- Email: [email protected]
Portal Hypertension and Esophageal Varices
James Cushman, MD, MPH, FACS
CHAPTER 44
PORTAL HYPERTENSION AND ESOPHAGEAL VARICES
1. Describe the common causes of upper gastrointestinal bleeding (UGIB) in US populations. Peptic ulcer disease is the number one cause of UGIB in the United States. The gram-negative bacteria Helicobacter pylori plays a significant role in the pathogenesis for many. Esophageal varices (EV) related to portal hypertension (PH) is another leading cause, followed by a number of disorders including Mallory-Weiss tears, and arteriovenous malformations. 2. What is the definition of PH? An hepatic venous pressure gradient (HVPG) >5 mm Hg defines PH. HVPG is measured between the portal vein and the inferior vena cava. In practice, the pressure is measured free and in a wedged fashion in the hepatic veins. PH becomes significant when the HVPG becomes >10 mm Hg. It should be noted that HVPG is not commonly tested or utilized in many US centers. 3. What are the causes of PH? Chronic injury to the liver from a variety of sources leads to increased resistance to portal blood flow. In the United States, this resistance is most commonly within the liver and the most common cause (>90%) is chronic alcohol abuse. Structural changes include distortion of liver microcirculation from fibrosis and vascular occlusion. The resistance can also be prehepatic (e.g., portal vein thrombosis) or posthepatic (e.g., Budd-Chiari syndrome). Worldwide causes of cirrhosis include schistosomiasis and other infectious sequelae. One way to stratify patients with cirrhosis is by characterizing them as either with compensated cirrhosis (i.e., those who do not have ascites, encephalopathy, jaundice, or variceal hemorrhage) versus decompensated. 4. How is PH diagnosed? PH is often asymptomatic until complications develop. Clinical signs may include abdominal wall collateral vessels, splenomegaly, and thrombocytopenia. Thus, the diagnosis of cirrhosis is a clinical one; however, imaging studies may reveal the characteristic nodular liver, ascites, and/or the existence of EV. Up to 60% of patients with newly diagnosed cirrhosis present with clinically significant PH. Additional diagnostic confirmation can be accomplished by obtaining an HVPG measurement if needed. 5. Describe screening and prevention strategies for patients with known PH. Among asymptomatic patients with cirrhosis, approximately 85% will have an elevated HVPG and 40% of these will have EV. Some literature suggests that gastroesophageal varices are present in almost half of patients with cirrhosis at the time of diagnosis. Given the 6-week mortality with each episode of variceal hemorrhage is approximately 15%–20%, it is prudent to offer screening and prevention strategies for such patients. The recommended screening method to determine the presence and size of gastroesophageal varices is esophagogastroduodenoscopy. The current consensus is that every known cirrhotic be endoscopically screened for varices at the time of diagnosis. The rationale behind screening is the existence of effective therapies that reduce the likelihood of first and subsequent bleeding episodes. 6. Describe the Child-Turcotte-Pugh classification of cirrhosis. Gastroesophageal varices occur with the highest rate in patients with Child’s class B or C cirrhosis, and the mortality for any given episode of variceal hemorrhage is higher in class B or C cirrhotics. (The table below is available from multiple sources. Class A= 5–6 points, Class B= 7–9 points, and Class C = 10–15 points.)
195
196 ABDOMINAL SURGERY Clinical Criteria
1 Point
2 Points
3 Points
Encephalopathy Ascites Bilirubin (mg/dL) Albumin (g/dL) Prothrombin time (seconds prolonged) International normalized ratio
None None <2 >3.5
Mild to moderate Mild to moderate 2–3 2.8–3.5
Severe Large or refractory to diuretics >3 <2.8
<4 <1.7
4–6 1.7–2.3
>6 >2.3
7. What is the pathogenesis of PH leading to varices, variceal hemorrhage, and portosystemic collaterals? Increased resistance to portal blood flow results from cirrhosis, and this leads to increases in portal venous pressure as stated. This results in decreased vasodilating factors (e.g., nitric oxide [NO]) and increased angiogenic factors (e.g., vascular endothelial growth factor) and the formation of new vessels. Splanchnic vasodilation occurs leading to increased portal blood flow, which completes a cycle by increasing portal venous pressure. Dilation of preexisting vessels leads to formation of varices and/or collaterals. Collaterals develop at watershed zones between the portal venous drainage (e.g., stomach, small bowel, large bowel, and spleen) and systemic venous drainage (e.g., esophagus, distal rectum). Collaterals can also develop from recanalization of embryonic connections (e.g., umbilical vein, persistent ductus venosus). Note: EV refers to esophageal varices, but it should be noted that gastric varices are present in 20% of patients with cirrhosis, either in isolation or in combination with EV. In this chapter, the term EV and gastroesophageal varices may be used interchangeably with this caveat. 8. Describe how the HVPG and Child’s classification help in both risk assessment and management of bleeding from EV in patients with cirrhosis and PH? In cirrhotic patients with an HVPG >10 mm Hg, a higher risk of complications such as ascites and varices exist. In addition, these patients have double the risk of developing EV (50% at 5 years) when compared to patients with HVPG below this threshold (25% at 5 years). With an HVPG >12 mm Hg, there is an increased risk of EV rupture and bleeding. As stated previously, patients with decompensated cirrhosis, Child’s class B and C, carry the highest rate of EV formation and a higher mortality for any given episode of variceal hemorrhage. 9. What are the current methods used for the primary and secondary prophylaxis of esophageal variceal bleeding and are they effective? Current evidence cannot recommend ß-adrenergic blockers for the primary prevention of the development of EV. However, once EV are present then criteria including varix size, characteristics, and patient’s Child class are evaluated for determination if prophylaxis of bleeding is warranted. Nonselective ß-blockers and endoscopic variceal ligation (EVL) are both effective in preventing first bleeding episodes in existing EV, according to a 2008 metaanalysis of randomized clinical trials, and would be used for medium- and large-sized EV, or in small-sized EV with red wale signs and/or Child’s class B or C cirrhosis. (Nonselective ß-blockers are effective by both ß1 and ß2 actions by reduction of cardiac output and splanchnic vasoconstriction respectively. The reader is referred to the references for further reading regarding the advantages and disadvantages between medical therapy and endoscopic therapy.) 10. What is the recommended treatment approach for the patient who has experienced an acute variceal bleed? Patients with Child class A or B disease or who have an HVPG <20 mm Hg have a low or intermediate risk. Standard therapy involves the combination of a safe vasoconstrictor (octreotide in the United States) administered from the time of admission for 2–5 days; endoscopic therapy (EVL) performed at <12 hours from admission on diagnostic endoscopy; and short-term prophylactic antibiotics (e.g., ciprofloxacin or ceftriaxone). Placement of a transjugular intrahepatic portosystemic shunt (TIPS) is currently considered salvage therapy for the 10%–20% of patients in whom standard medical therapy fails and will be discussed below. 11. What is the general approach to the patient who has survived one episode of EV bleed in an effort to reduce a recurrent bleed? A patient who survives an initial episode of bleeding secondary to EV has a 60% chance of recurrence. All such patients are thus recommended to have some form of treatment for the prevention of recurrent bleed prior to their discharge from the hospital, and treatment recommendations apply to all
Portal Hypertension and Esophageal Varices 197 patients with variceal hemorrhage. Examples of such treatments include medical therapy, EVL, TIPS, and surgical shunts. A number of metaanalyses discuss matching specific therapies or combination of therapies for differing patient characteristics. Patients with Child class A disease have a good response to current therapies with a 0%–5% mortality. As previously noted, patients in whom their HVPG decreases to <12 mm Hg (or reduced by >20% from baseline) have the lowest rate of recurrent variceal bleeding. 12. What are the specifics in current recommended therapy for patients who have survived one episode of EV bleed? Current guidelines (see reference 1) recommend the combined use of EVL and nonselective ß-blockers for the prevention of recurrent variceal bleed. This is based on a randomized controlled trial showing a significantly lower rate of variceal rebleeding with combined modalities. However, the rate of bleeding from all sources was not significantly different because of the bleeding from esophageal ulcers induced by the EVL (a known complication of EVL). Patients who have rebleeding despite this combined therapy should undergo early placement of a TIPS or surgical shunt. 13. A restrictive transfusion strategy, defined as a posttransfusion hemoglobin threshold of 7 g/dL, has been shown in various clinical settings to not increase, and perhaps decrease, mortality. Has such a strategy been shown to be similarly effective in cases of acute gastrointestinal (GI) bleeding? Current international guidelines recommend decreasing the hemoglobin threshold for transfusion in a variety of critical care settings, including the condition of normovolemic anemia seen in patients who have had a GI bleed. A recent study (see reference 2) demonstrates that even in patients with an acute bleed, a restrictive transfusion strategy significantly reduced the rates of therapeutic failure factors such as further rebleeding, need for salvage or rescue therapy, and reduced length of hospital stay. Such a strategy should be used cautiously in the patient with active GI hemorrhage and shock. 14. By what possible mechanisms is a restrictive strategy advantageous in acute GI bleeders, and those PH in particular? Transfusion of red blood cells may lead to an impairment in hemostasis by dilution of coagulation factors and platelets. Splanchnic vasoconstriction in the setting of hypovolemia may be ameliorated by transfusion, leading to increase in splanchnic blood flow. Restoring blood volume may induce a rebound increase in portal venous pressure and precipitate bleeding. These concerns have been validated by experimental evidence that patients undergoing a liberal transfusion strategy had a significant increase in portal pressure not seen in the restrictive strategy group. 15. Outpatient management of the patient with cirrhosis of the liver involves what major complications or sequelae in addition to variceal bleeding (name three)? The three primary clinical issues that are caused by PH are ascites, variceal bleeding, and hepatic encephalopathy (HE). Hepatorenal syndrome (HRS) and spontaneous bacterial peritonitis are two less common but severe manifestations of decompensation. 16. How common is ascites in the setting of cirrhosis and how is it managed? Ascites is the most common manifestation of decompensated cirrhosis and affects 60% of previously compensated cirrhotics within 10 years of diagnosis. Rates of mortality once ascites is manifested varies depending on the study but are uniformly grave. First-year mortality is described at 15%, and by 3–5 years ranges between 44% and 50%. The mainstay of medical therapy is sodium restriction in the diet to prevent volume overload. A goal of <2000 mg/day is recommended. The use of oral diuretics such as spironolactone and furosemide is considered standard medical therapy, with typical starting dosages being 100 mg and 40 mg daily, respectively. Persistent ascites despite a low salt diet and maximal diuretic therapy is defined as refractory ascites and generally leads to a referral for orthotopic liver transplant, repeated paracentesis, placement of a TIPS, or peritovenous shunt. Use of peritovenous shunts have declined because of high complication rates with one remaining indication for it being in a patient with refractory ascites but ineligible for a TIPS or repeated paracentesis. 17. How common is HE in the setting of cirrhosis and how is it managed? HE is a manifestation of cirrhosis that if it occurs in the hospitalized patient carries a 3.9-fold increased mortality risk. Estimates are that 30%–40% of patients with cirrhosis will develop HE during the course of their disease, and relapse rates are high despite maximal suppressive therapy.
198 ABDOMINAL SURGERY Pathophysiology is multifactorial including hyperammonemia, ammonia crossing the blood-brain barrier resulting in neuroinflammation, astrocyte swelling, and oxidative neuronal stress. There may be a net increase in the inhibitory neurotransmission mediated by gamma-aminobutyric acid. Systemic inflammation also occurs acting synergistically to cause HE. Placement of a TIPS may predispose patients to hepatic encephalopathy with an incidence of 5%–35% reported. HE is a clinical diagnosis and one of exclusion. Blood ammonia levels as a diagnostic criteria remain elusive according to a 2014 consensus guideline. Lactulose is the mainstay of therapy, which acts by acidification of the colon converting ammonia to ammonium. Recent studies suggest that polyethylene glycol may be superior, but further studies are needed. Antibiotics such as rifaximin in combination with other agents is the second line of therapy. There are recent reports of use of embolization of portosystemic communications as an emerging therapy. 18. How common is HRS in the setting of cirrhosis and how is it managed? According to a 2007 definition, HRS is cirrhosis with ascites, a serum Cr of >1.5 mg/dL, no improvement in serum Cr despite 48 hours of diuretic withdrawal and volume resuscitation, absence of shock, no recent exposure to nephrotoxic drugs, and no signs of intrarenal disease. Acute kidney injury occurs in approximately 20% of such hospitalized patients and of these, 25% are secondary to HRS. In patients unfortunate enough to develop HRS, the 1-month mortality is 58% and the 1-year mortality is 63%. Overall, the mortality for HRS is 80% (Type 1). The only definitive treatment for HRS is liver transplantation. Bridge therapy includes initial volume expansion, pharmacologic agents (midodrine and octreotide), and the use of renal replacement therapy, which is controversial. 19. What are the indications for use of TIPS in cirrhotic patients with recurrent variceal bleeding? The accepted indications for TIPS include refractory ascites, uncontrolled variceal bleeding, and recurrent variceal bleeding in patients who have failed standard initial medical and endoscopic means of control. Absolute contraindications include congestive heart failure, severe pulmonary hypertension, and severe tricuspid valve regurgitation. Early studies evaluating the role of TIPS in the prevention of recurrent variceal bleeding demonstrated that TIPS reduces the rebleeding rate, but at the expense of increasing HE without improving survival. As a result, TIPS has been recommended as rescue therapy for the up to 27% of patients who have failure to control bleeding after a variceal bleed and using conventional combined therapy of medications and EVL. More recent studies (see reference 8) have studied the effect of using coated stents in the TIPS procedure and moving to earlier (<72 hours) timing of the procedure. 20. What are the technical aspects of TIPS placement? TIPS is a side-to-side portosystemic shunt created within the liver parenchyma typically between the right hepatic vein and the right portal vein. Accessing the portal vein is the most critical step of the TIPS procedure technically and is facilitated by the use of both preprocedure cross-sectional imaging as well as transabdominal ultrasound to guide needle placement into the correct portal vein branch. The procedural complication rate of TIPS may be related to intraabdominal hemorrhage and occurs in 0.6%–4.2%. 21. Describe potential advantages of earlier use of TIPS and use of an extended polytetrafluoroethylene stent when compared to previous studies where TIPS was used only as a delayed rescue procedure with bare stents. Patients with Child’s class C or Child’s class B with recurrent bleeding who have persistent bleeding at endoscopy are at high risk for treatment failure and mortality. A recent study (see reference 8) randomized such patients to either early (<72 hours from endoscopy, preferably within 24 hours) versus continuation of medical therapy and TIPS within a conventional 3- to 5-day window. Protection from initial rebleeding, rebleeding within the first year of follow-up, and 1-year survival were all statistically significantly improved in the early TIPS group. 22. Characterize the endothelial dysfunction (ED) in hepatic cirrhosis and how ED may contribute to liver dysfunction and PH. The endothelium involves >1013 cells and has multiple functions and properties. Examples include barrier function, permeability regulation, vascular tone, platelet adhesion and aggregation, prevention of thrombosis, and acting as a framework for multiple inflammatory processes. Within the hepatic circulation, ED refers primarily to the impairment of the production and release of vasodilatory factors, especially NO, considered to be a key role in the initiation and progression of liver cirrhosis. Reduced
Portal Hypertension and Esophageal Varices 199 levels of NO in the cirrhotic liver contributes to increased intrahepatic vascular resistance. In addition, increased levels of vasoconstrictor agents such as thromboxane A2 and prostanoids are important in the pathophysiology as well. 23. Describe emerging therapies that may potentially ameliorate some of the ED, which is a component of the pathophysiology of cirrhosis. Experimental animal and human data (including clinical trials) have shown benefits to the use or intake of the following: Vitamins C and E (both improving NO bioavailability), folic acid and its active metabolite 5-methyltetrahydrofolate or 5-MTHF, flavonoids in the human diet that have antioxidant and vasodilatory actions including specifically resveratrol present in grapes as well as green tea polyphenol and dark chocolate. 24. Is it possible for a cirrhotic patient to become pregnant, and if so, are there special issues or precautions? Pregnancy is a rare event in patients with cirrhosis; however, improvements in the treatment of chronic liver disease have resulted in both higher conception rates and successful pregnancy outcomes in such patients. Maternal complications have been described in nearly half of pregnancies affected by cirrhosis, largely as a result from variceal hemorrhage. Variceal bleeding more commonly occurs in the second and third trimesters when maternal blood volume is maximally expanded and the large intrauterine fetus compresses the inferior vena cava and collateral vasculature. 25. Name the special treatment concerns for pregnant patients with cirrhosis. Upper endoscopy in general is safe during pregnancy, with the main risk being fetal hypoxia from sedative drugs or positioning. In women at high risk for bleeding, prophylaxis with nonselective ß-blockade drugs such as propranolol and nadolol, both designated as pregnancy category C drug (C+ risk cannot be ruled out; animal studies show an adverse effect, no controlled human studies available) may outweigh the potential fetal risk. Octreotide is designated as a pregnancy category B drug (B = no clear or reproducible risk shown in animal or human studies), yet theoretical concerns exist because of its vasoconstrictive properties. As of a 2008 report (see reference 9) only three cases of TIPS placement had been reported in pregnant cirrhotic patients, with one major risk being radiation exposure to the fetus. Among pregnant cirrhotic patients with known varices, up to 78% will have variceal hemorrhage during pregnancy and a mortality rate ranging between 18% and 50%. Bibliography 1. Garcia-Tsao G, Bosch J. Management of varices and variceal hemorrhage in cirrhosis. N Engl J Med. 2010;362(9):823–832. 2. Villanueva C, Colomo A, Bosch A, et al. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med. 2013;368(1):11–21. 3. Bleibel W, Chopra S. Portal hypertension in adults. Accessed 20.01.16. 4. Shah NL, Banaei YP. Management options in decompensated cirrhosis. Hepat Med. 2015;7:43–50. 5. Garcia-Pagan JC, De Gottardi A. Review article: the modern management of portal hypertension – primary and secondary prophylaxis of variceal bleeding in cirrhotic patients. Aliment Pharmacol Ther. 2008;28(2):178–186. 6. Vairappan B. Endothelial dysfunction in cirrhosis: role of inflammation and oxidative stress. World J Hepatol. 2015;7(3):443–459. 7. Pillai AK, Andring B. Portal hypertension: a review of portosystemic collateral pathways and endovascular interventions. Clin Radiol. 2015;70(10):1047–1059. 8. Garcia-Pagan JC, Caca K, Bureau C, et al. Early use of TIPS in patients with cirrhosis and variceal bleeding. N Engl J Med. 2010;362(25):2370–2379. 9. Tan J, Surti B. Pregnancy and cirrhosis. Liver Transpl. 2008;14(8):1081–1091. 10. Russell MA, Craigo SD. Cirrhosis and portal hypertension in pregnancy. Semin Perinatol. 1998;22(2):156–165.
CHAPTER 44
PORTAL HYPERTENSION AND ESOPHAGEAL VARICES
1. Describe the common causes of upper gastrointestinal bleeding (UGIB) in US populations. Peptic ulcer disease is the number one cause of UGIB in the United States. The gram-negative bacteria Helicobacter pylori plays a significant role in the pathogenesis for many. Esophageal varices (EV) related to portal hypertension (PH) is another leading cause, followed by a number of disorders including Mallory-Weiss tears, and arteriovenous malformations. 2. What is the definition of PH? An hepatic venous pressure gradient (HVPG) >5 mm Hg defines PH. HVPG is measured between the portal vein and the inferior vena cava. In practice, the pressure is measured free and in a wedged fashion in the hepatic veins. PH becomes significant when the HVPG becomes >10 mm Hg. It should be noted that HVPG is not commonly tested or utilized in many US centers. 3. What are the causes of PH? Chronic injury to the liver from a variety of sources leads to increased resistance to portal blood flow. In the United States, this resistance is most commonly within the liver and the most common cause (>90%) is chronic alcohol abuse. Structural changes include distortion of liver microcirculation from fibrosis and vascular occlusion. The resistance can also be prehepatic (e.g., portal vein thrombosis) or posthepatic (e.g., Budd-Chiari syndrome). Worldwide causes of cirrhosis include schistosomiasis and other infectious sequelae. One way to stratify patients with cirrhosis is by characterizing them as either with compensated cirrhosis (i.e., those who do not have ascites, encephalopathy, jaundice, or variceal hemorrhage) versus decompensated. 4. How is PH diagnosed? PH is often asymptomatic until complications develop. Clinical signs may include abdominal wall collateral vessels, splenomegaly, and thrombocytopenia. Thus, the diagnosis of cirrhosis is a clinical one; however, imaging studies may reveal the characteristic nodular liver, ascites, and/or the existence of EV. Up to 60% of patients with newly diagnosed cirrhosis present with clinically significant PH. Additional diagnostic confirmation can be accomplished by obtaining an HVPG measurement if needed. 5. Describe screening and prevention strategies for patients with known PH. Among asymptomatic patients with cirrhosis, approximately 85% will have an elevated HVPG and 40% of these will have EV. Some literature suggests that gastroesophageal varices are present in almost half of patients with cirrhosis at the time of diagnosis. Given the 6-week mortality with each episode of variceal hemorrhage is approximately 15%–20%, it is prudent to offer screening and prevention strategies for such patients. The recommended screening method to determine the presence and size of gastroesophageal varices is esophagogastroduodenoscopy. The current consensus is that every known cirrhotic be endoscopically screened for varices at the time of diagnosis. The rationale behind screening is the existence of effective therapies that reduce the likelihood of first and subsequent bleeding episodes. 6. Describe the Child-Turcotte-Pugh classification of cirrhosis. Gastroesophageal varices occur with the highest rate in patients with Child’s class B or C cirrhosis, and the mortality for any given episode of variceal hemorrhage is higher in class B or C cirrhotics. (The table below is available from multiple sources. Class A= 5–6 points, Class B= 7–9 points, and Class C = 10–15 points.)
195
196 ABDOMINAL SURGERY Clinical Criteria
1 Point
2 Points
3 Points
Encephalopathy Ascites Bilirubin (mg/dL) Albumin (g/dL) Prothrombin time (seconds prolonged) International normalized ratio
None None <2 >3.5
Mild to moderate Mild to moderate 2–3 2.8–3.5
Severe Large or refractory to diuretics >3 <2.8
<4 <1.7
4–6 1.7–2.3
>6 >2.3
7. What is the pathogenesis of PH leading to varices, variceal hemorrhage, and portosystemic collaterals? Increased resistance to portal blood flow results from cirrhosis, and this leads to increases in portal venous pressure as stated. This results in decreased vasodilating factors (e.g., nitric oxide [NO]) and increased angiogenic factors (e.g., vascular endothelial growth factor) and the formation of new vessels. Splanchnic vasodilation occurs leading to increased portal blood flow, which completes a cycle by increasing portal venous pressure. Dilation of preexisting vessels leads to formation of varices and/or collaterals. Collaterals develop at watershed zones between the portal venous drainage (e.g., stomach, small bowel, large bowel, and spleen) and systemic venous drainage (e.g., esophagus, distal rectum). Collaterals can also develop from recanalization of embryonic connections (e.g., umbilical vein, persistent ductus venosus). Note: EV refers to esophageal varices, but it should be noted that gastric varices are present in 20% of patients with cirrhosis, either in isolation or in combination with EV. In this chapter, the term EV and gastroesophageal varices may be used interchangeably with this caveat. 8. Describe how the HVPG and Child’s classification help in both risk assessment and management of bleeding from EV in patients with cirrhosis and PH? In cirrhotic patients with an HVPG >10 mm Hg, a higher risk of complications such as ascites and varices exist. In addition, these patients have double the risk of developing EV (50% at 5 years) when compared to patients with HVPG below this threshold (25% at 5 years). With an HVPG >12 mm Hg, there is an increased risk of EV rupture and bleeding. As stated previously, patients with decompensated cirrhosis, Child’s class B and C, carry the highest rate of EV formation and a higher mortality for any given episode of variceal hemorrhage. 9. What are the current methods used for the primary and secondary prophylaxis of esophageal variceal bleeding and are they effective? Current evidence cannot recommend ß-adrenergic blockers for the primary prevention of the development of EV. However, once EV are present then criteria including varix size, characteristics, and patient’s Child class are evaluated for determination if prophylaxis of bleeding is warranted. Nonselective ß-blockers and endoscopic variceal ligation (EVL) are both effective in preventing first bleeding episodes in existing EV, according to a 2008 metaanalysis of randomized clinical trials, and would be used for medium- and large-sized EV, or in small-sized EV with red wale signs and/or Child’s class B or C cirrhosis. (Nonselective ß-blockers are effective by both ß1 and ß2 actions by reduction of cardiac output and splanchnic vasoconstriction respectively. The reader is referred to the references for further reading regarding the advantages and disadvantages between medical therapy and endoscopic therapy.) 10. What is the recommended treatment approach for the patient who has experienced an acute variceal bleed? Patients with Child class A or B disease or who have an HVPG <20 mm Hg have a low or intermediate risk. Standard therapy involves the combination of a safe vasoconstrictor (octreotide in the United States) administered from the time of admission for 2–5 days; endoscopic therapy (EVL) performed at <12 hours from admission on diagnostic endoscopy; and short-term prophylactic antibiotics (e.g., ciprofloxacin or ceftriaxone). Placement of a transjugular intrahepatic portosystemic shunt (TIPS) is currently considered salvage therapy for the 10%–20% of patients in whom standard medical therapy fails and will be discussed below. 11. What is the general approach to the patient who has survived one episode of EV bleed in an effort to reduce a recurrent bleed? A patient who survives an initial episode of bleeding secondary to EV has a 60% chance of recurrence. All such patients are thus recommended to have some form of treatment for the prevention of recurrent bleed prior to their discharge from the hospital, and treatment recommendations apply to all
Portal Hypertension and Esophageal Varices 197 patients with variceal hemorrhage. Examples of such treatments include medical therapy, EVL, TIPS, and surgical shunts. A number of metaanalyses discuss matching specific therapies or combination of therapies for differing patient characteristics. Patients with Child class A disease have a good response to current therapies with a 0%–5% mortality. As previously noted, patients in whom their HVPG decreases to <12 mm Hg (or reduced by >20% from baseline) have the lowest rate of recurrent variceal bleeding. 12. What are the specifics in current recommended therapy for patients who have survived one episode of EV bleed? Current guidelines (see reference 1) recommend the combined use of EVL and nonselective ß-blockers for the prevention of recurrent variceal bleed. This is based on a randomized controlled trial showing a significantly lower rate of variceal rebleeding with combined modalities. However, the rate of bleeding from all sources was not significantly different because of the bleeding from esophageal ulcers induced by the EVL (a known complication of EVL). Patients who have rebleeding despite this combined therapy should undergo early placement of a TIPS or surgical shunt. 13. A restrictive transfusion strategy, defined as a posttransfusion hemoglobin threshold of 7 g/dL, has been shown in various clinical settings to not increase, and perhaps decrease, mortality. Has such a strategy been shown to be similarly effective in cases of acute gastrointestinal (GI) bleeding? Current international guidelines recommend decreasing the hemoglobin threshold for transfusion in a variety of critical care settings, including the condition of normovolemic anemia seen in patients who have had a GI bleed. A recent study (see reference 2) demonstrates that even in patients with an acute bleed, a restrictive transfusion strategy significantly reduced the rates of therapeutic failure factors such as further rebleeding, need for salvage or rescue therapy, and reduced length of hospital stay. Such a strategy should be used cautiously in the patient with active GI hemorrhage and shock. 14. By what possible mechanisms is a restrictive strategy advantageous in acute GI bleeders, and those PH in particular? Transfusion of red blood cells may lead to an impairment in hemostasis by dilution of coagulation factors and platelets. Splanchnic vasoconstriction in the setting of hypovolemia may be ameliorated by transfusion, leading to increase in splanchnic blood flow. Restoring blood volume may induce a rebound increase in portal venous pressure and precipitate bleeding. These concerns have been validated by experimental evidence that patients undergoing a liberal transfusion strategy had a significant increase in portal pressure not seen in the restrictive strategy group. 15. Outpatient management of the patient with cirrhosis of the liver involves what major complications or sequelae in addition to variceal bleeding (name three)? The three primary clinical issues that are caused by PH are ascites, variceal bleeding, and hepatic encephalopathy (HE). Hepatorenal syndrome (HRS) and spontaneous bacterial peritonitis are two less common but severe manifestations of decompensation. 16. How common is ascites in the setting of cirrhosis and how is it managed? Ascites is the most common manifestation of decompensated cirrhosis and affects 60% of previously compensated cirrhotics within 10 years of diagnosis. Rates of mortality once ascites is manifested varies depending on the study but are uniformly grave. First-year mortality is described at 15%, and by 3–5 years ranges between 44% and 50%. The mainstay of medical therapy is sodium restriction in the diet to prevent volume overload. A goal of <2000 mg/day is recommended. The use of oral diuretics such as spironolactone and furosemide is considered standard medical therapy, with typical starting dosages being 100 mg and 40 mg daily, respectively. Persistent ascites despite a low salt diet and maximal diuretic therapy is defined as refractory ascites and generally leads to a referral for orthotopic liver transplant, repeated paracentesis, placement of a TIPS, or peritovenous shunt. Use of peritovenous shunts have declined because of high complication rates with one remaining indication for it being in a patient with refractory ascites but ineligible for a TIPS or repeated paracentesis. 17. How common is HE in the setting of cirrhosis and how is it managed? HE is a manifestation of cirrhosis that if it occurs in the hospitalized patient carries a 3.9-fold increased mortality risk. Estimates are that 30%–40% of patients with cirrhosis will develop HE during the course of their disease, and relapse rates are high despite maximal suppressive therapy.
198 ABDOMINAL SURGERY Pathophysiology is multifactorial including hyperammonemia, ammonia crossing the blood-brain barrier resulting in neuroinflammation, astrocyte swelling, and oxidative neuronal stress. There may be a net increase in the inhibitory neurotransmission mediated by gamma-aminobutyric acid. Systemic inflammation also occurs acting synergistically to cause HE. Placement of a TIPS may predispose patients to hepatic encephalopathy with an incidence of 5%–35% reported. HE is a clinical diagnosis and one of exclusion. Blood ammonia levels as a diagnostic criteria remain elusive according to a 2014 consensus guideline. Lactulose is the mainstay of therapy, which acts by acidification of the colon converting ammonia to ammonium. Recent studies suggest that polyethylene glycol may be superior, but further studies are needed. Antibiotics such as rifaximin in combination with other agents is the second line of therapy. There are recent reports of use of embolization of portosystemic communications as an emerging therapy. 18. How common is HRS in the setting of cirrhosis and how is it managed? According to a 2007 definition, HRS is cirrhosis with ascites, a serum Cr of >1.5 mg/dL, no improvement in serum Cr despite 48 hours of diuretic withdrawal and volume resuscitation, absence of shock, no recent exposure to nephrotoxic drugs, and no signs of intrarenal disease. Acute kidney injury occurs in approximately 20% of such hospitalized patients and of these, 25% are secondary to HRS. In patients unfortunate enough to develop HRS, the 1-month mortality is 58% and the 1-year mortality is 63%. Overall, the mortality for HRS is 80% (Type 1). The only definitive treatment for HRS is liver transplantation. Bridge therapy includes initial volume expansion, pharmacologic agents (midodrine and octreotide), and the use of renal replacement therapy, which is controversial. 19. What are the indications for use of TIPS in cirrhotic patients with recurrent variceal bleeding? The accepted indications for TIPS include refractory ascites, uncontrolled variceal bleeding, and recurrent variceal bleeding in patients who have failed standard initial medical and endoscopic means of control. Absolute contraindications include congestive heart failure, severe pulmonary hypertension, and severe tricuspid valve regurgitation. Early studies evaluating the role of TIPS in the prevention of recurrent variceal bleeding demonstrated that TIPS reduces the rebleeding rate, but at the expense of increasing HE without improving survival. As a result, TIPS has been recommended as rescue therapy for the up to 27% of patients who have failure to control bleeding after a variceal bleed and using conventional combined therapy of medications and EVL. More recent studies (see reference 8) have studied the effect of using coated stents in the TIPS procedure and moving to earlier (<72 hours) timing of the procedure. 20. What are the technical aspects of TIPS placement? TIPS is a side-to-side portosystemic shunt created within the liver parenchyma typically between the right hepatic vein and the right portal vein. Accessing the portal vein is the most critical step of the TIPS procedure technically and is facilitated by the use of both preprocedure cross-sectional imaging as well as transabdominal ultrasound to guide needle placement into the correct portal vein branch. The procedural complication rate of TIPS may be related to intraabdominal hemorrhage and occurs in 0.6%–4.2%. 21. Describe potential advantages of earlier use of TIPS and use of an extended polytetrafluoroethylene stent when compared to previous studies where TIPS was used only as a delayed rescue procedure with bare stents. Patients with Child’s class C or Child’s class B with recurrent bleeding who have persistent bleeding at endoscopy are at high risk for treatment failure and mortality. A recent study (see reference 8) randomized such patients to either early (<72 hours from endoscopy, preferably within 24 hours) versus continuation of medical therapy and TIPS within a conventional 3- to 5-day window. Protection from initial rebleeding, rebleeding within the first year of follow-up, and 1-year survival were all statistically significantly improved in the early TIPS group. 22. Characterize the endothelial dysfunction (ED) in hepatic cirrhosis and how ED may contribute to liver dysfunction and PH. The endothelium involves >1013 cells and has multiple functions and properties. Examples include barrier function, permeability regulation, vascular tone, platelet adhesion and aggregation, prevention of thrombosis, and acting as a framework for multiple inflammatory processes. Within the hepatic circulation, ED refers primarily to the impairment of the production and release of vasodilatory factors, especially NO, considered to be a key role in the initiation and progression of liver cirrhosis. Reduced
Portal Hypertension and Esophageal Varices 199 levels of NO in the cirrhotic liver contributes to increased intrahepatic vascular resistance. In addition, increased levels of vasoconstrictor agents such as thromboxane A2 and prostanoids are important in the pathophysiology as well. 23. Describe emerging therapies that may potentially ameliorate some of the ED, which is a component of the pathophysiology of cirrhosis. Experimental animal and human data (including clinical trials) have shown benefits to the use or intake of the following: Vitamins C and E (both improving NO bioavailability), folic acid and its active metabolite 5-methyltetrahydrofolate or 5-MTHF, flavonoids in the human diet that have antioxidant and vasodilatory actions including specifically resveratrol present in grapes as well as green tea polyphenol and dark chocolate. 24. Is it possible for a cirrhotic patient to become pregnant, and if so, are there special issues or precautions? Pregnancy is a rare event in patients with cirrhosis; however, improvements in the treatment of chronic liver disease have resulted in both higher conception rates and successful pregnancy outcomes in such patients. Maternal complications have been described in nearly half of pregnancies affected by cirrhosis, largely as a result from variceal hemorrhage. Variceal bleeding more commonly occurs in the second and third trimesters when maternal blood volume is maximally expanded and the large intrauterine fetus compresses the inferior vena cava and collateral vasculature. 25. Name the special treatment concerns for pregnant patients with cirrhosis. Upper endoscopy in general is safe during pregnancy, with the main risk being fetal hypoxia from sedative drugs or positioning. In women at high risk for bleeding, prophylaxis with nonselective ß-blockade drugs such as propranolol and nadolol, both designated as pregnancy category C drug (C+ risk cannot be ruled out; animal studies show an adverse effect, no controlled human studies available) may outweigh the potential fetal risk. Octreotide is designated as a pregnancy category B drug (B = no clear or reproducible risk shown in animal or human studies), yet theoretical concerns exist because of its vasoconstrictive properties. As of a 2008 report (see reference 9) only three cases of TIPS placement had been reported in pregnant cirrhotic patients, with one major risk being radiation exposure to the fetus. Among pregnant cirrhotic patients with known varices, up to 78% will have variceal hemorrhage during pregnancy and a mortality rate ranging between 18% and 50%. Bibliography 1. Garcia-Tsao G, Bosch J. Management of varices and variceal hemorrhage in cirrhosis. N Engl J Med. 2010;362(9):823–832. 2. Villanueva C, Colomo A, Bosch A, et al. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med. 2013;368(1):11–21. 3. Bleibel W, Chopra S. Portal hypertension in adults.