THINK WILSON

What is Wilson disease?

Wilson disease is a rare, progressive, and inherited disease that leads to copper build-up in the brain, liver, and other tissues, and that requires lifelong management.1-4,7 Pathogenic mutations in the gene result in defective copper transporter ATP7B protein, leading to elevated copper levels that can then lead to a range of clinical consequences, including:

  • Hepatic symptoms: reported as the initial clinical manifestation in ~61% (711/1172) of patients in an Austrian cohort studya,8
    • In studies from neurology departments, 16–40% of patients present with hepatic symptomsb-d,9-11
  • Neurologic and/or psychiatric symptoms: reported as the initial clinical manifestation in ~39% (461/1172) of patients in an Austrian cohort studya,8
    • In studies from neurology departments, 59–82% of patients present with neurologic or psychiatric symptomsb-d,9-11
  • Ophthalmologic manifestations: in cohort studies in Austria,8,12 China,9 and Germany,6 Kayser–Fleischer rings were present in ~80% (49/61) to ~98% (329/337) of patients with predominantly neurologic symptoms, and in ~27% (38/140) to ~52% (50/96) of patients with predominantly hepatic symptoms.a,d-f,6,8,9,12 However, Kayser–Fleischer rings are not entirely specific to Wilson disease as they can also be found in patients with chronic cholestatic liver disease and in children with neonatal cholestasis1,2







HEPATIC SYMPTOMS: REPORTED AS THE INITIAL CLINICAL MANIFESTATION IN ~61% (711/1172) OF PATIENTS IN AN AUSTRIAN COHORT STUDYa,8

NEUROLOGIC OR PSYCHIATRIC SYMPTOMS: REPORTED AS THE INITIAL CLINICAL MANIFESTATION IN ~39% (461/1172) OF PATIENTS IN AN AUSTRIAN COHORT STUDYa,8

IN COHORT STUDIES IN AUSTRIA,8,12 CHINA,9 AND GERMANY,6 ~80% (49/61) TO ~98% (329/337) OF PATIENTS WITH NEUROLOGIC SYMPTOMS, AND ~27% (38/140) TO ~52% (50/96) OF PATIENTS WITH MAINLY HEPATIC SYMPTOMS, HAD KAYSER–FLEISCHER
RINGS.a-d,6,8,9,12

HOWEVER, KAYSER–FLEISCHER RINGS ARE NOT ENTIRELY SPECIFIC TO WILSON DISEASE AS THEY CAN ALSO BE FOUND IN PATIENTS WITH CHRONIC CHOLESTATIC LIVER DISEASE AND IN CHILDREN WITH NEONATAL CHOLESTASIS1,2

High liver copper levels in Wilson’s disease
Brain MRI assessment
Psychiatric symptoms & manifestations of Wilson’s disease
Excess copper can cause amber eyes (Kayser Fleischer rings) in Wilson’s disease

FOOTNOTES

  1. aBased on an Austrian registry study of 1357 patients from 1985 onwards, from different departments, including internal medicine, hepatology/gastroenterology, pediatrics, and neurology.8
  2. bBased on a retrospective cohort study of 119 patients with neurologic manifestations of Wilson disease at a center in Brazil between 1963 and 2004.11
  3. cBased on a study of 627 patients with Wilson disease at a center in Poland between 1958 and 2010 (retrospective until 2005).10
  1. dBased on a multicenter observational cohort study of 715 patients with Wilson disease in China between 2004 and 2019.9
  2. eBased on a retrospective study of 163 patients with Wilson disease at a center in Germany between 2000 and 2005.6
  3. fBased on a retrospective study of 229 patients diagnosed with Wilson disease in Austrian tertiary referral centers between 1961 and 2013.12
Michael L. Schilsky, MD, FAASLD. Professor of Medicine and Surgery, Yale University. Director of Center of Excellence for Wilson disease, Yale University. Explains the Overview of Wilson disease.

Think Wilson

michael schilsky - yale school of medicine, connecticut, usa

Copper builds up in the liver & brain in Wilson’s disease

Copper metabolism in Wilson disease

Copper is an essential trace element involved in a wide range of processes, including iron oxidation, cellular respiration, and neurotransmitter biosynthesis.13 Reduced capacity to remove copper can lead to intracellular copper accumulation and harmful effects, so regulating copper balance in the body is vital.1,14,15

Dietary copper is absorbed from the proximal small intestine and transported into the liver.1 Copper is normally transported in the blood in a variety of forms:

  • The majority of copper (65−71%) in the blood is tightly bound to ceruloplasmin (a protein also involved in iron metabolism)13
  • A smaller fraction is bound to albumin (15−19%), transcuprein (7−15%), or amino acids or small peptides (<2–5%) for transport (referred to as exchangeable or labile-bound copper).13 An excess of this fraction, in which copper is more loosely bound, is believed to facilitate subsequent cellular uptake by the liver and other organs, contributing to the pathology of Wilson disease16

Because the body requires only a small amount of absorbed copper, excess copper must be excreted.2 The main route of copper excretion is in the bile, which is mediated by the copper transporter ATP7B protein.14,15 The ATP7B protein also plays a role in the incorporation of copper into apoceruloplasmin in the liver for transport in the blood throughout the body.1,2

In Wilson disease, mutations in the ATP7B gene and reduced ATP7B protein activity in the liver lead to reduced copper excretion in the bile.14,17 Copper builds up and eventually spills out from the liver, increasing deposition in other organs and tissues and urinary copper excretion.1,2,15 This accumulation of excess copper leads to cellular damage and the various clinical manifestations of Wilson disease.14,15

Prevalence and genetics of Wilson disease

Comparing epidemiologic and genetic prevalence data for Wilson disease suggests that the disease may be underdiagnosed.3 The true prevalence of Wilson disease is unknown given the rare nature of the disease. Historically, the diagnosed prevalence has been estimated as 1 in 30,000 globally.1,2,7 However, recent large population-based studies from France estimate prevalence to be 1 in 67,00018 and from Hong Kong as 1 in 40,000.19 In contrast, genetic disease birth prevalence has been estimated at ~1 in 7026 to ~1 in 20,000.4,20

Numerous genetic alterations are associated with Wilson disease.3 A recent study reported that 782 pathogenic variants of the ATP7B gene have been identified.3 In addition, genetic variants where the pathogenicity is uncertain have also been reported.3

From a clinical standpoint, there is a poor genotype−phenotype correlation in Wilson disease.5,6 Differences in phenotype between monozygotic twins with the same mutation suggest that clinical outcomes in patients with Wilson disease are likely influenced by environmental factors, resulting in the inability to reliably predict disease severity by genetic testing.5 Also, patients with a confirmed ATP7B gene alteration may be clinically asymptomatic.3,4 This could be due to the patient being pre-symptomatic or harboring a non-pathogenic ATP7B variant.3,4

Video showing Sihoun Hahn, MD, PhD Professor, Department of Pediatrics and Medicine. Former Medical Director, Biochemical Genetics Program Director, Wilson Disease Center of Excellence. University of Washington School of Medicine. From Seattle, WA, USA. Explaining the Genetics of Wilson Disease

E-LEARNING MODULE:

Think Genetics

Sihoun Hahn – Seattle Children’s Hospital, Washington, USA

Video showing Sihoun Hahn, MD, PhD Professor, Department of Pediatrics and Medicine. Former Medical Director, Biochemical Genetics Program Director, Wilson Disease Center of Excellence. University of Washington School of Medicine. From Seattle, WA, USA. Explaining the Newborn screening for Wilson disease: active research

E-LEARNING MODULE:

THINK GENETICS SUPPLEMENT – NEWBORN SCREENING FOR WILSON DISEASE: ACTIVE RESEARCH

Sihoun Hahn – Seattle Children’s Hospital, Washington, USA

REFERENCES

  1. 1. Schilsky ML, Roberts EA, Bronstein JM et al. 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; doi: 10.1002/hep.32801.
  2. 2. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Wilson's disease. J Hepatol 2012; 56: 671-685.
  3. 3. Gao J, Brackley S, Mann JP. The global prevalence of Wilson disease from next-generation sequencing data. Genet Med 2019; 21: 1155-1163.
  4. 4. Coffey AJ, Durkie M, Hague S et al. A genetic study of Wilson's disease in the United Kingdom. Brain 2013; 136: 1476-1487.
  5. 5. Kegley KM, Sellers MA, Ferber MJ et al. Fulminant Wilson's disease requiring liver transplantation in one monozygotic twin despite identical genetic mutation. Am J Transplant 2010; 10: 1325-1329.
  6. 6. 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.
  7. 7. 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.
  8. 8. Ferenci P, Stremmel W, Członkowska A et al. Age and sex but not ATP7B genotype effectively influence the clinical phenotype of Wilson disease. Hepatology 2019; 69: 1464-1476.
  9. 9. Dong Y, Wang R-M, Yang G-M et al. Role for biochemical assays and Kayser-Fleischer rings in diagnosis of Wilson's disease. Clin Gastroenterol Hepatol 2021; 19: 590-596.
  10. 10. Litwin T, Gromadzka G, Członkowska A. Gender differences in Wilson's disease. J Neurol Sci 2012; 312: 31-35.
  1. 11. Machado A, Chien HF, Deguti MM et al. Neurological manifestations in Wilson's disease: report of 119 cases. Mov Disord 2006; 21: 2192-2196.
  2. 12. Beinhardt S, Leiss W, Stättermayer AF et al. Long-term outcomes of patients with Wilson disease in a large Austrian cohort. Clin Gastroenterol Hepatol 2014; 12: 683-689.
  3. 13. 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.
  4. 14. Forbes JR, Cox DW. Copper-dependent trafficking of Wilson disease mutant ATP7B proteins. Hum Mol Genet 2000; 9: 1927-1935.
  5. 15. Petrukhin K, Lutsenko S, Chernov I et al. Characterization of the Wilson disease gene encoding a P-type copper transporting ATPase: genomic organization, alternative splicing, and structure/function predictions. Hum Mol Genet 1994; 3: 1647-1656.
  6. 16. Woimant F, Djebrani-Oussedik N, Poujois A. New tools for Wilson's disease diagnosis: exchangeable copper fraction. Ann Transl Med 2019; 7: S70.
  7. 17. 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.
  8. 18. Poujois A, Woimant F, Samson S et al. Characteristics and prevalence of Wilson's disease: a 2013 observational population-based study in France. Clin Res Hepatol Gastroenterol 2018; 42: 57-63.
  9. 19. 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. 20. Wallace DF, Dooley JS. ATP7B variant penetrance explains differences between genetic and clinical prevalence estimates for Wilson disease. Hum Genet 2020; 139: 1065-1075.