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 stomach and 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.
One place that it can deposit that can be helpful for diagnosis, is in Descemet’s
membrane of the cornea, which is this membrane between the stroma and the endothelial layer
of the cornea, So you’ll look for something called Kayser-Fleischer rings, which are visible
copper deposits in the cornea.
Since it starts in the liver though, liver damage is usually seen first, and often progresses
from acute hepatitis to cirrhosis and liver failure.
Symptoms usually present in late childhood.
Typically when you look at someone’s blood with Wilson’s disease, you’ll note a couple
pretty key things.
One is that there’ll be an overall decreased level of ceruloplasmin in the blood, because
remember that you need apoceruloplasmin to bind to copper for it to be ceruloplasmin,
so without ATP7B binding copper to apoceruloplasmin, all you have is apoceruloplasmin which is
relatively unstable and doesn’t last very long in the plasma.
This can be important for diagnosing Wilson’s disease early on.
Another key feature to note, as hepatocytes are damaged and release free or unbound copper,
there’ll be increased levels of free copper in the blood, which will also lead to increased
free copper in the urine.
Other common complications from deposited copper in other tissues include an enlarged
liver and spleen, hepatosplenomegaly, renal disease due to damage to the proximal tubules
of the kidney, and hemolytic anemia due to direct damage that circulating free copper
causes to red blood cells.
Penicillamine will usually be used to treat Wilson’s disease, penicillamine is an alpha
amino acid metabolite of penicillin, but doesn’t share the same antibiotic properties as penicillin.
Instead, though, it’s a copper chelating agent, meaning it binds the free copper in
the serum and makes it easier to excrete.
Also though, patients can be given zinc or ammonium tetrathiomolybdate, both which reduce
copper reabsorption in the urine and therefore increase the amount of copper that’s ultimately
excreted in the urine.
Finally, if the liver’s been damaged to the point of cirrhosis and liver failure,
a liver transplant may be needed.