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
  • 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

• Mutations in the ATP7B gene result in defective biliary copper excretion and failure to incorporate copper into ceruloplasmin.
• Ceruloplasmin remains in its apo-form, which is rapidly degraded in plasma, leading to low serum ceruloplasmin levels.
• Diminished biliary elimination causes intracellular accumulation of copper in hepatocytes.

Hepatic Copper Accumulation and Injury

• Initially, copper binds to metallothionein in hepatocytes. Once saturated, unbound copper accumulates in lysosomes and cytosol.
• Excess copper generates reactive oxygen species (ROS), causing oxidative injury to mitochondria, ER, and DNA.
• This leads to both necrosis and apoptosis of hepatocytes.
• Mitochondrial dysfunction is central to hepatocellular damage. Copper excess also reduces glutathione, compounding oxidative stress.

Characteristic Biochemical Signature

• A hallmark is a disproportionately low ALP relative to total bilirubin (ALP:TB ratio <4), highly sensitive and specific for Wilson disease.
• Mechanisms may include copper-induced displacement of zinc (a required ALP cofactor) and enzyme inactivation.

Release and Distribution of Free Copper

• With hepatocyte necrosis, copper spills into systemic circulation as non–ceruloplasmin-bound (free) copper, which is highly toxic.
• Despite low total serum copper, free copper is elevated.
• In acute liver failure, massive necrosis may raise total copper concentrations.

Extrahepatic Copper Toxicity

Central Nervous System

• Copper deposits in basal ganglia, especially putamen and globus pallidus, causing neuronal injury and demyelination.
• Clinical features include tremor, dystonia, dysarthria, cognitive deficits, and psychiatric disturbances.
• MRI may show hyperintensities and the characteristic ‘face of the giant panda’ sign.

Ocular Manifestations

• Copper deposition in Descemet’s membrane causes Kayser-Fleischer rings (typically in the superior and inferior cornea).
• Sunflower cataracts may occur due to anterior lens capsule deposits.

Haematological and Renal Effects

• Copper-induced erythrocyte injury results in intravascular haemolysis and indirect hyperbilirubinaemia.
• Copper may also cause renal tubular injury and bile cast nephropathy in haemolysis settings.

Key Molecular Insights

• Low serum ceruloplasmin is a diagnostic marker but does not cause disease.
• Ceruloplasmin deficiency alone (e.g., in aceruloplasminemia) does not cause copper overload—ATP7B dysfunction is key.
• Apoptosis in Wilson disease is linked to copper-triggered activation of acid sphingomyelinase and reduced XIAP (X-linked inhibitor of apoptosis protein).

Phenotypic Classification of Wilson’s Disease

Hepatic Presentation

• H1: Acute hepatic Wilson’s disease – Jaundice in a previously healthy individual, often due to hepatitis-like illness or Coombs-negative haemolysis. May progress to liver failure needing emergency transplantation.
• H2: Chronic hepatic Wilson’s disease – Any form of chronic liver disease, symptomatic or not, possibly leading to decompensated cirrhosis. Diagnosis based on biochemical, radiological, or histological criteria.
• Hepatic classification requires exclusion of neurological symptoms via thorough neurological exam.

Neurological Presentation

• Patients show neurological and/or psychiatric symptoms at diagnosis.
• N1 – Neurological symptoms with symptomatic liver disease, often cirrhosis. Chronic liver disease may pre-date or coincide with neurological diagnosis.
• N2 – Neurological symptoms without symptomatic liver disease. Liver biopsy is needed to confirm absence of liver disease.
• NX – Presence or absence of liver disease not assessed.

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).

Wilson disease should be suspected in individuals under 40 presenting with unexplained hepatic, neurologic, or psychiatric features, particularly when accompanied by:

• 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

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.

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.

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.

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

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.

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.

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.

Non-Ceruloplasmin-Bound Copper (NCC)

• Elevated NCC supports diagnosis but is not routinely used due to complexity.

Electrocardiogram (ECG)

• May show ST-segment depression, T-wave inversion, and signs of ventricular hypertrophy or arrhythmias in some cases.

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

• The Leipzig score integrates clinical features and test results to assess the probability of Wilson disease:
  • ≥4: Diagnosis confirmed.
  • 3: Probable; requires further testing.
  • ≤2: Wilson disease unlikely.
• Scoring parameters include:
  • 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

Chelators

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.

Zinc Salts

• 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

Hepatic Presentation

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

Nazer score

• Evaluates prognosis based on serum bilirubin, AST, and prothrombin time (PT). Each parameter scores from 0 to 4:
  • 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

Combination Therapy

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

Liver Transplantation

• 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.

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