WILSON DISEASE - AN UPDATE ONDIAGNOSIS & TREATMENTGUIDE- DR.ATUL SHENDECANDIDATE-DR.SARATH MENON.RDIVISION OF GASTROENTERO...
INTRODUCTION   Copper Metabolism   Clinical Profile   Spectrum of disease   Diagnostic approach   Treatment & Monitor...
COPPER METABOLISM Recommended – 0.9 mg/d Absorbed from duodenum & prox.SI Transported in portal circulation bound prote...
HISTORY
WILSON DISEASE   1912- by Samuel alexander Kinnear Wilson-    ’progressive lenticular degeneration” Autosomal recessive...
CLINICAL PROFILE   Age – any individual b/w 3- 55 yr with liver    abnormalities of uncertain cause   Age alone is not a...
KF RINGS Kayser-Fleischer ring- Cu in descemets memb. Slit lamp examination Non-specific- c/c cholestatic disorders 30...
SPECTRUM OF DISEASE   Hepatic-               - asymptomatic hepatomegaly               - isolated splenomegaly           ...
   Neurological- often second-third decade                - movement disorder(tremor,dystonia)                - drooling,...
   Psychiatric-            - depression            - neurotic behavior            - personality changes            - fran...
 Ocular- KF rings, sunflower cataract Cutaneous- lunulae ceruleae Renal – nephrolithiasis Skeletal-premature osteoporo...
DIAGNOSIS Liver function tests S. ceruloplasmin Urinary copper excretion Hepatic parenchymal copper concentration Liv...
S.CERULOPLASMIN Synthesized in liver-acute phase reactant 6 Cu atoms incorporated Normal – 18-35 mg/dl < 20 mg/dl + KF...
S.COPPER Increased level of serum “free” copper Serum free Cu is non-ceruloplasmin bound Cu Total S.Cu (mcg/dl)- 3x ser...
URINARY COPPER 24 hr urinary Cu excretion Dx & monitoring Basal 24 hr urine Cu > 100 µg in symptomatic WD But > 40 µg ...
HEPATIC PARENCHYMAL COPPERCONCENTRATION   Normal - <40-50µg/g dry wt. liver   Critical value- > 250 µg/g dry wt.   Furt...
LIVER BIOPSY Mild steatosis- earliest Auto immune hepatitis histo.findings Cirrhotic changes-macronodular a/c liver fa...
NEURO-IMAGING MR imaging- evaluate neurologic WD & prior to                treatment MRI- T2 hyperintensity in basal gan...
GENETIC STUDIES   Mutation analysis by whole gene sequencing in pt    whom clinical & biochemical testing borderline   H...
SPECIFIC TARGET POPULATION “Mimic” liver disease-                 - young & adult with features of                   auto...
   Family screening-                        - 1st degree relatives                        - KF ring,24hr U.Cu            ...
Unexplained liver d/s KF Ring +          KF Ring +               KF Ring-             KF Ring –CPN <20mg/           CPN=20...
Neuropsychiatric +-liver                                d/s   KF Ring +            KF Ring-                   KF Ring +   ...
Sibling                                  Child>2 yr                                        (asymptomatic)                 ...
TREATMENT   Anti –copper drugs-                          -D-Pencillamine                          - Zinc                 ...
ANTI COPPPER DRUGSDrugs          Mode of    Neurologica S/E              Dosage          monitoring               action  ...
DRUGS       MODE OF           SIDE EFEECTS        DOSAGE            MONITOR            ACTION                             ...
   Tetra thiomolybdate-                    - inhibit CU absorption                    - bind with copper (chelator)      ...
ZINC – THE NEW PARADIGM Reduces free Cu toxicity Normalise free Cu level in blood Induces metallothionein Store Cu in ...
WILSON D/S- HEPATIC –INITIAL RXPatient type              1 st drug choice     2nd drug choiceTransaminases elevated,No hep...
NAZER PROGNOSTIC INDEXLab           normal   Score   Score     Score      Score       Scoremeasure      value      0      ...
NAZER INDEX   Mild hepatic failure- score <6   Moderate hep.failure- 7-9   Severe hep. Failure - >9
WILSON D/S-NEUROLOGIC –INITIAL RX   1st choice- TM + Zinc   2nd choice- Zinc alone
MAINTANANCE THERAPY Maintanance therapy-                        - after 2-4 month initial Rx. cut off value to begin-   ...
PRE-SYMPTOMATICS Diagnosed prior to clinically ill Siblings of affected patient d/t screening Incidental KF rings + Mi...
PREGNANT Ist choice- Zinc 2nd choice- trientine   D-pencillamine is teratogenic   Copper deficiency is teratogenic If...
DIAGNOSED WDpresymptomatic                  hepatic               neuropsychiatric   1.Zinc                               ...
DIET   Avoid liver ,shell fishes,nuts,chocolate,mushroom   After 6-12 months Rx, one meal + shell fish/ wk   If enteral...
ACUTE LIVER FAILURE Liver transplantation Nazer score > 9 ARF- hemofiltration       - plasmapheresis       - hemodialysis
LIVER TRANSPLANTATION   Indications-               - Nazer score >9 ,liver failure               - failure of medical the...
MONITORING Clinical & biochemical improvement LFT 24h U.Cu –             - 200-500µg/d (d-Pen or trientine)            ...
RECOVERY,PROGNOSIS In hepatic failure, Rx with Zn + trientine  Albumin,S.BR,SGOT -normal by 1 yr Cirrhosis,PHTN,hyperspl...
SUMMARY WD- is an medical enigma with wide spectrum Proper clinical examinations Integrated diagnostic approach Treatm...
THANK U….
Wilson’s disease   an update on diagnosis &
Wilson’s disease   an update on diagnosis &
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Wilson’s disease an update on diagnosis &

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division of gastroenterology, mgm medical college ,indore

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Wilson’s disease an update on diagnosis &

  1. 1. WILSON DISEASE - AN UPDATE ONDIAGNOSIS & TREATMENTGUIDE- DR.ATUL SHENDECANDIDATE-DR.SARATH MENON.RDIVISION OF GASTROENTEROLOGYMGM MEDICAL COLLEGE,INDORE
  2. 2. INTRODUCTION Copper Metabolism Clinical Profile Spectrum of disease Diagnostic approach Treatment & Monitoring Prognosis & recovery
  3. 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. 4. HISTORY
  5. 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. 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. 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. 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. 9.  Neurological- often second-third decade - movement disorder(tremor,dystonia) - drooling,dysarthria,spasticity - pseudo bulbar palsy - dysautonomia - migraine,headaches - insomnia - seizures
  10. 10.  Psychiatric- - depression - neurotic behavior - personality changes - frank psychosis Hematological- - Coombs neg. hemolytic anemia - transient jaundice - acute intra vascular hemolysis
  11. 11.  Ocular- KF rings, sunflower cataract Cutaneous- lunulae ceruleae Renal – nephrolithiasis Skeletal-premature osteoporosis,arthritis CVS- cardiomyopathy,arrhythmias Pancreatitis Hypoparathyroidism Infertility,miscarriages
  12. 12. DIAGNOSIS Liver function tests S. ceruloplasmin Urinary copper excretion Hepatic parenchymal copper concentration Liver biopsy Neuro radiological imaging Genetic studies
  13. 13. 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.
  14. 14. 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
  15. 15. 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
  16. 16. HEPATIC PARENCHYMAL COPPERCONCENTRATION 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
  17. 17. 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
  18. 18. NEURO-IMAGING MR imaging- evaluate neurologic WD & prior to treatment MRI- T2 hyperintensity in basal ganglia,thalami
  19. 19. 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.
  20. 20. 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
  21. 21.  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
  22. 22. Unexplained liver d/s KF Ring + KF Ring + KF Ring- KF Ring –CPN <20mg/ CPN=20 CPN <20 CPN<2024h.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
  23. 23. 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 Dx70-250 >250 Molecular testing Diagnosis WD
  24. 24. 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 >40Identical haplotype or2 mut. 70-250 Liver biopsy Diagnosis WD >250
  25. 25. TREATMENT Anti –copper drugs- -D-Pencillamine - Zinc - Trientene - Tetrathiomolybdate(TM) Diet Drinking water Concomitant hepatic,neurological management Liver transplantation
  26. 26. ANTI COPPPER DRUGSDrugs 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/dlpencillamine 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
  27. 27. DRUGS MODE OF SIDE EFEECTS DOSAGE MONITOR ACTION 24hr U.Cu & 750-1500mg/d Non-ceruloplas (2-3 doses) Bound copperTrientine 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
  28. 28.  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
  29. 29. 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
  30. 30. WILSON D/S- HEPATIC –INITIAL RXPatient type 1 st drug choice 2nd drug choiceTransaminases elevated,No hepatic failure Zinc TrientineCirrhosis presentcompensated Zinc TrientineCirrhosis decompensated Trientine + Zinc D-Pencillamine + ZincMild,Moderate hepaticfailureSevere hepatic failure Hepatic transplant Trientine + Zinc
  31. 31. NAZER PROGNOSTIC INDEXLab normal Score Score Score Score Scoremeasure value 0 1 2 3 4mentSerum 0.2-1.2 <5.8 5.8-8.8 8.9-11.7 11.8-17.5 >17.5bilirubinSGOT 10-35 <100 100-150 151-200 201-300 >300PT 12-14s <4s 4-8s 9-12 13-20 >20prolongation diff.
  32. 32. NAZER INDEX Mild hepatic failure- score <6 Moderate hep.failure- 7-9 Severe hep. Failure - >9
  33. 33. WILSON D/S-NEUROLOGIC –INITIAL RX 1st choice- TM + Zinc 2nd choice- Zinc alone
  34. 34. 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
  35. 35. 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)
  36. 36. 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
  37. 37. DIAGNOSED WDpresymptomatic hepatic neuropsychiatric 1.Zinc 1.TM+ Zinc 2.Trientine 2.Zinc Transaminase Elevation only Hepatic failure 1.Zinc Mild/mod Severe2.Trientine Nazer< 9 Nazer >9 1.Zn Liver +Trientine transplant
  38. 38. 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
  39. 39. ACUTE LIVER FAILURE Liver transplantation Nazer score > 9 ARF- hemofiltration - plasmapheresis - hemodialysis
  40. 40. LIVER TRANSPLANTATION Indications- - Nazer score >9 ,liver failure - failure of medical therapy in in decompensated failure Not indicated in neurological WD
  41. 41. 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
  42. 42. 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.
  43. 43. 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.
  44. 44. THANK U….

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