MCG doctor explores vision disorder, excess iron link

Looking into a key discovery



Fred Johnson, of North Augusta, was driving up to a stop sign when he noticed he could see it with his right eye but something was blocking his vision in his left eye.

"Like a big black blob," he said. Johnson, 79, was later diagnosed with the wet form of age-related macular degeneration, where blood vessels in the light-sensing retina at the back of the eye become leaky and cause damage.

It is a common form of vision loss but researchers at Medical College of Georgia think they have discovered a surprising cause for it -- iron overload.

Iron in the human body is a tricky thing.

It is necessary to make the oxygen-carrying hemoglobin in the blood.

"Without iron we cannot survive. Period," said Dr. Vadivel Ganapathy, the chair of the Department of Biochemistry and Molecular Biology at MCG.

Too much iron, however, is toxic and causes oxidative damage. There are about a dozen genes devoted to keeping iron at the right level, but a defect in a main one, called the human hemochromatosis protein gene, results in patients accumulating too much iron in the body.

It is the most common genetic disease in humans, affecting about one in 200. An even larger number, as many as one in eight, might be a carrier for the mutation, Ganapathy said.

"Most people do not worry about hemochromatosis because I believe it is one of the most underdiagnosed diseases," he said.

Damage accumulates over time in the organs and when patients get into their 50s and 60s, they can develop all kinds of problems, from diabetes to heart problems to liver cancer, and might not know that the underlying cause is toxic levels of iron, Ganapathy said.

"Most of the clinicians treat the clinical problem without diagnosing the underlying cause, because they treat the disease," he said.

But hemochromatosis had not yet been linked with age-related macular degeneration, Ganapathy said. Increased iron accumulation had been found in the retinas of patients with age-related macular degeneration, and a paper in 2006 looking at animal models made a case for iron-oxidative damage causing macular degeneration.

Intrigued, Ganapathy went looking for the HFE gene mutation in mice in an area at the back of the eye that serves as the "gatekeeper" for nutrients to get into the sensitive retina area, he said. The gene is normally found in the small intestine, where iron is absorbed from food. Ganapathy found it and four other genes linked with the iron-overload disorder, although HFE mutation accounts for about 85 percent of the cases.

Working in a mouse model that had that gene deleted, older mice appear to have the same cell death and damage that could lead to vision problems, Ganapathy said. He recently got a $1.5 million grant from the National Institutes of Health to continue the mouse studies.

But what about people?

Age-related macular degeneration is the leading cause of vision loss in people over age 60, according to the National Eye Institute. And there are some genes that have been linked to it, although they each account for only a small percentage of patients, Ganapathy said.

"The problem is we don't understand why some people develop more severe macular degeneration," said Dr. Julian Nussbaum, the chair of the Department of Ophthalmology at MCG, who is treating Johnson.

He and resident Dr. Emory Patterson are co-investigators on the clinical side of the study, through the Vision Discovery Institute. They are collecting blood samples from macular degeneration patients to look for evidence of the iron-overload problem.

When Ganapathy first talked to him about the initial discoveries, Nussbaum said he got excited "because it did seem to make sense. Putting those pieces together makes for a circumstantial case, but we still have a lot of scientific pieces to fit in."

The eye, constantly bombarded by light and heat, is a prime area for oxidative stress, and the eye has an efficient system for disposing of that damage and heat, Nussbaum told Johnson as he examined him in the clinic last week.

"The vitamin supplements and fish oil supplements you are taking are to help power that waste disposal system, to deal with the inflammation back there," Nussbaum said.

Excess iron could be causing a problem for those with the mutation, he said.

"They may be predisposed to more severe forms of macular degeneration," Nussbaum said. "But we don't know for sure."

It could even be that way for the carriers of the mutation, who do not develop the disease but who tend to accumulate more iron over time than those without it.

"We're thinking over this 60-70-80 years of this sub-clinical increase of iron levels in the body, particularly in the retina, that maybe that's what's actually causing or augmenting macular degeneration," Patterson said.

If true, it could open up a lot of possibilities, Ganapathy said. At one time, the NIH had proposed screening for the HFE mutation, which Ganapathy thinks could be justified by a test that would cost around $20. Knowing early on could help younger people, Nussbaum said.

"If you learn that you've got a gene that puts you at great risk -- and we don't know yet what that risk variable is -- then you might avoid the things that predispose you to more severe disease," he said.

Chelation -- drugs that bind to iron and make it easier to excrete it out of the body -- is one option, Ganapathy said. But he likes a simpler solution.

"My proposal is, why not start donating blood?" he said, which reduces iron levels. "It's a kind of double positive effect. It helps somebody and it helps you also."