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Mohr I, Brand M, Weber C, Langel A, Langel J, Michl P, Leidner VY, Olkus A, Köhrer S, Merle U. Mental and Physical Health in Wilson Disease Patients With SARS-CoV-2 Infection and Relevance of Long-COVID. JIMD Rep 2025; 66:e70021. [PMID: 40337099 PMCID: PMC12055521 DOI: 10.1002/jmd2.70021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Revised: 04/16/2025] [Accepted: 04/22/2025] [Indexed: 05/09/2025] Open
Abstract
SARS-CoV-2 infection and Long COVID (LC) might lead to a significant deterioration of physical and mental health. Wilson disease (WD) patients have a chronic liver and/or neuropsychiatric disease, making it particularly interesting to investigate LC in WD. 51 WD patients were retrospectively examined, evaluating physical and mental health by a survey and neuropsychological tests (SF-12, PSQI, ISI, Epworth, Chalder-fatigue scale, PHQ-9, GAD-7, PSS, FLei) before and ~11 months after SARS-CoV-2 infection. LC was defined as the development of new, at least moderately severe symptoms (shortness of breath, chest pain, fatigue, brain fog, exercise capacity, concentration disturbances) and/or worsening of pre-existing symptoms. 70.6% had predominant hepatic and 29.4% had neuropsychiatric symptoms at WD diagnosis. Median age was 39 years; 56.1% were female. Patients were in stable maintenance phase with a median treatment duration of 23 years. When compared to before COVID-19, WD patients had significantly worse physical life quality, sleeping quality, and fatigue. After COVID-19, a high percentage of WD patients reported concentration disorders (60%), fatigue (55%), reduced exercise capacity (50%), shortness of breath (40%), chest pain (20%) and feeling of brain fog (15%). 39.2% (n = 20) of the WD patients were classified as LC. This LC-WD subgroup showed significantly impaired quality of life, a high stress level, and sleeping disturbances, fatigue, depression, anxiety, and cognitive impairment. A large proportion of WD patients experience LC symptoms, reduced life quality, and sleeping disorders after SARS-CoV-2 infection. WD patients post-infection should be well monitored and supported if they develop persisting symptoms or neuro-psychological problems.
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Affiliation(s)
- Isabelle Mohr
- Internal Medicine IV, Department of GastroenterologyUniversity Hospital HeidelbergHeidelbergGermany
| | - Maximilian Brand
- Internal Medicine IV, Department of GastroenterologyUniversity Hospital HeidelbergHeidelbergGermany
| | - Christophe Weber
- Internal Medicine III Department of Internal Medicine and CardiologyUniversity Hospital HeidelbergHeidelbergGermany
| | - Andrea Langel
- Internal Medicine IV, Department of GastroenterologyUniversity Hospital HeidelbergHeidelbergGermany
| | - Jessica Langel
- Internal Medicine IV, Department of GastroenterologyUniversity Hospital HeidelbergHeidelbergGermany
| | - Patrick Michl
- Internal Medicine IV, Department of GastroenterologyUniversity Hospital HeidelbergHeidelbergGermany
| | - Viola Yuriko Leidner
- Internal Medicine IV, Department of GastroenterologyUniversity Hospital HeidelbergHeidelbergGermany
| | - Alexander Olkus
- Internal Medicine IV, Department of GastroenterologyUniversity Hospital HeidelbergHeidelbergGermany
| | - Sebastian Köhrer
- Internal Medicine IV, Department of GastroenterologyUniversity Hospital HeidelbergHeidelbergGermany
| | - Uta Merle
- Internal Medicine IV, Department of GastroenterologyUniversity Hospital HeidelbergHeidelbergGermany
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Baptista I, Alves P. Psychiatric Presentation of Wilson's Disease: A Rare Disease With an Unusual Manifestation. Cureus 2025; 17:e81645. [PMID: 40322335 PMCID: PMC12048889 DOI: 10.7759/cureus.81645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/02/2025] [Indexed: 05/08/2025] Open
Abstract
Wilson's disease is a rare disorder characterized by the accumulation of copper in multiple organs. Psychiatric symptoms are somewhat common but can take many different forms, which complicates their identification. We present a case where suicidal ideation and severe sleep disturbance were the central symptoms of the initial presentation. This case shows how psychiatric symptoms in uncompensated Wilson's disease can look like and how they are managed, as well as a psychological perspective into therapy nonadherence in chronic illness.
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Deloncle R, Guillard O, Pineau A. Copper in human health: From COVID 19 to neurodegenerative diseases. J Trace Elem Med Biol 2025; 89:127636. [PMID: 40184864 DOI: 10.1016/j.jtemb.2025.127636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Revised: 03/03/2025] [Accepted: 03/14/2025] [Indexed: 04/07/2025]
Abstract
Copper (Cu) exists in two oxidation states Cu+I and Cu+II yielding formation of enzymes involved in biological processes. In higher concentrations, by oxidative process and ROS production, Cu is toxic towards plants, humans and animals livers as observed in Wilson disease or sheep scrapie. Fighting according to the Fenton reaction against bacteria and viruses, has been proposed as a mean of combatting nosocomial diseases and complementary to COVID19 vaccination. In humans, Cu is stocked in liver, muscle or bound to brain protein as ß-APP, tau-protein, α-synuclein, ubiquitin or prion which present antioxidant properties when Cu-bonded. In abnormal ß-sheet conformation, they can trigger neurodegenerative diseases such as Alzheimer(AD), Parkinson(PD) and ALS. In these diseases, blood copper increase correlated with brain copper decrease has been described. In AD, abnormal D-serine has been detected in blood and cerebrospinal fluid. D-glutamate and D-alanine blood levels have been found in AD and could also be controlled with Cu and ceruloplasmin in a possible disease screening test. This abnormal D-conformation might result from epimerization of physiologically L-conformation brain peptides into protease-resistant D-enantiomers. This has previously been experimentally demonstrated for Bovine Spongiform Encephalopathy in a free Cu reductive medium with UV-induced free radicals. The Cu brain protective effect against free radicals was restored with cupric addition in oxidizing medium. Cupric supplementation in the brain, might restore Cu protection and slow down neurodegenerative processes. To lower side effects, Cu amino-acid complexes able to cross the blood brain barrier might be suggested for a Cu transfer to the brain.
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Affiliation(s)
- Roger Deloncle
- School of Pharmacy, Tours University, Tours 37200, France.
| | - Olivier Guillard
- School of Medicine and Pharmacy, Poitiers University, Poitiers 86022, France.
| | - Alain Pineau
- School of Pharmacy, Nantes University, Cedex 1, Nantes 44035, France.
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Khdair Ahmad F, Aburizeg D, Rayyan Y, Tamimi TA, Burayzat S, Ghanma A, Barbar M, Azab B. Genetic profiling of Wilson disease reveals a potential recurrent pathogenic variant of ATP7B in the Jordanian population. J Pediatr Gastroenterol Nutr 2025; 80:471-481. [PMID: 39763201 DOI: 10.1002/jpn3.12446] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 11/02/2024] [Accepted: 11/27/2024] [Indexed: 03/04/2025]
Abstract
OBJECTIVES Wilson disease (WD) is an autosomal-recessive disorder that disrupts copper homeostasis. ATPase copper transporting beta (ATP7B) gene is implicated as the disease-causing gene in WD. The common symptoms associated with WD include hepatic, neurological, psychiatric, and ophthalmic manifestations. The genetic landscape of WD is under-investigated in the Middle East and has never been studied in Jordan. We aimed to investigate the genetic profile of several unrelated Jordanian families with one or more patients affected by WD. METHODS Twenty-four Jordanian families with WD underwent clinical evaluation and genetic profiling by whole-exome and Sanger sequencing. RESULTS Surprisingly, the same variant (ATP7B:c.3551C>T;p.Ile1184Thr) was identified, for the first time, exclusively in the homozygous state, in eight consanguineous unrelated families. Before our study, the previous classification of this variant was either of uncertain significance (VUS) or likely pathogenic (LP). Interestingly, the patients harboring this variant displayed variable clinical manifestations on both the intra- and interfamilial levels, as previously described in cases with WD. The age of diagnosis, hepatic manifestations, neuropsychiatric involvements, and Kayser-Fleischer ring occurrence varied significantly in terms of existence and severity among the recruited individuals. Following our investigation, based on clinical data and co-segregation analysis, we re-classified the variant ATP7B:c.3551C>T;p.Ile1184Thr from VUS/LP to pathogenic, for the first time. Besides, our genetic analysis helped in resolving diagnostic ambiguity by either establishing or ruling out the diagnosis of WD. CONCLUSION Since the identified variant (ATP7B:p.Ile1184Thr) was discovered in multiple unrelated families, we create an avenue for the potential consideration of this variant as a recurrent, or possibly a founder variant, in the Jordanian population. Our work sheds light, for the first time, on the molecular underpinnings of WD in Jordan and compiles the WD-causing variants in the Middle East. Ultimately, the findings of our work can guide designing region-specific targeted genetic testing of WD in Jordan and provide valuable insights to direct clinical decisions for atypical WD presentations.
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Affiliation(s)
- Fareed Khdair Ahmad
- Section of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, School of Medicine, The University of Jordan, Amman, Jordan
- Jordan University Hospital, Amman, Jordan
- JOSPGHAN: Jordanian Society for Pediatric Gastroenterology, Hepatology, and Nutrition, Amman, Jordan
| | - Dunia Aburizeg
- Department of Pathology and Microbiology and Forensic Medicine, School of Medicine, The University of Jordan, Amman, Jordan
| | - Yaser Rayyan
- Jordan University Hospital, Amman, Jordan
- Section of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, The University of Jordan, Amman, Jordan
| | - Tarek A Tamimi
- Jordan University Hospital, Amman, Jordan
- Section of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, The University of Jordan, Amman, Jordan
| | - Salma Burayzat
- JOSPGHAN: Jordanian Society for Pediatric Gastroenterology, Hepatology, and Nutrition, Amman, Jordan
- Department of Pediatrics and Neonatology, Faculty of Medicine, The Hashemite University, Zarqa, Jordan
| | - Abdullah Ghanma
- JOSPGHAN: Jordanian Society for Pediatric Gastroenterology, Hepatology, and Nutrition, Amman, Jordan
- Pediatric Gastroenterology and Hepatology, Royal Medical Services, Amman, Jordan
| | - Maha Barbar
- JOSPGHAN: Jordanian Society for Pediatric Gastroenterology, Hepatology, and Nutrition, Amman, Jordan
- Pediatric Gastroenterology, Hepatology and Nutrition, King Hussein Cancer Center, Amman, Jordan
| | - Bilal Azab
- Department of Pathology and Microbiology and Forensic Medicine, School of Medicine, The University of Jordan, Amman, Jordan
- Division of Pathology and Laboratory Medicine, Phoenix Children's Hospital, Phoenix, Arizona, USA
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Socha P, Jańczyk W, Zanetto A, Burra P, Czlonkowska A, Debray D, Ferenci P, Merle U, Nicastro E, Poujois A, Schmidt H, Tsochatzis E. EASL-ERN Clinical Practice Guidelines on Wilson's disease. J Hepatol 2025; 82:S0168-8278(24)02706-5. [PMID: 40089450 DOI: 10.1016/j.jhep.2024.11.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Accepted: 11/08/2024] [Indexed: 03/17/2025]
Abstract
Wilson's disease is an autosomal recessive disorder of copper metabolism which affects the liver, brain and other organs. Diagnosis is based on: clinical features; biochemical tests, including plasma ceruloplasmin concentration, 24-h urinary copper excretion, copper content in the liver; and molecular analysis. Leipzig score and additionally relative exchangeable copper determination are recommended for diagnosis. Pharmacological therapy comprises chelating agents (penicillamine, trientine) and zinc salts, while only chelators are recommended for significant liver disease. Monitoring is based on clinical symptoms, liver tests and copper metabolism (urinary copper excretion, exchangeable copper) to detect poor compliance and over/under-treatment. Acute liver failure is challenging as making a diagnosis is difficult and pharmacological therapy may not be sufficient to save life. Liver transplantation has a well-defined role in Wilsonian acute hepatic failure but may also be considered in neurological disease.
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Mohr I, Lamade P, Weber C, Leidner V, Köhrer S, Olkus A, Lang M, Langel A, Dankert P, Greibich M, Wolf S, Zimmer H, Michl P, Poujois A, Weiss KH, Merle U. A comparative analysis in monitoring 24-hour urinary copper in wilson disease: sampling on or off treatment? Orphanet J Rare Dis 2025; 20:33. [PMID: 39838467 PMCID: PMC11748325 DOI: 10.1186/s13023-025-03545-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Accepted: 01/05/2025] [Indexed: 01/23/2025] Open
Abstract
BACKGROUND & AIM Twenty-four-hour urinary copper excretion (24 h-UCE) is the standard diagnostic tool for dose adjustments in maintenance therapy in Wilson disease (WD) patients. Guidelines lack data if both variants of 24 h-UCE measurement (with or without 48 h of treatment interruption) are equally interpretable. METHODS Eighty-four patients with a confirmed diagnosis of WD treated with chelators (50% of patients with D-Penicillamine and 50% with trientine) and with pairwise 24-h-UCE values on-therapy and off-therapy were included in the analysis. Pairwise urinary sampling between October 2022 (T0) and a 12-month FU (T2) was compared, and exchangeable copper (CuEXC) was additionally measured at T0. RESULTS Among the 84 patients, 65% had predominant hepatic symptoms, the median age was 42 years, and 58% were female. At T0, patients were in the stable maintenance phase, with a median treatment duration of 21.9 years. The levels of the biochemical markers liver and copper metabolism remained stable over the 12-month observation period for all patients. 24 h-UCE off-therapy significantly decreased from T0 to T2 (p = 0.03), whereas no statistically significant differences were detected for 24 h-UCE after therapy. Both sampling methods did not correlate. CuEXC was significantly correlated with 24 h-UCE after 48 h of dose interruption (p = 0.018) but not with 24 h-UCE after therapy. A total of 46% of the 24 h-UCE value pairs were discordant, laying out the aimed therapeutic ranges given in current international guidelines. CONCLUSION Off-therapy 24 h-UCE reflects the "free" copper pool more accurately than does urinary sampling. The study shows discordant results for both sampling methods in approximately half of the patients, revealing that interpretation of 24 h-UCE with respect to chelator-dosing decisions should be performed with caution.
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Affiliation(s)
- Isabelle Mohr
- Internal Medicine IV, Department of Gastroenterology, University Hospital Heidelberg, INF 410, Heidelberg, 69120, Germany.
| | - Patrick Lamade
- Internal Medicine IV, Department of Gastroenterology, University Hospital Heidelberg, INF 410, Heidelberg, 69120, Germany
| | - Christophe Weber
- Internal Medicine III Department of Internal Medicine and Cardiology, University Hospital Heidelberg, Heidelberg, Germany
| | - Viola Leidner
- Internal Medicine IV, Department of Gastroenterology, University Hospital Heidelberg, INF 410, Heidelberg, 69120, Germany
| | - Sebastian Köhrer
- Internal Medicine IV, Department of Gastroenterology, University Hospital Heidelberg, INF 410, Heidelberg, 69120, Germany
| | - Alexander Olkus
- Internal Medicine IV, Department of Gastroenterology, University Hospital Heidelberg, INF 410, Heidelberg, 69120, Germany
| | - Matthias Lang
- Internal Medicine IV, Department of Gastroenterology, University Hospital Heidelberg, INF 410, Heidelberg, 69120, Germany
| | - Andrea Langel
- Internal Medicine IV, Department of Gastroenterology, University Hospital Heidelberg, INF 410, Heidelberg, 69120, Germany
| | - Patrischia Dankert
- Internal Medicine IV, Department of Gastroenterology, University Hospital Heidelberg, INF 410, Heidelberg, 69120, Germany
| | - Melanie Greibich
- Internal Medicine IV, Department of Gastroenterology, University Hospital Heidelberg, INF 410, Heidelberg, 69120, Germany
| | - Silke Wolf
- Internal Medicine I, Department of Endocrinology, Diabetology, Metabolic Diseases and Clinical Chemistry, University Hospital Heidelberg, Heidelberg, Germany
| | - Holger Zimmer
- Internal Medicine I, Department of Endocrinology, Diabetology, Metabolic Diseases and Clinical Chemistry, University Hospital Heidelberg, Heidelberg, Germany
| | - Patrick Michl
- Internal Medicine IV, Department of Gastroenterology, University Hospital Heidelberg, INF 410, Heidelberg, 69120, Germany
| | - Aurélia Poujois
- Department of Neurology, Rothschild Foundation Hospital, National Reference Center for Wilson Disease, Paris, France
| | - Karl Heinz Weiss
- Internal Medicine, Salem Hospital Heidelberg, Heidelberg, Germany
| | - Uta Merle
- Internal Medicine IV, Department of Gastroenterology, University Hospital Heidelberg, INF 410, Heidelberg, 69120, Germany
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Fang S, Strader C, Costantino H, Weiss KH, Hedera P. Wilson disease in the USA: epidemiology and real-world patient characteristics based on a retrospective observational health claims study. BMJ Open 2024; 14:e089032. [PMID: 39806721 PMCID: PMC11667301 DOI: 10.1136/bmjopen-2024-089032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Accepted: 11/29/2024] [Indexed: 01/16/2025] Open
Abstract
OBJECTIVES To describe the epidemiology, patient characteristics and comorbidities in patients with Wilson disease (WD) in the USA. DESIGN Retrospective, population-based study. SETTING The study used the US Komodo claims database containing records regarding medical claims for over 120 million individuals. PARTICIPANTS Patients with WD were identified via ICD-10 (10th revision of the International Classification of Diseases) code during the study period 2016-2019 and no age restriction was applied. A further stratification by disease subtype ('hepatic', 'neurologic' and 'psychiatric') was performed. MAIN OUTCOME MEASURES WD prevalence was reported by age, sex and US census regions/divisions. Adjusted prevalence was calculated using age-specific prevalence standardised to the USA (2010 US census) and to the world (WHO 2000-2025) to enable comparisons across countries, using direct standardisation of prevalence estimates by age group. RESULTS Overall, 2115 patients with WD were identified during the study period. Among them, 56.8% had hepatic symptoms, 57.0% neurologic symptoms and 47.4% psychiatric symptoms. The most frequent manifestations in hepatic patients were liver signs and symptoms (90.8%), in neurologic patients cognitive defects (50.7%) and in psychiatric patients mood disorders (86.4%). The mean age in the overall cohort was 39.9 years. Prevalence estimation was based on 1481 patients with WD between 2017 and 2019. The 2017-2019 crude period prevalence was 21.2 patients per million (95% CI: 20.1 to 22.3), with similar prevalence observed for both sexes. CONCLUSIONS This study provides important real-world data on the diagnosed prevalence of WD in the USA and revealed the comorbidities associated with various disease subtypes, thereby providing a comprehensive basis for guiding physicians and policy makers in the management of this chronic disease.
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Affiliation(s)
- Shona Fang
- Alexion, AstraZeneca Rare Disease, Boston, Massachusetts, USA
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Garbuz M, Ovchinnikova E, Ovchinnikova A, Vinokurova V, Aristarkhova Y, Kuziakova O, Mashurova M, Kumeiko V. Spectrum of Pathogenic Variants of the ATP7B Gene and Genotype-Phenotype Correlation in Eastern Eurasian Patient Cohorts with Wilson's Disease. Biomedicines 2024; 12:2833. [PMID: 39767741 PMCID: PMC11673475 DOI: 10.3390/biomedicines12122833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2024] [Revised: 12/06/2024] [Accepted: 12/09/2024] [Indexed: 01/11/2025] Open
Abstract
Background/Objectives: Wilson's disease (WD) (OMIM 277900) or hepatolenticular degeneration is an autosomal recessive disorder caused by impaired copper excretion with subsequent accumulation in the liver, brain, and other tissues of the body. The defects in copper metabolism are based on various pathogenic variants of the ATP7B gene encoding copper-transporting P-type ATPase. The aim of this work is to search for pathogenic variants of the ATP7B gene among Eastern Eurasian patient cohorts and to pick correlations between pathogenic variants, gender, age of onset of the disease, and the course of the disease. Methods: The material for the study was the biomaterial of 100 people. The search for mutations was carried out by Sanger sequencing. Multiple alignment of nucleotide sequences and their analysis was performed using the MEGA-X software. To study the genotype-phenotypic correlation, an analysis of the medical records of each patient was carried out. Results: Most common pathogenic variant (48%) in the sample is p.His1069Gln (c.3207C>A), located in exon 14 of the ATP7B gene. Pathogenic variants of p.Glu1064Lys (c.3190G>A)-20%-and p.Met769HisfsTer26 (c.2304insC)-8%-of exons 14 and 8 were also common. For patients with pathogenic alleles p.His1069Gln (c.3207C>A) and p.Glu1064Lys (c.3190G>A), typical deviations are mental and neurological manifestations of WD. In patients with the pathogenic allele p.Met769HisfsTer26 (c.2304insC), deviations are more characteristic of the liver and a combination of various symptoms that are atypical for WD. Conclusions: In this study, we were able to obtain differences in symptoms in patients with different pathogenic alleles of the ATP7B gene.
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Affiliation(s)
- Mikhail Garbuz
- School of Medicine and Life Sciences, Far Eastern Federal University, Vladivostok 690922, Russia; (M.G.)
| | - Elena Ovchinnikova
- School of Medicine and Life Sciences, Far Eastern Federal University, Vladivostok 690922, Russia; (M.G.)
| | - Anna Ovchinnikova
- School of Medicine and Life Sciences, Far Eastern Federal University, Vladivostok 690922, Russia; (M.G.)
| | - Valeriya Vinokurova
- School of Medicine and Life Sciences, Far Eastern Federal University, Vladivostok 690922, Russia; (M.G.)
| | - Yulya Aristarkhova
- School of Medicine and Life Sciences, Far Eastern Federal University, Vladivostok 690922, Russia; (M.G.)
| | - Olga Kuziakova
- School of Medicine and Life Sciences, Far Eastern Federal University, Vladivostok 690922, Russia; (M.G.)
| | - Mariya Mashurova
- School of Medicine and Life Sciences, Far Eastern Federal University, Vladivostok 690922, Russia; (M.G.)
| | - Vadim Kumeiko
- School of Medicine and Life Sciences, Far Eastern Federal University, Vladivostok 690922, Russia; (M.G.)
- A.V. Zhirmunsky National Scientific Center of Marine Biology Far Eastern Branch of Russian Academy of Sciences, Vladivostok 690041, Russia
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Jin M, Zhou L, Lu C. Pregnancy With Wilson's Disease. MATERNAL-FETAL MEDICINE 2024; 6:265-268. [PMID: 40406175 PMCID: PMC12094332 DOI: 10.1097/fm9.0000000000000246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Accepted: 08/19/2024] [Indexed: 05/24/2025] Open
Affiliation(s)
- Meng Jin
- Department of Obstetrics and Gynecology, First Peoples Hospital of Kunshan, Suzhou, China
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Alanazi ST, Salama SA, Althobaiti MM, Alotaibi RA, AlAbdullatif AA, Musa A, Harisa GI. Alleviation of Copper-Induced Hepatotoxicity by Bergenin: Diminution of Oxidative Stress, Inflammation, and Apoptosis via Targeting SIRT1/FOXO3a/NF-κB Axes and p38 MAPK Signaling. Biol Trace Elem Res 2024:10.1007/s12011-024-04401-3. [PMID: 39347884 DOI: 10.1007/s12011-024-04401-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2024] [Accepted: 09/26/2024] [Indexed: 10/01/2024]
Abstract
Despite its biological importance, excess copper induces organ damage, especially to the liver. Disruption of critical signaling cascades that control redox status, inflammatory responses, and cellular apoptosis significantly contributes to the copper-induced hepatotoxicity. The present work explored the hepatoprotective ability of bergenin against the copper-induced hepatotoxicity using male Wistar rats as a mammalian model. The results revealed that bergenin suppressed the copper-evoked histopathological changes and hepatocellular necrosis as indicated by decreased activity of the liver enzymes ALT and AST in the sera of the copper-intoxicated rats. It decreased hepatic copper content and the copper-induced oxidative stress as revealed by reduced lipid peroxidation and improved activity of the antioxidant enzymes thioredoxin reductase, glutathione peroxidase, catalase, and superoxide dismutase. Bergenin downregulated the inflammatory cytokines TNF-α and IL-6, and the inflammatory cell infiltration to the liver tissues. Additionally, it inhibited the copper-induced apoptosis as indicated by significant reduction in caspase-3 activity. At the molecular level, bergenin activated the antioxidant transcription factor FOXO3a, inhibited the nuclear translocation of the inflammatory transcription factor NF-κB, and suppressed the inflammatory signaling molecules p38 MAPK and c-Fos. Interestingly, bergenin improved the expression of the anti-apoptotic protein Bcl2 and reduced the pro-apoptotic protein BAX. Bergenin markedly enhanced the expression of the histone deacetylase protein SIRT1 that regulates activity of NF-κB and FOXO3a. Collectively, these findings highlight the alleviating activity of bergenin against the copper-induced hepatotoxicity via controlling oxidative stress, inflammation, and apoptosis potentially through upregulation of SIRT1, activation of FOXO3a along with suppression of NF-κB and p38 MAPK signaling.
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Affiliation(s)
- Samyah T Alanazi
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, 11433, Riyadh, Saudi Arabia
| | - Samir A Salama
- Division of Biochemistry, Department of Pharmacology and Toxicology, College of Pharmacy, Taif University, P.O. Box 11099, 21944, Taif, Saudi Arabia.
| | - Musaad M Althobaiti
- Department of Pharmacology and Toxicology, College of Pharmacy, Taif University, P.O. Box 11099, 21944, Taif, Saudi Arabia
| | - Rana A Alotaibi
- College of Pharmacy, Taif University, P.O. Box 11099, 21944, Taif, Saudi Arabia
| | - Ammar A AlAbdullatif
- Pharmaceutical Care Services, Ministry of the National Guard-Health Affairs, P.O. Box 4616, 31412, Dammam, Saudi Arabia
| | - Arafa Musa
- Department of Pharmacognosy, College of Pharmacy, Jouf University, 72341, Sakaka, Aljouf, Saudi Arabia
| | - Gamaleldin I Harisa
- Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, 11451, Riyadh, Saudi Arabia
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Zhao Z, Jiao Y, Yang D, Yang Y. Carbon dots based AuAg@AuNPs with oxidase-like activity for SERS dual-readouts detection of D-penicillamine. Mikrochim Acta 2024; 191:604. [PMID: 39287838 DOI: 10.1007/s00604-024-06684-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Accepted: 09/03/2024] [Indexed: 09/19/2024]
Abstract
An oxidase (OXD) -like AuAg@AuNPs nanozyme was prepared by Au seeds growth using dopamine carbon dots as reducing and capping agents. The AuAg@AuNPs show excellent OXD-like and surface-enhanced Raman spectroscopy (SERS) activities and can oxidize the non-Raman-active leucomalachite green (LMG) into the Raman-active malachite green (MG). The research displays that D-penicillamine (D-PA) can effectively inhibit the OXD-like activity of Au@AgNPs and enhance the SERS signals as substrate. It is attributed to the formation of S-Au bond due to thiol (-SH) in D-PA. Therefore, a highly sensitive and specific SERS dual-readout sensing platform was proposed to assay D-PA with a limit of detection of 0.1 μg/mL (direct SERS mode) and 6.64 μg/L (indirect SERS mode). This approach was successfully used to determine D-PA in actual pharmaceutical formulations.
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Affiliation(s)
- Zhao Zhao
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Yunnan Province, 650500, China
| | - Yang Jiao
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Yunnan Province, 650500, China
| | - Dezhi Yang
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Yunnan Province, 650500, China
| | - Yaling Yang
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Yunnan Province, 650500, China.
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Fang S, Hedera P, Borchert J, Schultze M, Weiss KH. Epidemiology of Wilson disease in Germany - real-world insights from a claims data study. Orphanet J Rare Dis 2024; 19:335. [PMID: 39261850 PMCID: PMC11391731 DOI: 10.1186/s13023-024-03351-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Accepted: 09/02/2024] [Indexed: 09/13/2024] Open
Abstract
BACKGROUND Wilson disease (WD) is a rare disorder of copper metabolism, causing copper accumulation mainly in the liver and the brain. The prevalence of WD was previously estimated around 20 to 33.3 patients per million for the United States, Europe, and Asia, but data on the prevalence of WD in Germany are limited. OBJECTIVES To describe patient characteristics and to assess prevalence of WD in Germany using a representative claims database. METHODS WD patients were identified in the WIG2 (Wissenschaftliches Institut für Gesundheitsökonomie und Gesundheitssystemforschung; Scientific Institute for Health Economics and Health Systems Research) benchmark database of 4.5 million insured Germans by combining ICD-10-coding with WD-specific lab tests and treatments. The study period ranged from 2013 to 2016 for assessing patient characteristics, and to 2018 for prevalence, respectively. RESULTS Seventy unique patients were identified. Most patients (86%) were between 18 and 64 years of age and more often male (60%) than female. Two patients (3%) younger than 18 years were included, as well as 8 patients (11%) older than 64 years. Most common WD subtypes were hepatic (57%), psychiatric (49%), and neurologic (44%). Average prevalence was 20.3 patients per million (range: 17.8-24.4), with similar results for two-year prevalence. Generally, prevalence increased steadily over the study period. Observed mortality was low, with only one death during the study period. CONCLUSIONS This study adds valuable real-world data on the prevalence and patient characteristics of WD in Germany. Generally, our findings align with other reports and contribute to the global understanding of WD epidemiology. Still, regional and temporal trends remain to be investigated more thoroughly to further the understanding of the natural history and epidemiology of this rare disease.
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Affiliation(s)
- Shona Fang
- Alexion, AstraZeneca Rare Disease, 121 Seaport Avenue, Boston, 02210, MA, USA.
| | | | - Julia Borchert
- Scientific Institute for Health Economics and Health System Research (WIG2 GmbH), Leipzig, Germany
| | - Michael Schultze
- Berlin Center for Epidemiology and Health Research, ZEG Berlin GmbH, Berlin, Germany
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Zhang Y, Wang M, Tang L, Yang W, Zhang J. FoxO1 silencing in Atp7b -/- neural stem cells attenuates high copper-induced apoptosis via regulation of autophagy. J Neurochem 2024; 168:2762-2774. [PMID: 38837406 DOI: 10.1111/jnc.16136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 04/17/2024] [Accepted: 05/07/2024] [Indexed: 06/07/2024]
Abstract
Wilson disease (WD) is a severely autosomal genetic disorder triggered by dysregulated copper metabolism. Autophagy and apoptosis share common modulators that process cellular death. Emerging evidences suggest that Forkhead Box O1 over-expression (FoxO1-OE) aggravates abnormal autophagy and apoptosis to induce neuronal injury. However, the underlying mechanisms remain undetermined. Herein, the aim of this study was to investigate how regulating FoxO1 affects cellular autophagy and apoptosis to attenuate neuronal injury in a well-established WD cell model, the high concentration copper sulfate (CuSO4, HC)-triggered Atp7b-/- (Knockout, KO) neural stem cell (NSC) lines. The FoxO1-OE plasmid, or siRNA-FoxO1 (siFoxO1) plasmid, or empty vector plasmid was stably transfected with recombinant lentiviral vectors into HC-induced Atp7b-/- NSCs. Toxic effects of excess deposited copper on wild-type (WT), Atp7b-/- WD mouse hippocampal NSCs were tested by Cell Counting Kit-8 (CCK-8). Subsequently, the FoxO1 expression was evaluated by immunofluorescence (IF) assay, western blot (WB) and quantitative real-time polymerase chain reaction (qRT-PCR) analysis. Meanwhile, the cell autophagy and apoptosis were evaluated by flow cytometry (FC), TUNEL staining, 2,7-dichlorofluorescein diacetate (DCFH-DA), JC-1, WB, and qRT-PCR. The current study demonstrated a strong rise in FoxO1 levels in HC-treated Atp7b-/- NSCs, accompanied with dysregulated autophagy and hyperactive apoptosis. Also, it was observed that cell viability was significantly decreased with the over-expressed FoxO1 in HC-treated Atp7b-/- WD model. As intended, silencing FoxO1 effectively inhibited abnormal autophagy in HC-treated Atp7b-/- NSCs, as depicted by a decline in LC3II/I, Beclin-1, ATG3, ATG7, ATG13, and ATG16, whereas simultaneously increasing P62. In addition, silencing FoxO1 suppressed apoptosis via diminishing oxidative stress (OS), and mitochondrial dysfunction in HC-induced Atp7b-/- NSCs. Collectively, these results clearly demonstrate the silencing FoxO1 has the neuroprotective role of suppressing aberrant cellular autophagy and apoptosis, which efficiently attenuates neuronal injury in WD.
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Affiliation(s)
- Yu Zhang
- Department of Neurology, First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, China
- Department of Graduate School, Anhui University of Chinese Medicine, Hefei, China
| | - Meixia Wang
- Department of Neurology, First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, China
- Center for Xin'an Medicine and Modernization of Traditional Chinese Medicine of IHM, Anhui University of Chinese Medicine, Hefei, China
| | - Lulu Tang
- Department of Neurology, First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, China
| | - Wenming Yang
- Department of Neurology, First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, China
- Center for Xin'an Medicine and Modernization of Traditional Chinese Medicine of IHM, Anhui University of Chinese Medicine, Hefei, China
| | - Jing Zhang
- Department of Neurology, First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, China
- Center for Xin'an Medicine and Modernization of Traditional Chinese Medicine of IHM, Anhui University of Chinese Medicine, Hefei, China
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14
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Daniel-Robin T, Kumar P, Benichou B, Combal JP. Characteristics of patients with Wilson disease in the United States: An insurance claims database study. World J Hepatol 2024; 16:791-799. [PMID: 38818282 PMCID: PMC11135267 DOI: 10.4254/wjh.v16.i5.791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 03/07/2024] [Accepted: 03/25/2024] [Indexed: 05/22/2024] Open
Abstract
BACKGROUND Wilson disease (WD) is a progressive, potentially fatal degenerative disease affecting the liver and central nervous system. Given its low prevalence, collecting data on large cohorts of patients with WD is challenging. Comprehensive insurance claims databases provide powerful tools to collect retrospective data on large numbers of patients with rare diseases. AIM To describe patients with WD in the United States, their treatment and clinical outcome, using a large insurance claims database. METHODS This retrospective, longitudinal study was performed in the Clarivate Real-World Data Product database. All patients with ≥ 2 claims associated with an International Classification of Diseases 10 (ICD-10) diagnostic code for WD (E83.01) between 2016 and 2021 were included and followed until death or study end. Patients were divided into two groups by whether or not they were documented to have received a specific treatment for WD. Clinical manifestations, hospitalisations, liver transplantation and death were documented. RESULTS Overall, 5376 patients with an ICD-10 diagnostic code for WD were identified. The mean age at inclusion was 41.2 years and 52.0% were men. A specific WD treatment was documented for 885 patients (15.1%), although the number of patients taking zinc salts may be underestimated due to over the counter purchase. At inclusion, the mean age of patients with a documented treatment was 36.6 ± 17.8 years vs 42.2 ± 19.6 years in those without a documented treatment. During follow-up, 273 patients (5.1%) died. Compared with the American general population, the standardised mortality ratio was 2.19. The proportion of patients with a documented WD-specific treatment who died during follow-up was 4.0% and the mean age at death 52.7 years. CONCLUSION Patients treated for WD in the United States had an excess early mortality compared with the American population. These findings indicate that there is a significant unmet need for effective treatment for WD in the United States.
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Chen H, Wang X, Zhang J, Xie D. Effect of high-frequency repetitive transcranial magnetic stimulation on cognitive impairment in WD patients based on inverse probability weighting of propensity scores. Front Neurosci 2024; 18:1375234. [PMID: 38660222 PMCID: PMC11039870 DOI: 10.3389/fnins.2024.1375234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Accepted: 03/26/2024] [Indexed: 04/26/2024] Open
Abstract
Background Hepatolenticular degeneration [Wilson disease (WD)] is an autosomal recessive metabolic disease characterized by copper metabolism disorder. Cognitive impairment is a key neuropsychiatric symptom of WD. At present, there is no effective treatment for WD-related cognitive impairment. Methods In this study, high-frequency repetitive transcranial magnetic stimulation (rTMS) was used to treat WD-related cognitive impairment, and inverse probability weighting of propensity scores was used to correct for confounding factors. The Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Auditory Verbal Learning Test (AVLT), Boston Naming Test (BNT), Clock Drawing Test (CDT) and Trail Making Test (TMT) were used to evaluate overall cognition and specific cognitive domains. Results The MMSE, MoCA and CDT scores after treatment were significantly different from those before treatment (MMSE: before adjustment: OR = 1.404, 95% CI: 1.271-1.537; after adjustment: OR = 1.381, 95% CI: 1.265-1.497, p < 0.001; MoCA: before adjustment: OR = 1.306, 95% CI: 1.122-1.490; after adjustment: OR = 1.286, 95% CI: 1.104; AVLT: OR = 1.161, 95% CI: 1.074-1.248; after adjustment: OR = 1.145, 95% CI: 1.068-1.222, p < 0.05; CDT: OR = 1.524, 95% CI: 1.303-1.745; after adjustment: OR = 1.518, 95% CI: 1.294-1.742, p < 0.001). The BNT and TMT scores after adjustment were not significantly different from those before adjustment (BNT: before adjustment: OR = 1.048, 95% CI: 0.877-1.219; after adjustment: OR = 1.026, 95% CI: 0.863-1.189, p > 0.05; TMT: before adjustment: OR = 0.816, 95% CI: 1.122-1.490; after adjustment: OR = 0.791, 95% CI: 0.406-1.176, p > 0.05). Conclusion High-frequency rTMS can effectively improve cognitive impairment, especially memory and visuospatial ability, in WD patients. The incidence of side effects is low, and the safety is good.
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Affiliation(s)
- Hong Chen
- The First Clinical Mdical College of Anhui University of Chinese Medicine, Hefei, China
| | - Xie Wang
- The First Clinical Mdical College of Anhui University of Chinese Medicine, Hefei, China
| | - Juan Zhang
- Department of Neurology, The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, China
| | - Daojun Xie
- Department of Neurology, The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, China
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Ovchinnikova EV, Garbuz MM, Ovchinnikova AA, Kumeiko VV. Epidemiology of Wilson's Disease and Pathogenic Variants of the ATP7B Gene Leading to Diversified Protein Disfunctions. Int J Mol Sci 2024; 25:2402. [PMID: 38397079 PMCID: PMC10889319 DOI: 10.3390/ijms25042402] [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] [Received: 01/25/2024] [Revised: 02/14/2024] [Accepted: 02/16/2024] [Indexed: 02/25/2024] Open
Abstract
Wilson's disease (WD) is an autosomal recessive disorder characterized by toxic accumulation of copper in the liver, brain, and other organs. The disease is caused by pathogenic variants in the ATP7B gene, which encodes a P-type copper transport ATPase. Diagnosing WD is associated with numerous difficulties due to the wide range of clinical manifestations and its unknown dependence on the physiological characteristics of the patient. This leads to a delay in the start of therapy and the subsequent deterioration of the patient's condition. However, in recent years, molecular genetic testing of patients using next generation sequencing (NGS) has been gaining popularity. This immediately affected the detection speed of WD. If, previously, the frequency of this disease was estimated at 1:35,000-45,000 people, now, when conducting large molecular genetic studies, the frequency is calculated as 1:7026 people. This certainly points to the problem of identifying WD patients. This review provides an update on the performance of epidemiological studies of WD and describes normal physiological functions of the protein and diversified disfunctions depending on pathogenic variants of the ATP7B gene. Future prospects in the development of WD genetic diagnostics are also discussed.
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Affiliation(s)
- Elena Vasilievna Ovchinnikova
- Institute of Life Sciences and Biomedicine, School of Natural Sciences, Far Eastern Federal University, Vladivostok 690922, Russia (M.M.G.)
| | - Mikhail Maksimovich Garbuz
- Institute of Life Sciences and Biomedicine, School of Natural Sciences, Far Eastern Federal University, Vladivostok 690922, Russia (M.M.G.)
| | - Anna Aleksandrovna Ovchinnikova
- Institute of Life Sciences and Biomedicine, School of Natural Sciences, Far Eastern Federal University, Vladivostok 690922, Russia (M.M.G.)
| | - Vadim Vladimirovich Kumeiko
- Institute of Life Sciences and Biomedicine, School of Natural Sciences, Far Eastern Federal University, Vladivostok 690922, Russia (M.M.G.)
- A.V. Zhirmunsky National Scientific Center of Marine Biology, Far Eastern Branch of Russian Academy of Sciences, Federal University, Vladivostok 690041, Russia
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Moutapam-Ngamby-Adriaansen Y, Maillot F, Labarthe F, Lioger B. Blood cytopenias as manifestations of inherited metabolic diseases: a narrative review. Orphanet J Rare Dis 2024; 19:65. [PMID: 38355710 PMCID: PMC10865644 DOI: 10.1186/s13023-024-03074-4] [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] [Received: 11/03/2023] [Accepted: 02/03/2024] [Indexed: 02/16/2024] Open
Abstract
Inherited Metabolic Diseases (IMD) encompass a diverse group of rare genetic conditions that, despite their individual rarity, collectively affect a substantial proportion, estimated at as much as 1 in 784 live births. Among their wide-ranging clinical manifestations, cytopenia stands out as a prominent feature. Consequently, IMD should be considered a potential diagnosis when evaluating patients presenting with cytopenia. However, it is essential to note that the existing scientific literature pertaining to the link between IMD and cytopenia is limited, primarily comprising case reports and case series. This paucity of data may contribute to the inadequate recognition of the association between IMD and cytopenia, potentially leading to underdiagnosis. In this review, we synthesize our findings from a literature analysis along with our clinical expertise to offer a comprehensive insight into the clinical presentation of IMD cases associated with cytopenia. Furthermore, we introduce a structured diagnostic approach underpinned by decision-making algorithms, with the aim of enhancing the early identification and management of IMD-related cytopenia.
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Affiliation(s)
- Yannick Moutapam-Ngamby-Adriaansen
- Service de Médecine Interne, CHRU de Tours, Tours Cedex 1, France.
- Service de Médecine Interne Et Polyvalente, 2, Centre Hospitalier de Blois, Mail Pierre Charlot, 41000, Blois, France.
| | - François Maillot
- Service de Médecine Interne, CHRU de Tours, Tours Cedex 1, France
- Reference Center for Inborn Errors of Metabolism ToTeM, CHRU de Tours, Hôpital Clocheville, 49 Bd Béranger, 37000, Tours, France
- INSERM U1253, iBrain, Université François Rabelais de Tours, 10 Boulevard Tonnellé, 37000, Tours, France
- INSERM U1069, Nutrition, Croissance et Cancer, Faculté de Médecine, Université François Rabelais de Tours, 10 Boulevard Tonnellé, 37000, Tours, France
| | - François Labarthe
- Reference Center for Inborn Errors of Metabolism ToTeM, CHRU de Tours, Hôpital Clocheville, 49 Bd Béranger, 37000, Tours, France
- INSERM U1069, Nutrition, Croissance et Cancer, Faculté de Médecine, Université François Rabelais de Tours, 10 Boulevard Tonnellé, 37000, Tours, France
- Service de Pédiatrie, CHRU de Tours, Tours Cedex 1, France
| | - Bertrand Lioger
- Service de Médecine Interne Et Polyvalente, 2, Centre Hospitalier de Blois, Mail Pierre Charlot, 41000, Blois, France
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Więcek S, Paprocka J. Disorders of Copper Metabolism in Children-A Problem too Rarely Recognized. Metabolites 2024; 14:38. [PMID: 38248841 PMCID: PMC10818781 DOI: 10.3390/metabo14010038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 12/23/2023] [Accepted: 01/05/2024] [Indexed: 01/23/2024] Open
Abstract
Copper plays an important role in metabolic processes. Both deficiency and excess of this element have a negative effect and lead to pathological conditions. Copper is a cofactor of many enzymatic reactions. Its concentration depends on the delivery in the diet, the absorption in enterocytes, transport with the participation of ATP7A/ATP7B protein, and proper excretion. Copper homeostasis disorders lead to serious medical conditions such as Menkes disease (MD) and Wilson's disease (WD). A mutation in the ATP7A gene is the cause of Menkes disease, it prevents the supply of copper ions to enzymes dependent on them, such as dopamine β-hydroxylase and lysyl oxidase. This leads to progressive changes in the central nervous system and disorders of the connective tissue. In turn, Wilson's disease is an inherited autosomal recessive disease. It is caused by a mutation of the ATP7B gene encoding the ATP7B protein which means excess copper cannot be removed from the body, leading to the pathological accumulation of this element in the liver and brain. The clinical picture is dominated by the liver, neurological, and/or psychiatric symptoms. Early inclusion of zinc preparations and chelating drugs significantly improves the prognosis in this group of patients. The aim of the study is to analyse, based on the latest literature, the following factors: the etiopathogenesis, clinical picture, diagnostic tests, treatment, prognosis, and complications of disease entities associated with copper disturbances: Menkes disease and Wilson's disease. In addition, it is necessary for general practitioners, neurologists, and gastroenterologists to pay attention to these disease entities because they are recognized too late and too rarely, especially in the paediatric population.
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Affiliation(s)
- Sabina Więcek
- Department of Paediatrics, Faculty of Medical Sciences, Medical University of Silesia, 40-055 Katowice, Poland
| | - Justyna Paprocka
- Department of Paediatric Neurology, Faculty of Medical Sciences, Medical University of Silesia, 40-055 Katowice, Poland
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Delle Cave V, Di Dato F, Iorio R. Wilson's Disease with Acute Hepatic Onset: How to Diagnose and Treat It. CHILDREN (BASEL, SWITZERLAND) 2024; 11:68. [PMID: 38255382 PMCID: PMC10814100 DOI: 10.3390/children11010068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 12/19/2023] [Accepted: 01/05/2024] [Indexed: 01/24/2024]
Abstract
Wilson's disease (WD) with acute onset poses a diagnostic challenge because it is clinically indistinguishable from other acute liver diseases. In addition, serum ceruloplasmin and urinary copper excretion, the first-line diagnostic tools for WD, can show false positive results in the case of acute liver failure, and the diagnostic role of genetic analysis is limited by the time required to perform it. In the case of fulminant onset, there is a clear indication of liver transplantation. "New Wilson Index" is frequently used to discriminate between patients who need liver transplantation versus those who can be successfully managed by medical treatment, but its reliability remains controversial. Timely referral of patients with acute liver failure due to WD may be a key factor in improving patient survival. Although liver transplant very often represents the only chance for such patients, maximum effort should be made to promote survival with a native liver. The management of these aspects of WD is still a matter of debate and will be the subject of this review.
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Affiliation(s)
| | | | - Raffaele Iorio
- Department of Translational Medical Science, Section of Pediatrics, University of Naples Federico II, 80131 Naples, Italy; (V.D.C.); (F.D.D.)
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Ganesh S, Chithambaram T, Krishnan NR, Vincent DR, Kaliappan J, Srinivasan K. Exploring Huntington's Disease Diagnosis via Artificial Intelligence Models: A Comprehensive Review. Diagnostics (Basel) 2023; 13:3592. [PMID: 38066833 PMCID: PMC10706174 DOI: 10.3390/diagnostics13233592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Revised: 11/25/2023] [Accepted: 11/27/2023] [Indexed: 10/16/2024] Open
Abstract
Huntington's Disease (HD) is a devastating neurodegenerative disorder characterized by progressive motor dysfunction, cognitive impairment, and psychiatric symptoms. The early and accurate diagnosis of HD is crucial for effective intervention and patient care. This comprehensive review provides a comprehensive overview of the utilization of Artificial Intelligence (AI) powered algorithms in the diagnosis of HD. This review systematically analyses the existing literature to identify key trends, methodologies, and challenges in this emerging field. It also highlights the potential of ML and DL approaches in automating HD diagnosis through the analysis of clinical, genetic, and neuroimaging data. This review also discusses the limitations and ethical considerations associated with these models and suggests future research directions aimed at improving the early detection and management of Huntington's disease. It also serves as a valuable resource for researchers, clinicians, and healthcare professionals interested in the intersection of machine learning and neurodegenerative disease diagnosis.
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Affiliation(s)
- Sowmiyalakshmi Ganesh
- School of Computer Science and Engineering, Vellore Institute of Technology, Vellore 632014, Tamil Nadu, India; (S.G.); (T.C.); (J.K.)
| | - Thillai Chithambaram
- School of Computer Science and Engineering, Vellore Institute of Technology, Vellore 632014, Tamil Nadu, India; (S.G.); (T.C.); (J.K.)
| | - Nadesh Ramu Krishnan
- School of Computer Science Engineering and Information Systems, Vellore Institute of Technology, Vellore 632014, Tamil Nadu, India;
| | - Durai Raj Vincent
- School of Computer Science Engineering and Information Systems, Vellore Institute of Technology, Vellore 632014, Tamil Nadu, India;
| | - Jayakumar Kaliappan
- School of Computer Science and Engineering, Vellore Institute of Technology, Vellore 632014, Tamil Nadu, India; (S.G.); (T.C.); (J.K.)
| | - Kathiravan Srinivasan
- School of Computer Science and Engineering, Vellore Institute of Technology, Vellore 632014, Tamil Nadu, India; (S.G.); (T.C.); (J.K.)
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21
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Berenguer M, Vergara M, Almohalla C, Hernandez A, Blanco S, Testillano M, Girona E, Casado M, García M, Catalina MV, Muñoz C, Gutierrez ML, Molina E, Romero M, Otero A, Hernáez-Alsina T, Bernal-Monterde V, Lorente S, Masnou H, Bonet L, Soto S, Gisbert C, Valer MP, Gomez J, Pacheco G, Morillas J, Gonzalez M, Dominguez N, Lazaro M, Pascual S, Castelló I, Gonzalez R. Significant heterogeneity in the diagnosis and long-term management of Wilson disease: Results from a large multicenter Spanish study. GASTROENTEROLOGIA Y HEPATOLOGIA 2023; 46:577-584. [PMID: 36372257 DOI: 10.1016/j.gastrohep.2022.10.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 10/15/2022] [Accepted: 10/24/2022] [Indexed: 11/13/2022]
Abstract
There is uncertainty regarding Wilson's disease (WD) management. OBJECTIVES To assess, in a multicenter Spanish retrospective cohort study, whether the approach to WD is homogeneous among centers. METHODS Data on WD patients followed at 32 Spanish hospitals were collected. RESULTS 153 cases, 58% men, 20.6 years at diagnosis, 69.1% hepatic presentation, were followed for 15.5 years. Discordant results in non-invasive laboratory parameters were present in 39.8%. Intrahepatic copper concentration was pathologic in 82.4%. Genetic testing was only done in 56.6% with positive results in 83.9%. A definite WD diagnosis (Leipzig score ≥4) was retrospectively confirmed in 92.5% of cases. Chelating agents were standard initial therapy (75.2%) with frequent modifications (57%), particularly to maintenance zinc. Enzyme normalization was not achieved by one third, most commonly in the setting of poor compliance, lack of genetic mutations and/or presence of cardiometabolic risk factors. Although not statistically significant, there were trends for sex differences in number of diagnosed cases, age at diagnosis and biochemical response. CONCLUSIONS Significant heterogeneity in diagnosis and management of WD patients emerges from this multicenter study that includes both small and large reference centers. The incorporation of genetic testing will likely improve diagnosis. Sex differences need to be further explored.
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Affiliation(s)
- Marina Berenguer
- Hepatology - Liver Transplantation Unit, IIS La Fe and CIBER-EHD, Hospital Universitari i Politècnic La Fe, Valencia, Spain; Department of Medicine, Universitat de València, Valencia, Spain.
| | - Mercedes Vergara
- Parc Tauli Sabadell Hospital Universitari, Institut d'Investigació i Innovació Parc Tauli I3PT, Univ Autonoma de Barcelona, Sabadell, Barcelona, Spain; Dept Medicina, Universitat Autonoma de Barcelona and CIBERhed, Insituto Carlos III, Madrid, Spain
| | - Carolina Almohalla
- Servicio de Aparato Digestivo, Unidad de Hepatología, Hospital Universitario Río Hortega, Valladolid, Spain
| | - Alicia Hernandez
- Servicio de Aparato Digestivo, Hospital universitario de Ciudad Real, Ciudad real, Spain
| | - Sonia Blanco
- Servicio de Aparato Digestivo, Hospital Universitario Basurto, Euskadi, Spain
| | - Milagros Testillano
- Servicio de Aparato Digestivo, Unidad de Hepatología, Hospital Universitario Cruces, Bizkaia, Spain
| | - Eva Girona
- Servicio de Aparato Digestivo, Hospital de Elx, Alicante, Spain
| | - Marta Casado
- Servicio de Aparato Digestivo, Hospital Universitario Torrecárdenas, Almería, Spain
| | - Miren García
- Servicio de Aparato Digestivo, Hospital Universitario Virgen de La Victoria, Málaga, Spain
| | - Maria-Vega Catalina
- Servicio de Aparato Digestivo, Unidad de Hepatología, Hospital General Universitario Gregorio Marañon. Madrid, Spain
| | - Carolina Muñoz
- Servicio de Aparato Digestivo, Unidad de Hepatología, Hospital 12 de Octubre, Madrid, Spain
| | - Maria Luisa Gutierrez
- Servicio de Aparato Digestivo, Hospital Universitario Fundación Alcorcón, Madrid, Spain
| | - Esther Molina
- Servicio de Aparato Digestivo, Unidad de Hepatología, Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, Spain
| | - Miriam Romero
- Servicio de Aparato Digestivo, Unidad de Hepatología, Hospital La Paz, Madrid, Spain
| | - Alejandra Otero
- Servicio de Aparato Digestivo, Hospital Universitario de A Coruña, Coruña, Spain
| | | | - Vanessa Bernal-Monterde
- Servicio de Aparato Digestivo, Hospital Miguel Servet, Instituto de Investigación Sanitaria de Aragón, Zaragoza, Spain
| | - Sara Lorente
- Unidad de Hepatología y Trasplante Hepático, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain
| | - Helena Masnou
- Servei Aparell Digestiu, Unitat de Hepatologia, Hospital Germans Trias i Pujol, Badalona, Spain
| | - Lucia Bonet
- Servicio Aparato Digestivo, Hospital Universitari Son Espases, Spain
| | - Susana Soto
- Servicio de Aparato Digestivo, Hospital del Tajo, Aranjuez, Spain
| | - Concha Gisbert
- Servicio de Medicina Interna, Hospital de Dénia - Marina Salud, Denia, Spain
| | - María-Paz Valer
- Servicio de Aparato Digestivo, Hospital Universitario de Fuenlabrada, Madrid, Spain
| | - Judith Gomez
- Servicio de Aparato Digestivo, Hospital Universitario de Burgos, Burgos, Spain
| | - Gemma Pacheco
- Servicio de Aparato Digestivo, Hospital Universitario La Ribera, Spain
| | - Julia Morillas
- Servicio de Aparato Digestivo, Hospital Virgen de la Luz, Cuenca, Spain
| | - Martha Gonzalez
- Servicio de Aparato Digestivo, Hospital El Bierzo, Ponferrada, León, Spain
| | - Nuria Dominguez
- Servicio de Aparato Digestivo, Hospital University Infanta Cristina, Parla, Spain
| | - Maria Lazaro
- Servicio de Aparato Digestivo, Hospital General San Jorge, Huesca, Spain
| | - Sonia Pascual
- Servicio de Aparato Digestivo, Unidad Hepática, Hospital General Universitario de Alicante, Alicante, Spain; CiberEHD, Madrid, Spain
| | | | - Rocio Gonzalez
- Servicio de Aparato Digestivo, Hospital Regional Universitario de Málaga, Málaga, Spain
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22
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Haywood S, Swinburne J, Schofield E, Constantino-Casas F, Watson P. Copper toxicosis in Bedlington terriers is associated with multiple independent genetic variants. Vet Rec 2023; 193:e2832. [PMID: 37038639 DOI: 10.1002/vetr.2832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 02/25/2023] [Accepted: 03/02/2023] [Indexed: 04/12/2023]
Abstract
BACKGROUND Bedlington terrier copper toxicosis (CT) is due to a homozygous exon deletion in COMMD1. CT also occurs in Bedlingtons lacking this deletion. An association with two ABCA12 single nuceotide polymorphism (SNP) splice variants was reported. Labrador retriever CT is associated with a missense mutation in ATP7B, and with a protective mutation in ATP7A. METHODS Liver and DNA samples from 24 affected and 10 unaffected Bedlingtons were assessed for copper and genetic variants. Allelic frequencies were compared. The ATP7B mutation frequency was investigated in 144 dogs of other breeds. RESULTS The ABCA12 SNPs showed no differences between groups. The COMMD1 deletion was less frequent in unaffected than in affected dogs and in affected dogs post-2001 than pre-2001. The ATP7B mutation was more frequent in affected than unaffected Bedlingtons. Thirty-five of 144 dogs of other breeds were homo- or heterozygous for the ATP7B mutation. The ATP7A mutation was absent from Bedlingtons. LIMITATIONS Clinical information and qualitative copper measurements were unavailable for most dogs. CONCLUSION The COMMD1 deletion remains present in Bedlington terriers but is no longer the primary cause of CT. ABCA12 SNPs were not associated with CT. The ATP7B:c.4358G>A mutation was significantly associated with Bedlington CT and was more common in dogs of this breed than in the 144 dogs of other breeds.
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Affiliation(s)
- Susan Haywood
- School of Veterinary Science, University of Liverpool, Liverpool, UK
| | | | - Ellen Schofield
- Kennel Club Genetics Centre, Department of Veterinary Medicine, University of Cambridge, Cambridge, UK
| | - Fernando Constantino-Casas
- Queen's Veterinary School Hospital, Department of Veterinary Medicine, University of Cambridge, Cambridge, UK
| | - Penny Watson
- Queen's Veterinary School Hospital, Department of Veterinary Medicine, University of Cambridge, Cambridge, UK
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23
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Yamkate P, Funke S, Steiger K, Gold RM, Lidbury JA, Karst U, Steiner JM. Quantitative bioimaging of copper in frozen liver specimens from cats using laser ablation-inductively coupled plasma-mass spectrometry. J Feline Med Surg 2023; 25:1098612X231186919. [PMID: 37522313 PMCID: PMC10812054 DOI: 10.1177/1098612x231186919] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/01/2023]
Abstract
OBJECTIVES The aim of this study was to assess laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) as a tool for measuring concentrations and determining accumulation of copper in frozen liver specimens from cats. METHODS Six frozen liver specimens were evaluated by qualitative copper staining and quantitative flame atomic absorption spectroscopy. Tissue specimens were cryo-sectioned and quantitative bioimaging of copper was performed using LA-ICP-MS. Results were compared with those obtained using conventional methods. RESULTS Of the six specimens, only one showed positive staining for copper with rhodanine. Using flame atomic absorption spectroscopy (FAAS), one specimen showed a deficient copper level (<100 µg/g dry weight), two specimens had copper within the reference interval (RI; 150-180 µg/g) and three specimens had copper concentrations above the RI. Bioimaging from LA-ICP-MS showed inhomogeneous distribution of hepatic copper. The areas with dense copper accumulation were represented as hotspots in the liver specimens. Hepatic copper quantification by LA-ICP-MS correlated well with copper quantified by FAAS (r = 0.96, P = 0.002). CONCLUSIONS AND RELEVANCE Our findings suggest that quantitative bioimaging by LA-ICP-MS could be used to demonstrate the distribution and concentration of copper in frozen liver specimens from cats. The distribution of copper in these specimens was inhomogeneous with dense accumulation represented as hotspots on tissue sections. A positive correlation of hepatic copper concentrations determined by LA-ICP-MS and FAAS was found. Further studies to establish an RI for hepatic copper using this technique and to further determine its clinical utility are warranted.
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Affiliation(s)
- Punyamanee Yamkate
- Gastrointestinal Laboratory, Department of Small Animal Clinical Sciences, School of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA
- Department of Veterinary Medicine, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, Thailand
| | - Sabrina Funke
- Institute for Inorganic and Analytical Chemistry, University of Münster, Münster, Germany
| | - Katja Steiger
- Institute of Pathology, School of Medicine, Technical University Munich, Munich, Germany
| | - Randi M Gold
- Gastrointestinal Laboratory, Department of Small Animal Clinical Sciences, School of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA
| | - Jonathan A Lidbury
- Gastrointestinal Laboratory, Department of Small Animal Clinical Sciences, School of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA
| | - Uwe Karst
- Institute for Inorganic and Analytical Chemistry, University of Münster, Münster, Germany
| | - Joerg M Steiner
- Gastrointestinal Laboratory, Department of Small Animal Clinical Sciences, School of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA
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24
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Tang X, Yan Z, Miao Y, Ha W, Li Z, Yang L, Mi D. Copper in cancer: from limiting nutrient to therapeutic target. Front Oncol 2023; 13:1209156. [PMID: 37427098 PMCID: PMC10327296 DOI: 10.3389/fonc.2023.1209156] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 06/13/2023] [Indexed: 07/11/2023] Open
Abstract
As an essential nutrient, copper's redox properties are both beneficial and toxic to cells. Therefore, leveraging the characteristics of copper-dependent diseases or using copper toxicity to treat copper-sensitive diseases may offer new strategies for specific disease treatments. In particular, copper concentration is typically higher in cancer cells, making copper a critical limiting nutrient for cancer cell growth and proliferation. Hence, intervening in copper metabolism specific to cancer cells may become a potential tumor treatment strategy, directly impacting tumor growth and metastasis. In this review, we discuss the metabolism of copper in the body and summarize research progress on the role of copper in promoting tumor cell growth or inducing programmed cell death in tumor cells. Additionally, we elucidate the role of copper-related drugs in cancer treatment, intending to provide new perspectives for cancer treatment.
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Affiliation(s)
- Xiaolong Tang
- The First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
- The Second Department of Gastrointestinal Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Zaihua Yan
- The First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
- The Second Department of Gastrointestinal Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Yandong Miao
- Department of Oncology, Yantai Affiliated Hospital of Binzhou Medical University, The Second Clinical Medical College of Binzhou Medical University, Yantai, Shandong, China
| | - Wuhua Ha
- The First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
| | - Zheng Li
- Division of Thoracic Tumor Multimodality Treatment and Department of Radiation Oncology, Cancer Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Lixia Yang
- Gansu Academy of Traditional Chinese Medicine, Lanzhou, Gansu, China
| | - Denghai Mi
- The First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
- Gansu Academy of Traditional Chinese Medicine, Lanzhou, Gansu, China
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25
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Jagota P, Lim S, Pal PK, Lee J, Kukkle PL, Fujioka S, Shang H, Phokaewvarangkul O, Bhidayasiri R, Mohamed Ibrahim N, Ugawa Y, Aldaajani Z, Jeon B, Diesta C, Shambetova C, Lin C. Genetic Movement Disorders Commonly Seen in Asians. Mov Disord Clin Pract 2023; 10:878-895. [PMID: 37332644 PMCID: PMC10272919 DOI: 10.1002/mdc3.13737] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Revised: 02/27/2023] [Accepted: 03/21/2023] [Indexed: 11/21/2023] Open
Abstract
The increasing availability of molecular genetic testing has changed the landscape of both genetic research and clinical practice. Not only is the pace of discovery of novel disease-causing genes accelerating but also the phenotypic spectra associated with previously known genes are expanding. These advancements lead to the awareness that some genetic movement disorders may cluster in certain ethnic populations and genetic pleiotropy may result in unique clinical presentations in specific ethnic groups. Thus, the characteristics, genetics and risk factors of movement disorders may differ between populations. Recognition of a particular clinical phenotype, combined with information about the ethnic origin of patients could lead to early and correct diagnosis and assist the development of future personalized medicine for patients with these disorders. Here, the Movement Disorders in Asia Task Force sought to review genetic movement disorders that are commonly seen in Asia, including Wilson's disease, spinocerebellar ataxias (SCA) types 12, 31, and 36, Gerstmann-Sträussler-Scheinker disease, PLA2G6-related parkinsonism, adult-onset neuronal intranuclear inclusion disease (NIID), and paroxysmal kinesigenic dyskinesia. We also review common disorders seen worldwide with specific mutations or presentations that occur frequently in Asians.
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Affiliation(s)
- Priya Jagota
- Chulalongkorn Centre of Excellence for Parkinson's Disease and Related Disorders, Department of Medicine, Faculty of MedicineChulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross SocietyBangkokThailand
| | - Shen‐Yang Lim
- Division of Neurology, Department of Medicine, Faculty of MedicineUniversity of MalayaKuala LumpurMalaysia
- The Mah Pooi Soo & Tan Chin Nam Centre for Parkinson's & Related Disorders, Faculty of MedicineUniversity of MalayaKuala LumpurMalaysia
| | - Pramod Kumar Pal
- Department of NeurologyNational Institute of Mental Health & Neurosciences (NIMHANS)BengaluruIndia
| | - Jee‐Young Lee
- Department of NeurologySeoul Metropolitan Government‐Seoul National University Boramae Medical Center & Seoul National University College of MedicineSeoulRepublic of Korea
| | - Prashanth Lingappa Kukkle
- Center for Parkinson's Disease and Movement DisordersManipal HospitalBangaloreIndia
- Parkinson's Disease and Movement Disorders ClinicBangaloreIndia
| | - Shinsuke Fujioka
- Department of Neurology, Fukuoka University, Faculty of MedicineFukuokaJapan
| | - Huifang Shang
- Department of Neurology, Laboratory of Neurodegenerative Disorders, Rare Diseases CenterWest China Hospital, Sichuan UniversityChengduChina
| | - Onanong Phokaewvarangkul
- Chulalongkorn Centre of Excellence for Parkinson's Disease and Related Disorders, Department of Medicine, Faculty of MedicineChulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross SocietyBangkokThailand
| | - Roongroj Bhidayasiri
- Chulalongkorn Centre of Excellence for Parkinson's Disease and Related Disorders, Department of Medicine, Faculty of MedicineChulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross SocietyBangkokThailand
- The Academy of Science, The Royal Society of ThailandBangkokThailand
| | - Norlinah Mohamed Ibrahim
- Neurology Unit, Department of Medicine, Faculty of MedicineUniversiti Kebangsaan MalaysiaKuala LumpurMalaysia
| | - Yoshikazu Ugawa
- Deprtment of Human Neurophysiology, Faculty of MedicineFukushima Medical UniversityFukushimaJapan
| | - Zakiyah Aldaajani
- Neurology Unit, King Fahad Military Medical ComplexDhahranSaudi Arabia
| | - Beomseok Jeon
- Department of NeurologySeoul National University College of MedicineSeoulRepublic of Korea
- Movement Disorder CenterSeoul National University HospitalSeoulRepublic of Korea
| | - Cid Diesta
- Section of Neurology, Department of NeuroscienceMakati Medical Center, NCRMakatiPhilippines
| | | | - Chin‐Hsien Lin
- Department of NeurologyNational Taiwan University HospitalTaipeiTaiwan
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26
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Gromadzka G, Grycan M, Przybyłkowski AM. Monitoring of Copper in Wilson Disease. Diagnostics (Basel) 2023; 13:1830. [PMID: 37296680 PMCID: PMC10253047 DOI: 10.3390/diagnostics13111830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 05/16/2023] [Accepted: 05/19/2023] [Indexed: 06/12/2023] Open
Abstract
(1) Introduction: Wilson's disease (WND) is an autosomal recessive disorder of copper (Cu) metabolism. Many tools are available to diagnose and monitor the clinical course of WND. Laboratory tests to determine disorders of Cu metabolism are of significant diagnostic importance. (2) Methods: A systematic review of the literature in the PubMed, Science Direct, and Wiley Online Library databases was conducted. (Results): For many years, Cu metabolism in WND was assessed with serum ceruloplasmin (CP) concentration, radioactive Cu test, total serum Cu concentration, urinary copper excretion, and Cu content in the liver. The results of these studies are not always unambiguous and easy to interpret. New methods have been developed to calculate non-CP Cu (NCC) directly. New parameters, such as relative Cu exchange (REC), reflecting the ratio of CuEXC to total serum Cu, as well as relative Cu exchange (REC), reflecting the ratio of CuEXC to total serum Cu, have been shown to be an accurate tool for the diagnosis of WND. Recently, a direct and fast LC-ICP-MS method for the study of CuEXC was presented. A new method to assess Cu metabolism during treatment with ALXN1840 (bis-choline tetrathiomolybdate [TTM]) has been developed. The assay enables the bioanalysis of CP and different types of Cu, including CP-Cu, direct NCC (dNCC), and labile bound copper (LBC) in human plasma. Conclusions: A few diagnostic and monitoring tools are available for patients with WND. While many patients are diagnosed and adequately assessed with currently available methods, diagnosis and monitoring is a real challenge in a group of patients who are stuck with borderline results, ambiguous genetic findings, and unclear clinical phenotypes. Technological progress and the characterization of new diagnostic parameters, including those related to Cu metabolism, may provide confidence in the more accurate diagnosis of WND in the future.
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Affiliation(s)
- Grażyna Gromadzka
- Medical Faculty, Collegium Medicum, Cardinal Stefan Wyszyński University in Warsaw, Wóycickiego Street 1/3, 01-938 Warsaw, Poland
| | - Marta Grycan
- Students Research Club, Maria Sklodowska-Curie Medical Academy, 03-411 Warsaw, Poland
| | - Adam M. Przybyłkowski
- Department of Gastroenterology and Internal Medicine, Medical University of Warsaw, 02-091 Warsaw, Poland
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27
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Kipker N, Alessi K, Bojkovic M, Padda I, Parmar MS. Neurological-Type Wilson Disease: Epidemiology, Clinical Manifestations, Diagnosis, and Management. Cureus 2023; 15:e38170. [PMID: 37252588 PMCID: PMC10224700 DOI: 10.7759/cureus.38170] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Accepted: 04/14/2023] [Indexed: 05/31/2023] Open
Abstract
Wilson disease (WD) is a complex metabolic disorder caused by disruptions to copper regulation within the body, leading to an unregulated accumulation of copper within various tissues. A less understood organ affected by the collection of copper is the brain, which further leads to the generation of oxygen-free radicals and resultant demyelination. Healthcare providers must keep the neurological form of WD in their list of differentials when patients present with diverse neurological manifestations. The initial step to diagnosis will be to distinguish the characteristic disease presentation with a thorough history and physical and neurological examination. A high clinical disease suspicion of WD should warrant further investigation by laboratory workup and imaging modalities to support the clinical findings and confirm the diagnosis of WD. Once a WD diagnosis is established, the healthcare provider should treat the underlying biological process of WD symptomatically. This review article discusses the epidemiology and pathogenesis of the neurological form of WD, its clinical and behavioral implications, diagnostic features, and treatment modalities (current and emerging therapies), further aiding healthcare professionals in early diagnosis and management strategies.
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Affiliation(s)
- Nathaniel Kipker
- Foundational Sciences, Nova Southeastern University Dr. Kiran C. Patel College of Osteopathic Medicine, Clearwater, USA
| | - Kaitlyn Alessi
- Foundational Sciences, Nova Southeastern University Dr. Kiran C. Patel College of Osteopathic Medicine, Clearwater, USA
| | | | - Inderbir Padda
- Internal Medicine, Richmond University Medical Center, New York, USA
| | - Mayur S Parmar
- Foundational Sciences, Nova Southeastern University Dr. Kiran C. Patel College of Osteopathic Medicine, Clearwater, USA
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28
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Lucena-Valera A, Ruz-Zafra P, Ampuero J. [Wilson's disease: overview]. Med Clin (Barc) 2023; 160:261-267. [PMID: 36697289 DOI: 10.1016/j.medcli.2022.12.016] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Revised: 12/27/2022] [Accepted: 12/28/2022] [Indexed: 01/25/2023]
Abstract
Wilson's disease (WD) is an uncommon hereditary disorder caused by a deficiency in the ATP7B transporter. The protein codified by this gene facilitates the incorporation of the copper into ceruloplasmin. Therefore, WD accumulates copper primary in the liver and secondary in other organs, such as the central nervous system. It represents a wide spectrum of disease, ranging from being asymptomatic in some patients to promote an acute liver failure in others. The diagnosis requires a combination of clinical signs and symptoms, as well as some diagnostic tests such as the measurement of serum ceruloplasmin, the urinary excretion of copper, the liver biopsy or the genetic testing. The treatment must be maintained lifelong and includes some drugs such as chelating agents (penicillamine and trientine) and inhibitors of the copper absorption (zinc salts). Lastly, the liver transplant should be an option for patients with end-stage liver disease.
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Affiliation(s)
- Ana Lucena-Valera
- Departamento de Enfermedades Digestivas, Hospital Universitario Virgen del Rocío, Sevilla, España
| | - Pilar Ruz-Zafra
- Departamento de Enfermedades Digestivas, Hospital Universitario Virgen del Rocío, Sevilla, España
| | - Javier Ampuero
- Departamento de Enfermedades Digestivas, Hospital Universitario Virgen del Rocío, Sevilla, España; Instituto de Biomedicina de Sevilla (IBiS), Sevilla, España; Universidad de Sevilla, Sevilla, España; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, España.
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29
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Farag CM, Antar R, Akosman S, Ng M, Whalen MJ. What is hemoglobin, albumin, lymphocyte, platelet (HALP) score? A comprehensive literature review of HALP's prognostic ability in different cancer types. Oncotarget 2023; 14:153-172. [PMID: 36848404 PMCID: PMC9970084 DOI: 10.18632/oncotarget.28367] [Citation(s) in RCA: 62] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/27/2023] Open
Abstract
Since its inception, the Hemoglobin, Albumin, Lymphocyte, Platelet Score (HALP) has gained attention as a new prognostic biomarker to predict several clinical outcomes in a multitude of cancers. In our review, we searched PubMed for articles between the first paper on HALP in 2015 through September 2022, yielding 32 studies in total that evaluated HALP's association with various cancers, including Gastric, Colorectal, Bladder, Prostate, Kidney, Esophageal, Pharyngeal, Lung, Breast, and Cervical cancers, among others. This review highlights the collective association HALP has with demographic factors such as age and sex in addition to TNM staging, grade, and tumor size. Furthermore, this review summarizes HALP's prognostic ability to predict overall survival, progression-free survival, recurrence-free survival, among other outcomes. In some studies, HALP has also been able to predict response to immunotherapy and chemotherapy. This review article also aims to serve as a comprehensive and encyclopedic report on the literature that has evaluated HALP as a biomarker in various cancers, highlighting the heterogeneity surrounding HALP's utilization. Because HALP requires only a complete blood count and albumin - already routinely collected for cancer patients - HALP shows potential as a cost-effective biomarker to aid clinicians in improving outcomes for immuno-nutritionally deficient patients.
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Affiliation(s)
- Christian Mark Farag
- Department of Urology, George Washington University School of Medicine, Washington, DC 20052, USA
| | - Ryan Antar
- Department of Urology, George Washington University School of Medicine, Washington, DC 20052, USA
| | - Sinan Akosman
- Department of Urology, George Washington University School of Medicine, Washington, DC 20052, USA
| | - Matthew Ng
- Department of Surgery, George Washington University School of Medicine, Washington, DC 20052, USA
| | - Michael J Whalen
- Department of Urology, George Washington University School of Medicine, Washington, DC 20052, USA
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30
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Nilles C, Obadia MA, Sobesky R, Dumortier J, Guillaud O, Laurencin C, Moreau C, Vanlemmens C, Ory-Magne F, de Ledinghen V, Bardou-Jacquet E, Fluchère F, Collet C, Oussedik-Djebrani N, Woimant F, Poujois A. Diagnosis and Outcomes of Late-Onset Wilson's Disease: A National Registry-Based Study. Mov Disord 2023; 38:321-332. [PMID: 36573661 DOI: 10.1002/mds.29292] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 11/07/2022] [Accepted: 11/16/2022] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Wilson's disease (WD) is usually diagnosed in children and young adults; limited data exist on late-onset forms. OBJECTIVE The aim was to characterize the clinical and paraclinical presentations, therapeutic management, and outcomes in patients with late-onset WD. METHODS Patients diagnosed with WD after age 40 years were identified from the French Wilson's Disease Registry (FWDR). Clinical, laboratory, and imaging findings and treatment were reported at diagnosis and last follow-up. RESULTS Forty-five patients were identified (median age: 49, range: 40-64) and placed in three groups according to their clinical presentation: neurological (n = 20, median diagnostic delay: 20 months), hepatic (n = 13, diagnostic delay: 12 months), and family screening (n = 12), all confirmed genetically. Six neurological patients had an atypical presentation (1 torticollis, 2 writer's cramps, 2 functional movement disorders, and 1 isolated dysarthria), without T2/fluid-attenuated inversion recovery brain magnetic resonance imaging (MRI) hyperintensities; 5 of 6 had no Kayser-Fleischer ring (KFR); 5 of 6 had liver involvement. In the neurological group, 84% of patients improved clinically, and 1 developed copper deficiency. In the hepatic group, 77% had cirrhosis; 6 patients required liver transplantation. In the screened group, 43% had mild liver involvement; 3 were not treated and remained stable; 24-h urinary copper excretion was normal in 33% of patients at diagnosis. CONCLUSIONS In the FWDR, late-onset forms of WD affect 8% of patients, mostly with neurological presentations. Thirty percent of the neurological forms were atypical (isolated long-lasting symptoms, inconspicuous brain MRI, no KFR). With personalized treatment, prognosis was good. This study emphasized that WD should be suspected at any age and even in cases of atypical presentation. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Christelle Nilles
- Department of Neurology, Rothschild Foundation Hospital, Paris, France.,National Reference Center for Wilson's Disease and Other Copper-Related Rare Diseases, Rothschild Foundation Hospital, Paris, France
| | - Mickael Alexandre Obadia
- Department of Neurology, Rothschild Foundation Hospital, Paris, France.,National Reference Center for Wilson's Disease and Other Copper-Related Rare Diseases, Rothschild Foundation Hospital, Paris, France
| | - Rodolphe Sobesky
- Centre Hépato-Biliaire, AP-HP, DHU Hepatinov, INSERM UMR-S 1193, Hôpital Paul Brousse, Villejuif, France
| | - Jérôme Dumortier
- National Reference Center for Wilson's Disease and Other Copper-Related Rare Diseases, Femme Mère Enfant Hospital, Hospices Civils de Lyon, Bron, France.,Department of Hepatologie-Gastroenterologie, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France
| | - Olivier Guillaud
- National Reference Center for Wilson's Disease and Other Copper-Related Rare Diseases, Femme Mère Enfant Hospital, Hospices Civils de Lyon, Bron, France.,Service d'explorations fonctionnelles digestives, CHU Lyon, Lyon, France
| | - Chloé Laurencin
- National Reference Center for Wilson's Disease and Other Copper-Related Rare Diseases, Femme Mère Enfant Hospital, Hospices Civils de Lyon, Bron, France.,Service de Neurologie HFME-GHE, Bron Cedex, France
| | - Caroline Moreau
- Service de neurologie et pathologies du mouvement, INSERM UMR, CHU Lille, Lille, France
| | - Claire Vanlemmens
- Service d'Hépatologie et soins intensifs digestifs, CHU Besançon, Hôpital Jean Minjoz, Besançon, France
| | - Fabienne Ory-Magne
- Service de Neurologie, Neurology Department, CHU Toulouse, Hôpital Purpan, Toulouse, France
| | - Victor de Ledinghen
- Service d'Hépatologie-Gastroentérologie, Hôpital Haut-Lévêque, CHU Bordeaux, Pessac & INSERM U1312, Université de Bordeaux, Bordeaux, France
| | | | - Frederique Fluchère
- Service de Neurologie, Neurology Department, CHU Marseille, Hôpital de la Timone, Marseille, France
| | - Corinne Collet
- National Reference Center for Wilson's Disease and Other Copper-Related Rare Diseases, Rothschild Foundation Hospital, Paris, France.,Département de Génétique, Hôpital Robert Debré AP-HP, Paris, France
| | - Nouzha Oussedik-Djebrani
- National Reference Center for Wilson's Disease and Other Copper-Related Rare Diseases, Rothschild Foundation Hospital, Paris, France.,Laboratoire de Toxicologie Biologique, Hôpital Lariboisière AP-HP, Paris, France
| | - France Woimant
- National Reference Center for Wilson's Disease and Other Copper-Related Rare Diseases, Rothschild Foundation Hospital, Paris, France
| | - Aurélia Poujois
- Department of Neurology, Rothschild Foundation Hospital, Paris, France.,National Reference Center for Wilson's Disease and Other Copper-Related Rare Diseases, Rothschild Foundation Hospital, Paris, France
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31
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EFSA Scientific Committee, More SJ, Bampidis V, Benford D, Bragard C, Halldorsson TI, Hernández‐Jerez AF, Bennekou SH, Koutsoumanis K, Lambré C, Machera K, Mullins E, Nielsen SS, Schlatter JR, Schrenk D, Turck D, Younes M, Boon P, Ferns GAA, Lindtner O, Smolders E, Wilks M, Bastaki M, de Sesmaisons‐Lecarré A, Ferreira L, Greco L, Kass GEN, Riolo F, Leblanc J. Re-evaluation of the existing health-based guidance values for copper and exposure assessment from all sources. EFSA J 2023; 21:e07728. [PMID: 36694841 PMCID: PMC9843535 DOI: 10.2903/j.efsa.2023.7728] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Copper is an essential micronutrient and also a regulated product used in organic and in conventional farming pest management. Both deficiency and excessive exposure to copper can have adverse health effects. In this Scientific Opinion, the EFSA 2021 harmonised approach for establishing health-based guidance values (HBGVs) for substances that are regulated products and also nutrients was used to resolve the divergent existing HBGVs for copper. The tightly regulated homeostasis prevents toxicity manifestation in the short term, but the development of chronic copper toxicity is dependent on copper homeostasis and its tissue retention. Evidence from Wilson disease suggests that hepatic retention is indicative of potential future and possibly sudden onset of copper toxicity under conditions of continuous intake. Hence, emphasis was placed on copper retention as an early marker of potential adverse effects. The relationships between (a) chronic copper exposure and its retention in the body, particularly the liver, and (b) hepatic copper concentrations and evidence of toxicity were examined. The Scientific Committee (SC) concludes that no retention of copper is expected to occur with intake of 5 mg/day and established an Acceptable Daily Intake (ADI) of 0.07 mg/kg bw. A refined dietary exposure assessment was performed, assessing contribution from dietary and non-dietary sources. Background copper levels are a significant source of copper. The contribution of copper from its use as plant protection product (PPP), food and feed additives or fertilisers is negligible. The use of copper in fertilisers or PPPs contributes to copper accumulation in soil. Infant formula and follow-on formula are important contributors to dietary exposure of copper in infants and toddlers. Contribution from non-oral sources is negligible. Dietary exposure to total copper does not exceed the HBGV in adolescents, adults, elderly and the very elderly. Neither hepatic copper retention nor adverse effects are expected to occur from the estimated copper exposure in children due to higher nutrient requirements related to growth.
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Chen L, Min J, Wang F. Copper homeostasis and cuproptosis in health and disease. Signal Transduct Target Ther 2022; 7:378. [PMID: 36414625 PMCID: PMC9681860 DOI: 10.1038/s41392-022-01229-y] [Citation(s) in RCA: 599] [Impact Index Per Article: 199.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Revised: 08/19/2022] [Accepted: 10/11/2022] [Indexed: 11/24/2022] Open
Abstract
As an essential micronutrient, copper is required for a wide range of physiological processes in virtually all cell types. Because the accumulation of intracellular copper can induce oxidative stress and perturbing cellular function, copper homeostasis is tightly regulated. Recent studies identified a novel copper-dependent form of cell death called cuproptosis, which is distinct from all other known pathways underlying cell death. Cuproptosis occurs via copper binding to lipoylated enzymes in the tricarboxylic acid (TCA) cycle, which leads to subsequent protein aggregation, proteotoxic stress, and ultimately cell death. Here, we summarize our current knowledge regarding copper metabolism, copper-related disease, the characteristics of cuproptosis, and the mechanisms that regulate cuproptosis. In addition, we discuss the implications of cuproptosis in the pathogenesis of various disease conditions, including Wilson's disease, neurodegenerative diseases, and cancer, and we discuss the therapeutic potential of targeting cuproptosis.
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Affiliation(s)
- Liyun Chen
- grid.13402.340000 0004 1759 700XThe Fourth Affiliated Hospital, The First Affiliated Hospital, Institute of Translational Medicine, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou, China ,grid.412017.10000 0001 0266 8918The First Affiliated Hospital, Basic Medical Sciences, School of Public Health, Hengyang Medical School, University of South China, Hengyang, China
| | - Junxia Min
- The Fourth Affiliated Hospital, The First Affiliated Hospital, Institute of Translational Medicine, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou, China.
| | - Fudi Wang
- The Fourth Affiliated Hospital, The First Affiliated Hospital, Institute of Translational Medicine, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou, China. .,The First Affiliated Hospital, Basic Medical Sciences, School of Public Health, Hengyang Medical School, University of South China, Hengyang, China.
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Yang Y, Wang Y, Wang C, Xu X, Liu C, Huang X. Identification of hub genes of Parkinson's disease through bioinformatics analysis. Front Neurosci 2022; 16:974838. [PMID: 36440267 PMCID: PMC9683342 DOI: 10.3389/fnins.2022.974838] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 09/15/2022] [Indexed: 12/03/2024] Open
Abstract
Parkinson's disease (PD) is a common neurodegenerative disease, and there is still a lack of effective diagnostic and treatment methods. This study aimed to search for hub genes that might serve as diagnostic or therapeutic targets for PD. All the analysis was performed in R software. The expression profile data of PD (number: GSE7621) was acquired from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) associated with PD were screened by the "Limma" package of the R software. Key genes associated with PD were screened by the "WGCNA" package of the R software. Target genes were screened by merging the results of "Limma" and "WGCNA." Enrichment analysis of target genes was performed by Gene Ontology (GO), Disease Ontology (DO), and Kyoto Enrichment of Genes and Genomes (KEGG). Machine learning algorithms were employed to screen for hub genes. Nomogram was constructed using the "rms" package. And the receiver operating characteristic curve (ROC) was plotted to detect and validate our prediction model sensitivity and specificity. Additional expression profile data of PD (number: GSE20141) was acquired from the GEO database to validate the nomogram. GSEA was used to determine the biological functions of the hub genes. Finally, RPL3L, PLEK2, PYCRL, CD99P1, LOC100133130, MELK, LINC01101, and DLG3-AS1 were identified as hub genes of PD. These findings can provide a new direction for the diagnosis and treatment of PD.
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Affiliation(s)
- Yajun Yang
- Department of Neurosurgery, The First Hospital of Shanxi Medical University, Taiyuan, China
- The First School of Clinical Medicine, Shanxi Medical University, Taiyuan, China
| | - Yi Wang
- Department of Neurosurgery, The First Hospital of Shanxi Medical University, Taiyuan, China
- The First School of Clinical Medicine, Shanxi Medical University, Taiyuan, China
| | - Ce Wang
- Department of Neurosurgery, The First Hospital of Shanxi Medical University, Taiyuan, China
- The First School of Clinical Medicine, Shanxi Medical University, Taiyuan, China
| | - Xinjuan Xu
- Department of Neurosurgery, The First Hospital of Shanxi Medical University, Taiyuan, China
- The First School of Clinical Medicine, Shanxi Medical University, Taiyuan, China
| | - Cai Liu
- Department of Neurosurgery, The First Hospital of Shanxi Medical University, Taiyuan, China
- The First School of Clinical Medicine, Shanxi Medical University, Taiyuan, China
| | - Xintao Huang
- Department of Neurosurgery, The First Hospital of Shanxi Medical University, Taiyuan, China
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Aksoy F, Arslan İE, Ozgur T, Dundar HZ, Çelik F, Bican Demir A, Erer Ozbek S, Kiyici M, Ozkan TB, Kaya E. Does Liver Transplant Improve Neurological Symptoms in Wilson Disease? Report of 24 Cases. EXP CLIN TRANSPLANT 2022; 20:1009-1015. [PMID: 36524887 DOI: 10.6002/ect.2022.0206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
OBJECTIVES Wilson disease is an inherited disorder that results in copper accumulation in the tissues with liver injury and failure. Orthotopic liver transplant is one of the treatments of choice for this disease. The aim of this study was to compare the neurological symptoms, before and after orthotopic livertransplant, of patients with liver cirrhosis due to Wilson disease, who represent a special group of patients with liver failure. MATERIALS AND METHODS Between 2007 and 2020, there were 24 patients with Wilson disease resistant to medical treatment who underwent deceased donor orthotopic livertransplant and were followed up for 1 year, 5 years, and 10 years for evaluation with neurological scoring systems. Patients were also evaluated for postoperative complications and survival. RESULTS Of the 24 patients evaluated, there were 13 (54.2%) female patients and 11 (45.8%) male patients, and the mean age was 34 years (range, 14-57 years). One of the patients died from early postoperative sepsis. After orthotopic livertransplant, disease scores returned to normal in 16 patients and improved in the remaining patients. Before transplant, all patients required help in their daily activities. After transplant, there were significant improvements in some symptoms, and the patients became more independent in their daily lives. CONCLUSIONS Our study shows that orthotopic liver transplant provides significant improvement in neurological symptoms and quality of life in patients with Wilson disease.
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Affiliation(s)
- Fuat Aksoy
- From the Organ Transplantation Center, Medical Faculty, Bursa Uludag University, Bursa, Turkey
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The Molecular Mechanisms of Defective Copper Metabolism in Diabetic Cardiomyopathy. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:5418376. [PMID: 36238639 PMCID: PMC9553361 DOI: 10.1155/2022/5418376] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 08/22/2022] [Accepted: 09/09/2022] [Indexed: 11/17/2022]
Abstract
Copper is an essential trace metal element that significantly affects human physiology and pathology by regulating various important biological processes, including mitochondrial oxidative phosphorylation, connective tissue crosslinking, and antioxidant defense. Copper level has been proved to be closely related to the morbidity and mortality of cardiovascular diseases such as atherosclerosis, heart failure, and diabetic cardiomyopathy (DCM). Copper deficiency can induce cardiac hypertrophy and aggravate cardiomyopathy, while copper excess can mediate various types of cell death, such as autophagy, apoptosis, cuproptosis, pyroptosis, and cardiac hypertrophy and fibrosis. Both copper excess and copper deficiency lead to redox imbalance, activate inflammatory response, and aggravate diabetic cardiomyopathy. This defective copper metabolism suggests a specific metabolic pattern of copper in diabetes and a specific role in the pathogenesis and progression of DCM. This review is aimed at providing a timely summary of the effects of defective copper homeostasis on DCM and discussing potential underlying molecular mechanisms.
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Wang L, Yang W, Li L, Hu S, Yuan M, Yang Z, Han K, Wang H, Xu X. Simultaneous Observation of Visible Upconversion and Near-Infrared Downconversion in SrF 2:Nd 3+/Yb 3+/Er 3+ Nanocrystals and Their Application for Detecting Metal Ions under Dual-Wavelength Excitation. ACS OMEGA 2022; 7:27230-27238. [PMID: 35967025 PMCID: PMC9366768 DOI: 10.1021/acsomega.2c01968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 07/14/2022] [Indexed: 06/15/2023]
Abstract
In this work, a sequence of Nd3+, Yb3+, and Er3+ tridoped SrF2 nanocrystals (NCs) is synthesized by a hydrothermal method. Both the efficient near-infrared downconversion luminescence (DCL) and visible upconversion luminescence (UCL) of the Er3+ and Nd3+ ions are simultaneously observed and systematically demonstrated under dual-wavelength excitation (808 and 980 nm continuous-wave lasers). Subsequently, the SrF2:Nd3+/Yb3+/Er3+ (15/4/0.2 mol %) NCs with the strongest luminescence were utilized for detecting the metal ion concentrations under 808 nm excitation. The results reveal that both the UCL and DCL gradually decrease as the metal ion concentrations increase, and high sensitivity is obtained for Cu2+ ions with a detection limit of 0.22 nM (∼650 nm) and 0.63 nM (∼976 nm). In addition, these SrF2:Nd3+/Yb3+/Er3+ NCs are further demonstrated to achieve a solid-state display under 980 nm excitation, exhibiting obvious "red" and "green" patterns by varying the doping rare earth ion concentrations.
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Affiliation(s)
- Linxuan Wang
- College
of Advanced Interdisciplinary Studies, National
University of Defense Technology, Changsha 410073, China
- State
Key Laboratory of Pulsed Power Laser Technology, National University of Defense Technology, Changsha 410073, China
| | - Weiqiang Yang
- College
of Advanced Interdisciplinary Studies, National
University of Defense Technology, Changsha 410073, China
- Institute
of Optics and Electronics, Chinese Academy
of Sciences, Chengdu 610209, China
- Key
Laboratory of Optical Engineering, Chinese
Academy of Sciences, Chengdu 610209, China
- University
of Chinese Academy of Sciences, Beijing 100049, China
| | - Liang Li
- College
of Advanced Interdisciplinary Studies, National
University of Defense Technology, Changsha 410073, China
- State
Key Laboratory of Pulsed Power Laser Technology, National University of Defense Technology, Changsha 410073, China
| | - Shuai Hu
- College
of Advanced Interdisciplinary Studies, National
University of Defense Technology, Changsha 410073, China
- State
Key Laboratory of Pulsed Power Laser Technology, National University of Defense Technology, Changsha 410073, China
| | - Maohui Yuan
- College
of Advanced Interdisciplinary Studies, National
University of Defense Technology, Changsha 410073, China
- State
Key Laboratory of Pulsed Power Laser Technology, National University of Defense Technology, Changsha 410073, China
| | - Zining Yang
- College
of Advanced Interdisciplinary Studies, National
University of Defense Technology, Changsha 410073, China
- State
Key Laboratory of Pulsed Power Laser Technology, National University of Defense Technology, Changsha 410073, China
- Hunan
Provincial Key Laboratory of High Energy Laser Technology, National University of Defense Technology, Changsha 410073, China
| | - Kai Han
- College
of Advanced Interdisciplinary Studies, National
University of Defense Technology, Changsha 410073, China
- State
Key Laboratory of Pulsed Power Laser Technology, National University of Defense Technology, Changsha 410073, China
- Hunan
Provincial Key Laboratory of High Energy Laser Technology, National University of Defense Technology, Changsha 410073, China
| | - Hongyan Wang
- College
of Advanced Interdisciplinary Studies, National
University of Defense Technology, Changsha 410073, China
- State
Key Laboratory of Pulsed Power Laser Technology, National University of Defense Technology, Changsha 410073, China
- Hunan
Provincial Key Laboratory of High Energy Laser Technology, National University of Defense Technology, Changsha 410073, China
| | - Xiaojun Xu
- College
of Advanced Interdisciplinary Studies, National
University of Defense Technology, Changsha 410073, China
- State
Key Laboratory of Pulsed Power Laser Technology, National University of Defense Technology, Changsha 410073, China
- Hunan
Provincial Key Laboratory of High Energy Laser Technology, National University of Defense Technology, Changsha 410073, China
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Liposome-encapsulated curcumin attenuates HMGB1-mediated hepatic inflammation and fibrosis in a murine model of Wilson's disease. Biomed Pharmacother 2022; 152:113197. [PMID: 35687913 DOI: 10.1016/j.biopha.2022.113197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Revised: 05/21/2022] [Accepted: 05/23/2022] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND AND AIMS Wilson's disease (WD) is an inherited disorder of copper metabolism with predominant hepatic manifestations. Left untreated, it can be fatal. Current therapies focus on treating copper overload rather than targeting the pathophysiology of copper-induced liver injuries. We sought to investigate whether liposome-encapsulated curcumin (LEC) could attenuate the underlying pathophysiology of WD in a mouse model of WD. APPROACH AND RESULTS Subcutaneous administration in a WD mouse model with ATP7B knockout (Atp7b-/-) resulted in robust delivery of LEC to the liver as determined by in-vitro and in-vivo imaging. Treatment with LEC attenuated hepatic injuries, restored lipid metabolism and decreased hepatic inflammation and fibrosis, and thus hepatosplenomegaly in Atp7b-/- mice. Mechanistically, LEC decreased hepatic immune cell and macrophage infiltration and attenuated the hepatic up-regulation of p65 by preventing cellular translocation of high-mobility group box-1 (HMGB-1). Moreover, decreased translocation of HMGB1 was associated with reduced splenic CD11b+/CD43+/Ly6CHi inflammatory monocyte expansion and circulating level of proinflammatory cytokines. Nevertheless there was no change in expression of oxidative stress-related genes or significant copper chelation effect of LEC in Atp7b-/- mice. CONCLUSION Our results indicate that treatment with subcutaneous LEC can attenuate copper-induced liver injury in an animal model of WD via suppression of HMGB1-mediated hepatic and systemic inflammation. These findings provide important proof-of-principle data to develop LEC as a novel therapy for WD as well as other inflammatory liver diseases.
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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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Rowan DJ, Mangalaparthi KK, Singh S, Moreira RK, Mounajjed T, Lamps L, Westerhoff M, Cheng J, Bellizzi AM, Allende DS, Pandey A, Graham RP. Metallothionein immunohistochemistry has high sensitivity and specificity for detection of Wilson disease. Mod Pathol 2022; 35:946-955. [PMID: 34934154 DOI: 10.1038/s41379-021-01001-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 12/07/2021] [Accepted: 12/09/2021] [Indexed: 11/09/2022]
Abstract
Diagnosis of Wilson disease (WD) can be difficult because of its protean clinical presentations, but early diagnosis is important because effective treatment is available and can prevent disease progression. Similarly, diagnosis of WD on liver biopsy specimens is difficult due to the wide range of histologic appearances. A stain that could help identify WD patients would be of great value. The goal of this study was to use mass spectrometry-based proteomics to identify potential proteins that are differentially expressed in WD compared to controls, and could serve as potential immunohistochemical markers for screening. Several proteins were differentially expressed in WD and immunohistochemical stains for two (metallothionein (MT) and cytochrome C oxidase copper chaperone (COX17)) were tested and compared to other methods of diagnosis in WD including copper staining and quantitative copper assays. We found diffuse metallothionein immunoreactivity in all liver specimens from patients with WD (n = 20); the intensity of the staining was moderate to strong. This staining pattern was distinct from that seen in specimens from the control groups (none of which showed strong, diffuse staining), which included diseases that may be in the clinical or histologic differential of WD (steatohepatitis (n = 51), chronic viral hepatitis (n = 40), autoimmune hepatitis (n = 50), chronic biliary tract disease (n = 42), and normal liver (n = 20)). COX17 immunostain showed no significant difference in expression between the WD and control groups. MT had higher sensitivity than rhodanine for diagnosis of WD. While the quantitative liver copper assays also had high sensitivity, they require more tissue, have a higher cost, longer turnaround time, and are less widely available than an immunohistochemical stain. We conclude that MT IHC is a sensitive immunohistochemical stain for the diagnosis of WD that could be widely deployed as a screening tool for liver biopsies in which WD is in the clinical or histologic differential diagnosis.
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Affiliation(s)
- Daniel J Rowan
- Department of Laboratory Medicine and Pathology, Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA
| | | | - Smrita Singh
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.,Institute of Bioinformatics, International Technology Park, Bangalore, 560066, Karnataka, India.,Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
| | - Roger K Moreira
- Department of Laboratory Medicine and Pathology, Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA
| | - Taofic Mounajjed
- Department of Laboratory Medicine and Pathology, Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA
| | - Laura Lamps
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Maria Westerhoff
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Jerome Cheng
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | | | | | - Akhilesh Pandey
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Rondell P Graham
- Department of Laboratory Medicine and Pathology, Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA.
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Majid Z, Abrar G, Laeeq SM, Khan SA, Ismail H, Soomro GB, Mehmood N, Tasneem AA, Hanif FM, Mandhwani R, Luck NH. Clinical Characteristics and Comparison of Different Prognostic Scores in Wilson's Disease. Euroasian J Hepatogastroenterol 2022; 12:69-72. [PMID: 36959988 PMCID: PMC10028702 DOI: 10.5005/jp-journals-10018-1379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/14/2023] Open
Abstract
AIM Wilson's disease (WD) is a rare autosomal recessive disease, that can involve any organ of the body, the main ones being the liver and the brain. These patients can have varied presentations, ranging from having no symptoms to having neurological manifestations to features of chronic liver disease (CLD). Those patients that end up having CLD are prognosticated via the Child-Turcotte-Pugh (CTP) score and the Model for End-stage Liver Disease (MELD) score. However, two specific scores exist for prognostication in patients having WD, namely, the Nazar score and the Dhawan score. However, these are yet to be validated nor has their use been implemented in clinical practice. MATERIALS AND METHODS Our study involved 65 patients with WD, comprising both the pediatric and the adult population. We aimed at evaluating the clinical manifestations the lab parameters and the management of these patients. Furthermore, we tried validating the Nazar and the Dhawan score and later compared them with the CTP and the MELD score, which are well-known prognostic tools in CLD. RESULTS Our patients were subdivided into the pediatric (more than 50%) and the adult group. The most common presenting complaint noted in both groups was abdominal distension. Values of the urine copper and serum ceruloplasmin did not defer between the pediatric and adult patients. Hepatic involvement is frequently seen in the pediatric age-group. Also, CTP class C was chiefly seen in pediatrics 17/33 (51.5%), while CTP class B was in adults 13/32 (40.6%). The mean Nazar score was 3 ± 3, while the mean Dhawan score was 5 ± 4. The main treatment offered for both groups was zinc along with penicillamine. CONCLUSION Our study showed the Dhawan score was comparable to the CTP and the MELD score in terms of predicting the disease severity of WD in our patient population. HOW TO CITE THIS ARTICLE Majid Z, Abrar G, Laeeq SM, et al. Clinical Characteristics and Comparison of Different Prognostic Scores in Wilson's Disease. Euroasian J Hepato-Gastroenterol 2022;12(2):69-72.
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Affiliation(s)
- Zain Majid
- Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation (SIUT), Karachi, Pakistan
| | - Ghazi Abrar
- Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation (SIUT), Karachi, Pakistan
| | - Syed Mudassir Laeeq
- Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation (SIUT), Karachi, Pakistan
| | - Shoaib Ahmed Khan
- Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation (SIUT), Karachi, Pakistan
| | - Hina Ismail
- Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation (SIUT), Karachi, Pakistan
| | - Ghous Bux Soomro
- Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation (SIUT), Karachi, Pakistan
| | - Nasir Mehmood
- Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation (SIUT), Karachi, Pakistan
| | - Abbas Ali Tasneem
- Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation (SIUT), Karachi, Pakistan
| | - Farina Muhammad Hanif
- Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation (SIUT), Karachi, Pakistan
| | - Rajesh Mandhwani
- Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation (SIUT), Karachi, Pakistan
| | - Nasir Hasan Luck
- Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation (SIUT), Karachi, Pakistan
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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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Wang J, Hu M, Zhu Q, Sun L. Liver stiffness assessed by real-time two-dimensional shear wave elastography predicts hypersplenism in patients with Wilson's disease: a prospective study. BMC Med Imaging 2022; 22:25. [PMID: 35148699 PMCID: PMC8832652 DOI: 10.1186/s12880-022-00749-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 01/26/2022] [Indexed: 12/12/2022] Open
Abstract
Background The current study aimed to explore the value of liver stiffness assessed by two-dimensional real-time shear wave elastography (2D-SWE) to predict hypersplenism occurrence in Wilson’s disease (WD) patients. Methods Ninety WD patients were enrolled in this prospective study between May 2018 and December 2018. Baseline clinical data and ultrasound imaging including 2D-SWE liver stiffness of WD patients were collected. After enrollment, patients had follow-ups for 24 months or until they developed hypersplenism. The hypersplenism risk factors were determined using Cox regressions and receiver operating characteristic curves (ROC). Results Twenty-nine (32.2%) patients developed hypersplenism. Age, portal vein diameter, and liver stiffness were independent hypersplenism risk factors in WD patients. The cutoff value of liver stiffness to predict hypersplenism was 10.45 kPa, with sensitivity and specificity of 75.9% and 73.8%, respectively. Patients were divided into two groups according to liver stiffness: ≥ 10.45 kPa (57.9% with hypersplenism) or < 10.45 kPa (13.5% with hypersplenism). The median time between enrollment and hypersplenism development was 15 months vs. 22 months (p < 0.001) for the two groups, respectively. Conclusion The measurement of liver stiffness by 2D-SWE can be a reliable hypersplenism predictor in WD patients. Therefore, dynamic monitoring of WD patients using 2D-SWE is crucial for the early diagnosis of hypersplenism.
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Affiliation(s)
- Jiajia Wang
- Department of Diagnostic Ultrasound, Beijing Tongren Hospital, Capital Medical University, No. 1, Dong Jiao Min Xiang Street, Dongcheng District, Beijing, 100730, China.,Department of Ultrasound, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China
| | - Minxia Hu
- Department of Diagnostic Ultrasound, Beijing Tongren Hospital, Capital Medical University, No. 1, Dong Jiao Min Xiang Street, Dongcheng District, Beijing, 100730, China
| | - Qiang Zhu
- Department of Diagnostic Ultrasound, Beijing Tongren Hospital, Capital Medical University, No. 1, Dong Jiao Min Xiang Street, Dongcheng District, Beijing, 100730, China.
| | - Lanting Sun
- Department of Encephalopathy, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China
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Have you caught that outlier yet? Evaluate the utility of repeat testing in nutritional and toxic element assessment. Clin Chim Acta 2022; 528:84-89. [PMID: 35104463 DOI: 10.1016/j.cca.2022.01.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 01/21/2022] [Accepted: 01/25/2022] [Indexed: 11/21/2022]
Abstract
Repeat testing is routinely required by regulatory bodies as a measure to rule out contamination in trace elements and heavy metal analysis, especially when the initial analysis result is outside the reference interval. However, its clinical utilities in detecting analytical measurement outliers have not been systematically evaluated in different clinical testing scenarios. In this study, we present an extensive evaluation of repeat testing and its comparison with the initial analysis in four serum and plasma trace element assays performed by inductively coupled plasma mass spectrometry. We demonstrate that the patient population distributions for these elements differ significantly from the reference interval established by healthy individuals. Accordingly, a significant proportion of the patient specimens required repeat testing when using reference intervals as the threshold to perform repeat analysis. Crucially, comparison of the first analysis and repeat analysis revealed the limited utility of performing repeat measurements. The relative differences between the first and second measurements are consistent with the observed analytical imprecision of the assay and the likelihood of detecting actual analytical outliers is very low.
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Beier JI, Arteel GE. Environmental exposure as a risk-modifying factor in liver diseases: Knowns and unknowns. Acta Pharm Sin B 2021; 11:3768-3778. [PMID: 35024305 PMCID: PMC8727918 DOI: 10.1016/j.apsb.2021.09.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 06/24/2021] [Accepted: 08/19/2021] [Indexed: 02/07/2023] Open
Abstract
Liver diseases are considered to predominantly possess an inherited or xenobiotic etiology. However, inheritance drives the ability to appropriately adapt to environmental stressors, and disease is the culmination of a maladaptive response. Thus “pure” genetic and “pure” xenobiotic liver diseases are modified by each other and other factors, identified or unknown. The purpose of this review is to highlight the knowledgebase of environmental exposure as a potential risk modifying agent for the development of liver disease by other causes. This exercise is not to argue that all liver diseases have an environmental component, but to challenge the assumption that the current state of our knowledge is sufficient in all cases to conclusively dismiss this as a possibility. This review also discusses key new tools and approaches that will likely be critical to address this question in the future. Taken together, identifying the key gaps in our understanding is critical for the field to move forward, or at the very least to “know what we don't know.”
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Affiliation(s)
- Juliane I. Beier
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Pittsburgh Liver Research Center and University of Pittsburgh, Pittsburgh, PA 15213, USA
- Department of Environmental and Occupational Health, University of Pittsburgh, PA 15213, USA
- Corresponding authors.
| | - Gavin E. Arteel
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Pittsburgh Liver Research Center and University of Pittsburgh, Pittsburgh, PA 15213, USA
- Corresponding authors.
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Hruby M, Martínez IIS, Stephan H, Pouckova P, Benes J, Stepanek P. Chelators for Treatment of Iron and Copper Overload: Shift from Low-Molecular-Weight Compounds to Polymers. Polymers (Basel) 2021; 13:3969. [PMID: 34833268 PMCID: PMC8618197 DOI: 10.3390/polym13223969] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 11/09/2021] [Accepted: 11/15/2021] [Indexed: 12/18/2022] Open
Abstract
Iron and copper are essential micronutrients needed for the proper function of every cell. However, in excessive amounts, these elements are toxic, as they may cause oxidative stress, resulting in damage to the liver and other organs. This may happen due to poisoning, as a side effect of thalassemia infusion therapy or due to hereditary diseases hemochromatosis or Wilson's disease. The current golden standard of therapy of iron and copper overload is the use of low-molecular-weight chelators of these elements. However, these agents suffer from severe side effects, are often expensive and possess unfavorable pharmacokinetics, thus limiting the usability of such therapy. The emerging concepts are polymer-supported iron- and copper-chelating therapeutics, either for parenteral or oral use, which shows vivid potential to keep the therapeutic efficacy of low-molecular-weight agents, while avoiding their drawbacks, especially their side effects. Critical evaluation of this new perspective polymer approach is the purpose of this review article.
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Affiliation(s)
- Martin Hruby
- Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic Heyrovského Náměstí 2, 162 06 Prague, Czech Republic;
| | - Irma Ivette Santana Martínez
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research Bautzner Landstraße 400, 01328 Dresden, Germany; (I.I.S.M.); (H.S.)
| | - Holger Stephan
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research Bautzner Landstraße 400, 01328 Dresden, Germany; (I.I.S.M.); (H.S.)
| | - Pavla Pouckova
- Institute of Biophysics and Informatics, First Faculty of Medicine, Charles University in Prague, Salmovska 1, 120 00 Prague, Czech Republic; (P.P.); (J.B.)
| | - Jiri Benes
- Institute of Biophysics and Informatics, First Faculty of Medicine, Charles University in Prague, Salmovska 1, 120 00 Prague, Czech Republic; (P.P.); (J.B.)
| | - Petr Stepanek
- Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic Heyrovského Náměstí 2, 162 06 Prague, Czech Republic;
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Jacquelet E, Poujois A, Pheulpin MC, Demain A, Tinant N, Gastellier N, Woimant F. Adherence to treatment, a challenge even in treatable metabolic rare diseases: A cross sectional study of Wilson's disease. J Inherit Metab Dis 2021; 44:1481-1488. [PMID: 34480375 DOI: 10.1002/jimd.12430] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 08/26/2021] [Accepted: 09/01/2021] [Indexed: 11/09/2022]
Abstract
Wilson's disease (WD), a rare genetic disorder responsible for copper accumulation in the body, is fatal if left untreated. Although there are effective treatments, adherence to treatment tends to be low. We evaluated the medication adherence of 139 patients using the Morisky scale. Adherence was correlated with age at diagnosis and at inclusion in the study, the form of the disease, the treatment, the duration of treatment, delivery and storage problems, depression, anxiety, the level of education, and the biological data. 32.4% of the patients had low adherence; their levels of exchangeable copper were significantly higher than those of the patients with high or medium adherence (P = .049). The average age of the patients at the time of the study was significantly higher in those with high adherence than in those with medium or low adherence (P = .043). 75.9% of the patients with high adherence had a neurological form and 26.7% of the patients with low adherence were asymptomatic (P = .0090). The duration of treatment was significantly longer in the patients with high adherence than in those with medium or low adherence (P = .0192). The type of treatment (chelators or zinc) had no impact on the level of adherence. Forty-four percent of the patients experienced problems dispensing and storing medications. Despite the availability of effective treatments for this rare disease, adherence problems occur with Wilson's disease in particular in asymptomatic patients. Although different factors are involved, sustained multidisciplinary management on a case-by-case basis is necessary.
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Affiliation(s)
- Elodie Jacquelet
- Department of Neurology, Lariboisière University Hospital, AP-HP, Paris, France
- Department of Neurology, National Reference Centre for Wilson's Disease, Hôpital Fondation Adolphe de Rothschild, Paris, France
| | - Aurelia Poujois
- Department of Neurology, National Reference Centre for Wilson's Disease, Hôpital Fondation Adolphe de Rothschild, Paris, France
- Department of Neurology, Rothschild Foundation Hospital, Paris, France
| | | | - Adèle Demain
- Department of Neurology, Lariboisière University Hospital, AP-HP, Paris, France
- Department of Neurology, National Reference Centre for Wilson's Disease, Hôpital Fondation Adolphe de Rothschild, Paris, France
| | - Nadège Tinant
- Department of Neurology, Lariboisière University Hospital, AP-HP, Paris, France
- Department of Neurology, National Reference Centre for Wilson's Disease, Hôpital Fondation Adolphe de Rothschild, Paris, France
| | - Nathalie Gastellier
- Department of Neurology, Lariboisière University Hospital, AP-HP, Paris, France
| | - France Woimant
- Department of Neurology, Lariboisière University Hospital, AP-HP, Paris, France
- Department of Neurology, National Reference Centre for Wilson's Disease, Hôpital Fondation Adolphe de Rothschild, Paris, France
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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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Rustgi VK, Gupta K, Tait C, Bhurwal A, Kabaria S, Catalano C, Li Y, Minacapelli CD. Wilson's Disease: An Analysis of Health Care Use and Cost Burden of Commercially Insured Adults in the United States. Hepatol Commun 2021; 6:389-398. [PMID: 34559472 PMCID: PMC8793990 DOI: 10.1002/hep4.1812] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 07/07/2021] [Accepted: 08/05/2021] [Indexed: 12/19/2022] Open
Abstract
The economic and health care use burdens of Wilson’s disease (WD) are unknown. In this study, we aimed to quantify this health care resource use and economic burden. We performed a retrospective case‐control analysis of individuals in the Truven Health MarketScan Commercial Claims database (2007‐2017). Using propensity scores, 424 WD cases were matched 1:1 to chronic liver disease (CLD) controls without WD. Total and service‐specific parameters, expressed in monthly averages, were quantified for the 6‐month pre‐WD diagnosis versus the 12‐month period after diagnosis. Wilcoxon signed‐rank tests and McNemar tests were used to examine incremental differences in burden between cases and controls. Adjusted multivariable generalized linear regression models were used to compare health care burdens. Relative to the 6‐month pre‐WD diagnosis, the 12 months after diagnosis had more claims per patient (2.87 vs. 3.35; P < 0.0001) and increased per patient health care costs (US $2,089 vs. US $3,887; P < 0.0001). WD cases incurred US $1,908 more in total unadjusted costs compared to controls in the 12‐month postindex date monthly averages. The increase in claims was primarily due to outpatient visits (1.62 vs. 1.82) and pharmaceutical claims (1.11 vs. 1.37). Cases also had higher health care costs for inpatient admissions (US $559 vs. US $1,264), outpatient visits (US $770 vs. US $1,037), and pharmaceutical claims (US $686 vs. US $1,489). Conclusion: WD is associated with significant health care cost and use burdens driven by increased inpatient admissions, outpatient visits, and pharmaceutical claims.
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Affiliation(s)
- Vinod K Rustgi
- Division of Gastroenterology and Hepatology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.,Center for Liver Diseases and Masses, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - Kapil Gupta
- Division of Gastroenterology and Hepatology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.,Center for Liver Diseases and Masses, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - Christopher Tait
- Division of Gastroenterology and Hepatology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.,Center for Liver Diseases and Masses, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - Abhishek Bhurwal
- Division of Gastroenterology and Hepatology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.,Center for Liver Diseases and Masses, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - Savan Kabaria
- Internal Medicine, Robert Wood Johnson Medical School, Rutgers Biomedical and Health Sciences, Rutgers University, New Brunswick, NJ, USA
| | - Carolyn Catalano
- Division of Gastroenterology and Hepatology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.,Center for Liver Diseases and Masses, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - You Li
- Division of Gastroenterology and Hepatology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.,Center for Liver Diseases and Masses, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - Carlos D Minacapelli
- Division of Gastroenterology and Hepatology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.,Center for Liver Diseases and Masses, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
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Sánchez-Monteagudo A, Ripollés E, Berenguer M, Espinós C. Wilson's Disease: Facing the Challenge of Diagnosing a Rare Disease. Biomedicines 2021; 9:1100. [PMID: 34572285 PMCID: PMC8471362 DOI: 10.3390/biomedicines9091100] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 08/20/2021] [Accepted: 08/25/2021] [Indexed: 02/06/2023] Open
Abstract
Wilson disease (WD) is a rare disorder caused by mutations in ATP7B, which leads to the defective biliary excretion of copper. The subsequent gradual accumulation of copper in different organs produces an extremely variable clinical picture, which comprises hepatic, neurological psychiatric, ophthalmological, and other disturbances. WD has a specific treatment, so that early diagnosis is crucial to avoid disease progression and its devastating consequences. The clinical diagnosis is based on the Leipzig score, which considers clinical, histological, biochemical, and genetic data. However, even patients with an initial WD diagnosis based on a high Leipzig score may harbor other conditions that mimic the WD's phenotype (Wilson-like). Many patients are diagnosed using current available methods, but others remain in an uncertain area because of bordering ceruloplasmin levels, inconclusive genetic findings and unclear phenotypes. Currently, the available biomarkers for WD are ceruloplasmin and copper in the liver or in 24 h urine, but they are not solid enough. Therefore, the characterization of biomarkers that allow us to anticipate the evolution of the disease and the monitoring of new drugs is essential to improve its diagnosis and prognosis.
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Affiliation(s)
- Ana Sánchez-Monteagudo
- Rare Neurodegenerative Diseases Laboratory, Centro de Investigación Príncipe Felipe (CIPF), 46012 Valencia, Spain; (A.S.-M.); (E.R.)
- Joint Unit on Rare Diseases CIPF-IIS La Fe, 46012 Valencia, Spain;
| | - Edna Ripollés
- Rare Neurodegenerative Diseases Laboratory, Centro de Investigación Príncipe Felipe (CIPF), 46012 Valencia, Spain; (A.S.-M.); (E.R.)
- Joint Unit on Rare Diseases CIPF-IIS La Fe, 46012 Valencia, Spain;
| | - Marina Berenguer
- Joint Unit on Rare Diseases CIPF-IIS La Fe, 46012 Valencia, Spain;
- Hepatology-Liver Transplantation Unit, Digestive Medicine Service, IIS La Fe and CIBER-EHD, Hospital Universitari i Politècnic La Fe, 46026 Valencia, Spain
- Department of Medicine, Universitat de València, 46010 Valencia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Carmen Espinós
- Rare Neurodegenerative Diseases Laboratory, Centro de Investigación Príncipe Felipe (CIPF), 46012 Valencia, Spain; (A.S.-M.); (E.R.)
- Joint Unit on Rare Diseases CIPF-IIS La Fe, 46012 Valencia, Spain;
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