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Background and Objectives: Wilson's disease (WD) in children and adolescents is predominantly asymptomatic or oligo-symptomatic. The symptoms are nonspecific and difficult to distinguish from other hepatic or neuropsychiatric disorders. In this study, we present the experience of a pediatric referral center for WD diagnosis and treatment., Patients and Methods: We retrospectively analyzed clinical and laboratory data from 99 patients with WD of Sardinian origin, including physical examination, laboratory biochemical testing, liver biopsy, and genetic analysis., Results: Patients were prevalently oligo-symptomatic or asymptomatic. The median age of diagnosis was 8.78 years. Ceruloplasmin values were lower than normal values in all analyzed patients. Twenty-four-hour urinary copper levels were higher than 40 μg/24-h in 92/96 patients. In all analyzed patients with the exception of one, liver copper was higher than 250 μg/g of dry weight but all had >75 μg/g of dry weight. Statistical analysis showed correlation between the age at diagnosis, serum copper, and 24-h urinary copper. Correlation was also found between serum copper and 24-h urinary copper. Molecular analysis of ATP7B gene allowed complete characterization in all the analyzed patients., Conclusion: A high index of clinical suspicion and biochemical tests including liver tests, serum ceruloplasmin, and basal 24-h urinary copper excretion and genotype determination are key to WD diagnosis. The long experience that a referral center for WD possesses is an important factor in making WD diagnosis a more accurate process. Studies in animal models on WD could be used as a guide to further investigate the molecular mechanisms that regulate copper metabolism and influence the natural history of WD., (© 2024 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background and Aims: Few studies have focused on the outcomes of Wilson's disease (WD) diagnosed before age of 5 years. This study aimed to summarize the clinical features of early diagnosed WD and analyse treatment outcomes and the risk factors associated with treatment failure., Methods: A total of 139 children confirmed with WD before 5 years were enrolled in this study. Only patients with follow-up over 1 year were analysed with Kaplan-Meier survival analysis. The composite outcomes included death, progression to liver failure or acute hepatitis, development of renal or neurological symptoms and persistent elevation of alanine aminotransferase (ALT). The treatment failure was defined as occurrence of at least one of above outcomes., Results: Among 139 WD patients at diagnosis, two (1.4%) WD patients presented with symptomatic liver disease, whereas 137 (98.6%) were phenotypically asymptomatic, including 135 with elevated ALT and 2 with normal liver function. Median serum ceruloplasmin (Cp) was 3.1 mg/dL, and urinary copper excretion was 87.4 μg/24-h. There were 71 variants identified in the the copper-transporting ATPase beta gene, and 29 were loss of function (LOF). 51 patients with LOF variant were younger at diagnosis and had lower Cp than 88 patients without LOF. Among 93 patients with over 1 year of follow-up, 19 (20.4%) received zinc monotherapy, and 74 (79.6%) received a zinc/D-penicillamine combination therapy. 14 (15.1%) patients underwent treatment failure, and its occurrence was associated with poor compliance (p < .01)., Conclusions: Cp is a reliable biomarker for early diagnosis, and zinc monotherapy is an effective treatment for WD during early childhood. Good treatment compliance is critical to achieve a favourable outcome., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Copper is an essential metal for virtually all organisms, yet little is known about the extracellular sources of this micronutrient. In serum, the most abundant extracellular Cu-binding molecule is the multi‑copper oxidase ceruloplasmin (Cp). Cp levels increase during infection and inflammation, and pathogens can be exposed to high Cp at sites of infection. It is not known whether Cp might serve as a Cu source for microbial pathogens and we tested this using the opportunistic fungal pathogen Candida albicans. We find that C. albicans can use whole serum as a Cu source and that this Cu is sensed by the transcription factor protein Mac1. Mac1 activates expression of Mn-SOD3 superoxide dismutase and represses Cu/Zn-SOD1 during Cu starvation and both responses are regulated by serum Cu. We also show that purified human Cp can act as a sole source of Cu for the fungus and likewise modulates the Mac1 Cu stress response. To investigate whether Cp is a Cu source in serum, we compared the ability of C. albicans to use serum from wild type versus Cp -/- mutant mice. We find that serum lacking Cp is deficient in its ability to trigger the Mac1 Cu response. C. albicans did accumulate Cu from Cp -/- serum, but this Cu was not efficiently sensed by Mac1. We conclude that Cp and non-Cp Cu sources are not equivalent and are handled differently by the fungal cell. Overall, these studies are the first to show that Cp is a preferred source of Cu for a pathogen., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The patient was a 64-year-old man presented with difficulty in walking, articulation, and swallowing, as well as cognitive impairment. He had refractory microcytic anemia and diabetes mellitus. His serum levels of iron, copper, and ceruloplasmin were low. Magnetic resonance imaging suggested iron deposition in the basal ganglia, thalami, cerebellar dentate nuclei, and cerebral and cerebellar cortices. He was diagnosed with aceruloplasminemia after a ceruloplasmin gene analysis. Iron chelation therapy with deferasirox improved his anemia and cerebellar symptoms, which included dysarthria and limb ataxia. The present study and previous reports indicate that cerebellar symptoms with aceruloplasminemia might respond to deferasirox in less than one year.

Objective: The aim of this study was to investigate the maternal serum concentrations of copper (Cu) and ceruloplasmin (CP) in patients with mild preeclampsia, severe preeclampsia, hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome, and to determine their association with the severity of the disease. Methods: This study was carried out at the largest tertiary care health center in the southeast region in Turkey and Department of Obstetrics and Gynecology, Dicle University Hospital. A total of 179 pregnant women, including 58 healthy pregnant women and 71 mild preeclampsia, 26 severe preeclampsia, and 24 HELLP syndrome cases classified according to the American College of Obstetricians and Gynecologists' 2013 guidelines were included in this prospective study. Blood samples were taken from all the pregnant women to evaluate the serum Cu and CP levels. The Cu level was determined via atomic absorption/emission spectroscopy, while the serum CP level was assessed with a nephelometric assay using an automatic image analyzer. Spearman's rank correlation tests were used to determine the correlations between the serum levels of the antioxidative markers and the preeclampsia severity. Results: The mean ± SD of the Cu was 81.2 ± 11.84 µg/dl in the mild preeclampsia cases and 160.2 ± 20.89 µg/dl in the severe preeclampsia cases ( p  < .001). The mean ± SD of the CP was 33.0 ± 4.81 mg/dl in the mild preeclampsia cases and 65.3 ± 9.17 mg/dl in the severe preeclampsia cases ( p  < .001). The Cu and CP levels were significantly higher in the patients with HELLP syndrome, which is an advanced and more severe form of severe preeclampsia, than in the mild and severe preeclampsia patients ( p  < .001 and p  < .001, respectively). Therefore, the serum Cu and CP levels were correlated with the severity of preeclampsia ( r  = 859, p  < .001 and r  = 786, p  < .001, respectively). In addition, there was a positive correlation between the serum Cu and CP levels and the systolic and diastolic blood pressure values and aspartate amino transferase levels (AST), and a negative correlation between the serum Cu and CP levels and the platelet count. Conclusion: This was the first study in which the ceruloplasmin and Cu levels were investigated in HELLP syndrome patients. When considering the results obtained in the present study, there were significant relationships between the Cu, CP levels which are the markers of oxidative stress and the preeclampsia severity.

Background The main aim of this study was to assess the serum levels of copper (Cu), zinc (Zn) with lipid peroxidation, Cu/Zn superoxide dismutase (Cu/Zn SOD) activity, and ceruloplasmin (Cp) in multiple myeloma (MM) patients. Materials and methods The study was conducted in 34 MM patients at stage I. Serum Cu and Zn levels were measured by atomic absorption spectrometry. Also, spectrophotometric assays of malondialdehyde (MDA) levels in addition to Cp and Cu/Zn SOD were quantitated. Results The results showed a significant decrease in the serum Zn levels in patients with MM (p < 0.0001). Also, serum Cu levels were significantly higher (p < 0.0001). However, the serum Cu/Zn ratio was significantly higher in the cancer patients (p < 0.0001). A significant difference was observed in the patients group compared with the control group according to the Cu/Zn SOD activity (p < 0.0001). Moreover, serum levels of Cp and MDA were significantly increased in patients (p < 0.0001, both). Conclusions The elevated levels of serum Cu and MDA with a decrease in Zn and Cu/Zn SOD might explain the increased oxidative stress in MM disease. As the high Cu level was observed in MM patients, therefore, Cu levels should be concentrated in the pathogenesis and progression of MM disease.

This study was to investigate the alterations of serum copper homeostasis after hypertensive intracerebral hemorrhage (ICH), which is not yet clear. We recruited 85 hypertensive ICH patients and determined their serum levels of total copper (TCu), small molecule copper (SMC), and ceruloplasmin (Cp). Sera from 32 healthy persons and 12 primary hypertension patients were collected and analyzed as well. Serum TCu levels in ICH patients were tested at three time points (on admission, day 3, and day 7) and found to be higher than that in hypertension patients (p < 0.05). The serum SMC levels in hypertension patients and ICH patients at three time points were higher than that in healthy controls (p < 0.05). Higher serum SMC levels on days 3 and 7 were associated with death in the hospital. Additionally, higher serum SMC levels on the seventh day were associated with poor outcome at discharge. High serum Cp levels on admission, as well as low serum Cp levels on the seventh day, were associated with death in the hospital (p = 0.002 and p = 0.034, respectively). Our findings indicated that declines in serum Cp and increases in serum SMC are correlated with lethal or poor outcome in hypertensive ICH patients, possibly as a result of contributions to secondary injury of brain after hemorrhage due to impairment of iron transport and enhanced oxidative stress.

Although many studies have been carried out in order to understand the implication of copper (Cu) in the pathogenesis of multiple sclerosis (MS), the exact role that this metal plays in the disease is not still clear. Because of the lack of information in this subject, the present study compared the serum and cerebrospinal (CSF) levels of copper in MS patients in respect to a control group, matched for age and sex, finding a significant increase of metal concentrations, in both biological fluids of MS subjects. To confirm the possible impairment of Cu metabolism, we analyzed ceruloplasmin (Cp) level and activity, seeing as this protein is an established peripheral marker in diseases associated with Cu imbalance. By comparing these two parameters between control and MS subjects, we found an increase of Cp levels, associated with a decrease in Cp activity, in the second group. By analysing these data, free copper levels were calculated, significantly increased in serum of MS subjects; the increase in free copper could be one of the predisposing factors responsible for the Cu altered levels in CSF of MS patients. At the same time, this alteration could be attributable to the inability to incorporate Cu by Cp, probably due to the high oxidative environment found in serum of MS patients. Overall, all these copper alterations may play a role in MS pathogenesis., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and Study Aims: Hepatobiliary cholestatic disorders produce excess copper (Cu) retention in the liver, which is toxic and may cause hepatitis, fulminant hepatic failure, cirrhosis and death. In this study, we measured hepatic Cu and tested its correlation with serum Cu (S. Cu) and serum ceruloplasmin (S. ceruloplasmin) in cholestatic infants., Patients and Methods: 41 cholestatic infants were enrolled as cases and 11 healthy infants as control subjects. S. Cu and S. ceruloplasmin were done for all infants and hepatic Cu was measured in the liver specimen in cases., Results: Cases were 63.5% males with their age ranging between 1 and 7 months, while control subjects were 45.5% males with an age range between 3 and 18 months. Among cases, 41.5% had biliary atresia and 58.5% had intrahepatic cholestasis. Cholestatic infants had significantly higher levels of S. Cu and S. ceruloplasmin than control subjects and their hepatic Cu concentration was significantly higher than literature control. Infants with biliary atresia showed higher levels of Cu indices, with no statistical significance. Serum and hepatic Cu levels positively correlated with each other and with S. ceruloplasmin. Results of ROC curve showed that S. Cu was highly sensitive and specific for predicting hepatic Cu concentration at cut-off 181 μg/dl., Conclusion: Serum and hepatic Cu concentrations were markedly elevated in patients with cholestasis and positively correlated with each other and with S. ceruloplasmin. S. Cu level can predict hepatic Cu concentration., (Copyright © 2018 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.)

Wilson disease (WD) is a rare and treatable genetic disorder. This paper describes the new advances and author's long-term experiences in the diagnosis of WD. The characteristics in clinical and routine tests are: the age of presentation can be quite broad, the WD could not be excluded based on age only; the patients usually have mild digestive symptoms but obvious chronic liver disease signs; liver function tests may reveal normal or a mild elevation in bilirubin, ALT and AST, but quite abnormal in serum albumin and prothrombin time in most patients; Coombs-negative hemolytic anemia, normal or markedly subnormal serum alkaline phosphatase (typically < 40 IU/L) are useful for the diagnosis of fulminant WD. In china, Kayser-Fleischer rings are present in 72.2% of patients at the time of diagnosis, the positive rate is significantly higher in patients with a neurological presentation (93.4%) than patients presenting with liver disease (63.3%), however, they are usually absent in children under 6 years old, occasionly present in patients with chronic cholestatic liver disease. The mean serum ceruloplamin level in WD patients is 71.1 ± 48.7 mg/L, the level is < 200 mg/L in 98.9% of patients, < 100 mg/L in about three fourths patients, < 50 mg/L in about half patients, but it may be low in 50% of patients with severe end-stage liver disease of any etiology too, and even lower than 50 mg/L in patients with nephritic syndrome. Basal 24-hour urinary copper excretion may be≥100 g at presentation in 86.7% of patients with WD, but also in 22% of Patients with certain chronic liver diseases, the sensitivity of penicillamine challenge test is lower than basal urinary copper excretion, however, the specificity is significantly higher than former (97% versus 78%). Hepatic copper determination remains the gold standard for the diagnosis of WD. We have designed a standard method for hepatic copper determination. The most useful cut-off value is 209 g/g dry wt using our method, with the sensitivity of 99.4%, and specificity of 96.1%. However, long-standing hepatic failure and or obstruction can cause heptic copper elevations into the WD area. In recent years, direct complete DNA sequencing has become easy, rapid, less expensive and commercially available. Currently reported mutation detection rate is 90%, the specificity is almost 100%. The limitation to the method has been the ability to identify all the affected alleles in suspected individuals. If no mutation is identified, the diagnosis of WD could not be excluded. None of the laboratory parameters alone allows a definite diagnosis of WD. The WD diagnostic scoring system based on a composite of key parameters helps clinicians to gauge the degree of certainty of the diagnosis: WD scores greater than 4, the diagnosis of WD is highly likely; score 0 or 1, the diagnosis is unlikely. However, the WD diagnosis could not be excluded in suspected patients who do not perform genetic test and hepatic copper determination. Patients with chronic cholestatic liver disease may have scores more than 4.

Background US and European guidelines suggest the use of calculated non-caeruloplasmin-bound copper (free copper index) for the diagnosis and management of Wilson's Disease. However, there is concern that the required analytical measurements of caeruloplasmin and copper may not be sufficiently robust at the concentrations usually found. Methods Aliquots of six plasma specimens were sent to laboratories participating in the UK National External Quality Assessment Scheme for copper and caeruloplasmin. The variability of these two reported measurements and the calculated non-caeruloplasmin-bound copper concentrations were compared. The variability of caeruloplasmin reference ranges quoted by laboratories was also investigated. Results No laboratories use the required enzymatic methods in the calculation of non-caeruloplasmin-bound copper. The interlaboratory variations in caeruloplasmin concentrations and calculated non-caeruloplasmin-bound copper concentrations were very considerable so making clinical interpretation unreliable. Wide differences in the caeruloplasmin reference ranges used were also found. Conclusions Such variations of the calculated non-caeruloplasmin-bound copper concentrations and the predominant use of immunological methods for measuring caeruloplasmin preclude a clinical role for this calculated value in the investigation of Wilson's disease.

We investigated oxidative stress markers and metal ions in patients with Alzheimer's disease (AD). The serum levels of ceruloplasmin (CER), C-reactive protein (CRP), uric acid (UA), homocysteine (Hcy), copper, iron, and zinc were determined in 125 patients with AD (mild, n = 2 8; moderate, n = 42; and severe, n = 55) and 40 healthy control (HC) participants. Compared to HC, CER and UA levels were significantly lower in moderate and severe AD groups, whereas CRP and Hcy levels were significantly higher in the severe AD group. Copper level was significantly higher in moderate and severe AD groups than the other groups. Compared to HC, iron level was significantly higher in patients with AD, whereas zinc level was significantly lower in patients with AD. In patients with AD, the severity of cognitive impairment was positively correlated with CER, UA, and zinc levels, whereas it was negatively correlated with copper level. Taken together, our findings provide a novel approach to assess AD progression.

Inhibition of the mitogen-activated protein kinase/extracellular signal-regulated (MAPK/ERK) pathway is an attractive therapeutic approach for human cancer therapy. In the course of evaluating structurally distinct small molecule inhibitors that target mitogen-activated protein kinase kinase (MEK) and ERK kinases in this pathway, we observed an unusual, dose-related increase in the incidence of green serum in preclinical safety studies in rats. Having ruled out changes in bilirubin metabolism, we demonstrated a 2- to 3-fold increase in serum ceruloplasmin levels, likely accounting for the observed green color. This was not associated with an increase in α-2-macroglobulin, the major acute phase protein in rats, indicating that ceruloplasmin levels increased independently of an inflammatory response. Elevated serum ceruloplasmin was also not correlated with changes in total hepatic copper, adverse clinical signs, or pathology findings indicative of copper toxicity, therefore discounting copper overload as the etiology. Both ERK and MEK inhibitors led to increased ceruloplasmin secretion in rat primary hepatocyte cultures in vitro, and this increase was associated with activation of the Forkhead box, class O1 (FOXO1) transcription factor. In conclusion, increased serum ceruloplasmin induced by MEK and ERK inhibition is due to increased synthesis by hepatocytes from FOXO1 activation and results in the nonadverse development of green serum in rats.

Aceruloplasminaemia is an autosomal recessive disorder of iron metabolism which is characterised by diabetes, neurodegeneration and anaemia. It should be considered in the differential diagnosis of adult onset, antibody-negative diabetes associated with persistent mild anaemia and hyperferritinaemia and/or progressive neuropsychiatric impairments., (© 2017 Royal Australasian College of Physicians.)

Human serum samples were evaluated for oxidative stress with the d-ROMs test. The ceruloplasmin (CP) and copper contents of the samples was independently measured and compared to those calculated on the basis of the d-ROMs test results for pure CP solutions. The d-ROMs readings did not show any significant correlation with either the CP or copper contents of the samples. Critical interference of CP on the d-ROMs test was therefore excluded and the usefulness of the test in the evaluation of global oxidative status of a biological sample could be reassessed.

In this study, Cyprinus carpio was exposed to 0.25mgL(-1) copper as either copper sulfate (CuSO4) or copper oxide nanoparticles (nano-Cu), and 25mgL(-1) copper as nano-Cu for 14days. CuSO4 and high concentration of nano-Cu led to a significant increase in plasma total copper levels. Plasma free copper levels increased significantly in all copper-exposed treatments. Except for low concentration of nano-Cu after 7 and 14days, copper exposure generally led to a significant decrease in plasma ceruloplasmin levels. Plasma iron levels increased significantly in CuSO4 (all times) and nano-Cu (7th and 14th days) treatments. A significant elevation in plasma total iron binding capacity (TIBC) was observed after 3days in the fish exposed to low concentration nano-Cu, and after 14days in all copper-exposed treatments. Transferrin saturation (TSA) ratio showed significant increase in CuSO4 (3rd and 7th days) and the high concentration nano-Cu (7th day) treatments. Decrease in plasma chloride (7th and 14th days) and sodium (14th days) was observed in CuSO4 treatment. In conclusion, the results suggest that ionic copper is mainly absorbed via fish gill, whereas, nano-copper are more likely absorbed via gut. Also, data suggest that ionic copper has more adverse effects on the examined plasma biochemical characteristics compared to the equivalent nano-copper concentration, which may be due to the lower copper absorption by fish in the nano-copper suspension., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Meta-analyses demonstrate copper involvement in Alzheimer's disease (AD), and the systemic ceruloplasmin status in relation to copper is an emerging issue. To deepen this matter, we evaluated levels of ceruloplasmin concentration, ceruloplasmin activity, ceruloplasmin specific activity (eCp/iCp), copper, non-ceruloplasmin copper iron, transferrin, the ceruloplasmin/transferrin ratio, and the APOE genotype in a sample of 84 AD patients and 58 healthy volunteers. From the univariate logistic analyses we found that ceruloplasmin concentration, eCp/iCp, copper, transferrin, the ceruloplasmin/transferrin ratio, and the APOE genotype were significantly associated with the probability of AD. In the multivariable logistic regression analysis, we selected the best subset of biological predictors by the forward stepwise procedure. The analysis showed a decrease of the risk of having AD for eCp/iCp (p = 0.001) and an increase of this risk for non-ceruloplasmin copper (p = 0.008), age (p = 0.001), and APOE-ɛ4 allele (p <  0.001). The estimated model showed a good power in discriminating AD patients from healthy controls (area under curve: 88% ; sensitivity: 66% ; specificity 93%). These data strength the breakdown of copper homeostasis and propose eCp/iCp as a reliable marker of ceruloplasmin status.

Objective: Iron homeostasis appears altered in Parkinson's disease (PD). Recent genetic studies and meta-analyses have produced heterogeneous and inconclusive results. In order to verify the possible role of iron status in PD, we have screened some of the main metal gene variants, evaluated their effects on iron systemic status, and checked for possible interactions with PD., Materials and Methods: In 92 PD patients and 112 healthy controls, we screened the D544E and R793H variants of the ceruloplasmin gene (CP), the P589S variant of the transferrin gene (TF), and the H63D and C282Y variants of the HFE gene, encoding for homologous proteins, respectively. Furthermore, we analyzed serum concentrations of iron, copper and their related proteins., Results: The genetic investigation revealed no significant differences in allelic and genotype distributions between patients and controls. Two different multivariable forward stepwise logistic models showed that, when the effect of sex is considered, an increase of the probability of having PD is associated with low iron concentration and Tf-saturation., Conclusions: This study provides new evidence of the involvement of iron metabolism in PD pathogenesis and reveals a biological effect of sex.

In a randomized clinical trial of calorie restriction (CR), we demonstrated that important cardiovascular disease (CVD) biomarkers were favorably influenced by CR alone and in conjunction with physical exercise. The aim of this study was to examine the effects of CR with or without exercise on copper bound to ceruloplasmin (CuCp), a well-known biomarker for CVD, in overweight men and women enrolled in the CALERIE phase 1 study. Forty-six individuals were randomized to one of four groups for 6 months: control, healthy weight maintenance; CR, 25% CR from baseline energy requirements; CR+exercise, 12.5% CR and 12.5% through aerobic exercise; and low-calorie diet, low-calorie diet until 15% reduction in body weight followed by weight maintenance diet. CuCp was determined in fasting blood samples by a high-performance liquid chromatography-inductively coupled plasma mass spectrometry methodology and compared with changes in body composition and markers of CVD. After 6 months, CR combined with exercise induced a decrease in plasma concentration of CuCp. CuCp was inversely correlated with insulin sensitivity at baseline and after 6 months of intervention. A cluster analysis showed that the percent change of weight after 6 months of intervention was the most important variable that could discriminate the intervention groups. The percent change of CuCp was the only other variable selected by the analysis. Decreased CuCp in overweight subjects by CR combined with exercise suggests a positive effect of this intervention on metabolic health. Further studies to explain the relationship between weight loss and CuCp and its relevance for cardiovascular health are needed., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Acute leukaemia is characterized by fast growth of abnormal clones of haemopoietic precursor cells inside bone marrow leading to undue accumulation in the bone marrow. Acute lymphoblastic leukemia (ALL) is the most common form of childhood cancer., Materials and Methods: The study concerned 50 children diagnosed with ALL (mean age, 8.55±2.54) compared to 40 healthy controls (mean age, 8.00±1.85). The Hb, serum copper, ceruloplasmin oxidase, advanced oxidation protein products (AOPPs), total antioxidant activity (TAA) and protein were measured in all groups. One proteinous component was isolated by gel filtration chromatography from the precipitate produced by polyethylene glycol., Results: Significantly higher levels of AOPP, copper and decrease in total antioxidant activity were noted in the cases. Statistical analysis also showed a significant increase (p<0.01) in the activity of serum ceruloplasmin oxidase in patients with ALL compared to normal subjects. The maximum velocity (Vmax) and Michaelis constant had values of 104.2 U/L and 11.7 mM, respectively. The ΔH* values for ceruloplasmin oxidase in ALL patients were positive, confirming the reaction to be endothermic., Conclusions: The results from this study showed a significant increase in AOPP, ceruloplasmine oxidase and decrease in total antioxidant activity .These parameters may play a role in development of DNA damage in childhood patients with acute lymphoblastic leukemia (ALL). The ΔS* and ΔG* values were negative, these refer that the reaction of ES formation is spontaneous, but needs energy in a so-called endergonic reaction. Also the negative ΔS* value of ceruloplasmin oxidase indicates that the complex [ES*] is further modulated through increasing structure arrangement.

Alzheimer's disease (AD) is the most common form of dementia. A myriad of complex factors contribute to AD, promoting the deposition in plaques of amyloid-beta (Aβ), which is the main constituent of this pathognomonic sign of AD at autopsy brain inspection. Aβ toxicity is related to oxidative stress, which results in synaptic loss in specific brain areas, eventually leading to cognitive decline. Metal, and especially copper, dyshomeostasis is a key factor in these processes. Recent studies have demonstrated that the serum fraction of copper that is not bound to ceruloplasmin (Non-Cp copper, also known as 'free' or labile copper) increases in a percentage of AD patients and mild cognitive impairment (MCI) subjects; this is considered a precursor of AD. Non-Cp copper is the exchangeable fraction of low molecular weight copper in serum. It is distinguished from the copper structurally bound to the ceruloplasmin protein, a master protein of iron metabolism. Non-Cp copper levels are higher than normal reference values (range 0-1.6μmol/L) in about 50% of amnestic MCI subjects and 60% of AD patients, typifying them in a subset of AD. Meta-analyses, genetic studies and a prognostic study evaluating the predictive value of Non-Cp copper in MCI conversion to full AD demonstrate the existence of this copper phenotype of AD., (Copyright © 2014 Elsevier GmbH. All rights reserved.)

Background: Copper and its main transport protein ceruloplasmin have been suggested to promote the development of atherosclerosis. Most of the data come from experimental and animal model studies. Copper and mortality have not been simultaneously evaluated in patients undergoing coronary angiography., Methods and Results: We examined whether serum copper and ceruloplasmin concentrations are associated with angiographic coronary artery disease (CAD) and mortality from all causes and cardiovascular causes in 3253 participants of the Ludwigshafen Risk and Cardiovascular Health Study. Age and sex-adjusted hazard ratios (HR) for death from any cause were 2.23 (95% CI, 1.85-2.68) for copper and 2.63 (95% CI, 2.17-3.20) for ceruloplasmin when we compared the highest with the lowest quartiles. Corresponding hazard ratios (HR) for death from cardiovascular causes were 2.58 (95% CI, 2.05-3.25) and 3.02 (95% CI, 2.36-3.86), respectively. Further adjustments for various risk factors and clinical variables considerably attenuated these associations, which, however, were still statistically significant and the results remained consistent across subgroups., Conclusions: The elevated concentrations of both copper and ceruloplasmin are independently associated with increased risk of mortality from all causes and from cardiovascular causes.

The fraction of copper not bound to ceruloplasmin seems altered in Alzheimer's disease (AD). We have addressed this notion evaluating all the studies carried out from 1996 until March 2013 by means of meta-analysis. We performed our analysis on diverse indices evaluating the relationship between copper and ceruloplasmin in general circulation, namely 'Non-Cp copper', '% Non-Cp copper', and 'Adjusted copper'. For Non-Cp copper and % Non-Cp copper, the correct stoichiometry between copper and ceruloplasmin (6-8 atoms of copper for each ceruloplasmin molecule) in healthy controls has been adopted as criterion for the study to be included in the meta-analysis evaluating data with the canonic Walshe's formula for Non-Cp copper. Copper to ceruloplasmin ratio (Cu:Cp), which is an internal quality control check for ceruloplasmin calibration, was used as an index of the actual stoichiometry in the specimens. Adjusted (Adj-Cp) copper, even though less reliable, was calculated, allowing the evaluation of all the studies selected. An additional meta-analysis of systemic total copper was re-calculated accounting for all the studies carried out from 1983 to March 2013. Ten studies were analyzed in the meta-analysis for Non-Cp copper and % Non-Cp copper reaching a pooled total of 599 AD subjects and 867 controls. For Adj-Cp copper, 14 studies were analyzed with a pooled total of 879 AD and 1,712 controls. 27 studies were considered for systemic total copper meta-analysis, with a pooled total of 1,393 AD and 2,159 controls. All the copper indices analyzed were significantly higher in AD subjects compared to healthy controls.

To understand the role of the key copper-regulating gene, ATP7B, in copper dyshomeostasis associated with Alzheimer's disease (AD), we analyzed the serum levels of copper, ceruloplasmin and 'free' (i.e., non-ceruloplasmin bound) copper in 399 patients with AD and 303 elderly healthy controls. We also performed analyses of informative variants of ATP7B. AD patients had higher levels of copper and free copper than controls. Individuals with free copper levels higher than 1.6 μmol/L (the upper value of the normal reference range) were more frequent among cases (p < 0.001). Among these individuals, those who were carriers of the ATP7B variants accounted for a large proportion of the free copper levels, specifically in the AD group (p < 0.01). Our results suggest the existence of a 'copper dysfunction' phenotype of sporadic AD which has a genetic basis. They also suggest that free copper is a risk factor for this disorder, modulating additional pathways leading to the disease cascade.

Copper and iron dyshomeostasis has been implicated directly or indirectly in the pathogenesis of neurodegenerative diseases. Previously, we have shown the first in vivo evidence of significant increase in the hippocampus copper and zinc content with spatial memory impairments, astrocytes swelling (Alzheimer type-II cells) coupled with increase in the number of astrocytes, copper deposition in the choroid plexus, and degenerated neurons in copper-intoxicated Wistar rats. In continuation with our previous study, the aim of this study was to further investigate the effects of intraperitoneally injected copper lactate (0.15 mg Cu/100 g body weight) daily for 90 days on serum "free" copper levels, iron levels in the liver, and hippocampus by atomic absorption spectrophotometry and histopathological study of the liver and brain tissues of Wistar rats using Perls' Prussian blue (PPB) stain. A massive significant increase in serum "free" copper (79.48% increase) along with strong correlation (r = 0.978) was found between serum copper and serum "free" copper in copper-intoxicated rats. No significant difference was detected in hepatic and hippocampus iron levels between control and copper-intoxicated rats. PPB stain demonstrated very few scattered grade 1 haemosiderin deposits within sinusoidal cells predominantly Kupffer cells; however, brain sections were negatively stained with PPB stain. In conclusion, the current study demonstrates that chronic copper toxicity causes increase in serum "free" copper, which may serve as predisposing factor for the development of neurodegeneration and memory deficits, and grade 1 haemosiderin deposition in Kupffer cells without altering hepatic and hippocampus iron levels in male Wistar rats.

Aim: To compare patients with advanced stage endometriosis with control patients without endometriosis with respect to serum Copper (Cu) and Ceruloplasmin (Cp) levels and oxidative stress markers in order to evaluate the importance of these parameters in the pathogenesis of endometriosis., Patients and Methods: A total of 72 women who underwent laparoscopy or laparotomy for evaluation of infertility, pelvic pain, pelvic mass, tubal ligation or endometriosis were enrolled for this prospective clinical study. Patients were divided into two groups by visual diagnosis at surgery and histological confirmation of endometriosis: control patients (n=41) without endometriosis and study group (n=31) with stage III/IV (advanced stage) endometriosis. Serum Cu, Cp, total antioxidant status (TAS), total oxidant status (TOS), oxidative stress index (OSI), paraoxonase-1 (PON-1), malondialdehyde (MDA), triglyceride (TG), total cholesterol (TC), high-density lipoprotein (HDL) and low-density lipoprotein (LDL) levels were compared between the two groups. Correlations between Cu, Cp and oxidative stress markers were determined., Results: Serum TOS, OSI, Cu, Cp, TG, TC, LDL were significantly higher, whereas TAS, PON-1 activity and HDL were significantly lower, in women with advanced-stage endometriosis than in control groups. There was no difference in serum MDA activities between the two groups. Positive correlations were found between Cu and TOS, Cu and OSI, Cu and Cp, while a negative correlation was found between Cu and PON-1 in the advanced-stage endometriosis group. Positive correlations were found between Cp and TOS, and Cp and OSI in the advanced-stage endometriosis group., Conclusions: Cu and Cp appear to be associated with the etiopathogenesis of and oxidative stress in endometriosis.

Objectives: Nonalcoholic fatty liver disease (NAFLD) in adolescents and children is rapidly becoming one of the most common causes of chronic liver disease worldwide. NAFLD varies from simple fatty liver to nonalcoholic steatohepatitis (NASH) with possible fibrosis. Several studies suggest that oxidative stress plays a central role in several metabolic abnormalities and cellular damage that characterize NAFLD. We investigated whether transition metals and their related proteins were related to NAFLD symptoms and their underlying processes., Methods: We measured copper, iron, ceruloplasmin (Cp) concentration and activity, transferrin (Tf), ferroxidase activity, and ferritin, and we calculated Tf saturation and Cp to Tf ratio (Cp/Tf) as an index of the activity of the antioxidant Cp-Tf system in 100 children with biopsy-proven NAFLD. Pediatric patients were grouped by nonalcoholic fatty liver disease score (NAS) ≥ 5 (30 subjects) and NAS < 5 (70)., Results: Cp distinguished children with NAS ≥ 5 from those with NAS < 5 with an accuracy of 82%. Specifically, a receiver operator characteristics curve showed that a cutoff of 28.6 mg/dL separated NAS ≥ 5 from NAS < 5 with a specificity of 92% and a sensitivity of 76%. The Cp/Tf ratio, as well as copper concentration and Cp activity, decreased in the NAS ≥ 5 group, pointing out an imbalance in metal regulation. Either copper or Cp concentrations were lower in subjects having ballooning., Conclusions: Serum antioxidant capacity owing to Cp failure is strongly associated with NAFLD-related damage. Further studies are, however, required to clarify the role of Cp in NAFLD pathogenesis and to evaluate its potential application as diagnostic marker.

Introduction: Rheumatoid arthritis (RA) is a chronic, autoimmune-based disease of the connective tissue with still unknown etiology. Numerous studies have indicated the association between Copper (Cu) and ceruloplasmin (Cp) concentrations and pathogenesis of RA., Objective: To compare the concentrations of Cu and Cp in different biological samples and their correlation with the inflammatory process, between a group of patients with RA and a control group of healthy individuals., Materials and Methods: The study enrolled 74 Caucasian patients (20 men and 54 women), aged 29-50 (mean age 39.8±6.1 years) diagnosed with RA. The control group consisted of 30 healthy Caucasian individuals. Copper levels were assessed by atomic absorption spectroscopy., Results: Among RA patients the mean Cu level was significantly higher in serum and hair compartments and significantly lower in erythrocytes, compared with the control group (p<0.01). The Cp concentration was also higher in serum of RA patients (p<0.001). A statistically significant, positive correlation between the Cp serum concentration and the ESR values (r(s)=0.38; p<0.007) was found. No significant influence of pharmaceutical treatment (methotrexate, non-steroidal anti-inflammatory drugs, glucocorticoids, calcium, vitamin D3 and sulphasalazine) on serum Cu was found., Conclusions: It seems that the 'copper status' in patients with RA, based on the measurement of Cu and Cp levels in blood serum is correlated with presence of the inflammatory process. The hair could serve as a useful, additional diagnostic material. Some other factors, different from the applied treatment, can probably influence the Cu levels in patients with RA.

Background: Several studies have reported that peripheral levels of copper and ceruloplasmin (CP) can differentiate patients with Alzheimer's disease (AD) from non-AD cases. The aim of this study was to determine the diagnostic value of serum copper, CP, and non-CP copper levels in a large cohort of AD subjects., Methods: Serum copper and CP concentrations were measured at baseline and at 18-months in participants from the Australian Imaging Biomarkers and Lifestyle Study of Ageing. Cross-sectional and longitudinal analyses were conducted using both univariate and multivariate testing adjusting for age, gender, total protein, and ApoE ε4 genotype status., Results: There was no significant difference in levels of serum copper or CP between the AD and healthy control groups, however, we identified a near-significant decrease in non-CP copper in the mild cognitive impairment and AD groups at baseline (p = 0.02) that was significant at 18-months (p = 0.003)., Conclusion: Our results suggest that there may be decreased non-CP copper levels in mild cognitive impairment and AD, which is consistent with diminished copper-dependent biochemical activities described in AD.

The study objective was to evaluate the effect of occupational lead exposure on blood concentrations of zinc, iron, copper, selenium and proteins related to them, such as transferrin, caeruloplasmin and haptoglobin. The examined group consisted of 192 healthy male employees of zinc-lead works. By the degree of lead exposure, the exposed group was subdivided into three subgroups. The control group was composed of 73 healthy male administrative workers. The markers of lead exposure (blood levels of lead and zinc protoporphyrin) were significantly elevated in the exposed group compared with the control group. Additionally, concentrations of copper and caeruloplasmin were raised. The significant increase in haptoglobin level was observed only in the low exposure group. Selenium levels were significantly decreased, whereas iron, zinc and transferrin levels were unchanged in the exposed group compared with the control group. There were positive correlations between the lead toxicity parameters and the copper and caeruloplasmin levels. In conclusion, the effect of occupational exposure to lead on the metabolism of trace metals appears to be limited. However, significant associations between lead exposure and levels of copper and selenium were shown. Changed levels of positive acute-phase proteins, such as caeruloplasmin and haptoglobin, were also observed.

The copper concentration in serum can be affected by the presence of other trace elements such as silver. Low serum copper may result in decreased caeruloplasmin synthesis. We report the case of a 59-year-old woman, who was admitted to hospital with acute psychosis and who had been ingesting chronically, colloidal silver.

Variations of copper (Cu) concentration and ceruloplasmin (Cp) activity in serum and plasma of dairy cows at different stages of lactation were assessed in 240 Holstein dairy cows. Furthermore, ceruloplasmin to copper ratios were also investigated. The cows were classified according to their lactation stages into four different groups as close-up stage (3-1 week(s) antepartum), fresh lactation stage (0-1 week postpartum), early lactation stage (3-5 weeks postpartum), and mid-lactation stage (15-18 weeks postpartum). Each group consisted of 60 multiparous cows. Serum and heparinised plasma samples were obtained from each cow. Concentrations of serum copper (sCu) and plasma copper (pCu) as well as activities of plasma Cp (pCp) were higher in the group of fresh lactation stage than other groups (P < 0.05). Serum Cp (sCp) exhibited no significant difference between fresh lactation and early lactation groups (P > 0.05). Low correlations were obtained between sCp and pCu, sCp and sCu, and sCu and pCu. Plasma copper concentration and plasma ceruloplasmin activity were higher than serum copper concentration and serum ceruloplasmin activity, respectively (P < 0.001). The ratios of Cp activity to Cu concentration (Cp/Cu) were not significantly changed in the different lactation stages of dairy cows (P > 0.05). Use of sCp/pCu and sCp/sCu rather than pCp/pCu will reduce the calculated value of Cp/Cu. Furthermore, for evaluation of copper status, use of sCp/sCu or sCp/pCu identified more animals as 'low' and 'marginal' than using pCp/pCu (P < 0.001). It can be concluded that ceruloplasmin and copper undergo a physiological increase just after calving; thus, their values should be interpreted with caution during assessment of copper status. Plasma measurements should be used for calculation of Cp/Cu, and further research is required to refine diagnosis criteria for use of such ratio in determining copper status in dairy cows.

Low copper and ceruloplasmin in serum are the diagnostic hallmarks for Menkes disease, Wilson disease, and aceruloplasminemia. We report on five patients from four unrelated families with these biochemical findings who presented with a lethal autosomal-recessive syndrome of congenital cataracts, hearing loss, and severe developmental delay. Cerebral MRI showed pronounced cerebellar hypoplasia and hypomyelination. Homozygosity mapping was performed and displayed a region of commonality among three families at chromosome 3q25. Deep sequencing and conventional sequencing disclosed homozygous or compound heterozygous mutations for all affected subjects in SLC33A1 encoding a highly conserved acetylCoA transporter (AT-1) required for acetylation of multiple gangliosides and glycoproteins. The mutations were found to cause reduced or absent AT-1 expression and abnormal intracellular localization of the protein. We also showed that AT-1 knockdown in HepG2 cells leads to reduced ceruloplasmin secretion, indicating that the low copper in serum is due to reduced ceruloplasmin levels and is not a sign of copper deficiency. The severity of the phenotype implies an essential role of AT-1 in proper posttranslational modification of numerous proteins, without which normal lens and brain development is interrupted. Furthermore, AT-1 defects are a new and important differential diagnosis in patients with low copper and ceruloplasmin in serum., (Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Laparoscopic adjustable gastric banding (LAGB) causes significant weight loss in morbidly obese adults. However, its consequences on nutritional status still remain unclear. There are a few studies determining the nutritional status after LAGB and none have focused on the serum levels of zinc (Zn), copper (Cu), and ceruloplasmin (CP). We aimed to investigate the effects of LAGB surgery on plasma Zn, Cu, and CP levels. Thirty patients with LAGB with morbid obesity were included. Blood samples were collected preooperatively and in the postoperative third month to determine plasma Zn, Cu, and CP levels. The mean preoperative and postoperative body mass indexes (BMI) were 44.9 ± 7.4 kg/m(2) and 44.1 ± 6.5 kg/m(2), respectively. The mean weight loss was 12.9 ± 3.3 kg at the postoperative third month. The postoperative Zn (500 ± 130 ng/ml), Cu (280 ± 80 ng/ml), and CP (23.9 ± 8.8 mg/dl) values were statistically significantly lower than the preooperative Zn (740 ± 230 ng/ml), Cu (370 ± 80 ng/ml) and CP (33.3 ± 15.7 mg/dl) levels (p < 0.05). Decreases in the plasma levels of Zn, Cu, and CP were seen postoperatively following LAGB surgery. The nutritional status of LAGB-applied patients should be monitored and mineral supplementation may be considered.

Increases in serum and liver copper content are noted during iron deficiency in mammals, suggesting that copper-dependent processes participate during iron deprivation. One point of intersection between the 2 metals is the liver-derived, multicopper ferroxidase ceruloplasmin (Cp) that is important for iron release from certain tissues. The current study sought to explore Cp expression and activity during physiologic states in which hepatic copper loading occurs (eg, iron deficiency). Weanling rats were fed control or low iron diets containing low, normal, or high copper for ∼ 5 weeks, and parameters of iron homeostasis were measured. Liver copper increased in control and iron-deficient rats fed extra copper. Hepatic Cp mRNA levels did not change; however, serum Cp protein was higher during iron deprivation and with higher copper consumption. In-gel and spectrophotometric ferroxidase and amine oxidase assays demonstrated that Cp activity was enhanced when hepatic copper loading occurred. Interestingly, liver copper levels strongly correlated with Cp protein expression and activity. These observations support the possibility that liver copper loading increases metallation of the Cp protein, leading to increased production of the holo enzyme. Moreover, this phenomenon may play an important role in the compensatory response to maintain iron homeostasis during iron deficiency.

Setting: Investigation of trace metal behaviour during the treatment of active pulmonary tuberculosis (PTB) patients residing in Romania., Objective: To assess, follow and identify serum iron (Fe), copper (Cu) and zinc (Zn) levels in patients diagnosed and treated for active PTB., Design: Chemical and statistical analysis of various biochemical parameters in 47 subjects diagnosed with active PTB and 170 healthy Romanian residents., Results: Copper and ceruloplasmin levels were increased in patients with active PTB compared to the control group (P < 0.01), while the serum Zn level was significantly lower than in healthy subjects (P < 0.01) or within the normal range. The present study shows that there is a significant correlation between serum Cu concentrations and ceruloplasmin., Conclusions: This study provides preliminary evidence that Zn and Fe redistribution is operating as a primary host defence mechanism to reduce the availability of metals for microbial metabolism during infection. The study also calls attention to the fact that anti-tuberculosis treatment is sufficient to enhance the concentration of the antioxidant species (Cu and ceruloplasmin). The data obtained suggest that serum Cu, Zn and Cu/Zn levels may serve as indirect pointers in the diagnosis of a disease but they cannot be considered as specific markers for TB.

The blue copper protein ceruloplasmin has been of interest to psychiatrists for decades following Heilmeyer's observation of elevated serum copper levels in schizophrenic patients. Immunoturbidimetry, however, does not yield elevated serum ceruloplasmin concentrations in schizophrenia while ceruloplasmin-related oxidase activity appears to be elevated in patients with schizophrenia and reduced in patients with Alzheimer's disease. Low serum concentrations of immuno-turbidimetrically measured ceruloplasmin, and of oxidase activity, are typical of Wilson's disease, Menkes' disease, and aceruloplasminemia, three familial neurodegenerative disorders of pronounced variability, with regard to both genotype and phenotype. Especially patients with Wilson's disease may exhibit behavioural symptoms only over a long period. Heterozygous carriers of Wilson's disease and aceruloplasminaemia may have low serum ceruloplasmin concentrations; they will not develop somatic symptoms, but the significance of these carrier states, or of "hypoceruloplasminaemia", with regard to mental disorders is unknown., (© Georg Thieme Verlag KG Stuttgart · New York.)

The idea that copper may play a role in the pathogenesis of Alzheimer's disease is gaining momentum. Serum copper and ceruloplasmin were measured by both enzymatic (eCp) and immunologic (iCp) methods in 28 patients with Alzheimer's disease and 29 age-matched controls. ''Free copper'' was determined by subtracting copper accounted for in the eCp assay from total serum copper. Percentage free copper, that is the proportion of serum copper not bound to ceruloplasmin, was significantly elevated in patients with Alzheimer's compared to controls. There was significantly more ''defective'' ceruloplasmin, which is apoceruloplamin lacking its copper, in Alzheimer's disease than in normal controls. This abnormality may precede the clinical onset of the disease and help predict risk of disease onset. Increased exposure to environmental copper (eg, the spread of copper plumbing and the use of copper in supplements) and/or defective ceruloplasmin function may play a role in the current epidemic of Alzheimer's disease.

Aim: To evaluate the relationship between the concentration of elemental Cu and activity of caeruloplasmin (CP) in the plasma and serum of farmed red deer (Cervus elaphus)., Methods: Paired serum and heparinised plasma samples taken from 142 deer from 10 herds in the North Island of New Zealand were tested for the concentration of elemental Cu and activity of CP. Additionally, liver biopsy samples were taken from 49 of the deer (all one herd). The relationship between individual results for the concentration of elemental Cu and activity of CP was examined using a segmented model, with random slope and intercept and threshold., Results: The activity of CP in plasma and that in serum were strongly correlated (R2=0.994), with a high level of agreement. The concentration of Cu and activity of CP also showed a strong association (R2>0.88 for both plasma and serum), although there were significant differences between herds, with the segmented regression model providing the best fit rather than a linear mixed model. Using the current thresholds for elemental Cu, the relationship between the concentration of Cu and activity of CP suggested that an activity of CP of <4 IU/L indicates Cu deficiency, and that deer with an activity of CP of >or=7 IU/L have adequate Cu status., Conclusions: The relationship between elemental Cu and CP is markedly different from the simple linear relationship previously reported for cattle. Above a threshold of 10 IU/L, the rise in elemental Cu per unit increase in activity of CP was 50% of that below 10 IU/L. This is probably because above this threshold the oxidative activity of CP per enzyme unit was greater., Clinical Relevance: The association between concentration of Cu and activity of CP was robust enough to define provisional thresholds for determining Cu status. However, the proximity of the deficiency threshold to the limit of detection of the CP test, the effect of herd on the association, and the inherent disadvantages of using an enzymatic system, mean that activity of CP should not be used routinely to estimate Cu status in deer. When assessing the Cu status of deer based on blood samples, the concentration of Cu in plasma or serum should be used.

High intracranial pressure (ICP) is a prominent secondary pathology after traumatic brain injury (TBI) and is a major contributor to morbidity and mortality. Currently, there are no clinically proven methods for predicting which TBI patients will develop high ICP. In the present study, we examined whether the serum levels of the copper-binding protein ceruloplasmin are differentially altered in patients with elevated ICP (> or =25 mmHg) vs. those whose ICP remained below 20 mmHg throughout the study period. Consistent with its role as an acute-phase reactant, we found that ceruloplasmin levels were significantly increased by 3 days post-TBI compared with healthy volunteers. However, prior to this delayed increase, ceruloplasmin levels during the first 24 hr following injury were found to be significantly reduced in patients who subsequently developed high ICP. This decrease was found to have prognostic accuracy in delineating TBI patients based on their ICP status (cutoff of 140 microg/ml; sensitivity: 87%, specificity: 73%), Likewise, low total serum copper (below 1.32 microg/ml) was also found to be predictive of high ICP (sensitivity 86%, specificity 73%). These results suggest that initial serum ceruloplasmin/copper levels may have diagnostic value in predicting patients at risk for developing high intracranial pressure.

The electron paramagnetic resonance technique was used to study the venous blood levels of ceruloplasmin (CP) in 93 cancer patients with Stages I-IV malignancies of the urinary bladder and kidneys. Two groups were selected as a control; one of them comprised 44 donors who were considered to be apparently healthy and the other included 32 outpatients, some of whom had noncancer diseases. It has been established that in urological cancer, the level of the paramagnetic phase of Cu2+ -CP may vary in the wide range: from the lower to exceeding upper normal range in noncancer disease. The content of Cu2+ -CP does not virtually depend on the site and differentiation of a tumor. A correlation between the blood concentration of Cu2+ -CP and erythrocyte sedimentation rate (ESR) in urological cancer patients has been considered. Determination of CP levels at the ESR exceeding the normal values may be expedient for the early diagnosis of cancer and also an addition to the biological individual screening of patients in the preoperative period to choose the correct and effective treatment tactics.

The concentration of plasma copper, ceruloplasmin (CRP), non-ceruloplasmin-bound Cu (NCBC), and metallothioneins (MTs) were studied as putative biomarkers for neurodegenerative diseases in patients and in their first-degree relatives. We found increased levels of Cu in the plasma of Alzheimer's disease (AD), Parkinson's disease (PD), and vascular dementia (VD) patients, and the increase observed in VD group was linked to the evolution of the disease. CRP was also elevated in response to the inflammatory component of the diseases, however, a correlation with illness progression was only observed in VD patients. The level of MTs is proportional to the evolution of VD. The Cu/CRP and Cu/MTs ratios are both indicative of disease progression for AD patients but not for those with PD or VD. Moreover, there is a correlation between the NCBC levels and the cognitive impairment estimated through the Mini-mental State Examination (MMSE) scale. This dependence is linear for AD and PD patients and non-linear for the VD ones. The relative values of NCBC showed dependence on the disease duration, especially for AD. Copper measurement and the Cu/CRP ratio may be predictive markers of risk for the first-degree relatives of AD patients. We believe that these results are valuable as a reliable clinical tool., (Copyright 2009 Elsevier B.V. All rights reserved.)

Abiogenic Ag(I) ions have electronic structure, similar to Cu(I) ions and can compete with Cu(I) for binding sites of proteins which transport copper from extracellular media to sites of cuproenzyme formation in the cell. Rodents receiving Ag-salts with food develop extracellular deficiency of copper associated with ceruloplasmin (Cp, the major copper-transporting protein in blood serum of vertebrates). The present work focuses on the studies of biochemical and physicochemical properties of Cp, obtained from blood serum of rats, which received AgCl with food for 4 weeks (Ag-rats). Cp-fractions from blood serum of Ag-rats (Ag-Cp) were obtained by ion-exchange chromatography with stepped gradient of NaCl. Each fraction was tested for oxidase and ferroxidase activities by direct measurement of catalytic activity in the gel, and for specific activity in holo-Cp in oxidation of chromogenic substrate. Molecular mass, electrophoretic mobility and ratio of apo- and holo-forms in Ag-Cp fractions were evaluated by immunoblotting. Ag-Cp samples did not contain products of spontaneous partial proteolytic degradation, characteristic of holo-Cp samples. Fractions of Ag-Cp and holo-Cp (from blood serum of control rats) were compared by optical spectra, tertiary structure, susceptibility to thermal denaturation, and by atomic Cu and Ag content. Ag-Cp contained 1-2% Cp, which is similar by spectral and catalytic properties with holo-Cp. [Ag]:[Cu] ration in Ag-Cp samples was about 4:1. As evidenced by circular dichroism and differential scanning calorimetric studies, the major apo-fraction of Ag-Cp lacked tertiary structure of native Cp and was significantly misfolded, which might explain its resistance to spontaneous partial proteolytic degradation.

Objective: To explore the relationship between hypoceruloplasminemia-related movement disorder (HCMD) without Kayser-Fleischer rings in Wilson disease (WD) and ATP7B gene mutation., Methods: Clinical feature, serum ceruloplasmin (CP), total serum copper, non-CP-bound serum copper (nCC), urine copper, and ATP7B gene sequence were investigated in 24 patients with HCMD., Results: The patients with HCMD exhibited a long-term stable course of diseases. Serum CP in HCMD group (0.178 +/- 0.025 g/l) was lower than healthy control group (0.291 +/- 0.049 g/l, P < 0.05). Total serum copper in HCMD group was 0.578 +/- 0.284 microg/l and was lower than normal lower limit obviously (

Heart surgery with cardiopulmonary bypass (CPB) nowadays has become a routine procedure. However, under nonadequate hemodynamic conditions and because of the changes related to ischemia-reperfusion, there is a possibility to provoke oxidative stress with all undesirable consequences. Copper (Cu) is closely related to this stress, taking part in the formation of the hazardous-free radicals. Meanwhile, at least in the pediatric area, little is known about Cu kinetics during cardiac surgery. The purpose of the present work was to study Cu and ceruloplasmin (Cp) dynamics during surgery with CPB in children. Twenty-one patients of both genders from Campo Grande, Brazil with congenital heart conditions were enrolled in the investigation. Blood samples were collected before the surgery and during and 24 h after it. Cu and Cp levels were measured at selected moments and the influence of hemodilution studied. It was concluded that serum Cu dynamics during cardiopulmonary bypass reflects the protective effects of this trace element. Ceruloplasmin levels correlate positively with copper.

Background: The diagnosis of copper deficiency and excess states is challenging. It was hoped that the non-caeruloplasmin-bound ("free") copper would reduce this difficulty; however, it has its own problems. The copper/caeruloplasmin ratio has been advocated as an alternative index of copper status, especially as it would not need gender-derived or age-derived reference intervals. However, there are no comparative data for different populations using different assays., Method: Independent paired copper and caeruloplasmin data were retrospectively obtained for three laboratories. From these data, the copper/caeruloplasmin ratio was calculated, and descriptive statistics for the populations and methods were obtained. The relationship between the copper/caeruloplasmin ratio and both copper and caeruloplasmin were also investigated for the three laboratories., Results: All three datasets displayed a non-Gaussian distribution. The Burton median was statistically different from the two other medians, which did not differ significantly from each other. The regression lines for both copper and caeruloplasmin with the ratio differed from each other., Conclusion: The copper/caeruloplasmin ratio behaves differently depending on the laboratory, the population studied, or both. Thus, cut-offs in the literature are not transferable. Each laboratory should therefore derive its own cut-offs.