Wilson’s disease (hepatocellular degeneration) is a rare congenital disorder affecting the copper metabolism in the body, characterized by the abnormal storage of copper in the various tissues.
Wilson’s disease is a rare autosomal recessive inherited disorder which affects the copper metabolism in the body and causes its deposition in the liver, brain, kidneys, cornea, bones and other tissues. Stored copper has a toxic influence on the liver and brain by causing oxidant (free-radical) damage to the cells. It is crucial to recognize the disease and initiate treatment as soon as possible as the disease is fatal if not treated.
Wilson’s disease affects 1 child in 30000-40000 neonates, whereas the ATP7B mutation is identified in approximately 1% of the population.
The disease develops as the abnormality of copper metabolism in the body. Normally, every day a person with an average diet consumes about 2-5 mg of copper with food, whereas the daily requirement is significantly lower – 1.3-1.7 mg daily. Approximately 40-60% of the copper is absorbed in the stomach and small intestine – these values are still too high and since copper has toxic properties, the body has to regulate its copper levels and provide its excretion. In the liver, copper is incorporated into several proteins such as ceruloplasmin, copper/zinc superoxide dismutase, and cytochrome c oxidase as well as into the lysosomes to be excreted with the bile (in healthy human up to 80% of copper is secreted this way).
Wilson’s disease is caused by a mutation of the ATP7B gene located on the long arm of the chromosome 13 which controls the functioning of a membrane-bind, copper-transporting P-type adenosine triphosphatase (ATP) of the liver cells, copper excretion into bile and the synthesis of ceruloplasmin (protein-bind copper). This mutation is inherited as an autosomal recessive trait. It means that the two copies of the abnormal gene (one copy inherited from a mother and another one – from a father, however, both parents are typically healthy) should be present for the disease to develop.
As the result of this genetic abnormality, the copper metabolism is impaired – the substance is then stored in the liver, gets into the bloodstream and reaches the central nervous system and other tissues where it is also accumulated. It should be noted, that copper is a toxic metal, the increased value of which impair the liver function and even cause liver failure and cirrhosis, damage the nervous system by accumulating in the pons, medulla, thalamus, cerebellum and basal ganglia.
Usually, the disease symptoms develop when a child is older than 3 years, although typically the symptoms become obvious during the teenage and adolescence with the most common disease onset between 10 and 20 years of age. The younger is a person when the first symptoms occur, the more likely liver-related symptoms will develop at first.
Liver involvement in Wilson’s disease may vary from fulminant hepatitis to cirrhosis with jaundice, fluid builds up in the abdomen, peripheral edema, bloody vomiting due to esophageal varices. Neurological symptoms of the disease are typically more evident, they include tremor, involuntary choreiform grotesque movements and body positions, lack of movement coordination, deterioration in performance at school, worsening of handwriting and migraines. Difficulties swallowing and impaired speaking ability are also common. Memory loss and seizures may also occur. Psychiatric disturbances may also occur in persons with Wilson’s disease such as mood swings, depression, hyperactivity, dementia, neuroses, schizophrenia, psychosis, or antisocial behavior.
The most characteristic and obvious feature of Wilson’s disease is the presence of Kayser-Fleischer ring in the ocular cornea, which appears as a green-brown-colored ring at the edge of the cornea and doesn’t influence person’s vision. Nevertheless, the absence of Kayser-Fleischer rings doesn’t exclude the diagnosis of Wilson’s disease.
Women suffering from the disorder may have no periods (be amenorrheic) or experience repeated spontaneous abortions.
MEDNIK syndrome: Wilson’s disease
Rarely a complex disease affecting the copper metabolism, which merges the features of both Wilson’s and Menkes diseases, is observed. The disorder is referred to as the MEDNIK syndrome and is characterized by the mental retardation, enteropathy (impaired digestion), deafness, neuropathy (peripheral nerves are affected), ichthyosis (scaly skin) and keratodermia (hornlike skin). The syndrome is caused by the AP1S1 gene mutations.
Diagnosis: Wilson’s disease
- In Wilson’s disease, the ceruloplasmin without copper is being produced – this substance is called apoceruloplasmin and has a shorter half-life than ceruloplasmin – therefore, ceruloplasmin concentration in the blood is decreased.
- Increased levels of copper in the circulating blood may be detected by collecting the 24-hour urine. In case of Wilson’s disease, the copper values in the urine are more than twofold increased.
- Liver enzymes (ALT, AST) in the blood are moderately elevated; bilirubin concentration is significantly elevated.
- The renal involvement is confirmed by the presence of blood, protein, phosphates in the urine.
- CT and MRI scans of the brain reveal the cerebral lesions even if there are no neurologic symptoms at the moment.
- The diagnosis is confirmed by the measurement of liver copper concentration via liver biopsy. The normal hepatic copper content is less than 50 μg of copper/g dry liver, while in Wilson’s disease it is more than 250 μg/g.
Treatment: Wilson’s disease
Early diagnosis and treatment initiation is considered very important for individuals with Wilson’s disease as the treatment in highly-effective, and if started in time it may prevent the irreversible tissue and organ damage, whereas untreated disease may be even fatal.
Wilson’s disease treatment implies the removal of excessive amounts of copper with copper chelation by the life-long administration of either D-penicillamine or trientine, zinc therapy and low-copper diet (avoidance of nuts, chocolates, mushrooms, liver, and fish) are also recommended. However, chelation therapy should not be prescribed for individuals with acute liver failure or advanced stages of cirrhosis. In these cases, copper is removed with the help of plasmapheresis, hemodialysis, or hemofiltration, although such condition requires liver transplantation as soon as possible.
Applicable medicines: Wilson’s disease
D-penicillamine treatment starts with a dose of 15–20 mg/kg/day divided into four daily doses half an hour before meals and before going to bed. If it is not effective within 4-6 months after the treatment initiation the dose is increased up to 1.5 g/day. D-penicillamine has antipyridoxine properties, therefore, pyridoxine should be given simultaneously. Side effects of penicillamine include bone marrow suppression, proteinuria, nephrotic syndrome, systemic lupus erythematosus, Goodpasture syndrome, aphthous ulceration, arthralgia, and loss of the sense of taste.
Alternatively, trientine is administered with an initial dose of 0.5-1.0 g/day. The dose may be increased if within 6 months of treatment there is no response. In comparison with D-penicillamine trientine has a lower possibility of side effects.
Zinc sulfate or acetate at dose 150 mg is taken 3 times a day. Zinc compounds interfere with the copper absorption from the gut and increase binding of the copper in the liver with metallothionein. Side effects of zinc therapy include gastritis and microcytic anemia.