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Schwarz M, Simbrunner B, Jachs M, Hartl L, Balcar L, Bauer DJM, Semmler G, Hofer BS, Scheiner B, Pinter M, Stättermayer AF, Trauner M, Reiberger T, Mandorfer M. High histamine levels are associated with acute-on-chronic liver failure and liver-related death in patients with advanced chronic liver disease. Liver Int 2024; 44:2904-2914. [PMID: 39136222 DOI: 10.1111/liv.16056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 06/20/2024] [Accepted: 07/22/2024] [Indexed: 10/25/2024]
Abstract
BACKGROUND AND AIMS The role of histamine in advanced chronic liver disease (ACLD) is poorly understood. We investigated plasma histamine levels across ACLD stages and their prognostic value. METHODS We included patients with evidence of ACLD, defined by portal hypertension (hepatic venous pressure gradient [HVPG] ≥6 mmHg) and/or a liver stiffness measurement by transient elastography ≥10 kPa, who underwent HVPG measurement between 2017 and 2020. Acute-on-chronic liver failure (ACLF) and/or liver-related death were defined as composite endpoint. RESULTS Of 251 patients, 82.5% had clinically significant portal hypertension (median HVPG: 17 mmHg [interquartile range (IQR) 12-21]) and 135 patients (53.8%) were decompensated at baseline. Median plasma histamine was 8.5 nmol/L (IQR: 6.4-11.5), 37.1% of patients showed elevated values (>9.9 nmol/L). Histamine levels did not differ significantly across Child-Turcotte-Pugh (CTP) stages nor strata of model for end-stage liver disease (MELD) or HVPG. Histamine levels correlated with markers of circulatory dysfunction (i.e. sodium, renin and aldosterone). During a median follow-up of 29.2 months, 68 patients developed ACLF or liver-related death. In univariate as well as in multivariate analysis (adjusting for age, sex, HVPG as well as either MELD, clinical stage, and serum albumin or CTP and serum sodium), elevated histamine levels remained associated with the composite endpoint. CTP-based multivariate model adjusted sub-distribution hazard ratio (asHR): 1.010 (95% CI: 1.004-1.021), p < .001; MELD-based multivariate model asHR: 1.030 (95% CI: 1.017-1.040), p < .001. CONCLUSION High levels of histamine were linked to circulatory dysfunction in ACLD patients and independently associated with increased risks of ACLF or liver-related death. Further mechanistic studies on the link between histamine signalling and development of hyperdynamic circulation and ACLF are warranted.
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Affiliation(s)
- Michael Schwarz
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Benedikt Simbrunner
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
- Christian-Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
| | - Mathias Jachs
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Lukas Hartl
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Lorenz Balcar
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - David J M Bauer
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Georg Semmler
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Benedikt S Hofer
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
- Christian-Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
| | - Bernhard Scheiner
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Matthias Pinter
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Albert F Stättermayer
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
- Christian-Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
| | - Mattias Mandorfer
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
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Liu PMF, de Carvalho ST, Fradico PF, Cazumbá MLB, Campos RGB, Simões E Silva AC. Hepatorenal syndrome in children: a review. Pediatr Nephrol 2021; 36:2203-2215. [PMID: 33001296 PMCID: PMC7527294 DOI: 10.1007/s00467-020-04762-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 08/01/2020] [Accepted: 09/05/2020] [Indexed: 02/07/2023]
Abstract
Hepatorenal syndrome (HRS) occurs in patients with cirrhosis or fulminant hepatic failure and is a kind of pre-renal failure due to intense reduction of kidney perfusion induced by severe hepatic injury. While other causes of pre-renal acute kidney injury (AKI) respond to fluid infusion, HRS does not. HRS incidence is 5% in children with chronic liver conditions before liver transplantation. Type 1 HRS is an acute and rapidly progressive form that often develops after a precipitating factor, including gastrointestinal bleeding or spontaneous bacterial peritonitis, while type 2 is considered a slowly progressive form of kidney failure that often occurs spontaneously in chronic ascites settings. HRS pathogenesis is multifactorial. Cirrhosis causes portal hypertension; therefore, stasis and release of vasodilator substances occur in the hepatic vascular bed, leading to vasodilatation of splanchnic arteries and systemic hypotension. Many mechanisms seem to work together to cause this imbalance: splanchnic vasodilatation; vasoactive mediators; hyperdynamic circulation states and subsequent cardiac dysfunction; neuro-hormonal mechanisms; changes in sympathetic nervous system, renin-angiotensin system, and vasopressin. In patients with AKI and cirrhosis, fluid expansion therapy needs to be initiated as soon as possible and nephrotoxic drugs discontinued. Once HRS is diagnosed, pharmacological treatment with vasoconstrictors, mainly terlipressin plus albumin, should be initiated. If there is no response, other options can include surgical venous shunts and kidney replacement therapy. In this regard, extracorporeal liver support can be a bridge for liver transplantation, which remains as the ideal treatment. Further studies are necessary to investigate early biomarkers and alternative treatments for HRS.
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Affiliation(s)
- Priscila Menezes Ferri Liu
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais, UFMG, Avenida Alfredo Balena, 190, 2nd floor, #281 room, Belo Horizonte, Minas Gerais, 30130-100, Brazil
| | - Sarah Tayná de Carvalho
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais, UFMG, Avenida Alfredo Balena, 190, 2nd floor, #281 room, Belo Horizonte, Minas Gerais, 30130-100, Brazil
| | - Pollyanna Faria Fradico
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais, UFMG, Avenida Alfredo Balena, 190, 2nd floor, #281 room, Belo Horizonte, Minas Gerais, 30130-100, Brazil
| | - Maria Luiza Barreto Cazumbá
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais, UFMG, Avenida Alfredo Balena, 190, 2nd floor, #281 room, Belo Horizonte, Minas Gerais, 30130-100, Brazil
| | - Ramon Gustavo Bernardino Campos
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais, UFMG, Avenida Alfredo Balena, 190, 2nd floor, #281 room, Belo Horizonte, Minas Gerais, 30130-100, Brazil
| | - Ana Cristina Simões E Silva
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais, UFMG, Avenida Alfredo Balena, 190, 2nd floor, #281 room, Belo Horizonte, Minas Gerais, 30130-100, Brazil.
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Elzeftawy A, Mansour L, Kobtan A, Mourad H, El-Kalla F. Evaluation of the blood ammonia level as a non-invasive predictor for the presence of esophageal varices and the risk of bleeding. TURKISH JOURNAL OF GASTROENTEROLOGY 2019; 30:59-65. [PMID: 30465524 DOI: 10.5152/tjg.2018.17894] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
BACKGROUND/AIMS The development of esophageal varices (EV) and resultant bleeding are the most critical complications of portal hypertension. Upper gastrointestinal endoscopy is the gold standard for diagnosis of EV. To find a non-invasive method for diagnosis of EV and to predict the bleeding risk is appealing and would decrease the cost and discomfort of upper endoscopy. The aim of our study was to evaluate the blood ammonia level as a predictor of the presence of EV and of a high risk of bleeding. MATERIALS AND METHODS In this cross-sectional study, a total of 359 patients with cirrhosis were examined for the presence of EV by upper endoscopy. Abdominal ultrasonography, calculation of the Child-Pugh score, and measurement of blood ammonia were performed for each patient. RESULTS The blood ammonia level was significantly higher in patients with EV than in those without it (p<0.001), and in patients with a high risk of variceal bleeding than in those with a low risk (p=0.026). CONCLUSION An increased blood ammonia level and splenic vein diameter are predictors for the presence of EV and bleeding risk factors. The blood ammonia level may be clinically useful as it correlates with and is an independent predictor for both the endoscopic risk signs and risk factors of bleeding, and therefore, it could be used in patients with cirrhosis to decrease the number of screening endoscopies they are subjected to.
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Affiliation(s)
- Asmaa Elzeftawy
- Department of Tropical Medicine and Infectious Diseases, Tanta University School of Medicine, Tanta, Egypt
| | - Loai Mansour
- Department of Tropical Medicine and Infectious Diseases, Tanta University School of Medicine, Tanta, Egypt
| | - Abdelrahman Kobtan
- Department of Tropical Medicine and Infectious Diseases, Tanta University School of Medicine, Tanta, Egypt
| | - Heba Mourad
- Department of Clinical Pathology, Tanta University School of Medicine, Tanta, Egypt
| | - Ferial El-Kalla
- Department of Tropical Medicine and Infectious Diseases, Tanta University School of Medicine, Tanta, Egypt
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El-Kalla F, Mansour L, Kobtan A, Elzeftawy A, Abo Ali L, Abd-Elsalam S, Elyamani S, Yousef M, Amer I, Mourad H, Elhendawy M. Blood Ammonia Level Correlates with Severity of Cirrhotic Portal Hypertensive Gastropathy. Gastroenterol Res Pract 2018; 2018:9067583. [PMID: 30151003 PMCID: PMC6087568 DOI: 10.1155/2018/9067583] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Revised: 06/23/2018] [Accepted: 07/02/2018] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Portal hypertensive gastropathy (PHG) is a common anomaly with potential for bleeding found in portal hypertension. Blood ammonia levels correlate well with liver disease severity and existence of portosystemic shunts. Increased ammonia results in vasodilation and hepatic stellate cell activation causing and exacerbating portal hypertension. OBJECTIVE To assess the relation of blood ammonia to the presence and severity of portal hypertensive gastropathy in cirrhosis. METHODS This cross-sectional study included 381 cirrhotics undergoing screening for esophageal varices (EV) divided into a portal hypertensive gastropathy group (203 patients with EV and PHG), esophageal varix group (41 patients with EV but no PHG), and control group (137 patients with no EV or PHG). A full clinical examination, routine laboratory tests, abdominal ultrasonography, child score calculation, and blood ammonia measurement were performed for all patients. RESULTS Blood ammonia, portal vein, splenic vein, and splenic longitudinal diameters were significantly higher and platelet counts lower in patients with EV and EV with PHG than controls. Patients having EV with PHG had significantly higher bilirubin and ammonia than those with EV but no PHG. Severe PHG was associated with significantly higher ammonia, EV grades, and superior location and a lower splenic longitudinal diameter than mild PHG. The PHG score showed a positive correlation with blood ammonia and a negative correlation with splenic longitudinal diameter. CONCLUSIONS Blood ammonia levels correlate with the presence, severity, and score of portal hypertensive gastropathy in cirrhosis suggesting a causal relationship and encouraging trials of ammonia-lowering treatments for the management of severe PHG with a tendency to bleed.
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Affiliation(s)
- Ferial El-Kalla
- Tropical Medicine and Infectious Diseases Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Loai Mansour
- Tropical Medicine and Infectious Diseases Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Abdelrahman Kobtan
- Tropical Medicine and Infectious Diseases Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Asmaa Elzeftawy
- Tropical Medicine and Infectious Diseases Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Lobna Abo Ali
- Tropical Medicine and Infectious Diseases Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Sherief Abd-Elsalam
- Tropical Medicine and Infectious Diseases Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Sahar Elyamani
- Tropical Medicine and Infectious Diseases Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Mohamed Yousef
- Tropical Medicine and Infectious Diseases Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - I. Amer
- Hepatology and Gastroenterology Department, Faculty of Medicine, Kafrelsheikh University, Kafr Elsheikh, Egypt
| | - H. Mourad
- Clinical Pathology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Mohamed Elhendawy
- Tropical Medicine and Infectious Diseases Department, Faculty of Medicine, Tanta University, Tanta, Egypt
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Abstract
More than 4 decades after the creation of the Brooke and Parkland formulas, burn practitioners still argue about which formula is the best. So it is no surprise that there is no consensus about how to resuscitate a thermally injured patient with a significant comorbidity such as heart failure or cirrhosis or how to resuscitate a patient after an electrical or inhalation injury or a patient whose resuscitation is complicated by renal failure. All of these scenarios share a common theme in that the standard rule book does not apply. All will require highly individualized resuscitations.
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Affiliation(s)
- David T Harrington
- Rhode Island Burn Center, Rhode Island Hospital, Warren Alpert Medical School of Brown University, 593 Eddy Street, APC 444, Providence, RI 02903, USA.
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Granger DN, Holm L, Kvietys P. The Gastrointestinal Circulation: Physiology and Pathophysiology. Compr Physiol 2016; 5:1541-83. [PMID: 26140727 DOI: 10.1002/cphy.c150007] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The gastrointestinal (GI) circulation receives a large fraction of cardiac output and this increases following ingestion of a meal. While blood flow regulation is not the intense phenomenon noted in other vascular beds, the combined responses of blood flow, and capillary oxygen exchange help ensure a level of tissue oxygenation that is commensurate with organ metabolism and function. This is evidenced in the vascular responses of the stomach to increased acid production and in intestine during periods of enhanced nutrient absorption. Complimenting the metabolic vasoregulation is a strong myogenic response that contributes to basal vascular tone and to the responses elicited by changes in intravascular pressure. The GI circulation also contributes to a mucosal defense mechanism that protects against excessive damage to the epithelial lining following ingestion of toxins and/or noxious agents. Profound reductions in GI blood flow are evidenced in certain physiological (strenuous exercise) and pathological (hemorrhage) conditions, while some disease states (e.g., chronic portal hypertension) are associated with a hyperdynamic circulation. The sacrificial nature of GI blood flow is essential for ensuring adequate perfusion of vital organs during periods of whole body stress. The restoration of blood flow (reperfusion) to GI organs following ischemia elicits an exaggerated tissue injury response that reflects the potential of this organ system to generate reactive oxygen species and to mount an inflammatory response. Human and animal studies of inflammatory bowel disease have also revealed a contribution of the vasculature to the initiation and perpetuation of the tissue inflammation and associated injury response.
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Affiliation(s)
- D Neil Granger
- Department of Molecular and Cellular Physiology, LSU Health Science Center-Shreveport, Shreveport, Louisiana, USA
| | - Lena Holm
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Peter Kvietys
- Department of Physiological Sciences, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
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Changes in gene expression of cytochrome P-450 in liver, kidney and aorta of cirrhotic rats. Prostaglandins Other Lipid Mediat 2015; 120:134-8. [DOI: 10.1016/j.prostaglandins.2015.03.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2014] [Revised: 03/21/2015] [Accepted: 03/26/2015] [Indexed: 11/19/2022]
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Bolognesi M, Verardo A, Pascoli MD. Peculiar characteristics of portal-hepatic hemodynamics of alcoholic cirrhosis. World J Gastroenterol 2014; 20:8005-8010. [PMID: 25009370 PMCID: PMC4081669 DOI: 10.3748/wjg.v20.i25.8005] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2013] [Revised: 12/31/2013] [Accepted: 02/27/2014] [Indexed: 02/06/2023] Open
Abstract
Alcohol-related cirrhosis is a consequence of heavy and prolonged drinking. Similarly to patients with cirrhosis of other etiologies, patients with alcoholic cirrhosis develop portal hypertension and the hepatic, splanchnic and systemic hemodynamic alterations that follow. However, in alcoholic cirrhosis, some specific features can be observed. Compared to viral cirrhosis, in alcohol-related cirrhosis sinusoidal pressure is generally higher, hepatic venous pressure gradient reflects portal pressure better, the portal flow perfusing the liver is reduced despite an increase in liver weight, the prevalence of reversal portal blood flow is higher, a patent paraumbilical vein is a more common finding and signs of hyperdynamic circulations, such as an increased cardiac output and decreased systemic vascular resistance, are more pronounced. Moreover, alcohol consumption can acutely increase portal pressure and portal-collateral blood flow. Alcoholic cardiomyopathy, another pathological consequence of prolonged alcohol misuse, may contribute to the hemodynamic changes occurring in alcohol-related cirrhosis. The aim of this review was to assess the portal-hepatic changes that occur in alcohol-related cirrhosis, focusing on the differences observed in comparison with patients with viral cirrhosis. The knowledge of the specific characteristics of this pathological condition can be helpful in the management of portal hypertension and its complications in patients with alcohol-related cirrhosis.
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Bolognesi M, Di Pascoli M, Verardo A, Gatta A. Splanchnic vasodilation and hyperdynamic circulatory syndrome in cirrhosis. World J Gastroenterol 2014; 20:2555-2563. [PMID: 24627591 PMCID: PMC3949264 DOI: 10.3748/wjg.v20.i10.2555] [Citation(s) in RCA: 147] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2013] [Revised: 11/08/2013] [Accepted: 11/30/2013] [Indexed: 02/06/2023] Open
Abstract
Portal hypertension is a clinical syndrome which leads to several clinical complications, such as the formation and rupture of esophageal and/or gastric varices, ascites, hepatic encephalopathy and hepato-renal syndrome. In cirrhosis, the primary cause of the increase in portal pressure is the enhanced resistance to portal outflow. However, also an increase in splanchnic blood flow worsens and maintains portal hypertension. The vasodilatation of arterial splanchnic vessels and the opening of collateral circulation are the determinants of the increased splanchnic blood flow. Several vasoactive systems/substances, such as nitric oxide, cyclooxygenase-derivatives, carbon monoxide and endogenous cannabinoids are activated in portal hypertension and are responsible for the marked splanchnic vasodilatation. Moreover, an impaired reactivity to vasoconstrictor systems, such as the sympathetic nervous system, vasopressin, angiotensin II and endothelin-1, plays a role in this process. The opening of collateral circulation occurs through the reperfusion and dilatation of preexisting vessels, but also through the generation of new vessels. Splanchnic vasodilatation leads to the onset of the hyperdynamic circulatory syndrome, a syndrome which occurs in patients with portal hypertension and is characterized by increased cardiac output and heart rate, and decreased systemic vascular resistance with low arterial blood pressure. Understanding the pathophysiology of splanchnic vasodilatation and hyperdynamic circulatory syndrome is mandatory for the prevention and treatment of portal hypertension and its severe complications.
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Chen XL, Chen TW, Zhang XM, Li ZL, Li H, Zeng NL, Tang HJ, Pu Y, Chen N, Yang Q, Li L, Xie XY, Hu J. Spleen magnetic resonance diffusion-weighted imaging for quantitative staging hepatic fibrosis in miniature pigs: An initial study. Hepatol Res 2013; 43:1231-1240. [PMID: 23421793 DOI: 10.1111/hepr.12076] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2012] [Revised: 01/15/2013] [Accepted: 01/16/2013] [Indexed: 02/05/2023]
Abstract
AIM To determine whether spleen diffusion-weighted imaging (DWI) parameters might classify liver fibrosis stage. METHODS Sixteen miniature pigs were prospectively used to model liver fibrosis, and underwent spleen DWI by using b = 300, 500 and 800 s/mm(2) on 0, 5th, 9th, 16th and 21st weekend after the beginning of modeling. Signal intensity ratio of spleen to paraspinous muscles (S/M), spleen exponential apparent diffusion coefficient (eADC) and apparent diffusion coefficient (ADC) for each b-value were statistically analyzed. RESULTS With increasing stages of fibrosis, S/M for all b-values showed a downward trend; and spleen eADC and ADC for b = 300 s/mm(2) showed downward and upward trends, respectively (all P < 0.05). The area under the receiver-operator curve (AUC) of spleen DWI parameters was 0.777 or more by S/M for classifying each fibrosis stage, and 0.65 or more by eADC and 0.648 or more by ADC for classifying stage ≥3 or cirrhosis. Among the spleen DWI parameters, S/M for b = 300 s/mm(2) was the best parameter in classifying stage 1 or more, 2 or more and 3 or more with AUC of 0.875, 0.851 and 0.843, respectively; and spleen eADC for b = 300 s/mm(2) was best in classifying stage 4 with an AUC of 0.988. CONCLUSION Spleen DWI may be used to stage liver fibrosis.
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Affiliation(s)
- Xiao-Li Chen
- Sichuan Key Laboratory of Medical Imaging, Department of Radiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
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Seo YS, Shah VH. Pathophysiology of portal hypertension and its clinical links. J Clin Exp Hepatol 2011; 1:87-93. [PMID: 25755320 PMCID: PMC3940250 DOI: 10.1016/s0973-6883(11)60127-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2011] [Accepted: 07/27/2011] [Indexed: 02/08/2023] Open
Abstract
Portal hypertension is a major cause of morbidity and mortality in patients with liver cirrhosis. Intrahepatic vascular resistance due to architectural distortion and intrahepatic vasoconstriction, increased portal blood flow due to splanchnic vasodilatation, and development of collateral circulation have been considered as major factors for the development of portal hypertension. Recently, sinusoidal remodeling and angiogenesis have been focused as potential etiologic factors and various researchers have tried to improve portal hypertension by modulating these new targets. This article reviews potential new treatments in the context of portal hypertension pathophysiology concepts.
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Key Words
- AT, angiotensin
- ET-1, endothelin-1
- HSC, hepatic stellate cell
- HVPG, hepatic venous pressure gradient
- NO, nitric oxide
- PDGF, platelet-derived growth factor
- PIGF, placenta! growth factor
- RAS, renin-angiotensin system
- RCT, randomized controlled trial
- VEGF, vascular endothelial growth factor
- angiogenesis
- eNOS, endothelial nitric oxide synthase
- pathophysiology
- portal hypertension
- sinusoids
- treatment
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Affiliation(s)
- Yeon Seok Seo
- Gastroenterology Research Unit, Mayo Clinic, Rochester, MN - 55905, USA
| | - Vijay H Shah
- Gastroenterology Research Unit, Mayo Clinic, Rochester, MN - 55905, USA,Mayo Clinic Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, MN - 55905, USA,Address for correspondence: Dr Vijay H Shah, Gastroenterology Research Unit, Mayo Clinic, 200 First Street SW, Rochester, MN - 55905, USA
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Portale Hypertension. PRAXIS DER VISZERALCHIRURGIE. GASTROENTEROLOGISCHE CHIRURGIE 2011. [PMCID: PMC7123479 DOI: 10.1007/978-3-642-14223-9_38] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
Während die Pathologie, die zur portalen Hypertension führt, im prähepatischen, hepatischen und posthepatischen venösen Gefäßbett liegen kann, machen die intrahepatischen Erkrankungen mit Abstand den Großteil aus. In unseren Breitengraden ist es die durch Alkoholabusus bedingte ethyltoxische Leberzirrhose, weltweit die durch Infektionen (HCV, HBV) bedingten Zirrhosen. Die chronische Hepatitis C mit ihren Komplikationen (Leberzellversagen, portale Hypertension und hepatozelluläres Karzinom) wird in den kommenden Jahren trotz moderner Therapieverfahren noch an Bedeutung gewinnen.
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Abstract
Liver cirrhosis is associated with a wide range of cardiovascular abnormalities including hyperdynamic circulation, cirrhotic cardiomyopathy, and pulmonary vascular abnormalities. The pathogenic mechanisms of these cardiovascular changes are multifactorial and include neurohumoral and vascular dysregulations. Accumulating evidence suggests that cirrhosis-related cardiovascular abnormalities play a major role in the pathogenesis of multiple life-threatening complications including hepatorenal syndrome, ascites, spontaneous bacterial peritonitis, gastroesophageal varices, and hepatopulmonary syndrome. Treatment targeting the circulatory dysfunction in these patients may improve the short-term prognosis while awaiting liver transplantation. Careful fluid management in the immediate post-transplant period is extremely important to avoid cardiac-related complications. Liver transplantation results in correction of portal hypertension and reversal of all the pathophysiological mechanisms that lead to the cardiovascular abnormalities, resulting in restoration of a normal circulation. The following is a review of the pathogenesis and clinical implications of the cardiovascular changes in cirrhosis.
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Affiliation(s)
- Waleed K. Al-Hamoudi
- Gastroenterology and Hepatology Unit, Department of Medicine, King Saud University, Riyadh, Saudi Arabia,Address for correspondence: Dr. Waleed Al-Hamoudi, Gastroenterology and Hepatology Unit (59), Department of Medicine, King Saud University, P.O. Box 2925, Riyadh 11461, Saudi Arabia. E-mail:
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Moleda L, Jurzik L, Froh M, Gäbele E, Hellerbrand C, Straub RH, Schölmerich J, Wiest R. Role of HSP-90 for increased nNOS-mediated vasodilation in mesenteric arteries in portal hypertension. World J Gastroenterol 2010; 16:1837-44. [PMID: 20397260 PMCID: PMC2856823 DOI: 10.3748/wjg.v16.i15.1837] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore the role of heat shock protein-90 (HSP-90) for nitrergic vasorelaxation in the splanchnic circulation in rats with and without portal hypertension.
METHODS: Neuronal nitric oxide synthase (nNOS) and HSP-90 were analyzed by immunofluorescence, western blotting and co-immunoprecipitation in the mesenteric vasculature and isolated nerves of portal-vein-ligated (PVL) rats and sham operated rats. In vitro perfused de-endothelialized mesenteric arterial vasculature was preconstricted with norepinephrine (EC80) and tested for nNOS-mediated vasorelaxation by periarterial nerve stimulation (PNS, 2-12 Hz, 45V) before and after incubation with geldanamycin (specific inhibitor of HSP-90 signalling, 3 μg/mL) or L-NAME (non-specific NOS-blocker, 10-4 mol/L).
RESULTS: nNOS and HSP-90 expression was significantly increased in mesenteric nerves from PVL as compared to sham rats. Moreover, nNOS and HSP-90 were visualized in mesenteric nerves by immunofluorescence and immunoprecipitation of nNOS co-immunoprecitated HSP-90 in sham and PVL rats. PNS induced a frequency-dependent vasorelaxation which was more pronounced in PVL as compared to sham rats. L-NAME and geldanamycin markedly reduced nNOS-mediated vasorelaxation abrogating differences between the study groups. The effect of L-NAME and geldanamycin on nNOS-mediated vasorelaxation was significantly greater in PVL than in sham animals. However, no difference in magnitude of effect between L-NAME and geldanamycin was noted.
CONCLUSION: HSP-90 acts as a signalling mediator of nNOS-dependent nerve mediated vascular responses in mesenteric arteries, and the increased nitrergic vasorelaxation observed in portal hypertension is mediated largely by HSP-90.
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Scallan J, Huxley VH, Korthuis RJ. Capillary Fluid Exchange: Regulation, Functions, and Pathology. ACTA ACUST UNITED AC 2010. [DOI: 10.4199/c00006ed1v01y201002isp003] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Vilas-Boas WW, Ribeiro-Oliveira Jr A, Pereira RM, Ribeiro RDC, Almeida J, Nadu AP, Simões e Silva AC, Santos RASD. Relationship between angiotensin-(1-7) and angiotensin II correlates with hemodynamic changes in human liver cirrhosis. World J Gastroenterol 2009; 15:2512-9. [PMID: 19469002 PMCID: PMC2686910 DOI: 10.3748/wjg.15.2512] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To measure circulating angiotensins at different stages of human cirrhosis and to further evaluate a possible relationship between renin angiotensin system (RAS) components and hemodynamic changes.
METHODS: Patients were allocated into 4 groups: mild-to-moderate liver disease (MLD), advanced liver disease (ALD), patients undergoing liver transplantation, and healthy controls. Blood was collected to determine plasma renin activity (PRA), angiotensin (Ang) I, Ang II, and Ang-(1-7) levels using radioimmunoassays. During liver transplantation, hemodynamic parameters were determined and blood was simultaneously obtained from the portal vein and radial artery in order to measure RAS components.
RESULTS: PRA and angiotensins were elevated in ALD when compared to MLD and controls (P < 0.05). In contrast, Ang II was significantly reduced in MLD. Ang-(1-7)/Ang II ratios were increased in MLD when compared to controls and ALD. During transplantation, Ang II levels were lower and Ang-(1-7)/Ang II ratios were higher in the splanchnic circulation than in the peripheral circulation (0.52 ± 0.08 vs 0.38 ± 0.04, P < 0.02), whereas the peripheral circulating Ang II/Ang I ratio was elevated in comparison to splanchnic levels (0.18 ± 0.02 vs 0.13 ± 0.02, P < 0.04). Ang-(1-7)/Ang II ratios positively correlated with cardiac output (r = 0.66) and negatively correlated with systemic vascular resistance (r = -0.70).
CONCLUSION: Our findings suggest that the relationship between Ang-(1-7) and Ang II may play a role in the hemodynamic changes of human cirrhosis.
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Gatta A, Bolognesi M, Merkel C. Vasoactive factors and hemodynamic mechanisms in the pathophysiology of portal hypertension in cirrhosis. Mol Aspects Med 2007; 29:119-29. [PMID: 18036654 DOI: 10.1016/j.mam.2007.09.006] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2007] [Accepted: 09/28/2007] [Indexed: 02/08/2023]
Abstract
Portal hypertension is primarily caused by the increase in resistance to portal outflow and secondly by an increase in splanchnic blood flow, which worsens and maintains the increased portal pressure. Increased portal inflow plays a role in the hyperdynamic circulatory syndrome, a characteristic feature of portal hypertensive patients. Almost all the known vasoactive systems/substances are activated in portal hypertension, but most authors stress the pathogenetic role of endothelial factors, such as COX-derivatives, nitric oxide, carbon monoxide. Endothelial dysfunction is differentially involved in different vascular beds and consists in alteration in response both to vasodilators and to vasoconstrictors. Understanding the pathogenesis of portal hypertension could be of great utility in preventing and curing the complications of portal hypertension, such as esophageal varices, hepatic encephalopathy, ascites.
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Affiliation(s)
- Angelo Gatta
- Department of Clinical and Experimental Medicine, University of Padova, Via Giustiniani 2, 35128 Padova, Italy.
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Arroyo V, Terra C, Ruiz‐del‐Arbol L. Pathogenesis, Diagnosis and Treatment of Ascites in Cirrhosis. TEXTBOOK OF HEPATOLOGY 2007:666-710. [DOI: 10.1002/9780470691861.ch7e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Arroyo V, Terra C, Ginès P. Advances in the pathogenesis and treatment of type-1 and type-2 hepatorenal syndrome. J Hepatol 2007; 46:935-46. [PMID: 17391801 DOI: 10.1016/j.jhep.2007.02.001] [Citation(s) in RCA: 95] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
- Vicente Arroyo
- Liver Unit, Institute of Digestive and Metabolic Diseases, Hospital Clinic, University of Barcelona, Barcelona, Spain.
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Affiliation(s)
- Robert E Shangraw
- Department of Anesthesiology, School of Medicine, Oregon Health and Science University, Portland, OR 97201, USA
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Takiguchi F, Irisawa A, Saito A, Sakamoto H, Obara K, Kasukawa R, Ohira H. EFFECT OF ISOSORBIDE DINITRATE ON GASTRIC BLOOD FLOW IN RATS WITH LIVER CIRRHOSIS DETERMINED BY ANALYZING GASTRIC BLOOD FLOW, PORTAL VEIN PRESSURE AND BLOOD GAS. Fukushima J Med Sci 2006; 52:111-24. [PMID: 17427762 DOI: 10.5387/fms.52.111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
We investigated the effects of isosorbide dinitrate (IDN) on gastric blood flow (GBF), portal venous pressure (PVP) and blood gas of rats with liver cirrhosis (LC) accompanied by portal hypertension. Thirty male Wistar rats (LC in 17 and normal in 13) were used. Before and after IDN administration, GBF, PVP and blood gas in the femoral artery and portal vein were measured. Portal blood oxygen concentration was estimated by calculating the ratio of PO2 in portal blood and that in arterial blood (PpvO2/PaO2) of each rat. The GBF in the LC rats was significantly lower than that in the normal rats. In the LC group, IDN administration significantly increased the GBF. The PpvO2/PaO2 value in the group with LC was significantly lower after IDN administration than that before IDN administration. In the investigation whether changes in PVP or Ppv/PaO2 contributed more to the change in GBF after IDN administration, a significant correlation was found between rates of change in GBF and PpvO2/PaO2 were significantly correlated (r= -0.733, p <0.05). The effect of IDN on changes in the stomach accompanying portal hypertension is mainly attributable to a decrease in preload, which suppresses inflow to the stomach, as reflected by a decrease in PpvO2/ PaO2, rather than to a decrease in afterload on GBF, as reflected by a decrease in PVP.
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Affiliation(s)
- Fujio Takiguchi
- Department of Internal Medicine II, Fukushima Medical University, School of Medicine, Fukushima, 960-1295, Japan
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Jurzik L, Froh M, Straub RH, Schölmerich J, Wiest R. Up-regulation of nNOS and associated increase in nitrergic vasodilation in superior mesenteric arteries in pre-hepatic portal hypertension. J Hepatol 2005; 43:258-65. [PMID: 15963596 DOI: 10.1016/j.jhep.2005.02.036] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2004] [Revised: 02/03/2005] [Accepted: 02/16/2005] [Indexed: 02/08/2023]
Abstract
BACKGROUND/AIMS Splanchnic arterial vasodilation in portal hypertension has been attributed largely to vascular NO overproduction. Three NO-synthase (NOS) isoforms have been identified of which e(ndothelial)-NOS has been found up-regulated and i(nducible)-NOS not expressed in the splanchnic circulation in portal hypertension. So far, n(euronal)-NOS has not been investigated and hence, the current study evaluates nNOS-expression and nNOS-mediated vasorelaxation in a model of portal vein-ligated rats (PVL). METHODS Mesenteric vasculature of PVL and sham rats was evaluated for nNOS-protein (immunohistochemically and Western blotting). In vitro perfused de-endothelialized mesenteric arterial vasculature was pre-constricted with norepinephrine (EC(80)) and tested for nNOS-mediated vasorelaxation by periarterial nerve stimulation (PNS, 2-12 Hz, 45V) before and after incubation with the NOS-inhibitor L-NAME (10(-4)M). RESULTS nNOS was localized to the adventitia of the mesenteric arterial tree showing more intense staining and increased protein expression in PVL as compared to sham rats. PNS induced a frequency-dependent vasorelaxation, which was more pronounced in PVL rats. L-NAME abolished this difference in nerval-mediated vasorelaxation, the effect being significantly greater in PVL than in sham animals. CONCLUSIONS Perivascular nNOS-protein expression is enhanced in mesenteric arteries in portal hypertension mediating an increased nerval NO-mediated vasorelaxation. This nNOS-derived NO overproduction may play an important role in the pathogenesis of arterial vasodilation in portal hypertension.
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MESH Headings
- Animals
- Blotting, Western
- Disease Models, Animal
- Endothelium, Vascular/enzymology
- Endothelium, Vascular/pathology
- Enzyme Inhibitors/pharmacology
- Hypertension, Portal/enzymology
- Hypertension, Portal/physiopathology
- Immunohistochemistry
- Male
- Mesenteric Artery, Superior/drug effects
- Mesenteric Artery, Superior/enzymology
- Mesenteric Artery, Superior/pathology
- Mesenteric Artery, Superior/physiopathology
- NG-Nitroarginine Methyl Ester/pharmacology
- Nerve Tissue Proteins/biosynthesis
- Nitric Oxide/biosynthesis
- Nitric Oxide Synthase/biosynthesis
- Nitric Oxide Synthase Type I
- Rats
- Rats, Sprague-Dawley
- Up-Regulation/drug effects
- Up-Regulation/physiology
- Vasodilation/drug effects
- Vasodilation/physiology
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Affiliation(s)
- Lars Jurzik
- Department of Internal Medicine, University School of Medicine, 93042 Regensburg, Germany
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Abraldes JG, García-Pagán JC, Bosch J. Componente funcional de la hipertensión portal. GASTROENTEROLOGIA Y HEPATOLOGIA 2004; 27:377-87. [PMID: 15207139 DOI: 10.1016/s0210-5705(03)70480-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Affiliation(s)
- J G Abraldes
- Hepatic Hemodynamic Laboratory, VA Healthcare System, West Haven, USA.
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Cárdenas A, Arroyo V. Mechanisms of water and sodium retention in cirrhosis and the pathogenesis of ascites. Best Pract Res Clin Endocrinol Metab 2003; 17:607-22. [PMID: 14687592 DOI: 10.1016/s1521-690x(03)00052-6] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Patients with advanced cirrhosis and portal hypertension often show an abnormal regulation of extracellular fluid volume, resulting in the accumulation of fluid as ascites, pleural effusion or oedema. The mechanisms responsible for ascites formation include alterations in the splanchnic circulation as well as renal functional abnormalities that favour sodium and water retention. Renal abnormalities occur in the setting of a hyperdynamic state characterized by an increase cardiac output, a reduction in total vascular resistance and an activation of neurohormonal vasoactive systems. This circulatory dysfunction, due mainly to intense arterial vasodilation in the splanchnic circulation, is considered to be a primary feature in the pathogenesis of ascites. A major factor involved in the development of splanchnic arterial vasodilation is nitric oxide (NO), a potent vasodilator that is elevated in the splanchnic circulation of patients with cirrhosis. This event decreases effective arterial blood volume and leads to fluid accumulation and renal function abnormalities which are a consequence of the homeostatic activation of vasoconstrictor and antinatriuretic factors triggered to compensate for a relative arterial underfilling. The net effect is avid retention of sodium and water as well as renal vasoconstriction. The mechanisms of sodium and water retention and ascites formation in patients with cirrhosis are discussed in this review.
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Affiliation(s)
- Andrés Cárdenas
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Ave, Dana 501, Boston, MA 02215, USA
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Hsieh JS, Wang JY, Lin SR, Lian ST, Chen FM, Hsieh MC, Huang TJ. Overexpression of inducible nitric oxide synthase in gastric mucosa of rats with portal hypertension: correlation with gastric mucosal damage. J Surg Res 2003; 115:24-32. [PMID: 14572769 DOI: 10.1016/s0022-4804(03)00309-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND An increased biosynthesis of nitric oxide (NO) has been implicated in the hyperdynamic circulation and development of collaterals of portal hypertension (PHT) because of its potent vasodilatory effects. NO is synthesized from L-arginine by three different isozymes of nitric oxide synthase (nNOS, iNOS and eNOS). Thus, the expression of inducible NOS (iNOS) might account for NO overproduction in PHT. However, in previous investigations, the role of iNOS in the pathogenesis of PHT gastropathy remained controversial. Our current study was in both molecular and protein levels to determine whether the expression of iNOS is responsible for PHT gastropathy. MATERIALS AND METHODS PHT was induced experimentally by partial ligation of the portal vein. Fourteen days after partial ligation of the portal vein, the rats were randomly assigned to receive either vehicle or L-NAME (NOS inhibitor) at doses of 5 mg/kg/day, 10 mg/kg/day, or 25 mg/kg/day by gastric lavage twice a day for 1 week. Sham operated rats served as controls. Northern hybridization and in situ hybridization are used to compare the expression of gastric mucosa iNOS mRNA in the PHT rats and the controls. NO was measured by the Griess method after reduction of nitrate to nitrite with nitrate reductase. Immunohistochemical staining was carried out to detect the iNOS protein. In addition, the severity of gross gastric mucosal lesions was evaluated macroscopically by a gross ulcer index. RESULTS The iNOS expression at both mRNA and protein was prominently increased in PHT rats, accompanied with the enhanced NO production. The gastric mucosa iNOS mRNA and serum NO levels were significantly decreased after L-NAME administration (P < 0.05). However, the markedly reduced gastric mucosal damage in PHT rats was observed only at high does of L-NAME (25 mg/kg/day) administration. CONCLUSION PHT triggers overexpression of iNOS mRNA and proteins in rat gastric mucosa, but that this alone does not account for PHT gastropathy.
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Affiliation(s)
- Jan-Sing Hsieh
- Department of Surgery, Kaohsiung Medical University, Kaohsiung, Taiwan.
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Birney Y, Redmond EM, Sitzmann JV, Cahill PA. Eicosanoids in cirrhosis and portal hypertension. Prostaglandins Other Lipid Mediat 2003; 72:3-18. [PMID: 14626493 DOI: 10.1016/s1098-8823(03)00080-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
In the last decade, the knowledge of the pathogenesis of portal hypertension and cirrhosis has increased dramatically. In portal hypertension, almost all the known vasoactive systems/substances are activated or increased and the most recent studies have stressed the importance of the endothelial factors, in particular, prostaglandins. Prostaglandins are formed following the oxygenation of arachidonic acid by the cyclooxygenase (Cox) pathway. An important consideration in portal hypertension and cirrhosis in the periphery is the altered hemodynamic profile and its contributory role in controlling endothelial release of these vasoactive substances. Prostaglandins are released from the endothelium in response to both humoral and mechanical stimuli and can profoundly affect both intrahepatic and peripheral vascular resistance. Within the liver, intrahepatic resistance is altered due to a diminution in sinusoidal responsiveness to vasodilators and an increase in prostanoid vasoconstrictor responsiveness. This review will examine the contributory role of both hormonal and/or hemodynamic force-induced changes in prostaglandin production and signaling in cirrhosis and portal hypertension and the consequence of these changes on the structural and functional response of both the vasculature and the liver.
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Affiliation(s)
- Yvonne Birney
- School of Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland
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Cárdenas A, Sánchez-Fueyo A. [Circulatory dysfunction in cirrhosis. Physiopathology and clinical implications]. GASTROENTEROLOGIA Y HEPATOLOGIA 2003; 26:447-55. [PMID: 12887860 DOI: 10.1016/s0210-5705(03)70388-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Affiliation(s)
- A Cárdenas
- Division of Gastroenterology and Hepatology. Beth Israel Deaconess Medical Center. Harvard Medical School. Boston. MA 02215, USA.
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Abstract
In liver cirrhosis, an increase in hepatic resistance is the initial phenomenon leading to portal hypertension. This is primarily due to the structural distortion of the intrahepatic microcirculation caused by cirrhosis. However, similar to other vascular conditions, architectural changes in the liver are associated with a deficient nitric oxide (NO) production, which results in an increased vascular tone with a further increase in hepatic resistance and portal pressure. New therapeutic strategies are being developed to selectively provide the liver with NO, overcoming the deleterious effects of systemic vasodilators. On the other hand, a strikingly opposite process occurs in splanchnic arterial circulation, where NO production is increased. This results in splanchnic vasodilatation and subsequent increase in portal inflow, which contributes to portal hypertension. Systemic blockade of NO in portal hypertension attenuates the hyperdynamic circulation, but its effects increasing hepatic resistance may offset the benefit of reducing portal inflow, thus preventing an effective reduction of portal pressure. Moreover, it cannot be ruled out that NO blockade may have a deleterious action on cirrhosis progression, which raises caution about their use in patients with cirrhosis.
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Affiliation(s)
- Juan González-Abraldes
- Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic, IDIBAPS, University of Barcelona, Spain
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Abstract
Ascites is one of the most frequent complications of cirrhosis. Its appearance is considered as the marker of the transition from the compensated to the decompensated stage of the disease. Appearance of ascites also has prognostic significance, as it causes a sharp drop in the expected survival rate. Portal hypertension is a sine qua-non for the development of ascites. Although no precise portal pressure threshold has been defined for the development of ascites, the latter rarely develops with portal pressures below 12 mmHg. In addition, in patients treated with interventions that markedly decrease portal pressure, such as surgical porta-caval shunts or transjugular intrahepatic portalsystemic shunts, a disappearance or a marked reduction of ascites can be observed. The currently most accepted theory of ascites formation is the so-called 'forward' theory. According to this theory, the development of ascites is related to the presence of severe sinusoidal portal hypertension, which causes marked splanchnic arterial vasodilation and a forward increase in the splanchnic production of lymph. Splanchnic arterial vasodilation also causes a significant reduction of the effective blood volume, leading to activation of sodium and water-retaining mechanisms. The retained sodium and water, however, while increasing total plasma volume, are unable to compensate for the reduced effective blood volume, initiating a vicious cycle. In the advanced stages of cirrhosis, the extreme underfilling of the arterial circulation leads to a maximal stimulation of the vasoconstrictor mechanisms which override the protective effect of renal vasodilator factors and cause renal vasoconstriction, further aggravating ascites and leading to functional renal insufficiency. Renal insufficiency is also one of the main causes of resistance to diuretic therapy. While several studies have investigated the predictors of survival in cirrhotic patients with ascites, this has not been done for the occurrence of resistance to therapy. However, as the mechanisms of refractoriness are associated with advanced disease and short survival, the models developed for predicting survival should be employed also to verify if they can exert such additional prediction.
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Affiliation(s)
- Roberto De Franchis
- Gastroenterology and Gastrointestinal Endoscopy Service, IRCCS Ospedale Policlinico, Department of Internal Medicine, University of Milan, Milan, Italy.
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Marshall MM, Beese RC, Muiesan P, Sarma DI, O'Grady J, Sidhu PS. Assessment of portal venous system patency in the liver transplant candidate: a prospective study comparing ultrasound, microbubble-enhanced colour Doppler ultrasound, with arteriography and surgery. Clin Radiol 2002; 57:377-83. [PMID: 12014935 DOI: 10.1053/crad.2001.0839] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
AIM To determine the role of microbubble-enhanced colour Doppler ultrasound (CDUS) in assessing portal venous patency prior to liver transplantation. MATERIALS AND METHODS Over a 2-year period, all patients with chronic liver disease undergoing routine pre-transplant CDUS examination in whom the portal venous system was inadequately demonstrated were recruited to the study. CDUS was performed in 368 patients and 33 patients (9%) were recruited. A repeat CDUS examination following an intravenous bolus injection of the microbubble contrast agent Levovist (Schering Healthcare AG, Berlin, Germany) was performed. Diagnostic confidence was recorded on a free linear analogue scale for both examinations. Findings were compared with indirect portography and surgery. RESULTS Of the 33 patients with sub-optimal baseline examinations, improvement in portal vein visualization was achieved in 31 patients (94%). Median diagnostic confidence increased from 50% (interquartile range 30-60) to 90% (interquartile range 75-98) (P < 0.001) following administration of Levovist. Overall accuracy of portal vein assessment using microbubble-enhanced CDUS in 15 patients in whom a definitive diagnosis was made within 2 months was 87%. CONCLUSION Microbubble-enhanced CDUS is a simple, inexpensive adjunct to standard pre liver transplant screening of the portal vein. It is particularly helpful in patients with end-stage cirrhosis who are at high risk of portal vein thrombosis and in whom the conventional examination is sub-optimal.
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Affiliation(s)
- M M Marshall
- Department of Radiology, King's College Hospital, London, U.K.
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Bolognesi M, Merkel C, Sacerdoti D, Nava V, Gatta A. Role of spleen enlargement in cirrhosis with portal hypertension. Dig Liver Dis 2002; 34:144-50. [PMID: 11926560 DOI: 10.1016/s1590-8658(02)80246-8] [Citation(s) in RCA: 172] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The possible relationships between splenomegaly and portal hypertension have been analysed in patients with cirrhosis. In this condition, splenomegaly is not only caused by portal congestion, but it is mainly due to tissue hyperplasia and fibrosis. The increase in spleen size is followed by an increase in splenic blood flow, which participates in portal hypertension actively congesting the portal system.
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Affiliation(s)
- M Bolognesi
- Department of Clinical and Experimental Medicine, University of Padua, Italy.
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Albornoz L, Motta A, Alvarez D, Estevez A, Bandi JC, McCormack L, Matera J, Bonofiglio C, Ciardullo M, De Santibañes E, Gimeno M, Gadan A. Nitric oxide synthase activity in the splanchnic vasculature of patients with cirrhosis: relationship with hemodynamic disturbances. J Hepatol 2001; 35:452-6. [PMID: 11682028 DOI: 10.1016/s0168-8278(01)00168-4] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
BACKGROUND/AIMS It has been demonstrated that an overproduction of nitric oxide plays an important role in the pathogenesis of the hyperdynamic circulation exhibited by cirrhotic patients. Nevertheless, evidence is supported by studies performed in experimental models or by indirect measurements in humans. The purpose of this study has been to evaluate nitric oxide production in splanchnic vasculature of patients with cirrhosis and to investigate its possible relationship with systemic and splanchnic hemodynamics. METHODS Nitric oxide synthase (NOS) activity was measured in hepatic artery and portal vein tissues of nine cirrhotic patients. Samples were obtained during liver transplantation. Control samples were obtained simultaneously from the corresponding tissues of the liver donors. Hemodynamic parameters were determined with Doppler ultrasonography. RESULTS NOS activity was significantly higher in hepatic artery of cirrhotic patients than in controls (8.17 +/- 1.30 vs 4.57 +/- 0.61 pmoles/g of tissue/min, P < 0.05). Patients with ascites showed a higher hepatic artery NOS activity than patients without ascites. Highly significant correlation was observed between cardiac output and hepatic artery NOS activity as well as between portal blood flow and hepatic artery NOS activity. CONCLUSIONS The present study demonstrates an enhanced production of nitric oxide in the splanchnic vasculature of patients with cirrhosis.
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Affiliation(s)
- L Albornoz
- Sección de Hígado, Servicio de Clínic a Medica, Hospital Italiano, Buenos Aires, Argentina
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Fábrega E, Crespo J, Rivero M, Casafont F, Castro B, García-Unzueta MT, Amado JA, Pons-Romero F. Dendroaspis natriuretic peptide in hepatic cirrhosis. Am J Gastroenterol 2001; 96:2724-9. [PMID: 11569702 DOI: 10.1111/j.1572-0241.2001.04131.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Dendroaspis natriuretic peptide (DNP) is a novel peptide that is structurally similar to atrial, brain, and C-type natriuretic peptides. Many natriuretic peptides are increased in hepatic cirrhosis, but the role of DNP in cirrhosis is unknown at present. The aim of the study was to investigate plasma levels of dendroaspis natriuretic-like immunoreactivity in cirrhosis. METHODS We measured plasma concentrations of DNP by radioimmunoassay methods in 12 cirrhotic patients without ascites and 44 cirrhotic patients with ascites, and compared these values with 20 age-matched healthy subjects. Renal function, plasma cGMP concentration, plasma renin activity, and plasma endothelin concentration were measured in each patient. RESULTS Patients without ascites had circulating levels of DNP similar to those of healthy subjects. By contrast, patients with ascites had increased circulating DNP levels compared to both patients without ascites and healthy subjects. In addition, circulating levels of DNP increased in relation to the severity of cirrhosis. Significant positive correlations were also found between DNP levels, endothelin concentrations, and plasma renin activity. CONCLUSIONS The results of this study indicate that plasma DNP is increased in cirrhotic patients with ascites.
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Affiliation(s)
- E Fábrega
- Gastroenterology and Hepatology Unit, University Hospital Marquis de Valdecilla, Santander, Spain
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36
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Abstract
Each variceal bleed is associated with 20% to 30% risk of dying. Management of portal hypertension after a bleed consists of (1) control of bleeding and (2) prevention of rebleeding. Effective control of bleeding can be achieved either pharmacologically by administering somatostatin or octreotide or endoscopically via sclerotherapy or variceal band ligation. In practice, both pharmacologic and endoscopic therapy are used concomitantly. Rebleeding can be prevented by endoscopic obliteration of varices. In this setting, variceal ligation is the preferred endoscopic modality. B-blockade is as effective as endoscopic therapy and, in combination, the two modalities may be additive.
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Affiliation(s)
- V A Luketic
- Division of Gastroenterology, Medical College of Virginia Commonwealth University, Richmond, Virginia, USA.
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Huang YT, Lee TY, Lin HC, Chou TY, Yang YY, Hong CY. Hemodynamic effects of Salvia miltiorrhiza on cirrhotic rats. Can J Physiol Pharmacol 2001. [DOI: 10.1139/y01-029] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Salvia miltiorrhiza (Sm) administration has been shown to reduce hepatic fibrosis in rats. We investigated the hemodynamic effects of Sm on bile duct ligated (BDL) rats. Hemodynamic, histological, and vascular contractile studies were conducted in rats 4 weeks after bile duct ligation. An aqueous extract of Sm (0.2 g twice per day) or vehicle was administered for 4 weeks to BDL rats. Sm treatment in BDL rats significantly reduced histological grades of fibrosis and ameliorated the portal hypertensive state (including portal venous pressure, superior mesenteric artery blood flow, cardiac index, and total peripheral resistance) as compared with vehicle treatment. Moreover, Sm treatment enhanced the vascular sensitivity of mesenteric arteries to phenylephrine in BDL rats. Sm treatment had no effect on plasma biochemical profiles of either BDL or normal rats. Our results suggest that 4-week Sm treatment ameliorates the portal hypertensive state in BDL rats.Key words: hemodynamics, fibrosis, portal hypertension, vascular contractile response, Salvia miltiorrhiza.
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38
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Abstract
The hyperdynamic circulation begins in the portal venous bed as a consequence of portal hypertension due to the increased resistance to flow from altered hepatic vascular morphology of chronic liver disease. Dilatation of the portal vein is associated with increased blood flow, as well as the opening up or formation of veno-venous shunts and splenomegaly. At the same time, portal hypertension leads to subclinical sodium retention resulting in expansion of all body fluid compartments, including the systemic and central blood volumes. This blood volume expansion is associated with vasorelaxation, as manifested by suppression of the renin--angiotensin--aldosterone system, initially only when the patient is in the supine position. Acute volume depletion in such patients results in normalisation of the hyperdynamic circulation, whilst acute volume expansion results in exaggerated natriuresis. As liver disease progresses and liver function deteriorates, the systemic hyperdynamic circulation becomes more manifest with activation of the renin--angiotensin--aldosterone system. The presence of vasodilatation in the presence of highly elevated levels of circulating vasoconstrictors may be explained by vascular hyporesponsiveness due to increased levels of vasodilators such as nitric oxide, as well as the development of an autonomic neuropathy. However, vasodilatation is not generalised, but confined to certain vascular beds, such as the splanchnic and pulmonary beds. Even here, the status may change with the natural history of the disease, since even portal blood flow may decrease and become reversed with advanced disease. The failure of these changes to reverse following liver transplantation may be due to remodelling and angiogenesis.
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Affiliation(s)
- L Blendis
- Institute of Gastroenterology, Sourasky Tel Aviv Medical Center, 6 Weizman Street, Tel Aviv 64239, Israel.
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Uriz J, Cárdenas A, Arroyo V. Pathophysiology, diagnosis and treatment of ascites in cirrhosis. Best Pract Res Clin Gastroenterol 2000; 14:927-43. [PMID: 11139347 DOI: 10.1053/bega.2000.0139] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/18/2023]
Abstract
Ascites is the most common complication of patients with cirrhosis; its development constitutes the first and most important manifestation of the disease and is an indication for liver transplantation. During the last decade significant advances have been made in regard to the pathogenesis and treatment of ascites. The description of a new hypothesis, the identification of new vasoactive factors involved in the pathogenesis of arterial vasodilation and the introduction of different therapeutic modalities (therapeutic paracentesis, transjugular intrahepatic portosystemic shunt, aquaretics drugs and liver transplantation) are all proof of this. Similarly, the description of predictive factors for the survival of patients with cirrhosis has been of major importance for the identification of candidates for liver transplantation. This chapter reviews current knowledge on the pathophysiology, diagnosis and treatment of ascites in patients with cirrhosis.
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Affiliation(s)
- J Uriz
- Liver Unit, IDIBAPS, University of Barcelona, Spain
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40
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41
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Les aspects endoscopiques de l’hypertension portale: diagnostic et classification. ACTA ACUST UNITED AC 2000. [DOI: 10.1007/bf03026171] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
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Luketic VA, Sanyal AJ. Esophageal varices. I. Clinical presentation, medical therapy, and endoscopic therapy. Gastroenterol Clin North Am 2000; 29:337-85. [PMID: 10836186 DOI: 10.1016/s0889-8553(05)70119-9] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The last half century has witnessed great advances in the understanding of the pathogenesis and natural history of portal hypertension in cirrhotics. Several pharmacologic and endoscopic techniques have been developed for the treatment of portal hypertension. The use of these agents in a given patient must be based on an understanding of the stage in the natural history of the disease and the relative efficacy and safety of the available treatment options.
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Affiliation(s)
- V A Luketic
- Department of Medicine, Medical College of Virginia Commonwealth University, Richmond, USA.
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43
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Abstract
Ascites is the most common complication of cirrhosis. It is associated with profound changes in the splanchnic and systemic circulation and with renal abnormalities. The development of ascites is related to the existence of severe sinusoidal portal hypertension that causes marked splanchnic arterial vasodilation and a forward increase in the splanchnic production of lymph. Splanchnic arterial vasodilation also produces arterial vascular underfilling, arterial hypotension, compensatory activation of the RAAS, SNS, and AVP, and a continuous sodium and water retention, leading to ascites formation. Now, therefore, the splanchnic arterial circulation, rather than the venous portal system, is believed to be involved in the pathogenesis of ascites formation.
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Affiliation(s)
- A Cárdenas
- Liver Unit, Institut de Malaties Digestives, Hospital Clínic, Barcelona, Spain
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44
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Abstract
Increased resistance to portal blood flow is the primary factor in the pathophysiology of portal hypertension, and is mainly determined by the morphological changes occurring in chronic liver diseases. This is aggravated by a dynamic component, due to the active-reversible- contraction of different elements of the porto-hepatic bed. A decreased synthesis of NO in the intrahepatic circulation is the main determinant of this dynamic component. This provides a rationale for the use of vasodilators to reduce intrahepatic resistance and portal pressure. Another factor contributing to aggravate the portal hypertension is a significant increase in portal blood flow, caused by arteriolar splanchnic vasodilation and hyperkinetic circulation. Splanchnic arteriolar vasodilation is a multifactorial phenomenon, which may involve local (endothelial) mechanisms as well as neurogenic and humoral pathways. Most pharmacological treatments have been aimed at correcting the increased portal blood inflow by the use of splanchnic vasoconstrictors, such as beta-blockers, vasopressin derivatives and somatostatin. Several studies have demonstrated that changes in the hepatic venous pressure gradient (HVPG) during maintenance therapy are useful to identify those patients who are going to have a variceal bleeding or rebleeding. The wide individual variation in the HVPG response to pharmacological treatment makes it desirable to schedule follow-up measurements of HVPG during pharmacological therapy. A priority for research in the forthcoming years is to develop accurate non-invasive methods to assess prognosis, which can be used to substitute or as surrogate indicators of the HVPG response. In the clinical management of portal hypertension, beta-blockers are at present the only accepted treatment for the prevention of variceal bleeding. Whether the association of isosorbide-5-mononitrate will improve the high efficacy of beta-blockers is questionable. The efficacy of more aggressive techniques, such as endoscopic band ligation, should be further tested against beta-blockers in patients with a high risk of bleeding. In the treatment of acute variceal bleeding, administration of somatostatin or terlipressin is an established therapy. It may be used alone or, preferably, as an initial treatment before sclerotherapy or endoscopic band ligation. No more than two sessions of endoscopic treatment should be used to control the bleeding. If the bleeding is not easily controlled, other alternatives such as transjugular intrahepatic portosystemic shunts (TIPS) or derivative surgery should be considered, the former being the best in patients with poor liver function. Recent studies suggest that early measurement of HVPG during variceal bleeding may be used as a guide for therapeutic decisions in the treatment of patients with acute variceal bleeding. Those patients with a high HVPG have a high risk of poor evolution, and may be candidates for more intensive and aggressive therapy, such as surgery or TIPS. Those with lower HVPG have a very high probability of an uneventful evolution, and may thus be managed more conservatively using medical and endoscopic treatments. Pharmacological agents (propranolol or nadolol), endoscopic treatment (preferably banding ligation) or surgery can be used to prevent rebleeding. A pending task for the new millennium is to assess whether the early treatment of asymptomatic, compensated cirrhotic patients with portal pressure reducing agents can prevent the development of esophageal varices and of other complications of portal hypertension.
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Affiliation(s)
- J Bosch
- Hepatic Hemodynamic Laboratory, IMD, Hospital Clinic, IDIBAPS, University of Barcelona, Spain
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45
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Gentilini P, Laffi G, La Villa G, Romanelli RG, Blendis LM. Ascites and hepatorenal syndrome during cirrhosis: two entities or the continuation of the same complication? J Hepatol 1999; 31:1088-97. [PMID: 10604585 DOI: 10.1016/s0168-8278(99)80324-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Affiliation(s)
- P Gentilini
- Institute of Internal Medicine, University of Florence, Italy
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46
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Li CP, Lee FY, Hwang SJ, Chang FY, Lin HC, Lu RH, Hou MC, Chu CJ, Chan CC, Luo JC, Lee SD. Role of substance P in the pathogenesis of spider angiomas in patients with nonalcoholic liver cirrhosis. Am J Gastroenterol 1999; 94:502-7. [PMID: 10022654 DOI: 10.1111/j.1572-0241.1999.883_l.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Cutaneous spider angioma is a common sign observed in patients with liver cirrhosis, but its pathogenesis is still unclear. Increased plasma levels of estrogen, vascular dilation, and neovascularization are possible etiologies. This study was designed to investigate the relationship of spider angiomas in patients with nonalcoholic liver cirrhosis to the plasma levels of sex hormones and various vasodilators and hemodynamic parameters. METHODS A total of 60 patients with nonalcoholic liver cirrhosis and 20 healthy subjects were included in this study. The number, size, and location of the spider angiomas were recorded. Plasma levels of estradiol, testosterone, substance P, calcitonin gene-related peptide, and nitrate/nitrite and forearm hemodynamics were measured. RESULTS Cirrhotic patients showed higher plasma estradiol/testosterone ratios (28.3+/-47.2 x 10(-3), median 10.5 x 10(-3) vs 8.2+/-8.3 x 10(-3), median 5.7 x 10(-3), p = 0.003) and levels of nitrate/ nitrite (29.9+/-17.5, median 23.8 vs 21.4+/-10.0, median 20.6 micromol/L, p = 0.01) and substance P (47.5+/-62.5, median 29.2 vs 15.2+/-7.7, median 12.3 pg/ml, p < 0.001) than healthy controls. Sixteen (27%) of the 60 cirrhotic patients had spider angiomas. Cirrhotic patients with spider angiomas disclosed higher plasma levels of substance P (84.7+/-105.3, median 53.1 vs 34.5+/-30.7, median 25.8 pg/ml, p = 0.006) and serum levels of bilirubin (3.9+/-3.8, median 1.9 vs 1.9+/-1.9, median 1.2 mg/dl, p = 0.02) than those without. Stepwise logistic regression showed substance P was the only significant and independent predictor associated with the presence of spider angiomas in cirrhotic patients (odds ratio = 3.0, 95% confidence interval = 1.4-6.6, p = 0.01). CONCLUSION Plasma levels of substance P are elevated in patients with nonalcoholic cirrhosis and may play an important role in the pathogenesis of spider angiomas.
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Affiliation(s)
- C P Li
- Department of Medicine, Veterans General Hospital-Taipei and National Yang-Ming University School of Medicine, Taiwan, Republic of China
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Huang YT, Lin HC, Tsai JF, Hou MC, Lee SD, Hong CY. Vascular hyporeactivity persists despite increased contractility after long-term administration of isosorbide dinitrate in portal hypertensive rats. J Hepatol 1998; 28:1037-44. [PMID: 9672181 DOI: 10.1016/s0168-8278(98)80354-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND/AIMS Portal hypertension is associated with decreased vascular responsiveness to vasoconstrictors, which may contribute to the hyperdynamics. Isosorbide dinitrate is an effective portal hypotensive drug. The present study aimed to investigate whether chronic administration of isosorbide dinitrate could affect vascular responsiveness in portal hypertensive rats. METHODS Portal hypertension was induced by partial portal vein ligation. Sham-operated (Sham) rats served as controls. There were four animal groups for this study: portal vein ligation-isosorbide dinitrate group, portal vein ligation-vehicle (Veh) group, Sham-isosorbide dinitrate group and Sham-Veh group. Isosorbide dinitrate (5 mg x kg(-1) x 12 h(-1) was given by gavage for 8 days starting 1 day before ligation and continuing thereafter. Mesenteric arteries were removed for contractile study after hemodynamic measurement. RESULTS Contractile responses to KCI (15-90 mM) and phenylephrine (10(-9)-10(-4) M) were recorded. Both vascular reactivity and sensitivity were significantly reduced in portal vein ligation rats as compared to Sham rats. Chronic isosorbide dinitrate treatment reduced portal venous pressure in portal vein ligation rats. Moreover, the maximal contractile responses to KCl and phenylephrine were significantly enhanced in both portal vein ligation and Sham rats after isosorbide dinitrate treatment, but relative hyporeactivity persisted in portal vein ligation rats. In contrast, a single dose of isosorbide dinitrate did not alter the contractile sensitivity or reactivity to KCl or phenylephrine in either portal vein ligation or Sham rats. CONCLUSION Our results show that long-term administration of isosorbide dinitrate enhanced vascular contractility in both portal vein ligation and Sham rats, but relative hyporeactivity persisted in portal vein ligation rats.
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Affiliation(s)
- Y T Huang
- Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
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Iwao T, Oho K, Sakai T, Tayama C, Sato M, Nakano R, Yamawaki M, Toyonaga A, Tanikawa K. Splanchnic and extrasplanchnic arterial hemodynamics in patients with cirrhosis. J Hepatol 1997; 27:817-23. [PMID: 9382968 DOI: 10.1016/s0168-8278(97)80318-2] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND/AIMS This study was designed to assess the contribution of splanchnic and extrasplanchnic vascular hemodynamics to the hyperdynamic circulation in patients with cirrhosis. METHODS Cardiac index and flow volume index and pulsatility index (PI) of superior mesenteric artery (SMA) and femoral artery (FA) were measured with Doppler ultrasonography in 40 controls and 86 patients with cirrhosis (Child-Pugh grade A=41, grade B=30, and grade C=15). Mean arterial pressure was also recorded to calculate systemic vascular resistance index. RESULTS Systemic vascular resistance index was significantly lower in each Child-Pugh group than in controls. SMA blood flow index was significantly higher in each Child-Pugh group than in controls and the increase in SMA blood flow index paralleled the degree of liver dysfunction. SMA-PI was significantly lower in each Child-Pugh group than in controls and the decrease in SMA-PI paralleled the degree of liver dysfunction. FA blood flow index was slightly higher in Child-Pugh grade A patients and significantly higher in grade B patients than in controls, whereas grade C patients had normal FA blood flow index. FA-PI was significantly lower in grade A and grade B patients than in controls, whereas grade C patients had normal FA-PI. When all patients were examined together, SMA-PI significantly correlated with systemic vascular resistance index (r=0.69, p<0.01). In contrast, FA-PI did not significantly correlate with systemic vascular resistance index (r=0.15, p=0.18). CONCLUSIONS Splanchnic arterial vasodilatation plays an important role in the pathogenesis of decreased systemic vascular resistance seen in patients with cirrhosis.
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Affiliation(s)
- T Iwao
- Department of Medicine II, Kurume University School of Medicine, Japan
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49
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Affiliation(s)
- A J Stanley
- Department of Medicine, Royal Infirmary of Edinburgh, UK
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50
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Abstract
In the past few years, there have been important advances in the field of pathogenesis and management of ascites and spontaneous bacterial peritonitis in cirrhosis. A new pathogenic theory of ascites and renal dysfunction in cirrhosis has been presented, and previously ill-defined conditions, such as refractory ascites and hepatorenal syndrome, have been defined precisely. The reintroduction of therapeutic paracentesis has modified markedly the way in which patients hospitalized for ascites are treated. The use of potent and safe antibiotics has improved the resolution rate and survival of patients with spontaneous bacterial peritonitis, and the use of oral antibiotics will simplify the management of this condition in the near future. Finally, prophylactic antibiotic regimens represent a major step forward in the prevention of spontaneous bacterial peritonitis in subsets of cirrhotic patients with a great risk of developing this complication.
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Affiliation(s)
- P Ginès
- University of Barcelona School of Medicine, Liver Unit, Hospital Clínic i Provincial, Barcelona, Spain
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