EASL Clinical Practice Guidelines

Treatment

A number of drugs are available for the treatment of Wilson's disease, including D-penicillamine, trientine, zinc, tetrathiomolybdate, and dimercaprol. Once the diagnosis has been made, treatment needs to be life-long. There is a lack of high-quality evidence to estimate the relative treatment effects of the available drugs in Wilson's disease. Therefore, multicentre prospective randomized controlled comparative trials are necessary [87].

D-Penicillamine

The major effect of D-penicillamine in Wilson's disease is to promote the urinary excretion of copper. D-penicillamine may also act by inducing metallothionein [88]. The maintenance dose is usually 750–1500 mg/day administered in two or three divided doses. Dosing in children is 20 mg/kg/day rounded off to the nearest 250 mg and given in two or three divided doses. D-Penicillamine is best administered 1 h prior to meals, because food inhibits its absorption. Since D-penicillamine tends to interfere with pyridoxine action, supplemental pyridoxine should be provided (25–50 mg/day). D-penicillamine interferes with collagen cross-linking [89] and has some immunosuppressant actions [[90], [91]].

Adequacy of treatment can be monitored by measuring 24-hour urinary copper excretion while on treatment. This is highest immediately after starting treatment and may exceed 16 μmol (1000 μg) per 24 h at that time. For long-term treatment, the most important sign of efficacy is a maintained clinical and laboratory improvement. Serum ceruloplasmin may decrease after initiation of treatment. Urinary copper excretion should run in the vicinity of 3–8 μmol per 24 h on treatment. To document therapeutic efficiency, urinary copper excretion after 2 days of D-penicillamine cessation should be ⩽1.6 μmol/24 h. In addition, the estimate of non-ceruloplasmin bound copper shows normalization of non-ceruloplasmin bound copper concentration with effective treatment [92]. Values of urine copper excretion >1.6 μmol/24 h after two days of D-penicillamine cessation may indicate non-adherence to therapy (in those patients non-ceruloplasmin-bound copper is elevated >15 μg/L).

D-penicillamine is rapidly absorbed from the gastrointestinal tract with a double-peaked curve for intestinal absorption [[93], [94]]. If D-penicillamine is taken with a meal, its absorption is decreased overall by about 50%. Once absorbed, 80% of D-penicillamine circulates bound to plasma proteins. Greater than 80% of D-penicillamine excretion is via the kidneys. The excretion half-life of D-penicillamine is on the order of 1.7–7 h, but there is considerable inter-individual variation.

Numerous studies attest to the effectiveness of D-penicillamine as treatment for Wilson's disease [[95], [96], [97]]. In patients with symptomatic liver disease, recovery of synthetic liver function and improvement in clinical signs occur typically during the first 2–6 months of treatment, but further recovery can occur during the first year of treatment. Failure to comply with therapy leads to significant progression of liver disease and liver failure within 1–12 months following discontinuation of treatment.

In patients with neurologic Wilson's disease, improvement of symptoms is slower and may be observed even after three years [97]. Worsening of neurologic symptoms has been reported in 10–50% of patients treated with D-penicillamine during the initial phase of treatment. In a recent series, neurologic worsening occurred on all three treatments used for Wilson's disease (D-penicillamine, trientine, zinc), but mainly with D-penicillamine, where 13.8% were adversely affected [27]. Tolerability of D-penicillamine may be enhanced by starting with incremental doses, 125–250 mg/day increased by 250 mg increments every 4–7 days to a maximum of 1000–1500 mg/day in 2–4 divided dosages. Administration of doses 1500 mg per day or higher at once may lead to rapid and often irreversible neurological deterioration. Rapid re-administration of the treatment in patients who stopped it for longer time may also evoke irreversible neurological signs.

D-penicillamine is associated with numerous side effects. Severe side effects requiring the drug to be discontinued occur in approximately 30% of patients [[95], [98]]. Early sensitivity reactions marked by fever and cutaneous eruptions, lymphadenopathy, neutropenia or thrombocytopenia, and proteinuria may occur during the first 1–3 weeks.

Significant bone marrow toxicity includes severe thrombocytopenia or total aplasia. In these conditions, D-penicillamine should be discontinued immediately. Late reactions include nephrotoxicity, usually heralded by proteinuria or the appearance of other cellular elements in the urine, for which discontinuation of D-penicillamine should be immediate. Other late reactions include a lupus-like syndrome marked by hematuria, proteinuria, and positive antinuclear antibody, and with higher dosages of D-penicillamine no longer typically used for treating Wilson's disease, Goodpasture syndrome. Dermatological toxicities reported include progeric changes in the skin and elastosis perforans serpingosa [99], and pemphigous or pemphigoid lesions, lichen planus, and aphthous stomatitis. Very late side effects are rare and include nephrotoxicity, myasthenia gravis [100], polymyositis, loss of taste, immunoglobulin A depression, and serous retinitis. Hepatic siderosis has been reported in treated patients with reduced levels of serum ceruloplasmin and non-ceruloplasmin bound copper [101]. Overtreatment with penicillamine may lead to a reversible sideroblastic anemia and hemosiderosis.

Trientine

Trientine (triethylene tetramine dihydrochloride or 2,2,2-tetramine) was introduced in 1969 as an alternative to D-penicillamine. Trientine is a chelator with a polyamine-like structure chemically distinct from D-penicillamine. It lacks sulfhydryl groups and copper is chelated by forming a stable complex with the four constituent nitrogens in a planar ring. Like D-penicillamine, trientine promotes urinary copper excretion.

Few data exist about the pharmacokinetics of trientine. It is poorly absorbed from the gastrointestinal tract, and what is absorbed is metabolized and inactivated [102]. About 1% of the administered trientine and about 8% of the biotransformed trientine metabolite, acetyltrien, ultimately appear in the urine. The amounts of urinary copper, zinc and iron increase in parallel with the amount of trientine excreted in the urine [103]. The potency of trientine as copper chelator in comparison to D-penicillamine is controversial [[95], [104]]. Trientine and D-penicillamine may mobilize different pools of body copper [105].

Typical dosages of trientine are 900–2700 mg/day in two or three divided doses, with 900–1500 mg/day used for maintenance therapy. In children, the weight-based dose is not established, but the dose generally used is 20 mg/kg/day rounded off to the nearest 250 mg, given in two or three divided doses. Trientine should be administered 1 h before or 3 h after meals. Taking it closer to meals is acceptable if this ensures compliance. Trientine tablets may not be stable for prolonged periods at high ambient temperature, which is a problem for patients travelling to warm climates.

Trientine is an effective treatment for Wilson's disease [[106], [107]]. Trientine, while being developed for use in patients who are intolerant of penicillamine, has also been shown to be an effective initial therapy, even with patients with decompensated liver disease at the outset [[108], [109]]. In general, adverse effects due to D-penicillamine resolve when it is substituted for trientine and do not recur during prolonged treatment with trientine.

Neurological worsening after beginning of treatment with trientine has been reported but appears less common than with D-penicillamine. Trientine also chelates iron, and co-administration of trientine and iron should be avoided because the complex with iron is toxic. A reversible sideroblastic anemia may be a consequence of overtreatment and resultant copper deficiency. Lupus-like reactions have also been reported in some Wilson's disease patients treated with trientine. However, these patients were almost all uniformly treated previously with D-penicillamine, so the true frequency of this reaction when trientine is used de novo is unknown.

Adequacy of treatment is monitored by measuring 24-hour urinary copper excretion (after 2 days of cessation of therapy) and by measuring non-ceruloplasmin bound copper.

Ammonium tetrathiomolybdate

Ammonium tetrathiomolybdate (TM) is a very strong decoppering agent. TM complexes with copper; in the intestinal tract it prevents absorption, and in the circulation renders copper unavailable for cellular uptake [110]. TM can directly and reversibly down-regulate copper delivery to secreted metalloenzymes [111]. At low doses, TM removes copper from metallothionein, but at higher doses it forms an insoluble copper complex, which is deposited in the liver [112]. TM remains an experimental therapy, and it is not commercially available. As yet, clinical experience with this drug is limited. The control of free copper was prospectively studied as initial anti-copper treatment in neurologically presenting Wilson's disease patients [113]. Patients were treated for 8 weeks with TM, and thereafter with zinc. In an open-label trial, TM showed very strong control of free copper levels. In a double-blind trial, TM significantly better controlled free copper levels than trientine. On trientine, five patients worsened neurologically and this was associated with significant spikes in serum free copper levels. Other data also indicate its utility because it may less likely cause neurological deterioration [[114], [115]]. Potential adverse effects include bone marrow depression [116], hepatotoxicity [117], and overly aggressive copper removal, which causes neurological dysfunction. TM also has anti-angiogenic effects due to its extensive decoppering effect [118].

Zinc

Zinc was first used to treat Wilson's disease by Schouwink in Holland in the early 1960s [119]. Its mechanism of action is different from that of penicillamine and trientine: zinc interferes with the uptake of copper from the gastrointestinal tract. Zinc induces enterocyte metallothionein, a cysteine-rich protein that is an endogenous chelator of metals. Metallothionein has greater affinity for copper than for zinc and, thus, preferentially binds copper present in the enterocyte and inhibits its entry into the portal circulation. Once bound, the copper is not absorbed but is lost into the fecal contents as enterocytes are shed by normal turnover [120]. Because copper also enters the gastrointestinal tract from saliva and gastric secretions, zinc treatment can generate a negative balance for copper and thereby remove stored copper [[121], [122]]. Zinc may also act by inducing levels of hepatocellular metallothionein [[123], [124]], thus binding excess of toxic copper to prevent hepatocellular injury.

Different zinc salts (sulphate, acetate, gluconate) are used. The recommended dose is 150 mg elemental zinc/day (for children <50 kg in body weight 75 mg) administered in three divided doses, 30 min before meals. Whether a combination therapy with chelators has advantages is not yet known. However, to avoid the neutralization of zinc efficiency by chelators, different times of dosing have to be considered. The compliance with the three times per day dosage may be problematic. The zinc salt used does not make a difference with respect to efficacy but may affect tolerability. Taking the zinc medication with food interferes with its absorption [125]. Adequacy of treatment with zinc is judged by clinical and biochemical improvement and by measuring 24-hour urinary excretion of copper, which should be less than 1.6 μmol per 24 h on stable treatment. Additionally, non-ceruloplasmin-bound copper should drop with effective treatment. Urinary excretion of zinc may be measured from time to time to check compliance.

Zinc has few side effects. Gastric irritation is a common problem and may be dependent on the salt employed. Zinc may have immunosuppressant effects and reduce leukocyte chemotaxis. Elevations in serum lipase and/or amylase may occur, without clinical or radiologic evidence of pancreatitis. Neurological deterioration is uncommon with zinc [[96], [126], [127]]. Whether high-dose zinc is safe for patients with impaired renal function is not yet established.

Most data on zinc come from uncontrolled studies of dosages ranging from 75 to 250 mg per day [[87], [128]]. Zinc is probably less effective than chelating agents in the treatment of established Wilson's disease, although data are limited and uncontrolled [129]. Although zinc is currently reserved for maintenance treatment, it has also been used as first-line therapy, most commonly for asymptomatic or presymptomatic patients. It appears to be equally effective as D-penicillamine but better tolerated [96]. Reports of large studies in adults with Wilson's disease indicate good efficacy [122]. While zinc monotherapy appears to be effective and safe in neurologic Wilson's disease and in asymptomatic siblings, great caution is needed in patients with hepatic Wilson's disease. Hepatic deterioration has been occasionally reported when zinc was commenced and was fatal in one case [127]. Thus, exclusive monotherapy with zinc in symptomatic Wilson's liver disease is controversial. In the Netherlands, 17 symptomatic patients with Wilson's disease were treated with zinc only with a median follow-up of 14 years [128]. The outcome of exclusive zinc therapy was generally good in cases of neurologic disease. A less satisfactory outcome in hepatic disease may relate to less efficient de-coppering. Two patients with hepatic Wilson's disease progressed to a decompensated state and two patients with neurologic Wilson's disease developed symptomatic liver disease. Long-term outcomes of different treatments in 288 German and Austrian Wilson's disease patients indicated that, in the majority of patients, treatment with chelating agents or zinc salts was effective. However, there was an advantage for chelating agents to prevent hepatic deterioration [129]. In contrast, in a Polish cohort of 164 patients there were no differences in survival of patients who started therapy with zinc sulfate or D-penicillamine [38]. Current guidelines recommend that all symptomatic patients with Wilson disease should receive a chelating agent (penicillamine or trientine) [[130], [131]]. Zinc may have a role as a first line therapy in neurological patients.

Other treatments

Antioxidants, mainly vitamin E, may have a role as adjunctive treatment [[132], [133]]. Serum and hepatic vitamin E levels have been found to be low in Wilson's disease [[134], [135], [136]]. Symptomatic improvement when vitamin E was added to the treatment regimen has been occasionally reported but no rigorous studies have been conducted. One study suggests no correlation of antioxidant deficiency with clinical symptoms [135].

Animal data suggest a role for amitriptyline in impending liver failure due to Wilson's disease, as it reduces the copper-induced apoptosis of liver cells, and thereby increases survival of ATP7B-deficient rats [137]. However, no human data are available yet.

In vitro, treatment with pharmacological chaperones 4-phenylbutyrate and curcumin, partially restored protein expression of most ATP7B mutants and might enable novel treatment strategies in Wilson's disease, by directly enhancing the protein expression of mutant ATP7B with residual copper export activity [138]. Furthermore, curcumin is an ideal antioxidant and an effective scavenger of reactive oxygen species [139] and can act as a copper-chelating agent [140]. Clinical data in patients with Wilson's disease are not yet available.

Liver transplantation

Transplantation is frequently necessary for patients presenting with acute liver failure or decompensated cirrhosis due to Wilson's disease [141]. Because the biochemical defect resides mainly in the liver, orthotopic liver transplantation (OLT) corrects the underlying problem. Schilsky analyzed 55 transplants performed in 33 patients with decompensated cirrhosis and 21 with acute liver failure due to Wilson's disease in the United States and Europe [142]. The median survival after OLT was 2.5 years, the longest survival time after OLT was 20 years. Survival at 1 year was 79%. Nonfatal complications occurred in five patients. Fifty-one OLT were performed on 39 patients (16 pediatric, 23 adults) at the University of Pittsburgh [143]. The rate of primary graft survival was 73% and patient survival was 79%. Survival was better for those with a chronic advanced liver disease presentation (90%) than it was for those with an acute liver failure (73%) presentation. Living related donor transplantation (where the donor is an obligate heterozygote) is feasible and gives excellent results [[144], [145], [146]]. Survival is satisfactory and appears to be better for patients having a transplant for chronic advanced liver disease than for those with acute liver failure. Overall survival is improving; the longest recorded survival is 20 years. A limited observation suggests that the neurologic symptoms of patients who need OLT may also improve as a result [145]. However, severe neurological deterioration was also observed after successful OLT [147].