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Abstract A lack of biomarkers that detect drug-induced liver injury (DILI) accurately continues to hinder early- and late-stage drug development and remains a challenge in clinical practice. The Innovative Medicines Initiative’s TransBioLine consortium comprising academic and industry partners is developing a prospective repository of deeply phenotyped cases and controls with biological samples during liver injury progression to facilitate biomarker discovery, evaluation, validation and qualification. In a nested case–control design, patients who meet one of these criteria, alanine transaminase (ALT) ≥ 5 × the upper limit of normal (ULN), alkaline phosphatase ≥ 2 × ULN or ALT ≥ 3 ULN with total bilirubin > 2 × ULN, are enrolled. After completed clinical investigations, Roussel Uclaf Causality Assessment and expert panel review are used to adjudicate episodes as DILI or alternative liver diseases (acute non-DILI controls). Two blood samples are taken: at recruitment and follow-up. Sample size is as follows: 300 cases of DILI and 130 acute non-DILI controls. Additional cross-sectional cohorts (1 visit) are as follows: Healthy volunteers (n = 120), controls with chronic alcohol-related or non-alcoholic fatty liver disease (n = 100 each) and patients with psoriasis or rheumatoid arthritis (n = 100, 50 treated with methotrexate) are enrolled. Candidate biomarkers prioritised for evaluation include osteopontin, glutamate dehydrogenase, cytokeratin-18 (full length and caspase cleaved), macrophage-colony-stimulating factor 1 receptor and high mobility group protein B1 as well as bile acids, sphingolipids and microRNAs. The TransBioLine project is enabling biomarker discovery and validation that could improve detection, diagnostic accuracy and prognostication of DILI in premarketing clinical trials and for clinical healthcare application.

Diagnosis of rare, unpredictable, drug-induced liver injury (DILI) is a significant challenge for patients, clinicians, and drug development. Here, the authors discover, evaluate, and validate potential blood biomarkers to diagnose DILI and distinguish it from alternative causes of liver injury.

Background & Aims: Progression of chronic liver disease (CLD) to liver cirrhosis and liver cancer is a major global cause of morbidity and mortality. Treatment options capable of inhibiting progression of liver fibrosis when etiological treatment of CLD is not available or fails have yet to be established. We investigated the role of serine/threonine kinase p70 ribosomal protein S6 kinase (p70S6K) as checkpoint of fibrogenesis in hepatic stellate cells (HSCs) and as target for the treatment of liver fibrosis. Approach & Results: Immunohistochemistry was used to assess p70S6K expression in liver resection specimen. Primary human or murine HSCs from wild-type or p70S6K–/– mice as well as LX-2 cells were used for in vitro experiments. Specific small interfering RNA or CEP-1347 were used to silence or inhibit p70S6K and assess its functional relevance in viability, contraction and migration assays, fluorescence-activated cell sorting, and Western blot. These results were validated in vivo by a chemical model of fibrogenesis using wild-type and p70S6K–/– mice. Expression of p70S6K was significantly increased in human cirrhotic vs noncirrhotic liver-tissue and progressively increased in vitro through activation of primary human HSCs. Conversely, p70S6K induced fibrogenic activation of HSCs in different models, including the small interfering RNA–based silencing of p70S6K in HSC lines, experiments with p70S6K–/– cells, and the pharmacological inhibition of p70S6K by CEP-1347. These findings were validated in vivo as p70S6K–/– mice developed significantly less fibrosis upon exposure to CCl4. Conclusions: We establish p70S6K as a checkpoint of fibrogenesis in vitro and in vivo and CEP-1347 as potential treatment option that can safely be used for long-term treatment.

Chronic HCV infections represent a major worldwide public health problem and are responsible for a large proportion of liver related deaths, mostly because of HCV-associated hepatocellular carcinoma and cirrhosis. The treatment of HCV has undergone a rapid and spectacular revolution. In the past 5 years, the launch of direct acting antiviral drugs has seen sustained virological response rates reach 90% and above for many patient groups. The new treatments are effective, well tolerated, allow for shorter treatment regimens and offer new opportunities for previously excluded groups. This therapeutic revolution has changed the rules for treatment of HCV, moving the field towards an interferon-free era and raising the prospect of HCV eradication. This manuscript addresses the new challenges regarding treatment optimisation in the real world, improvement of antiviral efficacy in 'hard-to-treat' groups, the management of patients whose direct acting antiviral drug treatment was unsuccessful, and access to diagnosis and treatment in different parts of the world.

Medical faculties have the responsibility to train tomorrow's doctors and in a crisis face the challenge of delivering students into the workforce promptly and safely. Worldwide, medical faculties have faced unprecedented disruptions from viral outbreaks and pandemics including SARS, Ebola, H1N1 and COVID-19 which bring unique challenges. Currently there is worldwide disruption to medical faculties and medical education due to COVID-19. Despite close links with clinical medicine and the known risks of pandemics, many medical faculties have been caught off guard without pandemic planning in place, to deal with an exponential rise in infections and deaths, overwhelmed health services and widespread community risk of transmission. Assessing transmission risk of COVID-19 in teaching, clinical and community attachments and continuing medical education is paramount as medical faculties face subsequent pandemics waves. Consensus statements based on best available evidence and international expertise from medical faculties in Asia, Australia and Europe were developed to help guide the protection of staff and students, priorities on teaching activities and further educational development. Infection prevention, infection control, contact tracing and medical surveillance are detailed to minimise transmission and to enhance safety. Recommendations on teaching activities planning can enhance responsiveness of medical faculties to tackle subsequent waves of COVID-19 infection. A global approach and dialogue are encouraged.

Drug-induced liver injury (DILI) is a rare but potentially severe adverse drug event, which is also a major cause of study cessation and market withdrawal during drug development. Since no acknowledged diagnostic tests are available, DILI diagnosis poses a major challenge both in clinical practice as well as in pharmacovigilance. Differentiation from other liver diseases and the identification of the causative agent in the case of polymedication are the main issues that clinicians and drug developers face in this regard. Thus, efforts have been made to establish diagnostic testing methods and biomarkers in order to safely diagnose DILI and ensure a distinguishment from alternative liver pathologies. This review provides an overview of the diagnostic methods used in differential diagnosis, especially with regards to autoimmune hepatitis (AIH) and drug-induced autoimmune hepatitis (DI-AIH), in vitro causality methods using individual blood samples, biomarkers for diagnosis and severity prediction, as well as experimental predictive models utilized in pre-clinical settings during drug development regimes.

Background: Systemic inflammation and severe fibrosis can reduce serum zinc levels, while zinc supplementation is reported to improve the prognosis of patients with chronic liver disease (CLD). Objectives: We aimed to investigate the clinical application of serum zinc in patients with CLD and the anti-infective mechanism of zinc supplementation. Methods: Based on the serum zinc level, 149 CLD patients were divided into 3 groups and their clinical parameters were compared. In in-vitro experiments, microbial isolates derived from patients were used to stimulate human liver non-parenchymal cells, and the zinc sulfate solution was added in certain experiments. The effect of zinc was compared by LDH and thromboxane A2 levels in the cell supernatant. Result: Compared with other groups, patients with low serum zinc levels had significantly higher C-reactive protein (CRP), total bilirubin, INR, creatinine, and MELD scores, while albumin and GOT levels were reduced. Only CRP and albumin were significantly correlated with serum zinc in both low and normal-zinc groups. Bacterial isolates significantly increased LDH levels in Kupffer cells (KCs) and stellate cells but had no effect on sinusoidal endothelial cells, whereas zinc pretreatment protected KCs but not stellate cells. Thromboxane A2 secreted by KCs can also be induced by bacterial stimulation, accompanied by increased gene expression of Myd88, MAPK and NF-kB, while zinc pretreatment can attenuate that. Conclusion: Serum zinc levels can be used to estimate infection and liver fibrosis in CLD patients. As a new antibacterial weapon, zinc supplementation acts on KCs through Myd88-MAPK related pathways.

Abstract Background The allocation of any scarce health care resource, especially a lifesaving resource, can create profound ethical and legal challenges. Liver transplant allocation currently is based upon urgency, a sickest-first approach, and does not utilize capacity to benefit. While urgency can be described reasonably well with the MELD system, benefit encompasses multiple dimensions of patients’ well-being. Currently, the balance between both principles is ill-defined. Methods This survey with 502 participants examines how urgency and benefit are weighted by different stakeholders (medical staff, patients on the liver transplant list or already transplanted, medical students and non-medical university staff and students). Results Liver transplant patients favored the sickest-first allocation, although all other groups tended to favor benefit. Criteria of a successful transplantation were a minimum survival of at least 1 year and recovery of functional status to being ambulatory and capable of all self-care (ECOG 2). An individual delisting decision was accepted when the 1-year survival probability would fall below 50%. Benefit was found to be a critical variable that may also trigger the willingness to donate organs. Conclusions The strong interest of stakeholder for successful liver transplants is inadequately translated into current allocation rules.

The data presented in this article describe the fatty acid composition of chow, liver tissue and isolated liver mitochondria from mice fed for 6â24 weeks with a high caloric western diet (WD) in comparison to control diet (normal diet, ND). The fatty acid composition was measured via gas chromatography flame ionization detection (GC-FID). Moreover, WD-induced mitochondrial protein changes are presented in this work and were analyzed by mass spectrometry (LCâMS/MS). For further interpretation and discussion of the presented data please refer to the research article entitled âMitochondrial adaptation in steatotic miceâ (Einer et al., 2017) [1].

Primary sclerosing cholangitis (PSC) represents a chronic liver disease characterized by poor prognosis and lacking causal treatment options. Yes-associated protein (YAP) functions as a critical mediator of fibrogenesis; however, its therapeutic potential in chronic biliary diseases such as PSC remains unestablished. The objective of this study is to elucidate the possible significance of YAP inhibition in biliary fibrosis by examining the pathophysiology of hepatic stellate cells (HSC) and biliary epithelial cells (BEC). Human liver tissue samples from PSC patients were analyzed to assess the expression of YAP/connective tissue growth factor (CTGF) relative to non-fibrotic control samples. The pathophysiological relevance of YAP/CTGF in HSC and BEC was investigated in primary human HSC (phHSC), LX-2, H69, and TFK-1 cell lines through siRNA or pharmacological inhibition utilizing verteporfin (VP) and metformin (MF). The Abcb4-/- mouse model was employed to evaluate the protective effects of pharmacological YAP inhibition. Hanging droplet and 3D matrigel culture techniques were utilized to investigate YAP expression and activation status of phHSC under various physical conditions. YAP/CTGF upregulation was observed in PSC patients. Silencing YAP/CTGF led to inhibition of phHSC activation and reduced contractility of LX-2 cells, as well as suppression of epithelialmesenchymal transition (EMT) in H69 cells and proliferation of TFK-1 cells. Pharmacological inhibition of YAP mitigated chronic liver fibrosis in vivo and diminished ductular reaction and EMT. YAP expression in phHSC was effectively modulated by altering extracellular stiffness, highlighting YAP's role as a mechanotransducer. In conclusion, YAP regulates the activation of HSC and EMT in BEC, thereby functioning as a checkpoint of fibrogenesis in chronic cholestasis. Both VP and MF demonstrate effectiveness as YAP inhibitors, capable of inhibiting biliary fibrosis. These findings suggest that VP and MF warrant further investigation as potential therapeutic options for the treatment of PSC. [ABSTRACT FROM AUTHOR]

Chronic liver diseases (CLDs) are complex diseases that cause long-term inflammation and infection, which in turn accelerate their development. The usage of albumin in patients with CLDs has been debated for years. Human serum albumin (HSA) plays a key role in immunomodulation during the process of CLDs. The correlation between albumin and C-reactive protein (CRP) in CLD patients was analyzed by linear regression with the Pearson statistic. The damage of THP-1 and primary cells was evaluated by measuring the lactate dehydrogenase (LDH) in the supernatant. Immunofluorescence staining was performed to determine underlying pathways in Kupffer cells (KCs). Albumin negatively correlated with infection in patients with CLDs. In vitro experiments with THP-1 cells and KCs showed that albumin reduced LDH release after stimulation with bacterial products, while no differences in hepatic stellate cells (HSCs) and sinusoidal endothelial cells (SECs) were detected. Moreover, immunofluorescence staining revealed an increase of p-ERK and p-NF-kB p65 density after albumin treatment of KCs stimulated by bacterial products. In conclusion, albumin could assist CLD patients in alleviating inflammation caused by bacterial products and might be beneficial to patients with CLDs by securing KCs from bacteria-induced damage, providing a compelling rationale for albumin therapy in patients with CLDs.