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## Complete Summary

#### GUIDELINE TITLE

Diagnosis and treatment of Wilson disease: an update.

#### BIBLIOGRAPHIC SOURCE(S)

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. \[253 references\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=18506894)

#### GUIDELINE STATUS

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.

### COMPLETE SUMMARY CONTENT

 SCOPE\
 METHODOLOGY - including Rating Scheme and Cost Analysis\
 RECOMMENDATIONS\
 EVIDENCE SUPPORTING THE RECOMMENDATIONS\
 BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS\
 CONTRAINDICATIONS\
 QUALIFYING STATEMENTS\
 IMPLEMENTATION OF THE GUIDELINE\
 INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT
CATEGORIES\
 IDENTIFYING INFORMATION AND AVAILABILITY\
 DISCLAIMER

### SCOPE

#### DISEASE/CONDITION(S)

Wilson disease (WD; hepatolenticular degeneration)

#### GUIDELINE CATEGORY

Diagnosis\
Management\
Screening\
Treatment

#### CLINICAL SPECIALTY

Family Practice\
Gastroenterology\
Internal Medicine\
Medical Genetics\
Pediatrics

#### INTENDED USERS

Physicians

#### GUIDELINE OBJECTIVE(S)

To provide a data-supported approach to the diagnosis and treatment of
patients with Wilsons disease

#### TARGET POPULATION

-   Children and adults with suspected Wilson disease (e.g., with
    unexplained hepatic, neurological, or neuropsychiatric
    abnormalities)

-   Children and adults diagnosed with Wilson disease

-   First-degree relatives of patients diagnosed with Wilson disease
    (*screening*)

#### INTERVENTIONS AND PRACTICES CONSIDERED

**Diagnosis/Screening**

1.  History and physical examination

2.  Diagnostic testing

    -   Complete blood count

    -   Serum ceruloplasmin

    -   Slit-lamp examination (Kayser-Fleischer rings)

    -   Basal 24-hour urinary excretion of copper

    -   Penicillamine challenge studies in children

    -   Liver biopsy for hepatic parenchymal copper content

    -   Neurologic evaluation and radiologic imaging of the brain by
        magnetic resonance imaging (MRI)

    -   Mutation analysis by whole gene sequencing

    -   Genetic screening of first-degree relatives based on haplotype
        analysis or specific testing for known mutations

**Treatment**

1.  Chelating agent (D-penicillamine or trientine)

2.  Diet (avoiding intake of foods and water with high copper
    concentrations)

3.  Zinc

4.  Liver transplantation

5.  Treatment options considered but not specifically recommended:

    -   Antioxidants (e.g., vitamin E)

    -   Tetrathiomolybdate (not commercially available in the U.S.)

**Management/Monitoring**

1.  Serum copper and ceruloplasmin

2.  Liver biochemistries and international normalized ratio

3.  Physical examination

4.  Complete blood count with differential

5.  Urinalysis for patients receiving chelators

6.  Repeat Kayser-Fleischer ring examination for patients with
    questionable compliance

7.  Yearly measurement of 24-hour urinary excretion of copper for
    patients on medication or more frequently if there are issues of
    compliance

8.  Lifelong treatment unless a liver transplantation has been performed

#### MAJOR OUTCOMES CONSIDERED

-   Side effects of pharmacologic treatment

-   Effectiveness of treatment options (e.g., survival rates following
    liver transplantation, associated morbidity)

### METHODOLOGY

#### METHODS USED TO COLLECT/SELECT EVIDENCE

Hand-searches of Published Literature (Primary Sources)\
Searches of Electronic Databases

#### DESCRIPTION OF METHODS USED TO COLLECT/SELECT THE EVIDENCE

These guidelines are based on the following: (1) formal review and
analysis of the recently-published literature on the topic including
Medline search; (2) American College of Physicians Manual for Assessing
Health Practices and Designing Practice Guidelines; (3) guideline
policies, including the American Association for the Study of Liver
Diseases (AASLD) Policy on the Development and Use of Practice
Guidelines and the American Gastroenterological Association Policy
Statement on Guidelines; (4) the experience of the authors in the
specified topic.

#### NUMBER OF SOURCE DOCUMENTS

Not stated

#### METHODS USED TO ASSESS THE QUALITY AND STRENGTH OF THE EVIDENCE

Weighting According to a Rating Scheme (Scheme Given)

#### RATING SCHEME FOR THE STRENGTH OF THE EVIDENCE

**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

#### METHODS USED TO ANALYZE THE EVIDENCE

Systematic Review

#### DESCRIPTION OF THE METHODS USED TO ANALYZE THE EVIDENCE

Not stated

#### METHODS USED TO FORMULATE THE RECOMMENDATIONS

Expert Consensus

#### DESCRIPTION OF METHODS USED TO FORMULATE THE RECOMMENDATIONS

Not stated

#### RATING SCHEME FOR THE STRENGTH OF THE RECOMMENDATIONS

**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

#### COST ANALYSIS

A formal cost analysis was not performed and published cost analyses
were not reviewed.

#### METHOD OF GUIDELINE VALIDATION

Peer Review

#### DESCRIPTION OF METHOD OF GUIDELINE VALIDATION

This guideline has been approved by the American Association for the
Study of Liver Diseases (AASLD) and represents the position of the
association. The guideline was produced in collaboration with the
Practice Guidelines Committee of the AASLD which provided extensive peer
review of the manuscript.

### RECOMMENDATIONS

#### MAJOR RECOMMENDATIONS

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]{.underline}**

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]{.underline}**

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]{.underline}**:

**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

#### CLINICAL ALGORITHM(S)

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

### EVIDENCE SUPPORTING THE RECOMMENDATIONS

#### TYPE OF EVIDENCE SUPPORTING THE RECOMMENDATIONS

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.

### BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS

#### POTENTIAL BENEFITS

-   Effective and timely diagnosis and treatment of persons with Wilson
    disease (WD)

-   Improved compliance with treatment

-   Reduction in treatment side effects

-   Reduction in WD-associated morbidity

#### POTENTIAL HARMS

**D-Penicillamine**

-   Worsening of neurologic symptoms has been reported in 10% to 50% of
    patients with Wilson disease (WD) treated with penicillamine during
    the initial phase of treatment.

-   Severe side effects requiring the drug to be discontinued occur in
    approximately 30% of patients. Early sensitivity reactions marked by
    fever and cutaneous eruptions, lymphadenopathy, neutropenia or
    thrombocytopenia, and proteinuria may occur during the first 1 to 3
    weeks.

-   Late reactions include nephrotoxicity, usually heralded by
    proteinuria or the appearance of other cellular elements in the
    urine, for which discontinuation of D-penicillamine should be
    immediate. Other late reactions include a lupus-like syndrome marked
    by hematuria, proteinuria, positive antinuclear antibody, and with
    higher dosages of D-penicillamine, no longer typically used for
    treating WD, Goodpasture\'s syndrome. Significant bone marrow
    toxicity includes severe thrombocytopenia or total aplasia.
    Dermatologic toxicities reported include progeric changes in the
    skin and elastosis perforans serpiginosa, and pemphigus or
    pemphigoid lesions, lichen planus, and aphthous stomatitis. Very
    late side effects include nephrotoxicity, severe allergic response
    upon restarting the drug after it has been discontinued, myasthenia
    gravis, polymyositis, loss of taste, immunoglobulin A depression,
    and serous retinitis. Hepatotoxicity has been reported. Hepatic
    siderosis has been reported in association with treated patients
    with reduced levels of serum ceruloplasmin and non-ceruloplasmin
    bound copper.

**Trientine**

-   Neurological worsening after beginning treatment with trientine has
    been reported but appears much less common than with penicillamine.

-   No hypersensitivity reactions have been reported with trientine,
    although a fixed cutaneous drug reaction was observed in one
    patient. Pancytopenia has rarely been reported. Trientine also
    chelates iron, and coadministration of trientine and iron should be
    avoided because the complex with iron is toxic. A reversible
    sideroblastic anemia may be a consequence of overtreatment and
    resultant copper deficiency. Lupus-like reactions have also been
    reported in some WD patients treated with trientine; however, these
    patients were almost all uniformly treated previously with
    penicillamine, so the true frequency of this reaction when trientine
    is used *de novo* is unknown.

-   Use in patients with primary biliary cirrhosis revealed that
    trientine may cause hemorrhagic gastritis, loss of taste, and
    rashes. Recent evidence suggests that copper deficiency induced by
    trientine can result in iron overload in livers of patients with WD.

**Zinc**

-   Gastric irritation is the main problem with zinc and may be
    dependent on the salt employed. Hepatic deterioration has been
    occasionally reported when zinc was commenced, fatal in one case.
    Also, zinc may have immunosuppressant effects and reduce leukocyte
    chemotaxis.

-   Elevations in serum lipase and/or amylase may occur, without
    clinical or radiologic evidence of pancreatitis. Whether high-dose
    zinc is safe for patients with impaired renal function is not yet
    established.

### CONTRAINDICATIONS

#### CONTRAINDICATIONS

Women taking D-penicillamine should not breast-feed because the drug is
excreted into breast milk and might harm the infant. Little is known
about the safety of trientine and zinc in breast milk.

### QUALIFYING STATEMENTS

#### QUALIFYING STATEMENTS

-   Intended for physicians, these recommendations suggest preferred
    approaches to the diagnostic, therapeutic, and preventive aspects of
    care. They are intended to be flexible, in contrast to standards of
    care, which are inflexible policies to be followed in every case.

-   A significant problem with the literature on Wilson disease is that
    patients are sufficiently rare to preclude large cohort studies or
    randomized controlled trials; moreover, most treatment modalities
    were developed at a time when conventions for drug assessment were
    less stringent than at present.

### IMPLEMENTATION OF THE GUIDELINE

#### DESCRIPTION OF IMPLEMENTATION STRATEGY

An implementation strategy was not provided.

#### IMPLEMENTATION TOOLS

Clinical Algorithm\
Personal Digital Assistant (PDA) Downloads

For information about
[availability](#identifying-information-and-availability), see the
\"Availability of Companion Documents\" and \"Patient Resources\" fields
below.

### INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT CATEGORIES

#### IOM CARE NEED

Getting Better\
Living with Illness

#### IOM DOMAIN

Effectiveness

### IDENTIFYING INFORMATION AND AVAILABILITY

#### BIBLIOGRAPHIC SOURCE(S)

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. \[253 references\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=18506894)

#### ADAPTATION

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

#### DATE RELEASED

2003 Jun (revised 2008 Jun)

#### GUIDELINE DEVELOPER(S)

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

#### SOURCE(S) OF FUNDING

American Association for the Study of Liver Diseases

#### GUIDELINE COMMITTEE

Practice Guidelines Committee

#### COMPOSITION OF GROUP THAT AUTHORED THE GUIDELINE

*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

#### FINANCIAL DISCLOSURES/CONFLICTS OF INTEREST

Potential conflict of interest: Nothing to report.

#### GUIDELINE STATUS

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.

#### GUIDELINE AVAILABILITY

Electronic copies: Available in Portable Document Format (PDF) from the
[American Association for the Study of Liver Diseases Web
site](http://www.aasld.org/practiceguidelines/Documents/WilsonDisease2008.pdf).

Print copies: Available from the American Association for the Study of
Liver Diseases, 1729 King Street, Suite 200; Alexandria, VA 22314;
Phone: 703-299-9766; Web site: [www.aasld.org](http://www.aasld.org/);
e-mail: <aasld@aasld.org>.

#### AVAILABILITY OF COMPANION DOCUMENTS

This guideline is available as a Personal Digital Assistant (PDA)
download via the APPRISOR™ Document Viewer from
[www.apprisor.com](http://www.apprisor.com/).

#### PATIENT RESOURCES

None available

#### NGC STATUS

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.

#### COPYRIGHT STATEMENT

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

### DISCLAIMER

#### NGC DISCLAIMER

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© 1998-2008 National Guideline Clearinghouse

Date Modified: 12/15/2008