This is the current release of the guideline.

This guideline updates a previous version: Roberts EA, Schilsky ML. A practice guideline on Wilson disease. Hepatology 2003 Jun;37(6):1475-92.

The grading system for the class of recommendations (I, II, IIa, IIb, III) and the levels of evidence (A–C) is defined at the end of the "Major Recommendations."

Clinical Features

1. Wilson Disease (WD) should be considered in any individual between the ages of 3 and 55 years with liver abnormalities of uncertain cause. Age alone should not be the basis for eliminating a diagnosis of WD (Class I, Level B).
2. WD must be excluded in any patient with unexplained liver disease along with neurological or neuropsychiatric disorder (Class I, Level B).
3. In a patient in whom WD is suspected, Kayser-Fleischer rings should be sought by slit-lamp examination by a skilled examiner. The absence of Kayser-Fleischer rings does not exclude the diagnosis of WD, even in patients with predominantly neurological disease (Class I, Level B).

Diagnostic Testing

Ceruloplasmin

4. An extremely low serum ceruloplasmin level (<50 mg/L or <5 mg/dL) should be taken as strong evidence for the diagnosis of WD. Modestly subnormal levels suggest further evaluation is necessary. Serum ceruloplasmin within the normal range does not exclude the diagnosis (Class I, Level B).

Urinary Copper Excretion

5. Basal 24-hour urinary excretion of copper should be obtained in all patients in whom the diagnosis of WD is being considered. The amount of copper excreted in the 24-hour period is typically >100 micrograms (1.6 micromols) in symptomatic patients, but finding >40 micrograms (>0.6 micromol or >600 nmol) may indicate WD and requires further investigation (Class I, Level B).
6. Penicillamine challenge studies may be performed for the purpose of obtaining further evidence for the diagnosis of WD in symptomatic children if basal urinary copper excretion is <100 micrograms/24 hours (1.6 micromols/24 hours). Values for the penicillamine challenge test of >1600 micrograms copper/24 hours (>25micromols/24 hours) following the administration of 500 mg of D-penicillamine at the beginning and again 12 hours later during the 24-hour urine collection are found in patients with WD. The predictive value of this test in adults is unknown (Class I, Level B).

Hepatic Parenchymal Copper Concentration

7. Hepatic parenchymal copper content >250 micrograms/g dry weight provides critical diagnostic information and should be obtained in cases where the diagnosis is not straightforward and in younger patients. In untreated patients, normal hepatic copper content (<40 to 50 micrograms/g dry weight) almost always excludes a diagnosis of WD. Further diagnostic testing is indicated for patients with intermediate copper concentrations (70 to 250 micrograms/g dry weight) especially if there is active liver disease or other symptoms of WD (Class I, Level B).

Neurological Evaluation and Radiologic Imaging of the Brain

8. Neurologic evaluation and radiologic imaging of the brain, preferably by magnetic resonance (MR) imaging, should be considered prior to treatment in all patients with neurologic WD and should be part of the evaluation of any patient presenting with neurological symptoms consistent with WD (Class I, Level C).

Genetic Studies

9. Mutation analysis by whole-gene sequencing is possible and should be performed on individuals in whom the diagnosis is difficult to establish by clinical and biochemical testing. Haplotype analysis or specific testing for known mutations can be used for family screening of first-degree relatives of patients with WD. A clinical geneticist may be required to interpret the results (Class I, Level B).

Diagnostic Considerations in Specific Target Populations

"Mimic" Liver Diseases and Acute Liver Failure

10. Patients in the pediatric age bracket who present a clinical picture of autoimmune hepatitis should be investigated for WD (Class I, Level B).
11. Adult patients with atypical autoimmune hepatitis or who respond poorly to standard corticosteroid therapy should also be investigated for WD (Class I, Level C).
12. WD should be considered in the differential diagnosis of patients presenting with nonalcoholic fatty liver disease or who have pathologic findings of nonalcoholic steatohepatitis (Class IIb, Level C).
13. WD should be suspected in any patient presenting with acute hepatic failure with Coombs-negative intravascular hemolysis, modest elevations in serum aminotransferases, or low serum alkaline phosphatase and ratio of alkaline phosphatase to bilirubin of <2 (Class I, Level B).

Family Screening

14. First-degree relatives of any patient newly diagnosed with WD must be screened for WD. (Class I, Level A).

Treatment

15. Initial treatment for symptomatic patients should include a chelating agent (D-penicillamine or trientine). Trientine may be better tolerated (Class I, Level B).
16. Patients should avoid intake of foods and water with high concentrations of copper, especially during the first year of treatment (Class I, Level C).
17. Treatment of presymptomatic patients or those on maintenance therapy can be accomplished with a chelating agent or with zinc. Trientine may be better tolerated (Class I, Level B).

Treatment in Specific Clinical Situations

18. Patients with acute liver failure due to WD should be referred for and treated with liver transplantation immediately (Class I, Level B).
19. Patients with decompensated cirrhosis unresponsive to chelation treatment should be evaluated promptly for liver transplantation (Class I, Level B).
20. Treatment for WD should be continued during pregnancy, but dosage reduction is advisable for D-penicillamine and trientine (Class I, Level C).
21. Treatment is lifelong and should not be discontinued, unless a liver transplant has been performed (Class I, Level B).

Treatment Targets and Monitoring of Treatment

22. For routine monitoring, serum copper and ceruloplasmin, liver biochemistries and international normalized ratio, complete blood count and urinalysis (especially for those on chelation therapy), and physical examination should be performed regularly, at least twice annually. Patients receiving chelation therapy require a complete blood count and urinalysis regularly, no matter how long they have been on treatment (Class I, Level C).
23. The 24-hour urinary excretion of copper while on medication should be measured yearly, or more frequently if there are questions on compliance or if dosage of medications is adjusted. The estimated serum non–ceruloplasmin bound copper may be elevated in situations of non-adherence and extremely low in situations of overtreatment (Class I, Level C).

Definitions:

Levels of Evidence

Level A Data derived from multiple randomized clinical trials or meta-analyses

Level B Data derived from a single randomized trial, or nonrandomized studies

Level C Only consensus opinion of experts, case studies, or standard-of-care

Grading System for Recommendations

Class I Conditions for which there is evidence and/or general agreement that a given procedure or treatment is beneficial, useful, and effective

Class II Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of a procedure or treatment

Class IIa Weight of evidence/opinion is in favor of usefulness efficacy

Class IIb Usefulness efficacy is less well established by evidence/opinion

Class III Conditions for which there is evidence and/or general agreement that a procedure/treatment is not useful/effective and in some cases may be harmful

Algorithms are provided in the original guideline document for the following:

• The approach to diagnosis of Wilson disease (WD) in a patient with unexplained liver disease
• The approach to the diagnosis of WD in a patient with a neurological disorder or psychiatric disease with or without liver disease
• Screening for WD in sibling or child of a patient with secure diagnosis of WD

The guidelines are based on review of the published literature and the personal experience of the authors. The type of supporting evidence is identified and graded for each recommendation.

Not applicable: The guideline was not adapted from another source.

2003 Jun (revised 2008 Jun)

American Association for the Study of Liver Diseases - Private Nonprofit Research Organization

American Association for the Study of Liver Diseases

Practice Guidelines Committee

Primary Authors: Eve A. Roberts; Michael L. Schilsky

Committee Members: Margaret C. Shuhart, MD, MS, (Committee Chair); Gary L. Davis, MD (Board Liaison); Kiran Bambha, MD; Andres Cardenas, MD, MMSc; Timothy J. Davern, MD; Christopher P. Day, MD, PhD; Steven-Huy B. Han, MD; Charles D. Howell, MD; Lawrence U. Liu, MD; Paul Martin, MD; Nancy Reau, MD; Bruce A. Runyon, MD; Jayant A. Talwalkar, MD, MPH; John B. Wong, MD; Colina Yim, RN, MN

Potential conflict of interest: Nothing to report.

This is the current release of the guideline.

This guideline updates a previous version: Roberts EA, Schilsky ML. A practice guideline on Wilson disease. Hepatology 2003 Jun;37(6):1475-92.

None available

This NGC summary was completed by ECRI on February 17, 2004. The information was verified by the guideline developer on March 16, 2004. This NGC summary was updated by ECRI Institute on October 13, 2008. The updated information was verified by the guideline developer on November 24, 2008.

This NGC summary is based on the original guideline, which is subject to the American Association for the Study of Liver Diseases' copyright restrictions.