Wilson disease – causes, symptoms, diagnosis, treatment & pathology

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much more. Try it free today! 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. 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. For symptoms, Wilson disease typically causes
liver damage first in younger children and pre-teens and this often progresses from acute
hepatitis to cirrhosis and liver failure. If someone older has the disease, neurological
problems will likely manifest first. Typically when you look at someone’s blood
with Wilson 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
disease early on. Another key feature to note, as hepatocytes
are damaged and release free or unbound copper which will 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. Treatment for Wilson disease involves an initial
acute de-coppering therapy followed by maintenance therapy to keep copper levels within the normal
range. Treatment options include copper chelators
including trientine, penicillamine, an alpha amino acid metabolite of penicillin without
antibiotic properties; and tetrathiomolybdate; and zinc salts. Copper chelating agents bind free copper in
the blood and tissues to facilitate excretion Also though, patients can be given zinc salts,
which increases the production of metallothionein proteins in intestinal cells. This protein binds to copper and traps it
in the cell which are shed and excreted in the feces. Finally, if the liver’s been damaged to
the point of cirrhosis and liver failure, a liver transplant may be needed. All right, as a quick recap, Wilson disease
occurs when there’s an autosomal recessive defect in the ATP7B gene, which encodes a
protein that’s essential for copper transport and excretion. Excess copper is detrimental to the body because
it can accumulate in the brain and liver where they generate free radicals, leading to neurological
disorders or liver failure. Treatment involves an initial de-coppering
therapy with continued maintenance therapy to keep copper levels within the normal range.