Metabolic dysfunction-associated steatotic liver disease (MASLD) affects over 30% of individuals worldwide, and with the continued rise in both obesity and type 2 diabetes, is projected to affect more than half of the global population within the next two decades [
1,
2]. Given this steep rise in MASLD prevalence, it is important to improve both detection and management in an impactful yet cost-effective manner. Recent data demonstrate that, histologically, fibrosis stage is the strongest determinant of mortality and liver-related events (LRE) in MASLD [
3]. While the gold standard for detecting fibrosis remains liver biopsy, it is often impractical as it is costly, invasive, and carries risk of procedural complications. Thus, noninvasive liver disease assessments (NILDA), both biochemical and radiologic, have become foundational to assessing liver fibrosis. International guidelines currently endorse a two-step approach to assess for liver fibrosis: first using a low-cost blood-based screening test with high negative predictive value such as the Fibrosis-4 index (FIB-4), followed by a confirmatory test with high positive predictive value, such as a liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE) as second line testing [
4,
5]. This pathway has proven to be cost-effective, scalable, and has been adopted in both specialty hepatology and primary care settings [
6].
While this two-step strategy is widely accepted, its performance in patients with discordant FIB-4 and LSM results remains incompletely understood. Specifically, it is unclear how often discordance between these two measures occurs, which test better reflects true histologic severity, and whether this mismatch translates into meaningful differences in prognosis as measured by clinical outcomes. Existing literature has focused largely on the diagnostic accuracy of NILDAs in relation to liver fibrosis rather than how well they predict patient outcomes [
7-
9]. This may be due to utilization of registry or cross-sectional data whereas prognostic studies require longitudinal tracking of patient outcomes such as liver decompensation, hepatocellular carcinoma, and mortality. Similarly, existing data on NILDAs have had limited histologic correlation due to the nature of their study design. Thus, there is little guidance on whether patients with discordant FIB-4 and LSM results require closer disease surveillance with additional noninvasive or invasive testing, and which test is more reliable in predicting fibrosis. Addressing these gaps is essential to refine risk stratification strategies, limit unnecessary invasive testing, and advance cost-effective care to improve patient outcomes.
To address these knowledge gaps, Rabbat et al. [
10] present a large, multinational, multicenter analysis from the VCTE-prognosis study that investigates the histological severity as well as incidence of LREs and mortality in patients with concordant and discordant paired FIB-4 and LSM through VCTE. This study included nearly 13,000 patients with MASLD and categorized patients into four groups using guideline relevant cutoffs: low FIB-4 and low LSM, high FIB-4 and low LSM, low FIB-4 and high LSM, and high FIB-4 and high LSM. Patients were followed for a median of 4 years and included a substantial liver biopsy subset of approximately 3,000 patients for histological comparison. Discordance among FIB-4 and LSM results was common, occurring in over one third of patients. Histology also demonstrated a clear association with LSM: patients with elevated LSM, regardless of high or low FIB-4, had more advanced fibrosis (LSM≥8 kPa and FIB-4>1.3; median fibrosis stage, 3; interquartile range [IQR], 2–3; LSM≥8 kPa and FIB-4<1.3; median fibrosis stage, 2; IQR, 1–3). Among the discordant groups, patients with low FIB-4 and high LSM had more F3–F4 fibrosis than the converse, 30.6% and 13.7% respectively. Concordant high FIB-4 and LSM identified patients at increased risk of LREs (subdistribution hazard ratio [sHR], 32.91; 95% confidence interval [CI], 20.37–53.15). Discordant groups had a lower rate of LREs, but risk was higher when LSM (sHR, 3.92; 95% CI, 2.01–7.63) rather than FIB-4 (sHR, 1.83; 95% CI, 0.94–3.57) was elevated. Collectively, the data suggest that LSM more closely reflects true disease severity when FIB-4 and LSM disagree.
Importantly, this study validates the population level performance of the established two-step approach of using NILDAs to assess stage of fibrosis in chronic liver disease. Although a subset of patients with low FIB-4 and elevated LSM demonstrate higher risk, the cumulative 5-year incidence of LREs in this group remains low (1.13%; 95% CI, 0.61–1.93), reinforcing prior data showing that persistently low FIB-4 identifies patients at lower short-term risk [
11,
12]. The strength of FIB-4 based testing lies in its high negative predictive value, low cost, and feasibility at the population level [
6,
13]. Thus, longitudinal reassessment at 1–3 years intervals may be effective in capturing the subset of patients with low FIB-4 and high LSM who have advanced fibrosis while preserving the efficiency of this currently recommended screening strategy [
14,
15]. The results also suggest that LSM has prognostic performance that is comparable to histologic staging.
However, this study highlights a clinically important subset of patients with low FIB-4 and high LSM with advanced fibrosis who may experience delayed identification and referral for specialty care based on the current screening guidelines. These findings therefore introduce important nuance in the use of NILDAs. Elevated LSM along with low FIB-4 should not be dismissed and warrants further evaluation with repeat noninvasive or invasive testing to more accurately assess fibrosis stage. How to identify these patients in an efficient, cost-effective manner remains a knowledge gap, as current guidelines do not recommend transient elastography in the setting of low FIB-4 and normal liver enzymes. Certain populations, such as those with obesity or diabetes, which comprise a significant portion of MASLD patients, may warrant additional risk assessment with LSM despite low FIB-4. Clinically, the data inform a measured, pragmatic approach that supports reassurance and longitudinal monitoring for most discordant patients, and selective repeat testing and further evaluation when LSM is elevated.
Table 1 summarizes the clinical implications of concordant and discordant FIB-4 and LSM.
A major strength of this study is its multicenter, prospective nature that captured a large cohort of patients needed to assess outcomes by FIB-4 and LSM. However, this study had limitations. First, this tertiary care cohort limits the generalizability of these results to primary care settings, where a larger subset of patients can be screened for MASLD and may represent different risk and clinical phenotypes. Second, liver biopsy was available in only a subset of patients, with inherent sampling and observer variability [
16,
17]. Third, the follow up duration captures intermediate but not lifetime risk of LREs and mortality, limiting its ability to demonstrate how NILDAs inform long term patient prognosis. Despite its large size, the number of events was relatively modest, resulting in wide confidence intervals for point estimates among subgroups. Fourth, this study does not address other recommended NILDAs such as the enhanced liver fibrosis test and magnetic resonance elastography [
7,
8]. Future studies should validate these findings in primary care and population-based cohorts and consider the development of dynamic risk models that incorporate longitudinal changes in NILDAs and patient outcomes. Further, it is important to clarify the cost-effectiveness and referral thresholds for specialty hepatology care, additional noninvasive testing, and invasive testing when discordance is detected.
Rabbat et al. [
10] showed that discordant noninvasive fibrosis tests are common and that LSM better reflects histologic severity when tests disagree. These data support current guideline recommended pathways for noninvasive fibrosis assessment at the population level while emphasizing the importance of clinical context, selective additional testing for high-risk groups, and longitudinal assessment.
FOOTNOTES
-
Authors’ contribution
GB - Literature review, writing (original draft). BPL - Conceptualization, funding acquisition, resources, supervision, writing (review & editing).
-
Acknowledgements
Research reported in this publication was supported by the National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health under Award Number K23AA029752 (BPL). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
-
Conflicts of Interest
The authors have no conflicts to disclose.
Table 1.Clinical interpretation of concordant and discordant FIB-4 and LSM in MASLD
Table 1.
|
FIB-4 |
VCTE-LSM (kPa) |
Likelihood of advanced fibrosis |
Observed risk of liver related events |
Suggested clinical interpretation |
|
Low (<1.3) |
Low (<8) |
Low |
Low |
Routine follow-up with repeat FIB-4 in 1–3 years per established guidelines |
|
No indication for LSM or specialty hepatology referral |
|
High (>1.3) |
High (≥8) |
High |
High |
Refer to hepatology for specialty care, close surveillance to evaluate for complications of advanced fibrosis such as portal hypertension and HCC, and intensify metabolic risk factor mitigation |
|
Low (<1.3) |
High (≥8) |
Intermediate to high |
Intermediate |
LSM more likely reflects fibrosis severity |
|
Consider hepatology referral for specialty care in high risk populations (diabetes, obesity), optimization of metabolic risk factors, and repeat or alternative NILDA to confirm fibrosis stage |
|
High (>1.3) |
Low (<8) |
Low to intermediate |
Low to intermediate |
LSM more likely reflects fibrosis severity and elevated FIB-4 may be a false positive |
|
Consider repeat or alternative NILDA to confirm fibrosis stage and optimize metabolic risk factors |
Abbreviations
liver stiffness measurement
metabolic dysfunction associated steatotic liver disease
noninvasive liver disease assessment
subdistribution hazard ratio
vibration controlled transient elastography
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