The portal venous system carries capillary blood from the esophagus, stomach, small and large intestine, pancreas, gallbladder, and spleen to the liver. The portal vein is formed by the confluence of the splenic vein and the superior mesenteric vein behind the neck of the pancreas.¹ The inferior mesenteric vein usually drains into the splenic vein. The left gastric vein, also called the left coronary vein, usually drains into the portal vein at the confluence of the splenic vein and superior mesenteric vein (Fig. 90-1). The portal vein is approximately 7.5 cm in length and runs dorsal to the hepatic artery and bile duct into the hilum of the liver. The uppermost 5 cm of the portal vein does not receive any tributaries.² In the hilum of the liver, the portal vein divides into the left and right portal vein branches, which supply the left and right sides of the liver, respectively. The umbilical vein drains into the left portal vein. The cystic vein from the gallbladder drains into the right portal vein, whereas the portal venules drain into hepatic sinusoids that, in turn, are drained by the hepatic veins into the inferior vena cava. The left and middle hepatic veins usually join and drain into the inferior vena cava separately but adjacent to the confluence of the right hepatic vein with the inferior vena cava. The caudate lobe drains separately into the inferior vena cava (see Chapter 71).

Figure 90-1. Anatomy of the portal circulation. Blood vessels that constitute the portal circulation and hepatic outflow tracts are depicted.

The circulatory system of the normal liver is a high-compliance, low-resistance system that is able to accommodate a large blood volume, as occurs after a meal, without substantially increasing portal pressure. The liver receives a dual blood supply from the portal vein and the hepatic artery that constitutes nearly 30% of total cardiac output. Portal venous blood derived from the mesenteric venous circulation constitutes approximately 75% of total hepatic blood flow, whereas the remainder of blood to the liver is derived from the hepatic artery, which provides highly oxygenated blood directly from the celiac trunk of the aorta. Portal vein–derived and hepatic artery–derived blood flow converge in high-compliance, specialized vascular channels termed hepatic sinusoids. A dynamic and compensatory interplay occurs between hepatic blood flow derived from the portal vein and that from the hepatic artery. Specifically, when portal venous blood flow to the liver is diminished, as occurs in portal vein thrombosis, arterial inflow increases in an attempt to maintain total hepatic blood flow at a constant level. Similarly, after hepatic artery occlusion, portal venous inflow increases in a compensatory manner. This autoregulatory mechanism, aimed at maintaining total hepatic blood flow at a constant level, is termed the hepatic arterial buffer response.

The sinusoids are highly permeable and thus facilitate the transport of macromolecules to the parenchymal hepatocytes that reside on the extraluminal side of the endothelial cells. The hepatic sinusoids are highly permeable because they lack a proper basement membrane and because the endothelial cells that line the sinusoids contain fenestrae. Other unique aspects of the hepatic sinusoids are the space of Disse, a virtual space located extraluminal to the endothelial cell and adjacent to the hepatocyte, and its cellular constituents, the hepatic stellate cell (HSC) and the Kupffer cell (Fig. 90-2; see also Chapters 71 and 72). These two cell types probably play an important role, in concert with the endothelial cell, in regulating sinusoidal hemodynamics and homeostasis and may contribute to the sinusoidal derangements that occur in portal hypertension. Under basal conditions, HSCs maintain a quiescent phenotype and accumulate vitamin A. On activation, however, as occurs in cirrhosis and portal hypertension, these cells are postulated to develop contractile abilities that permit them to function as sinusoidal pericytes. Kupffer cells contribute to vascular homeostasis by generating cytokines with potent cellular and vasoregulatory actions, including tumor necrosis factor. Endothelial cells and smooth muscle cells in nonsinusoidal hepatic vessels such as the portal venule and the terminal hepatic venule are important in hepatic vasoregulation, particularly in the normal liver, where HSCs are quiescent, unactivated, and presumably less contractile.

Figure 90-2. Anatomy of the hepatic microvasculature. A, Normal sinusoidal microanatomy is depicted. The sinusoidal lumen is lined by fenestrated sinusoidal endothelial cells that allow the transport of macromolecules to the abluminal space of Disse. Quiescent hepatic stellate cells reside within this space, adjacent to hepatocytes and endothelial cells. B, In cirrhosis, a number of changes occur in the hepatic microcirculation, including loss of fenestrae in endothelial cells (defenestration), constriction of sinusoids, and activation of hepatic stellate cells with ensuing deposition of collagen and increased contractility.

Many studies have established the important role of nitric oxide (NO), derived from endothelial NO synthase (eNOS), in hepatic vasodilatation. Shear stress, caused by the frictional force of blood within the sinusoids, is one of the most potent physiologic stimuli of eNOS-derived NO production in hepatic sinusoids. By contrast, endothelin-1 (ET-1), also released by endothelial cells, promotes hepatic vasoconstriction by binding to ET-A receptors located on HSCs. ET-1 also appears to be generated within HSCs themselves and promotes HSC contraction through an autocrine loop. Of interest, ET-1 may alternatively bind to ET-B receptors on endothelial cells. This signaling pathway paradoxically promotes vasodilatation by activating eNOS. Other vascular mediators implicated in hepatic vasoregulation include carbon monoxide generated by the heme oxygenase system, the sympathetic adrenergic agonist norepinephrine, the renin-dependent vasoconstrictor angiotensin, prostaglandins, thromboxane, leukotrienes, and hydrogen sulfide. Of these mediators, angiotensin is of particular interest because it is a potent constrictor of HSCs and is released in increased amounts in cirrhosis owing to systemic sympathetic hyperactivity. A number of angiotensin receptor blockers are undergoing evaluation for the treatment of portal hypertension.

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 (ΔP) 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 lower-pressure 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 hypertension focus on correction of hemodynamic alterations in the portal circulation. Approaches include use of nonselective β-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, ηL 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 levels⁹^,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 cirrhosis¹⁰ 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 in portal hypertension is not known, but this effect may be secondary to transforming growth factor-β (TGF-β), 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-1–dependent 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.³¹^–³⁹ 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 stress–dependent and shear stress–independent 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-α (TNF-α) because inhibitors of TNF improve portal pressure and the splanchnic circulatory disturbances in both human and experimental portal hypertension. TNF-α 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 pressure–reducing 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 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 vein–systemic 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 intra-abdominal 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.

MEASUREMENT OF PORTAL PRESSURE

Portal pressure may be measured indirectly or directly. The most commonly used method of measuring portal pressure is determination of the hepatic vein pressure gradient (HVPG), which is an indirect method. Measurement of splenic pulp pressure and direct measurement of the portal vein pressure are invasive, cumbersome, and infrequently used approaches. Variceal pressure also can be measured but is not routinely performed in clinical practice. Measurement of liver stiffness using ultrasound fibroelastography or magnetic resonance elastography (MRE) may indicate the presence of portal hypertension but cannot yet be used to measure portal pressure.

HEPATIC VEIN PRESSURE GRADIENT

The HVPG is the difference between the wedged hepatic venous pressure (WHVP) and free hepatic vein pressure (FHVP). The HVPG has been used to assess portal hypertension since its first description in 1951,⁷⁸ and has been validated as the best predictor for the development of complications of portal hypertension.

Measurement of the HVPG requires passage of a catheter into the hepatic vein under radiologic guidance until the catheter can be passed no further, that is, until the catheter has been “wedged” in the hepatic vein. The catheter can be passed into the hepatic vein through the femoral vein or using a transjugular venous approach. The purpose of wedging the catheter is to form a column of fluid that is continuous between the hepatic sinusoids and the catheter. Therefore, the measured pressure of fluid within the catheter reflects hepatic sinusoidal pressure. One of the drawbacks of using a catheter that is wedged in the hepatic vein is that the WHVP measured in a more fibrotic area of liver may be higher than the pressure measured in a less fibrotic area because of regional variation in the degree of fibrosis. Using a balloon-occluding catheter in the right hepatic vein to create a stagnant column of fluid in continuity with the hepatic sinusoids eliminates this variation in measurement of WHVP because the balloon catheter measures the WHVP averaged over a wide segment of the liver.⁷⁹ HVPG is not effective for detecting presinusoidal causes of portal hypertension. For example, in portal hypertension secondary to portal vein thrombosis, the HVPG is normal. Moreover, the HVPG may underestimate sinusoidal pressure in primary biliary cirrhosis and other presinusoidal causes of portal hypertension.⁸⁰ Therefore, HVPG is accurate for detecting only sinusoidal and postsinusoidal causes of portal hypertension.

The HVPG represents the gradient between the pressure in the portal vein and the intra-abdominal inferior vena caval pressure. An elevation in intra-abdominal pressure increases both WHVP and FHVP equally, so that the HVPG is unchanged. The advantage of the HVPG is that variations in the “zero” reference point have no impact on the HVPG.⁸¹ The HVPG is measured at least three times to demonstrate that the values are reproducible. Total occlusion of the hepatic vein by the inflated balloon to confirm that the balloon is in a wedged position is demonstrated by injecting contrast into the hepatic vein. A sinusoidal pattern should be seen, with no collateral circulation to other hepatic veins. The contrast washes out promptly with deflation of the balloon. Correct positioning of the balloon also is demonstrated by a sharp increase in the recorded pressure on inflation of the balloon. The pressure then becomes steady until the balloon is deflated, when the pressure drops sharply. In experienced hands, measurement of the HVPG is highly reproducible, accurate, and safe.

Measurement of the HVPG has been proposed for the following indications: (1) to monitor portal pressure in patients taking drugs used to prevent variceal bleeding; (2) as a prognostic marker ⁸²; (3) as an end-point in trials using pharmacologic agents for the treatment of portal hypertension⁸³; (4) to assess the risk of hepatic resection in patients with cirrhosis; and (5) to delineate the cause of portal hypertension (i.e., presinusoidal, sinusoidal, or postsinusoidal (Table 90-1), usually in combination with venography, right-sided heart pressure measurements, and transjugular liver biopsy. Although the indication for HVPG measurement with the most potential for widespread use is monitoring the efficacy of therapies to reduce portal pressure, HVPG monitoring is not done routinely in clinical practice because no controlled trials have yet demonstrated its usefulness.⁸⁴

Table 90-1 The Use of Hepatic Venous Pressure Gradient in the Differential Diagnosis of Portal Hypertension

SPLENIC PULP PRESSURE

Determination of splenic pulp pressure is an indirect method of measuring portal pressure and involves puncture of the splenic pulp with a needle catheter. Splenic pulp pressure is elevated in presinusoidal portal hypertension, when the HVPG is normal. Because of the potential risk of complications, especially bleeding, associated with splenic puncture, however, the procedure is rarely used.

PORTAL VEIN PRESSURE

Direct measurement of the pressure in the portal vein is a rarely used method that can be carried out through a percutaneous transhepatic route, transvenous approach, or, rarely, intraoperatively (although anesthesia can affect portal pressure). The transhepatic route requires portal vein puncture performed under ultrasound guidance. A catheter is then threaded over a guidewire into the main portal vein. With increasing use of the transjugular intrahepatic portosystemic shunt (TIPS) (see later), radiologists have gained expertise in puncturing the portal vein and measuring portal vein pressure by a transjugular route. Direct portal pressure measurements are carried out when HVPG cannot be measured, as in patients with occluded hepatic veins caused by the Budd-Chiari syndrome, in whom a surgical portosystemic shunt is being contemplated,⁸⁵ or in patients with intrahepatic, presinusoidal causes of portal hypertension, such as idiopathic portal hypertension, in which the HVPG may be normal.

ENDOSCOPIC VARICEAL PRESSURE

Varices rupture and bleed when the expanding force of intravariceal pressure exceeds variceal wall tension. Measurement of the difference between intravariceal pressure and pressure within the esophageal lumen (the transmural pressure gradient across the varices) is potentially a more important indicator of bleeding risk than measurement of HVPG,⁸⁶^,⁸⁷ especially in patients with portal vein thrombosis and other causes of portal hypertension associated with a normal HVPG.

Variceal pressure can be measured by inserting a needle connected to a pressure transducer, through a fluid-filled catheter, into a varix; this approach is currently not justified except when measurement of variceal pressure is followed by variceal injection sclerotherapy. Because variceal sclerotherapy has fallen out of favor (see later), measurement of variceal pressure by variceal puncture is seldom carried out.

A miniature pneumatic pressure sensitivity gauge attached to the tip of an endoscope (Varipres Solid Components, Barcelona, Spain) allows noninvasive measurement of variceal pressure. Patients with previous variceal bleeding have been demonstrated to have higher variceal pressures than those in patients without previous bleeding.⁸⁸ A variceal pressure greater than 18 mm Hg during a bleeding episode is associated with failure to control bleeding and predicts early rebleeding.⁸⁹ Moreover, patients on pharmacologic therapy who show a decrease in variceal pressure of greater than 20% from baseline have a low probability of bleeding, as compared with patients who do not demonstrate a greater than 20% decrease in variceal pressure, in whom the risk of variceal bleeding is 46%.⁸⁸ Variceal pressure measurements determined with use of Varipres are considered satisfactory when they meet the following criteria: (1) a stable intraesophageal pressure; (2) absence of artifacts caused by esophageal peristalsis; and (3) correct placement of the gauge over the varix, as shown by fine fluctuations in the pressure tracing that correspond to the cardiac cycle and respirations. Therefore, measurement of variceal pressure requires both a skilled endoscopist and a cooperative patient, and, even in expert hands, accurate variceal pressure measurements cannot be obtained in 25% of patients.

Manometry using an endoscopic balloon to measure variceal pressure is subject to observer bias because it relies on visual appearance to determine whether the varices have collapsed.⁹⁰^–⁹² With this technique, a balloon is inserted into the esophagus and inflated until the varices are noted on endoscopy to collapse. The pressure in the balloon required to collapse the varices represents the variceal pressure. In general, techniques of measuring variceal pressure are still considered experimental and not suitable for routine clinical use.

DETECTION OF VARICES

UPPER GASTROINTESTINAL ENDOSCOPY

Upper gastrointestinal endoscopy is the most commonly used method to detect varices. The current consensus is that all patients with cirrhosis of the liver should be screened for esophageal varices by endoscopy. In patients in whom no varices are detected on initial endoscopy, endoscopy to look for varices should be repeated in 2 to 3 years. If small varices are detected on the initial endoscopy, endoscopy should be repeated in 1 to 2 years.⁹³^,⁹⁴ None of the various noninvasive methods of determining which patients benefit most from endoscopic screening are accurate enough to recommend for routine use in clinical practice.⁹⁵ The role of noninvasive markers in predicting the risk of large esophageal varices requires study in large multicenter trials. Preliminary data suggest that wireless video capsule endoscopy (see Chapter 19)⁹⁶ and computed tomography (CT) imaging are alternative screening modalities in patients who are not candidates for upper endoscopy. Moreover, CT screening may be more cost-effective than endoscopy.⁹⁷

Endoscopic grading of esophageal varices is subjective. Various criteria have been used to try to standardize the reporting of esophageal varices. The best known of these criteria are those compiled by the Japanese Research Society for Portal Hypertension. The descriptors include red color signs, color of the varix, form (size) of the varix, and location of the varix.⁹⁸ Red color signs include red “wale” markings, which are longitudinal whip-like marks on the varix; cherry-red spots, which usually are 2 to 3 mm or less in diameter; hematocystic spots, which are blood-filled blisters 4 mm or greater in diameter; and diffuse redness. The color of the varix can be white or blue. The form of the varix at endoscopy is described most commonly. Esophageal varices may be small and straight (grade I); tortuous and occupying less than one third of the esophageal lumen (grade II); or large and occupying more than one third of the esophageal lumen (grade III). Varices can be in the lower third, middle third, or upper third of the esophagus. Of all of the aforementioned descriptors, the size of the varices in the lower third of the esophagus is the most important. The size of the varices in the lower third of the esophagus is determined during withdrawal of the endoscope (Fig. 90-6). As much air as possible should be aspirated from the stomach while the esophageal lumen is fully inflated. Small varices, that is, those occupying less than one third of the lumen, are less than 5 mm in diameter, whereas large varices are greater than 5 mm in diameter.⁹⁸^,⁹⁹ As a point of reference, any varix larger in diameter than an open pinch biopsy forceps is likely to be greater than 5 mm in diameter. Patients with large esophageal varices, Child (or Child-Pugh) class C cirrhosis (see later), and red color signs on varices have the highest risk of variceal bleeding within 1 year.¹⁰⁰ The increase in bleeding risk attributable to the presence of red color signs, however, is not independent of the risk associated with large variceal size. Therefore, prophylactic treatment to prevent variceal bleeding is recommended in all patients with large esophageal varices irrespective of the presence or absence of red color signs (see later).

Figure 90-6. Endoscopic appearances of esophageal varices. A, Upper gastrointestinal endoscopy demonstrates dilated and straight veins (small esophageal varices) in the distal esophagus (arrows). B, Upper gastrointestinal endoscopy demonstrates large esophageal varices, greater than 5 mm in diameter, with a fibrin plug (arrow) representing the site of a recent bleed.

ULTRASONOGRAPHY

Ultrasound examination of the liver with Doppler study of the vessels has been used widely to assess patients with portal hypertension. Features suggestive of portal hypertension on ultrasonography include splenomegaly, portosystemic collateral vessels, and reversal of the direction of flow in the portal vein (hepatofugal flow). Some studies have demonstrated that a portal vein diameter greater than 13 mm and the absence of respiratory variations in the splenic and mesenteric veins are sensitive but nonspecific markers of portal hypertension.¹⁰¹^,¹⁰² These criteria are not used routinely in clinical practice in most centers. Ultrasound examination can detect thrombosis of the portal vein, which appears as nonvisualization or cavernous transformation (a cavernoma) of the portal vein; the latter finding indicates an extensive collateral network in place of the portal vein.¹⁰³ Splenic vein thrombosis also can be demonstrated. Portal blood flow can be measured by Doppler ultrasonography, which is the easiest research method for detecting postprandial increases in splanchnic blood flow.¹⁰⁴ Although Doppler ultrasonography is clinically useful in the initial evaluation of portal hypertension, the technique is not widely used to provide quantitative assessments of the degree of portal hypertension. Transient elastography may be useful in detecting portal hypertension but is not sufficiently sensitive to recommend as a modality to monitor decreases in portal pressure in patients on pharmacotherapy (see Chapter 73).¹⁰⁵

COMPUTED TOMOGRAPHY

Computed tomography (CT) is useful for demonstrating many features of portal hypertension, including abnormal configuration of the liver, ascites, splenomegaly, and collateral vessels (Fig. 90-7). Detection of varices may be an emerging indication for CT. Diagnosis of fundal varices by multidetector row CT (MDCT) is at least as accurate as endoscopic ultrasonography (see later). CT is especially helpful in distinguishing submucosal from perigastric fundal varices¹⁰⁶ and is considered a less invasive alternative to conventional angiographic portography in assessing portosystemic collaterals. At present, however, CT is not a recommended screening method for detecting large esophageal varices, but it may be a cost-effective method of screening for varices and preferred to endoscopy by patients.⁹⁷

Figure 90-7. Abdominal computed tomography (CT) in patients with portal hypertension. A, CT scan shows an irregular contour of the liver typical of cirrhosis (arrowheads). A small right pleural effusion is evident (straight arrow). The liver is hypointense relative to the spleen (curved arrow), typical of fatty infiltration of the liver in alcoholic cirrhosis. B, Coronal section of a CT scan showing contrast-enhanced esophageal varices (cursor). C, CT scan demonstrating two large esophageal varices (arrows) 5 mm and 6 mm in diameter. Varices are almost opposed to each other. D, CT scan demonstrates a tuft of gastroesophageal collaterals (straight arrow). The enlarged spleen also is seen (curved arrow).

MAGNETIC RESONANCE IMAGING

Gadolinium-enhanced magnetic resonance imaging (MRI) is becoming recognized as a potentially useful method of detecting esophageal varices.¹⁰⁷ In addition, MRI can be used to measure portal and azygous blood flow, which is increased in patients with portal hypertension.¹⁰⁸ MRI provides excellent detail of the vascular structures of the liver and can detect portal venous thrombosis and spleen stiffness in patients with portal hypertension, but the role of MRI in the assessment of portal hypertension requires further study. Unlike transient elastography using ultrasound, MRI can accurately assess the stiffness of even fatty livers.¹⁰⁹

ENDOSCOPIC ULTRASONOGRAPHY

Endoscopic ultrasound examination (endosonography) using radial or linear array echo-endoscopes or endoscopic ultrasound mini-probes passed through the working channel of a diagnostic endoscope has been applied as an investigational tool in the evaluation of patients with varices. Endoscopic ultrasonography has been used to study several aspects of esophageal varices, including the cross-sectional area of varices to identify patients at increased risk of bleeding ⁷⁷; size of and flow in the left gastric vein, azygous vein, and paraesophageal collaterals; changes after endoscopic therapy; and recurrence of esophageal varices following variceal ligation (see later).¹¹⁰ Endosonography can be combined with endoscopic measurement of transmural variceal pressure to allow estimation of variceal wall tension, which is a predictor of variceal bleeding (see earlier).¹¹¹^–¹¹³

CAUSES OF PORTAL HYPERTENSION

The usual classification of causes of portal hypertension is based on the site of increased resistance to portal blood flow—namely, prehepatic, intrahepatic, and posthepatic—and is outlined in Figure 90-5. Intrahepatic sites of increased resistance can be presinusoidal, sinusoidal, or postsinusoidal. Many causes of portal hypertension are associated with an increase in resistance at more than one site. For example, alcoholic cirrhosis may be associated with increased resistance at the presinusoidal, sinusoidal, and postsinusoidal levels. Therefore, classification based on the site of resistance may not be possible for all diseases that cause portal hypertension. A more useful classification is clinically based and considers common and less common causes of portal hypertension (Table 90-2).

Table 90-2 Causes of Portal Hypertension

Common

Cirrhosis

Extrahepatic portal vein thrombosis

Idiopathic portal hypertension

Schistosomiasis

Less Common

Fibropolycystic liver disease

Hereditary hemorrhagic telangiectasia

Malignancy

Myeloproliferative disorders

Nodular regenerative hyperplasia

Partial nodular transformation of the liver

Sarcoidosis

Splanchnic arteriovenous fistula

COMMON CAUSES

Cirrhosis

Complications related to portal hypertension are the usual clinical manifestations of cirrhosis of the liver. Although all causes of cirrhosis are associated with portal hypertension, some features are disease specific. In alcoholic liver disease, elevation of the portal pressure is accurately reflected by the HVPG; moreover, portal hypertension may occur in the absence of cirrhosis but is more marked when cirrhosis is present. Perivenular lesions implicated in the pathogenesis in noncirrhotic alcoholic liver injury account for the presinusoidal component of portal hypertension in these patients.¹¹⁴ Autoimmune hepatitis also may be associated with portal hypertension in the absence of cirrhosis¹¹⁵; however, the risk of variceal bleeding is low in patients with autoimmune hepatitis. In patients with hemochromatosis, portal hypertension may be seen even before cirrhosis; the severity of portal hypertension increases with increasing fibrosis. Patients with hemochromatosis may bleed from varices despite an HVPG less than 12 mm Hg, indicating a presinusoidal component of portal hypertension. Phlebotomy therapy in patients with hemochromatosis may result in a decrease in portal hypertension.¹¹⁶ In patients with primary biliary cirrhosis, portal hypertension also may occur before cirrhosis has developed. The risk of variceal bleeding increases with an increase in the histologic stage of the disease.¹¹⁷ In earlier stages of primary biliary cirrhosis, portal hypertension is predominantly presinusoidal, but as the disease progresses, a sinusoidal component develops. Therefore, the HVPG may underestimate portal pressure in patients with primary biliary cirrhosis.⁸⁰ Portal hypertension occurs in patients with primary sclerosing cholangitis and in those with biliary strictures. A long duration of biliary obstruction usually is required, although portal hypertension has been known to develop in a few months in patients with chronic bile duct obstruction caused by chronic alcoholic pancreatitis.¹¹⁸ Portal hypertension in patients with biliary obstruction regresses following relief of the biliary obstruction.

Schistosomiasis

Schistosomiasis may be the most common cause of portal hypertension worldwide (see Chapter 82). Bleeding from esophageal varices is a major cause of death in patients with hepatosplenic schistosomiasis. Portal hypertension results from presinusoidal obstruction caused by deposition of eggs of Schistosoma mansoni and Schistosoma japonicum in the presinusoidal portal venules. The host reaction results in granulomatous inflammation, which causes presinusoidal and periportal fibrosis.¹¹⁹ The fibrosis that results is sometimes called “clay pipestem” or simply “pipestem” fibrosis and usually is associated with sustained heavy infection. The periportal collagen deposition leads to progressive obstruction of portal blood flow, portal hypertension, and variceal bleeding, along with splenomegaly and hypersplenism. Lobular architecture usually is preserved. Coinfection with hepatitis B or C virus in patients with hepatic schistosomiasis can result in more rapid progression of fibrosis, hepatic failure, and an increased risk of hepatocellular carcinoma.¹²⁰

In the initial stages of schistosomiasis, the HVPG is normal owing to the presinusoidal nature of the obstruction. Some patients with schistosomiasis and portal hypertension also may have portal vein thrombosis. Patients with schistosomiasis often undergo portosystemic shunt surgery to treat variceal bleeding, with excellent long-term outcomes.

Extrahepatic Portal Vein Thrombosis

Extrahepatic portal vein thrombosis is a prehepatic, presinusoidal cause of portal hypertension and a common cause of portal hypertension in children (see Chapter 83). The most common causes of portal vein thrombosis include hematologic disorders such as polycythemia vera or other myeloproliferative disorders. Other causes include a prothrombotic state, such as antithrombin, protein C, or protein S deficiency; antiphospholipid syndrome (or antiphospholipid antibody syndrome); paroxysmal nocturnal hemoglobinuria; oral contraceptive use; a neoplasm, usually intra-abdominal; an inflammatory disease, such as pancreatitis, inflammatory bowel disease, or diverticulitis; abdominal trauma; and postoperative states, especially postsplenectomy. Cirrhosis is a cause of portal vein thrombosis.¹²¹ Older studies suggested that portal vein thrombosis occurs in approximately 6% of patients with cirrhosis and in up to 25% of those with cirrhosis and hepatocellular carcinoma.¹²² With improved imaging, portal vein thrombosis is now known to be a more common complication of cirrhosis, and the association with hepatocellular carcinoma may not be as strong as previously thought. Isolated splenic vein thrombosis caused by a pancreatic neoplasm or pancreatitis usually is not associated with a thrombophilia. Umbilical vein sepsis may be an etiologic factor in children with portal vein thrombosis, but even in these cases, an associated prothrombotic state may predispose the patient to portal vein thrombosis.

Acute and subacute portal vein thrombosis usually does not manifest with variceal bleeding.¹ Chronic portal vein thrombosis is suggested by nonvisualization of the portal or splenic vein and an extensive collateral circulation. Patients may present with nonspecific symptoms or with variceal bleeding and hypersplenism. Bleeding usually is from gastroesophageal varices but may be from duodenal varices and, rarely, other ectopic sites. Gallbladder varices (Fig. 90-8) also have been described in patients with portal vein thrombosis.¹²³

Figure 90-8. Computed tomography image of choledochal varices (arrows).

The treatment of portal vein thrombosis is symptomatic, with the aim of controlling variceal bleeding or preventing recurrent variceal bleeding. Patients in whom esophageal varices are not large, and a thrombophilia is detected, are best managed with anticoagulation because in these patients, the benefits of anticoagulation outweigh the risks.¹²⁴ Local or systemic thrombolytic therapy is seldom required and is generally reserved for patients in whom a portal vein thrombus extends into the superior mesenteric vein, with danger of impending intestinal ischemia. Endoscopic therapy is used to control acute variceal bleeding and to prevent recurrent bleeding. Use of pharmacologic agents such as beta blockers to prevent variceal bleeding is probably also effective in patients with portal vein thrombosis, but this approach has not been well studied. Patients with portal vein thrombosis have lower mortality and morbidity rates from variceal bleeding than those reported in patients with cirrhosis and variceal bleeding, owing to the lack of coagulopathy and synthetic liver dysfunction. Surgical portosystemic shunt procedures are carried out in patients in whom bleeding cannot be controlled by conservative measures. If a suitable vein is not available for anastomosis, a large collateral vein may be anastomosed to a systemic vein.¹²⁵ Placement of a TIPS is possible in some patients with chronic portal vein thrombosis.

Idiopathic Portal Hypertension

Idiopathic portal hypertension is uncommon in Western countries but is common in parts of Asia such as India and Japan. This disorder is diagnosed when the portal pressure is elevated in the absence of significant histologic changes in the liver or extrahepatic portal vein obstruction.¹²⁶ A liver biopsy specimen from affected patients may be entirely normal,¹²² although increased concentrations of ET-1 have been noted in the periportal hepatocytes, portal venules, and hepatic sinusoids of patients with idiopathic portal hypertension.¹²⁷ Various terms used (rather loosely) to describe idiopathic portal hypertension include hepatoportal sclerosis, noncirrhotic portal fibrosis, and Banti’s syndrome.¹²⁸^,¹²⁹ Use of the term idiopathic portal hypertension probably is best restricted to portal hypertension in patients in whom no hepatic lesion is found on light microscopy. The term hepatoportal sclerosis suggests obliterative portal venopathy with subendothelial thickening of the intrahepatic portal veins; thrombosis and recanalization of these veins may follow. Fibrosis of the portal tracts is prominent later in the course.

The cause of idiopathic portal hypertension is unclear in a majority of patients, although chronic arsenic intoxication, exposure to vinyl chloride, and hypervitaminosis A have been implicated (see Chapter 87). These etiologic factors are present in only a minority of patients. The dominant clinical features of the condition are variceal bleeding and hypersplenism related to a markedly enlarged spleen. Liver biochemical test levels are usually normal, although the serum alkaline phosphatase level may be mildly elevated. Ascites is uncommon. The HVPG in this disorder usually is normal because the site of increased resistance is presinusoidal.¹³⁰ Surgical portosystemic shunts are well tolerated in these patients, although hepatic encephalopathy may occur on long-term follow-up evaluation.¹²² Liver transplantation is rarely required in these patients.

Idiopathic portal hypertension may be confused with incomplete septal cirrhosis, which probably is an unrelated condition characterized by incomplete septa and liver nodularity.¹³¹ Patients with incomplete septal cirrhosis are clinically similar to patients with cirrhosis and may progress to end-stage liver disease and require liver transplantation.

LESS COMMON CAUSES

Nodular Regenerative Hyperplasia

Nodular regenerative hyperplasia is a histopathologic diagnosis characterized by atrophy of zone 3 hepatocytes and hypertrophy of zone 1 hepatocytes without significant fibrosis (see Chapters 35 and 94).¹³² This disorder has been recognized increasingly as a cause of portal hypertension and may even occur after liver transplantation.¹³³ Similar histologic changes may be seen in well-established Budd-Chiari syndrome.¹³⁴ The nodular hyperplasia may not be apparent on histologic examination unless a reticulin stain is carried out to demonstrate the micronodules. These regenerative nodules are believed to result from an imbalance between hyperperfused areas of the liver, with resulting regenerative nodules, and poorly perfused areas, with resulting atrophy. Nodular regenerative hyperplasia is associated with a variety of conditions, predominantly hematologic and rheumatologic in nature. Liver biochemical abnormalities include mild elevation of the serum aminotransferase levels. Portal hypertension manifesting as variceal bleeding is the predominant clinical presentation. Ascites also may develop in these patients, suggesting that an increase in sinusoidal pressure occurs.¹³⁵ Hepatocellular carcinoma does not occur, but liver transplantation may be required in some patients.

Partial Nodular Transformation of the Liver

Partial nodular transformation of the liver is an uncommon lesion that is characterized by large nodules in the perihilar region.¹³⁶ These nodules may be visible on imaging studies of the liver. The rest of the liver may be normal or may show changes of nodular regenerative hyperplasia. Liver biochemical test levels usually are normal. Like nodular regenerative hyperplasia, partial nodular transformation of the liver is believed to be related to an imbalance in portal perfusion of the liver, but the abnormality is restricted to the hilar branches, whereas in nodular regenerative hyperplasia the abnormality is more diffuse. Variceal bleeding is the predominant presentation in partial nodular transformation of the liver, although patients with large nodules may experience abdominal pain. Hepatocellular carcinoma may rarely develop in these regenerating nodules. Treatment with a surgical portosystemic shunt is associated with good long-term results.

Fibropolycystic Liver Disease

Fibropolycystic liver disease is a term which encompasses Caroli’s disease, Caroli’s complex (Caroli’s disease with congenital hepatic fibrosis), congenital hepatic fibrosis, and polycystic liver disease. Congenital hepatic fibrosis usually occurs in association with Caroli’s disease of the liver, polycystic disease of the kidney, and medullary sponge kidney (see Chapter 62). The major manifestation of congenital hepatic fibrosis is variceal bleeding.¹³⁷ A portosystemic shunt may be placed in these patients to treat refractory variceal bleeding, with a low long-term risk of hepatic encephalopathy. Patients with polycystic liver disease, whether associated with polycystic kidney disease or not, rarely present with portal hypertension (see Chapter 94).¹³⁸ Portal hypertension may decrease after treatment of the cysts.

Sarcoidosis

Portal hypertension is an uncommon manifestation of hepatic sarcoidosis (see Chapter 35).¹³⁹ The site of increased intrahepatic resistance in patients with sarcoidosis seems to be postsinusoidal, in view of the elevated HVPG. In early disease, however, the resistance is predominantly at a presinusoidal level. Treatment with glucocorticoids may decrease portal hypertension in some patients with hepatic sarcoidosis.

Malignancy

Portal hypertension has been associated with leukemias, lymphomas, and systemic mastocytosis (see Chapters 34 and 35).¹⁴⁰ Portal hypertension also may occur in patients with hepatocellular carcinoma independent of the presence of cirrhosis (see Chapter 94). The pathogenesis of portal hypertension in patients with hepatocellular carcinoma is thought to be multifactorial; contributing factors include portal vein thrombosis, pressure by the tumor on the portal vein, and, in some cases, a hepatic artery–portal vein fistula. Esophageal varices may be seen in patients with hepatic metastases, although variceal bleeding is unusual.¹⁴¹

Splanchnic Arteriovenous Fistula

Splanchnic arteriovenous fistula should be suspected when the onset of ascites and variceal bleeding is acute, especially in the presence of an abdominal bruit. When a splanchnic artery ruptures into a mesenteric vein, the portal pressure increases acutely, reaching levels of systemic arterial pressure.¹⁴² The result is acute portal hypertension with development of ascites and variceal bleeding. A bruit may be heard in the left upper quadrant of the abdomen with a splenic arteriovenous fistula and in the right upper quadrant with a hepatic artery–portal vein fistula. With a long-standing fistula, secondary hepatic changes of perisinusoidal fibrosis related to an increase in portal venous inflow may be present. In the early stages, embolization or ligation of the fistula will ameliorate the portal hypertension. In late stages, however, portal fibrosis may be advanced, and the portal hypertension may not correct completely with embolization of the fistula.

Hereditary Hemorrhagic Telangiectasia

Hereditary hemorrhagic telangiectasia (HHT), or Osler-Weber-Rendu disease, is an unusual cause of portal hypertension (see also Chapters 19 and 36). Diagnostic criteria include mucocutaneous telangiectasias, epistaxis, arteriovenous fistulas of the viscera (usually lung or liver), and a family history of the disorder. Manifestations of HHT depend on the site of fistula formation. A fistula between the hepatic artery and hepatic vein manifests predominantly as biliary disease, mainly biliary strictures and cholangitis, and high-output cardiac failure. A fistula between the hepatic artery and portal vein results in portal hypertension and biliary strictures, whereas a fistula between the portal vein and hepatic vein, which is rare, results in hepatic encephalopathy.¹⁴³ Nodular regenerative hyperplasia, which develops in some patients with HHT, may worsen portal hypertension.¹⁴⁴ Although symptomatic liver disease in HHT is rare, involvement of the liver is found in a majority of patients.¹⁴⁵

CLINICAL ASSESSMENT OF PATIENTS WITH PORTAL HYPERTENSION-RELATED BLEEDING

Patients with esophageal or gastric variceal bleeding present with hematemesis or melena (or both). Chronic blood loss is a more common presentation of portal hypertensive gastropathy or gastrointestinal vascular ectasia. The classic presentation of patients with variceal bleeding is with effortless and recurrent hematemesis; the vomitus is described as dark red in color.

Portal hypertension should be suspected in all patients with gastrointestinal bleeding and peripheral stigmata of liver disease—namely, jaundice, spider angiomata, palmar erythema, Dupuytren’s contractures, parotid enlargement, testicular atrophy, loss of secondary sexual characteristics, ascites, and encephalopathy. Splenomegaly is an important clue to the presence of portal hypertension, and the presence of ascites makes the presence of esophageal varices even more likely. Caput medusae, suggestive of an intrahepatic cause of portal hypertension, is present around the umbilicus; the flow of blood is away from the umbilicus. In Budd-Chiari syndrome, by contrast, veins are dilated in the flanks and back, and blood flows in a cephalic direction.⁸⁵ A bruit may be heard in the left or the right upper quadrant in a patient with a splanchnic arteriovenous fistula. A venous hum may be heard in the epigastrium of a patient with portal hypertension and represents collateral flow in the falciform ligament.

Laboratory studies frequently reveal evidence of hepatic synthetic dysfunction, including prolongation of the prothrombin time, hypoalbuminemia, and hyperbilirubinemia, as well as anemia. Thrombocytopenia and leukopenia, reflecting hypersplenism and, in alcoholics, bone marrow suppression, may be noted. Patients with severe bleeding may present with hypovolemic shock and renal insufficiency. Abdominal imaging studies frequently reveal splenomegaly, collateral vessels, abnormal liver echotexture and contour, and ascites.

TREATMENT OF PORTAL HYPERTENSION-RELATED BLEEDING

The treatment of portal hypertension is aimed either at reducing portal blood flow with pharmacologic agents—such as beta blockers or vasopressin and its analogs—or at decreasing intrahepatic resistance, with pharmacologic agents—such as nitrates or by radiologic or surgical creation of a portosystemic shunt. Treatment also may be directed at the varices with use of endoscopic or radiologic techniques.

PHARMACOLOGIC THERAPY

The pharmacologic agents used in the treatment of portal hypertension are divided into two groups: those that decrease splanchnic blood flow and those that decrease intrahepatic vascular resistance (Table 90-3). The agents that decrease splanchnic blood flow acutely are vasopressin and its analogs and somatostatin and its analogs. β-adrenergic blocking agents (beta blockers) also decrease portal blood flow but are used only to prevent variceal bleeding and rebleeding. Agents that target intrahepatic vascular resistance include α-adrenergic blocking agents, angiotensin receptor blocking agents, and nitrates, but only nitrates are now considered for clinical use. Diuretics, by decreasing plasma volume, may reduce portal pressure but are not recommended as sole agents for the treatment of portal hypertension. Metoclopramide and other gastric prokinetic agents may decrease intravariceal pressure by contracting the lower esophageal sphincter, but these agents have not been evaluated in clinical trials and are not recommended.

Table 90-3 Drugs Used in the Treatment of Portal Hypertension

Drugs That Decrease Portal Blood Flow

Nonselective β-adrenergic blocking agents

Somatostatin and its analogs

Vasopressin

Drugs That Decrease Intrahepatic Resistance

α₁-Adrenergic blocking agents (e.g., prazosin)

Angiotensin receptor blocking agents

Nitrates

Vasopressin and Its Analogs

Vasopressin is an endogenous peptide hormone that causes splanchnic vasoconstriction, reduces portal venous inflow, and reduces portal pressure. This drug is associated with serious systemic side effects, however. By causing constriction of systemic vessels, vasopressin may result in necrosis of the bowel. Additionally, vasopressin has direct negative inotropic and chronotropic effects on the myocardium that lead to reduced cardiac output and bradycardia, respectively. An increase in cardiac afterload can result in myocardial infarction, and antidiuresis, resulting from the action of vasopressin on the kidney, can result in hyponatremia.

Terlipressin, or triglycyl-lysine-vasopressin, is a semisynthetic analog of vasopressin that is cleaved by endothelial peptidases to release lysine vasopressin. Compared with vasopressin, terlipressin results in lower circulatory levels of the vasopressin analog and a lower rate of systemic side effects. Vasopressin and terlipressin have been used in combination with nitrates to decrease the risk of systemic side effects. Terlipressin is preferred over vasopressin because of its superior safety profile. In addition, an increase in survival has been demonstrated in patients with variceal bleeding treated with terlipressin. Terlipressin is not currently available in the United States, although it is undergoing evaluation by the U.S. Food and Drug Administration (FDA).

Somatostatin and Its Analogs

Somatostatin is a 14-amino-acid peptide. Five somatostatin receptors—SRTR 1 to SRTR 5—are recognized, but the actual distribution of the receptors in humans is not clear. Following intravenous injection, somatostatin has a half-life in the circulation of one to three minutes; therefore, longer-acting analogs of somatostatin have been synthesized. The best known of these analogs are octreotide, lanreotide, and vapreotide.¹⁴⁶ Somatostatin decreases portal pressure and collateral blood flow by inhibiting release of glucagon.¹⁴⁷ The optimal dose and duration of use of somatostatin have not been adequately studied. Following a single 250-µg bolus injection of somatostatin, portal and azygous blood flow decrease, but the effect lasts only a few minutes.¹⁴⁸ Use of higher doses is associated with a more impressive decrease in HVPG. Somatostatin also decreases portal hypertension by decreasing postprandial splanchnic blood flow.¹⁴⁹ Following a variceal bleed, blood in the gastrointestinal tract acts like a meal, leading to an increase in portal flow and elevation in the portal pressure; this elevation in pressure is ameliorated by the use of somatostatin.

Following intravenous administration, octreotide has a half-life in the circulation of 80 to 120 minutes. Its effect on reducing portal pressure is not prolonged, however. Moreover, continuous infusion of octreotide does not decrease portal pressure despite decreasing the postprandial increase in portal pressure.⁶²^,¹⁵⁰

Available evidence is insufficient to prove the superiority of somatostatin and its analogs to placebo in the control of acute variceal bleeding.¹³⁴ Some randomized controlled trials, however, support the view that somatostatin or octreotide may be equivalent in efficacy to sclerotherapy or terlipressin for controlling acute variceal bleeding. Also, early administration of vapreotide may be associated with improved control of bleeding but without a significant reduction in mortality rate.¹⁵¹ In clinical practice, treatment with somatostatin or octreotide is combined with endoscopic management of variceal bleeding (see later).

β-Adrenergic Blocking Agents

Nonselective β-adrenergic blocking agents have been used extensively since the landmark study of Lebrec and colleagues demonstrated the efficacy of these agents in preventing variceal rebleeding.¹⁵² Nonselective beta blockers such as propranolol or nadolol are preferred. Blockade of β₁-adrenergic receptors in the heart decreases cardiac output. Blockade of β₂-adrenergic receptors, which cause vasodilatation in the mesenteric circulation, allows unopposed action of α₁-adrenergic receptors and results in decreased portal flow. The combination of decreased cardiac output and decreased portal flow leads to a decrease in portal pressure. Nadolol has advantages over propranolol in that it is excreted predominantly by the kidney, has low lipid solubility, and is associated with a lower risk of central nervous system side effects such as depression. The effectiveness of beta blockers is assessed most accurately by monitoring the HVPG; this approach is not widely used in clinical practice. The usual method of monitoring the efficacy of beta blockers is to observe a decrease in the heart rate, which is a measure of β₁-adrenergic receptor blockade. Despite adequate β₁-adrenergic receptor blockade, however, some patients might benefit from a further increase in the dose of beta blocker, to increase the degree of β₂-adrenergic blockade. Raising the dose, however, results in more side effects and the likelihood that treatment will need to be withdrawn.¹⁵³

Nitrates

Short-acting (nitroglycerin) or long-acting (isosorbide mononitrate) nitrates result in vasodilatation. The vasodilatation results from a decrease in intracellular calcium in vascular smooth muscle cells. Nitrates cause venodilatation, rather than arterial dilatation, and decrease portal pressure predominantly by decreasing portal venous blood flow. The effect on intrahepatic resistance is less impressive than generally has been believed. Nitroglycerin has been used in combination with vasopressin to control acute variceal bleeding. The rate of infusion of nitroglycerin is 50 to 400 µg per minute, provided that the systolic blood pressure is greater than 90 mm Hg; however, the combination of vasopressin and nitroglycerin is seldom used nowadays. Nitrates are no longer recommended, either alone or in combination with a beta blocker, for primary prophylaxis to prevent first variceal bleeds. For secondary prophylaxis (to prevent variceal rebleeding), isosorbide mononitrate may be added to a beta blocker if the beta blocker alone has not resulted in an appropriate decrease in HVPG. In clinical practice, it is unusual for patients to tolerate nitrates for any length of time because of side effects, especially hypotension and headaches.

Drugs That Decrease Intrahepatic Vascular Resistance

The ideal agent for treatment of portal hypertension would be a drug that decreases intrahepatic vascular resistance. Unfortunately, such a drug is not currently available. A desirable drug would be one that selectively decreases intrahepatic vascular resistance without worsening systemic vasodilatation. Agents that may decrease intrahepatic resistance include α₁-adrenergic blockers such as prazosin,¹⁵⁴ but long-term administration of prazosin causes worsening of the systemic hyperdynamic circulation associated with portal hypertension and consequent sodium retention and ascites.¹⁵⁴ The addition of propranolol to prazosin may ameliorate the adverse affects of prazosin on the systemic circulation. Losartan, an angiotensin II receptor type I antagonist, causes a reduction in portal pressure without significant effects on the systemic circulation.¹⁵⁵ In randomized, controlled trials of losartan or another angiotensin II receptor antagonist, irbesartan, however, portal pressure was not reduced significantly. In fact, renal function has worsened in patients given losartan or irbesartan.¹⁵⁶^,¹⁵⁷ ET-receptor blockers and liver-selective NO donors are promising investigational agents for therapies that target intrahepatic vascular resistance.¹⁶ Studies suggest that simvastatin may decrease intrahepatic resistance and maintain hepatic blood flow while decreasing portal pressure. This effect probably results from simvastatin-mediated NO release.¹⁵⁸

ENDOSCOPIC THERAPY

Endoscopic therapy is the only treatment modality that is widely accepted for the prevention of variceal bleeding, control of acute variceal bleeding, and prevention of variceal rebleeding. Endoscopic variceal therapy includes variceal sclerotherapy and band ligation.

Sclerotherapy

Endoscopic sclerotherapy has largely been supplanted by endoscopic band ligation, except when poor visualization precludes effective band ligation of bleeding varices. Available evidence does not support emergency sclerotherapy as first-line treatment of variceal bleeding (Table 90-4).¹⁵⁹ The technique involves injection of a sclerosant into (intravariceal) or adjacent to (paravariceal) a varix. Some paravariceal injection usually takes place during attempted intravariceal therapy. The sclerosants used include sodium tetradecyl sulfate, sodium morrhuate, ethanolamine oleate, and absolute alcohol; the choice of a sclerosant is based on availability, rather than on superior efficacy of one agent over another.

Table 90-4 Complications of Endoscopic Variceal Therapy *

During Procedure

Aspiration pneumonia

Retrosternal chest pain

Following Procedure

Bleeding

Esophageal dysmotility

Systemic (Usually with Sclerotherapy)

Mesenteric venous thrombosis

Pulmonary embolism

Sepsis

* Sclerotherapy and band ligation.

Complications of endoscopic sclerotherapy may arise during or after the procedure. During injection, the patient may experience some degree of retrosternal discomfort, which may persist postoperatively. More serious complications include sclerosant-induced esophageal ulcer-related bleeding, strictures, and perforation. The risk of ulcers caused by sclerotherapy may be reduced by use of oral sucralfate or a proton pump inhibitor after sclerotherapy.

Variceal Ligation

Endoscopic variceal ligation is the preferred endoscopic modality for control of acute esophageal variceal bleeding and prevention of rebleeding; however, the utility of band ligation in the treatment of gastric varices is limited. Variceal ligation is simpler to perform than injection sclerotherapy. The procedure involves suctioning of the varix into the channel of an endoscope and deploying a band around the varix. The band strangulates the varix, thereby causing thrombosis. Multi-band devices can be used to apply several bands without requiring withdrawal and reinsertion of the endoscope. Varices at the gastroesophageal junction are banded initially, and then more proximal varices are banded in a spiral manner at intervals of approximately 2 cm; the endoscope is then withdrawn. Varices in the mid- or proximal esophagus do not need to be banded. Endoscopic variceal ligation is associated with fewer complications than sclerotherapy and requires fewer sessions to achieve variceal obliteration. Moreover, esophageal variceal ligation during an acute bleed is not associated with a sustained elevation in HVPG, as occurs with sclerotherapy.¹⁶⁰

Endoscopic variceal ligation can cause local complications, including esophageal ulcers (Fig. 90-9), strictures, and dysmotility, albeit less frequently than does sclerotherapy. Banding-induced ulcers can be large and potentially serious if gastric fundal varices are banded. Now that overtubes are no longer used to facilitate repeated insertion of the endoscope during a banding session, the mechanical complications seen in the past (mucosal tears and esophageal perforations) are uncommon. A proton pump inhibitor is usually recommended after variceal ligation even though data to support the use of a proton pump inhibitor are limited.

Figure 90-9. Endoscopic views of gastric varices and esophageal variceal ligation-related ulcers. A, The gastroesophageal junction is seen on a retroflexed view following ligation of multiple gastric varices (arrowheads), which resemble polyps. B, Upper endoscopy in the same patient 4 weeks later demonstrates ulcers at the sites of earlier ligation (arrowheads).

TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNT

A transjugular intrahepatic portosystemic shunt (TIPS)—also referred to as a transjugular intrahepatic portosystemic stent shunt (TIPSS)—reduces elevated portal pressure by creating a communication between the hepatic vein and an intrahepatic branch of the portal vein. A percutaneous transjugular approach is used to insert the shunt. A TIPS functions as a side-to-side portacaval shunt and has been used to treat complications of portal hypertension, mainly variceal bleeding and refractory ascites, as well as Budd-Chiari syndrome, hepatic hydrothorax, and hepatorenal syndrome (see Chapters 83, 91, and 92). A TIPS can be placed by an interventional radiologist, with a mortality rate of less than 1% to 2%. TIPS placement usually is carried out with the patient under sedation. A platelet count greater than 60,000/mm³ and an acceptable prothrombin time as reflected by an international normalized ratio (INR) less than 1.4 usually are recommended but are not essential in an emergency. Broad-spectrum antibiotic coverage is recommended when TIPS placement is carried out in a patient with primary sclerosing cholangitis and as an emergency procedure.

For this procedure, the hepatic vein is cannulated through a transjugular approach, and using a Rosch needle, the portal vein is cannulated. A guidewire is then passed to connect the hepatic vein and a branch of the portal vein. Following dilation of the tract, a stent is placed and dilated as required to reduce the portacaval pressure gradient (the pressure difference between the portal vein and the inferior vena cava at the confluence of the hepatic vein) to below 12 mm Hg (Fig. 90-10). Whether a lesser reduction of portacaval pressure gradient, to only 15 mm Hg or so (instead of 12 mm Hg), could be associated with reduced bleeding or a lower frequency of hepatic encephalopathy requires further study.

Figure 90-10. Creation of a transjugular intrahepatic portosystemic shunt (TIPS). A, Portogram with a catheter in the portal venous system (arrowheads). The portal venous system is clearly outlined (straight arrows). Gastroesophageal collaterals are also demonstrated (curved arrows). B, A stent (arrow) has been placed to bridge the hepatic vein and the portal vein. A balloon (arrowheads) is being used to dilate the parenchymal tract within the liver. C, Following expansion of the stent (arrow), injection into the portal vein demonstrates persistence of the gastroesophageal varices (arrowheads). D, Following embolization of the varices with steel coils (arrowheads), the intrahepatic portal vasculature is no longer demonstrated, indicative of hepatofugal flow of portal blood through the shunt.

In the past, the stents most commonly used for a TIPS were the Wallstent and the Palmaz stent. Nowadays, a coated stent is used (Viatorr, Gore, Flagstaff, Arizona). This stent has an uncoated portion that anchors the stent to the portal vein and a polytetrafluoroethylene-coated portion that lines the tract in the liver parenchyma and the draining hepatic vein. The frequency of shunt stenosis is reduced when coated stents are used instead of uncoated stents.¹⁶¹

A TIPS can be placed successfully by an experienced operator in greater than 95% of cases. Complications following the procedure are classified as procedure related, early (occurring before 30 days), or late (after 30 days) (Table 90-5). The prevention and treatment of procedure-related, early, and late post-TIPS complications are outlined in Table 90-6.

Table 90-5 Complications of Transjugular Intrahepatic Portosystemic Shunt Placement

TIMING OF COMPLICATION	COMPLICATION
Procedure-related (life-threatening)	Cardiopulmonary failure
	Carotid artery puncture
	Intraperitoneal hemorrhage
	Sepsis
Early post-procedure (1-30 days)	Cardiac arrhythmias
	Fever
	Hematoma at puncture site
	Hemolytic anemia
	Hepatic encephalopathy
	Pain
	Progressive hepatic failure
	Pulmonary artery hypertension
	Shunt thrombosis
	Stent migration
	Reactions to contrast media
Late post-procedure (>30 days)	Hepatic encephalopathy
	Liver failure
	Portal vein thrombosis
	Progressive hepatic failure
	Shunt stenosis

Modified from Kamath PS, McKusick M. Transjugular portosystemic shunt (TIPS). Bailliere Clin Gastroenterol 1997; 11:327-49.

Table 90-6 Prevention and Treatment of Transjugular Intrahepatic Portosystemic Shunt-Related Complications

COMPLICATION	PREVENTION	TREATMENT
Inadvertent injury to carotid artery during jugular vein access	Perform with ultrasound guidance to facilitate venous access	Manual compression of carotid puncture site to prevent hematoma
Hepatic capsular laceration during portal vein access	Avoid atrophic lobes and limit needle passes to 3-4 cm of excursion	Usually requires no treatment
Hepatic capsular laceration during portal vein access		For severe hemorrhage, transfuse with blood products until stable; obtain abdominal CT and surgical consultation
Extrahepatic puncture of portal venous system	Delineate bifurcation of portal vein on preprocedure CT	Leave catheter in place for portogram; use as a guide for intrahepatic portal vein puncture
		Work quickly to establish a functioning shunt, then remove the errant catheter
Intrahepatic arterial or biliary puncture	Work centrally within the liver	Usually no treatment is required; remove the catheter and continue
		If a fistula develops, embolize the arterial feeder with steel coils
Sepsis after shunt placement	Give prophylactic antibiotics	Broad-spectrum antibiotic coverage
	Adhere to strict sterile technique
Early shunt thrombosis	Avoid sharp angles when placing the stent Ends should not abut against the intima of the vein	Shunt venogram and clot lysis using tPA delivered by pulse-spray techniqueExtend the shunt to ensure stent coverage of the intrahepatic tract and to ensure adequate length in hepatic and portal veins
Uncontrollable encephalopathy after shunt placement	Use narrow shunts in high-risk patients	Reduce the diameter of the shunt with additional concentrically placed stents
		Embolize the shunt with steel coils
Shunt stenosis	Use wider or covered stents	Dilation or atherectomy of the shunt
	Avoid bile duct injury	Place an additional stent if necessary
Post-shunt liver failure	Avoid procedure in patients with a MELD score ≥24	Consider early liver transplantation

CT, computed tomography; MELD, Model for End-stage Liver Disease; tPA, tissue plasminogen activator.

Modified from Kamath PS, McKusick M. Transjugular portosystemic shunt (TIPS). Bailliere Clin Gastroenterol 1997; 11:327-49.

Portal Hypertension-Related Bleeding

The most common indication for placement of a TIPS is refractory variceal bleeding. TIPS has been used to control acute variceal bleeding and to prevent variceal rebleeding when pharmacologic and endoscopic therapies have failed, especially in patients with Child class B or C cirrhosis, in whom bleeding is more likely to be refractory to therapy than in patients with Child class A cirrhosis. Refractory ascites and prevention of variceal rebleeding are the only indications for TIPS that have been subjected to controlled trials. When bleeding from varices cannot be controlled after two sessions of endoscopic therapy within a 24-hour period, TIPS placement is the usual salvage treatment. TIPS also is used to treat bleeding from isolated gastric fundal varices, for both control of bleeding and prevention of rebleeding. A surgical portosystemic shunt may be preferred over a TIPS in patients with preserved synthetic liver function (Child class A) in centers that have the surgical expertise.

TIPS has been effective in the management of uncontrolled esophageal variceal bleeding in patients with decompensated cirrhosis of the liver.¹⁶² Hemorrhage is controlled in more than 90% of patients, but the mortality rate in such patients is high—greater than 60% within 90 days. A similar outcome is observed in patients who undergo TIPS placement for refractory gastric variceal bleeding.¹⁶³

In a meta-analysis of twelve randomized controlled trials that compared TIPS with endoscopic therapy, the rate of rebleeding was lower with TIPS, but the frequency of encephalopathy was higher, and no effect on survival was observed.¹⁶⁴ Therefore, TIPS cannot be recommended as a first choice of treatment for preventing variceal rebleeding; rather, it is reserved for patients who have failed endoscopic or pharmacologic therapy.

Follow-up Evaluation

The frequency of stenosis of a TIPS is high, ranging from 20% to 78% depending on the surveillance technique used and the definition of stenosis. Neither the optimal interval nor the most cost-effective method of surveillance for TIPS stenosis has been determined. Doppler ultrasound evaluation generally is used to identify TIPS stenosis, but the negative predictive value of this approach is low and the positive predictive value is only acceptable. The best indicator that the shunt has stenosed is recurrence of the problem that necessitated the TIPS. The only certain method of demonstrating shunt patency is by means of a TIPS venogram and measurement of the portacaval pressure gradient. An increase in the gradient to greater than 12 mm Hg warrants dilation of the stent or placement of an additional stent.

Selection of Patients

The presence of a TIPS may worsen liver function by depriving the liver of portal venous blood, thereby increasing the risk of hepatic encephalopathy, with decreased survival in some patients. Therefore, the procedure should be used selectively. Emergency TIPS is clearly associated with a high mortality rate.¹⁶⁵^,¹⁶⁶ In patients in whom TIPS placement has been carried out to prevent variceal rebleeding, 30-day mortality rates may be as high as 44%. Factors associated with a poor prognosis include a serum alanine aminotransferase (ALT) level greater than 100 U/L, serum bilirubin level greater than 3 mg/dL, and pre-TIPS hepatic encephalopathy unrelated to bleeding.¹⁶⁶ Patients with a high CTP score (Table 90-7) also have reduced survival. The Child classification has some limitations, however; for example, it does not discriminate survival well among patients within each Child class. Furthermore, some parameters that make up the CTP score, such as ascites and encephalopathy, are assessed by subjective interpretation. The need for a more accurate method to assess survival in patients undergoing TIPS has led to creation of a new tool to predict survival, the Model for End-stage Liver Disease (MELD) (see http://www.mayoclinic.org/gi-rst/mayomodel6.html and Chapter 73).¹⁶⁵ With data from four centers within the United States, this mathematical model originally was composed of the serum creatinine level, INR as a measure of the prothrombin time, serum bilirubin level, and etiology of liver disease. Subsequently, the MELD formula was modified to include only the first three parameters (creatinine, INR, and bilirubin).¹⁶⁷ The MELD has been widely validated for predicting survival in patients with cirrhosis, including patients who have undergone TIPS placement, and is more accurate for this purpose than the Child classification.

Table 90-7 Child-Turcotte-Pugh Scoring System and Classification

Patients with a MELD score of 14 or less have an excellent survival rate after TIPS placement; therefore, TIPS may be carried out routinely in such patients when indicated. Patients with a MELD score higher than 24 have reduced survival following TIPS placement, with a mortality rate approaching 30% at three months. Because these patients are at high priority for liver transplantation, TIPS should be avoided unless needed to control acute variceal bleeding. In the intermediate group with MELD scores ranging from 15 to 24, TIPS placement can be carried out depending on the patient’s preference and the physician’s judgment and taking into consideration the likelihood of liver transplantation. This approach has been validated independently.¹⁶⁸

SURGICAL THERAPY

Surgical treatment of portal hypertension falls into three groups: non-shunt procedures, portosystemic shunt procedures, and liver transplantation. Surgical procedures are used as salvage therapy when standard management with pharmacologic and endoscopic therapy fails in patients with Child class A cirrhosis. Surgical treatment also may be considered early in the course of portal hypertension in patients who live at a great distance from centers that can manage variceal bleeding adequately or in whom cross-matching blood products (in case of bleeding) is difficult. How failure of standard therapy is defined depends on the specific circumstances of the patient’s presentation, availability of surgical expertise, and outcome of conservative management.

Liver transplantation should be considered in all patients with variceal bleeding who meet minimal listing criteria for liver transplantation (currently, a CTP score of 7 or greater). Selection and prioritization of patients for liver transplantation are discussed in Chapter 95.

Non-shunt Procedures

Non-shunt procedures include esophageal transection and gastroesophageal devascularization. They are performed infrequently but may be required in selected cases.

Esophageal Transection

Esophageal transection, in which the esophagus is stapled and transected, is highly effective in controlling variceal bleeding and is associated with a lower risk of encephalopathy than that for portosystemic shunts. Esophageal transection was considered in the past when two sessions of endoscopic therapy had failed to control variceal bleeding within a 24-hour period.⁷⁹ Mortality rates are not improved over those observed with endoscopic sclerotherapy, however. With the advent of TIPS, esophageal staple transection is now seldom used.

Devascularization Procedures

Devascularization procedures typically have been used to prevent recurrent variceal bleeding in patients with extensive splenic and portal vein thrombosis when a suitable vein is not available for creation of a portosystemic shunt.¹⁶⁹ In the original operation described by Sugiura and Futagawa, both a thoracotomy and a laparotomy were carried out.¹⁷⁰ Subsequently, the operation has been carried out through an abdominal approach and combined with a splenectomy. The procedure consists of total devascularization of the greater curvature of the stomach combined with devascularization of the upper two thirds of the lesser curvature of the stomach and circumferential devascularization of the lower 7.5 cm of the esophagus. The rate of recurrent bleeding following this procedure is variable but may be as high as 40%, depending on the population being treated and duration of follow-up.

Portosystemic Shunts

With the increasing availability of TIPS, the use of surgical shunts for refractory variceal bleeding has declined markedly. Surgical portosystemic shunts are categorized as selective shunts such as distal splenorenal shunts, partial shunts such as the side-to-side calibrated portacaval shunt, and total portosystemic shunts such as the side-to-side portacaval shunt or end-to-side portacaval shunt.

Selective Shunts

The most widely used selective shunt is the distal splenorenal shunt, originally described by Warren and colleagues.¹⁷¹ With this shunt, only varices at the gastroesophageal junction and spleen are decompressed, and portal hypertension is maintained in the superior mesenteric vein and portal vein; therefore, variceal bleeding is controlled, but ascites persists. The shunt procedure involves a portal-azygous disconnection and subsequent anastomosis between the splenic vein and left renal vein in an end-to-side fashion (Fig. 90-11). The entire length of the pancreas must be mobilized, and the left adrenal vein must be ligated. The distal splenorenal shunt has been associated with control of variceal bleeding in approximately 90% of patients and a lower rate of hepatic encephalopathy than that reported for total shunts.¹⁷²

Figure 90-11. Distal splenorenal shunt. Surgical anatomy following completion of a distal splenorenal shunt is depicted. For this procedure, the splenic vein is disconnected from the superior mesenteric vein and is separated from the pancreas; all its collaterals are ligated. The portal system is thus disconnected from the azygous system so that all flow from the gastroesophageal junction is through the short gastric veins into the splenic vein. The splenic vein is then anastomosed to the left renal vein in an end-to-side fashion.

Partial Portosystemic Shunts

A partial portosystemic shunt is carried out using a synthetic interposition graft between the portal vein and the inferior vena cava. When the shunt diameter is 8 mm, portal pressure is reduced below 12 mm Hg, and antegrade flow to the liver is maintained in most patients.¹⁷³ Rates of preventing variceal rebleeding and encephalopathy following the shunt are similar to those seen with a distal splenorenal shunt. As in patients who have had a distal splenorenal shunt, ascites may occur in approximately 20% of patients who have had a partial portosystemic shunt because hepatic sinusoidal pressure is not reduced.¹⁷⁴^,¹⁷⁵

Portacaval Shunts

End-to-side and side-to-side portacaval shunts have been described, but nowadays only the side-to-side portacaval shunt is in use.¹⁷⁶ Any portacaval shunt that is greater than 12 mm in diameter is likely to result in a total shunting of portal blood. A shunt with a diameter <12 mm is created with an interposition graft, or alternatively a direct vein-to-vein anastomosis may be constructed. Variceal bleeding, as well as ascites, is well controlled because the hepatic sinusoids are decompressed. Variceal rebleeding following a total shunt is seen in less than 10% of patients, but hepatic encephalopathy occurs in 30% to 40% of patients.⁹⁹ Liver transplantation in patients who have had a portacaval shunt is associated with increased operative morbidity and intraoperative transfusion requirements. The outcome of liver transplantation is not otherwise significantly different, however, from that for patients who have not had a portacaval shunt. Nonetheless, surgical portacaval shunts should be avoided in patients who are potential candidates for liver transplantation.

MANAGEMENT OF SPECIFIC LESIONS

ESOPHAGEAL VARICES

Natural History

Esophageal varices are present in approximately 40% of patients with cirrhosis and in as many as 60% of patients with cirrhosis and ascites.⁹⁹ In cirrhotic patients who do not have esophageal varices at initial endoscopy, new varices will develop at a rate of approximately 5% per year. In patients with small varices at initial endoscopy, progression to large varices occurs at a rate of 10% to 15% per year and is related predominantly to the degree of liver dysfunction.¹⁷⁷ On the other hand, improvement in liver function in patients with alcoholic liver disease who abstain from alcohol is associated with a decreased risk, and sometimes even disappearance, of varices.¹⁷⁸

Up to 25% of patients with newly diagnosed varices will bleed within two years.¹⁷⁷ The best clinical predictor of bleeding appears to be variceal size. The risk of bleeding in patients with varices less than 5 mm in diameter is 7% by two years, and the risk in patients with varices greater than 5 mm in diameter is 30% by two years.¹⁷⁷ Even more important, however, is the HVPG because the risk of bleeding is virtually absent when the HVPG is below 12 mm Hg.⁸⁷ Nevertheless, measurement of HVPG is not routinely performed in clinical practice to assess bleeding risk.

The prognosis for variceal bleeding in patients with cirrhosis has improved since the 1980s. Initial treatment is associated with cessation of bleeding in approximately 90% of patients.¹⁷⁷^,¹⁷⁹ Approximately one half of patients with a variceal bleed stop bleeding spontaneously because hypovolemia leads to splanchnic vasoconstriction, which results in a decrease in portal pressure. Excessive transfusions may, in fact, increase the chance of rebleeding.¹⁸⁰ Active bleeding at endoscopy, a lower initial hematocrit value, higher serum aminotransferase levels, higher Child class, bacterial infection, an HVPG greater than 20 mm Hg, and portal vein thrombosis are associated with failure to control bleeding at five days.¹⁷⁹^,¹⁸¹^–¹⁸³ Of patients who have stopped bleeding, approximately one third will rebleed within the next six weeks. Of all rebleeding episodes, approximately 40% will take place within five days of the initial bleed.¹⁸⁴ Predictors of rebleeding include active bleeding at emergency endoscopy, bleeding from gastric varices, hypoalbuminemia, renal insufficiency, and an HVPG greater than 20 mm Hg.¹⁷⁷ The risk of death with acute variceal bleeding is 5% to 8% at one week and about 20% at six weeks.¹⁷⁷ Patients who rebleed early, have a MELD score >18, require >4 units of packed red blood cell transfusions,¹⁸⁵ and in whom renal failure develops have the highest risk of death. Alcohol as the cause of cirrhosis, a higher serum bilirubin level, a lower serum albumin level, hepatic encephalopathy, and hepatocellular carcinoma are additional factors associated with an increased six-week mortality rate.

Treatment of esophageal variceal bleeding is classified as either primary prophylaxis, that is, prevention of variceal hemorrhage in patients who have never bled; control of acute variceal bleeding; or secondary prevention of rebleeding in patients who have survived an initial bleeding episode. Effective treatments to prevent the development of varices and ascites in patients with cirrhosis are not yet available, although beta blockers may slow enlargement of small varices into large varices.

Prevention of Bleeding

The utility of pre-primary prophylaxis, that is, the efficacy of beta blockers to prevent the formation of varices, has not been demonstrated.⁷⁹^,¹⁸⁶ Patients with Class C cirrhosis who have small varices may be considered for treatment with a beta blocker. All patients with large varices (diameter greater than 5 mm) should be considered for prophylactic therapy (“primary prophylaxis”) to prevent variceal bleeding. The presence of additional endoscopic signs such as red wales does not influence the decision regarding prophylactic therapy. Twelve trials have addressed the use of a nonselective beta blocker for primary prophylaxis of variceal bleeding and have demonstrated a decrease in the risk of variceal bleeding from 25% in patients in the control group to 15% in patients taking a beta blocker. The absolute risk reduction is thus approximately 10%, and the number needed to treat to prevent one variceal bleed is approximately 10 patients. The mortality rate is reduced from 28.4% in control patients to 23.9% in patients taking a beta blocker; the absolute risk reduction is 4.5%. The number of patients needed to be treated to prevent one death is approximately 22. In patients who do not bleed during therapy and who do not experience side effects, treatment should be continued indefinitely because withdrawal of a beta blocker can result in an increased risk of bleeding.¹⁸⁷^,¹⁸⁸

The side effects of beta-blocker treatment are probably overemphasized because only approximately 15% of patients need to discontinue the drug.¹⁸⁹ A baseline heart rate and blood pressure recording will help determine whether a patient is a candidate for pharmacologic treatment with a beta blocker. A resting heart rate of less than 55 to 60 beats per minute or a systolic blood pressure less than 90 mm Hg indicates that the patient is likely to be intolerant of beta blockers. In other patients, the HVPG ideally should be measured at baseline (Fig. 90-12). A long-acting preparation of propranolol or nadolol may be started; the usual starting dose of long-acting propranolol is 60 mg once daily and that of nadolol is 20 mg once daily. Because the risk of bleeding is greatest at night, the beta blocker should probably be administered in the evening.¹⁰⁸ The dose of propranolol or nadolol can be increased gradually every three to five days until the target heart rate of 25% below baseline or 55 to 60 beats per minute or the maximum tolerated dose is reached, provided that the systolic blood pressure remains above 90 mm Hg. The daily dose of long-acting propranolol or nadolol required to reach the target heart rate ranges from 40 to 160 mg. Patients with a decrease in systolic blood pressure below 90 mm Hg are most likely to experience side effects.

Figure 90-12. Algorithm for primary prophylaxis of esophageal variceal hemorrhage. The hepatic venous pressure gradient (HVPG) may be measured before a nonselective β-adrenergic blocking agent is started and one month after the maximum tolerated dose of the beta blocker is reached. The goal of treatment is to reduce the HVPG to <12 mm Hg or by ≥20%. EVL, endoscopic variceal ligation; HVPG, hepatic venous pressure gradient.

In patients on pharmacologic therapy, follow-up endoscopy is unnecessary unless gastrointestinal bleeding occurs. When the target heart rate is reached, however, a repeat HVPG measurement may be carried out as close to one month as possible. In patients in whom the HVPG has decreased to less than 12 mm Hg, the risk of bleeding is virtually eliminated. Patients in whom the HVPG decreases by at least 20% have a risk of variceal bleeding of less than 10%. Unfortunately, only 30% to 40% of patients respond to a beta blocker; those with better liver function show the best response.¹⁸⁹ In patients who are intolerant of or who have contraindications to beta blockers, isosorbide mononitrate has been tried but is no better than placebo in preventing variceal bleeding.¹⁹⁰ In these patients, endoscopic prophylaxis should be pursued. Unfortunately, patients who do not achieve a decrease in the HVPG to less than 12 mm Hg, or of greater than 20%, on a beta blocker may not respond well to endoscopic variceal ligation either.¹⁹¹

Endoscopic Prevention

Prophylactic sclerotherapy for the prevention of variceal bleeding has been studied extensively but cannot be recommended.¹⁹² The preferred method of endoscopic treatment is variceal band ligation. Variceal band ligation has been compared with no treatment in five trials. A meta-analysis of these studies demonstrated that, compared with no treatment, endoscopic variceal ligation decreases the risk of first bleeding and the mortality rate.¹⁹³ Meta-analysis of the nine trials that compared endoscopic variceal ligation with a beta blocker demonstrated a lower bleeding risk with endoscopic variceal ligation, with no difference in mortality rates.¹⁹⁴ A subsequent study has suggested that nonbleeding-related mortality may actually be reduced by beta blockers.¹⁹⁵ Side effects with beta blockers are more frequent than with variceal ligation, but complications of variceal ligation can be potentially life threatening. Therefore, current evidence does not support endoscopic variceal ligation as the preferred method of primary prophylaxis against variceal bleeding. The risks and benefits of the alternative therapies should be discussed and treatment individualized. Beta blockers are cheaper and more convenient to use and may potentially reduce the risk of bleeding from gastric varices and portal hypertensive gastropathy. Band ligation is the only option for patients with high-risk varices who have contraindications to beta blockers or who have not responded to or are intolerant of beta blockers. Combined use of propranolol and endoscopic variceal ligation to prevent primary prophylaxis is not currently recommended.

Control of Acute Bleeding

Acute esophageal variceal bleeding constitutes a life-threatening emergency and requires management by a well-trained team of hepatologists, endoscopists, intensive care personnel, radiologists, and surgeons. Treatment is aimed at resuscitating the patient, controlling the bleeding, and preventing complications (see Chapter 19). Two large-bore intravenous access lines should be inserted immediately. Red blood cells should be transfused with the goal of maintaining the hematocrit value around 25%. Normal saline may be infused intravenously until packed red blood cells are available for transfusion. In patients with active bleeding, the airway needs to be protected, and endotracheal intubation is advised. Antibiotics should be administered to all patients to prevent bacteremia and spontaneous bacterial peritonitis. Norfloxacin, 400 mg orally twice daily for seven days, is the preferred choice.¹⁹⁶ When oral intake is not possible, intravenous ciprofloxacin, 400 mg every 12 hours; levofloxacin, 500 mg every 24 hours; or ceftriaxone, 1 g every 24 hours for 7 days is recommended. The addition of recombinant factor VIIa to standard therapy has not been shown to improve control of bleeding.¹⁹⁷

A combination of endoscopic therapy and pharmacologic therapy of variceal bleeding may be superior to pharmacologic treatment alone. Pharmacologic agents should be started as early as possible; in some centers, they are started while the patient is being transferred by ambulance to the hospital. Somatostatin, octreotide, terlipressin, and vasopressin plus nitroglycerin are the options for pharmacologic therapy. The specific agent chosen depends on availability and physician preference. In the United States, octreotide is the agent used most commonly. Terlipressin is the first choice in many other countries because it is the only drug that has been associated with improved survival.¹⁹⁸ Pharmacologic treatment should be continued for up to five days to prevent early rebleeding.

Endoscopic therapy is carried out as soon as the patient is hemodynamically stabilized. At upper endoscopy, bleeding from esophageal varices is diagnosed if active bleeding from the varices is seen; signs of recent hemorrhage, such as a white fibrin plug or a red blood clot over a varix, are present; varices with risk signs for bleeding, such as a cherry-red spot, hematocystic spot, or red wale sign, are seen; or esophageal varices are seen in the absence of any other lesion that could give rise to gastrointestinal bleeding. Endoscopic treatment is recommended at the time of initial endoscopy, and endoscopic variceal ligation is the preferred method.

At upper endoscopy, the actively bleeding varix is ligated (Fig. 90-13). Ligation initially should be at or immediately below the bleeding site. Other large varices also should be banded during the same session. If active bleeding is not seen, ligation should be carried out beginning with varices at the gastroesophageal junction and proceeding proximally at intervals of 2 cm in a spiral fashion. If bleeding obscures the varices, then multiple bands are placed at the gastroesophageal junction circumferentially until bleeding can be controlled, but the long-term risks of esophageal stricture are increased in such patients. Bleeding can be controlled in up to 90% of patients with a combination of pharmacologic and endoscopic treatment.

Figure 90-13. Band ligation for control of esophageal variceal bleeding. A, On upper endoscopy, an actively bleeding varix can be seen in the distal esophagus (arrow). B, With the variceal banding device in position, the varix is suctioned into the device at the site of active bleeding (arrow). C, After the band is in place (arrow) and the varix has been ligated, the bleeding has stopped. D, Visualization of the varix with the band in place with complete control of bleeding.

(Images courtesy of Dr. Louis M. Wong Kee Song, Rochester, Minn.)

Bleeding cannot be controlled in approximately 10% of patients, as defined by any of the following three factors: (1) transfusion of four units of red blood cells or more to maintain the hematocrit value between 25% and 30%; (2) inability to increase the systolic blood pressure by 20 mm Hg or to greater than 70 mm Hg; or (3) persistence of a heart rate greater than 100 beats per minute.¹⁹⁹ Rebleeding is defined as recurrence of bleeding after initial control for 24 hours during which the vital signs and hemoglobin level are stable. When two sessions of endoscopic treatment within a 24-hour period have failed to control variceal bleeding, salvage therapies such as TIPS should be carried out (Fig. 90-14), although the mortality rate in this group of patients is high. Surgical portosystemic shunts, although extremely effective in controlling variceal bleeding, have largely been abandoned because of high mortality rates. Balloon tamponade sometimes is used to stabilize the patient until definitive treatment can be carried out.

Figure 90-14. Algorithm for the management of bleeding esophageal varices. TIPS, transjugular intrahepatic portosystemic shunt.

Prevention of Rebleeding

All patients who have had a variceal bleed should receive prophylactic therapy (“secondary prophylaxis”) to reduce the risk of rebleeding, which otherwise occurs in up to 80% of patients at two years. Patients with a CTP score of 7 or greater also should be evaluated for liver transplantation. Options for preventing variceal rebleeding are pharmacologic therapy, endoscopic therapy, and portosystemic shunts (surgical or radiologic), or combinations of these therapies.

Combined therapy with endoscopic variceal ligation and a nonselective beta blocker is the preferred treatment, and long-acting propranolol or nadolol may be used. Ideally, the hemodynamic response to a beta blocker should be monitored with the goal of reducing the HVPG by greater than 20% or to less than 12 mm Hg. If these goals are not achieved, isosorbide mononitrate may be added. The extended-release form of isosorbide mononitrate is preferred, with an initial starting dose of 30 mg/day. Unfortunately, it is unusual for patients in our practice to tolerate nitrates after they have achieved beta blockade. Hypotension and headaches are the usual reasons for discontinuing isosorbide mononitrate.

Endoscopic variceal ligation alone may be performed to prevent variceal rebleeding in patients who have poor liver function (Fig. 90-15). In practice, the first endoscopic session is carried out 7 to 14 days after the initial variceal ligation to control bleeding. Endoscopic therapy is then repeated at three- to four-week intervals; this approach has been suggested because bands might still be in place if endoscopy is repeated earlier. If the HVPG is monitored, a reduction in HVPG to less than 12 mm Hg or by greater than 20% should obviate the need for variceal ligation. For patients who bleed during pharmacologic treatment, variceal ligation should be carried out. Conversely, for patients who have undergone variceal ligation alone and experience recurrent bleeding, a beta blocker should be started. Patients who have a variceal rebleed despite receiving optimal pharmacologic and endoscopic treatment require a portosystemic shunt. Even in patients with Child class A cirrhosis, a TIPS may be as effective as a distal splenorenal shunt, and the choice of therapy should depend on local expertise.²⁰⁰

Figure 90-15. Algorithm for the prevention of recurrent variceal bleeding (secondary prophylaxis). EVL, endoscopic variceal ligation; HVPG, hepatic venous pressure gradient.

GASTRIC VARICES

The most widely used classification of gastric varices is the Sarin classification.²⁰¹ According to this classification, type 1 gastroesophageal varices (GOV1) extend 2 to 5 cm below the gastroesophageal junction and are in continuity with esophageal varices; type 2 gastroesophageal varices (GOV2) are in the cardia and fundus of the stomach and in continuity with esophageal varices; varices that occur in the fundus of the stomach in the absence of esophageal varices are called isolated gastric varices type 1 (IGV1), whereas varices that occur in the gastric body, antrum, or pylorus are called isolated gastric varices type 2 (IGV2).

Approximately 25% of patients with portal hypertension have gastric varices, most commonly GOV1, which comprise approximately 70% of all gastric varices. Intrahepatic causes of portal hypertension may be associated with both GOV1 and GOV2. Splenic vein thrombosis usually results in IGV1, but the most common cause of fundal gastric varices may be cirrhosis.

Because controlled studies evaluating pharmacologic therapy for gastric variceal bleeding are lacking, the agents used are based on extension of the data relating to esophageal varices. Medical management with vasoactive agents should be started as early as possible, preferably at least 30 minutes before endoscopic therapy is carried out. The preferred endoscopic therapy for fundal gastric variceal bleeding is injection of polymers of cyanoacrylate, usually N-butyl-2-cyanoacrylate,²⁰⁶^,²⁰⁷ but these tissue adhesives are not currently available in the United States. Obliteration of the varices occurs when the injected cyanoacrylate adhesive hardens on contact with blood. The mucosa overlying the varix eventually sloughs, and the hardened polymer is extruded. Fortunately, the resulting ulcers occur late, and the risk of bleeding is lower than that associated with sclerotherapy-related ulcers. Cyanoacrylate injection has been found to be superior to both variceal band ligation and sclerotherapy using alcohol.²⁰⁷ Complications of cyanoacrylate injection include bacteremia and variceal ulceration. Pulmonary and cerebral emboli have been reported on occasion, usually in patients with spontaneous large portosystemic or intrapulmonary shunts. The endoscope may be damaged by the glue, but the risk is minimized if silicone gel is used and suction is avoided for 15 to 20 seconds following injection.²⁰⁸

For injection of GOV2 or IGV1, a retroflexed endoscopic approach is recommended. Sclerosants such as sodium tetradecyl sulfate, ethanolamine oleate, and sodium morrhuate are not particularly effective for control of gastric variceal bleeding.²⁰⁹ When sclerotherapy is carried out for gastric varices, the volume of sclerosant required is larger than that used for esophageal varices, and fever and retrosternal pain are more common. It is much easier to obliterate GOV1 than GOV2 or IGV1. IGV1 are the most difficult gastric varices to obliterate and, when present, should prompt early consideration of definitive treatment such as portosystemic shunting if cyanoacrylate is not available.

Although some investigators recommend ligation of gastric varices up to 20 mm in diameter,²¹⁰ this recommendation is not supported by our experience. Band ligation of varices greater than 10 mm in diameter usually is unsafe. Ligation is safest if the varices are in the cardia of the stomach. Because gastric fundal varices are covered by mucosa, drawing the entire varix into the ligation device is often not possible. Application of bands results in creation of a large ulcer on the varix, sometimes with disastrous results (see Fig. 90-9).

If endoscopic and pharmacologic therapies fail to control gastric variceal bleeding, then a Linton-Nachlas tube, which has a 600-mL balloon, may be passed as a temporizing measure. The commonly used Minnesota tube and Sengstaken-Blakemore tube, with only 250-mL gastric balloons, are not as effective as the Linton-Nachlas tube for controlling bleeding from gastric fundal varices.²¹¹^,²¹² Nevertheless, most patients in whom endoscopic and pharmacologic treatment fails to control gastric variceal bleeding will require a TIPS, which can control bleeding in greater than 90% of patients—a rate of efficacy equivalent to that for TIPS in controlling esophageal variceal bleeding (Fig. 90-17).¹⁶³^,²¹³

Figure 90-17. Algorithm for the management of bleeding gastric varices in patients with portal hypertension. TIPS, transjugular intrahepatic portosystemic shunt.

Prevention of Rebleeding

Endoscopic Therapy

In the absence of large, well-conducted trials, recommendations regarding pharmacologic or endoscopic therapy to prevent gastric variceal rebleeding are derived from retrospective studies. Cyanoacrylate glue has been used to prevent gastric variceal rebleeding, with favorable results.²¹⁴ In a small study, the 2-octyl-cyanoacrylate polymer (Dermabond) has been used to prevent gastric variceal rebleeding, with excellent results.²¹⁵ Patients require an average of two or three sessions for obturation of gastric varices with cyanoacrylate polymers. Detachable snares have been used to ligate gastric varices that may be too large for band ligation, but the experience with this procedure is limited.²¹⁶

Transvenous Obliteration of Gastric Varices

Balloon-occluded retrograde transvenous obliteration of gastric fundal varices is carried out in patients with demonstrable splenorenal shunts. Such shunts can be demonstrated on multidetector CT in a large number of patients with bleeding gastric varices. In these patients, a catheter is passed into the left renal vein, usually through a transfemoral approach, and into the varices, which drain into the renal vein. Following balloon occlusion of the varices, a sclerosant is injected retrograde into the varix under fluoroscopic guidance. An extension of this technique is to occlude the varix through a transfemoral approach, while, at the same time, the other end of the varix is approached through a percutaneous transhepatic portal venous route. This technique allows occlusion of the varices at both ends, after which sclerosant can be injected.²¹⁷ The use of these techniques, which require considerable radiologic skill, is currently limited to some centers in the Far East.

Portosystemic Shunts

Limited data are available regarding use of surgical portosystemic shunts for the treatment of gastric varices in patients with cirrhosis. Two studies performed in patients with good liver function, most of whom had extrahepatic portal vein thrombosis, demonstrated excellent results, with a low long-term risk of bleeding and encephalopathy, after creation of a surgical shunt.²¹⁸^,²¹⁹

TIPS also is effective in preventing gastric variceal rebleeding. Because TIPS for this indication does not always result in a decrease in the size of gastric varices,²²⁰ the target HVPG is uncertain in these patients.²⁰⁴

Patients with an HVPG less than 12 mm Hg after TIPS are protected from esophageal variceal bleeding but have been known to bleed from gastric varices. Therefore, if the HVPG is reduced to a level below 12 mm Hg but gastric fundal varices are still prominent when contrast is injected into the portal vein (especially if the patient has bled from gastric fundal varices), the gastric varices should be embolized.

ECTOPIC VARICES

Varices that occur at a site other than the gastroesophageal junction are termed ectopic varices and account for less than 5% of all varix-related bleeding episodes. Ectopic varices most commonly manifest with melena or hematemesis. They also may manifest with hemobilia, hematuria, hemoperitoneum, or retroperitoneal bleeding. Ectopic varices occur with both extrahepatic portal vein obstruction and cirrhosis. The duodenum is a common site of ectopic varices, and varices typically are associated with portal vein obstruction, but in the West, the usual cause of duodenal varices is cirrhosis. The common occurrence of duodenal varices in patients with portal vein obstruction probably relates to the formation of collateral vessels around the thrombosed portal vein, which connect pancreaticoduodenal veins to retroduodenal veins, which drain into the inferior vena cava.²²¹ In some of those patients with extrahepatic portal vein obstruction, varices form around the gallbladder and bile duct.

The other common site of ectopic varices is peristomal, in patients with inflammatory bowel disease and primary sclerosing cholangitis who have undergone a proctocolectomy with creation of an ileostomy.²²² Varices develop at the level of the mucocutaneous border of the stoma and are termed stomal varices. They are recognized by a bluish halo surrounding the stoma and by a dusky appearance and friable consistency of the stomal tissue; no obvious variceal lesions are seen.

Anorectal varices are reported in 10% to 40% of cirrhotic patients who undergo colonoscopy and must be distinguished from hemorrhoids (Fig. 90-18). Rectal varices are dilated superior and middle hemorrhoidal veins, whereas hemorrhoids are dilated vascular channels above the dentate line. Rectal varices collapse with digital pressure, but hemorrhoids do not.

Figure 90-18. Endoscopic image of a colonic varix (arrow).

Bleeding from stomal varices is readily apparent on presentation. Ectopic variceal bleeding should be considered in all patients with portal hypertension and overt gastrointestinal bleeding without an obvious bleeding source on endoscopy or a drop in the hemoglobin level associated with abdominal pain and increasing abdominal girth. CT of the abdomen demonstrates layering of free fluid in the peritoneal cavity in patients who have intra-abdominal hemorrhage, typical of fresh blood mixed with ascitic fluid. The diagnosis of intra-abdominal hemorrhage secondary to ectopic variceal bleeding is confirmed by a paracentesis that yields bloody ascitic fluid with clots.

Management

In patients suspected of having ectopic variceal bleeding, vasoactive drugs may be administered initially to control the bleeding. If the bleeding ectopic varix is visualized at endoscopy, as typically is the case with duodenal or colonic varices, then endoscopic therapy can be carried out.²²³ Endoscopic glue injection or band ligation is the preferred approach for bleeding duodenal varices. Colonic varices tend to be larger in diameter and may require application of hemostatic clips. Patients with bleeding stomal varices can be trained to compress the site locally if bleeding is obvious. Because bleeding from stomal varices is visible and detected early, the mortality rate for bleeding stomal varices is low.²²⁴

At present, no recommendations support primary prophylaxis to prevent bleeding from ectopic varices. To prevent rebleeding from ectopic varices, pharmacologic treatment with a beta blocker is usually tried, although no studies are available to support this approach. If the portal vein is patent, then transhepatic embolization of stomal varices can be carried out (Fig. 90-19). Embolization of varices using a transhepatic approach can control bleeding in most patients with stomal varices. The rate of rebleeding is high, however, because the portal hypertension persists. In patients in whom embolization fails to prevent rebleeding, TIPS placement may be considered. A surgical portosystemic shunt is recommended in patients with Child class A cirrhosis and in patients with portal hypertension from extrahepatic portal vein thrombosis in whom a vein suitable for a shunt is available. Placement of a nonselective portosystemic shunt, such as a portacaval shunt, mesocaval shunt, or central splenorenal shunt, should be carried out in a patient with stomal varices.

Figure 90-19. Algorithm for the management of bleeding from ectopic varices in patients with portal hypertension. TIPS, transjugular intrahepatic portosystemic shunt.

Patients with ectopic varices who present with intraperitoneal hemorrhage have a poor outcome because the diagnosis usually is not considered and often is made at laparotomy. Acute bleeding may be controlled by transhepatic obliteration or surgical ligation of the varices. In patients who are critically ill, a TIPS should be placed, followed by embolization of the bleeding varix.

PORTAL HYPERTENSIVE GASTROPATHY AND GASTRIC VASCULAR ECTASIA

Mucosal changes in the stomach in patients with portal hypertension include portal hypertensive gastropathy (PHG) and gastric vascular ectasia. In all likelihood, these lesions are distinct, as demonstrated by histologic features and differences in the response to a TIPS. An appearance analogous to PHG in the colon is termed portal hypertensive colopathy (see Chapter 36).

The diagnosis of PHG is based on the presence of a characteristic mosaic-like pattern of the gastric mucosa on endoscopic examination. This pattern is characterized by small polygonal areas with a depressed border. Superimposed on this mosaic-like pattern may be red point lesions that usually are greater than 2 mm in diameter. PHG is considered mild when only a mosaic-like pattern is present and severe when superimposed discrete red spots are also seen (Fig. 90-20).²²⁵ The cause and pathogenesis of PHG are poorly understood. Development of PHG correlates with the duration of cirrhosis but not necessarily the degree of liver dysfunction. The frequency of PHG following endoscopic treatment of esophageal varices is increased—possibly a result of longer duration of portal hypertension in these patients.

Figure 90-20. Endoscopic views of portal hypertensive gastropathy. A, Mild portal hypertensive gastropathy is characterized by a mosaic appearance without red color signs. B, Severe portal hypertensive gastropathy is characterized by a cobblestone appearance with superimposed red spots.

In gastric vascular ectasia, aggregates of ectatic vessels can be seen on endoscopic examination as red spots without a mosaic background.²²⁶ When the aggregates are confined to the antrum of the stomach, the term gastric antral vascular ectasia (GAVE) is used (see Chapters 19 and 36). If aggregates in the antrum are linear, the term watermelon stomach is used to describe the lesion (Fig. 90-21). When the red spots are distributed diffusely, in both the distal and the proximal stomach, the term diffuse gastric vascular ectasia is preferred.²²⁷

Figure 90-21. Endoscopic images of watermelon stomach.

Distinguishing PHG from GAVE is sometimes difficult. A background mosaic pattern and proximal distribution favor PHG (Table 90-8). GAVE is less common, occurs in the absence of a background mosaic pattern, and typically is antral in location, although lesions may be present in the proximal stomach. Mucosal biopsies are recommended when the endoscopic diagnosis is uncertain. GAVE appears histologically as dilated mucosal capillaries with focal areas of fibrin thrombi or ectasia in combination with proliferation of spindle cells.²²⁸ Similar ectatic lesions may be seen in the small bowel and may cause acute or chronic gastrointestinal blood loss.

Table 90-8 Comparison of Portal Hypertensive Gastropathy (PHG) and Gastric Antral Vascular Ectasia (GAVE)

FEATURE	PHG	GAVE
Distribution	Proximal stomach	Distal stomach
Mosaic pattern	Present	Absent
Red color signs	Present	Present
Findings on gastric mucosal biopsy
Thrombi	−	+++
Spindle cell proliferation	+	++
Fibrohyalinosis	−	+++
Treatment	β-adrenergic blockers	?Antrectomy
	TIPS	?Liver transplantation

TIPS, transjugular intrahepatic portosystemic shunt.

Management

PHG accounts for approximately one fourth of all cases of bleeding (acute and chronic) in patients with portal hypertension, but for less than 10% of all acute bleeding episodes. The more common presentation is one of chronic, slow bleeding and anemia. Pharmacologic therapy to prevent bleeding (primary prophylaxis) in patients with severe portal hypertensive gastropathy is not currently recommended. Small studies have suggested that octreotide may be useful for controlling acute bleeding.²²⁹ Beta blockers are recommended for preventing chronic blood loss in patients who have bled from severe PHG.²³⁰^,²³¹ When patients are transfusion-dependent despite beta blockade and iron supplementation, a TIPS may be inserted (Fig. 90-22). A TIPS decreases transfusion requirements and results in reversal of the mucosal lesions on endoscopic examination.²²⁷

Figure 90-22. Algorithm for the management of chronic bleeding from portal hypertensive gastropathy. TIPS, transjugular intrahepatic portosystemic shunt.

Management of GAVE is more problematic. Initial treatment involves repletion of iron and red blood cell transfusions to treat symptomatic anemia. If lesions are localized, the platelet count is greater than approximately 45,000/mm³, and the INR is less than 1.4, thermoablative therapy, as with argon plasma coagulation, may be helpful (Fig. 90-23). The usual settings for argon plasma coagulation are an energy level of 60 to 90 watts and a gas flow rate of 1 to 2 L per minute. If the coagulation parameters are suboptimal, thermal coagulation is associated with an increase in mucosal bleeding in many patients. When the vascular ectasias are diffuse and extensive in the stomach, cryotherapy using liquid nitrogen or CO₂ may be used.²³² If endoscopic therapy fails, therapy with an oral estrogen-progesterone combination may be useful in reducing transfusion requirements.²³³ The usual dose is estradiol, 35 µg, plus norethindrone, 1 mg, daily. Because the medication is taken daily, no risk of breakthrough vaginal bleeding exists. Rarely, painful gynecomastia may limit use of this combination in men. In the patient with preserved hepatic synthetic function who continues to bleed despite thermoablative therapy and an estrogen-progesterone combination, a surgical antral resection may be carried out. TIPS does not reduce the bleeding risk in patients with GAVE and is associated with a substantial risk of hepatic encephalopathy.²²⁷ Therefore, TIPS placement is not recommended as therapy for GAVE. Nevertheless, GAVE is reversed with liver transplantation, even in the presence of portal hypertension, suggesting that GAVE is related to liver failure, rather than to portal hypertension.⁵⁰^,²³⁴