Splanchnic vasodilation and hyperdynamic circulatory syndrome in cirrhosis

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,angiotensinⅡand 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 pa-tients 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.     

Effect of terlipressin on blood volume distribution in patients with cirrhosis

BACKGROUND: Patients with cirrhosis and portal hypertension have an altered blood volume distribution and a hyperdynamic systemic circulation. Terlipressin is known to reduce portal pressure by decreasing splanchnic inflow, but its effect on the blood volume distribution is unknown. The aim of the study was to investigate changes in regional blood volume distribution and systemic haemodynamics after administration of terlipressin to patients with cirrhosis. METHODS: Blood volume distribution was determined in 13 patients with cirrhosis and portal hypertension by a dual-head gamma-camera technique and systemic haemodynamics was measured before and after intravenous administration of terlipressin (2 mg). RESULTS: Terlipressin increased the blood volume in the thorax region (+6.0%, P < 0.002) and the liver region (+12.2%, P < 0.002), whereas blood volume in the splanchnic region remained unchanged. Systemic vascular resistance (SVR) and mean arterial blood pressure increased after terlipressin (+34 and +21%, P < 0.001). The increase in liver blood volume correlated directly with the increase in SVR (r = 0.88. P < 0.001). CONCLUSIONS: Terlipressin ameliorates the hyperdynamic circulation, increases thorax and liver blood volumes, but produces no effect on the splanchnic blood volume. Besides decreasing the splanchnic inflow, terlipressin may affect portal pressure by causing vasodilatation of intrahepatic vessels.     

Nitric Oxide and Portal Hypertension

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.     

Splanchnic and systemic vasodilatation: the patient

Arterial vasodilatation is one of the most important characteristics of cirrrhosis and portal hyptertension. Nowadays, it has been known that progressive vasodilatation is an essential factor contributing to hyperdynamic circulation and multiple organ dysfunction in liver cirrhosis. Over the past decades, numerous investigations have originated from the clinical observations. Clinicians and investigators have learned and applied new concepts of the pathophysiology of portal hypertension. For example, we now have effective pharmacologic treatment for hepatorenal syndrome. This review summarizes the developement of progressive vasodilatation syndrome in liver cirrhosis and portal hypertension with focus on the patients.     

Effect of terlipressin on blood volume distribution in patients with cirrhosis

Background: Patients with cirrhosis and portal hypertension have an altered blood volume distribution and a hyperdynamic systemic circulation. Terlipressin is known to reduce portal pressure by decreasing splanchnic inflow, but its effect on the blood volume distribution is unknown. The aim of the study was to investigate changes in regional blood volume distribution and systemic haemodynamics after administration of terlipressin to patients with cirrhosis. Methods: Blood volume distribution was determined in 13 patients with cirrhosis and portal hypertension by a dual‐head gamma‐camera technique and systemic haemodynamics was measured before and after intravenous administration of terlipressin (2?mg). Results: Terlipressin increased the blood volume in the thorax region (+6.0%, P?P?P?r?=?0.88, P?Conclusions: Terlipressin ameliorates the hyperdynamic circulation, increases thorax and liver blood volumes, but produces no effect on the splanchnic blood volume. Besides decreasing the splanchnic inflow, terlipressin may affect portal pressure by causing vasodilatation of intrahepatic vessels.     

The molecules: mechanisms of arterial vasodilatation observed in the splanchnic and systemic circulation in portal hypertension

A hyperdynamic splanchnic and systemic circulation is typical of cirrhotic patients and has been observed in all experimental forms of portal hypertension. The hyperdynamic circulation is most likely initiated by arterial vasodilatation, leading to central hypovolemia, sodium retention, and an increased intravascular volume. Arterial vasodilatation is regulated by a complex interplay of various vasodilator molecules and factors that influence the production of those vasodilator molecules. Nitric oxide (NO) has been recognized as the most important vasodilator molecule that mediates the excessive arterial vasodilatation observed in portal hypertension. The aims of this review are (1) to categorize NO synthase isoforms involved in NO overproduction; (2) to explain the mechanisms of endothelial NO synthase up-regulation; and (3) to summarize other molecules involved in the arterial vasodilatation.     

Vascular,hemodynamic and renal effects of low‐dose losartan in rats with secondary biliary cirrhosis

Background: In cirrhosis, splanchnic and systemic vasodilatation induce a hyperdynamic circulatory dysfunction, portal hypertension and renal sodium retention. This vasodilatation is in part because of an impaired vascular response to α1‐adrenoceptor agonists. Recently, the angiotensin II type 1‐receptor antagonist losartan has been shown to attenuate portal hypertension. We hypothesized that losartan decreases portal pressure by counteracting the impaired vascular responsive to α1‐adrenoceptor agonists. Methods: We studied, in rats with secondary biliary cirrhosis and sham‐operated rats, the effect of 0.5 and 10 mg losartan/kg × day on aortic responsiveness to α1‐adrenoceptor stimulation with methoxamine and angiotensin II (myograph), splanchnic and systemic hemodynamics (colored microspheres), plasma noradrenaline levels and kidney function. Results: In cirrhotic rats, 10 mg losartan/kg × day completely inhibited aortic contractility to angiotensin II, decreased vascular resistance and arterial pressure and induced renal failure. In contrast, 0.5 mg losartan/kg × day only partially inhibited aortic contractility to angiotensin II, but improved aortic contractility to methoxamine, increased splanchnic and systemic vascular resistance, decreased portal pressure, decreased plasma norepinephrine levels and induced natriuresis. Conclusions: In cirrhotic rats, losartan at a very low dose increases splanchnic vascular resistance, decreases portal pressure and improves kidney function, possibly by an increased vascular responsiveness to α1‐adrenoceptor agonists.     

Mechanisms of water and sodium retention in cirrhosis and the pathogenesis of ascites

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.     

Gut microflora in the pathogenesis of the complications of cirrhosis

The gut flora plays an important role in the pathogenesis of the complications of cirrhosis. Cirrhotic patients are prone to develop bacterial infections, mainly the 'spontaneous' infection of ascites or spontaneous bacterial peritonitis. Other complications of cirrhosis, such as variceal haemorrhage and ascites, occur mostly or solely as a consequence of portal hypertension. Portal pressure increases initially as a consequence of an increased intrahepatic resistance but, once collaterals have formed, high portal pressure is maintained by an increased splanchnic blood inflow secondary to vasodilatation. Splanchnic vasodilatation is the initiating event in the hyperdynamic circulatory state that aggravates the complications of cirrhosis. The gut flora plays a role in both the development of infections and in the hyperdynamic circulatory state of cirrhosis and, although less prominently, it also plays a role in the pathogenesis of hepatic encephalopathy. This chapter presents evidence regarding gut flora and its modification in the pathogenesis and management of these complications of cirrhosis.     

Extrahepatic complications to cirrhosis and portal hypertension: Haemodynamic and homeostatic aspects

In addition to complications relating to the liver, patients with cirrhosis and portal hypertension develop extrahepatic functional disturbances of multiple organ systems. This can be considered a multiple organ failure that involves the heart, lungs, kidneys, the immune systems, and other organ systems. Progressive fibrosis of the liver and subsequent metabolic impairment leads to a systemic and splanchnic arteriolar vasodilatation. This affects both the haemodynamic and functional homeostasis of many organs and largely determines the course of the disease. With the progression of the disease, the circulation becomes hyperdynamic with cardiac, pulmonary as well as renal consequences for dysfunction and reduced survival. Infections and a changed cardiac function known as cirrhotic cardiomyopathy may be involved in further aggravation of other complications such as renal failure precipitating the hepatorenal syndrome. Patients with end-stage liver disease and related complications as for example the hepatopulmonary syndrome can only radically be treated by liver transplantation. As a bridge to this treatment, knowledge on the mechanisms of the pathophysiology of complications is essential for the choice of vasoactive drugs, antibiotics, drugs with specific effects on fibrogenesis and inflammation, and drugs that target specific receptors.     

Pathogenesis of Portal Hypertension: Extrahepatic Mechanisms

Chronic liver diseases, including hepatic cirrhosis, chronic hepatitis, alcoholic liver disease, and hepatocellular carcinoma, are one of the commonest causes of death and liver transplantation in adults worldwide. They are accompanied by profound disturbances that are not limited to the intrahepatic circulation, but involve also the splanchnic and systemic vascular beds. These hemodynamic disturbances are responsible for the development of portal hypertension, the most frequent and severe of cirrhosis. This syndrome is characterized by a pathological increase of blood pressure in the portal vein and concomitant increases in splanchnic blood flow and portosystemic collateral vessel formation. Increased blood flow in splanchnic organs draining into the portal vein augments in turn the portal venous inflow. Such increased portal venous inflow perpetuates and exacerbates portal pressure elevation and determines the formation of ascites during chronic liver disease. In addition, portosystemic collateral vessels include the gastroesophageal varices, which are particularly prone to rupture causing massive gastroesophageal bleeding. Collateral vessels are also responsible for other major consequences of chronic liver disease, including portosystemic encephalopathy and sepsis. Extrahepatic mechanisms are clearly of major importance for disease progression and aggravation of the portal hypertensive syndrome. Accordingly, most of the therapies currently used in portal hypertension do not act inside the liver but they actually target the increased splanchnic blood flow. This paper reviews the consequences of the splanchnic circulatory abnormalities in portal hypertension and the complex signals capable of increasing vasodilatation, hyporesponsiveness to vasoconstrictors and angiogenesis in the splanchnic vascular bed and the portosystemic collateral circulation in this pathological setting.     

Endothelial dysfunction in the regulation of cirrhosis and portal hypertension

Portal hypertension is caused by an increased intrahepatic resistance, a major consequence of cirrhosis. Endothelial dysfunction in liver sinusoidal endothelial cells (LSECs) decreases the production of vasodilators, such as nitric oxide, and favours vasoconstriction. This contributes to an increased vascular resistance in the intrahepatic/sinusoidal microcirculation and develops portal hypertension. Portal hypertension, in turn, causes endothelial dysfunction in the extrahepatic, i.e. splanchnic and systemic, circulation. Unlike dysfunction in LSECs, endothelial dysfunction in the splanchnic and systemic circulation causes overproduction of vasodilator molecules, leading to arterial vasodilation. In addition, portal hypertension leads to the formation of portosystemic collateral vessels. Both arterial vasodilation and portosystemic collateral vessel formation exacerbate portal hypertension by increasing the blood flow through the portal vein. Pathological consequences, such as oesophageal varices and ascites, result. While the sequence of pathological vascular events in cirrhosis and portal hypertension has been elucidated, the underlying cellular and molecular mechanisms causing endothelial dysfunctions are not yet fully understood. This review article summarizes the current cellular and molecular studies on endothelial dysfunctions found during the development of cirrhosis and portal hypertension with a focus on the intra‐ and extrahepatic circulations. The article ends by discussing the future directions of the study for endothelial dysfunction.     

Complications of cirrhosis. A 50 years flashback

Abstract

In patients with cirrhosis and portal hypertension, it is largely the frequency and severity of complications relating to the diseased liver, degree of portal hypertension and hemodynamic derangement that determine the prognosis. It can be considered as a multiple organ failure that apart from the liver involves the heart, lungs, kidneys, the immune systems and other organ systems. Progressive fibrosis of the liver and subsequent metabolic impairment leads to a systemic and splanchnic arteriolar vasodilatation. With the progression of the disease development of portal hypertension leads to formation of esophageal varices and ascites. The circulation becomes hyperdynamic with cardiac, pulmonary as well as renal consequences for dysfunction and reduced survival. Infections and a changed cardiac function known as cirrhotic cardiomyopathy may be involved in further aggravation of other complications such as renal failure precipitating the hepatorenal syndrome. Patients with end-stage liver disease and related complications as for example the hepatopulmonary syndrome can only radically be treated by liver transplantation.     

Cirrhotic portal hypertension: From pathophysiology to novel therapeutics

Portal hypertension and bleeding from gastroesophageal varices is the major cause of morbidity and mortality in patients with cirrhosis. Portal hypertension is initiated by increased intrahepatic vascular resistance and a hyperdynamic circulatory state. The latter is characterized by a high cardiac output, increased total blood volume and splanchnic vasodilatation, resulting in increased mesenteric blood flow. Pharmacological manipulation of cirrhotic portal hypertension targets both the splanchnic and hepatic vascular beds. Drugs such as angiotensin converting enzyme inhibitors and angiotensin Ⅱ type receptor 1 blockers, which target the components of the classical renin angiotensin system(RAS), are expected to reduce intrahepatic vascular tone by reducing extracellular matrix deposition and vasoactivity of contractile cells and thereby improve portal hypertension. However, these drugs have been shown to produce significant offtarget effects such as systemic hypotension and renal failure. Therefore, the current pharmacological mainstay in clinical practice to prevent variceal bleeding and improving patient survival by reducing portal pressure is non-selective-blockers(NSBBs). These NSBBs work by reducing cardiac output and splanchnic vasodilatation but most patients do not achieve an optimal therapeutic response and a significant proportion of patients are unable to tolerate these drugs.Although statins, used alone or in combination with NSBBs, have been shown to improve portal pressure and overall mortality in cirrhotic patients, further randomized clinical trials are warranted involving larger patient populations with clear clinical end points. On the other hand, recent findings from studies that have investigated the potential use of the blockers of the components of the alternate RAS provided compelling evidence that could lead to the development of drugs targeting the splanchnic vascular bed to inhibit splanchnic vasodilatation in portal hypertension. This review outlines the mechanisms related to the pathogenesis of portal hypertension and attempts to provide an update on currently available therapeutic approaches in the management of portal hypertension with special emphasis on how the alternate RAS could be manipulated in our search for development of safe, specific and effective novel therapies to treat portal hypertension in cirrhosis.     

Vascular endothelial dysfunction in cirrhosis

Endothelial dysfunction is regarded as an early key event in multiple diseases. The assessment of vascular nitric oxide (NO) level is an indicative of endothelial dysfunction. In liver cirrhosis, on one hand, endothelial dysfunction is known as impaired endothelium-dependent relaxation in the liver microcirculation and contributes to increased intra-hepatic vascular resistance, leading to portal hypertension. On the other, increased production of vasodilator molecules mainly NO contributes to increased endothelium-dependent relaxation in the arteries of the systemic and splanchnic circulation. The aims of this review are to summarize and discuss: (1) unique characteristics of sinusoidal endothelial cell (SECs) and SEC dysfunctions in cirrhosis, and (2) endothelial dysfunctions in the arterial splanchnic and systemic circulation in cirrhosis with portal hypertension.     

Modulation of splanchnic circulation:Role in perioperative management of liver transplant patients

Splanchnic circulation is the primary mechanism thatregulates volumes of circulating blood and systemic blood pressure in patients with cirrhosis accompanied by portal hypertension. Recently, interest has been expressed in modulating splanchnic circulation in patients with liver cirrhosis, because this capability might produce beneficial effects in cirrhotic patients undergoing a liver transplant. Pharmacologic modulation of splanchnic circulation by use of vasoconstrictors might minimize venous congestion, replenish central blood flow, and thus optimize management of blood volume during a liver transplant operation. Moreover, splanchnic modulation minimizes any high portal blood flow that may occur following liver resection and the subsequent liver transplant. This effect is significant, because high portal flow impairs liver regeneration, and thus adversely affects the postoperative recovery of a transplant patient. An increase in portal blood flow can be minimized by either surgical methods(e.g., splenic artery ligation, splenectomy or portocaval shunting) or administration of splanchnic vasoconstrictor drugs such as Vasopressin or terlipressin. Finally, modulation of splanchnic circulation can help maintain perioperative renal function. Splanchnic vasoconstrictors such as terlipressin may help protect against acute kidney injury in patients undergoing liver transplantation by reducing portal pressure and the severity of a hyperdynamic state. These effects are especially important in patients who receive a too small for size graft. Terlipressin selectively stimulates V1 receptors, and thus causes arteriolar vasoconstriction in the splanchnic region, with a consequent shift of blood from splanchnic to systemic circulation. As a result, terlipressin enhances renal perfusion by increasing both effective blood volume and mean arterial pressure.     

Hemodynamic effects of a clonidine-induced decrease in sympathetic tone in patients with cirrhosis

A decrease in plasma noradrenaline--a reflection of sympathetic nervous system activity--by clonidine, a centrally acting alpha 2-agonist, could reduce the hyperdynamic circulation observed in cirrhosis and may thereby decrease portal hypertension. Plasma noradrenaline concentration and plasma renin activity as well as systemic and splanchnic hemodynamics were measured in 12 patients with cirrhosis and ascites before and after administration of either 150 micrograms of clonidine or placebo. Plasma noradrenaline concentration significantly decreased in all patients after clonidine administration, whereas plasma renin activity did not change significantly. There were statistically significant reductions of cardiac output (-17.4%), mean arterial pressure (-12.2%), hepatic venous pressure gradient (-19.7%) and azygos blood flow (-26.6%) after administration of clonidine. No significant correlation was found between the reduction of plasma noradrenaline concentration and changes in systemic or splanchnic hemodynamics. Hepatic blood flow was not changed by clonidine. Placebo administration had no effect on any laboratory or hemodynamic measurement. We conclude that the reduction in sympathetic nervous system activity by clonidine and the subsequent decrease in the hyperdynamic circulation suggests that sympathetic overactivity contributes to the circulatory derangements in patients with cirrhosis.     

Cardiovascular Changes in Cirrhosis: Pathogenesis and Clinical Implications

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.     

Pathophysiology of portal hypertension

Portal hypertension is a common clinical syndrome associated with chronic liver diseases, and is characterized by a pathological increase in portal pressure that leads to the formation of portosystemic collaterals resulting in shunting of portal blood into the systemic circulation. The increase in portal pressure is due to an increase in vascular resistance and an elevated portal blood flow. The site of increased resistance is variable, and dependent upon the disease process. The site of relative obstruction may be prehepatic, hepatic, or posthepatic. There are several intrahepatic lesions that lead to increased resistance. Some of these lesions are irreversible, like fibrosis, regenerating nodules, and capillarization of the space of Disse; however, there is a functional component, increased vascular tone, which contributes to increased intrahepatic resistance and is potentially reversible. Another important factor contributing to the increased portal pressure is elevated portal blood flow. Peripheral vasodilatation initiates the classical profile of decreased systemic resistance, expanded plasma volume, elevated splanchnic blood flow, and elevated cardiac index, which characterize the hyperdynamic circulatory state. This hyperdynamic circulation is responsible for various complications of portal hypertension.     

Cardiopulmonary complications in chronic liver disease

Patients with cirrhosis and portal hypertensionexhibit characteristic cardiovascular and pulmonaryhemodynamic changes.A vasodilatatory state anda hyperdynamic circulation affecting the cardiacand pulmonary functions dominate the circulation.The recently defined cirrhotic cardiomyopathy mayaffect systolic and diastolic functions,and implyelectromechanical abnormalities.In addition,thebaroreceptor function and regulation of the circulatoryhomoeostasis is impaired.Pulmonary dysfunctioninvolves diffusing abnormalities with the developmentof the hepatopulmonary syndrome and portopulmonaryhypertension in some patients.Recent research hasfocused on the assertion that the hemodynamic andneurohumoral dysregulation are of major importance forthe development of the cardiovascular and pulmonarycomplications in cirrhosis.This aspect is important totake into account in the management of these patients.