Wilson’s Disease (Inherited Copper Toxicity Disease)

What is Wilson’s disease?

Wilson’s disease is a genetic disorder that hampers the body’s ability to bind and transport copper thereby leading to accumulation of copper in the body. Over time copper deposition occurs in various different organs and tissues. Copper in its free form is toxic and damages the organs where it accumulates. As the body is not able to manage the copper appropriately, the metal builds up in the body from the time of birth. However, symptoms may only be noted by the age of 5 years or even later in life. Wilson’s disease is rare and only affects about 1 in 30,000 people.

Copper Accumulation in the Body

Copper is present in small quantities in the human body. It is primarily sourced from food absorbed in the gut. Copper is toxic in the free state and is normally bound to certain proteins (ceruloplasmin) which renders it non-toxic. Copper toxicity arises when :

  • abnormally large amounts of copper is introduced into the body, or
  • when then body cannot handle even normal amounts of copper appropriately.

The intake of large amounts of copper happens for various reasons during the course of life. In this instance it is known as acquired copper toxicity. When inherited genetic defects affects the binding of copper with proteins, its transport in the body and subsequent elimination, it is known as inherited copper toxicity. Wilson’s disease is a condition of inherited copper toxicity.

Copper Deposition in Organs

Copper is processed in the liver. Normally excess copper would be excreted in the bile but in Wilson’s disease, the impaired processing of copper means that it accumulates within the liver. Eventually the liver tissue is severely damaged and liver cells degenerated – cirrhosis. Copper in the liver diffuses out into the bloodstream and can accumulate in various organs. The brain is one of the main organs where this copper deposition occurs and this destroys brain tissue.

The process does not occur overnight. It happens over years and decades and essentially starts from the time of the birth. The first symptoms of copper toxicity are seen as early as 5 years of age. It is mainly symptoms of liver dysfunction but these symptoms can sometimes go unnoticed. Eventually the other symptoms become evident, sometimes as late as in the 30s. At this point neurological symptoms become evident and this may be the first indication of the disease.

Stages of Wilson’s Disease

Wilson’s disease can be categorized by four stages as the condition progresses and copper deposition extends to various organs in the body.

Stage 1

This is the stage during which copper accumulates at specific sites within the liver.

Stage 2

Copper spreads throughout the liver and passes out into the bloodstream.

Stage 3

Long term copper deposition occurs in various organs throughout the body. The disease progresses during this stage possibly culminating in death if the appropriate medical treatment is not forthcoming.

Stage 4

Stabilization of the copper imbalance and reversal of the disease to some extent with the appropriate medical treatment.

Signs and Symptoms

The signs and symptoms of Wilson’s disease depends on the stage of the disease and which organ is infiltrated with copper. Liver symptoms are first seen but at times missed, followed by the neurological symptoms at a later stage. In late diagnosis, the liver symptoms and neurological symptoms are detected at the same time. Other signs and symptoms may also be present.

Liver symptoms

  • Jaundice – yellowing of the skin, inner lining of the mouth and ‘whites’ of the eye (sclera).
  • Fluid retention most notably in the legs (evident as swollen feet and ankles) and in the abdomen (abdominal distension).
  • Enlarged liver (hepatomegaly) or spleen (splenomegaly) or both (hepatosplenomegaly).
  • Easy bruising.
  • Severe fatigue.

Neurological symptoms

  • Tremors and chorea (involuntary movements).
  • Muscle weakness and stiffness.
  • Poor coordination.
  • Difficulty swallowing and talking.
  • Changes in personality.

Eye symptoms

One of the characteristic features of Wilson’s disease is the buildup of copper in the eyes. It is seen externally as a rusty-brown ring around the iris and cornea. This is known as Kayser-Fleischer rings.

Picture of Kayser-Fleischer rings from Wikimedia Commons

Other symptoms

Copper toxicity has a wide range of effects on different organs and systems, not only the liver and central nervous system (CNS).

  • Low red blood cell and hemoglobin levels (anemia).
  • Clotting disorders.
  • Low platelet count (thrombocytopenia).
  • Low white blood cell count  (leukopenia).
  • Protein in urine (proteinuria).
  • High uric acid levels in the urine (uricosuria).
  • Joint inflammation (arthritis).
  • Early osteoporosis.

Causes of Copper Toxicity

Copper toxicity can be acquired when large amounts of copper are ingested or absorbed through the skin. Even using copper pots for cooking can be a source of copper toxicity. In Wilson’s disease, the cause of the copper toxicity is due to an inherited defect in the way the body handles copper. The body retains very little copper and copper that is absorbed from the gut is usually eliminated in bile. With Wilson’s disease there is a defect in the ATP7B gene which affects the liver’s ability to excrete copper in bile. Copper then overloads the liver and eventually spreads throughout the body.

Risk factors

Wilson’s disease is inherited. Mutated genes are passed on from the parent to the child. It is an autosomal recessive inherited disorder meaning that two defective copies of the gene are necessary for the disease to arise – one copy from each parent. However, the parents of children with Wilson’s disease may not have the disease themselves despite carrying the defective genes (carriers).

Tests and Diagnosis

Apart from the characteristic rusty-brown to golden-brown rings around the iris (Kayser-Fleischer rings), Wilson’s disease is difficult to diagnose solely on the signs and symptoms. Even Kayser-Fleischer rings are not overtly obvious and is only detected during an opthalmic examination. Overall Wilson’s disease is a rare condition and many other more common diseases have similar clinical features. Therefore various laboratory tests are needed.

Body Fluids

The blood and urine can be tested to detect the amount of copper within it. Other blood tests aid with assessing the liver function or the levels of the protein (ceruloplasmin) that carries copper in the blood. While copper levels in the blood are high with Wilson’s disease, the level of ceruloplasmin is generally low.

Liver biopsy

A small sample of liver tissue can be collected (biopsy) and sent for laboratory testing to assess the levels of copper within the liver tissue. Microscopic examination will also reveal the degree of liver damage.

Genes

Genetic testing to detect the defective genes that cause Wilson’s disease helps to confirm the diagnosis. It is also useful in screening the siblings of a patient with Wilson’s disease and possibly commence with early treatment in patients who have not as yet displayed notable symptoms of the disease.

Treatment of Wilson’s Disease

The main approach to treating Wilson’s disease is to remove the excess copper in the body (chelation therapy) and reduce the intake of copper through the diet.

Chelation Therapy

Chelating agents help remove the excess copper in the body by stimulating the organs to release copper into the bloodstream. Although copper cannot be excreted to a sufficient degree through the bile as it normally would, the kidney is able to filter out the copper and pass it out in the urine. Penicillamine is the main chelating agent used in Wilson’s disease. If this is not well tolerated then trientine hydrochloride is used as an alternative.

Chelating agents may need to be used for life but in low doses (maintenance therapy) once the excess copper is excreted from the system.

Zinc

Sometimes zinc acetate is prescribed when chelation therapy is not viable for long periods. Zinc acetate prevents accumulation of copper in the tissues and is an option, along with a low copper diet, in patients who cannot tolerate chelation therapy. It is important to note that zinc acetate should not be used with chelating agents.

Foods High in Copper

Copper is present in trace amounts in many foods. It is not possible to avoid dietary copper altogether. However, foods high in copper should be avoided or at the very least consumed in moderation. These foods that are abundant in copper include :

  • avocados
  • beans (dried)
  • cashew nuts
  • cocoa and chocolate
  • fruit (dried)
  • lentils (dried)
  • liver
  • mushrooms
  • nuts
  • peas (dried)
  • shellfish
  • vegetable juice or other vegetable concentrates

Vitamin and mineral supplements containing copper should be avoided.

References :

http://www.mayoclinic.com/health/wilsons-disease/DS00411

http://www.merckmanuals.com/professional/nutritional_disorders/mineral_deficiency_and_toxicity/copper.html

http://emedicine.medscape.com/article/183456-overview

http://digestive.niddk.nih.gov/ddiseases/pubs/wilson/

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