Introduction.
The definition of retinal degeneration covers a wide variety of diseases which show a progressive loss of vision due to a damage to photoreceptors. Another point of contact between the different forms of retinal degeneration is the absence of a definitive cure.
Several studies have been completed over the years to test the potential of nutritional compounds – vitamin A, lutein and ω-3 fatty acids – to determine a sensible improvement to the course of retinal degeneration diseases, often with encouraging results. Considering the lack of resolutive therapies, it is evident that the nutritional therapy represents a crucial passage to improve life quality of patients, because it allows to lengthen the duration of the disease course and so to delay the onset of the typical symptoms of the different phases.
Vitamin A.
The first clinical trials (A randomized trial of vitamin A and vitamin E supplementation for retinitis pigmentosa, 1993) with the target to verify the utility of the vitamin A administration in the nutritional therapy projected for patients with retinal degeneration have been concluded by 1993. The starting point consisted in the comparison between two different administrations, one based on vitamin A and the other based on vitamin E. Six hundred and one patients aged 18 through 49 years have been divided in four groups, according to the levels of vitamin A and vitamin E taken: the first group received high doses of vitamin A and the second was treated with high doses of vitamin E; the third group got a high dosage of both vitamins and the fourth group was given only traces of them. The results were assessed by electroretinogram: the two groups receiving high doses of vitamin A had on average a slower rate of decline of retinal function than the two groups not receiving that dosage. This evidence shows – with a p value of 0.01 – that the intake of vitamin A has a beneficial effect on the course of retinal degeneration diseases.
We should take into account that the long term intake of excessive levels of vitamin A has to be considered toxic; therefore the nutritional therapy, based on the administration of a dosage which is higher than the biological need, must be kept under a safety limit, within there is no risk for the patient.
The trial (Safety of <7500 RE (<25000 IU) vitamin A daily in adults with retinitis pigmentosa, 1999) that stated definitely the daily level of vitamin A intake within the patient is not exposed to any health trouble has been concluded by 1999: the background is that the daily biological need of vitamin A is estimated to be 800 retinol equivalents (RE)/d (2667 IU/d) for adult women and 1000 RE/d (3300 IU/d) for adult men. Patients who participated in the trial have been divided into two groups: the group A received a dosage of 4500 RE/d (15000 IU/d) of vitamin A and the control group took only traces. The results highlighted an increase in mean serum retinol concentration and no retinol value exceeded the upper normal limit; at the same time no evidence of liver toxicity has been found.
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Vitamin A, also known as retinol, is a fat soluble vitamin involved in several biological functions and the vision is one of them. The mechanism used by the compound to participate to the visual process is based on several phases. The retinol is converted to the retinal, an aldehyde, by the enzyme alcol dehydrogenase; the retinal, in 11-cis form, joins a retinal protein called opsin using a covalent bond with a Lys-296 residue. The new compound, the rhodopsin, can modify his conformation because of the exposure to a photon: the 11-cis form is isomerized to the trans form, so there is the activation of a molecular cascade mediated by a G protein which conduces to the generation of electrical pulses intended to be headed to CNS.
Transport through the bloodstream.
Vitamin A taken by food is stored in liver tissue and also in fat tissue as retinyl ester. The first step in the direction of mobilization is converting retinyl ester into retinol: about 90% of the retinol molecules is transported by the plasma using a bond with a carrier protein called retinol binding protein (RBP); a wide percentage of the RBP molecules is associated, with a stoichiometric 1:1 ratio, to another carrier protein, named TTR-tiroxine. Both RBP and TTR are involved in the regulation of the retinol hematic concentration: the harshness of the regulator mechanisms makes the hematic retinol remain to a constant level.
Considered that the hematic concentration of that compound does not change, we can understand the connection between the bloodstream speed and the retinol efficacy into the organism: a bloodstream which is too much slow may frustrate the benefits of vitamin A supplementation, not allowing the retinol to reach the retinal tissue in higher concentrations and so to perform its benefic effects.
Over the years the administration of vitamin A has become a consolidated usage to treat patients with retinal degeneration; at the same time trials with the target to improve the nutritional therapy have been carried out, attempting to discover new compounds able to produce a further improvement to the course of the disease.
Folic acid and MTHFR.
A correlation between the onset of retinal degeneration diseases and the hematic concentration of homocysteine has been found experimentally. Homocysteine derives from a transporter of methyl groups called S-adenosylmethionine: in fact homocysteine is the demethylated form of methionine, an amino acid.
A trial (Folic Acid, Pyridoxine, and Cyanocobalamin Combination Treatment and Age-Related Macular Degeneration in Women, 2009) was carried out to assess the ability of folic acid, pyridoxine hydrochloride (vitamin B6) and cyanocobalamin (vitamin B12) to decrease the incidence of retinal degeneration diseases; results were published in 2009 and showed a significant reduction of the risk to get a retinal disease. In particular, folic acid intake is directly involved in the decrease of homocysteine hematic levels: in fact folic acid is the precursor of tetrahydrofolate, which is important as methyl groups transporter to methylate homocysteine and so to restore S-adenosylmethionine. Methyl-tetrahydrofolate is assembled by an enzyme called methyl-tetrahydrofolate reductase; a mutation affecting the enzyme may determine the slowing down of the reaction and so perform its effects on the passage from homocysteine to methionine, contributing to the increase of homocysteine hematic levels.
Choline.
Another compound able to perform a benefic effect for the retinal tissue is represented by choline: the administration of high choline levels leads to the composition of acetylcholine (ACh), a neurotransmitter which stimulates vasodilation; this way the hematic transport of oxygen to tissues, and in particular to the retinal tissue, will improve.
A deterioration affecting the bloodstream and so the retinal oxygenation may be due to aging: in fact arterial walls are going to become even more thick over the years, so the vascular system which supplies the retina loses its efficiency; these factors raise the risk of thrombosis and, more generally, a sight deterioration can occur.
Hypothyroidism: coenzyme Q, iodium and selenium.
In a situation of decreased oxygen supply through the bloodstream we can contextualize the condition of hypothyroidism, which is related with aging: the lower T3 production determine a slowing down of methabolism and this affects also the mechanism of oxidative phosphorylation. The respiratory chain processes need the presence of consistent quantities of coenzyme Q: a lack of that compound may be due to hypercholesterolemia, because the ubiquinone production is based on farnesyl pyrophosphate, a substrate which is important also in the synthesis of cholesterol. Low levels of coenzyme Q determine a slowing down of methabolism: considering the retina, several trials (Retinal coenzyme Q in the bovine eye, 2011) have been carried out to demonstrate the correlation between low ubiquinone levels and the deteriorating of retinal degeneration diseases.
Told about the effects of hypothyroidism on methabolism and so on the retinal tissue, it is evident the importance of the iodine intake, because it is a structural component of thyroid hormones.
Selenium is another significant element for the regulation of thyroid functions: this element, in the form of selenocysteine, is a part of deiodinase, an enzyme which is fundamental to convert T4 to the active form T3. Another function of selenium concerns glutathione peroxidase, an enzyme whose antioxidant action reduces the tissue damage due to oxidative stress; in fact this is a process particularly important for the thyroid tissue, because the organ is exposed to oxidative damages by the reactive oxygen species H2O2, a compound produced as a cofactor in the synthesis of thyroid hormones.
Lutein.
The results of a clinical double-masked trial (Clinical trial of lutein in patients with retinitis pigmentosa receiving vitamin A, 2010) of 225 nonsmoking patients aged 18 to 60 years have been published in 2010. Patients have been divided into two groups: the background is that both of them were subjected to the administration of 15.000 IU/d of vitamin A – palmitate; furthermore, the first group had to take 12 mg/d of lutein and the other a control tablet daily. The results of the trial show that the supplementation of lutein slowed the loss of mid-peripheral visual field on average among nonsmoking adults taking vitamin A; no significant toxic effects of lutein supplementation were observed.
Omega-3 fatty acids.
Another way to explore has been identified in the nutritional intake of long chain ω-3 fatty acids; the results of the trial (ω-3 intake and visual acuity in patients with retinitis pigmentosa receiving vitamin A, 2012) carried out in relation to the loss of visual acuity have been published in 2012. The sample examined is composed by subjects who are given daily doses of 15.000 IU of vitamin A; rates of visual acuity decline were compared between patients with high (≥ 0.20 g/d) and low (< 0.20 g/d) ω-3 intake. The results showed that the intake of high levels of ω-3 is related to the slowing of visual acuity decline.
In conclusion, researches and clinical trials carried out from the beginning of the 90s brought to the development of a nutritional therapy that, although not resolutive, may be very useful, because it determines an improvement of the prognosis for retinal degeneration diseases, with a clear impact on improving the life quality of patients.
Marco Cannizzaro, Giulia Brach del Prever
