Dear Editors,
We read with considerable interest the recent report by Rabbat et al. [
1] regarding discordant non-invasive liver assessments in metabolic dysfunction-associated steatotic liver disease (MASLD). Their analysis of 12,950 patients across 16 centers offers timely insights into a common clinical dilemma: what to do when Fibrosis-4 index (FIB-4) and liver stiffness measurements (LSM) disagree. LSM was found to better reflect true histological severity, especially when FIB-4 underestimates risk. This finding has clinical value and challenges simplistic reliance on serum scores alone. After careful consideration of their data, we would like to make three comments regarding the application of these findings to daily practice.
First, there is a tertiary medical paradox. The authors acknowledge that their results reflect the performance of noninvasive liver disease assessment (NILDA) in tertiary centers, where approximately 30% of patients exhibited discordant results. However, this setting introduces a significant selection bias that may limit external validity. As emphasized in recent global health frameworks, the overwhelming majority of patients with MASLD are managed in primary care settings, not tertiary hepatology centers [
2,
3]. Tertiary cohorts typically comprise patients with advanced comorbidities, higher metabolic burden, and complex histological phenotypes, which likely inflate the prevalence and prognostic impact of discordant NILDA compared with community populations. Furthermore, the skill level of operators performing vibration-controlled transient elastography (VCTE) and the availability of FibroScan devices vary substantially between academic centers and resource-limited primary care clinics. Consequently, implementing the study’s findings, specifically the recommendation to pursue further evaluation in low-FIB-4/high-LSM patients, across diverse healthcare settings may yield different risk profiles and cost implications. We suggest the authors discuss how operator dependency and referral bias might affect the reproducibility of their findings in primary care, and whether their conclusions necessitate validation in population-based cohorts prior to widespread adoption.
Second, the “gray zone” of clinical decision making was not elucidated. While the study elegantly identifies patients with discordant results as having intermediate risk (e.g., low FIB-4 but elevated LSM≥8 kPa showing 5-year liver-related events incidence of 1.13%), it offers limited practical guidance on subsequent management steps. The current American Association for the Study of Liver Diseases (AASLD) practice guidance and American Gastroenterological Association (AGA) clinical care pathways recommend a two-step approach using FIB-4 followed by VCTE, yet provide minimal instruction for managing the approximately 10–30% of cases where these tests disagree [
4,
5]. Rabbat et al. [
1] suggest that patients with low FIB-4 but high LSM “may require further evaluation to confirm or exclude advanced fibrosis,” but stop short of defining what constitutes appropriate evaluation, whether this entails repeating LSM in 3–6 months, proceeding directly to liver biopsy, or utilizing second-line serum biomarkers such as the enhanced liver fibrosis score or magnetic resonance elastography. This ambiguity creates a clinical conundrum: subjecting all such patients to liver biopsy is neither feasible nor safe given the invasive nature and associated morbidity, while empirical surveillance without clear intervals may lead to patient anxiety and healthcare resource strain. We propose that the authors develop a risk-stratified algorithm based on their data, perhaps stratifying by LSM thresholds (8–12 kPa vs. >12 kPa) or incorporating metabolic comorbidities, to provide clinicians with actionable decision trees rather than generic recommendations for “further evaluation.”
Third, issues of economic feasibility and resource allocation have not received sufficient attention. The suggestion that LSM should prioritize FIB-4 when results are inconsistent raises important health economic questions. Literally, monitoring one third of patients with discordant results, especially those with low FIB-4 but high LSM requires widespread acceptance of VCTE in primary care, followed by specialist referral for a subset of patients [
6]. While the two-step approach is recommended by current guidelines, recent analyses indicate that widespread VCTE implementation in primary care populations with low pre-test probability may substantially increase per-case detection costs without proportional gains in liver-related mortality reduction [
7]. FibroScan’s cost and personnel costs further limit feasibility in resource-limited settings. Of note, the lack of LRE in the high FIB-4/low LSM group was at increased risk, indicating that false positive FIB-4 may occur, leading to unnecessary downstream testing. We encourage authors to include cost-effectiveness analyses, or at least discuss the impact of reimbursement, and refined risk stratification, such as lowering the LSM threshold (≥10 or ≥12 kPa) for patients with low FIB-4 to improve efficiency and reduce false positive referrals.
In conclusion, Rabbat et al. [
1] have provided compelling evidence that LSM often captures fibrosis severity more accurately than FIB-4 in discordant cases, challenging the dogma of serum-based screening alone. However, to maximize the clinical utility of these findings, future research must address the generalizability to primary care populations, establish concrete management protocols for discordant cases, and rigorously evaluate the economic implications of expanded VCTE utilization. We commend the authors for this seminal contribution and believe these considerations will help bridge the gap between research excellence and real-world clinical practice.
FOOTNOTES
-
Authors’ contribution
J.Z. writing - review and editing, writing - original draft; L.L. writing - review and editing.
-
Conflicts of Interest
All authors declare no conflict of interest in this study.
Abbreviations
American Association for the Study of Liver Diseases
American Gastroenterological Association
liver stiffness measurements
metabolic dysfunction-associated steatotic liver disease
non-invasive liver disease assessment
vibration-controlled transient elastography
REFERENCES
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Citations
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