INTRODUCTION: The diagnosis of Wilson disease (WD) is plagued by biochemical and clinical uncertainties. Thus, calculated parameters have been proposed. This study aimed to: (a) compare the diagnostic values of non-caeruloplasmin copper (NCC), NCC percentage (NCC%), copper-caeruloplasmin ratio (CCR) and adjusted copper in WD; and (b) derive and evaluate a discriminant function in diagnosing WD. METHODS: A total of 213 subjects across all ages who were investigated for WD were recruited. WD was confirmed in 55 patients, and the rest were WD free. Based on serum copper and caeruloplasmin values, NCC, NCC%, CCR and adjusted copper were calculated for each subject. A function was derived using discriminant analysis, and the cut-off value was determined through receiver operating characteristic analysis. Classification accuracy was found by cross-tabulation. RESULTS: Caeruloplasmin, total copper, NCC, NCC%, CCR, adjusted copper and discriminant function were significantly lower in WD compared to non-WD. Discriminant function showed the best diagnostic specificity (99.4%), sensitivity (98.2%) and classification accuracy (99.1%). Caeruloplasmin levels <0.14 g/L showed higher accuracy than the recommended 0.20 g/L cut-off value (97.7% vs. 87.8%). Similarly, molar NCC below the European cut-off of 1.6 umol/L showed higher accuracy than the American cut-off of 3.9 umol/L (80.3% vs. 59.6%) (P < 0.001). NCC%, mass NCC, CCR and adjusted copper showed poorer performances. CONCLUSION Discriminant function differentiates WD from non-WD with excellent specificity, sensitivity and accuracy. Performance of serum caeruloplasmin <0.14 g/L was better than that of <0.20 g/L. NCC, NCC%, CCR and adjusted copper are not helpful in diagnosing WD.
Humans ; Hepatolenticular Degeneration/diagnosis* ; Copper/analysis* ; Ceruloplasmin/metabolism* ; Repressor Proteins

Objectives: To summarize the clinical phenotypes and the variation spectrum of ATP7B gene in Chinese children with Wilson's disease (WD) and to investigate their significance for early diagnosis. Methods: Retrospective analysis was performed on the clinical data of 316 children diagnosed as WD in Guangzhou Women and Children's Medical Center during the period from January 2010 to June 2021. The general situations, clinical manifestations, lab test results, imaging examinations, and ATP7B gene variant characteristics were collected. The patients were divided into asymptomatic WD group and symptomatic WD group based on the presence or absence of clinical symptoms at the time that WD diagnosis was made. The χ² test, t test or Mann-Whitney U test were used to compare the differences between groups. Results: Among the 316 children with WD, 199 were males and 117 were females, with the age of 5.4 (4.0, 7.6) years at diagnosis; 261 cases (82.6%) were asymptomatic with the age of 4.9 (3.9, 6.4) years; whereas 55 cases (17.4%) were symptomatic with the age of 9.6 (7.3, 12.0) years. The main symptoms invloved liver, kidney, nervous system, or skin damage. Of all the patients, 95.9% (303/316) had abnormal liver function at diagnosis; 98.1% (310/316) had the serum ceruloplasmin lever lower than 200 mg/L; 97.7% (302/309) had 24-hour urine copper content exceeding 40 μg; only 7.4% (23/310) had positive corneal K-F rings, 8.2% (23/281) had abnormal MRI signals in the lenticular nucleus, and all of them had symptoms of damage in liver, kidney or nervous system. Compared with the group of symptomatic WD, asymptomatic group had higher levels of serum alanine aminotransferase and lower levels ceruloplasmin and 24-hour urine copper [(208±137) vs. (72±78) U/L, (55±47) vs. (69±48) mg/L, 103 (72, 153) vs. 492 (230, 1 432) μg; t=9.98, -1.98, Z=-4.89, all P<0.001]. Among the 314 patients completing genetic sequencing, a total of 107 mutations in ATP7B gene were detected, of which 10 are novel variants, and 3 cases (1.0%) had large heterozygous deletion (exons 10 to exon 11) in ATP7B gene. The percentage of missense mutation in asymptomatic WD children was significantly higher than that in symptomatic WD (81.5% (422/518) vs. 69.1% (76/110), χ²=8.47, P<0.05). WD patients carrying homozygous variant of c.2 333G>T had significantly low levels of ceruloplasmin than those not carrying this variant ((23±5) vs. (61±48) mg/L, t=-2.34, P<0.001). Conclusions: The elevation of serum ALT is an important clue for early diagnosis of WD in children, while serum ceruloplasmin and 24-hour urine copper content are specific markers for early diagnosis of WD. In order to confirm the diagnosis of WD, it is necessary to combine the Sanger sequencing with multiplex ligation-dependent probe amplification or other testing technologies.
Ceruloplasmin/metabolism* ; Child ; Child, Preschool ; Copper/metabolism* ; Copper-Transporting ATPases/genetics* ; Female ; Hepatolenticular Degeneration/genetics* ; Humans ; Male ; Mutation ; Phenotype ; Retrospective Studies

Objective: To analyze the clinical characteristics of Wilson's disease (WD) with onset of acute liver failure (ALF) in children. Methods: Clinical data of 19 children diagnosed with WD presented with ALF in Xi'an Children's Hospital from January 2016 to April 2021 were retrospectively analyzed, including general condition, clinical manifestation, laboratory examination, and gene detection. The children were divided into the death group and survival group according to the clinical outcome. The children who had hepatic WD with non-ALF onset during the same period were selected as the control. The general conditions and laboratory indexes were compared between death group and survival group, ALF group and non-ALF group. T-test, Mann Whitney U test or χ² test were used to compare the differences between the two groups. Results: Of the 19 WD children with ALF onset, 10 were females and 9 were males. The age of admission was (10.1±2.6) years and time to onset of first visit was 9 (4, 15) days. Among the WD children with ALF onset, 4 children were lost to follow-up, 5 cases death (death group) and 10 cases survived (survival group). The ceruloplasmin in the death group was higher than that in the survival group (0.078 (0.055, 0.105) vs. 0.033 (0.027, 0.058) g/L, Z=-2.33, P=0.020). There were 95 children who had hepatic WD with non-ALF onset. The WD patients with ALF onset were older at admission (9.9 (8.0, 11.1) vs. 5.4 (3.7, 6.9) years, Z=-5.25, P<0.001), had higher ceruloplasmin (0.060 (0.030, 0.078) vs. 0.024 (0.006, 0.060) g/L, Z=-3.11, P=0.002), 24 h urinary copper (674 (205, 1 803) vs. 149 (108, 206) μg, Z=-4.25, P<0.001), and positive rate of K-F ring [17/19 vs. 7%(7/95), χ²=50.17, P<0.001] while shorter onset time at initial visit (0.3 (0.1, 0.5) vs. 1.0 (0.7, 6.0) months, Z=-4.28, P<0.001). There was no gender difference between the two groups [9/19 vs. 61%(58/95), χ²=1.22, P=0.269]. Of the 19 WD children with ALF onset, 13 had the ATP7B gene tested, and 15 reported variants were detected. The main variations were c.2333G>T (p. Arg778Leu), c.2621C>T (p. Ala874Val) and c.2975C>T (p. Pro992Leu). The allele frequencies were 6/26(23%), 4/26(15%) and 3/26(12%), respectively. Conclusions: Children of WD onset with ALF are school-aged and above. They have an acute onset, a short course of the disease, and poor prognosis. The positive rate of K-F ring, ceruloplasmin and urinary copper are higher than those of the hepatic WD children with non-ALF onset.
Ceruloplasmin/metabolism* ; Child ; Copper/metabolism* ; Female ; Hepatolenticular Degeneration/genetics* ; Humans ; Liver Failure, Acute/therapy* ; Male ; Retrospective Studies

BACKGROUND: Menkes disease (MD) is a rare X-linked hereditary multisystemic disorder that is caused by dysfunction of copper metabolism. Patients with MD typically present with progressive neurodegeneration, some connective tissue abnormalities, and characteristic “kinky” hair. In addition, various types of urological complications are frequent in MD because of underlying connective tissue abnormalities. In this study, we studied the clinical features and outcomes of MD, focusing on urological complications. METHODS: A total of 14 unrelated Korean pediatric patients (13 boys and 1 girl) with MD were recruited, and their phenotypes and genotypes were analyzed by retrospective review of their medical records. RESULTS: All the patients had early-onset neurological deficit, including developmental delay, seizures, and hypotonia. The girl patient showed normal serum copper and ceruloplasmin levels as well as milder symptoms. Mutational analysis of the ATP7A gene revealed 11 different mutations in 12 patients. Bladder diverticula was the most frequent urological complication: 8 (57.1%) in the 14 patients or 8 (72.7%) in the 11 patients who underwent urological evaluation. Urological imaging studies were performed essentially for the evaluation of accompanying urinary tract infections. Four patients had stage II chronic kidney disease at the last follow-up. CONCLUSION: Urologic problems occurred frequently in MD, with bladder diverticula being the most common. Therefore, urological imaging studies and appropriate management of urological complications, which may prevent or reduce the development of urinary tract infections and renal parenchymal damage, are required in all patients with MD.
Ceruloplasmin ; Connective Tissue ; Copper ; Diverticulum ; Female ; Follow-Up Studies ; Genotype ; Hair ; Humans ; Medical Records ; Menkes Kinky Hair Syndrome* ; Metabolism ; Muscle Hypotonia ; Phenotype ; Renal Insufficiency, Chronic ; Retrospective Studies ; Seizures ; Urinary Bladder ; Urinary Tract Infections

PURPOSE: Urosepsis in adults comprises approximately 25% of all sepsis cases, and is due to complicated urinary tract infections in most cases. However, its mechanism is not fully clarified. Urosepsis is a very complicated disease with no effective strategy for early diagnosis and treatment. This study aimed to identify possible target-related proteins involved in urosepsis using proteomics and establish possible networks using bioinformatics. METHODS: Fifty patients admitted to the Urology Unit of Lanzhou General PLA (Lanzhou, China), from October 2012 to October 2015, were enrolled in this study. The patients were further divided into shock and matched-pair non-shock groups. 2-DE technique, mass spectrometry and database search were used to detect differentially expressed proteins in serum from the two groups. RESULTS: Six proteins were found at higher levels in the shock group compared with non-shock individuals, including serum amyloid A-1 protein (SAA1), apolipoprotein L1 (APOL1), ceruloplasmin (CP), haptoglobin (HP), antithrombin-III (SERPINC1) and prothrombin (F2), while three proteins showed lower levels, including serotransferrin (TF), transthyretin (TTR) and alpha-2-macroglobulin (A2M). CONCLUSION Nine proteins were differentially expressed between uroseptic patients (non-shock groups) and severe uroseptic patients (shock groups), compared with non-shock groups, serum SAA1, APOL1,CP, HP, SERPINC1and F2 at higher levels, while TF, TTR and A2M at lower levels in shock groups.these proteins were mainly involved in platelet activation, signaling and aggregation, acute phase protein pathway, lipid homeostasis, and iron ion transport, deserve further research as potential candidates for early diagnosis and treatment. (The conclusion seems too simple and vague, please re-write it. You may focus at what proteins have been expressed and introduce more detail about its significance.).
Adult ; Aged ; Antithrombin III ; Apolipoprotein L1 ; blood ; Ceruloplasmin ; Female ; Haptoglobins ; Humans ; Male ; Middle Aged ; Prealbumin ; Pregnancy-Associated alpha 2-Macroglobulins ; Proteomics ; Prothrombin ; Sepsis ; blood ; diagnosis ; etiology ; genetics ; Serum Amyloid A Protein ; Transferrin ; Urinary Tract Infections ; complications

BACKGROUND: Mutations in ATP7B cause Wilson disease (WD). However, direct DNA full sequencing cannot detect all mutations in patients with WD. Multiplex ligation-dependent probe amplification (MLPA) analysis is reportedly useful in increasing the diagnostic yield in other genetic disorders with large deletions or insertions. The aim of this study was to evaluate whether the detection rate of ATP7B mutations can be increased by using MLPA. METHODS: We enrolled 114 children with WD from 104 unrelated families based on biochemical tests and direct DNA full sequencing. The patients with one or zero mutant allele were investigated using MLPA. We analyzed phenotypic correlations. RESULTS: Total allele frequency by full sequencing was 87.5%. Full sequencing revealed two mutant alleles in 80 of 104 unrelated children. One mutant allele was detected in 22 children, and no mutations were found in two children. Novel mutations including small deletions with frameshift mutations were identified by DNA sequencing. MLPA revealed no gross deletion or duplication in 24 children with one or zero mutant alleles. The number of detected mutations was not associated with hepatic manifestation, age of onset, Kayser-Fleischer ring, ceruloplasmin, and urinary Cu concentrations. CONCLUSION: MLPA showed a limited role to increase the mutation detection rate in children who do not receive a definite genetic diagnosis of WD through DNA full sequencing. This finding suggests that large deletions or duplications might be extremely rare in WD. Further development is needed to improve the genetic diagnosis of WD.
Age of Onset ; Alleles ; Ceruloplasmin ; Child* ; Diagnosis ; DNA* ; Frameshift Mutation ; Gene Frequency ; Hepatolenticular Degeneration* ; Humans ; Multiplex Polymerase Chain Reaction* ; Phenotype* ; Sequence Analysis ; Sequence Analysis, DNA

PURPOSE: Pleural effusion, an accumulation of fluid in the pleural space, usually occurs in patients when the rate of fluid formation exceeds the rate of fluid removal. The differential diagnosis of tuberculous pleurisy and malignant pleural effusion is a difficult task in high tuberculous prevalence areas. The aim of the present study was to identify novel biomarkers for the diagnosis of pleural fluid using proteomics technology. MATERIALS AND METHODS: We used samples from five patients with transudative pleural effusions for internal standard, five patients with tuberculous pleurisy, and the same numbers of patients having malignant effusions were enrolled in the study. We analyzed the proteins in pleural fluid from patients using a technique that combined two-dimensional liquid-phase electrophoresis and matrix assisted laser desorption/ionization-time of flight-mass spectrometry. RESULTS: We identified a total of 10 proteins with statistical significance. Among 10 proteins, trasthyretin, haptoglobin, metastasis-associated protein 1, t-complex protein 1, and fibroblast growth factor-binding protein 1 were related with malignant pleural effusions and human ceruloplasmin, lysozyme precursor, gelsolin, clusterin C complement lysis inhibitor, and peroxirexdoxin 3 were expressed several times or more in tuberculous pleural effusions. CONCLUSION: Highly expressed proteins in malignant pleural effusion were associated with carcinogenesis and cell growth, and proteins associated with tuberculous pleural effusion played a role in the response to inflammation and fibrosis. These findings will aid in the development of novel diagnostic tools for tuberculous pleurisy and malignant pleural effusion of lung cancer.
Biomarkers* ; Carcinogenesis ; Ceruloplasmin ; Chaperonin Containing TCP-1 ; Clusterin ; Diagnosis ; Diagnosis, Differential ; Electrophoresis ; Fibroblasts ; Fibrosis ; Gelsolin ; Haptoglobins ; Humans ; Inflammation ; Lung Neoplasms ; Methods* ; Muramidase ; Pleural Effusion ; Pleural Effusion, Malignant ; Prevalence ; Proteomics ; Spectrum Analysis ; Tuberculosis ; Tuberculosis, Pleural

The coexistence of Wilson disease with Alport syndrome has not previously been reported. The diagnosis of Wilson disease and its ongoing monitoring is challenging when associated with an underlying renal disease such as Alport syndrome. Proteinuria can lead to low ceruloplasmin since it is among serum proteins inappropriately filtered by the damaged glomerulus, and can also lead to increased urinary loss of heavy metals such as zinc and copper. Elevated transaminases may be attributed to dyslipidemia or drug induced hepatotoxicity. The accurate diagnosis of Wilson disease is essential for targeted therapy and improved prognosis. We describe a patient with a diagnosis of Alport syndrome who has had chronic elevation of transaminases eventually diagnosed with Wilson disease based on liver histology and genetics.
Blood Proteins ; Ceruloplasmin ; Copper ; Diagnosis ; Dyslipidemias ; Genetics ; Hepatolenticular Degeneration* ; Humans ; Liver ; Metals, Heavy ; Nephritis, Hereditary ; Prognosis ; Proteinuria* ; Transaminases ; Zinc

In this study, we evaluated the performance of a recently developed immunoassay analyser, the VISTA 500 (Siemens, Germany). Precision, linearity, and comparison studies were performed according to the Clinical and Laboratory Standards Institute guidelines. The test items evaluated included IgG, IgA, IgM, C3, C4, ceruloplasmin, prealbumin, transferrin, haptoglobin, rheumatoid factor, anti-streptolysin O, and cystatin C. Commercial control materials (BioRad Laboratories, USA), commercial linearity validation materials (Maine Standards, USA), and patient samples were used for the evaluation. For the correlation study, analysis with a BN-II nephelometer (Siemens) was used as a comparative method. Total coefficients of variation of analytes were found to be between 1.9% and 5.5%. Results of the linearity evaluation were also acceptable for the range tested. Correlations with comparative methods were acceptable. The VISTA 500 analyser showed satisfactory analytical performance with respect to precision, linearity, and comparison. We conclude that the VISTA 500 is likely a good candidate as an immunology analyser.
Allergy and Immunology ; Ceruloplasmin ; Cystatin C ; Evaluation Studies as Topic ; Haptoglobins ; Humans ; Immunoassay ; Immunoglobulin A ; Immunoglobulin G ; Immunoglobulin M ; Prealbumin ; Rheumatoid Factor ; Statistics as Topic ; Transferrin

Wilson's disease is a rare genetic disorder that has abnormal copper metabolism. Although the disease's main problems are found in liver and brain, some studies revealed manifestation of various musculoskeletal problems in the patients. In this report, we encountered a young patient who had fracture in the forearm bone. Initially, exception to a previous history of fracture from a motorcycle accident, the patient did not have any medical or drug use history, and laboratory work-ups were insignificant. However, with suspicion on his bone's integrity, bone densitometry was recommended and revealed osteopenic change. To disclose a cause for the change, questions were made to recall any particular history or event, and his complaint of recent vision loss led to ophthalmologic consultation where under slit-lamp test found Kayser-Fleischer ring. Further laboratory work-up found low levels of serum copper and ceruloplasmin and high copper level in 24-hr urine sample that led to the diagnosis of Wilson's disease. Although Wilson's disease has been frequently noticed with considerable musculoskeletal manifestation, it rarity makes the diagnosis illusive to a physician. Hence, despite of its rarity, it is imperative to remember the disease's bony manifestation, and it should be suspected in young patients with demineralized bone when the reason for brittle bone cannot be answered with other better known conditions.
Brain ; Ceruloplasmin ; Copper ; Densitometry ; Diagnosis* ; Forearm ; Hepatolenticular Degeneration* ; Humans ; Liver ; Male ; Metabolism ; Motorcycles