Progress is impossible without change: understanding the evolving nomenclature of steatotic liver disease and its effect on hepatology practice.

The American, European, and Latin American liver societies have proposed a change in the nomenclature we use to describe alcohol-related liver disease and non-alcoholic fatty liver disease. Additionally, a term encompassing both is now advocated: steatotic liver disease, which includes metabolic dysfunction associated steatotic liver disease (MASLD) and MASLD with greater alcohol consumption (MetALD). These classifications offer increased relevance for clinicians, researchers, and patients alike. In this Viewpoint, we discuss the basis for this nomenclature shift and how it was developed. We also explore the challenges that will be faced in the adoption of such change. The proposed change seeks to banish stigma associated with phrasing such as alcoholic and fatty. However stigma, particularly related to the term fatty, is culturally nuanced, and reflects different entities depending on location. If such a change is internationally accepted, there will be wide-reaching effects on practitioners in primary care and metabolic medicine, and on patients. We discuss those effects and the opportunities the nomenclature change could offer, particularly for patients with alcohol and metabolic risk factors who represent a group previously ignored by clinical trials.

The challenges and potential of microRNA-based therapy for patients with liver failure syndromes and hepatocellular carcinoma.

INTRODUCTION: Morbidity and mortality from liver disease continues to rise worldwide. There are currently limited curative treatments for patients with liver failure syndromes, encompassing acute liver failure and decompensated cirrhosis states, outside of transplantation. Whilst there have been improvements in therapeutic options for patients with hepatocellular carcinoma (HCC), there remain challenges necessitating novel therapeutic agents. microRNA have long been seen as potential therapeutic targets but there has been limited clinical translation. AREAS COVERED: We will discuss the limitations of conventional non-transplant management of patients with liver failure syndromes and HCC. We will provide an overview of microRNA and the challenges in developing and delivering microRNA-based therapeutic agents. We will finally provide an overview of microRNA-based therapeutic agents which have progressed to clinical trials. EXPERT OPINION: microRNA have great potential to be developed into therapeutic agents due to their association with critical biological processes which govern health and disease. Utilizing microRNA sponges to target multiple microRNA associated with specific biological processes may improve their therapeutic efficacy. However, there needs to be significant improvements in delivery systems to ensure the safe delivery of microRNA to target sites and minimize systemic distribution. This currently significantly impacts the clinical translation of microRNA-based therapeutic agents.

The challenges and potential in developing microRNA associated with regeneration as biomarkers to improve prognostication for liver failure syndromes and hepatocellular carcinoma.

INTRODUCTION: Determining the need for liver transplantation remains critical in the management of hepatocellular carcinoma (HCC) and liver failure syndromes (including acute liver failure and decompensated cirrhosis states). Conventional prognostic models utilize biomarkers of liver and non-liver failure and have limitations in their application. Novel biomarkers which predict regeneration may fulfil this niche. microRNA are implicated in health and disease and are present in abundance in the circulation. Despite this, they have not translated into mainstream clinical biomarkers. AREAS COVERED: We will discuss current challenges in the prognostication of patients with liver failure syndromes as well as for patients with HCC. We will discuss biomarkers implicated with liver regeneration. We then provide an overview of the challenges in developing microRNA into clinically tractable biomarkers. Finally, we will provide a scoping review of microRNA which may have potential as prognostic biomarkers in liver failure syndromes and HCC. EXPERT OPINION: Novel biomarkers are needed to improve prognostic models in liver failure syndromes and HCC. Biomarkers associated with liver regeneration are currently lacking and may fulfil this niche. microRNA have the potential to be developed into clinically tractable biomarkers but a consensus on standardizing methodology and reporting is required prior to large-scale studies.

UK national trainee survey of hepatology training, research and the future workforce.

Objective: The increasing prevalence of liver disease in the UK means there is a pressing need to expand the hepatology workforce. This survey aims to evaluate current hepatology training provision, and trainee attitudes towards future careers in hepatology. Method: An electronic survey was distributed to higher specialty gastroenterology and hepatology trainees in the UK between March and May 2022. Results: 138 trainees completed the survey covering all training grades and regions of the UK. 73.7% reported receiving adequate hepatology training currently, with 55.6% intending to become future hepatologists. Trainee preference for future hepatology consultant posts in specialist liver centres were almost threefold higher compared with district general hospitals (60.9% vs 22.6%). All trainees, irrespective of training grade reported high confidence in managing decompensated cirrhosis in both inpatient and outpatient settings. Senior trainees (grade ST6 and higher), without advanced training programme (ATP) experience reported significantly lower confidence in managing viral hepatitis, hepatocellular carcinoma and post-transplant patients compared with equivalent trainees with ATP experience. For junior trainees (IMT3-ST5), remaining in their current deanery was the most important factor when considering future hepatology training application. Conclusions: There is a significant need to deliver widely available training on the management of complex liver disease to improve non-ATP trainee confidence. Innovative job planning strategies are required to encourage trainees to pursue careers outside of specialist liver centres. Expansion of hepatology training networks with wider geographical coverage are needed to address the growing need for more hepatologists around the UK.

Satellite liver transplant centres significantly improve transplant assessment outcomes for patients with chronic liver disease but not hepatocellular carcinoma: a retrospective cohort study.

Introduction: Liver transplantation (LT) remains integral to the management of end-stage chronic liver disease (CLD). However, referral thresholds and assessment pathways remain poorly defined. Distance from LT centre has been demonstrated to impact negatively on patient outcomes resulting in the development of satellite LT centres (SLTCs). We aimed to evaluate the impact of SLTCs on LT assessment in patients with CLD and hepatocellular carcinoma (HCC). Methods: A retrospective cohort study was undertaken including all patients with CLD or HCC assessed for LT at King's College Hospital (KCH) between October 2014 and October 2019. Referral location, social, demographic, clinical and laboratory data were collected. Univariable and multivariable analyses (MVA) were performed to assess the impact of SLTCs on patients being accepted as LT candidates and contraindications being identified. Results: 1102 and 240 LT assessments were included for patients with CLD and HCC, respectively. MVA demonstrated significant associations with; patients living greater than 60 min from KCH/SLTCs and LT candidacy acceptance in CLD, and less deprived patients and LT candidacy acceptance in HCC. However, neither variable was associated with identification of LT contraindications. MVA demonstrated that referrals from SLTCs were more likely to result in acceptance of LT candidacy and less likely to result in a contraindication being identified in CLD. However, such associations were not demonstrated in HCC. Conclusion: SLTCs improve LT assessment outcomes in CLD but not HCC reflecting the standardised HCC referral pathway. Developing a formal regional LT assessment pathway across the UK would improve equity of access to transplantation.

Reduced survival after upper gastrointestinal bleed endoscopy in the COVID-19 era is a secondary effect of the response to the global pandemic: a retrospective cohort study.

OBJECTIVE: The COVID-19 pandemic has placed increased strain on healthcare systems worldwide with enormous reorganisation undertaken to support 'COVID-centric' services. Non-COVID-19 admissions reduced secondary to public health measures to halt viral transmission. We aimed to understand the impact of the response to COVID-19 on the outcomes of upper gastrointestinal (UGI) bleeds. DESIGN/METHODS: A retrospective observational multicentre study comparing outcomes following endoscopy for UGI bleeds from 24 March 2020 to 20 April 2020 to the corresponding dates in 2019. The primary outcome was in-hospital survival at 30 days with secondary outcomes of major rebleeding within 30 days postprocedure and intervention at the time of endoscopy. RESULTS: 224 endoscopies for 203 patients with UGI bleeds were included within this study. 19 patients were diagnosed with COVID-19. There was a 44.4% reduction in the number of procedures performed between 2019 and 2020. Endoscopies performed for UGI bleeds in the COVID-19 era were associated with an adjusted reduced 30-day survival (OR 0.25, 95% CI 0.08-0.67). There was no increased risk of major rebleeding or interventions during this era. Patients with COVID-19 did not have reduced survival or increased complication rates. CONCLUSION: Endoscopy for UGI bleeds in the COVID-19 era is associated with reduced survival. No clear cause has been identified but we suspect that this is a secondary effect of the response to the COVID-19 pandemic. Urgent work is required to encourage the public to seek medical help if required and to optimise patient pathways to ensure that the best possible care is provided.

Regeneration linked miRNA modify tumor phenotype and can enforce multi-lineage growth arrest in vivo.

Regulated cell proliferation is an effector mechanism of regeneration, whilst dysregulated cell proliferation is a feature of cancer. We have previously identified microRNA (miRNA) that regulate successful and failed human liver regeneration. We hypothesized that these regulators may directly modify tumor behavior. Here we show that inhibition of miRNAs -503 and -23a, alone or in combination, enhances tumor proliferation in hepatocyte and non-hepatocyte derived cancers in vitro, driving more aggressive tumor behavior in vivo. Inhibition of miRNA-152 caused induction of DNMT1, site-specific methylation with associated changes in gene expression and in vitro and in vivo growth inhibition. Enforced changes in expression of two miRNA recapitulating changes observed in failed regeneration led to complete growth inhibition of multi-lineage cancers in vivo. Our results indicate that regulation of regeneration and tumor aggressiveness are concordant and that miRNA-based inhibitors of regeneration may constitute a novel treatment strategy for human cancers.

A novel microRNA-based prognostic model outperforms standard prognostic models in patients with acetaminophen-induced acute liver failure.

BACKGROUND & AIMS: Acetaminophen (APAP)-induced acute liver failure (ALF) remains the most common cause of ALF in the Western world. Conventional prognostic models, utilising markers of liver injury and organ failure, lack sensitivity for mortality prediction. We previously identified a microRNA signature that is associated with successful regeneration post-auxiliary liver transplant and with recovery from APAP-ALF. Herein, we aimed to use this microRNA signature to develop outcome prediction models for APAP-ALF. METHODS: We undertook a nested, case-control study using serum samples from 194 patients with APAP-ALF enrolled in the US ALF Study Group registry (1998-2014) at early (day 1-2) and late (day 3-5) time-points. A microRNA qPCR panel of 22 microRNAs was utilised to assess microRNA expression at both time-points. Multiple logistic regression was used to develop models which were compared to conventional prognostic models using the DeLong method. RESULTS: Individual microRNAs confer limited prognostic value when utilised in isolation. However, incorporating them within microRNA-based outcome prediction models increases their clinical utility. Our early time-point model (AUC = 0.78, 95% CI 0.71-0.84) contained a microRNA signature associated with liver regeneration and our late time-point model (AUC = 0.83, 95% CI 0.76-0.89) contained a microRNA signature associated with cell-death. Both models were enhanced when combined with model for end-stage liver disease (MELD) score and vasopressor use and both outperformed the King's College criteria. The early time-point model combined with clinical parameters outperformed the ALF Study Group prognostic index and the MELD score. CONCLUSIONS: Our findings demonstrate that a regeneration-linked microRNA signature combined with readily available clinical parameters can outperform existing prognostic models for ALF in identifying patients with poor prognosis who may benefit from transplantation. LAY SUMMARY: While acute liver failure can be reversible, some patients will die without a liver transplant. We show that blood test markers that measure the potential for liver recovery may help improve identification of patients unlikely to survive acute liver failure who may benefit from a liver transplant.

Serum MicroRNA Signatures in Recovery From Acute and Chronic Liver Injury and Selection for Liver Transplantation.

We previously demonstrated a distinct hepatic microRNA (miRNA) signature (down-regulation of miRNA-23a, -150, - 200b, -503, and -663 and up-regulation of miRNA-20a) is associated with successful regeneration in auxiliary liver transplantation (ALT). This study aimed to evaluate whether the serum expression of this regeneration-linked miRNA signature is associated with clinical outcomes in acute and chronic liver disease. These were represented by patients with acetaminophen-induced acute liver failure (ALF; n = 18) and patients with hepatitis C virus (HCV) undergoing treatment with direct-acting antivirals (n = 56), respectively. Patients were grouped depending on their clinical outcome. Global serum miRNA expression was analyzed using polymerase chain reaction (PCR) arrays and selected miRNA expression using targeted PCR. We demonstrate that specific regeneration-linked miRNAs discriminate outcomes in both clinical scenarios. We further show that miRNA-20a, -23a, -150, -200b, -503, and -663 undergo concordant changes in expression in 3 distinct clinical settings: liver regeneration accompanying successful ALT, clinical recovery after ALF, and clinical recompensation after cure of HCV. This miRNA signature represents a potentially novel biomarker to predict outcome and optimize patient selection for liver transplantation in both acute and chronic liver disease.

A 'real-world' analysis of risk factors for post liver transplant delirium and the effect on length of stay.

BACKGROUND: The development of delirium has been previously demonstrated to be associated with an increased risk of mortality and length of stay post liver transplant (LTx) with multiple risk factors being identified in previous studies. In this study, we have aimed to identify the most important variables associated with the onset of post-LTx delirium and understand the effect on length of stay (LOS). METHODS: All liver transplants for chronic liver disease between 1 August 2012 and 1 August 2017 were included (n = 793). Data were collected for analysis retrospectively from electronic patient records. RESULTS: Delirium is associated with an overall increased hospital and ICU LOS but not one-year mortality. The risk of developing post-LTx delirium was the greatest among patients: with post-LTx sepsis, who required renal sparing immunosuppression, who received donation after cardiac death (DCD) grafts and who were older. Patients with autoimmune hepatitis, primary biliary cholangitis or primary sclerosing cholangitis seemed to be at lower risk of post-LTx delirium. However, global patient LOS was only prolonged in patients with sepsis and renal failure. CONCLUSION: Many of the risk factors previously described to be associated with the development of post-LTx delirium were not demonstrated to be significant in this study. Sepsis, renal failure, older age and DCD use are associated with delirium post-LTx. It is unclear if this syndrome is an independent risk factor for increased LOS or if it is a symptom of well established syndromes associated with increased LOS. The role for prophylactic strategies to reduce the incidence of post-LTx delirium is therefore unclear.

How to manage: acute liver failure.

Acute liver failure (ALF) is a rare but life-threatening clinical syndrome with a broad range of causes. Significant improvements in outcome have occurred over the last 50 years, resulting not only from incremental improvements in specialist critical care and a step-change following the introduction of transplantation for this indication, but also better and more effective treatment started early at the site of first presentation.1 2 Emergency liver transplantation (LTx) remains an important intervention and the decision regarding the need for LTx remains key to management, though non-transplant therapies now appear effective for many causes of the condition. In this short review, we will outline issues in the recognition and management of ALF and ongoing challenges in its treatment.