Hepatolenticular Degeneration

1. Wilson’s disease
(Hepatolenticular Degeneration)
Dr. Kamal Ahmed
MBBS, FCPS (Medicine)
Associate Professor of Medicine
North East Medical College Hospital, Sylhet,
Bangladesh
docdrkamal@yahoo.com

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

3. Wilson's disease is an autosomal recessive
disorder caused by mutations in the ATP7B
gene, a membrane-bound, copper-transporting
ATPase, located on chromosome 13.
 Impaired normal excretion of copper causes
accumulation of copper in…
 liver
 brain
 other organs

4. 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 skin, 20%is absorbed in enterocyte by
metallothionein.
 Copper is then exported from enterocyte to the portal
blood with the help of transport protein

7. Pathogenesis:

8. Wilson’s disease should be considered
in children and teenagers with :
1. Unexplained acute or chronic liver disease
2. Neurologic symptoms of unknown cause
3. Acute hemolysis
4. Psychiatric illnesses
5. Behavioral changes

9. Epidemiology
 Occurs worldwide
 Incidence: 1/50,000-100,000 births
 The age at onset of symptoms: ranges from 6 to about 40 years
 Siblings of a diagnosed patient have a 1 in 4 risk of Wilson's disease,
whereas children of an affected patient have about a 1 in 200 risk

10. Autosomal recessive inborn error of copper
transport

11. Clinical features
1. Hepatic
2. Neuro-psychiatric
3. Other system

12. Clinical features
Forms of hepatic disease:
Include :
1.Asymptomatic hepatomegaly
(with or without splenomegaly)
2.Subacute or chronic hepatitis
3.Fulminant hepatic failure

13. Other manifestations of Wilson’s disease
 Cryptogenic cirrhosis
 Portal hypertension
 Ascites
 Variceal bleeding

14. Neurological manifestations
 Resting & intention tremor
 Spasticity
 Rigidity
 Chorea
 dysphasia
 dysarthria
 Dystonia
 Deterioration in school performance or
behavioral changes

15. In the eye
• Copper deposition in the descemet’s
membrane of cornea as golden brown
structure at sclero-corneal junction as
“ Kayser-Fleischer” (K.F) ring
• It dose not interfere with vision.
• Usually seen by slit lamp examination but
occasionally can be seen by naked eye also

16. K.F. Ring

17. Copper deposit in brain

18. Psychiatric changes
 Present in most of the patients as
schizophrenia, manic depressive
psychosis & classic neurosis

19. Useful tools for diagnosis of WD
1) S.ceruloplasmin
2) KF rings
3) 24-h urine Cu
4) Liver Cu
5) Haplotype analysis

20. Test Useful
ness
Normal Value Heterozygous
Carriers
Wilson’s disease
S.cerulopl
asmin
+ 180–350 mg/L
(18–35 mg/dL)
Low in 20% Low in 90%
KF rings ++ Absent Absent 1. 99% + if neurologic or
psychiatric symptoms.
2. 30–50% in hepatic
presentation &
presymptomatic state
24-h urine
Cu
+++ 0.3–0.8 μmol
(20–50 μg)
Normal to 1.3
μmol (80 μg)
1. >1.6 μmol (>100 μg) in
symptomatic pts
2. 0.9 to >1.6 μmol (60 to
>100 μg)- presymptomatic
pts
Liver Cu ++++ 0.3–0.8 μmol/g
(20–50 μg)
tissue
Normal to 2.0
μmol (125 μg)
>3.1 μmol (>200 μg/g dry wt
of liver)
Haplotyp
e analysis
++++
(sibling)
0 Matches 1 Match

21. www.slideshare.com

22. Screening siblings of patient
By:
1. Serum ceruloplasmin level
2. Urinary copper excretion.

23. Treatment options:
1. Zinc acetate
2. Trientine
3. Penicillamine
4. Tetrathiomolybdate

24. 10/29/2014 Wilson Disease Prof. Dr. Saad S Al Ani 24

25. All presymptomatic pts should
treated prophylactically,
because the disease is close to
100% penetrant

26. Disease Status First Choice Second Choice
A) Initial hepatic
1. Hepatitis or cirrhosis without
decompensation
Zinc Trientine
2. Hepatic decompensation
I) Mild Trientine and zinc Penicillamine and zinc
II) Moderate Trientine and zinc Hepatic transplantation
III) Severe Hepatic transplantation Trientine and zinc
B) Initial neurologic or
psychiatric
Tetrathiomolybdate and
zinc
Zinc
I) Maintenance Zinc Trientine
II) Presymptomatic Zinc Trientine
III) Pediatric Zinc Trientine
C) Pregnant Zinc Trientine

27. Hepatic presenting can be estimated using
the nazer prognostic index
Score (in Points)
Lab
Measurement
Normal
Value
0 1 2 3 4
Serum bilirubin 0.2–1.2 mg/dL <5.8 5.8–8.8 8.8–11.7 11.7–
17.5
>17.5
Serum aspartate
transferase (AST)
10–35 IU/L <100 100–150 151–200 201–300 >300
Prolongation of
PT (sec)
— <4 4–8 9–12 13–20 >20
aIf hemolysis is present, the serum bilirubin cannot be used as a measure of liver
function until the hemolysis subsides
Source: Modified from H Nazer et al: Gut 27:1377, 1986; with permission from BMJ
Publishing Group

28. scores < 7: managed with medical therapy.
scores > 9: considered immediately for liver
transplantation
scores 7- 9: clinical judgment for
transplantation or medical therapy.
 A combination of trientine & zinc used to treat
with Nazer scores as high as 9.
 such pts should watched carefully for
indications of hepatic deterioration, which
mandates transplantation

29. Zinc acetate (1st line)
Indications:
1. Hepatitis or cirrhosis without decompensation
2. Initial neurologic / psychiatric menifestation
3. Maintenance dose
4. Presymptomatic case
5. Pediatric case
6. Pregnant women

30. Dose
• 50 mg of elemental zinc…t.d.s
• Each dose separated from food &
beverages at least 1 h.
• At least 1 hr separated from trientine or
penicillamine doses

31. Side effect of Zinc
• Gastric burning or nausea in ~10% of pts usually
with the first morning dose
▼
• This can be mitigated by taking the first dose 1 hr
after breakfast or taking the zinc with a small
amount of protein

32. Monitoring of Zinc Rx
 Zinc treatment does not require blood or urine monitoring for
toxicity.
 Because zinc mainly affects stool copper, 24-h urine copper can be
used to reflect body loading.
 The typical value in untreated symptomatic patients is >3.1 mmol
(>200 mg) per 24 h.
 This level should decrease during the first 1–2 years of therapy to
<2.0 mmol (<125 mg) per 24 h.
 A normal value [0.3 to 0.8 mmol (20 to 50 mg)] is rarely reached
during first decade of therapy & should raise concern about
overtreatment (copper deficiency), the first sign of which is anemia
and/or leukopenia

33. Trientine
1. Hepatic decompensation
2. Trientine is a less toxic chelator
3. Recommended adult dosage is 500
mg twice daily
4. Each dose at least 1/2 hr before or
2 h after meals

34. Penicillamine
1. Previously the primary anti copper Rx
(Dose: 0.5-0.75 g/day for patients younger than
10 yr,1 g/day in two doses before meals for
adults)
2. Now plays a minor role because of its toxicity &
often worsens existing neurologic disease if used
as initial therapy.
3. It should always be accompanied by 25 mg/d of
pyridoxine

35. Monitoring of Trientine &
Penicillamine Rx
S/E (developed about 1/3rd pts)
1. Rash
2. Bone marrow depression
3. Nephropathy
4. Drug induce lupus

36. Monitoring of Trientine &
Penicillamine Rx
When first using trientine or penicillamine, it
necessary to monitor drug toxicity—particularly
bone marrow suppression & proteinuria.
 CBC, standard biochemical profiles, & urinalysis
performed at weekly intervals for 1 month,
 then 2 weekly intervals for 2-3 months
 then 1 month intervals for 3-4 months
 4-6 month intervals thereafter

37. Monitoring of Trientine & Penicillamine
Rx (cont..)
 Anticopper effects of trientine & penicillamine can
monitored by following 24-h "free" serum copper.
 Changes in urine copper more difficult to interpret
because excretion reflects effect of the drug, as
well as body loading with copper.
 Free serum copper is calculated by subtracting the
ceruloplasmin copper from the total serum copper.

38. Remember
Foods such as:
liver, shellfish, nuts, and chocolate
should be avoided

39. In asymptomatic siblings of affected
patients
Early institution of chelation therapy can
prevent expression of the disease.

40. Prognosis:
Anticopper therapy must be lifelong.
With treatment, liver function usually recovers after
about a year, although residual liver damage is
usually present.
Neurologic and psychiatric symptoms usually
improve after 6 to 24 months of treatment
Untreated pts die of the hepatic, neurologic, renal, or
hematologic complications

41. Global Considerations:
Age of onset of clinical disease may be
considerably younger in India and far Eastern
countries, often occurring in children only five or
six years of age.
In countries where penicillamine, trientine, and
zinc acetate are not available or cannot be
afforded, zinc salts such as the gluconate or sulfate
provide an alternative treatment option

42. Take home massage
Where we consider Wilson’s disease ?
1.If "routine liver function tests" are
unexplained abnormal in a child / teenager
2.In a child / teenager with haemolysis and
negative Coombs test
3. Changes in mood or school performance or
movement disorder in a teenager,
especially with speech slurring