HEMODYNAMIC PRINCIPLES OF PORTAL HYPERTENSION

In cirrhosis, as well as in most noncirrhotic causes of portal hypertension, portal hypertension results from changes in portal 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) is a function of portal flow (F) and resistance to flow (R). Increases in portal resistance or portal flow can contribute to increased pressure. 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 an increase in portal flow in the absence of an increase in resistance. The mechanism of the increase in portal resistance depends on the site and cause of portal hypertension; in the Western world, the most common cause is liver cirrhosis (see later). Because of the increase in hepatic resistance and the decrease in hepatic compliance, small changes in flow that do not increase pressure in the normal liver can have a prominent stimulatory effect on portal pressure in the cirrhotic liver. The increase 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 lowerpressure systemic veins. Unfortunately, this process of angiogenesis and collateralization is insufficient for normalizing portal pressure and actually causes complications of portal 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 venous flow 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 the remodeling that is recognized to occur in the systemic and splanchnic vasculature in response to the chronic increases in flow and 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 the hyperdynamic circulatory state. The vascular factors that contribute to portal hypertension are particularly important because they are reversible and dynamic and therefore compelling targets for experimental therapies (Fig. 90-4). Conversely, effective therapies for the fixed, mechanical component of portal hypertension caused by scar, regenerative nodules, and vascular remodeling are currently lacking. Indeed, most available therapies for portal hypertensionfocus on correction of hemodynamic 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 splanchnic vasodilatation.[4],[5] Alternative agents reduce the increased intrahepatic resistance and include angiotensin receptor blockers and mononitrates.
Figure 90-4. Representative vasodilator and vasoconstrictor molecules implicated in the vascular abnormalities in portal hypertension.

INCREASED INTRAHEPATIC RESISTANCE

In cirrhosis, increased portal resistance occurs in great part as a result of mechanical factors that reduce vessel diameter. In addition to regenerative nodules and fibrotic bands, these mechanical factors include capillarization of the sinusoids and swelling of cells, including hepatocytes and Kupffer cells. As discussed earlier, however, reduced hepatic vessel diameter resulting in increased portal resistance, even when caused by cirrhosis, is not a purely mechanical phenomenon.[6] Hemodynamic changes in the hepatic circulation also contribute to increased intrahepatic resistance.[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 vessel radius causing prominent increases in resistance. Blood viscosity and vessel length also can influence resistance, albeit to a much 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 in cirrhosis, subsequent studies have suggested that these figures actually may underestimate the contribution of hepatic vasoconstriction to the increased resistance observed in the cirrhotic liver. In noncirrhotic causes of portal hypertension, the increase in resistance may occur at sites upstream (prehepatic) or downstream (posthepatic) of the liver, as in portal vein thrombosis and hepatic vein thrombosis, respectively (Fig. 90-5). Furthermore, the site of increased intrahepatic resistance can 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, and sinusoidal obstruction syndrome, respectively. Pressure is increased only in the portal circulation behind the site of increased resistance, and in isolated portal vein thrombosis, hepatic function frequently remains largely preserved despite prominent portal hypertension.

Figure 90-5. Classification of portal 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 the vasoconstrictor ET-1 jointly contribute to the increase in hepatic vascular resistance. In experimental models of cirrhosis, the bioavailability of hepatic NO is diminished because of a reduction in the production of NO by endothelial cells.[7],[9],[10] A similar paradigm 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 eNOS protein. For example, increases in the production of the eNOS-inhibiting protein caveolin-1 have been observed in experimental models of cirrhosis[10] and in human cirrhosis. Another pathway that contributes to deficient generation of NO by eNOS is a reduction in the level of AKT (protein kinase B) phosphorylation of eNOS and upregulation of the eNOS inhibiting protein, GRK (G protein-coupled receptor kinase), in the cirrhotic liver.[12] Irrespective of the mechanism of deficiency, the lack of availability of NO is thought to allow HSCs, which are activated and highly contractile in liver cirrhosis, to constrict the sinusoids 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 the sinusoids, where stellate cells reside, or the pre- or postsinusoidal venules (or both), which are devoid of stellate cells and in which endothelial cells signal smooth muscle cells. Furthermore, increasing evidence points toward diverse origins of these myofibroblastic cells within the cirrhotic sinusoids, with portal myofibroblasts as well as HSC postulated to play important roles.[13] In this regard, therapies that target myofibroblast migration may be a compelling therapeutic target by limiting the density of these contractile cells within the hepatic sinusoids.[14]Finally, the contribution of HSCs to hepatic angiogenesis may also 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 beneficial effects in part by relaxing the actively contractile stellate cells.[16],[17] The systemic actions of these agents, however, tend to cause 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 consequent relaxation of HSCs.[18] In cirrhosis, however, deficient endothelial cell NO generation may be accompanied by impaired stellate cell relaxation in response to NO,[19] perhaps because of diminished response of the NO second messenger cyclic guanosine monophosphate (cGMP) in activated cells.[16] In this situation, a prominent beneficial effect of NO donors is less predictable. Excessive ET-1 also contributes to increased intrahepatic vasoconstriction in portal hypertension through vasoconstrictive effects in the liver, presumably by enhancing HSC contractility.[20],[21] In experimental models, ET-1 protein and receptor expression are increased, most notably in HSCs and endothelial cells.[20],[22],[23] In humans with portal hypertension, plasma and 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 of ET antagonists in patients with portal hypertension are in progress; however, the variable effects of ET modulation in experimental models of portal hypertension, as well as the possible hepatotoxicity of these compounds, have limited enthusiasm for studies in humans.[25] Other therapies for portal hypertension may provide benefit through the ET pathway. For example, somatostatin, which reduces portal pressure by constricting the splanchnic circulation, also may act by inhibiting ET-1dependent HSC contraction.[26] Other vasoactive mediators, including cysteinyl leukotrienes, thromboxane, angiotensin, and hydrogen sulfide, also have been implicated in the development of increased intrahepatic resistance in cirrhosis.[27],[28] Some of these mediators, particularly angiotensin, which causes contraction of HSCs, have been studied in humans. Attempts to reduce portal pressure using pharmacologic agents that inhibit angiotensin activation of HSC contraction have met with mixed results thus far.[29]

HYPERDYNAMIC CIRCULATION
In addition to the increases in portal resistance discussed earlier, a major factor in the development and perpetuation of portal hypertension is an increase in portal venous flow, or the hyperdynamic circulation. The term portal venous inflow indicates the total blood that drains into the portal circulation, not the blood flow in the portal vein itself, which may actually be diminished in portal hypertension because of portosystemic collateral shunts. The hyperdynamic circulation is characterized 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 primarily responsible for mediating splanchnic vasodilatation and enhanced portal venous inflow through excess generation of NO.[3139] This excess generation of NO and ensuing vasodilatation, hyperdynamic circulation, and hyperemia in the splanchnic and systemic 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 an area of active investigation. Some of the increase in NO production probably occurs from shear stressdependent and shear stressindependent increases in the expression of eNOS, which can be corrected in part by beta blockers. [37],[40-45] Activation of existing eNOS by cytokines or mechanical factors also seems to contribute to excess systemic and splanchnic NO generation through pathways that include eNOS phosphorylation and protein interactions.[42-46] The physiologic stimuli that mediate this process are not well understood but may include ET-1, which is increased in the serum of patients with portal hypertension, and the cytokine tumor necrosis factor- (TNF-) because inhibitors of TNF improve portal pressure and the splanchnic circulatory disturbances in both human and experimental portal hypertension. TNF- may be derived from intestinal endotoxin, and intestinal decontamination appears to correct the hyperdynamic circulation in humans, suggesting a link 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 mixed clinical results.

In one study, inhibition of NOS corrected altered systemic hemodynamics,[49] but other studies have not demonstrated significant 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],[5456] and cyclooxygenase.[57] Compelling evidence also supports a primary defect in smooth muscle cells in portal hypertension, perhaps because of defects in potassium channels.[58-62] In fact, many pharmacologic therapies for portal hypertension target the splanchnic arteriolar smooth muscle cells, rather than endothelial cells, to reduce splanchnic vasodilatation. For example, octreotide, a synthetic analog of somatostatin, causes marked but transient reductions in portal pressure 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 portal venous inflow usually do not normalize portal pressure entirely but often blunt the prominent increases in portal venous inflow that occur in response to a meal. Combination therapy with an agent that reduces increased intrahepatic resistance, such as a nitrate, and an agent that reduces portal venous inflow, such as a beta blocker, are more effective in reducing portal pressure than is either agent alone.

COLLATERAL CIRCULATION AND VARICES

The portal veinsystemic collateral circulation develops and expands in response to elevation of the portal pressure.[63] Blood flow in the low volumes that normally perfuse these collaterals and flow toward the portal circulation is reversed in portal hypertension because the increased portal pressure exceeds systemic venous pressure. Therefore, flow is reversed in these collateral 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 rectal varices develop; the umbilicus, where the vestigial umbilical vein communicates with the left portal vein and gives rise to prominent 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, where gastroesophageal 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 of esophageal varices.[64] The gastric zone, which extends for 2 to 3 cm below the gastroesophageal junction, comprises veins that are longitudinal and located in the submucosa and lamina propria. They come together at the upper end of the cardia of the stomach and drain into short gastric and left gastric veins. The palisade zone extends 2 to 3 cm proximal to the gastric zone into the lower esophagus. Veins in this zone run longitudinally and in parallel in four groups corresponding to the esophageal mucosal folds. These veins anastomose with veins in the lamina propria. The perforating veins in the palisade zone do not communicate with extrinsic (periesophageal) veins in the distal esophagus. The palisade zone is the dominant watershed area between the portal and systemic circulations. More proximal to the palisade zone in the esophagus is the perforating zone, where there is a network of veins. These veins are less likely to be longitudinal and are termed perforating veins because they connect the veins in the esophageal submucosa and the external veins. The truncal zone, the longest zone, is approximately 10 cm in length, located proximally to the perforating zone in the esophagus, and usually characterized by 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 the veins in the submucosa with the periesophageal veins. Varices in the truncal zone are unlikely to bleed because the perforating vessels communicate with the periesophageal veins, allowing the varices in the truncal zone to decompress. The periesophageal veins drain into the azygous system, and as a result, an increase in azygous blood flow is a hallmark of portal hypertension. 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 of portal hypertension, varices may therefore form in the fundus of the stomach. Splenic vein thrombosis usually results in isolated gastric fundal varices. Because of the proximity of the splenic vein to the renal vein, spontaneous splenorenal shunts may develop and are more 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, with only a small portion of flow through the short gastric veins. Therefore, most patients with intrahepatic causes of portal hypertension have esophageal varices or gastric varices in continuity with esophageal varices. Unfortunately, portal hypertension caused by cirrhosis generally persists and progresses despite the development of even an extensive collateral circulation. Progression of portal 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 bed develops through a combination of angiogenesis, the development of new blood vessels, and dilatation and increased flow through preexisting collaterals.[3],[67] Experimental evidence suggests that VEGF, a key NO stimulatory growth factor, may contribute to both the angiogenic and collateral vessel responses.[55],[68] Inhibition of VEGF or NO may attenuate the collateral vessel propagation by inhibiting angiogenic responses in experimental models of portal hypertension and collateralization.[67-72] Some pharmacologic agents used in the management of portal hypertension, such as beta blockers and 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 portal pressure gradient of at least 12 mm Hg is thought to be required for varices to bleed; other local factors that increase variceal wall tension also are needed[77] because all patients with a portal pressure gradient of greater than 12 mm Hg do not necessarily 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 and esophageal lumen, r is the variceal radius, and w is the variceal wall thickness. When the variceal wall thins and the varix increases in diameter and pressure, the tolerated wall tension is exceeded and the varix will rupture. These physiologic observations are manifested clinically by the observation that patients with larger varices (r) in sites of limited soft tissue support (w), with elevated portal pressure (P), tend to be at greatest risk for variceal rupture from variceal wall tension (T) that becomes excessive. One notable site in which soft tissue support is limited is at the gastroesophageal junction. The lack of tissue support and high vessel density may contribute to the greater frequency of bleeding from varices at the

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