Dear Editor,
We thank Drs. Huang and Chen for their thoughtful comments on our paper [
1,
2]. They highlighted that although patients with discrepant fibrosis-4 index (FIB-4) and vibration-controlled transient elastography (VCTE) results had a significantly higher risk of F3-F4 fibrosis and major adverse liver outcomes (MALO) compared to those with normal FIB-4 and VCTE results, the absolute incidence of MALO remained low. This supports current guideline recommendations for using FIB-4 as a first-line fibrosis assessment in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) [
3]. This is precisely the message we aimed to convey.
They also pointed out the potential impact of confounding factors on the performance of noninvasive tests. Obesity is known to reduce the success rate and accuracy of VCTE; however, the introduction of the XL probe has largely mitigated this limitation [
4]. While acute viral hepatitis or a flare of chronic hepatitis B may falsely increase liver stiffness measurements [
5], the degree of inflammation in MASLD has not shown to confound measurements [
6]. In contrast, since liver enzymes and platelet count are components of FIB-4, acute hepatitis and non-hepatic causes of thrombocytopenia can indeed confound FIB-4 results. Clinicians and researchers must understand the nuances of these tests and refrain from using them in inappropriate contexts.
The point about the setting of assessment is also relevant. Both FIB-4 and VCTE were initially tested in tertiary centers, but the prognostic performance of these tests has since been confirmed in registry studies involving individuals from the general population or primary care settings [
7]. It is important to note, however, that VCTE can be operator-dependent. Proper training and the adoption of reliability criteria would ensure a more robust interpretation of test results [
8].
They also discussed the follow-up duration. The VCTE-Prognosis study benefits from a large number of participants and events, providing sufficient statistical power to examine clinical outcomes [
9]. We agree that chronic liver diseases can take years, if not decades, to progress, making longer follow-up periods desirable. Nevertheless, current guidelines recommend re-evaluation of MASLD at 1- to 3-year intervals [
3], so the median follow-up of 47 months in the current study is clinically relevant.
Finally, Drs. Huang and Chen emphasized the importance of evaluating other noninvasive tests in clinical care pathways for MASLD. Several new fibrosis scores have been proposed in recent years, generally demonstrating superior diagnostic accuracy compared to FIB-4, as well as prognostic value. However, their dynamic role as monitoring and response biomarkers requires further study. Ultimately, a concerted effort is needed to refine and implement a clinical care pathway that benefits patients with this common and significant liver disease.
FOOTNOTES
-
Data Availability
Data are available upon reasonable request to corresponding authors.
-
Authors’ contributions
The authors contributed equally to the literature review and drafting of the reply letter. They all approved the final version of the manuscript.
-
Acknowledgements
The study was supported in part by the Noncommunicable Chronic Diseases-National Science and Technology Major Project of China (2023ZD0508700), General Research Fund by the Hong Kong SAR Government (14106923), and Direct Grant of The Chinese University of Hong Kong (2024.065).
The funder of the study did not have a role in study design, data collection, data analysis, data interpretation, or manuscript preparation. Echosens provided logistic support for investigator coordination and meeting organization, but did not provide funding for this study.
-
Conflicts of Interest
Terry Yip has served as an advisory committee member for Altimmune, Gilead Sciences and GSK, and a speaker for Gilead Sciences. He has received a research grant from Gilead Sciences. Vincent Wong served as a consultant or advisor for AbbVie, AstraZeneca, Boehringer Ingelheim, Echosens, Eli Lilly, Gilead Sciences, Merck, Novartis, Novo Nordisk, Pfizer, Roche Diagnostics, and TARGET PharmaSolutions; a speaker for Abbott, AbbVie, AstraZeneca, Echosens, Gilead Sciences, and Novo Nordisk; an independent non-executive director for Furui; and a co-founder of Illuminatio Medical Technology. He has received a research grant from Gilead Sciences. Seung Up Kim has served on the advisory committee for Gilead Sciences, GSK, Bayer, Novo Nordisk, and Eisai; served as a speaker for Gilead Sciences, GSK, Bayer, Eisai, AbbVie, Echosens, MSD, Bristol- Myers Squibb, Hanhwa, Yuhan, Samil, PharmaKing, Celltrion, and Bukwang; and received research grants from AbbVie and Bristol-Myers Squibb.
Abbreviations
major adverse liver outcomes
metabolic dysfunction-associated steatotic liver disease
vibration-controlled transient elastography
REFERENCES
- 1. Rabbat J, Yang B, Lee HW, Lin H, Tsochatzis E, Petta S, et al. Histological severity and hepatic outcomes in patients with metabolic dysfunction-associated steatotic liver disease and discrepant FIB-4 and liver stiffness measurement. Clin Mol Hepatol 2026;32:289-304.
- 2. Huang D, Chen J. Clinical implications of discordant FIB-4 and LSM in MASLD: Integrating evidence and optimizing pathways: Letter to the editor on “Histological severity and hepatic outcomes in patients with metabolic dysfunction-associated steatotic liver disease and discrepant FIB-4 and liver stiffness measurement”. Clin Mol Hepatol 2026;32:e294-e296.
- 3. European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). J Hepatol 2024;81:492-542.
- 4. Wong VW, Irles M, Wong GL, Shili S, Chan AW, Merrouche W, et al. Unified interpretation of liver stiffness measurement by M and XL probes in non-alcoholic fatty liver disease. Gut 2019;68:2057-2064.
- 5. Wong GL, Wong VW, Choi PC, Chan AW, Chim AM, Yiu KK, et al. Increased liver stiffness measurement by transient elastography in severe acute exacerbation of chronic hepatitis B. J Gastroenterol Hepatol 2009;24:1002-1007.
- 6. Wong VW, Vergniol J, Wong GL, Foucher J, Chan HL, Le Bail B, et al. Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver disease. Hepatology 2010;51:454-462.
- 7. Hagström H, Talbäck M, Andreasson A, Walldius G, Hammar N. Repeated FIB-4 measurements can help identify individuals at risk of severe liver disease. J Hepatol 2020;73:1023-1029.
- 8. Boursier J, Zarski JP, de Ledinghen V, Rousselet MC, Sturm N, Lebail B, et al. Determination of reliability criteria for liver stiffness evaluation by transient elastography. Hepatology 2013;57:1182-1191.
- 9. Lin H, Lee HW, Yip TC, Tsochatzis E, Petta S, Bugianesi E, et al. Vibration-Controlled Transient Elastography Scores to Predict Liver-Related Events in Steatotic Liver Disease. JAMA 2024;331:1287-1297.
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