fig3

Figure 3. Depiction of the potential hepatotoxic effects of copper accumulation in Wilson disease. Initially, excess copper is sequestered within cytosolic metallothionein. Once these stores are full, copper can be re-excreted through CTR1 into the bloodstream. From there, it is transported as non-ceruloplasmin-bound copper within a histidine/albumin shuttle complex to other organs, such as the brain, and eventually excreted in urine. In hepatocytes, additional copper buildup leads to lysosomal deposition, which can be detected by positive Rhodanine staining. The reactive nature of Cu⁺ damages the lysosomal membrane, causing rupture and the release of Cu⁺ into the cytoplasm, resulting in damage to hepatocytes. This process also renders the plasma membrane permeable, allowing Cu⁺ to leak into the bloodstream and contribute to erythrocyte membrane destruction (hemolysis). Cu⁺: Cuprous form; Cu²⁺: cupric form; ATOX1: antioxidant copper chaperone; ATP7B: ATPase copper transporter beta; CTR1: copper transporter 1.