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Li Y, Wu YT, Wu H. Management of hepatic encephalopathy following transjugular intrahepatic portosystemic shunts: Current strategies and future directions. World J Gastroenterol 2025; 31:103512. [PMID: 40309228 PMCID: PMC12038546 DOI: 10.3748/wjg.v31.i15.103512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 03/04/2025] [Accepted: 04/02/2025] [Indexed: 04/18/2025] Open
Abstract
Transjugular intrahepatic portosystemic shunts (TIPSs) are generally used for the management of complications of portal hypertension in patients with decompensated cirrhosis. However, hepatic encephalopathy (HE), which impairs neuropsychiatric function and motor control, remains the primary adverse effect of TIPS, limiting its utility. Prompt prevention and treatment of post-TIPS HE are critical, as they are strongly associated with readmission rates and poor quality of life. This review focuses on the main pathophysiological mechanisms underlying post-TIPS HE, explores advanced biomarkers and predictive tools, and discusses current management strategies and future directions to prevent or reverse HE following TIPS. These strategies include preoperative patient assessment, individualized shunt diameter optimization, spontaneous portosystemic shunt embolization during the TIPS procedure, postoperative preventive and therapeutic measures such as nutrition management, medical therapy, fecal microbiota transplantation, and stent reduction.
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Affiliation(s)
- Ying Li
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Yu-Tong Wu
- Chongqing Medical University-University of Leicester Joint Institute, Chongqing Medical University, Chongqing 400016, China
| | - Hao Wu
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
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Gallego JJ, Ballester MP, Fiorillo A, Casanova-Ferrer F, López-Gramaje A, Urios A, Arenas YM, Ríos MP, Durbán L, Megías J, San-Miguel T, Benlloch S, Lluch P, Jalan R, Montoliu C. Ammonia and beyond - biomarkers of hepatic encephalopathy. Metab Brain Dis 2025; 40:100. [PMID: 39812958 PMCID: PMC11735499 DOI: 10.1007/s11011-024-01512-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Accepted: 12/17/2024] [Indexed: 01/16/2025]
Abstract
Ammonia is a product of amino acid metabolism that accumulates in the blood of patients with liver cirrhosis, leading to neurotoxic effects and hepatic encephalopathy (HE). HE manifestations can range from mild, subclinical disturbances in cognition, or minimal HE (mHE) to gross disorientation and coma, a condition referred to as overt HE. Many blood-based biomarkers reflecting these neurotoxic effects of ammonia and liver disease can be measured in the blood allowing the development of new biomarkers to diagnose cirrhosis patients at risk of developing HE. The effect of ammonia on the brain is modulated by severity of systemic inflammation, and both hyperammonemia and inflammation can induce oxidative stress, which may mediate the neurological alterations associated to HE. This review aims to provide the latest evidence on biomarkers of HE beyond ammonia. We present different approaches to predict overt HE based on the combination of blood ammonia with some analytical and clinical parameters. Magnetic resonance analysis of brain images could also provide sensitive diagnostic biomarkers based on neuroimaging parameters. Some reports suggest that markers of systemic inflammation, oxidative stress, and central nervous system-derived components, may serve as additional biomarkers of HE. The involvement of extracellular vesicles and microbiota in the pathophysiology of mHE and HE has recently acquired importance and it would be interesting to explore their usefulness as early biomarkers of the disease. It is important to have a biomarker or a combination of them for early diagnosis of mHE to improve its treatment and prevent progression to overt HE.
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Affiliation(s)
- Juan-José Gallego
- Fundación de Investigación Hospital Clínico Universitario de Valencia-INCLIVA, Valencia, 46010, Spain
- Departamento de Patología, Universidad de Valencia, Valencia, 46010, Spain
| | - María-Pilar Ballester
- Fundación de Investigación Hospital Clínico Universitario de Valencia-INCLIVA, Valencia, 46010, Spain
- Servicio de Medicina Digestiva, Hospital Clínico Universitario de Valencia, Valencia, 46010, Spain
| | - Alessandra Fiorillo
- Fundación de Investigación Hospital Clínico Universitario de Valencia-INCLIVA, Valencia, 46010, Spain
| | - Franc Casanova-Ferrer
- Fundación de Investigación Hospital Clínico Universitario de Valencia-INCLIVA, Valencia, 46010, Spain
| | | | - Amparo Urios
- Fundación de Investigación Hospital Clínico Universitario de Valencia-INCLIVA, Valencia, 46010, Spain
| | - Yaiza María Arenas
- Departamento de Patología, Universidad de Valencia, Valencia, 46010, Spain
| | - María-Pilar Ríos
- Servicio de Medicina Digestiva, Hospital Arnau de Vilanova, 46015, Valencia, Spain
| | - Lucía Durbán
- Servicio de Medicina Digestiva, Hospital Arnau de Vilanova, 46015, Valencia, Spain
| | - Javier Megías
- Departamento de Patología, Universidad de Valencia, Valencia, 46010, Spain
| | - Teresa San-Miguel
- Departamento de Patología, Universidad de Valencia, Valencia, 46010, Spain
| | - Salvador Benlloch
- Servicio de Medicina Digestiva, Hospital Arnau de Vilanova, 46015, Valencia, Spain
- CIBERehd. Instituto de Salud Carlos III, Madrid, 28029, Spain
- Universidad Cardenal Herrera-CEU Universities, Valencia, 46115, Spain
| | - Paloma Lluch
- Servicio de Medicina Digestiva, Hospital Clínico Universitario de Valencia, Valencia, 46010, Spain
| | - Rajiv Jalan
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK.
- European Foundation for the Study of Chronic Liver Failure (EF Clif), Barcelona, 08021, Spain.
| | - Carmina Montoliu
- Fundación de Investigación Hospital Clínico Universitario de Valencia-INCLIVA, Valencia, 46010, Spain.
- Departamento de Patología, Universidad de Valencia, Valencia, 46010, Spain.
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Vidal-Cevallos P, Chávez-Tapia NC, Uribe M. Current approaches to hepatic encephalopathy. Ann Hepatol 2022; 27:100757. [PMID: 36115576 DOI: 10.1016/j.aohep.2022.100757] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 09/07/2022] [Indexed: 02/04/2023]
Abstract
Hepatic encephalopathy (HE) is a brain dysfunction caused by liver insufficiency and/or portosystemic shunts. Between 30%-40% of patients with cirrhosis will present overt HE during their lifetime. While the pathophysiology of HE is not entirely understood, three critical factors have been identified: hyperammonaemia, systemic inflammation and oxidative stress by glutaminase gene alterations. Minimal HE is defined by the presence of signs of cognitive abnormalities in a patient without asterixis or disorientation; it can only be diagnosed with neuropsychological or psychometric tests. The diagnosis of overt HE is based on clinical examination with clinical scales. Currently, only overt HE should be routinely treated. The aims of treatment in an acute episode should be to improve the mental status, identify and treat the precipitating factor, reduce duration and limit consequences. Treatment strategies are targeted at reducing ammonia production and/or increasing its elimination. Even though minimal HE has negative effects on the patient's quality of life and effects on prognosis, indications for treatment are still controversial. There are still many unanswered questions regarding the pathophysiology and management of HE. We should also endeavor to develop more accurate and objective diagnostic methods for overt HE that would permit early detection and help improve outcomes on quality of life and economic burden.
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Affiliation(s)
- Paulina Vidal-Cevallos
- Obesity and Digestive Disease Unit, Medica Sur Clinic and Foundation, Puente de Piedra 150, col. Toriello Guerra, C.P. 14050, Mexico City, Mexico
| | - Norberto C Chávez-Tapia
- Obesity and Digestive Disease Unit, Medica Sur Clinic and Foundation, Puente de Piedra 150, col. Toriello Guerra, C.P. 14050, Mexico City, Mexico
| | - Misael Uribe
- Obesity and Digestive Disease Unit, Medica Sur Clinic and Foundation, Puente de Piedra 150, col. Toriello Guerra, C.P. 14050, Mexico City, Mexico.
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Kroupina K, Bémeur C, Rose CF. Amino acids, ammonia, and hepatic encephalopathy. Anal Biochem 2022; 649:114696. [PMID: 35500655 DOI: 10.1016/j.ab.2022.114696] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 03/30/2022] [Accepted: 04/21/2022] [Indexed: 11/30/2022]
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Development and Validation of a Clinical-Genetic Risk Score to Predict Hepatic Encephalopathy in Patients With Liver Cirrhosis. Am J Gastroenterol 2021; 116:1238-1247. [PMID: 33852451 DOI: 10.14309/ajg.0000000000001164] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 12/30/2020] [Indexed: 12/11/2022]
Abstract
INTRODUCTION We aimed to define the impact of the genetic background on overt hepatic encephalopathy (HE) in patients with liver cirrhosis by developing a combined clinical-genetic risk score. METHODS Patients suffering from liver cirrhosis from the outpatient clinics of 4 hospitals (n = 600) were included and followed up for at least 5 years until HE bouts, liver transplant, or death. Patients were genotyped for 60 candidate single nucleotide polymorphisms together with the microsatellite in the promoter region of the gene GLS. RESULTS Single nucleotide polymorphisms rs601338 (FUT2), rs5743836 (TRL9), rs2562582 (SLC1A3), rs313853 (SLC1A5), and GLS microsatellite did predict independently the incidence and severity of overt HE and were included as genetic score. Competing risk analysis revealed that bilirubin (subhazard ratio [sHR] 1.30 [1.15-1.48], P < 0.001), albumin (sHR 0.90 [0.86-0.93], P < 0.001), genetic score (sHR 1.90 [1.57-2.30], P < 0.001), and previous episodes of overt HE (sHR 2.60 [1.57-4.29], P < 0.001) were independently associated to HE bouts during the follow-up with an internal (C-index 0.83) and external validation (C-index 0.74). Patients in the low-risk group had 5% and 12% risk of HE at 1 (log-rank 92.1; P < 0.001) and 5 (log-rank 124.1; P < 0.001) years, respectively, whereas 36% and 48% in the high-risk group. DISCUSSION The genetic background influenced overt HE risk and severity. The clinical-genetic HE Risk score, which combined genetic background together with albumin, bilirubin, and previous episodes of overt HE, could be a useful tool to predict overt HE in patients with cirrhosis.
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Ampuero J, Gil A, Viloria MDM, Rico MC, Millán R, Camacho I, Romero-Gómez M. Oral glutamine challenge is a marker of altered ammonia metabolism and predicts the risk of hepatic encephalopathy. Liver Int 2020; 40:921-930. [PMID: 31729816 DOI: 10.1111/liv.14297] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 10/22/2019] [Accepted: 10/25/2019] [Indexed: 02/13/2023]
Abstract
BACKGROUND The current therapies for hepatic encephalopathy (HE) are not completely effective in all patients, probably due to the physiopathological heterogeneity and the different conditions underlying the bout of HE. We hypothesized that oral glutamine challenge (OGC) is able to predict the risk of HE through the identification of various features and types of HE. METHODS We included 238 cirrhotic patients (198 without and 40 with a previous HE episode) that underwent OGC, obtaining baseline and 60 minutes post-load ammonia levels. Combined evaluation of baseline hyperammonemia (>78 mcg/dL) and impaired OGC (Δ >32 mcg/dL) defined low-, intermediate- and high-risk groups. Patients were censored at HE, liver transplantation and death or 6 years of follow-up. RESULTS The 28.3% (56/198) of the main cohort suffered from HE during the follow-up. In the competing risk analysis, both intermediate- (subhazard ratio (sHR) 2.01 (95% CI 1.00-4.14); P = .048) and high-risk groups (sHR 4.67 (95% CI 2.19-9.98); P = .0001) were associated with the first HE episode, together with age and albumin. Similar results were found for repeated HE events. The cumulative incidence for HE of the high-risk group was two and four times greater than the intermediate- and low-risk groups, respectively. The HE grade was also higher in individuals with the greatest risk (P = .035). The most common precipitant factor was diuretics in the high-risk group, while infections and electrolyte imbalance predominated in the rest of patients. CONCLUSION Oral glutamine challenge identified patients at risk of HE and defined specific features of the episodes. This tool could be useful in the decision-making process for the adequate management of HE.
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Affiliation(s)
- Javier Ampuero
- Hospital Universitario Virgen del Rocío, Sevilla, Spain.,Instituto de Biomedicina de Sevilla, Sevilla, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain.,Universidad de Sevilla, Sevilla, Spain
| | - Antonio Gil
- Instituto de Biomedicina de Sevilla, Sevilla, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
| | | | - María Carmen Rico
- Instituto de Biomedicina de Sevilla, Sevilla, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
| | - Raquel Millán
- Instituto de Biomedicina de Sevilla, Sevilla, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
| | - Inés Camacho
- Hospital Universitario Virgen de Valme, Sevilla, Spain
| | - Manuel Romero-Gómez
- Hospital Universitario Virgen del Rocío, Sevilla, Spain.,Instituto de Biomedicina de Sevilla, Sevilla, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain.,Universidad de Sevilla, Sevilla, Spain
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Li Y, Peer J, Zhao R, Xu Y, Wu B, Wang Y, Tian C, Huang Y, Zheng J. Serial deletion reveals structural basis and stability for the core enzyme activity of human glutaminase 1 isoforms: relevance to excitotoxic neurodegeneration. Transl Neurodegener 2017; 6:10. [PMID: 28439409 PMCID: PMC5399437 DOI: 10.1186/s40035-017-0080-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Accepted: 04/06/2017] [Indexed: 12/16/2022] Open
Abstract
Background Glutaminase 1 is a phosphate-activated metabolic enzyme that catalyzes the first step of glutaminolysis, which converts glutamine into glutamate. Glutamate is the major neurotransmitter of excitatory synapses, executing important physiological functions in the central nervous system. There are two isoforms of glutaminase 1, KGA and GAC, both of which are generated through alternative splicing from the same gene. KGA and GAC both transcribe 1–14 exons in the N-terminal, but each has its unique C-terminal in the coding sequence. We have previously identified that KGA and GAC are differentially regulated during inflammatory stimulation and HIV infection. Furthermore, glutaminase 1 has been linked to brain diseases such as amyotrophic lateral sclerosis, Alzheimer’s disease, and hepatic encephalopathy. Core enzyme structure of KGA and GAC has been published recently. However, how other coding sequences affect their functional enzyme activity remains unclear. Methods We cloned and performed serial deletions of human full-length KGA and GAC from the N-terminal and the C-terminal at an interval of approximately 100 amino acids (AAs). Prokaryotic expressions of the mutant glutaminase 1 protein and a glutaminase enzyme activity assay were used to determine if KGA and GAC have similar efficiency and efficacy to convert glutamine into glutamate. Results When 110 AAs or 218 AAs were deleted from the N-terminal or when the unique portions of KGA and GAC that are beyond the 550 AA were deleted from the C-terminal, KGA and GAC retained enzyme activity comparable to the full length proteins. In contrast, deletion of 310 AAs or more from N-terminal or deletion of 450 AAs or more from C-terminal resulted in complete loss of enzyme activity for KGA/GAC. Consistently, when both N- and C-terminal of the KGA and GAC were removed, creating a truncated protein that expressed the central 219 AA - 550 AA, the protein retained enzyme activity. Furthermore, expression of the core 219 AA - 550 AA coding sequence in cells increased extracellular glutamate concentrations to levels comparable to those of full-length KGA and GAC expressions, suggesting that the core enzyme activity of the protein lies within the central 219 AA - 550 AA. Full-length KGA and GAC retained enzyme activities when kept at 4 °C. In contrast, 219 AA - 550 AA truncated protein lost glutaminase activities more readily compared with full-length KGA and GAC, suggesting that the N-terminal and C-terminal coding regions are required for the stability KGA and GAC. Conclusions Glutaminase isoforms KGA and GAC have similar efficacy to catalyze the conversion of glutamine to glutamate. The core enzyme activity of glutaminase 1 protein is within the central 219 AA - 550 AA. The N-terminal and C-terminal coding regions of KGA and GAC help maintain the long-term activities of the enzymes.
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Affiliation(s)
- Yuju Li
- Center for Translational Neurodegeneration and Regenerative Therapy, Shanghai Tenth People's Hospital affiliated to Tongji University School of Medicine, Shanghai, China.,Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE USA
| | - Justin Peer
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE USA
| | - Runze Zhao
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE USA
| | - Yinghua Xu
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE USA
| | - Beiqing Wu
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE USA
| | - Yi Wang
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE USA
| | - Changhai Tian
- Center for Translational Neurodegeneration and Regenerative Therapy, Shanghai Tenth People's Hospital affiliated to Tongji University School of Medicine, Shanghai, China.,Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE USA
| | - Yunlong Huang
- Center for Translational Neurodegeneration and Regenerative Therapy, Shanghai Tenth People's Hospital affiliated to Tongji University School of Medicine, Shanghai, China.,Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE USA.,Shanghai Tenth People's Hospital affiliated with Tongji University School of Medicine, Shanghai, 200072 China.,Laboratory of Neuroimmunology and Regenerative Therapy, Departments of Pharmacology and Experimental Neuroscience and Pathology and Microbiology, 985930 Nebraska Medical Center, Omaha, NE 68198-5930 USA
| | - Jialin Zheng
- Center for Translational Neurodegeneration and Regenerative Therapy, Shanghai Tenth People's Hospital affiliated to Tongji University School of Medicine, Shanghai, China.,Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE USA.,Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE USA.,Shanghai Tenth People's Hospital affiliated with Tongji University School of Medicine, Shanghai, 200072 China.,Laboratory of Neuroimmunology and Regenerative Therapy, Departments of Pharmacology and Experimental Neuroscience and Pathology and Microbiology, 985930 Nebraska Medical Center, Omaha, NE 68198-5930 USA
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Ahn JM, Kim CH, Um SH, Kim KM, Kim TH, Yim SY, Choi HS, Kim ES, Keum B, Seo YS, Yim HJ, Jeen YT, Lee HS, Chun HJ, Kim CD, Ryu HS. Validation study associating glutaminase promoter variations with hepatic encephalopathy in East Asian populations. J Gastroenterol Hepatol 2017; 32:901-907. [PMID: 27749985 DOI: 10.1111/jgh.13618] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/11/2016] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIM In a recent study, microsatellite variations (GCA tandem repeats) in the promoter region of the (kidney-type) glutaminase gene were associated with the development of hepatic encephalopathy (HE) in Spanish patients with cirrhosis. The objective of this study was to validate the relation between microsatellite variations in the glutaminase promoter region and the development of overt HE in Korean patients with liver cirrhosis. METHODS We performed a prospective cohort study of 154 cirrhotic patients who underwent a glutaminase microsatellite study without previous overt HE history at baseline. The primary end point was the first episode of overt HE. The microsatellite length was categorized into three groups based on its repeated number, with a cutoff value of 14; 65 (42.2%), 70 (45.5%), and 19 (12.3%) patients had the short-short, short-long, and long-long alleles, respectively. RESULTS Over a median 3.5 years of follow-up (range = 0.1-4.4), overt HE developed in 28 patients (18.2%). The 3-year cumulative incidence of overt HE was 18.4%. Multivariate Cox model indicated that past hepatocellular carcinoma history, alcoholic etiology for cirrhosis, higher Model for End-Stage Liver Disease scores and their deterioration, and serum ammonium levels were independently associated with HE development. However, microsatellite length was not associated with the development of overt HE. CONCLUSIONS In Korean patients with cirrhosis, microsatellite variations in the glutaminase promoter region were not associated with development of overt HE. Thus, additional studies are needed to identify other genetic factors related to glutaminase activity in Asians with overt HE.
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Affiliation(s)
- Jem Ma Ahn
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Chang Ha Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Soon Ho Um
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Kyung Mee Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Tae Hyung Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Sun Young Yim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Hyuk Soon Choi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Eun Sun Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Bora Keum
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Yeon Seok Seo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Hyung Joon Yim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Yoon Tae Jeen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Hong Sik Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Hoon Jai Chun
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Chang Duck Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Ho Sang Ryu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
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