Traditional treatment of WD focuses on promotion of copper excretion and reduction of copper intake. Initial treatment for symptomatic patients with WD should include a chelating agent, D-penicillamine or trientine (bettered tolerated than D-penicillamine). Zinc is recommended by some experts as a first line therapy in neurological patients[
27]. Maintenance therapy of presymptomatic patients or those with neurological symptoms usually requires a chelating agent or zinc[
27]. Ammonium tetrathiomolybdate shows optimal effect in treating patients presented with neurological symptoms, though not yet commercially available[
28,
29]. The efficacy of copper excretion is measured by the levels of urinary copper.
D-penicillamine
D-penicillamine chelates copper inside the body. It mobilizes intracellular copper into the circulation and enhances urinary excretion of copper. McArdle et al.[
30] found that D-penicillamine increases metallothionein mRNA levels without changing either the rate of copper uptake or the amount of copper within mouse hepatocytes. Metallothionein chelates the excessive copper to form a non-toxic combination[
31]. On the contrary, Xu et al.[
32] discovers that in Long-Evans Cinnamon (LEC) rats, an animal model of WD, excessive copper accumulation induces metallothionein in hepatocytes whereas D-penicillamine reduces the level of both metallothionein-l mRNA and metallothionein protein.
The initial dose of penicillamine is 750–1500 mg per day in two to four divided doses for adults. Dosing in children is 20 mg/kg/day to the nearest 250 mg, divided in two or three divided doses[
27]. The treatment is best taken 1 hour before or 2 hours after food. Absorption is estimated to be only 50% if it is taken with a meal. The use of lower initial doses, 125–250 mg per day, increasing over a few weeks, can enhance tolerance to the agent. Pyridoxine (vitamin B6) is added routinely to the treatment regimen in a dosage of 20–50 mg daily, as its deficiency is associated with neurological worsening induced by D-penicillamine[
33], which is irreversible in some cases.
The use of D-penicillamine remains controversial for decades due to its adverse effects. Someone suggests that D-penicillamine should not be used as initial therapy in WD[
34,
35]. Apart from neurological worsening, they include early reactions such as fever, rash, lymphadenopathy or late reactions such as bone marrow and renal toxicity[
36]. Newly reported unfavorable effects consist of ANCA-vasculitis in WD[
37] and dermatology toxicity, such as progeric changes in the skin, such as pemphigous or pemphigoid lesions[
38]. Severe adverse effects necessitate discontinuation of D-penicillamine and change of regimen in 20-30% of patients[
39,
40].
The reasons for the neurological deterioration of the D-penicillamine are still unknown. Depletion of pyridoxine may be one of them[
33]. Radical therapies that drastically lower serum copper level are found to induce partial status epilepticus as well as severe deterioration of neurological symptoms in one patient, whose conditions improved shortly after discontinuing D-penicillamine and having a high copper diet[
41]. Increased free copper concentrations are found in the serum and brain, and declined protein-bound copper concentrations are found in the brain of toxic milk mice during D-penicillamine administration[
42]. Immunoflurescence staining shows intense staining of ATP7A in the choroid plexus but rare ATP7A and copper transporter 1 (CTR1) on the blood–brain-barrier, which suggests that D-penicillamine mobilizes free copper from the brain parenchyma rather than from the blood.
During administration of D-penicillamine, periodic clinical, hematological, biochemical and routine urinary parameters are monitored weekly for 1 month, then monthly for 6 months and at 6-month intervals thereafter. It’s notable that cessation of penicillamine without replacement treatment causes rapid progression to fatal fulminant hepatitis[
43].
Trientine
Trientine has a polyamine structure, which chelates copper by the formation of stable complexes with the four constituent nitrogens in a planar ring. It is debatable whether the two agents mobilize different pools of copper. The initial dose is 900–2700 mg per day in two to three divided doses. Maintenance therapy is 900–1500 mg per day. As in the case of penicillamine, trientine should be given orally 1 hour before or 2 hours after food[
27].
Trientine is a less potent copper remover than D-penicillamine with its toxic profile similar to that of D-penicillamine, although side effects are less frequent and generally milder[
44]. It is believed that neurological deteriorations are less frequent in trientine than in D-penicillamine[
45]. However, Weiss et al.[
46,
47] reported a less frequent neurological deterioration in patients treated with D-penicillamine than with trientine while the extent of improvement was similar. Weiss et al.[
47] reported that neurological deteriorations happened to patients in all treatment regimen including D-penicillamine, trientine, zinc and combination therapy, and the P values were not significant.
Evidence grows for the effectiveness of trientine. Askari et al.[
48] studied 9 adults with severe liver disease identified over a 10 year period. They received initial treatment with trientine (1000 mg/day) and zinc (150 mg/day). Only one patient had hepatic encephalopathy. One patient developed mild neurological symptoms so the patient was given ammonium tetrathiomolybdate and zinc after 2 weeks of the original treatment. In the eight patients receiving trientine and zinc, the combination was given for at least 4 months and then maintenance zinc treatment was used. Over the first 12 months of treatment, prothrombin time and raised bilirubin and albumin concentrations returned to normal, and ascites disappeared. Benefit was maintained over 12 months to 14 years of follow-up. Taylor et al.[
40] provides evidence that trientine is as efficacious as penicillamine with a lower side effect profile in pediatric patients. However, trientine is not yet commercially available in China.
Zinc
Zinc induces intestinal metallothionein, which preferentially binds to copper within the duodenal enterocytes. Thus, copper absorption into the circulation is reduced, and copper is lost when the enterocytes are shed during normal cell turnover. Continuing copper losses in combination with reduced absorption lead to a negative copper balance. Furthermore zinc can induce copper-binding metallothionein in hepatocytes, thereby reducing the damaging effects of free copper.
Zinc has been used successfully in asymptomatic or presymptomatic patients. Wu et al.[
26] have identified 17 presymptomatic patients with WD by genetic analysis and prophylactic treatment of 14 patients with zinc over 3 to 5 years resulted in lowered level of urinary copper. None of the patients developed clinical symptoms of WD or adverse effects of zinc therapy by the end of the study period. In contrast, 3 patients who refused treatment had symptomatic progression. Brewer et al.[
49] conclude that zinc is effective as a sole therapy and that it has low toxicity based on data from the long-term follow-up of maintenance zinc treatment of 141 symptomatic and presymptomatic patients with WD. It’s the same for children and pregnant women, although more data should be acquired. In patients with severe hepatic disease, maintenance therapy with zinc was effective after an initial period of treatment with trientine and zinc[
48].
When the patients are given zinc monotherapy, liver functions should be regularly monitored. Among patients with hepatic manifestations, non-response to zinc monotherapy is not uncommon. This is not due to noncompliance. If the level of AST, ALT and γ-GT remains in a high level after the initiation of the zinc therapy, it often suggests a poor response and a change in therapy should be considered as soon as possible[
50].
Patients discontinue zinc therapy mostly due to gastrointestinal discomfort. It is more common with zinc sulfate than zinc acetate. During a long-term follow-up by Bruha et al., with a median follow-up of 12 years, no adverse events were reported with zinc acetate[
50].
Ammonium tetrathiomolybdate
Tetrathiomolybdate has a unique mechanism of action. Its four sulfur groups allow it to form a stable tripartite complex with copper and protein[
51,
52]. Ammonium tetrathiomolybdate is well-absorbed with or without food. It forms a complex with copper in the food. When it is given away from food, it forms a complex with available copper and albumin so that it can’t be up-taken or utilized for intracellular process[
29].
Although not yet commercially available, its high efficacy and rare neurological deterioration compared with trientine makes it a potential cure for WD patients with neurological symptoms[
53]. One out of 25 (4%) patients treated with tetrathiomolybdate while 6 of 23 (26%) patients treated with trientine showed neurological deterioration during an 8-week study[
45]. Unlike trientine, tetrathiomolybdate stably lowers the serum “free copper” level, which may explain uncommon neurological deterioration. Its recommended dose is 120 mg daily as 20 mg with meals and 20 mg between meals for 2 weeks, and then 60 mg daily as 10 mg 3 times daily with meals and 10 mg 3 times daily between meals[
53].
Symptomatic treatment
Despite the generally well response to chelation therapy with zinc, additional treatments to control the disturbing symptoms are still necessary for some patients. Neurological symptoms are usually more refractory than hepatic damages. Neurological symptoms can be categorized into parkinsonism, dysarthria, dystonia, tremor, pseudosclerosis[
54]. Parkinsonism can be treated with L-dopa, dopamine agonists[
54] and anticholinergics(trihexyphenidyl)[
55]. Essential tremor-like tremor is treated with beta-blocker (propranolol) or barbituate (primidone)[
55]. Dystonia can be treated with trihexyphenidyl, baclofen, valium or dopamine antagonist (tiapride) and botulinem injection[
56,
57]. Proxysmal dystonic movement can be treated with oxcarbazepine[
56]. Gabapentine can be used when dealing with penicillamine-induced dystonia when other options fail[
58]. However, there are only a small number of case reports regarding symptomatic treatments and the conclusions are inconsistent.
Experience from China
In China, most Departments of Neurology treat WD patients according to WD guideline. A few neurologists choose traditional Chinese medicine (TCM) and decoppering agents other than D-penicillamine and trientine. Besides, aggressive decoppering therapies involving intravenous 2, 3-dimercaptopropane-1-sulfonate (DMPS) will also be applied. Unfortunately, there are only a limited number of reports regarding this aspect. Aggressive decoppering therapies are theoretically dangerous for patients because rapid mobilization and depletion of deposited copper are associated with neurological worsening. However, according to the aggressive therapy reported by Yang et al.[
59], 84.85% of the patients showed improvement and 11.11% of the patients were symptom free based on Goldstein activity of daily life scale. However, the account of adverse events was not given.
TCM is mostly used in combination with decoppering agents. The most commonly used TCM agents include Gandou Decoction, Gandou Tablets, and oxymatrine. The choice of TCM agents is empirical and lacking consensus among neurologists. So far, there is no strong evidence to recommend TCM in treating WD due to the methodical limitations of these clinical researches. Most researches did not provide information on how the random allocation was generated and concealed. Based on a systematic review of 9 randomized controlled trials[
60], TCM therapy are generally associated with better response and fewer adverse events. However, 8 out of the 9 randomized control trials mentioned above lacked blinding methods and none of them reported dropout. As a result, the optimistic outcomes of TCM therapy are questionable.