Wilson's disease: Revisiting an old friend

Table 1 Clinical manifestations

Wilson's Disease Clinical Manifestations
Liver	Hepatomegaly, jaundice, pain in right hypochondria, asthenia, elevation of transaminases, acute liver injury, acute liver failure, cirrhosis (compensated and decompensated), ACLF, steatosis
Neurological	Dystonia, tremor, dysarthria, dysphagia, Parkinson, chorea
Psychiatric	Behavioral changes, depression, anxiety, psychosis, school performance deficit, sexual disinhibition
Eye	Kayser-Fleischer Ring, Cataract
Hematologic	Hemolytic anemia, coagulopathy, thrombopenia
Renal	Acute renal failure, nephrolithiasis, urolithiasis, renal tubular acidosis
Musculoskeletal	Arthropathy, muscle weakness
Other	Heart disease, pancreatitis, hypoparathyroidism

ACLF: Acute-on-Chronic Liver Failure.

Table 2 Diagnosis tests for Wilson’s disease

Test	Normal values	Wilson disease	False negative	False positive
Ceruloplasmin	0.2-0.4 g/L	< 0.2 g/L	Increased levels:	Low levels:
			Hepatic inflammation	Malabsorption
				Malnutrition
			Estrogen	Aceruloplasminemia
			Pregnancy	Menkes’ disease
			Infection	Terminal liver disease
			Children	Nephropathy with renal protein loss
			Overestimation by immunological assay	Excess zinc ingestion
				Healthy heterozygotes WD
Non ceruloplasmin bound copper	< 0.3 μg/dL	> 10 μg/dL	Overestimation of ceruloplasmin by immunological assay	Increased levels:
				Cholestatic syndromes
				Acute liver failure
				Copper intoxication
Urinary copper excretion	< 0.6 μmol/24 h; < 40 μg/24 h	> 1.6 μmol/24 h; > 100 μg/24 h	Incomplete collection; Children	Increased levels:
				Cholestatic syndromes
				Autoimmune hepatitis
				Chronic active liver disease or hepatocellular necrosis
				Healthy heterozygotes WD
Liver biopsy	< 50 μg/g; < 0.8 μmol/g	> 250 μg/g; > 4 μmol/g	Uneven copper distribution	Increased levels:
				Cholestatic syndromes
				Idiopathic copper toxicosis disorders
Kayser Fleischer rings	Absence	Present: Neurological WD		Primary biliary cholangitis
		Absence:
		50% hepatic WD
		Asymptomatic WD

WD: Wilson’s disease.

Table 3 Leipzig scoring for Wilson’s disease

Typical clinical signs and symptoms
Kayser-Fleischer ring
Present	2
Absent	0
Neurologic symptoms or typical abnormalities on MRI
Severe	2
Mild	1
Absent	0
Serum ceruloplasmin
Normal (> 0.2 g/L)	0
0.1-0-2 g/L	1
< 0.1 g/L	2
Coombs negative hemolytic anemia
Present	1
Absent	0
Other tests
Liver copper1
> 4 μmol/g	2
0.8-4 μmol/g	1
< 0.8 μmol/g	-1
Rhodamine positive granules2	1
Urinary copper excretion3
Normal	0
1-2 times ULN	1
> 2 times ULN	2
5 times ULN after penicillamine	2
Mutation analysis detected
Both chromosomes	4
One chromosome	1
No mutations	0
Total Leipzig score
Score	Evaluation
≥ 4	Diagnosis established
3	Diagnosis possible
≤ 2	Diagnosis very unlikely

¹In the absence of cholestasis.

²If no quantitative liver copper available.

³In the absence of acute hepatitis. MRI: Magnetic resonance imaging; ULN: Upper limit of normal.

Table 4 Monitoring urinary copper excretion in the treatment of Wilson’s disease

Treatment	Initial treatment	Maintenance treatment	Undertreatment or non-compliance	Overtreatment or non-compliance
D penicillamine	> 500 μg/24 h	200-500 μg/24 h	> 500 μg/24 h	< 200 μg/24 h
Trientine	> 500 μg/24 h	200-500 μg/24 h	> 500 μg/24 h	< 100 μg/24 h
Zinc	> 100-500 μg/24 h	< 75 μg/24 h	> 15 μg/24 h	< 5 μg/24 h

Table 5 Adverse effects of medical therapy used in the treatment of Wilson’s disease

Medication	Side effects
D penicillamine	Early (1-3 wk):
	Fever, cutaneous eruptions, myelosuppression, lymphadenopathy, proteinuria
	Late: (> 3 wk-yr)
	Renal: Nephrotoxicity, nephrotic syndrome
	Lungs: Goodpasture syndrome
	Bone marrow: Aplasia
	Eye: Optic neuritis, retinitis
	Skin: Pemphigus, pemphigoid lesions, aphthous stomatitis, hair loss
	Autoimmunity: Lupus erythematosus, myasthenia gravis, polymyositis, immunoglobulin A depression
	Dose-dependent:
	Pyridoxine deficiency
	Mammary hypertrophy
	Skin: Elastosis serpiginosa, lichen planus, progeria-like skin changes
	Neurological deterioration (10%-50%)
Trientine	Few side effects:
	Bone marrow depression
	Sideroblastic anemia
	Hemorrhagic gastritis, loss of taste, and skin rash
	Neurological deterioration is less common
Zinc	Very few side effects:
	Gastric irritation
	Elevation of serum amylase and lipase
	Bone marrow depression
	Neurological deterioration is very uncommon
Tetrathiomolybdate	Few side effects:
	Bone marrow suppression
	Increased serum aminotransferase levels
	Anemia
	No neurological deterioration