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Wang RX, Serper M, Taddei TH, Kaplan DE, Mahmud N. The Association Between Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker Exposure and Key Cirrhosis-Related Outcomes. Am J Gastroenterol 2025; 120:1057-1065. [PMID: 39051649 PMCID: PMC12036742 DOI: 10.14309/ajg.0000000000002976] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 07/12/2024] [Indexed: 07/27/2024]
Abstract
INTRODUCTION Angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARB) may have hepatic benefits in patients with primarily chronic liver disease. ACE-I/ARB have not been evaluated in broad cohorts inclusive of those with decompensated cirrhosis. We analyzed the real-world association between ACE-I/ARB exposure and cirrhosis-related outcomes in a national cohort. METHODS We performed a retrospective, active comparator new user study of patients with cirrhosis in the Veterans Health Administration. We identified new initiators of ACE-I/ARB or calcium channel blockers (comparator). Inverse probability treatment weighting balanced key confounders and Cox regression evaluated the association between ACE-I/ARB and outcomes of mortality, cirrhosis decompensation, and hepatocellular carcinoma (HCC). In exploratory analysis, cause-specific competing risk models evaluated liver-related vs cardiovascular (CV)-related vs nonliver/non-CV-related mortality. RESULTS There were 904 ACE-I/ARB and 352 calcium channel blocker new initiators. In inverse probability treatment weighting Cox regression, ACE-I/ARB exposure was associated with reduced mortality (hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.61-0.81, P < 0.001). In patients with compensated cirrhosis, ACE-I/ARB were not associated with hepatic decompensation or HCC. Cause-specific hazard models showed ACE-I/ARB exposure was associated with reduction in nonliver/non-CV-related mortality (cause-specific HR 0.49, 95% CI 0.38-0.62, P < 0.001) but not liver-related or CV-related mortality. In Child-Turcotte-Pugh A patients, ACE-I/ARB were associated with decreased CV-related mortality (cause-specific HR 0.41, 95% CI 0.26-0.65, P < 0.001). DISCUSSION ACE-I/ARB exposure was associated with reduced mortality, potentially through CV and other (renal, malignancy-related) mechanisms. In patients with compensated disease, ACE-I/ARB were not associated with hepatic decompensation or HCC. Future research should identify subsets of patients who benefit from ACE-I/ARB exposure.
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Affiliation(s)
- Roy X. Wang
- Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Marina Serper
- Department of Medicine, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA
- Division of Gastroenterology and Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | | | - David E. Kaplan
- Department of Medicine, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA
- Division of Gastroenterology and Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Nadim Mahmud
- Department of Medicine, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA
- Division of Gastroenterology and Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
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Ronsin C, Braud P, Kandel-Aznar C, Dujardin A, Petit C, Larmet D, Garandeau C, Deltombe C, Le Clech A, Leman C, Blancho G, Schurder J, Couvrat-Desvergnes G, Ville S. Clinical Presentation, Pathological Spectrum, and Outcomes of Alcoholic Cirrhosis-Related Immunoglobulin A Nephropathy. Kidney Int Rep 2024; 9:1369-1378. [PMID: 38707818 PMCID: PMC11069013 DOI: 10.1016/j.ekir.2024.02.1397] [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: 12/03/2023] [Revised: 01/24/2024] [Accepted: 02/12/2024] [Indexed: 05/07/2024] Open
Abstract
Introduction Immunoglobulin A nephropathy (IgAN) associated with cirrhosis is frequent but often overlooked because it is largely considered silent. Until now, little has been known about their presentation and outcomes. Methods We conducted a retrospective multicenter study on patients with kidney biopsy-proven cirrhosis-related IgAN (cirrhosis-IgAN), diagnosed between 2009 and 2022. We mixed them up with 83 primary IgAN (pIgAN) diagnosed during the same period, using a partitioning clustering approach, to determine common clinicopathological profiles. Results All the 46 patients with cirrhosis-IgAN had an excessive alcoholic consumption. Clinical presentation was severe with acute kidney injury (AKI) in 79%; alternative causes of AKI was found in 62% of cases. Three clinicopathological clusters were identified as follows: the first one represented chronic involvement, the second one could be assimilated to mild disease, and the third one corresponded to a membranoproliferative glomerulonephritis (MPGN) pattern and was associated with heavy proteinuria and intrinsic AKI (without alternative causes). Whereas the first 2 clusters were equally distributed between pIgAN and cirrhosis-IgAN, the third was more frequent in patients with cirrhosis. The cumulative mortality rate in cirrhosis-IgAN was 26% and 46% at 1-year and 3-years, respectively. Steroid exposure and moderate or severe AKI were associated with higher mortality and steroid exposure was associated with the occurrence of severe infection. Conclusion Our results suggest that high AKI incidence is related to extrinsic causes in most cases but can also be driven by IgA-dominant MPGN in a subset of patients. Steroid use was associated with infectious disease and mortality. Further studies are needed to clarify the role of immunosuppressive treatment in cirrhosis-IgAN patients.
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Affiliation(s)
- Charles Ronsin
- Department of Nephrology and Immunology, Centre Hospitalier Universitaire de Nantes, Nantes, France
| | - Pierre Braud
- Department of Nephrology, Dialysis and Transplantation, Departmental Hospital of Vendée, La Roche-sur-Yon, France
| | | | | | - Clémence Petit
- Department of Nephrology, Saint Nazaire Hospital, Saint Nazaire, France
| | - David Larmet
- Department of Nephrology, Saint Nazaire Hospital, Saint Nazaire, France
| | - Claire Garandeau
- Department of Nephrology and Immunology, Centre Hospitalier Universitaire de Nantes, Nantes, France
| | - Clément Deltombe
- Department of Nephrology and Immunology, Centre Hospitalier Universitaire de Nantes, Nantes, France
| | - Alice Le Clech
- Department of Nephrology and Immunology, Centre Hospitalier Universitaire de Nantes, Nantes, France
| | - Claire Leman
- Department of Nephrology and Immunology, Centre Hospitalier Universitaire de Nantes, Nantes, France
| | - Gilles Blancho
- Department of Nephrology and Immunology, Centre Hospitalier Universitaire de Nantes, Nantes, France
| | - Juliet Schurder
- Department of Nephrology, Broussais Hospital, Saint-Malo, France
| | - Grégoire Couvrat-Desvergnes
- Department of Nephrology, Dialysis and Transplantation, Departmental Hospital of Vendée, La Roche-sur-Yon, France
| | - Simon Ville
- Department of Nephrology and Immunology, Centre Hospitalier Universitaire de Nantes, Nantes, France
- Centre de Recherche en Transplantation et Immunologie UMR 1064, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Nantes, Nantes, France
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Lee S, Saffo S. Evolution of care in cirrhosis: Preventing hepatic decompensation through pharmacotherapy. World J Gastroenterol 2023; 29:61-74. [PMID: 36683719 PMCID: PMC9850948 DOI: 10.3748/wjg.v29.i1.61] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 10/22/2022] [Accepted: 12/14/2022] [Indexed: 01/04/2023] Open
Abstract
Cirrhosis is a leading cause of morbidity and mortality, impacting more than 120 million people worldwide. Although geographic differences exist, etiologic factors such as alcohol use disorder, chronic viral hepatitis infections, and non-alcoholic fatty liver disease are prevalent in nearly every region. Historically, significant effort has been devoted to modifying these risks to prevent disease progression. Nevertheless, more than 11% of patients with compensated cirrhosis experience hepatic decompensation each year. This transition signifies the most important prognostic factor in the natural history of the disease, corresponding to a decline in median survival to below 2 years. Over the past decade, the need for pharmacotherapies aimed at reducing the risk for hepatic decompensation has been emphasized, and non-selective beta-blockers have emerged as the most effective option to date. However, a critical therapeutic gap still exists, and additional therapies have been proposed, including statins, rifaximin, and sodium-glucose cotransporter-2 inhibitors. Based on the results of innovative retrospective analyses and small-scale prospective trials, these pharmacotherapies represent promising options, but further studies, including randomized controlled trials, are necessary before they can be incorporated into clinical use. This report highlights the potential impact of these agents and others in preventing hepatic decompensation and discusses how this paradigm shift may pave the way for guideline-directed medical therapy in cirrhosis.
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Affiliation(s)
- Seohyuk Lee
- Department of Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, CT 06520-8019, United States
| | - Saad Saffo
- Department of Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, CT 06520-8019, United States
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Chan W, Tan S, Chan S, Lee Y, Tee H, Mahadeva S, Goh K, Ramli AS, Mustapha F, Kosai NR, Raja Ali RA. Malaysian Society of Gastroenterology and Hepatology consensus statement on metabolic dysfunction-associated fatty liver disease. J Gastroenterol Hepatol 2022; 37:795-811. [PMID: 35080048 PMCID: PMC9303255 DOI: 10.1111/jgh.15787] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 12/19/2021] [Accepted: 01/10/2022] [Indexed: 12/19/2022]
Abstract
The Malaysian Society of Gastroenterology and Hepatology saw the need for a consensus statement on metabolic dysfunction-associated fatty liver disease (MAFLD). The consensus panel consisted of experts in the field of gastroenterology/hepatology, endocrinology, bariatric surgery, family medicine, and public health. A modified Delphi process was used to prepare the consensus statements. The panel recognized the high and increasing prevalence of the disease and the consequent anticipated increase in liver-related complications and mortality. Cardiovascular disease is the leading cause of mortality in MAFLD patients; therefore, cardiovascular disease risk assessment and management is important. A simple and clear liver assessment and referral pathway was agreed upon, so that patients with more severe MAFLD can be linked to gastroenterology/hepatology care, while patients with less severe MAFLD can remain in primary care or endocrinology, where they are best managed. Lifestyle intervention is the cornerstone in the management of MAFLD. The panel provided a consensus on the use of statin, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, sodium-glucose cotransporter-2 inhibitor, glucagon-like peptide-1 agonist, pioglitazone, vitamin E, and metformin, as well as recommendations on bariatric surgery, screening for gastroesophageal varices and hepatocellular carcinoma, and liver transplantation in MAFLD patients. Increasing the awareness and knowledge of the various stakeholders on MAFLD and incorporating MAFLD into existing noncommunicable disease-related programs and activities are important steps to tackle the disease. These consensus statements will serve as a guide on MAFLD for clinicians and other stakeholders.
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Affiliation(s)
- Wah‐Kheong Chan
- Gastroenterology and Hepatology Unit, Department of Medicine, Faculty of MedicineUniversity of MalayaKuala LumpurMalaysia
| | - Soek‐Siam Tan
- Department of HepatologySelayang HospitalBatu CavesSelangorMalaysia
| | | | - Yeong‐Yeh Lee
- School of Medical SciencesUniversiti Sains MalaysiaKota BharuKelantanMalaysia
| | - Hoi‐Poh Tee
- KPJ Pahang Specialist CentreKuantanPahangMalaysia
| | - Sanjiv Mahadeva
- Gastroenterology and Hepatology Unit, Department of Medicine, Faculty of MedicineUniversity of MalayaKuala LumpurMalaysia
| | - Khean‐Lee Goh
- Gastroenterology and Hepatology Unit, Department of Medicine, Faculty of MedicineUniversity of MalayaKuala LumpurMalaysia
| | - Anis Safura Ramli
- Department of Primary Care Medicine, Faculty of MedicineUniversiti Teknologi MARA, Selayang CampusBatu CavesSelangorMalaysia
- Institute of Pathology, Laboratory and Forensic Medicine, Centre of Excellence for Research on Atherosclerosis and CVD PreventionUniversiti Teknologi MARA, Sungai Buloh CampusSungai BulohSelangorMalaysia
| | - Feisul Mustapha
- Disease Control DivisionMinistry of Health, MalaysiaPutrajayaMalaysia
| | - Nik Ritza Kosai
- Upper Gastrointestinal, Metabolic and Bariatric Surgery Unit, Department of SurgeryUniversiti Kebangsaan MalaysiaKuala LumpurMalaysia
| | - Raja Affendi Raja Ali
- Gastroenterology Unit, Department of MedicineUniversiti Kebangsaan MalaysiaKuala LumpurMalaysia
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Plaz MC, Tsochatzis EA. Metabolic Complications Before and After Liver Transplantation. TEXTBOOK OF LIVER TRANSPLANTATION 2022:357-371. [DOI: 10.1007/978-3-030-82930-8_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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ACE2: from protection of liver disease to propagation of COVID-19. Clin Sci (Lond) 2020; 134:3137-3158. [PMID: 33284956 DOI: 10.1042/cs20201268] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 11/19/2020] [Accepted: 11/23/2020] [Indexed: 01/08/2023]
Abstract
Twenty years ago, the discovery of angiotensin-converting enzyme 2 (ACE2) was an important breakthrough dramatically enhancing our understanding of the renin-angiotensin system (RAS). The classical RAS is driven by its key enzyme ACE and is pivotal in the regulation of blood pressure and fluid homeostasis. More recently, it has been recognised that the protective RAS regulated by ACE2 counterbalances many of the deleterious effects of the classical RAS. Studies in murine models demonstrated that manipulating the protective RAS can dramatically alter many diseases including liver disease. Liver-specific overexpression of ACE2 in mice with liver fibrosis has proved to be highly effective in antagonising liver injury and fibrosis progression. Importantly, despite its highly protective role in disease pathogenesis, ACE2 is hijacked by SARS-CoV-2 as a cellular receptor to gain entry to alveolar epithelial cells, causing COVID-19, a severe respiratory disease in humans. COVID-19 is frequently life-threatening especially in elderly or people with other medical conditions. As an unprecedented number of COVID-19 patients have been affected globally, there is an urgent need to discover novel therapeutics targeting the interaction between the SARS-CoV-2 spike protein and ACE2. Understanding the role of ACE2 in physiology, pathobiology and as a cellular receptor for SARS-CoV-2 infection provides insight into potential new therapeutic strategies aiming to prevent SARS-CoV-2 infection related tissue injury. This review outlines the role of the RAS with a strong focus on ACE2-driven protective RAS in liver disease and provides therapeutic approaches to develop strategies to prevent SARS-CoV-2 infection in humans.
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Sansoè G, Aragno M, Wong F. Pathways of hepatic and renal damage through non-classical activation of the renin-angiotensin system in chronic liver disease. Liver Int 2020; 40:18-31. [PMID: 31580514 DOI: 10.1111/liv.14272] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Revised: 09/24/2019] [Accepted: 09/30/2019] [Indexed: 12/17/2022]
Abstract
In liver cirrhosis, renin-angiotensin system (RAS) activation sustains renal sodium retention and hepatic fibrogenesis. New information has recently enlivened the traditional concept of RAS. For instance, renin and prorenin bind their ubiquitous receptors, resulting in the local production of angiotensin (Ang) II; increased serum calcium and calcimimetic agents, through stimulation of extracellular calcium-sensing receptors (CaSR), blunt renin production and lead to natriuretic effects in human and experimental cirrhosis. Alongside systemic production, there is Ang II tissue production within various organs through RAS enzymes different from angiotensin-converting enzyme (ACE), that is chymase, tissue plasminogen activator and several cathepsins. In experimental cirrhosis, inhibition of chymase leads to natriuretic and hepatic antifibrotic effects, without changes in systemic haemodynamics. In the kidney, local RAS coordinates proximal and distal tubular sodium reabsorption. However, renalase, whose plasma and tissue levels are severely altered in experimental cirrhosis, degrades systemic and renal tubule catecholamines, antagonizing the effects of renal RAS. Angiotensinogen-derived natriuretic and vasodilating peptides (Ang1-9, Ang1-7, Ang3-8) and their receptors have been described. Receptor agonists or antagonists are available to affect portal hypertension and sodium retention in cirrhosis. ACE2-dependent generation of Ang1-7 may inhibit experimental liver fibrosis. inhibition of Ang1-7 clearance by means of neprilysin blockade has portal hypotensive and natriuretic effects. Ang1-12, whose production renin does not regulate, is converted to several different angiotensin peptides via chymase. Finally, Ang II behaves as either an antinatriuretic or a natriuretic agent, based on the tissue content of AT1 R and AT2 R receptors, their ratio being prone to pharmacological modulation.
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Affiliation(s)
- Giovanni Sansoè
- Division of Gastroenterology, Humanitas Gradenigo Hospital, Torino, Italy
| | - Manuela Aragno
- Department of Clinical and Biological Sciences, University of Torino, Torino, Italy
| | - Florence Wong
- Department of Medicine, Toronto General Hospital, University of Toronto, Toronto, ON, Canada
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8
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You Y, Huang Y, Wang D, Li Y, Wang G, Jin S, Zhu X, Wu B, Du X, Li X. Angiotensin (1-7) inhibits arecoline-induced migration and collagen synthesis in human oral myofibroblasts via inhibiting NLRP3 inflammasome activation. J Cell Physiol 2018; 234:4668-4680. [PMID: 30246378 DOI: 10.1002/jcp.27267] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Accepted: 07/24/2018] [Indexed: 12/15/2022]
Abstract
Arecoline induces oral submucous fibrosis (OSF) via promoting the reactive oxygen species (ROS). Angiotensin (1-7) (Ang-(1-7)) protects against fibrosis by counteracting angiotensin II (Ang-II) via the Mas receptor. However, the effects of Ang-(1-7) on OSF remain unknown. NOD-like receptors (NLRs) family pyrin domain containing 3 (NLRP3) inflammasome is identified as the novel mechanism of fibrosis. Whereas the effects of arecoline on NLRP3 inflammasome remain unclear. We aimed to explore the effect of Ang-(1-7) on NLRP3 inflammasome in human oral myofibroblasts. In vivo, activation of NLRP3 inflammasomes with an increase of Ang-II type 1 receptor (AT1R) protein level and ROS production in human oral fibrosis tissues. Ang-(1-7) improved arecoline-induced rats OSF, reduced protein levels of NADPH oxidase 4 (NOX4) and the NLRP3 inflammasome. In vitro, arecoline increased ROS along with upregulation of the angiotensin-converting enzyme (ACE)/Ang-II/AT1R axis and NLRP3 inflammasome/interleukin-1β axis in human oral myofibroblasts, which were reduced by NOX4 inhibitor VAS2870, ROS scavenger N-acetylcysteine, and NOX4 small interfering RNA (siRNA). Furthermore, arecoline induced collagen synthesis or migration via the Smad or RhoA-ROCK pathway respectively, which could be inhibited by NLRP3 siRNA or caspase-1 blocker VX-765. Ang-(1-7) shifted the balance of RAS toward the ACE2/Ang-(1-7)/Mas axis, inhibited arecoline-induced ROS and NLRP3 inflammasome activation, leading to attenuation of migration or collagen synthesis. In summary, Ang-(1-7) attenuates arecoline-induced migration and collagen synthesis via inhibiting NLRP3 inflammasome in human oral myofibroblasts.
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Affiliation(s)
- Yuehua You
- Department of Emergency, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Department of Stomatology, The People's Hospital of Longhua, Shenzhen, China
| | - Yun Huang
- Department of Emergency, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Department of Cadre's Ward, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Dan Wang
- Department of Emergency, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yang Li
- Department of Emergency, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Guozhen Wang
- Department of Emergency, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Siyi Jin
- Department of Gastroenterology, Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xintao Zhu
- Department of Emergency and Critical Care Medicine, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Bin Wu
- Department of Stomatology, The People's Hospital of Longhua, Shenzhen, China
| | - Xinya Du
- Department of Stomatology, The People's Hospital of Longhua, Shenzhen, China
| | - Xu Li
- Department of Emergency, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Saffo S, Taddei T. SGLT2 inhibitors and cirrhosis: A unique perspective on the comanagement of diabetes mellitus and ascites. Clin Liver Dis (Hoboken) 2018; 11:141-144. [PMID: 30992805 PMCID: PMC6385962 DOI: 10.1002/cld.714] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Affiliation(s)
- Saad Saffo
- Department of Internal MedicineYale University School of MedicineNew HavenCT
| | - Tamar Taddei
- Section of Digestive DiseasesYale University School of MedicineNew HavenCT
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10
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Santos SHS, Andrade JMO. Angiotensin 1-7: a peptide for preventing and treating metabolic syndrome. Peptides 2014; 59:34-41. [PMID: 25017239 DOI: 10.1016/j.peptides.2014.07.002] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2014] [Revised: 07/02/2014] [Accepted: 07/02/2014] [Indexed: 12/14/2022]
Abstract
Angiotensin-(1-7) is one of the most important active peptides of the renin-angiotensin system (RAS) with recognized cardiovascular relevance; however several studies have shown the potential therapeutic role of Ang-(1-7) on treating and preventing metabolic disorders as well. This peptide achieves a special importance considering that in the last few decades obesity and metabolic syndrome (MS) have become a growing worldwide health problem. Angiotensin (Ang) II is the most studied component of RAS and is increased during obesity, diabetes and dyslipidemia (MS); some experimental evidence has shown that Ang II modulates appetite and metabolism as well as mechanisms that induce adipose tissue growth and metabolism in peripheral organs. Recent articles demonstrated that Ang-(1-7)/Mas axis modulates lipid and glucose metabolism and counterregulates the effects of Ang II. Based on these data, angiotensin-converting enzyme 2 (ACE2)/Ang-(1-7)/Mas pathway activation have been advocated as a new tool for treating metabolic diseases. This review summarizes the new evidence from animal and human experiments indicating the use of Ang-(1-7) in prevention and treatment of obesity and metabolic disorders.
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Affiliation(s)
- Sérgio Henrique Sousa Santos
- Pharmacology Department, Biological Sciences Institute, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil; Laboratory of Health Science, Postgraduate Program in Health Sciences, Universidade Estadual de Montes Claros (UNIMONTES), Montes Claros, Minas Gerais, Brazil.
| | - João Marcus Oliveira Andrade
- Laboratory of Health Science, Postgraduate Program in Health Sciences, Universidade Estadual de Montes Claros (UNIMONTES), Montes Claros, Minas Gerais, Brazil
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Abstract
Cirrhosis can be sub-classified in clinical stages with distinct differences in prognosis and can even be reversed in some cases with successful etiological treatment. In this article, we review potential future therapies of cirrhosis, mainly focusing in the expansion of indications of currently licensed drugs. We strongly advocate that future therapies should focus on preventing the advent of complications and further progression of liver disease and should involve both primary and secondary care physicians. Such strategies could be based on the combination of currently licensed, relatively safe and inexpensive drugs and such randomized controlled trials should be prioritized in patients with advanced liver disease. The paradigm should be similar to that of prevention in cardiovascular diseases and long-term follow-up trials are needed.
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Affiliation(s)
- Emmanuel A Tsochatzis
- The Royal Free Sheila Sherlock Liver Centre, Royal Free Hospital and UCL Institute of Liver and Digestive Health, London, UK
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12
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Abstract
Cirrhosis is an increasing cause of morbidity and mortality in more developed countries, being the 14th most common cause of death worldwide but fourth in central Europe. Increasingly, cirrhosis has been seen to be not a single disease entity, but one that can be subclassified into distinct clinical prognostic stages, with 1-year mortality ranging from 1% to 57% depending on the stage. We review the current understanding of cirrhosis as a dynamic process and outline current therapeutic options for prevention and treatment of complications of cirrhosis, on the basis of the subclassification in clinical stages. The new concept in management of patients with cirrhosis should be prevention and early intervention to stabilise disease progression and to avoid or delay clinical decompensation and the need for liver transplantation. The challenge in the 21st century is to prevent the need for liver transplantation in as many patients with cirrhosis as possible.
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Affiliation(s)
- Emmanuel A Tsochatzis
- Royal Free Sheila Sherlock Liver Centre, Royal Free Hospital and UCL Institute of Liver and Digestive Health, London, UK
| | - Jaime Bosch
- Hepatic Hemodynamic Laboratory, Hospital Clínic-IDIBAPS, University of Barcelona, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
| | - Andrew K Burroughs
- Royal Free Sheila Sherlock Liver Centre, Royal Free Hospital and UCL Institute of Liver and Digestive Health, London, UK.
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Bernstein KE, Ong FS, Blackwell WLB, Shah KH, Giani JF, Gonzalez-Villalobos RA, Shen XZ, Fuchs S, Touyz RM. A modern understanding of the traditional and nontraditional biological functions of angiotensin-converting enzyme. Pharmacol Rev 2013; 65:1-46. [PMID: 23257181 PMCID: PMC3565918 DOI: 10.1124/pr.112.006809] [Citation(s) in RCA: 217] [Impact Index Per Article: 18.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Angiotensin-converting enzyme (ACE) is a zinc-dependent peptidase responsible for converting angiotensin I into the vasoconstrictor angiotensin II. However, ACE is a relatively nonspecific peptidase that is capable of cleaving a wide range of substrates. Because of this, ACE and its peptide substrates and products affect many physiologic processes, including blood pressure control, hematopoiesis, reproduction, renal development, renal function, and the immune response. The defining feature of ACE is that it is composed of two homologous and independently catalytic domains, the result of an ancient gene duplication, and ACE-like genes are widely distributed in nature. The two ACE catalytic domains contribute to the wide substrate diversity of ACE and, by extension, the physiologic impact of the enzyme. Several studies suggest that the two catalytic domains have different biologic functions. Recently, the X-ray crystal structure of ACE has elucidated some of the structural differences between the two ACE domains. This is important now that ACE domain-specific inhibitors have been synthesized and characterized. Once widely available, these reagents will undoubtedly be powerful tools for probing the physiologic actions of each ACE domain. In turn, this knowledge should allow clinicians to envision new therapies for diseases not currently treated with ACE inhibitors.
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Affiliation(s)
- Kenneth E Bernstein
- Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Davis 2021, Los Angeles, CA 90048, USA.
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Abstract
Cirrhosis is a major health problem, being the 5th cause of death in the U.K. and 12th in the U.S., but 4th in the 45 to 54 age group. Until recently cirrhosis was considered a single and terminal disease stage, with an inevitably poor prognosis. However, it is now clear that 1-year mortality can range from 1% in early cirrhosis to 57% in decompensated disease. As the only treatment for advanced cirrhosis is liver transplantation, what is urgently needed is strategies to prevent transition to decompensated stages. The evidence we present in this review clearly demonstrates that management of patients with cirrhosis should change from an expectant algorithm that treats complications as they occur, to preventing the advent of all complications while in the compensated phase. This requires maintaining patients in an asymptomatic phase and not significantly affecting their quality of life with minimal impairment due to the therapies themselves. This could be achieved with lifestyle changes and combinations of already licensed and low-cost drugs, similar to the paradigm of treating risk factors for cardiovascular disease. The drugs are propranolol, simvastatin, norfloxacin, and warfarin, which in combination would cost £128/patient annually-equivalent to U.S. $196/year. This treatment strategy requires randomized controlled trials to establish improvements in outcomes. In the 21st century, cirrhosis should be regarded as a potentially treatable disease with currently available and inexpensive therapies.
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Chang CC, Lee WS, Huang HC, Lee FY, Wang SS, Lin HC, Nong JY, Lee SD. Aliskiren reduces portal pressure in portal hypertensive rats. Eur J Clin Invest 2012; 42:526-33. [PMID: 22023532 DOI: 10.1111/j.1365-2362.2011.02611.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Aliskiren is a direct renin inhibitor used in the treatment for arterial hypertension. It can also augment nitric oxide (NO) production, which plays a crucial role in the pathogenesis of portal hypertension and modulation of porto-systemic collaterals. This study investigated the effects of aliskiren on portal pressure and porto-systemic collaterals of portal vein-ligated (PVL) rats. MATERIALS AND METHODS Sham-operated and PVL rats received aliskiren (50 mg/kg per day) or distilled water (control) treatment for 10 days. The mean arterial pressure and portal pressure were measured by catheterization of the right femoral artery and mesenteric vein, while the superior mesenteric arterial blood flow was measured by Doppler technique. The left adrenal vein and superior mesentery artery were dissected for mRNA study. The PVL rats also underwent preincubation with (i) Krebs solution (control); (ii) 10(-4) M aliskiren; or (iii) 10(-4) M aliskiren plus nonselective NO inhibitor N(ω)-nitro-L-arginine (10(-4) M), followed by the addition of arginine vasopressin (AVP) to evaluate the collateral vascular responsiveness. RESULTS Aliskiren had systemic arterial pressure- and portal pressure-lowering effects in PVL rats. Superior mesentery arterial resistance also decreased. The constitutive NO synthase was enhanced in the left adrenal vein and superior mesentery artery after aliskiren treatment. Aliskiren attenuated the collateral vasoconstrictive effects of AVP, but the vasodilatory effects were abolished after nonselective NO synthase inhibition. CONCLUSIONS Chronic aliskiren use reduces portal pressure in portal hypertensive rats partly due to the modulation of splanchnic and collateral NO synthase.
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Affiliation(s)
- Ching-Chih Chang
- Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
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16
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Levitt DG, Levitt MD. Quantitative modeling of the physiology of ascites in portal hypertension. BMC Gastroenterol 2012; 12:26. [PMID: 22453061 PMCID: PMC3361476 DOI: 10.1186/1471-230x-12-26] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2011] [Accepted: 03/27/2012] [Indexed: 02/06/2023] Open
Abstract
Although the factors involved in cirrhotic ascites have been studied for a century, a number of observations are not understood, including the action of diuretics in the treatment of ascites and the ability of the plasma-ascitic albumin gradient to diagnose portal hypertension. This communication presents an explanation of ascites based solely on pathophysiological alterations within the peritoneal cavity. A quantitative model is described based on experimental vascular and intraperitoneal pressures, lymph flow, and peritoneal space compliance. The model's predictions accurately mimic clinical observations in ascites, including the magnitude and time course of changes observed following paracentesis or diuretic therapy.
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17
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Effects of Angiotensin Converting Enzyme Inhibitors on Liver Fibrosis in HIV and Hepatitis C Coinfection. AIDS Res Treat 2012; 2012:978790. [PMID: 23193466 PMCID: PMC3501811 DOI: 10.1155/2012/978790] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2012] [Accepted: 09/26/2012] [Indexed: 01/13/2023] Open
Abstract
Background. Liver fibrosis is accelerated in HIV and hepatitis C coinfection, mediated by profibrotic effects of angiotensin. The objective of this study was to determine if angiotensin converting enzyme inhibitors (ACE-Is) attenuate liver fibrosis in coinfection. Methods. A retrospective review of 156 coinfected subjects was conducted to analyze the association between exposure to ACE-Is and liver fibrosis. Noninvasive indices of liver fibrosis (APRI, FIB-4, Forns indices) were compared between subjects who had taken ACE-Is and controls who had not taken them. Linear regression was used to evaluate ACE-I use as an independent predictor of fibrosis. Results. Subjects taking ACE-Is for three years were no different than controls on the APRI and the FIB-4 but had significantly higher scores than controls on the Forns index, indicating more advanced fibrosis. The use of ACE-Is for three years remained independently associated with an elevated Forns score when adjusted for age, race, and HIV viral load (P < 0.001). There were significant associations between all of the indices and significant fibrosis, as determined clinically and radiologically. Conclusions. There was not a protective association between angiotensin inhibition and liver fibrosis in coinfection. These noninvasive indices may be useful for ruling out significant fibrosis in coinfection.
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Thalheimer U, Triantos C, Goulis J, Burroughs AK. Management of varices in cirrhosis. Expert Opin Pharmacother 2011; 12:721-35. [PMID: 21269241 DOI: 10.1517/14656566.2011.537258] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Acute variceal bleeding is a medical emergency and one of the main causes of mortality in patients with cirrhosis. Timely and effective treatment of the acute bleeding episode results in increased survival, and appropriate prophylactic treatment can prevent bleeding or rebleeding from varices. AREAS COVERED We discuss the prevention of development and growth of varices, the primary and secondary prophylaxis of bleeding, the treatment of acute bleeding, and the management of gastric varices. We systematically reviewed studies, without time limits, identified through Medline and searches of reference lists, and provide an overview of the evidence underlying the -treatment options in the management of varices in cirrhosis. EXPERT OPINION The management of variceal hemorrhage relies on nonspecific interventions (e.g., adequate fluid resuscitation, airway protection) and on specific interventions. These are routine prophylactic antibiotics, vasoactive drugs and endoscopic treatment. Procedures such as the placement of a Sengstaken-Blakemore tube or a transjugular intrahepatic portosystemic shunt (TIPS) can be lifesaving. The primary and secondary prophylaxis of bleeding is based on nonselective beta-blockers and endoscopy, even though TIPS or, less frequently, surgery have a role in selected cases.
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Affiliation(s)
- Ulrich Thalheimer
- The Royal Free Sheila Sherlock Liver Centre, University Department of Surgery, Royal Free Hospital, Pond Street, NW3 2QG, London, UK.
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19
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Tandon P, Abraldes JG, Berzigotti A, Garcia-Pagan JC, Bosch J. Renin-angiotensin-aldosterone inhibitors in the reduction of portal pressure: a systematic review and meta-analysis. J Hepatol 2010; 53:273-82. [PMID: 20570385 DOI: 10.1016/j.jhep.2010.03.013] [Citation(s) in RCA: 96] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2010] [Revised: 03/03/2010] [Accepted: 03/04/2010] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Renin-angiotensin-aldosterone antagonists [ACE inhibitors (ACEi), angiotensin receptor blockers (ARB), aldosterone antagonists (AA)] are potential therapies for portal hypertension. We evaluated the efficacy and safety of RAAS inhibitors in hepatic venous pressure gradient (HVPG) reduction. METHODS We included full-text controlled trials in patients with cirrhosis and portal hypertension. The primary outcome was mean change in HVPG between treatment and control. Two independent reviewers performed trial selection and quality assessment. An individual patient meta-analysis based on the data of three studies was performed. RESULTS From 193 citations, 19 controlled trials (n=678) were included. When compared to placebo, ARB/ACEi resulted in significant HVPG reduction. The best quality trials compared ARB/ACEi to beta-blockers (BB). Pooled individual patient data for three of four of these trials showed that BB decreased the HVPG more than ARB/ACEi. In patients with Child Pugh A cirrhosis, the HVPG reduction with ARB/ACEi (-17%; 95% CI: -28 to -6), was similar to that of BB (-21%; 95% CI: -32 to -9). Significant variation in the comparison groups of AA trials precluded pooling. There was no difference in adverse events in any group but selected studies noted adverse hemodynamic effects in decompensated patients on ARB/ACEi. CONCLUSIONS ARB/ACEi reduce portal pressure in patients with Child Pugh A cirrhosis without adverse events. The efficacy and safety in this group may be secondary to a targeted effect on the local hepatic RAAS system, as compared to decompensated patients who risk hypotension and renal insufficiency due to activation of the systemic RAAS. Further studies should determine the potential of these drugs as an alternative or adjunct to BB.
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20
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Lubel JS, Herath CB, Burrell LM, Angus PW. Liver disease and the renin-angiotensin system: recent discoveries and clinical implications. J Gastroenterol Hepatol 2008; 23:1327-38. [PMID: 18557800 PMCID: PMC7166336 DOI: 10.1111/j.1440-1746.2008.05461.x] [Citation(s) in RCA: 98] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The renin-angiotensin system (RAS) is a key regulator of vascular resistance, sodium and water homeostasis and the response to tissue injury. Historically, angiotensin II (Ang II) was thought to be the primary effector peptide of this system. Ang II is produced predominantly by the effect of angiotensin converting enzyme (ACE) on angiotensin I (Ang I). Ang II acts mainly through the angiotensin II type-1 receptor (AT(1)) and, together with ACE, these components represent the 'classical' axis of the RAS. Drug therapies targeting the RAS by inhibiting Ang II formation (ACE inhibitors) or binding to its receptor (angiotensin receptor blockers) are now in widespread clinical use and have been shown to reduce tissue injury and fibrosis in cardiac and renal disease independently of their effects on blood pressure. In 2000, two groups using different methodologies identified a homolog of ACE, called ACE2, which cleaves Ang II to form the biologically active heptapeptide, Ang-(1-7). Conceptually, ACE2, Ang-(1-7), and its putative receptor, the mas receptor represent an 'alternative' axis of the RAS capable of opposing the often deleterious actions of Ang II. Interestingly, ACE inhibitors and angiotensin receptor blockers increase Ang-(1-7) production and it has been proposed that some of the beneficial effects of these drugs are mediated through upregulation of Ang-(1-7) rather than inhibition of Ang II production or receptor binding. The present review focuses on the novel components and pathways of the RAS with particular reference to their potential contribution towards the pathophysiology of liver disease.
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Affiliation(s)
- John S Lubel
- Department of Medicine, The University of Melbourne, Austin and Northern Health, Melbourne, Victoria, Australia
| | - Chandana B Herath
- Department of Medicine, The University of Melbourne, Austin and Northern Health, Melbourne, Victoria, Australia
| | - Louise M Burrell
- Department of Medicine, The University of Melbourne, Austin and Northern Health, Melbourne, Victoria, Australia
| | - Peter W Angus
- Department of Medicine, The University of Melbourne, Austin and Northern Health, Melbourne, Victoria, Australia
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Khashab MA, Liangpunsakul S, Chalasani N. Nonalcoholic fatty liver disease as a component of the metabolic syndrome. Curr Gastroenterol Rep 2008; 10:73-80. [PMID: 18417046 DOI: 10.1007/s11894-008-0012-0] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/26/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is an important cause of liver-related morbidity and mortality. The association between NAFLD and the metabolic syndrome is well established: the presence of the metabolic syndrome signifies advanced histology in NAFLD patients. Emerging data indicate that patients with NAFLD have a significantly higher prevalence of cardiovascular disease. This article reviews the definitions of the two syndromes, their association, and the cardiovascular risk conferred by both when they occur separately and together. This review also discusses management options for the syndromes, including treating the individual components of the metabolic syndrome in NAFLD patients.
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Affiliation(s)
- Mouen A Khashab
- Indiana University School of Medicine, RG 4100, 1050 Wishard Boulevard, Indianapolis, IN 46202, USA
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22
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The Role of the Renin-Angiotensin System in Hepatic Fibrosis. FRONTIERS IN RESEARCH OF THE RENIN-ANGIOTENSIN SYSTEM ON HUMAN DISEASE 2007. [PMCID: PMC7121340 DOI: 10.1007/978-1-4020-6372-5_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
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Abstract
GOALS To characterize beta blocker therapy for the primary and secondary prevention of variceal hemorrhage. BACKGROUND Variceal hemorrhage is one of the more frequent and severe complications of portal hypertension due to liver disease. Beta blocker therapy has been demonstrated to decrease risk of first bleed in patients with evidence of varices and recurrent bleeding and mortality in patients with history of prior variceal hemorrhage. STUDY A total of 106 patients with liver disease hospitalized with suspected variceal hemorrhage were retrospectively reviewed. RESULTS Half of patients had known varices, 44 (41.5%) of whom had experienced prior variceal hemorrhage. Only 21 (20%) were receiving beta blocker therapy at admission and 41 (48%) at discharge. The majority were not receiving therapy for primary prophylaxis (94%). Specific characteristics associated with beta blocker use could not be identified, although more patients with history of greater than two variceal hemorrhages were receiving beta blocker at admission (73% vs. 41%, P = 0.04) CONCLUSIONS This study suggests that liver disease patients with varices are often not receiving beta blocker therapy to reduce risk of first or subsequent variceal hemorrhage. Opportunity exists to optimize use of this proven prophylactic treatment and bridge an apparent gap in standard of care.
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Affiliation(s)
- Kerry Wilbur
- Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
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24
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Samonakis DN, Triantos CK, Thalheimer U, Patch DW, Burroughs AK. Management of portal hypertension. Postgrad Med J 2005; 80:634-41. [PMID: 15537846 PMCID: PMC1743143 DOI: 10.1136/pgmj.2004.020446] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Treatment of portal hypertension is evolving based on randomised controlled trials. In acute variceal bleeding, prophylactic antibiotics are mandatory, reducing mortality as well as preventing infections. Terlipressin or somatostatin combined with endoscopic ligation or sclerotherapy is the best strategy for control of bleeding but there is no added effect of vasoactive drugs on mortality. Non-selective beta-blockers are the first choice therapy for both secondary and primary prevention; if contraindications or intolerance to beta-blockers are present then band ligation should be used. Novel therapies target the increased intrahepatic resistance caused by microcirculatory intrahepatic deficiency of nitric oxide and contraction of activated intrahepatic stellate cells.
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Affiliation(s)
- D N Samonakis
- Liver Transplant and Hepatobiliary Medicine Unit, Royal Free Hospital, Pond Street, London NW3 2QG, UK.
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25
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Møller S, Henriksen JH. Review article: pathogenesis and pathophysiology of hepatorenal syndrome--is there scope for prevention? Aliment Pharmacol Ther 2004; 20 Suppl 3:31-41; discussion 42-3. [PMID: 15335398 DOI: 10.1111/j.1365-2036.2004.02112.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The hepatorenal syndrome (HRS) is a functional impairment of the kidneys in chronic liver disease caused by a circulatory failure. The prognosis is poor, particularly with type 1 HRS, but also type 2, and only liver transplantation is of lasting benefit. However, recent research into the pathophysiology of ascites and HRS has stimulated new enthusiasm in their prevention and treatment. Patients with HRS have hyperdynamic circulatory dysfunction with reduced arterial blood pressure and reduced central blood volume, owing to preferential splanchnic arterial vasodilatation. Activation of potent vasoconstricting systems, including the sympathetic nervous and renin-angiotensin-aldosterone systems, counteracts the arterial vasodilatation and leads to a pronounced renal vasoconstriction with renal hypoperfusion, a reduced glomerular filtration rate, and intense sodium-water retention. Thus prevention of HRS should seek to improve liver function, limit arterial hypotension and central hypovolaemia, and reduce renal vasoconstriction and the renal and interstitial pressures. Portal pressure can be reduced with beta-adrenergic blockers and transjugular intrahepatic portosystemic shunt (TIPS). Precipitating events, like infections, bleeding, and postparacentesis circulatory syndrome, should be treated to avoid further circulatory failure. Improvement in arterial blood pressure and central hypovolaemia can be achieved with vasoconstrictors, such as terlipressin (Glypressin), and plasma expanders such as human albumin. In the future endothelins, adenosine antagonists, long-acting vasoconstrictors, and antileukotriene drugs may play a role in preventing and treating HRS.
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Affiliation(s)
- S Møller
- Department of Clinical Physiology, Hvidovre Hospital, University of Copenhagen, Denmark.
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26
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Watson PJ. Chronic hepatitis in dogs: a review of current understanding of the aetiology, progression, and treatment. Vet J 2004; 167:228-41. [PMID: 15080872 DOI: 10.1016/s1090-0233(03)00118-7] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/10/2003] [Indexed: 12/25/2022]
Abstract
Chronic hepatitis is common in dogs in primary and referral practice but the cause is usually unknown. This paper reviews the literature on potential causes of chronic hepatitis in dogs (infectious, autoimmune, metabolic, toxic, and breed-associated) together with the literature on the progression of the disease and on treatments. This is compared with the current understanding of aetiology, progression, and treatment of chronic hepatitis in man. Unfortunately, little is known about the aetiology and progression of the canine disease and very few therapies have been subjected to critical trials. It is difficult therefore to draw conclusions about causes and effective treatment in dogs. Even the histological description for canine chronic hepatitis has yet to be standardised. Much research remains to be done and this review suggests some potential areas for future investigation.
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Affiliation(s)
- P J Watson
- Department of Clinical Veterinary Medicine, Madingley Road, Cambridge CB3 OES, UK.
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27
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Benlloch S, Beltrán B, Moreno R, Berenguer M. [Fibrogenesis and liver transplantation]. GASTROENTEROLOGIA Y HEPATOLOGIA 2003; 26:381-95. [PMID: 12809575 DOI: 10.1016/s0210-5705(03)70375-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Affiliation(s)
- S Benlloch
- Servicio de Medicina Digestiva. Hospital La Fe. Valencia. España
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28
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Weng YI, Shukla SD. Effects of chronic ethanol treatment on the angiotensin II-mediated p42/p44 mitogen-activated protein kinase and phosphorylase a activation in rat hepatocytes. Alcohol 2003; 29:83-90. [PMID: 12782249 DOI: 10.1016/s0741-8329(02)00325-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
We have demonstrated previously that 24 h of ethanol treatment potentiates angiotensin II (ANG II)-stimulated p42/p44 mitogen-activated protein kinase (MAPK) activity in hepatocytes. This potentiation of p42/p44 MAPK by ethanol exhibited agonist selectivity. To compare the effects of acute (24 h) versus chronic (6 weeks) ethanol treatment, ANG II-induced intracellular signaling was examined in (1) rat hepatocytes treated with ethanol for 24 h and (2) hepatocytes obtained from rats fed ethanol for 6 weeks. In hepatocytes obtained from rats fed ethanol for 6 weeks, ANG II-stimulated phosphorylase a was reduced, and this activity was calcium dependent and p42/p44 MAPK independent. Surprisingly, ANG II-stimulated p42/p44 MAPK activation was not affected in hepatocytes obtained from rats fed ethanol chronically (6 weeks). However, chronic (6 weeks) ethanol treatment decreased ethanol potentiation of p42/p44 MAPK by about 56.3% +/- 3.6% for p42 MAPK and 61.3% +/- 11.7% for p44 MAPK. Furthermore, ethanol had no effect on the expression of angiotensinogen and c-myc mRNA in hepatocytes. A decrease in ANG II-activated phosphorylase a, but not in p42/p44 MAPK activation, after chronic (6 weeks) ethanol treatment leads to the conclusion that they may not be dependent on each other.
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Affiliation(s)
- Yu I Weng
- Department of Pharmacology, School of Medicine, University of Missouri-Columbia, One Hospital Drive, Columbia, MO 65212, USA
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29
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Affiliation(s)
- Juan G Abraldes
- Hepatic Hemodynamic Laboratory. Liver Unit, IMD, Hospital Clínic, IDIBAPS, University of Barcelona, Spain
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Abstract
The spectrum of renal disease in patients with liver disease is expanding. The recognition of renal complications of liver diseases is essential in the management of these patients. As liver transplantation is a treatment option for many patients with chronic liver disease, the presence of renal complications impacts the decision regarding transplantation and influences the course of these patients after transplantation, especially with regard to the use of immunosuppressive therapy. The involvement of the liver and kidney in systemic conditions is common and adds to the morbidity and mortality of patients.
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Affiliation(s)
- Florence Wong
- Department of Medicine, Division of Gastroenterology, Toronto General Hospital, University of Toronto, 200 Elizabeth Street, Room 220, 9th Floor, Eaton Wing, M5G 2C4, ON, Canada.
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31
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Wong F, Liu P, Blendis L. The mechanism of improved sodium homeostasis of low-dose losartan in preascitic cirrhosis. Hepatology 2002; 35:1449-58. [PMID: 12029630 DOI: 10.1053/jhep.2002.33637] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Renal sodium retention on standing is one aspect of the abnormal renal sodium handling in preascitic, well-compensated patients with cirrhosis. Recently, it has been shown that low doses (7.5 mg) of the angiotensin II (Ang II) receptor antagonist, losartan, can reverse renal sodium retention on high, 200-mmol sodium/d diet in these patients and restore them to sodium balance. Therefore, the effect of 7.5 mg of losartan on sodium excretion, when changing from supine to erect posture for 2 hours, was examined in 10 well-compensated patients with cirrhosis and 9 age- and sex-matched controls on the same sodium diet, under strictly controlled metabolic conditions. In contrast to control subjects, in whom sodium excretion was unaffected, single 7.5-mg doses of losartan again restored the preascitic patients with cirrhosis to sodium balance. In addition, it blunted the fall in erect posture- induced renal sodium excretion by a reduction in proximal and distal tubular reabsorption of sodium. These changes occurred without any significant changes in blood volumes, systemic and renal hemodynamics, or glomerular filtration rate (GFR) and filtered sodium load compared with controls, and despite activation of the systemic renin-angiotensin-aldosterone system, which was still within normal levels. In conclusion, the beneficial natriuretic effects of low-dose losartan on erect posture - induced sodium retention in preascitic cirrhosis supports the suggestion that the pathophysiology of sodium retention in preascites is in part caused by an intrarenal tubular effect of Ang II in that posture.
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Affiliation(s)
- Florence Wong
- Department of Medicine, Divisions of Gastroenterology and Cardiology, Toronto General Hospital, University of Toronto, Toronto, ON, Canada.
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Abstract
Although the year 2001 did not see any prescription drugs withdrawn because of drug-induced liver disease, the US Food and Drug Administration requested that dietary supplements containing comfrey be taken off the market because of the danger of hepatic injury. The Food and Drug Administration remains very involved in the process by which drug-induced liver disease can be detected early in drug development and in the determination of how best to prevent hepatotoxicity after drug approval. A workshop on drug-induced liver disease cosponsored by the Food and Drug Administration, the Pharmaceutical Research and Manufacturers Association, and the American Association for the Study of Liver Diseases was held in Washington, DC, in February 2001, and the resulting white paper outlined several areas for research. A number of agents were newly described as causing various forms of liver injury, and several others had drug-induced liver disease confirmed by additional reports. Several investigators dealt with the difficulties inherent in establishing causality of drug-induced liver disease and the potential negative consequences of wrongly attributing hepatotoxicity to a particular agent. In one recent series, more than half the instances of alleged drug-induced liver disease were found to have other causes, often leading to a delay in the actual diagnosis and appropriate management. Case reports in particular were often misleading. Although several drug assessment scales have been developed, none appears to be foolproof.
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Affiliation(s)
- James H Lewis
- Georgetown University Medical Center, Washington, District of Columbia 20007, USA.
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