Epidemiology

• Wilson's disease is inherited as an autosomal recessive trait. It is a rare condition and can often be difficult to diagnose.^[3]
• The worldwide prevalence of Wilson's disease is estimated 1 in 30,000, with a gene frequency of 0.56% and a carrier frequency of 1 in 90.^[4]
• A Slavic type has a late age of onset and predominantly neurological features.
• There is a juvenile type, which occurs in Western Europeans and several other ethnic groups. This has onset before age 16 years and mainly affects the liver.^[5]
• There is also a rare atypical type in which heterozygotes have only half the normal level of caeruloplasmin.
• The most common mutation in patients from Europe is H1069Q.
• A unique 15-bp deletion in the 5-prime region is frequent in Sardinia.
• M645R is common in Spain and R778L is often found in patients from eastern Asia.

Presentation

A high index of suspicion is required for prompt diagnosis. Wilson's disease should be considered in any child or young adult with unexplained liver abnormalities and also in patients with movement disorders.

Wilson's disease usually presents as liver disease in children and adolescents - the typical age of onset is 6-20 years - and as neuropsychiatric illness in young adults. However, younger children and older adults can also present with this condition.

Most patients who present with neurological features already have cirrhosis.

Hepatic features

Hepatic disease due to Wilson's disease is diverse. Patients may simply present with persistent asymptomatic hepatomegaly or elevation of serum aminotransferases. The major patterns of hepatic involvement are:

• Acute hepatitis.
• Steatosis.
• Severe chronic liver disease with small, shrunken liver, splenomegaly and ascites.
• Fulminant hepatic failure ± haemolytic anaemia.

Psychiatric features

Psychiatric disorders may be the main clinical feature in up to 20% of patients. Severe depression or various neurotic behavioural patterns are the most common presentations.

Neurological features

Patients usually present with movement disorders:

• The most common early neurological sign is an asymmetrical tremor, in about half of patients.
• The character of the tremor is variable and may be predominantly resting, postural or kinetic.
• Other early symptoms include difficulty speaking, excessive salivation, ataxia, mask-like facies, clumsiness with the hands and personality changes. Some of these features are suggestive of Parkinson's disease.
• There may be choreiform movements that can be accompanied by gait disturbances, dysarthria and pseudobulbar palsy.

Ophthalmological features

• The characteristic ophthalmological feature of this disease is the Kayser-Fleischer ring that is present in up to 90% of those with symptomatic (especially neurological) disease:
  • A greenish gold or brown ring on the cornea may be visible to the naked eye or via the ophthalmoscope but usually a slit lamp examination is required.
  • This feature is not pathognomonic of Wilson's disease, as it may occur in partial biliary atresia, primary biliary cirrhosis, primary sclerosing cholangitis, and cryptogenic cirrhosis.
• The other characteristic feature is 'sunflower cataracts'. They are brilliantly multi-coloured but are visible only by slit-lamp examination. They do not impair vision.
• Less common findings include night blindness, exotropic strabismus, optic neuritis and optic disc pallor.

Other features

• Renal:
  • A renal Fanconi's syndrome may occur with hypercalciuria and nephrocalcinosis along with renal loss of amino acids, glucose, phosphate and excess uric acid.

• Rheumatological:
  • Rheumatological features include osteopenia that may be apparent on normal X-rays and arthritis, which is a common feature over the age of 20, occurring in 20-50% of patients.
  • The spine and large appendicular joints such as the knees, wrists, and hips are most often involved. Osteochondritis dissecans, chondromalacia patellae and chondrocalcinosis have also been described.
  • The chondrocalcinosis and osteoarthritis of Wilson's disease may be due to copper accumulation similar to the arthropathy of haemochromatosis.
  • Cardiac arrhythmias can occur.
  • Haemolytic anaemia occurs in 10-15%. It is Coombs-negative and due to high copper levels.
  • Azure lunulae of the fingernails have been described and are presumably due to deposition of copper.

Investigation

Although the diagnosis of Wilson's disease depends on the evaluation of clinical and laboratory evidence of abnormal copper metabolism, there is no single test that is reliable in isolation.^[6] Wilson's disease should be considered in any patient, at any age, presenting with unusual liver or neurological abnormalities.

• The presence of Kayser-Fleischer rings and a low serum caeruloplasmin (<0.1g/l) is sufficient to esatblish a diagnosis.^[7] 
• Biochemical findings include low serum caeruloplasmin, elevated basal 24-hour urinary excretion of copper and increased hepatic parenchymal copper concentration.
• Genetic diagnosis remains limited, largely because most patients are compound heterozygotes. Almost all the known mutations have a low prevalence.
• Assay by the enzymatic method seems most accurate.^[8]
• Diagnosis can be made from the presence of Kayser-Fleischer rings in a patient with neurological signs or symptoms suggestive of Wilson's disease.
• A patient with hepatitis and a raised urine copper of >100 micrograms/24 hours also has Wilson's disease and does not need further investigations.
• Blood caeruloplasmin is not always diagnostic because 10-25% of patients have results within normal range.
• Urinary excretion of copper is raised.
• Liver biopsy is often diagnostic. Histological findings may include steatosis, glycogenated nuclei in hepatocytes, focal hepatocellular necrosis, fibrosis or cirrhosis.
• MRI scan may show lesions at sites compatible with the neurological features. It is common to find increased density in the basal ganglia.
• ECG may indicate cardiac involvement.

Family screening of first-degree relatives should occur, as the chance of a sibling being homozygous (and therefore developing clinical symptoms) are 25%.^[7]  This is done by genetic analysis of the ATP7B gene, especially in patients with indeterminate clinical and biochemical features.

Management

Unlike many genetic disorders, Wilson's disease is treatable. The goal of treatment is to remove toxic levels of copper from the body and prevent copper from re-accumulating.

General measures

• Monitor hepatic and renal function, FBC and clotting.^[9]
• Avoid alcohol and drugs that are possibly hepatotoxic.
• Patients should avoid food high in copper, such as liver, chocolate, nuts, mushrooms, legumes and shellfish, especially lobster.
• Annual slit-lamp examination of Kayser-Fleischer rings should document fading or disappearance if copper is being adequately removed. If the rings return, it suggests poor compliance with treatment.
• All patients need lifelong follow-up by specialist units to monitor progress, both clinical and biochemical, and to be alert to the side-effects of drugs, and encourage compliance.

Pharmacological

The mainstay of treatment for Wilson's disease is the use of chelating agents and medications to block copper absorption from the gastrointestinal tract:

• Penicillamine is most commonly used. It forms soluble complexes with metals and is excreted in urine. About one third of patients treated with penicillamine have to change to trientine or zinc because of major adverse effects, including skin disorders, protein-losing nephropathy, lupus-like systemic inflammatory conditions and bone marrow suppression.^[7]  About 15-20% of patients with neurological Wilson's disease experience severe, although usually transient, worsening of their neurological symptoms when starting treatment with penicillamine.
• Zinc may be useful before symptoms appear, for maintenance after initial therapy or in pregnancy. Zinc prevents the absorption of copper but chelation should continue for 2 to 3 weeks after it has been started, as the onset is slow. Zinc is generally regarded as maintenance therapy, for use after the patient has been treated successfully with a chelator for 1-5 years.
• Trientine was initially used for the treatment of Wilson's disease only in patients intolerant of penicillamine but it is now gaining acceptance as first-line therapy for hepatic and neurological disease. It may be the best option and it may be even more effective when used in combination with zinc.

Pregnancy in Wilson's disease

• Women with Wilson's disease who become pregnant require anti-copper therapy during their pregnancy.
• Counselling should include chance that offspring will be homozygous is 0.5%
• The major goal of treatment is to protect the mother from copper toxicity while protecting the fetus from possible teratogenesis due to low copper levels.
• There is no contra-indication to pregnancy in women with Wilson's disease in the maintenance phase of treatment except if liver function is poor.
• Treatment should not be stopped during pregnancy, although conversion to zinc treatment may be advantageous since D-penicillamine is classified as a teratogen.

Liver transplant

In selected cases, a liver transplant can reverse the basic metabolic abnormality and improve both hepatic and neurological symptoms. It is usually reserved for patients with fulminant hepatic failure and liver disease unresponsive to standard treatment.

Heterozygotes can serve as living donors; however, a sibling requires genetic testing before donation, to be certain that he or she is not affected but pre-symptomatic.

Complications

• Cirrhosis is a frequent presentation and this may lead to liver failure.
• Liver cancer is extremely uncommon in patients with Wilson's disease.

Prognosis

• Early initiation of treatment usually leads to a normal length and quality of life. Without treatment, Wilson's disease is usually fatal, typically before the age of 40.
• Early treatment gives the best results and so, if there is a family history, screening may allow treatment to start in childhood before the onset of symptoms.
  Active treatment of early disease, as in children, may lead to some reversal of neurological signs.
• Both Kayser-Fleischer rings and sunflower cataracts are reversible with treatment.
• Only limited reversibility occurs with treatment of established hepatic and neurological disease but progression can be affected.
• It is essential to educate the patient as to the need for lifelong treatment. Patients are often relaxed about taking medication when they feel well.