wilsonsdisease-181218143004.pdf

1. Wilson's disease
Insp Dr Mahadev Deuja
Tuesday, December 18, 2018

2. Outlines
• INTRODUCTION​
• EPIDEMIOLOGY​
• PATHOGENESIS
• CLINICAL PRESENTATION
• DIAGNOSTIC TEST
• TREATMENT
• PROGNOSIS
• MCQ’S

3. Introduction
• Rare AR inherited disorder of
impaired copper excretion.
• Characterized by excessive deposition
of copper in many tissues and organs,
principally the liver, brain, and eye.
• Discovered by Samuel Alexander
kinnier Wilson (1878-1937)

4. Normal copper metabolism
Normal Cu uptake is 2–5mg daily,
of which 40–60% are absorbed in
the stomach and upper
duodenum.
It is then incorporated mainly into
ceruloplasmin (CP) in the liver
Ceruloplasmin bound copper is
secreted into plasma which
accounts for 90-95% of serum
copper
1
2
3

5. Normal copper metabolism
CP binds six to seven Cu atoms firmly,
is apparently important for the
oxidation of Fe2+ in plasma
Cu that is bound to transcuprin and
albumin is released into tissue for
metabolic needs.
Old (desialysed) CP is broken down in
the liver and the liberated Cu binds to
biliary proteins and excreted into the
bile.
4 5
6

6. What happens in wilson’s disease?
Initial steps of copper absorption and
transport to the liver are normal.
But liver fails to excrete sufficient Cu via
the bile, and the ability to incorporate Cu
into CP is diminished
Due to loss of function mutations of the
ATP7B gene on chromosome 13, which
encodes a copper-transporting ATPase
(ATP7B)

7. What happens in wilson’s disease?
Free or only loosely bound Cu
progressively accumulates in the liver.
Free copper escape from the overloaded,
damaged hepatocytes into the
circulation.
And in other organs

8. Cont….What happens in wilson’s disease?
Free copper is cytotoxic because it promotes the
formation of O2 radical
Causing hemolytic anemia and chronic active
hepatitis that can later change to cirrhosis.
If the hepatitis takes a fulminant course, large
amounts of Cu are suddenly released from the
necrotic liver and this may trigger a hemolytic
crisis.

9. Cont….What happens in wilson’s disease?
Accumulation of Cu in the CNS cause
neurological, neuromuscular, and
psychogenic abnormalities.
Cu deposited in Descemet’s membrane
of the eye giving a Kayser–Fleischer ring
The kidneys, skeleton and heart can also
be affected.

10. Clinical presentation
• Vary widely, but key features of Wilson disease are
• Corneal Kayser- Fleischer rings
• Liver disease and cirrhosis
• Neuropsychiatric disturbances
• Acute episodes of hemolysis
• Most common presentations are with liver disease or neuro-
psychiatric disturbances
• Symptoms usually arise between the ages of 5 and 45 years although
it can present in adults in their fifties.

11. Kayser–Fleischer ring
• The clinical hallmark of WD.
• Caused by deposition of copper in Desçemet’s membrane of cornea
• Characterised by greenish-brown discoloration of the corneal margin
appearing first at the upper periphery.
• Present in 95% of patients with neurologic symptoms and in >50% of those
without neurologic symptoms
• Sometimes visible only by slit-lamp examination.
• They disappear with treatment
• Not entirely specific for WD (i.e. in chronic cholestatic diseases such as PBC
or in children with neonatal cholestasis)

12. Liver disease
• The liver manifestations may be of almost any variety and severity.
• Presentation include
• Asymptomatic hepatomegaly
• Abnormal LFT even as early as the first year of life
• Fatty liver
• Acute hepatitis
• Resembling autoimmune hepatitis
• Cirrhosis: compensated or decompensated
• Acute liver failure
The important practical message therefore is: suspect Wilson disease
in any child with undiagnosed liver disease

13. Clinical presentation- Blood
• Coombs-negative haemolytic anemia
• May be the only initial symptom.
• Low-grade hemolysis may be associated with WD even when liver
disease is not clinically evident.
• Marked hemolysis is commonly associated with severe liver disease.
• Decay of liver cells may result in the release of large amounts of
stored copper, which further aggravates hemolysis.

14. Neurological disease
• Movement disorders (tremor, involuntary movements)
• Drooling, dysarthria
• Rigid dystonia
• Pseudobulbar palsy
• Dysautonomia
• Migraine headaches
• Insomnia
• Seizures

15. Cont…..Neurological disease
• May be first clinical manifestation, appearing simultaneously with
hepatic signs, or years later.
• Can be extremely subtle, and inter- mingled for many years.
• May also develop very rapidly, leading within a few months to
complete disability

16. Psychiatric disease
• Upto 30% of patients initially present with psychiatric abnormalities
• Presentation includes
• Depression
• Neurotic behaviours
• Personality changes
• Psychosis
• In children declining school performance, personality changes,
impulsiveness, labile mood and inappropriate behavior are observed
• Are frequently misdiagnosed as behavioral problems associated with puberty.

17. Diagnostic test
Serum ceruloplasmin level
24-hour urinary copper
MRI of brain
Ophthalmologic examination
Liver biopsy
Genetic testing

18. Serum ceruloplasmin level
• Typically decreased in patients with
neurologic Wilson disease
• May be in the low normal range in
50% of patients with active Wilson’s
liver disease
Serum ceruloplasmin level
24-hour urinary copper
MRI of brain
Ophthalmologic examination
Liver biopsy
Genetic testing

19. 24-hour urinary copper
• More than 0.6 μmol/24 hrs (38 μg/24
hrs)
• Measuring 24-hour urinary copper
excretion while giving D-penicillamine
is a useful confirmatory test; more
than 25 μmol/24 hrs is considered
diagnostic of Wilson’s disease.
Serum ceruloplasmin level
24-hour urinary copper
MRI of brain
Ophthalmologic examination
Liver biopsy
Genetic testing

20. MRI of brain
• MRI is the most important diagnostic
tool in patients with neurological
presentation
• Almost all patients show an MRI
abnormality:
• Non-specific changes in the brain such as
diffuse brain atrophy and focal
abnormalities.
Serum ceruloplasmin level
24-hour urinary copper
MRI of brain
Ophthalmologic examination
Liver biopsy
Genetic testing

21. Liver biopsy
• Method of choice for diagnosis of WD
• Hepatic copper content of >250ug/g
(4umol/g) dry weight is confirmative
of WD (sensi3vity 83.3%, specificity
98.6%)
Serum ceruloplasmin level
24-hour urinary copper
MRI of brain
Ophthalmologic examination
Liver biopsy
Genetic testing

22. Genetic testing
• Developments of new techniques in
genetic and molecular biology have
provided useful tools in the diagnosis
in recent years.
• PCR is to detect mutations.
• H1069Q mutation is the most
common mutation among the WD
Serum ceruloplasmin level
24-hour urinary copper
MRI of brain
Ophthalmologic examination
Liver biopsy
Genetic testing

23. Treatment
• With proper therapy, disease progress can be halted and oftentimes
symptoms can be improved.
• Treatment is aimed at
• Removing excess accumulated copper
• Best accomplished by copper chelation therapy using
• Penicillamine
• Trientine
• Ammonium tetrathiomolybdate
• Preventing its reaccumulation.
• Accomplished by zinc ingestion and by omitting copper-rich dietary components

24. Treatment
• Treatment for Wilson disease is a lifelong process.
• Treatment should be given to all affected individuals, even if they are
asymptomatic.

25. Penicillamine
• Drug of choice.
• The dose given must be sufficient to produce cupriuresis and most
patients require 1.5 μg/day (range 1–4 μg).
• The dose can be reduced once the disease is in remission but
treatment must continue for life, even through pregnancy.
• Care must be taken to ensure that re-accumulation of copper does
not occur.
• Abrupt discontinuation of treatment must be avoided because this
may precipitate acute liver failure

26. Zinc
• Acts by blocking the absorption of copper in the intestinal tract.
• This action both depletes accumulated copper and prevents its
reaccumulation.

27. Liver transplantation
• May require in patients with severe hepatitis or liver failure.
• The value of liver transplantation in severe neurological Wilson’s
disease is unclear.

28. Prognosis
• Excellent, provided treatment is started before there is irreversible
damage

29. Take home message
• Wilson’s disease, the most common inherited disease of copper
metabolism
• Clinical presentation of WD is vary variable.
• Most common presentations are with liver disease or neuro-
psychiatric disturbances
• Characterized by low serum copper and ceruloplasmin concentrations
coupled with the pathological accumulation of copper in tissue.
• WD can be treated successfully but treatment must be lifelong.

30. Mcq’s
• Kayser-Fleischer ring is seen in
a) Wilson disease
b) Primary biliary cirrhosis
c) Primary sclerosing cholangitis
d) All of the above

31. • What is the inheritance pattern of Wilson's disease?
a) AD
b) AR
c) X-linked
d) None

32. • What is the primary abnormality in Wilson's disease
a) Reduced synthesis of ceruloplasmin
b) Increased intestinal absorption of copper
c) Reduced urinary excretion of copper.
d) Decreased excretion of copper in to bile

33. References
Available at:
http://www.eurowilson.org/en/professional/diagnosis/index.phtml.
Accessed December 2, 2018.
Available at: http://wilsonsdisease.ca/about-wilson-
disease/treatments. Accessed December 5, 2018.
De bie P, Muller P, Wijmenga C, Klomp LW. Molecular pathogenesis of
Wilson and Menkes disease: correlation of mutations with molecular
defects and disease phenotypes. J Med Genet. 2007;44(11):673-88.
Liu J, Luan J, Zhou X, Cui Y, Han J. Epidemiology, diagnosis, and
treatment of Wilson's disease. Intractable Rare Dis Res.
2017;6(4):249-255.

34. THANK YOU

35. Poet- “eyes are the
window to the soul”
Doctor- “eyes are the
window to the
diagnosis of various
diseases like wilson’s
disease”