Abstract: The management of portal hypertension should be based on an updated knowledge of its natural history. Portal hypertension is an almost unavoidable complication of cirrhosis, and it is responsible for the more lethal complications of this syndrome: gastro-esophageal varices and massive gastrointestinal bleeding, ascites, hepatorenal syndrome, and hepatic encephalopathy. Appearance of these complications represents the major cause of death and liver transplantation in patients with cirrhosis. The prevalence of esophageal varices is very high: when cirrhosis is diagnosed, varices are present in about 40% of compensated patients and in 60% of those with ascites [1Schepis F. Camma C. Niceforo D. Magnano A. Pallio S. Cinquegrani M. et al.Which patients with cirrhosis should undergo endoscopic screening for esophageal varices detection.Hepatology. 2001; 33: 333-338Crossref PubMed Scopus (164) Google Scholar, 2D'Amico G. Luca A. Natural history. Clinical-haemodynamic correlations. Prediction of the risk of bleeding.Baillieres Best Pract Res Clin Gastroenterol. 1997; 11: 243-256Google Scholar]. After initial diagnosis of cirrhosis, the expected incidence of newly developed varices is about 5% per year [[3]D'Amico G. Pagliaro L. Bosch J. Pharmacological treatment of portal hypertension: an evidence-based approach.Semin Liver Dis. 1999; 19: 475-505Crossref PubMed Google Scholar]. Once developed, varices increase in size from small to large at an overall rate of 10–15% per year [[3]D'Amico G. Pagliaro L. Bosch J. Pharmacological treatment of portal hypertension: an evidence-based approach.Semin Liver Dis. 1999; 19: 475-505Crossref PubMed Google Scholar]. Progression of liver failure seems to be the factor with the greatest influence on overall growth [[4]Zoli M. Merkel C. Magalotti D. Gueli C. Grimaldi M. Gatta A. et al.Natural history of cirrhotic patients with small esophageal varices: a prospective study.Am J Gastroenterol. 2000; 95: 503-508Crossref PubMed Google Scholar]. On the other side, improvement in liver function and abstinence from alcohol may result in decrease or even disappearance of varices [[5]Vorobioff J. Groszmann R.J. Picabea E. Gamen M. Villavicencio R. Bordato J. et al.Prognostic value of hepatic venous pressure gradient measurements in alcoholic cirrhosis: a 10-year prospective study.Gastroenterology. 1996; 111: 701-709Abstract Full Text Full Text PDF PubMed Google Scholar]. Once diagnosed, the overall incidence of variceal bleeding is to the order of 25% at 2 years in non-selected patients [[6]de Franchis R. Primignani M. Natural history of portal hypertension in patients with cirrhosis.Clin Liver Dis. 2001; 5: 645-663Abstract Full Text Full Text PDF PubMed Google Scholar]. Many efforts have been made to define risk criteria for the development of variceal bleeding. The most important predictive factors related to the risk of bleeding are variceal size,presence of red weal marks in the varices, and severity of liver dysfunction expressed by the Child–Pugh classification. These risk indicators have been combined in the north Italian endoscopic club (NIEC) index [[7]NIECPrediction of the first variceal hemorrhage in patients with cirrhosis of the liver and esophageal varices. A prospective multicenter study. The north Italian endoscopic club for the study and treatment of esophageal varices.N Engl J Med. 1988; 319: 983-989Crossref PubMed Google Scholar] which allows to classify patients into different groups with predicted 1-year bleeding risk ranging from 6 to 76%. However, the predictive power of this index is far from satisfactory. In a recent report, variceal size was found to be the best predictor of variceal bleeding, and this is the variable used to decide whether a patient should be given prophylactic therapy or not. The risk of variceal bleeding is about 7% at 2 years in patients with small varices (less than 5 mm), and increases to 30% at 2 years in patients with large varices [[6]de Franchis R. Primignani M. Natural history of portal hypertension in patients with cirrhosis.Clin Liver Dis. 2001; 5: 645-663Abstract Full Text Full Text PDF PubMed Google Scholar]. Variceal size and red color signs are associated with increased bleeding risk probably because they contribute to marked increase in the tension of the wall of the varices, the decisive factor determining variceal rupture [[8]Polio J. Groszmann R.J. Hemodynamic factors involved in the development and rupture of esophageal varices: a pathophysiologic approach to treatment.Semin Liver Dis. 1986; 6: 318-331Crossref PubMed Google Scholar]. According to Frank's modification of Laplace's law, variceal wall tension is directly proportional to the transmural variceal pressure (the gradient between intravariceal and esophageal luminal pressures) and the radius of the varix, and inversely proportional to the thickness of the variceal wall. While variceal size is a function of variceal radius, red weal marks may represent areas of reduced wall thickness. Hepatic venous pressure gradient (HVPG) may constitute a good surrogate marker of transmural variceal pressure [[9]Escorsell A. Bordas J.M. Castaneda B. Llach J. Garcia-Pagan J.C. Rodes J. et al.Predictive value of the variceal pressure response to continued pharmacological therapy in patients with cirrhosis and portal hypertension.Hepatology. 2000; 31: 1061-1067Crossref PubMed Google Scholar]. Indeed, cross-sectional and longitudinal studies demonstrated that variceal bleeding does not occur if HVPG remains below 12 mmHg [5Vorobioff J. Groszmann R.J. Picabea E. Gamen M. Villavicencio R. Bordato J. et al.Prognostic value of hepatic venous pressure gradient measurements in alcoholic cirrhosis: a 10-year prospective study.Gastroenterology. 1996; 111: 701-709Abstract Full Text Full Text PDF PubMed Google Scholar, 9Escorsell A. Bordas J.M. Castaneda B. Llach J. Garcia-Pagan J.C. Rodes J. et al.Predictive value of the variceal pressure response to continued pharmacological therapy in patients with cirrhosis and portal hypertension.Hepatology. 2000; 31: 1061-1067Crossref PubMed Google Scholar, 10Garcia-Tsao G. Groszmann R.J. Fisher R.L. Conn H.O. Atterbury C.E. Glickman M. Portal pressure, presence of gastroesophageal varices and variceal bleeding.Hepatology. 1985; 5: 419-424Crossref PubMed Scopus (346) Google Scholar, 11Groszmann R.J. Bosch J. Grace N.D. Conn H.O. Garcia-Tsao G. Navasa M. et al.Hemodynamic events in a prospective randomized trial of propranolol versus placebo in the prevention of a first variceal hemorrhage (see comments).Gastroenterology. 1990; 99: 1401-1407Abstract PubMed Google Scholar, 12Feu F. Garcia-Pagan J.C. Bosch J. Luca A. Teres J. Escorsell A. Relation between portal pressure response to pharmacotherapy and risk of recurrent variceal haemorrhage in patients with cirrhosis.Lancet. 1995; 346: 1056-1059Abstract Full Text PDF PubMed Google Scholar]. It has been reported that 30–50% of cirrhotic patients with an acute variceal bleeding episode will die within 6 weeks [[2]D'Amico G. Luca A. Natural history. Clinical-haemodynamic correlations. Prediction of the risk of bleeding.Baillieres Best Pract Res Clin Gastroenterol. 1997; 11: 243-256Google Scholar], but it is likely that this figure overestimates the current mortality from variceal bleeding [[13]McCormick P.A. O'Keefe C. Improving prognosis following a first variceal haemorrhage over four decades.Gut. 2001; 49: 682-685Crossref PubMed Scopus (118) Google Scholar]. A more accurate, current figure may be a mortality of 20% at 6 weeks. Immediate mortality from uncontrolled bleeding is in the range of 5–8% [2D'Amico G. Luca A. Natural history. Clinical-haemodynamic correlations. Prediction of the risk of bleeding.Baillieres Best Pract Res Clin Gastroenterol. 1997; 11: 243-256Google Scholar, 6de Franchis R. Primignani M. Natural history of portal hypertension in patients with cirrhosis.Clin Liver Dis. 2001; 5: 645-663Abstract Full Text Full Text PDF PubMed Google Scholar]. Active bleeding at endoscopy [[14]Ben Ari Z. Cardin F. McCormick A.P. Wannamethee G. Burroughs A.K. A predictive model for failure to control bleeding during acute variceal haemorrhage.J Hepatol. 1999; 31: 443-450Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar], bacterial infection [[15]Goulis J. Armonis A. Patch D. Sabin C. Greenslade L. Burroughs A.K. Bacterial infection is independently associated with failure to control bleeding in cirrhotic patients with gastrointestinal hemorrhage.Hepatology. 1998; 27: 1207-1212Crossref PubMed Scopus (220) Google Scholar] and HVPG >20 mmHg measured early after admission [[16]Moitinho E. Escorsell A. Bandi J.C. Salmeron J.M. Garcia-Pagan J.C. Rodes J. Bosch J. Prognostic value of early measurements of portal pressure in acute variceal bleeding.Gastroenterology. 1999; 117: 626-631Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar] are significant prognostic indicators of failure to control bleeding. It is important to emphasize that variceal bleeding ceases spontaneously in 40–50% of patients. This is probably influenced by the fact that hypovolemia leads to reflex splanchnic vasoconstriction with reduced portal pressure and blood flow, a beneficial response that is nullified by blood transfusion [17Kravetz D. Sikuler E. Groszmann R.J. Splanchnic and systemic hemodynamics in portal hypertensive rats during hemorrhage and blood volume restitution.Gastroenterology. 1986; 90: 1232-1240PubMed Google Scholar, 18Castaneda B. Morales J. Lionetti R. Moitinho E. Andreu V. Perez-del-Pulgar S. et al.Effects of blood volume restitution following a portal hypertensive-related bleeding in anesthetized cirrhotic rats.Hepatology. 2001; 33: 821-825Crossref PubMed Scopus (52) Google Scholar]. The incidence of early rebleeding ranges between 30 and 40% within the first 6 weeks [[6]de Franchis R. Primignani M. Natural history of portal hypertension in patients with cirrhosis.Clin Liver Dis. 2001; 5: 645-663Abstract Full Text Full Text PDF PubMed Google Scholar]. The risk peaks in the first 5 days with 40% of all rebleeding episodes occurring in this very early period [[19]Graham D. Smith J. The course of patients after variceal hemorrhage.Gastroeneterology. 1981; 80: 800-806PubMed Google Scholar]. Bleeding gastric varices, active bleeding at emergency endoscopy, low serum albumin levels, renal failure and HVPG >20 mmHg have been reported as significant indicators of early rebleeding risk [[6]de Franchis R. Primignani M. Natural history of portal hypertension in patients with cirrhosis.Clin Liver Dis. 2001; 5: 645-663Abstract Full Text Full Text PDF PubMed Google Scholar]. Early rebleeding [14Ben Ari Z. Cardin F. McCormick A.P. Wannamethee G. Burroughs A.K. A predictive model for failure to control bleeding during acute variceal haemorrhage.J Hepatol. 1999; 31: 443-450Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar, 19Graham D. Smith J. The course of patients after variceal hemorrhage.Gastroeneterology. 1981; 80: 800-806PubMed Google Scholar]and renal failure [[20]Cärdenas A. Ginès P. Uriz J. Bessa X. Salmerön J.M. Mas A. et al.Renal failure after upper gastrointestinal bleeding in cirrhosis: incidence, clinical course, predictive factors, and short-term prognosis.Hepatology. 2001; 34: 671-676Crossref PubMed Scopus (133) Google Scholar] are probably the most important prognostic factors for 6-week mortality, suggesting that their prevention should be a primary objective in the therapeutic approach to variceal bleeding. Patients surviving a first episode of variceal bleeding have a very high risk of rebleeding and death. Median rebleeding incidence within 1–2 years in untreated controls of randomized controlled trials (RCTs) of non-surgical treatment for prevention of recurrent bleeding reported after 1981 is 63%. The corresponding mortality figure is 33% [[2]D'Amico G. Luca A. Natural history. Clinical-haemodynamic correlations. Prediction of the risk of bleeding.Baillieres Best Pract Res Clin Gastroenterol. 1997; 11: 243-256Google Scholar]. Because of these high risks, all patients surviving a variceal bleeding should be treated for prevention of rebleeding independently of other risk indicators [3D'Amico G. Pagliaro L. Bosch J. Pharmacological treatment of portal hypertension: an evidence-based approach.Semin Liver Dis. 1999; 19: 475-505Crossref PubMed Google Scholar, 21Grace N.D. Groszmann R.J. Garcia-Tsao G. Burroughs A.K. Pagliaro L. Makuch R.W. et al.Portal hypertension and variceal bleeding: an AASLD single topic symposium.Hepatology. 1998; 28: 868-880Crossref PubMed Google Scholar]. Risk indicators of rebleeding and death are variceal size, Child–Pugh class, continued alcohol abuse and hepatocellular carcinoma [[2]D'Amico G. Luca A. Natural history. Clinical-haemodynamic correlations. Prediction of the risk of bleeding.Baillieres Best Pract Res Clin Gastroenterol. 1997; 11: 243-256Google Scholar]. A very important concept which has been strongly substantiated in recent years is that the major factor determining the development of the complications and the clinical significance of portal hypertension is that portal pressure increases above a critical threshold value. HVPG [[22]Groszmann R.J. Glickman M. Blei A.T. Storer E. Conn H.O. Wedged and free hepatic venous pressure measured with a balloon catheter.Gastroenterology. 1979; 76: 253-258PubMed Google Scholar], which accurately reflects portal pressure in the majority of liver diseases [23Perello A. Escorsell A. Bru C. Gilabert R. Moitinho E. Garcia-Pagan J.C. et al.Wedged hepatic venous pressure adequately reflects portal pressure in hepatitis C virus-related cirrhosis.Hepatology. 1999; 30: 1393-1397Crossref PubMed Google Scholar, 24Wongcharatrawee S. Groszmann R.J. Diagnosing portal hypertension.Baillieres Best Pract Res Clin Gastroenterol. 2000; 14: 881-894Abstract Full Text PDF PubMed Scopus (15) Google Scholar], is the most commonly used method to assess portal pressure in clinical practice. Varices do not develop until the HVPG increases to 10–12 mmHg, and the HVPG should be of at least 12 mmHg for the appearance of other complications, such as variceal bleeding and ascites [10Garcia-Tsao G. Groszmann R.J. Fisher R.L. Conn H.O. Atterbury C.E. Glickman M. Portal pressure, presence of gastroesophageal varices and variceal bleeding.Hepatology. 1985; 5: 419-424Crossref PubMed Scopus (346) Google Scholar, 25Viallet A. Marleau D. Huet M. Martin F. Farley A. Villeneuve J.P. et al.Hemodynamic evaluation of patients with intrahepatic portal hypertension. Relationship between bleeding varices and the portohepatic gradient.Gastroenterology. 1975; 69: 1297-1300PubMed Google Scholar, 26Casado M. Bosch J. Garcia-Pagan J.C. Bru C. Banares R. Bandi J.C. et al.Clinical events after transjugular intrahepatic portosystemic shunt: correlation with hemodynamic findings.Gastroenterology. 1998; 114: 1296-1303Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar]. Implicit in this concept is that preventing the HVPG to increase above these values will prevent the development of the complications of portal hypertension. The question that follows is if by reducing the HVPG below these thresholds, could complications of portal hypertension be prevented. Indeed longitudinal studies have demonstrated that if HVPG decreases below 12 mmHg by means of pharmacological treatment [11Groszmann R.J. Bosch J. Grace N.D. Conn H.O. Garcia-Tsao G. Navasa M. et al.Hemodynamic events in a prospective randomized trial of propranolol versus placebo in the prevention of a first variceal hemorrhage (see comments).Gastroenterology. 1990; 99: 1401-1407Abstract PubMed Google Scholar, 12Feu F. Garcia-Pagan J.C. Bosch J. Luca A. Teres J. Escorsell A. Relation between portal pressure response to pharmacotherapy and risk of recurrent variceal haemorrhage in patients with cirrhosis.Lancet. 1995; 346: 1056-1059Abstract Full Text PDF PubMed Google Scholar] or spontaneously due to an improvement in liver disease [[5]Vorobioff J. Groszmann R.J. Picabea E. Gamen M. Villavicencio R. Bordato J. et al.Prognostic value of hepatic venous pressure gradient measurements in alcoholic cirrhosis: a 10-year prospective study.Gastroenterology. 1996; 111: 701-709Abstract Full Text Full Text PDF PubMed Google Scholar], variceal bleeding is totally prevented and varices may decrease in size. Besides, if this target is not achieved, a substantial decrease in portal pressure from baseline levels offers an almost total protection from variceal bleeding. This 'substantial' decrease in baseline HVPG needed to achieve protection was found to be of at least 20% [[12]Feu F. Garcia-Pagan J.C. Bosch J. Luca A. Teres J. Escorsell A. Relation between portal pressure response to pharmacotherapy and risk of recurrent variceal haemorrhage in patients with cirrhosis.Lancet. 1995; 346: 1056-1059Abstract Full Text PDF PubMed Google Scholar], a finding confirmed in a number of subsequent studies [9Escorsell A. Bordas J.M. Castaneda B. Llach J. Garcia-Pagan J.C. Rodes J. et al.Predictive value of the variceal pressure response to continued pharmacological therapy in patients with cirrhosis and portal hypertension.Hepatology. 2000; 31: 1061-1067Crossref PubMed Google Scholar, 27Merkel C. Bolognesi M. Sacerdoti D. Bombonato G. Bellini B. Bighin R. et al.The hemodynamic response to medical treatment of portal hypertension as a predictor of clinical effectiveness in the primary prophylaxis of variceal bleeding in cirrhosis.Hepatology. 2000; 32: 930-934Crossref PubMed Google Scholar, 28Villanueva C. Balanzo J. Novella M.T. Soriano G. Sainz S. Torras X. et al.Nadolol plus isosorbide mononitrate compared with sclerotherapy for the prevention of variceal rebleeding.N Engl J Med. 1996; 334: 1624-1629Crossref PubMed Scopus (231) Google Scholar, 29Villanueva C. Minana J. Ortiz J. Gallego A. Soriano G. Torras X. et al.Endoscopic ligation compared with combined treatment with nadolol and isosorbide mononitrate to prevent recurrent variceal bleeding.N Engl J Med. 2001; 345: 647-655Crossref PubMed Scopus (198) Google Scholar]. This reduction in the HVPG of more than 20% and or a reduction below 12 mmHg are now accepted as the therapeutic targets in the treatment of portal hypertension. Moreover, the achievement of these targets may be associated with a lower risk of developing ascites [29Villanueva C. Minana J. Ortiz J. Gallego A. Soriano G. Torras X. et al.Endoscopic ligation compared with combined treatment with nadolol and isosorbide mononitrate to prevent recurrent variceal bleeding.N Engl J Med. 2001; 345: 647-655Crossref PubMed Scopus (198) Google Scholar, 30Tarantino I. Abraldes J.G. Turnes J. Garcia-Pagan J.C. Bosch J. Rodes J. The HVPG-response to pharmacological treatment of portal hypertension predicts prognosis and the risk of developing complications of cirrhosis.J Hepatol. 2002; 36: 15AAbstract Full Text PDF Google Scholar], spontaneous bacterial peritonitis [[30]Tarantino I. Abraldes J.G. Turnes J. Garcia-Pagan J.C. Bosch J. Rodes J. The HVPG-response to pharmacological treatment of portal hypertension predicts prognosis and the risk of developing complications of cirrhosis.J Hepatol. 2002; 36: 15AAbstract Full Text PDF Google Scholar], hepatorenal syndrome [[30]Tarantino I. Abraldes J.G. Turnes J. Garcia-Pagan J.C. Bosch J. Rodes J. The HVPG-response to pharmacological treatment of portal hypertension predicts prognosis and the risk of developing complications of cirrhosis.J Hepatol. 2002; 36: 15AAbstract Full Text PDF Google Scholar] and death in the follow-up [29Villanueva C. Minana J. Ortiz J. Gallego A. Soriano G. Torras X. et al.Endoscopic ligation compared with combined treatment with nadolol and isosorbide mononitrate to prevent recurrent variceal bleeding.N Engl J Med. 2001; 345: 647-655Crossref PubMed Scopus (198) Google Scholar, 30Tarantino I. Abraldes J.G. Turnes J. Garcia-Pagan J.C. Bosch J. Rodes J. The HVPG-response to pharmacological treatment of portal hypertension predicts prognosis and the risk of developing complications of cirrhosis.J Hepatol. 2002; 36: 15AAbstract Full Text PDF Google Scholar], thus demonstrating the reversibility of the portal hypertensive syndrome by means of pharmacological therapy. These findings provide the rationale for treatments aimed to reduce portal pressure. Over the past decade, a better knowledge of the pathophysiology of portal hypertension and of the mechanism of variceal bleeding have provided the rationale for developing new agents capable of decreasing portal pressure. Unfortunately, only some of these new agents have been tested in clinical trials, which makes drug therapy in portal hypertension not much different today than it was 10 years ago. Experimental studies have shown that the initial factor in the pathophysiology of portal hypertension is the increase in vascular resistance to portal blood flow. In cirrhosis this increase in resistance occurs at the hepatic microcirculation (sinusoidal portal hypertension). It is important to emphasize that, contrary to what was traditionally thought, increased hepatic vascular resistance in cirrhosis is not only a mechanical consequence of the hepatic architectural disorder caused by the liver disease, but there is also a dynamic component, due to the active contraction of portal/septal myofibroblasts, activated stellate cells and portal venules [31Wiest R. Groszmann R.J. The paradox of nitric oxide in cirrhosis and portal hypertension: too much, not enough.Hepatology. 2002; 35: 478-491Crossref PubMed Scopus (234) Google Scholar, 32Pinzani M. Gentilini P. Biology of hepatic stellate cells and their possible relevance in the pathogenesis of portal hypertension in cirrhosis.Semin Liver Dis. 1999; 19: 397-410Crossref PubMed Google Scholar, 33Rockey D.C. Weisiger R.A. 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The paradox of nitric oxide in cirrhosis and portal hypertension: too much, not enough.Hepatology. 2002; 35: 478-491Crossref PubMed Scopus (234) Google Scholar, 40Gupta T.K. Toruner M. Chung M.K. Groszmann R.J. Endothelial dysfunction and decreased production of nitric oxide in the intrahepatic microcirculation of cirrhotic rats.Hepatology. 1998; 28: 926-931Crossref PubMed Scopus (210) Google Scholar, 41Rockey D.C. Chung J.J. Reduced nitric oxide production by endothelial cells in cirrhotic rat liver: endothelial dysfunction in portal hypertension.Gastroenterology. 1998; 114: 344-351Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar]. This deficient intrahepatic NO production is the result of an endothelial dysfunction in the liver microvascultature [40Gupta T.K. Toruner M. Chung M.K. Groszmann R.J. 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Another way of overcoming the increased resistance through the cirrhotic liver is by means of portal-systemic shunt surgery and transjugular intrahepatic portalsystemic shunts (TIPS). These procedures are highly effective in decreasing portal pressure, but have the detrimental effect that, by further decreasing portal blood flow through the liver and by increasing portal-systemic shunting, may enhance liver failure and facilitate hepatic encephalopathy. A second and major contributing factor to portal hypertension is an increase in blood flow through the portal venous system, due to splanchnic arteriolar vasodilatation, which is caused by an excessive release of endogenous vasodilators (endothelial, neural and humoral) [42Vorobioff J. Bredfeldt J. Groszmann R.J. Hyperdynamic circulation in a portal hypertensive rat model: a primary factor for maintenance of chronic portal hypertension.Am J Physiol. 1983; 244: G52-G56PubMed Google Scholar, 43Benoit J.N. Barrowman J.A. Harper S.L. 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This contributes to aggravate the increase in portal pressure and explains why portal hypertension persists despite the establishment of an extensive network of portosystemic collaterals that may divert over 80% of the portal blood flow. The increased portal venous inflow can be corrected pharmacologically by means of splanchnic vasoconstrictors such as vasopressin and its derivatives, somatostatin and its analogues and non-selective beta-adrenergic blockers, which are the drugs that have been more widely used in the treatment of portal hypertension. It should be theoretically possible to modulate splanchnic blood flow by acting on the mechanism responsible for the vasodilatation; however, this approach faces the difficulty of acting selectively on the splanchnic circulation Splanchnic vasodilatation is accompanied by systemic vasodilatation, increased cardiac index and hypervolemia, representing the hyperkynetic circulatory syndrome associated with portal hypertension [47Schrier R.W. 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Publication Year: 2003
Publication Date: 2003-01-01
Language: en
Type: review
Indexed In: ['crossref', 'pubmed']
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