Pseudocholinesterase as a Biomarker for Untreated Wilson’s Disease
Abstract
:1. Introduction
2. Methods
2.1. Patients with Definite WD (WD-DEF-Group)
2.2. Patients with Suspected WD (WD-SUS-Group)
2.3. Clinical Neurological Findings in the WD-DEF- and WD-SUS-Group
2.4. Biochemical Parameters
2.5. Statistics
3. Results
3.1. Demographical Data and Spectrum of Clinical Symptoms in the WD-DEF-Group
3.2. Demographical Data and Spectrum of Clinical Cymptoms in the WD-SUS-Group
3.3. Analysis of Blood and Urine in the WD-SUS-Group and in the WD-DEF-Group before Therapy
3.4. Analysis of Blood and Urine in the WD-SUS-Group and in the WD-DEF-Group after Therapy
3.5. Probability for Correct Classification of WD-DEF- and WD-SUS-Patients
4. Discussion
4.1. The Difficulty of Diagnosing WD
4.2. Classification by Means of Biomarkers
4.3. Classification Using Pseudocholinesterase (CHE)
4.4. 100% Correct Classification by Means of CHE and Ceruloplasmin
4.5. Cholinesterase Deficiency Syndrome as a Pitfall for the Use of CHE as a Biomarker for WD
4.6. Probative Treatment does Not Improve Classification
4.7. Clinical Recommendation
4.8. Strengths and Limitations of the Study
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Wilson, K.S.A. Progressive lenticular degeneration: A familial nervous disease associated with cirrhosis of the liver. Brain 1912, 34, 295–507. [Google Scholar] [CrossRef]
- Cumings, J.N. The copper and iron content of brain and liver in the normal and in hepato-lenticular degeneration. Brain 1948, 71, 410–415. [Google Scholar] [CrossRef] [PubMed]
- Nose, Y.; Kim, B.E.; Thiele, D.J. Ctr1 drives intestinal copper absorption and is essential for growth, iron metabolism, and neonatal cardiac function. Cell Metab. 2006, 4, 235–244. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ferenci, P. Wilson’s disease. Clin. Gastroenterol. Hepatol. 2005, 3, 726–733. [Google Scholar] [CrossRef]
- Stremmel, W.; Merle, U.; Weiskirchen, R. Clinical features of Wilson disease. Ann. Transl. Med. 2019, 7, S61. [Google Scholar] [CrossRef]
- Mukhopadhyay, C.K.; Attieh, Z.K.; Fox, P.L. Role of ceruloplasmin in cellular iron uptake. Science 1998, 279, 714–717. [Google Scholar] [CrossRef]
- Hellman, N.E.; Gitlin, J.D. Ceruloplasmin metabolism and function. Ann. Rev. Nutr. 2002, 22, 439–458. [Google Scholar] [CrossRef]
- Bull, P.C.; Thomas, G.R.; Rommens, J.M.; Forbes, J.R.; Cox, D.W. The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. Nat. Genet. 1993, 5, 327–337. [Google Scholar] [CrossRef]
- Petruhkin, K.; Fischer, S.G.; Pirastu, M.; Tanzi, R.E.; Chernov, I.; Devoto, M.; Brzustowicz, L.M.; Cayanis, L.; Vitale, E.; Russo, J.J.; et al. Mapping, cloning and genetic characterization of the region containing the Wilson disease gene. Nat. Genet. 1993, 5, 338–343. [Google Scholar] [CrossRef]
- Tanzi, R.E.; Petrukhin, K.; Chernov, I.; Pellequeret, J.L.; Wasco, W.; Ross, B.; Romano, D.M.; Parano, E.; Pavone, L.; Brzustowicz, L.M.; et al. The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. Nat. Genet. 1993, 5, 344–350. [Google Scholar] [CrossRef]
- Walshe, J.M. Penicillamine. A new oral therapy for Wilson’s disease. Am. J. Med. 1956, 21, 487–495. [Google Scholar] [CrossRef]
- Ghika, J.; Vingerhoets, F.; Maeder, P.; Borruat, F.-X.; Bogousslavsky, J. Maladie de Wilson. Wilson’s disease. EMC Neurol. 2004, 1, 481–511. [Google Scholar] [CrossRef]
- Merle, U.; Schaefer, M.; Ferenci, P.; Stremmel, W. Clinical presentation, diagnosis and long-term outcome of Wilson’s disease: A cohort study. Gut 2007, 56, 115–120. [Google Scholar] [CrossRef]
- Bandmann, O.; Weiss, K.H.; Kaler, S.G. Wilson’s disease and other neurological copper disorders. Lancet Neurol. 2015, 15, 103–113. [Google Scholar] [CrossRef] [Green Version]
- Hefter, H. Wilson’s disease. Review of pathophysiology, clinical features and drug treatment. CNS Drugs 1994, 2, 26–39. [Google Scholar] [CrossRef]
- Ferenci, P.; Caca, K.; Loudianos, G.; Mieli-Vergani, G.; Tanner, S.; Sternlieb, I.; Schilsky, M.; Cox, D.; Berr, F. Diagnosis and phenotypic classification of Wilson disease. Liver Int. 2003, 23, 139–142. [Google Scholar] [CrossRef]
- European Association for Study of the Liver EASL. Clinical practice guidelines: Wilson’s disease. J. Hepatol. 2012, 56, 671–685. [Google Scholar] [CrossRef] [Green Version]
- Shribman, S.; Warner, T.T.; Dooley, J.S. Clinical presentations of Wilson disease. Ann. Transl. Med. 2019, 7, S60. [Google Scholar] [CrossRef]
- Merle, U.; Eisenbach, C.; Weiss, K.H.; Tuma, S.; Stremmel, W. Serum ceruloplasmin oxidase activity is a sensitive and highly specific diagnostic marker for Wilson’s disease. J. Hepatol. 2009, 51, 925–930. [Google Scholar] [CrossRef]
- Ryan, A.; Nevitt, S.J.; Tuohy, O.; Cook, P. Biomarkers for diagnosis of Wilson’s disease. Cochrane Database Syst. Rev. 2019, 11, CD012267. [Google Scholar] [CrossRef]
- Santarpia, L.; Grandome, I.; Contaldo, F.; Pasanisi, F. Butyrylcholinesterase as a prognostic marker: A review of the literature. J. Cachexia Sarcopenia Muscle 2013, 4, 31–39. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ramachandran, J.; Sajith, K.G.; Priya, S.; Dutta, A.K.; Balasubramanian, K.A. Serum cholinesterase is an excellent biomarker of liver cirrhosis. Trop. Gastroenterol. 2014, 35, 15–20. [Google Scholar] [CrossRef] [PubMed]
- Sine, H.; El Grafel, K.; Alkhammal, S.; Achbani, A.; Filali, K. Serum cholinesterase biomarker study in farmers—Souss Massa region-, Morocco: Case-control study. Biomarkers 2019, 24, 771–775. [Google Scholar] [CrossRef] [PubMed]
- Sato, T.; Yamauchi, H.; Suzuki, S.; Yoshihisa, A.; Yamaki, T.; Sugimoto, K.; Kunii, H.; Nakazato, K.; Suzuki, H.; Saitoh, S.-I.; et al. Serum cholinesterase is an important prognostic factor in chronic heart failure. Heart Vessels 2015, 30, 204–210. [Google Scholar] [CrossRef] [Green Version]
- Seo, M.; Yamada, T.; Tamaki, S.; Hikoso, S.; Yasumura, Y.; Higuchi, Y.; Nakagawa, Y.; Uematsu, M.; Abe, H.; Fuji, H.; et al. Prognostic significance of serum cholinesterase level in patients with acute decompensated heart failure with preserved ejection fraction: Insights from the PURSUIT-HFpEF Registry. J. Am. Heart Assoc. 2020, 9, ee014100. [Google Scholar] [CrossRef]
- Nakajima, K.; Abe, T.; Saji, R.; Ogawa, F.; Taniguchi, H.; Yamaguchi, K.; Sakai, K.; Nakagawa, T.; Matsumura, R.; Oi, Y.; et al. Serum cholinesterase associated with COVID-19 pneumonia severity and mortality. J. Infect. 2021, 82, 321–323. [Google Scholar] [CrossRef]
- Broniek-Kowalik, K.; Dzieżyc, K.; Litwin, T.; Członkowska, A.; Szaflik, J.P. Anterior segment optical coherence tomography (AS-OCT) as a new method of detecting copper deposits forming the Kayser–Fleischer ring in patients with Wilson disease. Acta Ophthalmol. 2019, 97, e757–e760. [Google Scholar] [CrossRef]
- Yap, W.W.; Kirke, R.; Yoshida, E.M.; Owen, D.; Harris, A.C. Non-invasive assessment of liver fibrosis using ARFI with pathological correlation, a prospective study. Ann. Hepatol. 2013, 12, 440–447. [Google Scholar] [CrossRef]
- Li, Y.; Ma, J.; Li, B.; Zhu, X.; Wang, J. Cirrhosis of Wilson’s disease: High and low cutoff using acoustic radiation force impulse (ARFI)-comparison and combination of serum fibrosis index. Clin. Hemorheol. Microcirc. 2021, 79, 575–585. [Google Scholar] [CrossRef]
- Członkowska, A.; Litwin, T.; Dusek, P.; Ferenci, P.; Lutsenko, S.; Medici, V.; Rybakowski, J.K.; Weiss, K.H.; Schilsky, M.L. Wilson disease. Nat. Rev. Dis. Primers 2018, 4, 21. [Google Scholar] [CrossRef]
- Hefter, H.; Tezayak, O.; Rosenthal, D. Long-term outcome of neurological Wil-son’s disease. Park. Relat. Disord. 2018, 49, 48–53. [Google Scholar] [CrossRef]
- Tezayak, O.; Rosenthal, D.; Hefter, H. Mild gait impairment in long-term treated patients with neurological Wilson’s disease. Ann. Transl. Med. 2019, 7, S57. [Google Scholar] [CrossRef]
- Burke, J.F.; Dayalu, P.; Nan, B.; Askari, F.; Brewer, G.J.; Lorincz, M.T. Prognostic significance of neurologic examination findings in Wilson disease. Park. Relat. Disord. 2011, 17, 551–556. [Google Scholar] [CrossRef]
- Hefter, H.; Weiss, P.; Wesch, H.; Stremmel, W.; Feist, D.; Freund, H.J. Late diagnosis of Wilson’s disease in a case without onset of symptoms. Acta Neurol. Scand. 1995, 91, 302–305. [Google Scholar] [CrossRef]
- GDB 2016 Parkinson’s Disease Collaborators. Global, regional, and national burden of Parkinson’s disease, 1990–2016: A systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2018, 17, 939–953. [Google Scholar] [CrossRef] [Green Version]
- Louis, E.D.; Ferreira, J.J. How common is the most common adult movement disorder? Update on the worldwide prevalence of essential tremor. Mov. Disord. 2010, 25, 534–541. [Google Scholar] [CrossRef]
- Kluska, A.; Kulecka, M.; Litwin, T.; Dziezyc, K.; Balabas, A.; Piatkowska, M.; Paziewska, A.; Dabrowska, M.; Mikula, M.; Kaminska, D.; et al. Whole-exome sequencing identifies novel pathogenic variants across the ATP7B gene and some modifiers of Wilson’s disease genotype. Liver Int. 2019, 39, 177–186. [Google Scholar] [CrossRef] [Green Version]
- El Balkhi, S.; Poupon, J.; Trocello, J.M.; Leyendecker, A.; Massicot, F.; Galliot-Guilley, M.; Woimant, F. Determination of ultrafiltrable and exchangeable copper in plasma: Stability and reference values in healthy subjects. Anal. Bioanal. Chem. 2009, 394, 1477–1484. [Google Scholar] [CrossRef]
- Woitmant, F.; Djebrani-Oussedik, N.; Poujois, A. New tools for Wilson’s disease diagnosis: Exchangeable copper fraction. Ann. Transl. Med. 2019, 7, S70. [Google Scholar] [CrossRef]
- Jung, S.; Whiteaker, J.R.; Zhao, L.; Yoo, H.-W.; Paulovich, A.G.; Hahn, S.H. Quantification of ATP7B protein in dried blood spots by peptide Immuno-SRM as a potential screen for Wilson’s disease. J. Proteome Res. 2017, 16, 862–871. [Google Scholar] [CrossRef]
- Członkowska, A.; Rodo, M.; Wierzchowska-Ciok, A.; Smolinski, L.; Litwin, T. Accuracy of the radioactive copper incorporation test in the diagnosis of Wilson disease. Liver Int. 2018, 38, 1860–1866. [Google Scholar] [CrossRef] [PubMed]
- Sandahl, T.D.; Gormsen, L.C.; Kjærgaard, K.; Vendelbo, M.H.; Munk, D.E.; Munk, O.L.; Bender, D.; Keiding, S.; Vase, K.H.; Frisch, K.; et al. The pathophysiology of Wilson’s disease visualized: A human 64CU PET study. Hepatology 2022, 75, 1461–1470. [Google Scholar] [CrossRef] [PubMed]
- Antos, A.; Litwin, T.; Skowrońska, M.; Kurkowska-Jastrzębska, I.; Członkowska, A. Pitfalls in diagnosing Wilson’s disease by genetic testing alone: The case of a 47-year-old woman with two pathogenic variants of the ATP7B gene. Neurol. Neurochir. Pol. 2020, 54, 478–480. [Google Scholar] [CrossRef] [PubMed]
- Siotto, M.; Squitti, R. Coppr imbalance in Alzheimer’s disease: Overview of the exchangeable copper component in plasma and the intriguing role albumib plays. Coord. Chem. Rev. 2018, 371, 86–95. [Google Scholar] [CrossRef]
- Stättermayer, A.F.; Entenmann, A.; Gschwantler, M.; Zoller, H.; Hofer, H.; Ferenci, P. The dilemma to diagnose Wilson disease by genetic testing alone. Eur. J. Clin. Investig. 2019, 49, e13147. [Google Scholar] [CrossRef]
- Alexander, D.R. Pseudocholinesterase deficiency. Medscape 2017, 14, 1–6. [Google Scholar]
- Arslan, M.; Novak, M.; Rosenthal, D.; Hartmann, C.J.; Albrecht, P.; Samadzadeh, S.; Hefter, H. Cholinesterase Deficiency Syndrome—A Pitfall in the Use of Butyrylcholinesterase as a Biomarker for Wilson’s Disease. Biomolecules 2022, 12, 1398. [Google Scholar] [CrossRef]
- Samadzadeh, S. Long-Term Follow-Up of 115 Patients with Wilson’s Disease. Ph.D. Dissertation, University of Düsseldorf, Düsseldorf, Germany, 2022. Available online: https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=59305 (accessed on 6 July 2022).
WD-DEF-Group | WD-SUS-Group | ||||
---|---|---|---|---|---|
Clinical subgroup | n= | Main symptom | n= | Main symptom | Final diagnosis |
ASYMPT | 1 | n.a. | 8 | n.a. | Gene carrier |
HEP | 4 | 2 patients with reduced daily activities 1 patient with intellectual decline 1 patient with acute hepatic failure | 1 | 1 patient with reduced daily activities | Hepatitis |
N-TRE | 7 | Tremor of extremities and trunk | 6 | 3 patients with symmetric tremor of hands and head 3 patients with asymmetric hand tremor | Essential tremor Idiopathic PD |
N-PARK | 5 | Symmetric bradykinesia | 2 | Reduced arm swing | Idiopathic PD |
N-OTHMD | 3 | Cerebellar ataxia, Chorea, generalized dystonia | 4 | Psychogenic movement disorder | Confirmed |
N-PAIN | 0 | 3 | Pain in muscles and joints | Rheumatism, joint degeneration, Complex regional pain syndrome, CRPS | |
N-INFL | 0 | 3 | Paresthesia, spasticity | Neuroinflammatory disease (MS, NMO) | |
N-FATIQUE | 0 | 2 | Severe tiredness | MS, CFS | |
N-DEGEN | 0 | 1 | Loss of balance | MAS | |
N-PSYCH | 0 | 1 | Fatigue | Depression |
Area under ROC-Curve | Rank | Parameter | WD-DEF MV/SD before Therapy | p-Value | WD-SUS MV/SD | p-Value | WD-DEF MV/SD after Therapy | Rank | Area under ROC-Curve |
---|---|---|---|---|---|---|---|---|---|
0.97 | 1 | CHE | 2999/1801 | 4.58 × 10−14 | 8035/1388 | 8.12 × 10−8 | 5048/1634 | 1 | 0.93 |
0.93 | 2 | Cerulo | 10.1/4.1 | 1.69 × 10−7 | 20.2/6.4 | 3.98 × 10−7 | 9.7/5.1 | 3 | 0.91 |
0.89 | 3 | Thromb | 139/57 | 1.80 × 10−6 | 249/72 | 1.19 × 10−5 | 154/47 | 5 | 0.89 |
0.88 | 4 | Quick | 68.3/22.1 | 2.36 × 10−5 | 93.5/15.4 | 2.89 × 10−3 | 79.3/17.0 | 7 | 0.86 |
0.82 | 5 | Cu (serum) | 51.6/27.2 | 1.96 × 10−4 | 93.0/36.8 | 2.49 × 10−7 | 35.1/22.1 | 2 | 0.96 |
0.96 | 6 | Cu (24 h) | 966/1292 | 4.42 × 10−4 | 31.0/42.5 | 1.19 × 10−5 | 160.1/138.1 | 4 | 0.88 |
0.88 | 7 | GPT | 91.0/95.1 | 1.17 × 10−3 | 24.0/16.1 | 3.38 × 10−2 | 47.7/47.1 | >7 | 0.65 |
0.95 | >7 | Cu (mg/L) | 519/753 | 1.47 × 10−3 | 24.5/44.8 | 6.76 × 10−4 | 113.3/121.2 | 6 | 0.86 |
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Hefter, H.; Arslan, M.; Kruschel, T.S.; Novak, M.; Rosenthal, D.; Meuth, S.G.; Albrecht, P.; Hartmann, C.J.; Samadzadeh, S. Pseudocholinesterase as a Biomarker for Untreated Wilson’s Disease. Biomolecules 2022, 12, 1791. https://doi.org/10.3390/biom12121791
Hefter H, Arslan M, Kruschel TS, Novak M, Rosenthal D, Meuth SG, Albrecht P, Hartmann CJ, Samadzadeh S. Pseudocholinesterase as a Biomarker for Untreated Wilson’s Disease. Biomolecules. 2022; 12(12):1791. https://doi.org/10.3390/biom12121791
Chicago/Turabian StyleHefter, Harald, Max Arslan, Theodor S. Kruschel, Max Novak, Dietmar Rosenthal, Sven G. Meuth, Philipp Albrecht, Christian J. Hartmann, and Sara Samadzadeh. 2022. "Pseudocholinesterase as a Biomarker for Untreated Wilson’s Disease" Biomolecules 12, no. 12: 1791. https://doi.org/10.3390/biom12121791