What is Wilson’s Disease? Symptoms, Diagnosis and Treatment

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Wilson’s disease is a metabolic disease characterized by copper deposition in various organs, primarily liver, pancreas, brain, kidney, bone marrow and eye, as a result of a congenital defect in copper metabolism. It occurs approximately once in every 30,000 people. It is a fatal disease if left untreated.

Copper Metabolism in Our Body

wilson hastalığı tedavisi Copper is one of the trace elements that the body needs in very small amounts. It plays an important role in the healthy development of nerves, bones and connective tissue in our body and in the production of melanin, a skin pigment.

The total amount of copper in the body is around 100 mg. After the copper taken with food is absorbed from the first 45-50 cm of the small intestine, it is transported to the liver by binding to albumin and an amino acid histidine from blood proteins.

Copper is taken in the amount of 1.5-4 mg per day in the diet. Absorbed copper is stored with metallothionein in both the intestinal cells and the liver. The liver uses copper in some metabolic events.

Copper is a cofactor for many proteins involved in various chemical reactions that occur in the liver. Ceruloplasmin, a protein made in the liver, binds copper in the blood. Copper bound with ceruloplasmin is excreted from the liver cells (hepatocytes) into the bile ducts and removed from the body. The normal human body has the ability to remove excess copper from the body.

In Wilson’s disease, the excretion of copper from the liver through bile is impaired. Copper accumulated in the liver is returned to the bloodstream and accumulates in other organs in the body, creating a harmful (toxic) effect.

Etiology

Wilson’s disease is an autosomal recessive (recessive) disease that occurs as a result of a defect in the ATP7B gene located on the 13th chromosome in the human genome and manifests itself with findings related to copper accumulation in the body as a result of the insufficiency of the mechanisms in the excretion of copper from the liver to the bile.

Although over 60 mutations have been identified in this gene, the most common mutation, His1069Gly, is found in almost half of patients in North America and Europe. The reason for the rare appearance of the disease is that it is carried by genes with weak effect level.

The effectiveness of recessively mutated genes in an individual depends on the presence of mutated (mutant) genes in the chromosomes of the mother and father as carrier, (Gene mutation: Change in the number, ratio and sequence order of amino acids that make up the structure of the gene).

In order for the disease to occur, the diseased gene must be inherited from both the mother and father. When both parents are carriers, 25% of their children will be born healthy, 50% will be carriers, and 25% will be sick.

People who carry only one diseased gene may show no symptoms of the disease. Symptoms of the disease can be found in only 1% of such carriers. The disease is more common in countries where consanguineous marriage is common. A family history of Wilson’s disease is the only known risk factor for this disease.

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What Are The Symptoms Of Wilson's Disease?

Symptoms of the disease usually appear between the ages of 6-20 and almost always before the age of 40. In children, the first signs of the disease usually begin to appear around the age of 4. 40% of the patients apply to the physician with liver findings. Neurological findings are more common in advanced ages.

Symptoms due to excessive copper accumulation in the liver; Jaundice, abdominal bloating, abdominal pain, weakness, fatigue and nausea may occur. Symptoms of liver cirrhosis, which occur when liver disease progresses, do not differ from those of liver cirrhosis of other etiologies (See Liver cirrhosis).

Symptoms Related To Excessive Copper Accumulation İn The Brain

  • There may be depression, behavioral disorder, poor school performance, sudden personality changes, sleep disorder, speech and swallowing difficulties, tremors in the hands, muscle spasms, gait and balance disorders.
  • The accumulation of copper in the eyes causes a green-brown ring around the pupil (Kayser-Fleischer ring, KF). Although this ring can be seen with the naked eye, some patients may require special techniques during eye examination to identify the ring.
  • The disease usually presents with a liver problem in children, while neurological findings are more common in young adults. Liver disease may present with a picture ranging from acute fulminant (very rapidly progressing) hepatitis to chronic hepatitis or cirrhosis of the liver.
  • Wilson’s disease should be considered in patients with the following findings;
    Elevated liver enzymes that cannot be attributed to any other cause
  • Difficulty swallowing and speech disorder that cannot be attributed to another neurological disease
  • Immobility and tremors in hands
  • Liver dysfunction accompanied by psychiatric symptoms
  • Behavioral disorder accompanied by mild impairment in liver function tests in adolescence
  • Coombs negative hemolytic anemia (breakdown of red blood cells)
  • Cirrhosis of the liver that cannot be attributed to any other cause
  • Acute / fulminant hepatic failure that cannot be attributed to any other cause

Diagnosing Wilson's Disease

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Since Wilson’s disease is a rare disease, the thought of the doctor is the most important step in diagnosis. Wilson’s disease should be considered in the presence of unexplained liver dysfunction and/or neurological and psychiatric symptoms. Specific tests for Wilson’s disease should be performed in a patient with fatty liver in the absence of metabolic causes or alcohol use. Early prenatal diagnosis can be achieved by performing amniocentesis in pregnant patients.

Blood tests: Aminotransferase levels (ALT and AST) in the blood are slightly increased, which does not always reflect the severity of the disease. (See Liver function tests). The AST level may have increased further. Serum copper and ceruloplasmin levels are usually reduced but may be normal. In cases where the ceruloplasmin level is <20 mg/dl, Wilson’s disease should be considered if there is a CF ring in the eye examination. Serum uric acid level is low in patients with hepatic and/or neurological findings.

Urine tests: The amount of copper in the 24-hour urine is usually increased. While this amount is normally <40mg/day, it can reach as high as 100-1000mg/day in Wilson’s patients.
Eye examination: A ring of CF, which forms as a thin green-brown ring around the pupil, can be seen in the eye.

Liver biopsy: Findings specific to Wilson’s disease can be seen in liver biopsy. In this method, it is pathological that the copper amount in the liver tissue exceeds 200ug/g.
Hematological findings: Hemolysis (breakdown of red blood cells) and anemia (anemia) may be seen.

Genetik analiz: Its value is limited as more than 200 mutations have been identified at the ATP7B locus. Genetic testing may be helpful in cases where other tests are negative.

Radiological methods: The most common findings in cranial MR (Magnetic resonance) are changes in signal intensity in gray and white matter and atrophy in the caudate nucleus, brain stem, brain and cerebellum.

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Treatment in Wilson's Disease

Wilson’s disease can be cured with early diagnosis and effective treatment. The aim of treatment is to reduce the accumulation of copper in the body. For this purpose, excessive copper accumulation and toxicity in the tissues are tried to be reduced by using treatment methods that reduce the absorption of copper from the intestines and increase its excretion in the urine. In a patient diagnosed with Wilson’s disease, treatment is continued for life. Neurological damage is usually permanent. Siblings and children of Wilson’s patients should be screened and if there is evidence of copper accumulation in the body, treatment should be started even if there are no symptoms.

Penicillamine (Penicillamine) and trientine hydrochloride are drugs that bind copper in the body and allow it to be excreted in the urine. Clinical and biochemical improvement may occur if treatment with these drugs is started early. Drug doses can be reduced after 2-3 years from the start of treatment. Up to 10% of patients using penicillamine may experience serious drug-related side effects such as skin rashes, decrease in white blood cells (leukopenia) and kidney damage.

Zinc acetate (Zinc acetate) is a substance that acts by reducing the absorption of copper from the intestines and can be used instead of penicillamine because it has no obvious side effects. Trientine hydrochloride is the most preferred drug today due to its low side effects. It may be more effective if used with a zinc preparation. In patients with severe hepatic and neurological findings, the combined use of these 2 drugs is preferred in the first few months. Tetrathiomolybdolate is another drug that can be used in treatment.

Liver transplantation is the most effective treatment for Wilson’s disease in terms of providing definitive treatment. However, a limited number of applications can be made due to the lack of donor and the problems that may occur after transplantation. Fulminant liver failure or decompensated liver cirrhosis should be treated with liver transplantation.

In Wilson patients, consumption of certain foods with high copper content, such as giblets, lobster, mussels, crab, chocolate, soybeans, peas, mushrooms, dried kernels and peanuts, and beer and mineral drinks should be restricted. Since cooking foods in copper pots will increase the amount of copper taken, copper pots should not be used for cooking and storage.

If there is more than 0.1 ppm copper in drinking water, the use of this water may be risky for Wilson’s patients. Copper-containing intrauterine device (spirals) should not be used for birth control in women with Wilson’s disease.

Wilson's Disease and Pregnancy

wilson hastalığı ve gebelikThere are limited studies on the effect of Wilson’s disease on pregnancy. Hormonal imbalance resulting from copper deposition in the pituitary and gonads in Wilson’s disease can cause amenorrhea in women (amenorrhea) and affect fertility (conceiving). In addition, copper accumulation in the uterus (uterus, uterus) can lead to recurrent miscarriages.

These risks are significantly reduced in patients under treatment. In a small number of studies, it has been reported that D-penicillamine, which is the most frequently preferred drug in the treatment of Wilson’s disease, is safe to use at low doses during pregnancy. Since D-penicillamine is an agent that inhibits connective tissue formation, abnormalities of connective tissue development can be expected in newborns.

In some studies, inguinal hernia etc. in the babies of women with Wilson’s disease using this drug. Anomalies have been reported to be common. Currently, D-penicillamine is considered safe in pregnancy in doses not exceeding 600mg.

Since the drug may cause vitamin B6 (pyridoxine) deficiency, vitamin B6 supplementation should be given to pregnant women taking this drug. Trientine, another drug used in the treatment of Wilson’s disease, is known to be safe during pregnancy.

Since the drug causes iron deficiency, iron supplementation should be given to pregnant women taking trientine. Except for a few rare case reports, no teratogenic effects related to zinc use in pregnancy have been observed.

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