(Ministry of Education and Scientific Research)

(Al-Muthanna University College of Medicine)

Student Name : Hussein Haider Ahmayed.

Stage : 4th.

Subject : Wilson Disease .

Supervise by : Dr. Ali Adnan .

Data: 2020/6/30

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 Wilson Disease
 Normally copper found in majority food like Like wheat, barley, legumes,
meats, shellfish, chocolate, and potatoes.
 The standard approximate total body copper content is between 50 and
100 mg , and the average daily intake is between 1 and 5 mg.. It helps
maintain healthy bones, blood vessels, nerves, and immune function, and
it contributes to iron absorption. Copper is an important component of
several metabolic enzymes, including lysyl oxidase, cytochrome c oxidase,
superoxide dismutase, and dopamine beta-hydroxylase.
 COPPER METABOLISM done by liver enzymes that excreted by bile with
feces about 90% and in urine about 10%.
 In Wilson disease there is defect in excretion of copper by liver
metabolism.

 Wilson 's disease -hepatolenticular degeneration- is a rare, but severe,

autosomal recessive copper metabolism disorder caused by a number of
ATP7B gene mutations on chromosome 13.
 Overall body copper is increased, with excess copper deposited in many
organs and causing damage.

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Epidemiology
 The carrier frequency in the United States is 1 in every 90 individuals.
Wilson disease prevalence is 1 in every 30,000 individuals.
 The prevalence of Wilson disease is between 10 and 30 million cases, and
the heterozygous carrier rate is 1 case per 100 individuals, with genetic
mutation rates ranging from 0.3% to 0.7%. In Japan the average is 1 case
per 30 000 men, compared to 1 case per 100 000 in Australia.
 The increased frequency in certain countries is due to high rates of
consanguinity. The fulminant presentation of Wilson disease is more
common in females than in males.
 A German study of patients with Wilson disease illustrated that patients
presenting earlier show predominantly hepatic symptoms , while those
presenting later more often present with neurological symptoms .

Age-related

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Pathophysiology
 About 50% -75% of intestinal copper is absorbed and then transported
to the hepatocytes. In the case of Wilson disease this mechanism is
deterioration .
 copper reaches the hepatocyte, it is incorporated into copper-
containing enzymes and copper-binding proteins (CBPs), including
ceruloplasmin, a serum ferroxidase.
 Many of the gene defects for ATP7B , which response for formation
protein that Facilitates the linking process copper with cerulopalsmin,
lead to failure transporting .

 The accumulation of excessive copper in the body is ultimately

prevented by its excretion , disorder of excretion lead to become free
radical deposition in tissue and damage it.

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 The excess copper resulting from Wilson disease promotes free radical
formation that results in oxidation of lipids and proteins. Ultrastructural
abnormalities in the earliest stages of hepatocellular injury, involving
the endoplasmic reticulum, mitochondria, peroxisomes, and nuclei,
have been identified. Initially, the excess copper accumulates in the
liver, leading to damage to hepatocytes. Eventually, as liver copper
levels increase, it increases in the circulation and is deposited in other
organs like basal ganglia of the brain, eyes, kidneys and skeleton.

Prognosis
 Patients with a prognostic index (score) of 7 or greater should be
considered for liver transplantation.
 All patient who exceeded this score died within 2 months of diagnosis.
 Prognosis after liver transplantation is relatively good , the 1-year
survival rate was 79% and the overall survival rate was 72% at 3
months to 20 years.

Score 0 1 2 3 4

Serum bilirubin
(reference range, 3-20 < 100 100-150 151-200 201-300 >300
mmol/L)

Serum aspartate
transaminase (reference < 100 100-150 151-200 201-300 >300
range, 7-40 IU/L)

Prothrombin time
<4 4-8 9-12 13-20 >30
prolongation (seconds)

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Approach patient with Wilson disease.
 Wilson disease has a variety of clinical manifestations, ranging from
asymptomatic to fulminating hepatic failure, chronic liver disease with
or without cirrhosis, neurological, and psychiatric.
 Symptoms typically occur between age 5 and age 45. Hepatic disease
occurs primarily in infancy and early adolescence, though it may occur
in adults in their 50yrs .
 ON HISTORY
1. Neurological symptoms : who present with neuropsychiatric
manifestations have cirrhosis . asymmetrical tremor difficulty speaking ,
excessive salivation, ataxia, and personality changes. Late
manifestations include dystonia, spasticity, grand mal seizures, rigidity,
and flexion contractures.
2. Musculoskeletal symptoms : osteopenia , Osteochondritis ,
chondromalacia and chondrocalcinosis have also been described.
3. Hematologic symptoms: Hemolytic anemia , hemolysis most often
occurs as a consequence of oxidative damage to the erythrocytes by the
higher copper concentration.
4. Renal symptoms: renal tubular damage, renal Fanconi syndrome
rarely presenting features.
 on examination:

1. liver manifestation : Ascites and prominent abdominal veins ,Spider

nevi , Palmar erythema Digital clubbing and Hematemesi Jaundice.
2. Neurologicl manifestation : Drooling ,Dysphagia , Dystonia,
Incoordination , Difficulty with fine motor tasks , Masklike facies and
Gait disturbance.
3. Ophthalmologic sign : Kayser-Fleischer rings: These are the most
important single clinical indication for the diagnosis and can be seen in
60 per cent of adults with Wilson 's disease (less frequently in children
but almost always with Wilson's neurological disease), often diagnosed
only by slit-lamp inspection. Kayser-Fleischer rings are distinguished by
a greenish-brown discolouration of the corneal margin that first occurs
at the upper periphery. Upon treatment, they eventually disappear.
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4. cardiac symptoms : such as rhythm abnormalities and increased
autonomic tone were identified.

differential diagnosis of Wilson disease

1. Hepatocellular adenoma
2. Cirrhosis
3. Multiple sclerosis
4. Huntington disease
5. Depression
6. Antisocial personality disorder
7. Parkinson disease
8. CNS vasculitis
9. Neurodegenerative disease
10. α1-antitrypsin deficiency
11. Chronic anemia
12. Hereditary hemochromatosis
13. Viral hepatitis
14. Glycogen-storage disease type

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Investigation

 Serum Ceruloplasmin: Approximately 90 per cent of all Wilson disease

patients have ceruloplasm levels below 20 mg / dL (reference range, 20-
40 mg / dL).
 Urine test for copper : The urinary copper excretion rate is greater than
100 mcg/d (reference range, < 40 mcg/d) in most patients with
symptomatic Wilson disease. treated with d-penicillamine (DPA) with
routine follow-up studies, 24-hour urinary copper excretion analysis 48
hours after interruption of chelating therapy was a reliable method to
confirm patient
 Liver biopsy : . A liver biopsy with sufficient tissue reveals levels of more
than 250 mcg/g of dry weight even in asymptomatic patients. that is
characterized by excessive deposition of copper in the liver, brain, and
other tissues.

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  Genetic Testing: Mutation analysis is a particularly valuable diagnostic
strategy for certain well-defined populations with a limited spectrum of
mutations with ATP7B.

 CT and MRI of the brain appears to be more sensitive than CT scanning in

detecting early lesions of Wilson disease. MRI studies have identified
focal abnormalities in the white matter, pons, and deep cerebellar nuclei.

Figure: Wilson's disease with neurological copper disorders.

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Treatment
 chelating agent : nhibitor of copper absorption from the GI tract.,
reatment for patients who present with neurologic or psychiatric
manifestations.

 Penicillamine (Cuprimine, Depen): 250 mg PO QID; dosage range

500-1500 mg/day Pregnancy: Not to exceed 500-750 mg/day , It was the
drug of choice before newer regimens were available.
 trientine dihydrochloride (1.2–2.4 g/day) and Zinc (50 mg 3 times
daily): are alternative to D-penicillamine.
 Pyridoxine (Aminoxin, Pyri-500): Pyridoxine is involved in synthesis
of GABA within the CNS.
 liver transplantation is curative treatment for Wilson disease.
 Diet : Patients should generally avoid eating foods with a high copper
content, such as liver, chocolate, nuts, mushrooms, legumes, and shellfish
(especially lobster).
 Pediatrists : any child with hepatic anomalies should find the Wilson
disease. The initial tests should be carried out, and if concern remains
high, more testing by a pediatric gastroenterologist may be needed.
 Treatment impairment Neurological :It is also important to
remember that when therapy is begun some patients may experience
worsening neurological symptoms. The chelating agent needs to be
stopped in some of these cases, and the patient should be operated on
zinc acetate alone. In long-term recovery patients who exhibit signs of
progressive neurological symptoms on chelating agents.

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