Predicting disease progression in metabolic dysfunction-associated steatotic liver disease (MASLD) is challenging, and current non-invasive tests (NITs) lack the precision to replace liver biopsy. This study aimed to identify plasma biomarkers for different stages of fibrosis using affinity-based proteomics in two biopsy-proven cohorts. The primary objective was to identify biomarkers capable of distinguishing between low-to-no fibrosis (F0-1) and significant fibrosis (F2-4) in MASLD.

Participants in the discovery cohort were recruited from Uppsala University Hospital and Swedish CArdioPulmonary bioImage Study (SCAPIS), while the validation cohort was included from Linköping University Hospital. All participants diagnosed with MASLD underwent liver biopsy and were categorized by fibrosis stage (F0-1 or F2-4). A total of 276 plasma proteins were analyzed using Olink® panels, with biomarkers identified through ordinal logistic regression, random forest (RF) analysis and the Boruta algorithm.

The discovery cohort included 60 participants, with 60% having fibrosis stage F0-1 and 40% having F2-4. The validation cohort had 59 participants, of whom 35 had fibrosis stage F0-1 (59.3%) and 24 had stage F2-4 (40.7%). Five biomarkers were significantly associated with fibrosis stage in the discovery cohort, with four confirmed in the validation cohort. A model combining angiotensin converting enzyme-2 (ACE2), hepatocyte growth factor (HGF) and insulin-like growth factor-binding protein-7 (IGFBP-7) demonstrated strong predictive performance for significant fibrosis (c-statistics 0.82-0.83), outperforming fibrosis-4 (FIB-4) (c-statistics 0.61-0.72).

A biomarker model including ACE2, HGF and IGFBP7 shows promise in distinguishing between low-stage and significant fibrosis.

Both liver fibrosis and osteoporosis share inflammatory pathways, with liver fibrosis potentially contributing to decreased bone mineral density (BMD). The rising prevalence of non-alcoholic fatty liver disease (NAFLD) and associated liver fibrosis, especially in older populations, may increase the risk of osteoporosis, but evidence remains inconclusive. This study aims to investigate the relationship between liver fibrosis and osteoporosis in individuals over 50 years old.

This cross-sectional study used data from the Bushehr Elderly Health Program (BEHP), a cohort of 2,000 participants aged 50 and older, selected through multistage stratified random sampling. BMD and trabecular bone score (TBS) measurements were assessed. The Fibrosis-4 (FIB-4) index, a surrogate marker for liver fibrosis, was also calculated to examine its association with these bone health indicators. Multiple linear regression was applied to assess the relationship between FIB-4 and lumbar, hip, femoral neck BMD, and TBS scores, while logistic regression was used to evaluate osteoporosis as the dependent variable.

A total of 1,959 participants with adequate data were included in our analysis. 538 participants had osteoporosis, 936 participants had osteopenia, and 485 participants had normal bone density. FIB-4 index was higher in osteoporotic groups (1.45 ± 0.90) than in osteopenic (1.26 ± 0.58, p < 0.001) and normal groups (1.17 ± 0.48, p < 0.001). After controlling for confounders, FIB-4 index was negatively associated with hip BMD (βmen=-0.0162; 95% CI: -0.0313, -0.0012 and βwomen=-0.0221; 95% CI: -0.0340, -0.0102), femoral neck BMD (βmen=-0.0216; 95% CI: -0.0356, -0.0076 and βwomen=-0.0233; 95% CI: -0.0342, 0.0124), and TBS (βmen=-0.0154; 95% CI: -0.0264, -0.0043 and βwomen=-0.0244; 95% CI: -0.0338, -0.0149) in both genders and with lumbar BMD in women (β=-0.0176; 95% CI: -0.0307, -0.0045). An increase in the FIB-4 index was associated with more than a twofold rise in the risk of developing osteoporosis in women (OR = 2.123; 95% CI: 1.503, 3.000; p < 0.001) and a 36% higher risk in men (OR = 1.366; 95% CI: 1.012, 1.844; p = 0.042).

Liver fibrosis is associated with decreased bone density and attenuated bone architecture. Elevated FIB-4 index has been identified as a risk factor for osteoporosis, indicating a potential link between liver fibrosis and deteriorating bone health.

Screening for advanced fibrosis (AF) resulting from metabolic dysfunction-associated steatotic liver disease (MASLD) is recommended in diabetology. This study aimed to compare the performance of noninvasive tests (NITs) with that of two-step algorithms for detecting patients at high risk of AF requiring referral to hepatologists.

We conducted a planned interim analysis of a prospective multicenter study including participants with type 2 diabetes and/or obesity and MASLD with comprehensive liver assessment comprising blood-based NITs, vibration-controlled transient elastography (VCTE), and two-dimensional shear-wave elastography (2D-SWE). AF risk stratification was determined by a composite criterion of liver biopsy, magnetic resonance elastography, or VCTE ≥12 kPa depending on availability.

Of 654 patients (87% with type 2 diabetes, 56% male, 74% with obesity), 17.6% had an intermediate/high risk of AF, and 9.3% had a high risk of AF. The area under the empirical receiver operating characteristic curves of NITs for detection of high risk of AF were as follows: fibrosis-4 index (FIB-4) score, 0.78 (95% CI 0.72-0.84); FibroMeter, 0.74 (0.66-0.83); FibroTest, 0.78 (0.72-0.85); Enhanced Liver Fibrosis (ELF) test, 0.82 (0.76-0.87); and SWE, 0.84 (0.78-0.89). Algorithms with FIB-4 score/VCTE showed good diagnostic performance for referral of patients at intermediate/high risk of AF to specialized care in hepatology. An alternative FIB-4 score/ELF test strategy showed a high negative predictive value (NPV; 88-89%) and a lower positive predictive value (PPV; 39-46%) at a threshold of 9.8. The FIB-4 score/2D-SWE strategy had an NPV of 91% and a PPV of 58-62%. The age-adapted FIB-4 score threshold resulted in lower NPVs and PPVs in all algorithms.

The FIB-4 score/VCTE algorithm showed excellent diagnostic performance, demonstrating its applicability for routine screening in diabetology. The ELF test using an adapted low threshold at 9.8 may be used as an alternative to VCTE.

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) may be as high as 38% in the adult population with potential serious complications, multiple comorbidities and a high socioeconomic burden. However, there is a general lack of awareness and knowledge about MASLD and its progressive stages (metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis). Therefore, MASLD is still far underdiagnosed. The 'Global Research Initiative for Patient Screening on MASH' (GRIPonMASH) consortium focuses on this unmet public health need. GRIPonMASH will help (primary) healthcare providers to implement a patient care pathway, as recommended by multiple scientific societies, to identify patients at risk of severe MASLD and to raise awareness. Furthermore, GRIPonMASH will contribute to a better understanding of the pathophysiology of MASLD and improved identification of diagnostic and prognostic markers to detect individuals at risk.

This is a prospective multicentre observational study in which 10 000 high-risk patients (type 2 diabetes mellitus, obesity, metabolic syndrome or hypertension) will be screened in 10 European countries using at least two non-invasive tests (Fibrosis-4 index and FibroScan). Blood samples and liver biopsy material will be collected and biobanked, and multiomics analyses will be conducted.

The study will be conducted in compliance with this protocol and applicable national and international regulatory requirements. The study initiation package is submitted at the local level. The study protocol has been approved by local medical ethical committees in all 10 participating countries. Results will be made public and published in scientific, peer-reviewed, international journals and at international conferences.

NCT05651724, registration date: 15 Dec 2022.

Background/Objectives: Bariatric surgery (BS), drugs approved for type-2-diabetes (T2D), obesity, and liver fibrosis (resmetirom) announce the widespread use of fibrosis tests in patients with metabolic liver disease (MASLD). An unmet need is to reduce the uncertainty of biomarkers for the diagnosis of the early stage of clinically significant fibrosis (eF). This can be achieved if three essential but neglected STARD methods (3M) are used, which have a more sensitive histological score than the standard comparator (five-tiers), the weighted area under the characteristic curve (wAUROC) instead of the binary AUROC, and biopsy length. We applied 3M to FibroTest-T2D to demonstrate this reduction of uncertainty and constructed proxies predicting eF in large populations. Methods: For uncertainty, seven subsets were analyzed, four included biopsies (n = 1903), and to assess eF incidence, three MASLD-populations (n = 299,098). FibroTest-T2D classification rates after BS and in outpatients-T2D (n = 402) were compared with and without 3M. In MASLD, trajectories of proxies and incidence against confounding factors used hazard ratios. Results: After BS (110 biopsies), reversal of eF was observed in 16/29 patients (84%) using seven-tier scores vs. 3/20 patients (47%) using five-tier scores (p = 0.005). When the biopsy length was above the median, FibroTest-T2D wAUROC was 0.90 (SD = 0.01), and the wAUROC was 0.88 (SD = 0.1) when the length was below the median (p < 0.001). For the first time, obesity was associated with eF before T2D (p < 0.001), and perimenopausal age with apoA1 and haptoglobin increases (p < 0.0001). Conclusions: Validations of circulating biomarkers need to assess their uncertainty. FibroTest-T2D predicts fibrosis regression after BS. Applying 3M and adjustments could avoid misinterpretations in MASLD surveillance.

Noninvasive tests (NITs) are used to risk-stratify metabolic dysfunction-associated steatotic liver disease. The aim was to survey global patterns of real-world use of NITs.

A 38-item survey was designed by the Global NASH Council. Providers were asked about risks for advanced fibrosis, which NITs (cutoff values) they use to risk-stratify liver disease, monitor progression, and which professional guidelines they follow.

A total of 321 participants from 43 countries completed the survey (54% hepatologists, 28% gastroenterologists, and 18% other). Of the respondents, 85% would risk-stratify patients with type 2 diabetes, obesity (82%), or abnormal liver enzymes (73%). Among NITs to rule out significant or advanced fibrosis, transient elastography (TE) and fibrosis-4 (FIB-4) were most used, followed by NAFLD Fibrosis Score, Enhanced Liver Fibrosis, and magnetic resonance elastography. The cutoffs for ruling out significant fibrosis varied considerably between practices and from guidelines, with only 50% using TE <8 kPa, 65% using FIB-4 <1.30 for age <65, and 41% using FIB-4 <2.00 for age ≥65. Similar variability was found for ruling in advanced fibrosis, where thresholds of FIB-4 ≥2.67 and TE ≥10 kPa were used by 20% and 17%, respectively. To establish advanced fibrosis, 48% would use 2 NITs while 23% would consider 1 NIT, and 17% would confirm with liver biopsy. TE was used by >75% to monitor, and 66% would monitor (intermediate or high risk) annually. Finally, 65% follow professional guideline recommendations regarding NITs.

In clinical practice, there is variability in NIT use and their thresholds. Additionally, there is suboptimal adherence to professional societies' guidelines.

Metabolic dysfunction-associated steatotic liver disease (MASLD) covers a broad spectrum of profile from simple fatty liver, evolving to metabolic dysfunction-associated steatohepatitis (MASH), to hepatic fibrosis, further progressing to cirrhosis and hepatocellular carcinoma (HCC). MASLD has become a prevalent disease with 25% in average over the world. MASH is an active stage, and requires pharmacological intervention when there is necroptotic damage with fibrotic progression. Although there is an increased understanding of MASH pathogenesis and newly approved resmetirom, given its complexity and heterogeneous pathophysiology, there is a strong necessity to develop more drug candidates with better therapeutic efficacy and well-tolerated safety profile. With an increased list of pharmaceutical candidates in the pipeline, it is anticipated to witness successful approval of more potential candidates in this fast-evolving field, thereby offering different categories of medications for selective patient populations. In this review, we update the advances in MASH pharmacotherapeutics that have completed phase II or III clinical trials with potential application in clinical practice during the latest 2 years, focusing on effectiveness and safety issues. The overview of fast-evolving status of pharmacotherapeutic candidates for MASH treatment confers deep insights into the key issues, such as molecular targets, endpoint selection and validation, clinical trial design and execution, interaction with drug administration authority, real-world data feedback and further adjustment in clinical application.

Metabolic dysfunction-associated steatohepatitis (MASH) is associated with a >10-fold increase in liver-related mortality. However, biomarkers predicting both MASH and mortality in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) are missing. We developed a metabolome-derived prediction score for MASH and examined whether it predicts mortality in Chinese and European cohorts.

The MASH prediction score was developed using a multi-step machine learning strategy, based on 44 clinical parameters and 250 serum metabolites measured by proton nuclear magnetic resonance in 311 Chinese adults undergoing a liver biopsy. External validation was conducted in a Finnish liver biopsy cohort (n = 305). We investigated associations of the score with all-cause and cause-specific mortality in the population-based Shanghai Changfeng study (n = 5,893) and the UK biobank (n = 111,673).

A total of 24 clinical parameters and 194 serum metabolites were significantly associated with MASH in the Chinese liver biopsy cohort. The final MASH score included BMI, aspartate aminotransferase, tyrosine, and the phospholipid-to-total lipid ratio in VLDL. The score identified patients with MASH with AUROCs of 0.87 (95% CI 0.83-0.91) and 0.81 (95% CI 0.75-0.88) in the Chinese and Finnish cohorts, with high negative predictive values. Participants with a high or intermediate risk of MASH based on the score had a markedly higher risk of MASLD-related mortality than those with a low risk in Chinese (hazard ratio 23.19; 95% CI 4.80-111.97) and European (hazard ratio 20.15; 95% CI 10.95-37.11) individuals after 7.2 and 12.6 years of follow-up, respectively. The MASH prediction score was superior to the Fibrosis-4 index and the NAFLD fibrosis score in predicting MASLD-related mortality.

The metabolome-derived MASH prediction score accurately predicts risk of MASH and MASLD-related mortality in both Chinese and European individuals.

Metabolic dysfunction-associated steatohepatitis (MASH) is associated with more than a 10-fold increase in liver-related death. However, biomarkers predicting not only MASH, but also death due to liver disease, are missing. We established a MASH prediction score based on 44 clinical parameters and 250 serum metabolites using a machine learning strategy. This metabolome-derived MASH prediction score could accurately identify patients with MASH among both Chinese and Finnish individuals, and it was superior to the Fibrosis-4 index and the NAFLD fibrosis score in predicting MASLD-related death in the general population. Thus, the new MASH prediction score is a useful tool for identifying individuals with a markedly increased risk of serious liver-related outcomes among at-risk and general populations.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is often regarded in society as a disease caused by personal lifestyle and dietary choices. Healthcare providers who have empathy and are able to explain the disease trajectory can better engage with people with MASLD and actively work with them to improve their metabolic health on a sustainable basis. Non-invasive tests can assist in this process, but healthcare providers must ensure they explain their advantages and limitations. Discussing and setting lifestyle goals are priorities before initiating specific pharmacological treatment, since living a healthy lifestyle will remain the backbone of the multimodal management of MASLD. In this review, we discuss challenges and opportunities to actively engage with people living with MASLD in a multimodal treatment framework as a healthcare provider.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), encompasses a spectrum of liver diseases characterized by hepatic steatosis, the presence of at least one cardiometabolic risk factor, and no other apparent cause. Metabolic syndrome (MetS) is a cluster of clinical conditions associated with increased risk of cardiovascular disease, type 2 diabetes, and overall morbidity and mortality. This narrative review summarizes the changes in the management of people with MetS and NAFLD/MASLD from screening to therapeutic strategies that have occurred in the last decades. Specifically, we underline the clinical importance of considering the different impacts of simple steatosis and advanced fibrosis and provide an up-to-date overview on non-invasive diagnostic tests (i.e., imaging and serum biomarkers), which now offer acceptable accuracy and are globally more accessible. Early detection of MetS and MASLD is a top priority as it allows for timely interventions, primarily through lifestyle modification. The liver and cardiovascular benefits of a global and multidimensional approach are not negligible. Therefore, a holistic approach to both conditions, MetS and related chronic liver disease, should be applied to improve overall health and longevity.

Metabolic hepatic steatosis (MetHS) is a clinically heterogeneous, multisystemic, dynamic, and complex disease, whose progression is one of the main causes of cirrhosis and hepatocarcinoma. This clinical practice guideline aims to respond to its main challenges, both in terms of disease burden and complexity. To this end, recommendations have been proposed to experts through the Delphi method. The consensus was optimal in recommendations regarding type 2 diabetes as a risk factor (1.5.1, 4.5.1), in which cases early detection of MetHS should be carried out (4.5.2). Its results also emphasize the importance of the use of non-invasive tests (FIB-4, NFS, HFS) for the exclusion of significant fibrosis in patients with suspected MetHS (2.3.1, 2.3.3). Diagnosis should be carried out through the sequential combination of non-invasive indices and transient elastography by FibroScan® for its risk stratification (2.3.3). A nearly unanimous consensus was reached regarding the role of early prevention in the impact on the quality of life and survival of patients (5.1.2), as well as on the effectiveness of the Mediterranean diet and physical exercise in relation to the improvement of steatosis, steatohepatitis and fibrosis in MetHS patients (5.2.2) and on the positive results offered by resmiterom and semaglutide in promoting fibrosis regression (5.4.1). Finally, a great consensus has been reached regarding the importance of multidisciplinary management in MetHS, for which it is essential to agree on multidisciplinary protocols for referral between levels in each health area (6.2.1), as well as ensuring that referrals to Hepatology/Digestive and Endocrinology or Internal Medicine services are effective and beneficial to prevent the risk of disease progression (6.2.3, 6.3.1).

Metabolic dysfunction-associated fatty liver disease (MAFLD) affects over one-fourth of the global adult population and is the leading cause of liver disease worldwide. To address this, the Asian Pacific Association for the Study of the Liver (APASL) has created clinical practice guidelines focused on MAFLD. The guidelines cover various aspects of the disease, such as its epidemiology, diagnosis, screening, assessment, and treatment. The guidelines aim to advance clinical practice, knowledge, and research on MAFLD, particularly in special groups. The guidelines are designed to advance clinical practice, to provide evidence-based recommendations to assist healthcare stakeholders in decision-making and to improve patient care and disease awareness. The guidelines take into account the burden of clinical management for the healthcare sector.

Metabolic dysfunction-associated steatohepatitis (MASH) is a significant risk factor for gallstone formation, but mechanisms underlying MASH-related gallstone formation remain unclear. Golgi membrane protein 1 (GOLM1) participates in hepatic cholesterol metabolism and is upregulated in MASH. Here, we aimed to explore the role of GOLM1 in MASH-related gallstone formation.

The UK Biobank cohort was used for etiological analysis. GOLM1 knockout (GOLM1-/-) and wild-type (WT) mice were fed with a high-fat diet (HFD). Livers were excised for histology and immunohistochemistry analysis. Gallbladders were collected to calculate incidence of cholesterol gallstones (CGSs). Biles were collected for biliary lipid analysis. HepG2 cells were used to explore underlying mechanisms. Human liver samples were used for clinical validation.

MASH patients had a greater risk of cholelithiasis. All HFD-fed mice developed MASH, and the incidence of gallstones was 16.7% and 75.0% in GOLM1-/- and WT mice, respectively. GOLM1-/- decreased biliary cholesterol concentration and output. In vivo and in vitro assays confirmed that GOLM1 facilitated cholesterol efflux through upregulating ATP binding cassette transporter subfamily G member 5 (ABCG5). Mechanistically, GOLM1 translocated into nucleus to promote osteopontin (OPN) transcription, thus stimulating ABCG5-mediated cholesterol efflux. Moreover, GOLM1 was upregulated by interleukin-1β (IL-1β) in a dose-dependent manner. Finally, we confirmed that IL-1β, GOLM1, OPN, and ABCG5 were enhanced in livers of MASH patients with CGSs.

In MASH livers, upregulation of GOLM1 by IL-1β increases ABCG5-mediated cholesterol efflux in an OPN-dependent manner, promoting CGS formation. GOLM1 has the potential to be a molecular hub interconnecting MASH and CGSs.

Therapeutic trials in metabolic dysfunction-associated steatohepatitis (MASH) are hampered by a high 70-80% screen failure rate mostly because of the absence of fibrotic MASH on baseline liver biopsies, underscoring the need for better selection of candidates. We compared the performance of eight non-invasive tests, designed or not for the diagnosis of fibrotic MASH.

A total of 1,005 patients with histologically proven MASLD were included in five tertiary care centers. Three non-invasive tests developed for fibrotic MASH were evaluated: the simple blood test Fibrotic NASH Index (FNI), the specialized blood test MACK-3, and the elastography-based test FAST. Five non-invasive tests recommended for advanced fibrosis were evaluated as well: the simple blood test FIB-4, the specialized blood tests FibroTest and Enhanced Liver Fibrosis test (ELF™), and the elastography-based tests FibroScan and Agile3+. Fibrotic MASH was defined as MASH with MASLD activity score ≥4 and fibrosis score F ≥2.

Among simple blood tests (n = 1,005), FNI had a significantly higher area under the receiver operating characteristic (AUROC) for fibrotic MASH than FIB-4 (0.709 [0.677-0.741] vs. 0.662 [0.628-0.695], p = 0.019). Among elastography-based tests (n = 817), FAST had a significantly higher AUROC (0.774 [0.743-0.806]) than FibroScan (0.728 [0.694-0.763], p = 0.013) and Agile3+ (0.708 [0.672-0.744], p = 0.004). Among specialized blood tests (n = 545), MACK-3 had a significantly higher AUROC (0.772 [0.734-0.811]) than FibroTest (0.615 [0.568-0.663], p <0.001) and ELF (0.700 [0.656-0.744], p = 0.028). Sequential combination (FAST then Agile3+; MACK-3 then ELF) identified a subset including one-third of patients in whom the false-positive rate was only 30%.

Sequential combinations using first-line tests designed for fibrotic MASH improves the identification of candidates for MASH therapeutic trials.

Drug development in metabolic dysfunction-associated steatohepatitis (MASH) is hampered by a high screen failure rate, one of the main reasons being the absence of MASH and significant fibrosis (fibrotic MASH) on the baseline liver biopsy, a key inclusion criterion in MASH therapeutic trials. Non-invasive tests represent an attractive opportunity to better select candidates for these trials, but most of them have been developed for advanced fibrosis and the new tests designed for the diagnosis of fibrotic MASH remain poorly validated. In this work, we demonstrate that the tests specifically designed for fibrotic MASH are more accurate for this diagnostic target than the tests currently recommended and initially developed for advanced fibrosis. We propose sequential combinations that will facilitate the identification of patients with fibrotic MASH in need of treatment, and their inclusion in MASH therapeutic trials.

In recent years, the utilization of artificial intelligence (AI) technology has gained prominence in the field of liver disease.

To analyzes AI research in the field of liver disease, summarizes the current research status and identifies hot spots.

We searched the Web of Science Core Collection database for all articles and reviews on hepatopathy and AI. The time spans from January 2007 to August 2023. We included 4051 studies for further collection of information, including authors, countries, institutions, publication years, keywords and references. VOS viewer, CiteSpace, R 4.3.1 and Scimago Graphica were used to visualize the results.

A total of 4051 articles were analyzed. China was the leading contributor, with 1568 publications, while the United States had the most international collaborations. The most productive institutions and journals were the Chinese Academy of Sciences and Frontiers in Oncology. Keywords co-occurrence analysis can be roughly summarized into four clusters: Risk prediction, diagnosis, treatment and prognosis of liver diseases. "Machine learning", "deep learning", "convolutional neural network", "CT", and "microvascular infiltration" have been popular research topics in recent years.

AI is widely applied in the risk assessment, diagnosis, treatment, and prognosis of liver diseases, with a shift from invasive to noninvasive treatment approaches.

The recent US Food and Drug Administration approval of resmetirom for treating metabolic dysfunction-associated steatohepatitis in patients necessitates patient selection for significant fibrosis or higher (≥F2). No existing vibration-controlled transient elastography (VCTE) algorithm targets ≥F2.

The mAchine Learning ADvanceD fibrosis and rIsk metabolic dysfunction-associated steatohepatitis Novel predictor (ALADDIN) study addressed this gap by introducing a machine-learning-based web calculator that estimates the likelihood of significant fibrosis using routine laboratory parameters with and without VCTE. Our study included a training set of 827 patients, a testing set of 504 patients with biopsy-confirmed metabolic dysfunction-associated steatotic liver disease from 6 centers, and an external validation set of 1,299 patients from 9 centers. Five algorithms were compared using area under the curve (AUC) in the test set: ElasticNet, random forest, gradient boosting machines, XGBoost, and neural networks. The top 3 (random forest, gradient boosting machines, and XGBoost) formed an ensemble model.

In the external validation set, the ALADDIN-F2-VCTE model, using routine laboratory parameters with VCTE (AUC 0.791, 95% confidence interval [CI]: 0.764-0.819), outperformed VCTE alone (0.745, 95% CI 0.717-0.772, P < 0.0001), FibroScan-aspartate aminotransferase (0.710, 0.679-0.748, P < 0.0001), and Agile-3 model (0.740, 0.710-0.770, P < 0.0001) regarding the AUC, decision curve analysis, and calibration. The ALADDIN-F2-Lab model, using routine laboratory parameters without VCTE, achieved an AUC of 0.706 (95% CI: 0.668-0.749) and outperformed Fibrosis-4, steatosis-associated fibrosis estimator, and LiverRisk scores.

Along with the steatosis-associated fibrosis estimator model developed to target significant fibrosis or higher, ALADDIN-F2-VCTE ( https://aihepatology.shinyapps.io/ALADDIN1 ) uniquely supports a refined noninvasive approach to patient selection for resmetirom without the need for liver biopsy. In addition, ALADDIN-F2-Lab ( https://aihepatology.shinyapps.io/ALADDIN2 ) offers an effective alternative when VCTE is unavailable.

The objective of this study was to validate the diagnostic accuracy of the acFibroMASH index in a population of metabolic dysfunction-associated steatotic liver disease (MASLD) patients with at-risk metabolic dysfunction-associated steatohepatitis (MASH) and to compare it with other scoring systems.

394 patients with biopsy-proven MASLD were retrospectively enrolled. The patients were divided into the at-risk MASH (NAFLD activity score ≥ 4 and significant fibrosis) group (n = 103) and the non-at-risk MASH group (n = 291). The diagnostic performance of the acFibroMASH index was compared to that of fibroScan-aspartate aminotransferase (FAST) and other noninvasive fibrosis scores by plotting the receiver operating characteristic curve (ROC), including the area under the curve (AUC), sensitivity, and specificity. Cut-offs of the acFibroMASH index for sensitivity (≥ 0.90) and specificity (≥ 0.90) were obtained in our cohort.

The AUC of the acFibroMASH index in assessing at-risk MASH was 0.780, while the AUC of FAST was 0.770. The comparison of acFibroMASH with FAST showed no significant difference (P = 0.542). When the cut-off value for acFibroMASH was < 0.15, 95.5% of at-risk MASH patients could be excluded in 89 patients correctly. Conversely, when the cut-off value was set at > 0.39, 49.3% of at-risk MASH patients could be diagnosed in 140 patients correctly. When the NPV was set at 0.900, the critical value for exclusion was determined to be 0.23, with a sensitivity of 0.835 and a specificity of 0.526.

This study validated the efficacy of the acFibroMASH index in predicting at-risk MASH in a population of MASLD patients, demonstrating comparable performance to that of the FAST. The acFibroMASH index may provide a valuable clinical basis for screening and identifying at-risk MASH in primary care settings.

To address the need for a simple model to predict ≥ F2 fibrosis in metabolic dysfunction-associated steatotic liver disease (MASLD) patients, a study utilized data from 791 biopsy-proven MASLD patients from the NASH Clinical Research Network and Jinan University First Affiliated Hospital. The data were divided into training and internal testing sets through randomized stratified sampling. A multivariable logistic regression model using key categorical variables was developed to identify ≥ F2 fibrosis. External validation was performed using data from the FLINT trial and multiple centers in China. The DA-GAG score, incorporating diabetes, age, GGT, aspartate aminotransferase/ platelet ratio, and globulin/ total protein ratio, demonstrated superior performance in distinguishing ≥ F2 fibrosis with an area under the receiver operating characteristic curve of 0.79 in training and over 0.80 in testing datasets. The DA-GAG score efficiently identifies MASLD patients with ≥ F2 fibrosis, significantly reducing the medical burden.

Previous studies indicated that the Fibrosis-4 Index (FIB-4), an evaluation metric for liver fibrosis, is associated with adverse outcomes in coronary artery disease. However, the correlation between FIB-4 and myocardial infarction (MI) in Chinese patients with Type 2 Diabetes Mellitus (T2DM) has not been well-defined. Thus, this study aims to elucidate the association between FIB-4 and MI in Chinese T2DM patients.

Cross-sectional data were collected from T2DM patients at two hospitals in China, designated as the discovery and validation centers. The exposure variable, FIB-4 index, was derived from patient age, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and platelet count. This index was stratified into four distinct clusters via k-means clustering analysis. The primary outcome was defined as the incidence of co-occurring MI. Logistic and restricted cubic spline regression was conducted to assess the association between the FIB-4 index and MI in Chinese T2DM patients.

In the discovery phase, data were analyzed from 2,980 T2DM patients, including 1,114 females (37.38%), with 58 years average age (SD: 10.4). Among them, 190 were also MI patients. Based on the fully adjusted logistic regression analysis, the odds ratio (OR) for the second cluster was 1.00 (95% CI, 0.60-1.40); for the third cluster, it was 1.94 (95% CI, 1.32-2.57), and for the poorest controlled cluster it was 16.18 (95% CI, 14.97-17.39) in comparison to the best-controlled cluster of FIB-4. Restricted cubic spline regression revealed a linear relationship between the FIB-4 index and MI risk. Subgroup analysis demonstrated that this association was significant in elderly adults, females with high BMI, and those with comorbidities such as hypertension, coronary artery disease, and chronic heart failure. These findings yield consistent results in the validation set (n = 224).

Among Chinese patients with T2DM, elevated FIB-4 levels have been independently associated with MI, particularly among females and individuals with concomitant hypertension. Consequently, the FIB-4 index is anticipated to serve as a promising tool for early detection and risk stratification in this population.

Fibrosis is a pathological condition characterised by excessive accumulation of extracellular matrix (ECM) components, particularly collagens, leading to tissue scarring and organ dysfunction. In fibrosis, an imbalance between collagen synthesis (fibrogenesis) and degradation (fibrolysis) results in the deposition of fibrillar collagens disrupting the structural integrity of the ECM and, consequently, tissue architecture. Fibrosis is associated with a wide range of chronic diseases, including cirrhosis, kidney fibrosis, pulmonary fibrosis, and autoimmune diseases. Recently, the concept of "hot" and "cold" fibrosis has emerged, referring to the immune status within fibrotic tissues and the nature of fibrogenic signalling. Hot fibrosis is characterised by active immune cell infiltration and inflammation, while cold fibrosis is associated with auto- and paracrine myofibroblast activation, immune cell exclusion and quiescence. In this article, we explore the relationship between hot and cold fibrosis, the role of various types of collagens and their biologically active fragments in modulating the immune system, and how serological ECM biomarkers can help improve our understanding of the disease-relevant interactions between immune and mesenchymal cells in fibrotic tissues. Additionally, we draw lessons from immuno-oncology research in solid tumours to shed light on potential strategies for fibrosis treatment and highlight the advantage of having a "hot fibrotic environment" to treat fibrosis by enhancing collagen degradation through modulation of the immune system.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the umbrella term that comprises metabolic dysfunction-associated steatotic liver, or isolated hepatic steatosis, through to metabolic dysfunction-associated steatohepatitis, the progressive necroinflammatory disease form that can progress to fibrosis, cirrhosis and hepatocellular carcinoma. MASLD is estimated to affect more than one-third of adults worldwide. MASLD is closely associated with insulin resistance, obesity, gut microbial dysbiosis and genetic risk factors. The obesity epidemic and the growing prevalence of type 2 diabetes mellitus greatly contribute to the increasing burden of MASLD. The treatment and prevention of major metabolic comorbidities such as type 2 diabetes mellitus and obesity will probably slow the growth of MASLD. In 2023, the field decided on a new nomenclature and agreed on a set of research and action priorities, and in 2024, the US FDA approved the first drug, resmetirom, for the treatment of non-cirrhotic metabolic dysfunction-associated steatohepatitis with moderate to advanced fibrosis. Reliable, validated biomarkers that can replace histology for patient selection and primary end points in MASH trials will greatly accelerate the drug development process. Additionally, noninvasive tests that can reliably determine treatment response or predict response to therapy are warranted. Sustained efforts are required to combat the burden of MASLD by tackling metabolic risk factors, improving risk stratification and linkage to care, and increasing access to therapeutic agents and non-pharmaceutical interventions.

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects roughly 1 in 3 adults and is a leading cause of liver transplants and liver related mortality. A deeper understanding of disease pathogenesis is essential to assist in developing blood-based biomarkers.

Here, we use data-independent acquisition mass spectrometry to assess disease-state associated protein profiles in human liver, blood plasma, and white adipose tissue (WAT).

In liver, we find that MASLD is associated with an increased abundance of proteins involved in immune response and extracellular matrix (ECM) and a decrease in proteins involved in metabolism. Cell type deconvolution of the proteome indicates liver endothelial and hepatic stellate cells are the main source of ECM rearrangements, and hepatocytes are the major contributor to the changes in liver metabolism. In the blood, profiles of several MASLD-associated proteins correlate with expression in WAT rather than liver and so could serve as suitable liver disease predictors in a multi-protein panel marker. Moreover, our proteomics-based logistic regression models perform better than existing methods for predicting MASLD and liver fibrosis from human blood samples.

Our comprehensive proteomic analysis deepens the understanding of liver function and MASLD pathology by elucidating key cellular mechanisms and multi-organ interactions, and demonstrates the robustness of a proteomics-based biomarker panel to enhance diagnosis of MASLD and significant fibrosis.

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.

Objective Identifying patients at high risk of steatotic liver disease (SLD) is crucial. The liver fibrosis stage is the most reliable marker of liver-related mortality. However, noninvasive risk stratification methods remain controversial. Therefore, we analyzed the risk of liver-related events in patients who underwent a liver biopsy for metabolic dysfunction-associated steatotic liver disease (MASLD) or cryptogenic SLD at our hospital. Methods We retrospectively reviewed the clinical course of the patients to identify the occurrence of liver-related events. Patients This study included 146 patients diagnosed with SLD through a liver biopsy. Results Liver-related events occurred in 20 patients and were more frequent in those with advanced fibrosis than in those without advanced fibrosis. However, patients with advanced steatosis exhibit reduced disease progression. Patients with obesity and/or diabetes complications had a lower stage of fibrosis and better prognosis than the others. The non-invasive fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease (NAFLD) prognosis-related "NAFLD outcomes score (NOS)" effectively differentiated patients with disease progression. Standard laboratory data analyses revealed that high total bilirubin and low albumin levels were risk factors. A multivariate analysis with significant factors other than NOS score revealed that the absence of obesity and/or diabetes complications, a high FIB-4 index, and a high total bilirubin level were independent factors for liver-related events. Conclusion A high NOS score, absence of obesity and/or diabetes complications, a high FIB-4 index, and high total bilirubin levels are risk factors for disease progression. Patients with lean phenotypes or non-diabetic SLD should also be assessed using noninvasive markers to determine their risks and potential outcomes.

In managing metabolic dysfunction-associated steatotic liver disease, which affects over 30% of the general population, effective noninvasive biomarkers for assessing disease severity, monitoring disease progression, predicting the development of liver-related complications, and assessing treatment response are crucial. The advantage of simple fibrosis scores lies in their widespread accessibility through routinely performed blood tests and extensive validation in different clinical settings. They have shown reasonable accuracy in diagnosing advanced fibrosis and good performance in excluding the majority of patients with a low risk of liver-related complications. Among patients with elevated serum fibrosis scores, a more specific fibrosis and imaging biomarker has proved useful to accurately identify patients at risk of liver-related complications. Among specific fibrosis blood biomarkers, enhanced liver fibrosis is the most widely utilized and has been approved in the United States as a prognostic biomarker. For imaging biomarkers, the availability of vibration-controlled transient elastography has been largely improved over the past years, enabling the use of liver stiffness measurement (LSM) for accurate assessment of significant and advanced fibrosis, and cirrhosis. Combining LSM with other routinely available blood tests enhances the ability to diagnose at-risk metabolic dysfunction-associated steatohepatitis and predict liver-related complications, some reaching an accuracy comparable to that of liver biopsy. Magnetic resonance imaging-based modalities provide the most accurate quantification of liver fibrosis, though the current utilization is limited to research settings. Expanding their future use in clinical practice depends on factors such as cost and facility availability.

The performance of non-invasive liver tests (NITs) is known to vary across settings and subgroups. We systematically evaluated whether the performance of three NITs in detecting advanced fibrosis in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) varies with age, sex, body mass index (BMI), type 2 diabetes mellitus (T2DM) status or liver enzymes.

Data from 586 adult LITMUS Metacohort participants with histologically characterised MASLD were included. The diagnostic performance of the Fibrosis-4 Index (FIB-4), enhanced liver fibrosis (ELF) and vibration-controlled transient elastography liver stiffness measurement (VCTE LSM) was evaluated. Performance was expressed as the area under the receiver operating characteristics curve (AUC). Thresholds for detecting advanced fibrosis (≥F3) were calculated for each NIT for fixed (high) sensitivity, specificity and predictive values.

Differences in AUC between all subgroups were small and statistically not significant, indicating comparable performance in detecting ≥F3, irrespective of these clinical factors. However, different thresholds were needed to achieve the same level of accuracy with each test. For example, for a fixed sensitivity and specificity, the thresholds for all three NITs were higher in patients with T2DM. Effects for sex, age and liver enzymes were less pronounced.

Performance of the selected NITs in detecting advanced liver fibrosis does not vary substantially with clinical characteristics. However, different thresholds have to be selected to achieve the same sensitivity, specificity and predictive values in the respective subgroups. Large prospective studies are called for to study NIT accuracy considering multiple patient characteristics.

Current guidelines recommend a two-step approach for risk stratification in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) involving Fibrosis-4 index (FIB-4) followed by liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE) or similar second-line tests. This study aimed to examine the prognostic performance of this approach.

The VCTE-Prognosis study was a longitudinal study of patients with MASLD who had undergone VCTE examinations at 16 centres from the US, Europe and Asia with subsequent follow-up for clinical events. The primary endpoint was incident liver-related events (LREs), defined as hepatic decompensation and/or hepatocellular carcinoma.

Of 12,950 patients (mean age 52 years, 41% female, 12.1% LSM >12 kPa), baseline FIB-4, at cut-offs of 1.3 (or 2.0 for age ≥65) and 2.67, classified 66.3% as low-risk and 9.8% as high-risk, leaving 23.9% in the intermediate-risk zone. After classifying intermediate FIB-4 patients as low-risk if LSM was <8.0 kPa and high-risk if LSM was >12.0 kPa, 81.5%, 4.6%, and 13.9% of the full cohort were classified as low-, intermediate-, and high-risk, respectively. At a median (IQR) follow-up of 47 (23-72) months, 248 (1.9%) patients developed LREs. The 5-year cumulative incidence of LREs was 0.5%, 1.0% and 10.8% in the low-, intermediate- and high-risk groups, respectively. Replacing LSM with Agile 3+, Agile 4, and FAST did not reduce the intermediate-risk zone or improve event prediction. Classifying intermediate FIB-4 patients by LSM <10 kPa (low-risk) and >15 kPa (high-risk) reduced the intermediate-risk zone while maintaining predictive performance.

The non-invasive two-step approach of FIB-4 followed by LSM is effective in classifying patients at different risks of LREs.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is emerging as one of the leading causes of cirrhosis and hepatocellular carcinoma worldwide, but only a minority of patients will develop these complications. Therefore, it is necessary to use non-invasive tests instead of liver biopsy for risk stratification. Additionally, as most patients with MASLD are seen in primary care instead of specialist settings, cost and availability of the tests should be taken into consideration. In this multicentre study, the use of the Fibrosis-4 index followed by liver stiffness measurement by vibration-controlled transient elastography effectively identified patients who would later develop liver-related events. The results support current recommendations by various regional guidelines on a clinical care pathway based on non-invasive tests to diagnose advanced liver fibrosis.