WILSON DISEASE - AN UPDATE ON DIAGNOSIS & TREATMENT

GUIDE- DR.ATUL SHENDE CANDIDATE-DR.SARATH MENON.R DIVISION OF GASTROENTEROLOGY MGM MEDICAL COLLEGE,INDORE

INTRODUCTION

Copper Metabolism Clinical Profile Spectrum of disease Diagnostic approach

Treatment & Monitoring

Prognosis & recovery

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

HISTORY

WILSON DISEASE

1912- by Samuel alexander Kinnear Wilsonprogressive 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

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

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 doesnt exclude diagnosis even in neurological disease

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

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

Psychiatric-

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

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

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

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 doesnt exclude Dx.

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 (g/dl) Normal level- <15 mcg/dl > 25 mcg/dl in untreated WD < 5mcg/dl indicates over-treated

URINARY COPPER
24 hr urinary Cu excretion Dx & monitoring Basal 24 hr urine Cu > 100 g in symptomatic WD But > 40 g 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 g Cu/24 hr urine - positive

HEPATIC PARENCHYMAL COPPER

CONCENTRATION

Normal - <40-50g/g dry wt. liver Critical value- > 250 g/g dry wt.

Further evaluation needed if 70- 250g/g ,if active liver d/s or symptoms of WD

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

NEURO-IMAGING
MR imaging- evaluate neurologic WD & prior to treatment MRI- T2 hyperintensity in basal ganglia,thalami

GENETIC STUDIES

Mutation analysis by whole gene sequencing in pt whom clinical & biochemical testing borderline Haplotype analysis based on polymorphism or spf.mutation testingfamily screening of 1st.degree relative of WD.

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

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

Unexplained liver d/s

KF Ring + CPN <20mg/ 24h.U.cu>40

KF Ring + CPN=20 24h.U.cu>40

KF RingCPN <20 24h.U.cu=>40

KF Ring CPN<20 24h.U.cu >40

Liver biopsyhistology &cu quantification

>250mcg/g

70250mcg/g

<50 mcg/g

Molecular testing

Other diagnosis

Diagnosis of WD

Neuropsychiatric +-liver d/s

KF Ring + CPN>=20 24hU.cu>40

KF RingCPN <20 24hU.cu>40

KF Ring + CPN <20 24hU.cu>40

KF Ring + CPN>20 24hU.cu<40

Liver biopsy cu quantification Other Dx 70-250 >250

Molecular testing

Diagnosis WD

Sibling

Child>2 yr (asymptomatic)

Haplotype/ Mutation analysis

Slit lamp(>4 yr) CPN LFT INR 24 h U.cu

Abn.LFT CPN<20 24h U.cu >40

Identical haplotype or2 mut. 70-250 Liver biopsy

Diagnosis WD

>250

TREATMENT

Anti copper drugs-

-D-Pencillamine - Zinc - Trientene - Tetrathiomolybdate(TM)

Diet Drinking water Concomitant hepatic,neurological management Liver transplantation

ANTI COPPPER DRUGS

Drugs Mode of action Neurologica S/E l deterioratio n Dosage monitoring

Dpencillamine

Chelator induces cupuria

20-40 % in initial phase

250500mg/d,incr emental BM 250mg4-7d suppression, Max.1-1.5g/d nephrotic ( 2-4 doses) syndrome, MaintHepatotoxicit 750mg-1g y,fever, Pyridoxine25mg/d

24hr.U Cu200-500g Free Cu10-15g/dl 1,3,6,12,18, 24 months Then annually

DRUGS

MODE OF ACTION

SIDE EFEECTS

DOSAGE

MONITOR

Trientine

Chelator induces Gastritis,aplastic cupuria anemia rare, Sideroblastic anemia

750-1500mg/d (2-3 doses) 20mg/kg/d(child Maint750-1000mg

24hr U.Cu & Non-ceruloplas Bound copper 1,3,6,12,18,24 monthsannually

Zinc

Metallothione inducer, Inhibits Cu absoption

Gastritis,pancrea 150mg/d in 3 titis,Zn divided doses accumulation 75mg/d (child, <50 kg)

24hr .U.Cu50-125g/d & 24h.U.Zn > 2mg/d 3,6 months,6 month 2yr,then yearly

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

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

WILSON D/S- HEPATIC INITIAL RX

Patient type 1 st drug choice 2nd drug choice

Transaminases elevated, No hepatic failure Cirrhosis present compensated

Zinc

Trientine

Zinc

Trientine

Cirrhosis decompensated Trientine + Zinc Mild,Moderate hepatic failure Severe hepatic failure Hepatic transplant Trientine + Zinc D-Pencillamine + Zinc

NAZER PROGNOSTIC INDEX

Lab measure ment Serum bilirubin normal value Score 0 Score 1 Score 2 Score 3 Score 4

0.2-1.2

<5.8

5.8-8.8

8.9-11.7

11.8-17.5

>17.5

SGOT

10-35

<100

100-150

151-200

201-300

>300

PT prolongati on diff.

12-14s

<4s

4-8s

9-12

13-20

>20

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- U.cu < 150g/24h (if Zinc is used alone) - S.Free Cu- < 25g/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

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)

PREGNANT
Ist choice- Zinc 2nd choice- trientine

D-pencillamine is teratogenic Copper deficiency is teratogenic

If Zn used- urine Cu- 75- 150g/24hr If Trientine used- S.free Cu- 15-25g/dl Monitor every 3 months

DIAGNOSED WD

presymptomatic

hepatic

neuropsychiatric

1.Zinc 2.Trientine

1.TM+ Zinc 2.Zinc

Transaminase Elevation only

Hepatic failure

1.Zinc 2.Trientine

Mild/mod Nazer< 9

Severe Nazer >9

1.Zn +Trientine

Liver transplant

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

ACUTE LIVER FAILURE

Liver transplantation Nazer score > 9 ARF- hemofiltration - plasmapheresis - hemodialysis

LIVER TRANSPLANTATION

Indications- Nazer score >9 ,liver failure - failure of medical therapy in in decompensated failure Not indicated in neurological WD

MONITORING Clinical & biochemical improvement LFT 24h U.Cu - 200-500g/d (d-Pen or trientine) - 50- 125 g/d (Zinc)

Non-ceruloplasmin bd.Cu(free cu) - 10- 15 g/d 24 h U.Zn - >= 2mg/d

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.

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.

THANK U.