This study, from the perspective of early intervention, explored a particular relationship between serum biochemical variables and corneal biomechanics through CCA among a relatively healthy adult population. Consistent with the hypothesis, the most significant association identified by CCA was between the corneal biomechanical characteristics, including A1t, A2t, and bIOP, and serum biochemical variables, including ALT and UA. The results show that people with increased ALT and UA would have lower IOP and corneas with slower A1, faster A2, and greater deformity.
During the corneal biomechanical measurement by CST, the cornea deforms under an air puff, and its response depends on corneal biomechanics, including elasticity, viscidity, and stiffness. Elasticity refers to the ability of the cornea to deform under an external force and to return to its original shape. Viscidity evaluates the corneal ability to dissipate external energy, and stiffness describes the corneal resistance against elastic deformation. When the cornea is exposed to the air puff and bends inward, a portion of the energy from the air puff is converted to elastic potential energy, and the other is dissipated due to the corneal viscidity. In addition to the air puff, IOP is another external force on the cornea; hence, the corneal response at A1 depends on corneal stiffness, viscidity, and IOP. When the cornea reaches the HC and rebounds outward, the elastic potential energy is converted to kinetic energy and dissipated through corneal viscidity. Therefore, the corneal response at A2 depends on corneal elasticity, viscidity, and IOP. The effect of external forces on the cornea is minimized at the HC, and HC-DeflA can reflect corneal stiffness. The results suggest that people with increased ALT and UA would have softer corneas with greater elasticity and viscidity. Although the correlation coefficients are not high, their significance in healthy populations still aids in deepening our understanding of the association between liver and kidney diseases and ocular lesions, especially during the preclinical phase, which is crucial for implementing primary preventive measures. For example, regular monitoring of ocular health is necessary for patients with liver and kidney diseases. Moreover, specific changes in eye diseases can also serve as an effective tool for risk stratification among individuals with liver and kidney dysfunction.
To the best of our knowledge, this study is the first to investigate the relationships between serum biochemical variables and corneal biomechanics. Previously, several studies have discussed the association between liver or kidney diseases and ocular disorders. Various congenital liver diseases have been reported to be associated with corneal changes,
15–17 especially those with cholestasis. Corneal ulcers and dry eye are common in chronic HBV and HCV patients.
6 CKD has been reported to be associated with AMD, DR, glaucoma, and cataract.
7 Patients with gout have been reported to have corneal endothelial changes.
18 Therefore, these studies indicate common pathologies of liver, kidney, and ocular changes. Moreover, Asaoka et al.
9 suggested that greater ALT and AST were associated with higher IOP, and Lee et al.
19 argued that an increasing AST/ALT ratio was one of the risk factors for the vertical cup-to-disc ratio. CKD patients with greater serum urea levels showed increased central corneal thickness and decreased endothelial cell density.
10 These studies demonstrate that existing liver or kidney diseases can lead to changes in the biomechanical properties of the cornea from a clinical perspective. Moreover, current study, focused on a relatively healthy population, also reveals a correlation between changes in corneal biomechanical indicators and serum biochemical markers for liver and kidney function. These findings hint at a potential link between the two systems in the early stages of disease, suggesting that alterations in one may reflect changes in the other, which could facilitate the early implementation of preventive and control measures.
Although the mechanism of the relationship between serum biochemical variables and corneal biomechanics remains unclear, it could be attributed to increasing oxidative stress. Glutathione (GSH) is an essential antioxidant that prevents cells from oxidative stress and maintains corneal hydration,
20 which is also vital for ocular tissues.
21 In the cornea, GSH is predominantly synthesized in corneal epithelium, whereas its accumulation in corneal endothelium largely depends on the uptake of GSH from the aqueous humor.
22 Although corneal biomechanics is mainly defined by the stroma, the corneal epithelium and endothelium can indirectly affect corneal biomechanics by regulating hydration.
5 ALT and AST play critical roles in producing glutamate, one of the precursor amino acids for GSH biosynthesis. Therefore, as the liver is the predominant source of GSH in plasma, liver diseases would influence corneal biomechanical properties by affecting the concentration of GSH.
23
In terms of urea, increasing urea levels induces the production of intracellular reactive oxygen species.
24 The level of urea in aqueous humor would increase with serum urea,
25 leading to corneal endothelial dysfunction.
26 Similarly, accumulated UA aggregates inflammatory response and inhibits nitric oxide production, arousing corneal endothelial changes.
27
Moreover, liver and kidney disorders are associated with increased levels of transforming growth factor β (TGF-β),
28 a kind of pro-inflammatory cytokines. Previous studies have suggested that TGF-β is increased in the aqueous humor of glaucoma patients, indicating a correlation between TGF-β and ocular changes.
29,30 TGF-β can promote the development of corneal fibroblasts into myofibroblasts. Corneal fibroblasts produce collagen and other ECM components that play critical roles in maintaining stromal integrity.
31 Because ECM components are determinants of corneal biomechanics, the relationship between serum biochemical variables and corneal biomechanics could be due to elevated TGF-β. Furthermore, TGF-β accumulated at the trabecular meshwork can contribute to the elevation of IOP,
32 in agreement with the association between bIOP and serum biochemical variables found in our study. Nevertheless, few studies have investigated the corneal biomechanical properties in patients with liver or kidney disorders, and further studies are necessary to clarify the relationship and underlying mechanisms.
Although the entire relationship was significant in both men and women, some nuances existed among the groups. HC-DelfA was only significantly associated with W
1 in men. Hormonal fluctuations could cause this divergence between genders. Previous studies have shown corneal biomechanical variations during the menstrual cycle,
33 indicating the influence of estrogen. Furthermore, AST and urea were slightly associated with V
1 in women, which could be attributed to the difference in corneal biochemical variables between genders.
The results identified A1DeflA and bIOP as suppressors in all groups, HC-t and AST as a suppressor in the whole population and men, HC-DeflA as a suppressor in women and men, and creatinine as a suppressor only in women. Although A1DeflA and bIOP were positively associated with W
1, their canonical coefficients were negative in the entire CCA model. This result suggests that A1DeflA and bIOP would be positively correlated with serum biochemical variables without consideration of other corneal biomechanical parameters. However, considering all of the canonical variables, the relationship between A1DeflA or bIOP and serum biochemical variables would be the opposite. Similarly, the other suppressors can be interpreted in this way. These results indicate interactions among corneal biomechanical characteristics, but further research is required to determine the exact relationships. For AST, the seemingly paradoxical relationship could be due to the AST/ALT ratio, whose high or low levels indicate liver disorders.
34
Through CCA, the results identified significant associations between serum biochemical variables and corneal biomechanics in both men and women, adding novel evidence of the relationship between liver or kidney disorders and ocular changes. Current study also pointed to a new direction for research on the pathophysiology and treatment of corneal biomechanical-related diseases.
There are several strengths of this study. First, we considered corneal biomechanics and serum biochemical variables as separate entities, which can help reveal the interactions between variables. Second, we included the basic dynamic corneal response parameters to avoid the bias introduced by other parameters calculated by algorithms, making the results easier to understand. However, the study still has some limitations. Because this was a cross-sectional study, we could not determine the sequence of changes in corneal biomechanics and serum biochemical variables. Furthermore, as the participants in the current study were enrolled from a single university with a limited age range, the results of the current study may not be extrapolated to other groups with different ethnicities or ages. Third, the study subjects were relatively healthy adults, but their serum indicators were not entirely within the normal range; however, these few deviations did not affect the purpose of the study but may have made the results more pronounced. Finally, this study took into account the effects of gender and refractive status and conducted subgroup analyses; however, it lacked consideration of other potential confounding factors such as age, lifestyle, and genetic predispositions, which should be controlled for in future studies.
In conclusion, this study suggests that greater ALT and UA are associated with softer corneas with greater elasticity and viscidity, providing new evidence for the relationship between serum biochemical variables and ocular changes. However, further studies are warranted to verify the relationship in other populations and to investigate the underlying mechanisms.