Retinal risks of high-dose ornithine supplements: a review

Abstract

We reviewed the literature on ornithine supplementation and related topics. Nutritionists and physicians have reported that ornithine supplementation is useful. Paediatricians and biochemists have reported that ornithine is supplemented for NH 3 detoxification in the hyperornithinaemia -hyperammonaemia -homocitrullinuria (HHH) syndrome. In contrast, ophthalmic researchers have reported retinotoxicity associated with high-dose ornithine. In vivo and in vitro experiments have shown that high concentrations of ornithine or its metabolites are toxic to the retinal pigment epithelial (RPE) cells. Long-term (exceeding a few years) and high concentrations (exceeding 600 mmol/l) of ornithine in the blood induce retinal toxicity in gyrate atrophy of the choroid and retina (GA). Intermittent high levels of ornithine do not lead to retinal lesions. Constant blood ornithine levels between 250 and 600 mmol/l do not induce retinal lesions or cause a very slowly progressive retinal degeneration. Blood ornithine levels below 250 mmol/l do not produce retinal alteration. We concluded that short-term, low-dose or transient high-dose ornithine intake is safe for the retina; its nutritional usefulness and effect on NH 3 detoxification are supported by many researchers, but the effect may be limited; and long-term, high-dose ornithine intake may be risky for the retina. Patients with GA should avoid taking ornithine; amino acid supplementation should be administered carefully for patients with the HHH syndrome, relatives of patients with GA (heterozygotes) and subjects with RPE lesions; and blood ornithine levels and retinal conditions should be evaluated in individuals taking long-term, high-dose ornithine.

Arginase in retinopathy

“…P5C is further metabolized to L-proline. The OAT gene mutation results in a decrease in OAT activity, leading to excessive accumulation of L-ornithine which is toxic to RPE cells [for review, please see (Hayasaka et al, 2011)]. Fundus examination of patients with gyrate atrophy shows retinal lesions similar to that seen in age-related macular degeneration with chorioretinal atrophy that becomes larger with age (Takki, 1974).…”

“…Activation of the arginase/ornithine pathway may contribute to tissue fibrosis due to increases in formation of proline which promotes collagen formation or polyamines which enhance cell growth. Also, polyamine metabolism and products of polyamine oxidation have been shown to be involved in the pathogenesis of ischemic brain damage (Ivanova et al, 2002; Takano et al, 2005; Wood et al, 2006), gyrate atrophy of the retina and choroid (Takki, 1994), injury of the retinal pigment epithelium (Hayasaka et al, 2011) and diabetes-induced alterations in the function of potassium channels in the retinal microvasculature (Matsushita and Puro, 2006). …”

Impact of Cationic Amino Acid Transporter 1 on Blood-Retinal Barrier Transport of L-Ornithine

“…ingestion caused higher plasma concentrations of L-ornithine in OAT þ/À than in OAT þ/þ , and the in vitro study revealed the concurrent addition of 5-FMO and L-ornithine upregulates the expression of CAT1 mRNA. 26,47,48 These findings suggest that L-ornithine accumulation increases the expression of CAT1 at the basal side, showing a risk that L-ornithine ingestion could cause the degeneration of RPE cells in humans with impairment of L-ornithine elimination, such as OAT þ/À .…”

Effect of Long-Term Treatment of L-Ornithine on Visual Function and Retinal Histology in the Rats

“…13,[18][19][20] In addition, L-Orn-loaded GA relatives and patients of HHH syndrome did not develop retinal degeneration, although the plasma concentration of them were 600-1100 µM. 31) Thus, it is unlikely that only L-Orn accumulation in the plasma would be a direct cause of RPE degeneration in GA.…”