Diseases

Wilson's Disease

Wilson's disease occurs when copper builds up in the body. Its toxic effects can leave patients seriously handicapped. Medicines have helped halt disease progress. Further research is aimed at improving treatment.

What is Wilson’s disease? Top

Wilson’s disease is a genetic disorder that is fatal unless detected and treated before the onset of a serious condition develops through excessive build-up of copper in tissues of the human body. The estimated total copper content in the body is 50-100mg, with an average daily intake of 1-2mg. Copper is an essential trace element and an important component of metabolic enzymes and other proteins in the human organism. Copper ions are present in many foods. In case the intake of copper surpasses the body’s needs, it has the means to excrete the surplus.

In 1912, an English neurologist, Samuel Alexander Kinnier Wilson, first described it a familial disorder associated with neurological symptoms and cirrhosis. The major physiological aberration in patients with Wilson’s disease is the impairment of incorporation of copper into the copper-carrying protein ceruloplasmin and a defective excretion of excess copper into the bile. The excess copper acts as a promoter of free radical formation and causes oxidation of lipids and proteins. Copper begins to accumulate immediately after birth. Excess copper is stored primarily in the liver and, eventually, as liver copper levels increase, the element is released into the circulation and deposited in the nervous system and other organs, resulting in hepatitis, and psychiatric or neurological symptoms.

The symptoms usually start to become manifest in late adolescence. Symptoms and findings are jaundice, abdominal swelling and pain, as well as vomiting of blood. In about 50 per cent of Wilson’s disease patients, the liver is the only organ affected. When hepatitis develops, patients are often thought to have viral hepatitis or infectious mononucleosis. Any unexplained abnormal liver test should trigger suspicions of Wilson’s disease.

Patients can have tremors, difficulty in walking, talking and swallowing. They can develop all degrees of mental illness, including suicidal behaviour, depression and aggression. Women may suffer from menstrual irregularities, infertility or multiple miscarriages. The late stage of Wilson’s disease is characterised by liver failure, severe dementia and finally, death.

The diagnosis is confirmed by measurement of a low level of serum ceruloplasmin, by the amount of urinary copper excretion, and by a liver biopsy to determine the hepatic copper content. In the eyes of patients, precipitated copper may be detected as so called Kayser-Fleischer rings. These tests help to diagnose the disease in both symptomatic patients and people without signs of Wilson’s disease.

Who does Wilson’s disease affect? Top

The incidence ranges worldwide from one case per 30,000 live births in Japan to one case per 100,000 in Australia. The increased frequency in certain countries is due to higher rates of consanguinity. In the EU, the yearly incidence is estimated at 12,000 cases. Worldwide, the number of cases is considered to be between 10 and 30 million.

The condition is transmitted as an autosomal recessive inherited disease, which means it occurs equally in men and women. But the sudden development of the condition is four times more common in females than males. In order to inherit it, both parents must carry the causative deficient gene ATP7B, which is located on chromosome arm 13q. The identification of the Wilson’s disease gene was made in 1993. The defect was shown to affect the copper-transporting adenosine triphosphatase (ATPase) gene which is found active predominantly in liver, kidney, and placenta, and to a lesser extent in heart, brain, lung, muscle, and pancreas. People with one abnormal gene are so-called carriers. They do not become ill and do not need any treatment.

Most patients have no family history of Wilson’s disease, which means that a large part of cases occur due to spontaneous mutations in the gene. More than 70 different mutations have been identified thus far. Therefore it has been difficult to devise a simple genetic screening test. However, in a particular family, if the precise mutation is identified, a genetic diagnosis is possible. This helps in detecting symptom-free relatives, so that they may be treated before they fall ill or become handicapped.

Present treatments Top

Medical treatment is aimed at removing excess accumulated copper and preventing its re-accumulation. With proper therapy, disease progress can be halted and symptoms can often be improved. Therapy must therefore be for life. Patients with Wilson’s disease should generally avoid eating foods with a high copper content such as liver, chocolate, nuts, mushrooms, legumes such as broccoli, and shellfish. Drinking water from unfamiliar sources should be replaced with purified water if the copper content is greater than 0.2 parts per million.

Medicines approved for use in Wilson’s disease include a sulphur-containing degradation product of the antibiotic penicillin and a tetramine compound. Both compounds are taken orally and act by chelating or binding of copper, which leads to soluble complexes that can be excreted by the kidneys.

In 2004, a positive opinion for an orphan medicine for the treatment of Wilson’s disease was rendered. Demonstration of its effectiveness was based on 15 years of clinical experience. The product works by slowly depleting the body’s excess copper, thus maintaining sub-toxic levels in pre-symptomatic Wilson’s disease patients. It also prevents the re-accumulation of copper and copper toxicity in symptomatic Wilson’s disease patients. The medicine works through the action of the zinc-cation which blocks the intestinal absorption of copper from the diet and the reabsorption of endogenously secreted copper. A major advantage of zinc therapy is its safety profile, which also allows it to be used during pregnancy.

Critical liver disease is treated with plasma exchange and exchange transfusion, as well as peritoneal dialysis. Intravenous infusions of chelating and copper-binding compounds may also be given. These patients will need liver transplantation.

Copper content of food

Food Copper concentration (µg/g wet) Size of typical serving (g) Copper/serving 

(mg)

Meats

Fish 0.61 120 0.07
Chicken 0.34 120 0.04
Steak 1.20 120 0.14

Dairy

Egg  0.8 40 0.03
Single Sliced Cheese 0.43 120 0.05

Bread

Whole Wheat 1.07 30 0.03

Shellfish

Scallops

0.27 120 0.03

Clams

6.08  120 0.73

Oysters

2.89 120 0.35

Smoked Oysters

15.00 120 1.80

Mussels

4.75 120 0.57

Lobster

36.60 120 4.39

Chocolate

Syrup

43.36 15 0.65

Candy Bar

1.18 15 0.02

Milk

0.33 120 0.04

Vegetables

Peas 2.38 120 0.29
Navy Beans 3.95 120 0.47

Fruits

Applesauce (can) 0.20 120 0.02
Avocado 1.68 120 0.20
Raisins 1.68 30 0.05

Soups

Onion 1.49 15 0.02

Beverages

Tea 0.025 120 0.03
Cola (bottle) 0.001 356 0.00

What’s in the development pipeline? Top

A compound containing molybdenum is under investigation for initial treatment of Wilson’s disease in the hope that it will not cause neurological deterioration. It is being used as an initial treatment for those who present with neurological or psychiatric manifestations. This medicine works as both a chelating agent and as an inhibitor of copper absorption from the gastrointestinal tract. Its side effect profile has still not been clearly established.

Research groups are determining the effectiveness of a new paediatric screening method to identify affected individuals and begin treatment prior to the onset of life-threatening symptoms. The test is a blood sample collected from the child’s finger on a filter paper card.

Since June 2005, a European clinical database to collect information on newly presenting cases has been in operation. Patients are allocated a unique identification number at initial diagnosis and then followed up on an annual basis. So far, nearly 60 country coordinators have registered on the EuroWilson clinical database.

The longer-term future Top

A more general approach in the long run will be the isolation of stem cells with the potential to turn into various kinds of tissue. In Wilson’s disease, the gene product is a 1411 amino acid protein with highest levels of expression in the liver, kidneys, and placenta. The treatment would include inserting the gene capable of correcting the deficiency to make the affected cells capable of producing the missing compound and transfer it to the patient.

Another long-term project is a genetic test that may help in prenatal diagnosis.