Wilsons Disease
Also called hepatolenticular degeneration
Described by S.A.Kinnear Wilson in 1912
Autosomal recessive
Highly variable estimates of prevalence:
o UK 1 in 7000
o Other studies 1 in 30,000
1 in 30,000 live births (1 in 55,000 in US study)
Defect in gene ATP7A
Encodes an ATPase that transports copper across cellular membranes.
This can be into vesicles or the plasma membrane.
Multiple mutations present (>600) most patients are compound heterozygotes.
Gene defect results in two problems:
o Decreased secretion of copper from hepatocytes into bile
o Decreased delivery to vesicles for incorporation into protein to form ceruloplasmin.
The overall result is copper accumulation in the hepatocytes and resultant toxicity.
Low ceruloplasmin in itself does not cause injury, it is simply a marker of disease.
Copper induced damage to the liver causes breakdown of hepatocytes which releases the copper to the circulation this results in deposition in other organs particularly the brain.
Histology hepatocellular necrosis is observed, similar to autoimmune hepatitis
Staining can be done to demonstrate copper in tissues.
Usually become clinically evident between age 6 and 30.
Initial symptom in 40-50%, onset ~11-16yrs
Chronic hepatitis with eventual cirrhosis
Acute liver failure in some cases, may be associated with haemolytic anaemia
Fleeting episodes of jaundice can be seen.
Initial symptom in 40-60%, median onset age 20 (range 6-72)
Movement disorders large varieties of presentations
o Tremor (50%)
- proximal or distal, classic presentation is coarse proximal tremor (bird flapping wings)
o Dystonia (69%)
o Parkinsonism (40%)
o Choreform movements, myoclonus
Dysarthria (cerebellar or hypokinetic)
Dysphagia (50%)
Facial change characteristic, dull loo, grinning (risus sardonicus) and drooling.
Others autonomic dysfunction, seizures, headache.
Not usual - Sensory disturbance, upper motor neurone signs
30-40% (10% in other estimates)
Subtle personality changes through to overt depression or psychosis
Kayser-Fleischer rings gold, brown or green pigment in Descemet membrane in cornea
o 98% of patient with neuro signs, 59% of asymptomatic patients
o Not necessarily 100% specific pigmented rings seen in other disorders of hepatic dysfunction
Sunflower cataracts (2-17%)
o Asymptomatic
Coombs-negative haemolytic anaemia (10-15)%
o Combination of this anaemia with liver dysfunction highly suggestive of Wilsons disease
Renal Fanconi syndrome, renal tubular acidosis.
Arthritis fleeting episodes of pain.
Osteoporosis
Cardiac hypertrophy and electrical abnormalities can occur
Hyperpigmentation of legs
Combination of:
o Clinical features
o Abnormal LFTs
o Low serum ceruloplasmin concentration
o High Urinary copper excretion
o Liver biopsy
o Abnormal MRI brain
o Genetic testing
Ceruloplasmin
o Sensitivity - 95% - i.e. low in 95% of homozygotes
- Can be falsely normal in inflammatory conditions (acute phase reactant)
o Not specific
o Can be low in protein wasting diseases (including severe lever disease)
o Rare genetic condition of aceruloplasminaemia
o Menkes disease defective copper absorption
o Low in 20% of asymptomatic heterozygotes
Urinary copper excretion 24hour
o High in Wilsons (>100mcg/day)
o May be normal in early disease if liver is still able to store excess copper
o Elevated in some heterozygotes and other liver disease/inflammation.
o Probably the best performing single screening test.
Serum copper high (not very specific or sensitive)
o Free copper can be calculated based on Ceruloplasmin level however does not add much.
Liver biopsy
o High copper quite specific (most specific individual test)
o Can be falsel low in late fibrosis and falsely high in prolonged cholestasis
Imaging MRI Brain
o High T2 signal and low T1 in basal ganglia +/- brainstem and thalamus
o Face of the giant panda n the midbrain
o Miniature panda in the pons
o Bright claustrum
Penacillamine challenge may be useful in children
Two phases
o Removal of copper
o Prevention of reaccumulation
Initial therapy
o There is debate as to whether zinc, penicillamine or trientine is best as first line agent
o There is probably a preference of trientine in neurological presentations to prevent initial worsening.
Aim for 24hour urinary copper level 200-500mcg/day
<200mcg/day may indicate either non-compliance or, with time, overtreatment
<35mcg/day indicates severe overtreatment and likely development of copper deficiency symptoms.
Penacillamine
o 250-500mg qid (some suggest starting lower and titrating up over several weeks)
o Take on empty stomach, otherwise low bioavailability
o Can deplete pyridoxine consider supplementation
o Neurological symptoms may transiently worsen (and may not then be reversible)
o SE include:
- Sensitivity reactions can occur resulting in the need for alternative agents
- Proteinuria
- Worsening LFTs
- Autoimmune disease: SLE, Glomerulonephritis, Myasthenia gravis, polymyositis, Goddpastures, pemphigus
Trientine
o Less potent decoppering action compared to penicillamine thus perhaps less prone to exacerbating neurological problems.
o Take on empty stomach
o 750-2000mg/day
Dietary restriction
o Not very effective
o Avoid shellfish, liver, nuts, copper, mushrooms
Zinc
o Has been used in:
- pre-symptomatic individuals
- As an adjunct to chelators
- To prevent reaccumulation
o ?competes for copper uptake
o Induces metallothionein which then bonds copper and is sloughed off in intestine
o 50mg of elemental zinc 3x/day
New liver is free of mutation and can thus excrete excess copper
Generally reserved for liver failure although has been proposed as treatment for neurological presentations