Leukemia (Blood Cancer)

 

One essential mineral that our body needs to get through the diet is copper, and typically we take in about 1 to 2mg/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 a 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. Just like iron, free copper reacts with hydrogen peroxide in the body to form the hydroxyl radical. These reactive oxygen species are 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 the 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 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 hepatocytes 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; for this reason, Wilson's 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 of 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.

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