BACKGROUND & AIMS:Patients with decompensated cirrhosis are at high risk of developing bacterial infections. The most common infection is spontaneous bacterial peritonitis in ascites fluid, caused by gut bacterial translocation and facilitated by cirrhosis associated immune dysfunction. Common causative agents of spontaneous bacterial peritonitis are thought to represent pathobionts that increase in abundance in the gut with cirrhosis severity, rather than opportunistic commensals. Despite this there have been few studies describing the characteristics of spontaneous bacterial peritonitis pathogens and immune responses to them. METHODS:We investigated the bactericidal capacity of cell-free ascites fluid and ascites macrophages. RESULTS:Nonpathogenic Escherichia coli K12 was rapidly killed in cell-free ascites fluid, whereas extraintestinal pathogenic E coli and Klebsiella pneumoniae strains, representative of the most common causes of spontaneous bacterial peritonitis, were resistant. A transposon-based genome-wide screen identified a requirement for genes involved in O-antigen biosynthesis for survival of both organisms in cell-free ascites fluid, including the transcription factor RfaH, which controls expression of surface polysaccharides. Although extraintestinal pathogenic E coli were resistant to fluid-mediated killing, ascites macrophages, especially VSIG4Hi cells, phagocytosed and killed extraintestinal pathogenic E coli and nonpathogenic E coli K-12 with similar efficacy. Mice with toxin-induced cirrhosis had higher bacterial burdens in the liver compared with control mice when infected with extraintestinal pathogenic E coli, but rapidly cleared an rfaH mutant attenuated for capsule and O-antigen biosynthesis. CONCLUSIONS:These data highlight the importance of understanding bacterial virulence profiles in addition to taxonomy in cirrhosis dysbiosis and identify critical roles for capsule and O-antigen in host evasion by spontaneous bacterial peritonitis-associated pathogens. Targeting bacterial virulence factors and/or host macrophage functions may reduce the risk of spontaneous bacterial peritonitis in cirrhosis.

Background Chronic diseases are a significant health concern in Australia. Understanding community preferences for health screening services is vital for enhancing service delivery. We conducted a study to determine community preferences for health screening services for chronic diseases in Australia using a discrete choice experiment (DCE). This paper aims to present the development of the final DCE design using priors estimated from a survey. Methods A DCE was conducted in Australia. An online survey was administered to a general Australian population over 18. The final attribute list of five attributes with three levels each was designed. A D-efficient design with 30 pair-wise choice tasks was developed using a fractional factorial design. A pre-test was conducted to assess comprehension and understanding of the online DCE survey. The pilot survey aimed to compute priors (i.e. coefficients) associated with attributes. A multinomial logit model was used to analyse the pilot DCE data. Results The survey included 30 choice tasks in three blocks, with 119 participants responding. The best DCE design was selected based on D-error, with a lower D-error indicating the most efficient design. The pilot survey results indicated a strong preference for highly accurate screening tests, with coefficients for 85% and 95% accuracy being positive. Coefficients estimated from the pilot survey were used as priors to design the DCE choice tasks for the main survey. The final DCE design showed a notable improvement in the attribute level overlap compared to the design used for the pilot survey. Conclusions A rigorous approach was taken to develop a DCE survey that could effectively determine the preferences of the community for health screening services. The resulting DCE design consisted of 30 choice tasks presented in pairs and was deemed efficient enough to gather comprehensive information in the final survey.

Background & Aims:Granular detail about the location and nature of liver cell interactions and the metabolic, inflammatory and fibrogenic pathways driving progressive fibrosis in metabolic dysfunction-associated steatotic liver disease (MASLD) is needed to identify novel therapeutic targets. Methods:We generated Visium spatial transcriptomic data from 33 human liver biopsies across the spectrum of MASLD. Gene expression data were overlaid with histological annotations to integrate spatial molecular and histopathological information, enabling interrogation of disease progression. Differential gene expression, pathway, cellular deconvolution and ligand-receptor interaction analyses were conducted for each annotated anatomical category, with specific protein expression validated using immunohistochemistry staining. Results:Unsupervised clustering based on gene expression data classified the annotated spots into two main clusters enriched for fibro-inflammatory vs. parenchymal regions. Transcriptomic cellular deconvolution aligned well with manually annotated histopathological features. Fibrotic regions were enriched for genes involved in extracellular matrix/receptor interactions and inflammatory pathways (Benjamini-Hochberg adjusted p values <0.05), underscoring known pathological mechanisms. We also identified immunoglobulin gene induction in late-stage fibrosis, which was spatially associated with a senescence signature, as has previously been reported in aging tissues. Dynamic changes in metabolic gene expression from early to late fibrosis were observed, suggesting MASLD progression is accompanied by a decline in normal liver metabolic function and reprogramming of metabolic fuel utilisation from oxidative to glycolytic metabolism, which may be both a cause and a consequence of senescence. Conclusions:Taken together, our valuable discovery dataset highlights the complex crosstalk between metabolic perturbations and inflammation underpinning fibrosis progression in MASLD. Impact and implications:Metabolic dysfunction-associated steatotic liver disease (MASLD) has a complex pathogenesis driven by cell and matrix interactions in inflammatory niches. In this study, we identify a senescence signature in fibroinflammatory regions, characterised by high immunoglobulin expression and associated with a shift from oxidative to glycolytic metabolism. We identify spatially co-expressed ligand-receptor pairs, including senescence-associated factors, correlated with progressive fibrosis. This discovery dataset highlights the complex crosstalk between metabolic perturbations and inflammation underpinning fibrosis progression in MASLD and lays the groundwork for future research into the role of senescence in MASLD.

Background:Liver disease is an important contributor to high mortality in First Nations Australians. We describe cause-specific mortality by First Nations status in people with cirrhosis. Methods:Population-based retrospective cohort analysis of all adults with cirrhosis admitted to hospitals in the state of Queensland (2007-2022). Patients (1909 First Nations and 20,584 non-First Nations) were followed from the first admission with cirrhosis until date of death, liver transplant, or 31 December 2022, whichever came first. Multivariable Cox regression and Fine and Gray proportional subhazard models were used to assess differences in mortality according to First Nations status. Findings:During a median follow-up of 6.9 years (IQR 3.5-11.1), 995 (52.1%) First Nations and 11,367 (55.2%) non-First Nations patients died. First Nations people died on average 9.4 years younger than non-First Nations Australians (57.0 years (SD = 12.1) vs 66.4 years (SD = 12.2), respectively). Approximately half of First Nations (48.9%) and non-First Nations (50.4%) deaths had liver disease as their underlying cause, and the 10-year liver-related mortality did not differ according to First Nations status (adjusted-sHR = 0.92, 95% CI 0.83-1.01). First Nations patients had a 1.6-fold increased risk of 10-year mortality due to cardiovascular disease (adjusted-sHR = 1.59, 95% CI 1.29-1.96), diabetes (adjusted-sHR = 1.60, 95% CI 1.07-1.52), and infections/parasitic diseases (adjusted-sHR = 1.61, 95% CI 1.12-2.23) vs non-First Nations patients. Interpretation:Mortality due to cardiovascular disease, diabetes, and infections/parasitic diseases are 60% higher in First Nations Australians with cirrhosis. The higher non-liver disease mortality in First Nations Australians reinforces the need for a holistic approach to management of metabolic comorbidities in patients with cirrhosis. Funding:This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

With the high burden of Metabolic dysfunction-associated steatotic liver disease (MASLD), (previously known as Non-Alcoholic Fatty Liver Disease - NAFLD) in the community, current models of care that require specialist review for disease risk stratification overwhelm hospital clinic capacity and create inefficiencies in care. The LOCal Assessment and Triage Evaluation of Non-Alcoholic Fatty Liver Disease (LOCATE-NAFLD) randomised trial compared usual care to a community-based nurse delivered liver risk assessment. This study evaluates the implementation strategy of the LOCATE model. The evaluation used mixed methods (quantitative trial data and qualitative framework analysis of semi-structured interviews) to explore the general practitioner (GP) and patient perspectives of acceptability (Acceptability Framework), and factors associated with reach, effectiveness, adoption, implementation, and maintenance (RE-AIM framework) of the LOCATE model of care. The LOCATE model was considered highly acceptable by both patients and GPs. The model of care achieved appropriate reach across the participating health services, reaching high-risk patients faster than usual care and with predominantly positive patient experiences. A notable reduction in anxiety and stress was experienced in the intervention group due to the shorter waiting times between referral and assessment. There was an overall perception of confidence in nursing staff capability to perform the community-based screening and GPs indicated confidence in managing low-risk MASLD without the need for specialist review. Challenges to implementation, adoption and maintenance included variable prioritisation of liver disease assessment in complex cases, the need for further GP training in MASLD assessment and treatment pathways, available funding and referral pathways for community screening, and accessibility of effective diet and exercise professional support. Nurse delivered community-based liver screening is highly acceptable to GPs and patients and has shown to be an effective mechanism to identify high risk patients. Adoption and maintenance of the model of care faces significant challenges related to affordable access to screening, prioritisation of liver disease in complex patient cohorts, and unresolved difficulties in prescribing effective strategies for sustained lifestyle intervention in the primary care setting. The trial was registered on 30 January 2020 and can be found via Australian New Zealand Clinical Trials Registry (ANZCTR) – ACTRN12620000158965.

OBJECTIVE:To determine the cumulative incidence of overall and cause-specific mortality among Queensland residents admitted to hospital with cirrhosis during 2007-22, by cirrhosis aetiology. STUDY DESIGN:Retrospective cohort study; analysis of linked Queensland Hospital Admitted Patient Data Collection and Queensland Registry of Births, Deaths and Marriages data. SETTING, PARTICIPANTS:Adult Queensland residents (18 years or older) admitted to Queensland hospitals with cirrhosis during 1 July 2007 - 31 December 2022. MAIN OUTCOME MEASURES:Ten-year mortality, all-cause and cause-specific (liver-related, extrahepatic cancer, cardiovascular disease), by cirrhosis aetiology. RESULTS:A total of 22 525 people were followed for a median of 6.9 years (interquartile range, 3.5-11.1 years). Their mean age at the index admission with cirrhosis was 61.2 years (standard deviation, 13.0 years), 14 895 were men (66.1%), and the most frequent causes of cirrhosis were alcohol use (9550 people, 42.4%), metabolic dysfunction-associated steatotic liver disease (MASLD; 5108 people, 22.7%), and chronic hepatitis C virus (HCV) infection (4780 people, 21.2%). A total of 12 387 people (55.0%) had died by 31 December 2022; overall mortality among people with alcohol-related cirrhosis was 57.9%, with MASLD cirrhosis 52.1%, and with HCV-related cirrhosis 51.6%. The proportions of deaths attributed to liver disease were larger for people who experienced decompensation during follow-up than those who did not (alcohol-related cirrhosis: 2538 of 3890 deaths [65.2%] v 523 of 1637 [31.9%]; HCV-related cirrhosis: 1158 of 1714 deaths [67.6%] v 331 of 753 [44.0%]). Ten-year liver-related mortality was highest among people with alcohol-related cirrhosis (48.8%; 95% confidence interval [CI], 47.2-50.4%) or HCV-related cirrhosis (44.3%; 95% CI, 42.3-46.3%); ten-year extrahepatic cancer mortality (18.8%; 95% CI, 16.8-20.9%) and cardiovascular disease mortality (15.6%; 95% CI, 13.8-17.7%) were highest among people with MASLD cirrhosis. In multivariable competing risks regression analyses, people with MASLD cirrhosis were less likely than people with alcohol-related cirrhosis to die of liver disease (adjusted subdistribution hazard ratio [sHR], 0.55; 95% CI, 0.51-0.60) and more likely to die of extrahepatic cancer (adjusted sHR, 1.21; 95% CI, 1.04-1.41). CONCLUSIONS:Mortality among people who have been hospitalised with cirrhosis is high, and there is substantial variation in cause-specific mortality by cirrhosis aetiology. Care for these patients could be improved by identifying chronic liver disease earlier, and by treating cardiovascular disease and extrahepatic malignancies in people with MASLD.

INTRODUCTION:Metabolic dysfunction-associated fatty liver disease (MAFLD) is common. This evidence-based consensus statement summary provides recommendations for the assessment and monitoring of adults with MAFLD in primary care. MAIN RECOMMENDATIONS:Adults with type 2 diabetes, obesity or two or more other metabolic risk factors should be tested for MAFLD. Hepatic steatosis should be evaluated using ultrasound, whereas the presence and complications of type 2 diabetes and obesity should be assessed according to current Australian guidelines. Cardiovascular disease, chronic kidney disease and obstructive sleep apnoea are common in people with MAFLD and should be considered as part of a holistic health assessment. Alternative causes of hepatic steatosis, including excess alcohol consumption, must be considered, and patients with elevated serum aminotransferase levels should be tested for hepatitis B and C infection and iron overload. The risk of advanced liver fibrosis requires assessment using the Fibrosis-4 (FIB-4) Index; a low score (< 1.3) is associated with a more than 95% negative predictive value for advanced liver fibrosis. People with an indeterminate FIB-4 score (between 1.3 and 2.7) should undergo second-line assessment with liver elastography or a direct liver fibrosis serum test or, if these tests are unavailable, should be referred to an expert clinician in liver disease. People with MAFLD and a high FIB-4 score (> 2.7), an elevated direct liver fibrosis serum test, high elastography results or with clinical, laboratory or imaging evidence of cirrhosis should be referred for further evaluation. Individuals with a low FIB-4 score (< 1.3), low elastography or direct liver fibrosis serum test results should be monitored with a repeat FIB-4 test at least every three years. Monitoring of weight, body mass index and/or waist circumference and for emergence of type 2 diabetes (in individuals without) should be performed at least annually. CHANGE IN MANAGEMENT AS A RESULT OF THIS CONSENSUS STATEMENT SUMMARY: Appropriate identification, assessment and risk stratification of people with MAFLD will aid referral pathways, further investigation and management.

Hepatic steatosis or fatty liver disease is a rapidly emerging health issue and is closely linked to an increase in cardiometabolic conditions such as obesity and type 2 diabetes. The nomenclature surrounding fatty liver has recently undergone multiple reviews to better reflect its underlying causes. This article reviews recent guidelines and nomenclature changes to fatty liver disease and will explore the various ultrasound technologies that are available for liver fat quantification, emphasising ultrasound's importance in diagnosing and monitoring steatosis. Sonographers must remain informed of classification changes and criteria as they directly impact their role in detecting and assessing liver steatosis.

Abstract Background Liver disease is an important contributor to the mortality gap between First Nations Peoples and non-Indigenous Australian adults. Despite a high burden of metabolic comorbidities among First Nations Peoples, data about the epidemiology of metabolic dysfunction-associated steatotic liver disease (MASLD) in this population is scarce. Methods A retrospective analysis of all adults hospitalized with MASLD or metabolic dysfunction-associated steatohepatitis (MASH) with/without cirrhosis during 2007–2019 in the state of Queensland was performed. Patients were followed from the first admission with MASLD/MASH (identified based on validated algorithms) to decompensated cirrhosis and overall mortality. We explored differences according to Indigenous status using Multivariable Cox regression. Findings 439 First Nations Peoples and 7,547 non-Indigenous Australians were followed for a median of 4.6 years (interquartile range 2.7–7.2). Overall, women were overrepresented, but more so in the First Nations cohort (72.7% vs. 57.0%, p < 0.001). First Nations patients were younger, a higher proportion lived in remote and socioeconomic disadvantaged areas, and had higher comorbidity compared to non-Indigenous Australians (all p < 0.001). Diabetes, the most common comorbidity affecting both groups, was overrepresented in First Nations Peoples versus non-Indigenous Australians (43.5% vs. 30.8%, p < 0.001, respectively). Nineteen (4.3%) First Nations Peoples and 332 (4.4%) of non-Indigenous patients progressed to cirrhosis decompensation (9.0% [95%CI 4.5–17.7] vs. 7.7% [95%CI 6.6–8.9; p = 0.956] respectively within 10 years). In multivariable analysis, there was no association between Indigenous status and progression to decompensated cirrhosis (p = 0.759) and survival (p = 0.437). Conclusions This study provides the first population-based epidemiological data on MASLD in First Nations Australians. The high prevalence of diabetes (that is associated with advanced fibrosis and liver disease mortality) among young First Nations Peoples with MASLD raises concern about future risk of progressive liver disease in this patient population. These data highlight the importance of early identification of MASLD, and providing culturally appropriate intervention to reduce disease progression in parallel with the management of cardiometabolic comorbidities.

Abstract Background and Aim Metabolic dysfunction‐associated steatotic liver disease (MASLD) is associated with an increased risk of extrahepatic morbidity. We compared the incidence of cancers in adults admitted to Queensland hospitals with MASLD with that for the Queensland population and examined the association between cirrhosis and type 2 diabetes and the development of extrahepatic cancers. Methods In this retrospective study, we identified all cancers (Queensland Cancer Registry) after the first hospitalization with MASLD during Jul‐2007 to Dec‐2019, estimated age‐standardized incidence (ASI) of cancers, and compared that with the ASI in the Queensland population (incidence rate ratios [IRR]). Among the MASLD cohort, we examined the association between diabetes and cancer risk (Cox regression). Median follow‐up was 3.8 years (54 204 person‐years). Results Totally 1104 new cancers were diagnosed in 1018 patients (8.9% of 9771 non‐cirrhotic and 1712 adults with cirrhosis). The ASI (all cancers) of 1668.2 per 100 000 person‐years in men (95% CI 1523.7–1827.4) and 1284.0 per 100 000 person‐years in women (95% CI 1169.6–1408.2) was 2‐fold higher than that of the Queensland population (IRR = 1.94, 95% CI 1.75–2.16 and IRR = 1.99, 95% CI 1.78–2.22, respectively). Incidence of stomach cancer, unknown primary, and pancreas was 3‐ to 5‐fold higher compared to the general population (all P < 0.001). In multivariable analysis of the MASLD cohort, older age (e.g. ≥70 years adjusted hazard ratio [adj‐HR] = 4.59, 95% CI 3.61–5.83), male gender (adj‐HR = 1.20, 95% CI 1.05–1.37), and cirrhosis (adj‐HR = 1.37, 95% CI 1.11–1.70) were independently associated with extrahepatic cancer risk, while diabetes was not. Conclusions Our findings will help to raise awareness among clinicians about the importance of cancer vigilance in this patient group.

Background:Although clinical guidelines endorse screening for metabolic dysfunction-associated steatotic liver disease (MASLD) with advanced fibrosis in people with type 2 diabetes (T2D), the feasibility of and barriers and considerations relevant to implementing this approach in the community remain unclear. Methods:Sequential adults with T2D attending selected community clinics during 2021-2023 were invited to receive a "liver health check" (n=543). A further 95 participants were referred directly from their general practitioner (GP) or self-referred to the study. A total of 302 participants underwent a point of care assessment of hepatic steatosis and stiffness (FibroScan) and were advised to see their GP to discuss the results. "Template" letters containing key results, their interpretation and advice about management of cardiometabolic risk, patient follow-up and referral criteria, were sent to participants' GPs. Results:Referral to a tertiary liver clinic was advised in GP letters for 45 (15%) participants with an increased risk of clinically significant fibrosis (liver stiffness measurement ≥8), 15 participants with 'red flags' (eg splenomegaly, thrombocytopenia) and 2 with unsuccessful FibroScan examinations. A referral from GPs to the liver clinic was received for 27 (44%) of these 62 participants. Approximately 90% of GPs rated the "template" letters favourably on a Likert rating scale. Conclusion:The low rate of participation in the "liver health check" and liver clinic referral reflects a real-world scenario and may stem from societal under-recognition and engagement with MASLD, competing health priorities or under-appreciation of the link between liver fibrosis severity and mortality risk. Further studies need to address strategies to enhance participation in liver health assessments and determine their impact on liver-related morbidity/mortality and overall survival.

Background With the high burden of Non-Alcoholic Fatty Liver Disease (NAFLD) in the community, current models of care that require specialist review for disease risk stratification overwhelm hospital clinic capacity and create inefficiencies in care. The LOCal Assessment and Triage Evaluation of Non-Alcoholic Fatty Liver Disease (LOCATE-NAFLD) randomised trial compared usual care to a community-based nurse delivered liver risk assessment. This study evaluates the implementation strategy of LOCATE-NAFLD. Methods The evaluation used multiple methods (quantitative trial data and qualitative framework analysis of semi-structured interviews) to explore the general practitioner (GP) and patient perspectives of acceptability (Acceptability Framework), and factors associated with reach, effectiveness, adoption, implementation, and maintenance (RE-AIM framework) of the LOCATE model of care. Results LOCATE-NAFLD was considered highly acceptable by both patients and GPs. The model of care achieved appropriate reach across the participating health services, reaching high-risk patients faster than usual care and with predominantly positive patient experiences. A notable reduction in anxiety and stress was experienced in the intervention group due to the shorter waiting times between referral and assessment. There was an overall perception of confidence in nursing staff capability to perform the community-based screening and GPs indicated confidence in managing low-risk NAFLD without the need for specialist review. Challenges to implementation, adoption and maintenance included variable prioritisation of liver disease assessment in complex cases, the need for further GP training in NAFLD assessment and treatment pathways, available funding and referral pathways for community screening, and accessibility of effective diet and exercise professional support. Conclusion Nurse delivered community-based liver screening is highly acceptable to GPs and patients and has shown to be an effective mechanism to identify high risk patients. Adoption and maintenance of the model of care faces significant challenges related to affordable access to screening, prioritisation of liver disease in complex patient cohorts, and unresolved difficulties in prescribing effective strategies for sustained lifestyle intervention in the primary care setting. Trial registration The trial was registered on 30 January 2020 and can be found via Australian New Zealand Clinical Trials Registry (ANZCTR) – ACTRN12620000158965.