APRI and FIB-4 indices as systemic fibrosis markers in proliferative vitreoretinopathy

Abstract

Objective

This study aimed to investigate the relationship between systemic fibrosis markers, including the Aspartate Aminotransferase–to–Platelet Ratio Index (APRI) and the Fibrosis-4 Index (FIB-4), and the development of proliferative vitreoretinopathy (PVR).

Methods

The medical records of patients who underwent surgery for rhegmatogenous retinal detachment between January 2019 and October 2025 were retrospectively reviewed. A total of 394 participants were included and divided into three groups: PVR-positive retinal detachment group (PVR (+) RD; n = 150), PVR-negative retinal detachment group (PVR (−) RD; n = 175), and a healthy control group (n = 69). APRI and FIB-4 scores were calculated using preoperative complete blood count and liver function test parameters. Demographic data and clinical characteristics of the patients were recorded.

Results

The mean age of the 394 participants included in the study was 59.9 ± 13.2 years (range: 22–89 years). Of the patients, 184 (46.7%) were female, and 210 (53.3%) were male. Although the mean FIB-4 and APRI values tended to be higher in the PVR (+) group compared with the PVR (−) and control groups, no statistically significant differences were observed (p = 0.062 and p = 0.835, respectively). In multivariate logistic regression analysis, longer symptom duration was independently associated with an increased risk of proliferative vitreoretinopathy (OR = 1.04, 95% CI: 1.02–1.06; p = 0.001). Diabetes mellitus was also identified as an independent risk factor for PVR development (OR = 2.51, 95% CI: 1.22–5.17; p = 0.013), and inferior rhegmatogenous retinal detachment was significantly associated with PVR (OR = 0.48, 95% CI: 0.25–0.93; p = 0.029).

Conclusion

The APRI and FIB-4 indices did not reveal a statistically significant difference in distinguishing the development of proliferative vitreoretinopathy. These findings support that the pathogenesis of PVR is primarily driven by inflammatory and fibroproliferative processes occurring within the local vitreoretinal microenvironment rather than by systemic fibrosis.

Introduction

Proliferative vitreoretinopathy (PVR) is a serious complication of retinal detachment that threatens vision and represents the leading cause of postoperative surgical failure. PVR arises from a combination of multistage biological events, including the displacement of retinal pigment epithelial (RPE) cells, initiation of epithelial–mesenchymal transition (EMT) processes, activation of glial cells, inflammatory cell infiltration, and excessive extracellular matrix (ECM) production. These pathological mechanisms lead to the formation of contractile fibrocellular membranes, the tractional forces of which predispose to recurrent retinal detachment [1–5]. Although ocular risk factors such as large retinal tears, chronic retinal detachment, and vitreous hemorrhage are well defined, the relationship between systemic fibrotic markers and the development of PVR has not yet been sufficiently established [6, 7].

Two serum-based indices commonly used in hepatology and systemic disease research—the Aspartate Aminotransferase–to–Platelet Ratio Index (APRI) and the Fibrosis-4 Index (FIB-4)—are noninvasive biomarkers used to assess chronic inflammation and tissue fibrosis [8]. These indices are derived from routine hematological and biochemical parameters and are considered to reflect systemic fibrotic activity. In recent years, increasing evidence has suggested that FIB-4 and APRI, originally developed as markers of liver fibrosis, may influence not only hepatic pathologies but also ocular microvascular structures [9]. A large-scale study demonstrated that elevated FIB-4 levels were significantly associated with retinal microvascular changes [10], while another study reported a close relationship between liver fibrosis and the presence of diabetic retinopathy [11]. In addition, machine learning–based models capable of predicting advanced liver fibrosis using retinal findings have also been described in the literature [12]. Collectively, these studies support the concept that systemic fibrotic processes may be reflected in retinal structures and suggest that fibrosis-related indices such as FIB-4 could serve as potential surrogate biomarkers in ocular diseases.

Establishing the relationship between systemic fibrosis markers and the development of proliferative vitreoretinopathy could significantly contribute to a deeper understanding of the pathophysiological basis of PVR, facilitate the early identification of patients at high risk for disease development, and support the development of targeted treatment strategies in the future. In this context, the present study aimed to evaluate how noninvasive serum fibrosis indices, including APRI and FIB-4, vary across different clinical subgroups. By comparing these noninvasive systemic indices, we sought to shed light on the systemic fibrotic component of PVR and to evaluate the usability of APRI and FIB-4 as accessible biomarkers for proliferative vitreoretinopathy.

Materials and methods

Between January 2019 and October 2025, data from patients who underwent surgery for retinal detachment at the Department of Ophthalmology, Faculty of Medicine, Ondokuz Mayıs University, were retrospectively analyzed. The study included patients diagnosed with primary rhegmatogenous retinal detachment (RRD). Demographic data, preoperative liver function tests (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]), and platelet counts were recorded for all patients.

All participants underwent a comprehensive ophthalmological examination, including refraction measurement using an autorefractometer (KR 8100P, Topcon, Japan), best-corrected visual acuity (BCVA) assessment using the Snellen chart, intraocular pressure measurement with a Goldmann applanation tonometer, anterior segment examination by slit-lamp biomicroscopy, and dilated fundus examination following the administration of 1% cyclopentolate hydrochloride (Sikloplejin^®, Abdi İbrahim Pharmaceuticals, Istanbul, Turkey) three times at five-minute intervals. Visual acuity values obtained using the Snellen chart were converted to logarithm of the minimum angle of resolution (logMAR) units for statistical analysis. Symptom duration (days) was defined as the time interval between the onset of patient-reported visual symptoms (including decreased visual acuity, photopsia, or visual field defect) and the date of surgical intervention.

Preoperative visual acuity, macular status, extent of retinal detachment, and surgical techniques were recorded. Patients aged 18 years or older were included in the study. Exclusion criteria comprised traumatic retinal detachment, uveitis, retinal vasculitis, intraocular tumors, and a history of previous retinal surgery. In addition, patients with conditions that could influence laboratory parameters—including advanced liver disease (hepatitis, cirrhosis, alcoholic liver disease), hematological malignancies, bone marrow disorders, acute infection, or systemic inflammatory conditions that might affect APRI or FIB-4 calculations—were excluded from the analysis.

A total of 394 participants were included in the study: patients with retinal detachment accompanied by PVR (PVR (+) RD, n = 150), patients with retinal detachment without PVR (PVR (−) RD, n = 175), and healthy control subjects (n = 69). Healthy control subjects were selected from individuals with no known retinal pathology and no history of systemic inflammatory or hepatic disease. The diagnosis of PVR was established based on the presence of any PVR grade (A, B, or C) according to the Retina Society’s updated PVR classification system [13]. The collected data were analyzed to compare APRI and FIB-4 levels among the three study groups.

Systemic fibrosis indices were calculated using routine blood samples obtained from the antecubital vein. Two noninvasive fibrosis scores, APRI and FIB-4, were derived from serum aspartate aminotransferase, alanine aminotransferase and platelet count values.

The upper limit of normal for AST (AST _ULN) was defined as 40 U/L.

Statistical analysis

Statistical analyses were performed using IBM SPSS Statistics software (version 27.0; IBM Corp., Armonk, NY, USA). The distribution of continuous variables was assessed for normality using the Kolmogorov–Smirnov test. Continuous variables were expressed as mean ± standard deviation (SD) in normally distributed variables and median (min–max) in not normally distributed variables. For normally distributed variables, comparisons among groups were conducted using One-way analysis of variance (ANOVA). A Wilcoxon signed-rank test was performed to evaluate paired preoperative and postoperative visual acuity changes, and a Mann-Whitney U test was carried out to compare preoperative and postoperative VA between PVR (+) and PVR (−) groups. Binary logistic regression was used to identify independent factors associated with PVR development. A p-value of less than 0.05 was considered statistically significant.

Results

The mean age of the entire study population was 59.9 ± 13.2 years. Of the participants, 184 (46.7%) were female and 210 (53.3%) were male. Age distribution across the study groups showed a mean age of 61.25 ± 12.40 years in the PVR (+) RD group, 61.13 ± 11.68 years in the PVR (−) RD group, and 54.12 ± 16.76 years in the control group. No statistically significant difference in age was observed between the PVR (+) RD and PVR (−) RD groups (p = 0.81). Regarding diabetes mellitus, 82 patients (54.7%) in the PVR (+) RD group had diabetes mellitus, whereas only 42 patients (24.0%) in the PVR (−) RD group were diabetic.

In macular status evaluation, 246 patients (75.7%) presented with macular detachment, whereas macular attachment was preserved in 79 patients (24.3%). The mean number of retinal tears was 1.77 ± 1.51, and a single retinal tear was identified in 50% of cases. Multiple surgical procedures were performed in 72% of patients in the PVR (+) RD group, compared with 29% in the PVR (−) RD group.

The median preoperative logMAR visual acuity was 1.9 (1.4–2.4) in the PVR (+) RD group and 1.9 (1.0–2.4) in the PVR (−) RD group. No statistically significant difference in preoperative visual acuity was observed between the PVR (+) RD and PVR (−) RD groups (p = 0.677). Postoperative median logMAR visual acuity values were 0.9 (0.5–1.4) in the PVR (+) RD group and 0.5 (0.3–0.9) in the PVR (−) RD group. Postoperative visual acuity was significantly worse in the PVR (+) RD group compared with the PVR (−) RD group (p < 0.001). In matched pre- and postoperative analyses, a statistically significant improvement in visual acuity was observed in both the PVR (+) RD group and the PVR (−) RD group (p < 0.001, for both). However, postoperative logMAR visual acuity values remained significantly better in the PVR (−) RD group (p < 0.001). The mean number of surgical procedures was 1.95 in the PVR (+) group, whereas it was 1.33 in the PVR (−) group. The difference between the two groups was statistically significant (p < 0.001). Clinical and demographic characteristics of the study patients were presented in Table 1.

Table 1.

Clinical and demographic characteristics of the study patients

Variable	PVR (+) RD (n: 150)	PVR (−) RD (n: 175)	p value
Gender
Female, n (%)	84(56.0)	99(56.8)	p = 0.993**
Male, n (%)	66(44.0)	76(43.4)
DM
DM (+) n (%)	82(54.7)	42(24.0)	p < 0.001**
DM (−) n (%)	68(45.3)	133(76.0)
Macular Status
Macula on, n (%)	44(29.3)	35(20.0)	p = 0.068**
Macula off, n (%)	106(70.6)	140(80.0)
Visual Acuity
Preop LogMAR VA median (min–max)	1.9 (1.4–2.4)	1.9 (1.0–2.4)	p = 0.677*
Postop LogMAR VA median (min–max)	0.9 (0.5–1.4)	0.5 (0.3–0.9)	p < 0.001*
Number of Retinal Tears median (min–max)	1 (1–5)	1 (1–10)	p = 0.285*

RD; retinal detachment, PVR; proliferative vitreoretinopathy, VA; visual acuity, DM; diabetes mellitus

* Mann–Whitney U test

** Pearson chi-square test with Yates’ continuity correction

Comparison of FIB-4 and APRI values across the study groups revealed a mean FIB-4 score of 1.22 ± 0.80 in the PVR (+) group, 1.19 ± 0.83 in the PVR (−) group, and 0.98 ± 0.41 in the control group. Although the mean FIB-4 value was higher in the PVR (+) group compared with the other groups, this difference did not reach statistical significance (p = 0.062).

The mean APRI value was 0.21 ± 0.16 in the PVR (+) group, 0.19 ± 0.13 in the PVR (−) group, and 0.18 ± 0.09 in the control group. Similar to the FIB-4 findings, APRI values were higher in the PVR (+) group than in the other two groups; however, the difference was not statistically significant (p = 0.835) (Table 2).

Table 2.

Comparison of FIB-4 and APRI values among the three study groups

Variable	PVR (+) n (150)	PVR (–) n (175)	Control Group n (69)	p value
FIB-4 Mean ± SD	1.22 ± 0.80	1.19 ± 0.83	0.98 ± 0.41	0.062*
APRI Mean ± SD	0.21 ± 0.16	0.19 ± 0.13	0.18 ± 0.09	0.835*

PVR; proliferative vitreoretinopathy, FIB-4; Fibrosis-4 Index, APRI; Aspartate aminotransferase-to-platelet ratio index

*One-Way ANOVA

Macular status did not differ significantly between the PVR (+) and PVR (−) groups (p = 0.068). Inferior quadrant retinal detachments were observed significantly more frequently in the PVR (+) RD group than in the PVR (−) RD group (p = 0.024). In addition, the distribution of intraocular tamponade types differed significantly between the groups. Silicone oil tamponade was used significantly more frequently in the PVR (+) group, whereas SF6 and C3F8 gas tamponades were more commonly preferred in the PVR (−) group (p < 0.001).

In the multivariate logistic regression analysis, longer symptom duration was independently associated with proliferative vitreoretinopathy, with each unit increase in symptom duration corresponding to a higher likelihood of PVR development (OR = 1.035, 95% CI: 1.015–1.056; p = 0.001). Diabetes mellitus was also identified as an independent risk factor for PVR development (OR = 2.51, 95% CI: 1.22–5.17; p = 0.013). In addition, inferior rhegmatogenous retinal detachment was significantly associated with PVR development (OR = 0.48, 95% CI: 0.25–0.93; p = 0.029). Age, sex, macular status, APRI, and FIB-4 were not significantly associated with PVR development (Table 3).

Table 3.

Factors affecting PVR development in binary logistic regression analysis

Variable	B	S.E.	Wald	p value.	Exp(B)	95% CI Lower	95% CI Upper
Age	0.020	0.019	1.170	0.279	1.020	0.984	1.058
Sex	− 0.145	0.340	0.183	0.669	0.865	0.444	1.682
DM	0.921	0.369	6.235	0.013	2.511	1.219	5.173
Macular status	0.022	0.398	0.003	0.955	1.023	0.468	2.233
Symptom duration	0.035	0.010	11.663	0.001	1.035	1.015	1.056
Inferior RRD*	− 0.741	0.339	4.769	0.029	0.477	0.245	0.927
APRI	0.737	2.272	0.105	0.746	2.090	0.024	179.633
FIB-4	− 0.065	0.416	0.024	0.876	0.937	0.415	2.119
Constant	-1.986	1.159	2.936	0.087	0.137

APRI; Aspartate Aminotransferase–to–Platelet Ratio Index, FIB-4; Fibrosis-4 Index, DM; Diabetes mellitus, RRD; rhegmatogenous retinal detachment

*Retinal detachment quadrant was coded as inferior vs. non-inferior

Discussion

This retrospective study aimed to comprehensively evaluate the clinical, anatomical, and biochemical determinants that could influence the development of proliferative vitreoretinopathy in patients treated for retinal detachment. In addition to known risk factors such as the number and location of retinal tears, macular status, surgical requirements, and visual outcomes, the relationship between systemic fibrosis markers, including the Fibrosis-4 Index, the Aspartate Aminotransferase–Platelet Ratio Index, and PVR development, was investigated. Although APRI and FIB-4 levels did not demonstrate statistically significant differences among the three groups, a trend toward statistical significance was observed for FIB-4 values. Furthermore, mean APRI and FIB-4 values were higher in the PVR (+) group compared with the PVR (−) and control groups.

Given that FIB-4 and APRI are widely used biomarkers for the assessment of liver fibrosis, the question of whether these indices reflect intraocular fibrotic responses is of clinical relevance [14]. To our knowledge, this study represents one of the first comprehensive analyses evaluating the potential role of FIB-4 and APRI in the development of PVR. The findings suggest that, in addition to anatomical and surgical factors, systemic metabolic and inflammatory processes may also contribute to the pathogenesis of PVR.

The pathogenesis of PVR represents a complex wound-healing response involving multiple sequential steps, including the migration of RPE cells into the vitreous cavity, activation of glial cells, cytokine release, EMT, fibroblast proliferation, and ECM accumulation [15]. Numerous studies have demonstrated the pivotal roles of cytokines such as transforming growth factor-beta (TGF-β), platelet-derived growth factor (PDGF), interleukin-6 (IL-6), interleukin-8 (IL-8), and monocyte chemoattractant protein-1 (MCP-1) in PVR development [16]. Sustained activation of this inflammatory and fibrotic cascade leads to membrane contraction and increases the risk of recurrent retinal detachment [17–19].

FIB-4 and APRI are easy-to-administer, non-invasive tools that reflect fibrotic remodeling in multiple organs, primarily the liver. These indices have increasingly been applied in a wide range of clinical conditions, including cardiovascular diseases, renal failure, cerebrovascular events, metabolic syndrome, diabetic complications, and vascular predisposition, to estimate fibrosis risk [20, 21]. Previous studies investigating the association between retinal findings and systemic fibrosis markers have suggested that FIB-4 may be linked not only to hepatic fibrosis but also to retinal microvascular health [22]. For this purpose, retinal fundus images were examined using non-invasive markers of liver fibrosis such as FIB-4 [10]. Their analysis revealed that high FIB-4 values were associated with microvascular changes in the retina and demonstrated a systemic effect on retinal integrity. The scope of this study focused on widespread microvascular changes rather than localized fibroproliferative retinal conditions. However, evidence regarding the role of these systemic fibrosis markers in ocular fibrotic processes remains limited. Given that ECM accumulation, fibroblast activation, and TGF-β mediated profibrotic pathways play a central role in the pathogenesis of PVR, the potential utility of these indices—reflecting systemic fibrotic burden—as markers of susceptibility to PVR represents an important clinical question [23].

In our study, mean FIB-4 and APRI values were higher in the PVR (+) group; however, this difference did not reach statistical significance. This finding suggests that although proliferative vitreoretinopathy is primarily associated with intraocular inflammation and localized fibrotic responses, systemic fibrotic burden may have a modest contributory role. APRI and FIB-4 were originally developed to assess hepatic fibrosis and therefore may not fully reflect the microinflammatory environment and fibrotic remodeling occurring within ocular tissues. Nevertheless, the higher mean FIB-4 and APRI values observed in PVR (+) cases in our cohort indicate that systemic fibrosis markers may have a potential contributory role in the ocular fibrotic response. Although statistical significance was not achieved, these findings suggest that the contribution of systemic fibrotic burden to PVR development cannot be entirely excluded; rather, this relationship is likely multifactorial and indirect.

In addition to the local vitreoretinal mechanisms discussed above, diabetes mellitus represents an important systemic condition linking chronic inflammation, fibrotic pathways, and retinal pathology. Previous studies have shown that diabetes is associated with increased systemic inflammatory burden and altered fibrosis-related biomarkers, including APRI and FIB-4, which may influence retinal microvascular integrity and wound-healing responses [9, 10, 21, 22]. In the present study, diabetes mellitus was significantly more prevalent in the PVR-positive group and was identified as an independent risk factor for PVR development in multivariate logistic regression analysis. These findings suggest that diabetes may act as a systemic modifier contributing to the complex pathophysiology of PVR through inflammatory and profibrotic mechanisms and should therefore be considered an important confounding and contributory factor when interpreting the relationship between systemic fibrosis markers and PVR. Accordingly, we also evaluated established clinical predictors of PVR in our cohort.

In addition, longer symptom duration was independently associated with an increased risk of PVR development, which may reflect prolonged retinal detachment–related inflammation and sustained exposure of retinal pigment epithelial cells to the vitreous cavity. Delayed surgical intervention may therefore facilitate fibroproliferative responses that predispose to PVR formation [24]. Furthermore, inferior retinal detachment was significantly associated with PVR development, potentially due to gravitational effects, prolonged persistence of subretinal fluid, and increased accumulation of inflammatory mediators at the inferior vitreoretinal interface [25].

Our study has several limitations. First, the relatively limited sample size may have reduced the statistical power to detect significant differences, particularly among subgroups. Therefore, large-scale prospective studies are required to more clearly define the role of systemic fibrosis markers in the development of PVR. In addition, biomarker levels were assessed at a single time point; however, PVR is a progressive condition with a dynamic course over time, and longitudinal measurements might better reflect the stages of fibrotic response and temporal changes in biomarker levels. Moreover, this study focused exclusively on systemic fibrosis markers and did not evaluate the specific biochemical components of the intraocular microenvironment. Another limitation of this study is the lack of complete and standardized data regarding PVR severity for all cases, which precluded subgroup analyses based on PVR grade. Future prospective studies with systematic PVR grading may allow a more detailed evaluation of the relationship between disease severity and systemic fibrosis markers. Despite these limitations, our findings provide important preliminary evidence regarding the potential association between systemic fibrosis markers and PVR, highlighting an area that warrants further investigation with larger sample sizes and multi–time point biomarker analyses.

Conclusion

The results of this study suggest that the development of proliferative vitreoretinopathy is primarily driven by intraocular inflammatory and fibroproliferative processes occurring at the vitreoretinal interface rather than by systemic fibrotic status. Although no statistically significant differences were observed in APRI or FIB-4 levels between the study groups, the tendency toward higher mean values—particularly for FIB-4—in PVR-positive cases suggests that systemic fibrosis markers may have an indirect and contributory association with the disease process. Given the borderline statistical significance observed for FIB-4, larger prospective or multicenter studies may be required to better elucidate subtle systemic effects and to clarify the potential role of systemic fibrotic burden in PVR development. From a clinical perspective, these findings underscore the predominant role of local mechanisms in PVR formation and may help inform future studies focusing on risk assessment and personalized surgical approaches in retinal detachment.

Author contributions

EZK conceived the study design, collected the clinical and laboratory data, and drafted the initial version of the manuscript. NK conceptualized the study, contributed to the generation of the main research idea, provided scientific mentorship throughout the study process, and critically revised the manuscript for important intellectual content. EZK and NK jointly performed the statistical analyses and interpreted the results. Both authors reviewed and approved the final version of the manuscript and agree to be accountable for all aspects of the work.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethical approval

This study was conducted in accordance with the Declaration of Helsinki. Ethical approval was obtained from the Ondokuz Mayıs University Clinical Research Ethics Committee with a number of (2025/348).

Consent to participate

Informed consent was obtained from all individual participants included in the study.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.