Approach

Wilson's disease is treated with lifelong pharmacotherapy and dietary restrictions.[4][5][24][25][41][42] The goal of treatment is to reduce total levels of copper in the body to ultimately maintain a copper balance. Treatment is divided into initial and maintenance for each category of presentation.

Current recommendations are the use of chelation or zinc to remove excess copper from the body via the faeces, urine, or potentially both.[5] Depending on the clinical presentation and whether the patient is in the initial phases of treatment or the maintenance phase, treatment regimens may vary.

A multidisciplinary approach to treatment (nutritionist, psychiatrist, neurologist, physiotherapist, speech therapist) is essential due to the systemic effects of the illness.

Pharmacological therapy

Pharmacological therapy includes the oral chelators penicillamine (as the D-isomer) and trientine, which increase urinary copper excretion, and zinc salts, which decrease alimentary copper absorption.[4] Chelators are usually used first line.[5][24][25][42] Comparative data from prospective head-to-head clinical trials are lacking.[4]

Penicillamine

Penicillamine is absorbed in the gastrointestinal tract, but decreased absorption can occur if taken with a meal. 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]

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. 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]

Trientine

Trientine, like penicillamine, is an oral chelator that promotes renal excretion of copper. 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] 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]

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 2.4 to 8 micromol/day (150-500 micrograms/day) on maintenance treatment.[5]

Zinc

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 rare with zinc therapy.[5][49][50]​ One case of fatal deterioration of hepatic Wilson's disease after initiation of zinc therapy has been reported.[51] Combination therapy with zinc and a chelator has been used in those with severe disease.

Target 24-hour urinary copper excretion is <1.6 micromol/day (<100 micrograms/day).[5]

Maintenance therapy

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/day).[5]

Hepatic presentation

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; also called the Revised WD prognostic index or Revised King's College Score) 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:[52]

  • 0: Bilirubin <100 micromol/L; AST <100 units/L; PT <4

  • 1: Bilirubin 100-150 micromol/L; AST 100-150 units/L; PT 4-8

  • 2: Bilirubin 151-200 micromol/L; AST 151-200 units/L; PT 9-12

  • 3: Bilirubin 201-300 micromol/L; AST 201-300 units/L; PT 13-20

  • 4: Bilirubin >300 micromol/L; AST >300 units/L; PT >30

Transplantation is recommended for people with Nazer score ≥10. People with Nazer score ≤6 should be treated with pharmacological therapy. Those with scores of 7 to 9 are evaluated using clinical judgement.[52]

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]​ The difficulty in utilisation of the Nazer and the NWI occurs around the break point (Nazer 6-7 points, NWI 10-11 points) as to whether transplant or salvage therapy with chelation therapy is preferable. In these cases the trend of the score can be helpful.

The main goal of treatment in those who receive pharmacological treatment is to achieve copper balance while limiting any further inflammation or injury to the liver.

Adults and children with decompensated liver failure but without hepatic encephalopathy can often be treated successfully with pharmacological therapy.[5][25] In patients with liver failure who are candidates for pharmacological treatment, therapy is a combination of a chelator (trientine or penicillamine) plus zinc.[5][25]  Twenty-four-hour urinary copper should be monitored closely in addition to clinical and biochemical improvement.

Liver transplantation should be considered for patients with liver failure whose liver function deteriorates while receiving pharmacological treatment.

Neurological/psychiatric presentation

The main goal of initial treatment is to eliminate further copper toxicity while preventing additional loss in neurological function. Zinc monotherapy can be used initially for severe neurological symptoms.[42][48]​ Guidelines recommend chelation therapy with penicillamine or trientine.[5][24][42]​ Trientine is often better tolerated.[42]

Patients who present with neurological symptoms may be more likely to experience paradoxical worsening of neurological symptoms during initiation of therapy. The risk of paradoxical neurological worsening is greatest with penicillamine, but it can also occur with trientine or less commonly zinc.[5][49]​​[50]​ In patients with neurological symptoms, start chelation therapy slowly and closely monitor for paradoxical worsening during initiation.

Asymptomatic patients

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.

Symptomatic children

Treatment with penicillamine, trientine, or zinc should begin promptly in symptomatic children to prevent progression of liver and/or neurological disease. The treatment strategy should be individualised and depends on the type and severity of organ involvement. Zinc may be used as maintenance therapy after copper reduction using chelators. Combination therapy with zinc and a chelating agent may be effective in patients with decompensated chronic liver disease.[25]

NWI score may be used to predict the need for liver transplantation. Children who present with decompensated liver cirrhosis and liver failure but no hepatic encephalopathy can often be treated successfully with chelation.[55] Response to medical treatment takes at least 1 month; normalisation of prothrombin time may take 3-12 months.[25][55]

Pregnant women

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. Genetic predisposition and safety of medicines in pregnancy should be discussed.[5]​ 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.[40]​ A dose reduction of zinc is not required.[5][40]​ 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.[40][59][60]

Dietary advice

Dietary restriction of copper is not sufficient to treat Wilson's disease. 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.

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