Wilson Disease

Clinical Feature
Diagnosis
Management
 Introduction
Autosomal recessive disorder
Caused by mutation in the ATP7B Gene
Incidence: 1 in 30-4000 people
Frequency of carriers of mutated gene - 1%
 Pathogenesis
Mutation in ATP7B gene ( a mambrane Liver (oxidant) damage begins
bound Cu transporting ATPase ) (Once storage capacity is
exceeded)
ATP7B Proein Deficiency

Impair Biliary Cu excretion Defective Cu Incorporation in to
apoceruloplasmin


+ve Cu Balance
Excess catabolism and low blood
Hepatic Cu accumulation levels of ceruloplasmin

Excess Cu initially bound to
Free Cu level es
Metallothionein

Cu builds in other organs

 Clinical Feature
Hepatic: present as

1.Hepatitis- blood transaminase

with or without jaundice
Spontaneous regression f/b recurrance

2. Cirrhosis

3. Hepatic Decompensation
S. Bil
S.albumin and coagulation factors
Ascitis
hepatic encephalopathy
Hemolytic Anemia ( in severe cases )
Neurological:
Age of onset-early twenties to sixth decade
Damage in- basal ganglia
occasionally in pons, medulla, thalamus, cerebellum and
subcortical areas
Movement disorder: Common
1.Dystonia- may involve any part of body
eventually leads to grotesque position of limb,
neck and trunk
2.Incordination
3.Tremors
Others-
Dysarthria and Dysphagia
Memory loss
Migraine type headache
Seizures
Difficulty in focusing on tasks
Autonomic disturbances
Cognition is not grossly impaired
Sensory and muscular abnormalities are not the feature
Psychiatric:
Behavioral disturbances:
Five yrs before the diagnosis ( in 50 % neurological
cases)
Features : loss of emotional control ( temper, tanrtum,
crying bouts)
Depression
Hyperactivity
Loss of sexual inhibition
Other Manifestations:
Spontaneous abortions
Cholelithiasis and nephrolithiasis
OA esp. knee jt
 Diagnosis

1.S.ceruloplasmin:
Normal 18-35 mg/dl
Low in 90% cases
Not used as definitive diagnostic test b/c
- normal in 10% of affected pts
- reduced in 20% of carriers
2.Kayser-Fleischer ring :
On slit lamp ophthalmoscopy
Present in > 99% case of neuro/ psychiatric form
30-50% in hepatic/ presymptomatic state
3.24 hr Urinary Cu:
Normal - 20-50 ug
Carriers - up to 80ug
Presymptomatic - 60-100 ug
Symptomatic- > 100 ug
4. Liver Bx with quantitative Cu assay:
Gold standard for Dx
Normal - 20-50 ug/g
Carriers -125 ug/g
Case - > 200ug/g
obstructive liver ds give false +ve result
5.Haplotype analysis
 Treatment : Anti Cu Drugs
1.Penicillamine:
Use ed doe to toxicity esp neurological
If given should be used with pyridoxine (25 mg/d)
2.Trientine:
less toxic chelator
500 mg BD
3.Zinc:
DOC for pts with hepatitis with out decompensation and Neuro/psychiaric
symptoms
Nontoxic
Block intestinal absorption of copper
Induces hepatic metallothionein
Dose: 50 mg TDS; each dose shd be separated from meals, trientine and
penicillamine by atleast 1 hr
4.Tetrathiomolybidate::
DOC for initial neurological therapy b/c of
Rapid action
Preservation of neurological Fn
Low toxicity
 Prognostic index of Nazer

Used to establish disease severity in hepatic decompensation

Lab measurement includes:

1. S. Bil : < 5.8 17.5 mg/dl (Normal - 0.2-1.2 mg/dl)
2. AST: <100 - >500 IU/L (Normal 10-35 IU/ dl )
3. PT prolongation: < 4s - >20s

Inference: Score <7 Medical tt

7-9 clinical judgement
> 9 liver transplantation
 Recommended anti Cu drugs for wilson ds
Disease status First choice Second choice

Initial Hepatic:
Heapatitis/cirrhosis with out Zinc Trientine
decompensation
Hepatic Decompensation:
Mild Trientine + Zn Penicillamin + Zn
Moderate Trientine + Zn Hepatic Transplantation
Severe Hepatic Transplantation Trientine + Zn

Initial Neuro / psychiatric Tetrathiomolybidate + Zn Zn

Maintenance Zn Trientine

Presymptomatic Zn Trientine

Pediatric Zn Trientine
Pregnant Zn Trientine
Duration of treatment:
Anti Cu tt must be life long
Hepatic fn- recovers in a yr
Neuro/psychiatric symptoms- improves in 6-24 months

Monitoring of therapy:
Chelating agents: monitor for bone marrow suppression
and proteinuria
Routine biochemistry with urine analysis
( inc 24 hr urine Ca)-
First month- weekly
2- 3 month- 2 wkly
Next 3- 4 months- monthly
Then 4-6 monthly
Zinc: doesnt require blood /urine monitoring