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HEMODYNAMIC PRINCIPLES OF PORTAL HYPERTENSION

In cirrhosis, as well as in most noncirrhotic causes ofportal hypertension, portal hypertension results from changes inportal resistance in combination with changes in portal inflow. The influence of flow and resistance on pressure can be

represented by the formula for Ohm's law: in which the pressure gradient in the portal circulation (P) isa function of portal flow (F) and resistance to flow (R). Increases in portal resistance or portal flow can contribute to increasedpressure. Portal hypertension almost always results from increases in both portal resistance and portal flow (Fig. 90-3). One

exception is that of an arteriovenous fistula, which in the initial stages causes portal hypertension largely through anincrease in portal flow in the absence of an increase in resistance. The mechanism of the increase in portal resistancedepends on the site and cause ofportal hypertension; in the Western world, the most common cause is liver cirrhosis (seelater). Because of the increase in hepatic resistance and the decrease in hepatic compliance, small changes in flow that donot increase pressure in the normal liver can have a prominent stimulatory effect on portal pressure in the cirrhotic liver. Theincrease in portal venous inflow is part of a generalized systemic derangement termed the hyperdynamic circulatory state.Collateral vessels that dilate and new vascular sprouts that form connect the high-pressure portal venous system with lower-pressure systemic veins. Unfortunately, this process of angiogenesis and collateralization is insufficient for normalizing portalpressure and actually causes complications ofportal hypertension, such as esophageal varices.

[3]Approaches to block this

angiogenic process are a compelling target for drug development.

Figure 90-3. Vascular disturbances in portal hypertension and sites of action of portal pressure-reducing therapies. Portal

hypertension typically results from increased resistance, usually from within the liver, in combination with increased portal

venous flow. The increase in hepatic resistance results from mechanical factors in combination with dynamic vasoconstriction

mediated by decreased nitric oxide (NO) production and increased endothelin-1 (ET-1) production. The increase in portal venousflow occurs as a result of vasodilatation in the splanchnic circulation that is mediated by increased NO production. A collateral

circulation, including esophageal varices, develops between the hypertensive portal vasculature and systemic venous system;

however, these collaterals are inadequate to decompress the hypertensive portal circulation fully. Collateral development is

mediated by dilatation of existing collateral vessels, as well as development of new blood vessels and sprouts (angiogenesis).

Therapies aimed at the different sites of hemodynamic disturbances are shown. CC, contractile cell (e.g., hepatic stellate cell,

vascular smooth muscle cell); EC, endothelial cell.

The changes in portal flow and resistance also can be viewed as originating from mechanical and vascular factors.Mechanical factors include the fibrosis and nodularity of the cirrhotic liver with distortion of the vascular architecture and theremodeling that is recognized to occur in the systemic and splanchnic vasculature in response to the chronic increases in flowand shear stress that characterize the hyperdynamic circulatory state. Vascular factors include intrahepatic vasoconstriction,which contributes to increased intrahepatic resistance, and the splanchnic and systemic vasodilatation that accompanies thehyperdynamic circulatory state. The vascular factors that contribute to portal hypertension are particularly importantbecause they are reversible and dynamic and therefore compelling targets for experimental therapies (Fig. 90-4). Conversely,effective therapies for the fixed, mechanical component ofportal hypertension caused by scar, regenerative nodules, andvascular remodeling are currently lacking. Indeed, most available therapies forportal hypertensionfocus on correction ofhemodynamic alterations in the portal circulation. Approaches include use of nonselective -adrenergic blocking agents,octreotide, and vasopressin to reduce the hyperdynamic circulation, portal venous inflow, and splanchnicvasodilatation.[4],[5]Alternative agents reduce the increased intrahepatic resistance and include angiotensin receptor blockersand mononitrates.

Figure 90-4. Representative vasodilator and vasoconstrictor molecules implicated in the vascular abnormalities in portalhypertension.

INCREASED INTRAHEPATIC RESISTANCEIn cirrhosis, increased portal resistance occurs in great part as a result of mechanical factors that reduce vessel diameter. Inaddition to regenerative nodules and fibrotic bands, these mechanical factors include capillarization of the sinusoids andswelling of cells, including hepatocytes and Kupffer cells. As discussed earlier, however, reduced hepatic vessel diameterresulting in increased portal resistance, even when caused by cirrhosis, is not a purely mechanicalphenomenon.[6]Hemodynamic changes in the hepatic circulation also contribute to increased intrahepaticresistance.[7],[8]These changes are characterized by hepatic vasoconstriction and impaired responses to vasodilatory stimuli.The increase in intrahepatic resistance is determined largely by changes in vessel radius, with small reductions in vesselradius causing prominent increases in resistance. Blood viscosity and vessel length also can influence resistance, albeit to amuch smaller extent. The factors that regulate resistance can be viewed in the context of the law of Poiseuille:

in which R is resistance, L is the product of blood viscosity and vessel length, and r is vessel radius.Although vasoactive changes were estimated initially to account for 10% to 30% of the increase in portal resistance incirrhosis, subsequent studies have suggested that these figures actually may underestimate the contribution of hepaticvasoconstriction to the increased resistance observed in the cirrhotic liver. In noncirrhotic causes ofportal hypertension,the increase in resistance may occur at sites upstream (prehepatic) or downstream (posthepatic) of the liver, as in portal ve inthrombosis and hepatic vein thrombosis, respectively (Fig. 90-5). Furthermore, the site of increased intrahepatic resistancecan be further delineated as the sinusoids (sinusoidal), upstream from the sinusoids within the portal venules (presinusoidal),or downstream from the sinusoids in the hepatic venules (postsinusoidal), as in alcoholic cirrhosis, schistosomiasis, andsinusoidal obstruction syndrome, respectively. Pressure is increased only in the portal circulation behind the site of increasedresistance, and in isolated portal vein thrombosis, hepatic function frequently remains largely preserved despiteprominent portal hypertension.

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Figure 90-5. Classification ofportal hypertension. The different sites of increased resistance to portal flow (posthepatic,

intrahepatic, and prehepatic) and associated diseases are shown. Many diseases cause a mixed pattern. Portal

hypertension rarely can occur exclusively as a result of increased portal flow, as occurs with arteriovenous shunts (not shown).

Most evidence suggests that a decrease in the production of the vasodilator NO and an increase in the production of thevasoconstrictor ET-1 jointly contribute to the increase in hepatic vascular resistance. In experimental models of cirrhosis, thebioavailability of hepatic NO is diminished because of a reduction in the production of NO by endothelial cells.[7],[9],[10]A similarparadigm is observed in the human cirrhotic liver.

[11]Most studies indicate that the reduction in NO production occurs not

through a reduction in hepatic eNOS protein levels[9],[10]but through defects in the steps necessary to activate existing eNOSprotein. For example, increases in the production of the eNOS-inhibiting protein caveolin-1 have been observed inexperimental models of cirrhosis[10]and in human cirrhosis. Another pathway that contributes to deficient generation of NO byeNOS is a reduction in the level of AKT (protein kinase B) phosphorylation of eNOS and upregulation of the eNOS inhibitingprotein, GRK (G protein-coupled receptor kinase), in the cirrhotic live r.[12]Irrespective of the mechanism of deficiency, the lackof availability of NO is thought to allow HSCs, which are activated and highly contractile in liver cirrhosis, to constrict thesinusoids that they envelop, thereby increasing portal pressure. The role of the HSCs in this process remains controversial,however, because evidence is mixed regarding whether the site of the increase in intrahepatic resistance in cirrhosis is thesinusoids, where stellate cells reside, or the pre- or postsinusoidal venules (or both), which are devoid of stellate cells and inwhich endothelial cells signal smooth muscle cells. Furthermore, increasing evidence points toward diverse origins of thesemyofibroblastic cells within the cirrhotic sinusoids, with portal myofibroblasts as well as HSC postulated to play importantroles.[13]In this regard, therapies that target myofibroblast migration may be a compelling therapeutic target by limiting thedensity of these contractile cells within the hepatic sinusoids.[14]Finally, the contribution of HSCs to hepatic angiogenesis mayalso be an important target for treating fibrosis and portal hypertension.[15]In clinical practice, NO can be delivered by NO donor agents such as mononitrates. NO donor agents exert their beneficialeffects in part by relaxing the actively contractile stellate cells.[16],[17]The systemic actions of these agents, however, tend tocause side effects and exacerbate the hyperdynamic circulatory state. In studies utilizing a liver-specific NO donor compound,the increased intrahepatic vascular resistance could be corrected by the generation of additional NO and consequentrelaxation of HSCs.[18]In cirrhosis, however, deficient endothelial cell NO generation may be accompanied by impairedstellate cell relaxation in response to NO,[19]perhaps because of diminished response of the NO second messenger cyclicguanosine monophosphate (cGMP) in activated cells.[16]In this situation, a prominent beneficial effect of NO donors is lesspredictable.Excessive ET-1 also contributes to increased intrahepatic vasoconstriction in portal hypertension through vasoconstrictiveeffects in the liver, presumably by enhancing HSC contractility.[20],[21]In experimental models, ET-1 protein and receptorexpression are increased, most notably in HSCs and endothelial cells.[20],[22],[23]In humans with portal hypertension, plasmaand liver ET-1 levels also are increased.[24]The reason for activation of the ET-1 system inportal hypertension is not known,but this effect may be secondary to transforming growth factor- (TGF-), a key fibrogenic growth factor.[23]Clinical trials ofET antagonists in patients with portal hypertension are in progress; however, the variable effects of ET modulation inexperimental models ofportal hypertension, as well as the possible hepatotoxicity of these compounds, have limitedenthusiasm for studies in humans.[25]Other therapies forportal hypertension may provide benefit through the ET pathway.

For example, somatostatin, which reduces portal pressure by constricting the splanchnic circulation, also may act by inhibitingET-1dependent HSC contraction.[26]Other vasoactive mediators, including cysteinyl leukotrienes, thromboxane, angiotensin, and hydrogen sulfide, also have beenimplicated in the development of increased intrahepatic resistance in cirrhosis.[27],[28]Some of these mediators, particularlyangiotensin, which causes contraction of HSCs, have been studied in humans. Attempts to reduce portal pressure usingpharmacologic agents that inhibit angiotensin activation of HSC contraction have met with mixed results thus far.[29]

HYPERDYNAMIC CIRCULATIONIn addition to the increases in portal resistance discussed earlier, a major factor in the development and perpetuationofportal hypertension is an increase in portal venous flow, or the hyperdynamic circulation. The termportal venousinflowindicates the total blood that drains into the portal circulation, not the blood flow in the portal vein itself, which mayactually be diminished in portal hypertension because of portosystemic collateral shunts. The hyperdynamic circulation ischaracterized by peripheral and splanchnic vasodilatation, reduced mean arterial pressure, and increased cardiac output.Vasodilatation, particularly in the splanchnic bed, permits an increase in inflow of systemic blood into the portal circulation.[30]Splanchnic vasodilatation is caused in large part by relaxation of splanchnic arterioles and ensuing splanchnic hyperemia.Studies of experimental portal hypertension have demonstrated that splanchnic vascular endothelial cells are primarilyresponsible for mediating splanchnic vasodilatation and enhanced portal venous inflow through excess generation of NO.[31-39]This excess generation of NO and ensuing vasodilatation, hyperdynamic circulation, and hyperemia in the splanchnic andsystemic circulation contrasts with the hepatic circulation, in which NO deficiency contributes to increased intrahepatic

resistance.The mechanism of excess NO production from the endothelial cells of the systemic and splanchnic arterial circulation is anarea of active investigation. Some of the increase in NO production probably occurs from shear stressdependent and shearstressindependent increases in the expression of eNOS, which can be corrected in part by beta blockers.[37],[40-45]Activationof existing eNOS by cytokines or mechanical factors also seems to contribute to excess systemic and splanchnic NOgeneration through pathways that include eNOS phosphorylation and protein interactions.[42-46]The physiologic stimuli thatmediate this process are not well understood but may include ET-1, which is increased in the serum of patients with portalhypertension, and the cytokine tumor necrosis factor- (TNF-) because inhibitors of TNF improve portal pressure and thesplanchnic circulatory disturbances in both human and experimental portal hypertension. TNF- may be derived fromintestinal endotoxin, and intestinal decontamination appears to correct the hyperdynamic circulation in humans, suggesting alink with intestinal inflammation.

[47]Vascular endothelial growth factor (VEGF) has also been implicated in this process by

excessively activating eNOS.[48]In humans with portal hypertension, therapeutic inhibition of NOS has met with mixedclinical results.

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7/28/2019 Hemodinamia HPNC

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In one study, inhibition of NOS corrected altered systemic hemodynamics,[49]but other studies have not demonstratedsignificant portal pressurereducing effects of systemic NOS inhibition.

[50]Other mediators that may contribute to systemic

and splanchnic vasodilatation include anandamide, an endogenous vasodilatory cannabinoid,[51-53]heme oxygenase,[17],[54-56]and cyclooxygenase.[57]Compelling evidence also supports a primary defect in smooth muscle cells in portalhypertension, perhaps because of defects in potassium channels.[58-62]In fact, many pharmacologic therapies forportalhypertension target the splanchnic arteriolar smooth muscle cells, rather than endothelial cells, to reduce splanchnicvasodilatation. For example, octreotide, a synthetic analog of somatostatin, causes marked but transient reductions in portalpressure by contracting splanchnic smooth muscle cells, thereby limiting portal venous inflow, especially after meals.Nonselective beta blockers and vasopressin also reduce portal pressure by constricting splanchnic arterioles and thereby

reducing portal venous inflow. Because intrahepatic resistance persists, therapies targeted toward the increase in portalvenous inflow usually do not normalize portal pressure entirely but often blunt the prominent increases in portal venous inflowthat occur in response to a meal. Combination therapy with an agent that reduces increased intrahepatic resistance, such asa nitrate, and an agent that reduces portal venous inflow, such as a beta blocker, are more effective in reducing portalpressure than is either agent alone.

COLLATERAL CIRCULATION AND VARICESThe portal veinsystemic collateral circulation develops and expands in response to elevation of the portal pressure.[63]Bloodflow in the low volumes that normally perfuse these collaterals and flow toward the portal circulation is reversed in portalhypertension because the increased portal pressure exceeds systemic venous pressure. Therefore, flow is reversed in thesecollateral vessels, and blood flows out of the portal circulation toward the systemic venous circulation.

The sites of collateral formation are the rectum, where the inferior mesenteric vein connects with the pudendal vein and rectalvarices develop; the umbilicus, where the vestigial umbilical vein communicates with the left portal vein and gives rise toprominent collaterals around the umbilicus (caput medusae); the retroperitoneum, where collaterals, especially in women,communicate between the ovarian vessels and iliac veins; and the distal esophagus and proximal stomach, wheregastroesophageal varices are the major collaterals formed between the portal venous system and systemic venous system.

Four distinct zones of venous drainage at the gastroesophageal junction are particularly relevant to the formation ofesophageal varices.[64]The gastric zone, which extends for 2 to 3 cm below the gastroesophageal junction, comprises veinsthat are longitudinal and located in the submucosa and lamina propria. They come together at the upper end of the cardia ofthe stomach and drain into short gastric and left gastric veins. The palisade zone extends 2 to 3 cm proximal to the gastriczone into the lower esophagus. Veins in this zone run longitudinally and in parallel in four groups corresponding to theesophageal mucosal folds. These veins anastomose with veins in the lamina propria. The perforating veins in the palisadezone do not communicate with extrinsic (periesophageal) veins in the distal esophagus. The palisade zone is the dominantwatershed area between the portal and systemic circulations. More proximal to the palisade zone in the esophagus is theperforating zone, where there is a network of veins. These veins are less likely to be longitudinal and are termed perforatingveins because they connect the veins in the esophageal submucosa and the external veins. The truncal zone, the longestzone, is approximately 10 cm in length, located proximally to the perforating zone in the esophagus, and usually characterizedby four longitudinal veins in the lamina propria.Veins in the palisade zone in the esophagus are most prone to bleeding because no perforating veins at this level connect theveins in the submucosa with the periesophageal veins. Varices in the truncal zone are unlikely to bleed because theperforating vessels communicate with the periesophageal veins, allowing the varices in the truncal zone to decompress. Theperiesophageal veins drain into the azygous system, and as a result, an increase in azygous blood flow is a hallmark ofportalhypertension. The venous drainage of the lower end of the esophagus is through the coronary vein, which also drains the

cardia of the stomach, into the portal vein.The fundus of the stomach drains through short gastric veins into the splenic vein. In the presence ofportal hypertension,varices may therefore form in the fundus of the stomach. Splenic vein thrombosis usually results in isolated gastric fundalvarices. Because of the proximity of the splenic vein to the renal vein, spontaneous splenorenal shunts may develop and aremore common in patients with gastric varices than in those with esophageal varices.[65],[66]The predominant collateral flow pattern in intrahepatic portal hypertension is through the right and left coronary veins, withonly a small portion of flow through the short gastric veins. Therefore, most patients with intrahepatic causes ofportalhypertension have esophageal varices or gastric varices in continuity with esophageal varices. Unfortunately, portalhypertension caused by cirrhosis generally persists and progresses despite the development of even an extensive collateralcirculation. Progression ofportal hypertension results from (1) the prominent obstructive resistance in the liver; (2)resistance within the collaterals themselves; and (3) continued increase in portal vein inflow. The collateral circulatory beddevelops through a combination of angiogenesis, the development of new blood vessels, and dilatation and increased flowthrough preexisting collaterals.[3],[67]Experimental evidence suggests that VEGF, a key NO stimulatory growth factor, maycontribute to both the angiogenic and collateral vessel responses.[55],[68]Inhibition of VEGF or NO may attenuate the collateralvessel propagation by inhibiting angiogenic responses in experimental models ofportal hypertension andcollateralization.[67-72]Some pharmacologic agents used in the management ofportal hypertension, such as beta blockersand octreotide, may act in part by constricting collateral vessels.

[73-76]Approaches to inhibiting VEGF and angiogenesis are

worth studying therapeutically.[48]

The development of gastroesophageal varices requires a portal pressure gradient of at least 10 mm Hg. Furthermore, a portalpressure gradient of at least 12 mm Hg is thought to be required for varices to bleed; other local factors that increase varicealwall tension also are needed[77]because all patients with a portal pressure gradient of greater than 12 mm Hg do notnecessarily bleed. Factors that influence variceal wall tension can be viewed in the context of the law of Laplace:

where T is variceal wall tension, P is the transmural pressure gradient between the variceal lumen andesophageal lumen, r is the variceal radius, and w is the variceal wall thickness. When the variceal wall thins and the varixincreases in diameter and pressure, the tolerated wall tension is exceeded and the varix will rupture. These physiologicobservations are manifested clinically by the observation that patients with larger varices (r) in sites of limited soft tissuesupport (w), with elevated portal pressure (P), tend to be at greatest risk for variceal rupture from variceal wall tension (T) thatbecomes excessive. One notable site in which soft tissue support is limited is at the gastroesophageal junction. The lack oftissue support and high vessel density may contribute to the greater frequency of bleeding from varices at the

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gastroesophageal junction. The law of Laplace also has implications for the relevance of pharmacologic therapies aimed atreducing portal pressure. Reductions in portal pressure will reduce the variceal transmural pressure gradient, therebyreducing the risk that variceal wall tension will become excessive and varices will rupture. Clinically, a reduction in the hepaticvenous pressure gradient to less than 12 mm Hg almost negates the risk of variceal hemorrhage. The changes in portalpressure and local variceal factors, however, are dynamic and influenced by a number of physiologic (an increase in intra-abdominal pressure, meal-induced increases in portal pressure), diurnal (circadian changes in portal pressure), andpathophysiologic (acute alcohol use) factors, and portal pressure and esophageal variceal pressure may vary at differenttimes.