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Mohamed Rela - One of the best experts on this subject based on the ideXlab platform.
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auxiliary partial orthotopic Liver transplantation for selected noncirrhotic Metabolic Liver Disease
Liver Transplantation, 2019Co-Authors: Ashwin Rammohan, Mettu Srinivas Reddy, Rajesh Rajalingam, Mohamed Rela, Naresh Shanmugam, Gomathy Narasimhan, Ilankumaran KaliamoorthyAbstract:: Auxiliary partial orthotopic Liver transplantation (APOLT) in selected noncirrhotic Metabolic Liver Diseases (NCMLDs) is a viable alternative to orthotopic Liver transplantation (OLT) as it supplements the function of the native Liver with the missing functional protein. APOLT for NCMLD is not universally accepted due to concerns of increased technical complications and longterm graft atrophy. Review of a prospectively collected database of all pediatric patients (age ≤16 years) who underwent Liver transplantation for NCMLD from August 2009 up to June 2017 was performed. Patients were divided into 2 groups: group 1 underwent APOLT and group 2 underwent OLT. In total, 18 OLTs and 12 APOLTs were performed for NCMLDs during the study period. There was no significant difference in the age and weight of the recipients in both groups. All APOLT patients needed intraoperative portal flow modulation. Intraoperative peak and end of surgery lactate were significantly higher in the OLT group, and cold ischemia time was longer in the APOLT group. There were no differences in postoperative Liver function tests apart from higher peak international normalized ratio in the OLT group. The incidence of postoperative complications, duration of hospital stay, and 1- and 5-year survivals were similar in both groups. In conclusion, we present the largest series of APOLT for NCMLD. APOLT is a safe and effective alternative to OLT and may even be better than OLT due to lesser physiological stress and the smoother postoperative period for selected patients with NCMLD.
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Auxiliary Partial Orthotopic Liver Transplantation for Monogenic Metabolic Liver Diseases: Single-Centre Experience
JIMD reports, 2018Co-Authors: Naresh Shanmugam, Mettu Srinivas Reddy, Joseph J. Valamparampil, Khoula Julenda Al Said, Khalid Al-thihli, Nadia Al-hashmi, Emtithal Al-jishi, Anil B. Jalan, Mohamed RelaAbstract:Purpose: Auxiliary partial orthotopic Liver transplantation (APOLT) in Metabolic Liver Disease (MLD) has the advantage of correcting the Metabolic defect, preserving the native Liver for gene therapy in the future with the possibility of withdrawal of immunosuppression.
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Revisiting APOLT for Metabolic Liver Disease: A new Look at an old Idea.
Transplantation, 2017Co-Authors: Mettu Srinivas Reddy, Rajesh Rajalingam, Mohamed RelaAbstract:: Even though auxiliary partial orthotopic Liver transplantation (APOLT) as a technique was popularized in the late 80s, its role in Metabolic Liver Disease remains controversial. The slow progress in gene therapy research, high incidence of technical complications, and the problem of long term graft atrophy have been roadblocks to its wider application. Better understanding of reciprocal dynamics of portal flow and regeneration between the graft and native Liver along with multiple refinements in surgical technique have improved the outcomes of this operation, making it a safe alternative to orthotopic Liver transplantation for patients with a wide range of noncirrhotic Metabolic Liver Diseases (NCMLD). The ability to perform APOLT safely has also opened up a range of exciting indications in the setting of NCMLD. This article reviews the current status of APOLT for NCMLD, technical refinements which have improved outcomes and novel indications, which have rekindled fresh interest in this procedure.
Anil Dhawan - One of the best experts on this subject based on the ideXlab platform.
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OSH Paediatric Gastroenterology, Hepatology and Nutrition - Metabolic Liver Disease
Oxford Medicine Online, 2020Co-Authors: Mark Beattie, Anil Dhawan, John W. L. PuntisAbstract:Background 390Clinical features 390Investigations 392Clinical presentations of Metabolic disorders 394General management 402The diagnostic approach to a child with Metabolic Liver Disease requires a high degree of suspicion, detailed history and physical examination, and extensive blood and urine tests; Liver, skin, and muscle biopsy are usually necessary to establish the diagnosis....
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pediatric Liver transplantation for Metabolic Liver Disease experience at king s college hospital
Transplantation, 2009Co-Authors: Anil Dhawan, Rachel M Taylor, Sanjay Bansal, Giorgina Mielivergani, Mohammed Rela, Nigel HeatonAbstract:AIMS: The aims of this article were to report a single-center experience of pediatric Liver transplantation for Liver-based Metabolic disorders and to compare the outcome of cirrhotic versus noncirrhotic Metabolic Liver Disease. METHODS: The medical records of 96 patients younger than 18 years undergoing transplantation for Liver-based Metabolic disorders from 1989 to 2005 were reviewed. RESULTS: Hundred twelve transplants were performed in 96 patients at a median age of 59.7 months (range, 0-208 months). The cumulative 1-, 5-, and 10-year graft and patient survival rates were 83%, 77%, and 62% and 91%, 86%, and 82%, respectively. Acute Liver failure at first presentation (hazard ratio [HR] 3.0; 95% confidence interval [CI] 1.1-8.1), age less than 1 year at time of transplantation (HR 4.6; 95% CI 1.7-12.4) and hospitalization (HR 3.2; 95% CI 1.1-9.3) were significant predictors of worse patient survival. For noncirrhotic disorders, the long-term patient (100% vs. 100%, 90% vs. 100%, and 90% vs. 75%, P=0.87) and graft survivals (93% vs. 100%, 70% vs. 100%, and 70 vs. 75%, P=0.12) at 1, 5, and 7 years for auxiliary versus orthotopic transplantation were not significantly different. CONCLUSIONS: Long-term patient survival after transplantation for Metabolic disorders is excellent for both cirrhotic and noncirrhotic Metabolic disorders. For noncirrhotic Metabolic disorders, auxiliary transplantation has similar patient and graft survival compared with orthotopic transplantation, but further research is recommended.
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hepatocyte transplantation for Metabolic Liver Disease uk experience
Journal of the Royal Society of Medicine, 2005Co-Authors: R. D. Hughes, Ragai R Mitry, Anil DhawanAbstract:For end-stage Liver Disease and Liver-based Metabolic conditions the accepted treatment is Liver transplantation. With developments in surgical techniques and immunosuppressive drug therapy the survival of patients and grafts is now good. In the conventional procedure the patient's whole Liver is replaced with a Liver obtained from a braindead or living donor. When the donor Liver is too big it can be reduced to a compatible size; and, recently, split-Liver procedures have been performed whereby the right lobe is transplanted into an adult and the smaller left lobe into a child,1 thus increasing the effective donor pool. Another important advance in surgical technique is the use of auxiliary Liver transplantation for patients with acute Liver failure and certain Liver-based Metabolic defects such as Crigler–Najjar syndrome type I, urea cycle defects, and familial hypercholesterolaemia. In this procedure, part of the patient's Liver, often the left lobe, is replaced with part of a donor Liver. In a patient with acute Liver failure this leaves open the possibility of regeneration of the native Liver, in which case immunosuppression can be stopped and the graft allowed to atrophy; and in a patient with a Metabolic disorder the native Liver will be available for future gene therapy. The results of auxiliary Liver transplantation in man2 have supported observations in animals that small amounts of Liver tissue can provide sufficient function to correct an underlying Metabolic defect. This finding was a spur to work on hepatocyte transplantation for such disorders. The aim is to repopulate the Liver with donor hepatocytes, injected either directly into the Liver or into the spleen, from which they migrate to the Liver. If the technique proves successful, hepatocyte transplantation offers several potential advantages. In terms of supply, there is the possibility of using cells from Livers that are unsuitable for conventional transplantation because of steatosis or trauma. The patient does not have to undergo major surgery; moreover, in Metabolic conditions the native Liver provides a safety net in case of failure. One of the most important advantages is the availability of the Liver as a target organ for gene therapy when this becomes a clinical reality. Experience of hepatocyte transplantation has been gained in patients with acute Liver failure3,4 and Metabolic Liver Diseases such as Crigler–Najjar syndrome type I,5 glycogen storage Disease type 1a,6 and urea cycle defects.7 The background to this work has been described elsewhere.8–11 The current paper discusses the sources of hepatocytes, the isolation process, preclinical studies and clinical experience in the UK, especially in the treatment of Liver-based inborn errors of metabolism.
George V. Mazariegos - One of the best experts on this subject based on the ideXlab platform.
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Evolving Trends in Liver Transplant for Metabolic Liver Disease in the United States
Liver Transplantation, 2019Co-Authors: Pat Mckiernan, James E. Squires, Robert H Squires, George V. Mazariegos, Armando Ganoza, Jerry Vockley, Kyle Soltys, Rakesh SindhiAbstract:: Indications for Liver transplantation (LT) in Metabolic Disease are evolving. We reviewed the US experience with primary LT for Metabolic Disease in the Scientific Registry for Transplant Recipients (October 1987 to June 2017) to determine the following: temporal changes in indications, longterm outcomes, and factors predicting survival. Patients were grouped by the presence of structural Liver Disease (SLD) and whether the defect was confined to the Liver. There were 5996 patients who underwent LT for Metabolic Disease, 2354 (39.3%) being children. LT for Metabolic Disease increased in children but not in adults. Children experienced a 6-fold increase in LT for Metabolic Disease without SLD. Indications for LT remained stable in adults. Living donor Liver transplantation increased between era 1 and era 3 from 5.6% to 7.6% in children and 0% to 4.5% in adults. Patient and graft survival improved with time. The latest 5-year patient survival rates were 94.5% and 81.5% in children and adults, respectively. Outcomes were worse in adults and in those with extrahepatic Disease (P
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Liver transplantation for pediatric Metabolic Disease
Molecular Genetics and Metabolism, 2014Co-Authors: George V. Mazariegos, Benjamin L Shneider, Barbara K Burton, Nedim Hadzic, Priya S Kishnani, Holmes D Morton, Sara Mcintire, Ronald J Sokol, Marshall L SummarAbstract:Abstract Liver transplantation (LTx) was initially developed as a therapy for Liver Diseases known to be associated with a high risk of near-term mortality but is based upon a different set of paradigms for inborn Metabolic Diseases. As overall outcomes for the procedure have improved, LTx has evolved into an attractive approach for a growing number of Metabolic Diseases in a variety of clinical situations. No longer simply life-saving, the procedure can lead to a better quality of life even if not all symptoms of the primary disorder are eliminated. Juggling the risk-benefit ratio thus has become more complicated as the list of potential disorders amenable to treatment with LTx has increased. This review summarizes presentations from a recent conference on Metabolic Liver transplantation held at the Children's Hospital of Pittsburgh of UPMC on the role of Liver or hepatocyte transplantation in the treatment of Metabolic Liver Disease.
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Model for end-stage Liver Disease (MELD) exception for unusual Metabolic Liver Diseases.
Liver Transplantation, 2006Co-Authors: Sue V. Mcdiarmid, Simon Horslen, Robert G. Gish, George V. MazariegosAbstract:Metabolic Liver Disease is the underlying diagnosis in only a small proportion of patients who undergo Liver transplantation (LT), but for these patients, LT is lifesaving. Patients with Metabolic Liver Disease often do not present with typical findings of end-stage Liver Disease and require special consideration and scrutiny concerning the appropriateness and timing of LT. Liverbased Metabolic Disease is classified into 3 types: (1) Disease that causes structural Liver damage with Liver failure or cirrhosis, (2) Metabolic Disease without structural Liver damage that affects other organs (especially the central nervous system), and (3) Metabolic Disease with systemic deficiencies that are partially represented in the Liver. There may be overlap in presentation, with some Disease forms presenting either with or without structural Liver Disease. General considerations that affect review board decisions may include the relative contraindication of the use of living-related donor organs and the unpredictable Metabolic course that may cause severe central nervous system complications in several of these Disease states. Also, although many of these Diseases present mostly in children, adolescents and adults previously managed medically are increasingly presenting for LT consideration when medical management becomes more difficult or complex as they mature.
Clara T Nicolas - One of the best experts on this subject based on the ideXlab platform.
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ex vivo hepatocyte reprograming promotes homology directed dna repair to correct Metabolic Disease in mice after transplantation
Hepatology Communications, 2019Co-Authors: Caitlin J Vanlith, Kari L Allen, Rebekah M Guthman, Clara T Nicolas, Robert A Kaiser, Jennifer Chilton, Zachariah P Tritz, Scott L Nyberg, Joseph B LillegardAbstract:Ex vivo CRISPR/Cas9‐mediated gene editing in hepatocytes using homology‐directed repair (HDR) is a potential alternative curative therapy to organ transplantation for Metabolic Liver Disease. However, a major limitation of this approach in quiescent adult primary hepatocytes is that nonhomologous end‐joining is the predominant DNA repair pathway for double‐strand breaks (DSBs). This study explored the hypothesis that ex vivo hepatocyte culture could reprogram hepatocytes to favor HDR after CRISPR/Cas9‐mediated DNA DSBs. Quantitative PCR (qPCR), RNA sequencing, and flow cytometry demonstrated that within 24 hours, primary mouse hepatocytes in ex vivo monolayer culture decreased Metabolic functions and increased expression of genes related to mitosis progression and HDR. Despite the down‐regulation of hepatocyte function genes, hepatocytes cultured for up to 72 hours could robustly engraft in vivo. To assess functionality long‐term, primary hepatocytes from a mouse model of hereditary tyrosinemia type 1 bearing a single‐point mutation were transduced ex vivo with two adeno‐associated viral vectors to deLiver the Cas9 nuclease, target guide RNAs, and a 1.2‐kb homology template. Adeno‐associated viral Cas9 induced robust cutting at the target locus, and, after deLivery of the repair template, precise correction of the point mutation occurred by HDR. Edited hepatocytes were transplanted into recipient fumarylacetoacetate hydrolase knockout mice, resulting in engraftment, robust proliferation, and prevention of Liver failure. Weight gain and biochemical assessment revealed normalization of Metabolic function. Conclusion: The results of this study demonstrate the potential therapeutic effect of ex vivo hepatocyte‐directed gene editing after reprogramming to cure Metabolic Disease in a preclinical model of hereditary tyrosinemia type 1.
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hepatocyte spheroids as an alternative to single cells for transplantation after ex vivo gene therapy in mice and pig models
Surgery, 2018Co-Authors: Raymond D Hickey, Kari L Allen, Zeji Du, Rebekah M Guthman, Bruce Amiot, Clara T Nicolas, Robert A Kaiser, Aditya BansalAbstract:Abstract Background Autologous hepatocyte transplantation after ex vivo gene therapy is an alternative to Liver transplantation for Metabolic Liver Disease. Here we evaluate ex vivo gene therapy followed by transplantation of single-cell or spheroid hepatocytes. Methods Pig and mouse hepatocytes were isolated, labeled with zirconium-89 and returned to the Liver as single cells or spheroids. Biodistribution was evaluated through positron emission tomography–computed tomography. Fumarylacetoacetate hydrolase–deficient pig hepatocytes were isolated and transduced with a lentiviral vector containing the Fah gene. Animals received portal vein infusion of single-cell or spheroid autologous hepatocytes after ex vivo gene deLivery. Portal pressures were measured and ultrasound was used to evaluate for thrombus. Differences in engraftment and expansion of ex vivo corrected single-cell or spheroid hepatocytes were followed through histologic analysis and animals’ ability to thrive off 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione. Results Positron emission tomography–computed tomography imaging showed spheroid hepatocytes with increased heterogeneity in biodistribution as compared with single cells, which spread more uniformly throughout the Liver. Animals receiving spheroids experienced higher mean changes in portal pressure than animals receiving single cells (P Conclusion Ex vivo gene correction of autologous hepatocytes in fumarylacetoacetate hydrolase–deficient pigs can be performed using hepatocyte spheroids or single-cell hepatocytes, with spheroids showing a more heterogeneous distribution within the Liver and higher risks for portal vein thrombosis and increased portal pressures.
R. D. Hughes - One of the best experts on this subject based on the ideXlab platform.
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improving the techniques for human hepatocyte transplantation report from a consensus meeting in london
Cell Transplantation, 2012Co-Authors: Juliana Puppi, Ewa Ellis, R. D. Hughes, Stephen C Strom, Sanjay Bansal, Bo Goran Ericzon, Jose V Castell, Ibrahim Dagher, Greg Nowak, Jose M GomezlechonAbstract:On September 6 and 7, 2009 a meeting was held in London to identify and discuss what are perceived to be current roadblocks to effective hepatocyte transplantation as it is currently practiced in the clinics and, where possible, to offer suggestions to overcome the blocks and improve the outcomes for this cellular therapy. Present were representatives of most of the active clinical hepatocyte transplant programs along with other scientists who have contributed substantial basic research to this field. Over the 2-day sessions based on the experience of the participants, numerous roadblocks or challenges were identified, including the source of cells for the transplants and problems with tracking cells following transplantation. Much of the discussion was focused on methods to improve engraftment and proliferation of donor cells posttransplantation. The group concluded that, for now, parenchymal hepatocytes isolated from donor Livers remain the best cell source for transplantation. It was reported that investigations with other cell sources, including stem cells, were at the preclinical and early clinical stages. Numerous methods to modulate the immune reaction and vascular changes that accompany hepatocyte transplantation were proposed. It was agreed that, to obtain sufficient levels of repopulation of Liver with donor cells in patients with Metabolic Liver Disease, some form of Liver preconditioning would likely be required to enhance the engraftment and/or proliferation of donor cells. It was reported that clinical protocols for preconditioning by hepatic irradiation, portal vein embolization, and surgical resection had been developed and that clinical studies using these protocols would be initiated in the near future. Participants concluded that sharing information between the groups, including standard information concerning the quality and function of the transplanted cells prior to transplantation, clinical information on outcomes, and standard preconditioning protocols, would help move the field forward and was encouraged.
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hepatocyte transplantation for Metabolic Liver Disease uk experience
Journal of the Royal Society of Medicine, 2005Co-Authors: R. D. Hughes, Ragai R Mitry, Anil DhawanAbstract:For end-stage Liver Disease and Liver-based Metabolic conditions the accepted treatment is Liver transplantation. With developments in surgical techniques and immunosuppressive drug therapy the survival of patients and grafts is now good. In the conventional procedure the patient's whole Liver is replaced with a Liver obtained from a braindead or living donor. When the donor Liver is too big it can be reduced to a compatible size; and, recently, split-Liver procedures have been performed whereby the right lobe is transplanted into an adult and the smaller left lobe into a child,1 thus increasing the effective donor pool. Another important advance in surgical technique is the use of auxiliary Liver transplantation for patients with acute Liver failure and certain Liver-based Metabolic defects such as Crigler–Najjar syndrome type I, urea cycle defects, and familial hypercholesterolaemia. In this procedure, part of the patient's Liver, often the left lobe, is replaced with part of a donor Liver. In a patient with acute Liver failure this leaves open the possibility of regeneration of the native Liver, in which case immunosuppression can be stopped and the graft allowed to atrophy; and in a patient with a Metabolic disorder the native Liver will be available for future gene therapy. The results of auxiliary Liver transplantation in man2 have supported observations in animals that small amounts of Liver tissue can provide sufficient function to correct an underlying Metabolic defect. This finding was a spur to work on hepatocyte transplantation for such disorders. The aim is to repopulate the Liver with donor hepatocytes, injected either directly into the Liver or into the spleen, from which they migrate to the Liver. If the technique proves successful, hepatocyte transplantation offers several potential advantages. In terms of supply, there is the possibility of using cells from Livers that are unsuitable for conventional transplantation because of steatosis or trauma. The patient does not have to undergo major surgery; moreover, in Metabolic conditions the native Liver provides a safety net in case of failure. One of the most important advantages is the availability of the Liver as a target organ for gene therapy when this becomes a clinical reality. Experience of hepatocyte transplantation has been gained in patients with acute Liver failure3,4 and Metabolic Liver Diseases such as Crigler–Najjar syndrome type I,5 glycogen storage Disease type 1a,6 and urea cycle defects.7 The background to this work has been described elsewhere.8–11 The current paper discusses the sources of hepatocytes, the isolation process, preclinical studies and clinical experience in the UK, especially in the treatment of Liver-based inborn errors of metabolism.