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Ganaraja VH, Holla VV, Pal PK. Current Management of Neurological Wilson's Disease. Tremor Other Hyperkinet Mov (N Y) 2025; 15:17. [PMID: 40351566 PMCID: PMC12063596 DOI: 10.5334/tohm.938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Accepted: 02/03/2025] [Indexed: 05/14/2025] Open
Abstract
Wilson's disease (WD) is a disorder of copper metabolism due to variants in the ATP7B gene. This autosomal recessively inherited disorder is characterized by the accumulation of copper in various body parts, mainly the liver, brain, and kidneys. Initially, WD was described to involve the hepatic and neurological systems. Subsequently, diverse presentations have been reported with skeletal and hematological manifestations and various constellations of symptoms. Neurological manifestations of WD are varied, ranging from asymptomatic neurological state to refractory dystonia. Earlier, the diagnosis was based only on measuring serum ceruloplasmin levels, urinary copper levels, and imaging. Advanced genetic testing has provided an additional mode of diagnosis in the patient, screening of the family members and, a way to better understand the genotype-phenotype associations of the disease if there are any. In the last few decades, the treatment of WD has evolved from symptomatic treatment and chelation therapy to many new advanced measures for both copper chelation and symptomatic relief. With a better understanding of the genetic aspects of WD in recent years, there has been more focus on gene therapy, novel therapies targeting ATP7B genes, and therapies targeting mutant proteins to prevent copper accumulation. This article highlights the advances in diagnostic methods and treatment modalities in WD.
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Affiliation(s)
- V. H. Ganaraja
- Department of Neurology, National Institute of Mental Health and Neuro Sciences, Bengaluru, India-560029
| | - Vikram V. Holla
- Department of Neurology, National Institute of Mental Health and Neuro Sciences, Bengaluru, India-560029
| | - Pramod Kumar Pal
- Department of Neurology, National Institute of Mental Health and Neuro Sciences, Bengaluru, India-560029
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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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Arefhosseini S, Tutunchi H, Arefhosseini SR, Ghavami SZ, Ebrahimi-Mameghani M. Copper status and its relation to abdominal obesity indices and liver function in non-alcoholic fatty liver disease: a case-control study. BMC Res Notes 2024; 17:370. [PMID: 39702499 DOI: 10.1186/s13104-024-07025-x] [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: 05/21/2024] [Accepted: 12/02/2024] [Indexed: 12/21/2024] Open
Abstract
OBJECTIVE This study investigated copper (Cu) status in relation to abdominal obesity indices and liver function in patients with non-alcoholic fatty liver disease (NAFLD). This case-control study was carried out on 80 overweight/obese patients with NAFLD and 80 apparently healthy age, sex, and body mass index (BMI)-matched controls. A validated and reliable 168-item semi-quantitative food frequency questionnaire was completed for each subject and fasting serum levels of liver aminotransferases, ferritin, Cu and ceruloplasmin were assessed. RESULTS Mean intakes of energy and carbophydrate were significantly lower in patients with NAFLD than the control group while mean protein intake was highre (p < 0.05). Although mean Cu intake was greater in cases than controls, low dietary intake of Cu was found in 7.5% and 32.5% of the cases and controls, respectively. Apart from serum levels of liver aminotransferases (p < 0.001) and ferritin (p = 0.010), no significant differences were found in serum levels of Cu and ceruloplasmin. Serum and dietary Cu were positively correlated with obesity indices and serum ceruloplasmin was correlated with waist to height ratio and ferritin only in cases (p < 0.05). Low Cu intake (< 0.95 mg/day) was more likely to increase the odds of NAFLD (p for trend = 0.002), after adjusting for potential confounders.
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Affiliation(s)
- Sara Arefhosseini
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Helda Tutunchi
- Endocrine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Seyed Rafie Arefhosseini
- Department of Biochemistry and Diet Therapy, Faculty of Nutrition & Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Seyede Zoha Ghavami
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehrangiz Ebrahimi-Mameghani
- Nutrition Research Center, Department of Biochemistry and Diet Therapy, Faculty of Nutrition & Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
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Pelucchi S, Risca G, Lanzafame C, Scollo CM, Garofalo A, Martinez D, Mariani R, Botti M, Capitoli G, Rossi F, Casati M, Piperno A, Galimberti S. Reference Values of Ceruloplasmin across the Adult Age Range in a Large Italian Healthy Population. J Appl Lab Med 2024; 9:1053-1063. [PMID: 39239918 DOI: 10.1093/jalm/jfae098] [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: 04/29/2024] [Accepted: 07/29/2024] [Indexed: 09/07/2024]
Abstract
BACKGROUND Ceruloplasmin (Cp) is the most important serum copper transport protein playing a key role in the binding of iron to transferrin. It is a positive acute-phase response protein and the first-level diagnostic marker for Wilson disease and aceruloplasminemia. However, standardization of Cp measurement has not been successful, and assay specific reference levels of Cp are required. METHODS From May 2019 to July 2022, we enrolled 1706 consecutive healthy Italian blood donors (1285 men and 421 women, 18 to 65 years) to identify the reference intervals of serum Cp through quantile regression and evaluate the relationship of Cp with age, sex, iron, and metabolic status through linear regression. RESULTS We found that mean serum Cp was influenced by sex and slightly by age. The lower reference Cp value rose slightly with increasing age in both men and women. The upper reference value increased, reaching a plateau of about 25 mg/dL around 25 years in men, while in women it initially increased to around 45 mg/dL in young adults to fall sharply below 30 mg/dL for adults after their fifties. CONCLUSIONS We showed that the normal reference curves of serum Cp vary according to sex in a large population of healthy adults. While the lower reference values did not appear to be influenced by age and sex, the upper ones differed according to sex and age showing a particularly high variability in women, possibly reflecting different hormonal status.
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Affiliation(s)
- Sara Pelucchi
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Giulia Risca
- Department of Medicine and Surgery, Bicocca Bioinformatics Biostatistics and Bioimaging B4 Center, University of Milan-Bicocca, Monza, Italy
| | - Corradina Lanzafame
- Immunotransfusional Unit, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
| | | | - Andrea Garofalo
- Department of Laboratory Medicine, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
| | - Davide Martinez
- Department of Laboratory Medicine, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
| | - Raffaella Mariani
- SSD Rare Diseases-European Reference Network for Rare Hematological Diseases-EuroBloodNet-Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
| | - Mara Botti
- SSD Rare Diseases-European Reference Network for Rare Hematological Diseases-EuroBloodNet-Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
| | - Giulia Capitoli
- Department of Medicine and Surgery, Bicocca Bioinformatics Biostatistics and Bioimaging B4 Center, University of Milan-Bicocca, Monza, Italy
| | - Fabio Rossi
- Immunotransfusional Unit, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
| | - Marco Casati
- Department of Laboratory Medicine, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
| | | | - Stefania Galimberti
- Department of Medicine and Surgery, Bicocca Bioinformatics Biostatistics and Bioimaging B4 Center, University of Milan-Bicocca, Monza, Italy
- Biostatistics and Clinical Epidemiology, Fondazione IRCCS San Gerardo Dei Tintori, Monza, Italy
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Loudianos G, Satta S, Lepori MB, Anni F, Balloi R, Soddu C, Fenu ML, Lilliu F, Nurchi AM, De Virgiliis S. Wilson's disease in Sardinian population: The experience of a pediatric referral center. J Pediatr Gastroenterol Nutr 2024; 79:807-817. [PMID: 39113473 DOI: 10.1002/jpn3.12343] [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: 05/22/2024] [Revised: 07/18/2024] [Accepted: 07/21/2024] [Indexed: 10/02/2024]
Abstract
BACKGROUND AND OBJECTIVES Wilson's disease (WD) in children and adolescents is predominantly asymptomatic or oligo-symptomatic. The symptoms are nonspecific and difficult to distinguish from other hepatic or neuropsychiatric disorders. In this study, we present the experience of a pediatric referral center for WD diagnosis and treatment. PATIENTS AND METHODS We retrospectively analyzed clinical and laboratory data from 99 patients with WD of Sardinian origin, including physical examination, laboratory biochemical testing, liver biopsy, and genetic analysis. RESULTS Patients were prevalently oligo-symptomatic or asymptomatic. The median age of diagnosis was 8.78 years. Ceruloplasmin values were lower than normal values in all analyzed patients. Twenty-four-hour urinary copper levels were higher than 40 μg/24-h in 92/96 patients. In all analyzed patients with the exception of one, liver copper was higher than 250 μg/g of dry weight but all had >75 μg/g of dry weight. Statistical analysis showed correlation between the age at diagnosis, serum copper, and 24-h urinary copper. Correlation was also found between serum copper and 24-h urinary copper. Molecular analysis of ATP7B gene allowed complete characterization in all the analyzed patients. CONCLUSION A high index of clinical suspicion and biochemical tests including liver tests, serum ceruloplasmin, and basal 24-h urinary copper excretion and genotype determination are key to WD diagnosis. The long experience that a referral center for WD possesses is an important factor in making WD diagnosis a more accurate process. Studies in animal models on WD could be used as a guide to further investigate the molecular mechanisms that regulate copper metabolism and influence the natural history of WD.
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Affiliation(s)
- Georgios Loudianos
- Clinica Pediatrica e Malattie Rare, Università degli Studi di Cagliari, Ospedale Pediatrico Microcitemico, Antonio Cao, Cagliari, Italy
| | - Stefania Satta
- Laboratorio di Genetica e Genomica, Dipartimento di Scienze Mediche e Sanità Pubblica, Università degli Studi di Cagliari, Cagliari, Italy
| | - Maria B Lepori
- Laboratorio di Genetica e Genomica, Dipartimento di Scienze Mediche e Sanità Pubblica, Università degli Studi di Cagliari, Cagliari, Italy
| | - Franco Anni
- Laboratorio di Genetica e Genomica, Dipartimento di Scienze Mediche e Sanità Pubblica, Università degli Studi di Cagliari, Cagliari, Italy
| | - Roberta Balloi
- SSD Endocrinologia Pediatrica e Centro Screening Neonatale, Ospedale Pediatrico, Microcitemico, A. Cao, Cagliari, Italy
| | - Consolata Soddu
- Clinica Pediatrica e Malattie Rare, Università degli Studi di Cagliari, Ospedale Pediatrico Microcitemico, Antonio Cao, Cagliari, Italy
| | - Maria L Fenu
- Clinica Pediatrica e Malattie Rare, Università degli Studi di Cagliari, Ospedale Pediatrico Microcitemico, Antonio Cao, Cagliari, Italy
| | - Franco Lilliu
- Clinica Pediatrica e Malattie Rare, Università degli Studi di Cagliari, Ospedale Pediatrico Microcitemico, Antonio Cao, Cagliari, Italy
| | - Anna M Nurchi
- Clinica Pediatrica e Malattie Rare, Università degli Studi di Cagliari, Ospedale Pediatrico Microcitemico, Antonio Cao, Cagliari, Italy
| | - Stefano De Virgiliis
- Clinica Pediatrica e Malattie Rare, Università degli Studi di Cagliari, Ospedale Pediatrico Microcitemico, Antonio Cao, Cagliari, Italy
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Lonardo A, Weiskirchen R. Copper and liver fibrosis in MASLD: the two-edged sword of copper deficiency and toxicity. METABOLISM AND TARGET ORGAN DAMAGE 2024. [DOI: 10.20517/mtod.2024.47] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Copper is a trace metal whose absence or deficiency can cause structural and functional alterations that can be corrected by copper administration. Copper excess is associated with significant liver toxicity, such as that seen in Wilson’s disease, which often exhibits liver steatosis and can be managed by copper sequestrants. Copper, due to its ability to either accept or donate electrons, is a cofactor in many physiological redox reactions, playing an essential role in cell energy homeostasis, detoxification of reactive oxygen species, and hepatic immunometabolism. Given these facts, it is reasonable to speculate that copper might be involved in the pathogenesis of liver fibrosis in the setting of metabolic dysfunction-associated fatty liver disease (MASLD). To address this research question, a narrative review of published studies was conducted, spanning from the needs, sources, and toxicity of copper to Menkes and Wilson’s disease. Most epidemiological studies have demonstrated that MASLD is associated with copper deficiency. However, several studies show that MASLD is associated with copper excess and very few conclude that copper is not associated with MASLD. Therefore, the putative pathomechanisms associating both copper excess and deficiency with MASLD development and progression are reviewed. In conclusion, epidemiological and pathogenic data support the notion that well-balanced copper homeostasis is a prerequisite for liver health. Accordingly, both copper excess and deficiency may potentially predispose to liver fibrosis via the development of MASLD. Therefore, studies aimed at restoring normal bodily stores of copper should be tailored according to precision medicine approaches based on the specific features of copper metabolism in individual MASLD patients.
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Nguyen KT, Nguyen DD, Montecinos L, Hlaing PP, Khatri S. Investigation of Markedly Elevated Liver Enzymes With Serendipitous Underlying Wilson's Disease With Chronic Alcohol Abuse. Cureus 2024; 16:e59025. [PMID: 38803772 PMCID: PMC11128335 DOI: 10.7759/cureus.59025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/25/2024] [Indexed: 05/29/2024] Open
Abstract
Acute hepatitis can result from a wide variety of noninfectious causes that include, but are not limited to, drugs (drug-induced hepatitis), alcohol (alcoholic hepatitis), immunologic (autoimmune hepatitis, primary biliary cholangitis), or as a result of indirect insult secondary to biliary tract dysfunction (cholestatic hepatitis), pregnancy-related liver dysfunction, shock, or metastatic disease. In clinical settings, these causes are not uncommon to overlap with each other or are masked by obviously visible causes in medical history. We reported our scenario of a patient who has a heavy history of alcohol use and presented with alcohol withdrawal symptoms and a marked elevation of liver enzymes. Interestingly, further investigations suggested Wilson's disease could be an underlying culprit of acute hepatitis in this patient. This case again emphasized that Wilson's disease can be masked under multiple causes and various scenarios, which alerts clinicians that a broad approach should be made for every case of acute hepatitis.
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Affiliation(s)
| | - Dat D Nguyen
- Interventional Cardiology, Gia Dinh People's Hospital, Ho Chi Minh, VNM
| | | | - Pwint P Hlaing
- Internal Medicine, Interfaith Medical Center, New York, USA
| | - Samridhi Khatri
- Internal Medicine, Eastern Maine Medical Center, Bangor, USA
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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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9
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Quaglia A, Roberts EA, Torbenson M. Developmental and Inherited Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:122-294. [DOI: 10.1016/b978-0-7020-8228-3.00003-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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10
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Ghosh U, Sen Sarma M, Samanta A. Challenges and dilemmas in pediatric hepatic Wilson's disease. World J Hepatol 2023; 15:1109-1126. [PMID: 37970614 PMCID: PMC10642431 DOI: 10.4254/wjh.v15.i10.1109] [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: 07/31/2023] [Revised: 09/23/2023] [Accepted: 10/08/2023] [Indexed: 10/24/2023] Open
Abstract
Wilson disease is an autosomal recessive disorder affecting the ATP7B gene located on chromosome 13q. This leads to copper deposition in various organs, most importantly in the liver and brain. The genetic mutations are vast, well reported in the West but poorly documented in developing countries. Hence the diagnosis is made with a constellation of clinico-laboratory parameters which have significant overlap with other liver diseases and often pose a significant dilemma for clinicians. Diagnostic scoring systems are not fool-proof. The availability and affordability of chelators in developing countries impact the drug compliance of patients. While D-penicillamine is a potent drug, its side effects lead to drug discontinuation. Trientine is cost-prohibitive in developing countries. There is no single test to assess the adequacy of chelation. Exchangeable urinary copper is an essential upcoming diagnostic and prognostic tool. In the presence of cirrhosis, hypersplenism clouds the assessment of myelosuppression of drugs. Similarly, it may be difficult to distinguish disease tubulopathy from drug-induced glomerulonephritis. Neurological worsening due to chelators may appear similar to disease progression. Presentation as fulminant hepatic failure requires rapid workup. There is a limited window of opportunity to salvage these patients with the help of plasmapheresis and other liver-assisted devices. This review addresses the challenges and clinical dilemmas faced at beside in developing countries.
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Affiliation(s)
- Upasana Ghosh
- Department of Pediatric Gastroenterology, Sanjay Gandhi Post graduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
| | - Moinak Sen Sarma
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India.
| | - Arghya Samanta
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
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Affiliation(s)
- Eve A Roberts
- From the Departments of Paediatrics, Medicine, and Pharmacology and Toxicology, University of Toronto, and the Hospital for Sick Children Research Institute - both in Toronto; and the History of Science and Technology Programme, University of King's College, Halifax, NS, Canada (E.A.R.); and the Departments of Medicine and Surgery, Yale University School of Medicine, New Haven, CT (M.L.S.)
| | - Michael L Schilsky
- From the Departments of Paediatrics, Medicine, and Pharmacology and Toxicology, University of Toronto, and the Hospital for Sick Children Research Institute - both in Toronto; and the History of Science and Technology Programme, University of King's College, Halifax, NS, Canada (E.A.R.); and the Departments of Medicine and Surgery, Yale University School of Medicine, New Haven, CT (M.L.S.)
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12
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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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Schilsky ML, Roberts EA, Bronstein JM, Dhawan A, Hamilton JP, Rivard AM, Washington MK, Weiss KH, Zimbrean PC. A multidisciplinary approach to the diagnosis and management of Wilson disease: Executive summary of the 2022 Practice Guidance on Wilson disease from the American Association for the Study of Liver Diseases. Hepatology 2023; 77:1428-1455. [PMID: 36152019 DOI: 10.1002/hep.32805] [Citation(s) in RCA: 69] [Impact Index Per Article: 34.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 09/13/2022] [Indexed: 12/08/2022]
Affiliation(s)
- Michael L Schilsky
- Medicine and Surgery , Yale University School of Medicine , New Haven , Connecticut , USA
| | - Eve A Roberts
- Paediatrics, Medicine, Pharmacology and Toxicology , University of Toronto , Toronto , Ontario , Canada
| | - Jeff M Bronstein
- Neurology , University of California Los Angeles , Los Angeles , California , USA
| | - Anil Dhawan
- Paediatric Liver, GI and Nutrition Centre and MowatLabs , King's College Hospital , London , UK
| | - James P Hamilton
- Medicine , Johns Hopkins University School of Medicine , Baltimore , Maryland , USA
| | - Anne Marie Rivard
- Food and Nutrition Services , Yale New Haven Hospital , New Haven , Connecticut , USA
| | - Mary Kay Washington
- Pathology, Immunology and Microbiology , Vanderbilt University Medical Center , Nashville , Tennessee , USA
| | | | - Paula C Zimbrean
- Psychiatry , Yale University School of Medicine , New Haven , Connecticut , USA
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14
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Guillaud O, Dumortier J, Couchonnal-Bedoya E, Ruiz M. Wilson Disease and Alpha1-Antitrypsin Deficiency: A Review of Non-Invasive Diagnostic Tests. Diagnostics (Basel) 2023; 13:diagnostics13020256. [PMID: 36673066 PMCID: PMC9857715 DOI: 10.3390/diagnostics13020256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Accepted: 01/03/2023] [Indexed: 01/12/2023] Open
Abstract
Wilson disease and alpha1-antitrypsin deficiency are two rare genetic diseases that may impact predominantly the liver and/or the brain, and the liver and/or the lung, respectively. The early diagnosis of these diseases is important in order to initiate a specific treatment, when available, ideally before irreversible organ damage, but also to initiate family screening. This review focuses on the non-invasive diagnostic tests available for clinicians in both diseases. These tests are crucial at diagnosis to reduce the potential diagnostic delay and assess organ involvement. They also play a pivotal role during follow-up to monitor disease progression and evaluate treatment efficacy of current or emerging therapies.
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Affiliation(s)
- Olivier Guillaud
- Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, Centre National de Référence pour la Maladie de Wilson, 69500 Bron, France
- Ramsay Générale de Santé, Clinique de la Sauvegarde, 69009 Lyon, France
- Hospices Civils de Lyon, Hôpital Edouard Herriot, Fédération des Spécialités Digestives, 69003 Lyon, France
- Correspondence: ; Tel.: +33-4-72-11-95-19
| | - Jérôme Dumortier
- Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, Centre National de Référence pour la Maladie de Wilson, 69500 Bron, France
- Hospices Civils de Lyon, Hôpital Edouard Herriot, Fédération des Spécialités Digestives, 69003 Lyon, France
- Faculté de Médecine Lyon Est, Université Claude Bernard Lyon 1, 69003 Lyon, France
| | - Eduardo Couchonnal-Bedoya
- Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, Centre National de Référence pour la Maladie de Wilson, 69500 Bron, France
- Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, Service d’Hépatogastroentérologie et Nutrition Pédiatrique, 69500 Bron, France
| | - Mathias Ruiz
- Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, Service d’Hépatogastroentérologie et Nutrition Pédiatrique, 69500 Bron, France
- Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, Centre National de Référence pour l’Atrésie des Voies Biliaires et les Cholestases Génétiques, 69500 Bron, France
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15
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Chen L, Shi Y, Wang N, Lou Z, Pan L, Xu X, Wu C, Han Y, Yang R, Hu W, Ruan B. Age and Serum Creatinine Can Differentiate Wilson Disease Patients with Pseudonormal Ceruloplasmin. Int J Clin Pract 2023; 2023:9344891. [PMID: 36915635 PMCID: PMC10008117 DOI: 10.1155/2023/9344891] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 02/12/2023] [Accepted: 02/23/2023] [Indexed: 03/06/2023] Open
Abstract
METHODS We retrospectively screened individuals with serum Cp ≥ 140 mg/L from 1032 WD patients who were hospitalised for the first time. Logistic regression analyses were performed in a case-control study between the WD cohort and another liver disease cohort to explore the independent risk factors for WD diagnosis and establish a regression model to identify them. The follow-up medical records of the WD cohort were subjected to mixed-effects model analysis in a longitudinal study to discover factors associated with Cp normalisation. RESULTS Eighty-six WD patients and their 353 medical records and another 98 non-WD liver disease patients were included in the present study. Cp normalisation was significantly associated with the copper burden and liver function indexes, such as urinary copper, γ-glutamyltransferase, and albumin (p ≤ 0.001). Logistic regression analysis showed that age and serum creatinine (p ≤ 0.001) were independent risk factors associated with WD. The AUC value of the regression model in the total cohort was 0.926 (p ≤ 0.001). At a cutoff value of ≥0.617 and ≥-1, the positive and negative predictive values were both 90.8% for WD. CONCLUSION Increased serum Cp in WD patients is related to excessive copper burden and hepatic injury, and common tests can effectively distinguish WD patients from other liver injury patients.
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Affiliation(s)
- Lin Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
- Department of Neurology, The Affiliated Hospital of the Neurology Institute of Anhui University of Chinese Medicine, Hefei, Anhui Province, China
| | - Yongguang Shi
- Department of Neurology, The Affiliated Hospital of the Neurology Institute of Anhui University of Chinese Medicine, Hefei, Anhui Province, China
| | - Nan Wang
- Department of Geriatric Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
| | - Zhuoqi Lou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Liya Pan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Xiaolan Xu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Chensi Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Yongzhu Han
- Department of Neurology, The Affiliated Hospital of the Neurology Institute of Anhui University of Chinese Medicine, Hefei, Anhui Province, China
| | - Renmin Yang
- Department of Neurology, The Affiliated Hospital of the Neurology Institute of Anhui University of Chinese Medicine, Hefei, Anhui Province, China
| | - Wenbin Hu
- Department of Neurology, The Affiliated Hospital of the Neurology Institute of Anhui University of Chinese Medicine, Hefei, Anhui Province, China
| | - Bing Ruan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
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16
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Schilsky ML, Roberts EA, Bronstein JM, Dhawan A, Hamilton JP, Rivard AM, Washington MK, Weiss KH, Zimbrean PC. A multidisciplinary approach to the diagnosis and management of Wilson disease: 2022 Practice Guidance on Wilson disease from the American Association for the Study of Liver Diseases. Hepatology 2022:01515467-990000000-00207. [PMID: 36151586 DOI: 10.1002/hep.32801] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 09/13/2022] [Indexed: 01/18/2023]
Affiliation(s)
- Michael L Schilsky
- Medicine and Surgery , Yale University School of Medicine , New Haven , Connecticut , USA
| | - Eve A Roberts
- Paediatrics, Medicine, Pharmacology and Toxicology , University of Toronto , Toronto , Ontario , Canada
| | - Jeff M Bronstein
- Neurology , University of California Los Angeles , Los Angeles , California , USA
| | - Anil Dhawan
- Paediatric Liver, GI and Nutrition Centre and MowatLabs , King's College Hospital , London , UK
| | - James P Hamilton
- Medicine , Johns Hopkins University School of Medicine , Baltimore , Maryland , USA
| | - Anne Marie Rivard
- Food and Nutrition Services , Yale New Haven Hospital , New Haven , Connecticut , USA
| | - Mary Kay Washington
- Pathology, Immunology and Microbiology , Vanderbilt University Medical Center , Nashville , Tennessee , USA
| | | | - Paula C Zimbrean
- Psychiatry , Yale University School of Medicine , New Haven , Connecticut , USA
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Yang Y, Hao W, Wei T, Tang L, Qian N, Yang Y, Xi H, Zhang S, Yang W. Role of serum ceruloplasmin in the diagnosis of Wilson's disease: A large Chinese study. Front Neurol 2022; 13:1058642. [PMID: 36570465 PMCID: PMC9768184 DOI: 10.3389/fneur.2022.1058642] [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: 09/30/2022] [Accepted: 11/03/2022] [Indexed: 12/12/2022] Open
Abstract
Background Conventionally, serum ceruloplasmin levels below the lower reference limit (0. 20 g/L) is considered a diagnostic cutoff point for Wilson's disease (WD). However, the lower reference limit varies with assay methodologies and the individuals in the included studies. The objective of this study was to determine the optimal cutoff value of serum ceruloplasmin levels for the diagnosis of WD in a large Chinese cohort and to identify factors associated with serum ceruloplasmin. Methods The cutoff value of ceruloplasmin levels was developed based on a retrospective derivation cohort of 3,548 subjects (1,278 patients with WD and 2,270 controls) and was validated in a separate validation cohort of 313 subjects (203 patients with WD and 110 controls). The performance of immunoassay was tested by receiver operating characteristic curve (ROC) analysis, and differences among the groups were analyzed by using the Mann-Whitney U-test and the Kruskal-Wallis test. Results The conventional cutoff of serum ceruloplasmin levels of <0.2 g/L had an accuracy of 81.9%, which led to a false-positive rate of 30.5%. The optimal cutoff of the serum ceruloplasmin level for separating patients with WD from other participants was 0.13 g/L, as determined by ROC analysis. This cutoff value had the highest AUC value (0.99), a sensitivity of 97.0%, and a specificity of 96.1%. Moreover, it prevented unnecessary further investigations and treatments for 492 false-positive patients. By determining the correlation between serum ceruloplasmin and phenotypes/genotypes in patients with WD, we found that the serum ceruloplasmin level was lower in early-onset patients and higher in late-onset patients. Interestingly, patients with the R778L/R919G genotype had higher serum ceruloplasmin levels than patients with other hot spot mutation combinations. Conclusion Our work determined the optimal cutoff value of serum ceruloplasmin levels for the diagnosis of WD and identified differences in serum ceruloplasmin levels with respect to the age of symptom onset and ATP7B mutations, which may provide some valuable insights into the diagnosis and counsel of patients with WD.
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Affiliation(s)
- Yue Yang
- Department of Graduate, Anhui University of Chinese Medicine, Hefei, Anhui, China
| | - Wenjie Hao
- Department of Graduate, Anhui University of Chinese Medicine, Hefei, Anhui, China
| | - Taohua Wei
- Department of Neurology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui, China
| | - LuLu Tang
- Department of Neurology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui, China
| | - Nannan Qian
- Department of Neurology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui, China
| | - Yulong Yang
- Department of Graduate, Anhui University of Chinese Medicine, Hefei, Anhui, China
| | - Hu Xi
- Department of Graduate, Anhui University of Chinese Medicine, Hefei, Anhui, China
| | - Shijie Zhang
- Department of Neurology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui, China,Shijie Zhang
| | - Wenming Yang
- Department of Neurology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui, China,Xin'an Medical Education Ministry Key Laboratory, Hefei, Anhui, China,*Correspondence: Wenming Yang
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Durankuş F, Albayrak Y, Tokgöz Y, Beşer ÖF, Durankuş R, Çam S, Sünnetçi E, Akarsu Ö, Nural C, Erel Ö. Investigation of Thiol/Disulfide Homeostasis and Ischemia-Modified Albumin Levels in Children with Wilson Disease. Fetal Pediatr Pathol 2022; 41:576-583. [PMID: 33945395 DOI: 10.1080/15513815.2021.1918298] [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: 10/21/2022]
Abstract
BackgroundThe aim of the present study was to assess thiol/disulfide homeostasis (TDH) parameters and ischemia-modified albumin (IMA) levels in children with Wilson Disease (WD) and to compare them to healthy controls. Methods: Based on the inclusion and exclusion criteria, fifteen children with WD and twenty-nine healthy children were enrolled, and serum thiol/disulfide and IMA levels were compared between groups. Results: The mean values of native and total thiols were significantly lower in the WD group than in the control group. The mean value of disulfide was significantly higher in the WD group than in the control group. The mean percentages of disulfide/total thiol and native thiol/total thiol were higher in the WD group than in the control group. The IMA value was also higher in the WD group than in the control group. Conclusion: The present study demonstrating altered thiol/disulfide parameters indicates increased oxidative stress in children with WD.
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Affiliation(s)
- Ferit Durankuş
- Department of Pediatrics, Göztepe Education and Research Hospital, Istanbul Medeniyet University, İstanbul, Turkey
| | - Yakup Albayrak
- Faculty of Medicine, Department of Psychiatry, Tekirdağ Namık Kemal University, Tekirdağ, Turkey
| | - Yavuz Tokgöz
- Department of Pediatrics, Keçiören Education and Research Hospital, Health Sciences University, Ankara, Turkey
| | - Ömer Faruk Beşer
- Medical School, Department of Pediatric Gastroenterology, Cerrahpaşa University, İstanbul, Turkey
| | - Ramazan Durankuş
- Department of Pediatrics, Göztepe Education and Research Hospital, Istanbul Medeniyet University, İstanbul, Turkey
| | - Sebahat Çam
- Department of Pediatrics, Göztepe Education and Research Hospital, Istanbul Medeniyet University, İstanbul, Turkey
| | - Eda Sünnetçi
- Medical School, Department of Pediatrics, Acıbadem University, İstanbul, Turkey
| | - Ömer Akarsu
- Department of Microbiology, Göztepe Education and Research Hospital, Istanbul Medeniyet University, İstanbul, Turkey
| | - Cemil Nural
- Department of Clinical Biochemistry, Medical Faculty, Yildirim Beyazit University, Ankara, Turkey
| | - Özcan Erel
- Department of Clinical Biochemistry, Medical Faculty, Yildirim Beyazit University, Ankara, Turkey
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Comparative Proteomic Assessment of Normal vs. Polyhydramnios Amniotic Fluid Based on Computational Analysis. Biomedicines 2022; 10:biomedicines10081821. [PMID: 36009368 PMCID: PMC9404943 DOI: 10.3390/biomedicines10081821] [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: 06/08/2022] [Revised: 07/21/2022] [Accepted: 07/22/2022] [Indexed: 11/17/2022] Open
Abstract
Mass spectrometry-based proteomics have become a valued tool for conducting comprehensive analyses in amniotic fluid samples with pathologies. Our research interest is the finding and characterization of proteins related to normal vs. polyhydramnios (non-immune hydrops) pregnancy. Proteomic analysis was performed on proteins isolated from fresh amniotic fluid samples. Proteins were fractionated by 2DE using a different pI range (pI 3–11, pI 4–7) and analyzed with MALDI-TOF-MS. Furthermore, by using computational analysis, identified proteins in protein maps specific to normal vs. polyhydramnios pregnancy were compared and the quantities of expressed proteins were evaluated mathematically. Comparative analysis of proteome characteristic for the same polyhydramnios pregnancy fractionated by 2DE in different pI range (3–11 and 4–7) was performed and particular protein groups were evaluated for the quantification of changes within the same protein level. Proteins of normal and polyhydramnios pregnancies were fractionated by 2DE in pI range 3–11 and in pI range 4–7. Mass spectrometry analysis of proteins has revealed that the quantity changes of the main identified proteins in normal vs. polyhydramnios pregnancy could be assigned to immune response and inflammation proteins, cellular signaling and regulation proteins, metabolic proteins, etc. Specifically, we have identified and characterized proteins associated with heart function and circulatory system and proteins associated with abnormalities in prenatal medicine. The following are: serotransferrin, prothrombin, haptoglobin, transthyretin, alpha-1-antitrypsin, zinc-alpha-2-glycprotein, haptoglobin kininogen-1, hemopexin, clusterin, lumican, afamin, gelsolin. By using computational analysis, we demonstrated that some of these proteins increased a few times in pathological pregnancy. Computer assistance analysis of 2DE images suggested that, for the better isolation of the proteins’ isoforms, those levels increased/decreased in normal vs. polyhydramnios pregnancy, and the fractionation of proteins in pI rage 3–11 and 4–7 could be substantial. We analyzed and identified by MS proteins specific for normal and polyhydramnios pregnancies. Identified protein levels increased and/or modification changed in case of non-immune hydrops fetus and in cases of cardiovascular, anemia, growth restriction, and metabolic disorders. Computational analysis for proteomic characterization empower to estimate the quantitative changes of proteins specific for normal vs. polyhydramnios pregnancies.
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Shribman S, Marjot T, Sharif A, Vimalesvaran S, Ala A, Alexander G, Dhawan A, Dooley J, Gillett GT, Kelly D, McNeill A, Warner TT, Wheater V, Griffiths W, Bandmann O. Investigation and management of Wilson's disease: a practical guide from the British Association for the Study of the Liver. Lancet Gastroenterol Hepatol 2022; 7:560-575. [PMID: 35429442 DOI: 10.1016/s2468-1253(22)00004-8] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 01/04/2022] [Accepted: 01/05/2022] [Indexed: 02/07/2023]
Abstract
Wilson's disease is an autosomal-recessive disorder of copper metabolism with hepatic, neurological, psychiatric, ophthalmological, haematological, renal, and rheumatological manifestations. Making a diagnosis can be challenging given that no single test can confirm or exclude the disease, and diagnostic delays are common. Treatment protocols vary and adverse effects, including paradoxical neurological worsening, can occur. In this Review, we provide a practical guide to the diagnosis of Wilson's disease. We include recommendations on indications for testing, how to interpret results, and when additional investigations are required. We also cover treatment initiation, ideally under the guidance of a specialist centre for Wilson's disease, and the principles behind long-term management. This guidance was developed by a multidisciplinary group of Wilson's disease experts formed through the British Association for the Study of the Liver. The guidance has been endorsed by the British Society of Gastroenterology and approved by the Association of British Neurologists.
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Affiliation(s)
- Samuel Shribman
- Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, London, UK
| | - Thomas Marjot
- Oxford Liver Unit, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Abubakar Sharif
- Liver Unit, Birmingham Women and Children's Hospital, Birmingham, UK
| | - Sunitha Vimalesvaran
- Paediatric Liver, GI and Nutrition Centre and Mowat Labs, King's College Hospital, Denmark Hill, London, UK
| | - Aftab Ala
- Department of Gastroenterology and Hepatology, Royal Surrey NHS Foundation Trust, Guildford; Institute of Liver Studies, King's College Hospital, London, UK
| | - Graeme Alexander
- University College London Institute of Liver and Digestive Health, London, UK
| | - Anil Dhawan
- Paediatric Liver, GI and Nutrition Centre and Mowat Labs, King's College Hospital, Denmark Hill, London, UK
| | - James Dooley
- University College London Institute of Liver and Digestive Health, London, UK
| | - Godfrey T Gillett
- Laboratory Medicine, Northern General Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | - Deirdre Kelly
- Liver Unit, Birmingham Women and Children's Hospital, Birmingham, UK
| | | | - Thomas T Warner
- Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, London, UK
| | | | | | - Oliver Bandmann
- Sheffield Institute for Translational Neuroscience (SITraN), Department of Neuroscience, University of Sheffield, UK.
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Serum copper, ceruloplasmin, and their relations to metabolic factors in nonalcoholic fatty liver disease: a cross-sectional study. Eur J Gastroenterol Hepatol 2022; 34:443-448. [PMID: 34860704 DOI: 10.1097/meg.0000000000002325] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
OBJECTIVE Nonalcoholic fatty liver disease (NAFLD) characterized by excessive intrahepatic fat accumulation is increasing worldwide. This study aimed to investigate serum copper (Cu) and ceruloplasmin (Cer) levels and their relations to metabolic factors in NAFLD. METHODS This cross-sectional study was conducted on 141 subjects with NAFLD diagnosed using abdominal ultrasonography. Personal information, anthropometric measures, glucose and lipid profile, and serum levels of liver enzymes were assessed. Fasting serum levels of Cu and Cer were determined using colorimetry and nephelometry assay, respectively. Odds ratios (ORs) were used to examine the associations of serum Cu and Cer levels with NAFLD risk. RESULTS The results on 85 patients with NAFLD and 56 apparently healthy participants showed that all NAFLD cases and 53.6% of the healthy subjects were overweight or obese. More than half of the patients (58.8%) showed mild NAFLD. Age, weight, BMI, lipid profile, uric acid, and ferritin were significantly higher in NAFLD patients than the healthy cases. No significant differences were found in the concentrations of Cu and Cer between the groups. Only 7.4% of the healthy subjects and 2.4% of the patients were Cu deficient (<70 µg/dl). No association was found between the risk of NAFLD and serum Cu [OR: 0.994; 95% confidence interval (CI): 0.981-1.006] and Cer levels (OR: 0.414; 95% CI: 0.001-123.604) after adjusting for the confounders. CONCLUSION Our findings revealed no association between Cu deficiency and NAFLD risk. Further human studies with larger sample sizes are required to investigate how Cu and Cer status may affect NAFLD.
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Lu X, Li S, Zhang W, Lin Y, Lu Z, Cai Y, Su X, Shao Y, Liu Z, Sheng H, Huang Y, Liu L, Zeng C. Assessment of the diagnostic value of serum ceruloplasmin for Wilson's disease in children. BMC Gastroenterol 2022; 22:124. [PMID: 35296237 PMCID: PMC8928661 DOI: 10.1186/s12876-022-02186-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Accepted: 02/25/2022] [Indexed: 11/14/2022] Open
Abstract
Background Serum ceruloplasmin is one of the major diagnostic parameters for Wilson’s disease (WD). Age and gender difference of serum ceruloplasmin remain controversy. This study aims to assess diagnostic value of serum ceruloplasmin level for WD in children up to age of 15 years.
Methods Serum ceruloplasmin levels were measured in 317 WD patients, 21 heterozygotes, 372 healthy control children and 154 non-WD patients with other liver diseases. Receiver operating characteristic (ROC) curve was used to determine the diagnostic accuracy of serum ceruloplasmin for WD in children.
Results Among healthy controls, serum ceruloplasmin level was slightly low in the infants younger than 6 months, and then maintained from 26 to 33 mg/dl after age of 6 months. A total of 8.1% of healthy children had levels of serum ceruloplasmin < 20 mg/dL. Serum ceruloplasmin level was 5.7 ± 4.7 mg/dl in WD patients, and 25.6 ± 5.9 mg/dl in heterozygous carriers. Only 1.9% of WD patients had serum ceruloplasmin levels > 20 mg/dL. Serum ceruloplasmin levels had gender difference, being higher in healthy boys than healthy girls, and higher in asymptomatic WD boys than asymptomatic WD girls (p < 0.01, p < 0.05). Serum ceruloplasmin levels also presented genotypic difference. WD patients with R778L homozygotes exhibited lower levels of serum ceruloplasmin than the patients without R778L (p < 0.05). The ROC curve revealed that serum ceruloplasmin level, at a cutoff value of 16.8 mg/dL, had the highest AUC value (0.990) with a sensitivity of 95.9% and a specificity of 93.6%. Conclusions Serum ceruloplasmin is one of sensitive diagnostic biomarkers for WD in children. Gender and genotypic difference of serum ceruloplasmin level should be considered. The cutoff value of serum ceruloplasmin level < 16.8 mg/dL may provide the highest accuracy for diagnosis of WD in children. Supplementary Information The online version contains supplementary material available at 10.1186/s12876-022-02186-0.
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Affiliation(s)
- Xinshuo Lu
- Department of Genetics and Endocrinology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 9 Jinsui Rd, Guangzhou, 510623, China
| | - Simin Li
- Department of Genetics and Endocrinology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 9 Jinsui Rd, Guangzhou, 510623, China
| | - Wen Zhang
- Department of Genetics and Endocrinology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 9 Jinsui Rd, Guangzhou, 510623, China
| | - Yunting Lin
- Department of Genetics and Endocrinology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 9 Jinsui Rd, Guangzhou, 510623, China
| | - Zhikun Lu
- Department of Genetics and Endocrinology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 9 Jinsui Rd, Guangzhou, 510623, China
| | - Yanna Cai
- Department of Genetics and Endocrinology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 9 Jinsui Rd, Guangzhou, 510623, China
| | - Xueying Su
- Department of Genetics and Endocrinology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 9 Jinsui Rd, Guangzhou, 510623, China
| | - Yongxian Shao
- Department of Genetics and Endocrinology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 9 Jinsui Rd, Guangzhou, 510623, China
| | - Zongcai Liu
- Department of Genetics and Endocrinology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 9 Jinsui Rd, Guangzhou, 510623, China
| | - Huiying Sheng
- Department of Genetics and Endocrinology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 9 Jinsui Rd, Guangzhou, 510623, China
| | - Yonglan Huang
- Department of Genetics and Endocrinology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 9 Jinsui Rd, Guangzhou, 510623, China
| | - Li Liu
- Department of Genetics and Endocrinology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 9 Jinsui Rd, Guangzhou, 510623, China.
| | - Chunhua Zeng
- Department of Genetics and Endocrinology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 9 Jinsui Rd, Guangzhou, 510623, China.
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Abstract
Wilson disease (WD) is an autosomal recessive disorder caused by mutations of the ATP7B gene, with a reported prevalence of 1:30,000-50,000. ATP7B encodes an enzyme called transmembrane copper-transporting ATPase, which is essential for copper incorporation into ceruloplasmin and for copper excretion into the bile. A lack or dysfunction of this enzyme results in a progressive accumulation of copper in several organs, especially in the liver, the nervous system, corneas, kidneys, and heart. Children with WD can present with asymptomatic liver disease, cirrhosis, or acute liver failure, with or without neurological and psychiatric symptoms. Approximately 20%-30% of WD patients present with ALF, while most of the other patients have chronic progressive hepatitis or cirrhosis if untreated. Although genetic testing has become a more important diagnostic tool for WD, the diagnosis remains based on both clinical features and laboratory investigations. The aims of treatment are to reduce copper levels and prevent its accumulation in the liver and other organs, especially in the central nervous system. Liver transplantation in WD is a life-saving option for patients presenting with liver failure and encephalopathy. For WD patients treated with chelating agents, adherence to the therapy is essential for long-term success. In this review, we also address specific issues in young adults as compared to children.
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Affiliation(s)
- Atchariya Chanpong
- Paediatric Liver, GI and Nutrition Centre, MowatLabs, King's College Hospital, Denmark Hill, London, United Kingdom,Division of Gastroenterology and Hepatology, Department of Pediatrics, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand
| | - Anil Dhawan
- Paediatric Liver, GI and Nutrition Centre, MowatLabs, King's College Hospital, Denmark Hill, London, United Kingdom,Address for correspondence: Prof. Anil Dhawan, Paediatric Liver, GI and Nutrition Centre, MowatLabs, King's College Hospital, Denmark Hill, London SE5 9RH, United Kingdom. E-mail:
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Feng CX, Chen XQ, He XL, Lan LC, Tang Q, Huang L, Shan QW. Screening for Wilson's disease in acute liver failure: A new scoring system in children. Front Pediatr 2022; 10:1003887. [PMID: 36210929 PMCID: PMC9534029 DOI: 10.3389/fped.2022.1003887] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 09/02/2022] [Indexed: 11/20/2022] Open
Abstract
BACKGROUND Wilson's disease (WD) is a rare cause of acute liver failure (ALF) and has a high fatality rate. Rapid and accurate diagnosis is important for ALF because of WD (ALF-WD). Our objective was to establish a simple, rapid, and accurate diagnostic test to distinguish ALF-WD from non-WD ALF (NWDALF) in children. MATERIALS AND METHODS The data from all cases with pediatric ALF were retrospectively collected and analyzed. We performed receiver operator characteristics curve (ROC) analysis and confirmed the optimum cut-off points. RESULTS Fifty-eight patients with pediatric ALF (12 with WD, 46 with other etiologies) were included. Older age was observed in ALF-WD compared to NWDALF (11.16 ± 2.51 years vs. 3.34 ± 3.81 years, p < 0.001). An analysis based on routine biochemical testings revealed that total bilirubin (TBil), direct bilirubin, indirect bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), AST:ALT ratio, alkaline phosphatase (ALP), ALP:TBil ratio, serum albumin, gamma-glutamyl transferase, cholinesterase, hemoglobin, and platelet were statistically significant between the ALF-WD and NWDALF groups. The optimum cut-off points were obtained through ROC analysis. A scoring system was formed by assigning a score of 1 or 0 to patients who met the 13 cut-off points. Using ROC analysis, we determined a cut-off point of ≥ 6.5 for ALF-WD with 91.7% sensitivity and 97.8% specificity (p < 0.0001). In addition, a best cut-off point of ≥ 1.5 based on only five variables (ALT, AST, AST:ALT ratio, ALP, and ALP:TBil ratio), had 100% sensitivity and 91.3% specificity for ALF-WD (p < 0.0001). Based on this, when age was calculated as the sixth indicator, the best cut-off value of ≥ 2.5 had 100% sensitivity and 97.8% specificity (p < 00.0001). CONCLUSION Our study developed a new scoring system that consists of simple laboratory tests with good sensitivity and specificity and can be used by clinicians to quickly distinguish ALF-WD from NWDALF in children.
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Affiliation(s)
- Cai-Xia Feng
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Xiu-Qi Chen
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Xiao-Li He
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Lian-Cheng Lan
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Qing Tang
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Li Huang
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Qing-Wen Shan
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
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Salman HM, Amin M, Syed J, Sarfraz Z, Sarfraz A, Sarfraz M, Farfán Bajaña MJ, Felix M, Cherrez-Ojeda I. Biochemical testing for the diagnosis of Wilson's disease: A systematic review. J Clin Lab Anal 2021; 36:e24191. [PMID: 34951059 PMCID: PMC8842170 DOI: 10.1002/jcla.24191] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 12/08/2021] [Accepted: 12/08/2021] [Indexed: 11/28/2022] Open
Abstract
Background Wilson's disease (WD) is a rare inherited disorder that leads to copper accumulation in the liver, brain, and other organs. WD is prevalent worldwide, with an occurrence of 1 per 30,000 live births. Currently, there is no gold standard diagnostic test for WD. The objective of this systematic review is to determine the diagnostic accuracy for WD of three biochemical tests, namely hepatic copper, 24‐hour urinary copper, and ceruloplasmin using the Leipzig criteria. Methods Adhering to PRISMA guidelines, databases including PubMed/MEDLINE, CINAHL Plus, Web of Science, and Cochrane were searched. Studies that comprised of confirmed or suspected WD along with normal populations were included with adult and pediatric group. The sensitivity, specificity, negative predictive value and positive predictive value were computed using RevMan 5.4. Results Nine studies were included. The best practice evidence for 24‐hour urinary copper test ranged from a cutoff value of 0.64–1.6 μmol/24 h (N = 268; sensitivity = 75.6%, specificity = 98.3%). Hepatic copper test was optimally cutoff based on the ROC curve analysis at 1.2 μmol/g yielding a power of 96.4% sensitivity and 95.4% specificity (N = 1,150); however, the tried and tested 4 μmol/g cutoff, with 99.4% sensitivity and 96.1% specificity, is more widely accepted. The ceruloplasmin test cutoff value was found to be ranging from 0.14 to 0.2 g/L (N = 4,281; sensitivity = 77.1%–99%, specificity = 55.9%–82.8%). Conclusion This paper provides a large‐scale analysis of current evidence pertaining to the biochemical diagnosis of WD employing the Leipzig criteria. The laboratory values are typically based on specific subgroups based on age, ethnicity, and clinical subgroups. The findings of this systematic review must be used with caution, given the over‐ or under‐estimation of the index tests.
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Affiliation(s)
| | - Mahwish Amin
- Sir Ganga Ram Hospital, Lahore, Punjab, Pakistan
| | | | | | | | | | - Maria Jose Farfán Bajaña
- Universidad Espíritu Santo, Samborondón, Ecuador.,Respiralab, Respiralab Research Group, Guayaquil, Ecuador
| | - Miguel Felix
- Universidad Espíritu Santo, Samborondón, Ecuador.,Respiralab, Respiralab Research Group, Guayaquil, Ecuador
| | - Ivan Cherrez-Ojeda
- Universidad Espíritu Santo, Samborondón, Ecuador.,Respiralab, Respiralab Research Group, Guayaquil, Ecuador
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26
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Lam CW. Ending diagnostic odyssey using clinical whole-exome sequencing (CWES). J LAB MED 2021. [DOI: 10.1515/labmed-2021-0127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Abstract
Objectives
Most rare diseases are genetic diseases. Due to the diversity of rare diseases and the high likelihood of patients with rare diseases to be undiagnosed or misdiagnosed, it is not unusual that these patients undergo a long diagnostic odyssey before they receive a definitive diagnosis. This situation presents a clear need to set up a dedicated clinical service to end the diagnostic odyssey of patients with rare diseases.
Methods
Therefore, in 2014, we started an Undiagnosed Diseases Program in Hong Kong with the aim of ending the diagnostic odyssey of patients and families with rare diseases by clinical whole-exome sequencing (CWES), who have not received a definitive diagnosis after extensive investigation.
Results
In this program, we have shown that genetic diseases diagnosed by CWES were different from that using traditional approaches indicating that CWES is an essential tool to diagnose rare diseases and ending diagnostic odysseys. In addition, we identified several novel genes responsible for monogenic diseases. These include the TOP2B gene for autism spectrum disorder, the DTYMK gene for severe cerebral atrophy, the KIF13A gene for a new mosaic ectodermal syndrome associated with hypomelanosis of Ito, and the CDC25B gene for a new syndrome of cardiomyopathy and endocrinopathy.
Conclusions
With the incorporation of CWES in an Undiagnosed Diseases Program, we have ended diagnostic odysseys of patients with rare diseases in Hong Kong in the past 7 years. In this program, we have shown that CWES is an essential tool to end diagnostic odysseys. With the declining cost of next-generation sequencers and reagents, CWES set-ups are now affordable for clinical laboratories. Indeed, owing to the increasing availability of CWES and treatment modalities for rare diseases, precedence can be given to both common and rare medical conditions.
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Affiliation(s)
- Ching-Wan Lam
- Department of Pathology , The University of Hong Kong , Hong Kong , P.R. China
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Fang WY, Abuduxikuer K, Shi P, Qiu YL, Zhao J, Li YC, Zhang XY, Wang NL, Xie XB, Lu Y, Knisely AS, Wang JS. Pediatric Wilson disease presenting as acute liver failure: Prognostic indices. World J Clin Cases 2021; 9:3273-3286. [PMID: 34002136 PMCID: PMC8107887 DOI: 10.12998/wjcc.v9.i14.3273] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 02/28/2021] [Accepted: 03/17/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Acute liver failure (ALF) can be a primary presentation of Wilson disease (WD). Mortality rates are high in WD with ALF (WDALF). Predictions of mortality in WDALF vary by model and are sometimes contradictory, perhaps because few patients are studied or WD diagnoses are questionable.
AIM To determine the outcomes among well-documented WDALF patients and assess mortality model performance in this cohort.
METHODS We reviewed the medical records of our pediatric WDALF patients (n = 41 over 6-years-old, single-center retrospective study) and compared seven prognostic models (King’s College Hospital Criteria, model for end-stage liver disease/pediatric end-stage liver disease scoring systems, Liver Injury Unit [LIU] using prothrombin time [PT] or international normalized ratio [INR], admission LIU using PT or INR, and Devarbhavi model) with one another.
RESULTS Among the 41 Han Chinese patients with ALF, WD was established by demonstrating ATP7B variants in 36. In 5 others, Kayser-Fleischer rings and Coombs-negative hemolytic anemia permitted diagnosis. Three died during hospitalization and three underwent liver transplantation (LT) within 1 mo of presentation and survived (7.3% each); 35 (85.4%) survived without LT when given enteral D-penicillamine and zinc-salt therapy with or without urgent plasmapheresis. Parameters significantly correlated with mortality included encephalopathy, coagulopathy, and gamma-glutamyl transpeptidase activity, bilirubin, ammonia, and serum sodium levels. Area under the receiver operating curves varied among seven prognostic models from 0.981 to 0.748 with positive predictive values from 0.214 to 0.429.
CONCLUSION WDALF children can survive and recover without LT when given D-penicillamine and Zn with or without plasmapheresis, even after enlisting for LT.
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Affiliation(s)
- Wei-Yuan Fang
- Center for Pediatric Liver Diseases, Children’s Hospital of Fudan University, Shanghai 201102, China
| | - Kuerbanjiang Abuduxikuer
- Center for Pediatric Liver Diseases, Children’s Hospital of Fudan University, Shanghai 201102, China
| | - Peng Shi
- Medical Statistics Department, Children’s Hospital of Fudan University, Shanghai 201102, China
| | - Yi-Ling Qiu
- Center for Pediatric Liver Diseases, Children’s Hospital of Fudan University, Shanghai 201102, China
| | - Jing Zhao
- Center for Pediatric Liver Diseases, Children’s Hospital of Fudan University, Shanghai 201102, China
| | - Yu-Chuan Li
- Center for Pediatric Liver Diseases, Children’s Hospital of Fudan University, Shanghai 201102, China
| | - Xue-Yuan Zhang
- Center for Pediatric Liver Diseases, Children’s Hospital of Fudan University, Shanghai 201102, China
| | - Neng-Li Wang
- Center for Pediatric Liver Diseases, Children’s Hospital of Fudan University, Shanghai 201102, China
| | - Xin-Bao Xie
- Center for Pediatric Liver Diseases, Children’s Hospital of Fudan University, Shanghai 201102, China
| | - Yi Lu
- Center for Pediatric Liver Diseases, Children’s Hospital of Fudan University, Shanghai 201102, China
| | - A S Knisely
- Institut für Pathologie, Medizinische Universität Graz, Graz 8010, Austria
| | - Jian-She Wang
- Center for Pediatric Liver Diseases, Children’s Hospital of Fudan University, Shanghai 201102, China
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García-Villarreal L, Hernández-Ortega A, Sánchez-Monteagudo A, Peña-Quintana L, Ramírez-Lorenzo T, Riaño M, Moreno-Pérez R, Monescillo A, González-Santana D, Quiñones I, Sánchez-Villegas A, Olmo-Quintana V, Garay-Sánchez P, Espinós C, González JM, Tugores A. Wilson disease: revision of diagnostic criteria in a clinical series with great genetic homogeneity. J Gastroenterol 2021; 56:78-89. [PMID: 33159804 DOI: 10.1007/s00535-020-01745-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 10/24/2020] [Indexed: 02/04/2023]
Abstract
BACKGROUND Wilson disease is an autosomal recessive disorder of copper metabolism caused by mutations in the ATP7B gene. An early diagnosis is crucial to prevent evolution of the disease, as implantation of early therapeutic measures fully prevents its symptoms. As population genetics data predict a higher than initially expected prevalence, it was important to define the basic diagnostic tools to approach population screening. METHODS A highly genetically homogeneous cohort of 70 patients, belonging to 50 unrelated families, has been selected as a framework to analyze all their clinical, biochemical and genetic characteristics, to define the disease in our population, with an estimated prevalence of 1 in 12,369, and determine the most useful features that reach diagnostic value. RESULTS Serum ceruloplasmin below 11.5 mg/dL and cupremia below 60 μg/mL, were the best analytical predictors of the disease in asymptomatic individuals, while cupruria or hepatic copper determination were less powerful. Genetic analysis reached a conclusive diagnosis in all 65 patients available for complete testing. Of them, 48 were carriers of at least one p.Leu708Pro mutant allele, with 24 homozygotes. Nine patients carried a promoter deletion mutation, revealing that extended sequencing beyond the ATP7B gene-coding region is essential. All mutations caused hepatic damage since early ages, increasing its severity as diagnosis was delayed, and neurological symptoms appear. CONCLUSION Serum ceruloplasmin determination followed by genetic screening would reduce costs and favor the prioritization of non-invasive procedures to reach a definitive diagnosis, even for asymptomatic cases.
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Affiliation(s)
- Luis García-Villarreal
- Unidad de Investigación, Complejo Hospitalario Universitario Insular Materno-Infantil, Avda Maritima del Sur, s/n, 35016, Las Palmas de Gran Canaria, Spain
| | - Andrea Hernández-Ortega
- Unidad de Gastroenterología, Hepatología y Nutrición Pediátrica, Complejo Hospitalario Universitario Insular Materno-Infantil, Las Palmas de Gran Canaria, Spain
| | - Ana Sánchez-Monteagudo
- Unit of Genetics and Genomics of Neuromuscular and Neurodegenerative Disorders, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain
| | - Luis Peña-Quintana
- Unidad de Gastroenterología, Hepatología y Nutrición Pediátrica, Complejo Hospitalario Universitario Insular Materno-Infantil, Las Palmas de Gran Canaria, Spain.,Asociación Canaria Para Investigación Pediátrica. Centro de Investigación Biomédica en Red, Fisiopatología de La Obesidad y Nutrición (CIBER OBN), Instituto Universitario de Investigación en Ciencias Biomédicas y Sanitarias (IUIBS), Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain
| | - Teresa Ramírez-Lorenzo
- Unidad de Investigación, Complejo Hospitalario Universitario Insular Materno-Infantil, Avda Maritima del Sur, s/n, 35016, Las Palmas de Gran Canaria, Spain
| | - Marta Riaño
- Department of Clinical Biochemistry and Clinical Analyses, Complejo Hospitalario Universitario Insular Materno-Infantil, Las Palmas de Gran Canaria, Spain
| | | | - Alberto Monescillo
- Department of Gastroenterology, Complejo Hospitalario Universitario Insular Materno-Infantil, Las Palmas de Gran Canaria, Spain
| | - Daniel González-Santana
- Unidad de Gastroenterología, Hepatología y Nutrición Pediátrica, Complejo Hospitalario Universitario Insular Materno-Infantil, Las Palmas de Gran Canaria, Spain
| | - Ildefonso Quiñones
- Department of Gastroenterology. Hospital, Universitario Dr Negrín, Las Palmas de Gran Canaria, Spain
| | - Almudena Sánchez-Villegas
- Department of Public Health, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain
| | | | - Paloma Garay-Sánchez
- Unidad de Investigación, Complejo Hospitalario Universitario Insular Materno-Infantil, Avda Maritima del Sur, s/n, 35016, Las Palmas de Gran Canaria, Spain
| | - Carmen Espinós
- Unit of Genetics and Genomics of Neuromuscular and Neurodegenerative Disorders, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain
| | - Jesús M González
- Unidad de Investigación, Complejo Hospitalario Universitario Insular Materno-Infantil, Avda Maritima del Sur, s/n, 35016, Las Palmas de Gran Canaria, Spain
| | - Antonio Tugores
- Unidad de Investigación, Complejo Hospitalario Universitario Insular Materno-Infantil, Avda Maritima del Sur, s/n, 35016, Las Palmas de Gran Canaria, Spain.
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Wilson disease: 30-year data on epidemiology, clinical presentation, treatment modalities and disease outcomes from two tertiary Greek centers. Eur J Gastroenterol Hepatol 2020; 32:1545-1552. [PMID: 32118851 DOI: 10.1097/meg.0000000000001670] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
OBJECTIVE Wilson disease is a rare genetic disorder of copper metabolism with a wide range of clinical presentations. The aim of this study is to describe the 30-year clinical experience in the management of Wilson disease patients followed at two Greek referral centers. METHODS A retrospective chart review was performed to identify past and present Wilson disease patients diagnosed during the last 30 years. RESULTS Sixty-three patients were included. The median age of diagnosis was 19 (3-59) years, while nine (14%) patients were older than 40 years old. Clinical presentation included asymptomatic liver disease (57.1%), neurological disease (20.6%), overt liver disease (12.7%), acute liver failure (6.3%) and other (3.2%). Kayser-Fleischer rings were detected in 27/62 with a higher frequency in neurologic patients (P < 0.001). Ceruloplasmin values were low in 55/63 with significantly lower values in patients with neurological disease (P = 0.048) and in cirrhotic patients (P = 0.017). Increased 24-hour urine copper was measured in 59/63 patients. D-penicillamine was administered in 56/63 patients (88.8%), followed by trientine (6/63, 9.5%), while one patient needed liver transplantation at baseline. At least one treatment switch was performed in 18 patients. By the end of follow-up, all non-cirrhotic patients (25/25) were stable, 3/23 (13%) cirrhotic developed decompensated liver disease, two developed HCC, three received a liver transplant and two died. Five out of 13 neurologic patients had persisting symptoms despite treatment. CONCLUSION Wilson disease presents with a wide spectrum of clinical manifestations and should be investigated even in older patients, as early diagnosis, close follow-up and treatment monitoring usually provide favorable outcomes.
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Caplan DN, Rapalino O, Karaa A, Rosovsky RP, Uljon S. Case 35-2020: A 59-Year-Old Woman with Type 1 Diabetes Mellitus and Obtundation. N Engl J Med 2020; 383:1974-1983. [PMID: 33176089 DOI: 10.1056/nejmcpc2002412] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Affiliation(s)
- David N Caplan
- From the Departments of Neurology (D.N.C.), Radiology (O.R.), Pediatrics (A.K.), Medicine (R.P.R.), and Pathology (S.U.), Massachusetts General Hospital, and the Departments of Neurology (D.N.C.), Radiology (O.R.), Pediatrics (A.K.), Medicine (R.P.R.), and Pathology (S.U.), Harvard Medical School - both in Boston
| | - Otto Rapalino
- From the Departments of Neurology (D.N.C.), Radiology (O.R.), Pediatrics (A.K.), Medicine (R.P.R.), and Pathology (S.U.), Massachusetts General Hospital, and the Departments of Neurology (D.N.C.), Radiology (O.R.), Pediatrics (A.K.), Medicine (R.P.R.), and Pathology (S.U.), Harvard Medical School - both in Boston
| | - Amel Karaa
- From the Departments of Neurology (D.N.C.), Radiology (O.R.), Pediatrics (A.K.), Medicine (R.P.R.), and Pathology (S.U.), Massachusetts General Hospital, and the Departments of Neurology (D.N.C.), Radiology (O.R.), Pediatrics (A.K.), Medicine (R.P.R.), and Pathology (S.U.), Harvard Medical School - both in Boston
| | - Rachel P Rosovsky
- From the Departments of Neurology (D.N.C.), Radiology (O.R.), Pediatrics (A.K.), Medicine (R.P.R.), and Pathology (S.U.), Massachusetts General Hospital, and the Departments of Neurology (D.N.C.), Radiology (O.R.), Pediatrics (A.K.), Medicine (R.P.R.), and Pathology (S.U.), Harvard Medical School - both in Boston
| | - Sacha Uljon
- From the Departments of Neurology (D.N.C.), Radiology (O.R.), Pediatrics (A.K.), Medicine (R.P.R.), and Pathology (S.U.), Massachusetts General Hospital, and the Departments of Neurology (D.N.C.), Radiology (O.R.), Pediatrics (A.K.), Medicine (R.P.R.), and Pathology (S.U.), Harvard Medical School - both in Boston
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31
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Linking molecular targets of Cd in the bloodstream to organ-based adverse health effects. J Inorg Biochem 2020; 216:111279. [PMID: 33413916 DOI: 10.1016/j.jinorgbio.2020.111279] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 10/05/2020] [Accepted: 10/05/2020] [Indexed: 12/25/2022]
Abstract
The chronic exposure of human populations to toxic metals remains a global public health concern. Although chronic Cd exposure is linked to kidney damage, osteoporosis and cancer, the underlying biomolecular mechanisms remain incompletely understood. Since other diseases could also be causally linked to chronic Cd exposure, a systems toxicology-based approach is needed to gain new insight into the underlying exposure-disease relationship. This approach requires one to integrate the cascade of dynamic bioinorganic chemistry events that unfold in the bloodstream after Cd enters with toxicological events that unfold in target organs over time. To this end, we have conducted a systematic literature search to identify all molecular targets of Cd in plasma and in red blood cells (RBCs). Based on this information it is impossible to describe the metabolism of Cd and the toxicological relevance of it binding to molecular targets in/on RBCs is elusive. Perhaps most importantly, the role that peptides, amino acids and inorganic ions, including HCO3-, Cl- and HSeO3- play in terms of mediating the translocation of Cd to target organs and its detoxification is poorly understood. Causally linking human exposure to this metal with diseases requires a much better integration of the bioinorganic chemistry of Cd that unfolds in the bloodstream with target organs. This from a public health point of view important goal will require collaborations between scientists from different disciplines to untangle the complex mechanisms which causally link Cd exposure to disease.
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Diouf I, Bush AI, Ayton S. Cerebrospinal fluid ceruloplasmin levels predict cognitive decline and brain atrophy in people with underlying β-amyloid pathology. Neurobiol Dis 2020; 139:104810. [PMID: 32087292 PMCID: PMC7150625 DOI: 10.1016/j.nbd.2020.104810] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Revised: 02/03/2020] [Accepted: 02/18/2020] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVES The mechanisms leading to neurodegeneration in Alzheimer's disease (AD) may involve oxidative stress and neuroinflammation. Ceruloplasmin (Cp) is a circulating protein that intersects both these pathways, since its expression is increased during the acute phase response, and the protein acts to lower pro-oxidant iron in cells. Since the role of Cp in AD, and its potential for use as a biomarker is not established, we investigated CSF Cp and its association with longitudinal outcome measures related to AD. METHODS This was an observational study of 268 people from the Alzheimer's Disease Neuroimaging (ADNI) cohort. Subjects were classified clinically as having AD, mild cognitive impairment (MCI) or were cognitively normal (CN), and were also classified as being positive for β-amyloid using established thresholds in the CSF t-tau/Aβ42 ratio. Subjects underwent cognitive tests and MRI studies every 6 months for 2 years, then yearly thereafter for up to 6 years. RESULTS At baseline, CSF Cp was not associated with clinical or pathological diagnosis, but we found an unexpected association between CSF Cp and levels of CSF apolipoprotein E. In longitudinal analysis, high level of CSF Cp was associated with accelerated cognitive decline (as assessed by ADAS-Cog, CDR-SB, and MMSE) and ventricular volume enlargement in people classified as MCI and who had underlying β-amyloid pathology. CONCLUSION These results raise new questions into the role of Cp in neuroinflammation, oxidative stress, and APOE pathways involved in AD, and reveal the potential for this protein to be used as a biomarker in disease prognostication.
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Affiliation(s)
- Ibrahima Diouf
- Melbourne Dementia Research Centre, The Florey Institute for Neuroscience and Mental Health, The University of Melbourne, Victoria, Australia; CSIRO Health and Biosecurity/Australian E-Health Research Centre, Brisbane, Australia
| | - Ashley I Bush
- Melbourne Dementia Research Centre, The Florey Institute for Neuroscience and Mental Health, The University of Melbourne, Victoria, Australia
| | - Scott Ayton
- Melbourne Dementia Research Centre, The Florey Institute for Neuroscience and Mental Health, The University of Melbourne, Victoria, Australia.
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Fernando M, van Mourik I, Wassmer E, Kelly D. Wilson disease in children and adolescents. Arch Dis Child 2020; 105:499-505. [PMID: 31974298 DOI: 10.1136/archdischild-2018-315705] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Revised: 12/18/2019] [Accepted: 12/19/2019] [Indexed: 12/13/2022]
Abstract
Wilson disease (WD) is a rare, recessively inherited disorder of copper metabolism mainly affecting liver and brain. In childhood, it is known to have a predominant hepatic phenotype. It is likely that the low awareness for WD-associated neuropsychiatric signs and symptoms in this age group means that neurological Wilson's disease is underdiagnosed in children and young people. Practitioners should be alert for this complication in children with or without liver disease. Management of children with WD requires a dedicated multidisciplinary approach involving hepatologists, geneticists, neurologists and psychiatrists to ensure subtle neuropsychiatric symptoms are identified early and addressed appropriately. This review highlights recent advances in hepatic and neuropsychiatric symptoms of WD in childhood, specific diagnostic tools and pitfalls and summarises existing and potential future treatment options.
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Affiliation(s)
- Meranthi Fernando
- Liver Unit, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, West Midlands, UK
| | - Indra van Mourik
- Liver Unit, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, West Midlands, UK
| | - Evangeline Wassmer
- Department of Neurology, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, West Midlands, UK
| | - Deirdre Kelly
- Liver Unit, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, West Midlands, UK
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Güngör Ş, Selimoğlu MA, Bağ HGG, Varol FI. Is it possible to diagnose fulminant Wilson's disease with simple laboratory tests? Liver Int 2020; 40:155-162. [PMID: 31568639 DOI: 10.1111/liv.14263] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 08/20/2019] [Accepted: 09/16/2019] [Indexed: 12/26/2022]
Abstract
BACKGROUND Wilson's disease is a rare cause of acute liver failure and is highly fatal without liver transplantation. Fast and accurate diagnostic methods are needed for fulminant Wilson's disease (FWD). In this study, we aimed to develop an early, simple and accurate diagnostic method to differentiate FWD from nonwilsonian acute liver failure (NWALF) causes using routine biochemical data. METHODS The medical records of 24 paediatric FWD and 120 paediatric NWALF cases diagnosed at the Department of Pediatric Gastroenterology, Hepatology, and Nutrition between January 2007 and February 2017 were retrospectively reviewed. RESULTS Using receiver operator characteristics curve (ROC) analysis, we have determined the best cut-off point for laboratory findings in FWD. Patients meeting these cut-off points were assigned one point and others were assigned zero point. We then formed a new variable consisting of the combination of 14 variables and performed a new ROC analysis. We obtained a cut-off point of ≥4.5 for FWD. The diagnostic performance of the score was characterized by a sensitivity of 0.889, a specificity of 0.879 (P < .001). A scoring system based only on aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, AST/ALT ratio, uric acid and haemoglobin had a best cut-off point of ≥2.5 for FWD, which had a sensitivity of 0.875, a specificity of 0.867 (P < .001). CONCLUSIONS Our study demonstrated that biochemical markers offer almost as reliable, fast and accurate diagnosis of FWD as offered by ceruloplasmin and 24-hour urinary copper.
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Affiliation(s)
- Şükrü Güngör
- Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Faculty of Medicine, İnönü University, Malatya, Turkey
| | - Mukadder A Selimoğlu
- Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Faculty of Medicine, İnönü University, Malatya, Turkey
| | - Harika G G Bağ
- Department of Biostatistics and Medical Information, Faculty of Medicine, İnönü University, Malatya, Turkey
| | - Fatma I Varol
- Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Faculty of Medicine, İnönü University, Malatya, Turkey
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Ryan A, Nevitt SJ, Tuohy O, Cook P, Cochrane Cystic Fibrosis and Genetic Disorders Group. Biomarkers for diagnosis of Wilson's disease. Cochrane Database Syst Rev 2019; 2019:CD012267. [PMID: 31743430 PMCID: PMC6953362 DOI: 10.1002/14651858.cd012267.pub2] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Wilson's disease, first described by Samuel Wilson in 1912, is an autosomal recessive metabolic disorder resulting from mutations in the ATP7B gene. The disease develops as a consequence of copper accumulating in affected tissues. There is no gold standard for the diagnosis of Wilson's disease, which is often delayed due to the non-specific clinical features and the need for a combination of clinical and laboratory tests for diagnosis. This delay may in turn affect clinical outcome and has implications for other family members in terms of diagnosis. The Leipzig criteria were established to help standardise diagnosis and management. However, it should be emphasised that these criteria date from 2003, and many of these have not been formally evaluated; this review examines the evidence behind biochemical testing for Wilson's disease. OBJECTIVES To determine the diagnostic accuracy of three biochemical tests at specified cut-off levels for Wilson's disease. The index tests covered by this Cochrane Review are caeruloplasmin, 24-hour urinary copper and hepatic copper content. These tests were evaluated in those with suspected Wilson's disease and appropriate controls (either healthy or those with chronic liver disease other than Wilson's). In the absence of a gold standard for diagnosing Wilson's disease, we have used the Leipzig criteria as a clinical reference standard. To investigate whether index tests should be performed in all individuals who have been recommended for testing for Wilson's disease, or whether these tests should be limited to subgroups of individuals. SEARCH METHODS We identified studies by extensive searching of, e.g. the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Embase, the Web of Science and clinical trial registries (29 May 2019). Date of the most recent search of the Cochrane Cystic Fibrosis and Genetic Disorders Inborn Errors of Metabolism Register: 29 May 2019. SELECTION CRITERIA We included prospective and retrospective cohort studies that assessed the diagnostic accuracy of an index test using the Leipzig criteria as a clinical reference standard for the diagnosis of Wilson's disease. DATA COLLECTION AND ANALYSIS Two review authors independently reviewed and extracted data and assessed the methodological quality of each included study using the QUADAS-2 tool. We had planned to undertake meta-analyses of the sensitivity, specificity at relevant cut-offs for each of the biochemical tests for Wilson's, however, due to differences in the methods used for each biochemical index test, it was not possible to combine the results in meta-analyses and hence these are described narratively. MAIN RESULTS Eight studies, involving 5699 participants (which included 1009 diagnosed with Wilson's disease) were eligible for inclusion in the review. Three studies involved children only, one adults only and the four remaining studies involved both children and adults. Two evaluated participants with hepatic signs and six with a combination of hepatic and neurological signs and symptoms of Wilson's disease, as well as pre-symptomatic individuals. The studies were of variable methodological quality; with high risk if bias for participant selection and the reference standard used being of greatest methodological concern. Key differences between studies include differences in assay methodology, different cut-off values for diagnostic thresholds, different age and ethnicity groups. Concerns around study design imply that diagnostic accuracy figures may not transfer to populations outside of the relevant study. INDEX TEST caeruloplasmin Five studies evaluated various thresholds of caeruloplasmin (4281 participants, of which 541 had WD). For caeruloplasmin a cut-off of 0.2 g/L as in the Leipzig criteria achieved a sensitivity of 77.1% to 99%, with variable specificity of 55.9% to 82.8%. Using the cut-off of 0.1 g/L of the Leipzig criteria seemed to lower the sensitivity overall, 65% to 78.9%, while increasing the specificity to 96.6% to 100%. INDEX TEST hepatic copper Four studies evaluated various thresholds of hepatic copper (1150 participants, of which 367 had WD). The hepatic copper cut-off of 4 μmol/g used in the Leipzig criteria achieved a sensitivity of 65.7% to 94.4%, with a variable specificity of 52.2% to 98.6%. INDEX TEST 24-hour urinary copper Three studies evaluated various thresholds of 24-hour urinary copper (268 participants, of which 101 had WD). For 24-hour urinary copper, a cut-off of 0.64 to 1.6 μmol/24 hours used in the Leipzig criteria achieved a variable sensitivity of 50.0% to 80.0%, with a specificity of 75.6% to 98.3%. AUTHORS' CONCLUSIONS The cut-offs used for caeruloplasmin, 24-hour urinary copper and hepatic copper for diagnosing Wilson's disease are method-dependent and require validation in the population in which such index tests are going to be used. Binary cut-offs and use of single-test strategies to rule Wilson's disease in or out is not supported by the evidence in this review. There is insufficient evidence to inform testing in specific subgroups, defined by age, ethnicity or clinical subgroups.
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Affiliation(s)
- Aidan Ryan
- University Hospital Southampton NHS Foundation TrustDepartment of Clinical Biochemistry17 Tremona RoadSouthamptonUKSO16 6YD
| | - Sarah J Nevitt
- University of LiverpoolDepartment of BiostatisticsBlock F, Waterhouse Building1‐5 Brownlow HillLiverpoolUKL69 3GL
| | - Orla Tuohy
- University Hospital SouthamptonWessex Neurological CentreSouthamptonUK
| | - Paul Cook
- University Hospital Southampton NHS Foundation TrustDepartment of Clinical Biochemistry17 Tremona RoadSouthamptonUKSO16 6YD
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Abstract
Wilson disease (WD) is an inherited disorder of copper metabolism. The resultant defective handling of copper results in toxic effects on the hepatocytes and increased copper in the circulation. Copper accumulates in other organ sites especially the central nervous system. WD occurs worldwide, usually between 5 and 35 years; a wider age range is now recognized. Clinical presentations are diverse and include combinations of hepatic, neurological, ophthalmic and psychiatric manifestations. Biochemical abnormalities such as serum ceruloplasmin and 24-h urinary copper excretion are important for the diagnosis but are not always abnormal in WD. They can overlap with non-WD causes. Patients may present with hepatic or neurological disease or combinations thereof. Approx. 50% of WD patients present with liver disease. Liver presentation is variable: asymptomatic abnormal liver tests, chronic hepatitis picture, cirrhosis, and acute liver failure. Similarly, the histology has several different patterns: mild nonspecific changes, steatosis or steatohepatitis, chronic hepatitis, and acute hepatitis with submassive or massive necrosis. None of these are specific for WD. Aids to the histologic diagnosis include special stains for copper and copper associated protein, and copper concentration in liver tissue. The biopsy is performed in the context of the clinical algorithms for the diagnosis of WD put forth by the clinical hepatology organizations such as the European Association for the Study of Liver Disease and the American Association for the Study of Liver Disease. The discovery of the responsible gene ATP7B has made the molecular diagnosis feasible through genetic testing and sequencing of the gene.
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Affiliation(s)
- Maha Guindi
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles CA 90048, USA.
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Abstract
Wilson disease (WD) is an autosomal recessively-inherited disorder of copper metabolism and characterised by a pathological accumulation of copper. The ATP7B gene encodes for a transmembrane copper transporter essential for biliary copper excretion. Depending on time of diagnosis, severity of disease can vary widely. Almost all patients show evidence of progressive liver disease. Neurological impairments or psychiatric symptoms are common in WD patients not diagnosed during adolescence. WD is a treatable disorder, and early treatment can prevent the development of symptoms in patients diagnosed while still asymptomatic. This is why the early diagnosis of WD is crucial. The diagnosis is based on clinical symptoms, abnormal measures of copper metabolism and DNA analysis. Available treatment includes chelators and zinc salts which increase copper excretion and reduce copper uptake. In severe cases, liver transplantation is indicated and accomplishes a phenotypic correction of the hepatic gene defect. Recently, clinical development of the new copper modulating agent tetrathiomolybdate has started and direct genetic therapies are being tested in animal models. The following review focuses especially on biochemical markers and how they can be utilised in diagnosis and drug monitoring.
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Orlien SMS, Ismael NY, Ahmed TA, Berhe N, Lauritzen T, Roald B, Goldin RD, Stene-Johansen K, Dyrhol-Riise AM, Gundersen SG, Morgan MY, Johannessen A. Unexplained chronic liver disease in Ethiopia: a cross-sectional study. BMC Gastroenterol 2018; 18:27. [PMID: 29439653 PMCID: PMC5812015 DOI: 10.1186/s12876-018-0755-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Accepted: 01/31/2018] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) infection is assumed to be the major cause of chronic liver disease (CLD) in sub-Saharan Africa. The contribution of other aetiological causes of CLD is less well documented and hence opportunities to modulate other potential risk factors are being lost. The aims of this study were to explore the aetiological spectrum of CLD in eastern Ethiopia and to identify plausible underlying risk factors for its development. METHODS A cross-sectional study was undertaken between April 2015 and April 2016 in two public hospitals in Harar, eastern Ethiopia. The study population comprised of consenting adults with clinical and radiological evidence of chronic liver disease. The baseline evaluation included: (i) a semi-structured interview designed to obtain information about the ingestion of alcohol, herbal medicines and local recreational drugs such as khat (Catha edulis); (ii) clinical examination; (iii) extensive laboratory testing; and, (iv) abdominal ultrasonography. RESULTS One-hundred-and-fifty patients with CLD (men 72.0%; median age 30 [interquartile range 25-40] years) were included. CLD was attributed to chronic HBV infection in 55 (36.7%) individuals; other aetiological agents were identified in a further 12 (8.0%). No aetiological factors were identified in the remaining 83 (55.3%) patients. The overall prevalence of daily khat use was 78.0%, while alcohol abuse, defined as > 20 g/day in women and > 30 g/day in men, was rare (2.0%). Histological features of toxic liver injury were observed in a subset of patients with unexplained liver injury who underwent liver biopsy. CONCLUSION The aetiology of CLD in eastern Ethiopia is largely unexplained. The widespread use of khat in the region, together with histopathological findings indicating toxic liver injury, suggests an association which warrants further investigation.
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Affiliation(s)
| | - Nejib Yusuf Ismael
- Department of Internal Medicine, Hiwot Fana Specialized University Hospital, Harar, Ethiopia.,Haramaya University College of Health and Medical Sciences, Harar, Ethiopia
| | - Tekabe Abdosh Ahmed
- Haramaya University College of Health and Medical Sciences, Harar, Ethiopia.,Department of Internal Medicine, Jugal Hospital, Harar, Ethiopia
| | - Nega Berhe
- Regional Centre for Imported and Tropical Diseases, Oslo University Hospital Ullevål, Oslo, Norway.,Aklilu Lemma Institute of Pathobiology, Addis Ababa University, Addis Ababa, Ethiopia
| | - Trine Lauritzen
- Department of Medical Biochemistry, Vestre Viken Hospital Trust, Drammen, Norway
| | - Borghild Roald
- Department of Pathology, Oslo University Hospital Ullevål, Oslo, Norway.,Institute of Clinical Medicine, Faculty of Medicine, Oslo University, Oslo, Norway
| | | | | | - Anne Margarita Dyrhol-Riise
- Institute of Clinical Medicine, Faculty of Medicine, Oslo University, Oslo, Norway.,Department of Infectious Diseases, Oslo University Hospital Ullevål, Oslo, Norway.,Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Svein Gunnar Gundersen
- Research Unit, Sørlandet Hospital HF, Kristiansand, Norway.,Department of Global Development and Planning, University of Agder, Kristiansand, Norway
| | - Marsha Yvonne Morgan
- UCL Institute for Liver & Digestive Health, Division of Medicine, University College London, Royal Free Campus, London, UK
| | - Asgeir Johannessen
- Regional Centre for Imported and Tropical Diseases, Oslo University Hospital Ullevål, Oslo, Norway. .,Department of Infectious Diseases, Vestfold Hospital Trust, Tønsberg, Norway.
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Socha P, Janczyk W, Dhawan A, Baumann U, D'Antiga L, Tanner S, Iorio R, Vajro P, Houwen R, Fischler B, Dezsofi A, Hadzic N, Hierro L, Jahnel J, McLin V, Nobili V, Smets F, Verkade HJ, Debray D. Wilson's Disease in Children: A Position Paper by the Hepatology Committee of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2018; 66:334-344. [PMID: 29341979 DOI: 10.1097/mpg.0000000000001787] [Citation(s) in RCA: 149] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Clinical presentations of Wilson's disease (WD) in childhood ranges from asymptomatic liver disease to cirrhosis or acute liver failure, whereas neurological and psychiatric symptoms are rare. The basic diagnostic approach includes serum ceruloplasmin and 24-hour urinary copper excretion. Final diagnosis of WD can be established using a diagnostic scoring system based on symptoms, biochemical tests assessing copper metabolism, and molecular analysis of mutations in the ATP7B gene. Pharmacological treatment is life-long and aims at removal of copper excess by chelating agents as D-penicillamine, trientine, or inhibition of intestinal copper absorption with zinc salts. Acute liver failure often requires liver transplantation. This publication aims to provide recommendations for diagnosis, treatment, and follow-up of WD in children. METHODS Questions addressing the diagnosis, treatment, and follow-up of WD in children were formulated by a core group of ESPGHAN members. A systematic literature search on WD using MEDLINE, EMBASE, Cochrane Database from 1990 to 2016 was performed focusing on prospective and retrospective studies in children. Quality of evidence was assessed according to the GRADE system. Expert opinion supported recommendations where the evidence was regarded as weak. The ESPGHAN core group and ESPGHAN Hepatology Committee members voted on each recommendation, using the nominal voting technique.
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Affiliation(s)
- Piotr Socha
- Department of Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland
| | - Wojciech Janczyk
- Department of Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland
| | - Anil Dhawan
- Paediatric Liver GI and Nutrition Center, King's College Hospital, London, UK
| | - Ulrich Baumann
- Division of Paediatric Gastroenterology and Hepatology, Department of Paediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany
| | - Lorenzo D'Antiga
- Paediatric Hepatology, Gastroenterology and Transplantation, Hospital Papa Giovanni XXIII, Bergamo, Italy
| | | | - Raffaele Iorio
- Department of Translational Medical Science, Section of Pediatrics, University of Naples Federico II, Naples
| | - Pietro Vajro
- Dipartimento di Medicina e Chirurgia, University of Salerno, Fisciano SA, Italy
| | - Roderick Houwen
- Department of Paediatrics, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Björn Fischler
- Department of Paediatrics, CLINTEC, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
| | - Antal Dezsofi
- First Department of Paediatrics, Semmelweis University, Budapest, Hungary
| | - Nedim Hadzic
- Paediatric Centre for Hepatology, Gastroenterology and Nutrition, King's College Hospital, London, UK
| | - Loreto Hierro
- Paediatric Hepatology Service, Hospital Infantil Universitario "La Paz," Madrid, Spain
| | - Jörg Jahnel
- Department of Paediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
| | - Valérie McLin
- Paediatric Gastroenterology Unit, Department of Pediatrics, University Hospitals Geneva, Geneva, Switzerland
| | - Valerio Nobili
- Hepatometabolic Unit, Bambino Gesu Children's Hospital, Rome, Italy
| | - Francoise Smets
- Université Catholique de Louvain-IREC-Cliniques Universitaires Saint-Luc-Pediatric Gastroenterology and Hepatology Unit, Brussels, Belgium
| | - Henkjan J Verkade
- Department of Paediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Dominique Debray
- Pediatric Hepatology Unit, Centre National de Référence de la Maladie de Wilson, Hôpital Necker-APHP, Paris, France
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Xu R, Jiang YF, Zhang YH, Yang X. The optimal threshold of serum ceruloplasmin in the diagnosis of Wilson's disease: A large hospital-based study. PLoS One 2018; 13:e0190887. [PMID: 29324775 PMCID: PMC5764328 DOI: 10.1371/journal.pone.0190887] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2017] [Accepted: 12/21/2017] [Indexed: 01/08/2023] Open
Abstract
Background and aims A ceruloplasmin (CP) concentration <200 mg/L is conventionally considered as one of the major diagnostic criteria for Wilson’s disease (WD). However, the diagnostic accuracy of this threshold has never been investigated in a sufficiently large group of patients. This study aims to present the results of serum CP measurements in various patients and to identify the optimal cutoff value of CP for the diagnosis of WD. Materials and methods We identified patients whose CP levels were evaluated from January 1, 2016 to December 31, 2016 using a laboratory information database. Data related to CP measurement were retrieved. We carefully reviewed patients’ electronic medical records to correct errors and to obtain other necessary data. Data related to WD were retrieved from a special document containing medical records of patients with WD, which were created, modified, and maintained by authors. Results CP level was determined in 4048 patients (WD, 297; non-WD, 3751). The mean serum CP level in patients with WD was 50.6±44.2 mg/L, which was significantly lower than that in non-WD patients (293.2±117.3 mg/L, p<0.001). Only 1.0% of patients with WD had CP ≥200 mg/L. The sensitivity and specificity of CP for the diagnosis of WD were 99.0 and 80.9%, respectively, for the conventional cutoff value <200 mg/L and 95.6 and 95.5%, respectively, for the cutoff value <150 mg/L; the latter provided a higher diagnostic accuracy for WD. 53.0% of patients with liver failure, 37.7% of patients with nephrotic syndrome, and 23.0% of patients age 1 to 6 months had serum CP <200 mg/L. Patients who were pregnant and those with malignant tumors, and infectious and inflammatory diseases had significantly higher mean serum CP levels. Conclusion The optimal cutoff value of CP for the diagnosis of WD in China is 150 mg/L, with a sensitivity of 95.6% and specificity of 95.5%, thereby providing the highest diagnostic accuracy for WD.
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Affiliation(s)
- Rong Xu
- Institute of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Yong-fang Jiang
- Department of Infectious Diseases/ Liver Disease Research Center, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Yong-hong Zhang
- Department of Infectious Diseases/ Liver Disease Research Center, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Xu Yang
- Department of Infectious Diseases/ Liver Disease Research Center, The Second Xiangya Hospital, Central South University, Changsha, China
- * E-mail: ,
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Guttmann S, Bernick F, Naorniakowska M, Michgehl U, Groba SR, Socha P, Zibert A, Schmidt HH. Functional Characterization of Novel ATP7B Variants for Diagnosis of Wilson Disease. Front Pediatr 2018; 6:106. [PMID: 29761093 PMCID: PMC5937294 DOI: 10.3389/fped.2018.00106] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2018] [Accepted: 04/03/2018] [Indexed: 12/14/2022] Open
Abstract
Background: Diagnosis of rare Wilson disease (WD) in pediatric patients is difficult, in particular when hepatic manifestation is absent. Genetic analysis of ATP7B represents the single major determinant of the diagnostic scoring system in WD children having mild symptoms. Objectives: To assess the impact of molecularly expressed ATP7B gene products in order to assist diagnosis of Wilson disease in pediatric patients having a novel mutation and subtle neuropsychiatric disease. Methods: The medical history, clinical presentation, biochemical parameters, and the genetic analysis of ATP7B were determined. Due to ambiguous clinical and biochemical findings and identification of a novel compound ATP7B mutation with unknown disease-causing status, a molecular analysis of the ATP7B gene products in a previously well characterized cell model was performed. Results: The ATP7B variants were transgenically expressed and the respective gene function molecularly characterized. Despite normal mRNA expression, low ATP7B protein expression of the mutants p.L168P and p.S1423N was observed (34.3 ± 8% and 66.0 ± 8%, respectively). Copper exposure did not result in decreased viability of transgenic cells as compared to wild type. Intracellular copper accumulation was reduced (≤47.9 ± 8%) and intracellular protein trafficking was impaired. Conclusion: Our report suggests that functional characterization of novel ATP7B mutants can assist diagnosis; however mild functional impairments of ATP7B variants may hamper the value of such approaches.
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Affiliation(s)
- Sarah Guttmann
- Medizinische Klinik B für Gastroenterologie und Hepatologie, Universitätsklinikum Münster, Münster, Germany
| | - Friedrich Bernick
- Medizinische Klinik B für Gastroenterologie und Hepatologie, Universitätsklinikum Münster, Münster, Germany
| | - Magdalena Naorniakowska
- Department of Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland
| | - Ulf Michgehl
- Internal Medicine D, Molecular Nephrology, University Hospital of Münster, Münster, Germany
| | - Sara Reinartz Groba
- Medizinische Klinik B für Gastroenterologie und Hepatologie, Universitätsklinikum Münster, Münster, Germany
| | - Piotr Socha
- Internal Medicine D, Molecular Nephrology, University Hospital of Münster, Münster, Germany
| | - Andree Zibert
- Medizinische Klinik B für Gastroenterologie und Hepatologie, Universitätsklinikum Münster, Münster, Germany
| | - Hartmut H Schmidt
- Medizinische Klinik B für Gastroenterologie und Hepatologie, Universitätsklinikum Münster, Münster, Germany
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Quaglia A, Roberts EA, Torbenson M. Developmental and Inherited Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2018:111-274. [DOI: 10.1016/b978-0-7020-6697-9.00003-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Abstract
In paediatrics, one of our main aims in the diagnostic process is to identify any treatable conditions. The copper metabolism disorder Wilson's disease (WD) is one such condition that is caused by mutations in the ATP7B gene. Delay in treatment could result in irreversible disability or even death. Although liver disease is the most common presenting feature in children, some children may initially present with a subtle neurological presentation only. In patients presenting with dystonia, tremor, dysarthria or with a deterioration in school performance, there should be a high index of suspicion for WD. However, the differential of these clinical presentations is wide and exclusion of WD is difficult. No single diagnostic test can exclude WD and each of the biochemical tests has limitations. In this article, we discuss copper metabolism disorders including WD and Menke's disease. We then discuss the available diagnostic tests and how to investigate children for these rare disorders.
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Affiliation(s)
- Jane Armer
- Department of Clinical Laboratory Medicine, Royal Blackburn Hospital, Blackburn, UK
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Abstract
Consideration of a diagnosis of Wilson disease is still the critical factor in testing for and establishing disease diagnosis. In association with other clinical and biochemical tests, liver biopsy results and molecular genetic testing can also be used to generate a score for diagnosing Wilson disease. Medical therapy is effective for most patients; liver transplant can rescue those with acute liver failure or those with advanced liver disease who fail to respond to or discontinue medical therapy. Treatment monitoring must be done at regular intervals and includes clinical evaluation, liver tests and blood counts, and copper metabolic parameters.
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Affiliation(s)
- Michael L Schilsky
- Yale University Medical Center, 333 Cedar Street, LMP 1080, New Haven CT 06520, USA.
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Abstract
Wilson disease (WD) is an inherited disorder mainly of hepatocellular copper disposition, due to dysfunction of the Wilson ATPase, a P1B-ATPase encoded by the gene ATP7B. In children, as in older age brackets, clinical disease is highly diverse. Although hepatic disease is the common presentation in children/adolescents, neurologic, psychiatric, and hematologic clinical presentations do occur. Very young children may have clinically evident liver disease due to WD. Early diagnosis, preferably when the child/adolescent is asymptomatic, is most likely to result in near-normal longevity with generally good health so long as the patient tolerates effective medication, is adherent to the lifelong treatment regimen, and has consistent access to the medication. Apart from a lively index of clinical suspicion on the part of physicians, biochemical tests including liver tests, serum ceruloplasmin, and basal 24-hour urinary copper excretion and genotype determination are key to diagnosis. Oral chelation treatment remains central to medical management, although zinc appears to be an attractive option for the presymptomatic child. Pediatric patients presenting with Wilsonian fulminant hepatic failure must be differentiated from those with decompensated cirrhosis, since the latter may respond to intensive medical interventions and not require liver transplantation. Recently identified WD-mimic disorders reveal important aspects of WD pathogenesis.
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Affiliation(s)
- Eve A Roberts
- Departments of Paediatrics, Medicine and Pharmacology and Toxicology, University of Toronto, Toronto, Canada.
| | - Piotr Socha
- Departments of Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland
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Affiliation(s)
- Aidan Ryan
- University Hospital Southampton NHS Foundation Trust; Department of Clinical Biochemistry; 17 Tremona Road Southampton UK SO16 6YD
| | - Sarah J Nolan
- University of Liverpool; Department of Biostatistics; Block F, Waterhouse Building 1-5 Brownlow Hill Liverpool UK L69 3GL
| | - Paul Cook
- University Hospital Southampton NHS Foundation Trust; Department of Clinical Biochemistry; 17 Tremona Road Southampton UK SO16 6YD
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Kim JA, Kim HJ, Cho JM, Oh SH, Lee BH, Kim GH, Choi JH, Kim KM, Yoo HW. Diagnostic Value of Ceruloplasmin in the Diagnosis of Pediatric Wilson's Disease. Pediatr Gastroenterol Hepatol Nutr 2015; 18:187-92. [PMID: 26473139 PMCID: PMC4600703 DOI: 10.5223/pghn.2015.18.3.187] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2015] [Revised: 04/21/2015] [Accepted: 06/16/2015] [Indexed: 12/25/2022] Open
Abstract
PURPOSE Measurement of serum ceruloplasmin level is the first step in screening for Wilson's disease (WD). Despite the rarity of WD in the general population, ceruloplasmin levels are routinely measured through hepatitis screening in both adults and children. Herein, we evaluated the diagnostic value of ceruloplasmin for the diagnosis of WD among children with hepatitis. METHODS We retrospectively reviewed data on serum ceruloplasmin levels measured as a serologic marker for patients with hepatitis at Asan Medical Center (Seoul, Korea) between from January 2004 to November 2013. The diagnosis of WD was confirmed by the identification of pathogenic variants in the ATP7B gene. To determine the diagnostic accuracy of ceruloplasmin, receiver operation characteristic (ROC) curves were constructed and the area under curve (AUC) were calculated. RESULTS Measurements of serum ceruloplasmin were performed in 2,834 children who had hepatitis. Among these, 181 (6.4%) children were diagnosed with WD. The sensitivity, specificity, and accuracy of a ceruloplasmin level of <20 mg/dL in the discrimination of WD were 93.4%, 84.2%, and 84.8%, respectively. In this study, 418 (14.7%) false-positive cases and 12 (0.4%) false-negative cases were noted. Using a ROC curve, a ceruloplasmin level of ≤16.6 mg/dL showed the highest AUC value (0.956) with a sensitivity of 91.2%, a specificity of 94.9%, and an accuracy of 94.7%. CONCLUSION The measurement of serum ceruloplasmin was frequently used for the screening of WD in children, despite a low positive rate. The diagnostic value of ceruloplasmin may be strengthened by adopting a new lower cut-off level.
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Affiliation(s)
- Jung Ah Kim
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Hyun Jin Kim
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Jin Min Cho
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Seak Hee Oh
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Beom Hee Lee
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Gu-Hwan Kim
- Medical Genetics Center, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Jin-Ho Choi
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Kyung Mo Kim
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Han-Wook Yoo
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
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Guo W, He XY, Li XF, Qian DX, Yan JQ, Bu DL, Duan CZ. Meta-analysis of diagnostic significance of sixty-four-row multi-section computed tomography angiography and three-dimensional digital subtraction angiography in patients with cerebral artery aneurysm. J Neurol Sci 2014; 346:197-203. [PMID: 25194636 DOI: 10.1016/j.jns.2014.08.023] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2014] [Revised: 08/15/2014] [Accepted: 08/17/2014] [Indexed: 01/23/2023]
Abstract
OBJECTIVE Imaging methods are essential in evaluating cerebral artery aneurysms and they have evolved with recent technical advances. Sixty-four-row multi-section computed tomography (64-MSCT) angiography and three-dimensional digital subtraction angiography (3D-DSA) are two of the most popular methods. We sought to systematically explore and find out which one would be better in imaging cerebral artery aneurysm, and try to investigate the potential use and value of 64-MSCT angiography and 3D-DSA in cerebral artery aneurysm. METHOD Followed by a predefined comprehensive literature search, we carefully searched both English and Chinese electronic databases for potentially relevant studies following our meta-analysis. Two reviewers independently assessed the methodological quality of the included eligible trials based on quality assessment of studies of diagnostic accuracy studies (QUADAS). Pooled summary statistics for sensitivity, specificity, positive and negative likelihood ratios (positive LR and negative LR), and diagnostic odds ratio (ORs) with their 95% confidence intervals (CIs) were utilized. RESULTS Final meta-analysis of 923 cerebral artery aneurysm cases were incorporated from eight cohort studies and selected for statistical analysis. Pooled sensitivity and specificity of 64-MSCT angiography in the diagnosis of cerebral artery aneurysm were 0.97 (95% CI, 0.96-0.98) and 0.91 (0.88-0.94), respectively. The pooled positive LR was 7.68 (95% CI, 3.34-17.67); and the pooled negative LR was 0.04 (95% CI, 0.03-0.05). The pooled diagnostic OR was 263.69 (95% CI, 121.19-573.77). The area under the SROC curve was 0.9934 (standard error [SE] = 0.0031). No significant evidence of publication bias was detected (P > 0.05). CONCLUSION The main finding of our meta-analysis revealed that 64-MSCT angiography relative to the 3D-DSA may have a high diagnostic accuracy for the cerebral artery aneurysm. Thus, 64-MSCT angiography may be an effective tool for the early detection of cerebral artery aneurysm.
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Affiliation(s)
- Wei Guo
- Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, PR China; Department of Neurosurgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, PR China
| | - Xu-Ying He
- Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, PR China
| | - Xi-Feng Li
- Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, PR China
| | - Dong-Xiang Qian
- Department of Neurosurgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, PR China
| | - Jian-Quan Yan
- Department of Neurosurgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, PR China
| | - De-Lin Bu
- Department of Neurosurgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, PR China
| | - Chuan-Zhi Duan
- Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, PR China.
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Swart C, Zakel S, Frank C, Fisicaro P, Goenaga-Infante H. Metrological Approach for the Quantification of Metalloproteins (EMRP Project HLT05). EPJ WEB OF CONFERENCES 2014. [DOI: 10.1051/epjconf/20147700007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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Superoxide dismutase1 levels in North Indian population with age-related macular degeneration. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2013; 2013:365046. [PMID: 24363822 PMCID: PMC3864086 DOI: 10.1155/2013/365046] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/16/2013] [Revised: 10/20/2013] [Accepted: 10/28/2013] [Indexed: 12/21/2022]
Abstract
Aim. The aim of the study was to estimate the levels of superoxide dismutase1 (SOD1) in patients of age-related macular degeneration (AMD) and examine the role of oxidative stress, smoking, hypertension, and other factors involved in the pathogenesis of AMD. Methods. 115 AMD patients and 61 healthy controls were recruited for this study. Serum SOD1 levels were determined by ELISA and were correlated to various risk factors. Logistic regression model of authenticity, by considering SOD1 as independent variable, has been developed along with ROC curve. Results. The SOD1 levels were significantly higher in AMD patients as compared to those of the controls. The difference was not significant for wet and dry AMD. However, the difference was significant between wet AMD subtypes. Nonsignificance of the Hosmer-Lemeshow goodness of fit statistic (χ2 = 10.516, df = 8, P = 0.231) indicates the appropriateness of logistic regression model to predict AMD. Conclusion. Oxidative stress in AMD patients may mount compensatory response resulting in increased levels of SOD1 in AMD patients. To predict the risk of AMD on the basis of SOD1, a logistic regression model shows authenticity of 78%, and area under the ROC curve (0.827, P = .0001) with less standard error of 0.033 coupled with 95% confidence interval of 0.762–0.891 further validates the model.
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