Systemic inflammation in metabolic dysfunction-associated steatotic liver disease: Biological relevance and diagnostic limits

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized as a systemic condition characterized by both hepatic and extrahepatic manifestations, in which chronic low-grade inflammation plays a key role. Insulin resistance, adipose tissue dysfunction, and lipotoxicity are among the primary drivers of this inflammatory state. These mechanisms maintain a chronic pro-inflammatory environment that promotes hepatocellular damage and fibrosis. Disruptions in the gut-liver axis also exacerbate liver inflammation, adding another dimension to the systemic nature of MASLD. Although chronic low-grade inflammation is important in MASLD, it has not translated into useful clinical biomarkers. This is largely because it is not specific to liver damage, it may also reflect other underlying metabolic conditions. Making it difficult to determine whether changes in these markers are truly due to liver fibrosis. Several blood cell-derived inflammatory markers have been proposed as accessible, low-cost tools for detecting fibrosis. However, their validation has proven difficult, as MASLD is often accompanied by metabolic comorbidities that independently trigger immune activation. In this context, Duarte et al recently published a study in World Journal of Hepatology, providing population data based on the latest cycle of the National Health and Nutrition Examination Survey and concluding that indices such as the neutrophil-to-lymphocyte ratio and the systemic inflammatory response index are associated with liver fibrosis, but show limited discriminatory accuracy compared to C-reactive protein. This editorial contextualizes these findings, analyzes why this association has not led to reliable biomarkers, and discusses how inflammation-based markers could be better integrated into existing noninvasive models.

Key Words: Metabolic dysfunction-associated steatotic liver disease; Systemic inflammation; Liver fibrosis; C-reactive protein; Biological relevance; Diagnostic limit

Core Tip: Several markers have been developed to assess systemic inflammation in metabolic dysfunction-associated steatotic liver disease, including blood cell-derived indices and C-reactive protein. Yet, a statistical association with fibrosis does not make them clinically useful. Duarte et al confirm this using National Health and Nutrition Examination Survey data. Although indices such as the neutrophil-to-lymphocyte ratio and systemic inflammatory response index are associated with fibrosis, their discriminatory power is limited. C-reactive protein performs only slightly better. This suggests that inflammatory markers should be considered contextual risk modifiers. Not standalone diagnostic tools for fibrosis detection. Future strategies should prioritize biomarkers that more directly capture fibrogenic activity.

This editorial refers to "Inflammatory parameters and liver fibrosis in patients with steatosis: A cross-sectional analysis" by Duarte et al, 2026; https://doi.org/10.4254/wjh.v18.i3.111569.

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INTRODUCTION

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most prevalent chronic liver disease worldwide, reflecting the global increase in obesity and type 2 diabetes mellitus[1]. Current estimates indicate that MASLD affects 38% of the adult population, and projections suggest a continued increase in prevalence and disease burden over the coming decades[2]. Beyond its hepatic manifestation, MASLD is now a major contributor to cardiovascular and metabolic risk. In terms of hepatic systemic metabolic dysfunction, insulin resistance (IR), adipose tissue inflammation and altered immune responses interact to promote chronic liver injury and disease progression[3]. This perspective has redefined the conceptual framework of MASLD, emphasizing the need to understand the mechanisms of diseases that operate systemically rather than focusing exclusively on the liver[4].

Among these mechanisms, chronic systemic inflammation has become a central factor in the development and progression of MASLD. In obesity and IR, adipose tissue dysfunction causes adipocyte hypertrophy, macrophage infiltration, and dysregulated adipokine secretion, promoting a proinflammatory environment[5]. This process keeps innate immune pathways active, leading to an increase in circulating proinflammatory cytokines, chemokines, and immune cell activation and establishing a persistent low-grade inflammatory state rather than a transient acute response[6]. In the liver, these inflammatory mechanisms generate hepatocellular stress, which, combined with lipotoxicity, oxidative stress, and mitochondrial dysfunction, activates hepatic stellate cells (HSCs). This activation leads to increased extracellular matrix deposition and progressive architectural remodeling of the liver, thereby linking systemic metabolic inflammation with the development of hepatic fibrosis[7,8].

However, the inflammatory burden of MASLD extends beyond the liver. Systemic inflammation contributes to the pathogenesis of cardiovascular disease, chronic kidney disease, and other extrahepatic complications that significantly influence morbidity and mortality in this population. These extrahepatic manifestations reinforce the concept of MASLD as a multisystemic disease in which liver fibrosis represents one component of a broader metabolic - immunological continuum[9].

Despite this well-established mechanistic relevance, the translation of systemic inflammation into clinically applicable tools for assessing fibrosis in MASLD remains limited[10]. Although inflammatory pathways are clearly implicated in disease progression, systemic inflammatory signals are inherently nonspecific and influenced by various metabolic and extrahepatic conditions. As a result, markers reflecting overall inflammatory burden may not accurately predict the presence of hepatic fibrosis or discriminate its severity, highlighting a critical gap between biological plausibility and diagnostic performance in clinical practice[11]. In this context, the article by Duarte et al[12] recently published in the World Journal of Hepatology, provides timely population data that address this gap. Using data from the latest cycles of the National Health and Nutrition Examination Survey (NHANES), the authors evaluated several systemic inflammatory indices derived from routine blood counts and demonstrated that although these markers are statistically associated with hepatic fibrosis, their overall discriminatory accuracy is limited and consistently inferior to that of C-reactive protein (CRP). These findings highlight the difficulties of translating systemic inflammation into reliable, independent biomarkers for assessing hepatic fibrosis in MASLD. The aim of this editorial is to contextualize the findings of Duarte et al[12] within the pathophysiological framework of MASLD, critically examine the biological significance and clinical limitations of systemic inflammatory markers, and discuss how inflammation-based signals can be more effectively integrated into existing models of noninvasive fibrosis assessment rather than being used as independent diagnostic tools.

SYSTEMIC INFLAMMATION IN MASLD: PATHOPHYSIOLOGY AND TRANSLATIONAL RELEVANCE

Systemic inflammation in MASLD reflects a sustained state of metabolic-immune activation driven by chronic overconsumption of nutrients and IR. This condition is characterized by persistent activation of innate immune pathways, including nuclear factor kappa B, inflammasome activation, and cytokine-mediated signaling, which collectively amplify cellular stress responses across multiple organs. Therefore, MASLD-associated inflammation is not an isolated inflammatory disorder but arises from coordinated dysfunction involving hepatocytes, immune cells, and extrahepatic metabolic tissues[13]. In the liver, chronic lipid excess promotes the accumulation of lipotoxic intermediates, which induce oxidative stress, endoplasmic reticulum stress, and mitochondrial dysfunction in hepatocytes. These stress signals activate resident macrophages (Kupffer cells) and facilitate the recruitment of circulating monocytes, leading to the increased production of proinflammatory and profibrotic mediators, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and transforming growth factor-β. The resulting inflammatory microenvironment promotes HSC activation, extracellular matrix deposition, and progressive fibrotic remodeling, linking systemic metabolic inflammation to structural liver damage[14,15].

In addition, systemic inflammation is influenced by extrahepatic factors that modulate immune tone and metabolic flux through interconnected pathways. Dysfunctional adipose tissue contributes to the sustained release of TNF-α and IL-6, along with qualitative and quantitative alterations in adipokine signaling, including decreased adiponectin levels and relative hyperleptinemia. In parallel, increased adipose tissue lipolysis elevates circulating free fatty acid levels, which increase lipid entry into the liver and activate innate immune pathways in immune and hepatic cells through lipotoxic and toll-like receptor-dependent mechanisms[16,17].

Moreover, alterations in the gut - liver axis provide an additional inflammatory stimulus. Increased intestinal permeability facilitates the translocation of pathogen-associated molecular patterns, including lipopolysaccharides and bacterial DNA, into the portal circulation. These microbial products activate pattern recognition receptors, such as toll-like receptors and nucleotide-binding oligomerization domain-like receptors, in Kupffer cells and HSCs, amplifying intrahepatic inflammatory and profibrotic signaling. Additionally, dysbiosis-related changes in bile acid composition and signaling further modulate immune responses and hepatic metabolism, reinforcing both systemic and liver-centered inflammation[18,19].

This multisource inflammatory network explains both the biological relevance and clinical limitations of inflammation-based assessment in MASLD. Circulating inflammatory signals reflect the integrated outcome of metabolic stress, immune activation, and microbiota-derived stimuli rather than the liver-specific fibrotic burden[20]. Furthermore, inflammatory activity is highly dynamic and fluctuates with metabolic control, body weight, and extrahepatic inflammatory conditions, whereas fibrosis represents the cumulative consequence of chronic injury and maladaptive repair[21,22]. This dissociation helps explain why systemic inflammatory markers are consistently associated with fibrosis but show limited discriminatory accuracy for fibrosis staging[20]. These considerations raise the question of how systemic inflammation should be assessed in clinical practice. Although inflammation is part of the progression of MASLD, its translation into measurable biomarkers inevitably requires simplification.

INFLAMMATION-BASED INDICES IN MASLD: BIOLOGICAL SIGNAL AND DIAGNOSTIC LIMITATIONS

CRP remains the most established and widely used biomarker of systemic inflammation in clinical medicine. As an acute-phase reactant derived from hepatocytes and induced primarily by IL-6 signaling, CRP provides a robust, analytically stable, and readily accessible readout of inflammatory activation in liver injury. Studies have reported that CRP levels are consistently correlated with obesity, IR, cardiovascular risk, and the presence of MASLD, making it an intuitive reference marker for evaluating inflammation-based approaches to disease assessment[23-26]. Nevertheless, CRP also exemplifies the central limitation of systemic inflammation as a diagnostic target in MASLD. By reflecting the overall inflammatory burden rather than specific liver injury, CRP integrates signals from adiposity, metabolic dysfunction, infections, and comorbid inflammatory states. As a result, although increased CRP levels are frequently associated with fibrosis, their ability to discriminate the stage or severity of fibrosis in patients is modest and inconsistent across cohorts[26-29].

In addition to single-marker approaches, several inflammation-based indices derived from routine blood counts have been proposed as pragmatic tools for detecting immunometabolic alterations in MASLD. Parameters such as the neutrophil-to-lymphocyte ratio (NLR), the systemic inflammatory response index (SIRI), the aggregate systemic inflammation index, and the prognostic nutritional index integrate leukocyte subpopulations and nutritional status to reflect overall immune activation[30]. In recent years, several studies have evaluated the usefulness of these indices in identifying liver fibrosis and other complications associated with MASLD. Zheng et al[31] reported that higher SIRI was independently associated with cardiovascular events and all-cause mortality in people with MASLD, outperforming high-sensitivity CRP in risk reclassification. Similarly, Yin et al[32] reported that an increased SIRI was independently associated with advanced fibrosis and long-term mortality in a nationally representative MASLD cohort. In populations at high metabolic risk, Tang et al[33] reported that the NLR and SIRI correlated with fibrosis severity, as assessed by fibrosis-4 (FIB-4), in hospitalized patients with type 2 diabetes mellitus and MASLD, whereas platelet-based indices showed inverse associations. Extending this concept to disease phenotypes, Verma et al[34] reported that MASLD, metabolic dysfunction and alcohol-related liver disease, and alcohol-related liver disease have distinct inflammatory profiles, with a progressively higher neutrophilic burden across all phenotypes, and that the NLR was consistently associated with fibrosis severity. These studies have supported the existence of a relationship between inflammation-based indices and fibrosis progression. However, they also revealed substantial heterogeneity driven by population selection, disease stage, and outcome definition. Most positive associations arise in cohorts with a high index of advanced disease, acute inflammatory states, or high cardiometabolic burden, settings in which systemic inflammation is amplified and closely related to overall disease severity. Whether these associations translate into clinically useful diagnostic discrimination in unselected populations with MASLD remains a fundamental question. In this context, the comprehensive NHANES-based analysis by Duarte et al[12] offers a fundamental and unifying perspective. Using two contemporary NHANES cycles (2017-2020 and 2021-2023), they evaluated multiple inflammatory indices derived from whole blood, including the NLR, SIRI, aggregate systemic inflammation index, and prognostic nutritional index, along with the CRP level, in more than 4200 adults with steatosis, nearly 1000 of whom met the elastography-based criteria for fibrosis. Although the CRP level, NLR, and SIRI were independently associated with fibrosis according to the multivariable regression models, none of the evaluated indices demonstrated clinically meaningful discriminatory performance. The area under the receiver operating characteristic curve ranged from only 0.53 to 0.61, with CRP consistently outperforming cell-based indices but still falling well below accepted thresholds for diagnostic utility. Importantly`1, the results of this study demonstrate that the statistical association and diagnostic performance differ considerably. Even in a large, well-phenotyped population sample, inflammation-derived indices lack sufficient sensitivity, specificity, or predictive value to function as reliable independent tools for fibrosis detection[12]. This interpretation is reinforced by data from mechanistic and cohort-based studies focusing on circulating cytokines. In a well-characterized cohort of MASLD patients, Eid et al[20] reported that circulating IL-6, TNF-α and high-sensitivity CRP levels were markedly elevated but showed no consistent associations with fibrosis severity on multiple validated noninvasive tools, such as transient elastography, FIB-4, aspartate aminotransferase to platelet ratio index, non-alcoholic fatty liver disease fibrosis score, and fatty liver, activity, fibrosis score. Instead, these inflammatory markers correlated more closely with central adiposity, lipid profiles, and cardiometabolic risk indices, supporting the concept that systemic inflammation in MASLD predominantly reflects metabolic dysfunction rather than the degree of fibrotic remodeling[20].

Collectively, these data indicate that inflammation-based indices in MASLD provide crucial biological information but have limited diagnostic specificity for liver fibrosis. Although they strongly reflect systemic immunometabolic stress, their performance as independent markers of fibrosis is inconsistent and often clinically inadequate, as clearly illustrated by large population-based analyses. These limitations highlight the need to reconsider how inflammatory markers are interpreted in MASLD, shifting from diagnostic surrogates to contextual risk modifiers, and lead us to the following question: How should they be applied, integrated, or replaced in clinical practice and future research?

CLINICAL IMPLICATIONS AND FUTURE PERSPECTIVES

From a clinical standpoint, the limited diagnostic performance of inflammation-based indices requires a pragmatic redefinition of their role in MASLD care pathways. Rather than positioning themselves as tools for fibrosis staging, these markers are better understood as global risk modifiers that inform the systemic context in which liver disease evolves. In routine practice, increases in CRP-derived indices or leukocytes should therefore prompt clinicians to intensify the evaluation and treatment of metabolic comorbidities rather than inferring the severity of fibrosis[31,35]. Therefore, fibrosis assessment should continue to be based on validated, liver-specific noninvasive strategies. Simple scores such as FIB-4 remain effective first-line tools for ruling out advanced fibrosis, with elastography reserved for patients with intermediate-risk or high-risk profiles[36]. Inflammation-based indices may complement this approach by helping to identify confounding inflammatory states that could influence liver stiffness or serum markers, but their use as standalone diagnostic tools is not supported by current evidence[12,37]. From a research perspective, these findings underscore the need to move beyond generic markers of systemic inflammation and toward biomarkers that more directly capture fibrogenic activity and tissue remodeling. Emerging candidates include circulating markers of extracellular matrix turnover, collagen neoepitopes and multianalytical panels integrating metabolic, inflammatory and liver-specific pathways[38-40]. Future studies should prioritize longitudinal designs, cohorts enriched with advanced fibrosis and outcome-based validation to distinguish biological association from true diagnostic or prognostic utility.

CONCLUSION

Systemic inflammation is a central component of the pathophysiology of MASLD and provides significant information about the underlying immunometabolic environment; however, current evidence suggests that inflammation-based markers and indices lack sufficient specificity and discriminatory power to serve as reliable independent tools for fibrosis assessment. These findings underscore a critical distinction between biological relevance and clinical utility and highlight the need to move beyond generic inflammatory surrogates toward biomarkers that directly capture tissue remodeling and disease progression. Future strategies in MASLD should integrate inflammation as contextual information within multimodal, noninvasive, pathway-based frameworks, prioritizing fibrosis-specific biomarkers, longitudinal validation, and outcome-based relevance to improve risk stratification and precision-guided clinical care.