Liver disease of less common aetiology - Wilson disease
Description
- Autosomal recessive disorder of copper transport: ATP7B mutation on chromosome 13
- ATP7B does two jobs in the hepatocyte, and both fail:
1. Loads copper onto apocaeruloplasmin -> dec serum caeruloplasmin
2. Excretes copper into bile -> copper accumulates
- Biliary excretion is the only route of copper elimination - so accumulation is inevitable and progressive
- Copper saturates the liver -> spills into the circulation as free (non-caeruloplasmin-bound) copper -> deposits in brain (basal ganglia), cornea, kidney, joints, heart
- Free ionic copper impairs mitochondrial ATP production and generates free radicals -> hepatocyte and neuronal injury
- *Treatable and, untreated, fatal - the reason to test every young person with unexplained liver or movement disorder*
Epidemiology
- Prevalence ~1 in 30,000; carrier frequency ~1 in 90
- >500 ATP7B mutations - most patients are compound heterozygotes, so genotype-phenotype correlation is poor
- Hepatic presentation earlier (median ~10-13 yrs), neurological later (median ~20-25 yrs)
- *Consider it in anyone aged 3-55 with unexplained liver disease - presentations beyond 40 are described, so age does not exclude it*
- Higher in consanguineous populations (Sardinia, Costa Rica)
Aetiopathogenesis
- Copper accumulates first in hepatocyte cytosol, then lysosomes
- Hepatic phase: steatosis -> chronic hepatitis -> fibrosis -> cirrhosis
- Overflow phase: sudden hepatocyte necrosis releases a bolus of free copper
- -> acute liver failure and Coombs-negative haemolytic anaemia (copper is directly toxic to red cells)
- Neurological phase: deposition in putamen, caudate, globus pallidus, midbrain
- Corneal Descemet membrane -> Kayser-Fleischer rings
- Renal tubules -> Fanconi syndrome, hypercalciuria, nephrolithiasis
Trigger to think of it
- Any of: unexplained hepatitis or cirrhosis under 40; ALF with haemolysis; a new movement disorder or psychiatric illness in a young person; unexplained Coombs-negative haemolysis
Diagnosis
Presentations - three domains, often mixed
- Hepatic - asymptomatic transaminitis, acute hepatitis, chronic hepatitis, cirrhosis, or acute liver failure with haemolytic anaemia
- Neurological - intention/wing-beating tremor, dysarthria, dystonia, choreiform movements, parkinsonism, dysphagia, drooling, gait disturbance
- Behavioural change and declining school or work performance often precede the movement disorder
- Cognition is relatively preserved - a discriminator from other young-onset dementias
- Psychiatric (~1/3 at presentation) - depression, personality change, anxiety, psychosis, impulsivity
The tests - no single test is diagnostic
| Test | Wilson | Trap |
|---|---|---|
| Serum caeruloplasmin | Low (<0.2 g/L) | *An acute-phase reactant - falsely NORMAL or high with infection, inflammation, pregnancy or oestrogen*. Also low in nephrotic syndrome, malabsorption, Menkes |
| 24-h urinary copper | >1.6 micromol/24h (>100 microgram); >40 microgram in children | Raised in any cholestasis and in acute liver failure |
| Serum copper | Usually low (tracks caeruloplasmin) | Confusing - the toxic species is FREE copper, which is high |
| Free (non-caeruloplasmin-bound) copper | Raised | Calculated, error-prone |
| Slit-lamp for Kayser-Fleischer rings | Present in ~95% of neurological, ~50% of hepatic | Absence does NOT exclude hepatic Wilson. Also seen in chronic cholestasis |
| Liver biopsy copper | >250 microgram/g dry weight | Sampling variability; raised in chronic cholestasis |
| ATP7B genetic testing | Confirmatory; needed for family screening | Many private mutations |
- Leipzig score combines these; >=4 = diagnosis established
- MRI brain: T2 hyperintensity in basal ganglia; "face of the giant panda" in the midbrain (specific but uncommon)
The acute liver failure clue
- ALP:bilirubin ratio <4 and AST:ALT >2.2 - highly suggestive of Wilsonian ALF
- Low or normal ALP with deep jaundice and Coombs-negative haemolysis in a young person = Wilson until proven otherwise
- Penicillamine challenge test - unreliable in adults, no longer recommended
Screen all first-degree relatives
- LFT, caeruloplasmin, 24-h urine copper, slit lamp, and ATP7B testing once the proband's mutations are known
Management
Verified against the EASL-ERN Clinical Practice Guidelines on Wilson's disease (2025).
Principles
- Lifelong therapy. Stopping causes decompensation and death - non-adherence is the commonest cause of deterioration
- Two phases: de-copper (chelation), then maintain (lower-dose chelator or zinc)
A. Chelation - first line for symptomatic disease
- D-penicillamine - the drug of choice in both EASL 2025 and AASLD; start low and escalate
- Give pyridoxine (vitamin B6) alongside - penicillamine is an antipyridoxine agent
- Adverse effects: early hypersensitivity (fever, rash, proteinuria, cytopenias), later nephrotic syndrome, lupus-like syndrome, myasthenia gravis, elastosis perforans serpiginosa, aplastic anaemia
- *Paradoxical neurological worsening in 10-20% when starting in neurological disease* - start low, escalate slowly
- Trientine - equally effective, substantially better tolerated; the preferred alternative and increasingly used first
- Fewer hypersensitivity and renal effects; can cause sideroblastic anaemia from over-chelation
- Chelators, not zinc, for significant liver disease
B. Zinc
- Induces enterocyte metallothionein -> binds dietary copper -> lost in shed enterocytes -> blocks absorption
- Role: maintenance therapy, and treatment of presymptomatic/asymptomatic patients
- Gastric irritation; less effective than chelation for established hepatic disease
- Do not take at the same time as a chelator - separate doses by several hours or they bind each other
C. Diet
- Avoid high-copper foods: liver and offal, shellfish, nuts, chocolate, mushrooms, dried fruit
- Check drinking water copper if from a private supply or copper piping
- Diet alone is never sufficient
D. Monitoring
- 24-h urinary copper - on chelation, target 3-8 micromol/24h; on zinc, target <1.6 micromol/24h with urinary zinc >2 mg/24h confirming adherence
- A very low urinary copper on chelation suggests over-treatment (copper deficiency), not good control
- Free copper; LFT, FBE, UEC, urinalysis for proteinuria (penicillamine)
- Neurological and psychiatric assessment; adherence at every visit
E. Acute liver failure
- Transplantation is the treatment - chelation is far too slow
- Bridge with albumin dialysis / plasma exchange / continuous renal replacement to remove copper
- Transplantation is curative - it replaces the defective ATP7B, and copper handling normalises
- Use the Wilson-specific prognostic index (Nazer/King's) to decide - a score >=11 predicts death without transplant
F. Pregnancy
- Continue anti-copper therapy - the benefit outweighs the teratogenic risk to the fetus; dose is usually reduced (~25-50%) in the third trimester to aid wound healing
- Zinc is a reasonable option in pregnancy
- Breastfeeding on penicillamine is generally avoided
G. Neurological/psychiatric symptoms
- Supportive: physiotherapy, speech pathology, treat dystonia and tremor symptomatically
- *Avoid dopamine antagonists (metoclopramide, antipsychotics) where possible - they worsen the movement disorder*
Associations
- Coombs-negative haemolytic anaemia - especially in acute presentations
- Kayser-Fleischer rings; sunflower cataract
- Renal Fanconi syndrome, hypercalciuria, nephrolithiasis, renal tubular acidosis
- Arthropathy - premature osteoarthritis, chondrocalcinosis, osteoporosis
- Cardiomyopathy and arrhythmia
- Pancreatitis; hypoparathyroidism; amenorrhoea and recurrent miscarriage
- HCC and cholangiocarcinoma - lower risk than other cirrhoses but not zero
- Menkes disease - the mirror-image ATP7A defect: copper deficiency, kinky hair, seizures, infantile death
Natural history & complications
- Untreated: uniformly fatal - from liver failure, or progressive neurological disability
- Treated early: normal life expectancy
- Hepatic disease responds well; neurological recovery is slower, incomplete, and may take 1-3 years
- Established severe neurological damage may not reverse - the case for early diagnosis
- Non-adherence -> decompensation within months, sometimes irreversibly
- Post-transplant: corrects the metabolic defect; neurological improvement is variable
Monitor
- 24-h urinary copper and free copper at least twice yearly
- LFT, FBE, UEC, urinalysis
- Neurological and psychiatric review
- Cirrhosis -> 6-monthly HCC surveillance and variceal screening
- Screen and genotype all first-degree relatives - treatment of presymptomatic disease prevents it entirely
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