Genetic disorder of biliary copper excretion.
Autosomal recessive pattern of transmission.
Characterized by cirrhosis of the liver, bilateral softening of the lenticular nucleus, involuntary movements, spasticity, dysphagia, and psychiatric symptoms.
An important cause of dystonia and parkinsonism.
A disorder of copper excretion with myriad hepatic and neuropsychiatric manifestations.
Caused by mutation of the ATPase copper transporting beta gene ATP7B on the long arm of chromosome 13, which codes for a protein responsible for incorporating excess copper into ceruloplasmin in order for it to be excreted from the body.
In Wilson’s disease, functional ATP 7B is decreased or absent, and excessive copper accumulates in hepatocytes.
Serum copper levels are low, because of decreased holo-ceruloplasmin levels, as copper induced liver injury progresses, extrahepatic sites, especially the CNS are affected.
Initially the cumulative copper is distributed throughout the cytoplasm after binding with metallothionein.
As the disease progresses the capacity of metallothionein to bind copper is exceeded, leading to liver injury and release of copper into the blood.
Copper accumulates in several organs, particularly the liver, brain, corneas, and more than 600 pathologic variants of ATP7B exist, with progression to hepatic and neurologic dysfunction
Affects between one in 30,000 and one in 100,000 people.
Characterized by ineffective hepatic copper metabolism.
Caused by inactivating mutations in the ATP7B gene, whiich encodes a copper-transporting adenosine triphosphatase.
Deficiency of this protein manifests in impaired excretion of copper into bile and reduced incorporation of copper into precursors of ceruloplasmin, the main copper carrying protein in the circulation.
As copper accumulates in liver cells, it is released into the plasma and deposited in other organs such as the brain, eyes, kidneys, and skin.
Liver manifestations range from asymptomatic biochemical abnormalities to acute or chronic hepatitis and cirrhosis.
Most patients present with symptoms in the second and third decades of life.
WD can manifest at any age, although usually before the age of 50 years.
It can present as liver disease, a neurologic disorder, a psychiatric illness, or a combination of these disorders.
Hepatic Wilson’s disease tends to develop earlier than neuropsychiatric Wilson’s disease, and ranges from mild liver disease to cirrhosis.
In children fatty liver is common.
Infrequently WD manifests as acute liver failure.
Neurologic movement disorders with increased movement, trimmer, dystonia, or decreased movement, resembling, Perkinson rigidity can be seen.
Tremors, poor coordination, and loss of fine motor control may occur early.
Dysarthria is often the first prominent symptom.
Drooling, difficulty swallowing, sleep disorders and restless leg syndrome, clumsiness, loss of athletic skills, deterioration in school performance are increasingly recognized.
Clumsiness, loss of athletic skills, deterioration in school performance may be initial findings in adolescence.
Cognitive function is intact, although differences in executive abilities and integrative capacities may occur.
Patients may experience, bipolar disorder and psychosis, and anxiety, compulsive behaviors and aggressive or antisocial behavior may occur.
Kayser-Fleisher rings are the main ophthalmologic sign.
Patients may have renal, cardiac, musculoskeletal, and endocrine abnormalities.
Wilson’s disease can manifest at any age, although usually for the age of 50 years.
Patients may manifest renal, cardiac, musculoskeletal, and endocrine abnormalities.
Clinical onset usually between 5 and 25 years but should be considered up to the age of 40 years.
Initial screening test is measurement of serum ceruloplasmin.
Clinical diagnosis involves history and physical exam with liver, neurologic and psychiatric disease evaluation.
Laboratory assessments include serum ceruloplasmin levels, and basal 24 hour urinary excretion of copper.
Serum ceruloplasmin level of less than 20 mg/dL, and 24 hour urine copper level of greater than 40 µg help in the diagnosis.
The cerulpplasmin level can be normal in Wilson’s disease,although that is uncommon.
Basal 24 hour urinary cop per expression is typically more than 40 µg with higher values in symptomatic patients.
Patients had decreased production of ceruloplasmin, a major copper transport protein as well as poor biliary copper excretion with accumulation of copper in the liver and extrahepatic organs and causes systemic toxicity.
Kaise-Fleischer rings are due to copper deposition in the corneal Descement’s membrane, which can be visualized by slit-lamp examination, or optical tomography.
Kaiser-Fleisher rings are often absent in younger patients and are also absent in 50% of patients with hepatic Wilson’s disease.
Liver biopsy and copper quantification establishes degree of liver damage.
Metallothionein immunohistochemical staining may be positive and hepatic parenchymal copper level is classically more than 250 µg per gram of dry weight.
In many patients with Wilson’s disease, that manifest with neurologic findings, brain MRI can identify structural abnormalities in the basal, ganglia and elsewhere.
Maybe associated with Fanconi’s syndrome.
Patients experience a combination of hepatic, neurological, and psychiatric symptoms.
The level is reduced in approximately 85% of affected patients.
Patients should be examined for Kayser-Fleisher rings by an ophthalmologist.
Accumulation of excess copper in the liver caused by reduced excretion of copper in bile.
Early accumulation of copper associated with macrosteatosis and microsteatosis.
Initial liver changes progress to an intermediate stage with periportal inflammation and other changes indistinguishable from autoimmune hepatitis.
Mallory bodies seen in up to 50% of liver biopsy specimens.
Urinary excretion of more than 100 mcg of copper per day.
A 24-hour urine for measurement of free copper excretion is the screening test of choice.
Associated with a low serum copper level.
Normal or low levels of alkaline phosphatase are seen.
A combination of the ratio of alkaline phosphatase to total serum bilirubin of less than four and a ratio of aspartate aminotransferase to alanine aminotransferase of more than 2.2 has a high percent sensitivity and specificity for the diagnosis of Wilson’s disease in patients with acute liver dysfunction (Korman JD et al.).
Diagnosis suggested by a clinical process of intravascular hemolysis and liver dysfunction.
Neurologic manifestations occur late stages of the disease and reflects copper accumulation in the liver.
Can cause foraminal symptoms with prominent bulbar features.
Cirrhosis follows intermediate disease with a either a macronodular or mixed macronodular-micronodular pattern.
Rarely fulminant hepatic failure can occur and patients may have neurologic disease in the absence of cirrhosis.
Differential diagnosis includes autoimmune hepatitis and metabolic dysfunction steatotic associated liver diseases.
Without treatment the process is fatal.
Early diagnosis is challenging due to the wide variations in clinical presentation.
More than 50% of patients present with hepatic abnormalities including a large liver, hepatitis, elevation in functions, cirrhosis, and acute hepatic insufficiency.
One third of patients have neurologic manifestations and include movement disorders such as tremor, ataxia, dystonia, dysarthria, and memory loss.
10% of patients present with psychiatric alterations: including behavioral disorders, depression, and psychosis.
Ocular manifestations include Kayser Fleischer rings or sunflower cataracts.
Ocular findings are best evaluated with a slit-lamp examination.
Kayser Fleischer rings are copper accumulations that form golden-brown or green rings in the deep corneal periphery.
Kayser-Fleischer rings are highly characteristics of Wilson’s disease and correlate with the development of neuropsychiatric symptoms such as difficulty speaking, mask like facies, excessive salivation and emotional liability.
Kayser-Fleischer rings correlate with systemic manifestations such as cirrhosis, hepatitis, or hepatic failure.
Kayser-Fleischer rings are found in all cases with neurologic findings and 70-90% of cases with liver disease.
Liver damage is a result of oxidative effects of copper on liver cells and results in elevated aminotransferase levels.
When hepatic necrosis occurs massive quantities of copper are released that inhibit red blood cell enzymes and cause oxidative damage to erythrocyte membranes.
As a result of erythrocyte membrane damage denatured hemoglobin forms intracellular inclusions identified on peripheral blood smears by Heinz-body preparations.
A leukemoid reaction may be seen as a result of severe hemolysis.
The most reliable diagnostic test is copper quantitation in tissue-values greater than 250 µg per gram of the dry weight have 83.3% sensitivity and a 98.6% specificity for Wilson’s disease.
A value of greater than 1000 µg per gram weight of dry weight copper level is diagnostic.
Treatment is determined by the clinical presentation, and asymptomatic patients can be treated with zinc.
Zinc acts in the enterocytes and induces an endogenous metal chelator, metallothionein.
In patients with neurological hepatic involvement, chelation therapy with penicillamine or trientine is indicated.
Treatments include chelating agents that induce urinary copper excretion such as penicillamine or trientine, and copper absorption inhibitors such as zincacetate.
Penicillamine may increase neuropsychiatric symptoms in 50% of patients who have such problems and those patients should not receive this drug.
Patients with neurological disease initially treated with trientine have higher rates of neurologic deterioration than patients treated with penicillamine and the latter drug is the pref2242ed agent in this group of patients.
Penicillamine associate with high rates of adverse events as compared with trientine.
Patient unresponsive to chelation therapy and who have hepatic failure are ref2242ed for a liver transplant.
Zinc therapy is utilized for maintenance therapy in this disease and is often used in presymptomatic patients or those with isolated aminotransferase elevations.
Copper chelating agents with or without zinc are effective for rapid reduction of copper levels in patients with mild to moderate liver dysfunction.
Copper chelating agents and zinc acetate reduce morbidity and mortality in Wilson’s disease, but will be utilized indefinitely to prevent re-accumulation of copper.
In the presence of severe liver dysfunction medical therapy is ineffective and liver transplantation is required.
All first-degree relatives of an affected person should be screened by ATP7B genotype analysis, comprehensive clinical, and biochemical evaluations.
Prognosis: clinically evident WD is relentless, progressive, and if untreated, ultimately fatal.
The advent of oral chelators, including both penicillamine and trientine remain the principal treatments.
Zinc salts, or effective maintenance treatments.
The initiation of therapy may be associated with neurologic worsening, and the starting dose of oral chelators is low and gradually increased.
All patients should be treated once diagnosed with lifelong medical therapy.
Copper rich foods should be avoided.
While most patients with WD can be treated medically, liver transplantation can be life-saving and is reserved for patients with liver failure.
Neurologic Wilson’s disease as the primary indication for transplantation, but is controversial.