Therapeutic strategies in Wilson disease: pathophysiology and mode of action.

Wilson disease is a copper overload disease treatable with the chelators D-penicillamine and trientine to enhance urinary excretion or with zinc which predominantly inhibits absorption. By lifelong treatment a normal life expectancy and significant improvement of hepatic injury as well as neurologic manifestation is achievable. Here we evaluate the mode of action for effective therapy of Wilson disease. We postulate that there is no quantitative removal of copper from the liver possible. The therapeutic goal is the removal of toxic free copper (non-ceruloplasmin, but albumin bound copper). This is achievable by the induction of metallothionein which is accomplished by chelators and in particular by zinc. For control of therapy the option of a direct measurement of free copper would be preferable over the less reliable calculation of this fraction. A therapeutic challenge is still the full restoration of neurological deficits which can hardly be reached by the available chelators. Whether bis-choline-tetrathiomolybdate as intracellular copper chelator is an option has to be awaited. It is concluded that the goal of actual drug therapy in Wilson disease is the normalization of free copper in serum.
Competing Interests: Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-3090). The series “Unresolved Basic Issues in Hepatology” was commissioned by the editorial office without any funding or sponsorship. RW and Wolfgang Stremmel served as the unpaid Guest Editors of the series. RW serves as an unpaid editorial board member of Annals of Translational Medicine from Aug 2018–Jul 2022. The authors have no other conflicts of interest to declare.
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