Wilson's Disease

Authors:

Muhammad Roshan Asghar MD,

Muhammad Umair MD,

Adeel Memon MD

Introduction

• 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

• 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

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

• 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

• Slit-lamp examination; the presence of Kayser-Fleischer Rings strongly supports Wilson's disease diagnosis.

• 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

• 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

A score of 11 or more has a high probability of death without liver transplantation and is an indication for liver transplantation.

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

• Classification and differential diagnosis of Wilson’s disease. (n.d.). PubMed Central (PMC). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531651/

• 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

• Genetics, autosomal recessive - StatPearls - NCBI bookshelf. (2021, May 8). National Center for Biotechnology Information. https://www.ncbi.nlm.nih.gov/books/NBK546620/

• 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

• Wilson disease - StatPearls - NCBI bookshelf. (2021, August 11). National Center for Biotechnology Information. https://www.ncbi.nlm.nih.gov/books/NBK441990/

• Clinical features of Wilson disease. (n.d.). PubMed Central (PMC). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531660/

• 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 & Psychiatry, 78(11), 1199-1201. https://doi.org/10.1136/jnnp.2006.108415