Wilson Disease 

  • Author: Richard K Gilroy, MBBS, FRACP; Chief Editor: Julian Katz, MD   more...
 
Updated: Mar 1, 2012
 

Background

Wilson disease is a rare autosomal recessive inherited disorder of copper metabolism. The condition is characterized by excessive deposition of copper in the liver, brain, and other tissues. The major physiologic aberration is excessive absorption of copper from the small intestine and decreased excretion of copper by the liver. (See Etiology.)

The genetic defect, localized to arm 13q, has been shown to affect the copper-transporting adenosine triphosphatase (ATPase) gene (ATP7B) in the liver. Patients with Wilson disease more often initially present with hepatic manifestations when identified in the first decade of life as compared with more neuropsychiatric illness later, and the latter most commonly occurs during the third decade. The diagnosis is established by no individual test but requires the use of some combination of serum ceruloplasmin level, urinary copper excretion, presence of Kayser-Fleischer rings, and hepatic copper content when biopsy is required. (See Etiology, Clinical, and Workup.)

Although it is extremely rare in clinical practice, Wilson disease is important because it is often fatal if not recognized and treated when symptomatic. Often, the diagnosis is not made until adulthood, despite manifestations of the disease beginning to develop in childhood. (See Differentials, Treatment, and Medications.)

Staging

The natural history of Wilson disease may be considered in 4 stages, as follows:

  • Stage I - The initial period of accumulation of copper within hepatic binding sites
  • Stage II - The acute redistribution of copper within the liver and its release into the circulation
  • Stage III - The chronic accumulation of copper in the brain and other extrahepatic tissue, with progressive and eventually fatal disease
  • Stage IV - Restoration of copper balance by the use of long-term chelation therapy

Patient education

For patient education information, see the Digestive Disorders Center, as well as Cirrhosis.

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Etiology

The normal estimated total body copper content is 50-100 mg, and the average daily intake 2-5 mg, depending on an individual’s intake of legumes, meats, shellfish, and chocolate. Copper is an important component of several metabolic enzymes, including lysyl oxidase, cytochrome c oxidase, superoxide dismutase, and dopamine beta-hydroxylase.

Around 50-75% of intestinal copper is absorbed and then transported to the hepatocytes. This pathway is intact in Wilson disease. After copper reaches the hepatocyte, it is incorporated into copper-containing enzymes and copper-binding proteins (CBPs), including ceruloplasmin, a serum ferroxidase. Within the liver, the majority of in-infancy (< 6 mo) CBP granules staining positive may be normal. After 6 months, positive staining of CBPs for copper is almost exclusively found in association with liver diseases such as Wilson disease, chronic biliary disorders (eg, primary biliary cirrhosis, primary sclerosing cholangitis), cirrhosis/extensive fibrosis, and primary liver tumors (most often fibrolamellar hepatocellular carcinoma).

Excess copper may be rendered nontoxic by forming complexes with apo-metallothionein to produce copper-metallothionein, or it may be excreted into bile. Normal copper balance is maintained by regulation of excretion, rather than absorption, and the predominant route of copper excretion (approximately 95%) is hepatobiliary in nature.

In Wilson disease, the processes of incorporation of copper into ceruloplasmin and excretion of excess copper into bile are impaired.[1] The transport of copper by the copper-transporting P-type ATPase is defective in Wilson disease secondary to one of several mutations in the ATP7B gene. By genetic linkage studies, Bowcock and colleagues narrowed the assignment of the Wilson disease locus to 13q14-q21.[2]

Many of the gene defects for ATP7B are small deletions, insertions, or missense mutations. Most patients carry different mutations on each of their 2 chromosomes. More than 40 different mutations have been identified, the most common of which is a change from a histidine to a glutamine (H1069Q). Stapelbroek et al linked the H1069Q mutation to a late and neurologic presentation.[3]

The excess copper resulting from Wilson disease promotes free radical formation that results in oxidation of lipids and proteins. Ultrastructural abnormalities in the earliest stages of hepatocellular injury, involving the endoplasmic reticulum, mitochondria, peroxisomes, and nuclei, have been identified. Initially, the excess copper accumulates in the liver, leading to damage to hepatocytes. Eventually, as liver copper levels increase, it increases in the circulation and is deposited in other organs.

Stuehler et al reported that base pair changes in the MURR1 gene were associated with an earlier presentation of Wilson disease.[4] MURR1 had previously been established to cause canine copper toxicosis in Bedlington terriers.

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Epidemiology

In the United States, the carrier frequency is 1 per 90 individuals. The prevalence of Wilson disease is 1 per 30,000 individuals.

Worldwide, the incidence of Wilson disease is 10-30 million cases, and the heterozygote carrier rate is 1 case per 100 persons, with the genetic mutation frequency varying from 0.3-0.7%. In Japan, the rate is 1 case per 30,000 population, compared with 1 case per 100,000 population in Australia. The increased frequency in certain countries is due to high rates of consanguinity. The fulminant presentation of Wilson disease is more common in females than in males.

Age-related presentations

A German study of patients with Wilson disease illustrated that patients presenting earlier show predominantly hepatic symptoms (15.5 [9.6] y), while those presenting later more often present with neurological symptoms (20.2 [10.8] y).[5]

Thomas and colleagues reviewed the mutations found in the ATP7B gene, and their findings suggested a wide age span in the onset of Wilson disease, perhaps wider than previously considered typical. Mutations that completely disrupt the gene can produce liver disease in early childhood, at a time when Wilson disease may not be considered in the differential diagnosis.[6]

In general, the upper age limit for considering Wilson Disease is 40 years and the lower age limit is 5 years, although the disorder has been detected in children younger than 3 years and in adults older than 70 years.[7]

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Prognosis

Patients with a prognostic index (ie, score) of 7 or greater should be considered for liver transplantation (see Table 1, below). All patients in the study associated with this prognostic index who exceeded this score died within 2 months of diagnosis, irrespective of the institution of appropriate medical therapy.

Table. Prognostic Index in Fulminant Wilsonian Hepatitis (Open Table in a new window)

Score01234
Serum bilirubin (reference range, 3-20 mmol/L)< 100100-150151-200201-300>300
Serum aspartate transaminase (reference range, 7-40 IU/L)< 100100-150151-200201-300>300
Prothrombin time prolongation (seconds)< 44-89-1213-20>30

Prognosis after liver transplantation is relatively good. In a study involving 55 patients with Wilson disease who underwent hepatic transplantation, the 1-year survival rate was 79% and the overall survival rate was 72% at 3 months to 20 years. Another study of 32 patients reported a 1-year survival of 90.6%, a 5-year survival rate of 83.7%, and a 10-year survival rate of 79.9% after living donor liver transplantation.[8]

Important clues for the diagnosis of Wilson disease that a clinician must recognize are a younger patient with hemolytic anemia, impaired hepatic synthetic function, and normal alkaline phosphatase values.

Complications

The major complications in patients with untreated Wilson disease are those associated with acute liver failure, chronic hepatic dysfunction with either portal hypertension or hepatocellular carcinoma, and the sometimes-relentless course to cirrhosis, which is characterized by a progressive lassitude, fatigue, anorexia, jaundice, spider angiomas, splenomegaly, and ascites. Bleeding from varices, hepatic encephalopathy, hepatorenal syndrome, and coagulation abnormalities occur as liver failure ensues. Death occurs, generally at age 30 years, if emergent liver transplantation is not performed.

Unfortunately, Wilson disease has other systemic consequences of copper overload. Most patients who present with neuropsychiatric manifestations have cirrhosis. 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 extends from behavioral/mood state disturbances through movement disorders (occasionally choreoathetoid) or parkinsonian features. These features, on occasion, can be made worse with chelation therapy.

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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: genetech, gilead, NPS pharmaceuticals Salary 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 and American Society for Gastrointestinal Endoscopy

Disclosure: Takeda Consulting fee Speaking and teaching

Michael H Piper, MD, FACG, FACP  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, FACG, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Gastroenterology, American College of Physicians, and 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, and Physicians for Social Responsibility

Disclosure: Nothing to disclose.

Additional Contributors

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.

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.

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.

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

  2. 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. Nov 1988;43(5):664-74. [Medline]. [Full Text].

  3. 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. Nov 2004;41(5):758-63. [Medline].

  4. 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). Sep 2004;82(9):629-34. [Medline].

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

  6. 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. Jan 2009;48(1):72-7. [Medline].

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

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

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

  10. 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. Jun 27 2009;epub ahead of print. [Medline].

  11. 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. Aug 7 2009;epub ahead of print. [Medline].

  12. 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. Sep 2009;15(8):582-6. [Medline].

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

  14. 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. Apr 2011;140(4):1189-1198.e1. [Medline].

  15. 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. Oct 2009;51(10):627-33. [Medline].

  16. 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. Aug 2009;154(2):70-7. [Medline].

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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
Score01234
Serum bilirubin (reference range, 3-20 mmol/L)< 100100-150151-200201-300>300
Serum aspartate transaminase (reference range, 7-40 IU/L)< 100100-150151-200201-300>300
Prothrombin time prolongation (seconds)< 44-89-1213-20>30
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