Can Patients with Wilson's Disease Develop Copper Deficiency?

Abstract

BackgroundWilson's disease (WD) is a rare genetic condition characterized by a copper overload in organs secondary to mutation in ATP7B gene. Lifelong decoppering treatments are the keystone of the treatment but must be regularly adapted to obtain a correct copper balance and could lead to copper deficiency (CD).ObjectivesStudy the characteristics of CD in WD patients.MethodsCD cases from our cohort of 338 WD patients have been investigated. CD was defined by the association of serum copper, exchangeable copper and urinary copper excretion assays less than two standard deviations from the mean with cytopenia and/or neurological damage of spinal cord origin. A systematic review of literature about cases of CD in WD patient was performed in PubMed database according to PRISMA guidelines.ResultsThree WD patients were diagnosed with CD in our cohort. Review of the literature found 17 other patients. Most of the patients had anemia and neutropenia associated with neurological symptoms (especially progressive posterior cord syndrome). All the patients were treated with Zinc salts and the symptoms occurred more than a decade after the initiation of treatment. The adaptation of the treatment allowed a correction of the cytopenia but only a partial improvement of the neurological symptoms.ConclusionsWD patients can develop CD after many years of zinc therapy. Anemia and neutropenia are red flags that should evoke CD.

Redox homeostasis in cardiac fibrosis: Focus on metal ion metabolism

“…Patients with liver and kidney insufficiency are unable to transport the ingested copper ions in the body in time, resulting in the deposition of copper ions in the body. In addition, some inherited or acquired disorders can cause copper ion homeostasis [ 33 , 34 ]. Since copper is essential for the proper functioning of cells, and copper overload is cytotoxic, the amount and distribution of available copper in the body must be tightly controlled to minimize the potential toxicity of copper while meeting metabolic needs.…”

The Paradox of Copper Deficiency in Wilson's Disease Patients

“…The study of Chevalier et al 1 also raises the question of how to monitor the status of body deposits of copper and those of zinc in WD patients on therapy. It is widely accepted that during zinc therapy, the levels of zincuria must be higher than 2000 μg (61 μmol)/24 hours, whereas the cupruria must be lower than 75 μg (1.2 μmol)/24 hours 4,5 .…”

“…In recent American Association for the Study of Liver Diseases guidelines, it is reported that the development of cytopenias, an increase in serum ferritin, and/or disproportionately low 24‐hour urinary copper excretion (<100 μg/24 hour for chelation therapy; <20 μg/24 hour [<0.3 μmol/24 hour] for zinc therapy) may be indicative of overtreatment 4 . Information on the behavior of ferritin is lacking in the Chevalier et al's 1 study and in the literature review. This study once again underlines the role of free copper determination in monitoring a WD patient under therapy, but as is well known, despite the initial encouraging studies, it is not a test for routine use 4 …”

“…It is also paradoxical that this deficiency develops in patients treated with zinc rather than in those treated with chelators, which have a stronger action in decoppering the organism. Based on the Chevalier et al's 1 series and the literature review, therapy‐induced CD in WD patients seems to be a rare event, which, however, must be kept in mind by clinicians managing WD because the clinical and laboratory signs of CD can be overlooked and because they can be erroneously attributed to other causes. Furthermore, it is clinically relevant that, differently from cytopenia because of CD, neurological symptoms induced by CD (especially those of spinal cord involvement) tend to persist despite treatment of CD.…”

“…Less easily explained is why CD occurs in only a small subset of cases. In Chevalier et al's 1 study a patient with CD received, for unexplained reasons, a much higher dose of zinc sulfate than is usually recommended, but in other cases zinc doses were adequate. Unfortunately, however, any predictive factors of CD have been identified.…”