Wilson’s Disease

You might be knowing that copper is an important micronutrient required for normal growth, maintenance, repair, and regulation of vital body functions. 

‘Too much of anything is bad’. In Wilson's disease, copper levels are increased in the body leading to alterations in the physiology of the body. To understand better about this disease, let us first have a brief look at the metabolism of copper in our body.

The Journey of Copper

Copper in food is absorbed by the stomach and duodenum. After absorption, they enter the portal vein to reach the liver.

Copper can’t be taken up by different organs in its elemental form. For better bioavailability, it must get attached to a carrier protein called ceruloplasmin, which is present in the Golgi apparatus of liver cells.

So, in the liver, copper is taken up by the hepatocytes and enters the Golgi apparatus to bind with the ceruloplasmin.

Now copper is ready for distribution.

Wisdom: Ceruloplasmin is naturally present in its precursor form called apo-ceruloplasmin. Copper has to bind with this to form ceruloplasmin.

Our body takes up only that amount of copper, which is sufficient enough to maintain a total body copper of 100mg. The extra copper is excreted by our liver in the bile and by the kidney in the urine.

What Goes Wrong in Wilson’s?

Wilson’s disease is an autosomal recessive disorder in which a variety of mutations in the ATP7 gene on chromosome 13 are noted. This gene codes for a copper-transporting protein, which exports copper from various cell types. There is also a failure of the synthesis of ceruloplasmin in this disease. 

This ultimately leads to the accumulation of free copper in the body.

Clinical Features

Most of the complaints are due to the accumulation of copper in different organs. The first organ to be affected is the liver, followed by other organs having an increased number of  CTR receptors in them. They include the brain, cornea, kidney, skeleton, etc. Of these, the liver, brain, and cornea are the most common organs to be affected.

Copper in its free state is usually toxic to the cell as they react with hydrogen peroxide, and this forms oxygen radicals, which can damage the cell.

• Liver: Copper damages the hepatocyte, which is compensated by regeneration. This forms cirrhosis and can also cause hepatitis, liver failure. This is called hepatolenticular degeneration.
• Brain: The symptoms depend upon the portion of the brain where copper gets deposited. If it deposits in the basal ganglia, it can cause movement disorder. In the cerebral cortex, it can lead to degeneration of neurons leading to dementia
• Eye:
  • In the cornea, copper gets deposited in the Descemet’s membrane, the layer between the stroma and the endothelium. This appears as a greenish-brown or golden brown ring called the “Kayser-Fleischer” ring
  • in Lens, it causes sunflower cataracts.

• Kidneys: Tubular damage
• Skeleton: Osteoporosis, arthropathy
• Anemia is evident as copper is toxic to the RBC and causes hemolysis. Also, ceruloplasmin is required for the binding of iron. Low levels of ceruloplasmin results in defective hemoglobin synthesis leading to anemia.

Investigations

• Low serum ceruloplasmin levels –this is explained by the fact that apo-ceruloplasmin has a half-life of 5hrs and gets degraded quickly, and there is no formation of ceruloplasmin because copper cannot bind to the apo-ceruloplasmin.
• Increased total serum copper levels
• Increased levels of copper in the urine: greater than 38 micrograms per hour
• Penicillamine test: Penicillamine is a chelating agent that can remove copper by binding with it. In this test, 500mg of penicillamine is administered at the beginning. Two urine samples are collected at the starting of the test and 12hrs. Any value of urinary copper excretion greater than 1600micrograms per hr is suggestive of Wilson’s disease.
• Slit-lamp examination: it reveals the presence of kayser Fleischer’s ring
• A liver biopsy can show the presence of an increased amount of copper.
• Dry weight of copper in the liver is often a very useful parameter to diagnose Wilson’s disease. Hepatic parenchymal copper content of < 40-50 μg/g dry weight almost always excludes the diagnosis of Wilson’s disease, and a dry weight of more than 250 μg/g is highly suggestive of Wilson’s disease.

Treatment

As excess copper is the main problem, the patient is advised to decrease copper intake in their diet. Copper-rich foods like nuts, liver, etc., are restricted. Drinking water from copper vessels should be avoided by the patients.

Apart from these lifestyle changes, patients are also medically managed with Chelating agents. They act by binding with excess copper and get excreted, thereby preventing its toxic accumulation in the body.

For this, Penicillamine is the drug of choice. Tab. Penicillamine, 1-1.5 g orally, is given daily.

Also, remember to give Pyridoxine 25 mg/d to prevent vitamin deficiency in these patients.

In chronic cases with cirrhosis or hepatic failure, liver transplantation may be required.

References

1. Harrison’s Principles of Internal Medicine 19^th edition, Page no: 2519 - 2520
2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5735277/

Authors footnote

Penicillamine is an effective drug in the treatment of Wilson’s disease. But severe toxic effects like bone marrow depression, lupus-like syndrome, etc., can develop in 1/3rd of the patients. In these patients, zinc and trientine dihydrochloride is used as an alternative.

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