Copper in Eye Health

A PubMed search of vision and copper revealed that copper deficiency can contribute to loss of vision. Mitosynergy has encountered a variety of opinions as to whether or not copper deficiency occurs in the human population in developed countries. Copper deficiency may be related to age related macular degeneration in India (Bharathselvi 2016). A subpopulation of developed countries is at risk for vision loss as a result of copper deficiency: gastric bypass patients. Vision loss appears to be rare and may take several years or decades to manifest itself.

Gastric bypass and related copper deficiencies

Gastric bypass surgery has been reported to cause myelopathy mimicking vitamin B12/cobalamin deficiency (Kumar 2004). Many anecdotal reports have appeared in the literature documenting apparent optic nerve neuropathy as the result of gastric bypass copper deficiency.  A 55 year old woman who had had a gastric bypass 22 years ago awoke one morning with bilateral blindness (Naismith 2009). After one year of copper supplementation, the patient saw stabilization of the progressive neuropathy and improved leukopenia and anemia. Copper supplementation had no effect on the optic neuropathy. (Naismith 2009). Two other gastric bypass patients presented with optic neuropathy and myelopathy (Pineles 2010) B12 deficiency was suspected; supplementation was without effect. These patients were found to be copper deficient (Pinelles 2010). Rapoport (2016) reported loss of vision in another middle aged female gastric bypass patient.  In gastric bypass patients, both B12 and copper deficiency may result in treatable optic neuropathy. Most recommended screening for both deficiencies. In patients with suspected copper deficiency, testing for zinc excess was also recommended because zinc containing compounds, e.g. denture cream, can potentiate copper deficiency.

Genetics and denture cream may contribute to copper deficiency.

Yarandi (2014) presented a case of a gastric bypass patient who had the usual copper deficiency symptoms of anemia, neutropenia, myelopathy, respiratory failure, and bilateral optic neuropathy, which caused major vision loss. Possibly contributing to copper deficiency were use of a Zn containing denture adhesive and heterozygous for a polymorphism of the 5,10-methylenetetrahydrofolate reductase A1298C gene that is associated with altered copper metabolism. Unfortunately intravenous copper supplementation only modestly improved vision loss (Yarandi 2014). Early detection is key. A more favorable outcome was noted by Shah and Tamkandar (2014) who treated a gastric bypass patient presenting with bilateral vision loss just two years after her surgery. In this case copper supplementation resulted in dramatic recovery of vision.

Medication may redispose to copper deficiency

Clioquinol is an antifungal that has recently seen use as a treatment for degenerative diseases. In Alzheimer’s the goal is to chelate Cu(II) from amyloid plaques. Pushie (2014) made a more recent effort to characterize the structure and function of this Cu(II) chelator. This brings us back to the optic nerve neuropathy related to the use of this drug for fungal infections as well as Alzheimer’s and other neurodegenerative diseases. Brain and cervical MRI were obtained from optical neuropathy patients who had acquired this disorder in the 1960’s when chlioquinol was in use as an anti-fungal (Kimura 2011). The results resembled those reported for copper deficient optic neuropathy patients (Kimura 2011). Those taking Clioquinol for early stage neurodegenerative diseases may be at risk for vision loss in the long term.

Copper deficiency and copper toxicity, a dietary conundrum

A reduced copper diet has been recommended for those at risk for developing Alzheimer’s Disease (Squitti 2014). Others have suggested that the Western diet may not be adequate in copper (Klevay 2011). George Brewer, a colleague of Mitosynergy, has published many papers on Cu²⁺ in supplements in drinking water, and in residues on produce and their link to Alzheimer’s Disease (Brewer 2015). Dr. Brewer has endorsed Mitosynergy Cu⁺ supplement.

A closer look at the gastric bypass surgery

It is not immediately evident how gastric bypass surgery predisposes a patient for copper deficiency. Some possibilities include

• improper digestion of copper containing proteins.
• Copper conjugated peptides are not small enough to be transported by peptide transporters
• no absorption by Ctr1 and the divalent metal ion transporters in portions of stomach and duodenum that were removed.
• decreased intake of copper in diet as a result of eating less.

These possibilities stated, a 1984 study by Urban and coworkers addressed the adaptive responses of the rat small intestine when major portions were removed. Rats were subjected to 50% proximal or 50% distal small bowel resection or sham operation. Four weeks later intestinal absorption of copper was measured in vivo using a recirculation technique. These authors found increases in mucosal mass of non-resected regions as well as increased copper absorption of copper.
A preventative therapy for gastric bypass patients is where things get really interesting for Cu(I)NA₂. Nicolin and coworkers (2005) demonstrated the presence of the niacin transporting bilitranslocase in the acid secreting parietal cells of the stomach. These cells reside in the fundus, a region that is spared somewhat in the bypass surgery. These authors found the bilitranslocase in the mucous secreting cells of the stomach. This same group found the bilitranslocase in vascular endothelial cells (Maestro 2010 )

A list of copper containing proteins.

Myelin

Myelin is a fatty white substance that surrounds the axon of some nerve cells, forming an electrically insulating layer. This “fatty white substance” also contains a structural protein called myelin basic protein (MBP). In a study of copper deficient rats (Dake 1991), myelin formation was extremely delayed and damaged in the post laminar portion of the optic nerve (Dake 1991). Copper deficiency appeared to cause demyelination or dysmyelination in the optic nerves of rats. MBP is a Cu²⁺ and 0 Zn²⁺ binding protein. The of MBP have been studied with electron paramagnetic resonance spectroscopy revealing role of copper in assembly of this important myelin protein (Bund 2010). These same authors noted that the copper chelator cuprizone is used to induce an experimental model of the demyelinating disease multiple sclerosis. As an added note, Dodani and coworkers (2014) performed Cu⁺ imaging and X-ray fluorescence imaging in the rat developing retina and cultured hippocampus neurons. Disruption by copper chelation or genetic knock down of the CRT1 copper channel altered the spatio temporal properties of spontaneous activity. What role doesCu²⁺ binding MBP play in buffering this Cu⁺ activity?

Monoamine oxidases and SSAO

The activities of MAO-A, MAO-B and the semicarbazide-sensitive amine oxidase (SSAO) were determined in bovine lens, retina, optic nerve, iris and epithelium. No activities were detected in lens but the SSAO activity was found to be rather evenly distributed in the other tissues (Fernandez de Arriba 1990). SSAO activity towards dopamine was present in the choroid and the retina, but not in the iris or the optic nerve. (Fernández de Arriba 1991). In a later study SSAO, but not its activity, was localized by immunohistochemistry in the human eye (Almulki 2010). SSAO (also known more recently as vascular adhesion protein 1) staining was confined to the vasculature. SSAO labeling showed the highest intensity in both arteries and veins of neuronal tissues: retina and optic nerve, and the lowest intensity in the iris vasculature (p < 0.05). Scleral and choroidal vessels showed moderate staining for SSAO. SSAO intensity was significantly higher in the arteries compared to veins (p < 0.05). More research on the part of Mitosynergy is needed in this area.

Kaitaniemi (2209) found that the eye version, coded by the AOC2 gene has different substrate specificity than the  general smooth muscle version coded by the AOC3 gene. Protein Atlas data has the expression of AOC2 confined to the retina, though the AOC3 version may be part of the eye and optic verve blood supply.

Lysyl oxidase

Dudakova and coauthors (2015) published a medical hypothesis that keratoconus, cornea thinning, may be linked to copper deficiency.  Many copper cofactor enzymes have been shown to be altered in keratoconic cornea

•   superoxide dismutases
• cytochrome c oxidase
• lysyl oxidase

These authors also report a decrease in copper in diseased cornea.

Some additional copper containing enzymes

These copper containing enzymes may or may not be important in eye health.

• L-ascorbate oxidase
• Superoxide dismutase, Cu/Zn, SOD1 and SOD3.
• Dopamine beta-monooxygenase
• Nitrite reductase (NO-forming)
• Ceruloplasmin (ferroxidase I)
• Cytochrome c oxidase
• Dopamine β-hydroxylase
• Peptidyl glycine alpha-amidating mono-oxygenase (PAM)

Conclusions

Gastric bypass patients are sadly at risk of becoming copper deficient and prone to eye problems  We don’t have exact mechanism.  A few possibilities include (1) defects in myelin basic protein, (2) decreased activity of the SSAO monoamine oxidase coded by the AOC2 gene, (3) decreased collagen cross linking performed by lysyl oxidase.  We’ll post more as we learn more.  You may also want to learn more about Copper One Niacin in particular.

References

Almulki L, Noda K, Nakao S, Hisatomi T, Thomas KL, Hafezi-Moghadam A.(2010) Localization of vascular adhesion protein-1 (VAP-1) in the human eye. Exp Eye Res.90(1):26-32.
Bharathselvi M, Biswas S, Raman R, Selvi R, Coral K, Narayanansamy A (2016) Homocysteine & its metabolite homocysteine-thiolactone & deficiency of copper in patients with age related macular degeneration – A pilot study. Indian J Med Res. 2016;143:756–62.

Brewer GJ (2015) Copper-2 Ingestion, Plus Increased Meat Eating Leading to Increased Copper Absorption, Are Major Factors Behind the Current Epidemic of Alzheimer’s Disease.Nutrients. 7(12):10053-64. Review.

Bund T, Boggs JM, Harauz G, Hellmann N, Hinderberger D.(2010)Copper uptake induces self-assembly of 18.5 kDa myelin basic protein (MBP). Biophys J. 99(9):3020-8
Dake Y, Amemiya T.(1991) Electron microscopic study of the optic nerve in copper deficient rats. Exp Eye Res. 52(3):277-81.
Dodani SC, Firl A, Chan J, Nam CI, Aron AT, Onak CS, Ramos-Torres KM, Paek J, Webster CM, Feller MB, Chang CJ.(2014) Copper is an endogenous modulator of neural circuit spontaneous activity.Proc Natl Acad Sci U S A. 111(46):16280-5.

Dudakova L, Liskova P, Jirsova K. 2015) Is copper imbalance an environmental factor influencing keratoconus development?. Med Hypotheses. 84(5):518‐524.
Fernandez de Arriba A, Balsa D, Tipton KF, Unzeta M. (1990)Monoamine oxidase and semicarbazide-sensitive amine oxidase activities in bovine eye.J Neural Transm Suppl.32:327-30.
Fernández de Arriba A, Lizcano JM, Balsa D, Unzeta M.(1991) Contribution of different amine oxidases to the metabolism of dopamine in bovine retina.Biochem Pharmacol.42(12):2355-61.
Hirayama Y, Dake Y, Amemiya T.(1992) Cytochrome oxidase in rat ocular tissues with special reference to copper.Acta Histochem.93(1):307-12.
Kimura E, Hirano T, Yamashita S, Hirai T, Uchida Y, Maeda Y, Uchino M. (2011) Cervical MRI of subacute myelo-optico-neuropathy. Spinal Cord. 49(2):182-5.
Klevay LM.(2011) Is the Western diet adequate in copper? J Trace Elem Med Biol. 2011 Dec;25(4):204-12. Review.

Kaitaniemi S., Elovaara H., Groen K., Kidron H., Liukkonen J., Salminen T., Salmi M., Jalkanen S., Elima K. (2009)The unique substrate specificity of human AOC2, a semicarbazide-sensitive amine oxidase. Cell. Mol. Life Sci. 66:2743-2757
Kumar N, Ahlskog JE, Gross JB Jr. (2004) Acquired hypocupremia after gastric surgery. Clin Gastroenterol Hepatol. 2(12):1074-9.
Maestro A, Terdoslavich M, Vanzo A, Kuku A, Tramer F, Nicolin V, Micali F, Decorti G, Passamonti S.(2010)Expression of bilitranslocase in the vascular endothelium and its function as a flavonoid transporter.Cardiovasc Res.85(1):175-83

Moss HE. (2016) Bariatric Surgery and the Neuro-Ophthalmologist. J Neuroophthalmol. 36(1):78-84.
Naismith RT, Shepherd JB, Weihl CC, Tutlam NT, Cross AH.(2009) Acute and bilateral blindness due to optic neuropathy associated with copper deficiency. Arch Neurol. 66(8):1025-7.
Nicolin V, Grill V, Micali F, Narducci P, Passamonti S.(2005)Immunolocalisation of bilitranslocase in mucosecretory and parietal cells of the rat gastric mucosa. J Mol Histol. 36(1-2):45-50.
Pineles SL, Wilson CA, Balcer LJ, Slater R, Galetta SL. (2010) Combined optic neuropathy and myelopathy secondary to copper deficiency. Surv Ophthalmol. 55(4):386-92.
Pushie MJ, Nienaber KH, Summers KL, Cotelesage JJ, Ponomarenko O, Nichol HK, Pickering IJ, George GN. (2014)The solution structure of the copper clioquinol complex.J Inorg Biochem. 133:50-6.

Rapoport Y, Lavin PJ. (2016) Nutritional Optic Neuropathy Caused by Copper Deficiency After Bariatric Surgery. J Neuroophthalmol. 36(2):178-81.
Shah AR, Tamhankar MA.(2014) Optic neuropathy associated with copper deficiency after gastric bypass surgery. Retin Cases Brief Rep.8(1):73-6.
Urban E, Campbell ME.(1884) Copper absorption by remnant small bowel after extensive intestinal resection in the rat. Am J Clin Nutr. 1984 Sep;40(3):528-35.
Yarandi SS, Griffith DP, Sharma R, Mohan A, Zhao VM, Ziegler TR.(2014) Optic neuropathy, myelopathy, anemia, and neutropenia caused by acquired copper deficiency after gastric bypass surgery. J Clin Gastroenterol. 48(10):862-5