Beyond the Cornea: Systemic Diseases and Their Impact on Endothelial Health—A Narrative Review

Background/Objectives: The corneal endothelium maintains corneal transparency through its barrier function and active pumping mechanism that regulates stromal hydration. Limited regenerative capacity makes these cells vulnerable to progressive cell loss. Although local ocular factors are well known, recent data suggest that numerous systemic diseases may contribute to endothelial dysfunction and reduce endothelial reserve before the onset of clinically apparent corneal pathology. The purpose of this narrative review is to synthesize current evidence on the impact of systemic diseases on corneal endothelial health and to highlight the underlying mechanisms and clinical implications. Methods: A narrative literature review was conducted using the PubMed, MEDLINE, and Google Scholar databases for articles published between January 2000 and December 2025. Observational studies, case series, and review articles that evaluated structural or functional changes in the corneal endothelium in association with systemic diseases were included. Results: Reviewed literature shows that several categories of systemic diseases are associated with signs of corneal endothelial stress. These changes include decreased endothelial cell density, increased cell size variability, reduced hexagonality, and, in some cases, increased central corneal thickness. Metabolic, cardiovascular, renal, autoimmune, and hypoxic conditions, as well as extracellular matrix disorders and aging, show consistent associations with these changes. Conclusions: Systemic diseases can compromise corneal endothelial integrity and reduce functional reserve even in the absence of clinically evident corneal pathology. Recognition of these associations underscores the importance of evaluating the patient’s systemic context, including a detailed medical history and corneal endothelial analysis, particularly before intraocular surgery.