Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

hepatic failure, severe (Nazer score ≥10 or New Wilson Index score ≥11)

1st line – liver transplantation

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ACUTE
|
hepatic failure, severe (Nazer score ≥10 or New Wilson Index score ≥11)
1st line – 

liver transplantation

About 20% of patients with Wilson's disease present with acute liver failure (jaundice, coagulopathy, ascites, renal failure, and encephalopathy).[24] Adults and children with acute liver failure due to Wilson's disease should be urgently referred to a liver transplantation centre.[5][24]

Scoring systems such as the Nazer score and the New Wilson Index (NWI) can be helpful in triaging patients who present with acute liver failure.[52][53]​ Scoring can provide insight into the need for liver transplantation versus salvage therapy with chelation treatment.

The Nazer score is based on severity of abnormality for each of serum aspartate aminotransferase (AST), bilirubin, and prothrombin time (PT) at admission.[52] A score from 0 to 4 is awarded for each blood parameter, depending on the degree of abnormality. The maximum score is 12.

Nazer score:

0 points for bilirubin <100 micromol/L; AST <100 units/L; PT <4

1 point for bilirubin 100-150 micromol/L; AST 100-150 units/L; PT 4-8

2 points for bilirubin 151-200 micromol/L; AST 151-200 units/L; PT 9-12

3 points for bilirubin 201-300 micromol/L; AST 201-300 units/L; PT 13-20

4 points for bilirubin >300; AST >300 units/L; PT >30.

The NWI was developed based on paediatric Wilson's disease cases and has been validated in adult cohorts.[53] The score incorporates bilirubin, international normalised ratio (INR), AST, white cell count, and albumin values to give a score between 0 and 20. A score of ≥11 suggests high mortality without transplantation.[53][54]

Transplantation is recommended for people with Nazer score ≥10 or NWI score ≥11.[52][53][54]

hepatic failure, mild to moderate (Nazer score ≤9 or New Wilson Index score ≤10)

1st line – oral chelation therapy plus zinc

Back
ACUTE
|
hepatic failure, mild to moderate (Nazer score ≤9 or New Wilson Index score ≤10)
1st line – 

oral chelation therapy plus zinc

Scoring systems such as the Nazer score and the New Wilson Index (NWI) can be helpful in triaging patients who present with acute liver failure.[52][53]​ Scoring can provide insight into the need for liver transplantation versus salvage therapy with chelation treatment.

The Nazer score is based on severity of abnormality for each of serum aspartate aminotransferase (AST), bilirubin, and prothrombin time (PT) at admission.[52] A score from 0 to 4 is awarded for each blood parameter, depending on the degree of abnormality. The maximum score is 12.

Nazer score:

0 points for bilirubin <100 micromol/L; AST <100 units/L; PT <4

1 point for bilirubin 100-150 micromol/L; AST 100-150 units/L; PT 4-8

2 points for bilirubin 151-200 micromol/L; AST 151-200 units/L; PT 9-12

3 points for bilirubin 201-300 micromol/L; AST 201-300 units/L; PT 13-20

4 points for bilirubin >300; AST >300 units/L; PT >30.

The NWI was developed based on paediatric Wilson's disease cases and has been validated in adult cohorts.[53] The score incorporates bilirubin, international normalised ratio (INR), AST, white cell count, and albumin values to give a score between 0 and 20. A score of ≥11 suggests high mortality without transplantation.[53][54]

Adults and children with decompensated liver failure but without hepatic encephalopathy can often be treated successfully with pharmacological therapy.[5][25][55] A combination of an oral chelator plus zinc is used.[5][25] Twenty-four-hour urinary copper should be monitored closely in addition to clinical and biochemical improvement. Response to medical treatment takes at least 1 month; normalisation of PT may take 3-12 months.[25][55]

Penicillamine and trientine are oral chelators that promote the renal excretion of copper. A paradoxical worsening of neurological symptoms can occur in 10% to 50% of patients starting treatment with penicillamine.[5] Initial adverse effects include fever, lymphadenopathy, thrombocytopenia, and proteinuria, and sensitivity reactions should prompt discontinuation of the medications. Other long-term adverse effects include nephrotoxicity, bone marrow toxicity, and dermatological changes. Approximately 30% of patients discontinue treatment with penicillamine due to adverse effects.[5] Trientine is associated with a much lower risk of worsening neurological symptoms after starting therapy, compared with penicillamine.[5] Guidelines recommend use of trientine for patients who are intolerant of penicillamine.[5][24][42][43][44] However, trientine is increasingly used as initial therapy, due to its better adverse effect profile.[45] Rare adverse effects of trientine include pancytopenia, colitis, iron deficiency, systemic lupus erythematosus, dystonia, muscular spasm, and myasthenia gravis.[45][46]

Patients should be closely monitored for paradoxical worsening of neurological symptoms during initiation of chelation therapy. Start chelation therapy slowly in patients who present with neurological symptoms; these patients may be more likely to experience paradoxical worsening during initiation.[5][49][50]​

Oral chelators should be taken 1 hour prior to or 2 hours after meals. Penicillamine, trientine, or zinc may all be used during pregnancy. The dose of penicillamine or trientine should be reduced to the minimum necessary dose, which is usually 25% to 50% of the pre-pregnancy dose. A dose reduction of zinc is not required.[5]

Zinc inhibits the intestinal absorption of copper. Gastric irritation is the main adverse effect.[5] Changing to a different zinc salt can help alleviate symptoms.[42][47]

Response to treatment is assessed by measurement of 24-hour urinary copper excretion. This may exceed 16 micromol/day (1000 micrograms/day) initially, stabilising to 3-8 micromol/day (200-500 micrograms/day) on maintenance treatment with penicillamine and to 2.4 to 8 micromol/day (150-500 micrograms/day) on maintenance treatment with trientine.[5]​ Non-ceruloplasmin-bound copper concentration normalises on effective treatment. Urine copper excretion <1.6 micromol/day (<100 micrograms/day) may indicate over-treatment or non-adherence.[5]

Primary options

trientine hydrochloride: children <13 years of age: 20 mg/kg/day orally given in 2-3 divided doses, maximum 1500 mg/day; children ≥13 years of age and adults: 750-1250 mg/day orally given in 2-4 divided doses, maximum 2000 mg/day

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or

penicillamine: children: 20 mg/kg/day orally given in 2-4 divided doses, maximum 1000 mg/day; adults: 750-1500 mg/day orally given in 3-4 divided doses

More

-- AND --

zinc acetate: children <10 years of age: 25 mg orally two to three times daily; children ≥10 years of age and adults: 25-50 mg orally three times daily

Plus – dietary restriction of copper

Back
ACUTE
|
hepatic failure, mild to moderate (Nazer score ≤9 or New Wilson Index score ≤10)
Plus – 

dietary restriction of copper

Treatment recommended for ALL patients in selected patient group

Most patients should be counselled on foods that are high in concentrations of copper: these include nuts, chocolate, most shellfish, soy-based products, organ meats, and mushrooms. Supplements and water supply should be reviewed for high levels of copper. Diet has the most important impact on the initial phase of treatment, and a low-copper diet is recommended for the first year of treatment.[5] There are few studies that support a prolonged copper-restricted diet. Referral to a registered dietician may be considered. Dietary restriction of copper alone is not sufficient to treat Wilson's disease.

2nd line – liver transplantation

Back
ACUTE
|
hepatic failure, mild to moderate (Nazer score ≤9 or New Wilson Index score ≤10)
2nd line – 

liver transplantation

Liver transplantation should be considered for patients with liver failure whose liver function deteriorates while receiving pharmacological treatment. However, the decision to proceed to transplant must be based on clinical judgement.

ONGOING

symptomatic (neurological disease or hepatic disease without liver failure)

1st line – initial therapy: oral chelation therapy or zinc

Back
ONGOING
|
symptomatic (neurological disease or hepatic disease without liver failure)
1st line – 

initial therapy: oral chelation therapy or zinc

The main goal of initial treatment is to eliminate further copper toxicity while preventing additional loss in neurological or hepatic function.

Guidelines recommend initial chelation therapy with penicillamine or trientine for patients with Wilson's disease.[5][24][42]​ Trientine is often better tolerated.[42] Zinc monotherapy can also be used initially for severe neurological symptoms.[42][48]

Penicillamine and trientine are oral chelators that promote the renal excretion of copper. A paradoxical worsening of neurological symptoms can occur in 10% to 50% of patients starting treatment with penicillamine.[5] Initial adverse effects include fever, lymphadenopathy, thrombocytopenia, and proteinuria, and sensitivity reactions should prompt discontinuation of the medications. Other long-term adverse effects include nephrotoxicity, bone marrow toxicity, and dermatological changes. Approximately 30% of patients discontinue treatment with penicillamine due to adverse effects.[5] Trientine is associated with a much lower risk of worsening neurological symptoms after starting therapy, compared with penicillamine.[5] Guidelines recommend use of trientine for patients who are intolerant of penicillamine.[5][24][42][43][44]​ However, trientine is increasingly used as initial therapy, due to its better adverse effect profile.[45] Rare adverse effects of trientine include pancytopenia, colitis, iron deficiency, systemic lupus erythematosus, dystonia, muscular spasm, and myasthenia gravis.[45][46]​

Patients should be closely monitored for paradoxical worsening of neurological symptoms during initiation of chelation therapy. Start chelation therapy slowly in patients who present with neurological symptoms; these patients may be more likely to experience paradoxical worsening during initiation.[5][49][50]​

Oral chelators should be taken 1 hour prior to or 2 hours after meals.

Zinc monotherapy can be used initially for severe neurological symptoms.[42][48]​​ Zinc inhibits the intestinal absorption of copper. It has minimal adverse effects. Gastric irritation is the main adverse effect.[5] Changing to a different zinc salt can help alleviate symptoms.[42][47]​​ Zinc appears to have comparable efficacy to penicillamine and is better tolerated.[48] The paradoxical worsening of neurological symptoms that can occur with chelators is less common with zinc.[5][49][50]

Patients with Wilson's disease who intend to become pregnant should have discussions with their physicians prior to becoming pregnant, to ensure stability of their disease prior to conception. There may be some difficulty conceiving if disease is not adequately treated. Those with decompensated cirrhosis should be counselled to avoid pregnancy if possible, due to health risks to both mother and child. Treatment should be continued throughout pregnancy.[5] Penicillamine, trientine, or zinc may all be used. The dose of penicillamine or trientine should be reduced to the minimum necessary dose, which is usually 25% to 50% of the pre-pregnancy dose. A dose reduction of zinc is not required.[5] Changing of chelator therapy to zinc should depend on clinical status of the patient, and a multidisciplinary approach should be considered.

Penicillamine and trientine have been associated with birth defects and are categorised as teratogens.[56][57]​ One cohort study reported a rate of birth defects of 3% in women treated with chelators during pregnancy.[57] One small case series also reported birth defects in children born to women taking zinc during pregnancy.[58] However, due to the rarity of Wilson's disease, it is difficult to determine if there is a true causal relation to birth defects with chelator therapy or if birth defects are occurring at the same frequency as in the general population.[57]

Breastfeeding can be potentially harmful to the infant, due to potential lack of copper in the breast milk and inadequate amount for the newborn for development. Penicillamine can be excreted into the breast milk as well. Thus the role of breastfeeding should be discussed with medical providers on an individual basis.[59][60]

Response to treatment is assessed by measurement of 24-hour urinary copper excretion. This may exceed 16 micromol/day (1000 micrograms/day) initially, stabilising to 3-8 micromol/day (200-500 micrograms/day) on maintenance treatment with penicillamine and to 2.4 to 8 micromol/day (150-500 micrograms/day) on maintenance treatment with trientine.[5]​ Non-ceruloplasmin-bound copper concentration normalises on effective treatment. Urine copper excretion <1.6 micromol/day (<100 micrograms/day) may indicate over-treatment or non-adherence.[5] Target 24-hour urinary copper excretion is <1.6 micromol/day (<100 micrograms/day) while taking zinc.[5]

Primary options

trientine hydrochloride: children <13 years of age: 20 mg/kg/day orally given in 2-3 divided doses, maximum 1500 mg/day; children ≥13 years of age and adults: 750-1250 mg/day orally given in 2-4 divided doses, maximum 2000 mg/day

More

OR

penicillamine: children: 20 mg/kg/day orally given in 2-4 divided doses, maximum 1000 mg/day; adults: 750-1500 mg/day orally given in 3-4 divided doses

More

OR

zinc acetate: children <10 years of age: 25 mg orally two to three times daily; children ≥10 years of age and adults: 25-50 mg orally three times daily

Plus – maintenance therapy: zinc or oral chelation therapy

Back
ONGOING
|
symptomatic (neurological disease or hepatic disease without liver failure)
Plus – 

maintenance therapy: zinc or oral chelation therapy

Treatment recommended for ALL patients in selected patient group

After initial treatment with a chelating agent, stable patients may continue taking a lower dose of chelating agent, or change to treatment with full dose zinc.[5] Zinc is more selective for removing copper than penicillamine or trientine and is associated with fewer adverse effects.[5]

Patients will usually have received 1-5 years of initial therapy before stabilisation. Patients may be switched to zinc when they are clinically well, and have normal hepatic synthetic function, and serum aminotransferase and non-ceruloplasmin-bound copper concentrations are in the normal range. Twenty-four-hour urinary copper excretion should be 1.6 micromol/day (<100 micrograms) on chelation therapy.[5]

Patients with Wilson's disease who intend to become pregnant should have discussions with their physicians prior to becoming pregnant, to ensure stability of their disease prior to conception. There may be some difficulty conceiving if disease is not adequately treated. Those with decompensated cirrhosis should be counselled to avoid pregnancy if possible, due to health risks to both mother and child. Treatment should be continued throughout pregnancy.[5] Penicillamine, trientine, or zinc may all be used. The dose of penicillamine or trientine should be reduced to the minimum necessary dose, which is usually 25% to 50% of the pre-pregnancy dose. A dose reduction of zinc is not required.[5] Changing of chelator therapy to zinc should depend on clinical status of the patient, and a multidisciplinary approach should be considered.

Penicillamine and trientine have been associated with birth defects and are categorised as teratogens.[56][57]​ One cohort study reported a rate of birth defects of 3% in women treated with chelators during pregnancy.[57] One small case series also reported birth defects in children born to women taking zinc during pregnancy.[58] However, due to the rarity of Wilson's disease, it is difficult to determine if there is a true causal relation to birth defects with chelator therapy or if birth defects are occurring at the same frequency as in the general population.[57]

Breastfeeding can be potentially harmful to the infant, due to potential lack of copper in the breast milk and inadequate amount for the newborn for development. Penicillamine can be excreted into the breast milk as well. Thus the role of breastfeeding should be discussed with medical providers on an individual basis.[59][60]

Primary options

zinc acetate: children <10 years of age: 25 mg orally two to three times daily; children ≥10 years of age and adults: 25-50 mg orally three times daily

Secondary options

trientine hydrochloride: children <13 years of age: 20 mg/kg/day orally given in 2-3 divided doses, maximum 1500 mg/day; children ≥13 years of age and adults: 750-1250 mg/day orally given in 2-4 divided doses, maximum 2000 mg/day

More

OR

penicillamine: children: 20 mg/kg/day orally given in 2-4 divided doses, maximum 1000 mg/day; adults: 750-1500 mg/day orally given in 3-4 divided doses

More

Plus – dietary restriction of copper

Back
ONGOING
|
symptomatic (neurological disease or hepatic disease without liver failure)
Plus – 

dietary restriction of copper

Treatment recommended for ALL patients in selected patient group

Most patients should be counselled on foods that are high in concentrations of copper: these include nuts, chocolate, most shellfish, soy-based products, organ meats, and mushrooms. Supplements and water supply should be reviewed for high levels of copper. Diet has the most important impact on the initial phase of treatment, and a low-copper diet is recommended for the first year of treatment.[5]​ There are few studies that support a prolonged copper-restricted diet. Referral to a registered dietitian may be considered. Dietary restriction of copper alone is not sufficient to treat Wilson's disease.

asymptomatic

1st line – zinc or oral chelation therapy

Back
ONGOING
|
asymptomatic
1st line – 

zinc or oral chelation therapy

Asymptomatic patients require treatment with a focus of maintaining copper balance to prevent organ damage from inflammation caused by copper injury. Penicillamine, trientine, or zinc can be used as treatment.[5] Treatment should be initiated in asymptomatic children at 2-3 years of age.[25] Zinc may be used in asymptomatic children identified through family screening, due to its favourable safety profile.[25] It is unclear if zinc should be used for very young children without organ damage, due to concerns for developmental stunting.

Primary options

zinc acetate: children <10 years of age: 25 mg orally two to three times daily; children ≥10 years of age and adults: 25-50 mg orally three times daily

OR

trientine hydrochloride: children <13 years of age: 20 mg/kg/day orally given in 2-3 divided doses, maximum 1500 mg/day; children ≥13 years of age and adults: 750-1250 mg/day orally given in 2-4 divided doses, maximum 2000 mg/day

More

OR

penicillamine: children: 20 mg/kg/day orally given in 2-4 divided doses, maximum 1000 mg/day; adults: 750-1500 mg/day orally given in 3-4 divided doses

More

Plus – dietary restriction of copper

Back
ONGOING
|
asymptomatic
Plus – 

dietary restriction of copper

Treatment recommended for ALL patients in selected patient group

Most patients should be counselled on foods that are high in concentrations of copper: these include nuts, chocolate, most shellfish, soy-based products, organ meats, and mushrooms. Supplements and water supply should be reviewed for high levels of copper. Diet has the most important impact on the initial phase of treatment, and a low-copper diet is recommended for the first year of treatment.[5] There are few studies that support a prolonged copper-restricted diet. Referral to a registered dietitian may be considered. Dietary restriction of copper alone is not sufficient to treat Wilson's disease.

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Choose a patient group to see our recommendations

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

Use of this content is subject to our disclaimer