Prognostic value of liver fibrosis-4 index in acute ischemic stroke after reperfusion treatment: A meta-analysis

INTRODUCTION

The global health burden of acute ischemic stroke (AIS) remains a significant issue, as it continues to be a major cause of mortality and long-term disability, and its incidence is projected to rise across all age groups, both sexes, and all population regions.^[1,2] Significant progress has been made in reperfusion therapies for AIS over the past decades. Intravenous thrombolysis (IVT) and/or endovascular thrombectomy (EVT) have significantly improved clinical outcomes in AIS patients by enabling the immediate restoration of cerebral function perfusion.^[3-5] However, a subset of patients still experiences an unfavorable short-term prognosis, encompassing poor functional outcome, symptomatic intracranial hemorrhage (sICH), and mortality.^[6-8] Variability in outcomes indicates that better risk stratification tools are still needed to identify high-risk patients, even after successful reperfusion therapy. It underscores the importance of recognizing patients at risk of adverse events, including reperfusion injury and underlying systemic issues, even following successful recanalization therapies.

Recent evidence indicates that liver fibrosis (FIB) is associated with an elevated risk of stroke and unfavorable clinical outcomes.^[9] The FIB-4 index is a blood biomarker originally designed to estimate liver FIB in patients with chronic HIV/hepatitis C virus coinfection, combining age, liver enzyme levels (aspartate aminotransferase and alanine aminotransferase), and platelet counts.^[10] Beyond hepatic pathology, higher FIB-4 levels have been linked to systemic inflammation, endothelial dysfunction, atherosclerosis, and adverse cardiovascular events.^[11-13] All of which may negatively impact stroke recovery and increase complications after reperfusion therapy. Several studies have shown that a high FIB-4 index is linked to a greater risk of stroke recurrence, hemorrhagic transformation, and mortality in AIS patients.^[14,15] Understanding this association could offer novel insights into stroke risk stratification and guide individualized post-reperfusion care.

Currently, there is no systematic review and meta-analysis exploring the role of FIB-4 as a prognostic biomarker in AIS patients undergoing reperfusion therapy. Given the increasing global prevalence of liver FIB and the widespread application of reperfusion interventions, understanding this association is both timely and clinically relevant. Therefore, our study aimed to assess the prognostic significance of the FIB-4 index in patients with AIS undergoing reperfusion therapy, focusing on three clinical outcomes (poor functional outcome at 3 months, sICH, and 3-month mortality).

MATERIALS AND METHODS

Selection and data collection process

The electronic database was uploaded into the Rayyan AI website, and duplicates were automatically eliminated. DAR and TMA screened the titles and/or abstracts for relevance. DAR and TMA then assessed the full texts of potential articles using the inclusion criteria. The discussion between DAR and TMA resolved any disagreements in sequence. Articles from these criteria and relevant references cited in those articles were reviewed. The PRISMA flowchart is described in Figure 1, and the PRISMA checklist is described in Supplement File 1.

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Figure 1: The preferred reporting items for systematic reviews and meta-analyses flowchart.

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RESULTS

High FIB-4 increases the risk of poor functional outcome (3-month mRS score ≥3)

Eight studies involving 4.925 subjects assessed the association of the FIB-4 index and risk of poor functional outcome (3-month mRS score ≥3) following reperfusion therapy for AIS.^{[14,15,17-22]} The cut-off value ranged from 1.3 to 3.25. The pooled results showed that a higher FIB-4 index was significantly linked to a 1.72-fold increased risk of poor functional outcomes at 3 months (OR = 1.72, 95% CI: 1.51– 1.96; Z = 8.10, p < 0.00001). Heterogeneity among studies may represent moderate and not statistically significant (χ²= 11.86, df = 7, p = 0.10; I² = 41%), suggesting acceptable variability between studies. Therefore, a fixed-effects model was used for the pooled analysis. The forest plot is shown in Figure 2.

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Figure 2: The forest plot. (a) Showing the association between high FIB-4 and poor functional (b) Forest plot showing the association between high FIB-4 and symptomatic intracranial hemorrhage, (c) Showing the association between high FIB-4 and 3-month mortality. FIB: Fibrosis. CI: Confidence interval; OR: Odds ratio; FIB-4: Fibrosis-4 index; sICH: Symptomatic intracranial hemorrhage. IV: Inverse variance; SE: Standard error. A p-value of < 0.05 was considered statistically significant.

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Publication bias

According to the NOS critical appraisal, all included studies were of high quality, with scores ranging from 8 to 9, as assessed by DAR [Supplementary File 2]. The funnel plots in Figure 3 show some asymmetry, indicating potential bias, but caution is needed in interpretation due to the limited number of studies. Consequently, statistical tests for publication bias were not performed. Meta-regression was also not carried out because the number of studies per outcome was small, and Egger’s regression test was omitted since fewer than 10 studies were included for each outcome.

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Figure 3: Funnel plots assessing publication bias in the meta-analyses. The horizontal axis represents the odds ratio (OR), and the vertical axis represents the standard error (SE) of the log odds ratio (SE [log OR]). (a) Association between high FIB-4 and the risk of poor functional outcome; (b) Association between high FIB-4 and the risk of symptomatic intracranial hemorrhage; (c) Association between FIB-4 and the risk of 3-month mortality. (FIB 4: Fibrosis-4 index, sICH: Symptomatic intracranial hemorrhage.)

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DISCUSSION

This study represents the first comprehensive meta-analytic evidence examining the role of the FIB-4 index as a prognostic biomarker in AIS patients undergoing reperfusion therapy. Our meta-analysis revealed that AIS patients with a higher FIB-4 index were associated with a significantly increased risk of poor 3-month functional outcomes, sICH, and 3-month mortality. These findings suggest that the FIB-4 index can serve as a practical prognostic biomarker, crucial for early risk assessment and personalized monitoring planning.

Our study aligns with previous evidence linking liver FIB markers to poor prognosis in stroke patients. An observational study from Greece on the clinical outcomes of AIS patients during hospitalization has shown that a high FIB-4 index correlates with higher mRS scores at discharge and increased in-hospital mortality in AIS patients.^[26]These findings are consistent with our subgroup analysis for mortality, which suggested that the prognostic value of FIB-4 was more pronounced in the European population. Subjects with a high FIB-4 index indicate the presence of liver steatosis and are used to rule in the presence of advanced FIB and are associated with a more complex comorbidities profile.^[27]An elevated FIB-4 index has been further associated with a higher risk of developing a cardiovascular disease event.^[11,13,28] Recent epidemiological evidence highlights an increasing global burden of chronic hepatic conditions, including liver FIB.^[29] In this study, approximately one in four AIS patients across the included studies showed elevated FIB-4 levels. The importance of liver-related comorbidities in stroke prognosis deserves further attention, and greater recognition is warranted. Our study is consistent with earlier cohort studies demonstrating that the FIB-4 index is associated with all-cause mortality in cardiovascular and cerebrovascular populations.^[12,30-32] This highlights the need to integrate liver function markers, such as the FIB-4 index, into comprehensive stroke risk assessment frameworks.

The pathophysiological mechanisms underlying the role of the FIB-4 index in predicting poor outcomes in AIS patients undergoing reperfusion therapy are complex and diverse. Hepatic FIB is often accompanied by systemic metabolic disturbances, such as insulin resistance, dyslipidemia, and chronic inflammation.^[19] These conditions contribute to vascular endothelial dysfunction, increased arterial stiffness, and a prothrombotic state, which may impair cerebral perfusion and hinder neurological recovery following reperfusion.^[33] Prothrombotic events associated with liver dysfunction may also increase the risk of new thrombus formation or vascular re-occlusion, despite successful reperfusion therapy. Furthermore, liver FIB is associated with impaired immune regulation, including Kupffer cell dysfunction and cytokine overproduction, which may exacerbate systemic inflammatory responses after stroke.^[34]This inflammatory condition can trigger ischemic–reperfusion damage by triggering an excessive brain inflammatory response, increasing blood–brain barrier permeability, and contributing to cerebral edema. The coexistence of atrial fibrillation, frequently observed in patients with non-alcoholic fatty liver disease (NAFLD), may further amplify the risk of cardioembolic events and hemorrhagic transformation, particularly in those undergoing reperfusion therapy.^[20,35,36]Collectively, these mechanisms underscore the biological plausibility of FIB-4 as a surrogate marker for stroke vulnerability and poor post-treatment prognosis.

The FIB-4 index is highly advantageous for its simplicity, cost-effectiveness, and derivation from routinely available laboratory parameters. FIB-4 can be rapidly calculated upon admission, enabling early identification of high-risk AIS patients before or immediately after reperfusion therapy. Incorporating FIB-4 into standard stroke assessment protocols may enable more personalized post-treatment surveillance strategies, such as closer hemodynamic monitoring or early rehabilitation planning in patients with a high index score. The FIB-4 index is especially useful in rural areas with limited resources, particularly in countries with low- and medium-level economic development outcomes. Furthermore, FIB-4 could enhance existing clinical assessments such as the NIHSS score and/or Alberta stroke program early computed tomography score, providing a multidimensional view of patient prognosis and potentially improving personalized care pathways.^[37-40] Several factors, notably pre-existing diabetes, advanced age, and atrial fibrillation, can influence the clinical recovery of stroke patients following reperfusion therapy.^[41-43]

Reperfusion therapy remains the cornerstone of AIS treatment because it can improve clinical outcomes.^[44,45] Meanwhile,the treatment of ischemic stroke with coexisting chronic liver disease has a special emphasis on antithrombotic selection, statin therapy, antihypertensive selection, and coagulopathy management.^[46] However, unfavorable clinical outcomes still occur in some AIS patients undergoing reperfusion therapy. FIB-4 may serve as a prognostic marker and a tool to personalize reperfusion strategies, balancing the benefits of recanalization against the potential risks of hepatic dysfunction and systemic inflammation. Such tailored approaches may help mitigate complications and optimize recovery trajectories in this vulnerable subgroup. The FIB-4 index facilitates a paradigm shift from reactive to proactive, integrated post-stroke care. Its utility in enabling more targeted post-treatment surveillance strategies and early rehabilitation planning is evident. Furthermore, by complementing existing predictors, FIB-4 offers a multidimensional view of patient risk. This approach encourages clinicians to consider underlying systemic vulnerabilities beyond the acute stroke event, thereby enabling anticipatory interventions such as tighter metabolic control or targeted anti-inflammatory strategies. Ultimately, this comprehensive perspective addresses the root causes of adverse outcomes, leading to a more holistic and effective long-term management plan extending beyond the acute phase.

The predictive utility of several other liver FIB indices for post-stroke complications has also been well demonstrated. Notably, an extensive cohort study independently linked a range of these indices, specifically the modified FIB-4, alanine aminotransferase to platelet ratio index, Forns index, Fibrosis quotient (FibroQ), and aspartate aminotransferase to platelet ratio index (AARPRI), to an increased risk of both sICH among AIS patients who underwent IVT. The FibroQ demonstrated the highest predictive performance for hemorrhagic transformation (area under the curve [AUC] 0.707). Conversely, FIB-4 maintained superior predictive capability for sICH, achieving an AUC of 0.802. A study found that the Forns index and easy liver fibrosis test (eLIFT) were significantly associated with unfavorable neurological outcomes and 3-month mortality in patients undergoing mechanical thrombectomy, similarly to FIB-4. Notably, these indices identified a larger proportion of patients with liver FIB, 38.0% by the Forns index and 58.9% by eLIFT, compared to 22.6% using FIB-4.^[22]

Our meta-analysis has several limitations that must be acknowledged. First, most included studies employed retrospective observational designs, which are inherently prone to selection bias, residual confounding, and limited control over data quality. Second, there is variability in FIB-4 cutoff values across studies, reflecting the lack of a universally accepted threshold for predicting adverse outcomes in AIS patients. In studies of patients outside stroke with extensive validation, the FIB-4 index cutoff values for detecting NAFLD FIB are generally divided into three groups: Low-risk FIB (FIB-4 ≤ 1.3), intermediate-risk FIB (1.3 < FIB-4 < 2.67), and high-risk FIB (FIB-4 ≥ 2.67). In other words, FIB-4 ≤ 1.3 indicates undetectable advanced FIB and FIB-4 ≥ 2.67 indicates detectable advanced FIB.^[47] Establishing a standard cutoff value through prospective trials in AIS patients is crucial for clinical application. Third, although publication bias was assessed visually using funnel plots, the small number of studies precluded thorough statistical testing. Finally, most studies were conducted in East Asia, with only a small proportion originating from European cohorts. Ethnic differences in genetic background, prevalence of liver disease, metabolic profiles, and stroke risk factors may influence the relationship between the FIB-4 index and clinical outcomes in patients with AIS.

Future research should address these limitations by incorporating prospective, multi-center designs with standardized protocols and extended follow-up. Future investigations should focus on validating the FIB-4 index through large-scale samples and prospective cohort studies with standardized cut-off values. Integrating FIB-4 into predictive models alongside clinical, imaging, and genetic markers could enhance the precision of outcome forecasting in AIS patients. Moreover, given the underlying metabolic and inflammatory components reflected by a high FIB-4 index, there is a compelling need to explore whether targeted interventions such as statin therapy, glycemic control, or lifestyle modifications aimed at reducing liver FIB can positively influence stroke recovery. Randomized trials assessing the effect of these interventions in high FIB-4 subgroups may offer new avenues to mitigate risk and improve post-stroke clinical outcomes. In addition, future studies should investigate the longitudinal changes in the FIB-4 index following stroke, and their association with neurocognitive function decline, recurrent events, and functional recovery to determine its potential role in long-term stroke management.

CONCLUSION

This study found that a higher FIB-4 index is associated with an increased risk of poor 3-month functional outcomes, sICH, and 3-month all-cause mortality after reperfusion treatment in patients with AIS. The FIB-4 comprises routine demographic and laboratory data collected from AIS patients. Given the high number of advanced liver FIB among AIS patients and the growing epidemiological evidence on chronic liver diseases, we recommend including the FIB-4 index in standard care for AIS patients undergoing reperfusion therapy. This approach will aid in early risk assessment and the stratification of unfavorable outcomes.