Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + Download Section PDF Listen ++ For further information, see CMDT Part 16-14: Wilson Disease + Key Features Download Section PDF Listen +++ +++ Essentials of Diagnosis ++ Rare autosomal recessive disorder that usually manifests in persons between 3 and 55 years old Excessive deposition of copper in the liver and brain Serum ceruloplasmin, the plasma copper-carrying protein, is low Urinary excretion and hepatic concentration of copper are high +++ General Considerations ++ A genetic defect, localized to chromosome 13, affects a copper-transporting adenosine triphosphatase (ATP7B) in the liver and leads to oxidative damage of hepatic mitochondria Over 600 different mutations in the Wilson disease gene have been identified The major physiologic aberration is excessive absorption of copper from the small intestine and decreased excretion of copper by the liver, resulting in increased tissue deposition, especially in the liver, brain, cornea, and kidney +++ Demographics ++ Tends to present as liver disease in adolescents (more common in females) and neuropsychiatric disease in young adults (more common in males), but there is great variability Onset of symptoms after age 40 is more common than previously thought + Clinical Findings Download Section PDF Listen +++ +++ Symptoms and Signs ++ Consider the diagnosis in any child or young adult with the following Hepatitis, splenomegaly with hypersplenism, portal hypertension Coombs-negative hemolytic anemia Neurologic or psychiatric abnormalities Chronic hepatitis Acute liver failure Hepatic involvement may range from elevated liver tests (although the alkaline phosphatase may be low) to fulminant hepatitis, cirrhosis and portal hypertension Neurologic manifestations Dysarthria, dysphagia, incoordination, and spasticity Migraines, insomnia, and seizures Related to basal ganglia dysfunction Psychiatric features include behavioral and personality changes and emotional lability Corneal Kayser-Fleischer ring Pathognomonic sign Brownish or gray-green pigmented granular deposits in Descemet membrane in the cornea close to the endothelial surface Usually most marked at the superior and inferior poles of the cornea Sometimes seen with the naked eye; readily detected by slit-lamp examination It may be absent in patients with hepatic manifestations only but is usually present in those with neuropsychiatric disease Other manifestations Renal calculi Aminoaciduria Renal tubular acidosis Hypoparathyroidism Infertility Hemolytic anemia Subcutaneous lipomas +++ Differential Diagnosis ++ Acute hepatitis Cholestasis Acute liver failure Chronic hepatitis Cirrhosis Hepatomegaly Other cause of liver disease, eg, viral infections, toxins, hemochromatosis Tremor due to other causes, eg, Parkinson disease, essential tremor Dementia due to other causes, eg, Huntington disease Behavior change due to other medical illness, eg, neurosyphilis, brain tumor + Diagnosis Download Section PDF Listen +++ +++ Laboratory Tests ++ Increased urinary copper excretion (> 40 mcg/24 h and usually > 100 mcg/24 h); low serum ceruloplasmin levels (< 14 mg/dL [140 mg/L] and usually < 10 mg/dL [100 50 mg/L]); and elevated hepatic copper concentration (>250 mcg/g of dry liver) strongly suggests the diagnosis However, increased urinary copper (on 3 separate 24-hour collections) and low serum ceruloplasmin levels are useful but not completely sensitive or specific for Wilson disease; an enzymatic assay for ceruloplasmin appears to be more accurate; lipemia can interfere with the measurement of ceruloplasmin In equivocal cases (eg, when the serum ceruloplasmin level is normal), demonstration of a rise in urinary copper after a penicillamine challenge was used in the past, although the test has been validated only in children, lacks sensitivity, and is rarely used +++ Imaging Studies ++ MRI of the brain may show evidence of increased basal ganglia, brainstem, and cerebellar copper even early in the course of the disease +++ Diagnostic Procedures ++ Liver biopsy may show acute or chronic hepatitis or cirrhosis If available, molecular analysis of ATP7B mutations can be diagnostic + Treatment Download Section PDF Listen +++ ++ Initially, restriction of dietary copper (shellfish, organ foods, nuts, mushrooms, and chocolate) may be of value +++ Medications ++ Oral D-penicillamine (0.75–2.0 g/day in divided doses) Drug of choice Enhances urinary excretion of chelated copper Add pyridoxine, 50 mg/wk, since penicillamine is an antimetabolite of this vitamin Oral trientine, 250–500 mg three times a day Consider if penicillamine treatment cannot be tolerated because of Gastrointestinal, hypersensitivity, or autoimmune reactions Nephrotoxicity Bone marrow toxicity Increasingly used as first-line therapy However, cost is exorbitant Oral zinc acetate, 50 mg three times a day Interferes with intestinal absorption of copper Promotes fecal copper excretion Has been used as first-line therapy in asymptomatic or pregnant patients Has been used as maintenance therapy after decoppering with a chelating agent However, adverse gastrointestinal effects often lead to discontinuation Also, its long-term efficacy and safety (including a risk of hepatotoxicity) have been questioned Ammonium tetrathiomolybdate, which complexes copper in the intestinal tract, showed promise as initial therapy for neurologic Wilson disease, and a newer formulation, bis-choline tetrathiomolybdate, is more chemically stable and appears to be effective Treatment should continue indefinitely Once the serum nonceruloplasmin copper level is within the normal range (50–150 mcg/L), the dose of chelating agent can be reduced to the minimum necessary for maintaining that level +++ Surgery ++ Indications for liver transplantation Acute liver failure (often after plasma exchange as a stabilizing measure) Decompensated cirrhosis Liver transplantation is not generally recommended for intractable neurologic disease Survival is lower when transplantation is undertaken for neurologic disease than for liver disease +++ Therapeutic Procedures ++ Early chelation to remove excess copper is essential before it can produce hepatic or neurologic damage + Outcome Download Section PDF Listen +++ +++ Follow-Up ++ Serum nonceruloplasmin copper 24-hour urinary copper excretion +++ Prognosis ++ The prognosis is good if effective treatment occurs before liver or brain damage, but long-term survival is reduced in patients with cirrhosis at diagnosis (84% after 20 years) The disease may stabilize with treatment even in those with cirrhosis +++ Prevention ++ All first-degree relatives, especially siblings, require screening with serum ceruloplasmin, liver chemistry tests, and slit-lamp examination +++ When to Refer ++ All patients should be referred for diagnosis and treatment +++ When to Admit ++ Acute liver failure Gastrointestinal bleeding Stage 3–4 hepatic encephalopathy Worsening kidney function Severe hyponatremia Profound hypoxia + References Download Section PDF Listen +++ + +Ferenci P et al. Age and sex but not ATP7B genotype effectively influence the clinical phenotype of Wilson disease. Hepatology. 2019 Apr;69(4):1464–76. [PubMed: 30232804] + +Martínez-Morillo E et al. Pancytopenia and peripheral neuropathy in a woman with altered liver function tests. Clin Chem. 2019 Aug;65(8):956–60. [PubMed: 31358500] + +Pfeiffenberger J et al. Pregnancy in Wilson's disease: management and outcome. Hepatology. 2018 Apr;67(4):1261–9. [PubMed: 28859232] + +Poujois A et al. Answer to challenging issues in the management of Wilson's disease. Res Hepatol Gastroenterol. 2019 Feb;43(1):e7–8. [PubMed: 30166252] + +Schilsky ML. Wilson disease: diagnosis, treatment, and follow-up. Clin Liver Dis. 2017 Nov;21(4):755–67. [PubMed: 28987261] + +Shribman S et al. Clinical presentations of Wilson disease. Ann Transl Med. 2019 Apr;7(Suppl 2):S60. [PubMed: 31179297]