Wilson disease

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

ATP7B normally supports incorporation of copper into caeruloplasmin and excretion into bile. Biallelic pathogenic variants allow copper to accumulate first in hepatocytes and later spill into the circulation and other organs. Presentation ranges from incidental aminotransferase elevation, steatosis and chronic liver disease to acute liver failure. Neurological disease may include wing-beating or postural tremor, dystonia, dysarthria, drooling, ataxia, chorea, parkinsonism and swallowing difficulty. Depression, irritability, cognitive or personality change and psychosis can coexist or dominate early referral.

No solitary laboratory result safely proves or excludes Wilson disease. Very low caeruloplasmin is persuasive, but intermediate values overlap with other conditions. Twenty-four-hour urinary copper supports increased copper excretion but collection quality, acute hepatitis and prior treatment matter. Slit-lamp examination identifies corneal copper; MRI may show basal ganglia and brainstem abnormalities. If uncertainty persists, specialist use of ATP7B testing, liver copper quantification and the Leipzig score integrates the evidence.

Treatment removes accumulated copper or blocks absorption and must continue lifelong, including during pregnancy under specialist advice. Abrupt discontinuation can precipitate severe hepatic or neurological deterioration. Diet can reduce very high copper exposure early but never replaces pharmacological therapy. Chelator selection and interpretation of exchangeable copper require an expert hepatology–neurology centre with access to transplantation and genomic counselling.

Key points

Wilson disease is an autosomal recessive ATP7B disorder that impairs biliary copper excretion, causing toxic accumulation in liver, brain, cornea and other tissues; it is treatable but delays can create irreversible disability.
Think of it in children and younger adults with unexplained liver disease, progressive dystonia, tremor, dysarthria, parkinsonism, behavioural change or Coombs-negative haemolytic anaemia.
Kayser–Fleischer rings are best sought by experienced slit-lamp examination and are common in neurological disease, but their absence does not exclude a hepatic presentation.
Low caeruloplasmin supports the diagnosis but is not definitive: values can be reduced by other liver or protein-losing states and can be misleadingly normal during inflammation or some presentations.
Use convergent evidence—clinical features, caeruloplasmin, 24-hour urinary copper, slit lamp, ATP7B variants and sometimes hepatic copper—with the specialist Leipzig framework.
Total serum copper may be low because caeruloplasmin-bound copper falls even while harmful non-caeruloplasmin copper is increased; a simple total result should not be interpreted intuitively.
Symptomatic disease requires lifelong treatment, usually a chelator such as penicillamine or trientine; zinc is not a simple first-line substitute for significant symptomatic liver disease.
Neurological symptoms can transiently worsen when chelation begins, so experienced services use careful selection, low starting exposure and close early monitoring.
Screen siblings and relevant relatives through specialist biochemical and genomic pathways, because treatment before symptoms can prevent organ injury.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Biallelic ATP7B variants

Wilson disease is an autosomal-recessive disorder caused by pathogenic variants impairing hepatic copper transport and biliary excretion.

Familial susceptibility

Siblings and relatives have increased probability according to inheritance, while variable variants and modifiers produce very different ages and organ presentations.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Impaired biliary copper excretion
Defective ATP7B function prevents normal incorporation of copper into caeruloplasmin and biliary excretion, causing progressive hepatic accumulation.
2
Hepatocyte injury and copper release
Stored copper drives oxidative damage, fibrosis and cell death before spilling into blood and depositing in other tissues.
3
Brain and corneal deposition
Copper accumulates particularly in basal-ganglia and corneal tissues, producing dystonia, tremor, dysarthria, parkinsonism and Kayser–Fleischer rings.
4
Systemic free-copper toxicity
Circulating non-caeruloplasmin copper can damage red cells, kidneys and other organs, causing haemolysis and additional systemic injury.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Hepatic presentationRed flag

Unexplained steatosis, hepatitis, cirrhosis, portal hypertension or acute liver failure in a child or younger adult should keep Wilson disease active even without neurological signs or corneal rings.

Neurological presentation

Progressive dysarthria, tremor, dystonia, drooling, parkinsonism, gait change or chorea with psychiatric symptoms in a young person is a characteristic but variable syndrome.

Haemolytic clueRed flag

Acute Coombs-negative intravascular haemolysis, especially with jaundice and liver dysfunction, can reflect abrupt copper release and should trigger urgent specialist assessment.

Kayser–Fleischer ring

Brownish peripheral corneal copper in Descemet membrane is strongly supportive when confirmed at slit lamp, particularly with neurological disease, but is neither universally present nor entirely unique.

Affected relative

A sibling of a person with confirmed biallelic ATP7B disease has substantial inherited risk and needs proactive specialist testing before biochemical or clinical injury becomes obvious.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Serum caeruloplasmin and copper studiesFirst step
Why
Provide accessible biochemical evidence of disordered copper handling.
Interpretation and limitations
Very low caeruloplasmin strongly supports Wilson disease, but moderately low or normal values need context. Total serum copper can be paradoxically low and calculated non-caeruloplasmin copper has analytical limitations.
02
Twenty-four-hour urinary copper
Why
Estimate excessive copper excretion and later help assess treatment or adherence.
Interpretation and limitations
Elevation supports the diagnosis, while contamination, incomplete collection, active hepatitis and chelation alter results. Interpretation and units must follow the specialist laboratory rather than a memorised threshold alone.
03
Slit-lamp examination
Why
Detect Kayser–Fleischer rings and occasionally sunflower cataract through expert ocular assessment.
Interpretation and limitations
A ring carries greatest weight in a compatible neurological phenotype. Absence is common enough in liver-predominant disease that investigation must continue when other evidence persists.
04
Liver tests, blood count and haemolysis screen
Why
Define hepatic severity and identify intravascular haemolysis or portal-hypertension consequences.
Interpretation and limitations
Assess bilirubin, enzymes, albumin, INR, platelets, reticulocytes, LDH, haptoglobin and direct antiglobulin testing as appropriate. Coagulopathy and encephalopathy demand transplant-centre escalation, not diagnostic delay.
05
ATP7B genomic testing
Why
Confirm biallelic pathogenic variants and enable precise family screening when biochemical evidence is equivocal or supportive.
Interpretation and limitations
Variant classification requires an accredited genomic service. One variant does not usually establish autosomal-recessive disease, and negative testing may not exclude every pathogenic mechanism.
06
MRI brain or hepatic copper quantification
Why
Characterise neurological injury or resolve a difficult hepatic diagnosis when results will alter management.
Interpretation and limitations
Basal ganglia and brainstem signal can support neurological Wilson disease. Liver biopsy provides histology and quantitative copper but sampling variability and procedural risk require specialist selection.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Autoimmune or other liver disease

Viral, autoimmune, metabolic and drug-related hepatitis can mimic hepatic Wilson disease; convergent copper and genomic evidence is required.

Primary movement disorder

Young-onset dystonia, tremor or parkinsonism may be genetic or drug-induced, but liver, psychiatric and haemolytic clues support Wilson disease.

Huntington or psychiatric disease

Behavioural change and chorea may suggest Huntington disease or primary psychiatry; hepatic and copper abnormalities materially redirect assessment.

Other haemolytic disorders

Coombs-negative haemolysis with liver failure supports copper toxicity, while immune or inherited red-cell disorders have different laboratory patterns.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01SuspectBuild convergent diagnostic evidenceFirst stepA young person has unexplained hepatic, movement, psychiatric or haemolytic features.

1Escalation1. Assess liver severity and neurological state immediately, escalating coagulopathy, encephalopathy or haemolysis to hepatology and a transplant centre.
22. Obtain caeruloplasmin, copper studies, quality-controlled 24-hour urine, liver and haemolysis tests and experienced slit-lamp examination without relying on one answer.
33. Arrange ATP7B testing and MRI or liver copper assessment through the specialist team when the initial pattern is incomplete or confirmation is needed.
4Alternative4. Integrate findings with a validated specialist score and revisit mimics such as autoimmune hepatitis, other cholestatic disease and alternative movement disorders.

02TreatRemove copper without destabilising diseaseWilson disease is confirmed or specialist confidence justifies treatment before every result returns.

11. Select a chelator or zinc strategy according to hepatic severity, neurological phenotype, pregnancy, previous intolerance and current specialist guidance.
22. In neurological disease, introduce therapy cautiously and explain possible early worsening, maintaining rapid access to the prescribing centre.
33. Provide medicine-specific administration instructions, interaction spacing and adherence support; diet is adjunctive and should remain nutritionally adequate.
44. For acute liver failure or decompensation unresponsive to treatment, complete urgent transplant assessment and bridging support under the liver centre.

03Family and follow-upPrevent recurrence and presymptomatic injuryAfter diagnosis and initiation of decoppering treatment.

11. Refer siblings and appropriate relatives for genetic counselling, targeted variants and biochemical assessment rather than reassuring from absence of symptoms.
22. Monitor symptoms, liver function and copper balance frequently during initiation, then at planned lifelong intervals to detect undertreatment, overtreatment and non-adherence.
33. Coordinate neurology, hepatology, mental health, dietetic, speech and rehabilitation input around the dominant functional burdens.
44. Reinforce that treatment must not stop during apparent wellness, pregnancy or transfer between services without specialist substitution and monitoring.

Key medicines and prescribing safety3 treatments · regimens, roles and cautions

Binds copper and increases urinary excretion, providing established first-line decoppering therapy for many symptomatic patients in England.

D-penicillamine

Specialist treatment is introduced at a low divided dose and titrated gradually to the current weight- and phenotype-appropriate chelation regimen, usually taken away from food with precise local instructions.

Early neurological worsening can occur. Monitor rash, fever, cytopenia, proteinuria, renal and autoimmune toxicity; give pyridoxine when prescribed and never stop suddenly without a replacement plan.

Alternative copper chelator, particularly when penicillamine is not tolerated or is otherwise unsuitable.

Trientine

Use a specialist-selected salt and total daily dose in two to four divided administrations on an empty stomach, separated from food, minerals and other medicines as the product information specifies.

Trientine formulations are not dose-equivalent. Monitor copper balance, iron status, liver response and neurological change; under-treatment from missed doses or incorrect administration can permit renewed organ injury.

Induces intestinal metallothionein and reduces copper absorption rather than rapidly removing a large established tissue burden.

Zinc salt

A specialist may prescribe an elemental-zinc regimen in divided fasting doses for selected presymptomatic or maintenance contexts, using the exact licensed preparation and monitoring response.

Not first-line monotherapy for significant symptomatic liver disease. Gastrointestinal intolerance and administration timing impair adherence, and biochemical monitoring is required to avoid treatment failure or excessive copper depletion.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Acute or chronic liver failure

Copper-mediated hepatitis and fibrosis can progress to decompensation, coagulopathy, portal hypertension and a need for liver transplantation.

Irreversible neurological disability

Delayed diagnosis and treatment can leave fixed dystonia, dysarthria, gait impairment, cognitive change and substantial loss of independence.

Coombs-negative haemolysis

Copper released from severely injured hepatocytes can cause Coombs-negative intravascular haemolysis, worsening anaemia and signalling a potentially fulminant hepatic presentation.

Treatment interruption or early worsening

Stopping lifelong therapy permits renewed organ injury, while chelation initiation can transiently worsen neurological symptoms and requires specialist monitoring.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Follow liver enzymes, bilirubin, albumin, INR and clinical portal-hypertension or decompensation features at a frequency matched to presentation and treatment stage.
Use specialist urinary and other copper measures to distinguish adherence, inadequate decoppering and overtreatment, ensuring collection method and treatment timing are recorded.
Check full blood count, renal function and urinalysis for protein or blood during chelation, with medicine-specific surveillance for immune and haematological toxicity.
Document tremor, dystonia, gait, speech, swallowing, weight, mood and cognition because biochemical improvement and neurological function can move at different rates.
Review treatment technique, food and mineral spacing, supply continuity and family screening repeatedly; unplanned interruption is a clinical emergency risk.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Total copper seems paradoxical

Because most circulating copper is carried by caeruloplasmin, total serum copper may fall even though the toxic loosely bound fraction and tissue copper are excessive.

Rings depend on phenotype

Kayser–Fleischer rings are frequent in neurological Wilson disease but can be absent in liver-only presentation, particularly in children.

Haemolysis can herald failure

Copper released from severely injured hepatocytes can trigger Coombs-negative intravascular haemolysis, providing a valuable clue in otherwise unexplained acute liver failure.

Early worsening is real

Neurological deterioration after rapid mobilisation of copper is a recognised treatment hazard and explains cautious initiation in experienced centres rather than therapeutic nihilism.

Presymptomatic treatment matters

Relatives with confirmed disease can begin therapy before irreversible hepatic or neurological injury, making family cascade assessment a core treatment outcome.

11Common pitfallsFrequent interpretation and management errors.

01
Excluding Wilson disease from a normal caeruloplasmin or absent corneal ring allows a multi-system and treatable disorder to progress.
02
Interpreting low total serum copper as evidence against copper overload ignores its dependence on reduced caeruloplasmin-bound copper.
03
Starting full-intensity chelation without neurological expertise can worsen movement and swallowing symptoms during initial copper mobilisation.
04
Using dietary restriction alone in confirmed symptomatic disease offers inadequate decoppering and risks false reassurance.
05
Stopping treatment when liver tests normalise can cause severe relapse, including acute hepatic decompensation and new neurological injury.