August 01, 2001
5 min read

Genetics, oxidative stress suspected causes of keratoconus

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COLUMBUS, Ohio — While the treatment of keratoconus is fairly straightforward, with well-fitted specialty lenses or corneal transplant, theories on the causes of the condition may differ. Some have pointed to allergies, contact lens wear, eye rubbing and connective tissue disease, while researchers are investigating genetics and oxidative stress as possible etiologies.

“There is a high association between keratoconus and allergy,” said Joseph T. Barr, OD, assistant dean for clinical affairs at the Ohio State University College of Optometry here. “In fact, about half the people who have keratoconus also have allergy.”

But for contact lens wear, “you need to ask the question: Which came first, the keratoconus or the contact lens wear? The answer is probably the keratoconus,” Dr. Barr continued. “If keratoconus were caused by contact lenses there would be an increased prevalence of keratoconus today compared to 20 years ago, which is probably not the case.”

Genetic link

image---Contact lenses and keratoconus: Nearly all patients with keratoconus who wear contacts need a rigid gas-permeable lens in a modern material that is, preferably, designed specifically for keratoconus.

Dr. Barr also discounts the association between connective tissue disease and keratoconus. “With keratoconus, there is an imbalance of enzymes in the tissue,” he said, “which is probably due to genetics. About 10% of people with keratoconus have a relative with keratoconus.” In addition, there are numerous case reports of twins with keratoconus.

“I personally believe that the cause of keratoconus is genetic,” said Dr. Barr, who is also director of the Collaborative Longitudinal Evaluation of Keratoconus (CLEK) Photography Reading Center. “That genetic constituency results in abnormal enzymes in the cornea. I believe such enzyme activity causes all the problems that we encounter: distorted cornea, breakdown of the tissue, etc.”

The literature indicates that there are fewer protease inhibitors in keratoconus patients. Furthermore, “you end up with too many enzymes that break down the collagen in the stroma,” Dr. Barr noted. “These two factors lead to the thinning of the cornea.”

At least one federally funded research project is currently investigating the relationship between genetics and keratoconus, he said.

Oxidative stress

M. Cristina Kenney, MD, PhD, a research scientist at Cedars-Sinai Medical Center in Los Angeles, has studied keratoconus corneas for about 15 years. “The first part of our studies focused on enzymes and demonstrating that there is increased enzyme activity in keratoconus corneas,” Dr. Kenney said. “This makes sense because, if there is increased enzyme activity, that in turn will digest the matrix in the stroma and can make the cornea thinner. But then the question becomes: Why do you have this increased enzyme activity?”

One of Dr. Kenney’s theories is that keratoconus is related to oxidative stress. “I hypothesize that keratoconus corneas do not process the oxidative-stress molecules as well as normal corneas,” she said.

More recently, Dr. Kenney has studied byproducts of oxidative stress. “When ultraviolet light or any kind of stress occurs in a tissue, free radicals are formed,” she said.

Dr. Kenney and her colleagues have compared normal, keratoconus and other diseased corneas for damaging byproducts from the lipid peroxidation and nitric oxide pathways. “We found that in both pathways, the keratoconus corneas have more damaging byproducts,” Dr. Kenney said. “This results in the build-up of oxidative-stress byproducts.”

Subsequently, these byproducts damage tissue, leading to increased enzyme activity and apoptosis.

Dr. Kenney believes that there is certainly a genetic component to keratoconus. However, in general, “what I’ve seen so far is that most of the abnormalities are related to enzymes and not the structural components per se of the cornea, such as the collagens or the other major matrices of the cornea,” she said. On the other hand, “I think we will find that environmental influences make a difference. Rubbing the eyes, for example, may precipitate more oxidative stimuli. This could start a cycle.”

More support for genetic cause

An epidemiology study conducted at Cedars-Sinai Medical Center disputes the theory that keratoconus is caused by hand rubbing and contact lens wear. After interviewing hundreds of family members, “we demonstrated without doubt that a major component of keratoconus is genetic,” said Yaron S. Rabinowitz, MD, chief of ophthalmology at the institute.

“But just because it is a major component doesn’t necessarily mean it is always clearly inherited,” he continued. “Only 10% to 15% of keratoconus patients have a family history of keratoconus.” Furthermore, “this doesn’t mean that contact lenses or eye rubbing can’t aggravate the disease, but I don’t think they are the causes. After all, there are a lot of people who rub their eyes or wear hard contact lenses who never develop keratoconus,” Dr. Rabinowitz said.

Dr. Rabinowitz, who is a recipient of a National Institutes of Health grant on genetic factors in keratoconus, also helped conduct some molecular studies on a very large family. “We found the gene locus on chromosome 21,” he said. However, “the problem with the area in which we found the gene locus is that it is a very gene-poor area, so we really don’t know what genes cause the condition.”

Corneal topography to diagnose

According to Dr. Barr, keratoconus is not a difficult to diagnose. “I think that modern corneal topography has helped better identify the candidates for keratoconus,” he said. “A low steepened apex is the hallmark sign.” Once this apex is detected, “we look for slit-lamp signs: Vogt’s striae, Fleischer’s ring and corneal scarring,” Dr. Barr said. “If there is an irregular cornea along with one of these three slit-lamp signs, one can be fairly certain that the patient has keratoconus.” However, “those signs can be very subtle, especially early striae and early ring,” he said.

Repeated measurement of topography, refraction and keratometry helps in detecting change. “You may have a suspect, but it can take a few years to verify,” Dr. Barr said. Moreover, nearly all keratoconics who wear contact lenses need a rigid gas-permeable lens in a modern material and preferably designed specifically for keratoconus.

“The tissue is going to break down anyway; however, the better we fit the lens, the healthier we can maintain the eye,” Dr. Barr said. “We don’t believe we can retard the progression, but we are committed to achieving the best possible vision and comfortable lens wear.”

Added Dr. Kenney, “I definitely believe that having well-fit contact lenses is extremely important. If the lenses don’t fit well, that constant irritation will cause more free radical and localized damage. Minimizing stress to the cornea will help.”

A corneal transplant should also be considered. Contrary to popular belief, “corneal transplants actually are not dangerous. They are extremely successful,” Dr. Rabinowitz said. “People who are contact lens intolerant or who have corneal passes in their visual axis have a 96% to 98% chance of a successful corneal transplant if they are compliant. They often see much better than with rigid lenses. Of course, there is always the risk of rejection, but that risk is extremely low.”

Dr. Rabinowitz has performed about 20 LASIK procedures after keratoplasty. “The results have been excellent. They vary between 20/20 and 20/30,” he said.

However, Dr. Barr said refractive surgery should only be used as a last resort. “You will weaken and violate an already weakened and violated corneal tissue,” he said. In any event, “I think most optometrists can handle most of their keratoconus patients. But when they have trouble, they should seek out a practitioner with more experience.”

For Your Information:
  • Joseph T. Barr, OD, can be reached at the Ohio State College of Optometry, 320 W. 10th Ave., Columbus, OH 43210; (614) 292-0437; fax: (614) 688-3285; e-mail:
  • M. Cristina Kenney, MD, PhD, can be reached at Cedars-Sinai Medical Center, 8700 Beverly Blvd., Room 5069, Los Angeles, CA 90048; (310) 423-6458; fax: (310) 423-0225; e-mail:
  • Yaron S. Rabinowitz, MD, can be reached at Suite 1102, 444 S. San Vicente Blvd., Los Angeles, CA 90048; (310) 423-9640; fax: (310) 423-9649; e-mail: