-up biopsies., Results: Median CIT in livers with moderate steatosis and in controls was below 8 h in both groups. Although short- and long-term patient/graft survival rates and results of liver function tests were similar, serum markers of hepatic injury and postoperative complications (especially grade IVa) were significantly higher in recipients of a moderate steatotic liver. Reversal of steatosis was seen in 9 of the 11 (82%) recipients with follow-up liver biopsies., Conclusion: Despite the association with severe postoperative complications, moderate macrovesicular steatotic livers can be used successfully for transplantation if the CIT is kept very short., (© 2014 Steunstichting ESOT.)

Although normothermic machine perfusion of donor livers may allow assessment of graft viability prior to transplantation, there are currently no data on what would be a good parameter of graft viability. To determine whether bile production is a suitable biomarker that can be used to discriminate viable from non-viable livers we have studied functional performance as well as biochemical and histological evidence of hepatobiliary injury during ex vivo normothermic machine perfusion of human donor livers. After a median duration of cold storage of 6.5 h, twelve extended criteria human donor livers that were declined for transplantation were ex vivo perfused for 6 h at 37 °C with an oxygenated solution based on red blood cells and plasma, using pressure controlled pulsatile perfusion of the hepatic artery and continuous portal perfusion. During perfusion, two patterns of bile flow were identified: (1) steadily increasing bile production, resulting in a cumulative output of ≥ 30 g after 6 h (high bile output group), and (2) a cumulative bile production <20 g in 6 h (low bile output group). Concentrations of transaminases and potassium in the perfusion fluid were significantly higher in the low bile output group, compared to the high bile output group. Biliary concentrations of bilirubin and bicarbonate were respectively 4 times and 2 times higher in the high bile output group. Livers in the low bile output group displayed more signs of hepatic necrosis and venous congestion, compared to the high bile output group. In conclusion, bile production could be an easily assessable biomarker of hepatic viability during ex vivo machine perfusion of human donor livers. It could potentially be used to identify extended criteria livers that are suitable for transplantation. These ex vivo findings need to be confirmed in a transplant experiment or a clinical trial.

Background: Livers derived from donation after circulatory death (DCD) are increasingly accepted for transplantation. However, DCD livers suffer additional donor warm ischemia, leading to biliary injury and more biliary complications after transplantation. It is unknown whether oxygenated machine perfusion results in better preservation of biliary epithelium and the peribiliary vasculature. We compared oxygenated hypothermic machine perfusion (HMP) with static cold storage (SCS) in a porcine DCD model., Methods: After 30 min of cardiac arrest, livers were perfused in situ with HTK solution (4°C) and preserved for 4 h by either SCS (n = 9) or oxygenated HMP (10°C; n = 9), using pressure-controlled arterial and portal venous perfusion. To simulate transplantation, livers were reperfused ex vivo at 37°C with oxygenated autologous blood. Bile duct injury and function were determined by biochemical and molecular markers, and a systematic histological scoring system., Results: After reperfusion, arterial flow was higher in the HMP group, compared to SCS (251±28 vs 166±28 mL/min, respectively, after 1 hour of reperfusion; p = 0.003). Release of hepatocellular enzymes was significantly higher in the SCS group. Markers of biliary epithelial injury (biliary LDH, gamma-GT) and function (biliary pH and bicarbonate, and biliary transporter expression) were similar in the two groups. However, histology of bile ducts revealed significantly less arteriolonecrosis of the peribiliary vascular plexus in HMP preserved livers (>50% arteriolonecrosis was observed in 7 bile ducts of the SCS preserved livers versus only 1 bile duct of the HMP preserved livers; p = 0.024)., Conclusions: Oxygenated HMP prevents arteriolonecrosis of the peribiliary vascular plexus of the bile ducts of DCD pig livers and results in higher arterial flow after reperfusion. Together this may contribute to better perfusion of the bile ducts, providing a potential advantage in the post-ischemic recovery of bile ducts.

Plasma levels of coagulation factors differ profoundly between adults and children, but are remarkably stable throughout adulthood. It is unknown which factors determine plasma levels of coagulation factors in a given individual. We hypothesized that the liver, which synthesizes coagulation factors, also controls plasma levels. We measured a panel of coagulation factors in samples taken from either adults or young children who underwent a liver transplantation with adult donor livers. Samples were taken 1-3 months after transplantation, when the patients were clinically stable with adequate graft function. After liver transplantation, the hemostatic profile of the pediatric group was remarkably different from that of the adult group, and resembled the hemostatic profile of normal children. Thus, children transplanted with an adult liver graft maintain a pediatric hemostatic profile after transplantation despite receiving an adult liver graft. These findings suggest that plasma levels of hemostatic proteins are not controlled by the liver.

To investigate the hypothesis that during the development of biliary atresia, early changes in hepatobiliary transport are mainly related to the inflammatory process and lead to intrahepatic cholestasis and subsequent liver injury, livers from mice with rhesus rotavirus-induced biliary atresia were analyzed for mRNA expression of hepatobiliary transporters, nuclear receptors, and inflammatory cytokines. Seven days after inoculation, despite high bile acid concentrations in the liver, gene expression of canalicular and basolateral hepatobiliary transporters and their regulatory nuclear receptors was down-regulated with concomitant increase in gene expression of inflammatory cytokines and rise in serum unconjugated bilirubin. At 14 d, hepatobiliary transporters and nuclear receptors remained down-regulated although the inflammatory response subsided. The percentage of conjugated bilirubin started to increase as extrahepatic biliary obstruction occurred. At 18 d, expression of hepatobiliary transporters remained low, expression of nuclear receptors returned to normal, while expression of inflammatory cytokines decreased further. Moreover, histology demonstrated progressive inflammation, bile duct damage, ductular proliferation, and hepatocyte necrosis. In conclusion, intrahepatic cholestasis due to inflammation-related down-regulation of basolateral and canalicular hepatobiliary transporters is an early event in the development of biliary atresia. Intrahepatic cholestasis contributes to the development of jaundice and liver injury.

Upregulation of heme oxygenase-1 (HO-1) has been proposed as a critical mechanism protecting against cellular stress during liver transplantation, providing a potential target for new therapeutic interventions. We investigated the feasibility of in vivo bioluminescence imaging (BLI) to noninvasively quantify the spatiotemporal expression of HO-1 after warm hepatic ischemia in living animals. Luciferase activity was measured by BLI as an index of HO-1 transcription in transgenic reporter mice (Ho1-luc) at standardized time points after 60 minutes of warm hepatic ischemia. HO-1 mRNA levels were measured in postischemic livers of mice sacrificed at the same time points in separate experiments. Bioluminescent signals from postischemic liver lobes were first detected at 3 hours after reperfusion. Peak levels were reached at 9 hours, after which bioluminescent activity declined and returned to baseline values at 48 hours after reperfusion. Upregulation of HO-1 as detected by in vivo BLI was preceded by increased HO-1 mRNA expression and confirmed by enhanced immunohistochemical staining of hepatocytes. In conclusion, this study shows that in vivo BLI allows a sensitive assessment of HO-1 expression after hepatic ischemia in living animals. The capability of whole-body temporal imaging of HO-1 expression provides a valuable tool in the development of novel strategies to modulate HO-1 expression in liver transplantation., ((c) 2006 AASLD)

The exact frequency and clinical consequences of surgical hepatic injuries during organ procurement are unknown. We analyzed the incidence, risk factors, and clinical outcome of surgical injuries in 241 adult liver grafts. Hepatic injuries were categorized as parenchymal, vascular, or biliary. Outcome variables were bleeding complications, hepatic artery thrombosis (HAT), and graft survival. In 82 livers (34%), 96 injuries were detected. Most injuries were minor, but clinically relevant injuries were detected in 6.6% (16/241) of the livers. Fifty (21%) liver grafts had some degree of parenchymal or capsular injury, 40 (17%) had vascular injury, and 6 (2%) had an injury to the bile duct. Procurement region was the only risk factor significantly associated with surgical injury. The rate of hepatic artery injury was significantly higher in livers with aberrant arterial anatomy. Bleeding complications were found in 18% of patients who received livers with a parenchymal or capsular injury in contrast to 9% without parenchymal injury (P = 0.065). HAT was found in 23% of the patients who received a liver with arterial injury compared to 4% without arterial injury (P = 0.001). Overall graft survival rates were not significantly different for grafts with or without anatomical injury. In conclusion, surgical injuries of donor livers are an underestimated problem in liver transplantation and can be observed in about one-third of all cases. Clinically relevant injuries are detected in 6.6% of all liver grafts. Arterial injuries are associated with an increased risk of HAT.

Upregulation of heme oxygenase-1 (HO-1) has been proposed as an adaptive mechanism protecting against ischemia/reperfusion (I/R) injury. We investigated HO-1 expression in 38 human liver transplants and correlated this with I/R injury and graft function. Before transplantation, median HO-1 mRNA levels were 3.4-fold higher (range: 0.7-9.3) in donors than in normal controls. Based on the median value, livers were divided into two groups: low and high HO-1 expression. These groups had similar donor characteristics, donor serum transaminases, cold ischemia time, HSP-70 expression and the distribution of HO-1 promoter polymorphism. After reperfusion, HO-1 expression increased significantly further in the initial low HO-1 expression group, but not in the high HO-1 group. Postoperatively, serum transaminases were significantly lower and the bile salt secretion was higher in the initial low HO-1 group, compared to the high expression group. Immunofluorescence staining identified Kupffer cells as the main localization of HO-1. In conclusion, human livers with initial low HO-1 expression (<3.4 times controls) are able to induce HO-1 further during reperfusion and are associated with less injury and better function than initial high HO-1 expression (>3.4 times controls). These data suggest that an increase in HO-1 during transplantation is more protective than high HO-1 expression before transplantation.

Introduction: Six to eight children are diagnosed with a malignant liver tumour yearly in the Netherlands. The majority of these tumours are hepatoblastoma (HB) and hepatocellular carcinoma (HCC), for which radical resection, often in combination with chemotherapy, is the only curative treatment option. We investigated the surgical outcome of children with a malignant liver tumour in a consecutive cohort in the Netherlands. Methods: In this nationwide, retrospective observational study, all patients (age < 18 years) diagnosed with a malignant liver tumour, who underwent partial liver resection or orthotopic liver transplantation (OLT) between January 2014 and April 2021, were included. Children with a malignant liver tumour who were not eligible for surgery were excluded from the analysis. Data regarding tumour characteristics, diagnostics, treatment, complications and survival were collected. Outcomes included major complications (Clavien–Dindo ≥ 3a) within 90 days and disease-free survival. The results of the HB group were compared to those of a historical HB cohort. Results: Twenty-six children were analysed, of whom fourteen (54%) with HB (median age 21.5 months), ten (38%) with HCC (median age 140 months) and one with sarcoma and a CNSET. Thirteen children with HB (93%) and three children with HCC (30%) received neoadjuvant chemotherapy. Partial hepatic resection was possible in 19 patients (12 HB, 6 HCC, and 1 sarcoma), whilst 7 children required OLT (2 HB, 4 HCC, and 1 CNSET). Radical resection (R0, margin ≥ 1.0 mm) was obtained in 24 out of 26 patients, with recurrence only in the patient with CNSET. The mean follow-up was 39.7 months (HB 40 months, HCC 40 months). Major complications occurred in 9 out of 26 patients (35% in all, 4 of 14, 29% for HB). There was no 30- or 90-day mortality, with disease-free survival after surgery of 100% for HB and 80% for HCC, respectively. Results showed a tendency towards a better outcome compared to the historic cohort, but numbers were too small to reach significance. Conclusion: Survival after surgical treatment for malignant liver tumours in the Netherlands is excellent. Severe surgical complications arise in one-third of patients, but most resolve without long-term sequelae and have no impact on long-term survival. [ABSTRACT FROM AUTHOR]

Summary: Due to the growing number of liver transplantations (LTs), there is an increasing number of patients requiring retransplantation (reLT). Data on the use of grafts from extended criteria donors (ECD), especially donation after circulatory death (DCD), for reLT are lacking. We aimed to assess the outcome of patients undergoing reLT using a DCD graft in the Netherlands between 2001 and July 2018. Propensity score matching was used to match each DCD‐reLT with three DBD‐reLT cases. Primary outcomes were patient and graft survival. Secondary outcome was the incidence of biliary complications, especially nonanastomotic strictures (NAS). 21 DCD‐reLT were compared with 63 matched DBD‐reLTs. Donors in the DCD‐reLT group had a significantly lower BMI (22.4 vs. 24.7 kg/m2, P‐value = 0.02). Comparison of recipient demographics and ischemia times yielded no significant differences. Patient and graft survival rates were comparable between the two groups. However, the occurrence of nonanastomotic strictures after DCD‐reLT was significantly higher (38.1% vs. 12.7%, P‐value = 0.02). ReLT with DCD grafts does not result in inferior patient and graft survival compared with DBD grafts in selected patients. Therefore, DCD liver grafts should not routinely be declined for patients awaiting reLT. [ABSTRACT FROM AUTHOR]

Selective portal vein embolization (PVE) before extended liver surgery is an accepted method to stimulate growth of the future liver remnant. Portal vein thrombosis (PVT) of the main stem and the non-targeted branches to the future liver remnant is a rare but major complication of PVE, requiring immediate revascularization. Without revascularization, curative liver surgery is not possible, resulting in a potentially life-threatening situation. We here present a new surgical technique to revascularize the portal vein after PVT by combining a surgical thrombectomy with catheter-based thrombolysis via the surgically reopened umbilical vein. This technique was successfully applied in a patient who developed thrombosis of the portal vein main stem, as well as the left portal vein and its branches to the left lateral segments after selective right-sided PVE in preparation for an extended right hemihepatectomy. The advantage of this technique is the avoidance of an exploration of hepatoduodenal ligament and a venotomy of the portal vein. The minimal surgical trauma facilitates additional intravascular thrombolytic therapy as well as the future right extended hemihepatectomy. We recommend this technique in patients with extensive PVT in which percutaneous less invasive therapies have been proven unsuccessful. [ABSTRACT FROM AUTHOR]

There continues to be a significant shortage of donor livers for transplantation. One impediment is the discard rate of fatty, or steatotic, livers because of their poor post-transplant function. Steatotic livers are prone to significant ischemia-reperfusion injury (IRI) and data regarding how best to improve the quality of steatotic livers is lacking. Herein, we use normothermic (37°C) machine perfusion in combination with metabolic and lipidomic profiling to elucidate deficiencies in metabolic pathways in steatotic livers, and to inform strategies for improving their function. During perfusion, energy cofactors increased in steatotic livers to a similar extent as non-steatotic livers, but there were significant deficits in anti-oxidant capacity, efficient energy utilization, and lipid metabolism. Steatotic livers appeared to oxidize fatty acids at a higher rate but favored ketone body production rather than energy regeneration via the tricyclic acid cycle. As a result, lactate clearance was slower and transaminase levels were higher in steatotic livers. Lipidomic profiling revealed ω-3 polyunsaturated fatty acids increased in non-steatotic livers to a greater extent than in steatotic livers. The novel use of metabolic and lipidomic profiling during ex situ normothermic machine perfusion has the potential to guide the resuscitation and rehabilitation of steatotic livers for transplantation. [ABSTRACT FROM AUTHOR]

Background: Liver grafts from donation after circulatory death (DCD) donors are increasingly accepted as an extension of the organ pool for transplantation. There is little data on the outcome of liver transplantation with DCD grafts from a pediatric donor. The objective of this study was to assess the outcome of liver transplantation with pediatric DCD grafts and to compare this with the outcome after transplantation of livers from pediatric donation after brain death (DBD) donors. Method: All transplantations performed with a liver from a pediatric donor (≤16 years) in the Netherlands between 2002 and 2015 were included. Patient survival, graft survival, and complication rates were compared between DCD and DBD liver transplantation. Results: In total, 74 liver transplantations with pediatric grafts were performed; twenty (27%) DCD and 54 (73%) DBD. The median donor warm ischemia time (DWIT) was 24 min (range 15–43 min). Patient survival rate at 10 years was 78% for recipients of DCD grafts and 89% for DBD grafts (p = 0.32). Graft survival rate at 10 years was 65% in recipients of DCD versus 76% in DBD grafts (p = 0.20). If donor livers in this study would have been rejected for transplantation when the DWIT ≥30 min (n = 4), the 10-year graft survival rate would have been 81% after DCD transplantation. The rate of non-anastomotic biliary strictures was 5% in DCD and 4% in DBD grafts (p = 1.00). Other complication rates were also similar between both groups. Conclusions: Transplantation of livers from pediatric DCD donors results in good long-term outcome especially when the DWIT is kept ≤30 min. Patient and graft survival rates are not significantly different between recipients of a pediatric DCD or DBD liver. Moreover, the incidence of non-anastomotic biliary strictures after transplantation of pediatric DCD livers is remarkably low. [ABSTRACT FROM AUTHOR]

Assessment of fatty liver grafts during orthotopic liver transplantation is a challenge due to the lack of real-time analysis options during surgery. Diffuse reflectance spectroscopy ( DRS) could be a new diagnostic tool to quickly assess steatosis. Eight hundred and seventy-eight optical measurements were performed in vivo in 17 patients in liver tissue during surgery and ex vivo on liver resection specimens from 41 patients. Liver steatosis was quantified from the collected optical spectra and compared with the histology analysis from the measurement location by three independent pathologists. Twenty two patients were diagnosed with <5% steatosis, 15 patients had mild steatosis, and four had moderate steatosis. Severe steatosis was not identified. Intraclass correlation between the pathologists analysis was 0.949. A correlation of 0.854 was found between the histology and DRS analyses of liver steatosis ex vivo. For the same liver tissue, a correlation of 0.925 was demonstrated between in vivo and ex vivo DRS analysis for steatosis quantification. DRS can quantify steatosis in liver tissue both in vivo and ex vivo with good agreement compared to histopathology analysis. This analysis can be performed real time and may therefore be useful for fast objective assessment of liver steatosis in liver surgery. [ABSTRACT FROM AUTHOR]

Oxygenated ex situ machine perfusion of donor livers is an alternative for static cold preservation that can be performed at temperatures from 0 °C to 37 °C. Organ metabolism depends on oxygen to produce adenosine triphosphate and temperatures below 37 °C reduce the metabolic rate and oxygen requirements. The transport and delivery of oxygen in machine perfusion are key determinants in preserving organ viability and cellular function. Oxygen delivery is more challenging than carbon dioxide removal, and oxygenation of the perfusion fluid is temperature dependent. The maximal oxygen content of water-based solutions is inversely related to the temperature, while cellular oxygen demand correlates positively with temperature. Machine perfusion above 20 °C will therefore require an oxygen carrier to enable sufficient oxygen delivery to the liver. Human red blood cells are the most physiological oxygen carriers. Alternative artificial oxygen transporters are hemoglobin-based oxygen carriers, perfluorocarbons, and an extracellular oxygen carrier derived from a marine invertebrate. We describe the principles of oxygen transport, delivery, and consumption in machine perfusion for donor livers using different oxygen carrier-based perfusion solutions and we discuss the properties, advantages, and disadvantages of these carriers and their use. [ABSTRACT FROM AUTHOR]

There continues to be significant debate regarding the most effective mode of ex situ machine perfusion of livers for transplantation. Subnormothermic (SNMP) and normothermic machine perfusion (NMP) are two methods with different benefits. We examined the metabolomic profiles of discarded steatotic human livers during three hours of subnormothermic or normothermic machine perfusion. Steatotic livers regenerate higher stores of ATP during SNMP than NMP. However, there is a significant depletion of available glutathione during SNMP, likely due to an inability to overcome the high energy threshold needed to synthesize glutathione. This highlights the increased oxidative stress apparent in steatotic livers. Rescue of discarded steatotic livers with machine perfusion may require the optimization of redox status through repletion or supplementation of reducing agents. [ABSTRACT FROM AUTHOR]

The larger ducts of the biliary tree contain numerous tubulo-alveolar adnexal glands that are lined with biliary epithelial cells and connected to the bile duct lumen via small glandular canals. Although these peribiliary glands (PBG) were already described in the 19th century, their exact function and role in the pathophysiology and development of cholangiopathies have not become evident until recently. While secretion of serous and mucinous components into the bile was long considered as the main function of PBG, recent studies have identified PBG as an important source for biliary epithelial cell proliferation and renewal. Activation, dilatation, and proliferation of PBG (or the lack thereof) have been associated with various cholangiopathies. Moreover, PBG have been identified as niches of multipotent stem/progenitor cells with endodermal lineage traits. This has sparked research interest in the role of PBG in the pathogenesis of various cholangiopathies as well as bile duct malignancies. Deeper understanding of the regenerative capacity of the PBG may contribute to the development of novel regenerative therapeutics for previously untreatable hepatobiliary diseases. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen. [ABSTRACT FROM AUTHOR]