Plasma copper and antioxidant status in wilson's disease

Abstract

It has been demonstrated that the level of serum copper unbound to ceruloplasmin (loosely bound copper) is increased in Wilson's disease, although the total serum copper concentration is usually low, reflecting a low ceruloplasmin level. To assess the contribution of free radical reactions catalyzed by nonceruloplas-min copper to the development of complications in this disease, we investigated copper and antioxidant status in four untreated patients who had hepatic dysfunction with or without hemolytic anemia and made a comparison with five patients controlled on penicillamine therapy and 19 age-matched healthy children. We found that loosely bound copper in plasma measured by the phenanthroline assay was detectable in three of four untreated patients with Wilson's disease, but was not detectable in the patients during therapy or in the healthy controls. Among the various antioxidants, the ascorbate and urate levels were markedly reduced before treatment (mean ± SD, 23 ± 16 μM for ascorbate and 90 ± 59 μM for urate) compared with the values in the patients during treatment with penicillamine (67 ± 19 and 302 ± 78 μM, p < 0.05) and in control children (60 ± 8 and 254 ± 48 μM, p < 0.05). We also demonstrated that the plasma concentration of allantoin, an oxidation product of uric acid and a possible marker of radical generation in vivo, was markedly elevated in the untreated patients (11.0 ± 1.8 versus 4.3 ± 0.5 μM in patients on therapy and 6.5 ± 0.8 μM in controls, p < 0.05). The low plasma urate level together with the elevation of I allantoin were thought to be responsible for the degradation of uric acid as a sacrificial antioxidant. In contrast, the plasma levels of a-tocopherol and thiobarbituric acid reactive substances did not differ in these three groups. The value of the total radical-trapping antioxidant parameter was reduced in the patients before the initiation of therapy (372 ± 146 versus 942 ± 79 μM in patients on therapy and 856 ± 104 μM in controls, p < 0.05), and this was mainly attributed to the depletion of ascorbic acid and uric acid. These findings suggest that the elevation of loosely bound copper leads to transition metal catalyzed free radical reactions in the aqueous phase of plasma, which may play a role in the clinical complications of Wilson's disease. © 1995 International Pediatric Research Foundation, Inc.