Guideline sources The following summarized guidelines for the evaluation and management of Wilson's disease (WD) are prepared by our editorial team based on guidelines from the American Association for the Study of Liver Diseases (AASLD 2022), the European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN 2018), the American Gastroenterological Association (AGA 2017), the European Association for the Study of the Liver (EASL 2017; 2012), and the American College of Gastroenterology (ACG 2016). 1 2 3 4 5 6 Calculator Calculator Ferenci scoring system for Wilso Revised King's score for liver tra Guidelines https://web.pathway.md/diseases/recmlNdhDpmZ9BtF8 1/9 6/29/23, 3:15 AM Wilson's disease Pathway 1. Screening and diagnosis Indications for testing, symptomatic patients: As per AASLD 2022 guidelines, suspect and assess for WD in patients with any of the following: liver abnormalities of uncertain cause; do not rule out WD solely based on age ALF with non-immune hemolytic anemia, including acute intravascular hemolysis unexplained liver disease associated with a neurological or psychiatric disorder; consider obtaining an assessment by a neurologist specializing in movement disorders recurrent self-limited non-immune hemolysis. E As per ESPGHAN 2018 guidelines: Include WD in the differential diagnosis of pediatric patients aged > 1 year presenting with any sign of liver disease ranging from asymptomatically increased serum transaminases to cirrhosis with hepatosplenomegaly and ascites or ALF. A Exclude WD in any adolescent with unexplained cognitive, psychiatric, or movement disorder. A As per AGA 2017 guidelines, avoid obtaining routine testing for WD in patients presenting with ALF. D As per EASL 2017 guidelines, evaluate patients with Coombs-negative hemolytic anemia and high bilirubin-to-ALP ratio for WD. B As per EASL 2012 guidelines, test for WD in patients with liver abnormalities or neurological movement disorders of uncertain cause. A Indications for testing, family relatives: As per AASLD 2022 guidelines, screen first-degree relatives of patients with newly diagnosed WD for WD. E As per ESPGHAN 2018 guidelines, screen first-degree relatives (including siblings, offspring, and parents) of patients with WD diagnosis, once the diagnosis is confirmed in the proband, by obtaining LFTs, explorations of copper metabolism, and targeted molecular analysis. A As per EASL 2012 guidelines, screen first-degree relatives of patients with WD using genetic testing for known mutations or haplotype analysis. B Diagnostic criteria: As per AASLD 2022 guidelines, consider using diagnostic scoring systems to help in establishing or refuting a diagnosis of WD in patients not meeting classic descriptions of the disease. E As per ESPGHAN 2018 guidelines, use the Ferenci scoring system for the diagnosis of WD in pediatric patients. A As per EASL 2012 guidelines, avoid eliminating the diagnosis of WD based on age alone. D 2. Classification and risk stratification https://web.pathway.md/diseases/recmlNdhDpmZ9BtF8 2/9 6/29/23, 3:15 AM Wilson's disease Pathway Prognostic scores: consider using prognostic scoring systems to help in determining the potential for successful medical therapy for WD. Consider applying such a score serially over time to improve accuracy. E 3. Diagnostic investigations History and physical examination: recognize that WD at clinical presentation may involve organ systems besides the liver and nervous system, such as renal, musculoskeletal, cardiac, or endocrine systems. E Show 2 more Liver function tests: As per AASLD 2022 guidelines, obtain liver biochemistries in patients with suspected WD. E As per ESPGHAN 2018 guidelines, obtain LFTs including serum transaminases, conjugated and TBIL, ALP, and PT/INR in patients with suspected WD. A Complete blood count: obtain CBC and INR in patients with suspected WD. E Serum ceruloplasmin: As per AASLD 2022 guidelines: Obtain serum ceruloplasmin, and serum copper in selected cases, in patients with suspected WD. E Recognize that an extremely low serum ceruloplasmin level (< 5 mg/dL) more strongly suggests a diagnosis of WD than modestly subnormal levels, but serum ceruloplasmin by itself is insufficient for making a diagnosis of WD. Do not exclude WD based on normal serum ceruloplasmin levels. E As per ESPGHAN 2018 guidelines, obtain serum ceruloplasmin in patients with suspected WD. A As per EASL 2012 guidelines, suspect the diagnosis of WD in patients with a low serum ceruloplasmin level. Obtain further evaluation in patients with borderline levels. Do not exclude WD in patients with normal serum ceruloplasmin levels. A 24-hour urinary copper excretion: As per AASLD 2022 guidelines: Obtain basal 24-hour urinary copper excretion measurement in patients with suspected WD. E Recognize that basal 24-hour urinary excretion of copper in WD is typically > 100 g/24 hours in symptomatic patients, but a lower reference value of > 40 g/24 hours may indicate WD in asymptomatic patients or pediatric patients, and therefore requires clinical correlation and further investigation. E As per ESPGHAN 2018 guidelines, assess 24-hour urinary copper excretion in patients with suspected WD. A As per EASL 2012 guidelines: Recognize that basal 24-hour urinary excretion of copper > 1.6 mcmol is typical in symptomatic patients. B https://web.pathway.md/diseases/recmlNdhDpmZ9BtF8 3/9 6/29/23, 3:15 AM Wilson's disease Pathway Consider using a lower threshold value of basal 24-hour urinary excretion of copper (> 0.64 mcmol/day) for detecting asymptomatic patients, recognizing that this threshold is less sensitive and may be met in patients with other causes of liver injury. B Genetic testing: As per AASLD 2022 guidelines, obtain molecular genetic investigation of ATP7B (depending on logistics) in patients with suspected WD. Consider obtaining genetic testing for ATP7B mutations as part of a routine evaluation, and to provide diagnostic confirmation when biochemical testing is not definitive. E As per ESPGHAN 2018 guidelines, consider obtaining mutation analysis of the ATPB7 gene to facilitate the diagnosis. B Slit-lamp examination: As per AASLD 2022 guidelines, obtain slit-lamp or optical tomography examination for Kayser-Fleischer rings in patients with suspected WD. E As per EASL 2012 guidelines, perform, or refer to a skilled examiner who can perform, slit- lamp examination to assess for Kayser-Fleischer rings. Do not exclude WD in the absence of Kayser-Fleischer rings, even in patients with predominantly neurological disease. A Brain imaging: As per AASLD 2022 guidelines, consider obtaining brain imaging, preferably MRI, to establish baseline status and exclude other potential causes in patients with neurological abnormalities. E As per EASL 2012 guidelines: Obtain neurologic evaluation and brain imaging, preferably by MRI, in any patient presenting with neurological symptoms consistent with WD. B Consider obtaining neurologic evaluation and imaging of the brain, preferably by MRI, before treatment in all patients with neurologic WD. B 4. Diagnostic procedures Liver biopsy: As per AASLD 2022 guidelines, consider performing a liver biopsy to aid in the diagnosis of WD by identifying findings consistent with WD, allowing quantification of hepatic copper, and permitting disease staging/grading, as well as identifying an alternative or concurrent diagnosis of liver disease. E Show 2 more As per ESPGHAN 2018 guidelines, consider assessing the copper content in the liver tissue in pediatric patients where the diagnosis is uncertain. B As per EASL 2012 guidelines, assess the hepatic parenchymal copper content in cases where the diagnosis is not straightforward, and in younger patients. Exclude WD in untreated patients with normal hepatic copper content (< 0.64-0.8 mcmol/g dry weight). B 5. Medical management https://web.pathway.md/diseases/recmlNdhDpmZ9BtF8 4/9 6/29/23, 3:15 AM Wilson's disease Pathway Chelating agents: As per AASLD 2022 guidelines, initiate lifelong medical therapy in all patients with newly diagnosed WD. Individualize timing of treatment in < 3 years old pediatric patients to the degree of organ damage. E Show 2 more As per ESPGHAN 2018 guidelines: Initiate copper chelating agents in pediatric patients with signs of significant liver disease, such as cirrhosis or abnormal INR. B Discontinue penicillamine in case of adverse events and switch to trientine or zinc salts according to the severity of liver disease. B As per EASL 2012 guidelines, initiate a chelating agent, such as D-penicillamine or trientine, as first-line therapy in symptomatic patients with WD. Recognize that trientine may be better tolerated. B Show 2 more Zinc salts: As per AASLD 2022 guidelines: Consider initiating either a chelating agent (D-penicillamine or trientine at a lower dose than for initial therapy) or zinc for the treatment of asymptomatic patients with WD. E Switch to maintenance therapy (a lower dose of a chelating agent or full-dose zinc) based on time on therapy (generally > 1 year) and favorable clinical and biochemical response to therapy. E As per ESPGHAN 2018 guidelines: Consider offering zinc salts, preferably zinc acetate, in presymptomatic pediatric patients identified through family screening, or as maintenance therapy after de-coppering with chelators as long as serum transaminase levels remain normal. C Consider assessing for non-adherence to zinc by measuring serum zinc levels and/or urinary zinc/copper 24-hour excretion. C As per EASL 2012 guidelines, consider offering zinc salts as first-line therapy in patients with neurological manifestations. C Show 3 more Management of neurologic and psychiatric symptoms: recognize that effective treatment restoring normal copper balance may lead to improved neurological and psychiatric features of WD. E Show 2 more 6. Nonpharmacologic interventions Dietary modifications: As per AASLD 2022 guidelines: Advise avoiding intake of foods and water containing high concentrations of copper, especially during the first year of treatment in patients with WD. Consider offering supervision by a registered dietitian to avoid overly restrictive meal patterns or undue anxiety about diet. E https://web.pathway.md/diseases/recmlNdhDpmZ9BtF8 5/9 6/29/23, 3:15 AM Wilson's disease Pathway Offer dietary management including supplements formulated to meet dietary needs while avoiding excess copper intake in patients with WD unable to maintain adequate nutritional intake. E As per ESPGHAN 2018 guidelines, advise restricting consumption of copper-rich foods until remission of symptoms and normalization of liver enzymes in pediatric patients treated with copper-chelating agents. B As per EASL 2012 guidelines, advise avoiding intake of foods and water with high concentrations of copper, especially during the first year of treatment. B 7. Surgical interventions Liver transplantation: As per AASLD 2022 guidelines, refer patients with ALF due to WD for immediate liver transplant evaluation. E Show 3 more As per ESPGHAN 2018 guidelines, transfer and manage pediatric patients with ALF or decompensated liver cirrhosis in pediatric liver transplantation centers. A Show 2 more As per EASL 2012 guidelines: Perform liver transplantation in patients with ALF due to WD when the revised King's score is 11. B Evaluate patients with decompensated cirrhosis unresponsive to chelation treatment promptly for liver transplantation. B 8. Specific circumstances Pregnant patients: As per AASLD 2022 guidelines, provide genetic counseling and discussion of medication safety in pregnancy during preconception counseling taking into account the prospective mother's health. E Show 2 more As per ACG 2016 guidelines, continue treatment with penicillamine, trientine, or zinc, with dose reduction if possible, in pregnant patients with WD. B As per EASL 2012 guidelines, continue treatment for WD during pregnancy, but reduce doses of D-penicillamine and trientine accordingly. B Patients with advanced liver disease: Consider administering an intensive medical regimen in patients with WD and severe hepatic disease (irrespective of the severity of the neurological disease). Offer liver transplantation evaluation as a backup. Consider obtaining longitudinal assessment with a prognostic scoring system to help identify cases where medical therapy is likely to succeed. E Consider offering prompt liver transplantation in patients with WD and advanced chronic liver disease not responding to or tolerating medical therapy. E https://web.pathway.md/diseases/recmlNdhDpmZ9BtF8 6/9 6/29/23, 3:15 AM Wilson's disease Pathway 9. Follow-up and surveillance Serial monitoring: As per AASLD 2022 guidelines, perform a physical examination regularly and obtain liver biochemistries, INR, CBC, and routine urinalysis (especially in patients on chelation therapy with D-penicillamine or trientine) at least twice per year for regular monitoring. Obtain CBC and urinalysis regularly in patients receiving chelation therapy, irrespective of how long they have been on treatment. E Show 4 more As per ESPGHAN 2018 guidelines, obtain close follow-up in all pediatric patients during the first month following initiation of therapy, then every 1-3 months until remission, and every 3- 6 months thereafter. B Show 4 more As per EASL 2012 guidelines, obtain serum copper and ceruloplasmin, liver enzymes and function tests, CBC, urinalysis, and perform physical and neurological examinations regularly for routine monitoring, at least twice annually. B Show 2 more Management of treatment failure: recognize that treatment failure may occur during treatment initiation or while on chronic treatment, and can complicate any WD medication. E Show 2 more Surveillance for malignancy: Obtain screening and surveillance for HCC in patients with WD with cirrhosis or regressed cirrhosis according to pertinent guidelines. E Do not obtain screening and surveillance for cholangiocarcinoma in patients with WD. Consider screening for cholangiocarcinoma in the differential diagnosis of liver tumors not meeting strict radiologic criteria for HCC. D Clinical findings Patient demographics Symptoms Age 5-35 years Dysarthria Dysphagia Family history Fatigue Handwriting difficulty Wilson's disease Hypersalivation Neurological exam Stiffness Altered mental status Vascular exam Ataxia Leg edema Cogwheel rigidity Dystonia Ocular exam Intention tremor Involuntary movements Kayser-fleischer ring Progressive ataxia https://web.pathway.md/diseases/recmlNdhDpmZ9BtF8 7/9 6/29/23, 3:15 AM Wilson's disease Pathway Tremor Abdominal exam Head and neck exam Ascites Hepatomegaly Mask-like facies Lab findings Integument exam liver enzymes Jaundice serum AST urine copper Hematological findings serum ceruloplasmin Hemolytic anemia serum total copper Genetic testing Imaging findings Atp7b gene mutation Osteopenia Histological findings brain copper content Likelihood Ratios Pertinent positives The following findings increase the probability of Wilson's disease in adults. 7 8 Finding LR+ Value Decreased serum ceruloplasmin (< 20 mg/dL) 88 Increased liver copper content (> 250 g/g) 83 Pertinent negatives The following findings decrease the probability of Wilson's disease in adults. 7 8 Finding LR- Value serum ceruloplasmin not decreased ( 20 mg/dL) 0.12 liver copper content not increased ( 250 g/g) 0.17 References 1. 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