Introduction

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent cause of chronic liver disease, with a global prevalence of 30% [1]. It encompasses a spectrum of conditions, ranging from simple steatosis to non-alcoholic steatohepatitis, fibrosis, and cirrhosis [2]. Given that NAFLD can progress to hepatocellular carcinoma, the assessment of liver fibrosis in patients with NAFLD is critical for determining prognosis and directing management strategies.

Liver biopsy has long been regarded as the gold standard for evaluating liver fibrosis [3]. However, its invasiveness, associated costs, and potential complications have prompted the development of various non-invasive markers. Among these, the fibrosis-4 (FIB-4) index, which includes age, aspartate aminotransferase, alanine aminotransferase, and platelet count, has been extensively validated and is frequently utilized in clinical practice to estimate the degree of liver fibrosis [4,5].

Mean platelet volume (MPV) is a hematologic parameter that reflects platelet size and serves as an index of platelet activation [6]. Previous studies involving patients with hepatitis B and C have demonstrated that increased MPV is associated with liver fibrosis [7–9]. However, the relationship between MPV and the degree of liver fibrosis in individuals with NAFLD remains uncertain. Notably, only one study has indicated that MPV does not correlate with fibrosis in patients with NAFLD [10].

In this study, we aimed to investigate the association between MPV and liver fibrosis in patients with NAFLD, utilizing the FIB-4 index to assess the potential of MPV as a biomarker for evaluating liver fibrosis. Understanding this relationship could enhance the utility of MPV as a non-invasive marker for the stratification and management of patients with NAFLD.

Methods

Results

Study participants were categorized into three groups based on the FIB-4 index: low (<1.30), indeterminate (1.30–2.67), and high (>2.67). The proportions of patients in the low, indeterminate, and high FIB-4 index groups were 91.9% (65,070/70,830), 7.7% (5,441/70,830), and 0.5% (319/70,830), respectively. The characteristics of the participants are summarized in Table 1. All examined variables showed statistically significant differences among the three groups (p < 0.001), except for BMI, which showed no significant difference between the low and high FIB-4 index groups (p = 0.694) (Table 2). The median MPV for the low, indeterminate, and high FIB-4 index groups were 10.4 fL, 10.6 fL, and 10.9 fL, respectively (Fig 1). Spearman correlation analysis indicated a statistically significant, albeit weak, positive correlation between MPV and the FIB-4 index (rho =  0.170, p < 0.001). On multivariable linear regression adjusted for age, BMI, DM, albumin, AST, ALT, and platelet count, MPV remained significantly associated with FIB-4 index (β =  0.01, p <  0.001) (Table 3).

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Table 1. Characteristics of the study population.

https://doi.org/10.1371/journal.pone.0318847.t001

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Table 2. Comparison of variables among groups categorized by the FIB-4 index.

https://doi.org/10.1371/journal.pone.0318847.t002

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Table 3. Multivariable linear regression analysis of the association between MPV and FIB-4 index with adjustment for covariates.

https://doi.org/10.1371/journal.pone.0318847.t003

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Fig 1. Distribution of MPV across the FIB-4 index categories in patients with NAFLD.

MPV, mean platelet volume; FIB-4, fibrosis-4; NAFLD, non-alcoholic fatty liver disease.

https://doi.org/10.1371/journal.pone.0318847.g001

Discussion

The relationship between MPV and FIB-4 index in patients with NAFLD was investigated in the present study. Our findings revealed significant differences in MPV values across the three FIB-4 index categories. Additionally, a weak but statistically significant positive correlation was identified between MPV and the FIB-4 index. These results underscore the potential utility of MPV as a complementary marker for assessing fibrosis severity in patients with NAFLD.

The differentiation of hepatic stellate cells into myofibroblasts represents a crucial mechanism in the development of liver fibrosis. In this process, platelets play a significant role by releasing profibrotic cytokines such as transforming growth factor-beta and platelet-derived growth factor-beta [15,16]. Transforming growth factor-beta stimulates the activation and differentiation of hepatic stellate cells into myofibroblasts, resulting in excessive extracellular matrix deposition [15]. Platelet-derived growth factor-beta acts as a mitogen and chemotactic factor for activated hepatic stellate cells and myofibroblasts, thereby promoting fibrosis [16,17]. The synergistic effect of these cytokines accelerates the progression of liver fibrosis.

MPV serves as an indicator of platelet size and activity, with larger platelets typically reflecting increased systemic inflammation and platelet activation [6]. In the context of NAFLD, where chronic inflammation drives disease progression [18], increased MPV may signify more severe liver injury and fibrosis. According to a previous study by Miele et al. [19], pro-inflammatory changes in platelets have been observed in patients with NAFLD, further supporting this relationship. Additionally, prior research has demonstrated an association between MPV and the severity of fibrosis in chronic liver diseases such as hepatitis B and C [7–9]. In patients with hepatitis B, elevated MPV was associated with advanced fibrosis, revealing a significant difference between mild and advanced fibrosis categories. Similarly, in patients with hepatitis C, MPV was significantly higher in those with advanced fibrosis, thereby reinforcing the potential of MPV as a non-invasive marker of fibrosis progression.

Conversely, our study specifically focused on patients with NAFLD and analyzed the MPV according to FIB-4 index categories. Our findings revealed that patients classified within the high FIB-4 index category exhibited higher MPV compared to those in the low and indeterminate FIB-4 index categories. This observation suggests that MPV may be associated with the severity of liver fibrosis in NAFLD and aligns with the understanding that platelet activation contributes to the pathogenesis of fibrosis. The significant differences in MPV among the FIB-4 categories highlight the potential role of MPV in identifying patients at higher risk for advanced fibrosis in the context of NAFLD. Furthermore, MPV may serve as an early indicator of disease progression or treatment response, facilitating more effective management of NAFLD.

This study demonstrated a weak yet statistically significant positive correlation between MPV and the FIB-4 index. This finding aligns with the established understanding that increased platelet activation plays a role in fibrosis progression [15]. However, the weak correlation indicates that MPV alone is not a robust predictor of fibrosis severity in individuals with NAFLD and may have limited utility as a standalone marker for risk stratification in clinical practice. Despite these limitations, MPV remained independently associated with the FIB-4 index after adjusting for covariates, including age, BMI, DM, albumin, AST, ALT, and platelet count. This finding highlights the potential role of MPV as a complementary marker for fibrosis assessment. Although MPV alone may not significantly improve the identification of advanced fibrosis, its inclusion in a composite scoring system could provide incremental value in improving diagnostic accuracy. Further studies incorporating MPV alongside other noninvasive fibrosis markers are needed to improve the accuracy of fibrosis risk stratification and reduce the dependence on liver biopsy.

A previous study revealed a moderate correlation between MPV and FibroScan results, yielding a correlation coefficient of 0.476 [7]. FibroScan provides a direct measurement of liver stiffness, which may offer a more accurate reflection of fibrosis severity compared to the FIB-4 index [20]. The stronger correlation between MPV and FibroScan indicates that MPV may be more closely associated with the physical alterations linked to fibrosis, as opposed to the indirect markers utilized in the FIB-4 index. This observation suggests that increased MPV is more directly related to these alterations, highlighting its potential as a valuable marker for assessing fibrosis severity.

This study has some limitations. First, its cross-sectional design limits our ability to establish causal relationships between elevated MPV and fibrosis progression. Longitudinal studies are necessary to ascertain whether changes in MPV over time are directly correlated with disease progression. Second, fibrosis assessment was conducted using the FIB-4 index rather than liver biopsy or FibroScan, owing to the reliance on health examination data where liver biopsy and FibroScan were not feasible. Third, variability existed in the sizes of groups categorized by the FIB-4 index.

In conclusion, our study illustrates that MPV is significantly associated with the severity of liver fibrosis in patients with NAFLD. These findings underscore the potential of MPV as a valuable, non-invasive marker for assessing fibrosis risk and guiding the management of patients with NAFLD. As a non-invasive and easily measurable parameter, MPV could be integrated into routine clinical practice to enhance the evaluation of fibrosis severity in this patient population.