Wilson’s disease(Hepatolenticular Degeneration)

Dr. Kamal AhmedMBBS, FCPS (Medicine)

Associate Professor of Medicine

North East Medical College Hospital, Sylhet, Bangladesh

docdrkamal@yahoo.com

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

SAMUEL ALEXANDER KINNIER WILSONThesis, Univ. of Edinburgh,

1912.

Wilson's disease is an autosomal recessive

disorder caused by mutations in the ATP7B

gene, a membrane-bound, copper-transporting

ATPase, located on chromosome 13.

Impaired normal excretion of copper causes

accumulation of copper in…

liver

brain

other organs

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 skin, 20%is absorbed in enterocyte by

metallothionein.

Copper is then exported from enterocyte to the portal

blood with the help of transport protein

THE COPPER PATHWAY

Pathogenesis:

1. Unexplained acute or chronic liver disease

2. Neurologic symptoms of unknown cause

3. Acute hemolysis

4. Psychiatric illnesses

5. Behavioral changes

Wilson’s disease should be considered

in children and teenagers with :

Epidemiology

Occurs worldwide

Incidence: 1/50,000-100,000 births

The age at onset of symptoms: ranges from 6 to about 40 years

Siblings of a diagnosed patient have a 1 in 4 risk of Wilson's disease, whereas children of an affected patient have about a 1 in 200 risk

Autosomal recessive inborn error of copper

transport

Clinical features

1. Hepatic

2. Neuro-psychiatric

3. Other system

Clinical featuresForms of hepatic disease:

Include :

1.Asymptomatic hepatomegaly

(with or without splenomegaly)

2.Subacute or chronic hepatitis

3.Fulminant hepatic failure

Other manifestations of Wilson’s disease

Cryptogenic cirrhosis

Portal hypertension

Ascites

Variceal bleeding

Neurological manifestations Resting & intention tremor

Spasticity

Rigidity

Chorea

dysphasia

dysarthria

Dystonia

Deterioration in school performance or

behavioral changes

In the eye• Copper deposition in the descemet’s

membrane of cornea as golden brown structure at sclero-corneal junction as “ Kayser-Fleischer” (K.F) ring

• It dose not interfere with vision.

• Usually seen by slit lamp examination but occasionally can be seen by naked eye also

K.F. Ring

Copper deposit in brain

Psychiatric changes Present in most of the patients as

schizophrenia, manic depressive psychosis & classic neurosis

Useful tools for diagnosis of WD

1) S.ceruloplasmin

2) KF rings3) 24-h urine Cu4) Liver Cu5) Haplotype analysis

Test Useful

ness

Normal Value Heterozygous

Carriers

Wilson’s disease

S.cerulopl

asmin

+ 180–350 mg/L

(18–35 mg/dL)

Low in 20% Low in 90%

KF rings ++ Absent Absent 1. 99% + if neurologic or

psychiatric symptoms.

2. 30–50% in hepatic

presentation &

presymptomatic state

24-h urine

Cu

+++ 0.3–0.8 µmol

(20–50 µg)

Normal to 1.3

µmol (80 µg)

1. >1.6 µmol (>100 µg) in

symptomatic pts

2. 0.9 to >1.6 µmol (60 to

>100 µg)- presymptomatic

pts

Liver Cu ++++ 0.3–0.8 µmol/g

(20–50 µg)

tissue

Normal to 2.0

µmol (125 µg)

>3.1 µmol (>200 µg/g dry wt

of liver)

Haplotyp

e analysis

++++

(sibling)

0 Matches 1 Match

www.slideshare.com

By:

1. Serum ceruloplasmin level

2. Urinary copper excretion.

Screening siblings of patient

Treatment options:1. Zinc acetate

2. Trientine

3. Penicillamine

4. Tetrathiomolybdate

10/29/2014 Wilson Disease Prof. Dr. Saad S Al Ani 24

All presymptomatic pts should

treated prophylactically,

because the disease is close to

100% penetrant

Disease Status First Choice Second Choice

A) Initial hepatic1. Hepatitis or cirrhosis without

decompensation

Zinc Trientine

2. Hepatic decompensation

I) Mild Trientine and zinc Penicillamine and zinc

II) Moderate Trientine and zinc Hepatic transplantation

III) Severe Hepatic transplantation Trientine and zinc

B) Initial neurologic or

psychiatric

Tetrathiomolybdate and

zinc

Zinc

I) Maintenance Zinc Trientine

II) Presymptomatic Zinc Trientine

III) Pediatric Zinc Trientine

C) Pregnant Zinc Trientine

Hepatic presenting can be estimated using the nazer prognostic index

Score (in Points)

Lab

Measurement

Normal

Value

0 1 2 3 4

Serum bilirubin 0.2–1.2 mg/dL <5.8 5.8–8.8 8.8–11.7 11.7–

17.5

>17.5

Serum aspartate

transferase (AST)

10–35 IU/L <100 100–150 151–200 201–300 >300

Prolongation of

PT (sec)

— <4 4–8 9–12 13–20 >20

aIf hemolysis is present, the serum bilirubin cannot be used as a measure of liver

function until the hemolysis subsides

Source: Modified from H Nazer et al: Gut 27:1377, 1986; with permission from BMJ

Publishing Group

scores < 7: managed with medical therapy.

scores > 9: considered immediately for liver transplantation

scores 7- 9: clinical judgment for transplantation or medical therapy.

A combination of trientine & zinc used to treat with Nazer scores as high as 9.

such pts should watched carefully for indications of hepatic deterioration, which mandates transplantation

Zinc acetate (1st line)

Indications:1. Hepatitis or cirrhosis without decompensation

2. Initial neurologic / psychiatric menifestation

3. Maintenance dose

4. Presymptomatic case

5. Pediatric case

6. Pregnant women

Dose

• 50 mg of elemental zinc…t.d.s

• Each dose separated from food & beverages at least 1 h.

• At least 1 hr separated from trientine or penicillamine doses

Side effect of Zinc

• Gastric burning or nausea in ~10% of pts usually with the first morning dose

▼

• This can be mitigated by taking the first dose 1 hr after breakfast or taking the zinc with a small amount of protein

Monitoring of Zinc Rx Zinc treatment does not require blood or urine monitoring for

toxicity.

Because zinc mainly affects stool copper, 24-h urine copper can be used to reflect body loading.

The typical value in untreated symptomatic patients is >3.1 mmol(>200 mg) per 24 h.

This level should decrease during the first 1–2 years of therapy to <2.0 mmol (<125 mg) per 24 h.

A normal value [0.3 to 0.8 mmol (20 to 50 mg)] is rarely reached during first decade of therapy & should raise concern about overtreatment (copper deficiency), the first sign of which is anemia and/or leukopenia

Trientine

1. Hepatic decompensation

2. Trientine is a less toxic chelator

3. Recommended adult dosage is 500 mg twice daily

4. Each dose at least 1/2 hr before or 2 h after meals

Penicillamine

1. Previously the primary anti copper Rx

(Dose: 0.5-0.75 g/day for patients younger than 10 yr,1 g/day in two doses before meals for adults)

2. Now plays a minor role because of its toxicity & often worsens existing neurologic disease if used as initial therapy.

3. It should always be accompanied by 25 mg/d of pyridoxine

Monitoring of Trientine & Penicillamine Rx

S/E (developed about 1/3rd pts)

1. Rash

2. Bone marrow depression

3. Nephropathy

4. Drug induce lupus

When first using trientine or penicillamine, it necessary to monitor drug toxicity—particularly bone marrow suppression & proteinuria. CBC, standard biochemical profiles, & urinalysis

performed at weekly intervals for 1 month,

then 2 weekly intervals for 2-3 months

then 1 month intervals for 3-4 months

4-6 month intervals thereafter

Monitoring of Trientine & Penicillamine Rx

Monitoring of Trientine & PenicillamineRx (cont..)

Anticopper effects of trientine & penicillamine can monitored by following 24-h "free" serum copper.

Changes in urine copper more difficult to interpret because excretion reflects effect of the drug, as well as body loading with copper.

Free serum copper is calculated by subtracting the ceruloplasmin copper from the total serum copper.

Remember

Foods such as:

liver, shellfish, nuts, and chocolate

should be avoided

In asymptomatic siblings of affected

patients

Early institution of chelation therapy can

prevent expression of the disease.

Prognosis:Anticopper therapy must be lifelong.

With treatment, liver function usually recovers after about a year, although residual liver damage is usually present.

Neurologic and psychiatric symptoms usually improve after 6 to 24 months of treatment

Untreated pts die of the hepatic, neurologic, renal, or hematologic complications

Global Considerations:Age of onset of clinical disease may be considerably younger in India and far Eastern countries, often occurring in children only five or six years of age.

In countries where penicillamine, trientine, and zinc acetate are not available or cannot be afforded, zinc salts such as the gluconate or sulfate provide an alternative treatment option

1.If "routine liver function tests" are

unexplained abnormal in a child / teenager

2.In a child / teenager with haemolysis and

negative Coombs test

3. Changes in mood or school performance or movement disorder in a teenager, especially with speech slurring

Take home massage Where we consider Wilson’s disease ?