Wilson's Disease: An Update

Shyamal K Das; Kunal Ray

Disclosures

Nat Clin Pract Neurol. 2006;2(9):482-493. 

In This Article

Diagnosis and Monitoring

Achieving a diagnosis of WD is dependent on maintaining a high index of suspicion. On the basis of a recent case report,[25] it is recommended that all subjects presenting with symptomatic or asymptomatic liver disease with no apparent cause, or with extrapyramidal features along with a past or family history of similar hepatic or neurological illnesses in other siblings, should be screened for WD.

As a consequence of the varied clinical manifestations of WD, the condition is commonly underdiagnosed.[34] Table 1 provides a comprehensive list of disorders for which WD should always be considered in the differential diagnosis. The KF ring is an important marker in neurological WD, and in strongly suspected cases a repeat slit lamp examination should be undertaken by an experienced ophthalmologist if the initial result is negative.

Recently, a scoring system based on clinical and biochemical parameters was proposed at the 8th International Conference on Wilson Disease and Menkes Disease, 2001 for the diagnosis of WD (scoring ranges from 0 to 4; a score of 4 = definitive WD; a score of 2-3 = likely WD; and a score of 0-1 = improbable WD).[35]

WD is biochemically characterized by low ceruloplasmin and total serum copper levels, increased 24-hour urinary copper excretion, and abnormally high hepatic copper content.[36]

Measurement of the serum ceruloplasmin level is important. Normal values, which range from 200 to 400 mg/l, can show some variation depending on the method of estimation—nephelometry is commonly performed, and an oxidase assay can also used. The latter method will provide near-actual values. Because ceruloplasmin acts as an acute phase reactant as well as a copper transporter, falsely high levels will be seen when patients have active inflammation, are pregnant, or are taking estrogens. Any value below 200 mg/l is abnormal, and reduced levels are seen in up to 95% cases of WD. Low levels of ceruloplasmin can also be found in cases of Menkes disease, hereditary aceruloplasminemia, protein-losing enteropathy including celiac disease and severe hepatic insufficiency, and in heterozygous carriers of WD.[21]

An estimation of 24-hour urinary copper excretion is another reliable test for confirmation of WD. Normal excretion is between 20 and 50 µg per day; in cases of WD, excretion is increased to in excess of 100 µg per day. Increased hepatocellular necrosis with spillage of copper into the blood can also lead to higher values. Samples from children might show reduced urinary copper excretion because of difficulties with sample collection. In pediatric cases of WD—in particular those of the hepatic variety—a provocative test for urinary copper excretion using the chelating agent D-penicillamine has been undertaken, with high levels of sensitivity reported.[37]

Serum-free copper estimation is a measure of nonceruloplasmin toxic copper in the blood, and normal values range from 1.3 to 1.9 µmol/l (8-12 µg/dl). This value increases in WD to over 3.9 µmol/l (>25 µg/dl) in parallel with the increased urinary copper excretion, because of saturation of the hepatic storage of copper. This measurement is valuable in cases in which falsely high levels of serum ceruloplasmin are suspected, and when a measurement of urinary copper is difficult to obtain. The value is determined by subtracting three times the ceruloplasmin level (mg/dl) from the total serum copper level (µg/dl).

In suspected cases of hepatic WD, if the clinical and biochemical parameters are not supportive, a hepatic biopsy can be carried out and a measurement of its copper content obtained by mass spectroscopy or atomic absorption spectroscopy.[38] Normal values are up to 250 µg per gram of dry tissue weight, and in WD this value is exceeded in about 80% of cases. Following biopsy, histochemical testing with rhodamine can also show copper and copper-associated protein, but their absence does not exclude a diagnosis of WD, particularly in children.

In cases in which a biopsy is contraindicated, measurement of radioactive copper uptake is another noninvasive method for assessing copper metabolism. In WD, incorporation of radioactive copper into the hepatocytes will be severely restricted.[39]

The use of mutation screening to identify defects in the ATP7B gene can provide unequivocal confirmation of WD in an affected symptomatic or presymptomatic individual. Because of the large size of the gene, however, and the potential for a mutation anywhere along its entire length, identification of mutations is very challenging. Identification of the prevalent mutations in a given population is therefore desirable in order to provide direct mutation-based molecular diagnosis for a larger segment of the affected population. Progress in the diagnosis of WD has been made by studying microsatellite markers flanking the ATP7B gene and using linkage analysis to elucidate disease transmission in siblings of affected individuals.[14] Marker-based diagnosis should be undertaken when the specific defect in the ATP7B gene is not known.

With a diagnosis of WD, it is mandatory to counsel family members on the importance of biochemical or genetic screening of siblings and other family members, to identify those who might be presymptomatic gene mutation carriers. Monitoring of the presymptomatic individual and placement on a treatment regimen before the onset of clinical symptoms can then be carried out as appropriate.[40,41] The probability of family members of an affected individual being similarly affected (carrying two mutated genes) is 25% for siblings and 0.5% for offspring. A protocol for the screening of family members is shown in Table 2 . For prenatal screening, both linkage and mutational analysis is needed.[41]

Imaging plays an important role in both the diagnosis of WD and the monitoring of patients during therapy. Brain CT scans are relatively insensitive, but can reveal hypodensities and atrophy of the bilateral basal ganglia, brainstem, cerebellum and cerebral cortex. MRI is a very sensitive method for revealing abnormalities in WD.[42,43] On T1-weighted images, generalized brain atrophy is seen in three-quarters of cases, and hypointensities in the basal ganglia in two-thirds of cases. On T2-weighted images, one-third of cases demonstrate hyperintensity in the basal ganglia, white matter, thalamus or brainstem (Figure 4). These abnormalities are caused by neuronal loss, gliosis, degeneration of fibers, and vacuolization associated with increased water content in the brain. Signal abnormalities vary according to the stage of the disease, and can be reversible with therapy in the early stages.

Hyperintensities in the bilateral basal ganglia and thalami shown by T2-weighted MRI of the brain. These features can also be seen in other conditions, as described in the text.

Some WD-related changes exhibit characteristic features on MRI, for instance 'face of the giant panda', which is seen in T2-weighted images of the midbrain (Figure 5),[43] and 'face of the miniature panda', which can be seen in the tegmentum region of the pons in the same sequence. Sometimes, T2-weighted images show hypointensity in the basal ganglia region as a result of deposition of iron in exchange for copper after chelation. MRI findings can be similar to those seen in several other disorders, including Leigh disease, hypoxic-ischemic encephalopathy, methyl alcohol poisoning, Japanese B encephalitis, and selective extrapontine myelinolysis caused by osmotic disequilibrium syndrome. It is essential, therefore, to correlate the imaging with clinical features and biochemical markers of WD.

The typical 'face of the giant panda' seen in the midbrain on T2-weighted MRI of the brain.

Proton magnetic resonance spectroscopy (MRS) provides noninvasive information about the biochemistry of a defined volume of brain.[44,45,46,47] In WD, N-acetylaspartate (NAA):creatine and choline:creatine ratios are reduced. To determine the abnormality in MRS analysis, it is important to compare the results with those from a control person. One MRS report on patients with WD found the mean NAA:creatine ratio to be 1.30 ± 0.40, the mean NAA:choline ratio to be 1.43 ± 0.45, and the mean choline:creatine ratio to be 0.96 ± 0.34, compared with control values of NAA:creatine -1.60 ± 0.34, NAA:choline -1.83 ± 0.44, and choline:creatine -0.89 ± 0.12.[44] As creatine is relatively stable and is present in the glial cells that are least affected in WD, a reduction in both the choline:creatine and NAA:creatine ratios is indicative of a loss of neurons. In hepatic WD, these ratios remain normal, thus helping to distinguish primary brain involvement in WD from hepatic encephalopathy. MRS has shown decreased levels of myo-inositol in patients with portosystemic shunting, which is usually a secondary consequence of portal hypertension in hepatic WD.[46] PET scans have shown a decrease in dopamine transporter function and in D2 receptors in the striatum.[48]

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