Wilson Disease - Our Wilson Disease - Our Experience Experience - - PowerPoint PPT Presentation

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Wilson Disease - Our Wilson Disease - Our Experience Experience - - PowerPoint PPT Presentation

Aug 16, 2022 137 likes •560 views

Wilson Disease - Our Wilson Disease - Our Experience Experience Hussein Shamaly M.D . . Pediatric Gastroenterology Unit Clalit Health Services Pediatric Department French Hospital, Nazareth Key Concepts Key Concepts Wilson disease is

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Wilson Disease - Our Wilson Disease - Our Experience Experience

. Pediatric Gastroenterology Unit Pediatric Department French Hospital, Nazareth

Hussein Shamaly M.D.

Clalit Health Services

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Key Concepts Key Concepts

  • Wilson disease is more often considered than

found, but if not considered will not be found.

  • Prevalence 1:30.000
  • Rarely before 3-4 y old. Usually appears IIed –IVth

decade

  • WD should be considered in the D.D. of any

unexplained liver disease, especially in these with liver disease & neurological or psychiatric symptoms.

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  • Autosomal recessive – gene localized to

chromosome 13q14.3-q21.1.

  • Gene encodes a p-type ATP-ase ATP7B.
  • It is responsible for copper excretion in bile and

copper incorporation in ceruloplasmin

  • biliary copper excretion
  • Hepatic copper accumulation
  • Copper deposition in extra hepatic sites
  • Pathophysiology related to copper over load

Key Concepts

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Ceruloplasmin Ceruloplasmin

  • 132 kd protein, synthesized in liver.
  • Acute phase reactant, copper carrying

protein. Increased Inflammation Neonatal period Heperestrogenemia Pregnancy Oral contraceptive Decreased Aceruloplasminemia Renal disease Enteric loss End stage liver disease Copper deficiency Early infancy

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Indications for Indications for Testing Testing

  • Unexplained abnormal liver

enzymes

  • Unexplained hemolysis
  • Neurological disturbances
  • Fanconi’s syndrome
  • Hypouricemia
  • Keiser- Fleisher ring
  • Siblings of affected patients
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Clinical Features Clinical Features

  • Hepatic (50%)
  • Neurologic ( 40-50%)
  • Psychiatric (10-25%)
  • Hemolytic anemia (15%)
  • Renal – Fanconi’s syndrome

(rare)

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Hepatic Manifestations Hepatic Manifestations

  • Hepatomegaly
  • Elevated liver enzymes
  • “Recurrent” hepatitis
  • Chronic Active hepatitis
  • Cirrhosis
  • portal hypertension
  • Acute liver failure, fulminant hepatitis
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Neurologic Neurologic Manifestations Manifestations

  • Movement disorders: tremor &

chorea

  • Dystonia
  • Pseudobulbar palsy
  • Seizures
  • Hypokinesis
  • Drooling
  • Dysarthria
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Psychiatric Psychiatric Manifestations Manifestations

  • Personality

disturbances

  • Depression
  • Neurosis
  • Psychosis
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Other Systems Other Systems

  • Blood- hemolytic anemia
  • Renal – aminoaciduria,

nephrolithiasis

  • Skeletal – osteoporosis, arthritis
  • Cardiac – cardiomyopathy,

dysrhytmias

  • GYN – infertility, amenorrhea,

repeated miscarriages

  • Pancreatitis
  • Hypoparathyroidism
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Wilson Disease Wilson Disease

Diagnosis Diagnosis

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Disease Disease Mean Hepatic Mean Hepatic Cu Cu

( mcg/gr dry weight) ( mcg/gr dry weight)

Wilson’s Disease 730 Primary Biliary Cirrhosis 410 Primary Sclerosing Cholangitis 245 Extra hepatic Biliary Obstruction 130 Indian Childhood Cirrhosis 1830 Alcoholic /Cryptogenic Cirrhosis 40

Normal 30

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Kayser-Fleischer Ring

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  • A. D. Patel and M. Bozdech Arch Ophthalmol. 2001;119:1556-1557

Wilson Normal

MRI

Deposition of Copper in the Basal Ganglia

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Genetic Test Genetic Test

  • Large gene & protein
  • >200 mutation
  • Compound heterozygote
  • Homozygote
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Treatment Treatment

  • Lifelong treatment
  • Asymptomatic & active disease
  • Diet
  • D-Penicillamine
  • Trientine
  • Zinc
  • Ammonium tetrathiomolybdate
  • Liver Transplantation
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Diet: Eliminate Copper Diet: Eliminate Copper Rich Diet Rich Diet

  • Organ meats
  • Shellfish
  • Nuts
  • Chocolate
  • Mushrooms
  • Dried fruits or beans
  • Water supply
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D-Penicillamine D-Penicillamine

  • General chelator
  • Induce cupriuria
  • Induce metallothionein
  • Well absorbed, meal decrease

absorption

  • Monitoring: urinary copper 250-

500ug

  • Normalization of nonceruloplasmin-

copper

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D-Penicillamine Side D-Penicillamine Side Effects Effects

  • Neurologic deterioration at initial

treatment - common

  • Hypersensitivity reaction: fever, rash,

lupus like

  • Bone marrow suppresion: aplastic

anemia, leukopenia, thrombocytopenia

  • Renal: Nephritis, nephrosis
  • Dermatologic: interferes with collagen

synthesis - Degenerative changes, wound healing

  • Hepatotoxicity
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Trientine Trientine

  • General chelator; induces cupriuria
  • Better safety profile than

penicillamine

  • Ideal drug to Pt with penicillamine

intolerance

  • Poorly absorbed
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Trientine Trientine

Side effects:

  • Neurologic deterioration at

initial treatment – rare

  • Gastritis

Rare side effects

  • Aplastic anemia
  • Sideroblastic anemia
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Zinc Zinc

Mode of action:

  • Mettallothionenin inducers
  • Blocks intestinal absorption of

copper

Usage:

  • For asymptomatic, maintenance

pregnancy and in combination therapy

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Zinc Zinc

No neurologic deterioration Poorly absorbed with food Side effects:

  • Gastric irritation, Gastritis
  • Pancreatitis – biochemical
  • Zinc accumulation
  • Possible change in immunologic function
  • Monitoring: urinary copper < 75ug,
  • normalization of nonceruloplasmin- copper
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Tetrathiomolybdat Tetrathiomolybdat e e

Mode of action:

  • General chelator
  • Blocks intestinal absorption of

copper

  • Induces intestinal and urinary copper

loss Side effects:

  • Anemia
  • Neutropenia
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Fulminant Hepatic Fulminant Hepatic Failure Failure

Liver transplant remains the treatment of choice for fulminant hepatic failure

May cause fatigue,hepatic insufficiency , extreme jaunduce ( because of accompanying hemolysis) ,severe coagulopathy ,ascites ,hepatic coma ,renal failure and death if liver transplantation is not performed Interventions to reduce secondary organ injury while awaiting a suitable donor organ: albumin dialysis, plasmapheresis, exchange transfusion

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Our Patients Our Patients

  • 7 children with elevated liver enzymes

which were found in routine blood testing

  • 3 of them were diagnosed as WD
  • No patient was found with hepatic,

neurological, psychiatric or hemolytic manifestations

  • Clinical examination – normal
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Viral:

  • HBsAg
  • HCV Ab
  • HAV Ab
  • EBV IgM
  • CMV IgM

Immunologic:

  • Immunoglobulins
  • Antiparietal cell Ab
  • Anti mithochondril

Ab

  • Anti smooth muscle

Ab

  • ANA
  • LKM
  • Anti endomesial Ab
  • AFP

Laboratory Tests

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Abed Age (years) 5 Gender M Relatives with Wilson

  • AST (u/l)

95 ALT (u/l) 125 US Fatty liver Ceruloplasmin(mg/dl) 18 Cu in serum (mcg/l) 95 Cu in urine (24h) ( mcg/l) 171 Cu after penicillamin (mcg/l) 575 Keiser-Fleisher ring

  • Liver histology:

Steatosis + Orcein

  • Rhodenin
  • Cirrhosis
  • Cu in liver( mcg/gr

dry weight))

940

Moad 10 M + 159 90 N 22 85 330 4800 _ +

  • 1520

Nur 6 F

  • 170

125 Fatty liver 9 26 106 477

  • +

+

  • +

1480

Homoz L568R

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Adham Age (years) 12.11 Gender M Relatives with Wilson + AST(u/l) 28 ALT(u/l) 64 US Fatty liver Ceruloplasmin(mg/dl) 23.6 Cu in serum( mcg/dl) 110 Cu in urine (24h) (mcg/dl) 140 Cu after penicillamin(mcg/dl) 456 Keiser-Fleisher ring

  • Liver histology:

Steatosis + Orcein

  • Rhodenin
  • Cirrhosis
  • Cu in liver (mcg/gr dry

weight)

48

Hadil 9.5 F

  • 66

95 N 25 129 168 760 _

  • 37

Loay 13 M

  • 43

52 Fatty liver 2.5 148 45 645

  • +
  • 16

Ali 8 M

  • 63

73 Fatty liver 32 15 140 904 _

  • 16
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Abed Moad Nur Ali Adham Hadil Loay

Age(year)

5 10 6 8 12.11 9.5 13

Gender

M M F M M F M

Relatives with Wilso

  • +
  • +
  • AST(u/l)

95 159 170 63 28 66 43

ALT(u/l)

125 90 125 73 31 95 52

US

Fatty liver N Fatty liver Fatty liver Fatty liver N Fatty liver

Ceruloplasmin(mg/dl)

18 22 9 32 23.6 25 2.5

Cu in serum(mcg/dl)

95 85 26 110 129 148

Cu in urine (24h)(mcg dl)

171 330 106 140 168 45

Cu after penicilineam (mcg/dl)

575 4800 477 904 456 760 645

Keiser-Fleisher ring

  • _
  • _
  • _
  • Liver histology:

Steatosis

+ + + +

  • +

Orcein

  • +
  • Rhodenin
  • Cirrhosis
  • +
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Conclusions Conclusions

  • All were asymotomatics
  • All were found within normal

examination

  • All without Keiser- Fleischer ring
  • US of Abdomen was not informative,

liver mostly fatty

  • AST not always > ALT
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  • Ceruloplasmin was low in 2 patients
  • Ceruloplasmin >20mg% in 1 patients
  • Cu in serum low in 1 patient . Normal

in others

  • Cu in urine in 24 hours collections is

indicative

  • Cu in urine after penicillamine is

indicative

Conclusions – Conclusions – Cont. Cont.

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Conclusions - Cont Conclusions - Cont

Liver Histology:

  • Most with steatosis
  • Orcein stain Positive in 1 patient
  • Rhodanin stain Negative
  • Cirrhosis in 1 patient (6 years old)
  • Cu level in hepatic tissue is

diagnostic

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Take Home Message Take Home Message

Consider WD Do large evaluation Send to specialist Early diagnosis & TRT may prevent complications and save lives

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