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Kurihara T, Itoh S, Toshima T, Toshida K, Tomiyama T, Kosai Y, Tomino T, Yoshiya S, Nagao Y, Morita K, Ninomiya M, Harada N, Yoshizumi T. Prediction of portal venous pressure in living donor liver transplantation: A retrospective study. Liver Transpl 2025; 31:428-437. [PMID: 38995149 DOI: 10.1097/lvt.0000000000000433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Accepted: 06/08/2024] [Indexed: 07/13/2024]
Abstract
Liver transplantation is the definitive treatment for advanced liver cirrhosis with portal hypertension. In Japan, the scarcity of deceased donors leads to reliance on living donors, often resulting in smaller grafts. Managing portal venous pressure (PVP) is critical to prevent fatal posttransplant complications. This study explored the possibility of predicting intraoperative PVP. We analyzed 475 living donor liver transplant cases from 2006 to 2023, excluding those with acute liver failure or prior splenectomy or splenic artery embolization. Patients were divided into a training group (n = 425) and a test group (n = 50). We evaluated the correlation between preoperative factors and PVP at laparotomy to predict PVP at laparotomy and closure. The predictive model was validated with the test group data. PVP at laparotomy could be predicted using correlated preoperative factors: prothrombin time ( p < 0.001), predicted splenic volume ( p < 0.001), and presence of a portosystemic shunt ( p = 0.002), as follows: predicted PVP at laparotomy (mm Hg)=25.818 - 0.077 × (prothrombin time [%]) + 0.004 × (predicted splenic volume [mL]) - 2.067 × (1: with a portosystemic shunt) ( p < 0.001; R = 0.346). In addition, PVP at closure could be predicted using correlated operative factors, including measured PVP at laparotomy, as follows: predicted PVP at closure (mm Hg)=14.268 + 0.149 × (measured PVP at laparotomy [mm Hg]) - 0.040 × (GV/SLV [%]) - 0.862 × (1: splenectomy [if yes]) - 3.511 × (1: splenic artery ligation without splenectomy [if yes]) ( p < 0.001; R = 0.339). This study demonstrated the feasibility of predicting intraoperative PVP using preoperative factors in patients with decompensated cirrhosis undergoing liver transplant. This predictive approach could refine surgical planning, potentially improving patient outcomes.
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Affiliation(s)
- Takeshi Kurihara
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Mandorfer M, Abraldes JG, Berzigotti A. Non-invasive assessment of portal hypertension: Liver stiffness and beyond. JHEP Rep 2025; 7:101300. [PMID: 40034396 PMCID: PMC11874574 DOI: 10.1016/j.jhepr.2024.101300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 11/08/2024] [Accepted: 12/05/2024] [Indexed: 03/05/2025] Open
Abstract
Portal hypertension (PH) leads to life-threatening clinical manifestations such as bleeding from gastro-oesophageal varices, ascites and its complications, and portosystemic encephalopathy. It can develop because of advanced chronic liver disease (ACLD) or due to rarer causes such as vascular liver disease. Reference standard methods to assess PH in ACLD include the measurement of hepatic venous pressure gradient and endoscopy, which have limitations due to their high resource utilisation and invasiveness. Non-invasive tests (NITs) have entered clinical practice and allow invasive procedures to be reserved for patients with indeterminate findings on NITs or for specific clinical questions. In this review, we present an update on the role of NITs, and in particular ultrasound elastography, to diagnose PH in ACLD and vascular liver disease, and to stratify the risk of liver-related events. We also provide insights into the open research questions and design of studies in this field.
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Affiliation(s)
- Mattias Mandorfer
- Department of Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Department of Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Juan G. Abraldes
- Division of Gastroenterology (Liver Unit). University of Alberta, Edmonton, Alberta, Canada
| | - Annalisa Berzigotti
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland
- Department for BioMedical Research, Visceral Surgery and Medicine, University of Bern, Switzerland
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Thiele M, Johansen S, Israelsen M, Trebicka J, Abraldes JG, Gines P, Krag A. Noninvasive assessment of hepatic decompensation. Hepatology 2025; 81:1019-1037. [PMID: 37801593 PMCID: PMC11825506 DOI: 10.1097/hep.0000000000000618] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Accepted: 07/19/2023] [Indexed: 10/08/2023]
Abstract
Noninvasive tests (NITs) are used in all aspects of liver disease management. Their most prominent break-through since the millennium has been in advancing early detection of liver fibrosis, but their use is not limited to this. In contrast to the symptom-driven assessment of decompensation in patients with cirrhosis, NITs provide not only opportunities for earlier diagnoses but also accurate prognostication, targeted treatment decisions, and a means of monitoring disease. NITs can inform disease management and decision-making based on validated cutoffs and standardized interpretations as a valuable supplement to clinical acumen. The Baveno VI and VII consensus meetings resulted in tangible improvements to pathways of care for patients with compensated and decompensated advanced chronic liver disease, including the combination of platelet count and transient elastography to diagnose clinically significant portal hypertension. Furthermore, circulating NITs will play increasingly important roles in assessing the response to interventions against ascites, variceal bleeding, HE, acute kidney injury, and infections. However, due to NITs' wide availability, there is a risk of inaccurate use, leading to a waste of resources and flawed decisions. In this review, we describe the uses and pitfalls of NITs for hepatic decompensation, from risk stratification in primary care to treatment decisions in outpatient clinics, as well as for the in-hospital management of patients with acute-on-chronic liver failure. We summarize which NITs to use when, for what indications, and how to maximize the potential of NITs for improved patient management.
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Affiliation(s)
- Maja Thiele
- Department of Gastroenterology and Hepatology, Fibrosis, Fatty Liver and Steatohepatitis Research Center Odense (FLASH), Odense University Hospital, Odense, Denmark
- Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
| | - Stine Johansen
- Department of Gastroenterology and Hepatology, Fibrosis, Fatty Liver and Steatohepatitis Research Center Odense (FLASH), Odense University Hospital, Odense, Denmark
- Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
| | - Mads Israelsen
- Department of Gastroenterology and Hepatology, Fibrosis, Fatty Liver and Steatohepatitis Research Center Odense (FLASH), Odense University Hospital, Odense, Denmark
- Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
| | - Jonel Trebicka
- Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
- Department of Internal Medicine B, University of Münster, Münster, Germany
- European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain
| | - Juan G. Abraldes
- Division of Gastroenterology, University of Alberta, Edmonton, Canada
| | - Pere Gines
- Liver Unit, Hospital Clínic of Barcelona, Barcelona, Spain
- Faculty of Medicine and Health Sciences, University of Barcelona, Spain
- Institute of Biomedical Investigation August Pi I Sunyer (IDIBAPS), Barcelona, Spain
- Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, Spain
| | - Aleksander Krag
- Department of Gastroenterology and Hepatology, Fibrosis, Fatty Liver and Steatohepatitis Research Center Odense (FLASH), Odense University Hospital, Odense, Denmark
- Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
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Gaspar R, Macedo G. Non-Invasive versus Invasive Assessment of Portal Hypertension in Chronic Liver Disease. GE PORTUGUESE JOURNAL OF GASTROENTEROLOGY 2024; 31:377-387. [PMID: 39633911 PMCID: PMC11614439 DOI: 10.1159/000538484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Accepted: 03/05/2024] [Indexed: 12/07/2024]
Abstract
Background Cirrhosis is one of the major causes of morbidity and mortality worldwide and the second leading cause of digestive disease mortality. Portal hypertension is the main driver of cirrhosis-related complications such as ascites and variceal bleeding. Portal hypertension is defined as a hepatic venous pressure gradient >5 mm Hg, although it is clinically significant and associated with clinical complications when >10 mm Hg. Summary Therefore, detection of clinically significant portal hypertension (CSPH) in chronic advanced liver disease or compensated cirrhosis is of paramount importance to guide the management of these patients. Key Messages This study aimed at revising the non-invasive and invasive tools for assessment of portal hypertension and risk stratification for CSPH in patients with chronic liver disease.
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Affiliation(s)
- Rui Gaspar
- Department of Gastroenterology, Centro Hospitalar e Universitário de São João, Porto, Portugal
- Faculty of Medicine of University of Porto, Porto, Portugal
| | - Guilherme Macedo
- Department of Gastroenterology, Centro Hospitalar e Universitário de São João, Porto, Portugal
- Faculty of Medicine of University of Porto, Porto, Portugal
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Burra P, Zanetto A, Schnabl B, Reiberger T, Montano-Loza AJ, Asselta R, Karlsen TH, Tacke F. Hepatic immune regulation and sex disparities. Nat Rev Gastroenterol Hepatol 2024; 21:869-884. [PMID: 39237606 DOI: 10.1038/s41575-024-00974-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/25/2024] [Indexed: 09/07/2024]
Abstract
Chronic liver disease is a major cause of morbidity and mortality worldwide. Epidemiology, clinical phenotype and response to therapies for gastrointestinal and liver diseases are commonly different between women and men due to sex-specific hormonal, genetic and immune-related factors. The hepatic immune system has unique regulatory functions that promote the induction of intrahepatic tolerance, which is key for maintaining liver health and homeostasis. In liver diseases, hepatic immune alterations are increasingly recognized as a main cofactor responsible for the development and progression of chronic liver injury and fibrosis. In this Review, we discuss the basic mechanisms of sex disparity in hepatic immune regulation and how these mechanisms influence and modify the development of autoimmune liver diseases, genetic liver diseases, portal hypertension and inflammation in chronic liver disease. Alterations in gut microbiota and their crosstalk with the hepatic immune system might affect the progression of liver disease in a sex-specific manner, creating potential opportunities for novel diagnostic and therapeutic approaches to be evaluated in clinical trials. Finally, we identify and propose areas for future basic, translational and clinical research that will advance our understanding of sex disparities in hepatic immunity and liver disease.
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Affiliation(s)
- Patrizia Burra
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padua University Hospital, Padua, Italy.
| | - Alberto Zanetto
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
- Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Aldo J Montano-Loza
- Division of Gastroenterology and Liver Unit, Department of Medicine, University of Alberta Hospital, Edmonton, Alberta, Canada
| | - Rosanna Asselta
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Tom Hemming Karlsen
- Department of Transplantation Medicine, Clinic of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital and University of Oslo, Oslo, Norway
- Research Institute of Internal Medicine, Clinic of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital and University of Oslo, Oslo, Norway
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM), Berlin, Germany
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Cavazza A, Triantafyllou E, Savoldelli R, Mujib S, Jerome E, Trovato FM, Artru F, Sheth R, Huang XH, Ma Y, Dazzi F, Pirani T, Antoniades CG, Lee WM, McPhail MJ, Karvellas CJ. Macrophage activation markers are associated with infection and mortality in patients with acute liver failure. Liver Int 2024; 44:1900-1911. [PMID: 38588014 PMCID: PMC11466005 DOI: 10.1111/liv.15928] [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: 11/03/2023] [Revised: 03/18/2024] [Accepted: 03/21/2024] [Indexed: 04/10/2024]
Abstract
BACKGROUND AND AIMS Acute liver failure is a multisystem disorder with a high mortality and frequent need for emergency liver transplantation. Following massive innate immune system activation, soluble markers of macrophage activation are released during liver damage and their association with disease severity and prognosis requires exploration. METHODS Patients ALF from the United States Acute Liver Failure Study Group (USALFSG, n = 224) and King's College Hospital (n = 40) together with healthy controls (HC, n = 50) were recruited. Serum from early (Days 1-3) and late (>Day 3) time points were analysed for MAMs by enzyme-linked immunosorbent assay correlated to markers of illness severity and 21-day spontaneous survival. Surface expression phenotyping was performed via Flow Cytometry on CD14+ monocytes. RESULTS All MAMs serum concentrations were significantly higher in ALF compared to controls (p < .0001). sCD206 concentration was higher in early and late stages of the disease in patients with bacteraemia (p = .002) and infection in general (p = .006). In MELD-adjusted multivariate modelling, sCD206 and sCD163 were independently associated with mortality. CD14+ monocyte expression of CD206 (p < .001) was higher in patients with ALF compared with controls and correlated with SOFA score (p = .018). sCD206 was independently validated as a predictor of infection in an external cohort. CONCLUSIONS sCD206 is increased in serum of ALF patients with infections and poor outcome and is upregulated on CD14+ monocytes. Later measurements of sCD163 and sCD206 during the evolution of ALF have potential as mechanistic predictors of mortality. sCD206 should be explored as a biomarker of sepsis and mortality in ALF.
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Affiliation(s)
- Anna Cavazza
- Department of Inflammation Biology, School of Inflammation and Microbial Science, Institute of Liver StudiesKing's College LondonLondonUK
- Liver Intensive Therapy UnitInstitute of Liver Studies, King's College HospitalLondonUK
| | - Evangelos Triantafyllou
- Section of Hepatology and Gastroenterology, Department of Metabolism, Digestion and ReproductionImperial College LondonLondonUK
| | - Roberto Savoldelli
- School of Cardiovascular and Metabolic Medicine and ScienceKing's College LondonLondonUK
| | - Salma Mujib
- Department of Inflammation Biology, School of Inflammation and Microbial Science, Institute of Liver StudiesKing's College LondonLondonUK
- Liver Intensive Therapy UnitInstitute of Liver Studies, King's College HospitalLondonUK
| | - Ellen Jerome
- Department of Inflammation Biology, School of Inflammation and Microbial Science, Institute of Liver StudiesKing's College LondonLondonUK
- Liver Intensive Therapy UnitInstitute of Liver Studies, King's College HospitalLondonUK
| | - Francesca M. Trovato
- Department of Inflammation Biology, School of Inflammation and Microbial Science, Institute of Liver StudiesKing's College LondonLondonUK
- Liver Intensive Therapy UnitInstitute of Liver Studies, King's College HospitalLondonUK
| | - Florent Artru
- Department of Inflammation Biology, School of Inflammation and Microbial Science, Institute of Liver StudiesKing's College LondonLondonUK
- Liver Intensive Therapy UnitInstitute of Liver Studies, King's College HospitalLondonUK
| | - Roosey Sheth
- Department of Inflammation Biology, School of Inflammation and Microbial Science, Institute of Liver StudiesKing's College LondonLondonUK
- Liver Intensive Therapy UnitInstitute of Liver Studies, King's College HospitalLondonUK
| | - Xiao Hong Huang
- Department of Inflammation Biology, School of Inflammation and Microbial Science, Institute of Liver StudiesKing's College LondonLondonUK
| | - Yun Ma
- Department of Inflammation Biology, School of Inflammation and Microbial Science, Institute of Liver StudiesKing's College LondonLondonUK
| | - Francesco Dazzi
- School of Cardiovascular and Metabolic Medicine and ScienceKing's College LondonLondonUK
| | - Tasneem Pirani
- Department of Inflammation Biology, School of Inflammation and Microbial Science, Institute of Liver StudiesKing's College LondonLondonUK
- Liver Intensive Therapy UnitInstitute of Liver Studies, King's College HospitalLondonUK
| | - Charalambos G. Antoniades
- Department of Inflammation Biology, School of Inflammation and Microbial Science, Institute of Liver StudiesKing's College LondonLondonUK
- Liver Intensive Therapy UnitInstitute of Liver Studies, King's College HospitalLondonUK
| | - William M. Lee
- Division of Digestive and Liver DiseasesUT Southwestern Medical CenterDallasTexasUSA
| | - Mark J. McPhail
- Department of Inflammation Biology, School of Inflammation and Microbial Science, Institute of Liver StudiesKing's College LondonLondonUK
- Liver Intensive Therapy UnitInstitute of Liver Studies, King's College HospitalLondonUK
| | - Constantine J. Karvellas
- Division of Gastroenterology (Liver Unit), Department of Critical Care MedicineUniversity of AlbertaEdmontonCanada
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Ye Y, Xia C, Hu H, Tang S, Huan H. Metabolomics reveals altered metabolites in cirrhotic patients with severe portal hypertension in Tibetan population. Front Med (Lausanne) 2024; 11:1404442. [PMID: 39015788 PMCID: PMC11250582 DOI: 10.3389/fmed.2024.1404442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Accepted: 06/17/2024] [Indexed: 07/18/2024] Open
Abstract
Background Portal hypertension (PHT) presents a challenging issue of liver cirrhosis. This study aims to identify novel biomarkers for severe PHT (SPHT) and explore the pathophysiological mechanisms underlying PHT progression. Methods Twenty-three Tibetan cirrhotic patients who underwent hepatic venous pressure gradient (HVPG) measurement were included. Eleven patients had an HVPG between 5 mmHg and 15 mmHg (MPHT), while 12 had an HVPG ≥16 mmHg (SPHT). Peripheral sera were analyzed using liquid chromatograph-mass spectrometer for metabolomic assessment. An additional 14 patients were recruited for validation of metabolites. Results Seven hundred forty-five metabolites were detected and significant differences in metabolomics between MPHT and SPHT patients were observed. Employing a threshold of p < 0.05 and a variable importance in projection score >1, 153 differential metabolites were identified. A significant number of these metabolites were lipids and lipid-like molecules. Pisumionoside and N-decanoylglycine (N-DG) exhibited the highest area under the curve (AUC) values (0.947 and 0.9091, respectively). Additional differential metabolites with AUC >0.8 included 6-(4-ethyl-2-methoxyphenoxy)-3,4,5-trihydroxyoxane-2-carboxylic acid, sphinganine 1-phosphate, 4-hydroxytriazolam, 4,5-dihydroorotic acid, 6-hydroxy-1H-indole-3-acetamide, 7alpha-(thiomethyl)spironolactone, 6-deoxohomodolichosterone, glutaminylisoleucine, taurocholic acid 3-sulfate, and Phe Ser. Enzyme-linked immunosorbent assay further confirmed elevated levels of sphinganine 1-phosphate, N-DG, and serotonin in SPHT patients. Significant disruptions in linoleic acid, amino acid, sphingolipid metabolisms, and the citrate cycle were observed in SPHT patients. Conclusion Pisumionoside and N-DG are identified as promising biomarkers for SPHT. The progression of PHT may be associated with disturbances in lipid, linoleic acid, and amino acid metabolisms, as well as alterations in the citrate cycle.
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Affiliation(s)
- Yanting Ye
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China
| | - Chao Xia
- Department of Radiology, and Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, China
- Huaxi MR Research Center (HMRRC), West China Hospital, Sichuan University, Chengdu, China
| | - Hong Hu
- Department of Gastroenterology, Hospital of Chengdu Office of People’s Government of Tibetan Autonomous Region, Chengdu, China
| | - Shihang Tang
- Department of Gastroenterology, Chongqing University Cancer Hospital, Chongqing, China
| | - Hui Huan
- Department of Gastroenterology, Hospital of Chengdu Office of People’s Government of Tibetan Autonomous Region, Chengdu, China
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Zhang Y, Wu D, Tian X, Chen B. From hepatitis B virus infection to acute-on-chronic liver failure: The dynamic role of hepatic macrophages. Scand J Immunol 2024; 99:e13349. [PMID: 38441398 DOI: 10.1111/sji.13349] [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: 08/26/2023] [Revised: 11/15/2023] [Accepted: 12/11/2023] [Indexed: 03/07/2024]
Abstract
Acute-on-chronic liver failure (ACLF) is a progressive disease that is associated with rapid worsening of clinical symptoms and high mortality. A multicentre prospective study from China demonstrated that patients with hepatitis B virus-related ACLF (HBV-ACLF) exhibited worse clinical characteristics and higher mortality rates compared to non-HBV-ACLF patients. Immune dysregulation is closely linked to the potential mechanisms of initiation and progression of ACLF. Innate immune response, which is represented by monocytes/macrophages, is up-regulated across ACLF development. This suggests that monocytes/macrophages play an essential role in maintaining the immune homeostasis of ACLF. Information that has been published in recent years shows that the immune status and function of monocytes/macrophages vary in ACLF precipitated by different chronic liver diseases. Monocytes/macrophages have an immune activation effect in hepatitis B-precipitated-ACLF, but they exhibit an immune suppression in cirrhosis-precipitated-ACLF. Therefore, this review aims to explain whether this difference affects the clinical outcome in HBV-ACLF patients as well as the mechanisms involved. We summarize the novel findings that highlight the dynamic polarization phenotype and functional status of hepatic macrophages from the stage of HBV infection to ACLF development. Moreover, we discuss how different HBV-related liver disease tissue microenvironments affect the phenotype and function of hepatic macrophages. In summary, increasing developments in understanding the differences in immune phenotype and functional status of hepatic macrophages in ACLF patients will provide new perspectives towards the effective restoration of ACLF immune homeostasis.
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Affiliation(s)
- Yu Zhang
- Department of Hepatology, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan Province, China
| | - Dongsheng Wu
- Department of Anorectal Surgical, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan Province, China
| | - Xiaoling Tian
- Department of Hepatology, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan Province, China
| | - Bin Chen
- Department of Hepatology, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan Province, China
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Aprilia A, Handono K, Sujuti H, Sabarudin A, Winaris N. sCD163, sCD28, sCD80, and sCTLA-4 as soluble marker candidates for detecting immunosenescence. Immun Ageing 2024; 21:9. [PMID: 38243300 PMCID: PMC10799430 DOI: 10.1186/s12979-023-00405-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Accepted: 12/11/2023] [Indexed: 01/21/2024]
Abstract
BACKGROUND Inflammaging, the characteristics of immunosenescence, characterized by continuous chronic inflammation that could not be resolved. It is not only affect older people but can also occur in young individuals, especially those suffering from chronic inflammatory conditions such as autoimmune disease, malignancy, or chronic infection. This condition led to altered immune function and as consequent immune function is reduced. Detection of immunosenescence has been done by examining the immune risk profile (IRP), which uses flow cytometry. These tests are not always available in health facilities, especially in developing countries and require fresh whole blood samples. Therefore, it is necessary to find biomarkers that can be tested using stored serum to make it easier to refer to the examination. Here we proposed an insight for soluble biomarkers which represented immune cells activities and exhaustion, namely sCD163, sCD28, sCD80, and sCTLA-4. Those markers were reported to be elevated in chronic diseases that caused early aging and easily detected from serum samples using ELISA method, unlike IRP. Therefore, we conclude these soluble markers are beneficial to predict pathological condition of immunosenescence. AIM To identify soluble biomarkers that could replace IRP for detecting immunosenescence. CONCLUSION Soluble costimulatory molecule suchsCD163, sCD28, sCD80, and sCTLA-4 are potential biomarkers for detecting immunosenescence.
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Affiliation(s)
- Andrea Aprilia
- Doctoral Program in Medical Science, Faculty of Medicine, Universitas Brawijaya, Malang, Indonesia
| | - Kusworini Handono
- Clinical Pathology Department, Faculty of Medicine, Universitas Brawijaya, Veteran Street, Malang, East Java, 65145, Indonesia.
| | - Hidayat Sujuti
- Opthamology Department, Faculty of Medicine, Universitas Brawijaya, Malang, Indonesia
| | - Akhmad Sabarudin
- Chemistry Department, Faculty of Mathematics and Science, Universitas Brawijaya, Malang, Indonesia
| | - Nuning Winaris
- Department of Parasitology, Faculty of Medicine, Universitas Brawijaya, Malang, Indonesia
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Selvakumar SC, Auxzilia Preethi K, Veeraiyan DN, Sekar D. The role of microRNAs on the pathogenesis, diagnosis and management of portal hypertension in patients with chronic liver disease. Expert Rev Gastroenterol Hepatol 2022; 16:941-951. [PMID: 36315408 DOI: 10.1080/17474124.2022.2142562] [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] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Portal hypertension (PH) is the elevated pressure in the portal vein, which results in poor functioning of the liver and is influenced by various factors like liver cirrhosis, nonalcoholic fatty liver disease, schistosomiasis, thrombosis, and angiogenesis. Though the diagnosis and treatment have been advanced, early diagnosis of the disease remains a challenge, and the diagnosis methods are often invasive. Hence, the clear understanding of the molecular mechanisms of PH can give rise to the development of novel biomarkers which can pave way for early diagnosis in noninvasive methods, and also the identification of target genes can elucidate an efficient therapeutic target. AREAS COVERED PubMed and Embase database was used to search articles with search terms 'Portal Hypertension' or 'pathophysiology' and 'diagnosis' and 'treatment' or "role of miRNAs in portal hypertension. EXPERT OPINION Interestingly, biomarkers like microRNAs (miRNAs) have been studied for their potential role in various diseases including hypertension. In recent years, miRNAs have been proved to be an efficient biomarker and therapeutic target and few studies have assessed the roles of miRNAs in PH. The present paper highlights the potential roles of miRNAs in PH.
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Affiliation(s)
- Sushmaa Chandralekha Selvakumar
- Centre for Cellular and Molecular Research, Saveetha Dental College & Hospitals, Saveetha Institute of Medical & Technical Sciences (SIMATS), Saveetha University, Chennai, India
| | - K Auxzilia Preethi
- Centre for Cellular and Molecular Research, Saveetha Dental College & Hospitals, Saveetha Institute of Medical & Technical Sciences (SIMATS), Saveetha University, Chennai, India
| | - Deepak Nallaswamy Veeraiyan
- Department of Prosthodontics, Saveetha Dental College & Hospitals, Saveetha Institute of Medical & Technical Sciences (SIMATS), Saveetha University, Chennai, India
| | - Durairaj Sekar
- Centre for Cellular and Molecular Research, Saveetha Dental College & Hospitals, Saveetha Institute of Medical & Technical Sciences (SIMATS), Saveetha University, Chennai, India
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Sun X, Ni HB, Xue J, Wang S, Aljbri A, Wang L, Ren TH, Li X, Niu M. Bibliometric-analysis visualization and review of non-invasive methods for monitoring and managing the portal hypertension. Front Med (Lausanne) 2022; 9:960316. [PMID: 36186776 PMCID: PMC9520322 DOI: 10.3389/fmed.2022.960316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Accepted: 08/22/2022] [Indexed: 11/13/2022] Open
Abstract
BackgroundPortal hypertension monitoring is important throughout the natural course of cirrhosis. Hepatic venous pressure gradient (HVPG), regarded as the golden standard, is limited by invasiveness and technical difficulties. Portal hypertension is increasingly being assessed non-invasively, and hematological indices, imaging data, and statistical or computational models are studied to surrogate HVPG. This paper discusses the existing non-invasive methods based on measurement principles and reviews the methodological developments in the last 20 years.MethodsFirst, we used VOSviewer to learn the architecture of this field. The publications about the non-invasive assessment of portal hypertension were retrieved from the Web of Science Core Collection (WoSCC). VOSviewer 1.6.17.0 was used to analyze and visualize these publications, including the annual trend, the study hotspots, the significant articles, authors, journals, and organizations in this field. Next, according to the cluster analysis result of the keywords, we further retrieved and classified the related studies to discuss.ResultsA total of 1,088 articles or review articles about our topic were retrieved from WoSCC. From 2000 to 2022, the number of publications is generally growing. “World Journal of Gastroenterology” published the most articles (n = 43), while “Journal of Hepatology” had the highest citations. “Liver fibrosis” published in 2005 was the most influential manuscript. Among the 20,558 cited references of 1,088 retrieved manuscripts, the most cited was a study on liver stiffness measurement from 2007. The highest-yielding country was the United States, followed by China and Italy. “Berzigotti, Annalisa” was the most prolific author and had the most cooperation partners. Four study directions emerged from the keyword clustering: (1) the evaluation based on fibrosis; (2) the evaluation based on hemodynamic factors; (3) the evaluation through elastography; and (4) the evaluation of variceal bleeding.ConclusionThe non-invasive assessment of portal hypertension is mainly based on two principles: fibrosis and hemodynamics. Liver fibrosis is the major initiator of cirrhotic PH, while hemodynamic factors reflect secondary alteration of splanchnic blood flow. Blood tests, US (including DUS and CEUS), CT, and magnetic resonance imaging (MRI) support the non-invasive assessment of PH by providing both hemodynamic and fibrotic information. Elastography, mainly USE, is the most important method of PH monitoring.
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Affiliation(s)
- XiaoHan Sun
- Department of Interventional Radiology, The First Hospital of China Medical University, Shenyang, China
| | - Hong Bo Ni
- Department of Interventional Radiology, The First Hospital of China Medical University, Shenyang, China
| | - Jian Xue
- Department of Interventional Radiology, The First Hospital of China Medical University, Shenyang, China
| | - Shuai Wang
- Department of Interventional Radiology, The First Hospital of China Medical University, Shenyang, China
| | - Afaf Aljbri
- Department of Interventional Radiology, The First Hospital of China Medical University, Shenyang, China
| | - Liuchun Wang
- Department of Interventional Radiology, The First Hospital of China Medical University, Shenyang, China
| | - Tian Hang Ren
- Department of Interventional Radiology, The First Hospital of China Medical University, Shenyang, China
| | - Xiao Li
- Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- *Correspondence: Xiao Li,
| | - Meng Niu
- Department of Interventional Radiology, The First Hospital of China Medical University, Shenyang, China
- Meng Niu,
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12
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Zhao X, Li L, Li S, Liu J, Wang H, Lin Y, Cai D. Diammonium glycyrrhizinate ameliorates portal hypertension by regulating portal macrophage oxidation and superoxide dismutase 3. Eur J Pharmacol 2022; 929:175115. [PMID: 35738453 DOI: 10.1016/j.ejphar.2022.175115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 06/16/2022] [Accepted: 06/17/2022] [Indexed: 11/16/2022]
Abstract
Portal hypertension (PHT) is a complication of liver diseases. Increased intrahepatic vascular resistance is attributed to reduced bioavailability of vasodilator substances. The macrophage activation and superoxide dismutase 3 (SOD3) involve in the pathogenesis of PHT. Diammonium glycyrrhizinate (DG) is the salt form of glycyrrhizin derived from Radix glycyrrhizae, exerting anti-oxidant activities and be beneficial for liver injury. Here, we aimed to investigate effects of DG on PHT and explore its underlying mechanisms on regulation of macrophages and SOD3. The carbon tetrachloride induced PHT rats received administration of liposome-encapsulated clodronate for hepatic macrophage depletion, or PBS liposomes for matched control. DG (25 mg/kg) or vehicle was gavaged. Portal pressure in vivo, and serum biomarkers of macrophage activation were measured. The nitric oxide (NO) and prostacyclin (PGI2) bioavailability was evaluated in the isolated portal perfused rat livers. Liver tissues were collected to evaluate cirrhosis, macrophage oxidation, and SOD3 activity. Depletion of hepatic macrophages decreased portal pressure, increased bioavailability of NO and PGI2, and restored SOD3 activity. DG effectively decreased portal pressure, relieved cirrhosis, inhibited macrophage activation. DG increased bioavailability of NO and PGI2 to relax portal veins. DG relieved portal macrophage oxidation through decreasing nicotinamide adenine dinucleotide phosphate oxidase 2 and inducible NO synthase expressions, elevated SOD3 activities and increased SOD3 expressions at portal triads. These findings indicated that DG restored SOD3 activity, against portal macrophage oxidation, protected bioavailability of NO and PGI2, thereby reduced portal pressure. It suggested a potential use of DG for PHT treatment.
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Affiliation(s)
- Xin Zhao
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100193, China
| | - Lingyu Li
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100193, China
| | - Shuang Li
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100193, China
| | - Jinyu Liu
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100193, China
| | - Hongya Wang
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100193, China
| | - Yulin Lin
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100193, China.
| | - Dayong Cai
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100193, China.
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13
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Miao L, Targher G, Byrne CD, Valenti L, Qi X, Zheng M. Portal hypertension in nonalcoholic fatty liver disease: Challenges and perspectives. PORTAL HYPERTENSION & CIRRHOSIS 2022; 1:57-65. [DOI: 10.1002/poh2.8] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Accepted: 04/21/2022] [Indexed: 04/16/2025]
Abstract
AbstractNonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide. NAFLD‐related cirrhosis is often complicated by portal hypertension (PHT). Recent evidence showed that portal venous pressure (PVP) starts to rise in the early stages of NAFLD, even in absence of advanced fibrosis or cirrhosis. However, the precise pathological mechanisms of this process are still poorly understood. Lipid accumulation, hepatocellular ballooning, sinusoidal endothelial cell dysfunction, capillarization, microthrombosis, increased angiogenesis, and pericellular fibrosis may all be involved in the early development of increased PVP in NAFLD. Direct measurement of PHT is invasive and impractical in noncirrhotic NAFLD individuals and may also underestimate its severity. Thus, the development and validation of noninvasive and more accurate measurements, including new serum biomarkers, scoring models, and imaging techniques (such as ultrasonography, elastography, and magnetic resonance imaging), are urgently needed. Owing to the increasing morbidity, challenges in the prevention and management of PHT in NAFLD are unprecedented. This review article aims to briefly discuss these challenges and summarizes the mechanisms, diagnosis, and emerging therapies for PHT in people with NAFLD.
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Affiliation(s)
- Lei Miao
- Department of Gastroenterology The Second Affiliated Hospital of Wenzhou Medical University Wenzhou Zhejiang China
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine University and Azienda Ospedaliera Universitaria Integrata of Verona Verona Italy
| | - Christopher D. Byrne
- Southampton National Institute for Health Research Biomedical Research Centre, Southampton General Hospital University Hospital Southampton Southampton UK
| | - Luca Valenti
- Translational Medicine, Department of Transfusion Medicine and Hematology Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico Milano Italy
- Department of Pathophysiology and Transplantation Università degli Studi di Milano Milano Italy
| | - Xiaolong Qi
- CHESS Center, Institute of Portal Hypertension The First Hospital of Lanzhou University Lanzhou Gansu China
| | - Ming‐Hua Zheng
- Department of Hepatology, NAFLD Research Center The First Affiliated Hospital of Wenzhou Medical University Wenzhou Zhejiang China
- Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province Wenzhou Zhejiang China
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14
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Sturm L, Bettinger D, Roth L, Zoldan K, Stolz L, Gahm C, Huber JP, Reincke M, Kaeser R, Boettler T, Kreisel W, Thimme R, Schultheiss M. Plasma Cyclic Guanosine Monophosphate Is a Promising Biomarker of Clinically Significant Portal Hypertension in Patients With Liver Cirrhosis. Front Med (Lausanne) 2022; 8:803119. [PMID: 35059421 PMCID: PMC8764357 DOI: 10.3389/fmed.2021.803119] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 12/08/2021] [Indexed: 11/16/2022] Open
Abstract
Introduction: Despite intensive research, reliable blood-derived parameters to detect clinically significant portal hypertension (CSPH) in patients with cirrhosis are lacking. As altered homeostasis of cyclic guanosine monophosphate (cGMP), the central mediator of vasodilatation, is an essential factor in the pathogenesis of portal hypertension, the aim of our study was to evaluate plasma cGMP as potential biomarker of cirrhotic portal hypertension. Methods: Plasma cGMP was analyzed in cirrhotic patients with CSPH (ascites, n = 39; esophageal varices, n = 31), cirrhotic patients without CSPH (n = 21), patients with chronic liver disease without cirrhosis (n = 11) and healthy controls (n = 8). cGMP was evaluated as predictor of CSPH using logistic regression models. Further, the effect of transjugular intrahepatic portosystemic shunt (TIPS) placement on plasma cGMP was investigated in a subgroup of cirrhotic patients (n = 13). Results: Plasma cGMP was significantly elevated in cirrhotic patients with CSPH compared to cirrhotic patients without CSPH [78.1 (67.6–89.2) pmol/ml vs. 39.1 (35.0–45.3) pmol/l, p < 0.001]. Of note, this effect was consistent in the subgroup of patients with esophageal varices detected at screening endoscopy who had no prior manifestations of portal hypertension (p < 0.001). Cirrhotic patients without CSPH displayed no significant elevation of plasma cGMP compared to patients without cirrhosis (p = 0.347) and healthy controls (p = 0.200). Regression analyses confirmed that cGMP was an independent predictor of CSPH (OR 1.042, 95% CI 1.008–1.078, p = 0.016). Interestingly, portal decompression by TIPS implantation did not lead to normalization of plasma cGMP levels (p = 0.101). Conclusions: Plasma cGMP is a promising biomarker of CSPH in patients with cirrhosis, especially with respect to screening for esophageal varices. The lacking normalization of plasma cGMP after portal decompression suggests that elevated plasma cGMP in cirrhotic portal hypertension is mainly a correlate of systemic and splanchnic vasodilatation, as these alterations have been shown to persist after TIPS implantation.
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Affiliation(s)
- Lukas Sturm
- Department of Medicine II, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.,Berta-Ottenstein-Program, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Dominik Bettinger
- Department of Medicine II, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Lisa Roth
- Department of Medicine II, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Katharina Zoldan
- Department of Medicine II, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Laura Stolz
- Department of Medicine II, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Chiara Gahm
- Department of Medicine II, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Jan Patrick Huber
- Department of Medicine II, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Marlene Reincke
- Department of Medicine II, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Rafael Kaeser
- Department of Medicine II, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.,IMM-PACT-Program, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Tobias Boettler
- Department of Medicine II, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Wolfgang Kreisel
- Department of Medicine II, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Robert Thimme
- Department of Medicine II, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Michael Schultheiss
- Department of Medicine II, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
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15
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Palaniyappan N, Fallowfield JA. Emerging Non-invasive Markers: Imaging, Blood, and Liver Clearance Tests. PORTAL HYPERTENSION VII 2022:135-151. [DOI: 10.1007/978-3-031-08552-9_13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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16
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Rittig N, Aagaard NK, Villadsen GE, Sandahl TD, Jessen N, Grønbaek H, George J. Randomised clinical study: acute effects of metformin versus placebo on portal pressure in patients with cirrhosis and portal hypertension. Aliment Pharmacol Ther 2021; 54:320-328. [PMID: 34165199 DOI: 10.1111/apt.16460] [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: 03/29/2021] [Revised: 04/17/2021] [Accepted: 05/18/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND Portal hypertension is the main determinant of clinical decompensation in patients with liver cirrhosis. In preclinical data metformin lowers portal pressure, but there are no clinical data for this beneficial effect. AIMS To investigate the acute effects of metformin on hepatic venous pressure gradient (HVPG) and liver perfusion. METHODS In a randomised, double-blinded study design, we investigated 32 patients with cirrhosis before and 90 minutes after ingestion of 1000-mg metformin (n = 16) or placebo (n = 16). Liver vein catherisation was performed to evaluate HVPG and indocyanine green (ICG) infusion for investigation of hepatic blood flow. RESULTS The mean relative change in HVPG was -16% (95% CI: -28% to -4%) in the metformin group compared with 4% (95% CI: -6% to 14%) in the placebo group (time × group interaction, P = 0.008). In patients with baseline HVPG ≥12 mm Hg clinically significant improvements in HVPG (HVPG <12 mm Hg or a >20% reduction in HVPG) were observed in 46% (6/13) of metformin-treated and in 8% (1/13) of placebo-treated patients (P = 0.07). There were no changes or differences in systemic blood pressure, heart rate, hepatic plasma and blood flow, hepatic ICG clearance, hepatic O2 uptake or inflammation markers between groups. CONCLUSIONS A single oral metformin dose acutely reduces HVPG in patients with portal hypertension without affecting systemic or liver hemodynamics or inflammatory biomarkers. This offers a promising perspective of a safe and inexpensive treatment option that should be investigated in larger-scale clinical studies with long-term outcomes in patients with cirrhosis and portal hypertension.
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Affiliation(s)
- Nikolaj Rittig
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark.,Department and Laboratories of Diabetes and Hormone diseases, Aarhus University Hospital, Aarhus, Denmark
| | - Niels Kristian Aagaard
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | | | | | - Niels Jessen
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark.,Department of Clinical Pharmacology, Aarhus University Hospital, Aarhus, Denmark.,Research laboratories for Biochemical Pathology, Aarhus University Hospital, Aarhus, Denmark
| | - Henning Grønbaek
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, Australia
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17
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Vuille-Lessard É, Rodrigues SG, Berzigotti A. Noninvasive Detection of Clinically Significant Portal Hypertension in Compensated Advanced Chronic Liver Disease. Clin Liver Dis 2021; 25:253-289. [PMID: 33838850 DOI: 10.1016/j.cld.2021.01.005] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Patients with compensated advanced chronic liver disease have different prognoses depending on the presence of portal hypertension. Current non-invasive diagnostic methods allow identification of clinically significant portal hypertension. Portosystemic collaterals on imaging or liver stiffness of more than 20 to 25 kPa by using transient elastography identifies patients with clinically significant portal hypertension. Patients with liver stiffness of less than 20 kPa and platelet count of greater than 150 g/L can avoid endoscopy. This rule could be expanded using spleen stiffness. Methods to risk stratify for portal hypertension in compensated advanced chronic liver disease and successfully treated chronic hepatitis C and B are subject of research.
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Affiliation(s)
- Élise Vuille-Lessard
- Hepatology, University Clinic for Visceral Surgery and Medicine (UVCM), Inselspital, University Hospital of Bern, Freiburgstrasse, 3010 Bern, Switzerland; Department of Biomedical Research, University of Bern, Switzerland
| | - Susana G Rodrigues
- Hepatology, University Clinic for Visceral Surgery and Medicine (UVCM), Inselspital, University Hospital of Bern, Freiburgstrasse, 3010 Bern, Switzerland; Department of Biomedical Research, University of Bern, Switzerland
| | - Annalisa Berzigotti
- Hepatology, University Clinic for Visceral Surgery and Medicine (UVCM), Inselspital, University Hospital of Bern, Freiburgstrasse, 3010 Bern, Switzerland; Department of Biomedical Research, University of Bern, Switzerland.
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18
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Bossen L, Vesterhus M, Hov JR, Färkkilä M, Rosenberg WM, Møller HJ, Boberg KM, Karlsen TH, Grønbæk H. Circulating Macrophage Activation Markers Predict Transplant-Free Survival in Patients With Primary Sclerosing Cholangitis. Clin Transl Gastroenterol 2021; 12:e00315. [PMID: 33646203 PMCID: PMC7925135 DOI: 10.14309/ctg.0000000000000315] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 01/13/2021] [Indexed: 02/08/2023] Open
Abstract
INTRODUCTION Primary sclerosing cholangitis (PSC) is a progressive liver disease characterized by bile duct inflammation and fibrosis. The role of macrophages in PSC development and progression is less studied. Macrophage activation markers soluble (s)CD163 and mannose receptor (sMR) are associated with disease severity and outcome in other liver diseases, but not previously investigated in PSC. We evaluated sCD163 and sMR regarding disease severity and prognosis in patients with PSC. METHODS We investigated 2 independent PSC cohorts from Oslo (n = 138) and Helsinki (n = 159) and analyzed blood sCD163 and sMR levels. The Mayo score, Enhanced Liver Fibrosis Test, and Amsterdam-Oxford model were assessed for comparison. RESULTS Median (interquartile range) sCD163 was 3.32 (2.27-5.60) and 1.96 (1.47-2.70) mg/L in the Oslo and Helsinki cohorts, respectively, reflecting differences in disease severity between cohorts. Median sMR was similar in both cohorts, 0.28 (0.22-0.44) and 0.28 mg/L (0.20-0.36), respectively. In both cohorts, sCD163 and sMR levels raised with increasing disease severity (liver enzymes, Mayo score, and enhanced liver fibrosis test). Patients with high baseline levels of sCD163 had shorter transplant-free survival than patients with low baseline levels. Furthermore, sCD163 was associated with transplant-free survival in univariate cox-regression analyses. Both sCD163 and sMR performed better in the Oslo cohort of more severely diseased patients than those in the Helsinki cohort of more mildly diseased patients. DISCUSSION Macrophage activation markers are elevated according to disease severity suggesting an important role of macrophages in PSC. Furthermore, sCD163 was identified as a prognostic marker and predictor of transplant-free survival in PSC (see Visual Abstract, Supplementary Digital Content 4, http://links.lww.com/CTG/A516).
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MESH Headings
- Adult
- Antigens, CD/analysis
- Antigens, CD/metabolism
- Antigens, Differentiation, Myelomonocytic/analysis
- Antigens, Differentiation, Myelomonocytic/metabolism
- Biomarkers/blood
- Biomarkers/metabolism
- Case-Control Studies
- Cholangitis, Sclerosing/blood
- Cholangitis, Sclerosing/immunology
- Cholangitis, Sclerosing/mortality
- Cholangitis, Sclerosing/surgery
- Disease Progression
- End Stage Liver Disease/blood
- End Stage Liver Disease/epidemiology
- End Stage Liver Disease/immunology
- End Stage Liver Disease/surgery
- Female
- Finland/epidemiology
- Humans
- Liver Transplantation/statistics & numerical data
- Macrophage Activation
- Macrophages/immunology
- Macrophages/metabolism
- Male
- Membrane Glycoproteins/analysis
- Membrane Glycoproteins/metabolism
- Middle Aged
- Norway/epidemiology
- Prognosis
- Receptors, Cell Surface/analysis
- Receptors, Cell Surface/metabolism
- Receptors, Immunologic/analysis
- Receptors, Immunologic/metabolism
- Registries/statistics & numerical data
- Retrospective Studies
- Risk Assessment/methods
- Severity of Illness Index
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Affiliation(s)
- Lars Bossen
- Department of Hepatology & Gastroenterology, and European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Aarhus University Hospital, Aarhus, Denmark;
| | - Mette Vesterhus
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, and European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Oslo University Hospital Rikshospitalet, Oslo, Norway;
- Department of Medicine, Haraldsplass Deaconess Hospital, Bergen, Norway;
- Department of Clinical Science, University of Bergen, Bergen, Norway;
| | - Johannes R. Hov
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, and European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Oslo University Hospital Rikshospitalet, Oslo, Norway;
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway;
- Section of Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway;
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway;
| | - Martti Färkkilä
- Helsinki University, Clinic of Gastroenterology, Helsinki University Hospital, Helsinki, Finland;
| | - William M. Rosenberg
- UCL Institute for Liver and Digestive Health, Division of Medicine, University College London & Royal Free London, NHS Foundation Trust, London, UK;
| | - Holger J. Møller
- Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark.
| | - Kirsten M. Boberg
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, and European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Oslo University Hospital Rikshospitalet, Oslo, Norway;
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway;
- Section of Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway;
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway;
| | - Tom H. Karlsen
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, and European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Oslo University Hospital Rikshospitalet, Oslo, Norway;
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway;
- Section of Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway;
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway;
| | - Henning Grønbæk
- Department of Hepatology & Gastroenterology, and European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Aarhus University Hospital, Aarhus, Denmark;
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19
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Gantzel RH, Kjær MB, Laursen TL, Kazankov K, George J, Møller HJ, Grønbæk H. Macrophage Activation Markers, Soluble CD163 and Mannose Receptor, in Liver Fibrosis. Front Med (Lausanne) 2021; 7:615599. [PMID: 33490096 PMCID: PMC7820116 DOI: 10.3389/fmed.2020.615599] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 12/11/2020] [Indexed: 12/19/2022] Open
Abstract
Macrophages are essential components of the human host immune system, which upon activation facilitates a broad pallet of immunomodulatory events including release of pro- or anti-inflammatory cytokines and chemokines, restoration of immune homeostasis and/or wound healing. Moreover, some macrophage phenotypes are crucially involved in fibrogenesis through stimulation of myofibroblasts, while others promote fibrolysis. During the last decades, the role of resident liver macrophages viz. Kupffer cells and recruited monocytes/macrophages in acute and chronic liver diseases has gained interest and been extensively investigated. Specifically, the scavenger receptors CD163 and mannose receptor (CD206), expressed by macrophages, are of utmost interest since activation by various stimuli induce their shedding to the circulation. Thus, quantifying concentrations of these soluble biomarkers may be of promising clinical relevance in estimating the severity of inflammation and fibrosis and to predict outcomes such as survival. Here, we review the existing literature on soluble CD163 and soluble mannose receptor in liver diseases with a particular focus on their relationship to hepatic fibrosis in metabolic associated fatty liver disease, as well as in chronic hepatitis B and C.
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Affiliation(s)
| | - Mikkel Breinholt Kjær
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Tea Lund Laursen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Konstantin Kazankov
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.,Institute for Liver and Digestive Health, University College London, London, United Kingdom
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, University of Sydney and Westmead Hospital, Westmead, NSW, Australia
| | - Holger Jon Møller
- Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
| | - Henning Grønbæk
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
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20
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Mandorfer M, Hernández-Gea V, García-Pagán JC, Reiberger T. Noninvasive Diagnostics for Portal Hypertension: A Comprehensive Review. Semin Liver Dis 2020; 40:240-255. [PMID: 32557480 DOI: 10.1055/s-0040-1708806] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Noninvasive diagnostics for portal hypertension include imaging and functional tests, as well as blood-based biomarkers, and capture different features of the portal hypertensive syndrome. Definitive conclusions regarding their clinical utility require assessment of their diagnostic value in specific clinical settings (i.e., diagnosing a particular hemodynamic condition within a well-defined target population). Several noninvasive methods are predictive of clinically significant portal hypertension (CSPH; hepatic venous pressure gradient [HVPG] ≥ 10 mm Hg; the threshold for complications of portal hypertension); however, only a minority of them have been evaluated in compensated advanced chronic liver disease (i.e., the target population). Importantly, most methods correlate only weakly with HVPG at high values (i.e., in patients with CSPH). Nevertheless, selected methods show promise for diagnosing HVPG ≥ 16 mm Hg (the cut-off for increased risks of hepatic decompensation and mortality) and monitoring HVPG changes in response to nonselective beta-blockers or etiological treatments. Finally, we review established and potential future clinical applications of noninvasive methods.
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Affiliation(s)
- Mattias Mandorfer
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.,Barcelona Hepatic Hemodynamic Lab, Liver Unit, Hospital Clínic, Barcelona, Spain
| | - Virginia Hernández-Gea
- Barcelona Hepatic Hemodynamic Lab, Liver Unit, Hospital Clínic, Barcelona, Spain.,Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Juan Carlos García-Pagán
- Barcelona Hepatic Hemodynamic Lab, Liver Unit, Hospital Clínic, Barcelona, Spain.,Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Thomas Reiberger
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
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21
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Simbrunner B, Marculescu R, Scheiner B, Schwabl P, Bucsics T, Stadlmann A, Bauer DJM, Paternostro R, Eigenbauer E, Pinter M, Stättermayer AF, Trauner M, Mandorfer M, Reiberger T. Non-invasive detection of portal hypertension by enhanced liver fibrosis score in patients with different aetiologies of advanced chronic liver disease. Liver Int 2020; 40:1713-1724. [PMID: 32358998 PMCID: PMC7383870 DOI: 10.1111/liv.14498] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 04/03/2020] [Accepted: 04/27/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS The enhanced liver fibrosis (ELF) score comprises serum markers of fibrogenesis and matrix remodelling and was developed to detect liver fibrosis, however, it may also be useful for the non-invasive detection of portal hypertension (PHT). METHODS ELF score and its single components (TIMP1/PIIINP/HA) were analysed in 201 patients with advanced chronic liver disease (ACLD; ie hepatic venous pressure gradient (HVPG) ≥6 mm Hg). Patients with pre-/post-hepatic PHT, hepatocellular carcinoma beyond Milan criteria, and history of TIPS implantation or liver transplantation were excluded. RESULTS ELF and its single components correlated with HVPG in the overall cohort: ELF: r = .443, TIMP1: r = .368, PIIINP:r = .332, and HA:r = .419 (all P < .001). The strength of the correlation between ELF and HVPG decreased in higher HVPG strata: 6-9 mm Hg:r = .569(P = .004), 10-19 mm Hg:r = .304 (P = .001) and ≥20 mm Hg:r = -.023(P = .853). Area under the receiver operating characteristics (AUROC) of ELF score to detect clinically significant PHT (CSPH; HVPG ≥ 10 mm Hg) was 0.833. Importantly, HA alone yielded an AUROC of 0.828. Detection of CSPH in strictly compensated ACLD (cACLD) patients was less accurate: AUROC: 0.759 (P < .001). CSPH was ruled-in by ELF ≥ 11.1 with a PPV of 98% (sensitivity: 61%/specificity: 92%/NPV:24%), but CSPH could not be ruled-out. ELF score had a low AUROC of 0.677 (0.60-0.75; P < .001) for the diagnosis of high-risk PHT (HRPH; HVPG ≥ 20mm Hg) and, thus, HRPH could not be ruled-in by ELF. However, ELF < 10.1 ruled-out HRPH with a NPV of 95% (sensitivity: 97%/specificity: 26%/PPV: 39%). CONCLUSION The ELF score correlates with HVPG at values <20 mm Hg. An ELF ≥ 11.1 identifies patients with a high probability of CSPH, while an ELF < 10.1 may be used to rule-out HRPH.
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Affiliation(s)
- Benedikt Simbrunner
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Hepatic Hemodynamic LaboratoryMedical University of ViennaViennaAustria,Ludwig Boltzmann Institute for Rare and Undiagnosed DiseasesViennaAustria,CeMM Research Center for Molecular Medicine of the Austrian Academy of SciencesViennaAustria
| | - Rodrig Marculescu
- Department of Laboratory MedicineMedical University of ViennaViennaAustria
| | - Bernhard Scheiner
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Hepatic Hemodynamic LaboratoryMedical University of ViennaViennaAustria
| | - Philipp Schwabl
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Hepatic Hemodynamic LaboratoryMedical University of ViennaViennaAustria,Ludwig Boltzmann Institute for Rare and Undiagnosed DiseasesViennaAustria,CeMM Research Center for Molecular Medicine of the Austrian Academy of SciencesViennaAustria
| | - Theresa Bucsics
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Hepatic Hemodynamic LaboratoryMedical University of ViennaViennaAustria
| | - Alexander Stadlmann
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Hepatic Hemodynamic LaboratoryMedical University of ViennaViennaAustria,Hospital HietzingViennaAustria
| | - David J. M. Bauer
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Hepatic Hemodynamic LaboratoryMedical University of ViennaViennaAustria
| | - Rafael Paternostro
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Hepatic Hemodynamic LaboratoryMedical University of ViennaViennaAustria
| | - Ernst Eigenbauer
- IT‐Systems & CommunicationsMedical University of ViennaViennaAustria
| | - Matthias Pinter
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Albert Friedrich Stättermayer
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Michael Trauner
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Mattias Mandorfer
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Hepatic Hemodynamic LaboratoryMedical University of ViennaViennaAustria
| | - Thomas Reiberger
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Hepatic Hemodynamic LaboratoryMedical University of ViennaViennaAustria,Ludwig Boltzmann Institute for Rare and Undiagnosed DiseasesViennaAustria,CeMM Research Center for Molecular Medicine of the Austrian Academy of SciencesViennaAustria
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22
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Ryou M, Stylopoulos N, Baffy G. Nonalcoholic fatty liver disease and portal hypertension. EXPLORATION OF MEDICINE 2020; 1:149-169. [PMID: 32685936 DOI: 10.37349/emed.2020.00011] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a substantial and growing problem worldwide and has become the second most common indication for liver transplantation as it may progress to cirrhosis and develop complications from portal hypertension primarily caused by advanced fibrosis and erratic tissue remodeling. However, elevated portal venous pressure has also been detected in experimental models of fatty liver and in human NAFLD when fibrosis is far less advanced and cirrhosis is absent. Early increases in intrahepatic vascular resistance may contribute to the progression of liver disease. Specific pathophenotypes linked to the development of portal hypertension in NAFLD include hepatocellular lipid accumulation and ballooning injury, capillarization of liver sinusoidal endothelial cells, enhanced contractility of hepatic stellate cells, activation of Kupffer cells and pro-inflammatory pathways, adhesion and entrapment of recruited leukocytes, microthrombosis, angiogenesis and perisinusoidal fibrosis. These pathological events are amplified in NAFLD by concomitant visceral obesity, insulin resistance, type 2 diabetes and dysbiosis, promoting aberrant interactions with adipose tissue, skeletal muscle and gut microbiota. Measurement of the hepatic venous pressure gradient by retrograde insertion of a balloon-tipped central vein catheter is the current reference method for predicting outcomes of cirrhosis associated with clinically significant portal hypertension and guiding interventions. This invasive technique is rarely considered in the absence of cirrhosis where currently available clinical, imaging and laboratory correlates of portal hypertension may not reflect early changes in liver hemodynamics. Availability of less invasive but sufficiently sensitive methods for the assessment of portal venous pressure in NAFLD remains therefore an unmet need. Recent efforts to develop new biomarkers and endoscopy-based approaches such as endoscopic ultrasound-guided measurement of portal pressure gradient may help achieve this goal. In addition, cellular and molecular targets are being identified to guide emerging therapies in the prevention and management of portal hypertension.
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Affiliation(s)
- Marvin Ryou
- Department of Medicine, Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Nicholas Stylopoulos
- Division of Endocrinology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA.,The Broad Institute of MIT and Harvard, Cambridge MA
| | - Gyorgy Baffy
- Department of Medicine, Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.,Department of Medicine, VA Boston Healthcare System, Harvard Medical School, Boston, MA
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23
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Kaji K, Yoshiji H. Can portal hypertension and hepatic decompensation be predicted? J Gastroenterol 2020; 55:662-663. [PMID: 31965301 DOI: 10.1007/s00535-020-01669-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2019] [Accepted: 01/09/2020] [Indexed: 02/04/2023]
Affiliation(s)
- Kosuke Kaji
- Department of Gastroenterology, Nara Medical University, Kashihara, Nara, 634-8521, Japan.
| | - Hitoshi Yoshiji
- Department of Gastroenterology, Nara Medical University, Kashihara, Nara, 634-8521, Japan
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24
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Gorin JB, Malone DFG, Strunz B, Carlsson T, Aleman S, Björkström NK, Falconer K, Sandberg JK. Plasma FABP4 is associated with liver disease recovery during treatment-induced clearance of chronic HCV infection. Sci Rep 2020; 10:2081. [PMID: 32034167 PMCID: PMC7005788 DOI: 10.1038/s41598-020-58768-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Accepted: 01/20/2020] [Indexed: 12/17/2022] Open
Abstract
Direct-acting antivirals (DAAs) have dramatically improved the management of chronic hepatitis C (CHC). In this study, we investigated the effects of hepatitis C virus clearance on markers of systemic inflammation measured in plasma samples from CHC patients before, during and after DAA therapy. We identified a plasma soluble protein profile associated with CHC. Successful DAA therapy rapidly normalised the plasma inflammatory milieu, with the notable exception of soluble (s)CD163, a marker of macrophage activation, which remained elevated after viral clearance and segregated patients with high and low levels of cirrhosis. Patients who received DAA in combination with Ribavirin maintained elevated levels of CXCL10, consistent with an immune-stimulatory role of Ribavirin. As anticipated, DAA-treated patients experienced durable improvement in liver fibrosis measurements. Interestingly, pre-treatment levels of fatty acid-binding protein 4 (FABP4) were inversely associated with reduction of APRI and FIB-4 scores during treatment. Together, these results support the notion of a rapid restoration of many aspects of the inflammatory state in CHC patients in response to DAA therapy. Furthermore, the associations with sCD163 and FABP4 warrant further investigation into the role of macrophages in residual liver disease and fibrosis resolution after viral clearance.
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Affiliation(s)
- Jean-Baptiste Gorin
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - David F G Malone
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Benedikt Strunz
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Tony Carlsson
- Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - Soo Aleman
- Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden
- Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Niklas K Björkström
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Karolin Falconer
- Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - Johan K Sandberg
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
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25
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Patel PJ, Connoley D, Rhodes F, Srivastava A, Rosenberg W. A review of the clinical utility of the Enhanced Liver Fibrosis test in multiple aetiologies of chronic liver disease. Ann Clin Biochem 2020; 57:36-43. [PMID: 31529981 DOI: 10.1177/0004563219879962] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The rising incidence of chronic liver disease continues to be an increasing health burden. The morbidity and mortality associated with chronic liver disease typically occur in patients with advanced fibrosis. Hence, early identification of those at-risk is of vital importance to ensure appropriate ongoing management. Currently, tools for appropriate risk stratification remain limited. Increasing awareness of the limitations of liver biopsy has driven research into alternative non-invasive methods of fibrosis assessment including serological markers assessing functional changes. One such biomarker, the Enhanced Liver Fibrosis test, was initially validated in a cohort of 1021 patients with mixed aetiology chronic liver disease and shown to perform well. Since this pathfinder study, it has been independently validated in cohorts of hepatitis C, non-alcoholic fatty liver disease, alcoholic liver disease, primary biliary cirrhosis and primary sclerosing cholangitis. In addition to performing well as a diagnostic tool, the Enhanced Liver Fibrosis test has been shown to outperform liver biopsy in prognostic studies and is the only non-invasive marker to do so. However, questions remain regarding the use of this test, particularly regarding the possible effect age and alcohol may have on test scores. This review examines the current literature published in relation to the Enhanced Liver Fibrosis test and its clinical utility and highlights areas requiring further study.
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Affiliation(s)
- Preya Janubhai Patel
- The Institute for Liver and Digestive Health, UCL Division of Medicine, UCL, London, UK
| | - Declan Connoley
- The Institute for Liver and Digestive Health, UCL Division of Medicine, UCL, London, UK.,Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia
| | - Freya Rhodes
- The Institute for Liver and Digestive Health, UCL Division of Medicine, UCL, London, UK
| | - Ankur Srivastava
- The Institute for Liver and Digestive Health, UCL Division of Medicine, UCL, London, UK.,Department of Gastroenterology & Hepatology, Southmead Hospital, North Bristol Trust, Bristol, UK
| | - William Rosenberg
- The Institute for Liver and Digestive Health, UCL Division of Medicine, UCL, London, UK
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26
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Rana R, Wang S, Li J, Basnet S, Zheng L, Yang C. Diagnostic accuracy of non-invasive methods detecting clinically significant portal hypertension in liver cirrhosis: a systematic review and meta-analysis. Minerva Med 2019; 111:266-280. [PMID: 31638361 DOI: 10.23736/s0026-4806.19.06143-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
INTRODUCTION We attempted to investigate non-invasive techniques and their diagnostic performances for evaluating clinically significant portal hypertension. EVIDENCE ACQUISITION The systematic search was performed on PubMed, Embase, Scopus, and Web of Science TM core index databases before 13 December 2018 restricted to English language and human studies. EVIDENCE SYNTHESIS Thirty-two studies were included, with total populations of 3,987. The overall pooled analysis was performed by bivariate random effect model, which revealed significantly higher sensitivity and specificity of 77.1% (95% confidence interval, 76.8-78.5%) and 80.1% (95% confidence interval, 78.2-81.9%), respectively; positive likelihood ratio (3.67), negative likelihood ratio (0.26); and diagnostic odd ratio (16.24). Additionally, the area under curve exhibited significant diagnostic accuracy of 0.871. However, notable heterogeneity existed in between studies (I2=87.1%), therefore, further subgroup analysis was performed. It demonstrated ultrasonography, elastography, biomarker, and computed tomography scan had a significant overall summary sensitivity (specificity) of 89.6% (78.9%), 81.7% (83.2%), 72.2% (76.8%), and 77.2% (81.2%), respectively. Moreover, the areas under curve values were significantly higher in elastography (0.906), followed by computed tomography scan (0.847), biomarker (0.825), and ultrasonography (0.803). CONCLUSIONS In future, non-invasive techniques could be the future choice of investigations for screening and diagnosis of clinically significant portal hypertension in cirrhosis. However, standardization of diagnostic indices and their cut-off values in each non-invasive method needs to be addressed.
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Affiliation(s)
- Ramesh Rana
- Division of Gastroenterology and Hepatology, Digestive Disease Institute, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China.,Department of Internal Medicine, Gautam Buddha Community Heart Hospital, Butwal, Nepal
| | - Shenglan Wang
- Division of Gastroenterology and Hepatology, Digestive Disease Institute, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jing Li
- Division of Gastroenterology and Hepatology, Digestive Disease Institute, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Shiva Basnet
- Department of Gastrointestinal Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Liang Zheng
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Changqing Yang
- Division of Gastroenterology and Hepatology, Digestive Disease Institute, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China -
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27
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Simbrunner B, Mandorfer M, Trauner M, Reiberger T. Gut-liver axis signaling in portal hypertension. World J Gastroenterol 2019; 25:5897-5917. [PMID: 31660028 PMCID: PMC6815800 DOI: 10.3748/wjg.v25.i39.5897] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 08/15/2019] [Accepted: 09/28/2019] [Indexed: 02/06/2023] Open
Abstract
Portal hypertension (PHT) in advanced chronic liver disease (ACLD) results from increased intrahepatic resistance caused by pathologic changes of liver tissue composition (structural component) and intrahepatic vasoconstriction (functional component). PHT is an important driver of hepatic decompensation such as development of ascites or variceal bleeding. Dysbiosis and an impaired intestinal barrier in ACLD facilitate translocation of bacteria and pathogen-associated molecular patterns (PAMPs) that promote disease progression via immune system activation with subsequent induction of proinflammatory and profibrogenic pathways. Congestive portal venous blood flow represents a critical pathophysiological mechanism linking PHT to increased intestinal permeability: The intestinal barrier function is affected by impaired microcirculation, neoangiogenesis, and abnormal vascular and mucosal permeability. The close bidirectional relationship between the gut and the liver has been termed “gut-liver axis”. Treatment strategies targeting the gut-liver axis by modulation of microbiota composition and function, intestinal barrier integrity, as well as amelioration of liver fibrosis and PHT are supposed to exert beneficial effects. The activation of the farnesoid X receptor in the liver and the gut was associated with beneficial effects in animal experiments, however, further studies regarding efficacy and safety of pharmacological FXR modulation in patients with ACLD are needed. In this review, we summarize the clinical impact of PHT on the course of liver disease, discuss the underlying pathophysiological link of PHT to gut-liver axis signaling, and provide insight into molecular mechanisms that may represent novel therapeutic targets.
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Affiliation(s)
- Benedikt Simbrunner
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna 1180, Austria
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna 1180, Austria
| | - Mattias Mandorfer
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna 1180, Austria
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna 1180, Austria
| | - Michael Trauner
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna 1180, Austria
| | - Thomas Reiberger
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna 1180, Austria
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna 1180, Austria
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28
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Liang LY, Wong VWS, Tse YK, Yip TCF, Lui GCY, Chan HLY, Wong GLH. Improvement in enhanced liver fibrosis score and liver stiffness measurement reflects lower risk of hepatocellular carcinoma. Aliment Pharmacol Ther 2019; 49:1509-1517. [PMID: 31025388 DOI: 10.1111/apt.15269] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 02/06/2019] [Accepted: 03/28/2019] [Indexed: 12/19/2022]
Abstract
BACKGROUND The Liver stiffness measurement hepatocellular carcinoma (LSM-HCC) score predicts HCC accurately in patients with chronic hepatitis B (CHB). AIM To assess the ability of LSM-HCC combined with enhanced liver fibrosis (ELF) score to predict HCC in CHB patients who received anti-viral treatment. METHODS CHB patients who had transient elastography examinations in 2006-2013 with intermediate and high risk of HCC by LSM-HCC score (ie 11 or above) were assessed by repeat transient elastography at least 3 years later. ELF score was assessed by retrieving the stored serum samples 4 weeks within transient elastography examination. The primary endpoint was the cumulative incidence of HCC. RESULTS A total of 453 CHB patients (mean age 51.7 ± 10.3 years; male 74.4%) were recruited, 45 patients (9.9%) developed HCC during the mean follow-up of 56 months. Regarding LSM-HCC score, 71.4%, 24.3% and 4.3% of patients had LSM-HCC score improved, remained static and deteriorated respectively; whereas 36.9%, 57.8% and 5.3% of patients had ELF score improved, remained static and deteriorated respectively. The sensitivity (86.7%) and negative predictive value (NPV) (95.3%) of combined LSM-HCC and ELF score were higher than that of each score alone. Kaplan-Meier analysis showed that ELF score would help further differentiate the HCC risk in patients with intermediate risk by LSM-HCC score (P = 0.026), but not in patients with high risk by LSM-HCC score (P = 0.770). CONCLUSIONS The two-step algorithm combining LSM-HCC score and ELF score could improve the accuracy of predicting HCC of CHB patients receiving anti-viral treatment.
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Affiliation(s)
- Lilian Yan Liang
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, Hong Kong.,Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, Hong Kong
| | - Vincent Wai-Sun Wong
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, Hong Kong.,Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, Hong Kong.,State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, Hong Kong
| | - Yee-Kit Tse
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, Hong Kong.,Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, Hong Kong
| | - Terry Cheuk-Fung Yip
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, Hong Kong.,Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, Hong Kong
| | - Grace Chung-Yan Lui
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, Hong Kong
| | - Henry Lik-Yuen Chan
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, Hong Kong.,Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, Hong Kong.,State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, Hong Kong
| | - Grace Lai-Hung Wong
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, Hong Kong.,Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, Hong Kong.,State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, Hong Kong
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29
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Qi X, Berzigotti A, Cardenas A, Sarin SK. Emerging non-invasive approaches for diagnosis and monitoring of portal hypertension. Lancet Gastroenterol Hepatol 2019; 3:708-719. [PMID: 30215362 DOI: 10.1016/s2468-1253(18)30232-2] [Citation(s) in RCA: 100] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Revised: 05/13/2018] [Accepted: 06/25/2018] [Indexed: 02/08/2023]
Abstract
Clinically significant portal hypertension is associated with an increased risk of developing gastro-oesophageal varices and hepatic decompensation. Hepatic venous pressure gradient measurement and oesophagogastroduodenoscopy are the gold-standard methods for assessing clinically significant portal hypertension (hepatic venous pressure gradient ≥10 mm Hg) and gastro-oesophageal varices, respectively. However, invasiveness, cost, and feasibility limit their widespread use, especially if repeated and serial evaluations are required to assess the efficacy of pharmacotherapy. Although new techniques for non-invasive portal pressure measurement have been pursued for many decades, only recently have new tools been assessed and validated for larger clinical application. This Review focuses on the recent advances in non-invasive approaches for the diagnosis and serial monitoring of portal hypertension and varices for clinical practice.
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Affiliation(s)
- Xiaolong Qi
- CHESS Group, Hepatic Hemodynamic Lab, Institute of Hepatology, Nanfang Hospital, Southern Medical University, Guangzhou, China; CHESS Frontier Center, Lanzhou University, Lanzhou, China.
| | - Annalisa Berzigotti
- Hepatology Group, Swiss Liver Center, University Clinic for Visceral Surgery and Medicine, Inselspital, University of Bern, Bern, Switzerland
| | - Andres Cardenas
- GI/Liver Unit, Institute of Digestive Diseases and Metabolism, Hospital Clinic, University of Barcelona, Barcelona, Spain
| | - Shiv Kumar Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
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30
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Kimer N, Gudmann NS, Pedersen JS, Møller S, Nielsen MJ, Leeming DJ, Karsdal MA, Møller HJ, Bendtsen F, Grønbæk H. No effect of rifaximin on soluble CD163, mannose receptor or type III and IV neoepitope collagen markers in decompensated cirrhosis: Results from a randomized, placebo controlled trial. PLoS One 2018; 13:e0203200. [PMID: 30183743 PMCID: PMC6124759 DOI: 10.1371/journal.pone.0203200] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Accepted: 08/16/2018] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND AND AIMS Macrophages play a significant role in chronic liver disease as reflected by elevated soluble (s)CD163 and mannose receptor (sMR) levels and associated with liver disease severity and prognosis. Extracellular matrix remodelling associated with fibrogenesis may be affected by systemic inflammation induced by bacterial translocation. Therefore, we aimed to investigate the effect of rifaximin-α, an antibiotic with effect on gut bacteria, on sCD163, sMR, and collagen metabolites. METHODS Fifty-four clinically stable patients with decompensated cirrhosis were randomized to 4 weeks treatment with rifaximin-α (n = 36) or placebo (n = 18). Macrophage markers sCD163, sMR and markers of collagen fibrogenesis (C3M and C4M) and formation (PRO-C3 and P4NPS7) were analysed in plasma before and after treatment. RESULTS sCD163 and sMR levels were associated with liver disease severity (MELD score, sCD163 rho = 0.47, p<0.001 and sMR rho = 0.37, p = 0.005). There was no effect of Rifaximin-α on sCD163 levels (median (range) sCD163 5.64(2.02 to 10.8) at baseline versus 4.42(1.98 to 8.92) at follow-up in the rifaximin-α group and 4.85 (2.29 to 12.1) at baseline versus 4.32 (1.98 to 12.4) at follow-up in the placebo-group), p = 0.34); nor sMR levels, p = 0.34. Also in patients with elevated lipopolysaccharide binding protein (> 5.9 μg/ml, 38 patients) there was no effect of rifaximin-α on sCD163 (p = 0.49) or sMR levels (p = 0.32). CONCLUSION We confirmed that macrophage activation markers sCD163 and sMR are directly associated to liver disease severity (MELD score). However, rifaximin-α has no effect on sCD163, sMR or collagen markers in decompensated cirrhosis and does therefore not seem to interfere with macrophage activation or fibrogenesis.
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Affiliation(s)
- Nina Kimer
- Gastro Unit, Medical Division, Copenhagen University Hospital Amager Hvidovre, Hvidovre, Denmark
- Centre of Diagnostic Imaging and Research, Department of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | | | - Julie Steen Pedersen
- Gastro Unit, Medical Division, Copenhagen University Hospital Amager Hvidovre, Hvidovre, Denmark
| | - Søren Møller
- Centre of Diagnostic Imaging and Research, Department of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | | | | | | | - Holger Jon Møller
- Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
| | - Flemming Bendtsen
- Gastro Unit, Medical Division, Copenhagen University Hospital Amager Hvidovre, Hvidovre, Denmark
| | - Henning Grønbæk
- Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
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Enhanced liver fibrosis (ELF) score: Reference ranges, biological variation in healthy subjects, and analytical considerations. Clin Chim Acta 2018; 483:291-295. [DOI: 10.1016/j.cca.2018.05.027] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Revised: 05/13/2018] [Accepted: 05/13/2018] [Indexed: 12/13/2022]
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Laursen TL, Wong GLH, Kazankov K, Sandahl T, Møller HJ, Hamilton-Dutoit S, George J, Chan HLY, Grønbaek H. Soluble CD163 and mannose receptor associate with chronic hepatitis B activity and fibrosis and decline with treatment. J Gastroenterol Hepatol 2018; 33:484-491. [PMID: 28618015 DOI: 10.1111/jgh.13849] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2017] [Revised: 05/19/2017] [Accepted: 06/10/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIM Liver macrophages are activated in chronic hepatitis B virus (CHB) infection and play a pivotal role in hepatic inflammation and fibrosis. However, their role during antiviral treatment is unclear. The soluble (s) macrophage activation markers, sCD163 and mannose receptor (sMR), are released during liver damage, and their serum levels reflect liver disease severity and portal hypertension. We aimed to investigate associations between sCD163 and sMR and histopathological activity and fibrosis and changes in sCD163, sMR, and hepatic CD163-expression following antiviral treatment in CHB patients. METHODS We assessed Ishak histological necroinflammatory activity and fibrosis scores in liver biopsies from 254 CHB patients and serially in 71 patients before and after nucleoside-analogue treatment. Liver CD163-expression was semi-quantitatively determined by immunohistochemistry and serum sCD163 and sMR measured by enzyme-linked immunosorbent assays. RESULTS Before treatment, the mean levels of sCD163 and sMR were 3.57 (SD 1.72) mg/L and 0.35 (0.12) mg/L. sCD163 and sMR increased with histological inflammatory activity (sCD163: r = 0.46, P < 0.00001; sMR: r = 0.48, P < 0.00001) and correlated positively with fibrosis (sCD163: OR 1.16, 95% CI:1.03-1.31; sMR: OR 1.34, 95% CI:1.13-1.59); both were markers of fibrosis independent of other biochemical parameters and risk factors. Antiviral treatment significantly reduced sCD163 (3.76 [1.46] vs 2.31 [0.95], P < 0.00001), sMR (0.37 [0.1] vs 0.29 [0.07], P < 0.00001) and hepatic CD163-expression (P = 0.0002). CONCLUSION The macrophage activation markers sCD163 and sMR were associated with activity and fibrosis in liver biopsies from CHB patients. Both serum markers decreased with antiviral treatment, along with decreased hepatic CD163 expression.
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Affiliation(s)
- Tea Lund Laursen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Grace Lai-Hung Wong
- Department of Medicine and Therapeutics and Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong
| | - Konstantin Kazankov
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Thomas Sandahl
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Holger Jon Møller
- Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
| | | | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Westmead, New South Wales, Australia
| | - Henry Lik-Yuen Chan
- Department of Medicine and Therapeutics and Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong
| | - Henning Grønbaek
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
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The soluble mannose receptor (sMR) is elevated in alcoholic liver disease and associated with disease severity, portal hypertension, and mortality in cirrhosis patients. PLoS One 2017; 12:e0189345. [PMID: 29236785 PMCID: PMC5728513 DOI: 10.1371/journal.pone.0189345] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Accepted: 11/24/2017] [Indexed: 12/13/2022] Open
Abstract
Background and aims Hepatic macrophages (Kupffer cells) are involved in the immunopathology of alcoholic liver disease (ALD). The mannose receptor (MR, CD206), expressed primarily by macrophages, mediates endocytosis, antigen presentation and T-cell activation. A soluble form, sMR, has recently been identified in humans. We aimed to study plasma sMR levels and its correlation with disease severity and survival in ALD patients. Methods We included 50 patients with alcoholic hepatitis (AH), 68 alcoholic cirrhosis (AC) patients (Child-Pugh A (23), B (24), C (21)), and 21 healthy controls (HC). Liver status was described by the Glasgow Alcoholic Hepatitis Score (GAHS), Child-Pugh (CP) and MELD-scores, and in AC patients the hepatic venous pressure gradient (HVPG) was measured by liver vein catheterisation. We used Kaplan-Meier statistics for short-term survival (84-days) in AH patients and long-term (4 years) in AC patients. We measured plasma sMR by ELISA. Results Median sMR concentrations were significantly elevated in AH 1.32(IQR:0.69) and AC 0.46(0.5) compared to HC 0.2(0.06) mg/L; p<0.001 and increased in a stepwise manner with the CP-score (p<0.001). In AC sMR predicted portal hypertension (HVPG ≥10 mmHg) with an area under the Receiver Operator Characteristics curve of 0.86 and a high sMR cut-off (>0.43 mg/l) was associated with increased mortality (p = 0.005). Conclusion The soluble mannose receptor is elevated in alcoholic liver disease, especially in patients with AH. Its blood level predicts portal hypertension and long-term mortality in AC patients.
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Assessment of Haemodynamic Response to Nonselective Beta-Blockers in Portal Hypertension by Phase-Contrast Magnetic Resonance Angiography. BIOMED RESEARCH INTERNATIONAL 2017; 2017:9281450. [PMID: 28698881 PMCID: PMC5494094 DOI: 10.1155/2017/9281450] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Revised: 04/08/2017] [Accepted: 05/04/2017] [Indexed: 02/07/2023]
Abstract
A significant unmet need exists for accurate, reproducible, noninvasive diagnostic tools to assess and monitor portal hypertension (PHT). We report the first use of quantitative MRI markers for the haemodynamic assessment of nonselective beta-blockers (NSBB) in PHT. In a randomized parallel feasibility study in 22 adult patients with PHT and a clinical indication for NSBB, we acquired haemodynamic data at baseline and after 4 weeks of NSBB (propranolol or carvedilol) using phase-contrast MR angiography (PC-MRA) in selected intra-abdominal vessels. T1 mapping of liver and spleen was undertaken to assess changes in tissue composition. Target NSBB dose was achieved in 82%. There was a substantial reduction from baseline in mean average flow in the superior abdominal aorta after 4 weeks of NSBB therapy (4.49 ± 0.98 versus 3.82 ± 0.86 L/min, P = 0.03) but there were no statistically significant differences in flow in any other vessels, even in patients with >25% decrease in heart rate (47% of patients). Mean percentage change in liver and spleen T1 following NSBB was small and highly variable. In conclusion, PC-MRA was able to detect reduction in cardiac output by NSBB but did not detect significant changes in visceral blood flow or T1. This trial was registered with the ISRCTN registry (ISRCTN98001632).
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Grønbaek H, Kreutzfeldt M, Kazankov K, Jessen N, Sandahl T, Hamilton-Dutoit S, Vilstrup H, J Møller H. Single-centre experience of the macrophage activation marker soluble (s)CD163 - associations with disease activity and treatment response in patients with autoimmune hepatitis. Aliment Pharmacol Ther 2016; 44:1062-1070. [PMID: 27679428 DOI: 10.1111/apt.13801] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Revised: 06/27/2016] [Accepted: 08/24/2016] [Indexed: 12/17/2022]
Abstract
BACKGROUND Autoimmune hepatitis (AIH) is characterised by liver inflammation with reversibility upon anti-inflammatory treatment. Soluble (s)CD163, a specific macrophage activation marker, is associated with inflammation in other liver diseases, but never investigated in AIH. AIM To investigate sCD163 in patients with acute AIH and in complete and incomplete responders to standard anti-inflammatory pharmacotherapy, and during follow-up in treatment naive patients. METHODS In a cross-sectional design, we studied 121 AIH patients (female/male 89/32, median age 49 years); of these, we prospectively studied 10 treatment naïve AIH patients during prednisolone treatment and tapering. Twenty patients had variant syndromes of AIH and primary biliary cholangitis or primary sclerosing cholangitis. sCD163 was compared with markers of disease activity, severity and treatment response. RESULTS In the patients with acute AIH (n = 21), sCD163 was sixfold increased compared with the normalised levels in patients (n = 32) with complete response to standard treatment [9.5 (3.3-28.8) vs. 1.6 (0.8-3.2) mg/L, P < 0.01)], while the patients (n = 27) with incomplete response had higher sCD163 [2.2 (1.3-7.9), P < 0.05] than the complete responders. sCD163 was positively associated with ALAT, IgG and bilirubin (rho: 0.45-0.59, P < 0.001, all), and negatively to external coagulation factors (rho:-0.34, P < 0.001). In the treatment naïve patients, sCD163 fell during high-dose prednisolone treatment and tapering. Immunohistochemical staining confirmed increased CD163 expression in liver biopsies from patients with acute AIH. CONCLUSIONS sCD163 was markedly elevated in AIH in the acute phase, normalised by successful treatment in complete responders, but remained higher in the incompletely responding cases. Our results demonstrate macrophage activation in AIH paralleling disease activity, severity and treatment response, suggesting a role for macrophage activation in AIH.
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Affiliation(s)
- H Grønbaek
- Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
| | - M Kreutzfeldt
- Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - K Kazankov
- Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - N Jessen
- Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - T Sandahl
- Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | | | - H Vilstrup
- Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - H J Møller
- Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
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Snowdon VK, Fallowfield JA. Editorial: measuring inflammatory and fibrotic components of portal hypertension - a noninvasive hepatic venous pressure gradient? Aliment Pharmacol Ther 2016; 44:204-5. [PMID: 27296685 DOI: 10.1111/apt.13667] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Affiliation(s)
- V K Snowdon
- UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK
| | - J A Fallowfield
- MRC/University of Edinburgh Centre for Inflammation Research, Edinburgh, UK.
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Sandahl TD, Møller HJ, Møller S, Garcia-Pagan JC, Vilstrup H, Grønbaek H. Editorial: measuring inflammatory and fibrotic components of portal hypertension - a non-invasive hepatic venous pressure gradient? Authors' reply. Aliment Pharmacol Ther 2016; 44:205-6. [PMID: 27296686 DOI: 10.1111/apt.13683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/08/2022]
Affiliation(s)
- T D Sandahl
- Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
| | - H J Møller
- Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
| | - S Møller
- Department of Clinical Physiology and Nuclear Medicine, 239 Center for Functional and Diagnostic Imaging and Research, Faculty of Health Sciences Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark
| | - J C Garcia-Pagan
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic, Institut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Barcelona, Spain
| | - H Vilstrup
- Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - H Grønbaek
- Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
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