Zinc supplementation lowers complement overactivation in patients with age-related macular degeneration

Abstract

 

Purpose

 

Complement-mediated inflammation plays a pivotal role in the pathogenesis of age-related macular degeneration (AMD). Oral zinc administration can reduce the progression of AMD. The purpose of this study was to determine wether zinc supplementation in AMD patients has a direct measurable effect on the complement system, explaining the mechanism through which zinc exerts its protective influence on AMD progression.

 

Methods

 

In this open-label study, 72 patients in various stages of AMD received a daily supplement of 50 mg zinc sulphate for three months. Serum complement catabolism— defined as the C3d/C3 ratio—was measured at baseline, throughout the three-month of zinc supplementation and after discontinuation of zinc administration. The high-risk genetic variants in CFH Y402H and ARMS2 A69S were determined, and the stage of the disease was assessed in accordance with clinical age-related maculopathy staging.

 

Results

 

Serum zinc concentration increased significantly during the supplementation period (p<0.0001) and returned to baseline levels two months after the zinc supplements were discontinued. AMD patients with high levels of complement catabolism at baseline exhibited a steep decline in serum complement activation (p<0.0001) during the 3-month zinc supplementation period. Serum complement catabolism in AMD patients who already had a relatively low C3d/C3 ratio at baseline did not change significantly throughout the study period (Fig. 1). Individuals who were homozygous for the CFH Y402H high-risk genotype had a significantly faster decline in their C3d/C3 ratio (p=0.016). Patients with late-stage AMD in both eyes but no evidence of disease activity had significantly lower levels of serum complement activation than patients with intermediate-stage AMD (p=0.005).

 

Conclusions

 

Increased levels of complement catabolism in AMD patients can be lowered towards normal values by daily administration of 50 mg zinc sulphate.

 

 

AMD patients with relatively high baseline serum complement catabolism (C3d/C3 ≥2.1, n=16) had a steep decline in C3d/C3 ratio during the administration of 50 mg zinc sulphate (p<0.0001 vs. baseline) as opposed to patients with low baseline C3d/C3 (<2.1, n=56). The horizontal dashed line shows the mean C3d/C3 ratio in the age-matched control group plus one standard deviation from the mean.

 

Keywords: 412 age-related macular degeneration • 557 inflammation