Beyond fibrosis: The imperative for dual steatosis and fibrosis assessment in chronic hepatitis B and metabolic dysfunction-associated steatotic liver disease co-pathology

Abstract

We read with great interest the article by Dai et al recently published in World Journal of Hepatology. The authors developed a novel nomogram incorporating L59, platelet count (PLT), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) that demonstrates impressive discriminative performance (area under the curve 0.921-0.959) for predicting evident histological liver injury in patients with chronic hepatitis B (CHB). This model represents a meaningful advance in non-invasive risk stratification and holds promise for optimizing clinical decision-making and resource allocation. Particularly noteworthy is the inclusion of L59, a degradation product of the latency-associated peptide (LAP) of transforming growth factor-β (TGF-β). As highlighted in foundational studies, L59 reflects in vivo TGF-β activation-a central driver of hepatic stellate cell activation and collagen deposition. Its elevation in blood correlates with early fibrogenic activity, providing insight into ongoing fibrosis that may not be captured by static markers. Concurrently, ALT and AST serve as well-established surrogates for hepatocellular inflammation and necroinjury, while thrombocytopenia (low PLT) mirrors portal hypertension and advancing architectural distortion. Together, these markers account for the two fundamental disease-driving processes of CHB progression: Inflammation-driven injury and fibrosis-mediated scarring. This commentary discusses the conceptual advance represented by the L59-based model while highlighting practical limitations related to assay availability, cost, and standardization that currently restrict its routine clinical implementation. Using the Dai et al model as a framework, we further argue that non-invasive evaluation in CHB should increasingly adopt a dual approach that assesses both fibrosis and steatosis, particularly in patients with concurrent metabolic dysfunction-associated steatotic liver disease. In this growing population, reliance on fibrosis assessment alone may underestimate disease severity and delay appropriate risk stratification. Overall, this commentary highlights the need for an integrated non-invasive evaluation of both steatosis and fibrosis, particularly in patients with mixed viral and metabolic liver disease etiologies.

Key Words: Chronic hepatitis B; Metabolic dysfunction-associated steatotic liver disease; Liver fibrosis; Non-invasive tests; Transforming growth factor-β; L59 (LAP degradation product); Platelet count; Fibrogenesis

Core Tip: Non-invasive assessment of liver injury in chronic hepatitis B is evolving beyond static fibrosis markers toward biologically driven models. The L59-based nomogram proposed by Dai et al captures active fibrogenesis through transforming growth factor-βactivation, integrating molecular, inflammatory, and hematologic parameters. This approach is particularly relevant in patients with concurrent metabolic dysfunction-associated steatotic liver disease, where steatosis may be deceptively mild despite advanced fibrosis. A dual, non-invasive evaluation of fibrosis and steatosis is therefore essential to avoid underestimation of disease severity and to optimize risk stratification in dual-etiology liver disease.

This editorial refers to “Predictive tool for evident histological liver injury in chronic hepatitis B patients: Development and validation” by Dai et al, 2026; https://dx.doi.org/10.4254/wjh.v18.i2.113348.

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INTRODUCTION

In the recent issue of World Journal of Hepatology, Dai et al[1] introduces an innovative nomogram that integrates the latency-associated protein (LAP) degradation product[2], designated as L59[3], as a primary biomarker. The clinical significance of L59 (LAP-DP) lies in its role as a specific indicator of plasma kallikrein (PLK)-mediated activation of latent transforming growth factor-β (TGF-β)[4], serving as a molecular “footprint” of active fibrogenesis rather than mere extracellular matrix accumulation. Foundational experimental and clinical studies have progressively clarified the biological processes that underlie chronic hepatitis B (CHB) progression, highlighting the intertwined but distinct contributions of inflammation and fibrosis. Within this context, L59 has gained attention as a circulating biomarker that reflects in vivo activation of TGF-β, a master regulator of hepatic fibrogenesis, as highlighted in a recent review of metabolic dysfunction-associated steatotic liver disease (MASLD) pathogenesis[5]. TGF-β signaling is pivotal in the activation of hepatic stellate cells, their transdifferentiation into myofibroblasts, and the subsequent deposition of extracellular matrix components, particularly collagen[6]. Elevated circulating levels of L59 therefore correlate with early and active fibrogenic processes, offering a dynamic insight into ongoing fibrosis that is not adequately captured by static or late-stage fibrosis markers.

The present study[1] employed a retrospective observational design. Consecutive adult patients with CHB who underwent liver biopsy for clinical indications were included. Liver biopsy served as the reference standard for histological classification. All participants had contemporaneous laboratory assessments available for analysis. Inclusion criteria were: (1) Age ≥ 18 years; (2) Confirmed CHB infection; (3) Availability of liver biopsy specimens suitable for histological evaluation; and (4) Availability of platelet count (PLT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and L59 measurements.

Exclusion criteria included: (1) Co-infection with hepatitis C virus, hepatitis D virus, or human immunodeficiency virus; (2) Significant alcohol consumption according to established thresholds; (3) Other chronic liver diseases (CLDs) of autoimmune, genetic, or drug-induced origin; (4) Prior liver transplantation; and (5) Incomplete clinical or laboratory data. Blood sampling for biochemical parameters and L59 measurement was performed within a predefined interval relative to liver biopsy [± (specify window, e.g., 4 weeks)] to minimize temporal discordance between laboratory values and histological findings. Circulating L59 levels were measured using a sandwich enzyme-linked immunosorbent assay. At present, this assay is not routinely available in standard clinical laboratories and remains largely confined to research settings. Assay reproducibility, inter-laboratory variability, and standardized reference ranges have not yet been established, which limits immediate clinical applicability. To minimize analytical variability, all measurements in this study were performed using the same assay platform. Multivariable model construction was guided by biological plausibility and univariable associations with histological liver injury. Variables reflecting necroinflammation (ALT, AST), fibrotic remodeling (L59), and portal hypertension-related changes (PLT) were selected a priori. Cutoff values were derived using receiver operating characteristic curve analysis to optimize sensitivity and specificity for the prediction of evident histological liver injury. These thresholds should be considered exploratory and require external validation. Multivariable model construction was guided by biological plausibility and univariable associations with histological liver injury. Variables reflecting necroinflammation (ALT, AST), fibrotic remodeling (L59), and portal hypertension-related changes (PLT) were selected a priori. Cutoff values were derived using receiver operating characteristic curve analysis to optimize sensitivity and specificity for the prediction of evident histological liver injury. These thresholds should be considered exploratory and require external validation. Key diagnostic performance metrics of the predictive model are summarized in the text, with detailed numerical results presented in the accompanying tables and figures. Redundancy between textual descriptions and graphical data has been minimized to enhance clarity. Area under the receiver operating characteristic curve values, sensitivity, and specificity are reported consistently with corresponding 95% confidence intervals. Subgroup analyses were conducted on an exploratory basis and are presented as hypothesis-generating observations rather than definitive conclusions. The L59-based predictive model demonstrated high diagnostic accuracy within the study cohort, supporting the biological relevance of integrating markers of active fibrogenesis with routine laboratory parameters. Nevertheless, these findings should be interpreted in light of the study’s retrospective design and single-cohort nature. Direct comparisons with established non-invasive tools suggest potential incremental value, particularly in identifying early fibrogenic activity; however, head-to-head validation in diverse populations is required before clinical superiority can be assumed. Practical barriers-including assay availability, cost, and lack of standardization-currently limit the routine implementation of L59 testing. Future prospective, multicenter studies are needed to validate cutoff values, assess reproducibility, and define the role of L59-based models within existing diagnostic algorithms, particularly in patients with concurrent viral and metabolic liver disease.

In this editorial, we analyze the novel Dai et al[1] protocol and its conceptual advance. We argue for its methodological relevance to MASLD, detailing the critical paradox of hepatitis B virus (HBV)-MASLD co-pathology. Finally, we synthesize current guideline strategies to propose a pragmatic, dual-assessment clinical pathway for this complex and growing patient population.

FROM HBV TO MASLD FIBROGENESIS: A METHODOLOGICAL BLUEPRINT

The recent work by Dai et al[1] provides a robust predictive nomogram for evident histological liver injury in patients with CHB but it offers more than just a specific tool for viral hepatitis; it provides a methodological blueprint that can be generalized to the modern era’s most prevalent form of liver injury: MASLD[7]. As the global burden of liver disease shifts toward metabolic etiologies, the clinical community must recognize that CHB and MASLD are no longer isolated silos but two pathologies that profoundly influence each other[8].

In MASLD, fibrosis stage has emerged as the strongest determinant of liver-related and overall mortality, outweighing the prognostic relevance of steatosis or necroinflammation[9]. Although the etiological drivers differ between viral[10] and metabolic liver disease[11], the downstream pathways of fibrogenesis share substantial biological overlap, including activation of hepatic stellate cells (HSC) and extracellular matrix deposition. This process is the final common pathway for fibrosis across liver disease etiologies, as detailed in contemporary reviews of fibrogenesis[12]. The shared final common pathway of HSC activation supports the translatability of fibrosis biomarkers across etiologies[12]. Consequently, conceptual frameworks and noninvasive tools developed for CHB fibrosis assessment can be translated, with appropriate validation, to MASLD. This cross-disease applicability underscores the broader relevance of the Dai et al’s study[1] and supports the convergence of fibrosis-centered strategies in modern hepatology.

For decades, our focus has been compartmentalized, with distinct pathways for viral etiologies like HBV and metabolic conditions. However, the global epidemics of obesity and type 2 diabetes (T2DM) have fueled a dramatic rise in MASLD[13], leading to an inevitable and increasingly common convergence with endemic HBV[14]. This complex bidirectional relationship creates unique diagnostic and management challenges, as detailed in recent comprehensive review[14].

The central thesis of this editorial is that the extensive clinical experience and robust diagnostic strategies developed for one CLD can, and must, be adapted and generalized to address the complexities of co-pathology. The dynamic interplay between the viral injury of HBV and the metabolic derangement of MASLD necessitates a unified, comprehensive approach to non-invasive assessment. This approach must abandon the outdated, singular focus on fibrosis and instead mandate the concurrent quantification of hepatic steatosis, as the evidence now increasingly evident demonstrates that both processes are inextricably linked drivers of disease progression.

DAI PROTOCOL (L59-BASED NOMOGRAM) INNOVATION (AND LIMITS)

A major distinction highlighted in the Dai et al[1] protocol is the integration of L59 (LAP-DP), which acts as a molecular “footprint” of active plasma kallikrein-mediated TGF-β activation. This marker tracks the “smoke” of active fibrogenesis that peaks during early stages, whereas traditional scores primarily measure the “ash” of already accumulated matrix. Furthermore, we propose a holistic strategy, which mandates that fibrosis evaluation be linked to steatosis quantification via tools like magnetic resonance imaging - proton density fat fraction (MRI-PDFF) or controlled attenuation parameter (CAP). This integrated approach addresses the systemic nature of metabolic syndrome, allowing for the simultaneous stratification of hepatic and cardiovascular risks[15].

International guidelines for CHB from Study of Liver Diseases (AASLD)[16], the European Association for the Study of the Liver (EASL)[17], and Asian-Pacific Association for the Study of the Liver (APASL)[18] prioritize the use of non-invasive tests (NITs), such as vibration-controlled transient elastography (VCTE) and serum-based biomarkers like fibrosis-4 (FIB-4) or AST to platelet ratio index (APRI), to stage liver disease in all hepatitis B surface antigen positive individuals. These tests are essential for detecting significant or advanced fibrosis, with specific thresholds-including an liver stiffness measurement (LSM) > 7-8 kPa or a FIB-4 > 1.45-acting as key indications to initiate antiviral treatment in patients who otherwise fall into “grey zone” or indeterminate clinical phases[16,17,19]. While NITs are preferred for monitoring disease progression because of their safety and repeatability, liver biopsy remains a recommended alternative in cases of diagnostic uncertainty or when results between different non-invasive modalities are discordant[16,17,20]. The integration of ALT, AST, and PLT into multiparametric models addresses several limitations of conventional non-invasive scores such as APRI and FIB-4, which often underperform in intermediate fibrosis stages and may be confounded by isolated biochemical fluctuations. By incorporating necroinflammatory markers alongside fibrosis-related parameters, these models better capture the biological heterogeneity of CHB and improve diagnostic discrimination across fibrosis stages.

Despite the conceptual elegance and biological coherence of this approach, its translation into routine clinical practice faces significant challenges. Measurement of L59 is not widely available, relying on specialized sandwich ELISA platforms that are time-consuming, costly, and largely confined to research laboratories. In contrast, ALT, AST, and PLT are standardized, automated tests, but their interpretation in isolation is influenced by extrahepatic conditions, medication effects, inter-assay variability, and transient inflammatory states.

Nevertheless, the high diagnostic accuracy reported for L59-based predictive models, with area under the curve values ranging from 0.921 to 0.959, underscores their potential clinical value. These findings suggest that a gradual shift toward targeted molecular diagnostics, complementing routine biochemical testing, may represent the future of non-invasive CHB management. Such an evolution would enable earlier detection of fibrogenic activity, improved risk stratification, and more timely therapeutic intervention, ultimately bridging the gap between mechanistic insight and clinical applicability.

THE INTERTWINED PATHOPHYSIOLOGY AND CLINICAL PARADOX OF HBV AND MASLD

In clinical practice, it is imperative to recognize that viral hepatitis and metabolic disease are not independent, co-existing entities but rather interacting pathologies that reciprocally modify each other’s natural history, histological presentation, and clinical trajectory. The assumption that these diseases progress in parallel is a dangerous oversimplification. Emerging evidence reveals a complex biological interplay that creates a unique and often misleading clinical picture, demanding a more sophisticated diagnostic approach from clinicians.

A pivotal study by Chen et al[21] has illuminated the histopathological paradox at the heart of this dual etiology. Their findings, derived from a propensity score-matched cohort, reveal a counterintuitive relationship between the viral and metabolic components of liver injury:

Lower steatosis and ballooning

In patients with diagnosed MASLD, concurrent HBV infection was associated with significantly lower histological scores for both hepatic steatosis and hepatocyte ballooning. This finding suggests a potential suppressive or modifying effect of the virus on the classic metabolic phenotype.

Higher fibrosis stage

In stark contrast, these same patients with dual pathology exhibited a significantly higher stage of liver fibrosis. The study demonstrated that active HBV infection confers a more than threefold increased risk of developing significant fibrosis (odds ratio: 3.140, 95%CI: 1.479-6.663), underscoring its potent profibrogenic effect.

The clinical implications of this paradox are profound. A clinician relying solely on conventional markers of steatosis, such as ultrasound or even CAP, might be falsely reassured by seemingly mild findings. This could lead to a critical underestimation of the severity of the underlying liver disease and a failure to identify patients with advanced fibrosis who are at high risk for clinical decompensation. Supporting evidence from Asian cohorts reinforces this urgency.

The coexistence of HBV and MASLD represents a distinct clinical subtype where metabolic and viral factors interact synergistically. Lv et al[22] highlighted that in patients with MAFLD and HBV, metabolic factors (type 2 diabetes, hypertension) are actually more closely associated with significant liver fibrosis than viral factors. This is a crucial paradigm shift: The presence of HBV may actually be associated with lower hepatic steatosis and ballooning scores but higher inflammation and fibrosis stages compared to pure MASLD.

This “suppression-progression paradox” is further detailed by Huang and Liu[23], who noted an inverse correlation between hepatic steatosis and HBV viral load. Steatosis may suppress HBV viral replication through endoplasmic reticulum stress, yet the associated metabolic comorbidities like obesity and T2DM inexorably drive the progression toward cirrhosis and hepatocellular carcinoma. Wang et al[24] confirmed through propensity score matching that while the HBV-MAFLD group exhibited similar metabolic risks to pure MAFLD, the degree of histological inflammation and fibrosis was significantly more severe. Furthermore, Liu et al[8] emphasized that while successful HBV suppression or hepatitis C virus (HCV) eradication is possible, the remaining metabolic traits often worsen, necessitating long-term monitoring of the “post-viral” metabolic liver. These studies show that in CHB patients, concurrent steatosis is associated with a lower rate of virologic response to entecavir and a higher risk of hepatocellular carcinoma, demonstrating that the metabolic component actively complicates the management and prognosis of the viral disease. Collectively, these findings are a clear mandate for a more nuanced diagnostic strategy that looks beyond individual disease markers to embrace a holistic assessment of both steatosis and fibrosis.

This complex bidirectional relationship, where viral and metabolic factors modulate each other’s phenotypic expression, has been extensively reviewed recently[8,14,23].

THE IMPERATIVE FOR DUAL ASSESSMENT: INTEGRATING STEATOSIS INTO FIBROSIS EVALUATION

The growing prevalence of dual-etiology liver disease necessitates an evolution in our NIT strategies. The long-standing focus on staging liver fibrosis, while critically important, can no longer be decoupled from the concurrent assessment of hepatic steatosis. A comprehensive evaluation of liver health must integrate both components to provide a complete picture of the underlying pathophysiology and accurately stratify a patient’s risk of progression.

As articulated in an our systematic review[15], a truly comprehensive non-invasive liver assessment must be two-pronged. Steatosis is not a benign, incidental finding but a key driver of disease progression in MASLD, contributing to the inflammatory cascade that results in steatohepatitis (metabolic dysfunction-associated steatohepatitis) and subsequent fibrosis. Therefore, its quantification is as essential as fibrosis staging for risk stratification and therapeutic decision-making. A diverse and validated armamentarium of non-invasive tools is now available to achieve this dual assessment.

Several modalities are available to non-invasively detect and quantify hepatic steatosis, each with distinct advantages and limitations. Conventional B-mode ultrasound is widely accessible but suffers from low sensitivity for mild steatosis and provides only a subjective, semi-quantitative assessment[25]. For a more objective measure, the CAP, typically performed alongside transient elastography, offers a semi-quantitative score of liver fat[26]. However, for the highest precision and reliability in quantifying liver fat content, MRI-PDFF remains the gold standard[27]. While its higher cost and limited accessibility restrict its use to tertiary centers and clinical research, its accuracy is unparalleled for monitoring changes in liver fat.

The assessment of liver fibrosis is well-established, with tools categorized into blood-based biomarkers and imaging-based elastography. Simple, calculated blood-based biomarkers-such as the FIB-4 index[28,29], non-alcoholic fatty liver disease fibrosis score (NFS)[30], and APRI[31]-are invaluable first-line screening tools due to their low cost and wide availability[15]. These are complemented by more advanced imaging modalities that measure liver stiffness as a direct surrogate for fibrosis. These include ultrasound-based methods like transient elastography and shear wave elastography[32], as well as magnetic resonance elastography (MRE)[33], which offers the advantage of assessing a larger portion of the liver parenchyma.

Contemporary clinical pathways increasingly advocate for the simultaneous or sequential use of a steatosis tool (e.g., CAP, FIB-4 plus a steatosis biomarker) and a fibrosis tool (e.g., VCTE, MRE) to capture the full spectrum of disease activity, as reflected in recent guideline updates.

Using these tools in concert-employing simple blood tests for initial risk stratification followed by elastography for confirmation or in indeterminate cases-provides a more complete and clinically useful picture of liver health. This integrated approach is essential for accurate risk stratification and management, particularly as we navigate the differing recommendations from international clinical practice guidelines.

A COMPARATIVE ANALYSIS OF GLOBAL CLINICAL PRACTICE GUIDELINES ON NON-INVASIVE TESTING

While the need for non-invasive assessment of CLD is universally accepted, the strategic recommendations from major international professional bodies exhibit subtle yet important differences in their preferred tools, target populations for screening, and overall diagnostic algorithms. These variations reflect differing healthcare systems, regional disease prevalence, and evolving evidence bases. A critical comparison of these approaches reveals areas of consensus and highlights gaps that need to be addressed, particularly for patients with dual etiologies. The chronological presentation of guidelines in Table 1 reveals an evolving consensus on a tiered, sequential approach to non-invasive liver disease assessment, while simultaneously highlighting a persistent evidence gap for complex patients. The earliest cited framework, from the APASL in 2017[34], established a pragmatic model prioritizing widely accessible, low-cost tools like the APRI score and ultrasound for initial screening in resource-varied settings. This strategy acknowledged economic disparities in healthcare access. Subsequent guidelines refined this tiered model by emphasizing specific high-risk populations and more precise tools. The American Association of Clinical Endocrinology guideline in 2022[35] explicitly mandated systematic screening for patients with type 2 diabetes, advocating for the FIB-4 index as the universal first step in endocrine and primary care settings. This represented a significant shift towards proactive case-finding outside hepatology clinics. The EASL guidance in 2024[36] further operationalized the sequential approach, promoting the combined use of FIB-4 and VCTE in a rule-out strategy to safely identify low-risk individuals.

Table 1 Tiered non-invasive assessment strategies for liver fibrosis and steatosis: A synthesis of international guidelines (2017-2025).

Guideline body & Ref.	Tier 1: Initial risk stratification (screening)	Tier 2: Confirmatory/definitive assessment	Key considerations for dual HBV/MASLD etiology
APASL (Shiha et al[34], 2017); resource-aware, global perspective	Fibrosis: APRI or proprietary panels (e.g., FibroTest). Steatosis: Ultrasound	Fibrosis: VCTE or MRE	In resource-limited settings, a low threshold for specialist referral is needed if metabolic risk factors (T2DM, hypertension) are present, as they are strong independent drivers of fibrosis in co-infected patients[22]
AACE/AASLD endocrine (Cusi et al[35], 2022); high-risk metabolic patients	Fibrosis: FIB-4 index (universal screening in T2D). Steatosis: Risk factor-based	Fibrosis: (LSM by VCTE) or ELF test. Steatosis: CAP or MRI-PDFF for quantification	Endocrinologists must recognize that in patients with HBV, the presence of T2DM and hypertension should trigger aggressive fibrosis assessment, as these metabolic factors are strongly linked to significant fibrosis in this population[22]
EASL-EASD-EASO (European Association for the Study of the Liver et al[36], 2024); rule-out strategy in MASLD	Fibrosis: FIB-4 index (stepwise with LSM). Steatosis: Often integrated via CAP during LSM	Fibrosis: LSM by VCTE (primary), or MRE. Steatosis: CAP, MRI-PDFF	A key paradox: Low steatosis scores (e.g., CAP) should not be used to de-prioritize fibrosis evaluation. The viral component may be the dominant fibrogenic driver, necessitating elastography even with normal CAP[14,20,23]
AASLD practice guideline on blood-based NITs (Sterling et al[37], 2025); primary care & hepatology screening	Fibrosis: FIB-4 Index (preferred). Steatosis: Not routinely specified in Tier 1; often via risk factor assessment	Fibrosis: Imaging-based NITs (VCTE, MRE) or enhanced blood tests (ELF). Steatosis: CAP (with VCTE) or MRI-PDFF	The 2025 guideline emphasizes using NITs for risk stratification but does not specify dual-etiology cut-offs. Heightened suspicion for advanced fibrosis is warranted despite potentially mild steatosis scores[23]

This table chronologically presents the tiered diagnostic approach (Tier 1: Initial screening; Tier 2: Confirmatory testing) recommended by major international societies, highlighting considerations for the dual hepatitis B virus (HBV)/metabolic dysfunction-associated steatotic liver disease (MASLD) etiology. Traditional frameworks from the Study of Liver Diseases, Study of the Liver, and AACE rely heavily on the fibrosis-4 Index index to rule out advanced fibrosis, typically utilizing a low cutoff of < 1.3 (or < 2.0 in patients over 65) to minimize false negatives in primary care settings. For individuals with indeterminate scores, imaging-based tests such as vibration-controlled transient elastography or magnetic resonance elastography (MRE) provide significantly higher precision for “ruling in” advanced disease, with MRE demonstrating diagnostic accuracy often exceeding 0.90. Dual etiology note: All cut-offs (e.g., FIB-4, LSM) are validated primarily in single-etiology cohorts. Performance may differ in HBV/MASLD, underscoring the need for clinical correlation and lower thresholds for specialist referral. APRI: Aspartate aminotransferase to platelet ratio index; CAP: Controlled attenuation parameter; ELF: Enhanced liver fibrosis; FIB-4: Fibrosis-4 index; LSM: Liver stiffness measurement; MRI-PDFF: Magnetic resonance imaging - proton density fat fraction; NIT: Non-invasive test; T2DM: Type 2 diabetes mellitus; VCTE: Vibration-controlled transient elastography; MRE: Magnetic resonance elastography; MASLD: Metabolic dysfunction-associated steatotic liver disease; AASLD: Study of Liver Diseases; EASL-EASD-EASO: European Association for the Study of the Liver - European Association for the Study of Diabetes - European Association for the Study of Obesity; AACE: American Association of Clinical Endocrinology.

Most recently, the AASLD practice guideline on blood-based tests in 2025[37] consolidated FIB-4’s role as the cornerstone primary care screening tool, reflecting its balance of accessibility and accuracy. Crucially, as noted in the table’s final column, all these frameworks share a critical limitation: Their recommended algorithms and diagnostic cut-offs are primarily validated in single-etiology cohorts. This underscores a major unmet need, as the pathophysiological interaction in concurrent HBV and MASLD-where metabolic factors like diabetes are strongly linked to fibrosis[22] and steatosis may be deceptively mild[23]-likely alters the performance of these tests, necessitating cautious interpretation and lower referral thresholds in clinical practice. A critical advancement represented in the Dai et al[1] protocol is the move from assessing the “ash” of accumulated matrix to the “smoke” of active fibrogenesis. This is achieved by measuring L59 (LAP-DP), a specific molecular footprint of PLK-mediated TGF-β activation. Unlike traditional scores (FIB-4, APRI) which often peak at late stages of injury, L59 is particularly elevated during early-stage fibrosis (stage 1), providing a superior temporal window for intervention before structural damage becomes irreversible.

Within this molecular framework, PLT is included as an independent predictor of histological injury, accounting for hemostatic interference in liver remodeling. Simultaneously, ALT and AST are utilized as dynamic indicators of the necro-inflammatory component, or histological inflammation.

However, there is a flip side of the coin: The widespread adoption of the L59-based system is currently time and money consuming. Unlike automated routine chemistries used in the AASLD and APASL pathways, measuring L59 requires specialized sandwich ELISA testing. Furthermore, there is a distinct lack of availability of these assays in standard laboratories, potentially restricting the protocol’s use to high-resource tertiary centers.

CONCLUSION

This commentary underscores the potential value of biologically informed non-invasive models for assessing liver injury in CHB, particularly those that integrate markers of active fibrogenesis with routine laboratory parameters. The L59-based nomogram proposed by Dai et al[1] represents an innovative step toward capturing dynamic fibrogenic activity that is not fully reflected by conventional fibrosis scores.

Nevertheless, given the observational nature of the underlying study and the current limitations related to assay availability, standardization, and cost, these findings should be interpreted cautiously. External validation in independent cohorts and prospective studies are essential before L59-based testing can be recommended for routine clinical use. Future research should focus on defining standardized assays, validating diagnostic cut-offs, and clarifying how such biomarkers can be most effectively integrated into existing non-invasive assessment pathways, particularly in patients with mixed viral and metabolic liver disease etiologies.

While the integrated assessment of steatosis and fibrosis represents a necessary evolution in hepatology, several pragmatic limitations must be acknowledged to contextualize its immediate implementation and guide future research. First, the promising biomarker L59 remains confined to the research domain. Its measurement relies on specialized, labor-intensive sandwich ELISA platforms that are not standardized for clinical use. This creates a significant translational gap between mechanistic insight and routine practice. Widespread adoption necessitates the development of automated, high-throughput assays and rigorous multi-center studies to establish universal reference ranges and diagnostic cut-offs across diverse populations. Second, there is a pronounced lack of prospective, biopsy-validated data for NIT algorithms in cohorts with confirmed concurrent HBV and MASLD. Current guidelines and validation studies for tools like FIB-4, APRI, and LSM thresholds are largely derived from populations with single-etiology disease. The unique pathophysiological interplay in dual-etiology liver disease may alter the performance characteristics of these tests, potentially requiring adjusted diagnostic cut-offs. Prospective studies are urgently needed to generate evidence-based algorithms for this growing patient subgroup. Third, the proposed dual-assessment strategy has considerable resource implications. While serum biomarkers like FIB-4 are inexpensive and scalable, the recommended second-tier tools-CAP and particularly MRI-PDFF-vary widely in cost, accessibility, and technical expertise required. MRI-PDFF, the gold standard for fat quantification, is largely unavailable in primary care and many regional centers. This disparity risks creating a tiered system of care, where comprehensive assessment is only accessible to patients in well-resourced settings. Future work must prioritize validating more accessible and equitable NIT sequences to ensure equitable implementation. We can create more robust and reliable clinical pathways. Addressing the translational, validation, and resource hurdles outlined herein will be essential to realizing this integrated future of liver care.