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Liver cyst infections often necessitate long-term hospital admission and are associated with considerable morbidity and mortality. We conducted a modified Delphi study to reach expert consensus for a clinical decision framework. The expert panel consisted of 24 medical specialists, including 12 hepatologists, from nine countries across Europe, North America, and Asia. The Delphi had three rounds. The first round (response rate 21/24 [88%]) was an online survey with questions constructed from literature review and expert opinion, in which experts were asked about their management preferences and rated possible management strategies for seven clinical scenarios. Experts also rated 14 clinical decision-making items for relevancy and defined treatment outcomes. During the second round (response rate 13/24 [54%]), items that did not reach consensus and newly suggested themes were discussed in an online panel meeting. In the third round (response rate 16/24 [67%]), experts voted on definitions and management strategies using an online survey based on previous answers. Consensus was predefined as a vote threshold of at least 75%. We identified five subclassifications of liver cyst infection according to cyst phenotypes and patient immune status and consensus on episode definitions (new, persistent, and recurrent) and criteria for treatment success or failure was reached. The experts agreed that fever and elevated C-reactive protein are pivotal decision-making items for initiating and evaluating the management of liver cyst infections. Consensus was reached on 26 management statements for patients with liver cyst infections across multiple clinical scenarios, including two treatment algorithms, which were merged into one after comments. We provide a clinical decision framework for physicians managing patients with liver cyst infections. This framework will facilitate uniformity in the management of liver cyst infections and can constitute the basis for the development of future guidelines., Competing Interests: Declaration of interests JH has received a grant from Deutsche Forschungsgemeinschaft—German Research Foundation. JC has received support from Secretaria d'Universitats i Recerca del Departament d'Economia i Coneixement (Agency for Management of University and Research Grants 2021; SGR 01331), Instituto Carlos III (PI22/01234) co-funded by the EU; a research grant by Asociación Española Estudio del Hígado (2022–23); and consulting fees, honoraria, and support for travel or attending meetings from Astellas, Chiesi, and Novartis. MS has received a grant from the Dutch Kidney Foundation (19OK002 and 23OK1044). MCH received a research grant from Camarus Pharmaceuticals. Hôpital Beaujon, Clichy, France, received, on behalf of MR, consulting fees from Quantum Surgical. MR has received honoraria from Guerbet, Angiodynamics, AstraZeneca, General Electric, Terumo, and Servier. VV has received consulting fees from Guerbet; honoraria from Canon Medical, GE Healthcare, Roche, and Sirtex; payment for expert testimony from Bayer, Guerbet, Sirtex, Boston Scientific, and Quantum Surgical; support for attending meetings or travel from Canon Medical, GE Healthcare, Roche, and Sirtex; and is Scientific Director of European School of Radiology without financial compensation. PS has received grants from Arrowhead, Grifols, CSL Behring, Vertex, and Dicerna; consulting fees from Biomarin, Intellia, Dicerna, NovoNordisk, GSK, Ono, and Takeda; honoraria from Advanz, Sanofi, CSL Behring, Grifols, and Sobi; support for attending meetings or travel from CSL Behring, Takeda, and Biogen; participates on data and safety monitoring boards for Albireo, Dicerna, Takeda, Biomarin, Intellia, and Sobi; has a leadership role in Alpha1 Global and Alpha1-Deutschland; and received materials from Takeda. RTa received grants from Chronix Biomedical/Oncocyte; consulting fees from MSD (2022), Tiefenbacher AEG (2022), Chiesi (2023), Pierre Fabre (2023), and Chronix Biomedical/Oncocyte (2023); speaker fees from Orphalan, Biotest, Alexion, and Chiesi; is co-inventor of a patent of Hannover Medical School, Hanover, Germany (autoantibodies tests against HIP1R to diagnose autoimmunhepatitis in adults and children; European patent number 18789434.0); and has received provision of consumables from Innova and Euroimmun. RTo is President-elect of European Renal Association. TJGG received grants from the Dutch Digestive Foundation and Gilead for the development of mylivercoach and received travel support from AbbVie to attend International Liver Congress 2022. VC received honoraria from Ipseon and Albireo. On behalf of JPHD, Radboudumc received a research grant from AbbVie. JPHD acts as a board member of the European Reference Network RARE-Liver and principal investigator of the POSITANO study by Camarus. MAL received grants from the Dutch Digestive Foundation, Vaillant fonds, and NVGE Gastrostart. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: 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., Methods: 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., Results: 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., Conclusion: 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., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: To evaluate the results of isolated liver and combined liver and kidney transplantation in a retrospective series of 32 patients with hepatorenal liver and kidney disease., Materials and Methods: A retrospective observational study that enrolled patients with polycystic liver disease (PLD) and polycystic liver and kidney disease (PLKD) who were evaluated for transplantation between January 1999 and December 2019 at Hospital Clínic de Barcelona [Clinical Hospital of Barcelona]., Results: We included a total of 53 patients enrolled, 32 (60.3%) had indication for transplantation, of which 12 received a single liver transplant and 20 received a double liver and kidney transplant. The mean age was 52 years and 83.9% of the recipients were women. The main indication for liver transplantation was disabling symptomatic hepatomegaly (93.5%). Among the postoperative complications, in the combined liver and kidney transplant group, hepatic artery thrombosis in one case and renal artery thrombosis in other were detected. In both groups there was one case of inferior vena cava lesion. Three patients presented acute cellular rejection responding to corticosteroids and one presented humoral rejection which was treated with plasmapheresis. During the follow-up period of 80 (27-121) months, the liver transplant survival rate was 100% and the kidney transplant survival rate was 90%. Two patients in the combined liver and kidney transplant group died (one due to cardiovascular causes and the other due to intestinal adenocarcinoma)., Conclusions: Isolated liver transplantation or combined liver and kidney transplantation in selected patients with polycystic disease yields excellent results, with few complications, very good transplant survival and excellent patient survival (93.8%)., (Copyright © 2021 Elsevier España, S.L.U. All rights reserved.)

Purpose of Review: It is our opinion that there is an unmet need in hepatology for a minimally or noninvasive test of liver function and physiology. Quantitative liver function tests define the severity and prognosis of liver disease by measuring the clearance of substrates whose uptake or metabolism is dependent upon liver perfusion or hepatocyte function. Substrates with high-affinity hepatic transporters exhibit high 'first-pass' hepatic extraction and their clearance measures hepatic perfusion. In contrast, substrates metabolized by the liver have low first-pass extraction and their clearance measures specific drug metabolizing pathways., Recent Findings: We highlight one quantitative liver function test, the dual cholate test, and introduce the concept of a disease severity index linked to clinical outcome that quantifies the simultaneous processes of hepatocyte uptake, clearance from the systemic circulation, clearance from the portal circulation, and portal-systemic shunting., Summary: It is our opinion that dual cholate is a relevant test for defining disease severity, monitoring the natural course of disease progression, and quantifying the response to therapy.

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 alpha-actin content, as well as decreased pro-collagen-alpha1(I) and transforming growth factor-beta1 gene expression. Bradykinin infusion reduced hepatocellular apoptosis induced by anti-Fas-receptor antibody. HSCs responded to bradykinin with intracellular calcium mobilization. Bradykinin reduced procollagen-alpha1(I) and transforming growth factor-beta1 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.

Obesity and insulin resistance accelerate the progression of fibrosis during chronic liver disease. Resistin antagonizes insulin action in rodents, but its role in humans is still controversial. The aims of this study were to investigate resistin expression in human liver and to evaluate whether resistin may affect the biology of activated human hepatic stellate cells (HSCs), key modulators of hepatic fibrogenesis. Resistin gene expression was low in normal human liver but was increased in conditions of severe fibrosis. Up-regulation of resistin during chronic liver damage was confirmed by immunohistochemistry. In a group of patients with alcoholic hepatitis, resistin expression correlated with inflammation and fibrosis, suggesting a possible action on HSCs. Exposure of cultured HSCs to recombinant resistin resulted in increased expression of the proinflammatory chemokines monocyte chemoattractant protein-1 and interleukin-8, through activation of nuclear factor (NF)-kappaB. Resistin induced a rapid increase in intracellular calcium concentration, mainly through calcium release from intracellular inositol triphosphate-sensitive pools. The intracellular calcium chelator BAPTA-AM blocked resistin-induced NF-kappaB activation and monocyte chemoattractant protein-1 expression. In conclusion, this study shows a role for resistin as an intrahepatic cytokine exerting proinflammatory actions in HSCs, via a Ca2+/NF-kappaB-dependent pathway and suggests involvement of this adipokine in the pathophysiology of liver fibrosis.

Background: Activated hepatic stellate cells (HSC) and other fibrogenic cell types are frequently found around hepatocellular carcinoma. It is unknown whether hepatocarcinoma cells regulate the biological functions of HSC. Aims: This study aimed to investigate the paracrine effects of hepatocarcinoma cells on human HSC using a co-culture system. Methods: Huh7 or HepG2 cells, human hepatocarcinoma cell lines, were co-cultured with primary human HSC. Intracellular calcium mobilization, proliferation, migration, expression of pro-angiogenic and fibrogenic genes, smooth muscle α-actin (α-SMA) protein expression, inflammatory properties (nuclear factor kappa B activation and interleukin 8 secretion) and intracellular signalling pathways (AKT and ERK) were analysed in HSC. Results: Culture of HSC with Huh7 cells for 24 h stimulated HSC proliferation, migration and expression of pro-angiogenic genes. The migration effect was corroborated with HepG2 cells. The effects of Huh7 cells on cell proliferation and migration were mediated mainly by PI3K/AKT activation. Moreover, Huh7 cells reduced the expression of genes involved in fibrogenesis, while they did not modify the inflammatory properties of HSC. The expression of α-SMA was induced by Huh7 cells. Because hepatitis C virus (HCV) infection is a major cause of hepatocarcinoma, we next investigated whether these effects are regulated by the expression of HCV in hepatocarcinoma cells. Expression of a subgenomic replicon expressing HCV nonstructural proteins (NS3–NS5) in Huh7 cells did not affect paracrine actions in HSC (cell proliferation and migration). Conclusions: These results suggested that there is a cross-talk between hepatocarcinoma cells and HSC. Activated HSC may be stimulated by cancer cells to accumulate and express angiogenic genes. [ABSTRACT FROM AUTHOR]

See Article on Page 1011 [ABSTRACT FROM AUTHOR]

Angiotensin II promotes liver fibrogenesis by stimulating nonphagocytic NADPH oxidase (NOX)-induced oxidative stress. Angiotensin II type 1 (AT1) receptor blockers attenuate experimental liver fibrosis, yet their effects in human liver fibrosis are unknown. We investigated the effects of losartan on hepatic expression of fibrogenic, inflammatory, and NOX genes in patients with chronic hepatitis C (CHC). Fourteen patients with CHC and liver fibrosis received oral losartan (50 mg/ day) for 18 mo. Liver biopsies were performed at baseline and after treatment. The degree of inflammation and fibrosis was evaluated by histological analysis (METAVIR). Collagen content was measured by morphometric quantification of Sirius red staining. Overall collagen content and fibrosis stage remained stable in the whole series, yet the fibrosis stage decreased in seven patients. Inflammatory activity improved in seven patients. The effect of losartan on hepatic expression of 31 profibrogenic and inflammatory genes and components of the NOX complex was assessed by quantitative PCR. Losartan treatment was associated with a significant decrease in the expression of several profibrogenic and NOX genes including procollagen α1(I) and α1 (IV), urokinase-type plasminogen activator, metalloproteinase type 2, NOX activator I (NOXA1) and organizer I (NOXO1), and RacI. Losartan was well tolerated in all patients and was effective in attenuating the activity of the systemic renin-angiotensin system. No effects on serum liver tests or viral load were observed. We conclude that prolonged administration of losartan, an oral AT1 receptor blocker, is associated with downregulation of NOX components and fibrogenic genes in patients with CHC. Controlled studies are warranted to assess the effect of AT1 receptor blockers in chronic liver injury. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Prognostic stratification of patients with alcoholic hepatitis (AH) may improve the clinical management and facilitate clinical trials. We aimed at developing a scoring system capable of providing prognostic stratification of patients with AH. METHODS: Patients with biopsy-proven AH were prospectively included between 2000 and 2006. The biochemical, clinical, portal hemodynamic and histological parameters were evaluated. A Cox regression model was used for univariate and multivariate analyses. A predictive score was built using variables obtained at admission identified in the multivariate analysis. The resulting score was validated in an independent prospective cohort. RESULTS: In total, 103 patients with biopsy-proven AH were included in the study cohort. Age, serum bilirubin, serum creatinine, and international normalized ratio (INR) independently predicted 90-day mortality. We generated the Age, serum Bilirubin, INR, and serum Creatinine (ABIC) score: (age × 0.1) + (serum bilirubin × 0.08) + (serum creatinine × 0.3) + (INR × 0.8). The area under the curve (AUC) was 0.82. Using the Kaplan-Meier analysis with the cutoff values of 6.71 and 9.0, we identified patients with low, intermediate, and high risk of death at 90 days (100%, 70%, and 25% of survival rate, respectively). Using the same cutoff values, the ABIC score also stratified patients according to their risk of death at 1 yr. These results were validated by a confirmatory cohort (N = 80). CONCLUSIONS: The ABIC score is a new tool that allows the stratification of risk of death in patients with AH at 90 days and 1 yr. This score can help improve the management of these patients and also help to perform clinical trials. [ABSTRACT FROM AUTHOR]

Catecholamines participate in the pathogenesis of portal hypertension and liver fibrosis through α1-adrenoceptors. However, the underlying cellular and molecular mechanisms are largely unknown. Here, we investigated the effects of norepinephrine (NE) on human hepatic stellate cells (HSC), which exert vasoactive, inflammatory, and fibrogenic actions in the injured liver. Adrenoceptor expression was assessed in human HSC by RT-PCR and immunocytochemistry. Intracellular Ca2+ concentration ([Ca2+]i) was studied in fura-2-loaded cells. Cell contraction was studied by assessing wrinkle formation and myosin light chain II (MLC II) phosphorylation. Cell proliferation and collagen-α1(I) expression were assessed by ³H]thymidine incorporation and quantitative PCR, respectively. NF-κB activation was assessed by luciferase reporter gene and p65 nuclear translocation. Chemokine secretion was assessed by ELISA. Normal human livers expressed α1A-adrenoceptors, which were markedly upregulated in livers with advanced fibrosis. Activated human HSC expressed α1A-adrenoceptors. NE induced multiple rapid [Ca2+]i oscillations (Ca2+ spikes). Prazosin (α1-blocker) completely prevented NE-induced Ca2+ spikes, whereas propranolol (nonspecific β-blocker) partially attenuated this effect. NE caused phosphorylation of MLC II and cell contraction. In contrast, NE did not affect cell proliferation or collagen-α1(I) expression. Importantly, NE stimulated the secretion of inflammatory chemokines (RANTES and interleukin-8) in a dose-dependent manner. Prazosin blocked NE-induced chemokine secretion. NE stimulated NF-κB activation. BAY 11-7082, a specific NF-κB inhibitor, blocked NE-induced chemokine secretion. We conclude that NE stimulates NF-κB and induces cell contraction and proinflammatory effects in human HSC. Catecholamines may participate in the pathogenesis of portal hypertension and liver fibrosis by targeting HSC. [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]