Wilson’s Disease
Pathophysiology:
-Autosomal recessive disorder of impaired copper excretion, due to mutation on chromosome 13
(MANY different types of gene mutations, >700). Get defective copper transport with normal
absorption, causing increased circulating copper that accumulates in brain and liver, causing damage
to the tissue.
-Peak incidence around 17 years, but can present as late as 60’s (and maybe even later).
-Neuropathology: Diffuse atrophy, enlarged ventricles, particularly putamen/caudate and frontal lobes.
Opalaski cells in the globus pallidus are a classic finding.
Signs/Symptoms:
A) Hepatic (hepatitis, cirrhosis, fulminant liver failure)
B) Psychiatric (frontal lobe behavior/personality changes, depression)
C) Neurologic:
-Classically presents as either akinetic rigidity, generalized dystonia, or postural/intention tremor with
ataxia, titubation, and dysarthria.
-Dysarthria (97%; usually early)
-Tremor (20-60% get action or rest tremor; classically the “wing beating” tremor of deltoids)
-Parkinsonism (20-60%), Dystonia (10-60%; classically can see risus sardonicus or vocal cord
dystonia)
-chorea, seizures (6%), ataxia (30%), drooling, hyperreflexia.
-Ophthalmologic: Kayser-Fleischer rings (almost 100% who also have neuro symptoms will
have this, though not everyone with KF rings has Wilson’s), eye movement abnormalities.
-Untreated, becomes a severe dystonic akenetic mute state with retained cognition
DDX:
-Essential tremor, early onset Parkinsons, generalized dystonia, Huntington’s, SCAs.
Diagnosis:
-Serum ceruloplasmin (90% sensitive), 24 hour urine copper (<50 is not Wilson’s, >>100 is consistent
with Wilson’s, 50-100 is a gray zone).
-Opthy slit lamp exam for Keyser Fleisher rings
-MRI brain: high T2 signal in the lentiform and caudate nuclei, thalamus, midbrain, and white matter;
sometimes can also get in frontal lobes. Basically tracks up from the midbrain. Basal ganglia with
“giant panda sign”.
-Gold standard: Liver biopsy with quantitative copper levels (>280 mcg is consistent; not necessary
for diagnosis, though can be useful if clinical question remains; )
Treatment:
-Generally, the order of things is 1) Confirm the diagnosis, 2) Chelate the copper, 3) Deal with any
residual/miscellaneous neurologic symptoms symptomatically once things settle down.
1) Copper chelation:
-If clinically declining or symptomatic: start Trientine monotherapy (24 hour urine copper will spike
then fall); once 24 hour urine copper normalizes and stabilizes, add Zinc and continue to monitor;
once stable levels on both meds for at least 2 months, stop Trientine.
-If SUPER MILD, or asymptomatic, could CONSIDER starting with zinc
A) Zinc acetate (Galzin, first line particularly if asymptomatic): 50mg TID. Best option; minimal
side effects and no evidence of neurologic worsening due to treatment, BUT takes 4-8 months
to kick in (during which time neurologic worsening from the elevated copper can continue).
USE PERSCRIPTION FORM, NOT OVER-THE-COUNTER FORM. Dose 1 hour before food,
or 3 hours after food.
B) Trientine (second line due to side effects, use if very symptomatic): 250mg BID
-Also give pyridoxine 25mg/day.
-Works fast, BUT can cause major neurologic worsening early in treatment (50% have
worsening, 50% of those who worsen never get back to their pre-penicillamine baseline, and
up to 30% of treated patients can becomes disabled or die). Hypothesized to be due to
mobilized large hepatic copper stores getting into blood and affecting brain.
-Worsening tends to occur in the first 4 weeks of treatment. No way to predict who will get side
effects, which can include allergy, marrow suppression, neurologic worsening.
-Improvement in neurologic symptoms tends to occur beginning in 3-6 months.
-Maintenance chelation is required life-long.
-Avoid eating liver, chocolate, nuts, coffee, and shellfish during the initial de-coppering phase, as
these are foods high in copper. Probably good idea to avoid these foods in general.
-If symptoms worsen despite treatment, recheck 24 hour urine copper and urine zinc, and consider if
medication non-compliance could be a factor. It may also be a result of Trientine.
2) Screening:
-Goal is 24 hour urine copper level in a certain range (lower could mean copper deficiency, higher
means poor control), monitored every 6 months at least, along with LFTs, serum copper, serum
ceruloplasmin. Also check 24 hour urine zinc if on zinc to ensure patient is compliant with meds
-Goal 24 urine copper on Trientene alone: 250-500
-Goal 24 hour urine copper on Zinc acetate alone, or Zinc acetate + Trientene: 50-100
-Goal 24 hour urine zinc: 2500-3000 mg
3) GI referral; also consider referrals to psych, SLP, PT/OT.
4) Liver transplant: curative, but often not necessary.
5) Screen 1st degree relatives, cousins, nephews/nieces as well with 24 hour urine copper; usually
start kids around age 5 (when they can pee for 24 hours reliably), and again at age 10-15. Place on
prophylactic zinc therapy if positive.
Prognosis for neurologic recovery:
-Hard to predict. Appropriate treatment prevents further worsening, but may not reverse existing
damage/symptomsDysarthria + tremor types do best (82% chance to become symptom-free or
have minor symptoms), followed by chorea (75%), parkinsonism (65%), and dystonia (53%)
-Generally, unlikely to get further neurologic recovery >18 months from time that urine copper
normalizes
RESOURCES: Neurologic Wilson’s disease. Matthew T. Lorincz. Annals of the New York
Academy of Sciences (2010)