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Liver and intrahepatic bile ducts-nontumor

Metabolic diseases

Wilsonís disease


Reviewers: Komal Arora, M.D. (see Reviewers page)
Revised: 30 April 2012, last major update April 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
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● Also called hepatolenticular degeneration
● Autosomal recessive disorder affecting 1/30,000 people, causing accumulation of toxic levels of copper in tissues/organs, usually liver, brain, eye (Clin Gastroenterol Hepatol 2005;3:726)

Pathophysiology
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● Total body copper is 50-150 mg; 40% of ingested copper is normally absorbed in stomach and duodenum and transported to liver loosely bound to albumin
● Free copper dissociates and is transferred to hepatocytes, where it is incorporated into an alpha2 globulin to form ceruloplasmin, and resecreted into plasma
● 99% of plasma copper is bound to ceruloplasmin
● Senescent ceruloplasmin is endocytosed by the liver, degraded within lysosomes and excreted into bile, which is the primary route for copper elimination
● The gene for Wilsonís disease is ATP7B on #13q, which encodes a transmembrane copper-transporting ATPase located on the hepatocyte canalicular membrane, which assists with copper excretion into bile
● Most affected patients are compound heterozygotes with different mutations of ATP7B on each allele that cause defective biliary excretion of copper
● Copper accumulates within the liver, exceeding the capacity for ceruloplasmin binding and causing liver injury

Clinical features
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● By age 5 years, nonceruloplasmin-bound copper causes acute or chronic liver disease, hemolytic anemia, deposition in putamen with frank psychosis or Parkinsonian symptoms, deposition in cornea, kidneys, bones, joints, parathyroid gland; also increased urinary excretion of copper (which is normally minimal)
Diagnosis: serum ceruloplasmin < 20 mg/dl, increased liver copper using rhodamine stain, urinary copper excretion > 50 micrograms/24 hours
● Biochemical determination from liver biopsy (can use formalin-fixed tissue, > 250 micrograms/g dry weight)
● Serum copper levels are not helpful

Treatment
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● Long-term copper chelation therapy with D-penicillamine
● Liver transplantation

Micro description
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Liver - fatty change with vacuolated nucleus (due to glycogen or water), focal hepatocyte necrosis
● An acute or chronic hepatitis may be present and mimic acute or chronic viral hepatitis
● Chronic hepatitis may have Mallory bodies
● Cirrhosis develops late; usually no/minimal eosinophils or plasma cells
Note: copper deposition is focal and may not be present on needle biopsies
Fulminant hepatitis: liver collapse with abundant lipofuscin due to degraded membrane fragments; remaining liver shows low-grade disease with fibrosis
Brain - injury to putamen in basal ganglia
Eye - Kayser-Fleischer rings (green to brown deposits of copper in Descemetís membrane in limbus of cornea)

Micro images
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Liver histology - rhodamine staining for copper

Electron microscopy description
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● Microvesicular steatosis, glycogen nuclei, copper deposits, mitochondrial enlargement with increased matrical body size, increased matrix density, crystalline inclusions, swollen cristae that are separated due to flocculent material in cyst-like dilations

Differential diagnosis
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● Copper accumulation also present in primary biliary cirrhosis, other cholestatic states

Additional references
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Dig Liver Dis 2007;39:601, Semin Liver Dis 2011;31:245

End of Liver and intrahepatic bile ducts-nontumor > Metabolic diseases > Wilsonís disease


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