About Wilson’s Disease and Laboratory Testing

Wilson’s disease is caused by abnormal copper metabolism. It leads to excessive storage of copper in the body, especially in the brain and liver area. It is an inherited genetic disorder. Copper is an essential mineral required by the body, and the primary source of copper is diet. Enzymes in the body use it for various functions. These enzymes play an important role in various things, including iron metabolism regulation, production of energy at cellular level, connective tissue generation, and melanin production as well as in the functioning of the brain and nervous system.

Intestines absorb copper where a carrier protein binds with it and transports it to the liver. Some of the copper is stored in the liver, and the rest binds to a protein known as apoceruloplasmin, which is used to produce an enzyme called ceruloplasmin. Almost 95% of the copper found in the blood is bound to ceruloplasmin, whereas the remaining is bound to various other proteins, including albumin. Copper in a free state is present only in a very small amount in the blood. Typically, any excess copper is removed from the body as it is excreted into the bile and goes out through the stool. Kidneys are also responsible for removing some of the copper through urine.

Wilson’s disease is described as an autosomal recessive disorder. Simply put, it means that this disorder is caused due to two altered gene copies where one gene each is inherited from each parent. An individual that carries only one copy becomes a carrier, and they can pass on this mutation onto the children but do not show any symptoms of this disease.

In Wilson’s disease, the gene mutation is at the ATP7B gene. The human body needs this gene for binding copper to develop ceruloplasmin molecule and for excretion of excessive copper into the bile. When these gene copies are altered (homozygous), it causes excessive copper in the lover, which leads to a lower level of ceruloplasmin in the bloodstream. Once the copper storage reaches toxic levels, it leads to tissue and cell damage in the liver. It also gets in the blood and leads to the formation of deposits in various other organs, including the kidneys and the brain. Concentration levels of free copper keep increasing in the blood, and that may lead to oxidative damage to cells. Individuals affected by this disease typically display symptoms and signs associated with neurological damage, liver dysfunction, or both. The severity of this disease partly depends on the presence of gene mutations but also varies from one person to another.

It is estimated that in the United States, around 1 in 30,000 people suffer from Wilson’s disease, whereas the carriers are estimated to be as high as 1 in 90. ATP7B gene is currently known to have 40 normal variants, and more than 260 mutations of this gene are associated with the Wilson’s disease. While the number of commonly occurring, mutations is restricted to a few, but the prevalence of these mutations varies with ethnicity all around the world. People suffering from Wilson’s disease might carry two copies of one genetic mutation or two completely different genetic mutations.

Symptoms and Signs

An individual suffering from Wilson’s disease with liver involvement starts to develop symptoms of the disease during their early childhood. On the other hand, people with brain involvement usually start developing psychiatric and neurologic symptoms in their early 20s or teens. However, the age range for both these can be as low as three years and more than 50 years.

Copper deposits in the liver might cause chronic, acute, and progressive hepatitis and cirrhosis. The symptoms and signs of these conditions include:

Abdominal pain, fatigue, nausea, jaundice causing yellowing of the whites of the eyes and the skin, and abdomen fluid accumulation known as ascites.

Individuals with brain involvement display a wide range of symptoms that might include:

  • Tremors
  • Stiffening of face muscles
  • Abnormal eye movements
  • Persistent muscle contractions causing repetitive movements and limb twitching (dystonia)
  • Difficulty in swallowing
  • Speaking and walking
  • Altered gait

People suffering from it might also experience certain behavioral changes, including obsessive behavior, shortened attention span, aggression, impulsiveness, paranoia, and depression.

Around 50% of individuals with liver involvement and around 90% of people with brain involvement typically also have Kayser-Fleischer rings. It is the name given to the copper deposit rings around the cornea in the eye, and these can be detected with an eye exam known as slit-lamp examination. Some of the people suffering from Wilson’s disease might also experience joint pain, easy bruising, anemia as well as kidney dysfunction.

If not treated, this disease becomes progressively worse, and it is eventually fatal. People suffering from this disease can live a relatively normal life when it is detected and treated at the early stages. The neurologic and liver damage caused by excessive copper deposits prior to treatment is often permanent, but it might improve with treatment.

Laboratory Testing

Tests are done to diagnose the existence of Wilson’s disease and determine its severity. It is also used to distinguish individuals who are carriers from those who have the disease, and it helps in ruling out any other cause of neurological and liver dysfunction. Testing also helps in monitoring the effectiveness of treatment. Testing can also be used for the identification of family members who are carriers or pre-symptomatic. Sometimes, it is also used for prenatal evaluation.

Here is a list of the laboratory tests that are used for checking Wilson’s disease. It is recommended to repeat the tests in case of any abnormal results. Test results of carriers might overlap with test results of individuals with Wilson’s disease who are currently pre-symptomatic. In addition to Wilson’s disease, excessive copper storage and increased levels of copper in the blood are also caused by some other diseases. It might be difficult to distinguish acute Wilson’s disease from other types of hepatitis.

Laboratory testing may include:

Ceruloplasmin – This test is done for the diagnosis of Wilson’s disease. Wilson’s disease sufferers usually have lower ceruloplasmin levels, but around 5% of people with neurological symptoms display completely normal ceruloplasmin levels, whereas around 40% of individuals with liver involvement also display normal ceruloplasmin levels.

Total Serum Copper Test – This test is also helpful for diagnosis. Lower than normal levels of serum copper is an indication of the presence of this disease.

Free Serum Copper – This refers to copper that is not bound to ceruloplasmin. It is useful for diagnosis as well as continuous monitoring. Individuals with this disease usually have higher levels of free copper.

24 Hour Urine Copper – This test is used for diagnosis as well as for monitoring. Individuals with the disease have higher levels of urine copper.

Hepatic Copper – This test is used for diagnosis. In this test, a liver tissue biopsy is done. Copper deposits in the liver may not be evenly distributed.

Genetic Testing – As the name suggests, it’s a special test that is not available widely, and only a limited number of research and reference laboratories perform this test. It is useful for the diagnosis of Wilson’s disease and for the identification of carriers and mutations. This test can also be used for establishing disease severity to a certain level as per the presence of certain mutations, but testing cannot be used for the determination of complications, organ involvement, or severity of the disease for an individual. The severity of the disease varies significantly, even between various family members who carry the same mutations.

ATP7B Gene – In this case, panels of the most common mutations in an ethnic population or in a region may be performed. In case a person with Wilson’s disease carries certain mutations, other family members can also be tested for those mutations.

Gene Sequencing – It can be used for checking the entire gene for various mutations, and it is typically the most thorough testing.

Linkage Analysis – In this test, blood samples are required from siblings, parents, as well as the affected family member. In this case, genetic information close to the ATP7B gene is compared.

Some other tests might also be performed for evaluation of blood cell status as well as organ functionality, and some of these tests may include liver panel, complete blood count, and comprehensive metabolic panel.