Copper in Keratoconic Corneas

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To the Editor:
We have read with interest the original report by Kiotaliotac et al1 (2016) assessing systemic oxidant/antioxidant status in patients with keratoconus (KC), and we believe that a few points should be added.
KC is a relatively common condition and one of the most frequent indications for corneal grafting. Despite extensive research, the pathological mechanism underlying KC remains unknown, although it is widely accepted that oxidative stress plays a critical role in its development and progression.2 Copper is an integral component of many antioxidant enzymes (eg, COX, ATOX1, SOD1, and SOD3); however, in their study, Kiotaliotac et al (2016) did not find a significant association between serum copper levels in patients with KC compared with controls.
It has been previously shown that serum copper levels are decreased only in cases of moderate to severe copper deficiency.3 However, as the activity of cuproenzymes may also be impaired in the presence of mild copper deficiency,4 the utility of serum level testing is limited. The situation is further complicated by a lack of standardized assays.5 In addition, changes in the serum copper level are influenced by age, sex, body mass index, pregnancy, and other conditions not related to copper status, such as inflammatory or infectious processes, neoplasm, and estrogen replacement therapy.3,6 These factors should be taken into consideration for a more accurate comparison of serum copper levels in KC patients versus controls.
Current evidence suggests that the development of KC depends on the interplay between genetic and environmental factors in the majority of patients. We have previously hypothesized that copper deficiency may be an unrecognized factor that increases susceptibility to KC.7 Our hypothesis is supported by X-ray structural analysis performed by Avetisov et al,8 who found diminished copper levels in KC corneas and proposed a plausible explanation that the higher pH of tears of patients with KC leads to oxidization of dichlorocuprate (Cu+) into cupric oxide (Cu2+), which cannot be used by cells. Furthermore, most keratoconic corneas display decreased activity of lysyl oxidase, an important collagen cross-linking enzyme that requires copper as a cofactor.9
In summary, although the study by Kiotaliotac et al1 does not provide evidence that serum copper levels are related to KC, this does not exclude a role for cornea-specific dysregulation of copper levels in the pathogenesis of KC. Further research is necessary to explore the role of this trace element in the etiopathology of KC.
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