Close
New

Medscape is available in 5 Language Editions – Choose your Edition here.

 

Wilson Disease Clinical Presentation

  • Author: Richard K Gilroy, MBBS, FRACP; Chief Editor: Julian Katz, MD  more...
 
Updated: Jan 11, 2016
 

History

Wilson disease has a range of clinical manifestations, from an asymptomatic state to fulminant hepatic failure, chronic liver disease with or without cirrhosis, neurologic, and psychiatric manifestations.[2]

Consider hepatic Wilson disease in the differential diagnosis of any unexplained chronic liver disease, especially in individuals younger than 40 years. The condition may also manifest as acute hepatitis. Hepatic dysfunction is the presenting feature in more than half of patients. The 3 major patterns of hepatic involvement are as follows: (1) chronic active hepatitis, (2) cirrhosis, and (3) fulminant hepatic failure. The most common initial presentation is cirrhosis.

Neuropsychiatric symptoms

An estimated 50% of patients with Wilson disease have neurologic or psychiatric symptoms.[11] Most patients who present with neuropsychiatric manifestations have cirrhosis. The most common presenting neurologic feature is asymmetrical tremor, occurring in approximately half of individuals with Wilson disease. The character of the tremor is variable and may be predominantly resting, postural, or kinetic. Kayser-Fleischer rings are seen in at least 98% of patients with neurological Wilson disease who have not received chelation therapy.

Frequent early symptoms include difficulty speaking, excessive salivation, ataxia, masklike facies, clumsiness with the hands, and personality changes.

Late manifestations (now rare because of earlier diagnosis and treatment) include dystonia, spasticity, grand mal seizures, rigidity, and flexion contractures.

One study described 4 distinct diagnostic categories based on patients' major neurologic findings, as follows[12] :

  • Patients in the parkinsonian group (45%) - Distinguished by paucity of expression and movement
  • Patients in the pseudosclerotic group (24%) - Had tremor resembling multiple sclerosis
  • Patients in the dystonic group (15%) - Characterized by hypertonicity associated with abnormal limb movements.
  • Patients in the choreic group (11%) - Predominantly characterized by choreoathetoid abnormal movements associated with dystonia

Psychiatric features include emotional lability, impulsiveness, disinhibition, and self-injurious behavior. The reported percentage of patients with psychiatric symptoms as the presenting clinical feature is 10-20%. The range of psychiatric abnormalities associated with Wilson disease has been divided into 4 basic categories, as follows:

  • Behavioral
  • Affective
  • Schizophrenic-like
  • Cognitive

Musculoskeletal symptoms

Skeletal involvement is a common feature of Wilson disease, with more than half of patients exhibiting osteopenia on conventional radiologic examination.

The arthropathy of Wilson disease is a degenerative process that resembles premature osteoarthritis. Symptomatic joint disease, which occurs in 20-50% of patients, usually arises late in the course of the disease, frequently after age 20 years. The arthropathy generally involves the spine and large appendicular joints, such as knees, wrists, and hips. Osteochondritis dissecans, chondromalacia patellae, and chondrocalcinosis have also been described.

Hematologic symptoms

Hemolytic anemia is a recognized, but rare (10-15%), complication of the disease. Coombs-negative acute intravascular hemolysis most often occurs as a consequence of oxidative damage to the erythrocytes by the higher copper concentration. Any patient in whom acute hepatic failure occurs with a Coombs-negative intravascular hemolysis, modest elevations in serum aminotransferases, and a low serum alkaline phosphatase or ratio of alkaline phosphatase to bilirubin of less than 2 must be considered for a diagnosis of Wilson disease.

Renal symptoms

The Wilson disease gene is expressed in kidney tissue; therefore, any renal manifestations may be primary or secondary to release of copper from the liver.

Clinically, patients may resemble those with Fanconi syndrome, demonstrating defective renal acidification and excess renal losses of amino acids, glucose, fructose, galactose, pentose, uric acid, phosphate, and calcium. The frequency of renal manifestations is variable.

Urolithiasis, found in up to 16% of patients with Wilson disease, may be the result of hypercalciuria or poor acidification.

Hematuria and nephrocalcinosis are reported, and proteinuria and peptiduria can occur before treatment as part of the disease process and after therapy as adverse effects of D-penicillamine.[13]

Fulminant Wilson disease

Although no individual clinical or laboratory finding is definitively diagnostic for fulminant Wilson disease, the combination of low serum transaminases, low serum alkaline phosphatase, hemolysis, and evidence of renal Fanconi syndrome is characteristics of a fulminant presentation of Wilson disease. Critically important is early recognition.

Next

Physical Examination

Hepatic symptoms

Hepatic insufficiency and cirrhosis may slowly develop and can result in signs of fulminant hepatic failure, including the following:

  • Ascites and prominent abdominal veins
  • Spider nevi
  • Palmar erythema
  • Digital clubbing
  • Hematemesis
  • Jaundice

Neurologic symptoms

Central nervous system (CNS) pathology in patients with Wilson disease results from copper deposition in the basal ganglia. The resulting signs include the following:

  • Drooling
  • Dysphagia
  • Dystonia
  • Incoordination
  • Difficulty with fine motor tasks
  • Masklike facies
  • Gait disturbance

Ophthalmologic symptoms

Kayser-Fleischer rings are formed by the deposition of copper in the Descemet membrane in the limbus of the cornea. The color may range from greenish gold to brown; when well developed, rings may be readily visible to the naked eye or with an ophthalmoscope set at +40. When not visible to the unaided eye, the rings may be identified using slit-lamp examination or gonioscopy.

Kayser-Fleischer rings are observed in up to 90% of individuals with symptomatic Wilson disease and are almost invariably present in those with neurologic manifestations.

Although Kayser-Fleischer rings are a useful diagnostic sign, they are no longer considered pathognomonic of Wilson disease unless accompanied by neurologic manifestations. They may also be observed in patients with chronic cholestatic disorders, such as partial biliary atresia, primary biliary cirrhosis, primary sclerosing cholangitis, and cryptogenic cirrhosis.

Kayser-Fleischer rings consist of electron-dense granules rich in copper and sulfur. The rings form bilaterally, initially appearing at the superior pole of the cornea, then the inferior pole, and, ultimately, circumferentially.

Sunflower cataract appears to be a rare and reversible ophthalmologic finding in Wilson disease.[14] This finding may occur only at the time of diagnosis of Wilson disease and is thus not a pathognomonic sign.

Additional symptoms

Skeletal abnormalities in patients with Wilson disease widely vary and include osteoporosis, osteomalacia, rickets, spontaneous fractures, and polyarthritis.

Cardiac manifestations, such as rhythm abnormalities and increased autonomic tone, have been described in patients with Wilson disease. Autopsy findings have included hypertrophy, small vessel disease, and focal inflammation.[15]

Patients with Wilson disease exhibit signs of anemia, presumably due to oxidative injury of the cell membrane caused by excess copper. Skin pigmentation and a bluish discoloration at the base of the fingernails (azure lunulae) have been described in patients with Wilson disease.

Previous
 
 
Contributor Information and Disclosures
Author

Richard K Gilroy, MBBS, FRACP Associate Professor, Medical Director of Liver Transplantation and Hepatology, Department of Internal Medicine, Kansas University Medical Center

Disclosure: Received salary from gilead, NPS pharmaceuticals, salix pharmaceuticals, AbbVie for speaking and teaching.

Coauthor(s)

Rahil Shah, MD Consulting Staff, Lebanon Endoscopy Center

Rahil Shah, MD is a member of the following medical societies: American College of Gastroenterology, American Society for Gastrointestinal Endoscopy

Disclosure: Received consulting fee from Takeda for speaking and teaching.

Michael H Piper, MD Clinical Assistant Professor, Department of Internal Medicine, Division of Gastroenterology, Wayne State University School of Medicine; Consulting Staff, Digestive Health Associates, PLC

Michael H Piper, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Gastroenterology, American College of Physicians, Michigan State Medical Society

Disclosure: Nothing to disclose.

Chief Editor

Julian Katz, MD Clinical Professor of Medicine, Drexel University College of Medicine

Julian Katz, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Geriatrics Society, American Medical Association, American Society for Gastrointestinal Endoscopy, American Society of Law, Medicine & Ethics, American Trauma Society, Association of American Medical Colleges, Physicians for Social Responsibility

Disclosure: Nothing to disclose.

Acknowledgements

Erawati V Bawle, MD, FAAP, FACMG Retired Professor, Department of Pediatrics, Wayne State University School of Medicine

Erawati V Bawle, MD, FAAP, FACMG is a member of the following medical societies: American College of Medical Genetics and American Society of Human Genetics

Disclosure: Nothing to disclose.

Selim R Benbadis, MD Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, Tampa General Hospital, University of South Florida College of Medicine

Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association

Disclosure: UCB Pharma Honoraria Speaking, consulting; Lundbeck Honoraria Speaking, consulting; Cyberonics Honoraria Speaking, consulting; Glaxo Smith Kline Honoraria Speaking, consulting; Sleepmed/DigiTrace Honoraria Speaking, consulting; Sunovion Consulting fee None

Bruce Buehler, MD Professor, Department of Pediatrics and Genetics, Director RSA, University of Nebraska Medical Center

Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association

Disclosure: Nothing to disclose.

Beth A Carter, MD Assistant Professor of Pediatrics, Department of Pediatric Gastroenterology, Hepatology and Nutrition, Baylor College of Medicine; Medical Director, Pediatric Intestinal Rehabilitation Program, Texas Children's Hospital

Beth A Carter, MD is a member of the following medical societies: American Gastroenterological Association, American Liver Foundation, and North American Society for Pediatric Gastroenterology, Hepatology and Nutrition

Disclosure: Nothing to disclose.

Celia H Chang, MD Health Sciences Clinical Professor, Chief, Division of Child Neurology, Department of Neurology/MIND Institute, University of California, Davis, School of Medicine

Celia H Chang is a member of the following medical societies: American Academy of Neurology and Child Neurology Society

Disclosure: Nothing to disclose.

Robert J Fingerote, MD, MSc, FRCPC Consultant, Clinical Evaluation Division, Biologic and Gene Therapies, Directorate Health Canada; Consulting Staff, Department of Medicine, Division of Gastroenterology, York Central Hospital, Ontario

Robert J Fingerote, MD, MSc, FRCPC is a member of the following medical societies: American Association for the Study of Liver Diseases, American Gastroenterological Association, Canadian Medical Association, Ontario Medical Association, and Royal College of Physicians and Surgeons of Canada

Disclosure: Nothing to disclose.

Nestor Galvez-Jimenez, MD, MSc, MHA Chairman, Department of Neurology, Program Director, Movement Disorders, Department of Neurology, Division of Medicine, Cleveland Clinic Florida

Nestor Galvez-Jimenez, MD, MSc, MHA is a member of the following medical societies: American Academy of Neurology, American College of Physicians, and Movement Disorders Society

Disclosure: Nothing to disclose.

Christopher Luzzio, MD Clinical Assistant Professor, Department of Neurology, University of Wisconsin at Madison School of Medicine and Public Health

Christopher Luzzio, MD is a member of the following medical societies: American Academy of Neurology

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

References
  1. Dusek P, Roos PM, Litwin T, Schneider SA, Flaten TP, Aaseth J. The neurotoxicity of iron, copper and manganese in Parkinson's and Wilson's diseases. J Trace Elem Med Biol. 2015 Jul. 31:193-203. [Medline].

  2. Rodriguez-Castro KI, Hevia-Urrutia FJ, Sturniolo GC. Wilson's disease: A review of what we have learned. World J Hepatol. 2015 Dec 18. 7 (29):2859-70. [Medline].

  3. Schilsky ML. Wilson disease: Current status and the future. Biochimie. 2009 Jul 30. [Medline].

  4. Bowcock AM, Farrer LA, Hebert JM, Agger M, Sternlieb I, Scheinberg IH, et al. Eight closely linked loci place the Wilson disease locus within 13q14-q21. Am J Hum Genet. 1988 Nov. 43(5):664-74. [Medline]. [Full Text].

  5. Stapelbroek JM, Bollen CW, van Amstel JK, et al. The H1069Q mutation in ATP7B is associated with late and neurologic presentation in Wilson disease: results of a meta-analysis. J Hepatol. 2004 Nov. 41(5):758-63. [Medline].

  6. Stuehler B, Reichert J, Stremmel W, Schaefer M. Analysis of the human homologue of the canine copper toxicosis gene MURR1 in Wilson disease patients. J Mol Med (Berl). 2004 Sep. 82(9):629-34. [Medline].

  7. Merle U, Schaefer M, Ferenci P, Stremmel W. Clinical presentation, diagnosis and long-term outcome of Wilson's disease: a cohort study. Gut. 2007 Jan. 56(1):115-20. [Medline]. [Full Text].

  8. Manolaki N, Nikolopoulou G, Daikos GL, Panagiotakaki E, Tzetis M, Roma E, et al. Wilson disease in children: analysis of 57 cases. J Pediatr Gastroenterol Nutr. 2009 Jan. 48(1):72-7. [Medline].

  9. Roberts EA, Schilsky ML; American Association for Study of Liver Diseases (AASLD). Diagnosis and treatment of Wilson disease: an update. Hepatology. 2008 Jun. 47(6):2089-111. [Medline].

  10. Yoshitoshi EY, Takada Y, Oike F, et al. Long-term outcomes for 32 cases of Wilson's disease after living-donor liver transplantation. Transplantation. 2009 Jan 27. 87(2):261-7. [Medline].

  11. Li WJ, Chen C, You ZF, Yang RM, Wang XP. Current drug managements of Wilson's disease: from West to East. Curr Neuropharmacol. 2015 Nov 30. [Medline].

  12. Walshe JM. Copper: its role in the pathogenesis of liver disease. Semin Liver Dis. 1984 Aug. 4(3):252-63. [Medline].

  13. Dastych M, Prochazkova D, Pokorny A, Zdrazil L. Copper and zinc in the serum, urine, and hair of patients with Wilson's disease treated with penicillamine and zinc. Biol Trace Elem Res. 2009 Jun 27. epub ahead of print. [Medline].

  14. Langwinska-Wosko E, Litwin T, Dziezyc K, Członkowska A. The sunflower cataract in Wilson's disease: pathognomonic sign or rare finding?. Acta Neurol Belg. 2015 Nov 17. [Medline].

  15. Soni D, Shukla G, Singh S, Goyal V, Behari M. Cardiovascular and sudomotor autonomic dysfunction in Wilson's disease-Limited correlation with clinical severity. Auton Neurosci. 2009 Aug 7. epub ahead of print. [Medline].

  16. Dziezyc K, Litwin T, Chabik G, Członkowska A. Measurement of urinary copper excretion after 48-h d-penicillamine cessation as a compliance assessment in Wilson's disease. Funct Neurol. 2015 Nov 25. 1-8. [Medline].

  17. Tarnacka B, Szeszkowski W, Golebiowski M, Czlonkowska A. Metabolic changes in 37 newly diagnosed Wilson's disease patients assessed by magnetic resonance spectroscopy. Parkinsonism Relat Disord. 2009 Sep. 15(8):582-6. [Medline].

  18. Sen S, Felldin M, Steiner C, et al. Albumin dialysis and Molecular Adsorbents Recirculating System (MARS) for acute Wilson's disease. Liver Transpl. 2002 Oct. 8(10):962-7. [Medline].

  19. Weiss KH, Thurik F, Gotthardt DN, Schäfer M, Teufel U, Wiegand F, et al. Efficacy and safety of oral chelators in treatment of patients with Wilson disease. Clin Gastroenterol Hepatol. 2013 Aug. 11(8):1028-1035.e2. [Medline].

  20. Weiss KH, Gotthardt DN, Klemm D, Merle U, Ferenci-Foerster D, Schaefer M, et al. Zinc monotherapy is not as effective as chelating agents in treatment of Wilson disease. Gastroenterology. 2011 Apr. 140(4):1189-1198.e1. [Medline].

  21. da Costa Mdo D, Spitz M, Bacheschi LA, Leite CC, Lucato LT, Barbosa ER. Wilson's disease: two treatment modalities. Correlations to pretreatment and posttreatment brain MRI. Neuroradiology. 2009 Oct. 51(10):627-33. [Medline].

  22. Brewer GJ, Askari F, Dick RB, Sitterly J, Fink JK, Carlson M, et al. Treatment of Wilson's disease with tetrathiomolybdate: V. control of free copper by tetrathiomolybdate and a comparison with trientine. Transl Res. 2009 Aug. 154(2):70-7. [Medline].

 
Previous
Next
 
Computed tomography (CT) scan in a 15-year-old boy who presented with central nervous system findings consistent with Wilson disease. The CT scan reveals hypodense regions in the basal ganglia (caudate nucleus, putamen, globus pallidus). The differential diagnosis based on this image alone included leukodystrophy, vasculitis, and, less likely, infection. Ventricular enlargement and posterior fossa atrophy may also be seen on brain CT scans in a patient with Wilson disease. The extent of involvement as depicted on CT scans does not provide prognostic information.
Approach to the diagnosis of Wilson disease (WD) in a patient with unexplained liver disease. KF = Kayser-Fleischer ring; CPN = ceruloplasmin. From the American Association for the Study of Liver Diseases Practice Guidelines.
In this particular case, there is abundant Mallory hyaline. Another notable finding is the moderate to marked chronic inflammation which involved most portal tracts and periportal/perinodular areas.
Prismaflex eXeed II adds citrate anticoagulation with integrated calcium management. Image courtesy of Gambro.
Molecular adsorbents recirculating system (MARS) circuit.
Biopsy specimen showing hepatocellular injury in an explant specimen from a patient transplanted for Wilson Disease.
Biopsy specimen showing a more detailed image of the cellular injury in acute Wilson disease.
Wilson disease biopsy specimen with rhodanine stain.
Wilson disease biopsy specimen with rhodanine stain (stain specific for copper deposition).
Table. Prognostic Index in Fulminant Wilsonian Hepatitis
Score 0 1 2 3 4
Serum bilirubin (reference range, 3-20 mmol/L) < 100 100-150 151-200 201-300 >300
Serum aspartate transaminase (reference range, 7-40 IU/L) < 100 100-150 151-200 201-300 >300
Prothrombin time prolongation (seconds) < 4 4-8 9-12 13-20 >30
Previous
Next
 
 
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.