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)
- case with action tremor > resting tremor
- most prominent when arms held in a wing position[3]
- rigidity
- bradykinesia
- micrographia
- sialorrhea
- masked facies
- tremor (may present as tremor)
- confusion, disorientation[3]
- altered speech
- personality changes
- dystonia
- diffuculty chewing food
- speech interrupted by involuntary jaw closure[3]
- ataxia variable
- 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
- ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 Medical Knowledge Self Assessment Program (MKSAP) 11, 15, 16, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2009, 2012, 2015, 2018, 2021.
Medical Knowledge Self Assessment Program (MKSAP) 20 American College of Physicians, Philadelphia 2025 - ↑ 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://pubmed.ncbi.nlm.nih.gov/15560044
- ↑ Valentina Medici. Wilson's disease Medical Grand Rounds, UC Davis, 4/19/07
- ↑ 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://pubmed.ncbi.nlm.nih.gov/17433323
- ↑ 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://pubmed.ncbi.nlm.nih.gov/20146697
- ↑ Eapen CE, Kumar S, Fleming JJ et al Copper and liver disease. Gut. 2012 Jan;61(1):63. PMID: https://pubmed.ncbi.nlm.nih.gov/22139599
- ↑ 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://pubmed.ncbi.nlm.nih.gov/27509123 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMimc1512611
- ↑ 11.0 11.1 11.2 NEJM Knowledge+
- ↑ Mulligan C, Bronstein JM. Wilson disease: an overview and approach to management. Neurol Clin. 2020;38:417-432. PMID: https://pubmed.ncbi.nlm.nih.gov/32279718
- ↑ 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