Zinc treatment for symptomatic Wilson disease: moving forward by looking back.

Treatment with oral chelation therapy withD-penicillamine for copper accumulation inWilson disease was first developed in the 1950s, and preemptive treatment became the standard of care for patients.1 An alternative chelating agent, trientine, was developed more than a decade later and has gained more acceptance as first-line treatment due to its safety profile and demonstration of efficacy.2,3 Zinc was first utilized in veterinary medicine as a treatment for copper accumulation in sheep by Dick et al.4 in 1954. Borrowing from this experience, the first human use of zinc for patients with Wilson disease were conducted by the Dutch investigator Schouwink in 1961.5 He recognized that zinc could block copper absorption, and later discoveries revealed that this occurred indirectly by the stimulation of a unique endogenous chelator, metallothionein (MT).6 MT, a mainly cytosolic peptide with a 30% content of cysteine, binds metals such as zinc and copper avidly, and copper with a higher affinity. When present in the cytosol of enterocytes, MT binds newly absorbed copper and prevents it from passing from the gut into the circulation where it is ordinarily utilized for metabolic needs. However, in those afflicted with Wilson disease, copper that is absorbed by the gut accumulates pathologically in the liver and neurological systems due to the altered function of the copper-transporting adenosine triphosphatase, ATP7b, that is mainly expressed in the liver.7 The shedding of enterocytes with copper still bound to MT results in a higher fecal copper content and net loss of copper from the body because copper does not undergo enterohepatic recirculation and other losses occur via secretions and cell loss. The vast majority of early reports on the use of zinc therapy for Wilson disease focus on the role of zinc in maintenance therapy for patients treated with prior chelation therapy, or for treating asymptomatic patients. Even though this evidence base has grown over the years, many treating physicians still believe that only chelating agents can be safely used for treatment of Wilson disease. Some investigators reported over the years about many of their patients maintained on zinc, but information about howwell they did and failures of treatment was not as well documented. In the United States, George Brewer at the University ofMichigan performed pharmacokinetic studies of copper absorption of patients treated with zinc, demonstrating that this agent—when used in multiple daily doses and not as a single daily dose—effectively blocked copper absorption.8 This blockage of copper absorption eventually reduced the body’s copper burden over time in most patients, but in some tissue copper seemed not to change significantly despite clinical improvement. This suggested detoxification by zinc by other means than removal of copper. One such possibility is for zinc treatment to stimulate the production of MT in other cell types in addition to enterocytes. This has been shown to occur in vitro for liver cell lines,9 but whether MT is maximally stimulated already in liver cells with high copper content and whether zinc can further protect these already copper-laden cells is uncertain. Further studies demonstrated that zinc could be used alone as a single agent to treat adults, pediatric patients, and pregnant patients with Wilson disease.10-13 The dosage for treatment of pediatric patients was 25 mg given thrice daily, and for adults was 50 mg given with the same frequency. Although balance studies showed twice daily was adequate, many patients miss dosages and so the third dose was established mainly for safety to prevent undertreatment. There are some reports of symptomatic patients being treated with zinc in the early stages of their disease, but these are usually after intolerance to D-penicillamine or worsening of their neurological disease on D-penicillamine. Though some clinicians report successful treatment, systematic evaluation of a cohort of symptomatic patients withWilson disease being solely treated with zinc without chelation therapy were lacking until the report by Linn et al.14 This unique report focuses on 17 patients followed for a median of 14 years with Wilson disease who presented with symptomatic disease, either with neurological or with hepatic disease or with both. These patients were carefully evaluated and then placed on zinc therapy. Linn et al. observed that many patients improved with this therapy alone, although this occurred more consistently for those with neurological disease without adAbbreviation: MT, metallothionein. Address reprint requests to: Michael Schilsky, M.D., Yale University Medical Center, 333 Cedar Street LMP1080, New Haven, CT 06520. E-mail: [email protected]; fax: 203-785-6645. Copyright © 2009 by the American Association for the Study of Liver Diseases. Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hep.23355 Potential conflict of interest: Nothing to report.