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A difficulty score to predict intraoperative surgical complexity in liver transplantation has never been developed. The aim of this study was to assess factors associated with a difficult liver transplant and develop a score to predict difficult surgery. All patients undergoing deceased donor whole liver transplantation from 2012 to 2019 at a single center were included. Estimated intraoperative blood loss (mL/kg) and surgery duration (skin-to-arterial reperfusion time) were used as surrogates of difficulty. Based on these variables, the study population was divided into 2 groups: high risk and standard risk of difficulty. Univariate and multivariate analyses were performed to identify predictors associated with a demanding liver transplantation and develop a difficulty score. A total of 515 patients were included in the study population, and 101 (20%) were considered difficult operations. Patients with a higher risk of difficulty showed a significantly higher rate of Clavien-Dindo ≥III complications (50.5% vs 24.4%, P =.001) and a longer hospital stay (19 vs 16 days, P =.001). Preoperative factors associated with difficulty were retransplantation (odds ratio 4.34, P =.001), preoperative portal vein thrombosis (odds ratio 3.419, P =.001), previous upper abdominal surgery (odds ratio 2.161, P =.003), spontaneous bacterial peritonitis (odds ratio 1.985, P <.02), and prior variceal bleeding (odds ratio 1.401, P =.051). A 10-point difficulty score was created, showing a negative predictive value of 84% at 4 points. Difficult liver transplantation surgery, as assessed by skin-to-arterial reperfusion time and estimated blood loss, is associated with worse perioperative outcomes. We developed a simple score with clinical preoperative variables that predicts difficult surgery, and therefore, it may help to optimize allocation policies and perioperative logistics. [ABSTRACT FROM AUTHOR]

The incidence and outcomes of coronavirus disease 2019 (COVID-19) in immunocompromised patients are a matter of debate. We performed a prospective nationwide study including a consecutive cohort of liver transplant patients with COVID-19 recruited during the Spanish outbreak from 28 February to 7 April, 2020. The primary outcome was severe COVID-19, defined as the need for mechanical ventilation, intensive care, and/or death. Age- and gender-standardised incidence and mortality ratios (SIR and SMR) were calculated using data from the Ministry of Health and the Spanish liver transplant registry. Independent predictors of severe COVID-19 among hospitalised patients were analysed using multivariate Cox regression. A total of 111 liver transplant patients were diagnosed with COVID-19 (SIR = 191.2 [95% CI 190.3–192.2]). The epidemiological curve and geographic distribution overlapped widely between the liver transplant and general populations. After a median follow-up of 23 days, 96 patients (86.5%) were admitted to hospital and 22 patients (19.8%) required respiratory support. A total of 12 patients were admitted to the ICU (10.8%). The mortality rate was 18%, which was lower than in the matched general population (SMR = 95.5 [95% CI 94.2–96.8]). Overall, 35 patients (31.5%) met criteria of severe COVID-19. Baseline immunosuppression containing mycophenolate was an independent predictor of severe COVID-19 (relative risk = 3.94; 95% CI 1.59–9.74; p = 0.003), particularly at doses higher than 1,000 mg/day (p = 0.003). This deleterious effect was not observed with calcineurin inhibitors or everolimus and complete immunosuppression withdrawal showed no benefit. Being chronically immunosuppressed, liver transplant patients have an increased risk of acquiring COVID-19 but their mortality rates are lower than the matched general population. Upon hospital admission, mycophenolate dose reduction or withdrawal could help in preventing severe COVID-19. However, complete immunosuppression withdrawal should be discouraged. In liver transplant patients, chronic immunosuppression increases the risk of acquiring COVID-19 but it could reduce disease severity. Complete immunosuppression withdrawal may not be justified. However, mycophenolate withdrawal or temporary conversion to calcineurin inhibitors or everolimus until disease resolution could be beneficial in hospitalised patients. • The incidence of coronavirus disease 2019 (COVID-19) is higher in liver transplant patients. • Mortality rates are lower than those observed in the matched general population. • Immunosuppression withdrawal may not be justified. • Mycophenolate may increase the risk of severe COVID-19 in a dose-dependent manner. • Calcineurin inhibitors and everolimus are not deleterious for COVID-19. [ABSTRACT FROM AUTHOR]

The article provides information on the therapeutic use of mesenchymal stromal cells (MSCs) including reducing liver injury, liver fibrosis, and boost liver regeneration. Particular focus is given to the application of MSCs in immunomodulation, inhibiting monocyte maturation, and T lymphocyte activation. Also discussed is the disadvantages of using MSCs including the development of tumors, opportunistic infections, and inflammatory response.

Background & Aims: c-Jun N-terminal kinase (JNK) is activated by multiple profibrogenic mediators; JNK activation occurs during toxic, metabolic, and autoimmune liver injury. However, its role in hepatic fibrogenesis is unknown. Methods: JNK phosphorylation was detected by immunoblot analysis and confocal immunofluorescent microscopy in fibrotic livers from mice after bile duct ligation (BDL) or CCl4 administration and in liver samples from patients with chronic hepatitis C and non-alcoholic steatohepatitis. Fibrogenesis was investigated in mice given the JNK inhibitor SP600125 and in JNK1- and JNK2-deficient mice following BDL or CCl4 administration. Hepatic stellate cell (HSC) activation was determined in primary mouse HSCs incubated with pan-JNK inhibitors SP600125 and VIII. Results: JNK phosphorylation was strongly increased in livers of mice following BDL or CCl4 administration as well as in human fibrotic livers, occurring predominantly in myofibroblasts. In vitro, pan-JNK inhibitors prevented transforming growth factor (TGF) β-, platelet-derived growth factor-, and angiotensin II-induced murine HSC activation and decreased platelet-derived growth factor and TGF-β signaling in human HSCs. In vivo, pan-JNK inhibition did not affect liver injury but significantly reduced fibrosis after BDL or CCl4. JNK1-deficient mice had decreased fibrosis after BDL or CCl4, whereas JNK2-deficient mice displayed increased fibrosis after BDL but fibrosis was not changed after CCl4. Moreover, patients with chronic hepatitis C who displayed decreased fibrosis in response to the angiotensin receptor type 1 blocker losartan showed decreased JNK phosphorylation. Conclusions: JNK is involved in HSC activation and fibrogenesis and represents a potential target for antifibrotic treatment approaches. [Copyright &y& Elsevier]

Background & Aims: Alcoholic hepatitis (AH) is characterized by hepatocellular damage, inflammation, and fibrosis. We performed a prospective study to associate hepatic expression of the CXC subfamily of chemokines with histology findings and prognosis of patients with AH. Methods: Liver biopsy samples from 105 patients with AH and 5 normal liver samples (controls) were evaluated for steatosis, inflammation, fibrosis, and cholestasis. Computer-based morphometric analysis assessed the numbers of infiltrating CD3 + T cells and CD15 + cells (neutrophils); terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling staining was used to quantify apoptosis. Expression of CXC and CC chemokines and selected signaling components were assessed by quantitative reverse-transcription polymerase chain reaction; protein levels of interleukin (IL)-8 and Gro-α also were determined by immunohistochemistry. Serum levels of IL-8 and Gro-α were measured by enzyme-linked immunosorbent assay. The Cox regression model identified variables associated with mortality. Results: Most patients (75%) had severe AH; their 90-day mortality rate was 21.9%. In AH liver samples, expression of the CXC subfamily members IL-8, Gro-α, CXCL5, CXCL6, CXCL10, and platelet factor 4 was up-regulated and compared with controls. The CC chemokine CCL2, but not CCL5, also was up-regulated. Higher expression levels of IL- 8, CXCL5, Gro-γ, and CXCL6 were associated with worse prognosis. Expression of CXC components correlated with neutrophil infiltration and the severity of portal hypertension. In the multivariate analysis, IL-8 protein levels were an independent predictor of 90-day mortality. IL-8 and Gro-α serum levels did not correlate with prognosis. Conclusions: Hepatic expression of CXC components correlates with prognosis of patients with AH. Reagents that target CXC chemokines might be developed as therapeutics. [Copyright &y& Elsevier]

Background & Aims: Recent studies have suggested that the kallikrein-kinin system regulates tissue fibrogenesis. We hypothesize that bradykinin (BK), the main effector peptide of this system, regulates hepatic fibrogenesis. Methods: Kallikrein-kinin system components were studied by quantitative reverse-transcription polymerase chain reaction analysis, immunohistochemistry, and Western blotting. The effect of bradykinin on liver injury was studied by infusing saline or bradykinin (1 and 100 ng/kg/min) through a subcutaneous pump into carbon tetrachloride–treated rats and mice treated with Fas-stimulating antibody. Bradykinin effects were studied in cultured hepatic stellate cells (HSCs) and hepatocytes. Results: Bradykinin receptors and kallikrein-1 were detected in both normal and fibrotic human livers and HSCs. BK receptors were up-regulated in fibrotic livers and activated HSCs. Bradykinin infusion reduced liver damage, as indicated by decreased aminotransferase serum levels and reduced histologic necroinflammatory score without inducing changes in arterial pressure. Moreover, bradykinin attenuated hepatic fibrosis, as indicated by reduced collagen accumulation, smooth muscle α-actin content, as well as decreased pro-collagen-α1(I) and transforming growth factor-β1 gene expression. Bradykinin infusion reduced hepatocellular apoptosis induced by anti–Fas-receptor antibody. HSCs responded to bradykinin with intracellular calcium mobilization. Bradykinin reduced procollagen-α1(I) and transforming growth factor-β1 gene expression and induced matrix metalloproteinase-2 activation. Finally, BK induced prosurvival and proliferative intracellular signaling in primary hepatocytes. Conclusions: Bradykinin attenuates liver damage and fibrosis development in a rat model of chronic liver injury. Therefore, activation of the kallikrein-kinin system may be a new therapeutic approach to the management of chronic liver disease. [Copyright &y& Elsevier]

Background & Aims: Alcoholic hepatitis (AH) is a form of acute-on-chronic liver failure for which current therapy is not fully effective. We investigated the hepatic expression of candidate genes in patients with AH to identify new targets for therapy. Methods: Hepatic expression of candidate genes (n = 46) was assessed by quantitative polymerase chain reaction in patients with AH (n = 23) and in normal livers (n = 6). Disease severity was assessed by the Maddrey’s discriminant function and the occurrence of clinical complications. Histologic analysis included the assessment of myofibroblasts (smooth muscle α-actin), collagen deposition (Sirius red), and inflammatory infiltrate (CD43). Portal hypertension was assessed by hepatic venous pressure gradient. Predictive association between gene expression and disease severity was assessed by k-nearest neighbor analysis. Results: Patients with AH showed profound hepatocellular dysfunction advanced fibrosis, and severe portal hypertension. Livers with AH showed up-regulation of genes encoding extracellular matrix proteins (procollagen I), fibrogenesis mediators, inflammatory cytokines, and apoptosis regulators. Key components of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase were markedly up-regulated, whereas cytochrome p450 2E1 and angiotensinogen were down-regulated. The expression of tissue inhibitor of metalloproteinases-1, growth-related oncogene α, and several components of NADPH oxidase (dual oxidases 1 and 2) correlated with histologic findings and parameters indicative of disease severity. Conclusions: Genes involved in hepatic fibrogenesis, inflammatory response, and oxidative stress are overexpressed in AH. Some candidate genes correlate with histologic findings and disease severity, suggesting that they may be potential targets for therapy. [Copyright &y& Elsevier]

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The pretransplant diagnosis of liver malignancies in nodular cirrhotic livers remains a diagnostic challenge despite current advances. Although the prognostic impact of incidental hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (iCC) in liver transplant recipients is well documented, there are no data on the impact in simultaneous liver kidney transplant (LKT) recipients. This is a single-center observational, retrospective study of all LKT performed from May 1993 to April 2022. Among these patients, demographic data, immunosuppressive therapy, rejection episodes, and prevalence of incidental HCC or iCC were evaluated. One hundred eight LKTs were performed and 6 were excluded. There were 13 patients with incidental carcinomas in the explanted liver: one of them with both an HCC and iCC, one with an iCC, and the remaining with an HCC. One case of iCC died. No other recurrences occurred. There were no cases of incidental HCC nor iCC in patients with a hereditary or metabolic LKT indication. We found no differences in the 5-year patient survival, and death-censored kidney and liver graft survival rates for those LKT with an incidental HCC and those without it (76.9% vs 84.2%, P =.5; 100% vs 91.6%, P =.28; and 100% vs 94.7%, P = 0.39, respectively). Finally, there were no significant associations between explant carcinoma and rejections of the liver (7.7% vs 17.9%, P =.34) or kidney graft (0% vs 16.8%, P = 0.11). Despite a high prevalence of incidental HCC or iCC, patient, kidney, and liver graft 5-year survival were unaffected by incidental HCC. [ABSTRACT FROM AUTHOR]

More than a half of patients undergoing liver transplantation (LT) receive intraoperative transfusion. Portal hypertension (PHT) may contribute to perioperative blood loss. We study the relationship between preoperative hepatic venous pressure gradient (HVPG) values and intraoperative transfusion requirements in adult patients undergoing LT. 160 cirrhotic patients undergoing first elective LT (2009–2019) with an HVPG measurement within the previous 6 months were included. Surgical technique was piggyback with portocaval shunt (PCS). The association of HVPG and other variables with transfusion requirements and blood loss were studied. Blood loss (ml/kg) was positively correlated with HVPG, among other variables, but at multivariable analysis it only remained associated with MELD-Na and HCC indication. Regarding RBC transfusion, MELD-Na and hemoglobin were independently associated with the need and magnitude of RBC transfusion. Subanalysis by surgical stage (hepatectomy, anhepatic, neohepatic) and by serial HVPG cut-offs found no clear associations with either bleeding or transfusion. The severity of PHT plays a minor role on bleeding and transfusion during LT in a contemporary cohort with systematic PCS. Main determinants of transfusion are liver function and baseline hemoglobin, which would seem the suitable goal to optimize transfusion in LT. [ABSTRACT FROM AUTHOR]

Background & Aims: The transcription factor nuclear factor-κB (NF)-κB promotes survival of hepatic myofibroblasts and fibrogenesis through poorly defined mechanisms. We investigated the activities of angiotensin II and IκB kinase (IKK) in regulation of NF-κB activity and the role of these proteins in liver fibrosis in rodents and humans. Methods: Phosphorylation of the NF-κB subunit RelA at serine 536 (P-Ser536-RelA) was detected by immunoblot and immunohistochemical analyses. P-Ser536-RelA function was assessed using vectors that expressed mutant forms of RelA, cell-permeable blocking peptides, and assays for RelA nuclear transport and apoptosis. Levels of P-Ser536-RelA were compared with degree of fibrosis in liver sections from chronically injured rats and patients with hepatitis C virus-mediated fibrosis who had been treated with the AT1 antagonist losartan. Results: Constitutive P-Ser536-RelA is a feature of human hepatic myofibroblasts, both in vitro and in situ in diseased livers. Autocrine angiotensin II stimulated IKK-mediated phosphorylation of RelA at Ser536, which was required for nuclear transport and transcriptional activity of NF-κB. Inhibition of angiotensin II, the angiotensin II receptor type 1 (AT1), or IKK blocked Ser536 phosphorylation and stimulated myofibroblast apoptosis. Treatment of fibrotic rodent liver with the angiotensin converting enzyme (ACE) inhibitor captopril or the IKK inhibitor sulphasalazine resulted in loss of P-Ser536-RelA-positive myofibroblasts and fibrosis regression. In human liver samples, increased numbers of P-Ser536-RelA-positive cells were associated with fibrosis that regressed following exposure to losartan. Conclusions: An autocrine pathway that includes angiotensin II, IKK, and P-Ser536-RelA regulates myofibroblast survival and can be targeted to stimulate therapeutic regression of liver fibrosis. [Copyright &y& Elsevier]

To what extent patients with alcohol-related decompensated cirrhosis can improve until recovery from decompensation remains unclear. We aimed to investigate the probability of recovery and delisting due to improvement in patients with alcohol-related decompensated cirrhosis on the waiting list (WL) for liver transplantation (LT). We conducted a registry-based, multicenter, retrospective study including all patients admitted to the LT WL in Catalonia (Spain) with the indication of alcohol-, HCV-, cholestasis- or non-alcoholic steatohepatitis-related decompensated cirrhosis between January 2007 and December 2018. Competing-risk analysis was used to investigate variables associated with delisting due to improvement in patients with alcohol-related decompensated cirrhosis. Criteria for delisting after improvement were not predefined. Outcomes of patients after delisting were also studied. One-thousand and one patients were included, 420 (37%) with alcohol-related decompensated cirrhosis. Thirty-six (8.6%) patients with alcohol-related decompensated cirrhosis were delisted after improvement at a median time of 29 months after WL admission. Lower model for end-stage liver disease (MELD) score, higher platelets and either female sex or lower height were independently associated with delisting due to improvement, while time of abstinence did not reach statistical significance in multivariate analysis (p = 0.055). Five years after delisting, the cumulative probability of remaining free from liver-related death or LT was 76%, similar to patients with HCV-related decompensated cirrhosis delisted after improvement. A significant proportion of LT candidates with alcohol-related cirrhosis can be delisted due to improvement, which is predicted by low MELD score and higher platelet count at WL admission. Women also have a higher probability of being delisted after improvement, partially due to reduced early access to LT for height discrepancies. Early identification of patients with potential for improvement may avoid unnecessary transplants. Patients with alcohol-related cirrhosis can improve until being delisted in approximately 9% of cases. Low model for end-stage liver disease score and high platelet levels at admission predict delisting after improvement, and women have higher probabilities of being delisted due to improvement. Long-term outcomes after delisting are generally favorable. [Display omitted] • Around 9% of patients with alcohol-related cirrhosis are delisted for improvement. • MELD score is the main determinant of improvement. • Women have higher probabilities of being delisted for improvement. • Outcomes after delisting are globally favorable and affected by alcohol relapse. [ABSTRACT FROM AUTHOR]

• Uhl's anomaly is an extremely rare congenital heart defect usually fatal in the perinatal period. • We report the first successful combined heart-liver transplant for this disease in an adult. Uhl's anomaly is an extremely rare congenital heart defect characterized by absence of the right ventricle myocardium and preserved left ventricular myocardium. Although the disease has a poor prognosis and is generally fatal in the perinatal period, some patients may reach adulthood. We describe a case of Uhl's anomaly complicated with heart failure and decompensated cardiac cirrhosis in a 42-year-old man treated by combined heart-liver transplant. The patient underwent heart transplant using the bicaval technique followed by subsequent liver transplant with the piggyback technique without venovenous bypass. Total ischemia time was 108 minutes for the heart and 360 and 25 minutes of cold and warm ischemia, respectively, for the liver. No intraoperative complications occurred. The patient was discharged without severe complications on postoperative day 22. Pathologic examination of the organs reported advanced cirrhosis of the liver and severe dilated myocardiopathy of right ventricle with absence of myocardium and a normal left ventricle. Twenty-seven months after the transplant the patient has been free from hospital admissions, with normal function of both transplanted organs. We report the first successful combined heart-liver transplant for Uhl's anomaly indication in an adult patient. Despite of the insufficient knowledge of natural history of this exceptional disease, we successfully apply the management principles of other end-stage right heart disorders complicated with liver failure. [ABSTRACT FROM AUTHOR]

Background & Aims Antiviral therapy for the treatment of hepatitis C (HCV) infection has proved to be safe and efficacious in patients with cirrhosis awaiting liver transplantation (LT). However, the information regarding the clinical impact of viral eradication in patients on the waiting list is still limited. The aim of the study was to investigate the probability of delisting in patients who underwent antiviral therapy, and the clinical outcomes of these delisted patients. Methods Observational, multicenter and retrospective analysis was carried out on prospectively collected data from patients positive for HCV, treated with an interferon-free regimen, while awaiting LT in 18 hospitals in Spain. Results In total, 238 patients were enrolled in the study. The indication for LT was decompensated cirrhosis (with or without hepatocellular carcinoma [HCC]) in 171 (72%) patients, and HCC in 67 (28%) patients. Sustained virologic response (SVR) rate was significantly higher in patients with compensated cirrhosis and HCC (92% vs. 83% in patients with decompensated cirrhosis with or without HCC, p = 0.042). Among 122 patients with decompensated cirrhosis without HCC, 29 (24%) were delisted due to improvement. No patient with baseline MELD score >20 was delisted. After delisting (median follow-up of 88 weeks), three patients had clinical decompensations and three had de novo HCC. Only two of the patients with HCC had to be re-admitted onto the waiting list. The remaining 23 patients remained stable, with no indication for LT. Conclusions Antiviral therapy is safe and efficacious in patients awaiting LT. A quarter of patients with decompensated cirrhosis can be delisted as a result of clinical improvement, which appears to be remain stable in most patients. Thus, delisting is a safe strategy that could spare organs and benefit other patients with a more urgent need. Lay summary Antiviral therapy in patients awaiting liver transplantation is safe and efficacious. Viral eradication allows removal from the waiting list of a quarter of treated patients. Delisting because of clinical improvement is a safe strategy that can spare organs for patients in urgent need. [ABSTRACT FROM AUTHOR]

Background & Aims There is an increasing discrepancy between the number of potential liver graft recipients and the number of organs available. Organ allocation should follow the concept of benefit of survival, avoiding human-innate subjectivity. The aim of this study is to use artificial-neural-networks (ANNs) for donor-recipient (D-R) matching in liver transplantation (LT) and to compare its accuracy with validated scores (MELD, D-MELD, DRI, P-SOFT, SOFT, and BAR) of graft survival. Methods 64 donor and recipient variables from a set of 1003 LTs from a multicenter study including 11 Spanish centres were included. For each D-R pair, common statistics (simple and multiple regression models) and ANN formulae for two non-complementary probability-models of 3-month graft-survival and -loss were calculated: a positive-survival (NN-CCR) and a negative-loss (NN-MS) model. The NN models were obtained by using the Neural Net Evolutionary Programming (NNEP) algorithm. Additionally, receiver-operating-curves (ROC) were performed to validate ANNs against other scores. Results Optimal results for NN-CCR and NN-MS models were obtained, with the best performance in predicting the probability of graft-survival (90.79%) and -loss (71.42%) for each D-R pair, significantly improving results from multiple regressions. ROC curves for 3-months graft-survival and –loss predictions were significantly more accurate for ANN than for other scores in both NN-CCR (AUROC-ANN = 0.80 vs. –MELD = 0.50; -D-MELD = 0.54; -P-SOFT = 0.54; -SOFT = 0.55; –BAR = 0.67 and -DRI = 0.42) and NN-MS (AUROC-ANN = 0.82 vs. –MELD = 0.41; -D-MELD = 0.47; -P-SOFT = 0.43; -SOFT = 0.57, -BAR = 0.61 and -DRI = 0.48). Conclusions ANNs may be considered a powerful decision-making technology for this dataset, optimizing the principles of justice, efficiency and equity. This may be a useful tool for predicting the 3-month outcome and a potential research area for future D-R matching models. [ABSTRACT FROM AUTHOR]