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Aboalam HS, Hassan MK, El-domiaty N, Ibrahim NF, Ali AM, Hassan W, Abu El Wafa EG, Elsaghier A, Hetta HF, Elbadry M, El-Kassas M. Challenges and Recent Advances in Diagnosing Wilson Disease. J Clin Exp Hepatol 2025; 15:102531. [PMID: 40160676 PMCID: PMC11952840 DOI: 10.1016/j.jceh.2025.102531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Accepted: 02/18/2025] [Indexed: 04/02/2025] Open
Abstract
Wilson disease (WD) is a rare autosomal recessive disorder caused by ATP7B gene mutations, leading to pathological copper accumulation that primarily affects the liver, brain, and eyes. Diagnosing WD remains a significant challenge due to its highly variable clinical presentation, which ranges from asymptomatic biochemical abnormalities to acute liver failure and severe neuropsychiatric manifestations. Traditional diagnostic markers, such as serum ceruloplasmin, urinary copper excretion, and liver biopsy, lack sufficient specificity and sensitivity, often leading to delays in diagnosis and misclassification. Additionally, the absence of a single gold-standard test and the overlap with other hepatic and neurological disorders further complicate early detection. Recent advances in diagnostic techniques offer promising solutions to overcome these limitations. Novel biomarkers, including relative exchangeable copper (REC) and ATP7B protein quantification in dried blood spots have demonstrated improved accuracy in distinguishing WD from other conditions. Advanced imaging modalities, such as anterior segment optical coherence tomography (AS-OCT), quantitative susceptibility mapping (QSM), and copper-64 positron emission tomography imaging provide noninvasive tools for detecting early disease-related changes. Furthermore, next-generation sequencing (NGS) enhances genetic screening, facilitating earlier diagnosis, and family screening. A comprehensive approach integrating conventional and emerging diagnostic methodologies is essential for improving early detection and patient outcomes. Greater awareness of the limitations of traditional tests and the incorporation of novel biomarkers and imaging techniques into clinical practice can help refine diagnostic accuracy, reduce delays, and optimize treatment strategies for WD.
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Affiliation(s)
- Hani S. Aboalam
- Tropical Medicine and Gastroenterology Department, Assiut Liver Center, Assiut, Egypt
| | - Marwa K. Hassan
- Tropical Medicine and Gastroenterology Department, Assiut Liver Center, Assiut, Egypt
| | - Nada El-domiaty
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo, Egypt
| | - Nagat F. Ibrahim
- Tropical Medicine and Gastroenterology Department, Assiut Liver Center, Assiut, Egypt
| | - Anwar M. Ali
- Neuropsychiatry Department, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Wesam Hassan
- Tropical Medicine and Gastroenterology Department, Assiut Liver Center, Assiut, Egypt
| | | | - Ashraf Elsaghier
- Pediatric Department, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Helal F. Hetta
- Medical Microbiology and Immunology Department, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Mohamed Elbadry
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo, Egypt
| | - Mohamed El-Kassas
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo, Egypt
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Gadde R, Shah S, Böhlke M, Kim J, Betharia S. N,N'-bis(2-mercaptoethyl)isophthalamide (NBMI) as a novel chelator for Wilson's disease. Free Radic Biol Med 2025; 232:421-436. [PMID: 40032031 DOI: 10.1016/j.freeradbiomed.2025.02.046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Revised: 02/15/2025] [Accepted: 02/27/2025] [Indexed: 03/05/2025]
Abstract
Wilson's Disease (WD) is a rare autosomal recessive disorder caused by mutations in the ATP7B gene. These mutations lead to defective copper (Cu) transport and to accumulation of Cu in tissues, primarily in the liver and brain. Current treatment options such as D-penicillamine, trientine, and zinc salts focus on increasing Cu excretion or reducing Cu absorption, but often cause debilitating side effects. N,N'-bis(2-mercaptoethyl)isophthalamide (NBMI) is a lipophilic thiol-based compound originally developed for environmental decontamination. It has been shown to chelate toxic metals such as mercury, lead, and cadmium. This study was designed to evaluate the efficacy of NBMI to mitigate Cu overload using both in vitro and in vivo models of WD. HepG2 cells with the ATP7B gene knocked down had increased sensitivity to copper sulfate (CuSO4) compared to wild-type (WT) cells, validating the cell model for WD. Pretreatment with NBMI (2.5-50 μM) improved cell viability, reduced Cu-induced oxidative stress, decreased metallothionein levels, mitigated resulting DNA damage, and reduced overall levels of free intracellular Cu. In an established toxic milk mouse (tx-J) model of WD, 1% dietary NBMI effectively lowered hepatic, cerebral, and renal Cu levels. Treatment with 1% NBMI also improved liver function, as evidenced by reduced ALT levels and normalized hepatocyte morphology. Tx-J mice displayed higher liver-to-body weight ratios compared to WT mice, and treatment with 1% NBMI effectively reduced this ratio. While NBMI did not impact the elevated white blood cell counts and low platelet levels characteristic of tx-J mice, it also did not cause any detrimental effects on red blood cell, hemoglobin, and hematocrit levels. This dose of NBMI also restored homeostasis of other dysregulated essential metal ions in tx-J mice. These findings suggest that dietary administration of NBMI effectively chelates excess free Cu, ameliorates WD symptoms and offers a promising alternative to existing chelators.
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Affiliation(s)
- Rajitha Gadde
- Department of Pharmaceutical Sciences, MCPHS University, School of Pharmacy, Boston, MA, USA
| | - Shrey Shah
- Department of Pharmaceutical Sciences, MCPHS University, School of Pharmacy, Boston, MA, USA
| | - Mark Böhlke
- Department of Pharmaceutical Sciences, MCPHS University, School of Pharmacy, Boston, MA, USA
| | - Jonghan Kim
- Department of Biomedical and Nutritional Sciences, Zuckerberg College of Health Sciences, University of Massachusetts Lowell, MA, USA
| | - Swati Betharia
- Department of Pharmaceutical Sciences, MCPHS University, School of Pharmacy, Boston, MA, USA.
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Calinas F, Cardoso H, Carvalhana S, Ferreira J, Gonçalves C, Magalhães M, Miranda HP, Presa J, Rolanda C, Santos A, Santos RM. Practical and Multidisciplinary Review on Wilson Disease: The Portuguese Perspective. GE PORTUGUESE JOURNAL OF GASTROENTEROLOGY 2025; 32:78-94. [PMID: 40143934 PMCID: PMC11936444 DOI: 10.1159/000541208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Accepted: 08/15/2024] [Indexed: 03/28/2025]
Abstract
Wilson disease (WD) is a genetic disorder of copper metabolism caused by mutations in the ATP7B gene resulting in toxic copper accumulation in several organs. WD can manifest as liver disease, a progressive neurological disorder, a psychiatric illness, or a combination of these. Other clinical manifestations can also occur. Diagnosis is challenging and typically requires a range of biochemical tests, imaging, genetic testing for ATP7B, and/or liver biopsy. WD is treatable with chelating agents, such as d-penicillamine and trientine, and/or zinc salts alongside with dietary copper restriction. Liver transplantation may be indicated in WD patients with severe hepatic disease, and cautiously considered in patients with neurological WD. Treatment success highly depends on patient adherence and treatment persistence. Therefore, effective interventions for improving patient adherence and close monitoring are key for preventing WD progression. In Portugal, there are no reference centers for WD, and patients are dispersed across numerous medical specialists. This review aimed to summarize the most recent and relevant information for the diagnosis, treatment, and monitoring of WD in Portugal, as well as possible interventions for stimulating adherence to treatment.
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Affiliation(s)
- Filipe Calinas
- Centro de Responsabilidade Integrado de Gastrenterologia, Unidade Local de Saúde de São José, Lisbon, Portugal
- Centro Clínico Académico de Lisboa, Lisbon, Portugal
| | - Hélder Cardoso
- Serviço de Gastrenterologia, Unidade Local de Saúde de São João, Porto, Portugal
- Faculdade de Medicina da Universidade do Porto, Porto, Portugal
| | - Sofia Carvalhana
- Serviço de Gastrenterologia, Hospital de Santa Maria, Unidade Local de Saúde de Santa Maria, Lisbon, Portugal
| | - José Ferreira
- Serviço de Gastrenterologia, Unidade Local de Saúde de Santo António, Porto, Portugal
| | - Cristina Gonçalves
- Unidade de Gastrenterologia e Hepatologia Pediátricas, Hospital Dona Estefânia, Unidade Local de Saúde de São José, Lisbon, Portugal
| | - Marina Magalhães
- Serviço de Neurologia, Unidade Local de Saúde de Santo António, Porto, Portugal
| | - Helena Pessegueiro Miranda
- Unidade de Transplantação Hepática e Pancreática, Centro Hospitalar e Universitário do Porto, Porto, Portugal
| | - José Presa
- Unidade de Hepatologia, Unidade Local de Saúde Trás-os-Montes e Alto Douro (ULSTMAD), Vila Real, Portugal
| | - Carla Rolanda
- Serviço de Gastrenterologia, Hospital de Braga, Unidade Local de Saúde de Braga, Braga, Portugal
- Escola de Medicina e Instituto de Investigação em Ciências da Vida e da Saúde (ICVS) – Universidade do Minho, Braga, Portugal
| | - Arsénio Santos
- Serviço de Medicina Interna, Hospitais da Universidade de Coimbra, Unidade Local de Saúde de Coimbra, Coimbra, Portugal
- Faculdade de Medicina da Universidade de Coimbra, Coimbra, Portugal
| | - Rui M. Santos
- Faculdade de Medicina da Universidade de Coimbra, Coimbra, Portugal
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Minisola S, Cipriani C, Colangelo L, Labbadia G, Pepe J, Magnusson P. Diagnostic Approach to Abnormal Alkaline Phosphatase Value. Mayo Clin Proc 2025; 100:712-728. [PMID: 40019430 DOI: 10.1016/j.mayocp.2024.11.019] [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: 07/09/2024] [Revised: 11/04/2024] [Accepted: 11/20/2024] [Indexed: 03/01/2025]
Abstract
Alkaline phosphatase (ALP) is abundantly represented in nature, being fundamental for a number of processes. In addition to its fundamental function in skeletal mineralization, its roles in the pathogenesis of other diseases are being explored. The measurement of total ALP activity in serum or in plasma is a useful biomarker in clinical practice. Indeed, routine measurement of serum total ALP is a long-standing established part of initial biochemical evaluation of patients both in the hospital setting and on an ambulatory basis. Raised or reduced values of this enzyme activity are indicative of a number of diseases, most commonly affecting the skeleton and the biliary tract. Electrophoretic assays are preferable for visualizing and investigating the cause of increased serum total ALP activities, and bone ALP immunoassays are preferable for investigating and monitoring individuals with bone and mineral metabolic abnormalities. Here, we give a holistic vision of this fundamental enzyme, suggesting a clinical approach to the identification of diseases causing abnormal values. Finally, a therapeutic role has emerged as substitutive therapy in patients with hypophosphatasia, even though ongoing and future studies are exploring its role in other therapeutic areas. This narrative review was based on articles found by searching PubMed from its inception until July 2024 for the terms alkaline phosphatases, isozymes, isoforms, bone alkaline phosphatase, liver alkaline phosphatase, intestinal alkaline phosphatase, placental alkaline phosphatase, liver function tests, γ-glutamyltransferase, skeletal diseases, and liver diseases. We limited our research to papers published in the English language, with emphasis placed on those describing differential diagnosis whenever available.
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Affiliation(s)
- Salvatore Minisola
- Department of Clinical, Internal, Anesthesiologic, and Cardiovascular Sciences, "Sapienza" University of Rome, Rome, Italy.
| | - Cristiana Cipriani
- Department of Clinical, Internal, Anesthesiologic, and Cardiovascular Sciences, "Sapienza" University of Rome, Rome, Italy
| | - Luciano Colangelo
- Department of Clinical, Internal, Anesthesiologic, and Cardiovascular Sciences, "Sapienza" University of Rome, Rome, Italy
| | - Giancarlo Labbadia
- Department of Clinical, Internal, Anesthesiologic, and Cardiovascular Sciences, "Sapienza" University of Rome, Rome, Italy
| | - Jessica Pepe
- Department of Clinical, Internal, Anesthesiologic, and Cardiovascular Sciences, "Sapienza" University of Rome, Rome, Italy
| | - Per Magnusson
- Department of Clinical Chemistry and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
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Spirea D, Vanlemmens C, Parant F, Antonini T, Bost M, Lachaux A, Belmalih A, Guillaud O, Dumortier J, Couchonnal E. Performance of Relative Exchangeable Copper for the Diagnosis of Wilson Disease in Acute Liver Failure. J Inherit Metab Dis 2025; 48:e70024. [PMID: 40097333 PMCID: PMC11913634 DOI: 10.1002/jimd.70024] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2024] [Revised: 03/06/2025] [Accepted: 03/10/2025] [Indexed: 03/19/2025]
Abstract
Acute liver failure (ALF) can be one of the manifestations of Wilson disease (WD), and due to its severity, prompt diagnosis is essential. A ratio > 15% of the exchangeable copper to total serum copper, known as relative exchangeable copper (REC), has been shown to have a 100% sensitivity and specificity for the diagnosis of WD but this has not yet been studied in an ALF setting. Patients diagnosed with ALF from 1 November 2011 to 31 December 2023, with available REC determination during the acute event, were included. Thirty-three patients were included (11 with WD and 22 without WD). The median age [IQR] at ALF was 12.9 [8.9-20.2] years, range: 0.6-71.0 years. Serum ceruloplasmin (Cp) < 0.20 g/L and 24 h urinary copper excretion > 1.6 μmol/L had both a sensitivity (Se) and specificity (Sp) for the diagnosis of WD of 100% and 72.7%, respectively. A ROC analysis of REC determined that the best cut-off point was 14.4% (AUC 1, p < 0.01). All the WD patients had REC values > 14.4%, yielding a sensitivity and specificity of 100. Relative exchangeable copper has 100% sensitivity and specificity for diagnosing Wilson disease in acute liver failure. Relative exchangeable copper has excellent performance in diagnosing Wilson disease in acute liver failure.
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Affiliation(s)
- Daniela Spirea
- Pediatric GastroenterologyChildren Clinical Hospital of BrasovBrasovRomania
| | - Claire Vanlemmens
- Hepatology and Intensive Digestive Care DepartmentHôpital Jean MinjozBesançonFrance
| | - François Parant
- Department of BiochemistryHôpital Lyon Sud, Hospices Civils de LyonPierre‐BéniteFrance
- National Reference Center for Wilson DiseaseHôpital Femme‐Mère‐Enfant, Hospices Civils de LyonBronFrance
| | - Teresa Antonini
- Department of HepatologyCroix Rousse University Hospital, Hospices Civils de LyonLyonFrance
| | - Muriel Bost
- Department of BiochemistryHôpital Lyon Sud, Hospices Civils de LyonPierre‐BéniteFrance
- National Reference Center for Wilson DiseaseHôpital Femme‐Mère‐Enfant, Hospices Civils de LyonBronFrance
| | - Alain Lachaux
- National Reference Center for Wilson DiseaseHôpital Femme‐Mère‐Enfant, Hospices Civils de LyonBronFrance
- Claude Bernard Lyon 1 UniversityLyonFrance
| | - Abdelouahed Belmalih
- National Reference Center for Wilson DiseaseHôpital Femme‐Mère‐Enfant, Hospices Civils de LyonBronFrance
| | - Olivier Guillaud
- National Reference Center for Wilson DiseaseHôpital Femme‐Mère‐Enfant, Hospices Civils de LyonBronFrance
- Department of Digestive DiseasesHôpital Edouard Herriot, Hospices Civils de LyonLyonFrance
| | - Jerome Dumortier
- Claude Bernard Lyon 1 UniversityLyonFrance
- Department of Digestive DiseasesHôpital Edouard Herriot, Hospices Civils de LyonLyonFrance
| | - Eduardo Couchonnal
- National Reference Center for Wilson DiseaseHôpital Femme‐Mère‐Enfant, Hospices Civils de LyonBronFrance
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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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Garbuz M, Ovchinnikova E, Ovchinnikova A, Vinokurova V, Aristarkhova Y, Kuziakova O, Mashurova M, Kumeiko V. Spectrum of Pathogenic Variants of the ATP7B Gene and Genotype-Phenotype Correlation in Eastern Eurasian Patient Cohorts with Wilson's Disease. Biomedicines 2024; 12:2833. [PMID: 39767741 PMCID: PMC11673475 DOI: 10.3390/biomedicines12122833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2024] [Revised: 12/06/2024] [Accepted: 12/09/2024] [Indexed: 01/11/2025] Open
Abstract
Background/Objectives: Wilson's disease (WD) (OMIM 277900) or hepatolenticular degeneration is an autosomal recessive disorder caused by impaired copper excretion with subsequent accumulation in the liver, brain, and other tissues of the body. The defects in copper metabolism are based on various pathogenic variants of the ATP7B gene encoding copper-transporting P-type ATPase. The aim of this work is to search for pathogenic variants of the ATP7B gene among Eastern Eurasian patient cohorts and to pick correlations between pathogenic variants, gender, age of onset of the disease, and the course of the disease. Methods: The material for the study was the biomaterial of 100 people. The search for mutations was carried out by Sanger sequencing. Multiple alignment of nucleotide sequences and their analysis was performed using the MEGA-X software. To study the genotype-phenotypic correlation, an analysis of the medical records of each patient was carried out. Results: Most common pathogenic variant (48%) in the sample is p.His1069Gln (c.3207C>A), located in exon 14 of the ATP7B gene. Pathogenic variants of p.Glu1064Lys (c.3190G>A)-20%-and p.Met769HisfsTer26 (c.2304insC)-8%-of exons 14 and 8 were also common. For patients with pathogenic alleles p.His1069Gln (c.3207C>A) and p.Glu1064Lys (c.3190G>A), typical deviations are mental and neurological manifestations of WD. In patients with the pathogenic allele p.Met769HisfsTer26 (c.2304insC), deviations are more characteristic of the liver and a combination of various symptoms that are atypical for WD. Conclusions: In this study, we were able to obtain differences in symptoms in patients with different pathogenic alleles of the ATP7B gene.
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Affiliation(s)
- Mikhail Garbuz
- School of Medicine and Life Sciences, Far Eastern Federal University, Vladivostok 690922, Russia; (M.G.)
| | - Elena Ovchinnikova
- School of Medicine and Life Sciences, Far Eastern Federal University, Vladivostok 690922, Russia; (M.G.)
| | - Anna Ovchinnikova
- School of Medicine and Life Sciences, Far Eastern Federal University, Vladivostok 690922, Russia; (M.G.)
| | - Valeriya Vinokurova
- School of Medicine and Life Sciences, Far Eastern Federal University, Vladivostok 690922, Russia; (M.G.)
| | - Yulya Aristarkhova
- School of Medicine and Life Sciences, Far Eastern Federal University, Vladivostok 690922, Russia; (M.G.)
| | - Olga Kuziakova
- School of Medicine and Life Sciences, Far Eastern Federal University, Vladivostok 690922, Russia; (M.G.)
| | - Mariya Mashurova
- School of Medicine and Life Sciences, Far Eastern Federal University, Vladivostok 690922, Russia; (M.G.)
| | - Vadim Kumeiko
- School of Medicine and Life Sciences, Far Eastern Federal University, Vladivostok 690922, Russia; (M.G.)
- A.V. Zhirmunsky National Scientific Center of Marine Biology Far Eastern Branch of Russian Academy of Sciences, Vladivostok 690041, Russia
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Fettiplace A, Marcinak J, Merz M, Zhang HT, Kikuchi L, Regev A, Palmer M, Rockey D, Fontana R, Hayashi PH, Tillmann HL, Di Bisceglie AM, Lewis JH. Review article: Recommendations for detection, assessment and management of suspected drug-induced liver injury during clinical trials in oncology patients. Aliment Pharmacol Ther 2024; 60:1293-1307. [PMID: 39300766 DOI: 10.1111/apt.18271] [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: 03/13/2024] [Revised: 04/07/2024] [Accepted: 09/02/2024] [Indexed: 09/22/2024]
Abstract
BACKGROUND Drug-induced liver injury (DILI) is a major concern for oncology drugs in clinical practice and under development. Monitoring cancer patients for hepatotoxicity is challenging as these patients may have abnormal liver tests pre-treatment or on-study for many reasons including liver injury due to past oncology treatments, hepatic metastases, medical co-morbidities such as heart failure, and concomitant medications. At present, there are no regulatory guidelines or position papers that systematically address best practices pertaining to DILI detection, assessment and management in oncology patients. AIMS The goals of this review are (1) to examine and interpret the available evidence and (2) to make recommendations for detection, monitoring, adjudication, and management of suspected hepatocellular DILI during oncology clinical trials. METHODS This manuscript was developed by the IQ Consortium (International Consortium for Innovation and Quality in pharmaceutical development) DILI Initiative that consists of members from 17 pharmaceutical companies, in collaboration with academic and regulatory DILI experts. The manuscript is based on extensive literature review, expert interpretation of the literature, and several rounds of consensus discussions. RESULTS This review highlights recommendations for patient eligibility for clinical trials with or without primary/metastatic liver involvement, as well as changes in liver tests that should trigger increased monitoring and/or discontinuation of study drug. Guidance regarding causality assessment for suspected DILI events, rechallenge and dose-modification is provided. CONCLUSIONS This review brings together evidence-based recommendations and expert opinion to provide the first dedicated consensus for best practices in detection, assessment, and management of DILI in oncology clinical trials.
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Affiliation(s)
| | - John Marcinak
- Pharmacovigilance and Patient Safety, AbbVie, North Chicago, Illinois, USA
| | | | - Hui-Talia Zhang
- Benefit-Risk Management and Pharmacovigilance, Bayer Pharmaceuticals, USA
| | | | - Arie Regev
- Global Patient Safety, Eli Lilly and Company, Indianapolis, Indiana, USA
| | | | - Don Rockey
- Digestive Disease Research Center, Charleston, South Carolina, USA
| | | | - Paul H Hayashi
- Food and Drug Administration, Silver Spring, Maryland, USA
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Srinivasan R, Dominic S, George A. Clinical and laboratory profile and outcome in children with Wilson disease: an observational study in South India. Paediatr Int Child Health 2024; 44:131-140. [PMID: 39245999 DOI: 10.1080/20469047.2024.2396716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Accepted: 08/21/2024] [Indexed: 09/10/2024]
Abstract
BACKGROUND Wilson disease is an autosomal recessive disorder owing to defective copper metabolism which causes abnormal accumulation of copper and damage to the liver, brain, kidneys and other organs. AIM To describe the clinical features, laboratory investigations and outcome of Wilson disease in children. METHODS A retrospective observational study was conducted in the paediatric department of a tertiary- care hospital in South India by reviewing medical records between January 2018 and March 2023. The diagnosis of Wilson disease was confirmed by the presence of low serum ceruloplasmin and/or high urine copper excretion in combination with clinical and ophthalmological features. RESULTS A total of 32 cases were analysed. The mean (SD) age at presentation was 110 (36) months with a M:F ratio of 1.6:1. Isolated hepatic involvement was seen in 19 (60%) patients while 13 (40%) patients had a neurological presentation, either as an isolated entity or in combination with hepatic manifestations. Low serum ceruloplasmin levels were detected in 31 (96%) patients. Urine copper levels were elevated in all patients. Twenty-one patients were commenced on D penicillamine while 11 patients were treated with a combination chelation therapy with zinc. Eighteen patients (56%) were on regular follow-up. CONCLUSION The clinical presentation of Wilson disease in children is diverse, varying from the more common hepatic or neurological manifestations to the less common atypical forms of the disease. Diagnosis is based on clinical and ophthalmological features in combination with biochemical abnormalities in the form of low ceruloplasmin and high urinary copper. The majority of patients can be medically managed with chelation therapy.
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Affiliation(s)
- Ranjini Srinivasan
- Department of Pediatrics, St John's Medical College Hospital, Bengaluru, India
| | - Shilpa Dominic
- Department of Pediatrics, St John's Medical College Hospital, Bengaluru, India
| | - Antony George
- Department of Pediatrics, St John's Medical College Hospital, Bengaluru, India
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Pan C, Ji Z, Wang Q, Zhang Z, Wang Z, Li C, Lu S, Ge P. Cuproptosis: Mechanisms, biological significance, and advances in disease treatment-A systematic review. CNS Neurosci Ther 2024; 30:e70039. [PMID: 39267265 PMCID: PMC11392831 DOI: 10.1111/cns.70039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 08/16/2024] [Accepted: 08/22/2024] [Indexed: 09/17/2024] Open
Abstract
BACKGROUND Copper is an essential trace element for biological systems, as it plays a critical role in the activity of various enzymes and metabolic processes. However, the dysregulation of copper homeostasis is closely associated with the onset and progression of numerous diseases. In recent years, copper-induced cell death, a novel form of cellular demise, has garnered significant attention. This process is characterized by the abnormal accumulation of intracellular copper ions, leading to cellular dysfunction and eventual cell death. Copper toxicity occurs through the interaction of copper with acylated enzymes in the tricarboxylic acid (TCA) cycle. This interaction results in subsequent protein aggregation, causing proteotoxic stress and ultimately resulting in cell death. Despite the promise of these findings, the detailed mechanisms and broader implications of cuproptosis remain underexplored. Therefore, our study aimed to investigate the role of copper in cell death and autophagy, focusing on the molecular mechanisms of cuproptosis. We also aimed to discuss recent advancements in copper-related research across various diseases and tumors, providing insights for future studies and potential therapeutic applications. MAIN BODY This review delves into the biological significance of copper metabolism and the molecular mechanisms underlying copper-induced cell death. Furthermore, we discuss the role of copper toxicity in the pathogenesis of various diseases, emphasizing recent advancements in the field of oncology. Additionally, we explore the therapeutic potential of targeting copper toxicity. CONCLUSION The study highlights the need for further research to explore alternative pathways of copper-induced cell death, detailed mechanisms of cuproptosis, and biomarkers for copper poisoning. Future research should focus on exploring the molecular mechanisms of cuproptosis, developing new therapeutic strategies, and verifying their safety and efficacy in clinical trials.
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Affiliation(s)
- Chengliang Pan
- Department of Neurosurgery, First Hospital of Jilin University, Changchun, P.R. China
| | - Zhilin Ji
- Department of Neurosurgery, First Hospital of Jilin University, Changchun, P.R. China
| | - Qingxuan Wang
- Department of Neurosurgery, First Hospital of Jilin University, Changchun, P.R. China
| | - Zhao Zhang
- Department of Neurosurgery, First Hospital of Jilin University, Changchun, P.R. China
| | - Zhenchuan Wang
- Department of Neurosurgery, First Hospital of Jilin University, Changchun, P.R. China
| | - Chen Li
- Department of Neurosurgery, First Hospital of Jilin University, Changchun, P.R. China
| | - Shan Lu
- Department of Neurosurgery, First Hospital of Jilin University, Changchun, P.R. China
| | - Pengfei Ge
- Department of Neurosurgery, First Hospital of Jilin University, Changchun, P.R. China
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11
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Delle Cave V, Di Dato F, Calvo PL, Spagnuolo MI, Iorio R. Successful treatment of acute liver failure due to Wilson's disease: Serendipity or fortuity? World J Hepatol 2024; 16:1111-1119. [PMID: 39221095 PMCID: PMC11362907 DOI: 10.4254/wjh.v16.i8.1111] [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: 04/27/2024] [Revised: 05/28/2024] [Accepted: 06/18/2024] [Indexed: 08/21/2024] Open
Abstract
BACKGROUND Acute liver failure (ALF) may be the first and most dramatic presentation of Wilson's disease (WD). ALF due to WD (WD-ALF) is difficult to distinguish from other causes of liver disease and is a clear indication for liver transplantation. There is no firm recommendation on specific and supportive medical treatment for this condition. AIM To critically evaluate the diagnostic and therapeutic management of WD-ALF patients in order to improve their survival with native liver. METHODS A retrospective analysis of patients with WD-ALF was conducted in two pediatric liver units from 2018 to 2023. RESULTS During the study period, 16 children (9 males) received a diagnosis of WD and 2 of them presented with ALF. The first was successfully treated with an unconventional combination of low doses of D-penicillamine and zinc plus steroids, and survived without liver transplant. The second, exclusively treated with supportive therapy, needed a hepatotransplant to overcome ALF. CONCLUSION Successful treatment of 1 WD-ALF patient with low-dose D-penicillamine and zinc plus steroids may provide new perspectives for management of this condition, which is currently only treated with liver transplantation.
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Affiliation(s)
- Valeria Delle Cave
- Department of Translational Medical Science, Section of Pediatrics, University of Naples Federico II, Naples 80131, Italy
| | - Fabiola Di Dato
- Department of Translational Medical Science, Section of Pediatrics, University of Naples Federico II, Naples 80131, Italy
| | - Pier Luigi Calvo
- Pediatric Gastroenterology Unit, Regina Margherita Children's Hospital, Azienda Ospedaliera-Universitaria Città della Salute e della Scienza, Turin 10126, Italy
| | - Maria Immacolata Spagnuolo
- Department of Translational Medical Science, Section of Pediatrics, University of Naples Federico II, Naples 80131, Italy
| | - Raffaele Iorio
- Department of Translational Medical Science, Section of Pediatrics, University of Naples Federico II, Naples 80131, Italy.
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12
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Koenig AB, Tan A, Abdelaal H, Monge F, Younossi ZM, Goodman ZD. Review article: Hepatic steatosis and its associations with acute and chronic liver diseases. Aliment Pharmacol Ther 2024; 60:167-200. [PMID: 38845486 DOI: 10.1111/apt.18059] [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: 04/04/2024] [Revised: 04/23/2024] [Accepted: 05/13/2024] [Indexed: 06/28/2024]
Abstract
BACKGROUND Hepatic steatosis is a common finding in liver histopathology and the hallmark of metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), whose global prevalence is rising. AIMS To review the histopathology of hepatic steatosis and its mechanisms of development and to identify common and rare disease associations. METHODS We reviewed literature on the basic science of lipid droplet (LD) biology and clinical research on acute and chronic liver diseases associated with hepatic steatosis using the PubMed database. RESULTS A variety of genetic and environmental factors contribute to the development of chronic hepatic steatosis or steatotic liver disease, which typically appears macrovesicular. Microvesicular steatosis is associated with acute mitochondrial dysfunction and liver failure. Fat metabolic processes in hepatocytes whose dysregulation leads to the development of steatosis include secretion of lipoprotein particles, uptake of remnant lipoprotein particles or free fatty acids from blood, de novo lipogenesis, oxidation of fatty acids, lipolysis and lipophagy. Hepatic insulin resistance is a key feature of MASLD. Seipin is a polyfunctional protein that facilitates LD biogenesis. Assembly of hepatitis C virus takes place on LD surfaces. LDs make important, functional contact with the endoplasmic reticulum and other organelles. CONCLUSIONS Diverse liver pathologies are associated with hepatic steatosis, with MASLD being the most important contributor. The biogenesis and dynamics of LDs in hepatocytes are complex and warrant further investigation. Organellar interfaces permit co-regulation of lipid metabolism to match generation of potentially toxic lipid species with their LD depot storage.
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Affiliation(s)
- Aaron B Koenig
- Beatty Liver and Obesity Research Program, Inova Health System, Falls Church, Virginia, USA
| | - Albert Tan
- Beatty Liver and Obesity Research Program, Inova Health System, Falls Church, Virginia, USA
- Center for Liver Diseases, Inova Fairfax Hospital, Falls Church, Virginia, USA
| | - Hala Abdelaal
- Beatty Liver and Obesity Research Program, Inova Health System, Falls Church, Virginia, USA
- Center for Liver Diseases, Inova Fairfax Hospital, Falls Church, Virginia, USA
| | - Fanny Monge
- Beatty Liver and Obesity Research Program, Inova Health System, Falls Church, Virginia, USA
- Center for Liver Diseases, Inova Fairfax Hospital, Falls Church, Virginia, USA
| | - Zobair M Younossi
- Beatty Liver and Obesity Research Program, Inova Health System, Falls Church, Virginia, USA
- The Global NASH Council, Center for Outcomes Research in Liver Diseases, Washington, DC, USA
| | - Zachary D Goodman
- Beatty Liver and Obesity Research Program, Inova Health System, Falls Church, Virginia, USA
- Center for Liver Diseases, Inova Fairfax Hospital, Falls Church, Virginia, USA
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13
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Teschke R. Copper, Iron, Cadmium, and Arsenic, All Generated in the Universe: Elucidating Their Environmental Impact Risk on Human Health Including Clinical Liver Injury. Int J Mol Sci 2024; 25:6662. [PMID: 38928368 PMCID: PMC11203474 DOI: 10.3390/ijms25126662] [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: 05/27/2024] [Revised: 06/12/2024] [Accepted: 06/14/2024] [Indexed: 06/28/2024] Open
Abstract
Humans are continuously exposed to various heavy metals including copper, iron, cadmium, and arsenic, which were specifically selected for the current analysis because they are among the most frequently encountered environmental mankind and industrial pollutants potentially causing human health hazards and liver injury. So far, these issues were poorly assessed and remained a matter of debate, also due to inconsistent results. The aim of the actual report is to thoroughly analyze the positive as well as negative effects of these four heavy metals on human health. Copper and iron are correctly viewed as pollutant elements essential for maintaining human health because they are part of important enzymes and metabolic pathways. Healthy individuals are prepared through various genetically based mechanisms to maintain cellular copper and iron homeostasis, thereby circumventing or reducing hazardous liver and organ injury due to excessive amounts of these metals continuously entering the human body. In a few humans with gene aberration, however, liver and organ injury may develop because excessively accumulated copper can lead to Wilson disease and substantial iron deposition to hemochromatosis. At the molecular level, toxicities of some heavy metals are traced back to the Haber Weiss and Fenton reactions involving reactive oxygen species formed in the course of oxidative stress. On the other hand, cellular homeostasis for cadmium and arsenic cannot be provided, causing their life-long excessive deposition in the liver and other organs. Consequently, cadmium and arsenic represent health hazards leading to higher disability-adjusted life years and increased mortality rates due to cancer and non-cancer diseases. For unknown reasons, however, liver injury in humans exposed to cadmium and arsenic is rarely observed. In sum, copper and iron are good for the human health of most individuals except for those with Wilson disease or hemochromatosis at risk of liver injury through radical formation, while cadmium and arsenic lack any beneficial effects but rather are potentially hazardous to human health with a focus on increased disability potential and risk for cancer. Primary efforts should focus on reducing the industrial emission of hazardous heavy metals.
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Affiliation(s)
- Rolf Teschke
- Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, 63450 Hanau, Germany; ; Tel.: +49-6181/21859; Fax: +49-6181/2964211
- Academic Teaching Hospital of the Medical Faculty, Goethe University Frankfurt/Main, 60590 Hanau, Germany
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14
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Teschke R, Eickhoff A. Wilson Disease: Copper-Mediated Cuproptosis, Iron-Related Ferroptosis, and Clinical Highlights, with Comprehensive and Critical Analysis Update. Int J Mol Sci 2024; 25:4753. [PMID: 38731973 PMCID: PMC11084815 DOI: 10.3390/ijms25094753] [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: 03/06/2024] [Revised: 04/18/2024] [Accepted: 04/20/2024] [Indexed: 05/13/2024] Open
Abstract
Wilson disease is a genetic disorder of the liver characterized by excess accumulation of copper, which is found ubiquitously on earth and normally enters the human body in small amounts via the food chain. Many interesting disease details were published on the mechanistic steps, such as the generation of reactive oxygen species (ROS) and cuproptosis causing a copper dependent cell death. In the liver of patients with Wilson disease, also, increased iron deposits were found that may lead to iron-related ferroptosis responsible for phospholipid peroxidation within membranes of subcellular organelles. All topics are covered in this review article, in addition to the diagnostic and therapeutic issues of Wilson disease. Excess Cu2+ primarily leads to the generation of reactive oxygen species (ROS), as evidenced by early experimental studies exemplified with the detection of hydroxyl radical formation using the electron spin resonance (ESR) spin-trapping method. The generation of ROS products follows the principles of the Haber-Weiss reaction and the subsequent Fenton reaction leading to copper-related cuproptosis, and is thereby closely connected with ROS. Copper accumulation in the liver is due to impaired biliary excretion of copper caused by the inheritable malfunctioning or missing ATP7B protein. As a result, disturbed cellular homeostasis of copper prevails within the liver. Released from the liver cells due to limited storage capacity, the toxic copper enters the circulation and arrives at other organs, causing local accumulation and cell injury. This explains why copper injures not only the liver, but also the brain, kidneys, eyes, heart, muscles, and bones, explaining the multifaceted clinical features of Wilson disease. Among these are depression, psychosis, dysarthria, ataxia, writing problems, dysphagia, renal tubular dysfunction, Kayser-Fleischer corneal rings, cardiomyopathy, cardiac arrhythmias, rhabdomyolysis, osteoporosis, osteomalacia, arthritis, and arthralgia. In addition, Coombs-negative hemolytic anemia is a key feature of Wilson disease with undetectable serum haptoglobin. The modified Leipzig Scoring System helps diagnose Wilson disease. Patients with Wilson disease are well-treated first-line with copper chelators like D-penicillamine that facilitate the removal of circulating copper bound to albumin and increase in urinary copper excretion. Early chelation therapy improves prognosis. Liver transplantation is an option viewed as ultima ratio in end-stage liver disease with untreatable complications or acute liver failure. Liver transplantation finally may thus be a life-saving approach and curative treatment of the disease by replacing the hepatic gene mutation. In conclusion, Wilson disease is a multifaceted genetic disease representing a molecular and clinical challenge.
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Affiliation(s)
- Rolf Teschke
- Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, D-63450 Hanau, Germany;
- Academic Teaching Hospital of the Medical Faculty, Goethe University Frankfurt, D-60590 Frankfurt, Germany
| | - Axel Eickhoff
- Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, D-63450 Hanau, Germany;
- Academic Teaching Hospital of the Medical Faculty, Goethe University Frankfurt, D-60590 Frankfurt, Germany
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15
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Samanta A, Poddar U. Pediatric acute liver failure: Current perspective in etiology and management. Indian J Gastroenterol 2024; 43:349-360. [PMID: 38466551 DOI: 10.1007/s12664-024-01520-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 12/28/2023] [Indexed: 03/13/2024]
Abstract
Pediatric acute liver failure (PALF) is a catastrophic clinical condition with very high morbidity and mortality without early detection and intervention. It is characterized by the acute onset of massive hepatocellular injury that releases circulating inflammatory mediators, resulting in metabolic disturbances, coagulopathy, hepatic encephalopathy and multi-organ failure. The etiological spectrum is dominated by hepatotropic viruses, drug-induced liver injury, metabolic and genetic disorders and immune-mediated diseases. Unlike adults, indeterminate causes for acute liver failure constitute a considerable proportion of cases of acute liver failure in children in the west. The heterogeneity of age and etiology in PALF has led to difficulties in developing prognostic scoring. The recent guidelines emphasize prompt identification of PALF, age-appropriate evaluation for hepatic encephalopathy and laboratory evaluation with careful monitoring. Current therapy focuses on supporting the failing liver and other organs, pending either spontaneous recovery or liver transplantation. Targeted therapy is available for a select group of etiologies. Liver transplantation can be lifesaving and a plan for the same should be organized, whenever indicated. The aim of this review is to define PALF, understand its etiopathogenesis, address the challenges encountered during the management and update the latest advances in liver transplantation and non-transplant treatment options in PALF.
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Affiliation(s)
- Arghya Samanta
- Department of Pediatric Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Lucknow, 226 014, India
| | - Ujjal Poddar
- Department of Pediatric Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Lucknow, 226 014, India.
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16
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Khan AA, Brandi ML, Rush ET, Ali DS, Al-Alwani H, Almonaei K, Alsarraf F, Bacrot S, Dahir KM, Dandurand K, Deal C, Ferrari SL, Giusti F, Guyatt G, Hatcher E, Ing SW, Javaid MK, Khan S, Kocijan R, Linglart A, M'Hiri I, Marini F, Nunes ME, Rockman-Greenberg C, Roux C, Seefried L, Simmons JH, Starling SR, Ward LM, Yao L, Brignardello-Petersen R, Lewiecki EM. Hypophosphatasia diagnosis: current state of the art and proposed diagnostic criteria for children and adults. Osteoporos Int 2024; 35:431-438. [PMID: 37982857 PMCID: PMC10866785 DOI: 10.1007/s00198-023-06844-1] [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: 12/29/2022] [Accepted: 06/23/2023] [Indexed: 11/21/2023]
Abstract
BACKGROUND This manuscript provides a summary of the current evidence to support the criteria for diagnosing a child or adult with hypophosphatasia (HPP). The diagnosis of HPP is made on the basis of integrating clinical features, laboratory profile, radiographic features of the condition, and DNA analysis identifying the presence of a pathogenic variant of the tissue nonspecific alkaline phosphatase gene (ALPL). Often, the diagnosis of HPP is significantly delayed in both adults and children, and updated diagnostic criteria are required to keep pace with our evolving understanding regarding the relationship between ALPL genotype and associated HPP clinical features. METHODS An International Working Group (IWG) on HPP was formed, comprised of a multidisciplinary team of experts from Europe and North America with expertise in the diagnosis and management of patients with HPP. Methodologists (Romina Brignardello-Petersen and Gordon Guyatt) and their team supported the IWG and conducted systematic reviews following the GRADE methodology, and this provided the basis for the recommendations. RESULTS The IWG completed systematic reviews of the literature, including case reports and expert opinion papers describing the phenotype of patients with HPP. The published data are largely retrospective and include a relatively small number of patients with this rare condition. It is anticipated that further knowledge will lead to improvement in the quality of genotype-phenotype reporting in this condition. CONCLUSION Following consensus meetings, agreement was reached regarding the major and minor criteria that can assist in establishing a clinical diagnosis of HPP in adults and children.
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Affiliation(s)
- Aliya A Khan
- Division of Endocrinology and Metabolism, McMaster University, Hamilton, Canada.
| | - Maria Luisa Brandi
- F.I.R.M.O. Italian Foundation for the Research On Bone Diseases, Florence, Italy
- Donatello Bone Clinic, Villa Donatello Hospital, Florence, Italy
| | - Eric T Rush
- Division of Clinical Genetics, Children's Mercy Kansas City, Kansas City, MO, USA
- Division of Endocrinology, Metabolism, Osteoporosis and Genetics, Department of Internal Medicine, University of Kansas School of Medicine, Kansas City, KS, USA
- Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA
| | - Dalal S Ali
- Division of Endocrinology and Metabolism, McMaster University, Hamilton, Canada
| | - Hatim Al-Alwani
- Division of Endocrinology and Metabolism, McMaster University, Hamilton, Canada
| | - Khulod Almonaei
- Division of Endocrinology and Metabolism, McMaster University, Hamilton, Canada
| | - Farah Alsarraf
- Division of Endocrinology and Metabolism, McMaster University, Hamilton, Canada
| | - Severine Bacrot
- Department of Genetics, Centre Hospitalier de Versailles, Hôpital André Mignot, Versailles, France
| | - Kathryn M Dahir
- Division of Endocrinology and Metabolism, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Karel Dandurand
- Department of Medicine, Endocrinology and Metabolism, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Chad Deal
- Center for Osteoporosis and Metabolic Bone Disease, Department of Rheumatology, The Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Serge Livio Ferrari
- Division of Bone Diseases, Department of Internal Medicine Specialties, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland
| | - Francesca Giusti
- Donatello Bone Clinic, Villa Donatello Hospital, Florence, Italy
| | - Gordon Guyatt
- Department of Health Research Methods, Evidence and Impact at McMaster University, Hamilton, Canada
| | - Erin Hatcher
- Neuromuscular Clinic, McMaster University Medical Centre, Hamilton Health Sciences, Hamilton, Canada
| | - Steven W Ing
- Division of Endocrinology, Diabetes & Metabolism, Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Muhammad Kassim Javaid
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
| | - Sarah Khan
- Bone Research and Education Centre, Oakville, ON, Canada
| | - Roland Kocijan
- Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of OEGK and AUVA, Trauma Centre Meidling, 1St Medical Department Hanusch Hospital, 1140, Vienna, Austria
| | - Agnes Linglart
- APHP, Bicêtre Paris-Sud, UniversityParis Sud, Paris-Saclay, Le Kremlin Bicêtre, Paris, France
| | - Iman M'Hiri
- Bone Research and Education Centre, Oakville, ON, Canada
| | - Francesca Marini
- F.I.R.M.O. Italian Foundation for the Research On Bone Diseases, Florence, Italy
| | - Mark E Nunes
- Division of Medical Genetics and Metabolism, Valley Children's HealthCare, Madera, CA, USA
| | | | - Christian Roux
- INSERM CRESS UMR 1153, Paris, France
- Université Paris-Cité, Department of Rheumatology, APHP-Centre, Cochin Hospital, Paris, France
| | - Lothar Seefried
- Musculoskeletal Center Wuerzburg, University of Würzburg, Würzburg, Germany
| | - Jill H Simmons
- Division of Endocrinology and Metabolism, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Susan R Starling
- Division of Clinical Genetics, Children's Mercy Kansas City, Kansas City, MO, USA
| | - Leanne M Ward
- Children's Hospital of Eastern Ontario, Department of Pediatrics, University of Ottawa, Ottawa, ON, Canada
| | - Liang Yao
- Department of Health Research Methods, Evidence and Impact at McMaster University, Hamilton, Canada
| | | | - E Michael Lewiecki
- New Mexico Clinical Research & Osteoporosis Center, Albuquerque, NM, USA
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Morton A. Investigating gastrointestinal disorders in pregnancy. Obstet Med 2024; 17:5-12. [PMID: 38660319 PMCID: PMC11037196 DOI: 10.1177/1753495x231206211] [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: 04/13/2023] [Revised: 08/21/2023] [Accepted: 09/20/2023] [Indexed: 04/26/2024] Open
Abstract
This article reviews anatomical and physiological changes and alterations in reference intervals for laboratory tests in healthy pregnancy, pertinent to investigation of the gastrointestinal system. The safety of procedures and radiological investigations relevant to the investigation of gastrointestinal disorders in pregnancy are also reviewed.
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Affiliation(s)
- Adam Morton
- Mater Health, Raymond Terrace, South Brisbane, QLD, 4101, Australia
- Department of Medicine, University of Queensland, Herston, Brisbane, QLD, 4029, Australia
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18
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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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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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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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21
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Mazhar A, Piper MS. Updates on Wilson disease. Clin Liver Dis (Hoboken) 2023; 22:117-121. [PMID: 37908869 PMCID: PMC10615495 DOI: 10.1097/cld.0000000000000079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Accepted: 06/26/2023] [Indexed: 11/02/2023] Open
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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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Biswas S, Shalimar. Liver Transplantation for Acute Liver Failure- Indication, Prioritization, Timing, and Referral. J Clin Exp Hepatol 2023; 13:820-834. [PMID: 37693253 PMCID: PMC10483009 DOI: 10.1016/j.jceh.2023.01.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 01/17/2023] [Indexed: 09/12/2023] Open
Abstract
Acute liver failure (ALF) is a major success story in gastroenterology, with improvements in critical care and liver transplant resulting in significant improvements in patient outcomes in the current era compared to the dismal survival rates in the pretransplant era. However, the ever-increasing list of transplant candidates and limited organ pool makes judicious patient selection and organ use mandatory to achieve good patient outcomes and prevent organ wastage. Several scoring systems exist to facilitate the identification of patients who need a liver transplant and would therefore need an early referral to a specialized liver unit. The timing of the liver transplant is also crucial as transplanting a patient too early would lead to those who would recover spontaneously receiving an organ (wastage), and a late decision might result in the patient becoming unfit for transplant (delisted) or have an advanced disease which would result in poor post-transplant outcomes. The current article reviews the indications and contraindications of liver transplant in ALF patients, the various prognostic scoring systems, etiology-specific outcomes, prioritization and timing of referral.
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Affiliation(s)
- Sagnik Biswas
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences New Delhi, India
| | - Shalimar
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences New Delhi, India
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24
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Wungjiranirun M, Sharzehi K. Wilson's Disease. Semin Neurol 2023; 43:626-633. [PMID: 37607588 DOI: 10.1055/s-0043-1771465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/24/2023]
Abstract
Wilson's disease (WD) can present with liver disease, neurological deficits, and psychiatric disorders. Results of genetic prevalence studies suggest that WD might be much more common than previously estimated. Early recognition of WD remains challenging because it is a great imitator and requires a high index of suspicion for correct and timely diagnosis. Early diagnosis of WD is crucial to ensure that patients can be started on adequate treatment. In association with other clinical and biochemical tests, liver biopsy results and molecular genetic testing can also be used for diagnosing WD. 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. Although novel therapies, such as gene therapy, are on the horizon, screening and prevention of delayed diagnosis remains paramount.
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Affiliation(s)
- Manida Wungjiranirun
- Division of Gastroenterology, Department of Medicine, Oregon Health and Science University, Portland, Oregon
| | - Kaveh Sharzehi
- Division of Gastroenterology, Department of Medicine, Oregon Health and Science University, Portland, Oregon
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Alkhouri N, Gonzalez-Peralta RP, Medici V. Wilson disease: a summary of the updated AASLD Practice Guidance. Hepatol Commun 2023; 7:02009842-202306010-00006. [PMID: 37184530 DOI: 10.1097/hc9.0000000000000150] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 03/15/2023] [Indexed: 05/16/2023] Open
Abstract
Wilson disease (WD) is caused by autosomal variants affecting the ATP7B gene on chromosome 13, resulting in alterations in physiological copper homeostasis and copper accumulation. Excess copper clinically manifests in many organs, most often in the central nervous system and liver, ultimately causing cirrhosis and death. Often considered a pediatric or young adult disease, WD actually affects patients of all ages, and aging patients need to be regularly managed with long-term follow-up. Despite over a century of advances in diagnosis and treatment, WD is still associated with diagnostic challenges and considerable disability and death, in part due to delays in diagnosis and limitations in treatment. Standard-of-care treatments are considered generally effective when the diagnosis is timely but are also limited by efficacy, safety concerns, multiple daily dosing, and adherence. This expert perspective review seeks to facilitate improvements in the awareness, understanding, diagnosis, and management of WD. The objectives are to provide a full overview of WD and streamline updated diagnosis and treatment guidance, as recently published by the American Association for the Study of Liver Diseases, in a practical way for clinical use.
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Affiliation(s)
| | | | - Valentina Medici
- Division of Gastroenterology and Hepatology, University of California Davis, Sacramento, California, USA
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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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Manivannan A, Husain S, Shukr B. Wilson Disease: Uncommon but Not to Be Forgotten. Cureus 2023; 15:e39247. [PMID: 37342740 PMCID: PMC10277656 DOI: 10.7759/cureus.39247] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/19/2023] [Indexed: 06/23/2023] Open
Abstract
Wilson disease (WD) is an autosomal recessive genetic disorder caused by mutations of ATP7B, a copper transporter, which results in impaired copper clearance. Its clinical manifestations are varied and can result in a mix of hepatic and neuropsychiatric symptoms. We present the case of a 26-year-old female with a past medical history of alcohol use who presented with right upper quadrant abdominal pain with associated vomiting, jaundice, and fatigue. She was found to have signs and symptoms of decompensated cirrhosis and was initially concerned about superimposed alcoholic hepatitis. With low ceruloplasmin and alkaline phosphatase, the suspicion for WD remained, and the patient underwent liver transplantation due to her worsening clinical status. The quantitative hepatic copper content of the explanted liver was elevated, and genetic testing confirmed the diagnosis of WD. Our case highlights the importance of including WD in the differential of a young patient with severe liver disease, and it highlights the utility of the phosphatidyl ethanol (PEth) test as a marker for chronic severe alcohol use. In patients with a significant alcohol use history, the diagnosis of WD should still be considered for those with reasonable clinical suspicion.
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Affiliation(s)
| | - Sanam Husain
- Pathology, Henry Ford Health System, Detroit, USA
| | - Batool Shukr
- Internal Medicine, Henry Ford Health System, Detroit, USA
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28
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Zou YG, Wang H, Li WW, Dai DL. Challenges in pediatric inherited/metabolic liver disease: Focus on the disease spectrum, diagnosis and management of relatively common disorders. World J Gastroenterol 2023; 29:2114-2126. [PMID: 37122598 PMCID: PMC10130973 DOI: 10.3748/wjg.v29.i14.2114] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 01/09/2023] [Accepted: 03/21/2023] [Indexed: 04/13/2023] Open
Abstract
The clinical scenario of pediatric liver disease is becoming more intricate due to changes in the disease spectrum, in which an increasing number of inherited/ metabolic liver diseases are reported, while infectious diseases show a decreasing trend. The similar clinical manifestations caused by inherited/metabolic diseases might be under-recognized or misdiagnosed due to nonspecific characteristics. A delayed visit to a doctor due to a lack of symptoms or mild symptoms at an early stage will result in late diagnosis and treatment. Moreover, limited diagnostic approaches, especially liver biopsy, are not easily accepted by pediatric patients, leading to challenges in etiological diagnosis. Liver dysfunction due to inherited/metabolic diseases is often caused by a variety of metabolites, so precision treatment is difficult; symptomatic treatment is a compelling option for inherited disorders.
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Affiliation(s)
- Yi-Gui Zou
- Key Laboratory for Precision Diagnosis and Treatment of Pediatric Digestive System Diseases and Endoscopy Center, Shenzhen Children's Hospital, Shenzhen 518026, Guangdong Province, China
| | - Huan Wang
- Key Laboratory for Precision Diagnosis and Treatment of Pediatric Digestive System Diseases and Endoscopy Center, Shenzhen Children's Hospital, Shenzhen 518026, Guangdong Province, China
| | - Wen-Wen Li
- Key Laboratory for Precision Diagnosis and Treatment of Pediatric Digestive System Diseases and Endoscopy Center, Shenzhen Children's Hospital, Shenzhen 518026, Guangdong Province, China
| | - Dong-Ling Dai
- Key Laboratory for Precision Diagnosis and Treatment of Pediatric Digestive System Diseases and Endoscopy Center, Shenzhen Children's Hospital, Shenzhen 518026, Guangdong Province, China
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Schilsky ML, Roberts EA, Bronstein JM, Dhawan A, Hamilton JP, Rivard AM, Washington MK, Weiss KH, Zimbrean PC. A multidisciplinary approach to the diagnosis and management of Wilson disease: Executive summary of the 2022 Practice Guidance on Wilson disease from the American Association for the Study of Liver Diseases. Hepatology 2023; 77:1428-1455. [PMID: 36152019 DOI: 10.1002/hep.32805] [Citation(s) in RCA: 68] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 09/13/2022] [Indexed: 12/08/2022]
Affiliation(s)
- Michael L Schilsky
- Medicine and Surgery , Yale University School of Medicine , New Haven , Connecticut , USA
| | - Eve A Roberts
- Paediatrics, Medicine, Pharmacology and Toxicology , University of Toronto , Toronto , Ontario , Canada
| | - Jeff M Bronstein
- Neurology , University of California Los Angeles , Los Angeles , California , USA
| | - Anil Dhawan
- Paediatric Liver, GI and Nutrition Centre and MowatLabs , King's College Hospital , London , UK
| | - James P Hamilton
- Medicine , Johns Hopkins University School of Medicine , Baltimore , Maryland , USA
| | - Anne Marie Rivard
- Food and Nutrition Services , Yale New Haven Hospital , New Haven , Connecticut , USA
| | - Mary Kay Washington
- Pathology, Immunology and Microbiology , Vanderbilt University Medical Center , Nashville , Tennessee , USA
| | | | - Paula C Zimbrean
- Psychiatry , Yale University School of Medicine , New Haven , Connecticut , USA
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30
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Ghaffar TYA, Abo-Alam HS, Emam M, El-Shabrawi M, Soliman AIA, Badwei N. Pitfalls in the management of metabolic liver diseases (debate). EGYPTIAN LIVER JOURNAL 2023; 13:11. [DOI: 10.1186/s43066-023-00246-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 02/11/2023] [Indexed: 02/19/2023] Open
Abstract
Abstract
Background
The liver has an important role in the different metabolic processes. So, inborn errors of metabolism will result in several metabolic disorders, which can cause acute or chronic liver disease leading to cirrhosis and liver cancer.
Main body
In one of our Egyptian conferences, the United Conference of Hepatogastroenterology and Infectious Diseases (UCHID) 2022, our authors discussed the debates on the management of Wilson’s disease, hereditary hemochromatosis, and alpha one anti-trypsin deficiency.
Conclusion
The session summarized the pitfalls in the management of the 3 serious metabolic liver disorders with focused take-home messages to every physician.
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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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Noujaim MG, Oloruntoba OO, Jeck WR, Brady CW. The needle in the haystack: deciphering diagnostic data in a case of acute on chronic liver failure. Clin Liver Dis (Hoboken) 2023; 21:13-18. [PMID: 36937779 PMCID: PMC9875790 DOI: 10.1097/cld.0000000000000002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 10/19/2022] [Indexed: 01/25/2023] Open
Affiliation(s)
- Michael G. Noujaim
- Division of Gastroenterology, Duke University Medical Center, Durham, NC
| | | | | | - Carla W. Brady
- Division of Gastroenterology, Duke University Medical Center, Durham, NC
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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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34
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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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35
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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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36
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Sadhukhan S, Mehta P, Rajender S, Gupta SK, Chattopadhyay N. Proposing a clinical algorithm for better diagnosis of hypophosphatasia in resource-limiting situations. Osteoporos Int 2022; 33:2479-2493. [PMID: 35776147 DOI: 10.1007/s00198-022-06480-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 06/16/2022] [Indexed: 10/17/2022]
Abstract
Early diagnosis of hypophosphatasia (HPP) is challenging. Here, we propose to broaden the diagnostic criteria of HPP by reviewing published data on BMD and fractures in HPP patients. Non-osteoporotic fractures and higher than normal lumbar BMD were recurrent in HPP patients and could be included as diagnostic criteria. HPP is a genetic disorder caused by autosomal recessive or dominant loss-of-function mutations in the ALPL gene that encodes for tissue-nonspecific alkaline phosphatase (TNSALP). Expressive genetic heterogeneity and varying severity of TNSALP deficiency lead to a wide-ranging presentation of skeletal diseases at different ages that coupled with HPP's rarity and limitation of biochemical and mutational studies present serious hurdles to early diagnosis and management of HPP. To widen the scope of HPP diagnosis, we assessed the possibility of areal bone mineral density (BMD) as an additional clinical feature of this disease. PubMed, Web of Science, and ScienceDirect were searched with the following keywords: ("Hypophosphatasia OR HPP") AND ("Bone Mineral Density OR BMD") AND "Human". Studies and case reports of subjects with age ≥ 18 years and having BMD data were included. We pooled data from 25 publications comprising 356 subjects (90 males, 266 females). Only four studies had a control group. Biochemical hallmarks, pyridoxal 5'-phosphate (PLP) and phosphoethanolamine (PEA), were reported in fifteen and six studies, respectively. Twenty studies reported genetic data, nineteen studies reported non-vertebral fractures, all studies reported lumbar spine (LS) BMD, and nineteen reported non-vertebral BMD. Higher than normal and normal BMD at LS were reported in three and two studies, respectively. There was marked heterogeneity in BMD at the non-vertebral sites. Higher than normal or normal LS BMD in an adult with minimal or insufficient fractures, pseudofractures, non-healing fractures, fragility fractures, and stress fractures may be included in the diagnostic protocol of HPP. However, genetic testing is recommended for a definitive diagnosis.
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Affiliation(s)
- Sreyanko Sadhukhan
- Division of Endocrinology and Centre for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), CSIR-Central Drug Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research, Ghaziabad, 201002, India
| | - Poonam Mehta
- Division of Endocrinology and Centre for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), CSIR-Central Drug Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research, Ghaziabad, 201002, India
| | - Singh Rajender
- Division of Endocrinology and Centre for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), CSIR-Central Drug Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research, Ghaziabad, 201002, India
| | - Sushil Kumar Gupta
- Department of Endocrinology, Sanjay Gandhi Post-Graduate Institute of Medical Sciences, Lucknow, India
| | - Naibedya Chattopadhyay
- Division of Endocrinology and Centre for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), CSIR-Central Drug Research Institute, Lucknow, India.
- Academy of Scientific and Innovative Research, Ghaziabad, 201002, India.
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37
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Jindal A, Sarin SK. Epidemiology of liver failure in Asia-Pacific region. Liver Int 2022; 42:2093-2109. [PMID: 35635298 DOI: 10.1111/liv.15328] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 05/26/2022] [Accepted: 05/27/2022] [Indexed: 02/13/2023]
Abstract
The global burden of deaths caused by liver failure is substantial. The Asia-Pacific region is home to more than half of the global population and accounted for 62.6% of global deaths because of liver diseases in 2015. The aetiology of liver failure varies in different countries at different times. Viruses (Hepatitis A, B and E), drugs (herbs and anti-tuberculous drugs), toxins (alcohol use) and autoimmune flares are mainly responsible of majority of liver failure in individuals with normal liver (acute liver failure; ALF); else these may precipitate liver failure in those with chronic liver disease (acute-on-chronic liver failure; ACLF). Concomitant increases in alcohol misuse and metabolic syndrome in recent years are concerning. Ongoing efforts to address liver failure-related morbidity and mortality require accurate contemporary estimates of epidemiology and outcomes. In light of the ever-changing nature of liver disease epidemiology, accurate estimates for the burden of liver failure across the countries are vital for setting clinical, research and policy priorities. In this review, we aimed to describe the current as well as changing epidemiological trends of common liver failure syndromes, ALF and ACLF in the Asia-Pacific region.
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Affiliation(s)
- Ankur Jindal
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Shiv K Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
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Rowan DJ, Mangalaparthi KK, Singh S, Moreira RK, Mounajjed T, Lamps L, Westerhoff M, Cheng J, Bellizzi AM, Allende DS, Pandey A, Graham RP. Metallothionein immunohistochemistry has high sensitivity and specificity for detection of Wilson disease. Mod Pathol 2022; 35:946-955. [PMID: 34934154 DOI: 10.1038/s41379-021-01001-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 12/07/2021] [Accepted: 12/09/2021] [Indexed: 11/09/2022]
Abstract
Diagnosis of Wilson disease (WD) can be difficult because of its protean clinical presentations, but early diagnosis is important because effective treatment is available and can prevent disease progression. Similarly, diagnosis of WD on liver biopsy specimens is difficult due to the wide range of histologic appearances. A stain that could help identify WD patients would be of great value. The goal of this study was to use mass spectrometry-based proteomics to identify potential proteins that are differentially expressed in WD compared to controls, and could serve as potential immunohistochemical markers for screening. Several proteins were differentially expressed in WD and immunohistochemical stains for two (metallothionein (MT) and cytochrome C oxidase copper chaperone (COX17)) were tested and compared to other methods of diagnosis in WD including copper staining and quantitative copper assays. We found diffuse metallothionein immunoreactivity in all liver specimens from patients with WD (n = 20); the intensity of the staining was moderate to strong. This staining pattern was distinct from that seen in specimens from the control groups (none of which showed strong, diffuse staining), which included diseases that may be in the clinical or histologic differential of WD (steatohepatitis (n = 51), chronic viral hepatitis (n = 40), autoimmune hepatitis (n = 50), chronic biliary tract disease (n = 42), and normal liver (n = 20)). COX17 immunostain showed no significant difference in expression between the WD and control groups. MT had higher sensitivity than rhodanine for diagnosis of WD. While the quantitative liver copper assays also had high sensitivity, they require more tissue, have a higher cost, longer turnaround time, and are less widely available than an immunohistochemical stain. We conclude that MT IHC is a sensitive immunohistochemical stain for the diagnosis of WD that could be widely deployed as a screening tool for liver biopsies in which WD is in the clinical or histologic differential diagnosis.
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Affiliation(s)
- Daniel J Rowan
- Department of Laboratory Medicine and Pathology, Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA
| | | | - Smrita Singh
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.,Institute of Bioinformatics, International Technology Park, Bangalore, 560066, Karnataka, India.,Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
| | - Roger K Moreira
- Department of Laboratory Medicine and Pathology, Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA
| | - Taofic Mounajjed
- Department of Laboratory Medicine and Pathology, Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA
| | - Laura Lamps
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Maria Westerhoff
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Jerome Cheng
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | | | | | - Akhilesh Pandey
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Rondell P Graham
- Department of Laboratory Medicine and Pathology, Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA.
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Yasmin A, Rukunuzzaman M, Karim ASMB, Alam R, Hossen K, Sonia ZF. Ratio of aspartate aminotransferase to alanine aminotransferase and alkaline phosphatase to total bilirubin in Wilsonian acute liver failure in children. Indian J Gastroenterol 2022; 41:224-230. [PMID: 35838867 DOI: 10.1007/s12664-022-01244-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Accepted: 01/15/2022] [Indexed: 02/04/2023]
Abstract
BACKGROUND Acute liver failure (ALF) caused by Wilson disease (WD) is always fatal. Therefore, a quick diagnosis of WD is needed to start immediate management. This study aims to determine the ratio of aspartate aminotransferase to alanine aminotransferase (AST/ALT) and the ratio of alkaline phosphatase to total bilirubin (ALP/TB) in diagnosing Wilsonian acute liver failure (WALF) in children. METHODS Sixty children with acute liver failure were included in this study, of whom 40 had WALF and 20 had a non-Wilsonian acute liver failure (non-WALF). The serum ALT, AST, alkaline phosphatase, and total bilirubin of each blood sample were measured. We evaluated the sensitivity and specificity of AST/ALT ratio and ALP/TB ratio in WALF diagnosis. RESULTS Consanguinity and Kayser-Fleischer (K-F) rings were found in 32.5% and 72.5% of WALF cases, respectively. The mean hemoglobin, median ALT, median alkaline phosphatase, and mean ceruloplasmin of children with WALF were lower than those in the non-WALF group. In WALF cases, the median AST/ALT ratio was higher than in non-WALF cases. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy of the ratio of AST to ALT were 70%, 95%, 96.5%, 61.3% and 78.3%, respectively. However, when the cutoff value is ≥ 1.85, the maximum sensitivity produced by the AST/ALT ratio is 77.5% and the specificity is 95%. The sensitivity, specificity, PPV, NPV, and diagnostic accuracy of the ratio of ALP/TB < 4 were 32.5%, 100%, 100%, 42.5%, and 55%, respectively. The overall mortality rate was 50%, while the WALF mortality was 60%. CONCLUSION A positive AST/ALT and ALP/TB ratio strongly suggest WALF, but a negative result does not exclude WALF. We cannot use these ratios as a diagnostic tool for children with WALF. In WALF cases, the mortality rate is remarkably high, and the high score of the new Wilson index predicts the mortality rate without liver transplantation.
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Affiliation(s)
- Afsana Yasmin
- Department of Pediatrics, Evercare Hospital Dhaka, Dhaka, Bangladesh. .,Department of Gastroenterology, Evercare Hospital Dhaka, Dhaka, Bangladesh.
| | - Md Rukunuzzaman
- Department of Pediatric Gastroenterology and Nutrition, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - A S M Bazlul Karim
- Department of Pediatric Gastroenterology and Nutrition, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Rubaiyat Alam
- Department of Pediatric Gastroenterology and Nutrition, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Kamal Hossen
- Dhaka Medical College Hospital, Dhaka, Bangladesh
| | - Zannatul Ferdous Sonia
- Department of Pediatric Gastroenterology and Nutrition, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
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Abstract
Acute liver failure (ALF) in children, irrespective of cause, is a rapidly evolving catastrophic clinical condition that results in high mortality and morbidity without prompt identification and intervention. Massive hepatocyte necrosis impairs the synthetic, excretory, and detoxification abilities of the liver, with resultant coagulopathy, jaundice, metabolic disturbance, and encephalopathy. Extrahepatic organ damage, multiorgan failure, and death result from circulating inflammatory mediators released by the hepatocytes undergoing necrosis. There are yet no treatment options available for reversing or halting hepatocellular necrosis, thus current therapy focuses on supporting failing organs and preventing life threatening complications pending either spontaneous liver recovery or transplantation. The aims of this review are to define pediatric acute liver failure (PALF), understand the pathophysiologic processes that lead to multiorgan failure, to describe the consequences of a failing liver on extrahepatic organs, to enumerate the critical care challenges encountered during PALF management, and to describe pharmacologic and extracorporeal options available to support a critically ill child with ALF in the intensive care unit.
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Affiliation(s)
- Divya G Sabapathy
- Department of Pediatrics, Division of Pediatric Critical Care Medicine and Liver ICU, Baylor College of Medicine, 1, Baylor Plaza, Houston, TX 77030, USA
| | - Moreshwar S Desai
- Department of Pediatrics, Division of Pediatric Critical Care Medicine and Liver ICU, Baylor College of Medicine, 1, Baylor Plaza, Houston, TX 77030, USA.
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Martínez-Morillo E, Bauça JM. Biochemical diagnosis of Wilson's disease: an update. ADVANCES IN LABORATORY MEDICINE 2022; 3:103-125. [PMID: 37361868 PMCID: PMC10197364 DOI: 10.1515/almed-2022-0020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 01/26/2022] [Indexed: 06/28/2023]
Abstract
Wilson's disease (WD) is an inherited disorder of copper metabolism caused by mutations in the ATP7B gene. This condition is characterized by the accumulation of copper in the liver and other organs and tissues causing hepatic and neuropsychiatric manifestations. This paper reviews the diagnostic performance and limitations of the biochemical tests commonly used to detect this underdiagnosed disease. It also provides some recommendations and suggests a set of standardized laboratory comments. At present, a rapid, simple, reliable biochemical test that confirms diagnosis of WD is not available. However, diagnosis can be established based on serum ceruloplasmin and urinary copper excretion. Total serum copper should be employed with caution, since it has a low negative predictive value. The use of estimated non-ceruloplasmin-bound copper is not recommended. Nevertheless, measured relative exchangeable copper has very high sensitivity and specificity and emerges as a potential gold standard for the biochemical diagnosis of WD. The development of novel assays for WD detection makes this disorder a potential candidate to be included in newborn screening programs.
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Affiliation(s)
- Eduardo Martínez-Morillo
- Department of Laboratory Medicine, Complejo Asistencial Universitario de Salamanca (CAUSA), Salamanca, Spain
| | - Josep Miquel Bauça
- Department of Laboratory Medicine, Hospital Universitario Son Espases, Palma de Mallorca, Spain
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Jagadisan B, Dhawan A. Emergencies in paediatric hepatology. J Hepatol 2022; 76:1199-1214. [PMID: 34990749 DOI: 10.1016/j.jhep.2021.12.027] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 12/17/2021] [Accepted: 12/21/2021] [Indexed: 12/12/2022]
Abstract
The aetiology of several liver diseases in children is age specific and many of these conditions have significant and potentially long-term clinical repercussions if not diagnosed early and managed in a timely fashion. We address 5 clinical scenarios that cover most of the diagnostic and therapeutic emergencies in children: infants with liver disease; acute liver failure; management of bleeding varices; liver-based metabolic disorders; and liver tumours and trauma. A wide spectrum of conditions that cause liver disease in infants may present as conjugated jaundice, which could be the only symptom of time-sensitive disorders - such as biliary atresia, metabolic disorders, infections, and haematological/alloimmune disorders - wherein algorithmic multistage testing is required for accurate diagnosis. In infantile cholestasis, algorithmic multistage tests are necessary for an accurate early diagnosis, while vitamin K, specific milk formulae and disease-specific medications are essential to avoid mortality and long-term morbidity. Management of paediatric acute liver failure requires co-ordination with a liver transplant centre, safe transport and detailed age-specific aetiological work-up - clinical stabilisation with appropriate supportive care is central to survival if transplantation is indicated. Gastrointestinal bleeding may present as the initial manifestation or during follow-up in patients with portal vein thrombosis or chronic liver disease and can be managed pharmacologically, or with endoscopic/radiological interventions. Liver-based inborn errors of metabolism may present as encephalopathy that needs to be recognised and treated early to avoid further neurological sequelae and death. Liver tumours and liver trauma are both rare occurrences in children and are best managed by a multidisciplinary team in a specialist centre.
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Affiliation(s)
- Barath Jagadisan
- Pediatric Liver GI and Nutrition Centre and MowatLabs, King's College Hospital, London, UK
| | - Anil Dhawan
- Pediatric Liver GI and Nutrition Centre and MowatLabs, King's College Hospital, London, UK.
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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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Adhikari S, Shah PK, Sharma YR. Case Report: Using basic liver function tests as a guide to suspected Wilson’s disease. F1000Res 2022; 10:608. [PMID: 35475033 PMCID: PMC9010801 DOI: 10.12688/f1000research.54569.2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/01/2022] [Indexed: 11/20/2022] Open
Abstract
We present a case of a 36-year-old female patient who presented with subacute liver disease with a history of alcohol abuse. On basic liver function tests (LFT), she had aspartate transaminase / alanine transaminase > 2.2 and alkaline phosphatase / total bilirubin < 4. This pattern in acute liver failure patients signifies Wilson’s disease. Its presence in our patient with subacute liver disease also prompted us to suspect Wilson’s disease and we extended the liver disease screen to include slit lamp eye examination for Kayser-Fleischer rings, serum ceruloplasmin and 24-hour urinary copper level, which led to the diagnosis. She improved clinically and biochemically with zinc acetate therapy. As screening for rare diseases is not always possible in low-income countries, this case demonstrates the usefulness of the basic LFT as a guide for suspecting Wilson’s disease in patients with liver disease.
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Affiliation(s)
- Sudeep Adhikari
- Department of Internal Medicine, Pyuthan Hospital, Pyuthan, 22300, Nepal
| | - Prashant Kumar Shah
- Department of Internal Medicine, Patan Academy of Health Sciences, Kathmandu, 26500, Nepal
| | - Yuba Raj Sharma
- Department of Internal Medicine, Patan Academy of Health Sciences, Kathmandu, 26500, Nepal
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Levitt MD, Hapak SM, Levitt DG. Alkaline Phosphatase Pathophysiology with Emphasis on the Seldom-Discussed Role of Defective Elimination in Unexplained Elevations of Serum ALP – A Case Report and Literature Review. Clin Exp Gastroenterol 2022; 15:41-49. [PMID: 35313457 PMCID: PMC8934114 DOI: 10.2147/ceg.s345531] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 03/03/2022] [Indexed: 12/30/2022] Open
Abstract
While serum alkaline phosphatase activity has become a routine clinical measurement, we have found that physicians’ knowledge of the pathophysiology of this enzyme is almost solely limited to the concept that an elevated serum alkaline phosphatase suggests disease of liver or bone. For example, physicians at all levels of training had no understanding of such basic physiological information as the function of alkaline phosphatase in the liver or how this enzyme is eliminated from the serum. Based on a patient with an enormously elevated alkaline phosphatase, this report provides a review of existing clinically relevant information concerning the pathophysiology of alkaline phosphatase with emphasis on the mechanisms involved in the homeostasis of this enzyme. A novel aspect of this paper is the discussion of the previously neglected concept that defective enzyme elimination could play a major role in the pathogenesis of serum alkaline phosphatase elevations.
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Affiliation(s)
- Michael D Levitt
- Medicine Service, Veterans Affairs Medical Center, Minneapolis, MN, 55417, USA
| | - Sophie M Hapak
- Department of Medicine, University of Minnesota, Minneapolis, MN, 55455, USA
| | - David G Levitt
- Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN, 55455, USA
- Correspondence: David G Levitt, Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN, 55455, USA, Email
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Squires JE, Alonso EM, Ibrahim SH, Kasper V, Kehar M, Martinez M, Squires RH. North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition Position Paper on the Diagnosis and Management of Pediatric Acute Liver Failure. J Pediatr Gastroenterol Nutr 2022; 74:138-158. [PMID: 34347674 DOI: 10.1097/mpg.0000000000003268] [Citation(s) in RCA: 77] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
ABSTRACT Pediatric acute liver failure (PALF) is a rare, rapidly progressive clinical syndrome with significant morbidity and mortality. The phenotype of PALF manifests as abrupt onset liver dysfunction, which can be brought via disparate etiology. Management is reliant upon intensive clinical care and support, often provided by the collaborative efforts of hepatologists, critical care specialists, and liver transplant surgeons. The construction of an age-based diagnostic approach, the identification of a potential underlying cause, and the prompt implementation of appropriate therapy can be lifesaving; however, the dynamic and rapidly progressive nature of PALF also demands that diagnostic inquiries be paired with monitoring strategies for the recognition and treatment of common complications of PALF. Although liver transplantation can provide a potential life-saving therapeutic option, the ability to confidently determine the certainness that liver transplant is needed for an individual child has been hampered by a lack of adequately tested clinical decision support tools and accurate predictive models. Given the accelerated progress in understanding PALF, we will provide clinical guidance to pediatric gastroenterologists and other pediatric providers caring for children with PALF by presenting the most recent advances in diagnosis, management, pathophysiology, and associated outcomes.
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Affiliation(s)
- James E Squires
- Division of Gastroenterology, Hepatology and Nutrition, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA
| | - Estella M Alonso
- Department Pediatric Hepatology, Ann and Robert H Lurie Children's Hospital, Chicago, Illinois, USA
| | - Samar H Ibrahim
- Department of Pediatrics, Division of Pediatric Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Vania Kasper
- Division of Pediatric Gastroenterology, Nutrition and Liver Diseases, Hasbro Children's Hospital, Providence, RI
| | - Mohit Kehar
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Children Hospital of Eastern Ontario, Ottawa, Ontario, Canada
| | - Mercedes Martinez
- Department of Pediatrics, Vagelos College of Physician and Surgeons, Columbia University, New York, NY
| | - Robert H Squires
- Division of Gastroenterology, Hepatology and Nutrition, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA
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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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Cioancă GL, Grama A, Petrescu L, Căinap S, Mateescu BR, Benţa G, Bulata B, Pop TL. Insuficienţă hepatică acută asociată cu infecţie recentă cu SARS-CoV-2 la un copil – prezentare de caz. PEDIATRU.RO 2022; 1:42. [DOI: 10.26416/pedi.65.1.2022.6336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
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Limdi JK. Editorial commentary on the Indian Journal of Gastroenterology-May-June 2022. Indian J Gastroenterol 2022; 41:213-217. [PMID: 35704177 PMCID: PMC9198610 DOI: 10.1007/s12664-022-01266-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Affiliation(s)
- Jimmy K Limdi
- grid.451052.70000 0004 0581 2008Section of Inflammatory Bowel Diseases, Division of Gastroenterology, Northern Care Alliance NHS Foundation Trust, Manchester, UK ,grid.5379.80000000121662407University of Manchester, Manchester, UK ,grid.25627.340000 0001 0790 5329Manchester Metropolitan University, Manchester, UK
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Kalas MA, Chavez L, Leon M, Taweesedt PT, Surani S. Abnormal liver enzymes: A review for clinicians. World J Hepatol 2021; 13:1688-1698. [PMID: 34904038 PMCID: PMC8637680 DOI: 10.4254/wjh.v13.i11.1688] [Citation(s) in RCA: 84] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 07/24/2021] [Accepted: 08/23/2021] [Indexed: 02/06/2023] Open
Abstract
Liver biochemical tests are some of the most commonly ordered routine tests in the inpatient and outpatient setting, especially with the automatization of testing in this technological era. These tests include aminotransferases, alkaline phosphatase, gamma-glutamyl transferase, bilirubin, albumin, prothrombin time and international normalized ratio (INR). Abnormal liver biochemical tests can be categorized based on the pattern and the magnitude of aminotransferases elevation. Generally, abnormalities in aminotransferases can be classified into a hepatocellular pattern or cholestatic pattern and can be further sub-classified based on the magnitude of aminotransferase elevation to mild [< 5 × upper limit of normal (ULN)], moderate (> 5-< 15 × ULN) and severe (> 15 × ULN). Hepatocellular pattern causes include but are not limited to; non-alcoholic fatty liver disease/non-alcoholic steatohepatitis, alcohol use, chronic viral hepatitis, liver cirrhosis (variable), autoimmune hepatitis, hemochromatosis, Wilson's disease, alpha-1 antitrypsin deficiency, celiac disease, medication-induced and ischemic hepatitis. Cholestatic pattern causes include but is not limited to; biliary pathology (obstruction, autoimmune), other conditions with hyperbilirubinemia (conjugated and unconjugated). It is crucial to interpret these commonly ordered tests accurately as appropriate further workup, treatment and referral can greatly benefit the patient due to prompt treatment which can improve the natural history of several of the diseases mentioned and possibly reduce the risk of progression to the liver cirrhosis.
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Affiliation(s)
- M Ammar Kalas
- Department of Internal Medicine, Texas Tech University Health Science Center, El Paso, TX 79905, United States
| | - Luis Chavez
- Department of Internal Medicine, Texas Tech University Health Science Center, El Paso, TX 79905, United States
| | - Monica Leon
- Department of General Surgery, University of Mexico, Ciudad de Mexico 01120, Mexico
| | - Pahnwat Tonya Taweesedt
- Department of Medicine, Corpus Christi Medical Center, Corpus Christi, TX 78412, United States
| | - Salim Surani
- Department of Medicine, Texas A&M University, College Station, TX 77843, United States
- Department of Anesthesiology, Mayo Clinic, Rochester, MN 55905, United States.
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