Wilson’s Disease

Wilson’s disease is an inherited disorder of copper metabolism which leads to accumulation of copper in the brain, liver, eyes, and other organs.

Epidemiology

Wilson’s has a prevalence of 1 / 30000. It is slightly more common in men. The age of onset is between 5 – 35.

Genetics

Wilson’s is normally inherited in an autosomal recessive manner due to mutations in the ATP7B gene on chromosome 13.  There are >500 recognised disease-causing mutations of which the most common in H1069Q.

Pathophysiology

ATP7B is an ATP-dependent transport protein which actively transports extracellular copper across the cell membrane. It is involved in incorporating copper molecules into caeruloplasmin, which transports 6 copper atoms per molecule in the serum. Apocaeruloplasmin (the unbound form) is far less stable than holocaeruloplasmin (the bound form). The defect in ATP7B leads to a decreased conversion of apocaeruloplasmin to holocaeruloplasmin. This leads to reduced excretion of copper in the bile and accumulation of free copper in the tissues. The most clinically important tissues are neurons and hepatocytes. While the total serum copper is therefore reduced (due to caeruloplasmin deficiency), the free serum copper is raised.

Clinical manifestations

Wilson’s presents in a highly variable way. The first onset of symptoms is usually in adolescence.

The age of onset determines the mode of presentation. Liver disease is the earliest manifestations in children, whereas neurological manifestations are the more common presenting feature in late teens (15 – 21).

Wilson’s disease can cause a broad range of neurological and neuropsychiatric manifestations. The most common manifestations are movement disorders, which may co-exist and may mimic many other conditions. Common presenting features include dysarthria, cerebellar ataxia, dystonia (focal or generalised), tremor (any type), parkinsonism, and chorea. Other possible features include dementia, seizures, and risus sardonicus (a grimace caused by facial muscle dystonia).

While psychiatric manifestations usually occur with neurological disease, they may be an early feature of Wilson’s that is often missed. Common presentations include depression, behavioural disturbance, and irritability; these are all non-specific.

There is a broad spectrum of liver disease in Wilson’s, from asymptomatic deranged liver function tests to fulminant hepatic failure. Many people with this disease will develop chronic hepatitis which, over time, causes cirrhosis.

Kayser-Fleischer rings are light-brown copper deposits in the cornea which are pathognomonic (highly specific) but not sensitive for Wilson’s disease. They are seen in 98% of people with neurological involvement and 50% with hepatic involvement.

 

Kayser-Fleischer_ring

Kayser-Fleischer ring

 

Other (rarer) manifestations include haemolytic anaemia (associated with the presence of hepatic disease), proximal tubular dysfunction (Fanconi syndrome), pseudogout, cardiomyopathy, and various other rarities.

Diagnosis

Wilson’s disease is rare and so diagnosing it relies on having a high clinical suspicion.

Clinical suspicion should be raised in any young patient presenting with one or multiple unexplained movement disorders, psychiatric disturbance, and/or hepatic impairment. The presence of a family history should be sought.

Initial investigations:

  • Deranged LFTs
    • Hepatitic picture
    • AST:ALT (>2)
  • FBC
    • Anaemia (may indicated haemolysis)
    • Thrombocytopaenia (indicated hypersplenism)
  • Low serum caeruloplasmin
  • Low serum copper

Further investigations

  • Slit lamp examination: Kayser-Fleischer rings
  • High 24 hour urinary excretion of copper
  • Genetic testing for ATP7B mutations
  • Liver biopsy

In the presence of a typical clinical picture, supportive biochemistry, and Kayser-Fleischer rings, the diagnosis of Wilson’s is likely. In indeterminate cases, further investigation (i.e. genetic testing, liver biopsy) may be required.

Management

The mainstay of management is lifelong chelation of free serum copper with chelating agents such as D-penicillamine and trientine. D-penicillamine is a nasty drug which causes various side effects, including:

  • Nausea, vomiting, and anorexia
  • Allergy (especially if penicillin-allergic)
  • Bone marrow suppression
  • Nephrotic syndrome (membranous nephropathy)
  • Myaesthenia gravis
  • Worsening of neurological disease on initiation