Wilson Disease

Pathogenesis and Clinical Considerations in Diagnosis and Treatment

Richard Rosencrantz, M.D.; Michael Schilsky, M.D.

Disclosures

Semin Liver Dis. 2011;31(3):245-259. 

In This Article

History

The disease is named after the American-born British neurologist, Dr. Samuel Alexander Kinnier Wilson who, in 1912, composed his doctoral thesis on the pathologic findings of "lenticular degeneration" in the brain associated with cirrhosis of the liver.[1] Dr. Wilson's report was preceded almost 30 years earlier by Dr. Carl Westphal's clinical description of what he termed "pseudosclerosis" in patients suffering from tremors without anatomic findings on autopsy.[2] Dr. Wilson's work built upon the experience in part from a series of patients collected by Sir William Gowers,[3] who similarly identified the combination of neurologic and liver disease in 1888. Although the medicinal and toxic effects of copper have been known since antiquity,[4] it was A.J. Glazebrook[5] in 1945 and John Cumings[6] in 1948 that linked copper accumulation with the basal ganglia and hepatic pathology. The genetic inheritance was originally proposed by H.C. Hall[7] in 1921 as an autosomal recessive pattern, but subsequently confirmed by A.G. Bearn[8] in 1953 by genetic ratio analysis calculation. Over 30 years later, its genetic locus was assigned to the long arm of chromosome 13.[9] Ultimately, the genetic basis for Wilson disease (WD), the ATP7B mutation, was identified and cloned in 1993.[10,11]

The diagnosis of WD first was dependent on recognition of the syndrome of neurologic findings with associated cirrhosis, but this was dramatically changed when Kayser-Fleischer (K-F) rings were identified as present in clinically affected patients. Diagnostic testing improved further decades later by the routine adoption of testing for liver dysfunction using serum and blood tests and liver biopsy[12] to evaluate histology, quantify hepatic copper concentration, measure elevated urine copper excretion, and by the recognition that serum or plasma ceruloplasmin concentrations are reduced in most patients with WD.[13] These findings form the basis for most of the phenotypic characterization of patients that we still use to date. Other adjunctive testing included the use of radiocopper testing for labeled ceruloplasmin that was useful for identifying the minority of patients with WD with normal levels of ceruloplasmin, but this test is rarely used today. The most recent advance in testing is molecular genetic testing that has followed the identification of the gene for WD and disease-specific mutations.

We have been able to effectively treat WD for less than a century. Historically, the disease was diagnosed after the development of neurologic symptoms and was invariably fatal. The first treatment developed was British anti-lewisite (BAL), a compound developed for countering the toxic effects of mustard gas that was found to be a chelator of copper. This parenterally administered medication resulted in increased copper excretion and reversed neurologic symptoms in many patients.[14] The first oral treatment, d-penicillamine, was developed by John Walshe,[15] who recognized the potential for this compound to chelate copper and induce cupriuria with high efficiency. He was also instrumental in the development of another chelating agent, trientine,[16] and was the first to use tetrathiomolybdate in humans,[17] a compound originally used by veterinarians for copper-poisoned sheep. Confirmation of the utility of tetrathiomolybdate has also been performed by Brewer et al.[18] Schouwink[19] was the first to propose using zinc to block copper absorption to treat WD, and this has been another useful oral therapy currently in use for many patients. A very important historic milestone with respect to treatment of WD was the recognition that preemptive treatment could prevent the development of disease progression, something that seems almost incontrovertible at this time, but which was not initially accepted.[20] Liver transplantation is curative and represents a gross form of genetic therapy for WD.

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