Wilson’s Disease

Wilson disease (hepatolenticular degeneration) is an autosomal recessive disorder caused by various mutations in the ATP7B gene, which regulates copper transport within hepatocytes. Dysfunction of this transport mechanism leads to abnormal copper accumulations in the liver, brain, eyes, and other organs, with consequent major and variably expressed hepatic, neurologic, and psychiatric disturbances. Liver involvement may manifest as hepatitis, liver failure, or cirrhosis, while basal ganglia involvement causes the extrapyramidal signs. Most patients are diagnosed between the ages of 5 and 35 years (mean: 13 years). Diagnosis is established if the patient has low plasma ceruloplasmin, corneal deposits of copper (Kayser-Fleischer rings), and elevated copper levels in the urine. However, other tests are often needed since not all patients will have all these findings. The prognosis is good for patients without advanced liver disease and who are treated with the chelating agents penicillamine or trientine. Untreated Wilson disease is ultimately fatal, with patients dying from cirrhosis, acute liver failure, or complications due to progressive neurologic disease.

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Epidemiology and Pathophysiology

Epidemiology

  • Worldwide prevalence: 1 per 30,000 live births, with many genetic variant mutations with different pathogenicities in the ATP7B gene
  • Typical age of onset is 5–35 years (mean age: 13 years)

Pathophysiology

  • Normal copper metabolism:
    • Copper is absorbed in the stomach and duodenum → binds to circulating albumin → absorbed by various tissues
    • Excess copper is excreted into the bile → eliminated in feces
  • Wilson’s disease is an autosomal recessive disorder caused by mutations in the ATP7B gene found on chromosome 13.
    • Encodes a membrane-bound, copper transporting ATPase
      • Regulates copper transport within hepatocytes
    • ATP7B protein deficiency or dysfunction causes the following:
      • Impaired excretion of copper into bile → hepatic copper accumulation → copper toxicity from oxidant damage to the liver
      • Decreased incorporation of copper into apoceruloplasmin → copper accumulates in tissues with low circulating levels of ceruloplasmin (circulating copper transport protein)
    • Different/variant mutations in the ATP7B gene help explain some of the different clinical manifestations.
  • As the disease progresses, copper accumulates in the following:
    • Liver
    • Brain
    • Cornea
    • Kidneys

Clinical Presentation

Wilson’s disease usually presents in children and young adults. It rarely manifests after 40 years of age. Manifestations are primarily hepatic, neurologic, and psychiatric and may include:

  • Liver disease
    • Hepatomegaly +/– splenomegaly
    • Ascites
    • Abdominal pain
    • Jaundice
    • May include hepatitis, acute liver failure, or cirrhosis
  • Kayser-Fleischer rings
    • Copper deposits in Descemet’s membrane of the cornea, manifested as green-brown rings that encircle the iris
    • Present in:
      • > 90% of patients with neurologic or psychiatric presentations
      • 50%–60% of patients with hepatic disease
  • Neurologic symptoms: Copper deposits within the brain cause extrapyramidal motor disturbances.
    • In the basal ganglia → wing-flapping tremor and parkinsonism-like symptoms (Note: The term “lenticular degeneration” used in the original description by Wilson, who was a medical student at the time, refers to the lenticular nucleus [putamen + globus pallidus] portion of the basal ganglia.)
    • In the cerebellum → dysarthria, dysphagia, incoordination, and ataxia
    • In the cerebrum → psychosis, dementia, and affective disorder
  • Psychiatric symptoms: depression, irritability, or personality changes
  • Hemolytic disease: Coombs-negative hemolytic anemia (HA), often associated with jaundice at presentation. Hemolytic anemia is commonly seen in acute liver failure due to Wilson’s disease, but it may also be seen without liver failure as low-grade and chronic or episodic HA.
Wilson disease Kayser-Fleischer rings

Kayser-Fleischer ring: corneal copper deposition

Image: “Kayser-Fleischer rings” by Bentham Science Publishers, 2012. License: CC-BY-2.5

Mnemonic

Clinical presentation of Wilson’s disease: ABCD

  • A: Asterixis
  • B: Basal ganglia degeneration symptoms (parkinsonism)
  • C: Cirrhosis
    Corneal deposits (Kayser-Fleischer ring)
  • D: Dementia

Diagnosis and Management

Diagnosis

  • Testing for Wilson’s disease should be considered in any patient with unexplained liver, neurologic, or psychiatric abnormalities, and first-degree relatives of patients with Wilson’s disease should be screened for the disease. 
  • Physical examination: Kayser-Fleischer rings are usually only seen with slit-lamp examination (present only in 50%–60% of those with isolated hepatic involvement, and in > 90% of patients with neurologic involvement).
  • Initial work-up:
    • Transaminitis with AST to ALT ratio > 2
    • Decreased serum ceruloplasmin
    • Elevated 24-hour urinary copper excretion
    • CBC
  • Imaging: ultrasound may show:
    • Hepatic steatosis
    • Hepatomegaly or splenomegaly
    • Findings of cirrhosis
  • Gold standard tests:
    • Liver biopsy: increased copper detected by quantitative assay (used if initial work-up is indeterminate)
    • Molecular genetic analysis

Management

  • Lifestyle:
    • Low-copper diet: Avoid foods rich in copper such as organ meat, shellfish, nuts, and chocolate.
  • Medical management (required):
    • Chelation of copper with penicillamine or trientine
    • If poorly tolerated: oral zinc 
  • Liver transplant may be required in severe cases such as fulminant liver failure.

Prognosis

  • Untreated Wilson’s disease is fatal due to the continuous copper accumulation, with patients dying from cirrhosis, acute liver failure, or complications due to progressive neurologic disease.
  • The life expectancy is unknown but is variable. An approximate 5-year median survival after the appearance of neurologic symptoms was reported in one study. Of the patients who develop acute liver failure due to Wilson’s disease, 95% die within days to weeks without liver transplantation.
  • Survival with treatment is excellent, even in the presence of liver damage (but not if the liver disease is advanced). Lifelong treatment is required.

Differential Diagnosis

  • Huntington’s disease: can also present with neuropsychiatric manifestations in a patient < 40 years old. Symptoms include chorea, athetosis, aggression, depression, and dementia. Huntington’s disease is caused by an autosomal dominant trinucleotide repeat (CAG) in chromosome 4. Brain imaging shows atrophy of the caudate and putamen. Kayser-Fleischer rings are not seen in Huntington’s disease.
  • Parkinson’s disease: can also present with the following neuropsychiatric manifestations: pill-rolling tremor, cogwheel rigidity, bradykinesia, postural instability, and shuffling gait. Parkinson’s disease is associated with the loss of dopaminergic neurons of the substantia nigra. Histology shows deposits of α-synuclein (intracellular eosinophilic inclusions). Kayser-Fleischer rings are not seen in Parkinson’s disease.
  • Hepatitis due to other causes (e.g., alcohol, acetaminophen): Neuropsychiatric manifestations of Wilson’s disease help differentiate it from other causes of hepatitis (although hepatic encephalopathy can be associated with liver failure). Clinical history, labs, and imaging can help differentiate causes of hepatitis from Wilson’s disease.

References

  1. Michael L Schilsky, MD. Wilson disease: Clinical manifestations, diagnosis, and natural history. Retrieved on July 20, 2020, from https://www.uptodate.com/contents/wilson-disease-clinical-manifestations-diagnosis-and-natural-history
  2. Kasper, D. L., & Braunwald, F. (2017). Harrison’s Principle of Internal Medicine 19th edition Volume I. (Pages 2519-2520)
  3. Wilson SAK. Progressive Lenticular Degeneration: A Familial Nervous Disease Associated with Cirrhosis of the Liver. Brain, 1912;34(4):295–507. https://doi.org/10.1093/brain/34.4.295
  4. Kumar, M., Gaharwar, U., Paul, S., et al. WilsonGen a comprehensive clinically annotated genomic variant resource for Wilson’s Disease. Sci Rep10, 9037 (2020). https://doi.org/10.1038/s41598-020-66099-2
  5. Hermann W. Classification and differential diagnosis of Wilson’s disease. Ann Transl Med. 2019;7(Suppl 2):S63. doi:10.21037/atm.2019.02.07

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