Diagnosis and Treatment of Wilson's Disease Indu Subramanian, MD, Zeba F. Vanek, MD, DCN, DM, and Jeff M. Bronstein, MD, PhD Address Department of Neurology, UCLA School of Medicine, 710 Westwood Plaza, Los Angeles, CA 90095, USA. E-mail: jbronste@ucla.edu Current Neurology and Neuroscience Reports 2002, 2:317–323 Current Science Inc. ISSN 1528–4042 Copyright © 2002 by Current Science Inc. Introduction Wilson's disease (WD) is an autosomal recessive disorder of copper metabolism. Also known as hepatolenticular degeneration, WD was first reported in 1912 by Samuel Kinnear Wilson, a neurologist at Queens Square, London. He described seven patients with "a unique, progressive, familial syndrome of cirrhosis of the liver and a distur- bance of the motor system" [1]. He hypothesized that the causative agent was a toxin. Kayser in 1902 and Fleischer in 1912 independently reported bands of pigmentation around the cornea, which later became known as Kayser Fleischer (KF) rings in WD patients. Bearn described the autosomal recessive pattern of the disease, and in 1952, Scheinberg and Gitlin [2] found that there was a deficient amount of ceruloplasmin in the serum of patients with WD. Frydman et al. [3] mapped the gene responsible for WD to chromosome 13 in 1985. In 1993, the gene locus was cloned and was found to encode a cation transporting P-type adenosine triphosphatase (ATPase) [4,5]. Pathogenesis Copper (Cu) is an essential element that mediates an array of vital human functions. The Cu balance is mediated entirely by gastrointestinal (GI) absorption and biliary excretion. The adult human diet contains 4 to 6 mg/d of Cu. Forty percent of this is absorbed and equal amounts are returned to the GI tract in the form of bile. Total-body Cu can be modified by changes in diet, and Cu-binding medications can be utilized to inhibit Cu absorption in the GI tract. Ceruloplasmin is a protein that is abundant in the blood. Within 24 hours of administration, 10% of a test dose of radiolabeled Cu is found to be bound to cerulo- plasmin. However, patients with aceruloplasminemia still have normal copper homeostasis. Hence, it is unlikely that ceruloplasmin has a functional role in copper transport from the GI tract. Some plasma Cu also binds to amino acids, including histidine. Copper is believed to be taken up by hepatocytes using a Cu transporter (CTR 1 and 2), where it is subsequently stored [6]. Excretion of Cu is highly regulated and primarily into bile, and it is directly proportional to the hepatic Cu pool. Hepatocytes excrete copper depending on their intracellular copper concentra- tion through the regulation of a copper-transporting ATPase localized to the trans-Golgi network. An elevated intracellular copper concentration causes redistribution of copper to the vesicular compartment in the cytoplasm. This decreased Cu concentration in the cytoplasm signals return of the ATPase to the trans-Golgi network and Cu to be excreted in the bile (Fig. 1) [7,8]. The ceruloplasmin glycoprotein binds more than 95% of the total copper found in plasma. It is synthesized in hepatocytes and secreted as a holoprotein with six Cu atoms incorporated in it. If there is a failure to incor- porate the Cu, the ceruloplasmin gets secreted as an apoprotein that is quickly degraded in the plasma. Hence, if there is no Cu being secreted, then there is a resultant marked decrement in ceruloplasmin, as seen in WD patients [9,10,11••]. Wilson's disease (WD) is an autosomal recessive disease that causes increased copper deposition in the liver and basal ganglia with resultant hepatic and neurologic sequelae. In the past few years, dramatic new discoveries have changed our understanding of the pathophysiology of WD. Although there are potentially life-saving therapies for WD, there is much controversy surrounding the optimal treat- ments of patients in the various stages of the disease. Specifically, the relative roles of penicillamine, trientene, and tetrathiomolybdate in the initial treatment of the symptomatic patient with WD remain to be defined. Zinc monotherapy for maintenance treatment and in the treat- ment of asymptomatic patients with WD is still contro- versial. It is also unclear whether neurologic status alone is an indication for liver transplantation in WD. This paper reviews the pathogenesis, genetics, clinical presentation, and diagnosis, with a special emphasis on the treatment controversies that arise in the care of the WD patient.