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Chronic liver disease is a major cause of mortality, with approximately 2 million deaths worldwide each year, and it poses a significant economic burden. The most common cause of chronic liver disease in the United States and Europe is steatotic liver disease (SLD), which includes metabolic dysfunction-associated SLD, metabolic dysfunction and alcohol-associated SLD, and alcohol-associated liver disease (ALD). Effective treatment of these conditions is essential to reduce the liver disease burden, with promising approaches including treating cardiometabolic risk factors and excessive alcohol intake. Glucagon-like peptide 1 receptor agonists, both as monotherapy and in combination with other drugs, are gaining attention for their beneficial impact on cardiometabolic risk factors and excessive alcohol intake. In this review, we examine the molecular and clinical effects of glucagon-like peptide 1 receptor agonists, focusing on their direct hepatic steatohepatitis and liver fibrosis but also the indirect influence on cardiometabolic risk factors and excessive alcohol intake as key features of SLD. We also explore the future implications of glucagon-like peptide 1 receptor agonists for treating metabolic dysfunction-associated SLD, metabolic dysfunction and alcohol-associated SLD, alcohol-associated liver disease, and the potential challenges., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Although microbiome signatures have been identified in various contexts (ie, pathogenesis of non-communicable diseases and treatment response), qualified microbiome-based biomarkers are currently not in use in clinical practice. The Human Microbiome Action consortium initiated a Delphi survey to establish a consensus on the needs, challenges, and limitations in developing qualified microbiome-based biomarkers. The questionnaire was developed by a scientific committee via literature review and expert interviews. To ensure broad applicability of the results, 307 experts were invited to participate; 114 of them responded to the first round of the survey, 93 of whom completed the second and final round as well. The survey highlighted the experts' confidence in the potential of microbiome-based biomarkers for several indications or pathologies. The paucity of validated analytical methods appears to be the principal factor hindering the qualification of these biomarkers. The survey also showed that clinical implementation of these biomarkers would only be possible if kitted and validated molecular assays with simple interpretation are developed. This initiative serves as a foundation for designing and implementing public-private collaborative projects to overcome the challenges and promote clinical application of microbiome-based biomarkers., Competing Interests: Declaration of interests JD is a cofounder and scientific adviser of GMT Science and MaaT Pharma. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The rising prevalence of liver diseases related to obesity and excessive use of alcohol is fuelling an increasing demand for accurate biomarkers aimed at community screening, diagnosis of steatohepatitis and significant fibrosis, monitoring, prognostication and prediction of treatment efficacy. Breakthroughs in omics methodologies and the power of bioinformatics have created an excellent opportunity to apply technological advances to clinical needs, for instance in the development of precision biomarkers for personalised medicine. Via omics technologies, biological processes from the genes to circulating protein, as well as the microbiome - including bacteria, viruses and fungi, can be investigated on an axis. However, there are important barriers to omics-based biomarker discovery and validation, including the use of semi-quantitative measurements from untargeted platforms, which may exhibit high analytical, inter- and intra-individual variance. Standardising methods and the need to validate them across diverse populations presents a challenge, partly due to disease complexity and the dynamic nature of biomarker expression at different disease stages. Lack of validity causes lost opportunities when studies fail to provide the knowledge needed for regulatory approvals, all of which contributes to a delayed translation of these discoveries into clinical practice. While no omics-based biomarkers have matured to clinical implementation, the extent of data generated has enabled the hypothesis-free discovery of a plethora of candidate biomarkers that warrant further validation. To explore the many opportunities of omics technologies, hepatologists need detailed knowledge of commonalities and differences between the various omics layers, and both the barriers to and advantages of these approaches., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background & Aims: Liver stiffness measurement (LSM) is recommended for disease prognostication and monitoring. We evaluated if LSM, using transient elastography, and LSM changes predict decompensation and mortality in patients with alcohol-related liver disease (ALD)., Methods: We performed an observational cohort study of compensated patients at risk of ALD from Denmark and Austria. We evaluated the risk of decompensation and all-cause mortality, stratified for compensated advanced chronic liver disease (cACLD: baseline LSM ≥10 kPa) and LSM changes after a median of 2 years. In patients with cACLD, we defined LSM changes as (A) LSM increase ≥20% ("cACLD increasers") and (B) follow-up LSM <10 kPa or <20 kPa with LSM decrease ≥20% ("cACLD decreasers"). In patients without cACLD, we defined follow-up LSM ≥10 kPa as an LSM increase ("No cACLD increasers"). The remaining patients were considered LSM stable., Results: We followed 536 patients for 3,008 patient-years-median age 57 years (IQR 49-63), baseline LSM 8.1 kPa (IQR 4.9-21.7)-371 patients (69%) had follow-up LSM after a median of 25 months (IQR 17-38), 41 subsequently decompensated and 55 died. Of 125 with cACLD at baseline, 14% were "cACLD increasers" and 43% "cACLD decreasers", while 13% of patients without cACLD were "No cACLD increasers" (n = 33/246). Baseline LSM, follow-up LSM and LSM changes accurately predicted decompensation (C-index: baseline LSM 0.85; follow-up LSM 0.89; LSM changes 0.85) and mortality (C-index: baseline LSM 0.74; follow-up LSM 0.74; LSM changes 0.70). When compared to "cACLD decreasers", "cACLD increasers" had significantly lower decompensation-free survival and higher risks of decompensation (subdistribution hazard ratio 4.39, p = 0.004) and mortality (hazard ratio 3.22, p = 0.01)., Conclusion: LSM by transient elastography predicts decompensation and all-cause mortality in patients with compensated ALD both at diagnosis and when used for monitoring., Impact and Implications: Patients at risk of alcohol-related liver disease (ALD) are at significant risk of progressive disease and adverse outcomes. Monitoring is essential for optimal disease surveillance and patient guidance, but non-invasive monitoring tools are lacking. In this study we demonstrate that liver stiffness measurement (LSM), using transient elastography, and LSM changes after a median of 2 years, can predict decompensation and all-cause mortality in patients at risk of ALD with and without compensated advanced chronic liver disease. These findings are in line with results from non-alcoholic fatty liver disease, hepatitis C and primary sclerosing cholangitis, and support the clinical utility of LSM, using transient elastography, for disease prognostication and monitoring in chronic liver diseases including ALD, as recommended by the Baveno VII., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background & Aims: People who drink alcohol excessively are at increased risk of developing metabolic dysfunction and alcohol-related liver disease (MetALD) or the more severe form alcohol-related liver disease (ALD). One of the most significant challenges concerns the early detection of MetALD/ALD. Previously, we have demonstrated that the lysosomal enzyme cathepsin D (CTSD) is an early marker for metabolic dysfunction-associated steatohepatitis (MASH). Here, we hypothesized that plasma CTSD can also serve as an early indicator of MetALD/ALD., Methods: We included 303 persistent heavy drinkers classified as having MetALD or ALD (n = 152) and abstinent patients with a history of excessive drinking (n = 151). Plasma CTSD levels of patients with MetALD/ALD without decompensation were compared with 40 healthy controls. Subsequently, the relationship between plasma CTSD levels and hepatic histological scores was established. Receiver-operating characteristic curves were generated to assess the precision of plasma CTSD levels in detecting MetALD/ALD. Lastly, plasma CTSD levels were compared between abstainers and drinkers., Results: Plasma CTSD levels were higher in patients with MetALD/ALD compared to healthy controls. While hepatic disease parameters (AST/ALT ratio, liver stiffness measurement) were higher at advanced histopathological stages (assessed by liver biopsy), plasma CTSD levels were already elevated at early histopathological stages. Furthermore, combining plasma CTSD levels with liver stiffness measurement and AST/ALT ratio yielded enhanced diagnostic precision (AUC 0.872) in detecting MetALD/ALD in contrast to the utilization of CTSD alone (AUC 0.804). Plasma CTSD levels remained elevated in abstainers., Conclusion: Elevated levels of CTSD in the circulation can serve as an early indicator of MetALD/ALD., Impact and Implications: Alcohol-related liver disease is the leading cause of liver disease-related morbidity and mortality worldwide. However, the currently available non-invasive methods to diagnose MetALD/ALD are only able to detect advanced stages of MetALD/ALD. Here, we demonstrate that plasma levels of the lysosomal enzyme cathepsin D are already elevated at early stages of MetALD/ALD. Moreover, cathepsin D levels outperformed the currently available non-invasive methods to detect MetALD/ALD. Plasma levels of cathepsin D could therefore be a useful non-invasive marker for detection of MetALD/ALD., (© 2024 The Author(s).)

Background and Aims: Early detection of liver fibrosis is believed to promote lifestyle changes. We evaluated self-reported changes in alcohol intake, diet, exercise, and weight after participating in a screening study for liver fibrosis., Methods: We conducted a prospective screening study of individuals at risk of alcohol-related liver disease (ALD) or metabolic dysfunction-associated steatotic liver disease (MASLD). We provided lifestyle advice to all participants and evaluated lifestyle changes by questionnaires after 1 week and 6 months, with re-examination of a subgroup after 2 years., Results: A total of 1850 at risk of ALD and 2946 at risk of MASLD were included, of whom 383 (8%) were screening positive (transient elastography ≥8 kPa). A total of 84% replied to the 6-month questionnaire. In ALD participants, excessive drinking decreased from 46% to 32% after 6 months. Only 15% reported increased drinking, without differences between screening positive and negative individuals (P = .698). In high-risk drinkers, a positive screening test predicted abstinence or decreased alcohol use after 6 months (odds ratio, 2.45; 95% confidence interval, 1.32-4.57; P = .005). After 2 years, excessive drinking decreased from 52% to 41% in a subgroup of 752 individuals and a positive screening test predicted abstinence or decreased alcohol use after 2 years (odds ratio, 1.84; 95% confidence interval, 1.09-3.11, P = .023). MASLD participants showed similar improvements: 35% improved their diet, 22% exercised more, and 13% reported a weight loss ≥5% after 6 months., Conclusions: Screening for liver fibrosis is associated with sustained improvements in alcohol consumption, diet, weight, and exercise in at-risk ALD and MASLD. The changes are most pronounced in screening positive participants but not limited to this group., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Alcohol consumption is a global phenomenon and a major contributor to alcohol-associated liver disease (ALD). Detecting individuals at risk of ALD has been challenging, with only a small fraction of patients being identified at early stages compared to other chronic liver diseases. In response to this challenge, non-invasive tests (NITs) have become essential tools for the detection of ALD, offering opportunities for early identification and intervention to mitigate the disease burden. Noninvasive alcohol consumption biomarkers are crucial in estimating individuals' recent alcohol intake, providing valuable insights into their drinking patterns. Various NITs have been investigated for the initial screening of asymptomatic individuals at risk of ALD, as well as for identifying specific stages of the disease. These NITs are applied in 2 main clinical scenarios: population-based stratification for identifying and predicting liver-related symptoms and diagnosing and prognosticating compensated cirrhosis or advanced chronic liver disease in secondary or tertiary care settings. Moreover, NITs play a significant role in the prognostic assessment of patients with various manifestations of ALD, including alcohol-associated hepatitis (AH), decompensated cirrhosis, and metabolic-associated and ALD. These tests guide appropriate treatment decisions and predict outcomes. In this review, various NITs for the early detection and monitoring of alcohol consumption were discussed. Additionally, the evaluation of NITs for screening and predicting ALD and liver complications was addressed comprehensively. Future perspectives of NITs for ALD were explored, alongside a thorough discussion of the opportunities and challenges associated with NITs for ALD screening., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Background: Steatotic liver disease is a new overarching term that includes metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction and alcohol-related steatotic liver disease (MetALD), and alcohol-related liver disease (ALD). We aimed to validate the prognostic importance of MASLD, MetALD, and ALD as steatotic liver disease subclasses., Methods: Between April 18, 2013, and Sept 17, 2018, we prospectively recruited patients aged 18-75 years with current or previous excessive alcohol intake (>24 g/day for women and >36 g/day for men) for at least a year and no previous hepatic decompensation from the Department of Gastroenterology and Hepatology at Odense University Hospital (Odense, Denmark). Participants were followed up until Sept 15, 2022. Here, we characterise these patients according to steatotic liver disease subclasses. We classified patients as having MASLD, MetALD, or ALD in accordance with the nomenclature definitions, on the basis of metabolic comorbidity and self-reported average alcohol intake in the 3 months leading up to inclusion. Histological scoring was done by a pathologist who was masked to the clinical data. We compared prognoses between classes using Cox regression analyses on hepatic decompensation and overall mortality as the two outcome measures. Patients not meeting the criteria for steatotic liver disease were classified as no steatotic liver disease and served as a reference group., Findings: We enrolled 446 patients with a history of excessive alcohol intake were included in this analysis (334 [75%] were male and 112 [25%] were female; median age 56 years [SD 10]). Cirrhosis was present in 58 (13%), and 435 (98%) had at least one cardiometabolic risk factor. 321 (72%) met steatotic liver disease criteria and 125 (28%) did not have steatotic liver disease, meaning no evident liver steatosis and no significant fibrosis (≥F2). Of the 321 patients with steatotic liver disease, six (2%) were identified as having ALD due to the absence of cardiometabolic risk factors. The remaining 315 (98%) patients presented with at least one cardiometabolic risk factor. Of these patients, 153 (49%) had MASLD, 76 (24%) had MetALD, and 86 (27%) had ALD. During follow-up, 67 (15%) of 446 patients decompensated and 97 (22%) died (median follow-up 70 months [IQR 53-94]). Patients with steatotic liver disease had a significantly higher risk of hepatic decompensation and overall mortality than those without steatotic liver disease, independent of age, sex, and liver stiffness. The risk of decompensation increased in a stepwise manner from MASLD (hazard ratio 4·73 [95% CI 1·03-21·6]), through MetALD (7·69 [1·66-35·6]), to ALD (10·2 [2·24-46·4]). Similarly, overall mortality increased from MASLD (HR 2·30 [95% CI 1·08-4·90]), through MetALD (2·94 [1·31-6·58]), to ALD (3·57 [1·64-7·80]), independent of age, sex, and liver stiffness., Interpretation: Steatotic liver disease and its subclasses portend distinct prognoses. There is a need to specify how historical alcohol intake should be integrated into the nomenclature and risk stratification of steatotic liver disease., Funding: EU Horizon 2020 Research and Innovation Program., Competing Interests: Declaration of interests JKH has received speaking fees from Norgine. CW received an EASL bursary to attend the International Liver Congress (ILC) 2023. KPL received an EASL bursary to attend ILC 2023, has received consulting fees from Novo Nordisk and speaking fees and support for travel from Siemens, and owns stock in Evido. EAT has received consulting fees from Novo Nordisk, Boehringer, Pfizer, and Siemens, and speaking fees from Echosens, NovoNordisk, and Dr Falk. MT has received grants from the Novo Nordisk Foundation, consulting fees from GlaxoSmithKline, Boehringer Ingelheim, and AstraZeneca, speaking fees from Siemens Healthcare, Norgine, Echosens, Tillotts Pharma, Takeda, and Madrigal; and is vice chair on the board of non-governmental organisation Alcohol & Society and co-founder and board member for Evido. MER, in the past 24 months, has done scientific consulting for Boehringer Ingelheim, Intercept Pharmaceuticals, Madrigal, NGM Biopharmaceuticals, Novo Nordisk, GlaxoSmithKline, Sonic Incytes, Histoindex, Takeda, and CytoDyn, and has received support for travel to symposia from GlaxoSmithKline and Novo Nordisk. AK has received grants from EU Horizon 2020, the Novo Nordisk Foundation, Innovationfund Denmark, the Danish National Research Foundation, Region of Southern Denmark, and AstraZeneca; receives royalties from Gyldendal as a co-author on a textbook of internal medicine; served as speaker for Novo Nordisk, Norgine, Siemens, and Nordic Bioscience; and participated in advisory boards for Norgine, Siemens, Resalis Therapeutics, Boehringer Ingelheim, and Novo Nordisk, all outside the submitted work. AK has also received research support from Norgine, Siemens, Nordic Bioscience, AstraZeneca, and Echosens, does consulting for Takeda, Resalis Therapeutics, Zealand Pharma, and AlphaSights, and is a board member and co-founder Evido. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Human albumin is used in the treatment of complications of cirrhosis. However, the use of long-term human albumin administration is costly and resource demanding for both patients and healthcare systems. A precision medicine approach with biomarkers to predict human albumin treatment response, so-called predictive biomarkers, could make this a viable treatment option in patients with cirrhosis and ascites., Methods and Analysis: ALB-TRIAL is a multinational, double-blind, placebo-controlled randomised controlled trial. We aim to validate a predictive biomarker, consisting of a panel of circulating metabolites, to predict the treatment response to human albumin in patients with cirrhosis and ascites. All enrolled patients are stratified into a high-expected or low-expected effect stratum of human albumin based on the biomarker outcome. After stratification, patients in each group are randomised into either active treatment (20% human albumin) or corresponding placebo (0.9% NaCl) every 10th day for 6 months. The primary outcome is the cumulative number of liver-related events (composite of decompensation episodes, transjugular intrahepatic shunt insertion, liver transplantation and death). Key secondary outcomes include time-to-event analysis of primary outcome components, an analysis of the total healthcare burden and a health economic analysis., Ethics and Dissemination: The trial obtained ethical and regulatory approval in Denmark, Germany, the Netherlands, Belgium, Hungary and Spain through the Clinical Trials Information System (CTIS) from 13 February 2023, while UK approvals from the Health Regulatory Authority, Medicines and Healthcare products Regulatory Agency and Research Ethics Committee are pending. Findings will be published in peer-reviewed journals, presented at conferences, communicated to relevant stakeholders and in the public registry of CTIS, following trial completion., Trial Registration Number: NCT05056220 EU CT: 2022-501006-34-01., Competing Interests: Competing interests: PG received grants form Gilead and Grifols, served on advisory boards for Gilead, RallyBio, SeaBeLife, Merck Sharp and Dohme, Ocelot Bio, Behring and received speaking fees from Pfizer. JT has received speaking and/or consulting fees from Versantis, Gore, Boehringer-Ingelheim, Alexion, Falk, Mallinckrodt, Grifols and CSL Behring and was supported by the German Research Foundation (DFG) project ID 403224013-SFB 1382 (A09), by the German Federal Ministry of Education and Research (BMBF) for the DEEP-HCC project and by the Hessian Ministry of Higher Education, Research and the Arts (HMWK) for the ENABLE and ACLF-I cluster projects. The MICROB-PREDICT (project ID 825694), DECISION (project ID 847949), GALAXY (project ID 668031), LIVERHOPE (project ID 731875) and IHMCSA (project ID 964590) projects have received funding from the European Union’s Horizon 2020 research and innovation programme. AK has served as speaker for Novo Nordisk, Norgine, Siemens and Nordic Bioscience and participated in advisory boards for Norgine, Siemens, Resalis Therapeutics and Novo Nordisk, all outside the submitted work. Research support; Norgine, Siemens, Nordic Bioscience, Astra, Echosense. Consulting Takeda, Resalis Therapeutics, Zealand Pharma, Novo Nordisk, B&I. Board member and co-founder Evido. All other authors have no competing interests to declare., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background & Aims: Infections are frequent in patients with cirrhosis and worsen prognosis. We evaluated the incidence of infections and their impact on decompensation and death in patients with early alcohol-related liver disease (ALD) during long-term follow-up., Methods: We performed a prospective cohort study of patients in secondary care with a history of excess alcohol intake, no prior decompensation, and with liver biopsies along with clinical investigations conducted at baseline. During follow-up, we reviewed the patients' electronic healthcare records for cases of infections, hospitalizations, transient elastography measurements, decompensations, all-cause mortality, and alcohol intake., Results: We included 461 patients with a mean age of 56±10 years (76% males; fibrosis stage F0-1/F2/F3-4 = 259/107/93 [56%/23%/20%]). During a median follow-up of 4.5 years (IQR 2.9-6.3), 134 patients (29%) developed a total of 312 infections, most frequently pneumonia (106/312, 34%) and urinary tract infections (57/312, 18%). Excessive alcohol intake during follow-up, smoking ≥30 pack years, MELD score and elevated liver stiffness during follow-up were independent predictors of infections. Patients who developed at least one infection had a significantly increased risk of subsequent decompensation (hazard ratio 4.98, 95% CI 2.47-10.03) and death (hazard ratio 8.24, 95% CI 4.65-14.59). Infections increased the risk of decompensation and death independently of baseline fibrosis stage, age, gender, and MELD score., Conclusions: Almost one-third of patients with early ALD develop an infection, which worsens their prognosis by increasing the risk of decompensation and death. The risk of infections increases with liver disease severity and ongoing harmful use of alcohol., Impact and Implications: This study reveals that infections significantly worsen the prognosis of patients with early alcohol-related liver disease (ALD), increasing the likelihood of decompensation and death by up to eight times. These findings, pertinent to healthcare providers, researchers, and policymakers, emphasize the importance of early prevention and management of infections in patients with ALD, even those in early stages who may be asymptomatic. It was observed that nearly one-third of patients with early-stage ALD developed infections over 4.5 years, with risk factors including alcohol overuse, smoking, and higher MELD scores. The research underscores the critical need to incorporate these insights into clinical practice and public health policies to improve patient outcomes and mitigate the impact of infections in patients with ALD., Competing Interests: MT: Speaker’s fee for Echosens, Siemens Healthcare, Norgine, Madrigal, Takeda, and Tillotts Pharma. Advisory fee from GE Healthcare, Boehringer Ingelheim, GSK and AstraZeneca. Co-founder and board member for Evido. Board member for Alcohol & Society (non-governmental organisation). AK has received grants from EU Horizon 2020, Novo Nordisk Foundation, Innovationfund Denmark, Danish National Research Foundation, Region of Southern Denmark, and AstraZeneca, receives royalties from Gyldendal as a co-author on a textbook of internal medicine, served as speaker for Novo Nordisk, Norgine, Siemens and Nordic Bioscience, and participated in advisory boards for Norgine, Siemens, Resalis Therapeutics, Boehringer Ingelheim and Novo Nordisk. Research support; Norgine, Siemens, Nordic Bioscience, AstraZeneca, Echosens. Consulting Takeda, Resalis Therapeutics, Zealand Pharma, AlphaSights. Board member and co-founder of Evido. JKH: Speaker’s fee from Norgine. MK: Speaker’s fee from Siemens Healthcare. SJ, SL, DNR, MI, KL, CDH, KT, NT, PA, USJ, SD, HBJ, and TH have nothing to disclose. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2024 The Author(s).)

Background: Frequent binge drinking is a known contributor to alcohol-related harm, but its impact on systemic and hepatic inflammation is not fully understood. We hypothesize that changes in immune markers play a central role in adverse effects of acute alcohol intake, especially in patients with early liver disease., Aim: To investigate the effects of acute alcohol intoxication on inflammation-related markers in hepatic and systemic venous plasma in people with alcohol-related liver disease (ArLD), non-alcoholic fatty liver disease (NAFLD) and healthy controls., Methods: Thirty-eight participants (13 with ArLD, 15 with NAFLD and 10 healthy controls) received 2.5 mL of 40% ethanol per kg body weight via a nasogastric tube. Seventy-two inflammation-related markers were quantified in plasma from hepatic and systemic venous blood, at baseline, 60 and 180 min after intervention., Results: Alcohol intervention altered the levels of 31 of 72 and 14 of 72 markers in the systemic and hepatic circulation. All changes observed in the hepatic circulation were also identified in the systemic circulation after 180 min. Only FGF21 and IL6 were increased after alcohol intervention, while the remaining 29 markers decreased. Differences in response to acute alcohol between the groups were observed for 8 markers, and FGF21 response was blunted in individuals with steatosis., Conclusion: Acute alcohol intoxication induced changes in multiple inflammation-related markers, implicated in alcohol metabolism and hepatocellular damage. Differences identified between marker response to binge drinking in ArLD, NAFLD and healthy controls may provide important clues to disease mechanisms and potential targets for treatment., Clinical Trial Number: NCT03018990., (© 2023 The Authors. Liver International published by John Wiley & Sons Ltd.)

Noninvasive tests (NITs) are used in all aspects of liver disease management. Their most prominent break-through since the millennium has been in advancing early detection of liver fibrosis, but their use is not limited to this. In contrast to the symptom-driven assessment of decompensation in patients with cirrhosis, NITs provide not only opportunities for earlier diagnoses but also accurate prognostication, targeted treatment decisions, and a means of monitoring disease. NITs can inform disease management and decision-making based on validated cutoffs and standardized interpretations as a valuable supplement to clinical acumen. The Baveno VI and VII consensus meetings resulted in tangible improvements to pathways of care for patients with compensated and decompensated advanced chronic liver disease, including the combination of platelet count and transient elastography to diagnose clinically significant portal hypertension. Furthermore, circulating NITs will play increasingly important roles in assessing the response to interventions against ascites, variceal bleeding, HE, acute kidney injury, and infections. However, due to NITs' wide availability, there is a risk of inaccurate use, leading to a waste of resources and flawed decisions. In this review, we describe the uses and pitfalls of NITs for hepatic decompensation, from risk stratification in primary care to treatment decisions in outpatient clinics, as well as for the in-hospital management of patients with acute-on-chronic liver failure. We summarize which NITs to use when, for what indications, and how to maximize the potential of NITs for improved patient management., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Competing Interests: MT has received speaking fees from Siemens Healthcare, Norgine, Echosens, and Tillotts Pharma; consulting fees from GE Healthcare; and participated in advisory boards for ID Liver and Alcohol & Society. AK has served as speaker for Norgine, Siemens, and Nordic Bioscience; participated in advisory boards for Norgine and Siemens, all outside the submitted work; receives royalties from Gyldendal; and has received equipment, drugs, or other services from Norgine, Siemens, and Echosens. All other authors declare no competing interests.

Background & Aims: There is a need for accurate biomarkers of fibrosis for population screening of alcohol-related and non-alcoholic fatty liver disease (ALD, NAFLD). We compared the performance of the enhanced liver fibrosis (ELF) test to the fibrosis-4 index (FIB-4) and NAFLD fibrosis score (NFS), using transient elastography as the reference standard., Methods: We prospectively included participants from the general population, and people at risk of ALD or NAFLD. Screening positive participants (TE ≥8 kPa) were offered a liver biopsy. We measured concomitant ELF, FIB-4, and NFS using validated cut-offs: ≥9.8, ≥1.3, ≥-1.45, respectively., Results: We included 3,378 participants (1,973 general population, 953 at risk of ALD, 452 at risk of NAFLD), with a median age of 57 years (IQR: 51-63). Two hundred-and-forty-two were screening positive (3.4% in the general population, 12%/14% who were at-risk of ALD/NAFLD, respectively). Most participants with TE <8 kPa also had ELF <9.8 (88%) despite a poor overall correlation between ELF and TE (Spearman´s rho = 0.207). ELF was associated with significantly fewer false positives (11%) than FIB-4 and NFS (35% and 45%), while retaining a low rate of false negatives (<8%). A screening strategy of FIB-4 followed by ELF in indeterminate cases resulted in false positives in 8%, false negatives in 4% and the correct classification in 88% of cases. We performed a liver biopsy in 155/242 (64%) patients who screened positive, of whom 54 (35%) had advanced fibrosis (≥F3). ELF diagnosed advanced fibrosis with significantly better diagnostic accuracy than FIB-4 and NFS: AUROC 0.85 (95% CI 0.79-0.92) vs. 0.73 (0.64-0.81) and 0.66 (0.57-0.76), respectively., Conclusion: The ELF test alone or combined with FIB-4 for liver fibrosis screening in the general population and at-risk groups reduces the number of futile referrals compared to FIB-4 and NFS, without overlooking true cases., Impact and Implications: We need referral pathways that are efficient at detecting advanced fibrosis from alcohol-related and non-alcoholic fatty liver disease in the population, but without causing futile referrals or excessive use of resources. This study indicates that a sequential test strategy of FIB-4 followed by the ELF test in indeterminate cases leads to few patients referred for confirmatory liver stiffness measurement, while retaining a high rate of detected cases, and at low direct costs. This two-step referral pathway could be used by primary care for mass, targeted, or opportunistic screening for liver fibrosis in the population., Clinical Trial Number: Clinicaltrials.gov number NCT03308916., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Aims: Risk prediction in alcohol-related liver disease (ArLD) is an unmet need. We aimed to assess PRO-C3 models to predict liver-related events (LRE) in patients with a history of excessive alcohol use without an established diagnosis of chronic liver disease., Methods: A prospective cohort study of 462 patients with ArLD, split into a derivation cohort of 221 secondary care patients and a validation cohort of 241 primary care patients. Baseline variables, including fibrogenesis marker PRO-C3, were used to develop a prediction model. Prognostic accuracy was compared to enhanced liver fibrosis (ELF), fibrosis-4-index (FIB-4), transient elastography (TE) and ADAPT., Results: In the derivation and validation cohorts, 67 (30%) and 19 (8%) experienced an LRE during a median follow-up of 5.2 years (IQR: 3.2-6.8) and 4.0 years (IQR: 2.7-5.6). On top of PRO-C3 and ADAPT score, we generated a model (ALPACA) of independent predictors of LREs (PRO-C3, AST/ALT, platelets). ALPACA had high prognostic accuracy with a C-statistic of 0.85 in the derivation cohort, comparable to ELF (0.83) and TE (0.84) and significantly higher than FIB-4 (0.78), PRO-C3 (0.80) and ADAPT (0.81). In the validation cohort, all tests had comparable C-statistics. Compared to low-risk patients (ALPACA ≤11), high-risk patients (>11) had a subhazard ratio for LREs of 12.6 (95% CI 5.9-26.8, p < .001) and higher cumulative incidence (57% vs. 7%, p < .001; derivation cohort). We observed similar subhazard ratio in the validation cohort., Conclusions: PRO-C3-based scores are reliable tools to predict LREs in ArLD patients and are suitable for risk stratification in primary and secondary care., (© 2023 The Authors. Liver International published by John Wiley & Sons Ltd.)

Background: Alcohol is the leading cause of liver-related mortality worldwide. The gut-liver axis is considered a key driver in alcohol-related liver disease. Rifaximin-α improves gut-barrier function and reduces systemic inflammation in patients with cirrhosis. We aimed to compare the efficacy and safety of rifaximin-α with placebo in patients with alcohol-related liver disease., Methods: GALA-RIF was an investigator-initiated, randomised, double-blind, placebo-controlled, single-centre, phase 2 trial done at Odense University Hospital in Denmark. Eligible participants were adults (aged 18-75 years) who had current or previous alcohol overuse (at least 1 year with ≥24 g of alcohol per day for women and ≥36 g of alcohol per day for men), biopsy-proven alcohol-related liver disease, and no previous hepatic decompensation. Patients were randomly allocated (1:1) through a web-based randomisation system to receive oral rifaximin-α (550 mg) twice daily or matched placebo for 18 months. Randomisation was done in blocks of four and stratified according to fibrosis stage and alcohol abstinence. Participants, sponsor, investigators, and nurses involved in the study were masked to the randomisation outcome. The primary endpoint was a histological decrease from baseline to 18-month treatment of at least one fibrosis stage, according to the Kleiner fibrosis score. We also assessed the number of patients with progression by at least one fibrosis stage from baseline to 18 months. Primary analyses were done in the per-protocol and modified intention-to-treat populations; safety was assessed in the full intention-to-treat population. The per-protocol population was defined as all randomly assigned patients who did not present serious protocol violations, who ingested at least 75% of the treatment, and who were not withdrawn from the study due to non-adherence (interruption of treatment for 4 weeks or more). Participants receiving at least one dose of the intervention were included in the modified intention-to-treat analyses. This completed trial is registered with EudraCT, number 2014-001856-51., Findings: Between March 23, 2015, and Nov 10, 2021, we screened 1886 consecutive patients with a history of excessive alcohol consumption and no previous hepatic decompensation, of whom 136 were randomly assigned to either rifaximin-α (n=68) or placebo (n=68). All patients were White (100%), 114 (84%) were men, and 22 (16%) were women. 133 (98%) patients received at least one dose of the intervention and were included in the modified intention-to-treat analysis; 108 (79%) completed the trial per protocol. In the per-protocol analysis, 14 (26%) of 54 patients in the rifaximin-α group and 15 (28%) of 54 patients in the placebo group had a decrease in fibrosis stage after 18 months (odds ratio 1·10 [95% CI 0·45-2·68]; p=0·83). In the modified intention-to-treat analysis, 15 (22%) of 67 patients in the rifaximin-α group and 15 (23%) of 66 patients in the placebo group had a decrease in fibrosis stage at 18 months (1·05 [0·45-2·44]; p=0·91). In the per-protocol analysis, increase in fibrosis stage occurred in 13 (24%) patients in the rifaximin-α group and 23 (43%) patients in the placebo group (0·42 [0·18-0·98]; p=0·044). In the modified intention-to-treat analysis, increase in fibrosis stage occurred in 13 (19%) patients in the rifaximin-α group and 23 (35%) patients in the placebo group (0·45 [0·20-1·02]; p=0·055). The number of patients with adverse events (48 [71%] of 68 patients in the rifaximin-α group; 53 [78%] of 68 in the placebo group) and serious adverse events (14 [21%] in the rifaximin-α group; 12 [18%] in the placebo group) was similar between the groups. No serious adverse events were deemed related to treatment. Three patients died during the trial, but none of the deaths were considered treatment related., Interpretation: In patients with alcohol-related liver disease, rifaximin-α might reduce progression of liver fibrosis. These findings warrant confirmation in a multicentre phase 3 trial., Funding: The EU Horizon 2020 Research and Innovation Program and The Novo Nordisk Foundation., Competing Interests: Declaration of interests JKH has received speaking fees from Norgine. KPL has received speaking fees and support for travels from Siemens. MKj has received speaking fees from Siemens. MKa owns stock in Nordic Bioscience. MA has received speaking or consulting fees from Roche, Lundbeck Pharma, and SNIPR Biome. JT has received speaking or consulting fees from Versantis, Gore, Boehringer-Ingelheim, Alexion, Falk, Grifols, Genfit, and CSL Behring and participated in advisory boards for Versantis, Alexion, Sobi, Gore, Grifols, Genfit, and CSL Behring. MT has received speaking fees from Siemens Healthcare, Norgine, Echosens, and Tillotts Pharma; consulting fees from GE Healthcare; and participated in advisory boards for ID Liver and Alcohol & Society. AK has served as speaker for Norgine, Siemens, and Nordic Bioscience and participated in advisory boards for Norgine and Siemens, all outside the submitted work. AK receives royalties from Gyldendal and has received equipment, drugs, or other services from Norgine, Siemens, and Echosense. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background & Aims: Alcohol disturbs hepatic lipid synthesis and transport, but the role of lipid dysfunction in alcohol-related liver disease (ALD) is unclear. In this biopsy-controlled, prospective, observational study, we characterized the liver and plasma lipidomes in patients with early ALD., Methods: We performed mass spectrometry-based lipidomics of paired liver and plasma samples from 315 patients with ALD and of plasma from 51 matched healthy controls. We associated lipid levels with histologic fibrosis, inflammation, and steatosis with correction for multiple testing and adjustment for confounders. We further investigated sphingolipid regulation by means of quantitative real-time polymerase chain reaction sequencing of microRNA, prediction of liver-related events, and tested causality with Mendelian randomization., Results: We detected 198 lipids in the liver and 236 lipids in the circulation from 18 lipid classes. Most sphingolipids (sphingomyelins and ceramides) and phosphocholines were co-down-regulated in both liver and plasma, where lower abundance correlated with higher fibrosis stage. Sphingomyelins showed the most pronounced negative correlation to fibrosis, mirrored by negative correlations in both liver and plasma with hepatic inflammation. Reduced sphingomyelins predicted future liver-related events. This seemed to be characteristic of "pure ALD," as sphingomyelin levels were higher in patients with concomitant metabolic syndrome and ALD/nonalcoholic fatty liver disease overlap. Mendelian randomization in FinnGen and UK Biobanks indicated ALD as the cause of low sphingomyelins, and alcohol use disorder did not correlate with genetic susceptibility to low sphingomyelin levels., Conclusions: Alcohol-related liver fibrosis is characterized by selective and progressive lipid depletion in liver and blood, particularly sphingomyelins, which also associates with progression to liver-related events., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: It remains unclear if a low-carbohydrate, high-fat (LCHF) diet is a possible treatment strategy for type 2 diabetes mellitus (T2DM), and the effect on nonalcoholic fatty liver disease (NAFLD) has not been investigated., Objective: To investigate the effect of a calorie-unrestricted LCHF diet, with no intention of weight loss, on T2DM and NAFLD compared with a high-carbohydrate, low-fat (HCLF) diet., Design: 6-month randomized controlled trial with a 3-month follow-up. (ClinicalTrials.gov: NCT03068078)., Setting: Odense University Hospital in Denmark from November 2016 until June 2020., Participants: 165 participants with T2DM., Intervention: Two calorie-unrestricted diets: LCHF diet with 50 to 60 energy percent (E%) fat, less than 20E% carbohydrates, and 25E% to 30E% proteins and HCLF diet with 50E% to 60E% carbohydrates, 20E% to 30E% fats, and 20E% to 25E% proteins., Measurements: Glycemic control, serum lipid levels, metabolic markers, and liver biopsies to assess NAFLD., Results: The mean age was 56 years (SD, 10), and 58% were women. Compared with the HCLF diet, participants on the LCHF diet had greater improvements in hemoglobin A 1c (mean difference in change, -6.1 mmol/mol [95% CI, -9.2 to -3.0 mmol/mol] or -0.59% [CI, -0.87% to -0.30%]) and lost more weight (mean difference in change, -3.8 kg [CI, -6.2 to -1.4 kg]). Both groups had higher high-density lipoprotein cholesterol and lower triglycerides at 6 months. Changes in low-density lipoprotein cholesterol were less favorable in the LCHF diet group than in the HCLF diet group (mean difference in change, 0.37 mmol/L [CI, 0.17 to 0.58 mmol/L] or 14.3 mg/dL [CI, 6.6 to 22.4 mg/dL]). No statistically significant between-group changes were detected in the assessment of NAFLD. Changes were not sustained at the 9-month follow-up., Limitation: Open-label trial, self-reported adherence, unintended weight loss, and lack of adjustment for multiple comparisons., Conclusion: Persons with T2DM on a 6-month, calorie-unrestricted, LCHF diet had greater clinically meaningful improvements in glycemic control and weight compared with those on an HCLF diet, but the changes were not sustained 3 months after intervention., Primary Funding Source: Novo Nordisk Foundation.

Background & Aims: Individual risk for developing alcohol-related liver disease (ALD) varies greatly. We hypothesized that metabolic risk factors and genetic polymorphisms predict severity of ALD., Methods: Biopsy-controlled, cross-sectional study in patients with a history of excessive drinking. We measured the homeostatic model assessment of insulin resistance (HOMA-IR), plasma triglycerides, high- and low-density lipoproteins (HDL, LDL), and total cholesterol. Moreover, we genotyped four single nucleotide polymorphisms in PNPLA3 (rs738409C>G), TM6SF2 (rs58542926C>T), MBOAT7 (rs641738C>T), and HSD17B13 (rs72613567T>TA). We assessed predictors of higher fibrosis stage using multivariable ordered logistic regression., Results: Of 325 included patients, 25% had severe fibrosis or cirrhosis and 59% had HOMA-IR ≥2.5. HOMA-IR increased for each fibrosis stage, while there was a similar decrease in LDL and total cholesterol. Individuals with risk variant PNPLA3 rs738409-G or TM6SF2 rs58542926-T had higher fibrosis stage. In multivariable regression, HOMA-IR ≥2.5 (OR = 3.04, 95% CI 1.90-4.87), LDL <2.60 mmol/L (OR = 2.05, 95% CI 1.33-3.16), TM6SF2 rs58542926-T (OR = 1.99, 95% CI 1.17-3.37), age above 50 years (OR = 1.66, 95% CI 1.03-2.70), and PNPLA3 rs738409-G (OR = 1.54, 95% CI 1.11-2.12) independently predicted higher fibrosis stage. Independent predictors of hepatic inflammatory activity were HOMA-IR, active drinking, age, and PNPLA3 risk variant. Active drinking, elevated triglycerides, and PNPLA3 risk variant predicted steatosis., Conclusions: Insulin resistance is the strongest predictor of liver fibrosis stage and hepatic inflammation in patients with alcohol-related liver disease. Genetic susceptibility further aggravates this risk. These data highlight the clinical value of detailed metabolic and genetic profiling of patients with excessive alcohol use., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aims: There are several short-term prognostic scores for alcoholic hepatitis (AH) that combine demographical and biochemical parameters. The extent of liver fibrosis may also be relevant to the prognosis of AH with potential added value. We evaluated collagen proportionate area (CPA) as a predictor of short and long-term mortality in AH., Methods: We retrospectively included patients with biopsy-verified AH. Clinical, laboratory and outcome data were collected. CPA and five AH scores were calculated: Maddrey's DF, MELD, GAHS, ABIC, and the Lille Model. Predictors of short and long-term all-cause mortality were assessed using Cox regression analysis., Results: We included 140 patients with AH. In total, 67 (48%) patients died after a median follow-up of 66 (IQR 102) months, with 17 (12%) dying within the first 90-days. CPA was not a predictor of 90-days mortality and had no additional value to the prognostic AH scores on short-term mortality. However, CPA predicted long-term mortality independently of prognostic AH scores. Importantly, CPA and abstinence from alcohol were independent predictors of long-term mortality in patients alive 90 days after the biopsy., Conclusion: CPA predicts long-term mortality in patients with AH independently of abstinence from alcohol but has no prognostic value on short-term mortality., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2021. Published by Elsevier Ltd.)

Background & Aims: Binge drinking is associated with an increased risk of liver disease. Morbidity and mortality of alcohol-related liver disease (ALD) is associated with collagen deposition in the hepatic extracellular matrix (ECM). However, the acute effects of binge drinking on ECM turnover are unknown. We aimed to investigate the effects on hepatic ECM turnover following a binge drinking episode., Methods: We performed a pathophysiological intervention study with 15 non-alcoholic fatty liver disease (NAFLD) patients, 15 ALD patients and 10 healthy controls. We used 40% ethanol in 9 mg/mL NaCl administered through a nasogastric tube to simulate binge drinking. Hepatic vein catheterisation allowed simultaneous hepatic- and systemic vein sampling. Markers of ECM formation and degradation were measured with competitive ELISA., Results: The interstitial matrix formation marker PRO-C3 increased by 1.2 ng/mL (10%, P < .001) 24 hours after binge drinking. In participants with existing liver fibrosis determined by elevated baseline PRO-C3, hepatic levels increased by 0.09 ng/mL (95% CI: 0.03-0.15, P = .005) while systemic PRO-C3 decreased 0.11 ng/mL (95% CI: -0.15 to -0.06, P < .001) in 3 hours. PRO-C8 increased by 30% (+0.9 ng/mL, P = .014) in liver-diseased patients with F0-F1 but not in any other group. Twenty-four-hour changes in systemic C3M and PRO-C3 were not associated (P = .911)., Conclusions: Binge drinking induced an acute burst of PRO-C3 in healthy individuals and patients with liver disease. Markers of ECM degradation were not correlated to markers of ECM formation, suggesting that even a single episode of binge drinking promotes excessive hepatic fibrogenesis., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background & Aims: Alcohol is the most common cause of liver-related mortality and morbidity. We therefore aimed to assess and compare the prognostic performance of elastography and blood-based markers to predict time to the first liver-related event, severe infection, and all-cause mortality in patients with a history of excess drinking., Methods: We performed a prospective cohort study in patients with early, compensated alcohol-related liver disease. At baseline, we obtained a liver biopsy, transient elastography (TE), 2-dimensional shear-wave elastography (2D-SWE), enhanced liver fibrosis test (ELF), FibroTest, fibrosis-4 index (FIB-4), non-alcoholic fatty liver fibrosis score (NFS) and Forns index. We compared C-statistics and time-dependent AUC for prognostication. We used validated cut-off points to create 3 risk groups for each test: low, intermediate and high risk., Results: We followed 462 patients for a median of 49 months (IQR 31-70). Median age was 57 years, 76% were males, 20% had advanced fibrosis. Eighty-four patients (18%) developed a liver-related event after a median of 18 months (7-34). TE had the highest prognostic accuracy, with a C-statistic of 0.876, and time-dependent AUC at 5 years of 0.889, comparable to 2D-SWE and ELF. TE, ELF and 2D-SWE outperformed FibroTest, FIB4, NFS, Forns index and biopsy-verified fibrosis stage. Compared to patients with TE <10 kPa, the hazard ratios for liver-related events for TE 10-15 kPa were 8.1 (3.2-20.4), and 27.9 (13.8-56.8) for TE >15 kPa. Periods of excessive drinking during follow-up increased the risk of progressing to liver-related events, except for patients in the low-risk groups., Conclusion: TE, ELF and 2D-SWE are highly accurate prognostic markers in patients with alcohol-related liver disease. Easy-to-use cut-offs can distinguish between substantially different risk profiles., Lay Summary: Alcohol is the leading cause of death and illness due to liver disease. In this study, we assessed the ability of biomarkers to predict the risk of developing symptomatic liver disease in patients with early stages of alcohol-related liver disease. We found that several tests accurately predicted the risk of liver-related events such as ascites, esophageal varices and hepatic encephalopathy during an average follow-up of 4.1 years. Liver stiffness measurements by ultrasound elastography and the enhanced liver fibrosis test performed best. By using them, we were able to stratify patients into 3 groups with significantly different risks., Competing Interests: Conflicts of interest Aleksander Krag: Speakers fee and advisory board for Siemens Healthcare. Maja Thiele: Speakers fee for Echosens and Siemens Healthcare. Steen Antonsen: Speakers fee for Siemens Healthcare. Other authors: None. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background & Aims: In experimental models, alcohol induces acute changes in lipid metabolism that cause hepatocyte lipoapoptosis and inflammation. Here we study human hepatic lipid turnover during controlled alcohol intoxication., Methods: We studied 39 participants with 3 distinct hepatic phenotypes: alcohol-related liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), and healthy controls. Alcohol was administrated via nasogastric tube over 30 min. Hepatic and systemic venous blood was sampled simultaneously at 3 time points: baseline, 60, and 180 min after alcohol intervention. Liver biopsies were sampled 240 min after alcohol intervention. We used ultra-high performance liquid chromatography mass spectrometry to measure levels of more than 250 lipid species from the blood and liver samples., Results: After alcohol intervention, the levels of blood free fatty acid (FFA) and lysophosphatidylcholine (LPC) decreased, while triglyceride (TG) increased. FFA was the only lipid class to decrease in NAFLD after alcohol intervention, whereas LPC and FFA decreased and TG increased after intervention in ALD and healthy controls. Fatty acid chain uptake preference in FFAs and LPCs were oleic acid, linoleic acid, arachidonic acid, and docosahexaenoic acid. Hepatic venous blood FFA and LPC levels were lower when compared with systemic venous blood levels throughout the intervention. After alcohol intoxication, liver lipidome in ALD was similar to that in NAFLD., Conclusions: Alcohol intoxication induces rapid changes in circulating lipids including hepatic turnaround from FFA and LPC, potentially leading to lipoapoptosis and steatohepatitis. TG clearance was suppressed in NAFLD, possibly explaining why alcohol and NAFLD are synergistic risk factors for disease progression. These effects may be central to the pathogenesis of ALD., Clinical Trials Registration: The study is registered at Clinicaltrials.gov (NCT03018990)., Lay Summary: We report that alcohol induces hepatic extraction of free unsaturated fatty acids and lysophosphatidylcholines, hepatotoxic lipids which have not been previously associated with alcohol-induced liver injury. We also found that individuals with non-alcoholic fatty liver disease have reduced lipid turnover during alcohol intoxication when compared with people with alcohol-related fatty liver disease. This may explain why alcohol is particularly more harmful in people with non-alcoholic fatty liver and why elevated BMI and alcohol have a synergistic effect on the risk of liver-related death., Competing Interests: All authors declare no conflicts of interests. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2021 The Author(s).)

Background & Aims: Prognostic models of cirrhosis underestimate disease severity for patients with cirrhosis and ascites. Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix protein linked to hepatic neoangiogenesis and fibrogenesis. We investigated ascites MFAP4 as a predictor of transplant-free survival in patients with cirrhosis and ascites., Methods: A dual-centre observational study of patients with cirrhosis and ascites recruited consecutively in relation to a paracentesis was carried out. Patients were followed up for 1 year, until death or liver transplantation (LTx). Ascites MFAP4 was tested with the model for end-stage liver disease (MELD-Na), CLIF Consortium Acute Decompensation (CLIF-C AD), and Child-Pugh score in Cox regression models., Results: Ninety-three patients requiring paracentesis were included. Median ascites MFAP4 was 29.7 U/L [22.3-41.3], and MELD-Na was 19 [16-23]. A low MELD-Na score (<20) was observed in 49 patients (53%). During follow-up, 20 patients died (22%), and 6 received LTx (6%). High ascites MFAP4 (>29.7 U/L) was associated with 1-year transplant-free survival ( p  = 0.002). In Cox regression, ascites MFAP4 and MELD-Na independently predicted 1-year transplant-free survival (hazard ratio [HR] = 0.97, p  = 0.03, and HR = 1.08, p  = 0.01, respectively). Ascites MFAP4 and CLIF-C AD also predicted survival independently (HR = 0.96, p  = 0.02, and HR = 1.05, p  = 0.03, respectively), whereas only ascites MFAP4 did, controlling for the Child-Pugh score (HR = 0.97, p  = 0.03, and HR = 1.18, p  = 0.16, respectively). For patients with MELD-Na <20, ascites MFAP4 but not ascites protein predicted 1-year transplant-free survival (HR 0.91, p  = 0.02, and HR = 0.94, p  = 0.17, respectively)., Conclusions: Ascites MFAP4 predicts 1-year transplant-free survival in patients with cirrhosis and ascites. In patients with low MELD-Na scores, ascites MFAP4, but not total ascites protein, significantly predicted 1-year transplant-free survival., Lay Summary: Patients with cirrhosis who have fluid in the abdomen, ascites, are at an increased risk of death and in need for liver transplantation. Our study identified patients with ascites and a poor prognosis by measuring microfibrillar associated protein 4 (MFAP4), a protein present in the abdominal fluid. Patients with low levels of the MFAP4 protein are at particularly increased risk of death or liver transplantation, suggesting that clinical care should be intensified in this group of patients., Competing Interests: GLS is the inventor of U.S. Patent No. 9,988,442 and EP14743707.3 owned by the University of Southern Denmark. MT received personal fees from Echosens outside the submitted work. The remaining authors have nothing to declare. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2021 The Authors.)

Background: No prognostic tools are established for alcohol-related liver disease (ALD). Collagen proportionate area (CPA) measurement is a technique that quantifies fibrous tissue in liver biopsies using digital image analysis., Aim: To assess the predictive value of CPA on hepatic decompensation and liver-related mortality in ALD METHODS: In a multicentre cohort study, we included 386 patients with biopsy-verified ALD and with long-term follow-up. In the development cohort of 276 patients, we assessed the predictors of hepatic decompensation and liver-related death in standard and competing risk multivariable Cox regression analyses. The results were validated in an independent prospective cohort of 110 patients, where CPA was also correlated with liver stiffness measurement (LSM)., Results: In the development cohort, 231 (84%) patients had early/compensated ALD (non-cirrhotic or compensated cirrhosis) and 45 (16%) had decompensated cirrhosis. In the validation cohort, all patients had early/compensated ALD. Independent predictors of liver-related mortality were higher CPA values (HR = 1.04, 95% CI 1.02-1.04) and advanced fibrosis (HR = 2.80, 95% CI 1.29-6.05) with similar results in standard and competing risk multivariable Cox regression analysis. In early/compensated ALD, CPA was the only independent predictor of hepatic decompensation and liver-related death (HR = 1.08, 95% CI 1.06-1.11). In the prospective cohort, we validated that CPA independently predicts hepatic decompensation in early/compensated ALD. The predictive power of CPA and LSM was equally strong., Conclusions: CPA predicts liver-related mortality in ALD and hepatic decompensation and/or liver-related death in early/compensated ALD. Traditional histological assessment may benefit from the addition of CPA to the evaluation of ALD., (© 2020 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Purpose Persons with autism spectrum disorder (ASD) may demonstrate abnormal prosodic patterns in conversational speech, which can negatively affect social interactions. The purpose of this systematic review was to identify interventions measuring the improvement of expressive speech prosody in persons with ASD in order to support clinician's evidence-based decision making. Method We used 13 electronic databases to search for relevant articles using terms related to autism, intervention, and speech prosody. The databases identified a total of nine articles for the title, abstract, and full-text reviews. Five more articles were included after performing descendant and reference searches. One peer-reviewed article was excluded due to insufficient data received from the authors. We coded the resulting 13 articles for report, setting, intervention, outcome, and results characteristics and methodological quality. Results Results showed that interventions specifically targeting speech prosody using established and emerging evidence-based practices across more than 1 treatment day resulted in moderate to large improvements in speech prosody in persons with ASD. Interventions that indirectly targeted prosody or were very short resulted in small or nonsignificant effects. Discussion The results of this literature review suggest that interventions that directly target speech prosody using established evidence-based practices for ASD may be most effective for increasing typical prosodic patterns during speech for persons with ASD. Further research is needed to establish which interventions are most effective for each age range and context. Supplemental Material https://doi.org/10.23641/asha.12735926.

Purpose This systematic review synthesized a set of peer-reviewed studies published between 1985 and 2019 and addressed the effectiveness of existing narrative and expository discourse interventions for late elementary- and middle school-aged students with language-related learning disabilities. Method A methodical search of the literature for interventions targeting expository or narrative discourse structure for students aged 9-14 years with group experimental designs identified 33 studies, seven of which met specific criteria to be included in this review. Results An 8-point critical appraisal scale was applied to analyze the quality of the study design, and effect sizes were calculated for six of the seven studies; equivocal to small effects of far-transfer outcomes (i.e., generalizability to other settings) and equivocal to moderate near-transfer outcomes (i.e., within the treatment setting) were identified. The most effective intervention studies provided explicit instruction of expository texts with visual supports and student-generated learning materials (e.g., notes or graphic organizers) with moderate dosage (i.e., 180-300 min across 6-8 weeks) in a one-on-one or paired group setting. Greater intervention effects were also seen in children with reading and/or language disorders, compared to children with overall academic performance difficulties. Conclusions A number of expository discourse interventions showed promise for student use of learned skills within the treatment setting (i.e., near-transfer outcomes) but had limited generalization of skills (i.e., far-transfer outcomes). Supplemental Material https://doi.org/10.23641/asha.12449258.

Background & Aims: Liver stiffness measured with 2-dimensional shear wave elastography by Supersonic Imagine (2DSWE-SSI) is well-established for fibrosis diagnostics, but non-conclusive for portal hypertension., Methods: We performed an individual patient data meta-analysis of 2DSWE-SSI to identify clinically significant portal hypertension (CSPH), severe portal hypertension and large varices in cirrhosis patients, using hepatic venous pressure gradient and upper endoscopy as reference. We used meta-analytical integration of diagnostic accuracies with optimized rule-out (sensitivity-90%) and rule-in (specificity-90%) cut-offs., Results: Five studies from seven centres shared data on 519 patients. After exclusion, we included 328 patients. Eighty-nine (27%) were compensated and 286 (87%) had CSPH. 2DSWE-SSI < 14 kPa ruled out CSPH with a summary AUROC (sROC), sensitivity and specificity of 0.88, 91% and 37%, and correctly classified 85% of patients, with minimal between-study heterogeneity. The false negative rate was 60%, of which decompensated patients accounted for 78%. 2DSWE-SSI ≥ 32 kPa ruled in CSPH with sROC, sensitivity, specificity and correct classifications of 0.83, 47%, 89% and 55%. In a subgroup analysis, the 14 kPa cut-off showed consistent sensitivity and higher specificity for patients with compensated cirrhosis, without ascites, viral aetiology or BMI < 25 kg/m 2 . 2DSWE-SSI ruled out severe portal hypertension and large varices with fewer correctly classified and lower sROC, and with minimal benefit for ruling in., Conclusion: Liver stiffness using 2-dimensional shear wave elastography below 14 kPa may be used to rule out clinically significant portal hypertension in cirrhosis patients, but this would need validation in populations of compensated liver disease. 2DSWE-SSI cannot predict varices needing treatment., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Acute kidney injury and hepatorenal syndrome (HRS) are frequent complications in patients with cirrhosis and ascites. First-line treatment is terlipressin, which reverses HRS in ~40% of patients but also lowers cardiac output (CO). We aimed to investigate whether reversing the cardio-suppressive effect of terlipressin with the β-adrenoceptor agonist dobutamine would increase CO and thereby increase the glomerular filtration rate (GFR). We randomized 25 patients with cirrhosis, ascites, and impaired renal function (2:2:1): group A received terlipressin followed by the addition of dobutamine; group B received dobutamine and terlipressin as monotherapies; and group C received placebo. Renal and cardiac functions were assessed during 8 clearance periods of 30 min, and concentrations of vasoactive hormones were measured. Dobutamine as a monotherapy increased CO (1.03 L/min, P < 0.01) but had no significant effects on GFR. Renin ( P < 0.05), angiotensin II ( P < 0.005), and aldosterone ( P < 0.05) increased after dobutamine infusion. Terlipressin as a monotherapy improved GFR (18.9 mL·min -1 ·m -2 , P = 0.005) and mean arterial pressure (MAP) (14 mmHg, P = 0.001) but reduced CO (-0.92 L/min, P < 0.005) and renin ( P < .005). A combined treatment of dobutamine and terlipressin had a positive effect on CO (1.19 L/min, P < 0.05) and increased renin ( P < 0.005), angiotensin II ( P < 0.005), and aldosterone ( P < 0.05), but it had no significant effects on MAP or GFR. Dobutamine reversed the cardio-suppressive effect of terlipressin in cirrhosis, ascites, and impaired renal function. However, dobutamine reduced peripheral vascular resistance, activated renin-angiotensin-aldosterone system, and did not improve GFR compared with terlipressin as a monotherapy. Therefore, dobutamine cannot be recommended in cirrhosis and ascites. NEW & NOTEWORTHY This study shows that the cardio-suppressive effects of the vasopressin receptor agonist terlipressin can be reversed by dobutamine. This is a novel observation in patients with decompensated cirrhosis. Furthermore, we show that dobutamine reduced the peripheral vascular resistance and activated the renin-angiotensin system, whereas renal function was not further improved by terlipressin alone.

The Danish Medicines Agency recommends routine controls of liver enzymes in patients, who are treated with statins in order to prevent liver injury. In this review, much evidence showing that severe drug-induced hepatic injury is very rarely associated with statins is presented. No data support, that routine control of blood liver enzymes will improve prevention or detection of statin-induced liver injury. Furthermore, recent studies show, that statins are safe and may even have beneficial effects in chronic liver disease. In future revision of the Danish Medicines Agency recommendations, these new findings should be taken into consideration.