Wilson's disease

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Wilson's disease is uncommon and the diagnosis is often missed. This is due to its systemic involvement and varied clinical presentations with overlapping features. The mean delay from symptom onset to diagnosis is 2 years.[20] Wilson's disease can manifest as liver disease (with jaundice, and possibly ascites and oedema) or as a neurological movement disorder (with tremor, dystonia, rigidity), or it can be diagnosed at the asymptomatic stage.[21][22][23]

Early diagnosis is important because therapy is effective in achieving copper balance. Symptoms of the disease can be prevented or reversed if treated early, and thus family members of diagnosed patients should be screened.

Hepatic presentation

A patient presenting with liver disease secondary to Wilson's disease may have a history of unexplained hepatitis or aminotransferase elevations, thrombocytopenia, pancytopenia, indirect hyperbilirubinaemia, or Coombs-negative intravascular haemolysis.[5][20][24] Alternative presentations in adults and children include acute hepatitis, fatty liver, acute liver failure, or cirrhosis (compensated or decompensated).[5][25] Up to 20% of people with Wilson's disease present with acute liver failure, with symptoms of jaundice, hepatic encephalopathy, coagulopathy, ascites, and renal failure.[24] Children usually present after age 5 years and may be asymptomatic, with hepatomegaly or abnormal serum transaminases detected incidentally.[5][25] Patients may initially receive a diagnosis of acute viral hepatitis, metabolic dysfunction-associated steatotic liver disease (previously known as non-alcoholic fatty liver disease), or autoimmune hepatitis.[25]

Physical examination may reveal hepatomegaly or splenomegaly. There may be signs of chronic liver disease, such as spider angiomata, gynaecomastia, ascites, peripheral oedema, easy bruising, jaundice, or encephalopathy. The patient might have Kayser-Fleischer (KF) rings or sunflower cataracts (deposits of copper in the lens).[5] All patients with liver abnormalities of uncertain cause should be screened for Wilson's disease.[5]

Neurological presentation

A patient with neurological disease may have a history of symptoms of a movement disorder, including tremor, incoordination, sloppy handwriting, dysarthria, muscle stiffness, rigidity, postural abnormality, gait abnormality, chorea/athetosis, seizures, or drooling.[5][25][26] Neuropsychiatric symptoms usually develop in the second or third decade of life, but they have been reported in children under 10 years.[25] One or more psychiatric condition may be present at a time.[5] Patients often have abnormal behaviour, personality change, depression, psychosis, bipolar disorder, and cognitive impairment.[5][27][28] Other behavioural abnormalities that may be present are temper tantrums, anxiety, loss of memory, inability to focus on tasks, impulsiveness, and disinhibition.[24][28]

Patients can be mistaken for having Parkinson's disease or multiple sclerosis (although there is no sensory deficit).

On physical examination of the patient presenting with neurological disease, the following may be noted.

Tremor (of any type).
Dystonia and rigidity of any part of the body but most often the hands. This can cause postural and gait abnormalities. A dystonic smile may be seen.
Dysdiadochokinesis and evidence of clumsiness or lack of coordination.
Handwriting is often sloppy, but may be small (micrographia).
Speech may be abnormal, but the abnormalities are not specific for Wilson's disease. Words may be slurred and they may be of low volume (hypophonia). It may be almost stuttering in type (echolalia).
Dysphagia may cause the patient to drool and have difficulty with muscles of the lips and face.
Extra-ocular movements are occasionally abnormal.
Sensation is normal.
KF rings may be apparent (but should always be confirmed by slit-lamp examination). Sunflower cataracts may also be seen. [Figure caption and citation for the preceding image starts]: Eye demonstrating Kayser-Fleischer ringAdapted from BMJ (2009); used with permission [Citation ends].

Investigations

A detailed personal and family history should be collected from patients suspected to have Wilson's disease.[5] All patients should be investigated with liver function tests, slit-lamp examination for KF rings, serum ceruloplasmin, and 24-hour urinary copper measurement.[5] Further investigations may be indicated depending on the clinical presentation and results of the initial tests. No test is capable of diagnosing Wilson's disease in isolation.[29] The Leipzig score compiles clinical features and investigation results and calculates a score. A score of 4 or more is diagnostic for Wilson's disease.[5][6] See Diagnostic criteria.

Liver function tests, including prothrombin time

Liver function tests (LFTs) are almost always abnormal in patients with hepatic presentation.[5] Elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are present in 40% to 60% of patients at presentation.[24] Approximately 12% of patients have elevated bilirubin, due to liver injury, Coombs-negative haemolysis, or both.[6][24] Those with acute liver failure may have low albumin and prolonged international normalised ratio (INR). Those with decompensated cirrhosis may have prolonged INR, thrombocytopenia, mixed pattern of LFTs, and low albumin.[24]

In patients with neurological presentation, ALT and AST may also be abnormal because there can be overlap with liver involvement.[24]

24-hour urinary copper measurement

The sample should be collected in a container free of trace elements. Twenty-four-hour urinary copper >100 micrograms is consistent with Wilson's disease.[5] Twenty-four hour urinary copper >40 micrograms may suggest Wilson's disease and require further investigation.[5][24][25] Urinary copper excretion can also be high in cholestatic and autoimmune conditions or protein-losing enteropathy, so diagnosis of the disease should not be made on urine copper values alone.

Slit-lamp examination for KF rings

KF rings are gold-brown pigments representing copper deposition in the membrane of Descemet of the cornea. They usually appear in superior and inferior portions of the cornea and then become circumferential as copper deposition progresses.[24] KF rings are present in 95% of patients with neurological presentations and in 44% to 62% of patients with hepatic presentations.[5] They can disappear with adequate treatment for Wilson's disease.

Serum ceruloplasmin and non-ceruloplasmin-bound copper concentration (NCC)

Ceruloplasmin, synthesised in the liver, is the major copper-carrying protein in the blood. Normal serum ceruloplasmin level is 200-350 mg/L (20-35 mg/dL). A serum ceruloplasmin level of <50 mg/L (<5 mg/dL) strongly suggests Wilson's disease.[5] Further testing is required to make the diagnosis.

Serum ceruloplasmin is not always diagnostic because approximately 20% of patients with Wilson's disease have results within normal range.[5][25] Around 1% of the population are heterozygous for an ATP7B mutation and have an intermediate low ceruloplasmin level. Therefore, a normal serum ceruloplasmin does not exclude a diagnosis of Wilson's disease.[5] Serum ceruloplasmin <200 mg/L (<20 mg/dL) has a sensitivity of 77.1% to 99% and a specificity of 55.9% to 82.8% for diagnosis of Wilson's disease. Serum ceruloplasmin <100 mg/L (<10 mg/dL) has a sensitivity of 65.7% to 94.4%, and a specificity of 96.6% to 100%, for a diagnosis of Wilson's disease.[29]

Assay by the enzymatic method seems most accurate, but antibody-mediated assay can be used as an alternative. Ceruloplasmin can be increased in cases of inflammation as it is an acute phase reactant.[5] It can also be increased in pregnancy and oestrogen intake. It is usually low in infancy and is usually not measured until the child is >6 months.[5] Ceruloplasmin can also be low in cases of protein-losing enteropathy, non-selective renal protein loss, end-stage liver disease, nephrotic syndrome, neurological disorders (cervical dystonia), absolute copper deficiency (improper formulation of total parenteral nutrition omitting copper, after gastric or bariatric surgery, or chronic ingestion of zinc in excess), Menkes' disease, aceruloplasminaemia, MEDNIK syndrome, AP1B1 disorder, congenital glycosylation disorder (PGM1‐CDG, CCDC115‐CGD, or TMEM119‐CDG), or Niemann‐Pick's disease type C.[5][30]

Direct assay of free copper has been suggested to help in diagnosis.[31]

Serum copper is usually low in Wilson's disease due to decrease in circulating ceruloplasmin. The non-ceruloplasmin-bound copper concentration (NCC) can be calculated using the following equation:[5]

NCC = serum copper concentration (micrograms/dL) - (3.15 x serum ceruloplasmin concentration (mg/dL)).

A level greater than 25 micrograms/dL is often seen in untreated patients.[5] Elevated levels of NCC can be seen in cholestasis or excessive copper ingestion. Although often useful, the NCC cannot be interpreted if serum ceruloplasmin has been overestimated, because it may be a negative number.[5]

Liver biopsy

If the diagnosis is uncertain, the definitive diagnostic test is a liver biopsy with quantitative assay of copper (normal is 20 to 50 micrograms/g dry weight of tissue; in Wilson's disease the level is >250 micrograms/g).[5] Absence of copper stain on the liver tissue does not rule out Wilson's disease due to sporadic deposition of copper within the hepatocytes.[32][33]

Imaging

MRI of the brain is useful in neurological presentation. The most common findings are:[16][24][34]

Hyperintensity on T2-weighted images of the basal ganglia
Atrophy of the head of the caudate nucleus, brainstem, and cerebral and cerebellar hemispheres.

The 'face of the giant panda' sign is seen in T2-weighted images of the midbrain. It is uncommon but, if present, is characteristic of Wilson's disease.[35]

These findings are sensitive for Wilson's disease in cases of neurological presentation only. They are not specific for Wilson's disease. MRI findings can be similar in other neurological disorders.

DNA testing for mutations in the ATP7B gene

Although there are more than 700 pathogenic mutations in the ATP7B gene, next-generation sequencing can identify two pathogenic mutations in the majority of people with Wilson's disease.[24][25] The absence of two pathogenic mutations does not exclude Wilson's disease; clinical corroboration is required.[24]

Molecular testing is preferred before liver biopsy in children with suspected Wilson's disease.[25]

DNA analysis can be used to genotype siblings of a diagnosed Wilson's disease patient. It is not necessary to know the specific ATP7B mutation or mutations in the patient. DNA markers on both sides of both copies of the ATP7B gene in the patient are characterised. If a sibling matches both sets of markers they are affected, if they match one set they are a carrier, and if they match neither they are unlikely to have the disease.[19]

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