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Background & Aims: A noteworthy proportion of patients with metabolic dysfunction-associated steatotic liver disease (MASLD) have an indeterminate vibration-controlled transient elastography (VCTE). Among these patients, we aimed to identify candidates for MASLD treatment by diagnosing significant fibrosis., Methods: Real-world prospective study including a large dataset of MASLD patients with paired VCTE and liver biopsy from 6 centers. A total of n=1196 patients were recruited and divided in training (3 centers, Spain), internal validation (2 centers, Spain), and external validation (1 center, United States) cohorts. In patients with indeterminate liver stiffness measurements (LSM:8-12 kPa), a diagnostic algorithm was developed to identify significant fibrosis, defined as histological stage ≥F2. Statistical analysis was performed using gaussian mixture model (GMM) and k-means unsupervised clusterization., Results: From the eligible population, 33%, 29%, and 31% had indeterminate VCTE in the training, internal and external validation samples, respectively. Controlled attenuation parameter (CAP) allowed the differentiation of GMM clusters with a cut-off of 280 dB/m (AUC:0.89 [95%CI:0.86-0.97]). Within patients with <280 dB/m, a LSM between 8.0-9.0 kPa showed a 93% sensitivity and a 91% negative predictive value to exclude significant fibrosis. Among patients with ≥280 dB/m, a LSM between 10.3-12.0 kPa diagnosed significant fibrosis with a 91% specificity. Applying this algorithm to the validation cohorts, 36% of the indeterminate VCTE were re-allocated. The re-allocated high-risk group showed a prevalence of 86% significant fibrosis, opening the therapeutic window for MASLD patients., Conclusion: To identify candidates for MASLD treatment among indeterminate VCTE, an algorithm-based on the sequential combination of LSM and CAP thresholds can optimize the diagnosis of moderate-to-advanced fibrosis., (Copyright © 2024. Published by Elsevier Inc.)

Purpose:  Peripheral responses might be important in handcycling, given the involvement of small muscles compared to other exercise modalities. Therefore, the goal of this study was to compare changes in muscle oxygen saturation (∆SmO 2 ) and deoxyhemoglobin level (∆[HHb]) between different efforts and muscles., Methods:  Handcyclists participated in a Wingate, a maximal incremental test and a 20-min time-trial (TT). Oxygen uptake (VO 2 ) as well as ∆SmO 2 , ∆[HHb], deoxygenation and reoxygenation rates in the triceps brachii (TB), biceps brachii (BB), anterior deltoid (AD) and extensor carpi radialis brevis (ER) were measured., Results:  ER ∆[HHb]max was 37% greater in the incremental test than in the Wingate (ES = 0.392, P = 0.031). TT mean power (W/kg) was associated with BB ∆SmO 2 min measured in the incremental test (r = -0.998 [-1.190, -0.806], P = 0.002) and in the Wingate (r = -0.994 [-1.327, -0.661], P = 0.006). MAP (W/kg) was associated with Wingate BB ∆SmO 2 min (r = -0.983 [-0.999, -0.839], P = 0.003), and Wingate peak (r = 0.649 [0.379, 0.895], P = 0.008) and mean power (W/kg) (r = 0.925 [0.752, 0.972], P = 0.003) was associated with right handgrip force. The strongest physiological predictor for TT performance was BB ∆SmO 2 min in the incremental test (P = 0.002, r 2  = 0.993, SEE 0.016 W/kg), Wingate BB ∆SmO 2 min for MAP (P = 0.003, r 2  = 0.956, SEE 0.058 W/kg) and right handgrip force for Wingate peak power (P = 0.005, r 2  = 0.856, SEE 0.551 W/kg)., Conclusion:  Peripheral aerobic responses (muscle oxygenation) were predictive of handcycling performance., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Aims: Diagnosis of metabolic dysfunction-associated steatohepatitis (MASH) requires histology. In this study, a magnetic resonance imaging (MRI) score was developed and validated to identify MASH in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Secondarily, a screening strategy for MASH diagnosis was investigated., Methods: This prospective multicentre study included 317 patients with biopsy-proven MASLD and contemporaneous MRI. The discovery cohort (Spain, Portugal) included 194 patients. NAFLD activity score (NAS) and fibrosis were assessed with the NASH-CRN histologic system. MASH was defined by the presence of steatosis, lobular inflammation, and ballooning, with NAS ≥4 with or without fibrosis. An MRI-based composite biomarker of Proton Density Fat Fraction and waist circumference (MR-MASH score) was developed. Findings were afterwards validated in an independent cohort (United States, Spain) with different MRI protocols., Results: In the derivation cohort, 51% (n = 99) had MASH. The MR-MASH score identified MASH with an AUC = .88 (95% CI .83-.93) and strongly correlated with NAS (r = .69). The MRI score lower cut-off corresponded to 88% sensitivity with 86% NPV, while the upper cut-off corresponded to 92% specificity with 87% PPV. MR-MASH was validated with an AUC = .86 (95% CI .77-.92), 91% sensitivity (lower cut-off) and 87% specificity (upper cut-off). A two-step screening strategy with sequential MR-MASH examination performed in patients with indeterminate-high FIB-4 or transient elastography showed an 83-84% PPV to identify MASH. The AUC of MR-MASH was significantly higher than that of the FAST score (p < .001)., Conclusions: The MR-MASH score has clinical utility in the identification and management of patients with MASH at risk of progression., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To assess the prevalence of pancreatic steatosis and iron overload in non-alcoholic fatty liver disease (NAFLD) and their correlation with liver histology severity and the risk of cardiometabolic diseases., Method: A prospective, multicenter study including NAFLD patients with biopsy and paired Magnetic Resonance Imaging (MRI) was performed. Liver biopsies were evaluated according to NASH Clinical Research Network, hepatic iron storages were scored, and digital pathology quantified the tissue proportionate areas of fat and iron. MRI-biomarkers of fat fraction (PDFF) and iron accumulation (R2*) were obtained from the liver and pancreas. Different metabolic traits were evaluated, cardiovascular disease (CVD) risk was estimated with the atherosclerotic CVD score, and the severity of iron metabolism alteration was determined by grading metabolic hiperferritinemia (MHF). Associations between CVD, histology and MRI were investigated., Results: In total, 324 patients were included. MRI-determined pancreatic iron overload and moderate-to severe steatosis were present in 45% and 25%, respectively. Liver and pancreatic MRI-biomarkers showed a weak correlation (r=0.32 for PDFF, r=0.17 for R2*). Pancreatic PDFF increased with hepatic histologic steatosis grades and NASH diagnosis ( p <0.001). Prevalence of pancreatic steatosis and iron overload increased with the number of metabolic traits ( p <0.001). Liver R2* significantly correlated with MHF (AUC=0.77 [0.72-0.82]). MRI-determined pancreatic steatosis (OR=3.15 [1.63-6.09]), and iron overload (OR=2.39 [1.32-4.37]) were independently associated with high-risk CVD. Histologic diagnosis of NASH and advanced fibrosis were also associated with high-risk CVD., Conclusion: Pancreatic steatosis and iron overload could be of utility in clinical decision-making and prognostication of NAFLD., Competing Interests: AJ-P is employee of Quibim SL. AA-B is CEO and shareholder of Quibim SL. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Marti-Aguado, Ten-Esteve, Baracaldo-Silva, Crespo, Coello, Merino-Murgui, Fernandez-Paton, Alfaro-Cervello, Sánchez-Martín, Bauza, Jimenez-Pastor, Perez-Girbes, Benlloch, Pérez-Rojas, Puglia, Ferrández, Aguilera, Latorre, Monton, Escudero-García, Bosch-Roig, Alberich-Bayarri and Marti-Bonmati.)

Background Standardized manual region of interest (ROI) sampling strategies for hepatic MRI steatosis and iron quantification are time consuming, with variable results. Purpose To evaluate the performance of automatic MRI whole-liver segmentation (WLS) for proton density fat fraction (PDFF) and iron estimation (transverse relaxometry [R2*]) versus manual ROI, with liver biopsy as the reference standard. Materials and Methods This prospective, cross-sectional, multicenter study recruited participants with chronic liver disease who underwent liver biopsy and chemical shift-encoded 3.0-T MRI between January 2017 and January 2021. Biopsy evaluation included histologic grading and digital pathology. MRI liver sampling strategies included manual ROI (two observers) and automatic whole-liver (deep learning algorithm) segmentation for PDFF- and R2*-derived measurements. Agreements between segmentation methods were measured using intraclass correlation coefficients (ICCs), and biases were evaluated using Bland-Altman analyses. Linear regression analyses were performed to determine the correlation between measurements and digital pathology. Results A total of 165 participants were included (mean age ± standard deviation, 55 years ± 12; 96 women; 101 of 165 participants [61%] with nonalcoholic fatty liver disease). Agreements between mean measurements were excellent, with ICCs of 0.98 for both PDFF and R2*. The median bias was 0.5% (interquartile range, -0.4% to 1.2%) for PDFF and 2.7 sec -1 (interquartile range, 0.2-5.3 sec -1 ) for R2* (P < .001 for both). Margins of error were lower for WLS than ROI-derived parameters (-0.03% for PDFF and -0.3 sec -1 for R2*). ROI and WLS showed similar performance for steatosis (ROI AUC, 0.96; WLS AUC, 0.97; P = .53) and iron overload (ROI AUC, 0.85; WLS AUC, 0.83; P = .09). Correlations with digital pathology were high ( P < .001) between the fat ratio and PDFF (ROI r = 0.89; WLS r = 0.90) and moderate ( P < .001) between the iron ratio and R2* (ROI r = 0.65; WLS r = 0.64). Conclusion Proton density fat fraction and transverse relaxometry measurements derived from MRI automatic whole-liver segmentation (WLS) were accurate for steatosis and iron grading in chronic liver disease and correlated with digital pathology. Automated WLS estimations were higher, with a lower margin of error than manual region of interest estimations. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Moura Cunha and Fowler in this issue.

Traditional histological evaluation for grading liver disease severity is based on subjective and semi-quantitative scores. We examined the relationship between digital pathology analysis and corresponding scoring systems for the assessment of hepatic necroinflammatory activity. A prospective, multicenter study including 156 patients with chronic liver disease (74% nonalcoholic fatty liver disease-NAFLD, 26% chronic hepatitis-CH etiologies) was performed. Inflammation was graded according to the Nonalcoholic Steatohepatitis (NASH) Clinical Research Network system and METAVIR score. Whole-slide digital image analysis based on quantitative (I-score: inflammation ratio) and morphometric (C-score: proportionate area of staining intensities clusters) measurements were independently performed. Our data show that I-scores and C-scores increase with inflammation grades ( p < 0.001). High correlation was seen for CH ( ρ = 0.85-0.88), but only moderate for NAFLD ( ρ = 0.5-0.53). I-score ( p = 0.008) and C-score ( p = 0.002) were higher for CH than NAFLD. Our MATLAB algorithm performed better than QuPath software for the diagnosis of low-moderate inflammation ( p < 0.05). C-score AUC for classifying NASH was 0.75 (95%CI, 0.65-0.84) and for moderate/severe CH was 0.99 (95%CI, 0.97-1.00). Digital pathology measurements increased with fibrosis stages ( p < 0.001). In conclusion, quantitative and morphometric metrics of inflammatory burden obtained by digital pathology correlate well with pathologists' scores, showing a higher accuracy for the evaluation of CH than NAFLD.