Wilson Disease — Symptoms, Causes & Treatment | MyMedicPlus

Wilson disease (hepatolenticular degeneration) is an autosomal recessive disorder of copper metabolism caused by mutations in the ATP7B gene (chromosome 13q14.3), which encodes a P-type copper-transporting ATPase located in the hepatocyte trans-Golgi network. This ATPase fulfils two critical functions: incorporation of copper into ceruloplasmin (the principal circulating copper carrier) and excretion of excess copper into bile (the primary route of copper elimination). Loss of ATP7B function causes defective biliary copper excretion, leading to progressive copper accumulation first in the liver (hepatic disease), then in the basal ganglia, thalamus, and cerebellum (neurological and psychiatric disease), the cornea (Kayser-Fleischer rings), and the kidneys (Fanconi syndrome). Worldwide prevalence is approximately 1 in 30,000, with a carrier frequency of 1 in 90. It typically presents between ages 5 and 35 — one of the widest age ranges of any genetic disease. Over 600 ATP7B mutations are now catalogued. Wilson disease is one of the most clinically important treatable genetic disorders: when diagnosed early and treated lifelong with chelation or zinc therapy, patients can expect entirely normal life expectancy and quality of life. Untreated or undetected Wilson disease is invariably fatal — most commonly from liver failure or progressive neurological disability.

Wilson disease is caused exclusively by biallelic loss-of-function mutations in the ATP7B gene (chromosome 13q14.3). Over 600 mutations are catalogued — the most prevalent are H1069Q (accounts for 37-72% of alleles in Northern and Eastern European populations) and R778L (most common in East Asian populations — Han Chinese, Japanese, Korean). Most affected individuals are compound heterozygotes carrying two different mutations, which complicates genotype-phenotype correlation and means genetic testing must sequence the entire gene or use comprehensive panels. The mode of inheritance is autosomal recessive: both parents must carry a heterozygous ATP7B mutation for a child to be affected. With two carrier parents, each pregnancy has a 25% probability of Wilson disease, 50% probability of being an unaffected carrier, and 25% probability of neither mutation. Consanguinity increases the probability of inheriting identical mutations from both parents. The carrier frequency is approximately 1 in 90 in the general population, accounting for the prevalence of 1 in 30,000. No environmental risk factors cause Wilson disease — the entire pathogenesis derives from the genetic defect. However, very high dietary copper intake (shellfish, liver) may theoretically accelerate disease onset by overloading already-impaired copper excretion capacity.

Hepatic manifestations (most common initial presentation in children — 40-50%): acute hepatitis with jaundice and elevated transaminases (may be self-limiting or progress), compensated cirrhosis (often asymptomatic — discovered incidentally), or Wilsonian acute liver failure (the most dangerous presentation) — characterised by the triad of acute liver failure, Coombs-negative haemolytic anaemia (massive copper release into circulation lyses red blood cells), and acute kidney injury; 24-hour urine copper characteristically exceeds 100 micromol/24h during liver crises. Neurological manifestations (predominant in young adults — 35-50%): the hallmark 'wing-beating' tremor (wide-amplitude proximal arm tremor elicited by holding arms outstretched horizontally — flapping movement resembling a bird's wing), dysarthria (scanning or cerebellar-type speech), dysphagia, dystonia (involuntary sustained muscle contractions causing fixed abnormal postures), rigidity and bradykinesia (mimicking Parkinson's disease — but Wilson disease patients are too young for idiopathic PD), choreoathetosis, and gait ataxia. Neurological onset averages age 15-20. Psychiatric manifestations (initial presentation in 20-30%): personality change, disinhibition, emotional lability, depression, anxiety, obsessive-compulsive symptoms, psychosis, and deteriorating academic or occupational performance — Wilson disease must be excluded in any person under 40 presenting with unexplained psychiatric illness. Kayser-Fleischer rings: golden-brown to greenish-brown corneal deposits of copper in Descemet's membrane at the limbus — pathognomonic when present; seen in 95% with neurological disease but only 50-60% with isolated hepatic disease; requires slit-lamp examination by an experienced ophthalmologist to detect reliably. Other features: renal Fanconi syndrome (aminoaciduria, glycosuria, phosphaturia), osteoporosis, arthropathy, and cardiomyopathy (rare).

The Leipzig scoring system is the validated international diagnostic framework: a total score of 4 or more confirms Wilson disease; 3 is probable (further tests needed); 2 or fewer makes Wilson disease unlikely. Scoring criteria: Kayser-Fleischer rings on slit-lamp examination by an ophthalmologist (+2); serum ceruloplasmin below 0.1 g/L (+2) or 0.1-0.2 g/L (+1; above 0.2 g/L scores 0); Coombs-negative haemolytic anaemia (+1); neurological symptoms (+2); 24-hour urine copper above 2.0 micromol/24h (+1), or above 5.0 micromol/24h in symptomatic patients (+2); liver copper above 250 micrograms per gram dry weight on biopsy (+2) — this has the highest diagnostic specificity of any single test. Serum ceruloplasmin: below 0.2 g/L in 85-90% of Wilson disease patients; it can be falsely normal (up to 0.3 g/L) during acute-phase reactions, oestrogen therapy, and pregnancy — a normal ceruloplasmin does NOT exclude Wilson disease. 24-hour urine copper collection: the most practical screening and monitoring test — below 0.6 micromol/24h is normal; above 1.6 micromol/24h is highly suggestive; above 25 micromol/24h in acute liver failure is diagnostic. D-penicillamine challenge test (children): 500 mg D-penicillamine given twice before and during a 24-hour urine collection — urine copper exceeding 25 micromol/24h supports Wilson disease. ATP7B gene sequencing: identifies pathogenic mutations in 95-98% of cases — essential for presymptomatic first-degree relative screening once the proband's mutations are known. Liver biopsy with hepatic copper quantification: the most specific diagnostic test (above 250 mcg/g dry weight) — performed when non-invasive tests give a Leipzig score of 2-3. Brain MRI: T2 hyperintensity in basal ganglia, the 'face of the giant panda' sign in the midbrain, and signal changes in the putamen are characteristic of neurological Wilson disease.

Copper chelation therapy — initial treatment for symptomatic Wilson disease: D-penicillamine 750-1,500 mg/day in 2-4 divided doses, taken 30-60 minutes before meals (food reduces absorption by 50%); increases urinary copper excretion from below 2 micromol/24h (normal) to above 8 micromol/24h on initial decoppering treatment; target maintenance urine copper is 3-8 micromol/24h. Side effects occur in 30-50% of patients: early hypersensitivity reactions (fever, rash, lymphadenopathy, thrombocytopenia — in weeks 1-3, requiring temporary dose reduction or drug switch); nephrotic syndrome from membranous nephropathy (monitor urine protein monthly); bone marrow suppression — CBC monthly; and paradoxical early neurological worsening in 10-50% (copper redistribution from liver to brain at treatment initiation — the most serious limiting adverse effect, may cause irreversible neurological deterioration; pyridoxine 25 mg/day supplemented to prevent D-penicillamine-induced pyridoxine deficiency). Trientine (triethylene tetramine dihydrochloride) 750-1,500 mg/day: equally effective chelating agent with substantially fewer side effects — preferred first-line in many European and US guidelines (EASL 2012, AASLD 2008); causes less paradoxical neurological worsening than D-penicillamine. Also pyridoxine-supplemented. Zinc salts (zinc acetate or zinc gluconate 50 mg elemental zinc three times daily, 1 hour before meals or 2 hours after): blocks intestinal copper absorption by inducing intestinal metallothionein, which binds luminal copper and prevents transfer into portal circulation — non-toxic, used for maintenance after initial chelation-induced decoppering (when 24-hour urine copper has normalised), as monotherapy in presymptomatic or mildly symptomatic patients, and in pregnant women (safe in pregnancy — unlike chelating agents, which may cause connective tissue defects in the fetus if given in high doses). Liver transplantation: indicated for Wilsonian acute liver failure (MELD score above 15 or meeting King's WD criteria), decompensated cirrhosis with MELD above 15 unresponsive to 2-3 months of chelation, and occasionally for refractory severe neurological disease — liver transplantation corrects the underlying metabolic defect (the liver is the primary organ expressing ATP7B) and is curative for hepatic Wilson disease; neurological disease stabilises post-transplant but may not fully recover if already established. Monitoring during treatment: 24-hour urine copper every 3-6 months (target 3-8 micromol/24h on chelation, below 1 micromol/24h on zinc), LFTs, CBC, urine protein (D-penicillamine), ophthalmology for KF ring regression (indicator of copper decoppering success).

Wilsonian acute liver failure (the most life-threatening complication): the triad of acute liver failure, Coombs-negative haemolytic anaemia (intravascular haemolysis from massive copper release), and acute kidney injury — carries over 90% mortality without emergency liver transplantation; characterised by rapid progression with marked coagulopathy disproportionate to the degree of jaundice. Cirrhosis and portal hypertension develop in patients with delayed diagnosis or poor treatment compliance, causing oesophageal varices (variceal bleeding), ascites, spontaneous bacterial peritonitis, and hepatic encephalopathy. Progressive neurological disability: untreated neurological Wilson disease causes severe fixed tremor, rigidity, dystonia, dysarthria, and dysphagia — resulting in total dependence on carers, inability to communicate, and profound quality-of-life impairment. Renal complications: Fanconi syndrome (proximal tubular dysfunction — aminoaciduria, glycosuria, phosphaturia, hypophosphataemia) from copper deposition in renal tubules, leading to osteomalacia, pathological fractures, and nephrolithiasis (calcium phosphate stones). Psychiatric morbidity (depression, personality disorder, cognitive impairment) may persist even with adequate copper control, particularly when neurological involvement was severe before treatment. Osteoporosis: from Fanconi syndrome-induced phosphate wasting, renal tubular acidosis, and copper toxicity to bone — DEXA surveillance is recommended. Treatment complications: D-penicillamine hypersensitivity (early — fever, rash, thrombocytopenia; late — membranous nephropathy, drug-induced lupus-like syndrome), bone marrow suppression, and paradoxical neurological worsening at treatment initiation (copper redistribution from liver to brain — may be irreversible if severe).

Presymptomatic family screening is the most important prevention strategy: all first-degree relatives (parents, siblings, and children of the affected individual) must be screened — begin with serum ceruloplasmin, 24-hour urine copper, liver function tests, and slit-lamp examination for Kayser-Fleischer rings; then ATP7B genetic testing once the proband's mutations are known (this allows definitive screening of all family members at minimal cost). Presymptomatic individuals identified and started on zinc therapy before organ damage can expect an entirely normal prognosis and lifespan. Dietary copper restriction supplements (but does not replace) pharmacological therapy: during active decoppering, avoid foods with very high copper content — shellfish (oysters contain up to 4-5 mg copper per serving vs. the recommended intake of 0.9 mg/day), liver and organ meats, mushrooms, nuts, chocolate, and cocoa. Avoid drinking water from copper pipes (install an in-line water filter or run taps for 1-2 minutes before using). Once stable on maintenance therapy, strict dietary restriction is less critical. Lifelong treatment without interruption is non-negotiable: stopping chelation or zinc therapy — even for a few weeks — risks acute hepatic decompensation and potentially fatal liver failure; multiple deaths from treatment discontinuation have been documented in the literature. Routine monitoring every 3-6 months: LFTs, CBC (for D-penicillamine users — bone marrow suppression), 24-hour urine copper (target 3-8 micromol/24h on chelation; below 1.6 micromol/24h on zinc maintenance), urinalysis for proteinuria (D-penicillamine — membranous nephropathy). Annual ophthalmology assessment for KF ring regression confirms progressive decoppering. Annual DEXA scan in patients with hepatic involvement or Fanconi syndrome.

Go to A&E immediately if a known Wilson disease patient develops: jaundice with confusion or drowsiness (acute liver failure — Wilsonian crisis); or has stopped their chelation or zinc therapy — even brief treatment interruption can precipitate life-threatening acute hepatic decompensation requiring emergency liver transplant listing. Seek urgent hepatology review within 24–48 hours if: treatment side effects are suspected (D-penicillamine can cause lupus-like rash, nephrotic syndrome, or worsening neurological symptoms at initiation from copper mobilisation — if neurological deterioration occurs within weeks of starting D-penicillamine, switch to trientine). Refer for specialist assessment for any young person (age 5–35) who presents with unexplained liver disease (elevated transaminases, hepatitis, or cirrhosis), neurological signs (tremor, dysarthria, movement disorder), or psychiatric symptoms (personality change, depression in a young adult) — Wilson disease mimics many conditions and is fatal if untreated but fully manageable when diagnosed. All first-degree relatives of a diagnosed patient must be screened with serum ceruloplasmin, 24-hour urine copper, liver function tests, and slit-lamp examination, followed by ATP7B genetic testing — presymptomatic family members detected can be treated with zinc before organ damage occurs.