Wilson disease (WD) is an inherited disorder of copper metabolism https://youtu.be/ETWpj22Z04Q?si=Wrzvq1mNF10YYyX7

1. Wilson’s disese
( hepatolenticular disease )
By
Dr Mohammud Ibraheem

2. Epidemiology
Wilson disease (WD) is an inherited disorder
of copper metabolism with a reported
prevalence of 1 in 17,000 to 1 in 20,000 of
the global population with 1 in 65 to 1 in 70
as heterozygous carriers
Carriers rate of 1 in 90.

3. Pathophysiology

4. Genetics
WD is an AR disorder caused by mutations of
ATP7B gene, located on long arm of chromosome
13 encodes copper-transporting P-type ATPase.
The common mutations are missense and
nonsense and patients can be either homozygous
or heterozygous.
More than 700 mutations have been found to
cause WD, missense mutation H1069Q is the
most prevalent (50–80%) in European and
American population. Mutation R778L is more
common (14–49%) in Far East Asian countries

5. Function of copper
Copper facilitates
1) electron transfer in cellular respiration,
2) iron homeostasis,
3) pigment formation,
4) neurotransmitter production,
5) peptide biosynthesis,
6) connective tissue biosynthesis,
7) antioxidant defense.
In the brain, Cu is found in high concentrations in
catecholamine-containing neurons.

6. Copper Metabolism
1. Cu is absorbed through intestinal using
ATP7A transporter.
2. Cu enters hepatocytes through copper
transporter 1 before being transported into
the trans-Golgi network via ATP7B.
3. Cu incorporates into apoceruloplasmin (half-
life 5 hours) to form holoceruloplasmin (half-
life 5 days), and excretes into circulation.
ATP7B promotes Cu excretion into the bile. A
minority is excreted via the urine and sweat.

8. Pathophysiology
Mutations of the ATP7B gene reduces the levels of
ATP7B encoding protein and increases protein
degradation.
This leads to toxic accumulation of Cu in the liver
and subsequently to an excess of non-
ceruloplasmin bound Cu in the bloodstream. The
excess Cu is taken up by other tissues as brain,
eyes, heart.
Cu overload leads to oxidative damage to cellular
proteins, lipids, DNA, RNA and mitochondria

9. Pathophysiology
Liver injury is the earliest and most frequent
manifestation in WD.
Initially, Cu binds with metallothioneins. This is
detected with rhodanine and orcein stain.
With time, Cu accumulates in lysosomes and
causes mitochondrial damage leading to hepatic
steatosis, hepatitis, fibrosis and subsequently
macronodular cirrhosis.
Non-ceruloplasmin bound (toxic) Cu leaks into
the blood and accumulates in other tissues.

11. Pathophysiology
In the brain, chronic toxicity of Cu leads to
damaged astrocytes, demyelination and tissue
disintegration in the BG, thalamus, cerebellum and
upper brainstem.
Free Cu in the blood leads to Coombs-negative
hemolysis by oxidative damage of haemoglobin
and cell membrane. This is associated with
rhabdomyolysis due to Cu-induced inhibition of
Na+/K+-ATPase activity in the muscle.
Excess Cu in renal medulla causes renal
tubulopathy

13. Clinical presentation

14. Hepatic Manifestations
Early stage, patients may be asymptomatic,
but present with elevated liver enzymes or
findings of hyperechogenic liver on U/S.
During the disease progression, the patients
present with:
A. signs/symptoms of chronic liver disease e.g.
hepatosplenomegaly
B. complications from liver cirrhosis e.g.
ascites, gastrointestinal bleeding.

15. Hepatic Manifestations
ALF is a severe form of WD characterized by
jaundice, hepatitis, hepatomegaly,
coagulopathy with or without encephalopathy.
Some children have past history of acute self-
limited hepatitis like illness, recurrent
jaundice, haemolytic anemia or elevated
transaminases
Pediatric Acute Liver Failure (PALF) study
suggests the definition of ALF: an INR of
≥1.5 in the presence of encephalopathy, or an
INR of ≥2.0 regardless of the encephalopathy.

16. Neurological Manifestation
30% present with neurological symptoms at
age <10 years.
5–15% of children presenting with liver
disease have neurological symptoms.
presentations up to age 51 have been
reported
The course may be acute, but in most
cases, it is slowly progressive.

17. Neurological Manifestation
Psychiatric symptoms can be:
1) Declining performance at school,
2) Mild cognitive impairment such as working
memory,
3) Behavioural and personality problems
(aggressive and impulsive),
4) Mood disorders (depression, anxiety,
bipolar),
5) Psychosis.

18. Neurological Manifestation
All types of movement disorder can be seen.
Four major clinical types are recognized:
1. The dystonic form,
2. The pseudosclerotic type,
3. Parkinsonian–rigid form,
4. Choreic form.

19. Neurological Manifestation
Most cases of the neurological form with onset
before adulthood are of the dystonic type with
facio-linguo-pharyngeal involvement causing
facial masking(risus sardonicus) and drooling.
Dysarthria and dysphagia are associated with
or preceded by or psychiatric problems.
Choreic and myoclonic movements and painful
spasms are common.
Pyramidal signs are infrequent.

20. Neurological Manifestation
The pseudosclerotic form of WD is rare in
adolescents. In such cases, dysarthria,
intention tremor and asterixis are prominent.
Hypokinesia and rigidity, tremor at rest are
features of the rigid–akinetic type.
In many cases, several different syndromes
occur in succession.

21. Neurological Manifestation
Tremors range from subtle in the outstretched
fingers to severe, coarse, It is proximal tremors.
Upper extremity coarse tremors are common.
These tremors are posturally dependent.
Tremors are prominent when the arms are
elevated and flexed at the elbow, giving the
appearance of “wing beating” or “chest beating.
The reduced facial expression, bradykinesia, and
tremors are sometimes confused with PD in old
age presentation of WD.

22. Neurological Manifestation
Speech manifestations vary from rapid
articulation to hypophonia and dysarthria.
Speech is often severely impaired.
In a few cases, tongue dyskinesia or tongue
tremor with dysarthria are the sole
manifestations.
Any young adult patient who develops
unexplained speech impairment needs to be
evaluated for WD.

23. Neurological Manifestation
In late stages:
A. Muscular rigidity is generalised,
B. Bizarre dyskinesias and the patients are
severely incapacitated.
C. Psychiatric manifestations are prominent
with severe psychotic or depressive
symptoms.

24. Other manifestations
1. Ophthalmologic
Kayser-Fleischer rings: gold or grey-brown opacity
in the peripheral cornea (copper deposition on
Descemet membrane), seen by slit-lamp
examination or with naked eye. Always present in
neurological involvement
2. Haematological
Coombs negative acute intermittent/chronic
haemolytic anaemia
3. Renal
Renal tubular dysfunction, Nephrolithiasis,
Nephrocalcinosis

26. Other manifestations
4. Cardiac
Cardiomyopathy, heart failure, Arrhythmia
5. Musculoskeletal
Rickets/osteopenia/osteoporosis, Arthropathy
6. Endocrine
Hypoparathyroidism, Infertility and miscarriages
7. Skin
Lipomas, hyperpigmentation
8. Pancreas
Pancreatitis

27. investigations

28. Urinary Copper
For baseline 24-h urinary copper, a cut-off of
0.64 to 1.6 μmol/24 h has been used
providing a sensitivity of 50% to 80%, and a
specifcity of 76% to 98% , as this value can
be <1.6 μmol/24 h at presentation in 16–
23% of WD patients, particularly in
asymptomatic or mild liver disease patients.

29. Serum ceruloplasmin
low circulating levels of ceruloplasmin.
A serum ceruloplasmin value <20 mg/dL and
concomitant slit-lamp definition of a KF ring are
diagnostic of WD.
In acute liver damage, ceruloplasmin levels
may be normal because it is an acute-phase
reactant; therefore, a low ceruloplasmin
concentration is not an absolute diagnostic test;
this may also be seen in hypoproteinemic state

30. MRI
Typical abnormalities in WD brain MRI include
hyperactive intensity lesions visualized on T2
located in the BG (mainly putamen and
caudate nuclei), thalamus, midbrain, and
pontine WM.
High-signal intensity lesions in the BG on T1
can be secondary to chronic liver.
It is used for treatment monitoring as some
findings may reverse during copper chelating
therapy.

33. Face of giant panda
Face of giant panda in WD is due to
I. High signal intensity in tegmentum
II. Normal signals in red nuclei forming the
eyes,
III. Normal signals of pars reticulata (lateral
portion) of substantia nigra forming the ears,
IV. Hypointensity of superior colliculus forming
the chin.

35. face of the giant panda sign

36. Genetic testing
Prenatal diagnosis and detection of
presymptomatic cases is possible with
molecular techniques demonstrating
mutations in the ATP7B gene

37. Wilson diagnostic score
0–1: unlikely; 2–3: probable; 4 or more: highly
likely

38. Treatment

39. Treatment
Low copper diet is recommended in all cases.
Chelators of copper, including
1) D-penicillamine,
2) Triethylene tetramine (trientine)
3) Oral zinc sulphate
Chelators are used to produce a negative
copper balance and decrease the copper load.

40. D-penicillamine
The first effective chelating treatment is D-
penicillamine (15–25mg/kg/day; 0.5–0.75 mg/day
for children under 10 years, 1 mg/day in older
patients), given orally in divided doses. Pyridoxine
25mg/kg/day is added.
Treatment should be started progressively and the
dosage should be slowly increased.
Side effects are frequent and may be severe in up
to a quarter of cases. They include lupus
erythematosus, nephrotic syndrome, fever, rashes,
pyridoxine deficiency, thrombocytopenia and, rarely,
myasthenic symptoms.

41. Triethylene tetramine
Triethylene tetramine (trientine) at a dose of 40–
50mg/kg/day is very efficacious; it is well
tolerated and is regarded as the first-choice
drug by some authorities. Its association with
zinc seems particularly effective. It is clearly
indicated when penicillamine is poorly tolerated
or as initial treatment in moderate or severe
forms of the disorder. However, it may also
produce transient aggravation

42. Oral zinc sulphate
Oral zinc sulphate treatment, at a dosage of 300–
600mg/day, decrease toxic free copper by binding
it to metallothionine, decreasing gut absorption of
copper. It is used as a complement to chelators
and is also effective alone.
Zinc has been used successfully for
presymptomatic children with subclinical liver
involvement, pregnant, and as a maintenance after
de-coppering treatment.
Gastrointestinal intolerance may occur.

43. liver transplantation
Patients with advanced liver disease or
acute liver failure can benefit from liver
transplantation, which is often practiced in
refractory disease and acute liver failure

44. Prognosis
Most children who have isolated hepatic
disease usually do well on treatment.
Approximately 40–50% of those with
neurological manifestations become
asymptomatic.

45. CASE STUDY

46. Clinical
A 13-year-old boy of nonconsanguineous
parents presented with abnormal body
movements, gait difficulty, and slurring of
speech for 2 years.
Examination, rigidity, dystonia, dysarthria
and drooling. Ophthalmologic examination
revealed bilateral Kayser-Fleischer rings.

47. Laboratory tests
He had elevated serum “free” copper levels
(41.2 μg/dL [range:10–15]), 24-hour urine
copper levels (895.7 μg/d [range:<60]), and
reduced serum ceruloplasmin levels (4.3
mg/dL (range: 20–40]).

48. MRI
1. “face of giant panda” appearance,
2. Frontal cystic encephalomalacic changes.
3. Bilateral cystic changes are less
commonly reported in WD.
Recognizing diverse neuroimaging
signatures beyond well known findings in
WD enhances diagnostic accuracy

50. Thank you