Wilson's Disease: An Update

Shyamal K Das; Kunal Ray

Disclosures

Nat Clin Pract Neurol. 2006;2(9):482-493. 

In This Article

Treatment and Management

The aim of medical treatment for WD is to remove the toxic deposit of copper from the body to produce a negative copper balance, and to prevent its reaccumulation. Successful therapy is measured in terms of a restoration of normal levels of free serum copper and its excretion in the urine.

Copper chelating agents are the first-line therapy for WD ( Table 3 ).[49,50,51,52] In the initial phase of treatment, toxic levels of copper are controlled, and dietary copper is restricted. Patients should avoid copper-rich food such as chocolate, nuts, shellfish and liver, and abstain from cooking or taking food from copper bowls and plates. The average daily diet contains 2-4 mg of copper, and 0.8 mg of copper is normally lost through the feces each day. Chelating agents are therefore prescribed to promote 24-hour excretion of approximately 2 mg of copper in the urine, to induce a negative copper balance. In the maintenance phase, the dosage can be reduced and zinc salt added to prevent the systemic absorption of copper.[53,54] Studies have demonstrated that the majority of presymptomatic WD patients treated indefinitely with either zinc or copper chelators achieve a successful outcome.[39,55]

Since 1955, D-penicillamine has been the most commonly used chelating agent,[49] and an animal model of WD has demonstrated its efficacy as a chelator.[56] Other chelating agents that can be used include triethylene tetramine dihydrochloride (trientine). Table 3 shows the dosage, mode of action and side effects of various chelating agents. In addition, zinc salt (sulfate or acetate) helps in the prevention of copper absorption from the gut.[53,54]

D-penicillamine not only chelates copper from tissue, but also detoxifies tissue copper by promoting the synthesis of metallothionein, which forms a non-toxic combination with copper. During administration of D-penicillamine, periodic clinical, hematological, biochemical (transaminases) and routine urinary parameters are monitored weekly for 1 month, then monthly for 6 months and at 6-monthly intervals thereafter. An improvement in clinical features is usually noted after 2-3 months, continuing over a period of 1-2 years. Regular measurement of the 24-hour urinary excretion of copper provides an important index of copper removal from the body. If the excretion level in a compliant patient decreases to less than 0.5 mg daily, the dose can be lowered. At this point, a zinc salt should be added to the treatment regimen, preferably before meals. D-penicillamine should be taken 2 hours after meals to avoid any interaction with the zinc.

Side effects from D-penicillamine can occur both early and late in the treatment period.[57] Early side effects include a hypersensitivity reaction characterized by fever, skin rash and lymphadenopathy that commonly occurs within 3 weeks of commencing medication. In 20-30% of cases, an exacerbation of the neurological symptoms occurs over a period of 2 weeks to 12 months (commonly after 6 weeks). This occurrence is caused by the rapid mobilization of liver copper in the circulation, and can sometimes be permanent. An early hypersensitivity reaction can be managed by temporary withdrawal of the drug, followed by its reintroduction after a course of oral steroids. Neurological deterioration can be attenuated by withdrawing the drug, and then reinstituting it at a smaller dosage with a slow escalation to the optimum dosage. If neurological deterioration recurs, D-penicillamine should be withdrawn and substituted with other chelators or zinc salt alone.[51] Pyridoxine (vitamin B6) is added routinely to the treatment regimen in a dosage of 25-50 mg daily, as its deficiency has been documented during D-penicillamine therapy.

Delayed side effects occur in about 5% of cases, and can be caused by immunological factors, interference with collagen and elastin synthesis, or idiopathic factors ( Table 3 ). Immunological side effects are managed with steroids and a reduction in the D-penicillamine dosage. In cases in which the patient cannot tolerate treatment with D-penicillamine, trientine can be used as a substitute, which is usually effective except in cases with systemic lupus erythematosus or elastosis perforans.[50]

Trientine[50] and ammonium tetrathiomolybdate[52] are considered to be safer alternatives to D-penicillamine. Trientine is a less potent copper remover than D-penicillamine, and its toxic profile is similar to that of D-penicillamine, although side effects are less frequent and generally milder.[50] Ammonium tetrathiomolybdate, an agent previously used to treat copper toxicosis in animals, has been advocated because of its lower toxic profile,[51,52] but it is still an experimental drug that is not routinely available, and its long-term safety and efficacy is unknown.

One of the authors has personally treated about 40 cases of WD over the past decade using D-penicillamine, starting at a smaller dose of 250 mg daily on the basis of the principal of 'start low and go slow' (SK Das, unpublished data). The dose is subsequently increased by a total of 250 mg after an interval of 1-2 weeks to the desired therapeutic level based on clinical and investigational parameters. When this regimen was followed, side effects were observed in fewer than 10% of patients, a finding similar to those of some studies.[27,29] Disadvantages of this schedule include the longer time needed for stabilization of symptoms, and the slower disappearance of the signs of copper toxicity.[27]

Pregnant women with WD can have a successful pregnancy while undergoing chelation therapy. These patients should continue on the same agent but with a slightly reduced dosage, particularly in the third trimester.[51] Abrupt cessation of the drug treatment can be fatal. If the patient is completely free of toxic copper, she should be advised to take only zinc salt. Although D-penicillamine and trientine are potentially teratogenic, there are currently insufficient data concerning their teratogenic effects in pregnant patients with WD to warrant cessation of treatment.[50,58]

Symptomatic treatment for dystonia and parkinsonian features, psychiatric disturbances, and encephalopathy can be very successful and reassuring for the patient with WD. The treatment of dystonia and parkinsonian features includes the administration of anticholinergics, tizanidine, baclofen, levodopa, or γ-aminobutyric acid (GABA) agonists—particularly clonazepam. Comparative studies of the use of these medications for symptomatic therapy are, however, lacking.[51] Botulinum toxin injection is a useful adjunct therapy in cases with severe limb dystonias when other treatments are unsuccessful (SK Das, unpublished data). Convulsions can be controlled with both traditional and newer antiepileptic drugs; in our opinion, more than one drug is often required to achieve control. Psychiatric disturbance is usually managed with atypical neuroleptics, and occasionally with traditional neuroleptics. Hepatic encephalopathy is managed with a standard regimen of protein restriction and lactulose.

In patients with progressive liver failure or acute liver failure from fulminant hepatitis with or without intravenous hemolysis, orthotropic hepatic transplantation is an efficient treatment,[59] and can reverse the abnormal pathology mediated by the liver in patients with WD. Hepatic transplantation is also indicated in the absence of liver failure in patients with neurological WD in whom chelation therapy has proved ineffective, and significant improvements in neurological features have been reported, which include the disappearance of the KF ring.[60]

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