Calculated Parameters for the Diagnosis of Wilson Disease

Overview

Journal Singapore Med J

Specialty General Medicine

Date 2022 Feb 10

PMID 35139628

Authors

Nada Syazana Zulkufli

Pavai Sthaneshwar

Wah-Kheong Chan

Affiliations

Soon will be listed here.

Abstract

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.

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References

Twomey P, Wierzbicki A, House I, Viljoen A, Reynolds T . Percentage non-caeruloplasmin bound copper. Clin Biochem. 2007; 40(9-10):749-50. DOI: 10.1016/j.clinbiochem.2007.04.002. View

Sato M, Schilsky M, Stockert R, Morell A, Sternlieb I . Detection of multiple forms of human ceruloplasmin. A novel Mr 200,000 form. J Biol Chem. 1990; 265(5):2533-7. View

Twomey P, Viljoen A, Reynolds T, Wierzbicki A . Non-ceruloplasmin-bound copper in routine clinical practice in different laboratories. J Trace Elem Med Biol. 2008; 22(1):50-3. DOI: 10.1016/j.jtemb.2007.11.001. View

Castaldo G, Oriani G, Lofrano M, Cimino L, TOPA M, Budillon G . Differential diagnosis between hepatocellular carcinoma and cirrhosis through a discriminant function based on results for serum analytes. Clin Chem. 1996; 42(8 Pt 1):1263-9. View

Arredondo M, Nunez M . Iron and copper metabolism. Mol Aspects Med. 2005; 26(4-5):313-27. DOI: 10.1016/j.mam.2005.07.010. View

Catalani S, Paganelli M, Gilberti M, Rozzini L, Lanfranchi F, Padovani A . Free copper in serum: An analytical challenge and its possible applications. J Trace Elem Med Biol. 2017; 45:176-180. DOI: 10.1016/j.jtemb.2017.11.006. View

Takahashi N, Ortel T, Putnam F . Single-chain structure of human ceruloplasmin: the complete amino acid sequence of the whole molecule. Proc Natl Acad Sci U S A. 1984; 81(2):390-4. PMC: 344682. DOI: 10.1073/pnas.81.2.390. View

Twomey P, Viljoen A, House I, Reynolds T, Wierzbicki A . Adjusting copper concentrations for caeruloplasmin levels in routine clinical practice. J Clin Pathol. 2006; 59(8):867-9. PMC: 1860450. DOI: 10.1136/jcp.2005.034876. View

Macintyre G, Gutfreund K, Martin W, Camicioli R, Cox D . Value of an enzymatic assay for the determination of serum ceruloplasmin. J Lab Clin Med. 2004; 144(6):294-301. DOI: 10.1016/j.lab.2004.08.005. View

10.

Mak C, Lam C, 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(8):1356-62. DOI: 10.1373/clinchem.2008.103432. View

11.

. EASL Clinical Practice Guidelines: Wilson's disease. J Hepatol. 2012; 56(3):671-85. DOI: 10.1016/j.jhep.2011.11.007. View

12.

Roberts E, Schilsky M . Diagnosis and treatment of Wilson disease: an update. Hepatology. 2008; 47(6):2089-111. DOI: 10.1002/hep.22261. View

13.

Walshe J . Wilson's disease: the importance of measuring serum caeruloplasmin non-immunologically. Ann Clin Biochem. 2003; 40(Pt 2):115-21. DOI: 10.1258/000456303763046021. View

14.

Barth J, Fiddy J, PAYNE R . Adjustment of serum total calcium for albumin concentration: effects of non-linearity and of regression differences between laboratories. Ann Clin Biochem. 1996; 33 ( Pt 1):55-8. DOI: 10.1177/000456329603300108. View

15.

McMillin G, Travis J, Hunt J . Direct measurement of free copper in serum or plasma ultrafiltrate. Am J Clin Pathol. 2009; 131(2):160-5. DOI: 10.1309/AJCP7Z9KBFINVGYF. View

16.

Poujois A, Woimant F . Wilson's disease: A 2017 update. Clin Res Hepatol Gastroenterol. 2018; 42(6):512-520. DOI: 10.1016/j.clinre.2018.03.007. View

17.

Matsuda I, Pearson T, Holtzman N . Determination of apoceruloplasmin by radioimmunoassay in nutritional copper deficiency, Menkes' kinky hair syndrome, Wilson's disease, and umbilical cord blood. Pediatr Res. 1974; 8(10):821-4. DOI: 10.1203/00006450-197410000-00001. View

18.

Twomey P, Viljoen A, House I, Reynolds T, Wierzbicki A . Copper:caeruloplasmin ratio. J Clin Pathol. 2007; 60(4):441-2. PMC: 2001115. DOI: 10.1136/jcp.2006.041756. View

19.

Duncan A, Yacoubian C, Beetham R, Catchpole A, Bullock D . The role of calculated non-caeruloplasmin-bound copper in Wilson's disease. Ann Clin Biochem. 2016; 54(6):649-654. DOI: 10.1177/0004563216676843. View

20.

Ferenci P, Caca K, Loudianos G, Mieli-Vergani G, Tanner S, Sternlieb I . Diagnosis and phenotypic classification of Wilson disease. Liver Int. 2003; 23(3):139-42. DOI: 10.1034/j.1600-0676.2003.00824.x. View