wilsons disease

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WILSON’S DISEASE:

WILSON’S DISEASE Presented By: Amin Younis Sajid Rehman Medical University of Lodz

Wilson’s Disease:

Wilson’s Disease Progressive lenticular degeneration, a familial nervous disase associated with cirrhosis of the liver. SAK Wilson Thesis, Univ. of Edinburgh, 1911

Wilson’s Disease:

Wilson’s Disease Wilson disease is a disorder of copper transport resulting in copper deposition in multiple organs Clinical manifestations may be severe, but the disease is treatable if diagnosed early

Epidemology :

Epidemology Occurs worldwide Incidence of one in 30,000 The age at onset of symptoms ranges from 6 to about 40 years .

Copper Physiology:

Copper Physiology Most abundant in unprocessed wheat, dried beans, peas, shellfish, chocolate, liver, kidney Impair copper absorption Zinc, cadmium, ascorbic acid Vegetarian diet Aid copper absorption Gastrointestinal secretions Absorbed copper is bound to the protein metallothionein or complexed to amino acids and transported into portal system

Copper Metabolism:

Copper Metabolism

Copper Metabolism:

Copper Metabolism Copper is transported into hepatocytes by the human copper transporter (hCTR) In hepatocyte, copper interacts with the ligands metallothionein, glutathione and HAH1 Bind and detoxify excess copper Transfer or store copper Provide copper to chaperones Chaperones incorporate copper into essential proteins or assist in copper excretion into bile CCS COX17 ATOX/HAH1

ATP7B:

ATP7B Makes copper available for ceruloplasmin synthesis and transport of copper into vesicles ATP7B defects involve transport of copper into the vesicular pathway from Golgi apparatus to the canaliculus

ATP7B:

ATP7B >200 mutations identified Most small deletions or missense mutations Missense: neurologic and later presentation Deletions: hepatic and earlier presentation Highly expressed in liver and kidney

WD - Pathophysiology:

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

Clinical Presentation:

Clinical Presentation Age Hepatic symptoms Neuropsychiatric symptoms < 10 years 83% 17% 10-18 years 52% 48% > 18 years 24% 74% Combined date from Walshe and Scheinberg & Sternleib

Hepatic:

Hepatic Acute hepatitis 25% Fulminant hepatic failure Liver transplant May also present after discontinuing copper chelation Chronic active hepatitis 10-30% Absence of other symptoms in Wilson’s patients should prompt biochemical screening in those <40 years Cirrhosis Absence of other symptoms in Wilson’s patients should prompt evaluation >4 years

Laboratory:

Laboratory Mildly elevated serum aminotransferase levels Low alkaline phosphatase Serum alkaline phosphatase to total bilirubin ratio ratio < 2

Neuropsychiatric:

Neuropsychiatric 40-45% as presentation Most common 2 nd to 3 rd decades of life Extrapyramidal and cerebrellar dysfunction Migraine headaches Seizures Denning et al found 13 of 200 patients with Wilson’s disease had seizures Prevalence rate 6.2%, exceeding epilepsy frequency by tenfold Gait disturbances secondary to tremor and dystonia

Imaging:

Imaging CT abnormalities 73% ventricular dilation 63% cortical atrophy 55% brainstem atrophy 45% hypodensity in basal ganglia 10% posterior fossa atrophy Williams and Walshe

Kayser-Fleischer Ring:

Kayser-Fleischer Ring Superior poles of cornea, then inferior involvement Copper chelators result in resolution over 3-5 years Occurs after hepatic saturation of copper Virtually always present when neurological or psychiatric symptoms develop Frequently absent in children without neurolgic involvement but with hepatic symptoms False positive: hepatitis, cholestasis, primary biliary cirrhosis, TPN

Sunflower Cataract:

Sunflower Cataract Copper deposition in anterior and posterior lens capsule False positive with foreign body lodged intraocularly (chalcosis)

Other:

Other Renal Proximal renal tubular dysfunction (Fanconi’s syndrome) Renal insufficiency Nephrocalcinosis Hematologic Coombs negative hemolytic anemia Cardiac Autonomic dysfunction Cardiomyopathy Skeletal Bone demineralization Dermatologic Acanthosis nigrans

 Biochemical Parameters :

  Biochemical Parameters

Treatment Goals:

Treatment Goals Reduce copper accumulation by Enhancing urinary excretion Decreasing intestinal absorption

Therapy:

Therapy Oral Chelating Agents D- Penicillamine Trientine Ammonium tetrathiomolybdate Many side effects Fewer side effects Experimental Zinc acetate Inhibits Cu absorption Stimulates hepatic metallothionein Vitamin E Antioxidant Interferes in Vitamin K- dependent clotting factors Additional Recommendations Low Cu diet Antioxidants

Drug Choice:

Drug Choice

Liver Transplant:

Liver Transplant Life-saving Acute fulminant hepatic failure Decompensated cirrhosis with progressive end stage liver disease

Thank You:

Thank You

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