Mechanisms of action of zinc sulphate in the treatment of Wilson disease

Abstract

Wilson disease (WD) can be effectively treated with zinc: the mechanisms of action are still debated and probably involve induction of metallothionein (MT) synthesis. We measured MT, zinc and copper concentrations in the duodenal mucosa and in the hepatic tissue of WD pts on long term treatment either with zinc sulphate or D-penicillamine. Fifteen WD pts (3F, 12M, mean age: 25.8 years) underwent endoscopy with duodenal biopsies and liver biopsy as part of the diagnostic or follow up protocol. 12 pts were receiving zinc sulphate (ZnSO4, 220 mg po rid), 2 D-PCA (1200 mg/day) and one patient was studied at diagnosis. Two groups of patients were included as controls: 17 pts (8F, 9M, mean age 32 years) undergoing endoscopy for dyspepsia and 8 pts (5F, 3M, mean age 41 years) undergoing liver biopsy for chronic viral hepatitis. MT concentration (ug/mg protein) was measured by the Silver saturation method, zinc (ug/mg dry wt) and copper (ug/mg dry wt) by atomic absorption spectrophotometry. Duodenal findings: MT concentration was significantly increased in WD pts on zinc therapy (11.66 _+ 9) with respect to controls with negative endoscopy (0.76 _+ 0.38), pts with duodenitis (1.4 _+ 0.5) and pts on D-PCA (1.2 + 0.04) (p<0.005). The WD pt observed at diagnosis had MT concentration of 0.6 ug/mg protein. Zinc concentration was significantly increased in the duodenal mucosa of WD pts receiving zinc (594.1 _+ 318) with respect to controls (138.7 _+ 26 dry wt). A significant correlation was found between MT and zinc concentration in WD pts treated with zinc (r=0.916). Copper concentration was not measurable in the duodenal mucosa either in WD pts and in controls. Liver findings: WD pts, treated with zinc, had significanly increased MT concentration (1890_+516) with respect to controls (259_+ 240) (p<0.05). Hepatic zinc concentration was significantly increased in WD pts receiving zinc (1111 _+ 811) than in WD pts receiving D-PCA (272 ± 172) and in controls (308 _+ 253) (p<0.05). Copper concentration was above 250 ~tg/mg dry wt in WD pts and less than 50 ~ag/mg dry wt in controls:no significant difference in liver copper concentration was found according to treatment. In conclusion, zinc administration induces both intestinal and hepatic MT in WD patients. The blockade of copper absorption and its elimination in the stool on desquamation of the intestinal cells may explain one of the mechanisms of action of zinc therapy MT induced synthesis in the liver cells may bind copper in non-toxic complexes.