Clinical Information

Copper (Cu) is an important trace element that is associated with a number of metalloproteins. Copper in biological material is complexed with proteins, peptides, and other organic ligands. The majority of copper in plasma is bound to the enzyme ceruloplasmin, a copper-dependent multifunction oxidase enzyme. Up to 90% of copper exported from the liver into peripheral blood is tightly protein bound. The remaining copper fraction is often referred to as "free" copper, however a more accurate description is labile bound copper (LBC), as it is not truly circulating freely but is loosely bound to various smaller proteins, including albumin, transcuprein, tetrapeptides, and other amino acids.

This test involves measurement of both the LBC concentration and total copper. The LBC will be divided by the measured total copper concentration to calculate a LBC fraction result. The LBC fraction (%) may be more useful than LBC in some disease states, such as Wilson disease, as it represents the fraction of LBC normalized against potential variation in total copper burden.

Low serum copper, most often due to excess iron or zinc ingestion and infrequently due to dietary copper deficit, may result in altered growth and in impaired erythropoiesis. Low total serum copper is also observed in hepatolenticular degeneration (Wilson disease) due to a decrease in the synthesis of ceruloplasmin and allelic variances in cellular metal ion transporters. In Wilson disease, the albumin-bound copper may actually be increased, but ceruloplasmin-bound copper is low, resulting in low serum copper. However, during the acute phase of Wilson disease (fulminant hepatic failure), ceruloplasmin and copper levels may be normal; in this circumstance, hepatic inflammation causes increased release of ceruloplasmin. It is useful to relate the degree of liver inflammation to ceruloplasmin and copper (see the following discussion on hypercupremia). Significant hepatic inflammation with normal ceruloplasmin and copper suggest acute Wilson disease.

As WD is characterized by a loss of ceruloplasmin-copper binding function, the concentration of non-ceruloplasmin bound labile copper (NCC) is an attractive target as a diagnostic aid. NCC has been historically estimated by the following formula: NCC = total serum copper (mcg/dL) - [3.15 x ceruloplasmin (mcg/dL)]. This calculated estimate has limitations, as it is difficult to directly measure ceruloplasmin, and assumes that all available ceruloplasmin is fully saturated with copper. As such, a clinical assay that can directly quantify the proportion of "free" or labile bound (LBC fraction) of total copper in serum may be preferable. While measurement of LBC fraction has been shown to be a promising diagnostic tool for Wilson disease, it may be applicable to other copper-related disorders as well.

Additional disorders associated with decreased serum copper concentrations include malnutrition, hypoproteinemia, malabsorption, nephrotic syndrome, Menkes disease, copper toxicity, and megadosing of zinc-containing vitamins (zinc interferes with normal copper absorption from the gastrointestinal [GI] tract). Hypercupremia is found in primary biliary cholangitis (formerly primary biliary cirrhosis), primary sclerosing cholangitis, hemochromatosis, malignant diseases (including leukemia), thyrotoxicosis, and various infections. Serum copper concentrations are also elevated in patients taking contraceptives or estrogens and during pregnancy. Since the GI tract effectively excludes excess copper, it is the GI tract that is most affected by copper ingestion. Increased copper serum concentration, LBC copper, and LBC fraction alone do not directly indicate copper toxicity.