ilson's disease is a genetic disorder in which excess copper builds up in the body. Symptoms are typically related to the brain and liver. Liver-related symptoms include vomiting, weakness, fluid build up in the abdomen, swelling of the legs, yellowish skin and itchiness. Brain-related symptoms include tremors, muscle stiffness, trouble in speaking, personality changes, anxiety, and psychosis.

Wilson's disease is caused by a mutation in the Wilson disease protein (ATP7B) gene. This protein transports excess copper into bile, where it is excreted in waste products. The condition is autosomal recessive; for a person to be affected, they must inherit a mutated copy of the gene from both parents. Diagnosis may be difficult and often involves a combination of blood tests, urine tests and a liver biopsy. Genetic testing may be used to screen family members of those affected.

Wilson's disease is typically treated with dietary changes and medication. Dietary changes involve eating a low-copper diet and not using copper cookware. Medications used include chelating agents such as trientine and d-penicillamine and zinc supplements. Complications of Wilson's disease can include liver failure, liver cancer and kidney problems. A liver transplant may be helpful to those for whom other treatments are not effective or if liver failure occurs.

Wilson's disease occurs in about 1 in 30,000 people. Symptoms usually begin between the ages of 5 and 35 years. It was first described in 1854 by a German pathologist Friedrich Theodor von Frerichs and is named after British neurologist Samuel Wilson.

Signs and symptoms

The main sites of copper accumulation are the liver and the brain, and consequently liver disease and neuropsychiatric symptoms are the main features that lead to diagnosis. People with liver problems tend to come for medical attention earlier, generally as children or teenagers, than those with neurological and psychiatric symptoms, who tend to be in their twenties or older. Some are identified only because relatives have been diagnosed with Wilson's disease; many of these, when tested, turn out to have been experiencing symptoms of the condition but have not received a diagnosis.

Liver disease

Liver disease may present itself as tiredness, jaundice, increased bleeding tendency or confusion (due to hepatic encephalopathy) and portal hypertension. The latter, a condition in which the pressure in the portal vein is markedly increased, leads to esophageal varices, blood vessels in the esophagus that may bleed in a life-threatening fashion, as well as enlargement of the spleen (splenomegaly) and accumulation of fluid in the abdominal cavity (ascites). On examination, signs of chronic liver disease such as spider angiomata (small distended blood vessels, usually on the chest) may be observed. Chronic active hepatitis has caused cirrhosis of the liver in most by the time they develop symptoms. While most people with cirrhosis have an increased risk of hepatocellular carcinoma (liver cancer), this risk is relatively very low in Wilson's disease.

About 5% of all people are diagnosed only when they develop fulminant acute liver failure, often in the context of a hemolytic anemia (anemia due to the destruction of red blood cells). This leads to abnormalities in protein production (identified by deranged coagulation) and metabolism by the liver. The deranged protein metabolism leads to the accumulation of waste products such as ammonia in the bloodstream. When these irritate the brain, the person develops hepatic encephalopathy (confusion, coma, seizures and finally life-threatening swelling of the brain).

Neuropsychiatric symptoms

About half of the people with Wilson's disease have neurological or psychiatric symptoms. Most initially have mild cognitive deterioration and clumsiness, as well as changes in behavior. Specific neurological symptoms usually then follow, often in the form of parkinsonism (cogwheel rigidity, bradykinesia or slowed movements and a lack of balance are the most common parkinsonian features) with or without a typical hand tremor, masked facial expressions, slurred speech, ataxia (lack of coordination) or dystonia (twisting and repetitive movements of part of the body). Seizures and migraine appear to be more common in Wilson's disease. A characteristic tremor described as "wing-beating tremor" is encountered in many people with Wilson's; this is absent at rest but can be provoked by abducting the arms and flexing the elbows toward the midline.

Cognition can also be affected in Wilson's disease. This comes in two, not mutually exclusive, categories: frontal lobe disorder (may present as impulsivity, impaired judgement, promiscuity, apathy and executive dysfunction with poor planning and decision making) and subcortical dementia (may present as slow thinking, memory loss and executive dysfunction, without signs of aphasia, apraxia or agnosia). It is suggested that these cognitive involvements are related and closely linked to psychiatric manifestations of the disease.

Psychiatric problems due to Wilson's disease may include behavioral changes, depression, anxiety disorders, and psychosis. Psychiatric symptoms are commonly seen in conjunction with neurological symptoms and are rarely manifested on their own. These symptoms are often poorly defined and can sometimes be attributed to other causes. Because of this, diagnosis of Wilson's disease is rarely made when only psychiatric symptoms are present./p>

Other organ systems

Medical conditions have been linked with copper accumulation in Wilson's disease:

Eyes: Kayser-Fleischer rings (KF rings) may be visible in the cornea of the eyes, either directly or on slit lamp examination as deposits of copper form a ring around the cornea. This is due to copper deposition in Descemet's membrane. These rings can be either dark brown, golden, or reddish-green, are 1 to 3 mm wide, and appear at the corneal limbus. They do not occur in all people with Wilson's disease and may be seen in people with chronic cholestasis. Wilson's disease is also associated with sunflower cataracts exhibited by brown or green pigmentation of the anterior and posterior lens capsule. Neither causes significant visual loss. KF rings occur in approximately 66% of diagnosed cases (more often in those with neurological symptoms rather than with liver problems).

Kidneys: renal tubular acidosis (Type 2), a disorder of bicarbonate handling by the proximal tubules leads to nephrocalcinosis (calcium accumulation in the kidneys), a weakening of bones (due to calcium and phosphate loss), and occasionally aminoaciduria (loss of essential amino acids needed for protein synthesis).

Heart: cardiomyopathy (weakness of the heart muscle) is a rare but recognized problem in Wilson's disease; it may lead to heart failure (fluid accumulation due to decreased pump function) and cardiac arrhythmias (episodes of irregular and/or abnormally fast or slow heart beat).

Hormones: hypoparathyroidism (failure of the parathyroid glands leading to low calcium levels), infertility, and recurrent miscarriage.

Diagnosis

Location of the basal ganglia, the part of the brain affected by Wilson's disease

Wilson's disease may be suspected on the basis of any of the symptoms mentioned above, or when a close relative has been found to have Wilson's. Most have slightly abnormal liver function tests such as a raised aspartate transaminase, alanine transaminase and bilirubin level. If the liver damage is significant, albumin may be decreased due to an inability of damaged liver cells to produce this protein; likewise, the prothrombin time (a test of coagulation) may be prolonged as the liver is unable to produce proteins known as clotting factors. Alkaline phosphatase levels are relatively low in those with Wilson's-related acute liver failure. If there are neurological symptoms, magnetic resonance imaging (MRI) of the brain is usually performed; this shows hyperintensities in the part of the brain called the basal ganglia in the T2 setting. MRI may also demonstrate the characteristic "face of the giant panda" pattern.

There is no totally reliable test for Wilson's disease, but levels of ceruloplasmin and copper in the blood, as well of the amount of copper excreted in urine during a 24-hour period, are together used to form an impression of the amount of copper in the body. The gold standard-or most ideal test-is a liver biopsy.

Ceruloplasmin

Levels of ceruloplasmin are abnormally low (<0.2 g/L) in 80-95% of cases. It can, however, be present at normal levels in people with ongoing inflammation as it is an acute phase protein. Low ceruloplasmin is also found in Menkes disease and aceruloplasminemia, which are related to, but much rarer than Wilson's disease.

The combination of neurological symptoms, eye signs and a low ceruloplasmin level is considered sufficient for the diagnosis of Wilson's disease. In many cases, however, further tests are needed.

Serum and urine copper

Serum copper is low, which may seem paradoxical given that Wilson's disease is a disease of copper excess. However, 95% of plasma copper is carried by ceruloplasmin which is often low in Wilson's disease. Urine copper is elevated in Wilson's disease and is collected for 24 hours in a bottle with a copper-free liner. Levels above 100 μg/24h (1.6 μmol/24h) confirm Wilson's disease, and levels above 40 μg/24h (0.6 μmol/24h) are strongly indicative. High urine copper levels are not unique to Wilson's disease; they are sometimes observed in autoimmune hepatitis and in cholestasis (any disease obstructing the flow of bile from the liver to the small bowel).

In children, the penicillamine test may be used. A 500 mg oral dose of penicillamine is administered, and urine collected for 24 hours. If this contains more than 1600 μg (25 μmol), it is a reliable indicator of Wilson's disease.[clarification needed] This test has not been validated in adults.

Slit-lamp examination

The eyes of the patient are examined using a slit-lamp to look for Kayser-Fleischer rings, which are strongly associated with Wilson's Disease and are caused by copper deposition on the inner cornea in Descemet's membrane.

Liver biopsy

Once other investigations have indicated Wilson's disease, the ideal test is the removal of a small amount of liver tissue through a liver biopsy. This is assessed microscopically for the degree of steatosis and cirrhosis, and histochemistry and quantification of copper are used to measure the severity of the copper accumulation. A level of 250 μg of copper per gram of dried liver tissue confirms Wilson's disease. Occasionally, lower levels of copper are found; in that case, the combination of the biopsy findings with all other tests could still lead to a formal diagnosis of Wilson's.

In the earlier stages of the disease, the biopsy typically shows steatosis (deposition of fatty material), increased glycogen in the nucleus, and areas of necrosis (cell death). In more advanced disease, the changes observed are quite similar to those seen in autoimmune hepatitis, such as infiltration by inflammatory cells, piecemeal necrosis and fibrosis (scar tissue). In advanced disease, finally, cirrhosis is the main finding. In acute liver failure, degeneration of the liver cells and collapse of the liver tissue architecture is seen, typically on a background of cirrhotic changes. Histochemical methods for detecting copper are inconsistent and unreliable, and taken alone are regarded as insufficient to establish a diagnosis.

Genetic testing

Mutation analysis of the ATP7B gene, as well as other genes linked to copper accumulation in the liver, may be performed. Once a mutation is confirmed, it is possible to screen family members for the disease as part of clinical genetics family counseling. Regional distributions of genes associated with Wilson's disease are important to follow, as this can help clinicians design appropriate screening strategies. Since mutations of the WD gene vary between populations, research and genetic testing done in countries like the USA or United Kingdom can pose problems as they tend to have more mixed populations.

Treatment

Diet

In general, a diet low in copper-containing foods is recommended with the avoidance of mushrooms, nuts, chocolate, dried fruit, liver, sesame seeds and sesame oil, and shellfish.

Medication

Medical treatments are available for Wilson's disease. Some increase the removal of copper from the body, while others prevent the absorption of copper from the diet.

Generally, penicillamine is the first treatment used. This binds copper (chelation) and leads to excretion of copper in the urine. Hence, monitoring of the amount of copper in the urine can be done to ensure a sufficiently high dose is taken. Penicillamine is not without problems: about 20% experience a side effect or complication of penicillamine treatment, such as drug-induced lupus (causing joint pains and a skin rash) or myasthenia (a nerve condition leading to muscle weakness). In those who presented with neurological symptoms, almost half experience a paradoxical worsening in their symptoms. While this phenomenon is observed in other treatments for Wilson's, it is usually taken as an indication for discontinuing penicillamine and commencing second-line treatment. Those intolerant to penicillamine may instead be commenced on trientine hydrochloride, which also has chelating properties. Some recommend trientine as first-line treatment, but experience with penicillamine is more extensive. A further agent, under clinical investigation by Wilson Therapeutics, with known activity in Wilson's disease is tetrathiomolybdate. This is regarded as experimental, though some studies have shown a beneficial effect.

Once all results have returned to normal, zinc (usually in the form of a zinc acetate prescription called Galzin) may be used instead of chelators to maintain stable copper levels in the body. Zinc stimulates metallothionein, a protein in gut cells that binds copper and prevents their absorption and transport to the liver. Zinc therapy is continued unless symptoms recur or if the urinary excretion of copper increases.

In rare cases where none of the oral treatments are effective, especially in severe neurological disease, dimercaprol (British anti-Lewisite) is occasionally necessary. This treatment is injected intramuscularly (into a muscle) every few weeks and has unpleasant side effects such as pain.

People who are asymptomatic (for instance, those diagnosed through family screening or only as a result of abnormal test results) are generally treated, as the copper accumulation may cause long-term damage in the future. It is unclear whether these people are best treated with penicillamine or zinc acetate.

Physical and occupational therapies

Physiotherapy and occupational therapy are beneficial for patients with the neurologic form of the disease. The copper chelating treatment may take up to six months to start working, and these therapies can assist in coping with ataxia, dystonia, and tremors, as well as preventing the development of contractures that can result from dystonia.

Transplantation

Liver transplantation is an effective cure for Wilson's disease but is used only in particular scenarios because of the risks and complications associated with the procedure. It is used mainly in people with fulminant liver failure who fail to respond to medical treatment or in those with advanced chronic liver disease. Liver transplantation is avoided in severe neuropsychiatric illnesses, in which its benefit has not been demonstrated.

Prognosis

Left untreated, Wilson's disease tends to become progressively worse and is eventually fatal. Serious complications include liver cirrhosis, acute kidney failure and psychosis. With early detection and treatment, most of those affected can live relatively normal lives. Liver and neurologic damage that occurs prior to treatment may improve, but it is often permanent

Incorrect Option Explanations:

Option A. Corneal Ulcer - Atropine is often used in corneal ulcers to provide pain relief by paralyzing the ciliary muscle and preventing ciliary spasm. It also helps reduce secondary uveitis associated with corneal infections.

Option B. Angle-Closure Glaucoma (ACG) - Atropine is contraindicated in primary ACG because it dilates the pupil, which can further narrow the drainage angle and precipitate an acute attack by significantly increasing IOP. However, in some secondary glaucomas, atropine may have a role in stabilizing the eye, but it is generally avoided in angle closure.

Option D. Malignant Glaucoma - Atropine is actually used in the management of malignant glaucoma (aqueous misdirection syndrome). It helps by relaxing the ciliary body, shifting the lens-iris diaphragm posteriorly, and reducing aqueous misdirection, thereby relieving the condition.

Key Takeaway:

Topical atropine is contraindicated in acute anterior uveitis (AAU) due to its potential to increase intraocular pressure and worsen inflammation. It is beneficial in conditions like corneal ulcers and malignant glaucoma but should be avoided in primary angle-closure glaucoma.

https://en.wikipedia.org/wiki/Wilson%27s_disease

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