Wilson's Disease

Synonym: hepatolenticular degeneration

Wilson's disease was originally described by Dr Samuel Alexander Kinnier Wilson in 1912.¹ The primary abnormality would appear to be a deficiency in the protein caeruloplasmin that is involved in the transport of copper, leading to deposition of copper in various organs of the body. Wilson's disease is particularly characterised by hepatic and neurological disease. Wilson's disease is caused by a mutation on chromosome 13 at the site 13q14.3-q21.1.² There are many different mutations and they may present differently.³

• Wilson's disease is inherited as an autosomal recessive trait. The worldwide prevalence of Wilson's disease is estimated to be 30 per million, with a gene frequency of 0.56% and a carrier frequency of 1 in 90.²
• There is a higher prevalence in Sardinia, where approximately 10-12 new cases per year are identified.²
• The fulminant presentation is 4 times more common in women than men.
• Wilson's disease in Asia seems to manifest differently from in Europe and America.⁴
• A juvenile type is the commonest form in Western Europeans and several other racial groups. Onset is before 16 years old with predominantly hepatic problems.
• A Slavic type has a late age of onset and predominantly neurological features.
• There is also a rare atypical type in which heterozygotes have only half the normal level of caeruloplasmin.

Wilson's disease presents as liver disease in children and adolescents, peaking between 10 and 13 years, and as neuropsychiatric illness in young adults around 19 or 20. It should be considered in anyone under 40 who presents with unexplained chronic liver disease. It can present as acute hepatitis. Hepatic dysfunction is the first feature in over half of patients. Most patients who present with neurological features already have cirrhosis.

Hepatic features

The major patterns of hepatic involvement are:

• Chronic active hepatitis
• Cirrhosis may be compensated or decompensated
• Fulminant hepatic failure ± haemolytic anaemia
• Persistently elevated serum aminotransferases

Neuropsychiatric features

Patients who present with neurological or psychiatric features without hepatic problems tend to be older but there may well be undiagnosed liver disease including cirrhosis. Neuropsychiatric features include:

• The commonest 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.
• Late features include dystonia, spasticity, grand mal seizures, rigidity and flexion contractures but they are rarely seen nowadays because of earlier diagnosis and more effective treatment.
• Between 10 and 20% have psychiatric problems that may be behavioural, affective, schizophrenic in nature or cognitive. They include emotional lability, impulsiveness, disinhibition and self-injury.
• Neuropsychiatric symptoms may be as vague as migraine headaches and insomnia.

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 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 multicoloured 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.
    Renal stones occurred in 16% of one series - many at presentation.⁵
• Rheumatological:
  • Rheumatological features include osteopenia that may be apparent on normal X-rays and arthritis is a common feature over the age of 20, occurring in 20 to 50% of patients.
  • The spine and large appendicular joints such as knees, wrists, and hips are most often involved. Osteochondritis dissecans, chondromalacia patellae and chondrocalcinosis have also been described.⁶
  • The chondrocalcinosis and osteoarthritis of Wilson's disease may be due to copper accumulation similar to the arthropathy of haemochromatosis.
• Cardiomyopathy:
  • Cardiomyopathy is not often regarded as a major feature of the disease but it may be rather more common than generally thought.
  • A study of 53 patients showed ECG abnormalities in 34%.⁷ There was left ventricular hypertrophy, biventricular hypertrophy and potentially serious conduction defects. There were 2 cardiac deaths, 1 from recurrent ventricular fibrillation and the other from dilated cardiomyopathy.
• Haemolytic anaemia occurs in 10 to 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.

No one test is diagnostic but, if a patient presents with neurological symptoms, Kayser-Fleischer rings and a low caeruloplasmin concentration, the diagnosis would seem certain. However, presentation and findings can be highly variable and clinical suspicion is essential. Even liver copper content may be misleading.⁸

• Diagnosis is made by the presence of Kayser-Fleischer rings and caeruloplasmin levels of less than 20 mg/dL in a patient with neurological signs or symptoms suggestive of Wilson's disease.
• Copper and caeruloplasmin:
  • If a patient is asymptomatic, has isolated liver disease and no corneal rings, an elevated hepatic copper concentration and a low serum caeruloplasmin level is sufficient to establish the diagnosis.
  • Low levels of caeruloplasmin also occur in severe protein malnutrition.
  • Caeruloplasmin levels in neonates are always low but a plasma isoform has been identified that is low only in Wilson's disease and cord blood or dried blood spots may permit neonatal diagnosis, before substantial tissue damage has occurred.⁹
  • Urinary excretion of copper is raised.
  • Liver biopsy will show elevated levels of copper.
• MRI scan may show lesions at sites compatible with the neurological features but it is unlikely to add much to the diagnosis. Clinical features have been correlated with MRI studies of copper deposition.^10,11
• ECG may indicate cardiac involvement.

The following recommendations are made for diagnosis:³

• The disease should be considered when there is recent onset of movement disorders and abnormal liver function tests.
• Assessment should include history, physical examination, liver function tests, full blood count, serum copper and caeruloplasmin and 24-hour urinary copper excretion. There should also be liver biopsy, as quantitative copper concentrations remain the best biochemical evidence for Wilson's disease.
• Kayser-Fleischer rings should be sought using slit-lamp examination by an ophthalmologist.
• Family screening of first-degree relatives should occur and, where possible, genetic diagnosis should be used, especially in patients with indeterminate clinical and biochemical features.

Non-drug

• Monitor hepatic and renal function.
• 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; however, the mainstay of treatment is chelation therapy.
• 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.

Drugs

The mainstay of treatment for Wilson's disease is the use of chelating agents and medications to block copper absorption from the gastrointestinal tract. Expert opinion about medication for Wilson's disease is in a state of transition.³

• Penicillamine has been the agent most commonly used. It forms soluble complexes with metals and is excreted in urine. It has been used for many years.
• 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 toxicity does not seem to be a problem.
• Dimercaprol can be used in refractory cases. Its other name is British anti-Lewisite (BAL). It was used as an antidote to mustard gas (Lewis agent) in the First World War and was the first treatment for Wilson's disease in 1951.
• 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.¹²
• Penicillamine-induced systemic lupus erythematosus may not resolve on transfer to trientine.
• Tetrathiomolybdate is a new agent that is under investigation. Results so far seem very promising¹³ but it is not yet available in the UK.

Surgical

In selected cases, an orthotropic liver transplant can reverse the basic metabolic abnormality and improve both hepatic and neurological symptoms.¹⁴

• Cirrhosis is a frequent presentation and this may lead to liver failure.
• Cirrhosis can progress to hepatocellular carcinoma. Excess metals cause oxidative stress and so Wilson's disease and haemochromatosis are both rather susceptible to malignant change.
• High levels of copper in the uterus may account for a high rate of spontaneous abortion but once cirrhosis occurs then pregnancy is unlikely.

• Treatment in pregnancy seems contentious. It appears that high copper levels impair fertility and recurrent abortion is common, and that pregnancy does not have an adverse effect on the disease.¹⁵
• There may be difficulties with conception but this may be related to cirrhosis.¹⁶ Hence chelation therapy should be used before pregnancy.
• Some authors advise that penicillamine should be continued in pregnancy and that in low dose and with zinc, teratogenesis is not a problem.¹⁷
• Teratogenesis with penicillamine does occur but is uncommon.¹⁸ After discussion with the patient, it may well be that treatment should be continued therapy throughout pregnancy.¹⁹

• Early initiation of treatment may allow a normal length and quality of life. Without treatment, Wilson's disease is usually fatal, usually 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. People are often lax about taking medication when they feel well.