Wilson's Disease

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Movement Disorder
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Introduction

☝️
Also known as Progressive Hepatolenticular Degeneration.
  • Genetic disorder of copper metabolism leading to copper accumulation.
  • Autosomal Recessive inheritance.
  • Caused by mutations in the ATP7B gene that encodes a transmembrane copper-transporting ATPase.
  • Defective ATP7B leads to an overload of copper in various organs, most commonly including the liver and basal ganglia.

Epidemiology

☝️
Males are more likely than females to develop the neuropsychiatric disease, whereas females are more likely than males to develop acute liver failure due to Wilson's disease.
  • Rare disorder
  • Occurs in approximately 1 in 30,000 to 40,000 people worldwide.
  • Approximately 1 person in 90 carries an abnormal copy of the ATP7B gene.
  • Affects males and females in equal numbers.
  • Found in all races and ethnic groups.

Genetics

  • It is inherited as an Autosomal Recessive trait; most commonly presenting between the ages of 5 to 35 years.
  • Gene encoding ATP7B is located on the short arm of chromosome 13.
  • According to the Human Gene Mutation Database, more than 700 mutations of the gene have been described.
  • Patients can either carry the same mutated allele and be homozygotes or they can carry two different mutations as compound heterozygotes.

Figure 1: Inheritance of Wilson's Disease

notion image

Pathophysiology

  • There is a faulty copper excretory mechanism.
  • This results in impaired trafficking of copper in and through the hepatocytes.
  • The pathogenesis of hepatic and neurologic Wilson disease is a direct consequence of copper accumulation.
  • Copper accumulates in the liver and other organs and tissues like the subthalamus, putamen, and cortex of the brain, kidneys, and cornea.
  • Copper causes the formation of an oxidative toxic hydroxyl group.
  • Excessive oxidative stress results in cell destruction.
  • Oxidative damage occurs through a process known as Fenton Chemistry.

Clinical Manifestations

Neurological Manifestations

  • Tremor (intention, resting, holding/postural)
  • Dysarthria
  • Ataxia
  • Lack of motor coordination
  • Nystagmus
    • Impaired vertical smooth pursuits - 85%
    • Vertical optokinetic nystagmus - 41%
    • Impaired horizontal smooth pursuits - 41%
  • Spasticity
  • Dystonia
  • Hypokinesia/Bradykinesia
  • Chorea
  • Drooling
  • Migraine headaches
  • Insomnia
  • Seizures
  • Hemiballismus
  • Writing disorder

Psychiatric Manifestations

  • Depression; 20%-60%
  • Bipolar Disorder; 14%-18%
  • Psychosis; ∼3%
  • Behavior disorders
  • Cognitive disorders
  • Impulse control disorders

Gastrointestinal Manifestations

  • Abdominal pain
  • Jaundice
  • Steatosis
  • Acute liver failure
  • Chronic hepatitis
  • Cirrhosis with portal hypertension
  • Splenomegaly

Ocular Manifestations

  • Kayser-Fleischer rings
  • Cataracts

Renal Manifestations

  • Tubular dysfunction
  • Renal tubular acidosis

Cutaneous Manifestations

  • Lunulae Ceruleae; bluish discoloration at the base of fingernails
  • Acanthosis Nigricans

Other Manifestations

  • Premature osteoarthritis; involving both the axial skeleton and spine
  • Hemolytic Anemia; seen in 10-15% of patients

Differential Diagnosis

Hyperkinetic Disorders

  • Tourette Syndrome
  • Sydenham Chorea
  • Huntington's Disease
  • Neuroacanthocytosis
  • Essential Tremor
  • Cerebral Palsy

Hypokinetic Disorders

  • Parkinson's Disease
  • Atypical Parkinsonism
  • Juvenile onset Parkinsons-Disease (Hunt)
  • Parkinson-plus Syndromes

Associated Disorders

  • Autoimmune Hepatitis
  • Viral Hepatitis B
  • Hemochromatosis
  • Primary Biliary Cholangitis
  • Liver Cirrhosis
  • Heavy Metal Poisoning
    • Copper, Aluminum, Arsenic or Mercury
  • Menke's Disease

Diagnosis and Evaluation

Table 1: Routine Tests for diagnosis of Wilsons Disease

Tests
Typical Findings
Serum Ceruloplasmin
Decreased by 50% of the normal value
24 Hour Urinary Copper
>100mcg/24hr
Hepatic Copper
>250 mcg/g dry weight
Kayser-Fleischer Rings by slit-lamp examination
Present
  • Complete history and physical examination, including positive family history.
  • Serum ceruloplasmin; less than 20 mg/dL (normal range: 20 mg/dL to 40 mg/dL).
  • Serum copper (both bound and free).
  • 24-hour urinary copper excretion; urinary copper levels will be raised more than 100 mcg/dL.
  • Implementation of the direct assay of “free copper”, or exchangeable copper (CuEXC).
  • The Relative Exchangeable Copper (REC) that corresponds to the ratio between CuEXC and Total Serum Copper enables a diagnosis of WD with high sensitivity and specificity when REC > 18.5%.
  • Liver biopsy; measure of hepatic copper content, single most sensitive and accurate investigation for the disease.
  • Neuroimaging:
    • MRI; the presence of hyper-intense signals in the basal ganglia on T2-weighted images and generalized brain atrophy are the two most common findings.
    • PET scan
    • Transcranial Brain Parenchyma Sonography

Figure 2: MRI Scan Findings

Increased T2 signal of the symmetric basal ganglia, including the caudate nuclei, putamina, as well as ventrolateral thalami, without the restriction of diffusion.
Increased T2 signal of the symmetric basal ganglia, including the caudate nuclei, putamina, as well as ventrolateral thalami, without the restriction of diffusion.
  • Slit-lamp examination; the presence of Kayser-Fleischer Rings strongly supports Wilson's disease diagnosis.
💡
NOTE: The only other disorder with Kayser-Fleischer Rings is Primary Biliary Cirrhosis
  • ECG; reveals ventricular hypertrophy, arrhythmias, and non-specific changes in T-waves and ST segments.
  • Copper levels in the CSF may also be measured to provide a reflection of the brain's copper load.

Staging

☝️
Patients usually present to the clinic with Stage 3 of the disease
  • Stage 1: Initial accumulation of copper in the liver.
  • Stage 2: Acute redistribution of copper within the liver, followed by release into the systemic circulation.
  • Stage 3: Chronic accumulation of copper into extrahepatic tissues including the brain.
  • Stage 4: Use of chelation therapy to restore copper balance

Treatment and Management

Pharmacological Management

  • D-Penicillamine; 250-500 mg, four times a day.
  • Trientene; 750-2000 mg, divided into three doses over the day.
  • Zinc; 50 mg of Elemental Zinc, three times a day.
  • Tetrathiomolybdate; 20 mg, six times a day.

Surgical

Liver Transplantation

  • Indicated in patients with acute liver failure or decompensated chronic liver disease who fail to respond to the pharmacological modalities.

Non-pharmacological Management

  • Dietary restriction of copper; avoid beef liver, cashews, black-eyed peas, vegetable juice, shellfish, mushrooms, and cocoa.
  • Drink purified water.
  • Avoid supplements containing copper.

Complications

  • Liver failure
  • Encephalopathy
  • Splenomegaly
  • Ascites
  • Variceal bleeding
  • Hepatorenal syndrome
  • Neuropsychiatric manifestations
  • Death

Prognosis

Natural Progression of the Disease

  • Untreated Wilson's disease is universally fatal.
  • Common causes leading to death are:
    • Severe Liver Cirrhosis
    • Severe Dystonia
    • Brain damage

Treatment-related Prognosis

  • Prognosis depends upon the:
    • Severity of the liver disease
    • Severity of the neurologic disease
    • Compliance with the treatment
  • Liver functions become normal over 1-2 years in patients with no or compensated cirrhosis at presentation and remain stable with adherence to the treatment.
  • Medical therapy is rarely effective in patients presenting with acute liver failure.

Table 2: Prognostic Index for Wilson's Disease

Parameters
0 Points
1 Point
2 Points
3 Points
4 Points
Serum Bilirubin (micromoles/litre)
0-100
101-150
151-200
201-300
>301
AST (Units/litre)
0-100
101-150
151-300
301-400
>401
INR
0-1.29
1.3-1.6
1.7-1.9
2.0-2.4
>2.5
WBC Count (10^9 per litre)
0-6.7
6.8-8.3
8.4-10.3
10.4-15.3
>15.4
Albumin (grams/litre)
>45
34-44
25-33
21-24
<20
A score of 11 or more has a high probability of death without liver transplantation and is an indication for liver transplantation.
Source: Wilson disease. (2018, 6). Nature Reviews Disease Primers. https://www.nature.com/articles/s41572-018-0018-3

Further Reading

  • Członkowska, A., Litwin, T., Dusek, P., Ferenci, P., Lutsenko, S., Medici, V., … Schilsky, M. L. (2018). Wilson disease. Nature Reviews Disease Primers, 4(1). doi:10.1038/s41572-018-0018-3

Bibliography

  • Członkowska, A., Litwin, T., Dusek, P., Ferenci, P., Lutsenko, S., Medici, V., … Schilsky, M. L. (2018). Wilson disease. Nature Reviews Disease Primers, 4(1). doi:10.1038/s41572-018-0018-3
  • Brewer, G. J. (2005). Neurologically Presenting Wilson???s Disease. CNS Drugs, 19(3), 185–192. doi:10.2165/00023210-200519030-00001
  • Pfeiffer, R. (2007). Wilson’s Disease. Seminars in Neurology, 27(2), 123–132. doi:10.1055/s-2007-971173
  • Poujois, A., & Woimant, F. (2018). Wilson’s disease: A 2017 update. Clinics and Research in Hepatology and Gastroenterology. doi:10.1016/j.clinre.2018.03.007
  • Abuduxikuer, K., & Wang, J.-S. (2014). Zinc Mono-Therapy in Pre-Symptomatic Chinese Children with Wilson Disease: A Single Center, Retrospective Study. PLoS ONE, 9(1), e86168. doi:10.1371/journal.pone.0086168
  • Aggarwal, A., & Bhatt, M. (2013). Update on Wilson Disease. Metal Related Neurodegenerative Disease, 313–348. doi:10.1016/b978-0-12-410502-7.00014-4
  • Ingster-Moati, I., Bui Quoc, E., Pless, M., Djomby, R., Orssaud, C., Guichard, J. P., & Woimant, F. (2007). Ocular motility and Wilson's disease: A study on 34 patients. Journal of Neurology, Neurosurgery & Psychiatry78(11), 1199-1201. https://doi.org/10.1136/jnnp.2006.108415
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