Portal Hypertension and Variceal Bleeding

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. Hemodynamic changes in the hepatic circulation also contribute to increased intrahepatic resistance. ^, 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 Poiseuille’s law:

in which R is resistance, $\eta L$ is the product of blood viscosity and vessel length, and r is vessel radius.

Although vasoactive changes were estimated initially to account for 10% to 30% of the increase in portal resistance in cirrhosis, subsequent studies have suggested that these figures actually may underestimate the contribution of hepatic vasoconstriction to the increased resistance observed in the cirrhotic liver. In noncirrhotic causes of portal hypertension, the increase in resistance may occur at sites upstream (prehepatic) or downstream (posthepatic) of the liver, as in portal vein thrombosis and hepatic vein thrombosis, respectively ( Fig. 92.5 ). 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 alcohol-associated 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.

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. ^{, ,} A similar paradigm is observed in the human cirrhotic liver. Most relevant studies indicate that the reduction in NO production occurs not through a reduction in hepatic eNOS levels ^, but through defects in the steps necessary to activate existing eNOS. For example, increases in the production of the eNOS-inhibiting protein caveolin-1 have been observed in experimental models of cirrhosis 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 up-regulation of the eNOS inhibiting protein GRK (G protein–coupled receptor kinase) in the cirrhotic liver. 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. 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. ^, The systemic actions of these agents, however, tend to cause side effects and exacerbate the hyperdynamic circulatory state. Human and experimental studies suggest that statins may activate eNOS in the liver and thereby reduce portal hypertension. This is one of the more promising drug targets for new therapy of portal hypertension.

Excessive ET-1 also contributes to increased intrahepatic vasoconstriction in portal hypertension through vasoconstrictive effects in the liver, presumably by enhancing HSC contractility. ^, In experimental models, ET-1 protein and receptor expression are increased, most notably in HSCs and endothelial cells. ^{, ,} In humans with portal hypertension, plasma and liver ET-1 levels also are increased. 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, a key fibrogenic growth factor. The variable effects of ET antagonists in experimental models of portal hypertension, as well as the possible hepatotoxicity of these compounds, have limited enthusiasm for studies of these agents in humans. Somatostatin, which reduces portal pressure by constricting the splanchnic circulation, may also act by inhibiting ET-1–dependent HSC contraction.

Other vasoactive mediators, including cysteinyl leukotrienes, thromboxane, angiotensin, and hydrogen sulfide, have also been implicated in the development of increased intrahepatic resistance in cirrhosis. ^, Attempts to reduce portal pressure using pharmacologic agents that inhibit angiotensin activation of HSC contraction have met with mixed results. Promising approaches for human evaluation include statins and targeted kinase inhibitors such as sorafenib. ^, Carvedilol is of notable interest because it is a nonselective β-receptor blocking agent (beta blocker) (discussed later) that also improves hepatic sinusoidal perfusion through α-1 adrenergic receptor blockade.

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.

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. This excess generation of NO and ensuing vasodilatation, hyperdynamic circulation, and hyperemia in the splanchnic and systemic circulation contrast with the hepatic circulation, in which NO deficiency contributes to increased intrahepatic resistance.

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. ^, 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. 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 TNF-α. Inhibitors of TNF-α improve portal pressure and the splanchnic circulatory disturbances in both human and experimental portal hypertension; however, TNF-α inhibitors are not safe for use in patients with advanced liver disease and high MELD scores (see later and Chapter 97 ). TNF-α may be derived from intestinal endotoxin, and intestinal decontamination appears to correct the hyperdynamic circulation in humans, thereby suggesting a link with intestinal inflammation. Studies have linked intestinal microbes and lipopolysaccharide with portal hypertensive hemodynamics. Vascular endothelial growth factor (VEGF) has also been implicated in this process by excessively activating eNOS.

Other mediators that may contribute to systemic and splanchnic vasodilatation include anandamide, an endogenous vasodilatory cannabinoid, heme oxygenase, ^, COX, and agonists of the innate immune system such as lipopolysaccharide. Compelling evidence also supports a primary defect in smooth muscle cells in portal hypertension, perhaps because of defects in potassium channels. 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 that target 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. Carvedilol as a single agent has combined effects of beta blockade and relaxation of intrahepatic sinusoidal vessels.

Collateral Circulation and Varices

The portal vein–systemic collateral circulation develops and expands in response to elevation of the portal pressure. 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 distal esophagus and proximal stomach, where gastroesophageal varices are the major collaterals formed between the portal venous system and systemic venous system; 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 rectum, where the inferior mesenteric vein connects with the pudendal vein and rectal varices develop.

Four distinct zones of venous drainage at the gastroesophageal junction are particularly relevant to the formation of esophageal varices. 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 4 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 proximal to the perforating zone in the esophagus, and usually characterized by 4 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 azygos system, and as a result, an increase in azygos 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. ^,

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 an intrahepatic cause 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 and dilatation and increased flow through preexisting collaterals. ^, VEGF, a key NO stimulatory growth factor, may contribute to both the angiogenic and collateral vessel responses. ^, Inhibition of VEGF or NO may attenuate the collateral vessel propagation by inhibiting angiogenic responses in experimental models of portal hypertension and collateralization. Beta blockers and octreotide may act in part by constricting collateral vessels. Attempts to inhibit VEGF and angiogenesis have focused on targeted kinase inhibitors.

The development of gastroesophageal varices requires a portal pressure gradient of at least 10 mm Hg (see later). 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 are also needed because not all patients with a portal pressure gradient of greater than 12 mm Hg bleed. Factors that influence variceal wall tension can be viewed in the context of Laplace’s law:

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 ruptures. 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. Laplace’s law also has implications for the relevance of pharmacologic therapies aimed at reducing portal pressure. A reduction in portal pressure reduces the variceal transmural pressure gradient, thereby reducing the risk that variceal wall tension will become excessive and that varices will rupture. Clinically, a reduction in the hepatic venous pressure gradient to less than 12 mm Hg almost eliminates 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; moreover, portal pressure and esophageal variceal pressure may vary at different times.

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, 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 virtually eliminates this variation in measurement of WHVP because the balloon catheter measures the WHVP averaged over a wide segment of the liver. The pressure in the hepatic vein following deflation of the balloon is the FHVP.

HVPG measurement 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 PBC and presinusoidal causes of portal hypertension. Therefore, the 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 (FHVP). By contrast, using the right atrial pressure as a reference for intra-abdominal pressure gives an erroneous estimation of hepatic sinusoidal 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. The HVPG is measured at least 3 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 is also 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 ; (3) as an end point in trials using pharmacologic agents for the treatment of portal hypertension ; (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 92.1 ]), 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 to monitor the efficacy of therapies to reduce portal pressure, HVPG monitoring is not done routinely in clinical practice because controlled trials have yet to demonstrate its usefulness.

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 seldom used.

Portal Vein Pressure

Direct measurement of the pressure in the portal vein is also 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 US guidance. A catheter is then threaded over a guidewire into the main portal vein. With increasing use of 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 (see Chapter 85 ) in whom a surgical portosystemic shunt is being contemplated 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 (see earlier). 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, ^, especially in patients with portal vein thrombosis and other causes of portal hypertension associated with a normal HVPG.

Variceal pressure can be measured in various ways: by insertion of a needle connected to a pressure transducer, with use of a miniature pneumatic pressure sensitivity gauge at the tip of an endoscope, or by manometry using an endoscopic balloon. Patients with previous variceal bleeding have been demonstrated to have higher variceal pressures than those in patients without previous bleeding. A variceal pressure greater than 18 mm Hg during a bleeding episode is associated with failure to control bleeding and predicts early rebleeding. 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%. In general, techniques for measuring variceal pressure have not been found to be suitable or safe for routine clinical use.

EGD

EGD is the most commonly used method to detect esophageal varices. The 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 evaluation, endoscopy to screen for varices should be repeated in 2 to 3 years. If small varices are detected on the initial examination, endoscopy should be repeated in 1 to 2 years. ^, None of the various noninvasive methods of determining which patients benefit most from endoscopic screening is accurate enough to recommend for routine use in clinical practice. However, a platelet count less than 110,000/mm ³ and liver stiffness measurement by transient elastography greater than 25 kPa (see Chapters 73 and 74 ) may identify with a high degree of confidence the patients who may need therapy to prevent variceal bleeding. 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 20 ) and CT imaging are alternative screening modalities in patients who are not candidates for EGD. Moreover, CT screening may be more cost-effective than endoscopy (see later).

Endoscopic grading of esophageal varices is subjective. Various criteria have been used to try to standardize the reporting of esophageal varices. The best known 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. 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, and upper third of the esophagus. Of all 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. 92.6 ). Small varices are 5 mm or less in diameter, whereas large varices are greater than 5 mm in diameter. ^, 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-Pugh class C cirrhosis (see later), and red color signs on varices have the highest risk of variceal bleeding within one year. 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).

US

US 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 US 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. ^, These criteria are not used routinely in clinical practice in most centers. US 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 thrombosed portal vein. Splenic vein thrombosis also can be demonstrated. Although Doppler US 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. Shear-wave transient or acoustic radiation force impulse elastography of the liver and spleen 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 Chapters 73 and 74 ). A combination of liver and spleen stiffness measured by acoustic radiation force impulse elastography may also identify patients at risk for esophageal varices.

CT

CT is useful for demonstrating many features of portal hypertension, including abnormal configuration of the liver, ascites, splenomegaly, collateral vessels, and portosystemic shunts ( Figs. 92.7 and 92.8 ). Detection of varices may be an emerging indication for CT. The detection of fundal varices by multidetector CT is at least as accurate as EUS (see later). CT is especially helpful in distinguishing submucosal from perigastric fundal varices and is considered a less invasive alternative to conventional angiographic portography in assessing portosystemic collaterals. Nevertheless, CT is not yet a recommended screening method for detecting large esophageal varices but may ultimately be confirmed as a cost-effective method of screening for varices and preferable to endoscopy by patients.

MRI

Gadolinium-enhanced MRI is a potentially useful method of detecting esophageal varices. In addition, MRI can be used to measure portal and azygos blood flow, which is increased in patients with portal hypertension. MRI provides excellent detail of the vascular structures of the liver and can detect portal vein thrombosis and spleen stiffness in patients with portal hypertension. Unlike shear-wave transient elastography, MR elastography can accurately assess the stiffness of fatty livers. The role of MR elastography in the assessment of changes in portal pressure in response to pharmacologic agents requires further study.

EUS

EUS examination (endosonography) using radial or linear array echo-endoscopes or EUS mini-probes passed through the working channel of a diagnostic endoscope has been applied to the evaluation of patients with varices. EUS 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 ; size of and flow in the left gastric vein, azygos vein, and paraesophageal collaterals; changes after endoscopic therapy; and recurrence of esophageal varices following variceal ligation (see later). 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). Endosonography may be used to target varices for sclerotherapy or glue injection (see later).

Common

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 85 ). The most common causes of portal vein thrombosis include hematologic disorders such as polycythemia vera or other myeloproliferative neoplasms. 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, IBD, or diverticulitis; abdominal trauma; and postoperative states, especially post-splenectomy. Portal vein thrombosis may develop in up to 25% of patients with cirrhosis. The association with HCC 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 be an additional predisposing factor.

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

The treatment of chronic 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. Local or systemic thrombolytic therapy is seldom required and is generally reserved for patients in whom an acute 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. The mesenterico–left portal venous bypass discussed later is especially effective because it preserves portal blood flow and avoids hepatic encephalopathy while decompressing the portal venous system. Placement of a TIPS is possible in many patients with chronic portal vein thrombosis and cirrhosis, with excellent long-term patency. Portal vein thrombosis occurs in patients with cirrhosis at an annual frequency of 2% to 10% per year and is associated with severity of liver disease. CT or MRI is recommended in these patients to rule out HCC, which may be associated with tumor thrombus. Anticoagulation in patients with cirrhosis is safe and is associated with a high rate of recanalization of the portal vein and reduced rates of complications of cirrhosis. Comorbidity has a greater impact on outcome of GI bleeding in patients on anticoagulants than does the anticoagulation itself. TIPS has been possible in selected patients with good results after failure of endoscopic and pharmacologic therapy. Figure 92.9 provides an algorithmic approach to management of portal vein thrombosis in patients with cirrhosis.

Less Common