Investigations
1st investigations to order
LFTs
Test
Liver function tests (LFTs) are almost always abnormal in patients with hepatic presentation.[5] Elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are present in 40% to 60% of patients at presentation.[24] Approximately 12% of patients have elevated bilirubin, due to liver injury, Coombs-negative haemolysis, or both.[6][24] Those with acute liver failure may have low albumin and prolonged international normalised ratio (INR). Those with decompensated cirrhosis may have prolonged INR, thrombocytopenia, mixed pattern of LFTs, and low albumin.[24] In patients with neurological presentation, ALT and AST may also be abnormal because there can be overlap with liver involvement.[24]
Result
abnormal
24-hour urinary copper
Test
Sample collected in trace element-free containers. Level >100 micrograms indicates disease. Urinary copper excretion can also be high in cholestatic and autoimmune conditions or protein-losing enteropathy, so diagnosis of the disease should not be made on urine copper values alone.
Result
>100 micrograms (>40 micrograms may suggest Wilson's disease and require further investigation)
slit-lamp examination
Test
Kayser-Fleischer (KF) rings are gold-brown pigments representing copper deposition in the membrane of Descemet of the cornea. They usually appear in superior and inferior portions of the cornea and then become circumferential as copper deposition progresses.[24] KF rings are present in 95% of patients with neurological presentations and in 44% to 62% of patients with hepatic presentations.[5]
Result
KF rings
serum ceruloplasmin
Test
A normal serum ceruloplasmin (200-350 mg/L [20-35 mg/dL]) does not exclude Wilson's disease, as about 20% of affected patients have a normal ceruloplasmin level.[25] Serum ceruloplasmin <200 mg/L (<20 mg/dL) has a sensitivity of 77.1% to 99% and a specificity of 55.9% to 82.8% for diagnosis of Wilson's disease. Serum ceruloplasmin <100 mg/L (<10 mg/dL) has a sensitivity of 65.7% to 94.4%, and a specificity of 96.6% to 100%, for a diagnosis of Wilson's disease.[29] Assay by the enzymatic method seems most accurate, but antibody-mediated assay can be used as an alternative. Ceruloplasmin can be increased in cases of inflammation as it is an acute phase reactant.[5] It can also be increased in pregnancy and oestrogen intake. It is usually low in infancy and is usually not measured until the child is >6 months.[5] Ceruloplasmin can also be low in cases of protein-losing enteropathy, end-stage liver disease, or nephrotic syndrome.[5][30]
Result
level of <50 mg/L (<5 mg/dL) strongly suggests Wilson's disease but further testing is required to make the diagnosis
Investigations to consider
FBC
Test
Haematological abnormalities are present in one third of patients at diagnosis.[24] Haemolysis may cause anaemia, and portal hypertension may cause thrombocytopenia and/or low WBC count.
Result
normal or anaemia or low platelet count and low WBC count
liver biopsy
MRI brain
Test
Only useful in neurological presentation cases with a high index of suspicion of Wilson's disease.
Not specific for Wilson's disease. MRI findings can be similar in other neurological disorders.
Result
involvement of basal ganglia - most commonly, hyperintensity of T2-weighted images of the basal ganglia; atrophy of the head of the caudate nucleus, brainstem, cerebral and cerebellar hemispheres; 'face of the giant panda sign' seen in T2-weighted images of the midbrain
non-ceruloplasmin-bound copper concentration (NCC)
Test
NCC levels have been found to be elevated at least 6-fold in Wilson's disease.[31]
Result
elevated
DNA testing for ATP7B mutations
Test
Although there are more than 700 pathogenic mutations in the ATP7B gene, next-generation sequencing can identify two pathogenic mutations in the majority of people with Wilson's disease.[24][25] The absence of two pathogenic mutations does not exclude Wilson's disease; clinical corroboration is required.[24] Traditional sequencing cannot detect large deletions or duplications, and there are many single-nucleotide polymorphisms of unknown significance in the ATP7B gene.[36]
Result
causative mutations found on both copies of the gene definitively diagnose Wilson’s disease
Emerging tests
direct measurement of ATP7B peptide
Test
Direct measurement of ATP7B protein from dried blood spots is in development. ATP7B 887 analysis has a positive predictive value of 98% and a negative predictive value of 91.5% for Wilson's disease.[36]
Result
reduced ATP7B levels
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