wilson s disease

8/13/2019 Wilson s Disease

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Medical GeneticsAutosomal Recessive

DisorderWILSONS DISEASE/HEPATOLENTICULAR

DEGENERATION


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Plan Of Presentation

Overview of the Disease

-Background

-Etiology

-Epidemiology

-Prognosis

Clinical Presentations

Workup Of the Disease

Treatment And Management


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Background of the disease

Wilson disease is a rare autosomal recessive inherited disorder of copper m

The condition is characterized by excessive deposition of copper in the livother tissues. The major physiologic aberration is excessive absorption of csmall intestine and decreased excretion of copper by the liver.

The genetic defect, localized to arm 13q, has been shown to affect the cotransporting adenosine triphosphatase (ATPase) gene (ATP7B) in the liver.


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Copper metabolism in Wilson s dis


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Etiology of disease

The normal estimated total body copper content is 50-100 mg, and the avintake 2-5 mg, depending on an individuals food intake.

Impairment of incorporation of copper into ceruloplasmin and excretion ointo bile. (defective copper-transporting P-type ATPase. )

mutations in the ATP7B gene


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Epidemiology

In the United States, the carrier frequency is 1 per 90 individuals. The prevWilson disease is 1 per 30,000 individuals.

The fulminant presentation of Wilson disease is more common in females males.

Age-related presentations

-In general, the upper age limit for considering Wilson Disease is 40 years and

age limit is 5 years, although the disorder has been detected in children youyears and in adults older than 70 years.


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Prognosis

Score 0 1 2 3 4

Serum bilirubin(referencerange, 3-20mmol/L)

< 100 100-150 151-200 201-300 >300

Serumaspartatetransaminase(referencerange, 7-40IU/L)

< 100 100-150 151-200 201-300 >300

Prothrombintimeprolongation(seconds)

< 4 4-8 9-12 13-20 >30

Table. Prognostic Index in Fulminant Wilsonian Hepatitis

Patients with a prognostic index (ie, score) of 7 or greater should be considered for livtransplantation. All patients in the study associated with this prognostic index who excdied within 2 months of diagnosis, irrespective of the institution of appropriate medica


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Prognosis after liver transplantation is relatively good.

In a study involving 55 patients with Wilson disease who underwent hepatransplantation, the 1-year survival rate was 79% and the overall survival at 3 months to 20 years.


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Complications

The major complications in patients with untreated Wilson disease are thwith acute liver failure, chronic hepatic dysfunction with either portal hyphepatocellular carcinoma.

sometimes-relentless course to cirrhosis, which is characterized by a proglassitude, fatigue, anorexia, jaundice, spider angiomas, splenomegaly, a

Bleeding from varices, hepatic encephalopathy, hepatorenal syndromecoagulation abnormalities occur as liver failure ensues.


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Staging

The natural history of Wilson disease may be considered in 4 stages, as follow

Stage I - The initial period of accumulation of copper within hepatic bind

Stage II - The acute redistribution of copper within the liver and its releasecirculation

Stage III - The chronic accumulation of copper in the brain and other exttissue, with progressive and eventually fatal disease

Stage IV - Restoration of copper balance by the use of long-term chelati


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Clinical Presentations

Physical Examinations

Hepatic dysfunction is the presenting feature in more than half of patients. Thpatterns of hepatic involvement are as follows: (1) chronic active hepatitis, (2(3) fulminant hepatic failure.

1. Neuropsychiatric symptoms

Asymmetrical tremor

Frequent early symptoms(difficulty speaking, excessive salivation, ataxia, m

clumsiness with the hands, and personality changes.)

Late manifestations (dystonia, spasticity, grand mal seizures, rigidity, and flecontractures.)


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2. Musculoskeletal symptoms

arthropathy generally involves the spine and large appendicular joints, sucwrists, and hips.

Osteochondritis dissecans Chondromalacia patellae

Chondrocalcinosis


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3. Hematologic symptoms

Hemolytic anemia

Coombs-negative acute intravascular hemolysis (oxidative damage to thby the higher copper concentration.)

4. Renal symptoms

Any renal manifestations may be primary or secondary to release of copper

defective renal acidification and excess renal losses of amino acids, glucgalactose, pentose, uric acid, phosphate, and calcium.

Urolithiasis

Hematuria

Nephrocalcinosis


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Hepatic symptoms

Hepatic insufficiency and cirrhosis may

slowly develop and can result in signs of

fulminant hepatic failure, including thefollowing:

Ascites and prominent abdominal veins

Spider nevi

Palmar erythema

Digital clubbing

Hematemesis

Jaundice


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Neurologic symptoms

Central nervous system (CNS) pathology in

patients with Wilson disease results from

copper deposition in the basal ganglia. Theresulting signs include the following:

Drooling

Dysphagia

Dystonia

IncoordinationDifficulty with fine motor tasks

Masklike facies

Gait disturbance


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Ophthalmologic symptoms

-Kayser-Fleischer rings are formed by the

deposition of copper in the Descemet

membrane in the limbus of the cornea. The

color may range from greenish gold to brown.

-almost invariably present in those withneurologic manifestations.

-Kayser-Fleischer rings consist of electron-

dense granules rich in copper and sulfur. The

rings form bilaterally, initially appearing at thesuperior pole of the cornea, then the inferior

pole, and, ultimately, circumferentially.


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Additional symptoms

Osteoporosis

Osteomalacia

Rickets

Spontaneous fractures

Polyarthritis

Cardiac arrhythmia

Skin pigmentation

Bluish discoloration at the base of the fingernails (azure lunulae)


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Diagnostic Considerations

-Conditions to consider in the differential diagnosis of Wilson disease might include the following

Autoimmune chronic active hepatitis

Aceruloplasminemia

Glycogen-storage disease Cirrhosis

Multiple sclerosis

Huntington disease

Depression

Antisocial personality disorder

Parkinson disease

Leukodystrophy

CNS vasculitis

Neurodegenerative disease

1-antitrypsin deficiency

Chronic anemia

Hereditary hemochromatosis

Workup and Diagnosis


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Workup and Diagnosis

1. Genetic diagnosis

Linkage analysis has been used in family studies for presymptomatic testingthe multiplicity of mutations (>200 mutations of ATP7Bhave been identified

2. Computed tomography (CT) scanning, magnetic resonance imaging (MRI)ultrasonography

3. Electrocardiography

Resting electrocardiographic abnormalities include left ventricular or bivenhypertrophy, early repolarization, ST segment depression, T-wave inversion,arrhythmias.


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4. Serum Ceruloplasmin

Approximately 90% of all patients with Wilson disease have ceruloplasmin than 20 mg/dL (reference range, 20-40 mg/dL).

5. Urinary copper excretion

The urinary copper excretion rate is greater than 100 mcg/d (reference rangmcg/d) in most patients with symptomatic Wilson disease.

6. Hepatic copper concentration

A liver biopsy with sufficient tissue reveals levels of more than 250 mcg/g.

(reference range, 15-55 mcg/g)


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7. Radiolabeled Copper

Radiolabeled copper testing directly assays hepatic copper metabolism. Blo1, 2, 4, 24, and 48 hours after oral ingestion of radiolabeled copper (64Cu or67

radioactivity in serum.

8. Cranial CT Scanning

The cranial lesions observed on CT scans are typically bilaterainto 2 general categories:

(1) well-defined, slitlike, low-attenuation foci involving the basparticularly the putamen

(2) (2) larger regions of low attenuation in the basal ganglia, tdentate nucleus.

9 B i MRI


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9. Brain MRI

10. PET Scanning

-reveals a significantly reduced regional cerebral metabolic rate of glucose the cerebellum, striatum, and, to a lesser extent, in the cortex and thalamus.

11. Electron Microscopy

12. Histological Findings

Treatment and Management


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Treatment and Management

The mainstay of therapy for Wilson disease is pharmacologic treatment wagents.

The use of surgical decompression or transjugular intrahepatic shunting (T

treatment of portal hypertension is reserved for individuals with recurrent ovariceal bleeding that is unresponsive to standard conservative measures

Orthotopic liver transplantation

Diet

-avoid eating foods with a high copper content, such as liver, chocolate, nulegumes, and shellfish (especially lobster).


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Long-Term Monitoring

-Perform a physical examination, 24-hour urinary copper excretion assay, cblood count (CBC), urinalysis, serum free copper measurement, and renal function tests on a weekly basis for the first 4-6 weeks following initiation of

therapy.

Molecular Adsorbents Recirculating System (MARS)

- MARS is an extracorporeal liver support system using a hollow-fiber dialysis

which the patients blood is dialyzed across an albumin-impregnated memmaintaining a constant flow of albumin-rich (20%) dialysate in the extracapcompartment


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M di ti


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Medications

1) Chelators

Penicillamine (Cuprimine, Depen)- administered with pyridoxine 25 mg by mouth daily.

Trientine (Syprine)

2) Nutrients

Zinc (Galzin)Pyridoxine (Aminoxin, Pyri-500)
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The End

wilson s disease

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