Wilson Disease

Wilson disease is a rare disorder of copper metabolism. People with this condition have a genetic defect that reduces biliary copper secretion, allowing this trace element to accumulate in various organs including the liver, brain, kidneys, and cornea. The genetic defect that alters copper transport also impairs the incorporation of copper into cerulosplasmin, a protein that stores and transports copper around the body.

The clinical presentation of Wilson disease can be highly variable. Signs and symptoms may include:

• Hepatic fibrosis;
• Hepatic cirrhosis;
• Marked hyperbilirubinaemia
• Haemolytic anaemia;
• Kayser-Fleischer rings (dark rings encircling the iris due to copper deposition);
• Low serum ceruloplasmin concentration;
• Menstrual irregularity or amenorrhea;
• Repeated miscarriages;
• Infertility;
• Haematuria;
• Motor deficits (e.g. tremors, dystonia, dysarthria, dysphagia); and
• Cognitive or psychiatric abnormalities.

Some patients exhibit only minor hepatic or neurological symptoms while others may develop acute or chronic liver failure. Serious neurological impairment is not commonly seen in children and is typically associated with more advanced disease due to delayed diagnosis, poor treatment compliance, or treatment failure. The prognosis is usually good for patients who present early and begin appropriate therapy. Treatment must be continued lifelong, even if the patient is asymptomatic. Untreated, Wilson disease may be fatal.

Although Wilson disease cannot be managed by diet alone, it is often recommended to reduce copper intake during the initial phases of treatment. Copper may be ingested in the form of drinking water, vitamin supplements, and foods. Foods particularly high in copper include organ meats, shellfish, chocolate, nuts, and mushrooms. Medications are essential in the treatment of Wilson disease and include chelating agents and zinc.

Chelating agents

Two chelating agents used in the treatment of Wilson disease are D-penicillamine and trientine. These agents chelate with copper to form a stable, soluble complex that can be excreted by the kidneys.

Studies demonstrate that both chelating agents are equally and highly effective in controlling the hepatic symptoms of Wilson disease. A retrospective cohort study of treatment-naïve patients demonstrated improvements in hepatic symptoms in 90.7% of patients taking D-penicillamine and 92.6% of patients taking trientine. However, chelation therapy appears to be less effective for the management of neurological symptoms, with improvement observed in 67.5% of the D-penicillamine group and 55% of the trientine group.

While D-penicillamine and trientine are structurally unrelated compounds, they have similar administration requirements. Each drug must be administered on an empty stomach at least one hour before meals, two hours after meals, and at least one hour apart from any other drug, food or milk. This prevents inactivation of the chelating agent in the gastrointestinal tract due to metal binding.

Neurological worsening is perhaps the most concerning adverse effect of chelating therapy. It is thought to occur soon after initiation of therapy in around 10% of patients, although some studies suggest a higher incidence. While the mechanism is unclear, it is postulated that treatment leads to a sudden mobilisation of copper from the liver, into the bloodstream, and finally to the brain. This may result in free radical-induced tissue injury. A temporary dose reduction resolves most cases of neurological worsening, although the symptoms are irreversible in up to 3% of patients. Initiating therapy at low doses with close clinical monitoring has been suggested to avoid this issue.

In addition to chelating copper, D-penicillamine and trientine also bind to iron and may lead to iron deficiency. If iron supplements are required, they should be taken at least two hours away from the chelating agent to ensure adequate absorption. This is particularly important for trientine as it forms a toxic complex with iron.

Trientine is considered a second-line option and currently holds orphan drug designation with the Therapeutic Goods Administration (TGA). It is recommended to be reserved for patients who are intolerant of D-penicillamine. Discontinuation of D-penicillamine due to adverse effects is relatively common, occurring in up to 30% of patients. Some of its more serious adverse effects are bone marrow toxicity and nephrotoxicity. While clinical experience with trientine is less than D-penicillamine, trientine is associated with fewer adverse effects.

Zinc

Zinc can also reduce copper levels in Wilson disease. It achieves this by increasing the expression of enterocyte metallothioneins, a family of proteins that bind various metal ions. Zinc is a potent inducer of metallothioneins that then bind preferentially to copper. The bound copper is then sequestered within the enterocyte, preventing its absorption into the bloodstream. This copper can then be removed from the body via the faeces due to the normal and rapid turnover of the small intestinal epithelia.

Zinc therapy leads to a reduction in the absorption of dietary copper and also a reduction in the reabsorption of copper that is endogenously secreted in digestive fluids. Unlike chelating agents, zinc may not reduce the copper content in the liver. Deterioration of liver function has been reported during zinc therapy, including in previously asymptomatic patients. Some studies suggest that zinc may be more beneficial for the treatment of neurological impairment compared to hepatic impairment. However, like chelating agents, neurological deterioration has also been reported on zinc therapy.

One advantage of zinc over chelating agents is its very low level of toxicity. The main adverse effect of zinc therapy is gastrointestinal irritation. As food reduces the absorption of zinc, it should be given on an empty stomach. However, if gastric upset is troublesome, the treating physician may consider the following options:

• Administration with a small protein meal;
• Giving the first dose of the day mid-morning rather than before breakfast;
• Giving the daily dose in three divided doses rather than two; or
• Switching to an alternative zinc salt (the acetate and gluconate salts are generally better tolerated than sulfate salts; limited data suggests that all salt forms of oral zinc are effective).

Other therapies

Combination therapy with a chelator and zinc has been suggested due to their different mechanisms of action. However, if administered together, chelating agents will chelate zinc and result in reduced absorption of both agents. Therefore, doses of zinc and chelating agents should be given at least one hour apart from each other. As both agents also need to be given in divided doses spaced from food, the resulting dosing schedule is likely to be complicated which may significantly affect compliance. A systematic review also suggests that combination therapy is associated with a higher mortality rate (12.7%) compared to monotherapy (6.6%).

As copper accumulation causes oxidative stress-related damage, antioxidant supplementation has been suggested as an adjunctive therapy. Some studies have found that patients with Wilson disease often have low levels of vitamin E. Although there is a lack of high-quality data to support the use of antioxidants in Wilson disease, vitamin E or N-acetylcysteine may be considered.

Physiotherapy and occupational therapy may be indicated to improve independence and quality of life. In order to avoid additional hepatic injury, patients should be advised to avoid alcohol and ensure they are vaccinated against hepatitis A and B. Patients with hepatic involvement require management appropriate to their level of liver disease.