Skip to main content
SpringerLink
Log in

Practical Recommendations and New Therapies for Wilson’s Disease

  • Practical Therapeutics
  • Published:
Drugs Aims and scope Submit manuscript

Summary

Wilson’s disease is an inherited disorder of copper accumulation. The basic defect is a failure of excretion of excess copper in the bile by the liver for loss in the stool. The accumulating copper causes damage primarily to the liver and the brain. Patients typically present in the second to the fourth decades of life with liver disease, a neurological disease of the movement disorder type, or a wide array of behavioural disturbances. Because the manifestations of Wilson’s disease are so protean, and the disease masquerades so well as something else, recognition of the possibility of Wilson’s disease is a major problem, leading to serious under-diagnosis of the disease.

Excellent therapies exist for both the prophylaxis and treatment of Wilson’s disease. The longer recognition and diagnosis are delayed, the greater the risk of permanent damage to liver and/or brain. The availability of effective therapy and the risks in delay of therapy make the earliest possible diagnosis critical. Once the disease comes under consideration, a series of diagnostic steps can be undertaken which almost always establish or rule out the diagnosis of Wilson’s disease. These include urine copper, blood ceruloplasmin, slit lamp examination for Kayser-Fleischer rings, and liver biopsy with quantitative copper assay.

Currently, there are 4 drugs being used as anticopper agents in Wilson’s disease. These are zinc, which blocks intestinal absorption of copper, penicillamine and trientine, both of which are chelators that increase urinary excretion of copper, and tetrathiomolybdate which forms a tripartite complex with copper and protein, and can block copper absorption from the intestine, or render blood copper non-toxic.

Zinc is clearly the treatment of choice, in our opinion, for maintenance therapy, for the treatment of the presymptomatic patient from the beginning and for the treatment of the pregnant patient, because of its complete efficacy and lack of toxicity. For the initial treatment of the patient presenting with mild liver failure, we empirically use a combination of trientine and zinc. Trientine gives a strong, fast, negative copper balance, and zinc induces hepatic metallothionein, which sequesters hepatic copper. For the initial treatment of patients presenting with neurological disease we use an experimental drug, tetrathiomolybdate, which provides rapid, safe control of copper. These latter patients are at great risk of serious permanent neurological worsening with penicillamine, and zinc is too slow-acting, in our judgment, to be optimal.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Brewer GJ, Yuzbasiyan-Gurkan V. Wilson Disease. Medicine 1992; 71: 139–64

    Article  PubMed  CAS  Google Scholar 

  2. Scheinberg IH, Sternlieb I. Wilson’s disease. In: Smith Jr LH, editor. Major problems in internal medicine. Vol. 23. Philadelphia: W.B. Saunders Company, 1984

    Google Scholar 

  3. Danks DM. Disorders of copper transport. In: Scriver CR, Beaudet AL, Sly WS, et al., editors. Metabolic basis of inherited diseases. 6th ed. Vol. 1. New York: McGraw-Hill, 1989: 1411–31

    Google Scholar 

  4. Cartwright GE, Wintrobe MM. Copper metabolism in normal subjects. Am J Clin Nutr 1964; 14: 224–32

    PubMed  CAS  Google Scholar 

  5. Frommer DJ. Defective biliary excretion of copper in Wilson’s disease. Gut 1974; 15: 125–9

    Article  PubMed  CAS  Google Scholar 

  6. Gibbs K, Walshe JM. Biliary excretion of copper in Wilson’s disease. Lancet 1980; 2: 538–9

    Article  PubMed  CAS  Google Scholar 

  7. Starosta-Rubenstein S, Young AB, Kluin K, et al. Clinical assessment of 31 patients with Wilson’s disease: correlations with structural changes on magnetic resonance imaging. Arch Neurol 1987; 44: 365–70

    Article  Google Scholar 

  8. Akil M. Schwartz JA, Dutchak D, et al. The psychiatric presentations of Wilson’s disease. J Neuropsychiatry 1991; 3: 377–82

    CAS  Google Scholar 

  9. Brewer GJ, Yuzbasiyan-Gurkan V, Dick R, et al. Does a vegetarian diet control Wilson’s disease? J Am Coll Nutr 1993; 12 (5): 527–30

    PubMed  CAS  Google Scholar 

  10. Bull PC, Thomas GR, Rommens JM, et al. The Wilson’s disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. Nature Genet 1993; 5: 327–37

    Article  PubMed  CAS  Google Scholar 

  11. Tanzi RE, Petrukhin K, Chernov, et al. The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. Nature Genet 1993; 5: 344–50

    Article  PubMed  CAS  Google Scholar 

  12. Yamaguchi Y, Heiny ME, Gitlin JD. Isolation and characterization of a human liver cDNA as a candidate gene for Wilson’s disease. Biochem Biophys Res Commun 1993; 197: 271–7

    Article  PubMed  CAS  Google Scholar 

  13. Brewer GJ, Hill GM, Prasad AS, et al. The treatment of Wilson’s disease with zinc: IV. Efficacy monitoring using urine and plasma copper. Proc Soc Exp Biol Med 1987; 7: 446–55

    Google Scholar 

  14. Walshe JM. Penicillamine. A new oral therapy for Wilson’s disease. Am J Med 1956; 21: 487–95

    Article  PubMed  CAS  Google Scholar 

  15. Walshe JM. Treatment of Wilson’s disease with trientine (tri-ethylene tetramine) dihydrochloride. Lancet 1982; 1: 643–7

    Article  PubMed  CAS  Google Scholar 

  16. Yuzbasiyan-Gurkan V, Grider A, Nostrant T, et al. The treatment of Wilson’s disease with zinc: X. Intestinal metallothionein induction. J Lab Clin Med 1992; 120: 380–6

    PubMed  CAS  Google Scholar 

  17. Brewer GJ, Hill GM, Prasad AS, et al. Oral zinc therapy for Wilson’s disease. Ann Intern Med 1983; 99: 314–20

    PubMed  CAS  Google Scholar 

  18. Hill GM, Brewer GJ, Prasad AS, et al. Treatment of Wilson’s disease with zinc: 1. Oral zinc therapy regimens. Hepatology 1987; 7: 522–8

    Article  PubMed  CAS  Google Scholar 

  19. Brewer GJ, Yuzbasiyan-Gurkan V, Dick R. Zinc therapy of Wilson’s disease: VIII. Dose response studies. J Trace Elem Exp Med 1990; 3: 227–34

    Google Scholar 

  20. Brewer GJ, Yuzbasiyan-Gurkan V, Tankanow R, et al. Initial therapy of Wilson’s disease patients with tetrathiomolybdate. Arch Neurol 1991; 48: 42–7

    Article  PubMed  CAS  Google Scholar 

  21. Brewer GJ, Dick RD, Johnson V, et al. Treatment of Wilson’s disease with tetrathiomolybdate: I. Initial therapy in 17 neurologically affected patients. Arch Neurol 1994; 51: 545–54

    Article  PubMed  CAS  Google Scholar 

  22. 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: 490–3

    Article  PubMed  CAS  Google Scholar 

  23. Nazer H, Ede RJ, Mowat AP, et al. Wilson’s disease: clinical presentation and use of prognostic index. Gut 1986; 27: 1377–81

    Article  PubMed  CAS  Google Scholar 

  24. Hill GM, Brewer GJ, Juni JE, et al. Treatment of Wilson’s disease with zinc: II. Validation of oral 64copper uptake with copper balance. Am J Med Sci 1986; 12: 344–9

    Article  Google Scholar 

  25. Brewer GJ, Hill GM, Dick RD, et al. Treatment of Wilson’s disease with zinc: III. Prevention of reaccumulation of hepatic copper. J Lab Clin Med 1987; 109: 526–31

    PubMed  CAS  Google Scholar 

  26. Brewer GJ, Yuzbasiyan-Gurkan V, Young AB. Treatment of Wilson’s disease. Semin Neurol 1987; 7: 209–20

    Article  PubMed  CAS  Google Scholar 

  27. Yuzbasiyan-Gurkan V, Brewer GJ, Abrams GD, et al. Treatment of Wilson’s disease with zinc: V. Changes in serum levels of lipase, amylase and alkaline phosphatase in Wilson’s disease patients. J Lab Clin Med 1989; 114: 520–5

    PubMed  CAS  Google Scholar 

  28. Brewer GJ, Yuzbasiyan-Gurkan V, Lee D-Y, et al. The treatment of Wilson’s disease with zinc: VI. Initial treatment studies. J Lab Clin Med 1989; 114: 633–8

    PubMed  CAS  Google Scholar 

  29. Lee D-Y, Brewer GJ, Wang Y The treatment of Wilson’s disease with zinc: VII. Protection of the liver from copper toxicity by zinc induced metallothionein in a rat model. J Lab Clin Med 1989; 114: 639–45

    PubMed  CAS  Google Scholar 

  30. Brewer GJ, Yuzbasiyan-Gurkan V, Dick R. Zinc therapy of Wilson’s disease: VIII. Dose response studies. J Trace Elem Exp Med 1990; 3: 227–34

    Google Scholar 

  31. Brewer GJ, Yuzbasiyan-Gurkan V, Johnson V. The treatment of Wilson’s disease with zinc: IX. Response of serum lipids. J Lab Clin Med 1991; 118: 466–70

    PubMed  CAS  Google Scholar 

  32. Brewer GJ, Yuzbasiyan-Gurkan V, Johnson V, et al. Treatment of Wilson’s disease with zinc: XI. Interaction with other anti-copper agents. J Am Coll Nutr 1993; 12 (1): 26–30

    PubMed  CAS  Google Scholar 

  33. Brewer GJ, Yuzbasiyan-Gurkan V, Johnson V, et al. Treatment of Wilson’s disease with zinc: XII. Dose regimen requirements. Am J Med Sci 1993; 305 (4): 199–202

    Article  PubMed  CAS  Google Scholar 

  34. Brewer GJ, Dick RD, Yuzbasiyan-Gurkan V, et al. Treatment of Wilson’s disease with zinc: XIII. Therapy with zinc in presymptomatic patients from the time of diagnosis. J Lab Clin Med 1994; 123: 849–58

    PubMed  CAS  Google Scholar 

  35. Hoogenraad TU, Koevoet R, De Ruyter Korver EGWM. Oral zinc sulfate as long-term treatment in Wilson’s disease (hepatolenticular degeneration). Eur Neurol 1979; 18: 205–11

    Article  PubMed  CAS  Google Scholar 

  36. Hoogenraad TU, Van den Hamer CJA, Koevoet R, et al. Oral zinc in Wilson’s disease. Lancet 1978; 2: 1262–3

    Article  PubMed  CAS  Google Scholar 

  37. Hoogenraad TU, Van Hattum J, Van den Hammer CJA. Management of Wilson’s disease with zinc sulfate: experience in a series of 27 patients. J Neurol Sci 1987; 77: 137–46

    Article  PubMed  CAS  Google Scholar 

  38. Mjolnerod IK, Dommerud SA, Rasmussen K, et al. Congenital connective tissue defect probably due to D-penicillamine treatment in pregnancy. Lancet 1971; 1: 673–5

    Article  PubMed  CAS  Google Scholar 

  39. Solomon L, Abrams G, Dinner M, et al. Neonatal abnormalities associated with D-penicillamine treatment during pregnancy. N Engl J Med 1977; 296: 54–5

    Article  PubMed  CAS  Google Scholar 

  40. Keen CL, Lonnerdal B, Hurley LS. Teratogenic effect of copper deficiency and excess. In: Sorenson JRJ, editor. Inflammatory diseases and copper. Clifton: Humana Press, 1982: 109–21

    Chapter  Google Scholar 

  41. Teratologic evaluation of FDA 71-49 (zinc sulfate). Food and Drug Administration, Food and Drug Research Laboratories, Inc. Prepared for Food and Drug Administration, United States Department of Commerce Publications PD-221 805, February 1973, and PB 267, June 1974

  42. Harper PI, Walshe JM. Reversible pancytopenia secondary to treatment with tetrathiomolybdate. Br J Haematol 1986; 64: 851–3

    Article  PubMed  CAS  Google Scholar 

  43. Mills CF, El-Gallad TT, Bremner I. Effects of molybdate, sulfide, and tetrathiomolybdate on copper metabolism in rats. J Inorg Biochem 1981; 14: 189

    Article  PubMed  CAS  Google Scholar 

  44. Bremner I, Mills CF, Young BW. Copper metabolism in rats given Di- or trithiomolybdates. J Inorg Biochem 1982; 16: 109

    Article  PubMed  CAS  Google Scholar 

  45. Mills CR, El-Gallad TT, Bremner I, et al. Copper and molybdenum absorption by rats given ammonium tetrathiomolybdate. J Inorg Biochem 1981; 14: 163

    Article  PubMed  CAS  Google Scholar 

  46. Gooneratne SR, Howell JMc, Gawthorne JM. An investigation of the effects of intravenous administration of thiomolybdate on copper metabolism in chronic Cu-poisoned sheep. Br J Nutr 1981; 46: 469

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Human Genetics and Internal Medicine, University of Michigan Medical School, 4708 Medical Science Building II, Ann Arbor, Michigan, 48109-0618, USA

    George J. Brewer (Professor)

Authors
  1. George J. Brewer
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Brewer, G.J. Practical Recommendations and New Therapies for Wilson’s Disease. Drugs 50, 240–249 (1995). https://doi.org/10.2165/00003495-199550020-00004

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003495-199550020-00004

Keywords

Search

Navigation