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Pollutants are increasingly being evaluated as possible contributors to the progression of liver damage in metabolic dysfunction-associated steatotic liver disease (MASLD). Recently, we published a case-control study showing that patients with MASLD-related advanced chronic liver disease (ACLD) and/or hepatocellular carcinoma (HCC) were more likely to report workplace toxicant exposure compared to those with uncomplicated MASLD. Consequently, an extension of the accrual and a transition to a multicenter study were decided. To provide updated evidence following the first extension of the cohort from our original study, which aimed to assess the prevalence of self-reported occupational exposure to toxicants in patients with MASLD. After the extension, this hospital-based prospective pilot study include 224 patients with MASLD. Data on workplace toxicant exposure were collected systematically using a structured questionnaire. Subsequently, patients with ACLD and/or HCC (n = 65) were compared to controls (n = 159). Logistic regression analysis and propensity score models were used to investigate the associations between self-reported occupational exposure and ACLD and/or HCC. The updated data confirmed that patients with ACLD/HCC are more likely to report exposure to metals, halogenated refrigerants, paint/resins, and fuel emissions than the controls. Durations of 21-30 years and >30 years of occupational exposure to toxicants were also more frequently associated with ACLD/HCC, with odds ratios (ORs) of 2.42 (95% confidence interval [CI]: 1.11-4.94, p = 0.020) and 4.21 (95% CI: 2.36-7.53, p < 0.001), respectively. These associations were confirmed after corrections for demographics and other confounders. The extension of our cohort confirms that patients with MASLD complications are more likely to report workplace toxicant exposure than controls. A transition to a multicenter effort is underway. If confirmed, our results may help in developing prevention policies to reduce the risk of life-threatening diseases among exposed populations. [ABSTRACT FROM AUTHOR]

Different drugs became available for prescription for HCC patients in the last 5 years, paving the way for sequential treatments, up to the a third line. Unfortunately, not all patients starting a frontline systemic treatment will became eligible for further treatments, due to failing liver function or performance status (ECOG-PS). The proportion of such patients is ill-defined. Also, baseline factors associated with the eventual elegibility to further lines has not been explored. Retrospective analysis of the therapeutic sequences prescribed in our center in the 2008-2021 timelapse. To minimize bias, we divided the groups by historical availability of multiple systemic agents (2008-2017 vs 2018-2021). Patients were considered elegible for further lines in case of ECOG-PS≤2 and Child-Pugh≤B7) at the time of failure of the previous treatment. In the 2008-2017 timeframe, second-line options included clinical trials or metronomic capecitabine. This study included 333 patients (n=224 and n=109 in the older and most recent timeframe, respectively). The elegibility to second (51.0 vs 38.4%, p=0.040) and third (20.2 vs 9.8%, p=0.019) line treatments increased in the latest years, with different prescription patterns (Figure). Macrovascular invasion (OR 0.62, 95% CI 0.39-0.99), Child-Pugh B7(OR 0.05, 95% CI 0.16-0.98), and ECOG-PS>0 (OR 0.30, 95% CI 0.16-0.55) at the start of the frontine treatment decreased the likelyhood of being eligible for further lines. Similar results were found for the elegibility to third line treatments. Both regorafenib [15.0 months, HR 0.60(0.40-0.88)] and cabozantinib [12.8 months, HR 0.44(0.23-0.87)] increased the post-frontline survival compared to metronomic capecitabine (6.5 months). A relevant proportion of patients who started a frontline treatment after 2017 became eligible for further systemic treatments. ECOG-PS 0, Child-Pugh A, and absence of macrovascular invasion identified the patients who were most likely to receive multiple treatments. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The aim of our study was to explore the features of focal nodular hyperplasia (FNH) at Doppler ultrasonography, analyzing specifically the presence of intratumoral venous flow in patients with an established diagnosis of FNH. Previous studies showed that using a venous Doppler spectrum, intratumoral vessels are often depicted in hepatocellular adenoma (HCA) but less frequently in FNH. PATIENTS AND METHODS: Forty-five FNHs from thirty-three consecutive patients (26 female, 7 male; mean±SD age: 40±13) underwent color Doppler ultrasonography and spectral analysis according to a standardized protocol. FNH diagnosis was established by the presence of typical behavior at contrast-enhanced ultrasound (CEUS) associated with another imaging technique (contrast-enhanced computed tomography [ceCT] or contrast-enhanced magnetic resonance [ceMR]). A biopsy was performed when imaging was inconclusive. All data concerning Doppler analysis were reviewed by two more operators, blinded to the final diagnosis, and the interobserver agreement for the presence of venous Doppler signal was determined by Cohen's Kappa. RESULTS: Of the 33 patients, 24 had a single solitary focus, and 9 had multiple foci. Lesion diameter ranged between 1.2 and 8.9 cm (mean ± SD 3.2±1.6 cm). The central feeding artery with the typical arterial spectrum was detected in all 45 lesions, whereas the spoke-wheel sign was observed in 18 cases (40%). A venous Doppler signal was detected in 35 FNHs (77.8%), and in 60% of them, it was identified in the center of the lesion. CONCLUSIONS: Venous Doppler signal located in the center of the lesion suspected to be a hypervascular benign lesion cannot be considered a typical HCA feature since it has been detected in a high percentage of FNH cases. [ABSTRACT FROM AUTHOR]

Lenvatinib is indicated for the forefront treatment of advanced hepatocellular carcinoma (aHCC) but its use it is eventually limited by presence of esophagogastric varices (EGV) and bleeding-risk. This study aimed to assess prevalence and risk factors of EGV and bleeding in lenvatinib-treated patients with HCC. In this multicenter international retrospective study, cirrhotic patients treated with lenvatinib for aHCC with an upper-gastrointestinal endoscopy performed <6 months before treatment were enrolled. Primary endpoint: incidence and risk factors of EGV bleeding during treatment. Secondary endpoints: prevalence and risk factors for EGV and high-risk EGV (HR-EGV) at baseline. 535 patients were enrolled [median age 72 years, 78% male, 63% viral aetiology, 89% Child-Pugh-A, 16% neoplastic portal vein thrombosis (nPVT), 56% BCLC-C]: 301 (56%) patients were EGV-free, 234 had EGV (44%) and 70 (30%) HR-EGV. Presence of EGV and of HR-EGV were independently associated with Child-Pugh-B (OR 2.12; 95%CI 1.08-4.17, p=0.03), nPVT (OR 2.54; 95%CI 1.40-4.61, p=0.002) and platelets<150.000/uL (OR 2.47; 95%CI 1.35-4.50, p=0.003). During lenvatinib treatment, 17 patients bled from EGV, the 12-month cumulative incidence being 3%. The only independent predictor of bleeding was presence of HR-EGV (HR 6.94, 95% CI 2.23-21.57, p=0.001). Risk of EGV bleeding can be stratified according to Child-Pugh-B, presence of nPVT and platelets<150.000/uL into low (0/3 risk factors, 6-months cumulative incidence 0.77%), intermediate (1/3 risk factors, 6-months cumulative incidence 2.31%) and high (2/3 or 3/3 risk factors, 6-months cumulative incidence 7.40%). Among the 476 Child-Pugh-A patients, independent predictors of HR-EGV were nPVT (OR 2.53; 95%CI 1.24-5.16, p=0.008) and platelets<150.000/uL (OR 2.56; 95%CI 1.28-5.10, p=0.01). In HCC patients treated with lenvatinib, the risk of EGV bleeding is low but it increases in patients with HR-EGV at baseline. A risk stratification for HR-EGV can be applied according to liver reserve, platelet count and nPVT. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) can be treated with different treatment options, TACE is among the most effective options in patients at intermediate stage (BCLC B), however failure rate and its risk of liver function impairment are also well-known. Depending on local expertise patients belonging to BCLC-B stage are often treated with multiple loco-regional treatments even if unsuccessful rather than receive systemic therapy upfront. In this study we aimed to evaluate the impact of previous TACE on patients who received Sorafenib. Multicentric retrospective study involving patients who received Sorafenib between January 2010 and December 2018 in 6 different Italian hospitals. We included 668 patients from the ARPES database, 116 patients (17.6%) received more than two intraarterial treatments, 129 received only one treatment and 102 received 2 different TACE, while the remaining part of the population did not receive any TACE. We used a Cox-regression analysis to find predictors of survival. No changes in term of OS were found between patients who received >2 TACE (mOS 11.1 months) and patients who received two or less (mOS 12.4), a closer look to the curve shows how after the first 12 months there is a sustained separation between these groups. Thus we stratified our population according to response to sorafenib, median OS in Non-responder was not affected from the number of TACE they received, whereas in the Responder group patients who received ≤2 TACE had a significant prolonged median OS than patients who received ≥3 TACE (22.6 months vs 15.6 months, p=0.04). This was confirmed in the multivariate analysis where TACE was an independent predictor of mortality with an hazard ratio of 1,547 (p= 0,016). This study demonstrates how having received more than two TACE is an independent risk factor for mortality in patients who respond to Sorafenib. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) recurrence is common in patients treated with liver resection (LR). Salvage liver transplantation (LT) may be an option provided that a transplantable recurrence has occurred. We aimed to assess incidence and preoperative predictors of recurrence beyond Milan criteria (MC) in patients with small (≤ 5 cm) single HCC treated with first-line LR. Data of 512 patients with single HCC ≤5 cm treated with frontline LR were retrieved from the Italian Liver Cancer (ITA.LI.CA) database. Incidence and predictors of recurrence beyond MC was compared across two groups according to tumor diameter (HCC ≤3 cm vs. >3 cm). During a median follow-up of 4.2 years, the overall recurrence rate was 55.9%. Only 18.0% of patients had a first recurrence beyond MC (14.0% in the ≤3 cm group and 23.9% in the >3 group; p=0.005), while the overall recurrence rate beyond MC was 30.3% (25.1% and 38.0% patients in the ≤3 cm and >3 cm groups, respectively; p=0.002) (Figure). Compared to those with larger tumors, patients with HCC ≤3 cm had a longer recurrence-free survival (4.0 [95% CI 3.3-4.7] vs. 2.5 [95% CI 2.0-3.0] years; p=0.002) and overall survival (9.9 [95% CI 6.5-13.4] vs. 7.8 [95% CI 5.7-9.9] years; p=0.008). HCC size and alpha-fetoprotein (AFP) level at the time of LR were independent predictors of recurrence beyond MC. A subanalysis in patients with "ab initio" potentially transplantable HCC confirmed these results. Despite the high recurrence rate, LR for single HCC ≤ 5 cm offers excellent long-term survival. Recurrence beyond MC is predicted by HCC size and AFP levels. Referral for salvage LT should be immediate at the first HCC recurrence, but high-risk patients (HCC >3 cm and high AFP) could be considered for frontline LT or listed for transplantation even before recurrence. [ABSTRACT FROM AUTHOR]

Atezolizumab+bevacizumab improves survival of patients with advanced Hepatocarcinoma (HCC) in comparison to Sorafenib. No biomarker predicts responders from non-responders to atezolizumab+bevacizumab or patients who benefit from this combination instead of TKIs. To identify early on treatment predictive biomarkers, we investigated whether baseline and early on treatment variation of CD8+, PD1+, PD-L1+, CD8+PD1+, CD8+PDL1+ peripheral lymphocytes might offer a non-invasive, cheap and feasible assay. Methods A prospective cohort of 31 patients treated with atezolizumab+bevacizumab and a control prospective cohort of 15 patients treated with sorafenib or lenvatinib were subjected to repeated blood tests, at baseline and during the course of treatments. At first imaging re-evaluation, 11 patients receiving atezolizumab+bevacizumab showed objective response, 13 stable disease, accounting for the responder group, while 7 patients displayed tumor progression, corresponding to primary non-response. Baseline and early on treatment variation of CD8+, PD1+, PD-L1+, CD8+PD1+, CD8+PDL1+ peripheral lymphocytes were tested by cytofluorimetric analysis and compared in responders and non-responders. Results Baseline CD8+ and CD8+PDL1+ peripheral lymphocytes were lower in responders versus non-responders (mean±SD CD8+: 68±30 vs 95±5; T-test, p<0.0001; mean ±SD CD8+PD-L1+: 77± 9.4 vs 82±4.6; T-test: p=0.004 respectively). Dynamic changes in CD8+PD1+ lymphocytes assessed at 3-weeks, before the second drug infusion, were the most informative test: 22 of 24 responders displayed a rise of CD8+PD1+ peripheral lymphocytes with a positive mean fold change of 4.63 (±5.5 SD). Conversely, 6 of 7 non-responders displayed a negative mean fold change of 0.89 (±0.84 SD) of CD8+PD1+ lymphocytes. These changes were restricted to patients treated with atezolizumab+bevacizumab, while they were not documented in TKI patients, irrespective of the response. Conclusion. Early changes in circulating PD1+CD8+ lymphocytes predict the type of response to atezolizumab+bevacizumab and encourage evaluating this minimally invasive, cheap, easy and repeatable test in a larger cohort of patients to confirm its informativeness in this setting. [ABSTRACT FROM AUTHOR]

Even though hepatocellular carcinoma (HCC) is mainly characterized by a locoregional progression, the prognosis of some patients is burdened by the development of metastases. We aimed to identify risk factors of extrahepatic progression (EHP) in HCC patients undergoing transarterial chemoembolization (TACE). From the ITA.LI.CA database, 890 patients treated with first-line TACE were retrieved. Incidence and predictors of EHP were compared between patients with tumor burden score (TBS) ≤4.2 and >4.2 (cut-off determined by ROC curve analysis). Validation (n=442) and derivation (n=448) cohorts were used to create a predictive model for EHP after TACE (EHPaT score). During a median follow-up of 28.6 months (IQR, 14.0-50.0), 76.2% of patients showed progression after treatment. In the TBS >4.2 group, a significantly higher proportion of patients demonstrated extrahepatic spread at first progression (11.2% vs. 4.3%; p<0.001) and overall during follow-up (35.4% vs. 19.3%; p<0.001). The most common sites of metastases were lymph nodes and lung. Patients with TBS ≤4.2 had a significantly longer progression free survival (11.6 vs. 9.0 months; p<0.001) and overall survival (54.1 vs. 31.1 months; p<0.001). Independent predictors of EHP were TBS, radiological response and alpha-fetoprotein (AFP) levels. The Cox Score for the prediction of EHP (incorporating TBS, AFP, radiological response and etiology) yielded an AUROC of 0.743 (95% CI 0.656-0.830) at first progression and an AUROC of 0.701 (95% CI 0.645-0.757) overall during the follow-up in the derivation cohort. Similar results were obtained in the validation cohort. Although HCC is characterized by predominantly locoregional progression, identifying risk factors for metastases development is relevant for prognostic prediction and treatment allocation. Tumor burden, together with radiological response and AFP, has to be considered in the prediction of EHP after TACE. The EHPaT score revealed to be a useful tool in predicting of metastases development. [ABSTRACT FROM AUTHOR]

The epidemiology of hepatocellular carcinoma (HCC) in industrialized countries is increasingly related to metabolic syndrome and non-alcoholic steatohepatitis (NASH). Despite the approval of molecular targeted drugs, including immune checkpoint inhibitors, the lack of circulating biomarkers still impacts patient responsiveness to treatments, as evidenced by reduced sensitivity to immunotherapy in NASH-associated HCCs. In this context, there is an urgent need to identify new biomarkers to help stratify patients according to personalized therapeutic regimens. The aims of this work are to study metabolic mechanisms underlying miR-494 overexpression in HCC preclinical models and to assess miR-494 as a circulating biomarker associated with metabolic features and sorafenib resistance in HCC patients. We identified miR-494 metabolic targets through bioinformatics analysis. QPCR analysis of glucose 6-phosphatase catalytic subunit (G6pc) was performed in preclinical models and HCC patients. Functional and metabolic analyses assessed G6pc targeting and miR-494 involvement in metabolic change, mitochondrial dysfunction, and ROS production in HCC cells. Live-imaging analysis elucidated the involvement of miR-494/G6pc axis in cell proliferation of HCC cells under stressful conditions. Circulating miR-494 levels were assayed in sorafenib-treated HCC patients and DEN-HCC rats. We demonstrated that miR-494 promote a metabolic shift of HCC cells towards a glycolytic phenotype trough G6pc targeting. The miR-494/G6pc axis exhibits an active role in the metabolic plasticity of tumor cells promoted by glycogen and lipid droplets accumulation to be used under detrimental conditions. High miR-494 serum levels are predictive of sorafenib resistance in a small cohort of HCCs and identify patients with metabolic derangements. AntagomiR-494-based strategies showed a synergic effect with metabolic inhibitors and sorafenib in HCC cells. Our preliminary data suggest miR-494 as a possible target for combined treatments and a promising biomarker for the identification of patients with dysmetabolic HCCs who may be refractory to currently approved treatments. [ABSTRACT FROM AUTHOR]

Extrahepatic spread is a well-known negative prognostic factor in patients with advanced hepatocellular carcinoma (HCC). The prognostic role of different metastatic sites and their response rate to systemic treatment is still being debated. We considered 237 metastatic HCC patients treated with sorafenib as first-line therapy in five different Italian centers from 2010 to 2020. The most common metastatic sites were lymph nodes, lungs, bone and adrenal glands. In survival analysis, the presence of dissemination to lymph nodes (OS 7.1 vs 10.2 months; p = 0.007) and lungs (OS 5.9 vs 10.2 months; p <0.001) were significantly related to a worse survival. In the subgroup analysis of patients with a single metastatic site, this prognostic relationship remained statistically significant. Palliative radiation therapy on bone metastases significantly prolonged the survival in this cohort of patients (OS 19.4 vs 6.5 months; p <0.001). Furthermore, patients with lymph node and lung metastases had a worse disease control rate (39.4% and 30.5%, respectively) and a shorter radiological progression-free survival (3.4 and 3.1 months, respectively). Different site of metastases has a prognostic impact on survival; in particular, lymph node and lung metastases have worse prognosis and treatment response rate. [ABSTRACT FROM AUTHOR]

In phase II and III trials, Bulevirtide (BLV) significantly reduced HDV-RNA and aminotransferase (ALT) levels in patients with chronic hepatitis Delta virus (HDV) infection, however, data on efficacy and safety beyond week 48 in real-world settings are limited. HDV patients with compensated cirrhosis treated with BLV 2 mg monotherapy up to 72 weeks were retrospectively evaluated in this multicenter Italian real-life study. Clinical and virological variables were collected at baseline, weeks 4, 8 and every 8 weeks thereafter. 93 patients were included: median age 52 years, 52% males, liver stiffness measurement (LSM) 17.4 kPa, 55% with varices, 22% with previous ascites, 53% IFN-experienced, 97% under nucleos(t)ide (NUC) treatment. Median ALT levels were 79 U/L, albumin 3.9 g/dL, platelets 70 x 103/mm3, HDV RNA 5.2 Log IU/mL, CPT score A in all patients. A virological response (undetectable HDV RNA or ≥2 Log decline vs. baseline) was achieved by 67%, 77% and 75% of patients at weeks 24, 48 and 72, respectively, HDV RNA becoming undetectable in 10%, 16% and 38%. At the same timepoints, ALT normalization was observed in 67%, 67% and 81% of the patients while a combined response (virological + biochemical) was achieved by 45%, 56% and 63%. Besides ALT, significant on-treatment declines were also observed for AST, GGT, IgG (p<0.001 vs. baseline), while albumin values increased (p=0.02). Platelets, LSM and HBsAg levels remained unchanged. BLV was well tolerated, no patient discontinued treatment for adverse events, an asymptomatic increase in bile acids occurred in all patients. During BLV treatment, liver decompensation occurred in one patient, de-novo HCC in two, three underwent liver transplantation and one died for BLV-unrelated causes. Extension of BLV monotherapy to 72 weeks is safe and effective in patients with HDV-related compensated cirrhosis. Virological and clinical responses increase overtime. [ABSTRACT FROM AUTHOR]

High-fidelity transient simulations of turbulent flows usually require highly resolved grids, leading to unacceptable large computational wall times even on large supercomputers. In an attempt to address this limitation, a hybrid Large-Eddy/Reynolds-Averaged scale-adaptive turbulence model has been applied together with a Volume-Of-Fluid (VOF) solver in OpenFOAM to simulate cavitation in the injector nozzle and primary fuel atomization during the opening event of a GDI gasoline-injector for automotive applications. A dynamic mesh strategy based on topological changing grids has been used to handle the moving geometry. In addition, algorithmic developments are presented to improve parallel performance on modern supercomputers. The outcome of the scalability tests are reported together with results from simulations on the Continental XL3.0 6-hole injector performed at the Argonne National Laboratory. [ABSTRACT FROM AUTHOR]

Summary: Transarterial chemoembolization (TACE) is considered the gold standard for treating intermediate-stage hepatocellular carcinoma (HCC). However, intermediate-stage HCC includes a heterogeneous population of patients with varying tumour burdens, liver function (Child-Pugh A or B) and disease aetiology. This suggests that not all patients with intermediate-stage HCC will derive similar benefit from TACE, and that some patients may benefit from other treatment options. Results of an extensive literature review into the treatment of unresectable HCC with TACE were combined with our own clinical experience to identify factors that may predict survival after TACE. We also report contraindications to TACE and propose a treatment algorithm for the repetition of TACE. In addition, we have constructed a number of expert opinions that may be used as a guide to help physicians make treatment decisions for their patients with intermediate-stage HCC. The data included in the literature review related almost exclusively to conventional TACE, rather than to TACE with drug-eluting beads. Therefore, the findings and conclusions of the literature review are only applicable to the treatment of HCC with conventional TACE. Treating physicians may want to consider other treatment options for patients with intermediate-stage HCC who are not suitable for or do not respond to TACE. By distinguishing those patients who represent good candidates for TACE from those where little or no benefit might be expected, it may be possible to make better use of current treatment options and improve outcomes for patients. [ABSTRACT FROM AUTHOR]

Abstract: Background: Progression of recurrent hepatitis C is accelerated in liver transplant recipients, leading to special need of non-invasive validated methods to estimate liver fibrosis. Aim: To assess the efficacy of liver stiffness measurement by transient elastography (Fibroscan) and serum parameters in predicting fibrosis stage in HCV-infected transplant recipients. Methods: The correlation between liver fibrosis, assessed at liver histology on bioptic specimens obtained for clinical indications, and stiffness or clinico-serological indexes (Benlloch, APRI, Forns, Fibrotest and Doppler resistance index), was investigated in transplant recipients with recurrence of HCV chronic hepatitis. A total of 56 patients (of which 36 with all clinico-serological indexes), presenting with the following METAVIR fibrosis stage F1=38, F2=9, F3=8, F4=1, were enrolled in the study population. Differences between fibrosis stages were calculated by non-parametric analysis. The best cut-off for identifying significant fibrosis (F2–F4) was assessed by ROC curve analysis. Results: Stiffness (median and range) was 7.7KPa (range 4.2–13.9) in F1 and 17.0KPa (range 6.8–36.3) in ≥F2 (p <0.001). A stiffness cut-off of 10.1KPa revealed 94% Sensitivity, 89% Specificity, 81% PPV and 94% NPV in differentiating F1 from F2–F4. The area under the receiver operator curve in the assessment of fibrosis was significantly higher for Liver stiffness (AUROC 0.943) than for any of the other non-invasive indexes (AUROCs ranging 0.591–0.815). Conclusions: Transient elastography of the liver provides good accuracy in identifying patients with significant fibrosis and performs better than non-invasive indexes based on clinico-serological parameters in transplant recipients. [Copyright &y& Elsevier]

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Abstract: The introduction of second-generation microbubble ultrasound contrast agents and the development of contrast specific ultrasound techniques have improved the ability of contrast enhanced ultrasound in detecting and characterising liver lesions, offering new perspectives for its exploitation in clinical hepatology. Indeed, several studies have demonstrated a high diagnostic accuracy in focal lesion characterisation (85–96%) in patients either with or without underlying chronic liver disease. This review article describes the basic principles of contrast enhanced ultrasound, defines the different vascular features of benign and malignant liver lesions, and assesses its clinical impact in different clinical scenarios, according to the guidelines of the European Federation of Societies for Ultrasound in Medicine and Biology, contrast enhanced ultrasound enables the characterisation of focal liver lesions, regardless of the presence or absence of underlying chronic liver disease. Contrast enhanced ultrasound is also useful in staging and follow-up of cancer patients and in monitoring local ablative treatment. Contrast enhanced ultrasound is expected to be considerably increased and replace many computed tomography and magnetic resonance imaging examinations in near future, according to the European Federation of Societies for Ultrasound in Medicine and Biology guidelines. Therefore, it is necessary to take measures in order to meet the demand for an increasing number of these procedures. [Copyright &y& Elsevier]

Abstract: Background: Since the incidence of myocardial infarction and other cardiovascular ischaemic events is highest in early morning, on account of a relative hypercoagulable state occurring in this time period, an attempt was made to test whether reperfusion of the hepatic artery at this time of the day, at liver transplantation, produces an increased risk of early thrombosis. Methods: The records of 255 consecutive patients receiving a first transplant for chronic liver disease were retrospectively analysed. As possible risk factors, for early post-operative thrombosis (<30 days from transplantation), several medical and surgical parameters were taken into consideration. Arterial reperfusion was considered to have taken place at a time of high coagulability when occurred between 6.00a.m. and 10.00a.m. on the basis of previous reports. Results: Logistic regression identified donor age (OR for age >60: P =0.017), bench reconstruction of the artery (OR: 5.06, P =0.013) and time of high coagulability at reperfusion (OR 2.93, P =0.087), as independently associated with early hepatic artery thrombosis. Conclusions: The present findings identified three independent predictors of early hepatic thrombosis, warranting stricter post-surgical follow-up of patients presenting such conditions. Interestingly, these factors are consistent with arterial reperfusion in the early morning being associated with an increased risk of early hepatic artery thrombosis, suggesting relative coagulative imbalances to provide a contribution in the pathogenesis of this severe complication of liver transplantation. [Copyright &y& Elsevier]