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Metabolic dysfunction-associated steatotic liver disease (MASLD) has been traditionally associated with insulin resistance and obesity. Recently, pollutants have been shown to contribute to the development of MASLD. Given the global burden of MASLD, understanding whether pollutants are merely associated with steatosis or contribute to its progression to advanced chronic liver disease (ACLD) and hepatocellular carcinoma (HCC) is critical. Workers exposed to occupational toxicants represent an ideal population for assessing the potentially hazardous consequences of professional exposure. Confirming a link between occupational exposure and ACLD/HCC may not only provide further elements in understanding MASLD, but also contribute to preventive strategies for exposed workers. This study aimed to assess the prevalence of self-reported occupational exposure to toxicants in patients with MASLD. This hospital-based prospective pilot study included 201 patients with MASLD. Data on workplace toxicant exposure were collected systematically using a structured questionnaire. Subsequently, patients with ACLD and/or HCC (n = 55) were compared to controls (n = 146). Logistic regression analysis and propensity score models were used to investigate the associations between self-reported occupational exposure and ACLD and/or HCC. Patients with ACLD/HCC reported exposure to metals, halogenated refrigerants, pain/resins, and fuel emissions more often than the controls. After controlling for confounders, durations of 21–30 years and >30 years of occupational exposure to toxicants showed odds ratios (ORs) of 2.31 (95 % confidence interval [CI]: 1.09–4.88, p = 0.029) and 4.47 (95 % CI: 2.57–7.78, p <0.001), respectively. In this pilot study, patients with MASLD complications were more likely to report workplace toxicant exposure. Our results warrant future multicentre confirmatory studies, as implementing prevention policies may reduce the risk of life-threatening diseases among exposed populations. [ABSTRACT FROM AUTHOR]

Worldwide, hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death. The remarkable improvements in treating HCC achieved in the last years have increased the complexity of its management. Following the need to have updated guidelines on the multidisciplinary treatment management of HCC, the Italian Scientific Societies involved in the management of this cancer have promoted the drafting of a new dedicated document. This document was drawn up according to the GRADE methodology needed to produce guidelines based on evidence. Here is presented the second part of guidelines, focused on the multidisciplinary tumor board of experts and non-surgical treatments of HCC. [ABSTRACT FROM AUTHOR]

Artificial Intelligence (AI) has recently been shown as an excellent tool for the study of the liver; however, many obstacles still have to be overcome for the digitalization of real-world hepatology. The authors present an overview of the current state of the art on the use of innovative technologies in different areas (big data, translational hepatology, imaging, and transplant setting). In clinical practice, physicians must integrate a vast array of data modalities (medical history, clinical data, laboratory tests, imaging, and pathology slides) to achieve a diagnostic or therapeutic decision. Unfortunately, machine learning and deep learning are still far from really supporting clinicians in real life. In fact, the accuracy of any technological support has no value in medicine without the support of clinicians. To make better use of new technologies, it is essential to improve clinicians' knowledge about them. To this end, the authors propose that collaborative networks for multidisciplinary approaches will improve the rapid implementation of AI systems for developing disease-customized AI-powered clinical decision support tools. The authors also discuss ethical, educational, and legal challenges that must be overcome to build robust bridges and deploy potentially effective AI in real-world clinical settings. [ABSTRACT FROM AUTHOR]

The integration of human and artificial intelligence (AI) in medicine has only recently begun but it has already become obvious that intelligent systems can dramatically improve the management of liver diseases. Big data made it possible to envisage transformative developments of the use of AI for diagnosing, predicting prognosis and treating liver diseases, but there is still a lot of work to do. If we want to achieve the 21st century digital revolution, there is an urgent need for specific national and international rules, and to adhere to bioethical parameters when collecting data. Avoiding misleading results is essential for the effective use of AI. A crucial question is whether it is possible to sustain, technically and morally, the process of integration between man and machine. We present a systematic review on the applications of AI to hepatology, highlighting the current challenges and crucial issues related to the use of such technologies. [ABSTRACT FROM AUTHOR]

In the latest years, antineoplastic immunotherapy revolutionised the therapeutic landscape in oncology. First shown to be effective in melanoma and non-small cell lung carcinoma, immune checkpoint inhibitors are now being tested for the treatment of hepatocellular carcinoma (HCC). Preliminary results have been particularly promising. As a consequence, an increasing number of clinical trials are underway. The role of the immune system in carcinogenesis (with particular reference to tumour escape immune mechanisms), as well as the current immunotherapy trials for HCC in its different clinical scenarios, are the subject of this review. In particular, we aim to provide fresh updates about these novel therapeutic agents which promise to shape the future therapeutic scenario of HCC. [ABSTRACT FROM AUTHOR]

Although non-randomized, this study provides high-quality data emphasizing the performance of non-enhanced MRI as a surveillance tool for patients with cirrhosis at high risk of developing HCC. Conversely, the study suffers from some methodological limitations, worth noting before jumping to the conclusion that non-enhanced MRI should be immediately implemented as a surveillance imaging tool for every patient at risk of HCC. In conclusion, non-enhanced MRI cannot be considered a standard modality for HCC surveillance for all patients at risk of HCC, but it has potential, especially as it appears to be almost as sensitive but more applicable than contrast-enhanced liver imaging. 15 M.V. Chan, S.J. McDonald, Y.Y. Ong, K. Mastrocostas, E. Ho, Y.R. Huo, HCC screening: assessment of an abbreviated non-contrast MRI protocol. [Extracted from the article]

Background and aims Whether Fibroscan thresholds can be immediately adopted for none, some or all other shear wave elastography techniques has not been tested. The aim of the present study was to test the concordance of the findings obtained from 7 of the most recent ultrasound elastography machines with respect to Fibroscan. Methods Sixteen hepatitis C virus-related patients with fibrosis ≥2 and having reliable results at Fibroscan were investigated in two intercostal spaces using 7 different elastography machines. Coefficients of both precision (an index of data dispersion) and accuracy (an index of bias correction factors expressing different magnitudes of changes in comparison to the reference) were calculated. Results Median stiffness values differed among the different machines as did coefficients of both precision (range 0.54–0.72) and accuracy (range 0.28–0.87). When the average of the measurements of two intercostal spaces was considered, coefficients of precision significantly increased with all machines (range 0.72–0.90) whereas of accuracy improved more scatteredly and by a smaller degree (range 0.40–0.99). Conclusions The present results showed only moderate concordance of the majority of elastography machines with the Fibroscan results, preventing the possibility of the immediate universal adoption of Fibroscan thresholds for defining liver fibrosis staging for all new machines. [ABSTRACT FROM AUTHOR]

Previous meta-analyses demonstrated the safety and efficacy of anticoagulation in the recanalization of portal vein thrombosis in patients with cirrhosis. Whether this benefit translates into improved survival is unknown. We conducted an individual patient data (IPD) meta-analysis to assess the effect of anticoagulation on all-cause mortality in patients with cirrhosis and portal vein thrombosis. In this IPD meta-analysis, we selected studies comparing anticoagulation vs. no treatment in patients with cirrhosis and portal vein thrombosis from PubMed, Embase, and Cochrane databases (until June 2020) (PROSPERO no.: CRD42020140026). IPD were subsequently requested from authors. The primary outcome – the effect of anticoagulation on all-cause mortality – was assessed by a one-step meta-analysis based on a competing-risk model with liver transplantation as the competing event. The model was adjusted for clinically relevant confounders. A multilevel mixed-effects logistic regression model was used to determine the effect of anticoagulation on recanalization. Individual data on 500 patients from five studies were included; 205 (41%) received anticoagulation and 295 did not. Anticoagulation reduced all-cause mortality (adjusted subdistribution hazard ratio 0.59; 95% CI 0.49–0.70), independently of thrombosis severity and recanalization. The effect of anticoagulation on all-cause mortality was consistent with a reduction in liver-related mortality. The recanalization rate was higher in the anticoagulation arm (adjusted odds ratio 3.45; 95% CI 2.22–5.36). The non-portal-hypertension-related bleeding rate was significantly greater in the anticoagulation group. Anticoagulation reduces all-cause mortality in patients with cirrhosis and portal vein thrombosis independently of recanalization, but at the expense of increasing non-portal hypertension-related bleeding. CRD42020140026. Anticoagulation is effective in promoting recanalization of portal vein thrombosis in patients with cirrhosis, but whether this benefit translates into improved survival is controversial. Our individual patient data meta-analysis based on a competing-risk model with liver transplantation as the competing event shows that anticoagulation reduces all-cause mortality in patients with cirrhosis and portal vein thrombosis independently of recanalization. According to our findings, portal vein thrombosis may identify a group of patients with cirrhosis that benefit from long-term anticoagulation. [Display omitted] • Anticoagulation appears to reduce all-cause mortality in patients with cirrhosis and portal vein thrombosis. • The beneficial effect of anticoagulation on survival is independent of thrombosis severity and recanalization. • Anticoagulation increases the rate of portal vein recanalization at the expense of increased non-portal hypertension-related bleeding. [ABSTRACT FROM AUTHOR]

Background No standard second-line treatments are available for hepatocellular carcinoma patients who fail sorafenib therapy. We assessed the safety and efficacy of metronomic capecitabine after first-line sorafenib failure. Methods Retrospective analysis of consecutive hepatocellular carcinoma patients receiving metronomic capecitabine between January 2012 and November 2014. The primary end-point was safety, secondary end-point was efficacy, including time-to-progression and overall survival. Results Twenty-six patients (80% Child–Pugh A, 80% Barcelona Clinic Liver Cancer stage C) received metronomic capecitabine (500 mg/bid). Median treatment duration was 3.2 months (range 0.6–31). Fourteen (53%) patients experienced at least one adverse event. The most frequent drug-related adverse events were bilirubin elevation (23%), fatigue (15%), anaemia (11%), lymphoedema (11%), and hand–foot syndrome (7.6%). Treatment was interrupted in 19 (73%) for disease progression, in 4 (15%) for liver deterioration, and in 1 (3.8%) for adverse event. Disease control was achieved in 6 (23%) patients. Median time-to-progression was 4 months (95% confidence interval 3.2–4.7). Median overall survival was 8 months (95% confidence interval 3.7–12.3). Conclusions Metronomic capecitabine was well tolerated in hepatocellular carcinoma patients who had been treated with sorafenib. Preliminary data show potential anti-tumour activity with long-lasting disease control in a subgroup of patients that warrants further evaluation in a phase III study. [ABSTRACT FROM AUTHOR]

Abstract: Background: Few data exist on real-life adherence to international guidelines for the treatment of hepatocellular carcinoma. We analysed the rate of adherence to American Association for the Study of Liver Diseases guidelines, to identify reasons for discrepancy with treatments performed in our centre. Methods: 227 consecutive cirrhotics with a first hepatocellular carcinoma diagnosis (2005–2010) were retrospectively evaluated and stratified based on Barcelona Clinic Liver Cancer system: 126 early, 50 intermediate, 40 advanced, and 11 end stage. Results: Early hepatocellular carcinomas were theoretically eligible for resection (n =27), liver transplantation (n =36), and percutaneous treatment (n =63). In practice, 15/27 (55.5%), 31/36 (86.1%), and 22/63 (34.9%) respectively were treated as recommended. Reasons for discrepancy were age/comorbidity, tumour location, ultrasound visibility, surgical contraindications. Transarterial chemoembolisation was performed in 25/126 early hepatocellular carcinomas (19.8%), resection in 11/63 early hepatocellular carcinomas eligible for percutaneous treatment (17.5%). Transarterial chemoembolisation was excluded in 16/50 intermediate hepatocellular carcinomas (32%). Resection or transarterial chemoembolisation was performed in 6/40 advanced hepatocellular carcinomas (15%). Conclusion: Overall, 60% of patients were treated according to American Association for the Study of Liver Diseases guidelines. Approximately 28% of hepatocellular carcinomas were “under-treated” and 7% treated more aggressively than recommended. Peculiarities of individual patients can lead the multidisciplinary team to personalise real-life treatments. [Copyright &y& Elsevier]

Abstract: This review illustrates the state of the art clinical applications and the future perspectives of ultrasound elastographic methods for the evaluation of chronic liver diseases, including the most widely used and validated technique, transient elastography, followed by shear wave elastography and strain imaging elastography. Liver ultrasound elastography allows the non-invasive evaluation of liver stiffness, providing information regarding the stage of fibrosis, comparable to liver biopsy which is still considered the gold standard; in this way, it can help physicians in managing patients, including the decision as to when to start antiviral treatment. The characterization of focal liver lesions and the prognostic role of the elastographic technique in the prediction of complications of cirrhosis are still under investigation. [Copyright &y& Elsevier]

Abstract: Background: Whether to prefer hepatic resection or radiofrequency ablation as first line therapy for hepatocellular carcinoma is a matter of debate. Aims: To compare outcomes of resection and ablation, in the treatment of early hepatocellular carcinoma, through a decision-making analysis. Methods: Data of 388 cirrhotic patients undergoing resection and of 207 undergoing radiofrequency ablation were reviewed. Two distinct regression models were devised and used to perform sensitivity and probabilistic analyses, to overcome biases of covariate distributions. Results: Actuarial survival curves showed no difference between resection and ablation (P =0.270) despite the fact that ablated patients were older, with worse liver function and smaller, unifocal tumours (P <0.05), suggesting a complex, non-linear relationship between clinical, tumoral variables and treatments. Sensitivity and probabilistic analyses suggested that the superiority of resection over ablation decreased at higher Model for-End stage Liver Disease scores, and that ablation provided better results for smaller tumours and higher Model for-End stage Liver Disease scores. In patients with 2–3 tumours up to 3cm, the two treatments produced opposite comparative results in relation to the Model for-End stage Liver Disease score. Conclusions: The superiority, or the equivalence, of resection and ablation depends on the non-linear relationship existing between treatment, tumour number, size and degree of liver dysfunction. [Copyright &y& Elsevier]

Abstract: Background: The frequency with which patients in Child-Pugh B having hepatocellular carcinoma are treated following the international guidelines according to the Barcelona Clinic Liver Cancer stages is unknown. Aims: To investigate treatment allocation for Child-Pugh B patients in different tumour stages, with particular interest in the intermediate stage. Methods: Patients were retrospectively identified from a consecutively collected series. Treatment was carried out primarily according to the guidelines. Results: Of 86 Child-Pugh B patients, 45 were Barcelona early stage, of which the Child-Pugh scores were 46.7% B7, 33.3% B8, 20.0% B9; 27 patients were intermediate stage (B7 59.3%, B8 37.0% and B9 3.7% respectively), 12 were advanced (41.7% B7, 25.0% B8 and 33.3% B9) and 2 were terminal (both B9). In the intermediate stage, transarterial chemoembolization (or ablation) was performed in 68.8% of the Child-Pugh B7 patients, 50% of the B8 patients and 0% of the B9 patients. Median survival of the intermediate patients was 8.0 months (9.0 in B7 vs. 6.0 in -B8/B9, P =0.048). Survival of the intermediate stage patients undergoing chemoembolisation was 22.0 months in Child-Pugh B7 and 6.0 in B8. Conclusions: Approximately half of the intermediate stage patients can undergo locoregional treatment with good survival when in the Child-Pugh B7. The Child-Pugh numeric score impacts survival, suggesting that this tumour stage be refined. [Copyright &y& Elsevier]

Keywords: CEUS; Number needed to diagnose; Cost-effectiveness; Metastases; Focal liver lesions; Tumor staging EN CEUS Number needed to diagnose Cost-effectiveness Metastases Focal liver lesions Tumor staging 272 273 2 12/30/20 20210201 NES 210201 See Article, pages 419-427 Contrast-enhanced ultrasound (CEUS) was introduced around 20 years ago and hepatological applications have been the mainstay of its use since then. Since the early works, CEUS has also been shown to detect liver metastases missed by radiologic techniques.[5] However, the fact that CEUS can detect some lesions missed by other radiological techniques does not confirm whether it is worth recommending in all or in specified categories of patients. Therefore, considering this patient population (T3/T4 tumor stage without definite liver metastasis at CT), the number of CEUS exams needed to detect 1 additional metastasis would be 24.5. [Extracted from the article]

Abstract: Background: Acoustic Radiation Force Impulse Elastography is a new method for non-invasive evaluation of liver fibrosis. Aim: To evaluate the impact of elevated alanine aminotransferase levels on liver stiffness assessment by Acoustic Radiation Force Impulse Elastography. Methods: A multicentre retrospective study including 1242 patients with chronic liver disease, who underwent liver biopsy and Acoustic Radiation Force Impulse. Transient Elastography was also performed in 512 patients. Results: The best Acoustic Radiation Force Impulse cut-off for predicting significant fibrosis was 1.29m/s in cases with normal alanine aminotransferase levels and 1.44m/s in patients with alanine aminotransferase levels>5× the upper limit of normal. The best cut-off for predicting liver cirrhosis were 1.59 and 1.75m/s, respectively. Acoustic Radiation Force Impulse cut-off for predicting significant fibrosis and cirrhosis were relatively similar in patients with normal alanine aminotransferase and in those with alanine aminotransferase levels between 1.1 and 5× the upper limit of normal: 1.29m/s vs. 1.36m/s and 1.59m/s vs. 1.57m/s, respectively. For predicting cirrhosis, the Transient Elastography cut-offs were significantly higher in patients with alanine aminotransferase levels between 1.1 and 5× the upper limit of normal compared to those with normal alanine aminotransferase: 12.3kPa vs. 9.1kPa. Conclusion: Liver stiffness values assessed by Acoustic Radiation Force Impulse and Transient Elastography are influenced by high aminotransferase levels. Transient Elastography was also influenced by moderately elevated aminotransferase levels. [Copyright &y& Elsevier]

Abstract: Patients with hepatocellular carcinoma should be managed with a multidisciplinary approach framed in a network where all the diagnostic techniques and therapeutic resources are available in order to provide the optimal level of care. Given this assumption, the Coordinating Committee of the Italian Association for the Study of the Liver nominated a panel of experts to elaborate practical recommendations for the multidisciplinary management of hepatocellular carcinoma aiming to provide: (1) homogeneous and efficacious diagnostic and staging work-up, and (2) the best treatment choice tailored to patient status and tumour stage at diagnosis. The 2010 updated American Association for the Study of Liver Disease Guidelines for hepatocellular carcinoma were selected as the reference document. For each management issue, the American Association for the Study of Liver Disease recommendations were briefly summarised and discussed, according to both the scientific evidence published after their release and the clinical expertise of the Italian centres taking care of these patients. The Italian Association for the Study of the Liver expert panel recommendations are finally reported. [Copyright &y& Elsevier]

Background & Aims: Both hepatic resection and radiofrequency ablation (RFA) are considered curative treatments for hepatocellular carcinoma (HCC), but their economic impact still remains not determined. Aim of the present study was to analyze the cost-effectiveness (CE) of these two strategies in early stage HCC (Milan criteria). Methods: As first step, a meta-analysis of the pertinent literature of the last decade was performed. Seventeen studies fulfilled the inclusion criteria: 3996 patients underwent resection and 4424 underwent RFA for early HCC. Data obtained from the meta-analysis were used to construct a Markov model. Costs were assessed from the health care provider perspective. A Monte Carlo probabilistic sensitivity analysis was used to estimate outcomes with distribution samples of 1000 patients for each treatment arm. Results: In a 10-year perspective, for very early HCC (single nodule <2cm) in Child–Pugh class A patients, RFA provided similar life-expectancy and quality-adjusted life-expectancy at a lower cost than resection and was the most cost-effective therapeutic strategy. For single HCCs of 3–5cm, resection provided better life-expectancy and was more cost-effective than RFA, at a willingness-to-pay above €4200 per quality-adjusted life-year. In the presence of two or three nodules ⩽3cm, life-expectancy and quality-adjusted life-expectancy were very similar between the two treatments, but cost-effectiveness was again in favour of RFA. Conclusions: For very early HCC and in the presence of two or three nodules ⩽3cm, RFA is more cost-effective than resection; for single larger early stage HCCs, surgical resection remains the best strategy to adopt as a result of better survival rates at an acceptable increase in cost. [Copyright &y& Elsevier]

Background & Aims: Contrast enhanced computed tomography (CT-scan) is a standard of care for the radiological diagnosis of hepatocellular carcinoma (HCC) in patients with cirrhosis. This technique, however, is not validated to exclude intrahepatic cholangiocarcinoma (ICC) which may develop in patients with cirrhosis, as well. Methods: To assess the features of contrast CT-scan in the diagnosis of ICC, we reviewed all CT-scan films obtained in cirrhotic patients with a histologically documented ICC, taking in consideration the pattern and dynamics of the arterial, portal venous and delayed phases of contrast uptake. Results: Thirty-two patients had 40 nodules of ICC (22 male; median age 62years; 13 hepatitis C) that were identified either during surveillance with abdominal ultrasound (21 patients, 66%) or incidentally (11 patients, 34%). ICC was either multifocal or ⩾30mm in 11 of the former and 10 of the latter group (52% vs. 91%, p <0.05). Two nodules (5%) escaped detection by CT-scan, while the remaining 38 showed a heterogeneous contrast enhancement pattern, being the arterial peripheral-rim enhancement present in 19 (50%) cases and a progressive homogeneous contrast uptake in 16 (42%) cases during the three vascular phases, with no relation to tumor size. Importantly, all nodules lacked the radiological hallmark of HCC, the only ICC nodule showing a homogeneous wash-in during the arterial phase followed by a wash-out in the delayed venous phase, however showing a homogeneous wash-in during the portal phase too. Conclusions: ICC in cirrhotic patients displays distinct vascular patterns at CT-scan that allow for differentiation from HCC. [ABSTRACT FROM AUTHOR]

Abstract: Background: Radiofrequency Ablation is the most widely performed percutaneous treatment for Hepatocellular Carcinoma. This multicentre study was aimed at assessing the complication, overall survival and disease-free survival rates in cirrhotic patients with single Hepatocellular Carcinoma nodule ≤3cm undergoing Radiofrequency Ablation. Methods: Data of 365 patients (59% males; mean age 67±8 years), Child–Pugh A/B, with single Hepatocellular Carcinoma nodule ≤3cm (tumours >2–3cm=127/236), showing complete necrosis after Radiofrequency Ablation between 1998 and 2010 in 7 Italian Centers were retrospectively reviewed. Complication, overall survival and disease-free survival rates were analyzed as main clinical end-points. Results: Major complications were observed in 8 patients (2.2%) and minor complications in 23 patients (6.3%). The 3-, and 5-year overall survival rates were 80% and 64%. One hundred and seven patients (29.5%) died, being 41 deaths (38.3%) Hepatocellular Carcinoma-related. At multivariate analysis only age (p =0.04; OR 2.29), ascites (p <0.001; OR 3.74) and Child–Pugh class ≥B8 (p =0.003; OR 2.42) were confirmed as independent predictors for overall survival. The disease-free survival rates at 3- and 5-year were 50%, and 41.8%. Conclusions: Radiofrequency Ablation is an effective and safe tool for the treatment of single Hepatocellular Carcinoma ≤3cm providing excellent 5-year overall survival and disease-free survival rates. Patient''s age and liver status appeared as main determinants of outcome. [Copyright &y& Elsevier]