Diagnosis and Current Therapy of Wilson's Disease

P. Ferenci

Disclosures

Aliment Pharmacol Ther. 2004;19(2) 

In This Article

Diagnosis

The diagnosis of neurological Wilson's disease is usually made on the basis of clinical findings and laboratory abnormalities (see Table 1 ). No additional tests are required if Kayser-Fleischer rings are present and/or serum ceruloplasmin levels are low.[24] However, there are a few well-documented cases of neurological Wilson's disease without Kayser-Fleischer rings.[25] Clinical neurological examination is more sensitive than any other method for the detection of neurological abnormalities. Brain magnetic resonance imaging is useful for documenting the extent of changes in the central nervous system.[26] The most common abnormalities are changes in the signal intensity of grey and white matter and atrophy of the caudate nucleus, brainstem and cerebral and cerebellar hemispheres.

The diagnosis is more complex in patients presenting with liver diseases (see Figure 3). None of the commonly used parameters alone allows a certain diagnosis of Wilson's disease. Usually, a combination of various laboratory parameters is necessary to firmly establish the diagnosis. Kayser-Fleischer rings may be absent in up to 50% of patients with Wilsonian liver disease and in an even higher proportion with fulminant Wilson's disease. Serum ceruloplasmin may be in the low to normal range in up to 45% of patients with hepatic Wilson's disease.[27] On the other hand, even a low ceruloplasmin level is not diagnostic for Wilson's disease in the absence of Kayser-Fleischer rings. Ceruloplasmin can be decreased in severely malnourished subjects and in heterozygous carriers of the Wilson's disease gene.[28] Very low levels were found in a patient with autoimmune hepatitis, which increased following steroid treatment. Ceruloplasmin is undetectable in familial aceruloplasminaemia. Thus, in patients with liver disease, a normal ceruloplasmin level cannot exclude Wilson's disease, nor is a low level sufficient to make a diagnosis of Wilson's disease. Ceruloplasmin is an acute phase reactant and its serum concentration increases as a consequence of inflammation. Most patients with marked liver disease have normal ceruloplasmin levels. An over-estimation of serum ceruloplasmin can be suspected if the serum copper concentration is lower than expected from the measured ceruloplasmin level (which contains 0.3% of copper). The 'free' copper concentration can be calculated by subtracting from the total copper concentration the ceruloplasmin-bound copper (ceruloplasmin times 3.3). An increased 'free' copper is not useful diagnostically, but can be employed as an adjunct to diagnosis, and is more important for monitoring the response to treatment.

Figure 3.

An algorithm for the diagnosis of Wilson's disease. CPL, ceruloplasmin; KFR, Kayser-Fleischer rings. *Depends on availability. †In Europe: H1069Q, exons 8 and 15. Either at baseline or after D-penicillamine challenge.

Urinary copper excretion is increased in patients with Wilson's disease; however, its usefulness in clinical practice is limited. The estimation of urinary copper excretion may be misleading due to the incorrect collection of the 24-h urinary volume or to copper contamination. In pre-symptomatic patients, urinary copper excretion may be normal, but increases after D-penicillamine challenge.[29] However, urinary copper excretion is also increased in any disease with extensive hepatocellular necrosis.

The hepatic copper content is increased in 82% of patients with Wilson's disease and usually exceeds 250 µg/g dry weight (normal, up to 50 µg/g dry weight). In the absence of other tests suggestive of abnormal copper metabolism, a diagnosis of Wilson's disease cannot be made on the basis of an increased hepatic copper content alone. Patients with chronic cholestatic diseases, neonates and young children and possibly also subjects with exogenous copper overload have increased hepatic copper concentration of > 250 µg/g dry weight. In a recent study, we measured the hepatic copper content in 103 liver biopsies obtained at the diagnosis of Wilson's disease, in 212 patients with a variety of non-cholestatic liver diseases (including 144 with chronic hepatitis C and 44 with non-alcoholic fatty liver disease), in 27 patients with chronic cholestasis and in 26 patients without evidence of liver disease.[23] The liver copper content was > 250 µg/g dry weight in 85 (81%) Wilson's disease patients, between 50 and 250 µg/g dry weight in 15 and in the normal range in four. The liver copper content did not correlate with age, grade of fibrosis or presence of stainable copper. The liver copper content was > 250 µg/g dry weight or between 50 and 250 µg/g dry weight in three (1.4%) and 20 (9.1%) of the 219 patients with non-cholestatic liver diseases, respectively. By lowering the cut-off from > 250 to 75 µg/g dry weight, the sensitivity of liver copper content for the diagnosis of Wilson's disease increased from 81.2% to 96%, the negative predictive value increased from 88.2% to 97.1%, but the specificity (98.6% to 90.1%) and the positive predictive value (97.6% to 87.4%) decreased. It was concluded that, although liver copper content is a useful parameter, it neither proves or excludes Wilson's disease with certainty. The diagnosis requires a combination of a variety of clinical and biochemical tests. Recently, a group of international experts has discussed this issue and has proposed a score based on a variety of tests and clinical symptoms.[30] The validity of this score needs to be assessed prospectively.

Liver biopsy findings are generally non-specific and are not helpful for the diagnosis of Wilson's disease; however, the exclusion of other aetiologies may be equally important and may require a liver biopsy. The pathology includes early changes, such as fatty intracellular accumulations, which often proceed to marked steatosis. At later stages, portal and periportal lymphocytic infiltrates and the presence of necrosis and fibrosis may be indistinguishable from other forms of hepatitis. Some patients have cirrhosis without any inflammation. The detection of focal copper stores by the rhodanine stain is a pathognomonic feature of Wilson's disease, but is only present in a minority (about 10%) of patients.[31]

The ultrastructural abnormalities include changes in mitochondria and peroxisomes and are stage specific.

Mutation analysis for diagnosis is cumbersome because of the occurrence of many mutations, each of which is rare. Furthermore, most patients are compound heterozygotes (i.e. carry two different mutations). Direct mutation analysis for diagnosis is only helpful if a mutation occurs with a reasonable frequency in the population. In northern, central and eastern Europe,[12,14,15] the most common mutations are: H1069Q mutation (allele frequency, 43.5%), mutations of exon 8 (6.8%), 3400delC (3%) and P969Q (1.6%).[32] In other parts of the world, the pattern of mutations is different (Turkey, A1003T and P969Q;[33] Sardinia, UTR -441/-427del, 2463delC;[34] Far East, R778L[35,36]). Eventually, a multiplex polymerase chain reaction for the most frequent Wilson's disease mutations in the region should make direct mutation analysis for diagnosis feasible and obtainable within a week.

Once a diagnosis of Wilson's disease is made in an index patient, an evaluation of his or her family is mandatory. The likelihood of finding a homozygote amongst the siblings is 25% and amongst the children 0.5%. Testing of second-degree relatives is only useful if the gene is found in one of the immediate members of the relative's family. No single test is able to identify affected siblings or heterozygote carriers of the Wilson's disease gene with sufficient certainty.[37] Today, mutation analysis is the only reliable tool for screening the family of an index case with known mutations; otherwise haplotype analysis can be used. A number of highly polymorphic microsatellite markers that closely flank the gene allow the Wilson's disease gene to be traced in a family.[38] For such an analysis, at least one first-degree relative and the index patient are required.

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