Wilson's disease
medical conditions

Wilson's disease

Explore the available health information, treatment context, and integrative evidence for Wilson's disease.

Background
  • Wilson's disease is a rare inherited disorder that causes copper to accumulate in the liver, brain, and other vital organs. In individuals with Wilson's disease, copper is not eliminated properly and instead accumulates, possibly to a life-threatening level. Left untreated, Wilson's disease is fatal. When diagnosed early, Wilson's disease is easily treated, and many people with the disorder live normal lives. Copper can accumulate in and damage the liver.
  • Wilson's disease is listed as a "rare disease" by the Office of Rare Diseases (ORD) of the National Institutes of Health (NIH). This means that Wilson's disease affects less than 200,000 people in the U.S. population.
  • Copper is necessary for the growth, development, and maintenance of bone, connective tissue, brain, heart, and many other body organs. Copper is involved in the formation of red blood cells, the absorption and utilization of iron, and the synthesis and release of proteins and enzymes. These enzymes in turn produce cellular energy and regulate nerve transmission, blood clotting, and oxygen transport. Copper helps stimulate the immune system to fight infections, repair injured tissues, and to promote healing. Copper also acts as an antioxidant, helping to neutralize "free-radicals" that can cause severe damage to cells. Copper is involved in the functioning of the nervous system, in maintaining the balance of other useful metals in the body such as zinc and molybdenum, and possibly other body functions. Copper is a natural ingredient in many foods. It is typically present in mineral rich foods like vegetables (potatoes), legumes (beans and peas), nuts (peanuts and pecans), grains (wheat and rye), fruits (peach and raisin), and chocolate.
  • If an individual is supplementing their diet with zinc, it is especially important to take copper supplements; zinc interferes with the body's ability to absorb copper. Most multiple vitamins contain zinc and copper, but some do not include copper. For most individuals, 1-2 milligrams of copper daily is sufficient. Individuals with poor diets, often including the elderly who may not able to care for themselves and people in places where it is difficult to get proper nutrition, may not take in enough copper to meet the body's needs. In addition, a small number of individuals in rare cases have genetic sensitivities that make it difficult for them to either absorb copper when the body needs it (Menke's disease), or get rid of it when the body does not need it (Wilson's disease).
  • Because copper first accumulates in the liver, most individuals with Wilson's disease initially have signs of liver damage, including abdominal pain and yellowing of the skin and whites of the eyes (jaundice).
  • The liver is the largest solid organ in the body and is essential in keeping the body functioning properly. The liver is located in the upper right-hand side of the abdomen. It performs many functions in the body, including processing the body's nutrients, manufacturing bile to help digest fats, synthesizing many important proteins, regulating blood clotting, and breaking down potentially toxic substances into harmless ones that the body can use or excrete. Inflammation may (in severe cases) interfere with these processes and allow potentially toxic substances to accumulate. Liver cells, called hepatocytes, become damaged and cannot filter toxins from the blood as effectively. These toxins build up, causing further liver damage.
  • The liver is able to regenerate or repair up to two-thirds of injured tissue, including hepatocytes (liver cells), biliary epithelial cells, and endothelial cells. Healthy cells take over the function of damaged cells, either indefinitely or until the damage is repaired.
Risk Factors and Causes
  • A number of foods, especially liver, shellfish, nuts, avocados, and mushrooms, contain abundant amounts of copper. When individuals eat these foods, the copper is absorbed by the small intestine, bound to circulating proteins in the blood, and delivered to the liver. Any copper the body does not use is carried away by bile, a substance produced in the liver that helps digest fats.
  • In Wilson's disease, a genetic mutation affects ATP7B, a protein that helps transport copper into the bile. ATP7B is also involved in incorporating copper into ceruloplasmin, a protein that carries the mineral through the bloodstream. The defects in the ATP7B gene mean that copper is not eliminated properly, and instead builds up in the liver, where it can cause serious and sometimes irreversible damage. In time, excess copper spills out of the liver and begins accumulating in and harming other organs, especially the brain, eyes, kidneys, and joints.
  • Although some ATP7B mutations occur spontaneously, most are passed from one generation to the next. These individuals are considered carriers of Wilson's disease. Wilson's disease is inherited as an autosomal recessive trait, which means that in order to develop the disease, individuals must inherit two copies of the defective gene, one from each parent. If an individual receives only one abnormal gene, they will not become ill themselves, but are considered a carrier and can pass the gene to their children. The incidence of Wilson's disease is rare, but as many as one in 100 people have one defective ATP7B gene.

Risk Factors

  • If both parents are carriers of one abnormal Wilson's gene, they have a 25% chance of having a child with two normal genes, a 50% chance of having a child who also is a carrier, and a 25% chance of having a child with two recessive genes who will develop the disease. These chances are the same in each pregnancy.
  • Healthcare professionals recommend that all children and siblings of people with Wilson's be tested for the disease. A doctor may want to test the individual if they had a parent or grandparent who died of unexplained liver disease. Although Wilson's disease is found among all nationalities, it is more common among people of Eastern European and Southern Italian descent due in part to genetics.
Signs and Symptoms
  • In people with Wilson's disease, copper begins accumulating in the liver immediately after birth, but signs and symptoms rarely occur before the age of five or six and sometimes not until ages 40-50.
  • The most characteristic symptom of Wilson's disease is the Kayser-Fleisher ring - a rusty brown ring around the cornea of the eye that can best be viewed using an ophthalmologist's (eye doctor) slit lamp. The primary consequence for most of those with Wilson's disease is liver disease, appearing in late childhood or early adolescence as acute hepatitis, liver failure, or progressive chronic liver disease in the form of chronic active hepatitis or cirrhosis of the liver.
  • The main symptom of liver disease is jaundice. Jaundice is the yellowish staining of the skin and sclerae (the whites of the eyes) that is caused by high levels of the chemical bilirubin in blood. Bilirubin is a brownish yellow substance found in bile. It is produced when the liver breaks down old red blood cells. Bilirubin is then removed from the body through the stool (feces) and gives stool its normal brown color. The color of the skin and sclerae vary depending on the level of bilirubin. When the bilirubin level is mildly elevated, they are yellowish. When the bilirubin level is high, they tend to be brown. Icterus is the term for yellowing of the sclerae.
  • Other signs and symptoms of liver toxicity include: abdominal pain and swelling; chronic itchy skin; dark urine color; pale stool color; joint pain; bloody or tar-colored stool; chronic fatigue; nausea; loss of appetite; fatty liver, fibrosis, cirrhosis, and liver failure (called fulminant liver failure).
  • In others, the first symptoms occur later in adulthood and most commonly include slurred speech (dysarthria), difficulty swallowing (dysphagia), and drooling. Other symptoms may include tremor of the head, arms, or legs; impaired muscle tone, and sustained muscle contractions that produce abnormal postures, twisting, and repetitive movements (dystonia); and slowness of movements (bradykinesia). Individuals may also experience clumsiness (ataxia) and loss of fine motor skills.
  • A third of those with Wilson's disease will also experience psychiatric symptoms such as an abrupt personality change, bizarre and inappropriate behavior, depression accompanied by suicidal thoughts, neurosis, or psychosis.
Diagnosis
  • History and physical :
  • If Wilson's disease is suspected, the doctor will take a complete history and physical. History includes family history, past conditions, surgeries, and medications. During a physical, the doctor will look for signs and symptoms of liver toxicity. These signs may include jaundice (yellow skin), abdominal pain, vomiting, and ascites (fluid in the abdomen). On physical examination, a doctor looks for liver tenderness and enlargement using palpation. Palpation is a method of examination in which the examiner uses their hands to feel the liver and to determine its size, shape, and firmness.
  • Blood tests :
  • A combination of blood tests will be used to determine if Wilson's disease is present.
  • Genetic tests: Because more than 200 mutations of ATP7B exist, researchers have not been able to develop a simple genetic test that can help screen or diagnose Wilson's disease in the general population. However, a procedure called haplotype analysis can identify people within a single family who may have inherited the disorder.
  • Copper levels: Levels of copper in the blood will be determined with a blood test.
  • Albumin: Serum albumin levels measure the main protein made by the liver and reveal how well the liver is making this protein.
  • Bilirubin: Bilirubin is a waste product made from old blood cells; it is a yellow compound that causes jaundice and dark urine when present in increased amounts. Tests for bilirubin levels help determine if the liver is functioning appropriately.
  • Liver enzymes: Another blood test may be performed to check for elevated levels of liver enzymes, such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST). These enzymes leak into the bloodstream when liver cells are injured. Also, alkaline phosphatase (ALP) levels may be checked. ALP is an enzyme related to the bile ducts. ALP levels are often increased when they are blocked.
  • Total protein: Total protein tests measure albumin and all other proteins in blood, including antibodies made to help fight off infections.
  • Diagnostic tests :
  • In diagnosing liver toxicity, the doctor may use images of the liver obtained by an ultrasound test, a computerized tomography (CT) scan, or a magnetic resonance imaging (MRI) scan. These diagnostic tests can determine if the presence of liver damage exists.
  • Liver biopsy: A liver biopsy may be performed to determine the extent of liver damage and to determine the best treatment option for the patient. During the procedure, a needle is inserted into the liver and a small tissue sample is removed. The tissue is then analyzed under a microscope in a laboratory.
  • Liver scan: A liver scan is a diagnostic procedure to evaluate the liver for suspected disease. A harmless amount of a radioactive substance that concentrates in the liver is injected intravenously (IV or into the veins) and the image of its distribution in the liver is analyzed to diagnose abnormalities. Women who are pregnant or breastfeeding should not have this test.
Complications
  • Wilson's disease can increase the risk of bone fractures (osteoporosis) of serious infections and may greatly impair kidney function. But one of the most serious complications is liver damage, which may be so severe that only a liver transplant can prolong life. If not treated, Wilson's disease is fatal.
  • Fatty liver: Fatty liver, also known as steatorrhoeic hepatosis, is the build-up of excess fat in the liver cells. It is normal for the liver to contain some fat. But, if fat accounts for more than 10% of the liver's weight, the individual has fatty liver. In countries where obesity is becoming a serious health issue, fatty liver is predicted to affect approximately 25% of the general population.
  • Inflammation: Hepatitis is an inflammation of the liver that can be caused by viruses, chemicals, drugs, alcohol, inherited diseases, or the individual's own immune system. This inflammation can be acute (short-term), flaring up and then resolving within a few weeks to months, or chronic (long-term), lasting many years. Chronic hepatitis may simmer for 20 years or more before causing significant symptoms related to progressive liver damage such as cirrhosis (scarring and loss of function), liver cancer, or death.
  • Fatty liver may cause no damage, but sometimes the excess fat leads to inflammation of the liver. This inflammatory condition, called steatohepatitis, does cause liver damage. Sometimes, inflammation from a fatty liver is linked to alcohol abuse, known as alcoholic steatohepatitis. Otherwise, the condition is called nonalcoholic steatohepatitis, or NASH. NASH is very common in overweight persons over the age of 30. The liver is invaded by an excessive amount of fat and a normal healthy liver tissue is partially replaced with areas of unhealthy fats. In such a liver, the liver cells and the spaces in the liver are filled with fat so the liver becomes slightly enlarged and heavier.
  • In the early stage of any liver disease, the liver may become inflamed, tender, and enlarged. However, an inflamed liver may cause no discomfort at all.
  • Fibrosis: If left untreated, the inflamed liver will start to scar. As excess scar tissue (a type of fibrous tissue) grows, it replaces healthy liver tissue. This process is called fibrosis. Scar tissue cannot function as healthy liver tissue can. Scar tissue may keep blood from flowing through the liver. The healthy part of the liver now has to work harder. Scar tissue can block blood flow through a blood vessel due to its inability to constrict and expand as a normal blood vessel tissue does.
  • Cirrhosis: If left untreated, the liver may become so seriously scarred that it can no longer heal itself. At this stage, the damage cannot be reversed. This stage, when the damage cannot be reversed, is called cirrhosis. Cirrhosis can lead to a number of complications, including liver cancer. In some individuals, the symptoms of cirrhosis may be the first signs of liver disease. Symptoms of cirrhosis include: easy bruising; fluid buildup in the legs and/or abdomen; the skin and eyes may take on a yellow color, a condition called jaundice; the skin may itch intensely; blood may back up in vessels leading to the liver because of blockage - these blood vessels may burst; increased sensitivity to medications and their side effects; insulin resistance and type-2 diabetes; or buildup of toxins in the brain, causing problems with concentration, memory, sleeping, or other mental functions.
  • Liver failure: Liver failure means that the liver is losing or has lost all of its function. It is a life-threatening condition that demands urgent medical care. The first symptoms of liver failure are often nausea, loss of appetite, fatigue, and diarrhea. Because these symptoms can have any number of causes, it may be hard to tell that the liver is failing. Since glucose (sugar) is made in the liver, liver damage due to Wilson's disease can lead to blood sugar regulation problems, including type 2 diabetes.
  • As liver failure progresses, the symptoms become more serious. The individual may become confused and disoriented, and extremely sleepy. There is a risk of coma and death. Immediate treatment is needed. The medical team will try to save whatever part of the liver that still works. The liver can function with partial damage. However, when the damage becomes severe enough, complete liver failure is possible. The only option then may be a liver transplant.
  • Nervous system damage: Many functions of the liver have a direct influence on the nervous system, particularly the brain. The liver cells convert glycogen (complex sugar) into glucose that, besides oxygen and water, is the major nutrient for the nervous system. Glucose provides most of its energy requirements. The brain, although it constitutes only one fiftieth of the body weight, contains about one fifth of the total blood volume in the body. The liver also forms the plasma proteins and most of the blood clotting factors from the available amino acids.
  • Damage to the central nervous system may include uncontrollable repetitive movements, stiffness, speech problems, and the loss of the ability to function at work or at home. Coordination may also be affected, resulting in clumsiness and awkwardness in mobility.
  • Psychological problems: The most common psychological complications associated with Wilson's disease include mood swings, depression, inappropriate behavior, agitation, loss of memory, and confusion.
Treatment
  • The goal in treating Wilson's disease is to remove excess copper and to prevent the mineral from building up again. Once treatment starts, the disease stops progressing and many signs and symptoms improve. But some problems may take time to resolve and others, especially liver scarring and certain neurological or psychiatric symptoms, may not be completely reversible. Untreated Wilson's disease is always fatal.
  • Doctors usually prescribe one of three medications to help treat Wilson's disease, including penicillamine, trientine, and zinc.
  • Penicillamine (Cuprimine®): Penicillamine (Cuprimine®) was the first copper chelating drug approved for use in Wilson's disease. Penicillamine works by binding to copper and creating a water-soluble complex that's excreted in the urine. Although it is an effective treatment, penicillamine can cause serious side effects, including skin problems, bone marrow suppression, worsening of neurological symptoms, and birth defects. Penicillamine should not be taken by individuals with kidney disease or those who are allergic to penicillin. Individuals being treated with penicillamine will be advised to take vitamin B6 (pyridoxine) supplements because penicillamine can cause a serious deficiency of this vitamin.
  • Trientine (Syprine®): Trientine (Syprine®) is another chelating agent. Trientine binds to copper and helps eliminate it from the body. Trientine is generally less toxic than penicillamine, and many doctors consider it a first-line therapy, especially in people with liver or neurological symptoms.
  • Zinc acetate: Zinc helps prevent copper from being absorbed in the stomach and small intestine. Zinc has few side effects, but it is slower acting than penicillamine and trientine. It is usually considered an initial treatment only for pregnant women, for people without symptoms or liver damage, or for those who cannot tolerate stronger medications. Doctors may switch people taking penicillamine or trientine to zinc once their symptoms improve, or zinc may be used in combination with penicillamine for people with neurological symptoms.
  • Individuals with Wilson's disease will need to continue taking a copper-reducing medication for life. Healthcare providers may also recommend avoiding tap water containing more than 100mcg of copper per liter, copper-containing vitamin and mineral supplements, and foods high in copper such as avocados, beans and lentils, bran products, chocolate, dried fruit, dried peas, liver, mushrooms, nuts, and shellfish.
  • See "Liver toxicity" condition monograph for the medical treatment of liver toxicity.
  • Early onset of the disease is worse than late onset in terms of prognosis. If the disorder is detected early and treated appropriately, an individual with Wilson's disease can usually enjoy normal health and a normal lifespan. If not treated, Wilson's disease can cause severe brain damage, liver failure, and death. The disease requires lifelong treatment.
Prevention
  • Copper content in water reduction: If the water contains copper over 0.1ppm (parts per million) (which is 0.1 milligrams/liter), healthcare professionals recommend using alternative sources, such as bottled water. While 0.1ppm is not particularly hazardous, it indicates that significant copper is being consumed in the diet. Those with Wilson's disease should severely limit their intake of copper. Copper can be found in drinking water; healthcare professionals recommend that individuals who need to limit their intake of copper drink filtered, reverse osmosis, water.
  • Alcohol and drug avoidance: It is recommended by healthcare professionals to drink alcohol in moderation, if at all. Over many years, more than one drink a day for women and more than two drinks a day for men may be enough to lead to cirrhosis. Use of certain drugs, including some illegal drugs, also can cause liver disease. If fatty liver or hepatitis exists, no alcohol should be consumed. Individuals diagnosed with Wilson's disease should not drink alcohol.
  • Only use prescription and nonprescription drugs when needed and take only the recommended doses. Acetaminophen (Tylenol®) dosages should be followed specifically as stated by the manufacturer or by a healthcare provider. The manufacturer has set a maximum dose of 4 grams of acetaminophen (the equivalent of eight extra-strength tablets or capsules, 500 milligrams each) per day. However, healthcare professionals recommend that individuals who take prescription medications or drink alcohol daily should only take a maximum of 2-3 grams per 24 hours. Many over-the-counter (OTC) products may also contain acetaminophen (Tylenol®). It is important not to exceed the total daily dosage of 4 grams acetaminophen. Particular caution is need in dosing infants with acetaminophen to ensure that the correct dose is given.
  • Do not mix other drugs with alcohol. Acetaminophen (Tylenol®) can be toxic to the liver even if individuals drink in moderation.
  • Hepatitis vaccination: If an individual has Wilson's disease or is at increased risk of contracting hepatitis or if they already been infected with any form of the hepatitis virus, a doctor will recommend the hepatitis B vaccine. A vaccine is also available for hepatitis A.
  • Dietary supplements: Beware of certain supplements. Herbal supplements that can be toxic to the liver may include kava (Piper methysticum), chaparral (Larrea taridentata), comfrey (Symphytum officinale), germander (Teucrium chamaedrys), kombucha tea, mistletoe (Viscum album), pennyroyal (Mentha pulegium), and skullcap (Scutellaria laterifolia). Also avoid high doses of fat soluble vitamins, including vitamins A, D, E, and K.
  • Chemical toxin avoidance: When using toxic chemicals such as cleaners, ventilating the room or wearing a mask is important. Take similar protective measures when spraying insecticides, fungicides, paint, and other toxic chemicals. When using insecticides and other toxic chemicals, covering the skin with gloves, long sleeves, a hat, and a mask is recommended by healthcare professionals.
  • Weight control: Maintaining proper weight through diet and exercise is important. Even if an individual does not drink alcohol, obesity can cause nonalcoholic fatty liver disease, which may include fatty liver, hepatitis, and cirrhosis.
References

Natural Standard developed the above evidence-based information based on a thorough systematic review of the available scientific articles. For comprehensive information about alternative and complementary therapies on the professional level, go to www.naturalstandard.com. Selected references are listed below.

  1. Ahmed S, Naeem S, Ahmed I. Wilson's disease with neurological presentation. J Coll Physicians Surg Pak. 2007;17(7):433-4. View Abstract
  2. American Liver Foundation. . Accessed May 9, 2009.
  3. American Gastroenterological Association. . Accessed May 9, 2009.
  4. Centers for Disease Control and Prevention. . Accessed May 9, 2009.
  5. Ingster-Moati I, Bui Quoc E, Pless M, et al. Ocular motility and Wilson's disease: A study on 34 patients. J Neurol Neurosurg Psychiatry. 2007; [Epub ahead of print]. View Abstract
  6. Khanna S, Gopalan S. Role of branched-chain amino acids in liver disease: the evidence for and against. Curr Opin Clin Nutr Metab Care. 2007;10(3):297-303. View Abstract
  7. Muller T, Koppikar S, Taylor RM, et al. Re-evaluation of the penicillamine challenge test in the diagnosis of Wilson's disease in children. J Hepatol. 2007;47(2):270-6. View Abstract
  8. National Institute of Neurological Disorders and Stroke. . Accessed May 9, 2009.
  9. Natural Standard: The Authority on Integrative Medicine. . Copyright © 2009. Accessed May 9, 2009.
  10. Maher JJ. Alcoholic steatohepatitis: management and prognosis. Curr Gastroenterol Rep. 2007;9(1):39-46. View Abstract
  11. Taly AB, Meenakshi-Sundaram S, Sinha S, et al. Wilson disease: description of 282 patients evaluated over 3 decades. Medicine (Baltimore). 2007;86(2):112-21. View Abstract
  12. Wilson's Disease Association International. . Accessed May 9, 2009.