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Villanueva C, Tripathi D, Bosch J. Preventing the progression of cirrhosis to decompensation and death. Nat Rev Gastroenterol Hepatol 2025; 22:265-280. [PMID: 39870944 DOI: 10.1038/s41575-024-01031-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/06/2024] [Indexed: 01/29/2025]
Abstract
Two main stages are differentiated in patients with advanced chronic liver disease (ACLD), one compensated (cACLD) with an excellent prognosis, and the other decompensated (dACLD), defined by the appearance of complications (ascites, variceal bleeding and hepatic encephalopathy) and associated with high mortality. Preventing the progression to dACLD might dramatically improve prognosis and reduce the burden of care associated with ACLD. Portal hypertension is a major driver of the transition from cACLD to dACLD, and a portal pressure of ≥10 mmHg defines clinically significant portal hypertension (CSPH) as the threshold from which decompensating events may occur. In recent years, innovative studies have provided evidence supporting new strategies to prevent decompensation in cACLD. These studies have yielded major advances, including the development of noninvasive tests (NITs) to identify patients with CSPH with reasonable confidence, the demonstration that aetiological therapies can prevent disease progression and even achieve regression of cirrhosis, and the finding that non-selective β-blockers can effectively prevent decompensation in patients with cACLD and CSPH, mainly by reducing the risk of ascites, the most frequent decompensating event. Here, we review the evidence supporting new strategies to manage cACLD to prevent decompensation and the caveats for their implementation, from patient selection using NITs to ancillary therapies.
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Affiliation(s)
- Càndid Villanueva
- Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain.
- Department of Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain.
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Ministerio de Sanidad, Madrid, Spain.
| | - Dhiraj Tripathi
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham Health Partners, Birmingham, UK
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Jaume Bosch
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Ministerio de Sanidad, Madrid, Spain
- Department of Visceral Surgery and Medicine (Hepatology), Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
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Yun B, Park H, Lee J, Kim BK, Yoon JH. Statin use and liver-related prognosis among patients with MASLD. JHEP Rep 2025; 7:101313. [PMID: 40124167 PMCID: PMC11929059 DOI: 10.1016/j.jhepr.2024.101313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 12/17/2024] [Accepted: 12/19/2024] [Indexed: 03/25/2025] Open
Abstract
Background & Aims Metabolic dysfunction-associated steatotic liver disease (MASLD) is a highly prevalent liver condition. We investigated whether statin use reduces liver-related events (LREs) risk among patients with MASLD or MASLD with increased alcohol intake (MetALD). Methods This nationwide cohort study included individuals aged ≥40 years with MASLD/MetALD undergoing health examinations between 2012 and 2013. The primary outcome was LREs; hepatocellular carcinoma (HCC), decompensated liver cirrhosis (DLC), and liver-related mortality. Secondary outcomes included HCC, DLC, and steatotic liver disease (SLD) regression, all-cause mortality, cardiovascular diseases (CVD)-related mortality, and liver-related mortality, respectively. Multivariable Cox regression was performed to estimate the risk of LREs associated with statin use. Results Among 516,575 individuals (median follow-up: 10.1 years), statin users experienced significantly lower LRE rates (1.6%) compared with non-users (2.0%, p <0.001). Multivariable Cox regression analysis revealed that statin use was associated with reduced risks of LREs (adjusted hazard ratio [aHR] 0.64, 95% CI 0.61-0.68), HCC (aHR 0.52, 95% CI 0.47-0.58), DLC (aHR 0.58, 95% CI 0.52-0.65), all-cause mortality (aHR 0.81, 95% CI 0.78-0.84), CVD-related mortality (aHR 0.87, 95% CI 0.80-0.95), and liver-related mortality (aHR 0.51, 95% CI 0.46-0.57). Furthermore, statin use was associated with SLD regression (aHR 1.18, 95% CI 1.15-1.21). Stratified analyses consistently demonstrated risk reductions across all subgroups, particularly in patients with elevated alanine aminotransferase levels. Sensitivity analyses confirmed the robustness of these associations. Conclusions Statins are significantly associated with reduced LRE risk in patients with MASLD, especially among those with elevated alanine aminotransferase levels, suggesting a viable preventive strategy for such population. Impact and implications Our study provides critical evidence supporting the role of statins in reducing liver-related events in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), a condition with significant global health impact. These findings are particularly relevant for clinicians managing high-risk patients with MASLD, especially those with elevated alanine aminotransferase levels, as they highlight the potential for statins to mitigate both liver and cardiovascular risks. By demonstrating the robustness of these results through comprehensive sensitivity and stratified analyses, our research underscores the importance of integrating statin therapy into the management of MASLD. This has practical implications for physicians, researchers, and policymakers in developing guidelines and preventive strategies to improve long-term liver and cardiovascular outcomes.
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Affiliation(s)
- Byungyoon Yun
- Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- The Institute for Occupational Health, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute for Innovation in Digital Healthcare, Yonsei University Health System, Seoul, Republic of Korea
| | - Heejoo Park
- Department of Public Health, Graduate School, Yonsei University, Seoul, Republic of Korea
| | - Jian Lee
- Department of Public Health, Graduate School, Yonsei University, Seoul, Republic of Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea
| | - Jin-Ha Yoon
- Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- The Institute for Occupational Health, Yonsei University College of Medicine, Seoul, Republic of Korea
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Bosch J. Statins for MAFLD/MASH: another brick in the wall while waiting for final answers. Gut 2025; 74:518-520. [PMID: 39299766 DOI: 10.1136/gutjnl-2024-333426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Accepted: 09/06/2024] [Indexed: 09/22/2024]
Affiliation(s)
- Jaime Bosch
- Department of Visceral Surgery and Medicine (Hepatology), Inselspital Universitätsspital Bern, Bern, Switzerland
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Alvarado-Tapias E, Brujats A, Puente A, Ardevol A, Rodriguez-Arias A, Fajardo J, Pavel O, Garcia-Guix M, Aracil C, Poca M, Cuyàs B, Cantó E, Montañés R, Garcia-Osuna A, Escorsell À, Torras X, Villanueva C. Hemodynamic effects of carvedilol plus simvastatin in cirrhosis with severe portal hypertension and suboptimal response to β-blockers: A double-blind, placebo-controlled, randomized trial. Hepatology 2024:01515467-990000000-01072. [PMID: 39509369 DOI: 10.1097/hep.0000000000001148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Accepted: 10/08/2024] [Indexed: 11/15/2024]
Abstract
BACKGROUND AND AIMS Carvedilol is a nonselective β-blocker (NSBB) with anti-α1-adrenergic activity, more effective than traditional NSBBs in reducing portal pressure hepatic venous pressure gradient (HVPG). However, 35%-45% of patients still have insufficient HVPG decrease. Statins ameliorate endothelial dysfunction, reduce hepatic vascular resistance, and have pleiotropic effects. We investigated whether the addition of simvastatin improves the efficacy of carvedilol on HVPG in cirrhosis with severe portal hypertension and suboptimal response to traditional NSBBs. METHODS Patients with cirrhosis and high-risk varices referred for primary prophylaxis were consecutively included. HVPG was measured at baseline and again after i.v. propranolol. Suboptimal responders (HVPG decrease <20%) were treated with carvedilol and were randomized to double-blind administration of placebo or simvastatin. Chronic HVPG response was assessed after 4-6 weeks, repeating HVPG measurements after a standard liquid meal to estimate endothelial dysfunction. Plasma samples were obtained before each study to investigate inflammatory parameters. RESULTS Of 184 eligible patients, 82 were randomized to carvedilol + simvastatin (N = 41) or carvedilol + placebo (N = 41). Baseline characteristics were similar. HVPG significantly decreased with both, carvedilol + simvastatin (18.6 ± 4 to 15.7 ± 4 mm Hg, p < 0.001) and carvedilol + placebo (18.9 ± 3 to 16.9 ± 3 mm Hg, p < 0.001). The decrease was greater with carvedilol + simvastatin (2.97 ± 2.5 vs. 2.05 ± 1.6 mm Hg, p = 0.031). An HVPG decrease ≥20% occurred in 37% versus 15% of patients, respectively (OR: 3.37, 95% CI = 1.15-9.85; p = 0.021). With test meal, HVPG increased in both groups ( p < 0.01), although carvedilol + simvastatin attenuated such increment (12 ± 8% vs. 23 ± 16%, p < 0.001). Cytokine levels (Interleukine-6, monocyte-chemoattractant protein-1, and malondialdehyde) decreased significantly more with carvedilol + simvastatin ( p < 0.01). The incidence of adverse events was similar. CONCLUSIONS In patients with severe portal hypertension (all with high-risk varices) and suboptimal hemodynamic response to traditional NSBBs, combined therapy with carvedilol plus simvastatin significantly enhances the portal pressure reduction achieved with carvedilol monotherapy, improves endothelial dysfunction, and reduces proinflammatory cytokines.
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Affiliation(s)
- Edilmar Alvarado-Tapias
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain
- Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Department of Medicine, Autonomous University of Barcelona (UAB), Barcelona, Spain
| | - Anna Brujats
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain
- Department of Medicine, Autonomous University of Barcelona (UAB), Barcelona, Spain
| | - Angela Puente
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain
- Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Alba Ardevol
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain
| | | | - Javier Fajardo
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain
| | - Oana Pavel
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain
| | - Marta Garcia-Guix
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain
- Department of Medicine, Autonomous University of Barcelona (UAB), Barcelona, Spain
| | - Carles Aracil
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain
| | - Maria Poca
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain
- Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Department of Medicine, Autonomous University of Barcelona (UAB), Barcelona, Spain
| | - Berta Cuyàs
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain
- Department of Medicine, Autonomous University of Barcelona (UAB), Barcelona, Spain
| | - Elisabet Cantó
- Inflammatory Diseases Department, Institut Recerca Hospital Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
| | - Rosa Montañés
- Inflammatory Diseases Department, Institut Recerca Hospital Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
| | - Alvaro Garcia-Osuna
- Department of Biochemistry, Hospital Santa Creu i Sant Pau, Barcelona, Spain
| | - Àngels Escorsell
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain
- Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Department of Medicine, Autonomous University of Barcelona (UAB), Barcelona, Spain
| | - Xavier Torras
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain
- Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Department of Medicine, Autonomous University of Barcelona (UAB), Barcelona, Spain
| | - Càndid Villanueva
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain
- Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Department of Medicine, Autonomous University of Barcelona (UAB), Barcelona, Spain
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Guixé-Muntet S, Quesada-Vázquez S, Gracia-Sancho J. Pathophysiology and therapeutic options for cirrhotic portal hypertension. Lancet Gastroenterol Hepatol 2024; 9:646-663. [PMID: 38642564 DOI: 10.1016/s2468-1253(23)00438-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 11/28/2023] [Accepted: 11/28/2023] [Indexed: 04/22/2024]
Abstract
Portal hypertension represents the primary non-neoplastic complication of liver cirrhosis and has life-threatening consequences, such as oesophageal variceal bleeding, ascites, and hepatic encephalopathy. Portal hypertension occurs due to increased resistance of the cirrhotic liver vasculature to portal blood flow and is further aggravated by the hyperdynamic circulatory syndrome. Existing knowledge indicates that the profibrogenic phenotype acquired by sinusoidal cells is the initial factor leading to increased hepatic vascular tone and fibrosis, which cause increased vascular resistance and portal hypertension. Data also suggest that the phenotype of hepatic cells could be further impaired due to the altered mechanical properties of the cirrhotic liver itself, creating a deleterious cycle that worsens portal hypertension in the advanced stages of liver disease. In this Review, we discuss recent discoveries in the pathophysiology and treatment of cirrhotic portal hypertension, a condition with few pharmacological treatment options.
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Affiliation(s)
- Sergi Guixé-Muntet
- Liver Vascular Biology Research Group, IDIBAPS Biomedical Research Institute, CIBEREHD, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Sergio Quesada-Vázquez
- Liver Vascular Biology Research Group, IDIBAPS Biomedical Research Institute, CIBEREHD, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Jordi Gracia-Sancho
- Liver Vascular Biology Research Group, IDIBAPS Biomedical Research Institute, CIBEREHD, Hospital Clínic de Barcelona, Barcelona, Spain; Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
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Sanfeliu-Redondo D, Gibert-Ramos A, Gracia-Sancho J. Cell senescence in liver diseases: pathological mechanism and theranostic opportunity. Nat Rev Gastroenterol Hepatol 2024; 21:477-492. [PMID: 38485755 DOI: 10.1038/s41575-024-00913-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/12/2024] [Indexed: 06/30/2024]
Abstract
The liver is not oblivious to the passage of time, as ageing is a major risk factor for the development of acute and chronic liver diseases. Ageing produces alterations in all hepatic cells, affecting their phenotype and function and worsening the prognosis of liver disease. The ageing process also implies the accumulation of a cellular state characterized by a persistent proliferation arrest and a specific secretory phenotype named cellular senescence. Indeed, senescent cells have key roles in many physiological processes; however, their accumulation owing to ageing or pathological conditions contributes to the damage occurring in chronic diseases. The aim of this Review is to provide an updated description of the pathophysiological events in which hepatic senescent cells are involved and their role in liver disease progression. Finally, we discuss novel geroscience therapies that could be applied to prevent or improve liver diseases and age-mediated hepatic deregulations.
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Affiliation(s)
- David Sanfeliu-Redondo
- Liver Vascular Biology Laboratory, IDIBAPS Biomedical Research Institute - Hospital Clínic de Barcelona & CIBEREHD, Barcelona, Spain
| | - Albert Gibert-Ramos
- Liver Vascular Biology Laboratory, IDIBAPS Biomedical Research Institute - Hospital Clínic de Barcelona & CIBEREHD, Barcelona, Spain
| | - Jordi Gracia-Sancho
- Liver Vascular Biology Laboratory, IDIBAPS Biomedical Research Institute - Hospital Clínic de Barcelona & CIBEREHD, Barcelona, Spain.
- Department of Visceral Surgery and Medicine, Inselspital - University of Bern, Bern, Switzerland.
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Mohammed OA, Youssef ME, Doghish AS, Hamad RS, Abdel-Reheim MA, Alghamdi M, Alamri MMS, Alfaifi J, Adam MIE, Alharthi MH, Alhalafi AH, Bahashwan E, Rezigalla AA, BinAfif DF, Abdel-Ghany S, Attia MA, Elmorsy EA, Al-Noshokaty TM, Fikry H, Saleh LA, Saber S. A novel combination therapy targets sonic hedgehog signaling by the dual inhibition of HMG-CoA reductase and HSP90 in rats with non-alcoholic steatohepatitis. Eur J Pharm Sci 2024; 198:106792. [PMID: 38714237 DOI: 10.1016/j.ejps.2024.106792] [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: 02/22/2024] [Revised: 05/03/2024] [Accepted: 05/04/2024] [Indexed: 05/09/2024]
Abstract
Non-alcoholic steatohepatitis (NASH) is characterized by liver inflammation, fat accumulation, and collagen deposition. Due to the limited availability of effective treatments, there is a pressing need to develop innovative strategies. Given the complex nature of the disease, employing combination approaches is essential. Hedgehog signaling has been recognized as potentially promoting NASH, and cholesterol can influence this signaling by modifying the conformation of PTCH1 and SMO activity. HSP90 plays a role in the stability of SMO and GLI proteins. We revealed significant positive correlations between Hedgehog signaling proteins (Shh, SMO, GLI1, and GLI2) and both cholesterol and HSP90 levels. Herein, we investigated the novel combination of the cholesterol-lowering agent lovastatin and the HSP90 inhibitor PU-H71 in vitro and in vivo. The combination demonstrated a synergy score of 15.09 and an MSA score of 22.85, as estimated by the ZIP synergy model based on growth inhibition rates in HepG2 cells. In a NASH rat model induced by thioacetamide and a high-fat diet, this combination therapy extended survival, improved liver function and histology, and enhanced antioxidant defense. Additionally, the combination exhibited anti-inflammatory and anti-fibrotic potential by influencing the levels of TNF-α, TGF-β, TIMP-1, and PDGF-BB. This effect was evident in the suppression of the Col1a1 gene expression and the levels of hydroxyproline and α-SMA. These favorable outcomes may be attributed to the combination's potential to inhibit key Hedgehog signaling molecules. In conclusion, exploring the applicability of this combination contributes to a more comprehensive understanding and improved management of NASH and other fibrotic disorders.
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Affiliation(s)
- Osama A Mohammed
- Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt; Department of Pharmacology, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia.
| | - Mahmoud E Youssef
- Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 11152, Egypt
| | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo, 11829, Egypt; Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Al-Azhar University, Nasr City, Cairo 11231, Egypt.
| | - Rabab S Hamad
- Biological Sciences Department, College of Science, King Faisal University, Al Ahsa 31982, Saudi Arabia; Central Laboratory, Theodor Bilharz Research Institute, Giza 12411, Egypt.
| | - Mustafa Ahmed Abdel-Reheim
- Department of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, Shaqra 11961, Saudi Arabia; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni Suef 62521, Egypt.
| | - Mushabab Alghamdi
- Department of Internal Medicine, Division of Rheumatology, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia
| | - Mohannad Mohammad S Alamri
- Department of Family and Community Medicine, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia
| | - Jaber Alfaifi
- Department of Child Health, College of Medicine, University of Bisha, Bisha, 61922, Saudi Arabia
| | - Masoud I E Adam
- Department of Medical Education and Internal Medicine, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia
| | - Muffarah Hamid Alharthi
- Department of Family and Community Medicine, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia
| | - Abdullah Hassan Alhalafi
- Department of Family and Community Medicine, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia
| | - Emad Bahashwan
- Department of Internal Medicine, Division of Dermatology, College of medicine, University of Bisha, Bisha 61922, Saudi Arabia
| | - Assad Ali Rezigalla
- Department of Anatomy, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia
| | - Daad Fuad BinAfif
- Department of Medicine, King Abdullah Medical City, Makkah 24246, Saudi Arabia
| | - Sameh Abdel-Ghany
- Department of Clinical Pharmacology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt; Department of basic medical sciences, Ibn Sina University for medical sciences, Amman 16197, Jordan
| | - Mohammed A Attia
- Department of Clinical Pharmacology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt; Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, Riyadh 11597, Saudi Arabia
| | - Elsayed A Elmorsy
- Department of Pharmacology and Therapeutics, College of Medicine, Qassim University, Saudi Arabia; Clinical Pharmacology Department, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt.
| | - Tohada M Al-Noshokaty
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Heba Fikry
- Department of Histology and Cell Biology, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt
| | - Lobna A Saleh
- Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt; Department of Pharmacology and Toxicology, Collage of Pharmacy, Taif University, Taif 21944, Saudi Arabia
| | - Sameh Saber
- Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 11152, Egypt
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Pham N, Benhammou JN. Statins in Chronic Liver Disease: Review of the Literature and Future Role. Semin Liver Dis 2024; 44:191-208. [PMID: 38701856 DOI: 10.1055/a-2319-0694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/05/2024]
Abstract
Chronic liver disease (CLD) is a major contributor to global mortality, morbidity, and healthcare burden. Progress in pharmacotherapeutic for CLD management is lagging given its impact on the global population. While statins are indicated for the management of dyslipidemia and cardiovascular disease, their role in CLD prevention and treatment is emerging. Beyond their lipid-lowering effects, their liver-related mechanisms of action are multifactorial and include anti-inflammatory, antiproliferative, and immune-protective effects. In this review, we highlight what is known about the clinical benefits of statins in viral and nonviral etiologies of CLD and hepatocellular carcinoma (HCC), and explore key mechanisms and pathways targeted by statins. While their benefits may span the spectrum of CLD and potentially HCC treatment, their role in CLD chemoprevention is likely to have the largest impact. As emerging data suggest that genetic variants may impact their benefits, the role of statins in precision hepatology will need to be further explored.
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Affiliation(s)
- Nguyen Pham
- Department of Medicine, University of California, Los Angeles, Los Angeles, California
| | - Jihane N Benhammou
- Department of Medicine, University of California, Los Angeles, Los Angeles, California
- Veterans Affairs Greater Los Angeles, Los Angeles, California
- Comprehensive Liver Research Center at University of California, Los Angeles, Los Angeles, California
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Colombo C, Lanfranchi C, Tosetti G, Corti F, Primignani M. Management of liver disease and portal hypertension in cystic fibrosis: a review. Expert Rev Respir Med 2024; 18:269-281. [PMID: 38962827 DOI: 10.1080/17476348.2024.2365842] [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: 12/20/2023] [Accepted: 06/05/2024] [Indexed: 07/05/2024]
Abstract
INTRODUCTION Cystic fibrosis (CF)-associated liver disease can significantly affect the quality of life and survival of people with CF. The hepatobiliary manifestations in CF are various, with focal/multilobular biliary cirrhosis more common in children and porto-sinusoidal vascular disease (PSVD) in young adults. Portal hypertensive complications, particularly bleeding from esophagogastric varices and hypersplenism are common, while liver failure is rarer and mainly linked to biliary disease. AREAS COVERED This review explores current therapeutic options for CF-associated liver disease, presenting ongoing studies and new insights into parthenogenesis for potential future therapies. EXPERT OPINION Monitoring for signs of portal hypertension is essential. Limited evidence supports ursodeoxycholic acid (UDCA) efficacy in halting CF liver disease progression. The effect of cystic fibrosis transmembrane conductance regulator (CFTR) modulators on liver outcomes lacks definitive data, since patients with CF-related liver disease were excluded from trials due to potential hepatotoxicity. A proposed approach involves using UDCA and modulators in early stages, along with anti-inflammatory agents, with further therapeutic strategies awaiting randomized trials. Prevention of portal hypertensive bleeding includes endoscopic sclerotherapy or ligation of esophageal varices. Nonselective beta-blockers may also prevent bleeding and could be cautiously implemented. Other non-etiological treatments require investigation.
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Affiliation(s)
- Carla Colombo
- Cystic Fibrosis Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Chiara Lanfranchi
- Cystic Fibrosis Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Giulia Tosetti
- Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Fabiola Corti
- Cystic Fibrosis Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Massimo Primignani
- Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
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Zhao BW, Chen YJ, Zhang RP, Chen YM, Huang BW. Angiotensin-converting enzyme 2 alleviates liver fibrosis through the renin-angiotensin system. World J Gastroenterol 2024; 30:607-609. [PMID: 38463024 PMCID: PMC10921144 DOI: 10.3748/wjg.v30.i6.607] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 12/17/2023] [Accepted: 01/15/2024] [Indexed: 02/05/2024] Open
Abstract
The present letter to the editor is related to the study titled 'Angiotensin-converting enzyme 2 improves liver fibrosis in mice by regulating autophagy of hepatic stellate cells'. Angiotensin-converting enzyme 2 can alleviate liver fibrosis by regulating autophagy of hepatic stellate cells and affecting the renin-angiotensin system.
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Affiliation(s)
- Bai-Wei Zhao
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou 510060, Guangdong Province, China
| | - Ying-Jia Chen
- Health Science Center, Peking University, Beijing 100191, China
| | - Ruo-Peng Zhang
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou 510060, Guangdong Province, China
| | - Yong-Ming Chen
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou 510060, Guangdong Province, China
| | - Bo-Wen Huang
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou 510060, Guangdong Province, China
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11
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Fernández-Iglesias A, Gracia-Sancho J. Role of liver sinusoidal endothelial cells in the diagnosis and treatment of liver diseases. SINUSOIDAL CELLS IN LIVER DISEASES 2024:467-481. [DOI: 10.1016/b978-0-323-95262-0.00023-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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12
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Kronborg TM, Schierwagen R, Trošt K, Gao Q, Moritz T, Bendtsen F, Gantzel RH, Andersen ML, Teisner AS, Grønbæk H, Hobolth L, Møller S, Trebicka J, Kimer N. Atorvastatin for patients with cirrhosis. A randomized, placebo-controlled trial. Hepatol Commun 2023; 7:e0332. [PMID: 38051553 PMCID: PMC10697620 DOI: 10.1097/hc9.0000000000000332] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Accepted: 09/15/2023] [Indexed: 12/07/2023] Open
Abstract
BACKGROUND Patients with cirrhosis and portal hypertension face a high risk of complications. Besides their anti-inflammatory and antifibrotic effects, statins may reduce portal pressure and thus the risk of complications and mortality. We aimed to investigate the effects of atorvastatin on hospital admissions, mortality, inflammation, and lipidomics in cirrhosis with portal hypertension. METHODS We performed a double-blinded, randomized, placebo-controlled clinical trial among patients with cirrhosis and portal hypertension. Atorvastatin (10-20 mg/d) was administered for 6 months. We measured splanchnic hemodynamics, analyzed inflammatory markers, and performed lipidomics at baseline and after 6 months. RESULTS Seventy-eight patients were randomized, with 38 patients allocated to atorvastatin and 40 patients to placebo. Fifty-nine patients completed 6 months of intervention. Comparisons between changes in each group were calculated. Liver-related complications and mortality were similar between the groups. The HVPG and Model for End-stage Liver Disease score did not change between groups (p=0.95 and 0.87, respectively). Atorvastatin decreased 3 of 42 inflammatory markers, CD62-L-selectin, matrix metalloproteinases-2, and TNF-α (p-values: 0.005, 0.011, and 0.023, respectively), while lipidomics was not significantly changed. CONCLUSIONS In patients with cirrhosis, atorvastatin was safe to use, but did not reduce mortality, the risk of liver-related complications, or the HVPG. Atorvastatin induced minor anti-inflammatory effects and minor effects on lipids during a 6-month treatment period.
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Affiliation(s)
- Thit M. Kronborg
- Gastro Unit, Medical Division, Copenhagen University Hospital, Hvidovre, Denmark
| | - Robert Schierwagen
- Department of Internal Medicine B, University of Münster, Münster, Germany
| | - Kajetan Trošt
- Novo Nordisk Foundation Centre for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Qian Gao
- Novo Nordisk Foundation Centre for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Thomas Moritz
- Novo Nordisk Foundation Centre for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Flemming Bendtsen
- Gastro Unit, Medical Division, Copenhagen University Hospital, Hvidovre, Denmark
- Department of Clinical Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Rasmus H. Gantzel
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, and Clinical Institute, Aarhus University, Aarhus, Denmark
| | - Mette L. Andersen
- Department of Gastroenterology and Hepatology, Copenhagen University Hospital, Herlev, Denmark
| | - Ane S. Teisner
- Department of Gastroenterology and Hepatology, Copenhagen University Hospital, Herlev, Denmark
| | - Henning Grønbæk
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, and Clinical Institute, Aarhus University, Aarhus, Denmark
| | - Lise Hobolth
- Gastro Unit, Medical Division, Copenhagen University Hospital, Hvidovre, Denmark
| | - Søren Møller
- Department of Clinical Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Physiology and Nuclear Medicine, Centre of Functional Imaging and Research, Copenhagen University Hospital, Hvidovre, Denmark
| | - Jonel Trebicka
- Department of Internal Medicine B, University of Münster, Münster, Germany
| | - Nina Kimer
- Gastro Unit, Medical Division, Copenhagen University Hospital, Hvidovre, Denmark
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13
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Felli E, Selicean S, Guixé-Muntet S, Wang C, Bosch J, Berzigotti A, Gracia-Sancho J. Mechanobiology of portal hypertension. JHEP Rep 2023; 5:100869. [PMID: 37841641 PMCID: PMC10568428 DOI: 10.1016/j.jhepr.2023.100869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 06/28/2023] [Accepted: 07/03/2023] [Indexed: 10/17/2023] Open
Abstract
The interplay between mechanical stimuli and cellular mechanobiology orchestrates the physiology of tissues and organs in a dynamic balance characterized by constant remodelling and adaptative processes. Environmental mechanical properties can be interpreted as a complex set of information and instructions that cells read continuously, and to which they respond. In cirrhosis, chronic inflammation and injury drive liver cells dysfunction, leading to excessive extracellular matrix deposition, sinusoidal pseudocapillarization, vascular occlusion and parenchymal extinction. These pathological events result in marked remodelling of the liver microarchitecture, which is cause and result of abnormal environmental mechanical forces, triggering and sustaining the long-standing and progressive process of liver fibrosis. Multiple mechanical forces such as strain, shear stress, and hydrostatic pressure can converge at different stages of the disease until reaching a point of no return where the fibrosis is considered non-reversible. Thereafter, reciprocal communication between cells and their niches becomes the driving force for disease progression. Accumulating evidence supports the idea that, rather than being a passive consequence of fibrosis and portal hypertension (PH), mechanical force-mediated pathways could themselves represent strategic targets for novel therapeutic approaches. In this manuscript, we aim to provide a comprehensive review of the mechanobiology of PH, by furnishing an introduction on the most important mechanisms, integrating these concepts into a discussion on the pathogenesis of PH, and exploring potential therapeutic strategies.
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Affiliation(s)
- Eric Felli
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland
- Department for BioMedical Research, Visceral Surgery and Medicine, University of Bern, Switzerland
| | - Sonia Selicean
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland
- Department for BioMedical Research, Visceral Surgery and Medicine, University of Bern, Switzerland
| | - Sergi Guixé-Muntet
- Liver Vascular Biology Research Group, IDIBAPS Biomedical Research Institute, CIBEREHD, Spain
| | - Cong Wang
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland
- Department for BioMedical Research, Visceral Surgery and Medicine, University of Bern, Switzerland
| | - Jaume Bosch
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland
- Department for BioMedical Research, Visceral Surgery and Medicine, University of Bern, Switzerland
- Liver Vascular Biology Research Group, IDIBAPS Biomedical Research Institute, CIBEREHD, Spain
| | - Annalisa Berzigotti
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland
- Department for BioMedical Research, Visceral Surgery and Medicine, University of Bern, Switzerland
| | - Jordi Gracia-Sancho
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland
- Department for BioMedical Research, Visceral Surgery and Medicine, University of Bern, Switzerland
- Liver Vascular Biology Research Group, IDIBAPS Biomedical Research Institute, CIBEREHD, Spain
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Shaffer LR, Mahmud N. Statins in Cirrhosis: Hope or Hype? J Clin Exp Hepatol 2023; 13:1032-1046. [PMID: 37975036 PMCID: PMC10643276 DOI: 10.1016/j.jceh.2023.05.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Accepted: 05/01/2023] [Indexed: 11/19/2023] Open
Abstract
In recent years, studies have demonstrated the benefits of statins in a range of chronic diseases separate from cardiovascular outcomes. Early studies in the context of chronic liver disease have suggested favorable effects of statins leading to slowed fibrosis progression, reduced portal pressures, decreased rates of hepatic decompensation, and improved survival. This has increased interest in the potential role that statins may have in the management of chronic liver disease and cirrhosis, though many questions remain unanswered, including concerns regarding the safety of higher dose statins in patients with advanced decompensated cirrhosis. In this review, we provide an update on the current literature addressing the use of statins in patients with cirrhosis and highlight areas in which additional studies are needed.
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Affiliation(s)
- Lauren R. Shaffer
- Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Nadim Mahmud
- Division of Gastroenterology and Hepatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
- Gastroenterology Section, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA
- Leonard David Institute of Health Economics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
- Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, PA, USA
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15
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Marginean CM, Pirscoveanu D, Popescu M, Vasile CM, Docea AO, Mitruț R, Mărginean IC, Iacob GA, Firu DM, Mitruț P. Challenges in Diagnosis and Therapeutic Approach of Acute on Chronic Liver Failure-A Review of Current Evidence. Biomedicines 2023; 11:1840. [PMID: 37509478 PMCID: PMC10376368 DOI: 10.3390/biomedicines11071840] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 06/23/2023] [Accepted: 06/25/2023] [Indexed: 07/30/2023] Open
Abstract
Acute-on-chronic liver failure (ACLF) is a syndrome characterized by acute and severe decompensation of chronic liver disease (CLD) correlated with multiple organ failure, poor prognosis, and increased mortality. In 40-50% of ACLF cases, the trigger is not recognized; for many of these patients, bacterial translocation associated with systemic inflammation is thought to be the determining factor; in the other 50% of patients, sepsis, alcohol consumption, and reactivation of chronic viral hepatitis are the most frequently described trigger factors. Other conditions considered precipitating factors are less common, including acute alcoholic hepatitis, major surgery, TIPS insertion, or inadequate paracentesis without albumin substitution. Host response is likely the primary factor predicting ACLF severity and prognosis, the host immune response having a particular significance in this syndrome, together with the inflammatory cascade. The management of ACLF includes both the prevention of the precipitating factors that lead to acute liver decompensation and the support of vital functions, the prevention and management of complications, the estimation of prognosis, and the opportunity for liver transplantation.
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Affiliation(s)
- Cristina Maria Marginean
- Department of Internal Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Denisa Pirscoveanu
- Department of Neurology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Mihaela Popescu
- Department of Endocrinology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Corina Maria Vasile
- Department of Pediatric Cardiology, "Marie Curie" Emergency Children's Hospital, 041451 Bucharest, Romania
| | - Anca Oana Docea
- Department of Toxicology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Radu Mitruț
- Department of Cardiology, University and Emergency Hospital, 050098 Bucharest, Romania
| | | | - George Alexandru Iacob
- Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Dan Mihai Firu
- Ph.D. School Department, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Paul Mitruț
- Department of Internal Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
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Airola C, Pallozzi M, Cerrito L, Santopaolo F, Stella L, Gasbarrini A, Ponziani FR. Microvascular Thrombosis and Liver Fibrosis Progression: Mechanisms and Clinical Applications. Cells 2023; 12:1712. [PMID: 37443746 PMCID: PMC10341358 DOI: 10.3390/cells12131712] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 06/14/2023] [Accepted: 06/16/2023] [Indexed: 07/15/2023] Open
Abstract
Fibrosis is an unavoidable consequence of chronic inflammation. Extracellular matrix deposition by fibroblasts, stimulated by multiple pathways, is the first step in the onset of chronic liver disease, and its propagation promotes liver dysfunction. At the same time, chronic liver disease is characterized by alterations in primary and secondary hemostasis but unlike previously thought, these changes are not associated with an increased risk of bleeding complications. In recent years, the role of coagulation imbalance has been postulated as one of the main mechanisms promoting hepatic fibrogenesis. In this review, we aim to investigate the function of microvascular thrombosis in the progression of liver disease and highlight the molecular and cellular networks linking hemostasis to fibrosis in this context. We analyze the predictive and prognostic role of coagulation products as biomarkers of liver decompensation (ascites, variceal hemorrhage, and hepatic encephalopathy) and liver-related mortality. Finally, we evaluate the current evidence on the application of antiplatelet and anticoagulant therapies for prophylaxis of hepatic decompensation or prevention of the progression of liver fibrosis.
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Affiliation(s)
- Carlo Airola
- Hepatology Unit, CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Rome, Italy; (C.A.); (M.P.); (L.C.); (F.S.); (L.S.); (A.G.)
| | - Maria Pallozzi
- Hepatology Unit, CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Rome, Italy; (C.A.); (M.P.); (L.C.); (F.S.); (L.S.); (A.G.)
| | - Lucia Cerrito
- Hepatology Unit, CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Rome, Italy; (C.A.); (M.P.); (L.C.); (F.S.); (L.S.); (A.G.)
| | - Francesco Santopaolo
- Hepatology Unit, CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Rome, Italy; (C.A.); (M.P.); (L.C.); (F.S.); (L.S.); (A.G.)
| | - Leonardo Stella
- Hepatology Unit, CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Rome, Italy; (C.A.); (M.P.); (L.C.); (F.S.); (L.S.); (A.G.)
| | - Antonio Gasbarrini
- Hepatology Unit, CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Rome, Italy; (C.A.); (M.P.); (L.C.); (F.S.); (L.S.); (A.G.)
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Francesca Romana Ponziani
- Hepatology Unit, CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Rome, Italy; (C.A.); (M.P.); (L.C.); (F.S.); (L.S.); (A.G.)
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
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17
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Lazaro A, Stoll P, von Elverfeldt D, Kreisel W, Deibert P. Close Relationship between Systemic Arterial and Portal Venous Pressure in an Animal Model with Healthy Liver. Int J Mol Sci 2023; 24:9963. [PMID: 37373109 DOI: 10.3390/ijms24129963] [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: 03/01/2023] [Revised: 05/31/2023] [Accepted: 06/02/2023] [Indexed: 06/29/2023] Open
Abstract
It is unclear to what extent systemic arterial blood pressure influences portal pressure. This relationship is clinically important as drugs, which are conventionally used for therapy of portal hypertension, may also influence systemic arterial blood pressure. This study investigated the potential correlation between mean arterial (MAP) and portal venous pressure (PVP) in rats with healthy livers. In a rat model with healthy livers, we investigated the effect of manipulation of MAP on PVP. Interventions consisted of 0.9% NaCl (group 1), 0.1 mg/kg body weight (bw) Sildenafil (low dose), an inhibitor of phosphodiesterase-5 (group 2), and 1.0 mg/kg bw Sildenafil (high dose, group 3) in 600 µL saline injected intravenously. Norepinephrine was used to increase MAP in animals with circulatory failure while PVP was monitored. Injection of the fluids induced a transient drop in MAP and PVP, probably due to a reversible cardiac decompensation. The drop in MAP and drop in PVP are significantly correlated. The time lag between change in MAP and change in PVP by 24 s in all groups suggests a cause-and-effect relationship. Ten minutes after the injection of the fluid, cardiac function was normalized. Thereafter, MAP gradually decreased. In the NaCl group, PVP decreases by 0.485% for a 1% drop of MAP, by 0.550% in the low-dose sildenafil group, and by 0.651% in the high-dose sildenafil group (p < 0.05 for difference group two vs. group one, group three vs. group one, and group three vs. group two). These data suggest that Sildenafil has an inherent effect on portal pressure that exceeds the effect of MAP. Injection of norepinephrine led to a sudden increase in MAP followed by an increase in PVP after a time lag. These data show a close relationship between portal venous pressure and systemic arterial pressure in this animal model with healthy livers. A change in MAP is consequently followed by a change in PVP after a distinct time lag. This study, furthermore, suggests that Sildenafil influences portal pressure. Further studies should be performed in a model with cirrhotic livers, as these may be important in the evaluation of vasoactive drugs (e.g., PDE-5-inhibitors) for therapy of portal hypertension.
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Affiliation(s)
- Adhara Lazaro
- Institute of Exercise and Occupational Medicine, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany
| | | | - Dominik von Elverfeldt
- Department of Diagnostic and Interventional Radiology, Division of Medical Physics, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany
| | - Wolfgang Kreisel
- Department of Medicine II, Gastroenterology, Hepatology, Endocrinology and Infectious Diseases, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany
| | - Peter Deibert
- Institute of Exercise and Occupational Medicine, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany
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Singh S, Sharma N, Shukla S, Behl T, Gupta S, Anwer MK, Vargas-De-La-Cruz C, Bungau SG, Brisc C. Understanding the Potential Role of Nanotechnology in Liver Fibrosis: A Paradigm in Therapeutics. Molecules 2023; 28:molecules28062811. [PMID: 36985782 PMCID: PMC10057127 DOI: 10.3390/molecules28062811] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Revised: 03/15/2023] [Accepted: 03/17/2023] [Indexed: 03/30/2023] Open
Abstract
The liver is a vital organ that plays a crucial role in the physiological operation of the human body. The liver controls the body's detoxification processes as well as the storage and breakdown of red blood cells, plasma protein and hormone production, and red blood cell destruction; therefore, it is vulnerable to their harmful effects, making it more prone to illness. The most frequent complications of chronic liver conditions include cirrhosis, fatty liver, liver fibrosis, hepatitis, and illnesses brought on by alcohol and drugs. Hepatic fibrosis involves the activation of hepatic stellate cells to cause persistent liver damage through the accumulation of cytosolic matrix proteins. The purpose of this review is to educate a concise discussion of the epidemiology of chronic liver disease, the pathogenesis and pathophysiology of liver fibrosis, the symptoms of liver fibrosis progression and regression, the clinical evaluation of liver fibrosis and the research into nanotechnology-based synthetic and herbal treatments for the liver fibrosis is summarized in this article. The herbal remedies summarized in this review article include epigallocathechin-3-gallate, silymarin, oxymatrine, curcumin, tetrandrine, glycyrrhetinic acid, salvianolic acid, plumbagin, Scutellaria baicalnsis Georgi, astragalosides, hawthorn extract, and andrographolides.
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Affiliation(s)
- Sukhbir Singh
- Department of Pharmaceutics, MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala 133207, Haryana, India
| | - Neelam Sharma
- Department of Pharmaceutics, MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala 133207, Haryana, India
| | - Saurabh Shukla
- Chitkara College of Pharmacy, Chitkara University, Punjab 140401, India
| | - Tapan Behl
- School of Health Sciences &Technology, University of Petroleum and Energy Studies, Dehradun 248007, Uttarakhand, India
| | - Sumeet Gupta
- Department of Pharmacology, MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala 133207, Haryana, India
| | - Md Khalid Anwer
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj 11942, Saudi Arabia
| | - Celia Vargas-De-La-Cruz
- Department of Pharmacology, Bromatology and Toxicology, Faculty of Pharmacy and Biochemistry, Universidad Nacional Mayor de San Marcos, Lima 150001, Peru
- E-Health Research Center, Universidad de Ciencias y Humanidades, Lima 15001, Peru
| | - Simona Gabriela Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania
- Doctoral School of Biomedical Sciences, University of Oradea, 410087 Oradea, Romania
| | - Cristina Brisc
- Department of Medical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania
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Licata A, Russo GT, Giandalia A, Cammilleri M, Asero C, Cacciola I. Impact of Sex and Gender on Clinical Management of Patients with Advanced Chronic Liver Disease and Type 2 Diabetes. J Pers Med 2023; 13:jpm13030558. [PMID: 36983739 PMCID: PMC10051396 DOI: 10.3390/jpm13030558] [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: 12/28/2022] [Revised: 02/22/2023] [Accepted: 03/13/2023] [Indexed: 03/30/2023] Open
Abstract
Gender differences in the epidemiology, pathophysiological mechanisms and clinical features in chronic liver diseases that may be associated with type 2 diabetes (T2D) have been increasingly reported in recent years. This sexual dimorphism is due to a complex interaction between sex- and gender-related factors, including biological, hormonal, psychological and socio-cultural variables. However, the impact of sex and gender on the management of T2D subjects with liver disease is still unclear. In this regard, sex-related differences deserve careful consideration in pharmacology, aimed at improving drug safety and optimising medical therapy, both in men and women with T2D; moreover, low adherence to and persistence of long-term drug treatment is more common among women. A better understanding of sex- and gender-related differences in this field would provide an opportunity for a tailored diagnostic and therapeutic approach to the management of T2D subjects with chronic liver disease. In this narrative review, we summarized available data on sex- and gender-related differences in chronic liver disease, including metabolic, autoimmune, alcoholic and virus-related forms and their potential evolution towards cirrhosis and/or hepatocarcinoma in T2D subjects, to support their appropriate and personalized clinical management.
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Affiliation(s)
- Anna Licata
- Internal Medicine & Hepatology Unit, University Hospital of Palermo, PROMISE, University of Palermo, 90127 Palermo, Italy
| | - Giuseppina T Russo
- Internal Medicine and Diabetology Unit, University of Messina, 98125 Messina, Italy
| | - Annalisa Giandalia
- Internal Medicine and Hepatology Unit, University Hospital of Messina, 98124 Messina, Italy
- Department of Clinical and Experimental Medicine, University of Messina, 98124 Messina, Italy
| | - Marcella Cammilleri
- Internal Medicine & Hepatology Unit, University Hospital of Palermo, PROMISE, University of Palermo, 90127 Palermo, Italy
| | - Clelia Asero
- Internal Medicine and Hepatology Unit, University Hospital of Messina, 98124 Messina, Italy
- Department of Clinical and Experimental Medicine, University of Messina, 98124 Messina, Italy
| | - Irene Cacciola
- Internal Medicine and Hepatology Unit, University Hospital of Messina, 98124 Messina, Italy
- Department of Clinical and Experimental Medicine, University of Messina, 98124 Messina, Italy
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20
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Bitto N, Ghigliazza G, Lavorato S, Caputo C, La Mura V. Improving Management of Portal Hypertension: The Potential Benefit of Non-Etiological Therapies in Cirrhosis. J Clin Med 2023; 12:jcm12030934. [PMID: 36769582 PMCID: PMC9917703 DOI: 10.3390/jcm12030934] [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: 12/30/2022] [Revised: 01/17/2023] [Accepted: 01/20/2023] [Indexed: 01/27/2023] Open
Abstract
Portal hypertension is the consequence of cirrhosis and results from increased sinusoidal vascular resistance and hepatic blood inflow. Etiological therapies represent the first intervention to prevent a significant increase in portal pressure due to chronic liver damage. However, other superimposed pathophysiological drivers may worsen liver disease, including inflammation, bacterial translocation, endothelial dysfunction, and hyperactivation of hemostasis. These mechanisms can be targeted by a specific class of drugs already used in clinical practice. Albumin, rifaximin, statins, aspirin, and anticoagulants have been tested in cirrhosis and were a topic of discussion in the last Baveno consensus as non-etiological therapies. Based on the pathogenesis of portal hypertension in cirrhosis, our review summarizes the main mechanisms targeted by these drugs as well as the clinical evidence that considers them a valid complementary option to manage patients with cirrhosis and portal hypertension.
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Affiliation(s)
- Niccolò Bitto
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, 20122 Milan, Italy
| | - Gabriele Ghigliazza
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Division of Sub-Intensive Care Medicine, 20122 Milan, Italy
| | - Stanislao Lavorato
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, 20122 Milan, Italy
| | - Camilla Caputo
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, 20122 Milan, Italy
| | - Vincenzo La Mura
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, 20122 Milan, Italy
- Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy
- Correspondence:
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21
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Guo T, Wantono C, Tan Y, Deng F, Duan T, Liu D. Regulators, functions, and mechanotransduction pathways of matrix stiffness in hepatic disease. Front Physiol 2023; 14:1098129. [PMID: 36711017 PMCID: PMC9878334 DOI: 10.3389/fphys.2023.1098129] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 01/06/2023] [Indexed: 01/15/2023] Open
Abstract
The extracellular matrix (ECM) provides physical support and imparts significant biochemical and mechanical cues to cells. Matrix stiffening is a hallmark of liver fibrosis and is associated with many hepatic diseases, especially liver cirrhosis and carcinoma. Increased matrix stiffness is not only a consequence of liver fibrosis but is also recognized as an active driver in the progression of fibrotic hepatic disease. In this article, we provide a comprehensive view of the role of matrix stiffness in the pathological progression of hepatic disease. The regulators that modulate matrix stiffness including ECM components, MMPs, and crosslinking modifications are discussed. The latest advances of the research on the matrix mechanics in regulating intercellular signaling and cell phenotype are classified, especially for hepatic stellate cells, hepatocytes, and immunocytes. The molecular mechanism that sensing and transducing mechanical signaling is highlighted. The current progress of ECM stiffness's role in hepatic cirrhosis and liver cancer is introduced and summarized. Finally, the recent trials targeting ECM stiffness for the treatment of liver disease are detailed.
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Affiliation(s)
- Ting Guo
- Department of Gastroenterology, The Second Xiangya Hospital of Central South University, Changsha, China,Research Center of Digestive Disease, Central South University, Changsha, China
| | - Cindy Wantono
- Department of Gastroenterology, The Second Xiangya Hospital of Central South University, Changsha, China,Research Center of Digestive Disease, Central South University, Changsha, China
| | - Yuyong Tan
- Department of Gastroenterology, The Second Xiangya Hospital of Central South University, Changsha, China,Research Center of Digestive Disease, Central South University, Changsha, China
| | - Feihong Deng
- Department of Gastroenterology, The Second Xiangya Hospital of Central South University, Changsha, China,Research Center of Digestive Disease, Central South University, Changsha, China
| | - Tianying Duan
- Department of Gastroenterology, The Second Xiangya Hospital of Central South University, Changsha, China,Research Center of Digestive Disease, Central South University, Changsha, China
| | - Deliang Liu
- Department of Gastroenterology, The Second Xiangya Hospital of Central South University, Changsha, China,Research Center of Digestive Disease, Central South University, Changsha, China,*Correspondence: Deliang Liu,
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22
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Costa GS, Julião-Silva LS, Belo VS, de Oliveira HCF, Chaves VE. A systematic review and meta-analyses on the effects of atorvastatin on blood pressure and heart rate. EUROPEAN HEART JOURNAL. CARDIOVASCULAR PHARMACOTHERAPY 2022; 9:100-115. [PMID: 36138492 DOI: 10.1093/ehjcvp/pvac053] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 08/26/2022] [Accepted: 09/20/2022] [Indexed: 11/14/2022]
Abstract
AIMS Considering the inconsistencies in the literature on the atorvastatin effect on blood pressure (BP), we performed these meta-analyses. METHODS AND RESULTS Through a search of the Excerpta Medica Database (EMBASE), PubMed, and Web of Science databases, 1412 articles were identified, from which 33 randomized clinical trials (RCT) and 44 pre-clinical were selected. Populations from RCT were stratified according to baseline BP and lipid levels. We performed meta-analyses of the effect of atorvastatin on systolic (SBP), diastolic and mean BP; heart rate (HR); HR variability, and baroreflex. Atorvastatin reduced SBP in the overall population (P = 0.05 vs. placebo; P = 0.03 vs. baseline), in normotensive and hyperlipidaemic (P = 0.04 vs. placebo; P = 0.0001 vs. baseline) and in hypertensive and hyperlipidaemic (P = 0.02 vs. placebo; P = 0.008 vs. baseline) individuals in parallel RCT, but it did not affect SBP in normotensive and normolipidaemic individuals (P = 0.51 vs. placebo; P = 0.4 vs. baseline). Although an effect of atorvastatin was detected in hyperlipidaemic individuals, the meta-regression coefficient for the association of low density lipoprotein (LDL)-cholesterol reduction with SBP reduction in the overall population demonstrated that SBP reduction is not dependent on the changes in LDL-cholesterol. A meta-analysis of preclinical reports demonstrated that SBP was reduced in atorvastatin-treated hypertensive and normolipidaemic rats (spontaneously hypertensive rats: P < 0.00001), but not in normotensive and normolipidaemic rats (control rats: P = 0.97). Atorvastatin also reduced the HR in spontaneously hypertensive rat. CONCLUSION Atorvastatin lowers BP independent of LDL-cholesterol levels. Additional studies are needed to estimate the involvement of the autonomic nervous system in the BP-lowering effect of atorvastatin.
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Affiliation(s)
- Gabriel S Costa
- Laboratory of Physiology, Federal University of São João del-Rei, Avenue Sebastião Gonçalves Coelho, 400, 35.501-296, Divinópolis, Minas Gerais, Brazil
| | - Letícia S Julião-Silva
- Laboratory of Physiology, Federal University of São João del-Rei, Avenue Sebastião Gonçalves Coelho, 400, 35.501-296, Divinópolis, Minas Gerais, Brazil
| | - Vinícius S Belo
- Laboratory of Parasitology, Federal University of São João del-Rei, Avenue Sebastião Gonçalves Coelho, 400, 35.501-296, Divinópolis, Minas Gerais, Brazil
| | - Helena C F de Oliveira
- Department of Structural and Functional Biology, Biology Institute, State University of Campinas, Monteiro Lobato Street, 255, 13.083-862, Campinas, São Paulo, Brazil
| | - Valéria E Chaves
- Laboratory of Physiology, Federal University of São João del-Rei, Avenue Sebastião Gonçalves Coelho, 400, 35.501-296, Divinópolis, Minas Gerais, Brazil
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23
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Nonalcoholic Fatty Liver Disease and Chronic Kidney Disease: Epidemiology, Pathogenesis, and Clinical and Research Implications. Int J Mol Sci 2022; 23:ijms232113320. [PMID: 36362108 PMCID: PMC9654863 DOI: 10.3390/ijms232113320] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 10/25/2022] [Accepted: 10/28/2022] [Indexed: 11/06/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease worldwide, affecting up to ~30% of adult populations. NAFLD defines a spectrum of progressive liver conditions ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma, which often occur in close and bidirectional associations with metabolic disorders. Chronic kidney disease (CKD) is characterized by anatomic and/or functional renal damage, ultimately resulting in a reduced glomerular filtration rate. The physiological axis linking the liver and kidneys often passes unnoticed until clinically significant portal hypertension, as a major complication of cirrhosis, becomes apparent in the form of ascites, refractory ascites, or hepatorenal syndrome. However, the extensive evidence accumulated since 2008 indicates that noncirrhotic NAFLD is associated with a higher risk of incident CKD, independent of obesity, type 2 diabetes, and other common renal risk factors. In addition, subclinical portal hypertension has been demonstrated to occur in noncirrhotic NAFLD, with a potential adverse impact on renal vasoregulation. However, the mechanisms underlying this association remain unexplored to a substantial extent. With this background, in this review we discuss the current evidence showing a strong association between NAFLD and the risk of CKD, and the putative biological mechanisms underpinning this association. We also discuss in depth the potential pathogenic role of the hepatorenal reflex, which may be triggered by subclinical portal hypertension and is a poorly investigated but promising research topic. Finally, we address emerging pharmacotherapies for NAFLD that may also beneficially affect the risk of developing CKD in individuals with NAFLD.
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24
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Sakiani S, Heller T, Koh C. Current and investigational drugs in early clinical development for portal hypertension. Front Med (Lausanne) 2022; 9:974182. [PMID: 36300180 PMCID: PMC9589453 DOI: 10.3389/fmed.2022.974182] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 09/05/2022] [Indexed: 11/13/2022] Open
Abstract
Introduction The development of portal hypertension leads to a majority of complications associated with chronic liver disease. Therefore, adequate treatment of portal hypertension is crucial in the management of such patients. Current treatment options are limited and consist mainly of medications that decrease the hyperdynamic circulation, such as non-selective beta blockers, and treatment of hypervolemia with diuretics. Despite these options, mortality rates have not improved over the last two decades. Newer, more effective treatment options are necessary to help improve survival and quality of life in these patients. Areas covered Multiple preclinical models and clinical studies have demonstrated potential efficacy of a variety of new treatment modalities. We introduce treatment options including the use of vasodilation promotors, vasoconstriction inhibitors, anticoagulants, antiangiogenics, and anti-inflammatory drugs. We examine the most recent studies for treatment options within these drug classes and offer insights as to which show the most promise in this field. Methodology Published studies that identified novel medical treatment options of portal hypertension were searched using PubMed (https://pubmed.ncbi.nlm.nih.gov/). Clinical trials listed in Clinicaltrials.gov were also searched with a focus on more recent and ongoing studies, including those with completed recruitment. Searching with key terms including "portal hypertension" as well as individually searching specific treatment medications that were listed in other publications was carried out. Finally, current societal guidelines and recent review articles relevant to the management of portal hypertension were evaluated, and listed references of interest were included. Conclusion Many ongoing early phase studies demonstrate promising results and may shape the field of portal hypertension management in future. As concrete results become available, larger RCTs will be required before making definitive conclusions regarding safety and efficacy and whether or not they can be incorporated into routine clinical practice. Statins, anticoagulants, and PDE inhibitors have been among the most studied and appear to be most promising.
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Affiliation(s)
- Sasan Sakiani
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Baltimore, MD, United States
| | - Theo Heller
- Liver Diseases Branch, Division of Intramural Research, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Christopher Koh
- Liver Diseases Branch, Division of Intramural Research, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
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25
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Niaz Q, Tavangar SM, Mehreen S, Ghazi-Khansari M, Jazaeri F. Evaluation of statins as a new therapy to alleviate chronotropic dysfunction in cirrhotic rats. Life Sci 2022; 308:120966. [PMID: 36150464 DOI: 10.1016/j.lfs.2022.120966] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 09/06/2022] [Accepted: 09/12/2022] [Indexed: 11/28/2022]
Abstract
AIMS Liver cirrhosis defines by regenerative nodules and fibrotic septa, causing a complication called cirrhotic cardiomyopathy (CCM) with chronotropic hypo-responsiveness. In addition to lowering cholesterol levels, statins yield antioxidant and anti-inflammatory effects. In liver diseases animal models, statins have been shown to decrease hepatic inflammation, fibrogenesis, and portal pressure (PP). Therefore, we evaluated the atorvastatin effect on the heart in cirrhotic rats. MATERIALS AND METHODS Bile duct ligation (BDL) or sham operation performed on male Wistar rats and grouped as cirrhotic; BDL/Saline, BDL/Ator-7d(days) (Atorvastatin 15 mg/kg/day), and BDL/Ator-14d groups, or control; Sham/Saline, Sham/Ator-7d, and Sham/Ator-14d groups. Corrected QT interval (QTc interval), chronotropic responses, serum brain natriuretic peptides (BNP), heart tumor necrosis factor-α (TNF-α), nuclear factor erythroid 2-related factor 2 (Nrf2), and malondialdehyde (MDA) levels were studied along with atrial Ras homolog family member A (RhoA) and endothelial nitric oxide synthase (eNOS) gene expression. KEY FINDINGS The chronotropic responses decreased in BDL/Saline and increased in BDL/Ator-7d group. The QTc interval, BNP, TNF-α, and MDA levels increased in BDL/Saline and decreased in BDL/Ator-14d group. The Nrf2 level did not change in BDL/Saline and increased in BDL/Ator-14d group. The liver inflammation and fibrosis increased in BDL/Saline and did not affect BDL/Ator-7d and BDL/Ator-14d groups. The RhoA expression was down-regulated in BDL/Saline, BDL/Ator-7d, and BDL/Ator-14d groups. The eNOS expression did not change in BDL/Saline and down-regulated in BDL/Ator-14d group. SIGNIFICANCE Atorvastatin alleviates the chronotropic hypo-responsiveness and down-regulates the atrial RhoA and eNOS gene expression along with anti-inflammatory, antioxidant, and anti-stress effects in CCM.
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Affiliation(s)
- Qamar Niaz
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology and Toxicology, Faculty of Bio-Sciences, University of Veterinary and Animal Sciences, Lahore, Pakistan
| | - Seyed Mohammad Tavangar
- Department of Pathology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Sania Mehreen
- Department of Zoology, Faculty of Fisheries and Wildlife, University of Veterinary and Animal Sciences, Lahore, Pakistan
| | - Mahmoud Ghazi-Khansari
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Farahnaz Jazaeri
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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26
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Nasiri-Ansari N, Androutsakos T, Flessa CM, Kyrou I, Siasos G, Randeva HS, Kassi E, Papavassiliou AG. Endothelial Cell Dysfunction and Nonalcoholic Fatty Liver Disease (NAFLD): A Concise Review. Cells 2022; 11:2511. [PMID: 36010588 PMCID: PMC9407007 DOI: 10.3390/cells11162511] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 08/07/2022] [Accepted: 08/10/2022] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide. It is strongly associated with obesity, type 2 diabetes (T2DM), and other metabolic syndrome features. Reflecting the underlying pathogenesis and the cardiometabolic disorders associated with NAFLD, the term metabolic (dysfunction)-associated fatty liver disease (MAFLD) has recently been proposed. Indeed, over the past few years, growing evidence supports a strong correlation between NAFLD and increased cardiovascular disease (CVD) risk, independent of the presence of diabetes, hypertension, and obesity. This implies that NAFLD may also be directly involved in the pathogenesis of CVD. Notably, liver sinusoidal endothelial cell (LSEC) dysfunction appears to be implicated in the progression of NAFLD via numerous mechanisms, including the regulation of the inflammatory process, hepatic stellate activation, augmented vascular resistance, and the distortion of microcirculation, resulting in the progression of NAFLD. Vice versa, the liver secretes inflammatory molecules that are considered pro-atherogenic and may contribute to vascular endothelial dysfunction, resulting in atherosclerosis and CVD. In this review, we provide current evidence supporting the role of endothelial cell dysfunction in the pathogenesis of NAFLD and NAFLD-associated atherosclerosis. Endothelial cells could thus represent a "golden target" for the development of new treatment strategies for NAFLD and its comorbid CVD.
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Affiliation(s)
- Narjes Nasiri-Ansari
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Theodoros Androutsakos
- Department of Pathophysiology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Christina-Maria Flessa
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
| | - Ioannis Kyrou
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
- Laboratory of Dietetics and Quality of Life, Department of Food Science and Human Nutrition, School of Food and Nutritional Sciences, Agricultural University of Athens, 11855 Athens, Greece
| | - Gerasimos Siasos
- Third Department of Cardiology, ‘Sotiria’ Thoracic Diseases General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Harpal S. Randeva
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
| | - Eva Kassi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Endocrine Unit, 1st Department of Propaedeutic Internal Medicine, ‘Laiko’ General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Athanasios G. Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
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27
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Wasim R, Ansari TM, Ahsan F, Siddiqui MH, Singh A, Shariq M, Parveen S. Pleiotropic Benefits of Statins in Cardiovascular Diseases. Drug Res (Stuttg) 2022; 72:477-486. [PMID: 35868336 DOI: 10.1055/a-1873-1978] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
In 1976, Japanese microbiologist Akira Endo discovered the first statin as a product of the fungus Penicillium citrinum that inhibited the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Their primary mode of action is to lower the blood cholesterol by decreasing hepatic cholesterol production, which upregulates hepatic low-density lipoprotein (LDL) receptors and increases LDL-cholesterol clearance. In addition to cholesterol lowering, statins inhibit other downstream products of the mevalonate pathway, causing the so-called pleiotropic effects. As a result of their pleiotropic effects statins modulate virtually all known processes of atherosclerosis and have beneficial effects outside the cardiovascular system Statins inhibit the post-translational prenylation of small GTP-binding proteins such as Rho, Rac, as well as their downstream effectors such as Rho kinase and nicotinamide adenine dinucleotide phosphate oxidases since they suppress the synthesis of isoprenoid intermediates in the cholesterol biosynthetic pathway altering the expression of endothelial nitric oxide synthase, the stability of atherosclerotic plaques, production of proinflammatory cytokines, reactive oxygen species, platelet reactivity, development of cardiac hypertrophy and fibrosis in cell culture and animal experiments. Inhibition of Rho and Rho-associated coiled-coil containing protein kinase (ROCK), has emerged as the principle mechanisms underlying the pleiotropic effects of statins. However, the relative contributions of statin pleiotropy to clinical outcomes are debatable and difficult to measure because the amount of isoprenoid inhibition by statins corresponds to some extent with the amount of LDL-cholesterol decrease. This article examines some of the existing molecular explanations underlying statin pleiotropy and discusses if they have clinical relevance in cardiovascular diseases.
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Affiliation(s)
- Rufaida Wasim
- Department of Pharmacology, Faculty of Pharmacy, Integral University, Lucknow, India
| | | | - Farogh Ahsan
- Department of Pharmacology, Faculty of Pharmacy, Integral University, Lucknow, India
| | | | - Aditya Singh
- Department of Pharmacology, Faculty of Pharmacy, Integral University, Lucknow, India
| | - Mohammad Shariq
- Department of Pharmacology, Faculty of Pharmacy, Integral University, Lucknow, India
| | - Saba Parveen
- Department of Pharmacology, Faculty of Pharmacy, Integral University, Lucknow, India
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28
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Abbas N, Rajoriya N, Elsharkawy AM, Chauhan A. Acute-on-chronic liver failure (ACLF) in 2022: have novel treatment paradigms already arrived? Expert Rev Gastroenterol Hepatol 2022; 16:639-652. [PMID: 35786130 DOI: 10.1080/17474124.2022.2097070] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Acute-on-chronic failure (ACLF) is a recognized syndrome in patients with chronic liver disease and is characterized by acute decompensation, organ failure(s), and a high short-term mortality. ACLF is often triggered by ongoing alcohol consumption, gastrointestinal bleeding and/or infections, and is pathophysiologically characterized by uncontrolled systemic inflammation coupled with paradoxical immunoparesis. Patients with ACLF require prompt and early recognition. Management requires extensive utilization of clinical resources often including escalation to intensive care. AREAS COVERED Currently, there are no specific targeted treatments for established ACLF, and management revolves around treating underlying precipitants and providing organ support. In this article, we review the epidemiology and pathophysiology of ACLF and summarize recent advances in management strategies of this syndrome, focusing specifically on novel emerging therapies. EXPERT COMMENTARY ACLF is a challenging condition with rapid clinical course, high short-term mortality and varying clinical phenotypes. Management of ACLF is broadly focused on supportive care often in an intensive care setting with liver transplantation proving to be an increasingly relevant and effective rescue therapy. This disease has clear pathogenesis and epidemiological burden, thus distinguishing it from decompensated cirrhosis; there is clear clinical need for the development of specific and nuanced therapies to treat this condition.
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Affiliation(s)
- Nadir Abbas
- Liver Unit, Queen Elizabeth Hospital, Birmingham, UK.,Centre for Liver Research, Institute of Immunology and Inflammation, and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, the Medical School, University of Birmingham, Birmingham, UK.,National Institute for Health Research Biomedical Research Centre, University Hospitals Birmingham, Birmingham, UK
| | - Neil Rajoriya
- Liver Unit, Queen Elizabeth Hospital, Birmingham, UK.,Centre for Liver Research, Institute of Immunology and Inflammation, and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, the Medical School, University of Birmingham, Birmingham, UK
| | - Ahmed M Elsharkawy
- Liver Unit, Queen Elizabeth Hospital, Birmingham, UK.,Centre for Liver Research, Institute of Immunology and Inflammation, and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, the Medical School, University of Birmingham, Birmingham, UK.,National Institute for Health Research Biomedical Research Centre, University Hospitals Birmingham, Birmingham, UK
| | - Abhishek Chauhan
- Liver Unit, Queen Elizabeth Hospital, Birmingham, UK.,Centre for Liver Research, Institute of Immunology and Inflammation, and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, the Medical School, University of Birmingham, Birmingham, UK
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29
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Du W, Wang L. The Crosstalk Between Liver Sinusoidal Endothelial Cells and Hepatic Microenvironment in NASH Related Liver Fibrosis. Front Immunol 2022; 13:936196. [PMID: 35837401 PMCID: PMC9274003 DOI: 10.3389/fimmu.2022.936196] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 06/03/2022] [Indexed: 11/13/2022] Open
Abstract
Chronic liver injury can be caused by many factors, including virus infection, alcohol intake, cholestasis and abnormal fat accumulation. Nonalcoholic steatohepatitis (NASH) has become the main cause of liver fibrosis worldwide. Recently, more and more evidences show that hepatic microenvironment is involved in the pathophysiological process of liver fibrosis induced by NASH. Hepatic microenvironment consists of various types of cells and intercellular crosstalk among different cells in the liver sinusoids. Liver sinusoidal endothelial cells (LSECs), as the gatekeeper of liver microenvironment, play an irreplaceable role in the homeostasis and alterations of liver microenvironment. Many recent studies have reported that during the progression of NASH to liver fibrosis, LSECs are involved in various stages mediated by a series of mechanisms. Therefore, here we review the key role of crosstalk between LSECs and hepatic microenvironment in the progression of NASH to liver fibrosis (steatosis, inflammation, and fibrosis), as well as promising therapeutic strategies targeting LSECs.
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Affiliation(s)
- Wei Du
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Lin Wang
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, The Fourth Military Medical University, Xi'an, China
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30
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Lin C, Yu B, Chen L, Zhang Z, Ye W, Zhong H, Bai W, Yang Y, Nie B. Obeticholic Acid Induces Hepatoxicity Via FXR in the NAFLD Mice. Front Pharmacol 2022; 13:880508. [PMID: 35614939 PMCID: PMC9124937 DOI: 10.3389/fphar.2022.880508] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Accepted: 04/25/2022] [Indexed: 11/13/2022] Open
Abstract
Objective: Obeticholic acid (OCA), a potent farnesoid X receptor (FXR) agonist, is a promising drug for nonalcoholic fatty liver disease (NAFLD); however, it can cause liver injury, especially at high doses. Here, we investigated the role of FXR in the high-dose OCA-induced hepatoxicity in the condition of the NAFLD mouse model. Methods: Wild-type (WT) mice and FXR−/− mice were administered with over-dose OCA (0.40%) and high-dose OCA (0.16%), in a high-fat diet. RNA-seq on liver samples of mice fed with high-dose OCA was performed to dig out the prominent biological events contributing to hepatic fibrosis. Results: Over-dose OCA induced liver injury and shortened survival in WT mice, but not FXR−/− mice. High-dose OCA caused hepatic stellate cell activation and liver fibrosis in the presence of FXR. Furthermore, high-dose OCA induced cholesterol accumulation in livers via the upregulation of genes involved in cholesterol acquisition and downregulation of genes regulating cholesterol degradation in liver, leading to the production of interleukin -1β and an FXR-mediated inflammatory response. Conclusion: The high-dose OCA induced FXR-dependent hepatic injury via cholesterol accumulation and interleukin -1β pathway in the NAFLD mice.
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Affiliation(s)
- Chuangzhen Lin
- Department of Gastroenterology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
| | - Bingqing Yu
- Department of Gastroenterology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
| | - Lixin Chen
- Department of Gastroenterology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
| | - Zhaohui Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
| | - Weixiang Ye
- Department of Gastrointestinal Endoscopy of Dongpu Branch, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
| | - Hui Zhong
- Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Wenke Bai
- Department of Gastroenterology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
| | - Yuping Yang
- Department of Gastroenterology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
| | - Biao Nie
- Department of Gastroenterology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
- *Correspondence: Biao Nie,
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31
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Li H. Intercellular crosstalk of liver sinusoidal endothelial cells in liver fibrosis, cirrhosis and hepatocellular carcinoma. Dig Liver Dis 2022; 54:598-613. [PMID: 34344577 DOI: 10.1016/j.dld.2021.07.006] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 07/09/2021] [Accepted: 07/12/2021] [Indexed: 12/12/2022]
Abstract
Intercellular crosstalk among various liver cells plays an important role in liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Capillarization of liver sinusoidal endothelial cells (LSECs) precedes fibrosis and accumulating evidence suggests that the crosstalk between LSECs and other liver cells is critical in the development and progression of liver fibrosis. LSECs dysfunction, a key event in the progression from fibrosis to cirrhosis, and subsequently obstruction of hepatic sinuses and increased intrahepatic vascular resistance (IHVR) contribute to development of portal hypertension (PHT) and cirrhosis. More importantly, immunosuppressive tumor microenvironment (TME), which is closely related to the crosstalk between LSECs and immune liver cells like CD8+ T cells, promotes advances tumorigenesis, especially HCC. However, the connections within the crosstalk between LSECs and other liver cells during the progression from liver fibrosis to cirrhosis to HCC have yet to be discussed. In this review, we first summarize the current knowledge of how different crosstalk between LSECs and other liver cells, including hepatocytes, hepatic stellate cells (HSCs), macrophoges, immune cells in liver and extra cellular matrix (ECM) contribute to the physiological function and the progrssion from liver fibrosis to cirrhosis, or even to HCC. Then we examine current treatment strategies for LSECs crosstalk in liver fibrosis, cirrhosis and HCC.
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Affiliation(s)
- Hui Li
- Central Laboratory, Hospital of Chengdu University of Traditional Chinese Medicine, NO. 39 Shi-er-qiao Road, Chengdu, 610072, Sichuan Province, PR China.
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Wegner E, Slotina E, Mickan T, Truffel S, Arand C, Wagner D, Ritz U, Rommens PM, Gercek E, Drees P, Baranowski A. Pleiotropic Long-Term Effects of Atorvastatin on Posttraumatic Joint Contracture in a Rat Model. Pharmaceutics 2022; 14:pharmaceutics14030523. [PMID: 35335899 PMCID: PMC8950153 DOI: 10.3390/pharmaceutics14030523] [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: 01/15/2022] [Revised: 02/18/2022] [Accepted: 02/25/2022] [Indexed: 11/19/2022] Open
Abstract
The antifibrotic effect of atorvastatin has already been demonstrated in several organ systems. In the present study, a rat model was used to investigate the effect of atorvastatin on posttraumatic joint contracture. Forty-eight Sprague Dawley rats were equally randomized into an atorvastatin group and a control group. After initial joint trauma, knee joints were immobilized for intervals of 2 weeks (n = 16) or 4 weeks (n = 16) or immobilized for 4 weeks with subsequent remobilization for another 4 weeks (n = 16). Starting from the day of surgery, animals received either atorvastatin or placebo daily. After euthanasia at week 2, 4 or 8, joint contracture was determined, histological examinations were performed, and gene expression was assessed. The results suggest that the joint contracture was primarily arthrogenic. Atorvastatin failed to significantly affect contracture formation and showed a reduction in myofibroblast numbers to 98 ± 58 (control: 319 ± 113, p < 0.01) and a reduction in joint capsule collagen to 60 ± 8% (control: 73 ± 9%, p < 0.05) at week 2. Gene expression of α-smooth muscle actin (α-SMA), collagen type I, transforming growth factor β1 (TGF-β1) and interleukin-6 (IL-6) was not significantly affected by atorvastatin. Atorvastatin decreases myofibroblast number and collagen deposition but does not result in an improvement in joint mobility.
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Liedtke C, Nevzorova YA, Luedde T, Zimmermann H, Kroy D, Strnad P, Berres ML, Bernhagen J, Tacke F, Nattermann J, Spengler U, Sauerbruch T, Wree A, Abdullah Z, Tolba RH, Trebicka J, Lammers T, Trautwein C, Weiskirchen R. Liver Fibrosis-From Mechanisms of Injury to Modulation of Disease. Front Med (Lausanne) 2022; 8:814496. [PMID: 35087852 PMCID: PMC8787129 DOI: 10.3389/fmed.2021.814496] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Accepted: 12/15/2021] [Indexed: 12/12/2022] Open
Abstract
The Transregional Collaborative Research Center "Organ Fibrosis: From Mechanisms of Injury to Modulation of Disease" (referred to as SFB/TRR57) was funded for 13 years (2009-2021) by the German Research Council (DFG). This consortium was hosted by the Medical Schools of the RWTH Aachen University and Bonn University in Germany. The SFB/TRR57 implemented combined basic and clinical research to achieve detailed knowledge in three selected key questions: (i) What are the relevant mechanisms and signal pathways required for initiating organ fibrosis? (ii) Which immunological mechanisms and molecules contribute to organ fibrosis? and (iii) How can organ fibrosis be modulated, e.g., by interventional strategies including imaging and pharmacological approaches? In this review we will summarize the liver-related key findings of this consortium gained within the last 12 years on these three aspects of liver fibrogenesis. We will highlight the role of cell death and cell cycle pathways as well as nutritional and iron-related mechanisms for liver fibrosis initiation. Moreover, we will define and characterize the major immune cell compartments relevant for liver fibrogenesis, and finally point to potential signaling pathways and pharmacological targets that turned out to be suitable to develop novel approaches for improved therapy and diagnosis of liver fibrosis. In summary, this review will provide a comprehensive overview about the knowledge on liver fibrogenesis and its potential therapy gained by the SFB/TRR57 consortium within the last decade. The kidney-related research results obtained by the same consortium are highlighted in an article published back-to-back in Frontiers in Medicine.
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Affiliation(s)
- Christian Liedtke
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Yulia A. Nevzorova
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
- Department of Immunology, Ophthalmology and Otolaryngology, School of Medicine, Complutense University Madrid, Madrid, Spain
| | - Tom Luedde
- Medical Faculty, Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Duesseldorf, Heinrich Heine University, Duesseldorf, Germany
| | - Henning Zimmermann
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Daniela Kroy
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Pavel Strnad
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Marie-Luise Berres
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Jürgen Bernhagen
- Chair of Vascular Biology, Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München (KUM), Ludwig-Maximilians-University (LMU), Munich, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany
| | - Jacob Nattermann
- Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany
| | - Ulrich Spengler
- Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany
| | - Tilman Sauerbruch
- Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany
| | - Alexander Wree
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany
| | - Zeinab Abdullah
- Institute for Molecular Medicine and Experimental Immunology, University Hospital of Bonn, Bonn, Germany
| | - René H. Tolba
- Institute for Laboratory Animal Science and Experimental Surgery, RWTH Aachen University Hospital, Aachen, Germany
| | - Jonel Trebicka
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt, Germany
| | - Twan Lammers
- Institute for Experimental Molecular Imaging, RWTH Aachen University Hospital, Aachen, Germany
| | - Christian Trautwein
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), University Hospital RWTH Aachen, Aachen, Germany
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Pollo-Flores P, Trebicka J. Statins After Variceal Bleeding Are Beneficial, but Still an Unexplained Mystery? Gastroenterology 2021; 161:2067-2068. [PMID: 34464629 DOI: 10.1053/j.gastro.2017.01.065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Accepted: 01/09/2017] [Indexed: 12/02/2022]
Affiliation(s)
- Priscilla Pollo-Flores
- Internal Medicine Department, Fluminense Federal University, Niteroi, Rio de Janeiro, Brazil; Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brazil
| | - Jonel Trebicka
- Department of Internal Medicine I, Goethe University Frankfurt, Frankfurt, Germany; Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark; European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain
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Francis P, Forman LM. Statins Show Promise Against Progression of Liver Disease. Clin Liver Dis (Hoboken) 2021; 18:280-287. [PMID: 34976372 PMCID: PMC8688902 DOI: 10.1002/cld.1143] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Revised: 04/28/2021] [Accepted: 05/05/2021] [Indexed: 02/04/2023] Open
Abstract
Content available: Audio Recording.
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Affiliation(s)
- Prashanth Francis
- Division of Gastroenterology and HepatologyUniversity of ColoradoAuroraCO
| | - Lisa M. Forman
- Division of Gastroenterology and HepatologyUniversity of ColoradoAuroraCO
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The Hepatic Sinusoid in Chronic Liver Disease: The Optimal Milieu for Cancer. Cancers (Basel) 2021; 13:cancers13225719. [PMID: 34830874 PMCID: PMC8616349 DOI: 10.3390/cancers13225719] [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: 10/15/2021] [Revised: 11/08/2021] [Accepted: 11/11/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary During the development of chronic liver disease, the hepatic sinusoid undergoes major changes that further compromise the hepatic function, inducing persistent inflammation and the formation of scar tissue, together with alterations in liver hemodynamics. This diseased background may induce the formation and development of hepatocellular carcinoma (HCC), which is the most common form of primary liver cancer and a major cause of mortality. In this review, we describe the ways in which the dysregulation of hepatic sinusoidal cells—including liver sinusoidal cells, Kupffer cells, and hepatic stellate cells—may have an important role in the development of HCC. Our review summarizes all of the known sinusoidal processes in both health and disease, and possible treatments focusing on the dysregulation of the sinusoid; finally, we discuss how some of these alterations occurring during chronic injury are shared with the pathology of HCC and may contribute to its development. Abstract The liver sinusoids are a unique type of microvascular beds. The specialized phenotype of sinusoidal cells is essential for their communication, and for the function of all hepatic cell types, including hepatocytes. Liver sinusoidal endothelial cells (LSECs) conform the inner layer of the sinusoids, which is permeable due to the fenestrae across the cytoplasm; hepatic stellate cells (HSCs) surround LSECs, regulate the vascular tone, and synthetize the extracellular matrix, and Kupffer cells (KCs) are the liver-resident macrophages. Upon injury, the harmonic equilibrium in sinusoidal communication is disrupted, leading to phenotypic alterations that may affect the function of the whole liver if the damage persists. Understanding how the specialized sinusoidal cells work in coordination with each other in healthy livers and chronic liver disease is of the utmost importance for the discovery of new therapeutic targets and the design of novel pharmacological strategies. In this manuscript, we summarize the current knowledge on the role of sinusoidal cells and their communication both in health and chronic liver diseases, and their potential pharmacologic modulation. Finally, we discuss how alterations occurring during chronic injury may contribute to the development of hepatocellular carcinoma, which is usually developed in the background of chronic liver disease.
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Chiu WC, Shan JC, Yang YH, Chen VCH, Chen PC. Statins and the risks of decompensated liver cirrhosis and hepatocellular carcinoma determined in patients with alcohol use disorder. Drug Alcohol Depend 2021; 228:109096. [PMID: 34600254 DOI: 10.1016/j.drugalcdep.2021.109096] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 08/12/2021] [Accepted: 08/28/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND Alcohol-related liver disease (ALD) is the most common cause of liver disease. No medication can improve ALD and abstinence from alcohol is the sole effective strategy. Statin use has been demonstrated to have protective effects against liver cirrhosis and hepatocellular carcinoma (HCC) in patients with virus-related liver diseases. Whether statin use has a similar association among patients with alcohol use disorder (AUD) that can lead to ALD, is unknown. METHOD We conducted a population-based cohort study using Taiwan's National Health Insurance Research Database from 1997 to 2013 to compare risks of decompensated liver cirrhosis and hepatocellular carcinoma (HCC) between the statin exposed and unexposed groups in the patients with AUD. The incidence rates of decompensated liver cirrhosis and HCC were calculated between patients exposed and unexposed to statins with 1:4 propensity score matching. Cox proportional hazard regressions were performed to evaluate hazard ratios (HRs). RESULTS The incidence rates of decompensated liver cirrhosis and HCC in the statin-exposed group differed from those in the unexposed group (decompensated cirrhosis: 269.9 vs. 628.9 cases per 100,000 person-years; HCC: 116.7 vs. 318.3 cases per 100,000 person-years). The HRs for decompensated liver cirrhosis and HCC were 0.43 (95% CI, 0.37-0.51) and 0.40 (95% CI, 0.31-0.51), respectively, after adjustment. CONCLUSIONS Statin use was associated with reduced risk of decompensated liver cirrhosis and HCC among AUD patients in a cumulative dose effect manner. Statins might have some potential effects on mitigating ALD progression beside abstinence from alcohol. Further research is needed.
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Affiliation(s)
- Wei-Che Chiu
- Department of Psychiatry, Cathay General Hospital, Taipei, Taiwan; School of Medicine, Fu Jen Catholic University, Taipei, Taiwan
| | - Jia-Chi Shan
- Department of Psychiatry, Cathay General Hospital, Taipei, Taiwan; Department of Psychiatry, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
| | - Yao-Hsu Yang
- Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Chia-Yi, Taiwan; Center of Excellence for Chang Gung Research Datalink, Chang Gung Memorial Hospital, Chia-Yi, Taiwan; School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Vincent Chin-Hung Chen
- Department of Psychiatry, Chang Gung Medical Foundation, Chiayi Chang Gung Memorial Hospital, Chia-Yi, Taiwan; School of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Pau-Chung Chen
- Institute of Environmental and Occupational Health Sciences, National Taiwan University College of Public Health, Taipei, Taiwan; Department of Environmental and Occupational Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan; Department of Public Health, National Taiwan University College of Public Health, Taipei, Taiwan; National Institute of Environmental Health Sciences, National Health Research Institutes, Miaoli, Taiwan.
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Zaccherini G, Tufoni M, Bernardi M, Caraceni P. Prevention of Cirrhosis Complications: Looking for Potential Disease Modifying Agents. J Clin Med 2021; 10:4590. [PMID: 34640608 PMCID: PMC8509683 DOI: 10.3390/jcm10194590] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 09/29/2021] [Accepted: 10/04/2021] [Indexed: 02/07/2023] Open
Abstract
The current therapeutic strategies for the management of patients with cirrhosis rely on the prevention or treatment of specific complications. The removal of the causative agents (i.e., viruses or alcohol) prevents decompensation in the vast majority of patients with compensated cirrhosis. In contrast, even when etiological treatment has been effective, a significant proportion of patients with decompensated cirrhosis remains at risk of further disease progression. Therefore, therapies targeting specific key points in the complex pathophysiological cascade of decompensated cirrhosis could represent a new approach for the management of these severely ill patients. Some of the interventions currently employed for treating or preventing specific complications of cirrhosis or used in other diseases (i.e., poorly absorbable oral antibiotics, statins, albumin) have been proposed as potential disease-modifying agents in cirrhosis (DMAC) since clinical studies have shown their capacity of improving survival. Additional multicenter, large randomized clinical trials are awaited to confirm these promising results. Finally, new drugs able to antagonize key pathophysiological mechanisms are under pre-clinical development or at the initial stages of clinical assessment.
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Affiliation(s)
- Giacomo Zaccherini
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy; (G.Z.); (M.B.)
| | - Manuel Tufoni
- IRCCS AOU di Bologna—Policlinico di S. Orsola, 40138 Bologna, Italy;
| | - Mauro Bernardi
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy; (G.Z.); (M.B.)
| | - Paolo Caraceni
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy; (G.Z.); (M.B.)
- IRCCS AOU di Bologna—Policlinico di S. Orsola, 40138 Bologna, Italy;
- Center for Biomedical Applied Research, University of Bologna, 40138 Bologna, Italy
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Merkel M, Schneider C, Greinert R, Zipprich A, Ripoll C, Lammert F, Reichert MC. Protective Effects of Statin Therapy in Cirrhosis Are Limited by a Common SLCO1B1 Transporter Variant. Hepatol Commun 2021; 5:1755-1766. [PMID: 34558822 PMCID: PMC8485882 DOI: 10.1002/hep4.1753] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 04/30/2021] [Accepted: 05/06/2021] [Indexed: 12/14/2022] Open
Abstract
Complications of cirrhosis and portal hypertension (PH) can be reduced by statin therapy. The common loss-of-function variant p.V174A in the solute carrier organic anion transporter gene 1B1 (SLCO1B1) gene encoding the organic anion transporting polypeptide 1B1 results in decreased hepatic uptake of statins. Our specific aim was to assess the impact of this variant in patients with cirrhosis and statin treatment while controlling for the stage of cirrhosis and other potential confounders with propensity score matching (PSM), availing of a large cohort of genotyped study patients. In total, from 1,088 patients with cirrhosis in two German academic medical centers, PSM yielded 154 patients taking statins and 154 matched controls. The effect on PH was assessed by the liver stiffness-spleen size-to-platelet score (LSPS), and complications of cirrhosis were retrospectively recorded applying consensus criteria. As hypothesized, patients on statin treatment presented less frequently with signs of PH: Esophageal varices (41% vs. 62%; P < 0.001) were less common, and LSPS (4.8 ± 11.5 vs. 5.6 ± 6.4; P = 0.01) was reduced. Correspondingly, decompensation events were also reduced in patients on statins (odds ratio [OR] = 0.54, 95% confidence interval [CI] 0.32-0.90; P = 0.02). When the variant in SLCO1B1 was present in patients on statins, esophageal varices (OR = 2.68, 95% CI 1.24-5.81; P = 0.01) and bacterial infections (OR = 2.50, 95% CI 1.14-5.47; P = 0.02) were more common as compared with wild type carriers on statins. Conclusion: In this cohort, signs and complications of PH were reduced in patients with cirrhosis treated with statins. Notably, this effect was diminished by the common loss-of-function variant in SLCO1B1. Further prospective studies in independent cohorts are warranted to confirm these genotype-specific observations.
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Affiliation(s)
- Melissa Merkel
- Department of Medicine IISaarland University Medical CenterSaarland UniversityHomburgGermany
| | - Christina Schneider
- Department of Medicine IISaarland University Medical CenterSaarland UniversityHomburgGermany
| | - Robin Greinert
- Department of Medicine IMartin Luther University Halle‐WittenbergHalleGermany
| | - Alexander Zipprich
- Department of Medicine IMartin Luther University Halle‐WittenbergHalleGermany
| | - Cristina Ripoll
- Department of Medicine IMartin Luther University Halle‐WittenbergHalleGermany
| | - Frank Lammert
- Department of Medicine IISaarland University Medical CenterSaarland UniversityHomburgGermany
- Hannover Health Sciences CampusHannover Medical School (MHH)HannoverGermany
| | - Matthias C. Reichert
- Department of Medicine IISaarland University Medical CenterSaarland UniversityHomburgGermany
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Kreisel W, Lazaro A, Trebicka J, Grosse Perdekamp M, Schmitt-Graeff A, Deibert P. Cyclic GMP in Liver Cirrhosis-Role in Pathophysiology of Portal Hypertension and Therapeutic Implications. Int J Mol Sci 2021; 22:10372. [PMID: 34638713 PMCID: PMC8508925 DOI: 10.3390/ijms221910372] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 09/20/2021] [Accepted: 09/21/2021] [Indexed: 01/10/2023] Open
Abstract
The NO-cGMP signal transduction pathway plays a crucial role in tone regulation in hepatic sinusoids and peripheral blood vessels. In a cirrhotic liver, the key enzymes endothelial NO synthase (eNOS), soluble guanylate cyclase (sGC), and phosphodiesterase-5 (PDE-5) are overexpressed, leading to decreased cyclic guanosine-monophosphate (cGMP). This results in constriction of hepatic sinusoids, contributing about 30% of portal pressure. In contrast, in peripheral arteries, dilation prevails with excess cGMP due to low PDE-5. Both effects eventually lead to circulatory dysfunction in progressed liver cirrhosis. The conventional view of portal hypertension (PH) pathophysiology has been described using the "NO-paradox", referring to reduced NO availability inside the liver and elevated NO production in the peripheral systemic circulation. However, recent data suggest that an altered availability of cGMP could better elucidate the contrasting findings of intrahepatic vasoconstriction and peripheral systemic vasodilation than mere focus on NO availability. Preclinical and clinical data have demonstrated that targeting the NO-cGMP pathway in liver cirrhosis using PDE-5 inhibitors or sGC stimulators/activators decreases intrahepatic resistance through dilation of sinusoids, lowering portal pressure, and increasing portal venous blood flow. These results suggest further clinical applications in liver cirrhosis. Targeting the NO-cGMP system plays a role in possible reversal of liver fibrosis or cirrhosis. PDE-5 inhibitors may have therapeutic potential for hepatic encephalopathy. Serum/plasma levels of cGMP can be used as a non-invasive marker of clinically significant portal hypertension. This manuscript reviews new data about the role of the NO-cGMP signal transduction system in pathophysiology of cirrhotic portal hypertension and provides perspective for further studies.
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Affiliation(s)
- Wolfgang Kreisel
- Department of Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany
| | - Adhara Lazaro
- Institute for Exercise and Occupational Medicine, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany; (A.L.); (P.D.)
| | - Jonel Trebicka
- Translational Hepatology, Department of Internal Medicine I, Goethe University Clinic Frankfurt, 60590 Frankfurt, Germany;
| | - Markus Grosse Perdekamp
- Institute of Forensic Medicine, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany;
| | | | - Peter Deibert
- Institute for Exercise and Occupational Medicine, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany; (A.L.); (P.D.)
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Elshazly H, Zaghlah H, Tharwa ES, Abuamer A, Nor-Eldin D, El Sheemy R, El Kassas M. Survival benefits of adding simvastatin to standard therapy for secondary prevention of bleeding esophageal varices in patients with hepatitis C-related liver cirrhosis. EGYPTIAN LIVER JOURNAL 2021. [DOI: 10.1186/s43066-021-00143-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
The combination of endoscopic band ligation and beta-blockers is the standard of care treatment for secondary prevention of variceal bleeding; however, rebleeding still occurs with associated high mortality. Simvastatin (a lipid-lowering agent) was found to reduce portal hypertension and decrease hepatic fibrosis. This study aimed to assess the effect of adding simvastatin to the standard therapy to prevent variceal rebleeding and its impact on survival in patients with liver cirrhosis.
Results
This single-center randomized controlled clinical trial included 80 patients with cirrhosis receiving the standard secondary prophylaxis for variceal bleeding composed of endoscopic variceal ligation and non-selective β-blockers (either propranolol or carvedilol). Two weeks after the first attack of hematemesis, patients were randomized into two groups: group I who received the standard therapy (40 patients) and group II who administered simvastatin (20 mg daily for 2 weeks and 40 mg daily after that). Patients were followed up for 1 year. The primary endpoints were rebleeding and overall survival. Thirty patients of group I completed the study while ten patients died during the follow-up period. The simvastatin group showed a significantly better overall 1-year survival (3 deaths during follow-up) compared to the control group (37/40, 92.5% vs. 30/40; 75%) (p-value 0.034); however, this was lacking in Child C patients. No similar difference was present in rebleeding rates between the two groups (5/40, 12.5% vs. 3/40, 7.5%) (p-value 0.456) in groups I and II, respectively.
Conclusions
Adding simvastatin to the standard therapy in secondary prevention of variceal bleeding could be associated with survival benefits in patients with Child A and B cirrhosis, while was incapable of reducing rebleeding.
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Iwakiri Y, Trebicka J. Portal hypertension in cirrhosis: Pathophysiological mechanisms and therapy. JHEP Rep 2021; 3:100316. [PMID: 34337369 PMCID: PMC8318926 DOI: 10.1016/j.jhepr.2021.100316] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 04/19/2021] [Accepted: 05/12/2021] [Indexed: 12/14/2022] Open
Abstract
Portal hypertension, defined as increased pressure in the portal vein, develops as a consequence of increased intrahepatic vascular resistance due to the dysregulation of liver sinusoidal endothelial cells (LSECs) and hepatic stellate cells (HSCs), frequently arising from chronic liver diseases. Extrahepatic haemodynamic changes contribute to the aggravation of portal hypertension. The pathogenic complexity of portal hypertension and the unsuccessful translation of preclinical studies have impeded the development of effective therapeutics for patients with cirrhosis, while counteracting hepatic and extrahepatic mechanisms also pose a major obstacle to effective treatment. In this review article, we will discuss the following topics: i) cellular and molecular mechanisms of portal hypertension, focusing on dysregulation of LSECs, HSCs and hepatic microvascular thrombosis, as well as changes in the extrahepatic vasculature, since these are the major contributors to portal hypertension; ii) translational/clinical advances in our knowledge of portal hypertension; and iii) future directions.
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Key Words
- ACE2, angiogenesis-converting enzyme 2
- ACLF, acute-on-chronic liver failure
- AT1R, angiotensin II type I receptor
- CCL2, chemokine (C-C motif) ligand 2
- CCl4, carbon tetrachloride
- CLD, chronic liver disease
- CSPH, clinically significant portal hypertension
- Dll4, delta like canonical Notch ligand 4
- ECM, extracellular matrix
- EUS, endoscopic ultrasound
- FXR
- FXR, farnesoid X receptor
- HCC, hepatocellular carcinoma
- HRS, hepatorenal syndrome
- HSC
- HSCs, hepatic stellate cells
- HVPG, hepatic venous pressure gradient
- Hsp90, heat shock protein 90
- JAK2, Janus kinase 2
- KO, knockout
- LSEC
- LSEC, liver sinusoidal endothelial cells
- MLCP, myosin light-chain phosphatase
- NET, neutrophil extracellular trap
- NO
- NO, nitric oxide
- NSBB
- NSBBs, non-selective beta blockers
- PDE, phosphodiesterase
- PDGF, platelet-derived growth factor
- PIGF, placental growth factor
- PKG, cGMP-dependent protein kinase
- Rho-kinase
- TIPS
- TIPS, transjugular intrahepatic portosystemic shunt
- VCAM1, vascular cell adhesion molecule 1
- VEGF
- VEGF, vascular endothelial growth factor
- angiogenesis
- eNOS, endothelial nitric oxide synthase
- fibrosis
- liver stiffness
- statins
- β-Arr2, β-arrestin 2
- β1-AR, β1-adrenergic receptor
- β2-AR, β2-adrenergic receptor
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Affiliation(s)
- Yasuko Iwakiri
- Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Jonel Trebicka
- Translational Hepatology, Department of Internal Medicine I, University Clinic Frankfurt, Frankfurt, Germany
- European Foundation for the Study of Chronic Liver Failure-EF Clif, Barcelona, Spain
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43
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Sauerbruch T, Hennenberg M, Trebicka J, Beuers U. Bile Acids, Liver Cirrhosis, and Extrahepatic Vascular Dysfunction. Front Physiol 2021; 12:718783. [PMID: 34393832 PMCID: PMC8358446 DOI: 10.3389/fphys.2021.718783] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 06/29/2021] [Indexed: 12/12/2022] Open
Abstract
The bile acid pool with its individual bile acids (BA) is modulated in the enterohepatic circulation by the liver as the primary site of synthesis, the motility of the gallbladder and of the intestinal tract, as well as by bacterial enzymes in the intestine. The nuclear receptor farnesoid X receptor (FXR) and Gpbar1 (TGR5) are important set screws in this process. Bile acids have a vasodilatory effect, at least according to in vitro studies. The present review examines the question of the extent to which the increase in bile acids in plasma could be responsible for the hyperdynamic circulatory disturbance of liver cirrhosis and whether modulation of the bile acid pool, for example, via administration of ursodeoxycholic acid (UDCA) or via modulation of the dysbiosis present in liver cirrhosis could influence the hemodynamic disorder of liver cirrhosis. According to our analysis, the evidence for this is limited. Long-term studies on this question are lacking.
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Affiliation(s)
- Tilman Sauerbruch
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Martin Hennenberg
- Department of Urology I, University Hospital, LMU Munich, Munich, Germany
| | - Jonel Trebicka
- Translational Hepatology, Medical Department, University of Frankfurt, Frankfurt, Germany
| | - Ulrich Beuers
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, location AMC, Amsterdam, Netherlands
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44
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Muñoz AE, Pollarsky FD, Marino M, Cartier M, Vázquez H, Salgado P, Romero G. Addition of statins to the standard treatment in patients with cirrhosis: Safety and efficacy. World J Gastroenterol 2021; 27:4639-4652. [PMID: 34366626 PMCID: PMC8326251 DOI: 10.3748/wjg.v27.i28.4639] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 02/26/2021] [Accepted: 07/05/2021] [Indexed: 02/06/2023] Open
Abstract
This review summarizes the safety and efficacy of statins in patients with cirrhosis. Due to concerns about the safety of statins in patients with impaired liver function, they have recently been investigated as a potential treatment option in cirrhosis. The most clinically significant adverse event is statin-related myopathy, and this may be related to the high serum statin concentrations in the setting of severely impaired liver function. Rhabdomyolysis is the most serious and potentially life-threatening manifestation. It has recently been demonstrated that the recommended dose of simvastatin in patients with decompensated cirrhosis would be 20 mg/d because higher values, such as 40 mg/d, are associated with many adverse events, especially muscle injury. Likewise, simvastatin should not be administered to patients with Model for End-stage Liver Disease score > 12 and/or Child-Pugh class C because of the high risk of severe muscle injury. Due to the pleiotropic effects, the focus on statins has shifted from being considered harmful to something useful. Through these effects, statins could prevent liver-related morbidity and mortality in cirrhotic patients. Observational studies in large populations of patients with cirrhosis have shown that treatment with statins to decrease high cholesterol levels was associated with a reduced risk of hepatic decompensation, hepatocellular carcinoma development and death. The few randomized controlled trials in patients with cirrhosis and portal hypertension showed that statins lower portal pressure, quite likely through a reduction in hepatic resistance. Another large randomized controlled trial in patients with variceal bleeding showed that simvastatin in addition to standard of care did not prevent rebleeding but improved survival rate. Despite these encouraging outcomes, the quality of the evidence regarding the use of statins is low or very low due to the observational characteristics of most of the studies involved. Therefore, it is advisable to perform further randomized controlled trials on a large series of patients with hard clinical endpoints, using different statin types and varying doses. The objectives would be to prevent liver-related morbidity and mortality rather than treating cirrhosis complications to take additional information that makes it possible to add statins to the standard of care of these patients.
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Affiliation(s)
- Alberto E Muñoz
- Sección Hepatología, Hospital de Gastroenterología Dr. Carlos Bonorino Udaondo, Facultad de Medicina, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires 1264, Argentina
- Instituto de Investigaciones en Salud Pública, Facultad de Odontología, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires 1122, Argentina
| | - Florencia D Pollarsky
- Sección Hepatología, Hospital de Gastroenterología Dr. Carlos Bonorino Udaondo, Facultad de Medicina, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires 1264, Argentina
| | - Mónica Marino
- Sección Hepatología, Hospital de Gastroenterología Dr. Carlos Bonorino Udaondo, Facultad de Medicina, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires 1264, Argentina
| | - Mariano Cartier
- Sección Hepatología, Hospital de Gastroenterología Dr. Carlos Bonorino Udaondo, Facultad de Medicina, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires 1264, Argentina
| | - Horacio Vázquez
- Unidad Clínica, Hospital de Gastroenterología Dr. Carlos Bonorino Udaondo, Investigador Asociado del Gobierno de la Ciudad Autónoma de Buenos Aires, Ciudad Autónoma de Buenos Aires 1264, Argentina
| | - Pablo Salgado
- Instituto de Investigaciones en Salud Pública, Facultad de Odontología, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires 1122, Argentina
| | - Gustavo Romero
- Sección Hepatología, Hospital de Gastroenterología Dr. Carlos Bonorino Udaondo, Facultad de Medicina, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires 1264, Argentina
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45
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Vitiello A, Ferrara F. Plausible Positive Effects of Statins in COVID-19 Patient. Cardiovasc Toxicol 2021; 21:781-789. [PMID: 34255300 PMCID: PMC8275916 DOI: 10.1007/s12012-021-09674-x] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 07/07/2021] [Indexed: 01/08/2023]
Abstract
Since the onset of the global COVID-19 pandemic, there has been much discussion about the advantages and disadvantages of ongoing chronic drug therapies in SARS-CoV-2-positive patients. These discussions include also statins treatment. The statins are among the most widely used drugs in the global population. Statins aim to lower cholesterol, which is essential for many biological processes but can lead to heart disease if levels are too high; however, also the pleiotropic effects of statins are well known. So could the anti-inflammatory or the potential antiviral effects of statins be helpful in avoiding extreme inflammation and severity in COVID-19? To date, there are conflicting opinions on the effects of statins in the course of COVID-19 infection. The aim of this article is to describe the molecular and pharmacological basis of the pleiotropic effects of statins that could be more involved in the fight against COVID-19 infection and to investigate the current epidemiological evidence in the literature on the current and important topic.
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Affiliation(s)
- Antonio Vitiello
- Clinical Pharmacologist, Pharmaceutical Department, Usl Umbria 1, A.Migliorati street, 06132, Perugia, Italy
| | - Francesco Ferrara
- Hospital Pharmacist Manager, Pharmaceutical Department, Usl Umbria 1, A.Migliorati street, 06132, Perugia, Italy.
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46
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Caraceni P, Abraldes JG, Ginès P, Newsome PN, Sarin SK. The search for disease-modifying agents in decompensated cirrhosis: From drug repurposing to drug discovery. J Hepatol 2021; 75 Suppl 1:S118-S134. [PMID: 34039483 DOI: 10.1016/j.jhep.2021.01.024] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Revised: 01/14/2021] [Accepted: 01/15/2021] [Indexed: 02/06/2023]
Abstract
Patients with decompensated cirrhosis are currently managed through targeted strategies aimed at preventing or treating specific complications. In contrast, a disease-modifying agent should, by definition, be aimed at globally addressing 'decompensated cirrhosis'. To be defined as a disease-modifying agent in decompensated cirrhosis, interventions need to demonstrate an unequivocal benefit on the course of disease in well-designed and adequately powered randomised clinical trials with hard endpoints (i.e. patient survival). These trials also need to define the target population, dosage and timing of administration, factors guiding treatment, temporary or permanent stopping rules, transferability to daily clinical practice, cost-effectiveness, and global treatment access. By eliminating the underlying cause of cirrhosis, aetiologic treatments can still influence the course of decompensated disease by halting or slowing down disease progression or even inducing reversion to the compensated state. In contrast, there remains an unmet clinical need for disease-modifying agents which can antagonise key pathophysiological mechanisms of decompensated cirrhosis, such as portal hypertension, gut translocation, circulatory dysfunction, systemic inflammation, and immunological dysfunction. However, in the last few years, the repurposing of "old drugs" that have already been prescribed for more limited indications in hepatology or for other diseases has provided a few candidates, including human albumin, statins, and poorly absorbable oral antibiotics, which are under further evaluation in large-scale randomised clinical trials. New disease-modifying agents are also expected to be identified in the next decade through the systematic repurposing of existing drugs and the development of novel molecules which are currently undergoing pre-clinical or early clinical testing.
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Affiliation(s)
- Paolo Caraceni
- Division of Medical Semeiotics, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy; Department of Medical and Surgical Sciences and Center for Biomedical Applied Research, Alma Mater Studiorum University of Bologna, Italy.
| | - Juan G Abraldes
- Liver Unit, Division of Gastroenterology, University of Alberta, Canada
| | - Pere Ginès
- Hospital Clinic of Barcelona, University of Barcelona, IDIBAPS, CIBEReHD, Barcelona, Catalonia, Spain
| | - Phil N Newsome
- National Institute for Health Research Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, UK; Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, UK; Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Shiv K Sarin
- Hepatology, Institute of Liver and Biliary Sciences (ILBS), New Delhi, India
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47
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Engelmann C, Clària J, Szabo G, Bosch J, Bernardi M. Pathophysiology of decompensated cirrhosis: Portal hypertension, circulatory dysfunction, inflammation, metabolism and mitochondrial dysfunction. J Hepatol 2021; 75 Suppl 1:S49-S66. [PMID: 34039492 PMCID: PMC9272511 DOI: 10.1016/j.jhep.2021.01.002] [Citation(s) in RCA: 185] [Impact Index Per Article: 46.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 12/31/2020] [Accepted: 01/04/2021] [Indexed: 02/07/2023]
Abstract
Patients with acutely decompensated cirrhosis have a dismal prognosis and frequently progress to acute-on-chronic liver failure, which is characterised by hepatic and extrahepatic organ failure(s). The pathomechanisms involved in decompensation and disease progression are still not well understood, and as specific disease-modifying treatments do not exist, research to identify novel therapeutic targets is of the utmost importance. This review amalgamates the latest knowledge on disease mechanisms that lead to tissue injury and extrahepatic organ failure - such as systemic inflammation, mitochondrial dysfunction, oxidative stress and metabolic changes - and marries these with the classical paradigms of acute decompensation to form a single paradigm. With this detailed breakdown of pathomechanisms, we identify areas for future research. Novel disease-modifying strategies that break the vicious cycle are urgently required to improve patient outcomes.
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Affiliation(s)
- Cornelius Engelmann
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany; Institute for Liver and Digestive Health, University College London, London, United Kingdom; Section Hepatology, Clinic for Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany; Berlin Institute of Health (BIH), Berlin, Germany.
| | - Joan Clària
- European Foundation for the Study of Chronic Liver Failure (EF-Clif) and Grifols Chair, Barcelona, Spain,Biochemistry and Molecular Genetics Service, Hospital ClínicIDIBAPS and CIBERehd, Spain,Department of Biomedical Sciences, University of Barcelona, Barcelona, Spain
| | - Gyongyi Szabo
- Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA
| | - Jaume Bosch
- IDIBAPS and CIBERehd, University of Barcelona, Barcelona, Spain,Department for Biomedical Research (DBMR), Bern University, Bern, Switzerland
| | - Mauro Bernardi
- Department of Medical and Surgical Sciences; Alma Mater Studiorum – University of Bologna; Italy
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48
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Bravo M, Raurell I, Barberá A, Hide D, Gil M, Estrella F, Salcedo MT, Augustin S, Genescà J, Martell M. Synergic effect of atorvastatin and ambrisentan on sinusoidal and hemodynamic alterations in a rat model of NASH. Dis Model Mech 2021; 14:268318. [PMID: 34014280 PMCID: PMC8188885 DOI: 10.1242/dmm.048884] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 03/23/2021] [Indexed: 12/15/2022] Open
Abstract
In non-alcoholic steatohepatitis (NASH), decreased nitric oxide and increased endothelin-1 (ET-1, also known as EDN1) released by sinusoidal endothelial cells (LSEC) induce hepatic stellate cell (HSC) contraction and contribute to portal hypertension (PH). Statins improve LSEC function, and ambrisentan is a selective endothelin-receptor-A antagonist. We aimed to analyse the combined effects of atorvastatin and ambrisentan on liver histopathology and hemodynamics, together with assessing the underlying mechanism in a rat NASH model. Diet-induced NASH rats were treated with atorvastatin (10 mg/kg/day), ambrisentan (30 mg/kg/day or 2 mg/kg/day) or a combination of both for 2 weeks. Hemodynamic parameters were registered and liver histology and serum biochemical determinations analysed. Expression of proteins were studied by immunoblotting. Conditioned media experiments were performed with LSEC. HSCs were characterized by RT-PCR, and a collagen lattice contraction assay was performed. Atorvastatin and ambrisentan act synergistically in combination to completely normalize liver hemodynamics and reverse histological NASH by 75%. Atorvastatin reversed the sinusoidal contractile phenotype, thus improving endothelial function, whereas ambrisentan prevented the contractile response in HSCs by blocking ET-1 response. Additionally, ambrisentan also increased eNOS (also known as Nos3) phosphorylation levels in LSEC, via facilitating the stimulation of endothelin-receptor-B in these cells. Furthermore, the serum alanine aminotransferase of the combined treatment group decreased to normal levels, and this group exhibited a restoration of the HSC quiescent phenotype. The combination of atorvastatin and ambrisentan remarkably improves liver histology and PH in a diet-induced NASH model. By recovering LSEC function, together with inhibiting the activation and contraction of HSC, this combined treatment may be an effective treatment for NASH patients. Summary: Combining atorvastatin with ambrisentan is safe and effective in reducing intrahepatic resistance and portal hypertension in an experimental model of NASH. This liver histology amelioration highlights a promising therapeutic strategy.
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Affiliation(s)
- Miren Bravo
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
| | - Imma Raurell
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona 08035, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid 28029, Spain
| | - Aurora Barberá
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
| | - Diana Hide
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona 08035, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid 28029, Spain
| | - Mar Gil
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
| | - Federico Estrella
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
| | - María Teresa Salcedo
- Department of Pathology, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona 08035, Spain
| | - Salvador Augustin
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona 08035, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid 28029, Spain
| | - Joan Genescà
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona 08035, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid 28029, Spain
| | - María Martell
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona 08035, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid 28029, Spain
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Abstract
PURPOSE OF REVIEW Statins are a class of lipid lower medications used primarily in patients with high-risk cardiovascular disease. Since their development, statins have been considered to be harmful in patients with liver disease, and many of the prescribing information labels consider them to be contraindicated in patients with active liver disease. However, recent studies have shown the contrary, warranting further investigation and discussion. This review aims to describe the latest literature on the mechanism, safety profile and potential benefits of statins use on the natural history of chronic liver disease (CLD) progression and its complications. RECENT FINDINGS A number of recently published studies have added to the existing body of literature supporting the concept that statins are safe and likely to be beneficial for treating patients with CLD. Patients with CLD including hepatitis B virus infection, hepatitis C virus infection, nonalcoholic fatty liver disease and alcohol on statins have been shown to have a lower rate of decompensating events, lower incidence of hepatocellular cancer, a lower rate of infections, and increased survival. However, the majority of the available literature supporting statin use in patients with liver disease comes from retrospective observational studies with high potential for bias. SUMMARY Statins appear to be safe in patients with compensated cirrhosis, and evidence suggests that they may reduce fibrosis, even in patients with advanced fibrosis and cirrhosis. Further high-quality research on this topic is needed to fully delineate the effect of statins in patients with liver disease.
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Affiliation(s)
- Mohamad Kareem Marrache
- Digestive Disease Research Center, Medical University of South Carolina, Charleston, South Carolina, USA
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50
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Fallowfield JA, Jimenez-Ramos M, Robertson A. Emerging synthetic drugs for the treatment of liver cirrhosis. Expert Opin Emerg Drugs 2021; 26:149-163. [PMID: 33856246 DOI: 10.1080/14728214.2021.1918099] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Introduction: The number of deaths and prevalent cases of cirrhosis are increasing worldwide, but there are no licensed antifibrotic or pro-regenerative medicines and liver transplantation is a limited resource. Cirrhosis is characterized by extreme liver fibrosis, organ dysfunction, and complications related to portal hypertension. Advances in our understanding of liver fibrosis progression and regression following successful etiological therapy betray vulnerabilities in common and disease-specific mechanisms that could be targeted pharmacologically.Area covered: This review summarizes the cellular and molecular pathogenesis of cirrhosis as a preface to discussion of the current drug development landscape. The dominant indication for global pharma R&D pipelines is cirrhosis related to nonalcoholic steatohepatitis (NASH). We searched Clinicaltrials.gov, GlobalData, Pharmaprojects and PubMed for pertinent information on emerging synthetic drugs for cirrhosis, with a focus on compounds listed in phase 2 and phase 3 trials.Expert opinion: Although cirrhosis can regress following successful etiological treatment, there are no specific antifibrotic or pro-regenerative drugs approved for this condition. Obstacles to drug development in cirrhosis include intrinsic biological factors, a heterogeneous patient population, and lack of acceptable surrogate endpoints. Nevertheless, several synthetic drugs are being evaluated in clinical trials and the NASH field is rapidly embracing a drug combination approach.
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