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Endocrine Disease and the Cornea
Key Concepts
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Diabetes mellitus affects all layers of the cornea, both morphologically and biochemically.
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The epithelium of diabetics is more prone to damage and recurrent erosions and exhibits delayed healing compared with nondiabetics.
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Diabetes changes the biomechanical properties of the corneal stroma.
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The endothelium is under more stress and has decreased reserves in patients with diabetes.
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Syndromes that feature hypoparathyroidism and associated corneal findings include autoimmune polyendocrinopathy syndrome, type 1; Kenny-Caffey syndrome, type 1; and hypoparathyroidism-retardation-dysmorphism syndrome.
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Hyperparathyroidism and associated hypercalcemia can lead to calcium deposition in the conjunctiva, cornea, and anterior chamber.
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Corneal findings in Graves disease include exposure keratopathy, keratoconjunctivitis sicca, and superior limbic keratoconjunctivitis.
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An important early diagnostic sign in multiple endocrine neoplasia 2b is prominent corneal nerves.
Diabetes Mellitus
Diabetes mellitus is the most common endocrine disorder an ophthalmologist will encounter. The anterior segment findings of this disorder are less extensively described than the retinopathy. Before the 1970s, descriptions of diabetic changes in the anterior segment included conjunctival microaneurysms, ectropion uveae, an increased incidence of Descemet folds, and pigment deposition on the corneal endothelium, anterior iris surface, and trabecular meshwork. Extensive corneal pathology was not noticed. However, in the 1970s, Schwartz and Hyndiuk noted a decreased corneal sensitivity and sterile neurotrophic corneal ulcers in diabetics. The advent of vitrectomy heightened interest in the diabetic cornea because diabetics were found to have increased problems with epithelial healing and stromal edema after vitrectomy. Since this time, research has focused on the biochemical and anatomic changes in the cornea.
Biochemistry
Past studies of the biochemistry of the diabetic cornea have examined the role of the sorbitol pathway. In this pathway, glucose is metabolized to sorbitol by aldose reductase and further to fructose by sorbitol dehydrogenase. More recent studies have focused on factors that can alter cell adhesion and tissue repair. Findings include changes in the adhesive molecules of the extracellular matrix and basement membrane. The induction of other pathologic pathways, such as generation of reactive oxidative stress (ROS), advanced glycation end products (AGEs), and protein kinase C activation as the pathogenesis for anterior segment disease in diabetics, has been explored. ,
Animal Studies
Many investigators have identified the presence of aldose reductase and by-products of the sorbitol pathway in various animal models, including in the corneal epithelium and endothelium of dogs, the corneal epithelium of normal and diabetic rabbits, and the corneal endothelium of rats.
The next level of investigation focused on whether aldose reductase inhibitors could improve epithelial healing problems in diabetic animals. Reepithelialization of corneal defects occurred faster in one study when animals were treated with an aldose reductase inhibitor. Another study compared morphologic changes in rats treated with and without aldose reductase inhibitors. The epithelium of treated rats not only healed more quickly, but also showed a thicker multilayered epithelium. Untreated rats had an irregularly shaped epithelium that was not as transparent. Finally, endothelial changes were less significant in diabetic rats treated with aldose reductase inhibitor compared with controls. ,
Despite these studies, questions remain about precisely how the sorbitol pathway contributes to abnormalities. Unlike diabetes-induced cataract formation, osmotic forces do not seem to be important. , In addition, not all studies demonstrate abnormal epithelial healing in diabetic animals or find high enough levels of by-products of the sorbitol pathway to account for problems.
A heterogeneous chemical substance, known as AGEs, has been found in all layers of the cornea in diabetic monkeys. Their presence is thought to be a result of prolonged hyperglycemia and superimposed oxidative stress. These substances can cause changes in the structure of various proteins, including crosslinking of collagen fibers.
The accumulation of AGE in the corneal epithelium further promotes proapoptotic and antiproliferative local cell signaling pathways. A marker of oxidative stress, 8-hydroxydeoxyguanosine, was increased in the diabetic rat cornea in an experimental study, suggesting the possible role of oxidative stress in the apoptosis of diabetic corneal cells.
Corneal edema was observed in diabetic rats. The thickness of cornea was higher than in control rats. AGEs accumulated in corneal tissues. The expression of 8-hydroxy-2’-deoxyguanosine and nuclear factor-κB, which were identified in corneal epithelium, stroma, and endothelium, was greater in diabetic than in that of control rats. Diabetes induced significant alterations in rat corneal tissue structure.
Degradative enzymes known as matrix metalloproteinases are elevated in healing corneal epithelium of diabetic rats as compared with controls. This finding suggests that these enzymes are responsible for the slowed epithelial healing in a high glucose state. Finally, cytokines and Ki-67-positive cells are increased as corneal epithelial wounds heal in rats with type 2 diabetes (Goto-Kakizaki rats). , Changes in the structural and proliferative capacity of the epithelial cells result.
An experimental study revealed a high concentration of antigen-presenting cells including Langerhans cells and dendritic cells in the cornea and aggregation of the cells around corneal nerve fibers of a diabetic mouse model. There was a negative correlation between the number of dendritic cells and corneal nerve fiber density, suggesting the possible role of inflammation in the development of corneal neuropathy in diabetes mellitus.
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