Serum Ceruloplasmin Research Articles

POS-426 IgAN in a patient with Wilson's Disease: a very rare association

Wilson's disease (WD) is a genetic autosomal recessive disease, due to a mutation of the ATP7B gene, characterized by copper accumulation in the liver, eyes, and nerves. Renal involvement has been reported very rarely, affecting only 5 % of WD cases. We present a case of WD associated with IgA nephropathy (IgAN). Male patient with a diagnosis of WD established 11 years before the access at the Nephrology Unit. The patient initially presented with abdominal discomfort, undetectable serum ceruloplasmin levels, liver cirrhosis with an initial lenticular degeneration; the liver biopsy highlighted a hepatic copper concentration of 2930 mcg/g, also genetic investigations confirmed the diagnosis, with double heterozygosis for ATP7B gene. The patient started the therapy with copper chelators with a good clinical response through the years. At the age of 21 he presented for proteinuria (1062 mg/24h) and hematuria, with renal function in the normal range (glomerular filtration rate 121 mL/min). IgA levels in the blood were slightly above the range (489 mg/dl). Renal biopsy showed mesangial cell proliferation, IgA deposition, and electron-dense deposit in the mesangial areas, all of which are consistent with IgAN and steroid therapy was started (Figure 1,2,3).Figure 1. Figure 2. Figure 3. The occurrence of two rare disorders is a very uncommon event. Both diseases have a similar incidence rate with about 1 case per 30,000 live births. In literature 3 clinical cases of WD associated with IgAN have been reported. Two were reported in children and one case occurred in an adult patient. However, in the previous adult case both diseases were diagnosed contemporary and WD treatment with trientine hydrochloride and zinc acetate caused a decrease in the serum level of IgA levels after initiating chelating agents and also improvement in renal manifestations (reduced proteinuria and increased e-GFR). Our case’s uniqueness is the occurrence many years later the beginning of the therapy with zinc acetate dihydrate. This contrasts with previous theory since renal involvement with IgA nephropathy occurred despite the adequate pharmacological control of the copper dysregulation. This makes necessary steroid treatment in these patients.In conclusion, we suggest adding a screening for renal damage (creatinine and urinalysis) in the follow-up of patients with MW although under treatment and liver disease in remission.

A215 MDR3 DEFICIENCY MIMICKING WILSON DISEASE

Abstract Background The chronic phenotype of ALF includes a broad differential diagnosis. Class III multi-drug resistance P-glycoprotein 3 (MDR3) deficiency, also referred to as progressive familial intrahepatic cholestasis type 3, is an autosomal recessive genetic disorder. It is caused by a defect on the ABCB4 gene located on chromosome 7, which encodes MDR3. MDR3 is responsible for transporting phosphatidylcholine across the canalicular membrane, thereby allowing it to be incorporated into bile micelles. MDR3 deficiency results in increased levels of free bile acids and detergent bile. Progressive cholangiopathy ensues from this detergent bile and indirectly leads to cholestasis and liver failure in severe cases. Significantly increased urinary and hepatic copper (Cu), which are hallmarks of Wilson disease, have also been reported in patients with acute hepatitis and cholestasis including patients with MDR3 deficiency Aims We report a case of a girl who presented with a chronic phenotype of PALF, who had multiple features of Wilson disease and so was treated as such until genetic analysis confirmed MDR3 deficiency Methods Results A 6 year old girl presented to the ED with a 1mth history of epistaxis and a 1wk history of abdominal pain and distension, facial edema, pallor and fever. Her family history was significant for parental consanguinity and maternal itch during pregnancy. On examination she had clubbing, scleral icterus and a distended abdomen with hepatosplenomegaly. Her bloodwork showed bicytopenia (HGB 53 & Plts 63) along with liver dysfunction (INR 2.9, albumin 25, conjugated bilirubin 9) and raised liver enzymes (transaminases & GGT >10xULN). Her total serum bile acids were raised at 134. An US showed hepatosplenomegaly with multiple hyperechoic nodules and perisplenic varices. She was extensively worked up for malignancy, autoimmune and metabolic disease. Serum ceruloplasmin was reduced, ophthalmology examination showed no KF rings and her 24hr urinary Cu was 10xULN. Liver Cu quantification was markedly raised at 40xULN. Liver biopsy showed cirrhosis with fibrosis related minimal non-specific portal and septal inflammation. Additionally, complete loss of canalicular staining on immunohistochemistry for MDR3 protein was noted, suggestive of MDR3 deficiency. Based on the Cu levels, a provisional diagnosis of Wilson disease was made and Cu chelation therapy was commenced pending genetic testing. A cholestatic gene panel subsequently showed homozygous pathogenic variant for the ABCB4 gene. Trientine was stopped and she was commenced on ursodeoxycholic acid. Though biochemically she remains largely unchanged, she is clinically stable whilst awaiting a liver transplant Conclusions This case highlights the diagnostic difficulties associated with Cu test result interpretation in patients with chronic cholestatic liver disease and urges a thorough consideration of alternative diagnoses of PALF Funding Agencies None

A193 DGAT1 DEFICIENCY WITHOUT DIARRHEA

Abstract Background Acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) catalyzes the final step in triglyceride (TG) synthesis and is highly expressed in enterocytes (EC). DGAT1 deficiency (DGAT1D) is a rare autosomal recessive protein losing enteropathy (PLE) classified as a congenital diarrheal disorder (CDD). Presumably, fat ingestion causes accumulation of DGAT1 substrates within the EC causing lipotoxicity-induced EC dysfunction and death. Aims Report a presentation of DGAT1D atypical for a CDD. Methods We present an infant with DGAT1D with protracted emesis and failure to thrive (FTT) in the absence of diarrhea despite enteral nutrition with varied fat containing formulas (FCF). Results A male infant presented with emesis and FTT requiring multiple admissions. He was initially diagnosed with cow’s milk protein allergy due to concurrent bloody stools, which resolved with hypoallergenic formula. Reportedly watery stools when exclusively breastfed became formed following switch to formula at 2 weeks of age. Interestingly, he subsequently required intermittent suppositories. However, emesis and malnutrition progressed, refractory to omeprazole, baclofen, and varied hypo- and non-allergenic FCF (all containing >0.02g/ml fat, mixtures of medium and long chain FA). He had persistently low serum albumin, ceruloplasmin, and IgG, but SA1AT was normal. TGs were normal, although not measured on FCF. Low fecal elastase (FE) normalized after nutritional support but sweat chloride was intermediate. CFTR sequencing revealed CFTR mutations S466X and R1070 in cis. TPN was started for severe malnutrition at 2 months. Emesis resolved while fasted or receiving enteral electrolyte solution. Endoscopic biopsies on FCF showed increased lamina propria cellularity, no villous abnormalities in the duodenum, chronic inflammation in the gastric body, and normal colonic mucosa. Whole exome sequencing at 2 months showed homozygous c.838C>T (p.Arg280Ter) mutations in DGAT1, explaining his clinical presentation and biochemical features of PLE. After diagnosis, he was started on Tolerex® formula (fat = 0.017g/ml), which was tolerated. Conclusions DGAT1D is classified as a CDD, with vomiting often reported. This case describes a unique presentation of this rare condition, with emesis the predominant symptom, and notable constipation, demonstrating the variable phenotype of this condition. Fat malabsorption may contribute to constipation by altering viscosity of luminal contents or activating the ileal brake. Thus, DGAT1D should be considered on the differential for congenital PLE, even without diarrhea. This case also demonstrates the limitations of stool testing in DGAT1D as random SA1AT concentrations may not reflect A1AT clearance in the diagnosis of PLE. Low FE has been detected in children with malnutrition or dietary restriction and has been reported in DGAT1D, where it likely represents a physiologic consequence of FTT. Funding Agencies None

Serum iron status in association with pregnancy outcomes in infertile women undergoing IVF/ICSI

Iron status can affect the outcome of in vitro-fertilization (IVF) in infertile women who undergoes this process. The aim of this study is to evaluate iron status, ceruloplasmin ferroxidase activity and their association with outcome of pregnancy prior to initiation of IVF/ICSI procedure. The participants were fertile women with male cause infertility (control; n=25), women with polycystic ovary syndrome (PCOS; n=21), women with low anti-Müllerian hormone level (AMH; n=26), and women with unexplained infertility (UI; n=27). Blood samples were obtained on the day of oocyte aspiration. Serum iron, ferritin, transferrin level, and ceruloplasmin ferroxidase activity were measured; the transferrin saturation, Total Iron Binding Capacity (TIBC), and Unsaturated Iron Binding Capacity (UIBC) were calculated. In the low AMH group, Ferritin showed a significantly lower level compared to the control and UI groups. In the PCOS group, ferritin, transferrin, TIBC, and UIBC showed a significantly lower level compared to the control and UI groups. Cp. ferroxidase activity in the PCOS group showed a lower level but of no significance compared to the other groups. In this study, it can be concluded that higher levels of iron, ferritin, and lower transferrin in pregnant PCOS women lead to increase chances of pregnancy following an IVF protocol.

Iron metabolism is disturbed and anti-copper treatment improves but does not normalize iron metabolism in Wilson\u2019s disease

Wilson’s disease (WD) is a rare hereditary disorder of copper metabolism. Some data suggest that iron metabolism is disturbed in WD and this may affect the course of the disease. The current study aimed to determine whether anti-copper treatment could affect iron metabolism in WD. One hundred thirty-eight WD patients and 102 controls were examined. Serum ceruloplasmin and copper were measured by colorimetric enzyme assay or atomic adsorption spectroscopy, respectively. Routine and non-routine parameters of iron metabolism were measured by standard laboratory methods or enzyme immunoassay, respectively. WD patients, both newly diagnosed and treated, had less serum copper and ceruloplasmin than controls (90.0, 63.0, 22.0 mg/dL, respectively, p < 0.001); in the treated patients blood copper and ceruloplasmin were lower than in untreated patients (p < 0.001). Untreated patients (n = 39) had a higher median blood iron (126.0 vs 103.5 ug/dL, p < 0.05), ferritin (158.9 vs 47.5 ng/mL, p < 0.001), hepcidin (32, 6 vs 12.1 ng/mL, p < 0.001) and sTfR (0.8 vs. 0.7 ug/mL, p < 0.001) and lower blood transferrin (2.4 vs. 2.7 g/L, p < 0.001), TIBC (303.0 vs 338.0 ug/dL, p < 0.001), hemoglobin (13.1 vs 13.9 g/dL, p < 0.01) and RBC (4.3 vs. 4.6, p < 0.002) than controls. Treated patients (n = 99) had a significantly lower median iron (88.0 vs. 126.0 ug/dL, p < 0.001), ferritin (77.0 vs. 158.9 ng/mL, p < 0.005) and hepcidin (16.7 vs. 32.6 ng/mL, p < 001) and higher transferrin (2.8 vs. 2.4 g/L, p < 0.005), TIBC (336.0 vs 303.0 ug/dL, p < 0.001), RBC (4.8 vs. 4.3 M/L, p < 0.001) and hemoglobin (14.4 vs. 13.1 g/dL, p < 0.001) than untreated; the median iron (p < 0.005) was lower, and ferritin (p < 0.005), RBC (p < 0.005) and hepcidin (p < 0.002) were higher in them than in the control group. Changes in copper metabolism are accompanied by changes in iron metabolism in WD. Anti-copper treatment improves but does not normalize iron metabolism.

Evaluation of Serum Ceruloplasmin Levels as a Biomarker for Oxidative Stress in Patients With Diabetic Retinopathy.

BackgroundElevated serum ceruloplasmin is a biomarker for oxidative stress. Diabetes mellitus (DM) is known to be a state of oxidative stress which causes complications of DM including diabetic retinopathy (DR). The role of ceruloplasmin in DR is still unclear.MethodsNinety patients of DM were included as cases and after evaluation sub-grouped as those with no DR, non-proliferative DR (NPDR) and proliferative DR (PDR). Serum ceruloplasmin levels were tested in all cases as well as in equal numbers of age and sex-matched controls without DM. Statistical analysis was done with p<0.05 taken as significant.Results Serum ceruloplasmin was significantly higher among cases as compared to controls (1222.82±306.15 IU/L versus 868.38±198.80 IU/L, p<0.01). There was no statistical difference between serum ceruloplasmin values in No DR, NPDR and PDR. On receiver operator characteristic curve (ROC) analysis for serum ceruloplasmin as a test for discriminating various parameters, it was seen that serum ceruloplasmin was a good test for discriminating DM from no DM (area under receiver operator characteristic {AUROC}=0.814, 95% CI=0.749-0.868, p<0.0001) with a cut point of >1093 IU/L yielding a sensitivity of 63.33% and specificity of 87.78%. Ceruloplasmin as a test was not found to significantly discriminate DR (total) from no DR, NPDR from no DR, PDR from no DR and PDR from NPDR.ConclusionSerum ceruloplasmin levels are significantly raised in patients with DM. However, serum ceruloplasmin levels do not correlate with DR severity.

Violations of antioxidant-prooxidant spleen index and ceruloplasmin content in serum during acute blood loss, complicated by ischemia-reperfusion of limb and the effectiveness of its correction with carbacetam

Antioxidant-prooxidant imbalance is one of the key mechanisms of acute blood loss and ischemic-reperfusion syndrome. Under these conditions, the level of ceruloplasmin (CP) plays an important role, enhancing antioxidant protection and promoting hematopoiesis, exhibiting ferrooxidase action. However, in this case, the state of antioxidant-prooxidant balance in the spleen and the content of CP in the serum is studied insufficiently, thus there is no data on the effectiveness of carbacetam, which revealed a pronounced protective effect on antioxidant protection of the spleen.Objective of research: to determine the dynamics of the antioxidant-prooxidant index of the spleen and the content of CP in the serum in acute blood loss complicated by ischemia-reperfusion of the limb, and to evaluate the effectiveness of carbacetam in correction of the identified disorders.Materials of the research and their discussion. 108 nonlinear male rats weighing 200–220 g were used in the experiments. All experiments were performed under thiopental-sodium anesthesia. In animals, limb ischemia-reperfusion and acute blood loss were modeled separately and in one of the groups these injuries were combined. In a separate group, the detected disorders were corrected with carbacetam. After 1 and 2 hours, as well as after 1, 7 and 14 days in the spleen of experimental animals was determined content of reagents to thiobarbituric acid and catalase activity, and according to these results the antioxidant-prooxidant index (API) was calculated and was determined the content of CP in serum.Results of the research and their discussion. Modeling of acute blood loss, complicated by ischemia-reperfusion of the limb, contributed to a decrease in the value of API in the spleen, which indicates a shift in antioxidant-prooxidation balance towards the dominance of prooxidant mechanisms. Under these conditions, the content of CP in the blood serum increases significantly, which on the one hand compensates the lack of antioxidant protection, on the other hand indicates on the activation of the mechanisms of the body's systemic response to inflammation. The use of carbacetam helped to shift the antioxidant-prooxidant balance of the spleen towards the dominance of antioxidant mechanisms and to reduction of the CP content in the serum, which indicates on a pronounced antioxidant and anti-inflammatory effect of the drug, as well as its prospects in cases connected with hemic hypoxia and ischemia-reperfusion syndrome.Conclusions: Complication of acute blood loss by limb ischemia-reperfusion contributes to the shift of antioxidant-prooxidant balance of the spleen towards the dominance of prooxidant mechanisms with a simultaneous increase in the content of CP of serum. The use of carbacetam helps to increase the value of API and reduce the content of CP in the serum.

Evaluation of serum analytes in pregnant and non-pregnant dairy cows as indicators of pregnancy

This study was conducted to reveal the dynamics of haematological indicators in pregnant and non-pregnant dairy cows. Sixty multiparous healthy dairy cows were divided into four groups based on the length of time they had been pregnant, namely first, second and third trimesters, and non-pregnant (n=15 each). Blood was collected from each animal, and serum was harvested and stored at -20 °C for biochemical profiling. Concentrations of serum total oxidants (TOC), ceruloplasmin oxidase (CpO) and triiodothyronine (T3) were higher (P &lt;0.05) during the third trimester compared with non-pregnant cows. Serum arylesterase (Ary) concentration was lower (P &lt;0.05) during the second and the third trimesters compared with the non-pregnant cows. The concentration of serum total homocysteine (tHcy) was higher (P &lt;0.05) the third trimester compared with the first and the second trimesters. The concentrations of serum total antioxidants (TAC), paraoxonase 1 (PON1), thyroxine (T4), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were not different in the pregnant and the non-pregnant cows. Thus, TOC, Ary, CpO, tHcy and T3 could be taken as biological markers to assess the progression of pregnancy and to develop management tools to improve health status during late gestation in dairy cows&#x0D; Keywords: ceruloplasmin, hepatic enzymes, late gestation, triiodothyronine

Serum Copper, Ceruloplasmin, Iron, Transferrin level in patients with Psoriasis and their relationship with severity of the disease

Psoriasis is a common, chronic, immune mediated inflammatory disease that involves the innate immunological system (keratinocyte, dendritic cell, histiocytes, mast cells and endothelial cells) and acquired immunological system (T lymphocytes). Essential trace elements like iron (Fe), copper (Cu) undergo redox cycling and have physiological significance in inflammatory process. This study is aimed at measuring the level of copper, ceruloplasmin, iron and transferrin in psoriasis patient and to assess its relationship with the severity of the disease. This is an observational cross sectional study. It was conducted at the department of Dermatology and Venereology, BSMMU, Dhaka. Age range of the patient was 18 to 65 years. The mean age of the patients was 39.1±13.54 years, 57.9% patients were male and 42.1% were female. Male: female ratio was 1.4:1. Male patients were predominant. Mean duration of disease 5.36±4.05 years with range from 1.0 to 14 years. Most of the (76.3%) patients had mild disease followed by 23.7% had moderate to severe disease. Serum level of trace elements was compared between mild and moderate to severe group of psoriasis patients but difference were not statistically significant (p&gt;0.05). Weak negative correlation was found between PASI score and serum levels of copper (r = “0.134, P = 0.423), iron (r = –0.080, p = 0.632), transferrin (r = –0.079, p = 0.638) and weak positive correlation was found with ceruloplasmin (r = 0.228, p = 0.168). The results of the present research provide valuable information and correlation between the measured biomarkers and severity of psoriasis. Serum Ceruloplasmin, copper, iron and serum transferrin could serve as a biomarker of psoriasis but not as a marker of psoriasis severity.&#x0D; J Dhaka Medical College, Vol. 29, No.1, April, 2020, Page 59-68

Serum ceruloplasmin as cancer marker in oral pre-cancers and cancers.

BACKGROUND AND AIM:Oxidative stress leads to a compensatory increase in levels of serum ceruloplasmin in patients with such imbalances. Greater than normal serum ceruloplasmin levels are noticed in numerous cancers including the leukemias and Hodgkin's lymphoma. The purpose of the present study was to estimate and evaluate the efficacy of serum ceruloplasmin levels as a potential biomarker in the early detection of oral potentially malignant epithelial lesions (PMELs) including leukoplakia, oral submucous fibrosis (OSMF), and oral squamous cell carcinoma (OSCC) patients.MATERIALS AND METHODS:The present observational study was conducted over a period of 2 years wherein 100 subjects aged between 18 to 60 years were divided into four groups with Group A consisting of 25 healthy controls, Group B and C with 25 patients each, clinically diagnosed with oral leukoplakia and OSMF and Group D with 25 patients clinically diagnosed and histopathologically proven OSCC. The patients were subjected to incisional biopsy after routine hematological investigation while the same sera samples were used for analysis of serum ceruloplasmin levels.STATISTICAL ANALYSIS USED:Comparison of serum ceruloplasmin levels between the groups was performed using one way analysis of variance (one way ANOVA) test while P < 0.05 was considered statistically significant.RESULTS:The mean serum ceruloplasmin levels were found to be 43.19 ± 1.90mg/dl in subjects of group A, 47.68 ± 1.51mg/dl in group B, 47.74 ± 1.45mg/dl in group C and 47.73 ± 0.74mg/dl in group D. Using one-way ANOVA, statistically significant variations were found in the values of mean serum ceruloplasmin levels in subjects of the four groups (F-value = 59.58, P = 0.0001).CONCLUSIONS:The observations of the present study revealed that serum ceruloplasmin levels were found to be raised in all 3 study groups including oral leukoplakia, OSMF and OSCC as compared to the controls while the results were found to be statistically significant.

Assessment of Serum Selenium and Ceruloplasmin in Potentially Malignant Disorders and Oral Cancer.

Introduction:Despite extensive research and development, potentially malignant disorders (PMDs) of the oral cavity and oral cancer remain a serious concern. Diet and immunity have been identified as important modifiable factors in such diseases.Materials and Methods:A total of 20 patients and 10 healthy individuals, aged 30–60 years, were chosen from the outpatient Department of Oral and Maxillofacial Surgery, Yenepoya Dental College and hospital, Karnataka. The participants were grouped into three: Group 1: (10 healthy individuals), Group 2: (10 oral leukoplakia patients) and Group 3: (10 squamous cell carcinoma patients). Blood was chosen as the investigative medium. Ceruloplasmin was estimated by the diamine oxidase method. The technique of atomic absorption developed by Sir Alan Walsh in 1950 has become the preferred method of elemental analysis of selenium (atomic absorption spectrometer). Statistical analysis of the data obtained was done using one-way ANOVA test and the Turkey multiple comparisons test.Results:The intergroup comparison of ceruloplasmin shows that the mean value of Group I (Control) was 31.746 mg/dl, the mean value of Group II (leukoplakia) was 81.411 mg/dl, and the mean value of Group III (squamous cell carcinoma) was 90.7120 mg/dl. The intergroup comparison of selenium levels shows that the mean value of Group I (Control) was 119.937 (ng/ml), the mean value of Group II (leukoplakia) was 109.17 (ng/ml), and the mean value of Group III (squamous cell carcinoma) was 99.6230 (ng/ml).Conclusion:Antioxidants are an important defense system against free radical damage to cells. Ceruloplasmin and selenium levels in serum could be used as disease markers in leukoplakia and squamous cell carcinoma.

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Artificial regulation and management of the numerical sex ratio of farm animals and poultry is one of the important prerequisites for intensive livestock management. The article considers the genetic characteristics of male turkeys produced via parthenogenesis and fertilized eggs according to blood serum transferrin (Tf), ceruloplasmin (Cp) and hemoglobin (Hb) loci. The findings of genetic and mathematical analyses conducted throughout experimental investigations can be used as genetic markers when implementing selection activities in the mentioned branch.

Value of Kayser-Fleischer ring as a diagnostic tool for Wilson’s disease in children

The Kayser-Fleischer(K-F) ring is the hallmark of Wilson’s disease (WD). In most adults or older children, the diagnosis of Wilson’s disease may be made easily when K-Frings and low ceruloplasmin levels are present. In this study presence of K-F ring has been evaluated among children with liver disease in Bangladesh to improve the management of Chronic liver disease due to WD and reduce complications. This cross-sectional study was carried out at the Department of Paediatric Gastroenterology and Nutrition, BSMMU, Dhaka on 60 children presented with liver disease. Thirty children over three years of age considered as cases (Group-I) and thirty children with non- Wilsonian liver disease as control (Group-II). Slit lamp examination for K-F ring and twenty-four hour urinary copper excretion after giving one gram d-penicillamine 12-hour apart were done in each patient. The efficacy of K-F ring was studied. Mean age of WD patients was 8.9± 2.78 years, with a male female ratio of 1.3: 1. There was significant low level of serum ceruloplasmin in 93.33% of cases (p&lt;.001). After penicillamine challenge, 24-hour urinary copper excretion was found significantly higher in patients with WD (median 3626.5±1698 μg/24h, range 1262- 195000) than non-Wilsonian liver disease (median 450±278.09 μg/24-h, range 47- 2062 μg/24h), (p&lt;.001). K-F ring was found in 15 (50%) patients, absent in all patients of non-Wilsonian liver disease group and the difference was statistically significant (p&lt;.001). Evaluation of Kayser-Fleischer ring is still a very essential diagnostic tool and is a non-invasive, affordable way to assist in the diagnosis of a potentially fatal disease.

The Ameliorative Effects of Arctiin and Arctigenin on the Oxidative Injury of Lung Induced by Silica via TLR-4/NLRP3/TGF-β Signaling Pathway.

Silicosis remains one of the most serious diseases worldwide, with no effective drug for its treatment. Our research results have indicated that arctiin and arctigenin could increase the mitochondrial membrane potential, which in turn reduces the production of reactive oxygen species (ROS), blocks the polarization of macrophages, and inhibits the differentiation of myofibroblasts to reduce oxidative stress, inflammation, and fibrosis. Further, our study revealed that arctiin and arctigenin suppressed the activation of NLRP3 inflammasome through the TLR-4/Myd88/NF-κB pathway and the silica-induced secretion of TNF-α, IL-1β, TGF-β, and α-SMA. Besides, the silica-induced increase in the levels of serum ceruloplasmin and HYP was also inhibited. Results of metabolomics indicated that arctiin and arctigenin could regulate the abnormal metabolic pathways associated with the development of silicosis, which involve pantothenate and CoA biosynthesis, cysteine and methionine metabolism, linoleic acid metabolism, and arginine and proline metabolism successively. Furthermore, the analysis of metabolomics, together with network topological analysis in different phases of silicosis, revealed that urine myristic acid, serum 4-hydroxyproline, and L-arginine could be regarded as diagnosis biomarkers in the early phase and formation of pulmonary fibrosis in the latter phases of silicosis. Arctiin and arctigenin could downregulate the increased levels of myristic acid in the early phase and serum 4-hydroxyproline in the latter phase of silicosis. Interestingly, the integration of TLR-4/NLRP3/TGF-β signaling and metabolomics verified the importance of macrophage polarization in the silicosis fibrosis process. To the best of our knowledge, this is the first study reporting that arctiin and arctigenin both can ameliorate silicosis effectively, and the former is a little stronger than its aglycone arctigenin because of its high oral bioavailability, low toxicity, and multimolecular active metabolites as determined by AdmetSAR and molecular docking analysis.

Treatment of copper deficiency in Texel-crossbred sheep by the feeding of a concentrate formulated for dairy cows

Six Texel-crossbred sheep, from a flock with a history of a dull appearance and mild diarrhea, were presented to the faculty of veterinary medicine (University of Utrecht) . The clinical signs were found to be related to Copper (Cu) deficiency as indicated by low hepatic Cu values. It was decided to treat the animals by feeding them concentrates specifically formulated for dairy cows because such concentrates have a rather high Cu content compared to concentrates designed for sheep. Sheep Cu status was monitored by measuring liver Cu concentrations. Current results indicate the potential of feeding cow concentrate as a practical method to treat Cu deficiency in Texel-crossbred sheep. In contrast to hepatic Cu concentrations, serum Ceruloplasmin concentration (Cp) values did not respond to the treatment thereby indicating that serum Cp is inferior to evaluate Cu status in sheep compared to liver Cu measurements.

Wilson disease: revision of diagnostic criteria in a clinical series with great genetic homogeneity.

Wilson disease is an autosomal recessive disorder of copper metabolism caused by mutations in the ATP7B gene. An early diagnosis is crucial to prevent evolution of the disease, as implantation of early therapeutic measures fully prevents its symptoms. As population genetics data predict a higher than initially expected prevalence, it was important to define the basic diagnostic tools to approach population screening. A highly genetically homogeneous cohort of 70 patients, belonging to 50 unrelated families, has been selected as a framework to analyze all their clinical, biochemical and genetic characteristics, to define the disease in our population, with an estimated prevalence of 1 in 12,369, and determine the most useful features that reach diagnostic value. Serum ceruloplasmin below 11.5mg/dL and cupremia below 60μg/mL, were the best analytical predictors of the disease in asymptomatic individuals, while cupruria or hepatic copper determination were less powerful. Genetic analysis reached a conclusive diagnosis in all 65 patients available for complete testing. Of them, 48 were carriers of at least one p.Leu708Pro mutant allele, with 24 homozygotes. Nine patients carried a promoter deletion mutation, revealing that extended sequencing beyond the ATP7B gene-coding region is essential. All mutations caused hepatic damage since early ages, increasing its severity as diagnosis was delayed, and neurological symptoms appear. Serum ceruloplasmin determination followed by genetic screening would reduce costs and favor the prioritization of non-invasive procedures to reach a definitive diagnosis, even for asymptomatic cases.

Commentary on "A New Onset of Mania in a 49-Year-Old Man: An Interesting Case of Wilson Disease".

Wilson disease is a rare copper metabolism disorder that generally occurs in individuals between 5 and 35 years of age. Common clinical manifestations are hepatic, neurological, and psychiatric symptoms. Roughly, 4% of all cases occur in patients over 40 years of age and, among these patients, the presenting symptoms are generally neuropsychiatric, which often leads to misdiagnosis as a primary psychiatric disorder and a delay in correct diagnosis. This report presents the case of a 49-year-old man with no formal psychiatric history who presented with a new onset of mania. We outline the distinctive characteristics that appeared inconsistent with a primary psychiatric disorder and pointed toward secondary mania. Despite low serum ceruloplasmin, the absence of brain abnormalities more typical of Wilson disease on magnetic resonance imaging led a neurology consultant to advise that the diagnosis was likely primarily psychiatric. Due to atypical components of the patient's presentation, such as his late age of onset for bipolar disorder and acute cognitive decline, the psychiatric team advocated for further diagnostic workup. The subsequent evaluation confirmed Wilson disease based on specific ophthalmological and hepatic abnormalities and further copper studies. In addition, once diagnosed, the management of Wilson disease involves distinct clinical considerations given patients' presumed vulnerability to neurological side effects. This case illustrates the role psychiatric providers play in advocating for diagnostic workup in patients with atypical presentations of primary psychiatric disorders and the distinct diagnostic and treatment considerations associated with Wilson disease.

Copper Ionophores as Novel Antiobesity Therapeutics.

The therapeutic utility of the copper ionophore disulfiram was investigated in a diet-induced obesity mouse model (C57BL/6J background), both through administration in feed (0.05 to 1% (w/w)) and via oral gavage (150 mg/kg) for up to eight weeks. Mice were monitored for body weight, fat deposition (perigonadal fat pads), metabolic changes (e.g., glucose dyshomeostasis) and pathologies (e.g., hepatic steatosis, hyperglycaemia and hypertriglyceridemia) associated with a high-fat diet. Metal-related pharmacological effects across major organs and serums were investigated using inductively coupled plasma mass spectrometry (ICP-MS). Disulfiram treatments (all modes) augmented hepatic copper in mice, markedly moderated body weight and abolished the deleterious systemic changes associated with a high-fat diet. Likewise, another chemically distinct copper ionophore H2(gtsm), administered daily (oral gavage), also augmented hepatic copper and moderated mouse body weight. Postmortem histological examinations of the liver and other major organs, together with serum aminotransferases, supported the reported therapeutic safety of disulfiram. Disulfiram specifically altered systemic copper in mice and altered hepatic copper metabolism, perturbing the incorporation of copper into ceruloplasmin (holo-ceruloplasmin biosynthesis) and subsequently reducing serum copper concentrations. Serum ceruloplasmin represents a biomarker for disulfiram activity. Our results establish copper ionophores as a potential class of antiobesity agents.

PREDICTIVE ROLE OF CERULOPLASMIN AND HIGH SENSITIVITE C-REACTIVE PROTEIN AS INFLAMMATORY MARKERS IN ATHEROSCLEROTIC CORONARY ARTERY DISEASE PATIENTS

Background: Coronary artery disease (CAD) remains the leading cause of morbidity and mortality in the industrialized world. The root cause of CAD is mainly atherosclerosis. It seems to be a chronic inflammatory condition, which later develops into an acute clinical event by the induction of plaque rupture, causing thrombosis. Ceruloplasmin is the major copper-carrying protein in the blood and in addition plays a role in iron metabolism. Objective: To assess the predictive value of ceruloplasmin and high-sensitivite C-reactive protein in diagnosis of atherosclerotic coronary artery disease. Patients and methods: The study was conducted on 60 patients presented with clinical features of coronary artery diseases, admitted to Cardiology Department at Sayed Galal University Hospital, throught the period from July 2017 and March 2020, and they were classified according to coronary angiography into 3 subgroups (one, two, multi-vessel disease). They were compared with 20 healthy individuals with identical demographic characteristics not suffering from any disease. Serum ceruloplasmin and serum hs-CRP levels were measured in both groups. Results: A significant increase in serum ceruloplasmin and hs-CRP levels were observed in all patients of coronary artery disease as compared to control group (p=<0.001). Conclusion: In patients of CAD, the serum ceruloplasmin and hs-CRP levels rise due to their property as acute phase proteins.

Difficulties with diagnosing Wilson's disease by genetic testing alone

Objective: Diagnosis of Wilson's disease (WD) is based on the presence of clinical symptoms, laboratory (serum ceruloplasmin, serum copper, urinary copper excretion) and genetic findings. Diagnostic criteria of WD are summarized in Leipzig scoring. Radioactive copper incorporation is used when standard diagnostic criteria are insufficient.