How is Wilson’s Disease Diagnosed? | Think Wilson

Diagnostic delay

Diagnosis of Wilson disease is often delayed or it is mistaken for other disorders, which can result in serious consequences for patients, including avoidable disease progression and death.6

A study of 163 patients with Wilson disease revealed:1

  • A mean delay of ~25 months from symptom onset to diagnosis
  • A roughly three-fold greater delay in patients with neurologic presentation versus hepatic presentation
    • Hepatic presentation: ~14-month delay
    • Neurologic presentation: ~44-month delay

If you see a patient presenting with liver abnormalities, unexplained neurologic movement disorders, or unexplained liver disease in combination with neurologic or neuropsychiatric disorders, a potential diagnosis of Wilson disease should be considered.2 Wilson disease should also be suspected in patients presenting with:3

  • Non-alcoholic fatty liver disease or pathologic findings of non-alcoholic steatohepatitis
  • Acute hepatic failure with Coombs-negative intravascular hemolysis
  • Elevations in serum aminotransferases
  • Low serum alkaline phosphate and ratio of alkaline phosphatase to bilirubin of <2

Wilson disease should be suspected in children older than 1 year presenting with liver disease, including symptoms ranging from increased liver enzymes to cirrhosis with hepatosplenomegaly and ascites or acute liver failure.4

Wilson disease can manifest at any age and diagnosis of Wilson disease should not be ruled out based on age alone.2







A study of 163 patients with Wilson disease revealed a mean delay of ~25 months from symptom onset to diagnosis1

A roughly three-fold greater delay in patients with neurologic presentation versus hepatic presentation1

Wilson’s disease diagnosis
Wilson’s disease diagnosis
Urinary copper and serum ceruloplasmin laboratory testing to diagnose Wilson’s disease

Diagnosis of Wilson disease

Diagnostic recommendations and algorithms for Wilson disease are available from AASLD, EASL, and ESPGHAN, providing approaches to diagnosis for adult and pediatric patients presenting with a variety of symptoms.2-4 The key components of diagnosis are laboratory testing and a physical exam.

A single diagnostic test may not provide definitive confirmation so multiple laboratory tests may be required to confirm a diagnosis of Wilson disease, including:2,4,7-9

Serum ceruloplasmin2,8

Measures the concentration of the copper-bound ceruloplasmin protein in the blood and is usually decreased in patients with Wilson disease


24-hour urinary copper excretion2,4

Reflects the amount of non-ceruloplasmin-bound copper in circulation and is usually elevated in patients with Wilson disease


Serum non-ceruloplasmin-bound copper2,4

Calculated by subtracting ceruloplasmin-bound copper from total serum copper and is usually elevated in patients with Wilson disease


Hepatic copper2,9

Measured by analyzing ≥1 cm biopsy samples and is often elevated in patients with Wilson disease


Relative exchangeable copper7

This is the pool of labile copper and is calculated as the ratio of exchangeable copper/total copper and is usually elevated in patients with Wilson disease


Copper transport in the blood in Wilson’s disease

Physical examination is an important aspect of diagnosis and it can detect a variety of manifestations, including hepatomegaly, portal hypertension (detected by the presence of hepatic encephalopathy, ascites, varices, and splenomegaly), and chronic liver disease, as well as altered sleep patterns and tremor.2,3,12

Ophthalmologic examination is another common tool used in the diagnosis of Wilson disease. Kayser–Fleischer rings result from copper deposition in the cornea and can be detected as a golden-brownish ring using the slit-lamp eye examination, but are not present in all patients and their absence should not rule out a diagnosis of Wilson disease.5,13-15

Absence of Kayser Fleischer rings does not exclude a diagnosis of Wilson’s disease

In cases where a final diagnosis cannot be reached based on clinical signs and symptoms and non-invasive tests, or if additional liver pathologies are suspected, liver biopsy may be required to quantify hepatic copper concentration and assess liver histology.2-4 Liver histology alone is not sufficient for Wilson disease diagnosis as the main features are non-specific and can overlap with other disorders, resulting in misdiagnosis.4 Copper staining methods often used on liver biopsies, such as rhodanine, produce highly variable results and can fail to identify increased liver copper content.4,17

Current diagnostic guidelines also recommend the use of brain imaging, including MRI, as over 90% of patients with Wilson disease with neurologic symptoms have brain pathologies detectable by MRI.2,3,18,19 A validated method for quantifying pathologies on brain MRI in Wilson disease was lacking until a novel, semi-quantitative, MRI visual rating scale was developed and validated for the assessment and classification of radiologic severity in Wilson disease.20 This semi-quantitative MRI rating scale may be useful for patient monitoring during therapy.20

Establishing a diagnosis of Wilson disease can require consideration of the results of multiple diagnostic investigations, and the Leipzig diagnostic scoring system was developed to aid this process.2 This system uses the results of common diagnostic tests and symptoms to provide a score indicating the likelihood of a patient having Wilson disease and whether further tests are required to confirm the diagnosis.21

Between 18% and 23% of patients with Wilson disease remain presymptomatic with only mild elevations in liver tests.12 It is, therefore, important that a thorough examination of patients is carried out so that subtle or mild manifestations are detected at an early stage.2,3,12

Think diagnosis

PIOTR SOCHA – THE CHILDREN’S MEMORIAL HEALTH INSTITUTE, WARSAW, POLAND

Practicalities of diagnosing a patient with Wilson disease and potential limitations of current diagnostic methods.

Assessment to establish a diagnosis of Wilson’s disease

Differential diagnosis

Wilson disease symptoms often mimic those of common disorders, leading to misdiagnosis and diagnostic delay.16 In a self-reported survey of 97 patients with Wilson disease:22

  • One-third reported receiving a misdiagnosis
  • Approximately one-third reported a delay of more than 1 year from symptom onset to diagnosis
  • 10% reported experiencing a delay of more than 5 years from symptom onset to diagnosis

It is important to consider Wilson disease in patients appearing to present with other disorders; differential diagnoses commonly observed include:2,23-27

By hepatologists:

  • Acute hepatitis in young patients2
  • Cirrhosis23
  • Fatty liver disease2
  • Congenital disorders of glycosylation in young patients25
  • Lysosomal acid lipase deficiency in young patients26


By neurologists:

  • Parkinson’s disease27
  • Essential tremor27


By psychiatrists:

  • Psychosis23,24
  • Schizophrenia23,24
  • Depression23


Family screening

Family screening should be performed for all patients diagnosed with Wilson disease to enable early detection and prevent disease progression among family members.2 The likelihood of a sibling of a patient being homozygous and developing the disease is 25%;28 for children or parents of a patient, the likelihood is 0.5%.2,28

Assessment should include physical and neurologic examination as well as biochemical tests and genetic testing for ATP7B mutations or haplotype screening, if available.2,28

ABBREVIATIONS

  1. AASLD, American Association for the Study of Liver Diseases; EASL, European Association for the Study of the Liver; ESPGHAN, European Society for Paediatric Gastroenterology, Hepatology and Nutrition; MRI, magnetic resonance imaging.

REFERENCES

  1. 1. Merle U, Schaefer M, Ferenci P et al. Clinical presentation, diagnosis and long-term outcome of Wilson's disease: a cohort study. Gut 2007; 56: 115-120.
  2. 2. European Association for Study of Liver. EASL Clinical Practice Guidelines: Wilson's disease. J Hepatol 2012; 56: 671-685.
  3. 3. Roberts EA, Schilsky ML. Diagnosis and treatment of Wilson disease: an update. Hepatology 2008; 47: 2089-2111.
  4. 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: 334-344.
  5. 5. Steindl P, Ferenci P, Dienes HP et al. Wilson's disease in patients presenting with liver disease: a diagnostic challenge. Gastroenterology 1997; 113: 212-218.
  6. 6. Walshe JM. Cause of death in Wilson disease. Mov Disord 2007; 22: 2216-2220.
  7. 7. El Balkhi S, Trocello JM, Poupon J et al. Relative exchangeable copper: a new highly sensitive and highly specific biomarker for Wilson's disease diagnosis. Clin Chim Acta 2011; 412: 2254-2260.
  8. 8. Mak CM, Lam CW, Tam S. Diagnostic accuracy of serum ceruloplasmin in Wilson disease: determination of sensitivity and specificity by ROC curve analysis among ATP7B-genotyped subjects. Clin Chem 2008; 54: 1356-1362.
  9. 9. Ludwig J, Moyer TP, Rakela J. The liver biopsy diagnosis of Wilson's disease. Methods in pathology. Am J Clin Pathol 1994; 102: 443-446.
  10. 10. Catalani S, Paganelli M, Gilberti ME et al. Free copper in serum: an analytical challenge and its possible applications. J Trace Elem Med Biol 2018; 45: 176-180.
  11. 11. Woimant F, Djebrani-Oussedik N, Poujois A. New tools for Wilson's disease diagnosis: exchangeable copper fraction. Ann Transl Med 2019; 7: S70.
  12. 12. Boga S, Ala A, Schilsky ML. Hepatic features of Wilson disease. Handb Clin Neurol 2017; 142: 91-99.
  13. 13. Litwin T, Dusek P, Szafrański T et al. Psychiatric manifestations in Wilson's disease: possibilities and difficulties for treatment. Ther Adv Psychopharmacol 2018; 8: 199-211.
  14. 14. Sánchez-Albisua I, Garde T, Hierro L et al. A high index of suspicion: the key to an early diagnosis of Wilson's disease in childhood. J Pediatr Gastroenterol Nutr 1999; 28: 186-190.
  1. 15. Pandey N, John S. Kayser-Fleischer Ring. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing, 2020.
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  3. 17. Kaščáková S, Kewish CM, Rouzière S et al. Rapid and reliable diagnosis of Wilson disease using X-ray fluorescence. J Pathol Clin Res 2016; 2: 175-186.
  4. 18. Litwin T, Gromadzka G, Członkowska A et al. The effect of gender on brain MRI pathology in Wilson's disease. Metab Brain Dis 2013; 28: 69-75.
  5. 19. Zhong W, Huang Z, Tang X. A study of brain MRI characteristics and clinical features in 76 cases of Wilson's disease. J Clin Neurosci 2019; 59: 167-174.
  6. 20. Dusek P, Smolinski L, Redzia-Ogrodnik B et al. Semiquantitative scale for assessing brain MRI abnormalities in Wilson disease: a validation study. Mov Disord 2020; 35: 994-1001.
  7. 21. Ferenci P, Caca K, Loudianos G et al. Diagnosis and phenotypic classification of Wilson disease. Liver Int 2003; 23: 139-142.
  8. 22. Miloh T, Graper M, Schilsky M. Evaluating diagnosis and management gaps in Wilson disease: results from a qualitative patient survey. Adv Rare Dis 2018; 4: 1.
  9. 23. Cheung KS, Seto WK, Fung J et al. Epidemiology and natural history of Wilson's disease in the Chinese: a territory-based study in Hong Kong between 2000 and 2016. World J Gastroenterol 2017; 23: 7716-7726.
  10. 24. Dening TR, Berrios GE. Wilson's disease. Psychiatric symptoms in 195 cases. Arch Gen Psychiatry 1989; 46: 1126-1134.
  11. 25. Vajro P, Zielinska K, Ng BG et al. Three unreported cases of TMEM199-CDG, a rare genetic liver disease with abnormal glycosylation. Orphanet J Rare Dis 2018; 13: 4.
  12. 26. Bay L, Canero Velasco C, Ciocca M et al. Liver disease and dyslipidemia as a manifestation of lysosomal acid lipase deficiency (LAL-D). Clinical and diagnostic aspects, and a new treatment. An update. Arch Argent Pediatr 2017; 115: 287-293.
  13. 27. Hermann W. Classification and differential diagnosis of Wilson's disease. Ann Transl Med 2019; 7: S63.
  14. 28. Maier-Dobersberger T, Mannhalter C, Rack S et al. Diagnosis of Wilson's disease in an asymptomatic sibling by DNA linkage analysis. Gastroenterology 1995; 109: 2015-2018.