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Chaturvedi A, Sharma S, Shukla R. Nano-Mediated Molecular Targeting in Diagnosis and Mitigation of Wilson Disease. Mol Neurobiol 2024; 61:4240-4258. [PMID: 38066399 DOI: 10.1007/s12035-023-03816-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 11/18/2023] [Indexed: 07/11/2024]
Abstract
Wilson disease, a rare genetic disorder resulting from mutations in the ATP7B gene disrupts copper metabolism, leading to its harmful accumulation in hepatocytes, the brain, and other organs. It affects roughly 1 in 30,000 individuals, with 1 in 90 being gene carriers. Beyond gene mutations, the disease involves complex factors contributing to copper imbalance. Ongoing research seeks to unravel intricate molecular pathways, offering fresh insights into the disease's mechanisms. Simultaneously, there is a dedicated effort to develop effective therapeutic strategies. Nanotechnology-driven formulations are showing promise for both treatment and early diagnosis of Wilson disease. This comprehensive review covers the entire spectrum of the condition, encompassing pathophysiology, potential biomarkers, established and emerging therapies, ongoing clinical trials, and innovative nanotechnology applications. This multifaceted approach holds the potential to improve our understanding, diagnosis, and management of Wilson's disease, which remains a challenging and potentially life-threatening disorder.
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Affiliation(s)
- Akanksha Chaturvedi
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research-Raebareli (NIPER-Raebareli), Bijnor-Sisendi Road, Sarojini Nagar, Near CRPF Base Camp, Lucknow, UP, 226002, India
| | - Swapnil Sharma
- Department of Pharmacy, Banasthali University, Banasthali, Rajasthan, 304022, India
| | - Rahul Shukla
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research-Raebareli (NIPER-Raebareli), Bijnor-Sisendi Road, Sarojini Nagar, Near CRPF Base Camp, Lucknow, UP, 226002, India.
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2
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Welham S, Rose P, Kirk C, Coneyworth L, Avery A. Mineral Supplements in Ageing. Subcell Biochem 2024; 107:269-306. [PMID: 39693029 DOI: 10.1007/978-3-031-66768-8_13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2024]
Abstract
With advancing age, achievement of dietary adequacy for all nutrients is increasingly difficult and this is particularly so for minerals. Various factors impede mineral acquisition and absorption including reduced appetite, depressed gastric acid production and dysregulation across a range of signalling pathways in the intestinal mucosa. Minerals are required in sufficient levels since they are critical for the proper functioning of metabolic processes in cells and tissues, including energy metabolism, DNA and protein synthesis, immune function, mobility, and skeletal integrity. When uptake is diminished or loss exceeds absorption, alternative approaches are required to enable individuals to maintain adequate mineral levels. Currently, supplementation has been used effectively in populations for the restoration of levels of some minerals like iron, zinc, and calcium, but these may not be without inherent challenges. Therefore, in this chapter we review the current understanding around the effectiveness of mineral supplementation for the minerals most clinically relevant for the elderly.
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Affiliation(s)
- Simon Welham
- Division of Food, Nutrition and Dietetics, School of Biosciences, University of Nottingham, Sutton Bonington Campus, Sutton Bonington, Leicestershire, UK.
| | - Peter Rose
- Division of Food, Nutrition and Dietetics, School of Biosciences, University of Nottingham, Sutton Bonington Campus, Sutton Bonington, Leicestershire, UK
| | - Charlotte Kirk
- Division of Food, Nutrition and Dietetics, School of Biosciences, University of Nottingham, Sutton Bonington Campus, Sutton Bonington, Leicestershire, UK
| | - Lisa Coneyworth
- Division of Food, Nutrition and Dietetics, School of Biosciences, University of Nottingham, Sutton Bonington Campus, Sutton Bonington, Leicestershire, UK
| | - Amanda Avery
- Division of Food, Nutrition and Dietetics, School of Biosciences, University of Nottingham, Sutton Bonington Campus, Sutton Bonington, Leicestershire, UK
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Quaglia A, Roberts EA, Torbenson M. Developmental and Inherited Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:122-294. [DOI: 10.1016/b978-0-7020-8228-3.00003-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Chevalier K, Obadia MA, Djebrani‐Oussedik N, Poujois A. Can Patients with Wilson's Disease Develop Copper Deficiency? Mov Disord Clin Pract 2023; 10:1306-1316. [PMID: 37772303 PMCID: PMC10525062 DOI: 10.1002/mdc3.13813] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 05/15/2023] [Accepted: 05/28/2023] [Indexed: 09/30/2023] Open
Abstract
Background Wilson's disease (WD) is a rare genetic condition characterized by a copper overload in organs secondary to mutation in ATP7B gene. Lifelong decoppering treatments are the keystone of the treatment but must be regularly adapted to obtain a correct copper balance and could lead to copper deficiency (CD). Objectives Study the characteristics of CD in WD patients. Methods CD cases from our cohort of 338 WD patients have been investigated. CD was defined by the association of serum copper, exchangeable copper and urinary copper excretion assays less than two standard deviations from the mean with cytopenia and/or neurological damage of spinal cord origin. A systematic review of literature about cases of CD in WD patient was performed in PubMed database according to PRISMA guidelines. Results Three WD patients were diagnosed with CD in our cohort. Review of the literature found 17 other patients. Most of the patients had anemia and neutropenia associated with neurological symptoms (especially progressive posterior cord syndrome). All the patients were treated with Zinc salts and the symptoms occurred more than a decade after the initiation of treatment. The adaptation of the treatment allowed a correction of the cytopenia but only a partial improvement of the neurological symptoms. Conclusions WD patients can develop CD after many years of zinc therapy. Anemia and neutropenia are red flags that should evoke CD.
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Affiliation(s)
- Kevin Chevalier
- Department of NeurologyRothschild Foundation HospitalParisFrance
- National Reference Center for Wilson's Disease and Other Copper‐Related Rare DiseasesRothschild Foundation HospitalParisFrance
| | - Mickaël Alexandre Obadia
- Department of NeurologyRothschild Foundation HospitalParisFrance
- National Reference Center for Wilson's Disease and Other Copper‐Related Rare DiseasesRothschild Foundation HospitalParisFrance
| | - Nouzha Djebrani‐Oussedik
- National Reference Center for Wilson's Disease and Other Copper‐Related Rare DiseasesRothschild Foundation HospitalParisFrance
- Toxicology LaboratoryLariboisière Hospital, APHPParisFrance
| | - Aurélia Poujois
- Department of NeurologyRothschild Foundation HospitalParisFrance
- National Reference Center for Wilson's Disease and Other Copper‐Related Rare DiseasesRothschild Foundation HospitalParisFrance
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Lubna S, Ahmad R. Clinical and biochemical understanding of Zinc interaction during liver diseases: A paradigm shift. J Trace Elem Med Biol 2023; 77:127130. [PMID: 36641955 DOI: 10.1016/j.jtemb.2023.127130] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Revised: 12/01/2022] [Accepted: 01/04/2023] [Indexed: 01/07/2023]
Abstract
Zinc (Zn) is an essential and the second most abundant trace element after Iron. It can apply antioxidant, anti-inflammatory, and anti-apoptotic activity. It is assumed to be indispensable for cell division, cellular differentiation and cell signalling. Zinc is essential for proper liver function which is also the site of its metabolism. Depleted Zn concentrations have been observed in both acute and chronic hepatic diseases. It is reported that Zn deficiency or abnormal Zn metabolism during majority of liver diseases is attributed to deficient dietary intake of Zn, augmented disposal of Zn in the urine, activation of certain Zn transporters, and expression of hepatic metallothionein. Undoubtedly, Zn is involved in generating many diseases but how and whether it plays role from acute to fulminant stage of all chronic liver diseases remains to be cleared. Here, we will discuss the role of Zn in development of different diseases specifically the involvement of Zn to understand the aetiology and intricate mechanism of dynamic liver diseases.
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Affiliation(s)
- Shiba Lubna
- Section of Genetics, Department of Zoology, Faculty of Life Sciences, Aligarh Muslim University, Aligarh 202001, India
| | - Riaz Ahmad
- Section of Genetics, Department of Zoology, Faculty of Life Sciences, Aligarh Muslim University, Aligarh 202001, India.
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Balasubramanian A, Holbrook JT, Canning BJ, Que LG, Castro M, Make BJ, Rogers L, Busk MF, Rea A, McCook-Veal AA, He J, McCormack MC, Wise RA. Efficacy and tolerability of zinc acetate for treatment of chronic refractory cough: pilot randomised futility trial. ERJ Open Res 2023; 9:00678-2022. [PMID: 37057088 PMCID: PMC10086688 DOI: 10.1183/23120541.00678-2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 01/13/2023] [Indexed: 03/11/2023] Open
Abstract
Background Cough is the most reported symptom in the United States, with chronic refractory cough representing significant morbidity to patients. Zinc acetate may have beneficial effects in the cough reflex pathway. We sought to assess the safety and efficacy of zinc acetate in the management of chronic refractory cough. Study design and methods This was a randomised, placebo-controlled, parallel-design pilot trial of individuals with chronic refractory cough. The effects of 6 weeks of zinc acetate versus placebo on quality of life and symptoms as measured by the Cough Quality-of-Life Questionnaire (CQLQ), Leicester Cough Questionnaire (LCQ), cough visual analogue score (C-VAS) and Global Assessment of Change in Cough (GACC) scores were evaluated. A futility analysis plan with a one-sided 80% confidence interval was used to compare treatment effect to published minimum clinically important differences (MCID) for each outcome. Results 34 participants, 17 in each group, were enrolled and randomised. Participants were primarily white females with moderate-severe cough. Participants assigned to zinc acetate had a significant increase in serum zinc levels after 6 weeks, while those assigned to placebo did not. Both groups showed improvement in CQLQ, LCQ, C-VAS and GACC scores, but the treatment effects of zinc acetate versus placebo were small with confidence intervals that did not include the MCIDs. Interpretation We observed no benefit of zinc therapy over placebo on cough symptoms or quality of life and conclude that larger trials of zinc for chronic cough are not warranted.
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Affiliation(s)
- Aparna Balasubramanian
- The Johns Hopkins University, School of Medicine, Pulmonary and Critical Care Medicine, Baltimore, MD, USA
| | - Janet T. Holbrook
- The Johns Hopkins University, Bloomberg School of Public Health, Epidemiology, Baltimore, MD, USA
| | - Brendan J. Canning
- The Johns Hopkins University, School of Medicine, Pulmonary and Critical Care Medicine, Baltimore, MD, USA
| | - Loretta G. Que
- Duke University School of Medicine, Pulmonary, Allergy, and Critical Care Medicine, Durham, NC, USA
| | - Mario Castro
- Kansas University Medical Center, Pulmonary, Critical Care and Sleep Medicine, Kansas City, KA, USA
| | - Barry J. Make
- National Jewish Health, Division of Pulmonary, Critical Care and Sleep Medicine, Denver, CO, USA
| | - Linda Rogers
- Icahn School of Medicine at Mount Sinai, Pulmonary, Critical Care and Sleep Medicine, New York, NY, USA
| | - Michael F. Busk
- St Vincent Health, Wellness and Preventive Care Institute, Indianapolis, IN, USA
| | - Alexis Rea
- The Johns Hopkins University, Bloomberg School of Public Health, Epidemiology, Baltimore, MD, USA
| | - Ashley A. McCook-Veal
- The Johns Hopkins University, Bloomberg School of Public Health, Epidemiology, Baltimore, MD, USA
| | - Jiaxian He
- The Johns Hopkins University, Bloomberg School of Public Health, Epidemiology, Baltimore, MD, USA
| | - Meredith C. McCormack
- The Johns Hopkins University, School of Medicine, Pulmonary and Critical Care Medicine, Baltimore, MD, USA
| | - Robert A. Wise
- The Johns Hopkins University, School of Medicine, Pulmonary and Critical Care Medicine, Baltimore, MD, USA
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Crystal Structure of the Human Copper Chaperone ATOX1 Bound to Zinc Ion. Biomolecules 2022; 12:biom12101494. [PMID: 36291703 PMCID: PMC9599288 DOI: 10.3390/biom12101494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 10/09/2022] [Accepted: 10/10/2022] [Indexed: 11/17/2022] Open
Abstract
The bioavailability of copper (Cu) in human cells may depend on a complex interplay with zinc (Zn) ions. We investigated the ability of the Zn ion to target the human Cu-chaperone Atox1, a small cytosolic protein capable of anchoring Cu(I), by a conserved surface-exposed Cys-X-X-Cys (CXXC) motif, and deliver it to Cu-transporting ATPases in the trans-Golgi network. The crystal structure of Atox1 loaded with Zn displays the metal ion bridging the CXXC motifs of two Atox1 molecules in a homodimer. The identity and location of the Zn ion were confirmed through the anomalous scattering of the metal by collecting X-ray diffraction data near the Zn K-edge. Furthermore, soaking experiments of the Zn-loaded Atox1 crystals with a strong chelating agent, such as EDTA, caused only limited removal of the metal ion from the tetrahedral coordination cage, suggesting a potential role of Atox1 in Zn metabolism and, more generally, that Cu and Zn transport mechanisms could be interlocked in human cells.
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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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Efficacy and Safety of Two Salts of Trientine in the Treatment of Wilson’s Disease. J Clin Med 2022; 11:jcm11143975. [PMID: 35887738 PMCID: PMC9325285 DOI: 10.3390/jcm11143975] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 06/30/2022] [Accepted: 07/06/2022] [Indexed: 11/24/2022] Open
Abstract
Background: Wilson’s disease (WD) is one of the few genetic disorders that can be successfully treated with pharmacological agents. Copper-chelating agents (D-penicillamine and Trientine salts) and zinc salts have been demonstrated to be effective. There are two salts of trientine. Trientine dihydrochloride salt (TETA 2HCL) is unstable at room temperature and requires storage at 2–8 °C. Trientine tetrahydrochloride (TETA 4HCL) is a more stable salt of trientine that can be stored at room temperature. No comparative study between both of the salts of trientine has been performed to date. As the two chemical forms were available in France between 1970 and 2009, we conducted a study to evaluate their efficacy and safety profiles. Methods: This retrospective cohort study was conducted by reviewing data from the national WD registry in France. Forty-three WD patients who received TETA 2HCL or TETA 4HCL monotherapy for at least one year until 2010 were included. The primary endpoints were hepatic and neurological outcomes. Secondary endpoints were the events leading to a discontinuation of medication. Results: Changes in medication were common, leading to the analysis of 57 treatment sequences of TETA 4HCL or TETA 2HCL. The mean duration of treatment sequence was significantly longer in the TETA 4 HCL group (12.6 years) than in the TETA 2HCL group (7.6 years) (p = 0.011). Ten patients experienced both trientine salts: eight stopped TETA 4 HCL (six had a hepatologic phenotype and two had a neurological phenotype) because this treatment was not available anymore (mean duration 7.4 years). Three of these patients already experienced TETA 2 HCL before the sequence. Two patients with a hepatologic phenotype (one had a previous sequence of TETA 4 HCL before) stopped TETA 2 HCL because of cold storage issues (mean duration 42.8 years). The total number of sequences was 57. All of the patients were clinically stable. No difference in efficacy was detected. Both treatments were well tolerated, except for a case of recurrence of lupus erythematosus-like syndrome in the TETA 2HCL group. The major reason for interruption of TETA 4HCL was due to a discontinuation in production of this salt. The reasons for stopping TETA 2HCL were mainly due to adherence issues largely attributed to the cold storage requirement. Conclusions: The two salts of trientine were effective in treating patients with WD. However, interruption of TETA 2HCL was frequent, linked to the cold storage requirement. As adherence to treatment is a key factor in the successful management of WD, physicians need to be even more vigilant in detecting adherence difficulties in patients receiving treatment with TETA 2HCL.
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Deme P, Sheffield A, Alick-Lindstrom S. Wilson's disease: neuropsychiatric presentation and delayed diagnosis. BMJ Case Rep 2022; 15:e246296. [PMID: 35787503 PMCID: PMC9255368 DOI: 10.1136/bcr-2021-246296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/18/2022] [Indexed: 11/03/2022] Open
Abstract
A woman in her 30s with unclear history of cirrhosis presented to the emergency department with 8 months of worsening bilateral hand tremors, falls, depressed mood, altered mental status, difficulty swallowing and faecal/urinary incontinence. The patient was diagnosed with liver cirrhosis 6 years prior based on outside hospital ultrasound and liver biopsy. The hospital inpatient neurology team was promptly consulted for evaluation of worsening mental status. Kayser-Fleischer rings were visible without slit-lamp examination on clinical exam, as were prominent hand tremors and ataxia on finger-nose-finger task. Brain MRI showed increased T2/FLAIR (fluid-attenuated inversion recovery) signal within the thalami, midbrain and pons demonstrating a 'double panda sign'. Laboratory findings confirmed a diagnosis of Wilson's disease. Penicillamine and subsequent zinc therapy were initiated. Patient was eventually discharged home with plans for outpatient physical therapy and hepatology management. Two months from presentation, the patient reported significant improvement in ataxia, motor function, swallow function and incontinence.
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Affiliation(s)
- Palvasha Deme
- Department of Plastic Surgery, UT Southwestern, Dallas, Texas, USA
| | - Adam Sheffield
- Department of Neurology, UT Southwestern, Dallas, Texas, USA
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Abbassi N, Bourrahouat A, Bedoya EC, Belmalih A, El Hanafi FZ, Bost M, Sedki A, Lachaux A. Epidemiology, clinical features, and mortality rate of Wilson disease in Moroccan children: A pediatric case series. Arch Pediatr 2022; 29:453-458. [PMID: 35705388 DOI: 10.1016/j.arcped.2022.03.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 01/17/2022] [Accepted: 03/26/2022] [Indexed: 11/28/2022]
Abstract
BACKGROUND AND STUDY AIMS Wilson's disease is an autosomal recessive disorder, that affects copper metabolism, leading to copper accumulation in the liver, nervous system, and cornea. Data are lacking on the epidemiology, the clinical and laboratory characteristics, treatment, and survival of Wilson's disease in Morocco. The aim of this study was to examine these features and the cause of death in a Moroccan pediatric population. PATIENTS AND METHODS The study was carried out at the University Hospital Center of Marrakesh, Morocco; 46 children were diagnosed with Wilson's disease from 2008 to 2019. The diagnosis was based on low serum ceruloplasmin, increased urinary copper concentrations, the presence of Kayser-Fleischer rings, a family history of Wilson's disease, and a Leipzig score of ≥ 4. RESULTS A total of 42 patients were referred to the center for hepatic or neurological manifestations; four patients were asymptomatic. Consanguineous marriage was found in 67.4% of the cases. The mean duration of illness (42 patients) was 4.9 ± 3.9 years. Kayser-Fleischer rings were found in 60.9% of 46 patients. Of the 42 symptomatic patients: 28 of 30 (93.3%) patients had low serum ceruloplasmin (<0.2 g/L), and 24 h urinary copper >100 μg/day was found in 34 of 35 (97.1%) cases. The treatment was established with D-penicillamine for 43 of the 46 patients, with zinc acetate for one patient and with zinc sulfate in for one patient, while one patient was not treated. D-penicillamine was discontinued in nine patients because of adverse effects such as thrombocytopenia, neurological deterioration, pancytopenia, severe vomiting and severe hypersensitivity. In total 28 patients were clinically and biologically stabilized, two patients experienced vision loss, and 16 patients died (38%). The main cause of death was diagnosis made at an advanced stage of disease and stopping treatment. CONCLUSION Wilson's disease is a rare condition associated with treatement efficacy, but late diagnosis and stopping treatment can lead to a high mortality rate.
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Affiliation(s)
- N Abbassi
- Laboratory LHEAC, Faculty of Science Semlalia, Cadi Ayyad University, Marrakesh 40000, Morocco; CarMeN Laboratory, INSERM, INRA, INSA Lyon, Claude Bernard Lyon 1 University, Lyon 69921, France.
| | - A Bourrahouat
- Padiatric Hospital, CHU Marrakesh, Marrakesh 40080, Morocco; Faculty of Medicine, Cadi Ayyad University, Marrakesh 40000, Morocco
| | - E Couchonnal Bedoya
- Gastroentrology, Hepatology and Nutrition unit, Pediatric Hospital, HCL, Lyon 69500, France; Reference Center for Wilson Disease, HCL, Lyon 69500, France
| | - A Belmalih
- Reference Center for Wilson Disease, HCL, Lyon 69500, France
| | - F Z El Hanafi
- Padiatric Hospital, CHU Marrakesh, Marrakesh 40080, Morocco; Faculty of Medicine, Cadi Ayyad University, Marrakesh 40000, Morocco
| | - M Bost
- Reference Center for Wilson Disease, HCL, Lyon 69500, France; Pharmaco-Toxicology and Trace Analysis Federation of Biochemistry Laboratory, HCL, Lyon 69310, France
| | - A Sedki
- Laboratory LHEAC, Faculty of Science Semlalia, Cadi Ayyad University, Marrakesh 40000, Morocco
| | - A Lachaux
- CarMeN Laboratory, INSERM, INRA, INSA Lyon, Claude Bernard Lyon 1 University, Lyon 69921, France; Gastroentrology, Hepatology and Nutrition unit, Pediatric Hospital, HCL, Lyon 69500, France; Reference Center for Wilson Disease, HCL, Lyon 69500, France
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12
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Lynch EN, Campani C, Innocenti T, Dragoni G, Forte P, Galli A. Practical insights into chronic management of hepatic Wilson’s disease. World J Clin Cases 2022; 10:4334-4347. [PMID: 35663095 PMCID: PMC9125272 DOI: 10.12998/wjcc.v10.i14.4334] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 10/07/2021] [Accepted: 03/26/2022] [Indexed: 02/06/2023] Open
Abstract
Wilson’s disease (WD) is a rare inherited disorder of human copper metabolism, with an estimated prevalence of 1:30000-1:50000 and a broad spectrum of hepatic and neuropsychiatric manifestations. In healthy individuals, the bile is the main route of elimination of copper. In WD patients, copper accumulates in the liver, it is released into the bloodstream, and is excreted in urine. Copper can also be accumulated in the brain, kidneys, heart, and osseous matter and causes damage due to direct toxicity or oxidative stress. Hepatic WD is commonly but not exclusively diagnosed in childhood or young adulthood. Adherent, non-cirrhotic WD patients seem to have a normal life expectancy. Nevertheless, chronic management of patients with Wilson’s disease is challenging, as available biochemical tests have many limitations and do not allow a clear identification of non-compliance, overtreatment, or treatment goals. To provide optimal care, clinicians should have a complete understanding of these limitations and counterbalance them with a thorough clinical assessment. The aim of this review is to provide clinicians with practical tools and suggestions which may answer doubts that can arise during chronic management of patients with hepatic WD. In particular, it summarises current knowledge on Wilson’s disease clinical and biochemical monitoring and treatment. It also analyses available evidence on pregnancy and the role of low-copper diet in WD. Future research should focus on trying to provide new copper metabolism tests which could help to guide treatment adjustments.
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Affiliation(s)
- Erica Nicola Lynch
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
| | - Claudia Campani
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
| | - Tommaso Innocenti
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
| | - Gabriele Dragoni
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
- Department of Medical Biotechnologies, University of Siena, Siena 53100, Italy
| | - Paolo Forte
- Division of Gastroenterology, University Hospital “Careggi”, Florence 50134, Italy
| | - Andrea Galli
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
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Abstract
Wilson disease (WD) is an autosomal recessive disorder caused by mutations of the ATP7B gene, with a reported prevalence of 1:30,000-50,000. ATP7B encodes an enzyme called transmembrane copper-transporting ATPase, which is essential for copper incorporation into ceruloplasmin and for copper excretion into the bile. A lack or dysfunction of this enzyme results in a progressive accumulation of copper in several organs, especially in the liver, the nervous system, corneas, kidneys, and heart. Children with WD can present with asymptomatic liver disease, cirrhosis, or acute liver failure, with or without neurological and psychiatric symptoms. Approximately 20%-30% of WD patients present with ALF, while most of the other patients have chronic progressive hepatitis or cirrhosis if untreated. Although genetic testing has become a more important diagnostic tool for WD, the diagnosis remains based on both clinical features and laboratory investigations. The aims of treatment are to reduce copper levels and prevent its accumulation in the liver and other organs, especially in the central nervous system. Liver transplantation in WD is a life-saving option for patients presenting with liver failure and encephalopathy. For WD patients treated with chelating agents, adherence to the therapy is essential for long-term success. In this review, we also address specific issues in young adults as compared to children.
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Affiliation(s)
- Atchariya Chanpong
- Paediatric Liver, GI and Nutrition Centre, MowatLabs, King's College Hospital, Denmark Hill, London, United Kingdom,Division of Gastroenterology and Hepatology, Department of Pediatrics, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand
| | - Anil Dhawan
- Paediatric Liver, GI and Nutrition Centre, MowatLabs, King's College Hospital, Denmark Hill, London, United Kingdom,Address for correspondence: Prof. Anil Dhawan, Paediatric Liver, GI and Nutrition Centre, MowatLabs, King's College Hospital, Denmark Hill, London SE5 9RH, United Kingdom. E-mail:
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14
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Osterode W, Falkenberg G, Wrba F. Copper and Trace Elements in Gallbladder form Patients with Wilson's Disease Imaged and Determined by Synchrotron X-ray Fluorescence. J Imaging 2021; 7:jimaging7120261. [PMID: 34940728 PMCID: PMC8705686 DOI: 10.3390/jimaging7120261] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 11/23/2021] [Accepted: 11/26/2021] [Indexed: 12/16/2022] Open
Abstract
Investigations about suspected tissue alterations and the role of gallbladder in Wilson’s disease (WD)—an inherited genetic disease with impaired copper metabolism—are rare. Therefore, tissue from patients with genetically characterised WD was investigated by microscopic synchrotron X-ray fluorescence (µSRXRF). For two-dimensional imaging and quantification of elements, X-ray spectra were peak-fitted, and the net peak intensities were normalised to the intensity of the incoming monochromatic beam intensity. Concentrations were calculated by fundamental parameter-based program quant and external standardisation. Copper (Cu), zinc (Zn) and iron (Fe) along with sulphur (S) and phosphorus (P) mappings could be demonstrated in a near histological resolution. All these elements were increased compared to gallbladder tissue from controls. Cu and Zn and Fe in WD-GB were mostly found to be enhanced in the epithelium. We documented a significant linear relationship with Cu, Zn and sulphur. Concentrations of Cu/Zn were roughly 1:1 while S/Cu was about 100:1, depending on the selected areas for investigation. The significant linear relationship with Cu, Zn and sulphur let us assume that metallothioneins, which are sulphur-rich proteins, are increased too. Our data let us suggest that the WD gallbladder is the first in the gastrointestinal tract to reabsorb metals to prevent oxidative damage caused by metal toxicity.
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Affiliation(s)
- Wolf Osterode
- Universitätsklinik für Innere Medizin II, Medical University of Vienna, A-1090 Vienna, Austria
- Correspondence:
| | - Gerald Falkenberg
- Deutsches Elektronen-Synchrotron (DESY), Photon Science, D-22603 Hamburg, Germany;
| | - Fritz Wrba
- Klinisches Institut für Klinische Pathologie, Medical University of Vienna, A-1090 Vienna, Austria;
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15
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Kasztelan-Szczerbinska B, Cichoz-Lach H. Wilson's Disease: An Update on the Diagnostic Workup and Management. J Clin Med 2021; 10:5097. [PMID: 34768617 PMCID: PMC8584493 DOI: 10.3390/jcm10215097] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Revised: 10/18/2021] [Accepted: 10/27/2021] [Indexed: 02/08/2023] Open
Abstract
Wilson's disease (WD) is a rare autosomal recessive disorder of hepatocellular copper deposition. The diagnostic approach to patients with WD may be challenging and is based on a complex set of clinical findings that derive from patient history, physical examination, as well as laboratory and imaging testing. No single examination can unequivocally confirm or exclude the disease. Timely identification of signs and symptoms using novel biomarkers and modern diagnostic tools may help to reduce treatment delays and improve patient prognosis. The proper way of approaching WD management includes, firstly, early diagnosis and prompt treatment introduction; secondly, careful and lifelong monitoring of patient compliance and strict adherence to the treatment; and, last but not least, screening for adverse effects and evaluation of treatment efficacy. Liver transplantation is performed in about 5% of WD patients who present with acute liver failure at first disease presentation or with signs of decompensation in the course of liver cirrhosis. Increasing awareness of this rare inherited disease among health professionals, emphasizing their training to consider early signs and symptoms of the illness, and strict monitoring are vital strategies for the patient safety and efficacy of WD therapy.
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Affiliation(s)
- Beata Kasztelan-Szczerbinska
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, 8 Jaczewski Street, 20-954 Lublin, Poland;
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16
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Omeish H, Hajjaj N, Abdulelah M, Bader H. You Only Find What You Are Looking for: Concurrent Alcoholic Liver Cirrhosis and Undiagnosed Wilson's Disease. Cureus 2021; 13:e17117. [PMID: 34527496 PMCID: PMC8433493 DOI: 10.7759/cureus.17117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/12/2021] [Indexed: 11/08/2022] Open
Abstract
Wilson’s disease (WD), a rare genetic disorder characterized by copper accumulation, leads to a spectrum of hepatic dysfunction including liver cirrhosis, fulminant liver failure, and chronic hepatitis. Its manifestations could involve musculoskeletal, hematologic, neuropsychiatric, or renal systems. We present the case of a 27-year-old female with a past medical history of alcohol use disorder who presented with acute confusion, worsening abdominal distension, bilateral lower limb edema, and jaundice.The initial presentation was concerning for acute alcoholic hepatitis and decompensated alcoholic cirrhosis attributed to ongoing heavy alcohol consumption. However, due to the patient’s young age, the severity of presentation, and the pattern of liver enzyme elevation, further workup was conducted to rule out concurrent pathologies. Viral, autoimmune, and metabolic workups were unrevealing. Subsequently, low ceruloplasmin levels and elevated urinary copper levels led to a diagnosis of WD with concomitant alcoholic liver disease. The coexistence of WD and alcohol-associated liver disease (ALD) has not been well described in the literature. Laboratory testing including alkaline phosphatase (ALP), bilirubin, and serum aminotransferases provides the most rapid and accurate method for diagnosing ALD due to WD, given that the conventional screening tests such as ceruloplasmin are less sensitive and specific in identifying patients with acute liver disease secondary to WD.
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Affiliation(s)
- Haya Omeish
- Department of Internal Medicine, Royal Jordanian Medical Centre, Amman, JOR
| | - Nada Hajjaj
- Department of Internal Medicine, The University of Jordan, Amman, JOR
| | | | - Husam Bader
- Department of Internal Medicine, Presbyterian Medical Center, Albuquerque, USA
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17
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Living with the enemy: from protein-misfolding pathologies we know, to those we want to know. Ageing Res Rev 2021; 70:101391. [PMID: 34119687 DOI: 10.1016/j.arr.2021.101391] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 04/19/2021] [Accepted: 06/09/2021] [Indexed: 12/12/2022]
Abstract
Conformational diseases are caused by the aggregation of misfolded proteins. The risk for such pathologies develops years before clinical symptoms appear, and is higher in people with alpha-1 antitrypsin (AAT) polymorphisms. Thousands of people with alpha-1 antitrypsin deficiency (AATD) are underdiagnosed. Enemy-aggregating proteins may reside in these underdiagnosed AATD patients for many years before a pathology for AATD fully develops. In this perspective review, we hypothesize that the AAT protein could exert a new and previously unconsidered biological effect as an endogenous metal ion chelator that plays a significant role in essential metal ion homeostasis. In this respect, AAT polymorphism may cause an imbalance of metal ions, which could be correlated with the aggregation of amylin, tau, amyloid beta, and alpha synuclein proteins in type 2 diabetes mellitus (T2DM), Alzheimer's and Parkinson's diseases, respectively.
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18
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McCarty MF. Nutraceutical, Dietary, and Lifestyle Options for Prevention and Treatment of Ventricular Hypertrophy and Heart Failure. Int J Mol Sci 2021; 22:ijms22073321. [PMID: 33805039 PMCID: PMC8037104 DOI: 10.3390/ijms22073321] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 03/22/2021] [Accepted: 03/22/2021] [Indexed: 12/12/2022] Open
Abstract
Although well documented drug therapies are available for the management of ventricular hypertrophy (VH) and heart failure (HF), most patients nonetheless experience a downhill course, and further therapeutic measures are needed. Nutraceutical, dietary, and lifestyle measures may have particular merit in this regard, as they are currently available, relatively safe and inexpensive, and can lend themselves to primary prevention as well. A consideration of the pathogenic mechanisms underlying the VH/HF syndrome suggests that measures which control oxidative and endoplasmic reticulum (ER) stress, that support effective nitric oxide and hydrogen sulfide bioactivity, that prevent a reduction in cardiomyocyte pH, and that boost the production of protective hormones, such as fibroblast growth factor 21 (FGF21), while suppressing fibroblast growth factor 23 (FGF23) and marinobufagenin, may have utility for preventing and controlling this syndrome. Agents considered in this essay include phycocyanobilin, N-acetylcysteine, lipoic acid, ferulic acid, zinc, selenium, ubiquinol, astaxanthin, melatonin, tauroursodeoxycholic acid, berberine, citrulline, high-dose folate, cocoa flavanols, hawthorn extract, dietary nitrate, high-dose biotin, soy isoflavones, taurine, carnitine, magnesium orotate, EPA-rich fish oil, glycine, and copper. The potential advantages of whole-food plant-based diets, moderation in salt intake, avoidance of phosphate additives, and regular exercise training and sauna sessions are also discussed. There should be considerable scope for the development of functional foods and supplements which make it more convenient and affordable for patients to consume complementary combinations of the agents discussed here. Research Strategy: Key word searching of PubMed was employed to locate the research papers whose findings are cited in this essay.
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Affiliation(s)
- Mark F McCarty
- Catalytic Longevity Foundation, 811 B Nahant Ct., San Diego, CA 92109, USA
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19
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Management of Wilson Disease Diagnosed in Infancy: An Appraisal of Available Experience to Generate Discussion. J Pediatr Gastroenterol Nutr 2020; 70:547-554. [PMID: 31899725 DOI: 10.1097/mpg.0000000000002608] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Increased access to molecular genetic testing is changing the demographics for diagnosing inherited disorders and imposing new challenges for medical management. Wilson disease (WD), typically diagnosed in older children and adults, can now be detected in utero and in infants (children younger than 24 months, including neonates) via genetic testing. An evidence-based approach to management of these neonates and extremely young children, who are typically asymptomatic, has been hampered by lack of clinical experience. We present a case of an infantile diagnosis of WD, review available experience, and discuss current trends in antenatal genetic testing of parents and fetus that may lead to a very early diagnosis of WD. Based on physiological and nutritional considerations, we propose an algorithmic approach to management of infantile WD as a starting point for further discussion. Future collaboration amongst specialists is essential to identify evidence-based approaches and best practice for managing treatment of infants with genetically diagnosed WD.
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20
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Synthesis and Biological Activity of Novel Zinc-Itraconazole Complexes in Protozoan Parasites and Sporothrix spp. Antimicrob Agents Chemother 2020; 64:AAC.01980-19. [PMID: 32152072 DOI: 10.1128/aac.01980-19] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 02/23/2020] [Indexed: 01/19/2023] Open
Abstract
The new complexes Zn(ITZ)2Cl2 (1) and Zn(ITZ)2(OH)2 (2) were synthetized by a reaction of itraconazole with their respective zinc salts under reflux. These Zn-ITZ complexes were characterized by elemental analyses, molar conductivity, mass spectrometry, 1H and 13C{1H} nuclear magnetic resonance, and UV-vis and infrared spectroscopies. The antiparasitic and antifungal activity of Zn-ITZ complexes was evaluated against three protozoans of medical importance, namely, Leishmania amazonensis, Trypanosoma cruzi, and Toxoplasma gondii, and two fungi, namely, Sporothrix brasiliensis and Sporothrix schenckii The Zn-ITZ complexes exhibited a broad spectrum of action, with antiparasitic and antifungal activity in low concentrations. The strategy of combining zinc with ITZ was efficient to enhance ITZ activity since Zn-ITZ-complexes were more active than the azole alone. This study opens perspectives for future applications of these Zn-ITZ complexes in the treatment of parasitic diseases and sporotrichosis.
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21
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Sekovanić A, Jurasović J, Piasek M. Metallothionein 2A gene polymorphisms in relation to diseases and trace element levels in humans. Arh Hig Rada Toksikol 2020; 71:27-47. [PMID: 32597135 PMCID: PMC7837243 DOI: 10.2478/aiht-2020-71-3349] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 10/01/2019] [Accepted: 03/01/2020] [Indexed: 02/08/2023] Open
Abstract
Human metallothioneins are a superfamily of low molecular weight intracellular proteins, whose synthesis can be induced by essential elements (primarily Zn and Cu), toxic elements and chemical agents, and stress-producing conditions. Of the four known isoforms in the human body MT2 is the most common. The expression of metallothioneins is encoded by a multigene family of linked genes and can be influenced by single nucleotide polymorphisms (SNPs) in these genes. To date, 24 SNPs in the MT2A gene have been identified with the incidence of about 1 % in various population groups, and three of them were shown to affect physiological and pathophysiological processes. This review summarises current knowledge about these three SNPs in the MT2A gene and their associations with element concentrations in the body of healthy and diseased persons. The most investigated SNP is rs28366003 (MT2A -5 A/G). Reports associate it with longevity, cancer (breast, prostate, laryngeal, and in paranasal sinuses), and chronic renal disease. The second most investigated SNP, rs10636 (MT2A +838G/C), is associated with breast cancer, cardiovascular disease, and type 2 diabetes. Both are also associated with several metal/metalloid concentrations in the organism. The third SNP, rs1610216 (MT2A -209A/G), has been studied for association with type 2 diabetes, cardiomyopathy, hyperglycaemia, and Zn concentrations. Metallothionein concentrations and MT2A polymorphisms have a potential to be used as biomarkers of metal exposure and clinical markers of a number of chronic diseases. This potential needs to be studied and verified in a large number of well-defined groups of participants (several hundreds and thousands) with a focus on particular physiological or pathological condition and taking into consideration other contributing factors, such as environmental exposure and individual genetic and epigenetic makeup.
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Affiliation(s)
- Ankica Sekovanić
- Analytical Toxicology and Mineral Metabolism Unit, Institute for Medical Research and Occupational Health,Zagreb, Croatia
| | - Jasna Jurasović
- Analytical Toxicology and Mineral Metabolism Unit, Institute for Medical Research and Occupational Health,Zagreb, Croatia
| | - Martina Piasek
- Analytical Toxicology and Mineral Metabolism Unit, Institute for Medical Research and Occupational Health,Zagreb, Croatia
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22
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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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23
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Targeting the lysyl oxidases in tumour desmoplasia. Biochem Soc Trans 2019; 47:1661-1678. [DOI: 10.1042/bst20190098] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 10/30/2019] [Accepted: 10/31/2019] [Indexed: 02/08/2023]
Abstract
The extracellular matrix (ECM) is a fundamental component of tissue microenvironments and its dysregulation has been implicated in a number of diseases, in particular cancer. Tumour desmoplasia (fibrosis) accompanies the progression of many solid cancers, and is also often induced as a result of many frontline chemotherapies. This has recently led to an increased interest in targeting the underlying processes. The major structural components of the ECM contributing to desmoplasia are the fibrillar collagens, whose key assembly mechanism is the enzymatic stabilisation of procollagen monomers by the lysyl oxidases. The lysyl oxidase family of copper-dependent amine oxidase enzymes are required for covalent cross-linking of collagen (as well as elastin) molecules into the mature ECM. This key step in the assembly of collagens is of particular interest in the cancer field since it is essential to the tumour desmoplastic response. LOX family members are dysregulated in many cancers and consequently the development of small molecule inhibitors targeting their enzymatic activity has been initiated by many groups. Development of specific small molecule inhibitors however has been hindered by the lack of crystal structures of the active sites, and therefore alternate indirect approaches to target LOX have also been explored. In this review, we introduce the importance of, and assembly steps of the ECM in the tumour desmoplastic response focussing on the role of the lysyl oxidases. We also discuss recent progress in targeting this family of enzymes as a potential therapeutic approach.
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24
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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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25
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Systemic lupus erythematosus, hypoparathyroidism, and hemolytic anemia in a patient with Wilson's disease. Reumatologia 2019; 57:239-242. [PMID: 31548751 PMCID: PMC6753600 DOI: 10.5114/reum.2019.87622] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Accepted: 07/19/2019] [Indexed: 12/13/2022] Open
Abstract
The authors report a female case of systemic lupus erythematosus (SLE) that was diagnosed as Wilson's disease (WD) when neurological manifestations were evident three years after the first admission. The brain imaging studies showed bilateral symmetrical basal ganglia involvement, slit lamp examination revealed Kayser-Fleischer ring of the cornea, and 24-hour urinary copper and serum ceruloplasmin also confirmed the diagnosis. The patient also had hemolytic anemia and hypoparathyroidism, which are rare presenting features of WD. SLE may be associated with WD, and presence of neurological, behavioral, or liver function abnormalities should raise the suspicion, even without apparent features of WD.
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26
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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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27
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Nemashkalova EL, Permyakov EA, Uversky VN, Permyakov SE, Litus EA. Effect of Cu 2+ and Zn 2+ ions on human serum albumin interaction with plasma unsaturated fatty acids. Int J Biol Macromol 2019; 131:505-509. [PMID: 30880051 DOI: 10.1016/j.ijbiomac.2019.03.085] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2018] [Revised: 03/11/2019] [Accepted: 03/13/2019] [Indexed: 01/15/2023]
Abstract
Human serum albumin (HSA) serves as a depot and carrier of multiple unrelated ligands including several participants of the pathogenesis of Alzheimer's disease (AD), such as amyloid β peptide (Aβ), Zn2+/Cu2+ ions, docosahexaenoic (DHA), linoleic (LA), and oleic (OA) acids. To explore the interplay between HSA interaction with Zn2+/Cu2+ and the plasma unsaturated fatty acids (DHA, LA, OA, and arachidonic acid (ArA)), we have studied the metal dependence of the fatty acid (FA) binding capacity of HSA (nmax) and structural consequences of the HSA-FA interactions. HSA loading with Zn2+ decreases nmax value by 0.3-1.5, while its saturation with Cu2+ causes the FA-dependent nmax changes by up to 0.9. The Cu2+-induced decline in nmax value for DHA is due to conformational rearrangements in HSA molecule. In other cases, the changes in nmax are attributed to steric hindarance/facilitation of the HSA-FA interaction because of the protein multimerization/monomerization, as confirmed by chemical crosslinking. The surface hydrophobicity of HSA is Cu2+-, Zn2+-, and FA-dependent and decreases upon the FA binding, according to bis-ANS fluorescence data. Overall, Zn2+ or Cu2+ binding selectively affect HSA interaction with the FAs studied, in part due to changes in quaternary structure of the protein.
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Affiliation(s)
- Ekaterina L Nemashkalova
- Institute for Biological Instrumentation of the Russian Academy of Sciences, Federal Research Center 'Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences', Institutskaya str., 7, Pushchino, Moscow region 142290, Russia
| | - Eugene A Permyakov
- Institute for Biological Instrumentation of the Russian Academy of Sciences, Federal Research Center 'Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences', Institutskaya str., 7, Pushchino, Moscow region 142290, Russia
| | - Vladimir N Uversky
- Institute for Biological Instrumentation of the Russian Academy of Sciences, Federal Research Center 'Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences', Institutskaya str., 7, Pushchino, Moscow region 142290, Russia; Department of Molecular Medicine and USF Health Byrd Alzheimer's Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
| | - Sergei E Permyakov
- Institute for Biological Instrumentation of the Russian Academy of Sciences, Federal Research Center 'Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences', Institutskaya str., 7, Pushchino, Moscow region 142290, Russia
| | - Ekaterina A Litus
- Institute for Biological Instrumentation of the Russian Academy of Sciences, Federal Research Center 'Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences', Institutskaya str., 7, Pushchino, Moscow region 142290, Russia.
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28
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Porlas RV, de Castillo LLC, Dioquino CPC. Neurologic Wilson disease: case series on a diagnostic and therapeutic emergency. DIALOGUES IN CLINICAL NEUROSCIENCE 2019. [PMID: 30936772 PMCID: PMC6436958 DOI: 10.31887/dcns.2018.20.4/rporlas] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Wilson disease is a rare genetic disease causing pathologic deposition of copper in the liver, brain, cornea, kidney, and cardiac muscles. Presented are two cases of neurologic Wilson disease with progressive movement disorder and Kayser-Fleischer rings with low serum copper, low ceruloplasmin, and increased 24-hour urine copper against a background of normal transaminases. Cranial imaging revealed symmetric basal ganglia hyperintensities in T2/FLAIR. More often than not, these cases go unnoticed and misdiagnosed because of its rarity and varied presentation. Extensive workup is necessary to confirm the diagnosis. As for management, the earlier the intervention is initiated, the better prognosis would be for recovery. There are several treatment options which should be tailored to every patient with neurologic Wilson disease. Neurologic Wilson disease is considered as a copper toxicity; immediate diagnostic evaluation and early treatment initiation is a must.
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Affiliation(s)
- Romeo V Porlas
- Department of Neurosciences, College of Medicine and Philippine General Hospital, University of the Philippines, Manila
| | - Lennie Lynn C de Castillo
- Department of Neurosciences, College of Medicine and Philippine General Hospital, University of the Philippines, Manila
| | - Carissa Paz C Dioquino
- Department of Neurosciences, College of Medicine and Philippine General Hospital, University of the Philippines, Manila; National Poison Management and Control Center, Philippine General Hospital, University of the Philippines, Manila, Philippines
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Aliev G, Li Y, Chubarev VN, Lebedeva SA, Parshina LN, Trofimov BA, Sologova SS, Makhmutova A, Avila-Rodriguez MF, Klochkov SG, Galenko-Yaroshevsky PA, Tarasov VV. Application of Acyzol in the Context of Zinc Deficiency and Perspectives. Int J Mol Sci 2019; 20:E2104. [PMID: 31035445 PMCID: PMC6539662 DOI: 10.3390/ijms20092104] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Revised: 04/22/2019] [Accepted: 04/24/2019] [Indexed: 12/23/2022] Open
Abstract
Zinc is one of the most important essential trace elements. It is involved in more than 300 enzyme systems and is an indispensable participant in many biochemical processes. Zinc deficiency causes a number of disorders in the human body, the main ones being the delay of growth and puberty, immune disorders, and cognitive dysfunctions. There are over two billion people in the world suffering from zinc deficiency conditions. Acyzol, a zinc-containing medicine, developed as an antidote against carbon monoxide poisoning, demonstrates a wide range of pharmacological activities: Anti-inflammatory, reparative, detoxifying, immunomodulatory, bacteriostatic, hepatoprotective, adaptogenic, antioxidant, antihypoxic, and cardioprotective. The presence of zinc in the composition of Acyzol suggests the potential of the drug in the treatment and prevention of zinc deficiency conditions, such as Prasad's disease, immune system pathology, alopecia, allergodermatoses, prostate dysfunction, psoriasis, stomatitis, periodontitis, and delayed mental and physical development in children. Currently, the efficiency of Acyzol in the cases of zinc deficiency is shown in a large number of experimental studies. So, Acyzol can be used as a highly effective drug for pharmacologic therapy of a wide range of diseases and conditions and it opens up new perspectives in the treatment and prevention of zinc deficiency conditions.
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Affiliation(s)
- Gjumrakch Aliev
- Department of Pharmacology and Pharmacy, Sechenov First Moscow State Medical University (Sechenov University), 8-2 Trubetskaya St., Moscow 119991, Russia.
- Institute of Physiologically Active Compounds Russian Academy of Sciences, Chernogolovka 142432, Russia.
- GALLY International Research Institute, 7733 Louis Pasteur Drive #330, San Antonio, TX 78229, USA.
| | - Yi Li
- Department of Biological and Health Sciences, Texas A&M University-Kingsville, TX 78363, USA.
| | - Vladimir N Chubarev
- Department of Pharmacology and Pharmacy, Sechenov First Moscow State Medical University (Sechenov University), 8-2 Trubetskaya St., Moscow 119991, Russia.
| | - Svetlana A Lebedeva
- Department of Pharmacology and Pharmacy, Sechenov First Moscow State Medical University (Sechenov University), 8-2 Trubetskaya St., Moscow 119991, Russia.
| | - Lidiya N Parshina
- A.E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences, 1 Favorsky Str., Irkutsk 664033, Russia.
| | - Boris A Trofimov
- A.E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences, 1 Favorsky Str., Irkutsk 664033, Russia.
| | - Susanna S Sologova
- Department of Pharmacology and Pharmacy, Sechenov First Moscow State Medical University (Sechenov University), 8-2 Trubetskaya St., Moscow 119991, Russia.
| | - Alfiya Makhmutova
- Institute of Physiologically Active Compounds Russian Academy of Sciences, Chernogolovka 142432, Russia.
| | - Marco F Avila-Rodriguez
- Universidad del Tolima, Facultad de Ciencias de la Salud, Barrio Santa Helena, Ibagué 730006, Colombia.
| | - Sergey G Klochkov
- Institute of Physiologically Active Compounds Russian Academy of Sciences, Chernogolovka 142432, Russia.
| | - Pavel A Galenko-Yaroshevsky
- Department of Pharmacology, Faculty of Pharmacy, Kuban State Medical University, 4 Sedin St., Krasnodar 350063, Russia.
| | - Vadim V Tarasov
- Department of Pharmacology and Pharmacy, Sechenov First Moscow State Medical University (Sechenov University), 8-2 Trubetskaya St., Moscow 119991, Russia.
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Ren F, Logeman BL, Zhang X, Liu Y, Thiele DJ, Yuan P. X-ray structures of the high-affinity copper transporter Ctr1. Nat Commun 2019; 10:1386. [PMID: 30918258 PMCID: PMC6437178 DOI: 10.1038/s41467-019-09376-7] [Citation(s) in RCA: 74] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Accepted: 03/06/2019] [Indexed: 02/02/2023] Open
Abstract
Copper (Cu) is an essential trace element for growth and development and abnormal Cu levels are associated with anemia, metabolic disease and cancer. Evolutionarily conserved from fungi to humans, the high-affinity Cu+ transporter Ctr1 is crucial for both dietary Cu uptake and peripheral distribution, yet the mechanisms for selective permeation of potentially toxic Cu+ ions across cell membranes are unknown. Here we present X-ray crystal structures of Ctr1 from Salmo salar in both Cu+-free and Cu+-bound states, revealing a homo-trimeric Cu+-selective ion channel-like architecture. Two layers of methionine triads form a selectivity filter, coordinating two bound Cu+ ions close to the extracellular entrance. These structures, together with Ctr1 functional characterization, provide a high resolution picture to understand Cu+ import across cellular membranes and suggest therapeutic opportunities for intervention in diseases characterized by inappropriate Cu accumulation. Copper (Cu) is an essential trace element for growth and development and the Cu+ transporter Ctr1 is crucial for both dietary Cu uptake and peripheral distribution. Here authors solve Cu+ -free and Cu+ -bound Ctr1 structures which adopt a homo-trimeric Cu+ -selective ion channel-like architecture
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Affiliation(s)
- Feifei Ren
- Department of Cell Biology and Physiology, Washington University School of Medicine, Saint Louis, MO, 63110, USA.,Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, Saint Louis, MO, 63110, USA
| | - Brandon L Logeman
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, 27710, USA.,Department of Molecular and Cellular Biology, Harvard University, 52 Oxford Street, Cambridge, MA, 02138, USA
| | - Xiaohui Zhang
- Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, MO, 63110, USA
| | - Yongjian Liu
- Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, MO, 63110, USA
| | - Dennis J Thiele
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, 27710, USA.,Department of Biochemistry, Duke University School of Medicine, Durham, NC, 27710, USA.,Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, 27710, USA
| | - Peng Yuan
- Department of Cell Biology and Physiology, Washington University School of Medicine, Saint Louis, MO, 63110, USA. .,Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, Saint Louis, MO, 63110, USA.
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Krishnan N, Felice C, Rivera K, Pappin DJ, Tonks NK. DPM-1001 decreased copper levels and ameliorated deficits in a mouse model of Wilson's disease. Genes Dev 2018; 32:944-952. [PMID: 29945887 PMCID: PMC6075031 DOI: 10.1101/gad.314658.118] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Accepted: 05/14/2018] [Indexed: 12/13/2022]
Abstract
The levels of copper, which is an essential element in living organisms, are under tight homeostatic control. Inactivating mutations in ATP7B, a P-type Cu-ATPase that functions in copper excretion, promote aberrant accumulation of the metal, primarily the in liver and brain. This condition underlies Wilson's disease, a severe autosomal recessive disorder characterized by profound hepatic and neurological deficits. Current treatment regimens rely on the use of broad specificity metal chelators as "decoppering" agents; however, there are side effects that limit their effectiveness. Here, we present the characterization of DPM-1001 {methyl 4-[7-hydroxy-10,13-dimethyl-3-({4-[(pyridin-2-ylmethyl)amino]butyl}amino)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl] pentanoate} as a potent and highly selective chelator of copper that is orally bioavailable. Treatment of cell models, including fibroblasts derived from Wilson's disease patients, eliminated adverse effects associated with copper accumulation. Furthermore, treatment of the toxic milk mouse model of Wilson's disease with DPM-1001 lowered the levels of copper in the liver and brain, removing excess copper by excretion in the feces while ameliorating symptoms associated with the disease. These data suggest that it may be worthwhile to investigate DPM-1001 further as a new therapeutic agent for the treatment of Wilson's disease, with potential for application in other indications associated with elevated copper, including cancer and neurodegenerative diseases.
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Affiliation(s)
- Navasona Krishnan
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA
| | - Christy Felice
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA
| | - Keith Rivera
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA
| | - Darryl J Pappin
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA
| | - Nicholas K Tonks
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA
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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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Quaglia A, Roberts EA, Torbenson M. Developmental and Inherited Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2018:111-274. [DOI: 10.1016/b978-0-7020-6697-9.00003-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Dietary copper restriction in Wilson's disease. Eur J Clin Nutr 2017; 72:326-331. [PMID: 29235558 DOI: 10.1038/s41430-017-0002-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Revised: 07/30/2017] [Accepted: 08/24/2017] [Indexed: 01/04/2023]
Abstract
Dietary copper restriction has long been considered an important aspect of treatment for Wilson's disease (WD). However, evidence supporting this approach is limited. There are no published randomised controlled trials examining this recommendation due to rarity of the disease and variable presentation. This review summarises current knowledge on the absorption and regulation of copper in humans and its relevance to patients with WD. Studies have demonstrated that as the level of dietary copper increases, the proportion absorbed decreases. This observation implies that 'high copper' foods that WD patients are generally advised to avoid would need to be consumed in large amounts to impact markedly on the quantity absorbed. Dietary copper restriction is unlikely to reduce the amount absorbed significantly and is not only difficult to manage but restricts food groups unnecessarily, detracting from the provision of substrates essential for improving nutritional status in a nutritionally compromised group. Medical management for WD is effective in compliant patients, allowing stabilisation of the liver disease. Based on current evidence, dietary copper restrictions in stable WD patients who are adherent to medical therapy are unnecessary with two food exceptions (shellfish and liver).
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Abstract
Wilson's disease (WD) is a neurodegenerative disorder due to copper metabolism. Schizophrenia-like psychosis and delusional disorder are rare forms of psychiatric manifestations of WD. The lack of recognition of these signs and symptoms as being attributable to WD often leads to delays in diagnosis and management. Knowledge about relationship of the psychiatric manifestations to WD can help with the administration of adequate management aimed at both the psychiatric issues and underlying WD. The objectives of this article are to review case reports whose subject is the incorrect diagnosis of schizophrenia or schizophrenia-like syndrome in patients with WD and to detail one case of this mismanagement of the disease. A 35-year-old unmarried Iranian woman presented to the consulting psychiatrist in the emergency room after a suicide attempt due to commanding auditory hallucination. She had previous eleven admissions in psychiatric hospital with major depressive episode with psychotic features, schizoaffective disorders, and then schizophrenia diagnosis. Nineteen years after her first symptoms, it was discovered that the patient was suffering from WD. We searched Google Scholar, Ovid, PsycINFO, CINHAL, and PubMed databases from 1985 to 2015. Finally, 14 researches were entered into the study. Psychiatric manifestations may precede the diagnosis of WD and other symptoms related to neurological or hepatic impairment. Early detection of WD is important to prevent catastrophic outcome. Young patients presenting with psychiatric presentations along with abnormal movement disorder, seizure, or conversion-like symptoms should be evaluate for WD even if signs and symptoms are typically suggestive of schizophrenia or manic episode. An interdisciplinary approach with good collaboration of psychiatrists and neurologists is crucial for WD because early diagnosis and management without delay is an important for good prognosis.
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Affiliation(s)
- Forouzan Elyasi
- Department of Psychiatry, Psychiatry and Behavioral Sciences Research Center, Addiction Institute, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
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Abstract
Analysis of human genetic data promises to uncover important disease targets. Genes known to cause or increase susceptibility for various diseases are being identified through analysis of genetic data, expression and metabolites. Future benefits to individuals are far-reaching, including improved gene therapy strategies, better drug development for disease treatment, pre-symptomatic disease intervention and risk susceptibility information. The rapid expansion of genetic databases has resulted in the emerging areas of genomics, transcriptomics, proteomics and metabolomics. The article presents a comprehensive overview of Internet databases, their trends over time and what 'omics' type they embody. With the completion of the human genome we are entering the postgenomic era. The use of microarrays and database software for genomic, transcriptomic, proteomic and metabolomic data for clinical assays and new diagnostic therapeutics will result in large, interlinked databases that will present unique issues of data management, standardization and information sharing.
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Affiliation(s)
- Michael G. Tyshenko
- McLaughlin Centre for Population Health Risk Assessment, Institute of
Population Health, University of Ottawa, 1 Stewart St, Ottawa, ON, Canada
K1N 6N5,
| | - William Leiss
- School of Policy Studies, Queen's University, Kingston, ON, Canada K7L 3N6
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Leggio L, Ferrulli A, Mirijello A, Abenavoli L, Di Giuda D, Funiciello S, Rotoli M, Gasbarrini G, Addolorato G. Penicillamine-Related Lichenoid Dermatitis and Utility of Zinc Acetate in a Wilson Disease Patient with Hepatic Presentation, Anxiety and Spect Abnormalities. Int J Immunopathol Pharmacol 2016; 20:185-90. [PMID: 17346443 DOI: 10.1177/039463200702000122] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Wilson disease is an autosomal recessive disorder of hepatic copper metabolism with consequent copper accumulation and toxicity in many tissues and consequent hepatic, neurologic and psychiatric disorders. We report a case of Wilson disease with chronic liver disease; moreover, in our patient, presenting also with high levels of state anxiety without depression 99mTc-ECD-SPECT showed cortical hypoperfusion in frontal lobes, more marked on the left frontal lobe. During the follow-up of our patient, penicillamine was interrupted after the appearance of a lichenoid dermatitis, and zinc acetate permitted to continue the successful treatment of the patient without side-effects. In our case the therapy with zinc acetate represented an effective treatment for a Wilson disease patient in which penicillamine-related side effects appeared. The safety of the zinc acetate allowed us to avoid other potentially toxic chelating drugs; this observation is in line with the growing evidence on the efficacy of the drug in the treatment of Wilson disease. Since most of Wilson disease penicillamine-treated patients do not seem to develop this skin lesion, it could be conceivable that a specific genetic factor is involved in drug response. Further studies are needed for a better clarification of Wilson disease therapy, and in particular to differentiate specific therapies for different Wilson disease phenotypes.
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Ghosh A, Ta S, Ghosh M, Karmakar S, Banik A, Dangar TK, Mukhopadhyay SK, Das D. Dual mode ratiometric recognition of zinc acetate: nanomolar detection with in vitro tracking of endophytic bacteria in rice root tissue. Dalton Trans 2016; 45:599-606. [DOI: 10.1039/c5dt03431k] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Structurally characterized naphthalene-based ratiometric probe detects zinc acetate (ZA) by colorimetric and fluorescence tools. In vitro tracking of ZA in endophytic bacteria in rice root tissue and human breast cancer cells (MCF7) is possible.
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Affiliation(s)
- Abhijit Ghosh
- Department of Chemistry
- The University of Burdwan
- Burdwan
- India
| | - Sabyasachi Ta
- Department of Chemistry
- The University of Burdwan
- Burdwan
- India
| | - Milan Ghosh
- Department of Chemistry
- The University of Burdwan
- Burdwan
- India
| | - Subhajit Karmakar
- University Science Instrumentation Center
- The University of Burdwan
- Burdwan
- India
| | - Avishek Banik
- Microbiology Laboratory
- Crop production division
- ICAR-Central Rice Research Institute
- Cuttack
- India
| | - Tushar Kanti Dangar
- Microbiology Laboratory
- Crop production division
- ICAR-Central Rice Research Institute
- Cuttack
- India
| | | | - Debasis Das
- Department of Chemistry
- The University of Burdwan
- Burdwan
- India
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Rodriguez-Castro KI, Hevia-Urrutia FJ, Sturniolo GC. Wilson’s disease: A review of what we have learned. World J Hepatol 2015; 7:2859-2870. [PMID: 26692151 PMCID: PMC4678372 DOI: 10.4254/wjh.v7.i29.2859] [Citation(s) in RCA: 98] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2015] [Revised: 08/21/2015] [Accepted: 12/02/2015] [Indexed: 02/06/2023] Open
Abstract
Wilson’s disease (WD), which results from the defective ATP7B protein product, is characterized by impaired copper metabolism and its clinical consequences vary from an asymptomatic state to fulminant hepatic failure, chronic liver disease with or without cirrhosis, neurological, and psychiatric manifestations. A high grade of suspicion is warranted to not miss cases of WD, especially less florid cases with only mild elevation of transaminases, or isolated neuropsychiatric involvement. Screening in first and second relatives of index cases is mandatory, and treatment must commence upon establishment of diagnosis. Treatment strategies include chelators such as D-penicillamine and trientine, while zinc salts act as inductors of methallothioneins, which favor a negative copper balance and a reduction of free plasmatic copper. As an orphan disease, research is lacking in this field, especially regarding therapeutic strategies which are associated with better patient compliance and which could eventually also reverse established injury.
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Xu J, Jiang H, Li J, Cheng KK, Dong J, Chen Z. 1H NMR-based metabolomics investigation of copper-laden rat: a model of Wilson's disease. PLoS One 2015; 10:e0119654. [PMID: 25849323 PMCID: PMC4388371 DOI: 10.1371/journal.pone.0119654] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2014] [Accepted: 02/02/2015] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND AND PURPOSE Wilson's disease (WD), also known as hepatoleticular degeneration (HLD), is a rare autosomal recessive genetic disorder of copper metabolism, which causes copper to accumulate in body tissues. In this study, rats fed with copper-laden diet are used to render the clinical manifestations of WD, and their copper toxicity-induced organ lesions are studied. To investigate metabolic behaviors of 'decoppering' process, penicillamine (PA) was used for treating copper-laden rats as this chelating agent could eliminate excess copper through the urine. To date, there has been limited metabolomics study on WD, while metabolic impacts of copper accumulation and PA administration have yet to be established. MATERIALS AND METHODS A combination of 1HNMR spectroscopy and multivariate statistical analysis was applied to examine the metabolic profiles of the urine and blood serum samples collected from the copper-laden rat model of WD with PA treatment. RESULTS Copper accumulation in the copper-laden rats is associated with increased lactate, creatinine, valine and leucine, as well as decreased levels of glucose and taurine in the blood serum. There were also significant changes in p-hydroxyphenylacetate (p-HPA), creatinine, alpha-ketoglutarate (α-KG), dimethylamine, N-acetylglutamate (NAG), N-acetylglycoprotein (NAC) in the urine of these rats. Notably, the changes in p-HPA, glucose, lactate, taurine, valine, leucine, and NAG were found reversed following PA treatment. Nevertheless, there were no changes for dimethylamine, α-KG, and NAC as a result of the treatment. Compared with the controls, the concentrations of hippurate, formate, alanine, and lactate were changed when PA was applied and this is probably due to its side effect. A tool named SMPDB (Small Molecule Pathway Database) is introduced to identify the metabolic pathway influenced by the copper-laden diet. CONCLUSION The study has shown the potential application of NMR-based metabolomic analysis in providing further insights into the molecular mechanism underlying disorder due to WD.
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Affiliation(s)
- Jingjing Xu
- Department of Electronic Science, Fujian Provincial Key Laboratory of Plasma and Magnetic Resonance, Xiamen University, Xiamen, 361005, P. R. China
| | - Huaizhou Jiang
- Anhui University of Chinese Medicine, Hefei, 230031, P. R. China
| | - Jinquan Li
- Department of Electronic Science, Fujian Provincial Key Laboratory of Plasma and Magnetic Resonance, Xiamen University, Xiamen, 361005, P. R. China
| | - Kian-Kai Cheng
- Department of Bioprocess Engineering & Innovation Centre in Agritechnology, Universiti Teknologi Malaysia, Johor Bahru, 81310, Malaysia
| | - Jiyang Dong
- Department of Electronic Science, Fujian Provincial Key Laboratory of Plasma and Magnetic Resonance, Xiamen University, Xiamen, 361005, P. R. China
| | - Zhong Chen
- Department of Electronic Science, Fujian Provincial Key Laboratory of Plasma and Magnetic Resonance, Xiamen University, Xiamen, 361005, P. R. China
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Verwilst P, Sunwoo K, Kim JS. The role of copper ions in pathophysiology and fluorescent sensors for the detection thereof. Chem Commun (Camb) 2015; 51:5556-71. [DOI: 10.1039/c4cc10366a] [Citation(s) in RCA: 81] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Copper ions are crucial to life, and some fundamental roles of copper in pathophysiology have been elucidated using fluorescent sensors.
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Affiliation(s)
- Peter Verwilst
- Department of Chemistry
- Korea Univesity
- Seoul 136-701
- Korea
| | - Kyoung Sunwoo
- Department of Chemistry
- Korea Univesity
- Seoul 136-701
- Korea
| | - Jong Seung Kim
- Department of Chemistry
- Korea Univesity
- Seoul 136-701
- Korea
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Beauchemin S, Rasmussen PE, MacKinnon T, Chénier M, Boros K. Zinc in house dust: speciation, bioaccessibility, and impact of humidity. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2014; 48:9022-9029. [PMID: 25041107 DOI: 10.1021/es5018587] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
Indoor exposures to metals arise from a wide variety of indoor and outdoor sources. This study investigates the impact of humid indoor conditions on the bioaccessibility of Zn in dust, and the transformation of Zn species during weathering. House dust samples were subjected to an oxygenated, highly humid atmosphere in a closed chamber for 4 to 5 months. Zinc bioaccessibility before and after the experiment was determined using a simulated gastric acid extraction. Bulk and micro X-ray absorption structure (XAS) spectroscopy was used to speciate Zn in dust. Exposure to humid conditions led to a significant increase in Zn bioaccessibility in all samples, which was due to a redistribution of Zn from inorganic forms toward the organic pools such as Zn adsorbed on humates. ZnO readily dissolved under humid conditions, whereas ZnS persisted in the dust. Elevated humidity in indoor microenvironments may sustain higher Zn bioaccessibility in settled dust compared to drier conditions, and part of this change may be related to fungal growth in humid dust. These results help to explain the greater bioaccessibility of certain metals in house dust compared to soils.
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Affiliation(s)
- Suzanne Beauchemin
- Natural Resources Canada , CanmetMINING, 555 Booth Street, Ottawa, Ontario Canada , K1A 0G1
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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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Quinn JF, Crane S, Harris C, Wadsworth TL. Copper in Alzheimer’s disease: too much or too little? Expert Rev Neurother 2014; 9:631-7. [DOI: 10.1586/ern.09.27] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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Zimbrean PC, Schilsky ML. Psychiatric aspects of Wilson disease: a review. Gen Hosp Psychiatry 2014; 36:53-62. [PMID: 24120023 DOI: 10.1016/j.genhosppsych.2013.08.007] [Citation(s) in RCA: 105] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2013] [Revised: 08/14/2013] [Accepted: 08/29/2013] [Indexed: 12/21/2022]
Abstract
OBJECTIVE To review the current evidence about psychiatric symptoms in Wilson's disease (WD). METHOD We searched Ovid, PsychInfo, CINHAL and PubMed databases from May 1946 to May 2012 using the key words Wilson('s) disease in combination with psychiatry, psychiatric, psychosis, schizophrenia, depression, mania, bipolar, mood, anxiety, personality and behavior. RESULTS Psychiatric symptoms occur before, concurrent with or after the diagnosis and treatment for WD. Thirty to forty percent of patients have psychiatric manifestations at the time of diagnosis, and 20% had seen a psychiatrist prior to their WD diagnosis. When psychiatric symptoms preceded neurological or hepatic involvement, the average time between the psychiatric symptoms and the diagnosis of WD was 864.3 days. The prevalence of psychiatric disorders in WD patients varies wildly (major depressive disorder, 4-47%; psychosis, 1.4-11.3%). Certain gene mutations of ATP7B may correlate with specific personality traits. CONCLUSIONS Psychiatric manifestations represent a significant part of the clinical presentation of WD and can present at any point in the course of the illness. Psychiatric manifestations occurring without overt hepatic or neurologic involvement may lead to misdiagnosis. A better understanding of the psychiatric presentations in WD may provide insights into the underlying mechanisms of psychiatric disorders.
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Affiliation(s)
- Paula C Zimbrean
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT; Wilson Disease Centers of Excellence at Yale University, New Haven, CT.
| | - Michael L Schilsky
- Wilson Disease Centers of Excellence at Yale University, New Haven, CT; Section of Digestive Disease and Transplant and Immunology, Yale University School of Medicine; Yale Transplantation Center, Yale New Haven Hospital, New Haven, CT
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Wu J, Wang L, He J, Zhu C. In vitro cytotoxicity of Cu2+, Zn2+, Ag+ and their mixtures on primary human endometrial epithelial cells. Contraception 2012; 85:509-18. [DOI: 10.1016/j.contraception.2011.09.016] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2011] [Revised: 09/15/2011] [Accepted: 09/29/2011] [Indexed: 11/28/2022]
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Cooper GJS. Therapeutic potential of copper chelation with triethylenetetramine in managing diabetes mellitus and Alzheimer's disease. Drugs 2011; 71:1281-320. [PMID: 21770477 DOI: 10.2165/11591370-000000000-00000] [Citation(s) in RCA: 82] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
This article reviews recent evidence, much of which has been generated by my group's research programme, which has identified for the first time a previously unknown copper-overload state that is central to the pathogenesis of diabetic organ damage. This state causes tissue damage in the blood vessels, heart, kidneys, retina and nerves through copper-mediated oxidative stress. This author now considers this copper-overload state to provide an important new target for therapeutic intervention, the objective of which is to prevent or reverse the diabetic complications. Triethylenetetramine (TETA) has recently been identified as the first in a new class of anti-diabetic molecules through the original work reviewed here, thus providing a new use for this molecule, which was previously approved by the US FDA in 1985 as a second-line treatment for Wilson's disease. TETA acts as a highly selective divalent copper (Cu(II)) chelator that prevents or reverses diabetic copper overload, thereby suppressing oxidative stress. TETA treatment of diabetic animals and patients has identified and quantified the interlinked defects in copper metabolism that characterize this systemic copper overload state. Copper overload in diabetes mellitus differs from that in Wilson's disease through differences in their respective causative molecular mechanisms, and resulting differences in tissue localization and behaviour of the excess copper. Elevated pathogenetic tissue binding of copper occurs in diabetes. It may well be mediated by advanced-glycation endproduct (AGE) modification of susceptible amino-acid residues in long-lived fibrous proteins, for example, connective tissue collagens in locations such as blood vessel walls. These AGE modifications can act as localized, fixed endogenous chelators that increase the chelatable-copper content of organs such as the heart and kidneys by binding excessive amounts of catalytically active Cu(II) in specific vascular beds, thereby focusing the related copper-mediated oxidative stress in susceptible tissues. In this review, summarized evidence from our clinical studies in healthy volunteers and diabetic patients with left-ventricular hypertrophy, and from nonclinical models of diabetic cardiac, arterial, renal and neural disease is used to construct descriptions of the mechanisms by which TETA treatment prevents injury and regenerates damaged organs. Our recent phase II proof-of-principle studies in patients with type 2 diabetes and in nonclinical models of diabetes have helped to define the pathogenetic defects in copper regulation, and have shown that they are reversible by TETA. The drug tightly binds and extracts excess systemic Cu(II) into the urine whilst neutralizing its catalytic activity, but does not cause systemic copper deficiency, even after prolonged use. Its physicochemical properties, which are pivotal for its safety and efficacy, clearly differentiate it from all other clinically available transition metal chelators, including D-penicillamine, ammonium tetrathiomolybdate and clioquinol. The studies reviewed here show that TETA treatment is generally effective in preventing or reversing diabetic organ damage, and support its ongoing development as a new medicine for diabetes. Trientine (TETA dihydrochloride) has been used since the mid-1980s as a second-line treatment for Wilson's disease, and our recent clinical studies have reinforced the impression that it is likely to be safe for long-term use in patients with diabetes and related metabolic disorders. There is substantive evidence to support the view that diabetes shares many pathogenetic mechanisms with Alzheimer's disease and vascular dementia. Indeed, the close epidemiological and molecular linkages between them point to Alzheimer's disease/vascular dementia as a further therapeutic target where experimental pharmacotherapy with TETA could well find further clinical application.
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Affiliation(s)
- Garth J S Cooper
- Centre for Advanced Discovery and Experimental Therapeutics, NIHR Manchester Biomedical Research Centre, Central Manchester University Hospitals NHS Foundation Trust, UK.
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Quarles Jr. CD, Randunu KM, Brumaghim JL, Marcus RK. Metal retention in human transferrin: Consequences of solvent composition in analytical sample preparation methods. Metallomics 2011; 3:1027-34. [DOI: 10.1039/c1mt00094b] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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Lu J, Gong D, Choong SY, Xu H, Chan YK, Chen X, Fitzpatrick S, Glyn-Jones S, Zhang S, Nakamura T, Ruggiero K, Obolonkin V, Poppitt SD, Phillips ARJ, Cooper GJS. Copper(II)-selective chelation improves function and antioxidant defences in cardiovascular tissues of rats as a model of diabetes: comparisons between triethylenetetramine and three less copper-selective transition-metal-targeted treatments. Diabetologia 2010; 53:1217-26. [PMID: 20221822 DOI: 10.1007/s00125-010-1698-8] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2009] [Accepted: 01/22/2010] [Indexed: 12/26/2022]
Abstract
AIMS/HYPOTHESIS Treatment with the Cu(II)-selective chelator triethylenetetramine (TETA) improves cardiovascular disease in human patients, and cardiac and vascular/renal disease in rats used as a model of diabetes. Here we tested two hypotheses: first, that TETA elicits greater improvement in organ function than less Cu-selective transition-metal-targeted treatments; second, that the therapeutic actions of TETA are consistent with mediation through suppression of oxidative stress. METHODS Rats were made diabetic with streptozotocin (55 mg/kg, i. v.) and treated from 8 weeks after disease induction for the following 8 weeks with effective dosages of oral TETA, or one of three less Cu-selective transition-metal-targeted treatments: D-penicillamine, deferiprone or Zn acetate. Treatment effects were measured in ex vivo cardiac and aortic tissues, plasma and urine. RESULTS Diabetes damaged both cardiac and renal/vascular function by impairing the ability of cardiac output to respond physiologically to rising afterload, and by significantly elevating the urinary albumin/creatinine ratio. Diabetes also lowered total antioxidant potential and heparan sulphate levels in cardiac and arterial tissues, and serum ferroxidase activity, whereas it elevated urinary heparan sulphate excretion. TETA treatment rectified or partially rectified all these defects, whereas the other three experimental treatments were ineffectual. By contrast, none of the four drug treatments lowered diabetes-mediated elevations of plasma glucose or lipid concentrations. CONCLUSIONS/INTERPRETATION TETA may limit the cardiac and renal/vascular damage inflicted by diabetes through its actions to reinforce antioxidant defence mechanisms, probably acting through selective chelation of 'loosely-bound'/chelatable Cu(II). It may also improve heparan sulphate homeostasis and bolster antioxidant defence by increasing vascular extracellular superoxide dismutase activity. Urinary albumin/creatinine ratio might prove useful for monitoring TETA treatment.
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Affiliation(s)
- J Lu
- School of Biological Sciences, Faculty of Science, University of Auckland, Private Bag, 92019 Auckland, New Zealand
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