Metabolic keratopathy is a general term for a group of diseases in which structural and functional changes occur in the cornea due to metabolic abnormalities. Abnormal accumulation of metabolites such as proteins, carbohydrates, and lipids in corneal tissue impairs transparency.
It includes both hereditary metabolic diseases caused by congenital enzyme deficiencies and acquired metabolic dysregulation represented by diabetes. Most hereditary metabolic diseases are autosomal recessive and caused by a single enzyme deficiency.
It is sometimes confused with corneal dystrophy, but they are distinguished by the following points:
Lesions extend not only to the central cornea but also to the peripheral cornea.
Changes occur in multiple layers of the cornea
Tends to progress over time
Diabetic keratopathy is the most common metabolic corneal disease in clinical practice, reported to occur in 47–64% of diabetic patients 3).
QHow is metabolic keratopathy different from corneal dystrophy?
A
Corneal dystrophy is a primary corneal tissue abnormality that mainly affects the central cornea. In contrast, metabolic keratopathy is a corneal change secondary to systemic metabolic disorders, presenting with extensive lesions including the peripheral cornea and involving multiple layers. It is often accompanied by systemic symptoms.
Subjective symptoms of metabolic keratopathy depend on the underlying disease and the degree of corneal damage. Mild deposits are often asymptomatic. As the condition progresses, patients notice decreased vision.
In diabetic keratopathy, reduced corneal sensitivity makes symptoms less noticeable. Dry eye symptoms (dryness, foreign body sensation) may occur 2). When corneal epithelial damage occurs, patients complain of pain, tearing, and photophobia.
In cystinosis, severe photophobia and blepharospasm due to corneal crystal deposits are characteristic.
Diabetic keratopathy findings are diverse. Punctate keratopathy, persistent corneal epithelial defects, and corneal edema are typical3). Decreased corneal endothelial cell density and increased pleomorphism are observed1). Confocal microscopy reveals decreased corneal nerve fiber density, shortened length, and reduced branching density2).
In mucopolysaccharidosis, types I (Hurler syndrome) and VI cause diffuse haze-like opacification of the entire cornea. This is due to deposition of mucopolysaccharides in the corneal stroma, while Bowman membrane and endothelium are spared. Types II and III generally do not show corneal opacification.
In Fabry disease, grayish whorl-like pigmentation (cornea verticillata) appears at the level of the corneal epithelial basement membrane from around age 6. Corneal opacity occurs in 50–80% of cases and is often observed in female carriers. The findings resemble corneal deposits caused by the antiarrhythmic drug amiodarone.
In Wilson disease, a yellow copper deposition (Kayser-Fleischer ring) is seen at the level of Descemet membrane in the entire peripheral cornea. It is present in 80–90% of patients and has high diagnostic value.
In cystinosis, corneal cystine crystals can be observed by slit-lamp microscopy from 16 months of age. They begin in the peripheral anterior stroma and extend to the full thickness.
Lysosomal storage diseases: Includes mucopolysaccharidoses, lipid storage diseases (Fabry disease, Gaucher disease, Niemann-Pick disease), mucolipidoses, and cystinosis. Enzyme deficiency leads to accumulation of substrates in systemic tissues.
Lipid metabolism disorders: LCAT deficiency, Tangier disease, Schnyder corneal dystrophy, etc. Lipids and cholesterol deposit in the corneal stroma.
Amino acid metabolism disorders: Tyrosinemia type 2 causes pseudodendritic corneal lesions. Alkaptonuria results in brownish oil-drop pigmentation of the cornea.
Copper metabolism disorders: In Wilson disease, impaired ceruloplasmin synthesis leads to copper deposition throughout the body. It is autosomal recessive and typically presents in the second to third decade of life.
Acquired Metabolic Disorders
Diabetes mellitus: Most common. Chronic hyperglycemia damages the corneal epithelium, nerves, stroma, and endothelium 3).
Chronic renal failure: Metastatic calcification and chronic inflammation cause calcium salt deposition in the cornea, leading to band keratopathy4). Leakage from the limbal vascular network is the mechanism of deposition 4).
Hyperlipidemia: Lipid deposition at the corneal limbus (arcus juvenilis) in individuals under 40 years suggests familial hypercholesterolemia.
QHow often does corneal damage occur in diabetic patients?
A
Diabetic keratopathy is reported to occur in 47–64% of diabetic patients 3). It manifests in various forms including epithelial damage, neuropathy, and endothelial dysfunction. Keratopathy may precede or occur simultaneously with retinopathy, and the two are not necessarily synchronized 1).
Slit-lamp microscopy: Evaluates the morphology, color, distribution, and depth of deposits. It is essential for confirming disease-specific findings such as vortex keratopathy in Fabry disease and Kayser-Fleischer rings in Wilson disease.
Confocal microscopy: Useful for evaluating corneal nerve fibers. In diabetic keratopathy, a decrease in nerve fiber density has been reported to precede retinopathy 2). In Fabry disease, intracellular inclusions can be observed.
The basis of treatment is management of the underlying disease and corneal disorders.
Treatment of the Underlying Disease
Diabetes: Strict glycemic control is most important.
Fabry disease: Enzyme replacement therapy with α-galactosidase is performed. It can reduce the appearance of vortex keratopathy.
Mucopolysaccharidosis: Enzyme replacement therapy is performed according to the disease type.
Wilson disease: Medical therapy to reduce serum copper or liver transplantation is performed.
Cystinosis: Oral cysteamine prevents progression of kidney and growth disorders. However, it is not effective for corneal cystine deposits.
Management of Corneal Disorders
Artificial tears: Use preservative-free formulations. Effective for diabetic dry eye.
Therapeutic contact lenses: Used for persistent corneal epithelial defects.
Corneal treatment for cystinosis: Cysteamine hydrochloride eye drops are effective for dissolving cystine crystals and reducing photophobia, but are not approved in Japan.
Corneal transplantation: Indicated for severe corneal opacity. Corneal transplantation may be effective in MPS types I and VI.
As topical treatment for diabetic keratopathy, the combination of substance P and IGF-1 is reported to improve corneal epithelial barrier function and promote wound healing 2). Cenegermin (recombinant human NGF) is a treatment option for neurotrophic keratopathy2).
For corneal lesions in tyrosinemia type 2, dietary restriction of tyrosine and phenylalanine from infancy is most effective.
QIs insulin eye drop effective for diabetic keratopathy?
A
Topical insulin eye drops have been reported effective for diabetic corneal epithelial defects in several studies 2). They promote corneal epithelial wound healing via the RTK-PI3K/Akt/mTOR pathway. However, this is not yet established as standard treatment and is still in clinical trials 2).
Diabetic keratopathy is caused by chronic hyperglycemia damaging all layers of the cornea. Multiple pathways are involved in its pathogenesis2)3).
Enhanced polyol pathway: Hyperglycemia activates aldose reductase, leading to sorbitol accumulation. This causes increased osmotic pressure and oxidative stress.
Accumulation of advanced glycation end products (AGEs): Non-enzymatic glycation of proteins promotes cross-linking of corneal collagen2). This increases corneal stromal stiffness and thickness1).
Activation of protein kinase C (PKC) pathway: Disrupts regulation of cell proliferation and differentiation.
Oxidative stress: Overproduction of mitochondrial superoxide causes DNA damage and reduced cellular antioxidant capacity2).
In the corneal epithelium, disruption of tight junctions, thickening of the basement membrane, and increased mucoid pemphigoid activity occur, leading to impaired epithelial barrier function3). In corneal nerves, small-diameter fibers (Aδ and C fibers) of the trigeminal nerve are damaged, reducing corneal sensitivity3). Loss of neurotrophic factors makes it difficult to maintain epithelial homeostasis.
The glucose content of tears reaches four times that of non-diabetic individuals1). Glucose content in the deep corneal stroma is higher than in the superficial layer, which is thought to cause white opacification in the deep stroma1).
In the corneal endothelium, decreased cell density, increased pleomorphism, and impaired Na⁺/K⁺-ATPase pump function occur, leading to corneal edema3). High HbA1c levels, long duration of diabetes, and progression of diabetic retinopathy are associated with decreased endothelial cell density3).
Corneal Pathophysiology in Congenital Metabolic Disorders
In lysosomal storage diseases, enzyme deficiencies cause undegraded substrates to accumulate within lysosomes, depositing in corneal stromal keratocytes and epithelial cells. In mucopolysaccharidoses, glycosaminoglycans (dermatan sulfate, heparan sulfate, keratan sulfate) accumulate in the corneal stroma, causing opacification. Glaucoma occurs due to increased resistance to aqueous humor outflow through Schlemm’s canal caused by abnormal accumulation of extracellular matrix in the trabecular meshwork.
In Fabry disease, deficiency of α-galactosidase leads to accumulation of globotriaosylceramide in corneal epithelial basal cells, forming a whorl-like deposition pattern.
In cystinosis, mutations in the cystinosin gene impair cystine transport from lysosomes, leading to accumulation of cystine crystals in cells throughout the body. Corneal deposition occurs by age 2.
QWhy does corneal sensitivity decrease in diabetes?
A
In diabetes, chronic hyperglycemia damages small-diameter fibers (Aδ and C fibers) of the trigeminal nerve3). Increased polyol pathway activity, accumulation of AGEs, and mitochondrial dysfunction reduce the density, length, and branching of corneal nerve fibers 2). Loss of neurotrophic factors also contributes to decreased corneal sensation.
Several nuclear proteins involved in the pathogenesis of diabetic keratopathy have been identified and are attracting attention as new therapeutic targets 3).
PPARδ expression is significantly reduced in the corneas of diabetic patients. Oral administration of fenofibrate, a PPARδ agonist, for 30 days was confirmed to promote corneal nerve fiber regeneration, reduce nerve edema, and improve density and width in 30 patients with type 2 diabetes 3).
HMGB1 expression is significantly increased in the corneas of diabetic mice. Inhibition of HMGB1 signaling by a micellar formulation of dipotassium glycyrrhizinate was reported to promote epithelial and nerve wound healing in diabetic corneas 3).
Topical administration of the PTEN inhibitor bpV(pic) promoted epithelial regeneration in diabetic corneas via reactivation of Akt signaling 3). Recovery of corneal nerve fiber density and corneal sensation was also confirmed 3).
Topical administration of calcitriol (active vitamin D₃) promoted wound healing and reinnervation in diabetic corneas through activation of Nrf2 antioxidant signaling and inhibition of the NLRP3 inflammasome 2).
Alpha-lipoic acid has been reported to reduce oxidative stress, inflammation, and apoptosis in corneal epithelial cells under high glucose conditions 2).
Overexpression of SIRT1 promoted diabetic corneal nerve regeneration via upregulation of miR-182. Overexpression of SIRT3 improved corneal wound healing under high glucose conditions through promotion of mitophagy 3).
EZH2 inhibitors (EPZ6438, 3-deazaneplanocin A) have been shown to suppress activation and fibrosis of corneal myofibroblasts in animal models 3).
Future challenges include further elucidation of the molecular mechanisms of these nuclear proteins and verification of efficacy in human clinical trials 3).
