Several organizations have published clinical practice guidelines for the diagnosis and management of Wilson disease. The American Association for the Study of Liver Diseases (AASLD) published guidelines in 2003 with a revision in 2008.1,2 The European Association for the Study of the Liver (EASL) published guidelines in 2012.1,3 The European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) published guidelines in 2018.1,4 Three associations in India—the Indian National Association for Study of the Liver, the Indian Society of Pediatric Gastroenterology, Hepatology and Nutrition, and the Movement Disorders Society of India—collaborated to formulate and publish the most recent clinical practice guidelines for Wilson disease in 2019.5

Diagnosis

The various guidelines differ in their approaches to the diagnosis of Wilson disease, particularly regarding the reliance on liver biopsy and genetic mutational analysis. 

The AASLD promotes a clinical and biochemical algorithmic approach to diagnosis, specifically slit lamp examination to confirm Kayser-Fleischer rings and measurements of 24-hour urinary copper excretion and serum ceruloplasmin levels. If initial tests are inconclusive, the AASLD suggests liver biopsy for hepatic copper quantification and histologic confirmation of Wilson disease. If liver biopsy remains inconclusive, the AASLD recommends molecular testing to confirm Wilson disease.1,2

The EASL and ESPGHAN promote the use of the Leipzig scoring system, while the 3 Indian associations updated the 1993 Leipzig score, recommending the use of a modified Leipzig scoring system to establish a diagnosis of Wilson disease. The Leipzig scoring system combines clinical, biochemical, and genetic testing, including the presence or absence of Kayser-Fleischer rings, Coombs-negative hemolytic anemia, neurological symptoms, and excessive concentrations of hepatic copper via biopsy; serum ceruloplasmin and urinary copper levels; and chromosomal mutations. The modified Leipzig scoring system adds brain magnetic resonance imaging features and family history to the scoring system and alters the point system slightly.1,3-5

Both the standard and modified Leipzig diagnostic criteria require scores of 4 or above to establish a diagnosis of Wilson disease. A score of 3 indicates that a diagnosis of Wilson disease is possible, but further testing is required, while scores of 2 or lower suggest that Wilson disease is unlikely.1,3-5

All guidelines concur that all first-degree relatives of affected patients should be screened for Wilson disease.1

The guidelines demonstrated very little consensus regarding the diagnosis of acute liver failure secondary to Wilson disease. The AASLD suggests that patients with acute liver failure due to Wilson disease frequently exhibit the following features: Coombs-negative hemolytic anemia, coagulopathy, renal failure, modest transaminitis, normal or markedly low alkaline phosphatase (ALP) concentrations, an ALP to bilirubin ratio of less than 2, and female sex.1,2

In contrast, the EASL suggests that the ALP to bilirubin ratio should be less than 4 and the ratio of aspartate transaminase (AST) to alanine transaminase (ALT) should be greater than 2.2, along with other signs and symptoms of liver failure.1,3 

According to the ESPGHAN, low transaminase and ALP concentrations, an ALP to bilirubin ratio of less than 1, and hyperbilirubinemia (>17.5 mg/dL) support, but are not necessarily characteristic of, acute liver failure secondary to Wilson disease.1,4

The Indian clinical practice guidelines indicate that acute liver failure predominates among children and adolescents with Wilson disease and correlates with Coombs-negative hemolytic anemia, coagulopathy, ascites, jaundice, encephalopathy, and renal failure. These guidelines also note that one study reported that the combination of an AST:ALT ratio greater than 2.2 and an ALP to bilirubin ratio of less than 4 demonstrated a 100% diagnostic sensitivity and specificity.5,6 

Read more about Wilson disease diagnosis

Management

Medical management is divided into initial and maintenance treatments.1

Treatments

All guidelines support the first-line use of chelating agents such as penicillamine or trientine to treat Wilson disease.1-5 The AASLD and ESPGHAN support the use of zinc for decompensated cirrhosis, while the EASL suggests the first-line use of zinc in neurological patients.1-4 

Following initial therapy, the AASLD and EASL recommend maintenance doses of chelating agents or zinc,1-3 while the ESPGHAN supports the use of zinc for maintenance therapy.1,4 

Read more about Wilson disease treatment

Diet

Most guidelines recommend a low-copper diet, especially during the first year of treatment.1-4 In contrast, the Indian guidelines mentioned that the promotion of dietary copper restriction in the other guidelines was based on 2 case studies that provided weak evidence to support this recommendation. They also mention the difficulty of dietary copper restriction in developing countries, particularly for vegetarians, which may also concurrently reduce protein intake.5 

Read more about Wilson disease diet and nutrition

Treatment Monitoring

All guidelines recommend treatment monitoring via the measurement of 24-hour urinary copper excretion and non-ceruloplasmin-bound (free) copper levels. Target 24-hour urine copper levels while on maintenance chelator therapy fall between 200 and 500 µg/day.1-5 

Guidelines for 24-hour urine copper excretion in patients receiving zinc maintenance therapy differed. The AASLD, ESPGHAN, and Indian guidelines recommended less than 75 µg/day, while the EASL recommended less than 100 µg/day.1-5

According to the AASLD and EASL guidelines, patients with Wilson disease must undergo physical assessments, liver biochemistry and function testing, and assessments of serum copper and ceruloplasmin levels at least twice a year, while urinary copper should be assessed annually.1-3 

The ESPGHAN suggests similar treatment monitoring conducted at more frequent intervals—progressing from weekly monitoring during the first month of therapy to every 1 to 3 months until disease remission to every 3 to 6 months after remission.1,4 

The Indian guidelines recommend that 24-hour urine copper assessments are performed after 1 month of treatment, progressing to every 3 months and eventually every 6 to 12 months to monitor for renal toxicity in patients treated with D-penicillamine. Patients with the hepatic form of Wilson disease should undergo complete blood counts and liver function tests after weeks 1, 2, and 4, progressing to every 3 months, every 6 months, and then annually.5

The Indian guidelines also recommend the use of the Global Assessment Scale for Wilson disease to monitor patients presenting with neurological symptoms.5

Liver Transplantation

All guidelines agreed that the indications for liver transplantation included acute liver failure and chronic liver disease (decompensated cirrhosis) that no longer responds to medical management.1-4 The Indian guidelines suggest that patients with Wilson disease presenting with encephalopathy should undergo urgent liver transplantation.5

The Indian guidelines recommend the use of total plasma exchange or the molecular absorption recirculating system to rapidly remove free copper in patients with the fulminant form of Wilson disease who are awaiting liver transplantation.5

The EASL and ESPGHAN recommend the use of the revised King’s score to predict mortality due to liver failure in patients with Wilson disease and to inform the need for liver transplantation if the King’s score is 11 or above.1,3,4

The Indian guidelines cite the use of the New Wilson Index (NWI), a revised version of the King’s score, to predict survival in patients with Wilson disease who have not undergone liver transplantation.5,7 The NWI—determined by serum bilirubin levels, the international normalized ratio, white blood cell counts, and AST levels—proved more sensitive and specific in predicting mortality without liver transplantation than the older King’s scoring system.7 NWI scores of 11 or greater indicate mortality without liver transplantation.5,7

References

  1. Saroli Palumbo C, Schilsky ML. Clinical practice guidelines in Wilson disease. Ann Transl Med. 2019;7(Suppl 2):S65. doi:10.21037/atm.2018.12.53
  2. Roberts EA, Schilsky ML. Diagnosis and treatment of Wilson disease: an update. Hepatology. 2008;47(6):2089-2111. doi:10.1002/hep.22261
  3. European Association for the Study of the Liver. EASL clinical practice guidelines: Wilson’s disease. J Hepatol. 2012;56(3):671-685. doi:10.1016/j.jhep.2011.11.007
  4. Socha P, Janczyk W, Dhawan A, et al. Wilson’s disease in children: a position paper by the Hepatology Committee of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 2018;66(2):334-344. doi:10.1097/MPG.0000000000001787
  5. Nagral A, Sarma MS, Matthai J, et al. Wilson’s disease: clinical practice guidelines of the Indian National Association for Study of the Liver, the Indian Society of Pediatric Gastroenterology, Hepatology and Nutrition, and the Movement Disorders Society of India. J Clin Exp Hepatol. 2019;9(1):74-98. doi:10.1016/j.jceh.2018.08.009
  6. Korman JD, Volenberg I, Balko J, et al; Pediatric and Adult Acute Liver Failure Study Groups. Screening for Wilson disease in acute liver failure: a comparison of currently available diagnostic tests. Hepatology. 2008;48(4):1167-1174. doi:10.1002/hep.22446
  7. Dhawan A, Taylor RM, Cheeseman P, De Silva P, Katsiyiannakis L, Mieli-Vergani G. Wilson’s disease in children: 37-year experience and revised King’s score for liver transplantation. Liver Transpl. 2005;11(4):441-448. doi:10.1002/lt.20352

Reviewed by Kyle Habet, MD, on 9/25/2022.