Wilson's Disease

, From the Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri

Semin Liver Dis. 2000;20(3) 

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Wilson's disease has been detected in all known ethnic groups and occurs worldwide with an estimated frequency of 1 in 30,000 and a carrier rate of 1 in 90. [84] This frequency is increased in populations where consanguinity was once a common practice. The presenting clinical features of Wilson's disease are protean, and the physician must be alert to the possibility of this diagnosis in anyone with unusual symptoms and tests indicative of abnormal liver function. [85] Nevertheless, most patients with Wilson's disease will have signs of neuropsychiatric or hepatic disease early in their course.[86,87] Hepatic dysfunction is the most common initial manifestation in childhood, with patients in this category presenting at an average age of 10-13 years, a decade or more sooner than those presenting with neurologic symptoms. [88] Liver disease ranges from mild elevation of the serum transaminases in asymptomatic individuals to chronic active hepatitis and cirrhosis. In certain circumstances, the initial presentation may be that of acute liver failure accompanied by the sudden release of excess copper into the bloodstream with resultant hemolytic anemia. This process of rapid hepatic degeneration in a previously well-appearing individual suggests the presence of a viral illness or external factor that has triggered injury in a copper-loaded liver. [89] Irrespective of the initial symptoms, almost all patients will have some evidence of cirrhosis on liver biopsy, reflecting the response to years of hepatic copper accumulation before clinical symptoms. Such biopsies may reveal micronodular cirrhosis with evidence of copper deposition in a variable distribution throughout the liver lobules. Eventually, this histology progresses to that of chronic hepatitis with nodular regeneration. [90] As mentioned above, hepatocellular carcinoma is a rare consequence of Wilson's disease.

Neurologic symptoms may occur at initial presentation in 60% of patients, usually in the third or fourth decade of life. Parkinsonian symptoms predominate and include diminution in facial expressions, tremors, dystonia, hypertonicity, and choreoathetosis. [91] As expected, these clinical features mirror the underlying pathologic changes of cavitary degeneration in the basal ganglia with extensive gliosis and neuronal loss in association with a marked increase of the copper content in this region of the brain. These underlying structural changes and the copper deposition can be detected by magnetic resonance imaging at an early stage in symptomatic patients and may be observed to decrease with chelation therapy. [92] Although it is apparent that this copper deposition arises from the steady release of hepatocyte copper into the bloodstream, the mechanisms resulting in specific involvement of the basal ganglia are unknown. Psychiatric illness may occur alone or in combination with other symptoms and includes abnormal behavior, personality changes, depression, and cognitive impairment indicative of schizophrenia. [93] Because these symptoms arise from copper deposition in the central nervous system, awareness of Wilson's disease as a possible cause can lead to early diagnosis and treatment with a rapid overall improvement.

In addition to these common hepatic and neurologic presentations, signs and symptoms of Wilson disease may arise as a result of dysfunction of any organ in which excess copper is deposited. [84] Clinical manifestations may include Fanconi syndrome with amino-aciduria, nephrolithiasis, cardiac dysrhythmias, arthritis or arthralgias, rhabdomyolisis, hemolytic anemia, hypothyroidism, hypoparathyroidism, and secondary amenorrhea. These features are often reversible with chelation therapy, confirming the etiology as copper accumulation rather than the underlying liver disease. Asymptomatic copper deposition may be detected in the limbus of the cornea by slit-lamp examination (Kayser-Fleischer rings) and as azure lunulae in the fingernails.

Laboratory evaluation to confirm the diagnosis of Wilson's disease is warranted in anyone with isolated elevation of serum transaminases, chronic hepatitis of undetermined cause, Kayser-Fleischer rings, basal ganglia symptoms, or unexplained psychiatric illness, including sudden behavioral changes. The impairment in copper transfer to the secretory pathway results in serum ceruloplasmin concentrations well below the normal range, making this a useful diagnostic test. Ceruloplasmin is an acute phase protein, and thus this value will be in the normal range in 5% of patients due to infection or inflammation. Nevertheless, in all cases evaluation of ceruloplasmin oxidase activity will be negative, revealing a circulating apoprotein devoid of copper.[94,95] Another inexpensive screening test is measurement of urinary copper concentration that is frequently elevated (usually >100 g Cu/24 h). In most cases, a liver biopsy will be warranted to obtain an accurate measurement of hepatic copper (>250 g/g dry wt) that will be elevated even in asymptomatic patients. Using history, physical examination, slit-lamp exam, and these laboratory data, the diagnosis of Wilson's dis-ease can usually be made with great accuracy. Patients with cholestatic liver disease of any cause may also have elevated hepatic copper content, but in these cases serum ceruloplasmin will be normal or elevated. Idiopathic (Indian) childhood cirrhosis is a disorder of progressive liver failure in early childhood with marked accumulation of hepatic copper. Although the etiology of this disorder is unknown, in all such cases the serum ceruloplasmin is elevated, suggesting a defect in biliary copper excretion beyond the point of entry into the secretory pathway96,97 (Fig. 2). Patients with aceruloplasminemia present with neurologic symptoms and absent serum ceruloplasmin but are easily distinguished by normal hepatic copper content and marked elevation of parenchymal iron. [98] The molecular heterogeneity in Wilson's disease precludes diagnostic testing at the DNA level in most cases; however, analysis for common mutations in patients of distinct ethnic origin may be helpful. [99] Where family studies are available, unique haplo-type analysis followed by direct mutation identification can also prove useful. [100] All these DNA studies are complicated by the fact that most patients will be compound heterozygotes carrying two distinct mutations.

Wilson's disease is a treatable genetic disorder, and therefore a rapid and sensitive screening test would be of enormous clinical value. However, the relatively low heterozygote frequency and the lack of a useful biochemical marker in the neonatal period when serum ceruloplasmin is normally very low means that such screening is currently confined to siblings and first-degree relatives of affected pataients. [75] In all such individuals, a careful history and physical examination should be performed and slit-lamp exam, serum ceruloplasmin and transaminases, and urinary copper determination. If this evaluation suggests the diagnosis even in otherwise asymptomatic individuals, a liver biopsy is warranted to measure hepatic copper. For obligate heterozygotes, these studies will all be normal with the exception of serum ceruloplasmin, which may be decreased in 20% of such cases. If the proband mutation has previously been identified, molecular screening of family members can also offer a rapid approach to diagnosis. In all cases of identified carriers, reproductive genetic counseling should be made available.


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