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Choi W, Cha S, Kim K. Navigating the CRISPR/Cas Landscape for Enhanced Diagnosis and Treatment of Wilson's Disease. Cells 2024; 13:1214. [PMID: 39056796 PMCID: PMC11274827 DOI: 10.3390/cells13141214] [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: 05/27/2024] [Revised: 07/15/2024] [Accepted: 07/17/2024] [Indexed: 07/28/2024] Open
Abstract
The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (Cas) system continues to evolve, thereby enabling more precise detection and repair of mutagenesis. The development of CRISPR/Cas-based diagnosis holds promise for high-throughput, cost-effective, and portable nucleic acid screening and genetic disease diagnosis. In addition, advancements in transportation strategies such as adeno-associated virus (AAV), lentiviral vectors, nanoparticles, and virus-like vectors (VLPs) offer synergistic insights for gene therapeutics in vivo. Wilson's disease (WD), a copper metabolism disorder, is primarily caused by mutations in the ATPase copper transporting beta (ATP7B) gene. The condition is associated with the accumulation of copper in the body, leading to irreversible damage to various organs, including the liver, nervous system, kidneys, and eyes. However, the heterogeneous nature and individualized presentation of physical and neurological symptoms in WD patients pose significant challenges to accurate diagnosis. Furthermore, patients must consume copper-chelating medication throughout their lifetime. Herein, we provide a detailed description of WD and review the application of novel CRISPR-based strategies for its diagnosis and treatment, along with the challenges that need to be overcome.
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Affiliation(s)
- Woong Choi
- Department of Physiology, Korea University College of Medicine, Seoul 02841, Republic of Korea;
| | - Seongkwang Cha
- Department of Physiology, Korea University College of Medicine, Seoul 02841, Republic of Korea;
- Neuroscience Research Institute, Korea University College of Medicine, Seoul 02841, Republic of Korea
| | - Kyoungmi Kim
- Department of Physiology, Korea University College of Medicine, Seoul 02841, Republic of Korea;
- Department of Biomedical Sciences, Korea University College of Medicine, Seoul 02841, Republic of Korea
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Panda K, Lal BB, Sood V, Khanna R, Alam S. Relapse following withdrawal of D-penicillamine from combination (D-penicillamine + zinc) therapy in hepatic Wilson disease. J Pediatr Gastroenterol Nutr 2024; 78:1017-1026. [PMID: 38695602 DOI: 10.1002/jpn3.12128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Revised: 12/11/2023] [Accepted: 12/24/2023] [Indexed: 06/16/2024]
Abstract
OBJECTIVES Long-term D-penicillamine (D-pen) therapy in Wilson disease (WD) has numerous adverse effects which advocates its withdrawal, but with an inherent risk of relapse. This prospective observational study was conducted with the objective of evaluating incidence of relapse following withdrawal of D-pen from combination (D-pen + zinc) therapy in maintenance phase of previously symptomatic hepatic WD. METHODS Hepatic WD patients <18 years of age and on combination therapy for >2 years with 6 months of biochemical remission were included. Biochemical remission was defined as achievement of (i) aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤1.5 times upper limit of normal (ULN), (ii) serum albumin >3.5 g/dL, international normalized ratio (INR) <1.5 and (iii) 24-h urinary copper excretion (UCE) <500 mcg/day, nonceruloplasmin-bound-copper (NCC) <15 mcg/dL. After D-pen withdrawal, monthly liver function test (LFT) and INR and 3 monthly UCE and NCC were done till 1 year or relapse (elevation of AST/ALT/both >2 times ULN or total bilirubin >2 mg/dL), whichever occurred earlier. RESULTS Forty-five patients enrolled with median combination therapy duration of 36 months. Sixty percent of them had their index presentation as decompensated cirrhosis. Fourteen patients (31.8%) relapsed (cumulative incidence: 4 at 3 months, 11 at 6 months, and 14 at 12 months after D-pen discontinuation). All relapsers had index presentation as decompensated cirrhosis. On Cox-regression, ALT at D-pen withdrawal was an independent predictor of relapse (hazard ratio [HR]: 1.077, 95% confidence interval [CI]: 1.014-1.145, p = 0.017) with area under the receiver operating characteristic (AUROC) of 0.860. ALT ≥40 U/L predicted risk of relapse with 85.7% sensitivity, 70.9% specificity. CONCLUSION Incidence of relapse after withdrawal of D-pen from combination therapy is 31.8% in hepatic WD. ALT ≥40 U/L, at the time of D-pen stoppage, predicts future relapse.
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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. Relapse following withdrawal of D‐penicillamine from combination (D‐penicillamine + zinc) therapy in hepatic Wilson disease. J Pediatr Gastroenterol Nutr 2024; 78:1017-1026. [DOI: https:/doi.org/10.1002/jpn3.12128] [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] [Indexed: 04/16/2025]
Abstract
AbstractObjectivesLong‐term D‐penicillamine (D‐pen) therapy in Wilson disease (WD) has numerous adverse effects which advocates its withdrawal, but with an inherent risk of relapse. This prospective observational study was conducted with the objective of evaluating incidence of relapse following withdrawal of D‐pen from combination (D‐pen + zinc) therapy in maintenance phase of previously symptomatic hepatic WD.MethodsHepatic WD patients <18 years of age and on combination therapy for >2 years with 6 months of biochemical remission were included. Biochemical remission was defined as achievement of (i) aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤1.5 times upper limit of normal (ULN), (ii) serum albumin >3.5 g/dL, international normalized ratio (INR) <1.5 and (iii) 24‐h urinary copper excretion (UCE) <500 mcg/day, nonceruloplasmin‐bound‐copper (NCC) <15 mcg/dL. After D‐pen withdrawal, monthly liver function test (LFT) and INR and 3 monthly UCE and NCC were done till 1 year or relapse (elevation of AST/ALT/both >2 times ULN or total bilirubin >2 mg/dL), whichever occurred earlier.ResultsForty‐five patients enrolled with median combination therapy duration of 36 months. Sixty percent of them had their index presentation as decompensated cirrhosis. Fourteen patients (31.8%) relapsed (cumulative incidence: 4 at 3 months, 11 at 6 months, and 14 at 12 months after D‐pen discontinuation). All relapsers had index presentation as decompensated cirrhosis. On Cox‐regression, ALT at D‐pen withdrawal was an independent predictor of relapse (hazard ratio [HR]: 1.077, 95% confidence interval [CI]: 1.014–1.145, p = 0.017) with area under the receiver operating characteristic (AUROC) of 0.860. ALT ≥40 U/L predicted risk of relapse with 85.7% sensitivity, 70.9% specificity.ConclusionIncidence of relapse after withdrawal of D‐pen from combination therapy is 31.8% in hepatic WD. ALT ≥40 U/L, at the time of D‐pen stoppage, predicts future relapse.
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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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Mahale RR, Stezin A, Prasad S, Kamble N, Holla VV, Netravathi M, Yadav R, Pal PK. Clinical Spectrum, Radiological Correlation and Outcome of Movement Disorders in Wilson's Disease. Tremor Other Hyperkinet Mov (N Y) 2023; 13:37. [PMID: 37840995 PMCID: PMC10573579 DOI: 10.5334/tohm.794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Accepted: 09/21/2023] [Indexed: 10/17/2023] Open
Abstract
Introduction Movement disorders are the commonest clinical presentation in patients with neurological Wilson's disease (NWD). There are very few studies evaluating the spectrum, severity and their correlation with magnetic resonance imaging (MRI) changes of movement disorders in NWD. Objective To study the spectrum, topographic distribution, radiological correlate, temporal course and outcome in our cohort of NWD patients. Methods Retrospective chart review of the NWD patients having movement disorders was performed and analyzed. Results Sixty-nine patients (males- 47) with NWD were analysed and the mean age at the onset of neurological symptoms was 13.6 ± 6.6 years (median 13 years; range 7-37 years). The first neurological symptom was movement disorder in 55 (79.7%) patients. Tremor (43.6%) and dystonia (41.8%) was the commonest movement disorder as the first neurological symptom. Dystonia (76.8%) was the most common overall movement disorder followed by parkinsonism (52.1%) and tremors (47.8%). Chorea (10.1%), myoclonus (1.4%) and ataxia (1.4%) were the least common movement disorder. Putamen was the most common affected site (95.6%) followed by caudate nucleus (73.9%), thalamus (60.8%), midbrain (59.4%), internal capsule (49.2%), pons (46.3%). Putamen was the most common area of abnormality in dystonia (98%), tremors (85%). Caudate (75%) and putamen (75%) was the most common areas of abnormality in parkinsonism. Favourable outcome was observed in 42 patients (60.8%) following treatment. Conclusion Dystonia is the most common movement disorder in NWD in isolation or in combination with parkinsonism and tremors. Putamen is the most common radiological site of lesions and more frequently affected in patients with dystonia and tremors. Favourable outcome does occur with appropriate medical and surgical treatment.
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Affiliation(s)
- Rohan R. Mahale
- Department of Neurology, National Institute of Mental Health and Neuro Sciences, Bengaluru, India
| | - Albert Stezin
- Department of Neurology, National Institute of Mental Health and Neuro Sciences, Bengaluru, India
- Department of Clinical Neurosciences, National Institute of Mental Health and Neuro Sciences, Bengaluru, India
| | - Shweta Prasad
- Department of Neurology, National Institute of Mental Health and Neuro Sciences, Bengaluru, India
- Department of Clinical Neurosciences, National Institute of Mental Health and Neuro Sciences, Bengaluru, India
| | - Nitish Kamble
- Department of Neurology, National Institute of Mental Health and Neuro Sciences, Bengaluru, India
| | - Vikram V. Holla
- Department of Neurology, National Institute of Mental Health and Neuro Sciences, Bengaluru, India
| | - Manjunath Netravathi
- Department of Neurology, National Institute of Mental Health and Neuro Sciences, Bengaluru, India
| | - Ravi Yadav
- Department of Neurology, National Institute of Mental Health and Neuro Sciences, Bengaluru, India
| | - Pramod Kumar Pal
- Department of Neurology, National Institute of Mental Health and Neuro Sciences, Bengaluru, India
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Litwin T, Antos A, Bembenek J, Przybyłkowski A, Kurkowska-Jastrzębska I, Skowrońska M, Członkowska A. Copper Deficiency as Wilson's Disease Overtreatment: A Systematic Review. Diagnostics (Basel) 2023; 13:2424. [PMID: 37510170 PMCID: PMC10377829 DOI: 10.3390/diagnostics13142424] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 07/11/2023] [Accepted: 07/16/2023] [Indexed: 07/30/2023] Open
Abstract
BACKGROUND Treatment of Wilson's disease (WD), an inherited disease characterized by copper overload, is lifelong and there is the possibility that copper deficiency (CD) may occur. We systematically reviewed the literature to describe treatment patterns, symptoms and outcomes associated with CD. METHODS Using preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines, the PubMed database was searched up to 6 April 2023. RESULTS Across 17 articles, 20 cases of CD were described, most commonly (15 cases) in WD patients treated with zinc salts (ZS), less often on combined chelator and ZS therapy (3 cases), molybdate salts plus ZS (1), or molybdate alone (1). CD symptoms occurred insidiously, including sideroblastic anemia, neutropenia, axonal sensory neuropathy, posterior cord myelopathy and increased ratio of epileptic seizures (or epilepsy). CD diagnosis was based on symptoms and severely reduced urinary copper excretion (<20 µg/24 h [<0.3 µmol/24 h] on ZS, or <100 µg/24 h [<1.6 µmol/24 h] on chelators) with low total serum copper and ceruloplasmin. CONCLUSIONS Awareness of CD and regular monitoring of copper metabolism is needed during WD treatment. Temporary cessation of anti-copper treatment usually reverses serum copper reductions as well as pancytopenia; however, some symptoms, especially neuropathy and myelopathy, may persist.
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Affiliation(s)
- Tomasz Litwin
- Second Department of Neurology, Institute of Psychiatry and Neurology, 02-957 Warsaw, Poland
| | - Agnieszka Antos
- Second Department of Neurology, Institute of Psychiatry and Neurology, 02-957 Warsaw, Poland
| | - Jan Bembenek
- Department of Clinical Neurophysiology, Institute of Psychiatry and Neurology, 02-957 Warsaw, Poland
| | - Adam Przybyłkowski
- Department of Gastroenterology and Internal Medicine, Medical University of Warsaw, 02-091 Warsaw, Poland
| | | | - Marta Skowrońska
- Second Department of Neurology, Institute of Psychiatry and Neurology, 02-957 Warsaw, Poland
| | - Anna Członkowska
- Second Department of Neurology, Institute of Psychiatry and Neurology, 02-957 Warsaw, Poland
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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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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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Munk DE, Lund Laursen T, Teicher Kirk F, Vilstrup H, Ala A, Gormsen LC, Ott P, Damgaard Sandahl T. Effect of oral zinc regimens on human hepatic copper content: a randomized intervention study. Sci Rep 2022; 12:14714. [PMID: 36038585 PMCID: PMC9424214 DOI: 10.1038/s41598-022-18872-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 08/22/2022] [Indexed: 11/26/2022] Open
Abstract
Zinc inhibits intestinal copper uptake, an effect utilized for treating Wilson’s disease (WD). We used copper-64 (64Cu) PET/CT to examine how much four weeks of treatment with different zinc regimens reduced the hepatic 64Cu content after oral 64Cu administration and test if alternative regimens were noninferior to the standard regimen of zinc acetate 50 mg × 3 daily. Forty healthy persons were randomized to four different zinc protocols. The WD standard treatment zinc acetate 50 mg × 3 reduced the hepatic 64Cu content from 26.9 ± 7.5% to 13.3 ± 5.6% of the administered 64Cu. Zinc gluconate 50 mg × 3 was noninferior (P = 0.02) (35.8 ± 9.0% to 17.4 ± 7.5%). Zinc acetate 150 mg × 1 (33.1 ± 9.9% to 17.4 ± 7.5%) and zinc gluconate 150 mg × 1 (28.1 ± 6.7% to 22.0 ± 6.7%) were less effective. These effects were intra- and inter-individually highly variable, and 14% had no effect of any zinc regimen, which may explain disparities in zinc treatment efficacy in WD patients.
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Affiliation(s)
- Ditte Emilie Munk
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus N, Denmark.
| | - Tea Lund Laursen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus N, Denmark
| | - Frederik Teicher Kirk
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus N, Denmark
| | - Hendrik Vilstrup
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus N, Denmark
| | - Aftab Ala
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, Denmark Hill, London, UK
| | - Lars Christian Gormsen
- Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus, Denmark
| | - Peter Ott
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus N, Denmark
| | - Thomas Damgaard Sandahl
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus N, Denmark
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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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Tang S, Bai L, Hou W, Hu Z, Chen X, Zhao J, Liang C, Zhang W, Duan Z, Zheng S. Comparison of the Effectiveness and Safety of d-Penicillamine and Zinc Salt Treatment for Symptomatic Wilson Disease: A Systematic Review and Meta-Analysis. Front Pharmacol 2022; 13:847436. [PMID: 35370752 PMCID: PMC8975209 DOI: 10.3389/fphar.2022.847436] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Accepted: 01/31/2022] [Indexed: 12/21/2022] Open
Abstract
Background: Pharmacological therapy is currently the main treatment method for patients with Wilson disease (WD). We aimed to evaluate the efficacy and safety of the common treatment regimens in these patients. Methods: We conducted a systemic review and meta-analysis by searching multiple databases for studies from inception to October 2021. Outcomes of interest were the improved rate and safety of d-penicillamine and zinc salts treatment in WD patients. Two independent reviewers performed the study selection and data extraction. Results: Sixteen studies were included in this meta-analysis. The pooled improved rate for all included symptomatic WD patients was 78.0% (95% CI: 70.8%-85.2%). In symptomatic hepatic WD patients, there is no difference in the treatment efficiency of d-penicillamine and zinc salts (RR: 0.98, 95% CI: 0.86%-1.12%; p = 0.765). In neurological WD patients, the pooled improved rate of those who received d-penicillamine and zinc salts was 56.3% (95% CI: 37.5%-75.1%) and 80.2% (95% CI: 67.2%-93.2%), respectively. The incidence of adverse effects (RR: 2.42, 95% CI: 1.20%-4.88%; p = 0.014) and neurological deterioration (RR: 1.96, 95% CI: 1.31%-2.93%; p = 0.001) in all symptomatic WD patients treated with d-penicillamine was both higher than that of patients treated with zinc salts. Conclusion: Our analysis suggests that symptomatic WD patients treated with d-penicillamine have higher incidence of adverse effects and neurological deterioration than that of zinc salts. The therapeutic effectiveness of these two regimens does not seem to be significantly different, and these results must be interpreted with caution. Systematic Review Registration: PROSPERO registration, identifier CRD 42021287126.
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Affiliation(s)
- Shan Tang
- The First Unit, Department of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Li Bai
- The Fourth Unit, Department of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing, China
| | - Wei Hou
- The First Unit, Department of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Zhongjie Hu
- The First Unit, Department of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Xinyue Chen
- The First Unit, Department of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Jing Zhao
- The First Unit, Department of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Chen Liang
- The First Unit, Department of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Wei Zhang
- The First Unit, Department of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Zhongping Duan
- The Fourth Unit, Department of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Sujun Zheng
- The First Unit, Department of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China
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Kumar S, Patra BR, Irtaza M, Rao PK, Giri S, Darak H, Gopan A, Kale A, Shukla A. Adverse Events with D-penicillamine Therapy in Hepatic Wilson's Disease: A Single-Center Retrospective Audit. Clin Drug Investig 2022; 42:177-184. [PMID: 35102516 DOI: 10.1007/s40261-022-01117-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/12/2022] [Indexed: 12/22/2022]
Abstract
UNLABELLED BACKGROUND AND OBJECTIVE: There are limited data on the adverse events of D-penicillamine in Wilson's disease (WD) that can result in dose modification or treatment discontinuation. The objective of this study was to observe the adverse events related to D-penicillamine in patients with hepatic WD. METHODS A retrospective audit of prospectively registered hepatic WD patients at a tertiary care center between December 2006 and January 2020 was carried out. Demographic variables, laboratory parameters, and details of treatment were noted. Adverse events (AEs) related to D-penicillamine treatment, the timing and management of these AEs were analysed. RESULTS The study included 112 patients with hepatic WD on D-penicillamine. D-penicillamine intolerance was seen in 28/112 (25%) over 179 person-years. Of the 28 AEs, severe AEs leading to permanent D-penicillamine discontinuation occurred in 16 (57%) [never reintroduced 12 (43%), discontinued after intolerant to rechallenge, 4 (14%)], temporary cessation followed by reintroduction to initial dose 13 (46%) and continuation with reduced dose in 3 (11%) patients. Overall, most common AEs were hematological [16, 57% (pancytopenia n = 8, bicytopenia n = 5 and hemolytic anemia n = 3)] while renal adverse events (n = 7, 25%) constituted the most common indication for permanent discontinuation. Cytopenias developed beyond 12 months of D-penicillamine initiation whereas hemolytic anemia developed within first 3 months. Following D-penicillamine discontinuation in 25 patients, it was reintroduced to initial dose in 13/25 (52%), switched to trientine due to neurological worsening in 2/25 (8%) and switched to zinc in 10/25 (40%). In patients with reintroduction, gradual dose escalation was tolerated in 9/13 (69%) with a recurrence of AEs leading to permanent discontinuation in 4/13 (31%). CONCLUSION D-penicillamine treatment is associated with significant AEs mainly related to blood, kidney, and skin. Temporary cessation of drug with reintroduction at a lower dose is an effective and safe option.
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Affiliation(s)
- Sanjay Kumar
- Department of Gastroenterology, Seth GS Medical College and KEM Hospital, Gastroenterology office, 9th floor, New Building, Parel, Mumbai, 400012, India
| | - Biswa Ranjan Patra
- Department of Gastroenterology, Seth GS Medical College and KEM Hospital, Gastroenterology office, 9th floor, New Building, Parel, Mumbai, 400012, India
| | - Mohammed Irtaza
- Department of Gastroenterology, Seth GS Medical College and KEM Hospital, Gastroenterology office, 9th floor, New Building, Parel, Mumbai, 400012, India
| | - Praveen Kumar Rao
- Department of Gastroenterology, Seth GS Medical College and KEM Hospital, Gastroenterology office, 9th floor, New Building, Parel, Mumbai, 400012, India
| | - Suprabhat Giri
- Department of Gastroenterology, Seth GS Medical College and KEM Hospital, Gastroenterology office, 9th floor, New Building, Parel, Mumbai, 400012, India
| | - Harish Darak
- Department of Gastroenterology, Seth GS Medical College and KEM Hospital, Gastroenterology office, 9th floor, New Building, Parel, Mumbai, 400012, India
| | - Amrit Gopan
- Department of Gastroenterology, Seth GS Medical College and KEM Hospital, Gastroenterology office, 9th floor, New Building, Parel, Mumbai, 400012, India
| | - Aditya Kale
- Department of Gastroenterology, Seth GS Medical College and KEM Hospital, Gastroenterology office, 9th floor, New Building, Parel, Mumbai, 400012, India
| | - Akash Shukla
- Department of Gastroenterology, Seth GS Medical College and KEM Hospital, Gastroenterology office, 9th floor, New Building, Parel, Mumbai, 400012, India.
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12
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Yoshioka H, Tominaga S, Suzui M, Shinohara Y, Maeda T, Miura N. Involvement of <i>Npas2</i> and <i>Per2</i> modifications in zinc-induced acute diurnal toxicity in mice. J Toxicol Sci 2022; 47:547-553. [DOI: 10.2131/jts.47.547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022]
Affiliation(s)
| | - Sarah Tominaga
- Department of Neurotoxicology, Nagoya City University Graduate School of Medical Sciences
| | - Masumi Suzui
- Department of Neurotoxicology, Nagoya City University Graduate School of Medical Sciences
| | | | - Tohru Maeda
- Department of Pharmacy, Kinjo Gakuin University
| | - Nobuhiko Miura
- Department of Health Science, Yokohoma University of Pharmacy
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13
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Schroeder SM, Matsukuma KE, Medici V. Wilson disease and the differential diagnosis of its hepatic manifestations: a narrative review of clinical, laboratory, and liver histological features. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1394. [PMID: 34733946 PMCID: PMC8506558 DOI: 10.21037/atm-21-2264] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 07/25/2021] [Indexed: 01/05/2023]
Abstract
Objective The goal of the present work is to provide an overview of the differential diagnosis of Wilson disease. Background Wilson disease is a rare condition due to copper accumulation primarily in the liver and brain. Although there is no definitive cure, current anti-copper treatments are associated with better outcomes if initiated early and if the diagnosis is made promptly. However, diagnostic delays are frequent and often Wilson disease represents a diagnostic challenge. The diagnosis ultimately relies on a combination of clinical, laboratory and genetic findings, and it is crucial that clinicians list Wilson disease in their differential diagnosis, especially in patients presenting with a hepatocellular pattern of liver injury. Some biochemical and liver histological features of Wilson disease overlap with those of more common conditions including nonalcoholic fatty liver disease, alcohol-associated liver disease, and autoimmune hepatitis. In particular, hepatic steatosis, hepatocyte glycogenated nuclei, ballooning degeneration, and Mallory-Denk bodies are often identified in Wilson disease as well as more common liver diseases. In addition, the natural history of liver damage in Wilson disease and the risk of developing liver cancer are largely understudied. Methods We conducted an enlarged review of published papers on Wilson disease focusing on its diagnosis and distinctive clinical and liver pathology features in relation to common non-cholestatic liver diseases with the final goal in aiding clinicians in the diagnostic process of this rare but treatable condition. Conclusions Aside from markedly altered copper metabolism, Wilson disease has essentially no pathognomonic features that can distinguish it from more common liver diseases. Clinicians should be aware of this challenge and consider Wilson disease in patients presenting with a hepatocellular pattern of liver injury.
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Affiliation(s)
- Shannon M Schroeder
- Department of Internal Medicine, University of California Davis, Sacramento, CA, USA
| | - Karen E Matsukuma
- Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, CA, USA
| | - Valentina Medici
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of California Davis, Sacramento, CA, USA
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14
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Zinc monotherapy for young patients with oligosymptomatic Wilson disease: A single center, retrospective study. Clin Res Hepatol Gastroenterol 2021; 45:101623. [PMID: 33662781 DOI: 10.1016/j.clinre.2021.101623] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 12/24/2020] [Accepted: 12/29/2020] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS Few studies have focused on the treatment failure of zinc monotherapy for oligosymptomatic Wilson disease (WD) patients. Therefore, we aimed to evaluate the long-term efficacy of zinc monotherapy in oligosymptomatic patients and to analyze the possible factors that may influence the outcome of this treatment. METHODS We retrospectively reviewed the medical records of oligosymptomatic WD patients who received zinc monotherapy from the time of diagnosis. Then, the characteristics of patients who were treated with zinc monotherapy successfully and those who experienced treatment failure were investigated. RESULTS Forty oligosymptomatic WD patients were identified that have received zinc monotherapy as initial treatment, with a median age of 3.83 years at the time of diagnosis. 36 (90%) patients had abnormal alanine transaminase/aspartate transaminase levels at baseline. None of the patients became symptomatic during zinc monotherapy. 28 (70%, Group 1) patients were treated with zinc monotherapy successfully for a median period of 2.4 years. In Group 1, serum aminotransferase levels significantly decreased 6 and 12 months after zinc therapy compared to the baseline levels (P < 0.05). 12 (30%, Group 2) patients experienced treatment failure with zinc monotherapy due to uncontrolled serum liver enzyme levels, and d-penicillamine was combined. The baseline 24-hour urine copper levels before treatment were significantly higher in Group 2 compared to that in Group 1 (182.5 vs 90.92 μg /day, P = 0.018). Comparing the age at onset; ceruloplasmin, serum copper, ALT, and AST levels; and proportions of abdominal ultrasonography abnormality at baseline between Group 1 and 2 revealed no statistically significant differences. CONCLUSIONS We found that high initial 24 -h urinary copper levels may lead to treatment failure of zinc monotherapy in oligosymptomatic WD patients. It might be reasonable to follow up liver function tests more closely during zinc monotherapy and to begin combination treatment with chelators early in patients with high level of 24 -h urinary copper.
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15
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Considerations for optimizing Wilson's disease patients' long-term follow-up. GASTROENTEROLOGIA Y HEPATOLOGIA 2021; 45:146-154. [PMID: 34052403 DOI: 10.1016/j.gastrohep.2021.03.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 03/18/2021] [Accepted: 03/29/2021] [Indexed: 11/23/2022]
Abstract
Wilson's disease is a sistemic genetic disease caused by the excessive accumulation of copper. The first and main involvement is in the liver, which can range from mild and transient elevation of transaminases to the onset of an overt cirrhosis or acute liver failure. It is known that up to 20-30% of these patients may evolve to liver cirrhosis during follow-up. In clinical practice, liver fibrosis is assessed mainly by using indirect and non-invasive tools (laboratory tests, liver elastography, ultrasound), similar to other prevalent chronic liver diseases. However, despite the fact that liver elastography is a valuable tool in general hepatology, the evidence of its usefulness and accuracy in Wilsońs disease is scarce. This review summarizes the available scientific data and their limitations in Wilson's disease.
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16
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Copper Toxicity Is Not Just Oxidative Damage: Zinc Systems and Insight from Wilson Disease. Biomedicines 2021; 9:biomedicines9030316. [PMID: 33804693 PMCID: PMC8003939 DOI: 10.3390/biomedicines9030316] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 03/13/2021] [Accepted: 03/17/2021] [Indexed: 12/13/2022] Open
Abstract
Essential metals such as copper (Cu) and zinc (Zn) are important cofactors in diverse cellular processes, while metal imbalance may impact or be altered by disease state. Cu is essential for aerobic life with significant functions in oxidation-reduction catalysis. This redox reactivity requires precise intracellular handling and molecular-to-organismal levels of homeostatic control. As the central organ of Cu homeostasis in vertebrates, the liver has long been associated with Cu storage disorders including Wilson Disease (WD) (heritable human Cu toxicosis), Idiopathic Copper Toxicosis and Endemic Tyrolean Infantile Cirrhosis. Cu imbalance is also associated with chronic liver diseases that arise from hepatitis viral infection or other liver injury. The labile redox characteristic of Cu is often discussed as a primary mechanism of Cu toxicity. However, work emerging largely from the study of WD models suggests that Cu toxicity may have specific biochemical consequences that are not directly attributable to redox activity. This work reviews Cu toxicity with a focus on the liver and proposes that Cu accumulation specifically impacts Zn-dependent processes. The prospect that Cu toxicity has specific biochemical impacts that are not entirely attributable to redox may promote further inquiry into Cu toxicity in WD and other Cu-associated disorders.
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17
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Tamai Y, Iwasa M, Eguchi A, Shigefuku R, Sugimoto K, Hasegawa H, Takei Y. Serum copper, zinc and metallothionein serve as potential biomarkers for hepatocellular carcinoma. PLoS One 2020; 15:e0237370. [PMID: 32857769 PMCID: PMC7455040 DOI: 10.1371/journal.pone.0237370] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 07/23/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Copper (Cu) and zinc (Zn) are essential nutrients and cofactors of enzymatic reactions with their binding partner. Metallothionein (MT) plays an important role in protecting against heavy metals and oxidative injury, however it may also portend drug resistance and a worse prognosis for hepatocellular carcinoma (HCC) patients. The aim of this study was to determine the amount of Cu, Zn, Cu/Zn and MT in evaluating a group of patients with HCC, including those treated with lenvatinib. METHODS We enrolled 175 patients with HCC (139 men, 36 women; mean age 71.1 years; hepatitis C virus n = 85, hepatitis B virus n = 19, hepatitis C virus and hepatitis B virus n = 2, non-alcoholic steatohepatitis n = 39, alcohol n = 25, others n = 5; Child-Pugh A n = 141, Child-Pugh B n = 30, Child-Pugh C n = 4; Barcelona clinic liver cancer (BCLC) stage 0 n = 38, stage A n = 56, stage B n = 39, stage C n = 38, stage D n = 4). We evaluated the associations between Cu, Zn and MT. The study outcome was liver cancer-specific survival. Moreover, we treated 12 HCC patients with lenvatinib and investigated the changes in MT during lenvatinib therapy. RESULTS The serum level of Cu was positively correlated with alanine aminotransferase and the BCLC stage. The serum level of Zn decreased concordant with liver disease progression. Patients with a Cu/Zn ratio≥0.999 had significantly improved rates of survival when compared to patients with a Cu/Zn ratio<0.999 (45.3 vs. 30.1 months, p<0.001). MT was significantly correlated with the Cu/Zn ratio and increased after the administration of lenvatinib. Using multivariate Cox regression analyses, it was determined that the Cu/Zn ratio (hazard ratio [HR]: 1.442, p = 0.008), alpha-fetoprotein (HR: 1.000, p<0.001) and BCLC stage (HR: 2.087, p<0.001) were independent predictors of survival. CONCLUSIONS The Cu/Zn ratio could serve as a useful predictive marker for survival in cases of HCC. MT levels increased in HCC patients receiving lenvatinib therapy, and maybe a predictor of reduced survival.
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Affiliation(s)
- Yasuyuki Tamai
- Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, Mie, Japan
- * E-mail:
| | - Motoh Iwasa
- Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, Mie, Japan
| | - Akiko Eguchi
- Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, Mie, Japan
| | - Ryuta Shigefuku
- Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, Mie, Japan
| | - Kazushi Sugimoto
- Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, Mie, Japan
| | - Hiroshi Hasegawa
- Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, Mie, Japan
| | - Yoshiyuki Takei
- Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, Mie, Japan
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18
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Zhang J, Xiao L, Yang W. Combined sodium Dimercaptopropanesulfonate and zinc versus D-penicillamine as first-line therapy for neurological Wilson's disease. BMC Neurol 2020; 20:255. [PMID: 32593295 PMCID: PMC7320536 DOI: 10.1186/s12883-020-01827-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Accepted: 06/10/2020] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Even though recent research has achieved significant advancement in the development of therapeutic approaches for Wilson's diseases (WD), the current treatment options available for WD are still limited, especially for WD patients with neurological symptoms. This study is intended to compare the therapeutic approaches for WD patients with neurological symptoms receiving either combined sodium 2, 3-dimercapto-1-propane sulfonate (DMPS) and zinc treatment or D-penicillamine (DPA) monotherapy as first-line therapy, and identify the more effective therapeutic approach. METHODS The case records of 158 patients diagnosed with neurological WD were retrospectively analyzed. These patients treated with intravenous DMPS + Zinc and in combination with oral zinc as a maintenance therapy (Group 1) or DPA alone (Group 2) for 1 year. During the period of treatment, the neurological symptoms of the patients were assessed using the Global Assessment Scale (GAS) and Barthel index. The key hematological and biochemical parameters of the patients (such as the levels of aminotransferase, serum ceruloplasmin, 24-h urine copper excretion), as well as adverse effects were recorded and analyzed. RESULTS Ninety-three patients in Group 1, displayed decreased GAS scores and increased Barthel indexes consistently in comparison with the baseline (P < 0.01). Among them, 82 patients (88.2%) exhibited significant neurological improvement after 1 year, while 8 patients (8.6%) experienced neurological deterioration. Among the 65 patients in Group 2, 37 patients (58.5%) exhibited neurological improvements, while 17 patients (26.2%) experienced neurological deterioration after 1-year follow up. Six patients discontinued their treatment midway due to their exacerbating neurological symptoms. A comprehensive comparison of the effectiveness of the two courses of treatment revealed that patients in group 1 demonstrated a higher improvement ratio (P < 0.01) and lower worsening ratio of the neurological symptoms for the patients (P < 0.01) in comparison to the patients in group 2. Meanwhile, renal function, liver enzyme and blood cell counts remained stabilized in group1. CONCLUSIONS This study indicates that the combined therapeutic approach of DPMS and zinc may be a preferred first-line therapy in treating the neurological symptoms of WD, in comparison to the treatment with DPA.
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Affiliation(s)
- Jing Zhang
- Department of Neurology, First Affiliated hospital of Anhui University of Traditional Chinese Medicine, Meishan Road 117, Hefei, 230031 China
| | - Lulu Xiao
- Department of Neurology, Jinling Hospital, Medical School of Nanjing University, 305 East Zhongshan Road, Nanjing, 210002 Jiangsu Province China
| | - Wenming Yang
- Department of Neurology, First Affiliated hospital of Anhui University of Traditional Chinese Medicine, Meishan Road 117, Hefei, 230031 China
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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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20
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The psychopharmacology of Wilson disease and other metabolic disorders. HANDBOOK OF CLINICAL NEUROLOGY 2019. [PMID: 31727212 DOI: 10.1016/b978-0-444-64012-3.00011-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/29/2023]
Abstract
Wilson disease (WD) is a hereditary metabolic disorder (HMD) caused by a mutation in the copper-transporting gene ATP7B affecting the liver and central nervous system. About 30% of patients with WD may initially present with psychiatric symptoms, and management can be difficult. More generally, HMDs are a rare but important cause of psychiatric disorders in adolescents and adults. Main signs of HMDs may remain isolated for years before the appearance of hepatic or neurologic signs. The incidence of HMDs has been estimated at approximately 40 cases per 100,000 live births. Some of them are treatable and new diagnostic methods and therapies have become available. HMDs that present purely with psychiatric symptoms are very difficult to diagnose due to low awareness of these rare diseases among psychiatrists and neurologists. However, it is important to identify HMDs in order to provide disease-specific treatment and possible prevention of irreversible physical and neurologic complications. Genetic counseling can also be provided. Psychotropic medications should be prescribed carefully in that indication. This chapter focuses on three HMD categories: chronic, treatable HMDs (e.g., WD); acute, treatable HMDs; and chronic HMDs that are difficult to treat. In this review we focus on the psychopharmacology of WD and other chronic and difficult-to-treat HMDs. We provide some keys to take into account the main side effects associated with common psychotropic medications.
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Appenzeller-Herzog C, Mathes T, Heeres MLS, Weiss KH, Houwen RHJ, Ewald H. Comparative effectiveness of common therapies for Wilson disease: A systematic review and meta-analysis of controlled studies. Liver Int 2019; 39:2136-2152. [PMID: 31206982 DOI: 10.1111/liv.14179] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 05/16/2019] [Accepted: 06/04/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Wilson disease (WD) is a rare disorder of copper metabolism. The objective of this systematic review was to determine the comparative effectiveness and safety of common treatments of WD. METHODS We included WD patients of any age or stage and the study drugs D-penicillamine, zinc salts, trientine and tetrathiomolybdate. The control could be placebo, no treatment or any other treatment. We included prospective, retrospective, randomized and non-randomized studies. We searched Medline and Embase via Ovid, the Cochrane Central Register of Controlled Trials, and screened reference lists of included articles. Where possible, we applied random-effects meta-analyses. RESULTS The 23 included studies reported on 2055 patients and mostly compared D-penicillamine to no treatment, zinc, trientine or succimer. One study compared tetrathiomolybdate and trientine. Post-decoppering maintenance therapy was addressed in one study only. Eleven of 23 studies were of low quality. When compared to no treatment, D-penicillamine was associated with a lower mortality (odds ratio 0.013; 95% CI 0.0010 to 0.17). When compared to zinc, there was no association with mortality (odds ratio 0.73; 95% CI 0.16 to 3.40) and prevention or amelioration of clinical symptoms (odds ratio 0.84; 95% CI 0.48 to 1.48). Conversely, D-penicillamine may have a greater impact on side effects and treatment discontinuations than zinc. CONCLUSIONS There are some indications that zinc is safer than D-penicillamine therapy while being similarly effective in preventing or reducing hepatic or neurological WD symptoms. Study quality was low warranting cautious interpretation of our findings.
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Affiliation(s)
| | - Tim Mathes
- Institute for Research in Operative Medicine, Faculty of Health, School of Medicine, Witten/Herdecke University, Cologne, Germany
| | - Marlies L S Heeres
- Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Karl Heinz Weiss
- Department of Internal Medicine IV, Medical University of Heidelberg, Heidelberg, Germany
| | - Roderick H J Houwen
- Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Hannah Ewald
- University Medical Library, University of Basel, Basel, Switzerland.,Basel Institute for Clinical Epidemiology and Biostatistics, Department of Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland
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22
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Cleymaet S, Nagayoshi K, Gettings E, Faden J. A review and update on the diagnosis and treatment of neuropsychiatric Wilson disease. Expert Rev Neurother 2019; 19:1117-1126. [DOI: 10.1080/14737175.2019.1645009] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Sean Cleymaet
- Department of Neurology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
| | - Katsuko Nagayoshi
- Department of Psychiatry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
| | - Edward Gettings
- Department of Neurology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
| | - Justin Faden
- Department of Psychiatry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
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23
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Camarata MA, Ala A, Schilsky ML. Zinc Maintenance Therapy for Wilson Disease: A Comparison Between Zinc Acetate and Alternative Zinc Preparations. Hepatol Commun 2019; 3:1151-1158. [PMID: 31388634 PMCID: PMC6671772 DOI: 10.1002/hep4.1384] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Accepted: 05/06/2019] [Indexed: 12/15/2022] Open
Abstract
We evaluate Wilson disease (WD) treatment with zinc acetate (U.S. Food and Drug Administration approved) and alternative zinc salts. Studies examining zinc therapy in WD are few, and data on alternative zinc salts are limited. We describe one of the largest recent studies of zinc therapy in WD. First, we conducted a single‐center retrospective review of 59 patients with WD (age 6‐88 years, 32 female patients) treated with zinc (50‐150 mg) for 0.8 to 52 years (median, 26 years); most were on prior chelation therapy (n = 39). Second, we developed a survey to explore patients' zinc therapy experience. Primary endpoints were alamine aminotransferase (ALT) and urine copper excretion (µg/24 hours). Urine copper was categorized as low <25 μg (possible overtreatment), target 25‐100 μg, or elevated >100 μg (possible noncompliance or treatment failure). The target range was reached in 81% of patients on zinc acetate, 73% on zinc gluconate, and 57% on alternative zinc. Low urine copper was not associated with a high ALT. ALT was normal in 77% of patients with target urine copper but only in 16% with urine copper >100 µg. ALT elevations were not significantly different between zinc salts (Kruskal‐Wallis, P = 0.26). Our survey demonstrated the mean age of starting zinc was 26.8 years (3.5‐65 years); most were treated with zinc acetate (45%) and zinc gluconate (42%). Before zinc treatment, 45% of patients were symptomatic; the majority of patients (80%) were asymptomatic on zinc. Gastrointestinal side effects were the predominant reason for changing zinc salts (38%), but most reported no side effects on current zinc therapy (67%). Conclusion: Effective treatment with zinc is possible in many patients with WD. The potential for treatment failure suggests close monitoring and consideration of alternative treatments are paramount for those without both a normal serum ALT and appropriate urine copper excretion. We describe one of the largest recent studies of Zn therapy in WD and include data on alternative Zn salts which is lacking thus far. In clinical practice, due to issues of intolerance and increased cost of WD medications, many patients have gravitated towards alternative Zn salts, some purchasing non‐prescription Zn over‐the‐counter. An understanding of the potential utility of different Zn preparations and required monitoring will provide benefit in expanding and optimizing treatment options for patients with WD.
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Affiliation(s)
- Michelle A Camarata
- Departments of Medicine and Surgery, Division of Digestive Diseases and Transplantation and Immunology Yale University Medical Center New Haven CT.,Department of Clinical and Experimental Medicine University of Surrey Guildford United Kingdom.,Department of Gastroenterology and Hepatology Royal Surrey County Hospital National Health Service Foundation Trust Guildford United Kingdom
| | - Aftab Ala
- Department of Clinical and Experimental Medicine University of Surrey Guildford United Kingdom.,Department of Gastroenterology and Hepatology Royal Surrey County Hospital National Health Service Foundation Trust Guildford United Kingdom.,Institute of Liver Studies King's College Hospital London United Kingdom
| | - Michael L Schilsky
- Departments of Medicine and Surgery, Division of Digestive Diseases and Transplantation and Immunology Yale University Medical Center New Haven CT
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Cai S, Gong JY, Yang J, Wang JS. Anemia following zinc treatment for Wilson's disease: a case report and literature review. BMC Gastroenterol 2019; 19:120. [PMID: 31288754 PMCID: PMC6617635 DOI: 10.1186/s12876-019-1038-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Accepted: 06/24/2019] [Indexed: 12/18/2022] Open
Abstract
Background Zinc therapy is considered an effective and safe treatment for Wilson’s disease. Hypocupremia-related anemia is rarely reported after long-term zinc administration or combination therapy with copper-chelating agent. Case presentation We herein report a 12-year-old girl with pre-symptomatic Wilson’s disease diagnosed 5 years ago who presented with severe anemia after high-dose oral zinc for 4 years and 4 months. Her hemoglobin was gradually restored to the normal range after the adjustment of zinc dose and diet therapy for 4 months. A review of the literature revealed eight patients with hypocupremia-associated anemia following zinc therapy for Wilson’s disease, including 7 adults and 1 child. The only child patient was a 16-year-old boy, in whom the zinc therapy was succession to penicillamine administration. Conclusions This is the first report worldwide that a child developed severe anemia following high-dose single zinc administration for Wilson’s disease. It highlights the importance of regular follow-up during zinc treatment and the involvement of specialists in the long-term management of Wilson’s disease. We hope that this will alert pediatricians the issue of zinc over-treatment.
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Affiliation(s)
- Sha Cai
- Department of Pediatrics, Jinshan Hospital of Fudan University, 1508 Longhang Road, Jinshan District, Shanghai, 201508, China
| | - Jing-Yu Gong
- Department of Pediatrics, Jinshan Hospital of Fudan University, 1508 Longhang Road, Jinshan District, Shanghai, 201508, China
| | - Jing Yang
- Department of Pediatrics, Jinshan Hospital of Fudan University, 1508 Longhang Road, Jinshan District, Shanghai, 201508, China
| | - Jian-She Wang
- Department of Pediatrics, Jinshan Hospital of Fudan University, 1508 Longhang Road, Jinshan District, Shanghai, 201508, China. .,Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai, 201102, China.
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Mohr I, Weiss KH. Current anti-copper therapies in management of Wilson disease. ANNALS OF TRANSLATIONAL MEDICINE 2019; 7:S69. [PMID: 31179306 DOI: 10.21037/atm.2019.02.48] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
In Wilson disease (WD) severity of disease can vary widely, depending on time of diagnosis. Early treatment can prevent the development of symptoms in patients. In all patients, lifelong medical treatment is indicated. Currently available medical regimens include the copper chelators for example D-penicillamine (DPA) or trientine (TETA), acting to increase copper excretion and zinc salts (ZS), which reduce copper uptake. In this chapter, we discuss considerations regarding choice of drug and safety limitations.
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Affiliation(s)
- Isabelle Mohr
- Internal Medicine IV, University Hospital Heidelberg, Heidelberg, Germany
| | - Karl Heinz Weiss
- Internal Medicine IV, University Hospital Heidelberg, Heidelberg, Germany
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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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Modality of treatment and potential outcome of Wilson disease in Taiwan: A population-based longitudinal study. J Formos Med Assoc 2018; 117:421-426. [DOI: 10.1016/j.jfma.2017.05.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Revised: 05/04/2017] [Accepted: 05/12/2017] [Indexed: 12/19/2022] Open
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Abstract
Many inherited metabolic diseases or inborn errors of metabolism (IEM) cause movement disorders in children. This review focuses on chorea, dystonia, myoclonus, tremor, and parkinsonism. Broad neurometabolic categories commonly responsible for pediatric movement disorders include mitochondrial cytopathies, organic acidemias, mineral metabolism and transport disorders, neurotransmitter diseases, purine metabolism abnormalities, lipid storage conditions, and creatine metabolism dysfunction. Each movement disorder can be caused by many IEM and several of them can cause multiple movement abnormalities. Dietary modifications, medications, and increasingly specific therapy can improve outcomes in children with movement disorders caused by IEM. Recognition and characterization of secondary movement disorders in children facilitate their management and diagnosis, and possible treatment of an underlying IEM.
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Affiliation(s)
- Celanie K Christensen
- Department of Neurology, Section of Child Neurology, Indiana University School of Medicine, Indianapolis, IN; Department of Pediatrics, Section of Developmental Pediatrics, Indiana University School of Medicine, Indianapolis, IN.
| | - Laurence Walsh
- Department of Neurology, Section of Child Neurology, Indiana University School of Medicine, Indianapolis, IN; Department of Pediatrics, Section of Developmental Pediatrics, Indiana University School of Medicine, Indianapolis, IN; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN
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Aggarwal A, Bhatt M. Advances in Treatment of Wilson Disease. TREMOR AND OTHER HYPERKINETIC MOVEMENTS (NEW YORK, N.Y.) 2018. [PMID: 29520330 PMCID: PMC5840318 DOI: 10.7916/d841881d] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Background Wilson disease (WD) is an inherited neurometabolic disorder that results in excessive copper deposition in the liver and the brain, affecting children and young adults. Without treatment the disease is invariably fatal. Though treatments for WD have been available since the 1950s, the disease continues to be associated with considerable morbidity and mortality because of missed diagnosis, and delayed or inadequate treatment. In this paper we survey WD-related literature in order to review recent advances in WD treatment. Methods We performed a literature search using the PubMed database for articles relating to WD and its medical treatment. We reviewed the articles, and cross-references of relevant articles, to summarize the current practices for treatment of WD. Results The survey shows that if WD is properly treated, in most patients the liver can be stabilized, even severe neurological disability reversed, and patients can resume normal lives. Discussion Medical treatment for WD includes use of copper chelators (penicillamine, trientine, dimercaprol, dimercaptopropane sulfonate, and ammonium tetrathiomolybdate) and drugs that decrease gastrointestinal copper absorption. Our knowledge of the treatment approaches has benefited from the large systematic clinical studies that have been conducted over the last decade. For each drug used to treat WD, we surveyed its development, indication for use, dosing, efficacy, and adverse effects.
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Affiliation(s)
- Annu Aggarwal
- Wilson Disease Clinic, Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute, Mumbai, India
| | - Mohit Bhatt
- Wilson Disease Clinic, Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute, Mumbai, India
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Socha P, Janczyk W, Dhawan A, Baumann U, D'Antiga L, Tanner S, Iorio R, Vajro P, Houwen R, Fischler B, Dezsofi A, Hadzic N, Hierro L, Jahnel J, McLin V, Nobili V, Smets F, Verkade HJ, Debray D. Wilson's Disease in Children: A Position Paper by the Hepatology Committee of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2018; 66:334-344. [PMID: 29341979 DOI: 10.1097/mpg.0000000000001787] [Citation(s) in RCA: 148] [Impact Index Per Article: 21.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Clinical presentations of Wilson's disease (WD) in childhood ranges from asymptomatic liver disease to cirrhosis or acute liver failure, whereas neurological and psychiatric symptoms are rare. The basic diagnostic approach includes serum ceruloplasmin and 24-hour urinary copper excretion. Final diagnosis of WD can be established using a diagnostic scoring system based on symptoms, biochemical tests assessing copper metabolism, and molecular analysis of mutations in the ATP7B gene. Pharmacological treatment is life-long and aims at removal of copper excess by chelating agents as D-penicillamine, trientine, or inhibition of intestinal copper absorption with zinc salts. Acute liver failure often requires liver transplantation. This publication aims to provide recommendations for diagnosis, treatment, and follow-up of WD in children. METHODS Questions addressing the diagnosis, treatment, and follow-up of WD in children were formulated by a core group of ESPGHAN members. A systematic literature search on WD using MEDLINE, EMBASE, Cochrane Database from 1990 to 2016 was performed focusing on prospective and retrospective studies in children. Quality of evidence was assessed according to the GRADE system. Expert opinion supported recommendations where the evidence was regarded as weak. The ESPGHAN core group and ESPGHAN Hepatology Committee members voted on each recommendation, using the nominal voting technique.
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Affiliation(s)
- Piotr Socha
- Department of Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland
| | - Wojciech Janczyk
- Department of Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland
| | - Anil Dhawan
- Paediatric Liver GI and Nutrition Center, King's College Hospital, London, UK
| | - Ulrich Baumann
- Division of Paediatric Gastroenterology and Hepatology, Department of Paediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany
| | - Lorenzo D'Antiga
- Paediatric Hepatology, Gastroenterology and Transplantation, Hospital Papa Giovanni XXIII, Bergamo, Italy
| | | | - Raffaele Iorio
- Department of Translational Medical Science, Section of Pediatrics, University of Naples Federico II, Naples
| | - Pietro Vajro
- Dipartimento di Medicina e Chirurgia, University of Salerno, Fisciano SA, Italy
| | - Roderick Houwen
- Department of Paediatrics, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Björn Fischler
- Department of Paediatrics, CLINTEC, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
| | - Antal Dezsofi
- First Department of Paediatrics, Semmelweis University, Budapest, Hungary
| | - Nedim Hadzic
- Paediatric Centre for Hepatology, Gastroenterology and Nutrition, King's College Hospital, London, UK
| | - Loreto Hierro
- Paediatric Hepatology Service, Hospital Infantil Universitario "La Paz," Madrid, Spain
| | - Jörg Jahnel
- Department of Paediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
| | - Valérie McLin
- Paediatric Gastroenterology Unit, Department of Pediatrics, University Hospitals Geneva, Geneva, Switzerland
| | - Valerio Nobili
- Hepatometabolic Unit, Bambino Gesu Children's Hospital, Rome, Italy
| | - Francoise Smets
- Université Catholique de Louvain-IREC-Cliniques Universitaires Saint-Luc-Pediatric Gastroenterology and Hepatology Unit, Brussels, Belgium
| | - Henkjan J Verkade
- Department of Paediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Dominique Debray
- Pediatric Hepatology Unit, Centre National de Référence de la Maladie de Wilson, Hôpital Necker-APHP, Paris, France
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Gupta P, Choksi M, Goel A, Zachariah U, Sajith KG, Ramachandran J, Chandy G, Kurian G, Rebekah G, Eapen CE. Maintenance zinc therapy after initial penicillamine chelation to treat symptomatic hepatic Wilson's disease in resource constrained setting. Indian J Gastroenterol 2018; 37:31-38. [PMID: 29457214 DOI: 10.1007/s12664-018-0829-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2017] [Accepted: 01/10/2018] [Indexed: 02/04/2023]
Abstract
BACKGROUND Experience with zinc in treating symptomatic hepatic Wilson's disease (WD) is limited. AIM To study the efficacy of Penicillamine followed by zinc in treating symptomatic hepatic Wilson's disease. METHODS We retrospectively analyzed case records of 31 symptomatic hepatic WD patients for whom disease severity scores (Child's, model for end-stage liver disease (MELD), Nazer's, and New Wilson Index (NWI) score) and 24-h urinary copper were compared at 3-time points-baseline at presentation, at transition from penicillamine to zinc and at end of follow up. RESULTS Thirty-one patients (median age 11 [5-24] years) with symptomatic hepatic WD were studied; ten had associated neuropsychiatric manifestations of WD. Penicillamine was changed to zinc sulfate either due to financial constraints (28 patients) or due to adverse effects of penicillamine (3 patients). At presentation (baseline), six patients belonged to Child's class A, five to Child's B, and 17 to Child's C. Duration of initial penicillamine chelation therapy was 134 (2-320) weeks, and of subsequent zinc therapy was 363 (35-728) weeks. There was a significant improvement in liver function tests and disease severity scores (Child's, MELD, Nazer's, and NWI score) at the transition from penicillamine to zinc compared to baseline. This improvement was maintained until the end of study period with 90% survival at 10 (2-20) years. Fifteen of the 17 Child's C cirrhotic patients showed significant improvement in disease severity scores from baseline until end of follow up. CONCLUSIONS Penicillamine followed by zinc may be a safe and effective treatment in resource-constrained setting for symptomatic hepatic WD patients in all grades of baseline disease severity. Some patients with decompensated cirrhosis due to WD may be managed with medical treatment, avoiding liver transplantation.
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Affiliation(s)
- Piyush Gupta
- Department of Hepatology, Christian Medical College, Vellore, 632 004, India.
| | - Mehul Choksi
- Department of Hepatology, Christian Medical College, Vellore, 632 004, India
| | - Ashish Goel
- Department of Hepatology, Christian Medical College, Vellore, 632 004, India
| | - Uday Zachariah
- Department of Hepatology, Christian Medical College, Vellore, 632 004, India
| | | | | | - George Chandy
- Department of Hepatology, Christian Medical College, Vellore, 632 004, India
| | - George Kurian
- Department of Hepatology, Christian Medical College, Vellore, 632 004, India
| | - Grace Rebekah
- Department of Biostatistics, Christian Medical College, Vellore, 632 004, India
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Hadžić N, Deheragoda M, Dhawan A. Managing pre-symptomatic Wilson disease in genetic era - More questions than answers. Clin Res Hepatol Gastroenterol 2017; 41:626-628. [PMID: 28330624 DOI: 10.1016/j.clinre.2017.02.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Revised: 01/21/2017] [Accepted: 02/02/2017] [Indexed: 02/04/2023]
Affiliation(s)
- Nedim Hadžić
- Paediatric Centre for Hepatology, Gastroenterology and Nutrition, King's College Hospital, Denmark Hill, London SE5 9RS, UK.
| | | | - Anil Dhawan
- Paediatric Centre for Hepatology, Gastroenterology and Nutrition, King's College Hospital, Denmark Hill, London SE5 9RS, UK
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Li Y, Mayer FP, Hasenhuetl PS, Burtscher V, Schicker K, Sitte HH, Freissmuth M, Sandtner W. Occupancy of the Zinc-binding Site by Transition Metals Decreases the Substrate Affinity of the Human Dopamine Transporter by an Allosteric Mechanism. J Biol Chem 2017; 292:4235-4243. [PMID: 28096460 PMCID: PMC5354487 DOI: 10.1074/jbc.m116.760140] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2016] [Revised: 12/16/2016] [Indexed: 11/06/2022] Open
Abstract
The human dopamine transporter (DAT) has a tetrahedral Zn2+-binding site. Zn2+-binding sites are also recognized by other first-row transition metals. Excessive accumulation of manganese or of copper can lead to parkinsonism because of dopamine deficiency. Accordingly, we examined the effect of Mn2+, Co2+, Ni2+, and Cu2+ on transport-associated currents through DAT and DAT-H193K, a mutant with a disrupted Zn2+-binding site. All transition metals except Mn2+ modulated the transport cycle of wild-type DAT with affinities in the low micromolar range. In this concentration range, they were devoid of any action on DAT-H193K. The active transition metals reduced the affinity of DAT for dopamine. The affinity shift was most pronounced for Cu2+, followed by Ni2+ and Zn2+ (= Co2+). The extent of the affinity shift and the reciprocal effect of substrate on metal affinity accounted for the different modes of action: Ni2+ and Cu2+ uniformly stimulated and inhibited, respectively, the substrate-induced steady-state currents through DAT. In contrast, Zn2+ elicited biphasic effects on transport, i.e. stimulation at 1 μm and inhibition at 10 μm. A kinetic model that posited preferential binding of transition metal ions to the outward-facing apo state of DAT and a reciprocal interaction of dopamine and transition metals recapitulated all experimental findings. Allosteric activation of DAT via the Zn2+-binding site may be of interest to restore transport in loss-of-function mutants.
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Affiliation(s)
- Yang Li
- From the Institute of Pharmacology, Center of Physiology and Pharmacology, Medical University Vienna, Waehringerstrasse 13a, 1090 Vienna, Austria
| | - Felix P Mayer
- From the Institute of Pharmacology, Center of Physiology and Pharmacology, Medical University Vienna, Waehringerstrasse 13a, 1090 Vienna, Austria
| | - Peter S Hasenhuetl
- From the Institute of Pharmacology, Center of Physiology and Pharmacology, Medical University Vienna, Waehringerstrasse 13a, 1090 Vienna, Austria
| | - Verena Burtscher
- From the Institute of Pharmacology, Center of Physiology and Pharmacology, Medical University Vienna, Waehringerstrasse 13a, 1090 Vienna, Austria
| | - Klaus Schicker
- From the Institute of Pharmacology, Center of Physiology and Pharmacology, Medical University Vienna, Waehringerstrasse 13a, 1090 Vienna, Austria
| | - Harald H Sitte
- From the Institute of Pharmacology, Center of Physiology and Pharmacology, Medical University Vienna, Waehringerstrasse 13a, 1090 Vienna, Austria
| | - Michael Freissmuth
- From the Institute of Pharmacology, Center of Physiology and Pharmacology, Medical University Vienna, Waehringerstrasse 13a, 1090 Vienna, Austria
| | - Walter Sandtner
- From the Institute of Pharmacology, Center of Physiology and Pharmacology, Medical University Vienna, Waehringerstrasse 13a, 1090 Vienna, Austria
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Abstract
Wilson disease (WD) is an inherited disorder mainly of hepatocellular copper disposition, due to dysfunction of the Wilson ATPase, a P1B-ATPase encoded by the gene ATP7B. In children, as in older age brackets, clinical disease is highly diverse. Although hepatic disease is the common presentation in children/adolescents, neurologic, psychiatric, and hematologic clinical presentations do occur. Very young children may have clinically evident liver disease due to WD. Early diagnosis, preferably when the child/adolescent is asymptomatic, is most likely to result in near-normal longevity with generally good health so long as the patient tolerates effective medication, is adherent to the lifelong treatment regimen, and has consistent access to the medication. Apart from a lively index of clinical suspicion on the part of physicians, biochemical tests including liver tests, serum ceruloplasmin, and basal 24-hour urinary copper excretion and genotype determination are key to diagnosis. Oral chelation treatment remains central to medical management, although zinc appears to be an attractive option for the presymptomatic child. Pediatric patients presenting with Wilsonian fulminant hepatic failure must be differentiated from those with decompensated cirrhosis, since the latter may respond to intensive medical interventions and not require liver transplantation. Recently identified WD-mimic disorders reveal important aspects of WD pathogenesis.
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Affiliation(s)
- Eve A Roberts
- Departments of Paediatrics, Medicine and Pharmacology and Toxicology, University of Toronto, Toronto, Canada.
| | - Piotr Socha
- Departments of Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland
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Verbandt S, Cammue BPA, Thevissen K. Yeast as a model for the identification of novel survival-promoting compounds applicable to treat degenerative diseases. Mech Ageing Dev 2016; 161:306-316. [PMID: 27287065 DOI: 10.1016/j.mad.2016.06.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Revised: 05/31/2016] [Accepted: 06/07/2016] [Indexed: 12/18/2022]
Abstract
Programmed cell death (PCD) plays an important role in development and normal metabolic functioning of organisms. Excessive cell death is the cause of many degenerative diseases, like neurodegenerative disorders and Wilson's disease, for which current therapies remain insufficient. Current therapies are mainly focused on decreasing the disease symptoms following cell death, rather than blocking the cell death process itself. The latter can be obtained by either decreasing the presence of the toxic trigger (like protein aggregation in case of many commonly known neurodegenerative diseases) or by blocking death-inducing signaling cascade(s). Given the high conservation in PCD processes between yeast and mammalian cells, in this review, we will focus on yeast as a model organism to study PCD-related diseases as well as on its use for drug discovery purposes. More specifically, we will provide a comprehensive overview of new compounds, which were identified in yeast-based drug screens, that either decrease the amount of toxic trigger or inhibit PCD signaling cascades under PCD-inducing conditions.
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Affiliation(s)
- Sara Verbandt
- Centre of Microbial and Plant Genetics CMPG, KU Leuven, Kasteelpark Arenberg 20, Box 2460, 3001, Leuven, Belgium
| | - Bruno P A Cammue
- Centre of Microbial and Plant Genetics CMPG, KU Leuven, Kasteelpark Arenberg 20, Box 2460, 3001, Leuven, Belgium; Department of Plant Systems Biology, VIB, Technologiepark 927, 9052 Ghent, Belgium.
| | - Karin Thevissen
- Centre of Microbial and Plant Genetics CMPG, KU Leuven, Kasteelpark Arenberg 20, Box 2460, 3001, Leuven, Belgium
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Abstract
BACKGROUND AND AIMS Zinc therapy is considered a good option in Wilson disease (WD), as a first-line treatment in presymptomatic children and a maintenance therapy after the initial chelator therapy. The aim of the study was to determine the practical use of zinc treatment in French pediatric centers. METHODS A national survey was conducted in the 6 French centers using zinc acetate to treat WD. Clinical and biological parameters, dosage, and outcome were recorded. RESULTS A total of 26 children were reported to be treated with zinc acetate, alone or in association with chelators. Of the 9 children (35%) who received zinc alone as a first-line therapy, 2 were switched to D-penicillamine because of inefficacy and 7 remained on zinc alone, but serum transaminase levels normalized in only 4 of them. Five children (19%) were initially treated with zinc in association with D-penicillamine (n = 4) or Trientine (n = 1) with good efficacy. Among the 12 children (46%) who received zinc as a maintenance therapy after D-penicillamine, no relapse of hepatic cytolysis occurred during a median follow-up of 5.2 years, but 2 of them were switched to Trientine because of zinc-related adverse effects. Epigastric pain was observed in 4 children, and a gastric perforation occurred in 1 child. CONCLUSIONS The present study demonstrates poor efficacy of zinc as first-line therapy to control liver disease in half presymptomatic children and a high incidence of related gastrointestinal adverse effects in children with WD.
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Schilsky ML, Roberts EA, Hahn S, Askari F. Costly choices for treating Wilson's disease. Hepatology 2015; 61:1106-8. [PMID: 25524500 DOI: 10.1002/hep.27663] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Revised: 10/31/2014] [Accepted: 12/11/2014] [Indexed: 01/28/2023]
Affiliation(s)
- Michael L Schilsky
- Yale-New Haven Transplantation Center, Yale School of Medicine, New Haven, CT
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Abstract
The copper metabolism disorder Wilson's disease was first defined in 1912. Wilson's disease can present with hepatic and neurological deficits, including dystonia and parkinsonism. Early-onset presentations in infancy and late-onset manifestations in adults older than 70 years of age are now well recognised. Direct genetic testing for ATP7B mutations are increasingly available to confirm the clinical diagnosis of Wilson's disease, and results from biochemical and genetic prevalence studies suggest that Wilson's disease might be much more common than previously estimated. Early diagnosis of Wilson's disease is crucial to ensure that patients can be started on adequate treatment, but uncertainty remains about the best possible choice of medication. Furthermore, Wilson's disease needs to be differentiated from other conditions that also present clinically with hepatolenticular degeneration or share biochemical abnormalities with Wilson's disease, such as reduced serum ceruloplasmin concentrations. Disordered copper metabolism is also associated with other neurological conditions, including a subtype of axonal neuropathy due to ATP7A mutations and the late-onset neurodegenerative disorders Alzheimer's disease and Parkinson's disease.
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Affiliation(s)
- Oliver Bandmann
- Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
| | - Karl Heinz Weiss
- University Hospital Heidelberg, Department of Internal Medicine IV, Heidelberg, Germany
| | - Stephen G Kaler
- Section on Translational Neuroscience, Molecular Medicine Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
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van Meer S, de Man RA, van den Berg AP, Houwen RHJ, Linn FHH, van Oijen MGH, Siersema PD, van Erpecum KJ. No increased risk of hepatocellular carcinoma in cirrhosis due to Wilson disease during long-term follow-up. J Gastroenterol Hepatol 2015; 30:535-9. [PMID: 25160780 DOI: 10.1111/jgh.12716] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/11/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Data on risk of hepatocellular carcinoma (HCC) in patients with Wilson disease are scarce. We determine HCC risk in a well-defined cohort of Wilson patients. METHODS All patients with a confirmed diagnosis of Wilson disease (Leipzig score ≥ 4) in three Dutch university referral hospitals were included in this retrospective cohort study. End of follow-up was defined as date of diagnosis of HCC, liver transplantation, death, or last available hospital visit. Also, a meta-analysis was performed to determine incidence and mortality rate of HCC in Wilson disease based on all published cohorts. RESULTS In total, 130 patients with Wilson disease were followed during a median follow-up of 15 years (range 0.1-51.2). At baseline, cirrhosis was present in 74 patients (57% of total: 64% compensated, and 36% decompensated). At end of follow-up, liver disease severity was improved, stable or deteriorated in 20%, 46%, and 24% of all cases (10% unknown), respectively. Two patients developed HCC (one despite excellent decoppering after 50 years follow-up, the other with newly diagnosed Wilson disease). Estimated annual HCC risk for all patients was 0.09% (95% confidence interval [CI]: 0.01-0.28). Subgroup analysis in cirrhotic patients revealed an annual HCC risk of 0.14% (95% CI: 0.02-0.46). The meta-analysis showed an annual HCC risk of 0.04% (95% CI: 0.01-0.10) and HCC mortality rate of 2.6/10 000 person-years (95% CI: 0.7-7.0). CONCLUSIONS Even in case of cirrhosis, HCC risk is low in Wilson disease. Our data do not support regular HCC surveillance in Wilson disease.
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Affiliation(s)
- Suzanne van Meer
- Department of Gastroenterology and Hepatology, University Medical Center, Utrecht, The Netherlands
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Jurowski K, Szewczyk B, Nowak G, Piekoszewski W. Biological consequences of zinc deficiency in the pathomechanisms of selected diseases. J Biol Inorg Chem 2014; 19:1069-79. [PMID: 24748223 PMCID: PMC4175048 DOI: 10.1007/s00775-014-1139-0] [Citation(s) in RCA: 93] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2014] [Accepted: 04/09/2014] [Indexed: 01/01/2023]
Abstract
From many points of view, zinc is one of the most important trace elements in biological systems. Many articles describe the well-known role of this metal in human physiology and pathophysiology, but in the related literature, there is a lack of current and reliable reviews of the role of zinc deficiency in many diseases. In this article, we describe the role of zinc deficiency in the oxidative stress control, immune response, proliferation, and pathogenesis and pathophysiology of selected diseases such as depression, cardiovascular diseases, diabetes mellitus, Alzheimer's disease, and Wilson's disease.
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Affiliation(s)
- Kamil Jurowski
- Department of Analytical Chemistry, Faculty of Chemistry, Jagiellonian University, R. Ingardena 3, 30-060 Kraków, Poland
- Malopolska Centre for Translational Medicine, Faculty of Medicine, Jagiellonian University Collegium Medicum, Kraków, Poland
| | | | - Gabriel Nowak
- Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland
- Faculty of Pharmacy, Jagiellonian University Collegium Medicum, Kraków, Poland
| | - Wojciech Piekoszewski
- Department of Analytical Chemistry, Faculty of Chemistry, Jagiellonian University, R. Ingardena 3, 30-060 Kraków, Poland
- Laboratory of High Resolution Mass Spectrometry, Regional Laboratory of Physicochemical Analysis and Structural Research, Faculty of Chemistry, Jagiellonian University, Kraków, Poland
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Weiss KH, Stremmel W. Clinical considerations for an effective medical therapy in Wilson's disease. Ann N Y Acad Sci 2014; 1315:81-5. [DOI: 10.1111/nyas.12437] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
- Karl Heinz Weiss
- Department of Gastroenterology; University Hospital Heidelberg; Heidelberg Germany
| | - Wolfgang Stremmel
- Department of Gastroenterology; University Hospital Heidelberg; Heidelberg Germany
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Ranucci G, Di Dato F, Spagnuolo MI, Vajro P, Iorio R. Zinc monotherapy is effective in Wilson's disease patients with mild liver disease diagnosed in childhood: a retrospective study. Orphanet J Rare Dis 2014; 9:41. [PMID: 24661374 PMCID: PMC4234980 DOI: 10.1186/1750-1172-9-41] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2013] [Accepted: 03/20/2014] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Wilson's disease (WD) evolves rapidly and is fatal if untreated. The treatment of WD patients with mild liver disease is not clearly defined. To address this issue, we evaluated long-term outcomes of three treatment regimens (D-penicillamine, zinc or both) in patients diagnosed in childhood. METHODS We retrospectively evaluated efficacy, compliance and reasons for treatment discontinuation in 42 WD patients (median age at diagnosis: 6 years; median follow-up: 12 years) with mild liver disease. Treatment duration for each treatment block until a medication change or completion of follow-up was analyzed. Events of change of treatment were evaluated using Kaplan-Meier analysis. RESULTS Total discontinuations due to treatment failure or adverse events were more frequent in patients receiving D-penicillamine (45%) or combination (36%) therapy than in patients receiving zinc (12%) (P = .001 and P = .02, respectively). Treatment failure was more frequent on D-penicillamine (28%) and combination therapy (36%) than on zinc (12%); the difference was statistically significant only between zinc and combination therapy (P = .03). First-line zinc monotherapy controlled WD-related liver disease in 13/15 patients (87%); the two subjects that failed on zinc were poor adherent. Zinc was effective in 3/5 (60%) patients that failed on D-penicillamine and combination regimens. All 15 D-penicillamine responders that switched to zinc had good control of liver disease at a median follow-up of 13.1 years. Among 6 D-penicillamine non-responders that switched to zinc, 4 (67%) responded. At follow-up completion, only 5/42 (12%) patients failed. Adverse event-induced discontinuation was significantly more frequent in patients on D-penicillamine than in patients receiving zinc (P = .03). CONCLUSIONS Zinc monotherapy is effective in controlling WD-related liver disease both as first-line and as maintenance treatment in patients with mild liver disease diagnosed in childhood.
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Affiliation(s)
- Giusy Ranucci
- Department of Translational Medical Science, Section of Pediatrics, University of Naples Federico II, Via Pansini 5, 80131 Naples, Italy
| | - Fabiola Di Dato
- Department of Translational Medical Science, Section of Pediatrics, University of Naples Federico II, Via Pansini 5, 80131 Naples, Italy
| | - Maria Immacolata Spagnuolo
- Department of Translational Medical Science, Section of Pediatrics, University of Naples Federico II, Via Pansini 5, 80131 Naples, Italy
| | - Pietro Vajro
- Chair of Pediatrics, Department of Medicine and Science, University of Salerno, 84081 Fisciano (Salerno), Italy
| | - Raffaele Iorio
- Department of Translational Medical Science, Section of Pediatrics, University of Naples Federico II, Via Pansini 5, 80131 Naples, Italy
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Zinc mono-therapy in pre-symptomatic Chinese children with Wilson disease: a single center, retrospective study. PLoS One 2014; 9:e86168. [PMID: 24475083 PMCID: PMC3901685 DOI: 10.1371/journal.pone.0086168] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2013] [Accepted: 12/06/2013] [Indexed: 01/02/2023] Open
Abstract
Background There is no official consensus regarding zinc therapy in pre-symptomatic children with Wilson Disease (WD); more data is needed. Objective To investigate the safety and efficacy of zinc gluconate therapy for Chinese children with pre-symptomatic WD. Methods We retrospectively analyzed pre-symptomatic children receiving zinc gluconate in a single Chinese center specialized in pediatric hepatology. Short-term follow-up data on safety and efficacy were presented, and effects of different zinc dosages were compared. Results 30 children (21 males) aged 2.7 to 16.8 years were followed for up to 4.4 years; 26 (87%) children had abnormal ALT at baseline. Most patients (73%) received higher than the currently recommended dose of elemental zinc. Zinc gluconate significantly reduced mean ALT (p<0.0001), AST (p<0.0001), GGT (p<0.0001) levels after 1 month, and urinary copper excretion after 6 months (p<0.0054). Mean direct bilirubin levels dropped significantly at 1 month (p = 0.0175), 3 months (p = 0.0010), and 6 months (p = 0.0036). Serum zinc levels gradually increased and reached a significantly higher level after 6 months (p<0.0026), reflecting good compliance with the therapy. Complete blood count parameters did not change throughout the analysis period. 8 children experienced mild and transient gastrointestinal side effects. The higher zinc dose did not affect treatment response and was not associated with different or increased side effects when compared to conventional zinc dose. Conclusion In our cohort, zinc gluconate therapy for Chinese children with pre-symptomatic WD was effective, and higher initial dose of elemental zinc had the same level of efficacy as the conventional dose.
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Xu SQ, Li XF, Zhu HY, Liu Y, Fang F, Chen L. Clinical efficacy and safety of chelation treatment with typical penicillamine in cross combination with DMPS repeatedly for Wilson's disease. ACTA ACUST UNITED AC 2013; 33:743-747. [PMID: 24142730 DOI: 10.1007/s11596-013-1190-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2013] [Revised: 08/16/2013] [Indexed: 11/26/2022]
Abstract
The aim of this study was to assess the clinical efficacy and safety of chelation treatment with penicillamine (PCA) in cross combination with sodium 2, 3-dimercapto-1-propane sulfonate (DMPS) repeatedly in patients with Wilson's disease (WD). Thirty-five patients with WD were enrolled. They were administrated intravenous DMPS in cross combination with oral PCA alternately which was practiced repeatedly, all with Zinc in the meantime. During the treatment, clinical observations and 24-h urine copper excretion as well as adverse effects of medicines were recorded and analyzed. Although the incidence of adverse effects was not significantly different after either intravenous DMPS or oral PCA treatment, levels of 24-h urine copper tended to be higher after short-term intravenous DMPS than that of oral PCA. Adverse effects in the course of intravenous DMPS were mainly neutropenia, thrombocytopenia, allergic reaction and bleeding tendency. As compared with oral PCA alone or intravenous DMPS alone, such repeated cross combination treatment could as much as possible avoid continued drug adverse effects or poor curative effect and had less chance to stop treatment in WD patients. Improved or recovered liver function in 71% of the patients, alleviated neurologic symptoms in 50% of the patients, and disappeared hematuria in 70% of the patients could be observed during the follow-up period of 6 months to 5 years after such combined chelation regimen. Chelation treatment repeatedly with oral penicillamine in cross combination with intravenous DMPS alternately could be more beneficial for WD patients to relieve symptoms, avoid continued drug adverse effects and maintain lifelong therapy.
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Affiliation(s)
- San-Qing Xu
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Xu-Fang Li
- Department of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou, 510120, China
| | - Hui-Yun Zhu
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yan Liu
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Feng Fang
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Ling Chen
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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Weiss KH, Thurik F, Gotthardt DN, Schäfer M, Teufel U, Wiegand F, Merle U, Ferenci-Foerster D, Maieron A, Stauber R, Zoller H, Schmidt HH, Reuner U, Hefter H, Trocello JM, Houwen RHJ, Ferenci P, Stremmel W. Efficacy and safety of oral chelators in treatment of patients with Wilson disease. Clin Gastroenterol Hepatol 2013; 11:1028-35.e352. [PMID: 23542331 DOI: 10.1016/j.cgh.2013.03.012] [Citation(s) in RCA: 132] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2013] [Accepted: 03/04/2013] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Wilson disease is a genetic copper storage disorder that causes hepatic and neurologic symptoms. Chelating agents (D-penicillamine, trientine) are used as first-line therapies for symptomatic patients, but there are few data from large cohorts. We assessed the safety of D-penicillamine and trientine therapy and outcomes of patients with Wilson disease. METHODS We performed a retrospective analysis of data on 380 patients with Wilson disease from tertiary care centers in Germany and Austria, and 25 additional patients from the EUROWILSON registry. Chelator-based treatment regimens were analyzed for their effect on neurologic and hepatic symptoms and for adverse events that led to discontinuation of therapy (Kaplan-Meier estimation; data were collected for a mean of 13.3 y after therapy began). RESULTS Changes in medication were common, resulting in analysis of 471 chelator monotherapies (326 patients receiving D-penicillamine and 141 receiving trientine). Nine of 326 patients treated with D-penicillamine and 3 of 141 patients given trientine underwent liver transplantation. Adverse events leading to discontinuation of treatment were more frequent among those receiving D-penicillamine than trientine (P = .039). Forty-eight months after therapy, hepatic deterioration was reported in only 4 of 333 patients treated initially with a chelating agent. Hepatic improvements were observed in more than 90%, and neurologic improvements were observed in more than 55%, of therapy-naive patients, and values did not differ significantly between treatments. However, neurologic deterioration was observed less frequently in patients given D-penicillamine first (6 of 295) than those given trientine first (4 of 38; P = .018). CONCLUSIONS Chelating agents are effective therapies for most patients with Wilson disease; D-penicillamine and trientine produce comparable outcomes, although D-penicillamine had a higher rate of adverse events. Few patients receiving chelation therapy had neurologic deterioration, which occurred more frequently in patients who received trientine.
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Affiliation(s)
- Karl Heinz Weiss
- Department of Gastroenterology, University Hospital Heidelberg, Heidelberg, Germany.
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Wiernicka A, Jańczyk W, Dądalski M, Avsar Y, Schmidt H, Socha P. Gastrointestinal side effects in children with Wilson's disease treated with zinc sulphate. World J Gastroenterol 2013; 19:4356-4362. [PMID: 23885147 PMCID: PMC3718904 DOI: 10.3748/wjg.v19.i27.4356] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2012] [Revised: 02/06/2013] [Accepted: 03/07/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the side effects of a zinc sulphate therapy in a cohort of Polish pediatric patients with Wilson’s disease.
METHODS: We retrospectively analyzed a cohort of 53 pediatric patients with Wilson’s disease treated at the Children’s Memorial Health Institute in Warsaw, Poland between the years 1996 and 2011 with zinc sulphate. Patients were diagnosed with Wilson’s disease according to the scoring system of Ferenci, with 49 cases confirmed by mutation analysis. Data about the dosage scheme of zinc sulphate, side effects and efficacy and toxicity of the treatment were collected and recorded in the patient’s medical chart at each visit to the hospital.
RESULTS: Mean age of diagnosis for the entire cohort was 10 years (range, 2.5-17 years). Duration of treatment with zinc sulfate was 83.3 wk (range, 8-344 wk). Side effects, all of gastrointestinal origin, were observed in 21 patients (40% - 9 males and 12 females), irrespective of the duration of therapy. Thirteen out of 21 patients were over the age of 10 years. The most common ATP7B mutation was p.H1069Q. Esophagogastroduodenoscopy, performed in 7 patients (33.3%) suffering from persistent and severe abdominal pain, revealed gastrointestinal ulcerations or erosions with negative Helicobacter pylori tests in all subjects investigated. The above mentioned 7 patients were treated with proton pump inhibitors. Three of those experienced resolution of symptoms, whereas proton-pump inhibitors failed to alleviate symptoms of the remaining four children and conversion of therapy to D-penicillamine was needed.
CONCLUSION: Zinc sulphate appears to cause significant gastrointestinal side effects, which children on therapy for Wilson’s disease should be closely monitored for.
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Gu S, Yang H, Qi Y, Deng X, Zhang L, Guo Y, Huang Q, Li J, Shi X, Song Z, Deng H. Novel ATPase Cu(2+) transporting beta polypeptide mutations in Chinese families with Wilson's disease. PLoS One 2013; 8:e66526. [PMID: 23843956 PMCID: PMC3699604 DOI: 10.1371/journal.pone.0066526] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2013] [Accepted: 05/06/2013] [Indexed: 12/24/2022] Open
Abstract
Wilson's disease (WD) is an autosomal recessive inherited disorder caused by mutations in the ATPase Cu(2+) transporting beta polypeptide gene (ATP7B). The detailed metabolism of copper-induced pathology in WD is still unknown. Gene mutations as well as the possible pathways involved in the ATP7B deficiency were documented. The ATP7B gene was analyzed for mutations in 18 Chinese Han families with WD by direct sequencing. Cell viability and apoptosis analysis of ATP7B small interfering RNA (siRNA)-treated human liver carcinoma (HepG2) cells were measured by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay and Hoechst 33342 staining. Finally, the expression of B-cell CLL/lymphoma 2 (BCL2), BCL2-associated X protein (BAX), sterol regulatory element binding protein 1 (SREBP1), and minichromosome maintenance protein 7 (MCM7) of ATP7B siRNA-treated cells were tested by real-time polymerase chain reaction (real-time PCR) and Western blot analysis. Twenty different mutations including four novel mutations (p.Val145Phe, p.Glu388X, p.Thr498Ser and p.Gly837X) in the ATP7B gene were identified in our families. Haplotype analysis revealed that founder effects for four mutations (p.Arg778Leu, p.Pro992Leu, p.Ile1148Thr and p.Ala1295Val) existed in these families. Transfection of HepG2 cells with ATP7B siRNA resulted in decreased mRNA expression by 86.3%, 93.1% and 90.8%, and decreased protein levels by 58.5%, 85.5% and 82.1% at 24, 48 and 72 hours, respectively (All P<0.01). In vitro study revealed that the apoptotic, cell cycle and lipid metabolism pathway may be involved in the mechanism of WD. Our results revealed that the genetic cause of 18 Chinese families with WD and ATP7B deficiency-induce apoptosis may result from imbalance in cell cycle and lipid metabolism pathway.
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Affiliation(s)
- Shaojuan Gu
- Center for Experimental Medicine, the Third Xiangya Hospital, Central South University, Changsha, China
- Department of Neurology, the Third Xiangya Hospital, Central South University, Changsha, China
| | - Huarong Yang
- Center for Experimental Medicine, the Third Xiangya Hospital, Central South University, Changsha, China
- Department of Neurology, the Third Xiangya Hospital, Central South University, Changsha, China
| | - Yong Qi
- Center for Experimental Medicine, the Third Xiangya Hospital, Central South University, Changsha, China
| | - Xiong Deng
- Center for Experimental Medicine, the Third Xiangya Hospital, Central South University, Changsha, China
| | - Le Zhang
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
| | - Yi Guo
- Department of Physiology, Xiangya Medical School, Central South University, Changsha, China
| | - Qing Huang
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
| | - Jing Li
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
| | - Xiaoliu Shi
- Department of Gastroenterology, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Zhi Song
- Department of Neurology, the Third Xiangya Hospital, Central South University, Changsha, China
| | - Hao Deng
- Center for Experimental Medicine, the Third Xiangya Hospital, Central South University, Changsha, China
- Department of Neurology, the Third Xiangya Hospital, Central South University, Changsha, China
- * E-mail:
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Chang H, Xu A, Chen Z, Zhang Y, Tian F, Li T. Long-term effects of a combination of D-penicillamine and zinc salts in the treatment of Wilson's disease in children. Exp Ther Med 2013; 5:1129-1132. [PMID: 23599735 PMCID: PMC3628594 DOI: 10.3892/etm.2013.971] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2012] [Accepted: 01/24/2013] [Indexed: 02/06/2023] Open
Abstract
The aim of this study was to investigate the effectiveness of a high-dose zinc sulfate and low-dose D-penicillamine combination in the treatment of pediatric Wilson's disease (WD). A retropective chart review of 65 patients with WD was conducted. These patients received D-penicillamine (8-10 mg/kg/day) and zinc sulfate as the primary treatment. The pediatric dose of elemental zinc is 68-85 mg/day until 6 years of age, 85-136 mg/day until 8 years of age, 136-170 mg/day until 10 years of age and then 170 mg/day, in 3 divided doses 1 h before meals. After clinical and biochemical improvement or stabilization, zinc sulfate alone was administered as the maintenance therapy. Under treatment, the majority of patients (89.2%) had a favourable outcome and 3 patients succumbed due to poor therapy compliance. No penicillamine-induced neurological deterioration was noted and side-effects were observed in <11% of patients over the entire follow-up period. Benefical results on the liver and neurological symptoms were reported following extremely long-term treatment with a combination of low-dose D-penicillamine and high-dose zinc sulfate. Therefore, this regimen is an effective and safe treatment for children with WD.
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Affiliation(s)
- Hong Chang
- Department of Pediatrics, Affiliated Hospital of Medical College, Qingdao University, Qingdao 266003
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Lozano Herrero J, Muñoz Bertrán E, Ortega González I, Gómez Espín R, López Espín MI. Myelopathy secondary to copper deficiency as a complication of treatment of Wilson's disease. GASTROENTEROLOGIA Y HEPATOLOGIA 2012; 35:704-7. [DOI: 10.1016/j.gastrohep.2012.03.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/05/2012] [Revised: 03/18/2012] [Accepted: 03/21/2012] [Indexed: 01/28/2023]
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