hepatolenticular degeneration; Wilson's disease
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Introduction
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
- rare: affect in 30,000 newborns[3]
- typically presents in 2nd or 3rd decade of life
- 4% present > 40 years of age[6]
Pathology
- aberrant expression of proteins
- ceruloplasmin is diminished
- defect in copper transporting ATPase-2 is seen
- copper cannot be incorporated into ceruloplasmin in liver
- cytochrome oxidase is reduced
- increased copper content of the liver, brain, & kidneys
- sudden release of copper from hepatocytes can result in hemolytic anemia
- splenomegaly may result from hemolytic anemia
- decreased biliary excretion of copper[3]
- hepatic cirrhosis
- degeneration of the basal ganglia
- deposition of green pigment in the periphery of the cornea
Genetics
- autosomal recessive
- mutations in the ATP7B (ATPase, Cu++ transporting, beta polypeptide) gene
Clinical manifestations
- neurologic manifestations
- parkinsonism is most common neurologic presentation[3]
- tremor (may present as tremor)
- rigidity
- bradykinesia
- micrographia
- sialorrhea
- masked facies
- confusion, disorientation[3]
- altered speech
- personality changes
- dystonia
- ataxia
- case presentaton with no mention of neurologic manifestations[10]
- parkinsonism is most common neurologic presentation[3]
- Kayser-Fleischer ring*
- Fanconi's syndrome (acute kidney injury)[3]
- hepatic manifestations
- melena[11]
- Coombs-negative hemolytic anemia: anemia, reticulocytosis[3]
- hematocrit may be normal[10]
- splenomegaly from hemolytic anemia
* case presentation without mention of eye findings[3]
Laboratory
- low serum copper
- low serum ceruloplasmin
- may be increased by estrogen, biliary obstruction
- may be decreased by liver failure
- serum bilirubin: hyperbilirubinemia (unconjugated)
- modest elevation
- normal or low serum alkaline phosphatase
- excess hepatic copper competitively inhibits zinc, a cofactor in hepatic alkaline phosphatase
- serum aminotransferases may be moderately elevated (> 1000 IU/L)
- INR may be very elevated; case of INR=3.9[11]
- complete blood count may show anemia[3]
- reticulocyte count may show reticulocytosis[3]
- increased 24 hour urine copper
- useful for diagnosis & assessment of therapy
- liver biopsy: high concentration of copper also seen with cholestatic syndromes
- ATP7B gene mutation
- TIBC may be low, iron saturation may be high[10]
- see ARUP consult[7]
Diagnostic procedures
- abdominal ultrasound may show splenomegaly with small liver[3]
- ophthalmic slit-lamp examination for Kayser-Fleischer ring
Differential diagnosis
Management
- trientine or penicillamine (copper chelators) dimercaprol has been used tetrathiomolybdate is investigational
- zinc supplementation
- liver transplantation corrects the metabolic defect
- indicated in severe or advanced cases[4]
- prognosis
- copper chelation therapy results in symptomatic improvement & normal life-expectancy[4]
More general terms
- genetic disease of the liver
- basal ganglia disease
- metabolic brain disease
- inborn error of copper metabolism
- neurodegenerative disease
Additional terms
- 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)
References
- ↑ Stedman's Medical Dictionary 24th ed, Williams & Wilkins, Baltimore, 1982
- ↑ Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 322-23
- ↑ Jump up to: 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 Medical Knowledge Self Assessment Program (MKSAP) 11, 15, 16, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2009, 2012, 2015, 2018, 2021.
- ↑ Jump up to: 4.0 4.1 4.2 Ferenci P. Wilson's disease. Clin Liver Dis. 1998 Feb;2(1):31-49, v-vi. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/15560044
- ↑ Valentina Medici. Wilson's disease Medical Grand Rounds, UC Davis, 4/19/07
- ↑ Jump up to: 6.0 6.1 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: https://www.ncbi.nlm.nih.gov/pubmed/17433323
- ↑ Jump up to: 7.0 7.1 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 - ↑ Lorincz MT. Neurologic Wilson's disease. Ann N Y Acad Sci. 2010 Jan;1184:173-87 PMID: https://www.ncbi.nlm.nih.gov/pubmed/20146697
- ↑ Eapen CE, Kumar S, Fleming JJ et al Copper and liver disease. Gut. 2012 Jan;61(1):63. PMID: https://www.ncbi.nlm.nih.gov/pubmed/22139599
- ↑ Jump up to: 10.0 10.1 10.2 10.3 10.4 10.5 10.6 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 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/27509123 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMimc1512611
- ↑ Jump up to: 11.0 11.1 11.2 NEJM Knowledge+
- ↑ 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
Patient information
hepatolenticular degeneration or Wilson's disease patient information