To the editor, With the maturity and popularity of the organ transplantation technology, hepatic artery thrombosis (HAT) after adult liver transplantation has rarely occurred. However, in adult living donor liver transplantation, the risk of HAT is high due to the small size, short artery length, and high portal perfusion with activation of hepatic artery buffer response. Studies have reported an occurrence rate of ~1.9% for HAT in adult living donor liver transplantation.1 The occurrence of HAT can lead to a compromised blood supply to the transplanted liver, resulting in the loss of the transplanted liver and even mortality in severe cases. This complication poses a significant challenge for transplant doctors. The most effective treatment for HAT is currently a topic of debate. Retransplantation is an early option, but is limited by donor shortages. The recent study by Hong et al,2 published in Liver Transplantation, evaluated the outcomes of adult living donor liver transplantation patients with HAT under an aggressive surgical intervention. The study found that successful revascularization saved the graft without retransplantation in 96.0% of the cases. We congratulate the authors on their achievements. However, we would like to add several comments. First, when dealing with HAT recurrence, it is important to consider the potential increase in surgical time, hepatic artery reconstruction time, and blood loss that may accompany repeated reconstructions. These can lead to an increased risk of biliary stenosis.3 Second, it is necessary for the authors to specify the criteria for artery matching in redo hepatic artery reconstruction, as well as which vessels should be selected in specific situations. It is worth noting that the use of the splenic artery in hepatic arterial revascularization has been associated with spleen infarction.4 Finally, redo hepatic artery reconstruction is a complex procedure that requires precision. To ensure accuracy, the authors opt to use a microscope or surgical loupes. On the one hand, surgical loupes offer a fixed working distance, magnification, a smaller field of view, and limited illumination. On the other hand, using a microscope demands high operation requirements, a long learning curve, and time-consuming preparation. Additionally, the surgical field is small, and the operation is relatively cumbersome and inconvenient, which can prolong the operation time. It would be beneficial for the authors to discuss their experience of using both methods in the discussion section.

OLT is known to be associated with a precarious perioperative hemostatic state due to dysregulation of procoagulant and anticoagulant factors, endothelial injury, and inflammation. Transmission of inherited bleeding and clotting disorders from the liver donor to the recipient may further complicate hemostasis during and after transplantation. As a result, consideration of congenital coagulation disorders in the liver donor is a practical concern for donor selection. However, there is no clear consensus regarding the selection of donors with known or suspected thrombophilia or bleeding disorders. While multiple case reports and retrospective studies, subject to reporting bias, describe donor-derived thrombophilic and bleeding disorders, there are no large-scale studies in the adult liver transplant literature that examine the frequency of transmission, utility of donor screening, or clinical impact of donor hemostatic disorders. Based on the reported literature, we summarize our approach for donor selection with an aim to balance improved organ utility and optimal post-transplant outcomes.

Liver transplantation (LT) teams must be adept at detecting, evaluating, and treating patients' alcohol use, given its prominence among psychological and behavioral phenomena which cause and contribute to liver diseases. Phosphatidylethanol (PEth) is a highly useful alcohol biomarker increasingly recommended for routine use in hepatology and LT. PEth is unique among alcohol biomarkers because of its wide detection window, high sensitivity and specificity, and the correlation of its numerical value with different patterns of alcohol use. Alongside myriad clinical opportunities in hepatology and LT, PEth also confers numerous challenges: little guidance exists about its clinical use; fearing loss of LT access and the reactions of their clinicians and families, candidates and recipients are incentivized to conceal their alcohol use; and liver clinicians report lack of expertise diagnosing and treating substance-related challenges. Discordance between patient self-reported alcohol use and toxicology is yet another common and particularly difficult circumstance. This article discusses the general toxicological properties of PEth; explores possible scenarios of concordance and discordance among PEth results, patient history, and self-reported drinking; and provides detailed clinical communication strategies to explore discordance with liver patients, a key aspect of its use.

1University of Iowa, Division of Gastroenterology and Hepatology, Iowa City, IA 2University of Iowa, Division of Transplantation and Hepatobiliary Surgery, Iowa City, IA Authorship page: AH participated in writing of the paper and performance of the research. DAA participated in research design and writing of the paper. TT participated in research design, writing of the paper, performance of the research, and final review. Correspondence Tomohiro Tanaka, 200 Hawkins Dr, Iowa City, IA 52242. Email: [email protected]

Hepatic hydrothorax (HH) is a significant complication of cirrhosis associated with increased mortality. Liver transplantation (LT) remains the best treatment modality. We aim to assess predictors of mortality and the survival benefit of LT in patients with HH. A prospectively maintained cohort of adult patients with cirrhosis, being evaluated for LT at our institution, was retrospectively reviewed from 2015 to 2020. The primary outcome was death or LT. Cox proportional hazard regression identified associations between covariates and death. We calculated the years saved due to LT by comparing patients who were on the waiting list with patients who received an LT. This was done by calculating the area under the Kaplan-Meier curve. Censoring occurred at the time of the last follow-up or death. Patients with refractory HH had the lowest median survival of only 0.26 years. Within the HH group, having a refractory HH group was significantly associated with an increased risk of mortality (HR 1.73; 95% CI 1.06-2.81; p -value 0.03). Refractory HH was also significantly associated with mortality when evaluated in the entire cohort and after adjusting for other covariates (HR 1.48, 95% CI 1.03-2.11; p -value 0.03). Patients with refractory HH had the highest 1-year survival benefit with LT (0.48y), followed by patients with non-refractory HH (0.28y), then patients with other complications of cirrhosis (0.19y). In this large study evaluating the prognostic impact of HH on patients with cirrhosis, refractory HH was an independent predictor of mortality. LT provides an additional survival benefit to patients with HH compared with those without HH.

In Italy, 20 minutes of continuous, flat-line electrocardiogram are required for death declaration, which significantly increases the risks of donation after circulatory death (DCD) LT. Despite prolonged warm ischemia time, Italian centers reported good outcomes in controlled donation after circulatory death LT by combining normothermic regional and end-ischemic machine perfusion. However, data on uncontrolled DCD (uDCD) LT performed by this approach are lacking. This was a multicenter, retrospective study performed at 3 large-volume centers comparing clinical outcomes of uncontrolled versus controlled DCD LT. The aim of the study was to assess outcomes of sequential normothermic regional perfusion and end-ischemic machine perfusion in uncontrolled DCD liver transplantation (LT). Of 153 DCD donors evaluated during the study period, 40 uDCD and 59 donation after circulatory death grafts were transplanted (utilization rate 52% vs. 78%, p = 0.004). Recipients of uDCD grafts had higher MEAF (4.9 vs. 3.5, p < 0.001) and CCI scores at discharge (24.4 vs. 8.7, p = 0.026), longer ICU stay (5 vs. 4d, p = 0.047), and a trend toward more severe AKI. At multivariate analysis, 90-day graft loss was associated with recipient BMI and lactate downtrend during normothermic regional perfusion. One-year graft survival was lower in uDCD (75% vs. 90%, p = 0.007) but became comparable when non-liver-related graft losses were treated as censors (77% vs. 90%, p = 0.100). The incidence of ischemic cholangiopathy was 10% in uDCD versus 3% in donation after circulatory death, p = 0.356. uDCD LT with prolonged warm ischemia is feasible by the sequential use of normothermic regional perfusion and end-ischemic machine perfusion. Proper donor and recipient selection are key to achieving good outcomes in this setting.

Avoidance of steroids in pediatric liver transplantation may reduce toxicity and morbidity. The aim of this study was to analyze the feasibility of a steroid-free tacrolimus-basiliximab immunosuppression scheme, the risk factors associated with steroid requirement, and safety parameters. Patients who underwent liver transplantation for biliary atresia between 2011 and 2019 were included and followed for 6 months after transplantation. Immunosuppression consisted of tacrolimus-based treatment with basiliximab induction. Steroid-free survival was estimated, and risk factors for steroid requirement were evaluated using multivariate Cox regression analysis. A total of 76 patients were included, of whom 42 (55.3%) required steroids (>14d) due to biopsy-proven acute rejection (47.6%, n = 20), instability in liver function tests (35.7%, n = 15), tacrolimus-related adverse drug reactions (14.3%, n = 6), or other reasons (bronchospasm episode, n = 1). Steroid-free survival was 45.9% (95% CI, 35.9-58.8). Independent factors associated with steroid requirement included tortuosity in tacrolimus trough levels (≥1.76 vs. <1.76: HR 5.8, 95% CI, 2.6-12.7; p < 0.001) and mean tacrolimus trough levels (≥ 6.4ng/mL vs. < 6.4ng/mL: HR 0.4, 95% CI, 0.2-0.7; p = 0.002). The rate of bacterial and viral infections was comparable between patients with and without steroids, although in the former group, cytomegalovirus infection developed earlier ( p = 0.03). Patients receiving steroids had higher total cholesterol, LDL, and HDL levels ( p < 0.05) during follow-up, but no changes in the height Z-score were observed 1 year after transplantation. Basiliximab induction in combination with tacrolimus-based treatment avoided steroid requirements in 45% of the patients. Tacrolimus variability and trough levels below 6.4ng/mL independently increased the risk of steroid requirement. Further efforts should be focused on personalizing immunosuppressive treatment.

Ischemia-reperfusion injury (IRI) remains a major cause of mortality and morbidity after liver surgery. Endoplasmic reticulum (ER) stress is a critical mechanism of inflammatory injury during hepatic IRI. In this study, we investigated the effect of sphingosine kinases 2 (SK2) on ER stress and hepatic IRI. We established hepatic IRI mice and hepatocellular hypoxia/reoxygenation in vitro model. We observed the SK2 and ER stress protein IRE1α expression. Then, we used an SK2 inhibitor and knocked down IRE1α/SK2, to observe the effect of SK2 during IRI. Our results showed that the expression of ER stress and SK2 was significantly elevated during hepatic IRI. Inhibition of SK2 ameliorated liver inflammation and reduced cell apoptosis in hepatic IRI mice. Consistently, we found that the inhibition of IRE1α also downregulated SK2 expression and reduced mitochondrial membrane permeability. Furthermore, the knockdown of SK2 could also reduce cell damage and reduce the expression of inflammatory factors but did not influence ER stress-related signaling pathway. Taken together, our results suggested that ER stress and SK2 played important and regulatory roles in hepatic IRI. Inhibition of ER stress and SK2 could significantly improve liver function after hepatic IRI.

Decisions about patient candidacy for liver transplant (LT) can mean the difference between life and death. We surveyed LT centers across the United States to assess their perceptions of and barriers to second-opinion referrals for inpatients declined for transplant. The medical and surgical directors of 100 unique US LT programs that had done >20 LTs in 2021 were surveyed with a 33-item questionnaire including both multiple-choice and free-response questions. The response rate was 60% (60 LT centers) and included 28 larger-volume ( ≥100 LTs in 2021) and 32 smaller-volume (<100 LTs in 2021) programs. The top 3 reasons for inpatient denial for LT included lack of social support (21%), physical frailty (20%), and inadequate remission duration from alcohol use (11%). Twenty-five percent of the programs reported "frequently" facilitating a second opinion for a declined inpatient, 52% of the programs reported "sometimes" doing so, and 7% of the programs reported never doing so. One hundred percent of the programs reported that they receive referrals for second opinions. Twenty-five percent of the programs reported transplanting these referrals frequently (over 20% of the time). Neither program size nor program location statistically impacted the findings. When asked if centers would be in favor of standardizing the evaluation process, 38% of centers would be in favor, 39% would be opposed, and 23% were unsure. The practices and perceptions of second opinions for hospitalized patients evaluated for LT varied widely across the United States. Opportunities exist to improve equity in LT but must consider maintaining individual program autonomy.

Brubaker, Aleah L.; Bensard, Claire; MacConmara, Malcolm; Elbetanony, Ahmed; Attia, Magdy; Sanchez, Ramon; Schnickel, Gabriel Author Information