Wilsons Disease Dr.M.Kaliratinname

• Progressive lenticular degeneration, a familial nervous disase associated with cirrhosis of the liver.

SAMUEL ALEXANDER KINNIER WILSONThesis, Univ. of Edinburgh,

1912.

HISTORY

• 1902-KAYSER&FLEISCHER• 1912-SAK WILSON• 1921-HALL• 1948-CUMMINGS• 1951-BAL IS INTRODUCED• 1952-SCHEINBERG&GITLIN-LOW

CERULOPLASMIN.• 1953-PATTERN OF INHERITANCE

• 1956-WALSHE –D-PENCILLAMINE• 1961-SCHOUWINK-EFFECTIVENESS OF ZINC• 1969-TRIENTINE• 1985-WILSONS CHROMOSOME• 1986-AMMONIUM TETRA THIO MOLYBDATE• 1993-MENKES GENE AND WILSONS GENE

IDENTIFIED

Epidemology

• Occurs worldwide• Incidence of one in 30,000• Prevalence

• Europe: 30/100,000• Asia : 33-68/100,000 Incidence 1/30000• El Salvador 1 in

186. • Carrier: 1/100 (El Salvador 1/4)• The age at onset of symptoms ranges from 6 to

about 40 years.

• India • Hepatic 19.7% Metabolic liver

disease in children commonest WD • NIMHANS : 15-20 New cases per year• Age of onset: 10-20 (<5 never, >50 rare)• Hepatic :10-15 • Neurologic 15-20 • Sex: M>F

.

THE COPPER PATHWAY

• Copper is a micro nutrient and an essential cofactor for many enzymes cytochrome c oxidase and superoxide dismutase.

• Daily copper intake is 1-4 mg• Of this 50%is unabsorbed and passed in

stool,30%lost through the skin,20%is absorbed in enterocyte by metallothionein.

• Copper is then exported from enterocyte to the portal blood with the help of menkes protein.

• In the portal blood copper is carried loosely bound to albumin,aminoacids esp,histidineand transcuprein.

• Copper is transported to the hepatocyte at the basolateral membrane,from the portal blood.

• The hepatocyte protects itself against copper toxicity by following mechanisms

• 1)controlling uptake of copper• 2)chaperoning copper to various locations• 3)binding free cytoplasmic copper• 4)actively transporting copper (by wisons

disease protein.)

Copper chaperone proteins

• 1)Hah 1• 2)Lys 7• 3)Cox 17.

Cu Metabolism

Foods rich in copper

• Liver,kidney,choclate,nuts,dried beans,green chillies ,mushroom,legumes,unprocessed meat,milk products,dried fishand shell fish.

WD – Genetic Link

• Autosomal recessive disorder• The WD gene, ATP7B is located on the

long arm of chrom. 13q14.21• The WD gene encodes a copper-

transporting P-Type ATPase) which is expressed predominantly in the liver

Mutations in WD gene (ATP7B)

ATP7B gene • Deletions 60• Insertions 21• Nonsense 19

• Missense 166

• Splice 23 total 289

• India• Chandigarh: T3305C,

C2975A, 29977ins A• Kolkata: C813A 19%• Vellore: G3182A 16%,

C813A 12%• 51 Mutation of ATP7B, 34

novel• C813A mutation

commonest• World

• European PH1069Q 60%• Chinese pR778L 45%

Molecular Mechanism

• The Wilson Disease Protein (WNDP) has two functions:

1. Export of copper from the cell and2. Incorporation into copper-

dependent enzymes

Copper Metabolism - Normal

Copper Metabolism – WD Mutations

WD protein (ATPase)

WD - Pathophysiology

• Mutations in the ATP7B gene result in 1. Retention of copper in the liver 2. Impaired incorporation of copper into ceruloplasmin • This accumulation is then followed by

hepatic and/or neurological symptoms due to copper toxicity

Pathology

• The earliest changes include the glycogen deposition in nuclei of periportal hepatocytes and microvesicular fatty infiltration.

• Then comes the infiltration of lymphocytes and plasma cells.

• If untreated it progresses to macronodular cirrhosis and fulminant hepatitis.

Histopathology

• Histologic abnormalities precede clinical appearance

• Helpful diagnostic clues: • Steatosis• Ballooned hepatocytes • Glycogenated nuclei• Moderate to marked copper deposition• Lymphocytic portal and interface hepatitis

• Untreated, progresses to cirrhosis

WD- cirrhotic stage (Rhodanine stain)

This reveals accumulation of copper , most in a nodular cluster of hepatocytes

DEISS’S STAGING OF WD

• Stage 1 : Begins at Birth , pts are Asymptomatic• Stage 2: liver is saturated , Copper is released into

serum• 2.a : It can debut with Hemolytic Anemia or• 2b. Liver failure

• Stage 3 : Copper accumulates in extra hepatic tissues like brain and Eyes (KF rings)

• Stage 4 : Neurological Symptoms Develop• Stage 5 : therapy is initiated and Symptoms to fade

away

HEPATIC PRESENTATION

• A hepatic presentation of Wilson disease is more common in children than in adults.

• Symptoms may be vague and nonspecific,• Pts may present with a self-limited clinical

illness – acute hepatitis, • Pts may present with severe, established chronic

liver disease— portal HTN.• Wilson disease may manifest as clinical liver disease indistinguishable from

autoimmune hepatitis.

• Wilson disease may also manifest as fulminant hepatic failure, with severe coagulopathy and encephalopathy .• Recurrent bouts of hemolysis may predispose to the development of gallstones .• Wilson disease is rarely complicated by

hepatocellular carcinoma.• Asymptomatic hepatomegaly.

NEUROLOGIC PRESENTATION

• Tends to occur in the 2nd and 3rd decades or later

• Two main patterns, 1. MOVEMENT DISORDER

2. RIGID DYSTONIA

PSYCHIATRIC PRESENTATION

• 20% of patients may present with purely psychiatric symptoms .• Phobias , compulsive behaviors,

aggressive and antisocial behaviors have been reported.

OCULAR SIGNS • The classic Kayser-Fleischer ring is

caused by copper deposition in Descemet's membrane of the cornea. • A careful slit-lamp examination is

mandatory. • Copper deposition in the lens (sunflower

cataract), which does not interfere with vision

• Pts with exclusively hepatic involvement have KF rings in 30 to 50 % • Pts with a neurologic or psychiatric presentation of WD have KF rings in

almost 95% . • KF rings are not specific for WD.• They may be found in other chronic liver disease, PBC, PSC, AIH, and familial cholestatic syndromes.

Extrahepatic disorders

• Hypoparathyroidism

• Pancreatitis

• Amenorrhea

• Hyperpigmentation.

• Testicular problems

• Infertility

• Hemolytic anemia

• Arthritis,

• Fanconi's syndrome

• Rhabdomyolysis.

• Nephrolithiasis

• Cardiomyopathy

Management

• High index of suspicion.• Classic triad include• Hepatic disease• Neurologic disease and KF ring.• No single test is diagnostic of WD,but the presence

of any two of the following is sufficient for the diagnosis.

• Low sr ceruloplasmin,KF ring,hepatic cu>250micrgm/gm dry wt.

1)serum ceruloplasmin2)KF ring3)serum copper4)serum free copper5)urine copper6)liver biopsy and liver copper7)features of hemolysis8)scanning of brain9)molecular genetic testing10)radio copper loading test.

Diagnosis of fulminant WD

• H/O consanguinity• Absence of other factors• h/o sibling death due to undiagnosed liver disease• h/o neuropsychiatric illness in family• High bilirubin with low transaminases• Bermans ratio <2• Evidence of hemolysis in peripheral smear• Siblings or parents with low ceruloplasmin levels• High urine copper.

MRI 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

Modified calicut score

score

Consanguinity 2

Sibling death due to liver disease 2

Low ceruloplasmin 3

Low ceruloplasmin and high SGPT in siblings and parents

3

KF ring 3

High urine copper 3

Sun flower cataract 4

 Biochemical Parameters

TREATMENT

1954 Peters BAL 1956 Walshe Penicillamine1969 Walshe Trientine 1984 Walshe Tetrathiomolybdate1983 Brewer zinc acetate

D-Penicillamine

• Mode : General chelator , induces urinary Cu excretion.

• Dose Initial: 1-1.5 g/day adults or 20 mg/kg/day children , Maintenance: 0.75-1 g/day

• Side effects : • Fever, rash Proteinuria Lupus like reaction • Aplastic anemia • Leukopenia • Thrombocytopenia

• Nephrotic syndrome • Degenerative

changes in skin • Hepatotoxicity• ND occurs in 10%-20% during initial phase .

Trientine (triethylene tetramine dihydrochloride)

• Mode :General chelator , induces urinary Cu excretion.

• Initial: 1-1.2 g/day ; Main : same

• Side effects : • Gastritis • Aplastic anemia rare • ND 10%-15% during initial phase .

Zinc

• Mode : Metallothionein inducer, blocks intestinal absorption of copper .• Dose : Initial: 50 mg T.I.D (adults)

• Side effects • Gastritis • Zinc accumulation • Possible changes in immune• ND can occur during initial phase .

Tetrathiomolybdate

• Mode : Chelator and also blocks copper absorption• Side effects : • BM suppresion • Hepatotoxicity • Rare reports of ND during initial phase of treatment

Drug choice

Prognostic Index of NazerScore points

• Pts with scores 6 - medical therapy. • Pts with scores 10 - OLT,• Pts with scores between 7 and

9 require clinical judgment .• Treatment is life long.

At present: Liver transplantation in liver failureAt present: Zinc acetate ,Trientine

authorised in the US and EU Tetrathiomolybdate used experimentally in the US and EU

In the future: Gene therapy, cell therapy…based on current molecular knowledge

THANK YOU