Wilson Disease

Genetic Basis and Inheritance

• Wilson disease is an autosomal recessive disorder caused by pathogenic mutations in the ATP7B gene, located on chromosome 13q14-q21.
• The ATP7B gene encodes a copper-transporting P-type ATPase essential for copper excretion into bile and incorporation into apoceruloplasmin.
• More than 700 mutations have been described globally, with most patients being compound heterozygotes—harbouring two distinct mutant alleles.
• Common mutations include H1069Q (associated with late-onset neurological presentations) and other deletions, insertions, or missense variants.
• Genetic linkage studies and molecular sequencing have confirmed the location and critical function of ATP7B in copper homeostasis.
  
  

Copper Physiology

• Copper is an essential trace element involved in the activity of several enzymes, such as cytochrome c oxidase, dopamine β-hydroxylase, lysyl oxidase, and superoxide dismutase.
• It plays key physiological roles in mitochondrial respiration, collagen synthesis, neurotransmitter metabolism, and antioxidant defence.
• Approximately 50–75% of dietary copper is absorbed in the intestine, particularly from foods such as shellfish, legumes, liver, and chocolate.
  
  

Copper Handling in the Liver

• Absorbed copper is transported to hepatocytes via albumin.
• In the liver, copper is either:
  • Incorporated into ceruloplasmin for systemic distribution,
  • Stored safely in complexes with apo-metallothionein, or
  • Excreted into bile for elimination (accounting for ~95% of total body copper excretion).
• Excretion—not absorption—is the primary regulated step in copper homeostasis.
  
  

Pathogenic Mechanism in Wilson Disease

• In Wilson disease, ATP7B mutations result in:
  • Impaired excretion of copper into bile.
  • Failure of copper incorporation into ceruloplasmin.
• The consequence is hepatic copper accumulation, initially within lysosomes and bound to metallothionein, followed by overflow into the blood and deposition in other organs (e.g., brain, kidneys, cornea).
• Copper toxicity results in oxidative stress via free radical generation, leading to lipid peroxidation, protein oxidation, and mitochondrial dysfunction.
• Early ultrastructural changes include damage to the endoplasmic reticulum, mitochondria, peroxisomes, and nuclei of hepatocytes.
• Over time, this culminates in hepatocellular injury, inflammation, fibrosis, and systemic manifestations.
  
  
  

Modifying Genes and Variability

• Genetic modifiers such as MURR1 (linked to copper toxicosis in Bedlington terriers) have been implicated in modulating the age of onset and phenotype severity.
• Variable expressivity and incomplete genotype-phenotype correlation exist; the same mutation may lead to hepatic, neurologic, or mixed disease in different individuals.
  
  
  
  

Copper Homeostasis in Health

• Copper is an essential trace metal required for the activity of multiple enzymes including cytochrome c oxidase, dopamine β-hydroxylase, superoxide dismutase, lysyl oxidase, and tyrosinase.
• Ingested copper is absorbed primarily in the duodenum and proximal jejunum via copper transporter 1 (CTR1/SLC31A1).
• Once absorbed, copper is transported to the liver bound to albumin and small molecules. In hepatocytes, it is distributed by chaperone proteins such as ATOX1 to the trans-Golgi network.
• ATP7B, a copper-transporting P-type ATPase, loads copper into apoceruloplasmin (creating ceruloplasmin) and facilitates the excretion of excess copper into bile.
• Under normal conditions, copper homeostasis is primarily maintained by biliary excretion (~95% of total excretion), with the remainder eliminated via renal pathways.
  
  

Pathophysiology

• Impaired ATP7B Function: Mutations in the ATP7B gene result in defective biliary copper excretion and failure to incorporate copper into ceruloplasmin.
  • As a result, ceruloplasmin remains in its apo-form, which is rapidly degraded in plasma, leading to characteristically low serum ceruloplasmin levels.
  • The diminished biliary elimination of copper causes its intracellular accumulation in hepatocytes.
    
    
• Hepatic Copper Accumulation and Injury:
  • Initially, copper binds to metallothionein within hepatocytes. Once this capacity is overwhelmed, unbound copper accumulates in lysosomes and cytosolic compartments.
  • Excess copper generates reactive oxygen species (ROS), initiating oxidative injury that targets mitochondria, endoplasmic reticulum, and DNA.
  • This leads to both necrosis and apoptosis of hepatocytes. Lipid peroxidation, protein misfolding, and disruption of cellular respiration contribute to liver inflammation and fibrosis.
  • Mitochondrial dysfunction is prominent and correlates with hepatocellular damage. Copper excess reduces glutathione, further exacerbating oxidative stress.
    
    
• Characteristic Biochemical Signature:
  • A hallmark of Wilson disease–associated liver dysfunction is a disproportionately low alkaline phosphatase (ALP) relative to total bilirubin (TB). An ALP:TB ratio <4 is highly sensitive and specific.
  • Hypothesised mechanisms for low ALP include copper-induced displacement of zinc (a required ALP cofactor) and conformational inactivation of the enzyme.
    
    
• Release and Distribution of Free Copper:
  • With progressive hepatocellular damage, copper spills into systemic circulation as non–ceruloplasmin-bound (free) copper, which is highly toxic.
  • Despite low total serum copper (due to low ceruloplasmin), the free copper fraction is increased.
  • In acute liver failure, massive hepatocyte necrosis may lead to very high total serum copper concentrations.
    
    
    

Extrahepatic Copper Toxicity

• Central Nervous System:
  • Free copper deposits predominantly in the basal ganglia (especially putamen and globus pallidus), causing neuronal injury and demyelination.
  • Neurological effects include tremor, dystonia, dysarthria, cognitive impairment, and psychiatric symptoms.
  • MRI may show hyperintensities in affected areas and characteristic features such as the ‘face of the giant panda’ sign in the midbrain.
    
    
• Ocular Manifestations:
  • Copper accumulation in Descemet’s membrane leads to Kayser-Fleischer rings, most commonly seen in the superior and inferior corneal periphery.
  • Sunflower cataracts may occur due to copper deposits in the anterior lens capsule.
    
    
• Haematological and Renal Effects:
  • Free copper can directly damage erythrocytes, inducing intravascular haemolysis and resulting in indirect hyperbilirubinaemia and anaemia.
  • Copper may also cause renal tubular injury and contribute to bile cast nephropathy in the setting of haemolysis.
    
    

Key Molecular Insights

• Low serum ceruloplasmin levels are a diagnostic marker but do not directly mediate disease pathogenesis.
• Ceruloplasmin deficiency alone (as in aceruloplasminemia) does not lead to copper overload, highlighting the primacy of ATP7B dysfunction.
• Enhanced hepatocyte apoptosis in Wilson disease is also linked to copper-induced activation of acid sphingomyelinase and reduced levels of X-linked inhibitor of apoptosis protein (XIAP), further tipping the balance toward cell death.
  
  

Phenotypic classification of Wilson's disease

• H1: Acute hepatic Wilson's disease: acutely occurring jaundice in a previously apparently healthy person, either due to a hepatitis-like illness or to Coombs-negative haemolytic disease, or a combination of both. May progress to liver failure necessitating emergency liver transplant.
• H2: Chronic hepatic Wilson's disease: any type of chronic liver disease, with or without symptoms. May lead to or present as decompensated cirrhosis. Diagnosis is based on standard biochemical, and/or radiological, or biopsy evidence.
• Hepatic presentation classification requires the exclusion of neurological symptoms by a detailed clinical neurological examination at the time of diagnosis.
  
  

• Patients in whom neurological and/or psychiatric symptoms are present at diagnosis.
• N1: associated with symptomatic liver disease. Usually patients have cirrhosis at the time of diagnosis of neurological Wilson's disease. Chronic liver disease may pre-date the occurrence of neurological symptoms by many years, or be diagnosed during the diagnostic work-up of a neurologically asymptomatic patient.
• N2: not associated with symptomatic liver disease. Documentation of the absence of marked liver disease requires a liver biopsy.
• NX: presence/absence of liver disease not investigated.
  
  

Global Prevalence and Carrier Frequency

• Wilson disease occurs worldwide with an estimated prevalence of 1 in 30,000 to 1 in 50,000 individuals in most populations.
• More recent molecular screening in some regions, such as the United Kingdom, suggests that true prevalence may be significantly higher—up to 1 in 7021 in some cohorts.
• The carrier frequency is consistently reported at approximately 1 in 90, reflecting a relatively high incidence of heterozygosity for ATP7B mutations in the general population.
• Some studies have indicated even greater carrier frequencies, such as 1 in 31 in a large French cohort, theoretically implying a disease prevalence closer to 1 in 1000 if complete penetrance were assumed. This discrepancy suggests a degree of incomplete penetrance for certain mutations.
  
  

High-Risk Populations

• The disease is found in all ethnic groups, but its prevalence is elevated in genetically isolated communities or areas with high rates of consanguinity.
• For instance, a remarkably high prevalence of 1 in 15 live births was reported in a small mountainous village in Crete due to consanguineous marriage patterns.
• Higher frequencies have also been reported in regions such as Israel, Sardinia, Gran Canaria, and parts of Japan.
  
  

Sex Distribution

• Although traditionally believed to affect males and females equally, some evidence suggests a slight male predominance.
• A registry study of 627 patients found 52% were male.
• Notably, females may be more prone to present with fulminant hepatic failure, whereas males are more likely to present with neurological or psychiatric symptoms.
  
  

Age of Onset and Presentation

• Clinical onset typically occurs between the ages of 10 and 40 years, but the disorder can manifest at any age.
• The youngest reported cases include children under age 3, and Wilson disease has been diagnosed in adults over 70 years of age.
• Presentation is often age-dependent:
  • Younger patients (mean age ~15 years) tend to present with hepatic manifestations.
  • Older patients (mean age ~20 years) are more likely to exhibit neurological or neuropsychiatric symptoms.
• Some ATP7B mutations can lead to very early-onset disease (even in infancy), which may not be considered in standard diagnostic algorithms, thus contributing to diagnostic delays.
  
  

General Presentation and Disease Course

• Wilson disease has a heterogeneous clinical presentation ranging from asymptomatic to fulminant hepatic failure, neuropsychiatric syndromes, and systemic manifestations.
• Onset typically occurs between ages 3 and 40 but may range from early childhood (<3 years) to late adulthood (>70 years).
• Disease progression varies: patients may initially present with hepatic, neurologic, psychiatric, or haematologic symptoms, with overlapping features often emerging over time.
  
  

Hepatic Manifestations (Historical Clues)

• Common early signs: fatigue, abdominal discomfort, anorexia, nausea, and jaundice.
• Hepatitis-like illness: may resemble acute viral hepatitis or present as unexplained chronic liver disease in patients <40 years.
• Chronic liver disease: presents with symptoms of portal hypertension, including gastrointestinal bleeding, ascites, and splenomegaly.
• Acute liver failure (ALF):
  • May present with jaundice, confusion (encephalopathy), and coagulopathy in previously well individuals.
  • ALF from Wilson disease may be suggested by:
    • Coombs-negative haemolytic anaemia,
    • Low serum alkaline phosphatase,
    • AST:ALT ratio >2,
    • Rapidly progressing renal dysfunction.
      
      

Neuropsychiatric Features

• Neurological symptoms (seen in 30–50% of patients):
  • Tremor (resting, postural, kinetic), with the “wing-beating” type being classic.
  • Dysarthria, hypophonia, incoordination, ataxia.
  • Dystonia (often segmental, sometimes generalised), chorea, and parkinsonism.
  • Early complaints may include slurred speech, handwriting deterioration (micrographia), or clumsiness.
    
    
• Psychiatric symptoms (in 10–20% as presenting feature):
  • Mood disturbances: depression, anxiety, irritability.
  • Behavioural changes: disinhibition, impulsivity, social withdrawal, temper tantrums.
  • Cognitive decline: impaired memory, attention, executive function.
  • Psychosis (less common).
    
    

Musculoskeletal History

• Joint symptoms:
  • Premature osteoarthritis (usually post-adolescence), often involving the knees, wrists, and spine.
  • Arthralgia or degenerative joint pain may be an initial complaint.
    
    
• Other features:
  • Osteopenia (detected radiologically).
  • Rare conditions: osteochondritis dissecans, chondrocalcinosis.
    
    

Haematologic Clues

• Haemolytic anaemia:
  • Acute onset of pallor, dark urine, and jaundice in the absence of immune-mediated causes.
  • Typically Coombs-negative.
  • May be episodic, low-grade, or part of fulminant hepatic failure.
  • Consider Wilson disease in patients with prior “unexplained jaundice.”
    
    

Renal Symptoms

• Tubular dysfunction:
  • History suggestive of Fanconi syndrome: polyuria, polydipsia, bone pain (due to phosphate loss).
  • May report recurrent urolithiasis or nephrocalcinosis.
  • Symptoms such as haematuria, proteinuria, or glucosuria without diabetes may also be noted.
    
    
• D-penicillamine use (if already diagnosed): history of worsening proteinuria or peptiduria.
  
  

Reproductive and Endocrine Clue

• Reproductive:
  • Menstrual irregularities, female infertility, or recurrent miscarriages.
  • Male sexual dysfunction.
    
    
• Endocrine:
  • Reports of early-onset hypoparathyroidism or signs of endocrine dysfunction.
  • History of growth abnormalities, including gigantism in rare cases.
    
    

Other Historical Features

• Kayser-Fleischer (KF) rings:
  • May be asymptomatic or reported as visual discolouration.
  • In patients with neuropsychiatric symptoms, >95% will have KF rings.
    
    
• Sunflower cataracts:
  • Rare, may cause subtle visual changes.
    
    
• Family history:
  • Consanguinity or known cases of Wilson disease in siblings or relatives.
  • Unexplained liver disease, movement disorders, or psychiatric illness in young relatives.

Risk Factors to Consider in History

• Family history of Wilson disease or early-onset liver/neurologic disease.
• High-risk ethnic or geographic background (e.g., consanguineous populations).
• Unexplained hepatic, psychiatric, or neurologic disease in patients under 40.
  
  
  
  

Hepatic Signs

• Jaundice – Suggests hepatocellular dysfunction or haemolysis.
• Hepatomegaly and splenomegaly – Common in early or chronic hepatic involvement.
• Ascites – Indicates portal hypertension or hepatic insufficiency.
• Peripheral stigmata of cirrhosis:
  • Spider naevi
  • Palmar erythema
  • Digital clubbing
  • Gynaecomastia
  • Caput medusae or prominent abdominal veins
  • Bruising due to coagulopathy and thrombocytopenia.
    
    
• Encephalopathy signs – Asterixis, confusion, and inappropriate behaviour may be noted in fulminant hepatic failure.
  
  
  

Neurological Findings

• Movement Disorders:
  • Tremor (wing-beating, intention, postural, rest)
  • Dystonia (focal or generalised; may cause risus sardonicus)
  • Parkinsonism: bradykinesia, rigidity, postural instability.
  • Chorea or choreoathetosis
  • Ataxia: truncal or gait instability; dysmetria, dysdiadochokinesis, dysrhythmia.
    
    
    
• Speech and Swallowing:
  • Dysarthria – Spastic, hypophonic, or athetoid types.
  • Dysphagia – Due to bulbar dysfunction.
  • Drooling
    
    
• Motor Coordination:
  • Clumsiness, impaired fine motor tasks (e.g., buttoning, handwriting)
  • Mask-like facies from rigidity or parkinsonism.
    
    
• Eye Movement Abnormalities:
  • Saccadic pursuit deficits
  • Esotropia and diplopia
    
    

Ophthalmologic Signs

• Kayser-Fleischer (KF) Rings:
  • Gold-brown or greenish-golden rings in Descemet's membrane of the cornea.
  • Initially seen at the superior and inferior poles, becoming circumferential.
  • Visible with slit-lamp examination; present in:
    • ~95% of neurologic cases.
    • ~50% of hepatic-only cases.
  • Not pathognomonic: may appear in other cholestatic liver diseases.
    
    
    
• Sunflower Cataracts:
  • Rare, reversible copper deposits in the lens.
  • Best visualised via slit-lamp; may fade with treatment.
    
    
    

Musculoskeletal and Rheumatologic Features

• Arthropathy:
  • Often resembles early-onset osteoarthritis.
  • Involves large joints and the spine.
  • Can present with polyarthritis or chondrocalcinosis.
• Osteomalacia and osteoporosis – May lead to spontaneous fractures.
• Myopathy – Weakness, especially of proximal muscles.
  
  

Cardiac Manifestations

• Arrhythmias – Palpitations, bradycardia, or tachycardia.
• Signs of autonomic dysfunction – Postural hypotension.
• Cardiomyopathy – Rare but may manifest as signs of heart failure.
  
  

Renal and Electrolyte Features

• Though more commonly inferred from investigations, some findings may be visible:
  • Dehydration signs from Fanconi syndrome-related losses.
  • Signs of nephrolithiasis: renal angle tenderness (if symptomatic).
    
    
    

Dermatologic and Other Signs

• Azure lunulae (blue lunulae) – Bluish discoloration at the base of fingernails.
• Acanthosis nigricans, pretibial hyperpigmentation – Occasionally described.
• Skin pallor or icterus – Reflective of anaemia or jaundice.
  
  

Additional 

• Sloppy or small handwriting (micrographia) – Reflects fine motor impairment.
• Dystonic gait – Wide-based, slow gait with abnormal postures.
• Postural instability – May resemble Parkinsonian features.
• Cognitive impairment – Assessed through bedside tasks (attention, memory, calculation).
  
  

• Low serum ceruloplasmin (<20 mg/dL).
• Neuropsychiatric symptoms.
• Coombs-negative haemolytic anaemia.
• Abnormal liver function tests (LFTs), particularly with ALP:bilirubin ratio <4.
• A positive family history of Wilson disease.
  
  

First-Line Investigations

1. Liver Function Tests (LFTs)
   • AST and ALT are elevated in 40–60% of cases.
   • Bilirubin may be raised due to hepatic injury or haemolysis.
   • ALP is often low or normal even in severe disease.
   • INR may be prolonged in acute liver failure or decompensated cirrhosis.
   • Albumin may be reduced in advanced liver disease.
     
     
2. Serum Ceruloplasmin
   • <20 mg/dL is suggestive.
   • <10 mg/dL is strongly supportive of diagnosis.
   • Ceruloplasmin is an acute phase reactant and may be falsely normal or elevated in pregnancy, inflammation, or oestrogen use.
   • Low levels may also occur in nephrotic syndrome, protein-losing enteropathy, or advanced liver disease.
     
     
3. 24-Hour Urinary Copper Excretion
   • 100 µg/24h is diagnostic.
   • 40–100 µg/24h may warrant further investigation.
   • Should be collected in trace element-free containers.
   • Elevated urinary copper is not specific and can occur in cholestasis and autoimmune hepatitis.
     
     
4. Ophthalmologic Slit-Lamp Examination
   • Detection of Kayser-Fleischer (KF) rings in Descemet’s membrane.
   • Found in ~95% of neurological cases and ~50% of hepatic-only presentations.
   • Presence is diagnostic when accompanied by neurologic or hepatic features.
   • Sunflower cataracts may also be detected but are less specific.
     
     
     

Confirmatory and Second-Line Investigations

1. Hepatic Copper Quantification (Liver Biopsy)
   • Hepatic copper >250 µg/g dry weight is diagnostic.
   • 50–250 µg/g requires genetic confirmation.
   • <50 µg/g excludes diagnosis.
   • Requires properly preserved liver tissue in a dry, metal-free container.
     
     
2. Genetic Testing
   • Identifies ATP7B mutations.
   • Most patients are compound heterozygotes; over 700 mutations reported.
   • Recommended for:
     • Confirmation in uncertain cases.
     • First- and second-degree relative screening.
   • Less useful as a first-line test due to complexity and genetic variability.
     
     
3. Neuroimaging (MRI Brain)
   • Indicated in patients with neurologic symptoms.
   • Shows hyperintensities in basal ganglia, brainstem, thalamus, and cerebellum on T2-weighted images.
   • Characteristic findings include the "face of the giant panda" sign in the midbrain.
     
     
4. Non-Ceruloplasmin-Bound Copper (NCC)
   • Elevated NCC supports diagnosis but is not routinely used due to complexity.
     
     
5. Electrocardiogram (ECG)
   • May show ST-segment depression, T-wave inversion, and signs of ventricular hypertrophy or arrhythmias in some cases.
     
     
6. Full Blood Count (FBC)
   • Anaemia and thrombocytopenia may result from haemolysis or portal hypertension.
   • White cell count may be low due to hypersplenism.

Diagnostic Scoring: Leipzig Criteria

• ≥4: Diagnosis confirmed.
• 3: Probable; requires further testing.
• ≤2: Wilson disease unlikely.
  
  

• Serum ceruloplasmin.
• KF rings.
• Neurologic features.
• 24-hour urinary copper.
• Liver copper content.
• Genetic testing.
  
  
  

Specialised and Emerging Tests

• Neurofilament light (NfL)
  • May serve as a biomarker for neurologic involvement.
  • Elevated in neurologically active disease.
    
    
• ATP7B Peptide Assays
  • Emerging blood test using dried blood spots.
  • Shows high positive predictive value.
    
    

Screening Asymptomatic Relatives

• Genetic testing of siblings of index cases is recommended.
• If mutations are unknown or testing unavailable, evaluate with ceruloplasmin, urinary copper, and ocular examination.
  
  
  
  

Hepatic Differentials

• Viral Hepatitis (Hepatitis B and C)
   May present with acute or chronic hepatic inflammation and aminotransferase elevation.
   Diagnosis: Serologic markers (HBsAg, anti-HCV antibodies).
• Alcohol-related Liver Disease / Alcoholic Hepatitis
   Overlaps in presentation with chronic liver disease.
   Clues: History of alcohol use, elevated gamma-glutamyl transferase, altered CDT.
• Autoimmune Hepatitis
   Often presents in young women with elevated aminotransferases.
   Clues: Autoantibodies (ANA, SMA, LKM), elevated IgG.
• Hereditary Haemochromatosis
   Iron overload with hepatic, cardiac, joint, and endocrine manifestations.
   Clues: Raised transferrin saturation, ferritin; HFE gene mutation testing.
• Alpha-1 Antitrypsin Deficiency
   Can mimic Wilson disease, presenting with liver and/or lung disease.
   Clues: Low serum AAT levels.
• Steatohepatitis (MASLD)
   Associated with metabolic risk factors and obesity.
   Diagnosis: Liver biopsy showing steatosis, hepatocyte ballooning, and inflammation.
• Drug-induced Liver Injury (DILI)
   Variable clinical picture. History of drug exposure is critical.
• Acute Liver Failure due to Other Causes
   Ischaemia, toxins (e.g., paracetamol), and autoimmune hepatitis must be considered. Wilson disease uniquely shows an AST:ALT ratio >2, low ALP, and Coombs-negative haemolysis.
  
  

Haematologic Differentials

• Other Haemolytic Anaemias
   Particularly Coombs-negative causes such as glucose-6-phosphate dehydrogenase deficiency, microangiopathies, and Evans syndrome.
   Clues: Additional testing (DAT, G6PD levels, blood smear, flow cytometry for CD55/CD59).
  
  
  

Neurological and Movement Disorder Differentials

• Parkinson’s Disease (Early-Onset)
   Presents with rigidity, tremor, bradykinesia; generally occurs >50 years.
   Clue: Dopaminergic response, no KF rings.
• Essential Tremor
   Tremor without other neurologic signs.
   Clue: Positive family history, no associated hepatic dysfunction.
• Huntington Disease
   Progressive movement disorder with cognitive decline.
   Diagnosis: HTT gene testing.
• Pantothenate Kinase-Associated Neurodegeneration (PKAN)
   Involves iron accumulation in the basal ganglia.
   Diagnosis: MRI shows ‘eye-of-the-tiger’ sign.
• Neuroacanthocytosis
   Features orofacial dyskinesias, cognitive impairment, and acanthocytosis on blood smear.
• Wernicke Encephalopathy
   Due to thiamine deficiency.
   Clue: Ophthalmoplegia, ataxia, confusion; history of malnutrition or alcohol use.
• Aceruloplasminaemia
   Causes iron accumulation in CNS with similar neurologic findings.
   Diagnosis: Undetectable ceruloplasmin, CP gene mutation.
  
  

Psychiatric Differentials

• Major depressive disorder
• Bipolar disorder
• Schizophrenia
• Personality disorders
• Substance-induced psychosis
  
  

Genetic and Metabolic Mimics

• MDR3 Deficiency (PFIC3)
   Involves canalicular transporter dysfunction; mimics cholestatic liver disease.
   Clues: Normal ceruloplasmin; ABCB4 gene mutation.
• Congenital Disorders of Glycosylation
   May present with elevated transaminases and copper.
   Diagnosis: Normal urinary copper; confirmed via genetic testing.
  
  

General Principles

• Wilson’s disease requires lifelong management to reduce systemic copper burden and prevent reaccumulation.
• Treatment includes pharmacological therapy, dietary modification, and coordinated care from a multidisciplinary team comprising hepatologists, neurologists, psychiatrists, physiotherapists, and dietitians.
• Therapeutic decisions are tailored based on clinical presentation: hepatic, neurological, asymptomatic, paediatric, or pregnancy-related.
  
  

Pharmacological Therapy

• Penicillamine (D-isomer):
  • Increases urinary copper excretion by binding loosely stored copper.
  • Initiation: 250–500 mg/day orally, gradually increased to 1000–1500 mg/day in divided doses.
  • Side effects: early hypersensitivity (fever, lymphadenopathy, rash, proteinuria), nephrotoxicity, bone marrow suppression, skin changes (e.g. lichen planus), and risk of worsening neurological symptoms.
  • Discontinuation rate of ~30% due to side effects.
  • Pyridoxine (vitamin B6) supplementation is advised due to risk of deficiency.
    
    
• Trientine:
  • Alternative chelator with a safer neurological profile, preferred in those intolerant to penicillamine.
  • Initial dose: 15–20 mg/kg/day (maximum 1500 mg/day), maintenance 10–15 mg/kg/day.
  • Fewer adverse effects, but rare risks include pancytopenia, autoimmune syndromes, and iron imbalance.
    
    

• Reduce copper absorption by inducing metallothionein in intestinal cells.
• Used as primary therapy in asymptomatic or neurologically affected patients or as maintenance following chelation.
• Dose: 150 mg elemental zinc/day in three divided doses.
• Gastric irritation is common; switching to a different zinc formulation may help.
  
  
  

Maintenance Therapy

• Aimed at maintaining copper balance and preventing tissue reaccumulation after initial de-coppering phase.
• May involve continued use of low-dose chelators or full-dose zinc salts.
• Criteria for transition:
  • Clinical improvement.
  • Normal or near-normal liver function tests.
  • 24-hour urinary copper: <500 mcg/day with chelators, <100 mcg/day with zinc.
• Regular follow-up includes copper studies, liver function tests, and adherence monitoring.
  
  

Dietary and Lifestyle Measures

• Recommended during the first year: avoid high-copper foods (shellfish, nuts, chocolate, mushrooms, organ meats, soy products).
• Patients should avoid well water or copper-piped water unless appropriately filtered or flushed.
• Complete alcohol abstinence is advised.
• Vaccination against hepatitis A and B is essential in non-immune individuals.
• Dietary restriction alone is insufficient and must be paired with pharmacologic treatment.
  
  

Clinical Subgroup Strategies

• Patients with acute liver failure require urgent evaluation for transplantation.
  
  

• 0: Bilirubin <100 micromol/L; AST <100 units/L; PT <4
• 1: Bilirubin 100-150 micromol/L; AST 100-150 units/L; PT 4-8
• 2: Bilirubin 151-200 micromol/L; AST 151-200 units/L; PT 9-12
• 3: Bilirubin 201-300 micromol/L; AST 201-300 units/L; PT 13-20
• 4: Bilirubin >300 micromol/L; AST >300 units/L; PT >30
  
  
• Score ≥10: indicates poor prognosis and need for liver transplantation.
• Score ≤6: likely to respond to pharmacological therapy.
• Score 7–9: managed based on clinical judgement and trend of clinical/laboratory parameters.
• Transplantation is curative and halts further copper accumulation.
  
  
  

Neurological and Psychiatric Presentation

• Goal is to prevent further copper-induced neurotoxicity.
• Start chelation therapy slowly to reduce risk of paradoxical neurological worsening.
• Zinc monotherapy may be considered in severe neurological involvement.
• Trientine is often preferred over penicillamine for neurological presentations.
  
  

Asymptomatic Patients

• Treated prophylactically to prevent disease progression.
• Children identified through screening should begin treatment at 2–3 years of age.
• Zinc is often preferred due to its favourable safety profile.
  
  

Symptomatic Children

• Require urgent initiation of chelators or zinc depending on liver or neurological involvement.
• Combination therapy may be used in advanced hepatic disease.
• Liver transplant is considered for children unresponsive to medical therapy.
  
  

Pregnancy

• Continue therapy to prevent maternal and fetal complications.
• Reduce penicillamine/trientine doses to 25–50% of pre-pregnancy levels; zinc dose unchanged.
• Risk of teratogenicity is low but present; informed discussions are essential.
• Breastfeeding considerations depend on maternal stability and medication exposure in breast milk.
  
  

Refractory or Severe Disease

• Combined chelator and zinc therapy may be effective in patients unresponsive to monotherapy.
• Requires careful monitoring for overtreatment and risk of sideroblastic anaemia.
  
  

• Indicated for acute liver failure, decompensated cirrhosis, hepatocellular carcinoma, or failure of medical therapy.
• Transplantation is curative; no further Wilson’s disease treatment is needed postoperatively.
• Long-term survival outcomes are excellent in both children and adults.
  
  
  
  

General Outlook

• With early diagnosis and appropriate therapy, individuals with Wilson disease can achieve a normal life expectancy and maintain good quality of life.
• Prognosis is highly dependent on the timing of treatment initiation, severity of organ involvement, and adherence to long-term therapy.
• In mild-to-moderate liver failure (e.g., Nazer score ≤9 or New Wilson Index ≤10), liver function may recover with medical management.
• Neurological symptoms often take longer to improve than hepatic ones, typically showing gradual progress over 1 to 3 years. However, approximately 40–50% of patients may have persistent neurological deficits, particularly if symptoms were severe at onset.
  
  

Clinical Course Without Treatment

• Untreated disease results in progressive hepatic copper accumulation, leading to cirrhosis and complications such as ascites, variceal haemorrhage, and encephalopathy.
• Neurologically, untreated patients may develop progressive dystonia, akinesia, and mutism. Sudden deterioration can occur, though more commonly the progression is insidious.
• Mortality is usually due to liver-related causes—acute liver failure or decompensated cirrhosis—but some patients may die from complications of advanced neurological disease.

Impact of Early and Ongoing Treatment

• Patients who initiate treatment before cirrhosis or irreversible neurological damage generally fare well. If copper balance is maintained through chelation or zinc therapy, disease progression halts and symptoms may improve.
• Liver function typically begins to recover within 2 to 6 months of treatment. Neurological symptoms take longer and may show a more variable trajectory.
• Provided that no further hepatic insults occur (e.g., drug hepatotoxicity, viral hepatitis), and compliance with therapy is good, liver function usually remains stable long-term.

Prognostic Scoring Tools

• Nazer Score:
  • Utilises bilirubin, AST, and prothrombin time to stratify severity of liver involvement.
  • Each parameter scores 0–4 points; a total score ≥7 is associated with poor prognosis and high mortality without liver transplantation.
  • Score ≤6 is associated with a favourable response to chelation therapy.
    
    
    
• Modified Wilson Index (New Wilson Index):
  • Incorporates bilirubin, INR, AST, white cell count, and albumin.
  • A score ≥11 predicts poor prognosis and high mortality without transplantation.
  • These tools assist in determining candidacy for urgent liver transplant and monitoring progression during therapy.
    
    
    
• Model for End-Stage Liver Disease (MELD 3.0):
  • Provides estimated 90-day mortality risk and is used for transplant prioritisation in patients with chronic liver disease.
    
    

Liver Transplantation and Survival

• Liver transplantation is indicated for acute liver failure, decompensated cirrhosis unresponsive to therapy, or hepatocellular carcinoma.
• Wilson disease is considered a curable condition with liver transplantation, as hepatic copper excretion is restored postoperatively.
• Survival rates post-transplant are high:
  • 1-year: ~90.6%
  • 5-year: ~83.7%
  • 10-year: ~79.9%
• Patients listed for transplant due to acute Wilsonian hepatitis are prioritised as UNOS Status 1A.
  
  

Neurological Outcomes Post-Transplant

• Liver transplantation has shown benefit for some patients with neurological presentations, especially where medical therapy fails.
• A systematic review found neurological improvement in over 70% of transplanted patients.
• However, a subset experienced no change, deterioration, or death, highlighting the need for careful selection and multidisciplinary care.
• The presence of severe neuropsychiatric symptoms may compromise post-transplant adherence and outcomes.
  
  

Risk of Hepatocellular Carcinoma (HCC)

• While Wilson disease-related cirrhosis carries a risk of hepatocellular carcinoma, it appears to be lower than in other forms of cirrhosis.
• Surveillance is generally recommended, though the cost-effectiveness of routine screening remains debated due to the low incidence.
• Some studies estimate an annual HCC risk of around 0.14% in patients with Wilson disease and cirrhosis.
• However, given reported cases of HCC, including studies where up to 7% developed the cancer, standard surveillance protocols are often applied.
  
  

Hepatic Complications

• Acute Liver Failure (ALF):
  • Patients may present acutely with jaundice, coagulopathy, encephalopathy, and renal dysfunction.
  • ALF often arises in younger patients and may be the first presentation of Wilson disease.
  • Non-immune haemolytic anaemia and a low alkaline phosphatase-to-bilirubin ratio (<4) are diagnostic clues.
  • Prognosis is poor without liver transplantation, with a reported mortality of up to 95% if untreated.
    
    
    
• Decompensated Cirrhosis:
  • Chronic hepatic copper accumulation can lead to fibrosis and cirrhosis, with complications such as:
    • Ascites
    • Variceal haemorrhage
    • Hepatic encephalopathy
    • Coagulopathy
    • Hepatorenal syndrome
  • These features mirror those seen in other causes of chronic liver disease, though onset may be earlier.
    
    
    
• Hepatocellular Carcinoma (HCC):
  • Risk of HCC is lower in Wilson disease compared to other chronic liver conditions, but cirrhosis remains a risk factor.
  • An estimated annual HCC risk of 0.14% has been reported in patients with cirrhosis.
  • Surveillance using ultrasound is recommended in patients with established cirrhosis, in line with hepatology society guidelines.
    
    

Neurological and Psychiatric Complications

• Extrapyramidal Motor Symptoms:
  • Include dystonia, tremor, ataxia, dysarthria, bradykinesia, and rigidity.
  • Movement abnormalities often impair daily function and may worsen before improvement during chelation therapy.
    
    
    
• Paradoxical Neurological Worsening:
  • Occurs in up to 10–50% of patients after initiating chelation therapy, particularly with penicillamine.
  • Trientine and zinc have lower rates of this phenomenon.
  • Gradual initiation of chelation and specialist neurological input are advised.
  • A systematic review showed:
    • 24.2% recovered fully
    • 27.3% partially improved
    • 39.8% did not improve
  • Regular monitoring by movement disorder specialists is recommended, especially in the first 12 months of treatment.
    
    
    
• Behavioural and Cognitive Changes:
  • Psychiatric manifestations include depression, personality changes, irritability, aggression, anxiety, and psychosis.
  • Neuropsychiatric involvement correlates with worse outcomes and delayed diagnosis.
    
    
    

Haematologic Complications

• Coombs-negative Haemolytic Anaemia:
  • Can occur spontaneously or in the context of acute liver decompensation.
  • Often presents with elevated lactate dehydrogenase, low haptoglobin, and indirect hyperbilirubinaemia.
  • Important diagnostic clue in younger patients with haemolysis and abnormal liver function.
    
    
    

Ocular Complications

• Kayser-Fleischer (KF) Rings:
  • Result from copper deposition in Descemet’s membrane of the cornea.
  • Typically asymptomatic but detectable on slit-lamp examination.
  • Present in almost all patients with neurological involvement and over 50% of those with hepatic presentations.
    
    
    
• Sunflower Cataracts:
  • Copper deposits in the anterior lens capsule can impair visual acuity.
  • Less common than KF rings and not pathognomonic.
    
    

Renal and Muscular Complications

• Renal Tubular Dysfunction:
  • May manifest as aminoaciduria, hypercalciuria, or nephrocalcinosis.
  • Rare but important in paediatric patients.
    
    
• Rhabdomyolysis:
  • Occasional complication, particularly in severe disease or during episodes of acute decompensation.
    
    

Cardiac Complications

• Cardiomyopathy:
  • Both dilated and restrictive patterns described.
  • Non-ischaemic in nature and attributed to copper toxicity.
    
    
• Arrhythmias and Conduction Abnormalities:
  • Patients may exhibit T-wave inversions, ST segment changes, or conduction blocks on ECG.
  • Clinical significance varies, but sudden cardiac events have been reported.
    
    

Treatment-Related Complications

• Chelation-Induced Neurological Worsening:
  • Particularly associated with D-penicillamine, but can also occur with trientine or, rarely, zinc.
  • Management includes slower dose escalation and consideration of switching agents.
    
    
    
• Zinc Therapy Risks:
  • Generally well tolerated but can cause gastric irritation.
  • Very rarely associated with hepatic decompensation if used inappropriately in advanced liver disease.
    
    

Liver Transplantation

• Liver transplant is curative for both hepatic and systemic copper overload.
• Indications include:
  • Acute liver failure
  • Decompensated cirrhosis unresponsive to medical therapy
  • Severe neurological disease not improving with chelation
• Outcomes are excellent, with survival rates exceeding 80% at 5 years.
• Post-transplant, no further chelation is necessary.
  
  

1. Ala A, Walker AP, Ashkan K, Dooley JS, Schilsky ML. Wilson’s disease. Lancet. 2007;369(9559):397-408
2. Antos A, Członkowska A, Smolinski L, et al. Early neurological deterioration in Wilson's disease: a systematic literature review and meta-analysis. Neurol Sci. 2023;44(10):3443-55.
3. Bowcock AM, Farrer LA, Cavalli-Sforza LL, et al. Genetic linkage studies of Wilson disease and assignment to chromosome 13q14-q21. Am J Hum Genet. 1987;41(5):804-811.
4. Brewer GJ, Hill GM, Prasad AS, et al. Oral zinc therapy for Wilson's disease. Ann Intern Med. 1983;99:314.
5. Bull PC, Thomas GR, Rommens JM, Forbes JR, Cox DW. The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. Nat Genet. 1993;5(4):327-337.
6. Camarata MA, Ala A, Schilsky ML. Zinc Maintenance Therapy for Wilson Disease: A Comparison Between Zinc Acetate and Alternative Zinc Preparations. Hepatol Commun. 2019;3(9):1151.
7. Chen Y, Jiang Y, Zhang Y, et al. Copper metabolism and the pathogenesis of Wilson disease. J Clin Invest. 2021;131(2):e145988.
8. Coffey AJ, Durkie M, Hague S, et al. A genetic study of Wilson’s disease in the United Kingdom. Brain. 2013;136(5):1476-1487.
9. Czlonkowska A, Gajda J, Rodo M. Effects of long-term treatment in Wilson's disease with D-penicillamine and zinc sulphate. J Neurol. 1996;243(3):269-73.
10. Dahlman T, Hartvig P, Löfholm M, et al. Long-term treatment of Wilson's disease with triethylene tetramine dihydrochloride (trientine). QJM. 1995;88:609.
11. Dhawan A, Taylor RM, Cheeseman P, et al. Wilson's disease in children: 37-year experience and revised King's score for liver transplantation. Liver Transpl. 2005;11(4):441-8.
12. Dusek P, Roos PM, Litwin T, et al. The neurotoxicity of iron, copper and manganese in Parkinson’s and Wilson’s diseases. J Trace Elem Med Biol. 2015;31:193-203.
13. European Association for Study of Liver (EASL). Clinical Practice Guidelines: Wilson’s disease. J Hepatol. 2012;56(3):671-685.
14. Ferenci P. Pathophysiology and clinical features of Wilson disease. Metab Brain Dis. 2004;19(1-2):229-239.
15. Ferenci P, Caca K, Loudianos G, et al. Diagnosis and phenotypic classification of Wilson disease. Liver Int. 2003;23(3):139-142.
16. Gromadzka G, Schmidt HHJ, Genschel J, et al. Wilson’s disease: clinical presentation in 261 genetically confirmed patients. J Neurol Sci. 2005;238(1-2):47-51.
17. Lang CJ, Rabas-Kolominsky P, Engelhardt A, et al. Fatal deterioration of Wilson's disease after institution of oral zinc therapy. Arch Neurol. 1993;50(10):1007-8.
18. Litwin T, Gromadzka G, Członkowska A. Neurological manifestations in Wilson’s disease. J Neurol Sci. 2012;312(1-2):1-5.
19. Lorincz MT. Neurologic Wilson’s disease. Ann N Y Acad Sci. 2010;1184:173-187.
20. Merle U, Schaefer M, Ferenci P, Stremmel W. Clinical presentation, diagnosis and long-term outcome of Wilson’s disease: a cohort study. Gut. 2007;56(1):115-120.
21. Mohr I, Pfeiffenberger J, Eker E, et al. Neurological worsening in Wilson disease – clinical classification and outcome. J Hepatol. 2023;79(2):321-8.
22. Müller T, Reuner U, Füllkrug J, et al. Methanobactin rescues copper-induced hepatotoxicity in Wilson disease models. J Hepatol. 2022;76(6):1314-1323.
23. Nazer H, Ede RJ, Mowat AP, et al. Wilson's disease: clinical presentation and use of prognostic index. Gut. 1986;27(11):1377-81.
24. Oder W, Grimm G, Kollegger H, et al. Neurological and neuropsychiatric spectrum of Wilson’s disease: a prospective study of 45 cases. J Neurol. 1991;238(5):281-287.
25. Ranucci G, Rossetti S, Puglielli C, et al. Early-onset Wilson disease with neurological involvement: case reports and literature review. Ital J Pediatr. 2020;46(1):1-6.
26. Roberts EA, Schilsky ML. A practice guideline on Wilson disease. Hepatology. 2008;47(6):2089-2111.
27. Scheinberg IH, Jaffe ME, Sternlieb I. The use of trientine in preventing the effects of interrupting penicillamine therapy in Wilson's disease. N Engl J Med. 1987;317:209.
28. Schilsky ML, Blank RR, Czaja MJ, et al. Hepatocellular copper toxicity and its attenuation by zinc. J Clin Invest. 1989;84:1562.
29. Shribman S, Warner TT, Dooley JS, et al. Serum neurofilament light chain: a biomarker of neurological disease in Wilson's disease. Lancet Neurol. 2021;20(3):238–247.
30. Stapelbroek JM, Peters TJ, van Beurden DH, et al. ATP7B-related copper transport and pathophysiology in Wilson disease. Acta Paediatr Suppl. 2006;95(451):33-41.
31. Stapelbroek JM, Bollen CW, van Amstel JK, Houwen RHJ. The H1069Q mutation in Wilson disease is associated with late-onset and predominantly neurologic presentation. Ann Neurol. 2004;55(4):580-583.
32. Stuehler B, McCarron S, Linder M, et al. MURR1 gene variants and Wilson disease presentation. J Inherit Metab Dis. 2007;30(5):792-797.
33. Taly AB, Meenakshi-Sundaram S, Sinha S, et al. Wilson disease: description of 282 patients evaluated over 3 decades. Medicine (Baltimore). 2007;86(2):112-121.
34. Terada K, Nakakoji Y, Hiraoka M, et al. Role of ATP7B in regulating intracellular copper homeostasis in hepatocytes. Biochem J. 1998;336(Pt 3):755-760.
35. Thomas GR, Forbes JR, Roberts EA, Cox DW. The Wilson disease gene: spectrum of mutations and their consequences. Nat Genet. 1995;9(2):210-217.
36. Weiss KH, Stremmel W. Clinical considerations for an effective medical therapy in Wilson’s disease. Ann N Y Acad Sci. 2014;1315:81-85.
37. Weiss KH, Thurik F, Gotthardt DN, et al. Efficacy and safety of oral chelators in treatment of patients with Wilson disease. Clin Gastroenterol Hepatol. 2013;11(8):1028-1035.e1-2.