hepatology cme- division of gastroenterology, mgm medical college ,indore

1. WILSON DISEASE - AN UPDATE ON
DIAGNOSIS & TREATMENT
GUIDE- DR.ATUL SHENDE
CANDIDATE-DR.SARATH MENON.R
DIVISION OF GASTROENTEROLOGY
MGM MEDICAL COLLEGE,INDORE

2. INTRODUCTION
 Copper Metabolism
 Clinical Profile
 Spectrum of disease
 Diagnostic approach
 Treatment & Monitoring
 Prognosis & recovery

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

4. HISTORY

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

8. SPECTRUM OF DISEASE
 Hepatic-
- asymptomatic hepatomegaly
- isolated splenomegaly
- persistent elevation of AST,ALT
- fatty liver
- acute hepatitis
- c/c hepatitis
- autoimmune hepatits
- cirrhosis-compensated/decompensated
- acute liver failure

9.  Neurological- often second-third decade
- movement disorder(tremor,dystonia)
- drooling,dysarthria,spasticity
- pseudo bulbar palsy
- dysautonomia
- migraine,headaches
- insomnia
- seizures

10.  Psychiatric-
- depression
- neurotic behavior
- personality changes
- frank psychosis
 Hematological-
- Coombs neg. hemolytic anemia
- transient jaundice
- acute intra vascular hemolysis

11.  Ocular- KF rings, sunflower cataract
 Cutaneous- lunulae ceruleae
 Renal – nephrolithiasis
 Skeletal-premature osteoporosis,arthritis
 CVS- cardiomyopathy,arrhythmias
 Pancreatitis
 Hypoparathyroidism
 Infertility,miscarriages

13. DIAGNOSIS
 Liver function tests
 S. ceruloplasmin
 Urinary copper excretion
 Hepatic parenchymal copper concentration
 Liver biopsy
 Neuro radiological imaging
 Genetic studies

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

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

26. Sibling Child>2 yr
(asymptomatic)
Slit lamp(>4 yr)
CPN
LFT
Haplotype/
INR
Mutation
24 h U.cu
analysis
Abn.LFT
CPN<20
24h U.cu >40
Identical haplotype
or2 mut.
70-250 Liver biopsy
Diagnosis
WD >250

27. TREATMENT
 Anti –copper drugs-
-D-Pencillamine
- Zinc
- Trientene
- Tetrathiomolybdate(TM)
 Diet
 Drinking water
 Concomitant hepatic,neurological management
 Liver transplantation

28. ANTI COPPPER DRUGS
Drugs Mode of Neurologica S/E Dosage monitoring
action l
deterioratio
n
1 250- 24hr.U Cu-
500mg/d,incr 200-500µg
emental Free Cu-
D- Chelator 20-40 % in BM 250mg4-7d 10-15µg/dl
pencillamine induces initial phase suppression, Max.1-1.5g/d
cupuria nephrotic ( 2-4 doses) 1,3,6,12,18,
syndrome, Maint- 24 months
Hepatotoxicit 750mg-1g Then
y,fever, Pyridoxine- annually
25mg/d

29. DRUGS MODE OF SIDE EFEECTS DOSAGE MONITOR
ACTION
24hr U.Cu &
750-1500mg/d Non-ceruloplas
(2-3 doses) Bound copper
Trientine Chelator induces Gastritis,aplastic 20mg/kg/d(child 1,3,6,12,18,24
cupuria anemia rare, Maint- months-
Sideroblastic 750-1000mg annually
anemia
24hr .U.Cu-
Metallothione Gastritis,pancrea 150mg/d in 3 50-125µg/d
Zinc inducer, titis,Zn divided doses &
Inhibits Cu accumulation 75mg/d 24h.U.Zn
absoption (child, <50 kg) > 2mg/d
3,6 months,6
month 2yr,then
yearly

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

35. WILSON D/S-NEUROLOGIC –INITIAL RX
 1st choice- TM + Zinc
 2nd choice- Zinc alone

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

39. DIAGNOSED WD
presymptomatic hepatic neuropsychiatric
1.Zinc 1.TM+ Zinc
2.Trientine 2.Zinc
Transaminase
Elevation only Hepatic failure
1.Zinc Mild/mod Severe
2.Trientine Nazer< 9 Nazer >9
1.Zn Liver
+Trientine transplant

40. DIET
 Avoid liver ,shell fishes,nuts,chocolate,mushroom
 After 6-12 months Rx, one meal + shell fish/ wk
 If enteral feeding,Cu <1.5 mg/d
 Drinking water - < 0.1 ppm Cu

41. ACUTE LIVER FAILURE
 Liver transplantation
 Nazer score > 9
 ARF- hemofiltration
- plasmapheresis
- hemodialysis

42. LIVER TRANSPLANTATION
 Indications-
- Nazer score >9 ,liver failure
- failure of medical therapy in
in decompensated failure
 Not indicated in neurological WD

43. MONITORING
 Clinical & biochemical improvement
 LFT
 24h U.Cu –
- 200-500µg/d (d-Pen or trientine)
- 50- 125 µg/d (Zinc)
 Non-ceruloplasmin bd.Cu(free cu)
- 10- 15 µg/d
 24 h U.Zn
- >= 2mg/d

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.

46. THANK U….