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Wilson disease

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Gastrointestinal system

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Wilson disease

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A 10-year-old boy comes to his pediatrician because of difficulty articulating his speech. His parents have noticed that he was previously very talkative but now appears taciturn and moody. When he does speak, he has difficulty forming his words correctly. Physical examination of the patient shows a well-developed male with mild tenderness to palpation in his right upper quadrant and hepatomegaly. Closer examination of his eyes shows yellow-brown deposits in the corneoscleral junction. The patient's symptoms are most likely caused by an inability to excrete the metabolite by which route?

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Transcript

Content Reviewers:

Rishi Desai, MD, MPH

One essential mineral that our body needs to get through the diet is copper, and typically we take in about 1 to 2 mg per day from the food we eat, things like whole grains, beans, nuts and potatoes; but really our body only needs about 0.75 mg / day, so that extra copper is excreted.

About 90% of the excess copper is excreted into the bile, where it eventually ends up as fecal copper, and the other 10% is excreted in the urine.

In Wilson disease, there’s genetic defect that results in the excess copper being kept in the body and deposited in various tissues...where it’s not supposed to be, and just like iron, free copper reacts with hydrogen peroxide in the body to form the hydroxyl radical, a reactive oxygen species that’s pretty good at damaging tissue, so over time those tissues are seriously damaged by free radical generation.

Now your liver cells, or hepatocytes, play a really important role in helping the body get rid of excess copper.

So usually the copper from the diet is absorbed in the small intestine via enterocytes, and passed off into the portal vein to the liver.

Once it’s in the liver it’s sent to a special transport protein called ATP7B, which has a couple super important jobs.

The first job, is that it binds copper to apoceruloplasmin, which is the major copper-carrying protein in the blood and is responsible for carrying 95% of the copper in blood.

After it binds copper it’s then just called ceruloplasmin, and this guy can haul 6 molecules of copper at once.

ATP7B’s other job is to gather up the rest of the copper into vesicles to be exocytosed into into the bile canaliculi, where it goes into the bile and is eventually excreted.

With Wilson disease, there’s an autosomal recessive defect in this ATP7B transport protein. As you could probably guess, that means it can’t incorporate the copper into ceruloplasmin or excrete it into the bile.

Since it’s not doing either of these things anymore, the copper builds up inside the hepatocyte and starts to produce free radicals.

Eventually, all this built up copper and free-radical damage injures or destroys the hepatocyte, causing free copper to spill out into the interstitial space and from there into the blood supply, where it’s circulated to and deposited in other tissues, where it also causes free radical damage over time.

One organ in particular is the brain, and for this reason Wilson disease can have serious neurological symptoms and complications.

Depending on where it deposits, it can cause different disorders, if it deposits in the basal ganglia, it can cause a movement disorder that’s a lot like parkinsonism.

If it gets to the cerebral cortex it can be toxic to neurons, and can lead to neuronal cell death and dementia.

Summary
Wilson's disease is an autosomal recessive genetic disorder in which copper accumulates in tissues; this manifests as neurological or psychiatric symptoms and liver disease. It is the result of inadequate copper excretion into bile and blood resulting in decreased serum ceruloplasmin, and increased copper in the urine. Copper then accumulates in the liver, brain, cornea, kidneys, joints. It is treated with chelation with penicillamine.
Sources
  1. "Robbins Basic Pathology" Elsevier (2017)
  2. "Harrison's Principles of Internal Medicine, Twentieth Edition (Vol.1 & Vol.2)" McGraw-Hill Education / Medical (2018)
  3. "Pathophysiology of Disease: An Introduction to Clinical Medicine 8E" McGraw-Hill Education / Medical (2018)
  4. "CURRENT Medical Diagnosis and Treatment 2020" McGraw-Hill Education / Medical (2019)
  5. "Molecular pathogenesis of Wilson and Menkes disease: correlation of mutations with molecular defects and disease phenotypes" Journal of Medical Genetics (2007)
  6. "Molecular pathogenesis of Wilson and Menkes disease: correlation of mutations with molecular defects and disease phenotypes" Journal of Medical Genetics (2007)
  7. "A practice guideline on Wilson disease" Hepatology (2003)