Elevated Serum Copper Research Articles

Research advancements in the association between prevalent trace metals and connective tissue diseases.

Connective tissue diseases (CTD) encompass a spectrum of autoimmune disorders, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjogren's syndrome (SS), inflammatory myopathy (IIM), systemic sclerosis (SSc), among others. Recent research has highlighted the significant role of trace metals in the pathogenesis of connective tissue diseases. This article provides an overview of recent advancements in understanding the correlation between common trace metals such as iron, copper, zinc and CTD, aiming to offer novel insights for the diagnosis and treatment of these conditions. Iron is implicated in the pathogenesis of SLE through various mechanisms, including alterations in serum iron concentration, disturbances in iron metabolism and homeostasis, as well as involvement in ferroptosis. Disorders affecting iron metabolism, ferroptosis, and the expression and regulation of associated genes and proteins contribute to the development and progression of RA. Elevated serum copper levels are observed in patients with both SLE and RA compared to healthy controls. Cuproptosis, a novel form of cell death, is also considered to be linked to their pathogenesis. Decreased serum zinc concentration is evident in patients with SLE, RA, and SS. Zinc finger proteins play a crucial role in the pathogenesis of these diseases.

Associations between serum mineral concentrations and mortality by renal function in the Ludwigshafen Risk and Cardiovascular Health Study

The association of serum concentrations of minerals and phosphate with overall and cardiovascular mortality based on renal function is poorly understood. 3307 patients (average age 62.7 ± 10.6 years) in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study were grouped by estimated glomerular filtration rate (eGFR) into three categories: < 60, 60–89, and ≥ 90 mL/min per 1.73 m2, per KDIGO 2022 guidelines and were analysed using Cox regression. Low serum sodium and iron concentrations were associated with poor renal function and increased overall mortality risk, whereas higher serum zinc concentrations were associated with reduced overall and cardiovascular mortality risk. Elevated serum copper concentrations were associated with increased mortality risk across all eGFR categories. Comparing low and normal eGFR, we observed a fourfold increase in all-cause mortality risk for eGFR < 60 mL/min per 1.73 m2 and a twofold increase for eGFR 60–89 mL/min per 1.73 m2, accompanied by changes in serum mineral concentrations. The optimal range of mineral and phosphate concentrations in serum was strongly related to renal function. To reduce mortality risk, it’s important to regularly monitor serum mineral and phosphate concentrations as well as renal function, especially in cardiovascular patients with compromised renal function.

Relationship Between Serum Copper, Zinc Level and Tumour Aggressiveness in Invasive Cervical Cancer

&amp;lt;i&amp;gt;Background: &amp;lt;/i&amp;gt;Cervical cancer, a leading cause of cancer-related morbidity and mortality, exhibits considerable variability in aggressiveness. The role of trace elements such as copper and zinc in influencing tumor behavior and progression has garnered attention. This study investigates the relationship between serum copper and zinc levels and tumor aggressiveness in invasive cervical cancer.&amp;lt;i&amp;gt; Methods:&amp;lt;/i&amp;gt; A cross-sectional comparative study was conducted among 150 women with invasive cervical cancer attending the outpatient department and Colposcopy Clinic of the Department of Gynecological Oncology, BSMMU, Dhaka, from April 2022 to March 2023. Participants were divided into two groups based on tumor aggressiveness: Group 1 (less aggressive) and Group 2 (more aggressive), with 75 women in each group. Serum copper and zinc levels were measured and analyzed for differences between groups. &amp;lt;i&amp;gt;Result:&amp;lt;/i&amp;gt; Serum copper levels were significantly higher in Group 2 (152.31 ± 41.81 µg/dL) compared to Group 1 (139.31 ± 25.52 µg/dL) with a p-value of 0.023. Conversely, serum zinc levels were significantly lower in Group 2 (55.24 ± 28.13 µg/dL) compared to Group 1 (66.29 ± 31.58 µg/dL) with a p-value of 0.025. The copper/zinc ratio was significantly higher in Group 2 (2.76 ± 1.20) compared to Group 1 (2.10 ± 1.00) with a p-value of &amp;lt;0.001. &amp;lt;i&amp;gt;Conclusion:&amp;lt;/i&amp;gt; Elevated serum copper levels and copper/zinc ratio, along with decreased zinc levels, are associated with more aggressive cervical cancer. These findings suggest that trace element imbalances may serve as biomarkers for assessing tumor aggressiveness and could inform future therapeutic strategies.

Evaluation of the Role of Trace Elements in Malignant Transformation of Oral Submucous Fibrosis: A Study in the Population of Krishna District, Andhra Pradesh, India.

Oral submucous fibrosis (OSMF) is a chronic, potentially malignant disorder linked predominantly to areca nut chewing. This study investigates the role of serum trace elements (Cu, Fe, Zn, Se) in the progression and malignant transformation of OSMF. A community-based cross-sectional study involved 80 participants from the Government Dental College, Vijayawada, Krishna District, AP. Participants were divided into four groups: areca nut users without OSMF, areca nut users with OSMF, areca nut users with malignant-transformed OSMF, and healthy controls. Blood samples were analyzed for serum iron, copper, zinc, and selenium levels. Significant differences were found in serum copper(P=0.032) and zinc levels (P=0.006), with elevated levels observed in the malignant-transformed OSMF group compared to controls. No significant differences were observed in serum iron (P=0.542) and selenium levels(P=0.062) across the groups. Elevated serum copper levels can serve as a reliable diagnostic marker for malignant transformation in OSMF. Future research should explore the potential therapeutic benefits of copper chelation in OSMF management.

Elevated Serum Copper, Zinc, Selenium, and Lowered α-Klotho Associations: Findings from NHANES 2011–2016 Dataset

Elevated Serum Copper, Zinc, Selenium, and Lowered α-Klotho Associations: Findings from NHANES 2011–2016 Dataset

Serum copper assessment in patients with polycystic ovary syndrome and tubal infertility: A retrospective 5-year study.

The association between serum copper and polycystic ovary syndrome (PCOS) lacks definitive conclusions, and the intricate interactions with invitro fertilization (IVF) cycle characteristics in infertility remain insufficiently explored. This retrospective study included 560 patients with tubal infertility (no-PCOS) and 266 patients with PCOS undergoing IVF at the Affiliated Suzhou Hospital of Nanjing Medical University from January 2018 to December 2022. Patients' basic characteristics, hormonal and metabolic parameters, essential trace elements, and IVF cycle characteristics were measured and analyzed. The results revealed a significantly elevated serum copper level in the PCOS group compared to the control group [17.27 (15.54, 19.67) vs 15.4 (13.87, 17.35), μmol/L; p < .001]. Spearman correlation analyses revealed a significant positive correlation between serum copper concentration and body mass index (BMI), fasting glucose (FG), triglyceride (TG), total cholesterol (TC), and low-density lipoprotein (LDL) in the no-PCOS group. Additionally, a notable negative correlation with high-density lipoprotein (HDL) was observed (r = -.184, p < .001). Within the PCOS group, serum copper concentration correlated significantly with BMI (r = .198, p = .004) and TG (r = .214, p = .002). The linear trend analysis indicated no significant relationship between serum copper concentration and ovarian response as well as preimplantation outcomes in both groups after adjusting for confounding factors. Our study provided evidence of elevated serum copper concentration in PCOS patients, closely associated with lipid metabolism but showing no correlation with IVF outcomes. These findings provide valuable real-world data, enriching our nuanced understanding of the role of copper in female fertility.

Evaluating serum electrolyte and trace element variations between Babesia ovis-infected and uninfected Lohi sheep

Babesiosis caused by Babesia ovis is a major threat to the livestock industry worldwide. In Pakistan, the Lohi sheep breed is an important economic resource, but limited information is available on the impact of B. ovis infection on this breed. This study aimed to investigate the serum electrolyte and trace element variations between B. ovis-infected and uninfected Lohi sheep from Pakistan. A total of 97 Lohi sheep was stratified based on the geographical distribution of Multan district, employing a multistage cluster sampling method. Blood and serum samples were collected from randomly selected sheep, and DNA extraction and PCR amplification were performed to detect B. ovis infection. Serum electrolyte and trace element levels were analyzed in infected (n=67) and uninfected (n=30) groups, stratified by age and gender. The study revealed a 69.07% overall infection rate of B. ovis in Lohi sheep. Infected sheep showed significantly elevated serum copper levels (p&lt;0.0001), with no substantial differences observed in serum iron, sodium, potassium, and chloride levels. However, age-wise variance analysis revealed statistically significant variations in sodium and potassium levels (p&lt;0.0001 and p&lt;0.05, respectively). Notably, serum chloride levels differed between infected and uninfected females in individuals younger than two years (p&lt;0.05). Serum iron levels remained consistent across different age groups. Comparative analysis indicated a higher prevalence of electrolyte imbalances, such as hyponatremia, hyperkalemia, hyperchloremia, and hypoferremia, in infected sheep compared to normal reference ranges, while instances of hypernatremia, hypokalemia, hypochloremia, and hyperferremia were less frequent. In conclusion, our study suggests that B. ovis infections could lead to alterations in serum electrolyte and trace element levels in Lohi sheep, emphasizing the importance of further research into the specific mechanisms driving these alterations to enhance disease management strategies tailored to this breed.

Copper Promotes LPS-Induced Inflammation via the NF-кB Pathway in Bovine Macrophages.

Inflammation is a complex physiological process that enables the clearance of pathogens and repairing damaged tissues. Elevated serum copper concentration has been reported in cases of inflammation, but the role of copper in inflammatory responses remains unclear. This study used bovine macrophages to establish lipopolysaccharide (LPS)-induced inflammation model. There were five groups in the study: a group treated with LPS (100ng/ml), a group treated with either copper chelator (tetrathiomolybdate, TTM) (20μmol) or CuSO4 (25μmol or 50μmol) after LPS stimulation, and a control group. Copper concentrations increased in macrophages after the LPS treatment. TTM decreased mRNA expression of pro-inflammatory factors (IL-1β, TNF-α, IL-6, iNOS, and COX-2), whereas copper supplement increased them. Compared to the control group, TLP4 and MyD88 protein levels were increased in the TTM and copper groups. However, TTM treatment decreased p-p65 and increased IкB-α while the copper supplement showed reversed results. In addition, the phagocytosis and migration of bovine macrophages decreased in the TTM treatment group while increased in the copper treatment groups. Results mentioned above indicated that copper could promote the LPS-induced inflammatory response in bovine macrophages, promote pro-inflammatory factors by activating the NF-кB pathway, and increase phagocytosis capacity and migration. Our study provides a possible targeted therapy for bovine inflammation.

The Correlation Between Serum Copper and Non-alcoholic Fatty Liver Disease in American Adults: an Analysis Based on NHANES 2011 to 2016.

Copper functions as an essential micronutrient influencing diverse metabolic processes in mammals, encompassing oxidative stress responses, lipid metabolism, and participation in enzymatic reactions. However, the impact of serum copper on non-alcoholic fatty liver disease (NAFLD) remains controversial. Our aim was to explore the precise correlation between serum copper and NAFLD in a large-scale population-based study. A total of 1377 participants from the National Health and Nutrition Examination Survey (NHANES) 2011-2016 were included in our study. The diagnosis of NAFLD and its progress to advanced liver fibrosis were based on serological indexes. One-way ANOVA, Kruskal-Wallis H test, and Chi-square test were used to access variations between quartiles groups of serum copper. We conducted multivariate-adjusted logistic regression models and subgroup analyses to investigate the association between serum copper and NAFLD, along with several metabolic diseases. Among the 1377 participants, 661 were diagnosed with NAFLD, and 141 of whom were classified into advanced liver fibrosis. Higher serum copper levels (≥ 21.00 μmol/L) were associated with an increased incidence of NAFLD (odds ratio (OR) = 2.07 (1.38-3.10), p < 0.001), as well as advanced liver fibrosis (OR = 2.40 (1.17-5.19), p = 0.025). Moreover, serum copper exhibited a positive correlation with hypertension, overweight, and abdominal obesity, all of which have been identified as risk factors of NAFLD. Additionally, female participants, under the age of 60, and with a higher body mass index (BMI) (> 24.9 kg/m2) emerged as the most vulnerable subgroup concerning the relationship between serum copper and NAFLD. In the U.S. population, a notable association has been identified, linking elevated serum copper to an increased susceptibility for both the onset and progression of NAFLD, along with several metabolic disorders associated with NAFLD. The adverse effects of excess copper warrant attention in the context of public health considerations.

The Association between Elevated Serum Copper (Cu) Levels and Its Complications in Cu T380a IntrauterineDevice (IUD) Users; a Cross-Sectional Study

The Association between Elevated Serum Copper (Cu) Levels and Its Complications in Cu T380a IntrauterineDevice (IUD) Users; a Cross-Sectional Study

The needle in the haystack: deciphering diagnostic data in a case of acute on chronic liver failure

The needle in the haystack: deciphering diagnostic data in a case of acute on chronic liver failure

Elevation of Serum Copper in the New Orleans Bariatric Clinic Population: the Norm or Geographically Localized Findings?

Circulating micronutrient levels of both serum copper and zinc have been studied to varying degrees in both the general public and patients having undergone bariatric surgery. According to the 2019 ASMBS clinical guidelines, copper supplementation is recommended for patients undergoing metabolic surgery, especially after Roux-en-Y gastric bypass and duodenal switch. Copper excess has not been previously reported to any significant degree in any population. In this study, we investigate an elevated serum copper level in the pre-surgical intervention population of the Bariatric Center of the University Medical Center-New Orleans, a primary safety net hospital for the state of Louisiana. Five hundred five consecutive patients from the bariatric surgery undergoing a workup for surgical intervention were assessed. Patients were included regardless of whether they proceeded to surgery. The study was conducted as a retrospective review of deidentified data that was collected as part of our routine workup for bariatric surgery. The study population of the clinic consisted of a mean BMI of approximately 50kg/m2, with 91% of the population reporting female and 69% recording an African American race. It was discovered in this population that 26% of the patients had an elevated copper level of > 155 mcg/dl. Additional analysis was performed attempting to elucidate an environmental role in the elevation by qualitative analysis of patient's location of residence using reported home address. Additional variables were studied as well including serum zinc concentration, age, BMI, and race to address any correlative variables with our findings. This study identifies an elevated serum copper concentration in a pre-intervention underserved bariatric centerpopulation positively associated with BMI, female gender, and African American race. Additional studies will be necessary to see if these trends are also apparent in normal weight controls, or if weight loss influences copper levels. Pre-existing serum copper deficiencies may be more prevalent in the bariatric populations than previously believed. Increased serum copper in this population was positively associated with increased BMI, age, and female gender compared to that of the male group. Increased serum copper was also associated more closely with African American ethnicity compared to Caucasian patients.

Biochemical Assessment of Some Trace Elements in Hypertensive Patients

Background: Hypertension is a chronic disease that has been recognized as an important global public health disorder. It is a leading risk factor for stroke, heart failure, kidney diseases, and sudden death; as such its effective management may go a long way in preventing some of these possible complications. In humans, trace elements play key roles in normal metabolic activities that are required for healthy living. It has been hypothesized that trace elements are key to normal heart functions. Thus, deficiency in one or more trace elements may result(s) in or accentuate heart disease(s). This study, therefore, assessed trace elements in hypertensive and control volunteers. Methods: A total number of two hundred and fifty-six(256) participants comprising of one hundred and sixtynine (169) hypertensive and eighty-seven (87) normotensive control volunteers participated in this study. Anthropometric data and blood samples were collected from all participants. The blood samples were collected into plain vacutainer and were allowed to clot. The samples were centrifuged and the serum from each sample was aspirated and analyzed for trace elements {Selenium (Se), Copper (Cu), Zinc (Zn), Iron (Fe)} using atomic absorption spectrophotometer and calcium using Cobas C-111. Results: There was no significant difference (p&gt;0.05) between the mean age and weight of the participants. However, the mean body mass index (BMI), systolic, and diastolic blood pressure in hypertensive volunteers were significantly higher (p&lt;0.05) than the controls. The mean Cu and Fe were higher (p&lt;0.05) in hypertensive volunteers whereas the mean Zn, Se, and calcium were not different (p&gt;0.05) between the two groups that participated in this study. There were positive associations between body mass index, systolic blood pressure (p&lt;0.05), and Cu whereas negative correlations existed between body mass index, Zn, and Se, among hypertensive volunteers. Conclusion: From this study, it appears that high blood pressure among Nigerian population is associated with elevated serum copper (Cu) and iron (Fe) trace elements. These may play a part in accentuation of hypertension in some of the volunteers if not properly monitored. Also hypertensive individuals also presented an increased body mass index (BMI) which could also complicate effective management of hypertension .

Are trace element concentrations suitable biomarkers for the diagnosis of cancer?

Despite advances in cancer research, cancer is still one of the leading causes of death worldwide. An early diagnosis substantially increases the survival rate and treatment success. Thus, it is important to establish biomarkers which could reliably identify cancer patients. As cancer is associated with changes in the systemic trace element status and distribution, serum concentrations of selenium, iron, copper, and zinc could contribute to an early diagnosis. To test this hypothesis, case control studies measuring trace elements in cancer patients vs. matched controls were selected and discussed focusing on lung, prostate, breast, and colorectal cancer. Overall, cancer patients had elevated serum copper and diminished zinc levels, while selenium and iron did not show consistent changes for all four cancer types. Within the tumor tissue, mainly copper and selenium are accumulating. Whether these concentrations also predict the survival probability of cancer patients needs to be further investigated.

Serum Copper and Risk of Cardiovascular Disease Mortality among Men without Diabetes: A 26-year Prospective Cohort Study

Background: Longitudinal studies assessing the association between copper and the risk of CVD mortality among aging populations without diabetes are scarce. We sought to examine the prospective association between serum copper and future risk of CVD mortality among a general population sample of men without diabetes in Finland. Method: We used the population-based data from the Kuopio Ischaemic Heart Disease Study, comprising men aged 42-60years at baseline. Serum copper concentrations were determined using Atomic Absorption Spectrometer and categorized into quartiles. The associations with CVD mortality were analyzed using multivariable Cox regression models. Results: After a median follow-up period of 26years, 524 CVD deaths occurred among 2,395 men. After adjustment for age, BMI, blood pressure, history of coronary heart disease(CHD), high-density cholesterol, total cholesterol, smoking, alcohol and socioeconomic status, the hazard ratios (and 95% CIs) for CVD mortality for serum copper concentrations in the second, third and fourth quartiles were 1.03(0.78-1.36), 1.32(1.04-1.68) and 1.50(1.18-1.91) respectively (using the first quartile as the referent). The association remained consistent following the exclusion of men with a history of CHD. Conclusions: This study reveals that elevated serum copper concentrations at baseline are associated with future risk of CVD mortality. Thus, prompting the possible role of serum copper levels as a biomarker for CVD mortality in men without diabetes. The role of serum copper as a putative risk factor for CVDs requires further exploration. The exact mechanisms underlying the association between elevated serum copper concentration and the risk of CVD mortality are yet to be unraveled.

The relationships between serum copper levels and overweight/total obesity and central obesity in children and adolescents aged 6-18 years

ObjectiveTo explore the relationships between serum copper levels and overweight/total obesity and central obesity in children and adolescents. MethodsWe included 2,000 children and adolescents from the 2011-2016 US National Health and Nutrition Examination Surveys. The multivariable linear model, logistic model and restricted cubic splines were adopted to assess the relationships. Models were adjusted for data release cycle, age, sex, race/ethnicity, ratio of family income to poverty, and dietary intakes of protein, total sugars, total fat, fiber, energy, calcium, vitamin D, vitamin C, and hours watch television or videos. ResultsThe prevalences of overweight/total obesity and central obesity were 37.38% and 33.40%, respectively. For per-quintile increment in serum copper levels, body mass index increased by 1.06 (0.79-1.33) (kg/m2) and waist circumference increased by 2.43 (1.58-3.27) (cm). The odds ratios (95% confidence intervals) for overweight/total obesity and central obesity among participants with the highest quintile compared with those with the lowest quintile of serum copper levels were 5.46 (3.31-8.98) and 5.64 (3.31-9.58), respectively. The above-mentioned associations were not modified by age (children: 6-12 years, adolescents: 13-18 years) and sex. Dose-response analysis showed that the odds of overweight/total obesity and central obesity increased with increasing serum copper levels to a level of approximate 140 ug/dL where the association seemed to reach a plateau, respectively. ConclusionsSerum copper levels were positively associated with body mass index and waist circumference, and elevated serum copper levels were associated with higher odds of overweight/total obesity and central obesity in children and adolescents.

Serum Copper Elevation Promotes Hepatic Ceruloplasmin Production and Excretion in Rat Model of Myocardial Infarction

Ceruloplasmin (Cp) is a major copper‐binding protein in blood, regulating copper homeostasis. High levels of serum copper and Cp are both risk factors for coronary artery disease, particularly in patients with acute myocardial infarction. However, the relationship between the changes in serum copper and Cp levels in response to myocardial ischemia remains unknown. It is known that myocardial ischemia causes copper efflux from the heart leading to copper elevation in the blood. The present study was undertaken to test the hypothesis that the elevation of serum copper leads to an increase in hepatic Cp production and excretion. Adult male Sprague‐Dawley rats were subjected to left anterior descending (LAD) coronary artery ligation to induce myocardial infarction. Serum copper and Cp levels, as well as changes in hepatic Cp and copper‐transporting P‐type ATPase (ATP7B), were determined from blood and liver samples harvested on day 1, 4, or 7 after the operation. Serum copper concentrations were significantly increased on day 4 after LAD ligation, accompanied by an increase in serum Cp levels and activities. Concomitantly, the protein levels of Cp and copper exporter, ATP7B, were also significantly increased in the liver. Taken together, these results indicate that the elevated serum Cp levels mostly likely result from the increase in Cp production and excretion in the liver in response to the elevated serum copper levels following myocardial ischemia.Support or Funding InformationWest China Hospital, Sichuan UniversityChanges in hepatic Cp levels. At the time of 1, 4 or 7 day after LAD ligation, the liver tissues were harvested for Western blot and mRNA analysis. (A–C) Changes in hepatic Cp protein levels. (D–E) Changes in the expression of Cp, measured by RT‐PCR. Data are presented as mean ± SD, n=5–6, *P &lt; 0.05. LAD: left anterior descending; MI: myocardial infarction.Figure 1Changes in hepatic ATP7B levels. The sample preparation was as the same as presented in Figure 3. (A–C) Western blot analysis was performed to detect the protein level at different time point. (D–E) Changes in the expression of ATP7B, measured by RT‐PCR. Data are presented as mean ± SD, n=4–6, *P &lt; 0.05. MI: myocardial infarction.Figure 2

Associations of decreased serum transthyretin with elevated high-sensitivity CRP, serum copper and decreased hemoglobin in ambulatory elderly women.

Transthyretin (TTR), a sensitive indicator of malnutrition and inflammation, has been shown to be associated with mortality in elderly population. We examined relationships between serum TTR and a range of risk factors for mortality in 185 free-living elderly women. Blood was drawn between breakfast and lunch. TTR was correlated negatively with age (r=-0.30, p<0.001). After controlling for age, TTR was negatively associated with log high-sensitivity CRP (hsCRP) and serum copper. It was positively associated with albumin, serum iron and hemoglobin. In addition, TTR was positively correlated with systolic and diastolic blood pressure and postprandial triglyceride (TG). In multiple regression analysis for TTR as a dependent variable, hemoglobin (standardized β, 0.244), serum copper (standardized β, -0.134), postprandial TG (standardized β, 0.223) and log hsCRP (standardized β, -0.190) emerged as determinants of TTR independently of age, albumin, serum iron, systolic and diastolic blood pressure, and explained 22.8% of TTR variability. Subclinical low-grade inflammation, elevated serum copper and decreased hemoglobin were associated with decreased serum TTR in community-living elderly Japanese women and may represent important confounders of the relationship between low TTR and mortality in the elderly. The positive association of TTR with postprandial TG warrants further investigation.

Autoimmune Hepatitis or Wilson’s Disease, a Clinical Dilemma

Dear Editor, The etiologic diagnosis of acute hepatitis and the correct therapeutic strategy may sometimes present several difficulties. We report the case of a young male patient with a severe acute hepatitis resembling features of both autoimmune hepatitis (AIH) and Wilson disease (WD). A 32-year old man presented with a seven days history of fatigue, low-grade fever and jaundice. The patient did not use tobacco, alcohol or illicit drugs. His parents and two siblings were in good health. Clinical examination revealed body temperature 37 oC, blood pressure 130/80 mmHg, heart rate 72 beats/min and respiratory rate 20/min. The liver was slightly enlarged, painless, without tenderness on palpation, and with splenomegaly. He had no signs of chronic liver disease. Laboratory investigations revealed normal blood count, ESR 29 mm/1 h, AST 1219 IU/L, ALT 2327 IU/L, γGT 59 IU/L (normal values: 10-75 IU/L) and Alkaline Phosphatase 172 IU/L (normal values: 20-130 IU/L). Total Bilirubin was 29 mg/dL (direct 24 mg/dL) and Prothrombin time was 19 sec (INR: 2). Total proteins were 7.9 g/dL, Albumin 3 g/dL with Polyclonal Hypergammaglobulinemia. Serologic testing for viral hepatitis HAV, HBV, HCV, EBV, CMV, and HSV were negative. The antinuclear antibodies were positive (titer 1/1280). Serum Ceruloplasmin was 20 mg/dL (normal values 20-60 mg/dL), serum copper 390 μg/dL (normal values < 150 μg/dL), free copper 315µg/dL (normal values < 10 µg/dL) and urine copper 855 μg/24 h (normal values < 100 μg/24 h). Split lamp analysis revealed no Kayser-Fleischer ring. It caused the question which of acute AIH or WD would be the correct diagnosis. According to the international scoring system for AIH he had a score of 19. However, elevated serum copper, substantially high 24-hourr urine copper with Ceruloplasmin at the very lower normal limit suggested acute WD. The association of WD with autoimmune features and with AIH has rarely been documented (1, 2), and the difficulties in the differential diagnosis WD and AIH have been underlined especially in the pediatric population (3, 4). A liver biopsy showed interface hepatitis, portal invasion with mononuclear cell infiltrate and absence of fibrosis. Histochemical analysis with Rhodanine and Orcein was negative. The patient started treatment with Prednisolone 60 mg/day and Azathioprine 75 mg/day with clinical and biochemical improvement. At the remission phase, serum and urine copper levels were within normal limits. Molecular genetic analysis for mutations specific for WD (H1069Q, R1069Q, L936X, I1148T, and Q289X) was negative. Rhodanine histochemistry may be absent in early stages of WD (5) and the characteristic mutations are found in < 40% of patients. Kayser-Fleischer ring and history of neuro-psychiatric symptoms could be absent but 24 h urine copper remains abnormal in 80-85% of untreated patients with Wilson disease. On the other hand, alterations of copper metabolism may occur in the acute phase of severe icteric hepatitis (6), of any etiology, resulting in a misleading suspicion of WD (7). Urine copper levels, although occasionally increased in severe acute icteric hepatitis, does not exceed usually the value of 200 μg/24 h (855μg in our case) (8). After three years, the patient is in good health with normal liver biochemistry and continues on maintenance therapy with Prednisolone 2.5 mg/day and Azathioprine 75 mg/day. He didn’t develop other symptoms during follow up. This report shows the clinical challenge for the right diagnosis and therapy decision in a rare case of severe acute hepatitis resembling WD and/or AIH.

Elevated serum copper and ceruloplasmin levels in Alzheimer's disease

Copper takes part in a variety of biological reduction-oxidation (redox) processes, and is an important cofactor of many redox enzymes. Ceruloplasmin, the copper-transporting protein, also possesses an important redox capacity. We assessed serum copper, ceruloplasmin and free-copper levels in 89 patients with Alzheimer's disease (AD) (mean age, 77.83 years; 41 men, 48 women) and in 118 healthy individuals (mean age, 69.93 years; 50 men, 68 women). High (≥75th percentile), medium, and low (≤25th percentile) copper, ceruloplasmin and free-copper groups were classified according to their serum level. Serum copper (P = 0.026) and ceruloplasmin (P = 0.001) levels were significantly higher in the AD group than in the control group. There was no significant difference in serum free-copper levels between AD and healthy elderly groups (P = 0.975). After adjusting for age differences, serum copper (P = 0.049) was still significantly higher in the AD group. Furthermore, serum copper levels correlated with scores on the Boston naming test (r = -0.151, P = 0.037), indicating a close relationship between copper levels and cognitive abilities. The significant association between the copper concentration in peripheral serum and AD with elevated copper levels found in patients with AD is likely linked to the evolution of AD. Serum copper levels were significantly negatively correlated with scores on cognitive test subscores. AD patients may have significantly more "defective" ceruloplasmin, that is, apo-ceruloplasmin lacking its copper, than in healthy controls.