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Socha P, Jańczyk W, Zanetto A, Burra P, Czlonkowska A, Debray D, Ferenci P, Merle U, Nicastro E, Poujois A, Schmidt H, Tsochatzis E. EASL-ERN Clinical Practice Guidelines on Wilson's disease. J Hepatol 2025; 82:S0168-8278(24)02706-5. [PMID: 40089450 DOI: 10.1016/j.jhep.2024.11.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Accepted: 11/08/2024] [Indexed: 03/17/2025]
Abstract
Wilson's disease is an autosomal recessive disorder of copper metabolism which affects the liver, brain and other organs. Diagnosis is based on: clinical features; biochemical tests, including plasma ceruloplasmin concentration, 24-h urinary copper excretion, copper content in the liver; and molecular analysis. Leipzig score and additionally relative exchangeable copper determination are recommended for diagnosis. Pharmacological therapy comprises chelating agents (penicillamine, trientine) and zinc salts, while only chelators are recommended for significant liver disease. Monitoring is based on clinical symptoms, liver tests and copper metabolism (urinary copper excretion, exchangeable copper) to detect poor compliance and over/under-treatment. Acute liver failure is challenging as making a diagnosis is difficult and pharmacological therapy may not be sufficient to save life. Liver transplantation has a well-defined role in Wilsonian acute hepatic failure but may also be considered in neurological disease.
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Mohr I, Lamade P, Weber C, Leidner V, Köhrer S, Olkus A, Lang M, Langel A, Dankert P, Greibich M, Wolf S, Zimmer H, Michl P, Poujois A, Weiss KH, Merle U. A comparative analysis in monitoring 24-hour urinary copper in wilson disease: sampling on or off treatment? Orphanet J Rare Dis 2025; 20:33. [PMID: 39838467 PMCID: PMC11748325 DOI: 10.1186/s13023-025-03545-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Accepted: 01/05/2025] [Indexed: 01/23/2025] Open
Abstract
BACKGROUND & AIM Twenty-four-hour urinary copper excretion (24 h-UCE) is the standard diagnostic tool for dose adjustments in maintenance therapy in Wilson disease (WD) patients. Guidelines lack data if both variants of 24 h-UCE measurement (with or without 48 h of treatment interruption) are equally interpretable. METHODS Eighty-four patients with a confirmed diagnosis of WD treated with chelators (50% of patients with D-Penicillamine and 50% with trientine) and with pairwise 24-h-UCE values on-therapy and off-therapy were included in the analysis. Pairwise urinary sampling between October 2022 (T0) and a 12-month FU (T2) was compared, and exchangeable copper (CuEXC) was additionally measured at T0. RESULTS Among the 84 patients, 65% had predominant hepatic symptoms, the median age was 42 years, and 58% were female. At T0, patients were in the stable maintenance phase, with a median treatment duration of 21.9 years. The levels of the biochemical markers liver and copper metabolism remained stable over the 12-month observation period for all patients. 24 h-UCE off-therapy significantly decreased from T0 to T2 (p = 0.03), whereas no statistically significant differences were detected for 24 h-UCE after therapy. Both sampling methods did not correlate. CuEXC was significantly correlated with 24 h-UCE after 48 h of dose interruption (p = 0.018) but not with 24 h-UCE after therapy. A total of 46% of the 24 h-UCE value pairs were discordant, laying out the aimed therapeutic ranges given in current international guidelines. CONCLUSION Off-therapy 24 h-UCE reflects the "free" copper pool more accurately than does urinary sampling. The study shows discordant results for both sampling methods in approximately half of the patients, revealing that interpretation of 24 h-UCE with respect to chelator-dosing decisions should be performed with caution.
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Affiliation(s)
- Isabelle Mohr
- Internal Medicine IV, Department of Gastroenterology, University Hospital Heidelberg, INF 410, Heidelberg, 69120, Germany.
| | - Patrick Lamade
- Internal Medicine IV, Department of Gastroenterology, University Hospital Heidelberg, INF 410, Heidelberg, 69120, Germany
| | - Christophe Weber
- Internal Medicine III Department of Internal Medicine and Cardiology, University Hospital Heidelberg, Heidelberg, Germany
| | - Viola Leidner
- Internal Medicine IV, Department of Gastroenterology, University Hospital Heidelberg, INF 410, Heidelberg, 69120, Germany
| | - Sebastian Köhrer
- Internal Medicine IV, Department of Gastroenterology, University Hospital Heidelberg, INF 410, Heidelberg, 69120, Germany
| | - Alexander Olkus
- Internal Medicine IV, Department of Gastroenterology, University Hospital Heidelberg, INF 410, Heidelberg, 69120, Germany
| | - Matthias Lang
- Internal Medicine IV, Department of Gastroenterology, University Hospital Heidelberg, INF 410, Heidelberg, 69120, Germany
| | - Andrea Langel
- Internal Medicine IV, Department of Gastroenterology, University Hospital Heidelberg, INF 410, Heidelberg, 69120, Germany
| | - Patrischia Dankert
- Internal Medicine IV, Department of Gastroenterology, University Hospital Heidelberg, INF 410, Heidelberg, 69120, Germany
| | - Melanie Greibich
- Internal Medicine IV, Department of Gastroenterology, University Hospital Heidelberg, INF 410, Heidelberg, 69120, Germany
| | - Silke Wolf
- Internal Medicine I, Department of Endocrinology, Diabetology, Metabolic Diseases and Clinical Chemistry, University Hospital Heidelberg, Heidelberg, Germany
| | - Holger Zimmer
- Internal Medicine I, Department of Endocrinology, Diabetology, Metabolic Diseases and Clinical Chemistry, University Hospital Heidelberg, Heidelberg, Germany
| | - Patrick Michl
- Internal Medicine IV, Department of Gastroenterology, University Hospital Heidelberg, INF 410, Heidelberg, 69120, Germany
| | - Aurélia Poujois
- Department of Neurology, Rothschild Foundation Hospital, National Reference Center for Wilson Disease, Paris, France
| | - Karl Heinz Weiss
- Internal Medicine, Salem Hospital Heidelberg, Heidelberg, Germany
| | - Uta Merle
- Internal Medicine IV, Department of Gastroenterology, University Hospital Heidelberg, INF 410, Heidelberg, 69120, Germany
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Ott P, Sandahl T, Ala A, Cassiman D, Couchonnal-Bedoya E, Cury RG, Czlonkowska A, Denk G, D’Inca R, de Assis Aquino Gondim F, Moore J, Poujois A, Twardowschy CA, Weiss KH, Zuin M, Kamlin CF, Schilsky ML. Non-ceruloplasmin copper and urinary copper in clinically stable Wilson disease: Alignment with recommended targets. JHEP Rep 2024; 6:101115. [PMID: 39139457 PMCID: PMC11321293 DOI: 10.1016/j.jhepr.2024.101115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 04/20/2024] [Accepted: 04/25/2024] [Indexed: 08/15/2024] Open
Abstract
Background & Aims Wilson disease (WD) is caused by accumulation of copper primarily in the liver and brain. During maintenance therapy of WD with D-penicillamine, current guidelines recommend on-treatment ranges of urinary copper excretion (UCE) of 200-500 μg/24 h and serum non-ceruloplasmin-bound copper (NCC) of 50-150 μg/L. We compared NCC (measured by two novel assays) and UCE from patients with clinically stable WD on D-penicillamine therapy with these recommendations. Methods This is a secondary analysis of data from the Chelate trial (NCT03539952) that enrolled physician-selected patients with clinically stable WD on D-penicillamine maintenance therapy (at an unaltered dose for at least 4 months). We analyzed laboratory samples from the first screening visit, prior to interventions. NCC was measured by either protein speciation (NCC-Sp) using anion exchange high-performance liquid chromatography protein speciation followed by copper determination with inductively coupled plasma mass spectroscopy or as exchangeable copper (NCC-Ex). NCC-Sp was also analyzed in healthy controls (n = 75). Results In 76 patients with WD with 21.3±14.3 average treatment-years, NCC-Sp (mean±SD: 56.6±26.2 μg/L) and NCC-Ex (mean±SD: 57.9±24.7 μg/L) were within the 50-150 μg/L target in 61% and 54% of patients, respectively. In addition, 36% and 31%, respectively, were even below the normal ranges (NCC-Sp: 46-213 μg/L, NCC-Ex: 41-71 μg/L). NCC-Ex positively correlated with NCC-Sp (r2 = 0.66, p <0.001) but with systematic deviation. UCE was outside the 200-500 μg/24 h target range in 58%. Only 14/69 (20%) fulfilled both the NCC-Sp and UCE targets. Clinical or biochemical signs of copper deficiency were not detected. Conclusion Clinically stable patients with WD on maintenance D-penicillamine therapy frequently have lower NCC-Sp or higher UCE than current recommendations without signs of overtreatment. Further studies are warranted to identify appropriate target ranges of NCC-Sp, NCC-Ex and UCE in treated WD. Impact and implications Chelator treatment of patients with Wilson disease (WD) is currently guided by measurements of non-ceruloplasmin-bound copper (NCC) and 24 h urinary copper excretion (UCE) but validation is limited. In 76 adults with ≈21 years history of treated WD and clinically stable disease on D-penicillamine therapy, NCC was commonly found to be below normal values and recommended target ranges whether measured by protein speciation (NCC-Sp) or as exchangeable copper (NCC-Ex), while UCE values were above the recommended target range in 49%. Common wisdom would suggest overtreatment in these cases, but no clinical or biochemical signs of copper deficiency were observed. Exploratory analysis of liver enzymes suggested that NCC below levels seen in controls may be beneficial, while the relation to UCE was less clear. The data calls for critical re-evaluation of target ranges for treatment of WD, specific for drug and laboratory methodology. Clinical trial number (NCT03539952).
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Affiliation(s)
- Peter Ott
- Dept. of Hepatology and Gastroenterology, Aarhus University Hospital,8200 Aarhus C, Denmark
| | - Thomas Sandahl
- Dept. of Hepatology and Gastroenterology, Aarhus University Hospital,8200 Aarhus C, Denmark
| | - Aftab Ala
- Institute of Liver Studies King's College Hospital NHS Foundation Trust, London, UK
| | - David Cassiman
- University Hospitals, Leuven - Department of Gastroenterology-Hepatology and Dept. of Chronic Diseases and Metabolism, Herestraat 49, 3000 Leuven, Belgium
| | - Eduardo Couchonnal-Bedoya
- Hospices Civils de Lyon- Hôpital Femme Mère Enfant - Hépatologie, Gastroentérologie et Nutrition pédiatrique, Centre de Référence de la maladie de Wilson, 59 boulevard Pinel, 69677 BRON, France
| | - Rubens Gisbert Cury
- Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, R. Dr. Eneas de Carvalho Aguiar, 255- Cerqueira César, Sao Paulo, Brazil
| | - Anna Czlonkowska
- 2 Depatment of Neurology, Institute of Psychiatry and Neurology, 02 957 Warsaw, Poland
| | - Gerald Denk
- Medizinische Klinik und Poliklinik II/Transplantation Center, LMU Klinikum, LMU Munich, Germany
| | - Renata D’Inca
- Department of Surgical, Oncological and Gastroenterological Sciences, University of Padova, Padova, Italy
| | - Francisco de Assis Aquino Gondim
- Nucleo de Pesquisa e Desenvolvimento de Medicamentos – Universidade Federal do Ceará - Rodolfo Teófilo R. Coronel Nunes de Melo 1000, Fortaleza CE60430-275, Brazil
| | - Joanna Moore
- Leeds Teaching Hospitals NHS Trust Merville Building, LS9 7TF Leeds, UK
| | - Aurelia Poujois
- Département de Neurologie, Centre de Reference de la Maladie de Wilson, Hopital Fondation Adolphe de Rothschild, Paris, France
| | | | - Karl Heinz Weiss
- Salem Medical Center, Dept. Of Internal Medicine, Zeppelinstr. 11-33, Heidelberg 69121, Germany
| | - Massimo Zuin
- U.O. Medicina Generale Epatologia e Gastroenterologia Medica ASST Santi Paolo e Carlo. Via A. Di Rudinì, 8, Milano, Italy
| | | | - Michael L. Schilsky
- Departments of Medicine and Surgery, Sections of Digestive Diseases and Transplant and Immunology, Yale School of Medicine, 333 Cedar St, LMP 1080, New Haven - Connecticut 06510, USA
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Zarei A, Rezaei A, Shahlaei M, Asani Z, Ramazani A, Wang C. Selective and sensitive CQD-based sensing platform for Cu 2+ detection in Wilson's disease. Sci Rep 2024; 14:13183. [PMID: 38851799 PMCID: PMC11162432 DOI: 10.1038/s41598-024-63771-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Accepted: 05/31/2024] [Indexed: 06/10/2024] Open
Abstract
Excessive Cu2+ intake can cause neurological disorders (e.g. Wilson's disease) and adversely affect the gastrointestinal, liver, and kidney organs. The presence of Cu2+ is strongly linked to the emergence and progression of Wilson's disease (WD), and accurately measuring the amount of copper is a crucial step in diagnosing WD at an early stage in a clinical setting. In this work, CQDs were fabricated through a facile technique as a novel fluorescence-based sensing platform for detecting Cu(II) in aqueous solutions, and in the serum samples of healthy and affected individuals by WD. The CQDs interact with Cu(II) ions to produce Turn-on and Turn-off states at nano-molar and micro-molar levels, respectively, with LODs of 0.001 µM and 1 µM. In fact, the Cu2+ ions can act like a bridge between two CQDs by which the charge and electron transfer between the CQDs may increase, possibly can have significant effects on the spectroscopic features of the CQDs. To the best of our knowledge, this is the first reported research that can detect Cu(II) at low levels using two different complexation states, with promising results in testing serum. The potential of the sensor to detect Cu(II) was tested on serum samples from healthy and affected individuals by WD, and compared to results obtained by ICP-OES. Astonishingly, the results showed an excellent correlation between the measured Cu(II) levels using the proposed technique and ICP-OES, indicating the high potential of the fluorimetric CQD-based probe for Cu(II) detection. The accuracy, sensitivity, selectivity, high precision, accuracy, and applicability of the probe toward Cu(II) ions make it a potential diagnostic tool for Wilson's disease in a clinical setting.
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Affiliation(s)
- Armin Zarei
- The Organic Chemistry Research Laboratory (OCRL), Department of Chemistry, University of Zanjan, Zanjan, 45371-38791, Iran
| | - Aram Rezaei
- Nano Drug Delivery Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran.
| | - Mohsen Shahlaei
- Nano Drug Delivery Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Zhaleh Asani
- Students Research Committee,, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Radiology Department, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Ali Ramazani
- The Organic Chemistry Research Laboratory (OCRL), Department of Chemistry, University of Zanjan, Zanjan, 45371-38791, Iran.
- The Convergent Sciences & Technologies Laboratory (CSTL), Research Institute of Modern Biological Techniques (RIMBT), University of Zanjan, Zanjan 45371-38791, Iran.
| | - Chuanyi Wang
- School of Environmental Science and Engineering, Shaanxi University of Science and Technology, Xi'an, 710021, People's Republic of China.
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Jagadisan B, Dhawan A. Combination Treatment With Chelators and Zinc for Wilson Disease: A Double-edged Sword. J Clin Exp Hepatol 2024; 14:101372. [PMID: 38495076 PMCID: PMC10940139 DOI: 10.1016/j.jceh.2024.101372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Accepted: 02/17/2024] [Indexed: 03/19/2024] Open
Affiliation(s)
- Barath Jagadisan
- Pediatric Liver GI and Nutrition Centre and Mowat Labs, King's College Hospital, London, UK
| | - Anil Dhawan
- Pediatric Liver GI and Nutrition Centre and Mowat Labs, King's College Hospital, London, UK
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Kirk FT, Munk DE, Swenson ES, Quicquaro AM, Vendelbo MH, Schilsky ML, Ott P, Sandahl TD. Effects of trientine and penicillamine on intestinal copper uptake: A mechanistic 64 Cu PET/CT study in healthy humans. Hepatology 2024; 79:1065-1074. [PMID: 38088886 PMCID: PMC11019997 DOI: 10.1097/hep.0000000000000708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Accepted: 11/17/2023] [Indexed: 02/24/2024]
Abstract
BACKGROUND AND AIMS Trientine (TRI) and D-penicillamine (PEN) are used to treat copper overload in Wilson disease. Their main mode of action is thought to be through the facilitation of urinary copper excretion. In a recent study, TRI was noninferior to PEN despite lower 24-hour urinary copper excretion than PEN. We tested whether TRI and/or PEN also inhibit intestinal copper absorption. APPROACH AND RESULTS Sixteen healthy volunteers were examined with positron emission tomography (PET)/CT 1 and 15 hours after an oral Copper-64 ( 64 Cu) dose. They then received 7 days of either PEN or TRI (trientine tetrahydrochloride), after which the 64 Cu PET/CT scans were repeated. Venous blood samples were also collected. Pretreatment to posttreatment changes of the hepatic 64 Cu uptake reflect the effect of drugs on intestinal absorption. 64 Cu activity was normalized to dose and body weight and expressed as the mean standard uptake value. TRI (n=8) reduced hepatic 64 Cu activity 1 hour after 64 Cu dose from 6.17 (4.73) to 1.47 (2.97) standard uptake value, p <0.02, and after 15 hours from 14.24 (3.09) to 6.19 (3.43), p <0.02, indicating strong inhibition of intestinal 64 Cu absorption. PEN (n=8) slightly reduced hepatic standard uptake value at 15 hours, from 16.30 (5.63) to 12.17 (1.44), p <0.04. CONCLUSIONS In this mechanistic study, we show that TRI inhibits intestinal copper absorption, in addition to its cupriuretic effect. In contrast, PEN has modest effects on the intestinal copper absorption. This may explain why TRI and PEN are equally effective although urinary copper excretion is lower with TRI. The study questions whether the same therapeutic targets for 24-hour urinary excretion apply to both drugs.
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Affiliation(s)
- Frederik Teicher Kirk
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Ditte Emilie Munk
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | | | | | - Mikkel Holm Vendelbo
- Department of Nuclear Medicine & PET-center, Aarhus University Hospital, Aarhus, Denmark
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Michael L. Schilsky
- Department of Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut, USA
- Department of Surgery, Section of Transplant and Immunology, Yale School of Medicine, New Haven, Connecticut, USA
| | - Peter Ott
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
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Panda K, Lal BB, Sood V, Khanna R, Alam S. Adequate Chelation and Cupriuresis in Hepatic Wilson Disease Patients Under Combination (Chelator + Zinc) Therapy at 2 Years of Follow-up. J Clin Exp Hepatol 2024; 14:101284. [PMID: 38544767 PMCID: PMC10964067 DOI: 10.1016/j.jceh.2023.09.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Accepted: 09/12/2023] [Indexed: 01/07/2025] Open
Abstract
BACKGROUND & AIM Role of 24-h urinary copper excretion (UCE) in monitoring Wilson disease (WD) on combination (chelator + Zinc) therapy is not well studied, especially in the pediatric population. Hence, the present study is conducted with an aim to evaluate UCE and its role in deciding therapeutic adequacy in pediatric WD on long-term follow-up. METHODS All WD patients <18 years of age and on combination therapy with at least one UCE available after the first year of treatment were included. Liver biochemistries, UCE, and serum non-ceruloplasmin bound copper (NCC) were assessed at diagnosis and various follow-ups. For assessment of treatment efficacy, criteria for adequate chelation (CAC) were defined as fulfillment of both (i) AST & ALT ≤1.5 times upper limit of normal, serum albumin >35 gm/L, INR <1.5 and (ii) UCE <500 mcg/day. RESULTS Of the 74 included children, 70 (94.5%), 45 (60.8%), 28 (37.8%) and 21 (28.3%) completed 2-, 3-, 5-, and 7-year follow-up, respectively. Liver biochemistries improved significantly within 1 year of treatment. UCE (mcg/day) decreased significantly from baseline of 654.08 ± 803.78 to 308.23 ± 175.93 at 2 years with no further change at 3- and 5-years follow-up. UCE (mcg/day) at 2 years was <200 in 28.5%, 200-500 in 55.7%, and >500 in 15.7%. 61% achieved CAC in 2 years. On multivariate cox regression, treatment compliance was predictor for CAC achievement (Odds ratio: 3.48, 95%CI: 1.36-8.86. P = 0.009). CONCLUSION UCE declines significantly from baseline to <500 mcg/day within 2 years. Majority of treatment-compliant patients achieve CAC within 2 years of combination therapy.
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Affiliation(s)
- Kalpana Panda
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Bikrant B. Lal
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Vikrant Sood
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Rajeev Khanna
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Seema Alam
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
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Panda K, Lal BB, Sood V, Khanna R, Alam S. Adequate Chelation and Cupriuresis in Hepatic Wilson Disease Patients Under Combination (Chelator + Zinc) Therapy at 2 Years of Follow-up. J Clin Exp Hepatol 2024; 14:101284. [DOI: https:/doi.org/10.1016/j.jceh.2023.09.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/16/2025] Open
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João Soares R, Monteiro N, Machado J, Silva Marques J, Nunes A. A Challenging Case of Wilson's Disease. Cureus 2023; 15:e42655. [PMID: 37644923 PMCID: PMC10461780 DOI: 10.7759/cureus.42655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/29/2023] [Indexed: 08/31/2023] Open
Abstract
Wilson's disease (WD) is an inherited disorder characterized by the accumulation of copper in various organs, particularly the liver, central nervous system, and cornea. The clinical presentation of WD can vary widely. Diagnosis requires a combination of clinical and biochemical findings. We present a case of a 20-year-old woman who presented to the Emergency Room with progressive motor decline. She exhibited characteristic neurological symptoms and signs, such as hypomimia, bradyphrenia, bradykinesia, dysarthria, sialorrhea, upper limb dystonia, and wing-beating tremor. Ophthalmological examination revealed corneal deposits known as Kayser-Fleischer rings. Laboratory investigations demonstrated low levels of ceruloplasmin and elevated serum copper. Brain MRI showed typical signs of copper deposition in the basal ganglia. The Leipzig criteria were used to confirm the diagnosis. Treatment with penicillamine and zinc acetate resulted in symptom improvement. This case highlights the diverse presentation of WD and the importance of early diagnosis and prompt treatment initiation.
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Affiliation(s)
- Rita João Soares
- Department of Internal Medicine, Centro Hospitalar Tondela-Viseu, Viseu, PRT
| | - Nuno Monteiro
- Department of Internal Medicine, Centro Hospitalar Tondela-Viseu, Viseu, PRT
| | - João Machado
- Department of Internal Medicine, Centro Hospitalar Tondela-Viseu, Viseu, PRT
| | - Joana Silva Marques
- Department of Internal Medicine, Centro Hospitalar Tondela-Viseu, Viseu, PRT
| | - Ana Nunes
- Department of Internal Medicine, Centro Hospitalar Tondela-Viseu, Viseu, PRT
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Zimny S, Bourhis H, Weber S, Reiter FP, Hohenester S, Kraft E, Mohr I, Merle U, Weiss KH, Denk G. Medical care of patients with Wilson disease in Germany: a multidisciplinary survey among university centers. Orphanet J Rare Dis 2023; 18:122. [PMID: 37226184 DOI: 10.1186/s13023-023-02731-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 05/14/2023] [Indexed: 05/26/2023] Open
Abstract
BACKGROUND Wilson disease (WD) is a rare, hereditary disorder of copper metabolism. Due to its variable symptoms and manifestations, diagnosis remains challenging. Affected patients must obtain lifelong medical treatment, as the disease is fatal if untreated. Patients require continuous monitoring, but little is known about the care of these patients in Germany. Therefore, we analyzed the medical care of WD patients at German university centers. We sent a questionnaire containing 20 questions to a total of 108 departments of pediatrics, neurology and gastroenterology in 36 university hospitals. Our questions referred to the characteristics of WD patients at the different sites and internal procedures regarding diagnosis, therapy and follow-up. A descriptive statistical analysis was performed. RESULTS Sixty-three departments (58%) returned our questionnaire. In total, approximately one-third of the estimated WD patients in Germany are seen annually in the outpatient clinics of these departments (approx. 950 patients). There are only a few departments which treat patients in a multidisciplinary setting (12%). Our survey revealed that for diagnosis, 51% of all departments used an algorithm based on the Leipzig score as recommended by international guidelines. Most departments apply essential parameters recommended by WD guidelines. Routine monitoring is performed at least biannually by 84% of the departments, and standard investigations for monitoring are regularly applied. A routine family screening is performed by 84% of all departments. A reduction in medical therapy during pregnancy is recommended by 46% of the departments. Only 14% suggested that WD patients should not breastfeed. Liver transplantation (LT) due to WD is a rare but repeatedly occurring event. Most departments of gastroenterology (72%) reported at least one patient with LT within the last decade. CONCLUSIONS Medical care of WD patients at German university centers follows the recommendations set forth by international guidelines, but only a few centers treat significant numbers of patients. The surveillance of patients does not follow specified standards, but most departments adhere to the accepted guidelines. The formation of central units and networks in a multidisciplinary setting should be evaluated to improve the care of WD patients.
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Affiliation(s)
- Sebastian Zimny
- Department of Medicine II, University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany.
| | - Hélène Bourhis
- Department of Medicine II, University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany
| | - Sabine Weber
- Department of Medicine II, University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany
| | - Florian Paul Reiter
- Department of Medicine II, University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany
- Department of Medicine II, University Hospital Würzburg, Oberdürrbacher Straße 6, 97080, Würzburg, Germany
| | - Simon Hohenester
- Department of Medicine II, University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany
| | - Eduard Kraft
- Department of Physical Medicine and Rehabilitation, University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany
| | - Isabelle Mohr
- Department of Internal Medicine IV, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
| | - Uta Merle
- Department of Internal Medicine IV, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
| | - Karl Heinz Weiss
- Internal Medicine, Salem Medical Center, Zeppelinstraße 11 - 33, 69121, Heidelberg, Germany
| | - Gerald Denk
- Department of Medicine II, University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany
- Transplant Center, University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany
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Schilsky ML, Roberts EA, Bronstein JM, Dhawan A, Hamilton JP, Rivard AM, Washington MK, Weiss KH, Zimbrean PC. A multidisciplinary approach to the diagnosis and management of Wilson disease: Executive summary of the 2022 Practice Guidance on Wilson disease from the American Association for the Study of Liver Diseases. Hepatology 2023; 77:1428-1455. [PMID: 36152019 DOI: 10.1002/hep.32805] [Citation(s) in RCA: 68] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 09/13/2022] [Indexed: 12/08/2022]
Affiliation(s)
- Michael L Schilsky
- Medicine and Surgery , Yale University School of Medicine , New Haven , Connecticut , USA
| | - Eve A Roberts
- Paediatrics, Medicine, Pharmacology and Toxicology , University of Toronto , Toronto , Ontario , Canada
| | - Jeff M Bronstein
- Neurology , University of California Los Angeles , Los Angeles , California , USA
| | - Anil Dhawan
- Paediatric Liver, GI and Nutrition Centre and MowatLabs , King's College Hospital , London , UK
| | - James P Hamilton
- Medicine , Johns Hopkins University School of Medicine , Baltimore , Maryland , USA
| | - Anne Marie Rivard
- Food and Nutrition Services , Yale New Haven Hospital , New Haven , Connecticut , USA
| | - Mary Kay Washington
- Pathology, Immunology and Microbiology , Vanderbilt University Medical Center , Nashville , Tennessee , USA
| | | | - Paula C Zimbrean
- Psychiatry , Yale University School of Medicine , New Haven , Connecticut , USA
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12
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Jopowicz A, Tarnacka B. Neurological Wilson's Disease Signs-Hepatic Encephalopathy or Copper Toxicosis? Diagnostics (Basel) 2023; 13:diagnostics13050893. [PMID: 36900037 PMCID: PMC10001333 DOI: 10.3390/diagnostics13050893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 02/17/2023] [Accepted: 02/25/2023] [Indexed: 03/03/2023] Open
Abstract
Wilson's disease (WD) is a rare autosomal recessive (AR) disorder resulting from mutations in the ATP7B gene, which is responsible for the encryption of transmembrane copper transporting ATPase. The symptomatic presentation of the disease is estimated to be about 1 in 30,000. The impairment of ATP7B function results in a copper overload in hepatocytes, which further leads to liver pathology. This copper overload also occurs in other organs, most particularly in the brain. This could then cause the occurrence of neurological and psychiatric disorders. Symptoms differ substantially and most often occur between the ages of 5 and 35 years. Early symptoms are commonly hepatic, neurological, or psychiatric. While disease presentation is most often asymptomatic, it could also range as far as to include fulminant hepatic failure, ataxia, and cognitive disorders. Various treatments are available for Wilson's disease, including chelation therapy and zinc salts, which can reverse copper overload through different mechanisms. In select cases, liver transplantation is recommended. New medications, such as tetrathiomolybdate salts, are currently being investigated in clinical trials. With prompt diagnosis and treatment, prognosis is favorable; however, diagnosing patients before the onset of severe symptoms is a significant concern. Early screening for WD could help in diagnosing patients earlier and improving treatment outcomes.
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Affiliation(s)
- Anna Jopowicz
- Department of Rehabilitation, Eleonora Reicher National Institute of Geriatrics, Rheumatology and Rehabilitation, Spartańska 1, 02-637 Warsaw, Poland
- Correspondence:
| | - Beata Tarnacka
- Department of Rehabilitation Medicine, Faculty of Medicine, Warsaw Medical University, Spartańska 1, 02-637 Warsaw, Poland
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13
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Guillaud O, Dumortier J, Couchonnal-Bedoya E, Ruiz M. Wilson Disease and Alpha1-Antitrypsin Deficiency: A Review of Non-Invasive Diagnostic Tests. Diagnostics (Basel) 2023; 13:diagnostics13020256. [PMID: 36673066 PMCID: PMC9857715 DOI: 10.3390/diagnostics13020256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Accepted: 01/03/2023] [Indexed: 01/12/2023] Open
Abstract
Wilson disease and alpha1-antitrypsin deficiency are two rare genetic diseases that may impact predominantly the liver and/or the brain, and the liver and/or the lung, respectively. The early diagnosis of these diseases is important in order to initiate a specific treatment, when available, ideally before irreversible organ damage, but also to initiate family screening. This review focuses on the non-invasive diagnostic tests available for clinicians in both diseases. These tests are crucial at diagnosis to reduce the potential diagnostic delay and assess organ involvement. They also play a pivotal role during follow-up to monitor disease progression and evaluate treatment efficacy of current or emerging therapies.
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Affiliation(s)
- Olivier Guillaud
- Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, Centre National de Référence pour la Maladie de Wilson, 69500 Bron, France
- Ramsay Générale de Santé, Clinique de la Sauvegarde, 69009 Lyon, France
- Hospices Civils de Lyon, Hôpital Edouard Herriot, Fédération des Spécialités Digestives, 69003 Lyon, France
- Correspondence: ; Tel.: +33-4-72-11-95-19
| | - Jérôme Dumortier
- Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, Centre National de Référence pour la Maladie de Wilson, 69500 Bron, France
- Hospices Civils de Lyon, Hôpital Edouard Herriot, Fédération des Spécialités Digestives, 69003 Lyon, France
- Faculté de Médecine Lyon Est, Université Claude Bernard Lyon 1, 69003 Lyon, France
| | - Eduardo Couchonnal-Bedoya
- Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, Centre National de Référence pour la Maladie de Wilson, 69500 Bron, France
- Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, Service d’Hépatogastroentérologie et Nutrition Pédiatrique, 69500 Bron, France
| | - Mathias Ruiz
- Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, Service d’Hépatogastroentérologie et Nutrition Pédiatrique, 69500 Bron, France
- Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, Centre National de Référence pour l’Atrésie des Voies Biliaires et les Cholestases Génétiques, 69500 Bron, France
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14
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Schilsky ML, Roberts EA, Bronstein JM, Dhawan A, Hamilton JP, Rivard AM, Washington MK, Weiss KH, Zimbrean PC. A multidisciplinary approach to the diagnosis and management of Wilson disease: 2022 Practice Guidance on Wilson disease from the American Association for the Study of Liver Diseases. Hepatology 2022:01515467-990000000-00207. [PMID: 36151586 DOI: 10.1002/hep.32801] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 09/13/2022] [Indexed: 01/18/2023]
Affiliation(s)
- Michael L Schilsky
- Medicine and Surgery , Yale University School of Medicine , New Haven , Connecticut , USA
| | - Eve A Roberts
- Paediatrics, Medicine, Pharmacology and Toxicology , University of Toronto , Toronto , Ontario , Canada
| | - Jeff M Bronstein
- Neurology , University of California Los Angeles , Los Angeles , California , USA
| | - Anil Dhawan
- Paediatric Liver, GI and Nutrition Centre and MowatLabs , King's College Hospital , London , UK
| | - James P Hamilton
- Medicine , Johns Hopkins University School of Medicine , Baltimore , Maryland , USA
| | - Anne Marie Rivard
- Food and Nutrition Services , Yale New Haven Hospital , New Haven , Connecticut , USA
| | - Mary Kay Washington
- Pathology, Immunology and Microbiology , Vanderbilt University Medical Center , Nashville , Tennessee , USA
| | | | - Paula C Zimbrean
- Psychiatry , Yale University School of Medicine , New Haven , Connecticut , USA
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15
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Weiss KH, Kruse C, Manolaki N, Zuin M, Ferenci P, van Scheppingen D, Wijnberg L, de Koning CE, Dhawan A. Multicentre, retrospective study to assess long-term outcomes of chelator based treatment with trientine in Wilson disease patients withdrawn from therapy with d -penicillamine. Eur J Gastroenterol Hepatol 2022; 34:940-947. [PMID: 35482910 DOI: 10.1097/meg.0000000000002387] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVES Trientine dihydrochloride (TETA-2HCl) has been used for the treatment of Wilson disease for over 30 years. The current study was designed to systematically evaluate existing data to further define the long-term outcome of the efficacy and tolerability of TETA-2HCl in Wilson disease patients. METHODS Medical records of 77 Wilson disease patients were reviewed to collect data on hepatic and neurologic symptoms, copper (Cu) homeostasis and adverse events. Data were collected for 48 months after initiation of TETA-2HCl after withdrawal of D-penicillamine treatment. RESULTS Mean duration of TETA-2HCl treatment was 8 years (range 5 months-32.5 years). Over the course of TETA-2HCl treatment, 35% of patients had no hepatic symptoms whereas in 49.4% of patients, hepatic symptoms improved. They remained unchanged in 10.4% of patients and worsened in 5.2% of patients. No patients progressed to acute hepatic failure or necessity of a liver transplant. During TETA-2HCl treatment, 46.7% of patients had no neurologic symptoms; in 14.3% of patients, neurologic symptoms improved whereas in 36.4% of patients, they remained stable and worsened in 2.6% of patients. During the evaluation period, 12 patients discontinued TETA-2HCl treatment due to: anemia ( N = 1), inadequate hepatic response ( N = 2), switch to zinc treatment ( N = 8) and patient's decision to withdraw from treatment ( N = 1). Treatment-emergent adverse events were reported by 24.7% of the patients of which gastrointestinal disorders (9.1%) and nervous system disorders (5.2%) were most reported. CONCLUSIONS TETA-2HCl is well-tolerated and effective in Wilson disease patients following the withdrawal of treatment with D-penicillamine. ClinicalTrials.govIdentifier : NCT02426905.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Anil Dhawan
- King's College Hospital London, London, United Kingdom
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16
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Avan A, Członkowska A, Gaskin S, Granzotto A, Sensi SL, Hoogenraad TU. The Role of Zinc in the Treatment of Wilson’s Disease. Int J Mol Sci 2022; 23:ijms23169316. [PMID: 36012580 PMCID: PMC9409413 DOI: 10.3390/ijms23169316] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 08/09/2022] [Accepted: 08/15/2022] [Indexed: 02/06/2023] Open
Abstract
Wilson’s disease (WD) is a hereditary disorder of copper metabolism, producing abnormally high levels of non-ceruloplasmin-bound copper, the determinant of the pathogenic process causing brain and hepatic damage and dysfunction. Although the disease is invariably fatal without medication, it is treatable and many of its adverse effects are reversible. Diagnosis is difficult due to the large range and severity of symptoms. A high index of suspicion is required as patients may have only a few of the many possible biomarkers. The genetic prevalence of ATP7B variants indicates higher rates in the population than are currently diagnosed. Treatments have evolved from chelators that reduce stored copper to zinc, which reduces the toxic levels of circulating non-ceruloplasmin-bound copper. Zinc induces intestinal metallothionein, which blocks copper absorption and increases excretion in the stools, resulting in an improvement in symptoms. Two meta-analyses and several large retrospective studies indicate that zinc is equally effective as chelators for the treatment of WD, with the advantages of a very low level of toxicity and only the minor side effect of gastric disturbance. Zinc is recommended as a first-line treatment for neurological presentations and is gaining acceptance for hepatic presentations. It is universally recommended for lifelong maintenance therapy and for presymptomatic WD.
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Affiliation(s)
- Abolfazl Avan
- Department of Public Health, School of Medicine, Mashhad University of Medical Sciences, Mashhad 93518-88415, Iran
- Correspondence:
| | - Anna Członkowska
- 2nd Department of Neurology, Institute of Psychiatry and Neurology, 02-957 Warsaw, Poland
| | - Susan Gaskin
- Department of Civil Engineering, McGill University, Montreal, QC H3A 0C3, Canada
| | - Alberto Granzotto
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
- Department of Neuroscience, Imaging, and Clinical Sciences (DNISC), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
- Sue and Bill Gross Stem Cell Research Center, University of California-Irvine, Irvine, CA 92697, USA
| | - Stefano L. Sensi
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
- Department of Neuroscience, Imaging, and Clinical Sciences (DNISC), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
- Institute for Advanced Biomedical Technologies (ITAB), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
| | - Tjaard U. Hoogenraad
- Department of Neurology, University Medical Centre Utrecht, 3584 CX Utrecht, The Netherlands
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17
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Shribman S, Marjot T, Sharif A, Vimalesvaran S, Ala A, Alexander G, Dhawan A, Dooley J, Gillett GT, Kelly D, McNeill A, Warner TT, Wheater V, Griffiths W, Bandmann O. Investigation and management of Wilson's disease: a practical guide from the British Association for the Study of the Liver. Lancet Gastroenterol Hepatol 2022; 7:560-575. [PMID: 35429442 DOI: 10.1016/s2468-1253(22)00004-8] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 01/04/2022] [Accepted: 01/05/2022] [Indexed: 02/07/2023]
Abstract
Wilson's disease is an autosomal-recessive disorder of copper metabolism with hepatic, neurological, psychiatric, ophthalmological, haematological, renal, and rheumatological manifestations. Making a diagnosis can be challenging given that no single test can confirm or exclude the disease, and diagnostic delays are common. Treatment protocols vary and adverse effects, including paradoxical neurological worsening, can occur. In this Review, we provide a practical guide to the diagnosis of Wilson's disease. We include recommendations on indications for testing, how to interpret results, and when additional investigations are required. We also cover treatment initiation, ideally under the guidance of a specialist centre for Wilson's disease, and the principles behind long-term management. This guidance was developed by a multidisciplinary group of Wilson's disease experts formed through the British Association for the Study of the Liver. The guidance has been endorsed by the British Society of Gastroenterology and approved by the Association of British Neurologists.
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Affiliation(s)
- Samuel Shribman
- Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, London, UK
| | - Thomas Marjot
- Oxford Liver Unit, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Abubakar Sharif
- Liver Unit, Birmingham Women and Children's Hospital, Birmingham, UK
| | - Sunitha Vimalesvaran
- Paediatric Liver, GI and Nutrition Centre and Mowat Labs, King's College Hospital, Denmark Hill, London, UK
| | - Aftab Ala
- Department of Gastroenterology and Hepatology, Royal Surrey NHS Foundation Trust, Guildford; Institute of Liver Studies, King's College Hospital, London, UK
| | - Graeme Alexander
- University College London Institute of Liver and Digestive Health, London, UK
| | - Anil Dhawan
- Paediatric Liver, GI and Nutrition Centre and Mowat Labs, King's College Hospital, Denmark Hill, London, UK
| | - James Dooley
- University College London Institute of Liver and Digestive Health, London, UK
| | - Godfrey T Gillett
- Laboratory Medicine, Northern General Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | - Deirdre Kelly
- Liver Unit, Birmingham Women and Children's Hospital, Birmingham, UK
| | | | - Thomas T Warner
- Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, London, UK
| | | | | | - Oliver Bandmann
- Sheffield Institute for Translational Neuroscience (SITraN), Department of Neuroscience, University of Sheffield, UK.
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18
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Lynch EN, Campani C, Innocenti T, Dragoni G, Forte P, Galli A. Practical insights into chronic management of hepatic Wilson’s disease. World J Clin Cases 2022; 10:4334-4347. [PMID: 35663095 PMCID: PMC9125272 DOI: 10.12998/wjcc.v10.i14.4334] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 10/07/2021] [Accepted: 03/26/2022] [Indexed: 02/06/2023] Open
Abstract
Wilson’s disease (WD) is a rare inherited disorder of human copper metabolism, with an estimated prevalence of 1:30000-1:50000 and a broad spectrum of hepatic and neuropsychiatric manifestations. In healthy individuals, the bile is the main route of elimination of copper. In WD patients, copper accumulates in the liver, it is released into the bloodstream, and is excreted in urine. Copper can also be accumulated in the brain, kidneys, heart, and osseous matter and causes damage due to direct toxicity or oxidative stress. Hepatic WD is commonly but not exclusively diagnosed in childhood or young adulthood. Adherent, non-cirrhotic WD patients seem to have a normal life expectancy. Nevertheless, chronic management of patients with Wilson’s disease is challenging, as available biochemical tests have many limitations and do not allow a clear identification of non-compliance, overtreatment, or treatment goals. To provide optimal care, clinicians should have a complete understanding of these limitations and counterbalance them with a thorough clinical assessment. The aim of this review is to provide clinicians with practical tools and suggestions which may answer doubts that can arise during chronic management of patients with hepatic WD. In particular, it summarises current knowledge on Wilson’s disease clinical and biochemical monitoring and treatment. It also analyses available evidence on pregnancy and the role of low-copper diet in WD. Future research should focus on trying to provide new copper metabolism tests which could help to guide treatment adjustments.
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Affiliation(s)
- Erica Nicola Lynch
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
| | - Claudia Campani
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
| | - Tommaso Innocenti
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
| | - Gabriele Dragoni
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
- Department of Medical Biotechnologies, University of Siena, Siena 53100, Italy
| | - Paolo Forte
- Division of Gastroenterology, University Hospital “Careggi”, Florence 50134, Italy
| | - Andrea Galli
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
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Munk DE, Björklund J, Lund Laursen T, Vilstrup H, Ott P, Grønbæk H, Damgaard Sandahl T. The galactose elimination capacity test to monitor liver disease course in patients with Wilson's disease. Scand J Gastroenterol 2022; 57:589-594. [PMID: 34994677 DOI: 10.1080/00365521.2021.2024248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND The prognosis of Wilson's disease (WD) has changed radically since the introduction of medical therapy with chelators and zinc. However, there is an unmet need for methods to evaluate the long-term treatment response and the liver disease progression in order to identify treatment failures. The galactose elimination capacity test (GEC) is a physiological measure of the total metabolic capacity of the liver, and a strong predictor of long- and short-term mortality in patients with liver cirrhosis. Our aim was to investigate if the GEC test is useful for evaluation of treatment response and prediction of treatment failures in WD patients. METHODS We included all patients with WD in Denmark from 1992 through 2017 and retrieved data on GEC along with data on transplantation and death. RESULTS In total, 37 patients had completed one or more GEC tests. Of these, 31 were alive (three transplanted) and six were dead (two transplanted). A total of 24 patients had completed more than one GEC test. All 18 alive, nontransplanted patients showed improvement in GEC values following onset of treatment, except one patient, who was clinically confirmed with treatment failure. All six patients who underwent liver transplantation or died had a prior decline in their GEC. The difference in GEC development between patients alive and not transplanted and patients dead or transplanted was significant (p < .001). Index GEC values could not predict transplantation or death (p = .26). CONCLUSION The GEC test is a promising tool for monitoring treatment response and identifying treatment failures in patients with WD.
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Affiliation(s)
- Ditte Emilie Munk
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N, Denmark
| | - Jessica Björklund
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N, Denmark
| | - Tea Lund Laursen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N, Denmark
| | - Hendrik Vilstrup
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N, Denmark
| | - Peter Ott
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N, Denmark
| | - Henning Grønbæk
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N, Denmark
| | - Thomas Damgaard Sandahl
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N, Denmark
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Plasma neurofilament light chain as a biomarker in Wilson's disease. Parkinsonism Relat Disord 2021; 95:5-10. [PMID: 34942565 DOI: 10.1016/j.parkreldis.2021.12.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 11/27/2021] [Accepted: 12/05/2021] [Indexed: 11/23/2022]
Abstract
INTRODUCTION Neurofilament light chain (NfL) was recently proposed as a promising blood biomarker for nervous system diseases, including Wilson's disease (WD). In this study, we investigated plasma NfL concentrations in patients with different types of WD and their correlations with clinical manifestations and brain atrophy. METHODS Seventy-five WD cases (54 neurological type, 21 hepatic type) and 27 age-matched healthy controls were included in this study. We compared plasma NfL concentrations between the different types and correlated them with Unified Wilson's Disease Rating Scale (UWDRS) scores. Patients were allocated to stable and unstable groups according to changes in UWDRS scores and clinical assessment. We compared the differences in plasma NfL concentrations between groups. Voxel-based morphometry (VBM) and FreeSurfer software were used to analyze MRI images. We investigated the correlation between plasma NfL concentrations and volume of gray matter, white matter, and several areas of interest in the brain MRI of 24 patients. RESULTS Plasma NfL concentrations were significantly higher in neurological type WD than in hepatic type WD (8.16 vs. 3.19 pg/mL, p < 0.001). Plasma NfL concentrations were positively correlated with UWDRS scores (r = 0.291, p = 0.035) in patients with neurological type WD. Plasma NfL was significantly higher in unstable patients than in stable patients (10.74 vs. 7.23 pg/mL, p = 0.004). Significant negative associations were found between plasma NfL level and the volumes of total gray matter, bilateral caudate nucleus, putamen, and nucleus accumbens. CONCLUSION Plasma NfL is valuable as a biomarker for neurological damage in patients with WD.
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21
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Ott P, Ala A, Askari FK, Czlonkowska A, Hilgers R, Poujois A, Roberts EA, Sandahl TD, Weiss KH, Ferenci P, Schilsky ML. Designing Clinical Trials in Wilson's Disease. Hepatology 2021; 74:3460-3471. [PMID: 34320232 PMCID: PMC9291486 DOI: 10.1002/hep.32074] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 06/29/2021] [Accepted: 07/14/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Wilson's disease (WD) is an autosomal-recessive disorder caused by ATP7B gene mutations leading to pathological accumulation of copper in the liver and brain. Adoption of initial treatments for WD was based on empirical observations. These therapies are effective, but there are still unmet needs for which treatment modalities are being developed. An increase of therapeutical trials is anticipated. APPROACH AND RESULTS The first Wilson Disease Aarhus Symposium (May 2019) included a workshop on randomized clinical trial design. The authors of the article were organizers or presented during this workshop, and this article presents their consensus on the design of clinical trials for WD, addressing trial population, treatment comparators, inclusion and exclusion criteria, and treatment endpoints. To achieve adequate recruitment of patients with this rare disorder, the study groups should include all clinical phenotypes and treatment-experienced as well as treatment-naïve patients. CONCLUSIONS The primary study endpoint should be clinical or a composite endpoint until appropriate surrogate endpoints are validated. Standardization of clinical trials will permit pooling of data and allow for better treatment comparisons, as well as reduce the future numbers of patients needed per trial.
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Affiliation(s)
- Peter Ott
- Department of Hepatology and GastroenterologyAarhus UniversityAarhusDenmark
| | - Aftab Ala
- Department of Gastroenterology and HepatologyThe Royal Surrey NHS Foundation TrustGuildfordUnited Kingdom
- Department of Clinical and Experimental MedicineUniversity of SurreyGuildfordUnited Kingdom
- Institute of Liver StudiesKing’s College HospitalLondonUnited Kingdom
| | | | - Anna Czlonkowska
- Second Department of NeurologyInstitute of Psychiatry and NeurologyWarsawPoland
| | | | - Aurélia Poujois
- Neurology Department and National Reference Centre for Wilson’s DiseaseRothschild Foundation HospitalParisFrance
| | - Eve A. Roberts
- Departments of Paediatrics, Medicine, and Pharmacology and ToxicologyUniversity of TorontoTorontoOntarioCanada
| | | | - Karl Heinz Weiss
- Salem Medical CenterHeidelbergGermany
- Department of Internal MedicineIV at University Hospital HeidelbergHeidelbergGermany
| | - Peter Ferenci
- Department of Gastroenterology and HepatologyMedical University of ViennaViennaAustria
| | - Michael L. Schilsky
- Departments of Medicine and SurgeryYale University Medical CenterNew HavenCTUSA
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22
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Sánchez-Monteagudo A, Ripollés E, Berenguer M, Espinós C. Wilson's Disease: Facing the Challenge of Diagnosing a Rare Disease. Biomedicines 2021; 9:1100. [PMID: 34572285 PMCID: PMC8471362 DOI: 10.3390/biomedicines9091100] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 08/20/2021] [Accepted: 08/25/2021] [Indexed: 02/06/2023] Open
Abstract
Wilson disease (WD) is a rare disorder caused by mutations in ATP7B, which leads to the defective biliary excretion of copper. The subsequent gradual accumulation of copper in different organs produces an extremely variable clinical picture, which comprises hepatic, neurological psychiatric, ophthalmological, and other disturbances. WD has a specific treatment, so that early diagnosis is crucial to avoid disease progression and its devastating consequences. The clinical diagnosis is based on the Leipzig score, which considers clinical, histological, biochemical, and genetic data. However, even patients with an initial WD diagnosis based on a high Leipzig score may harbor other conditions that mimic the WD's phenotype (Wilson-like). Many patients are diagnosed using current available methods, but others remain in an uncertain area because of bordering ceruloplasmin levels, inconclusive genetic findings and unclear phenotypes. Currently, the available biomarkers for WD are ceruloplasmin and copper in the liver or in 24 h urine, but they are not solid enough. Therefore, the characterization of biomarkers that allow us to anticipate the evolution of the disease and the monitoring of new drugs is essential to improve its diagnosis and prognosis.
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Affiliation(s)
- Ana Sánchez-Monteagudo
- Rare Neurodegenerative Diseases Laboratory, Centro de Investigación Príncipe Felipe (CIPF), 46012 Valencia, Spain; (A.S.-M.); (E.R.)
- Joint Unit on Rare Diseases CIPF-IIS La Fe, 46012 Valencia, Spain;
| | - Edna Ripollés
- Rare Neurodegenerative Diseases Laboratory, Centro de Investigación Príncipe Felipe (CIPF), 46012 Valencia, Spain; (A.S.-M.); (E.R.)
- Joint Unit on Rare Diseases CIPF-IIS La Fe, 46012 Valencia, Spain;
| | - Marina Berenguer
- Joint Unit on Rare Diseases CIPF-IIS La Fe, 46012 Valencia, Spain;
- Hepatology-Liver Transplantation Unit, Digestive Medicine Service, IIS La Fe and CIBER-EHD, Hospital Universitari i Politècnic La Fe, 46026 Valencia, Spain
- Department of Medicine, Universitat de València, 46010 Valencia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Carmen Espinós
- Rare Neurodegenerative Diseases Laboratory, Centro de Investigación Príncipe Felipe (CIPF), 46012 Valencia, Spain; (A.S.-M.); (E.R.)
- Joint Unit on Rare Diseases CIPF-IIS La Fe, 46012 Valencia, Spain;
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Abstract
OBJECTIVES In Wilson disease (WD), 24-hour urinary copper excretion (UCE) is recommended to be used for diagnosis. It may be a useful tool to assess the efficacy of treatment during follow-up; however, there are limited data regarding the cutoff value of 24-hour UCE during follow-up in children. Therefore, we aim to evaluate the clinical use of 24-hour UCE during follow-up in children with WD. PATIENTS AND METHODS Medical records of children diagnosed with WD at Kings' College Hospital from 2005 to 2018 were retrospectively reviewed. The UCE, serum copper, and ceruloplasmin levels, tested during follow-up, were statistically analyzed. RESULTS Over the median duration of 7 years (range 1.4-14.4), 28 patients (age ranged 3.8-17.3 years) had UCE tests during follow-up. Of those, 21 patients had at least one 24-hour UCE test and 7 children had only spot UCE tests. In comparison with the level of 24-hour UCE collected at the first visit after penicillamine challenge test, the median excretion rate was significantly reduced over the follow-up period (P < 0.001), from 26.2 to 8.9 μmol/day following 1-2 years of therapy (P = 0.15), then reduced significantly to 2.2 μmol/day after 3-4 years (P = 0.009), and 5.6 μmol/day at >5 years of follow-up (P = 0.003). CONCLUSIONS Our study suggests that within 1 year of treatment, the level of nonceruloplasmin-bound copper concentration (NCC) drops to <0.8 μmol/L. In the absence of progressive liver disease or signs of copper deficiency, 24-hour UCE decreases to ≤8 μmol/day and <6 μmol/day after 1 and 5 years of treatment, respectively.
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24
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Leung M, Wu Lanzafame J, Medici V. Switching Pharmacological Treatment in Wilson Disease: Case Report and Recommendations. J Investig Med High Impact Case Rep 2020; 8:2324709619896876. [PMID: 31920114 PMCID: PMC6956597 DOI: 10.1177/2324709619896876] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background. Available treatments for Wilson disease (WD) prevent longterm complications of copper accumulation. Current anti-copper agents include zinc salts, penicillamine, and trientine. Patients with WD may switch between the agents for a number of reasons. Due to the different mechanisms of action between the copper chelators and zinc salts, transitioning could require a period of overlap and increased monitoring. There are no large studies that investigate the best transition strategies between agents. In this article, we review the treatments for WD and how to monitor for treatment efficacy. Case Summary. The patient had been diagnosed with WD for over 20 years prior to establishing care in our Hepatology Clinic. During his initial course, he was transitioned from penicillamine to zinc due to evidence suggesting penicillamine had greater adverse effects in the long term. Later, he was switched to trientine. His liver enzymes and 24-hour urine copper were monitored. During these years, he intermittently had some financial hardship, requiring him to be on penicillamine rather than trientine. He also had developed acute kidney injury. Overall, his liver disease remained under control and he never had signs of decompensated cirrhosis, but had fluctuations of liver enzymes over the years. Conclusion. Anti-copper treatment for WD has to be tailored to medication side effects profile, patient's chronic and emerging comorbidities, as well as costs. Transitioning regimens is often challenging, and it requires closer monitoring, with no predictors of response.
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Affiliation(s)
- Marcia Leung
- University of California Davis, Sacramento, CA, USA
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25
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Abstract
BACKGROUND Wilson's disease, first described by Samuel Wilson in 1912, is an autosomal recessive metabolic disorder resulting from mutations in the ATP7B gene. The disease develops as a consequence of copper accumulating in affected tissues. There is no gold standard for the diagnosis of Wilson's disease, which is often delayed due to the non-specific clinical features and the need for a combination of clinical and laboratory tests for diagnosis. This delay may in turn affect clinical outcome and has implications for other family members in terms of diagnosis. The Leipzig criteria were established to help standardise diagnosis and management. However, it should be emphasised that these criteria date from 2003, and many of these have not been formally evaluated; this review examines the evidence behind biochemical testing for Wilson's disease. OBJECTIVES To determine the diagnostic accuracy of three biochemical tests at specified cut-off levels for Wilson's disease. The index tests covered by this Cochrane Review are caeruloplasmin, 24-hour urinary copper and hepatic copper content. These tests were evaluated in those with suspected Wilson's disease and appropriate controls (either healthy or those with chronic liver disease other than Wilson's). In the absence of a gold standard for diagnosing Wilson's disease, we have used the Leipzig criteria as a clinical reference standard. To investigate whether index tests should be performed in all individuals who have been recommended for testing for Wilson's disease, or whether these tests should be limited to subgroups of individuals. SEARCH METHODS We identified studies by extensive searching of, e.g. the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Embase, the Web of Science and clinical trial registries (29 May 2019). Date of the most recent search of the Cochrane Cystic Fibrosis and Genetic Disorders Inborn Errors of Metabolism Register: 29 May 2019. SELECTION CRITERIA We included prospective and retrospective cohort studies that assessed the diagnostic accuracy of an index test using the Leipzig criteria as a clinical reference standard for the diagnosis of Wilson's disease. DATA COLLECTION AND ANALYSIS Two review authors independently reviewed and extracted data and assessed the methodological quality of each included study using the QUADAS-2 tool. We had planned to undertake meta-analyses of the sensitivity, specificity at relevant cut-offs for each of the biochemical tests for Wilson's, however, due to differences in the methods used for each biochemical index test, it was not possible to combine the results in meta-analyses and hence these are described narratively. MAIN RESULTS Eight studies, involving 5699 participants (which included 1009 diagnosed with Wilson's disease) were eligible for inclusion in the review. Three studies involved children only, one adults only and the four remaining studies involved both children and adults. Two evaluated participants with hepatic signs and six with a combination of hepatic and neurological signs and symptoms of Wilson's disease, as well as pre-symptomatic individuals. The studies were of variable methodological quality; with high risk if bias for participant selection and the reference standard used being of greatest methodological concern. Key differences between studies include differences in assay methodology, different cut-off values for diagnostic thresholds, different age and ethnicity groups. Concerns around study design imply that diagnostic accuracy figures may not transfer to populations outside of the relevant study. INDEX TEST caeruloplasmin Five studies evaluated various thresholds of caeruloplasmin (4281 participants, of which 541 had WD). For caeruloplasmin a cut-off of 0.2 g/L as in the Leipzig criteria achieved a sensitivity of 77.1% to 99%, with variable specificity of 55.9% to 82.8%. Using the cut-off of 0.1 g/L of the Leipzig criteria seemed to lower the sensitivity overall, 65% to 78.9%, while increasing the specificity to 96.6% to 100%. INDEX TEST hepatic copper Four studies evaluated various thresholds of hepatic copper (1150 participants, of which 367 had WD). The hepatic copper cut-off of 4 μmol/g used in the Leipzig criteria achieved a sensitivity of 65.7% to 94.4%, with a variable specificity of 52.2% to 98.6%. INDEX TEST 24-hour urinary copper Three studies evaluated various thresholds of 24-hour urinary copper (268 participants, of which 101 had WD). For 24-hour urinary copper, a cut-off of 0.64 to 1.6 μmol/24 hours used in the Leipzig criteria achieved a variable sensitivity of 50.0% to 80.0%, with a specificity of 75.6% to 98.3%. AUTHORS' CONCLUSIONS The cut-offs used for caeruloplasmin, 24-hour urinary copper and hepatic copper for diagnosing Wilson's disease are method-dependent and require validation in the population in which such index tests are going to be used. Binary cut-offs and use of single-test strategies to rule Wilson's disease in or out is not supported by the evidence in this review. There is insufficient evidence to inform testing in specific subgroups, defined by age, ethnicity or clinical subgroups.
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Affiliation(s)
- Aidan Ryan
- University Hospital Southampton NHS Foundation TrustDepartment of Clinical Biochemistry17 Tremona RoadSouthamptonUKSO16 6YD
| | - Sarah J Nevitt
- University of LiverpoolDepartment of BiostatisticsBlock F, Waterhouse Building1‐5 Brownlow HillLiverpoolUKL69 3GL
| | - Orla Tuohy
- University Hospital SouthamptonWessex Neurological CentreSouthamptonUK
| | - Paul Cook
- University Hospital Southampton NHS Foundation TrustDepartment of Clinical Biochemistry17 Tremona RoadSouthamptonUKSO16 6YD
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26
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Abstract
Wilson disease (WD) is an autosomal recessively-inherited disorder of copper metabolism and characterised by a pathological accumulation of copper. The ATP7B gene encodes for a transmembrane copper transporter essential for biliary copper excretion. Depending on time of diagnosis, severity of disease can vary widely. Almost all patients show evidence of progressive liver disease. Neurological impairments or psychiatric symptoms are common in WD patients not diagnosed during adolescence. WD is a treatable disorder, and early treatment can prevent the development of symptoms in patients diagnosed while still asymptomatic. This is why the early diagnosis of WD is crucial. The diagnosis is based on clinical symptoms, abnormal measures of copper metabolism and DNA analysis. Available treatment includes chelators and zinc salts which increase copper excretion and reduce copper uptake. In severe cases, liver transplantation is indicated and accomplishes a phenotypic correction of the hepatic gene defect. Recently, clinical development of the new copper modulating agent tetrathiomolybdate has started and direct genetic therapies are being tested in animal models. The following review focuses especially on biochemical markers and how they can be utilised in diagnosis and drug monitoring.
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