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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: 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.)

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).)

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: 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: 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.)