WILSON`S DISEASE

WILSON`S DISEASE

1. Wilsons Disease
Dr.M.Kaliratinname

2. •Progressive lenticular
degeneration, a familial
nervous disase associated with
cirrhosis of the liver.
SAMUEL ALEXANDER
KINNIER WILSON
Thesis, Univ. of Edinburgh,
1912.

3. HISTORY
•1902-KAYSER&FLEISCHER
•1912-SAK WILSON
•1921-HALL
•1948-CUMMINGS
•1951-BAL IS INTRODUCED
•1952-SCHEINBERG&GITLIN-LOW CERULOPLASMIN.
•1953-PATTERN OF INHERITANCE

4. •1956-WALSHE –D-PENCILLAMINE
•1961-SCHOUWINK-EFFECTIVENESS OF ZINC
•1969-TRIENTINE
•1985-WILSONS CHROMOSOME
•1986-AMMONIUM TETRA THIO MOLYBDATE
•1993-MENKES GENE AND WILSONS GENE
IDENTIFIED

5. Epidemology
• Occurs worldwide
• Incidence of one in 30,000
• Prevalence
•Europe: 30/100,000
•Asia : 33-68/100,000 Incidence 1/30000
• El Salvador 1 in 186.
•Carrier: 1/100 (El Salvador 1/4)
• The age at onset of symptoms ranges from 6 to about 40
years.

6. •India
• Hepatic 19.7% Metabolic liver disease in
children commonest WD
•NIMHANS : 15-20 New cases per year
• Age of onset: 10-20 (<5 never, >50 rare)
•Hepatic :10-15
•Neurologic 15-20
•Sex: M>F
.

7. THE COPPER PATHWAY
•Copper is a micro nutrient and an essential cofactor for
many enzymes cytochrome c oxidase and superoxide
dismutase.
•Daily copper intake is 1-4 mg
•Of this 50%is unabsorbed and passed in stool,30%lost
through the skin,20%is absorbed in enterocyte by
metallothionein.
•Copper is then exported from enterocyte to the portal
blood with the help of menkes protein.

8. •In the portal blood copper is carried loosely bound to
albumin,aminoacids esp,histidineand transcuprein.
•Copper is transported to the hepatocyte at the basolateral
membrane,from the portal blood.
•The hepatocyte protects itself against copper toxicity by
following mechanisms
•1)controlling uptake of copper
•2)chaperoning copper to various locations
•3)binding free cytoplasmic copper
•4)actively transporting copper (by wisons disease protein.)

9. Copper chaperone proteins
•1)Hah 1
•2)Lys 7
•3)Cox 17.

10. Cu Metabolism

11. Foods rich in copper
•Liver,kidney,choclate,nuts,dried
beans,green chillies
,mushroom,legumes,unprocessed
meat,milk products,dried fishand shell fish.

12. WD – Genetic Link
•Autosomal recessive disorder
•The WD gene, ATP7B is located on the long arm
of chrom. 13q14.21
•The WD gene encodes a copper-transporting P-Type
ATPase) which is expressed predominantly in the
liver

13. Mutations in WD gene (ATP7B)
ATP7B gene
•Deletions 60
•Insertions 21
•Nonsense 19
•Missense 166
• Splice 23
total 289
•India
•Chandigarh: T3305C, C2975A,
29977ins A
•Kolkata: C813A 19%
•Vellore: G3182A 16%, C813A
12%
•51 Mutation of ATP7B, 34
novel
•C813A mutation commonest
•World
•European PH1069Q 60%
•Chinese pR778L 45%

14. Molecular Mechanism
•The Wilson Disease Protein (WNDP)
has two functions:
1. Export of copper from the cell and
2. Incorporation into copper-dependent
enzymes

15. Copper Metabolism - Normal

16. Copper Metabolism – WD Mutations

17. WD protein (ATPase)

18. WD - Pathophysiology
•Mutations in the ATP7B gene result in
1. Retention of copper in the liver
2. Impaired incorporation of
copper into ceruloplasmin
•This accumulation is then followed by hepatic
and/or neurological symptoms due to copper
toxicity

19. Pathology
•The earliest changes include the glycogen deposition
in nuclei of periportal hepatocytes and
microvesicular fatty infiltration.
•Then comes the infiltration of lymphocytes and
plasma cells.
•If untreated it progresses to macronodular cirrhosis
and fulminant hepatitis.

20. Histopathology
•Histologic abnormalities precede clinical appearance
•Helpful diagnostic clues:
•Steatosis
•Ballooned hepatocytes
•Glycogenated nuclei
•Moderate to marked copper deposition
•Lymphocytic portal and interface hepatitis
•Untreated, progresses to cirrhosis

21. WD- cirrhotic stage (Rhodanine stain)
This reveals accumulation of copper ,
most in a nodular cluster of hepatocytes

22. DEISS’S STAGING OF WD
•Stage 1 : Begins at Birth , pts are Asymptomatic
•Stage 2: liver is saturated , Copper is released into serum
•2.a : It can debut with Hemolytic Anemia or
•2b. Liver failure
•Stage 3 : Copper accumulates in extra hepatic tissues like
brain and Eyes (KF rings)
•Stage 4 : Neurological Symptoms Develop
•Stage 5 : therapy is initiated and Symptoms to fade away

23. HEPATIC PRESENTATION
•A hepatic presentation of Wilson disease is more common in
children than in adults.
•Symptoms may be vague and nonspecific,
•Pts may present with a self-limited clinical illness – acute
hepatitis,
•Pts may present with severe, established chronic liver disease
— portal HTN.
•Wilson disease may manifest as clinical
liver disease indistinguishable from autoimmune hepatitis.

24. •Wilson disease may also manifest as fulminant
hepatic failure, with severe coagulopathy and
encephalopathy .
•Recurrent bouts of hemolysis may
predispose to the development of gallstones .
•Wilson disease is rarely complicated by
hepatocellular carcinoma.
•Asymptomatic hepatomegaly.

25. NEUROLOGIC PRESENTATION
•Tends to occur in the 2nd and 3rd decades or later
•Two main patterns,
1. MOVEMENT DISORDER
2. RIGID DYSTONIA

26. PSYCHIATRIC PRESENTATION
•20% of patients may present with
purely psychiatric symptoms .
•Phobias , compulsive behaviors,
aggressive and antisocial behaviors have
been reported.

27. OCULAR SIGNS
•The classic Kayser-Fleischer ring is caused by
copper deposition in Descemet's membrane of
the cornea.
•A careful slit-lamp examination is mandatory.
•Copper deposition in the lens (sunflower cataract),
which does not interfere with vision

29. •Pts with exclusively hepatic involvement
have KF rings in 30 to 50 %
•Pts with a neurologic or psychiatric
presentation of WD have KF rings in almost 95% .
•KF rings are not specific for WD.
•They may be found in other chronic
liver disease, PBC, PSC, AIH, and
familial cholestatic syndromes.

30. Extrahepatic disorders
•Hypoparathyroidism
• Pancreatitis
• Amenorrhea
• Hyperpigmentation.
• Testicular problems
• Infertility
• Hemolytic anemia
• Arthritis,
• Fanconi's syndrome
• Rhabdomyolysis.
• Nephrolithiasis
•Cardiomyopathy

31. Management

32. •High index of suspicion.
•Classic triad include
•Hepatic disease
•Neurologic disease and KF ring.
•No single test is diagnostic of WD,but the presence of
any two of the following is sufficient for the diagnosis.
•Low sr ceruloplasmin,KF ring,hepatic
cu>250micrgm/gm dry wt.

34. 1)serum ceruloplasmin
2)KF ring
3)serum copper
4)serum free copper
5)urine copper
6)liver biopsy and liver copper
7)features of hemolysis
8)scanning of brain
9)molecular genetic testing
10)radio copper loading test.

35. Diagnosis of fulminant WD
•H/O consanguinity
•Absence of other factors
•h/o sibling death due to undiagnosed liver disease
•h/o neuropsychiatric illness in family
•High bilirubin with low transaminases
•Bermans ratio <2
•Evidence of hemolysis in peripheral smear
•Siblings or parents with low ceruloplasmin levels
•High urine copper.

36. MRI in WD
a.‘Face of giant panda’ sign;
b.MRSS: decreased NAA and
therefore a decreased ratio
with other products
c.Bright lateral putamen or
claustral sign;
d.Pallidal hyperintensity

37. Modified calicut score
score
Consanguinity 2
Sibling death due to liver disease 2
Low ceruloplasmin 3
Low ceruloplasmin and high SGPT in siblings
and parents
3
KF ring 3
High urine copper 3
Sun flower cataract 4

38.  Biochemical Parameters

39. TREATMENT
1954Peters BAL
1956Walshe Penicillamine
1969 Walshe Trientine
1984 Walshe Tetrathiomolybdate
1983 Brewer zinc acetate

40. D-Penicillamine
• Mode : General chelator , induces
urinary Cu excretion.
• Dose Initial: 1-1.5 g/day adults or
20 mg/kg/day children ,

Maintenance: 0.75-1 g/day

41. •Side effects :
• Fever, rash
Proteinuria
Lupus like reaction
• Aplastic anemia
• Leukopenia
• Thrombocytopenia

• Nephrotic syndrome
• Degenerative changes
in skin
• Hepatotoxicity
•ND occurs in
10%-20% during
initial phase .

42. Trientine (triethylene tetramine
dihydrochloride)
•Mode :General chelator , induces urinary Cu
excretion.
•Initial: 1-1.2 g/day ; Main : same
•Side effects : • Gastritis
• Aplastic anemia rare
• ND 10%-15% during
initial phase .

43. Zinc
•Mode : Metallothionein inducer, blocks
intestinal absorption of copper .
•Dose : Initial: 50 mg T.I.D (adults)
•Side effects • Gastritis
• Zinc accumulation
• Possible changes in immune
•ND can occur during initial phase .

44. Tetrathiomolybdate
• Mode : Chelator and also blocks
copper absorption
• Side effects : • BM suppresion
• Hepatotoxicity

• Rare reports of ND during initial
phase of treatment

45. Drug choice

46. Prognostic Index of Nazer
Score points

47. •Pts with scores 6 - medical therapy.
•Pts with scores 10 - OLT,
•Pts with scores between 7 and 9 require
clinical judgment .
•Treatment is life long.

48. At present: Liver transplantation in liver failure
At present: Zinc acetate ,Trientine
authorised in the US and EU
Tetrathiomolybdate used experimentally
in the US and EU
In the future: Gene therapy, cell therapy…
based on current molecular knowledge

49. THANK YOU