Pharmacologic management options
The main pharmacologic options in Wilson disease are the chelating agents D-penicillamine and trientine, which cause urinary copper excretion, and zinc, which reduces copper uptake from the gastrointestinal tract.9
There are two phases of treatment for patients with symptomatic Wilson disease: the initial phase in symptomatic patients is to remove excess copper from the body, which usually includes a chelating agent, and a maintenance phase once symptoms have stabilized to maintain copper levels, where the dose of the chelating agent is decreased or the patient is switched to zinc therapy.1-3 Zinc may be used as a monotherapy for both initial and maintenance therapy in pre-symptomatic and asymptomatic patients and patients with neurologic symptoms.1-3 Limited evidence is available on the use of zinc and chelating agents in combination.1-3 A systematic review of combination therapies found that, overall, they have a lower rate of effectiveness, a higher rate of adverse effects, and a higher rate of mortality than monotherapy with chelators or zinc alone.a,10
Treatment options for asymptomatic patients include chelating agents or zinc to effectively prevent disease progression and symptomatic disease.2 If there is evidence of organ damage due to either inflammation or structural damage, there is greater urgency to start treatment.2 However, there is no consensus on whether treatment should be started without evidence of organ damage in young children who are asymptomatic, due to possible adverse effects of treatment on development.2
Footnote
aBased on a systematic review evaluating 50 studies of therapy for Wilson disease, including 17 studies on combination therapies with chelation and zinc. The respective rates of effectiveness of therapies were: combination therapies (pooled) 60.4% (95% CI 55.8, 65.0); D-penicillamine monotherapy 73.7% (95% CI 65.1, 82.4); trientine monotherapy 82.6% (95% CI 75.4, 89.7); and zinc monotherapy 71.6% (95% CI 62.2, 81.0). There was a greater relative risk of adverse events with combination therapies compared with trientine or zinc monotherapy (trientine relative risk 1.67, 95% CI 1.04, 2.69: zinc relative risk 2.25, 95% CI 1.36, 3.73), but not D-penicillamine monotherapy (relative risk 1.10, 95% CI 0.87, 1.38). Mortality rates were 6.6% (95% CI 5.5, 7.6) for the pooled monotherapies and 12.7% (95% CI 9.5, 15.9) for the pooled combination therapies (relative risk 1.94; p<0.001).10
EFFICACY OF PHARMACOLOGIC THERAPIES
Clinical evidence has shown that patients with hepatic symptoms of Wilson disease had comparable rates of symptomatic improvement with D-penicillamine or trientine as first-line chelation therapya; patients with neurologic Wilson disease also showed relatively similar rates of symptomatic improvement with first-line D-penicillamine or trientine.b,11 First-line zinc therapy has also demonstrated clinical improvement of symptoms in patients with predominantly neurologic symptoms of Wilson disease, although a higher proportion of patients with hepatic symptoms showed improved liver enzymes with first-line D-penicillamine compared with zinc.c,12
- In a retrospective study of 405 patients, 90.7% (185/204) and 92.6% (25/27) of patients with hepatic symptoms of Wilson disease demonstrated improvements in liver symptoms when treated with first-line D-penicillamine or trientine, respectivelyb,11
- In the same study, 67.5% (77/114) and 55.0% (11/20) of patients with neurologic symptoms of Wilson disease showed improved neurologic symptoms with first-line D-penicillamine and trientine, respectivelyb,11
- In a separate retrospective study of 143 patients, 87.1% (27/31) and 80.0% (16/20) of patients with predominantly neurologic symptoms showed improved activities of daily living with first-line zinc or D-penicillamine, respectively; 77.4% (24/31) and 60.0% (12/20) of these patients showed improved neurologic clinical examinationc,12
- In the same study, 87.5% (28/32) and 68.1% (32/47) of patients with predominantly hepatic symptoms showed improved liver enzymes with first-line D-penicillamine and zinc, respectively (p=0.047)c,12
- In an ongoing randomized clinical trial comparing D-penicillamine with trientine therapy in 53 patients with hepatic or neurologic Wilson disease, mean serum non-ceruloplasmin-bound copper levels in patients treated with trientine were demonstrated to be not significantly different from those in patients treated with D-penicillamine at 24 weeks (primary efficacy endpoint: mean difference of −9.2 μg/L [95% CI −24.4, 6.0], demonstrating the non-inferiority of trientine)d,13-15
- In the same study, 50% and 24% of patients treated with trientine and D-penicillamine, respectively, were within the clinically recommended non-ceruloplasmin-bound copper and urinary copper excretion thresholds after 24 weeks of treatment (p=0.057)d,15
Footnote
aAvailable evidence on comparisons between treatments are weak as most of the studies were retrospective analyses.1
bBased on a retrospective European analysis of 405 patients aged 1–60 years at diagnosis with symptoms of Wilson disease; the analysis compared the efficacy and safety of D-penicillamine and trientine in terms of neurologic and hepatic outcomes.11
cBased on a retrospective study of 143 adults diagnosed with Wilson disease in Poland who received first-line zinc or D-penicillamine.12
dBased on a multicenter, randomized, open-label clinical trial of 53 patients with clinically stable Wilson disease who had been receiving D-penicillamine for at least 4 months; patients were randomized 1:1 to receive trientine (mean age of patients, 42.0 years) or D-penicillamine (mean age of patients, 45.2 years) treatment over 24 weeks, with a 24-week extension phase. At baseline, 36% (9/26) and 42% (10/27) of patients receiving trientine and D-penicillamine, respectively, had hepatic symptoms of Wilson disease at diagnosis, and 56% (14/26) and 58% (14/27) of patients receiving trientine and D-penicillamine, respectively, had neurologic symptoms of Wilson disease at diagnosis. Non-ceruloplasmin-bound copper and urinary copper excretion thresholds were based on a composite outcome of 25–150 μg/L and 200–500 μg/24h, respectively.13-15
Compliance, tolerability, and safety
D-penicillamine, trientine, and zinc all require multiple daily doses and should not be taken with food because food can interfere with drug absorption, leading to a decrease in effectiveness.1,2
The safety and tolerability profiles of these drugs are variable, with serious side effects and frequent treatment discontinuation having been reported.
- In a study of 138 patients receiving D-penicillamine, 70% of patients developed side effects, resulting in 75% of these patients switching to treatment with either trientine or zinca,16
- In a study of 141 patients with Wilson disease receiving trientine therapy, ~7% of patients discontinued treatment due to adverse eventsb,11
- Side effects leading to discontinuation of D-penicillamine or trientine have been reported to include arthralgia, leukopenia, erythema, and lupus erythematosus, among others11
- Zinc has been associated with few adverse effects, with the most common being gastric irritation1,2
- In a retrospective study of 42 patients with Wilson disease, the most common adverse effects reported in patients who received zinc therapy were mild gastric pain and mild elevation of serum lipase and amylase without symptoms of pancreatitis17
Footnotes
aBased on a retrospective study of 163 patients with Wilson disease in Germany, with a mean duration of analysis of 16.7 years (range 1–51). 97/138 patients developed side effects on D-penicillamine, of whom 39 patients and 34 patients switched to treatment with trientine and zinc, respectively.16
bBased on a retrospective analysis of 405 patients with Wilson disease, with 141 patients and 326 patients receiving trientine and D-penicillamine, respectively. 94/326 patients and 10/141 patients receiving D-penicillamine and trientine, respectively, discontinued due to adverse events.11
Paradoxical neurologic worsening
Drug-related neurologic deterioration has been reported to occur in patients with Wilson disease.16 Deterioration of neurologic symptoms has been reported early after treatment initiation; it is unclear whether it is due to an adverse event with the therapy, natural progression in spite of treatment, or co-administration of neuroleptics.18,19
- In a study of 163 patients, neurologic deterioration was most commonly reported to occur early after initiation of treatment with D-penicillamine, whereas neurologic deterioration while under treatment with trientine and zinc was reported to occur at any stage. However, most (~84%, 138/163) of the patients were treated with D-penicillamine as first-line therapy, followed by either trientine or zinca,16
- A lack of improvement in neurologic symptoms has been reported in ~13%a to 50%b of patients treated with D-penicillamine during the initial phase of treatment16,20
- Neurologic deterioration has been reported in ~8%a to ~26%c of patients after starting treatment with trientined,11,16,21
- Neurologic deterioration has been reported in ~4%a to 9.5%e of patients receiving zinc treatment16,22
- A retrospective cohort study of 163 patients with Wilson disease reported neurologic deterioration in 19 (13.8%) patients treated with D-penicillamine, 11 (8.0%) treated with trientine, and 6 (4.3%) treated with zinc16
However, findings can vary; a separate retrospective study of 405 patients with Wilson disease treated with chelating monotherapies found that 20% (4/20) of symptomatic patients receiving first-line trientine experienced symptomatic neurologic deterioration,11 while 5.3% (6/114) of symptomatic patients receiving D-penicillamine in the same study experienced deterioration of neurologic symptoms.11
Neurologic deterioration after starting treatment with D-penicillamine and zinc has also been reported in pediatric patients.23
Footnotes
aBased on a retrospective study of 163 patients with Wilson disease in Germany, with a mean duration of analysis of 16.7 years (range 1–51). Deterioration of neurologic symptoms was reported in 19/138 (13.8%) patients who received D-penicillamine, and 6/138 (4.3%) patients reported side effects while under treatment with zinc. Neurologic worsening was reported in 11/138 (~8%) of patients treated with trientine.16
bBased on a retrospective study of 25 patients with neurologic Wilson disease. 13/25 (52%) patients reported a deterioration of neurologic symptoms following initial treatment with D-penicillamine.20
cBased on a randomized, double-blind, controlled trial of 48 patients with neurologic presentation of Wilson disease treated with either trientine (n=23) or tetrathiomolybdate (n=25) in the USA. Neurologic deterioration was reported in 6/23 (26.1%) of patients in the trientine arm.21
dBased on a retrospective cohort study of 405 patients with Wilson disease examined at tertiary care centers in Germany and Australia, and patients from the EUROWILSON registry, 141 trientine treatments and 326 D-penicillamine treatments were evaluated. Neurologic deterioration was reported in 4/38 (10.5%) patients with trientine as first-line therapy.11
ceBased on a retrospective study of 288 patients with Wilson disease. 9/95 (9.5%) patients experienced neurologic deterioration while under zinc therapy.22
Liver transplantation
In patients with Wilson disease who have acute liver failure (formerly referred to as “fulminant” Wilson disease) with the classic presentation (intravascular hemolysis, progressive hepatic encephalopathy, relatively low serum aminotransferases, and very low serum alkaline phosphatase), or who have decompensated cirrhosis and are unresponsive to medical therapy, liver transplantation is indicated.1,2 Results from a liver transplantation study in patients with Wilson disease demonstrated mixed outcomes, with a 10-year graft survival rate of 79% and a 20-year graft survival rate of 70%, but with some patients experiencing transplant rejection or requiring retransplantation.a,24 When successful, liver transplantation corrects the underlying hepatic defect in Wilson disease, normalizing the patient’s copper metabolism.1,2 Neurologic and psychiatric symptoms may show improvement after liver transplantation2; however, neurologic deterioration has also been reported after otherwise successful transplantation.24,25
Footnotes
aBased on a retrospective study of 121 patients with Wilson disease who had a liver transplantation. 75 patients were adults (median age 29 years [range 18–66]) and 46 patients were children (median age 14 years [range 7–17]).24