WILSONS DISEASE

Presented by:-Dr.Mayur.C.Gwalani
 Wilsons disease

■ First described in 1854 by Friedrich Theodor von Frerichs

■ Named in honour of Samuel Alexander Kinnier Wilson (December 6, 1878 – May 12,
1937)
Epidemiology of Wilsons disease

■ 1 case in 30,000 live birth

■ One of the highest prevalence was found in mountain village on island of Crete
■ Men and women are equally affected
 Genetics Of Wilsons Disease
■ It is caused by mutation in the gene coding of
ATPase Copper Transporting Beta Polypeptide
(ATP7B) which is located on Chromosome 13
■ ATP7B is relatively large gene at around 80kb and it
contains 21 exons
■ Over 300 mutation has been identified in ATP7B
gene
■ Defects include insertion, deletion, splice site and
point mutation
■ Frame shift deletions and nonsense mutation that
cause truncation of the translated protein product
usually result in severe form of the disease because
of the loss of functional protein
■ The H1069Q mutation is one of the most common
mutation with an allelic frequency of 10 to 40
percent
■ Compound heterozygous for the ATP7B mutation are
frequent in WD which makes the genotype
phenotype correlation challenging
Pathophysiology Of Wilson’s Disease
■ ATP7B is mainly expressed in hepatocytes
as is critical for Biliary Copper and for
Copper incorporation in Ceruloplasmin
■ With type Biliary Copper is overloaded and
redistributed to other tissue including
Brain and Kidney
■ Which causes toxicity, primarily as a potent
inhibition of enzymatic processes
■ Ionic Copper inhibits pyruvate oxidase in
brain and Atpase in membranes leading to
decreased Adenosine Triphosphate
Phosphocreatine and Potassium content
 Clinical Features

■ Hepatic Features:
 Kayser Fleischer Rings visible in 50% cases with hepatic disease, 90% of individual
and almost invariably in neurologic manifestation
 Asymptomatic- Steatosis, Chronic Hepatitis, Compensated Cirrhosis
 Abdominal Pain – Acute Hepatitis, Acute Liver Failure
 Hepatomegaly – Acute & Chronic Hepatitis, Compensated Cirrhosis)
 Splenomegaly – Cirrhosis
 Ascites – Cirrhosis
 Upper GI Bleeding – Cirrhosis with varicocele or portal hypertensive gastropathy
 Peripheral Stigmata of Chronic Liver Disease – Cirrhosis
 Mental Status changes due to hepatic encephalopathy – Acute Liver Failure,
Cirrhosis
■ Neurologic Features:
 Dysarthria: 55%
 Gait Abnormality
 Dystonia
 Tremor
 Parkinsonism
 Drooling
■ Other Features
 Risus Sardonius- Sardonic expression produced by dystonic spasm of facial muscles
 Chorea
 Athetosis
 Cognitive Impairment/ Dementia
 Seizure
 Hyperreflexia
 Myoclonia
 Urinary Incontinence
 Autonomic Dysfunction
Keyser Fleischer Rings

■ Formed by the deposition of copper in Descement Membrane in the Limbus if the

Cornea
■ Colour may range from greenish gold to brown
■ Well developed rings may be readily visible to the naked eye or with an
ophthalmoscope set at +40
■ When not visible to the unaided eye, the ring may be identified using slit lamp
examination or Gonioscopy
 Wilson Facies
Various combinations of:
■ Vacuous smile,
■ Pseudo-laughter,
■ Open mouth
■ Dull look
■ Staring expression
They also demonstrates hand, nuchal,
and truncal dystonia in some of the
patients
 Rare Presentation
■ Haematological
Acute non immunological haemolytic anaemia and epistaxis
■ Orthopaedic
Chondrocalcinosis, osteoarthritis, metabolic bone disease, Juvenile Polyarthritis, recurrent
fracture and dislocation
■ Cardiovascular
Arrythmia, rheumatic fever like manifestation
■ Renal
RTA, hypercalciuria, microscopic haematuria minimal proteinuria
■ Skin
Hyperpigmentation
■ Ocular
Sunflower cataract
■ Gynaecological
Primary or Secondary Amenorrhea, repeated and unexplained spontaneous abortion
 Staging

■ Stage I  Initial Period of accumulation of copper within hepatic binding sites

■ Stage II Acute redistribution of copper within in liver and its release into
circulation
■ Stage III  Chronic accumulation of copper in the brain and other extrahepatic
tissue, with progressive and eventually fatal disease
■ Stage IV  Restoration of Copper balance by the case of long term chelation
therapy
 Investigations
Investigations
Urinary Copper
Comments
24 hour copper excretion >100μg in 65% of WD patients

Urinary copper penicillamine challenge with two dosages of 24 hour copper excretion > 1600 μg in patients with active
500mg 12 hours apart and measure urine copper liver disease

Serum Copper Serum copper may be low in asymptomatic cases (because

caeruloplasmin is low) or high in cases with active liver
disease (because free copper is raised)
Serum "free" copper Calculated on the basis that Free Copper >25μg/dl
caeruloplasmin contains 0.3% copper

Serum Caeruloplasmin < 20 mg/dl (in 95% of WD patients)

KF rings Identification in most patients requires an experienced
observer
Liver Copper >250 μg/gm of dry weight liver
Coombs negative haemolytic anaemia
Biochemical indices Abnormal liver function tests
MRI Scan Abnormal
Molecular diagnosis Over 200 mutations are known
Electrocardiography Resting electrocardiographic abnormalities include left
ventricular or biventricular hypertrophy, early repolarization,
ST segment depression, T-wave inversion, and various
arrhythmias

Positron emission tomography (PET) scanning Significantly reduced regional cerebral metabolic rate of
glucose consumption in the cerebellum, striatum, and, to a
lesser extent, in the cortex and thalamus.

They also demonstrated a marked reduction in the activity of

dopa-decarboxylase, indicative of impaired function of the
nigrostriatal dopaminergic pathway.

These abnormalities improve with chelation therapy,

indicating a reversible component of striatal neuron injury.
 AASLD recommendations for diagnosis
and screening for Wilson disease (WD)
Clinical Features:
■ WD should be considered in any individual between the ages of 3 and 55* years with liver
abnormalities of uncertain cause.

■ Age alone should not be the basis for eliminating a diagnosis of disease.

■ WD must be excluded in any patient with unexplained liver disease along with neurological or
neuropsychiatric disorder.

■ In a patient in whom WD is suspected, Kayser-Fleischer rings should be sought by slit-lamp

examination

■ The absence of Kayser-Fleischer rings does not exclude the diagnosis of WD, even in patients with
predominantly neurological disease.
Typical clinical symptoms and signs Other tests
Kayer Fleischer rings Liver copper ( in absence of cholestasis)
Present 2 >250 μg/g 2
Absent 0 50-250 μg/g 1
Neurologic symptom( or typical brain MRI) Normal ( 50 μg/g) -1
Present 2 Rhodamine-positive hepatocyte on biopsy 1
Absent 0 Urinary Copper (in absence of acute hepatitis)
Serum Ceruloplasmin Normal 0
Normal (>0.2 g/L) 0 1-2 x ULN 1
0.01-0.2 g/L 1 >2 x ULN 2
<0.1 g/L 2 Normal, but >5 x ULN after D-Penicillamine 2
Coombs negative haemolytic anaemia Mutation analysis
Present 1 Two chromosome mutations 4
Absent 0 One chromosome mutation 1
No mutations detect 0
Total Score Evaluation
≥4 Diagnosis highly likely
2-3 Diagnosis probable, more tests needed
≤1 Diagnosis very unlikely
 Treatment
■ Zinc Acetate: 25 mg 3 times a day
Blockage of Copper absorption by inducing metallothionein in enterocytes.
Side Effect- Mild Abdominal discomfort
■ Trientine: 1 gm/day in 3 divided day
Chelation and urinary excretion of copper
Side Effect- Sideroblastic Anaemia. Autoimmune disorders same as D- Penicillamine but
occur less frequently
■ D-Penicillamine: 20mg/kg/body weight in 2 divided dose before meals
Chelation and urinary excretion of copper
It is antimetabolic of vitamins B6
Side effect:
 initial neurological worsening. Acute Hypersensitivity proteinuria
 Delayed: Goodpasture's syndrome, Polymyositis, Neuropathy and neuromuscular
junction defect, systemic lupus erythematous, bone marrow suppression effects on
immune system, collagen and on skin during prolonged therapy
■ Ammonium Tetrathiomolybdate: 2-3 mg/kg/body weight
Complex with copper and protein within intestine
and circulation, thereby detoxifying copper in
plasma and blocking copper absorption from the
intestine
Side effect: Overtreatment produces in reversible Anaemia