Assessing Liver Viability: Insights From Mitochondrial Bioenergetics in Ischemia-Reperfusion Injury.

Orthotopic liver transplantation remains the definitive treatment for patients with end-stage liver disease. Unfortunately, the increasing demand for donor livers and the limited supply of viable organs have both led to a critical need for innovative strategies to expand the pool of transplantable organs. The mitochondrion, central to hepatic cellular function, plays a pivotal role in hepatic ischemic injury, with impaired mitochondrial function and oxidative stress leading to cell death. Mitochondrial protection strategies have shown promise in mitigating IRI and resuscitating marginal organs for transplant. Machine perfusion (MP) has been proven a valuable tool for reviving marginal organs with very promising results. Evaluation of liver viability during perfusion traditionally relies on parameters including lactate clearance, bile production, and transaminase levels. Nevertheless, the quest for more comprehensive and universally applicable viability markers persists. Normothermic regional perfusion has gained robust attention, offering extended recovery time for organs from donation after cardiac death donors. This approach has shown remarkable success in improving organ quality and reducing ischemic injury using the body's physiological conditions. The current challenge lies in the absence of a reliable assessment tool for predicting graft viability and post-transplant outcomes. To address this, exploring insights from mitochondrial function in the context of ischemia-reperfusion injury could offer a promising path toward better patient outcomes and graft longevity. Indeed, hypoxia-induced mitochondrial injury may serve as a surrogate marker of organ viability following oxygenated resuscitation techniques in the future.

Effects of Subnormothermic Regulated Hepatic Reperfusion on Mitochondrial and Transcriptomic Profiles in a Porcine Model.

OBJECTIVE: We sought to investigate the biological effects of pre-reperfusion treatments of the liver after warm and cold ischemic injuries in a porcine donation after circulatory death model. SUMMARY OF BACKGROUND DATA: Donation after circulatory death represents a severe form of liver ischemia and reperfusion injury that has a profound impact on graft function after liver transplantation. METHODS: Twenty donor pig livers underwent 60 minutes of in situ warm ischemia after circulatory arrest and 120 minutes of cold static preservation prior to simulated transplantation using an ex vivo perfusion machine. Four reperfusion treatments were compared: Control-Normothermic (N), Control- Subnormothermic (S), regulated hepatic reperfusion (RHR)-N, and RHR-S (n = 5 each). The biochemical, metabolic, and transcriptomic profiles, as well as mitochondrial function were analyzed. RESULTS: Compared to the other groups, RHR-S treated group showed significantly lower post-reperfusion aspartate aminotransferase levels in the reperfusion effluent and histologic findings of hepatocyte viability and lesser degree of congestion and necrosis. RHR-S resulted in a significantly higher mitochondrial respiratory control index and calcium retention capacity. Transcriptomic profile analysis showed that treatment with RHR-S activated cell survival and viability, cellular homeostasis as well as other biological functions involved in tissue repair such as cytoskeleton or cytoplasm organization, cell migration, transcription, and microtubule dynamics. Furthermore, RHR-S inhibited organismal death, morbidity and mortality, necrosis, and apoptosis. CONCLUSION: Subnormothermic RHR mitigates IRI and preserves hepatic mitochondrial function after warm and cold hepatic ischemia. This organ resuscitative therapy may also trigger the activation of protective genes against IRI. Sub- normothermic RHR has potential applicability to clinical liver transplantation.

Choledochoduodenostomy continues to be a safe alternative for biliary reconstruction in deceased-donor liver transplantation.

Debate continues as to whether choledochoduodenostomy (CDD) can be used instead of Roux-en-Y choledochojejunostomy (CDJ) when duct-to-duct (DTD) is not an option. We hypothesized that CDD and CDJ had similar rates of complications. All deceased-donor liver transplantations from September 2011 to March 2020 were categorized by biliary reconstruction. Primary outcomes were bleeding, bile leak, anastomotic stricture, and cholangitis. Of the 1,086 patients, 812 (74.8%) received a DTD; 225 (20.7%) received a CDD; and 49 (4.5%) received a CDJ. Cholangitis was significantly higher in CDJ compared to DTD and CDD (26.5% vs 6% vs 13.8%, p < 0.0001). When controlling for significant confounders, CDJ had 10.2 higher odds of cholangitis (95% CI 4.4-23.2) compared to DTD, and 3.3 higher odds compared to CDD (95% CI 1.4-7.8). When compared to DTD, CDJ and CDD had significantly lower odds of stricture. CDD continues to be a safe alternative for biliary reconstruction in deceased-donor liver transplantation.

Fluorescein clearance kinetics in blood and bile indicates hepatic ischemia-reperfusion injury in rats.

Quantitative measurement of the degree of hepatic ischemia-reperfusion injury (IRI) is crucial for developing therapeutic strategies for its treatment. We hypothesized that clearance of fluorescent dye through bile metabolism may reflect the degree of hepatic IRI. In this study, we investigated sodium fluorescein clearance kinetics in blood and bile for quantifying the degree of hepatic IRI. Warm ischemia times (WITs) of 0, 30, or 60 min followed by 1 h or 4 h of reperfusion, were applied to the median and lateral lobes of the liver in Sprague-Dawley rats. Subsequently, 2 mg/kg of sodium fluorescein was injected intravenously, and blood and bile samples were collected over 60 min to measure fluorescence intensities. The bile-to-plasma fluorescence ratios demonstrated an inverse correlation with WIT and were distinctly lower in the 60-min WIT group than in the control or 30-min WIT groups. Bile-to-plasma fluorescence ratios displayed superior discriminability for short versus long WITs when measured 1 h after reperfusion versus 4 h. We conclude that the bile-to-blood ratio of fluorescence after sodium fluorescein injection has the potential to enable the quantification of hepatic IRI severity.NEW & NOTEWORTHY Previous attempts to use fluorophore clearance to test liver function have relied on a single source of data. However, the kinetics of substrate processing via bile metabolism include decreasing levels in blood and increasing levels in bile. Thus, we analyzed data from blood and bile to better reflect fluorescein clearance kinetics.

Evaluation of visible diffuse reflectance spectroscopy in liver tissue: validation of tissue saturations using extracorporeal circulation.

SIGNIFICANCE: Real-time information about oxygen delivery to the hepatic graft is important to direct care and diagnose vascular compromise in the immediate post-transplant period. AIM: The current study was designed to determine the utility of visible diffuse reflectance spectroscopy (vis-DRS) for measuring liver tissue saturation in vivo. APPROACH: A custom-built vis-DRS probe was calibrated using phantoms with hemoglobin (Hb) and polystyrene microspheres. Ex vivo (extracorporeal circulation) and in vivo protocols were used in a swine model (n = 15) with validation via blood gas analysis. RESULTS: In vivo absorption and scattering measured by vis-DRS with and without biliverdin correction correlated closely between analyses. Lin's concordance correlation coefficients are 0.991 for µa and 0.959 for µs ' . Hb measured by blood test and vis-DRS with (R2 = 0.81) and without (R2 = 0.85) biliverdin correction were compared. Vis-DRS data obtained from the ex vivo protocol plotted against the PO2 derived from blood gas analysis showed a good fit for a Hill coefficient of 1.67 and P50 = 34 mmHg (R2 = 0.81). A conversion formula was developed to account for the systematic deviation, which resulted in a goodness-of-fit R2 = 0.76 with the expected oxygen dissociation curve. CONCLUSIONS: We show that vis-DRS allows for real-time measurement of liver tissue saturation, an indicator for liver perfusion and oxygen delivery.

Post-Covid-19 Cholangiopathy-A New Indication for Liver Transplantation: A Case Report.

Liver injury is one of the nonpulmonary manifestations described in coronavirus disease 2019 (COVID-19). Post-COVID-19 cholangiopathy is a special entity of liver injury that has been suggested as a variant of secondary sclerosing cholangitis in critically ill patients (SSC-CIP). In the general population, the outcome of SSC-CIP has been reported to be poor without orthotopic liver transplantation (OLT). However, the role of OLT for post-COVID-19 cholangiopathy is unknown. We present a case report of a 47-year-old man who recovered from acute respiratory distress syndrome from COVID-19 and subsequently developed end-stage liver disease from post-COVID-19 cholangiopathy. The patient underwent OLT and is doing well with normal liver tests for 7 months. To our knowledge, this is the first case report of a patient who underwent successful liver transplantation for post-COVID-19 cholangiopathy.

A novel escalation from veno-venous bypass to veno-venous ECMO during orthotopic liver transplantation. A case report.

We describe the challenging perioperative course of a 55-year-old patient with hepatic failure requiring liver transplantation (LT). Different modalities of the extracorporeal device were successfully used, ranging from veno-veno bypass to partial and full veno-veno extracorporeal membrane oxygenation (ECMO) in order to optimize preload, reduce bleeding from the collateral circulation, optimize acid base balance and/or improve oxygenation. The case highlights the potential use of the device as a rescue method in challenging cases. Furthermore this is the first documented case that extracorporeal CO2 removal (ECCO2R) is used to optimize the biochemistry profile intraoperatively during a LT. The patient was weaned off the device at the end of the case and has been discharged home.

Anticholestatic Effect of Bardoxolone Methyl on Hepatic Ischemia-reperfusion Injury in Rats.

BACKGROUND: Cholestasis is a sign of hepatic ischemia-reperfusion injury (IRI), which is caused by the dysfunction of hepatocyte membrane transporters (HMTs). As transcriptional regulation of HMTs during oxidative stress is mediated by nuclear factor erythroid 2-related factor 2, we hypothesized that bardoxolone methyl (BARD), a nuclear factor erythroid 2-related factor 2 activator, can mitigate cholestasis associated with hepatic IRI. METHODS: BARD (2 mg/kg) or the vehicle was intravenously administered into rats immediately before sham surgery, 60 min of ischemia (IR60), or 90 min of ischemia (IR90); tissue and blood samples were collected after 24 h to determine the effect on key surrogate markers of bile metabolism and expression of HMT genes (Mrp (multidrug resistance-associated protein) 2, bile salt export pump, Mrp3, sodium-taurocholate cotransporter, and organic anion-transporting polypeptide 1). RESULTS: Significantly decreased serum bile acids were detected upon BARD administration in the IR60 group but not in the IR90 group. Hepatic tissue analyses revealed that BARD administration increased mRNA levels of Mrp2 and Mrp3 in the IR60 group, and it decreased those of bile salt export pump in the IR90 group. Protein levels of multidrug resistance-associated protein 2, multidrug resistance-associated protein 3, and sodium-taurocholate cotransporter were higher in the IR90 group relative to those in the sham or IR60 groups, wherein the difference was notable only when BARD was administered. Immunohistochemical and morphometric analyses showed that the area of expression for multidrug resistance-associated protein 2 and for sodium-taurocholate cotransporter was larger in the viable tissues than in the necrotic area, and the area for multidrug resistance-associated protein 3 was smaller; these differences were notable upon BARD administration. CONCLUSIONS: BARD may have the potential to change HMT regulation to mitigate cholestasis in hepatic IRI.

Liver transplantation in the treatment of unresectable hepatic metastasis from neuroendocrine tumors.

Neuroendocrine tumors (NET) are rare neoplasms with generally indolent growth behavior. The liver is the most common site of NET metastasis. The NET metastatic spread to the liver are usually multiple tumors involving bilateral hemilivers. For patients with isolated NET metastasis to the liver, a complete extirpation (R0) resection of both the primary NET and liver metastasis provide the best chance of tumor recurrence-free patient survival. Orthotopic liver transplantation (OLT) presents a viable treatment option for patients with unresectable liver metastasis from NET. Post-OLT outcomes for the patients of NET with liver metastasis (5-year overall survival rate 47-71%) are comparable to those for other indications. However, the high rate of recurrence after OLT (31-57%) remains a clinical obstacle. As such, it is imperative to consider each patient individually and identify prognostic factors that would impact post-OLT outcomes. This article focuses on the role of OLT in the definitive treatment of metastatic liver NET, review patient selection criteria predictive of survival outcomes and post-OLT outcomes for patients.

Human Leukocyte Antigen Class I Antibodies and Response to Platelet Transfusion in Patients Undergoing Liver Transplantation.

BACKGROUND: Patients undergoing liver transplantation (LT) frequently receive platelet transfusion (PLT) to minimize their risk of hemorrhage. Alloimmunization to platelets may lead to refractoriness to PLT. Data on the implications of platelet alloimmunization in patients undergoing LT remain limited. We examined the effect of human leukocyte antigen class I (HLA-I) antibodies on PLT refractoriness and short-term outcomes after LT. METHODS: Peritransplant clinical and PLT factors were reviewed for all adult liver or simultaneous liver-kidney transplantations from 2012 to 2017. Sensitized patients (SE) with pretransplant HLA-I calculated panel-reactive antibody ≥20% were compared with unsensitized patients (US) with calculated panel-reactive antibody <20%. The mean follow-up was 21.4 mo. RESULTS: Alloimmunization was observed in 39% of the study cohort. SE (n = 28) received 272 PLTs, and US (n = 44) received 246 PLTs. History of pregnancy was higher among SE than US (P < 0.01); otherwise, both groups had similar clinical characteristics. SE had higher rates of PLT refractoriness (66% versus 47%; P < 0.01) than US. The mean platelet corrected count increment was lower among SE compared with US up to 100 min after PLT (P < 0.05). Alloimmunization and simultaneous liver-kidney transplantation independently predicted refractoriness on multivariate logistic regression (P < 0.05). Early allograft rejection and patient survival rates were comparable for both groups. CONCLUSIONS: LT patients experienced high rates of HLA-I alloimmunization and PLT refractoriness. SE had higher rates of refractoriness and lower mean corrected count increment after transfusion compared with US. Our study suggests that further research to evaluate the utility of HLA-matched PLTs in HLA-I alloimmunized LT patients is warranted.

Liver Transplantation Outcomes in a U.S. Multicenter Cohort of 789 Patients With Hepatocellular Carcinoma Presenting Beyond Milan Criteria.

BACKGROUND AND AIMS: The Organ Procurement and Transplantation Network recently approved liver transplant (LT) prioritization for patients with hepatocellular carcinoma (HCC) beyond Milan Criteria (MC) who are down-staged (DS) with locoregional therapy (LRT). We evaluated post-LT outcomes, predictors of down-staging, and the impact of LRT in patients with beyond-MC HCC from the U.S. Multicenter HCC Transplant Consortium (20 centers, 2002-2013). APPROACH AND RESULTS: Clinicopathologic characteristics, overall survival (OS), recurrence-free survival (RFS), and HCC recurrence (HCC-R) were compared between patients within MC (n = 3,570) and beyond MC (n = 789) who were down-staged (DS, n = 465), treated with LRT and not down-staged (LRT-NoDS, n = 242), or untreated (NoLRT-NoDS, n = 82). Five-year post-LT OS and RFS was higher in MC (71.3% and 68.2%) compared with DS (64.3% and 59.5%) and was lowest in NoDS (n = 324; 60.2% and 53.8%; overall P < 0.001). DS patients had superior RFS (60% vs. 54%, P = 0.043) and lower 5-year HCC-R (18% vs. 32%, P < 0.001) compared with NoDS, with further stratification by maximum radiologic tumor diameter (5-year HCC-R of 15.5% in DS/<5 cm and 39.1% in NoDS/>5 cm, P < 0.001). Multivariate predictors of down-staging included alpha-fetoprotein response to LRT, pathologic tumor number and size, and wait time >12 months. LRT-NoDS had greater HCC-R compared with NoLRT-NoDS (34.1% vs. 26.1%, P < 0.001), even after controlling for clinicopathologic variables (hazard ratio [HR] = 2.33, P < 0.001) and inverse probability of treatment-weighted propensity matching (HR = 1.82, P < 0.001). CONCLUSIONS: In LT recipients with HCC presenting beyond MC, successful down-staging is predicted by wait time, alpha-fetoprotein response to LRT, and tumor burden and results in excellent post-LT outcomes, justifying expansion of LT criteria. In LRT-NoDS patients, higher HCC-R compared with NoLRT-NoDS cannot be explained by clinicopathologic differences, suggesting a potentially aggravating role of LRT in patients with poor tumor biology that warrants further investigation.

Pathologic Response to Pretransplant Locoregional Therapy is Predictive of Patient Outcome After Liver Transplantation for Hepatocellular Carcinoma: Analysis From the US Multicenter HCC Transplant Consortium.

OBJECTIVE: The aim of the study was to determine the rate, predictors, and impact of complete pathologic response (cPR) to pretransplant locoregional therapy (LRT) in a large, multicenter cohort of hepatocellular carcinoma (HCC) patients undergoing liver transplantation (LT). BACKGROUND: LRT is used to mitigate waitlist dropout for patients with HCC awaiting LT. Degree of tumor necrosis found on explant has been associated with recurrence and overall survival, but has not been evaluated in a large, multicenter study. METHODS: Comparisons were made among patients receiving pre-LT LRT with (n = 802) and without (n = 2637) cPR from the United States Multicenter HCC Transplant Consortium (UMHTC), and multivariable predictors of cPR were identified using logistic regression. RESULTS: Of 3439 patients, 802 (23%) had cPR on explant. Compared with patients without cPR, cPR patients were younger; had lower Model for End-stage Liver Disease (MELD) scores, AFP levels, and neutrophil-lymphocyte ratios (NLR); were more likely to have tumors within Milan criteria and fewer LRT treatments; and had significantly lower 1-, 3-, and 5-year incidence of post-LT recurrence (1.3%, 3.5%, and 5.2% vs 6.2%, 13.5%, and 16.4%; P < 0.001) and superior overall survival (92%, 84%, and 75% vs 90%, 78%, and 68%; P < 0.001). Multivariable predictors of cPR included age, sex, liver disease diagnosis, MELD, AFP, NLR, radiographic Milan status, and number of LRT treatments (C-statistic 0.67). CONCLUSIONS: For LT recipients with HCC receiving pretransplant LRT, achieving cPR portends significantly lower posttransplant recurrence and superior survival. Factors predicting cPR are identified, which may help prioritize patients and guide LRT strategies to optimize posttransplant cancer outcomes.

Staged Biliary Reconstruction After Orthotopic Liver Transplantation: A Practical Surgical Strategy for High-Acuity Adult Recipients.

Biliary complications (BC) following orthotopic liver transplantation (OLT) is strongly associated with inferior patient outcomes and increased healthcare cost. BC in high-acuity patients can be lethal. While the utility of staged biliary reconstruction after liver transplantation (SBRALT) has been reported in adult and pediatric OLT, biliary outcome data are scarce. We sought to evaluate the clinical utility and outcomes of SBRALT in high-acuity transplant recipients. METHODS: We conducted an analysis from our prospective database of 149 adult OLT between January 1, 2012, and September 30, 2017. Mean follow-up was 26 months. Variables were compared for Group I: one-stage OLT with biliary reconstruction (N = 58) versus Group II: SBRALT (N = 91). RESULTS: Compared with Group I, patients in Group II had higher acuity of illness: median model for end-stage liver disease scores (19 vs 35 P = 0.002), requirement for pretransplant intensive care unit (29.3% vs 54.9%, P = 0.022), pretransplant renal replacement therapy (15.5% vs 48.4%), estimated blood loss (2000 vs 4750 mL, P < 0.001), and intraoperative packed red blood cells transfusion (4 vs 10 units, P < 0.001). For Group II, biliary reconstruction was performed between 1 and 6 days after OLT. Hepaticojejunostomy was performed in 8.6% (Group I) and 26.4% (Group II), P = 0.010. For Groups I and II, BC rates (8.6% vs 7.7%, P = 0.955) and 1-year graft failure-free survival rates (89.7% vs 88.2%, P = 0.845) were comparable. CONCLUSIONS: Graft failure-free survival and biliary outcomes of SBRALT in high-acuity recipients are excellent and comparable to one-stage OLT for low-risk patients. SBRALT is a practical surgical strategy in complex OLT.

Downstaging Locally Advanced Cholangiocarcinoma Pre-Liver Transplantation: A Prospective Pilot Study.

BACKGROUND: Orthotopic liver transplantation (OLT) after neoadjuvant therapy (NT) in well-selected patients with unresectable hilar cholangiocarcinoma (CCA) achieves excellent recurrence-free survival. Current criteria for NT-OLT exclude patients with locally advanced hilar and intrahepatic CCA from potential cure. We sought to evaluate the efficacy of NT in downstaging locally advanced CCA, and examine outcomes after OLT. METHODS: Among 24 patients referred for unresectable hilar and intrahepatic CCA from January 2013 through August 2017, 18 met center-specific inclusion criteria for the NT-OLT treatment protocol: hilar tumor size ≤3.5 cm or intrahepatic ≤8 cm, and regional lymphadenopathy but without distant metastasis. Median follow-up was 22.1 mo from diagnosis. RESULTS: Of 18 patients who initiated NT, 11 were removed from the protocol due to tumor progression (n = 6) or uncontrolled infection and failure-to-thrive (n = 5). Median NT duration tended to be shorter for patients progressing to dropout than for those surviving to OLT (5.5 versus 13.5 mo, P = 0.109). Among five patients who received OLT, 1-y post-OLT patient survival was 80%: three survive recurrence-free (14.5-29.2 mo post-OLT); one developed an isolated tumor recurrence in a single portacaval lymph node at 12 mo post-OLT; and one experienced non-tumor-related death. All dropout patients died at a median of 14.4 mo after diagnosis. CONCLUSIONS: This is the first prospective study to show successful NT downstaging of unresectable locally advanced hilar and intrahepatic CCA before OLT. NT-OLT for select patients with locally advanced hilar and intrahepatic CCA achieved acceptable short-term recurrence-free survival.

Effects of Hepatic Ischemia-Reperfusion Injuries and NRF2 on Transcriptional Activities of Bile Transporters in Rats.

BACKGROUND: The effect of hepatic ischemia-reperfusion injury (IRI) on bile transporter (BT) gene expression is unknown. We hypothesized that abnormal expression of BTs during hepatic IRI is dependent on nuclear factor erythroid 2-related factor 2 (NRF2), which contributes to the cholestasis after reperfusion. METHODS: Sham surgery and short (60 min) or long (90 min) periods of warm ischemia time (WIT) with or without reperfusion for 24 h were applied to wild-type Sprague-Dawley rats and Nrf2 knockout rats (n = 5 per group). At each stage of IRI, the serum levels of aminotransferase, total bilirubin, and bile acids were measured. In addition, hepatic tissue was sampled to determine the histologic score of IRI (Suzuki score), measure adenosine triphosphate (ATP), and identify the quantitative real-time polymerase chain reactions of BTs (Oatp1, Ntcp, Mrp2, Bsep, and Mrp3). RESULTS: In short periods of WIT, BT expression increased during the ischemia stage and returned to the baseline after reperfusion. However, in long periods of WIT, BT expression did not increase after ischemia and decreased further after reperfusion. Short WIT did not increase BT expression in Nrf2 knockout animals. The level of BT expression was correlated with the Suzuki score, the serum levels of aminotransferase, bilirubin, and bile acids, and tissue ATP level. Stepwise multiple regression analysis derived equations to predict the Suzuki score (R2 = 76.8, P < 0.001), serum total bilirubin (R2 = 61.2, P < 0.001), and tissue ATP (R2 = 61.1, P < 0.001). CONCLUSIONS: Short WIT induces the transcriptional activities of BT, whereas long WIT depresses them, and the effect was blunted by Nrf2 knockout status. BT expression can be considered a surrogate marker for hepatic IRI.

Staged biliary reconstruction after liver transplantation: A novel surgical strategy for high acuity pediatric transplant recipients.

INTRODUCTION: Biliary complications after pediatric orthotopic liver transplantation remain causes of significant patient morbidity. Staged operative approach in complex hepatobiliary surgery has improved postoperative outcomes but has not been evaluated in pediatric orthotopic liver transplantation. We sought to analyze the outcomes of staged biliary reconstruction after orthotopic liver transplantation in high acuity patients. METHODS: A retrospective analysis of 43 pediatric orthotopic liver transplantations at our center (January 2013 through December 2017). Median follow-up was 25 months. Variables were compared for group I: 1-stage orthotopic liver transplantation with biliary anastomosis (n = 6) versus group II: staged biliary reconstruction orthotopic liver transplantation (n = 37). RESULTS: Comparing groups I and II, median age (7.3 vs 4.8 years), weight (27 vs 19 kg), proportion of urgent orthotopic liver transplantation (50% vs 65%), partial graft orthotopic liver transplantation (33% vs 35%), and intraoperative red blood cell transfusion volume (11 vs 21 mL/kg) were comparable. Roux-en-Y hepaticojejunostomy was performed in 67% (group I) and 49% (group II). There was no biliary complication in both groups. For groups I and II, 3-year survival rates for graft (100% vs 92%, P = .477) and patient (100% vs 97%, P = .679) were comparable. CONCLUSION: Our study showed excellent outcomes with staged biliary reconstruction orthotopic liver transplantation in high acuity pediatric transplant recipients. This is the first report showing clinical applicability of staged biliary reconstruction orthotopic liver transplantation in children.

Optical imaging for the assessment of hepatocyte metabolic state in ischemia and reperfusion injuries.

Deterioration in mitochondrial function leads to hepatic ischemia and reperfusion injury (IRI) in liver surgery and transplantation. 3D optical cryoimaging was used to measure the levels of mitochondrial coenzymes NADH and FAD, and their redox ratio (NADH/FAD) gave a quantitative marker for hepatocyte oxidative stress during IRI. Using a rat model, five groups were compared: control, ischemia for 60 or 90 minutes (Isc60, Isc90), ischemia for 60 or 90 minutes followed by reperfusion of 24 hours (IRI60, IRI90). Ischemia alone did not cause a significant increase in the redox ratio; however, the redox ratio in both IRI60 and IRI90 groups was significantly decreased by 29% and 71%, respectively. A significant correlation was observed between the redox ratio and other markers of injury such as serum aminotransferase levels and the tissue ATP level. The mitochondrial redox state can be successfully measured using optical cryoimaging as a quantitative marker of hepatic IR injury.

Biliary reconstructive techniques and associated anatomic variants in adult living donor liver transplantations: The adult-to-adult living donor liver transplantation cohort study experience.

Living donor liver transplantation (LDLT) is a technically demanding endeavor, requiring command of the complex anatomy of partial liver grafts. We examined the influence of anatomic variation and reconstruction techniques on surgical outcomes and graft survival in the 9-center Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL). Data from 272 adult LDLT recipients (2011-2015) included details on anatomic characteristics and types of intraoperative biliary reconstruction. Associations were tested between reconstruction technique and complications, which included first biliary complication (BC; leak, stricture, or biloma) and first vascular complication (VC; hepatic artery thrombosis [HAT] or portal vein thrombosis [PVT]). Time to patient death, graft failure, and complications were estimated using Kaplan-Meier curves and tested with log-rank tests. Median posttransplant follow-up was 1.2 years. Associations were found between the type of biliary reconstruction and the incidence of VC (P = 0.03) and BC (P = 0.05). Recipients with Roux-en-Y hepaticojejunostomy had the highest probability of VC. Recipients with biliary reconstruction involving the use of high biliary radicals on the recipient duct had the highest likelihood of developing BC (56% by 1 year) compared with duct-to-duct (42% by 1 year). In conclusion, the varied surgical approaches in the A2ALL centers offer a novel opportunity to compare disparate LDLT approaches. The choice to use higher biliary radicals on the recipient duct for reconstruction was associated with more BC, possibly secondary to devascularization and ischemia. The use of Roux-en-Y biliary reconstruction was associated with VCs (HAT and PVT). These results can be used to guide biliary reconstruction decisions in the setting of anatomic variants and inform further improvements in LDLT reconstructions. Ultimately, this information may contribute to a lower incidence of technical complications after LDLT. Liver Transplantation 23 1519-1530 2017 AASLD.

Impact of Pretransplant Bridging Locoregional Therapy for Patients With Hepatocellular Carcinoma Within Milan Criteria Undergoing Liver Transplantation: Analysis of 3601 Patients From the US Multicenter HCC Transplant Consortium.

OBJECTIVE: To evaluate the effect of pretransplant bridging locoregional therapy (LRT) on hepatocellular carcinoma (HCC) recurrence and survival after liver transplantation (LT) in patients meeting Milan criteria (MC). SUMMARY BACKGROUND DATA: Pre-LT LRT mitigates tumor progression and waitlist dropout in HCC patients within MC, but data on its impact on post-LT recurrence and survival remain limited. METHODS: Recurrence-free survival and post-LT recurrence were compared among 3601 MC patients with and without bridging LRT utilizing competing risk Cox regression in consecutive patients from 20 US centers (2002-2013). RESULTS: Compared with 747 LT recipients not receiving LRT, 2854 receiving LRT had similar 1, 3, and 5-year recurrence-free survival (89%, 77%, 68% vs 85%, 75%, 68%; P = 0.490) and 5-year post-LT recurrence (11.2% vs 10.1%; P = 0.474). Increasing LRT number [3 LRTs: hazard ratio (HR) 2.1, P < 0.001; 4+ LRTs: HR 2.5, P < 0.001), and unfavorable waitlist alphafetoprotein trend significantly predicted post-LT recurrence, whereas LRT modality did not. Treated patients achieving complete pathologic response (cPR) had superior 5-year RFS (72%) and lower post-LT recurrence (HR 0.52, P < 0.001) compared with both untreated patients (69%; P = 0.010; HR 1.0) and treated patients not achieving cPR (67%; P = 0.010; HR 1.31, P = 0.039), who demonstrated increased recurrence compared with untreated patients in multivariate analysis controlling for pretransplant and pathologic factors (HR 1.32, P = 0.044). CONCLUSIONS: Bridging LRT in HCC patients within MC does not improve post-LT survival or HCC recurrence in the majority of patients who fail to achieve cPR. The need for increasing LRT treatments and lack of alphafetoprotein response to LRT independently predict post-LT recurrence, serving as a surrogate for underlying tumor biology which can be utilized for prioritization of HCC LT candidates.