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Manchia M, Paribello P, Pinna M, Faa G. The Role of Copper Overload in Modulating Neuropsychiatric Symptoms. Int J Mol Sci 2024; 25:6487. [PMID: 38928192 PMCID: PMC11204094 DOI: 10.3390/ijms25126487] [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: 05/10/2024] [Revised: 06/01/2024] [Accepted: 06/08/2024] [Indexed: 06/28/2024] Open
Abstract
Copper is a transition metal essential for growth and development and indispensable for eukaryotic life. This metal is essential to neuronal function: its deficiency, as well as its overload have been associated with multiple neurodegenerative disorders such as Alzheimer's disease and Wilson's disease and psychiatric conditions such as schizophrenia, bipolar disorder, and major depressive disorders. Copper plays a fundamental role in the development and function of the human Central Nervous System (CNS), being a cofactor of multiple enzymes that play a key role in physiology during development. In this context, we thought it would be timely to summarize data on alterations in the metabolism of copper at the CNS level that might influence the development of neuropsychiatric symptoms. We present a non-systematic review with the study selection based on the authors' judgement to offer the reader a perspective on the most significant elements of neuropsychiatric symptoms in Wilson's disease. We highlight that Wilson's disease is characterized by marked heterogeneity in clinical presentation among patients with the same mutation. This should motivate more research efforts to disentangle the role of environmental factors in modulating the expression of genetic predisposition to this disorder.
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Affiliation(s)
- Mirko Manchia
- Unit of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, 09124 Cagliari, Italy;
- Unit of Clinical Psychiatry, University Hospital Agency of Cagliari, 09124 Cagliari, Italy
- Department of Pharmacology, Dalhousie University, Halifax, NS B3H 4R2, Canada
| | - Pasquale Paribello
- Unit of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, 09124 Cagliari, Italy;
- Unit of Clinical Psychiatry, University Hospital Agency of Cagliari, 09124 Cagliari, Italy
| | - Martina Pinna
- Forensic Psychiatry Unit, Sardinia Health Agency, 09123 Cagliari, Italy;
| | - Gavino Faa
- Department of Medical Sciences and Public Health, University of Cagliari, 09124 Cagliari, Italy;
- Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA
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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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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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Dhakal B, Prabhat K, Karki A, Bhattarai AM, Sapkota S, Subedi B, Dahal A. Late onset Wilson Disease with normal neuro-psychiatric status: A case report. Ann Med Surg (Lond) 2022; 77:103678. [PMID: 35638048 PMCID: PMC9142667 DOI: 10.1016/j.amsu.2022.103678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Revised: 04/19/2022] [Accepted: 04/25/2022] [Indexed: 11/16/2022] Open
Abstract
Introduction Case presentation Clinical discussion Conclusions
Wilson disease (WD) has been one of the causes for chronic liver disease (CLD) but late onset WD is one of the rare forms in WD. Neurological manifestations are common in late onset WD which is absent in our case. There is common diagnostic delay of WD in later ages with chronic liver disease because of variability in presentations of WD. The treatment for WD has been updated but based on the availability d-penicillamine or zinc has been a common choice.
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Affiliation(s)
- Bishal Dhakal
- Nepalese Army Institute of Health Sciences, Sanobharyang, Kathmandu, Nepal
- Corresponding author. Shree Birendra Hospital, Kathmandu, 44600, Nepal.
| | - K.C. Prabhat
- Nepalese Army Institute of Health Sciences, Sanobharyang, Kathmandu, Nepal
| | - Abinash Karki
- Nepalese Army Institute of Health Sciences, Sanobharyang, Kathmandu, Nepal
| | | | - Sachin Sapkota
- Maulakalika Hospital Pvt. Ltd., Bharatpur, 10-Chitwan, Nepal
| | - Binaya Subedi
- Nepalese Army Institute of Health Sciences, Sanobharyang, Kathmandu, Nepal
| | - Abhinav Dahal
- Nepalese Army Institute of Health Sciences, Sanobharyang, Kathmandu, Nepal
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Lorente-Arencibia P, García-Villarreal L, González-Montelongo R, Rubio-Rodríguez LA, Flores C, Garay-Sánchez P, delaCruz T, Santana-Verano M, Rodríguez-Esparragón F, Benitez-Reyes JN, Fernández-Fuertes F, Tugores A. Wilson Disease Prevalence: Discrepancy Between Clinical Records, Registries and Mutation Carrier Frequency. J Pediatr Gastroenterol Nutr 2022; 74:192-199. [PMID: 34620762 DOI: 10.1097/mpg.0000000000003322] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVES Diagnosis of Wilson disease (WD) is difficult and, as early detection may prevent all symptoms, it is essential to know the exact prevalence to evaluate the cost-efficacy of a screening program. As the number of WD patients was high in our population, we wished to estimate prevalence by determining the carrier frequency for clinically relevant ATP7B mutations. METHODS To estimate prevalence, screening for the most prevalent mutation was performed in 1661 individuals with ancestry in Gran Canaria, and the frequency of other mutations was estimated from patient records. Alternatively, ATP7B mutations were detected from exomes and genomes from 851 individuals with Canarian ancestry, 236 from Gran Canaria, and a public Spanish exome database. RESULTS Estimated carrier frequencies in Gran Canaria ranged from 1 in 20 to 28, depending on the method used, resulting in prevalences of 1 case per 1547 to 3140 inhabitants. Alternatively, the estimated affected frequencies were 1 in 5985 to 7980 and 1 in 6278 to 16,510 in the archipelago or mainland Spain respectively. CONCLUSIONS The number of carriers predicts much higher prevalences than reported, suggesting that WD is underdiagnosed; specific mutations may remain unnoticed due to low penetrance or no signs of disease at all; regional prevalence rather than national prevalence should be considered in cost-efficacy models to approach preventive screening in the asymptomatic population and genetic screening strategies will have to deal with the genetic heterogeneity of ATP7B in the general population and in patients.
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Affiliation(s)
- Pascual Lorente-Arencibia
- Unidad de Investigación, Complejo Hospitalario Universitario Insular Materno-Infantil, Las Palmas de GC
| | - Luis García-Villarreal
- Unidad de Investigación, Complejo Hospitalario Universitario Insular Materno-Infantil, Las Palmas de GC
| | - Rafaela González-Montelongo
- Genomics Division, Instituto Tecnológico y de Energías Renovables (ITER)
- Instituto de Tecnologías Biomédicas (ITB), Universidad de La Laguna
| | | | - Carlos Flores
- Genomics Division, Instituto Tecnológico y de Energías Renovables (ITER)
- Instituto de Tecnologías Biomédicas (ITB), Universidad de La Laguna
- Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Universidad de La Laguna, Santa Cruz de Tenerif
- CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid
| | - Paloma Garay-Sánchez
- Unidad de Investigación, Complejo Hospitalario Universitario Insular Materno-Infantil, Las Palmas de GC
| | - Tanausú delaCruz
- Unidad de Investigación, Complejo Hospitalario Universitario Insular Materno-Infantil, Las Palmas de GC
| | - Milagros Santana-Verano
- Unidad de Investigación, Complejo Hospitalario Universitario Insular Materno-Infantil, Las Palmas de GC
| | | | - Juana N Benitez-Reyes
- Department of Haematology, Complejo Hospitalario Universitario Insular Materno-Infantil, Spain
| | | | - Antonio Tugores
- Unidad de Investigación, Complejo Hospitalario Universitario Insular Materno-Infantil, Las Palmas de GC
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Teufel A, Binder H. Clinical Decision Support Systems. Visc Med 2021; 37:491-498. [PMID: 35087899 PMCID: PMC8738909 DOI: 10.1159/000519420] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 09/03/2021] [Indexed: 11/25/2023] Open
Abstract
BACKGROUND By combining up-to-date medical knowledge and steadily increasing patient data, a new level of medical care can emerge. SUMMARY AND KEY MESSAGES Clinical decision support systems (CDSSs) are an arising solution to handling rich data and providing them to health care providers in order to improve diagnosis and treatment. However, despite promising examples in many areas, substantial evidence for a thorough benefit of these support solutions is lacking. This may be due to a lack of general frameworks and diverse health systems around the globe. We therefore summarize the current status of CDSSs in medicine but also discuss potential limitations that need to be overcome in order to further foster future development and acceptance.
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Affiliation(s)
- Andreas Teufel
- Department of Medicine II, Section of Hepatology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Clinical Cooperation Unit Healthy Metabolism, Center for Preventive Medicine and Digital Health Baden-Württemberg (CPDBW), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Harald Binder
- Institute of Medical Biometry and Statistics (IMBI), Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany
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Wang Y, Jia Z, Lyu Y, Dong Q, Li S, Hu W. Multimodal magnetic resonance imaging analysis in the characteristics of Wilson's disease: A case report and literature review. Open Life Sci 2021; 16:793-799. [PMID: 34458581 PMCID: PMC8374231 DOI: 10.1515/biol-2021-0071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 05/18/2021] [Accepted: 06/11/2021] [Indexed: 12/04/2022] Open
Abstract
Wilson’s disease (WD) is an inherited disorder of copper metabolism. Multimodal magnetic resonance imaging (MRI) has been reported to provide evidence of the extent and severity of brain lesions. However, there are few studies related to the diagnosis of WD with multimodal MRI. Here, we reported a WD patient who was subjected to Sanger sequencing, conventional MRI, and multimodal MRI examinations, including susceptibility-weighted imaging (SWI) and arterial spin labeling (ASL). Sanger sequencing demonstrated two pathogenic mutations in exon 8 of the ATP7B gene. Slit-lamp examination revealed the presence of Kayser–Fleischer rings in both eyes, as well as low serum ceruloplasmin and high 24-h urinary copper excretion on admission. Although the substantia nigra, red nucleus, and lenticular nucleus on T1-weighted imaging and T2-weighted imaging were normal, SWI and ASL showed hypointensities in these regions. Besides, decreased cerebral blood flow was found in the lenticular nucleus and the head of caudate nucleus. The patient recovered well after 1 year and 9 months of follow-up, with only a Unified Wilson Disease Rating Scale score of 1 for neurological symptom. Brain multimodal MRI provided a thorough insight into the WD, which might make up for the deficiency of conventional MRI.
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Affiliation(s)
- Yun Wang
- Department of Neurology, Beijing Chao-Yang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing 100020, China
| | - Zejin Jia
- Department of Neurology, Beijing Chao-Yang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing 100020, China
| | - Yuelei Lyu
- Department of Imaging, Beijing Chao-Yang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing 100020, China
| | - Qian Dong
- Department of Neurology, Beijing Chao-Yang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing 100020, China
| | - Shujuan Li
- Department of Neurology, Beijing Chao-Yang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing 100020, China
| | - Wenli Hu
- Department of Neurology, Beijing Chao-Yang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing 100020, China
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Abstract
PURPOSE OF REVIEW The aim of this article is to review recent developments in the areas of the disease features and treatment of Wilson disease, and survey disorders that share its pathophysiology or clinical symptoms. RECENT FINDINGS Knowledge of the clinical spectrum of Wilson disease has expanded with recognition of patients who present in atypical age groups - patients with very early onset (<5 years) and those in whom symptoms present in mid-to-late adulthood. A disease phenotype with dominant psychiatric features and increased risk of cardiac problems and various sleep disorders have been identified.In addition to a better understanding of the phenotype of Wilson disease itself, features of some related disorders ('Wilson disease-mimics') have been described leading to a better understanding of copper homeostasis in humans. These disorders include diseases of copper disposition, such as mental retardation, enteropathy, deafness, neuropathy, ichthyosis, keratoderma syndrome, Niemann-Pick type C, and certain congenital disorders of glycosylation, as well as analogous disorders of iron and manganese metabolism.Outcomes for existing treatments, including in certain patient subpopulations of interest, are better known. Novel treatment strategies being studied include testing of bis-choline tetrathiomolybdate in phase 2 clinical trial as well as various preclinical explorations of new copper chelators and ways to restore ATP7B function or repair the causative gene. SUMMARY Recent studies have expanded the phenotype of Wilson disease, identified rare inherited metal-related disorders that resemble Wilson disease, and studied long-term outcomes of existing treatments. These developments can be expected to have an immediate as well as a long-term impact on the clinical management of the disease, and point to promising avenues for future research.
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Affiliation(s)
- Annu Aggarwal
- Wilson Disease Clinic, Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute (KDAH)
- Memory Clinic, KDAH
| | - Mohit Bhatt
- Wilson Disease Clinic, Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute (KDAH)
- Movement Disorder Clinic, KDAH, Mumbai, Maharashtra, India
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Zinc Monotherapy as an Alternative Treatment Option for Decompensated Liver Disease due to Wilson Disease? Case Reports Hepatol 2020; 2020:1275940. [PMID: 32528738 PMCID: PMC7201455 DOI: 10.1155/2020/1275940] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 12/03/2019] [Accepted: 12/21/2019] [Indexed: 11/17/2022] Open
Abstract
Background Wilson disease is a rare metabolic disorder involving copper metabolism, and patients may present with a variable degree of hepatic, neurologic, and psychiatric manifestations. In the case of hepatic presentation, treatment is usually initiated with potentially toxic copper chelators (D-penicillamine or Trenton). Although zinc is of low toxicity and low cost for treatment of Wilson disease, it has been limited to the adjunctive as a single maintenance drug or for asymptomatic patients. The use of zinc monotherapy in patients suffering from a severe liver disease was not well studied. In our case report, we describe a pediatric patient who presented with liver failure and the use of zinc monotherapy in patients with severe hepatic manifestations. Case presentation. A 15-year-old male patient from Ethiopia presented with generalized body swelling (edema and ascites) with yellowish discoloration of his eyes and easy fatigability. He had hyperbilirubinemia, coagulopathy, hypoalbuminemia, and deranged liver enzymes. He had a Keyser–Fleischer ring visible with the naked eye, which was confirmed by slit-lamp examination. He had very low serum ceruloplasmin (<8 mg/L) and high 24-hour urine copper (150 mcg/dl). In accordance with the scoring system proposed by the 8th International Meeting on Wilson Disease and Menkes Disease, a diagnosis of Wilson disease was made. Zinc monotherapy with low copper diet was initiated for decompensated liver disease due to Wilson disease because of the inaccessibility of chelators (D-penicillamine or Trientine). After months of treatment with zinc, the patient experienced normalization of hepatic synthetic function and resolution of hypoalbuminemia and coagulopathy. The patient had also clinically stabilized (ascites, lower extremity swelling, edema, and jaundice were improved. Currently, the patient is on follow-up almost for the last four years in the gastrointestinal clinic. Conclusion Our case shows that zinc has the potential for treatment in improving liver function. Though zinc has its own side effects, it is important and maybe an alternative treatment option in those with limited resources (not able to access chelators). This example hopefully will encourage future investigations and researches on zinc monotherapy for treating symptomatic decompensated hepatic Wilson disease.
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Yousefi M, Yousefi M, Gharravi AM. Late-onset Wilson disease in older patient without ophthalmological findings, a case report. Clin Case Rep 2019; 7:1253-1258. [PMID: 31183105 PMCID: PMC6553562 DOI: 10.1002/ccr3.2203] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Revised: 04/19/2019] [Accepted: 04/28/2019] [Indexed: 11/12/2022] Open
Abstract
A 60-year-old man was referred to hospital for loss of consciousness. Her late-onset Wilson disease was diagnosed with elevated serum bilirubin, hepatic copper concentration, and urinary copper excretion. Zinc sulfate administration decreased the majority of clinical symptoms.
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Affiliation(s)
- Mehdi Yousefi
- Student Research CommitteeShahroud University of Medical SciencesShahroudIran
| | - Masoud Yousefi
- Department of Urology, Faculty of MedicineMashhad University of Medical SciencesMashhadIran
| | - Anneh M. Gharravi
- School of MedicineShahroud University of Medical SciencesShahroudIran
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Poujois A, Woimant F. Challenges in the diagnosis of Wilson disease. ANNALS OF TRANSLATIONAL MEDICINE 2019; 7:S67. [PMID: 31179304 PMCID: PMC6531657 DOI: 10.21037/atm.2019.02.10] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Accepted: 01/31/2019] [Indexed: 01/17/2023]
Abstract
The understanding and management of Wilson disease (WD) have dramatically improved since the first description of the disease by K. Wilson more than a century ago. However, the persistent long delay between the first symptoms and diagnosis emphasizes challenges in diagnosing earlier this copper overload disorder. As a treatable disease, WD should be detected early in the course of the disease by any health professionals at any care level, but the rare prevalence of the disease explains the lack of awareness of referring physicians. The most important challenge is to train physicians to recognize atypical or rare symptoms of WD that will lead to discuss the diagnosis more systematically. Atypia can come from the age of onset, the liver [non-alcoholic steatohepatitis (NASH) presentation], the central or peripheral nervous system (neuropathy, epilepsy, sleep disorders…) or may be due to lesions of other organs (renal manifestations, osteo-articular disorders or endocrine disturbances). Isolated biological anomalies, rare radiological findings or inadequate interpretation of copper test may also lead to misdiagnosis. The second challenge is to confirm the diagnosis faster and more effectively so as not to delay the initiation of treatment, and expand family screening as the genetic prevalence is higher than previously expected. Generalization of the exchangeable copper assay and the next generation sequencing (NGS) are two promising ways to overcome this ultimate challenge. By drawing attention to the earliest and rare symptoms and to new biomarkers and diagnostic tools, we hope that this article will increase diagnostic awareness and reduce delays so that patients can start their treatment earlier in the course of the illness and thus have a better disease prognosis.
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Affiliation(s)
- Aurélia Poujois
- Neurology Department, AP-HP, Lariboisière University Hospital, Paris, France
- National Reference Centre for Wilson Disease, AP-HP, Lariboisière University Hospital, Paris, France
| | - France Woimant
- Neurology Department, AP-HP, Lariboisière University Hospital, Paris, France
- National Reference Centre for Wilson Disease, AP-HP, Lariboisière University Hospital, Paris, France
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Poujois A, Woimant F. Wilson's disease: A 2017 update. Clin Res Hepatol Gastroenterol 2018; 42:512-520. [PMID: 29625923 DOI: 10.1016/j.clinre.2018.03.007] [Citation(s) in RCA: 70] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Revised: 02/27/2018] [Accepted: 03/08/2018] [Indexed: 02/04/2023]
Abstract
Wilson's disease (WD) is characterised by a deleterious accumulation of copper in the liver and brain. It is one of those rare genetic disorders that benefits from effective and lifelong treatments that have dramatically transformed the prognosis of the disease. In Europe, its clinical prevalence is estimated at between 1.2 and 2/100,000 but the genetic prevalence is higher, at around 1/7000. Incomplete penetrance of the gene or the presence of modifier genes may account for the difference between the calculated genetic prevalence and the number of patients diagnosed with WD. The clinical spectrum of WD is broader as expected with mild clinical presentations and late onset of the disease after the age of 40 in 6% of patients. WD is usually suspected when ceruloplasmin and serum copper levels are low and 24h urinary copper excretion is elevated. Recently, a major diagnostic advance was achieved with implementation of the direct assay of "free copper", or exchangeable copper (CuEXC). The relative exchangeable copper (REC) that corresponds to the ratio between CuEXC and total serum copper enables a diagnosis of WD with high sensitivity and specificity when REC>18.5%. Moreover, CuEXC values at diagnosis are a marker of extrahepatic involvement and its severity. A value of >2.08μmol/L is suggestive of corneal and brain involvement (Se=86%, Sp=94%), and the disease will be more clinically and radiologically severe as values rise. The use of FibroScan® is becoming more widespread to assess liver stiffness measurements in WD patients. 6.6kPa is considered to be a threshold value between mild and moderate fibrosis, whereas a value higher than 8.4 is indicative of severe fibrosis. More studies are now necessary to confirm the usefulness of Fibroscan® in managing chronic therapy for WD patients. Treatment of this disease is based on an initial active and prolonged chelating phase (with D-Penicillamine or Trientine) followed by maintenance with Trientine or zinc salt. The two major problems that may be encountered are neurological worsening during the initial phase and non-compliance with treatment during maintenance therapy. Liver transplantation is the recommended therapeutic option in WD with acute liver failure or end-stage liver cirrhosis; its indication should be considered when neurological status deteriorates rapidly despite effective chelation. Regular clinical, biological and liver ultrasound follow-up is essential to evaluate efficacy, tolerance and treatment compliance, but also to detect the onset of hepatocellular carcinoma on a cirrhotic liver. There are hopes in the near future with the introduction of a new chelator and inhibitor of copper absorption, tetrathiomolybdate (TTM) and the development of gene therapy.
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Affiliation(s)
- Aurélia Poujois
- Neurology Department, AP-HP, Lariboisière University Hospital, Paris, France; National Reference Centre for Wilson's Disease, AP-HP, Lariboisière University Hospital, Paris, France.
| | - France Woimant
- Neurology Department, AP-HP, Lariboisière University Hospital, Paris, France; National Reference Centre for Wilson's Disease, AP-HP, Lariboisière University Hospital, Paris, France
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Both α-1-antitrypsin Z phenotypes and low caeruloplasmin levels are over-represented in alcohol and nonalcoholic fatty liver disease cirrhotic patients undergoing liver transplant in Ireland. Eur J Gastroenterol Hepatol 2018; 30:364-367. [PMID: 29324588 DOI: 10.1097/meg.0000000000001056] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVES Alcoholic liver disease and nonalcoholic fatty liver disease (NAFLD) are steatotic liver diseases and major causes of cirrhosis. Only a minority of patients with risk factors develop cirrhosis and genetic cofactors may be important in pathogenesis. Mutations in the Wilson's and α-1-antitrypsin genes are not uncommon and we speculated that they may act as cofactors. METHODS We investigated α-1-antitrypsin phenotyes and caeruloplasmin levels in patients undergoing elective liver transplantation. We compared patients with alcohol and NAFLD with nonsteatotic liver disease patients: viral hepatitis B or C, autoimmune hepatitis, primary biliary cholangitis and primary sclerosing cholangitis. RESULTS Two hundred and thirty-one patients were included in the study. Pretransplant caeruloplasmin levels and α-1-antitrypsin phenotypes were available in 197 and 112 patients, respectively. α-1-Antitrypsin Z phenotypes were significantly more common in the alcohol and NAFLD group: 12/56 versus 3/56 (P<0.05). Serum caeruloplasmin (0.3±0.01 vs. 0.39±0.01 g/l, P<0.01) and serum copper levels (13.5±0.9 vs. 19.3±0.9 μmol/l, P<0.01) were significantly lower in the alcohol and NAFLD patients compared with the viral and autoimmune patients. CONCLUSION In this study, we found the α-1-antitrypsin Z phenotype was more common, and serum caeruloplasmin and copper levels were lower in patients with fatty liver diseases. We suggest that mutations in the α-1-antitrypsin and Wilson's genes may act as cofactors in the pathogenesis of fatty liver diseases.
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Abstract
A 64-year-old woman, presented with abdominal distention, jaundice and resting tremor, was found to have liver injury and abnormal liver enzymes. A computed tomography (CT) scan of the abdomen and pelvis showed abdominopelvic ascites and signs of liver cirrhosis. An extensive liver disease workup was performed and came back negative; therefore, a liver biopsy was obtained and showed evidence of cirrhosis with elevated liver copper consistent with Wilson’s disease (WD). We report a unique case of late-onset WD in which the ceruloplasmin level and 24-h urinary copper excretion were all normal.
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Affiliation(s)
- Talal El Imad
- Department of Internal Medicine, Staten Island University Hospital, New York
| | | | - Fady G Haddad
- Department of Gastroenterology and Hepatology, Staten Island University Hospital, New York
| | - Richard Felix
- Department of Pathology, Staten Island University Hospital, New York
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Amano T, Matsubara T, Nishida T, Shimakoshi H, Shimoda A, Sugimoto A, Takahashi K, Mukai K, Yamamoto M, Hayashi S, Nakajima S, Fukui K, Inada M. Clinically diagnosed late-onset fulminant Wilson's disease without cirrhosis: A case report. World J Gastroenterol 2018; 24:290-296. [PMID: 29375214 PMCID: PMC5768947 DOI: 10.3748/wjg.v24.i2.290] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Revised: 11/23/2017] [Accepted: 11/28/2017] [Indexed: 02/06/2023] Open
Abstract
A 64-year-old woman was referred to our hospital with jaundice of the bulbar conjunctiva and general fatigue. After admission, she developed hepatic encephalopathy and was diagnosed with fulminant hepatitis based on the American Association for the Study of Liver Disease (AASLD) position paper. Afterwards, additional laboratory findings revealed that serum ceruloplasmin levels were reduced, urinary copper levels were greatly elevated and Wilson's disease (WD)-specific routine tests were positive, but the Kayser-Fleischer ring was not clear. Based on the AASLD practice guidelines for the diagnosis and treatment of WD, the patient was ultimately diagnosed with fulminant WD. Then, administration of penicillamine and zinc acetate was initiated; however, the patient unfortunately died from acute pneumonia on the 28th day of hospitalization. At autopsy, the liver did not show a bridging pattern of fibrosis suggestive of chronic liver injury. Here, we present the case of a patient with clinically diagnosed late-onset fulminant WD without cirrhosis, who had positive disease-specific routine tests.
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Affiliation(s)
- Takahiro Amano
- Department of Gastroenterology and Hepatology, Toyonaka Municipal Hospital, Toyonaka, Osaka 560-8565, Japan
| | - Tokuhiro Matsubara
- Department of Gastroenterology and Hepatology, Toyonaka Municipal Hospital, Toyonaka, Osaka 560-8565, Japan
| | - Tsutomu Nishida
- Department of Gastroenterology and Hepatology, Toyonaka Municipal Hospital, Toyonaka, Osaka 560-8565, Japan
| | - Hiromi Shimakoshi
- Department of Gastroenterology and Hepatology, Toyonaka Municipal Hospital, Toyonaka, Osaka 560-8565, Japan
| | - Akiyoshi Shimoda
- Department of Gastroenterology and Hepatology, Toyonaka Municipal Hospital, Toyonaka, Osaka 560-8565, Japan
| | - Aya Sugimoto
- Department of Gastroenterology and Hepatology, Toyonaka Municipal Hospital, Toyonaka, Osaka 560-8565, Japan
| | - Kei Takahashi
- Department of Gastroenterology and Hepatology, Toyonaka Municipal Hospital, Toyonaka, Osaka 560-8565, Japan
| | - Kaori Mukai
- Department of Gastroenterology and Hepatology, Toyonaka Municipal Hospital, Toyonaka, Osaka 560-8565, Japan
| | - Masashi Yamamoto
- Department of Gastroenterology and Hepatology, Toyonaka Municipal Hospital, Toyonaka, Osaka 560-8565, Japan
| | - Shiro Hayashi
- Department of Gastroenterology and Hepatology, Toyonaka Municipal Hospital, Toyonaka, Osaka 560-8565, Japan
| | - Sachiko Nakajima
- Department of Gastroenterology and Hepatology, Toyonaka Municipal Hospital, Toyonaka, Osaka 560-8565, Japan
| | - Koji Fukui
- Department of Gastroenterology and Hepatology, Toyonaka Municipal Hospital, Toyonaka, Osaka 560-8565, Japan
| | - Masami Inada
- Department of Gastroenterology and Hepatology, Toyonaka Municipal Hospital, Toyonaka, Osaka 560-8565, Japan
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Abstract
Wilson's disease (WD) is a relatively rare autosomal recessive inherited disorder causing copper accumulation in different organs, mainly the liver and brain. Psychiatric disturbances represent a diagnostic and therapeutic issue in WD. A search for relevant articles was carried out on PubMed/Medline, Scopus, and Google Scholar, for papers focused on psychiatric disorders in WD published between 1985-2016. Ninety-two articles were included in this review, showing the findings from 35 observational and case-control studies and 57 case reports. This study discussed the findings on the prevalence of psychiatric symptoms in WD, their impact on the life of those diagnosed, and the efficacy of available treatments on the psychiatric outcomes of WD. Psychiatric disorders are confirmed frequent in WD, with a high prevalence of mood disorders, and contribute to worse Quality-of-Life and psychosocial outcomes. Because specific therapies for WD lead to a good life expectancy, adherence to medicaments and clinical monitoring should be warranted by a multidisciplinary approach, including a hepathologic, neurologic, and psychiatric careful evaluation and education of those affected and their relatives.
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Affiliation(s)
- Gioia Mura
- a Department of Medical Sciences and Public Health , University of Cagliari , Cagliari , Italy
| | - Paula C Zimbrean
- b Department of Psychiatry and Surgery (Transplant) , Yale University , New Haven , CT , USA
| | - Luigi Demelia
- a Department of Medical Sciences and Public Health , University of Cagliari , Cagliari , Italy
| | - Mauro G Carta
- a Department of Medical Sciences and Public Health , University of Cagliari , Cagliari , Italy
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Abstract
Wilson disease (WD) is an autosomal-recessive disorder of hepatocellular copper deposition caused by pathogenic variants in the copper-transporting gene, ATP7B. Early detection and treatment are critical to prevent lifelong neuropsychiatric, hepatic, and systemic disabilities. Due to the marked heterogeneity in age of onset and clinical presentation, the diagnosis of Wilson disease remains challenging to physicians today. Direct sequencing of the ATP7B gene is the most sensitive and widely used confirmatory testing method, and concurrent biochemical testing improves diagnostic accuracy. More than 600 pathogenic variants in ATP7B have been identified, with single-nucleotide missense and nonsense mutations being the most common, followed by insertions/deletions, and, rarely, splice site mutations. The prevalence of Wilson disease varies by geographic region, with higher frequency of certain mutations occurring in specific ethnic groups. Wilson disease has poor genotype-phenotype correlation, although a few possible modifiers have been proposed. Improving molecular genetic studies continue to advance our understanding of the pathogenesis, diagnosis, and screening for Wilson disease.
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Affiliation(s)
- Irene J Chang
- Division of Medical Genetics, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA
| | - Si Houn Hahn
- Division of Genetic Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle Children's Hospital, Seattle, WA, USA.
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