WILSON’S DISEASE- AN UPDATE

Dr Mrutunjay Dash
Professor, Department of Pediatrics
IMS AND SUM HOSPITAL,
SOA DEEMED TO BE UNIVERSITY,
BHUBANESWAR
 8 Year/ Boy

07/06/2023
EASTZONE CME DARBHANGA
om in a l d i st e nsion
i c e - -- - - -- - -  Abd
Jaund
2 ½ month 15 days
2
C/O

07/06/2023
• Difficulty writing
• Deteriorating school performance

EASTZONE CME DARBHANGA

• Slurring of speech
• Drooling of saliva

3
 07/06/2023
 No history OF
fever, altered sensorium or
 Past history: Not

EASTZONE CME DARBHANGA

sleep pattern, significant
Hemetemesis/ malena,  Family history: One

skin bleeding, cola sibling death @ 10 yr

coloured urine, Poor with h/o jaundice
scholastic performance,  Development: Age
behavioural change, appropriate
Thyroid swelling, joint  Immunisation : As per
pain, skin rash, vitiligo NIS
4
 EXAMINATION

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 PR-88/min, RR 20/min, Per Abdomen
 BP 110/70,Temp 98.9 F
 Anthropometry – WNL

EASTZONE CME DARBHANGA

Pallor -, Icterus+
CLD stigmata -,No Clubbing/Pedal
oedema
Liver- 2 cm BRSCM, Left lobe 4 cm,
Span 10 cm, Firm in consistency, well
defined margins
CNS: : NAD Spleen- 2 cm BCM
R/S / CVS: NAD Free fluid +, visible Veins +
5
 INVESTIGATIONS

LFT

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S.Bil (T/D)-(mg/dl) 7.8/4.5
AST/ALT(IU/L) 134/64
Hemogram
SAP/GGT 445/87

EASTZONE CME DARBHANGA

Hb(gm/dl) 10.5
Protein/albumin(g/dl) 5.8/2.1 TLC/N% 3700/62%
INR 2.53 Platelets 41000
Ammonia (μg/dl) 116 Na 138 meq/lt
K 3.4 meq/lt
Urea 12
Creatinine 0.3
Urine R/M Albumin/RBC- NIL

6
 07/06/2023
IgG 25

Anti LKM/ANA/pANCA -VE

EASTZONE CME DARBHANGA

DCT -VE

Retic 1.86

LDH

AFP 33

VIRAL MARKER -VE

7
 INVESTIGATIONS

07/06/2023
USG abdomen:
• Suggestive of chronic liver disease with portal hypertension

EASTZONE CME DARBHANGA

with portal vein 9 mm
• Spleen enlarged (12.7cm)

Upper GI endoscopy
Small Gr II esophageal varices

8
07/06/2023 EASTZONE CME DARBHANGA
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It Wilson’s Disease ??
 Is
 INTRODUCTION
 An autosomal recessive inborn error of metabolism

07/06/2023
characterized by toxic accumulation of copper in liver,
brain, cornea and other tissues.
 First described by Kinear Wilson in 1912 as an

EASTZONE CME DARBHANGA

"invariably fatal disorder of the nervous system caused by
a toxin generated in connection with hepatic cirrhosis that
is always found after death.
 In 1948, Cumings identified this toxin as Cu.

 1956- Walshe reported the success of Penicillamine and

1969- Trientine
 Unfortunately, diagnosis of WD is often delayed, causing
significant hepatic and neurological damage with resultant
death and morbidity. 10
PREVALENCE

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 WHO- 30-100/million
India- 15-20 new cases per year

EASTZONE CME DARBHANGA

11
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How to confirm WD
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DIAGNOSIS
 KF ring detection by slit lamp

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 Liver function tests

EASTZONE CME DARBHANGA

 S. ceruloplasmin level
 24 hour Urinary copper excretion
 Liver biopsy and Hepatic parenchymal copper estimation
 Neuro radiological imaging
 Genetic studies

14
KF RING (KAYSER-FLEISCHER RING)

 Greenish yellow/ brown ring due to accumulation of copper in Descemet

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membrane of cornea

 Found in

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 Almost all (95%) of Neurological WD

 45-60% of Hepatic WD

 20–30% of pre-symptomatic

 Usually starts from superior  f/b inferior pole of limbus Gradually

spreads to rest part of limbus

 Slit lamp examination by an experienced opthalomologist - necessary 15

Czlonkowska A et al.Wilson disease. Nat Rev Disease Primers,2018

KAYSER-FLEISCHER RING
Naked eye observation Slit lamp observation

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EASTZONE CME DARBHANGA
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Non-specific-

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Also detected in chronic cholestatic disorder

like Primary Billiary cirrhosis ,Primary

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sclerosing cholangitis

Absence of KF rings doesn’t exclude diagnosis

even in neurological disease

17
Ref: EASL Clinical Practice Guidelines: Wilson’s disease
LFT
 Provides some diagnostic clues
 Serum aminotransferase levels are characteristically only mild-to-moderately

07/06/2023
elevated
 Aspartate aminotransferase (AST) more than Alanine aminotransferase

EASTZONE CME DARBHANGA

(ALT)
 Serum alkaline phosphatase(SAP): usually in the low range, particularly in
acute liver failure settings
 Combination of an AST:ALT ratio >2.2 and an SAP:total bilirubin ratio <4
 an almost 100% diagnostic accuracy for WD in case of Liver failure

Korman et al, Pediatric and Adult Acute Liver Failure: Study Groups. Screening for Wilson disease in acute liver 18
failure: a comparison of currently available diagnostic tests. Hepatology,2008
SERUM CERULOPLASMIN
 Synthesis- Liver, An acute phase reactant

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 Normal range – 18-35 mg/dl
 Very low in neonatal period

EASTZONE CME DARBHANGA

 Gradually increase in infancy and peaks in mid childhood to 30-50 mg/dl
 Again decreases in adulthood to a plateau level

 Youngest age suitable for testing serum ceruloplasmin for

diagnosis of WD  1 year

ESPGHAN Position paper on Wilson Disease in Children, 2018

EASL Guidelines, 2012

19
 < 20 mg/dl - consistent with WD

< 5 mg/dl- strong possibility of WD

07/06/2023
 Subnormal levels - further testing
 Normal level - not excludes Dx Of WD

EASTZONE CME DARBHANGA

AASLD Guidelines, 2008

 At a cut-off serum ceruloplasmin <14 mg/dL  sensitivity 93% and

specificity 100%
Mak et al, Clin Chen, 2008

 Ceruloplasmin Cut off 0f <20 mg/dL sensitivity 95% & specificity

84.5%
20
Nicastro et al, Hepatology, 2010
LIMITATIONS
False high levels
 Acute inflammatory states
 Pregnancy
 Use of Oral contraceptives
 Estrogen supplementation
 Erroneus results of some
immunological assays as they
do not discriminate between
apo and holoceruloplasmin
False low levels
07/06/2023
 Marked renal or enteric protein
losing conditions
EASTZONE CME DARBHANGA
 End stage liver disease of any
etiology
 Malnutrition
 Menke’s disease
 Aceruloplasminaemia
 Heterozygote Carriers
21
Suchy 5 th Edition, Liver Disease in Children
URINARY COPPER

 24 hr urinary Copper excretion(UCE) measured

 Used both for Diagnosis & monitoring of therapy

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 Proper collection of sample in a copper free disposable container is crucial Plastic or
acid washed Glass containers

EASTZONE CME DARBHANGA

 >100 mcg/day (>1.6 µmol/day) in untreated symptomatic patients: Diagnostic
 >40 mcg/day(>0.6 µmol or >600 nmol) may indicate WD and requires further
investigation
AASLD Guidelines, 2008/ EASL Guideline, 2012

 UCE less than 100 mcg/24 h in 16–23% of patients, especially in children and
asymptomatic siblings
Steindl P et al. Gastroenterology 1997
Sanchez-Albisua I et al. J Pediatr Gastroenterol Nutr 1999

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 07/06/2023
 Caveats of UCE:
 Needs complete collection and Exact quantification of

EASTZONE CME DARBHANGA

24 hour urine volume
 Risk of Copper contamination from collecting containers
 Could not be done in patients with Renal Failure

 Falsely elevated
 Autoimmune hepatitis
 Chronic active liver disease
 Cholestasis
 Acute hepatic failure of any origin 23
 Heterozygotes
Penicillamine challenge test :

 Useful adjunctive in symptomatic patients with UCE <100 mcg/day

07/06/2023
 Standardized only in paediatric population

o 500 mg D-penicillamine orally stat and after 12 hr during 24hr urine collection

EASTZONE CME DARBHANGA

o > 1600 mcg/day (> 25 µmol/day) – sensitivity of 92% for diagnosing WD in symptomatic

Martins da Costa C. et al,

HEPATOLOGY, 1997

However, unreliable to rule out WD in asymptomatic children (sensitivity only 46%)

Muller et al, Hepatology, 2007,

Nicastroet al, Hepatology, 2010

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SERUM COPPER

 Total serum copper level (ceruloplasmin bound + free)

07/06/2023
usually decreased, BUT SERUM FREE Copper is

EASTZONE CME DARBHANGA

increased.

Serum free Cu ie Non-ceruloplasmin bound Cu (NCC)

= Total S.Cu (mcg/dL)- 3x serum ceruloplasmin (mg/dL)

25
 Normal level- <15 mcg/dl

07/06/2023
 > 25 mcg/dl - untreated WD

 < 5mcg/dl -over-treatment

EASTZONE CME DARBHANGA

Limitations :

i)False high level

1) Acute liver failure of any etiology

2) Chronic copper poisoning

3)Chronic cholestatic conditions

26
AASLD Guidelines, 2008/ EASL Guideline, 2012
LIVER BIOPSY
Only required
1) Clinical signs and noninvasive tests  could not conclude a final

07/06/2023
diagnosis
or
2) suspicion of other or additional liver pathologies

EASTZONE CME DARBHANGA

 Mild steatosis with microvesicular changes, glycogenated nuclei in hepatocytes,

and focal hepatocellular necrosis- earliest feature

 Later stage Cirrhotic changes-macronodular type, rarely micronodular

 Acute liver failure- marked hepatocellular degeneration & parenchymal

collapse 27
Ludwig J. et al, Am J Clin Pathol 1994
Strohmeyer FW et al, Am J Clin Pathol 1980
HEPATIC PARENCHYMAL COPPER CONCENTRATION

 Normal - <40-50µg/g dry wt. liver

07/06/2023
 Diagnostic confirmation- > 250 µg/g dry wt.

EASTZONE CME DARBHANGA

 Further evaluation - 50- 250µg/g , especially if there is active
liver disease or symptoms of WD

AASLD Guidelines, 2008/ EASL 28

Guideline, 2012
NEURO-IMAGING
 MRI- evaluation of neurologic WD & prior to

treatment for monitoring

07/06/2023
 T2 hyper intensity in basal ganglia

EASTZONE CME DARBHANGA

 Face of giant panda – characteristic of WD ,but found in minority
 PET
 SPECT
 TCS- (transcranial brain parenchyma sonography)- lenticular
nucleus hyperechogenicity

Ref: EASL Clinical Practice Guidelines: Wilson’s disease

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 Figure Brain MRI T2-weighted axial
(A) symmetric hyperintense signals in the putamen, posterior internal capsule, and thalami
(arrows),
(B) “face of the giant panda” in midbrain with high signal in tegmentum and normal red nuclei
(arrows)
(C) “face of the panda cub” in pons with hypointensity of central tegmental tracts with

07/06/2023
hyperintensity of aqueductal opening to fourth ventricle (arrows)

EASTZONE CME DARBHANGA

30

R. Shivakumar, and Sanjeev V. Thomas Neurology 2009

GENETIC STUDIES

 > 500 mutations of ATP7B (Location

07/06/2023
chromosome 13q14) known ; carrier state is

EASTZONE CME DARBHANGA

1%

 Kenney SM et al. Hum Mutat 2007

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 p.C271X: commonest mutation from Western India
Aggarwal A et al, Ann Hum Genet.2013

07/06/2023
 p.G1101R: commonest mutation from Eastern India
Mukherjee S et al. Parkinsonism Relat Disord. 2014

EASTZONE CME DARBHANGA

 813 C>A : 19% of patients from East India and 12% of patients
from South India
Santhosh S et al. Indian J Gastroenterol. 2006

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LEIPZIG SCORING SYSTEM FOR DX OF WD (1993)

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EASTZONE CME DARBHANGA
Modified Leipzig Score
Nagral et al, 2018

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Ferenci P et al. Liver Int, 2003.

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TREATMENT
 Diet

 Pharmacological therapy:

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-D-Penicillamine
- Zinc

EASTZONE CME DARBHANGA

- Trientene
- Tetrathiomolybdate(TM)

o Supportive neurological management

 Liver transplantation
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DIET
 Avoid

Liver

07/06/2023


 Shell Fish & Dried Fish

EASTZONE CME DARBHANGA

 Nuts, Legumes, Dried Beans

 Chocolate

 Mushroom, Green Chillies

 Unprocessed Wheat

 Vegetarian diet preferred

36

 Avoid copper and brass vessels

07/06/2023 EASTZONE CME DARBHANGA
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PHARMACOTHERAPY
D - PENICILLAMINE

Mechanism of action:

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 Sulfhydryl group chelates copper increase in urinary copper
excretion

EASTZONE CME DARBHANGA

Sheinberg IH. et al. Lancet 1987

o Induces metallothionein in hepatocyte

Siegel RC et al.J Biol Chem 1977

o Impairs collagen crosslinking- decreases hepatic fibrosis 38

Lipsky PE et al.J Immunol 1978
Dosage:

-20 mg/ kg/day in two or three divided doses

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-1 hr before or two hr after meal

EASTZONE CME DARBHANGA

-Maximum dose- 1- 1.5gm/day

-Interfers with pyridoxine action

 pyridoxine supplementation- 25 mg/ day

 Principle start low ,go slow

-Monthly expense- RS 1500-2000

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07/06/2023 EASTZONE CME DARBHANGA
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Nagral et al, JCEH, 2018

TRIENTINE

 Triethylene tetramine dihydrochloride

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Dosage profile - same as penicillamine

EASTZONE CME DARBHANGA

 Monthly expense:RS 10,000-12,000(costlier)

41
 Second line drug for children not tolerating

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penicillamine
SIDE EFFECTS:
 Neurolgical worsening less

EASTZONE CME DARBHANGA

 Gastritis

Better tolerated
 Aplastic
 due
anaemia rarely to less side effects
 Sideroblastic anaemia
 Cupriuretic effect - lower than penicillamine

 Monitoring - same as penicillamine

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ZINC
 Not a copper chelator
 Induces metallothinein in enterocytes which traps copper

07/06/2023
 Copper excreted in stool with sloughing of enterocytes

EASTZONE CME DARBHANGA

 Slow in action
 Not suitable for initial therapy
 Used for maintenance therapy
 First line drug for asymptomatic patients

43

AASLD Guidelines, 2008/ EASL

Guideline, 2012
 Dosage:

 50 mg TDS

07/06/2023
Side effects:
 < 50 kg – 25 mg TDS

EASTZONE CME DARBHANGA

 Neurological worsening rare
 1 hr before or two hr after meal

 MC side effect- gastritis (less with acetate salts)

 If used with penicillamine , the two should be given at

 Monthly expense: RS 200-250( very cheap)

least two hours gap to prevent nullification of each
 Tablet 50 mg, syp (20 mg/ 5 ml)
others effect

Wilson Disease Position paer in 44

Children, JPGN, 2010
AMMONIUM
TETRATHIOMOLYBEDATE(ATM)

07/06/2023
 Relatively new drug,still in experimental phase

EASTZONE CME DARBHANGA

 Not commercially available

 Interfers with copper absorption

 forms an insoluble complex with copper in

tissues and blood

45
 Dose -30 mg BD
 07/06/2023
No neurological worsening
Promising agent for neuro wilson disease

EASTZONE CME DARBHANGA

Side effects:
-anaemia
- bone marrow supression
-hepatitis

46
SUPPORTIVE MANAGEMENT OF NEURO
WD
 Central anticholinergics :

07/06/2023
trihexiphenydyl, benzhexol - parkinsonism feature

EASTZONE CME DARBHANGA

 Baclofen/tizanidine/botulinum toxin - dystonias

 Seizures- regular antiepileptics

 neuroleptics like haloperidol - psychotic

features
47
LIVER TRANSPLANTATION
Indications-

07/06/2023


- MLS score >9 ,

- Acute liver failure

EASTZONE CME DARBHANGA

- failure of medical therapy in
in decompensated cirrhosis

 Not indicated in neurological WD

AASLD Guidelines, 2008/ EASL 48

Guideline, 2012
OTHER MEASURES

07/06/2023
 Anti oxidants -Alpha tocopherol

EASTZONE CME DARBHANGA

Experimental therapy-
 Pharmacological chaperones- 4 phenyl butyrate &
curcumin
 Traditional chinese medicine - gandou tablets
 Gene therapy

AASLD Guidelines, 2008/ EASL 49

Guideline, 2012
07/06/2023 EASTZONE CME DARBHANGA
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KEY MESSAGES
 Early diagnosis is the key.
 Age is not a criteria for exclusion

 KF ring characteristic but not diagnostic of WD

07/06/2023
 Constellation of clinical features, biochemical parameters required for

EASTZONE CME DARBHANGA

Dx

 High index of suspicion to reach Dx

 Acute hepatic failure(more so if rapid onset jaundice+haemolytic

anaemia),

 Autoimmune hepatitis not responding to steroid ,

 NAFLD,
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 Patients presenting with neuropsychiatric features.

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THANK YOU