Serum ceruloplasmin concentrations

In mammals, phenobarbital and phenytoin increase serum ceruloplasmin concentrations (Aaseth and Norseth 1986). Chronic copper poisoning in sheep is exacerbated when diets contain heliotrope plants (Heliotropium sp., Echium spp., Senecio sp.). Aggravated effects of the heliotrope plants include reduced survival and a twofold to threefold increase in liver and kidney copper concentrations when compared to control animals fed copper without heliotropes (Howell et al. 1991). Rats given acutely toxic doses of 2,3,7,8-tetrachlorodibenzo-para-dioxin had elevated concentrations of copper in liver and kidney because of impaired biliary excretion of copper (Elsenhans et al. 1991). Morphine increases copper concentrations in the central nervous system of rats, and dithiocarbam-ates inhibit biliary excretion (Aaseth and Norseth 1986). In human patients, urinary excretion of copper is increased after treatment with D-penicillamine, calcium disodium EDTA, or calcium trisodium diethylenetriamine penta acetic acid (Flora 1991). 

A 17-year-old man with anaemia, leukopenia, and neutropenia had been self-medicating with over-the-counter zinc formulations for acne for almost 2 years at doses of up to 300 mg/day (10). Serum copper and serum ceruloplasmin concentrations were less than 100 (reference range 70-155) ng/ml and 20 (23-49) pg/ml respectively. His serum zinc concentration was 2 (0.6-1.3) pg/ml. Within 1 month of withdrawal, and without copper supplementation, the ceruloplasmin concentration had risen to 90 pg/ml. By 2 months his complete blood count was normal. 

Table III Serum Ceruloplasmin Concentrations in Normal Male Subjects as Reported by Various Authors...

Results. As depicted in Table V, the mean ages, serum copper and serum ceruloplasmin concentrations db standard deviation from 180 male and 44 female subjects were shown. As can be seen, there is no significant difference in serum copper between males and females. However, serum ceruloplasmin in the females was significantly higher than that in the males, with p < 0.01. This seems to agree with most of the reports mentioned earlier (Table IV). It must be pointed out that the mean age... 

Table V. Mean Age, Serum Copper, and Serum Ceruloplasmin Concentrations in Male and Female Subjects"...

Figure 3. Serum ceruloplasmin concentrations in 180 males vs. age. The results from each of the five lots of immunodiffusion plates used are shown by different symbols.

Studies in Copper Metabolism. XXIX. A Critical Analysis of Serum Copper and Ceruloplasmin Concentrations in Normal Subjects, Patients witn Wilson s Disease, Am. /. Med. (1960) 28, 55 563. 

The results of enzymatic determinations of ceruloplasmin are often expressed in arbitrary units, and the values judged in the light of a series of results obtained in normal subjects by the same method. Expression of the enzyme activity in milligrams of ceruloplasmin per unit volume of serum is also possible. The relation between oxidase activity and the amount of ceruloplasmin in serum can be determined by measuring in parallel samples of sera both the oxidase activity and the change of optical density at 610 mix before and after the addition of ascorbic acid or cyanide. On the basis of the known absorbancy index, the ceruloplasmin concentration can be calculated (see Section 2.2.1) and the relation between it and the enzyme activity determined. Alternatively, purified human ceruloplasmin can be used for standardization of the enzymatic method. The ceruloplasmin content of the purified preparation can be determined colorimetrically or, in the case of a highly purified preparation, by nitrogen analysis. Predetermined increments of ceruloplasmin can then be added to aliquots of a selected serum. It is convenient to select a serum with relatively low ceruloplasmin level to start with. Serum of a patient with Wilson s disease, some of whom have no measurable amount of enzyme activity, would be ideal for the purpose however, Walshe (W5) has recently found an inhibitor in these sera. 

C4. Cartwright, G. E., Markowitz, H., Shields, G. S., and Wintrobe, M. M., Studies on copper metabolism. XXIX. A critical analysis of serum copper and ceruloplasmin concentrations in normal subjects, patients with Wilson s disease and relatives of patients with Wilson s disease. Am. J. Med. 28, 555-563 (1960). 

In rodents, copper administered by single intraperitoneal or subcutaneous injection is lethal at 3.0-7.0mg Cu/kg BW. Mice died when their drinking water had 640.0 mg Cu/L. In rats, copper accumulation in kidneys and lungs are similar regardless of route of administration. Concentrations of copper in serum of rats (Rattus sp.) reflect dietary copper concentrations in liver and kidney are directly related to serum Cu and ceruloplasmin. As serum Cu concentrations rise in rats, levels fall for serum cholesterol, triglycerides, and phospholipids. 

In general, serum copper values parallel those of ceruloplasmin. Therefore, serum copper is frequently low in patients with Wilson disease. However, about half of patients have serum copper levels in the normal range. Patients with fulminant Wilson disease and/or hemolytic anemia may even have markedly increased levels. Most of the copper in serum is bound to ceruloplasmin, and nnder normal conditions, less than 5% circulates as free copper and does not exceed 10 pg dl in normal subjects. The free copper concentration can be calculated by subtracting from the total copper concentration the ceruloplasmin bound copper (ceruloplasmin times 3.3). 

Copper content of biological materials is determined by dicyclohexanoneoxalyldihydrazone (DCO) through a procedure which is a combination and modification of two frequently used methods in the literature [27,28]. The estimation is carried out by spectrophotometric measurement at 600 nm. As has been discussed previously, ceruloplasmin level in serum provides an important diagnostic feature of Wilson s and Menkes s diseases. This copper-containing metallopiotein in plasma can catalyze the oxidation of p-phenylenediamine (PPD) [29], The rate at which PPD is oxidized is proportional to the concentration of ceruloplasmin in serum. Under precisely defined conditions of composition of the medium, and at a given temperature, the rate of oxidation allows the calculation of the concentration of enzyme in the serum. 

Decreased serum ceruloplasmin concentration and the cumulated worktime along the week showed a linear relationship in aluminium welders exposed to ozone, which is the major pollutant in arc welding (Pierre et al. 1988). Ceruloplasmin may be a protective molecule against direct oxidant injury to the human lung in cigarette smoke and air pollution (Galdston et al. 1984). 

Treated rats had 1000 mg/kg FW liver (vs. 4.7 in controls) lowered hemoglobin, hematocrit, and red cell counts mean survival time of 67 days hepatic and renal histopathology Dose-time-dependent increase in copper concentrations in liver, spleen, and lung little accumulation in muscle and skin. Reduced growth at 2.5 and 3.75 mg/kg BW daily reduced survival at 3.75 mg/kg BW. Maximum copper concentrations recorded, in mg/kg FW (vs. saline controls,) were 710 in liver (<5), 212 in kidney (<10), 7 in lung (<1.5), 27 in spleen (<2.0) 6 in bone (<2.0) and 2.2 in testes (<1.6) Increased serum ceruloplasmin and white blood cell number... 

Fig. 3. Pattern of heterophile antibodies (HA reciprocal units of dilution), immunoglobulins (IgA, IgG, and IgM), transferrin (Tf), and ceruloplasmin (Cp) throughout gestation in malaria-protected pregnant women. The numbers of investigations at each period of gestation are indicated in parentheses at the bottom of the graph where this differs, as in the case of ceruloplasmin, the numbers are so indicated. Note the increase of serum IgM and transferrin until just before term, when there is also a decrease of the IgG. Ceruloplasmin and heterophile antibodies show a decrease in mean concentration from 25 to 28 weeks of gestation.

In recent history, the therapeutic potential for copper in the treatment of rheumatic diseases was recognized by Hangartner in 1939 when he learned that copper miners in Finland were free of rheumatism. Sorenson25 has reviewed the literature on changes in copper concentrations in patients with rheumatoid arthritis. In patients with active disease there are marked increases in serum or plasma copper, an accelerated turnover rate of ceruloplasmin, and an increase of synovial fluid copper. A number of copper-dependent enzymes are known to be required for repair of inflamed tissues. 

Hypoproteinemia may result in low levels of serum calcium, ceruloplasmin, and transferrin. Because losses of iron are at most 0.5-1.0 mg/24 hr, even with the heaviest proteinuria, other factors must operate to produce iron deficiency and microcytic hypochromic anemia. Although the copper-binding protein ceruloplasmin is lost in the urine in nephrotic subjects and its plasma levels are low, plasma and red cell copper concentrations are usually normal. Zinc circulates mainly bound to albumin and also to transferrin, and thus the reported reduction zinc concentration in plasma, hair, and white cells in nephrotic patients is not surprising. 

The disturbance of copper excretion, primarily due to a defect in the billiary excretion, is consistent with the biochemical findings in patients with Wilson disease. Urinary copper excretion is increased owing to total body overload of copper. Renal dysfunction includes albuminuria and renal rickets. Incorporation of copper in ceruloplasmin is impaired. Thus, there is a greater proportion of copper bound to albumin and amino acid complexes in the serum. But the overall copper concentration in serum is low. Ceruloplasmin is a multicopper oxidase see Copper Proteins Oxidases) that... 

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