Elevated C-Reactive Protein Linked to Age-Related Macular Degeneration

ROTTERDAM, The Netherlands, Oct. 8 -- Age-related macular degeneration appear linked with high baseline levels of C-reactive protein and associated inflammation, researchers here found.

As a patient's C-reactive protein level increased above the median of the study population, the risk of age-related macular degeneration increased, reported Paulus T.V.M deJong, M.D., Ph.D., of the Erasmus Medical Center here, and colleagues, in the October issue of Archives of Ophthalmology.

"Individuals with a high C-reactive protein level (>1.73 mg/L) within the normal range have a statistically significant higher risk of early and late aging macular degeneration," the researchers wrote.

The researchers added that they prefer the term "aging" to "age-related," given that age-related does not discriminate between the juvenile disorder and that associated with older age.

In a population-based study, they examined serum high-sensitivity C-reactive protein levels in 4,914 patients at risk for the disorder participating in the Rotterdam Study, a population-based study of chronic disabling diseases in older persons.

At the initial examination, from 1990 through 1993, blood samples were collected and color photos were taken of the macular area of each eye.

After a mean follow-up of 7.7 years, including three initial examinations, 561 cases of early and 97 cases of late incident age-related macular degeneration were identified.

After adjustment for age and sex, hazard ratios were 1.11 (95% CI, 1.02-1.21) per standard deviation increase in CRP level for early disease and 1.28 (CI, 1.02-1.60) for late disease.

Hazard ratios for early age-related disease increased per quartile increase in CRP level as follows: second quartile, 1.19 (CI, 0.94-1.52); third quartile, 1.29 (CI, 1.01-1.64); and fourth quartile, 1.33 (CI, 1.05-1.70).

The risk of late eye disease was higher in all the upper quartiles of high-sensitivity CRP, the researchers said.

This population based cohort confirmed data from three earlier clinic-based studies indicating that baseline high sensitivity CRP levels were associated with early and late incident age-related macular degeneration, with the highest risks for patients with late disease.

This finding, they said, supports the theory that inflammation is a mechanism involved in the pathogenesis of the disorder in the general population.

Injury to the retinal pigment epithelium cells and possibly to the choroid caused by smoking, obesity, the toxic effect of light, and low antioxidant intake may induce age-related macular degeneration through a state of chronic inflammation, they said.

Chronic inflammation seems to be involved in the development of drusen, the white subretinal extracellular deposits that are a hallmark of the disorder. Analysis has found that drusen contain proteins associated with inflammation, such as fibrinogen, complement components, and CRP, the researchers said.

Evidence is accumulating that inflammatory and immune-associated pathways have a role in other degenerative diseases associated with advancing age, such as atherosclerosis and Alzheimer's disease.

Drusen components have been found in atherosclerotic plaques and deposits in Alzheimer's so that macular degeneration, atherosclerosis, and Alzheimer's may share a similar inflammatory pathogenesis, the researchers wrote.

It is possible that reducing CRP levels might lower the risk for the eye disorder, the researchers said. However, a substance that can selectively inhibit CRP synthesis has not yet been developed, to their knowledge, the investigators said.

The pathogenesis of the disorder is unclear, although beneficial effects for some modifiable risk factors such as smoking and hypertension have been noted.

Smoking and high body mass index increase CRP levels. Moderate alcohol intake, diets with a low glycemic index, and statin and multivitamin use reduce the protein's levels.

However, additional correction for smoking and obesity did not change the estimates in this study, they said. Nevertheless, they added, reducing both might be protective.

Differential misclassification was unlikely in this study, the researchers said, because the macular degeneration graders were masked for CRP status and because the data were collected without knowledge of age-related macular degeneration status.

CRP was measured only once, the researchers said, but this should not have been a problem. The protein has a half-life of about 19 hours, and concentrations seem to have been fairly stable for at least five years in most of the individuals.

"We consider C-reactive protein level a potential useful biological marker in profiling the risk of aging macular degeneration for individual persons," the authors concluded.

This study was supported by the Netherlands Organization for Scientific Research and by the following foundations: Optimix, Physico Therapeutic Institute, Blindenpenning, Sint Laurens Institute, Bevordering van Volkskracht, Blindenhulp, Rotterdamse Blindenbelangen Association, OOG, kfHein, Prins Bernhard Cultuurfonds, Van Leeuwen Van Lignac, Verhagen, and Elise Mathilde. An unrestricted grant was obtained from Topcon Europe BV (all awarded to Dr. de Jong).