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Ramakrishna SH, Katheresan V, Kasala MB, Perumal K, Malleeswaran S, Varghese J, Patcha RV, Bachina P, Madhavapeddy PS, Reddy MS. Living Donor Liver Transplantation for Pediatric Wilson's Disease-related Acute Liver Failure-Hard Work With High Rewards. J Clin Exp Hepatol 2025; 15:102560. [PMID: 40337253 PMCID: PMC12053706 DOI: 10.1016/j.jceh.2025.102560] [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: 02/06/2025] [Accepted: 03/25/2025] [Indexed: 05/09/2025] Open
Abstract
Background Liver transplantation (LT) is indicated for children with Wilson's disease (WD) presenting with acute liver failure (ALF) or with chronic liver disease (CLD) that has progressed to decompensation. We present our experience of living donor liver transplantation (LDLT) for pediatric WD, discuss the challenges of managing WD-ALF and compare outcomes of children presenting with WD-ALF with WD-CLD. Methods We compared presentation and outcomes of the WD-ALF and WD-CLD cohorts. Fifty-three children (WD-ALF: 28 (53%), WD-CLD: 25 (47%)) underwent LDLT for WD. Results WD-ALF group had higher Kings New Wilson Index (KNWI) (15 vs 9, P = 0.001), higher pediatric end-stage liver disease/model for end-stage liver disease score (35 vs 20, P = 0.001), were more frequently encephalopathic (64% vs 4%, P = 0.001), and had ongoing hemolysis (86% vs 28%, <0.001). Preoperative mechanical ventilation, operative continuous renal replacement therapy (CRRT), therapeutic plasma exchange (TPE) was needed in 32%, 46.5%, and 89% of WD-ALF children, respectively. WD-ALF patients had longer postoperative ICU stay (4.5 days vs 3 days, P = 0.001), longer hospital stay (20.5 days vs 14 days, P = 0.001), more major complications (57% vs 20%, P = 0.006). WD-ALF cohort also had more postoperative neurological complications (42.9% vs 8%, P = 0.004) and invasive fungal infections (21.4% vs none, P = 0.024). There were two perioperative (90 day) mortalities in WD-ALF group and none in WD-CLD group. Patient survival of the entire cohort at median follow-up of 26 months was 94.3% and all survivors had good allograft function neurological sequelae. Patient survival was inferior for WD-ALF cohort though the difference was not statistically significant (88.5% vs 100%, log rank test, P = 0.089). Conclusion LDLT is a curative treatment for children with WD with excellent short-term and long-term outcomes. WD-ALF patients can have a complicated postoperative course but have good long-term survival.
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Affiliation(s)
- Somashekara H. Ramakrishna
- Department of Pediatric Hepatology & Transplant Hepatology, Rainbow Children's Hospital, Marathahalli, Bangalore, India
- Department of Pediatric Hepatology, Gleneagles Global Health City, Perumbakkam, Chennai, India
| | - Vellaichamy Katheresan
- Department of Liver Transplant and Hepatopancreaticobiliary Surgery, Gleneagles Global Health City, Perumbakkam, Chennai, India
| | - Mohan B. Kasala
- Department of Pediatric Intensive Care, Gleneagles Global Health City, Perumbakkam, Chennai, India
| | - Karnan Perumal
- Department of Pediatric Intensive Care, Gleneagles Global Health City, Perumbakkam, Chennai, India
| | - Selvakumar Malleeswaran
- Department of Liver Anesthesia and Critical Care, Gleneagles Global Health City, Perumbakkam, Chennai, India
| | - Joy Varghese
- Department of Hepatology, Gleneagles Global Health City, Perumbakkam, Chennai, India
| | - Rajanikanth V. Patcha
- Department of Liver Transplant and Hepatopancreaticobiliary Surgery, Gleneagles Global Health City, Perumbakkam, Chennai, India
| | - Prashant Bachina
- Department of Pediatric Gastroenterology, Rainbow Children's Hospitals, Banjara Hills, Hyderabad, India
| | - Poushya S. Madhavapeddy
- Department of Pediatric Gastroenterology, Rainbow Children's Hospitals, Banjara Hills, Hyderabad, India
| | - Mettu S. Reddy
- Department of Liver Transplant and Hepatopancreaticobiliary Surgery, Gleneagles Global Health City, Perumbakkam, Chennai, India
- Department of Pediatric Liver Transplantation and Hepatobiliary Surgery, Rainbow Children's Hospital, Hyderabad, India
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Mariño Z, García-Solà C, Ríos J, Bono A, García S, Miralpeix A, Andreu R, Aguado C, Forns X, Torra M, Berenguer M. Exchangeable copper for patients with Wilson disease at follow-up: Rethinking normal ranges or changing methodology. Hepatology 2025; 81:1728-1739. [PMID: 39316699 DOI: 10.1097/hep.0000000000001105] [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: 04/26/2024] [Accepted: 09/06/2024] [Indexed: 09/26/2024]
Abstract
BACKGROUND AND AIMS Determining suitable copper parameters for monitoring Wilson disease remains a topic of ongoing discussion. International recommendations currently rely on the combination of urinary copper excretion and nonspecific liver markers when considering therapy and time elapsed since diagnosis. The emergence of exchangeable copper (CuEX) as a novel measurement reflecting the "free copper pool" held promise as a valuable target to ensure metabolic stability during follow-up, although the validation of target ranges remains unknown. We aimed to evaluate CuEX quantification in repeated samples from 92 real-world patients with Wilson disease during a 2-year period. APPROACH Patients were classified as "stable" if a diagnosis had been made more than 1 year before and were compliant with stable anti-copper drug and dose. Otherwise, patients were classified as "nonstable." RESULTS Two hundred and thirteen CuEX samples were obtained per clinical practice. Overall, 57% of CuEX measurements fell below the reference "range of normality," whereas only 34% were within and 9% were above normal levels. There was no association of CuEX levels with therapy, elapsed time from diagnosis, or clinical stability, although most of the samples above normality corresponded to nonstable patients. Only 23.4% of the CuEX samples were aligned with data obtained from concomitant urinary copper excretion. CONCLUSIONS Our findings suggest that CuEX is a suboptimal tool for assessing copper homeostasis when used alone and should be used with caution if no additional information is available. Normal reference intervals for Wilson disease-treated patients should be redefined, as most CuEX quantifications fell in the lower range, with no sign of overtreatment in these patients.
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Affiliation(s)
- Zoe Mariño
- Liver Unit, Hospital Clínic Barcelona, IDIBAPS, Barcelona, Spain
- European Reference Network on Rare Liver Disorders (ERN-RARE Liver), Hospital Clínic Barcelona, Barcelona, Spain
- Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona (UB), Barcelona, Spain
- Centro de Investigación Biomédica en Red, Enfermedades hepáticas y digestivas (CIBERehd), Madrid, Spain
| | | | - José Ríos
- Department of Clinical Pharmacology, Hospital Clinic and Medical Statistics Core Facility, Institut d'Investigacions Biomèdiques August Pi i Sunyer (FCRB-IDIBAPS), Barcelona, Spain
- Biostatistics Unit, School of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Ariadna Bono
- Hepatology and Liver Transplantation Unit, Department of Gastroenterology, La Fe University Hospital, University of Valencia, Valencia, Spain
| | - Sonia García
- Hepatology and Liver Transplantation Unit, Department of Gastroenterology, La Fe University Hospital, University of Valencia, Valencia, Spain
| | - Anna Miralpeix
- Liver Unit, Hospital Clínic Barcelona, IDIBAPS, Barcelona, Spain
| | - Rocío Andreu
- Biochemistry Unit, La Fe University Hospital, Valencia, Spain
| | - Cristina Aguado
- Biochemistry Unit, La Fe University Hospital, Valencia, Spain
| | - Xavier Forns
- Liver Unit, Hospital Clínic Barcelona, IDIBAPS, Barcelona, Spain
- European Reference Network on Rare Liver Disorders (ERN-RARE Liver), Hospital Clínic Barcelona, Barcelona, Spain
- Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona (UB), Barcelona, Spain
- Centro de Investigación Biomédica en Red, Enfermedades hepáticas y digestivas (CIBERehd), Madrid, Spain
| | - Mercè Torra
- Biochemistry and Molecular Genetics Unit, Hospital Clínic, IDIBAPS, CIBERER, Barcelona, Spain
| | - Marina Berenguer
- Centro de Investigación Biomédica en Red, Enfermedades hepáticas y digestivas (CIBERehd), Madrid, Spain
- Hepatology and Liver Transplantation Unit, Department of Gastroenterology, La Fe University Hospital, University of Valencia, Valencia, Spain
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Vij M, Shah V, Shah AA. Indian Childhood Cirrhosis: Report of 2 Cases With Review of Literature and Implication of Metallothionein Immunohistochemical Expression. Pediatr Dev Pathol 2025; 28:197-203. [PMID: 39791459 DOI: 10.1177/10935266241312362] [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] [Indexed: 01/12/2025]
Abstract
Indian childhood cirrhosis is a chronic liver disease in infants and children. Indian childhood cirrhosis is unique to the Indian subcontinent and occurs from 6 months to 5 years of age. We report 2 cases in a period of 5 years, including 1 male and 1 female. Both children were less than 3 years of age. Presenting complaints were jaundice and hepatosplenomegaly. The clinical diagnosis was metabolic liver disease. Histological findings included diffuse hepatocellular ballooning degeneration, prominent Mallory Denk bodies, diffuse pericellular fibrosis, and marked copper/copper-associated protein deposits, along with the absence of steatosis and glycogenated nuclei. Mettalothionein immunohistochemistry was performed in 1 case and showed strong positivity. The first child developed liver failure and died. The second child was started on oral penicillamine therapy and is alive on the most recent follow-up. Whole-exome studies of both patients showed no significant findings. None of the children had exposure to excess dietary copper. Sporadic cases of Indian childhood cirrhosis continue to occur. There should be greater awareness among pediatricians and pathologists of the disease to enable earlier diagnosis. Awareness of metallothionein expression in biopsies of patients with Indian childhood cirrhosis is important to prevent misdiagnosis of Wilson disease.
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Affiliation(s)
- Mukul Vij
- Department of Pathology, Dr. Rela Institute & Medical Centre, Chennai, Tamil Nadu, India
| | - Vaibhav Shah
- Gujarat Super Speciality Clinic, Ahmedabad, Gujarat, India
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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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Ge S, Sun L, Wang H, Yang W, Xuan Q, Hua D. Case report: Co-occurrence of Wilson's and Alexander's diseases revealed by genetic analysis. Front Neurol 2025; 16:1514044. [PMID: 40144630 PMCID: PMC11938389 DOI: 10.3389/fneur.2025.1514044] [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: 10/19/2024] [Accepted: 02/13/2025] [Indexed: 03/28/2025] Open
Abstract
Wilson's disease (WD) and Alexander's disease (AxD) are two prevalent genetic illnesses in clinical practice. However, cases of concurrent WD and AxD have not been reported. A mutation in the ATP7B gene causes improper copper metabolism, whereas AxD is caused by a mutation in the GFAP gene, which causes glial fibrillary acidic protein to accumulate in astrocytes. We present the first instance of concurrent WD and AxD in order to increase the diagnosis accuracy of this type of disease and provide a more precise treatment plan for the patient. A 10-year-old girl who appeared with diminished speech, limb weakness, trouble walking, and mental behavioral problems within the last 2 months. The patient's copper biochemistry results and clinical manifestations supported the diagnosis of WD, however her uncommon bilateral frontal lobe cerebral white matter with considerable high signal in MRI differed from the normal neuroimaging presentations of WD. To clarify the patient's diagnosis, we did whole-exome sequencing testing. To further clarify the patient's diagnosis, we performed whole exome sequencing tests on the patient and her father and detected a single heterozygous mutation in the GFAP gene and a double heterozygous mutation in the ATP7B gene, with the two variant loci located on the same allele. Combined with the Leipzig score and characteristic MRI changes, the patient was diagnosed with co-morbid WD and AxD. The overlapping presentation of the two diseases on MRI suggests the importance of clinicians recognizing the features of both diseases. A comprehensive diagnostic strategy including genetic testing, neuroimaging, and detailed clinical evaluation is required.
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Affiliation(s)
- Shufan Ge
- Department of Neurology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Anhui University of Chinese Medicine, Hefei, China
| | - Lanting Sun
- Department of Neurology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Anhui University of Chinese Medicine, Hefei, China
| | - Han Wang
- Department of Neurology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Anhui University of Chinese Medicine, Hefei, China
- Center for Xin’an Medicine and Modernization of Traditional Chinese Medicine, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, China
| | - Wenming Yang
- Department of Neurology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Anhui University of Chinese Medicine, Hefei, China
- Center for Xin’an Medicine and Modernization of Traditional Chinese Medicine, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, China
| | - Qiaoyu Xuan
- Department of Neurology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Anhui University of Chinese Medicine, Hefei, China
| | - Daiping Hua
- Department of Neurology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Anhui University of Chinese Medicine, Hefei, China
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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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Carrera E, Alvarado J, Astudillo M, Pillajo G. Wilson's disease in two siblings from Ecuador: Two case reports. World J Clin Cases 2025; 13:99558. [PMID: 39866651 PMCID: PMC11577529 DOI: 10.12998/wjcc.v13.i3.99558] [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: 07/25/2024] [Revised: 10/09/2024] [Accepted: 10/29/2024] [Indexed: 11/12/2024] Open
Abstract
BACKGROUND Wilson's disease (WD) is a rare metabolic disorder of copper accumulation in organs such as liver, brain, and cornea. Diagnoses and treatments are challenging in settings, where advanced diagnostic tests are unavailable, copper chelating agents are frequently scarce, healthcare professionals lack disease awareness, and medical follow-ups are limited. Prompt diagnoses and treatments help prevent complications, improve patients' quality of life, and ensure a normal life expectancy. The clinical presentations and outcomes of WD can vary within a single family. CASE SUMMARY We present the cases of two siblings (19 and 27 years) from a consanguineous family in rural Ecuador, diagnosed as having WD during a family screening. The male patient, diagnosed at age 19 after his brother's death from acute liver failure, presented with compensated cirrhosis, neurological symptoms, and bilateral Kayser-Fleischer rings. He developed progressive neurological deterioration during an irregular treatment with D-penicillamine due to medication shortages. His condition improved upon switching to trientine tetrahydrochloride, and his neurological symptoms improved over an 8-year period of follow-ups. The female patient, diagnosed at age 10, exhibited only biochemical alterations. Her treatment history was similar; however, she remained asymptomatic without disease progression over the same follow-up period. We discuss the potential influence of epigenetic mechanisms and modifier genes on the various phenotypes, emphasizing the need for research in these areas to optimize therapeutic strategies. CONCLUSION Our patients' medical histories show how early diagnosis and treatment can prevent disease progression; and, how suboptimal treatments impact disease outcomes.
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Affiliation(s)
- Enrique Carrera
- Department of Gastroenterology and Hepatology, Hospital de Especialidades Eugenio Espejo, Quito 170136, Pichincha, Ecuador
| | - Jonathan Alvarado
- Faculty of Medicine, Pontificia Universidad Catolica del Ecuador, Quito 170143, Pichincha, Ecuador
| | - Martina Astudillo
- Faculty of Medicine, Pontificia Universidad Catolica del Ecuador, Quito 170143, Pichincha, Ecuador
| | - Galo Pillajo
- Department of Radiology, Hospital de Especialidades Eugenio Espejo, Quito 170136, Pichincha, Ecuador
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Mohr I, Lamade P, Weber C, Leidner V, Köhrer S, Olkus A, Lang M, Langel A, Dankert P, Greibich M, Wolf S, Zimmer H, Michl P, Poujois A, Weiss KH, Merle U. A comparative analysis in monitoring 24-hour urinary copper in wilson disease: sampling on or off treatment? Orphanet J Rare Dis 2025; 20:33. [PMID: 39838467 PMCID: PMC11748325 DOI: 10.1186/s13023-025-03545-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Accepted: 01/05/2025] [Indexed: 01/23/2025] Open
Abstract
BACKGROUND & AIM Twenty-four-hour urinary copper excretion (24 h-UCE) is the standard diagnostic tool for dose adjustments in maintenance therapy in Wilson disease (WD) patients. Guidelines lack data if both variants of 24 h-UCE measurement (with or without 48 h of treatment interruption) are equally interpretable. METHODS Eighty-four patients with a confirmed diagnosis of WD treated with chelators (50% of patients with D-Penicillamine and 50% with trientine) and with pairwise 24-h-UCE values on-therapy and off-therapy were included in the analysis. Pairwise urinary sampling between October 2022 (T0) and a 12-month FU (T2) was compared, and exchangeable copper (CuEXC) was additionally measured at T0. RESULTS Among the 84 patients, 65% had predominant hepatic symptoms, the median age was 42 years, and 58% were female. At T0, patients were in the stable maintenance phase, with a median treatment duration of 21.9 years. The levels of the biochemical markers liver and copper metabolism remained stable over the 12-month observation period for all patients. 24 h-UCE off-therapy significantly decreased from T0 to T2 (p = 0.03), whereas no statistically significant differences were detected for 24 h-UCE after therapy. Both sampling methods did not correlate. CuEXC was significantly correlated with 24 h-UCE after 48 h of dose interruption (p = 0.018) but not with 24 h-UCE after therapy. A total of 46% of the 24 h-UCE value pairs were discordant, laying out the aimed therapeutic ranges given in current international guidelines. CONCLUSION Off-therapy 24 h-UCE reflects the "free" copper pool more accurately than does urinary sampling. The study shows discordant results for both sampling methods in approximately half of the patients, revealing that interpretation of 24 h-UCE with respect to chelator-dosing decisions should be performed with caution.
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Affiliation(s)
- Isabelle Mohr
- Internal Medicine IV, Department of Gastroenterology, University Hospital Heidelberg, INF 410, Heidelberg, 69120, Germany.
| | - Patrick Lamade
- Internal Medicine IV, Department of Gastroenterology, University Hospital Heidelberg, INF 410, Heidelberg, 69120, Germany
| | - Christophe Weber
- Internal Medicine III Department of Internal Medicine and Cardiology, University Hospital Heidelberg, Heidelberg, Germany
| | - Viola Leidner
- Internal Medicine IV, Department of Gastroenterology, University Hospital Heidelberg, INF 410, Heidelberg, 69120, Germany
| | - Sebastian Köhrer
- Internal Medicine IV, Department of Gastroenterology, University Hospital Heidelberg, INF 410, Heidelberg, 69120, Germany
| | - Alexander Olkus
- Internal Medicine IV, Department of Gastroenterology, University Hospital Heidelberg, INF 410, Heidelberg, 69120, Germany
| | - Matthias Lang
- Internal Medicine IV, Department of Gastroenterology, University Hospital Heidelberg, INF 410, Heidelberg, 69120, Germany
| | - Andrea Langel
- Internal Medicine IV, Department of Gastroenterology, University Hospital Heidelberg, INF 410, Heidelberg, 69120, Germany
| | - Patrischia Dankert
- Internal Medicine IV, Department of Gastroenterology, University Hospital Heidelberg, INF 410, Heidelberg, 69120, Germany
| | - Melanie Greibich
- Internal Medicine IV, Department of Gastroenterology, University Hospital Heidelberg, INF 410, Heidelberg, 69120, Germany
| | - Silke Wolf
- Internal Medicine I, Department of Endocrinology, Diabetology, Metabolic Diseases and Clinical Chemistry, University Hospital Heidelberg, Heidelberg, Germany
| | - Holger Zimmer
- Internal Medicine I, Department of Endocrinology, Diabetology, Metabolic Diseases and Clinical Chemistry, University Hospital Heidelberg, Heidelberg, Germany
| | - Patrick Michl
- Internal Medicine IV, Department of Gastroenterology, University Hospital Heidelberg, INF 410, Heidelberg, 69120, Germany
| | - Aurélia Poujois
- Department of Neurology, Rothschild Foundation Hospital, National Reference Center for Wilson Disease, Paris, France
| | - Karl Heinz Weiss
- Internal Medicine, Salem Hospital Heidelberg, Heidelberg, Germany
| | - Uta Merle
- Internal Medicine IV, Department of Gastroenterology, University Hospital Heidelberg, INF 410, Heidelberg, 69120, Germany
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Samanta A, Srivastava A, Patel SS, Sen Sarma M, Poddar U, Mishra P. "Parvovirus B19-related Acute Hepatitis: Clinical Spectrum and Outcome in Children". J Clin Exp Hepatol 2025; 15:102416. [PMID: 39473446 PMCID: PMC11513682 DOI: 10.1016/j.jceh.2024.102416] [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: 06/05/2024] [Accepted: 09/19/2024] [Indexed: 01/12/2025] Open
Abstract
BACKGROUND/AIMS Acute liver injury is a common manifestation of parvovirus B19 (PVB19) infection in immunocompromised patients. However, literature in immunocompetent children is scarce. We aimed to study the clinicolaboratory features and outcome of hepatic involvement by PVB19 infection in hospitalized children. METHODS We retrospectively analyzed our prospectively kept database of all children (<18 years old) admitted with acute viral hepatitis (AVH), acute liver failure (ALF) or acute-on-chronic liver failure (ACLF), and PVB19 infection between January 2010 and December 2023. Clinical features, laboratory parameters, and complications were evaluated. Poor outcome was defined as death or liver transplantation. RESULTS A total of 35 children (19 boys [54%], median age: 7.25 [interquartile range: 4-10.8] years) with PVB19-related hepatitis were studied (28 [80%] isolated PVB19 infection and 7 [20%] coinfections [3 with Epstein-Barr virus, 2 with hepatitis A, and 1 each with hepatitis-E and cytomegalovirus]). AVH (17, 49%) was the most common presentation, followed by ALF (13, 37%) and acute insult in ACLF (5, 14%). Patients with coinfection had significantly higher bilirubin (14.6 [9.4-21.5] vs 6.8 [4.3-10.9] mg/dl; P=0.004) and transaminases (ALT: 697 [428-1296] vs. 277 [157-478] U/L; P=0.02) but similar mortality (1/7 vs 6/23; P=1.0) than PVB19 alone. Nine cases (25.7%) had extrahepatic complications (hemophagocytic lymphohistiocytosis [HLH]: 3, acute kidney injury: 3, aplastic anemia: 2, and myocarditis: 1). Poor outcome occurred in 38% (5/13) ALF, 11.7% (2/17) AVH (HLH: 1, myocarditis: 1), and none (0/5) of the ACLF cases. CONCLUSION PVB19 should be considered in children presenting with indeterminate acute liver injury, especially in younger children or those with complications such as aplastic anemia, HLH, or myocarditis.
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Affiliation(s)
- Arghya Samanta
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Anshu Srivastava
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Sangram S. Patel
- Department of Microbiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Moinak Sen Sarma
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Ujjal Poddar
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Prabhakar Mishra
- Department of Biostatistics and Health Informatics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
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11
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Kolbe AB, Acord MR, Khanna G, Morin CE, Nguyen HN, Rees MA, Ro E, Schooler GR, Squires JH, Syed AB, Tang ER, Towbin AJ, Alazraki A. Imaging Findings and Management Strategies for Liver Masses in Children with Predisposition Disorders: A Review by the Pediatric LI-RADS Group. Radiographics 2025; 45:e240063. [PMID: 39666572 DOI: 10.1148/rg.240063] [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: 12/14/2024]
Abstract
Liver masses in children with underlying systemic disease or a predisposing syndrome can be benign or malignant, ranging from focal fat to hepatocellular carcinoma (HCC). Knowledge of the underlying condition, the pathophysiologic effect on the liver, and the development of liver disease and specific liver lesions allows radiologists to guide imaging with regard to modality and frequency and give recommendations for biopsy when appropriate. In some predisposition disorders, such as Beckwith Wiedemann spectrum, familial adenomatous polyposis syndrome, and tuberous sclerosis complex, established guidelines for imaging screening exist. In many of the syndromes discussed, masses may occur outside of the liver and the liver may not be the primary focus of screening. For other entities, no consensus recommendations exist. Screening recommendations may be based on the risk of development of chronic liver disease. Once cirrhosis occurs, the risk of developing HCC is elevated. The authors summarize the spectrum of liver lesions that may be encountered in children with predisposing syndromes and systemic diseases, the imaging appearance of the lesions with various modalities, and screening guidelines where published. ©RSNA, 2024 See the invited commentary by Rutten and Chavan in this issue.
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Affiliation(s)
- Amy B Kolbe
- From the Department of Radiology, Mayo Clinic, 200 1st Ave SE, Rochester, MN 55905 (A.B.K.); Department of Radiology, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pa (M.R.A.); Department of Radiology and Imaging Sciences, Emory University and Children's Healthcare of Atlanta, Atlanta, Ga (G.K., A.A.); Department of Radiology, Cincinnati Children's Hospital, Department of Radiology, University of Cincinnati College of Medicine, Cincinnati, Ohio (C.E.M., A.J.T.); Department of Radiology, Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, Calif (H.N.N.); Department of Radiology, Nationwide Children's Hospital, Columbus, Ohio (M.A.R.); Department of Medical Imaging, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Ill (E.R.); Department of Radiology, UT Southwestern Medical Center, Dallas, Tex (G.R.S.); Department of Radiology, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pa (J.H.S.); Department of Radiology, Stanford University School of Medicine, Stanford, Calif (A.B.S.); and Department of Radiology, Children's Hospital Colorado, Aurora, Colo (E.R.T.)
| | - Michael R Acord
- From the Department of Radiology, Mayo Clinic, 200 1st Ave SE, Rochester, MN 55905 (A.B.K.); Department of Radiology, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pa (M.R.A.); Department of Radiology and Imaging Sciences, Emory University and Children's Healthcare of Atlanta, Atlanta, Ga (G.K., A.A.); Department of Radiology, Cincinnati Children's Hospital, Department of Radiology, University of Cincinnati College of Medicine, Cincinnati, Ohio (C.E.M., A.J.T.); Department of Radiology, Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, Calif (H.N.N.); Department of Radiology, Nationwide Children's Hospital, Columbus, Ohio (M.A.R.); Department of Medical Imaging, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Ill (E.R.); Department of Radiology, UT Southwestern Medical Center, Dallas, Tex (G.R.S.); Department of Radiology, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pa (J.H.S.); Department of Radiology, Stanford University School of Medicine, Stanford, Calif (A.B.S.); and Department of Radiology, Children's Hospital Colorado, Aurora, Colo (E.R.T.)
| | - Geetika Khanna
- From the Department of Radiology, Mayo Clinic, 200 1st Ave SE, Rochester, MN 55905 (A.B.K.); Department of Radiology, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pa (M.R.A.); Department of Radiology and Imaging Sciences, Emory University and Children's Healthcare of Atlanta, Atlanta, Ga (G.K., A.A.); Department of Radiology, Cincinnati Children's Hospital, Department of Radiology, University of Cincinnati College of Medicine, Cincinnati, Ohio (C.E.M., A.J.T.); Department of Radiology, Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, Calif (H.N.N.); Department of Radiology, Nationwide Children's Hospital, Columbus, Ohio (M.A.R.); Department of Medical Imaging, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Ill (E.R.); Department of Radiology, UT Southwestern Medical Center, Dallas, Tex (G.R.S.); Department of Radiology, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pa (J.H.S.); Department of Radiology, Stanford University School of Medicine, Stanford, Calif (A.B.S.); and Department of Radiology, Children's Hospital Colorado, Aurora, Colo (E.R.T.)
| | - Cara E Morin
- From the Department of Radiology, Mayo Clinic, 200 1st Ave SE, Rochester, MN 55905 (A.B.K.); Department of Radiology, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pa (M.R.A.); Department of Radiology and Imaging Sciences, Emory University and Children's Healthcare of Atlanta, Atlanta, Ga (G.K., A.A.); Department of Radiology, Cincinnati Children's Hospital, Department of Radiology, University of Cincinnati College of Medicine, Cincinnati, Ohio (C.E.M., A.J.T.); Department of Radiology, Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, Calif (H.N.N.); Department of Radiology, Nationwide Children's Hospital, Columbus, Ohio (M.A.R.); Department of Medical Imaging, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Ill (E.R.); Department of Radiology, UT Southwestern Medical Center, Dallas, Tex (G.R.S.); Department of Radiology, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pa (J.H.S.); Department of Radiology, Stanford University School of Medicine, Stanford, Calif (A.B.S.); and Department of Radiology, Children's Hospital Colorado, Aurora, Colo (E.R.T.)
| | - HaiThuy N Nguyen
- From the Department of Radiology, Mayo Clinic, 200 1st Ave SE, Rochester, MN 55905 (A.B.K.); Department of Radiology, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pa (M.R.A.); Department of Radiology and Imaging Sciences, Emory University and Children's Healthcare of Atlanta, Atlanta, Ga (G.K., A.A.); Department of Radiology, Cincinnati Children's Hospital, Department of Radiology, University of Cincinnati College of Medicine, Cincinnati, Ohio (C.E.M., A.J.T.); Department of Radiology, Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, Calif (H.N.N.); Department of Radiology, Nationwide Children's Hospital, Columbus, Ohio (M.A.R.); Department of Medical Imaging, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Ill (E.R.); Department of Radiology, UT Southwestern Medical Center, Dallas, Tex (G.R.S.); Department of Radiology, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pa (J.H.S.); Department of Radiology, Stanford University School of Medicine, Stanford, Calif (A.B.S.); and Department of Radiology, Children's Hospital Colorado, Aurora, Colo (E.R.T.)
| | - Mitchell A Rees
- From the Department of Radiology, Mayo Clinic, 200 1st Ave SE, Rochester, MN 55905 (A.B.K.); Department of Radiology, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pa (M.R.A.); Department of Radiology and Imaging Sciences, Emory University and Children's Healthcare of Atlanta, Atlanta, Ga (G.K., A.A.); Department of Radiology, Cincinnati Children's Hospital, Department of Radiology, University of Cincinnati College of Medicine, Cincinnati, Ohio (C.E.M., A.J.T.); Department of Radiology, Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, Calif (H.N.N.); Department of Radiology, Nationwide Children's Hospital, Columbus, Ohio (M.A.R.); Department of Medical Imaging, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Ill (E.R.); Department of Radiology, UT Southwestern Medical Center, Dallas, Tex (G.R.S.); Department of Radiology, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pa (J.H.S.); Department of Radiology, Stanford University School of Medicine, Stanford, Calif (A.B.S.); and Department of Radiology, Children's Hospital Colorado, Aurora, Colo (E.R.T.)
| | - Esther Ro
- From the Department of Radiology, Mayo Clinic, 200 1st Ave SE, Rochester, MN 55905 (A.B.K.); Department of Radiology, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pa (M.R.A.); Department of Radiology and Imaging Sciences, Emory University and Children's Healthcare of Atlanta, Atlanta, Ga (G.K., A.A.); Department of Radiology, Cincinnati Children's Hospital, Department of Radiology, University of Cincinnati College of Medicine, Cincinnati, Ohio (C.E.M., A.J.T.); Department of Radiology, Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, Calif (H.N.N.); Department of Radiology, Nationwide Children's Hospital, Columbus, Ohio (M.A.R.); Department of Medical Imaging, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Ill (E.R.); Department of Radiology, UT Southwestern Medical Center, Dallas, Tex (G.R.S.); Department of Radiology, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pa (J.H.S.); Department of Radiology, Stanford University School of Medicine, Stanford, Calif (A.B.S.); and Department of Radiology, Children's Hospital Colorado, Aurora, Colo (E.R.T.)
| | - Gary R Schooler
- From the Department of Radiology, Mayo Clinic, 200 1st Ave SE, Rochester, MN 55905 (A.B.K.); Department of Radiology, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pa (M.R.A.); Department of Radiology and Imaging Sciences, Emory University and Children's Healthcare of Atlanta, Atlanta, Ga (G.K., A.A.); Department of Radiology, Cincinnati Children's Hospital, Department of Radiology, University of Cincinnati College of Medicine, Cincinnati, Ohio (C.E.M., A.J.T.); Department of Radiology, Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, Calif (H.N.N.); Department of Radiology, Nationwide Children's Hospital, Columbus, Ohio (M.A.R.); Department of Medical Imaging, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Ill (E.R.); Department of Radiology, UT Southwestern Medical Center, Dallas, Tex (G.R.S.); Department of Radiology, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pa (J.H.S.); Department of Radiology, Stanford University School of Medicine, Stanford, Calif (A.B.S.); and Department of Radiology, Children's Hospital Colorado, Aurora, Colo (E.R.T.)
| | - Judy H Squires
- From the Department of Radiology, Mayo Clinic, 200 1st Ave SE, Rochester, MN 55905 (A.B.K.); Department of Radiology, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pa (M.R.A.); Department of Radiology and Imaging Sciences, Emory University and Children's Healthcare of Atlanta, Atlanta, Ga (G.K., A.A.); Department of Radiology, Cincinnati Children's Hospital, Department of Radiology, University of Cincinnati College of Medicine, Cincinnati, Ohio (C.E.M., A.J.T.); Department of Radiology, Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, Calif (H.N.N.); Department of Radiology, Nationwide Children's Hospital, Columbus, Ohio (M.A.R.); Department of Medical Imaging, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Ill (E.R.); Department of Radiology, UT Southwestern Medical Center, Dallas, Tex (G.R.S.); Department of Radiology, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pa (J.H.S.); Department of Radiology, Stanford University School of Medicine, Stanford, Calif (A.B.S.); and Department of Radiology, Children's Hospital Colorado, Aurora, Colo (E.R.T.)
| | - Ali B Syed
- From the Department of Radiology, Mayo Clinic, 200 1st Ave SE, Rochester, MN 55905 (A.B.K.); Department of Radiology, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pa (M.R.A.); Department of Radiology and Imaging Sciences, Emory University and Children's Healthcare of Atlanta, Atlanta, Ga (G.K., A.A.); Department of Radiology, Cincinnati Children's Hospital, Department of Radiology, University of Cincinnati College of Medicine, Cincinnati, Ohio (C.E.M., A.J.T.); Department of Radiology, Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, Calif (H.N.N.); Department of Radiology, Nationwide Children's Hospital, Columbus, Ohio (M.A.R.); Department of Medical Imaging, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Ill (E.R.); Department of Radiology, UT Southwestern Medical Center, Dallas, Tex (G.R.S.); Department of Radiology, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pa (J.H.S.); Department of Radiology, Stanford University School of Medicine, Stanford, Calif (A.B.S.); and Department of Radiology, Children's Hospital Colorado, Aurora, Colo (E.R.T.)
| | - Elizabeth R Tang
- From the Department of Radiology, Mayo Clinic, 200 1st Ave SE, Rochester, MN 55905 (A.B.K.); Department of Radiology, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pa (M.R.A.); Department of Radiology and Imaging Sciences, Emory University and Children's Healthcare of Atlanta, Atlanta, Ga (G.K., A.A.); Department of Radiology, Cincinnati Children's Hospital, Department of Radiology, University of Cincinnati College of Medicine, Cincinnati, Ohio (C.E.M., A.J.T.); Department of Radiology, Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, Calif (H.N.N.); Department of Radiology, Nationwide Children's Hospital, Columbus, Ohio (M.A.R.); Department of Medical Imaging, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Ill (E.R.); Department of Radiology, UT Southwestern Medical Center, Dallas, Tex (G.R.S.); Department of Radiology, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pa (J.H.S.); Department of Radiology, Stanford University School of Medicine, Stanford, Calif (A.B.S.); and Department of Radiology, Children's Hospital Colorado, Aurora, Colo (E.R.T.)
| | - Alexander J Towbin
- From the Department of Radiology, Mayo Clinic, 200 1st Ave SE, Rochester, MN 55905 (A.B.K.); Department of Radiology, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pa (M.R.A.); Department of Radiology and Imaging Sciences, Emory University and Children's Healthcare of Atlanta, Atlanta, Ga (G.K., A.A.); Department of Radiology, Cincinnati Children's Hospital, Department of Radiology, University of Cincinnati College of Medicine, Cincinnati, Ohio (C.E.M., A.J.T.); Department of Radiology, Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, Calif (H.N.N.); Department of Radiology, Nationwide Children's Hospital, Columbus, Ohio (M.A.R.); Department of Medical Imaging, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Ill (E.R.); Department of Radiology, UT Southwestern Medical Center, Dallas, Tex (G.R.S.); Department of Radiology, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pa (J.H.S.); Department of Radiology, Stanford University School of Medicine, Stanford, Calif (A.B.S.); and Department of Radiology, Children's Hospital Colorado, Aurora, Colo (E.R.T.)
| | - Adina Alazraki
- From the Department of Radiology, Mayo Clinic, 200 1st Ave SE, Rochester, MN 55905 (A.B.K.); Department of Radiology, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pa (M.R.A.); Department of Radiology and Imaging Sciences, Emory University and Children's Healthcare of Atlanta, Atlanta, Ga (G.K., A.A.); Department of Radiology, Cincinnati Children's Hospital, Department of Radiology, University of Cincinnati College of Medicine, Cincinnati, Ohio (C.E.M., A.J.T.); Department of Radiology, Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, Calif (H.N.N.); Department of Radiology, Nationwide Children's Hospital, Columbus, Ohio (M.A.R.); Department of Medical Imaging, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Ill (E.R.); Department of Radiology, UT Southwestern Medical Center, Dallas, Tex (G.R.S.); Department of Radiology, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pa (J.H.S.); Department of Radiology, Stanford University School of Medicine, Stanford, Calif (A.B.S.); and Department of Radiology, Children's Hospital Colorado, Aurora, Colo (E.R.T.)
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12
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Mariño Z, Schilsky ML. Wilson Disease: Novel Diagnostic and Therapeutic Approaches. Semin Liver Dis 2024. [PMID: 39496313 DOI: 10.1055/a-2460-8999] [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] [Indexed: 11/06/2024]
Abstract
The Wilson disease (WD) research field is rapidly evolving, and new diagnostic and therapeutical approaches are expected to be change-gamers in the disease for the incoming years, after decades of slow changing options. Non-ceruloplasmin-bound copper assays for circulating bioavailable copper are being tested for use in monitoring therapy and may also help in the diagnosis of new cases of WD. Other diagnostic advances include the use of quantitative detection of ATP7B peptides in dried blood spots, a method that is being tested for use in the newborn screening for WD, and the use of metallothionein immunostaining of liver biopsy specimens to differentiate WD from other liver diseases. Ongoing and future trials of gene therapy and use of methanobactin are expected to restore biliary copper excretion from the liver, thus making a cure for WD a plausible therapeutic objective. With the aim of helping updating physicians, this review summarizes the novel methods for WD diagnosis and future therapies. Advancing understanding of the scientific advances that can be applied to WD will be critical for ensuring that our patients will receive the best current and future care.
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Affiliation(s)
- Zoe Mariño
- Liver Unit, Hospital Clínic Barcelona, IDIBAPS, CIBERehd, ERN-RARE Liver, Universitat de Barcelona, Barcelona, Spain
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13
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La Rosa A, Covone AE, Coviello D, Arrigo S, Ferro J, Gandullia P, Madeo A. Early Onset of Wilson's Disease and Possible Role of Disease-Modifying Genes: A Case Report and Literature Review. Case Reports Hepatol 2024; 2024:3815089. [PMID: 39628766 PMCID: PMC11614511 DOI: 10.1155/crhe/3815089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Accepted: 11/01/2024] [Indexed: 12/06/2024] Open
Abstract
Wilson's disease (WD) is a rare autosomal recessive disorder caused by mutations in the ATP7B gene, resulting in copper accumulation. Symptoms rarely appear before the age of 5, almost never before 3. The phenotypic variability of WD suggests the presence of modifying factors, making early diagnosis challenging. We present a case of symptomatic WD in a toddler, emphasizing the importance of considering WD in differential diagnoses and exploring genetic modifiers influencing disease onset. Clinical and laboratory assessments, including liver biopsy, were performed on a 4.2-year-old boy presenting with hypertransaminasemia and mild hepatomegaly. Histological evaluation revealed chronic hepatitis with fibrosis and severe steatosis, indicating long-standing active disease. Genetic analysis identified a missense variant and a 15-nucleotide deletion in the 5' UTR promoter region of the ATP7B gene, confirming the WD diagnosis. Additionally, homozygosity for the HFE H63D variant was detected, with transferrin saturations at the upper limit of normal. The patient's clinical management included a trial of D-penicillamine, discontinued due to side effects, followed by successful zinc acetate therapy. This case underscores the consideration of WD in the differential diagnosis of toddlers. The Ferenci-Leipzig score remains a valid diagnostic tool for WD even in the presence of a single ATP7B variant, although extended genetic analysis should still be considered. Normal ceruloplasmin levels do not rule out WD. Environmental, epigenetic, and genetic factors appear to influence the WD phenotype; HFE variants may act as modifiers given the link between iron and copper homeostasis, possibly explaining the early symptomatic onset in our patient.
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Affiliation(s)
- Alessandro La Rosa
- Paediatric Gastroenterology and Digestive Endoscopy Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | | | - Domenico Coviello
- Laboratory of Human Genetics, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Serena Arrigo
- Paediatric Gastroenterology and Digestive Endoscopy Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Jacopo Ferro
- Department of Laboratory Medicine, Division of Anatomic Pathology, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Paolo Gandullia
- Paediatric Gastroenterology and Digestive Endoscopy Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Annalisa Madeo
- Paediatric Gastroenterology and Digestive Endoscopy Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
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14
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Romero-Gutiérrez M, Alonso P, Berenguer M, Olveira A, González-Diéguez ML, Iruzubieta P, Masnou H, Delgado M, Hernández-Guerra M, Lorente S, Lázaro M, Moreno-Planas JM, González C, Fernández-Álvarez P, Cuenca F, Gómez J, García-Villareal L, Rodríguez O, Mariño Z. Reproductive and pregnancy control in Wilson disease patients in Spain. Eur J Gastroenterol Hepatol 2024; 36:1340-1345. [PMID: 39166415 DOI: 10.1097/meg.0000000000002831] [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] [Indexed: 08/22/2024]
Abstract
BACKGROUND AND AIM Recommendations on pregnancy, lactation, and contraception in women with Wilson disease are briefly stated in international guidelines but are not entirely homogeneous. Data regarding the management of these special events among patients with Wilson disease in Spain are lacking. We used the Wilson Registry platform of the Spanish Association for the Study of the Liver to question patients on their reproductive and gestational lives. METHODS This was a multicentre ambispective study including adult women with Wilson disease in the Spanish Wilson Registry interviewed about their contraception, childbearing, pregnancy, and lactation experiences. Clinical and analytical data were extracted from the registry. RESULTS The study included 92 women from 17 centres in Spain. Most (63%) reported having a previous pregnancy history. The rate of spontaneous miscarriages was 21.6%, mainly occurring in the first trimester and up to one third among undiagnosed patients. Most pregnant women received chelator therapy during pregnancy, but dose reduction was recommended in less than 10%. After delivery, artificial lactation predominated (60.3%) and its use was mainly based on physician's recommendations (68%). Up to 40% of the women included reported some concerns about their reproductive lives, mainly related to the potential drug toxicity to their children. Most of the patients considered the information given by specialists to be sufficient. CONCLUSION Gestational management among women with Wilson disease in Spain was found to be highly heterogeneous and frequently different from what is described in international guidelines. Education on rare liver diseases should be a priority for scientific societies in order to homogenize patient follow-up and recommendations.
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Affiliation(s)
- Marta Romero-Gutiérrez
- Complejo Hospitalario Universitario de Toledo, Gastroenterology and Hepatology Department, Toledo
| | - Pablo Alonso
- Universidad Las Palmas Gran Canaria (ULPGC), Complejo Hospitalario Universitario Insular Materno Infantil, Gastroenterology and Hepatology Department, Las Palmas de Gran Canaria
| | - Marina Berenguer
- Hospital Universitari i Politècnic La Fe, Gastroenterology and Hepatology Department, IISLaFe, Ciberehd, Valencia
| | - Antonio Olveira
- Hospital Universitario La Paz, Gastroenterology and Hepatology Department, Madrid
| | | | - Paula Iruzubieta
- Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Hospital Universitario Marqués de Valdecilla, Gastroenterology and Hepatology Department, Santander
| | - Helena Masnou
- Hospital Universitario Germans Trias i Pujol, Gastroenterology and Hepatology Department, Badalona
| | - Manuel Delgado
- Hospital Universitario A Coruña, Gastroenterology and Hepatology Department, La Coruña
| | - Manuel Hernández-Guerra
- Hospital Universitario de Canarias, Gastroenterology and Hepatology Department, Santa Cruz Tenerife
| | - Sara Lorente
- Hospital Clínico Lozano Blesa de Zaragoza, Gastroenterology and Hepatology Department, IISS Aragón
| | - María Lázaro
- Hospital Universitario Miguel Servet, Gastroenterology and Hepatology Department, Zaragoza
| | - José María Moreno-Planas
- Complejo Hospitalario Universitario de Albacete, Gastroenterology and Hepatology Department, Albacete
| | - Concepción González
- Complejo Hospitalario Universitario de Toledo, Gastroenterology and Hepatology Department, Toledo
| | | | - Francisca Cuenca
- Hospital Clínico San Carlos, Gastroenterology and Hepatology Department, Madrid
| | - Judith Gómez
- Hospital Universitario de Burgos, Gastroenterology and Hepatology Department, Burgos
| | - Luis García-Villareal
- Complejo Hospitalario Universitario Insular Materno Infantil, Gastroenterology and Hepatology Department, IUIBS ULPGC, Las Palmas de Gran Canaria
| | - Olga Rodríguez
- Complejo Hospitalario Universitario de Toledo, Obstetrics and Gynaecology Department, Toledo
| | - Zoe Mariño
- Liver Unit, Hospital Clínic Barcelona, IDIBAPS, CIBERehd, ERN-RARE Liver, Universitat de Barcelona, Barcelona, Spain
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15
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Glotov OS, Zhuchenko NA, Balashova MS, Raspopova AN, Tsai VV, Chernov AN, Chuiko IV, Danilov LG, Morozova LD, Glotov AS. The Benefits of Whole-Exome Sequencing in the Differential Diagnosis of Hypophosphatasia. Int J Mol Sci 2024; 25:11728. [PMID: 39519277 PMCID: PMC11545870 DOI: 10.3390/ijms252111728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 10/20/2024] [Accepted: 10/22/2024] [Indexed: 11/16/2024] Open
Abstract
Hypophosphatasia (HPP) is a rare inherited disorder characterized by the decreased activity of tissue-nonspecific alkaline phosphatase (TNSALP), caused by mutations in the ALPL gene. The aim of this study was to conduct differential diagnostics in HPP patients using whole-exome sequencing (WES). The medical records of HPP patients and the genetic testing of the ALPL gene were reviewed. Seven patients were recruited and underwent WES using the Illumina or MGI sequencing platforms. All of the exome samples were matched onto a GRCh38.p13 reference genome assembly by using the Genome Analysis ToolKit (GATK) and the BWA MEM read aligner. We present the clinical and molecular findings of the seven patients referred for genetic analyses due to a clinical and biochemical suspicion of HPP. In two patients out of three (with identified heterozygous variants in the ALPL gene), we also identified c.682T>A in exon 3 of the WNT10A gene and c.3470del in exon 23 of the SMC1A gene variants for the first time. In four patients, variants in the ALPL gene were not detected, but WES allowed us to identify for the first time rare variants (c.5651A>C in exon 36 of the TRIO gene, c.880T>G in exon 6 of the TRPV4 gene, c.32078-1G>T in intron 159 of the TTN gene, c.47720_47721del in exon 235 of the TTN gene, and c.1946G>A in exon 15 of the SLC5A1 gene) and to conduct differential diagnostics with HPP. Using WES, for the first time, we demonstrate the possibility of early differential diagnostics in HPP patients with other rare genetic diseases.
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Affiliation(s)
- Oleg S. Glotov
- Department of Genomic Medicine, D. O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, 199034 Saint Petersburg, Russia; (M.S.B.); (V.V.T.); (A.S.G.)
- Department of Experimental Medical Virology, Molecular Genetics and Biobanking of Pediatric Research and Clinical Center for Infectious Diseases, 197022 Saint Petersburg, Russia
- CerbaLab Ltd., 199106 Saint Petersburg, Russia; (A.N.R.); (L.G.D.)
| | - Natalya A. Zhuchenko
- Department of Medical Genetics, N.V. Sklifosovsky ICM, I.M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia; (N.A.Z.); (L.D.M.)
| | - Maria S. Balashova
- Department of Genomic Medicine, D. O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, 199034 Saint Petersburg, Russia; (M.S.B.); (V.V.T.); (A.S.G.)
- Department of Medical Genetics, N.V. Sklifosovsky ICM, I.M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia; (N.A.Z.); (L.D.M.)
| | | | - Victoria V. Tsai
- Department of Genomic Medicine, D. O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, 199034 Saint Petersburg, Russia; (M.S.B.); (V.V.T.); (A.S.G.)
- Department of Experimental Medical Virology, Molecular Genetics and Biobanking of Pediatric Research and Clinical Center for Infectious Diseases, 197022 Saint Petersburg, Russia
- CerbaLab Ltd., 199106 Saint Petersburg, Russia; (A.N.R.); (L.G.D.)
| | - Alexandr N. Chernov
- Department of Genomic Medicine, D. O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, 199034 Saint Petersburg, Russia; (M.S.B.); (V.V.T.); (A.S.G.)
- Department of General Pathology and Pathological Physiology, Institute of Experimental Medicine, 197022 Saint Petersburg, Russia
- Department of Biological Chemistry, Federal State Budgetary Educational Institution of Higher Education Saint Petersburg State Pediatric Medical University of the Ministry of Health of Russia, 194100 Saint Petersburg, Russia
| | - Iana V. Chuiko
- Faculty of Bioengineering and Bioinformatics, Moscow State University, 119991 Moscow, Russia;
| | - Lavrentii G. Danilov
- CerbaLab Ltd., 199106 Saint Petersburg, Russia; (A.N.R.); (L.G.D.)
- Department of Genetics and Biotechnology, Saint-Petersburg State University, 199034 Saint Petersburg, Russia
| | - Lyudmila D. Morozova
- Department of Medical Genetics, N.V. Sklifosovsky ICM, I.M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia; (N.A.Z.); (L.D.M.)
| | - Andrey S. Glotov
- Department of Genomic Medicine, D. O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, 199034 Saint Petersburg, Russia; (M.S.B.); (V.V.T.); (A.S.G.)
- Department of Genetics and Biotechnology, Saint-Petersburg State University, 199034 Saint Petersburg, Russia
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Wu YC, Xiang XL, Yong JK, Li M, Li LM, Lv ZC, Zhou Y, Sun XC, Zhang ZJ, Tong H, He XY, Xia Q, Feng H. Immune remodulation in pediatric inherited metabolic liver diseases. World J Hepatol 2024; 16:1258-1268. [PMID: 39351516 PMCID: PMC11438594 DOI: 10.4254/wjh.v16.i9.1258] [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: 01/28/2024] [Revised: 05/28/2024] [Accepted: 08/19/2024] [Indexed: 09/23/2024] Open
Abstract
Inherited metabolic liver diseases arise from genetic mutations that lead to disruptions in liver metabolic pathways and are predominantly observed in pediatric populations. The spectrum of genetic metabolic liver disorders is diverse, encompassing a range of conditions associated with aberrations in iron, copper, carbohydrate, lipid, protein, and amino acid metabolism. Historically, research in the domain of genetic metabolic liver diseases has predominantly concentrated on hepatic parenchymal cell alterations. Nevertheless, emerging studies suggest that inherited metabolic liver diseases exert significant influences on the immune microenvironment, both within the liver and systemically. This review endeavors to encapsulate the immunological features of genetic metabolic liver diseases, aiming to expand the horizons of researchers in this discipline, and to elucidate the underlying pathophysiological mechanisms pertinent to hereditary metabolic liver diseases and to propose innovative therapeutic approaches.
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Affiliation(s)
- Yi-Chi Wu
- Department of Liver Surgery, Renji Hospital (Punan Branch), School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Xue-Lin Xiang
- Department of Liver Surgery, Renji Hospital (Punan Branch), School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - June-Kong Yong
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Meng Li
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University, Shanghai Institute of Transplantation, Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai 200127, China
| | - Lin-Man Li
- Department of Liver Surgery, Renji Hospital (Punan Branch), School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Zi-Cheng Lv
- Department of Liver Surgery, Renji Hospital (Punan Branch), School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Yi Zhou
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Xi-Cheng Sun
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Zi-Jie Zhang
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Huan Tong
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, Shanghai 200012, China
| | - Xiao-Ying He
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, Shanghai 200012, China
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University, Shanghai Institute of Transplantation, Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai 200127, China
| | - Hao Feng
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University, Shanghai Institute of Transplantation, Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai 200127, China.
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Zhang T, Song W, Mao Z. Phenotypic and genetic characterization of children with Wilson Disease from Northeast China. BMC Pediatr 2024; 24:576. [PMID: 39267050 PMCID: PMC11391784 DOI: 10.1186/s12887-024-05045-x] [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: 12/22/2023] [Accepted: 08/30/2024] [Indexed: 09/14/2024] Open
Abstract
BACKGROUND Wilson disease (WD) is an autosomal recessive inherited disease caused by ATP7B variants and characterized by copper metabolism defects. However, children with WD are often asymptomatic, making the clinical diagnosis difficult. Therefore, more accurate methods are required for clinical diagnosis. The objective of this study was to highlight the phenotypic and genetic characteristics of children with WD in northeast China. METHODS We retrospectively analyzed the clinical data and gene sequencing results of 65 children with WD from January 1, 2014, to December 31, 2022, at the Shengjing Hospital of China Medical University. All data refer to the time of diagnosis before treatment. RESULTS The median age at diagnosis was 5 years (range 1.2-15 years). In 50 cases (50/65, 76.9%) patients, routine physical examinations revealed only abnormal liver function. However, they had a significantly negative (p < 0.05) Kayser-Fleischer ring (KF). Children with acute liver failure had significantly increased 24 h urinary copper excretion (p < 0.05). We detected 46 genetic variants of ATP7B, including seven novel variants. The most frequent variant was p.R778L with an allele frequency of 38.7%. Phenotype-genotype correlation analysis suggested that p.R778L was significantly associated with lower serum ceruloplasmin levels and higher zinc levels (p < 0.05). The loss-of-function (LOF) variant was associated with significantly lower albumin levels (p < 0.05). CONCLUSION Most children with WD are asymptomatic, which makes early diagnosis of WD difficult. Therefore, clinical and laboratory characteristics as well as genetic testing are essential. p.R778L is the most frequent variant of ATP7B in China and may play an important role in lowering serum ceruloplasmin levels.
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Affiliation(s)
- Tianhe Zhang
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang City, Liaoning Province, People's Republic of China
| | - Wenliang Song
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang City, Liaoning Province, People's Republic of China
| | - Zhiqin Mao
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang City, Liaoning Province, People's Republic of China.
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Li S, Lin Y, Chen S, Zhang W, Chen YM, Lu X, Shao Y, Lu Z, Sheng H, Guan Z, Zheng R, Liang C, Chen Y, Liu L, Zeng C. Clinical characteristics and prognosis of early diagnosed Wilson's disease: A large cohort study. Liver Int 2024; 44:2424-2433. [PMID: 38847512 DOI: 10.1111/liv.16009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Revised: 05/17/2024] [Accepted: 05/27/2024] [Indexed: 08/30/2024]
Abstract
BACKGROUND AND AIMS Few studies have focused on the outcomes of Wilson's disease (WD) diagnosed before age of 5 years. This study aimed to summarize the clinical features of early diagnosed WD and analyse treatment outcomes and the risk factors associated with treatment failure. METHODS A total of 139 children confirmed with WD before 5 years were enrolled in this study. Only patients with follow-up over 1 year were analysed with Kaplan-Meier survival analysis. The composite outcomes included death, progression to liver failure or acute hepatitis, development of renal or neurological symptoms and persistent elevation of alanine aminotransferase (ALT). The treatment failure was defined as occurrence of at least one of above outcomes. RESULTS Among 139 WD patients at diagnosis, two (1.4%) WD patients presented with symptomatic liver disease, whereas 137 (98.6%) were phenotypically asymptomatic, including 135 with elevated ALT and 2 with normal liver function. Median serum ceruloplasmin (Cp) was 3.1 mg/dL, and urinary copper excretion was 87.4 μg/24-h. There were 71 variants identified in the the copper-transporting ATPase beta gene, and 29 were loss of function (LOF). 51 patients with LOF variant were younger at diagnosis and had lower Cp than 88 patients without LOF. Among 93 patients with over 1 year of follow-up, 19 (20.4%) received zinc monotherapy, and 74 (79.6%) received a zinc/D-penicillamine combination therapy. 14 (15.1%) patients underwent treatment failure, and its occurrence was associated with poor compliance (p < .01). CONCLUSIONS Cp is a reliable biomarker for early diagnosis, and zinc monotherapy is an effective treatment for WD during early childhood. Good treatment compliance is critical to achieve a favourable outcome.
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Affiliation(s)
- Simin Li
- Department of Genetics and Endocrinology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, China
- Department of Pediatrics, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yunting Lin
- Department of Genetics and Endocrinology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, China
| | - Shehong Chen
- Department of Genetics and Endocrinology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, China
- Department of Pediatrics, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Wen Zhang
- Department of Genetics and Endocrinology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, China
| | - Yu-Ming Chen
- Department of Epidemiology, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-Sen University, Guangzhou, China
| | - Xinshuo Lu
- Department of Genetics and Endocrinology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, China
| | - Yongxian Shao
- Department of Genetics and Endocrinology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, China
| | - Zhikun Lu
- Department of Genetics and Endocrinology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, China
| | - Huiying Sheng
- Department of Genetics and Endocrinology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, China
| | - Zhihong Guan
- Department of Genetics and Endocrinology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, China
| | - Ruidan Zheng
- Department of Genetics and Endocrinology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, China
| | - Cuili Liang
- Department of Genetics and Endocrinology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, China
| | - Yaoyong Chen
- Department of Pediatrics, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Li Liu
- Department of Genetics and Endocrinology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, China
| | - Chunhua Zeng
- Department of Genetics and Endocrinology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, China
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19
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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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20
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Engel B, Diestelhorst J, Hupa-Breier KL, Kirchner T, Henjes N, Loges S, Yuksel M, Janczyk W, Lalanne C, Zachou K, Oo YH, Gournay J, Pape S, Drenth JPH, Renand A, Dalekos GN, Muratori L, Socha P, Ma Y, Arikan C, Baumann U, Manns MP, Wedemeyer H, Junge N, Jaeckel E, Taubert R. Detection of polyreactive immunoglobulin G facilitates diagnosis in children with autoimmune hepatitis. Hepatol Int 2024; 18:1214-1226. [PMID: 38976227 PMCID: PMC11297808 DOI: 10.1007/s12072-024-10695-1] [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: 01/10/2024] [Accepted: 04/26/2024] [Indexed: 07/09/2024]
Abstract
OBJECTIVE The detection of autoantibodies is essential to diagnose autoimmune hepatitis (AIH). Particularly in children, specificity of autoantibodies decreases due to lower titers being diagnostic and being present not only in AIH but also in other liver diseases. Recently, quantification of polyreactive IgG (pIgG) for detection of adult AIH showed the highest overall accuracy compared to antinuclear antibodies (ANA), anti-smooth muscle antibodies (anti-SMA), anti-liver kidney microsomal antibodies (anti-LKM) and anti-soluble liver antigen/liver pancreas antibodies (anti-SLA/LP). We aimed to evaluate the diagnostic value of pIgG for pediatric AIH. DESIGN pIgG, quantified using HIP1R/BSA coated ELISA, and immunofluorescence on rodent tissue sections were performed centrally. The diagnostic fidelity to diagnose AIH was compared to conventional autoantibodies of AIH in training and validation cohorts from a retrospective, European multi-center cohort from nine centers from eight European countries composed of existing biorepositories from expert centers (n = 285). RESULTS IgG from pediatric AIH patients exhibited increased polyreactivity to multiple protein and non-protein substrates compared to non-AIH liver diseases and healthy children. pIgG had an AUC of 0.900 to distinguish AIH from non-AIH liver diseases. pIgG had a 31-73% higher specificity than ANA and anti-SMA and comparable sensitivity that was 6-20 times higher than of anti-SLA/LP, anti-LC1 and anti-LKM. pIgG had a 21-34% higher accuracy than conventional autoantibodies, was positive in 43-75% of children with AIH and normal IgG and independent from treatment response. CONCLUSION Detecting pIgG improves the diagnostic evaluation of pediatric AIH compared to conventional autoantibodies, primarily owing to higher accuracy and specificity.
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Affiliation(s)
- Bastian Engel
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, HepatologyHannover, Germany.
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany.
| | - Jana Diestelhorst
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, HepatologyHannover, Germany
- Division of Pediatric Gastroenterology and Hepatology, Department of Pediatric Nephrology, Hepatology and Metabolic Disorders, Hannover Medical School, Hannover, Germany
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
- Oncology, Hemostaseology and Palliative Care, Johannes Wesling Medical Center Minden, University Clinic for Haematology, UKRUB, University of Bochum, Minden, Germany
| | - Katharina Luise Hupa-Breier
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, HepatologyHannover, Germany
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
| | - Theresa Kirchner
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, HepatologyHannover, Germany
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
| | - Nicole Henjes
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, HepatologyHannover, Germany
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
| | - Stephanie Loges
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, HepatologyHannover, Germany
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
| | - Muhammed Yuksel
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Sciences, King's College Hospital, King's College London, London, UK
- Koç University Research Centre for Translational Medicine (KUTTAM)-Liver Immunology Lab, Istanbul, Turkey
- Department of Biomedical Sciences, College of Liberal Arts and Life Sciences, University of Westminster, London, UK
| | - Wojciech Janczyk
- Department of Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
| | - Claudine Lalanne
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
| | - Kalliopi Zachou
- Institute of Internal Medicine and Hepatology, Larissa, Greece
- l University Hospital of Larissa, Larissa, Greece
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
| | - Ye H Oo
- Centre for Liver and Gastro Research, National Institute of Health Research Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, The Medical School, Birmingham, United Kingdom & Liver transplant and Hepatobiliary Unit, University Hospital Birmingham NHS Foundation Trust, Birmingham, UK
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
| | - Jérôme Gournay
- Institut Des Maladies de L'Appareil Digestif (IMAD), Nantes Université, CHU Nantes, Hépato-Gastro-Entérologie, Inserm CIC 1413, 44000, Nantes, France
| | - Simon Pape
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
| | - Joost P H Drenth
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
| | - Amédée Renand
- Center for Research in Transplantation and Translational Immunology, Nantes Université, UMR 1064, Inserm, 44000, Nantes, France
| | - George N Dalekos
- Institute of Internal Medicine and Hepatology, Larissa, Greece
- l University Hospital of Larissa, Larissa, Greece
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
| | - Luigi Muratori
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
| | - Piotr Socha
- Department of Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
| | - Yun Ma
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Sciences, King's College Hospital, King's College London, London, UK
| | - Cigdem Arikan
- Koç University Research Centre for Translational Medicine (KUTTAM)-Liver Immunology Lab, Istanbul, Turkey
- Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Koç University School of Medicine, Istanbul, 34010, Turkey
| | - Ulrich Baumann
- Division of Pediatric Gastroenterology and Hepatology, Department of Pediatric Nephrology, Hepatology and Metabolic Disorders, Hannover Medical School, Hannover, Germany
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
| | - Michael P Manns
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, HepatologyHannover, Germany
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, HepatologyHannover, Germany
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
| | - Norman Junge
- Division of Pediatric Gastroenterology and Hepatology, Department of Pediatric Nephrology, Hepatology and Metabolic Disorders, Hannover Medical School, Hannover, Germany
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
| | - Elmar Jaeckel
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, HepatologyHannover, Germany
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
- Ajmera Transplant Center, Toronto General Hospital, United Health Network, University of Toronto, Toronto, Canada
| | - Richard Taubert
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, HepatologyHannover, Germany
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
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21
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Lee EJ, Woo MH, Moon JS, Ko JS. Efficacy and safety of D-penicillamine, trientine, and zinc in pediatric Wilson disease patients. Orphanet J Rare Dis 2024; 19:261. [PMID: 38982450 PMCID: PMC11234817 DOI: 10.1186/s13023-024-03271-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2023] [Accepted: 07/01/2024] [Indexed: 07/11/2024] Open
Abstract
OBJECTIVES Wilson disease (WD) is a rare genetic disease affecting copper metabolism and the biliary tract's copper excretion. Lifelong medication is necessary to prevent liver failure, neurological complications, and death. Although D-penicillamine (DPA), trientine, and zinc are used to treat WD, there is limited research on the long-term outcomes of these drugs, especially in children. This study aimed to evaluate the efficacy and safety of DPA, trientine, and zinc in patients diagnosed with WD during childhood. METHODS Ninety out of 92 patients were included in the analysis, excluding two patients who underwent liver transplantation without drug treatment due to an acute liver failure diagnosis. Treatment outcomes and reasons for discontinuation of therapy in 148 treatment blocks (37 DPA, 50 trientine, and 61 zinc) were analyzed using Kaplan-Meier analysis. RESULTS The median age at diagnosis was 8.3 years. There was a statistically significant difference in drug changes due to treatment ineffectiveness among the three drugs: trientine (22/50, 44%), zinc (15/61, 25%), and DPA (2/37, 5%) (all p < 0.05). Regarding drug changes due to adverse effects, the rate was the highest for DPA, followed by zinc and trientine. There were significant differences between DPA and zinc, zinc and trientine (all p < 0.05), but no significant difference was observed between DPA and zinc (p = 0.22). CONCLUSIONS In pediatric WD, DPA, zinc, and trientine have therapeutic effects in that order. However, DPA and zinc are associated with more adverse effects compared to trientine.
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Affiliation(s)
- Eun Joo Lee
- Department of Pediatrics, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Min Hyung Woo
- Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Jin Soo Moon
- Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Jae Sung Ko
- Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Korea.
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Pop TL, Grama A. New developments in the management of Wilson's disease in children. GLOBAL PEDIATRICS 2024; 8:100142. [DOI: 10.1016/j.gpeds.2024.100142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/02/2025]
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Abbassi N, Bourrahouat A, Bedoya EC, Pagan C, Qabli ME, Maidoumi S, Belmalih A, Guillaud O, Kissani N, Abkari A, Chahid I, Rafai MA, Mouane N, Kriouile Y, Aidi S, Hida M, Idrissi ML, Belahsen MF, Abkari ME, Rkain M, Ismaili Z, Sedki A, Bost M, Aboussair N, Lachaux A. Phenotype and molecular characterization of Wilson's disease in Morocco. Clin Res Hepatol Gastroenterol 2024; 48:102335. [PMID: 38588792 DOI: 10.1016/j.clinre.2024.102335] [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: 08/01/2022] [Revised: 01/29/2024] [Accepted: 03/29/2024] [Indexed: 04/10/2024]
Abstract
BACKGROUND AND STUDY AIMS In Morocco the prevalence of Wilson disease (WD) and the spectrum of mutations are not known. The aim of the present study was to estimate the prevalence of WD in Morocco, to evaluate the phenotype among a large cohort of WD patients, and to characterize ATP7B variants in a subgroup of WD patients. PATIENTS AND METHODS We collected data from 226 patients admitted to five university hospital centers in Morocco between 2008 and 2020. The diagnosis was based on clinical manifestations, function tests and biochemical parameters. The genotype was characterized in 18 families diagnosed at the University Hospital Center of Marrakesh, by next generation sequencing. RESULTS The mean annual prevalence in Morocco was 3.88 per 100,000 and the allele frequency was 0.15 %. Among the 226 patients included (121 males and 105 females), 196 were referred for a hepatic or neurological involvement and 30 were asymptomatic. The mean age at diagnosis was 13 ± 5.1 years (range: 5 - 42 years). Consanguinity was found in 63.3 % of patients. The mean duration of illness was 2.8 ± 1.9 years. Kayser-Fleischer rings were found in 131 (67.9 %) of 193 patients. Among the 196 symptomatic patients, 141/159 (88.7 %) had low serum ceruloplasmin (<0.2 g/L) and a high 24-hours urinary copper (>100 μg/day) was found in 173/182 (95.1 %) patients. The initial treatment was D-penicillamine in 207 patients, zinc acetate in five, zinc sulfate in five, and nine patients were not treated; 60/207 (29 %) patients have stopped treatment. A total of 72 patients died; the mortality rate was 31.9 %. Eight different ATP7B variants were identified among the 18 patients studied, of which two were novel (p.Cys1104Arg and p.Gln1277Hisfs*52), and six previously published (p.Gln289Ter, p.Cys305Ter, p.Thr1232Pro, p.Lys1020Arg, p.Glu583ArgfsTer25 and c.51+4A>T). All informative patients were homozygous for the disease-causing mutation. CONCLUSION In Morocco, a high prevalence due to consanguinity and a high mortality rate due to the difficulty of diagnosis and lack of treatment were observed in WD patients. NGS sequencing identified new ATP7B variants in WD patients from Morocco.
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Affiliation(s)
- Nadia Abbassi
- Université Cadi Ayyad, Faculté des Sciences Semlalia, LHEAC, 40000, Marrakech, Morocco; Université Claude Bernard Lyon 1, INSERM-U1060, INRA, INSA, Laboratoire CarMeN, 69500, Lyon, France.
| | - Aicha Bourrahouat
- Université Cadi Ayyad, Faculté de Médecine et de pharmacie, Laboratoire de recherche de l'enfance, la santé et le développement, 40000, Marrakech, Morocco; CHU Mohammed VI de Marrakech, Hôpital Mère-Enfant, Service de Pédiatrie, 40080, Marrakech, Morocco
| | - Eduardo Couchonnal Bedoya
- HCL, Centre de référence de la maladie de Wilson, 69500, Lyon, France; HCL, Hôpital Mère-Femme-Enfant, Unité de Gastroentrologie, Hépatologie et Nutrition, 69500, Lyon, France
| | - Cécile Pagan
- HCL, Centre de Biochimie et Biologie Moléculaire, LBMMS, 69500, Lyon, France
| | - Meriem El Qabli
- Université Cadi Ayyad, Faculté de Médecine et de pharmacie, Laboratoire de recherche de l'enfance, la santé et le développement, 40000, Marrakech, Morocco
| | - Sana Maidoumi
- Université Cadi Ayyad, Faculté des Sciences Semlalia, LHEAC, 40000, Marrakech, Morocco
| | | | - Olivier Guillaud
- HCL, Hôpital Mère-Femme-Enfant, Unité de Gastroentrologie, Hépatologie et Nutrition, 69500, Lyon, France
| | - Najib Kissani
- CHU Mohammed VI de Marrakech, Hôpital Arrazi, Service de Neurologie, 40080, Marrakech, Morocco
| | - Abdelhak Abkari
- CHU Ibn Rochd de Casablanca, Hôpital Mère-Enfant, Service de Gastro-Pédiatrie, 20360, Casablanca, Morocco
| | - Imane Chahid
- CHU Ibn Rochd de Casablanca, Hôpital Mère-Enfant, Service de Gastro-Pédiatrie, 20360, Casablanca, Morocco
| | - Mohammed Abdoh Rafai
- CHU Ibn Rochd de Casablanca, Service de Neurologie adulte, 20360, Casablanca, Morocco
| | - Nezha Mouane
- CHU Ibn Sina de Rabat, Hôpital Mère-Enfant, Service de Gastro-Pédiatrie, 10100, Rabat, Morocco
| | - Yamna Kriouile
- CHU Ibn Sina de Rabat, Hôpital Mère-Enfant, Service de Gastro-Pédiatrie, 10100, Rabat, Morocco
| | - Saadia Aidi
- CHU Ibn Sina de Rabat, Service de Neurologie adulte, 10100 Rabat, Morocco
| | - Moustpha Hida
- CHU Hassan II de Fès, Hôpital Mère-Enfant, Service de Pédiatrie, 30050 Fès, Morocco
| | | | | | - Mohammed El Abkari
- CHU Hassan II de Fès, Service de Gastroenterologie et Hépatologie adulte, 30050 Fès, Morocco
| | - Maria Rkain
- CHU Mohammed VI d'Oujda, Hôpital Mère-Enfant, Service de Pédiatrie, 60049 Oujda, Morocco
| | - Zahi Ismaili
- CHU Mohammed VI d'Oujda, Service de Gastroenterologie et Hépatologie adulte, 60049, Oujda, Morocco
| | - Azeddine Sedki
- Université Cadi Ayyad, Faculté des Sciences Semlalia, LHEAC, 40000, Marrakech, Morocco
| | - Muriel Bost
- HCL, Centre de référence de la maladie de Wilson, 69500, Lyon, France; HCL, Centre de Biochimie et Biologie Moléculaire, LBMMS, 69500, Lyon, France
| | - Nisrine Aboussair
- Université Cadi Ayyad, Faculté de Médecine et de pharmacie, Laboratoire de recherche de l'enfance, la santé et le développement, 40000, Marrakech, Morocco; CHU Mohammed VI de Marrakech, Centre de recherche clinique, Service de Génétique, 40080, Marrakech, Morocco
| | - Alain Lachaux
- HCL, Centre de référence de la maladie de Wilson, 69500, Lyon, France; HCL, Hôpital Mère-Femme-Enfant, Unité de Gastroentrologie, Hépatologie et Nutrition, 69500, Lyon, France; Université Claude Bernard Lyon 1, CIRI-INSERM-U1111, CNRS UMR5308, 69100, Lyon, France
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Panda K, Lal BB, Sood V, Khanna R, Alam S. Relapse following withdrawal of D-penicillamine from combination (D-penicillamine + zinc) therapy in hepatic Wilson disease. J Pediatr Gastroenterol Nutr 2024; 78:1017-1026. [PMID: 38695602 DOI: 10.1002/jpn3.12128] [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: 09/24/2023] [Revised: 12/11/2023] [Accepted: 12/24/2023] [Indexed: 06/16/2024]
Abstract
OBJECTIVES Long-term D-penicillamine (D-pen) therapy in Wilson disease (WD) has numerous adverse effects which advocates its withdrawal, but with an inherent risk of relapse. This prospective observational study was conducted with the objective of evaluating incidence of relapse following withdrawal of D-pen from combination (D-pen + zinc) therapy in maintenance phase of previously symptomatic hepatic WD. METHODS Hepatic WD patients <18 years of age and on combination therapy for >2 years with 6 months of biochemical remission were included. Biochemical remission was defined as achievement of (i) aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤1.5 times upper limit of normal (ULN), (ii) serum albumin >3.5 g/dL, international normalized ratio (INR) <1.5 and (iii) 24-h urinary copper excretion (UCE) <500 mcg/day, nonceruloplasmin-bound-copper (NCC) <15 mcg/dL. After D-pen withdrawal, monthly liver function test (LFT) and INR and 3 monthly UCE and NCC were done till 1 year or relapse (elevation of AST/ALT/both >2 times ULN or total bilirubin >2 mg/dL), whichever occurred earlier. RESULTS Forty-five patients enrolled with median combination therapy duration of 36 months. Sixty percent of them had their index presentation as decompensated cirrhosis. Fourteen patients (31.8%) relapsed (cumulative incidence: 4 at 3 months, 11 at 6 months, and 14 at 12 months after D-pen discontinuation). All relapsers had index presentation as decompensated cirrhosis. On Cox-regression, ALT at D-pen withdrawal was an independent predictor of relapse (hazard ratio [HR]: 1.077, 95% confidence interval [CI]: 1.014-1.145, p = 0.017) with area under the receiver operating characteristic (AUROC) of 0.860. ALT ≥40 U/L predicted risk of relapse with 85.7% sensitivity, 70.9% specificity. CONCLUSION Incidence of relapse after withdrawal of D-pen from combination therapy is 31.8% in hepatic WD. ALT ≥40 U/L, at the time of D-pen stoppage, predicts future relapse.
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Affiliation(s)
- Kalpana Panda
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Bikrant B Lal
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Vikrant Sood
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Rajeev Khanna
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Seema Alam
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
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Panda K, Lal BB, Sood V, Khanna R, Alam S. Relapse following withdrawal of D‐penicillamine from combination (D‐penicillamine + zinc) therapy in hepatic Wilson disease. J Pediatr Gastroenterol Nutr 2024; 78:1017-1026. [DOI: https:/doi.org/10.1002/jpn3.12128] [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] [Indexed: 04/16/2025]
Abstract
AbstractObjectivesLong‐term D‐penicillamine (D‐pen) therapy in Wilson disease (WD) has numerous adverse effects which advocates its withdrawal, but with an inherent risk of relapse. This prospective observational study was conducted with the objective of evaluating incidence of relapse following withdrawal of D‐pen from combination (D‐pen + zinc) therapy in maintenance phase of previously symptomatic hepatic WD.MethodsHepatic WD patients <18 years of age and on combination therapy for >2 years with 6 months of biochemical remission were included. Biochemical remission was defined as achievement of (i) aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤1.5 times upper limit of normal (ULN), (ii) serum albumin >3.5 g/dL, international normalized ratio (INR) <1.5 and (iii) 24‐h urinary copper excretion (UCE) <500 mcg/day, nonceruloplasmin‐bound‐copper (NCC) <15 mcg/dL. After D‐pen withdrawal, monthly liver function test (LFT) and INR and 3 monthly UCE and NCC were done till 1 year or relapse (elevation of AST/ALT/both >2 times ULN or total bilirubin >2 mg/dL), whichever occurred earlier.ResultsForty‐five patients enrolled with median combination therapy duration of 36 months. Sixty percent of them had their index presentation as decompensated cirrhosis. Fourteen patients (31.8%) relapsed (cumulative incidence: 4 at 3 months, 11 at 6 months, and 14 at 12 months after D‐pen discontinuation). All relapsers had index presentation as decompensated cirrhosis. On Cox‐regression, ALT at D‐pen withdrawal was an independent predictor of relapse (hazard ratio [HR]: 1.077, 95% confidence interval [CI]: 1.014–1.145, p = 0.017) with area under the receiver operating characteristic (AUROC) of 0.860. ALT ≥40 U/L predicted risk of relapse with 85.7% sensitivity, 70.9% specificity.ConclusionIncidence of relapse after withdrawal of D‐pen from combination therapy is 31.8% in hepatic WD. ALT ≥40 U/L, at the time of D‐pen stoppage, predicts future relapse.
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Affiliation(s)
- Kalpana Panda
- Department of Pediatric Hepatology Institute of Liver and Biliary Sciences New Delhi India
| | - Bikrant B. Lal
- Department of Pediatric Hepatology Institute of Liver and Biliary Sciences New Delhi India
| | - Vikrant Sood
- Department of Pediatric Hepatology Institute of Liver and Biliary Sciences New Delhi India
| | - Rajeev Khanna
- Department of Pediatric Hepatology Institute of Liver and Biliary Sciences New Delhi India
| | - Seema Alam
- Department of Pediatric Hepatology Institute of Liver and Biliary Sciences New Delhi India
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Youssef EM, Wu GY. Subnormal Serum Liver Enzyme Levels: A Review of Pathophysiology and Clinical Significance. J Clin Transl Hepatol 2024; 12:428-435. [PMID: 38638374 PMCID: PMC11022067 DOI: 10.14218/jcth.2023.00446] [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: 12/13/2023] [Revised: 02/09/2024] [Accepted: 02/18/2024] [Indexed: 04/20/2024] Open
Abstract
Subnormal levels of liver enzymes, below the lower limit of normal on local laboratory reports, can be useful diagnostically. For instance, subnormal levels of aminotransferases can be observed in vitamin B6 deficiency and chronic kidney disease. Subnormal alkaline phosphatase levels may indicate the presence of hypophosphatasia, Wilson's disease, deficiencies of divalent ions, or malnutrition. Subnormal levels of gamma glutamyl transferase may be seen in cases of acute intrahepatic cholestasis, the use of certain medications, and in bone disease. Finally, subnormal levels of 5'-nucleotidase have been reported in lead poisoning and nonspherocytic hemolytic anemia. The aim of this review is to bring attention to the fact that subnormal levels of these enzymes should not be ignored as they may indicate pathological conditions and provide a means of early diagnosis.
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Affiliation(s)
| | - George Y. Wu
- Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, CT, USA
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Alexander V, Benjamin SJ, Subramani K, Sathyendra S, Goel A. Acute liver failure in pregnancy. Indian J Gastroenterol 2024; 43:325-337. [PMID: 38691240 DOI: 10.1007/s12664-024-01571-9] [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: 11/25/2023] [Accepted: 03/09/2024] [Indexed: 05/03/2024]
Abstract
Liver function abnormalities are noted in a minority of pregnancies with multiple causes for the same. A small proportion of these develop severe liver injury and progress to acute liver failure (ALF). There is a discrete set of etiology for ALF in pregnancy and comprehensive understanding will help in urgent evaluation. Certain diseases such as acute fatty liver of pregnancy, hemolysis, elevated liver enzyme, low platelet (HELLP) syndrome and pre-eclampsia are secondary to pregnant state and can present as ALF. Quick and targeted evaluation with urgent institution of etiology-specific management, especially urgent delivery in patients with pregnancy-associated liver diseases, is the key to avoiding maternal deaths. Pregnancy, as also the fetal life, imparts a further layer of complication in assessment, prognosis and management of these sick patients with ALF. Optimal management often requires a multidisciplinary approach in a well-equipped centre. In this review, we discuss evaluation, assessment and management of pregnant patients with ALF, focussing on approach to pregnancy-associated liver diseases.
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Affiliation(s)
- Vijay Alexander
- Department of Hepatology, Christian Medical College, Vellore 632 004, India
| | - Santosh J Benjamin
- Department of Obstetrics and Gynaecology, Christian Medical College, Vellore 632 004, India
| | - Kandasamy Subramani
- Division of Critical Care, Christian Medical College, Vellore 632 004, India
| | - Sowmya Sathyendra
- Department of Obstetric Medicine, Christian Medical College, Vellore 632 004, India
| | - Ashish Goel
- Department of Hepatology, Christian Medical College, Vellore 632 004, India.
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Joshi D, Nayagam J, Clay L, Yerlett J, Claridge L, Day J, Ferguson J, Mckie P, Vara R, Pargeter H, Lockyer R, Jones R, Heneghan M, Samyn M. UK guideline on the transition and management of childhood liver diseases in adulthood. Aliment Pharmacol Ther 2024; 59:812-842. [PMID: 38385884 DOI: 10.1111/apt.17904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 10/15/2023] [Accepted: 02/03/2024] [Indexed: 02/23/2024]
Abstract
INTRODUCTION Improved outcomes of liver disease in childhood and young adulthood have resulted in an increasing number of young adults (YA) entering adult liver services. The adult hepatologist therefore requires a working knowledge in diseases that arise almost exclusively in children and their complications in adulthood. AIMS To provide adult hepatologists with succinct guidelines on aspects of transitional care in YA relevant to key disease aetiologies encountered in clinical practice. METHODS A systematic literature search was undertaken using the Pubmed, Medline, Web of Knowledge and Cochrane database from 1980 to 2023. MeSH search terms relating to liver diseases ('cholestatic liver diseases', 'biliary atresia', 'metabolic', 'paediatric liver diseases', 'autoimmune liver diseases'), transition to adult care ('transition services', 'young adult services') and adolescent care were used. The quality of evidence and the grading of recommendations were appraised using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. RESULTS These guidelines deal with the transition of YA and address key aetiologies for the adult hepatologist under the following headings: (1) Models and provision of care; (2) screening and management of mental health disorders; (3) aetiologies; (4) timing and role of liver transplantation; and (5) sexual health and fertility. CONCLUSIONS These are the first nationally developed guidelines on the transition and management of childhood liver diseases in adulthood. They provide a framework upon which to base clinical care, which we envisage will lead to improved outcomes for YA with chronic liver disease.
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Affiliation(s)
- Deepak Joshi
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, UK
| | - Jeremy Nayagam
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, UK
| | - Lisa Clay
- Paediatric Liver, GI and Nutrition service, King's College Hospital NHS Foundation Trust, London, UK
| | - Jenny Yerlett
- Paediatric Liver, GI and Nutrition service, King's College Hospital NHS Foundation Trust, London, UK
| | - Lee Claridge
- Leeds Liver Unit, St James's University Hospital, Leeds, UK
| | - Jemma Day
- Department of Psychology, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - James Ferguson
- National Institute for Health Research, Birmingham Biomedical Research Centre, University of Birmingham, Birmingham, UK
| | - Paul Mckie
- Department of Social Work, King's College Hospital NHS Foundation Trust, London, UK
| | - Roshni Vara
- Paediatric Liver, GI and Nutrition service, King's College Hospital NHS Foundation Trust, London, UK
- Evelina London Children's Hospital, London, UK
| | | | | | - Rebecca Jones
- Leeds Liver Unit, St James's University Hospital, Leeds, UK
| | - Michael Heneghan
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, UK
| | - Marianne Samyn
- Paediatric Liver, GI and Nutrition service, King's College Hospital NHS Foundation Trust, London, UK
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Ravindranath A, Yachha SK. An Approach to Investigations of Chronic Liver Disease. Indian J Pediatr 2024; 91:262-269. [PMID: 37702974 DOI: 10.1007/s12098-023-04751-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Accepted: 06/23/2023] [Indexed: 09/14/2023]
Abstract
Chronic liver disease (CLD) in children is more diverse compared to adults with respect to the etiology, progression and response to therapy. After history and clinical examination, the first step is to confirm the presence of CLD with basic blood investigations and ultrasonography. Markers of portal hypertension are splenomegaly, increased portal vein diameter, thrombocytopenia and presence of varices on endoscopy. The next step is to evaluate the etiology of CLD which will depend on the age of the child and needs targeted investigations as metabolic and inherited causes predominate in early childhood. CLD progression ought to be monitored regularly and several non-invasive markers are available but they have to be evaluated further in children. Since CLD progresses, complications have to be detected early not only to initiate appropriate treatment but also to prognosticate.
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Affiliation(s)
- Aathira Ravindranath
- Department of Pediatric Gastroenterology, Institute of Gastrointestinal Sciences, Apollo BGS Hospitals, Kuvempunagar, Mysore, Karnataka, 570023, India
| | - Surender Kumar Yachha
- Department of Pediatric Gastroenterology, Hepatology and Liver Transplantation, Sakra World Hospital, Bengaluru, Karnataka, 560103, India.
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Panda K, Lal BB, Sood V, Khanna R, Alam S. Adequate Chelation and Cupriuresis in Hepatic Wilson Disease Patients Under Combination (Chelator + Zinc) Therapy at 2 Years of Follow-up. J Clin Exp Hepatol 2024; 14:101284. [PMID: 38544767 PMCID: PMC10964067 DOI: 10.1016/j.jceh.2023.09.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Accepted: 09/12/2023] [Indexed: 01/07/2025] Open
Abstract
BACKGROUND & AIM Role of 24-h urinary copper excretion (UCE) in monitoring Wilson disease (WD) on combination (chelator + Zinc) therapy is not well studied, especially in the pediatric population. Hence, the present study is conducted with an aim to evaluate UCE and its role in deciding therapeutic adequacy in pediatric WD on long-term follow-up. METHODS All WD patients <18 years of age and on combination therapy with at least one UCE available after the first year of treatment were included. Liver biochemistries, UCE, and serum non-ceruloplasmin bound copper (NCC) were assessed at diagnosis and various follow-ups. For assessment of treatment efficacy, criteria for adequate chelation (CAC) were defined as fulfillment of both (i) AST & ALT ≤1.5 times upper limit of normal, serum albumin >35 gm/L, INR <1.5 and (ii) UCE <500 mcg/day. RESULTS Of the 74 included children, 70 (94.5%), 45 (60.8%), 28 (37.8%) and 21 (28.3%) completed 2-, 3-, 5-, and 7-year follow-up, respectively. Liver biochemistries improved significantly within 1 year of treatment. UCE (mcg/day) decreased significantly from baseline of 654.08 ± 803.78 to 308.23 ± 175.93 at 2 years with no further change at 3- and 5-years follow-up. UCE (mcg/day) at 2 years was <200 in 28.5%, 200-500 in 55.7%, and >500 in 15.7%. 61% achieved CAC in 2 years. On multivariate cox regression, treatment compliance was predictor for CAC achievement (Odds ratio: 3.48, 95%CI: 1.36-8.86. P = 0.009). CONCLUSION UCE declines significantly from baseline to <500 mcg/day within 2 years. Majority of treatment-compliant patients achieve CAC within 2 years of combination therapy.
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Affiliation(s)
- Kalpana Panda
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Bikrant B. Lal
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Vikrant Sood
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Rajeev Khanna
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Seema Alam
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
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Panda K, Lal BB, Sood V, Khanna R, Alam S. Adequate Chelation and Cupriuresis in Hepatic Wilson Disease Patients Under Combination (Chelator + Zinc) Therapy at 2 Years of Follow-up. J Clin Exp Hepatol 2024; 14:101284. [DOI: https:/doi.org/10.1016/j.jceh.2023.09.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/16/2025] Open
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Tornabene D, Bini P, Gastaldi M, Vegezzi E, Asteggiano C, Marchioni E, Diamanti L. Neurological complications due to copper deficiency in the context of Wilson disease treatment: a case report with long-term follow-up and review of the literature. Neurol Sci 2024; 45:987-996. [PMID: 37851293 PMCID: PMC10858109 DOI: 10.1007/s10072-023-07126-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 10/10/2023] [Indexed: 10/19/2023]
Abstract
The objective is to investigate the presentation, complications, management, and outcomes of copper deficiency-induced neurological pathologies due to Wilson disease (WD) overtreatment. We examined the case of a WD patient who developed a low thoracic dorsal myelopathy due to chronic hypocupremia from excessive zinc therapy. A comprehensive literature review was conducted to identify similar cases. Ten additional cases of neurological pathology resulting from copper deficiency in the context of WD over-treatment were identified, all occurring during therapy with zinc salts. Myelopathy and peripheral neuropathy were the most common complications, while two additional groups reported leukoencephalopathy. Early cytopenia was often associated with copper deficiency-related neurological pathology appearing early in the context of copper deficiency. WD patients undergoing treatment, especially with zinc salts, should be closely monitored to prevent over-treatment and the consequent copper deficiency. Regular complete blood counts could provide early detection of copper deficiency, avoiding irreversible neurological damage. Swift recognition of new neurological signs not consistent with WD and timely discontinuation of the decoppering therapy are critical for improving outcomes. The optimal management, including the potential benefit of copper supplementation in patients with WD and subsequent therapy adjustments, remains unclear and necessitates further investigation. Despite the general poor functional neurological outcomes, there were some exceptions that warrant further exploration.
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Affiliation(s)
- Danilo Tornabene
- Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.
- IRCCS Mondino Foundation, Via Mondino 2, 27100, Pavia, Italy.
| | - Paola Bini
- IRCCS Mondino Foundation, Via Mondino 2, 27100, Pavia, Italy
| | - Matteo Gastaldi
- IRCCS Mondino Foundation, Via Mondino 2, 27100, Pavia, Italy
| | - Elisa Vegezzi
- IRCCS Mondino Foundation, Via Mondino 2, 27100, Pavia, Italy
| | - Carlo Asteggiano
- Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy
- IRCCS Mondino Foundation, Via Mondino 2, 27100, Pavia, Italy
| | | | - Luca Diamanti
- IRCCS Mondino Foundation, Via Mondino 2, 27100, Pavia, Italy
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Ovchinnikova EV, Garbuz MM, Ovchinnikova AA, Kumeiko VV. Epidemiology of Wilson's Disease and Pathogenic Variants of the ATP7B Gene Leading to Diversified Protein Disfunctions. Int J Mol Sci 2024; 25:2402. [PMID: 38397079 PMCID: PMC10889319 DOI: 10.3390/ijms25042402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 02/14/2024] [Accepted: 02/16/2024] [Indexed: 02/25/2024] Open
Abstract
Wilson's disease (WD) is an autosomal recessive disorder characterized by toxic accumulation of copper in the liver, brain, and other organs. The disease is caused by pathogenic variants in the ATP7B gene, which encodes a P-type copper transport ATPase. Diagnosing WD is associated with numerous difficulties due to the wide range of clinical manifestations and its unknown dependence on the physiological characteristics of the patient. This leads to a delay in the start of therapy and the subsequent deterioration of the patient's condition. However, in recent years, molecular genetic testing of patients using next generation sequencing (NGS) has been gaining popularity. This immediately affected the detection speed of WD. If, previously, the frequency of this disease was estimated at 1:35,000-45,000 people, now, when conducting large molecular genetic studies, the frequency is calculated as 1:7026 people. This certainly points to the problem of identifying WD patients. This review provides an update on the performance of epidemiological studies of WD and describes normal physiological functions of the protein and diversified disfunctions depending on pathogenic variants of the ATP7B gene. Future prospects in the development of WD genetic diagnostics are also discussed.
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Affiliation(s)
- Elena Vasilievna Ovchinnikova
- Institute of Life Sciences and Biomedicine, School of Natural Sciences, Far Eastern Federal University, Vladivostok 690922, Russia (M.M.G.)
| | - Mikhail Maksimovich Garbuz
- Institute of Life Sciences and Biomedicine, School of Natural Sciences, Far Eastern Federal University, Vladivostok 690922, Russia (M.M.G.)
| | - Anna Aleksandrovna Ovchinnikova
- Institute of Life Sciences and Biomedicine, School of Natural Sciences, Far Eastern Federal University, Vladivostok 690922, Russia (M.M.G.)
| | - Vadim Vladimirovich Kumeiko
- Institute of Life Sciences and Biomedicine, School of Natural Sciences, Far Eastern Federal University, Vladivostok 690922, Russia (M.M.G.)
- A.V. Zhirmunsky National Scientific Center of Marine Biology, Far Eastern Branch of Russian Academy of Sciences, Federal University, Vladivostok 690041, Russia
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Więcek S, Paprocka J. Disorders of Copper Metabolism in Children-A Problem too Rarely Recognized. Metabolites 2024; 14:38. [PMID: 38248841 PMCID: PMC10818781 DOI: 10.3390/metabo14010038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 12/23/2023] [Accepted: 01/05/2024] [Indexed: 01/23/2024] Open
Abstract
Copper plays an important role in metabolic processes. Both deficiency and excess of this element have a negative effect and lead to pathological conditions. Copper is a cofactor of many enzymatic reactions. Its concentration depends on the delivery in the diet, the absorption in enterocytes, transport with the participation of ATP7A/ATP7B protein, and proper excretion. Copper homeostasis disorders lead to serious medical conditions such as Menkes disease (MD) and Wilson's disease (WD). A mutation in the ATP7A gene is the cause of Menkes disease, it prevents the supply of copper ions to enzymes dependent on them, such as dopamine β-hydroxylase and lysyl oxidase. This leads to progressive changes in the central nervous system and disorders of the connective tissue. In turn, Wilson's disease is an inherited autosomal recessive disease. It is caused by a mutation of the ATP7B gene encoding the ATP7B protein which means excess copper cannot be removed from the body, leading to the pathological accumulation of this element in the liver and brain. The clinical picture is dominated by the liver, neurological, and/or psychiatric symptoms. Early inclusion of zinc preparations and chelating drugs significantly improves the prognosis in this group of patients. The aim of the study is to analyse, based on the latest literature, the following factors: the etiopathogenesis, clinical picture, diagnostic tests, treatment, prognosis, and complications of disease entities associated with copper disturbances: Menkes disease and Wilson's disease. In addition, it is necessary for general practitioners, neurologists, and gastroenterologists to pay attention to these disease entities because they are recognized too late and too rarely, especially in the paediatric population.
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Affiliation(s)
- Sabina Więcek
- Department of Paediatrics, Faculty of Medical Sciences, Medical University of Silesia, 40-055 Katowice, Poland
| | - Justyna Paprocka
- Department of Paediatric Neurology, Faculty of Medical Sciences, Medical University of Silesia, 40-055 Katowice, Poland
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Delle Cave V, Di Dato F, Iorio R. Wilson's Disease with Acute Hepatic Onset: How to Diagnose and Treat It. CHILDREN (BASEL, SWITZERLAND) 2024; 11:68. [PMID: 38255382 PMCID: PMC10814100 DOI: 10.3390/children11010068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 12/19/2023] [Accepted: 01/05/2024] [Indexed: 01/24/2024]
Abstract
Wilson's disease (WD) with acute onset poses a diagnostic challenge because it is clinically indistinguishable from other acute liver diseases. In addition, serum ceruloplasmin and urinary copper excretion, the first-line diagnostic tools for WD, can show false positive results in the case of acute liver failure, and the diagnostic role of genetic analysis is limited by the time required to perform it. In the case of fulminant onset, there is a clear indication of liver transplantation. "New Wilson Index" is frequently used to discriminate between patients who need liver transplantation versus those who can be successfully managed by medical treatment, but its reliability remains controversial. Timely referral of patients with acute liver failure due to WD may be a key factor in improving patient survival. Although liver transplant very often represents the only chance for such patients, maximum effort should be made to promote survival with a native liver. The management of these aspects of WD is still a matter of debate and will be the subject of this review.
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Affiliation(s)
| | | | - Raffaele Iorio
- Department of Translational Medical Science, Section of Pediatrics, University of Naples Federico II, 80131 Naples, Italy; (V.D.C.); (F.D.D.)
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Begum F, Nahid KL, Jesmin T, Mazumder MW, Rukunuzzaman M. Could Urinary Copper/Zinc Ratio Be a Newer Tool to Replace 24-Hour Urinary Copper Excretion for Diagnosing Wilson Disease in Children? Pediatr Gastroenterol Hepatol Nutr 2024; 27:53-61. [PMID: 38249640 PMCID: PMC10796261 DOI: 10.5223/pghn.2024.27.1.53] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 07/06/2023] [Accepted: 10/25/2023] [Indexed: 01/23/2024] Open
Abstract
Purpose Although the 24-hours urinary copper excretion is useful for the diagnosis of Wilson disease (WD), there are practical difficulties in the accurate and timed collection of urine samples. The purpose of this study was to verify if the spot morning urinary Copper/ Zinc (Cu/Zn) ratio could be used as a replacement parameter of 24-hours urinary copper excretion in the diagnosis of WD. Methods A cross-sectional study was conducted at the Department of Pediatric Gastroenterology and Nutrition, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh, from June 2019 to May 2021 on 67 children over three years of age who presented with liver disease. Twenty-seven children who fulfilled the inclusion criteria for WD were categorized into the test group, and the remaining forty children were considered to have non-Wilsonian liver disease and were categorized into the control group. Along with other laboratory investigations, spot morning urinary samples were estimated for the urinary Cu/Zn ratio in all patients and were compared to the 24-hour urinary copper excretion. The diagnostic value of the Cu/Zn ratio was then analyzed. Results Correlation of spot morning urinary Cu/Zn ratio with 24-hours urinary copper excretion was found to be significant (r=0.60). The area under ROC curve with 95% confidence interval of morning urinary Cu/Zn ratio measured using 24-hours urine sample was 0.84 (standard error, 0.05; p<0.001). Conclusion Spot morning urinary Cu/Zn ratio seems to be a promising parameter for the replacement of 24-hours urinary copper excretion in the diagnosis of WD.
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Affiliation(s)
- Fahmida Begum
- Department of Paediatric Gastroenterology and Nutrition, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh
| | - Khan Lamia Nahid
- Department of Paediatric Gastroenterology and Nutrition, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh
| | - Tahmina Jesmin
- Department of Paediatric Nephrology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh
| | - Md. Wahiduzzaman Mazumder
- Department of Paediatric Gastroenterology and Nutrition, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh
| | - Md. Rukunuzzaman
- Department of Paediatric Gastroenterology and Nutrition, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh
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Orenstein N, Glassberg YM, Shkalim-Zemer V, Basel-Salmon L, Averbuch NS, Lagovsky I, Mark AG, Amir AZ, Bazak L, Cooper S, Goldberg Y. Severe early-onset Wilson disease caused by a common pathogenic variant in the Bukharan Jewish population in Israel. Gene 2023; 887:147728. [PMID: 37634880 DOI: 10.1016/j.gene.2023.147728] [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: 06/21/2023] [Revised: 07/30/2023] [Accepted: 08/21/2023] [Indexed: 08/29/2023]
Abstract
BACKGROUND Wilson disease is caused by pathogenic variants in the ATP7B gene which encodes a copper-transporting ATPase. AIMS Describe a common founder pathogenic variant among Bukharan Jews and to assess its prevalence, clinical features, and outcome. METHODS The cohort consisted of patients of Bukharan Jewish descent diagnosed with Wilson disease at a tertiary pediatric medical center in 2013-2018. Clinical and genetic data were collected and analyzed. RESULTS Six patients from 4 unrelated families who were homozygous for the c.3784G > T p.(Val1262Phe) pathogenic variant in ATP7B were identified. Five presented with elevated aminotransferase levels, and one, with acute liver failure. Mean age at diagnosis was 8.7 years (5-12.5). Serum ceruloplasmin level was extremely low in all patients (1.9-7 mg/dL; mean 3.2(. The variant was identified in a heterozygous state in 5/153 Bukharan Jews; 2/33 from our local exome database and 3/120 healthy unrelated Bukharan Jews in another cohort, for an estimated carrier frequency of ∼1:30. CONCLUSIONS We report a common founder pathogenic variant in the ATP7B gene among Bukharan Jews associated with severe early-onset Wilson disease. Given the clinical severity, high frequency of the variant, and being a treatable disease, its inclusion in pre-symptomatic screening in the Bukharan Jewish community should be considered. Furthermore, WD should be part of future genetic newborn screening programs in Israel and worldwide, to enable early treatment and prevention of future life-threatening complications.
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Affiliation(s)
- Naama Orenstein
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Pediatric Genetics Unit, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.
| | - Yael Mozer Glassberg
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center of Israel, Petach Tikva, Israel
| | - Vered Shkalim-Zemer
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Clalit Health Services, Petach Tikva, Israel
| | - Lina Basel-Salmon
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Raphael Recanati Genetics Institute, Rabin Medical Center - Beilinson Hospital, Petach Tikva, Israel
| | - Noa Shefer Averbuch
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Pediatric Genetics Unit, Schneider Children's Medical Center of Israel, Petach Tikva, Israel
| | - Irina Lagovsky
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Felsenstein Medical Research Center, Rabin Medical Center, Petach Tikva, Israel
| | - Anat Guz Mark
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center of Israel, Petach Tikva, Israel
| | - Achiya Z Amir
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Pediatric Gastroenterology, Hepatology & Nutrition Clinic, Dana-Dwek Children's Hospital, Tel Aviv, Israel
| | - Lily Bazak
- Raphael Recanati Genetics Institute, Rabin Medical Center - Beilinson Hospital, Petach Tikva, Israel
| | - Shiri Cooper
- Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center of Israel, Petach Tikva, Israel
| | - Yael Goldberg
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Raphael Recanati Genetics Institute, Rabin Medical Center - Beilinson Hospital, Petach Tikva, Israel
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38
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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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Ortigoza-Escobar JD. Catching the Culprit: How Chorea May Signal an Inborn Error of Metabolism. Tremor Other Hyperkinet Mov (N Y) 2023; 13:36. [PMID: 37810989 PMCID: PMC10558026 DOI: 10.5334/tohm.801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Accepted: 09/27/2023] [Indexed: 10/10/2023] Open
Abstract
Background Movement disorders, particularly chorea, are uncommon in inborn errors of metabolism, but their identification is essential for improved clinical outcomes. In this context, comprehensive descriptions of movement disorders are limited and primarily derived from single cases or small patient series, highlighting the need for increased awareness and additional research in this field. Methods A systematic review was conducted using the MEDLINE database and GeneReviews. The search included studies on inborn errors of metabolism associated with chorea, athetosis, or ballismus. The review adhered to PRISMA guidelines. Results The systematic review analyzed 76 studies out of 2350 records, encompassing the period from 1964 to 2022. Chorea was observed in 90.1% of the 173 patients, followed by athetosis in 5.7%. Various inborn errors of metabolism showed an association with chorea, with trace elements and metals being the most frequent. Cognitive and developmental abnormalities were common in the cohort. Frequent neurological features included seizures, dysarthria, and optic atrophy, whereas non-neurological features included, among others, facial dysmorphia and failure to thrive. Neuroimaging and biochemical testing played crucial roles in aiding diagnosis, revealing abnormal findings in 34.1% and 47.9% of patients, respectively. However, symptomatic treatment efficacy for movement disorders was limited. Discussion This study emphasizes the complexities of chorea in inborn errors of metabolism. A systematic approach with red flags, biochemical testing, and neuroimaging is required for diagnosis. Collaboration between neurologists, geneticists, and metabolic specialists is crucial for improving early detection and individualized treatment. Utilizing genetic testing technologies and potential therapeutic avenues can aid in the improvement of patient outcomes.
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Affiliation(s)
- Juan Darío Ortigoza-Escobar
- Department of Paediatric Neurology, Hospital Sant Joan de Déu, Barcelona, Spain
- European Reference Network for Rare Neurological Diseases (ERN-RND), Barcelona, Spain
- U-703 Centre for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, Barcelona, Spain
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Mariño Z, Molera-Busoms C, Badenas C, Quintero-Bernabeu J, Torra M, Forns X, Artuch R. Benefits of using exchangeable copper and the ratio of exchangeable copper in a real-world cohort of patients with Wilson disease. J Inherit Metab Dis 2023; 46:982-991. [PMID: 37254446 DOI: 10.1002/jimd.12639] [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: 02/14/2023] [Revised: 04/28/2023] [Accepted: 05/25/2023] [Indexed: 06/01/2023]
Abstract
Wilson disease (WD) is a complex disease in which diagnosis and long-term metabolic copper control remains challenging. The absence of accurate biomarkers requires the combination of different parameters to ensure copper homeostasis. Exchangeable copper and its ratio (REC) have been suggested to be useful biomarkers in this setting. We aimed at introducing these measurements and evaluate their performance and accuracy in our real-world cohort of WD patients. Exchangeable copper and REC were measured in 48 WD patients and 56 control individuals by inductively coupled plasma-mass-spectrometry. Demographic and clinical characteristics were collected. REC was shown to be significantly higher among WD patients compared to controls and useful for WD identification by using the previously established cutoffs: 71.4% of WD patients with a recent diagnosis had REC ≥18.5% and 95.1% of long-term treated WD had REC ≥14%; only four patients of the cohort presented discordant levels. Moreover, REC values were below 15% in all the control individuals. Exchangeable copper was significantly higher in WD patients compared to controls and tended to be reduced among WD patients who were compliant to medication. This real-life study confirmed that exchangeable copper and REC are useful serum biomarkers that can be used as complementary tests to ensure WD diagnosis (REC) and copper homeostasis whithin time (exchangeable copper). The desirable target levels for this last objective still needs to be validated in prospective cohorts.
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Affiliation(s)
- Zoe Mariño
- Liver Unit, Hospital Clínic, IDIBAPS, CIBERehd, Barcelona, Spain
- Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona (UB), Barcelona, Spain
- European Reference Network on Rare Liver Disorders (ERN-RARE Liver), Hospital Clinic Barcelona, Barcelona, Spain
| | - Cristina Molera-Busoms
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Hospital Sant Joan de Deu, Barcelona, Spain
- Comprehensive Unit of Complex Hepatology and Pediatric Liver Transplantation (Hospital Sant Joan de Deu and Hospital Vall d'Hebron), Barcelona, Spain
| | - Celia Badenas
- Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona (UB), Barcelona, Spain
- Biochemistry and Molecular Genetics Unit, Hospital Clínic, CIBERER and IDIBAPS, Barcelona, Spain
| | - Jesús Quintero-Bernabeu
- Comprehensive Unit of Complex Hepatology and Pediatric Liver Transplantation (Hospital Sant Joan de Deu and Hospital Vall d'Hebron), Barcelona, Spain
- Pediatric Hepatology and Liver Transplant Unit, Hospital Universitari Vall d'Hebron, Barcelona, Spain
- European Reference Network on Rare Liver Disorders (ERN-Liver), Metabolic Hereditary Disorders (MetabERN) and Transplantation in Children (Transplant Child), Hospital Universitari Vall d'Hebron, Barcelona, Spain
| | - Mercè Torra
- Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona (UB), Barcelona, Spain
- Biochemistry and Molecular Genetics Unit, Hospital Clínic, CIBERER and IDIBAPS, Barcelona, Spain
| | - Xavier Forns
- Liver Unit, Hospital Clínic, IDIBAPS, CIBERehd, Barcelona, Spain
- Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona (UB), Barcelona, Spain
- European Reference Network on Rare Liver Disorders (ERN-RARE Liver), Hospital Clinic Barcelona, Barcelona, Spain
| | - Rafael Artuch
- Clinical Biochemistry Department, Institut de Recerca Sant Joan de Deu, and CIBERER, Barcelona, Spain
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Mbala J, Belmalih A, Guillaud O, Lachaux A, Couchonnal Bedoya E. Evaluation of vitamin B 6 supplementation in Wilson's disease patients treated with D-penicillamine. BMJ Open Gastroenterol 2023; 10:e001211. [PMID: 37652551 PMCID: PMC10476132 DOI: 10.1136/bmjgast-2023-001211] [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: 07/10/2023] [Accepted: 08/15/2023] [Indexed: 09/02/2023] Open
Abstract
INTRODUCTION Wilson's disease (WD) is a copper metabolism disorder characterised by a progressive accumulation of this metal mainly in the liver and the brain. Treatment is based on the removal of copper operated by the chelators, among which, D-penicillamine (DP) is prescribed as a first-line treatment in most situations. There is some evidence in linking the use of DP with a risk of vitamin B6; therefore, vitamin supplementation is sometimes recommended, although non-consensually. The objective of our study was to evaluate the level of vitamin B6 in WD patients treated with DP with and without associated supplementation. METHODOLOGY All WD patients followed at the National Reference Centre for WD in Lyon between January 2019 and December 2020 treated with DP for more than 1 year were included and separated in two groups according to vitamin B6 supplementation. The level of vitamin B6 was measured by the determination of pyridoxal phosphate (PLP). RESULTS A total of 37 patients were included. Average age of 23.3±14.8 years, 15 patients with <18 years. Median duration of treatment was 51 (55.8) months. 15 patients were under vitamin B6 supplementation and 22 had interrupted it for more than 1 year. The median PLP level was significantly higher in the group with supplementation, 137.2 (86.7) nmol/L vs 64.9 (30.8) nmol/(p<0.01). No patient had a PLP level<35 nmol/L. CONCLUSION Long-term stable WD patients under DP treatment probably do not need vitamin B6 supplementation.
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Affiliation(s)
- Justin Mbala
- Department of Pediatric, Kinshasa University Hospital, Kinshasa, Congo
| | - Abdelouahed Belmalih
- Centre National de Référence Pour la Maladie de Wilson, Hospices Civils de Lyon, Lyon, France
| | - Olivier Guillaud
- Centre National de Référence Pour la Maladie de Wilson, Hospices Civils de Lyon, Lyon, France
- Ramsay Générale de Santé, Clinique de la Sauvegarde, Lyon, France
| | - Alain Lachaux
- Centre National de Référence Pour la Maladie de Wilson, Hospices Civils de Lyon, Lyon, France
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Cai L, Huang X, Ye Y, Yang D, Xie L, Fu D, Peng L, Zhou D, Liao J. Role of gender and age in features of Wilson's disease. Front Neurol 2023; 14:1176946. [PMID: 37475745 PMCID: PMC10354542 DOI: 10.3389/fneur.2023.1176946] [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: 03/09/2023] [Accepted: 06/19/2023] [Indexed: 07/22/2023] Open
Abstract
Background Wilson's disease (WD) is a recessive genetic disorder characterized by copper metabolism dysfunction. It is difficult to obtain an accurate diagnosis due to its variable clinical presentation. This study aimed to describe the clinical characteristics and diagnostic particularities in a series of Chinese WD patients. Methods The medical records of 371 patients with WD retrieved from January 2005 to December 2020 were retrospectively reviewed. Results The incidence of WD has a male predominance in the adult population. However, the difference in sex distribution is not significant in the pediatric population. Females have an earlier symptom onset than males. The most common initial symptoms were neuropsychiatric manifestations both in the pediatric population (49.7%) and adult population (69.8%), and there was a male predominance (61.8%). Eighty-two percent of patients presented with more than two neurologic symptoms. Fifty-two (14%) patients presented with psychiatric symptoms. The most common WD phenotype was the neuropsychiatric form (48%). The age of onset occurred earlier in patients with the hepatic phenotype than in those with the neuropsychiatric phenotype. Moreover, there was a significant difference in sex distribution regarding phenotype. Females presented with a hepatic phenotype more often than males, and the neuropsychiatric phenotype occurred more frequently in males with an older onset age. Further study showed that the age at onset was a deciding factor for predicting the neuropsychiatric phenotype among the hepatic phenotype. However, sex did not correlate with the phenotype. Conclusion Males seem to have a higher disease susceptibility, with symptom onset later than females. Males frequently present with a neuropsychiatric phenotype, while females present with a hepatic phenotype. Age at onset was a deciding factor for predicting the WD phenotype. Further studies focusing on the effect of estrogens on the pathology of WD are suggested.
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Affiliation(s)
- Lin Cai
- Department of Gastroenterology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
- Non-communicable Diseases Research Center, West China-PUMC C. C. Chen Institute of Health, Sichuan University, Chengdu, China
| | - Xiaotao Huang
- Department of Gastroenterology, 903 Hospital, Jiangyou, China
| | - Yan Ye
- Department of Gastroenterology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
- Non-communicable Diseases Research Center, West China-PUMC C. C. Chen Institute of Health, Sichuan University, Chengdu, China
| | - Dailan Yang
- Department of Gastroenterology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
- Non-communicable Diseases Research Center, West China-PUMC C. C. Chen Institute of Health, Sichuan University, Chengdu, China
| | - Linshen Xie
- Department of Occupational Disease and Toxicosis, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Daigang Fu
- Department of Occupational Disease and Toxicosis, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Lijun Peng
- Department of Occupational Disease and Toxicosis, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Dingzi Zhou
- Department of Occupational Disease and Toxicosis, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Juan Liao
- Department of Gastroenterology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
- Non-communicable Diseases Research Center, West China-PUMC C. C. Chen Institute of Health, Sichuan University, Chengdu, China
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Litwin T, Dusek P, Antos A, Członkowska A, Bembenek J. Tackling the neurological manifestations in Wilson's disease - currently available treatment options. Expert Rev Neurother 2023; 23:1249-1259. [PMID: 37842984 DOI: 10.1080/14737175.2023.2268841] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 10/05/2023] [Indexed: 10/17/2023]
Abstract
INTRODUCTION Wilson's disease (WD) is a potentially treatable, inherited disorder resulting from impaired copper metabolism. Pathological copper accumulation causes a range of symptoms, most commonly hepatic and a wide spectrum of neurological symptoms including tremor, dystonia, chorea, parkinsonism, dysphagia, dysarthria, gait and posture disturbances. To reduce copper overload, anti-copper drugs are used that improve liver function and neurological symptoms in up to 85% of patients. However, in some WD patients, treatment introduction leads to neurological deterioration, and in others, neurological symptoms persist with no improvement or improvement only after several years of treatment, severely affecting the patient's quality of life. AREAS COVERED This review appraises the evidence on various pharmacological and non-pharmacological therapies, neurosurgical procedures and liver transplantation for the management of neurological WD symptoms. The authors also discuss the neurological symptoms of WD, causes of deterioration and present symptomatic treatment options. EXPERT OPINION Based on case and series reports, current recommendations and expert opinion, WD treatment is focused mainly on drugs leading to negative copper body metabolism (chelators or zinc salts) and copper-restricted diet. Treatment of WD neurological symptoms should follow general recommendations of symptomatic treatment. Patients should be always considered individually, especially in the case of severe, disabling neurological symptoms.
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Affiliation(s)
- Tomasz Litwin
- Second Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland
| | - Petr Dusek
- Department of Neurology and Centre of Clinical Neuroscience, First Faculty of Medicine and General University Hospital, Prague, Czech Republic
| | - Agnieszka Antos
- Second Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland
| | - Anna Członkowska
- Second Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland
| | - Jan Bembenek
- Department of Clinical Neurophysiology, Institute of Psychiatry and Neurology, Warsaw, Poland
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Bailey KM, Sahota N, To U, Hedera P. "Because it is a rare disease…it needs to be brought to attention that there are things out of the norm": a qualitative study of patient and physician experiences of Wilson disease diagnosis and management in the US. Orphanet J Rare Dis 2023; 18:158. [PMID: 37349760 PMCID: PMC10288732 DOI: 10.1186/s13023-023-02778-3] [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: 11/07/2022] [Accepted: 06/18/2023] [Indexed: 06/24/2023] Open
Abstract
BACKGROUND Wilson disease (WD) is a genetic disorder of copper metabolism that leads to copper accumulation in various organs, primarily the liver and brain, resulting in heterogenous hepatic, neurologic, and psychiatric symptoms. Diagnosis can occur at any age, requiring lifelong treatment, which can involve liver transplantation. This qualitative study aims to understand the wider patient and physician experience of the diagnosis and management of WD in the US. METHODS Primary data were collected from 1:1 semi structured interviews with US-based patients and physicians and thematically analyzed with NVivo. RESULTS Twelve WD patients and 7 specialist WD physicians (hepatologists and neurologists) were interviewed. Analysis of the interviews revealed 18 themes, which were organized into 5 overarching categories: (1) Diagnosis journey, (2) Multidisciplinary approach, (3) Medication, (4) The role of insurance, and (5) Education, awareness, and support. Patients who presented with psychiatric or neurological symptoms reported longer diagnostic journeys (range 1 to 16 years) than those presenting with hepatic symptoms or through genetic screening (range 2 weeks to 3 years). All were also affected by geographical proximity to WD specialists and access to comprehensive insurance. Exploratory testing was often burdensome for patients, but receipt of a definitive diagnosis led to relief for some. Physicians emphasized the importance of multidisciplinary teams beyond hepatology, neurology, and psychiatry and recommended a combination of chelation, zinc, and a low-copper diet; however, only half the patients in this sample were on a chelator, and some struggled to access prescription zinc due to insurance issues. Caregivers often advocated for and supported adolescents with their medication and dietary regimen. Patients and physicians recommended more education and awareness for the healthcare community. CONCLUSIONS WD requires the coordination of care and medication among several specialists due to its complex nature, but many patients do not have access to multiple specialties due to geographical or insurance barriers. Because some patients cannot be treated in Centers of Excellence, easy access to reliable and up-to-date information is important to empower physicians, patients, and their caregivers in managing the condition, along with general community outreach programs.
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Affiliation(s)
| | | | - Uyen To
- Yale University, New Haven, Connecticut, United States
| | - Peter Hedera
- University of Louisville, Louisville, KY, USA.
- Department of Neurology Institution, University of Louisville, 220 Abraham Flexner Way, Suite 606, Louisville, KY, 40202, USA.
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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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Nehring P, Szeligowska J, Przybyłkowski A. Elastography of the Liver in Wilson's Disease. Diagnostics (Basel) 2023; 13:diagnostics13111898. [PMID: 37296749 DOI: 10.3390/diagnostics13111898] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 05/22/2023] [Accepted: 05/26/2023] [Indexed: 06/12/2023] Open
Abstract
Staging of liver fibrosis is of special significance in Wilson's disease as it determines the patient's prognosis and treatment. Histopathological examination is a standard method for fibrosis assessment; however, non-invasive methods like transient elastography and share wave elastography are believed to be reliable and repetitive and are expected to replace liver biopsy in Wilson's disease. This article presents a short description of available elastography techniques and the results of the most recent studies on elastography of the liver in patients with Wilson's disease.
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Affiliation(s)
- Piotr Nehring
- Department of Gastroenterology and Internal Medicine, Medical University of Warsaw, Banacha 1a, 02-097 Warsaw, Poland
| | - Jowita Szeligowska
- Department of Gastroenterology and Internal Medicine, Medical University of Warsaw, Banacha 1a, 02-097 Warsaw, Poland
| | - Adam Przybyłkowski
- Department of Gastroenterology and Internal Medicine, Medical University of Warsaw, Banacha 1a, 02-097 Warsaw, Poland
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Zimny S, Bourhis H, Weber S, Reiter FP, Hohenester S, Kraft E, Mohr I, Merle U, Weiss KH, Denk G. Medical care of patients with Wilson disease in Germany: a multidisciplinary survey among university centers. Orphanet J Rare Dis 2023; 18:122. [PMID: 37226184 DOI: 10.1186/s13023-023-02731-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 05/14/2023] [Indexed: 05/26/2023] Open
Abstract
BACKGROUND Wilson disease (WD) is a rare, hereditary disorder of copper metabolism. Due to its variable symptoms and manifestations, diagnosis remains challenging. Affected patients must obtain lifelong medical treatment, as the disease is fatal if untreated. Patients require continuous monitoring, but little is known about the care of these patients in Germany. Therefore, we analyzed the medical care of WD patients at German university centers. We sent a questionnaire containing 20 questions to a total of 108 departments of pediatrics, neurology and gastroenterology in 36 university hospitals. Our questions referred to the characteristics of WD patients at the different sites and internal procedures regarding diagnosis, therapy and follow-up. A descriptive statistical analysis was performed. RESULTS Sixty-three departments (58%) returned our questionnaire. In total, approximately one-third of the estimated WD patients in Germany are seen annually in the outpatient clinics of these departments (approx. 950 patients). There are only a few departments which treat patients in a multidisciplinary setting (12%). Our survey revealed that for diagnosis, 51% of all departments used an algorithm based on the Leipzig score as recommended by international guidelines. Most departments apply essential parameters recommended by WD guidelines. Routine monitoring is performed at least biannually by 84% of the departments, and standard investigations for monitoring are regularly applied. A routine family screening is performed by 84% of all departments. A reduction in medical therapy during pregnancy is recommended by 46% of the departments. Only 14% suggested that WD patients should not breastfeed. Liver transplantation (LT) due to WD is a rare but repeatedly occurring event. Most departments of gastroenterology (72%) reported at least one patient with LT within the last decade. CONCLUSIONS Medical care of WD patients at German university centers follows the recommendations set forth by international guidelines, but only a few centers treat significant numbers of patients. The surveillance of patients does not follow specified standards, but most departments adhere to the accepted guidelines. The formation of central units and networks in a multidisciplinary setting should be evaluated to improve the care of WD patients.
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Affiliation(s)
- Sebastian Zimny
- Department of Medicine II, University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany.
| | - Hélène Bourhis
- Department of Medicine II, University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany
| | - Sabine Weber
- Department of Medicine II, University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany
| | - Florian Paul Reiter
- Department of Medicine II, University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany
- Department of Medicine II, University Hospital Würzburg, Oberdürrbacher Straße 6, 97080, Würzburg, Germany
| | - Simon Hohenester
- Department of Medicine II, University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany
| | - Eduard Kraft
- Department of Physical Medicine and Rehabilitation, University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany
| | - Isabelle Mohr
- Department of Internal Medicine IV, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
| | - Uta Merle
- Department of Internal Medicine IV, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
| | - Karl Heinz Weiss
- Internal Medicine, Salem Medical Center, Zeppelinstraße 11 - 33, 69121, Heidelberg, Germany
| | - Gerald Denk
- Department of Medicine II, University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany
- Transplant Center, University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany
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Ungureanu IM, Iesanu MI, Boboc C, Cosoreanu V, Vatra L, Kadar A, Ignat EN, Galos F. Addressing the Challenges in the Diagnosis and Management of Pediatric Wilson's Disease-Case Report and Literature Review. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:medicina59040786. [PMID: 37109744 PMCID: PMC10144359 DOI: 10.3390/medicina59040786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 04/08/2023] [Accepted: 04/14/2023] [Indexed: 04/29/2023]
Abstract
Wilson's disease (WD) is an autosomal recessive disorder, in which the metabolism of copper is affected by metal accumulation in several organs that causes gradual organ degeneration. Since Wilson's initial description of WD over a century ago, there have been significant improvements in understanding and managing the condition. Nevertheless, the ongoing gap between the onset of symptoms and diagnosis highlights the difficulties in identifying this copper overload disorder early. Despite being a treatable condition, detecting WD early remains a challenge for healthcare professionals at all levels of care, likely due to its rarity. The key challenge is, therefore, to educate physicians on how to identify atypical or infrequent symptoms of WD, prompting them to consider the diagnosis more carefully. The purpose of our review is to draw attention to the difficulties associated with diagnosing pediatric WD, starting from our personal experience of a complex case and then examining relevant literature. In summary, the diagnosis of WD in children is intricate and requires a heightened level of suspicion to identify this infrequent condition. A thorough evaluation by a multidisciplinary team of physicians, along with genetic testing, histopathologic examination, and specialized imaging studies, may be necessary to confirm the diagnosis and guide treatment.
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Affiliation(s)
- Irene Maria Ungureanu
- Department of Pediatrics, Marie Curie Emergency Children's Hospital, 041451 Bucharest, Romania
| | - Mara Ioana Iesanu
- Department of Pediatrics, Marie Curie Emergency Children's Hospital, 041451 Bucharest, Romania
- Department of Physiology, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Catalin Boboc
- Department of Pediatrics, Marie Curie Emergency Children's Hospital, 041451 Bucharest, Romania
| | - Vlad Cosoreanu
- Department of Pediatric Surgery, Marie Curie Emergency Children's Hospital, 041451 Bucharest, Romania
| | - Lorena Vatra
- Department of Pediatric Surgery, Marie Curie Emergency Children's Hospital, 041451 Bucharest, Romania
| | - Anna Kadar
- Department of Pediatric Surgery, Marie Curie Emergency Children's Hospital, 041451 Bucharest, Romania
- Department of Pediatric Surgery, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | | | - Felicia Galos
- Department of Pediatrics, Marie Curie Emergency Children's Hospital, 041451 Bucharest, Romania
- Department of Pediatrics, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
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Costa JM, Pinto SM, Santos-Silva E, Moreira-Silva H. Incidental hypertransaminasemia in children-a stepwise approach in primary care. Eur J Pediatr 2023; 182:1601-1609. [PMID: 36697884 PMCID: PMC9877494 DOI: 10.1007/s00431-023-04825-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 01/10/2023] [Accepted: 01/15/2023] [Indexed: 01/27/2023]
Abstract
Children with elevated liver enzymes are occasionally discovered through laboratory work-up from different clinical scenarios. Although the majority will have transient and/or benign conditions, a subgroup will have underlying liver disorders. The differential diagnosis is broad and therefore, a systematic approach is of utmost importance. In this article, we reviewed the most recent and relevant literature to provide a comprehensive overview of the main disease processes that cause hypertransaminasemia in children. Ultimately, we propose a practical stepwise approach to guide primary care physicians in the evaluation of abnormal liver enzymes in asymptomatic children. The first step is to obtain a complete history along with a thorough physical examination to exclude red flags, which should dictate urgent consultation with a paediatric gastroenterologist or hepatologist. Conclusion: Hypertransaminasemia is a challenging scenario in the primary care setting. The aetiology can be broad, ranging from hepatic and extrahepatic to transient versus chronic liver disease. Timely referral to a specialised centre is of paramount importance for conducting targeted research and to not miss the chance of identifying a progressive, but still asymptomatic, treatable liver disease. What is Known: • Elevated liver enzyme is a challenging scenario in the primary care setting. • There are few studies guiding the evaluation of asymptomatic hypertransaminasemia in the paediatric population and a standardised approach is lacking. What is New: • We propose a practical stepwise approach to guide primary care physicians in the evaluation of abnormal liver enzymes.
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Affiliation(s)
- Joana Meneses Costa
- Valbom Family Health Unit, Group of Health Centers of Gondomar, Porto, Portugal
| | - Sara Martins Pinto
- Nascente Family Health Unit, Group of Health Centers of Gondomar, Porto, Portugal
| | - Ermelinda Santos-Silva
- Pediatrics Division, Gastroenterology Unit, Centro Hospitalar Universitário do Porto, Centro Materno Infantil do Norte, Largo da Maternidade No 45. 4050-651, Porto, Portugal
- Integrated Master in Medicine, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
- REQUIMTE, Laboratory of Biochemistry, Department of Biological Sciences, Faculdade de Farmácia, UCIBIO, Universidade do Porto, Porto, Portugal
| | - Helena Moreira-Silva
- Pediatrics Division, Gastroenterology Unit, Centro Hospitalar Universitário do Porto, Centro Materno Infantil do Norte, Largo da Maternidade No 45. 4050-651, Porto, Portugal.
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50
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Jopowicz A, Tarnacka B. Neurological Wilson's Disease Signs-Hepatic Encephalopathy or Copper Toxicosis? Diagnostics (Basel) 2023; 13:diagnostics13050893. [PMID: 36900037 PMCID: PMC10001333 DOI: 10.3390/diagnostics13050893] [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: 01/27/2023] [Revised: 02/17/2023] [Accepted: 02/25/2023] [Indexed: 03/03/2023] Open
Abstract
Wilson's disease (WD) is a rare autosomal recessive (AR) disorder resulting from mutations in the ATP7B gene, which is responsible for the encryption of transmembrane copper transporting ATPase. The symptomatic presentation of the disease is estimated to be about 1 in 30,000. The impairment of ATP7B function results in a copper overload in hepatocytes, which further leads to liver pathology. This copper overload also occurs in other organs, most particularly in the brain. This could then cause the occurrence of neurological and psychiatric disorders. Symptoms differ substantially and most often occur between the ages of 5 and 35 years. Early symptoms are commonly hepatic, neurological, or psychiatric. While disease presentation is most often asymptomatic, it could also range as far as to include fulminant hepatic failure, ataxia, and cognitive disorders. Various treatments are available for Wilson's disease, including chelation therapy and zinc salts, which can reverse copper overload through different mechanisms. In select cases, liver transplantation is recommended. New medications, such as tetrathiomolybdate salts, are currently being investigated in clinical trials. With prompt diagnosis and treatment, prognosis is favorable; however, diagnosing patients before the onset of severe symptoms is a significant concern. Early screening for WD could help in diagnosing patients earlier and improving treatment outcomes.
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Affiliation(s)
- Anna Jopowicz
- Department of Rehabilitation, Eleonora Reicher National Institute of Geriatrics, Rheumatology and Rehabilitation, Spartańska 1, 02-637 Warsaw, Poland
- Correspondence:
| | - Beata Tarnacka
- Department of Rehabilitation Medicine, Faculty of Medicine, Warsaw Medical University, Spartańska 1, 02-637 Warsaw, Poland
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