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hepatolenticular degeneration; Wilson's disease

A disease characterized by cirrhosis, degeneration of the basal ganglia & deposition of green pigment in the periphery of the cornea. Etiology: - due to mutation in the ATP7B gene. Epidemiology: 1) rare: affect in 30,000 newborns [3] 2) typically presents in 2nd or 3rd decade of life 3) 4% present > 40 years of age [6] Pathology: 1) aberrant expression of proteins a) ceruloplasmin is diminished b) defect in copper transporting ATPase-2 is seen - copper cannot be incorporated into ceruloplasmin in liver c) cytochrome oxidase is reduced 2) increased copper content of the liver, brain, & kidneys 3) sudden release of copper from hepatocytes can result in hemolytic anemia 4) splenomegaly may result from hemolytic anemia 5) decreased biliary excretion of copper [3] 6) hepatic cirrhosis 7) degeneration of the basal ganglia 8) deposition of green pigment in the periphery of the cornea Genetics: 1) autosomal recessive 2) mutations in the ATP7B (ATPase, Cu++ transporting, beta polypeptide) gene Clinical manifestations: 1) neurologic manifestations a) parkinsonism is most common neurologic presentation [3] 1] tremor (may present as tremor) 2] rigidity 3] bradykinesia 4] micrographia 5] sialorrhea 6] masked facies b) confusion, disorientation [3] c) altered speech d) personality changes e) dystonia f) ataxia g) case presentaton with no mention of neurologic manifestations [10] 2) Kayser-Fleischer ring* 3) Fanconi's syndrome (acute kidney injury) [3] 4) hepatic manifestations a) hepatomegaly b) cirrhosis c) acute liver failure [3] d) esophageal varices e) hepatic coma f) chronic right upper quadrant pain [10] - nausea/vomiting [10] - positive Murphy's sign [10] 5) melena [11] 6) Coombs-negative hemolytic anemia: anemia, reticulocytosis [3] - hematocrit may be normal [10] 7) splenomegaly from hemolytic anemia * case presentation without mention of eye findings [3] Laboratory: 1) low serum copper 2) low serum ceruloplasmin a) may be increased by estrogen, biliary obstruction b) may be decreased by liver failure 3) serum bilirubin: hyperbilirubinemia (unconjugated) - modest elevation 4) normal or low serum alkaline phosphatase - excess hepatic copper competitively inhibits zinc, a cofactor in hepatic alkaline phosphatase 5) serum aminotransferases may be moderately elevated (> 1000 IU/L) - serum AST/serum ALT ratio > 2 6) INR may be very elevated; case of INR=3.9 [11] 5) complete blood count may show anemia [3] 6) reticulocyte count may show reticulocytosis [3] 7) increased 24 hour urine copper - useful for diagnosis & assessment of therapy 8) liver biopsy: high concentration of copper also seen with cholestatic syndromes 9) ATP7B gene mutation 10) TIBC may be low, iron saturation may be high [10] 11) see ARUP consult [7] Special laboratory: - abdominal ultrasound may show splenomegaly with small liver [3] - ophthalmic slit-lamp examination for Kayser-Fleischer ring Differential diagnosis: - Menke's disease Management: 1) trientine or penicillamine (copper chelators) dimercaprol has been used tetrathiomolybdate is investigational 2) zinc supplementation 3) liver transplantation corrects the metabolic defect - indicated in severe or advanced cases [4] 4) prognosis - copper chelation therapy results in symptomatic improvement & normal life-expectancy [4]

Related

chromosomal aberration copper transporting ATPase-2; Cu+2-transporting ATPase beta polypeptide; copper pump-2; WIlson's disease-associated protein (ATP7B, PWD, WC1, WND) Kayser-Fleischer ring Menkes disease (kinky or steely hair disease) penicillamine (Cuprimine, Depen) trientine (Cuprid, Tecza, Syprine)

General

basal ganglia disease genetic disease of the liver inborn error of copper metabolism metabolic brain disease neurodegenerative disease

Database Correlations

OMIM correlations MORBIDMAP 606882

References

  1. Stedman's Medical Dictionary 24th ed, Williams & Wilkins, Baltimore, 1982
  2. Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 322-23
  3. Medical Knowledge Self Assessment Program (MKSAP) 11, 15, 16, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2009, 2012, 2015, 2018, 2021.
  4. Ferenci P. Wilson's disease. Clin Liver Dis. 1998 Feb;2(1):31-49, v-vi. Review. PMID: 15560044
  5. Valentina Medici. Wilson's disease Medical Grand Rounds, UC Davis, 4/19/07
  6. Ferenci P, Czlonkowska A, Merle U, Ferenc S, Gromadzka G, Yurdaydin C, Vogel W, Bruha R, Schmidt HT, Stremmel W. Late-onset Wilson's disease. Gastroenterology. 2007 Apr;132(4):1294-8. Epub 2007 Feb 25. PMID: 17433323
  7. ARUP Consult: Wilson Disease The Physician's Guide to Laboratory Test Selection & Interpretation https://arupconsult.com/content/wilson-disease - Wilson Disease Testing Algorithm https://arupconsult.com/algorithm/wilson-disease-testing-algorithm - ARUP Consult: Wilson Disease (ATP7B) Sequencing https://arupconsult.com/ati/wilson-disease-atp7b-sequencing
  8. Lorincz MT. Neurologic Wilson's disease. Ann N Y Acad Sci. 2010 Jan;1184:173-87 PMID: 20146697
  9. Eapen CE, Kumar S, Fleming JJ et al Copper and liver disease. Gut. 2012 Jan;61(1):63. PMID: 22139599
  10. Nayor J, Vaidya A, Srivastava A, Seifter JL, Rutherford AE. INTERACTIVE MEDICAL CASE. Tracing the Cause of Abdominal Pain. N Engl J Med 2016; 375:e8. August 11, 2016 PMID: 27509123 http://www.nejm.org/doi/full/10.1056/NEJMimc1512611
  11. NEJM Knowledge+
  12. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Wilson Disease https://www.niddk.nih.gov/health-information/liver-disease/wilson-disease - NINDS Wilson's Disease Information Page https://www.ninds.nih.gov/Disorders/All-Disorders/Wilson-Disease-Information-Page