WILSON DISEASE - AN UPDATE ON DIAGNOSIS & TREATMENTGUIDE- 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 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

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 doesn’t 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 doesn’t 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

(µg/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 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

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

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 testing-

family 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

Diagnosis of WD

KF Ring +CPN

<20mg/24h.U.cu>4

0

KF Ring +CPN=20

24h.U.cu>40

Liver biopsy-histology &cuquantification

Molecular testing

KF Ring-CPN <20

24h.U.cu=>40

KF Ring –CPN<2024h.U.cu

>40

>250mcg/g 70-250mcg/g

<50 mcg/g

Other diagnosis

Neuropsychiatric +-liver d/s

Diagnosis WD

KF Ring +CPN>=2024hU.cu>4

0

KF Ring +CPN>20

24hU.cu<40

Other Dx

KF Ring-CPN <20

24hU.cu>40

KF Ring +CPN <20

24hU.cu>40

Liver biopsy cuquantification

Molecular testing

>25070-250

Sibling Child>2 yr

(asymptomatic)

Haplotype/Mutation analysis

DiagnosisWD

Identical haplotype or2

mut.

Slit lamp(>4 yr)CPNLFTINR

24 h U.cu

Abn.LFTCPN<20

24h U.cu >40

Liver biopsy70-250

>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

Neurological deterioration

S/E Dosage monitoring

D-pencillamine

Chelator inducescupuria

1

20-40 % in initial phase

BM suppression,nephrotic syndrome,Hepatotoxicity,fever,

250-500mg/d,incremental 250mg4-7dMax.1-1.5g/d ( 2-4 doses)Maint-750mg-1gPyridoxine-25mg/d

24hr.U Cu-200-500µgFree Cu- 10-15µg/dl

1,3,6,12,18,24 monthsThenannually

DRUGS MODE OF ACTION

SIDE EFEECTS

DOSAGE MONITOR

Trientine Chelator induces cupuria

Gastritis,aplastic anemia rare,Sideroblastic anemia

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

24hr U.Cu &Non-ceruloplasBound copper1,3,6,12,18,24 months-annually

Zinc

Metallothione inducer,Inhibits Cuabsoption

Gastritis,pancreatitis,Zn accumulation

150mg/d in 3 divided doses75mg/d (child, <50 kg)

24hr .U.Cu-50-125µg/d &24h.U.Zn > 2mg/d3,6 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 RXPatient type 1 st drug choice 2nd drug choice

Transaminases elevated,No hepatic failure

Zinc Trientine

Cirrhosis presentcompensated Zinc Trientine

Cirrhosis decompensated

Mild,Moderate hepatic failure

Trientine + Zinc D-Pencillamine + Zinc

Severe hepatic failure

Hepatic transplant

Trientine + Zinc

NAZER PROGNOSTIC INDEX

Lab measurement

normalvalue

Score 0

Score 1

Score 2

Score 3

Score 4

Serumbilirubin

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 prolongation 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 < 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

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- 150µg/24hr If Trientine used- S.free Cu- 15-25µg/dl Monitor every 3 months

DIAGNOSED WD

presymptomatic

hepatic neuropsychiatric

1.Zinc2.Trientine

TransaminaseElevation only

Hepatic failure

Mild/modNazer< 9

SevereNazer >9

1.Zn +Trientine

Livertransplant

1.Zinc2.Trientine

1.TM+ Zinc2.Zinc

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 – - 200-500µg/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

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….