Generality
Wilson's disease, also called hepatolenticular degeneration, is a rare genetic disorder characterized by an accumulation of copper in the tissues and organs of the body.
It is a disease with a fatal outcome. Therefore, a therapeutic treatment is needed that removes the copper from the tissues and prevents their accumulation.
What is Wilson's disease
Wilson's disease, also known as hepatolenticular degeneration, is a genetic hereditary disease that causes excessive copper accumulation in some organs and tissues.
This is a rare disease, as it affects 1 individual every 30, 000 people.
The accumulation of copper is due to a defect in its metabolism. In fact, the copper absorbed with the diet is not adequately expelled, therefore it remains in the body and is deposited mainly in:
- liver;
- brain.
And to a lesser extent, also in:
- cornea;
- kidneys;
- other fabrics.
Excessive amounts of copper in these districts create cell damage. The most serious effects are found in the liver and brain. In the brain, it is the lenticular nucleus that undergoes the greatest consequences: this gives rise to the alternative name of hepatolenticular degeneration.
Causes
The cause of Wilson's disease is an alteration of the ATP7B gene, located on chromosome 13, which no longer performs its normal function.
The task of the ATP7B gene is to promote the excretion, through the bile, of excess copper, contained in the cells. When ATP7B does not work, copper accumulates in such massive doses that it escapes from the cells and flows into the blood. Thus, through the bloodstream, copper reaches the various tissues of the body.
Pathogenesis
Copper is taken with the diet. Its absorption occurs in the intestine: here it binds to albumin (a plasma protein) and reaches the liver. At this point:
in a healthy individual:
- ATP7B promotes the bond between copper and ceruloplasmin. Ceruloplasmin is a plasma protein used for the transport and excretion of copper.
In an individual with Wilson's disease, instead:
- ATP7B does not work. Therefore, it does not favor the bond between copper and ceruloplasmin.
- Copper remains bound to albumin, is not excreted and accumulates in liver cells.
- Liver cells saturate, within them, any copper storage capacity.
- The copper-albumin complex is therefore in excess. Therefore, it escapes from hepatocytes and enters the blood.
- Through the blood, copper reaches the other tissues of the body.
The first organ to pay the consequences is therefore the liver; they follow the brain, the kidneys and the cornea.
Why is copper spreading in tissues?
In individuals with Wilson's disease, copper circulates in the blood bound to albumin. The copper-albumin bond is much more labile than that between copper and ceruloplasmin. In fact, among the first two there is little affinity. When the albumin complexed copper reaches the tissues and the various organs, it encounters substances for which it has greater affinity and binds to them. The consequences are two:
- Tissues and organs are enriched with copper.
- The concentration of copper (cupremia) in the blood decreases.
From Wikipedia - Mother and father both have a mutated allele. Due to the recessive nature of this allele, they do not show any disease, but they are healthy carriers. The two parents can each transmit a mutated allele to a child. The child will be, in this case, homozygous for the given allele and will manifest the disease. In all other cases, the presence of one or both healthy alleles does not cause any disturbance.
inheritance
Wilson's disease is an autosomal recessive inherited disorder .
- Autosomal, because the ATP7B gene is located on chromosome 13, a non-sexual chromosome.
- Recessive, because the mutated allele, which determines the disease, is recessive compared to the healthy one. To get sick, an individual must have both mutated alleles. In fact, only one mutated allele is not sufficient to determine the disease. About one in 100 is a carrier of an altered ATP7B allele. The figure clearly explains this concept.
Symptoms
To learn more: Symptoms Wilson's disease
Although it is a hereditary genetic disease, there are no disturbances in the first few years of age. The first symptoms, located in the liver, occur around 6 years. This is usually the minimum time needed for copper to accumulate in harmful quantities. In some cases, the onset may occur in late adolescence or even around 30-40 years. Over time, disorders also appear in other tissues.
Liver symptomatology
The liver is the first affected organ, because it is the first district where copper absorbed through the diet reaches. Liver health progressively worsens. The evolution typically begins in adolescence and follows the following course:
- Hepatitis.
- Non severe cirrhosis.
- Severe cirrhosis.
A condition defined by the doctor with the term liver failure is created : the liver is no longer able to perform its functions.
The typical signs of liver failure are:
- Jaundice.
- Abdominal pain.
- He retched.
- Enlarged liver (hepatomegaly)
- Enlarged spleen (splenomegaly)
Brain symptomatology
Copper reaches the brain only when the liver can no longer keep it confined to its cells.
Deposits in the brain cause neurological damage of a different nature:
- Physical disorders.
- Limb tremors.
- Slowness in movement.
- Speech difficulties (dysarthria).
- Difficulty writing.
- Difficulty swallowing (dysphagia).
- Instability in walking.
- Migraine.
- Epilepsy.
- Muscle weakness and stiffness.
- Behavioral disorders.
- Mood changes.
- Depression.
- Inability to concentrate.
- Personality changes.
- Dementia.
If the patient is not treated, the neurological damage gets worse and worse: the individual becomes completely dependent on others, to feed and move.
Other fabrics
Furthermore, copper can also be deposited in the kidneys . It follows a renal damage, which determines:
- Aminoaciduria. Presence of amino acids in urine.
- Glycosuria. Presence of glucose in the urine.
- Phosphaturia. Presence of phosphorus in the urine
- Uricosuria. Presence of uric acid in the urine.
- Urinary calcium. Presence of calcium in the urine.
Under normal conditions, all these lost substances would be reabsorbed. Therefore, the renal accumulation of copper alters the structure and reabsorption of substances still useful to the body.
Other possible symptoms of Wilson's disease are:
- Anemia.
- Pancreatitis.
- Menstrual problems.
- Miscarriage.
- Premature osteoporosis.
Diagnosis
If Wilson's disease is suspected, useful diagnostic tests are:
- Blood tests, to test:
- Ceruloplasmin concentrations . A low level, below 20mg / 100ml, is indicative of the disease. The normal value is 30 mg / 100ml.
- The concentration of copper ( cupremia ). If it is lower than normal, it is indicative of the disease.
- Possible haemolytic type anemia.
- Hepatic and renal functions, via their respective markers (transaminases, azotemia, etc.)
- Urine test, to assess the amount of copper present ( cupruria ). Higher than normal levels are indicative of the disease. In general, those suffering from the pathology expel about 100μg of copper in the urine every 24 hours.
- Optometric examination, to find the presence of the Kaiser-Fleischer ring.
- Liver biopsy, to measure the copper content in liver cells. The pathological level of copper is over 100μg for one gram of liver. It is also useful for assessing the state of cirrhosis.
- A brain MRI, to assess the health of the lenticular nucleus, which we recall being the area of the brain affected by copper accumulation.
- A DNA genetic test .
The simultaneous presence of:
- Kaiser-Fleischer ring.
- Signs of liver cirrhosis.
- Lesion of the lenticular nucleus.
leave no doubt about the diagnosis.
Measured parameter | Quantity in healthy subjects | Quantity in sick subjects |
Cupremia | 110 μg / ml | <100μg / ml |
Cupruria | 100 μg / 24h | >> 100 μg / 24h |
ceruloplasmin | 30 mg / ml | <20 mg / ml |
Therapy
See also: Medications for the treatment of Adrenal insufficiency
If not treated, Wilson's disease is fatal . Death can occur even a couple of years after the first symptoms appear. The patient is subject to a progressive worsening of his / her conditions, becomes increasingly dependent on others, and in the absence of a specific treatment the damage to the liver and brain can be irreversible .
The therapy consists of:
- Reduce copper deposits in the liver.
- Check the absorption of copper in the intestine.
- Reduce the introduction of copper taken with the diet.
- Liver transplantation.
Reduce copper deposits
It is the most important step to save the patient's life. It is based on the administration of:
- Penicillamine.
- Trientine.
Penicillamine is the drug of choice. It is administered orally and should be taken for life. It represents a chelating agent able to sequester excess copper and lead it into the kidneys for excretion. However, it can cause undesirable effects in the kidneys. In these cases, it is advisable to stop the treatment to resolve the disorders that have arisen, and to adopt an alternative one based on Trieste.
The Trieste is also a chelating agent. It is administered orally and acts like penicillamine. It is not as effective, but the side effects are also lower.
Check the intestinal absorption of copper
It is possible to reduce the absorption of copper by taking zinc. Thus, the accumulation of copper in the liver is prevented. Zinc administration is recommended when Wilson's disease is in its early stages. In other words, when copper has not yet invaded the other fabrics. Therapy is effective when combined with penicillamine treatment.
Reduce the introduction of copper
The consumption of some foods rich in copper, such as:
- Nuts.
- Liver.
- Mushrooms.
- Chocolate.
- Seafood.
Overall, the daily dietary intake of copper should not exceed 2 mg.
Liver transplantation
It is the therapy required if:
- Liver damage is irreversible. In this case we speak of severe cirrhosis.
- The previous treatments have been ineffective.
Prognosis
The sooner you start therapy, the better your prognosis and quality of life will be.
Intervening late means limiting and improving only partially the liver and brain damage due to excess copper. Some functions, in fact, remain irreparably compromised.
In more severe cases, the only solution for a better prognosis is liver transplantation.
