Background and Objective: The therapeutic arsenal in Wilson disease is limited, but effective. It focuses on copper depletion, although this has never been defined nor measured. Accordingly, disorder adapted long term dosing strategies are missing. Goal of the analysis was the elucidation of copper metabolism in Wilson disease to detect critical mechanisms inducing cell injury and strategies for prevention. Methods: We seeked the literature between years 1980–2022 under the following key words: mechanism of liver injury in Wilson disease, therapeutic strategies, monitoring and outcome. Key Content and Findings: Copper is absorbed by intestinal mucosa depending on its content in diet. Release in bile controls the copper balance. In Wilson disease biliary copper excretion is genetically diminished and copper accumulates in hepatocytes mainly bound to metallothionein. Hepatocellular copper overload leads to release in blood for excretion in urine and distribution to other organs, preferentially to the basal ganglia of the brain. Excess of intracellular free copper bears the risk of parenchymal damage, e.g., hepatic and neurologic manifestation. One therapeutic approach intends the reduction of free copper in blood by chelation and consequent enhanced urinary excretion. As alternative therapy the oral application of zinc is possible. Zinc is a very potent metallothionein inducer operative mainly in mucosal cell, but also in hepatocytes. Metallothionein copper complexes caught in mucosal cells are lost with their desquamation and, thus, intestinal copper absorption is reduced. Conclusions: It is the free copper which induces the organ manifestation in Wilson disease and represents the target of therapy.
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