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
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
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 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
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 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
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
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 choiceTransaminases elevated,No hepatic failure Zinc TrientineCirrhosis presentcompensated Zinc TrientineCirrhosis decompensated Trientine + Zinc D-Pencillamine + ZincMild,Moderate hepaticfailureSevere hepatic failure Hepatic transplant Trientine + Zinc
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
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.