Diagnosis and Management of Wilson Disease
Publication Date: September 22, 2022
Last Updated: January 31, 2023
Clinical Spectrum of Disease
- WD should be considered in any individual with liver abnormalities of uncertain cause. Age alone should not be the basis for eliminating a diagnosis of WD.
- WD must be excluded in any patient with unexplained liver disease associated with neurological or psychiatric disorder. Assessment by a neurologist specializing in movement disorders may be advantageous. Psychiatric evaluation is essential for any patient with WD presenting with psychiatric or neuropsychiatric features of WD.
- WD should be suspected in any patient presenting with ALF with nonimmune hemolytic anemia including acute intravascular hemolysis. These patients require urgent evaluation for liver transplantation.
- Evaluation for WD is critical in patients exhibiting recurrent self-limited nonimmune hemolysis.
- At clinical presentation, WD may involve organ systems besides the liver and nervous system (such as renal, musculoskeletal, cardiac, or endocrine).
Diagnosis and Screening
- Once WD is considered, a detailed personal and family medical history should be conducted and a physical examination focused on evidence of liver, neurological, and psychiatric disease performed. Assessment should include the following:
- liver biochemistries;
- complete blood count and international normalized ratio (INR);
- serum ceruloplasmin and, in some patients, serum copper;
- basal 24-h urinary copper excretion;
- slit-lamp or optical tomography examination for KF rings;
- neurological evaluation; and
- molecular genetic investigation of ATP7B (depending on logistics).
- An extremely low serum ceruloplasmin level (<5 mg/dl) more strongly suggests a diagnosis of WD than modestly subnormal levels. Serum ceruloplasmin by itself is insufficient for making a diagnosis of WD. Serum ceruloplasmin within the normal range does not exclude the diagnosis of WD.
- Basal 24-h urinary excretion of copper in WD is typically >100 μg/24 h (>1.6 μmol/24 h) in symptomatic patients, but a lower reference value of >40 μg/24 h (>0.6 μmol/24 h) may indicate WD in asymptomatic individuals or children and therefore requires clinical correlation and further investigation.
- Liver biopsy for histology can aid in the diagnosis of WD by identifying findings consistent with WD and permitting disease staging/grading. It may also suggest an alternative or concurrent diagnosis of liver disease. It allows quantification of liver tissue copper. Hepatic parenchymal copper content more than >250 μg/g dry weight occurs in most patients; a lower content still above normal occurs less frequently but should prompt other confirmatory testing. In untreated patients, normal hepatic copper content (<50 μg/g dry weight) almost always excludes a diagnosis of WD. Electron microscopic evaluation of liver tissue may aid diagnosis of WD, notably in pediatric patients.
- If neurological evaluation reveals abnormalities, radiologic imaging of the brain, preferably by MRI, should be considered to establish baseline status and exclude other potential causes.
- Diagnostic scoring systems may aid clinicians in establishing or refuting a diagnosis of WD in patients not meeting classic descriptions of the disease and are also useful for purposes of research studies on WD.
- Prognostic scoring systems may help in determining the potential for successful medical therapy for WD. Applying such a score serially over time may be critical to improve accuracy.
- First-degree relatives of patients newly diagnosed with WD must be screened for WD. Within a pedigree where there is one or more individuals with WD, any person with signs or symptoms consistent with WD, irrespective of closeness of relationship, should be evaluated for WD. Available strategies are genotype assessment of ATP7B and comprehensive clinical evaluation (summarized in Figure 4).
Treatment and Monitoring
- All patients with a newly established diagnosis of WD should be initiated on lifelong medical therapy for WD. Timing of treatment in children who are less than 3 years-old should be individualized to the degree of organ damage.
- Initial treatment for symptomatic patients with WD should include a chelating agent (D-penicillamine or trientine). Trientine may be better tolerated.
- Treatment of asymptomatic patients with WD can be a chelating agent (D-penicillamine or trientine at a lower dose than for initial therapy) or zinc.
- The suitability for transition to maintenance therapy for WD includes time on therapy (generally more than 1 year) and favorable clinical and biochemical response to therapy. Maintenance therapy may be a lower dose of chelating agent (D-penicillamine or trientine) or full-dose zinc.
- For regular monitoring, liver biochemistries and INR, complete blood count and routine urinalysis (especially for those on chelation therapy with D-penicillamine or trientine), and physical examination should be performed regularly, at least twice per year. Patients receiving chelation therapy require a complete blood count and urinalysis regularly, no matter how long they have been on treatment.
- The 24-h urinary copper excretion while on medication, or in patients on D-penicillamine or trientine after a temporary period (48 h) off drug, should be measured yearly and more frequently if there are questions regarding adherence or if the medication dosage is adjusted. Serum copper and ceruloplasmin may be followed for trends: very high or very low serum copper or serum copper disproportionately high for simultaneous serum ceruloplasmin. These may disclose exogenous copper intake (higher copper) or total-body depletion (lower copper and ceruloplasmin).
- Overtreatment of WD by pharmacological therapy directed at removing or detoxifying copper may be indicated by development of cytopenias or retention of tissue iron associated with raised serum ferritin. It is confirmed by a low serum copper and a very low 24-h urinary copper output. For oral chelators, 24-h urinary copper excretion disproportionately low for the dose of chelator being administered (below therapeutic target, specifically <100 μg/24 h or <1.6 μmol/24 h) suggests overtreatment. For zinc therapy, 24-h urinary copper <20 μg/24 h (<0.3 μmol/24 h) suggests overtreatment. Once overtreatment is confirmed, dose reduction or brief interruption of medical therapy should be instituted, with close follow-up for reassessment.
- Treatment failure may occur during treatment initiation or while on chronic treatment. It can complicate any WD medication. Concurrent diseases and nonadherence must be excluded. Pharmacological therapy should be revised in patients with treatment failure; however, with more advanced liver disease or liver failure, liver transplantation may be required.
- Ensuring adherence to a well-defined treatment plan for WD is critically important for patients to achieve good outcomes with therapy. Regular clinical assessments and a broadly supportive approach, team-based if possible, are elements of achieving good adherence. Monitoring frequency should be increased in patients where nonadherence is suspected.
- Patients with WD and severe hepatic disease (irrespective of severity of their neurological disease) may respond to an intensive medical regimen. They require liver transplantation evaluation as backup. Longitudinal assessment with a prognostic scoring system may help identify those where medical therapy is likely to succeed.
- Patients with WD and advanced chronic liver disease who fail to respond to or tolerate medical therapy should be considered promptly for liver transplantation.
- Patients with ALF due to WD should be referred for a liver transplant evaluation and potential liver transplantation immediately.
- Patients with ALI due to WD may respond to medical therapy or may progress to ALF. They require early transplant referral and evaluation.
- After liver transplantation, medical treatment specific for WD is unnecessary.
- Liver failure and HCC are well-accepted indications for liver transplantation in WD; however, neurologic WD remains a controversial indication.
- Patients with WD with cirrhosis or regressed cirrhosis should undergo screening and surveillance for HCC according to the recommended guidelines. Screening and surveillance for CCA is not indicated in WD; however, CCA should be considered in the differential diagnosis of liver tumors not meeting strict radiologic criteria for HCC.
- Preconception counseling should include genetic counseling and discussion of medication safety in pregnancy and should consider the prospective mother's health.
- Treatment for WD should be continued during pregnancy. D-Penicillamine has known teratogenic potential; data for trientine are sparse. Clinical experience suggests that chelation therapy at a reduced dosage with monitoring of liver function each trimester is another option. Zinc is safe; however, if a prospective mother is switched to zinc prior to pregnancy, clinical stability on zinc should be established before the pregnancy occurs.
- Breastfeeding, despite its recognized benefits, entails potential harms to the infant while a lactating mother is on treatment for WD. The pros and cons should be weighed in each case.
- Effective treatment restoring normal copper balance may lead to improved neurological and psychiatric features of WD.
- Adjunctive medical treatment may alleviate symptoms of neurologic WD, including parkinsonism, dystonia, and chorea.
- Patients with WD with persisting or severe psychiatric features, despite adequate WD treatment, may benefit from psychotropic medications or counseling.
Recommendation Grading
Abbreviations
- WD: Wilson Disease
Overview
Title
Diagnosis and Management of Wilson Disease
Authoring Organization
American Association for the Study of Liver Diseases
Publication Month/Year
September 22, 2022
Last Updated Month/Year
April 1, 2024
Document Type
Guideline
Country of Publication
US
Inclusion Criteria
Male, Female, Adolescent, Adult, Child, Infant, Older adult
Health Care Settings
Ambulatory, Laboratory services, Outpatient
Intended Users
Nurse, nurse practitioner, physician, physician assistant
Scope
Diagnosis, Assessment and screening, Management
Keywords
Wilson disease, hepatolenticular degeneration, copper
Source Citation
Schilsky ML, Roberts EA, Bronstein JM, Dhawan A, Hamilton JP, Rivard AM, Washington MK, Weiss KH, Zimbrean PC. A multidisciplinary approach to the diagnosis and management of Wilson disease: 2022 practice guidance on Wilson disease from the American Association for the Study of Liver Diseases. Hepatology. 2022 Sep 23. doi: 10.1002/hep.32801. Epub ahead of print. PMID: 36151586.