Wilson’s disease (WD), also known as hepatolenticular degeneration, is familial disease of copper overload characterized by neurological and hepatic complications.
An autosomal recessive inheritance of a mutation in the gene called ATP7B is the underly pathology (see “Copper metabolism and pathophysiology” below).
Incidence = 1/30,000.
Prevalence = 3/100,000.
Copper is required as a co-factor in metabolic reactions. Most people ingest 1-2mg copper/day. It is absorbed by enterocytes in the stomach, duodenum and jejunum then transported to the liver bound to albumin.
Copper is processed by the liver in two ways (illustrated on the diagram opposite):
ATP7B (found on chromosome 13) is the gene for WDP, which is required for transmembrane movement of copper. The mutation present in WD reduces the excretion of copper and the incorporation of copper into caeruloplasmin. The accumulation of copper inside hepatocytes results in toxic damage to hepatocytes, leading to chronic hepatitis and ultimately cirrhosis.
Copper is also released into the blood where is it deposited in other organs, primarily:
Copper is also toxic to red blood cell membranes, resulting in haemolysis.
Most present at 3-40 years.
Childhood presentation is usually as a consequence of liver disease:
Adolescents and young adults tend to present with neurological or psychiatric features:
Kayser-Fleischer (K-F) rings are green-brown coloured areas around the edge of the corneas, resulting from copper deposition in Decement’s membrane.
See below for a full list of the features of WD.
Asymptomatic hepatomegaly or splenomegaly
Transient jaundice (as a result of haemolysis)
Acute hepatitis / liver failure
Compensated or decompensated cirrhosis
Aminoaciduria (due to a form of renal tubular acidosis)
Mentrual irregularity, miscarriage and infertility
Lunulae ceruleae (blue colour found at the base of the fingernails due to copper accumulation)
Pseudobulbar palsy (causing dysphagia and therefore at risk from aspiration)
A childhood presentation will give history of acute liver failure with rapid onset jaundice, nausea and vomiting, bleeding, confusion (from hepatic encephalopathy) and upper right quadrant pain (due to liver capsule stretch). They will have been very unwell.
An adolescent presenting with WD can give almost any variety of neuropsychiatric symptoms, with or without a tremor. They may describe difficulty in formulating words (dysarthria) or swallowing (dysphagia) however it would be rare to have limb weakness (which would point towards a diagnosis of motor neurone disease). A further history may be one of a personality change or psychosis that is unresponsive to conventional medication.
In practice diagnosis is difficult because biochemical results may be inconsistent.
Slit-lamp examination should be performed to examine for K-F rings.
24-hour urine collection for copper.
Serum caeruloplasmin is <200mg/L in 85% of patients.
Liver function tests:
Serum copper is usually low (<11mmol/L) however can be high from hepatocyte necrosis during acute hepatitis.
Liver biopsy gives histology and allows assessment of copper content.
Genetic analysis of ATP7B is difficult due to multiple potential mutations. The most common mutation is His1069Gly, which accounts for 50% of patients in Europe and the USA.
A CT or MRI scan of the head may show structural abnormalities of the basal ganglia.
Acute liver failure
More common in children and twice as frequent in women. Occurs when there is massive hepatocyte necrosis and causes release to large quantities of copper into the circulation. This results in intravascular haemolysis and acute kidney injury. Present with a coagulopathy unresponsive to intravenous vitamin K therapy. Management is the same as for acute failure of any cause however transplant is usually required to survive.
Chronic liver disease (in the absence of acute decompensation). Advise a low-copper diet, by avoidance of chocolate and shellfish.
D-penicillamine is chelator that promotes urinary excretion of copper.
Trientine is an alternative chelator that promotes urinary excretion. Its side effects are rash, gastritis and sideroblastic anaemia.
Zinc salts can be given to reduce gastrointestinal absorption of copper
First-degree relatives of those affected should be screened. When the patient has decompensated cirrhosis or early hepatocellular carcinoma, liver transplant is the treatment of choice. As the genetic abnormality is localised to the liver, transplant is curative because the ability to excrete copper is restored.
Early intervention helps to delay liver damage however transplant is usually ultimately required. Neurological degeneration is permanent and liver transplantation will not reverse the damage.
Most common causes of death are: infection, variceal bleeding or liver failure.
Image "Kayser-Fleischer rings" from: Fred H, van Dijk H. Images of Memorable Cases: Case 9 [Connexions Web site]. December 8, 2008. Available at: http://cnx.org/content/m15007/1.3/
Image "Hepatocyte copper handling: from: User:Jfdwolff. Copper Metabolism. 2008. English Wikipedia. Available at: http://en.wikipedia.org/wiki/File:Copper_metabolism.png
Roberts E., Schilsky M. Diagnosis and treatment of Wilson disease: An update. Hepatology (2008) 47;6:2089-2111
Kumar P., Clark M. Clinical Medicine 7th Edition (2009). Elsevier Saunders
Longmore M., Wilkinson I., et al. Oxford handbook of clinical medicine 8th Edition (2010). Oxford University Press
Bloom S., Webster G. Oxford handbook of gastroenterology and hepatology (2006). Oxford University Press
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