We have shown markedly increased levels of serum non-ceruloplasmin copper as well as erythrocytic copper in WD patients with hemolytic anemia. A review of such patients in the literature suggests that, rather than having low serum copper levels, patients with hemolysis accompanying WD have very high serum copper levels (5). A significant increase in the percentage of hemolysis in WD patients indicates the deleterious effects of free copper and possible mechanisms might include oxidant injury, inhibition of red cell enzymes, and, more directly, the adverse effects on membrane. It is very interesting that the plasma Hb in WD patients with hemolytic anemia reached 11 mg/dL (2 µmol/L). This is a level that has been associated with scavenging of nitric oxide by plasma Hb, which would deplete the body’s natural antioxidant capacity supplied normally by nitric oxide. It should be noted that hemolysis might be involved as a part of the mechanism of oxidant stress in these patients (26). Low ALP activity is an important and specific finding for fulminant hepatic failure of WD patients, but its mechanism is still unknown. Hoshino et al. (27) suggested that hydroxyl radicals or, alternatively, alkoxyl or peroxide radicals induced by Fenton reaction, may markedly reduce ALP activity through the Mg2+ site of the ALP molecule. We have shown 27.65% inhibition of ATPase activity in our WD patients during hemolytic anemia. Inhibition of ATPase might cause configurational change in erythrocytes making them more susceptible to hemolysis by free copper (28). Hexokinase was also found to be inhibited (50.29%) in our patients. The copper has been reported to be most effective in inhibiting hexokinase and hence glycolysis of rat brain extract, suggesting pathophysiological importance in copper poisoning and in WD (29).
We have observed significant decline of RBC GSH in WD patients with hemolytic crisis. GSH might have been depleted after excessive conjugation with reactive oxygen species, excess copper or with reactive intermediates like those formed during lipid peroxidation. Furthermore, excess copper inhibited the activity of both G-6-PD and glutathione reductase, both of which are necessary for the reduction of oxidized glutathione (GSSG) to GSH. Each of these effects would tend to decrease the reduced GSH content of erythrocytes and make them more vulnerable to oxidative effects of copper as erythrocyte GSH plays an important role in the preservation of red cell integrity, particularly under stressful situations. GSH protects against lipid peroxidation by maintaining protein thiols and consequently [alpha]-tocopherol in the reduced state (30). Lipid peroxidation was significantly greater in erythrocytes of WD patients during a hemolytic episode compared with healthy controls and WD follow-up patients on d-penicillamine. It has been widely recognized that trace amounts of transition metals including copper and iron play a major role in oxidant-induced tissue injury through participation in the generation of hydroxyl radicals, which rapidly react with polyunsaturated fatty acid residues of cell membranes and facilitates lipid peroxidation (31). Our finding is in contrast to that of Ogihara et al. (32), who did not observe increased levels of lipid peroxidation along with no change in plasma [alpha]-tocopherol levels. However, in the present study, increased lipid peroxidation is supported by decreased plasma [alpha]-tocopherol levels. von Herbay et al. (33) also reported 40% lower serum [alpha]-tocopherol levels in their WD patients with a high copper burden. A decrease in [alpha]-tocopherol might be due to its consumption during free radical scavenging as well as to a decrease in GSH and ascorbic acid content as both are involved in the recycling of vitamin E. It is also possible that copper ions catalyze the oxidation of ascorbic acid or sulfhydryl groups, in the process reducing molecular oxygen to generate reduced oxygen metabolites such as superoxide and hydrogen peroxide (34). Superoxide dismutases, catalases, and glutathione peroxidases constitute a mutually supportive team of enzymes, which provide a defense against reactive oxygen species. We observed inhibition of all three enzymes involved. Superoxide radicals when produced in excess may inactivate the H2O2 scavengers (35), and mechanisms involving oxidation of selenocysteine residue at the active site have been proposed. The decreased activities of catalase and glutathione peroxidase might have resulted in efficient removal of H2O2 and its buildup. Excess H2O2 present in the cellular milieu may inactivate superoxide dismutase (36).
In human plasma, ascorbic and uric acid are among the most widely cited forms of water-soluble antioxidants and appear to serve as the main defense against oxidizing species in the aqueous phase (37). Uric acid showed the greatest decrease among various plasma antioxidants in WD patients. Uric acid, a product of purine metabolism in humans, may act as a sacrificial antioxidant against hydroxyl and peroxyl radicals as well as other hazardous oxidants. Uric acid, if consumed as an antioxidant, is destroyed by bacteria in the intestine. However, inosine, which is a naturally occurring substance, increases plasma uric acid levels (38). Plasma ascorbate and sulfhydryl groups also showed a severe decline in WD patients with hemolytic crisis compared with other subjects involved in the study. The decrease of ascorbic acid and sulfhydryl groups in patients with WD may have resulted from their antioxidative degradation. However, in the presence of transition metals, ascorbic acid and sulfhydryl groups are readily oxidized to generate reactive oxygen species and other radical species (34). Accordingly, it is also possible that ascorbic acid and sulfhydryl groups acted as pro-oxidants rather than antioxidants in WD patients during hemolytic crisis. In recent studies, the TRAP assay has provided useful information about plasma antioxidant activity in newborns (23) and patients with cystic fibrosis (39). Plasma antioxidant capacity calculated as TRAP was significantly decreased in WD patients during a hemolytic episode.
Pediatr Res. 2006 Apr;59(4 Pt 1):593-7
Case 19. Опять кровотечения.
Модераторы: Ren_Yumi, AOkhotin, Pyankov Vasily, Алексей Живов, Alon, dr.Ira
... Я отправляю ребенка к гастроэнтерологу - теперь это его головная боль.Alon писал(а):
Пока мы думаем о том, что может вызвать хроническое поражение печени у ребенка 9-ти лет, анализы крови, взятые для исключения различных вирусных гепатитов, вернулись нормальными, аутоиммунный гепатит тоже был исключен.
И тут, переходя от строчки к строчке в списке дифдиагнозов хронических заболеваний печени у детей
На самом деле, спасибо всем за информацию. Мне было очень интересно.
Делай, что должен, и будь, что будет.