Serum Ceruloplasmin Levels Research Articles

Mutation analysis of the ATP7B gene and genotype\u2013phenotype correlation in Chinese patients with Wilson disease

AimTo discover the novel ATP7B mutations in 103 southern Chinese patients with Wilson disease (WD), and to determine the spectrum and frequency of mutations in the ATP7B gene and genotype–phenotype correlation in a large-scale sample of Chinese WD patients.MethodsOne hundred three WD patients from 101 unrelated families in southern China were enrolled in this study. Genomic DNA was extracted from the peripheral blood. Direct sequencing of all 21 exons within ATP7B was performed. Subsequently, an extensive study of the overall spectrum and frequency of ATP7B mutations and genotype–phenotype correlation was performed in all Chinese patients eligible from the literature, combined with the current southern group.ResultsIn 103 patients with WD, we identified 48 different mutations (42 missense mutations, 4 nonsense mutations and 2 frameshifts). Of these, 3 mutations had not been previously reported: c.1510_1511insA, c.2233C>A (p.Leu745Met) and c.3824T>C (p.Leu1275Ser). The c.2333G>T (p.Arg778 Leu) at exon 8, was the most common mutation with an allelic frequency of 18.8%, followed by c.2975C>T (p.Pro992Leu) at exon 13, with an allelic frequency of 13.4%. In the comprehensive study, 233 distinct mutations were identified, including 154 missense mutations, 23 nonsense mutations and 56 frameshifts. Eighty-five variants were identified as novel mutations. The c.2333G>T (p.Arg778 Leu) and c.2975C>T (p.Pro992Leu) were the most common mutations, with allelic frequencies of 28.6% and 13.0%, respectively. Exons 8, 12, 13, 16 and 18 were recognised as hotspot exons. Phenotype–genotype correlation analysis suggested that c.2333G>T (p.Arg778 Leu) was significantly associated with lower levels of serum ceruloplasmin (P = 0.034). c.2975C>T (p.Pro992Leu) was correlated with earlier age of disease onset (P = 0.002). Additionally, we found that the c.3809A>G (p.Asn1270Ser) mutation significantly indicated younger onset age (P = 0.012), and the c.3884C>T (p.Ala1295Val) mutation at exon 18 was significantly associated with hepatic presentation (P = 0.048). Moreover, the patients with mixed presentation displayed the initial WD features at an older onset age than the groups with either liver disease or neurological presentation (P = 0.039, P = 0.015, respectively). No significant difference was observed in the presence of KF rings among the three groups with different clinical manifestations.ConclusionIn this study, we identified three novel mutations in 103 WD patients from the southern part of China, which could enrich the previously established mutational spectrum of the ATP7B gene. Moreover, we tapped into a large-scale study of a Chinese WD cohort to characterise the overall phenotypic and genotypic spectra and assess the association between genotype and phenotype, which enhances the current knowledge about the population genetics of WD in China.

FOUR DIFFERENT PRESENTATIONS OF WILSON’S DISEASE IN ONE FAMILY

Wilson’s disease (WD) is an important differential to consider in any child presenting with hepatic, neurological or ophthalmological manifestations of the disease. We report here 4 individuals of the same family: 2 paediatric and 2 adult patients with a spectrum of manifestations of the disease presenting to Pak Emirates Military Hospital and Combined Military Hospital Rawalpindi, Rawalpindi, from January 2019 and September 2020. The index case had neuro-wilson; the brother was diagnosed preemptively during screening; the father being completely asymptomatic despite markedly raised 24 hours urinary copper levels; and the paternal uncle being diagnosed after many years of manifesting hepatic symptoms. The purpose of this publication is to sensitize the readers to the usage of scoring tools such as the Leipzig score, the importance of regular follow-up and family screening of hereditary diseases. We would also like to highlight the possibility of missed diagnosis with serum Copper levels (S.Copper) which were within normal limits (WNL) in all 4 of our patients; and Serumceruloplasmin (S.ceruloplasmin) levels which were within normal limits in 3\4 of these patients, that are often used as screening tools for WD.

Diagnosis of Wilson Disease and Its Phenotypes by Using Artificial Intelligence.

WD is caused by ATP7B variants disrupting copper efflux resulting in excessive copper accumulation mainly in liver and brain. The diagnosis of WD is challenged by its variable clinical course, onset, morbidity, and ATP7B variant type. Currently it is diagnosed by a combination of clinical symptoms/signs, aberrant copper metabolism parameters (e.g., low ceruloplasmin serum levels and high urinary and hepatic copper concentrations), and genetic evidence of ATP7B mutations when available. As early diagnosis and treatment are key to favorable outcomes, it is critical to identify subjects before the onset of overtly detrimental clinical manifestations. To this end, we sought to improve WD diagnosis using artificial neural network algorithms (part of artificial intelligence) by integrating available clinical and molecular parameters. Surprisingly, WD diagnosis was based on plasma levels of glutamate, asparagine, taurine, and Fischer’s ratio. As these amino acids are linked to the urea–Krebs’ cycles, our study not only underscores the central role of hepatic mitochondria in WD pathology but also that most WD patients have underlying hepatic dysfunction. Our study provides novel evidence that artificial intelligence utilized for integrated analysis for WD may result in earlier diagnosis and mechanistically relevant treatments for patients with WD.

Serum trace elements levels in patients transferred from the intensive care unit to wards.

Trace elements act as co-factors and/or in co-enzymes in many metabolic pathways and its deficiency contributes to metabolic and infectious complications. The aim of this study was to determine serum zinc, selenium, cobalt, chromium, copper and ceruloplasmin levels for identify the need for post intensive care unit (ICU) nutritional follow-up. This study was prospectively conducted in medical ICU. Adult patients (≥18 years) who stayed in ICU more than 48h and transferred to ward were included in the study. Blood samples of trace element levels were sampled at discharge. We enrolled 100 patients. The median age was 60 (40-70) years with Acute Physiology and Chronic Health Evaluation II (APACHE II) score 15 (11-21) . The median C-Reactive Protein (CRP) level was 53.9 (24.8-116.0) mg/L at discharge. Median serum zinc (24.4 mcg/dl:14.2-38.7) and chromium (0.22 mcg/dl:0.17-0.34) levels were below reference values, while median copper (111.9 (73.0-152.5) mcg/dl) and selenium (54.8 (36.4-95.25) mcg/L) values were within ranges. Serum concentrations of chromium, zinc, and selenium were lower than the normal values in 98, 90, and 36% of patients, respectively. The 28-day ICU mortality were correlated with low serum selenium levels (p=0.03). Serum chromium and zinc levels were below reference values at discharge, but this finding was in context of inflammation. Low serum selenium level observed in 36% was associated to 28-day ICU mortality.

Effect of dietary supplementation with grape residue flour on weight gain, metabolic profile, leukogram, proteinogram and antioxidant response in suckling lambs

The objective of this study was to determine whether the addition of grape residue flour (GRF) in the diet of suckling lambs would improve their health and consequently enhance their growth. We used 48 lambs, 30 days of age divided into four treatments with four repetitions each, with each repetition consisting of three animals. The groups were identified as follows: G-0%, used as a control (without GRF) and G-0.5%, G-1% and G-2% referring to treatment with grape residue flour in doses of 0.5%, 1%, and 2% of inclusion in the concentrate, respectively. Lambs in groups G-1% and G-2% had higher final body weights, weight gain and average daily gain (ADG) compared to the other groups. GRF dietary supplementation had good antioxidant potential, being able to stimulate glutathione S-transferase (GST) activity and consequently reduce levels of reactive oxygen species (ROS) in lambs that consumed the highest dose of GRF (G-2%). GRF supplementation improved humoral responses, with increased serum levels of heavy-chain and light-chain immunoglobulins; however, there was a reduction in serum ceruloplasmin levels in these lambs. We observed higher concentrations of glucose and triglycerides in lambs in the 2% group. There were lower lymphocyte counts in lambs that received GRF. Lambs supplemented with the highest doses of GRF (G-1% and G-2%) had lower total bacterial counts in the feces. We conclude that the use of GRF in the supplementation of suckling lambs improved animal health, as it stimulated the antioxidant and immune systems and consequently favored their growth.

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.

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.

Plasma oxalic acid as a trigger for oxidative processes in end-stage renal disease patients

The present study aimed to evaluate the changes in oxidative stress markers according to the concentration of plasma oxalic acid (POx) in end-stage renal disease (ESRD) patients.&#x0D; Methods. We conducted a cross-sectional observational study involving 72 ESRD patients and 30 relatively healthy individuals who served as a control reference group for evaluation of POx concentration. Among ESRD patients there were 32 hemodialysis (HD) patients and 40 peritoneal dialysis (PD). POx concentration was measured spectrophotometrically using a commercially available kit (MAK315, Sigma, Spain). Malonic dialdehyde (MDA), ceruloplasmin (CP), transferrin (TR), sulfhydryl groups (SH-groups), antioxidant blood capacity (AOC) and total peroxidase activity of erythrocytes (TPA) were measured and the oxidative stress index (OSI) was calculated in all examined patients.&#x0D; Results. A significant increase in POx concentration was observed in ESRD patients compared with healthy volunteers (p &lt; 0.0001). The concentrations of MDA in serum, OSI in erythrocytes and serum of the examined patients were gradually increased, while serum levels of CP, AOC, SH-groups and TPA in erythrocytes, on the contrary, were decreased in accordance with the increasing trend of POx concentrations. Correlation analysis demonstrated a statistically significant direct relationship between POx concentration and MDA (r = 0.57; p &lt;0.0001) and OSI (r = 0.64; p &lt;0.0001). The inverse correlation was determined between POx and antioxidant markers: CP (r = -0.35; p = 0.007), SH-groups in serum (r = -0.3; p = 0.04) and erythrocytes (r = -0.53 ; p &lt;0.0001).&#x0D; Conclusions. The intensity of oxidative-antioxidant balance disorders in the blood of ESRD patients has been associated with the POx concentration: the higher the concentration of POx was the more active oxidative processes and the more pronounced lack of antioxidant protective factors occurred. Further studies are needed to determine the role of POx in the initiation of oxidative stress and chronic inflammation in ESRD patients.

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.

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.

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.

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.

Thiols and ceruloplasmin levels in serum of children with attention deficit hyperactivity disorder: A cross-sectional study

Attention deficit hyperactivity disorder (ADHD) is a childhood onset disorder with well-known findings that include impulsivity, hyperactivity, and inattention. This study aims to explore the relationship between the levels of ceruloplasmin, native thiol, total thiol, and disulfide and ADHD by comparing case and control groups. The study case group comprised 50 children aged 6–16 years who had been diagnosed with ADHD. The control group included 47 healthy children. Clinical interviews were conducted and the Schedule for Affective Disorders and Schizophrenia for School-Age Children—Present and Lifetime Version Turkish Adaptation and the Conners Parent Rating Scale were administered. Additionally, blood samples were taken and native thiol, total thiol, disulfide, and ceruloplasmin levels measured. In the ADHD group, the mean native thiol, total thiol, and disulfide levels were significantly lower than the control group. There was no significant difference between the ADHD and control groups in ceruloplasmin levels. Total thiol and native thiol levels were inversely correlated with scores on the Conners Inattention and Hyperactivity subscales; total thiol was negatively correlated with the ADHD index. Thiol–disulfide homeostasis was impaired in ADHD children and was related to symptom severity. Oxidative stress balance may play a role in ADHD.

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.

S1121 Role of Markers of Heavy Metal Metabolism in Identification of Hepatic Fibrosis in Patients With Non-Alcoholic Fatty Liver Disease (NAFLD)

INTRODUCTION: Fibrosis & nonalcoholic steatohepatitis (NASH) are important predictors of long term prognosis in patients with non-alcoholic fatty liver disease (NAFLD). Oxidative stress (OS) has been shown to play a central role in progression of NAFLD, & changes in proteins associated with metal homeostasis may exacerbate OS. We investigated relationship of proteins related to transition metal metabolism with fibrosis in NAFLD. METHODS: Adult patients (>18y) who underwent liver biopsy for clinically suspected NAFLD at our institution were included. We retrospectively collected serum levels of ceruloplasmin (Cp), ferritin, iron, & transferrin saturation (Tsat) within 3 months of liver biopsy & calculated Cp/Tsat ratio (CT ratio) & Cp/Ferritin ratio (CF ratio). Histologic features were scored by an experienced pathologist using Non-alcoholic Steatohepatitis Clinical Research Network criteria. Fibrosis was staged as (0 - 4). Independent T test were used to compare the means & receiver operating characteristics (ROC) curves were plotted for assessing area under curve (AUC), sensitivity (Sn) & specificity (Sp). RESULTS: 174 patients were included in final analysis. The mean age of subjects was 48 y. Baseline features are depicted in Table 1. Biopsy proven NASH was seen in 61.5% of liver biopsies. No fibrosis was seen in 29.3% of liver biopsies & Stage 1, 2,3& 4 fibrosis were seen in 29.9%, 10.9%, 14.3% & 15.55% of samples. Mean Tsat was significantly higher (24.41% v/s 38.27%, P < 0.0001) & Cp (mg/dl) (27.82 v/s 24.91, P = 0.03) significantly lower between patients with advanced fibrosis (AF) (3-4) v/s early fibrosis (EF) (0-2). The mean CT ratio was also higher in patients with EF v/s AF (1.54 v/s 1.02, P = 0.01). The mean Tsat of patients with fibrosis v/s without fibrosis was higher (31.4% v/s 21.57% P < 0.005) however mean Cp (mg/dl) values were not significantly different (27.88 v/s 27.58, P = 0.42). The ROC curves show CF ratio (Figure 1) at a cut off of 0.10 had AUC = 0.61 (Sn = 70%, Sp = 52% P = 0.01) to detect any fibrosis & CT ratio (Figure 2) at a cut off 0.86 had AUC = 0.65 (Sn = 69%, Sp = 50% P = 0.002) for differentiating EF v/s AF. CONCLUSION: Our data reveals changes in ceruloplasmin: transferrin system, which decreases the content of toxic ions of Fe2+ in NAFLD. Tsat, Cp, CF ratio & CT ratio are useful non-invasive biomarkers in identifying NAFLD patients with fibrosis. Markers of heavy metal metabolism can spare patients from liver biopsies & can be potential therapeutic targets in future.Table 1.: Demographic and histological features of study populationFigure 1.: ROC curve for fibrosis stage determination (0 vs 1-4) based on CF RATIO.Figure 2.: ROC curve for fibrosis stage determination (0-2 vs 3-4) based on CT Ratio.

Elevated Serum Ceruloplasmin Levels Are Associated with Higher Impulsivity in People with Parkinson's Disease.

Background Heightened impulsivity has been reported in a subset of people with Parkinson's disease (PwP) and is considered a risk factor for the development of impulse control disorders (ICDs). However, at present, there are no recognised biochemical markers of heightened impulsivity. Objectives To determine if ceruloplasmin, a serum marker involved in the regulation of iron and copper homeostasis, is associated with trait impulsivity in PwP. Methods The study measured serum ceruloplasmin and impulsivity using the Barratt Impulsiveness Scale (BIS-11) in an Australian cohort of 214 PwP. Multivariate general linear models (GLMs) were used to identify whether higher serum ceruloplasmin levels (>75th percentile) were significantly predictive of BIS-11 scores. Results Serum ceruloplasmin was higher in females with PD (p < 0.001) and associated with MDS-UPDRS III, Hoehn and Yahr, and ACE-R scores (p < 0.05). When correcting for covariates, higher serum ceruloplasmin concentrations were associated with the 2nd order nonplanning impulsivity and with the 1st order self-control and cognitive complexity impulsivity domains. Conclusions Higher serum ceruloplasmin levels are independently associated with heightened nonplanning impulsivity in PwP. Thus, serum ceruloplasmin levels may have clinical utility as a marker for heightened impulsivity in PD.

Effects of Nano-copper on Antioxidant Function in Copper-Deprived Guizhou Black Goats.

Guizhou black goats are essential to the production system in the Wumeng prairie in the Western China. This study aimed to determine the influence of nano-copper on antioxidant system in copper-deprived Guizhou black goats. We analyzed mineral contents in soil, forage, and goats' tissues. Blood parameters were also determined. The results showed that copper concentrations in soil and forage were significantly lower, and the iron content was significantly higher in affected compared with healthy area (P < 0.01). Copper concentrations in animal tissues (blood, liver, and hair) were significantly lower and iron content was significantly higher in affected compared with healthy goats (P < 0.01). After supplementation of nano-copper or copper sulfate, copper concentration in blood was significantly increased and iron content was significantly lower (P < 0.01). Compared with nano-copper group, the effect of copper sulfate was slower. Hemoglobin levels, erythrocyte count, and packed cell volume from nano-copper and copper sulfate groups were significantly higher than those in copper-deprived goats (P < 0.01). Compared with the copper-deprived Guizhou black goats, serum ceruloplasmin levels in nano-copper and copper sulfate groups were significantly increased, while serum lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and creatinine were significantly decreased (P < 0.01). Compared with the copper-deprived animals, serum superoxide dismutase, glutathione peroxidase, catalase, and total antioxidant capacity in nano-copper and copper sulfate groups were significantly higher, while serum malondialdehyde content was significantly lower (P < 0.01). The effect of copper sulfate group was significantly lower than that in nano-copper group (P < 0.01). Consequently, nano-copper could not only markedly increase the copper content in blood in copper-deprived Guizhou black goats but also much improves the antioxidant capacity.

Evaluation and grading of Kayser–Fleischer ring in Wilson disease by Scheimpflug camera

Evaluation the anterior segment parameters of Wilson disease patients with Kayser-Fleischer ring, the diagnostic power of Scheimpflug imaging for Kayser-Fleischer ring and suggest a scoring system. A total of 44 eyes of 22 Wilson disease patients with Kayser-Fleischer ring and 40 right eyes of 40 healthy age matched subjects were enrolled to the study. Serum ceruloplasmin and urine copper/24 hours levels were recorded. Anterior segment parameters including steep and flat keratometry, corneal thickness at central, 2, 4, 6, 8 and 10 mm, anterior chamber angle width, volume and depth, corneal volume, pupillary diameter were evaluated by Scheimpflug imaging. Images of cornea were scored according to Kayser-Fleischer ring size. Serum ceruloplasmin level was below 10 mg/dL in 17 patients and was 12, 18.5, 20, 22, 37 mg/dl in the remaining five patients. Urinary copper/24 hours was 249.55 ± 304.14 (23-1050) µg/day. Central corneal thickness and corneal thickness at 2 mm were statistically different (p values 0.02, 0.04, respectively). Scheimpflug images apparently showed Kayser-Fleischer ring as a hyper-reflective band at the corneal endothelial surface. Kayser-Fleischer ring in 24 eyes was grade 1, 16 eyes were grade 2 and 4 eyes were grade 3. Scheimpflug imaging seems to be a helpful diagnostic tool for detecting and grading the Kayser-Fleischer ring. Corneal thickness in Wilson disease patients with Kayser-Fleischer ring tends to be higher, so that the possible affection in corneal thickness should be kept in mind for clinical evaluation of these patients.

Role for Biochemical Assays and Kayser-Fleischer Rings in Diagnosis of Wilson’s Disease

Wilson disease is an autosomal recessive disorder that impairs copper homeostasis and is caused by homozygous or compound heterozygous mutations in ATP7B, which encodes a copper-transporting P-type ATPase. Patients have variable clinical manifestations and laboratory test results, resulting in diagnostic dilemmas. We aimed to identify factors associated with symptoms and features of Wilson disease from a large cohort, over 15 years. We collected data from 715 patients (529 with symptoms, 146 without symptoms, and 40 uncategorized) and a genetic confirmation of Wilson's disease (mean age of diagnosis, 18.84 years), recruited from 3 hospitals in China from 2004 through 2019. We analyzed clinical data along with serum levels of ceruloplasmin (available from 636 patients), 24-hr urinary copper excretion (collected from 131 patients), Kayser-Fleisher rings (copper accumulation in eyes, with neurologic data from 355 patients), and magnetic resonance imaging (MRI) abnormalities. Differences among the groups were analyzed using 1-way analysis of variance followed by Tukey multiple comparison test. Of the 529 patients with symptoms, 121 had hepatic features, 355 had neurologic features, 28 had osteomuscular features (premature osteoarthritis, skeletal deformities, and pathological bone fractures), and 25 had psychiatric symptoms. Age of onset was significantly younger in patients with hepatic (16.94 ± 1.03 years; P= .0105) or osteomuscular features (13 ± 1.33 years; P= .0001) than patients with neurological features (19.48 ± 0.46 years). Serum levels of ceruloplasmin differed among asymptomatic patients and patients with osteomuscular or neurologic symptoms of Wilson disease. Serum levels of ceruloplasmin ranged from 18.93 mg/L to approximately 120.00 mg/L (quantiles of 0.025 to approximately 0.975). Fifty-one of 131 patients (39%) had urinary copper excretion levels below 100 μg/24 hr; there was significant variation in levels of urinary copper excretion between patients older than 14 years vs 14 years or younger. Of the 355 patients with neurologic features, 244 patients (69%) had abnormal findings from MRI and Kayser-Fleisher rings; only 1 patient with abnormal findings from brain MRI was negative for Kayser-Fleisher rings. Serum level of ceruloplasmin, 24-hour urinary copper excretion, and Kayser-Fleisher rings can be used to identify patients who might have Wilson disease. Patients with serum levels of ceruloplasmin below 120 mg/L and children with urinary copper excretion above 40 μg should undergo genetic testing for Wilson's disease. Patients with movement disorders and brain MRI abnormalities without Kayser-Fleisher rings are not likely to have Wilson disease.

Correlations Among mRNA Expression Levels of ATP7A, Serum Ceruloplasmin Levels, and Neuronal Metabolism in Unmedicated Major Depressive Disorder.

BackgroundPrevious studies have found that elevated copper levels induce oxidation, which correlates with the occurrence of major depressive disorder (MDD). However, the mechanism of abnormal cerebral metabolism of MDD patients remains ambiguous. The main function of the enzyme ATPase copper-transporting alpha (ATP7A) is to transport copper across the membrane to retain copper homeostasis, which is closely associated with the onset of mental disorders and cognitive impairment. However, less is known regarding the association of ATP7A expression in MDD patients.MethodsA total of 31 MDD patients and 21 healthy controls were recruited in the present study. Proton magnetic resonance spectroscopy was used to assess the concentration levels of N-acetylaspartate, choline (Cho), and creatine (Cr) in brain regions of interest, including prefrontal white matter (PWM), anterior cingulate cortex (ACC), thalamus, lentiform nucleus, and cerebellum. The mRNA expression levels of ATP7A were measured using polymerase chain reaction (SYBR Green method). The correlations between mRNA expression levels of ATP7A and/or ceruloplasmin levels and neuronal biochemical metabolite ratio in the brain regions of interest were evaluated.ResultsThe decline in the mRNA expression levels of ATP7A and the increase in ceruloplasmin levels exhibited a significant correlation in MDD patients. In addition, negative correlations were noted between the decline in mRNA expression levels of ATP7A and the increased Cho/Cr ratios of the left PWM, right PWM, and right ACC in MDD patients. A positive correlation between elevated ceruloplasmin levels and increased Cho/Cr ratio of the left PWM was noted in MDD patients.ConclusionsThe findings suggested that the decline in the mRNA expression levels of ATP7A and the elevated ceruloplasmin levels induced oxidation that led to the disturbance of neuronal metabolism in the brain, which played important roles in the pathophysiology of MDD. The decline in the mRNA expression levels of ATP7A and the elevated ceruloplasmin levels affected neuronal membrane metabolic impairment in the left PWM, right PWM, and right ACC of MDD patients.