Wilson Disease Treatment & Management

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

Approach Considerations

The mainstay of therapy for Wilson disease is pharmacologic treatment with chelating agents. The use of surgical decompression or transjugular intrahepatic shunting (TIPS) in the treatment of portal hypertension is reserved for individuals with recurrent or uncontrolled variceal bleeding that is unresponsive to standard conservative measures.

After the initiation of therapy with a chelating agent, the patient needs to be aware of potential adverse effects of the agents with which he or she is being treated. For instance, some of the concerning adverse effects are those commonly associated with penicillamine use. In addition, a patient must also be aware of the potential to develop worsening of some symptoms when chelation is started; in particular, patients with neurologic signs and symptoms can see worsening of these with chelation, and, in some instances, therapy needs to be reduced or stopped. Laboratory tests in patients started on penicillamine should include hematology and biochemical monitoring, as well as urinalysis.

With clinical progression, acute liver failure, or worsening hepatic function, the patient must be evaluated at a center with expertise in Wilson disease and the capability to perform liver transplantation.

Orthotopic liver transplantation is curative treatment for Wilson disease. Also see Liver Transplantation.

Diet

Patients should generally avoid eating foods with a high copper content, such as liver, chocolate, nuts, mushrooms, legumes, and shellfish (especially lobster). Drinking water from atypical sources (eg, well water) should be analyzed for copper content and replaced with purified water if the copper content is greater than 0.2 parts per million.

Pregnancy

Excessive intrauterine copper concentrations may be responsible for the high rate of spontaneous abortions in patients with Wilson disease. D-penicillamine (0.75-1.5 g/day) appears to pose no major risk to the fetus and should be continued throughout the pregnancy.

While pregnancy per se does not appear to have a deleterious effect on the course of treated patients, the risk of ascites or bleeding from gastroesophageal varices in pregnancy is increased for any individual with cirrhosis, regardless of the underlying etiology.

Pediatric

Pediatricians should consider Wilson disease in any child with hepatic abnormalities. The initial tests should be performed, and further workup by a pediatric gastroenterologist may be necessary if suspicion remains high.

Geriatric

Almost all patients have significant hepatic and neuropsychiatric symptoms before reaching the geriatric age group. Patients with Wilson disease who are untreated will most likely present with fulminant hepatic failure or with signs and symptoms of cirrhosis in the geriatric population. Consideration for liver transplantation is less likely with advancing age.

Neurologic deterioration with treatment

It is very important to recognize that some patients may develop worsening neurologic symptoms when therapy is initiated. In some of these instances, the chelating agent needs to be stopped and the patient should be run on zinc acetate alone. In patients on long-term treatment who show signs of progressive neurologic symptoms on chelating agents, medication compliance and dietary compliance require review, along with an assessment of the efficacy of laboratory testing.

Medicolegal concerns

Medicolegal issues may arise if the diagnosis is not considered in the face of appropirate clues.

Also critical is to provide the patient with information and to screen siblings of the index case for the possibility of Wilson disease, because the estimated frequency is 1 in 4 in situations in which the siblings have the same parents.

Consultations

Consider consultation with gastroenterologists with specialty training in hepatology for any patient with Wilson disease, especially when evidence of hepatic insufficiency is present. Consultation with surgeons may be sought for liver transplantation when deemed necessary.

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Long-Term Monitoring

Perform a physical examination, 24-hour urinary copper excretion assay, complete blood count (CBC), urinalysis, serum free copper measurement, and renal and liver function tests on a weekly basis for the first 4-6 weeks following initiation of chelation therapy.

The best way to monitor efficacy is to measure serum nonceruloplasmin-bound copper. This is measured by the following formula: Total serum copper (mcg/dL) - 3[ceruloplasmin (mg/dL)]. The reference range is less than 15 mcg/dL.

An adjunctive way to monitor efficacy is to measure urinary copper excretion. Urinary chelator levels usually measure 200-500 mcg/day. Urinary zinc levels usually measure less than 75 mcg/day.

Bimonthly evaluations are recommended through the first year, followed by yearly examinations thereafter. In patients with Kayser-Fleischer rings, a yearly slit-lamp examination should document fading or disappearance if patients are being adequately "decoppered."

Lifelong, uninterrupted chelation therapy is necessary in all patients with Wilson disease. Frequent follow-up with patients is necessary, secondary to patient decompensation due to noncompliance. This is one of the major causes of fulminant liver failure. Patients must avoid most alcohol consumption and potential hepatotoxic drug therapy.

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Molecular Adsorbents Recirculating System (MARS)

MARS is an extracorporeal liver support system using a hollow-fiber dialysis module in which the patient’s blood is dialyzed across an albumin-impregnated membrane while maintaining a constant flow of albumin-rich (20%) dialysate in the extracapillary compartment. Case reports and very small series have presented a role for this as a bridge to liver transplantation.[13]

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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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