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Wilson’s disease an update on diagnosis &
1. WILSON DISEASE - AN UPDATE ON
DIAGNOSIS & TREATMENT
GUIDE- DR.ATUL SHENDE
CANDIDATE-DR.SARATH MENON.R
DIVISION OF GASTROENTEROLOGY
MGM MEDICAL COLLEGE,INDORE
3. COPPER METABOLISM
Recommended – 0.9 mg/d
Absorbed from duodenum & prox.SI
Transported in portal circulation bound protein
to liver
Liver synthesize Cu bound ceruloplasmin &
excrete copper into bile
Stored in liver bound with metallathionein
5. WILSON DISEASE
1912- by Samuel alexander Kinnear Wilson-
’progressive lenticular degeneration”
Autosomal recessive
1993- ATP 7B gene in chromosome 13
Failure of excretion of Cu into bile
Failure of incorporate Cu to ceruloplasmin
Serum “Free” copper toxicity
Copper deposits in brain,kidney,cornea & organs
6. CLINICAL PROFILE
Age – any individual b/w 3- 55 yr with liver
abnormalities of uncertain cause
Age alone is not a criteria for exclusion
Majority -5- 40 yr
7. KF RINGS
Kayser-Fleischer ring- Cu in descemets memb.
Slit lamp examination
Non-specific- c/c cholestatic disorders
30-50% in hepatic cond. & pre-symptomatic
99% in neuro-psychiatric presentations
In children with liver d/s, KF rings usually absent
Absence of KF rings doesn’t exclude diagnosis
even in neurological disease
14. S.CERULOPLASMIN
Synthesized in liver-acute phase reactant
6 Cu atoms incorporated
Normal – 18-35 mg/dl
< 20 mg/dl + KF rings consistent with WD
LOW levels seen in renal d/s,ESLD
Level < 5 mg/dl- strong evidence of WD
Subnormal levels needs further test
Normal level doesn’t exclude Dx.
15. S.COPPER
Increased level of serum “free” copper
Serum free Cu is non-ceruloplasmin bound Cu
Total S.Cu (mcg/dl)- 3x serum ceruloplasmin Cu
(µg/dl)
Normal level- <15 mcg/dl
> 25 mcg/dl in untreated WD
< 5mcg/dl indicates over-treated
16. URINARY COPPER
24 hr urinary Cu excretion
Dx & monitoring
Basal 24 hr urine Cu > 100 µg in symptomatic WD
But > 40 µg may indicate WD , req. further test
Pencillamine challenge test
500 mg D-pencillamine orally at beginning and
repeat after 12 hr during 24hr urine collection
> 1600 µg Cu/24 hr urine - positive
17. HEPATIC PARENCHYMAL COPPER
CONCENTRATION
Normal - <40-50µg/g dry wt. liver
Critical value- > 250 µg/g dry wt.
Further evaluation needed if 70- 250µg/g ,if
active liver d/s or symptoms of WD
18. LIVER BIOPSY
Mild steatosis- earliest
Auto immune hepatitis histo.findings
Cirrhotic changes-macronodular
a/c liver failure- marked hepatocellular
degeneration & parenchymal collapse
Cu staining is variable- poor predictive value
19. NEURO-IMAGING
MR imaging- evaluate neurologic WD & prior to
treatment
MRI- T2 hyperintensity in basal ganglia,thalami
20.
21. GENETIC STUDIES
Mutation analysis by whole gene sequencing in pt
whom clinical & biochemical testing borderline
Haplotype analysis based on polymorphism or
spf.mutation testing-
family screening of 1st.degree relative of WD.
22. SPECIFIC TARGET POPULATION
“Mimic” liver disease-
- young & adult with features of
auto immune hepatitis
- not responding to steroid Rx.
- hepatic steatosis ≈ NAFLD
Acute liver failure
- coombs neg hemo.anemia
- a/c intravascular hemolysis
- a/c renal failure
-modest rise in ALT,AST <<1000U/L
- NL or subnormal ALP <40U/L
- ALP: S.Bil - < 2
- F:M – 2:1
23. Family screening-
- 1st degree relatives
- KF ring,24hr U.Cu
-ATP7B Mutation analysis
- Rx diagnosed case >3 yr age
Newborn screening-
- ceruloplasmin in blood spots
& urine samples
24. Unexplained liver d/s
KF Ring + KF Ring + KF Ring- KF Ring –
CPN <20mg/ CPN=20 CPN <20 CPN<20
24h.U.cu>40 24h.U.cu>40 24h.U.cu=>40 24h.U.cu >40
Liver biopsy-
histology &cu
quantification
>250mcg/g 70- <50 mcg/g
250mcg/g
Molecular testing Other diagnosis
Diagnosis of WD
25. Neuropsychiatric +-liver
d/s
KF Ring + KF Ring- KF Ring + KF Ring +
CPN>=20 CPN <20 CPN <20 CPN>20
24hU.cu>40 24hU.cu>40 24hU.cu>40 24hU.cu<40
Liver biopsy cu
quantification
Other Dx
70-250 >250
Molecular
testing
Diagnosis WD
30. Tetra thiomolybdate-
- inhibit CU absorption
- bind with copper (chelator)
- used in neurological WD
- S/E- anemia,neutropenia,
hepatotoxicity
- 120 mg/d ie. 20mg x 3 with meal
60mg bed time
- 8 weeks therapy
- weekly neurological examination
31. ZINC – THE NEW PARADIGM
Reduces free Cu toxicity
Normalise free Cu level in blood
Induces metallothionein
Store Cu in liver & in mucosal cells- promote Cu
excretion via stools
Less side effects
Dosage- < 6 yr – 25 mg elemental Zn bd
- 6-15 yr or 125 pds- 25 mg TDS
- > 16yr or >125 pds- 50 mg TDS
32. WILSON D/S- HEPATIC –INITIAL RX
Patient type 1 st drug choice 2nd drug choice
Transaminases elevated,
No hepatic failure Zinc Trientine
Cirrhosis present
compensated Zinc Trientine
Cirrhosis decompensated
Trientine + Zinc D-Pencillamine + Zinc
Mild,Moderate hepatic
failure
Severe hepatic failure Hepatic transplant Trientine + Zinc
33. NAZER PROGNOSTIC INDEX
Lab normal Score Score Score Score Score
measure value 0 1 2 3 4
ment
Serum 0.2-1.2 <5.8 5.8-8.8 8.9-11.7 11.8-17.5 >17.5
bilirubin
SGOT 10-35 <100 100-150 151-200 201-300 >300
PT 12-14s <4s 4-8s 9-12 13-20 >20
prolongati
on diff.
34. NAZER INDEX
Mild hepatic failure- score <6
Moderate hep.failure- 7-9
Severe hep. Failure - >9
36. MAINTANANCE THERAPY
Maintanance therapy-
- after 2-4 month initial Rx.
cut off value to begin-
- U.cu < 150µg/24h
(if Zinc is used alone)
- S.”Free” Cu- < 25µg/dl
Initiated from beginning in pre-symptomatics
(only elevation of transaminases)
1st drug choice- Zinc
2nd drug choice- Trientine
annual 24hr urine Cu & serum.free Cu monitor
37. PRE-SYMPTOMATICS
Diagnosed prior to clinically ill
Siblings of affected patient d/t screening
Incidental KF rings +
Mild rise in serum transaminases
Start directly maintenance regime with zinc(1st
choice ) or trientine (2nd choice)
38. PREGNANT
Ist choice- Zinc
2nd choice- trientine
D-pencillamine is teratogenic
Copper deficiency is teratogenic
If Zn used- urine Cu- 75- 150µg/24hr
If Trientine used- S.free Cu- 15-25µg/dl
Monitor every 3 months
42. LIVER TRANSPLANTATION
Indications-
- Nazer score >9 ,liver failure
- failure of medical therapy in
in decompensated failure
Not indicated in neurological WD
44. RECOVERY,PROGNOSIS
In hepatic failure, Rx with Zn + trientine
Albumin,S.BR,SGOT -normal by 1 yr
Cirrhosis,PHTN,hypersplenism – persists
Neurological improvement-5-6 months & improve
over 18 months
Residual abn. After 24 month of Rx- permanent
Speech improves afterwards also.
Psychiatric /behavioral improves by 1-2 yr.
45. SUMMARY
WD- is an medical enigma with wide spectrum
Proper clinical examinations
Integrated diagnostic approach
Treatment for various clinical profiles
Zinc as a new paradigm shift in Rx
Hepatic transplantation
Monitoring., and prognosis
Lifelong Rx and normal expectancy
Fatal if not treated.