Histological features of liver disease development in the Atp7b-/- mouse: a model of Wilson's disease.

Abstract

Aims: Wilson's disease (WD) is caused by mutations in the ATP7B gene, resulting in copper accumulation and toxicity in liver and brain tissues. Due to the initial asymptomatic liver involvement, the progression of liver injuries in WD stays primarily unknown. Atp7b-/- knockout mice have been shown to be an appropriate model of WD for liver involvement.

Methods: A total of 138 Atp7b-/- mice were included and separated into five groups according to age as follows: 6, 20, 39 and 50 weeks without treatment, and 50 weeks with copper chelator treatment from 39 to 50 weeks of age and compared with 101 wild-type (WT) mice at the same stages. The evolution of histological liver lesions was analysed and compared between groups.

Results: Significant changes were observed in Atp7b-/- mice compared with WT. Copper deposits in hepatocytes appeared as early as 6 weeks but no significant increase over time was observed. Inflammation appeared as early as 6 weeks and progressed henceforth. Lobular and periportal acidophilic bodies appeared after 20 weeks. Significant atypia was also observed at 20 weeks and increased over time to reach a severe stage at 39 weeks. Fibrosis also became apparent at 20 weeks, progressing subsequently to precirrhotic stages at 50 weeks. Copper content, inflammation and fibrosis scores were significantly reduced in the treated group. No bile duct lesions or dysplastic changes were noted.

Conclusions: Copper accumulation leads to progressive changes in Atp7b-/- mice regarding inflammation, fibrosis and atypia. The severity of liver damage is lessened by chelation therapy.