|
1
|
Ivashkin VT, Drapkina OM, Maevskaya MV, Raikhelson KL, Okovityi SV, Zharkova MS, Grechishnikova VR, Abdulganieva DI, Alekseenko SA, Ardatskaya MD, Bakulin IG, Bakulina NV, Bogomolov PO, Breder VV, Vinnitskaya EV, Geyvandova NI, Golovanova EV, Grinevich VB, Doshchitsin VL, Dudinskaya EN, Ershova EV, Kodzoeva KB, Kozlova IV, Komshilova KA, Konev YV, Korochanskaya NV, Kotovskaya YV, Kravchuk YA, Loranskaya ID, Maev IV, Martynov AI, Mekhtiev SN, Mishina EE, Nadinskaia MY, Nikitin IG, Osipenko MF, Ostroumova OD, Pavlov CS, Pogosova NV, Radchenko VG, Roytberg GE, Saifutdinov RG, Samsonov AA, Seliverstov PV, Sitkin SI, Tarasova LV, Tarzimanova AI, Tkacheva ON, Tkachenko EI, Troshina EA, Turkina SV, Uspenskiy YP, Fominykh YA, Khlynova OV, Tsyganova YV, Shamkhalova MS, Sharkhun OO, Shestakova MV. Clinical Guidelines of the Russian Society for the Study of the Liver, Russian Gastroenterological Association, Russian Society for the Prevention of Non-Communicable Diseases, Russian Association of Endocrinologists, Russian Scientific Medical Society of Therapists, National Society of Preventive Cardiology, Russian Association of Gerontologists and Geriatricians on Non-Alcoholic Fatty Liver Disease. RUSSIAN JOURNAL OF GASTROENTEROLOGY, HEPATOLOGY, COLOPROCTOLOGY 2025; 35:94-152. [DOI: 10.22416/1382-4376-2025-35-1-94-152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/28/2025]
Abstract
Aim. The clinical guidelines are intended to provide information support for making decisions by gastroenterologists, general practitioners and internists that will improve the quality of medical care for patients with non-alcoholic fatty liver disease, taking into account the latest clinical data and principles of evidence-based medicine. Key points. Clinical guidelines contain information about current views on etiology, risk factors and pathogenesis of nonalcoholic fatty liver disease, peculiarities of its clinical course. Also given recommendations provide information on current methods of laboratory and instrumental diagnostics, invasive and non-invasive tools for nonalcoholic fatty liver disease and its clinical phenotypes assessment, approaches to its treatment, considering the presence of comorbidities, features of dispensary monitoring and prophylaxis. The information is illustrated with algorithms of differential diagnosis and physician's actions. In addition, there is information for the patient and criteria for assessing the quality of medical care. Conclusion. Awareness of specialists in the issues of diagnosis, treatment and follow-up of patients with nonalcoholic fatty liver disease contributes to the timely diagnosis and initiation of treatment, which in the long term will significantly affect their prognosis and quality of life.
Collapse
Affiliation(s)
- V. T. Ivashkin
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - O. M. Drapkina
- National Medical Research Center for Therapy and Preventive Medicine
| | - M. V. Maevskaya
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - K. L. Raikhelson
- Saint Petersburg State University;
Academician I.P. Pavlov First Saint Petersburg State Medical University
| | - S. V. Okovityi
- Saint Petersburg State Chemical Pharmaceutical University
| | - M. S. Zharkova
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | | | | | | | - M. D. Ardatskaya
- Central State Medical Academy of the Department of Presidential Affairs
| | - I. G. Bakulin
- North-Western State Medical University named after I.I. Mechnikov
| | - N. V. Bakulina
- North-Western State Medical University named after I.I. Mechnikov
| | - P. O. Bogomolov
- Russian University of Medicine;
Moscow Regional Research Clinical Institute
| | - V. V. Breder
- National Medical Research Center of Oncology named after N.N. Blokhin
| | | | | | | | | | | | | | | | - K. B. Kodzoeva
- National Medical Research Center for Transplantology and Artificial Organs named after Academician V.I. Shumakov
| | - I. V. Kozlova
- Saratov State Medical University named after V.I. Razumovsky
| | | | | | | | | | | | | | | | | | - S. N. Mekhtiev
- Academician I.P. Pavlov First Saint Petersburg State Medical University
| | | | - M. Yu. Nadinskaia
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - I. G. Nikitin
- N.I. Pirogov Russian National Research Medical University;
National Medical Research Center “Treatment and Rehabilitation Center”
| | | | | | - Ch. S. Pavlov
- I.M. Sechenov First Moscow State Medical University (Sechenov University);
Moscow Multidisciplinary Scientific and Clinical Center named after S.P. Botkin
| | - N. V. Pogosova
- National Medical Research Center of Cardiology named after Academician E.I. Chazov
| | | | - G. E. Roytberg
- N.I. Pirogov Russian National Research Medical University
| | - R. G. Saifutdinov
- Kazan State Medical Academy — Branch Campus of the Russian Medical Academy of Continuous Professional Education
| | | | | | - S. I. Sitkin
- North-Western State Medical University named after I.I. Mechnikov;
V.A. Almazov National Medical Research Center
| | | | - A. I. Tarzimanova
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - O. N. Tkacheva
- N.I. Pirogov Russian National Research Medical University
| | | | | | | | - Yu. P. Uspenskiy
- Academician I.P. Pavlov First Saint Petersburg State Medical University;
Saint Petersburg State Pediatric Medical University
| | - Yu. A. Fominykh
- V.A. Almazov National Medical Research Center; Saint Petersburg State Pediatric Medical University
| | - O. V. Khlynova
- Perm State Medical University named after Academician E.A. Wagner
| | | | | | - O. O. Sharkhun
- N.I. Pirogov Russian National Research Medical University
| | | |
Collapse
|
|
2
|
Lai M, Dillon ST, Gu X, Morhardt TL, Xu Y, Chan NY, Xiong B, Can H, Ngo LH, Jin L, Zhang X, Moreira CC, Leite NC, Villela-Nogueira CA, Otu HH, Schattenberg JM, Schuppan D, Afdhal NH, Libermann TA. Serum protein risk stratification score for diagnostic evaluation of metabolic dysfunction-associated steatohepatitis. Hepatol Commun 2024; 8:e0586. [PMID: 39621304 PMCID: PMC11608748 DOI: 10.1097/hc9.0000000000000586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 09/08/2024] [Indexed: 01/03/2025] Open
Abstract
BACKGROUND Reliable, noninvasive tools to diagnose at-risk metabolic dysfunction-associated steatohepatitis (MASH) are urgently needed to improve management. We developed a risk stratification score incorporating proteomics-derived serum markers with clinical variables to identify high-risk patients with MASH (NAFLD activity score >4 and fibrosis score >2). METHODS In this 3-phase proteomic study of biopsy-proven metabolic dysfunction-associated steatotic fatty liver disease, we first developed a multi-protein predictor for discriminating NAFLD activity score >4 based on SOMAscan proteomics quantifying 1305 serum proteins from 57 US patients. Four key predictor proteins were verified by ELISA in the expanded US cohort (N = 168) and enhanced by adding clinical variables to create the 9-feature MASH Dx score, which predicted MASH and also high-risk MASH (F2+). The MASH Dx score was validated in 2 independent, external cohorts from Germany (N = 139) and Brazil (N = 177). RESULTS The discovery phase identified a 6-protein classifier that achieved an AUC of 0.93 for identifying MASH. Significant elevation of 4 proteins (THBS2, GDF15, SELE, and IGFBP7) was verified by ELISA in the expanded discovery and independently in the 2 external cohorts. MASH Dx score incorporated these proteins with established MASH risk factors (age, body mass index, ALT, diabetes, and hypertension) to achieve good discrimination between MASH and metabolic dysfunction-associated steatotic fatty liver disease without MASH (AUC: 0.87-discovery; 0.83-pooled external validation cohorts), with similar performance when evaluating high-risk MASH F2-4 (vs. MASH F0-1 and metabolic dysfunction-associated steatotic fatty liver disease without MASH). CONCLUSIONS The MASH Dx score offers the first reliable noninvasive approach combining novel, biologically plausible ELISA-based fibrosis markers and clinical parameters to detect high-risk MASH in patient cohorts from the United States, Brazil, and Europe.
Collapse
Affiliation(s)
- Michelle Lai
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
| | - Simon T. Dillon
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
- Division of Interdisciplinary Medicine and Biotechnology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
- Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - Xuesong Gu
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
- Division of Interdisciplinary Medicine and Biotechnology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
- Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - Tina L. Morhardt
- Division of Interdisciplinary Medicine and Biotechnology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
- Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - Yuyan Xu
- Division of Interdisciplinary Medicine and Biotechnology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
- Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - Noel Y. Chan
- Division of Interdisciplinary Medicine and Biotechnology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
- Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - Beibei Xiong
- Department of Electrical and Computer Engineering, University of Nebraska-Lincoln, Lincoln, Nebraska, USA
| | - Handan Can
- Department of Electrical and Computer Engineering, University of Nebraska-Lincoln, Lincoln, Nebraska, USA
| | - Long H. Ngo
- Harvard Medical School, Boston, Massachusetts, USA
- Divisions of General Medicine and Primary Care, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - Lina Jin
- Harvard Medical School, Boston, Massachusetts, USA
- Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA
| | - Xuehong Zhang
- Harvard Medical School, Boston, Massachusetts, USA
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Claudia C. Moreira
- Division of Hepatology, Department of Internal Medicine, School of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Nathalie C. Leite
- Division of Hepatology, Department of Internal Medicine, School of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Cristiane A. Villela-Nogueira
- Division of Hepatology, Department of Internal Medicine, School of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Hasan H. Otu
- Department of Electrical and Computer Engineering, University of Nebraska-Lincoln, Lincoln, Nebraska, USA
| | - Jörn M. Schattenberg
- Metabolic Liver Research Program, Department of Medicine, University Medical Center, Mainz, Germany
- Department of Internal Medicine II and University of the Saarland, University Medical Center Homburg, Homburg, Germany
| | - Detlef Schuppan
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
- Institute of Translational Immunology and Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Nezam H. Afdhal
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
| | - Towia A. Libermann
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
- Division of Interdisciplinary Medicine and Biotechnology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
- Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| |
Collapse
|
|
3
|
Boccatonda A, Del Cane L, Marola L, D’Ardes D, Lessiani G, di Gregorio N, Ferri C, Cipollone F, Serra C, Santilli F, Piscaglia F. Platelet, Antiplatelet Therapy and Metabolic Dysfunction-Associated Steatotic Liver Disease: A Narrative Review. Life (Basel) 2024; 14:473. [PMID: 38672744 PMCID: PMC11051088 DOI: 10.3390/life14040473] [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: 02/28/2024] [Revised: 03/29/2024] [Accepted: 04/03/2024] [Indexed: 04/28/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is not only related to traditional cardiovascular risk factors like type 2 diabetes mellitus and obesity, but it is also an independent risk factor for the development of cardiovascular disease. MASLD has been shown to be independently related to endothelial dysfunction and atherosclerosis. MASLD is characterized by a chronic proinflammatory response that, in turn, may induce a prothrombotic state. Several mechanisms such as endothelial and platelet dysfunction, changes in the coagulative factors, lower fibrinolytic activity can contribute to induce the prothrombotic state. Platelets are players and addresses of metabolic dysregulation; obesity and insulin resistance are related to platelet hyperactivation. Furthermore, platelets can exert a direct effect on liver cells, particularly through the release of mediators from granules. Growing data in literature support the use of antiplatelet agent as a treatment for MASLD. The use of antiplatelets drugs seems to exert beneficial effects on hepatocellular carcinoma prevention in patients with MASLD, since platelets contribute to fibrosis progression and cancer development. This review aims to summarize the main data on the role of platelets in the pathogenesis of MASLD and its main complications such as cardiovascular events and the development of liver fibrosis. Furthermore, we will examine the role of antiplatelet therapy not only in the prevention and treatment of cardiovascular events but also as a possible anti-fibrotic and anti-tumor agent.
Collapse
Affiliation(s)
- Andrea Boccatonda
- Internal Medicine, Bentivoglio Hospital, AUSL Bologna, 40010 Bentivoglio, Italy
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy;
| | - Lorenza Del Cane
- Nephrology Unit, Department of Life, Health & Environmental Sciences and Internal Medicine, University of L’Aquila, ASL Avezzano-Sulmona-L’Aquila, San Salvatore Hospital, 67100 L’Aquila, Italy; (L.D.C.); (L.M.); (N.d.G.); (C.F.)
| | - Lara Marola
- Nephrology Unit, Department of Life, Health & Environmental Sciences and Internal Medicine, University of L’Aquila, ASL Avezzano-Sulmona-L’Aquila, San Salvatore Hospital, 67100 L’Aquila, Italy; (L.D.C.); (L.M.); (N.d.G.); (C.F.)
| | - Damiano D’Ardes
- Institute of “Clinica Medica”, Department of Medicine and Aging Science, “G. D’Annunzio” University of Chieti, 66100 Chieti, Italy (F.C.)
| | | | - Nicoletta di Gregorio
- Nephrology Unit, Department of Life, Health & Environmental Sciences and Internal Medicine, University of L’Aquila, ASL Avezzano-Sulmona-L’Aquila, San Salvatore Hospital, 67100 L’Aquila, Italy; (L.D.C.); (L.M.); (N.d.G.); (C.F.)
| | - Claudio Ferri
- Nephrology Unit, Department of Life, Health & Environmental Sciences and Internal Medicine, University of L’Aquila, ASL Avezzano-Sulmona-L’Aquila, San Salvatore Hospital, 67100 L’Aquila, Italy; (L.D.C.); (L.M.); (N.d.G.); (C.F.)
| | - Francesco Cipollone
- Institute of “Clinica Medica”, Department of Medicine and Aging Science, “G. D’Annunzio” University of Chieti, 66100 Chieti, Italy (F.C.)
| | - Carla Serra
- Interventional, Diagnostic and Therapeutic Ultrasound Unit, IRCCS, Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy;
| | - Francesca Santilli
- Department of Medicine and Aging Sciences, Center for Advanced Studies and Technology, University of Chieti, 66100 Chieti, Italy;
| | - Fabio Piscaglia
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy;
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| |
Collapse
|
|
4
|
Arriola-Montenegro J, Beas R, Cerna-Viacava R, Chaponan-Lavalle A, Hernandez Randich K, Chambergo-Michilot D, Flores Sanga H, Mutirangura P. Therapies for patients with coexisting heart failure with reduced ejection fraction and non-alcoholic fatty liver disease. World J Cardiol 2023; 15:328-341. [PMID: 37576545 PMCID: PMC10415861 DOI: 10.4330/wjc.v15.i7.328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 06/09/2023] [Accepted: 06/21/2023] [Indexed: 07/25/2023] Open
Abstract
Heart failure with reduced ejection fraction (HFrEF) and nonalcoholic fatty liver disease (NAFLD) are two common comorbidities that share similar pathophysiological mechanisms. There is a growing interest in the potential of targeted therapies to improve outcomes in patients with coexisting HFrEF and NAFLD. This manuscript reviews current and potential therapies for patients with coexisting HFrEF and NAFLD. Pharmacological therapies, including angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, mineralocorticoids receptor antagonist, and sodium-glucose cotransporter-2 inhibitors, have been shown to reduce fibrosis and fat deposits in the liver. However, there are currently no data showing the beneficial effects of sacubitril/valsartan, ivabradine, hydralazine, isosorbide nitrates, digoxin, or beta blockers on NAFLD in patients with HFrEF. This study highlights the importance of considering HFrEF and NAFLD when developing treatment plans for patients with these comorbidities. Further research is needed in patients with coexisting HFrEF and NAFLD, with an emphasis on novel therapies and the importance of a multidisciplinary approach for managing these complex comorbidities.
Collapse
Affiliation(s)
- Jose Arriola-Montenegro
- Department of Internal Medicine, University of Minnesota, Minneapolis, MN 55455, United States.
| | - Renato Beas
- Department of Medicine, Indiana University School of Medicine, Indiana, IN 46202, United States
| | | | | | | | | | - Herson Flores Sanga
- Department of Telemedicine, Cardiology, Hospital Nacional Carlos Alberto Seguin Escobedo, Arequipa 8610, Peru
| | - Pornthira Mutirangura
- Department of Medicine, University of Minnesota, Minneapolis, MN 55415, United States
| |
Collapse
|
|
5
|
Liu Y, Song J, Wang W, Zhang K, Yang J, Wen J, Meng X, Gao J, Wang J, Shao C, Tang YD. Association between liver fibrosis and thrombotic or bleeding events in acute coronary syndrome patients. Thromb J 2022; 20:82. [PMID: 36578015 PMCID: PMC9798679 DOI: 10.1186/s12959-022-00441-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 12/12/2022] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND The prognostic implication of liver fibrosis in acute coronary syndrome (ACS) patients are scarce. We sought to evaluate whether liver fibrosis scores (LFS) were associated with thrombotic or bleeding events in patients with acute coronary syndrome. METHODS We included 6386 ACS patients who underwent percutaneous coronary intervention (PCI). This study determined liver fibrosis with aspartate aminotransferase to platelet ratio index (APRI), aspartate aminotransferase to alanine aminotransferase ratio (AST/ALT ratio), Forns score, and nonalcoholic fatty liver disease fibrosis score (NFS). The primary endpoint was major adverse cardiac and cerebrovascular events (MACCE), a composite of all-cause mortality (ACM), myocardial infarction (MI), and ischemic stroke (IS). RESULTS During the follow-up, 259 (4.06%) MACCE and 190 (2.98%) bleeding events were recorded. As a continuous variable or a categorical variable stratified by the literature-based cutoff, LFS was positively associated with MACCE (p > 0.05) but not with bleeding events. Compared with subjects with low APRI scores, AST/ALT ratio scores, Forns scores, and NFS scores, subjects with high scores had a 1.57- to 3.73-fold increase risk of MACCE after adjustment (all p < 0.05). The positive relationship between LFS and MACCE was consistent in different subgroups. CONCLUSIONS In ACS patients, increased LFS predicted an elevated risk of thrombotic events but not bleeding. LFS may contribute to thrombotic risk stratification after ACS.
Collapse
Affiliation(s)
- Yupeng Liu
- grid.410643.4Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Jingjing Song
- grid.506261.60000 0001 0706 7839Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wenyao Wang
- grid.411642.40000 0004 0605 3760Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital , Beijing, China ,grid.419897.a0000 0004 0369 313XKey Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
| | - Kuo Zhang
- grid.506261.60000 0001 0706 7839Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jie Yang
- grid.506261.60000 0001 0706 7839Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jun Wen
- grid.506261.60000 0001 0706 7839Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiangbin Meng
- grid.411642.40000 0004 0605 3760Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital , Beijing, China ,grid.419897.a0000 0004 0369 313XKey Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
| | - Jun Gao
- grid.411642.40000 0004 0605 3760Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital , Beijing, China ,grid.419897.a0000 0004 0369 313XKey Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
| | - Jingjia Wang
- grid.411642.40000 0004 0605 3760Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital , Beijing, China ,grid.419897.a0000 0004 0369 313XKey Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
| | - Chunli Shao
- grid.411642.40000 0004 0605 3760Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital , Beijing, China ,grid.419897.a0000 0004 0369 313XKey Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
| | - Yi-Da Tang
- grid.411642.40000 0004 0605 3760Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital , Beijing, China ,grid.419897.a0000 0004 0369 313XKey Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
| |
Collapse
|
|
6
|
Ivashkin VT, Maevskaya MV, Zharkova MS, Kotovskaya YV, Tkacheva ON, Troshina EA, Shestakova MV, Maev IV, Breder VV, Gheivandova NI, Doshchitsin VL, Dudinskaya EN, Ershova EV, Kodzoeva KB, Komshilova KA, Korochanskaya NV, Mayorov AY, Mishina EE, Nadinskaya MY, Nikitin IG, Pogosova NV, Tarzimanova AI, Shamkhalova MS. Clinical Practice Guidelines of the Russian Scientific Liver Society, Russian Gastroenterological Association, Russian Association of Endocrinologists, Russian Association of Gerontologists and Geriatricians and National Society for Preventive Cardiology on Diagnosis and Treatment of Non-Alcoholic Liver Disease. RUSSIAN JOURNAL OF GASTROENTEROLOGY, HEPATOLOGY, COLOPROCTOLOGY 2022; 32:104-140. [DOI: 10.22416/1382-4376-2022-32-4-104-140] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Aim:present clinical guidelines, aimed at general practitioners, gastroenterologists, cardiologists, endocrinologists, comprise up-to-date methods of diagnosis and treatment of non-alcoholic fatty liver disease.Key points.Nonalcoholic fatty liver disease, the most wide-spread chronic liver disease, is characterized by accumulation of fat by more than 5 % of hepatocytes and presented by two histological forms: steatosis and nonalcoholic steatohepatitis. Clinical guidelines provide current views on pathogenesis of nonalcoholic fatty liver disease as a multisystem disease, methods of invasive and noninvasive diagnosis of steatosis and liver fibrosis, principles of nondrug treatment and pharmacotherapy of nonalcoholic fatty liver disease and associated conditions. Complications of nonalcoholic fatty liver disease include aggravation of cardiometabolic risks, development of hepatocellular cancer, progression of liver fibrosis to cirrhotic stage.Conclusion.Progression of liver disease can be avoided, cardiometabolic risks can be reduced and patients' prognosis — improved by the timely recognition of diagnosis of nonalcoholic fatty liver disease and associated comorbidities and competent multidisciplinary management of these patients.
Collapse
Affiliation(s)
| | | | | | - Yu. V. Kotovskaya
- Russian Gerontology Research and Clinical Centre, Pirogov Russian National Research Medical University
| | - O. N. Tkacheva
- Russian Gerontology Research and Clinical Centre, Pirogov Russian National Research Medical University
| | | | | | - I. V. Maev
- Yevdokimov Moscow State University of Medicine and Dentistry
| | - V. V. Breder
- Blokhin National Medical Research Center of Oncology
| | | | | | - E. N. Dudinskaya
- Russian Gerontology Research and Clinical Centre, Pirogov Russian National Research Medical University
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
7
|
Maevskaya M, Kotovskaya Y, Ivashkin V, Tkacheva O, Troshina E, Shestakova M, Breder V, Geyvandova N, Doschitsin V, Dudinskaya E, Ershova E, Kodzoeva K, Komshilova K, Korochanskaya N, Mayorov A, Mishina E, Nadinskaya M, Nikitin I, Pogosova N, Tarzimanova A, Shamkhalova M. The National Consensus statement on the management of adult patients with non-alcoholic fatty liver disease and main comorbidities. TERAPEVT ARKH 2022; 94:216-253. [PMID: 36286746 DOI: 10.26442/00403660.2022.02.201363] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Indexed: 12/15/2022]
Abstract
The National Consensus was prepared with the participation of the National Medical Association for the Study of the Multimorbidity, Russian Scientific Liver Society, Russian Association of Endocrinologists, Russian Association of Gerontologists and Geriatricians, National Society for Preventive Cardiology, Professional Foundation for the Promotion of Medicine Fund PROFMEDFORUM.
The aim of the multidisciplinary consensus is a detailed analysis of the course of non-alcoholic fatty liver disease (NAFLD) and the main associated conditions. The definition of NAFLD is given, its prevalence is described, methods for diagnosing its components such as steatosis, inflammation and fibrosis are described.
The association of NAFLD with a number of cardio-metabolic diseases (arterial hypertension, atherosclerosis, thrombotic complications, type 2 diabetes mellitus (T2DM), obesity, dyslipidemia, etc.), chronic kidney disease (CKD) and the risk of developing hepatocellular cancer (HCC) were analyzed. The review of non-drug methods of treatment of NAFLD and modern opportunities of pharmacotherapy are presented.
The possibilities of new molecules in the treatment of NAFLD are considered: agonists of nuclear receptors, antagonists of pro-inflammatory molecules, etc. The positive properties and disadvantages of currently used drugs (vitamin E, thiazolidinediones, etc.) are described. Special attention is paid to the multi-target ursodeoxycholic acid (UDCA) molecule in the complex treatment of NAFLD as a multifactorial disease. Its anti-inflammatory, anti-oxidant and cytoprotective properties, the ability to reduce steatosis an independent risk factor for the development of cardiovascular pathology, reduce inflammation and hepatic fibrosis through the modulation of autophagy are considered.
The ability of UDCA to influence glucose and lipid homeostasis and to have an anticarcinogenic effect has been demonstrated. The Consensus statement has advanced provisions for practitioners to optimize the diagnosis and treatment of NAFLD and related common pathogenetic links of cardio-metabolic diseases.
Collapse
|
|
8
|
Chi ZC. Research status and progress of metabolic associated fatty liver disease. Shijie Huaren Xiaohua Zazhi 2022; 30:1-16. [DOI: 10.11569/wcjd.v30.i1.1] [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: 02/06/2023] Open
Abstract
Metabolic associated fatty liver disease (MAFLD) is a more appropriate general predicate to describe non-alcoholic fatty liver disease. The new definition lists metabolic dysfunction as an important cause of liver disease, demonstrates the high heterogeneity of this condition, and speeds up the transformation path to new treatment. The incidence of extrahepatic complications and related diseases of MAFLD far exceed that of the liver disease itself, which seriously threatens human health. In view of the current insufficient understanding of its severity, and the imperfect understanding of the disease scope, pathogenesis, and diagnosis of extrahepatic complications, especially the lack of effective drug treatment, this paper introduces and reviews the research status and progress of extrahepatic complications of MAFLD.
Collapse
Affiliation(s)
- Zhao-Chun Chi
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao 266011, Shandong Province, China
| |
Collapse
|
|
9
|
Virović-Jukić L, Stojsavljević-Shapeski S, Forgač J, Kukla M, Mikolašević I. Non-alcoholic fatty liver disease - a procoagulant condition? Croat Med J 2021; 62:25-33. [PMID: 33660958 PMCID: PMC7976878 DOI: 10.3325/cmj.2021.62.25] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2020] [Accepted: 02/15/2021] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is associated with a number of extrahepatic comorbidities and considerable cardiovascular morbidity and mortality, which is possibly related to coagulation changes associated with metabolic syndrome. Coagulation disorders are common in patients with liver disease of any etiology, and here we review possible alterations in coagulation cascade specific to NAFLD. We discuss derangements in the coagulation cascade and fibrinolysis, endothelial dysfunction, and platelet abnormalities as possible culprits for altered coagulation and explore the significance of these changes for potential treatment targets.
Collapse
Affiliation(s)
- Lucija Virović-Jukić
- Lucija Virović-Jukić, Department of Gastroenterology and Hepatology, Sestre Milosrdnice University Hospital Center, Vinogradska cesta 29, 10000 Zagreb, Croatia,
| | | | | | | | | |
Collapse
|
|
10
|
Translational insight into prothrombotic state and hypercoagulation in nonalcoholic fatty liver disease. Thromb Res 2020; 198:139-150. [PMID: 33340925 DOI: 10.1016/j.thromres.2020.12.002] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 11/17/2020] [Accepted: 12/07/2020] [Indexed: 02/08/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is an emerging and threatening pathological condition, ranging from fatty liver (FL) to chronic steatohepatitis (NASH), liver cirrhosis, and eventually to hepatocellular carcinoma (HCC). Recent findings suggest that patients with NAFLD have a higher risk of cardiovascular events and thromboembolism and that this risk is independent of metabolic diseases that are frequently associated with NAFLD, such as diabetes, hyperlipidaemia, and obesity. The vascular involvement of NAFLD might be considered its systemic burden, conditioning higher mortality in patients affected by the disease. These clinical findings suggested the existence of a prothrombotic state in NAFLD, which is partially unexplored and whose underlying mechanisms are to date not completely understood. Here, we review the mechanisms involved in the pathogenesis of the prothrombotic state in NAFLD across the progression from the healthy liver through the different stages of the disease. We focused on the possible role of several metabolic features of NAFLD possibly leading to hypercoagulation other than endothelial and platelet activation, such as insulin-resistance, nitric oxide production regulation, and gut microbiota homeostasis. Also, we analysed the involvement of plasminogen activator inhibitor-1 (PAI-1) and thromboinflammation taking place in NAFLD. Finally, we described factors striking a prothrombotic imbalance in NASH cirrhosis, with a particular focus on the pathogenesis of portal vein thrombosis.
Collapse
|
|
11
|
Mahmoud HEDA, Yousry WA, Saleh SA, El Badry M, Hussein A, Ali MH, El-Hariri HM. Renal resistive index in non-alcoholic fatty liver disease as an indicator of early renal affection. EGYPTIAN LIVER JOURNAL 2020. [DOI: 10.1186/s43066-019-0006-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Nonalcoholic fatty liver disease (NAFLD) is a possible risk factor for chronic kidney disease (CKD). Renal resistive index (RRI) which is a ratio of peak systolic and end diastolic velocity can test arterial stiffness and endothelial renal dysfunction. The aim of the work is to detect the relation between NAFLD and RRI as an indicator of early renal affection and its relation to the disease severity. This study included 150 subjects divided into 3 groups: patients with NASH, simple steatosis, and control group (50 patients each). All patients were subjected to full history taking, clinical examination, laboratory investigations, abdominal ultrasound examination, and RRI measurement.
Results
6.0% of NASH patients had significant fibrosis by NAFLD fibrosis score. RRI was significantly higher in NASH patients with fibrosis (mean = 0.74) than NASH patients without fibrosis (mean = 0.65) and patients with simple steatosis (mean = 0.63). It was the lowest in normal controls (mean = 0.61). There were significant correlations between RRI and age, BMI, serum lipids, liver enzymes, and NAFLD fibrosis score. Multiple linear regression analysis found that age and serum cholesterol were significant independent factors of increased RRI (p < 0.0001). RRI showed low diagnostic performance in differentiation between NASH and simple steatosis using ROC curve.
Conclusion
RRI was significantly higher in NASH patients with and without hepatic fibrosis. RRI correlates significantly with NAFLD fibrosis score. RRI can be used as an indicator of early renal affection in patients with NAFLD.
Collapse
|
|
12
|
Spinosa M, Stine JG. Nonalcoholic Fatty Liver Disease-Evidence for a Thrombophilic State? Curr Pharm Des 2020; 26:1036-1044. [PMID: 32003679 DOI: 10.2174/1381612826666200131101553] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Accepted: 12/16/2019] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease is the leading cause of liver disease worldwide. It has expansive extrahepatic morbidity and mortality including increased rates of both cardiovascular disease and venous thromboembolism. Derangements in primary, secondary and tertiary hemostasis are found in nonalcoholic fatty liver disease independent of those ascribed to end-stage liver disease. The abnormalities across all stages of hemostasis explain the increased rates of clinically relevant thrombotic events, including pulmonary embolism, deep vein thrombosis and portal vein thrombosis, which on an epidemiologic basis appears to be independent of obesity and other traditional venous thromboembolic risk factors. However, given the complex interaction between obesity, body composition and nonalcoholic fatty liver disease and the potential for exercise to benefit all three, more research is needed to further define the role of each in contributing to the prohemostatic state of nonalcoholic fatty liver disease in order to improve patient oriented outcomes.
Collapse
Affiliation(s)
- Margaret Spinosa
- Department of Medicine, Pennsylvania State University Milton S. Hershey Medical Center, PA 17033, United States
| | - Jonathan G Stine
- Division of Gastroenterology & Hepatology, Department of Medicine, Pennsylvania State University Milton S. Hershey Medical Center, United States.,Department of Public Health Sciences, Pennsylvania State University Milton S. Hershey Medical Center, PA 17033, United States
| |
Collapse
|
|
13
|
Bhangui P, Fernandes ESM, Di Benedetto F, Joo DJ, Nadalin S. Current management of portal vein thrombosis in liver transplantation. Int J Surg 2020; 82S:122-127. [PMID: 32387201 DOI: 10.1016/j.ijsu.2020.04.068] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 04/15/2020] [Accepted: 04/28/2020] [Indexed: 02/07/2023]
Abstract
Nontumoral portal vein thrombosis (PVT) is present at liver transplantation (LT) in 5-26% of cirrhotic patients, and is known to affect post LT outcomes. Up to 31% of patients who are found to have PVT at the time of LT, would have had PVT at the time of initial listing, but others develop PVT during the waiting period. Adequate screening and treatment of the PVT on the waiting list for LT is thus essential so that a portoportal anastomoses can be performed at the time of LT. Early PVT (Yerdel Grade I/II) can be usually managed by thrombectomy, whereas Grade III PVT may require a jump graft from the superior mesenteric vein to the graft PV. Complete portomesenteric thrombosis is a huge challenge, and sometimes a cause for denying a LT in these patients, with multivisceral transplant being the only alternative. The presence of spontaneous, or previously surgically created portosytemic shunts like the leinorenal shunt, may serve as a good inflow option (renoportal anastomosis) in these patients to establish a physiological reconstruction. Although challenging, good outcomes are possible in patients with complex PVT if the appropriate surgical technique is chosen to ensure portal inflow and resolution of PHT post LT.
Collapse
Affiliation(s)
- Prashant Bhangui
- Institute of Liver Transplantation and Regenerative Medicine, Medanta-The Medicity, Delhi-NCR, India.
| | - Eduardo S M Fernandes
- Department of Gastrointestinal Surgery - Rio de Janeiro Federal University and Liver Transplant Unit - São Lucas Hospital RJ, Brazil
| | - Fabrizio Di Benedetto
- HPB Surgery and Liver Transplant Unit, University of Modena and Reggio Emilia, Modena, Italy
| | - Dong-Jin Joo
- Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea
| | - Silvio Nadalin
- Department of General, Visceral and Transplantation Surgery, University Hospital Tuebingen, Tübingen, Germany
| |
Collapse
|
|
14
|
NAFLD and Extra-Hepatic Comorbidities: Current Evidence on a Multi-Organ Metabolic Syndrome. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2019; 16:ijerph16183415. [PMID: 31540048 PMCID: PMC6765902 DOI: 10.3390/ijerph16183415] [Citation(s) in RCA: 93] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 09/06/2019] [Accepted: 09/08/2019] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide and its incidence is definitely increasing. NAFLD is a metabolic disease with extensive multi-organ involvement, whose extra-hepatic manifestations include type 2 diabetes mellitus, cardiovascular disease, obstructive sleep apnea, chronic kidney disease, osteoporosis, and polycystic ovarian syndrome. Recently, further evidence has given attention to pathological correlations not strictly related to metabolic disease, also incorporating in this broad spectrum of systemic involvement hypothyroidism, psoriasis, male sexual dysfunction, periodontitis, and urolithiasis. The most common cause of mortality in NAFLD is represented by cardiovascular disease, followed by liver-related complications. Therefore, clinicians should learn to screen and initiate treatment for these extra-hepatic manifestations, in order to provide appropriate multidisciplinary assessments and rigorous surveillance. This review evaluates the current evidence regarding extra-hepatic associations of NAFLD, focusing on the pathogenic hypothesis and the clinical implications.
Collapse
|
|
15
|
Wang C, Wu YB, Wang AP, Jiang JD, Kong WJ. Evaluation of Anticoagulant and Antithrombotic Activities of Berberine: A Focus on the Ameliorative Effect on Blood Hypercoagulation. INT J PHARMACOL 2018. [DOI: 10.3923/ijp.2018.1087.1098] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
|
|
16
|
Kapuria D, Takyar VK, Etzion O, Surana P, O'Keefe JH, Koh C. Association of Hepatic Steatosis With Subclinical Atherosclerosis: Systematic Review and Meta-Analysis. Hepatol Commun 2018; 2:873-883. [PMID: 30094399 PMCID: PMC6078218 DOI: 10.1002/hep4.1199] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Revised: 04/24/2018] [Accepted: 04/24/2018] [Indexed: 12/19/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is becoming common in the United States and throughout the world and can progress to cirrhosis, hepatocellular carcinoma, and death. There is a strong association between coronary artery disease and NAFLD due to common risk factors, such as metabolic syndrome, obesity, and diabetes mellitus. Subclinical atherosclerosis, defined as coronary artery calcification in asymptomatic patients, has been shown to have a higher incidence in patients with NAFLD. We performed a meta‐analysis to examine the association of NAFLD with subclinical atherosclerosis measured by coronary artery calcium (CAC) scoring. Data were extracted from 12 studies selected using a predefined search strategy. NAFLD was diagnosed by abdominal ultrasound or computed tomography scans. The rate of coronary artery calcification was analyzed using random effects models, and publication bias was assessed using Egger's regression test. A total of 42,410 subjects were assessed, including 16,883 patients with NAFLD. Mean CAC score was significantly higher in subjects with NAFLD compared to those without NAFLD (odds ratio with random effects model, 1.64; 95% confidence inteval, 1.42‐1.89). This association remained significant through subgroup analyses for studies with >1,000 subjects and a higher CAC score cutoff of >100. Higher aspartate aminotransferase levels were also associated with increased subclinical atherosclerosis (mean difference 1.77; 95% confidence interval, 1.19‐2.34). Conclusion: There is an increased prevalence of subclinical atherosclerosis in patients with NAFLD, where subclinical atherosclerosis is defined using a “real world” clinical biomarker, namely the CAC score. Prospective studies are needed to establish a causative link between NAFLD and coronary artery disease. (Hepatology Communications 2018; 00:000‐000)
Collapse
Affiliation(s)
- Devika Kapuria
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health Bethesda MD
| | - Varun K Takyar
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health Bethesda MD
| | - Ohad Etzion
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health Bethesda MD
| | - Pallavi Surana
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health Bethesda MD
| | - James H O'Keefe
- Department of Cardiology Saint Luke's Mid-America Heart Institute Kansas City MO
| | - Christopher Koh
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health Bethesda MD
| |
Collapse
|
|
17
|
New insights into NAFLD and subclinical coronary atherosclerosis. J Hepatol 2018; 68:890-892. [PMID: 29410378 PMCID: PMC5903205 DOI: 10.1016/j.jhep.2018.01.023] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Accepted: 01/25/2018] [Indexed: 12/23/2022]
|
|
18
|
Stravitz RT. Hematological Issues in Liver Disease. HEPATIC CRITICAL CARE 2018:163-178. [DOI: 10.1007/978-3-319-66432-3_13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
|
|
19
|
Qi S, Wang C, Li C, Wang P, Liu M. Candidate genes investigation for severe nonalcoholic fatty liver disease based on bioinformatics analysis. Medicine (Baltimore) 2017; 96:e7743. [PMID: 28796060 PMCID: PMC5556226 DOI: 10.1097/md.0000000000007743] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver condition worldwide. However, its etiology and fundamental pathophysiology for the disease process are poorly understood. In this study, we thus used bioinformatics to identify candidate genes potentially causative of severe NAFLD. METHODS Gene expression profile data GSE49541 were downloaded from the Gene Expression Omnibus database. Tissues samples from 32 severe and 40 mild NAFLD patients were evaluated to identify differentially expressed genes (DEGs) between the 2 groups, followed by analyses of Gene Ontology (GO) functions and Kyoto Encyclopedia of Genes and Genomes pathways. Then, a weighted protein-protein interaction (PPI) network was constructed, and subnetworks and candidate genes were screened. Moreover, the GSE48452 data (14 normal liver tissue samples and 18 nonalcoholic steatohepatitis samples) were used to verify the results obtained from the above analyses. RESULTS A total of 100 upregulated genes and 24 downregulated ones were identified in severe NAFLD. Functional enrichment and pathway analyses showed that these DEGs were mainly associated with cell adhesion, inflammatory response, and chemokine activity. The top 5 subnetworks were selected based on the PPI network. A total of 5 hub genes, including ubiquilin 4 (UBQLN4), amyloid-beta precursor protein (APP), sex hormone-binding globulin (SHBG), cadherin-associated protein beta 1 (CTNNB1) and collagen type I alpha 1 (COL1A1), were considered to be candidate genes for NAFLD. In addition, the verification data confirmed the status of COL1A1, SHBG, and APP as candidate genes. CONCLUSION UBQLN4, APP, CTNNB1, SHBG, and COL1A1 might be involved in the development of NAFLD, and are proposed as the potential markers for predicting the development of this condition.
Collapse
Affiliation(s)
- Shan Qi
- Department of Traditional Chinese Medicine, China-Japan Union Hospital of Jilin University
| | - Changhong Wang
- Department of Traditional Chinese Medicine, China-Japan Union Hospital of Jilin University
| | - Chunfu Li
- Department of Traditional Chinese Medicine, China-Japan Union Hospital of Jilin University
| | - Pu Wang
- Clinical Medicine College, Jilin University, Changchun, Jilin Province, China
| | - Minghui Liu
- Department of Traditional Chinese Medicine, China-Japan Union Hospital of Jilin University
| |
Collapse
|
|
20
|
Kuo L, Chao TF, Liu CJ, Lin YJ, Chang SL, Lo LW, Hu YF, Tuan TC, Liao JN, Chung FP, Chen TJ, Lip GYH, Chen SA. Liver Cirrhosis in Patients With Atrial Fibrillation: Would Oral Anticoagulation Have a Net Clinical Benefit for Stroke Prevention? J Am Heart Assoc 2017; 6:e005307. [PMID: 28645935 PMCID: PMC5669162 DOI: 10.1161/jaha.116.005307] [Citation(s) in RCA: 79] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Accepted: 05/09/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND Patients with liver cirrhosis have been excluded from randomized clinical trials of oral anticoagulation therapy for stroke prevention in atrial fibrillation. We hypothesized that patients with liver cirrhosis would have a positive net clinical benefit for oral anticoagulation when used for stroke prevention in atrial fibrillation. METHODS AND RESULTS This study used the National Health Insurance Research Database in Taiwan. Among 289 559 atrial fibrillation patients aged ≥20 years, there were 10 336 with liver cirrhosis, and 9056 of them having a CHA2DS2-VASc score ≥2 were divided into 3 groups, that is, no treatment, antiplatelet therapy, and warfarin. Patients with liver cirrhosis had a higher risk of ischemic stroke (hazard ratio=1.10, P=0.046) and intracranial hemorrhage (hazard ratio=1.20, P=0.043) compared with those without. Among patients with liver cirrhosis, patients taking antiplatelet therapy had a similar risk of ischemic stroke (hazard ratio=1.02, 95%CI=0.88-1.18) compared to those without antithrombotic therapies, but the risk was significantly lowered among warfarin users (hazard ratio=0.76, 95%CI=0.58-0.99). For intracranial hemorrhage, there were no significant differences between those untreated and those taking antiplatelet therapy or warfarin. The use of warfarin was associated with a positive net clinical benefit compared with being untreated or receiving only antiplatelet therapy. CONCLUSIONS For atrial fibrillation patients with liver cirrhosis in the current analysis of an observational study, warfarin use was associated with a lower risk of ischemic stroke and a positive net clinical benefit compared with nontreatment, and thus, thromboprophylaxis should be considered for such patients.
Collapse
Affiliation(s)
- Ling Kuo
- Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
- Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan
| | - Tze-Fan Chao
- Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
- Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan
| | - Chia-Jen Liu
- Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Institute of Public Health and School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Yenn-Jiang Lin
- Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
- Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan
| | - Shih-Lin Chang
- Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
- Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan
| | - Li-Wei Lo
- Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
- Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan
| | - Yu-Feng Hu
- Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
- Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan
| | - Ta-Chuan Tuan
- Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
- Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan
| | - Jo-Nan Liao
- Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
- Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan
| | - Fa-Po Chung
- Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
- Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan
| | - Tzeng-Ji Chen
- Department of Family Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Gregory Y H Lip
- University of Birmingham Institute of Cardiovascular Sciences City Hospital, Birmingham, United Kingdom
| | - Shih-Ann Chen
- Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
- Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan
| |
Collapse
|
|
21
|
Montenovo M, Rahnemai-Azar A, Reyes J, Perkins J. Clinical Impact and Risk Factors of Portal Vein Thrombosis for Patients on Wait List for Liver Transplant. EXP CLIN TRANSPLANT 2017. [PMID: 28621635 DOI: 10.6002/ect.2016.0277] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVES The effect of portal vein thrombosis on the progression of liver disease is controversial, with no consensus on optimal treatment. We aimed to assess how portal vein thrombosis affects wait list outcomes, identify risk factors associated with its development while on a wait list, and assess its effects on patient and graft survival. MATERIALS AND METHODS This US-based retrospective cohort study analyzed 134 109 adult patients on wait lists for or undergoing primary orthotopic liver transplant between January 2002 and June 2014. Rate of portal vein thrombosis development, time from entry on wait list to transplant, comparisons of wait list drop-off rates between patients with versus those without portal vein thrombosis, risk factors associated with its development while on a wait list, and its effects on patient and graft survival were analyzed. RESULTS We found that the rate of portal vein thrombosis at listing increased. Patients with the disease at listing were more likely to be removed from wait lists because of being too sick. Portal vein thrombosis at listing was an independent risk factor for being removed from a wait list. Of 63 265 patients who underwent primary orthotopic liver transplant, those with the disease were more likely to have higher Model for End-Stage Liver Disease scores and incidence of nonalcoholic steatohepatitis and diabetes mellitus. Portal vein thrombosis had a negative effect on patient and graft survival. Nonalcoholic steatohepatitis, body mass index, diabetes, and hepatocellular carcinoma were identified as risk factors for its development. CONCLUSIONS Portal vein thrombosis represents an increasing management and outcome burden in liver transplant. Having this disease at listing and/or at time of transplant is associated with worse patient and graft survival. Nonalcoholic steatohepatitis and hepatocellular carcinoma are among the biggest risk factors for its development while on a wait list.
Collapse
Affiliation(s)
- Martin Montenovo
- From the Department of Surgery, Division of Transplantation, University of Washington, Seattle, Washington, USA
| | | | | | | |
Collapse
|
|
22
|
Stephen C, Nicolas I. A Summary of The 6th International Conference on Coagulation in Liver Disease: Discussion, Debate, Deliberations. Ann Hepatol 2017; 16:12-15. [PMID: 28051789 DOI: 10.5604/16652681.1226811] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Affiliation(s)
- Caldwell Stephen
- Division of Gastroenterology & Hepatology, University of Virginia, Charlottesville, Virginia, USA
| | - Intagliata Nicolas
- Division of Gastroenterology & Hepatology, University of Virginia, Charlottesville, Virginia, USA
| |
Collapse
|
|
23
|
Moeini A, Machida H, Takiuchi T, Blake EA, Hom MS, Miki T, Matsuo O, Matsuo K. Association of Nonalcoholic Fatty Liver Disease and Venous Thromboembolism in Women With Endometrial Cancer. Clin Appl Thromb Hemost 2016; 23:1018-1027. [PMID: 27582024 DOI: 10.1177/1076029616665925] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
OBJECTIVE Recent studies have demonstrated that surgical menopause results in a significantly increased risk of nonalcoholic fatty liver disease (NAFLD) in women with endometrial cancer. In addition, venous thromboembolism (VTE) is known to be one of the major prognostic factors for decreased survival in endometrial cancer. Given the fact that coagulation factors are produced in the liver, the correlation between NAFLD and VTE was examined in endometrial cancer. METHODS A retrospective study was conducted to examine patients with endometrial cancer who underwent surgical staging including oophorectomy between 2000 and 2013 (n = 714). Cumulative risk of VTE was examined based on the NAFLD status. A Cox proportional hazard regression model was used to determine the independent risk predictors of VTE. RESULTS Venous thromboembolism and NAFLD were seen in 57 (8.0%) and 181 (25.4%) cases, respectively. Two-year cumulative risks of VTE and NAFLD were 7.9% and 19.3%, respectively. In univariate analysis, VTE was significantly associated with decreased disease-free survival (2-year rate, 43.6% vs 91.4%, P < .001) and overall survival (65.8% vs 96.8%, P < .001), whereas NAFLD was associated with decreased risk of VTE (1.7% vs 10.4%, P < .001). In multivariate analysis controlling for clinicopathological factors, NAFLD remained an independent predictor of decreased risk of VTE (hazard ratio [HR]: 0.24, 95% confidence interval [CI]: 0.07-0.79, P = .02). Thrombocytosis (HR: 2.30, 95% CI: 1.22-4.35, P = .01), cancer antigen 125 ≥ 35 (HR: 3.81, 95% CI: 1.78-8.17, P < .001), and recurrent disease (HR: 4.57, 95% CI: 1.97-10.6, P < .001) remained as independent predictors of increased risk of VTE. CONCLUSION Our results suggest that NAFLD may be associated with decreased VTE risk in women with endometrial cancer.
Collapse
Affiliation(s)
- Aida Moeini
- 1 Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA
| | - Hiroko Machida
- 1 Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA
| | - Tsuyoshi Takiuchi
- 2 Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Erin A Blake
- 3 Department of Obstetrics and Gynecology, University of Colorado, Denver, CO, USA
| | - Marianne S Hom
- 1 Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA
| | - Toshio Miki
- 4 Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, CA, USA
| | - Osamu Matsuo
- 5 Department of Physiology, Faculty of Medicine, Kinki University, Osaka, Japan
| | - Koji Matsuo
- 1 Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA.,6 Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
| |
Collapse
|
|
24
|
Bleeding Risk and Management in Interventional Procedures in Chronic Liver Disease. J Vasc Interv Radiol 2016; 27:1665-1674. [PMID: 27595469 DOI: 10.1016/j.jvir.2016.05.039] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2016] [Revised: 05/25/2016] [Accepted: 05/31/2016] [Indexed: 12/14/2022] Open
Abstract
The coagulopathy of liver disease is distinctly different from therapeutic anticoagulation in a patient. Despite stable elevated standard clot-based coagulation assays, nearly all patients with stable chronic liver disease (CLD) have normal or increased clotting. Common unfamiliarity with the limitations of these assays in CLD may lead to inappropriate and sometimes harmful interventions, including blood product transfusions before a procedure. Knowledge of the distinct hemostatic alterations in CLD can allow identification of the small subset of patients with clinically significant coagulopathy who can benefit from hematologic optimization before invasive procedures.
Collapse
|
|
25
|
Atrial fibrillation, liver disease, antithrombotics and risk of cerebrovascular events: A population-based cohort study. Int J Cardiol 2016; 223:829-837. [PMID: 27580216 DOI: 10.1016/j.ijcard.2016.08.297] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2016] [Accepted: 08/19/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND Whether patients with atrial fibrillation (AF) and liver disease are also prone to cerebrovascular events and respond similarly favorably to antithrombotic therapy remains under-investigated. METHODS Patients ≥18years with newly-diagnosed AF in the period 2005 to 2009 were scrutinized from the "Longitudinal Health Insurance Database 2005" (1 million beneficiaries) of Taiwan's National Health Insurance Institute. Patients were categorized into the Liver (N=433) or the Non-liver (N=3490) cohort according to whether they had a diagnosis of advanced liver disease. Patients were then followed to determine cumulative incidence of hospitalization-requiring cerebrovascular events, preventive effects of antithrombotics, and predictors of cerebrovascular events by Cox regression analysis. RESULTS Within a mean follow-up of 3.3±1.4years, ischemic stroke (89.2 vs. 50.3 per 1000 person-years, adjusted HR 1.502, 95% CI 1.207-1.868, p<0.001) and overall cerebrovascular events (102.3 vs. 56.4 per 1000 person-years, adjusted HR 1.535, 95% CI 1.251-1.883, p<0.001) occurred significantly more often in the Liver than in the Non-liver cohort. Cox models identified aging (≥65years), DM, and CHA2DS-VASc score≥2 points as risk factors for overall cerebrovascular events in the Liver cohort, whereas antiplatelet agents (HR 0.932, 95% CI 0.128-6.803, p=NS) and vit-K antagonistic anticoagulants (HR 1.087, 95% CI 0.150-7.862, p=NS) showed no correlation. CONCLUSION AF patients comorbid with advanced liver disease are more vulnerable to ischemic and therein overall cerebrovascular events, especially in those with old age, DM, or high CHA2DS-VASc scores. This propensity to cerebrovascular events, however, can't be altered by antithrombotic therapy.
Collapse
|
|
26
|
Non-alcoholic fatty liver disease and cardiovascular risk: Pathophysiological mechanisms and implications. J Hepatol 2016; 65:425-43. [PMID: 27091791 DOI: 10.1016/j.jhep.2016.04.005] [Citation(s) in RCA: 364] [Impact Index Per Article: 40.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Revised: 03/25/2016] [Accepted: 04/01/2016] [Indexed: 12/12/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) has become one of the most frequent chronic liver diseases in the Western society and its prevalence is likely to rise even further. An increasing body of evidence shows that NAFLD is not only a potentially progressive liver disease, but also has systemic consequences. More specifically, evidence points out that NAFLD has to be considered as a significant independent risk factor for subclinical and clinical cardiovascular disease (CVD). Long-term follow-up studies demonstrate cardiovascular mortality to be the most important cause of death in NAFLD patients. Moreover, ample evidence associates NAFLD with endothelial dysfunction, increased pulse wave velocity, increased coronary arterial calcifications and increased carotid intima media thickness, all established markers for CVD. Despite of all this evidence, the mechanisms by which NAFLD causally contributes to CVD are not fully elucidated. Furthermore, an extensive overview of all potential pathophysiological mechanisms and the corresponding current data are lacking. In this review we summarise current knowledge, originating from fundamental and clinical research, that mechanistically links NAFLD to CVD. Subsequently, the impact of CVD on current clinical practice and future research in the area of NALFD are discussed.
Collapse
|
|
27
|
Kopec AK, Joshi N, Luyendyk JP. Role of hemostatic factors in hepatic injury and disease: animal models de-liver. J Thromb Haemost 2016; 14:1337-49. [PMID: 27060337 PMCID: PMC5091081 DOI: 10.1111/jth.13327] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2015] [Indexed: 12/14/2022]
Abstract
Chronic liver damage is associated with unique changes in the hemostatic system. Patients with liver disease often show a precariously rebalanced hemostatic system, which is easily tipped towards bleeding or thrombotic complications by otherwise benign stimuli. In addition, some clinical studies have shown that hemostatic system components contribute to the progression of liver disease. There is a strong basic science foundation for clinical studies with this particular focus. Chronic and acute liver disease can be modeled in rodents and large animals with a variety of approaches, which span chronic exposure to toxic xenobiotics, diet-induced obesity, and surgical intervention. These experimental approaches have now provided strong evidence that, in addition to perturbations in hemostasis caused by liver disease, elements of the hemostatic system have powerful effects on the progression of experimental liver toxicity and disease. In this review, we cover the basis of the animal models that are most often utilized to assess the impact of the hemostatic system on liver disease, and highlight the role that coagulation proteases and their targets play in experimental liver toxicity and disease, emphasizing key similarities and differences between models. The need to characterize hemostatic changes in existing animal models and to develop novel animal models recapitulating the coagulopathy of chronic liver disease is highlighted. Finally, we emphasize the continued need to translate knowledge derived from highly applicable animal models to improve our understanding of the reciprocal interaction between liver disease and the hemostatic system in patients.
Collapse
Affiliation(s)
- Anna K. Kopec
- Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, Michigan 48824
- Institute for Integrative Toxicology, Michigan State University, East Lansing, Michigan 48824
| | - Nikita Joshi
- Department of Pharmacology & Toxicology, Michigan State University, East Lansing, Michigan 48824
- Institute for Integrative Toxicology, Michigan State University, East Lansing, Michigan 48824
| | - James P. Luyendyk
- Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, Michigan 48824
- Department of Pharmacology & Toxicology, Michigan State University, East Lansing, Michigan 48824
- Institute for Integrative Toxicology, Michigan State University, East Lansing, Michigan 48824
| |
Collapse
|
|
28
|
Portal Vein Thrombosis Is a Risk Factor for Poor Early Outcomes After Liver Transplantation: Analysis of Risk Factors and Outcomes for Portal Vein Thrombosis in Waitlisted Patients. Transplantation 2016; 100:126-33. [PMID: 26050013 DOI: 10.1097/tp.0000000000000785] [Citation(s) in RCA: 115] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Portal vein thrombosis (PVT) is common in patients with cirrhosis, but the risk factors associated with PVT and its impact on outcomes following liver transplantation (LT) are not well defined. The objectives of this study were to determine the impact of PVT on post-LT patient and graft survival, waitlist outcomes, and the factors associated with PVT. METHODS A retrospective review of Organ Procurement and Transplant Network waitlist and LT data between 2002 and 2013 identified 48,570 patients undergoing their first LT, with 3321 (6.8%) reported to have PVT at LT. RESULTS Portal vein thrombosis was independently associated with increased 90-day mortality (odds ratio, 1.7; 95% confidence interval, 1.45-1.99; P < 0.001) and graft failure (odds ratio, 1.72; 95% confidence interval, 1.51-1.97; P < 0.001). Portal vein thrombosis at listing was not associated with lower transplant rates, or delisting for death, or deterioration. Only 31% of patients with PVT at LT had PVT reported at listing. The predictors of PVT at LT in patients without PVT at listing included: fatty or cryptogenic liver disease, ascites, diabetes mellitus, and obesity. "New" PVT at LT was associated with longer wait-time, higher rate of model of end-stage liver disease increase, and intermediate 90-day survival rates compared to patients with or without PVT at both listing and LT. CONCLUSIONS Portal vein thrombosis at LT is associated with early (90 days) mortality and graft failure, though a likely but undefined reporting bias for more extensive PVT would overstate estimated risks for all PVT. Further study is needed to better define risks of LT with PVT.
Collapse
|
|
29
|
VanWagner LB, Rinella ME. Extrahepatic Manifestations of Nonalcoholic Fatty Liver Disease. ACTA ACUST UNITED AC 2016; 15:75-85. [PMID: 27218012 DOI: 10.1007/s11901-016-0295-9] [Citation(s) in RCA: 82] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide with an increased prevalence of metabolic, macro- and microvascular complications. The primary causes of mortality in NAFLD are cardiovascular disease (CVD), malignancy and liver disease. NAFLD is a multisystem disease that affects a variety of extra-hepatic organ systems. The main focus of this review is to summarize the reported extra-hepatic associations, which include CVD, chronic kidney disease, obstructive sleep apnea, osteoporosis, psoriasis, colorectal cancer, iron overload and various endocrinopathies (e.g. type 2 diabetes mellitus, thyroid dysfunction, and polycystic ovarian syndrome). Due to the systemic manifestations of NAFLD patients require a multidisciplinary assessment and may benefit from more rigorous surveillance and early treatment interventions to decrease mortality related to malignancy or cardiometabolic diseases.
Collapse
Affiliation(s)
- Lisa B VanWagner
- Department of Preventive Medicine, Northwestern University Feinberg School of Medicine
| | - Mary E Rinella
- Department of Medicine, Division of Gastroenterology & Hepatology, Northwestern University Feinberg School of Medicine
| |
Collapse
|
|
30
|
Stine JG, Pelletier SJ, Schmitt TM, Porte RJ, Northup PG. Pre-transplant portal vein thrombosis is an independent risk factor for graft loss due to hepatic artery thrombosis in liver transplant recipients. HPB (Oxford) 2016; 18:279-86. [PMID: 27017168 PMCID: PMC4814623 DOI: 10.1016/j.hpb.2015.10.008] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2015] [Accepted: 10/12/2015] [Indexed: 12/12/2022]
Abstract
BACKGROUND Hepatic artery thrombosis is an uncommon but catastrophic complication following liver transplantation. We hypothesize that recipients with portal vein thrombosis are at increased risk. METHODS Data on all liver transplants in the U.S. during the MELD era through September 2014 were obtained from UNOS. Status one, multivisceral, living donor, re-transplants, pediatric recipients and donation after cardiac death were excluded. Logistic regression models were constructed for hepatic artery thrombosis with resultant graft loss within 90 days of transplantation. RESULTS 63,182 recipients underwent transplantation; 662 (1.1%) recipients had early hepatic artery thrombosis; of those, 91 (13.8%) had pre-transplant portal vein thrombosis, versus 7.5% with portal vein thrombosis but no hepatic artery thrombosis (p < 0.0001). Portal vein thrombosis was associated with an increased independent risk of hepatic artery thrombosis (OR 2.17, 95% CI 1.71-2.76, p < 0.001) as was donor risk index (OR 2.02, 95% CI 1.65-2.48, p < 0.001). Heparin use at cross clamp, INR, and male donors were all significantly associated with lower risk. DISCUSSION Pre-transplant portal vein thrombosis is associated with post-transplant hepatic artery thrombosis independent of other factors. Recipients with portal vein thrombosis might benefit from aggressive coagulation management and careful donor selection. More research is needed to determine causal mechanism.
Collapse
Affiliation(s)
- Jonathan G Stine
- Division of Gastroenterology & Hepatology, Department of Medicine, University of Virginia, United States
| | - Shawn J Pelletier
- Division of Transplant Surgery, Department of Surgery, University of Virginia, United States
| | - Timothy M Schmitt
- Division of Transplant Surgery, Department of Surgery, University of Kansas, United States
| | - Robert J Porte
- Department of Surgery, University of Groningen, University Medical Center Groningen, Netherlands
| | - Patrick G Northup
- Division of Gastroenterology & Hepatology, Department of Medicine, University of Virginia, United States.
| |
Collapse
|
|
31
|
Blasi A. Coagulopathy in liver disease: Lack of an assessment tool. World J Gastroenterol 2015; 21:10062-10071. [PMID: 26401071 PMCID: PMC4572787 DOI: 10.3748/wjg.v21.i35.10062] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2015] [Revised: 05/29/2015] [Accepted: 08/25/2015] [Indexed: 02/06/2023] Open
Abstract
There is a discrepancy between the information from clotting tests which have routinely been used in clinical practice and evidence regarding thrombotic and bleeding events in patients with liver disease. This discrepancy leads us to rely on other variables which have been shown to be involved in haemostasis in these patients and/or to extrapolate the behaviour of these patients to other settings in order to decide the best clinical approach. The aims of the present review are as follows: (1) to present the information provided by clotting tests in cirrhotic patients; (2) to present the factors that may influence clotting in these patients; (3) to review the clinical evidence; and (4) to put forward a clinical approach based on the first 3 points.
Collapse
|
|
32
|
Hugenholtz GCG, Northup PG, Porte RJ, Lisman T. Is there a rationale for treatment of chronic liver disease with antithrombotic therapy? Blood Rev 2014; 29:127-36. [PMID: 25468718 DOI: 10.1016/j.blre.2014.10.002] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2014] [Revised: 10/21/2014] [Accepted: 10/23/2014] [Indexed: 02/07/2023]
Abstract
Recent advances in the understanding of the coagulopathy in chronic liver disease have provided a strong support for anticoagulation as a new therapeutic paradigm for patients with cirrhosis. Laboratory studies indicate that the net effect of changes in hemostasis in many patients with chronic liver disease is a hypercoagulable status. In turn, clinical thrombosis is increasingly recognized as a complication of liver disease. When occurring within the liver, thrombosis may even progress the disease course. Exciting preliminary data regarding the potential of low-molecular-weight heparin to slow down the progression of liver disease indicate that this class of drugs may improve outcome without a major increase in bleeding risk. However, this new era for antithrombotic therapy in chronic liver disease is still hindered by a persistent false notion that patients with cirrhosis are "auto-anticoagulated" by their underlying liver disease. In addition, there is insufficient clinical evidence on safety and efficacy of anticoagulant therapy in cirrhosis and the studies conducted so far are limited by small sample sizes, uncontrolled treatment arms, or by their retrospective nature. Finally, a lack of knowledge on how or when to monitor antithrombotic treatment to optimize the risk-benefit ratio has restricted a widespread application of anticoagulant treatment in clinical management algorithms. Nonetheless, by systematically covering possibilities and pitfalls, this review highlights the potential of antithrombotic therapy to improve the quality of life and the clinical outcome of patients with chronic liver disease.
Collapse
Affiliation(s)
- Greg C G Hugenholtz
- Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Patrick G Northup
- Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, VA, United States
| | - Robert J Porte
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Ton Lisman
- Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
| |
Collapse
|
|
33
|
Fargion S, Porzio M, Fracanzani AL. Nonalcoholic fatty liver disease and vascular disease: State-of-the-art. World J Gastroenterol 2014; 20:13306-13324. [PMID: 25309067 PMCID: PMC4188888 DOI: 10.3748/wjg.v20.i37.13306] [Citation(s) in RCA: 165] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2014] [Revised: 05/02/2014] [Accepted: 07/30/2014] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), the most common of chronic liver disease in Western Country, is closely related to insulin resistance and oxidative stress and includes a wide spectrum of liver diseases ranging from steatosis alone, usually a benign and non-progressive condition, to nonalcoholic steatohepatitis (NASH), which may progress to liver fibrosis and cirrhosis. NAFLD is considered the hepatic manifestation of the metabolic syndrome with which shares several characteristics, however recent data suggest that NAFLD is linked to increased cardiovascular risk independently of the broad spectrum of risk factors of metabolic syndrome. Accumulating evidence suggests that the clinical burden of NAFLD is not restricted to liver-related morbidity and mortality, with the majority of deaths in NAFLD patients related to cardiovascular disease and cancer and not to the progression of liver disease. Retrospective and prospective studies provide evidence of a strong association between NAFLD and subclinical manifestation of atherosclerosis (increased intima-media thickness, endothelial dysfunction, arterial stiffness, impaired left ventricular function and coronary calcification). A general agreement emerging from these studies indicates that patients with NASH are at higher risk of cardiovascular diseases than those with simple steatosis, emphasizing the role of chronic inflammation in the pathogenesis of atherosclerosis of these patients. It is very likely that the different mechanisms involved in the pathogenesis of atherosclerosis in patients with NAFLD have a different relevance in the patients according to individual genetic background. In conclusion, in the presence of NAFLD patients should undergo a complete cardiovascular evaluation to prevent future atherosclerotic complications. Specific life-style modification and aggressive pharmaceutical modification will not only reduce the progression of liver disease, but also reduce morbidity for cardiovascular disease improving overall prognosis and survival.
Collapse
|
|
34
|
Tripodi A, Fracanzani AL, Primignani M, Chantarangkul V, Clerici M, Mannucci PM, Peyvandi F, Bertelli C, Valenti L, Fargion S. Procoagulant imbalance in patients with non-alcoholic fatty liver disease. J Hepatol 2014; 61:148-54. [PMID: 24657400 DOI: 10.1016/j.jhep.2014.03.013] [Citation(s) in RCA: 150] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2013] [Revised: 02/09/2014] [Accepted: 03/10/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Non-alcoholic fatty liver disease (NAFLD) is characterized by increased risk of cardiovascular events and liver-fibrosis. Both could be explained by a procoagulant-imbalance that was surmised but never directly demonstrated. We investigated 113 patients with varying histological liver damage [steatosis (n=32), steatohepatitis (n=51), metabolic-cirrhosis (n=30)], 54 with alcoholic/viral-cirrhosis and 179 controls. METHODS Plasma was evaluated for levels of pro- and anti-coagulants, and for thrombin-generation assessed as endogenous-thrombin-potential (ETP) with and without thrombomodulin or Protac® as protein C activators. The procoagulant-imbalance was defined as ETP-ratio (with-to-without thrombomodulin) or as Protac®-induced-coagulation-inhibition (PICI%). High ETP-ratios or low PICI% indicate resistance to thrombomodulin or Protac® and hence a procoagulant-imbalance. RESULTS ETP-ratio increased from controls [0.57 (0.11-0.89)] to steatosis [0.72 (0.33-0.86)] and metabolic-cirrhosis [0.80 (0.57-0.95)], (p<0.001), the latter being comparable to that for alcoholic/viral-cirrhosis [0.80 (0.57-0.95) vs. 0.80 (0.44-0.96)]. Factor VIII (a potent procoagulant for thrombin-generation) increased from steatosis [99% (71-150)] to metabolic-cirrhosis [157% (64-232)], p<0.001. Protein C (a powerful anticoagulant) decreased from steatosis [103% (77-228)] to metabolic-cirrhosis [77 (17-146)], p<0.001. As a consequence, factor VIII-to-protein C ratio increased from steatosis [0.96 (0.36-1.60)] to metabolic-cirrhosis [2.05 (0.81-12.1)], p<0.001 and was correlated with the ETP-ratio (rho=0.543, p<0.001). Similar results were obtained for PICI%. Patients with procoagulant-imbalance detected as ETP-ratio greater or PICI% lower than the median value of controls tended to have a higher risk of metabolic-syndrome, higher intima-media thickness, fibrosis, steatosis or lobular inflammation, all considered clinical manifestations of NAFLD. CONCLUSION NAFLD is characterized by a procoagulant-imbalance progressing from the less severe (steatosis) to the most severe form of the disease (metabolic-cirrhosis). This imbalance appears to result from increased factor VIII and reduced protein C and might play a role in the risk of cardiovascular events and liver-fibrosis commonly observed in NAFLD.
Collapse
Affiliation(s)
- Armando Tripodi
- Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy; IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy.
| | - Anna L Fracanzani
- Metabolic Liver Diseases Center, Department of Pathophysiology and Transplantation, Section of Internal Medicine, Università degli Studi di Milano, Italy; IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy
| | - Massimo Primignani
- First Division of Gastroenterology; IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy
| | - Veena Chantarangkul
- Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy; IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy
| | - Marigrazia Clerici
- Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy; IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy
| | | | - Flora Peyvandi
- Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy; IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy
| | - Cristina Bertelli
- Metabolic Liver Diseases Center, Department of Pathophysiology and Transplantation, Section of Internal Medicine, Università degli Studi di Milano, Italy; IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy
| | - Luca Valenti
- Metabolic Liver Diseases Center, Department of Pathophysiology and Transplantation, Section of Internal Medicine, Università degli Studi di Milano, Italy; IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy
| | - Silvia Fargion
- Metabolic Liver Diseases Center, Department of Pathophysiology and Transplantation, Section of Internal Medicine, Università degli Studi di Milano, Italy; IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy
| |
Collapse
|
|
35
|
Verrijken A, Francque S, Mertens I, Prawitt J, Caron S, Hubens G, Van Marck E, Staels B, Michielsen P, Van Gaal L. Prothrombotic factors in histologically proven nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Hepatology 2014; 59:121-9. [PMID: 24375485 DOI: 10.1002/hep.26510] [Citation(s) in RCA: 145] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2012] [Accepted: 04/30/2013] [Indexed: 02/06/2023]
Abstract
UNLABELLED An independent role of nonalcoholic fatty liver disease (NAFLD) in the development of cardiovascular disease has been suggested, probably mediated through increased levels of prothrombotic factors. Therefore, we examined whether NAFLD is linked to a prothrombotic state, independently of metabolic risk factors in a large single-center cohort of overweight/obese patients. Patients presenting to the obesity clinic underwent a detailed metabolic and liver assessment, including an extensive panel of coagulation factors. If NAFLD was suspected, a liver biopsy was proposed. A series of 273 consecutive patients (65% female) with a liver biopsy were included (age, 44 ± 0.76 years; body mass index: 39.6 ± 0.40 kg/m(2)). Increase in fibrinogen, factor VIII, and von Willebrand factor and decrease in antithrombin III correlated with metabolic features, but not with liver histology. Levels of plasminogen activator inhibitor-1 (PAI-1) increased significantly with increasing severity of steatosis (P < 0.001), lobular inflammation (P < 0.001), ballooning (P = 0.002), and fibrosis (P < 0.001). Patients with nonalcoholic steatohepatitis had significantly higher PAI-1 values than those with normal liver (P < 0.001). In multiple regression, including anthropometric and metabolic parameters, steatosis remained an independent predictor of PAI-1 levels, explaining, together with fasting C-peptide and waist circumference, 21% of the variance in PAI-1. No consistent correlations with histology were found for the other coagulation factors. CONCLUSION In obesity, NAFLD severity independently contributes to the increase in PAI-1 levels, whereas other coagulation factors are unaltered. This finding might, in part, explain the increased cardiovascular risk associated with NAFLD.
Collapse
Affiliation(s)
- An Verrijken
- Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
36
|
Krzanicki D, Sugavanam A, Mallett S. Intraoperative hypercoagulability during liver transplantation as demonstrated by thromboelastography. Liver Transpl 2013; 19:852-61. [PMID: 23696318 DOI: 10.1002/lt.23668] [Citation(s) in RCA: 93] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2013] [Accepted: 04/23/2013] [Indexed: 12/13/2022]
Abstract
Thrombotic complications are more common in liver disease than might be expected because of the coagulopathy described by conventional coagulation tests. Some of these complications may be life-threatening. The phenomenon of hypercoagulation is associated with complications in many populations, but the incidence in liver transplant recipients is unclear. We performed a retrospective database review of intraoperative thromboelastography (TEG) for 124 liver transplant recipients. We assessed the prevalence of hypercoagulation in this group and investigated the relative frequency of both shortened TEG reaction times (R times) and increased net clot strength (G) values. These findings were correlated with thrombotic complications. At the baseline, the prevalence of high G values was 15.53% on native TEG, and the prevalence of shortened R times was 6.80% on native-heparinase TEG. Patients with cholestatic pathologies had particularly high rates of hypercoagulation (42.9% with primary biliary cirrhosis and 85.7% with primary sclerosing cholangitis), but hypercoagulation was also common in patients with fulminant hepatic failure (50%) and nonalcoholic steatohepatitis (37.5%). There was a poor correlation between the TEG R time and the international normalized (INR), with 37.7% of TEG analyses demonstrating a short R time with an INR > 2. Six of the patients developed early hepatic artery thrombosis (5%); 3 of these patients had TEG evidence of high G values (P = 0.25), and 4 had short R times (not significant). In conclusion, intraoperative TEG evidence of high G values and short R times is relatively common in liver transplantation. It is unclear what bearing this condition has on thrombotic complications. Conventional coagulation tests have no ability to diagnose this condition. It is conceivable that such patients may come to harm if hypercoagulability is unrecognized and, therefore, inappropriately managed.
Collapse
Affiliation(s)
- Dominik Krzanicki
- Department of Anaesthesia, Royal Free Hospital, London, United Kingdom.
| | | | | |
Collapse
|
|
37
|
Anstee QM, Targher G, Day CP. Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat Rev Gastroenterol Hepatol 2013; 10:330-44. [PMID: 23507799 DOI: 10.1038/nrgastro.2013.41] [Citation(s) in RCA: 1312] [Impact Index Per Article: 109.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
NAFLD is a spectrum of progressive liver disease that encompasses simple steatosis, NASH, fibrosis and, ultimately, cirrhosis. NAFLD is recognized as the hepatic component of the metabolic syndrome, as these conditions have insulin resistance as a common pathophysiological mechanism. Therefore, NAFLD is strongly associated with type 2 diabetes mellitus and abdominal obesity. As lifestyles have become increasingly sedentary and dietary patterns have changed, the worldwide prevalence of NAFLD has increased dramatically and is projected to be the principal aetiology for liver transplantation within the next decade. Importantly, a growing body of clinical and epidemiological evidence suggests that NAFLD is associated not only with liver-related morbidity and mortality, but also with an increased risk of developing both cardiovascular disease and type 2 diabetes mellitus. This article reviews the evidence that suggests NAFLD is a multisystem disease and the factors that might determine interindividual variation in the development and progression of its major hepatic and extrahepatic manifestations (principally type 2 diabetes mellitus and cardiovascular disease).
Collapse
Affiliation(s)
- Quentin M Anstee
- Liver Research Group, Institute of Cellular Medicine, The Medical School, Newcastle University, Framlington Place, Newcastle-upon-Tyne NE2 4HH, UK
| | | | | |
Collapse
|