Wilson’s disease in children: Recent update on pathophysiology and management

Table 3 Usefulness and drawbacks of different diagnostic tests performed in Wilson’s disease

Investigations	Normal value	Diagnostic value	Usefulness	Drawbacks
Serum ceruloplasmin	20 mg/dL to 40 mg/dL	Less than 20 mg/dL	Traditionally, it is first line investigation for WD (Recommended in previous and current guidelines and position papers)	It cannot be recommended as a diagnostic tool for children aged less than one year as serum ceruloplasmin level is low in early infancy. The serum level of ceruloplasmin can be affected by other liver diseases, malnutrition, and acute inflammatory state. Ceruloplasmin is acute-phase protein. It may rise in acute inflammatory condition or decrease in any condition of protein losing enteropathy. So, it may give false positive or false negative result. Value of serum ceruloplasmin may differ by different methods like enzymatic assays and immunologic assays. Enzymatic assays are the preferred, rarely available method as it detects only holo-ceruloplasmin while immunologic assays measure both apoceruloplasmin and holo-ceruloplasmin, which could overestimate serum ceruloplasmin
Urinary copper test	< 40 μg/24 hour	> 100 μg/24 hour-high suspicion. 40-100 μg/24 hour-need for further evaluation	Traditionally, it is first line investigation for WD. (Recommended in previous and current guidelines and position papers)	Correct measurement needs exact collection timing and copper free container. It may increase in cholestatic liver disease
Relative exchangeable copper	3.4%-8%	> 15% (high suspicion)	It is recommended as highly useful test. This test does not depend on serum ceruloplasmin level, as ceruloplasmin may vary in different conditions	It is not widely available. It is costly. Toxic free copper fraction can be identified
Genetic test/mutational analysis	No mutation in ATP7B gene. Healthy heterozygote carrier of ATP7B gene	Mutation detected in both allele of ATP7B gene-confirmatory. Mutation detected in one allele of ATP7B gene-need further evaluation	The test is confirmatory. It can differentiate healthy heterozygote carriers from presymptomatic WD children. It is helpful for family screening	Rarely, children with WD may not have any identifiable mutation. Different diagnostic scores are established for minimizing the situation. WD cannot be excluded, if no mutation is found in one or both alleles
Liver copper estimation	Normal value < 50 μg/g dry weight	250 μg/g dry weight liver is recognized as a cut-off value for diagnosis of WD. The value between 50-250 μg/g dry weight liver is not specific for WD	It is done when Leipzig score is ≤ 3 or diagnosis is not certain	It is invasive procedure. Adequate size of liver specimen (> 1 cm) is needed. Inhomogeneous distribution of copper in liver makes the diagnosis less reliable
KF ring	Absent in WD	Present in WD	KF ring on slit lamp examination should always be checked	KF ring may be absent in younger children as it requires time to mature. KF ring is not pathognomonic for WD, as it is found in other cholestatic liver disease

WD: Wilson’s disease; KF: Kayser-Fleischer.