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Wilson disease: Clinical manifestations, diagnosis, and natural history

Michael L Schilsky, MD, FAASLD
Section Editors
Elizabeth B Rand, MD
Bruce A Runyon, MD
Michael J Aminoff, MD, DSc
Deputy Editor
Anne C Travis, MD, MSc, FACG, AGAF


Wilson disease (hepatolenticular degeneration) is due to a genetic abnormality inherited in an autosomal recessive manner that leads to impairment of cellular copper transport. It is found worldwide, with a prevalence of approximately 1 case in 30,000 live births in most populations. Impaired biliary copper excretion leads to accumulation of copper in several organs, most notably the liver, brain, and cornea. Over time, the liver is progressively damaged and eventually becomes cirrhotic. A small percent of patients develop acute liver failure, most often in the setting of advanced fibrosis of the liver. In addition, patients may develop neurologic complications, which can be severe.

This topic will review the clinical manifestations, diagnosis, and natural history of Wilson disease. The epidemiology, pathogenesis, and treatment of Wilson disease, as well as a detailed discussion of the individual tests used to diagnose Wilson disease, are discussed separately. (See "Wilson disease: Epidemiology and pathogenesis" and "Wilson disease: Diagnostic tests" and "Wilson disease: Treatment and prognosis".)


The clinical manifestations of Wilson disease are predominantly hepatic, neurologic, and psychiatric, with many patients having a combination of symptoms [1]. Hemolysis is also a common finding in patients with acute liver failure due to Wilson disease, but sometimes may occur episodically independent of liver failure.

Patients may present with a wide variety of symptoms (especially those with neurologic symptoms) [2]. Even within a given family, patients often present with different symptoms [3]. There is wide variability in the reported rates of the different clinical manifestations seen at the time of presentation [2,4-14]:

Liver disease: 18 to 84 percent of patients


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Literature review current through: Sep 2016. | This topic last updated: Nov 10, 2015.
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  1. European Association for Study of Liver. EASL Clinical Practice Guidelines: Wilson's disease. J Hepatol 2012; 56:671.
  2. Lorincz MT. Neurologic Wilson's disease. Ann N Y Acad Sci 2010; 1184:173.
  3. Takeshita Y, Shimizu N, Yamaguchi Y, et al. Two families with Wilson disease in which siblings showed different phenotypes. J Hum Genet 2002; 47:543.
  4. Gollan JL, Gollan TJ. Wilson disease in 1998: genetic, diagnostic and therapeutic aspects. J Hepatol 1998; 28 Suppl 1:28.
  5. Taly AB, Meenakshi-Sundaram S, Sinha S, et al. Wilson disease: description of 282 patients evaluated over 3 decades. Medicine (Baltimore) 2007; 86:112.
  6. Machado A, Chien HF, Deguti MM, et al. Neurological manifestations in Wilson's disease: Report of 119 cases. Mov Disord 2006; 21:2192.
  7. Soltanzadeh A, Soltanzadeh P, Nafissi S, et al. Wilson's disease: a great masquerader. Eur Neurol 2007; 57:80.
  8. Walshe JM, Yealland M. Wilson's disease: the problem of delayed diagnosis. J Neurol Neurosurg Psychiatry 1992; 55:692.
  9. Noureen N, Rana MT. Neurological Wilson disease in children: a three years experience from Multan. J Pak Med Assoc 2011; 61:743.
  10. Roberts EA, Cox DW. Wilson disease. Baillieres Clin Gastroenterol 1998; 12:237.
  11. Asadi Pooya AA, Eslami NS, Haghighat M. Wilson disease in southern Iran. Turk J Gastroenterol 2005; 16:71.
  12. Stremmel W, Meyerrose KW, Niederau C, et al. Wilson disease: clinical presentation, treatment, and survival. Ann Intern Med 1991; 115:720.
  13. Akil M, Brewer GJ. Psychiatric and behavioral abnormalities in Wilson's disease. Adv Neurol 1995; 65:171.
  14. Moores A, Fox S, Lang A, Hirschfield GM. Wilson disease: Canadian perspectives on presentation and outcomes from an adult ambulatory setting. Can J Gastroenterol 2012; 26:333.
  15. Manolaki N, Nikolopoulou G, Daikos GL, et al. Wilson disease in children: analysis of 57 cases. J Pediatr Gastroenterol Nutr 2009; 48:72.
  16. Saito T. Presenting symptoms and natural history of Wilson disease. Eur J Pediatr 1987; 146:261.
  17. Bachmann H, Lössner J, Biesold D. [Wilson's disease in the German Democratic Republic. I. Genetics and epidemiology]. Z Gesamte Inn Med 1979; 34:744.
  18. BEARN AG. A genetical analysis of thirty families with Wilson's disease (hepatolenticular degeneration). Ann Hum Genet 1960; 24:33.
  19. Dastur DK, Manghani DK, Wadia NH. Wilson's disease in India. I. Geographic, genetic, and clinical aspects in 16 families. Neurology 1968; 18:21.
  20. Sternlieb I, Scheinberg IH. Prevention of Wilson's disease in asymptomatic patients. N Engl J Med 1968; 278:352.
  21. Strickland GT, Frommer D, Leu ML, et al. Wilson's disease in the United Kingdom and Taiwan. I. General characteristics of 142 cases and prognosis. II. A genetic analysis of 88 cases. Q J Med 1973; 42:619.
  22. Walshe JM. Wilson's disease presenting with features of hepatic dysfunction: a clinical analysis of eighty-seven patients. Q J Med 1989; 70:253.
  23. Gitlin JD. Wilson disease. Gastroenterology 2003; 125:1868.
  24. Oder W, Grimm G, Kollegger H, et al. Neurological and neuropsychiatric spectrum of Wilson's disease: a prospective study of 45 cases. J Neurol 1991; 238:281.
  25. Ferenci P, Członkowska A, Merle U, et al. Late-onset Wilson's disease. Gastroenterology 2007; 132:1294.
  26. Ala A, Schilsky ML. Wilson disease: pathophysiology, diagnosis, treatment, and screening. Clin Liver Dis 2004; 8:787.
  27. Brewer GJ, Yuzbasiyan-Gurkan V. Wilson disease. Medicine (Baltimore) 1992; 71:139.
  28. Steindl P, Ferenci P, Dienes HP, et al. Wilson's disease in patients presenting with liver disease: a diagnostic challenge. Gastroenterology 1997; 113:212.
  29. Ferenci P. Pathophysiology and clinical features of Wilson disease. Metab Brain Dis 2004; 19:229.
  30. Huster D. Wilson disease. Best Pract Res Clin Gastroenterol 2010; 24:531.
  31. Scott J, Gollan JL, Samourian S, Sherlock S. Wilson's disease, presenting as chronic active hepatitis. Gastroenterology 1978; 74:645.
  32. Schilsky ML, Scheinberg IH, Sternlieb I. Liver transplantation for Wilson's disease: indications and outcome. Hepatology 1994; 19:583.
  33. Ferenci P, Caca K, Loudianos G, et al. Diagnosis and phenotypic classification of Wilson disease. Liver Int 2003; 23:139.
  34. Kumagi T, Horiike N, Michitaka K, et al. Recent clinical features of Wilson's disease with hepatic presentation. J Gastroenterol 2004; 39:1165.
  35. Korman JD, Volenberg I, Balko J, et al. Screening for Wilson disease in acute liver failure: a comparison of currently available diagnostic tests. Hepatology 2008; 48:1167.
  36. Roberts EA, Schilsky ML, American Association for Study of Liver Diseases (AASLD). Diagnosis and treatment of Wilson disease: an update. Hepatology 2008; 47:2089.
  37. Kraut JR, Yogev R. Fatal fulminant hepatitis with hemolysis in Wilson's disease. Criteria for diagnosis. Clin Pediatr (Phila) 1984; 23:637.
  38. Kiss JE, Berman D, Van Thiel D. Effective removal of copper by plasma exchange in fulminant Wilson's disease. Transfusion 1998; 38:327.
  39. Hartleb M, Zahorska-Markiewicz B, Ciesielski A. Wilson's disease presenting in sisters as fulminant hepatitis with hemolytic episodes. Am J Gastroenterol 1987; 82:549.
  40. Walia BN, Singh S, Marwaha RK, et al. Fulminant hepatic failure and acute intravascular haemolysis as presenting manifestations of Wilson's disease in young children. J Gastroenterol Hepatol 1992; 7:370.
  41. Pfeiffenberger J, Gotthardt DN, Herrmann T, et al. Iron metabolism and the role of HFE gene polymorphisms in Wilson disease. Liver Int 2012; 32:165.
  42. Ferenci P, Steindl-Munda P, Vogel W, et al. Diagnostic value of quantitative hepatic copper determination in patients with Wilson's Disease. Clin Gastroenterol Hepatol 2005; 3:811.
  43. Merle U, Schaefer M, Ferenci P, Stremmel W. Clinical presentation, diagnosis and long-term outcome of Wilson's disease: a cohort study. Gut 2007; 56:115.
  44. Bruha R, Marecek Z, Pospisilova L, et al. Long-term follow-up of Wilson disease: natural history, treatment, mutations analysis and phenotypic correlation. Liver Int 2011; 31:83.
  45. van Wassenaer-van Hall HN, van den Heuvel AG, Algra A, et al. Wilson disease: findings at MR imaging and CT of the brain with clinical correlation. Radiology 1996; 198:531.
  46. Prashanth LK, Sinha S, Taly AB, Vasudev MK. Do MRI features distinguish Wilson's disease from other early onset extrapyramidal disorders? An analysis of 100 cases. Mov Disord 2010; 25:672.
  47. Kodama H, Okabe I, Yanagisawa M, et al. Does CSF copper level in Wilson disease reflect copper accumulation in the brain? Pediatr Neurol 1988; 4:35.
  48. Hartard C, Weisner B, Dieu C, Kunze K. Wilson's disease with cerebral manifestation: monitoring therapy by CSF copper concentration. J Neurol 1993; 241:101.
  49. Cardoso F, Seppi K, Mair KJ, et al. Seminar on choreas. Lancet Neurol 2006; 5:589.
  50. Mai N, Bolsinger P, Avarello M, et al. Control of isometric finger force in patients with cerebellar disease. Brain 1988; 111 ( Pt 5):973.
  51. Massaquoi S, Hallett M. Kinematics of initiating a two-joint arm movement in patients with cerebellar ataxia. Can J Neurol Sci 1996; 23:3.
  52. Dening TR, Berrios GE. Wilson's disease: a longitudinal study of psychiatric symptoms. Biol Psychiatry 1990; 28:255.
  53. Dening TR, Berrios GE, Walshe JM. Wilson's disease and epilepsy. Brain 1988; 111 ( Pt 5):1139.
  54. Bhattacharya K, Velickovic M, Schilsky M, Kaufmann H. Autonomic cardiovascular reflexes in Wilson's disease. Clin Auton Res 2002; 12:190.
  55. Dening TR, Berrios GE. Wilson's disease. Psychiatric symptoms in 195 cases. Arch Gen Psychiatry 1989; 46:1126.
  56. Jackson GH, Meyer A, Lippmann S. Wilson's disease. Psychiatric manifestations may be the clinical presentation. Postgrad Med 1994; 95:135.
  57. Davis EJ, Borde M. Wilson's disease and catatonia. Br J Psychiatry 1993; 162:256.
  58. Shanmugiah A, Sinha S, Taly AB, et al. Psychiatric manifestations in Wilson's disease: a cross-sectional analysis. J Neuropsychiatry Clin Neurosci 2008; 20:81.
  59. Walshe JM. The liver in Wilson's disease. In: Diseases of the liver, 6th ed, SchiffL, Schiff ER. (Eds), Lippincott, Philadelphia 1987. p.1037-1050.
  60. Czlonkowska A. A study of haemolysis in Wilson's disease. J Neurol Sci 1972; 16:303.
  61. MORGAN HG, STEWART WK, LOWE KG, et al. Wilson's disease and the Fanconi syndrome. Q J Med 1962; 31:361.
  62. Wiebers DO, Wilson DM, McLeod RA, Goldstein NP. Renal stones in Wilson's disease. Am J Med 1979; 67:249.
  63. Menerey KA, Eider W, Brewer GJ, et al. The arthropathy of Wilson's disease: clinical and pathologic features. J Rheumatol 1988; 15:331.
  64. Hill VA, Seymour CA, Mortimer PS. Pencillamine-induced elastosis perforans serpiginosa and cutis laxa in Wilson's disease. Br J Dermatol 2000; 142:560.
  65. Deguti MM, Mucenic M, Cancado EL, Tietge UJ. Elastosis perforans serpiginosa secondary to D-penicillamine treatment in a Wilson's disease patient. Am J Gastroenterol 2002; 97:2153.
  66. Popadic S, Skiljevic D, Medenica L. Bullous pemphigoid induced by penicillamine in a patient with Wilson disease. Am J Clin Dermatol 2009; 10:36.
  67. Schilsky ML, Scheinberg IH, Sternlieb I. Prognosis of Wilsonian chronic active hepatitis. Gastroenterology 1991; 100:762.
  68. Roberts EA, Schilsky ML, Division of Gastroenterology and Nutrition, Hospital for Sick Children, Toronto, Ontario, Canada. A practice guideline on Wilson disease. Hepatology 2003; 37:1475.
  69. Faa G, Nurchi V, Demelia L, et al. Uneven hepatic copper distribution in Wilson's disease. J Hepatol 1995; 22:303.
  70. McDonald JA, Snitch P, Painter D, et al. Striking variability of hepatic copper levels in fulminant hepatic failure. J Gastroenterol Hepatol 1992; 7:396.
  71. Arnon R, Annunziato R, Schilsky M, et al. Liver transplantation for children with Wilson disease: comparison of outcomes between children and adults. Clin Transplant 2011; 25:E52.
  72. Kosminkova EN, Generalova SIu, Ponomarev AB. [The development of diffuse cholangiocarcinoma in a female patient with long-term undiagnosed Wilson's disease]. Ter Arkh 1995; 67:85.
  73. Madden JW, Ironside JW, Triger DR, Bradshaw JP. An unusual case of Wilson's disease. Q J Med 1985; 55:63.
  74. Walshe JM, Waldenström E, Sams V, et al. Abdominal malignancies in patients with Wilson's disease. QJM 2003; 96:657.
  75. Pfeiffenberger J, Mogler C, Gotthardt DN, et al. Hepatobiliary malignancies in Wilson disease. Liver Int 2015; 35:1615.
  76. van Meer S, de Man RA, van den Berg AP, et al. No increased risk of hepatocellular carcinoma in cirrhosis due to Wilson disease during long-term follow-up. J Gastroenterol Hepatol 2015; 30:535.