RISK FACTORS Many different chronic liver diseases and hepatotoxins
Medical Care: Treatment is directed at the cause of portal hypertension. Gastroesophageal variceal hemorrhage is the most dramatic and lethal complication of portal hypertension; therefore, most of the following discussion focuses on the treatment of variceal hemorrhage. Medical care includes emergent treatment, primary prophylaxis, and elective treatment.
" Emergent treatment
o Bleeding from esophageal varices
" This ceases spontaneously in as many as 40% of patients. Each episode of variceal bleeding is associated with a 30% mortality rate and occurs mostly in patients with severe liver disease and in those with early rebleeding. Rebleeding occurs in 40% of patients within 6 weeks.
" Following resuscitation, treatment of acute variceal bleeding includes control of bleeding (24 h without bleeding within the first 48 h after starting therapy) and prevention of early recurrence.
o Initial resuscitation with replacement of blood volume loss
" Blood should be replaced at a modest target of HCT of 25-30%.
" Avoid intravascular volume and variceal overexpansion to prevent rebleeding.
o Diagnosis of source of bleeding
o Prevention of complications (eg, hepatic encephalopathy, bronchial aspiration, renal failure, systemic infections, SBP)
" All patients with cirrhosis and upper GI bleeding are at a high risk of developing severe bacterial infections, which are associated with early rebleeding.
" The use of prophylactic antibiotics has been demonstrated to decrease the rate of bacterial infections and increase survival rates, thus prophylactic antibiotic use (norfloxacin 400 mg PO bid for 7 d; ciprofloxacin and other broad-spectrum antibiotics also could be used) in the setting of acute bleeding is recommended (Rimola, 2000).
o Specific treatment of bleeding lesion
o Pharmacological therapy
" Somatostatin (not available in the United States) is an endogenous hormone that decreases portal blood flow by splanchnic vasoconstriction at pharmacological doses, without significant systemic adverse effects.
" Octreotide is a synthetic analogue of somatostatin that usually is administered at a constant infusion of 50 mcg/h. Octreotide has been shown to be effective in reducing the complications of variceal bleeding after emergency sclerotherapy or variceal ligation.
" Vasopressin is the most potent splanchnic vasoconstrictor. It reduces blood flow to all splanchnic organs, decreasing portal venous inflow and decreasing portal pressure. Use of vasopressin is limited by adverse effects related to splanchnic vasoconstriction (eg, bowel ischemia) and systemic vasoconstriction (eg, hypertension, myocardial ischemia). Continuous infusion of 0.2-0.4 IU/min (not to exceed 0.8 IU/min) is recommended.
" Vasopressin always should be accompanied by intravenous nitroglycerin at a dose of 40 mcg/min (not to exceed 400 mcg/min) to maintain systolic blood pressure greater than 90 mm Hg.
" Adding nitrates to vasopressin therapy significantly improves efficacy, although adverse effects of combination therapy are higher than those associated with terlipressin or somatostatin.
" Terlipressin (not available in the United States) is a synthetic analogue of vasopressin that has longer biological activity and significantly fewer adverse effects than vasopressin.
" A recent randomized controlled trial showed that octreotide only transiently reduced portal pressure and flow, whereas the effects of terlipressin were sustained, suggesting that terlipressin may have more sustained hemodynamic effects in patients with bleeding varices.
o Endoscopic therapy
" Endoscopic therapy has the advantage of allowing specific therapy at the time of diagnosis.
" Efficacy in achieving hemostasis is higher than 80%, but its effectiveness declines to 70% at day 5 due to very early rebleeding in some patients.
" Failures of endoscopic treatments may be managed by a second session of endoscopic treatment, but no more than 2 sessions should be allowed before deciding to perform transjugular intrahepatic portosystemic shunt (TIPS) or surgery.
" Endoscopic injection sclerotherapy involves injecting a sclerosant solution into the bleeding varix, obliterating the lumen by thrombosis, or into the overlying submucosa, producing inflammation followed by fibrosis. Several different sclerosants are available: 5% sodium morrhuate, 1% to 3% sodium tetradecyl sulfate, and 5% ethanolamine oleate. The typical volume used per injection is 1-2 mL of sclerosant, with the total volume ranging from 10-15 mL.
" Complications of endoscopic injection sclerotherapy, which are more frequent in acute bleeding than in elective situations, are related to the toxicity of the sclerosant and include transient fever, stricture, dysphagia, perforation (rarely), chest pain, mediastinitis, ulceration, and pleural effusion.
" Endoscopic injection sclerotherapy is very effective emergency treatment for acute variceal bleeding (not optimal for patients bleeding from gastric fundal varices).
" Endoscopic variceal ligation (EVL) is achieved by a banding device attached to the tip of the endoscope. The varix is aspirated into the banding chamber, and a trip wire dislodges a rubber band carried on the banding chamber, ligating the entrapped varix. One to 3 bands are applied to each varix, resulting in thrombosis. EVL is less prone to complications than injection sclerotherapy. EVL has the same limitations of availability, cost, and difficulty in treating gastric varices as sclerotherapy.
" Overall current data demonstrate clear advantages for using variceal ligation over injection sclerotherapy. Endoscopic ligation requires fewer endoscopic treatment sessions and causes substantially less esophageal complications than injection sclerotherapy. However, there is no overall survival benefit of variceal ligation over injection sclerotherapy.
" Although ligation is being considered the treatment of choice for esophageal varices, the choice of technique should be left up to the experience of the operator, as well as the particular circumstances found during endoscopic therapy.
o Other interventions
" Balloon-tube tamponade should be used only in massive bleeding as a temporizing measure until definitive treatment can be instituted. An endotracheal tube should be placed to protect the airway before attempting to place the balloon tube. Complications are esophageal and gastric ulceration, aspiration pneumonia, and esophageal perforation. Continued bleeding during balloon tamponade indicates an incorrectly positioned tube or bleeding from another source.
" The Minnesota tube has 4 lumens, 1 for gastric aspiration, 2 to inflate the gastric and esophageal balloons, and 1 above the esophageal balloon to suction secretions to prevent aspiration. The tube is inserted through the mouth, and its position within the stomach is checked by auscultation while injecting air through the gastric lumen. The gastric balloon is inflated with 200 mL of air. Once fully inflated, the gastric balloon is pulled up against the esophagogastric junction, using approximately 0.5 kg of traction, compressing the submucosal varices. The esophageal balloon rarely is required.
" The Minnesota tube is an adaptation of the Sengstaken-Blakemore (S-B) tube, the difference is that the S-B tube does not have the esophageal suction port to prevent aspiration.
" Endoscopic administration of cyanoacrylate monomer (superglue) in gastric varices is another intervention.
" Primary prophylaxis: Primary prophylaxis is administered to patients at high risk of bleeding. These patients have large varices, red wale markings on the varices, and severe liver failure.
o Beta-blockers
" Beta-blockers include propranolol and nadolol. They are used most commonly. Beta-blockers are noncardioselective and reduce portal and collateral blood flow. Reduction in cardiac output (blockade of beta1-adrenoreceptors) occurs. Splanchnic vasoconstriction (blockade of vasodilatory adrenoreceptors of the splanchnic circulation) also occurs.
" A recent meta-analysis of 11 trials evaluating nonselective beta-blockers in the prevention of first variceal bleeding shows that the bleeding rate in controls (25%) is significantly reduced (to 15%) in patients treated with beta-blockers after a median follow-up of 24 months. The mortality rate also is lower in the beta-blocker group; however, the difference does not achieve statistical significance. The effect of beta-blockers as a function of variceal size also is analyzed. The risk of first variceal bleeding in patients with medium-to-large varices is 30% in controls, which is significantly reduced to 14% in patients treated with beta-blockers. In patients with small varices, a tendency exists for reduction in the first bleeding episode; however, the number of patients and the rate of first bleeding are too low to achieve statistical significance.
" Propranolol is administered at a dose of 20 mg every 12 h, which is increased or decreased every 3-4 days until a 25% reduction in the resting heart rate occurs or the heart rate is down to 55 beats per minute (bpm). The average dose of propranolol usually is 40 mg bid. Administering more than 320 mg/d is not recommended.
" Nadolol dosing is half the daily dose of propranolol, administered once a day.
" Response to treatment is monitored by a reduction of the portal pressure gradient by more than 20% of the baseline value or less than 12 mm Hg. Checking the HVPG response in primary prophylaxis is not mandatory because 60% of patients who do not achieve these targets do not bleed at 2-year follow-up evaluations.
" Propranolol is contraindicated in patients with asthma, chronic obstructive pulmonary disease (COPD), atrioventricular (AV) block, intermittent claudication, and psychosis. The most frequent adverse effects are light-headedness, fatigue, dyspnea upon exertion, bronchospasm, insomnia, impotence, and apathy. Reducing the dose of propranolol frequently controls these adverse effects.
" Beta-blockers are best continued for the patient's lifetime because the risk of variceal hemorrhage returns to that of the untreated population once beta-blockers are withdrawn.
o Vasodilators
" Isosorbide mononitrate (ISMN) is a vasodilator and has been demonstrated to reduce HVPG markedly in acute administration but significantly less after long-term administration due to probable development of patient tolerance.
" Vasodilators also reduce esophageal variceal pressure. The primary concern in patients with advanced cirrhosis is that vasodilators can reduce arterial blood pressure and promote the activation of endogenous vasoactive systems that may lead to sodium and water retention.
" One study reported ISMN to be as effective as propranolol in preventing first variceal bleeding, but long-term follow-up of these patients showed a higher mortality in patients older than 50 years in the ISMN group.
" Available evidence does not support the use of ISMN as monotherapy for primary prophylaxis, even in patients with contraindications or intolerance to beta-blockers
o Combination therapy
" This involves both beta-blockers and ISMN. A large, double-blind, placebo-controlled trial was unable to demonstrate a significantly lower rate of first hemorrhage in the group treated with combination therapy versus beta-blockers alone.
" Combination therapy appears to be associated with increased adverse effects and a higher rate of ascites.
" Combination therapy cannot be recommended presently until further studies prove efficacy.
o Prophylactic sclerotherapy
" Randomized controlled trials on the use of sclerotherapy for primary prophylaxis produced divergent results, with some studies showing worse outcome than controls.
" It has no role in primary prophylaxis.
o Prophylactic endoscopic variceal ligation
" EVL has been demonstrated to be more effective than no treatment in preventing the first variceal bleed.
" Prophylactic EVL has been demonstrated to have an efficacy similar to beta-blockers in prevention of first variceal bleed, but with increased adverse effects.
" Prophylactic EVL currently cannot be recommended as a routine measure for primary prevention but may be an option for patients with grade 3 varices who have contraindications to or cannot tolerate beta-blockers.
" Elective treatment: This is for the prevention of rebleeding. Variceal hemorrhage has a 2-year recurrence rate of approximately 80%.
o Nonselective beta-blockers
" Propranolol and nadolol significantly reduce the risk of rebleeding and are associated with prolongation of survival.
" Studies comparing propranolol with sclerotherapy in prevention of variceal rebleeding demonstrate comparable rates of variceal rebleeding and survival, but sclerotherapy was associated with significantly more complications.
o Endoscopic sclerotherapy
" This usually is performed at weekly intervals.
" Approximately 4-5 sessions are required for eradication of varices, which is achieved in nearly 70% of patients.
o Endoscopic variceal ligation
" EVL is associated with lower rebleeding rates and a lower frequency of esophageal strictures. Fewer sessions are required to achieve variceal obliteration when compared to sclerotherapy.
" EVL is considered the endoscopic treatment of choice in the prevention of rebleeding. Sessions are repeated at 7- to 14-day intervals until variceal obliteration (usually 2-4 sessions).
o Combination of EVL and pharmacologic therapy
" A recent randomized trial demonstrates that EVL plus nadolol plus sucralfate is more effective in preventing variceal rebleeding than EVL alone.
" Combination of EVL with beta-blockers seems to be reasonable for patients in whom pharmacological therapy has failed.
Surgical Care: Surgical care includes decompressive shunts, devascularization procedures, and liver transplantation.
" Decompressive shunts: These include total portal systemic shunts, partial portal systemic shunts, and other selective shunts.
o Total portal systemic shunts
" These include any shunt larger than 10 mm in diameter between the portal vein (or one of its main tributaries) and the IVC (or one of its tributaries).
" Eck fistula (classic end-to-side portacaval shunt described for historical interest only) was performed by Eck in dogs in the late 19th century. The portal vein is divided close to the liver, the hepatic end of the portal vein is ligated, and the splanchnic end is anastomosed to the IVC. This controls variceal bleeding and decompresses splanchnic hypertension but leaves high pressure in the hepatic sinusoids, thus ascites is not relieved.
" For the side-to-side portacaval shunt, the portal vein and the infrahepatic IVC are mobilized after dissection and anastomosed. All portal flow is directed through the shunt, and the portal vein itself acts as an outflow from the obstructed hepatic sinusoids. Excellent control of bleeding and ascites is achieved in more than 90% of patients. Encephalopathy (rate of 40-50%) and progressive liver failure are possible. The procedure has relatively limited indications, which include massive variceal bleeding with ascites or acute Budd-Chiari syndrome without evidence of liver failure.
o Partial portal systemic shunts
" These reduce the size of the anastomosis of a side-to-side shunt to 8 mm in diameter. Portal pressure is reduced to 12 mm Hg, and portal flow is maintained in 80% of patients.
" The operative approach is similar to side-to-side portacaval shunts, except the interposition graft must be placed between the portal vein and the IVC.
" Two prospective, randomized, controlled trials revealed a 90% rate for control of bleeding. Maintenance of some portal flow has decreased the incidence of encephalopathy and liver failure.
o Selective shunts
" These provide selective decompression of gastroesophageal varices to control bleeding while at the same time maintaining portal hypertension to maintain portal flow to the liver.
" One example is the distal splenorenal shunt, which is the most commonly used decompressive operation for refractory variceal bleeding. It is used primarily in patients who present with refractory bleeding and continue to have good liver function. It decompresses the gastroesophageal varices through the short gastric veins, the spleen, and the splenic vein to the left renal vein. Portal hypertension is maintained in the splanchnic and portal venous system, and it maintains portal flow to the liver. This shunt provides the best long-term maintenance of some portal flow and liver function with a lower incidence of encephalopathy (10-15%) compared to total shunts. The operation produces ascites because the retroperitoneal lymphatics are diverted.
" Devascularization procedures: These include splenectomy, gastroesophageal devascularization, and esophageal transection (at times). Incidence of liver failure and encephalopathy is low following devascularization procedures, presumably because of better maintenance of portal flow. Devascularization could be used in patients who are not candidates for decompression in whom first-line therapy has failed. This includes patients who have portal or splenic vein thrombosis in addition to cirrhosis.
o Splenectomy
" The spleen is one of the major inflow paths to gastroesophageal varices. Splenectomy also allows better access to the gastric fundus and the distal esophagus to complete the devascularization.
" Portal vein thrombosis of as much as 20% is reported following splenectomy. Ascites is a frequent early postoperative complication because portal hypertension is maintained.
o Gastroesophageal devascularization (Sugiura procedure)
" This should devascularize the whole greater curve of the stomach from the pylorus to the esophagus and the upper two thirds of the lesser curve of the stomach; the esophagus should be devascularized for a minimum of 7 cm.
" In patients who have undergone extensive and repeated sclerotherapy, the gastroesophageal junction is thickened and the ability to perform a satisfactory transection is limited.
" Liver transplantation
o Liver transplantation is the ultimate shunt because it relieves portal hypertension, prevents variceal rebleeding, and manages ascites and encephalopathy by restoring liver function.
o It is the treatment modality that has significantly improved the outcome of patients with Child-Pugh class C disease and variceal bleeding.
o Using liver transplantation in most patients is impractical because some patients can be managed successfully with lesser methods; therefore, transplant must be based on appropriate patient selections. For patients with Child class A disease, shunt surgery is recommended; for patients with Child class B disease, shunt surgery or TIPS is appropriate; and for people with Child C class disease, TIPS or orthotopic liver transplant is recommended.
" Primary prophylaxis: Surgery has no role for primary prophylaxis.
" Acute variceal bleeding
o The role of surgery in acute variceal bleeding is exceedingly limited because therapy with endoscopic treatment controls bleeding in 90% of patients.
o TIPS is a viable option and is less invasive for those whose bleeding is not controlled. However, if TIPS is not available, then staple transection of the esophagus is an option when endoscopic treatment and pharmacological therapy have failed.
" Prevention of rebleeding
o For prevention of rebleeding, when pharmacological therapy and/or endoscopic therapy have failed, consider surgery. Failure is defined as a single episode of clinically significant rebleeding (transfusion requirement of 2 U of blood or more within 24 h, a systolic blood pressure <100 mm Hg or a postural change of >20 mm Hg, and/or pulse rate greater than 100 bpm) as per the Baveno II consensus conference on portal hypertension.
o TIPS is a useful procedure for continued bleeding despite medical and endoscopic treatment in patients with Child class C disease and selected patients with Child class B disease. It is effective only in portal hypertension of hepatic origin.
" Technique: Under local anesthesia with sedation via the internal jugular vein, the hepatic vein is cannulated and a tract is created through the liver parenchyma from the hepatic to the portal vein with a needle. This is performed under ultrasonographic and fluoroscopic guidance. The tract is dilated, and an expandable metal stent is introduced, connecting hepatic and portal systems. Blood from the hypertensive portal vein and sinusoidal bed is shunted to the hepatic vein.
" Indications: Accepted (established in controlled trials) indications include (1) active variceal bleeding despite emergency endoscopic and/or pharmacological treatment and (2) recurrent variceal bleeding despite adequate endoscopic treatment. Potential (proven efficacy but not adequately compared with that of existing therapies) indications include (1) isolated bleeding from gastric fundic varices and (2) refractory ascites. Experimental (efficacy not established in large-scale trials) indications include (1) bleeding portal gastropathy, (2) Budd-Chiari syndrome, (3) venoocclusive disease, (4) hepatorenal syndrome, (5) hepatic hydrothorax, (6) bleeding ectopic varices, (7) and protein-losing enteropathy due to portal hypertension.
" Causes of recurrent portal hypertension and bleeding after TIPS: These include (1) continued esophageal bleeding; (2) stent dysfunction (as many as 50% of shunts may occlude in 1 y) due to stenosis, thrombosis, retraction, chinking, or displacement; (3) hemobilia; and (4) persistent gastric varices associated with spontaneous splenorenal collaterals or associated with massive splenomegaly.
" Complications of TIPS related to technique: These include (1) neck hematoma, (2) cardiac arrhythmia, (3) perihepatic hematoma, (4) rupture of liver capsule, (5) extrahepatic puncture of portal vein, (6) arterioportal fistula, and (7) portobiliary fistula.
" Complications of TIPS related to portosystemic shunting: These include (1) hepatic encephalopathy (approximately 30%), (2) increased susceptibility to bacteremia, and (3) liver failure.
" Other complications: These may include (1) TIPS-associated hemolysis (approximately 10%) and (2) infection of stent.
Diet: Manifestations of splanchnic vasodilatation include increased cardiac output, arterial hypotension, and hypervolemia. This explains the rationale for treating portal hypertension with a low-sodium diet and diuretics to attenuate the hyperkinetic state.
DRUG TREATMENT : Pharmacologic therapy is directed at treating acute bleeding and providing primary or secondary prophylaxis. Somatostatin or octreotide are used to treat acute bleeding. Propranolol, nadolol, or timolol provide primary or secondary prophylaxis.
1. ANTISECRETARY AGENTS :
- SOMATOSTATIN
- OCTREOTIDE
2. BETA BLOCKERS :
- PROPRANOLOL
- NADOLOL
- TIMOLOL
ALTERNATIVE DRUGS Terlipressin (Glypressin) - more selective splanchnic vasoconstrictor and may be associated with fewer complications. Studies are continuing.
PATIENT MONITORING Acute complications of portal hypertension require intensive monitoring of vital signs and organ function. Long-term management includes regular follow-up of all affected organ systems.
PREVENTION/AVOIDANCE Abstinence from alcohol. Adequate and appropriate nutrition.
POSSIBLE COMPLICATIONS As described above
EXPECTED COURSE/PROGNOSIS
β’ Variceal bleeding: 50% re-bleed, usually within 2 years unless portal pressure is reduced by shunt or TIPS
procedure
β’ Ascites: Generally recurs. Frequency and severity can be reduced if salt restriction is observed.
β’ Hepatic encephalopathy. Often recurs especially if re-bleeding develops. Low protein diet advised.