Challenges and dilemmas in pediatric hepatic Wilson’s disease

Table 1 Various laboratory investigations used in the diagnosis and monitoring of Wilson disease

Diagnostic tests	Cut-off values in diagnosis	Disease monitoring	Problems in interpretation
Serum ceruloplasmin	< 10 mg/dL (strong evidence), 10-20 mg/dL (needs further evaluation), 20-40 mg/dL (normal value, but does not exclude diagnosis)	Not helpful	Can be normal in fulminant presentation and acute inflammation as it is an acute phase reactant
24-h urine copper	> 100 mcg/d (virtually diagnostic in symptomatic patients), > 40 mcg/d (may indicate disease, needs further evaluation)	> 500 mcg/d during initial phase, 200-500 mcg/d in the maintenance phase	Difficult to perform, to be done in reliable laboratories
Hepatic copper	> 250 mcg/g dry weight (diagnostic), 50-250 mcg/g dry weight (needs further evaluation), < 50 mcg/g dry weight (normal)	Not recommended	Inhomogenous distribution of copper (sampling error), elevated in long-standing cholestasis
Serum total copper	> 25 micromol/L (needs further evaluation), 14-24 micromol/L (90-150 mg/dL) normal	N/Aa
Non-ceruloplasmin copper	10-15 mcg/dL (normal person), > 25 μg/dL (untreated patients), Not recommended for diagnosis	> 15 mg/dL (poor compliance)a < 5 mg/dL (over-chelation)
Exchangeable copper	> 2.08 micromol/L (more likelihood of extrahepatic organ involvement), 0.62 and 1.15 micromol/L (normal)	Experimental	Requires equipped laboratories and expertise
Relative exchangeable copper	> 15% (100% sensitivity and specificity for diagnosis)	Experimental	Requires equipped laboratories and expertise

^aThe serum free copper or NCC has a role in monitoring: Initial phase: > 25 mcg/dL, maintenance phase: 10-15 mcg/dL, under-chelation: > 15 mcg/dL, over-chelation: < 5 mcg/dL.

Table 2 Diagnostic tests for suspected Wilson disease patients and asymptomatic siblings

Parameters	Tests for suspected patients	Tests for asymptomatic siblings
Clinical examination	Yes	Yes
Liver function test	Yes	Yes
Slit lamp examination for Kayser–Fleischer ring	Yes	Yes
Serum ceruloplasmin	Yes	Yes
24 h urine copper	Yes	Yes
Genetic analysis for ATP7B gene mutation analysis	Yes, if feasible	Yes (if proband sample is available)
Liver biopsy	Yes, ancillary test	No
Hepatic copper	Yes, to be done in cases of ambiguity	No

Table 3 Differentiating features between Wilson disease-related renal tubular acidosis and D-penicillamine induced glomerulonephritis

	Wilson disease-related renal tubular acidosis	D-penicillamine induced glomerulonephritis
Mechanism	Copper induced tubular damage	Immune complex deposition
Presentation	Prior to starting chelation/during chelation	After starting chelation
Tests to differentiate	Normal anion gap metabolic acidosis, Urine pH, Urine for glucosuria, aminoaciduria, acidification test of urine	Urine for proteinuria, autoantibodies for glomerulonephritis, renal biopsy
Chelation	To be continued	To be stopped

Table 4 Risk factors for side effects of drug therapy in Wilson’s disease

Side effect of drugs	Risk factor	How to differentiate
Neurological worsening with D-penicillamine or trientine	Pre-existing neurological Wilson disease	Exchangeable copper and relative exchangeable copper
Cytopenia due to D-penicillamine	Co-existing hypersplenism due to portal hypertension	Bone marrow biopsy

Table 5 Drugs, their mechanism of action, dosage and side effects

Name of drug	Mechanism of action	Dose	When to start	Side effects
D-penicillamine	Induces cuprieuresis, induces hepatic metallothionine synthesis, reduces fibrosis (by preventing collagen formation)	20 mg/kg/d (maximum induction dose of 1500 mg/d and maintenance dose of 1000 mg/d), to be taken 1 h before or 2 h after meal, storage at room temperature	Chelator of choice in all hepatic phenotype	Early (1-3 wk): Fever, rash, arthralgia, cytopenia, proteinuria; Late: (1) Skin: degenerative dermatoses elastosis perforans serpingosa, cutis laxa, pseudoxanthoma elasticum, bullous dermatoses, psoriasiform dermatoses, lichen planus, seborrheic dermatitis alopecia, aphthous ulcerations, hair loss; (2) Connective tissue disorders: Lupus like syndrome, arthralgia, Rheumatoid arthritis, polymyositis; (3) Renal: proteinuria, hematuria, glomerulonephritis, nephrotic syndrome, renal vasculitis, Goodpasture’s syndrome; (4) Nervous system: Paradoxical neurological worsening, neuropathies, myasthenia, hearing abnormalities, serous retinitis; (5) Gastrointestinal: Nausea, vomiting, diarrhea, elevated transaminases, cholestasis, hepatic siderosis; (6) Respiratory: Pneumonitis, pulmonary fibrosis, pleural effusion; (7) Hematological: Cytopenia, agranulocytosis, aplastic anemia, hemolytic anemia; and (8) Others: Immunoglobulin deficiency, breast enlargement, pyridoxine deficiency
Trientine	Induces cuprieuresis, induces hepatic metallothionine synthesis	20 mg/kg/d (maximum induction dose of 1500 mg/d and maintenance dose of 1000 mg/d), to be taken 1 h before or 2 h after meal, storage at 20-80 temperature	Indicated if intolerant to D-penicillamine	Paradoxical neurological worsening (10%-50%), sideroblastic anemia, bone marrow suppression, gastritis, skin rash, arthralgia, myalgia, hirsutism
Zinc	Induces intestinal synthesis of metallothioneins, prevents copper absorption	25 mg thrice daily (weight < 50 kg), 50 mg thrice daily (weight > 50 kg), taken in empty stomach	Maintenance phase of symptomatic hepatic WD; First-line induction treatment in selected patient subgroups (neurologic WD, intolerant to chelators, pre-symptomatic patients)	Gastric irritation (30%-40%)
Ammonium Tetra-thiomolybdate	Forms complexes with copper in blood, binds the copper present in food		Neurological WD	Neurological dysfunction (rare), hepatotoxicity, bone marrow suppression

WD: Wilson disease.