academic base Harrisons 19th edition

1. Wilson’s disease
Dr kirankumar Bikkad

2. INTRODUCTION
• Autosomal recessive (AR)
• Mutations in the ATP7B gene
• Encodes a membrane-bound, copper
transporting ATPase.
• Clinical manifestations caused by copper
toxicity involveing liver and brain.

3. • Frequency :- 1 in 30,000–40,000
• Carriers of ATP7B mutations is ∼1%.
• Siblings have a 1 in 4 risk of Wilson’s disease
• Children have 1 in 200 risk.
• DNA haplotype analysis used to genotype
siblings

4. MEDNIK syndrome
• A rare multisystem disorder of copper metabolism
• mutations in AP1S1 gene
1. Mental retardation
2. Enteropathy
3. Deafness
4. Neuropathy
5. Ichthyosis
6. Keratodermia
• ATP7A (Menkes disease) and ATP7B (Wilson’s disease).

5. PATHOGENESIS
• ATP7B protein deficiency impairs biliary copper
excretion
• Positive copper balance
• Hepatic copper accumulation
• Copper toxicity from oxidant damage
• Excess hepatic copper is bound to
metallothionein
• Liver damage begins as this storage capacity is
exceeded

6. • Defective copper incorporation into
apoceruloplasmin  excess catabolism of
ceruloplasmin
• L/T low ceruloplasmin.
• Serum copper levels are low bcoz low blood
ceruloplasmin, which binds >90% of Sr copper.
• Non-ceruloplasmin serum copper “free” copper
increase  copper build up in other body parts
(e.g.brain neurologic and psychiatric disease)

7. CLINICAL PRESENTATION
• Hepatic Features
• Hepatitis
• Cirrhosis
• Hepatic decompensation
• Elevated serum aminotransferase levels, with or
without jaundice
• Hepatic decompensation :- elevated serum
bilirubin, reduced serum albumin and coagulation
factors, ascites, peripheral edema, and hepatic
encephalopathy.

8. • In severe hepatic failure  hemolytic anemia
• Copper derived from hepatocellular
necrosis released into the bloodstream.
• The association of hemolysis and liver disease
makes Diagnosis of Wilsons Likely
Patients age group:- teenage years and extends
till fifth decade.

9. Neurologic Features
• Early twenties & can be seen till sixth decade of
life.
• MRI and CT scans:- basal ganglia
– occasionally : pons, medulla, thalamus, cerebellum,
and subcortical areas.
• Main movement disorders
1. Dystonia
2. Incoordination
3. Tremor.
• Dysarthria and dysphagia.

10. • In some patients, the clinical picture closely
resembles Parkinson’s disease.
• Autonomic disturbances :
1. Orthostatic hypotension
2. Sweating abnormalities
3. Bowel, bladder dysfunction
4. Sexual dysfunction.

11. • Memory loss
• Migraine-type headaches
• Seizures may occur.
• Patients have difficulty focusing on tasks, but
cognition usually is not grossly impaired.
• There is no Sensory abnormalities and
muscular weakness.

12. Psychiatric Features
• Seen in Half of patients with neurologic
disease
• Onset - 5 years before diagnosis.
1. loss of emotional control (temper tantrums,
crying bouts)
2. Depression
3. Hyperactivity
4. Loss of sexual inhibition.

13. Other Manifestations
• Female :- Repeated spontaneous abortions,
become amenorrheic
• Cholelithiasis and nephrolithiasis
• Osteoarthritis (particularly of knee)
• Microscopic hematuria
• Sunflower cataracts
• Kayser-Fleischer rings (copper deposits in the
outer rim of the cornea)

14. • Increased Levels of urinary excretion of
1. Phosphates
2. Amino acids
3. Glucose
4. Urates
• (Features S/O Fanconi syndrome)

15. DIAGNOSIS
1. Serum ceruloplasmin
1. normal in up to 10% of affected patients & reduced in 20% of carriers.
2. Kayser-Fleischer rings
1. using a slit lamp.
2. present in >99% of patients with neurologic/psychiatric
3. 30–50% of patients diagnosed in the hepatic state
3. 24hr Urine copper measurement
1. Patients : >1.6 μmol (>100 μg) per 24 h
2. Heterozygotes : <1.3 μmol (<80 μg) per 24 h.
4. Liver biopsy : definitive diagnosis
1. Gold standard
2. Quantitative copper assays.
3. Affected patients have Cu >3.1 μmol/g (>200μg/g) [dry weight] of liver

16. TREATMENT
• Penicillamine: previously primary anticopper
treatment but now have minor role because
of its toxicity and worsens neurologic disease.
• Always given with pyridoxine(25 mg/d).
• Trientine: a less toxic chelator.

17. • For patients with hepatitis or cirrhosis without evidence of
hepatic decompensation or neurologic/psychiatric
symptoms
• zinc
• therapy of choice
• Nontoxic
1. Produces a negative copper balance by blocking intestinal
absorption of copper
2. Induces hepatic metallothionein synthesis (sequester
additional toxic Copper)
• All presymptomatic patients should be treated
prophylactically

18. • For initial medical treatment of patients with hepatic
decompensation :- chelator (trientine) + zinc.
• Zinc should not be ingested simultaneously with trientine,
which chelates zinc
• Administer 2 drugs at least 1 h apart.
• For initial neurologic therapy:- tetrathiomolybdate (DOC)
• because of its rapid control of free copper, preservation of
neurologic function, and low toxicity.
• Avoid :- Penicillamine and trientine
• (because both have risk of worsening neurologic condition)

19. • Tetrathiomolybdate & Hepatic transplantation:-
alleviate neurologic symptoms
• Pregnant patients treated with zinc or trientine
throughout pregnancy
• without tight copper control because copper
deficiency can be teratogenic.
• Anticopper therapy must be lifelong.
• Neurologic and psychiatric symptoms improve
after 6–24 months of treatment

20. Dosage
• Zinc acetate (Galzin) 50 mg TDS of elemental
zinc, with each dose separated by at least 1 h
from consumption of food and beverages other
than water as well as from trientine or
penicillamine doses.
• Trientine (Syprine) and penicillamine
(Cuprimine) adult dosage for both drugs is 500
mg BD, with each dose at least 0.5 h before or 2 h
after meals and separated by at least 1 h from
zinc administration.

21. Nazer prognostic index
• To establish disease severity
• Sr Bilirubin, AST, PT.
• Scores <7  managed with medical therapy.
• Scores >9  considered for liver transplantation.
• For patients with scores between 7 and 9 
clinical judgment
• Combination of trientine and zinc  to treat
patients with Nazer scores as high as 9, but (Look
for indications of hepatic deterioration)

22. MONITORING ANTICOPPER THERAPY
Trientine / penicillamine
• bone marrow suppression and proteinuria
• CBC & urinalys
– weekly intervals for 1 month
– Once in 2 week intervals for 2 or 3 months
– Monthly intervals for 3 or 4 months
– 4 to 6-month intervals thereafter.
• The anticopper effects of trientine and
penicillamine can be monitored by following
“free” serum copper levels.

23. • Zinc
• Treatment does not require monitoring of
blood or urine for toxicity.
• Side effect is gastric burning or nausea in
∼10% patients, with first morning dose.
• First dose taken an hour after breakfast or
taken with a small amount of protein.

24. • Free serum copper = total serum copper -
ceruloplasmin copper.
• Each 1 mg/dL ceruloplasmin contributes 3 μg/dL
serum copper.
• The normal serum free copper value is 10–15
μg/dL
• Level is often as high as 50 μg/dL in untreated
Wilson’s disease.
• With treatment, the serum free copper should be
<25 μg/dL.

25. THANK YOU