Autosomal recessive ATP7B mutation → impaired biliary copper excretion → hepatic, neurologic, and psychiatric disease.
Overview
Autosomal recessive disorder caused by mutations in the ATP7B gene on chromosome 13, encoding a hepatocyte copper-transporting ATPase. Loss of function impairs biliary excretion of copper and incorporation of copper into ceruloplasmin, resulting in pathologic copper accumulation in liver, brain, cornea, and other tissues.
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Risk factors
- Family history (autosomal recessive)
- Consanguinity
- More than 700 ATP7B mutations described — compound heterozygosity common
Pathophysiology
Dietary copper is absorbed in the duodenum and delivered to hepatocytes. ATP7B normally transports copper into bile and onto apoceruloplasmin to form ceruloplasmin. With ATP7B dysfunction, copper accumulates in hepatocytes (causing oxidative injury, steatosis, fibrosis, and eventually cirrhosis), is released into blood as free (non-ceruloplasmin-bound) copper, and deposits in brain (basal ganglia), cornea (Descemet membrane → Kayser-Fleischer rings), kidneys, and joints.
Clinical presentation
Symptoms
- Hepatic: asymptomatic LFT elevation, chronic hepatitis, cirrhosis, acute liver failure (especially adolescents/young adults)
- Neurologic: tremor (wing-beating), dysarthria, dystonia, parkinsonism, ataxia, drooling, dysphagia
- Psychiatric: depression, anxiety, personality change, psychosis, cognitive decline — often early or only finding
- Hemolytic anemia (Coombs-negative)
- Renal: Fanconi syndrome (proximal tubular dysfunction), nephrolithiasis
- Cardiac: arrhythmias, cardiomyopathy
- Endocrine: hypoparathyroidism, infertility, amenorrhea
Signs / physical exam
- Kayser-Fleischer rings: brownish corneal deposits at the limbus; present in ~95% with neurologic disease, ~50% with hepatic disease; require slit-lamp exam
- Sunflower cataracts
- Jaundice, ascites, splenomegaly in advanced hepatic disease
- Neurologic signs as above; risus sardonicus (fixed grin) in advanced cases
Classic findings
Adolescent with hepatitis, hemolytic anemia, and a movement disorder — think Wilson.
Differential diagnosis
- Viral hepatitis — Positive serologies, no neuropsychiatric findings, normal ceruloplasmin
- Autoimmune hepatitis — Positive ANA, ASMA, elevated IgG; can coexist with Wilson — copper studies still needed
- Alpha-1 antitrypsin deficiency — Low A1AT level/activity, ZZ phenotype, often with emphysema
- Nonalcoholic fatty liver disease — Metabolic syndrome, imaging steatosis, no neuro findings or Kayser-Fleischer rings
- Hereditary hemochromatosis — Iron overload (high ferritin, transferrin sat), HFE mutation; bronze skin, diabetes, cardiomyopathy
- Drug-induced parkinsonism / Huntington / early-onset dystonia (neuropsychiatric Wilson) — No hepatic abnormalities, normal copper studies; family history for HD
Diagnostic workup
Diagnostic criteria
Leipzig score (≥4 = diagnostic): combines Kayser-Fleischer rings, neuropsychiatric symptoms, Coombs-negative hemolytic anemia, urinary copper, hepatic copper, serum ceruloplasmin, and ATP7B mutation status.
Labs
- Serum ceruloplasmin (low <20 mg/dL in ~85%; can be falsely normal in inflammation, falsely low in malnutrition or other liver disease)
- 24-hour urinary copper (elevated >100 mcg/24 h in symptomatic Wilson; >40 mcg/24 h in presymptomatic)
- Serum free (non-ceruloplasmin-bound) copper (elevated >25 mcg/dL)
- LFTs, INR, CBC (hemolytic anemia)
- Coombs test (negative hemolysis in Wilson)
- Slit-lamp exam by ophthalmology for Kayser-Fleischer rings
- Liver biopsy with hepatic copper quantification (>250 mcg/g dry weight is diagnostic)
- Genetic testing for ATP7B mutations (confirmatory; useful for family screening)
Imaging
- Brain MRI — bilateral basal ganglia (putamen, globus pallidus) and brainstem T2 hyperintensities; 'face of giant panda' sign
- Abdominal imaging — features of chronic liver disease in advanced cases
Treatment
First-line
- Lifelong copper restriction: avoid shellfish, liver/organ meats, nuts, chocolate, mushrooms, dried fruit
- Symptomatic patients — chelation: penicillamine (with pyridoxine supplementation; risk of neurologic worsening early, autoimmune reactions, nephrotoxicity) OR trientine (better tolerated, often first-line in many centers, especially for neurologic disease)
- Asymptomatic / maintenance after chelation: zinc acetate (induces metallothionein, blocking GI copper absorption)
- Combination chelation + zinc may be used in severe disease
- Monitor 24-h urinary copper, free copper, LFTs to guide therapy
Complications
- Progression to cirrhosis with portal hypertension, varices, ascites
- Acute liver failure
- Hepatocellular carcinoma (lower risk than other cirrhosis etiologies but possible)
- Permanent neurologic deficits if treatment delayed
- Penicillamine-induced lupus, nephrotic syndrome, aplastic anemia, neurologic worsening
PANCE pearls
- Always consider Wilson in any patient <40 with unexplained hepatitis, ALF, hemolytic anemia, or new movement disorder.
- Ceruloplasmin is the screening test but is neither sensitive nor specific alone — combine with urinary copper and slit-lamp.
- Kayser-Fleischer rings absent in ~50% of patients with hepatic-only disease; their absence does not exclude Wilson.
- ALF clue: alkaline phosphatase:total bilirubin <4 and AST:ALT >2.2 — list for transplant.
- Penicillamine can paradoxically worsen neurologic symptoms in the first weeks — trientine may be preferred for neuropsychiatric Wilson.
References
- AASLD 2022 — AASLD Practice Guidance on Wilson Disease (Schilsky et al., Hepatology 2022)
- EASL 2012 — EASL Clinical Practice Guidelines: Wilson's disease (J Hepatol 2012)
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