APPROACH & RESULTS: NAFLD knowledge surveys containing 54 and 59 questions covering three domains (Epidemiology/Pathogenesis, Diagnostics, and Treatment) were completed electronically by hepatologists, gastroenterologists (GEs), endocrinologists (ENDOs) and primary care physicians (PCPs) from 40 countries comprising 5 Global Burden of Disease (GBD) super-regions. Over 24 months, 2202 surveys were completed (488 hepatologists, 758 GEs, 148 ENDOs, and 808 PCPs; 50% High-Income GBD super-region, 27% from North Africa and Middle East, 12% Southeast Asia, and 5% South Asian and Latin America). Hepatologists saw the greatest number of NAFLD patients annually: median (IQR) 150 (60-300) vs. 100 (35-200) for GEs, 100 (30-200) for ENDOs, and 10 (4-50) for PCPs (all p<0.0001). The primary sources of NAFLD knowledge acquisition for hepatologists were international conferences (33% vs. 8-26%) and practice guidelines for others (39-44%). Internet was the second most common source of NAFLD knowledge for PCPs (28%). NAFLD knowledge scores were higher for hepatologists than GEs: Epidemiology 62% vs. 53%, Diagnostics 80% vs. 73%, Treatment 61% vs. 58% (p<0.0001) and ENDOs scores were higher than PCPs: Epidemiology 70% vs. 60%, Diagnostics 71% vs. 64%, Treatment 79% vs. 68% (p<0.0001). Being a hepatologist or ENDO was associated with higher knowledge scores than GE or PCP, respectively (p<0.05). Higher NAFLD knowledge scores were independently associated with greater number of NAFLD patients seen (p<0.05).

METHODS: Clinical, laboratory, and PRO data (Chronic Liver Disease Questionnaire-nonalcoholic steatohepatitis [NASH], Functional Assessment of Chronic Illness Therapy-Fatigue, and the Work Productivity and Activity Index) were collected from NAFLD patients seen in real-world practices and enrolled in the Global NAFLD/NASH Registry encompassing 18 countries in 6 global burden of disease super-regions.

RESULTS: Across the global burden of disease super-regions, NAFLD patients (n = 5691) were oldest in Latin America and Eastern Europe and youngest in South Asia. Most men were enrolled at the Southeast and South Asia sites. Latin America and South Asia had the highest employment rates (>60%). Rates of cirrhosis varied (12%-21%), and were highest in North Africa/Middle East and Eastern Europe. Rates of metabolic syndrome components varied: 20% to 25% in South Asia and 60% to 80% in Eastern Europe. Chronic Liver Disease Questionnaire-NASH and Functional Assessment of Chronic Illness Therapy-Fatigue PRO scores were lower in NAFLD patients than general population norms (all P < .001). Across the super-regions, the lowest PRO scores were seen in Eastern Europe and North Africa/Middle East. In multivariate analysis adjusted for enrollment region, independent predictors of lower PRO scores included younger age, women, and nonhepatic comorbidities including fatigue (P < .01). Patients whose fatigue scores improved over time experienced a substantial PRO improvement. Nearly 8% of Global NAFLD/NASH Registry patients had a lean body mass index, with fewer metabolic syndrome components, fewer comorbidities, less cirrhosis, and significantly better PRO scores (P < .01).

METHODS: A total of 1924 patients with biopsy-proven nonalcoholic fatty liver disease from 10 centers in Asia, Australia, and Europe were included. The blood test MACK-3 was calculated for all patients. FibroScan-aspartate aminotransferase score (FAST), an elastography-based test for fibrotic NASH, also was available in a subset of 655 patients. Fibrotic NASH was defined as the presence of NASH on liver biopsy with a Nonalcoholic Fatty Liver Disease Activity Score of 4 or higher and fibrosis stage of F2 or higher according to the NASH Clinical Research Network scoring system.

RESULTS: The area under the receiver operating characteristic of MACK-3 for fibrotic NASH was 0.791 (95% CI 0.768-0.814). Sensitivity at the previously published MACK-3 threshold of less than 0.135 was 91% and specificity at a greater than 0.549 threshold was 85%. The MACK-3 area under the receiver operating characteristic was not affected by age, sex, diabetes, or body mass index. MACK-3 and FAST results were well correlated (Spearman correlation coefficient, 0.781; P < .001). Except for an 8% higher rate of patients included in the grey zone, MACK-3 provided similar accuracy to that of FAST. Both tests included 27% of patients in their rule-in zone, with 85% specificity and 35% false positives (screen failure rate).

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.

METHODS AND RESULTS: This was an individual patient data meta-analysis of 1780 patients with biopsy-proven NAFLD and T2D. The index tests of interest were FIB-4, NAFLD Fibrosis Score (NFS), aspartate aminotransferase-to-platelet ratio index, liver stiffness measurement (LSM) by vibration-controlled transient elastography, and AGILE 3+. The target conditions were advanced fibrosis, NASH, and fibrotic NASH(NASH plus F2-F4 fibrosis). The diagnostic performance of noninvasive tests. individually or in sequential combination, was assessed by area under the receiver operating characteristic curve and by decision curve analysis. Comparison with 2278 NAFLD patients without T2D was also made. In NAFLD with T2D LSM and AGILE 3+ outperformed, both NFS and FIB-4 for advanced fibrosis (area under the receiver operating characteristic curve:LSM 0.82, AGILE 3+ 0.82, NFS 0.72, FIB-4 0.75, aspartate aminotransferase-to-platelet ratio index 0.68; p < 0.001 of LSM-based versus simple serum tests), with an uncertainty area of 12%-20%. The combination of serum-based with LSM-based tests for advanced fibrosis led to a reduction of 40%-60% in necessary LSM tests. Decision curve analysis showed that all scores had a modest net benefit for ruling out advanced fibrosis at the risk threshold of 5%-10% of missing advanced fibrosis. LSM and AGILE 3+ outperformed both NFS and FIB-4 for fibrotic NASH (area under the receiver operating characteristic curve:LSM 0.79, AGILE 3+ 0.77, NFS 0.71, FIB-4 0.71; p < 0.001 of LSM-based versus simple serum tests). All noninvasive scores were suboptimal for diagnosing NASH.

DESIGN: Individual patient data meta-analysis of studies evaluating LSM-VCTE against liver histology was conducted. FIB-4 and NFS were computed where possible. Sensitivity, specificity and area under the receiver operating curve (AUROC) were calculated. Biomarkers were assessed individually and in sequential combinations.

RESULTS: Data were included from 37 primary studies (n=5735; 45% women; median age: 54 years; median body mass index: 30 kg/m2; 33% had type 2 diabetes; 30% had advanced fibrosis). AUROCs of individual LSM-VCTE, FIB-4 and NFS for advanced fibrosis were 0.85, 0.76 and 0.73. Sequential combination of FIB-4 cut-offs (<1.3; ≥2.67) followed by LSM-VCTE cut-offs (<8.0; ≥10.0 kPa) to rule-in or rule-out advanced fibrosis had sensitivity and specificity (95% CI) of 66% (63-68) and 86% (84-87) with 33% needing a biopsy to establish a final diagnosis. FIB-4 cut-offs (<1.3; ≥3.48) followed by LSM cut-offs (<8.0; ≥20.0 kPa) to rule out advanced fibrosis or rule in cirrhosis had a sensitivity of 38% (37-39) and specificity of 90% (89-91) with 19% needing biopsy.

METHODS: This was an individual participant data meta-analysis of the prognostic performance of histologically assessed fibrosis stage (F0-4), liver stiffness measured by vibration-controlled transient elastography (LSM-VCTE), fibrosis-4 index (FIB-4), and NAFLD fibrosis score (NFS) in patients with NAFLD. The literature was searched for a previously published systematic review on the diagnostic accuracy of imaging and simple non-invasive tests and updated to Jan 12, 2022 for this study. Studies were identified through PubMed/MEDLINE, EMBASE, and CENTRAL, and authors were contacted for individual participant data, including outcome data, with a minimum of 12 months of follow-up. The primary outcome was a composite endpoint of all-cause mortality, hepatocellular carcinoma, liver transplantation, or cirrhosis complications (ie, ascites, variceal bleeding, hepatic encephalopathy, or progression to a MELD score ≥15). We calculated aggregated survival curves for trichotomised groups and compared them using stratified log-rank tests (histology: F0-2 vs F3 vs F4; LSM: <10 vs 10 to <20 vs ≥20 kPa; FIB-4: <1·3 vs 1·3 to ≤2·67 vs >2·67; NFS: 0·676), calculated areas under the time-dependent receiver operating characteristic curves (tAUC), and performed Cox proportional-hazards regression to adjust for confounding. This study was registered with PROSPERO, CRD42022312226.

FINDINGS: Of 65 eligible studies, we included data on 2518 patients with biopsy-proven NAFLD from 25 studies (1126 [44·7%] were female, median age was 54 years [IQR 44-63), and 1161 [46·1%] had type 2 diabetes). After a median follow-up of 57 months [IQR 33-91], the composite endpoint was observed in 145 (5·8%) patients. Stratified log-rank tests showed significant differences between the trichotomised patient groups (p<0·0001 for all comparisons). The tAUC at 5 years were 0·72 (95% CI 0·62-0·81) for histology, 0·76 (0·70-0·83) for LSM-VCTE, 0·74 (0·64-0·82) for FIB-4, and 0·70 (0·63-0·80) for NFS. All index tests were significant predictors of the primary outcome after adjustment for confounders in the Cox regression.

INTERPRETATION: Simple non-invasive tests performed as well as histologically assessed fibrosis in predicting clinical outcomes in patients with NAFLD and could be considered as alternatives to liver biopsy in some cases.

METHODS: We analyzed data from 3004 individuals with biopsy-proven metabolic dysfunction-associated steatotic liver disease (MASLD) across 29 Chinese and 9 international cohorts to validate the acMASH index and develop the acFibroMASH index. Additionally, we utilized the independent external data from a multi-national cohort of 9034 patients with MASLD to examine associations between the acFibroMASH index and the risk of LREs.

RESULTS: In the pooled global cohort, the acMASH index identified MASH with an area under the receiver operating characteristic curve (AUROC) of 0.802 (95% confidence interval [CI], 0.786-0.818). The acFibroMASH index (including the acMASH index plus liver stiffness measurement) accurately identified fibrotic MASH with an AUROC of 0.808 in the derivation cohort and 0.800 in the validation cohort. Notably, the AUROC for the acFibroMASH index was 0.835 (95% CI, 0.786-0.882), superior to that of the FAST score at 0.750 (95% CI, 0.693-0.800; P < .01) in predicting the 5-year risk of LREs. Patients with acFibroMASH >0.39 had a higher risk of LREs than those with acFibroMASH <0.15 (adjusted hazard ratio, 11.23; 95% CI, 3.98-31.66).