THINK WILSON
Monitoring & evaluation during treatment & management of Wilson’s disease

Managing Wilson disease

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




Patient evaluation and monitoring in Wilson disease

Evaluation at diagnosis

Patient evaluation at diagnosis is essential to thoroughly assess symptoms and to ensure that mild or subtle manifestations are not overlooked.1,4,5

  • In 67 patients with hepatic manifestations, brain pathology was detected in ~42% of patients using MRIa,26
  • Two studies on patients with Wilson disease found that ~90% of patients with neurologic symptoms had pathology detectable by MRIa,b,26,27
  • A novel, semi-quantitative MRI assessment scale for the assessment and classification of radiologic severity of brain MRI abnormalities in patients with Wilson disease has been published28
  • In some patients, abnormalities were detected using MRI before the onset of symptomsa,b,26,27

All patients presenting with neurologic symptoms should have a comprehensive clinical assessment, performed by a neurologist or movement disorder specialist.2 Early assessment of psychiatric comorbidities is advisable, using appropriate screening instruments.2 

Footnotes

aBased on a retrospective study of 204 patients with newly diagnosed Wilson disease. 67 patients had the hepatic form of Wilson disease and brain pathology was found in 28 (41.8%) of those patients. 105 patients had the neuropsychiatric form of Wilson disease and brain pathology was found in 95 (90.5%) of those patients.26

bBased on a retrospective study of 76 patients with Wilson disease with neurologic symptoms. 68 patients (89.5%) showed MRI abnormalities.27




Routine treatment monitoring

Monitoring of patients during treatment is important to determine compliance and treatment efficacy and to identify any side effects.1-3 Biannual assessments for routine monitoring of patients with Wilson disease are recommended, with more frequent monitoring recommended in patients initiating treatment, or in certain cases such as pregnancy, worsening of symptoms, or poor compliance.1-3 Regular monitoring assessments may include:1-3

  • Serum copper
  • Serum ceruloplasmin
  • 24-hour urinary copper excretion
  • Estimated serum non-ceruloplasmin-bound coppera
  • Liver biochemistries
  • Complete blood count
  • Urinalysis
  • Clinical examination, including assessment of liver disease and psychiatric symptoms, Kayser–Fleischer rings using slit-lamp examination, anterior segment optical coherence tomography, Scheimpflug imaging or in vivo confocal microscopy, and signs of adverse effects
Footnote

aCalculated non-ceruloplasmin-bound copper may be used for monitoring adherence and for making therapeutic changes once improved assays are available.2



In patients receiving chelation therapy, regular complete blood count measurements and urinalysis are of particular importance to assess neutropenia, anemia, and hyperferritinemia, and to identify poor adherence or overtreatment.1,2 In patients receiving zinc therapy, transaminases should be carefully monitored as an indicator of hepatic deterioration2; if levels become too high, chelation therapy should be considered as an alternative.1 Liver biopsy is the gold standard for monitoring liver fibrosis2; however, it is not usually recommended for routine patient monitoring and can be contraindicated where patients have abnormal coagulation.2,29 Alternatively, non-invasive methods of monitoring the progression of liver fibrosis are available, including transient elastography and serum-based assays.2

Pediatric patients should be monitored once a week at the early stages of treatment, every 1−3 months until remission, and every 3−6 months after remission.3 Non-adherence can lead to life-threatening deterioration in pediatric patients and compliance can be challenging, particularly in adolescents.3

Common laboratory tests used for monitoring patients during treatment include:1-3

  • 24-hour urinary copper excretion1-3
    • Reflects the amount of non-ceruloplasmin-bound copper in circulation and is usually elevated in patients with Wilson disease. Levels should decrease when liver function normalizes
  • Serum copper1-3
    • Very low values may indicate systemic depletion of copper with prolonged therapy
  • Liver biochemistry1-3
    • Includes hepatic synthetic function and international normalized ratio.1,2 In pediatric patients, transaminases should progressively normalize within 3–12 months3
  • Estimated serum non-ceruloplasmin-bound coppera,1,2
    • Calculated by subtracting ceruloplasmin-bound copper from total serum copper and is usually elevated in patients with Wilson disease

Prognostic scoring systems such as the New Wilson Index, Devarbhavi score, and Alam score were developed to predict when patients with Wilson disease were likely to fail medical therapy.2 The serial application of such scores over time may critically improve accuracy for Wilson disease therapy.2

 

Footnote

aCalculated non-ceruloplasmin-bound copper may be used for monitoring adherence and for making therapeutic changes once improved assays are available.2




MONITORING FOR TREATMENT FAILURE, NON-ADHERENCE, AND OVERTREATMENT

Treatment failure at initiation of treatment is defined as failure to stabilize disease clinically or biochemically, or both.2 Treatment failure may also occur due to undertreatment, or during maintenance therapy, as worsening of disease or onset of new symptoms.2 Meanwhile, overtreatment with a chelator can result in copper deficiency, leading to reversible sideroblastic anemia and hemosiderosis in patients with Wilson disease.1,2

Non-adherence to treatment can cause rapid and life-threatening deterioration in patients with Wilson disease:1-3

  • Up to a third of patients with Wilson disease have low adherence to treatmenta,b,30,31
  • Non-adherence is associated with worsening of Wilson diseasea,b,30,31

Causes of non-adherence in Wilson disease are diverse and include incomplete acceptance of diagnosis in asymptomatic patients, false sense of security after prolonged treatment for Wilson disease, inconvenience of the treatment regimen and treatment supply, and cost.2 Adolescents may also question and reject the need for daily treatment as seen in most chronic cases, such as diabetes mellitus and cystic fibrosis.

Footnotes

aBased on a cross-sectional study of 139 patients with Wilson disease in France between December 2014 and November 2015. 45/139 (32.4%) of all patients and 12/22 (54.5%) of asymptomatic patients had low adherence, as measured on the Morisky scale.30

bBased on a retrospective analysis of 170 patients with Wilson disease in Poland who started treatment between January 1995 and December 2005. Non-persistence was defined as at least one reported break of >3 months or at least two breaks lasting >2 months within the treatment period. 44/170 (25.9%) of patients with Wilson disease had non-persistent drug use.31




 







Brain MRI assessment to monitor & evaluate progression of Wilson’s disease

Assessment scales in Wilson disease

There are two published assessment scales for use in patients with Wilson disease: the Global Assessment Scale (GAS) and the Unified Wilson’s Disease Rating Scale (UWDRS). Both scales have promising initial results but require further evaluation.6,8

GAS uses a two-tier scale to grade multisystemic manifestations:6

  • Tier 1 is a disability scale covering the liver, cognition and behavior, motor, and osseomuscular domains
  • Tier 2 is a detailed neurologic assessment of seven different aspects with 14 items:
    • Wilson facies
    • Cognition and behavior
    • Movement disorders
    • Bulbar symptoms
    • Posture and gait impairment
    • Kayser–Fleischer rings
    • Uncommon

GAS is a comparatively broad, general scale; more specialized scales may be required to assess some aspects of Wilson disease, such as gait or swallowing.6 In addition, a neurologist is required to carry out the tier 2 assessment, making the scale less accessible for use in clinical practice.6

UWDRS was initially developed for research purposes to assess the neurologic symptoms associated with Wilson disease and later modified to cover the entire spectrum of clinical symptoms.7,8,32 The expanded UWDRS consists of three subscales:8,32

  • Neurologic (27 items; 208 points)
  • Hepatic (9 items; 36 points)
  • Psychiatric (19 items; 76 points)

The UWDRS neurologic subscale contains many steps and, therefore, requires a relatively long duration to complete, while the hepatic subscale has been shown to have poor correlation with established scales, meaning that the results do not accurately reflect the liver status of the patient.8 The original neurologic-only version of the UWDRS has been widely used.33-38

ABBREVIATIONS

  1. GAS, Global Assessment Scale; MRI, magnetic resonance imaging; UWDRS, Unified Wilson’s Disease Rating Scale.

REFERENCES

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