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Ceruloplasmin is an alpha2 globulin that carries more than 95% of all copper in the body. Both ceruloplasmin production and copper binding take place in the liver. Copper absorbed from the gastrointestinal tract is bound to ceruloplasmin in the liver and transported to various tissues to be incorporated into cellular cytochrome oxidase and other copper containing enzymes. Copper bound to ceruloplasmin is nontoxic. The liver excretes excess copper into the bile.

Wilson disease is an autosomal recessive disorder that occurs in ~1 in 30, 000 individuals in Europe and North America. It is caused by a mutation of a gene on chromosome 13, coding for a membrane bound copper transporting ATPase known as ATP7B. More than 100 mutations of this gene have been discovered, explaining the variable clinical presentation of Wilson disease. This mutation results in 2 defects in hepatic copper metabolism: a decrease in the incorporation of copper into ceruloplasmin and diminished biliary excretion of copper. Hepatic copper concentration gradually increases and injures hepatocytes. Excess copper escapes into the circulation and is deposited in basal ganglia, cerebral cortex, kidney, and cornea. Free copper is toxic and damages these tissues.

Normally, ceruloplasmin is synthesized in hepatocytes as an apo-ceruloplasmin and secreted into the plasma after copper is incorporated into a metal-binding motif, forming holo-ceruloplasmin. Failure of copper incorlporation into cerulopalsmin results in loss of its enzymatic activity and rapid degradation by plasma proteases. In patients with Wilson disease, loss of ATP7b activity results in failure of copper incorporation into ceruloplasmin, secretion of apo-ceruloplasmin, and rapid degradation. Low plasma ceruolplasmin concentration is the hallmark of Wilson disease.

Individuals with Wilson disease are not usually diagnosed until after their 4th or 5th year. Some patients are not diagnosed until their early 20s. They usually present with liver disease, neurologic or psychiatric symptoms.

The most common laboratory finding is a low plasma ceruloplasmin. Other laboratory findings include:

  • Decreased ceruloplasmin (usually <10 mg/dL)
  • Decreased serum copper (<0.75 ng/mL)
  • Increased urine copper excretion (>60 ug per 24 hours)
  • Hepatic copper concentration >250 ug/g of dry weight of liver
  • Slightly elevated AST & ALT
  • AST is elevated disproportionately to ALT
  • Profound bilirubin increase with normal or low ALP
  • Hemolytic anemia.

Low ceruloplasmin is detected in 95% of homozygotes and 20% of heterozygotes. Low levels need to be interpreted cautiously because any type of severe liver disease may interfere with ceruloplasmin synthesis. Low concentrations also occur with malnutrition and protein loss. Falsely normal ceruloplasmin values can be seen with estrogen therapy, pregnancy, and acute inflammation.

First degree relatives of patients newly diagnosed with Wilson disease must be screened. Assessment includes history, physical examination, slit lamp examination of eyes, liver function tests, serum copper, ceruloplasmin, and 24 hour urinary copper. Individuals without Kayser Fleischer rings who have subnormal ceruloplasmin and abnormal liver function tests should undergo further testing for ATP7B gene mutations. In populations of Northern European descent, the H1069Q mutations accounts for at least 40% of disease alleles, whereas in Far East Asian populations an R778L mutation occurs in 30% of affected individuals.

Ceruloplasmin reference range is 20 - 45 mg/dL, serum copper 0.75 – 1.45 ng/mL, urine copper 15 – 60 ug/24 hour specimen.

Specimen requirement is one SST tube.

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