THINK WILSON
Management & treatment of Wilson’s disease

Standard of care in Wilson disease

Wilson disease requires lifelong management in order to prevent disease progression and serious consequences for patients, including liver failure, neurologic deterioration, and death.1-3 Current management options in Wilson disease include:

  • Several drugs, primarily D-penicillamine, trientine, and zinc9
  • Restricted intake of food and water with high levels of copper, particularly during the first year of pharmacologic treatment1,9
  • Liver transplantation in patients with acute liver failure who are resistant to treatment, or in severe cases2

Question goes here

Please select

NEXT

E-LEARNING MODULE:

Think treatment

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

Managing Wilson disease

Pharmacologic management options

Despite the widespread use of pharmacologic management options, there is currently a lack of clinical data investigating these therapies for the treatment of patients with Wilson disease.1 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.10

There are two phases of treatment for patients with 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 first-line treatment 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.9,11


Compliance, tolerability, and safety

Treatment compliance can be difficult to achieve because D-penicillamine, trientine, and zinc all require multiple daily doses and should not be taken with food because it can interfere with absorption, leading to a decrease in effectiveness.1,9

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,12
  • In a study of 141 patients with Wilson disease receiving trientine therapy, 7% of patients discontinued treatment due to adverse eventsb,13
    • Side effects of D-penicillamine and trientine can include arthralgia, leukopenia, erythema, and lupus erythematosus, among others; these are more common with D-penicillamine treatment than with trientine treatment13
  • Zinc is associated with comparatively 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 pancreatitis14

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.12

bBased on a retrospective analysis of 380 patients with Wilson disease and 471 chelator monotherapies, with 141 patients and 326 patients receiving trientine and D-penicillamine, respectively. 94/326 patients receiving D-penicillamine discontinued due to adverse events.13





Paradoxical neurologic worsening

Drug-related neurologic deterioration can occur in patients with Wilson disease.12 All three of the commonly used drugs have been reported to result in paradoxical neurologic worsening.

  • In a study of 163 patients, neurologic worsening with D-penicillamine commonly occurred early after initiation of treatment, whereas neurologic worsening while under treatment with trientine and zinc occurred at any stagea,12
  • Worsening of neurologic symptoms has been reported in ~13%a to 50%b of patients treated with D-penicillamine during the initial phase of treatment12,15
  • Neurologic worsening after starting treatment with trientine is also observed, reported in ~8% to 20% of patients, but may be less common than with D-penicillamine12,13
  • Neurologic worsening with zinc treatment is less common than with D-penicillamine and trientine, reported in ~4%a to 9.5%c of patients treated with zinc12,16
  • A retrospective cohort study of 163 patients with Wilson disease identified neurologic worsening in 19 (13.8%) patients treated with D-penicillamine, 11 (8.0%) treated with trientine, and 6 (4.3%) treated with zinc12

However, these findings can vary; a further retrospective study of 476 patients with Wilson disease treated with chelating monotherapies found that 20% (4/20) of patients treated with trientine experienced neurologic worsening13 while 5.3% (6/114) of patients treated with D-penicillamine in the same study experienced worsening neurologic symptoms.13 The differences observed in this study could reflect the gradual dose increase in D-penicillamine and trientine used in the study.13

Neurologic deterioration after starting treatment with D-penicillamine and zinc has also been reported in pediatric patients.17

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). Worsening 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.12

bBased on a retrospective study of 25 patients with neurologic Wilson disease. 13/25 (52%) patients reported a worsening of neurologic symptoms following initial treatment with D-penicillamine.15

cBased on a retrospective study of 288 patients with Wilson disease. 9/95 (9.5%) patients experienced neurologic deterioration while under zinc therapy.16




Liver transplantation

Patients with Wilson disease will rarely require liver transplantation; however, in patients with decompensated cirrhosis or fulminant liver failure, liver transplantation is indicated.18 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,18 Neurologic and psychiatric symptoms may show little improvement after liver transplantation, with neurologic deterioration having been reported after otherwise successful transplantation.18,19

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]).18




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,20
  • Two studies on patients with Wilson disease found that ~90% of patients with neurologic symptoms had pathology detectable by MRIa,b,20,21
  • 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 published22
  • In some patients, abnormalities were detected using MRI before the onset of symptomsa,b,20,21

All patients presenting with neurologic symptoms should have a thorough neurologic evaluation prior to starting treatment.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.20

bBased on a retrospective study of 76 patients with Wilson disease with neurologic symptoms. 68 patients (89.5%) showed MRI abnormalities.21




Routine treatment monitoring

Monitoring of patients during treatment is important to determine compliance and treatment efficacy and to identify any side effects.2 Biannual assessments for routine monitoring of patients with Wilson disease are recommended and include:1-3

  • Serum copper
  • Ceruloplasmin
  • Liver biochemistries
  • International normalized ratio
  • Complete blood count
  • Analysis of 24-hour urinary copper excretion
  • Physical and neurologic examination, including liver, neurologic, and psychiatric symptoms and signs of adverse effects

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; if levels become too high, chelation therapy should be considered as an alternative.1 Liver biopsy is not usually recommended for routine patient monitoring and can be contraindicated where patients have abnormal coagulation.2,23

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:1,3,24-26

  • Serum ceruloplasmin1,25
    • Measures the concentration of the copper-bound ceruloplasmin protein in the blood and is usually decreased in patients with Wilson disease
  • 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
  • Serum non-ceruloplasmin-bound copper1,3
    • Calculated by subtracting ceruloplasmin-bound copper from total serum copper and is usually elevated in patients with Wilson disease
  • Hepatic copper1,26
    • Measured by analyzing ≥1 cm biopsy samples and is often elevated in patients with Wilson disease
  • Relative exchangeable copper24
    • This is the pool of labile copper and is calculated as the ratio of exchangeable copper/total copper and is usually elevated in patients with Wilson disease








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 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 developed to assess the entire spectrum of clinical symptoms associated with Wilson disease and consists of three subscales:8,27

  • 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

ABBREVIATIONS

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

REFERENCES

  1. 1. European Association for Study of Liver. EASL Clinical Practice Guidelines: Wilson's disease. J Hepatol 2012; 56: 671-685.
  2. 2. Roberts EA, Schilsky ML. Diagnosis and treatment of Wilson disease: an update. Hepatology 2008; 47: 2089-2111.
  3. 3. Socha P, Janczyk W, Dhawan A et al. Wilson's disease in children: a position paper by the Hepatology Committee of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2018; 66: 334-344.
  4. 4. Boga S, Ala A, Schilsky ML. Hepatic features of Wilson disease. Handb Clin Neurol 2017; 142: 91-99.
  5. 5. Stremmel W, Meyerrose KW, Niederau C et al. Wilson disease: clinical presentation, treatment, and survival. Ann Intern Med 1991; 115: 720-726.
  6. 6. Aggarwal A, Aggarwal N, Nagral A et al. A novel Global Assessment Scale for Wilson's Disease (GAS for WD). Mov Disord 2009; 24: 509-518.
  7. 7. Członkowska A, Tarnacka B, Möller JC et al. Unified Wilson's Disease Rating Scale - a proposal for the neurological scoring of Wilson's disease patients. Neurol Neurochir Pol 2007; 41: 1-12.
  8. 8. Volpert HM, Pfeiffenberger J, Gröner JB et al. Comparative assessment of clinical rating scales in Wilson's disease. BMC Neurol 2017; 17: 140.
  9. 9. Aggarwal A, Bhatt M. Advances in treatment of Wilson disease. Tremor Other Hyperkinet Mov (N Y) 2018; 8: 525.
  10. 10. Kalita J, Kumar V, Chandra S et al. Worsening of Wilson disease following penicillamine therapy. Eur Neurol 2014; 71: 126-131.
  11. 11. Chen JC, Chuang CH, Wang JD et al. Combination therapy using chelating agent and zinc for Wilson's disease. J Med Biol Eng 2015; 35: 697-708.
  12. 12. Merle U, Schaefer M, Ferenci P et al. Clinical presentation, diagnosis and long-term outcome of Wilson's disease: a cohort study. Gut 2007; 56: 115-120.
  13. 13. Weiss KH, Thurik F, Gotthardt DN et al. Efficacy and safety of oral chelators in treatment of patients with Wilson disease. Clin Gastroenterol Hepatol 2013; 11: 1028-1035.e2.
  14. 14. Ranucci G, Di Dato F, Spagnuolo MI et al. Zinc monotherapy is effective in Wilson's disease patients with mild liver disease diagnosed in childhood: a retrospective study. Orphanet J Rare Dis 2014; 9: 41.
  1. 15. Brewer GJ, Terry CA, Aisen AM et al. Worsening of neurologic syndrome in patients with Wilson's disease with initial penicillamine therapy. Arch Neurol 1987; 44: 490-493.
  2. 16. Weiss KH, Gotthardt DN, Klemm D et al. Zinc monotherapy is not as effective as chelating agents in treatment of Wilson disease. Gastroenterology 2011; 140: 1189-1198.e1.
  3. 17. Noureen N, Rana MT. Neurological Wilson disease in children: a three years experience from Multan. J Pak Med Assoc 2011; 61: 743-748.
  4. 18. Guillaud O, Dumortier J, Sobesky R et al. Long term results of liver transplantation for Wilson's disease: experience in France. J Hepatol 2014; 60: 579-589.
  5. 19. Medici V, Mirante VG, Fassati LR et al. Liver transplantation for Wilson's disease: the burden of neurological and psychiatric disorders. Liver Transpl 2005; 11: 1056-1063.
  6. 20. Litwin T, Gromadzka G, Członkowska A et al. The effect of gender on brain MRI pathology in Wilson's disease. Metab Brain Dis 2013; 28: 69-75.
  7. 21. Zhong W, Huang Z, Tang X. A study of brain MRI characteristics and clinical features in 76 cases of Wilson's disease. J Clin Neurosci 2019; 59: 167-174.
  8. 22. Dusek P, Smolinski L, Redzia-Ogrodnik B et al. Semiquantitative scale for assessing brain MRI abnormalities in Wilson disease: a validation study. Mov Disord 2020; 35: 994-1001.
  9. 23. Gow PJ, Smallwood RA, Angus PW et al. Diagnosis of Wilson's disease: an experience over three decades. Gut 2000; 46: 415-419.
  10. 24. El Balkhi S, Trocello JM, Poupon J et al. Relative exchangeable copper: a new highly sensitive and highly specific biomarker for Wilson's disease diagnosis. Clin Chim Acta 2011; 412: 2254-2260.
  11. 25. Mak CM, Lam CW, Tam S. Diagnostic accuracy of serum ceruloplasmin in Wilson disease: determination of sensitivity and specificity by ROC curve analysis among ATP7B-genotyped subjects. Clin Chem 2008; 54: 1356-1362.
  12. 26. Ludwig J, Moyer TP, Rakela J. The liver biopsy diagnosis of Wilson's disease. Methods in pathology. Am J Clin Pathol 1994; 102: 443-446.
  13. 27. Leinweber B, Möller JC, Scherag A et al. Evaluation of the Unified Wilson's Disease Rating Scale (UWDRS) in German patients with treated Wilson's disease. Mov Disord 2008; 23: 54-62.