Wilson's disease

Synonym: hepatolenticular degeneration

Wilson's disease was originally described by Dr Samuel Alexander Kinnier Wilson in 1912. It is a disorder of hepatic copper disposition caused by mutations in the gene ATP7B, located on chromosome 13¹ . More than 800 gene mutations are currently known² .

This gene encodes a P-type adenosine triphosphatase (ATPase), known as Wilson's ATPase, which functions within hepatocytes to move copper across intracellular membranes. The copper-transporting action directly supports production of the ferroxidase caeruloplasmin, in which copper is incorporated, as well as excretion of copper into bile. Consequently, in Wilson's disease, serum concentrations of copper are low and hepatic retention of copper develops, leading to liver injury.

Genetic mutations may be homozygous or heterozygous, leading to a variety of clinical presentations.

Epidemiology

• Wilson's disease is inherited as an autosomal recessive trait. It is a rare condition and can often be difficult to diagnose³ .

• Wilson's disease affects about 1 in 30,000 individuals⁴ .

• 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 liver⁵ .

Presentation⁶

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.

The typical age of onset is during the second and third decades of life. Wilson's disease usually presents as liver disease in children and adolescents, 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 liver failure.

• Chronic hepatitis and cirrhosis.

• Severe chronic liver disease with small, shrunken liver, splenomegaly and ascites.

• Fulminant hepatic failure ± haemolytic anaemia.

Psychiatric features

Psychiatric disorders and behavioural problems are common and may be the main clinical feature. 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 95% 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 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 osteoarthritis.

  • 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.

  • Myopathy.

• Cardiac arrhythmias and cardiomyopathy can occur.

• Hypoparathyroidism.

• Pancreatitis.

• Infertility.

• Azure lunulae of the fingernails have been described and are presumably due to deposition of copper.

Investigation^{6 7}

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. 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 establish a diagnosis.

• 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. Advances in the automatic extraction, sequencing and analysis of DNA, however, makes this a more feasible prospect¹ .

• Assay by the enzymatic method seems most accurate⁸ .

• Diagnosis can be made from the presence of Kayser-Fleischer rings in a patient with neurological signs or symptoms suggestive of Wilson's disease.

• Urinary excretion of copper is raised.

• Liver biopsy is often diagnostic but is only required if clinical signs and non-invasive tests do not allow definitive diagnosis or if there is suspicion of additional liver pathology.

• MRI scan may show lesions at sites compatible with the neurological features. It is common to find increased density in the basal ganglia. Brain scan may show a typical 'face of the giant panda' appearance.

• 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) is 25%⁶ . This is done by genetic analysis of the ATP7B gene, especially in patients with indeterminate clinical and biochemical features.

Management⁶

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 clotting⁹ .

• 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 efficacy of the commonly used drugs is satisfactory for hepatic disease, but disappointing in patients with neurological disease, including the risk of neurological deterioration after the initiation of chelation therapy¹⁰ .

The mainstay of treatment for Wilson's disease is the use of chelating agents and medications to block copper absorption from the gastrointestinal tract¹¹ . Currently available treatments, including zinc acetate and trientine, are generally well tolerated and effective¹² .

• Penicillamine 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 suppression⁶ . 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 prevents the absorption of copper but chelation should continue for two to three weeks after it has been started, as the onset is slow.

• 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

• There is a range of practice regarding the treatment of women with Wilson's disease who become pregnant. Some authorities recommend continuing anti-copper therapy during the pregnancy. The British National Formulary (BNF) advises that fetal abnormalities have been reported with penicillamine, but only rarely. Nevertheless, the BNF advises avoiding penicillamine if possible¹¹ . Trientine has been associated with abnormalities in animal studies, and the BNF advice it to use it 'only if benefit outweighs risk'. The BNF identifies no fetotoxic concerns with zinc acetate, so this may be the safest option.

• An approach that has been suggested is to provide intense copper chelation therapy pre-pregnancy, and to stop therapy during the pregnancy itself¹³ .

• 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.

• Counselling should include that the chance that offspring will be homozygous is 0.5%.

Liver transplant¹⁴

Liver transplantation is indicated for the approximately 5% of patients with acute liver failure as the first presentation of disease, most commonly in the second decade of life, or those who present with end-stage liver disease and severe hepatic insufficiency, most commonly in the third and fourth decades.

Liver transplantation restores normal biliary copper excretion (and so prevents disease recurrence) and promotes removal of copper from extrahepatic sites. Outcomes of liver transplantation are excellent, from both cadaveric and living donors.

Deep brain stimulation¹⁵

Deep brain stimulation may be an effective approach to treat medically refractory residual neurological symptoms in carefully selected patients.

Complications

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

Prognosis

• Wilson's disease is a progressive disease and fatal if untreated¹⁶ .

• 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 effectively restricted.

• 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.