Wilson disease

What is Wilson disease

Wilson disease or hepatolenticular degeneration, is a rare inherited disorder (autosomal recessive disease) of copper metabolism that causes copper to accumulate in your liver, basal ganglia of the brain, kidneys, eyes and other vital organs, that can present with hepatic, neurologic, or psychiatric disturbances, or a combination of these, in individuals ranging from age three years to older than 50 years; symptoms vary among and within families 1).

Copper plays a key role in the development of healthy nerves, bones, collagen and the skin pigment melanin. You need a small amount of copper from food to stay healthy. Too much copper is poisonous. Normally, copper is absorbed from your food, and excess is excreted through a substance produced in your liver called bile (a digestive fluid). But in people with Wilson’s disease, copper isn’t eliminated properly and instead accumulates, possibly to a life-threatening level. When diagnosed early, Wilson’s disease is treatable, and many people with Wilson’s disease live normal lives. With early detection and proper treatment, you can enjoy good health.

Wilson disease is present at birth, but symptoms usually start between ages 5 and 35. It first attacks the liver, the central nervous system or both. The most characteristic sign is a rusty brown ring around the cornea of the eye. A physical exam and laboratory tests can diagnose it.

  • Liver disease includes recurrent jaundice, simple acute self-limited hepatitis-like illness, autoimmune-type hepatitis, fulminant hepatic failure, or chronic liver disease.
  • Neurologic presentations include movement disorders (tremors, poor coordination, loss of fine-motor control, chorea, choreoathetosis) or rigid dystonia (mask-like facies, rigidity, gait disturbance, pseudobulbar involvement).
  • Psychiatric disturbance includes depression, neurotic behaviors, disorganization of personality, and, occasionally, intellectual deterioration.
  • Kayser-Fleischer rings, frequently present, result from copper deposition in Descemet’s membrane of the cornea and reflect a high degree of copper storage in the body.

Treatment is with drugs to remove the extra copper from your body. You need to take medicine and follow a low-copper diet for the rest of your life. Don’t eat shellfish or liver, as these foods may contain high levels of copper. At the beginning of treatment, you’ll also need to avoid chocolate, mushrooms, and nuts. Have your drinking water checked for copper content and don’t take multivitamins that contain copper.

Figure 1. Kayser-Fleischer ring (the right eye showing a heavily pigmented red brown Kayser-Fleischer ring)

Kayser-Fleischer ring
[Source 2) ]

Is Wilson disease curable?

No. A abnormal gene cannot be corrected – it is present for life. Wilson’s disease a genetic disease that is inherited as an autosomal recessive trait. Wilson disease is caused by mutations in the ATP7B gene on chromosome 13, which codes for a membrane-bound copper transporting ATPase found mostly in the liver 3). ATP7B gene provides instructions for making a protein called copper-transporting ATPase 2, which plays a role in the transport of copper from the liver to other parts of the body. Copper is necessary for many cellular functions, but it is toxic when present in excessive amounts. The copper-transporting ATPase 2 protein is particularly important for the elimination of excess copper from the body. Mutations in the ATP7B gene prevent the transport protein from functioning properly. With a shortage of functional protein, excess copper is not removed from the body. As a result, copper accumulates to toxic levels that can damage tissues and organs, particularly the liver and brain.

The ATP7B mutations that cause Wilson disease are inherited, meaning they are passed from parent to child. These mutations are autosomal recessive , meaning that a person must inherit two ATP7B genes with mutations, one from each parent, to have Wilson disease. People who have one ATP7B gene without a mutation and one ATP7B gene with a mutation do not have Wilson disease, but they are carriers of the disease.

People can inherent Wilson disease if both parents are carriers who don’t have the disease. Figure 2 below shows the chance of inheriting Wilson disease from parents who are carriers.

People with specific questions about genetic risks or genetic testing for themselves or family members should speak with a genetics professional.

Resources for locating a genetics professional in your community are available online:

How common is Wilson disease?

Experts are still studying how common Wilson disease is. Older studies suggested that about 1 in 30,000 people have Wilson disease 4). These studies were conducted before researchers discovered the gene mutations that cause Wilson disease.

Newer studies of people’s genes suggest that Wilson disease may be more common. A study in the United Kingdom found that about 1 in 7,000 people have gene mutations that cause Wilson disease 5).

Experts aren’t sure why gene studies suggest that Wilson disease is more common than previously thought. One reason might be that some people with Wilson disease are not diagnosed. Another reason might be that some people have gene mutations for Wilson disease but don’t develop the disease.

Who is more likely to have Wilson disease?

People have a higher chance of having Wilson disease if they have a family history of Wilson disease, especially if a first-degree relative—a parent, sibling, or child—has the disease.

People who have Wilson disease typically develop symptoms when they are between ages 5 and 40 6). However, some people develop symptoms at younger or older ages. Doctors have found the first symptoms of Wilson disease in infants as young as 9 months and in adults older than 70 years 7).

Wilson disease causes

Wilson disease is caused by mutations in the ATP7B gene on chromosome 13, which codes for a membrane-bound copper transporting ATPase found mostly in the liver 8). ATP7B gene provides instructions for making a protein called copper-transporting ATPase 2, which plays a role in the transport of copper from the liver to other parts of the body. Copper is necessary for many cellular functions, but it is toxic when present in excessive amounts. The copper-transporting ATPase 2 protein is particularly important for the elimination of excess copper from the body. Mutations in the ATP7B gene prevent the transport protein from functioning properly. With a shortage of functional protein, excess copper is not removed from the body. As a result, copper accumulates to toxic levels that can damage tissues and organs, particularly the liver and brain.

Normally, the liver releases extra copper into bile. Bile carries the copper, along with other toxins and waste products, out of the body through the digestive tract. In Wilson disease, the liver releases less copper into bile, and extra copper stays in the body.

Research indicates that a normal variation in the PRNP gene may modify the course of Wilson disease. The PRNP gene provides instructions for making prion protein, which is active in the brain and other tissues and appears to be involved in transporting copper. Studies have focused on the effects of a PRNP gene variation that affects position 129 of the prion protein. At this position, people can have either the protein building block (amino acid) methionine or the amino acid valine. Among people who have mutations in the ATP7B gene, it appears that having methionine instead of valine at position 129 of the prion protein is associated with delayed onset of symptoms and an increased occurrence of neurological symptoms, particularly tremors. Larger studies are needed, however, before the effects of this PRNP gene variation on Wilson disease can be established.

Wilson disease inheritance pattern

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

It is rare to see any history of autosomal recessive conditions within a family because if someone is a carrier for one of these conditions, they would have to have a child with someone who is also a carrier for the same condition. Autosomal recessive conditions are individually pretty rare, so the chance that you and your partner are carriers for the same recessive genetic condition are likely low. Even if both partners are a carrier for the same condition, there is only a 25% chance that they will both pass down the non-working copy of the gene to the baby, thus causing a genetic condition. This chance is the same with each pregnancy, no matter how many children they have with or without the condition.

  • If both partners are carriers of the same abnormal gene, they may pass on either their normal gene or their abnormal gene to their child. This occurs randomly.
  • Each child of parents who both carry the same abnormal gene therefore has a 25% (1 in 4) chance of inheriting a abnormal gene from both parents and being affected by the condition.
  • This also means that there is a 75% ( 3 in 4) chance that a child will not be affected by the condition. This chance remains the same in every pregnancy and is the same for boys or girls.
  • There is also a 50% (2 in 4) chance that the child will inherit just one copy of the abnormal gene from a parent. If this happens, then they will be healthy carriers like their parents.
  • Lastly, there is a 25% (1 in 4) chance that the child will inherit both normal copies of the gene. In this case the child will not have the condition, and will not be a carrier.

These possible outcomes occur randomly. The chance remains the same in every pregnancy and is the same for boys and girls.

Figure 2 illustrates autosomal recessive inheritance. The example below shows what happens when both dad and mum is a carrier of the abnormal gene, there is only a 25% chance that they will both pass down the abnormal gene to the baby, thus causing a genetic condition.

Figure 2. Wilson disease autosomal recessive inheritance pattern

Wilson disease autosomal recessive inheritance pattern

Can I prevent Wilson disease?

No, you can’t prevent Wilson disease. If you have a first-degree relative—a parent, sibling, or child—with Wilson disease, talk with your doctor about testing you and other family members for Wilson disease. A doctor may be able to diagnose and begin treating Wilson disease before symptoms appear. Early diagnosis and treatment can reduce or prevent organ damage.

Wilson disease signs and symptoms

The symptoms of Wilson disease vary. Wilson disease is present at birth, but the symptoms don’t appear until the copper builds up in the liver, the brain, or other organs.

Some people do not have symptoms of Wilson disease before they are diagnosed with the disease and treated. If you do have symptoms, the symptoms may be related to your liver, nervous system and mental health, eyes, or other organs.

Liver symptoms

People with Wilson disease may develop symptoms of hepatitis, or inflammation of the liver. In some cases, people develop these symptoms when they have acute liver failure. These symptoms may include:

  • feeling tired
  • nausea and vomiting
  • poor appetite
  • pain over the liver, in the upper part of the abdomen
  • darkening of the color of urine
  • lightening of the color of stool
  • yellowish tint to the whites of the eyes and skin, called jaundice

Some people with Wilson disease have symptoms only if they develop chronic liver disease and complications from cirrhosis. These symptoms may include:

  • feeling tired or weak
  • losing weight without trying
  • bloating from a buildup of fluid in the abdomen, called ascites
  • swelling of the lower legs, ankles, or feet, called edema
  • itchy skin
  • jaundice

Nervous system and mental health symptoms

People with Wilson disease may develop nervous system and mental health symptoms after copper builds up in their body. These symptoms are more common in adults but sometimes occur in children. Nervous system symptoms may include:

  • problems with speech, swallowing, or physical coordination
  • stiff muscles
  • tremors or uncontrolled movements

Mental health symptoms may include:

  • anxiety
  • changes in mood, personality, or behavior
  • depression
  • psychosis

Eye symptoms

Many people with Wilson disease have Kayser-Fleischer rings, which are greenish, gold, or brownish rings around the edge of the corneas . A buildup of copper in the eyes causes Kayser-Fleischer rings. A doctor can see these rings during a special eye exam called a slit-lamp exam .

Among people who have nervous system symptoms of Wilson disease, more than 9 out of 10 have Kayser-Fleischer rings. However, among people who have only liver symptoms, 5 or 6 out of 10 have Kayser-Fleischer rings 9).

Other symptoms and health problems

Wilson disease can affect other parts of your body and cause symptoms or health problems, including:

  • a type of anemia called hemolytic anemia
  • bone and joint problems, such as arthritis or osteoporosis
  • heart problems, such as cardiomyopathy
  • kidney problems, such as renal tubular acidosis and kidney stones

Wilson disease liver

Wilson disease may lead to liver complications, but early diagnosis and treatment can lower your chances of developing them.

Acute liver failure

Wilson disease can cause acute liver failure, a condition in which your liver fails rapidly without warning. About 5 percent of people with Wilson disease have acute liver failure when they are first diagnosed 10). Acute liver failure most often requires a liver transplant.

Acute kidney failure and a type of anemia called hemolytic anemia often occur in people who have acute liver failure due to Wilson disease.

Cirrhosis

In cirrhosis, scar tissue replaces healthy liver tissue and prevents your liver from working normally. Scar tissue also partly blocks the flow of blood through the liver. As cirrhosis gets worse, the liver begins to fail.

Among people who are diagnosed with Wilson disease, 35 to 45 percent already have cirrhosis at the time of diagnosis 11)

Cirrhosis increases your chance of getting liver cancer. However, doctors have found that liver cancer is less common in people who have cirrhosis due to Wilson disease than in people who have cirrhosis due to other causes.

Liver failure

Cirrhosis may eventually lead to liver failure. With liver failure, your liver is badly damaged and stops working. Liver failure is also called end-stage liver disease. This condition may require a liver transplant.

Wilson disease complications

Untreated, Wilson’s disease can be fatal. Serious complications include:

  • Scarring of the liver (cirrhosis). As liver cells try to make repairs to damage done by excess copper, scar tissue forms in the liver, making it more difficult for the liver to function.
  • Liver failure. This can occur suddenly (acute liver failure), or it can develop slowly over years. A liver transplant might be a treatment option.
  • Persistent neurological problems. Tremors, involuntary muscle movements, clumsy gait and speech difficulties usually improve with treatment for Wilson’s disease. However, some people have persistent neurological difficulty despite treatment.
  • Kidney problems. Wilson’s disease can damage the kidneys, leading to problems such as kidney stones and an abnormal number of amino acids excreted in the urine.
  • Psychological problems. These might include personality changes, depression, irritability, bipolar disorder or psychosis.
  • Blood problems. These might include destruction of red blood cells (hemolysis) leading to anemia and jaundice.

Wilson disease diagnosis

Doctors diagnose Wilson disease based on your medical and family history, a physical exam, an eye exam, and tests.
Medical and family history

Your doctor will ask about your family and personal medical history of Wilson disease and other conditions that could be causing your symptoms.

Physical exam

During a physical exam, your doctor will check for signs of liver damage such as:

  • changes in the skin
  • enlargement of the liver or spleen
  • tenderness or swelling in the abdomen
  • swelling in the lower legs, feet, or ankles, called edema
  • yellowish color of the whites of the eyes

Eye exam

During a slit-lamp exam , a doctor will use a special light to look for Kayser-Fleischer rings in your eyes.

Doctors typically use blood tests and a 24-hour urine collection test to diagnose Wilson disease. Doctors may also use a liver biopsy and imaging tests.

Blood tests

For a blood test, a health care professional will take a blood sample from you and send the sample to a lab.

Your doctor may order one or more blood tests, including tests that check amounts of:

  • Ceruloplasmin, a protein that carries copper in the bloodstream. People with Wilson disease often have low ceruloplasmin levels, but not always.
  • Copper. People with Wilson disease may have lower than normal blood copper levels. Acute liver failure due to Wilson disease may cause high blood copper levels.
  • Liver enzymes alanine transaminase (ALT) and aspartate transaminase (AST). People with Wilson disease may have abnormal ALT and AST levels.
  • Red blood cells to look for signs of anemia.
  • Genetic testing. A blood test can identify the genetic mutations that cause Wilson’s disease. Knowing the mutations in your family allows doctors to screen siblings and begin treatment before symptoms arise.

Doctors may order a blood test to check for the gene mutations that cause Wilson disease if other medical tests don’t confirm or rule out a diagnosis of the disease.

24-hour urine collection test

For 24 hours, you will collect your urine at home in a special container that is copper-free, provided by a health care professional. A health care professional will send the urine to a lab, which will check the amount of copper in your urine. Copper levels in the urine are often higher than normal in people who have Wilson disease.

Liver biopsy

If the results of blood and urine tests don’t confirm or rule out a diagnosis of Wilson disease, your doctor may order a liver biopsy. During a liver biopsy, a doctor will take small pieces of tissue from your liver. A pathologist will examine the tissue under a microscope to look for features of specific liver diseases, such as Wilson disease, and check for liver damage and cirrhosis. A piece of liver tissue will be sent to a lab, which will check the amount of copper in the tissue.

Imaging tests

In people who have nervous system symptoms, doctors may use imaging tests to check for signs of Wilson disease or other conditions in the brain. Doctors may use

  • magnetic resonance imaging (MRI) , which uses radio waves and magnets to produce detailed images of organs and soft tissues without using x-rays
  • computed tomography (CT) scan , which uses a combination of x-rays and computer technology to create images

Wilson disease treatment

Your doctor might recommend medications called chelating agents, which bind copper and then prompt your organs to release the copper into your bloodstream. The copper is then filtered by your kidneys and released into your urine. And zinc, which prevents the intestines from absorbing copper.

Treatment then focuses on preventing copper from building up again. For severe liver damage, a liver transplant might be necessary.

In many cases, treatment can improve or prevent symptoms and organ damage. Doctors may also recommend changing your diet to avoid foods that are high in copper.

People who have Wilson disease need lifelong treatment. Stopping treatment may cause acute liver failure. Doctors regularly perform blood and urine tests to check how the treatment is working.

Chelating agents

Penicillamine (Cupramine, Depen) and trientine (Syprine) are two chelating agents used to treat Wilson disease. These medicines remove copper from the body.

Penicillamine is more likely to cause side effects than trientine. Side effects of penicillamine may include fever, rash, kidney problems, or bone marrow problems. Penicillamine may also reduce the activity of vitamin B6, and doctors may recommend taking a vitamin B6 supplement along with penicillamine. In some cases, when people with nervous system symptoms begin taking chelating agents, their symptoms get worse.

When treatment begins, doctors gradually increase the dose of chelating agents. People take higher doses of chelating agents until the extra copper in the body has been removed. When Wilson disease symptoms have improved and tests show that copper is at safe levels, doctors may prescribe lower doses of chelating agents as maintenance treatment. Lifelong maintenance treatment prevents copper from building up again.

Chelating agents may interfere with wound healing, and doctors may prescribe a lower dose of chelating agents for people who are planning to have surgery.

Zinc

Zinc acetate (Galzin) prevents the intestines from absorbing copper from the food you eat. Doctors may prescribe zinc as a maintenance treatment, after chelating agents (penicillamine or trientine) have removed extra copper from the body. Doctors may also prescribe zinc for people who have Wilson disease but do not yet have symptoms. Zinc acetate might be used as primary therapy if you can’t take penicillamine or trientine.  The most common side effect of zinc is stomach upset.

Surgery

If your liver damage is severe, you might need a liver transplant. During a liver transplant, a surgeon removes your diseased liver and replaces it with a healthy liver from a donor.

Most transplanted livers come from donors who have died. But in some cases a liver can come from a living donor, such as a family member. In that case, the surgeon removes your diseased liver and replaces it with a portion of the donor’s liver.

How do doctors treat Wilson disease in women who are pregnant?

Pregnant women should continue treatment for Wilson disease throughout pregnancy. Doctors may prescribe a lower dose of chelating agents for women who are pregnant. Since the fetus needs a small amount of copper, lowering the dose may keep copper at safe levels without removing too much copper.

In most cases, doctors recommend that women continue to take the full dose of zinc during pregnancy. Experts recommend that women with Wilson disease do not breastfeed if they are taking chelating agents. Penicillamine is present in breast milk and can be harmful to a baby. Experts have little information about the safety of trientine and zinc in breast milk.

How do doctors treat the complications of Wilson disease?

If Wilson disease leads to cirrhosis, doctors can treat health problems and complications related to cirrhosis with medicines, surgery, and other medical procedures.

If Wilson disease causes acute liver failure or liver failure due to cirrhosis, you may need a liver transplant. A liver transplant cures Wilson disease in most cases.

Wilson disease diet

If you have Wilson’s disease, your doctor will likely recommend that you limit the amount of copper you consume in your diet. You might also want to have your tap water’s copper levels tested if you have copper pipes in your home. And be sure to avoid multivitamins that contain copper.

When you start treatment for Wilson disease, your doctor may recommend avoiding foods that are high in copper, such as:

  • chocolate
  • liver
  • mushrooms
  • nuts
  • shellfish

After treatments have lowered your copper levels and you begin maintenance treatment, talk with your doctor about whether you can safely eat moderate amounts of these foods.

If your tap water comes from a well or runs through copper pipes, have the copper levels in your water checked. Water sitting in copper pipes may pick up copper. Run the water to flush the pipes before you drink the water or use it for cooking. You may need to use a water filter to remove copper from your tap water.

For safety reasons, talk with your doctor before using dietary supplements , such as vitamins, or any complementary or alternative medicines or medical practices. Some dietary supplements may contain copper.

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