WILSON’S DISEASEAn Update…

Dr.W.A.P.S.R.WEERARATHNARegistrar In Medicine

Ward 10/02

OBJECTIVES….WD- PATHOPHYSIOLOGY,C/F,VARIOUS

PRESENTATIONSWD-DIAGNOSTIC WORK-UPTREATMENT OPTIONS/ SCREENING TOOLSPROGNOSTIC INDICATORSLATEST PRACTICAL GUIDE

LINES/RECOMMENDATIONS ISSUED BY EASL & AASLD.

Wilson’s Disease Pathophysiology

Clinical Manifestations of WD

Lunulae ceruleae

KF Ring

Neuropsychiatric: 99% . Hepatic : 30 to 50 % KF rings are not specific for

WD. They may be found in other

chronic liver disease, PBC, PSC, AIH,

and familial cholestatic syndromes.

PSYCHIATRIC PRESENTATIONS

15-20% of patients may present with purely psychiatric symptoms .◦Phobias , ◦compulsive behaviors, ◦aggressive and antisocial behaviors◦Schizophrenia◦ Psychosis◦Cognitive decline

HEPATIC PRESENTATION

Acute hepatitis, Chronic liver disease— portal HTN.Autoimmune hepatitis. Fulminant hepatic failure, with sev.

coagulopathy and encephalopathy .Recurrent bouts of hemolysis may predispose to the development of gallstones .Wilson disease is rarely complicated by

hepatocellular carcinoma.

Extrahepatic disorders

Hemolytic anemia

Fanconi's syndromeNephrolithiasisHypoparathyroidismAmenorrhea Testicular problems Infertility

Arthritis, Rhabdomyolysis.CardiomyopathyPancreatitis

DIAGNOSTIC WORK-UP Biochemical

◦ Serum ceruloplasmin <20mg/dL(18-35) low in 90% WD

◦ 24hr Urinary Copper >100micg/d-in symptomatics/ (60-100 in pre symp.)-NR(20-50)

◦ Serum free copper >10micg/dL◦ Liver Copper >250micg/g-false + in

obstructive CLD Ophthalmological

◦ Slit lamp KF ring-absent in heterozygous carriers

Imaging◦ X-ray Osteoporosis◦ Ultrasound Cirrhosis◦ CT Scan◦ MRI

Genetics-DNA Haplotype analysis-genotype siblings only-polyorphism/specific mutation testing

MRI appearance in WD

a. ‘Face of giant panda’ sign;

b. MRSS: decreased NAA and therefore a decreased ratio with other products

c. Bright lateral putamen or claustral sign;

d. Pallidal hyperintensity

Unexplained CLD

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<20

24h.U.cu >40

>250mcg/g

70-250mcg/g

<50 mcg/g

Other diagnosis

Neuropsychiatric +-CLD

Diagnosis WD

KF Ring +CPN>=2024hU.cu>

40

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

Siblings 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 Options in WDReduced

Copper intake• Low copper diet

Reduce copper absorption

• Zinc acetate-50 mg tds-DOC-cirr without decomp.& neuro psyc.

Increase copper excretion

• Penicillamine-500mg bd+25mg pyridoxine

• Trentine-500mg bd-less toxic

Liver Transplantation

• May improve neurological manefestations.

Gene Therapy

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

AST Level

10-35 <100 100-150 151-200 201-300 >300

Prolongation of PT level (secs)

12-14s <4s 4-8s 9-12 13-20 >20

DISEASE SEVERITY ASSESMENT BY NAZAR PROGNOSTIC INDEX…

Scores< 7 medical theraphy>9 immediate LT7-9 clinical judjment – Rx or LT???

(trientine & Zinc acetate)With Rx-LFT usually recovers in about 1

year..Neurologic & psychiatric mane. usually

improve after 6-24 months….Residual liver damage may persist.

Family ScreeningBiochemical Testing

◦Children of patient: Begin at age 2 if asymptomatic, repeat once in 5 years unless reason to pursue further.  

Siblings of patient:◦Physical examination and brief history of any liver or

neurological symptoms.◦Liver Function Tests:  ALT, AST, Albumin, Bilirubin.◦Ceruloplasmin and Serum Copper.◦24 hour urine copper◦Slit-lamp exam of the eyes for Kayser-Fleischer ring◦ If no K-F rings, abnormal liver functions tests, and low

ceruloplasmin:  liver biopsy.

EASL Clinical Practice Guidelines: Wilson’s disease 

European Association for the Study of the Liver 

Journal of Hepatology Volume 56, Issue 3, Pages 671-685 (March 2012)

DOI: 10.1016/j.jhep.2011.11.007

Copyright © 2011 European Association for the Study of the Liver Terms and Conditions

Wilson’s disease should be considered in any individual with liver abnormalities or neurological movement disorders of uncertain cause.

Age alone should not be the basis for eliminating a diagnosis of Wilson’s disease

GRADE II-2, A, 1 AASLD Class I, Level B

Wilson’s disease must be considered in any patient with unexplained liver disease in combination with neurological or neuropsychiatric disorders

GRADE II-2, A, 1 AASLD Class I, Level B

Kayser-Fleischer rings should be sought by slit-lamp examination by a skilled examiner.

The absence of Kayser-Fleischer rings does not exclude the diagnosis of Wilson’s disease, even in patients with predominantly neurological disease

GRADE II-2, A, 1 AASLD Class I, Level B

Neurologic evaluation and imaging of the brain, preferably by MR imaging, should be considered prior to treatment in all patients with neurologic Wilson’s disease and should be part of the evaluation of any patient presenting with neurological symptoms consistent with Wilson’s disease

GRADE II-2, B, 1 AASLD Class I, Level C

A low serum ceruloplasmin level(<50mg/dl) should be taken as evidence for the diagnosis of WD.

Borderline levels require further evaluation.

Serum ceruloplasmin within the normal range does not necessarily exclude the diagnosis

GRADE II-2, A, 1 AASLD Class I, Level B

Basal 24-hour urinary excretion of copper >1.6 μmol/>100micg is typical in symptomatic patients.

>0.6mic may indicate WD & needs Ix.Penicillamine challenge test is rec. in pt with

<1.6mic In children with mild hepatic disease basal 24-

hour urinary excretion of copper can only be mildly elevated or may even be in the normal range.

Lowering the threshold to >0.64 μmol/24 hr may be useful for detecting asymptomatic patients but this will be less sensitive and will overlap with patients with other liver injury

GRADE II-2, B, 1AASLD Class I, Level C

Hepatic parenchymal copper content >4 μmol/g or >200micg dry weight provides critical diagnostic information and should be obtained in cases where the diagnosis is not straightforward and in younger patients.

In untreated patients, normal hepatic copper content (<0.64-0.8 μmol/g dry weight) almost always excludes a diagnosis of Wilson’s disease

GRADE III, B, 2 AASLD Class I, Level B

Mutation analysis with specific allelic probes or by whole-gene sequencing is currently possible and available.

Specific testing for known mutations or screening of first-degree relatives of patients with haplotype analysis should be the primary mode for Wilson’s disease

GRADE II-2, B, 1 AASLD Class I, Level B

Initial treatment for symptomatic patients with Wilson’s disease should include a chelating agent (D-penicillamine or trientine).

Trientine may be better tolerated GRADE II-1, B, 1 AASLD Class I, Level B

Zinc may have a role as a line therapy in neurological patients

GRADE II-2, C, 2 AASLD Class II, Level C

Treatment of presymptomatic patients or those with neurological disease on maintenance therapy can be accomplished with a chelating agent or with zinc

GRADE II-1, B, 1 AASLD Class I, Level B

Treatment is lifelong and should not be discontinued, unless liver transplantation is performed

GRADE II-1, B, 1 AASLD Class I, Level B

If zinc is used, careful monitoring of transaminases is needed, with changing to chelators if these laboratory parameters are increasing

GRADE C1 AASLD Class I, Level B

Patients should avoid intake of foods and water with high concentrations of copper, especially during the year of treatment

GRADE II-3, B, 2 AASLD Class I, Level C

Patients with acute liver failure due to Wilson’s disease should be treated with liver transplantation when the revised King’s score is 11 or higher.

GRADE II-2, B, 1 AASLD Class I, Level B [41

Patients with decompensated cirrhosis, unresponsive to chelation treatment, should be evaluated promptly for liver transplantation

GRADE II-2, B, 1 AASLD Class I, Level B

Treatment for Wilson’s disease should be continued during pregnancy, but dosage reduction is advisable for D-penicillamine and trientine

GRADE II-3, B, 1 AASLD Class I, Level C

For routine monitoring, serum copper and ceruloplasmin, liver enzymes an international normalized ratio, functional parameters, complete blood count and urine analysis as well as physical and neurologicalexaminations should be performed regularly, at least twice annually

GRADE II-2, B, 1 AASLD Class I, Level C

The 24-hour urinary copper excretion on medication and after 2 days of cessation of therapy should be measured at least yearly.

The estimated serum non-ceruloplasmin bound copper may be another useful parameter to control therapy

GRADE II-3, B, 1 AASLD Class I , Level C

REFFERENCES-EASL Clinical Practice Guidelines: Wilson’s

disease-European Association for the Study of the Liver-june 2012

AASLD PRACTICEGUIDELINES-Diagnosis and Treatment of Wilson Disease:An Update-Eve A. Roberts and Michael L. Schilsky-2012 vol 56

Harrison’s principles of Internal medicine-18th edition

THANK YOU!