Serum Ceruloplasmin Concentrations Research Articles

Changes in serum parameters associated with iron metabolism in male rat exposed to lead

Due to the severe hazardous influences of lead (Pb(2+)) on iron-related diseases, the effects of Pb(2+) on serum parameters associated with iron metabolism have been studied in this project. Male Wistar rats weighing 200-250 g were treated with Pb(2+) for the short and long period of times. The animals received daily intraperitoneal injection of 100 mg Pb(2+) kg(-1) body weight (BW) for 5 days and 4 mg kg(-1) BW of Pb(2+) for 30 and 45 days, respectively. The results show that when animals were treated with both low and high concentrations of Pb(2+), serum iron concentration decreased markedly, by 23.2, 32.8, and 39.9 %, while the sera TIBC and transferrin concentrations increased significantly (p < 0.05). Following short- and long-term exposures to Pb(2+), the percentage of serum transferrin saturation was also decreased in comparison with the untreated control group (p < 0.05). Concentrations of serum copper and ceruloplasmin following Pb(2+) treatments also reduced significantly (p < 0.05). The percentage of hematocrit and hemoglobin levels was reduced (p < 0.05) in all Pb(2+)-treated animals in comparison with the controls. These results suggest that Pb(2+) changes the serum parameters related to iron metabolism, which may play an important role in producing iron-related diseases.

Influence of endurance exercise on serum concentrations of iron and acute phase proteins in racing sled dogs

To determine effects of long-distance racing exercise on iron status in endurance racing sled dogs, with or without anemia. Prospective cohort study. 114 dogs that participated in the 2007 Iditarod Trail Sled Dog Race (59 and 55 dogs that did or did not complete the race, respectively). Stored serum samples obtained from 85 endurance-racing sled dogs that were expected to participate in the race were used to establish study reference intervals and prerace group values for iron-related variables. Blood samples collected from 114 study dogs before (ie, baseline) and after participation in the race were used to determine PCV and serum total protein concentrations before and after racing and assess iron-related variables after racing. Mean values for PCV and serum total protein concentration were decreased after racing, compared with baseline values in the same dogs. Mean serum iron concentration was low, and mean serum ceruloplasmin and C-reactive protein (CRP) concentrations were high in dogs after racing, compared with prerace group values. Mean serum ferritin concentration was high in dogs that did not complete the race, compared with the prerace group value and that of dogs that finished the race; 4 of 113 (3.5%) study dogs had low ferritin concentrations (< 73 ng/mL) after racing, suggestive of possible iron deficiency. Decreased PCV and serum total protein concentrations were consistently detected, whereas iron deficiency appeared to be uncommon, in study dogs after race participation. High serum concentrations of ceruloplasmin and CRP after racing suggested that changes indicative of iron deficiency may be masked by inflammation. Alternatively, changes in serum iron and CRP concentrations may reflect a physiologic response.

Serum zinc and copper status in Iranian patients with pemphigus vulgaris

The role of nutritional factors including trace elements has been reported in the pathogenesis of many autoimmune diseases. Regarding the relatively high prevalence of pemphigus vulgaris in Iran, we investigated the serum levels of zinc and copper as two important trace elements, together with the oxidative stress status in patients with pemphigus vulgaris. This case-control study was performed on 25 patients with newly diagnosed pemphigus vulgaris and 25 age- and sex-matched healthy control subjects. Serum concentrations of zinc, copper, ceruloplasmin as well as copper/zinc ratio were determined for each subject. Oxidative stress was also measured using a novel assay of peroxidant-antioxidant balance (PAB). Mean serum concentrations of zinc and copper as well as copper/zinc ratio were significantly lower in patients (mean age: 47.2±16.2 years; male/female: 14/11) compared with the controls (mean age: 47.3±12.8 years; male/female: 14/11; P<0.001). In contrast, PAB values were significantly elevated in patients compared with controls (P<0.01). No significant difference in serum ceruloplasmin concentrations was observed between the groups (P>0.05). Our findings indicate that low serum zinc and copper and increased oxidative stress may be associated with pemphigus vulgaris.

Mechanism underlying the anti-inflammatory effect of sulphated polysaccharide from Padina tetrastromatica against carrageenan induced paw edema in rats

The anti-inflammatory effect of sulphated polysaccharide (SP) isolated from an algae Padina tetrastromatica was studied. Even though the polysaccharide was found to be a fucan, the composition of this polysaccharide is different from those reported and the mechanism underlying the anti-inflammatory effect also has not been reported so far; perhaps this might be the first report in this regard. Paw edema in rats was induced by injecting 0.1 mL, 1% carrageenan suspension in 0.9% NaCl solution into the sub-plantar tissue of the right hind paw. SP was given intraperitoneally (i.p), 1 hour before the injection of carrageenan. Carrageenan caused a significant increase in the activity of inflammatory marker enzymes like lipoxygenases (LOX) and cyclooxygenase (COX) in peripheral blood mononuclear cells (PBMC) and increased the concentration of serum ceruloplasmin and myeloperoxidase (MPO). SP pre-treatment when compared to the reference drug significantly reduced the concentration of COX and LOX in PBMC, ceruloplasmin and MPO in serum and also inhibited the iNOS and COX-2 expression at mRNA level. As this polysaccharide has high anti-inflammatory activity when compared to the anti-inflammatory drug diclofenac, this natural biomolecule could be recommended as a new effective drug for inflammation.

Neurologic Dysfunction and Pancytopenia Secondary to Acquired Copper Deficiency Following Duodenal Switch

The duodenal switch (DS) procedure is a type of restrictive-malabsorptive bariatric surgery that is typically reserved for severe morbidly obese people (body mass index >50 kg/m(2)) with obesity-related comorbidities, when diet, lifestyle changes, and pharmacologic therapy fail to achieve adequate weight loss. Patients who undergo the DS procedure are at risk for malabsorption, malnutrition, and nutrient deficiencies. Copper deficiency is a commonly reported long-term complication of Roux-en-Y gastric bypass (RYGB) surgery. However, data are limited on copper deficiency-associated complications and their treatment in DS patients. This article presents a case of a patient who developed hypocupremia with associated pancytopenia, myeloneuropathy, and leukoencephalopathy following DS and reviews the literature related to the pathophysiology of copper deficiency and copper replacement in bariatric surgery patients. When severe diarrhea was present, intravenous elemental copper 4 mg (as cupric chloride)/d in addition to daily oral copper gluconate was necessary to correct the hypocupremia and improve the hematologic indices and neurologic symptoms of copper deficiency. When diarrhea subsided, oral elemental copper 4 mg (as copper gluconate) 3 times daily maintained normal serum copper concentrations and avoided the relapse of severe neurologic dysfunction. Regular monitoring of serum copper and ceruloplasmin concentrations is recommended following DS surgery to detect any copper deficiency before irreversible neurologic damage occurs. Long-term copper supplementation is likely necessary to maintain normal copper status in DS patients.

Inflammatory mediators and immune response in Mexican adolescents.

Low-grade inflammation and increased immunity related to cardiovascular diseases have been described in children and adults, however, studies in Mexican adolescents are being done at present. To evaluate inflammatory proteins and indicators of immunity in adolescents by gender and body mass index. 115 Mexican adolescents, 15-18 years old (36 men), were divided into non-overweight, risk of overweight and overweight by CDC pediatric criteria by body mass index. Serum concentrations of ceruloplasmin, C3 and C4 were quantified by nephelometry; IL-6 and TNF-α from stimulated supernatant were analyzed with Human Th1-Th2 cytokine CBA II kit (BD Biosciences Pharmigen, San Diego, CA), and detected by flow cytometry. Data were analysed by Mann-Whitney U. Gender differences were found in C3 (men: median 118.8, mean rank: 41.0; women: median: 143.9, mean rank: 65.7, p=0.001) and ceruloplasmin (men: median: 31.01, mean rank: 47.06; women: median: 31.0, mean rank: 62.9, p=0.015). Differences by BMI were found in C3 (women non-overweight: median: 137.00 mena rank: 36.52; women with risk of overweight/overweight: median: 175.80, mean rank: 57.69, p=0.002) and C4 (men non-overweight: median: 23.40, mean rank: 16.60; men with risk of overweight/overweight: median: 26.40, mean rank: 26.36, p=0.028; women non-overweight: median: 24.25, mean rank: 37.16 and women with risk of overweight/overweight: median: 32.80, mean rank: 54.42, p=0.013). Inflammatory proteins are increased in adolescents with risk of overweight and overweight, particularly in women.

Serum protein concentrations, including acute phase proteins, in calves experimentally infected with Salmonella Dublin

The aim of this study was to evaluate serum protein concentrations in calves experimentally inoculated with Salmonella Dublin. Twelve healthy 10 to 15-day-old Holstein calves were randomly allotted into two groups, control and infected with 10(8) CFU of Salmonella Dublin orally. The calves were subjected to physical evaluation and blood samples were collected shortly before administration of the bacteria and also 24, 48, 72, 96, 120 and 168 hours post-infection. The concentration of serum proteins was determined through sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE). Thirty serum proteins ranging from molecular weight of 24,000 Da to molecular weight of 236,000 Da were detected. Serum concentrations of ceruloplasmin (125,000 Da), haptoglobin (45,000 Da), acid glycoprotein (40,000 Da) and a 34,000 Da protein were significantly increased in the experimentally infected calves, when compared with their concentrations in the control animals. Therefore, this study showed that S. Dublin infection could lead to the increase of certain serum proteins in calves.

Systemic inflammatory response indicators in rabbits (Oryctolagus cuniculus) experimentally infected with sporulated oocysts of Eimeria stiedai (Apicomplexa: Eimeriidae)

Hemograms and acute-phase proteins in adult male New Zealand White rabbits that had been experimentally infected orally with sporulated oocysts of Eimeria stiedai were evaluated over a 28-day period. Fifty animals were used, divided into two groups: group A infected with 1 × 10(4) sporulated oocysts of E. stiedai and group B inoculated with distilled water. On the seventh day after infection, the infected animals presented anemia and leukocytosis with neutrophilia and monocytosis. Protein fractionation by means of electrophoresis identified 19 acute-phase proteins with molecular weights ranging from 24 to 238 kD. Ceruloplasmin, transferrin and haptoglobin showed high levels on the seventh day after infection, with gradual increases in their concentrations until the end of the experimental period. Thus, from the data of the present study, E. stiedai is considered to be a pyogenic etiological agent for which the infection level can be monitored through the leukocyte count and serum concentrations of ceruloplasmin, transferrin and haptoglobin, and these can be recommended as complementary tests.

Avances en el diagnóstico molecular de la enfermedad de Wilson

Wilsońs disease is an autosomal recessive disorder characterized by toxic copper accumulation in the liver and subsequently in the brain and other organs. Clinical diagnosis is based on the detection of low serum ceruloplasmin concentrations, increased urinary copper excretion, Kayser-Fleisher rings in the cornea, and/or high copper levels in hepatic tissue. Diagnosis can be difficult when the typical symptoms of the disease are absent, a situation that can lead to a lack of prophylactic therapy in these patients. Molecular study has improved the diagnosis of this disease, even in doubtful cases. The present article outlines the various techniques applied in the molecular diagnosis of Wilson's disease and the most commonly described mutations. Currently, direct sequencing of the ATP7B gene is the most widely used method to detect mutations. Molecular study and identification of ATP7B gene mutations allow diagnosis of individuals with Wilson's disease and their relatives, as well as the possibility of genetic counselling and prenatal and preimplantation genetic diagnosis.

P03-538 - Ceruloplasmin serum concentrations in a randomized population sample of 2,445 subjects

The metalloprotein ceruloplasmin has been of interest to psychiatrists for decades following early observations of elevated serum copper, and oxidase activity, in patients with schizophrenia. While immunological methods did not confirm elevated serum ceruloplasmin concentrations in schizophrenia, low serum concentrations of ceruloplasmin are typical of Wilson's disease, Menkes’ disease, and aceruloplasminemia making low ceruloplasmin an important marker of disease. Unfortunately, available normative values are of limited usefulness, the majority being derived from oxidase studies; very few immunoturbidimetric or nephelometric studies were performed on small samples, or did not account for known influencing factors. Therefore, the present study was planned to determine nephelometric ceruloplasmin serum concentrations in a large randomized population sample. 2,445 subjects between 12 and 65 years of age were randomly selected from a southern German town of 22,000 inhabitants. The mean ceruloplasmin serum concentration was 331 ± 104 mg/l. Ceruloplasmin serum concentration significantly correlated with gender and age and was higher by 23 mg/l on average in women than in men. There also were significant correlations with lipoprotein concentrations, but not with several other liver-associated features, parameters of metabolism, or markers of inflammation.

Beneficial Effects of a Synbiotic Supplement on Self-Perceived Gastrointestinal Well-Being and Immunoinflammatory Status of Healthy Adults

The use of synbiotics as health promoters is still poorly defined, and human intervention studies are scarce. This study was designed to evaluate the effects of a commercialized synbiotic product containing Lactobacillus acidophilus La5, Bifidobacterium animalis ssp. lactis Bb-12, Lactobacillus delbrueckii ssp. bulgaricus, Lactobacillus paracasei ssp. paracasei, Streptococcus thermophilus, and fructooligosaccharides on the self-reported gastrointestinal well-being and the immunoinflammatory status of healthy human subjects. In this randomized, double-blind, placebo-controlled study, 20 women and 16 men (25-45 years old) received either three tablets per day of the synbiotic product (2.4 × 10(9) colony-forming units/day) or placebo during 6 weeks. Gastrointestinal symptoms and bowel habits were evaluated through a self-administered questionnaire. In those subjects suffering from any kind of digestive disturbance (mild dyspepsia, flatulence, postprandial bloating, constipation, etc.), improvements in symptoms after product consumption were also evaluated. Blood lymphocyte subsets, phagocytic activity, serum C-reactive protein, ceruloplasmin, and adhesion molecules concentrations were analyzed prior and after treatment. A significant improvement in overall self-reported gastrointestinal symptoms and bowel habit was found in the synbiotic group. A marginal effect of treatment (analysis of variance P = .050) was observed with L-selectin, which showed a significant decrease in the synbiotic group (P = .019). In addition, basal L-selectin levels correlated with final intercellular adhesion molecule (ICAM)-1 levels (r = 0.468; P = .050), and basal ICAM-1 levels tended to correlate negatively with final L-selectin concentration (r = -0.457; P = .056). None of these correlations was found in the placebo group. The rest of the immunological parameters studied were not modified by the intervention. In conclusion, consumption of the synbiotic product improves self-perceived bowel habits and might facilitate a better profile of adhesion molecules in healthy adults.

Die Bedeutung des Coeruloplasmins für die Differenzialdiagnose neuropsychiatrischer Störungen

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.

Concurrent overexpression of serum p53 mutation related with Helicobacter pylori infection

Background & AimsIn the province of Cadiz (Spain), the adjusted mortality rate for gastric cancer in the coastal town of Barbate is 10/100.000 inhabitants, whereas in the inland town of Ubrique, the rate is twice as high. The rate of Helicobacter pylori (H. pylori) infection (H. pylori antibodies) in the normal population was 54% in Ubrique, but only 32% in Barbate. In the two decades since its original discovery, p53 has found a singularly prominent place in our understanding of human gastric cancer and H. pylori cause accumulation of reactive oxygen species in the mucosa compartment. This study was designed to compare serum levels of p53 in a population characterized by high mortality due to stomach cancer and a high prevalence of H. pylori infection and another population in which mortality from this cause and the prevalence of H. pylori infection are low.Materials and methods319 subjects from the low mortality population and 308 from the high mortality population were studied, as were 71 patients with stomach cancer. We measured serum immunoglobulin G antibody to H. pylori and serum mutant p53 protein and ceruloplasmin.ResultsThe difference between the two populations in the prevalence of H. pylori infection was significant (p < 0.001). Of the seropositive, 81% had elevated values of mutant p53, in comparison with 11% of the seronegative (p < 0.0001). Serum concentration of ceruloplasmin was significantly higher in seropositive with elevated mutant p53 protein than in seronegative with normal levels of p53 (p < 0.05).ConclusionsThere is a significant association between infection with H. pylori, elevated titers of H. pylori antibodies, and positivity for serum mutant p53 protein. Such information can significantly increase our basic knowledge in molecular pathology of gastric cancer and protection against H. pylori infection.

Serum ceruloplasmin oxidase activity is a sensitive and highly specific diagnostic marker for Wilson’s disease

A low serum ceruloplasmin concentration is considered diagnostic for Wilson's disease. We aimed to evaluate an enzymatic test for ceruloplasmin oxidase activity and to compare it with the routinely used immunological ceruloplasmin measurement. Serum ceruloplasmin was measured enzymatically with o-dianisidine dihydrochloride as substrate and immunologically. 110 Wilson's disease patients, 52 healthy controls, and 51 patients with impaired liver function not due to Wilson's disease were analyzed. Assay performance was tested by receiver operating characteristic curve analysis, McNemar test, and Spearman's rank correlation. The greatest sum of sensitivity and specificity was seen for the enzymatic ceruloplasmin assay at a cut-off point of 55 U/L (93.6% and 100%, respectively) and for the immunologic assay at a cut-off point of 0.19 g/L (93.6% and 78.8%, respectively). For healthy controls, the differences in specificity between both assays were statistically significant (McNemar, p=0.02). When additionally including patients with impaired liver function into the control group the specificity declined to 84.5% for the enzymatic assay and to 68.9% for the immunologic assay. The correlation between the enzymatic and immunologic assay was high in healthy controls (r=0.94), but weaker in Wilson's disease patients (r=0.70) and patients with impaired liver function not due to Wilson's disease (r=0.65). For the enzymatic assay the best cut-off point for predicting Wilson's disease was estimated to be 55 U/L. Our data suggest that the enzymatic ceruloplasmin assay is superior to the immunologic assay in diagnosing Wilson's disease and should become the preferred method.

Present situation of biomarkers for copper status

Serum or plasma copper and ceruloplasmin concentrations are the most widely used laboratory indicators to evaluate copper status. Both indicators are decreased in moderate or severe copper deficiency. The activity of several cuproenzymes is decreased in mild copper deficiency. However, their use is limited by the nonexistence of standardized assays and high interindividual variability and because some of these indicators are affected by other conditions. Recently, it was shown that the protein expression of the copper chaperone for superoxide dismutase (CCS) is increased in erythrocytes of rodents with mild copper deficiency. However, no traditional laboratory indicators have been identified as potential early markers of copper excess. It is possible that the biomarkers studied so far are not sensitive enough to detect an increase in body copper before the appearance of functional or clinical effects or that the homeostatic mechanisms are so strong that no significant changes in body copper occur with mild-to-moderate copper exposure. The identification of appropriate biomarkers for early detection of an increase in body copper represents a major challenge for further research, and the development of new approaches, such as network biology, allows us to search and propose new candidates to be studied. Recently, we found that CCS mRNA abundance in mononuclear blood cells significantly decreased after copper supplementation. The usefulness of this indicator to detect an increase in body copper should be assessed in clinical trials.

Diagnostic Accuracy of Serum Ceruloplasmin in Wilson Disease: Determination of Sensitivity and Specificity by ROC Curve Analysis among ATP7B-Genotyped Subjects

A serum ceruloplasmin concentration below 0.20 g/L is conventionally considered as one of the major diagnostic criteria for Wilson disease. This decision threshold has not been fully validated for its diagnostic characteristics, however. In this study, we evaluated various decision thresholds of serum ceruloplasmin concentration in the diagnosis of Wilson disease based on genotype-verified Wilson disease patients, carriers, and normal individuals. Serum ceruloplasmin concentration was measured by a nephelometric method in 57 Wilson disease patients and 71 family members (49 heterozygotes and 22 wild-type homozygotes), a validation group of 25 subjects clinically suspected of Wilson disease, and 690 normal individuals. We performed ROC analysis using Analyze-it software and confirmed the genotypes by direct DNA sequencing of ATP7B. Serum ceruloplasmin concentrations <0.20, 0.14, and 0.10 g/L showed positive predictive values of 48.3%, 100%, and 100%, respectively, and negative predictive values of 98.7%, 97.1%, and 91.9%. In the validation group, a serum ceruloplasmin threshold of 0.14 g/L rendered 100% sensitivity and specificity. Forty of 690 healthy subjects had serum ceruloplasmin concentrations <0.20 g/L; however, these 40 individuals had normal genotypes by DNA sequencing, and none of the 40 had ceruloplasmin concentrations <0.14 g/L. The diagnostic accuracy for Wilson disease using a serum ceruloplasmin concentration of 0.14 g/L as the local decision threshold was better than that using a threshold of 0.20 g/L. We suggest that laboratories providing ceruloplasmin assays determine decision thresholds based on local populations.

Alterations in Hypertrophic Gene Expression by Dietary Copper Restriction in Mouse Heart

Abstract. Dietary copper (Cu) restriction causes a hypertrophic cardiomyopathy similar to that induced by work overload in rodent models. However, a possible change in the program of hypertrophic gene expression has not been studied in the Cu-deficient heart. This study was undertaken to fill that gap. Dams of mouse pups were fed a Cu-deficient diet (0.35 mg/kg diet) or a Cu-adequate control diet (6.10 mg/kg) on the fourth day after birth, and weanling mice continued on the dams′ diet until they were sacrificed. After 5 weeks of feeding, Cu concentrations were dramatically decreased in the heart and the liver of the mice fed the Cu-deficient diet. Corresponding to these changes, serum ceruloplasmin concentrations and hepatic Cu,Zn-superoxide dismutase activities were significantly (P < 0.05) depressed. The size of the Cu-deficient hearts was greatly enlarged as estimated from the absolute heart weight and the ratio of heart weight to body weight. The abundances of mRNAs for atrial natriuretic factor, β-myosin heavy chain, and α-skeletal actin in left ventricles were all significantly increased in the Cu- deficient hearts. Furthermore, Cu deficiency activated the expression of the c-myc oncogene in the left ventricle. This study thus demonstrated that a molecular program of alterations in embryonic genes, similar to that shown in the work-overloaded heart, was activated in the hypertrophied heart induced by Cu deficiency.

Ceruloplasmin fragmentation is implicated in 'free' copper deregulation of Alzheimer disease

A dysfunction in copper homeostasis seems to occur in Alzheimer’s disease (AD). We recently demonstrated that an excess of non-ceruloplasmin-copper (i.e. ‘free’ copper) correlates with the main functional and anatomical deficits as well as the cerebrospinal markers of the disease, thus suggesting that copper contributes to AD neurodegeneration. Aim of this study was to investigate the profile of serum ceruloplasmin isoforms immunoreactive protein in relation to copper dysfunction in AD. Twenty-five AD patients and 25 controls were included in the study. All subjects underwent individual measurements of serum ceruloplasmin and copper concentrations, and the amount of ‘free’ copper was computed for each copper and ceruloplasmin pair. Serum samples were also pooled and analyzed by two dimensional polyacrylamide gel electrophoresis (2-D PAGE) and western blot analysis. The mean concentration of ’free’ copper resulted higher in AD patients than in controls. Ceruloplasmin 2-D PAGE western blot analysis of pooled sera showed in the AD samples low-molecular-weight spots in the <50 kDa range that were not detected in controls’ pooled sera (p < 0.029). Our data indicate a ceruloplasmin fragmentation in the serum of AD patients, possibly related to ‘free’ copper deregulation in this disease.

Diagnosis of Wilson's Disease: A Comprehensive Review

Wilson's disease is an autosomal recessive disorder of copper metabolism. The culprit gene is ATP7B. The worldwide prevalence is about 1 in 30,000, which may vary by population. Higher prevalence rates were reported using more sensitive screening techniques and pilot population screening. Typical presentations include neuropsychiatric and hepatic dysfunction, whereas atypical presentations are protean. Diagnosis relies on a high clinical suspicion, typical neurological symptoms, presence of Kayser-Fleischer rings, and reduced serum ceruloplasmin concentration. The conventional value of < 0.20 g/l is not a universal diagnostic value. Age of the subjects and analytical variations should be considered when interpreting these levels. Patients with inconclusive findings require further investigations such as 24 h urinary free-copper excretion, penicillamine challenge test, liver copper measurement, and detection of gene mutations. Direct molecular diagnosis remains the most decisive tool. Other tests such as non-ceruloplasmin–bound copper are unreliable. Potential pitfalls and limitations of these diagnostic markers are critically reviewed in this paper. The mainstays of therapy are trientine, penicillamine, and/or zinc. Liver transplantation is lifesaving for those with advanced disease. Ceruloplasmin oxidase activity and serum free-copper concentration should be monitored in patients on long-term de-coppering therapy to prevent iatrogenic copper deficiency.

Copper and Liver Function Indicators Vary Depending on the Female Hormonal Cycle and Serum Hormone Binding Globulin (SHBG) Concentration in Healthy Women

Previous studies showed that responses to chronic administration of copper were significantly associated with gender, raising the need to better characterize the relation between the effects observed and stradiols. The objective of this study was to measure copper and liver function indicators and the sex hormone binding globulin (SHBG) serum concentrations in healthy adults exposed to copper, grouped by sex and phase of the female hormonal cycle. Healthy females on day 7 (follicular phase, Group 1, n = 39), on day 21 (secretory phase, Group 2, n = 34) and males (comparison group, Group 3, n = 34) received 8 mg Cu/day (as copper sulfate), orally, for 6 months. On days 0, 30, 60, 120, and 180, the serum concentration of copper, ceruloplasmin, liver aminotransferases, and SHBG were measured. Analysis of results included analysis of variance (ANOVA; repeated measures) and the post hoc Bonferroni correction. Participants remained healthy throughout the study period, including aminotransferases below the cut off in all measures. GGT, AST, and ALT activities were significantly different by group and by time (ANOVA repeated measures P < 0.05). Six-month curves of serum copper and ceruloplasmin concentrations were different by group, by time and interaction group x time (all P < 0.001). SHBG curves were different by group and time (P < 0.01), and interaction group x time (P < 0.009). Serum copper, ceruloplasmin, and liver aminotranferases are influenced by estrogens/progesterone, something that should be considered when these indicators are used as outcomes of effects. Time of sampling was also significantly associated with the indicators and deserves further study.