Corneal Manifestations of Systemic Diseases
ABSTRACT: Systemic diseases can sometimes be difficult to diagnose, particularly in their early stages, as symptoms are often nonspecific. In some cases, however, ocular manifestations may provide the first clues to an underlying condition; thus, it is essential for primary care providers to have an understanding of how systemic diseases can impact ocular health. In this article, the authors focus on the corneal manifestations of a variety of systemic illnesses, providing an overview of several metabolic, autoimmune/inflammatory, infectious, and endocrine disorders.
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Patients often seek an evaluation from their eye care professional if they are experiencing ocular symptoms, such as pain, dryness, visual disturbances, or ocular discomfort. They may also visit their eye care professional in the absence of symptoms for a routine ocular examination. Whether or not symptoms are present, the ophthalmologist or optometrist may discover corneal signs and ocular changes that are suspicious of systemic diseases. As such, he or she may be the first healthcare professional to identify systemic disorders. Corneal changes are often the most prominent findings that alert eye care practitioners to significant systemic diseases; therefore, it is important for eye care providers and primary care physicians to be aware of the significance of corneal changes and the possible relationship between these changes and a systemic disease process. One of the most common changes identified is the accumulation of a variety of deposits (eg, calcium, amyloid, copper), which generally collect in the cornea’s periphery first, and because of the cornea’s clarity and avascular nature, these deposits become visible during slit lamp examination. This article discusses important metabolic, inflammatory, infectious, and endocrine disorders that manifest corneal signs and highlights how a careful slit lamp examination may provide the key to early diagnosis and treatment of these assorted systemic disorders.
Metabolic Disorders
Metabolic disorders result from an insufficiency to catabolize lipids, carbohydrates, and amino acids. A deficiency in metabolism causes an accumulation of products, which may deposit in the blood, urine, and a wide array of organs, including ocular tissue. Patients often present with a variety of systemic symptoms, but corneal findings may be the presenting sign of a particular disease; therefore, a thorough ocular examination combined with careful consideration of symptoms can be key in making a prompt and early diagnosis of a potentially serious condition. In the section that follows, we review several metabolic disorders that have corneal manifestations, including Wilson’s disease, gout, cystinosis, Fabry disease, and hyperlipoproteinemia. Corneal manifestations are also possible for many other metabolic disorders, including mucopolysaccharidosis, mucolipidosis, and amyloidosis, but these will not be discussed.
Wilson’s disease. Wilson’s disease, also known as hepatolenticular degeneration, is a rare autosomal recessive disorder of copper metabolism and excretion that generally manifests in the first two decades of life.1 In the United States, the prevalence is reported to be 1 per 30,000 individuals.2 Patients with this disease have decreased production of ceruloplasmin, a major copper transport protein, as well as poor biliary copper excretion, which leads to an accumulation of copper in the liver and extrahepatic organs and causes systemic toxicity. Patients may present with a combination of hepatic, neurological, and psychiatric symptoms.3
During an ocular examination, eye care practitioners may observe Kayser-Fleischer rings, which are copper accumulations that form golden-brown or green rings in the deep corneal periphery (Figure 1). This finding is highly characteristic of Wilson’s disease and is correlated with the development of clinical neuropsychiatric symptoms (eg, difficulty speaking, masklike facies, excessive salivation, emotional lability) and systemic manifestations (eg, cirrhosis, hepatitis, fulminant hepatic failure).4 Specifically, Kayser-Fleischer rings are found in all cases with neurologic findings and in 70% to 90% of cases with liver disease.1 Once Wilson’s disease is diagnosed, treatment is initiated with copper-chelating agents (eg, D-penicillamine) to reduce the excessive amounts of circulating copper, preventing long-term complications and alleviating symptoms. Healthcare providers need to keep in mind, however, that copper deposition in the cornea may be found with other hepatic disorders and can sometimes be seen with multiple myeloma.5
Figure 1. Kayser-Fleischer ring in a patient with Wilson’s disease.
Gout. Gout is caused by elevated levels of uric acid in the blood due to either underexcretion or overproduction of uric acid. It is thought to result from genetic predisposition and dietary causes. Both the incidence and prevalence of gout have almost doubled between 1990 and 2010, with approximately 8 per 1000 persons currently affected in North America.6 Patients may be asymptomatic until the elevated serum urate precipitates into uric acid crystals in synovial fluid. This leads to painful attacks of inflammatory arthritis in the hands and feet. The metatarsophalangeal joint of the big toe is most commonly affected, and such an attack is referred to as podagra.7
Depositions of monosodium urate crystals, known as tophi, may deposit in tissues throughout the body, including the eyes. During an ocular examination, eye care practitioners may observe these deposits as fine, refractile yellow crystals in the corneal epithelium and stroma.7 These deposits may also appear in the episclera and sclera, leading to bouts of episcleritis or scleritis, both of which manifest as red eye. Additionally, tophi may be present in the conjunctiva, appearing as transparent vesicles containing refractile deposits. Other ocular findings may include subconjunctival hemorrhage as well as dilated and tortuous conjunctival and episcleral vessels.6 After gout is diagnosed, treatment is aimed at reducing the pain of the arthritic attacks. This often involves the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids and reducing the consumption of foods high in purines (these tend to be foods that are also high in protein, such as seafood, chicken, meat, and beans). If corneal deposits affect the patient’s vision, they may be removed via corneal scrapings.8
Cystinosis. Cystinosis is a rare, autosomal recessive lysosomal storage disease causing widespread deposition of cystine crystals throughout the body, especially the kidneys.8 The prevalence of this disease is approximately 1 in 100,000 to 1 in 200,000.9 Unlike other lysosomal storage diseases, cystinosis is purely cellular, with no corresponding elevation of plasma cystine levels.10 The deposition of crystals leads to multiorgan dysfunction, which can vary in severity. The most serious form, infantile nephropathic cystinosis, begins in utero and may cause loss of kidney function, failure to thrive, growth retardation, developmental delays, and rickets.10 Less common is the juvenile form, which presents later in life with less serious effects. Adult-onset cystinosis does not affect the kidneys and manifests solely as photophobia secondary to cystine deposits in the cornea.5 It is important to note, however, that multiple myeloma can also masquerade as a keratopathy, including corneal crystals of ocular cystinosis (Figure 2);thus, this condition should be considered in the differential diagnosis of patients presenting with corneal crystals.
Figure 2. Keratopathy in a patient with multiple myeloma.
Eye care practitioners may suspect a diagnosis of cystinosis based on their findings of painful corneal erosions; peripheral corneal neovascularization; punctate, filamentary, or band keratopathy; iris crystals; and/or retinal degeneration.10 Once diagnosed, prompt treatment is necessary to decrease intralysosomal levels of cystine. Administration of cysteamine should begin immediately and be continued for life. Treatment using cysteamine can be either oral or topical. This treatment has been shown to be effective in postponing the deterioration of renal function and preventing extrarenal complications. A careful follow-up schedule is necessary, including growth monitoring as well as slit lamp and fundus examinations.
Fabry disease. Fabry disease is an X-linked lysosomal storage disorder characterized by a deficiency in activity of the enzyme alpha-galactosidase A, leading to an inability to metabolize the glycolipid ceramide trihexoside. This causes progressive deposition of ceramide trihexoside within the lysosomes of different cells and organs, impairing their function.11 Fabry disease is estimated to occur in 1 in every 40,000 to 117,000 male live births.12 As an X-linked disease, Fabry predominantly affects males, but there is increasing recognition of disease-related complications in heterozygotic females. Due to the involvement of multiple tissues and organs, Fabry disease may have variable presentations, leading to misdiagnosis or delayed diagnosis. Patients may present with peripheral neuropathy, renal failure, benign skin lesions, and possible stroke and myocardial infarction.13
Ocular abnormalities occur mostly at the level of the conjunctival and retinal vessels, the crystalline lens, and the cornea. These abnormalities generally do not affect the patient’s vision, but may be detected on routine ocular examination, aiding in early diagnosis. The most common ocular finding in Fabry disease is cornea verticillata, also known as vortex keratopathy. This finding presents as bilateral whorl-like opacities located in the epithelium and subepithelial layers, more commonly in the inferior half of the cornea. These opacities are usually cream-colored, but may range from whitish to golden brown.12 Because corneal verticillata are extremely rare in individuals without Fabry disease, this finding is highly sensitive and specific for a diagnosis of Fabry disease, and it is the most commonly reported eye abnormality in both hemizygous males and heterozygotic females.12 Although it is considered the most significant ocular marker for diagnosis, several systemic medications may also cause whorl keratopathy (Table 1); therefore, any patient presenting with whorl keratopathy and not on one of the suspected medications should be evaluated for Fabry disease. Additional ocular signs of Fabry disease include dilation and tortuosity of conjunctival blood vessels and a posterior subcapsular cataract. Once diagnosed, treatment involves the use of enzyme replacement infusion therapy to reduce the risk of kidney failure, alleviate pain, and minimize the potential for myocardial infarction and stroke. In addition, patients should receive regular ocular examinations to monitor disease progression.
Hyperlipoproteinemia. The most common form of hyperlipoproteinemia is hypercholesterolemia, in which elevated levels of cholesterol circulate in the blood. The Centers for Disease Control and Prevention report that 13.4% of US adults (aged ≥20 years) have high serum total cholesterol levels.14 This may result in several transient or permanent ocular manifestations, which can be easily detected via ocular examination. Most notably, corneal arcus, which is a gray, white, or yellowish circumferential band in the periphery of the cornea caused by lipid infiltration of the corneal stroma; it does not affect the corneal limbus.
This sign is generally bilateral and is a normal finding in middle-aged and older individuals, for whom it is referred to as arcus senilis; however, in a patient younger than 40 years, corneal arcus is more suggestive of hyperlipoproteinemia and may denote an increased relative risk of coronary artery disease or cardiovascular disease.15 The extent and position of lipid deposition and the evolution of lipid keratopathy may be related to the extent of circulating lipids and lipoproteins. Therefore, detection of corneal arcus in a young patient warrants a careful physical examination that includes a systemic lipid evaluation. When identified, treatment may include the use of lifestyle interventions (eg, reducing cholesterol intake, engaging in regular exercise) and/or the use of various pharmacotherapies, such as statins and cholesterol absorption inhibitors.
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Autoimmune and Inflammatory Diseases
Inflammation is an active response to injured tissue. Autoimmunity occurs when cells are unable to recognize self from nonself, resulting in destruction of the body’s own tissues. Most patients develop symptoms from the inflammatory response, which often manifests in systemic and ocular tissues. Early recognition of the associated ocular signs can lead to early diagnosis and treatment of the underlying systemic disease. In the section that follows, we review rheumatoid arthritis, Wegener’s granulomatosis, systemic lupus erythematosus, and antiphospholipid syndrome, which are just a few of the autoimmune diseases that manifest with corneal signs.
Rheumatoid arthritis. Rheumatoid arthritis is a chronic inflammatory disease typically affecting the small joints of the hands and feet. Affecting more than 2 million people in the United States, rheumatoid arthritis is more common among women and is associated with a number of extra-articular organs, including the skin, lungs, blood vessels, and eyes.16 The most common ocular sign of rheumatoid arthritis is keratoconjunctivitis sicca, or dry eyes caused by a secretory (aqueous tear) deficiency. This can lead patients to feel burning, stinging, grittiness, and a foreign body sensation in their eyes. Keratoconjunctivitis sicca may be detected with tear production tests, such as the Schirmer tear test and corneal staining tests. Additional ocular findings include episcleritis, scleritis, and retinal vascular abnormalities.16 Some studies have also reported cases of corneal melt and necrotizing scleritis in patients with rheumatoid arthritis following cataract surgery, and have suggested that these findings in a healthy patient may be the first manifestation of occult systemic disease.17 Once identified, treatment is aimed at reducing joint inflammation and pain, maximizing joint function, and preventing joint deformity. This may include the use of aspirin and corticosteroids to reduce inflammation and pain, as well as disease-modifying antirheumatic drugs to prevent joint deterioration and deformity.
Wegener’s granulomatosis. Wegener’s granulomatosis, now more commonly referred to as granulomatosis with polyangiitis, is a rare inflammatory disease causing a systemic, necrotizing vasculitis. In the United States, it has an estimated prevalence of 3 cases per 100,000 people.18 Although Wegener’s granulomatosis can manifest at any age, it typically presents between the third and fifth decades of life, and it is most commonly observed in persons of northern European descent.18 The etiology of Wegener’s is unknown; however, environmental factors, including respiratory infections, have been thought to initiate granuloma formation.18 Because the condition manifests diverse and sometimes ambiguous findings, early diagnosis is often difficult, and ocular involvement may be the sole clinical indicator prior to systemic symptoms.19 Common ocular findings include proptosis, orbital pseudotumor, and nasolacrimal duct obstruction. Additionally, patients may present with vasculitis of the anterior or posterior segment of the eye, which may result in conjunctivitis, scleritis, episcleritis, and uveitis.19 One report in the literature described the case of a 62-year-old woman whose first presenting sign of Wegener’s granulomatosis was bilateral peripheral ulcerative keratitis, which was caused by vasculitic involvement of the limbal vessels at the corneoscleral junction. The presence of this ocular finding, along with multiple vague symptoms, were essential for making the diagnosis.19 Although upper airway disease is the most common presenting feature, ocular involvement is the presenting feature in 16% of patients.20 Therefore, although a rare condition, careful attention to the ocular findings may result in early diagnosis and prompt treatment of this potentially fatal inflammatory disease. Once diagnosed, treatment includes a combination of corticosteroids and cytotoxic agents, with a goal to manage the patient’s symptoms while minimizing long-term toxicity.
Systemic lupus erythematosus. Systemic lupus erythematosus (SLE) is a systemic autoimmune connective tissue disease with a wide variety of symptoms that affect many tissues and organ systems. In the United States, it has a reported prevalence of 20 to 150 cases per 100,000 persons, with prevalence rates varying between different races.21 SLE is more common among Asians, African-Americans, African-Caribbeans, and Hispanic Americans compared with Americans of European descent.21 Similar to rheumatoid arthritis and Wegener’s granulomatosis, ocular signs in SLE are not the most common findings, but may aid in diagnosis and early treatment of the condition. Prompt identification and intervention are essential, as the condition may result in corneal damage, visual impairment, and, ultimately, blindness if left untreated.22 Several ocular findings occurring in SLE include conjunctivitis, optic nerve involvement, retinal vessel occlusion, and scleritis.22 The most common ocular finding in SLE is an aqueous-deficient dry eye caused by secondary Sjögren’s syndrome (an inflammatory disease that most commonly affects the tear and salivary glands). Although the aforementioned findings are not specific to SLE, they warrant further investigation to elucidate the systemic cause. Once diagnosed, treatment is focused on managing symptoms. For mild cases, treatment may include NSAIDs for joint symptoms and pleurisy, corticosteroid creams for skin rashes, and a combination of hydroxychloroquine and low-dose corticosteroids for skin and arthritis symptoms. More severe cases may require high-dose corticosteroids and cytotoxic drugs to suppress the immune system and reduce inflammation.
Primary Sjögren’s syndrome. Primary Sjögren’s syndrome, which is characterized by dry eyes and dry mouth, occurs in people with no other rheumatologic diseases (unlike secondary Sjögren’s syndrome, which is commonly found in persons with other autoimmune disorders). Approximately 1 to 2 million people in the United States has the condition, with one study estimating the incidence of physician-diagnosed primary Sjögren’s syndrome to be about 4 cases per 100,000 persons.23 Most patients are middle-aged women.24
Ocular symptoms are common, and slit lamp signs are often consistent with severe dry eye. One large prospective cohort study that included 400 patients with Sjögren’s syndrome found that 93% had xerophthalmia.24 Early diagnosis of the condition is essential for proper treatment, as once the salivary and lacrimal glands are damaged following the autoimmune attacks, they are unlikely to respond to treatment. Additionally, an increased risk for non-Hodgkin lymphoma exists, with reports indicating that these patients have 40 times the risk of the general population.23 A new test, aptly named the Sjö test (www.nicox.com/index.php/en/products/dry-eye-panel), is available to facilitate early diagnosis using a proprietary panel of biomarkers. Once diagnosed, treatment includes balanced fluid intake, use of preservative-free artificial tears, punctal occlusion (a procedure that blocks the puncta to improve lubrication of the eyes), and/or use of oral agents such as pilocarpine (for dry mouth), oral corticosteroids, and immunosuppressants.
Antiphospholipid syndrome. Antiphospholipid syndrome is an autoimmune disorder characterized by a history of vascular thrombosis in association with antiphospholipid antibodies. Although the exact prevalence is unknown, the condition is estimated to affect 2% to 4% of the general population.25 It may occur independently in approximately 40% to 50% of patients, for whom the condition is referred to as primary antiphospholipid syndrome, or in combination with other autoimmune diseases, known as secondary antiphospholipid syndrome.25 Secondary antiphospholipid syndrome has been associated with systemic lupus erythematosus and Sjögren’s syndrome.26 Other risk factors for antiphospholipid syndrome include infections (eg, syphilis, human immunodeficiency virus [HIV]/acquired immunodeficiency syndrome [AIDS], hepatitis C, Lyme disease), use of certain medications (eg, hydralazine, quinidine, phenytoin, amoxicillin), and a family history of the syndrome.26 The systemic features of the disorder depend on the organs affected, which may include the skin, lungs, liver, kidneys, heart, and eyes.
Ocular signs in the anterior segment are numerous, including conjunctival vessel abnormalities, episcleritis, limbal keratitis, and filamentary keratitis. Posterior segment findings may include vitritis, retinal detachment, retinal vein occlusions, and retinal hemorrhages.27 Ocular signs as the first presenting features of antiphospholipid syndrome are uncommon, but have occurred and should alert the primary care physician to the possibility of this differential diagnosis. Once identified, treatment includes the use of anticoagulants (eg, warfarin, heparin, aspirin) to prevent thrombosis. Although several newer anticoagulants are available, including dabigatran, rivaroxaban, and apixaban, these have not been approved to treat antiphospholipid syndrome and it is not yet clear if they are appropriate for this condition.
Infectious Diseases
Infectious diseases can be devastating to ocular tissue. The onset of ocular symptoms is usually sudden and may include pain, photophobia, and red eyes; however, some infections produce symptoms that are more chronic in nature, complicating the route to diagnosis. Some infections presenting with corneal signs include HIV, diphtheria, onchocerciasis, adenovirus, varicella zoster, tuberculosis, and syphilis.28 What follows is an overview of the corneal signs manifested by the latter two life-threatening infectious diseases.
Tuberculosis. Tuberculosis, a chronic bacterial infection caused by Mycobacterium tuberculosis, affects approximately one-third of the global population.29 These organisms are acquired when airborne particles (also known as droplet nuclei) carrying M tuberculosis are inhaled and become trapped in the alveoli of the lungs. Once in the lungs, these organisms may gain access to the lymphatic system and blood vessels, enabling dissemination to different sites of the body, including the eyes.
Ocular signs of tuberculosis infection may include lid abnormalities (eg, lupus vulgaris [usually in children], cold abscess mimicking a chalazion), conjunctivitis, episcleritis, scleritis, interstitial keratitis, corneal phlyctenules, chronic granulomatous uveitis, and phlyctenular keratoconjunctivitis (Figure 3).29 The absence of lung involvement does not rule out tuberculosis as a potential diagnosis for these findings, as approximately 60% of patients with extrapulmonary tuberculosis have no pulmonary findings29; thus, the presence of these ocular findings, especially in children or immunocompromised patients, may warrant a careful clinical examination. Treatment of tuberculosis varies, depending on if the disease is latent or active; however, the most commonly used agents for either condition include isoniazid, rifampin, ethambutol, and pyrazinamide, with patients generally receiving 6 to 9 months of treatment.
Figure 3. Phlyctenular keratoconjunctivitis in a patient with tuberculosis.
Syphilis. Syphilis is caused by the spirochete bacterium Treponema pallidum, which is predominantly spread through sexual contact (acquired syphilis), but can also be passed from mother to child during fetal development and birth (congenital syphilis). Between 2005 and 2013, the rate of reported acquired syphilis in the United States was 5.3 cases per 100,000 adults, and between 2009 and 2010, the rate of reported congenital syphilis was 8.7 per 100,000 US live births.30 Although clinical signs and symptoms of congenital syphilis can be present at birth, they generally manifest between the ages of 5 and 20 years and are twice as common in females as in males.28
The most common ocular finding in congenital syphilis is interstitial keratitis, presenting with peripheral stromal infiltration, central deep stromal infiltration with edema, or multiple stromal infiltrates.28 Symptoms include pain, tearing, photophobia, and red eyes. Vascularization can occur, progressing into the central cornea and later regressing to become nonperfused vascular channels, which are sometimes referred to as ghost vessels.31 Although a common finding, interstitial keratitis is not specific to congenital syphilis, and may be associated with other infectious conditions (Table 2). Acquired syphilis less commonly causes interstitial keratitis, but may be associated with other anterior segment findings, such as conjunctivitis, keratitis, ciliary injection, and iritis.32 If syphilis is suspected, serologic testing should be performed, including a venereal disease research laboratory test or rapid plasma regain among others, due to the serious nature of the disease. In general, if syphilis is caught early, it can be easily treated and cured with an intramuscular injection of penicillin. Although this same treatment can often cure the disease even in its later stages, the damage inflicted cannot be undone; thus, prompt diagnosis and treatment are essential.
Endocrine Disorders
Ocular changes are common in various endocrine disorders, including diabetes mellitus, parathyroid dysfunction, and many less common conditions (eg, Addison’s disease). Awareness of these associations is the first step in diagnosing and treating these complicated conditions. What follows is an overview of the corneal changes associated with diabetes mellitus, hyperthyroidism, hyperparathyroidism, and Addison’s disease.
Diabetes mellitus. Ocular changes in diabetes have been thoroughly studied. Metabolic, neuropathic, and vascular tissue damage leads to an inflammatory process and functional degeneration of ocular tissues,33 which can lead to blindness. Approximately 12,000 to 24,000 new cases of blindness are attributed to diabetic retinopathy annually,34 which is the most commonly recognized ocular complication of diabetes; however, corneal and other ocular tissue can also be affected. Although not the most common findings, corneal and anterior segment changes have been observed in patients with diabetes. Clinical studies have revealed an association between diabetes and ocular surface alterations such as dry eyes. Chronic tear secretion deficiency, peripheral neuropathy, and hyperglycemia can lead to a variety of complications, including punctate keratopathy, recurrent corneal erosions, persistent epithelial defects, delayed wound healing, and an increased risk of microbial keratitis.33 Additionally, patients with diabetes may experience neurotrophic keratopathy, where loss of corneal innervation leads to degeneration of anatomic integrity and function.35 Commonly caused by diabetes, neurotrophic keratopathy is also associated with ocular herpes zoster, ocular herpes simplex, trauma, contact lens wear, and ocular surgery.35 In some cases, patients may present to the eye care practitioner reporting dry eyes and foreign body sensation, or in the case of neurotrophic keratopathy, may have an absence of symptoms altogether. Once the corneal changes are known to result from diabetes, ocular treatment includes the use of artificial tears for those with mild disease and prophylactic antibiotics and surface protection (eg, tarsorrhaphy, amniotic membrane graft, bandage contact lenses) for those with ulcerations. In addition, the patient’s blood glucose levels need to be monitored and regulated to prevent further complications.
Hyperthyroidism. Hyperthyroidism results in excessive thyroid hormone levels and is usually caused by an underlying thyroid disorder, such as Graves’ disease, goiters, or thyroiditis. The condition is much more common in women than in men, with a reported prevalence of 100 cases per 100,000 women versus 33 cases per 100,000 men.36 Hyperthyroidism presents with several ocular signs and symptoms. Graves’ ophthalmopathy, also known as thyroid-associated orbitopathy, is an autoimmune disorder that affects the orbit and causes lid retraction and lag, lid and conjunctival swelling, and redness.31,37,38 Proptosis and an inability to close the eyes completely are not uncommon and can result in significant corneal exposure and resultant irritation. Nonspecific symptoms include photophobia, tearing, and blurred vision. Another condition that is almost always associated with thyroid dysfunction is Theodore’s superior limbic keratoconjunctivitis (Figure 4). Patients with this condition typically present with burning, redness, and irritation that progresses over time. Once hyperthyroidism is diagnosed, primary treatment starts with thyroid hormone level regulation and smoking cessation.37 Mild ocular involvement can be treated topically by simply using supportive therapy (eg, artificial tears). The use of supplements containing selenium may improve the condition.39 More advanced ocular involvement requires the use of steroids (oral, periorbital, or intravenous), occasional radiation to the orbit, and even decompression surgery when the optic nerve is at risk. Immunosuppressants (eg, rituximab) coordinated by a rheumatologist should be considered for refractory cases.39
Figure 4. Theodore’s superior limbic keratoconjunctivitis in a patient with an elevated thyroid peroxidase level.
Hyperparathyroidism. Hyperparathyroidism results when the parathyroid glands are overactive, resulting in excess production of parathyroid hormone. It can be classified as primary or secondary. The primary form results when the parathyroid glands become enlarged, causing hypercalcemia, whereas the secondary form results from an underlying disease that results in hypocalcemia. The etiology of primary hyperparathyroidism is often unclear, but certain risk factors have been identified, including postmenopausal status, long-term calcium and vitamin D deficiency, radiation exposure to the neck, and use of lithium.40 In the United States, approximately 100,000 persons develop hyperparathyroidism each year, with women twice as frequently affected as men.41
Figure 5. Band keratopathy in a patient with known parathyroid dysfunction.
Primary hyperparathyroidism may present with significant ocular manifestations. Increased levels of plasma calcium may lead to scleritis, conjunctival calcification, and conjunctivitis. The most commonly reported ocular manifestation of hyperparathyroidism is band keratopathy (Figure 5), a corneal degeneration characterized by the deposition of calcium at the level of Bowman’s layer.37 These deposits are grey or white and are located within the palpebral fissure, separated from the limbus by an area of clear cornea. The band may have a ‘Swiss cheese’ appearance, with holes within the band representing corneal nerves penetrating through Bowman’s layer.38 Although a common finding in hyperparathyroidism, band keratopathy is also associated with other conditions (Table 3). Once diagnosed, treatment decisions are based on a variety of factors, including the patient’s serum calcium levels, kidney function, bone density, and symptoms. Based on the severity of the disease, it may include watchful waiting (if the aforementioned factors are fine), surgery to remove any enlarged parathyroid glands, or pharmacotherapy with calcimimetics, bisphosphonates, and/or hormone replacement therapy.
Addison’s disease. Addison’s disease, also known as primary adrenal insufficiency, is characterized by primary hypoadrenalism, which may be autoimmune or infectious in nature or due to congenital adrenal hypoplasia.37 The condition is extremely rare, with a reported prevalence of 93 to 140 per million people and an annual incidence of 4.7 to 6.2 per million people in Western populations; however, there is some indication that the condition is often missed and may therefore be more prevalent than previously thought.42 This is likely attributable to the disease’s nonspecific clinical features, which include weakness, fatigue, nausea, abdominal pain, and joint pain. Although ocular findings are rare, they may facilitate an early diagnosis when identified.
Ocular findings may include corneal ulcers and keratoconjunctivitis resulting in extreme photophobia, as well as episcleritis, ptosis, blepharitis, and cataract formation.37 Once identified, treatment may include oral or injectable corticosteroids or androgen replacement therapy to correct the patient’s hormone levels.
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Take-Home Message
It is important for all primary care providers to recognize that many systemic diseases have ocular manifestations. Armed with this knowledge, they can refer patients for careful ocular examinations, which can reveal subtle diagnostic clues, which may be the first presenting sign of a serious systemic and potentially life-threatening condition. Although many corneal and other anterior segment findings are not specific to a particular systemic disease process, when they are associated with systemic symptoms, these findings may provide practitioners with valuable information. For example, it may enable them to determine which additional tests to order, facilitating accurate and early diagnosis and treatment. When systemic diseases are identified early, morbidity and mortality are minimized and the patient’s quality of life is improved. ■
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