Pediatric Gastroenterology, Hepatology & Nutrition

The Korean Society of Pediatric Gastroenterology, Hepatology and Nutrition (대한소아소화기영양학회)
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Diagnostic Value of Ceruloplasmin in the Diagnosis of Pediatric Wilson's Disease

  • Kim, Jung Ah (Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine) ;
  • Kim, Hyun Jin (Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine) ;
  • Cho, Jin Min (Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine) ;
  • Oh, Seak Hee (Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine) ;
  • Lee, Beom Hee (Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine) ;
  • Kim, Gu-Hwan (Medical Genetics Center, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine) ;
  • Choi, Jin-Ho (Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine) ;
  • Kim, Kyung Mo (Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine) ;
  • Yoo, Han-Wook (Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine)
  • Received : 2015.02.26
  • Accepted : 2015.06.16
  • Published : 2015.09.30
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Abstract

Purpose: Measurement of serum ceruloplasmin level is the first step in screening for Wilson's disease (WD). Despite the rarity of WD in the general population, ceruloplasmin levels are routinely measured through hepatitis screening in both adults and children. Herein, we evaluated the diagnostic value of ceruloplasmin for the diagnosis of WD among children with hepatitis. Methods: We retrospectively reviewed data on serum ceruloplasmin levels measured as a serologic marker for patients with hepatitis at Asan Medical Center (Seoul, Korea) between from January 2004 to November 2013. The diagnosis of WD was confirmed by the identification of pathogenic variants in the ATP7B gene. To determine the diagnostic accuracy of ceruloplasmin, receiver operation characteristic (ROC) curves were constructed and the area under curve (AUC) were calculated. Results: Measurements of serum ceruloplasmin were performed in 2,834 children who had hepatitis. Among these, 181 (6.4%) children were diagnosed with WD. The sensitivity, specificity, and accuracy of a ceruloplasmin level of <20 mg/dL in the discrimination of WD were 93.4%, 84.2%, and 84.8%, respectively. In this study, 418 (14.7%) false-positive cases and 12 (0.4%) false-negative cases were noted. Using a ROC curve, a ceruloplasmin level of ${\leq}16.6mg/dL$ showed the highest AUC value (0.956) with a sensitivity of 91.2%, a specificity of 94.9%, and an accuracy of 94.7%. Conclusion: The measurement of serum ceruloplasmin was frequently used for the screening of WD in children, despite a low positive rate. The diagnostic value of ceruloplasmin may be strengthened by adopting a new lower cut-off level.

Keywords

References

  1. Litwin T, Czlonkowska A. Wilson disease-factors affecting clinical presentation. Neurol Neurochir Pol 2013;47:161-9.
  2. Manolaki N, Nikolopoulou G, Daikos GL, Panagiotakaki E, Tzetis M, Roma E, et al. Wilson disease in children: analysis of 57 cases. J Pediatr Gastroenterol Nutr 2009;48:72-7. https://doi.org/10.1097/MPG.0b013e31817d80b8
  3. Huster D. Wilson disease. Best Pract Res Clin Gastroenterol 2010;24:531-9. https://doi.org/10.1016/j.bpg.2010.07.014
  4. Endo F, Taketa K, Nakamura K, Awata H, Tanoue A, Eda Y, et al. Measurement of blood holoceruloplasmin by EIA using a mouse monoclonal antibody directed to holoceruloplasmin. Implication for mass screening of Wilson disease. J Inherit Metab Dis 1994;17:616-20. https://doi.org/10.1007/BF00711601
  5. Ohura T, Abukawa D, Shiraishi H, Yamaguchi A, Arashima S, Hiyamuta S, et al. Pilot study of screening for Wilson disease using dried blood spots obtained from children seen at outpatient clinics. J Inherit Metab Dis 1999;22:74-80. https://doi.org/10.1023/A:1005455401076
  6. Yamaguchi Y, Aoki T, Arashima S, Ooura T, Takada G, Kitagawa T, et al. Mass screening for Wilson's disease: results and recommendations. Pediatr Int 1999;41:405-8. https://doi.org/10.1046/j.1442-200x.1999.01096.x
  7. Seo JK. Diagnosis of Wilson disease in young children: molecular genetic testing and a paradigm shift from the laboratory diagnosis. Pediatr Gastroenterol Hepatol Nutr 2012;15:197-209. https://doi.org/10.5223/pghn.2012.15.4.197
  8. Ala A, Borjigin J, Rochwarger A, Schilsky M. Wilson disease in septuagenarian siblings: raising the bar for diagnosis. Hepatology 2005;41:668-70. https://doi.org/10.1002/hep.20601
  9. Beyersdorff A, Findeisen A. Morbus Wilson: case report of a two-year-old child as first manifestation. Scand J Gastroenterol 2006;41:496-7. https://doi.org/10.1080/00365520500389453
  10. Schoen RE, Sternlieb I. Clinical aspects of Wilson's disease. Am J Gastroenterol 1990;85:1453-7.
  11. Mak CM, Lam CW, Tam S. Diagnostic accuracy of serum ceruloplasmin in Wilson disease: determination of sensitivity and specificity by ROC curve analysis among ATP7B-genotyped subjects. Clin Chem 2008; 54:1356-62. https://doi.org/10.1373/clinchem.2008.103432
  12. Robin X, Turck N, Hainard A, Tiberti N, Lisacek F, Sanchez JC, et al. pROC: an open-source package for R and S+ to analyze and compare ROC curves. BMC Bioinformatics 2011;12:77. https://doi.org/10.1186/1471-2105-12-77
  13. Hahn SH. Population screening for Wilson's disease. Ann N Y Acad Sci 2014;1315:64-9. https://doi.org/10.1111/nyas.12423
  14. Squires RH Jr, Shneider BL, Bucuvalas J, Alonso E, Sokol RJ, Narkewicz MR, et al. Acute liver failure in children: the first 348 patients in the pediatric acute liver failure study group. J Pediatr 2006;148:652-8. https://doi.org/10.1016/j.jpeds.2005.12.051
  15. Korman JD, Volenberg I, Balko J, Webster J, Schiodt FV, Squires RH Jr, et al; Pediatric and Adult Acute Liver Failure Study Groups. Screening for Wilson disease in acute liver failure: a comparison of currently available diagnostic tests. Hepatology 2008;48:1167-74. https://doi.org/10.1002/hep.22446
  16. Tapper EB, Rahni DO, Arnaout R, Lai M. The overuse of serum ceruloplasmin measurement. Am J Med 2013;126:926.e1-5. https://doi.org/10.1016/j.amjmed.2013.01.039
  17. Ferenci P, Caca K, Loudianos G, Mieli-Vergani G, Tanner S, Sternlieb I, et al. Diagnosis and phenotypic classification of Wilson disease. Liver Int 2003;23:139-42. https://doi.org/10.1034/j.1600-0676.2003.00824.x

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