Diagnosis and treatment of Wilson disease: An update

This guideline has been approved by the American Association for the Study of Liver Diseases (AASLD) and represents the position of the association. These recommendations provide a data-supported approach to the diagnosis and treatment of patients with Wilson disease. They are based on the following: (1) formal review and analysis of the recently-published world literature on the topic including Medline search; (2) American College of Physicians Manual for Assessing Health Practices and Designing Practice Guidelines1; (3) guideline policies, including the AASLD Policy on the Development and Use of Practice Guidelines and the American Gastroenterological Association Policy Statement on Guidelines2; (4) the experience of the authors in the specified topic. A significant problem with the literature on Wilson disease is that patients are sufficiently rare to preclude large cohort studies or randomized controlled trials; moreover, most treatment modalities were developed at a time when conventions for drug assessment were less stringent than at present. Intended for use by physicians, these recommendations suggest preferred approaches to the diagnostic, therapeutic, and preventive aspects of care. They are intended to be flexible, in contrast to standards of care, which are inflexible policies to be followed in every case. Specific recommendations are based on relevant published information. To characterize more fully the quality of evidence supporting recommendations, the Practice Guidelines Committee of the AASLD requires a class (reflecting benefit versus risk) and level (assessing strength or certainty) of evidence to be assigned and reported with each recommendation (Table 1, adapted from the American College of Cardiology and the American Heart Association Practice Guidelines3, 4). AASLD, American Association for the Study of Liver Diseases; BAL, British anti-Lewisite; MR, magnetic resonance; TM, tetrathiomolybdate; WD, Wilson disease. Copper is an essential metal that is an important cofactor for many proteins. The average diet provides substantial amounts of copper, typically 2-5 mg/day; the recommended intake is 0.9 mg/day. Most dietary copper ends up being excreted. Copper is absorbed by enterocytes mainly in the duodenum and proximal small intestine and transported in the portal circulation in association with albumin and the amino acid histidine to the liver, where it is avidly removed from the circulation. The liver utilizes some copper for metabolic needs, synthesizes and secretes the copper-containing protein ceruloplasmin, and excretes excess copper into bile. Processes that impair biliary copper excretion can lead to increases in hepatic copper content. Wilson disease (WD; also known as hepatolenticular degeneration) was first described in 1912 by Kinnear Wilson as “progressive lenticular degeneration,” a familial, lethal neurological disease accompanied by chronic liver disease leading to cirrhosis.5 Over the next several decades, the role of copper in the pathogenesis of WD was established, and the pattern of inheritance was determined to be autosomal recessive.6, 7 In 1993, the abnormal gene in WD was identified.8-10 This gene, ATP7B, encodes a metal-transporting P-type adenosine triphosphatase (ATPase), which is expressed mainly in hepatocytes and functions in the transmembrane transport of copper within hepatocytes. Absent or reduced function of ATP7B protein leads to decreased hepatocellular excretion of copper into bile. This results in hepatic copper accumulation and injury. Eventually, copper is released into the bloodstream and deposited in other organs, notably the brain, kidneys, and cornea. 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