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Wu JJ, Huang Y, Gao HN, Sheng GP. A successful case report of menstrual blood derived-mesenchymal stem cell-based therapy for Wilson's disease. Hepatobiliary Pancreat Dis Int 2025; 24:352-354. [PMID: 37978031 DOI: 10.1016/j.hbpd.2023.11.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 10/30/2023] [Indexed: 11/19/2023]
Affiliation(s)
- Jia-Jun Wu
- Department of Infectious Diseases, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University, Shulan International Medical College, Hangzhou 310022, China
| | - Yong Huang
- Department of Infectious Diseases, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University, Shulan International Medical College, Hangzhou 310022, China
| | - Hai-Nv Gao
- Department of Infectious Diseases, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University, Shulan International Medical College, Hangzhou 310022, China
| | - Guo-Ping Sheng
- Department of Infectious Diseases, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University, Shulan International Medical College, Hangzhou 310022, China.
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Verma S, Alam S, Lal BB, Biswas T, Sood V, Khanna R, Bajpai M. Plasma exchange improves survival with native liver in Wilson disease with new Wilson's index ≥ 11 & early hepatic encephalopathy. Hepatol Int 2025:10.1007/s12072-025-10821-7. [PMID: 40314913 DOI: 10.1007/s12072-025-10821-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2025] [Accepted: 03/07/2025] [Indexed: 05/03/2025]
Abstract
BACKGROUND AND AIM Decision about liver transplant is difficult in Wilson disease (WD) with liver failure, especially with conflicting reports about new Wilson index (NWI). Therapeutic plasma exchange (TPE) can provide survival with native liver (SNL) in WD. This study was done to see the effect of TPE on outcome and identify factors for SNL. METHODS All cases of WD with liver failure (INR. ≥ 2.5) from prospectively maintained data were included for propensity score matching (PSM) to select TPE (n = 48) and no-TPE (n = 48) groups. Three sessions of TPE on three consecutive days were given to TPE group. RESULTS One hundred fifty-nine cases were included in the PSM with NWI & hepatic encephalopathy (HE) grading as predictors. SNL was comparable (26 vs. 17 cases (OR 1.45, p = 0.05) when the analysis was done in the whole cohort of 96 patients. SNL significantly improved when performed in those with no to early HE: TPE group (24/37) versus no-TPE group (14/34) (OR = 1.70, p = 0.03). Kaplan-Meier survival curves were significantly (log rank 0.019) improved in the TPE group when analyzing in no to early HE. Lower INR (adjusted OR 0.47, 95%CI 0.28-0.79, p = 0.005) and TPE administration (adjusted OR 3.12, 95%CI 1.10-9.4, p = 0.032) at enrollment were independently associated with SNL. Lower NWI (adjusted OR 0.686, 95%CI 0.53-0.89, p = 0.005) at 96 h was independently associated with SNL. CONCLUSIONS TPE is independently associated with improvement in SNL by threefold in patients with NWI ≥ 11 and no to early HE. Patients with advanced HE should be offered immediate liver transplant. After 3 sessions of TPE, NWI < 11 increases SNL by 32%. Hence, NWI should be maintained below 11 with more sessions of TPE.
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Affiliation(s)
- Snigdha Verma
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, Delhi, India
| | - Seema Alam
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, Delhi, India.
| | - Bikrant Bihari Lal
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, Delhi, India
| | - Tamoghna Biswas
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, Delhi, India
| | - Vikrant Sood
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, Delhi, India
| | - Rajeev Khanna
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, Delhi, India
| | - Meenu Bajpai
- Department of Transfusion Medicine, Institute of Liver and Biliary Sciences, New Delhi, Delhi, India
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Choi W, Cha S, Kim K. Navigating the CRISPR/Cas Landscape for Enhanced Diagnosis and Treatment of Wilson's Disease. Cells 2024; 13:1214. [PMID: 39056796 PMCID: PMC11274827 DOI: 10.3390/cells13141214] [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: 05/27/2024] [Revised: 07/15/2024] [Accepted: 07/17/2024] [Indexed: 07/28/2024] Open
Abstract
The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (Cas) system continues to evolve, thereby enabling more precise detection and repair of mutagenesis. The development of CRISPR/Cas-based diagnosis holds promise for high-throughput, cost-effective, and portable nucleic acid screening and genetic disease diagnosis. In addition, advancements in transportation strategies such as adeno-associated virus (AAV), lentiviral vectors, nanoparticles, and virus-like vectors (VLPs) offer synergistic insights for gene therapeutics in vivo. Wilson's disease (WD), a copper metabolism disorder, is primarily caused by mutations in the ATPase copper transporting beta (ATP7B) gene. The condition is associated with the accumulation of copper in the body, leading to irreversible damage to various organs, including the liver, nervous system, kidneys, and eyes. However, the heterogeneous nature and individualized presentation of physical and neurological symptoms in WD patients pose significant challenges to accurate diagnosis. Furthermore, patients must consume copper-chelating medication throughout their lifetime. Herein, we provide a detailed description of WD and review the application of novel CRISPR-based strategies for its diagnosis and treatment, along with the challenges that need to be overcome.
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Affiliation(s)
- Woong Choi
- Department of Physiology, Korea University College of Medicine, Seoul 02841, Republic of Korea;
| | - Seongkwang Cha
- Department of Physiology, Korea University College of Medicine, Seoul 02841, Republic of Korea;
- Neuroscience Research Institute, Korea University College of Medicine, Seoul 02841, Republic of Korea
| | - Kyoungmi Kim
- Department of Physiology, Korea University College of Medicine, Seoul 02841, Republic of Korea;
- Department of Biomedical Sciences, Korea University College of Medicine, Seoul 02841, Republic of Korea
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Teschke R, Eickhoff A. Wilson Disease: Copper-Mediated Cuproptosis, Iron-Related Ferroptosis, and Clinical Highlights, with Comprehensive and Critical Analysis Update. Int J Mol Sci 2024; 25:4753. [PMID: 38731973 PMCID: PMC11084815 DOI: 10.3390/ijms25094753] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 04/18/2024] [Accepted: 04/20/2024] [Indexed: 05/13/2024] Open
Abstract
Wilson disease is a genetic disorder of the liver characterized by excess accumulation of copper, which is found ubiquitously on earth and normally enters the human body in small amounts via the food chain. Many interesting disease details were published on the mechanistic steps, such as the generation of reactive oxygen species (ROS) and cuproptosis causing a copper dependent cell death. In the liver of patients with Wilson disease, also, increased iron deposits were found that may lead to iron-related ferroptosis responsible for phospholipid peroxidation within membranes of subcellular organelles. All topics are covered in this review article, in addition to the diagnostic and therapeutic issues of Wilson disease. Excess Cu2+ primarily leads to the generation of reactive oxygen species (ROS), as evidenced by early experimental studies exemplified with the detection of hydroxyl radical formation using the electron spin resonance (ESR) spin-trapping method. The generation of ROS products follows the principles of the Haber-Weiss reaction and the subsequent Fenton reaction leading to copper-related cuproptosis, and is thereby closely connected with ROS. Copper accumulation in the liver is due to impaired biliary excretion of copper caused by the inheritable malfunctioning or missing ATP7B protein. As a result, disturbed cellular homeostasis of copper prevails within the liver. Released from the liver cells due to limited storage capacity, the toxic copper enters the circulation and arrives at other organs, causing local accumulation and cell injury. This explains why copper injures not only the liver, but also the brain, kidneys, eyes, heart, muscles, and bones, explaining the multifaceted clinical features of Wilson disease. Among these are depression, psychosis, dysarthria, ataxia, writing problems, dysphagia, renal tubular dysfunction, Kayser-Fleischer corneal rings, cardiomyopathy, cardiac arrhythmias, rhabdomyolysis, osteoporosis, osteomalacia, arthritis, and arthralgia. In addition, Coombs-negative hemolytic anemia is a key feature of Wilson disease with undetectable serum haptoglobin. The modified Leipzig Scoring System helps diagnose Wilson disease. Patients with Wilson disease are well-treated first-line with copper chelators like D-penicillamine that facilitate the removal of circulating copper bound to albumin and increase in urinary copper excretion. Early chelation therapy improves prognosis. Liver transplantation is an option viewed as ultima ratio in end-stage liver disease with untreatable complications or acute liver failure. Liver transplantation finally may thus be a life-saving approach and curative treatment of the disease by replacing the hepatic gene mutation. In conclusion, Wilson disease is a multifaceted genetic disease representing a molecular and clinical challenge.
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Affiliation(s)
- Rolf Teschke
- Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, D-63450 Hanau, Germany;
- Academic Teaching Hospital of the Medical Faculty, Goethe University Frankfurt, D-60590 Frankfurt, Germany
| | - Axel Eickhoff
- Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, D-63450 Hanau, Germany;
- Academic Teaching Hospital of the Medical Faculty, Goethe University Frankfurt, D-60590 Frankfurt, Germany
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Quaglia A, Roberts EA, Torbenson M. Developmental and Inherited Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:122-294. [DOI: 10.1016/b978-0-7020-8228-3.00003-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Affiliation(s)
- Eve A Roberts
- From the Departments of Paediatrics, Medicine, and Pharmacology and Toxicology, University of Toronto, and the Hospital for Sick Children Research Institute - both in Toronto; and the History of Science and Technology Programme, University of King's College, Halifax, NS, Canada (E.A.R.); and the Departments of Medicine and Surgery, Yale University School of Medicine, New Haven, CT (M.L.S.)
| | - Michael L Schilsky
- From the Departments of Paediatrics, Medicine, and Pharmacology and Toxicology, University of Toronto, and the Hospital for Sick Children Research Institute - both in Toronto; and the History of Science and Technology Programme, University of King's College, Halifax, NS, Canada (E.A.R.); and the Departments of Medicine and Surgery, Yale University School of Medicine, New Haven, CT (M.L.S.)
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Cai H, Cheng X, Wang X. ATP7B gene therapy of autologous reprogrammed hepatocytes alleviates copper accumulation in a mouse model of Wilson's disease. Hepatology 2022; 76:1046-1057. [PMID: 35340061 PMCID: PMC9790736 DOI: 10.1002/hep.32484] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 03/07/2022] [Accepted: 03/25/2022] [Indexed: 12/30/2022]
Abstract
BACKGROUND AND AIMS Wilson's disease (WD) is a rare hereditary disorder due to ATP7B gene mutation, causing pathologic copper storage mainly in the liver and neurological systems. Hepatocyte transplantation showed therapeutic potential; however, this strategy is often hindered by a shortage of quality donor cells and by allogeneic immune rejection. In this study, we aimed to evaluate the function and efficacy of autologous reprogrammed, ATP7B gene-restored hepatocytes using a mouse model of WD. APPROACH AND RESULTS Sufficient liver progenitor cells (LPCs) were harvested by reprogramming hepatocytes from ATP7B-/- mice with small molecules, which exhibited strong proliferation and hepatic differentiation capacity in vitro. After lentivirus-mediated mini ATP7B gene transfection and redifferentiation, functional LPC-ATP7B-derived hepatocytes (LPC-ATP7B-Heps) were developed. RNA sequencing data showed that, compared with LPC-green fluorescent protein-Heps (LPC-GFP-Heps) with enrichment of genes that were mainly in pathways of oxidative stress and cell apoptosis, in LPC-ATP7B-Heps under high copper stress, copper ion binding and cell proliferation pathways were enriched. LPC-ATP7B-Heps transplantation into ATP7B-/- mice alleviated deposition of excess liver copper with its associated inflammation and fibrosis, comparable with those observed using normal primary hepatocytes at 4 months after transplantation. CONCLUSIONS We established a system of autologous reprogrammed WD hepatocytes and achieved ATP7B gene therapy in vitro. LPC-ATP7B-Heps transplantation demonstrated therapeutic efficacy on copper homeostasis in a mouse model of WD.
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Affiliation(s)
- Hongxia Cai
- Department of NeurologyTong‐Ren HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Xing Cheng
- State Key Laboratory of Cell BiologyCAS Center for Excellence in Molecular Cell ScienceInstitute of Biochemistry and Cell BiologyUniversity of Chinese Academy of SciencesChinese Academy of SciencesShanghaiChina
| | - Xiao‐Ping Wang
- Department of NeurologyTong‐Ren HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
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Abstract
Wilson disease (WD) is an autosomal recessive disorder caused by mutations of the ATP7B gene, with a reported prevalence of 1:30,000-50,000. ATP7B encodes an enzyme called transmembrane copper-transporting ATPase, which is essential for copper incorporation into ceruloplasmin and for copper excretion into the bile. A lack or dysfunction of this enzyme results in a progressive accumulation of copper in several organs, especially in the liver, the nervous system, corneas, kidneys, and heart. Children with WD can present with asymptomatic liver disease, cirrhosis, or acute liver failure, with or without neurological and psychiatric symptoms. Approximately 20%-30% of WD patients present with ALF, while most of the other patients have chronic progressive hepatitis or cirrhosis if untreated. Although genetic testing has become a more important diagnostic tool for WD, the diagnosis remains based on both clinical features and laboratory investigations. The aims of treatment are to reduce copper levels and prevent its accumulation in the liver and other organs, especially in the central nervous system. Liver transplantation in WD is a life-saving option for patients presenting with liver failure and encephalopathy. For WD patients treated with chelating agents, adherence to the therapy is essential for long-term success. In this review, we also address specific issues in young adults as compared to children.
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Affiliation(s)
- Atchariya Chanpong
- Paediatric Liver, GI and Nutrition Centre, MowatLabs, King's College Hospital, Denmark Hill, London, United Kingdom,Division of Gastroenterology and Hepatology, Department of Pediatrics, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand
| | - Anil Dhawan
- Paediatric Liver, GI and Nutrition Centre, MowatLabs, King's College Hospital, Denmark Hill, London, United Kingdom,Address for correspondence: Prof. Anil Dhawan, Paediatric Liver, GI and Nutrition Centre, MowatLabs, King's College Hospital, Denmark Hill, London SE5 9RH, United Kingdom. E-mail:
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Tang S, Bai L, Duan Z, Zheng S. Stem Cells Treatment for Wilson Disease. Curr Stem Cell Res Ther 2022; 17:712-719. [PMID: 34615454 DOI: 10.2174/1574888x16666211006111556] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 07/21/2021] [Accepted: 07/27/2021] [Indexed: 11/22/2022]
Abstract
Wilson Disease (WD) is a copper excretion disorder, mainly caused by mutations in the ATP7B gene. Pharmacological therapies and liver transplantation are currently the main treatment methods for WD, but they face problems such as drug treatment compliance, adverse reactions, and shortage of liver donors. Stem cell therapy of WD may correct abnormal copper metabolism permanently, which is the focus of current research. In this review, we summarized the latest research on stem cells treatment for WD, as well as current challenges and future expectations.
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Affiliation(s)
- Shan Tang
- The First Unit, Department of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Li Bai
- The Fourth Unit, Department of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Liver Failure and Artificial Liver Treatment Research, China
| | - Zhongping Duan
- The Fourth Unit, Department of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Sujun Zheng
- The First Unit, Department of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China
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Wei R, Yang J, Cheng CW, Ho WI, Li N, Hu Y, Hong X, Fu J, Yang B, Liu Y, Jiang L, Lai WH, Au KW, Tsang WL, Tse YL, Ng KM, Esteban MA, Tse HF. CRISPR-targeted genome editing of human induced pluripotent stem cell-derived hepatocytes for the treatment of Wilson's disease. JHEP REPORTS : INNOVATION IN HEPATOLOGY 2021; 4:100389. [PMID: 34877514 PMCID: PMC8633686 DOI: 10.1016/j.jhepr.2021.100389] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 09/28/2021] [Accepted: 10/18/2021] [Indexed: 02/07/2023]
Abstract
Background & Aims Wilson’s disease (WD) is an autosomal recessive disorder of copper metabolism caused by loss-of-function mutations in ATP7B, which encodes a copper-transporting protein. It is characterized by excessive copper deposition in tissues, predominantly in the liver and brain. We sought to investigate whether gene-corrected patient-specific induced pluripotent stem cell (iPSC)-derived hepatocytes (iHeps) could serve as an autologous cell source for cellular transplantation therapy in WD. Methods We first compared the in vitro phenotype and cellular function of ATP7B before and after gene correction using CRISPR/Cas9 and single-stranded oligodeoxynucleotides (ssODNs) in iHeps (derived from patients with WD) which were homozygous for the ATP7B R778L mutation (ATP7BR778L/R778L). Next, we evaluated the in vivo therapeutic potential of cellular transplantation of WD gene-corrected iHeps in an immunodeficient WD mouse model (Atp7b-/-/ Rag2-/-/ Il2rg-/-; ARG). Results We successfully created iPSCs with heterozygous gene correction carrying 1 allele of the wild-type ATP7B gene (ATP7BWT/-) using CRISPR/Cas9 and ssODNs. Compared with ATP7BR778L/R778L iHeps, gene-corrected ATP7BWT/- iHeps restored in vitro ATP7B subcellular localization, its subcellular trafficking in response to copper overload and its copper exportation function. Moreover, in vivo cellular transplantation of ATP7BWT/- iHeps into ARG mice via intra-splenic injection significantly attenuated the hepatic manifestations of WD. Liver function improved and liver fibrosis decreased due to reductions in hepatic copper accumulation and consequently copper-induced hepatocyte toxicity. Conclusions Our findings demonstrate that gene-corrected patient-specific iPSC-derived iHeps can rescue the in vitro and in vivo disease phenotypes of WD. These proof-of-principle data suggest that iHeps derived from gene-corrected WD iPSCs have potential use as an autologous ex vivo cell source for in vivo therapy of WD as well as other inherited liver disorders. Lay summary Gene correction restored ATP7B function in hepatocytes derived from induced pluripotent stem cells that originated from a patient with Wilson’s disease. These gene-corrected hepatocytes are potential cell sources for autologous cell therapy in patients with Wilson’s disease.
Correction of the ATP7B R778L mutation restored the subcellular localization of ATP7B in iHeps. The copper exportation capability of ATP7B was restored in gene-corrected iHeps. Gene-corrected iHeps reduced hepatic copper accumulation and copper-induced hepatic toxicity in mice with Wilson’s disease. Gene-corrected iHeps are potential ex vivo cell sources for therapy in Wilson’s disease.
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Key Words
- AFP, alpha-fetoprotein
- ALB, albumin
- ATP7B, ATPase copper transporting beta
- ATPase copper transporting beta polypeptide (ATP7B)
- Clustered regularly interspaced palindromic repeats (CRISPR)/Cas9
- EB, embryoid body
- RFLP, restriction fragment length polymorphism
- Single-stranded Oligodeoxynucleotide (ssODN)
- TGN, trans-Golgi network
- WD, Wilson’s disease
- Wilson’s disease
- cell therapy
- gene correction
- iHep(s), iPSC-derived hepatocyte(s)
- iPSC, induced pluripotent stem cell
- iPSC-derived hepatocytes (iHeps)
- induced pluripotent stem cell (iPSC)
- sgRNA, single guide RNA
- ssODN, single-stranded oligodeoxynucleotide
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Affiliation(s)
- Rui Wei
- The Cardiology Division, Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- Hong Kong-Guangdong Stem Cell and Regenerative Medicine Research Centre, The University of Hong Kong and Guangzhou Institutes of Biomedicine and Health, Hong Kong, China
- Center for Translational Stem Cell Biology, Hong Kong, China
| | - Jiayin Yang
- The Cardiology Division, Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- Cell Inspire Therapeutics Co., Ltd and Cell Inspire Biotechnology Co., Ltd, Shenzhen 518102, China
| | - Chi-Wa Cheng
- The Cardiology Division, Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- Hong Kong-Guangdong Stem Cell and Regenerative Medicine Research Centre, The University of Hong Kong and Guangzhou Institutes of Biomedicine and Health, Hong Kong, China
| | - Wai-In Ho
- The Cardiology Division, Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- Hong Kong-Guangdong Stem Cell and Regenerative Medicine Research Centre, The University of Hong Kong and Guangzhou Institutes of Biomedicine and Health, Hong Kong, China
| | - Na Li
- The Cardiology Division, Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- Hong Kong-Guangdong Stem Cell and Regenerative Medicine Research Centre, The University of Hong Kong and Guangzhou Institutes of Biomedicine and Health, Hong Kong, China
| | - Yang Hu
- The Cardiology Division, Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- Hong Kong-Guangdong Stem Cell and Regenerative Medicine Research Centre, The University of Hong Kong and Guangzhou Institutes of Biomedicine and Health, Hong Kong, China
| | - Xueyu Hong
- The Cardiology Division, Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Jian Fu
- Cell Inspire Therapeutics Co., Ltd and Cell Inspire Biotechnology Co., Ltd, Shenzhen 518102, China
| | - Bo Yang
- Cell Inspire Therapeutics Co., Ltd and Cell Inspire Biotechnology Co., Ltd, Shenzhen 518102, China
| | - Yuqing Liu
- Cell Inspire Therapeutics Co., Ltd and Cell Inspire Biotechnology Co., Ltd, Shenzhen 518102, China
| | - Lixiang Jiang
- Cell Inspire Therapeutics Co., Ltd and Cell Inspire Biotechnology Co., Ltd, Shenzhen 518102, China
| | - Wing-Hon Lai
- The Cardiology Division, Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- Hong Kong-Guangdong Stem Cell and Regenerative Medicine Research Centre, The University of Hong Kong and Guangzhou Institutes of Biomedicine and Health, Hong Kong, China
| | - Ka-Wing Au
- The Cardiology Division, Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- Hong Kong-Guangdong Stem Cell and Regenerative Medicine Research Centre, The University of Hong Kong and Guangzhou Institutes of Biomedicine and Health, Hong Kong, China
| | - Wai-Ling Tsang
- The Cardiology Division, Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Yiu-Lam Tse
- The Cardiology Division, Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- Hong Kong-Guangdong Stem Cell and Regenerative Medicine Research Centre, The University of Hong Kong and Guangzhou Institutes of Biomedicine and Health, Hong Kong, China
| | - Kwong-Man Ng
- The Cardiology Division, Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- Hong Kong-Guangdong Stem Cell and Regenerative Medicine Research Centre, The University of Hong Kong and Guangzhou Institutes of Biomedicine and Health, Hong Kong, China
- Center for Translational Stem Cell Biology, Hong Kong, China
| | - Miguel A. Esteban
- Hong Kong-Guangdong Stem Cell and Regenerative Medicine Research Centre, The University of Hong Kong and Guangzhou Institutes of Biomedicine and Health, Hong Kong, China
- Laboratory of Integrative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou 510005, China
- Joint School of Life Sciences, Guangzhou Medical University and Guangzhou Institutes of Biomedicine and Health, Guangzhou 511436, China
- Corresponding authors. Address: Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China; Tel.: (852) 2255-4694, fax: (852) 2818-6304.
| | - Hung-Fat Tse
- The Cardiology Division, Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- Hong Kong-Guangdong Stem Cell and Regenerative Medicine Research Centre, The University of Hong Kong and Guangzhou Institutes of Biomedicine and Health, Hong Kong, China
- Center for Translational Stem Cell Biology, Hong Kong, China
- Heart and Vascular Center, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518053, China
- Corresponding authors. Address: Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China; Tel.: (852) 2255-4694, fax: (852) 2818-6304.
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Kasztelan-Szczerbinska B, Cichoz-Lach H. Wilson's Disease: An Update on the Diagnostic Workup and Management. J Clin Med 2021; 10:5097. [PMID: 34768617 PMCID: PMC8584493 DOI: 10.3390/jcm10215097] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Revised: 10/18/2021] [Accepted: 10/27/2021] [Indexed: 02/08/2023] Open
Abstract
Wilson's disease (WD) is a rare autosomal recessive disorder of hepatocellular copper deposition. The diagnostic approach to patients with WD may be challenging and is based on a complex set of clinical findings that derive from patient history, physical examination, as well as laboratory and imaging testing. No single examination can unequivocally confirm or exclude the disease. Timely identification of signs and symptoms using novel biomarkers and modern diagnostic tools may help to reduce treatment delays and improve patient prognosis. The proper way of approaching WD management includes, firstly, early diagnosis and prompt treatment introduction; secondly, careful and lifelong monitoring of patient compliance and strict adherence to the treatment; and, last but not least, screening for adverse effects and evaluation of treatment efficacy. Liver transplantation is performed in about 5% of WD patients who present with acute liver failure at first disease presentation or with signs of decompensation in the course of liver cirrhosis. Increasing awareness of this rare inherited disease among health professionals, emphasizing their training to consider early signs and symptoms of the illness, and strict monitoring are vital strategies for the patient safety and efficacy of WD therapy.
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Affiliation(s)
- Beata Kasztelan-Szczerbinska
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, 8 Jaczewski Street, 20-954 Lublin, Poland;
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Vimalesvaran S, Dhawan A. Liver transplantation for pediatric inherited metabolic liver diseases. World J Hepatol 2021; 13:1351-1366. [PMID: 34786171 PMCID: PMC8568579 DOI: 10.4254/wjh.v13.i10.1351] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 06/23/2021] [Accepted: 08/20/2021] [Indexed: 02/06/2023] Open
Abstract
Liver transplantation (LT) remains the gold standard treatment for end stage liver disease in the pediatric population. For liver based metabolic disorders (LBMDs), the decision for LT is predicated on a different set of paradigms. With improved outcomes post-transplantation, LT is no longer merely life saving, but has the potential to also significantly improve quality of life. This review summarizes the clinical presentation, medical treatment and indications for LT for some of the common LBMDs. We also provide a practical update on the dilemmas and controversies surrounding the indications for transplantation, surgical considerations and prognosis and long terms outcomes for pediatric LT in LBMDs. Important progress has been made in understanding these diseases in recent years and with that we outline some of the new therapies that have emerged.
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Affiliation(s)
- Sunitha Vimalesvaran
- Paediatric Liver GI and Nutrition Center, King's College Hospital, London SE5 9RS, United Kingdom
| | - Anil Dhawan
- Paediatric Liver GI and Nutrition Center, King's College Hospital, London SE5 9RS, United Kingdom
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Fernando M, van Mourik I, Wassmer E, Kelly D. Wilson disease in children and adolescents. Arch Dis Child 2020; 105:499-505. [PMID: 31974298 DOI: 10.1136/archdischild-2018-315705] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Revised: 12/18/2019] [Accepted: 12/19/2019] [Indexed: 12/13/2022]
Abstract
Wilson disease (WD) is a rare, recessively inherited disorder of copper metabolism mainly affecting liver and brain. In childhood, it is known to have a predominant hepatic phenotype. It is likely that the low awareness for WD-associated neuropsychiatric signs and symptoms in this age group means that neurological Wilson's disease is underdiagnosed in children and young people. Practitioners should be alert for this complication in children with or without liver disease. Management of children with WD requires a dedicated multidisciplinary approach involving hepatologists, geneticists, neurologists and psychiatrists to ensure subtle neuropsychiatric symptoms are identified early and addressed appropriately. This review highlights recent advances in hepatic and neuropsychiatric symptoms of WD in childhood, specific diagnostic tools and pitfalls and summarises existing and potential future treatment options.
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Affiliation(s)
- Meranthi Fernando
- Liver Unit, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, West Midlands, UK
| | - Indra van Mourik
- Liver Unit, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, West Midlands, UK
| | - Evangeline Wassmer
- Department of Neurology, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, West Midlands, UK
| | - Deirdre Kelly
- Liver Unit, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, West Midlands, UK
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Critical care management in patients with acute liver failure. Best Pract Res Clin Anaesthesiol 2020; 34:89-99. [PMID: 32334790 DOI: 10.1016/j.bpa.2020.01.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 12/19/2019] [Accepted: 01/08/2020] [Indexed: 12/19/2022]
Abstract
Acute liver failure (ALF) is defined as severe hepatic dysfunction (marked transaminases elevation, detoxification disorder (jaundice and coagulopathy with international normal ratio (INR) > 1.5), the presence of hepatic encephalopathy, and exclusion of underlying chronic liver disease, and a secondary cause like sepsis or cardiogenic shock. Reasons for ALF include paracetamol and warfarin toxicity, autoimmune and viral (mainly hepatitis B and E) hepatitis, and herbal and dietary supplements. Even in terms of meticulous and careful review of the patient, around 20-30% of the reasons remains unknown. In order of its rarity, a randomized controlled trial could hardly be done. However, because of improved ICU treatment, the mortality, even in the advanced stage of ALF decreased. However, in 5-10% of the cases an emergency transplantation is required. This justifies the treatment of this patient cohort in institutions that can provide this kind of treatment.
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Zhao Y, Xu B, Liang W, Ding Y, Li J, Zhang Y, Xu F, Zhou H, Xu Y. Multisite Injection of Bioengineered Hepatic Units from Collagen Hydrogel and Neonatal Liver Cells in Parenchyma Improves Liver Cirrhosis. Tissue Eng Part A 2019; 25:1167-1174. [PMID: 30608034 DOI: 10.1089/ten.tea.2018.0107] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Affiliation(s)
- Yunshan Zhao
- Institute of General Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Bingbing Xu
- Graduate School of Peking Union Medical College, Beijing, China
- Department of Biotechnology, Capital Institute of Pediatrics, Beijing, China
| | - Wentao Liang
- Institute of General Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Yi Ding
- Institute of Anorectal Diseases, The Third Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Jing Li
- Laboratory of Translational Medicine, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Yong Zhang
- Institute of General Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Fei Xu
- Institute of General Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Haiyang Zhou
- Institute of General Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Yingxin Xu
- Institute of General Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing, China
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Xu MB, Rong PQ, Jin TY, Zhang PP, Liang HY, Zheng GQ. Chinese Herbal Medicine for Wilson's Disease: A Systematic Review and Meta-Analysis. Front Pharmacol 2019; 10:277. [PMID: 31001112 PMCID: PMC6455065 DOI: 10.3389/fphar.2019.00277] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Accepted: 03/04/2019] [Indexed: 02/06/2023] Open
Abstract
Wilson's disease (WD) is a rare autosomal recessive inherited disorder of chronic copper toxicosis. Currently, Chinese herbal medicines (CHM) is widely used for WD. Here, we conducted an updated systematic review to investigate the efficacy and safety of CHM for WD and its possible mechanisms. Randomized-controlled clinical trials (RCTs), which compared CHM with Western conventional medicine or placebo for WD, were searched in six databases from inception to July 2017. The methodological quality was assessed using 7-item criteria from the Cochrane's collaboration tool. All the data were analyzed using Rev-Man 5.3 software. Eighteen studies involving 1,220 patients were identified for the final analyses. A score of study quality ranged from 2/7 to 4/7 points. Meta-analyses showed that CHM could significantly increase 24-h urinary copper excretion and improve liver function and the total clinical efficacy rate for WD compared with control (p < 0.05). Additionally, CHM was well tolerated in patients with WD. The underlying mechanisms of CHM for WD are associated with reversing the ATP7B mutants, exerting anti-oxidation, anti-inflammation, and anti-hepatic fibrosis effects. In conclusion, despite the apparent positive results, the present evidence supports, to a limited extent because of the methodological flaws and CHM heterogeneity, that CHM paratherapy can be used for patients with WD but could not be recommended as monotherapy in WD. Further rigorous RCTs focusing on individual CHM formula for WD are warranted.
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Affiliation(s)
| | | | | | | | | | - Guo-Qing Zheng
- Department of Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
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Fujiyoshi J, Yamaza H, Sonoda S, Yuniartha R, Ihara K, Nonaka K, Taguchi T, Ohga S, Yamaza T. Therapeutic potential of hepatocyte-like-cells converted from stem cells from human exfoliated deciduous teeth in fulminant Wilson's disease. Sci Rep 2019; 9:1535. [PMID: 30733544 PMCID: PMC6367569 DOI: 10.1038/s41598-018-38275-y] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Accepted: 12/20/2018] [Indexed: 02/08/2023] Open
Abstract
Wilson’s disease (WD) is an inherited metabolic disease arising from ATPase copper transporting beta gene (ATP7B) mutation. Orthotoropic liver transplantation is the only radical treatment of fulminant WD, although appropriate donors are lacking at the onset of emergency. Given the hepatogenic capacity and tissue-integration/reconstruction ability in the liver of stem cells from human exfoliated deciduous teeth (SHED), SHED have been proposed as a source for curing liver diseases. We hypothesized the therapeutic potential of SHED and SHED-converted hepatocyte-like- cells (SHED-Heps) for fulminant WD. SHED and SHED-Heps were transplanted into WD model Atp7b-mutated Long-Evans Cinnamon (LEC) rats received copper overloading to induce a lethal fulminant liver failure. Due to the superior copper tolerance via ATP7B, SHED-Hep transplantation gave more prolonged life-span of fulminant LEC rats than SHED transplantation. The integrated ATP7B-expressing SHED-Heps showed more therapeutic effects on to restoring the hepatic dysfunction and tissue damages in the recipient liver than the integrated naïve SHED without ATP7B expression. Moreover, SHED-Heps could reduce copper-induced oxidative stress via ATP7B- independent stanniocalcin 1 secretion in the fulminant LEC rats, suggesting a possible role for paracrine effect of the integrated SHED-Heps. Taken together, SHED-Heps offer a potential of functional restoring, bridging, and preventive approaches for treating fulminant WD.
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Affiliation(s)
- Junko Fujiyoshi
- Department of Pediatrics, Kyushu University Graduate School of Medical Sciences, Fukuoka, 812-8582, Japan
| | - Haruyoshi Yamaza
- Department of Pediatric Dentistry, Kyushu University Graduate School of Dental Science, Fukuoka, 812-8582, Japan
| | - Soichiro Sonoda
- Department of Molecular Cell Biology and Oral Anatomy, Kyushu University Graduate School of Dental Science, Fukuoka, 812-8582, Japan
| | - Ratih Yuniartha
- Department of Pediatric Surgery, Kyushu University Graduate School of Medical Sciences, Fukuoka, 812-8582, Japan
| | - Kenji Ihara
- Department of Pediatrics, Faculty of Medicine, Oita University, Yuhu, 879-5593, Japan
| | - Kazuaki Nonaka
- Department of Pediatric Dentistry, Kyushu University Graduate School of Dental Science, Fukuoka, 812-8582, Japan
| | - Tomoaki Taguchi
- Department of Pediatric Surgery, Kyushu University Graduate School of Medical Sciences, Fukuoka, 812-8582, Japan
| | - Shouichi Ohga
- Department of Pediatrics, Kyushu University Graduate School of Medical Sciences, Fukuoka, 812-8582, Japan
| | - Takayoshi Yamaza
- Department of Molecular Cell Biology and Oral Anatomy, Kyushu University Graduate School of Dental Science, Fukuoka, 812-8582, Japan.
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Nagral A, Sarma MS, Matthai J, Kukkle PL, Devarbhavi H, Sinha S, Alam S, Bavdekar A, Dhiman RK, Eapen CE, Goyal V, Mohan N, Kandadai RM, Sathiyasekaran M, Poddar U, Sibal A, Sankaranarayanan S, Srivastava A, Thapa BR, Wadia PM, Yachha SK, Dhawan A. Wilson's Disease: Clinical Practice Guidelines of the Indian National Association for Study of the Liver, the Indian Society of Pediatric Gastroenterology, Hepatology and Nutrition, and the Movement Disorders Society of India. J Clin Exp Hepatol 2019; 9:74-98. [PMID: 30765941 PMCID: PMC6363961 DOI: 10.1016/j.jceh.2018.08.009] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2018] [Accepted: 08/25/2018] [Indexed: 12/12/2022] Open
Abstract
Clinical practice guidelines for Wilson's disease (WD) have been published by the American Association for the Study of Liver Diseases and European Association for the Study of the Liver in 2008 and 2012, respectively. Their focus was on the hepatic aspects of the disease. Recently, a position paper on pediatric WD was published by the European Society of Pediatric Gastroenterology Hepatology and Nutrition. A need was felt to harmonize guidelines for the hepatic, pediatric, and neurological aspects of the disease and contextualize them to the resource-constrained settings. Therefore, experts from national societies from India representing 3 disciplines, hepatology (Indian National Association for Study of the Liver), pediatric hepatology (Indian Society of Pediatric Gastroenterology, Hepatology and Nutrition), and neurology (Movement Disorders Society of India) got together to evolve fresh guidelines. A literature search on retrospective and prospective studies of WD using MEDLINE (PubMed) was performed. Members voted on each recommendation, using the nominal voting technique. The Grades of Recommendation, Assessment, Development and Evaluation system was used to determine the quality of evidence. Questions related to diagnostic tests, scoring system, and its modification to a version suitable for resource-constrained settings were posed. While ceruloplasmin and 24-h urine copper continue to be important, there is little role of serum copper and penicillamine challenge test in the diagnostic algorithm. A new scoring system - Modified Leipzig score has been suggested with extra points being added for family history and serum ceruloplasmin lower than 5 mg/dl. Liver dry copper estimation and penicillamine challenge test have been removed from the scoring system. Differences in pharmacological approach to neurological and hepatic disease and global monitoring scales have been included. Rising bilirubin and worsening encephalopathy are suggested as indicators predicting need for liver transplant but need to be validated. The clinical practice guidelines provide recommendations for a comprehensive management of WD which will be of value to all specialties.
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Key Words
- AASLD, American Association for the Study of Liver Diseases
- ACLF, Acute on Chronic Liver Failure
- ALF, Acute Liver Failure
- ALT, Alanine Transaminase
- AST, Aspartate Transaminase
- Cu, Copper
- DP, D-Penicillamine
- EASL, European Association for the Study of the Liver
- GAS for WD, Global Assessment Scale for Wilson's Disease
- HCC, Hepatocellular Carcinoma
- INR, International Normalized Ratio
- KF, Kayser-Fleischer
- LT, Liver Transplantation
- MARS, Molecular Absorption Recirculating System
- MELD, Model for End-Stage Liver Disease
- MRI, Magnetic Resonance Imaging
- NGS, Next-Generation Sequencing
- NWI, New Wilson's Index
- PELD, Pediatric end stage liver disease
- TPE, Total Plasma Exchange
- TTM, Tetrathiomolybdate
- WD, Wilson's Disease
- Wilson's disease scoring
- genetic disorder
- modified Leipzig scoring
- rare disease
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Affiliation(s)
- Aabha Nagral
- Department of Gastroenterology, Jaslok Hospital and Research Centre, Mumbai, India
- Department of Gastroenterology, Apollo Hospitals, Navi Mumbai, India
| | - Moinak S. Sarma
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - John Matthai
- Department of Paediatric Gastroenterology, Masonic Medical Centre for Children, Coimbatore, India
| | | | - Harshad Devarbhavi
- Department of Gastroenterology and Hepatology, St. John's Medical College Hospital, Bangalore, India
| | - Sanjib Sinha
- Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - Seema Alam
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | | | - Radha K. Dhiman
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | | | - Vinay Goyal
- Department of Neurology, All India Institute of Medical Sciences, New Delhi, India
| | - Neelam Mohan
- Department of Pediatric Gastroenterology, Hepatology & Liver Transplantation, Medanta – The Medicity Hospital, Gurgaon, India
| | - Rukmini M. Kandadai
- Department of Neurology, Nizam's Institute of Medical Sciences, Hyderabad, India
| | - Malathi Sathiyasekaran
- Department of Pediatric Gastroenterology, Kanchi Kamakoti Childs Trust Hospital Chennai, India
| | - Ujjal Poddar
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Anupam Sibal
- Department of Pediatric Gastroenterology and Hepatology, Indraprastha Apollo Hospitals, New Delhi, India
| | | | - Anshu Srivastava
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Baburam R. Thapa
- Department of Gastroenterology & Pediatric Gastroenterology, MM Medical Institute of Medical Sciences and Research, Mullana, Ambala, India
| | - Pettarusp M. Wadia
- Department of Neurology, Jaslok Hospital and Research Centre, Mumbai, India
| | - Surendra K. Yachha
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Anil Dhawan
- Department of Pediatrics and Pediatric Liver GI and Nutrition Center and Mowat Labs, King's College Hospital, London, UK
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Poujois A, Woimant F. Wilson's disease: A 2017 update. Clin Res Hepatol Gastroenterol 2018; 42:512-520. [PMID: 29625923 DOI: 10.1016/j.clinre.2018.03.007] [Citation(s) in RCA: 70] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Revised: 02/27/2018] [Accepted: 03/08/2018] [Indexed: 02/04/2023]
Abstract
Wilson's disease (WD) is characterised by a deleterious accumulation of copper in the liver and brain. It is one of those rare genetic disorders that benefits from effective and lifelong treatments that have dramatically transformed the prognosis of the disease. In Europe, its clinical prevalence is estimated at between 1.2 and 2/100,000 but the genetic prevalence is higher, at around 1/7000. Incomplete penetrance of the gene or the presence of modifier genes may account for the difference between the calculated genetic prevalence and the number of patients diagnosed with WD. The clinical spectrum of WD is broader as expected with mild clinical presentations and late onset of the disease after the age of 40 in 6% of patients. WD is usually suspected when ceruloplasmin and serum copper levels are low and 24h urinary copper excretion is elevated. Recently, a major diagnostic advance was achieved with implementation of the direct assay of "free copper", or exchangeable copper (CuEXC). The relative exchangeable copper (REC) that corresponds to the ratio between CuEXC and total serum copper enables a diagnosis of WD with high sensitivity and specificity when REC>18.5%. Moreover, CuEXC values at diagnosis are a marker of extrahepatic involvement and its severity. A value of >2.08μmol/L is suggestive of corneal and brain involvement (Se=86%, Sp=94%), and the disease will be more clinically and radiologically severe as values rise. The use of FibroScan® is becoming more widespread to assess liver stiffness measurements in WD patients. 6.6kPa is considered to be a threshold value between mild and moderate fibrosis, whereas a value higher than 8.4 is indicative of severe fibrosis. More studies are now necessary to confirm the usefulness of Fibroscan® in managing chronic therapy for WD patients. Treatment of this disease is based on an initial active and prolonged chelating phase (with D-Penicillamine or Trientine) followed by maintenance with Trientine or zinc salt. The two major problems that may be encountered are neurological worsening during the initial phase and non-compliance with treatment during maintenance therapy. Liver transplantation is the recommended therapeutic option in WD with acute liver failure or end-stage liver cirrhosis; its indication should be considered when neurological status deteriorates rapidly despite effective chelation. Regular clinical, biological and liver ultrasound follow-up is essential to evaluate efficacy, tolerance and treatment compliance, but also to detect the onset of hepatocellular carcinoma on a cirrhotic liver. There are hopes in the near future with the introduction of a new chelator and inhibitor of copper absorption, tetrathiomolybdate (TTM) and the development of gene therapy.
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Affiliation(s)
- Aurélia Poujois
- Neurology Department, AP-HP, Lariboisière University Hospital, Paris, France; National Reference Centre for Wilson's Disease, AP-HP, Lariboisière University Hospital, Paris, France.
| | - France Woimant
- Neurology Department, AP-HP, Lariboisière University Hospital, Paris, France; National Reference Centre for Wilson's Disease, AP-HP, Lariboisière University Hospital, Paris, France
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Liu J, Luan J, Zhou X, Cui Y, Han J. Epidemiology, diagnosis, and treatment of Wilson's disease. Intractable Rare Dis Res 2017; 6:249-255. [PMID: 29259852 PMCID: PMC5735277 DOI: 10.5582/irdr.2017.01057] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Wilson's disease (WD) is an autosomal recessive disease caused by a mutation of the ATP7B gene, resulting in abnormal copper metabolism. The major clinical features of WD include liver disease, neurological disorders, K-F rings, and osteoporosis. The prevalence of WD in China is higher than that in Western countries. Early diagnosis and lifelong treatment will lead to better outcomes. Drugs such as sodium dimercaptosuccinate (Na-DMPS), Zn, and Gandou Decoction can be used to treat WD. Some studies have shown that the combination of traditional Chinese medicine and Western medicine is the best approach to treating WD. In order to identify better treatments, this article describes the specific clinical symptoms of Wilson's disease, its diagnosis, and treatment options.
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Affiliation(s)
- Jing Liu
- School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Science, Ji'nan, China
- Key Laboratory for Rare Disease Research of Shandong Province, Key Laboratory for Biotech Drugs of the Ministry of Health, Shandong Medical Biotechnological Center, Shandong Academy of Medical Sciences, Ji'nan, China
| | - Jing Luan
- Key Laboratory for Rare Disease Research of Shandong Province, Key Laboratory for Biotech Drugs of the Ministry of Health, Shandong Medical Biotechnological Center, Shandong Academy of Medical Sciences, Ji'nan, China
| | - Xiaoyan Zhou
- Key Laboratory for Rare Disease Research of Shandong Province, Key Laboratory for Biotech Drugs of the Ministry of Health, Shandong Medical Biotechnological Center, Shandong Academy of Medical Sciences, Ji'nan, China
| | - Yazhou Cui
- Key Laboratory for Rare Disease Research of Shandong Province, Key Laboratory for Biotech Drugs of the Ministry of Health, Shandong Medical Biotechnological Center, Shandong Academy of Medical Sciences, Ji'nan, China
| | - Jinxiang Han
- Key Laboratory for Rare Disease Research of Shandong Province, Key Laboratory for Biotech Drugs of the Ministry of Health, Shandong Medical Biotechnological Center, Shandong Academy of Medical Sciences, Ji'nan, China
- Address correspondence to: Dr. Jinxiang Han, Key Laboratory for Rare Disease Research of Shandong Province, Key Laboratory for Biotech Drugs of the Ministry of Health, Shandong Medical Biotechnological Center, Shandong Academy of Medical Sciences, Ji'nan, Shandong 250062, China. E-mail:
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Kido J, Matsumoto S, Momosaki K, Sakamoto R, Mitsubuchi H, Inomata Y, Endo F, Nakamura K. Plasma exchange and chelator therapy rescues acute liver failure in Wilson disease without liver transplantation. Hepatol Res 2017; 47:359-363. [PMID: 27007780 DOI: 10.1111/hepr.12711] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Revised: 03/15/2016] [Accepted: 03/16/2016] [Indexed: 01/21/2023]
Abstract
AIM Wilson disease (WD) in patients with a New Wilson Index (NWI) score ≥ 11 is fatal, and these patients are good candidates for liver transplantation (LT). However, plasma exchange and chelator therapy are indispensable and effective even for WD with a score ≥ 11. Moreover, continuous hemodiafiltration (CHDF) with these treatments is essential for acute liver failure (ALF) in WD with hepatic encephalopathy because CHDF can exclude toxic metabolites that may cause damage to the brain. Here, we describe four rescued patients presenting with ALF in WD and discuss the available treatment options. METHODS We have experienced 11 male and 8 female patients presenting with WD at the Department of Pediatrics, Kumamoto University Hospital between 1999 and 2014. A male and 4 female patients were diagnosed as WD with ALF using a combination of clinical findings and biochemical tests. RESULTS The NWI score was ≥ 11 in cases 1 to 3. Cases 1 and 2 with hepatic encephalopathy received plasma exchange, CHDF, coagulation factor replacement treatment (CFRT) and LT. Cases 3 and 4 without encephalopathy obtained stable status without LT by plasma exchange, blood infusion, and CFRT. CONCLUSIONS It is better to undergo LT for WD patients with a NWI score ≥ 11, however, there is a possibility of remission by plasma exchange and medical therapy even without LT. WD patients with a NWI score ≥ 11can be rescued by conservative therapy when the ALF of WD does not present with ALF and hepatic encephalopathy. Therefore, ALF with hepatic encephalopathy itself is an indication for LT in WD.
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Affiliation(s)
- Jun Kido
- Department of Pediatrics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto City, Japan
| | - Shirou Matsumoto
- Department of Pediatrics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto City, Japan
| | - Ken Momosaki
- Department of Pediatrics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto City, Japan
| | - Rieko Sakamoto
- Department of Pediatrics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto City, Japan.,Department of Transplantation and Pediatric Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto City, Japan
| | - Hiroshi Mitsubuchi
- Department of Pediatrics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto City, Japan
| | - Yukihiro Inomata
- Department of Transplantation and Pediatric Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto City, Japan
| | - Fumio Endo
- Department of Pediatrics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto City, Japan
| | - Kimitoshi Nakamura
- Department of Pediatrics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto City, Japan
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Rupp C, Stremmel W, Weiss KH. Novel perspectives on Wilson disease treatment. WILSON DISEASE 2017; 142:225-230. [DOI: 10.1016/b978-0-444-63625-6.00019-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
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Abstract
Wilson's disease (WD), albeit relatively rare, is an important genetic metabolic disease because of highly effective therapies that can be lifesaving. It is a great imitator and requires a high index of suspicion for correct and timely diagnosis. Neurologic, psychiatric and hepatologic problems in WD are very nonspecific, and we discuss the most common clinical phenotypes. The diagnosis remains laboratory based, and here we review the most important challenges and pitfalls in laboratory evaluation of WD, including the emerging role of genetic testing in WD diagnosis. WD is a monogenic disorder but has very high allelic heterogeneity with >500 disease-causing mutations identified, and new insights into phenotype-genotype correlations are also reviewed. The gold standard of therapy is chelation of excessive copper, but many unmet needs exist because of possible clinical deterioration in treated patients and potential adverse effects associated with currently available chelating medications. We also review the most promising novel therapeutic approaches, including chelators targeting specific cell types, cell transplantation and gene therapy.
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Affiliation(s)
- Peter Hedera
- Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA
- Correspondence: Peter Hedera, Department of Neurology, Vanderbilt University Medical Center, 465 21st Avenue South, 6140 MRB III, Nashville, TN 37232, USA, Tel +1 615 936 3920, Fax +1 615 322 0486, Email
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25
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Hu M, Li S, Menon S, Liu B, Hu MS, Longaker MT, Lorenz HP. Expansion and Hepatic Differentiation of Adult Blood-Derived CD34+ Progenitor Cells and Promotion of Liver Regeneration After Acute Injury. Stem Cells Transl Med 2016; 5:723-32. [PMID: 27075766 PMCID: PMC4878335 DOI: 10.5966/sctm.2015-0268] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2015] [Accepted: 01/13/2016] [Indexed: 12/27/2022] Open
Abstract
A new group of blood-derived CD34+ progenitor cells (BDPCs) with the ability to expand and differentiate into functional hepatocyte-like cells and promote liver regeneration is reported. With their ease of access, application through the peripheral blood, and the capability of rapid expansion and hepatic differentiation, BDPCs have great potential as a cell-based therapy for liver disease. The low availability of functional hepatocytes has been an unmet demand for basic scientific research, new drug development, and cell-based clinical applications for decades. Because of the inability to expand hepatocytes in vitro, alternative sources of hepatocytes are a focus of liver regenerative medicine. We report a new group of blood-derived CD34+ progenitor cells (BDPCs) that have the ability to expand and differentiate into functional hepatocyte-like cells and promote liver regeneration. BDPCs were obtained from the peripheral blood of an adult mouse with expression of surface markers CD34, CD45, Sca-1, c-kit, and Thy1.1. BDPCs can proliferate in vitro and differentiate into hepatocyte-like cells expressing hepatocyte markers, including CK8, CK18, CK19, α-fetoprotein, integrin-β1, and A6. The differentiated BDPCs (dBDPCs) also display liver-specific functional activities, such as glycogen storage, urea production, and albumin secretion. dBDPCs have cytochrome P450 activity and express specific hepatic transcription factors, such as hepatic nuclear factor 1α. To demonstrate liver regenerative activity, dBDPCs were injected into mice with severe acute liver damage caused by a high-dose injection of carbon tetrachloride (CCl4). dBDPC treatment rescued the mice from severe acute liver injury, increased survival, and induced liver regeneration. Because of their ease of access and application through peripheral blood and their capability of rapid expansion and hepatic differentiation, BDPCs have great potential as a cell-based therapy for liver disease. Significance Hematopoietic stem/progenitor cell expansion and tissue-specific differentiation in vitro are challenges in regenerative medicine, although stem cell therapy has raised hope for the treatment of liver diseases by overcoming the scarcity of hepatocytes. This study identified and characterized a group of blood-derived progenitor cells (BDPCs) from the peripheral blood of an adult mouse. The CD34+ progenitor-dominant BDPCs were rapidly expanded and hepatically differentiated into functional hepatocyte-like cells with our established coculture system. BDPC treatment increased animal survival and produced full regeneration in a severe liver injury mouse model caused by CCl4. BDPCs could have potential for liver cell therapies.
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Affiliation(s)
- Min Hu
- Division of Plastic Surgery, Department of Surgery, School of Medicine, Stanford University, Stanford, California, USA
| | - Shaowei Li
- Division of Plastic Surgery, Department of Surgery, School of Medicine, Stanford University, Stanford, California, USA
| | - Siddharth Menon
- Division of Plastic Surgery, Department of Surgery, School of Medicine, Stanford University, Stanford, California, USA
| | - Bo Liu
- Division of Pediatric Surgery, Department of Surgery, School of Medicine, Stanford University, Stanford, California, USA
| | - Michael S Hu
- Division of Plastic Surgery, Department of Surgery, School of Medicine, Stanford University, Stanford, California, USA Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Stanford, California, USA Department of Surgery, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA
| | - Michael T Longaker
- Division of Plastic Surgery, Department of Surgery, School of Medicine, Stanford University, Stanford, California, USA Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Stanford, California, USA
| | - H Peter Lorenz
- Division of Plastic Surgery, Department of Surgery, School of Medicine, Stanford University, Stanford, California, USA
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Oldhafer F, Bock M, Falk CS, Vondran FWR. Immunological aspects of liver cell transplantation. World J Transplant 2016; 6:42-53. [PMID: 27011904 PMCID: PMC4801804 DOI: 10.5500/wjt.v6.i1.42] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Revised: 10/21/2015] [Accepted: 12/08/2015] [Indexed: 02/05/2023] Open
Abstract
Within the field of regenerative medicine, the liver is of major interest for adoption of regenerative strategies due to its well-known and unique regenerative capacity. Whereas therapeutic strategies such as liver resection and orthotopic liver transplantation (OLT) can be considered standards of care for the treatment of a variety of liver diseases, the concept of liver cell transplantation (LCTx) still awaits clinical breakthrough. Success of LCTx is hampered by insufficient engraftment/long-term acceptance of cellular allografts mainly due to rejection of transplanted cells. This is in contrast to the results achieved for OLT where long-term graft survival is observed on a regular basis and, hence, the liver has been deemed an immune-privileged organ. Immune responses induced by isolated hepatocytes apparently differ considerably from those observed following transplantation of solid organs and, thus, LCTx requires refined immunological strategies to improve its clinical outcome. In addition, clinical usage of LCTx but also related basic research efforts are hindered by the limited availability of high quality liver cells, strongly emphasizing the need for alternative cell sources. This review focuses on the various immunological aspects of LCTx summarizing data available not only for hepatocyte transplantation but also for transplantation of non-parenchymal liver cells and liver stem cells.
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Park KM, Hussein KH, Hong SH, Ahn C, Yang SR, Park SM, Kweon OK, Kim BM, Woo HM. Decellularized Liver Extracellular Matrix as Promising Tools for Transplantable Bioengineered Liver Promotes Hepatic Lineage Commitments of Induced Pluripotent Stem Cells. Tissue Eng Part A 2016; 22:449-60. [PMID: 26801816 DOI: 10.1089/ten.tea.2015.0313] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Liver transplantation is the last resort for liver failure patients. However, due to the shortage of donor organs, bioengineered liver generated from decellularized whole liver scaffolds and induced pluripotent stem cell (iPSC)-derived hepatocytes (iPSC-Heps) is being studied as an alternative approach to treat liver disease. Nevertheless, there has been no report on both the interaction of iPSC-Heps with a liver extracellular matrix (ECM) and the analysis of recellularized iPSC-Heps into the whole liver scaffolds. In this study, we produced porcine iPSC-Heps, which strongly expressed the hepatic markers α-fetoprotein and albumin and exhibited hepatic functionalities, including glycogen storage, lipid accumulation, low-density lipoprotein uptake, and indocyanine green metabolism. Supplementation of ECM from porcine decellularized liver containing liver-derived growth factors stimulated the albumin expression of porcine iPSC-Heps during differentiation procedures. The iPSC-Heps were reseeded into decellularized liver scaffolds, and the recellularized liver was cultured using a continuous perfusion system. The recellularized liver scaffolds were transplanted into rats for a short term, and the grafts expressed hepatocyte markers and did not rupture. These results provide a foundation for development of bioengineered liver using stem cell and decellularized scaffolds.
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Affiliation(s)
- Kyung-Mee Park
- 1 Stem Cell Institute-KNU, Kangwon National University , Chuncheon, Korea.,2 School of Veterinary Medicine, Kangwon National University , Chuncheon, Korea
| | - Kamal Hany Hussein
- 1 Stem Cell Institute-KNU, Kangwon National University , Chuncheon, Korea.,2 School of Veterinary Medicine, Kangwon National University , Chuncheon, Korea
| | - Seok-Ho Hong
- 1 Stem Cell Institute-KNU, Kangwon National University , Chuncheon, Korea.,3 School of Medicine, Kangwon National University , Chuncheon, Korea
| | - Cheol Ahn
- 1 Stem Cell Institute-KNU, Kangwon National University , Chuncheon, Korea.,4 School of Biomedical Technology, Kangwon National University , Chuncheon, Korea
| | - Se-Ran Yang
- 1 Stem Cell Institute-KNU, Kangwon National University , Chuncheon, Korea.,3 School of Medicine, Kangwon National University , Chuncheon, Korea
| | - Sung-Min Park
- 1 Stem Cell Institute-KNU, Kangwon National University , Chuncheon, Korea.,3 School of Medicine, Kangwon National University , Chuncheon, Korea
| | - Oh-Kyeong Kweon
- 5 School of Veterinary Medicine, Seoul National University , Seoul, Korea
| | - Byeong-Moo Kim
- 6 Departments of Medicine/GI Unit, Massachusetts General Hospital , Harvard Medical School, Boston, Massachusetts
| | - Heung-Myong Woo
- 1 Stem Cell Institute-KNU, Kangwon National University , Chuncheon, Korea.,2 School of Veterinary Medicine, Kangwon National University , Chuncheon, Korea
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28
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Alfaro J, Pérez D, Jiménez C, Serrano M, Martínez-Flores JÁ, Grau M, Sánchez-Zapardiel E, Paz-Artal E, Serrano A. Blockade of cell adhesion molecules enhances cell engraftment in a murine model of liver cell transplantation. Transpl Immunol 2016; 35:7-11. [PMID: 26875547 DOI: 10.1016/j.trim.2016.01.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2015] [Revised: 12/13/2015] [Accepted: 01/30/2016] [Indexed: 11/26/2022]
Abstract
AIM OLT is the best alternative for patients with end-stage liver diseases. However, as the need for organs surpasses donor availability, alternatives to OLT are required. LCT could be a useful option versus OLT in several patients even though its low cell-engraftment hampers its efficiency. Endothelial cell barrier is the main obstacle for the implantation of cells into the parenchyma. Our study has focused on the modification of the endothelial barrier with monoclonal antibodies against adhesion molecules in order to increase cell engraftment in a mouse model of liver cell transplantation. METHODS Anti-mouse CD54 and anti-mouse CD61 antibodies were administered intrasplenically to healthy mice within 60 min prior to stem cell transplantation. Animals were sacrificed either short term at 2h or middle term seven days after transplantation. Immunohistochemical techniques to detect alkaline phosphatase activity were used to identify the transplanted cells within the liver parenchyma. RESULTS Anti-CD54 and anti-CD61 administration increases vascular patency and cell engraftment. This represents a 32% and 45% increase, respectively, of engrafted cells compared to the control (p<0.05). CONCLUSION Modification of the vascular wall with monoclonal antibodies against endothelial adhesion molecules before cell transplantation enhances cell engraftment into the mouse liver.
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Affiliation(s)
- Javier Alfaro
- Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain.
| | - Dolores Pérez
- Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Carlos Jiménez
- Department of General Surgery and Liver Transplantation, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Manuel Serrano
- Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain
| | | | - Montserrat Grau
- Department of General Surgery and Liver Transplantation, Hospital Universitario 12 de Octubre, Madrid, Spain
| | | | - Estela Paz-Artal
- Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain; Section of Immunology, Universidad San Pablo-CEU. Madrid, Spain
| | - Antonio Serrano
- Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain; Section of Immunology, Universidad San Pablo-CEU. Madrid, Spain
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Early Application of Auxiliary Partial Orthotopic Liver Transplantation in Murine Model of Wilson Disease. Transplantation 2016; 99:2317-24. [PMID: 26018347 DOI: 10.1097/tp.0000000000000787] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Liver transplantation (LT) is the only option of treatment for Wilson disease (WD) when chelation therapy fails, but it is limited due to the shortage of donor. Auxiliary partial orthotopic LT (APOLT) has been performed successfully in end-stage WD patients, which expands the donor pool. METHODS Atp7bmice were used as experimental model of WD. Eight- and 20-week-old mice were used as different timepoints to perform APOLT. Serum copper, tissue copper, serum ceruloplasmin (CP), and liver histological examination were observed after operation. RESULTS Hepatic and serum copper levels in Atp7b mice decreased after APOLT, and copper metabolism disorder of WD mice was relieved at both early and late stages. The progression of pathology in the native liver was delayed only when transplantation was performed at an early stage. CONCLUSIONS Auxiliary partial orthotopic LT can significantly improve copper metabolism disorder in the Atp7b mice, and early transplantation may prevent the disease progression.
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Rodriguez-Castro KI, Hevia-Urrutia FJ, Sturniolo GC. Wilson’s disease: A review of what we have learned. World J Hepatol 2015; 7:2859-2870. [PMID: 26692151 PMCID: PMC4678372 DOI: 10.4254/wjh.v7.i29.2859] [Citation(s) in RCA: 98] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2015] [Revised: 08/21/2015] [Accepted: 12/02/2015] [Indexed: 02/06/2023] Open
Abstract
Wilson’s disease (WD), which results from the defective ATP7B protein product, is characterized by impaired copper metabolism and its clinical consequences vary from an asymptomatic state to fulminant hepatic failure, chronic liver disease with or without cirrhosis, neurological, and psychiatric manifestations. A high grade of suspicion is warranted to not miss cases of WD, especially less florid cases with only mild elevation of transaminases, or isolated neuropsychiatric involvement. Screening in first and second relatives of index cases is mandatory, and treatment must commence upon establishment of diagnosis. Treatment strategies include chelators such as D-penicillamine and trientine, while zinc salts act as inductors of methallothioneins, which favor a negative copper balance and a reduction of free plasmatic copper. As an orphan disease, research is lacking in this field, especially regarding therapeutic strategies which are associated with better patient compliance and which could eventually also reverse established injury.
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Park KM, Hussein KH, Ghim JH, Ahn C, Cha SH, Lee GS, Hong SH, Yang S, Woo HM. Hepatic differentiation of porcine embryonic stem cells for translational research of hepatocyte transplantation. Transplant Proc 2015; 47:775-9. [PMID: 25891729 DOI: 10.1016/j.transproceed.2015.01.020] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2014] [Revised: 01/02/2015] [Accepted: 01/28/2015] [Indexed: 12/28/2022]
Abstract
Porcine embryonic stem cells (ES) are considered attractive preclinical research tools for human liver diseases. Although several studies previously reported generation of porcine ES, none of these studies has described hepatic differentiation from porcine ES. The aim of this study was to generate hepatocytes from porcine ES and analyze their characteristics. We optimized conditions for definitive endoderm induction and developed a 4-step hepatic differentiation protocol. A brief serum-free condition with activin A efficiently induced definitive endoderm differentiation from porcine ES. The porcine ES-derived hepatocyte-like cells highly expressed hepatic markers including albumin and α-fetoprotein, and displayed liver characteristics such as glycogen storage, lipid production, and low-density lipoprotein uptake. For the first time, we describe a highly efficient protocol for hepatic differentiation from porcine ES. Our findings provide valuable information for translational liver research using porcine models, including hepatic regeneration and transplant studies, drug screening, and toxicology.
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Affiliation(s)
- K M Park
- Stem Cell Institute, Kangwon National University, Chuncheon, Korea; College of Veterinary Medicine, Kangwon National University, Chuncheon, Korea
| | - K H Hussein
- Stem Cell Institute, Kangwon National University, Chuncheon, Korea
| | - J H Ghim
- Stem Cell Institute, Kangwon National University, Chuncheon, Korea; College of Veterinary Medicine, Kangwon National University, Chuncheon, Korea
| | - C Ahn
- Stem Cell Institute, Kangwon National University, Chuncheon, Korea; College of Biomedical Science, Kangwon National University, Chuncheon, Korea
| | - S H Cha
- Animal, Plant and Fisheries Quarantine and Inspection Agency, Anyang, Korea
| | - G S Lee
- College of Veterinary Medicine, Kangwon National University, Chuncheon, Korea
| | - S H Hong
- Stem Cell Institute, Kangwon National University, Chuncheon, Korea; College of Medicine, Kangwon National University, Chuncheon, Korea
| | - S Yang
- Stem Cell Institute, Kangwon National University, Chuncheon, Korea; College of Medicine, Kangwon National University, Chuncheon, Korea
| | - H M Woo
- Stem Cell Institute, Kangwon National University, Chuncheon, Korea; College of Veterinary Medicine, Kangwon National University, Chuncheon, Korea.
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Baimakhanov Z, Yamanouchi K, Sakai Y, Koike M, Soyama A, Hidaka M, Takatsuki M, Fujita F, Kanetaka K, Kuroki T, Eguchi S. Efficacy of Multilayered Hepatocyte Sheet Transplantation for Radiation-Induced Liver Damage and Partial Hepatectomy in a Rat Model. Cell Transplant 2015. [PMID: 26224253 DOI: 10.3727/096368915x688669] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Although cell sheet technology has recently been developed for use in both animal experiments and in the clinical setting, it remains unclear whether transplanted hepatocyte sheets improve the liver function in vivo. Radiation-induced liver damage (RILD) combined with partial hepatectomy (PH) has been reported to suppress the proliferation of host hepatocytes and induce critical liver failure. The aim of this study was to improve the liver function in the above-mentioned diseased rat model (RILD + PH) using multilayered hepatocyte sheet transplantation. In this study, we used Fischer rats as a donor for primary hepatocytes and dermal fibroblast isolation. Cocultured multilayered hepatocyte sheets were generated by disseminating hepatocytes onto fibroblasts cultured beforehand on temperature-responsive culture dishes. Four cell sheets were transplanted into the recipient rats subcutaneously. Prior to transplantation, RILD (50 Gy) with 2/3PH was induced in the recipients. The same model was applied in the control group without transplantation. The serum was collected each week. The rats in both groups were sacrificed at 2 months after transplantation for the histological analysis. Consequently, the serum albumin concentrations were significantly higher in the transplant group than in the control group (54.3 ± 9.6 vs. 32.7 ± 5.7 mg/ml; p < 0.01) after 2 months and comparable to the serum albumin levels in the normal rats (58.1 ± 6.4 mg/ml). In addition, treatment with the transplanted sheets significantly improved the survival rate (57% vs. 22%, p < 0.05), and the hepatocyte sheets showed the storage of albumin, glycogen, and bile canaliculus structures. Some hepatocytes and fibroblasts were positive for Ki-67, and vascularization was observed around the cell sheets. Transplanted multilayered hepatocyte sheets can survive with additional proliferative activity, thereby maintaining the liver function in vivo for at least 2 months, providing metabolic support for rats with RILD.
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Affiliation(s)
- Zhassulan Baimakhanov
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Sakamoto, Nagasaki, Japan
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Abstract
PURPOSE OF REVIEW Acute liver failure (ALF) is a rare but life-threatening systemic disorder. Survival rates with or without emergency liver transplantation (ELT) are increasing. The benefit of ELT in some cases has been questioned and the potential for survival with medical management alone is changing our approach to the management of this disease. RECENT FINDINGS Survival rates for all causes of ALF are increasing because of improvements in the care of the critically ill patient. A multifactorial approach involving support of respiratory, circulatory and renal function together with measures to avoid intracranial hypertension, metabolic disequilibrium and sepsis are required. For those who do not respond to these measures or specific antidotes, the selection methods for those likely to benefit from transplantation remain imperfect and novel methods based on the prediction of hepatic regeneration are required. For patients with ALF secondary to acetaminophen overdose, some experts believe a randomized controlled trial is required to find those most likely to benefit from ELT. SUMMARY ALF remains a life-threatening condition with a high mortality rate requiring prompt support of multiorgan failure. Historical listing criteria for ELT are being questioned and improvement in medical management offers the option of continued improvements in transplant-free survival.
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Koblihová E, Lukšan O, Mrázová I, Ryska M, Červenka L. Hepatocyte transplantation attenuates the course of acute liver failure induced by thioacetamide in Lewis rats. Physiol Res 2015; 64:689-700. [PMID: 25804092 DOI: 10.33549/physiolres.932914] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
Acute liver failure (ALF) is a clinical syndrome resulting from widespread damage of hepatocytes, with extremely high mortality rate. Urgent orthotopic liver transplantation was shown to be the most effective therapy for ALF but this treatment option is limited by scarcity of donor organs. Therefore, hepatocyte transplantation (Tx) has emerged as a new therapeutical measure for ALF, however, the first clinical applications proved unsatisfactory. Apparently, extensive preclinical studies are needed. Our aim was to examine if hepatocytes isolated from transgenic "firefly luciferase" Lewis rats into the recipient liver would attenuate the course of thioacetamide (TAA)-induced ALF in Lewis rats. Untreated Lewis rats after TAA administration showed a profound decrease in survival rate; no animal survived 54 h. The rats showed marked increases in plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, in plasma level of bilirubin and ammonia (NH(3)), and in a significant decrease in plasma albumin. Hepatocyte Tx attenuated the course of TAA-induced ALF Lewis rats which was reflected by improved survival rate and reduced degree of liver injury showing as lowering of elevated plasma ALT, AST, NH(3) and bilirubin levels and increasing plasma albumin. In addition, bioluminescence imaging analyses have shown that in the TAA-damaged livers the transplanted hepatocyte were fully viable throughout the experiment. In conclusion, the results show that hepatocyte Tx into the liver can attenuate the course of TAA-induced ALF in Lewis rats. This information should be considered in attempts to develop new therapeutic approaches to the treatment of ALF.
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Affiliation(s)
- E Koblihová
- Department of Surgery, Second Faculty of Medicine, Charles University and Central Military Hospital, Prague, Czech Republic, Department of Pathophysiology, Second Faculty of Medicine, Charles University, Prague, Czech Republic.
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Viswanathan P, Kapoor S, Kumaran V, Joseph B, Gupta S. Etanercept blocks inflammatory responses orchestrated by TNF-α to promote transplanted cell engraftment and proliferation in rat liver. Hepatology 2014; 60:1378-1388. [PMID: 24844924 PMCID: PMC4176524 DOI: 10.1002/hep.27232] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2014] [Accepted: 05/19/2014] [Indexed: 12/26/2022]
Abstract
UNLABELLED Engraftment of transplanted cells is critical for liver-directed cell therapy, but most transplanted cells are rapidly cleared from liver sinusoids by proinflammatory cytokines/chemokines/receptors after activation of neutrophils or Kupffer cells (KCs). To define whether tumor necrosis factor alpha (TNF-α) served roles in cell-transplantation-induced hepatic inflammation, we used the TNF-α antagonist, etanercept (ETN), for studies in syngeneic rat hepatocyte transplantation systems. After cell transplantation, multiple cytokines/chemokines/receptors were overexpressed, whereas ETN before cell transplantation essentially normalized these responses. Moreover, ETN down-regulated cell-transplantation-induced intrahepatic release of secretory cytokines, such as high-mobility group box 1. These effects of ETN decreased cell-transplantation-induced activation of neutrophils, but not of KCs. Transplanted cell engraftment improved by several-fold in ETN-treated animals. These gains in cell engraftment were repeatedly realized after pretreatment of animals with ETN before multiple cell transplantation sessions. Transplanted cell numbers did not change over time, indicating absence of cell proliferation after ETN alone. By contrast, in animals preconditioned with retrorsine and partial hepatectomy, cell transplantation after ETN pretreatment significantly accelerated liver repopulation, compared to control rats. CONCLUSION TNF-α plays a major role in orchestrating cell-transplantation-induced inflammation through regulation of multiple cytokines/chemokines/receptor expression. Because TNF-α antagonism by ETN decreased transplanted cell clearance, improved cell engraftment, and accelerated liver repopulation, this pharmacological approach to control hepatic inflammation will help optimize clinical strategies for liver cell therapy.
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Affiliation(s)
- Preeti Viswanathan
- Division of Pediatric Gastroenterology, Department of Pediatrics, Children’s Hospital at Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY
| | - Sorabh Kapoor
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY
| | - Vinay Kumaran
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY
| | - Brigid Joseph
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY
| | - Sanjeev Gupta
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY
- Departments of Medicine and Pathology, Marion Bessin Liver Research Center, Diabetes Center, Cancer Center, Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY
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Affiliation(s)
- Doo-Hoon Lee
- Biomedical Research Institute, Lifeliver Co. Ltd., Yongin, Korea
| | - Kwang-Woong Lee
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
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