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

Table 1 Clinical features of Wilson’s disease

Hepatic	Neurologic	Psychiatric	Eye	Hematologic	Renal	Skin	Osteoarticular	Endocrine	Reproductive system
Asymptomatic increased serum transaminases. Acute hepatitis. Hepatomegaly. Fatty liver. Acute liver failure with hemolysis. Portal hypertension. Decompensated cirrhosis with ascites	Deterioration of handwriting school performance. Dysarthria. Drooling, hypersalivation. Tremor. Dystonia. Coordination defect. Choreoathetosis. Ataxic gait. Fixed grin seizure	Organic dementia. Depression, anxiety. Psychosis. Behavioral changes. Emotional lability. Schizophrenia. Bipolar disorder. Obsessive- compulsive disorder. Antisocial behavior	Kayser-Fleischer ring. Sunflower cataract	Acute hemolytic anemia	Tubular dysfunction. Nephrolithiasis. Nephrocalcinosis. Hypercalciuria. Hyperphosphaturia	Hyperpigmentation. Azure lunulae of nails. Acanthosis nigricans	Osteoporosis. Rickets. Osteomalacia. Pathological fracture	Glucose intolerance. Hypoparathyroidism. Panhypopituitarism	Menstrual irregularity. Delayed puberty. Infertility. Miscarriage

Table 2 The modified Leipzig scoring system

Scoring items	Score
KF rings
Present	2
Absent	0
Serum ceruloplasmin
Normal > 20 (mg/dL)	0
0 to 5 (mg/dL)	3
6 to 11 (mg/dL)	2
11 to 20 (mg/dL)	1
24 hours urinary copper
> 100 (μg)	2
40-100 (μg)	1
< 40 (μg)	0
Coomb’s-negative hemolytic anemia with liver disease
Present	1
Absent	0
Mutational analysis
On both chromosomes	4
On one chromosome detected	1
No mutation detected/test not done	0
Liver biopsy for histology suggestive of WD
Orcein or rhodamine negative granules	0
Orcein or rhodamine positive granules	1
Neurobehavioral symptom
Present	2
Absent	0
Typical features on MRI brain
Present	1
Absent	0
History of WD in a family member/sibling death from liver disease/neurological disease
Suggestive of WD	1
Absent	0

Interpretation of the score: Score 4 or more: Confirmed Wilson disease, score 3: Diagnosis possible, score 2 or less: Unlikely (the score is taken from Wilson’s disease: Clinical Practice Guidelines of the Indian National Association for Study of the Liver, the Indian Society of Pediatric Gastroenterology, Hepatology and Nutrition, and the Movement Disorders Society of India). WD: Wilson’s disease; MRI: Magnetic resonance imaging; KF: Kayser-Fleischer.

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.

Table 4 Medications used in Wilson’s disease

Medication	Mechanism of action	Dose	Side effects
D-penicillamine	Cu chelator	Initial: 20 mg/kg/day, 3 times a day (one hour before and two hours after meal). Maintenance: 10-20 mg/kg/day. Oral pyridoxine: 25-50 mg/day. This drug is used as initial and maintenance	Early: Hypersensitivity reaction manifested as fever, rash, lymphadenopathy, pancytopenia. Late: Proteinuria, nephrotic syndrome, drug associated systemic lupus erythematosus, agranulocytosis, thrombocytopenia, Dermatopathy (cutis laxa)
Trientine	Cu chelator	Same as D-penicillamine	Less toxic than D-penicillamine. Toxicity includes sideroblastic anemia, nephrotoxicity, skin and mucosal lesion
Zinc	Inhibit Cu absorption. Stimulate hepatic metallothionein synthesis	< 50 kg-75 mg/day three times daily. > 50 kg-150 mg/day three times daily. It is used as maintenance and adjunctive therapy	Headache, gastrointestinal upset, iron deficiency
Ammonium tetrathiomolybdate	Inhibit Cu absorption. Cu chelator	100-200 mg/day. It is not yet Food and Drug Administration approved	Elevation of aminotransferase