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Background & Aims: Immune-related liver injury (irLI) is commonly observed in patients with cancer treated with immune checkpoint inhibitors (ICIs). We aimed to compare the incidence, clinical characteristics, and outcomes of irLI between patients receiving ICIs for hepatocellular carcinoma (HCC) vs. other solid tumours., Methods: Two separate cohorts were included: 375 patients with advanced/unresectable HCC, Child-Pugh A class treated with first-line atezolizumab+bevacizumab from the AB-real study, and a non-HCC cohort including 459 patients treated with first-line ICI therapy from the INVIDIa-2 multicentre study. IrLI was defined as a treatment-related increase of aminotransferase levels after exclusion of alternative aetiologies of liver injury. The incidence of irLI was adjusted for the duration of treatment exposure., Results: In patients with HCC, the incidence of any grade irLI was 11.4% over a median treatment exposure of 4.4 months (95% CI 3.7-5.2) vs. 2.6% in the INVIDIa-2 cohort over a median treatment exposure of 12.4 months (95% CI 11.1-14.0). Exposure-adjusted-incidence of any grade irLI was 22.1 per 100-patient-years in patients with HCC and 2.1 per 100-patient-years in patients with other solid tumours (p <0.001), with median time-to-irLI of 1.4 and 4.7 months, respectively. Among patients who developed irLI, systemic corticosteroids were administered in 16.3% of patients with HCC and 75.0% of those without HCC (p <0.001), and irLI resolution was observed in 72.1% and 58.3%, respectively (p = 0.362). In patients with HCC, rates of hepatic decompensation and treatment discontinuation due to irLI were 7%. Grade 1-2 irLI was associated with improved overall survival only in patients with HCC (hazard ratio 0.53, 95% CI 0.29-0.96)., Conclusions: Despite higher incidence and earlier onset, irLI in patients with HCC is characterised by higher rates of remission and lower requirement for corticosteroid therapy (vs. irLI in other solid tumours), low risk of hepatic decompensation and treatment discontinuation, not negatively affecting oncological outcomes., Impact and Implications: Immune-related liver injury (irLI) is common in patients with cancer receiving immune checkpoint inhibitors (ICIs), but whether irLI is more frequent or it is associated with a worse clinical course in patients with hepatocellular carcinoma (HCC), compared to other tumours, is not known. Herein, we compared characteristics and outcomes of irLI in two prospective cohorts including patients treated with ICIs for HCC or for other oncological indications. irLI is significantly more common and it occurs earlier in patients with HCC, also after adjustment for duration of treatment exposure. However, outcomes of patients with HCC who developed irLI are not negatively affected in terms of requirement for corticosteroid therapy, hepatic decompensation, treatment discontinuation and overall survival., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background & Aims: Detection of patients with early cirrhosis is of importance to prevent the occurrence of complications and improve prognosis. The SEAL program aimed at evaluating the usefulness of a structured screening procedure to detect cirrhosis as early as possible., Methods: SEAL was a prospective cohort study with a control cohort from routine care data. Individuals participating in the general German health check-up after the age of 35 ("Check-up 35") at their primary care physicians were offered a questionnaire, liver function tests (aspartate and alanine aminotransferase [AST and ALT]), and follow-up. If AST/ALT levels were elevated, the AST-to-platelet ratio index (APRI) score was calculated, and patients with a score >0.5 were referred to a liver expert in secondary and/or tertiary care., Results: A total of 11,859 participants were enrolled and available for final analysis. The control group comprised 349,570 participants of the regular Check-up 35. SEAL detected 488 individuals with elevated APRI scores (4.12%) and 45 incident cases of advanced fibrosis/cirrhosis. The standardized incidence of advanced fibrosis/cirrhosis in the screening program was slightly higher than in controls (3.83‰ vs. 3.36‰). The comparison of the chance of fibrosis/cirrhosis diagnosis in SEAL vs. in standard care was inconclusive (marginal odds ratio 1.141, one-sided 95% CI 0.801, +Inf). Of note, when patients with decompensated cirrhosis at initial diagnosis were excluded from both cohorts in a post hoc analysis, SEAL was associated with a 59% higher chance of early cirrhosis detection on average than routine care (marginal odds ratio 1.590, one-sided 95% CI 1.080, +Inf; SEAL 3.51‰, controls: 2.21‰)., Conclusions: The implementation of a structured screening program may increase the early detection rate of cirrhosis in the general population. In this context, the SEAL pathway represents a feasible and potentially cost-effective screening program., Registration: DRKS00013460 LAY SUMMARY: Detection of patients with early liver cirrhosis is of importance to prevent the occurrence of complications and improve prognosis. This study demonstrates that the implementation of a structured screening program using easily obtainable measures of liver function may increase the early detection rate of cirrhosis in the general population. In this context, the 'SEAL' pathway represents a feasible and potentially cost-effective screening program., Competing Interests: Conflict of interest The authors disclose no potential financial or non-financial conflict of interests regarding this study. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: IMbrave150 demonstrated that atezolizumab plus bevacizumab led to significantly improved overall survival (OS) and progression-free survival (PFS) compared with sorafenib in patients with unresectable hepatocellular carcinoma at the primary analysis (after a median 8.6 months of follow-up). We present updated data after 12 months of additional follow-up., Methods: Patients with systemic treatment-naive, unresectable hepatocellular carcinoma were randomized 2:1 to receive 1,200 mg atezolizumab plus 15 mg/kg bevacizumab intravenously every 3 weeks or 400 mg sorafenib orally twice daily in this open-label, phase III study. Co-primary endpoints were OS and PFS by independently assessed RECIST 1.1 in the intention-to-treat population. Secondary efficacy endpoints included objective response rates and exploratory subgroup efficacy analyses. This is a post hoc updated analysis of efficacy and safety., Results: From March 15, 2018, to January 30, 2019, 501 patients (intention-to-treat population) were randomly allocated to receive atezolizumab plus bevacizumab (n = 336) or sorafenib (n = 165). On August 31, 2020, after a median 15.6 (range, 0-28.6) months of follow-up, the median OS was 19.2 months (95% CI 17.0-23.7) with atezolizumab plus bevacizumab and 13.4 months (95% CI 11.4-16.9) with sorafenib (hazard ratio [HR] 0.66; 95% CI 0.52-0.85; descriptive p <0.001). The median PFS was 6.9 (95% CI 5.7-8.6) and 4.3 (95% CI 4.0-5.6) months in the respective treatment groups (HR 0.65; 95% CI 0.53-0.81; descriptive p < 0.001). Treatment-related grade 3/4 adverse events occurred in 143 (43%) of 329 and 72 (46%) of 156 safety-evaluable patients in the respective groups, and treatment-related grade 5 events occurred in 6 (2%) and 1 (<1%) patients., Conclusion: After longer follow-up, atezolizumab plus bevacizumab maintained clinically meaningful survival benefits over sorafenib and had a safety profile consistent with the primary analysis., Gov Identifier: NCT03434379., Lay Summary: The primary analysis of IMbrave150 showed that atezolizumab plus bevacizumab had significantly greater benefits than sorafenib in patients with advanced hepatocellular carcinoma, but survival data were not yet mature. At this updated analysis done 12 months later, median overall survival was 5.8 months longer with atezolizumab plus bevacizumab than sorafenib, and the severity profile of treatment-related side effects remained similar. These updated results confirm atezolizumab plus bevacizumab as the first-line standard of care for advanced hepatocellular carcinoma., Competing Interests: Conflicts of interest All authors received support from F. Hoffmann-La Roche/Genentech during the conduct of this study. ALC has received honoraria from AstraZeneca, Bristol Myers Squibb, Eisai, Merck Serono, Novartis, Ono Pharmaceutical, Exelixis, Nucleix, IPSEN Innovation, Bayer Healthcare, MSD, F. Hoffmann-La Roche/Genentech, BeiGene, CSR Pharma Group, and IQVIA; advisory/consulting fees from AstraZeneca, Bristol Myers Squibb, Eisai, Merck Serono, Novartis, Ono Pharmaceutical, Exelixis, Nucleix, IPSEN Innovation, Bayer Healthcare, MSD, Roche/Genentech, BeiGene, CSR Pharma Group, F. Hoffmann-La Roche, and IQVIA; speaker bureau fees from Bayer Yakuhin, Novartis, Eisai, Ono Pharmaceutical, and Amgen Taiwan; and travel and accommodation expenses from Bayer Yakuhin, F. Hoffmann-La Roche/Genentech, and IQVIA. SQ has no further interests to declare. MI has received institutional grant support Bayer, Eisai, Eli Lilly Japan, Chugai Pharmaceutical, AstraZeneca, MSD, Novartis, Bristol Myers Squibb, and Merck Serono; honoraria from Bayer, Eisai, Eli Lilly Japan, Chugai Pharmaceutical, and Sumitomo Dainippon Pharma, and Takeda; and had a consulting or advisory role for Bayer, Eisai, Eli Lilly Japan, Chugai Pharmaceutical, and Takeda. PRG has had a consulting or advisory role and received honoraria from AdaptImmune, AstraZeneca, Bayer, Bristol Myers Squibb, MSD, Eisai, Lilly, Ipsen, Roche, and Sirtex; has been on a speakers’ bureau for AstraZeneca, Bayer, Bristol Myers Squibb, MSD, Eisai, Lilly, Ipsen, Roche, and Sirtex; has received research funding from Bayer and Roche; has provided expert testimony for Lilly; and has received travel and accommodation expenses from AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Lilly, Ipsen, and F. Hoffmann-La Roche. MD has received honoraria and advisory/consultancy fees from F. Hoffmann-La Roche, Merck Serono, Bayer, Ipsen, Servier, Amgen, MSD, and Pierre Fabre; research funding from F. Hoffmann-La Roche, Merck Serono, and Bayer; and travel and accommodation expenses from F. Hoffmann-La Roche, MSD, and Servier. TYK reports grants and nonfinancial support from F. Hoffmann-La Roche. HYL has received advisory/consulting fees from Bayer, Eisai, Bristol Myers Squibb, Ono, AstraZeneca, and F. Hoffmann-La Roche. MK has received honoraria from Lilly, Bayer, Eisai, MSD, Bristol Myers Squibb, and EA Pharma; had a consulting or advisory role for Eisai, Ono, MSD, Bristol Myers Squibb, and F. Hoffmann-La Roche; and received research funding from Gilead Sciences, Taiho, Sumitomo Dainippon Pharma, Takeda, Otsuka, EA Pharma, AbbVie, and Eisai. VB has received advisory/consultancy fees from F. Hoffmann-La Roche, MSD, Eisai, Bristol Myers Squibb, and Ipsen; and travel and accommodation expenses from F. Hoffmann-La Roche, MSD, Eisai, Bristol Myers Squibb, and Bayer. PM has had a consulting or advisory role for Bayer, Ipsen, Lilly, Eisai, AstraZeneca, Bristol Myers Squibb, and MSD; received institutional research funding from Ipsen; and travel and accommodation expenses from Bayer and Ipsen. AOK has received research support from F. Hoffmann-La Roche, Bristol Myers Squibb, Exelixis, Bayer, AdaptImmune, Immatics, Merck, and Eisai; and advisory/consultancy fees from AstraZeneca. DL has received honoraria and advisory/consultancy fees from Lexicon, Ipsen, Eisai, Exelixis, Advanced Accelerator Applications, Coherus, Sun Pharma, Bayer, Genentech, Taiho, QED, Merck, Adagene, and TerSera; and received institutional research funding from Brooklyn Immunotherapeutics and AstraZeneca. WV, NM, and AN are full-time employees of and hold shareholder or stock options in Genentech. YW and LL are full-time employees of Roche (China) Holding Ltd. AXZ has had a consulting or advisory role for AstraZeneca, Bayer, Eisai, Exelixis, Gilead Sciences, Lilly, Merck, Roche/Genentech, and Sanofi/Aventis; and received institutional research funding from Bayer, Bristol Myers Squibb, Lilly, Merck, and Novartis. RSF has had a consulting or advisory role for and received consulting fees from AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Exelixis, F. Hoffmann-La Roche/Genentech, Lilly, Merck, Novartis, and Pfizer; has received institutional research funding from Bayer, Bristol Myers Squibb, Eisai, Lilly, Merck, Novartis, Pfizer, and F. Hoffmann-La Roche/Genentech; has provided expert testimony for Novartis; and participated on a data safety monitoring board or advisory board for AstraZeneca and Hengrui. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

There have been major advances in the armamentarium for hepatocellular carcinoma (HCC) since the last official update of the Barcelona Clinic Liver Cancer prognosis and treatment strategy published in 2018. Whilst there have been advances in all areas, we will focus on those that have led to a change in strategy and we will discuss why, despite being encouraging, data for select interventions are still too immature for them to be incorporated into an evidence-based model for clinicians and researchers. Finally, we describe the critical insight and expert knowledge that are required to make clinical decisions for individual patients, considering all of the parameters that must be considered to deliver personalised clinical management., Competing Interests: Conflict of interest MR: reports consultancy from Bayer, BMS, Roche, Ipsen, Astra Zeneca, Boston Science and Lilly; lecture fees from Bayer, BMS, Gilead, Lilly,Roche and UniversalDX and travel support from Bayer, BMS, Lilly and Astra Zeneca. Received research funding (to institution) from Bayer and Ipsen. AF: reports lecture fees from Bayer, Boston Science, Gilead, and MSD, consultancy fees from Bayer, Astra Zeneca, Roche, SIRTEX, AB Exact Science and Guerbert. JR: reports lectures and travel grants from Bayer and Roche. JFF: reports lecture fees from Bayer. MB: reports lectures and/or travel support from Boston Science, Terumo, Guerbet and Bayer. AGC: reports lectures fee from Boston Science, Terumo. KRK: reports consultancy fees (to self) from Exact Sciences, Genentech/Roche, Gilead. Received travel support from Ipsen. Received research funding (to institution) from Agios, Astra Zeneca, Bayer, BMS, Eli Lilly, EMD Serono, Exelixis, Genentech/Roche, Merck, Novartis, Partner Therapeutics, QED, Relay Therapeutics, Surface Oncology, Taiho. PRG: consultancy fees and/or travel support from Bayer, Boston Scientific, AstraZeneca, Adaptimmune, BMS, MSD, Sirtex, Lilly, Roche, Guerbet, Ipsen, Eisai. VM: Nothing to disclose. RS: reports consultancy fees from Boston Scientific, Cook, Bard, Genentech, Astrazeneca, Eisai, Sirtex, Siemens, research support from Boston Scientific. BS: reports consultancy fees from Adaptimmune, Astra Zeneca, Bayer, BMS, Boston Scientific, BTG, Eisai, Eli Lilly, H3 Biomedicine, Ipsen, Novartis, Merck, Roche, Sirtex Medical, Terumo; speaker fees from Astra Zeneca, Bayer, BMS, BTG, Eli Lilly, Ipsen, Novartis, Merck, Roche, Sirtex Medical, Terumo; research grants (to Institution) from BMS and Sirtex Medical. AS: has served on advisory boards or consulted for Genentech, Bayer, Eisai, AstraZeneca, BMS, and Exelixis. AV: Speaker, consultancy and advisory role: Amgen, Roche, Bayer, Sanofi, BMS, Lilly, Novartis, EISAI, AstraZeneca, Merck, Incyte, Ipsen, PierreFabre, MSD, Sirtex, BTG, Servier, Terumo, GSK. JFu: Nothing to disclose. CA: reports lectures fee from Bayer. JB: has consulted for Arqule, Bayer-Shering Pharma, Novartis, BMS, BTG- Biocompatibles, Eisai, Kowa, Terumo, Gilead, Bio-Alliance, Roche, AbbVie, MSD, Sirtex, Ipsen, Astra-Medimmune, Incyte, Quirem, Adaptimmune, Lilly, Basilea, Nerviano, Sanofi and UniversalDX; and received research/educational grants from Bayer, and lecture fees from Bayer-Shering Pharma, BTG-Biocompatibles, Eisai, Terumo, Sirtex, Ipsen. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

In light of a global rise in obesity and type 2 diabetes, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) represent an increasingly important underlying aetiology of hepatocellular carcinoma (HCC). HCCs arising from lipotoxicity-mediated chronic inflammation are characterised by several unique features: in contrast to virally driven HCC, up to 50% of NAFLD-HCC occurs in patients without cirrhosis and annual HCC incidence is comparatively low, complicating current surveillance strategies. On average, patients are older and are more frequently diagnosed at an advanced stage. While locoregional treatments are probably equally effective regardless of HCC aetiology, the picture is less clear for systemic therapy. Tyrosine kinase inhibitors are probably equally effective, while there have been initial signals that immune checkpoint inhibitors may be less effective in NAFLD-HCC than in viral HCC. Current international clinical practice guidelines for HCC do not consider aetiology, as there are insufficient data to draw specific conclusions or to recommend aetiology-specific modifications to the current management of patients with HCC. However, in light of the growing relevance of NAFLD-HCC, future clinical trials should assess whether HCC aetiology - and NAFLD/NASH in particular - influence the safety and efficacy of a given treatment., Competing Interests: Conflict of interest FF reports receiving consulting and lectures fees from Roche; lectures fees from Lilly and Pfizer. SJG and LM report no conflict of interest. PRG reports receiving consulting and lectures fees from Adaptimmune, AstraZeneca, Bayer, BMS, Eisai, Ipsen, Lilly, MSD, Roche, Sirtex. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Based on positive results from small single center studies, granulocyte-colony stimulating factor (G-CSF) is being widely used for the treatment of patients with acute-on-chronic liver failure (ACLF). Herein, we aimed to evaluate the safety and efficacy of G-CSF in patients with ACLF., Methods: In this multicenter, prospective, controlled, open-label phase II study, 176 patients with ACLF (EASL-CLIF criteria) were randomized to receive G-CSF (5 μg/kg daily for the first 5 days and every third day thereafter until day 26) plus standard medical therapy (SMT) (n = 88) or SMT alone. The primary efficacy endpoint was 90-day transplant-free survival analyzed by Cox regression modeling. The key secondary endpoints were overall and transplant-free survival after 360 days, the development of ACLF-related complications, and the course of liver function scores during the entire observation period., Results: Patients treated with G-CSF had a 90-day transplant-free survival rate of 34.1% compared to 37.5% in the SMT group (hazard ratio [HR] 1.05; 95% CI 0.711-1.551; p = 0.805). Transplant-free and overall survival at 360 days did not differ between the 2 arms (HR 0.998; 95% CI 0.697-1.430; p = 0.992 and HR 1.058; 95% CI 0.727-1.548; p = 0.768, respectively). G-CSF did not improve liver function scores, the occurrence of infections, or survival in subgroups of patients without infections, with alcohol-related ACLF, or with ACLF defined by the APASL criteria. Sixty-one serious adverse events were reported in the G-CSF+SMT group and 57 were reported in the SMT group. In total, 7 drug-related serious adverse reactions occurred in the G-CSF group. The study was prematurely terminated due to futility after conditional power calculation., Conclusions: In contrast to previous findings, G-CSF had no significant beneficial effect on patients with ACLF in this multicenter controlled trial, which suggests that it should not be used as a standard treatment for ACLF. CLINICALTRIALS., Gov Number: NCT02669680 LAY SUMMARY: Granulocyte-colony stimulating factor was considered as a novel treatment for acute-on-chronic liver failure (ACLF). We performed the first randomized, multicenter, controlled phase II trial, which showed that G-CSF did not improve survival or other clinical endpoints in patients with ACLF. Therefore, G-CSF should not be used to treat liver disease outside clinical studies., Competing Interests: Conflict of interest CE: has on-going research collaboration with Merz Pharmaceutical and Novartis. He has received speaker fees from Novartis, Gilead and Merz Pharmaceuticals. TB: Receipt of honoraria or consultation fees or participation in a company sponsored speaker’s bureau: Abbvie, Alexion, Bayer, Gilead, Eisai, Falk Foundation, Intercept, Ipsen, Janssen, MSD/Merck, Novartis, and Sequana Medical. Receipt of grants/research supports: Abbvie, BMS, Gilead, MSD/Merck, Humedics, Intercept, Merz, Sequana Medical. MS: Receipt of honoraria or consultation fees or participation in a company sponsored speaker’s bureau: Merck Serono GmbH, Bayer AG, ERBE Elektromedizin GmbH, Amgen Inc., Johnson&Johnson Medical GmbH, ERBE Elektromedizin GmbH, Takeda Pharmaceutical Limited, Olympus K.K., Medtronic GmbH, Intuitive Surgical Inc.. JT: has received speaking and/or consulting fees from Gore, Bayer, Alexion, MSD, Gilead, Intercept, Norgine, Grifols, Versantis, and Martin Pharmaceutical. All other authors declared no conflict of interest. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

The last 5 years have witnessed relevant advances in the systemic treatment of hepatocellular carcinoma. New data have emerged since the development of the EASL Clinical Practice Guidelines on the management of hepatocellular carcinoma in 2018. Drugs licensed in some countries now include 4 oral multi-tyrosine kinase inhibitors (sorafenib, lenvatinib, regorafenib and cabozantinib), 1 anti-angiogenic antibody (ramucirumab) and 4 immune checkpoint inhibitors, alone or in combination (atezolizumab in combination with bevacizumab, ipilimumab in combination with nivolumab, nivolumab and pembrolizumab in monotherapy). Prolonged survival in excess of 2 years can be expected in most patients with sensitive tumours and well-preserved liver function that renders them fit for sequential therapies. With different choices available in any given setting, the robustness of the evidence of efficacy and a correct matching of the safety profile of a given agent with patient characteristics and preferences are key in making sound therapeutic decisions. The recommendations in this document amend the previous EASL Clinical Practice Guidelines and aim to help clinicians provide the best possible care for patients today. In view of several ongoing and promising trials, further advances in systemic therapy of hepatocellular carcinoma are foreseen in the near future and these recommendations will have to be updated regularly., Competing Interests: Conflict of interest JB received received consulting fees from AbbVie, Adaptimmune, Arqule, AstraZeneca, Medimmune, Basilea, Bayer, Bio-Alliance, BMS, BTG, Eisai, Gilead, Incyte, Ipsen, Kowa, Lilly, MSD, Nerviano, Novartis, Polaris, Quirem, Roche, Sirtex, Sanofi, Terumo; institutional research grants from Bayer, BTG; educational grants from Bayer, BTG; and speaker fees from Bayer, BTG, Ipsen, Roche, Eisai, Terumo, Sirtex. SC Stephen L. Chan has acted as an advisor to AstraZeneca, Eisai, MSD and Novartis; received research grants from Bayer, Ipsen, MSD and SIRTEX; and received lecture fees from AstraZeneca,Bayer, Eisai, Roche and MSD. PRG received consulting and/or lecturing fees from Bayer, BMS, AstraZeneca, Sirtex, MSD, Eisai, Ipsen, Roche, Adaptimmune, Lilly. LR received consulting fees from Amgen, ArQule, AstraZeneca, Basilea, Bayer, BMS, Celgene, Eisai, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Lilly, MSD, Nerviano Medical Sciences, Roche, Sanofi, Zymeworks; lecture fees from AbbVie, Amgen, Bayer, Eisai, Gilead, Incyte, Ipsen, Lilly, Merck Serono, Roche, Sanofi; travel expenses from Ipsen; and institutional research funding from Agios, ARMO BioSciences, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, Zymeworks. BS received consulting fees from Adaptimmune, AstraZeneca, Bayer, BMS, BTG, Eisai, Exelixis, Eli-Lilly, IPSEN, Merck, Onxeo, Roche, Sirtex; lecture fees from AstraZeneca, Bayer, BMS, Eisai, Eli-Lilly, Incyte, IPSEN, Roche, Sirtex; institutional research grants from BMS and Sirtex. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Immune checkpoint inhibitors (ICIs) have reshaped cancer therapy. ICIs enhance T cell activation through various mechanisms and may help reverse the exhausted phenotype of tumour-infiltrating lymphocytes. However, disrupting the key role that checkpoint molecules play in immune homeostasis may result in autoimmune complications. A broad range of immune-related adverse events (irAEs) involve almost every organ but mostly affect the skin, digestive system, lung, endocrine glands, nervous system, kidney, blood cells, and musculoskeletal system. They are usually manageable but can be life-threatening. The incidence of irAEs is not very different in patients with hepatocellular carcinoma (HCC) compared to other tumour types, although there is a trend towards a higher incidence of hepatic irAEs. HCC usually develops on a background of cirrhosis with associated systemic manifestations. Extrahepatic organ dysfunction in cirrhosis may cause signs and symptoms that overlap with irAEs or increase their severity. Available guidelines for the management of irAEs have not specifically considered the assessment of toxicities in the context of patients with liver cancer and cirrhosis. This review addresses the toxicity profile of ICIs in patients with HCC, focusing on the challenges that the underlying liver disease poses to their diagnosis and management. Challenges include late recognition, inadequate work-up and delayed treatment, overdiagnosis and inappropriate interruption of ICIs, complications caused by immunosuppressive therapy, and increased cost. A specific algorithm for the management of hepatic irAEs is provided., (Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Hepatocellular carcinomas (HCCs) are characterised by considerable phenotypic and molecular heterogeneity. Treating HCC and designing clinical trials are particularly challenging because co-existing liver disease, present in most patients, limits aggressive therapeutic options. Positive results in recent phase III clinical trials have confirmed the high value of anti-angiogenic therapies for HCC in both first (sorafenib and lenvatinib) and second line (regorafenib and cabozantinib) treatment modalities. However, failure of several large randomised controlled clinical trials over the last 10 years underlines the necessity for innovative treatment strategies and implementation of translational findings to overcome the unmet clinical need. Furthermore, the promising results from novel immunotherapies are likely to complement the landscape of active compounds for HCC and will require a completely different approach to patients, as well as the development of prognostic/predictive biomarkers. Given our increasing understanding of the most abundant molecular alterations in HCC, effective enrichment of patients based on clinical and molecular biomarkers, as well as adaptive clinical trials, are now feasible and should be implemented. Herein, we aim to review important aspects of precision medicine approaches in HCC that might contribute to improving the molecular subclassification of patients in a clinical trial setting and pave the way for novel therapeutic strategies., (Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Interleukin (IL)-1-type cytokines including IL-1α, IL-1β and interleukin-1 receptor antagonist (IL-1Ra) are among the most potent molecules of the innate immune system and exert biological activities through the ubiquitously expressed interleukin-1 receptor type 1 (IL-1R1). The role of IL-1R1 in hepatocytes during acute liver failure (ALF) remains undetermined., Methods: The role of IL-1R1 during ALF was investigated using a novel transgenic mouse model exhibiting deletion of all signaling-capable IL-1R isoforms in hepatocytes (Il1r1 Hep-/- )., Results: ALF induced by D-galactosamine (D-GalN) and lipopolysaccharide (LPS) was significantly attenuated in Il1r1 Hep-/- mice leading to reduced mortality. Conditional deletion of Il1r1 decreased activation of injurious c-Jun N-terminal kinases (JNK)/c-Jun signaling, activated nuclear factor-kappa B (NF-κB) p65, inhibited extracellular signal-regulated kinase (ERK) and prevented caspase 3-mediated apoptosis. Moreover, Il1r1 Hep-/- mice exhibited reduced local and systemic inflammatory cytokine and chemokine levels, especially TNF-α, IL-1α/β, IL-6, CC-chemokine ligand 2 (CCL2), C-X-C motif ligand 1 (CXCL-1) and CXCL-2, and a reduced neutrophil recruitment into the hepatic tissue in response to injury. NLRP3 inflammasome expression and caspase 1 activation were suppressed in the absence of the hepatocellular IL-1R1. Inhibition of IL-1R1 using IL-1ra (anakinra) attenuated the severity of liver injury, while IL-1α administration exaggerated it. These effects were lost ex vivo and at later time points, supporting a role of IL-1R1 in inflammatory signal amplification during acute liver injury., Conclusion: IL-1R1 in hepatocytes plays a pivotal role in an IL-1-driven auto-amplification of cell death and inflammation in the onset of ALF., Lay Summary: Acute liver injury which can cause lethal liver failure is medicated by a class of proteins called cytokines. Among these, interleukin-1 (IL-1) and the corresponding receptor IL-1R1 play a prominent role in the immune system, but their role in the liver is undetermined. In the current study, a novel mouse model with defective IL-1R1 in liver cells was studied. Mice lacking this receptor in liver cells were protected from cell death to a certain extent. This protection occurred only in the presence of other, neighboring cells, arguing for the involvement of proteins derived from these cells. This effect is called paracrine signaling and the current study has for the first time shown that the IL-1R1 receptor on hepatocytes is involved in acute liver failure in this context. The approved drug anakinra - which blocks IL-1R1 - had the same effect, supporting the proposed mechanism of action. The findings of this study suggest new treatment options for patients with acute liver failure by blocking defined signals of the immune system., (Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Treatment of hepatocellular carcinoma (HCC) is dependent on the stage of the disease. Intermediate stage HCC encompasses the largest subgroup of patients with the disease, and is characterized by substantial heterogeneity. The standard therapeutic approach, transarterial chemoembolization (TACE), is probably over-used and may not be appropriate for all patients with intermediate stage HCC. In patients with extensive tumour bulk, multi-nodular spread or impaired liver function, TACE may not be optimal and other treatments can be considered as a first-line treatment. These include surgery, percutaneous ablation, radioembolization or systemic treatment. In addition, patients who do not achieve complete or partial necrosis (TACE failure) and patients with early recurrence after TACE, should be managed individually, considering systemic treatments usually reserved for advanced disease. In selected cases and in patients who achieve downstaging, radical approaches such as hepatic resection or even liver transplantation can be considered. In this review, we evaluate the current literature for the treatment strategies for patients with intermediate Barcelona Clinic Liver Cancer (BCLC) B stage HCC., (Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: The pathomechanisms underlying non-alcoholic fatty liver disease (NAFLD) and the involved molecular regulators are incompletely explored. The nuclear factor-kappa B (NF-κB)-cofactor gene B cell leukemia-3 (Bcl-3) plays a critical role in altering the transcriptional capacity of NF-κB - a key inducer of inflammation - but also of genes involved in cellular energy metabolism., Methods: To define the role of Bcl-3 in non-alcoholic steatohepatitis (NASH), we developed a novel transgenic mouse model with hepatocyte-specific overexpression of Bcl-3 (Bcl-3 Hep ) and employed a high-fat, high-carbohydrate dietary feeding model. To characterize the transgenic model, deep RNA sequencing was performed. The relevance of the findings was confirmed in human liver samples., Results: Hepatocyte-specific overexpression of Bcl-3 led to pronounced metabolic derangement, characterized by enhanced hepatic steatosis from increased de novo lipogenesis and uptake, as well as decreased hydrolysis and export of fatty acids. Steatosis in Bcl-3 Hep mice was accompanied by an augmented inflammatory milieu and liver cell injury. Moreover, Bcl-3 expression decreased insulin sensitivity and resulted in compensatory regulation of insulin-signaling pathways. Based on in vivo and in vitro studies we identified the transcription factors PPARα, PPARγ and PGC-1α as critical regulators of hepatic metabolism and inflammation downstream of Bcl-3. Metformin treatment improved the metabolic and inflammatory phenotype in Bcl-3 Hep mice through modulation of PPARα and PGC-1α. Remarkably, these findings were recapitulated in human NASH, which exhibited increased expression and nuclear localization of Bcl-3., Conclusions: In summary, Bcl-3 emerges as a novel regulator of hepatic steatosis, insulin sensitivity and inflammation in NASH., Lay Summary: Non-alcoholic fatty liver disease (NAFLD) is considered the most prevalent liver disease worldwide. Patients can develop end-stage liver disease resulting in liver cirrhosis or hepatocellular carcinoma, but also develop complications unrelated to liver disease, e.g., cardiovascular disease. Still there is no full understanding of the mechanisms that cause NAFLD. In this study, genetically engineered mice were employed to examine the role of a specific protein in the liver that is involved in inflammation and the metabolism, namely Bcl-3. By this approach, a better understanding of the mechanisms contributing to disease progression was established. This can help to develop novel therapeutic and diagnostic options for patients with NAFLD., (Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: The cancer stem cells (CSCs) have important therapeutic implications for multi-resistant cancers including hepatocellular carcinoma (HCC). Among the key pathways frequently activated in liver CSCs is NF-κB signaling., Methods: We evaluated the CSCs-depleting potential of NF-κB inhibition in liver cancer achieved by the IKK inhibitor curcumin, RNAi and specific peptide SN50. The effects on CSCs were assessed by analysis of side population (SP), sphere formation and tumorigenicity. Molecular changes were determined by RT-qPCR, global gene expression microarray, EMSA, and Western blotting., Results: HCC cell lines exposed to curcumin exhibited differential responses to curcumin and were classified as sensitive and resistant. In sensitive lines, curcumin-mediated induction of cell death was directly related to the extent of NF-κB inhibition. The treatment also led to a selective CSC-depletion as evidenced by a reduced SP size, decreased sphere formation, down-regulation of CSC markers and suppressed tumorigenicity. Similarly, NF-κB inhibition by SN50 and siRNA against p65 suppressed tumor cell growth. In contrast, curcumin-resistant cells displayed a paradoxical increase in proliferation and expression of CSC markers. Mechanistically, an important component of the CSC-depleting activity of curcumin could be attributed to a NF-κB-mediated HDAC inhibition. Co-administration of the class I/II HDAC inhibitor trichostatine sensitized resistant cells to curcumin. Further, integration of a predictive signature of curcumin sensitivity with human HCC database indicated that HCCs with poor prognosis and progenitor features are most likely to benefit from NF-κB inhibition., Conclusions: These results demonstrate that blocking NF-κB can specifically target CSC populations and suggest a potential for combined inhibition of NF-κB and HDAC signaling for treatment of liver cancer patients with poor prognosis., (Copyright © 2015 European Association for the Study of the Liver. All rights reserved.)

Background & Aims: Hepatocellular carcinoma (HCC) associated macrophages accelerate tumor progression by growth factor release. Therefore, tumor-associated macrophages (TAM) and their initiated signaling cascades are potential therapeutic targets. Aiming at understanding anticancer effects of systemic HCC therapy, we investigated the impact of sorafenib on macrophage function, focusing on macrophage-related growth factor secretion., Methods: Macrophage markers, cytokine and growth factor release were investigated in CSF-1 (M1) or GMCSF (M2) maturated monocyte-derived macrophages. Macrophages were treated with sorafenib (1.2-5.0 μg/ml) and culture supernatants were transferred to hepatoma cell cultures to assess growth propagation. Insulin-like growth factor (IGF) signaling was blocked with NVP-AEW541 to confirm the role of IGF-1 in macrophage-driven hepatoma cell propagation. Macrophage activation was followed by ELISA of serum soluble mCD163 in sorafenib-treated patients with HCC., Results: Alternative macrophages (M2), which showed higher IGF-1 (p=0.022) and CD163 mRNA (p=0.032) expression compared to classical macrophages (M1), increased hepatoma growth. This effect was mediated by M2-conditioned culture media. In turn, sorafenib lowered mCD163 and IGF-1 release by M2 macrophages, which decelerated M2 macrophage driven HuH7 and HepG2 proliferation by 47% and 64%, respectively. IGF-receptor blockage with NVP-AEW541 reduced growth induction by M2-conditioned culture media in a dose dependent manner. A transient mCD163 reduction during sorafenib treatment indicated a coherent M2 macrophage inhibition in patients with HCC., Conclusions: Sorafenib alters macrophage polarization, reduces IGF-1-driven cancer growth in vitro and partially inhibits macrophage activation in vivo. Thus macrophage modulation might contribute to the anti-cancer activity of sorafenib. However, more efficient macrophage-directed therapies are required., (Copyright © 2015. Published by Elsevier B.V.)

Background & Aims: Human hepatocarcinogenesis is as a multi-step process starting from dysplastic lesions to early carcinomas (eHCC) that ultimately progress to HCC (pHCC). However, the sequential molecular alterations driving malignant transformation of the pre-neoplastic lesions are not clearly defined. This lack of information represents a major challenge in the clinical management of patients at risk., Methods: We applied next-generation transcriptome sequencing to tumor-free surrounding liver (n = 7), low- (n = 4) and high-grade (n = 9) dysplastic lesions, eHCC (n = 5) and pHCC (n = 3) from 8 HCC patients with hepatitis B infection. Integrative analyses of genetic and transcriptomic changes were performed to characterize the genomic alterations during hepatocarcinogenesis., Results: We report that changes in transcriptomes of early lesions including eHCC were modest and surprisingly homogenous. Extensive genetic alterations and subsequent activation of prognostic adverse signaling pathways occurred only late during hepatocarcinogenesis and were centered on TGFβ, WNT, NOTCH, and EMT-related genes highlighting the molecular diversity of pHCC. We further identify IGFALS as a key genetic determinant preferentially down-regulated in pHCC., Conclusions: Our results define new hallmarks in molecular stratification and therapy options for patients at risk for HCC, and merit larger prospective investigations to develop a modified clinical-decision making algorithm based on the individualized next-generation sequencing analyses.

Background & Aims: The Sorafenib Hepatocellular Carcinoma (HCC) Assessment Randomized Protocol (SHARP) trial demonstrated that sorafenib improves overall survival and is safe for patients with advanced HCC. In this trial, 602 patients with well-preserved liver function (>95% Child-Pugh A) were randomized to receive either sorafenib 400mg or matching placebo orally b.i.d. on a continuous basis. Because HCC is a heterogeneous disease, baseline patient characteristics may affect individual responses to treatment. In a comprehensive series of exploratory subgroup analyses, data from the SHARP trial were analyzed to discern if baseline patient characteristics influenced the efficacy and safety of sorafenib., Methods: Five subgroup domains were assessed: disease etiology, tumor burden, performance status, tumor stage, and prior therapy. Overall survival (OS), time to progression (TTP), disease control rate (DCR), and safety were assessed for subgroups within each domain., Results: Subgroup analyses showed that sorafenib consistently improved median OS compared with placebo, as reflected by hazard ratios (HRs) of 0.50-0.85, similar to the complete cohort (HR=0.69). Sorafenib also consistently improved median TTP (HR, 0.40-0.64), except in HBV-positive patients (HR, 1.03), and DCR. Results are limited by small patient numbers in some subsets. The most common grade 3/4 adverse events included diarrhea, hand-foot skin reaction, and fatigue; the incidence of which did not differ appreciably among subgroups., Conclusions: These exploratory subgroup analyses showed that sorafenib consistently improved median OS and DCR compared with placebo in patients with advanced HCC, irrespective of disease etiology, baseline tumor burden, performance status, tumor stage, and prior therapy., (Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Despite great progress in diagnosis and management of hepatocellular carcinoma (HCC), the exact biology of the tumor remains poorly understood overall limiting the patients' outcome. Detailed analysis and characterization of the molecular mechanisms and subsequently individual prediction of corresponding prognostic traits would revolutionize both diagnosis and treatment of HCC and is the key goal of modern personalized medicine. Over the recent years systematic approaches for the analysis of whole tumor genomes and transcriptomes as well as epigenomes became affordable tools in translational research. This includes simultaneous analyses of thousands of molecular targets using microarray-based technologies as well as next-generation sequencing. Although currently diagnosis and classification of hepatocellular cancers still rely on histological examination of tumor sections, these technologies show great promise to advance the current knowledge of hepatocarcinogenesis, complement diagnostic classification in a setting of microarray-aided pathology, and rationalize the individual drug selection. This review aims to summarize recent progress of system biological approaches in hepatocarcinogenesis and outline potential areas for translational application in a clinical setting. Further, we give an update about known signaling pathways active in HCC, summarize the historical application of whole genomic approaches in liver cancer and indicate ongoing experimental research utilizing novel technologies in diagnosis and treatment of this deadly disease. This will also include the discussion and characterization of new molecular and cellular targets such as Cancer Stem Cells (CSCs)., (Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Apoptosis is crucially involved in acute and chronic liver injury, including viral, cholestatic, toxic, and metabolic liver disease. Additionally, dysregulation of apoptosis signaling pathways has been implicated in hepatocarcinogenesis. The most prominent members of the apoptosis-mediating tumor necrosis factor receptor superfamily are the TNF-R1 (CD120a) and the CD95 (Apo-1/Fas) receptor. Although extensively studied, the intracellular signaling events in hepatocytes are only incompletely understood., Methods: To examine the role of the caspase-8 homolog cellular FLICE-inhibitory protein (c-FLIP) in liver injury, we generated mice with hepatocyte specific deletion of c-FLIP. Three models of acute liver injury were employed: the agonistic anti-CD95 antibody Jo2, d-galactosamine and LPS (GalN/LPS), and concanavalin A., Results: Conditional ablation of c-FLIP in hepatocytes augmented liver injury and cell death in all three models of liver injury. CD95- and GalN/LPS-induced liver injury was ameliorated by a pancaspase inhibitor, while ConA-induced injury was unaffected by caspase inhibition. Augmented activation of the MAPK JNK was observed in parallel to liver injury in c-FLIP knockout mice in all injury models; however, inhibition of JNK only affected TNF- and ConA-mediated injury., Conclusions: In summary, c-FLIP is a central regulator of cell death in hepatocytes, involving increased activation of caspases and the MAPK JNK., (Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: LIM-domain-binding (Ldb) proteins have been demonstrated to be essential not only to key embryonic developmental processes but also to carcinogenesis. We have previously demonstrated Ldb1 to be of high biological and developmental relevance, as a targeted deletion of the Ldb1 gene in mice results in an embryonic lethal and pleiotropic phenotype., Methods: We have now established a liver-specific Ldb1 knock out to investigate the role of Ldb1 in carcinogenesis, in particular in hepatocellular carcinoma (HCC) development, in vivo., Results: These mice demonstrated a significantly enhanced growth of liver cancer by means of tumor size and number, advocating for an essential role of Ldb1 in HCC development. In addition, proliferation and resistance against apoptosis were increased. In order to identify the functional disturbances due to a lack of Ldb1, we performed a 15k mouse gene microarray expression analysis. We found the Myc oncogene to be regulated in the microarray analysis and were able to further confirm this regulation by demonstrating an over-expression of its downstream target Cyclin D1. Furthermore, we were able to demonstrate a down-regulation of the tumor suppressor p21. Finally, the liver stem cell marker EpCAM was also identified to be over expressed in Ldb1(-/-) knock out mice., Conclusions: We have established a significant role of Ldb1 in cancer development. Furthermore, we provided evidence for a myc/cyclin D1, p21, and EpCAM-dependent signalling to be key downstream regulators of this novel concept in HCC development., (Copyright © 2010. Published by Elsevier B.V.)

Background & Aims: Histopathology is the gold standard in the diagnosis of liver diseases but may be complicated by sampling error and bleeding. Confocal laser endomicroscopy (CLE) is a novel imaging modality providing in vivo histology. Previous studies using CLE for liver microscopy suffered from limited imaging depth using blue laser light and fluorescein. The aim of the current study was to evaluate a novel near-infrared (NIR) light probe with indocyanine green (ICG) contrast for in vivo confocal imaging of the human liver during mini-laparoscopy., Methods: The hand-held rigid laparoscopy probe (diameter 6.3mm) used a 780 nm diode laser. Subsurface images at different depths with < 1 microm lateral resolution were generated in real time by gently placing the sterile probe onto the liver in 22 patients under conscious analgo-sedation. Targeted biopsy was performed for histopathological correlation., Results: Maximum imaging depth was >350 microm. Typical aspects of normal liver architecture and liver diseases, such as nuclei, sinusoids, fibrous tissue, fatty inclusions, and bile ducts but not inflammation could be visualized at high resolution. The presence of steatosis and fibrosis was predicted correctly in 81% and 90%, respectively. No liver damage or severe adverse events occurred., Conclusions: For the first time, ICG-augmented confocal mini-laparoscopy with a novel NIR probe allowed in vivo microscopy of human liver diseases, and with deeper imaging compared to the so far available blue laser systems. Such an increase of imaging depth could potentially also be used for submucosal imaging of the GI tract., (Copyright 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background/aims: Multiple genes have been implicated in cholangiocellular carcinoma (CCC) development. However, the overall neoplastic risk is likely associated with a much lower number of critical physiological pathways., Methods: To investigate this hypothesis, we extracted all published genetic associations for the development of CCC from PubMed (genetic association studies, but also studies associating genes and CCC in general, i.e. functional studies in cell lines, genetic studies in humans, knockout mice etc.) and integrated CCC microarray data., Results: We demonstrated the MAPK pathway was consistently enriched in CCC. Comparing our data to genetic associations in HCC often successfully treated by a multityrosine kinase inhibitor, sorafenib, we demonstrated a similar overrepresentation of MAPK. In contrast, most cancer-related genetic studies focusing on genes related to transcription and cell cycle control, we consistently found genes coding for products in the extracellular environment to be significantly enriched. Thus, CCC must be regarded as developing in the context of an altered extracellular environment., Conclusions: Our study suggests the liver microenvironment holds essential functions and structures key to CCC progression. Furthermore, we identified the MAPK signaling pathway consistently enriched, pointing towards a critical role in CCC development. These data may provide a rationale for treatment of CCC with sorafenib.

Background/aims: Histopathology is essential in the diagnostic workup of most liver diseases. However, biopsy sampling might carry risks, is subject to sampling error, and does not provide dynamic tissue imaging. Therefore a newly developed miniaturised confocal probe was evaluated for in vivo microscopic imaging in rodent models of human liver diseases., Methods: The handheld laparoscopy probe used a 488nm single line laser for fluorophore excitation. Optical slice thickness was 7 microm, lateral resolution 0.7 microm. Imaging depth was 0-250 microm below the tissue surface. Imaging using different fluorescent staining protocols was performed in healthy mice, IFN-gamma- and IL-12-induced hepatitis, after bile duct ligation, and in ob/ob mice., Results: Confocal imaging permitted microscopic imaging of the liver in vivo at high resolution. Landmarks of liver diseases such as inflammatory infiltration, steatosis, bile duct proliferation, pericellular fibrosis and perfusion anomalies could be characterised, localised and differentiated in vivo., Conclusions: In vivo confocal microscopy with this newly developed probe allows real-time subsurface imaging and characterisation of normal and pathologic liver tissue at high resolution. Since this technology is suited for laparoscopy in humans, it has the potential to impact on the diagnostic workup of liver diseases and to permit dynamic monitoring of (patho-)physiologic events in vivo.

Background/aims: In hepatic fibrogenesis, stellate cells are activated leading to production and deposition of extracellular matrix. To clarify the role of PDGF-B in liver fibrogenesis, we overexpressed PDGF-B in the liver of transgenic mice., Methods: Transgenic mice for the conditional overexpression of PDGF-B in the liver under control of an albumin promoter were generated utilising the Cre/loxP system. Constitutive PDGF-B expression was achieved after breeding with mice expressing Cre-recombinase under actin promoter control. Tamoxifen inducible expression was achieved after breeding with mice expressing Cre under transthyretin receptor promoter control. Levels of fibrosis were assessed and the expression of regulators of matrix remodelling was measured., Results: PDGF-B expression caused hepatic stellate cell and myofibroblast activation marked by alpha-smooth muscle actin and PDGFR-beta expression. Liver fibrosis was verified macroscopically, histologically and by collagen I mRNA quantification in 4-6 week-old animals. MMP-2, MMP-9 and TIMP-1 were upregulated whereas TGF-beta expression was unchanged., Conclusions: We identified PDGF-B as a proliferative and profibrogenic stimulus and potential inducer of stellate cell transdifferentiation in vivo. PDGF-B overexpression causes liver fibrosis without significantly upregulating TGF-beta1, suggesting a TGF-beta-independent mechanism. The established model provides a tool for testing anti-PDGF-B therapeutic strategies in liver fibrosis in vivo.

Background/aims: Except for bleeding complications, other serious adverse reactions of coumarin anticoagulants such as hepatotoxicity or skin necrosis are comparatively rare. Nonetheless, a small number of coumarin-induced (sub-) acute liver failures has been published., Methods: A retrospective analysis was performed of patients treated for liver disease between 1992 and 2002 at our department to evaluate the incidence, clinical findings and histopathology of coumarin-induced hepatotoxicity., Results: The retrospective analysis revealed eight cases of phenprocoumon-induced hepatotoxicity, including three cases of (sub-) acute liver failure which resulted in two orthotopic liver transplantations and one fatal outcome. Five patients with phenprocoumon-induced hepatitis recovered well after anticoagulation was switched to another coumarin derivate or subcutaneous low molecular weight heparin. In all patients liver injury was predominantly of an hepatitic type. In the cases of (sub-) acute liver failure massive confluent liver cell necroses were histologically present, whereas among patients without liver failure mild portal to moderate active lobular hepatitis were observed. A retrospective analysis by BfArM (German Federal Institute for Drugs and Medical Devices) revealed 4390 cases of possible phenprocoumon-related adverse reactions since 1990, 2% of which had presented with hepatitis and 0.2% with liver failure., Conclusions: Phenprocoumon-induced liver disease is an uncommon complication, which can, however, cause (sub-) acute liver failure.