Wilson disease: Copper everywhere
Wilson disease is caused by mutation of the ATP7B gene, which results in impaired copper excretion and accumulation of toxic levels of copper in many organs principally the liver, brain, and eye.
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Pathogenesis
It is an autosomal recessive disorder having mutations in the ATP7B gene, which encodes a membrane-bound, copper-transporting ATPase. The defect in ATPase causes
- Impaired biliary secretion of copper which causes reduced copper excretion
- Impaired copper incorporation into ceruloplasmin hence serum ceruloplasmin is low and copper in liver is above toxic levels
Excessive copper accumulation in the liver and a decrease in plasma ceruloplasmin causes copper toxicity.
Accumulating copper causes liver injury through the production of reactive oxygen species and free radicles. Injured hepatocytes release free copper (non-ceruloplasmin–bound copper) into the circulation, causing red cell hemolysis and copper deposition in other tissues, such as the brain, corneas, kidneys, bones and joint.
Urinary excretion of copper increases markedly because of excessive serum copper levels.
Clinical manifestation
Liver and brain are most affected organs.
Liver abnormalities- patient most commonly presents with any of the following
- hepatitis
- cirrhosis
- hepatic decompensation and hepatic encephalopathy
- elevated liver function test
Neurological abnormalities- the neurological symptoms mimic Parkinson disease, patient has following symptoms and signs
- Dystonia
- Flapping tremors (liver flap)
- Incoordination
- Orthostatic hypotension
Eye lesions- Kayser-Fleischer rings (pathognomonic) where copper is deposited in the outer rim of the cornea is present in most cases who presents with neurological abnormalities.
Behavioral changes- loss of emotional control, crying bouts and depression.
Joint pain- osteoarthritis and synovitis.
Hypogonadism- testicular atrophy, amenorrhea and ovarian atrophy.
Hemolytic anemia- In severe hepatic failure, hemolytic anemia can develop because large amounts of copper from hepatocellular necrosis is released into the bloodstream causing hemolysis.
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Diagnosis
Liver Biopsy
- Liver copper content -it is Gold standard test, and Copper content in excess of 250 µg per gram dry weight of liver is taken to be diagnostic.
- Copper stain- Rhodamine stain and Orcein stain on liver biopsy
- Hepatic changes on histopathology- steatohepatitis, hepatocyte ballooning, Mallory-Denk bodies and fibrosis is frequently seen.
Serum ceruloplasmin- is low
Urinary copper excretion (per 24 hours)- urine copper levels >100 μg per 24 hours.
Kayser-Fleischer rings- greenish to brownish ring rimming the cornea can be observed by naked eye, and confirmation is done by slit-lamp examination. KF ring is pathognomonic for Wilson disease.
DNA sequencing - mutations in ATP7B gene.
Serum Copper levels- are of No diagnostic value because it can be low, normal or high depending upon stage of liver injury in Wilson disease.
Treatment
Copper chelator
- D-penicillamine – always give pyridoxine along with it, to reduce toxicity.
- Trientine - Zinc should not be ingested simultaneously with trientine, because it chelates zinc and forms therapeutically ineffective complexes. Ingestion of the two drugs should be separated by at least one hour.
- Tetra thiomolybdate is considered as drug of choice in initial stages because of its rapid control of free copper, preservation of neurologic function, and low toxicity.
Reducing copper absorption from gut
- Low copper diet
- Zinc based treatment
Liver transplantation – in cases with advanced liver cirrhosis.
Further reading https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4367052/
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