Metabolic dysfunction-associated steatotic liver disease has become the most common cause of hepatocellular carcinoma in Sweden: A nationwide cohort study.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease globally, and can lead to hepatocellular carcinoma (HCC), a leading cause of cancer-related death. We aimed to determine the extent to which MASLD is an increasing cause of HCC in Sweden and to determine clinical characteristics associated with underlying MASLD. Using the Swedish quality registry for liver cancer (SweLiv), we identified all adults with a diagnosis of HCC in Sweden between 2012 and 2018. Baseline data were retrieved from SweLiv and other nationwide registers. Totally, 3494 patients with HCC were identified. Of them, 757 patients (22%) had MASLD-HCC. The proportion with MASLD-HCC increased from 19% in 2012 to 25% in 2018 (ptrend = 0.012), and MASLD was since 2017 the leading cause of HCC, surpassing hepatitis C. MASLD was the fastest growing cause of HCC with a 33% increment during the study period. Compared to other patients with HCC, those with MASLD-HCC were older (75 vs. 67 years, p < .001), less commonly had cirrhosis (61% vs. 82%, p < .001), had larger tumours (median 5.5 vs. 4.3 cm, p < .001), and more often extrahepatic metastasis (22% vs. 16%, p < .001). Patients with HCC caused by MASLD or by other causes were equally likely to be diagnosed in an early stage (Barcelona Clinic Liver Cancer 0-A, 27% vs. 30%, p = .129). MASLD is now the leading cause of HCC in Sweden.

Persons with metabolic dysfunction-associated steatotic liver disease are at increased risk of severe depression.

BACKGROUND AND AIM: Few population-based studies have investigated the association between metabolic dysfunction-associated steatotic liver disease (MASLD) and depression. Additionally, it remains unclear if depression affects progression to major adverse liver outcomes (MALO) in MASLD. METHODS: All patients in Sweden with newly diagnosed MASLD between 2006 and 2020 were identified from the National Patient Register. Each patient was matched on age, sex, inclusion year, and municipality with up to 10 comparators from the general population. Cox regression was used to compare rates of severe depression in persons with MASLD to the comparators. In persons with MASLD, Cox regression was used to estimate rates of MALO using severe depression before baseline or diagnosed during follow-up as a time-varying exposure. RESULTS: We included 11 301 persons with MASLD and 104 205 comparators who were followed for a median of 3.9 (IQR 1.5-7.6) and 4.9 years (IQR 2.3-8.7), respectively. The median age was 56 years and 5576 of 11 301 (49.3%) persons with MASLD were male. Incident severe depression developed in 228 of 11 301 (2.0%) persons with MASLD and 1160 of 104 205 (1.1%) comparators (fully adjusted hazard ratio [HR] = 1.8, 95% CI = 1.5-2.1). Of persons with MASLD, 25 of 1229 (2.0%) of those with severe depression before or after baseline progressed to MALO compared to 322 of 10 326 (3.1%) of those without severe depression (fully adjusted HR = 1.0, 95% CI = .6-1.5). CONCLUSIONS: We confirm an association between MASLD and severe depression. However, no association between severe depression and incident MALO was found, but conclusions are limited by few observed outcomes.

Performance of novel collagen turnover biomarkers to detect increased liver stiffness in MASLD.

BACKGROUND: Cleavage products from collagen formation and degradation hold potential as first-line biomarkers for the risk of advanced fibrosis in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we evaluated the performance of PRO-C3, PRO-C6, C4M, PRO-C18L, and the clinical score ADAPT (age, diabetes, PRO-C3, and platelet count) to detect patients with an LSM >8 kPa or >12 kPa in comparison to the Fibrosis-4 Index (FIB-4). METHODS: Serum from patients with MASLD (n = 269) from six Swedish University Hospitals was analyzed using enzyme-linked immunosorbent assay-based methods. Liver stiffness measurement (LSM) by vibration-controlled transient elastography was performed. The area under the curve (AUC), calibration curves, and net benefit analysis were used. RESULTS: An LSM >8 kPa was found in 108 (40.1%) patients. PRO-C3, PRO-C6, C4M, and PRO-C18L had AUCs ranging from 0.48 to 0.62. ADAPT had the highest AUC (0.73, 95% confidence interval [CI] = 0.67-0.79) to detect patients >8 kPa, compared to FIB-4 (0.71, (95%CI = 0.64-0.77, p = 0.35), and had a higher net benefit compared to FIB-4 from a probability threshold of 15%. FIB-4 and ADAPT performed equally well to detect patients with an LSM >12 kPa, AUC 0.76 versus 0.76, p = 0.93. CONCLUSIONS: ADAPT seems to be marginally better than FIB-4 in identifying patients with an LSM >8 kPa. However, the clinical utility of ADAPT as a first line test is uncertain, especially in low-risk populations. The overall performance of FIB-4 was similar to that of ADAPT in detecting patients with an LSM of >12 kPa. Altogether, the results suggest that ADAPT might be useful to detect earlier stages of fibrosis in MASLD, but that FIB-4 remains a first-line test for advanced fibrosis.

Liver histology is associated with long-term clinical outcomes in patients with metabolic dysfunction-associated steatohepatitis.

BACKGROUND: Few studies have examined the risk of long-term clinical outcomes in patients with metabolic dysfunction-associated steatohepatitis in relation to liver histology. We aimed to study this using a real-world cohort. METHODS: Adults (N = 702) recorded on Vanderbilt University Medical Center's Synthetic Derivative database (1984-2021) with evidence of metabolic dysfunction-associated steatohepatitis on liver biopsy were followed from the first biopsy until the first clinical event or last database entry (median: 4.7 y). Risks of cirrhosis (N = 650), other noncirrhotic liver-related (N = 702) and cardiovascular-related outcomes (N = 660), and mortality due to liver, cardiovascular, or cancer events (N = 660) were determined as a function of baseline histology (fibrosis stage [F], lobular inflammation grade [LI], hepatocyte ballooning grade [HB], and steatosis score) adjusting for sex, age, diabetes, and weight-loss surgery. RESULTS: Cirrhosis risk was reduced for lower versus higher fibrosis stage (HR: F0-1 vs. F3: 0.22 [95% CI: 0.12-0.42]), LI1 versus LI2-3 (0.42 [0.19-0.97]), and HB1 versus HB2 (0.20 [0.08-0.50]). Lower fibrosis stage was associated with significantly lower risks of liver-related outcomes versus F4 cirrhosis (eg, F0-1: 0.12 [0.05-0.25]), whereas no differences were seen across baseline lobular inflammation, hepatocyte ballooning, and steatosis grades/scores. Lower versus higher lobular inflammation grade was associated with lower risks for liver-related outcomes in patients with weight-loss surgery. There was a trend for lower risks for cardiovascular-related and any long-term outcomes with lower versus higher fibrosis stage. CONCLUSIONS: Fibrosis stage and lobular inflammation and hepatocyte ballooning grades predict the risk of long-term outcomes, supporting the use of these histological features as potential surrogate markers of disease progression or clinical outcomes.

Evaluation of mucosal-associated invariant T-cells as a potential biomarker to predict infection risk in liver cirrhosis.

BACKGROUND AND AIMS: Infection is a serious complication in patients with cirrhosis. Mucosal-associated invariant T (MAIT) cells are involved in the immune defense against infections and known to be impaired in several chronic conditions, including cirrhosis. Here, we evaluated if MAIT cell levels in peripheral blood are associated with risk of bacterial infections in patients with cirrhosis. METHODS: Patients with cirrhosis seen at the Karolinska University Hospital, Stockholm, Sweden, between 2016 and 2019 were included. Levels of MAIT cells in peripheral blood were determined using flow cytometry. Baseline and follow-up data after at least two years of follow-up were collected by chart review for the primary outcome (bacterial infection) and secondary outcomes (decompensation and death). Competing risk and Cox regression were performed. RESULTS: We included 106 patients with cirrhosis. The median MAIT cells fraction in the circulation was 0.8% in cirrhosis compared to 6.1% in healthy controls. In contrast to our hypothesis, we found an association in the adjusted analysis between relatively preserved MAIT cell levels, and a slightly higher risk to develop bacterial infections (adjusted subdistribution hazard ratio (aSHR) 1.15 (95%CI = 1.01-1.31). However, MAIT cell levels were not associated with the risk of hepatic decompensation (aSHR 1.19 (95%CI = 0.91-1.56)) nor with death (adjusted hazard ratio 1.10 (95%CI = 0.97-1.22)). CONCLUSIONS: Relatively preserved MAIT cell levels in blood of patients with cirrhosis were associated with a somewhat higher risk of bacterial infections. The clinical relevance of this might not be strong. MAIT cells might however be an interesting biomarker to explore in future studies.

Diagnostic accuracy of non-invasive tests to screen for at-risk MASH-An individual participant data meta-analysis.

BACKGROUND & AIMS: There is a need to reduce the screen failure rate (SFR) in metabolic dysfunction-associated steatohepatitis (MASH) clinical trials (MASH+F2-3; MASH+F4) and identify people with high-risk MASH (MASH+F2-4) in clinical practice. We aimed to evaluate non-invasive tests (NITs) screening approaches for these target conditions. METHODS: This was an individual participant data meta-analysis for the performance of NITs against liver biopsy for MASH+F2-4, MASH+F2-3 and MASH+F4. Index tests were the FibroScan-AST (FAST) score, liver stiffness measured using vibration-controlled transient elastography (LSM-VCTE), the fibrosis-4 score (FIB-4) and the NAFLD fibrosis score (NFS). Area under the receiver operating characteristics curve (AUROC) and thresholds including those that achieved 34% SFR were reported. RESULTS: We included 2281 unique cases. The prevalence of MASH+F2-4, MASH+F2-3 and MASH+F4 was 31%, 24% and 7%, respectively. Area under the receiver operating characteristics curves for MASH+F2-4 were .78, .75, .68 and .57 for FAST, LSM-VCTE, FIB-4 and NFS. Area under the receiver operating characteristics curves for MASH+F2-3 were .73, .67, .60, .58 for FAST, LSM-VCTE, FIB-4 and NFS. Area under the receiver operating characteristics curves for MASH+F4 were .79, .84, .81, .76 for FAST, LSM-VCTE, FIB-4 and NFS. The sequential combination of FIB-4 and LSM-VCTE for the detection of MASH+F2-3 with threshold of .7 and 3.48, and 5.9 and 20 kPa achieved SFR of 67% and sensitivity of 60%, detecting 15 true positive cases from a theoretical group of 100 participants at the prevalence of 24%. CONCLUSIONS: Sequential combinations of NITs do not compromise diagnostic performance and may reduce resource utilisation through the need of fewer LSM-VCTE examinations.

Statin initiation after myocardial infarction in patients with alcohol-related liver disease: A nationwide population-based study.

BACKGROUND AND AIMS: Secondary prevention with statins improves clinical outcomes after myocardial infarction (MI). We aimed to compare odds of statin initiation after MI in patients with co-existing alcohol-related liver disease (ALD) to the general population, and the association between statin initiation and mortality in the patients with ALD. METHODS: All statin-naïve patients with ALD and a first-time MI between 2006 and 2020 were identified from Swedish healthcare registers and matched for age, sex, and year of MI with up to ten ALD-free general population controls with a first-time MI. Logistic regression was used to estimate adjusted odds ratios (OR) for statin initiation within 30 days after MI for ALD patients versus controls. Cox regression was used in patients with ALD to compare mortality between statin initiators and non-initiators. RESULTS: Of the 276 patients with a first-time MI and ALD, 206 (74.6%) were male, the median age was 67 (interquartile range 62-72), 151 (54.7%) had cirrhosis, and 62 (22.5%) had decompensated cirrhosis. 1769 matched controls were included. Initiation of statins was less common in ALD patients (50.0%) than controls (89.2%, adjusted OR = .15, 95% confidence interval [CI] = .10-.20). Among patients with ALD, statin initiators and non-initiators were followed for a median of 3.9 (interquartile range = 1.8-7.7) and 1.9 years (interquartile range = .5-4.4), respectively. Statin initiators had lower mortality than non-initiators (adjusted hazard ratio = .41, 95%CI = .28-.59). CONCLUSIONS: Patients with ALD less often initiated statins after MI than the general population. Statin initiation was associated with improved survival, suggesting that patients with ALD might be undertreated following MI.

Liver stiffness predicts progression to liver-related events in patients with chronic liver disease - A cohort study of 14 414 patients.

BACKGROUND & AIMS: Liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE) is a non-invasive diagnostic biomarker of liver fibrosis. It is uncertain if LSM can predict risk for future liver-related outcomes in large, heterogenous populations. METHODS: This Swedish multi-centre cohort study included patients (n = 14 414) from 16 sites who underwent LSM by VCTE between 2008 and 2020. Outcomes were ascertained from national registers. We investigated progression to cirrhosis with portal hypertension or hepatocellular carcinoma (HCC), separately. Cox regression was used to obtain hazard ratios (HRs). Harrel's C-index was used to measure discrimination of VCTE. RESULTS: Included patients had a median age of 46 (interquartile range 34-57), median LSM of 5.9 kPa (4.6-8.0), 59% were male, and the majority had hepatitis C (50.1%). During a median follow-up of 5.9 (4.3-8.0) years, 402 patients (2.7%) developed cirrhosis with portal hypertension. In patients with an LSM ≥25 kPa, 28.7% developed cirrhosis with portal hypertension within 5 years of follow-up, while only .6% of patients with an LSM <10 kPa did. This translated to a HR of 48.3 (95% confidence interval = 37.6-62.0). VCTE had a high discriminative ability, with C-indices above .80 for most liver diseases, including .82 for MASLD. Similar findings were seen for incident HCC. CONCLUSIONS: Increased LSM by VCTE was associated with an increased risk of progression to both cirrhosis with portal hypertension, and to HCC, and had a high discriminative ability across different aetiologies of chronic liver diseases. These results support the use of VCTE to guide follow-up and treatment decisions.

Prevalence and risk factors of metabolic dysfunction-associated steatotic liver disease in south Central Uganda: A cross-sectional survey.

BACKGROUND: Despite numerous risk factors and serious consequences, little is known about metabolic dysfunction-associated steatotic liver disease (MASLD) at population level in Africa. AIM: The aim of the study was to estimate the prevalence and risk factors of MASLD in people living with and without HIV in Uganda. METHODS: We collected data from 37 communities in South Central Uganda between May 2016 and May 2018. We estimated MASLD prevalence using the fatty liver index and advanced liver fibrosis using the dynamic aspartate-to-alanine aminotransferase ratio. We collected additional data on sociodemographics, HIV and cardiovascular disease (CVD) risk factors. We used multivariable logistic regression to determine the association between HIV, CVD risk factors and MASLD. RESULTS: We included 759 people with HIV and 704 HIV-negative participants aged 35-49. MASLD prevalence was 14% in women and 8% in men; advanced liver fibrosis prevalence was estimated to be <1%. MASLD prevalence was more common in women (15% vs. 13%) and men (9% vs. 6%) with HIV. Being female (odds ratio [OR] = 2.1; 95% confidence interval [CI] = 1.4-3.3) was associated with a higher odds of MASLD after adjustment for confounders; HIV infection was borderline associated with MASLD (OR = 1.4; 95% CI: 1.0-2.0). CONCLUSIONS: In a relatively young cohort in Uganda, 14% of women and 8% of men had MASLD. There was an indication of an association between HIV and MASLD in multivariable analysis. These data are the first to describe the population-level burden of MASLD in sub-Saharan Africa using data from a population-based cohort.

Developing and validating clinical prediction models in hepatology - An overview for clinicians.

Prediction models are everywhere in clinical medicine. We use them to assign a diagnosis or a prognosis, and there have been continuous efforts to develop better prediction models. It is important to understand the fundamentals of prediction modelling, thus, we herein describe nine steps to develop and validate a clinical prediction model with the intention of implementing it in clinical practice: Determine if there is a need for a new prediction model; define the purpose and intended use of the model; assess the quality and quantity of the data you wish to develop the model on; develop the model using sound statistical methods; generate risk predictions on the probability scale (0-100%); evaluate the performance of the model in terms of discrimination, calibration, and clinical utility; validate the model using bootstrapping to correct for the apparent optimism in performance; validate the model on external datasets to assess the generalisability and transportability of the model; and finally publish the model so that it can be implemented or validated by others.

Estrogen receptor activation remodels TEAD1 gene expression to alleviate hepatic steatosis.

Sex-based differences in obesity-related hepatic malignancies suggest the protective roles of estrogen. Using a preclinical model, we dissected estrogen receptor (ER) isoform-driven molecular responses in high-fat diet (HFD)-induced liver diseases of male and female mice treated with or without an estrogen agonist by integrating liver multi-omics data. We found that selective ER activation recovers HFD-induced molecular and physiological liver phenotypes. HFD and systemic ER activation altered core liver pathways, beyond lipid metabolism, that are consistent between mice and primates. By including patient cohort data, we uncovered that ER-regulated enhancers govern central regulatory and metabolic genes with clinical significance in metabolic dysfunction-associated steatotic liver disease (MASLD) patients, including the transcription factor TEAD1. TEAD1 expression increased in MASLD patients, and its downregulation by short interfering RNA reduced intracellular lipid content. Subsequent TEAD small molecule inhibition improved steatosis in primary human hepatocyte spheroids by suppressing lipogenic pathways. Thus, TEAD1 emerged as a new therapeutic candidate whose inhibition ameliorates hepatic steatosis.

Vibration-Controlled Transient Elastography Scores to Predict Liver-Related Events in Steatotic Liver Disease.

Importance: Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently the most common chronic liver disease worldwide. It is important to develop noninvasive tests to assess the disease severity and prognosis. Objective: To study the prognostic implications of baseline levels and dynamic changes of the vibration-controlled transient elastography (VCTE)-based scores developed for the diagnosis of advanced fibrosis (Agile 3+) and cirrhosis (Agile 4) in patients with MASLD. Design, Setting, and Participants: This cohort study included data from a natural history cohort of patients with MASLD who underwent VCTE examination at 16 tertiary referral centers in the US, Europe, and Asia from February 2004 to January 2023, of which the data were collected prospectively at 14 centers. Eligible patients were adults aged at least 18 years with hepatic steatosis diagnosed by histologic methods (steatosis in ≥5% of hepatocytes) or imaging studies (ultrasonography, computed tomography or magnetic resonance imaging, or controlled attenuation parameter ≥248 dB/m by VCTE). Main Outcomes and Measures: The primary outcome was liver-related events (LREs), defined as hepatocellular carcinoma or hepatic decompensation (ascites, variceal hemorrhage, hepatic encephalopathy, or hepatorenal syndrome), liver transplant, and liver-related deaths. The Agile scores were compared with histologic and 8 other noninvasive tests. Results: A total of 16 603 patients underwent VCTE examination at baseline (mean [SD] age, 52.5 [13.7] years; 9600 [57.8%] were male). At a median follow-up of 51.7 (IQR, 25.2-85.2) months, 316 patients (1.9%) developed LREs. Both Agile 3+ and Agile 4 scores classified fewer patients between the low and high cutoffs than most fibrosis scores and achieved the highest discriminatory power in predicting LREs (integrated area under the time-dependent receiver-operating characteristic curve, 0.89). A total of 10 920 patients (65.8%) had repeated VCTE examination at a median interval of 15 (IQR, 11.3-27.7) months and were included in the serial analysis. A total of 81.9% of patients (7208 of 8810) had stable Agile 3+ scores and 92.6% of patients (8163 of 8810) had stable Agile 4 scores (same risk categories at both assessments). The incidence of LREs was 0.6 per 1000 person-years in patients with persistently low Agile 3+ scores and 30.1 per 1000 person-years in patients with persistently high Agile 3+ scores. In patients with high Agile 3+ score at baseline, a decrease in the score by more than 20% was associated with substantial reduction in the risk of LREs. A similar trend was observed for the Agile 4 score, although it missed more LREs in the low-risk group. Conclusions and Relevance: Findings of this study suggest that single or serial Agile scores are highly accurate in predicting LREs in patients with MASLD, making them suitable alternatives to liver biopsy in routine clinical practice and in phase 2b and 3 clinical trials for steatohepatitis.

Metabolic Syndrome Traits Increase the Risk of Major Adverse Liver Outcomes in Type 2 Diabetes.

OBJECTIVE: Type 2 diabetes (T2D) increases the risk for major adverse liver outcomes (MALOs), including cirrhosis and its complications. Patients with T2D frequently have other traits of the metabolic syndrome (MetS). It remains uncertain whether there is a synergistic effect of accumulating MetS traits on future MALO risk. RESEARCH DESIGN AND METHODS: Patients with T2D without a history of liver disease were identified from national registers in Sweden from 1998 to 2021. MetS traits included hypertension, low HDL level, hypertriglyceridemia, obesity, and albuminuria, in addition to T2D. MALO events were identified based on administrative coding from national registers until 31 October 2022. Data were analyzed using Cox regression models. RESULTS: In total, 230,992 patients were identified (median age 64 years; 58% male), of whom 3,215 (1.39%) developed MALOs over a median follow-up of 9.9 years. Compared with patients with one MetS trait (only T2D) at baseline, those with more than one MetS trait had a higher rate of MALOs (adjusted hazard ratio [aHR] 2.33, 95% CI 1.53-3.54). The rate of MALOs increased progressively with increasing numbers of MetS traits at baseline (aHR 1.28 per added trait, 95% CI 1.23-1.33). During follow-up, patients who acquired additional MetS traits had a progressively higher rate of MALOs. The MetS trait with the largest association with incident MALOs was hypertension (aHR 2.06, 95% CI 1.57-2.71). CONCLUSIONS: Having or acquiring additional traits of MetS increase the rate of progression to MALOs in patients with T2D. These results could be used to inform screening initiatives for liver disease.

Interactions between the metabolic syndrome and alcohol consumption increases the risk of liver disease.

Alcohol-related liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD, recently renamed metabolic dysfunction-associated steatotic liver disease [MASLD]) share many features, including certain pathophysiological mechanisms, susceptibility genes, and histological lesions. However, the natural history of the two diseases, studied separately, is significantly different, with ALD being associated with a higher risk of cirrhosis and liver-related mortality. Moreover, evidence suggests an interactive effect between ALD and metabolic risk factors that are associated with NAFLD on the risk of progressive fibrosis and development of cirrhosis. Patients with both a high consumption of alcohol and metabolic risk factors, such as obesity or diabetes, should therefore be considered a particularly high-risk group for cirrhosis. Additional studies regarding the efficacy of screening for advanced liver fibrosis or cirrhosis in these risk groups are needed. The most effective and established method for reducing the risk of progression in ALD is alcohol abstinence, whereas weight loss is effective in NAFLD. In this narrative review, we introduce the reader to the literature of the field and present key studies showing this interactive effect.

Risk of major adverse liver outcomes among first-degree relatives of individuals with MASLD.

BACKGROUND & AIMS: Previous studies have suggested an increased risk of major adverse liver outcomes (MALO) in relatives of patients with metabolic dysfunction-associated steatotic liver disease (MASLD). However, granular and longitudinal evidence is lacking on the future risk of MALO among family members of individuals with MASLD. METHODS: We identified 3526 first-degree relatives (FDRs) and 11 079 general population comparators to 1328 patients with MASLD diagnosed between 1974 and 2021, with detailed clinical data, including liver histology in 71% of patients. MALO was defined through diagnostic coding for cirrhosis or its complications. Cox regression models were used to estimate adjusted hazard ratios (aHRs) for MALO among FDRs compared to general population comparators. Cumulative incidence accounting for competing risks was calculated. RESULTS: During a median follow-up of 13.4 years, there were 65 (2%, 1.12/1000 person-years) and 225 (2%, 1.26/1000 person-years) MALO events in FDRs and general population comparators respectively. After adjusting for demographic factors and comorbidities, FDRs were at no increased risk of MALO (aHR = 0.99, 95% CI: 0.74-1.33). Increased relative rates of MALOs were, however, observed in some subgroups, including parents, although absolute risk estimates were low and comparable to the general population. CONCLUSIONS: FDRs of patients with MASLD did not have a higher rate of incident MALO than the general population. Since the absolute risk of MALO in relatives of patients with MASLD was low, these results do not support systematic screening of MASLD-related fibrosis in relatives of patients with MASLD.

The future of International Classification of Diseases coding in steatotic liver disease: An expert panel Delphi consensus statement.

BACKGROUND: Following the adoption of new nomenclature for steatotic liver disease, we aimed to build consensus on the use of International Classification of Diseases codes and recommendations for future research and advocacy. METHODS: Through a two-stage Delphi process, a core group (n = 20) reviewed draft statements and recommendations (n = 6), indicating levels of agreement. Following revisions, this process was repeated with a large expert panel (n = 243) from 73 countries. RESULTS: Consensus ranged from 88.8% to 96.9% (mean = 92.3%). CONCLUSIONS: This global consensus statement provides guidance on harmonizing the International Classification of Diseases coding for steatotic liver disease and future directions to advance the field.

Misclassified Alcohol-related Liver Disease is Common in Presumed Metabolic Dysfunction-associated Steatotic Liver Disease and Highly Increases Risk for Future Cirrhosis.

BACKGROUND & AIMS: Alcohol overconsumption is a risk factor for disease progression in patients with presumed metabolic dysfunction-associated steatotic liver disease (MASLD). How commonly this occurs and how it affects progression to major adverse liver outcomes (MALOs) is not well known. METHODS: We did a register-based cohort study, including all patients with a diagnosis of MASLD in Sweden between 1987 and 2020. Patients were stratified on co-occurrence of diagnoses of alcohol-related liver disease (ALD) or alcohol use disorder (AUD) prior to MASLD diagnosis. Incident MALOs were derived from national registers. Cox regression was used to calculate hazard ratios (HRs) for incident MALO. RESULTS: A total of 15,107 patients with MASLD were identified. The median age was 55 years, and 52% were female. Of the patients, 1843 (12%) had a prior diagnosis of ALD or AUD. During follow-up, a further 787 patients (5.2%) received a diagnosis of ALD or AUD. Patients with previous ALD or AUD diagnoses at or before baseline had considerably higher rates of MALOs compared with patients without (19.5% vs 7.8%; adjusted HR, 3.12; 95% confidence interval, 2.74-3.55). Acquiring an ALD or AUD diagnosis after MASLD diagnosis was associated with higher rates of MALOs (adjusted HR, 5.81; 95% confidence interval, 4.90-6.88). CONCLUSIONS: ALD or AUD is commonly diagnosed prior to or after MASLD diagnosis. Such patients have considerably higher rates of progression to MALOs. Correctly separating between MASLD and ALD is vital to assess prognosis.

Glucagon-like peptide-1 receptor agonists and risk of major adverse liver outcomes in patients with chronic liver disease and type 2 diabetes.

OBJECTIVE: Phase II trials suggest glucagon-like peptide-1 receptor (GLP1) agonists resolve metabolic dysfunction-associated steatohepatitis but do not affect fibrosis regression. We aimed to determine the long-term causal effect of GLP1 agonists on the risk of major adverse liver outcomes (MALO) in patients with any chronic liver disease and type 2 diabetes. DESIGN: We used observational data from Swedish healthcare registers 2010-2020 to emulate a target trial of GLP1 agonists in eligible patients with chronic liver disease and type 2 diabetes. We used an inverse-probability weighted marginal structural model to compare parametric estimates of 10-year MALO risk (decompensated cirrhosis, hepatocellular carcinoma, liver transplantation or MALO-related death) in initiators of GLP1 agonists with non-initiators. We randomly sampled 5% of the non-initiators to increase computational efficiency. RESULTS: GLP1 agonist initiators had a 10-year risk of MALO at 13.3% (42/1026) vs 14.6% in non-initiators (1079/15 633) in intention-to-treat analysis (risk ratio (RR)=0.91, 95% CI=0.50 to 1.32). The corresponding 10-year per-protocol risk estimates were 7.4% (22/1026) and 14.4% (1079/15 633), respectively (RR=0.51, 95% CI=0.14 to 0.88). The per-protocol risk estimates at 6 years were 5.4% (21/1026) vs 9.0% (933/15 633) (RR=0.60, 95% CI=0.29 to 0.90) and at 8 years 7.2% (22/1026) vs 11.7% (1036/15 633) (RR=0.61, 95% CI=0.21 to 1.01). CONCLUSION: In patients with chronic liver disease and type 2 diabetes who adhered to therapy over time, GLP1 agonists may result in lower risk of MALO. This suggests that GLP1 agonists are promising agents to reduce risk of chronic liver disease progression in patients with concurrent type 2 diabetes, although this needs to be corroborated in randomised trials.