Chapter 6: Medical Management of Portal Hypertension Complications Portal hypertension (PHT) is caused by increased resistance to portal outflow and increased portal inflow resulting in portal venous pressure greater than 5 mm Hg. These hemodynamic changes result in increased blood volume in the splanchnic venous system and reduced circulating volume in the arterial and systemic venous systems. This abnormal distribution of blood volume leads to pathologic changes in most of the body’s systems, including the cardiovascular, renal, immune, central nervous, and pulmonary systems1,2 This chapter focuses on the medical managements of cirrhosis and PHT; endoscopic and interventional management will be discussed in a separate chapter. The vast majority of the blood draining from the gastrointestinal (GI) tract and spleen flows through the liver via the portal venous system. This allows the liver to manifest its significant metabolic, detoxifying, synthetic, and immunologic functions. The liver receives less than 25% of its blood supply via the hepatic artery, and in the hepatic sinusoids, arterial and portal venous blood mix together and drain into the hepatic vein. Branches of the portal venous system communicate with the vena cava system via watershed areas in the distal esophagus, superior and middle hemorrhoidal veins, paraumbilical veins, splenic venous bed and left renal vein, and retroperitoneum. In normal hemodynamic conditions, blood flow through these communications is minimal, but in cases of PHT and increased resistance in the portal venous routes, these communicating vessels significantly enlarge, thereby shunting major volumes of blood into the vena cava system ( Portal hypertension can be classified based on the site of vascular resistance leading to increased venous pressure. Most cases of PHT are caused by cirrhosis, which is the most common cause of intrahepatic PHT. Other causes leading to intrahepatic (also known as sinusoidal) PHT include primary biliary cirrhosis, primary sclerosing cholangitis, alcoholic hepatitis, acute hepatitis, nodular regenerative hyperplasia, and infiltrative liver diseases. Prehepatic (presinusoidal) PHT is most commonly seen in cases of schistosomiasis ( In cases of increased portal venous pressure, blood flow is diverted toward collateral of lower resistance. These collaterals are in the watershed areas that communicate with the systemic venous system. The communicating vessels enlarge over time and develop large vascular structures known as varices. Although these collaterals shunt large amounts of blood, they are not able to effectively decompress the portal venous system and reduce the pressure back to normal.3 The portosystemic shunts associated with PHT reduce the pressure in the portal venous system, yet they are associated with pathologic manifestations. The massive dilatation of these vascular structures predisposes them to bleeding, clinically known as variceal hemorrhage. In addition, the immunologic and detoxifying roles of the liver can be significantly reduced by the portosystemic shunting of blood, thereby leading to increased systemic inflammatory response and hepatic encephalopathy (HE). Increased pressure in the portal venous system leads to development of ascites and hepatic hydrothorax (HH). This pathologic accumulation of fluid predisposes it to microbial infection known as spontaneous bacterial peritonitis (SBP). The hemodynamic disturbances associated with pooled blood in the portal venous system and away from the systemic veins lead to disturbances in the renal and pulmonary vascular systems, which clinically manifest as hepatorenal, hepatopulmonary, and portopulmonary syndromes.4 Progression of PHT necessitates further decompression of the congested portal venous system via further dilatation of porto-systemic collateral or varices ( In the cirrhosis population, 8% of patients develop esophageal varices de novo annually, and preexisting small varices become large at the same annual rate.5 Varices are less commonly seen in well-compensated cirrhosis (40% of patients with Child-A cirrhosis), yet with progression of liver failure, the risk of varices (up to 85% of patients with Child-C cirrhosis) and variceal hemorrhage increases. Around 60% of the cases of variceal hemorrhage do not spontaneously stop, and each episode of bleeding continues to carry a mortality rate of 20% despite the currently available treatment. Survivors carry a 60% risk of rebleeding within 1 to 2 years.6–8 Medical management of esophageal varices is directed at three levels: primary prophylaxis, treatment of active or recent hemorrhage, and secondary prophylaxis of variceal bleeding. Pharmacologic therapy of high-risk varices is targeted at reducing portal resistance and portal pressure by using vasoconstrictors or venodilators. Splanchnic vasoconstriction can be achieved by using nonselective beta-blockers, vasopressin and its analogues, or somatostatin and its analogues. Splanchnic vasoconstriction results in reduction of portal venous inflow. Nitrates lead to reduction in systemic arterial pressure with resultant reduction in arterial hepatic blood flow and subsequent reduction in sinusoidal and portal pressures. The combination of a vasoconstrictor and a vasodilator has a synergistic effect on reducing portal pressure.7,8,10 Table 6.1 Causes of Noncirrhotic Portal Hypertension
Introduction
Anatomy and Physiology
Fig. 6.1).2
Clinical Pathophysiology
Table 6.1). Other causes of prehepatic PHT include portal vein thrombosis, splenic vein thrombosis, and extrinsic compression on the portal vein. The third form of PHT is postsinusoidal, which is caused by increased pressure in the hepatic venous system in cases of right-sided congestive heart failure, tricuspid valve disease, constrictive pericarditis, Budd-Chiari syndrome, and veno-occlusive disease (
Table 6.1).3
Gastrointestinal Varices
Fig. 6.1). At a certain point, these vascular structures become overwhelmed by their increased intraluminal pressure and blood flow. The clinically most significant forms of GI varices include esophageal, gastric, rectal, and less commonly ectopic varices of the GI tract. Esophageal varices are of the highest clinical significance because their rupture is the number one cause of death related to complications of cirrhosis.
Esophageal Varices
Fig. 6.2 and 
Fig. 6.3 show our proposed algorithms for the management of esophageal varices and upper GI bleeding in patients with known or suspected PHT. Given the high risk of developing varices and their associated bleeding complication, screening guidelines have been set by various hepatology societies. The predicted risk for esophageal variceal bleeding is determined by endoscopic evaluation and is based on the location of the varices (a higher risk is at the gastroesophageal junction and the palisade zone), size of the varices (larger varices are associated with higher risk to rupture), endoscopic finding of high-risk signs (red wale marks, cherry red spots, hematocystic spots, and diffuse erythema), and clinical manifestations of decompensated liver function. The 1-year risk of bleeding can be determined based on cumulative effect of these factors. This risk can be as low as 6% in a Child-A patient with small esophageal varices (grade F1) without high-risk stigmata and as high as 76% in a Child-C patient with large (grade F3) esophageal varices with significant high-risk stigmata (
Fig. 6.4).8,9
Intrahepatic Presinusoidal PHN | Sinusoidal PHN | Extrahepatic Postsinusoidal PHN |
Hepatic schistosomiasis | Cirrhosis | Budd-Chiari syndrome |
Congenital hepatic fibrosis | Noncirrhotic alcoholic liver disease | Right heart failure |
Noncirrhotic portal fibrosis | Infiltrative disorders: • Amyloidosis • Systemic mastocytosis • Malignancy • Myeloproliferative disorder | Constrictive pericarditis |
Nodular regenerative hyperplasia | Suprahepatic IVC thrombosis | |
Primary biliary cirrhosis or primary sclerosing cholangitis | Pulmonary hypertension | |
Tricuspid valve regurgitation | ||
Extrahepatic Presinusoidal PHN | Intrahepatic Postsinusoidal PHN | |
Portal vein thrombosis | Veno-occlusive disease | |
Superior mesenteric vein thrombosis | Peliosis hepatis |
|
Splenic vein thrombosis | Hypervitaminosis A |
|
IVC: inferior vena cava; PHN: portal hypertension. (Adapted with modifications from Molina E, Reddy KR. Noncirrhotic portal hypertension. Clin Liver Dis 2001;5:769–787.72)
Fig. 6.3 Algorithm for management of variceal bleeding. Abx: antibiotics; BRTO: balloon-retrograde transvenous obliteration; EGD: esophagogastroduodenoscopy; EV: esophageal varices; EVL: endoscopic band ligation; GI: gastrointestinal; GOV: gastroesophageal varices; GV: gastric varices; PHTN: portal hypertension; PPI: proton pump inhibitor; TIPS: transjugular intrahepatic portosystemic shunt.
Primary Prophylaxis
Nonselective beta-blockers (e.g., propranolol, nadolol, and carvedilol) have been shown to reduce the risk of first variceal bleeding (i.e., primary prophylaxis). The use of beta-blockers as primary prophylaxis is indicated for patients with small, medium, or large esophageal varices and decompensated liver disease (Child-A or -B cirrhosis). Although beta-blockers have been shown to reduce the risk of first bleeding from small esophageal varices in patients with Child-A cirrhosis, the risk of bleeding and the benefit of primary prophylaxis is small; therefore, the use of these medications is not currently recommended for this patient population (see 
Fig. 6.2).7,8,11,12
A meta-analysis of 11 trials that included 1189 patients showed that the risk of first variceal bleeding in patients with medium- or large-sized varices is significantly reduced by beta-blockers (30% in control participants vs. 14% in beta-blocker–treated patients) and indicated that treating 10 patients with beta-blockers results in preventing 1 variceal hemorrhage and reduces mortality in this patient group. The therapeutic target of beta-blockers is to reach a 25% reduction of heart rate from the baseline heart or to reach the maximum tolerated dose. When beta-blocker therapy is stopped, the PHT increases back to pretreatment levels; therefore, these medications should be given indefinitely.11,12,13
Reducing the hepatic venous pressure gradient to less than 12 mm Hg significantly diminishes the risk of variceal bleeding. Achieving this goal is not possible in many cases because of side effects of beta-blockers. About 15% of patients have contraindications for the use of beta-blockers, and another 15% of patients have to stop the medication because of significant side effects. Studies have shown a 10% to 20% reduction in hepatic venous pressure gradient significantly decreases the risk of variceal bleeding.14
Treatment of Variceal Hemorrhage
Survival analyses have shown reduction in mortality rates associated with active variceal bleeding with the currently available treatment. The management options include general medical measures, medical treatment, endoscopic interventions, interventional radiologic procedures, and surgery (
Fig. 6.3).15
The initial management measures include admission to intensive care setting, fluid resuscitation, and airway management to prevent aspiration and respiratory complications. Variceal bleeding could be massive, thereby leading to hemorrhagic shock with multiorgan failure. Caution should be taken not to overtransfuse with blood products and fluids because doing so may increase the portal venous pressure and thereby may increase the risk or rebleeding. Thus, the current recommendations indicate a hemoglobin level of 8.0 g/dL as a target for transfusion. Using recombinant factor VIIa (rFVIIa) may be of benefit in cases of difficult-to-control variceal bleeding (see 
Fig. 6.3).16–18
In addition to resuscitative measures, the prophylactic use of intravenous (IV) or oral antibiotics has been shown to reduce the mortality rate of patients with variceal bleeding. This recommendation is based on studies showing a higher risk of bacterial infections in patients with cirrhosis who have upper GI bleeding.19 The most commonly used antibiotic regimens include an IV quinolone or ceftriaxone or oral norfloxacin for 7 days.20
Pharmacologic therapy should be initiated in patients with suspected variceal bleeding even before diagnostic or therapeutic endoscopy. Studies have shown that treatment with vasopressin and nitroglycerin, terlipressin, somatostatin, or octreotide to reduce death associated with variceal hemorrhage (see 
Fig. 6.3). Pharmacologic treatment should be continued for at least 2 days after endoscopic intervention because studies have showed that the hepatic venous pressure gradient increases for 48 hours after band ligation and for more than 5 days after sclerotherapy of esophageal varices.7,21
Vasopressin is the most potent splanchnic vasoconstrictor, yet it is associated with a number of systemic side effects that limit its use in variceal hemorrhage. Coadministration of nitrates attenuates these side effects to some degree, but it does not render it as safe as the other available medications.22,23
Terlipressin is a synthetic analogue of vasopressin with a longer biologic activity and significantly fewer side effects. It has been widely used in Europe with studies showing its efficacy at controlling variceal bleeding and lowering its associated mortality rate, but currently it is not approved by the U.S. Food and Drug Administration.23
Somatostatin and analogues such as octreotide and vapreotide reduce portal pressure via a local vasodilatory effect. Recent meta-analysis has shown a limited value of octreotide as a single agent without endoscopic intervention. This could possibly be due to tachyphylaxis associated with its use.24
Secondary Prophylaxis
After an episode of variceal hemorrhage, close monitoring of hemodynamics for at least 24 hours is recommended. Shortly, after hemodynamic stability and with no further evidence of rebleeding, secondary prophylaxis should be initiated (see 
Fig. 6.3). If secondary prophylaxis is not undertaken, the risk of rebleeding could be as high as 60% within 2 years. If nonselective beta-blockers are used, then this risk may be reduced to less than 43%. Beta-blockers do not have to be used in patients who had surgical or radiologic portosystemic shunts. A combination of nonselective beta-blocker and a nitrate may be more efficient at reducing the risk of variceal bleeding, yet this regimen carries a higher rate of side effects, thereby limiting the practicality of its use. The combination of pharmaceutical and endoscopic treatment is most likely superior to either treatment alone in reducing the risk of variceal rebleeding with data showing that this risk may be reduced to 14% to 23% with the combined treatment.11,25
Gastric Varices
Gastric varices are less prevalent than esophageal varices and are present in 5% to 33% of patients with PHT with a reported incidence of bleeding of about 25% in 2 years, with a higher bleeding incidence for fundal varices (
Fig. 6.5; 
Fig. 6.6). The efficacy of pharmacologic treatment is not clear in cases of gastric variceal bleeding because of the limited number of studies. Vasoconstrictors and venodilators may be of little benefit in managing gastric variceal bleeding because of the difference in hemodynamics from esophageal variceal and the presence of large portosystemic shunts except for cases of gastroesophageal varices I (
Fig. 6.5a), which are typically treated as esophageal varices (see 
Fig. 6.3).24,26 The endoscopic and radiologic treatments of gastric variceal hemorrhage are discussed in separate chapters of this book.
Hepatic Encephalopathy
Hepatic encephalopathy or portosystemic encephalopathy is a syndrome of largely reversible impairment of the central nervous system occurring in patients with acute or chronic liver failure or in patients with major portosystemic shunts. This condition is associated with a wide spectrum of neurologic impairments ranging from subclinical disease to coma. The underlying cause of this disorder is a combination of impairment of liver function caused by hepatocellular disease and major portosystemic shunting, both of which result in large volumes of portal venous blood being poorly filtered through the liver or completely bypassing the detoxifying effect of the liver directly into the systemic venous system; then these toxins (ammonia and toxic fatty acids) attain a direct access to the brain.27
