Ceruloplasmin associated disease

Copper toxicity has been observed, althongh it is not a function of dietary overload. Abnormally low levels of ceruloplasmin associated with the genetic disorder, Wilson s disease, lead to excessive deposition of copper in the central nervous system, ocular tissue, liver, and other organs. Severe psychotic symptoms are observed. Urinary excretion of the copper can be achieved with specific chelating agents such as British anti-lewisite (BAL, 2,3-dimercaptopropanol) or penicillamine, orally administered. Symptoms of the disease are reversed as the copper levels return to normal. Reduction of dietary copper nptake by competition with relatively high levels of oral zinc is also effective. ... 

Ceruloplasmin Binds Copper, Low Levels of This Plasma Protein Are Associated With Wilson Disease... 

Solberg and co-workers have applied discriminate analysis of clinical laboratory tests combined with careful clinical and anatomic diagnoses of liver disease in order to determine which combinations of the many dozen liver diagnostic tests available are the bes t ( ). These authors found that the measurement of GPT, GMT, GOT, ALP and ceruloplasmin were the most useful enzymatic tests, when combined with other non-enzymatic tests such as the measurement of bilirubin, cholesterol, hepatitis-B associated Australian antigen, etc. Another group of highly useful enzymes, not discussed in this review, are those clotting factors and the enzyme cholinesterase which are synthesized by the liver cells. 

Ceruloplasmin is synthesized in the hver as a precursor with a signal peptide directing it to the endoplasmic reticulum. It incorporates Cu provided by the Wilsons disease-associated Cu-ATPase, ATP7B, and is secreted into the bloodstream. The copper-deficient ceruloplasmin in Wilson s disease patients has been found to rapidly degrade. A GPI-anchored form of ceruloplasmin has been recently identified as the product of an alternately spliced ceruloplasmin transcript that generates a hydrophobic C-terminal GPI-anchoring signal, similar to those found in phytocyanins (Patel and David, 1997). The GPI-anchored form of ceruloplasmin is preferentially expressed in brain. 

Ceruloplasmin has long been thought to be a ferroxidase and it has been proposed that ceruloplasmin has a custodial role in vivo, ensuring that Fe " " released from cells is oxidised to the potentially less toxic Fe + prior to its incorporation into apotransferrin. Aceruloplasminaemia is a neurodegenerative disease associated with the absence of functional ceruloplasmin due to the presence of inherited mutations within the ceruloplasmin gene. This condition results in disruption of iron homeostasis, with extensive iron accumulation in a number of tissues... 

In summary, reported results contribute to an understanding of altered copper metabolism associated with RA and osteoarthritis and its patterning in these and other degenerative diseases [113], Marked increases in serum copper were confirmed in patients with early active disease. The observed alteration in serum copper is now understood as being mediated by interleukin-1 [29]. The increased rate of synthesis and accelerated turnover-rate of Cp was found to be directly related to disease activity. Synovial fluid copper content was found to increase in RA and osteoarthritis. Ceruloplasmin, which accounted for most of the SF copper increase, was found to increase with increasing duration of disease. 

Golgi apparatus, endoplasmic reticulum, and plasma membrane, and are responsible for copper transport. A mutation of this gene is responsible for Wilson s disease. Copper is poorly incorporated into the ceruloplasmin when translocase is defective. Metal ions are also sequestrated into lyso-somes, especially under conditions of copper overload (Mohan etal. 1995). The liver, which is the only true storage site that may be mobilized in the case of a negative copper balance, retains 20% of body copper. Muscles and brain account for 40% and 20%, respectively, but this copper is not available to assess in copper balance maintenance. A carrier-mediated facilitated diffusion system for uptake of copper complexes, amino acids and small peptides was identified in the rat hypothalamus (Harttler and Barnea 1988). Copper transport into the bile takes place in association with the biliary excretion of glutathione (Freedman etal. 1989). 

Uzman and his associate [55] proposed that the disease results from a general disturbance in protein metabolism (possibly increased proteolytic activity) leading to the appearance in tissues of substances of great binding affinity for copper. The evidence in favor of this concept is twofold first, copper peptides were found in the urine of patients with Wilson s disease and, second, electrophoretic studies of liver proteins revealed the presence of abnormal copper proteins. This interesting hypothesis merits further confirmation. It will also be necessary to explain why abnormal copper polypeptides lead to lower ceruloplasmin levels. 

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