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Pandey N, Anand SK, Kaur H, Richard KSE, Chandaluri L, Butler ME, Zhang X, Pearson-Gallion B, Rohilla S, Das S, Magdy T, Sethu P, Núñez KG, Orr AW, Stokes KY, Thevenot PT, Cohen AJ, Rom O, Dhanesha N. Enhanced venous thrombosis and hypercoagulability in murine and human metabolic dysfunction-associated steatohepatitis. J Thromb Haemost 2024; 22:3572-3580. [PMID: 39306095 PMCID: PMC11608147 DOI: 10.1016/j.jtha.2024.08.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Revised: 08/12/2024] [Accepted: 08/13/2024] [Indexed: 09/25/2024]
Abstract
BACKGROUND Patients with metabolic dysfunction-associated steatohepatitis (MASH) are at an increased risk of developing venous thromboembolic events, including deep vein thrombosis (DVT). To date, the study of DVT in MASH has been hampered by the lack of reliable models that mimic the pathologic aspects of human disease. OBJECTIVES To evaluate DVT severity and hypercoagulability in murine and human MASH. METHODS Transcriptional changes in the liver, plasma markers of coagulation, and DVT severity were evaluated in mice fed a standard chow diet or a high-fructose, high-fat, and high-cholesterol MASH diet for 24 weeks. Plasma analyses of coagulation markers and thrombin generation assays were performed in a well-characterized cohort of patients with or without MASH. RESULTS Mice fed the MASH diet developed steatohepatitis and fibrosis, mimicking human MASH. Liver RNA sequencing revealed a significant upregulation of pathways related to inflammation and coagulation concomitant with increased levels of plasma coagulation markers including increased prothrombin fragment 1+2, thrombin-antithrombin complex, plasminogen activator inhibitor-1 levels, and endothelin 1. MASH exacerbated DVT severity in mice, as evidenced by increased thrombus weight and higher thrombosis incidence (15/15 vs 11/15 in controls, P = .0317). Higher endothelin 1 release and increased apoptosis were found in endothelial cells stimulated with supernatants of palmitate-stimulated HepG2 cells. Patients with MASH exhibited increased levels of plasma coagulation markers and delayed thrombin generation. CONCLUSION We report enhanced DVT severity and hypercoagulability, both in murine and human MASH. Our model of MASH-DVT can facilitate a better understanding of the fundamental mechanisms leading to increased venous thromboembolic events in patients with MASH.
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Affiliation(s)
- Nilesh Pandey
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
| | - Sumit Kumar Anand
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
| | - Harpreet Kaur
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
| | - Koral S E Richard
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
| | - Lakshmi Chandaluri
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
| | - Megan E Butler
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
| | - Xiaolu Zhang
- Bioinformatics and Modeling Core, The Center for Applied Immunology and Pathological Processes, Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA
| | - Brenna Pearson-Gallion
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
| | - Sumati Rohilla
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
| | - Sandeep Das
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
| | - Tarek Magdy
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
| | - Palaniappan Sethu
- Division of Cardiovascular Disease, Department of Medicine, School of Medicine and Department of Biomedical Engineering, School of Engineering, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Kelley G Núñez
- Institute of Translational Research, Ochsner Clinic Foundation, New Orleans, Louisiana, USA
| | - A Wayne Orr
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA; Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
| | - Karen Y Stokes
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
| | - Paul T Thevenot
- Institute of Translational Research, Ochsner Clinic Foundation, New Orleans, Louisiana, USA
| | - Ari J Cohen
- Institute of Translational Research, Ochsner Clinic Foundation, New Orleans, Louisiana, USA; Multi-Organ Transplant Institute, Ochsner Clinic Foundation, New Orleans, Louisiana, USA
| | - Oren Rom
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA; Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA.
| | - Nirav Dhanesha
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA.
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Wada Y, Okuda K, Sasaki S, Shimose S, Nishida T, Shimokobe H, Nagao Y, Torigoe T, Hayashi K, Akashi H, Taniwaki S, Imamura T. Impact of MASLD on Portal Vein Thrombosis Following Hepatectomy for Liver Cancer. Cancers (Basel) 2024; 16:3844. [PMID: 39594799 PMCID: PMC11592967 DOI: 10.3390/cancers16223844] [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: 10/09/2024] [Revised: 11/08/2024] [Accepted: 11/13/2024] [Indexed: 11/28/2024] Open
Abstract
Background: Due to the increasing global prevalence of non-alcoholic fatty liver disease (NAFLD), which is closely linked to metabolic disorders, there has been a rise in the number of patients with NAFLD undergoing hepatectomy. The metabolic disorders, as well as NAFLD, increase venous thrombotic risk. NAFLD was recently updated to a new concept of hepatic steatosis: metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to investigate the impact of MASLD on post-hepatectomy portal vein thrombosis (PH-PVT). Methods: A total of 106 patients who underwent hepatectomy for liver cancer were included. Steatotic liver disease (SLD) was diagnosed using a CT L/S ratio of <1.1. SLD was classified as follows: MASLD, SLD associated with metabolic factors without alcohol consumption; MetALD, SLD with metabolic factors and moderate alcohol consumption; Other SLD, alcohol or other specific etiology of SLD; and No SLD, no hepatic steatosis. Results: PH-PVT was detected in 12/106 patients (11.3%); MASLD, 7/20 (35%); MetALD, 1/5 (20%); Other SLD, 1/13 (8%); and No SLD, 3/68 (4.4%). Multivariate analysis showed that the MASLD group (including MASLD and MetALD) (odds ratio [OR], 9.27) and left lateral sectionectomy (OR, 6.22) were significant independent risk factors for PH-PVT. Additionally, the incidence of PH-PVT was significantly higher in patients with MASLD than in those without SLD, along with metabolic factors, excluding alcohol consumption. Conclusions: MASLD and MetALD were identified as independent and significant risk factors for PH-PVT. Consideration was given to the idea that hepatic steatosis and metabolic dysfunction play synergistic roles in PH-PVT development.
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Affiliation(s)
- Yoshito Wada
- Department of Surgery, Kyoaikai Tobata Kyoritsu Hospital, Kitakyushu 804-0093, Fukuoka, Japan; (Y.W.); (S.S.); (T.N.); (H.S.); (Y.N.); (T.T.); (K.H.); (H.A.); (S.T.); (T.I.)
| | - Koji Okuda
- Department of Surgery, Kyoaikai Tobata Kyoritsu Hospital, Kitakyushu 804-0093, Fukuoka, Japan; (Y.W.); (S.S.); (T.N.); (H.S.); (Y.N.); (T.T.); (K.H.); (H.A.); (S.T.); (T.I.)
| | - Shin Sasaki
- Department of Surgery, Kyoaikai Tobata Kyoritsu Hospital, Kitakyushu 804-0093, Fukuoka, Japan; (Y.W.); (S.S.); (T.N.); (H.S.); (Y.N.); (T.T.); (K.H.); (H.A.); (S.T.); (T.I.)
| | - Shigeo Shimose
- Department of Internal Medicine, Tobata Kyoritsu Hospital, Kitakyushu 804-0093, Fukuoka, Japan;
| | - Takamichi Nishida
- Department of Surgery, Kyoaikai Tobata Kyoritsu Hospital, Kitakyushu 804-0093, Fukuoka, Japan; (Y.W.); (S.S.); (T.N.); (H.S.); (Y.N.); (T.T.); (K.H.); (H.A.); (S.T.); (T.I.)
| | - Hisaaki Shimokobe
- Department of Surgery, Kyoaikai Tobata Kyoritsu Hospital, Kitakyushu 804-0093, Fukuoka, Japan; (Y.W.); (S.S.); (T.N.); (H.S.); (Y.N.); (T.T.); (K.H.); (H.A.); (S.T.); (T.I.)
| | - Yuichi Nagao
- Department of Surgery, Kyoaikai Tobata Kyoritsu Hospital, Kitakyushu 804-0093, Fukuoka, Japan; (Y.W.); (S.S.); (T.N.); (H.S.); (Y.N.); (T.T.); (K.H.); (H.A.); (S.T.); (T.I.)
| | - Takayuki Torigoe
- Department of Surgery, Kyoaikai Tobata Kyoritsu Hospital, Kitakyushu 804-0093, Fukuoka, Japan; (Y.W.); (S.S.); (T.N.); (H.S.); (Y.N.); (T.T.); (K.H.); (H.A.); (S.T.); (T.I.)
| | - Koji Hayashi
- Department of Surgery, Kyoaikai Tobata Kyoritsu Hospital, Kitakyushu 804-0093, Fukuoka, Japan; (Y.W.); (S.S.); (T.N.); (H.S.); (Y.N.); (T.T.); (K.H.); (H.A.); (S.T.); (T.I.)
| | - Hidetoshi Akashi
- Department of Surgery, Kyoaikai Tobata Kyoritsu Hospital, Kitakyushu 804-0093, Fukuoka, Japan; (Y.W.); (S.S.); (T.N.); (H.S.); (Y.N.); (T.T.); (K.H.); (H.A.); (S.T.); (T.I.)
| | - Satoshi Taniwaki
- Department of Surgery, Kyoaikai Tobata Kyoritsu Hospital, Kitakyushu 804-0093, Fukuoka, Japan; (Y.W.); (S.S.); (T.N.); (H.S.); (Y.N.); (T.T.); (K.H.); (H.A.); (S.T.); (T.I.)
| | - Tetsuo Imamura
- Department of Surgery, Kyoaikai Tobata Kyoritsu Hospital, Kitakyushu 804-0093, Fukuoka, Japan; (Y.W.); (S.S.); (T.N.); (H.S.); (Y.N.); (T.T.); (K.H.); (H.A.); (S.T.); (T.I.)
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Balaceanu LA, Dina I. D-dimers in advanced liver cirrhosis: Useful biomarker or not? Am J Med Sci 2024; 368:415-423. [PMID: 38788925 DOI: 10.1016/j.amjms.2024.05.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 02/03/2024] [Accepted: 05/20/2024] [Indexed: 05/26/2024]
Abstract
In clinical practice, the d-dimer levels rule out venous thromboembolism and diagnose disseminated intravascular coagulation. d-dimers increase in both physiological and pathological conditions. Liver cirrhosis, especially in the final stages, is characterized by complex coagulation and fibrinolysis factor disorders. Multiple mechanisms tried to explain the increased d-dimer levels in patients with liver cirrhosis and ascites. The d-dimer cut-off level used to rule out venous thromboembolism in cirrhosis is higher than that used to confirm the diagnosis of VTE or DIC in noncirrhotic patients. The cut-off d-dimer level used for the prognosis of thrombotic events is not standardized in advanced liver cirrhosis. Thus, it is necessary to update the clinical guidelines regarding the usefulness of d-dimer testing in advanced liver cirrhosis and the cut-off d-dimer levels, which should vary based on the detection method.
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Affiliation(s)
- Lavinia Alice Balaceanu
- Internal Medicine Department, "Carol Davila" University of Medicine and Pharmacy, Emergency Clinical Hospital "Sf. Ioan," Bucharest, Romania.
| | - Ion Dina
- Gastroenterology Department, "Carol Davila" University of Medicine and Pharmacy, Emergency Clinical Hospital "Sf. Ioan," Bucharest, Romania
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Amjad W, Jiang ZG, Lai M. Metabolic dysfunction-associated steatotic liver disease related cirrhosis and incidence of portal vein thrombosis. Eur J Gastroenterol Hepatol 2024; 36:1038-1045. [PMID: 38829950 DOI: 10.1097/meg.0000000000002800] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/05/2024]
Abstract
BACKGROUND There is heterogeneous data on whether metabolic-associated steatohepatitis is an independent risk factor for portal vein thrombosis (PVT). We aim to compare the incidence of PVT in patients with cirrhosis with and without metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS This is a single-center retrospective study of patients with cirrhosis seen between 1 January 2016 and 31 January 2021. Patients with a history of hepatocellular cancer, liver transplant, Budd-Chiari syndrome, and intra-abdominal malignancies were excluded. Patients with cirrhosis were followed from their first hepatology visit for 180 days to determine the incidence of PVT. Cox proportional hazard regression was used to determine the relationship between MASLD with PVT. RESULTS We analyzed data from 2785 patients with cirrhosis who met inclusion and exclusion criteria [mean age: 61.0 ± 12.3 years, 44.3% female, 63.8% Whites and mean model for end-stage liver disease-sodium (MELD-Na) score: 11.7 ± 6.1]. MASLD was present in 21.7% of patients. A total of 89 patients developed PVT during the follow-up, which was fewer in patients with MASLD [2.0% vs. 3.5%, P = 0.04, unadjusted heart rate (HR): 0.60, 95% confidence interval (CI): 0.27-0.96, P = 0.04]. After adjusting for the demographics, MASLD-related comorbid conditions and MELD-Na score, MASLD was associated with a lower incidence of PVT as compared to non-MASLD cirrhosis (HR: 0.44, 95% CI: 0.21-0.92, P = 0.03). After adjusting for the indicators of Child-Pugh Turcotte score, the risk of PVT in patients with MASLD compared to non-MASLD was not statistically significant (HR: 0.50, 95% CI: 0.22-1.13, P = 0.096). CONCLUSION PVT incidence was lower in patients with MASLD cirrhosis as compared to non-MASLD cirrhosis. However, the difference was not significantly different after adjusting for liver decompensation.
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Affiliation(s)
- Waseem Amjad
- Liver Disease Department, Beth Israel Deaconess Medical Center
- Clinical Investigation, Harvard Medical School, Boston, Massachusetts, USA
| | | | - Michelle Lai
- Liver Disease Department, Beth Israel Deaconess Medical Center
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Pemmasani G, Tremaine W, Karagozian R, John S. Impact of Cirrhosis Etiology on the Risk for Venous Thromboembolism. Dig Dis Sci 2024; 69:2691-2698. [PMID: 38700633 DOI: 10.1007/s10620-024-08440-7] [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: 06/05/2023] [Accepted: 04/09/2024] [Indexed: 07/19/2024]
Abstract
BACKGROUND Cirrhosis is associated with an increased risk for both bleeding and venous thromboembolic (VTE) complications. The data regarding the impact of etiology of cirrhosis on VTE risk is poorly understood. METHODS In this retrospective observational analysis of the US Nationwide readmissions database 2019, we identified hospitalized patients who had cirrhosis from alcohol, viral, or nonalcoholic steatohepatitis (NASH) etiologies. We identified patients who had acute VTE, chronic/history of VTE, and portal venous thrombosis (PVT). Overall VTE risk was defined as the composite of acute and chronic VTE or PVT. The impact of etiology of cirrhosis on the crude and risk adjusted rates of VTE and PVT was studied. RESULTS Of 432,383 patients with cirrhosis, 41.4% patients had NASH-cirrhosis, 39.7% had alcohol-related cirrhosis, and 18.9% had viral cirrhosis. The overall VTE rate was highest in patients with NASH cirrhosis (10.8%) followed by viral cirrhosis (9.7%) and alcohol-related cirrhosis (7.5%; P < 0.001). Similar results were observed for acute and chronic VTE. After risk adjustment, patients with NASH (OR 1.48 95% CI 1.42-1.54) and viral cirrhosis (OR 1.22 95% CI 1.17-1.29) had significantly higher overall VTE risk compared with alcohol-related cirrhosis. When separately evaluated, the adjusted risk for acute and chronic VTE was similar between patients with alcohol-related and viral cirrhosis but higher with NASH cirrhosis. PVT rate was highest with viral cirrhosis (4.3%) followed by NASH (2.8%) and alcohol-related cirrhosis (2.4%; P < 0.001). The adjusted risk of PVT was higher with viral (OR 1.61 95% CI 1.50-1.72) and NASH cirrhosis (OR 1.41 95% CI 1.31-1.52). CONCLUSION NASH cirrhosis was associated with a higher VTE risk compared with alcohol-related and viral etiologies. As NASH cirrhosis increases in prevalence as the major etiology of cirrhosis, it is important to understand the increased VTE risk associated with this condition to improve management strategies and patient outcomes.
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Affiliation(s)
- Gayatri Pemmasani
- Division of Gastroenterology and Hepatology, SUNY Upstate Medical University, 750 E Adam St, Syracuse, NY, 13202, USA.
| | - William Tremaine
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Raffi Karagozian
- Division of Gastroenterology and Hepatology, Tufts University School of Medicine, Boston, MA, USA
| | - Savio John
- Division of Gastroenterology and Hepatology, SUNY Upstate Medical University, 750 E Adam St, Syracuse, NY, 13202, USA
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Dehghani Firouzabadi M, Poopak A, Sheikhy A, Dehghani Firouzabadi F, Moosaie F, Rabizadeh S, Momtazmanesh S, Nakhjavani M, Esteghamati A. Nonalcoholic Fatty Liver Disease as a Potential Risk Factor for Cardiovascular Disease in Patients with Type 2 Diabetes: A Prospective Cohort Study. Int J Endocrinol 2024; 2024:5328965. [PMID: 38962375 PMCID: PMC11221952 DOI: 10.1155/2024/5328965] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 06/11/2024] [Accepted: 06/15/2024] [Indexed: 07/05/2024] Open
Abstract
Methods and Results In this prospective cohort study, 1197 patients with type 2 diabetes (T2D) were divided into two groups (360 patients with NAFLD and 847 without NAFLD) and were followed for a median of 5 years for the incidence of CVD. Cox regression analysis was used to assess the association between NAFLD, liver enzyme level, aspartate aminotransferase to platelet ratio index (APRI), and the incidence risk of CVD and its subgroups (i.e., myocardial infarction, chronic heart disease, coronary artery bypass grafting, and percutaneous coronary intervention). There was a significant positive association between CVD incidence and NAFLD (HR = 1.488, 95% CI = 1.041-2.124, p value = 0.029). Although patients with NAFLD had higher levels of ALT and AST levels (p value = <0.001), there was no significant association between liver enzymes and the incidence risk of CVD when adjusted for different variables. Furthermore, NAFLD was associated with NAFLD APRI Q (2), APRI Q (3), and APRIQ (4) (1.365 (1.046-1.781), 1.623 (1.234-2.135), and 3.373 (2.509-4.536)), respectively. Conclusion NAFLD increased the incidence risk of CVD in T2D. However, there was no association between liver enzymes (ALT, AST, ALK-P, and GGT) and a higher incidence risk of CVD in T2D when adjusted for confounding variables.
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Affiliation(s)
- Mohammad Dehghani Firouzabadi
- Endocrinology and Metabolism Research Center (EMRC)Vali-Asr HospitalTehran University of Medical Sciences, Tehran, Iran
| | - Amirhossein Poopak
- Endocrinology and Metabolism Research Center (EMRC)Vali-Asr HospitalTehran University of Medical Sciences, Tehran, Iran
| | - Ali Sheikhy
- Endocrinology and Metabolism Research Center (EMRC)Vali-Asr HospitalTehran University of Medical Sciences, Tehran, Iran
- Department of Radiology and Imaging SciencesClinical CenterNational Institutes of Health, Bethesda, USA
| | - Fatemeh Dehghani Firouzabadi
- Endocrinology and Metabolism Research Center (EMRC)Vali-Asr HospitalTehran University of Medical Sciences, Tehran, Iran
- Department of Radiology and Imaging SciencesClinical CenterNational Institutes of Health, Bethesda, USA
| | - Fatemeh Moosaie
- Endocrinology and Metabolism Research Center (EMRC)Vali-Asr HospitalTehran University of Medical Sciences, Tehran, Iran
| | - Soghra Rabizadeh
- Endocrinology and Metabolism Research Center (EMRC)Vali-Asr HospitalTehran University of Medical Sciences, Tehran, Iran
| | - Sara Momtazmanesh
- Endocrinology and Metabolism Research Center (EMRC)Vali-Asr HospitalTehran University of Medical Sciences, Tehran, Iran
| | - Manouchehr Nakhjavani
- Endocrinology and Metabolism Research Center (EMRC)Vali-Asr HospitalTehran University of Medical Sciences, Tehran, Iran
| | - Alireza Esteghamati
- Endocrinology and Metabolism Research Center (EMRC)Vali-Asr HospitalTehran University of Medical Sciences, Tehran, Iran
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Gato S, García-Fernández V, Gil-Gómez A, Rojas Á, Montero-Vallejo R, Muñoz-Hernández R, Romero-Gómez M. Navigating the Link Between Non-alcoholic Fatty Liver Disease/Non-alcoholic Steatohepatitis and Cardiometabolic Syndrome. Eur Cardiol 2024; 19:e03. [PMID: 38807856 PMCID: PMC11131154 DOI: 10.15420/ecr.2023.26] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Accepted: 12/27/2023] [Indexed: 05/30/2024] Open
Abstract
The global prevalence of non-alcoholic fatty liver disease (NAFLD) is nearly 25% and is increasing rapidly. The spectrum of liver damage in NAFLD ranges from simple steatosis to non-alcoholic steatohepatitis, characterised by the presence of lobular inflammation and hepatocyte ballooning degeneration, with or without fibrosis, which can further develop into cirrhosis and hepatocellular carcinoma. Not only is NAFLD a progressive liver disease, but numerous pieces of evidence also point to extrahepatic consequences. Accumulating evidence suggests that patients with NAFLD are also at increased risk of cardiovascular disease (CVD); in fact, CVDs are the most common cause of mortality in patients with NAFLD. Obesity, type 2 diabetes and higher levels of LDL are common risk factors in both NAFLD and CVD; however, how NAFLD affects the development and progression of CVD remains elusive. In this review, we comprehensively summarise current data on the key extrahepatic manifestations of NAFLD, emphasising the possible link between NAFLD and CVD, including the role of proprotein convertase substilisin/kenin type 9, extracellular vesicles, microbiota, and genetic factors.
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Affiliation(s)
- Sheila Gato
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de SevillaSeville, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD)Madrid, Spain
| | - Vanessa García-Fernández
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de SevillaSeville, Spain
| | - Antonio Gil-Gómez
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de SevillaSeville, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD)Madrid, Spain
| | - Ángela Rojas
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de SevillaSeville, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD)Madrid, Spain
| | - Rocío Montero-Vallejo
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de SevillaSeville, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD)Madrid, Spain
| | - Rocío Muñoz-Hernández
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de SevillaSeville, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD)Madrid, Spain
- Departamento de Fisiología, Facultad de Biología, Universidad de SevillaSeville, Spain
| | - Manuel Romero-Gómez
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de SevillaSeville, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD)Madrid, Spain
- Unidad de Gestión Clínica de Aparato Digestivo, Hospital Universitario Virgen del RocíoSeville, Spain
- Departamento de Medicina, Facultad de Medicina, Universidad de SevillaSeville, Spain
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Eichholz JC, Wedemeyer H, Maasoumy B. The Challenge of Anticoagulation in Liver Cirrhosis. Visc Med 2024; 39:169-176. [PMID: 38205270 PMCID: PMC10775854 DOI: 10.1159/000535438] [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: 09/12/2023] [Accepted: 11/22/2023] [Indexed: 01/12/2024] Open
Abstract
Background Advanced liver diseases are characterized by a number of changes in the hemostatic system. Due to the occurrence of bleeding events in patients with liver cirrhosis, there seems to be a hesitance to the administration of anticoagulant medications. This review summarizes challenges, recommendations, and current developments of anticoagulation in the cirrhotic patient. Summary The risk of thrombotic events in patients with liver cirrhosis is at least as high as in patients with healthy liver function if not even higher. Standard laboratory markers do not truly reflect the complexity of changes that take place in the coagulative system and therefore cannot be used as a reference for risk of thrombosis or hemorrhage. Potential options for anticoagulant therapy are heparins, vitamin K antagonists, and direct-acting oral anticoagulants which come with differences in safety, application, possible side effects, and data availability for the patient cohort. Key Message The administration of anticoagulation can be beneficial in patients with liver disease if the indication is present and bleeding prophylaxis has been established. Direct-acting oral anticoagulants appear to be a promising new approach with many improvements compared to conventional substances. Nevertheless, there is a need for further data and prospective trials on the use in patients with liver cirrhosis.
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Affiliation(s)
- Julia Carolin Eichholz
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- German Centre for Infection Research (DZIF), Hannover-Braunschweig, Hannover, Germany
- Excellence Cluster Resist, Hannover Medical School, Hannover, Germany
- D-SOLVE Consortium, Hannover, Germany
| | - Benjamin Maasoumy
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- Center for Individualized Infection Medicine (CIIM), Hannover, Germany
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Suresh MG, Gogtay M, Singh Y, Yadukumar L, Mishra AK, Abraham GM. Case-control analysis of venous thromboembolism risk in non-alcoholic steatohepatitis diagnosed by transient elastography. World J Clin Cases 2023; 11:8126-8138. [PMID: 38130793 PMCID: PMC10731178 DOI: 10.12998/wjcc.v11.i34.8126] [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: 10/30/2023] [Revised: 11/06/2023] [Accepted: 11/24/2023] [Indexed: 12/06/2023] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. Studies have shown a strong association between non-alcoholic steatohepatitis (NASH) cirrhosis and portal vein thrombosis. Specifically, there is paucity of data on the association of NASH and venous thromboembolism (VTE), with one such study predicting a 2.5-fold increased risk for VTE compared to other liver diseases in hospitalized patients. The mechanism is believed to be a hepatocellular injury, which causes a chronic inflammatory state leading to the unregulated activation of procoagulant factors. There has been no prior analysis of the degree of steatosis and fibrosis (measured using transient elastography, commonly known as FibroScan) in NASH and its association with VTE. AIM To examine the association between the degree of hepatic steatosis and fibrosis, quantified by transient elastography, and the incidence of VTE in patients with NASH. METHODS In our case-control study, we included patients with a documented diagnosis of NASH. We excluded patients with inherited thrombophilia, hemoglobinopathy, malignancy, alcohol use disorder, autoimmune hepatitis, and primary biliary cirrhosis. The collected data included age, demographics, tobacco use, recreational drug use, medical history, and vibration controlled transient elastography scores. VTE-specific data included the location, type of anticoagulant, need for hospital stay, and history of VTE recurrence. Steatosis was categorized as S0-S1 (mild) and S2-S3 (moderate to severe) based on the controlled attenuation parameter score. Fibrosis was classified based on the kilopascal score and graded as F0-F1 (Metavir stage), F2, F3, and F4 (cirrhosis). χ2 and Mann-Whitney U tests were used for the qualitative and quantitative variable analyses, respectively. Furthermore, we performed a logistic regression using VTE as the dependent variable. RESULTS A total of 415 patients were analyzed, and 386 met the inclusion criteria. 51 and 335 patients were included in the VTE and non-VTE groups, respectively. Patients with VTE had a mean age of 60.63 years compared to 55.22 years in the non-VTE group (P < 0.014). Patients with VTE had a higher body mass index (31.14 kg/m² vs 29.30 kg/m²) and a higher prevalence of diabetes mellitus (29.4% vs 13.1%). The history of NASH was significantly higher in the VTE group (45.1% vs 30.4%, P < 0.037). Furthermore, moderate-to-severe steatosis was significantly higher in the VTE group (66.7% vs 47.2%, P < 0.009). Similarly, the F2-F4 fibrosis grade had a prevalence of 58.8% in the VTE group compared to 38.5% in the non-VTE group (P < 0.006). On logistic regression, using VTE as a dependent variable, diabetes mellitus had an odds ratio (OR) =1.702 (P < 0.015), and F2-F4 fibrosis grade had an OR = 1.5 (P < 0.033). CONCLUSION Our analysis shows that NASH is an independent risk factor for VTE, especially deep vein thrombosis. There was a statistically significant association between the incidence of VTE, moderate-to-severe steatosis, and fibrosis. All hospitalized patients should be considered for medical thromboprophylaxis, particularly those with NASH.
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Affiliation(s)
- Mithil Gowda Suresh
- Department of Internal Medicine, Saint Vincent Hospital, Worcester, MA 01608, United States
| | - Maya Gogtay
- Department of Hematology and Oncology, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Yuvaraj Singh
- Department of Gastroenterology and Hepatology, University of Massachusetts, Worcester, MA 01605, United States
| | - Lekha Yadukumar
- Internal Medicine, The Wright Center for Graduate Medical Education, Scranton, PA 18505, United States
| | - Ajay Kumar Mishra
- Division of Cardiology, Saint Vincent Hospital, Worcester, MA 01608, United States
| | - George M Abraham
- Internal Medicine, Saint Vincent Hospital, Worcester, MA 01608, United States
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10
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Swan D, Lisman T, Tripodi A, Thachil J. The prothrombotic tendency of metabolic-associated fatty liver disease. J Thromb Haemost 2023; 21:3045-3055. [PMID: 37353082 DOI: 10.1016/j.jtha.2023.06.017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 05/12/2023] [Accepted: 06/12/2023] [Indexed: 06/25/2023]
Abstract
Our understanding of the function of the liver has evolved over the centuries. Early theories proposing that the liver could be used to divine the future have been superseded by our current knowledge of the importance of the liver in processes such as digestion and detoxification. Similarly, although liver disease was previously associated with only an increased risk of bleeding, there is now a substantial body of evidence demonstrating an increased thrombotic potential in patients with this disease. Metabolic-associated fatty liver disease (MAFLD) is increasing in frequency and is likely to overtake alcoholic liver disease as the primary indication for liver transplant in the future. In this review, we discuss the evidence linking liver disease, and MAFLD in particular, with arterial and venous thromboembolic disease. We review the safety and efficacy of anticoagulation in advanced liver disease and consider whether antithrombotic agents could slow or halt the progression of fibrosis in MAFLD.
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Affiliation(s)
- Dawn Swan
- Department of Haematology, Beaumont Hospital, Dublin, Ireland.
| | - Ton Lisman
- Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Armando Tripodi
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione Luigi Villa, Milano, Italy
| | - Jecko Thachil
- Department of Haematology, Manchester University Hospitals, Oxford Road, Manchester, UK
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11
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da Cruz Renó L, Tustumi F, Waisberg DR, Santos VR, Pinheiro RS, Macedo RA, Nacif LS, Ducatti L, De Martino RB, Trevisan AM, D’Albuquerque LC, Andraus W. Prevalence of chronic venous insufficiency and deep vein thrombosis in cirrhotic patients. Front Med (Lausanne) 2023; 10:1214517. [PMID: 37828947 PMCID: PMC10565485 DOI: 10.3389/fmed.2023.1214517] [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: 04/29/2023] [Accepted: 09/11/2023] [Indexed: 10/14/2023] Open
Abstract
SUMMARY People with cirrhosis of the liver are at risk for complications that can worsen their quality of life and increase morbidity and mortality. Contrary to previous beliefs, cirrhosis does not protect against the development of thromboembolic events, and cirrhotic patients may have higher rates of deep vein thrombosis (DVT). BACKGROUND AND AIMS The study of chronic venous disease and its impact on patients with cirrhosis is unknown in the literature and may be an important fact since this condition also had impact on quality of life and morbidity. The aim of this study is to evaluate the prevalence of DVT (Deep Venous thrombosis) in outpatients with cirrhosis and the degree of chronic venous insufficiency, evaluating possible correlations between clinical and laboratory aspects of cirrhotic patients with these pathologies. METHODS Patients with cirrhosis were evaluated in the outpatient clinic of the Liver Transplantation and Hepatology Service of HC-FMUSP from November 2018 to November 2022, with clinical evaluation, venous disease questionnaires, data collection of imaging and laboratory tests, and venous color Doppler ultrasound. The information was analyzed by the University of São Paulo (USP) Statistics Department. RESULTS There was a prevalence of 7.6% of DVT in studied patients, VCSS score 6.73 and severe CEAP classification (C4-6) 32.1%. There was no association of DVT with qualitative variables by the Fisher test such as Child Turcotte Pugh Scale (CTP) (p = 0.890), dichotomized INR values (p = 0.804), etiology of cirrhosis (p = 0.650) and chronic kidney disease (p > 0.999), nor with quantitative variables by t-student's such as age (p = 0.974), Body Mass Index (BMI) (p = 0.997), MELD score (p = 0.555), Albumin (p = 0.150) and Platelets (p = 0.403). We found that as the severity of ascites increases, there is an increase in the proportion of patients classified in the category indicating more severe clinical manifestations of chronic venous disease (C4 to C6). The mean age (54 years) was higher in patients with DVT than in those without. The mean BMI of patients without DVT (25.7 kg/m2) is lower than that of patients with DVT (27.0 kg/m2). The prevalence of DVT is higher in patients with thrombophilia (20.0%) than in those without (7.0%). This suggests an association between the two variables. The descriptive measures of the MELD score, the cirrhosis scale used for liver transplant waiting lists, did not indicate an association of this scale with the occurrence of DVT. CONCLUSION The incidence of VTE (Venous Thromboembolic Events) and CVD (Chronic Venous Disease) within the sample surpassed that of the general population; nevertheless, more studies are required to validate these results. Concerning venous thromboembolism, no correlation was observed between the variables within the sample and the augmented risk of VTE. Regarding chronic venous disease, studies have shown that edema and orthostatism are correlated with increased severity of CVD on the VCSS scales. Statistical dispersion methods suggest that patients with higher BMI and more severe liver disease (according to the Child-Pugh score) are more likely to experience worsening of CVD. About chronic venous disease, studies have shown that edema and orthostatism are correlated with increased severity of CVD on the VCSS scales.
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Affiliation(s)
- Leonardo da Cruz Renó
- Department of Gastroenterology, School of Medicine, University of São Paulo, São Paulo, Brazil
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12
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Kim CY, Kim N, Roh JH. Association of nonalcoholic fatty liver disease and venous thromboembolic disease in healthy adults in Korea: a nationwide study. Sci Rep 2023; 13:16069. [PMID: 37752202 PMCID: PMC10522768 DOI: 10.1038/s41598-023-42963-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 09/17/2023] [Indexed: 09/28/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) can lead to a prothrombotic state, which significantly burdens public healthcare systems. This study investigated the relationship between NAFLD and the incidence of venous thromboembolism (VTE) in Korea using National Health Insurance Service-National Sample Cohort 2.0 data. A population-based retrospective cohort analysis was conducted on 472,212 healthy individuals who underwent national health check-ups in Korea from 2009 to 2014. NAFLD was defined using the fatty liver index (FLI). Multivariate Cox proportional hazards regression models were used to analyze the association between FLI and VTE. Individuals were categorized into four quartiles according to FLI values (first quartile [Q1], 0-5.7; second quartile [Q2], 5.8-15.3; third quartile [Q3], 15.4-37.2; and fourth quartile [Q4], > 37.2). The incidence of VTE tended to increase with increasing FLI values (Q1, 598 [0.5%]; Q2, 1,033 [0.9%]; Q3, 1,443 [1.2%]; and Q4, 1,425 [1.2%]). In the age- and sex-adjusted multivariate model, the hazard ratio (HR) (95% confidence interval [CI]) was 1.47 (1.33‒1.62) for Q4 compared with Q1. After adjusting for clinical variables with P < 0.1 in the univariate analyses, the HR (95% CI) was 1.45 (1.30‒1.62) for Q4 compared with Q1. FLI was related to VTE risk, as confirmed after adjusting for other risk factors.
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Affiliation(s)
- Chang-Yeon Kim
- Department of Internal Medicine, School of Medicine, Daegu Catholic University Medical Center, Daegu, Republic of Korea
| | - Namkyun Kim
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea.
| | - Jae-Hyung Roh
- Department of Cardiology in Internal Medicine, School of Medicine, Chungnam National University, Chungnam National University Sejong Hospital, Sejong, Republic of Korea.
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Hvas CL, Larsen JB. The Fibrinolytic System and Its Measurement: History, Current Uses and Future Directions for Diagnosis and Treatment. Int J Mol Sci 2023; 24:14179. [PMID: 37762481 PMCID: PMC10532028 DOI: 10.3390/ijms241814179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 09/13/2023] [Accepted: 09/14/2023] [Indexed: 09/29/2023] Open
Abstract
The fibrinolytic system is a key player in keeping the haemostatic balance, and changes in fibrinolytic capacity can lead to both bleeding-related and thrombosis-related disorders. Our knowledge of the fibrinolytic system has expanded immensely during the last 75 years. From the first successful use of thrombolysis in myocardial infarction in the 1960s, thrombolytic therapy is now widely implemented and has reformed treatment in vascular medicine, especially ischemic stroke, while antifibrinolytic agents are used routinely in the prevention and treatment of major bleeding worldwide. Despite this, this research field still holds unanswered questions. Accurate and timely laboratory diagnosis of disturbed fibrinolysis in the clinical setting remains a challenge. Furthermore, despite growing evidence that hypofibrinolysis plays a central role in, e.g., sepsis-related coagulopathy, coronary artery disease, and venous thromboembolism, there is currently no approved treatment of hypofibrinolysis in these settings. The present review provides an overview of the fibrinolytic system and history of its discovery; measurement methods; clinical relevance of the fibrinolytic system in diagnosis and treatment; and points to future directions for research.
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Affiliation(s)
- Christine Lodberg Hvas
- Department of Anaesthesiology and Intensive Care, Aarhus University Hospital, 8200 Aarhus N, Denmark;
- Department of Clinical Medicine, Faculty of Health Sciences, Aarhus University, 8200 Aarhus N, Denmark
| | - Julie Brogaard Larsen
- Department of Clinical Medicine, Faculty of Health Sciences, Aarhus University, 8200 Aarhus N, Denmark
- Department of Clinical Biochemistry, Regional Hospital Horsens, 8700 Horsens, Denmark
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14
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Saner FH, Scarlatescu E, Broering DC, Bezinover D. The Yin and the Yang of Hemostasis in End-Stage Liver Disease. J Clin Med 2023; 12:5759. [PMID: 37685826 PMCID: PMC10488973 DOI: 10.3390/jcm12175759] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 08/28/2023] [Accepted: 08/29/2023] [Indexed: 09/10/2023] Open
Abstract
Patients with end-stage liver disease (ESLD) undergoing liver transplantation (LT) are prone to thromboses both while on the waiting list and in the perioperative period. This hypercoagulability is associated with significant endothelial dysfunction (ED) due to nitric oxide dysregulation. ED and increased thrombin generation are the main factors responsible for this hypercoagulability. Sepsis alone can significantly alter a patient's coagulation profile. In combination with ESLD, however, sepsis or septic shock are responsible for very complex changes. This makes both the assessment and management of coagulation in septic patients with ESLD very challenging. Viscoelastic testing (VET) is the preferred method of coagulation management in patients with cirrhosis because, as with standard laboratory testing, VET can assess the entire coagulation system including the interaction between both pro- and anticoagulants and platelets.
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Affiliation(s)
- Fuat H. Saner
- King Faisal Specialist Hospital & Research Center, Organ Transplant Center of Excellence, Riyadh 11564, Saudi Arabia;
| | - Ecaterina Scarlatescu
- Department of Anesthesia and Intensive Care Medicine III, Fundeni Clinical Institute, 022328 Bucharest, Romania;
- Anesthesia and Intensive Care Department, University of Medicine and Pharmacy “Carol Davila”, 050474 Bucharest, Romania
| | - Dieter Clemens Broering
- King Faisal Specialist Hospital & Research Center, Organ Transplant Center of Excellence, Riyadh 11564, Saudi Arabia;
| | - Dmitri Bezinover
- Department of Anesthesiology and Critical Care, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA;
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15
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Intagliata NM, Rahimi RS, Higuera-de-la-Tijera F, Simonetto DA, Farias AQ, Mazo DF, Boike JR, Stine JG, Serper M, Pereira G, Mattos AZ, Marciano S, Davis JPE, Benitez C, Chadha R, Méndez-Sánchez N, deLemos AS, Mohanty A, Dirchwolf M, Fortune BE, Northup PG, Patrie JT, Caldwell SH. Procedural-Related Bleeding in Hospitalized Patients With Liver Disease (PROC-BLeeD): An International, Prospective, Multicenter Observational Study. Gastroenterology 2023; 165:717-732. [PMID: 37271290 DOI: 10.1053/j.gastro.2023.05.046] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 05/04/2023] [Accepted: 05/11/2023] [Indexed: 06/06/2023]
Abstract
BACKGROUND & AIMS Hospitalized patients with cirrhosis frequently undergo multiple procedures. The risk of procedural-related bleeding remains unclear, and management is not standardized. We conducted an international, prospective, multicenter study of hospitalized patients with cirrhosis undergoing nonsurgical procedures to establish the incidence of procedural-related bleeding and to identify bleeding risk factors. METHODS Hospitalized patients were prospectively enrolled and monitored until surgery, transplantation, death, or 28 days from admission. The study enrolled 1187 patients undergoing 3006 nonsurgical procedures from 20 centers. RESULTS A total of 93 procedural-related bleeding events were identified. Bleeding was reported in 6.9% of patient admissions and in 3.0% of the procedures. Major bleeding was reported in 2.3% of patient admissions and in 0.9% of the procedures. Patients with bleeding were more likely to have nonalcoholic steatohepatitis (43.9% vs 30%) and higher body mass index (BMI; 31.2 vs 29.5). Patients with bleeding had a higher Model for End-Stage Liver Disease score at admission (24.5 vs 18.5). A multivariable analysis controlling for center variation found that high-risk procedures (odds ratio [OR], 4.64; 95% confidence interval [CI], 2.44-8.84), Model for End-Stage Liver Disease score (OR, 2.37; 95% CI, 1.46-3.86), and higher BMI (OR, 1.40; 95% CI, 1.10-1.80) independently predicted bleeding. Preprocedure international normalized ratio, platelet level, and antithrombotic use were not predictive of bleeding. Bleeding prophylaxis was used more routinely in patients with bleeding (19.4% vs 7.4%). Patients with bleeding had a significantly higher 28-day risk of death (hazard ratio, 6.91; 95% CI, 4.22-11.31). CONCLUSIONS Procedural-related bleeding occurs rarely in hospitalized patients with cirrhosis. Patients with elevated BMI and decompensated liver disease who undergo high-risk procedures may be at risk to bleed. Bleeding is not associated with conventional hemostasis tests, preprocedure prophylaxis, or recent antithrombotic therapy.
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Affiliation(s)
| | | | | | | | | | - Daniel F Mazo
- School of Medical Sciences of University of Campinas (UNICAMP), São Paulo, Brazil
| | - Justin R Boike
- Northwestern University Feinburg School of Medicine, Chicago, Illinois
| | - Jonathan G Stine
- Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania
| | - Marina Serper
- University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Gustavo Pereira
- Bonsucesso Federal Hospital (Ministry of Health), Rio de Janeiro, Brazil, and Estácio de Sá School of Medicine-Instituto de Educação Médica, Rio de Janeiro, Brazil
| | - Angelo Z Mattos
- Federal University of Health Sciences of Porto Alegre, Porto Alegre, Brazil
| | | | | | - Carlos Benitez
- Pontificia Universidad Católica de Chile, Santiago, Chile
| | | | - Nahum Méndez-Sánchez
- Medica Sur Clinic & Foundation and Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico
| | - Andrew S deLemos
- Wake Forest University School of Medicine, Atrium Health, Charlotte, North Carolina
| | - Arpan Mohanty
- Boston University School of Medicine and Boston Medical Center, Boston, Massachusetts
| | | | - Brett E Fortune
- Montefiore Einstein Center for Transplantation, New York, New York
| | | | - James T Patrie
- University of Virginia School of Medicine, Charlottesville, Virginia
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16
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Gong H, Zhong H, Xu HM, Liu XC, Li LP, Zhang DK. Insight into increased risk of portal vein thrombosis in nonalcoholic fatty liver disease. Eur J Intern Med 2023; 114:23-34. [PMID: 37330315 DOI: 10.1016/j.ejim.2023.06.011] [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: 05/24/2023] [Revised: 06/09/2023] [Accepted: 06/13/2023] [Indexed: 06/19/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the leading chronic liver diseases with increased morbidity and mortality rates for extrahepatic diseases (including cardiovascular disease, portal vein thrombosis, etc.). There is an increased risk of thrombosis in both the portal and systemic circulation in patients with NAFLD, independent of traditional liver cirrhosis. However, increased portal pressure, the most critical factor, is frequently observed in NAFLD patients, predisposing them to portal vein thrombosis (PVT). It has been reported that there is an 8.5% incidence of PVT among patients with non-cirrhotic NAFLD in a prospective cohort study. Based on the prothrombotic status of NAFLD itself, patients combined with cirrhosis may accelerate the development of PVT and lead to a poor prognosis. Moreover, PVT has been shown to complicate the procedure and adversely affect the outcome during liver transplantation surgery. NAFLD is in a prothrombotic state, and its underlying mechanisms have not been fully understood so far. Particularly noteworthy is that gastroenterologists currently overlook the higher risk of PVT in NAFLD. We investigate the pathogenesis of NAFLD complicated with PVT from the perspective of primary, secondary, and tertiary hemostasis, and also summarize relevant studies in humans. Some treatment options that may affect NAFLD and its PVT are also explored to improve patient-oriented outcomes.
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Affiliation(s)
- Hang Gong
- Department of Gastroenterology, Lanzhou University Second Hospital, Lanzhou, Gansu Province, China
| | - Huang Zhong
- Department of Gastroenterology, Zigong First People's Hospital, Zigong, Sichuan Province, China
| | - Hui-Mei Xu
- Department of Gastroenterology, Lanzhou University Second Hospital, Lanzhou, Gansu Province, China
| | - Xiong-Chang Liu
- Department of Gastroenterology, Lanzhou Second People's Hospital, Lanzhou, Gansu Province, China
| | - Liang-Ping Li
- Department of Gastroenterology, Sichuan Academy of Medical Sciences and Sichuan People's Hospital, Chengdu, Sichuan Province, China.
| | - De-Kui Zhang
- Department of Gastroenterology, Lanzhou University Second Hospital, Lanzhou, Gansu Province, China.
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Badmus OO, Kipp ZA, Bates EA, da Silva AA, Taylor LC, Martinez GJ, Lee WH, Creeden JF, Hinds TD, Stec DE. Loss of hepatic PPARα in mice causes hypertension and cardiovascular disease. Am J Physiol Regul Integr Comp Physiol 2023; 325:R81-R95. [PMID: 37212551 PMCID: PMC10292975 DOI: 10.1152/ajpregu.00057.2023] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 05/02/2023] [Accepted: 05/15/2023] [Indexed: 05/23/2023]
Abstract
The leading cause of death in patients with nonalcoholic fatty liver disease (NAFLD) is cardiovascular disease (CVD). However, the mechanisms are unknown. Mice deficient in hepatocyte proliferator-activated receptor-α (PPARα) (PparaHepKO) exhibit hepatic steatosis on a regular chow diet, making them prone to manifesting NAFLD. We hypothesized that the PparaHepKO mice might be predisposed to poorer cardiovascular phenotypes due to increased liver fat content. Therefore, we used PparaHepKO and littermate control mice fed a regular chow diet to avoid complications with a high-fat diet, such as insulin resistance and increased adiposity. After 30 wk on a standard diet, male PparaHepKO mice exhibited elevated hepatic fat content compared with littermates as measured by Echo MRI (11.95 ± 1.4 vs. 3.74 ± 1.4%, P < 0.05), hepatic triglycerides (1.4 ± 0.10 vs. 0.3 ± 0.01 mM, P < 0.05), and Oil Red O staining, despite body weight, fasting blood glucose, and insulin levels being the same as controls. The PparaHepKO mice also displayed elevated mean arterial blood pressure (121 ± 4 vs. 108 ± 2 mmHg, P < 0.05), impaired diastolic function, cardiac remodeling, and enhanced vascular stiffness. To determine mechanisms controlling the increase in stiffness in the aorta, we used state-of-the-art PamGene technology to measure kinase activity in this tissue. Our data suggest that the loss of hepatic PPARα induces alterations in the aortas that reduce the kinase activity of tropomyosin receptor kinases and p70S6K kinase, which might contribute to the pathogenesis of NAFLD-induced CVD. These data indicate that hepatic PPARα protects the cardiovascular system through some as-of-yet undefined mechanism.
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Affiliation(s)
- Olufunto O Badmus
- Department of Physiology and Biophysics, Cardiorenal, and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, Mississippi, United States
| | - Zachary A Kipp
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, United States
| | - Evelyn A Bates
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, United States
| | - Alexandre A da Silva
- Department of Physiology and Biophysics, Cardiorenal, and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, Mississippi, United States
| | - Lucy C Taylor
- Department of Physiology and Biophysics, Cardiorenal, and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, Mississippi, United States
| | - Genesee J Martinez
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, United States
| | - Wang-Hsin Lee
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, United States
| | - Justin F Creeden
- Department of Neurosciences, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, United States
| | - Terry D Hinds
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, United States
- Barnstable Brown Diabetes Center, University of Kentucky, Lexington, Kentucky, United States
- Markey Cancer Center, University of Kentucky, Lexington, Kentucky, United States
| | - David E Stec
- Department of Physiology and Biophysics, Cardiorenal, and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, Mississippi, United States
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18
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Samuel S, Abulawi A, Malik R. Hepatitis C and Nonalcoholic Steatohepatitis in the 21st Century: Impact on Liver Disease and Liver Transplantation. GASTROENTEROLOGY INSIGHTS 2023; 14:249-270. [DOI: 10.3390/gastroent14030018] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
Hepatitis C infection is a leading etiology of hepatic dysfunction and a major indication for liver transplantation due to the development of fibrosis, cirrhosis, and hepatocellular carcinoma. Nonalcoholic fatty liver disease (NAFLD) and, specifically, its subtype nonalcoholic steatohepatitis (NASH) is a rising cause of liver disease. It is predicted to surpass hepatitis C as a leading indication for transplant. The introduction of direct-acting antivirals (DAAs) decreased the prevalence of chronic hepatitis C infections, but the obesity epidemic and metabolic syndrome have increased the prevalence of NASH. Weight loss and dietary modifications are recommended NASH therapies, but unlike for hepatitis C, federally approved agents are lacking and currently under investigation. Clinical trials face many barriers in NASH treatment because of the difficulty of diagnosis and a lack of standardized and accurate clinical and histologic responses. Mortality and morbidity in NASH are heightened because of the presence of multiple comorbidities including cardiovascular disease, diabetes, and renal dysfunction. A liver transplant may be indicated, but a thorough screening of candidates, including a comprehensive cardiovascular assessment, is essential to ensuring successful outcomes pre- and post-transplant. Therapeutic agents for NASH are warranted before it becomes a significant and leading cause of morbidity and mortality worldwide.
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Affiliation(s)
- Sonia Samuel
- Division of Gastroenterology & Hepatology, Albany Medical Center, 47 New Scotland Ave, Albany, NY 12208, USA
| | - Ahmad Abulawi
- Division of Gastroenterology & Hepatology, Albany Medical Center, 47 New Scotland Ave, Albany, NY 12208, USA
| | - Raza Malik
- Division of Gastroenterology & Hepatology, Albany Medical Center, 47 New Scotland Ave, Albany, NY 12208, USA
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19
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Protopapas AA, Savopoulos C, Skoura L, Goulis I. Anticoagulation in Patients with Liver Cirrhosis: Friend or Foe? Dig Dis Sci 2023; 68:2237-2246. [PMID: 36961672 PMCID: PMC10188576 DOI: 10.1007/s10620-023-07858-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Accepted: 01/28/2023] [Indexed: 03/25/2023]
Abstract
Concepts regarding the status of the coagulation process in cirrhosis are rapidly changing. Instead of a disease defined by excessive bleeding risk, recent studies have shown cirrhosis to be associated with a fragile state of rebalanced hemostasis, easily swayed in either direction, thrombosis, or bleeding. These findings, combined with the ever-growing population of patients with cirrhosis with an indication for anticoagulation (AC) and the emergence of the non-alcoholic fatty liver disease epidemic, have prompted a reexamination of the use of AC in patients with cirrhosis, either as a treatment for a concurrent thrombotic disorder or even as a possible therapeutic option that could influence the natural course of the disease and its complications. In recent years, a significant number of studies have been formulated to evaluate these possibilities. These studies evaluated, among others, the efficacy and safety of AC in thrombotic disorders or thrombotic complications of cirrhosis, its effect on survival, and the class of anticoagulants which is more suitable for patients with cirrhosis, depending on disease severity. This review examines recent studies investigating the use of AC in patients with cirrhosis and attempts to provide a simple guide for clinicians regarding the use of AC in patients with cirrhosis and its potential risks and benefits.
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Affiliation(s)
- Adonis A Protopapas
- First Propaedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, AHEPA University Hospital, 54636, Thessaloniki, Greece.
| | - Christos Savopoulos
- First Propaedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, AHEPA University Hospital, 54636, Thessaloniki, Greece
| | - Lemonia Skoura
- Department of Microbiology, Aristotle University οf Thessaloniki, AHEPA University Hospital, 54636, Thessaloniki, Greece
| | - Ioannis Goulis
- Fourth Department of Internal Medicine, Aristotle University of Thessaloniki, Hippokration Hospital, 54642, Thessaloniki, Greece
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20
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Lisman T. Bleeding and thrombosis in cirrhosis. CARDIO-HEPATOLOGY 2023:165-202. [DOI: 10.1016/b978-0-12-817394-7.00010-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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21
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Zeina AR, Kopelman Y, Mari A, Ahmad HS, Artul S, Khalaila AS, Taher R, Villannueva FZ, Safadi R, Abu Mouch S, Abu Baker F. Pulmonary embolism risk in hospitalized patients with nonalcoholic fatty liver disease: A case-control study. Medicine (Baltimore) 2022; 101:e31710. [PMID: 36397431 PMCID: PMC9666162 DOI: 10.1097/md.0000000000031710] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 10/18/2022] [Indexed: 11/19/2022] Open
Abstract
Abundant research has associated nonalcoholic fatty liver disease (NAFLD) with atherosclerosis, but very few reports have evaluated the association between NAFLD and venous thromboembolism. We aimed to investigate the association between NAFLD and pulmonary embolism (PE) in hospitalized patients. In this retrospective case-control study, we included consecutive patients from 2 university-affiliated hospitals who were referred for CT pulmonary angiograms for a suspected PE. Patients with a history of excessive alcohol consumption, chronic liver diseases or cirrhosis were excluded. The imaging studies of the entire cohort were reviewed by 2 expert radiologists who confirmed the diagnosis of PE and examined the liver to detect and grade hepatic steatosis. Accordingly, patients were categorized into NAFLD patients and non-NAFLD controls. Patient demographics, medical history, hospitalization details as well as patients' outcomes were documented. Multivariate analysis was performed to identify predictors for developing PE and hazard ratios with corresponding 95% confidence intervals were estimated. A total of 377 patients (101 with NAFLD and 276 controls) were included. NAFLD patients had significantly higher BMI values (33.16 ± 6.78 vs 26.81 ± 5.6; P < .001) and prevalence of diabetes (41 (40%) vs 85 (30.8%); P = .03). The prevalence of PE was significantly higher in the NAFLD group (80 (79.2%) vs 147 (53.3%), P < .001). In a multivariate analysis, older age, recent surgery or trauma, active malignancy, smoking, and NAFLD (HR ratio = 4.339, P < .0001 and 95% CI = 2.196-8.572) were independently associated with PE development. Patients with NAFLD were associated with an increased risk of developing PE independent of other classical risk factors for PE.
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Affiliation(s)
- Abdel-Rauf Zeina
- Department of Radiology, Hillel Yaffe Medical Center, Hadera, Israel
| | - Yael Kopelman
- Department of Gastroenterology and Hepatology, Hillel Yaffe Medical Center, Hadera, Israel
| | - Amir Mari
- Department of Gastroenterology, Nazareth EMMS Hospital, Nazareth, Israel
| | - Helal Said Ahmad
- Department of Gastroenterology, Nazareth EMMS Hospital, Nazareth, Israel
| | - Suheil Artul
- Department of Radiology, Nazareth EMMS Hospital, Nazareth, Israel
| | | | - Randa Taher
- Department of Internal Medicine, Hillel Yaffe Medical Center, Hadera, Israel
| | | | - Rabea Safadi
- Department of Radiology, Hillel Yaffe Medical Center, Hadera, Israel
| | - Saif Abu Mouch
- Department of Internal Medicine, Hillel Yaffe Medical Center, Hadera, Israel
| | - Fadi Abu Baker
- Department of Gastroenterology and Hepatology, Hillel Yaffe Medical Center, Hadera, Israel
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22
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da Cruz Renó L, Tustumi F, Waisberg DR, Rocha-Santos V, Pinheiro RS, Macedo RA, Nacif LS, Ducatti L, De Martino RB, Trevisan AM, Carneiro-D’Albuquerque L, Andraus W. Venous thromboembolism in in-hospital cirrhotic patients: A systematic review. Front Med (Lausanne) 2022; 9:1027882. [PMID: 36419795 PMCID: PMC9676642 DOI: 10.3389/fmed.2022.1027882] [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: 08/25/2022] [Accepted: 10/14/2022] [Indexed: 08/30/2023] Open
Abstract
INTRODUCTION Patients with liver cirrhosis are at a higher risk of hospitalization. The present review aimed to assess the risk of thromboembolism and its burden on hospitalized cirrhotic patients. MATERIALS AND METHODS A systematic review (PROSPERO: CRD42021256869) was conducted in PubMed, Embase, Cochrane, Lilacs, and a manual search of references. It evaluated studies that compare cirrhotic patients with venous thromboembolism (VTE) with cirrhotic patients without VTE or studies that compare cirrhotic patients with non-cirrhotic patients. No restrictions were set for the date of publication or language. The last search was conducted in June 2021. RESULTS After selection, 17 studies were included from an initial search of 5,323 articles. The chronic liver disease etiologies comprise viral, alcohol, autoimmune, NASH (non-alcoholic steatohepatitis), cryptogenic, hemochromatosis, cholestasis, and drug-related. The included studies were conflicted regarding the outcomes of VTE, pulmonary embolism, or bleeding. Patients with cirrhosis associated with VTE had prolonged length of hospital stay, and patients with cirrhosis were at higher risk of portal thrombosis. CONCLUSION In-hospital cirrhotic patients are a heterogeneous group of patients that may present both thrombosis and bleeding risk. Clinicians should take extra caution to apply both prophylactic and therapeutic anticoagulation strategies. SYSTEMATIC REVIEW REGISTRATION [https://www.crd.york.ac.uk/PROSPERO/], identifier [CRD42021256869].
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Affiliation(s)
| | - Francisco Tustumi
- Transplantation Unit, Department of Gastroenterology, Universidade de São Paulo, São Paulo, Brazil
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23
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Sharma S, Stine JG, Verbeek T, Bezinover D. Management of Patients With Non-alcoholic Steatohepatitis Undergoing Liver Transplantation: Considerations for the Anesthesiologist. J Cardiothorac Vasc Anesth 2022; 36:2616-2627. [PMID: 34391652 DOI: 10.1053/j.jvca.2021.07.020] [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: 04/21/2021] [Revised: 06/24/2021] [Accepted: 07/09/2021] [Indexed: 11/11/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) currently affects more than 25% of the world population and is rising. NAFLD can progress to non-alcoholic steatohepatitis that is associated with hepatic inflammation and fibrosis and can result in cirrhosis with subsequent liver failure. Non-alcoholic steatohepatitis (NASH) has now emerged as one of the leading etiologies for a liver transplant among adults in the United States. Given the rising incidence of liver transplants in patients with NASH-related cirrhosis, it is essential for anesthesiologists to be familiar with this condition as well as with NASH-related comorbidities and perioperative complications. Not only is NASH linked to metabolic syndrome, but it also is independently associated with cardiovascular disease, renal and thyroid dysfunction, obstructive sleep apnea (OSA), and a hypercoagulable state. The association with these conditions can affect the perioperative outcome of these patients, particularly because of increased mortality from major adverse cardiovascular events and sepsis. In order to decrease the perioperative morbidity and mortality of patients with NASH undergoing a liver transplant, a multidisciplinary approach to their perioperative management is essential, along with careful preoperative evaluation and aggressive intraoperative and postoperative monitoring. The focus of this review article is to provide a comprehensive overview of challenges associated with liver transplants in patients with NASH and to provide suggestions for appropriate patient selection and perioperative management.
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Affiliation(s)
- Sonal Sharma
- Department of Anesthesiology and Perioperative Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, PA.
| | - Jonathan G Stine
- Liver Center, Pennsylvania State University, Penn State Health Milton S Hershey Medical Center, Hershey, PA; Department of Medicine and Public Health Sciences, Pennsylvania State University, Penn State Milton S Hershey Medical Center, Hershey, PA; Division of Gastroenterology and Hepatology, Department of Medicine, Pennsylvania State University, Penn State Milton S Hershey Medical Center, Hershey, PA; Cancer Institute, Pennsylvania State University, Penn State Milton S Hershey Medical Center, Hershey, PA
| | - Thomas Verbeek
- Department of Anesthesiology and Perioperative Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, PA
| | - Dmitri Bezinover
- Department of Anesthesiology and Perioperative Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, PA; Liver Center, Pennsylvania State University, Penn State Health Milton S Hershey Medical Center, Hershey, PA
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24
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Zanetto A, Campello E, Bulato C, Gavasso S, Saggiorato G, Shalaby S, Burra P, Angeli P, Senzolo M, Simioni P. Global hemostatic profiling in patients with decompensated cirrhosis and bacterial infections. JHEP Rep 2022; 4:100493. [PMID: 35647501 PMCID: PMC9131254 DOI: 10.1016/j.jhepr.2022.100493] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 04/13/2022] [Indexed: 02/08/2023] Open
Abstract
Background & Aims Bacterial infections in cirrhosis are associated with increased bleeding risk. To assess the factors responsible for bleeding tendency in patients with bacterial infections, we conducted a prospective study comparing all 3 aspects of hemostasis (platelets, coagulation, and fibrinolysis) in hospitalized patients with decompensated cirrhosis with vs. without bacterial infections. Methods Primary hemostasis assessment included whole blood platelet aggregation and von Willebrand factor (VWF). Coagulation assessment included procoagulant factors (fibrinogen, factor II, V, VII, VIII, IX, X, XI, XII, XIII), natural anticoagulants (protein C, protein S, antithrombin) and thrombomodulin-modified thrombin generation test. Fibrinolysis assessment included fibrinolytic factors (plasminogen, t-PA, PAI-1, α2-AP, TAFIa/ai) and plasmin-antiplasmin complex (PAP). Results Eighty patients with decompensated cirrhosis were included (40 with and 40 without bacterial infections). Severity of cirrhosis and platelet count were comparable between groups. At baseline, patients with cirrhosis and bacterial infections had significantly lower whole blood platelet aggregation, without significant differences in VWF. Regarding coagulation, bacterial infections were associated with reduced procoagulant factors VII and XII, and a significant reduction of all natural anticoagulants. However, thrombomodulin-modified thrombin generation was comparable between the study groups. Finally, although mixed potentially hypo-fibrinolytic (lower plasminogen) and hyper-fibrinolytic (higher t-PA) changes were present in bacterial infections, a comparable level of PAP was detected in both groups. Upon resolution of infection (n = 29/40), platelet aggregation further deteriorated whereas coagulation and fibrinolysis factors returned to levels observed in patients without bacterial infections. Conclusion In hospitalized patients with decompensated cirrhosis, bacterial infections are associated with reduced whole blood platelet aggregation and a significant decrease of all natural anticoagulants, which may unbalance hemostasis and potentially increase the risk of both bleeding and thrombosis. Lay summary Bacterial infections are a common issue in hospitalized patients with decompensated cirrhosis (i.e. patients hospitalized due to severe complications of advanced chronic liver disease). Patients with decompensated cirrhosis who acquire infections may be at increased risk of bleeding complications following invasive procedures (that is a procedure in which the body is penetrated or entered, for instance by a needle or a tube). As bleeding complications in decompensated cirrhosis are associated with a high risk of further decompensation and death, there is an urgent need to understand the factors responsible for such increased bleeding tendency. Herein, we investigated the alterations of hemostasis (that is the physiological process responsible for clot formation and stability) in patients with decompensated cirrhosis and bacterial infections. We found that development of bacterial infections in these patients is associated with alterations of hemostasis (particularly of platelets and clotting cascade) that may increase the risk of both bleeding and thrombotic complications.
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Key Words
- ACLF, acute-on-chronic liver failure
- AKI, acute kidney injury
- AT, antithrombin
- ETP, endogenous thrombin potential
- F, factor
- FXIII, fibrin-stabilizing factor XIII
- MELD, model for end-stage liver disease
- PAI-1, plasminogen activator inhibitor-1
- PAP, plasmin-antiplasmin complex
- PC, protein C
- PS, protein S
- TAFIa/ai, activated and inactivated thrombin-activatable fibrinolytic inhibitor
- TM, thrombomodulin
- VWF, von Willebrand factor
- cirrhosis
- coagulation
- fibrinolysis
- infections
- platelets
- t-PA, tissue-type plasminogen activator
- α2-AP, α2-antiplasmin
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Affiliation(s)
- Alberto Zanetto
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, Padova, Italy
| | - Elena Campello
- General Internal Medicine and Thrombotic and Hemorrhagic Diseases Unit, Department of Medicine, Padova University Hospital, Padova, Italy
| | - Cristiana Bulato
- General Internal Medicine and Thrombotic and Hemorrhagic Diseases Unit, Department of Medicine, Padova University Hospital, Padova, Italy
| | - Sabrina Gavasso
- General Internal Medicine and Thrombotic and Hemorrhagic Diseases Unit, Department of Medicine, Padova University Hospital, Padova, Italy
| | - Graziella Saggiorato
- General Internal Medicine and Thrombotic and Hemorrhagic Diseases Unit, Department of Medicine, Padova University Hospital, Padova, Italy
| | - Sarah Shalaby
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, Padova, Italy
| | - Patrizia Burra
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, Padova, Italy
| | - Paolo Angeli
- Unit of Internal Medicine and Hepatology, Department of Medicine, Padova University Hospital, Padova, Italy
| | - Marco Senzolo
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, Padova, Italy
| | - Paolo Simioni
- General Internal Medicine and Thrombotic and Hemorrhagic Diseases Unit, Department of Medicine, Padova University Hospital, Padova, Italy
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25
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Stine JG, Schreibman IR, Faust AJ, Dahmus J, Stern B, Soriano C, Rivas G, Hummer B, Kimball SR, Geyer NR, Chinchilli VM, Loomba R, Schmitz K, Sciamanna C, Strine C, Wentzel R, Marlin S, Sica C, Vesek J, Eyster E, Sinoway L, Bentz K, Handley N, Hershey Fell B, Mottilla S, Christ C, George S, Novchich T, Beyer M, Clarke K, Myers T, Glading‐Steinruck M, Krok K, Ma T, Riley T, Thompson E, Tressler H, Broach J, Doan T, Patrick S, Reed S, Hamilton C, Slavoski K, Tregea D. NASHFit: A randomized controlled trial of an exercise training program to reduce clotting risk in patients with NASH. Hepatology 2022; 76:172-185. [PMID: 34890063 PMCID: PMC9184303 DOI: 10.1002/hep.32274] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 11/04/2021] [Accepted: 12/01/2021] [Indexed: 12/20/2022]
Abstract
BACKGROUND AND AIMS NASH is a common disease associated with increased rates of thromboembolism (TE). Although exercise training can lessen thrombotic risk in patients with vascular disease, whether similar findings are observed in patients with NASH is open for study. APPROACH AND RESULTS We conducted a 20-week randomized controlled clinical trial involving patients with biopsy-confirmed NASH. Patients were randomly assigned (2:1 ratio) to receive either an exercise training program or standard clinical care. The primary endpoint was change in plasminogen activator inhibitor 1 (PAI-1) level, an established thrombotic biomarker. Twenty-eight patients were randomly assigned (18 exercise training and 10 standard clinical care). PAI-1 level was significantly decreased by exercise training when compared to standard clinical care (-40 ± 100 vs. +70 ± 63 ng/ml; p = 0.02). Exercise training decreased MRI proton density fat fraction (MRI-PDFF; -4.7 ± 5.6 vs. 1.2 ± 2.8% absolute liver fat; p = 0.01); 40% of exercise subjects had a ≥30% relative reduction in MRI-PDFF (histological response threshold) compared to 13% for standard of care (p < 0.01). Exercise training improved fitness (VO2 peak, +3.0 ± 5.6 vs. -1.8 ± 5.1 ml/kg/min; p = 0.05) in comparison to standard clinical care. CONCLUSIONS This clinical trial showed that, independent of weight loss or dietary change, exercise training resulted in a significantly greater decrease in thrombotic risk than standard clinical care in patients with NASH, in parallel with MRI-PDFF reduction and improvement in fitness. Future studies are required to determine whether exercise training can directly impact patient outcomes and lower rates of TE.
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Affiliation(s)
- Jonathan G. Stine
- Division of Gastroenterology and Hepatology, Department of
Medicine, The Pennsylvania State University- Milton S. Hershey Medical Center,
Hershey PA,Department of Public Health Sciences, The Pennsylvania
State University- College of Medicine, Hershey PA,Liver Center, The Pennsylvania State University- Milton S.
Hershey Medical Center, Hershey PA,Cancer Institute, The Pennsylvania State University-
Milton S. Hershey Medical Center, Hershey PA
| | - Ian R. Schreibman
- Division of Gastroenterology and Hepatology, Department of
Medicine, The Pennsylvania State University- Milton S. Hershey Medical Center,
Hershey PA,Liver Center, The Pennsylvania State University- Milton S.
Hershey Medical Center, Hershey PA
| | - Alison J. Faust
- Division of Gastroenterology and Hepatology, Department of
Medicine, The Pennsylvania State University- Milton S. Hershey Medical Center,
Hershey PA
| | - Jessica Dahmus
- Division of Gastroenterology and Hepatology, Department of
Medicine, The Pennsylvania State University- Milton S. Hershey Medical Center,
Hershey PA
| | - Benjamin Stern
- Division of Gastroenterology and Hepatology, Department of
Medicine, The Pennsylvania State University- Milton S. Hershey Medical Center,
Hershey PA
| | - Christopher Soriano
- Division of Gastroenterology and Hepatology, Department of
Medicine, The Pennsylvania State University- Milton S. Hershey Medical Center,
Hershey PA
| | - Gloriany Rivas
- Division of Gastroenterology and Hepatology, Department of
Medicine, The Pennsylvania State University- Milton S. Hershey Medical Center,
Hershey PA
| | - Breianna Hummer
- Division of Gastroenterology and Hepatology, Department of
Medicine, The Pennsylvania State University- Milton S. Hershey Medical Center,
Hershey PA
| | - Scot R. Kimball
- Department of Physiology, The Pennsylvania State
University- College of Medicine, Hershey PA
| | - Nate R. Geyer
- Department of Public Health Sciences, The Pennsylvania
State University- College of Medicine, Hershey PA
| | - Vernon M. Chinchilli
- Department of Public Health Sciences, The Pennsylvania
State University- College of Medicine, Hershey PA
| | - Rohit Loomba
- Division of Gastroenterology and Hepatology, Department of
Medicine, University of California San Diego, San Diego CA,NAFLD Research Center, University of California San Diego,
San Diego CA
| | - Kathryn Schmitz
- Department of Public Health Sciences, The Pennsylvania
State University- College of Medicine, Hershey PA,Cancer Institute, The Pennsylvania State University-
Milton S. Hershey Medical Center, Hershey PA,Department of Kinesiology, The Pennsylvania State
University- College of Medicine, Hershey PA,Department of Physical Medicine & Rehabilitation,
The Pennsylvania State University- Milton S. Hershey Medical Center, Hershey
PA
| | - Christopher Sciamanna
- Department of Public Health Sciences, The Pennsylvania
State University- College of Medicine, Hershey PA,Cancer Institute, The Pennsylvania State University-
Milton S. Hershey Medical Center, Hershey PA,Department of Medicine, The Pennsylvania State University-
Milton S. Hershey Medical Center, -Hershey PA
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26
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Ogresta D, Mrzljak A, Cigrovski Berkovic M, Bilic-Curcic I, Stojsavljevic-Shapeski S, Virovic-Jukic L. Coagulation and Endothelial Dysfunction Associated with NAFLD: Current Status and Therapeutic Implications. J Clin Transl Hepatol 2022; 10:339-355. [PMID: 35528987 PMCID: PMC9039716 DOI: 10.14218/jcth.2021.00268] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 09/24/2021] [Accepted: 10/08/2021] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is closely related to insulin resistance, type 2 diabetes mellitus and obesity. It is considered a multisystem disease and there is a strong association with cardiovascular disease and arterial hypertension, which interfere with changes in the coagulation system. Coagulation disorders are common in patients with hepatic impairment and are dependent on the degree of liver damage. Through a review of the literature, we consider and discuss possible disorders in the coagulation cascade and fibrinolysis, endothelial dysfunction and platelet abnormalities in patients with NAFLD.
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Affiliation(s)
- Doris Ogresta
- Department of Gastroenterology and Hepatology, Sestre Milosrdnice University Hospital Center, Zagreb, Croatia
| | - Anna Mrzljak
- Department of Gastroenterology and Hepatology, University Hospital Center Zagreb, Zagreb, Croatia
- Department of Medicine, University of Zagreb, School of Medicine, Zagreb, Croatia
| | - Maja Cigrovski Berkovic
- Department for Endocrinology, Diabetes and Pharmacology, University Hospital Dubrava, Zagreb, Croatia
- Department of Kinesiological Anthropology and Methodology, Faculty of Kinesiology, University of Zagreb
- Department of Pharmacology, Faculty of Medicine, University of JJ Strossmayer, Osijek, Croatia
| | - Ines Bilic-Curcic
- Department of Pharmacology, Faculty of Medicine, University of JJ Strossmayer, Osijek, Croatia
- Department of Diabetes, Endocrinology and Metabolism Disorders, University Hospital Osijek, Osijek, Croatia
| | | | - Lucija Virovic-Jukic
- Department of Gastroenterology and Hepatology, Sestre Milosrdnice University Hospital Center, Zagreb, Croatia
- Department of Medicine, University of Zagreb, School of Medicine, Zagreb, Croatia
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27
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Islam R, Kundu S, Jha SB, Rivera AP, Flores Monar GV, Islam H, Puttagunta SM, Sange I. Cirrhosis and Coagulopathy: Mechanisms of Hemostasis Changes in Liver Failure and Their Management. Cureus 2022; 14:e23785. [PMID: 35518552 PMCID: PMC9063731 DOI: 10.7759/cureus.23785] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/03/2022] [Indexed: 11/20/2022] Open
Abstract
Cirrhosis is an end-stage liver disease that can cause changes in any component of the hemostatic system. The net effects of the complicated hemostatic changes have long been unknown due to concurrent changes in pro-and antihemostatic drivers. Coagulation disorders are caused by various factors, including decreased clotting and inhibitor factor synthesis, reduced clearance of activated factors, quantitative and qualitative platelet defects, hyperfibrinolysis, and increased intravascular coagulation. This review discusses the pathogenesis of coagulopathy and multiple studies related to its clinical presentations. This article also highlights an additional problem in the diagnostic and therapeutic approach to this group of patients: the fact that traditional coagulation tests and transfusional strategies may not be reliable for assessing and managing bleeding or thrombotic risks. Hence, multiple management options have been assessed for bleeding and thrombosis in liver disease.
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28
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Tripodi A, Lombardi R, Primignani M, La Mura V, Peyvandi F, Fracanzani AL. Hypercoagulability in Patients with Non-Alcoholic Fatty Liver Disease (NAFLD): Causes and Consequences. Biomedicines 2022; 10:249. [PMID: 35203457 PMCID: PMC8869363 DOI: 10.3390/biomedicines10020249] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 01/11/2022] [Accepted: 01/13/2022] [Indexed: 12/11/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, and it is anticipated that it could become even more prevalent in parallel with an increase in the incidence of metabolic diseases closely related to NAFLD, such as obesity, type II diabetes, dyslipidemia, and arterial hypertension. In addition to liver impairment, NAFLD is associated with cardiovascular diseases. Fibrosis, atherosclerosis, and venous thrombosis are basically the pathogenic mechanisms behind these clinical manifestations, and all are plausibly associated with hypercoagulability that may, in turn, develop because of an imbalance of pro- vs. anticoagulants and the presence of such procoagulant molecular species as microvesicles, neutrophil extracellular traps (NETs), and inflammation. The assessment of hypercoagulability by means of thrombin generation is a global procedure that mimics the coagulation process occurring in vivo much better than any other coagulation test, and is considered to be the best candidate laboratory tool for assessing, with a single procedure, the balance of coagulation in NAFLD. In addition to defining the state of hypercoagulability, the assessment of thrombin generation could also be used to investigate, in clinical trials, the best approach (therapeutic and/or lifestyle changes) for minimizing hypercoagulability and, hence, the risk of cardiovascular diseases, progression to atherosclerosis, and liver fibrosis in patients with NAFLD.
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Affiliation(s)
- Armando Tripodi
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center and Fondazione Luigi Villa, 20122 Milan, Italy; (V.L.M.); (F.P.)
| | - Rosa Lombardi
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Unit of Internal Medicine and Metabolic Disease, 20122 Milan, Italy; (R.L.); (A.L.F.)
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122 Milan, Italy
| | - Massimo Primignani
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, First Division of Gastroenterology, 20122 Milan, Italy;
| | - Vincenzo La Mura
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center and Fondazione Luigi Villa, 20122 Milan, Italy; (V.L.M.); (F.P.)
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122 Milan, Italy
| | - Flora Peyvandi
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center and Fondazione Luigi Villa, 20122 Milan, Italy; (V.L.M.); (F.P.)
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122 Milan, Italy
| | - Anna L. Fracanzani
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Unit of Internal Medicine and Metabolic Disease, 20122 Milan, Italy; (R.L.); (A.L.F.)
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122 Milan, Italy
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29
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Wen X, Wang S, Taveira TH, Akhlaghi F. Required warfarin dose and time in therapeutic range in patients with diagnosed Nonalcoholic Fatty Liver Disease (NAFLD) or Nonalcoholic Steatohepatitis (NASH). PLoS One 2021; 16:e0251665. [PMID: 34525124 PMCID: PMC8443040 DOI: 10.1371/journal.pone.0251665] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 04/29/2021] [Indexed: 12/29/2022] Open
Abstract
Warfarin has been widely used to treat thromboembolism. The effect of nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH), on warfarin dosing remains unknown. This study aims to examine the effects of NAFLD/NASH on the average daily dose (ADD) of warfarin and the time in therapeutic range (TTR). This is a retrospective study utilizing an administrative data. We included patients with at least 2 months of warfarin dispensing and two subsequent consecutive INR measures. The ADD of warfarin to achieve therapeutic range INR levels, and TTR were compared between patients with and without NAFLD/NASH in four subgroups of patients accounting for the presence of obesity and diabetes. Generalized linear models (GLM) with Propensity score (PS) fine stratification were applied to evaluate the relative differences (RD) of warfarin ADD and TTR (>60%) in four subgroups. A total of 430 NAFLD/NASH patients and 38,887 patients without NAFLD/NASH were included. The ADD and TTR, were not significant in the overall cohort between those with and without NAFLD/NASH. However, GLM results in patients without diabetes or obesity (N = 26,685) showed a significantly lower warfarin ADD (RD: -0.38; 95%CI: -0.74–-0.02) and shorter TTR (OR: 0.71; 95%CI: 0.52–0.97) in patients diagnosed with NAFLD/NASH. The effects of NAFLD/NASH on warfarin dose or TTR were observed in patients without obesity and diabetes. Obesity and diabetes appear to be significant modifiers for the effects of NAFLD/NASH on warfarin dose and TTR.
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Affiliation(s)
- Xuerong Wen
- Health Outcomes, Department of Pharmacy Practice, College of Pharmacy, University of Rhode Island, Kingston, RI, United States of America
| | - Shuang Wang
- Health Outcomes, Department of Pharmacy Practice, College of Pharmacy, University of Rhode Island, Kingston, RI, United States of America
| | - Tracey H Taveira
- Health Outcomes, Department of Pharmacy Practice, College of Pharmacy, University of Rhode Island, Kingston, RI, United States of America.,Cardiovascular Department, Providence Veterans Affairs Medical Center, Providence, RI, United States of America.,Warren Alpert School of Medicine, Brown University, Providence, RI, United States of America
| | - Fatemeh Akhlaghi
- Clinical Pharmacokinetics Research Laboratory, Department of Biomedical and Pharmaceutical Science, College of Pharmacy, University of Rhode Island, Kingston, RI, United States of America
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30
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Rivas G, Hummer-Bair B, Bezinover D, Kadry Z, Stine J. Plasminogen activator inhibitor is significantly elevated in liver transplant recipients with decompensated NASH cirrhosis. BMJ Open Gastroenterol 2021; 8:bmjgast-2021-000683. [PMID: 34341018 PMCID: PMC8330585 DOI: 10.1136/bmjgast-2021-000683] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 06/12/2021] [Indexed: 12/16/2022] Open
Abstract
Background Non-alcoholic fatty liver disease is a prohaemostatic state with abnormal primary, secondary and tertiary haemostasis. Plasminogen activator inhibitor (PAI)-1 is the best-established marker for prohaemostasis in non-alcoholic fatty liver disease. While epidemiological studies demonstrate decompensated non-alcoholic steatohepatitis (NASH) cirrhosis patients have increased rates of venous thromboembolism, including portal vein thrombosis, mechanistic studies have focused exclusively on patients without or with compensated cirrhosis. We aimed to characterizecharacterise PAI-1 levels in decompensated NASH cirrhosis. Methods PAI-1 level was measured in consecutive adult liver transplant recipients immediately prior to liver transplantation. Multivariable models were constructed using linear regression to assess factors related to PAI-1 level. Results Forty-six subjects with mean age 57 (IQR 53–62) years and Model for Endstage Liver Disease (MELD) score of 34 (IQR 30–40) were enrolled. Baseline characteristics were similar between NASH (n=10) and non-NASH (n=36) subjects except for rates of diabetes and hyperlipidaemia. Mean PAI-1 level was greater in NASH (53.9, 95% CI 33.3 to 74.5 mg/mL) when compared with non-NASH (36.1, 95% CI 28.7 to 43.5), p=0.040. NASH remained independently predictive of PAI-1 level prior to transplant on adjusted multivariable modelling (β 40.13, 95% CI 14.41 to 65.86, p=0.003). Conclusions: PAI-1 level is significantly elevated in decompensated NASH cirrhosis independent of other pro-haemostatic factors. This may explain the greater rates of venous thromboembolism in decompensated NASH cirrhosis. Future study focusing on prevention of venous thromboembolism in this population is paramount to improve patient-oriented outcomes given the high morbidity and mortality of venous thromboembolism and the significant impact it has on transplant candidacy.
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Affiliation(s)
- Gloriany Rivas
- Medicine, Penn State College of Medicine, Hershey, Pennsylvania, USA
| | | | - Dmitri Bezinover
- Medicine, Penn State College of Medicine, Hershey, Pennsylvania, USA
| | - Zakiyah Kadry
- Medicine, Penn State College of Medicine, Hershey, Pennsylvania, USA
| | - Jonathan Stine
- Medicine, Penn State College of Medicine, Hershey, Pennsylvania, USA
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31
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Molinari M, Fernandez-Carrillo C, Dai D, Dana J, Clemente-Sanchez A, Dharmayan S, Kaltenmeier C, Liu H, Behari J, Rachakonda V, Ganesh S, Hughes C, Tevar A, Al Harakeh H, Emmanuel B, Humar A, Bataller R. Portal vein thrombosis and renal dysfunction: a national comparative study of liver transplant recipients for NAFLD versus alcoholic cirrhosis. Transpl Int 2021; 34:1105-1122. [PMID: 33780554 PMCID: PMC8360094 DOI: 10.1111/tri.13873] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 03/08/2021] [Accepted: 03/19/2021] [Indexed: 12/13/2022]
Abstract
The prevalence of portal vein thrombosis (PVT), renal dysfunction (RD), and simultaneous PVT/RD in liver transplantation (LT) is poorly understood. We analyzed the prevalence of PVT, RD, simultaneous PVT/RD, and the outcomes of adult recipients of LT for nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) between 2006 and 2016 in the United States. We found that the prevalence of PVT (7.2% → 11.3%), RD (33.8% → 39.2%), and simultaneous PVT/RD (2.4% → 4.5%) has increased significantly over the study period (all P‐values <0.05). NAFLD patients had a higher proportion of PVT (14.8% vs. 9.2%), RD (45.0% vs. 42.1%), and simultaneous PVT/RD (6.5% vs. 3.9%; all P‐values <0.05). 90‐day mortality was 3.8%, 6.3%, 6.8%, and 9.8% for PVT(−)/RD(−), PVT(−)/RD(+), PVT(+)/RD(−), and PVT(+)/RD(+) recipients, respectively (P < 0.01). 5‐year survival was 82.1%, 75.5%, 74.8%, and 71.1% for PVT(−)/RD(−), PVT(−)/RD(+), PVT(+)/RD(−), and PVT(+)/RD(+) recipients, respectively (P < 0.05). In conclusion, the prevalence of PVT, RD, and simultaneous PVT/RD has increased among LT recipients, especially for those with NAFLD. The short‐ and long‐term outcomes of recipients with PVT, RD, and simultaneous PVT/RD were inferior to patients without those risk factors irrespective of their indication for LT. No differences in patient outcomes were found between ALD and NAFLD recipients after stratification by risk factors.
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Affiliation(s)
- Michele Molinari
- Department of Surgery, UPMC Montefiore Hospital, Pittsburgh, PA, USA
| | - Carlos Fernandez-Carrillo
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.,Department of Surgery, University of Leeds, Leeds, UK
| | - Dongling Dai
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Jorgensen Dana
- Department of Surgery, UPMC Montefiore Hospital, Pittsburgh, PA, USA
| | - Ana Clemente-Sanchez
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Stalin Dharmayan
- Department of Surgery, UPMC Montefiore Hospital, Pittsburgh, PA, USA
| | | | - Hao Liu
- Department of Surgery, UPMC Montefiore Hospital, Pittsburgh, PA, USA
| | - Jaideep Behari
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Vikrant Rachakonda
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Swaytha Ganesh
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | | | - Amit Tevar
- Department of Surgery, UPMC Montefiore Hospital, Pittsburgh, PA, USA
| | - Hasan Al Harakeh
- Department of Surgery, UPMC Montefiore Hospital, Pittsburgh, PA, USA
| | - Bishoy Emmanuel
- Department of Surgery, UPMC Montefiore Hospital, Pittsburgh, PA, USA
| | - Abhinav Humar
- Department of Surgery, UPMC Montefiore Hospital, Pittsburgh, PA, USA
| | - Ramon Bataller
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
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32
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Abstract
Patients with liver disease acquire complex changes in their hemostatic system. Historically, these patients were considered to have a bleeding tendency related, in part, to a hyperfibrinolytic state. However, studies using more modern fibrinolysis tests have questioned the presence of a hyperfibrinolytic state in patients with liver disease and its association with bleeding risk. It may be that the sickest patients with liver disease do have fibrinolytic abnormalities. However, the debate on the fibrinolytic state of patients with (decompensated) cirrhosis or critically ill liver disease is complicated by the fact that hypo- and hyperfibrinolysis have been poorly defined. This could, in part, be explained by the lack of reliable tests that assess a patient's fibrinolytic status. Moreover, large clinical studies on the relationship between bleeding and fibrinolysis in patients with liver disease are scarce. Here, we provide an overview of the current knowledge on fibrinolysis in various types of liver diseases and possible implications as a target for therapeutic strategies in liver disease. As antifibrinolytic therapy has been shown to be safe and effective during liver transplantation, it could potentially be of use in patients with (either laboratory-established or suspected) hyperfibrinolysis-related bleeding.
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Affiliation(s)
- Fien A von Meijenfeldt
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Surgical Research Laboratory, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Ton Lisman
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Surgical Research Laboratory, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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33
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Aliyev SA, Aliyev ES. Evolution of views and modern concepts of the state of the hemostasis system in liver cirrhosis. ANNALY KHIRURGICHESKOY GEPATOLOGII = ANNALS OF HPB SURGERY 2021; 26:107-114. [DOI: 10.16931/1995-5464.20211107-114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Aim. To study the state of individual elements of the hemostasis system in liver cirrhosis according to modern literature.Summary. The review presents an analysis of literature data covering the state of the homeostasis system in liver cirrhosis. The pathophysiological and pathogenetic mechanisms that underlie the disorders that occur in various parts of the hemostatic system in this pathology are described in a polemical style. Literature data concerning a relatively littlestudied aspect of cirrhosis – hypercoagulation are analyzed. From the standpoint of modern concepts and taking into account the peculiarities of hemostasis disorders, the pathogenetic significance of the vascular endothelium and endothelial dysfunction is postulated. As well as the role of inflammatory mediators in the development of coagulopathy and intravascular coagulation syndrome in patients with cirrhosis of the liver.
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34
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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: 14] [Impact Index Per Article: 3.5] [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.
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Affiliation(s)
- Lucija Virović-Jukić
- Lucija Virović-Jukić, Department of Gastroenterology and Hepatology, Sestre Milosrdnice University Hospital Center, Vinogradska cesta 29, 10000 Zagreb, Croatia,
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35
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Zheng Z, Nakamura K, Gershbaum S, Wang X, Thomas S, Bessler M, Schrope B, Krikhely A, Liu RM, Ozcan L, López JA, Tabas I. Interacting hepatic PAI-1/tPA gene regulatory pathways influence impaired fibrinolysis severity in obesity. J Clin Invest 2021; 130:4348-4359. [PMID: 32657780 PMCID: PMC7410057 DOI: 10.1172/jci135919] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Accepted: 05/13/2020] [Indexed: 12/13/2022] Open
Abstract
Fibrinolysis is initiated by tissue-type plasminogen activator (tPA) and inhibited by plasminogen activator inhibitor 1 (PAI-1). In obese humans, plasma PAI-1 and tPA proteins are increased, but PAI-1 dominates, leading to reduced fibrinolysis and thrombosis. To understand tPA–PAI-1 regulation in obesity, we focused on hepatocytes, a functionally important source of tPA and PAI-1 that sense obesity-induced metabolic stress. We showed that obese mice, like humans, had reduced fibrinolysis and increased plasma PAI-1 and tPA, due largely to their increased hepatocyte expression. A decrease in the PAI-1 (SERPINE1) gene corepressor Rev-Erbα increased PAI-1, which then increased the tPA gene PLAT via a PAI-1/LRP1/PKA/p-CREB1 pathway. This pathway was partially counterbalanced by increased DACH1, a PLAT-negative regulator. We focused on the PAI-1/PLAT pathway, which mitigates the reduction in fibrinolysis in obesity. Thus, silencing hepatocyte PAI-1, CREB1, or tPA in obese mice lowered plasma tPA and further impaired fibrinolysis. The PAI-1/PLAT pathway was present in primary human hepatocytes, and associations among PAI-1, tPA, and PLAT in livers from obese and lean humans were consistent with these findings. Knowledge of PAI-1 and tPA regulation in hepatocytes in obesity may suggest therapeutic strategies for improving fibrinolysis and lowering the risk of thrombosis in this setting.
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Affiliation(s)
- Ze Zheng
- Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
| | - Keiko Nakamura
- Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA.,Graduate School of Medicine and.,Faculty of Medicine, University of Tokyo, Tokyo, Japan
| | - Shana Gershbaum
- Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA.,Neuroscience and Behavior Department, Barnard College, New York, New York, USA
| | - Xiaobo Wang
- Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
| | - Sherry Thomas
- Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
| | - Marc Bessler
- Department of Surgery, Columbia University Irving Medical Center, New York, New York, USA
| | - Beth Schrope
- Department of Surgery, Columbia University Irving Medical Center, New York, New York, USA
| | - Abraham Krikhely
- Department of Surgery, Columbia University Irving Medical Center, New York, New York, USA
| | - Rui-Ming Liu
- Division of Pulmonary Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Lale Ozcan
- Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
| | - José A López
- Department of Medicine, University of Washington, Seattle, Washington, USA.,Bloodworks Research Institute, Seattle, Washington, USA
| | - Ira Tabas
- Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA.,Department of Physiology and.,Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York, USA
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36
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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: 29] [Impact Index Per Article: 5.8] [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.
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37
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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: 19] [Impact Index Per Article: 3.8] [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.
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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
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38
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The Effect of Obesity on the State of Platelet-plasma Hemostasis in Patients with Essential Hypertension in Combination with Non-alcoholic Fatty Liver Disease. Fam Med 2020. [DOI: 10.30841/2307-5112.4.2020.217657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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39
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Pemmasani G, Yandrapalli S, Aronow W. Sex differences in cardiovascular diseases and associated risk factors in non-alcoholic steatohepatitis. AMERICAN JOURNAL OF CARDIOVASCULAR DISEASE 2020; 10:362-366. [PMID: 33224584 PMCID: PMC7675172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 09/25/2020] [Indexed: 06/11/2023]
Abstract
BACKGROUND Non-alcoholic steatohepatitis (NASH) is well recognized as an important cardiovascular disease (CVD) risk factor. However, not many studies have described the prevalence of traditional CVD risk factors and CV diseases, and respective sex differences, in patients with NASH. METHODS In this retrospective observational cohort study using the 2016 US National Readmissions Database, we studied adults with NASH to identify the prevalence of important CVD risk factors like age, obesity, hypertension, diabetes mellitus, renal failure, dyslipidemia, smoking, and drug abuse and cardiovascular diseases like coronary artery disease, myocardial infarction and coronary revascularization, peripheral vascular disease, cerebrovascular disease, and pulmonary vascular disease. We studied sex differences using the Pearson χ2 test for categorical variables, student t-test for continuous variables, and logistic regression for age-adjusted analysis. RESULTS Our study sample included 41,005 patients with NASH of which 15,758 (38.4%) were male and 25,247 (61.6%) were female. Hypertension was the most prevalent CVD risk factor (68%), followed by diabetes mellitus (62%), obesity (40%), dyslipidemia (37%), smoking (30%), and renal failure in 27%. Of the cardiovascular diseases studied, coronary artery disease (20.6%) and heart failure (19.6%) were highly prevalent followed by peripheral vascular disease (5.7%), stroke (4.7%), and pulmonary vascular disease (1.4%). Men had higher rates of most risk factors and diseases compared with women, except for higher rates of obesity and diabetes mellitus in women and a similar rate of drug abuse, stroke, and pulmonary vascular disease between the sex groups. CONCLUSION In patients with NASH, CVD risk factors and diseases were highly prevalent and important sex differences were present.
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40
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Northup P. A History of Coagulopathy in Liver Disease: Legends and Myths. Clin Liver Dis (Hoboken) 2020; 16:56-72. [PMID: 33042527 PMCID: PMC7538927 DOI: 10.1002/cld.954] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Accepted: 03/06/2020] [Indexed: 02/04/2023] Open
Abstract
Watch an interview with the author.
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Affiliation(s)
- Patrick Northup
- Division of Gastroenterology and HepatologyUniversity of VirginiaCharlottesvilleVA
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41
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Portal vein thrombosis prevalence and mortality among alcoholic cirrhosis in a nationwide inpatient cohort. Eur J Gastroenterol Hepatol 2020; 32:1160-1167. [PMID: 31834054 DOI: 10.1097/meg.0000000000001624] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Portal vein thrombosis is commonly associated with cirrhosis. The effect of alcoholic cirrhosis on portal vein thrombosis prevalence and mortality has not been well studied. METHODS We conducted a retrospective cohort study utilizing the 2000-2014 National Inpatient Sample Database. We included patients older than 18 years with decompensated cirrhosis without a history of liver transplantation or hepatocellular carcinoma. We further identified patients with alcoholic cirrhosis vs. non-alcoholic cirrhosis. Primary outcomes included the risk and mortality of portal vein thrombosis in alcoholic cirrhosis. Secondary outcomes included trends of portal vein thrombosis prevalence and mortality in alcoholic cirrhosis, implications of portal vein thrombosis on complications in alcoholic cirrhosis vs. non-alcoholic cirrhosis, and risk of venous thromboembolism in alcoholic cirrhosis. RESULTS Among 1 892 271 patients with decompensated alcoholic cirrhosis, portal vein thrombosis prevalence was 1.3%. Alcoholic cirrhosis was associated with lower risk of portal vein thrombosis (odds ratio 0.76, P < 0.001) and venous thromboembolism (odds ratio 0.69, P < 0.001) compared to non-alcoholic cirrhosis. Portal vein thrombosis contributed to increased mortality (odds ratio 1.19, P < 0.001) in alcoholic cirrhosis. Portal vein thrombosis prevalence among alcoholic cirrhosis increased while mortality declined during the study period. CONCLUSION Thrombotic events including portal vein thrombosis and venous thromboembolism were found in less frequent association with alcoholic cirrhosis compared with non-alcoholic cirrhosis. Despite this, the higher in-hospital mortality found among portal vein thrombosis with alcoholic cirrhosis should prompt careful consideration of management.
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42
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Stine JG, Schreibman I, Navabi S, Kang M, Dahmus J, Soriano C, Rivas G, Hummer B, Beyer M, Tressler H, Kimball SR, Patterson AD, Schmitz K, Sciamanna C. Nonalcoholic steatohepatitis Fitness Intervention in Thrombosis (NASHFit): Study protocol for a randomized controlled trial of a supervised aerobic exercise program to reduce elevated clotting risk in patients with NASH. Contemp Clin Trials Commun 2020; 18:100560. [PMID: 32309672 PMCID: PMC7154986 DOI: 10.1016/j.conctc.2020.100560] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 03/17/2020] [Accepted: 03/28/2020] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease worldwide affecting upwards of one third the global population. For reasons not fully understood, individuals with NAFLD and its more severe variant, nonalcoholic steatohepatitis (NASH), are at increased risk for venous thromboembolism which significantly increases morbidity and mortality. Lifestyle changes centering around exercise training are the mainstay of treatment for NAFLD/NASH. While exercise training can lessen venous thromboembolic risk in healthy persons and those with cardiovascular disease, whether or not this benefit is seen in patients with NAFLD/NASH remains unknown. In order to better understand how exercise training impacts thrombosis risk in NAFLD, we present the design of a thirty-two week randomized controlled clinical trial of 42 sedentary subjects age 18-69 with biopsy proven NASH. The main aim is to determine the impact of an aerobic exercise training program on the abnormal hemostatic system unique to NAFLD/NASH. The main outcome is change in plasminogen activator inhibitor one level, an established marker for venous thromboembolism. Secondary outcomes include body composition, cardiorespiratory fitness, control of comorbid metabolic conditions (e.g., obesity, hypertension, hyperlipidemia, diabetes), dietary composition, health related quality of life, liver enzymes and histology, NAFLD/NASH disease activity (e.g., biomarkers, clinical decision aids), microbiome, other markers of hemostasis, and PNPLA3 gene expression. The study represents the first clinical trial of an exercise training program to reduce elevated clotting risk in subjects with NAFLD/NASH.
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Affiliation(s)
- Jonathan G. Stine
- Division of Gastroenterology and Hepatology, Department of Medicine, The Pennsylvania State University- Milton S. Hershey Medical Center, Hershey, PA, USA
- Department of Public Health Sciences, The Pennsylvania State University- Milton S. Hershey Medical Center, Hershey, PA, USA
- Liver Center, The Pennsylvania State University- Milton S. Hershey Medical Center, Hershey, PA, USA
- Cancer Institute, The Pennsylvania State University- Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Ian Schreibman
- Division of Gastroenterology and Hepatology, Department of Medicine, The Pennsylvania State University- Milton S. Hershey Medical Center, Hershey, PA, USA
- Liver Center, The Pennsylvania State University- Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Seyedehsan Navabi
- Division of Gastroenterology and Hepatology, Department of Medicine, The Pennsylvania State University- Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Mitchell Kang
- Division of Gastroenterology and Hepatology, Department of Medicine, The Pennsylvania State University- Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Jessica Dahmus
- Division of Gastroenterology and Hepatology, Department of Medicine, The Pennsylvania State University- Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Christopher Soriano
- Department of Medicine, The Pennsylvania State University- Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Gloriany Rivas
- Division of Gastroenterology and Hepatology, Department of Medicine, The Pennsylvania State University- Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Breianna Hummer
- Division of Gastroenterology and Hepatology, Department of Medicine, The Pennsylvania State University- Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Megan Beyer
- Division of Gastroenterology and Hepatology, Department of Medicine, The Pennsylvania State University- Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Heather Tressler
- Division of Gastroenterology and Hepatology, Department of Medicine, The Pennsylvania State University- Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Scot R. Kimball
- Department of Physiology, The Pennsylvania State University- Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Andrew D. Patterson
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, USA
| | - Kathryn Schmitz
- Department of Public Health Sciences, The Pennsylvania State University- Milton S. Hershey Medical Center, Hershey, PA, USA
- Cancer Institute, The Pennsylvania State University- Milton S. Hershey Medical Center, Hershey, PA, USA
- Department of Kinesiology, The Pennsylvania State University- College of Medicine, Hershey, PA, USA
- Department of Physical Medicine & Rehabilitation, The Pennsylvania State University- Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Christopher Sciamanna
- Department of Public Health Sciences, The Pennsylvania State University- Milton S. Hershey Medical Center, Hershey, PA, USA
- Cancer Institute, The Pennsylvania State University- Milton S. Hershey Medical Center, Hershey, PA, USA
- Department of Medicine, The Pennsylvania State University- Milton S. Hershey Medical Center, Hershey, PA, USA
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McSweeney L, Breckons M, Fattakhova G, Oluboyede Y, Vale L, Ternent L, Balp MM, Doward L, Brass CA, Beyer F, Sanyal A, Anstee QM. Health-related quality of life and patient-reported outcome measures in NASH-related cirrhosis. JHEP Rep 2020; 2:100099. [PMID: 32435754 PMCID: PMC7229498 DOI: 10.1016/j.jhepr.2020.100099] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 02/04/2020] [Accepted: 02/22/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND & AIMS Non-alcoholic steatohepatitis (NASH) is known to have a negative impact on patients' health-related quality of life (HRQoL), even before progression to cirrhosis has occurred. The burden of NASH-related cirrhosis from the patient perspective remains poorly understood. Herein, we aimed to identify the burden of disease and HRQoL impairment among patients with NASH-related compensated cirrhosis. METHODS This targeted literature review sought first to identify the humanistic burden of disease from the perspective of patients with diagnosed NASH-cirrhosis and, secondly, to identify generic or disease-specific patient-reported outcome measures (PROMs) used to assess the impact of NASH-cirrhosis. Searches were conducted in bibliographical databases, grey or unpublished literature, liver disease websites, support group websites and online blogs. A quality assessment of specific PROMs was conducted. RESULTS Patients with NASH-cirrhosis are reported to suffer from lower HRQoL than patients with non-cirrhotic NASH and the general population with respect to physical health/functioning, emotional health and worry, and mental health. Thirteen PROMs were identified, of which 4 were liver-disease specific: CLDQ, CLDQ-NAFLD, LDQoL and LDSI. The most commonly used measures do not comply with current industry or regulatory standards for PROMs and/or are not validated for use in a cirrhotic NASH population. CONCLUSIONS Patients with NASH-cirrhosis have lower HRQoL and poorer physical health than patients with non-cirrhotic NASH. However, the literature lacked detail of the everyday impact on patients' lives. Currently, a number of PROMs are available to measure the impact of the disease in patients with chronic liver conditions. The lack of studies that include qualitative insights in this population mandates further exploration and research. LAY SUMMARY It is not well understood how having non-alcoholic fatty liver disease (NAFLD)-related cirrhosis affects a person's everyday wellbeing and quality of life. Some research has been done with patients who have early stages of liver disease but not people with cirrhosis. We found that patients with NAFLD-related cirrhosis tended to have poorer health than patients without cirrhosis. But there was not very much information from patients themselves and there were no tools or questionnaires just for this group of patients.
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Key Words
- CLDQ, chronic liver disease questionnaire
- COSMIN, The COnsensus-based Standards for the selection of health Measurement INstruments
- Cirrhosis
- EMA, European Medicines Agency
- FDA, United States Food and Drug Administration
- FIS, fatigue impact scale
- HRQoL, health-related quality of life
- LDQoL, liver disease quality of life questionnaire
- LDSI, liver disease symptom index
- MS, multiple sclerosis
- NAFL, non-alcoholic fatty liver
- NAFLD
- NAFLD, non-alcoholic fatty liver disease
- NASH, non-alcoholic steatohepatitis
- Non-alcoholic steatohepatitis
- PHAQ, patient-reported outcome measurement information system health assessment questionnaire
- PRO, patient-reported outcome
- PROM, patient-reported outcome measure
- QoL, quality of life
- RI, researcher interpretation
- SF-36, short form health profile 36
- health-related quality of life
- liver
- patient-reported outcome measures
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Affiliation(s)
- Lorraine McSweeney
- Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Matthew Breckons
- Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Gulnar Fattakhova
- Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Yemi Oluboyede
- Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Luke Vale
- Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Laura Ternent
- Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | | | - Lynda Doward
- RTI-Health Solutions, The Pavilion, Towers Business Park, Wilmslow Road, Didsbury, Manchester, UK
| | | | - Fiona Beyer
- Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Arun Sanyal
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, United States
| | - Quentin M. Anstee
- Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK & Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK
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Ballestri S, Capitelli M, Fontana MC, Arioli D, Romagnoli E, Graziosi C, Lonardo A, Marietta M, Dentali F, Cioni G. Direct Oral Anticoagulants in Patients with Liver Disease in the Era of Non-Alcoholic Fatty Liver Disease Global Epidemic: A Narrative Review. Adv Ther 2020; 37:1910-1932. [PMID: 32285340 PMCID: PMC7467481 DOI: 10.1007/s12325-020-01307-z] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Indexed: 12/15/2022]
Abstract
Atrial fibrillation (AF) and venous thromboembolism (VTE) are highly prevalent and relevant healthcare issues. Direct oral anticoagulants (DOACs) are now the first-choice for anticoagulant treatment of these conditions displaying a better efficacy/safety profile than vitamin-K antagonists, mainly due to significantly reduced risk of major bleeding, especially of intracranial haemorrhage. Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in developed countries showing a continuously growing prevalence. Nonalcoholic steatohepatitis (NASH), its evolutive form, will be the leading cause for liver transplantation by 2020. NAFLD is independently associated with an increased risk of abnormalities of cardiac structure and function, including cardiac rhythm disorders (mainly AF). Moreover, data suggest an increased risk of unprovoked VTE associated with NAFLD/NASH. Therefore, a growing number of patients with chronic liver disease (CLD) will be candidate for anticoagulant therapy in the near future. Cirrhosis of any etiology is characterized by an unstable thrombosis/bleeding haemostatic balance, making anticoagulant therapy particularly challenging in this condition. Given that patients with significant active liver disease and cirrhosis were excluded from all pivotal randomized controlled trials on DOACs, this comprehensive review aims at critically discussing real-world evidence, including the latest population studies, regarding the use of DOACs in patients with CLD/cirrhosis.
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Affiliation(s)
- Stefano Ballestri
- Internal Medicine Unit, Pavullo Hospital, Azienda USL, Modena, Italy.
| | - Mariano Capitelli
- Internal Medicine Unit, Pavullo Hospital, Azienda USL, Modena, Italy
| | | | - Dimitriy Arioli
- Internal Medicine and Critical Care Unit, Azienda Ospedaliero-Universitaria, Modena, Italy
| | - Elisa Romagnoli
- Internal Medicine and Critical Care Unit, Azienda Ospedaliero-Universitaria, Modena, Italy
| | - Catia Graziosi
- Internal Medicine Unit, Pavullo Hospital, Azienda USL, Modena, Italy
| | - Amedeo Lonardo
- Metabolic Syndrome Unit, Ospedale Civile di Baggiovara, Azienda Ospedaliero-Universitaria, Modena, Italy
| | - Marco Marietta
- Hematology Unit, Azienda Ospedaliero-Universitaria, Modena, Italy
| | - Francesco Dentali
- Department of Clinical and Experimental Medicine, Insubria University, Varese, Italy
| | - Giorgio Cioni
- Internal Medicine Unit, Pavullo Hospital, Azienda USL, Modena, Italy
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45
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Sigal SH, Sherman Z, Jesudian A. Clinical Implications of Thrombocytopenia for the Cirrhotic Patient. ACTA ACUST UNITED AC 2020; 12:49-60. [PMID: 32341665 PMCID: PMC7166072 DOI: 10.2147/hmer.s244596] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Accepted: 03/10/2020] [Indexed: 02/06/2023]
Abstract
Thrombocytopenia is a frequent complication in patients with cirrhosis. As many as 84% of patients with cirrhosis have thrombocytopenia, and it is an independent variable indicative of advanced disease and poor prognosis. Although there is great concern that it may aggravate bleeding during surgical procedures, there is limited evidence to inform decisions regarding the treatment of cirrhotic patients with thrombocytopenia undergoing invasive procedures. Finally, there is evidence that platelets play a significant role in liver regeneration. In this report, the clinical implications of thrombocytopenia in cirrhotic patients are reviewed. The utility of platelet counts in the prognosis of cirrhosis and relationship to complications of advanced liver disease, including portal hypertension, esophageal varices, and hepatocellular carcinoma. The impact of low platelet counts on bleeding complications during invasive procedures is outlined. Finally, the role of platelets and potential adverse impact in liver regeneration is reviewed.
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Affiliation(s)
- Samuel H Sigal
- Department of Medicine, Montefiore Medical Center, Bronx, NY, USA
| | - Zachary Sherman
- Department of Medicine, Weill Cornell Medical Center, New York, NY, USA
| | - Arun Jesudian
- Department of Medicine, Weill Cornell Medical Center, New York, NY, USA
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Abstract
Disorders of the mesenteric, portal, and hepatic veins and mesenteric and hepatic arteries have important clinical consequences and may lead to acute liver failure, chronic liver disease, noncirrhotic portal hypertension, cirrhosis, and hepatocellular carcinoma. Although literature in the field of vascular liver disorders is scant, these disorders are common in clinical practice, and general practitioners, gastroenterologists, and hepatologists may benefit from expert guidance and recommendations for management of these conditions. These guidelines represent the official practice recommendations of the American College of Gastroenterology. Key concept statements based on author expert opinion and review of literature and specific recommendations based on PICO/GRADE analysis have been developed to aid in the management of vascular liver disorders. These recommendations and guidelines should be tailored to individual patients and circumstances in routine clinical practice.
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Abstract
Direct oral anticoagulants are approved for use in the United States and Europe and are increasingly used in chronic liver disease patients who have or are at risk of thrombotic events. While these drugs are clinically attractive because no monitoring is required, the risks and benefits in patients with hepatic or renal insufficiency who undergo surgery remain unclear. In this report, we describe the perioperative consequences, safety issues, and lessons learned from a patient undergoing an orthotopic liver transplant who was anticoagulated with rivaroxaban due to partial superior mesenteric vein thrombosis.
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Cardiovascular Risk in Non-Alcoholic Fatty Liver Disease: Mechanisms and Therapeutic Implications. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2019; 16:ijerph16173104. [PMID: 31455011 PMCID: PMC6747357 DOI: 10.3390/ijerph16173104] [Citation(s) in RCA: 128] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/16/2019] [Revised: 08/18/2019] [Accepted: 08/21/2019] [Indexed: 02/06/2023]
Abstract
New evidence suggests that non-alcoholic fatty liver disease (NAFLD) has a strong multifaceted relationship with diabetes and metabolic syndrome, and is associated with increased risk of cardiovascular events, regardless of traditional risk factors, such as hypertension, diabetes, dyslipidemia, and obesity. Given the pandemic-level rise of NAFLD—in parallel with the increasing prevalence of obesity and other components of the metabolic syndrome—and its association with poor cardiovascular outcomes, the question of how to manage NAFLD properly, in order to reduce the burden of associated incident cardiovascular events, is both timely and highly relevant. This review aims to summarize the current knowledge of the association between NAFLD and cardiovascular disease, and also to discuss possible clinical strategies for cardiovascular risk assessment, as well as the spectrum of available therapeutic strategies for the prevention and treatment of NAFLD and its downstream events.
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Turco L, de Raucourt E, Valla DC, Villa E. Anticoagulation in the cirrhotic patient. JHEP Rep 2019; 1:227-239. [PMID: 32039373 PMCID: PMC7001584 DOI: 10.1016/j.jhepr.2019.02.006] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Revised: 01/29/2019] [Accepted: 02/11/2019] [Indexed: 12/11/2022] Open
Abstract
In the past, patients with liver cirrhosis were thought to be prone to increased bleeding risk. However, those with compensated liver cirrhosis actually have normal coagulative balance, which can become altered when liver function worsens, or infection, bleeding, or acute kidney insufficiency occur. When this happens, it is now recognized that patients with liver cirrhosis are at higher risk of thrombotic rather than haemorrhagic complications. Anticoagulation plays a favourable role both when used therapeutically or prophylactically. Successful anticoagulation is associated with a lower rate of decompensation and with improved survival. To date, treatment has involved the use of low molecular weight heparins and vitamin K antagonists. Preliminary data suggest that novel non-vitamin K antagonist oral anticoagulants can be used safely in patients with liver cirrhosis.
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Affiliation(s)
- Laura Turco
- Department of Gastroenterology, University of Modena & Reggio Emilia and Azienda Ospedaliero-Universitaria di Modena, Italy.,PhD Program in Clinical and Experimental Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Emmanuelle de Raucourt
- Service d'hématologie biologique, CHU Paris Nord-Val de Seine - Hôpital Beaujon, Clichy, France
| | | | - Erica Villa
- Department of Gastroenterology, University of Modena & Reggio Emilia and Azienda Ospedaliero-Universitaria di Modena, Italy
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50
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Hanna K, Khalid A, Hamidi M, Gries L, Haddadin Z, Kulvatunyou N, Zeeshan M, Joseph B. Chronic Alcohol Consumption and Risk of Deep Venous Thrombosis: A Propensity-Matched Analysis. J Surg Res 2019; 244:251-256. [PMID: 31301481 DOI: 10.1016/j.jss.2019.06.067] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Revised: 04/30/2019] [Accepted: 06/14/2019] [Indexed: 11/18/2022]
Abstract
BACKGROUND Alcoholism is associated with variable effects on the coagulation system. Therefore, the aim of our study was to analyze the currently unknown association between chronic alcohol consumption and the risk of venous thromboembolism, which includes deep vein thrombosis (DVT) and pulmonary embolism (PE). METHODS We performed a 2-y (2013-2014) analysis of the American College of Surgeons Trauma Quality Improvement Program database. All trauma patients with an Injury Severity Score (ISS) > 16 were included. We excluded patients with acute alcohol intoxication, hematologic disorders, and cancer. Patients were divided into two groups (alcoholic and nonalcoholic) and were matched using propensity score matching (1:1) for demographics, ISS, injury location, and admission vitals. Outcomes measures were the prevalence of venous thromboembolism in each group. RESULTS Of the 91,066 trauma patients included in our analysis, 35,460 patients were matched (alcoholics: 17,730; nonalcoholics: 17,730). The mean was age 45 ± 18 y, and 81% were males. Matched groups were similar in age (P = 0.32), heart rate (P = 0.31), systolic blood pressure (P = 0.46), location of injury (P = 0.85), ISS (P = 0.76), and Glasgow Coma Scale (P = 0.38). Prevalence of DVT was lower in alcoholics compared with nonalcoholics (2.34% versus 5.12%, P = 0.01). The overall incidence of PE was 1.2%, and there was no difference between the two groups (1.1% versus 1.3%, P = 0.22). Similarly, there was no difference in mortality (14.8% versus 15.4%, P = 0.32) between the groups. CONCLUSIONS Chronic alcohol consumption is associated with a low risk of DVT in trauma patients. This association warrants further investigation of the possible physiological effects of alcohol in trauma patients. LEVEL OF EVIDENCE Level III Prognostic.
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Affiliation(s)
- Kamil Hanna
- Division of Trauma, Critical Care, Emergency Surgery, and Burns, Department of Surgery, College of Medicine, University of Arizona, Tucson, Arizona
| | - Aizaz Khalid
- Division of Trauma, Critical Care, Emergency Surgery, and Burns, Department of Surgery, College of Medicine, University of Arizona, Tucson, Arizona
| | - Mohammad Hamidi
- Division of Trauma, Critical Care, Emergency Surgery, and Burns, Department of Surgery, College of Medicine, University of Arizona, Tucson, Arizona
| | - Lynn Gries
- Division of Trauma, Critical Care, Emergency Surgery, and Burns, Department of Surgery, College of Medicine, University of Arizona, Tucson, Arizona
| | - Zaid Haddadin
- Division of Trauma, Critical Care, Emergency Surgery, and Burns, Department of Surgery, College of Medicine, University of Arizona, Tucson, Arizona
| | - Narong Kulvatunyou
- Division of Trauma, Critical Care, Emergency Surgery, and Burns, Department of Surgery, College of Medicine, University of Arizona, Tucson, Arizona
| | - Muhammad Zeeshan
- Division of Trauma, Critical Care, Emergency Surgery, and Burns, Department of Surgery, College of Medicine, University of Arizona, Tucson, Arizona
| | - Bellal Joseph
- Division of Trauma, Critical Care, Emergency Surgery, and Burns, Department of Surgery, College of Medicine, University of Arizona, Tucson, Arizona.
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