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Therefore, some studies have attempted to determine the cutoff value of serum ceruloplasmin levels for the diagnosis of WD based on the local population. Serum ceruloplasmin is one of the major diagnostic parameters for Wilsons disease (WD). Although serum ceruloplasmin is never alone criteria for the diagnosis of WD, it is one of the major diagnostic parameters for reflecting abnormal copper metabolism. Effect of common ATP7B genotypes on serum ceruloplasmin levels of patients with WD. Mak et al. Of 261 asymptomatic WD children, serum ceruloplasmin was significantly lower and the age at diagnosis was much younger while compared with 56 WD children with various clinical symptoms and signs (p<0.05, p<0.001). The mean level of serum ceruloplasmin in heterozygotes was (25.65.9mg/dL), significantly lower than that of healthy controls (30.77.8mg/dL, p<0.05), but much higher than WD patients (5.74.7mg/dL, p<0.001) (Fig. 20 g/L) is considered a diagnostic cutoff point for Wilson's disease (WD). Bethesda, MD 20894, Web Policies Poor long-term adherence to drug therapy is common. The patients with the genotype of R778L homozygotes had much lower serum ceruloplasmin level (2.30.5mg/dL) than the patients without R778L (6.24.8mg/dL) (p<0.05). Serum ceruloplasmin levels were measured by immunonephelometry using the Beckman Coulter Immage 800 with standard reagents (Beckman Coulter, Brea, CA, USA). Re-evaluation of the diagnostic criteria for Wilson disease in children with mild liver disease. The study was approved by the Medical Ethics Committee for Clinical Ethical Review, Guangzhou Women and Childrens Medical Center ([2020] No.63901) and informed consent was obtained from a parent of each participant under 16years old. Previous study indicated that serum ceruloplasmin has no gender difference except being higher in girls during puberty due to estrogen stimulation [19, 20]. The optimal threshold of serum ceruloplasmin in the diagnosis of Wilson's disease: A large hospital-based study. XYS, YXS, HYS and ZKL analyzed the data. Wilson's disease (WD) is an autosomal recessive disorder of copper accumulation caused by mutations in the ATP7B gene (1). the contents by NLM or the National Institutes of Health. The site is secure. The performance of immunoassay was tested by receiver operating characteristic curve (ROC) analysis, and differences among the groups were analyzed by using the MannWhitney U-test and the KruskalWallis test. 2020xayx12), and the Natural Science Research Project of Anhui Universities (No. Careers, Unable to load your collection due to an error. HHS Vulnerability Disclosure, Help For asymptomatic siblings of index patients, mutation analysis is the most reliable approach. Conventionally, ceruloplasmin levels below the low reference limit (0.20 g/L) are considered a diagnostic cutoff for WD (1). Diagnosis All patients who underwent a serum ceruloplasmin test from 1 January 2016 to 2 September 2019 in the First Affiliated Hospital of Anhui University of Chinese Medicine were eligible for this study. 1Department of Graduate, Anhui University of Chinese Medicine, Hefei, Anhui, China, 2Department of Neurology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui, China, 3Xin'an Medical Education Ministry Key Laboratory, Hefei, Anhui, China. Despite the INTRODUCTION. o [ abdominal pain pediatric ] However, the lower reference limit varies with assay methodologies and the individuals in the included studies. In our previous study, we have noticed that serum ceruloplasmin level is decreased in the majority of WD children [15]. 10.1002/hep.22261 Serum ceruloplasmin is one of the major diagnostic criteria, however, it has been reported that only 85% of the asymptomatic WD had diagnostic ceruloplasmin levels [21]. Ceruloplasmin; Copper metabolism; Diagnosis; Wilson disease. 10.1136/gut.2005.087262 Of the 317 WD patients, 313 had genetic testing for pathogenic mutations in the ATP7B gene, with 307 bi-allelic mutations and 6 one allelic mutation. -. official website and that any information you provide is encrypted Clinical manifestations of Wilson disease in organs other than the liver and brain. The importance of commutability of reference materials used as calibrators: the example of ceruloplasmin. European Association for Study of Liver . (11) recommended that each laboratory should establish a cutoff value of serum ceruloplasmin levels for the diagnosis of WD according to the local population, rather than using the lower reference limit. Mutation analysis and the correlation between genotype and phenotype of Arg778Leu mutation in chinese patients with Wilson disease. Hahn S. Population screening for Wilson's disease. Considering the differences in assay methodology and individual selection, further studies with a larger number of patients are necessary. Demographic characteristics of patients with WD. The exonic sequences and the intronexon boundaries of ATP7B were amplified using a polymerase chain reaction, as previously described (12). Edited by: Huifang Shang, Sichuan University, China, Reviewed by: Rukmini Mridula Kandadai, Nizam's Institute of Medical Sciences, India; Yuto Uchida, Johns Hopkins Medicine, United States, This article was submitted to Neurogenetics, a section of the journal Frontiers in Neurology. In general, the reference range of serum ceruloplasmin concentrations by immunoassay in healthy adults is between 0.20 and 0.40 g/L. 10.1034/j.1600-0676.2003.00824.x The ROC curve revealed that serum ceruloplasmin level, at a cutoff value of 16.8mg/dL, had the highest AUC value (0.990) with a sensitivity of 95.9% and a specificity of 93.6%. National Library of Medicine Moreover, no significant difference was detected in ceruloplasmin levels in WD patients with or without KF rings (6). The site is secure. Before Composition of controls group in validation cohort and their serum ceruloplasmin levels. Liver biopsy results will show high copper content. Wilson disease is not just a disease of children and young adults, but may present at any age. Slit-lamp examination for Kayser-Fleischer rings, Serum ceruloplasmin, sometimes serum copper, and 24-hour urinary copper excretion, Sometimes confirmation by penicillamine provocation test or liver biopsy. Zhang S, Yang W, Li X, Pei P, Dong T, Yang Y, et al.. Clinical and genetic characterization of a large cohort of patients with Wilson's disease in China. However, false-negative results may occur because of a sampling error (due to large variations in copper concentrations in the liver) or fulminant hepatitis (causing necrosis that releases large amounts of copper). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. If levels are equivocal, measuring urinary copper excretion after penicillamine is given (penicillamine provocation test) may confirm the diagnosis; this test is not usually done in adults because cutoff values are not well-established. Careers, Unable to load your collection due to an error. Clinical presentation of Wilson disease can vary widely; therefore diagnosis is not always straightforward. Blood tests can monitor your liver function and check the level of a protein that binds copper in the blood (ceruloplasmin) and the level of copper in your blood. Disclaimer. However, these studies were mostly from Europe and used a small number of patients with WD (11, 1316). The impaired transport also interferes with incorporation of copper into the copper protein ceruloplasmin, thus decreasing serum levels of ceruloplasmin. Our results were consistent with previous reports, indicating that serum ceruloplasmin is not suitable for newborn screening [7, 1618]. To examine whether it is useful to detect presymptomatic patients with Wilson's disease, serum ceruloplasmin was determined by radial immunodiffusion (normal: 20-60 mg/dl) in all patients (n = 2867) admitted for evaluation of a liver disease GXXT-2020-025), the Natural Science Foundation of Anhui Province (Nos. The dash lines in DF represent the cutoff values obtained in the ROC curves of AC (16.9mg/dL, 16.0mg/dL and 16.9mg/dL), respectively. Conventionally, serum ceruloplasmin levels below the lower reference limit (0. The ratio of male to female in WD patients was 1.7:1. doi: 10.1371/journal.pone.0190887. Epub 2014 Mar 20. In almost half of patients, particularly adolescents, the first symptom is, Hepatitisacute, chronic active, or fulminant, In about 40% of patients, particularly young adults, the first symptoms reflect. Neuroimaging and electrophysiologic methods are helpful. Thus, we recruited a large Chinese cohort to determine the diagnostic accuracy of serum ceruloplasmin for WD diagnosis, which included 1,278 patients with WD from 30 different provinces of China. Among them, 30(8.1%) had serum ceruloplasmin level<20mg/dL, whereas 13 (3.5%) had the level<15mg/dL. Before Our finding was consistent with that in another Chinese study for WD adult patients, indicating that the threshold of serum ceruloplasmin of 16.8mg/dL may be more accurate and favor higher specialty for diagnosis of WD in children as well as adults [12]. Accessibility Interestingly, patients with the R778L/R919G genotype had higher serum ceruloplasmin levels than patients with other hot spot mutation combinations. Another study reported that low serum ceruloplasmin levels were associated with truncating mutations in the ATP7B gene (22). National Library of Medicine This study aims to assess diagnostic value of serum ceruloplasmin level for WD in children up to age of 15years. Overall, the optimal cutoff of 0.13 g/L provided both higher specificity and accuracy than the conventional cutoff level of 0.20 g/L. Only 1.9% of WD patients had serum ceruloplasmin levels>20mg/dL. Copyright 2022 Yang, Hao, Wei, Tang, Qian, Yang, Xi, Zhang and Yang. . European Association for Study of Liver . Front Neurol. U22A20366), National Natural Science Foundation of China (Nos. The positive and negative predictive values were 80.8% and 98.7%, respectively. Wilson's Disease: Clinical Practice Guidelines of the Indian National Association for Study of the Liver, the Indian Society of Pediatric Gastroenterology, Hepatology and Nutrition, and the Movement Disorders Society of India. Clifford SM, Bunker AM, Jacobsen JR, et al. Advise patients to follow a low copper diet, and treat them with penicillamine, trientine, or, if these drugs are intolerable or ineffective, oral zinc. diagnosis Diagnosis Learn more about the MSD Manuals and our commitment to Global Medical Knowledge. official website and that any information you provide is encrypted 2015. Diagnosis and treatment of Wilson disease: an update. In addition, 80 heterozygous subjects and 418 healthy controls were enrolled. Moreover, osteoporosis as well as elevated glucose and cholesterol levels can occur. Ceruloplasmin is an acute-phase reactive protein, which is often confounded by many other diseases, including decompensated liver failure, nephrotic syndrome, protein-losing enteropathy, and acquired copper deficiency. Dong Y, Wang RM, Yang GM, Yu H, Xu WQ, Xie JJ, Zhang Y, Chen YC, Ni W, Wu ZY. Confirm the diagnosis primarily with a slit-lamp examination (for Kayser-Fleischer rings) and measurement of serum ceruloplasmin (which is low) and 24-hour urinary copper excretion (which is high). Of the 317 WD patients, the mean age of boys was 6.22.8years, and that of girls was 5.92.9years. Int Urol Nephrol. Methods: Discrepant measurement results were also found for ceruloplasmin levels when measured using different immunoassay methods, which may vary by 20% (18). The area under the curve was 0.952 (95% confidence interval (CI), 0.8851). With respect to the age of symptom onset, the serum ceruloplasmin level was lower in patients with an age of symptom onset <10 years (0.022 g/L, IQR 0.013~0.043) and higher in patients with an age of symptom onset >30 years (0.059 g/L, IQR 0.029~0.088; Figure 2C). Serum ceruloplasmin level was measured in 154 patients with non-WD diseases, including acute liver failure, viral hepatitis and nephrotic syndrome. ZKL, SML and WZ recruited the family and collected data. Furthermore, no significant differences in ceruloplasmin levels were found based on sex (female vs. male; Figure 2D) or the presence of a KF ring (Figure 2B). The studies involving human participants were reviewed and approved by the Ethics Committee of the First Affiliated Hospital of Anhui University of Chinese Medicine. In the patients with PTV/PAV, the patients with PTV/V1106I (0.081 g/L, IQR 0.071~0.093) had higher serum ceruloplasmin levels than those with PTV/A874V (0.024 g/L, IQR 0.011~0.045), PTV/V1216M (0.027 g/L, IQR 0.009~0.048), and other PTV/PAV genotypes (0.033 g/L, IQR 0.017~0.066; Figure 3E). Neurological Wilson's Disease Signs-Hepatic Encephalopathy or Copper Toxicosis? Please confirm that you are a health care professional. Copper gets deposited in different organs, and the spectrum of clinical manifestations varies from progressive hepatic damage and neurological deterioration to atypical cardiac and osteoarticular involvement (2). and transmitted securely. Genetic analyses for the ATP7B gene mutation were performed in all WD patients and their siblings. 1). Untreated Wilson disease is fatal, usually by age 30. The KruskalWallis test and the post hoc test were used to compare differences among three or more groups. 81973825, 81903895, and 82205076), Collaborative Innovation Project of Anhui Colleges and Universities (No. The performance of immunoassay was tested by receiver operating characteristic curve (ROC) analysis, and differences among the groups were analyzed by using the Mann-Whitney U-test and the Kruskal-Wallis test. Zegers I, Beetham R, Keller T, Sheldon J, Bullock D, MacKenzie F, et al.. Serum ceruloplasmin levels also presented genotypic difference. (CAUTION: Penicillamine or trientine must not be taken at the same time as zinc because either drug can bind zinc, forming a compound with no therapeutic effect.). WebWilson disease is a rare genetic condition that occurs when your body accumulates too much copper, especially in the liver and brain. Serum ceruloplasmin test. Chinese cohort; Wilson's disease; diagnosis; genotype; phenotype; serum ceruloplasmin. WebAs a practical algorithm, there are three levels of tests used to confirm the diagnosis of Wilson's disease ().Level 1 tests consist of determination of the serum ceruloplasmin concentration, total serum copper concentration and, by derivation, the circulating nonceruloplasmin-bound copper concentration and 24-hour urine copper excretion, It has been well known that diagnosis of WD is difficult in the asymptomatic children, and in the patients with acute liver failure [35]. An official website of the United States government. PLoS One. Through family screening, 21 heterozygotes and 12 wild type siblings were identified. Occasionally, use of penicillamine can cause worsening neurologic symptoms. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Trientine hydrochloride, also a chelating drug, is an alternative treatment to penicillamine. Hepatic fibrosis develops, ultimately causing cirrhosis. However, the lower reference limit varies with assay methodologies and the individuals in the included studies. Shribman S, Warner TT, Dooley JS. In Wilson disease, 24-hour urinary copper excretion (normally, 30 mcg/day) is usually > 100 mcg/day. Unable to load your collection due to an error, Unable to load your delegates due to an error. Before 1908085QC90, 2108085QH366, and 2108085QH367), the Open Fund Project of Key Laboratory of Xin'An Medicine of Ministry of Education (No. Diagnostic performance of serum ceruloplasmin. These patients were categorized into three groups based on clinical manifestations at diagnosis: (1) Asymptomatic WD, including 236 of whom presented with isolated elevation of serum aminotransferases through occasional tests and 25 diagnosed through family screening (n=261); (2) WD with acute liver failure (n=15); (3) other types of WD, including acute hepatitis, chronic hepatic disease, neurological disease, renal disease and purpura (n=41). Diagnostic Value of Ceruloplasmin in the Diagnosis of Pediatric Wilson's Disease Abstract. EASL Clinical Practice Guidelines: Wilson's disease. Zinc acetate 50 mg orally 3 times a day can reduce intestinal copper absorption, thus preventing reaccumulation of copper in patients who cannot tolerate penicillamine or trientine or who have neurologic symptoms that do not respond to the other drugs. Diagnostic Value of Ceruloplasmin in the Diagnosis of Pediatric Wilson's Disease. The optimal cutoff of 0.13 g/L resulted in a sensitivity of 97.0%, a specificity of 96.1%, and an accuracy of 96.5%. Interestingly, patients with the R778L/R919G genotype had higher serum ceruloplasmin levels than patients with other common variants (PTV, R778L, P992L, A874V, and R919G; Supplementary Figure 1). The racial difference might be the cause for the difference in serum ceruloplasmin levels, and smaller subject number of those studies may also be a reason. Among the heterozygous patients, the patients with PAV/PAV (0.032 g/L, IQR 0.018~0.057) had higher serum ceruloplasmin levels than those with PTV/PAV (0.027 g/L, IQR 0.014~0.047; Figure 3C). Therefore, the use of low reference limit for serum ceruloplasmin may lead to unacceptably high numbers of false-positives, which may trigger further investigations and overtreatments. Epub 2022 Oct 29. A total of 6 (1.9%) in 317 WD patients had normal value of serum ceruloplasmin>20mg/dL, all of whom were asymptomatic (6/261, 2.3%). Accessibility Difficulty walking. Ceruloplasmin Our study further revealed R778L homozygotes may cause decreased serum ceruloplasmin and hepatic damage at very early age. (2007) 56:11520. Gut. WY, SZ, and YueY designed the study. An official website of the United States government. All non-WD patients had serum ceruloplasmin level>20mg/dL, with the mean level of serum ceruloplasmin (28.611.8mg/dL) much higher than that in WD patients (p<0.001), but lower than healthy controls (p<0.001). Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. For the homozygous patients, the patients with R778L/R778L (0.017 g/L, IQR 0.011~0.036) had lower serum ceruloplasmin levels than those with P992L/P992L (0.034 g/L, IQR 0.021~0.047) and other homozygous genotypes (0.045 g/L, IQR 0.017~0.071; Figure 3B). Rarely, these rings occur in other liver disorders (eg, biliary atresia, primary biliary cirrhosis), but ceruloplasmin levels should be unaffected. Truncating mutations in the Wilson disease gene ATP7B are associated with very low serum ceruloplasmin oxidase activity and an early onset of Wilson disease. National Library of Medicine HHS Vulnerability Disclosure, Help KJ2021A0555). In addition, healthy controls with no clinical evidence of WD were recruited for our study. Role for Biochemical Assays and Kayser-Fleischer Rings in Diagnosis of Wilson's Disease. XSL, SML, YTL and YNC performed the experiments. Clipboard, Search History, and several other advanced features are temporarily unavailable. Dong Y, Wang RM, Yang GM Yu H, Xu WQ, Xie JJ, et al.. Role for biochemical assays and Kayser-Fleischer rings in diagnosis of Wilson's disease, Deficiency of ceruloplasmin in patients with hepatolenticular degeneration (Wilson's disease), Diagnostic accuracy of serum ceruloplasmin in Wilson disease: determination of sensitivity and specificity by ROC curve analysis among ATP7B-genotyped subjects. 2022 Jun 9;26:98-106. doi: 10.1016/j.omtm.2022.06.001. Hepatology. EASL Clinical Practice Guidelines: Wilson's disease. 2023 Feb 27;13(5):893. doi: 10.3390/diagnostics13050893. Tasmeen R, Karim ASMB, Banu LA, Hossain E, Rokunuzzaman M, Majumder W, Alam ST, Rasid R, Benzamin M, Hasan MS. Indian J Gastroenterol. Conventionally, serum ceruloplasmin levels below the low reference limit (0.20 g/L) is considered a diagnostic cutoff point for WD (1). To further define the accuracy of serum ceruloplasmin for diagnosis of WD in the patients with elevated aminotransferases, the ROC curve was constructed by using the data of 256 asymptomatic WD patients with isolated elevated aminotransferases and 38 non-WD patients with viral hepatitis. After 1 to 5 years of therapy, lower dose maintenance drug therapy can be considered. Lu X, Li S, Zhang W, Lin Y, Lu Z, Cai Y, Su X, Shao Y, Liu Z, Sheng H, Huang Y, Liu L, Zeng C. BMC Gastroenterol. Serum copper levels are sometimes measured; however, they may be high, normal, or low. Wilson disease: revision of diagnostic criteria in a clinical series with great genetic homogeneity. Serum ceruloplasmin levels in WD children carrying R778L mutation, *Represents statistical significance of serum ceruloplasmin between WD children with and without R778L, p value<0.05. The https:// ensures that you are connecting to the Wu ZY, Wang N, Lin MT, et al. Spectrum of ATP7B mutations and genotype-phenotype correlation in large-scale Chinese patients with Wilson Disease, Mutation analysis of the ATP7B gene and genotype-phenotype correlation in Chinese patients with Wilson disease. Epub 2011 Sep 7. Therefore, as the second part of our study, we identified factors associated with serum ceruloplasmin. Because early treatment is most effective, screening is indicated for anyone who has a sibling, cousin, or parent with Wilson disease. 8600 Rockville Pike As a library, NLM provides access to scientific literature. WebKey Points. (2) A total of 1,772 patients with various diseases other than WD were recruited, including 1,118 patients with hepatic dysfunction, 414 patients with neurological deficits, and 240 patients with other diseases. Neurologic Wilson disease: case series on a diagnostic and therapeutic emergency. The cutoff value of ceruloplasmin levels was developed based on a retrospective derivation cohort of 3,548 subjects (1,278 patients with WD and 2,270 controls) and was validated in a separate validation cohort of 313 subjects (203 patients with WD and 110 controls). Funders were not involved in data analysis or interpretation. When a cutoff value of 0.13 g/L was used in the validation cohort, 197 patients with WD and 105 controls were correctly identified, with a sensitivity of 97.0%, a specificity of 95.5%, and an accuracy of 96.5%.