Peripheral Pigmented Corneal Ring: A New Finding in Hypercarotenemia

Carotenoids, specifically β-carotene, are the major source of vitamin A in the diet. β-Carotene is present in vegetables or may be taken as a single dietary supplement (beta carotene), sometimes combined with other vitamins and antioxidants. In humans, the conversion of β-carotene to vitamin A occurs in the small intestine. The daily vitamin A requirement is 2500 IU, which is equivalent to approximately 1.5 mg of beta carotene. β-Carotene is absorbed from the intestine and is primarily stored in liver and adipose tissue. It has been approved by the Food and Drug Administration as a color additive and is generally recognized as safe as a dietary supplement.¹

Studies in animal models have examined the effects of excessive intake of beta carotene with regard to its potential carcinogenicity, mutagenicity, embryotoxicity, effects on reproductive functions, and as a cause of hypervitaminosis A.² Data from both human and animal studies indicate that excessive consumption of beta carotene increases the serum β-carotene level but does not result in hypervitaminosis A. A regulatory process exists, such that a higher level of vitamin A triggers a reduction in the conversion process. Thus, high doses of beta carotene are safe, and doses of 30 to 180 mg/d taken for more than 15 years have no adverse effects.^3,4

Epidemiological studies have associated low dietary and/or plasma levels of carotenoids with a higher incidence of certain types of cancer.^5-7 The beta carotene supplement has been used in large clinical trials in an attempt to reduce the risk of cancer, ^8-10 cardiovascular disease, ¹⁰ and age-related macular degeneration.^11,12 Two of the studies have raised questions regarding the safety of beta carotene supplements in people who smoke due to a paradoxical increase in the risk of lung cancer among those who smoke and take beta carotene.^8,9 We describe ocular findings in 3 patients with hypercarotenemia, which, to our knowledge, have not previously been described.

Case 1. A 43-year-old white woman who was treated with laser photocoagulation for proliferative diabetic retinopathy and macular edema more than 10 years previously complained of floaters and occasional flashes. She had a history of hypertension, diabetic nephropathy, and poorly controlled diabetes. She had consumed 1 to 2 lbs of carrots per day during the past 10 years. Her medications included insulin, atorvastatin, famotidine, fosinopril, furosemide, and an estrogen/medroxyprogesterone combination agent. Estimates of her carotenoid intake based on daily consumption of carrots are as follows: 53.8 mg/d of beta carotene (range, 12.5-100.1 mg/d), 24.5 mg/d of alpha carotene (range, 3.6-57.9 mg/d), and 1.8 mg/d of a lutein-zeaxanthin combination.¹³

On examination, the patient had a best-corrected visual acuity of 20/30 OU. The external examination showed a yellow discoloration of the skin, most prominent in the palms. There was no evidence of scleral icterus. The pupils were equal and reactive to light. The slitlamp examination revealed a circumferential orange-yellow pigment deposit in the peripheral cornea. The deposits were heaviest in the deep stroma and extended approximately 1.5 mm from the limbus. They were more prominent superiorly and inferiorly (Figure 1 and Figure 2).There was no clear zone present at the limbus, and there was no evidence of corneal edema or corneal vascularization. The intraocular pressure was normal in each eye. The patient had retinal photocoagulation scars and old vitreous hemorrhage, without active neovascularization. There were fine refractile crystals deposited in the macular area of both eyes. The rest of the results of the ocular examination were unremarkable.

Laboratory evaluation showed a serum α-carotene level of greater than 0.50 µmol/L; normal range, 0.02-0.23 µmol/L; β-carotene: 80.6 µg/dL; normal range, 4.30-43.0 µg/dL (>1.50 µmol/L[normal range, 0.08-0.80 µmol/L]); glucose: 206 mg/dL (11.4 mmol/L); aspartate aminotransferase (SGOT): 75 U/L; normal range, 0-40 U/L; alanine aminotransferase (SGPT): 104 U/L; normal range, 0-48 U/L; alkaline phosphatase: 131 U/L; normal range, 30-115 U/L; albumin: 3.1 g/dL; normal range, 3.5-5.0 g/dL (31 g/L [normal range, 35-50 g/L]); total bilirubin: 0.6 mg/dL; normal range, 0.3-1.2 mg/dL (10.26 µmol/L [normal range, 5.13-20.52 µmol/L]); and direct serum bilirubin: 0.0 mg/dL; normal range, <0.2 mg/dL (<3.4µmol/L).

Case 2. A 78-year-old African American woman with a history of cataract and macular hole in the right eye had consumed 2 packages of Life Pack Prime (Pharmanex, Provo, Utah) and 1 capsule of Tegreen⁹⁷ (Pharmanex) per day for 2 years. Each pack of Life Pack Prime contained 7500 IU of vitamin A, 67% as beta carotene (equivalent to 4.5 mg of beta carotene), 4.5 mg of a carotenoid blend other than beta carotene (2.5 mg of lycopene, 1 mg of alpha carotene, and 1 mg of lutein), and 150 IU of vitamin E. Each capsule of Tegreen⁹⁷ contained 250 mg of green tea leaf extract. The patient reported eating a small and variable amount of carrots each day but her dietary history was not consistent. She also had a history of surgery for intracranial meningioma, a seizure disorder, Parkinson disease, hypothyroidism, hypercholesterolemia, and bladder dysfunction. Her medications included atorvastatin, thyroxine, tolterodine, metoprolol, carbamazepin, selegiline, and a carbidopa/levodopa preparation. Estimates of her carotenoid intake based on her daily supplements consumed are as follows: 9 mg/d of beta carotene, 2 mg/d of alpha carotene, 5 mg/d of lycopene, and 2 mg/d of lutein.

On examination, the patient had a best-corrected visual acuity of 20/40 OD and 20/50 OS. The external examination revealed yellow discoloration of the skin, most prominent in the palms. There was no evidence of scleral icterus. The pupils were equal and reactive to light. The slitlamp examination revealed a circumferential yellow-orange pigment deposit in the peripheral cornea and mild nuclear cataract. The deposits were present within the full thickness of the stroma, with no clear zone at the limbus. There was no evidence of corneal edema or vascularization. The intraocular pressure was normal in each eye. The fundus examination showed a spontaneously sealed macular hole in the right eye and pigmentary changes in the left macula. There were fine crystals deposited in the perifoveal area of both eyes, more prominent in the right eye. The rest of the results of the ocular examination were unremarkable.

Results of laboratory tests showed a serum α-carotene level of 2.35 µmol/L (normal range, 0.02-0.23 µmol/L); beta carotene: 324.7µg/dL (normal range, 4.30-43.0 µg/dL) (6.04 µmol/L [normal range, 0.08-0.80 µmol/L]); vitamin E: 2.0 mg/dL (normal range, 0.5-1.8 mg/dL) (46 µmol/L [normal range, 12-42 µmol/L]); glucose: 85 mg/dL(4.72 mmol/L); aspartate aminotransferase (SGOT): 30 U/L (normal range, 0-40 U/L); alanine aminotransferase (SGPT): 11 U/L (normal range, 0-48 U/L); alkaline phosphatase: 82 U/L (normal range, 30-115 U/L); albumin: 4.0 g/dL (normal range, 3.5-5.0 g/dL) (40 g/L [normal range, 35-50 g/L]); total bilirubin: 0.7 mg/dL (normal range, 0.3-1.2 mg/dL) (12 µmol/L [normal range, 5-21µmol/L]); and direct serum bilirubin: 0.0 mg/dL (normal range, <0.2 mg/dL) (<3.4 µmol/L]). Seven months later, the findings in the cornea were unchanged despite several months without vitamin/carotenoid supplements.

Case 3. A 35-year-old white woman with a history of corneal scar in both eyes, myopia, and a peripheral retinal hole admitted to eating 1 to 1.5 lbs of carrots each week for several years. She also had a history of taking 6 capsules of 100% Vegetarian Evening Primrose Oil (Health From The Sun, Bedford, Mass) and 1 soft gel of TruNature Grape Seed Extract (Leiner Health Products, Carson, Calif) per day for 3 months. Each capsule of 100% Vegetarian Evening Primrose Oil contained 50 mg of gamma-linolenic acid, 365 mg of linoleic acid, and 30 mg of oleic acid. Each softgel of Tru Nature Grape Seed Extract contained 100 mg of grape seed extract. Her medical history was unremarkable and she took no additional medications. Estimates of her carotenoid intake based on daily carrots and supplements consumed are as follows: 6.3 mg/d of beta carotene(range, 1.4-11.8 mg/d), 2.9 mg/d of alpha carotene (range, 0.4-6.8 mg/d), and 0.2 mg/d of a lutein-zeaxanthin combination.¹³

An examination showed a best-corrected visual acuity of 20/25 OD and 20/20 OS. The external examination revealed mild yellow discoloration of the skin. There was no scleral icterus. The pupils were equal and reactive to light. The slitlamp examination revealed a deep stromal, reticular, yellow-brown pigment deposit in the peripheral cornea. The deposits were most prominent in the superior cornea and extended up to 1.5 mm from the limbus (Figure 3). No clear zone was present at the limbus. There was no evidence of corneal edema or corneal vascularization. There were a few anterior stromal scars in the periphery of each cornea. The anterior lens capsule of each eye had a diffuse yellow-brown discoloration(Figure 4). The intraocular pressure was normal in each eye. The fundus examination showed a peripheral retinal hole in the left eye, surrounded by laser scars. No crystals were seen in the macula. The rest of the results of the ocular examination were unremarkable.

Laboratory tests showed a serum α-carotene level of 0.60 µmol/L; normal range, 0.02-0.23 µmol/L; β-carotene: 76.3 µg/dL; normal range, 4.30-43.0 µg/dL (1.42 µmol/L [normal range, 0.08-0.80 µmol/L]); and copper: 887 µg/dL; normal range, 700-1750 µg/dL (139.6 µmol/L[normal range, 110.2-275.5 µmol/L]). Serum liver enzyme and bilirubin levels were normal. Five months later, the findings in the cornea and anterior lens capsule were unchanged despite several months without ingestion of carrots or vitamin supplements, but her skin discoloration was less prominent.

With the recent proof of the benefit of antioxidants (including beta carotene) and zinc in preventing the progression of dry age-related macular degeneration, and with the widespread use of antiaging formulations and vitamins containing carotenoids, many patients may be expected to have high levels of carotenoids in their diet.^11,12 The patients in this report had physical signs and abnormal laboratory test results consistent with hypercarotenemia, including yellow discoloration of the skin. Yellow skin is most frequently associated with hyperbilirubinemia but may be caused by lycopenemia, riboflavinemia, hypercarotenemia, or ingestion of certain chemicals, such as canthaxantine (a carotenoid), fluorescein, saffron, and quinacrine. The unusual ocular findings in our patients were the pigment deposition in the peripheral cornea, retinal crystals near the fovea (cases 1 and 2), and pigmentation of the anterior lens capsule (case 3).

The peripheral cornea's transparency and proximity to the limbal circulation make it more susceptible to deposition of abnormal material from the blood. Different chemicals and substances may deposit at various levels of the cornea. The pattern, color, and depth of the deposit are often characteristic and guide the differential diagnosis. Many of the soluble chemicals may deposit in the deep stroma or at the level of the Descemet membrane.

Copper has an affinity for basement membranes and is deposited in the peripheral cornea at the level of the Descemet membrane and in the lens capsule in ocular chalcosis. Wilson disease is an autosomal dominant disorder, resulting in the accumulation of copper in body tissues. A Kayser-Fleischer ring may be seen in 95% of patients with Wilson disease. Clinically, it appears as a yellow-green-brown ring located in the corneal periphery at the level of Descemet membrane.¹⁴ Pigmented corneal rings may be seen in other chronic liver diseases, such as chronic active hepatitis and biliary cirrhosis.¹⁵

Advanced liver disease, such as hepatitis, biliary obstruction, or cirrhosis may cause elevation of the serum bilirubin level and yellow staining of the peripheral cornea, which is thought to diffuse from the limbal circulation.¹⁶ Bilirubin is found throughout the stroma but is more prominent in the deep stroma. It is also deposited in the conjunctiva, resulting in the yellow discoloration associated with jaundice. In contrast, in our patients with hypercarotenemia, no discoloration of the conjunctiva was noted.

Oral or intramuscular gold therapy may cause deposition of gold in the cornea and conjunctiva. The corneal deposits appear as yellow-brown granules located in the deep stroma and Descemet membrane.¹⁷ Silver deposition in the cornea and conjunctiva has been observed during the use of topical preparations containing silver or after industrial exposure to organic silver salts. The cornea may contain fine blue-gray or green deposits in the deep stroma and Descemet membrane.¹⁸ Chronic exposure to mercury vapor or ophthalmic mercury-containing medications can lead to greenish gray deposits in the periphery of the Descemet membrane.¹⁹ The cornea may occasionally be affected by siderosis. If the iron foreign body is localized in the anterior chamber, a yellow-brown iron deposit can be seen in the posterior corneal stroma.

The absence of scleral icterus, the negative history of exposure to heavy metals, and the laboratory evaluation in these cases mitigate against bilirubin or heavy metals as the source of corneal pigment deposition in our patients. It is likely that the pigment deposited in the corneas of our patients is one of the carotenoids (eg, α, β). Also, given that similar ocular findings have not been reported in clinical trials of beta carotene supplementation^8,20 and that ocular tissues selectively uptake luetin, zeaxanthin, and lycopene, it is possible that the rings are related to other carotenoids. In 2 of 3 cases, the corneal deposition was more prominent superiorly and inferiorly, in areas protected from light by the eyelids. Light is known to break down carotene, and blood samples are therefore protected from light after collection before being assayed for carotene.²¹

Discoloration of the anterior lens capsule may occur in siderosis and chalcosis or may be associated with the use of drugs, such as phenothiazines. Such deposits are more prominent in areas that are in close proximity of a foreign body, or in the case of phenothiazines, in areas that are associated with anterior subcapsular cataract.¹⁴ An iridescent brown deposition of copper on the anterior and posterior lens capsule with extreme hypercupremia, multiple myeloma, and pulmonary carcinoma has been described.²² In case 3, there was no history of an intraocular foreign body, no exposure to phenothiazines, and her serum copper level was normal. The other 2 cases did not show discoloration of the anterior lens capsule. The variation in corneal and lens findings between case 3 and the other cases may be a consequence of the relatively lower carotene level in case 3 or these findings may be among the spectrum of manifestations of hypercarotenemia.

Hypothyroidism may have contributed to the elevated blood carotene level in case 2.²³ This patient was taking at least 9 mg of oral carotenoids each day. The liver function abnormalities in case 1 were likely related to the diabetes rather than hypercarotenemia.

Retinal paramacular carotenoid crystal deposition has been previously reported in patients taking high doses of canthaxantine for tanning purposes^24,25 In 2 of our patients, retinal crystals were observed in the perifoveal area, which might be explained by diabetic retinopathy in 1 patient, but could not be explained in the other patient. We suspect that the crystal deposition may be related to the hypercarotenemia. The absence of crystals in the third patient may be attributed to a lower serum carotene level or perhaps to a shorter period of hypercarotenemia. Retinal crystal deposition has been reported in patients with retinitis pigmentosa who received a high dose oral beta carotene.²⁰ In another study, long-term follow-up of patients who received high doses of beta carotene for treatment of protoporphyria (only during the summer) failed to show any retinal deposits.²⁶ The significance of such retinal deposits and their long-term effect on visual function is unknown.

It is necessary to determine the nature of the deposited corneal pigment because it may be a sign of underlying systemic disease. Since we observed these 3 cases, we have noticed other patients who take beta carotene as part of their vitamin supplementation who have a slight yellow-brown hue to the perilimbal cornea. Peripheral corneal examination may thus be a useful clinical method of diagnosing excessive carotenoid ingestion. A careful evaluation of a patient's dietary habits and nutritional supplements, along with laboratory testing, may lead to the definitive diagnosis. Hypercarotenemia should be suspected in patients with a pigmented peripheral corneal ring in the presence of yellow discoloration of the skin and the absence of color change of the episclera and conjunctiva.

This research was supported in part by an unrestricted grant from Research to Prevent Blindness Inc, New York, NY, to Northwestern University, Department of Ophthalmology (Dr Jampol).

Corresponding author and reprints: Robert S. Feder, MD, Department of Ophthalmology, Feinberg School of Medicine, Northwestern University, 645 N Michigan Ave, Suite 440, Chicago, IL 60611 (e-mail: r-feder@northwestern.edu).