Wilson’s disease

WILSON’S DISEASE
An Update…
Dr.W.A.P.S.R.WEERARATHNA
Registrar In Medicine
Ward 10/02

 OBJECTIVES….
 WD- PATHOPHYSIOLOGY,C/F,VARIOUS
PRESENTATIONS
 WD-DIAGNOSTIC WORK-UP
 TREATMENT OPTIONS/ SCREENING
TOOLS
 PROGNOSTIC INDICATORS
 LATEST PRACTICAL GUIDE
LINES/RECOMMENDATIONS ISSUED BY
EASL & AASLD.

Wilson’s Disease Pathophysiology

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 syndrome
 Nephrolithiasis
 Hypoparathyroidism
 Amenorrhea
 Testicular problems
 Infertility
 Arthritis,
 Rhabdomyolysis.
 Cardiomyopathy
 Pancreatitis

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
< /
24h.U.cu>
40
KF Ring +
CPN=20
24h.U.cu>4
0
Liver biopsy-
histology &cu
quantification
Molecular
testing
KF Ring-
CPN <20
24h.U.cu=>4
0
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>=20
24hU.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 cu
quantification
Molecular
testing
>25070-
250

Siblings
Child>2 yr
(asymptomat
ic)
Haplotype/
Mutation
analysis
Diagnosis
WD
Identical
haplotype or2
mut.
Slit lamp(>4 yr)
CPN
LFT
INR
24 h U.cu
Abn.LFT
CPN<20
24h U.cu >40
Liver biopsy70-
250
>250

Treatment Options in WD
• Low copper dietReduced Copper
intake
• Zinc acetate-50 mg tds-
DOC-cirr without
decomp.& neuro psyc.
Reduce copper
absorption
• Penicillamine-500mg
bd+25mg pyridoxine
• Trentine-500mg bd-less toxic
Increase copper
excretion
• May improve neurological
manefestations.
Liver
Transplantation
Gene Therapy

Nazer prognostic index
Lab
measur
ement
normal
value
Score
0
Score
1
Score
2
Score
3
Score
4
Serum
bilirubin
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
Prolonga
tion 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 LT
 7-9 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 Screening
 Biochemical 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

 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

 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

 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

 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

 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

 Initial treatment for symptomatic patients
with Wilson’s disease should include a
chelating agent (D-penicillamine or
trientine).
 Trientine may be better tolerated

 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

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

 If zinc is used, careful monitoring of
transaminases is needed, with changing
to chelators if these laboratory
parameters are increasing
 GRADE C1

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

 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.
 AASLD Class I, Level B [41

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

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

 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

 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
 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

Wilson’s disease

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