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Wilson disease is a rare autosomal recessive inherited disorder of copper metabolism that is characterised by excessive deposition of copper in the liver, brain, and other tissues. Wilson’s disease is an autosomal recessive condition due to a mutation in the Wilson disease protein (ATP7B) gene.

Signs and symptoms

Hepatic dysfunction is the presenting feature in more than half of patients. Although the condition may manifest as acute hepatitis, the 3 major patterns of hepatic involvement are as follows:

  • Chronic active hepatitis

  • Cirrhosis (the most common initial presentation)

  • Fulminant hepatic failure

Signs of fulminant hepatic failure include the following:

  • Ascites and prominent abdominal veins

  • Spider nevi

  • Palmar erythema

  • Digital clubbing

  • Hematemesis

  • Jaundice

Neuropsychiatric features

Most patients who present with neuropsychiatric manifestations have cirrhosis. The most common presenting neurologic feature is asymmetric tremor, which is variable in character and may be predominantly resting, postural, or kinetic.

Frequent early symptoms include the following:

  • Difficulty speaking

  • Excessive salivation

  • Ataxia

  • Masklike facies

  • Clumsiness with the hands

  • Personality changes

Late manifestations (now rare because of earlier diagnosis and treatment) include the following:

  • Dystonia

  • Spasticity

  • Grand mal seizures

  • Rigidity

  • Flexion contractures

Psychiatric features (10-20% of patients) include the following:

  • Emotional lability

  • Impulsiveness

  • Disinhibition

  • Self-injurious behavior

Psychiatric abnormalities associated with Wilson disease has been divided into the following 4 basic categories:

  • Behavioral

  • Affective

  • Schizophrenic-like

  • Cognitive

Musculoskeletal manifestations

  • The arthropathy of Wilson disease is a degenerative process that resembles premature osteoarthritis

  • Symptomatic joint disease usually arises late in the course of the disease, frequently after age 20 years

  • The arthropathy generally involves the spine and large appendicular joints (eg, knees, wrists, hips)

  • Osteochondritis dissecans, chondromalacia patellae, and chondrocalcinosis have also been described

Hematologic and renal manifestations

  • Coombs-negative acute intravascular hemolysis (10-15%)

  • Urolithiasis

  • Hematuria

Kayser-Fleischer rings

  • Formed by the deposition of copper in the Descemet membrane in the limbus of the cornea

  • The color may range from greenish gold to brown

  • Well-developed rings may be readily visible to the naked eye or with an ophthalmoscope set at +40

  • When not visible to the unaided eye, the rings may be identified using slit-lamp examination or gonioscopy

  • Observed in up to 90% of individuals with symptomatic Wilson disease and almost invariably present in those with neurologic manifestations

  • No longer considered pathognomonic of Wilson disease unless accompanied by neurologic manifestations, as they may also be observed in patients with chronic cholestatic disorders.

Additional manifestations

  • Skeletal abnormalities (eg, osteoporosis, osteomalacia, rickets, spontaneous fractures, polyarthritis)

  • Cardiac manifestations (eg, rhythm abnormalities, increased autonomic tone)

  • Skin pigmentation and a bluish discoloration at the base of the fingernails

Diagnosis

Considerations in the workup of Wilson disease are as follows:

  • Serum ceruloplasmin levels are less than 20 mg/dL (reference range, 20-40 mg/dL) in approximately 90% of all patients with Wilson disease

  • The urinary copper excretion rate is greater than 100 mcg/day (reference range, < 40 mcg/day) in most patients with symptomatic Wilson disease, but it may also be elevated in other cholestatic liver diseases

  • In a patient with Kayser-Fleischer rings, a serum ceruloplasmin level < 0 mg/dL and 24-hoyr urine copper excretion >40 mcg/day establish the diagnosis of Wilson disease

  • Hepatic copper concentration (criterion standard) on a liver biopsy specimen is >250 mcg/g of dry weight even in asymptomatic patients; a normal result (15-55 mcg/g) effectively excludes the diagnosis of untreated Wilson disease, but elevation may be found in other chronic hepatic disorders

  • Radiolabeled copper testing directly assays hepatic copper metabolism

  • Genetic testing is limited to screening of family members for an identified mutation detected in the index patient

  • Brain imaging shows characteristic findings; MRI appears to be more sensitive than CT in detecting early lesions

  • Abdominal imaging findings are neither sensitive nor specific

  • Resting ECG abnormalities include left ventricular or biventricular hypertrophy, early repolarization, ST segment depression, T-wave inversion, and various arrhythmias

  • Electron microscopic detection of copper-containing hepatocytic lysosomes is helpful in the diagnosis of the early stages of Wilson disease, in addition to the quantification of hepatic copper by atomic absorption spectrophotometry

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 illness, in which its benefit has not been demonstrated.

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