Wilson disease

Wilson disease, also known as hepatolenticular degeneration, is a rare and potentially fatal autosomal recessive disorder caused by impairment of both biliary copper excretion and serum copper transport. Copper first accumulates in the liver causing slowly progressive disease and subsequently spills over into the bloodstream causing oxidative damage to the brain, kidneys and other organs. The range of manifestations and phenotypes adds to the diagnostic challenge.

Epidemiology

Wilson disease is autosomal recessive, 1 in 90 people are heterozygous carriers ¹⁸ and approximately 1 in 30,000 individuals are affected ¹² depending on rates of consanguinity.

Diagnosis

• low serum ceruloplasmin <20 mg/dL (also present in any protein deficiency) ^13,14

• elevated urinary copper >100 mcg/dL14, high 24-hour excretion

• elevated bilirubin, AST and ALT

• low alkaline phosphatase and albumin

• presence of Kayser-Fleischer rings

• high liver copper on biopsy >250 mcg/gm dry liver (gold standard)

Clinical presentation

The clinical features are non-specific and varied, typically manifesting between the ages of 4 and 40 years of age, range 3 to 70 years ^5,11,13,15:

• chronic active hepatitis begins in early childhood and culminates in cirrhosis, portal hypertension and cirrhosis with an increased risk of hepatocellular carcinoma

• neuropsychiatric manifestations manifest in young adults and are occasionally the first recognized manifestation:

  • dysarthria

  • movement disorders: dystonia, asymmetric tremor, choreoathetosis, parkinsonism, ataxia

  • dementia

  • mood disturbance and behavioral disorders

• ocular manifestations:

  • Kayser-Fleischer rings in Descemet membrane of the peripheral cornea ¹¹, characteristic but not pathognomonic

  • sunflower cataracts, uncommon but pathognomonic ^22,23

• other manifestations:

  • premature osteoarthritis

  • hemolytic anemia

  • azure lunulae (blue nail discolouration)

  • cardiomyopathy and arrhythmias

  • urolithiasis

Pathology

Wilson disease is caused by one of many mutations of the ATP7B gene on the long arm of chromosome 13 which codes for the ATP7B enzyme that enables biliary excretion of excess copper, normally accounting for 95% of copper excretion. Copper first accumulates in the liver, generating free radicals and causing oxidative damage to proteins and lipids, with early damage to mitochondria, nuclei and peroxisomes.

Chronic active hepatitis begins in early childhood and progresses to cirrhosis and its complications - portal hypertension and risk of hepatocellular carcinoma.

The enzyme ATP7B is also necessary to link copper to ceruloplasmin and its absence means that excess hepatic copper is eventually released into the bloodstream as free copper. Free copper deposition in the brain affects the basal ganglia which control coordination of movement, mood regulation and other neurocognitive functions.

Radiographic features

Please see individual articles:

• Wilson disease: hepatobiliary manifestations

• Wilson disease: CNS manifestations

• Wilson disease: musculoskeletal manifestations

Treatment and prognosis 

Management potentially incorporates ^7,18,22:

• dietary restriction of copper

• avoid hepatotoxins including alcohol

• oral zinc, which competes with copper for absorption

• chelating agents such as trientine (less toxic) or D-penicillamine (during pregnancy)

  • chelation may exacerbate neuropsychiatric features for several months

• treatment of complications of liver disease and management of neuropsychiatric symptoms

• liver transplantation

Without treatment the disease may cause death as early as 30 years of age, although some phenotypes may not even be diagnosed until 70 years of age. Fulminant disease may be more common in females.

First and second degree relatives should be screened.

History and etymology

It was initially described by Samuel Alexander Kinnier Wilson (1878-1937), an American-born British neurologist, in 1912 as "progressive lenticular degeneration". Wilson also coined the terms extrapyramidal system and syndrome ^10,20. Interestingly, Kayser-Fleischer rings were initially described a decade earlier by German physicians Bernhard Kayser (1869-1954) and Bruno Fleischer (1848-1904) in 1902 and 1903 respectively ^16,17,21.