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. 2024 Apr 16;331(15):1287-1297.
doi: 10.1001/jama.2024.1447.

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

Huapeng Lin  1   2 , Hye Won Lee  3 , Terry Cheuk-Fung Yip  1   2 , Emmanuel Tsochatzis  4 , Salvatore Petta  5 , Elisabetta Bugianesi  6 , Masato Yoneda  7 , Ming-Hua Zheng  8 , Hannes Hagström  9   10 , Jérôme Boursier  11   12 , José Luis Calleja  13 , George Boon-Bee Goh  14 , Wah-Kheong Chan  15 , Rocio Gallego-Durán  16 , Arun J Sanyal  17 , Victor de Lédinghen  18 , Philip N Newsome  19 , Jian-Gao Fan  20 , Laurent Castéra  21 , Michelle Lai  22 , Stephen A Harrison  23   24 , Céline Fournier-Poizat  25 , Grace Lai-Hung Wong  1   2 , Grazia Pennisi  5 , Angelo Armandi  6 , Atsushi Nakajima  7 , Wen-Yue Liu  26 , Ying Shang  9 , Marc de Saint-Loup  11 , Elba Llop  13 , Kevin Kim-Jun Teh  14 , Carmen Lara-Romero  16 , Amon Asgharpour  17 , Sara Mahgoub  19 , Mandy Sau-Wai Chan  25 , Clemence M Canivet  11   12 , Manuel Romero-Gomez  16 , Seung Up Kim  3 , Vincent Wai-Sun Wong  1   2 ; VCTE-Prognosis Study Group
Affiliations

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

Huapeng Lin et al. JAMA. .

Abstract

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Yip reported serving as an advisory committee member and a speaker for Gilead Sciences outside the submitted work. Dr Tsochatzis reported receiving personal fees as advisory board member for Boehringer, Novo Nordisk, Pfizer, and Siemens; receiving speaker fees from Echosens, Novo Nordisk, and AbbVie outside the submitted work. Dr Hagström reported personal fees from AstraZeneca, personal fees from Bristol Myers-Squibb, personal fees from MSD, personal fees from Novo Nordisk, personal fees from Boehringer Ingelheim, personal fees from KOWA, and personal fees from GW Phara outside the submitted work, and grants from AstraZeneca, grants from Echosens, grants from Gilead Sciences, grants from Intercept, grants from MSD, grants from Novo Nordisk, and grants from Pfizer outside the submitted work. Dr Boursier reported receiving grants and personal fees from Echosens outside the submitted work. Dr Calleja reported receiving other from Echosens Clinical Trials during the conduct of the study; grants from Roche Pharma and other from Gilead Advisory Board outside the submitted work. Dr W. Chan reported serving as consultant or advisory board member for Roche, AbbVie, Boehringer Ingelheim, and Novo Nordisk; and a speaker for Echosens, Viatris, and Hisky Medical. Dr Sanyal reported receiving grants from Intercept, personal consulting fees from Gilead, grants from Merck, personal consulting fees from Pfizer, grants and personal consulting fees from Eli Lilly, grants and personal consulting fees from Novo Nordisk, Boehringer Ingelheim, Novartis, Histoindex, and stock options from Genfit, Tiziana, Durect, Inversago, and personal consulting fees from Genentech, ALnylam, Regeneron, Zydus, LG chem, Hanmi, Madrigal, Path AI, 89 Bio, and stock options from Galmed outside the submitted work. Dr De Lédinghen reported receiving nonfinancial support from Echosens during the conduct of the study. Dr Newsome reported receiving grants from Novo Nordisk, advisory board and personal consulting fees, honoraria for lectures and travel expenses from Novo Nordisk, personal consulting and advisory board fees from Boehringer Ingelheim, Gilead, Intercept, Poxel Pharmaceuticals, Bristol-Myers Squibb, Pfizer, MSD, Sun Pharma, Eli Lilly, Madrigal, GSK, and nonfinancial support for educational events from AiCME outside the submitted work. Dr Castéra reported receiving personal fees for consulting and speakers bureau from Echosens during the conduct of the study; personal consultancy fees from Boston pharmaceutical and Gilead, speaker bureau and consultancy personal fees from GSK, personal speaker bureau fees from Inventiva, personal consultancy fees from Madrigal, personal Consultancy fees from MSD and Novo Nordisk, personal consultancy fees from Pfizer, Sagimet, and Siemens Healthineers outside the submitted work. Dr Harrison reported receiving grants from Akero, Altimmune, Axcella, Bristol-Myers Squibb, Corcept, Cymabay, Enyo, Galectin, Genentech, Genfit, Gilead, GSK, Hepion, Hightide, Immuron, Intercept, Inventiva, Ionis, Madrigal, NGM Bio, Novartis, Novo Nordisk, Northsea, Pfizer, Poxel, Sagimet, Terns, Viking., stock options from Akero, Chronwell, Galectin, Hepion, Hepta Bio, HistoIndex, and Northsea, and scientific advisor or consultant fees from Akero, Aligos, Altimmune, Arrowhead, Boxer Capital, Chronwell, Echosens, Foresite Labs, Galectin, Galecto, Gilead, GSK, Hepagene, Hepion, Hepta Bio, HistoIndex, Humana, Intercept, Ionis, Inventiva, Madrigal, Medpace, Merck, NeuroBo Pharmaceuticals, Northsea, Novo Nordisk, Perspectum, Pfizer, Sonic Incytes, Sagimet, Terns, and Viking outside the submitted work. Dr Fournier-Poizat reported being in the full-time employment of Echosens during the conduct of the study. Dr G. Wong reported receiving personal fees from Echosens during the conduct of the study; grants from Gilead Sciences Research outside the submitted work. Dr M. Chan reported being in the full-time employment of Echosens during the conduct of the study. Dr Romero-Gomez reported receiving personal fees from Echosens outside the submitted work. Dr Kim reported personal fees from Gilead Sciences, personal fees from GSK, personal fees from Bayer, personal fees from Eisai, personal fees from AbbVie, personal fees from Echosens, personal fees from MSD, personal fees from Bristol-Myers Squibb, and personal fees from AstraZeneca outside the submitted work, and grants from AbbVie, grants from Bristol-Myers Squibb, and grants from Gilead Sciences outside the submitted work. Dr V. Wong reported receiving personal speaker fees from Abbott, consultant and speaker fees from AbbVie, personal consultant fees from Boehringer Ingelheim, Echosens, Gilead Sciences, grants from Gilead Sciences, personal consultant fees from Intercept, Inventiva, Novo Nordisk, personal consultant fees from Pfizer, Sagimet Biosciences, TARGET PharmaSolutions, personal speaker fees from Unilab, personal consultant fees from Visirna, and being a cofounder of Illuminatio outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Study Participant Flow
HCC indicates hepatocellular carcinoma; MASLD, metabolic dysfunction–associated steatotic liver disease. VCTE, vibration-controlled transient elastography.
Figure 2.
Figure 2.. Prediction of Liver-Related Events (LREs) by Noninvasive Tests and Liver Histologic Findings
In panel B, the cut points for Agile 3+ score were based on the original publication. The low cut point (<0.451) achieved sensitivity of at least 85% to rule out patients of fibrosis stage 3 or greater; the high cut point (0.679) achieved specificity of at least 90% to rule in patients of fibrosis stage of 3 or greater. ALT indicates alanine aminotransferase; AST, aspartate aminotransferase; APRI, AST to platelets ratio index; BARD, BMI (body mass index), AST:ALT ratio, and diabetes; FAST, FibroScan-AST; FIB-4, Fibrosis-4 index; NAFLD, nonalcoholic fatty liver disease; NFS, NAFLD fibrosis score.
Figure 3.
Figure 3.. Agile 3+ Scores in the Serial Model
LREs indicates liver-related events; VCTE, vibration-controlled transient elastography. Whiskers indicate 95% CIs. aRepresents the Agile 3+ score decreasing at least 10%, 20%, or 30% from the first to last test. bRepresents the Agile 3+ remaining stable from first to last test in the remaining patients. cRepresents the Agile 3+ score increasing at least 10%, 20%, or 30% from the first to last test.
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