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Hepatology›Condition·Updated Jun 27, 2026·v1

Wilson Disease

Wilson disease is an autosomal recessive disorder of copper metabolism caused by ATP7B mutations, leading to toxic copper accumulation in the liver and brain. Diagnosis requires a high index of suspicion in young patients with unexplained liver disease, neuropsychiatric symptoms, or hemolytic anemia, and is confirmed by Kayser-Fleischer rings, low ceruloplasmin, elevated urinary copper, and ATP7B genetic testing. Management involves lifelong chelation (D-penicillamine or trientine) for symptomatic disease, with zinc for maintenance. Liver transplantation is curative for acute liver failure or decompensated cirrhosis. With early treatment, prognosis is excellent, but adherence and monitoring are critical to prevent progression and complications.

High Evidence81 references·12,109 words·49 min read·v1
Wilson diseasecopper overloadATP7Bhepatolenticular degenerationliver transplantationchelation therapy

Quick Reference

RxDrug of choiceD-penicillamine 750-1500 mg/day or trientine dihydrochloride 750-1500 mg/day for symptomatic disease
AltAlternativesZinc acetate 50 mg elemental zinc TID for maintenance; tetrathiomolybdate (investigational) for neurological disease
⊘AvoidZinc monotherapy for initial symptomatic disease; abrupt cessation of therapy; non-dihydropyridine CCBs (diltiazem, verapamil)
DxTest of choiceATP7B genetic sequencing (biallelic pathogenic variants confirm diagnosis)
ScKey scoreLeipzig score (≥4 diagnostic; includes KF rings, ceruloplasmin, urinary copper, genetic testing)
→When to referAcute liver failure, decompensated cirrhosis (Child-Pugh B/C), MELD ≥15, neurological worsening on therapy, consideration for liver transplantation
Wilson disease is a treatable cause of liver and neurologic disease; early diagnosis and lifelong chelation prevent progression and allow normal life expectancy.
Wilson disease is an autosomal recessive disorder of copper metabolism caused by ATP7B mutations, leading to toxic copper accumulation in the liver and brain. Untreated, it is uniformly fatal; with early diagnosis and lifelong chelation or zinc therapy, most patients achieve normal life expectancy. The key to management is early recognition in any young patient with unexplained liver disease, neuropsychiatric symptoms, or hemolytic anemia. Diagnosis relies on a combination of Kayser-Fleischer rings, low serum ceruloplasmin, elevated 24-hour urinary copper, and confirmatory ATP7B genetic testing. First-line treatment is chelation with D-penicillamine or trientine, with zinc used for maintenance. Liver transplantation is reserved for acute liver failure or decompensated cirrhosis. Lifelong monitoring of copper balance is essential to prevent disease progression and complications.

Overview and Recommendations

Background

  • •Wilson disease is an autosomal recessive disorder of copper metabolism caused by pathogenic variants in ATP7B, leading to toxic copper accumulation predominantly in the liver and brain; untreated, it is uniformly fatal, but early diagnosis and lifelong chelation or zinc therapy allow normal life expectancy.
  • •The disease affects approximately 1 in 30,000 to 1 in 50,000 live births globally, with a carrier frequency of ~1 in 90; it is pan-ethnic but shows regional mutation clustering (e.g., H1069Q in Europeans).
  • •The pathognomonic defect is loss-of-function of ATP7B, a copper-transporting P-type ATPase essential for biliary copper excretion and ceruloplasmin incorporation; failure leads to hepatic copper overload, then systemic spillover to brain, cornea, kidneys, and other tissues.
  • •Clinical presentations are classified into hepatic (40-50%), neurological (30-40%), mixed, and pre-symptomatic; acute liver failure with Coombs-negative hemolytic anemia is a medical emergency requiring urgent liver transplantation.
  • •The paradigm of management shifted from high-dose penicillamine to individualized chelation (trientine preferred for neurological disease) and zinc maintenance, with liver transplantation reserved for decompensated cirrhosis or fulminant failure.

Evaluation

  • •Suspect Wilson disease in any patient aged 3-55 years with unexplained liver disease (elevated aminotransferases, steatosis, cirrhosis), neurological symptoms (tremor, dysarthria, dystonia), or psychiatric disturbances (depression, personality change).
  • •Examine for Kayser-Fleischer rings on slit-lamp examination, golden-brown copper deposition in Descemet's membrane; present in ~95% of neurological presentations but only ~50% of hepatic presentations; absence does not exclude disease.
  • •Order serum ceruloplasmin (nephelometry) as first-line screening; a level <20 mg/dL supports Wilson disease, but acute-phase response can falsely elevate it, so a normal level does not rule out disease.
  • •Measure 24-hour urinary copper excretion; a basal excretion >100 µg/24 h (1.6 µmol/24 h) is classic for symptomatic Wilson disease; in children with mild disease, a cutoff >40 µg/24 h provides 85% sensitivity and 96% specificity.
  • •Calculate the Leipzig score using clinical, biochemical, and genetic criteria; a score ≥4 establishes the diagnosis, score 3 is suggestive, score ≤2 makes Wilson disease unlikely.
  • •Perform ATP7B sequencing as the confirmatory gold standard; biallelic pathogenic variants confirm diagnosis; if only one variant found, consider whole-genome sequencing for deep intronic variants.
  • •Consider liver biopsy for copper quantification (>250 µg/g dry weight) only when genetic results are uninformative and biochemical tests are borderline; biopsy also provides histologic grading of steatosis and fibrosis.
  • •Order brain MRI (T2-weighted/FLAIR) in any patient with neurological or psychiatric symptoms; characteristic hyperintensity in basal ganglia, thalamus, and brainstem (including the 'face of the giant panda' sign) supports neurological involvement.
  • •In acute liver failure, use the alkaline phosphatase:total bilirubin ratio <4 and ALT:AST ratio <1 to rapidly identify Wilson disease as the cause; these have high diagnostic accuracy in this setting.
  • •Also consider differential diagnoses: autoimmune hepatitis (can have false-positive autoantibodies), progressive familial intrahepatic cholestasis type 3 (PFIC3), citrullinemia type I, and Menkes disease.

Management

  • •Initiate chelation therapy immediately in all symptomatic patients with hepatic or neurological Wilson disease; first-line options are D-penicillamine 750-1500 mg/day orally in 2-4 divided doses on an empty stomach, or trientine dihydrochloride 750-1500 mg/day in 2-3 divided doses.
  • •For presymptomatic patients or those who have achieved metabolic stability on chelation, use zinc acetate 50 mg elemental zinc three times daily with meals as maintenance therapy; zinc monotherapy is not recommended for initial treatment of symptomatic disease due to higher failure rates.
  • •Titrate chelator doses based on 24-hour urinary copper excretion: target 200-500 µg/24h on chelation; if urinary copper is too high (>500 µg/24h), increase the chelator dose; if too low (<200 µg/24h), consider non-adherence or over-chelation.
  • •Monitor serum non-ceruloplasmin-bound copper (NCC) with a target <150 µg/L; exchangeable copper (CuEX) is an emerging alternative with target <15 µg/L; liver enzymes and neurological examination (Unified Wilson Disease Rating Scale) should be assessed at each visit.
  • •In acute liver failure due to Wilson disease, do not initiate chelation therapy, it does not reverse acute hepatic necrosis and may precipitate neurological worsening; instead, list for urgent liver transplantation (UNOS Status 1a) immediately.
  • •Use therapeutic plasma exchange or molecular adsorbents recirculating system (MARS) as a bridge to transplantation in acute liver failure; these can remove circulating copper and improve coagulopathy but should not delay transplant listing.
  • •For decompensated cirrhosis (Child-Pugh B/C), manage complications of portal hypertension per standard protocols: ascites with diuretics (spironolactone 100-400 mg/day, furosemide 40-160 mg/day), variceal hemorrhage with endoscopic band ligation and vasoactive drugs (terlipressin 2 mg IV q4h or octreotide 50 µg bolus + 50 µg/h), and hepatic encephalopathy with lactulose and rifaximin.
  • •If first-line chelation fails (progressive liver dysfunction, neurological worsening, or intolerable adverse effects), switch to the alternative chelator; trientine tetrahydrochloride (600-1200 mg/day) is a newer formulation with improved tolerability.
  • •Consider bis-choline tetrathiomolybdate (TTM, ALXN1840) 15-60 mg/day as an investigational option for neurological Wilson disease; it reduces intestinal copper absorption and may have lower risk of paradoxical neurological worsening.
  • •Liver transplantation is definitive therapy for Wilson disease and is indicated for fulminant hepatic failure, decompensated cirrhosis unresponsive to 3-6 months of medical therapy, and selected cases of severe neurological deterioration refractory to chelation; post-transplant survival is 82-87% at 5 years.
  • •Avoid abrupt cessation of therapy, copper rebound can cause acute hemolysis and liver failure; do not use non-dihydropyridine calcium channel blockers (diltiazem, verapamil) as they exacerbate hepatic dysfunction.
  • •Refer for liver transplantation evaluation in any patient with acute liver failure, Child-Pugh class C cirrhosis, MELD ≥15, or neurological worsening despite optimal medical therapy.

Board Review — High Yield

  • •Kayser-Fleischer rings, copper deposition in Descemet's membrane; pathognomonic when present, but absent in ~50% of hepatic presentations.
  • •Leipzig score ≥4, diagnostic threshold combining clinical, biochemical, and genetic criteria.
  • •D-penicillamine, first-line chelator; dose 750-1500 mg/day on empty stomach; monitor for autoimmune reactions and bone marrow suppression.
  • •Trientine, alternative chelator with fewer adverse effects; preferred for neurological disease due to lower risk of paradoxical worsening.
  • •Zinc acetate, maintenance therapy only; induces intestinal metallothionein to block copper absorption; not for initial symptomatic treatment.
  • •Acute liver failure in Wilson disease, characterized by Coombs-negative hemolytic anemia, low ALP:bilirubin ratio <4, and ALT:AST <1; requires urgent liver transplantation.
  • •Paradoxical neurological worsening, occurs in ~26% of neurological patients within first 3 months of chelation; manage by switching chelator or dose adjustment.
  • •Liver transplantation, definitive therapy; corrects copper metabolism; 5-year survival >82%; indicated for fulminant failure or decompensated cirrhosis.
  • •ATP7B mutation H1069Q, most common in Europeans; associated with later onset and milder phenotype compared to loss-of-function variants.
  • •24-hour urinary copper target, 200-500 µg/24h on chelation; <100 µg/24h on zinc; over-chelation can cause copper deficiency and neurological deterioration.

Deep Dive — Evidence Details

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