THINK WILSON
Symptoms & manifestations of Wilson’s disease in the liver, brain, & eyes

HEPATIC SYMPTOMS: REPORTED AS THE INITIAL CLINICAL MANIFESTATION IN ~61% (711/1172) OF PATIENTS IN AN AUSTRIAN COHORT STUDYa,9

NEUROLOGIC OR PSYCHIATRIC SYMPTOMS: REPORTED AS THE INITIAL CLINICAL MANIFESTATION IN ~39% (461/1172) OF PATIENTS IN AN AUSTRIAN COHORT STUDYa,9

IN COHORT STUDIES IN AUSTRIA, 9,12 CHINA, 10 AND GERMANY,4 ~80% (49/61) TO ~98% (329/337) OF PATIENTS WITH MAINLY NEUROLOGIC SYMPTOMS, AND ~27% (38/140) TO ~52% (50/96) OF PATIENTS WITH MAINLY HEPATIC SYMPTOMS, HAD KAYSER–FLEISCHER RINGSa-d,4,9,10,12

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

Overview of Wilson disease manifestations

Wilson disease can affect multiple organ systems, including:1-3

  • Hepatic
  • Neurologic
  • Psychiatric
  • Ophthalmologic
  • Cardiovascular
  • Cutaneous
  • Hematologic
  • Renal
  • Gynecologic
  • Musculoskeletal

Read on to learn more about the most common manifestations seen in patients with Wilson disease.

  • Hepatic symptoms: reported as the initial clinical manifestation in ~61% (711/1172) of patients in an Austrian cohort studya,9
    • In studies from neurology departments, 16–40% of patients present with hepatic symptomsb-d,8,10,11
  • Neurologic or psychiatric symptoms: reported as the initial clinical manifestation in ~39% (461/1172) of patients in an Austrian cohort studya,9
    • In studies from neurology departments, 59–82% of patients present with neurologic or psychiatric symptomsb-d,8,10,11
  • Kayser–Fleischer rings: in cohort studies in Austria,9,12 China,10 and Germany,4 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,4,9,10,12 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

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.9
  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).8
  1. dBased on a multicenter observational cohort study of 715 patients with Wilson disease in China between 2004 and 2019.10
  2. eBased on a retrospective study of 163 patients with Wilson disease at a center in Germany between 2000 and 2005.4
  3. fBased on a retrospective study of 229 patients diagnosed with Wilson disease in Austrian tertiary referral centers between 1961 and 2013.12

Hepatic manifestations of Wilson disease

A broad range of hepatic manifestations can occur in Wilson disease and can differ between pediatric patients and adult patients.13,14 Progression of hepatic manifestations can result in acute liver failure, requiring liver transplantation in some patients.4

Common hepatic manifestations reported in adults with Wilson disease include cirrhosis (either compensated or decompensated, with or without clinical signs of portal hypertension), ascites, and hepatic encephalopathy.a,2,14 In pediatric patients, commonly reported manifestations include acute liver failure, abdominal pain, ascites, jaundice, and hepatosplenomegaly.b,13,15

Some patients with Wilson disease can appear asymptomatic and do not present with clinical manifestations of liver disease, but show elevated liver enzymes.16

Wilson’s disease manifestations & symptoms

FOOTNOTES

  1. aBased on a retrospective study of 211 adult patients (mean age 27.9 years) with Wilson disease from Hong Kong.14
  1. bBased on two retrospective studies of children (N=57, median age at diagnosis 11.9 years; N=26, mean age at first medical visit 9.8±3.4 years) with Wilson disease in the UK and Spain, respectively.13,15
Video of Valentina Medici, MD, FAASLD. Professor, Division of Gastroenterology and Hepatology. University of California Davis Sacramento, Ca, USA. Explaining Hepatic manifestation of Wilson disease.

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Valentina Medici - Professor, Division of Gastroenterology and Hepatology, University of California Davis, Sacremento CA USA

An overview of hepatic manifestations of Wilson disease.

Mobility may be impaired in Wilson’s disease

Neurologic manifestations of Wilson disease

Neurologic symptoms such as tremor, fisting of the hands, and altered gait can cause significant impairments to mobility and affect everyday life.1,5 Dysphagia is a neurologic symptom of Wilson disease and, with disease progression, can be a major cause of death due to aspiration pneumonia.17

Among patients with Wilson disease, tremor is a commonly reported neurologic manifestation and is the initial symptom in ~53% of patients.a,18 Dysarthria is also commonly reported in adults.1,2,19

In pediatric patients with Wilson disease, dysarthria, dystonia, and cognitive dysfunction are among the most commonly reported neurologic symptoms.b,20 Pediatric patients may also present with writing difficulties.3,16

FOOTNOTES

  1. aBased on a French registry study of 619 patients with Wilson disease.18
  1. bBased on a cross-sectional study of 50 children (mean age at onset of symptoms 9.06±2.65 years) with Wilson disease in Pakistan.20
Aurelia Poujois, MD, PhD. Coordinator National Reference Centre of Wilson's Disease, Neurology Department, University Hospital Foundation Adolphe de Rothschild, Paris, France. Explaining the Neurologic manifestation in Wilson disease.

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Aurelia Poujois – Hôpital Fondation Adolphe de Rothschild, Paris, France

An overview of neurologic manifestations of Wilson disease.

Psychiatric manifestations of Wilson disease

Psychiatric manifestations of Wilson disease can have a severe impact on patients. It has been reported that 20−60% of patients develop depression over the course of the disease6 and ~4−16% of patients attempt suicide.6

Additional psychiatric problems in patients with Wilson disease may include:

  • Behavioral problems and personality changesa,21
  • Decreased scholastic performance in pediatric patients6
  • Psychosisa,21
  • Anxietya,21
  • Sleep problemsa,21

Psychiatric symptoms & manifestations of Wilson’s disease

FOOTNOTES

  1. aBased on a retrospective study of 195 patients (mean age 19.7±8.7 years) with Wilson disease.21
Paula Zimbrean, MD Associate Professor, Departments of Psychiatry and Surgery (Transplantation) Yale University School of Medicine explaining the Psychiatric disorders in Wilson disease

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Paula Zimbrean – Yale School of Medicine, Connecticut, USA

A practical look at the wide range of psychiatric manifestations of Wilson disease.

Excess copper can cause amber eyes (Kayser Fleischer rings) in Wilson’s disease

Ophthalmologic manifestations of Wilson disease

Kayser–Fleischer rings are a result of deposition of excess copper in the cornea and are most often visible as a golden-brown ring in the peripheral cornea.22 They do not affect vision and are a commonly reported ophthalmologic manifestation of Wilson disease often used for diagnosis, yet they are:6,8,15,22

  • Absent in ~10% of patients with neurologic manifestations2,6,8
  • Absent in ~60% of patients with hepatic manifestations2,6,8
  • Absent in ~70−80% of pre-symptomatic patients6
  • Absent in ~80% of pediatric patientsa,15

A diagnosis of Wilson disease should, therefore, not be ruled out based on the absence of Kayser–Fleischer rings.

Sunflower cataracts are also seen in Wilson disease, although these are rarer.23 Eye movement disturbances may be observed, particularly abnormal vertical smooth muscle pursuits.b,24

FOOTNOTES

  1. aBased on a retrospective study of 163 patients with Wilson disease at a center in Germany between 2000 and 2005.4
  2. bBased on an Austrian registry study of 1357 patients from 1985 onwards, from different departments, including internal medicine, hepatology/gastroenterology, pediatrics, and neurology.9
  3. cBased on a multicenter observational cohort study of 715 patients with Wilson disease in China between 2004 and 2019.10
  4. dBased on a retrospective study of 229 patients diagnosed with Wilson disease in Austrian tertiary referral centers between 1961 and 2013.12
  1. eBased on a retrospective review of clinical and laboratory findings from 26 children diagnosed with Wilson disease in Spain from 1982 to 1996.15
  2. fBased on a retrospective study of 57 children diagnosed with Wilson disease in Greece from 1983 to 2004. Kayser–Fleisher rings were present in 19/39 (48.7%) of patients who were symptomatic and had abnormal liver test results and/or hepatomegaly.23
  3. gBased on a prospective study of 34 patients (mean age at electro-oculography 29 years [range 14–55]) with Wilson disease.25

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jesper hjortdal - the danish cornea bank and aarhus university hospital, aarhus, denmark

An overview of ophthalmologic manifestations of Wilson disease.

HEMATOLOGIC MANIFESTATIONS OF WILSON DISEASE

Hematologic manifestations of untreated Wilson disease typically involve hemolysis, which is caused by copper-associated damage to red blood cell membranes, and can be seen via reduced red blood cell count, reduced hemoglobin levels, and reduced unconjugated hyperbilirubinemia:2

  • Severe, non-immune, intravascular hemolysis is a classic presentation of acute liver failure due to Wilson disease, resulting in a sudden, severe drop in hemoglobin2
  • Hemolysis may also occur transiently in Wilson disease presenting as chronic disease2
  • Patients with Wilson disease who have a history of transient jaundice may have had hemolysis independent of liver disease2

Hypersplenism may be a presenting or later feature of hepatic Wilson disease, and thrombocytopenia and leukopenia can occur regularly in these cases.2







Impact of age and sex in Wilson disease

Wilson disease can affect people of all ages, usually presenting in the first decades of life; however, symptomatic onset has been reported in an 8-month-old patient and a 59-year-old patient.8,10,26-28 A diagnosis of Wilson disease should not be ruled out due to patient age alone.1,2

Age at symptom onset in Wilson disease varies between patients with hepatic and neurologic manifestations:4

  • Age at symptom onset is typically lower in patients with hepatic symptoms (late teens to early 20s) than in patients with neurologic symptoms (typically mid- to late 20s)8-10

Wilson disease occurs with a similar frequency in males and females.8 However, manifestations of Wilson disease may be influenced by patient sex.8 In a study of 1357 patients, the hepatic form was more common in females, while neurologic manifestations were more common in males.a,9

  • Hepatic presentation
    • Males: 48.3%
    • Females: 56.5%
  • Neurologic presentation
    • Males: 38.1%
    • Females: 29.8%

Psychiatric symptoms & manifestations of Wilson’s disease

FOOTNOTES

  1. aBased on a prospective study of 1357 pediatric and adult patients (49.8% and 50.2%, respectively) with Wilson disease: 328/679 (48.3%) male patients and 383/678 (56.5%) female patients had hepatic presentation, while 259/679 (38.1%) male patients and 202/678 (29.8%) female patients had neurologic presentation.9
Tamir Miloh, MD Professor of Pediatrics, Medical Director, Pediatric Transplant Hepatology, Miami Transplant Institute. The University of Miami explains Wilson's disease in pediatric patients.

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Tamir Miloh – University of Miami Health System, Florida, USA

Wilson disease in pediatric patients, including both symptomatic and pre-symptomatic patients.

REFERENCES

  1. 1. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Wilson's disease. J Hepatol 2012; 56: 671-685.
  2. 2. 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.
  3. 3. 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.
  4. 4. 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.
  5. 5. Esezobor CI, Banjoko N, Rotimi-Samuel A et al. Wilson disease in a Nigerian child: a case report. J Med Case Rep 2012; 6: 200.
  6. 6. 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.
  7. 7. 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. 8. Litwin T, Gromadzka G, Członkowska A. Gender differences in Wilson's disease. J Neurol Sci 2012; 312: 31-35.
  9. 9. 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.
  10. 10. 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.
  11. 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.
  12. 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.
  13. 13. Dhawan A, Taylor RM, Cheeseman P et al. Wilson's disease in children: 37-year experience and revised King's score for liver transplantation. Liver Transpl 2005; 11: 441-448.
  14. 14. 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.
  1. 15. 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.
  2. 16. Stremmel W, Meyerrose KW, Niederau C et al. Wilson disease: clinical presentation, treatment, and survival. Ann Intern Med 1991; 115: 720-726.
  3. 17. da Silva-Junior FP, Carrasco AE, da Silva Mendes AM et al. Swallowing dysfunction in Wilson's disease: a scintigraphic study. Neurogastroenterol Motil 2008; 20: 285-290.
  4. 18. Poujois A, Girardot N, Brunet AS et al. Contribution of the French registry in the understanding of Wilson disease. Mov Disord 2018; 33 (Suppl 2): abs 467.
  5. 19. Vierling JM, Sussman NL. Chapter 16 - Wilson disease in adults: Clinical presentations, diagnosis, and medical management. In: Kerkar N, Roberts EA, eds. Clinical and Translational Perspectives on Wilson Disease. London: Academic Press, 2019: 165-177.
  6. 20. Noureen N, Rana MT. Neurological Wilson disease in children: a three years experience from Multan. J Pak Med Assoc 2011; 61: 743-748.
  7. 21. Dening TR, Berrios GE. Wilson's disease. Psychiatric symptoms in 195 cases. Arch Gen Psychiatry 1989; 46: 1126-1134.
  8. 22. Pandey N, John S. Kayser-Fleischer Ring. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing, 2020.
  9. 23. Manolaki N, Nikolopoulou G, Daikos GL et al. Wilson disease in children: analysis of 57 cases. J Pediatr Gastroenterol Nutr 2009; 48: 72-77.
  10. 24. Langwińska-Wośko E, Litwin T, Dzieżyc K et al. Optical coherence tomography as a marker of neurodegeneration in patients with Wilson's disease. Acta Neurol Belg 2017; 117: 867-871.
  11. 25. Ingster-Moati I, Bui Quoc E, Pless M et al. Ocular motility and Wilson's disease: a study on 34 patients. J Neurol Neurosurg Psychiatry 2007; 78: 1199-1201.
  12. 26. Abuduxikuer K, Li LT, Qiu YL et al. Wilson disease with hepatic presentation in an eight-month-old boy. World J Gastroenterol 2015; 21: 8981-8984.
  13. 27. Iorio R, D'Ambrosi M, Marcellini M et al. Persistence of elevated aminotransferases in Wilson's disease despite adequate therapy. Hepatology 2004; 39: 1173-1174.
  14. 28. Rukunuzzaman M, Karim AB, Nurullah M et al. Childhood Wilson disease: Bangladesh perspective. Mymensingh Med J 2017; 26: 406-413.