Ceruloplasmin (Cp)
TECHNICAL UPDATE

DESCRIPTION/BACKGROUND INFORMATION:

Most of the copper in the body is located in the liver, bones, and muscle, but traces of copper occur in all tissues of the body. The liver excretes excess copper into the bile for elimination from the body. Copper is a component of many enzymes. Some of these enzymes are necessary for energy production or for the formation of the hormone epinephrine, red blood cells, bone, or connective tissue. Ninety percent or more of the total serum copper is found in ceruloplasmin. Wilson's disease (hepatoenticular degeneration) results from disordered copper metabolism, in which hepatic excretion of copper into the bile is impaired leading to toxic deposition of copper in tissues. Normal metabolism of copper includes incorporation by the liver into ceruloplasmin (about six to seven copper atoms per molecule), which is then secreted into the plasma. In Wilson's disease, this process is impaired and copper that has been absorbed by the body and transported to the liver fails to re-enter the circulation as part of Cp. Normal excretion of copper through the bile is diminished with an overall increase in body copper deposits that are toxic to liver, brain, cornea, kidneys, bones, and parathyroids. Diagnosis of Wilson's disease is based on physical findings (liver disease, neurologic signs, Kayser-Fleischer ring in the cornea), measurement of low serum ceruloplasmin level, and increased copper concentrations in urine and on liver biopsy.

CLINICAL APPLICATION:

The most important clinical application of the ceruloplasmin test is in the diagnosis of Wilson's disease, where typically, concentrations of ceruloplasmin are reduced and concentration of dialyzable copper are increased. Unless treated with copper chelators, the disease is always progressive and fatal. Prompt diagnosis is important since the treatment takes 3-6 months to have the desired effect. Ceruloplasmin assay should be considered in cases of central nervous system disease of obscure etiology. Neurological symptoms include problem of coordination.

Excessive therapeutic zinc may lead to block of intenstinal absorption of copper and a copper deficiency syndrome characterized by hypochromic microcytic anemia with leukopenia/ neutropenia and zero level of ceruloplasmin. A prolonged period of time may be required to eliminate the excess zinc, overcome the block of intestinal copper absorption, and obtain increase in serum copper and ceruloplasmin levels.

Ceruloplasmin is low in Menkes kiny hair syndrome (in Menkes syndrome the defect is secondary to poor absorption and utilization of dietary copper), and with protein loss such as the nephrotic syndromes, malabsorption, and with some cases of advanced liver disease in which decreases of serum proteins have occurred.

Ceruloplasmin is high in a variety of neoplastic and inflammatory states since it behaves as an acute phase reactant, although levels rise more slowly than do those of other acute phase reactants. Increases are described in carcinomas, leukemia's, Hodgkin disease, primary biliary cirrhosis, systemic lupus erythematosus, and rheumatoid arthritis. High levels occur in pregnancy, with estrogens, and with oral contraceptive use when the agent contains estrogen as well as progesterone. It is also increased in copper intoxication.

Another reported role of Cp is in the oxidation of LDL. Oxidized LDL (Ox-LDL) is a well-known atherogenic factor. Therefore, an increase in serum Cp levels is expected to act as an atherogenic factor. Increases in serum Cp levels have been reported under many conditions, including diabetes. Therefore, in diabetes, observable increased serum Cp levels should cause LDL oxidization. An increased level of Ox-LDL is known to inhibit nitric oxide (NO) production and a decreased level of NO impairs the endothelium-dependent relaxation of arteries, the impairment of which is a factor causing atherosclerosis. Thus, increased serum Cp levels in diabetes might account for the early progression of atherosclerosis.

METHODOLOGY:

Nephelometry.

TEST NAME & NUMBER:

• 2615 Ceruloplasmin (Cp)

REFERENCES:

1. Gutteridge JMC, et al. Ceruloplasmin: physiological and pathological perspectives. CRC Crit Rev Clin Lab Sci 1981; 14:257-329.
2. Schaefer M and Gitlin JD. Genetic disorders of membrane transport. IV. Wilson's disease and Menkes disease. Am J Physiol 1999 Feb; 276(2 Pt 1): G311-314.
3. Vanhoutte PM. Endothelial dysfunction and atheroscelerosis. Eur Heart J 18 (Suppi. E): E19-E39, 1997.
4. Ehrenwald E. Chisolm GM, Fox PL. Intact human ceruloplasmin oxidatively modifies low density lipoprotein. J Clin Invest 93: 1493-1501, 1994.
5. Deiss A. Wilson's disease. In: Cecil Textbook of Medicine, Wyngaarden JB, Smith LH, Bennett JC (eds). Vol 1, 19th Edition. W.B. Saunders Co., Philadelphia, PA; pp: 1378-1527, 1992.
6. Gahl WA. Wilson's disease. In: Cecil Textbook of Medicine, 21st ed. Goldman L and Bennett JC (eds). W.B. SaundersCo., Philadelphia, PA. 1130-2, 2000.
7. Hoffman HN II. Phyliky RL and Fleming CR. Zinc-induced Copper Deficiency. Gastroenterology, 1988; 94(2): 508-12.
8. Cauza E. Maier-Dobersberger T. Polli C et .al. Screening for Wilson's Disease on Patients with Liver Diseases by Serum Ceruloplasmin. J Hepatol, 1997; 27(2): 358-62.