Serum copper concentrations

Blake, 1989 Winyard et al., 1989). We suggest that within the inflamed rheumatoid joint (or the artery wall in atherogenesis), the production of ROM and proteases by endothelial cells and/or macrophages may cause the release of copper ions from Cp (see Section 2.2.3.2). It has been reported that Cp is cleaved faster in serum from patients with inflammatory diseases when compared to normal serum (Laurell, 1985). The oxidative modification of LDL by Cp-derived copper ions may explain the observation that increased serum cholesterol values are associated with accelerated atherosclerotic progression in men with high serum copper concentrations (Salonen et al., 1991). 

Bert L. Vallee, "The Time Course of Serum Copper Concentrations of Individuals with Myocardial Infarctions. I," mimeographed paper, undated, p. 1. 

Serum copper concentrations have been shown to increase in active cancer and decrease in remission thus it seems likely that some copper-dependent process is required for response or remission. A number of copper complexes have been tested and found to have rodent antitumor activity. There appear to be copper complexes which serve in a homeostatic fashion to prevent development of neoplasms. If this physiologic response fails at some point, tumors may be allowed to grow. 

Neurophysiological evaluation of 40 patients with beta-thalassemia major showed abnormal findings in brain-stem-evoked potentials auditory (25%), visual (15%), and somatosensory (7.5%) some had abnormal nerve conduction velocity (25%) and 15% had involvement of multiple neural pathways (39). Subclinical involvement of the auditory pathway was statistically associated with a higher mean daily dose of deferoxamine and a longer duration of treatment. Abnormalities of the somatosensory pathways were related to old age, a long duration of deferoxamine use, and low serum copper concentrations. Multiple neural pathway involvement was related to the duration of treatment. However, deferoxamine is only partly responsible for the subclinical abnormalities of neural pathways often found in patients with beta-thalassemia major. 

Because copper is excreted primarily in the bile, some experts advocate reducing or curtailing copper supplementation in patients with chronic hyperbUrrubinemia. The earliest signs of copper deficiency are peripheral blood cytopenias (typically anemia and neutropenia) and occasionally thrombocytopenia, caused by reduced bone marrow production. The authors recommended that serum copper should be monitored quarterly and that copper should be included in the parenteral nutrition mixture three times a week, adjusting the frequency in response to serum copper concentrations. 

Copper deficiency has been reported in a patient with Crohn s disease after removal of copper from the parenteral nutrition because of severe cholestasis (59). The patient developed pancytopenia with severely depressed serum copper concentrations after 8 weeks. Bone-marrow biopsy confirmed the cause as copper deficiency. Although intravenous replacement of copper improved the patient s anemia and other markers, he suddenly died of cardiac tamponade. 

In patients with Wilson s disease, penicillamine is rapidly attached to copper and, although higher doses are used, taste disturbances develop in a lower frequency, about 4% (SED-8, 536). It has been suggested that dysgeusia is related to deficiency of copper or zinc, but a strong connection between taste impairment and urinary copper excretion has not been demonstrated (118). Serum copper concentrations remained within normal limits and copper supplements were not effective in prevention (119). 

Essential and Nonessential Metals. It is well known that elements in the biological systems may vary a great deal in their concentration from organ to organ and from species to species, but for the purpose of this chapter, the following classification of elemental concentrations has been adopted (17) major, > 1% minor, 0.10-1% micro, 0.01-0.1% trace, 0.01-0.001% ultratrace, < 0.001%. Since total copper in the average, "standard man (18) is approximately 150 mg (2), its classification would fall between trace and ultratrace concentration. However, as is the case with any other element, what is a trace in one organ may be an ultratrace in another, but for serum copper concentration, which is about 100 /xg%, the definition of copper as an ultratrace metal by the above classification may not be justifiable. If the criteria of the "standard man is taken into account, however, the definition seems appropriate. 

Except in genetic disorders such as Menkes Syndrome, caused by abnormalities in protein metabolism in children (62), hypocupremia has not been demonstrated to occur in man (49), Two other disorders, nephrosis and iron deficiency, are known to have low serum copper concentrations. 

In man, serum copper concentrations are reported to be increased in a number of chronic illnesses such as coronary atherosclerosis with or without infarction, cerebral atherosclerosis, essential hypertension, diabetes mellitus, chronic pulmonary diseases, and various hematological disorders (95,96). Diseases of hypercupremia and their manifestation have been described by Adelstein and Vallee (2). 

During the first few days after birth, serum copper concentration in the baby rises from 50-150 /xg/100 mL, presumably because of increases in ceruloplasmin synthesis, and then it subsides again to normal level of 100 /xg/100 mL and is maintained throughout life (119), Thus, an infant needs at least 14 /xg Cu/kg to maintain his copper balance while in children, 60-100 /xg Cu/kg would be the minimal requirement. It also can be seen that low intake of copper by the mother during gestation can diminish copper stores in the embryo and thus can contribute to newborn copper deficiency. 

Table I. Serum Copper Concentrations in Normal Male Subjects as Reported by Various Authors...

Serum copper concentrations in normal subjects have been defined by several authors (95,06,101,102,121-125), Table I lists selected studies by various authors, illustrating serum copper concentrations in normal males, and Table II lists separately reported normal values in the female. Serum copper values reported by us fall within the range reported by others in both males and females. As for the difference between males and females, reports do not seem to agree. For example. Rice (126) reported higher and more reliable values in the females, while... 

Figure 1 depicts the correlations between serum copper concentrations and age in the male population. It can be seen that there is a significant increase in serum copper concentrations in males with p < 0.025. No such difference could be detected in the females (Figure 2). However, when corrected for age differences, the females had higher serum concentrations than males did, although the difference was not statistically significant.

Figure 1. Serum copper concentrations in 180 males vs. age. solid line represents the calculated regression equation.

Discussion. Our findings of an increase in serum copper concentrations with age are in agreement with two previously reported studies, one by Harman et al. (139,140) and the other by Herring et al. (95). Harman demonstrated a linear increase with age with a mean serum concentration of 124 /xg/100 mL at age 20 years and 145 /xg/100 mL at age 60. Herring reported a positive correlation in subjects at age 10-50 years with few subjects over 40 years. 

Based on reports by other workers in this field and on our own findings, two hypotheses could be postulated to explain the increased serum copper concentration with age. Since tissues in these subjects were not examined for copper concentrations, increased serum copper concentration may either represent an increase in the total body pool of copper or, alternatively, the copper may have shifted from another organ, thus increasing plasma copper, plasma in this instance acting as a vehicle for transiently transporting the metal to other parts of the body where it is needed. 

Many epileptics receiving anticonvulsants excrete increased amounts of copper and zinc in their urine. Increased serum ceruloplasmin also increases the total serum copper concentration. In 20% to 30% of epileptic children receiving anticonvulsant therapy, erythrocyte aspartate aminotransferase activity is low, indicating a lowered pyridoxal (vitamin Bg) status. In as many as 50% of the adults receiving phenytoin for some time, there will be folate deficiency, manifested by reduced erythrocyte and serum folate concentrations. The mechanism for the deficiency has not yet been established conclusively. In about 10% of adults taking phenytoin, the serum vitamin is low. 

Ford ES. Serum copper concentration and coronary heart disease among US adults. Am J Epidemiol 2000 151 1182-8. 

V2. Vallee, B. L., Time course of serum copper concentrations of patients with myocardial infarctions. Metab. Clin. ExpU. 1, 420-434 (1952). 

Serum caeruloplasmin. The normal adult levels are 2(M)-6(K) mg/1. Caeruloplasmin is increased greatly in the acute phase reaction, and in some cases may be so high as to raise the total copper concentration to 30-45 Jmol/l. Caeruloplasmin levels may be helpful in the interpretation of serum copper concentrations. 

Copper toxicity is uncommon and is most usually due to administration of copper sulphate. solutions. Oral copper sulphate may lead to gastric perforation. Serum copper concentrations may be greatly elevated. Copper is toxic to many organs, but renal tubular damage is the major concern. Treatment is by chelation with penicillamine. 

Results published from 1938 to 1953 can be viewed as having clearly demonstrated that patients with RA had a higher mean serum copper concentration than do normal healthy individuals. Small sex-related differences in normal individuals were obscured by marked increases found for both male and female patients. The increase in serum copper associated with the onset and persistence of active disease returned to normal with disease remission. It is now known from animal studies [46, 47] that the rise in serum copper is accompanied by a fall in total serum zinc and iron. This fall in total serum zinc and iron is partially accounted for by their requirement for the synthesis of copper-containing components in the liver. 

Lorber, Cutler and Chang [75] were the first to report a statistically significant elevation of serum copper concentration in RA when compared with that in age-matched normal adults. (A recent comparison of age-matched children demonstrated that serum copper is elevated in patients with juvenile rheumatoid arthritis [76].) They also reported that almost the entire serum copper content of normal individuals was bound to Cp [75]. This was corroborated in a second group of normal individuals with the demonstration that serum copper contained only a small amount of non-Cp copper (7 /ig/100 mg), which was somewhat smaller than reported by others (24 16/tg/100 ml) [71]. In addition, their population of RA patients had a very large non-Cp copper concentration (103 ig/lOOml) [77], which was much larger than re-... 

Copper metabolism has been studied in a variety of neoplastic diseases [332]. It is now known that patients with acute leukaemia have elevated serum or plasma copper concentrations [333]. The elevation in serum copper correlated with an increase in number of bone marrow blast cells. A decline in symptoms or remission of disease following therapy correlated with a decrease in serum copper concentration [332-335], enabling accurate prognoses based upon serum copper determinations. 

A good correlation was also found between increased serum copper concentration and disease activity in non-Hodgkin s lymphomas [332]. Patients who responded to therapy had a return to normal serum copper levels, but nonresponders had a persistently elevated serum copper level [344]. Relapse was associated with an elevated copper concentration prior to the onset of symptomatic relapse. 

A. Specific levels. If copper salt ingestion is suspected, a semm copper level should be obtained. Normal serum copper concentrations average 1 mg/L, and this doubles during pregnancy. Semm copper levels above 5 mg/L are considered very toxic. Whole-blood copper levels may correlate better with acute intoxication because acute excess copper is carried in the red blood cells however, whole-blood copper levels are not as widely available. 

An overestimation of serum ceruloplasmin can be suspected if the serum copper concentration is lower than expected by the measured ceruloplasmin (which contains 0.3% of copper) level. Finally, ceruloplasmin is an acute phase reactant and its serum concentration increases as a consequence of inflammation. Most patients with normal ceruloplasmin had marked liver disease. Similarly serum ceruloplasmin may increase in pregnancy to high normal values. 

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